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Sample records for pyrimethamine

  1. Pyrimethamine nanosuspension with improved bioavailability: in vivo pharmacokinetic studies.

    Science.gov (United States)

    Dhapte, Vividha; Kadam, Vivek; Pokharkar, Varsha

    2013-10-01

    Pyrimethamine is a standard antiprotozoal drug recommended for prophylaxis and treatment of malarial infections. Limited bioavailability, slow onset of action, and life-threatening side effects restrict its use. Hence, in the present study, pyrimethamine nanosuspension was prepared with the objective to improve its dissolution rate and pharmacokinetic profile. Stable pyrimethamine nanosuspension with submicron particle size was prepared by nanoprecipitation and high-pressure homogenization techniques. Nanosizing and stabilizers modified the surface characteristics of drug particles resulting in considerable increase in the dissolution rate. The in vivo pharmacokinetic studies of the prepared nanosuspension were carried out and compared with plain pyrimethamine suspension and marketed pyrimethamine suspension. The in vivo pharmacokinetic profiling of pyrimethamine nanosuspension in rats showed higher AUC0-24 h and C max compared to the plain and marketed pyrimethamine suspensions. In contrast to its plain and marketed formulation, pyrimethamine nanosuspension showed rapid onset of action (T max 0.5 h vs. 2 h). Also, the low volume of distribution and reduced elimination half-life of the developed nanosuspension can lead to reduced side effects. Thus, improved in vitro-in vivo kinetics indicated that nanosuspension proved to be a suitable strategy for elevating the therapeutic profile of pyrimethamine.

  2. Effect of pyrimethamine and sulphadoxine on human lymphocyte proliferation

    DEFF Research Database (Denmark)

    Bygbjerg, I C; Odum, Niels; Theander, T G

    1986-01-01

    The in vitro effect of pyrimethamine (PYR) on human blood mononuclear cells stimulated with phytohaemagglutinin (PHA), pokeweed mitogen (PWM) and purified protein derivative of tuberculin (PPD) was studied by 14C-thymidine incorporation, by cell counting and by total DNA estimation. PYR in concen......The in vitro effect of pyrimethamine (PYR) on human blood mononuclear cells stimulated with phytohaemagglutinin (PHA), pokeweed mitogen (PWM) and purified protein derivative of tuberculin (PPD) was studied by 14C-thymidine incorporation, by cell counting and by total DNA estimation. PYR......-stimulated cells. The suppression of PHA-stimulated cells was reversed after one week. The increased 14C-thymidine incorporation observed in stimulated cells exposed to PYR in vitro in the early phase of proliferation did not reflect immunopotentiation but rather blocked endogenous thymidine synthesis...

  3. Fatal Intoxications Due to Administration of Isosorbide Tablets Contaminated with Pyrimethamine.

    Science.gov (United States)

    Imran, Muhammad; Shafi, Humera; Mahmood, Zahid; Sarwar, Mohammad; Usman, Hafiz Faisal; Tahir, Mohammad Ashraf; Ashiq, Muhammad Zar

    2016-09-01

    In January 2012, 664 cases of pyrimethamine toxicity and 151 deaths were reported among cardiac patients that had recently received free medicines from pharmacy of Punjab Institute of Cardiology, Lahore, Pakistan. These patients, ages ranged from 58 to 75 years, were prescribed simvastatin, clopidogrel, aspirin soluble, isosorbide mononitrate, and amlodipine. On examination of medications being given to them, it was found that a particular batch of isosorbide mononitrate tablets was contaminated with 50 mg pyrimethamine. Cardiac patients were taking isosorbide contaminated with pyrimethamine twice daily (100 mg pyrimethamine/day), whereas therapeutic dose of pyrimethamine for malaria is 25 mg/week. Postmortem urine, cardiac blood, and femoral blood specimens of three deceased males were submitted to author's laboratory for analysis. Postmortem toxicological analysis revealed that pyrimethamine concentration fell within the range of 1-10 μg/mL by liquid chromatography. Clinical, autopsy, histopathological, and toxicological findings strongly suggested toxicity due to pyrimethamine accumulation that resulted in deaths of these cardiac patients.

  4. Drug resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum malaria in Mlimba, Tanzania

    NARCIS (Netherlands)

    Mbugi, E.V.; Mutayoba, B.M.; Malisa, A.L.; Balthazary, S.T.; Nyambo, T.B.; Mshinda, H.

    2006-01-01

    Background - Sulphadoxine-pyrimethamine (SP) has been and is currently used for treatment of uncomplicated Plasmodium falciparum malaria in many African countries. Nevertheless, the response of parasites to SP treatment has shown significant variation between individuals. Methods - The genes for

  5. Health facility-based data on women receiving sulphadoxine-pyrimethamine during pregnancy in Tanzania

    DEFF Research Database (Denmark)

    Mubyazi, Godfrey M.; Byskov, Jens; Magnussen, Pascal;

    2014-01-01

    A study of health facility (HF) data on women receiving sulphadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria during pregnancy (IPTp) was carried out at antenatal care (ANC) clinics in Mkuranga and Mufindi districts.......A study of health facility (HF) data on women receiving sulphadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria during pregnancy (IPTp) was carried out at antenatal care (ANC) clinics in Mkuranga and Mufindi districts....

  6. Health facility-based data on women receiving sulphadoxine-pyrimethamine during pregnancy in Tanzania

    DEFF Research Database (Denmark)

    Mubyazi, Godfrey M.; Byskov, Jens; Magnussen, Pascal

    2014-01-01

    A study of health facility (HF) data on women receiving sulphadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria during pregnancy (IPTp) was carried out at antenatal care (ANC) clinics in Mkuranga and Mufindi districts.......A study of health facility (HF) data on women receiving sulphadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria during pregnancy (IPTp) was carried out at antenatal care (ANC) clinics in Mkuranga and Mufindi districts....

  7. Rational drug design approach for overcoming drug resistance: application to pyrimethamine resistance in malaria.

    Science.gov (United States)

    McKie, J H; Douglas, K T; Chan, C; Roser, S A; Yates, R; Read, M; Hyde, J E; Dascombe, M J; Yuthavong, Y; Sirawaraporn, W

    1998-04-23

    Pyrimethamine acts by selectively inhibiting malarial dihydrofolate reductase-thymidylate synthase (DHFR-TS). Resistance in the most important human parasite, Plasmodium falciparum, initially results from an S108N mutation in the DHFR domain, with additional mutation (most commonly C59R or N51I or both) imparting much greater resistance. From a homology model of the 3-D structure of DHFR-TS, rational drug design techniques have been used to design and subsequently synthesize inhibitors able to overcome malarial pyrimethamine resistance. Compared to pyrimethamine (Ki 1.5 nM) with purified recombinant DHFR fromP. falciparum, the Ki value of the m-methoxy analogue of pyrimethamine was 1.07 nM, but against the DHFR bearing the double mutation (C59R + S108N), the Ki values for pyrimethamine and the m-methoxy analogue were 71.7 and 14.0 nM, respectively. The m-chloro analogue of pyrimethamine was a stronger inhibitor of both wild-type DHFR (with Ki 0.30 nM) and the doubly mutant (C59R +S108N) purified enzyme (with Ki 2.40 nM). Growth of parasite cultures of P. falciparum in vitro was also strongly inhibited by these compounds with 50% inhibition of growth occurring at 3.7 microM for the m-methoxy and 0.6 microM for the m-chloro compounds with the K1 parasite line bearing the double mutation (S108N + C59R), compared to 10.2 microM for pyrimethamine. These inhibitors were also found in preliminary studies to retain antimalarial activity in vivo in P. berghei-infected mice.

  8. Association between prevalence of pyrimethamine resistance and double mutation in pfdhfr gene in West Bengal, India

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    Sabyasachi Das

    2012-02-01

    Full Text Available Objective: To find whether antifolate drug (pyrimethamine resistance has occurred in the two malaria endemic zones (Kolkata and Purulia of West Bengal, India. Methods: Parasitic bloods were collected from patients of Kolkata and Purulia, in vitro susceptibility test were performed in those 90 isolates. Now parasitic DNA was isolated by phenol chloroform extraction method and then polymerase chain reaction and restriction fragment length polymorphism analysis of different codons of pfdhfr gene (51, 59, and 108 were assessed in Plasmodium falciparum isolates from patients in India. Results: Among 45 isolates from Kolkata dhfr mutant isolates at codons 108, 51 and 59 were found in 71.11 %, 100% and 15.55% isolates respectively while in Purulia mutation found in those codons were 42.22%, 57.77% and 0%, respectively. In Kolkata, the isolate having double mutation (N108 + 51I were resistant to pyrimethamine (P < 0.01 whereas in Purulia N108 mutation is occurred with both mixed and mutant 51I mutation. Conclusions: Our present findings implicate that due to enormous drug (pyrimethamine pressure double mutation with dhfr S108N/T and N51I was highly correlated (P < 0.01 with in vitro pyrimethamine resistance in two malaria endemic region of West Bengal. The increase in the number of dhfr mutations was strongly correlated to resistance to pyrimethamine.

  9. Inclusion complexes of pyrimethamine in 2-hydroxypropyl-beta-cyclodextrin: characterization, phase solubility and molecular modelling.

    Science.gov (United States)

    de Araújo, Márcia Valéria Gaspar; Vieira, Elze Kelly Barbosa; Lázaro, Gilderman Silva; de Souza Conegero, Leila; Ferreira, Odair Pastor; Almeida, Lui S Eduardo; Barreto, Ledjane Silva; da Costa, Nivan Bezerra; Gimenez, Iara F

    2007-09-01

    The inclusion complexation of pyrimethamine in 2-hydroxypropyl-beta-cyclodextrin has been investigated by 2D (1)H NMR, FTIR and UV/visible spectroscopy and also by molecular modelling methods (AM1, PM3, MM3). From the phase-solubility diagram a linear increase was observed in pyrimethamine aqueous solubility in the presence of 2-hydroxypropyl-beta-cyclodextrin, evidencing the formation of a soluble inclusion complex. According to the continuous variation method (Job's plot) applied to fluorescence measurements, a 1:1 stoichiometry has been proposed for the complex. Concerning the structure of the complex, a Cl-in orientation of pyrimethamine in the 2-hydroxypropyl-beta-cyclodextrin cavity has been proposed from the theoretical calculations, being confirmed by two-dimensional (1)H NMR spectroscopy (ROESY). The thermal behaviour has also been studied, providing complementary evidences of complex formation.

  10. Intermittent preventive therapy for malaria: arguments in favour of artesunate and sulphamethoxypyrazine - pyrimethamine combination

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    Jansen Frans

    2011-03-01

    Full Text Available Abstract Recent publications put a serious warning regarding the inefficacy of sulphadoxine-pyrimethamine (SP for the intermittent preventive treatment of malaria in young children (IPTi. Recommendations for other therapies are being made. By using a different and better sulphonamide (sulphamethoxypyrazine, it is possible to manufacture fixed dose combination pills with artesunate and pyrimethamine. This combination permits a full therapy over 24 hours (dosing interval being 12 hours. It is recommended that this combination should be tested in future field studies of IPTi.

  11. Sulfadoxine-pyrimethamine impairs Plasmodium falciparum gametocyte infectivity and Anopheles mosquito survival.

    NARCIS (Netherlands)

    Kone, A.; Vegte-Bolmer, M.G. van de; Siebelink-Stoter, R.; Gemert, G.J.A. van; Dara, A.; Niangaly, H.; Luty, A.J.F.; Doumbo, O.K.; Sauerwein, R.W.; Djimde, A.A.

    2010-01-01

    Sulfadoxine-pyrimethamine (SP) is currently the drug of choice for intermittent preventive treatment of Plasmodium falciparum both in pregnancy and infancy. A prolonged parasite clearance time conferred by dhfr and dhps mutations is believed to be responsible for increased gametocyte prevalence in

  12. High level of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine in children in Tanzania

    DEFF Research Database (Denmark)

    Rønn, A M; Msangeni, H A; Mhina, J

    1996-01-01

    In many areas of tropical Africa affected by chloroquine-resistant Plasmodium falciparum, a combination of sulfadoxine and pyrimethamine (S-P) is used for alternative medication, especially in young children. In Magoda village in Muheza District, north-eastern Tanzania, 38 children 1-10 years...

  13. Effect of immunomodulator pyrimethamine and cimetidine on immunosuppression induced by burn blister fluid.

    Science.gov (United States)

    Gharegozloo, Behnaz; Hassan, Zuhair M; K Ardestani, Sussan; Tavassoli, Nasser

    2004-09-01

    Despite recent advances in burn wound management, sepsis remains the main cause of death in patients resuscitated after major thermal injury. Increased susceptibility to infections has been related to severe suppression of the immune system.The aim of this study was to induce immune suppression with blister fluid injection, and to modulate immune response by use of cimetidine and pyrimethamine in animal model.Male Balb/c mice were injected with blister fluid intrapritoneally (ip). Fluids were collected from parital-thickness burn blisters and then the delayed type hypersensitivity (DTH) to sheep red blood cell (SRBC) and the effects of different doses of immunomodulators (Cimetidine and Pyrimethamine) on this response were quantitated.A marked suppression of DTH was observed in mice injected with blister fluid. Pyrimethamine and Cimetidine at all three doses caused a significant enhancement of DTH response to SRBC compared with blister fluid injected in control group.This finding represents evidence of a host defense defect within the burn wound and also indicates the blister fluid exhibit immunosuppressor factor that can modulate with immunomadulatory drugs like cimetidine and pyrimethamine.

  14. Chloroquine- and sulfadoxine-pyrimethamine-resistant falciparum malaria in vivo - a pilot study in rural Zambia

    NARCIS (Netherlands)

    Bijl, HM; Kager, J; Koetsier, DW; van der Werf, TS

    2000-01-01

    BACKGROUND Chloroquine (CQ) and Sulfadoxine-Pyrimethamine (SP) are the predominantly used antimalarials in Zambia and other parts of East Africa, but increasing resistance of P. falciparum is a major concern. METHODS Seventy consecutive patients with uncomplicated falciparum malaria were enrolled.

  15. Drug resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum malaria in Mlimba, Tanzania

    NARCIS (Netherlands)

    Mbugi, E.V.; Mutayoba, B.M.; Malisa, A.L.; Balthazary, S.T.; Nyambo, T.B.; Mshinda, H.

    2006-01-01

    Background - Sulphadoxine-pyrimethamine (SP) has been and is currently used for treatment of uncomplicated Plasmodium falciparum malaria in many African countries. Nevertheless, the response of parasites to SP treatment has shown significant variation between individuals. Methods - The genes for dih

  16. Parasite clearance following treatment with sulphadoxine-pyrimethamine for intermittent preventive treatment in Burkina-Faso and Mali

    DEFF Research Database (Denmark)

    Coulibaly, Sheick O; Kayentao, Kassoum; Taylor, Steve;

    2014-01-01

    Intermittent Preventive Treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) is widely used for the control of malaria in pregnancy in Africa. The emergence of resistance to SP is a concern requiring monitoring the effectiveness of SP for IPTp.......Intermittent Preventive Treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) is widely used for the control of malaria in pregnancy in Africa. The emergence of resistance to SP is a concern requiring monitoring the effectiveness of SP for IPTp....

  17. Treatment of infants with congenital toxoplasmosis: tolerability and plasma concentrations of sulfadiazine and pyrimethamine

    DEFF Research Database (Denmark)

    Schmidt, Dorte Remmer; Høgh, Birthe; Andersen, O;

    2006-01-01

    acid 7.5 mg was administered twice weekly. Blood cell counts and body weight were recorded during follow-up. The plasma concentrations of pyrimethamine and sulfadiazine were analysed in a subgroup of seven children, using high performance liquid chromatography with ultraviolet and mass spectrometric...... detection. Of 48 infants, 41 completed the treatment without change in schedule. Six infants had neutrophil counts below 0.5×109/l, and one infant had an elevated bilirubin value. Twenty-nine children were tested by a series of neutrophil counts during treatment. The neutrophil count was 0.5×109/l or lower......A-antibodies on 3 mm blood spots collected from phenylketonuria [PKU cards (Guthrie cards)]. Toxoplasma-infected children received 3 months continuous treatment with 50–100 mg/kg per day sulfadiazine in two separate administrations and 1 mg/kg per day pyrimethamine after a 1-day loading dose of 2 mg/kg, and folinic...

  18. Status of ammonia, glutamate, lactate and pyruvate during Plasmodium yoelii infection and pyrimethamine treatment in mice.

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    Agarwal, A; Tripathi, L M; Pandey, V C

    1997-09-01

    Ammonia, lactate, glutamate and pyruvate levels in blood, liver, brain, spleen and kidney were determined during Plasmodium yoelii infection and pyrimethamine treatment in mice. Ammonia and lactate levels showed significant increase with rise in parasitaemia except in spleen where decrease in the lactate levels was observed. The glutamate level displayed a marked decrease in blood, liver and splenic tissues, whereas, significant increase in glutamate level in kidney was observed, although its level in cerebral tissue remained unaltered. The pyruvate level in blood and liver showed a noticeable decrease but brain, spleen and kidney registered an elevation of the same due to the parasitic infection. Pyrimethamine (oral) treatment (10 mg/kg body weight) to infected mice (5-10%) for four days brought back the altered levels of the above cellular constituents in different tissues to normal, a week after cessation of drug treatment.

  19. Toxoplasmic encephalitis relapse rates with pyrimethamine-based therapy: systematic review and meta-analysis.

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    Connolly, Mark P; Goodwin, Elizabeth; Schey, Carina; Zummo, Jacqueline

    2017-02-01

    Toxoplasmic encephalitis (TE) is caused by Toxoplasma gondii infection and can be a life-threatening disease in immunocompromised patients. This study evaluated the rate of relapse associated with pyrimethamine-based maintenance therapy (i.e. secondary prophylaxis) in patients with human immunodeficiency virus (HIV) or AIDs treated prior to and after the common use (i.e. 1996) of highly active antiretroviral therapy (HAART) (pre-HAART and post-HAART, respectively). PubMed, Google Scholar, and Cochrane databases were searched to 6 June 2016 using search terms: pyrimethamine, Daraprim, Fansidar, Metakelfin, Fansimef, 5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine, encephalitis, cerebral, toxoplasmosis, toxoplasmic, and gondii. Single-arm cohort, retrospective, and randomized studies were included. Twenty-six studies with 1,596 patients were included in the analysis; twenty pre-HAART (n = 1,228) studies and six post-HAART (n = 368) were performed. Pooled proportions test for pyrimethamine-based therapy from pre-HAART studies indicated a relapse rate of 19.2% and 18.9% from the fixed-effects and random-effects models, respectively. The relapse rate in the post-HAART studies was 11.1% (fixed and random effects). Continuous therapy was suggestive of lower incidence of relapse compared with intermittent therapy in the pre-HAART era (range, 18.7 to 17.3% vs. 20.9 to 25.6%, respectively). These findings indicate that the likelihood of relapse associated with pyrimethamine-based therepy in patients with HIV and TE decreased after the introduction of HAART to approximately 11%. The findings have important implications as relapse may affect a patient's disease severity and prognosis, increase utilization of health care resources, and result in additional health care expenditure.

  20. Anti-Toxoplasma effects of dapsone alone and combined with pyrimethamine.

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    Derouin, F; Piketty, C; Chastang, C; Chau, F; Rouveix, B; Pocidalo, J J

    1991-01-01

    The efficacy of dapsone alone or combined with pyrimethamine against Toxoplasma gondii was investigated experimentally. For in vitro studies, a sensitive immunoassay was used for assessment of Toxoplasma growth in tissue cultures; dapsone was found to have a significant inhibitory effect at a concentration of 0.5 micrograms/ml in the cultures, and the 50% inhibitory concentration was estimated to be 0.55 micrograms/ml. When pyrimethamine and dapsone were combined, an important synergistic effect which was associated with morphological alterations of the parasites was observed. In vivo studies were performed in a murine model of acute toxoplasmosis in which a tissue culture method was used to estimate the parasite burden in the blood, lungs, and brains of infected mice. Dapsone alone, which was administered at 100 mg/kg/day for 10 days from day 1 after infection, was unable to prevent parasite dissemination and only delayed the time to death of treated mice compared with the time of death of untreated controls. When dapsone and pyrimethamine (18.5 mg/kg/day) were administered in combination from day 4 after infection, parasites were cleared from blood and organs within 6 days, but relapses were observed 15 days after the cessation of therapy. When treatment was started at day 1 after infection, 100% of mice survived and relapses were not observed, suggesting a good efficacy of this combination for preventive therapy. PMID:2024957

  1. Molecular analysis of chloroquine and sulfadoxine-pyrimethamine resistance-associated alleles in Plasmodium falciparum isolates from Nicaragua.

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    Sridaran, Sankar; Rodriguez, Betzabe; Soto, Aida Mercedes; Macedo De Oliveira, Alexandre; Udhayakumar, Venkatachalam

    2014-05-01

    Chloroquine (CQ) is used as a first-line therapy for the treatment of Plasmodium falciparum malaria in Nicaragua. We investigated the prevalence of molecular markers associated with CQ and sulfadoxine-pyrimethamine (SP) resistance in P. falciparum isolates obtained from the North Atlantic Autonomous Region of Nicaragua. Blood spots for this study were made available from a CQ and SP drug efficacy trial conducted in 2005 and also from a surveillance study performed in 2011. Polymorphisms in P. falciparum CQ resistance transporter, dihydrofolate reductase, and dihydropteroate synthase gene loci that are associated with resistance to CQ, pyrimethamine, and sulfadoxine, respectively, were detected by DNA sequencing. In the 2005 dataset, only 2 of 53 isolates had a CQ resistance allele (CVIET), 2 of 52 had a pyrimethamine resistance allele, and 1 of 49 had a sulfadoxine resistance allele. In the 2011 dataset, none of 45 isolates analyzed had CQ or SP resistance alleles.

  2. Effects of pyrimethamine-sulphadoxine, chloroquine plus chlorpheniramine, and amodiaquine plus pyrimethamine-sulphadoxine on gametocytes during and after treatment of acute, uncomplicated malaria in children

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    A Sowunmi

    2006-12-01

    Full Text Available The effects of pyrimethamine-sulphadoxine (PS, chloroquine plus chlorpheniramine, a H1 receptor antagonist that reverses chloroquine resistance in Plasmodium falciparum in vitro and in vivo (CQCP, and amodiaquine plus pyrimethamine-sulphadoxine (AQPS on gametocyte production were evaluated in 157 children with acute, symptomatic, uncomplicated falciparum malaria who were treated with these drugs. PS was significantly less effective than CQCP or AQPS at clearing asexual parasitaemia or other symptoms of malaria. Gametocyte carriage on days 3, 7, and 14 were significantly higher in those treated with PS. The ratio of the density (per µl blood of peripheral young gametocyte (PYG, that is, < stage III to peripheral mature gametocyte (PMG, that is, stage IV and V, an index of continuing generation of gametocytes, rose to 1 by day 7 of treatment in those treated with PS, but remained consistently below 1 in the other treatment groups. PYG-PMG density ratio increased significantly from day 0-14 in those treated with PS and CQCP (chi2 = 76, P = 0.000001 and chi2 = 42.2, P = 0.00001, respectively but decreased significantly in those treated with AQPS (chi2 = 53.2, P = 0.000001. Both PS-sensitive and -resistant infections generated PYG (18 of 29 vs 13 of 20, chi2 = 0.04, P = 0.93 but PYG was present only in those with resistant response to CQCP. Combination of PS with amodiaquine (AQ, that is, (AQPS resulted in less production of PYG, but in this setting, PYG was not indicative of response to AQPS. These data indicate that PS enhanced production or release of young gametocytes when used alone, but generated less young gametocytes when used in combination with AQ. PYG may be used as an indicator of response to CQCP but not PS or PS-based combination drugs.

  3. Toxoplasma gondii Myocarditis after Adult Heart Transplantation: Successful Prophylaxis with Pyrimethamine

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    Tania Mara V. Strabelli

    2012-01-01

    Full Text Available Toxoplasma gondii primary infection/reactivation after solid organ transplantation is a serious complication, due to the high mortality rate following disseminated disease. We performed a retrospective study of all cases of T. gondii infections in 436 adult patients who had received an orthotopic cardiac transplant at our Institution from May 1968 to January 2011. Six patients (1.3% developed T. gondii infection/reactivation in the post-operative period. All infections/reactivations occurred before 1996, when no standardized toxoplasmosis prophylactic regimen or co-trimoxazole prophylaxis was used. Starting with the 112th heart transplant, oral pyrimethamine 75 mg/day was used for seronegative transplant recipients whose donors were seropositive or unknown. Two patients (33.3% presented with disseminated toxoplasmosis infection, and all patients (100% had myocarditis. Five patients (83.3% were seronegative before transplant and one patient did not have pre-transplant serology available. Median time for infection onset was 131 days following transplantation. Three patients (50% died due to toxoplasmosis infection. After 1996, we did not observe any additional cases of T. gondii infection/reactivation. In conclusion, toxoplasmosis in heart allographs was more frequent among seronegative heart recipients, and oral pyrimethamine was highly effective for the prevention of T. gondii infection in this population.

  4. Simultaneous determination of dapsone, monoacetyldapsone and pyrimethamine in whole blood and plasma by high-performance liquid chromatography

    DEFF Research Database (Denmark)

    Lemnge, M M; Rønn, A; Flachs, H

    1993-01-01

    A sensitive, selective and rapid reversed-phase high-performance liquid chromatographic method was developed for the simultaneous analysis of dapsone, monoacetyldapsone and pyrimethamine in human whole blood and plasma. The procedure involved extraction of the compounds and the internal standard...

  5. Characterizing the impact of sustained sulfadoxine/pyrimethamine use upon the Plasmodium falciparum population in Malawi

    DEFF Research Database (Denmark)

    Ravenhall, Matt; Benavente, Ernest Diez; Mipando, Mwapatsa

    2016-01-01

    BACKGROUND: Malawi experienced prolonged use of sulfadoxine/pyrimethamine (SP) as the front-line anti-malarial drug, with early replacement of chloroquine and delayed introduction of artemisinin-based combination therapy. Extended use of SP, and its continued application in pregnancy is impacting...

  6. Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with SOD1 mutations.

    Science.gov (United States)

    Lange, Dale J; Shahbazi, Mona; Silani, Vincenzo; Ludolph, Albert C; Weishaupt, Jochen H; Ajroud-Driss, Senda; Fields, Kara G; Remanan, Rahul; Appel, Stanley H; Morelli, Claudia; Doretti, Alberto; Maderna, Luca; Messina, Stefano; Weiland, Ulrike; Marklund, Stefan L; Andersen, Peter M

    2017-06-01

    Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose-dependent SOD1 reduction in cell culture systems. A previous phase 1 trial showed pyrimethamine lowers SOD1 levels in leukocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to familial amyotrophic lateral sclerosis (fALS/SOD1). A multicenter (5 sites), open-label, 9-month-duration, dose-ranging study was undertaken to determine the safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF in fALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effect assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS score, ALS Functional Rating Scale-Revised, and McGill Quality of Life Single-Item Scale were measured at screening, visit 6, and visit 9. We enrolled 32 patients; 24 completed 6 visits (18 weeks), and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p < 0.001) with a mean reduction of 13.5% (95% confidence interval [CI] = 8.4-18.5) and at visit 9 (p < 0.001) with a mean reduction of 10.5% (95% CI = 5.2-15.8). Pyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long-term studies are warranted to assess clinical efficacy. Ann Neurol 2017;81:837-848. © 2017 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

  7. Efficacy of Artesunate + Sulphadoxine-Pyrimethamine (AS + SP and Amodiaquine + Sulphadoxine-Pyrimethamine (AQ + SP for Uncomplicated falciparum Malaria in Equatorial Guinea (Central Africa

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    Pilar Charle

    2009-01-01

    Full Text Available Objectives. The objectives of the study were (i to evaluate the efficacy of combination drugs, such as artesunate + sulphadoxine-pyrimethamine (AS + SP and amodiaquine + sulphadoxine-pyripethamine (AQ + SP in treatment of uncomplicated falciparum malaria (ii to differentiate recrudescence from reinfection by analysing msp-1 and msp-2 genes of Plasmodium falciparum in treatment failure cases. Methods. We carried out an in vivo study in the year 2005 in 206 children between 6 to 59 months age groups. Of the 206, 120 received AQ + SP, and 86 received AS + SP. A clinical and parasitological followup during 14 days was undertaken. Finger-prick blood sample from each patient was taken on Whatman filter paper (no. 3 on days 0, 7, 14 and also the day when the parasite and symptoms reappeared for PCR analysis. Results. Late treatment failure was observed in 3.5% (4/114 with AQ + SP, and 2.5% (2/79 with AS + SP. The success rate was 96.5% with AQ + SP and 97.5% with AS + SP. No deaths and severe reactions were recorded. Out of the 6 treatment failure cases, one was reinfection as observed by PCR analysis of msp-1 and msp-2 genes on day 14. Discussion. Both the combinations found to be efficacious and safe and could be used as a first-line treatment for uncomplicated falciparum malaria in Equatorial Guinea.

  8. High prevalence of dhfr triple mutant and correlation with high rates of sulphadoxine-pyrimethamine treatment failures in vivo in Gabonese children

    NARCIS (Netherlands)

    G. Mombo-Ngoma; S. Oyakhirome; R. Ord; J.J. Gabor; K.C. Greutélaers; K. Profanter; B. Greutélaers; F. Kurth; B. Lell; J.F.J. Kun; S. Issifou; C. Roper; P.G. Kremsner; M.P. Grobusch

    2011-01-01

    Background: Drug resistance contributes to the global malaria burden. Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) polymorphisms confer resistance to sulphadoxine-pyrimethamine (SP). Methods: The study assessed the frequency of SP resistance-conferring pol

  9. The in vivo antimalarial activity of methylene blue combined with pyrimethamine, chloroquine and quinine

    Directory of Open Access Journals (Sweden)

    Giovanny Garavito

    2012-09-01

    Full Text Available The effectiveness of methylene blue (MB combined with pyrimethamine (PYR, chloroquine (CQ or quinine (Q was examined in a classical four-day suppressive test against a causative agent of rodent malaria, Plasmodium berghei. A marked potentiation was observed when MB was administered at a non-curative dose of 15 mg/kg/day in combination with PYR (0.19 mg/kg/day or Q (25 mg/kg/day. No synergy was found between MB (15 mg/Kg and CQ (0.75 mg/Kg. Our results suggest that the combination of MB with PYR or Q may improve the efficacy of these currently used antimalarial drugs.

  10. Pharmacokinetics of artesunate alone and in combination with sulfadoxine/pyrimethamine in healthy Sudanese volunteers.

    Science.gov (United States)

    Matar, Kamal M; Awad, Abdelmoneim I; Elamin, Sakina B

    2014-06-01

    Artesunate (AS) in combination with sulfadoxine/pyrimethamine (SP) is the first-line therapy for management of uncomplicated Plasmodium falciparum malaria in Sudan. The objective of this study was to assess the potential impact of SP on the pharmacokinetics of AS and its active metabolite, dihydroartemisinin (DHA), in healthy adults. A single-dose, randomized, open-label, crossover study design with a washout period of three weeks was performed with 16 volunteers. After oral administration of AS alone or in combination with SP, Tmax values of AS and DHA were significantly prolonged in the combination group (P 0.05). The t1/2 values of AS and DHA were significantly higher in females than in males (P < 0.05). The present findings suggest that co-administration of SP with AS has no clinically relevant impact on the pharmacokinetics of AS or DHA in healthy persons.

  11. Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant β-N-acetylhexosaminidase Activity.

    Science.gov (United States)

    Tropak, Michael B; Zhang, Jianmin; Yonekawa, Sayuri; Rigat, Brigitte A; Aulakh, Virender S; Smith, Matthew R; Hwang, Hee-Jong; Ciufolini, Marco A; Mahuran, Don J

    2015-06-11

    In order to identify structural features of pyrimethamine (5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine) that contribute to its inhibitory activity (IC50 value) and chaperoning efficacy toward β-N-acetylhexosaminidase, derivatives of the compound were synthesized that differ at the positions bearing the amino, ethyl, and chloro groups. Whereas the amino groups proved to be critical to its inhibitory activity, a variety of substitutions at the chloro position only increased its IC50 by 2-3-fold. Replacing the ethyl group at the 6-position with butyl or methyl groups increased IC50 more than 10-fold. Surprisingly, despite its higher IC50, a derivative lacking the chlorine atom in the para-position was found to enhance enzyme activity in live patient cells a further 25% at concentrations >100 μM, while showing less toxicity. These findings demonstrate the importance of the phenyl group in modulating the chaperoning efficacy and toxicity profile of the derivatives.

  12. High-performance liquid chromatography determination of dapsone, monoacetyldapsone, and pyrimethamine in filter paper blood spots

    DEFF Research Database (Denmark)

    Rønn, A M; Lemnge, M M; Angelo, H R

    1995-01-01

    A high-performance liquid chromatography method for the simultaneous analysis of dapsone (DDS), the major metabolite of DDS, monoacetyldapsone (MADDS), and pyrimethamine (PYR) was modified for capillary blood samples obtained by finger prick and dried on filter paper. Limit of quantitation using...... 150 microliters whole blood dried on filter paper was found to be 20 ng/ml for DDS and PYR and 15 ng/ml for MADDS (precision ... paper method and the original whole-blood method was almost comparable. Standardization could therefore be obtained by the more simple whole-blood method. Dried filter paper samples stored at 19-22 degrees C were stable for months and for 2 weeks stored at 35 degrees C. The concentrations...

  13. Molecular monitoring of Plasmodium falciparum super-resistance to sulfadoxine-pyrimethamine in Tanzania

    DEFF Research Database (Denmark)

    Kavishe, Reginald A; Kaaya, Robert D; Nag, Sidsel;

    2016-01-01

    and in private drug shops in sub-Saharan Africa. This study reports on the prevalence and distribution of Pfdhps mutations A540E and A581G in Tanzania. When found together, these mutations confer high-level SP resistance (sometimes referred to as 'super-resistance'), which is associated with loss in protective......BACKGROUND: Sulfadoxine-pyrimethamine (SP) is recommended for prophylactic treatment of malaria in pregnancy while artemisinin combination therapy is the recommended first-line anti-malarial treatment. Selection of SP resistance is ongoing since SP is readily available in health facilities...... = 85.3, p resistance. A high prevalence of Pfdhps-581G was observed in Tanga (56.6 %) in northeastern Tanzania and in Kagera (20.4 %) in northwestern Tanzania and the 540-581 EG haplotype was found at 54.5 and 19...

  14. Sulfadoxine-pyrimethamine impairs Plasmodium falciparum gametocyte infectivity and Anopheles mosquito survival.

    Science.gov (United States)

    Kone, Aminatou; van de Vegte-Bolmer, Marga; Siebelink-Stoter, Rianne; van Gemert, Geert-Jan; Dara, Antoine; Niangaly, Hamidou; Luty, Adrian; Doumbo, Ogobara K; Sauerwein, Robert; Djimde, Abdoulaye A

    2010-08-15

    Sulfadoxine-pyrimethamine (SP) is currently the drug of choice for intermittent preventive treatment of Plasmodium falciparum both in pregnancy and infancy. A prolonged parasite clearance time conferred by dhfr and dhps mutations is believed to be responsible for increased gametocyte prevalence in SP treated individuals. However, using a direct feeding assay in Mali, we showed that gametocytes present in peripheral venous blood post-SP treatment had reduced infectivity for Anopheles gambiae sensu stricto (ss) mosquitoes. We investigated the potential mechanisms involved in the dhfr and dhps quintuple mutant NF-135 and the single dhps 437 mutant NF-54. Concentrations of sulfadoxine (S) and pyrimethamine (P) equivalent to the serum levels of the respective drugs on day 3 (S=61 microg/ml, P=154.7 ng/ml) day 7 (S=33.8 microg/ml, P=66.6 ng/ml) and day 14 (S=14.2 microg/ml, P=15.7 ng/ml) post-SP treatment were used to study the effect on gametocytogenesis, gametocyte maturation and infectivity to Anopheles stephensi mosquitoes fed through an artificial membrane. The drugs readily induced gametocytogenesis in the mutant NF-135 strain but effectively killed the wild-type NF-54. However, both drugs impaired gametocyte maturation yielding odd-shaped non-exflagellating mature gametocytes. The concomitant ingestion of both S and P together with gametocytemic blood-meal significantly reduced the prevalence of oocyst positivity as well as oocyst density when compared to controls (Pmosquito survival by up to 65% (Pmosquito survival. Copyright 2010. Published by Elsevier Ltd.

  15. Effects of amodiaquine and artesunate on sulphadoxine-pyrimethamine pharmacokinetic parameters in children under five in Mali

    Directory of Open Access Journals (Sweden)

    Doumbo Ogobara K

    2011-09-01

    Full Text Available Abstract Background Sulphadoxine-pyrimethamine, in combination with artesunate or amodiaquine, is recommended for the treatment of uncomplicated malaria and is being evaluated for intermittent preventive treatment. Yet, limited data is available on pharmacokinetic interactions between these drugs. Methods In a randomized controlled trial, children aged 6-59 months with uncomplicated falciparum malaria, received either one dose of sulphadoxine-pyrimethamine alone (SP, one dose of SP plus three daily doses of amodiaquine (SP+AQ or one dose of SP plus 3 daily doses of artesunate (SP+AS. Exactly 100 μl of capillary blood was collected onto filter paper before drug administration at day 0 and at days 1, 3, 7, 14, 21 and 28 after drug administration for analysis of sulphadoxine and pyrimethamine pharmacokinetic parameters. Results Fourty, 38 and 31 patients in the SP, SP+AQ and SP+AS arms, respectively were included in this study. The concentrations on day 7 (that are associated with therapeutic efficacy were similar between the SP, SP+AQ and SP+AS treatment arms for sulphadoxine (median [IQR] 35.25 [27.38-41.70], 34.95 [28.60-40.85] and 33.40 [24.63-44.05] μg/mL and for pyrimethamine (56.75 [46.40-92.95], 58.75 [43.60-98.60] and 59.60 [42.45-86.63] ng/mL. There were statistically significant differences between the pyrimethamine volumes of distribution (4.65 [3.93-6.40], 4.00 [3.03-5.43] and 5.60 [4.40-7.20] L/kg; p = 0.001 and thus elimination half-life (3.26 [2.74 -3.82], 2.78 [2.24-3.65] and 4.02 [3.05-4.85] days; p . This study confirmed the lower SP concentrations previously reported for young children when compared with adult malaria patients. Conclusion Despite slight differences in pyrimethamine volumes of distribution and elimination half-life, these data show similar exposure to SP over the critical initial seven days of treatment and support the current use of SP in combination with either AQ or AS for uncomplicated falciparum malaria

  16. Efficacy and tolerability of artesunate plus sulfadoxine-pyrimethamine and sulfadoxine-pyrimethamine alone for the treatment of uncomplicated Plasmodium falciparum malaria in Peru.

    Science.gov (United States)

    Marquiño, Wilmer; Ylquimiche, Laura; Hermenegildo, Ygor; Palacios, Ana Maria; Falconí, Eduardo; Cabezas, César; Arróspide, Nancy; Gutierrez, Sonia; Ruebush, Trenton K

    2005-05-01

    To assist the Peruvian Ministry of Health in modifying the malaria treatment policy for their north Pacific coastal region, we conducted an in vivo efficacy trial of sulfadoxine-pyrimethamine (SP) and SP plus artesunate (SP-AS) for the treatment for uncomplicated Plasmodium falciparum infections. A total of 197 patients were randomized to therapy with either SP (25 mg/kg of the sulfadoxine component in a single dose on day 0) or a combination of SP plus AS (4 mg/kg on days 0, 1, and 2) and were followed for 28 days for symptoms and recurrence of parasitemia. No statistically significant differences between the two groups were observed on enrollment with respect to age, sex, history of malaria, or geometric mean parasite density. A total of 185 subjects completed the 28-day follow-up. Of the 91 subjects treated with SP alone, two had recurrences of parasitemia on day 7 and one on day 21. Of the 94 subjects treated with SP-AS, one had a recurrence of parasitemia on day 21. Fever and asexual parasite density decreased significantly more rapidly and the proportion of patients with gametocytemia on days 3-28 was significantly lower in subjects treated with combination therapy than in those who received SP alone. No severe adverse drug reactions were observed; however, self-limited rash and pruritus were significantly more common and an exacerbation of nausea, vomiting, and abdominal pain were observed significantly more frequently among patients who had received SP-AS. These results have contributed to a National Malaria Control Program decision to change to SP-AS combination therapy as the first-line treatment for uncomplicated P. falciparum malaria in northern coastal Peru in November 2001, making Peru the first country in the Americas to recommend this combination therapy.

  17. The susceptibility of Plasmodium falciparum to sulfadoxine and pyrimethamine: correlation of in vivo and in vitro results

    DEFF Research Database (Denmark)

    Schapira, A; Bygbjerg, Ib Christian; Jepsen, S;

    1986-01-01

    In 1982, 2 of 14 Plasmodium falciparum infections acquired in East Africa and diagnosed in Copenhagen were resistant to treatment with sulfadoxine plus pyrimethamine (Fansidar), while in 1983, 6 of 18 were so. The in vivo tests were supplemented by determinations of drug concentrations in serum......, and 4 isolates from in vivo-sensitive cases and 6 from in vivo-resistant cases were selected for in vivo tests. These were performed in ordinary RPMI 1640 medium and in a medium with physiological p-aminobenzoic acid and folic acid concentrations. Pharmacokinetic aberrations were found to be of possible...... importance in only 2 of the in vivo-resistant cases. In vitro susceptibility to sulfadoxine was found to be uniformly low in all isolates. Testing with a combination of sulfadoxine and pyrimethamine in the medium with physiological concentrations of cofactors probably reflects the in vivo situation most...

  18. Drug resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum malaria in Mlimba, Tanzania

    OpenAIRE

    Balthazary Sakurani T; Malisa Allen L; Mutayoba Benezeth M; Mbugi Erasto V; Nyambo Thomas B; Mshinda Hassan

    2006-01-01

    Abstract Background Sulphadoxine-pyrimethamine (SP) has been and is currently used for treatment of uncomplicated Plasmodium falciparum malaria in many African countries. Nevertheless, the response of parasites to SP treatment has shown significant variation between individuals. Methods The genes for dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) were used as markers, to investigate parasite resistance to SP in 141 children aged less than 5 years. Parasite DNA was extracte...

  19. Atovaquone and proguanil hydrochloride compared with chloroquine or pyrimethamine/sulfadoxine for treatment of acute Plasmodium falciparum malaria in Peru

    Directory of Open Access Journals (Sweden)

    Llanos-Cuentas A.

    2001-01-01

    Full Text Available The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (MalaroneTM were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive 1,000 mg atovaquone and 400 mg proguanil hydrochloride daily for 3 days (n=15 or 1,500 mg chloroquine (base over a 3 day period (n=14 (phase 1. The cure rate with chloroquine was lower than expected and patients were subsequently randomized to receive a single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine (n=9 or atovaquone/proguanil as before (n=5 (phase 2. In phase 1, atovaquone/proguanil was significantly more effective than chloroquine (cure rate 100% [14/14] versus 8% [1/13], P<0.0001. In phase 2, atovaquone/proguanil and pyrimethamine/sulfadoxine were both highly effective (cure rates 100% [5/5] and 100% [7/7]. There were no significant differences between treatment groups in parasite or fever clearance times. Adverse events were typical of malarial symptoms and did not differ significantly between groups. Overall efficacy of atovaquone/proguanil was 100% for treatment of acute falciparum malaria in a region with a high prevalence of chloroquine resistance.

  20. Changing the policy for intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy in Malawi.

    Science.gov (United States)

    Mwendera, Chikondi A; de Jager, Christiaan; Longwe, Herbert; Phiri, Kamija; Hongoro, Charles; Mutero, Clifford M

    2017-02-20

    The growing resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine (SP) treatment for uncomplicated malaria led to a recommendation by the World Health Organization for the use of artemisinin-based combination therapy. Inevitably, concerns were also raised surrounding the use of SP for intermittent prevention treatment of malaria during pregnancy (IPTp) amidst the lack of alternative drugs. Malawi was the first country to adopt intermittent prevention treatment with SP in 1993, and updated in 2013. This case study examines the policy updating process and the contribution of research and key stakeholders to this process. The findings support the development of a malaria research-to-policy framework in Malawi. Documents and evidence published from 1993 to 2012 were systematically reviewed in addition to key informant interviews. The online search identified 170 potential publications, of which eight from Malawi met the inclusion criteria. Two published studies from Malawi were instrumental in the WHO policy recommendation which in turn led to the updating of national policies. The updated policy indicates that more than two SP doses, as informed by research, overcome the challenges of the first policy of two SP doses only because of ineffectiveness by P. falciparum resistance and the global lack of replacement drugs to SP for IPTp. International WHO recommendations facilitated a smooth policy change driven by motivated local leadership with technical and financial support from development partners. Policy development and implementation should include key stakeholders and use local malaria research in a research-to-policy framework.

  1. Use of thin-layer chromatography to detect counterfeit sulfadoxine/pyrimethamine tablets with the wrong active ingredient in Malawi.

    Science.gov (United States)

    Khuluza, Felix; Kigera, Stephen; Jähnke, Richard W O; Heide, Lutz

    2016-04-14

    Substandard and falsified anti-malarial medicines pose a serious threat to public health, especially in low-income countries. Appropriate technologies for drug quality analysis in resource-limited settings are important for the surveillance of the formal and informal drug market. The feasibility of thin-layer chromatography (TLC) with different solvent systems was tested using the GPHF Minilab in a study of the quality of sulfadoxine/pyrimethamine tablets in Malawi. Twenty eight samples of sulfadoxine/pyrimethamine tablets were collected from randomly selected health facilities of four districts of southern Malawi. A mystery shopper approach was used when collecting samples from illegal street vendors, and an overt approach for the other facilities. Samples were subjected to visual inspection, disintegration testing and TLC analysis. 10 samples were further investigated according to the methods of the US Pharmacopeia using high performance liquid chromatography (HPLC). One sample was found to be falsified, containing a mixture of paracetamol tablets and co-trimoxazole tablets. These had been repackaged into paper strip packs labelled as a brand of sulfadoxine/pyrimethamine. TLC with different solvent systems readily proved that these tablets did not comply with their declaration, and provided strong evidence for the active pharmaceutical ingredients which were actually contained. Full pharmacopeial analysis by HPLC confirmed the results suggested by TLC for this sample, and showed two further samples to be of substandard quality. Due to the absence of the declared anti-malarial ingredients and due to the presence of other pharmaceutical ingredients, the identified falsified medicine represents a serious health risk for the population. Thin-layer chromatography (TLC) using different solvent systems proved to be a powerful method for the identification of this type of counterfeiting, presenting a simple and affordable technology for use in resource-limited settings.

  2. Plasmodium vivax dhfr and dhps mutations in isolates from Madagascar and therapeutic response to sulphadoxine-pyrimethamine

    Directory of Open Access Journals (Sweden)

    Jahevitra Martial

    2008-02-01

    Full Text Available Abstract Background Four of five Plasmodium species infecting humans are present in Madagascar. Plasmodium vivax remains the second most prevalent species, but is understudied. No data is available on its susceptibility to sulphadoxine-pyrimethamine, the drug recommended for intermittent preventive treatment during pregnancy. In this study, the prevalence of P. vivax infection and the polymorphisms in the pvdhfr and pvdhps genes were investigated. The correlation between these polymorphisms and clinical and parasitological responses was also investigated in P. vivax-infected patients. Methods Plasmodium vivax clinical isolates were collected in eight sentinel sites from the four major epidemiological areas for malaria across Madagascar in 2006/2007. Pvdhfr and pvdhps genes were sequenced for polymorphism analysis. The therapeutic efficacy of SP in P. vivax infections was assessed in Tsiroanomandidy, in the foothill of the central highlands. An intention-to-treat analysis of treatment outcome was carried out. Results A total of 159 P. vivax samples were sequenced in the pvdhfr/pvdhps genes. Mutant-types in pvdhfr gene were found in 71% of samples, and in pvdhps gene in 16% of samples. Six non-synonymous mutations were identified in pvdhfr, including two novel mutations at codons 21 and 130. For pvdhps, beside the known mutation at codon 383, a new one was found at codon 422. For the two genes, different combinations were ranged from wild-type to quadruple mutant-type. Among the 16 patients enrolled in the sulphadoxine-pyrimethamine clinical trial (28 days of follow-up and after adjustment by genotyping, 3 (19%, 95% CI: 5%–43% of them were classified as treatment failure and were pvdhfr 58R/117N double mutant carriers with or without the pvdhps 383G mutation. Conclusion This study highlights (i that genotyping in the pvdhfr and pvdhps genes remains a useful tool to monitor the emergence and the spread of P. vivax sulphadoxine-pyrimethamine

  3. Effect of cyclic, low dose pyrimethamine treatment in patients with Late Onset Tay Sachs: an open label, extended pilot study

    OpenAIRE

    Osher, Etty; Fattal-Valevski, Aviva; Sagie, Liora; Urshanski, Nataly; Sagiv, Nadav; Peleg, Leah; Lerman-Sagie, Tally; Zimran, Ari; Elstein, Deborah; Navon, Ruth; Valevski, Avi; Stern, Naftali

    2015-01-01

    Background Late Onset Tay- Sachs disease (LOTS) is a rare neurodegenerative lysosomal storage disease which results from mutations in the gene encoding the α subunit (HEXA) of β-hexosaminidase enzyme (HexA). At the present time, no effective treatment exists for LOTS and other neurodegenerative diseases involving the central nerve system (CNS). Pyrimethamine (PMT) was previously shown to act as a HexA chaperone in human fibroblasts in vitro carrying some (e.g., αG269S), but not all LOTS-relat...

  4. Efficacy of chloroquine, amodiaquine, sulphadoxine-pyrimethamine and combination therapy with artesunate in Mozambican children with non-complicated malaria

    DEFF Research Database (Denmark)

    Abacassamo, F; Enosse, S; Aponte, J J

    2004-01-01

    This paper reports a two-phase study in Manhiça district, Mozambique: first we assessed the clinical efficacy and parasitological response of Plasmodium falciparum to chloroquine (CQ), sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ), then we tested the safety and efficacy in the treatment of......% to AQ. Co-administration of AQ + SP, AR + SP and AQ + AR was safe and had 100% clinical efficacy at 14-day follow-up. The combination therapies affected rapid fever clearance time and reduced the incidence of gametocytaemia during follow-up....

  5. High rates of parasite recrudescence following intermittent preventive treatment with sulphadoxine-pyrimethamine during pregnancy in Benin

    DEFF Research Database (Denmark)

    Moussiliou, Azizath; Sissinto-Savi De Tove, Yolande; Doritchamou, Justin;

    2013-01-01

    BACKGROUND: Despite widespread parasite resistance to sulphadoxine-pyrimethamine (SP) its use for intermittent preventative treatment during pregnancy remains the policy in Benin and throughout most of sub-Saharan Africa. METHODS: In a prospective study, 982 pregnant women were recruited in Benin...... the persistence of parasites and malaria consequences, were investigated. Recurrent parasites were genotyped to identify recrudescences from re-infections. RESULTS: The prevalence of pfdhfr/pfdhps quadruple mutants (triple pfdhfr + single pfdhps) was consistently above 80% while quintuple and sextuple mutants...

  6. Artemisinin-based combinations versus amodiaquine plus sulphadoxine-pyrimethamine for the treatment of uncomplicated malaria in Faladje, Mali

    Directory of Open Access Journals (Sweden)

    Traore Boubacar

    2009-01-01

    Full Text Available Abstract Background Because of the emergence of chloroquine resistance in Mali, artemether-lumefantrine (AL or artesunate-amodiaquine (AS+AQ are recommended as first-line therapy for uncomplicated malaria, but have not been available in Mali until recently because of high costs. Methods From July 2005 to January 2006, a randomized open-label trial of three oral antimalarial combinations, namely AS+AQ, artesunate plus sulphadoxine-pyrimethamine (AS+SP, and amodiaquine plus sulphadoxine-pyrimethamine (AQ+SP, was conducted in Faladje, Mali. Parasite genotyping by polymerase chain reaction (PCR was used to distinguish new from recrudescent Plasmodium falciparum infections. Results 397 children 6 to 59 months of age with uncomplicated Plasmodium falciparum malaria were enrolled, and followed for 28 days to assess treatment efficacy. Baseline characteristics were similar in all three treatment groups. The uncorrected rates of adequate clinical and parasitologic response (ACPR were 55.7%, 90.8%, and 97.7% in AS+AQ, AS+SP, and AQ+SP respectively (p Conclusion The combination of AQ+SP provides a potentially low cost alternative for treatment of uncomplicated P. falciparum infection in Mali and appears to have the added value of longer protective effect against new infection.

  7. Efficacy of sulfadoxine-pyrimethamine and mefloquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon basin of Peru

    Directory of Open Access Journals (Sweden)

    Magill Alan J.

    2004-01-01

    Full Text Available In vivo antimalarial drug efficacy studies of uncomplicated Plasmodium falciparum malaria at an isolated site in the Amazon basin of Peru bordering Brazil and Colombia showed >50% RII/RIII resistance to sulfadoxine-pyrimethamine but no evidence of resistance to mefloquine.

  8. Polymorphisms in the dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) genes of Plasmodium falciparum and in vivo resistance to sulphadoxine/pyrimethamine in isolates from Tanzania

    DEFF Research Database (Denmark)

    Jelinek, T; Rønn, A M; Lemnge, M M

    1998-01-01

    The efficacy of sulphadoxine/pyrimethamine (S/P) in treatment of uncomplicated falciparum malaria in Africa is increasingly compromised by development of resistance. The occurrence of mutations associated with the active site sequence in the Plasmodium falciparum genes coding for dihydrofolate...

  9. A randomized, placebo-controlled, double-blind trial on sulfadoxine-pyrimethamine alone or combined with artesunate or amodiaquine in uncomplicated malaria.

    NARCIS (Netherlands)

    Mockenhaupt, F.P.; Ehrhardt, S.; Dzisi, S.Y.; Bousema, T.; Wassilew, N.; Schreiber, J.; Anemana, S.D.; Cramer, J.P.; Otchwemah, R.N.; Sauerwein, R.W.; Eggelte, T.A.; Bienzle, U.

    2005-01-01

    The therapeutic efficacy of sulfadoxine-pyrimethamine (SP) alone, SP plus amodiaquine (AQ), and SP plus artesunate (AS) was assessed in a randomized, placebo-controlled, and double-blind trial among 438 children with uncomplicated Plasmodium falciparum malaria in northern Ghana. Clinical and parasit

  10. Artesunate-amodiaquine versus artesunate-sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in children

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    Novie H. Rampengan

    2014-01-01

    Full Text Available Background Malaria is a major cause of morbidity and mortality in children, especially in developing countries. Artemisinin combination therapy (ACT has higher rates of parasite clearance and inhibition of anti-malarial drugs resistance than non-ACT. Hence, we compared the efficacies of artesunate-amodiaquine (AS-AQ versus artesunate-sulfadoxine pyrimethamine (AS-SP combination therapies in children with uncomplicated falciparum malaria. Objective To compare the fever clearance time, parasite clearance time, and length of hospital stay in uncomplicated falciparum malaria patients treated with AS-AQ and AS-SP. Methods We reviewed the medical records of children aged 1-14 years with uncomplicated falciparum malaria admitted to Prof. Dr. R. D. Kandou Hospital between January 2002 – June 2010. Treatment efficacy was evaluated by fever clearance time, parasite clearance time, and length of hospital stay. The differences of treatment efficacy between the two groups of therapy were analyzed by independent T-test. Results We identified 185 children with uncomplicated falciparum malaria, 104 cases were treated with AS-AQ while the other 81 received AS-SP. Parasite clearance time was shorter in AS-AQ group than in AS-SP group at 1.38 (SD 0.69 versus 1.91 (SD 0.93 days, respectively (95%CI of differences 0.30 to 0.76, P<0.05. The length of hospital stay was shorter in AS-AQ group than in the AS-SP group, at 5.01 (SD 1.22 versus 6.04 (SD 0.98 days, respectively (95%CI of differences 0.71 to 1.35, P<0.05. However, there was no statistically significant difference in fever clearance time between the groups. Conclusion AS-AQ combination therapy reduces parasite clearance time and length of hospital stay compared to AS-SP combination therapy in children with uncomplicated falciparum malaria. [Paediatr Indones. 2014;54:46-51.].

  11. Declining trend of Plasmodium falciparum dihydrofolate reductase (dhfr and dihydropteroate synthase (dhps mutant alleles after the withdrawal of Sulfadoxine-Pyrimethamine in North Western Ethiopia.

    Directory of Open Access Journals (Sweden)

    Sofonias K Tessema

    Full Text Available Antimalarial drug resistance is one of the major challenges in global efforts of malaria control and elimination. In 1998, chloroquine was abandoned and replaced with sulfadoxine/pyrimethamine, which in turn was replaced with artemether/lumefantrine for the treatment of uncomplicated falciparum malaria in 2004. Sulfadoxine/pyrimethamine resistance is associated with mutations in dihydrofolate reductase (Pfdhfr and dihydropteroate synthase (Pfdhps genes. The prevalence of mutation in Pfdhfr and Pfdhps genes were evaluated and compared for a total of 159 isolates collected in two different time points, 2005 and 2007/08, from Pawe hospital, in North Western Ethiopia. The frequency of triple Pfdhfr mutation decreased significantly from 50.8% (32/63 to 15.9% (10/63 (P<0.001, while Pfdhps double mutation remained high and changed only marginally from 69.2% (45/65 to 55.4% (40/65 (P = 0.08. The combined Pfdhfr/Pfdhps quintuple mutation, which is strongly associated with sulfadoxine/pyrimethamine resistance, was significantly decreased from 40.7% (24/59 to 13.6% (8/59 (P<0.0001. On the whole, significant decline in mutant alleles and re-emergence of wild type alleles were observed. The change in the frequency is explained by the reduction of residual drug-resistant parasites caused by the strong drug pressure imposed when sulfadoxine/pyrimethamine was the first-line drug, followed by lower fitness of these resistant parasites in the absence of drug pressure. Despite the decrease in the frequency of mutant alleles, higher percentages of mutation remain prevalent in the study area in 2007/08 in both Pfdhfr and Pfdhps genes. Therefore, further multi-centered studies in different parts of the country will be required to assess the re-emergence of sulfadoxine/pyrimethamine sensitive parasites and to monitor and prevent the establishment of multi drug resistant parasites in this region.

  12. Effects of chloroquine and sulfadoxine/pyrimethamine on gametocytes in patients with uncomplicated Plasmodium falciparum malaria in Colombia

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    Lyda Osorio

    2002-12-01

    Full Text Available The effect of antimalarials on gametocytes can influence transmission and the spread of drug resistance. In order to further understand this relationship, we determined the proportion of gametocyte carriers over time post-treatment in patients with uncomplicated Plasmodium falciparum malaria who were treated with either chloroquine (CQ or sulfadoxine/pyrimethamine (SP. The overall proportion of gametocyte carriers was high (85% and not statistically significantly different between the CQ and SP treatment groups. However, an increased risk of carrying gametocytes on day 14 of follow up (1.26 95% CI 1.10-1.45 was found among patients having therapeutic failure to CQ compared with patients having an adequate therapeutic response. This finding confirms and extends reports of increased risk of gametocytaemia among CQ resistant P. falciparum.

  13. Clinical trials of artesunate plus sulfadoxine-pyrimethamine for Plasmodium falciparum malaria in Afghanistan: maintained efficacy a decade after introduction.

    Science.gov (United States)

    Awab, Ghulam Rahim; Imwong, Mallika; Pukrittayakamee, Sasithon; Alim, Fazel; Hanpithakpong, Warunee; Tarning, Joel; Dondorp, Arjen M; Day, Nicholas P J; White, Nicholas J; Woodrow, Charles J

    2016-02-25

    Combination therapy with artesunate plus sulfadoxine-pyrimethamine (SP) was adopted as recommended treatment for Plasmodium falciparum infection in Afghanistan in 2003. A series of prospective clinical studies examining the efficacy of artesunate plus sulfadoxine-pyrimethamine (AS + SP) against P. falciparum were undertaken in sentinel sites in Afghanistan from 2007 to 2014, accompanied by relevant molecular studies. The first study was a randomized trial of AS + SP versus dihydroartemisinin-piperaquine, while two subsequent studies were standard therapeutic efficacy studies of AS + SP. Three hundred and three patients were enrolled across four provinces in the north and east of the country. Curative efficacy was high in all the trials, with an adequate clinical and parasitological response (ACPR) of more than 95 % in all groups and trial stages. Genotyping for drug-resistance alleles at dhfr indicated fixation of the S108 N mutation and a prevalence of the C59R mutation of approximately 95 % across all sites. Other mutations in dhfr and dhps remained rare or absent entirely, although five isolates from the first trial carried the dhps triple mutant SGEGA haplotype. In the last study undertaken in 2012-2014 the K13 artemisinin resistance marker was examined; only two of 60 successfully sequenced samples carried a K13-propeller mutation. These data confirm maintained efficacy 10 years after introduction of artesunate plus SP as combination treatment of P. falciparum in Afghanistan. The molecular data indicate that despite a substantial fall in incidence, resistance has not developed to artemisinins, or intensified to the ACT partner drug components. Trial Registration http://www.clinicaltrials.gov/ct NCT00682578, NCT01115439 and NCT01707199.

  14. Sulphadoxine/pyrimethamine versus amodiaquine for treating uncomplicated childhood malaria in Gabon: A randomized trial to guide national policy

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    Durand Rémy

    2008-02-01

    Full Text Available Abstract Background In Gabon, following the adoption of amodiaquine/artesunate combination (AQ/AS as first-line treatment of malaria and of sulphadoxine/pyrimethamine (SP for preventive intermittent treatment of pregnant women, a clinical trial of SP versus AQ was conducted in a sub-urban area. This is the first study carried out in Gabon following the WHO guidelines. Methods A random comparison of the efficacy of AQ (10 mg/kg/day × 3 d and a single dose of SP (25 mg/kg of sulphadoxine/1.25 mg/kg of pyrimethamine was performed in children under five years of age, with uncomplicated falciparum malaria, using the 28-day WHO therapeutic efficacy test. In addition, molecular genotyping was performed to distinguish recrudescence from reinfection and to determine the frequency of the dhps K540E mutation, as a molecular marker to predict SP-treatment failure. Results The day-28 PCR-adjusted treatment failures for SP and AQ were 11.6% (8/69; 95% IC: 5.5–22.1 and 28.2% (20/71; 95% CI: 17.7–38.7, respectively This indicated that SP was significantly superior to AQ (P = 0.019 in the treatment of uncomplicated childhood malaria and for preventing recurrent infections. Both treatments were safe and well-tolerated, with no serious adverse reactions recorded. The dhps K540E mutation was not found among the 76 parasite isolates tested. Conclusion The level of AQ-resistance observed in the present study may compromise efficacy and duration of use of the AQ/AS combination, the new first-line malaria treatment. Gabonese policy-makers need to plan country-wide and close surveillance of AQ/AS efficacy to determine whether, and for how long, these new recommendations for the treatment of uncomplicated malaria remain valid.

  15. Malaria chemoprophylaxis in travellers to east Africa: a comparative prospective study of chloroquine plus proguanil with chloroquine plus sulfadoxine-pyrimethamine

    DEFF Research Database (Denmark)

    Fogh, S; Schapira, A; Bygbjerg, Ib Christian

    1988-01-01

    As malaria caused by Plasmodium falciparum has become resistant to chloroquine alternative drug regimens need to be developed. The prophylactic efficacy against malaria and the side effects of chloroquine phosphate 500 mg weekly with proguanil hydrochloride 200 mg daily was compared...... with the efficacy of chloroquine 500 mg weekly with sulfadoxine 500 mg-pyrimethamine 25 mg weekly in a randomised study of Scandinavian travellers to Kenya and Tanzania during 1984-5. A total of 767 subjects (416 male and 351 female; 384 taking chloroquine phosphate with proguanil hydrochloride and 383 taking...... chloroquine with sulfadoxine-pyrimethamine) completed a diary on the breakthrough of malaria and the side effects of treatment while taking the drugs. They were also asked to make thick blood films when symptoms like those of malaria occurred, which were sent to and analysed in Denmark. Four subjects taking...

  16. Temporary Efficacy of Pyrimethamine in Juvenile-Onset Tay-Sachs Disease Caused by 2 Unreported HEXA Mutations in the Indian Population.

    Science.gov (United States)

    Udwadia-Hegde, Anaita; Hajirnis, Omkar

    2017-01-01

    Juvenile Tay-Sachs disease is rarer than other forms of Tay-Sachs disease and is usually seen in children between the age of 2 and 10 years. Pyrimethamine as a pharmacological chaperone was used to increase β-hexosaminidase A activity in this patient. We describe a patient with Tay-Sachs disease from the Indian population, a juvenile case who presented with developmental regression starting at the age of three, initially with motor followed by language regression. She is currently incapacitated with severe behavioral issues. This brief communication gives an insight into the efficacy of pharmacological chaperones. It also describes two unreported mutations in hexosaminidase A gene from the Indian population. After commencing Pyrimethamine, though initial benefits with increase in levels corresponded with briefly halting the motor regression, the observed increase was only transient and not associated with discernible beneficial neurological or psychiatric effects.

  17. High prevalence of mutations in the dihydrofolate reductase gene of Plasmodium falciparum in isolates from Tanzania without evidence of an association to clinical sulfadoxine/pyrimethamine resistance

    DEFF Research Database (Denmark)

    Jelinek, T; Rønn, A M; Curtis, J;

    1997-01-01

    Recently the efficacy of sulfadoxine/pyrimethamine (S/P) in treatment of uncomplicated falciparum malaria in Tanzania has been seriously compromised by the development of resistance. The occurrence of active site mutations in the Plasmodium falciparum gene sequence coding for dihydrofolate...... resistance to the S/P combination. It has been proposed earlier that sulfadoxine could itself act on DHFR, because of a false dihydrofolate produced by drug metabolism through DHPS and dihydrofolate synthase. The results of this treatment study suggest that such a possibility is unlikely....... reductase (DHFR) is known to confer resistance to pyrimethamine. This study investigates the occurrence of these mutations in infected blood samples taken from Tanzanian children before treatment with S/P and their relationship to parasite breakthrough by day 7. The results confirm the occurrence of one...

  18. Drug coverage in treatment of malaria and the consequences for resistance evolution - evidence from the use of sulphadoxine/pyrimethamine

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    Malisa Allen L

    2010-07-01

    Full Text Available Abstract Background It is argued that, the efficacy of anti-malarials could be prolonged through policy-mediated reductions in drug pressure, but gathering evidence of the relationship between policy, treatment practice, drug pressure and the evolution of resistance in the field is challenging. Mathematical models indicate that drug coverage is the primary determinant of drug pressure and the driving force behind the evolution of drug resistance. These models show that where the basis of resistance is multigenic, the effects of selection can be moderated by high recombination rates, which disrupt the associations between co-selected resistance genes. Methods To test these predictions, dhfr and dhps frequency changes were measured during 2000-2001 while SP was the second-line treatment and contrasted these with changes during 2001-2002 when SP was used for first-line therapy. Annual cross sectional community surveys carried out before, during and after the policy switch in 2001 were used to collect samples. Genetic analysis of SP resistance genes was carried out on 4,950 Plasmodium falciparum infections and the selection pressure under the two policies compared. Results The influence of policy on the parasite reservoir was profound. The frequency of dhfr and dhps resistance alleles did not change significantly while SP was the recommended second-line treatment, but highly significant changes occurred during the subsequent year after the switch to first line SP. The frequency of the triple mutant dhfr (N51I,C59R,S108N allele (conferring pyrimethamine resistance increased by 37% - 63% and the frequency of the double A437G, K540E mutant dhps allele (conferring sulphadoxine resistance increased 200%-300%. A strong association between these unlinked alleles also emerged, confirming that they are co-selected by SP. Conclusion The national policy change brought about a shift in treatment practice and the resulting increase in coverage had a substantial

  19. Effects of point mutations in Plasmodium falciparum dihydrofolate reductase and dihydropterate synthase genes on clinical outcomes and in vitro susceptibility to sulfadoxine and pyrimethamine.

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    David J Bacon

    Full Text Available BACKGROUND: Sulfadoxine-pyrimethamine was a common first line drug therapy to treat uncomplicated falciparum malaria, but increasing therapeutic failures associated with the development of significant levels of resistance worldwide has prompted change to alternative treatment regimes in many national malaria control programs. METHODOLOGY AND FINDING: We conducted an in vivo therapeutic efficacy trial of sulfadoxine-pyrimethamine at two locations in the Peruvian Amazon enrolling 99 patients of which, 86 patients completed the protocol specified 28 day follow up. Our objective was to correlate the presence of polymorphisms in P. falciparum dihydrofolate reductase and dihydropteroate synthase to in vitro parasite susceptibility to sulfadoxine and pyrimethamine and to in vivo treatment outcomes. Inhibitory concentration 50 values of isolates increased with numbers of mutations (single [108N], sextuplet [BR/51I/108N/164L and 437G/581G] and septuplet (BR/51I/108N/164L and 437G/540E/581G with geometric means of 76 nM (35-166 nM, 582 nM (49-6890- nM and 4909 (3575-6741 nM nM for sulfadoxine and 33 nM (22-51 nM, 81 nM (19-345 nM, and 215 nM (176-262 nM for pyrimethamine. A single mutation present in the isolate obtained at the time of enrollment from either dihydrofolate reductase (164L or dihydropteroate synthase (540E predicted treatment failure as well as any other single gene alone or in combination. Patients with the dihydrofolate reductase 164L mutation were 3.6 times as likely to be treatment failures [failures 85.4% (164L vs 23.7% (I164; relative risk = 3.61; 95% CI: 2.14 - 6.64] while patients with the dihydropteroate synthase 540E were 2.6 times as likely to fail treatment (96.7% (540E vs 37.5% (K540; relative risk = 2.58; 95% CI: 1.88 - 3.73. Patients with both dihydrofolate reductase 164L and dihydropteroate synthase 540E mutations were 4.1 times as likely to be treatment failures [96.7% vs 23.7%; RR = 4.08; 95% CI: 2.45 - 7.46] compared to

  20. [Comparison of efficacy of chloroquine versus sulfadoxine-pyrimethamine in malaria prevention in pregnant women in the Toamasina region (Madagascar)].

    Science.gov (United States)

    Randriambelomanana, J A; Rakotoarisoa, H; Herinirina, S A; Zafindravola, B A; Andrianampanalinarivo, H R

    2011-10-01

    Malaria still represents a great cause of death in sub-Saharan African areas, mainly among pregnant women. We conducted this prospective study during two years in a malaria-endemic stable region in the east of Madagascar (Toamasina) with an aim to compare the efficacy of weekly chloroquine (CQ) and the use of intermittent presumptive treatment by sulfadoxine-pyrimethamine (SP). 519 pregnant women were included in this study (CQ = 285; SP = 256). Socio-demographical characteristics of each group were identical. We found more peripheral parasitemia (CQ = 8.07% vs SP = 2.73%; P = 0.0068) and severe malaria in the CQ group (CQ = 1.75% vs SP = 0%; P = 0.0332). Anemia was more frequent in the CQ group (CQ = 4.21% vs SP = 0.35%; P = 0.0038). Placental infestation rate was also higher in the CQ group (CQ = 7.01% vs SP = 0.39%; P = 0.00001). Low birth weight and fetal death were lower in the SP group respectively [(CQ = 4.21% vs SP = 0.78%; P = 0.0121) and (CQ = 1.75%vs SP = 0%; P = 0.0332)].

  1. The impact of intermittent preventive treatment with sulfadoxine-pyrimethamine on the prevalence of malaria parasitaemia in pregnancy.

    Science.gov (United States)

    Umeh, Uchenna Anthony; Obi, Samuel N; Onah, Hyacinth E; Ugwu, Emmanuel Onyebuchi V; Ajah, Leonard Ogbonna; Umeh, Chioma Roseline; Okafor, Innocent Igwebuike

    2012-07-01

    The Roll Back Malaria initiatives were introduced to ensure that 60% of pregnant women receive intermittent preventive anti-malarial treatment by the end of 2005 in an attempt to halve the mortality from malaria by 2010. Our aim was to determine the prevalence of asymptomatic malaria parasitaemia in pregnant women on intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) compared with a control group. This comparative study involved testing the peripheral blood of pregnant women on IPT with SP and a control group that did not receive SP for the malaria parasite upon registration and at 34 weeks gestational age. The levels of parasitaemia in the intervention group upon registration (4.9%) and at 34 weeks (63.9%) were not significantly different (P > 0.05) from that of the control group (10%) and at 34 weeks gestation (68.3%). IPT with SP during pregnancy did not significantly reduce the prevalence of the malaria parasitaemia among the pregnant women in our environment.

  2. Haplotypes associated with resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum in two malaria endemic locations in Colombia.

    Science.gov (United States)

    Hernández, Diana Carolina; Guerra, Angela Patricia; Cucunubá, Zulma Milena; Nicholls, Ruben Santiago; Barrera, Sandra Milena

    2013-08-01

    Colombia has four main malaria transmission zones. In vivo efficacy studies carried out in these areas showed big differences in the response of Plasmodium falciparum to treatment with sulphadoxine-pyrimethamine. In addition, there is still insufficient information about the genetics of P. falciparum populations. The objective of this study was to determine the haplotypes in dhfr and dhps genes of P. falciparum circulating in two distinct endemic zones. Samples from patients with non-complicated P. falciparum malaria were collected: 135 from Tumaco and 206 from Tierralta. Alleles 108 and 51 of the dhfr gene, and 437 and 540 of the dhps gene were analyzed by PCR/enzymatic restriction, while alleles 59 and 164 (dhfr), and 581(dhps) by PCR/dot blot/hybridization. Five different haplotypes were found, of which the triple mutant 51I/C59/108N/I164/437G/K540/A581 was the most frequent (54.6%). In Tumaco, the parasites with wild haplotype predominated, while mutant parasites predominated in Tierralta. Another interesting finding is the presence of the C59R mutation in the dhfr gene in two samples, a mutation rarely found in South America. These data provide information about parasite population genetics and highlight the importance of starting a long term molecular surveillance program.

  3. Assessment of compliance to sulfadoxine-pyrimethamine 18 months after phasing out chloroquine in Mkuranga District, Coast region-Tanzania

    Institute of Scientific and Technical Information of China (English)

    Stephen ED Nsimba; Phare G Mujinja

    2010-01-01

    Objective:To observe and assess the compliance to sulfadoxine-pyrimethamine (SP) one and a half years after phasing out chloroquine (CQ) in Mkuranga District, Coast region, Tanzania. Methods:A randomly controlled baseline community study was conducted in rural areas of Mkuranga district, Tanzania. Semi-structured questionnaire consisted of open-and closed-ended questions including home stocking, home use, last fever episodes and treatment of underfives with malaria using CQ or SP. Results:The prevalence of fever or reported fever rate during the last 48 hours by their mothers or guardians was high (70%). Of all 117 blood samples, only 8 children after drug analysis were found to have CQ and 13 had SP concentrations within their blood respectively. None of these blood drug levels were above therapeutic ranges. Conclusions:Community interventions are urgently needed in rural communities and should specifically target households nucleus on early malaria fever recognition and provision of recommended antimalarials for the sick underfive children. However, sadly, there was an increase in underweight and undernourishment in the study areas, probably because of malaria in the area and poverty which are associated with poor nutrition in these youngsters.

  4. Emergence of sulfadoxine-pyrimethamine resistance in Indian isolates of Plasmodium falciparum in the last two decades.

    Science.gov (United States)

    Kumar, Amit; Moirangthem, Romilla; Gahlawat, Suresh Kumar; Chandra, Jagdish; Gupta, Purva; Valecha, Neena; Anvikar, Anup; Singh, Vineeta

    2015-12-01

    Genotyping the sulfadoxine-pyrimethamine (SP) genes will help in identifying the genes under drug selection and the emergence of resistance in dhfr and dhps genes. India is an important hotspot for studying malaria due to the immense climatic diversity prevalent in the country. The central and eastern parts of the country are most vulnerable sites where malaria cases are reported throughout the year. From different regions of the country 173 field isolates were genotyped at various loci in dhfr and dhps genes collected between 1994 and 2013. This encompasses the period before antimalarial resistance emerged and the period after the use of combination therapy was made mandatory in the country. We observed the rise of resistant SP alleles from very low frequencies (in the year 1994) to steadily rising (in the year 2000) and maintaining this increasing trend subsequently (in the year 2013) as shown by the sequence analysis of dhfr and dhps genes. This study assessed the prevalence of mutations in dhfr and dhps genes associated with SP resistance in samples indicative of increase in resistance levels of Plasmodium falciparum to SP even after the change in malaria treatment policy in the country.

  5. A fixed-dose 24-hour regimen of artesunate plus sulfamethoxypyrazine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan

    DEFF Research Database (Denmark)

    Adam, Ishag; Magzoub, Mamoun; Osman, Maha E

    2006-01-01

    -sulfamethoxypyrazine-pyrimethamine (AS+SMP f) administered at time intervals of 12 hours for a 24-hour therapy was compared with the efficacy of the same drug given as a loose combination (AS+SMP l) with a dose interval of 24 hours for 3 days for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan. RESULTS...... of the patients. CONCLUSION: both regimens of AS+SMP were effective and safe for the treatment of uncomplicated P. falciparum malaria in eastern Sudan. Due to its simplicity, the fixed dose one-day treatment regimen may improve compliance and therefore may be the preferred choice....

  6. Rapid increase of Plasmodium falciparum dhfr/dhps resistant haplotypes, after the adoption of sulphadoxine-pyrimethamine as first line treatment in 2002, in southern Mozambique

    DEFF Research Database (Denmark)

    Enosse, Sonia; Magnussen, Pascal; Abacassamo, Fatima

    2008-01-01

    BACKGROUND: In late 2002, the health authorities of Mozambique implemented sulphadoxine-pyrimethamine (SP)/amodiaquine (AQ) as first-line treatment against uncomplicated falciparum malaria. In 2004, this has been altered to SP/artesunate in line with WHO recommendations of using Artemisinin...... investigated the immediate impact of the change to SP on the frequency of SP and CQ resistance-related haplotypes in the Plasmodium falciparum genes Pfdhfr, Pfdhps and Pfcrt before and a year after the introduction of SP. METHODS: Samples were collected during two cross sectional surveys in early 2002 and 2003...

  7. A novel prediction approach for antimalarial activities of Trimethoprim, Pyrimethamine, and Cycloguanil analogues using extremely randomized trees.

    Science.gov (United States)

    Nattee, Cholwich; Khamsemanan, Nirattaya; Lawtrakul, Luckhana; Toochinda, Pisanu; Hannongbua, Supa

    2017-01-01

    Malaria is still one of the most serious diseases in tropical regions. This is due in part to the high resistance against available drugs for the inhibition of parasites, Plasmodium, the cause of the disease. New potent compounds with high clinical utility are urgently needed. In this work, we created a novel model using a regression tree to study structure-activity relationships and predict the inhibition constant, Ki of three different antimalarial analogues (Trimethoprim, Pyrimethamine, and Cycloguanil) based on their molecular descriptors. To the best of our knowledge, this work is the first attempt to study the structure-activity relationships of all three analogues combined. The most relevant descriptors and appropriate parameters of the regression tree are harvested using extremely randomized trees. These descriptors are water accessible surface area, Log of the aqueous solubility, total hydrophobic van der Waals surface area, and molecular refractivity. Out of all possible combinations of these selected parameters and descriptors, the tree with the strongest coefficient of determination is selected to be our prediction model. Predicted Ki values from the proposed model show a strong coefficient of determination, R(2)=0.996, to experimental Ki values. From the structure of the regression tree, compounds with high accessible surface area of all hydrophobic atoms (ASA_H) and low aqueous solubility of inhibitors (Log S) generally possess low Ki values. Our prediction model can also be utilized as a screening test for new antimalarial drug compounds which may reduce the time and expenses for new drug development. New compounds with high predicted Ki should be excluded from further drug development. It is also our inference that a threshold of ASA_H greater than 575.80 and Log S less than or equal to -4.36 is a sufficient condition for a new compound to possess a low Ki.

  8. Chloroquine resistant Plasmodium falciparum malaria in Osogbo Nigeria: efficacy of amodiaquine + sulfadoxine-pyrimethamine and chloroquine + chlorpheniramine for treatment

    Directory of Open Access Journals (Sweden)

    TO Ogungbamigbe

    2008-02-01

    Full Text Available Chloroquine (CQ resistance in Plasmodium falciparum contributes to increasing malaria-attributable morbidity and mortality in Sub-Saharan Africa. Despite a change in drug policy, continued prescription of CQ did not abate. Therefore the therapeutic efficacy of CQ in uncomplicated falciparum malaria patients was assessed in a standard 28-day protocol in 116 children aged between six and 120 months in Osogbo, Southwest Nigeria. Parasitological and clinical assessments of response to treatment showed that 72 (62.1% of the patients were cured and 44 (37.9% failed the CQ treatment. High initial parasite density and young age were independent predictors for early treatment failure. Out of the 44 patients that failed CQ, 24 received amodiaquine + sulphadoxine/pyrimethamine (AQ+SP and 20 received chlorpheniramine + chloroquine (CH+CQ combinations. Mean fever clearance time in those treated with AQ+SP was not significantly different from those treated with CH+CQ (p = 0.05. There was no significant difference in the mean parasite density of the two groups. The cure rate for AQ+SP group was 92% while those of CH+CQ was 85%. There was a significant difference in parasite clearance time (p = 0.01 between the two groups. The 38% treatment failure for CQ reported in this study is higher than the 10% recommended by World Health Organization in other to effect change in antimalarial treatment policy. Hence we conclude that CQ can no more be solely relied upon for the treatment of falciparum malaria in Osogbo, Nigeria. AQ+SP and CH+CQ are effective in the treatment of acute uncomplicated malaria and may be considered as useful alternative drugs in the absence of artemisinin-based combination therapies.

  9. Seasonal Malaria Chemoprevention with Sulphadoxine-Pyrimethamine and Amodiaquine Selects Pfdhfr-dhps Quintuple Mutant Genotype in Mali

    Science.gov (United States)

    Maiga, Hamma; Lasry, Estrella; Diarra, Modibo; Sagara, Issaka; Bamadio, Amadou; Traore, Aliou; Coumare, Samba; Bahonan, Soma; Sangare, Boubou; Dicko, Yeyia; Diallo, Nouhoum; Tembely, Aly; Traore, Djibril; Niangaly, Hamidou; Dao, François; Haidara, Aboubecrine; Dicko, Alassane; Doumbo, Ogobara K.; Djimde, Abdoulaye A.

    2016-01-01

    Background Seasonal malaria chemoprevention (SMC) with sulphadoxine-pyrimethamine (SP) plus amodiaquine (AQ) is being scaled up in Sahelian countries of West Africa. However, the potential development of Plasmodium falciparum resistance to the respective component drugs is a major concern. Methods Two cross-sectional surveys were conducted before (August 2012) and after (June 2014) a pilot implementation of SMC in Koutiala, Mali. Children aged 3–59 months received 7 rounds of curative doses of SP plus AQ over two malaria seasons. Genotypes of P. falciparum Pfdhfr codons 51, 59 and 108; Pfdhps codons 437 and 540, Pfcrt codon 76 and Pfmdr1codon 86 were analyzed by PCR on DNA from samples collected before and after SMC, and in non-SMC patient population as controls (November 2014). Results In the SMC population 191/662 (28.9%) and 85/670 (12.7%) of children were P. falciparum positive by microscopy and were included in the molecular analysis before (2012) and after SMC implementation (2014), respectively. In the non-SMC patient population 220/310 (71%) were successfully PCR analyzed. In the SMC children, the prevalence of all molecular markers of SP resistance increased significantly after SMC including the Pfdhfr-dhps quintuple mutant genotype, which was 1.6% before but 7.1% after SMC (p = 0.02). The prevalence of Pfmdr1-86Y significantly decreased from 26.7% to 15.3% (p = 0.04) while no significant change was seen for Pfcrt 76T. In 2014, prevalence of all molecular markers of SP resistance were significantly higher among SMC children compared to the non-SMC population patient (p falciparum resistance to SP in the treated children. However, there was no significant increase of these markers of resistance in the general parasite population after 2 years and 7 rounds of SMC. PMID:27662368

  10. Protective efficacy of intermittent preventive treatment of malaria in infants (IPTi using sulfadoxine-pyrimethamine and parasite resistance.

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    Jamie T Griffin

    Full Text Available BACKGROUND: Intermittent Preventive Treatment of malaria in infants using sulfadoxine-pyrimethamine (SP-IPTi is recommended by WHO for implementation in settings where resistance to SP is not high. Here we examine the relationship between the protective efficacy of SP-IPTi and measures of SP resistance. METHODS AND RESULTS: We analysed the relationship between protective efficacy reported in the 7 SP-IPTi trials and contemporaneous data from 6 in vivo efficacy studies using SP and 7 molecular studies reporting frequency of dhfr triple and dhps double mutations within 50 km of the trial sites. We found a borderline significant association between frequency of the dhfr triple mutation and protective efficacy to 12 months of age of SP-IPTi. This association is significantly biased due to differences between studies, namely number of doses of SP given and follow up times. However, fitting a simple probabilistic model to determine the relationship between the frequency of the dhfr triple, dhps double and dhfr/dhps quintuple mutations associated with resistance to SP and protective efficacy, we found a significant inverse relationship between the dhfr triple mutation frequency alone and the dhfr/dhps quintuple mutations and efficacy at 35 days post the 9 month dose and up to 12 months of age respectively. CONCLUSIONS: A significant relationship was found between the frequency of the dhfr triple mutation and SP-IPTi protective efficacy at 35 days post the 9 month dose. An association between the protective efficacy to 12 months of age and dhfr triple and dhfr/dhps quintuple mutations was found but should be viewed with caution due to bias. It was not possible to define a more definite relationship based on the data available from these trials.

  11. Anti-bacterial activity of intermittent preventive treatment of malaria in pregnancy: comparative in vitro study of sulphadoxine-pyrimethamine, mefloquine, and azithromycin

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    Mombo-Ngoma Ghyslain

    2010-10-01

    Full Text Available Abstract Background Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine (SP is recommended for the prevention of malaria in pregnancy in sub-Saharan Africa. Increasing drug resistance necessitates the urgent evaluation of alternative drugs. Currently, the most promising candidates in clinical development are mefloquine and azithromycin. Besides the anti-malarial activity, SP is also a potent antibiotic and incurs significant anti-microbial activity when given as IPTp - though systematic clinical evaluation of this action is still lacking. Methods In this study, the intrinsic anti-bacterial activity of mefloquine and azithromycin was assessed in comparison to sulphadoxine-pyrimethamine against bacterial pathogens with clinical importance in pregnancy in a standard microdilution assay. Results SP was highly active against Staphylococcus aureus and Streptococcus pneumoniae. All tested Gram-positive bacteria, except Enterococcus faecalis, were sensitive to azithromycin. Additionally, azithromycin was active against Neisseria gonorrhoeae. Mefloquine showed good activity against pneumococci but lower in vitro action against all other tested pathogens. Conclusion These data indicate important differences in the spectrum of anti-bacterial activity for the evaluated anti-malarial drugs. Given the large scale use of IPTp in Africa, the need for prospective clinical trials evaluating the impact of antibiotic activity of anti-malarials on maternal and foetal health and on the risk of promoting specific drug resistance of bacterial pathogens is discussed.

  12. Short-term Results of Two Treatment Regimens in Ocular Toxoplasmosis: Trimethoprim/Sulfamethoxazole versus Pyrimethamine and Sulfadiazine

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    Mohammad-Mehdi Sadoughi

    2008-12-01

    Full Text Available

    PURPOSE: To compare the efficacy of classic treatment for ocular toxoplasmosis (pyrimethamine, sulfadiazine and predinsolone with a regimen consisting of trimethoprim/sulfamethoxazole (TMP/SMX [co-trimoxazole] plus predinsolone. METHODS: In a prospective randomized single-blind clinical trial, 59 patients with active ocular toxoplasmosis were randomly assigned to two treatment groups: 29 were treated with pyrimethamine/sulfadiazine and 30 patients received TMP/SMX. Treatment consisted of six weeks treatment with antibiotics plus steroids. Anti-toxoplasmosis antibodies (IgM and IgG were measured using ELISA. Outcome measures included changes in retinochoroidal lesion size after six weeks of treatment, visual acuity before and after intervention, adverse drug reactions during follow up and rate of recurrence. RESULTS: Active toxoplasmosis retinochoroiditis resolved in all patients over six weeks of treatment with no significant difference in mean reduction in retinochoroidal lesion size between the two treatment groups (61% reduction in the classic treatment group and 59% in the TMP/SMX group, P=0.75. Similarly no significant difference was found in visual acuity after treatment between the two groups [mean visual acuity after treatment was 0.12 LogMAR (20/25 in classic treatment group and 0.09 LogMAR (20/25 in TMP/SMX group

  13. Identification of pyrimethamine- and chloroquine-resistant Plasmodium falciparum in Africa between 1984 and 1998: genotyping of archive blood samples

    Directory of Open Access Journals (Sweden)

    Saito-Nakano Yumiko

    2011-12-01

    Full Text Available Abstract Background Understanding the geographical distribution of drug resistance of Plasmodium falciparum is important for the effective treatment of malaria. Drug resistance has previously been inferred mainly from records of clinical resistance. However, clinical resistance is not always consistent with the parasite's genetic resistance. Thus, molecular identification of the parasite's drug resistance is required. In Africa, clinical resistance to pyrimethamine (Pyr and chloroquine (CQ was evident before 1980 but few studies investigating the genetic resistance to these drugs were conducted before the late 1990s. In this study, genotyping of genes involved in resistance to Pyr and CQ was performed using archive blood samples from Africa between 1984 and 1998. Methods Parasite DNA was extracted from P. falciparum-infected blood smears collected from travellers returning to Japan from Africa between 1984 and 1998. Genotypes of the dihydrofolate reductase gene (dhfr and CQ-resistance transporter gene (pfcrt were determined by polymerase chain reaction amplification and sequencing. Results Genotyping of dhfr and pfcrt was successful in 59 and 80 samples, respectively. One wild-type and seven mutant dhfr genotypes were identified. Three dhfr genotypes lacking the S108N mutation (NRSI, ICSI, IRSI; amino acids at positions 51, 59, 108, and 164 with mutations underlined were highly prevalent before 1994 but reduced after 1995, accompanied by an increase in genotypes with the S108N mutation. The dhfr IRNI genotype was first identified in Nigeria in 1991 in the present samples, and its frequency gradually increased. However, two double mutants (ICNI and NRNI, the latter of which was exclusively found in West Africa, were more frequent than the IRNI genotype. Only two pfcrt genotypes were found, the wild-type and a Southeast Asian type (CVIET; amino acids at positions 72-76 with mutations underlined. The CVIET genotype was already present as early as

  14. Economic evaluation of an alternative drug to sulfadoxine-pyrimethamine as intermittent preventive treatment of malaria in pregnancy.

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    Elisa Sicuri

    Full Text Available Intermittent preventive treatment in pregnancy (IPTp with sulfadoxine-pyrimethamine (SP is recommended in HIV-negative women to avert malaria, while this relies on cotrimoxazole prophylaxis (CTXp in HIV-positive women. Alternative antimalarials are required in areas where parasite resistance to antifolate drugs is high. The cost-effectiveness of IPTp with alternative drugs is needed to inform policy.The cost-effectiveness of 2-dose IPTp-mefloquine (MQ was compared with IPTp-SP in HIV-negative women (Benin, Gabon, Mozambique and Tanzania. In HIV-positive women the cost-effectiveness of 3-dose IPTp-MQ added to CTXp was compared with CTXp alone (Kenya, Mozambique and Tanzania. The outcomes used were maternal clinical malaria, anaemia at delivery and non-obstetric hospital admissions. The poor tolerability to MQ was included as the value of women's loss of working days. Incremental cost-effectiveness ratios (ICERs were calculated and threshold analysis undertaken.For HIV-negative women, the ICER for IPTp-MQ versus IPTp-SP was 136.30 US$ (2012 US$ (95%CI 131.41; 141.18 per disability-adjusted life-year (DALY averted, or 237.78 US$ (95%CI 230.99; 244.57, depending on whether estimates from Gabon were included or not. For HIV-positive women, the ICER per DALY averted for IPTp-MQ added to CTXp, versus CTXp alone was 6.96 US$ (95%CI 4.22; 9.70. In HIV-negative women, moderate shifts of variables such as malaria incidence, drug cost, and IPTp efficacy increased the ICERs above the cost-effectiveness threshold. In HIV-positive women the intervention remained cost-effective for a substantial (up to 21 times increase in cost per tablet.Addition of IPTp with an effective antimalarial to CTXp was very cost-effective in HIV-positive women. IPTp with an efficacious antimalarial was more cost-effective than IPTp-SP in HIV-negative women. However, the poor tolerability of MQ does not favour its use as IPTp. Regardless of HIV status, prevention of malaria in

  15. Evaluation of dihydrofolate reductase and dihydropteroate synthetase genotypes that confer resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum in Haiti.

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    Carter, Tamar E; Warner, Megan; Mulligan, Connie J; Existe, Alexander; Victor, Yves S; Memnon, Gladys; Boncy, Jacques; Oscar, Roland; Fukuda, Mark M; Okech, Bernard A

    2012-08-13

    Malaria caused by Plasmodium falciparum infects roughly 30,000 individuals in Haiti each year. Haiti has used chloroquine (CQ) as a first-line treatment for malaria for many years and as a result there are concerns that malaria parasites may develop resistance to CQ over time. Therefore it is important to prepare for alternative malaria treatment options should CQ resistance develop. In many other malaria-endemic regions, antifolates, particularly pyrimethamine (PYR) and sulphadoxine (SDX) treatment combination (SP), have been used as an alternative when CQ resistance has developed. This study evaluated mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes that confer PYR and SDX resistance, respectively, in P. falciparum to provide baseline data in Haiti. This study is the first comprehensive study to examine PYR and SDX resistance genotypes in P. falciparum in Haiti. DNA was extracted from dried blood spots and genotyped for PYR and SDX resistance mutations in P. falciparum using PCR and DNA sequencing methods. Sixty-one samples were genotyped for PYR resistance in codons 51, 59, 108 and 164 of the dhfr gene and 58 samples were genotyped for SDX resistance codons 436, 437, 540 of the dhps gene in P. falciparum. Thirty-three percent (20/61) of the samples carried a mutation at codon 108 (S108N) of the dhfr gene. No mutations in dhfr at codons 51, 59, 164 were observed in any of the samples. In addition, no mutations were observed in dhps at the three codons (436, 437, 540) examined. No significant difference was observed between samples collected in urban vs rural sites (Welch's T-test p-value = 0.53 and permutations p-value = 0.59). This study has shown the presence of the S108N mutation in P. falciparum that confers low-level PYR resistance in Haiti. However, the absence of SDX resistance mutations suggests that SP resistance may not be present in Haiti. These results have important implications for ongoing discussions on

  16. Evaluation of dihydrofolate reductase and dihydropteroate synthetase genotypes that confer resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum in Haiti

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    Carter Tamar E

    2012-08-01

    Full Text Available Abstract Background Malaria caused by Plasmodium falciparum infects roughly 30,000 individuals in Haiti each year. Haiti has used chloroquine (CQ as a first-line treatment for malaria for many years and as a result there are concerns that malaria parasites may develop resistance to CQ over time. Therefore it is important to prepare for alternative malaria treatment options should CQ resistance develop. In many other malaria-endemic regions, antifolates, particularly pyrimethamine (PYR and sulphadoxine (SDX treatment combination (SP, have been used as an alternative when CQ resistance has developed. This study evaluated mutations in the dihydrofolate reductase (dhfr and dihydropteroate synthetase (dhps genes that confer PYR and SDX resistance, respectively, in P. falciparum to provide baseline data in Haiti. This study is the first comprehensive study to examine PYR and SDX resistance genotypes in P. falciparum in Haiti. Methods DNA was extracted from dried blood spots and genotyped for PYR and SDX resistance mutations in P. falciparum using PCR and DNA sequencing methods. Sixty-one samples were genotyped for PYR resistance in codons 51, 59, 108 and 164 of the dhfr gene and 58 samples were genotyped for SDX resistance codons 436, 437, 540 of the dhps gene in P. falciparum. Results Thirty-three percent (20/61 of the samples carried a mutation at codon 108 (S108N of the dhfr gene. No mutations in dhfr at codons 51, 59, 164 were observed in any of the samples. In addition, no mutations were observed in dhps at the three codons (436, 437, 540 examined. No significant difference was observed between samples collected in urban vs rural sites (Welch’s T-test p-value = 0.53 and permutations p-value = 0.59. Conclusion This study has shown the presence of the S108N mutation in P. falciparum that confers low-level PYR resistance in Haiti. However, the absence of SDX resistance mutations suggests that SP resistance may not be present in Haiti. These

  17. Randomized trial of piperaquine with sulfadoxine-pyrimethamine or dihydroartemisinin for malaria intermittent preventive treatment in children.

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    Badara Cisse

    Full Text Available BACKGROUND: The long terminal half life of piperaquine makes it suitable for intermittent preventive treatment for malaria but no studies of its use for prevention have been done in Africa. We did a cluster randomized trial to determine whether piperaquine in combination with either dihydroartemisin (DHA or sulfadoxine-pyrimethamine (SP is as effective, and better tolerated, than SP plus amodiaquine (AQ, when used for intermittent preventive treatment in children delivered by community health workers in a rural area of Senegal. METHODS: Treatments were delivered to children 3-59 months of age in their homes once per month during the transmission season by community health workers. 33 health workers, each covering about 60 children, were randomized to deliver either SP+AQ, DHA+PQ or SP+PQ. Primary endpoints were the incidence of attacks of clinical malaria, and the incidence of adverse events. RESULTS: 1893 children were enrolled. Coverage of monthly rounds and compliance with daily doses was similar in all groups; 90% of children received at least 2 monthly doses. Piperaquine combinations were better tolerated than SP+AQ with a significantly lower risk of common, mild adverse events. 103 episodes of clinical malaria were recorded during the course of the trial. 68 children had malaria with parasitaemia >3000/microL, 29/671 (4.3% in the SP+AQ group, compared with 22/604 (3.6% in the DHA+PQ group (risk difference 0.47%, 95%CI -2.3%,+3.3%, and 17/618 (2.8% in the SP+PQ group (risk difference 1.2%, 95%CI -1.3%,+3.6%. Prevalences of parasitaemia and the proportion of children carrying Pfdhfr and Pfdhps mutations associated with resistance to SP were very low in all groups at the end of the transmission season. CONCLUSIONS: Seasonal IPT with SP+PQ in children is highly effective and well tolerated; the combination of two long-acting drugs is likely to impede the emergence of resistant parasites. TRIAL REGISTRATION: ClinicalTrials.gov NCT00529620.

  18. Sulfadoxine-pyrimethamine monotherapy in Tanzanian children gives rapid parasite clearance but slow fever clearance that is improved by chloroquine in combination therapy

    DEFF Research Database (Denmark)

    Tarimo, D S; Minjas, J N; Bygbjerg, I C

    2002-01-01

    Following widespread chloroquine (CQ) resistance, sulfadoxine plus pyrimethamine (SP) is now the first line antimalarial drug in a number of African countries including Tanzania. Unlike CQ, SP has no antipyretic effects, a feature that might delay fever clearance, and by acting on late stage...... parasites, SP could theoretical be slow in parasite clearance. We therefore assessed the antipyretic effects of CQ in therapeutic combination with SP, and the speed of parasite clearance by SP in an open-labelled, randomized trial of CQ alone (n=39), SP alone (n=39), SP plus CQ (n=37) and SP plus...... paracetamol (PCM) (n=38) in children with uncomplicated malaria. Over 72 h, there were eight (20.5%) treatment failures in the CQ group but none in the other groups. Although not significant (P > 0.1), irrespective of resistance CQ alone had a shorter median survival time to fever clearance than SP alone (54...

  19. Impact of Sulfadoxine-Pyrimethamine resistance on effectiveness of intermittent preventive therapy for malaria in pregnancy at clearing infections and preventing low birth weight

    DEFF Research Database (Denmark)

    Desai, Meghna; Gutman, Julie; Taylor, Steve M.

    2016-01-01

    BACKGROUND: Owing to increasing sulfadoxine-pyrimethamine (SP) resistance in sub-Saharan Africa, monitoring the effectiveness of intermittent preventive therapy in pregnancy (IPTp) with SP is crucial. METHODS: Between 2009 and 2013, both the efficacy of IPTp-SP at clearing existing peripheral....... An individual-level prospective pooled analysis was conducted. RESULTS: Among 1222 parasitemic pregnant women, overall polymerase chain reaction-uncorrected and -corrected failure rates by day 42 were 21.3% and 10.0%, respectively (39.7% and 21.1% in high-resistance areas; 4.9% and 1.1% in low-resistance areas......). Median time to recurrence decreased with increasing prevalence of Pfdhps-K540E. Among 6099 women at delivery, IPTp-SP was associated with a 22% reduction in the risk of LBW (prevalence ratio [PR], 0.78; 95% confidence interval [CI], .69-.88; P

  20. Pyrimethamine/sulfadoxine combination in the treatment of uncomplicated falciparum malaria: relation between dihydropteroate synthase/dihydrofolate reductase genotypes, sulfadoxine plasma levels, and treatment outcome

    DEFF Research Database (Denmark)

    Khalil, Insaf; Alifrangis, Michael; Rønn, Anita M;

    2002-01-01

    in relation to the frequency of dhfr and dhps mutations in 37 Plasmodium falciparum isolates sampled before treatment. Plasma levels of SDX measured at days 0, 3, 7, and 14 ascertained drug absorption. Point mutations were detected only at codons 51 and 108 of dhfr and codon 436 of dhps. The frequency of dhfr...... 51/108 and dhps 436 mutations was 79% and 8%. The plasma levels of SDX indicated adequate drug absorption by all patients. The presence of Ile 51 and Asn 108 mutations among parasites that cleared after treatment indicates that these mutations alone are insufficient to cause in vivo resistance......Several in vitro studies have shown the correlation between mutations in dhfr and dhps genes and resistance to pyrimethamine/sulfadoxine (PYR/SDX) combination, but the in vivo correlates of these mutations with PYR/ SDX efficacy have not been investigated fully. We assessed PYR/SDX efficacy...

  1. Cost effectiveness of seasonal intermittent preventive treatment using amodiaquine & artesunate or sulphadoxine-pyrimethamine in Ghanaian children.

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    Lesong Conteh

    Full Text Available BACKGROUND: Intermittent preventive treatment for malaria in children (IPTc involves the administration of a full course of an anti-malarial treatment to children under 5 years old at specified time points regardless of whether or not they are known to be infected, in areas where malaria transmission is seasonal. It is important to determine the costs associated with IPTc delivery via community based volunteers and also the potential savings to health care providers and caretakers due to malaria episodes averted as a consequence of IPTc. METHODS: Two thousand four hundred and fifty-one children aged 3-59 months were randomly allocated to four groups to receive: three days of artesunate plus amodiaquine (AS+AQ monthly, three days of AS+AQ bimonthly, one dose of sulphadoxine-pyrimethamine (SP bi-monthly or placebo. This paper focuses on incremental cost effectiveness ratios (ICERs of the three IPTc drug regimens as delivered by community based volunteers (CBV in Hohoe, Ghana compared to current practice, i.e. case management in the absence of IPTc. Financial and economic costs from the publicly funded health system perspective are presented. Treatment costs borne by patients and their caretakers are also estimated to present societal costs. The costs and effects of IPTc during the intervention period were considered with and without a one year follow up. Probabilistic sensitivity analysis was undertaken to account for uncertainty. RESULTS: Economic costs per child receiving at least the first dose of each course of IPTc show SP bimonthly, at US$8.19, is the cheapest to deliver, followed by AS+AQ bimonthly at US$10.67 and then by AS+AQ monthly at US$14.79. Training, drug delivery and supervision accounted for approximately 20-30% each of total unit costs. During the intervention period AS & AQ monthly was the most cost effective IPTc drug regimen at US$67.77 (61.71-74.75, CI 95% per malaria case averted based on intervention costs only, US$64

  2. Molecular evidence of increased resistance to anti-folate drugs in Plasmodium falciparum in North-East India: a signal for potential failure of artemisinin plus sulphadoxine-pyrimethamine combination therapy.

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    Mohapatra, Pradyumna Kishore; Sarma, Devojit Kumar; Prakash, Anil; Bora, Khukumoni; Ahmed, Md Atique; Sarma, Bibhas; Goswami, Basanta Kumar; Bhattacharyya, Dibya Ranjan; Mahanta, Jagadish

    2014-01-01

    North-east India, being a corridor to South-east Asia, is believed to play an important role in transmitting drug resistant Plasmodium falciparum malaria to India and South Asia. North-east India was the first place in India to record the emergence of drug resistance to chloroquine as well as sulphadoxine/pyrimethamine. Presently chloroquine resistance is widespread all over the North-east India and resistance to other anti-malarials is increasing. In this study both in vivo therapeutic efficacy and molecular assays were used to screen the spectrum of drug resistance to chloroquine and sulphadoxine/pyrimethamine in the circulating P. falciparum strains. A total of 220 P. falciparum positives subjects were enrolled in the study for therapeutic assessment of chloroquine and sulphadoxine/pyrimethamine and assessment of point mutations conferring resistances to these drugs were carried out by genotyping the isolates following standard methods. Overall clinical failures in sulphadoxine/pyrimethamine and chloroquine were found 12.6 and 69.5% respectively, while overall treatment failures recorded were 13.7 and 81.5% in the two arms. Nearly all (99.0%) the isolates had mutant pfcrt genotype (76 T), while 68% had mutant pfmdr-1 genotype (86 Y). Mutation in dhps 437 codon was the most prevalent one while dhfr codon 108 showed 100% mutation. A total of 23 unique haplotypes at the dhps locus and 7 at dhfr locus were found while dhps-dhfr combined loci revealed 49 unique haplotypes. Prevalence of double, triple and quadruple mutations were common while 1 haplotype was found with all five mutated codons (F/AGEGS/T) at dhps locus. Detection of quadruple mutants (51 I/59 R/108 N/164 L) in the present study, earlier recorded from Car Nicobar Island, India only, indicates the presence of high levels of resistance to sulphadoxine/pyrimethamine in north-east India. Associations between resistant haplotypes and the clinical outcomes and emerging resistance in sulphadoxine/pyrimethamine

  3. Molecular epidemiology of malaria in Cameroon. XXX. sequence analysis of Plasmodium falciparum ATPase 6, dihydrofolate reductase, and dihydropteroate synthase resistance markers in clinical isolates from children treated with an artesunate-sulfadoxine-pyrimethamine combination.

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    Menemedengue, Virginie; Sahnouni, Khalifa; Basco, Leonardo; Tahar, Rachida

    2011-07-01

    Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes are reliable molecular markers for antifolate resistance. The P. falciparum ATPase 6 (pfatp6) gene has been proposed to be a potential marker for artemisinin resistance. In our previous clinical study, we showed that artesunate-sulfadoxine-pyrimethamine is highly effective against uncomplicated malaria in Yaoundé, Cameroon. In the present study, dhfr, dhps, and pfatp6 mutations in P. falciparum isolates obtained from children treated with artesunate-sulfadoxine-pyrimethamine were determined. All 61 isolates had wild-type Pfatp6 263, 623, and 769 alleles, and 11 (18%) had a single E431K substitution. Three additional mutations, E643Q, E432K, and E641Q, were detected. The results did not indicate any warning signal of serious concern (i.e., no parasites were seen with quintuple dhfr-dhps, DHFR Ile164Leu, or pfatp6 mutations), as confirmed by the high clinical efficacy of artesunate-sulfadoxine-pyrimethamine. Further studies are required to identify a molecular marker that reliably predicts artemisinin resistance.

  4. Drug coverage in treatment of malaria and the consequences for resistance evolution--evidence from the use of sulphadoxine/pyrimethamine.

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    Malisa, Allen L; Pearce, Richard J; Abdulla, Salim; Mshinda, Hassan; Kachur, Patrick S; Bloland, Peter; Roper, Cally

    2010-07-05

    It is argued that, the efficacy of anti-malarials could be prolonged through policy-mediated reductions in drug pressure, but gathering evidence of the relationship between policy, treatment practice, drug pressure and the evolution of resistance in the field is challenging. Mathematical models indicate that drug coverage is the primary determinant of drug pressure and the driving force behind the evolution of drug resistance. These models show that where the basis of resistance is multigenic, the effects of selection can be moderated by high recombination rates, which disrupt the associations between co-selected resistance genes. To test these predictions, dhfr and dhps frequency changes were measured during 2000-2001 while SP was the second-line treatment and contrasted these with changes during 2001-2002 when SP was used for first-line therapy. Annual cross sectional community surveys carried out before, during and after the policy switch in 2001 were used to collect samples. Genetic analysis of SP resistance genes was carried out on 4,950 Plasmodium falciparum infections and the selection pressure under the two policies compared. The influence of policy on the parasite reservoir was profound. The frequency of dhfr and dhps resistance alleles did not change significantly while SP was the recommended second-line treatment, but highly significant changes occurred during the subsequent year after the switch to first line SP. The frequency of the triple mutant dhfr (N51I,C59R,S108N) allele (conferring pyrimethamine resistance) increased by 37% - 63% and the frequency of the double A437G, K540E mutant dhps allele (conferring sulphadoxine resistance) increased 200%-300%. A strong association between these unlinked alleles also emerged, confirming that they are co-selected by SP. The national policy change brought about a shift in treatment practice and the resulting increase in coverage had a substantial impact on drug pressure. The selection applied by first-line use

  5. Active case detection, treatment of falciparum malaria with combined chloroquine and sulphadoxine/pyrimethamine and vivax malaria with chloroquine and molecular markers of anti-malarial resistance in the Republic of Vanuatu

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    Rogers William O

    2010-04-01

    Full Text Available Abstract Background Chloroquine-resistant Plasmodium falciparum was first described in the Republic of Vanuatu in the early 1980s. In 1991, the Vanuatu Ministry of Health instituted new treatment guidelines for uncomplicated P. falciparum infection consisting of chloroquine/sulphadoxine-pyrimethamine combination therapy. Chloroquine remains the recommended treatment for Plasmodium vivax. Methods In 2005, cross-sectional blood surveys at 45 sites on Malo Island were conducted and 4,060 adults and children screened for malaria. Of those screened, 203 volunteer study subjects without malaria at the time of screening were followed for 13 weeks to observe peak seasonal incidence of infection. Another 54 subjects with malaria were followed over a 28-day period to determine efficacy of anti-malarial therapy; chloroquine alone for P. vivax and chloroquine/sulphadoxine-pyrimethamine for P. falciparum infections. Results The overall prevalence of parasitaemia by mass blood screening was 6%, equally divided between P. falciparum and P. vivax. Twenty percent and 23% of participants with patent P. vivax and P. falciparum parasitaemia, respectively, were febrile at the time of screening. In the incidence study cohort, after 2,303 person-weeks of follow-up, the incidence density of malaria was 1.3 cases per person-year with P. vivax predominating. Among individuals participating in the clinical trial, the 28-day chloroquine P. vivax cure rate was 100%. The 28-day chloroquine/sulphadoxine-pyrimethamine P. falciparum cure rate was 97%. The single treatment failure, confirmed by merozoite surface protein-2 genotyping, was classified as a day 28 late parasitological treatment failure. All P. falciparum isolates carried the Thr-76 pfcrt mutant allele and the double Asn-108 + Arg-59 dhfr mutant alleles. Dhps mutant alleles were not detected in the study sample. Conclusion Peak seasonal malaria prevalence on Malo Island reached hypoendemic levels during the study

  6. Quality of Sulfadoxine-Pyrimethamine Given as Antimalarial Prophylaxis in Pregnant Women in Selected Health Facilities in Central Region of Ghana

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    Danny F. Yeboah

    2016-01-01

    Full Text Available The use of sulfadoxine-pyrimethamine (SP as an intermittent preventive treatment (IPT against malaria during pregnancy has become a policy in most sub-Sahara African countries and crucially depends on the efficacy of SP. This study sets out to evaluate the effectiveness of the SP given to the pregnant women in some selected health facilities in the Central Region of Ghana to prevent maternal malaria in pregnant women. A total of 543 pregnant women recruited from 7 selected health centres in Central Region of Ghana participated in the study. Parasite density of Plasmodium falciparum was determined from peripheral blood of the pregnant women using microscopy. High performance liquid chromatography (HPLC and dissolution tester were used to determine the quality of the SP. Malaria infection was recorded in 11.2% of pregnant women who had a history of SP consumption. SP failed the dissolution test. Pregnant women who did not receive IPT-SP were 44%. Low haemoglobin level was recorded in 73.5% of the pregnant women. The results indicated that SP was substandard. IPT-SP is ineffective in preventing malaria infection.

  7. Effects of antifolates - co-trimoxazole and pyrimethamine-sulfadoxine - on gametocytes in children with acute, symptomatic, uncomplicated, Plasmodium falciparum malaria

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    A Sowunmi

    2005-07-01

    Full Text Available Antimalarial drugs including the antifolate, pyrimethamine-sulfadoxine (PS, can modulate the prevalence and intensities of gametocytaemia following treatment of acute malaria infections. They may also directly influence the transmission and spread of drug insensitivity. Little is known of the effects of co-trimoxazole (Co-T, another antifolate antimalarial, on gametocytes in children with acute malaria infections. We compared the effects of Co-T and PS on the prevalence and intensities of gametocytaemia and gametocyte sex ratios in 102 children aged 0.5-12 years presenting with acute and uncomplicated falciparum malaria. Compared to pre-treatment, both drugs significantly increased gametocyte carriage post-initiation of treatment. However, gametocyte carriage was significantly lower on day 14 in those treated with Co-T than PS. Significant increase in gametocytaemia with time occurred in PS - but not Co-T-treated children. Kaplan-Meier survival curve of the cumulative probability of remaining gametocyte-free in children who were agametocytaemic at enrolment showed that by day 7 of follow up, children treated with PS had a significantly higher propensity to have developed gametocytes than in Co-T-treated children (Log-rank statistic 5.35, df = 1, P = 0.02. Gametocyte sex ratio changes were similar following treatment with both drugs. PS and Co-T treatment of acute malaria infections in children from this endemic area is associated with significant increases in prevalence and intensities of gametocytaemia but these effects are more marked in those treated with PS than Co-T.

  8. The effectiveness and perception of the use of sulphadoxine-pyrimethamine in intermittent preventive treatment of malaria in pregnancy programme in Offinso district of ashanti region, Ghana

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    Tutu Emmanuel

    2011-12-01

    Full Text Available Abstract Background Malaria in pregnant women has been shown to be associated with low birth weight, stillbirth and mortality in newborns. The WHO has adopted the use of sulphadoxine-pyrimethamine (SP to control malaria, a disease which worsens the plight of pregnant women leading to low birth weight, stillbirths and increased neonatal mortality. The present study assessed the effectiveness of SP and perception of its use in pregnant women in Offinso district (Ashanti Region, Ghana. Method Pregnant women, gestational age 32 weeks prior to term, were studied from November 2006 to October 2007. Their haemoglobin levels (Hb, parasitaemia and other quantitative determinants were assessed. In-depth interviews (IDIs and focus group discussions (FGDs were used to assess the perception of SP usage and its effectiveness. Results Of the 306 study participants, 92 (30% took one dose, 100 (33% two doses and 114 (37% three doses of SP, respectively. There was significant association between gravidity and SP dosage taken (Pearson χ2 = 18.9, p χ2 = 2.3, p ≥ 0.32. Peripheral parasitaemia was present in 47 (15% of the subjects. There was a poor negative relationship of doses of SP with parasitaemia (r = -0.07, p ≥ 0.24. Mean Hb was 11.3 ± 1.6 g/dl, with 118 (39% of the subjects anaemic (Hb r = 0.15, p Conclusions This study points to the effectiveness of IPTp using SP as an evidence-based measure for control of malaria and malaria-related anaemia in pregnancy. Therefore, the Ghana Health Service should improve current programme strategies to increase the proportion of pregnant women who take three doses of SP, paying attention to improved face-to-face health education, focussed antenatal care and better social mobilization.

  9. Intermittent preventive treatment with sulfadoxine-pyrimethamine does not modify plasma cytokines and chemokines or intracellular cytokine responses to Plasmodium falciparum in Mozambican Children

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    Quelhas Diana

    2012-01-01

    Full Text Available Abstract Background Cytokines and chemokines are key mediators of anti-malarial immunity. We evaluated whether Intermittent Preventive Treatment in infants with Sulfadoxine-Pyrimethamine (IPTi-SP had an effect on the acquisition of these cellular immune responses in Mozambican children. Multiple cytokines and chemokines were quantified in plasma by luminex, and antigen-specific cytokine production in whole blood was determined by intracellular cytokine staining and flow cytometry, at ages 5, 9, 12 and 24 months. Results IPTi-SP did not significantly affect the proportion of CD3+ cells producing IFN-γ, IL-4 or IL-10. Overall, plasma cytokine or chemokine concentrations did not differ between treatment groups. Th1 and pro-inflammatory responses were higher than Th2 and anti-inflammatory responses, respectively, and IFN-γ:IL-4 ratios were higher for placebo than for SP recipients. Levels of cytokines and chemokines varied according to age, declining from 5 to 9 months. Plasma concentrations of IL-10, IL-12 and IL-13 were associated with current infection or prior malaria episodes. Higher frequencies of IFN-γ and IL-10 producing CD3+ cells and elevated IL-10, IFN-γ, MCP-1 and IL-13 in plasma were individually associated with increased malaria incidence, at different time points. When all markers were analyzed together, only higher IL-17 at 12 months was associated with lower incidence of malaria up to 24 months. Conclusions Our work has confirmed that IPTi-SP does not negatively affect the development of cellular immune response during early childhood. This study has also provided new insights as to how these cytokine responses are acquired upon age and exposure to P. falciparum, as well as their associations with malaria susceptibility. Trial Registration ClinicalTrials.gov: NCT00209795

  10. A study of toxicity and differential gene expression in murine liver following exposure to anti-malarial drugs: amodiaquine and sulphadoxine-pyrimethamine

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    Rath Srikanta

    2011-05-01

    Full Text Available Abstract Background Amodiaquine (AQ along with sulphadoxine-pyrimethamine (SP offers effective and cheaper treatment against chloroquine-resistant falciparum malaria in many parts of sub-Saharan Africa. Considering the previous history of hepatitis, agranulocytosis and neutrocytopenia associated with AQ monotherapy, it becomes imperative to study the toxicity of co-administration of AQ and SP. In this study, toxicity and resulting global differential gene expression was analyzed following exposure to these drugs in experimental Swiss mice. Methods The conventional markers of toxicity in serum, oxidative stress parameters in tissue homogenates, histology of liver and alterations in global transcriptomic expression were evaluated to study the toxic effects of AQ and SP in isolation and in combination. Results The combination therapy of AQ and SP results in more pronounced hepatotoxicity as revealed by elevated level of serum ALT, AST with respect to their individual drug exposure regimen. Furthermore, alterations in the activity of major antioxidant enzymes (glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase, indicating the development of oxidative stress, was more significant in AQ+SP combination therapy. cDNA microarray results too showed considerably more perturbed gene expression following combination therapy of AQ and SP as compared to their individual drug treatment. Moreover, a set of genes were identified whose expression pattern can be further investigated for identifying a good biomarker for potential anti-malarial hepatotoxicity. Conclusion These observations clearly indicate AQ+SP combination therapy is hepatotoxic in experimental Swiss mice. Microarray results provide a considerable number of potential biomarkers of anti-malarial drug toxicity. These findings hence will be useful for future drug toxicity studies, albeit implications of this study in clinical conditions need to be monitored with cautions.

  11. The usefulness of twenty-four molecular markers in predicting treatment outcome with combination therapy of amodiaquine plus sulphadoxine-pyrimethamine against falciparum malaria in Papua New Guinea

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    Reeder John C

    2008-04-01

    Full Text Available Abstract Background In Papua New Guinea (PNG, combination therapy with amodiaquine (AQ or chloroquine (CQ plus sulphadoxine-pyrimethamine (SP was introduced as first-line treatment against uncomplicated malaria in 2000. Methods We assessed in vivo treatment failure rates with AQ+SP in two different areas in PNG and twenty-four molecular drug resistance markers of Plasmodium falciparum were characterized in pre-treatment samples. The aim of the study was to investigate the association between infecting genotype and treatment response in order to identify useful predictors of treatment failure with AQ+SP. Results In 2004, Day-28 treatment failure rates for AQ+SP were 29% in the Karimui and 19% in the South Wosera area, respectively. The strongest independent predictors for treatment failure with AQ+SP were pfmdr1 N86Y (OR = 7.87, p pfdhps A437G (OR = 3.44, p pfcrt K76T, A220S, N326D, and I356L did not help to increase the predictive value, the most likely reason being that these mutations reached almost fixed levels. Though mutations in SP related markers pfdhfr S108N and C59R were not associated with treatment failure, they increased the predictive value of pfdhps A437G. The difference in treatment failure rate in the two sites was reflected in the corresponding genetic profile of the parasite populations, with significant differences seen in the allele frequencies of mutant pfmdr1 N86Y, pfmdr1 Y184F, pfcrt A220S, and pfdhps A437G. Conclusion The study provides evidence for high levels of resistance to the combination regimen of AQ+SP in PNG and indicates which of the many molecular markers analysed are useful for the monitoring of parasite resistance to combinations with AQ+SP.

  12. Comparison of protein patterns between Plasmodium falciparum mutant clone T9/94-M1-1(b3) induced by pyrimethamine and the original parent clone T9/94

    Institute of Scientific and Technical Information of China (English)

    Kanchana Rungsihirunrat; Wanna Chaijaroenkul; Napaporn Siripoon; Aree Seugorn; Sodsri Thaithong; Kesara Na-Bangchang

    2012-01-01

    Objective: To compare the protein patterns from the extracts of the mutant clone T9/94-M1-1(b3) induced by pyrimethamine, and the original parent clone T9/94 following separation of parasite extracts by two-dimensional electrophoresis (2-DE). Methods: Proteins were solubilized and separated according to their charges and sizes. The separated protein spots were then detected by silver staining and analyzed for protein density by the powerful image analysis software. Results:Differentially expressed protein patterns (up- or down-regulation) were separated from the extracts from the two clones. A total of 223 and 134 protein spots were detected from the extracts of T9/94 and T9/94-M1-1(b3) clones, respectively. Marked reduction in density of protein expression was observed with the extract from the mutant (resistant) clone compared with the parent (sensitive) clone. A total of 25 protein spots showed at least two-fold difference in density, some of which exhibited as high as ten-fold difference. Conclusions: These proteins may be the molecular targets of resistance of Plasmodium falciparum to pyrimethamine. Further study to identify the chemical structures of these proteins by mass spectrometry is required.

  13. Factors related to compliance to anti-malarial drug combination: example of amodiaquine/sulphadoxine-pyrimethamine among children in rural Senegal

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    Sow Diarietou

    2009-06-01

    Full Text Available Abstract Background The introduction of new anti-malarial treatment that is effective, but more expensive, raises questions about whether the high level of effectiveness observed in clinical trials can be found in a context of family use. The objective of this study was to determine the factors related to adherence, when using the amodiaquine/sulphadoxine-pyrimethamine (AQ/SP association, a transitory strategy before ACT implementation in Senegal. Methods The study was conducted in five rural dispensaries. Children, between two and 10 years of age, who presented mild malaria were recruited at the time of the consultation and were prescribed AQ/SP. The child's primary caretaker was questioned at home on D3 about treatment compliance and factors that could have influenced his or her adherence to treatment. A logistic regression model was used for the analyses. Results The study sample included 289 children. The adherence rate was 64.7%. Two risks factors for non-adherence were identified: the children's age (8–10 years (ORa = 3.07 [1.49–6.29]; p = 0.004; and the profession of the head of household (retailer/employee versus farmer (ORa = 2.71 [1.34–5.48]; p = 0.006. Previously seeking care (ORa = 0.28 [0.105–0.736], p=0.001] satisfaction with received information (ORa = 0.45 [0.24–0.84]; p = 0.013, and the quality of history taking (ORa = 0.38 [0.21–0.69]; p = 0.001 were significantly associated with good compliance. Conclusion The results of the study show the importance of information and communication between caregivers and health center staff. The experience gained from this therapeutic transition emphasizes the importance of information given to the patients at the time of the consultation and drug delivery in order to improve drug use and thus prevent the emergence of rapid drug resistance.

  14. Coverage of intermittent prevention treatment with sulphadoxine-pyrimethamine among pregnant women and congenital malaria in Côte d'Ivoire

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    Eholie Serge P

    2011-04-01

    Full Text Available Abstract Background The World Health Organization (WHO recommends using insecticide-treated mosquito nets (ITNs and intermittent preventive treatment with sulphadoxine-pyrimethamine (IPT-SP to prevent malaria in sub-Saharan Africa. Data on IPT-SP coverage and factors associated with placental malaria parasitaemia and low birth weight (LBW are scarce in Côte d'Ivoire. Methods A multicentre, cross-sectional survey was conducted in Côte d'Ivoire from March to September 2008 at six urban and semi-urban antenatal clinics. Standardized forms were used to collect the demographic information and medical histories of women and their offspring. IPT-SP coverage (≥2 doses as well as placental and congenital malaria prevalence parasitaemia were estimated. Regression logistics were used to study factors associated with placental malaria and LBW (birth weight of alive babies Results Overall, 2,044 women with a median age of 24 years were included in this study. Among them 1017 (49.8% received ≥2 doses of IPT-SP and 694 (34.0% received one dose. A total of 99 mothers (4.8% had placental malaria, and of them, four cases of congenital malaria were diagnosed. Factors that protected from maternal placental malaria parasitaemia were the use of one dose (adjusted odds ratio (aOR, 0.32; 95%CI: 0.19-0.55 or ≥2 doses IPT-SP (aOR: 0.18; 95%CI: 0.10-0.32; the use of ITNs (aOR: 0.47; 95%CI: 0.27-0.82. LBW was associated with primigravidity and placental malaria parasitaemia. Conclusion IPT-SP decreases the rate of placental malaria parasitaemia and has a strong dose effect. Despite relatively successful IPT-SP coverage in Côte d'Ivoire, substantial commitments from national authorities are urgently required for such public health campaigns. Strategies, such as providing IPT-SP free of charge and directly observing treatment, should be implemented to increase the use of IPT-SP as well as other prophylactic methods.

  15. Glucose-6-Phosphate Dehydrogenase Deficiency and Haemoglobin Drop after Sulphadoxine-Pyrimethamine Use for Intermittent Preventive Treatment of Malaria during Pregnancy in Ghana - A Cohort Study.

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    Ruth Owusu

    Full Text Available Sulphadoxine-Pyrimethamine (SP is still the only recommended antimalarial for use in intermittent preventive treatment of malaria during pregnancy (IPTp in some malaria endemic countries including Ghana. SP has the potential to cause acute haemolysis in G6PD deficient people resulting in significant haemoglobin (Hb drop but there is limited data on post SP-IPTp Hb drop. This study determined the difference, if any in proportions of women with significant acute haemoglobin drop between G6PD normal, partial deficient and full deficient women after SP-IPTp.Prospectively, 1518 pregnant women who received SP for IPTp as part of their normal antenatal care were enrolled. Their G6PD status were determined at enrollment followed by assessments on days 3, 7,14 and 28 to document any adverse effects and changes in post-IPTp haemoglobin (Hb levels. The three groups were comparable at baseline except for their mean Hb (10.3 g/dL for G6PD normal, 10.8 g/dL for G6PD partial deficient and 10.8 g/dL for G6PD full defect women.The prevalence of G6PD full defect was 2.3% and 17.0% for G6PD partial defect. There was no difference in the proportions with fractional Hb drop ≥ 20% as compared to their baseline value post SP-IPTp among the 3 groups on days 3, 7, 14. The G6PD full defect group had the highest median fractional drop at day 7. There was a weak negative correlation between G6PD activity and fractional Hb drop. There was no statistical difference between the three groups in the proportions of those who started the study with Hb ≥ 8g/dl whose Hb level subsequently fell below 8g/dl post-SP IPTp. No study participant required transfusion or hospitalization for severe anaemia.There was no significant difference between G6PD normal and deficient women in proportions with significant acute haemoglobin drop post SP-IPTp and lower G6PD enzyme activity was not strongly associated with significant acute drug-induced haemoglobin drop post SP-IPTp but a larger

  16. Treatment of uncomplicated malaria with artesunate plus sulfadoxine-pyrimethamine is failing in Somalia: evidence from therapeutic efficacy studies and Pfdhfr and Pfdhps mutant alleles.

    Science.gov (United States)

    Warsame, Marian; Hassan, Abdillahi Mohamed; Barrette, Amy; Jibril, Ali Mohamed; Elmi, Husein Haji; Arale, Abdulkadir Mohamed; Mohammady, Hanan El; Nada, Rania A; Amran, Jamal Ghilan Hefzullah; Muse, Abdikarim; Yusuf, Fahmi Essa; Omar, Abdiqani Sheikh

    2015-04-01

    Artesunate plus sulfadoxine-pyrimethamine (AS + SP) has been Somalia's national treatment policy since 2006. Routine monitoring of first-line malaria treatment is needed to ensure appropriate national malaria treatment policy and early detection of drug resistance. For this purpose, we conducted therapeutic efficacy studies of AS + SP for the treatment of uncomplicated malaria in Somalia in 2011. Studies were conducted in three sentinel sites. Eligible patients were evaluated for clinical and parasitological outcomes according to the WHO standard protocol. Molecular surveillance was conducted on resistance conferring mutations in the P.falciparum dihydrofolate reductase (dfhr) and dihydropteroate synthase (dhps) genes. The proportion of PCR-corrected treatment failures was high in Jamame (22%, 95% CI: 13.7-32.8%) and low (<5%) in Janale and Jowhar. All patients cleared parasites by day 3. Molecular markers associated with SP resistance were detected in all three sites. Treatment failure was associated with the presence of the double mutant dhps A437G/K540E (OR = 22.4, 95% CI: 5.1-98.1), quadruple mutant dhfr N51I/S108N+dhps A437G/K540E (OR = 5.5, 95% CI: 2.3-13.6), quintuple mutant dhfr N51I/C59R/S108N+dhps A437G/K540E (OR = 3.5, 95% CI: 1.4-8.8) and younger age (OR=0.86, 95% CI: 0.76-0.96). The high treatment failure rate observed in Jamame, together with the presence of molecular mutations associated with SP resistance, indicates P. falciparum resistance to SP. In Jowhar, high treatment failure rates were absent despite the presence of molecular mutations; signs of resistance in vivo may have been masked by the stronger immunity of the older study population. The study underscores the need to update Somalia's national malaria treatment policy. © 2015 John Wiley & Sons Ltd.

  17. Sulfadoxine-pyrimethamine-based combinations for malaria: a randomised blinded trial to compare efficacy, safety and selection of resistance in Malawi.

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    David J Bell

    Full Text Available BACKGROUND: In Malawi, there has been a return of Plasmodium falciparum sensitivity to chloroquine (CQ since sulfadoxine-pyrimethamine (SP replaced CQ as first line treatment for uncomplicated malaria. When used for prophylaxis, Amodiaquine (AQ was associated with agranulocytosis but is considered safe for treatment and is increasingly being used in Africa. Here we compare the efficacy, safety and selection of resistance using SP or CQ+SP or artesunate (ART+SP or AQ+SP for the treatment of uncomplicated falciparum malaria. METHODOLOGY AND FINDINGS: 455 children aged 1-5 years were recruited into a double-blinded randomised trial comparing SP to the three combination therapies. Using intention to treat analysis with missing outcomes treated as successes, and without adjustment to distinguish recrudescence from new infections, the day 28 adequate clinical and parasitological response (ACPR rate for SP was 25%, inferior to each of the three combination therapies (p<0.001. AQ+SP had an ACPR rate of 97%, higher than CQ+SP (81% and ART+SP (70%, p<0.001. Nineteen children developed a neutropenia of

  18. Randomized trial of artesunate+amodiaquine, sulfadoxine-pyrimethamine+amodiaquine, chlorproguanal-dapsone and SP for malaria in pregnancy in Tanzania.

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    Theonest K Mutabingwa

    Full Text Available BACKGROUND: Malaria in pregnancy is serious, and drug resistance in Africa is spreading. Drugs have greater risks in pregnancy and determining the safety and efficacy of drugs in pregnancy is therefore a priority. This study set out to determine the efficacy and safety of several antimalarial drugs and combinations in pregnant women with uncomplicated malaria. METHODS: Pregnant women with non-severe, slide proven, falciparum malaria were randomised to one of 4 regimes: sulfadoxine-pyrimethamine [SP]; chlorproguanil-dapsone [CD]; SP+amodiaquine [SP+AQ] or amodiaquine+artesunate [AQ+AS]. Randomisation was on a 1ratio2ratio2ratio2 ratio. Women were admitted for treatment, and followed at days 7, 14, 21, 28 after the start of treatment, at delivery and 6 weeks after delivery to determine adverse events, clinical and parasitological outcomes. Primary outcome was parasitological failure by day 28. RESULTS: 1433 pregnant women were screened, of whom 272 met entry criteria and were randomised; 28 to SP, 81 to CD, 80 to SP+AQ and 83 to AQ+AS. Follow-up to day 28 post treatment was 251/272 (92%, and to 6 weeks following delivery 91%. By day 28 parasitological failure rates were 4/26 (15%, 95%CI 4-35 in the SP, 18/77 (23%, 95%CI 14-34 in the CD, 1/73 (1% 95%CI 7-0.001 in the SP+AQ and 7/75 (9% 95%CI 4-18 in the AQ+AS arms respectively. After correction by molecular markers for reinfection the parasitological failure rates at day 28 were 18% for CD, 1% for SP+AQ and 4.5% for AQ+AS. There were two maternal deaths during the trial. There was no apparent excess of stillbirths or adverse birth outcomes in any arm. Parasitological responses were strikingly better in pregnant women than in children treated with the same drugs at this site. CONCLUSIONS: Failure rates with monotherapy were unacceptably high. The two combinations tested were efficacious and appeared safe. It should not be assumed that efficacy in pregnancy is the same as in children. TRIAL

  19. Molecular markers of resistance to sulphadoxine-pyrimethamine one year after implementation of intermittent preventive treatment of malaria in infants in Mali

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    Coulibaly Oumar M

    2010-01-01

    Full Text Available Abstract Background Intermittent preventive treatment in infants (IPTi with sulphadoxine-pyrimethamine (SP given during routine vaccinations is efficacious in preventing malaria disease and shows no interaction with the vaccines. However, there is a fear that IPTi may result in a rapid increase of parasite resistance to SP. Methods To evaluate the impact of IPTi on SP-resistance point mutations, the 22 health sub-districts in the district of Kolokani, Mali, were randomized in a 1:1 ratio and starting in December 2006, IPTi with SP was implemented in 11 health sub-districts (intervention zone, while the other 11 health sub-districts served as the control (non-intervention zone. Blood smears and blood dots on filter paper were obtained from children aged 0-5 years, randomly selected in each of heath sub-districts during two cross-sectional surveys. The first survey was conducted in May 2007 before the start of the transmission season to collect baseline prevalence of the molecular markers of resistance to SP and the second in December 2007 after the end of the transmission season and one year after implementation of IPTi. A total of 427 and 923 randomly selected blood samples from the first and second surveys respectively were analysed by PCR for dhfr and dhps mutations. Results Each of the three dhfr mutations at codons 51, 59 and 108 was present in 35% and 57% of the samples during the two surveys with no significant differences between the two zones. Dhps mutations at codons 437 and 540 were present respectively in about 20% and 1% of the children during the two surveys in both zones at similar proportion. The prevalence of quadruple mutants (triple dhfr-mutants + dhps-437G associated with in-vivo resistance to SP in Mali after one year implementation of IPTi was also similar between the two zones (11.6% versus 11.2%, p = 0.90 and to those obtained at baseline survey (10.3% versus 8.1%. Conclusion This study shows no increase in the frequency

  20. Implementation of intermittent preventive treatment in pregnancy with sulphadoxine/pyrimethamine (IPTp-SP at a district health centre in rural Senegal

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    Vaillant Michel

    2008-11-01

    Full Text Available Abstract Background Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP is recommended for reducing the risk of malaria in pregnancy and its consequences on mothers and babies (IPTp-SP. Indicators of implementation and effects of IPTp-SP were collected in a rural clinic in Southern Senegal. Methods Women seen routinely at the antenatal clinic (ANC of a rural dispensary during 2000–2007. Deployment of IPTp-SP started in January 2004. Inspection of antenatal and outpatient clinic registries of the corresponding period. Results Between 1st January 2000 and 30th April 2007, 1,781 women of all gravitidities and parities attended the ANC with 965 deliveries (606 and 398 respectively since 1st January 2004, when IPTp-SP was started. 69% of women were seen ≥ 3 times; 95% received at least one dose and 70% two doses of SP (from 61% in 2004 to 86% in 2007. The first visit, first and second dose of SP occurred at a median week 20, 22 and 31. The probability of receiving two doses was > 80% with ≥ 3 antenatal visits and a first dose of SP by week 20. The prevalence of maternal malaria was low and similar pre- (0.7% and during IPTp (0.8%. Effects on of low birth weight (LBW, Unfavourable pregnancy outcomes numbered 72 (7.5% of pregnancies with known outcome, including 30 abortions and 42 later deaths (late foetal deaths, stillbirth, peri-natal of which 13 with one or more malformations (1.35% of all recorded deliveries. Conclusion The implementation of IPTp-SP was high. Early attendance to ANC favours completion of IPTp-SP. The record keeping system in place is amenable to data extraction and linkage. A model was developed that predicts optimal compliance to two SP doses, and could be tested in other settings. Maternal malaria was infrequent and unaffected by IPTp-SP. The risk of LBW was lower during IPT implementation but the difference was non-significant and could have other explanations.

  1. Prediction of Plasmodium falciparum resistance to sulfadoxine/pyrimethamine in vivo by mutations in the dihydrofolate reductase and dihydropteroate synthetase genes: a comparative study between sites of differing endemicity

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Enosse, Sonja; Khalil, Insaf F;

    2003-01-01

    Plasmodium falciparum resistance to sulfadoxine/pyrimethamine (S/P) is due to mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhfr) genes. Large-scale screening of the prevalence of these mutations could facilitate the surveillance of the level of S/P resistance...... marker seems debatable. The differences may reflect variation in the duration and magnitude of S/P usage (or other antifolate drugs) between the sites. Thus, triple dhfr mutations may prove suitable only as a general guideline for detecting emerging S/P resistance in areas where S/P has been introduced...... in vivo. The prevalence of mutations in dhfr and dhps in relation to S/P efficacy was studied in four sites of differing endemicity in Sudan, Mozambique, and Tanzania. The sites were organized in order of increasing resistance and a significant increase in the prevalence of triple mutations in codons c51...

  2. Research influence on antimalarial drug policy change in Tanzania: case study of replacing chloroquine with sulfadoxine-pyrimethamine as the first-line drug

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    Gonzalez-Block Miguel A

    2005-10-01

    Full Text Available Abstract Introduction Research is an essential tool in facing the challenges of scaling up interventions and improving access to services. As in many other countries, the translation of research evidence into drug policy action in Tanzania is often constrained by poor communication between researchers and policy decision-makers, individual perceptions or attitudes towards the drug and hesitation by some policy decision-makers to approve change when they anticipate possible undesirable repercussions should the policy change as proposed. Internationally, literature on the role of researchers on national antimalarial drug policy change is limited. Objectives To describe the (a role of researchers in producing evidence that influenced the Tanzanian government replace chloroquine (CQ with sulfadoxine-pyrimethamine (SP as the first-line drug and the challenges faced in convincing policy-makers, general practitioners, pharmaceutical industry and the general public on the need for change (b challenges ahead before a new drug combination treatment policy is introduced in Tanzania. Methods In-depth interviews were held with national-level policy-makers, malaria control programme managers, pharmaceutical officers, general medical practitioners, medical research library and publications officers, university academicians, heads of medical research institutions and district and regional medical officers. Additional data were obtained through a review of malaria drug policy documents and participant observations were also done. Results In year 2001, the Tanzanian Government officially changed its malaria treatment policy guidelines whereby CQ – the first-line drug for a long time was replaced with SP. This policy decision was supported by research evidence indicating parasite resistance to CQ and clinical CQ treatment failure rates to have reached intolerable levels as compared to SP and amodiaquine (AQ. Research also indicated that since SP was also facing

  3. A community effectiveness trial of strategies promoting intermittent preventive treatment with sulphadoxine-pyrimethamine in pregnant women in rural Burkina Faso

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    Brabin Bernard

    2008-09-01

    Full Text Available Abstract Background Intermittent preventive treatment with sulphadoxine-pyrimethamine for pregnant women (IPTp-SP is currently being scaled up in many countries in sub-Saharan Africa. Despite high antenatal clinic (ANC attendance, coverage with the required two doses of SP remains low. The study investigated whether a targeted community-based promotion campaign to increase ANC attendance and SP uptake could effectively improve pregnancy outcomes in the community. Methods Between 2004 and 2006 twelve health centres in Boromo Health District, Burkina Faso were involved in this study. Four were strategically assigned to community promotion in addition to IPTp-SP (Intervention A and eight were randomly allocated to either IPTp-SP (Intervention B or weekly chloroquine (Control. Primi- and secundigravidae were enrolled at village level and thick films and packed cell volume (PCV taken at 32 weeks gestation and at delivery. Placental smears were prepared and newborns weighed. Primary outcomes were peripheral parasitaemia during pregnancy and at delivery, placental malaria, maternal anaemia, mean and low birth weight. Secondary outcomes were the proportion of women with ≥ 3 ANC visits and ≥ 2 doses of SP. Intervention groups were compared using logistic and linear regression with linearized variance estimations to correct for the cluster-randomized design. Results SP uptake (≥ 2 doses was higher with (Intervention A: 70% than without promotion (Intervention B: 49% (OR 2.45 95%CI 1.25–4.82 p = 0.014. Peripheral (33.3% and placental (30.3% parasite rates were significantly higher in the control arm compared to Intervention B (peripheral: 20.1% OR 0.50 95%CI 0.37–0.69 p = 0.001; placental: 20.5% OR 0.59 95%CI 0.44–0.78 p = 0.002 but did not differ between Intervention A (17.4%; 18.1% and Intervention B (20.1; 20.5% (peripheral: OR 0.84 95%CI 0.60–1.18 p = 0.280; placental: OR 0.86 95%CI 0.58–1.29 p = 0.430. Mean PCV and birth weight and

  4. Temporal trends of sulphadoxine-pyrimethamine (SP drug-resistance molecular markers in Plasmodium falciparum parasites from pregnant women in western Kenya

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    Iriemenam Nnaemeka C

    2012-07-01

    Full Text Available Abstract Background Resistance to sulphadoxine-pyrimethamine (SP in Plasmodium falciparum parasites is associated with mutations in the dihydrofolate reductase (dhfr and dihydropteroate synthase (dhps genes and has spread worldwide. SP remains the recommended drug for intermittent preventive treatment for malaria in pregnancy (IPTp and information on population prevalence of the SP resistance molecular markers in pregnant women is limited. Methods Temporal trends of SP resistance molecular markers were investigated in 489 parasite samples collected from pregnant women at delivery from three different observational studies between 1996 and 2009 in Kenya, where SP was adopted for both IPTp and case treatment policies in 1998. Using real-time polymerase chain reaction, pyrosequencing and direct sequencing, 10 single-nucleotide polymorphisms (SNPs of SP resistance molecular markers were assayed. Results The prevalence of quintuple mutant (dhfr N51I/C59R/S108N and dhps A437G/K540E combined genotype increased from 7 % in the first study (1996–2000 to 88 % in the third study (2008–2009. When further stratified by sample collection year and adoption of IPTp policy, the prevalence of the quintuple mutant increased from 2.4 % in 1998 to 44.4 % three years after IPTp policy adoption, seemingly in parallel with the increase in percentage of SP use in pregnancy. However, in the 1996–2000 study, more mutations in the combined dhfr/dhps genotype were associated with SP use during pregnancy only in univariable analysis and no associations were detected in the 2002–2008 and 2008–2009 studies. In addition, in the 2008–2009 study, 5.3 % of the parasite samples carried the dhps triple mutant (A437G/K540E/A581G. There were no differences in the prevalence of SP mutant genotypes between the parasite samples from HIV + and HIV- women over time and between paired peripheral and placental samples. Conclusions There was a significant increase in

  5. Research influence on antimalarial drug policy change in Tanzania: case study of replacing chloroquine with sulfadoxine-pyrimethamine as the first-line drug.

    Science.gov (United States)

    Mubyazi, Godfrey M; Gonzalez-Block, Miguel A

    2005-10-20

    Research is an essential tool in facing the challenges of scaling up interventions and improving access to services. As in many other countries, the translation of research evidence into drug policy action in Tanzania is often constrained by poor communication between researchers and policy decision-makers, individual perceptions or attitudes towards the drug and hesitation by some policy decision-makers to approve change when they anticipate possible undesirable repercussions should the policy change as proposed. Internationally, literature on the role of researchers on national antimalarial drug policy change is limited. To describe the (a) role of researchers in producing evidence that influenced the Tanzanian government replace chloroquine (CQ) with sulfadoxine-pyrimethamine (SP) as the first-line drug and the challenges faced in convincing policy-makers, general practitioners, pharmaceutical industry and the general public on the need for change (b) challenges ahead before a new drug combination treatment policy is introduced in Tanzania. In-depth interviews were held with national-level policy-makers, malaria control programme managers, pharmaceutical officers, general medical practitioners, medical research library and publications officers, university academicians, heads of medical research institutions and district and regional medical officers. Additional data were obtained through a review of malaria drug policy documents and participant observations were also done. In year 2001, the Tanzanian Government officially changed its malaria treatment policy guidelines whereby CQ--the first-line drug for a long time was replaced with SP. This policy decision was supported by research evidence indicating parasite resistance to CQ and clinical CQ treatment failure rates to have reached intolerable levels as compared to SP and amodiaquine (AQ). Research also indicated that since SP was also facing rising resistance trend, the need for a more effective drug was

  6. Adherence to intermittent preventive treatment for malaria with sulphadoxine-pyrimethamine and outcome of pregnancy among parturients in South East Nigeria

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    Onyebuchi AK

    2014-04-01

    Full Text Available Azubike Kanario Onyebuchi,1 Lucky Osaheni Lawani,2 Chukwuemeka Anthony Iyoke,3 Chukwudi Robinson Onoh,1 Nwabunike Ekene Okeke4 1Department of Obstetrics and Gynecology, Federal Teaching Hospital, Abakaliki, Nigeria; 2School of Postgraduate Studies, Department of Community Medicine, University of Nigeria; 3Department of Obstetrics and Gynecology, University of Nigeria Teaching Hospital, Enugu, Nigeria; 4Department of Obstetrics and Gynecology, Mile Four Catholic Hospital, Abakaliki, Nigeria Background: Intermittent preventive treatment of malaria for pregnant women (IPTp is a very important strategy for the control of malaria in pregnancy in malaria-endemic tropical countries, where mosquito bites easily occur during evening outdoor activities. Issues related to provision, cost, and acceptability may affect the use of IPTp in some developing countries. The aim of the study was to assess the uptake and adherence to sulphadoxine-pyrimethamine-based intermittent preventive treatment of malaria during pregnancy and the relationship of IPTp use to pregnancy outcomes in two major obstetric centers in South East Nigeria. Methods: This was a prospective descriptive study involving women who received antenatal and delivery services. All recruited women were followed-up from booking until delivery, and statistical analysis was done with Epi Info version 7. Results: A total of 516 parturients were studied. The mean gestational age at booking was 21.8±6.9 weeks while the mean number of antenatal visits throughout the pregnancy was 5.5±3.1. The rate of uptake of at least one dose of prescribed IPTp was 72.1% (367/516. Of the 367 who took prescribed IPTp, adherence to second doses of IPTp was 59.7% (219/367, and only 4.9% (18/367 took a third dose. Clinical malaria occurred in 85% (127/149 of women who did not receive IPTp at all compared to 20.5% of those who received at least one dose of IPTp. All those who had clinical malaria despite IPTp had only one

  7. Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin-piperaquine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for the control of malaria during pregnancy in western Kenya: an open-label, three-group, randomised controlled superiority trial.

    Science.gov (United States)

    Desai, Meghna; Gutman, Julie; L'lanziva, Anne; Otieno, Kephas; Juma, Elizabeth; Kariuki, Simon; Ouma, Peter; Were, Vincent; Laserson, Kayla; Katana, Abraham; Williamson, John; ter Kuile, Feiko O

    2015-12-19

    Every year, more than 32 million pregnancies in sub-Saharan Africa are at risk of malaria infection and its adverse consequences. The effectiveness of the intermittent preventive treatment with sulfadoxine-pyrimethamine strategy recommended by WHO is threatened by high levels of parasite resistance. We aimed to assess the efficacy and safety of two alternative strategies: intermittent screening with malaria rapid diagnostic tests and treatment of women who test positive with dihydroartemisinin-piperaquine, and intermittent preventive treatment with dihydroartemisinin-piperaquine. We did this open-label, three-group, randomised controlled superiority trial at four sites in western Kenya with high malaria transmission and sulfadoxine-pyrimethamine resistance. HIV-negative pregnant women between 16 and 32 weeks' gestation were randomly assigned (1:1:1), via computer-generated permuted-block randomisation (block sizes of three, six, and nine), to receive intermittent screening and treatment with dihydroartemisinin-piperaquine, intermittent preventive treatment with dihydroartemisinin-piperaquine, or intermittent preventive treatment with sulfadoxine-pyrimethamine. Study participants, study clinic nurses, and the study coordinator were aware of treatment allocation, but allocation was concealed from study investigators, delivery unit nurses, and laboratory staff. The primary outcome was malaria infection at delivery, defined as a composite of peripheral or placental parasitaemia detected by placental histology, microscopy, or rapid diagnostic test. The primary analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01669941. Between Aug 21, 2012, and June 19, 2014, we randomly assigned 1546 women to receive intermittent screening and treatment with dihydroartemisinin-piperaquine (n=515), intermittent preventive treatment with dihydroartemisinin-piperaquine (n=516), or intermittent preventive treatment with sulfadoxine-pyrimethamine

  8. Estimated impact on birth weight of scaling up intermittent preventive treatment of malaria in pregnancy given sulphadoxine-pyrimethamine resistance in Africa: A mathematical model

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    Floyd, Jessica; ter Kuile, Feiko; Cairns, Matt

    2017-01-01

    Background Malaria transmission has declined substantially in the 21st century, but pregnant women in areas of sustained transmission still require protection to prevent the adverse pregnancy and birth outcomes associated with malaria in pregnancy (MiP). A recent call to action has been issued to address the continuing low coverage of intermittent preventive treatment of malaria in pregnancy (IPTp). This call has, however, been questioned by some, in part due to concerns about resistance to sulphadoxine-pyrimethamine (SP), the only drug currently recommended for IPTp. Methods and findings Using an existing mathematical model of MiP, we combined estimates of the changing endemicity of malaria across Africa with maps of SP resistance mutations and current coverage of antenatal access and IPTp with SP (IPTp-SP) across Africa. Using estimates of the relationship between SP resistance mutations and the parasitological efficacy of SP during pregnancy, we estimated the varying impact of IPTp-SP across Africa and the incremental value of enhancing IPTp-SP uptake to match current antenatal care (ANC) coverage. The risks of MiP and malaria-attributable low birthweight (mLBW) in unprotected pregnancies (i.e., those not using insecticide-treated nets [ITNs]) leading to live births fell by 37% (33%–41% 95% credible interval [crI]) and 31% (27%–34% 95% crI), respectively, from 2000 to 2015 across endemic areas in sub-Saharan Africa. However, these gains are fragile, and coverage is far from optimal. In 2015, 9.5 million (8.3 million–10.4 million 95% crI) of 30.6 million pregnancies in these areas would still have been infected with Plasmodium falciparum without intervention, leading to 750,000 (390,000–1.1 million 95% crI) mLBW deliveries. In all, 6.6 million (5.6 million–7.3 million 95% crI) of these 9.5 million (69.3%) pregnancies at risk of infection (and 53.4% [16.3 million/30.6 million] of all pregnancies) occurred in settings with near-perfect SP curative

  9. Estimated impact on birth weight of scaling up intermittent preventive treatment of malaria in pregnancy given sulphadoxine-pyrimethamine resistance in Africa: A mathematical model.

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    Patrick G T Walker

    2017-02-01

    Full Text Available Malaria transmission has declined substantially in the 21st century, but pregnant women in areas of sustained transmission still require protection to prevent the adverse pregnancy and birth outcomes associated with malaria in pregnancy (MiP. A recent call to action has been issued to address the continuing low coverage of intermittent preventive treatment of malaria in pregnancy (IPTp. This call has, however, been questioned by some, in part due to concerns about resistance to sulphadoxine-pyrimethamine (SP, the only drug currently recommended for IPTp.Using an existing mathematical model of MiP, we combined estimates of the changing endemicity of malaria across Africa with maps of SP resistance mutations and current coverage of antenatal access and IPTp with SP (IPTp-SP across Africa. Using estimates of the relationship between SP resistance mutations and the parasitological efficacy of SP during pregnancy, we estimated the varying impact of IPTp-SP across Africa and the incremental value of enhancing IPTp-SP uptake to match current antenatal care (ANC coverage. The risks of MiP and malaria-attributable low birthweight (mLBW in unprotected pregnancies (i.e., those not using insecticide-treated nets [ITNs] leading to live births fell by 37% (33%-41% 95% credible interval [crI] and 31% (27%-34% 95% crI, respectively, from 2000 to 2015 across endemic areas in sub-Saharan Africa. However, these gains are fragile, and coverage is far from optimal. In 2015, 9.5 million (8.3 million-10.4 million 95% crI of 30.6 million pregnancies in these areas would still have been infected with Plasmodium falciparum without intervention, leading to 750,000 (390,000-1.1 million 95% crI mLBW deliveries. In all, 6.6 million (5.6 million-7.3 million 95% crI of these 9.5 million (69.3% pregnancies at risk of infection (and 53.4% [16.3 million/30.6 million] of all pregnancies occurred in settings with near-perfect SP curative efficacy (>99% based on the most recent

  10. Estimated impact on birth weight of scaling up intermittent preventive treatment of malaria in pregnancy given sulphadoxine-pyrimethamine resistance in Africa: A mathematical model.

    Science.gov (United States)

    Walker, Patrick G T; Floyd, Jessica; Ter Kuile, Feiko; Cairns, Matt

    2017-02-01

    Malaria transmission has declined substantially in the 21st century, but pregnant women in areas of sustained transmission still require protection to prevent the adverse pregnancy and birth outcomes associated with malaria in pregnancy (MiP). A recent call to action has been issued to address the continuing low coverage of intermittent preventive treatment of malaria in pregnancy (IPTp). This call has, however, been questioned by some, in part due to concerns about resistance to sulphadoxine-pyrimethamine (SP), the only drug currently recommended for IPTp. Using an existing mathematical model of MiP, we combined estimates of the changing endemicity of malaria across Africa with maps of SP resistance mutations and current coverage of antenatal access and IPTp with SP (IPTp-SP) across Africa. Using estimates of the relationship between SP resistance mutations and the parasitological efficacy of SP during pregnancy, we estimated the varying impact of IPTp-SP across Africa and the incremental value of enhancing IPTp-SP uptake to match current antenatal care (ANC) coverage. The risks of MiP and malaria-attributable low birthweight (mLBW) in unprotected pregnancies (i.e., those not using insecticide-treated nets [ITNs]) leading to live births fell by 37% (33%-41% 95% credible interval [crI]) and 31% (27%-34% 95% crI), respectively, from 2000 to 2015 across endemic areas in sub-Saharan Africa. However, these gains are fragile, and coverage is far from optimal. In 2015, 9.5 million (8.3 million-10.4 million 95% crI) of 30.6 million pregnancies in these areas would still have been infected with Plasmodium falciparum without intervention, leading to 750,000 (390,000-1.1 million 95% crI) mLBW deliveries. In all, 6.6 million (5.6 million-7.3 million 95% crI) of these 9.5 million (69.3%) pregnancies at risk of infection (and 53.4% [16.3 million/30.6 million] of all pregnancies) occurred in settings with near-perfect SP curative efficacy (>99%) based on the most recent

  11. Efficacy of antimalarial treatment in Guinea: in vivo study of two artemisinin combination therapies in Dabola and molecular markers of resistance to sulphadoxine-pyrimethamine in N'Zérékoré

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    Coulibaly Léonie

    2007-05-01

    Full Text Available Abstract Background In the last five years, countries have been faced with changing their malaria treatment policy to an artemisinin-based combination therapy (ACT, many with no national data on which to base their decision. This is particularly true for a number of West African countries, including Guinea, where these studies were performed. Two studies were conducted in 2004/2005 in programmes supported by Medecins Sans Frontieres, when chloroquine was still national policy, but artesunate (AS/sulphadoxine-pyrimethamine (SP had been used in refugee camps for two years. Methods In Dabola (central Guinea, 220 children aged 6–59 months with falciparum malaria were randomized to receive either AS/amodiaquine (AQ or AS/SP. In vivo efficacy was assessed following the 2003 World Health Organization guidelines. In a refugee camp in Laine (south of Guinea, where an in vivo study was not feasible due to the unstable context, a molecular genotyping study in 160 patients assessed the prevalence of mutations in the dihydrofolate reductase (dhfr (codons 108, 51, 59 and dihydropteroate synthase (dhps (codons 436, 437, 540 genes of Plasmodium falciparum, which have been associated with resistance to pyrimethamine and sulphadoxine, respectively. Results In Dabola, after 28 days of follow-up, Polymerase Chain Reaction (PCR-adjusted failure rates were 1.0% (95%CI 0–5.3 for AS/AQ and 1.0% (95%CI 0–5.5 for AS/SP. In the refugee camp in Laine, the molecular genotyping study found three dhfr mutations in 85.6% (95%CI 79.2–90.7 patients and quintuple dhfr/dhps mutations in 9.6% (95%CI 5.2–15.9. Conclusion Both AS/AQ and AS/SP are highly efficacious in Dabola, whereas there is molecular evidence of established SP resistance in Laine. This supports the choice of the national programme of Guinea to adopt AS/AQ as first line antimalarial treatment. The results highlight the difficulties faced by control programmes, which have gone through the upheaval of

  12. High prevalence of pfdhfr-pfdhps triple mutations associated with anti-malarial drugs resistance in Plasmodium falciparum isolates seven years after the adoption of sulfadoxine-pyrimethamine in combination with artesunate as first-line treatment in Iran.

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    Rouhani, Maryam; Zakeri, Sedigheh; Pirahmadi, Sakineh; Raeisi, Ahmad; Djadid, Navid Dinparast

    2015-04-01

    The spread of anti-malarial drug resistance will challenge any malaria control and elimination strategies, and routine monitoring of resistance-associated molecular markers of commonly used anti-malarial drugs is very important. Therefore, in the present investigation, the extent of mutations/haplotypes in dhfr and dhps genes of Plasmodium falciparum isolates (n=72) was analyzed seven years after the introduction of sulfadoxine-pyrimethamine (SP) plus artesunate (AS) as first-line anti-malarial treatment in Iran using PCR-RFLP methods. The results showed that the majority of the patients (97.2%) carried both 59R and 108N mutations in pure form with wild-type genotype at positions N51 and I164. Additionally, a significant increase (Pdrug for treatment of falciparum patients in these malaria-endemic areas of Iran. However, no quintuple mutations associated with treatment failure were detected. In conclusion, the present results along with in vivo assays suggest that seven years after the adoption of SP-AS as the first-line treatment in Iran, this drug remains efficacious for treatment of uncomplicated falciparum malaria, as a partner drug with AS in these malaria-endemic areas.

  13. Avaliação da eficácia da azitromicina e pirimetamina em camundongos infectados por cepa cistogênica de Toxoplasma gondii Evaluation of the efficacy of azithromycin and pyrimethamine, for treatment of experimental infection of mice with Toxoplasma gondii cystogenic strain

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    Susana A.Z. Lescano

    2004-12-01

    Full Text Available Foi avaliada a eficácia da administração prolongada de azitromicina e pirimetamina em camundongos infectados com cepa cistogênica de Toxoplasma gondii. Os animais foram inoculados intraperitonealmente com um cisto de T. gondii e, após 20 dias, divididos em quatro grupos: GI infectados não tratados, GII infectados e tratados concomitantemente com pirimetamina (12,5mg/kg/dia e azitromicina (100mg/kg/dia, GIII infectados e tratados com a mesma dose de pirimetamina e GIV infectados e tratados da mesma forma com azitromicina. O tratamento, via oral, estendeu-se por 120 dias; após este período os animais foram sacrificados e foi feita a contagem dos cistos no cérebro. A associação de ambos os medicamentos proporcionou melhores resultados, diminuindo a contagem de cistos no cérebro dos animais tratados de forma concomitante.The efficacy of prolonged administration of azithromycin and pyrimethamine was evaluated in mice experimentally infected with cystogenic strain of Toxoplasma gondii. The animals were intraperitoneally inoculated with one cyst of T. gondii and after 20 days were allocated into four groups: GI, infected without treatment; GII, infected and treated with the association of pyrimethamine (12.5mg/kg/day and azithromycin (100mg/kg/day; GIII, infected and treated with the same dose of pyrimethamine; and GIV, infected and treated in the same way with azithromycin. The oral treatment lasted 120 days, after this period all the animals were sacrificed and the count of cysts in the brain was done. The association of both drugs provided the best results, by diminishing the cyst count in the brain of the animals treated in this way.

  14. Scheduled Intermittent Screening with Rapid Diagnostic Tests and Treatment with Dihydroartemisinin-Piperaquine versus Intermittent Preventive Therapy with Sulfadoxine-Pyrimethamine for Malaria in Pregnancy in Malawi: An Open-Label Randomized Controlled Trial

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    Madanitsa, Mwayiwawo; Kalilani, Linda; Mwapasa, Victor; van Eijk, Anna M.; Khairallah, Carole; Ali, Doreen; Pace, Cheryl; Smedley, James; Thwai, Kyaw-Lay; Levitt, Brandt; Kang’ombe, Arthur; Faragher, Brian; Taylor, Steve M.; Meshnick, Steve; ter Kuile, Feiko O.

    2016-01-01

    Background In Africa, most plasmodium infections during pregnancy remain asymptomatic, yet are associated with maternal anemia and low birthweight. WHO recommends intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). However, sulfadoxine-pyrimethamine (SP) efficacy is threatened by high-level parasite resistance. We conducted a trial to evaluate the efficacy and safety of scheduled intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with dihydroartemisinin-piperaquine (DP) as an alternative strategy to IPTp-SP. Methods and Findings This was an open-label, two-arm individually randomized superiority trial among HIV-seronegative women at three sites in Malawi with high SP resistance. The intervention consisted of three or four scheduled visits in the second and third trimester, 4 to 6 wk apart. Women in the IPTp-SP arm received SP at each visit. Women in the intermittent screening and treatment in pregnancy with DP (ISTp-DP) arm were screened for malaria at every visit and treated with DP if RDT-positive. The primary outcomes were adverse live birth outcome (composite of small for gestational age, low birthweight [<2,500 g], or preterm birth [<37 wk]) in paucigravidae (first or second pregnancy) and maternal or placental plasmodium infection at delivery in multigravidae (third pregnancy or higher). Analysis was by intention to treat. Between 21 July 2011 and 18 March 2013, 1,873 women were recruited (1,155 paucigravidae and 718 multigravidae). The prevalence of adverse live birth outcome was similar in the ISTp-DP (29.9%) and IPTp-SP (28.8%) arms (risk difference = 1.08% [95% CI −3.25% to 5.41%]; all women: relative risk [RR] = 1.04 [95% CI 0.90–1.20], p = 0.625; paucigravidae: RR = 1.10 [95% CI 0.92–1.31], p = 0.282; multigravidae: RR = 0.92 [95% CI 0.71–1.20], p = 0.543). The prevalence of malaria at delivery was higher in the ISTp-DP arm (48.7% versus 40.8%; risk difference

  15. Varying efficacy of artesunate+amodiaquine and artesunate+sulphadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in the Democratic Republic of Congo: a report of two in-vivo studies

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    van Overmeir Chantal

    2009-08-01

    Full Text Available Abstract Background Very few data on anti-malarial efficacy are available from the Democratic Republic of Congo (DRC. DRC changed its anti-malarial treatment policy to amodiaquine (AQ and artesunate (AS in 2005. Methods The results of two in vivo efficacy studies, which tested AQ and sulphadoxine-pyrimethamine (SP monotherapies and AS+SP and AS+AQ combinations in Boende (Equatorial province, and AS+SP, AS+AQ and SP in Kabalo (Katanga province, between 2003 and 2004 are presented. The methodology followed the WHO 2003 protocol for assessing the efficacy of anti-malarials in areas of high transmission. Results Out of 394 included patients in Boende, the failure rates on day 28 after PCR-genotyping adjustment of AS+SP and AS+AQ were estimated as 24.6% [95% CI: 16.6–35.5] and 15.1% [95% CI: 8.6–25.7], respectively. For the monotherapies, failure rates were 35.9% [95% CI: 27.0–46.7] for SP and 18.3% [95% CI: 11.6–28.1] for AQ. Out of 207 patients enrolled in Kabalo, the failure rate on day 28 after PCR-genotyping adjustment was 0 [1-sided 95% CI: 5.8] for AS+SP and AS+AQ [1-sided 95% CI: 6.2]. It was 19.6% [95% CI: 11.4–32.7] for SP monotherapy. Conclusion The finding of varying efficacy of the same combinations at two sites in one country highlights one difficulty of implementing a uniform national treatment policy in a large country. The poor efficacy of AS+AQ in Boende should alert the national programme to foci of resistance and emphasizes the need for systems for the prospective monitoring of treatment efficacy at sentinel sites in the country.

  16. Efficacy and safety of a fixed dose artesunate-sulphamethoxypyrazine-pyrimethamine compared to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria across Africa: a randomized multi-centre trial

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    Djimdé Abdoulaye

    2009-04-01

    Full Text Available Abstract Background The efficacy of artemisinin-based combination therapy has already been demonstrated in a number of studies all over the world, and some of them can be regarded as comparably effective. Ease of administration of anti-malarial treatments with shorter courses and fewer tablets may be key determinant of compliance. Methods Patients with uncomplicated falciparum malaria and over six months of age were recruited in Cameroon, Mali, Rwanda and Sudan. 1,384 patients were randomly assigned to receive artesunate-sulphamethoxypyrazine-pyrimethamine (AS-SMP three-day (once daily for 3 days regimen (N = 476 or AS-SMP 24-hour (0 h, 12 h, 24 h regimen (N = 458 or artemether-lumefantrine (AL, the regular 6 doses regimen (N = 450. The primary objective was to demonstrate non-inferiority (using a margin of -6% of AS-SMP 24 hours or AS-SMP three days versus AL on the PCR-corrected 28-day cure rate. Results The PCR corrected 28-day cure rate on the intention to treat (ITT analysis population were: 96.0%(457/476 in the AS-SMP three-day group, 93.7%(429/458 in the AS-SMP 24-hour group and 92.0%(414/450 in the AL group. Likewise, the cure rates on the PP analysis population were high: 99.3%(432/437 in the AS-SMP three-day group, 99.5%(416/419 in the AS-SMP 24-hour group and 99.7(391/394% in the AL group. Most common drug-related adverse events were gastrointestinal symptoms (such as vomiting and diarrhea which were slightly higher in the AS-SMP 24-hour group. Conclusion AS-SMP three days or AS-SMP 24 hours are safe, are as efficacious as AL, and are well tolerated. Trial registration NCT00484900 http://www.clinicaltrials.gov.

  17. Safety of Seasonal Malaria Chemoprevention (SMC) with Sulfadoxine-Pyrimethamine plus Amodiaquine when Delivered to Children under 10 Years of Age by District Health Services in Senegal: Results from a Stepped-Wedge Cluster Randomized Trial

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    NDiaye, J. L.; Cissé, B.; Ba, E. H.; Gomis, J. F.; Ndour, C. T.; Molez, J. F.; Fall, F. B.; Sokhna, C.; Faye, B.; Kouevijdin, E.; Niane, F. K.; Cairns, M.; Trape, J. F.; Rogier, C.; Gaye, O.; Greenwood, B. M.; Milligan, P. J. M.

    2016-01-01

    Background It is recommended that children aged 3 months to five years of age living in areas of seasonal transmission in the sub-Sahel should receive Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) during the malaria transmission season. The purpose of this study was to evaluate the safety of SMC with SPAQ in children when delivered by community health workers in three districts in Senegal where SMC was introduced over three years, in children from 3 months of age to five years of age in the first year, then in children up to 10 years of age. Methods A surveillance system was established to record all deaths and all malaria cases diagnosed at health facilities and a pharmacovigilance system was established to detect adverse drug reactions. Health posts were randomized to introduce SMC in a stepped wedge design. SMC with SPAQ was administered once per month from September to November, by nine health-posts in 2008, by 27 in 2009 and by 45 in 2010. Results After three years, 780,000 documented courses of SMC had been administered. High coverage was achieved. No serious adverse events attributable to the intervention were detected, despite a high level of surveillance. Conclusions SMC is being implemented in countries of the sub-Sahel for children under 5 years of age, but in some areas the age distribution of cases of malaria may justify extending this age limit, as has been done in Senegal. Our results show that SMC is well tolerated in children under five and in older children. However, pharmacovigilance should be maintained where SMC is implemented and provision for strengthening national pharmacovigilance systems should be included in plans for SMC implementation. Trial Registration ClinicalTrials.gov NCT 00712374 PMID:27764102

  18. Increase in EPI vaccines coverage after implementation of intermittent preventive treatment of malaria in infant with Sulfadoxine -pyrimethamine in the district of Kolokani, Mali: Results from a cluster randomized control trial

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    Salomon Roger

    2011-07-01

    Full Text Available Abstract Background Even though the efficacy of Intermittent Preventive Treatment in infants (IPTi with Sulfadoxine-Pyrimethamine (SP against clinical disease and the absence of its interaction with routine vaccines of the Expanded Immunization Programme (EPI have been established, there are still some concerns regarding the addition of IPTi, which may increase the work burden and disrupt the routine EPI services especially in Africa where the target immunization coverage remains to be met. However IPTi may also increase the adherence of the community to EPI services and improve EPI coverage, once the benefice of strategy is perceived. Methods To assess the impact of IPTi implementation on the coverage of EPI vaccines, 22 health areas of the district of Kolokani were randomized at a 1:1 ratio to either receive IPTi-SP or to serve as a control. The EPI vaccines coverage was assessed using cross-sectional surveys at baseline in November 2006 and after one year of IPTi pilot-implementation in December 2007. Results At baseline, the proportion of children of 9-23 months who were completely vaccinated (defined as children who received BGG, 3 doses of DTP/Polio, measles and yellow fever vaccines was 36.7% (95% CI 25.3% -48.0%. After one year of implementation of IPTi-SP using routine health services, the proportion of children completely vaccinated rose to 53.8% in the non intervention zone and 69.5% in the IPTi intervention zone (P The proportion of children in the target age groups who received IPTi with each of the 3 vaccinations DTP2, DTP3 and Measles, were 89.2% (95% CI 85.9%-92.0%, 91.0% (95% CI 87.6% -93.7% and 77.4% (95% CI 70.7%-83.2% respectively. The corresponding figures in non intervention zone were 2.3% (95% CI 0.9% -4.7%, 2.6% (95% CI 1.0% -5.6% and 1.7% (95% CI 0.4% - 4.9%. Conclusion This study shows that high coverage of the IPTi can be obtained when the strategy is implemented using routine health services and implementation results

  19. Mortality, Morbidity, and Developmental Outcomes in Infants Born to Women Who Received Either Mefloquine or Sulfadoxine-Pyrimethamine as Intermittent Preventive Treatment of Malaria in Pregnancy: A Cohort Study

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    Rupérez, María; González, Raquel; Mombo-Ngoma, Ghyslain; Kabanywanyi, Abdunoor M.; Sevene, Esperança; Ouédraogo, Smaïla; Kakolwa, Mwaka A.; Vala, Anifa; Accrombessi, Manfred; Briand, Valérie; Aponte, John J.; Manego Zoleko, Rella; Adegnika, Ayôla A.; Cot, Michel; Kremsner, Peter G.; Massougbodji, Achille; Abdulla, Salim; Ramharter, Michael; Macete, Eusébio; Menéndez, Clara

    2016-01-01

    Background Little is known about the effects of intermittent preventive treatment of malaria in pregnancy (IPTp) on the health of sub-Saharan African infants. We have evaluated the safety of IPTp with mefloquine (MQ) compared to sulfadoxine-pyrimethamine (SP) for important infant health and developmental outcomes. Methods and Findings In the context of a multicenter randomized controlled trial evaluating the safety and efficacy of IPTp with MQ compared to SP in pregnancy carried out in four sub-Saharan countries (Mozambique, Benin, Gabon, and Tanzania), 4,247 newborns, 2,815 born to women who received MQ and 1,432 born to women who received SP for IPTp, were followed up until 12 mo of age. Anthropometric parameters and psychomotor development were assessed at 1, 9, and 12 mo of age, and the incidence of malaria, anemia, hospital admissions, outpatient visits, and mortality were determined until 12 mo of age. No significant differences were found in the proportion of infants with stunting, underweight, wasting, and severe acute malnutrition at 1, 9, and 12 mo of age between infants born to women who were on IPTp with MQ versus SP. Except for three items evaluated at 9 mo of age, no significant differences were observed in the psychomotor development milestones assessed. Incidence of malaria, anemia, hospital admissions, outpatient visits, and mortality were similar between the two groups. Information on the outcomes at 12 mo of age was unavailable in 26% of the infants, 761 (27%) from the MQ group and 377 (26%) from the SP group. Reasons for not completing the study were death (4% of total study population), study withdrawal (6%), migration (8%), and loss to follow-up (9%). Conclusions No significant differences were found between IPTp with MQ and SP administered in pregnancy on infant mortality, morbidity, and nutritional outcomes. The poorer performance on certain psychomotor development milestones at 9 mo of age in children born to women in the MQ group compared

  20. An open randomized clinical trial in comparing two artesunate-based combination treatments on Plasmodium falciparum malaria in Nigerian children: artesunate/sulphamethoxypyrazine/pyrimethamine (fixed dose over 24 hours versus artesunate/amodiaquine (fixed dose over 48 hours

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    Sowunmi Akintunde

    2010-12-01

    Full Text Available Abstract Background Several studies have demonstrated the efficacy of artemisinin-combination therapy (ACT across malaria zones of the world. Fixed dose ACT with shorter courses and fewer tablets may be key determinants to ease of administration and compliance. Methods Children aged one year to 13 years presenting with uncomplicated Plasmodium falciparum malaria were recruited in Ibadan, south-western Nigeria. A total of 250 children each were randomly assigned to receive three doses of artesunate/sulphamethoxypyrazine/pyrimethamine (AS + SMP (12 hourly doses over 24 hours or three doses of artesunate/amodiaquine (AS + AQ (daily doses over 48 hours. Efficacy and safety of the two drugs were assessed using a 28-day follow-up and the primary outcome was PCR- corrected parasitological cure rate and clinical response. Results There were two (0.4% early treatment failures, one in each treatment arm. The PCR corrected cure rates for day 28 was 97.9% in the AS + AQ arm and 95.6% in the AS + SMP arm (p = 0.15. The re-infection rate was 1.7% in the AS + AQ arm and 5.7% in the AS + SMP arm (p = 0.021. The fever clearance time was similar in the two treatment groups: 1 - 2 days for both AS + SMP and AS + AQ (p = 0.271. The parasite clearance time was also similar in the two treatment groups with 1 - 7 days for AS + SMP and 1 - 4 days for AS + AQ (p = 0.941. The proportion of children with gametocytes over the follow-up period was similar in both treatment groups. Serious Adverse Events were not reported in any of the patients and in all children, laboratory values (packed cell volume, liver enzymes, bilirubin remained within normal levels during the follow-up period but the packed cell volume was significantly lower in the AS + SMP group. Conclusions This study demonstrates that AS + SMP FDC given as three doses over 24 hours (12-hour intervals has similar efficacy as AS + AQ FDC given as three doses over 48 hours (24-hour interval for the treatment of

  1. Validation of a liquid chromatographic method for determination of sulphadoxine and pyrimethamine in whole blood spotted on filter paper Validación de un método de cromatografía líquida para determinar la presencia de sulfadoxina y pirimetamina en muestra de sangre secada sobre papel de filtro

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    Diana Margarita Márquez Fernández

    2012-09-01

    Full Text Available Objective: to validate an analytical method for simultaneous determination and quantification of sulphadoxine and pyrimethamine in human blood dried onto filter paper, whose cost and analysis time can be reduced. Methods: whole blood spotted on filter paper of a healthy volunteer and solutions of sulphadoxine-pyrimethamine standard mixture were used. HPLC separations were carried out on Agilent equipment using a LiChrospher® column C18 with a mobile phase acetonitrile/0.1 M potassium phosphate buffer at pH 3.0 (1:1 for eight minutes under isocratic conditions. A flow rate of 0.7 mL/min, and a 20 mL volume injection were used. External standard method for quantitation of analytes was used. Results: the HPLC method described for the simultaneous determination of sulphadoxine and pyrimethamine in 100 mL of whole blood spotted on filter paper has been found to be linear, precise, accurate and selective. In this method, the sample preparation is simple using liquid-liquid extraction, and HPLC with ultraviolet detection is used. Conclusions: a simple, fast and sensitive method for determination of sulphadoxine and pyrimethamine in human blood dried onto filter paper was validated. This method can be used for the monitoring of both metabolites in pharmacokinetic and clinical studies.Objetivo: validar un método de análisis para la determinación y cuantificación simultánea de sulfadoxina y pirimetamina en sangre humana secada sobre papel de filtro que sea rápido y barato. Métodos: se usó sangre de un voluntario sano impregnada sobre papel de filtro y soluciones estándar de la mezcla sulfadoxina y pririmetamina. Las separaciones por cromatografía líquida de alta resolución (CLAR se hicieron en un equipo Agilent sobre una columna C18 LiChrospher® con acetonitrilo/buffer fosfato de potasio 0,1 M a pH 3,0 como fase móvil, usando condiciones isocráticas durante 8 min. Se usó un flujo de 0,7 mL/min y un volumen de inyección de 20 mL. Para la

  2. Efficacy and Safety of Azithromycin-Chloroquine versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: An Open-Label, Randomized Trial.

    Directory of Open Access Journals (Sweden)

    Joshua Kimani

    Full Text Available The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp with sulfadoxine-pyrimethamine (SP in African regions with moderate to high malaria transmission. However, growing resistance to SP threatens the effectiveness of IPTp-SP, and alternative drugs are needed. This study tested the efficacy, tolerability, and safety of a fixed-dose combination azithromycin-chloroquine (AZCQ; 250 mg AZ/155 mg CQ base for IPTp relative to IPTp-SP.A randomized, Phase 3, open-label, multi-center study was conducted in sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda between October 2010 and November 2013. Pregnant women received 3 IPTp courses with AZCQ (each course: 1,000/620 mg AZCQ QD for 3 days or SP (each course 1,500/75 mg SP QD for 1 day at 4- to 8-week intervals during the second and third trimester. Long-lasting insecticide-treated bednets were also provided at enrollment. Study participants were followed up until day 28 post delivery (time window: day 28-42. The primary endpoint was the proportion of participants with sub-optimal pregnancy outcomes (a composite endpoint comprising live-borne neonates with low birth weight [LBW, 28 weeks], abortion [≤28 weeks], lost to follow-up prior to observation of pregnancy outcome, or missing birth weight. The study was terminated early after recruitment of 2,891 of the planned 5,044 participants, due to futility observed in a pre-specified 35% interim analysis. In the final intent-to-treat dataset, 378/1,445 (26.2% participants in the AZCQ and 342/1,445 (23.7% in the SP group had sub-optimal pregnancy outcomes, with an estimated risk ratio (RR of 1.11 (95% CI: 0.97, 1.25; p = 0.12. There was no significant difference in the incidence of LBW between treatment groups (57/1138 [5.0%] in the AZCQ group, 68/1188 [5.7%] in the SP group, RR 0.87 [95% CI: 0.62, 1.23]; p = 0.44. IPTp-AZCQ was less well-tolerated in mothers than IPTp-SP. Occurrences of congenital anomalies

  3. Resistência à sulfadoxina-pirimetamina em Maputo, Moçambique: presença de mutações nos genes dhfr e dhps do Plasmodium falciparum Sulfadoxine-pyrimethamine resistance in Maputo, Mozambique: presence of mutations in the dhfr and dhps genes of Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Natércia Emília Pedro Fernandes

    2007-08-01

    Full Text Available Foram analisadas a freqüência e distribuição de mutações nos genes dihidrofolato redutase e dihidropteroato sintetase do Plasmodium falciparum, usando a metodologia de reação em cadeia da polimerase e polimorfismos de hidrólise por enzimas de restrição, em amostras de sangue infectado proveniente de crianças moçambicanas, residentes em Maputo. A análise foi feita antes e 7 dias após o tratamento com sulfadoxina-pirimetamina (S/P. Os resultados mostraram a ocorrência de mutações pontuais nos genes estudados e a presença de combinações de três alelos em dhfr (51Ile, 59Arg e 108Asn e do quintúplo mutante (dhfr 51Ile, 59Arg, 108Asn e dhps 437Gly, 540Glu, ambas situações associadas à falha terapêutica no sétimo dia após tratamento com S/P. Esses achados mostram a importância de se estudar a resistência à S/P em Moçambique, e como os marcadores moleculares de resistência aos antimaláricos podem fornecer dados importantes para a política nacional de controlo da malária.The frequency and distribution of mutations in Plasmodium falciparum, dihydrofolate reductase and dihydropteroate synthase genes were analyzed, using the polymerase chain reaction and restriction fragment length polymorphism methodology, in infected blood samples from Mozambican children living in Maputo, before and seven days after treatment with sulfadoxine/pyrimethamine (S/P. The results showed the occurrence of point mutations in the genes studied and the presence of combinations of three alleles in dhfr (51Ile, 59Arg and 108Asn and "quintuple" mutant (dhfr 51Ile, 59Arg, 108Asn and dhps 437Gly, 540Glu. Both of these situations were associated with seven-day therapeutic failure, following treatment with S/P. These findings show the importance of studying S/P resistance in Mozambique, and how molecular markers for antimalarial resistance can provide important data for national malaria control policy.

  4. Pyrimethamine-induced alterations in human lymphocytes in vitro. Mechanisms and reversal of the effect

    DEFF Research Database (Denmark)

    Bygbjerg, Ib Christian

    1985-01-01

    . The effects of PYR were completely corrected by low concentrations of folinic acid and high concentrations of folic acid, indicating that the basic mechanism of action of PYR is competitive blocking of dihydrofolate reductase. However, the effect of PYR was poorly corrected by exogenous thymidine; therefore...

  5. In vitro activities of pentamidine, pyrimethamine, trimethoprim, and sulfonamides against Aspergillus species.

    NARCIS (Netherlands)

    Afeltra, J.; Meis, J.F.G.M.; Vitale, R.G.; Mouton, J.W.; Verweij, P.E.

    2002-01-01

    The susceptibilities of 70 strains of Aspergillus species were tested against seven different sulfa drugs and pentamidine by a microdilution method with RPMI 1640 and yeast nitrogen base media. Sulfamethoxazole, sulfadiazine, and pentamidine were active in vitro. The MICs obtained with RPMI 1640 wer

  6. Molecular monitoring of Plasmodium falciparum super-resistance to sulfadoxine-pyrimethamine in Tanzania

    DEFF Research Database (Denmark)

    Kavishe, Reginald A; Kaaya, Robert D; Nag, Sidsel

    2016-01-01

    and in private drug shops in sub-Saharan Africa. This study reports on the prevalence and distribution of Pfdhps mutations A540E and A581G in Tanzania. When found together, these mutations confer high-level SP resistance (sometimes referred to as 'super-resistance'), which is associated with loss in protective...... efficacy of SP-IPTp. METHODS: DNA samples were extracted from malaria-positive blood samples on filter paper, used malaria rapid diagnostic test strips and whole blood collected from eight sites in seven administrative regions of Tanzania. PCR-RFLP and SSOP-ELISA techniques were used to genotype the A540E...... = 85.3, p Tanzania and in Kagera (20.4 %) in northwestern Tanzania and the 540-581 EG haplotype was found at 54.5 and 19...

  7. Comparative efficacy of chloroquine and sulphadoxine - pyrimethamine in pregnant women and children: a meta-analysis

    NARCIS (Netherlands)

    G.C. Kalanda; J. Hill; F.H. Verhoeff; B.J. Brabin

    2006-01-01

    Objective: To compare the efficacy of chloroquine and sulphadoxine-pyremethamine against Plasmodium falciparum infection in pregnant women and in children from the same endemic areas of Africa, with the aim of determining the level of correspondence in efficacy determinations in these two risk group

  8. Continued efficacy of sulfadoxine-pyrimethamine as second line treatment for malaria in children in Guinea-Bissau

    DEFF Research Database (Denmark)

    Kofoed, Poul-Erik; Rodrigues, Amabelia; Aaby, Peter;

    2006-01-01

    sensitivity, the efficacy of S/P was studied immediately before the introduction of the drug and 6-9 years later. METHODS: Children participating in clinical in vivo studies were given S/P if having late clinical treatment failure following the treatment with quinine, chloroquine, or amodiaquine...

  9. Molecular monitoring of Plasmodium falciparum super-resistance to sulfadoxine-pyrimethamine in Tanzania

    DEFF Research Database (Denmark)

    Kavishe, Reginald A; Kaaya, Robert D; Nag, Sidsel;

    2016-01-01

    and A581G Pfdhps. Data were analysed using SPSS version 18 while Chi square and/or Fischer Exact tests were used to compare prevalence between regions. RESULTS: A high inter-regional variation of Pfdhps-540E was observed (χ(2) = 76.8, p

  10. Assessment of efficacy and safety of artesunate plus sulfadoxine pyrimethamine combination for treatment of uncomplicated falciparum malaria

    Directory of Open Access Journals (Sweden)

    Yash N. Goyal

    2014-06-01

    Conclusion: AS + SP is safe and effective drug for the treatment of uncomplicated falciparum malaria. However, the efficacy of this ACT needs to be carefully monitored periodically since treatment failure can occur due to resistance. [Int J Basic Clin Pharmacol 2014; 3(3.000: 465-469

  11. Antibodies to malaria vaccine candidates are associated with chloroquine or sulphadoxine/pyrimethamine treatment efficacy in children in an endemic area of Burkina Faso

    DEFF Research Database (Denmark)

    Diarra, Amidou; Nebie, Issa; Tiono, Alfred

    2012-01-01

    of the value of suboptimal vaccines. The study aim was to investigate relationship between antibodies and anti-malarial drug treatment outcomes. METHODS: Some 248 children aged 0.5 and 15 years were recruited prior to the high malaria transmission season. Venous blood (5 ml) was obtained from each child...

  12. Community-based distribution of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria during pregnancy improved coverage but reduced antenatal attendance in southern Malawi

    NARCIS (Netherlands)

    K.P. Msyamboza; E.J. Savage; P.N. Kazembe; S. Gies; G. Kalanda; U. D'Alessandro; B.J. Brabin

    2009-01-01

    To evaluate the impact of a 2-year programme for community-based delivery of sulfadoxine-pyremethamine (SP) on intermittent preventive treatment during pregnancy coverage, antenatal clinic attendance and pregnancy outcome. Fourteen intervention and 12 control villages in the catchment areas of Chikw

  13. Effects of Point Mutations in Plasmodium falciparum Dihydrofolate Reductase and Dihydropterate Synthase Genes on Clinical Outcomes and In Vitro Susceptibility to Sulfadoxine and Pyrimethamine

    Science.gov (United States)

    2009-08-01

    parasitological responses [23]. To distinguish between recrudescence and reinfection, malaria parasites collected on day of enrollment (day 0) and day of...Alejandro Llanos-Cuentas4, Coralith Garcia4, Lelv Solari4, Dennis Kyle5, Alan J. Magill3 1 Parasitology Program, Naval Medical Research Center...objective was to correlate the presence of polymorphisms in P. falciparum dihydrofolate reductase and dihydropteroate synthase to in vitro parasite

  14. The efficacy of sulfadoxine-pyrimethamine alone and in combination with chloroquine for malaria treatment in rural Eastern Sudan: the interrelation between resistance, age and gametocytogenesis

    DEFF Research Database (Denmark)

    A-Elbasit, Ishraga E; Elbashir, Mustafa I; Khalil, Insaf F;

    2006-01-01

    OBJECTIVE: To compare the efficacy of sulfadoxine-pyremethamine (SP)+chloroquine (CQ) combination treatment against falciparum malaria with SP treatment alone. METHOD: In-vivo study of 254 patients with uncomplicated Plasmodium falciparum malaria in rural eastern Sudan, where the population is semi......-immune. RESULTS: Sulfadoxine-pyremethamine treatment alone cured 68.3% (41/60) and SP+CQ cured 63.4% (123/194). Early and late treatment failures occurred in both treatment groups. Host age (as a marker for immunity) and parasite gametocytogenesis (as a marker for transmissibility) were significantly associated...... with SP resistance. Patients who were cured were significantly older (median age 21 years) than patients whose treatment failed (median age 12 years). Gametocyte production was significantly higher in patients with treatment failure (0.72 vs 0.45) and associated with younger age. Gametocyte counts were...

  15. Antibodies to malaria vaccine candidates are associated with chloroquine or sulphadoxine/pyrimethamine treatment efficacy in children in an endemic area of Burkina Faso

    Directory of Open Access Journals (Sweden)

    Diarra Amidou

    2012-03-01

    Full Text Available Abstract Background Patient immune status is thought to affect the efficacy of anti-malarial chemotherapy. This is a subject of some importance, since evidence of immunity-related interactions may influence our use of chemotherapy in populations with drug resistance, as well as assessment of the value of suboptimal vaccines. The study aim was to investigate relationship between antibodies and anti-malarial drug treatment outcomes. Methods Some 248 children aged 0.5 and 15 years were recruited prior to the high malaria transmission season. Venous blood (5 ml was obtained from each child to measure antibody levels to selected malaria antigens, using ELISA. Blood smears were also performed to assess drug efficacy and malaria infection prevalence. Children were actively followed up to record clinical malaria cases. Results IgG levels to MSP3 were always higher in the successfully treated group than in the group with treatment failure. The same observation was made for GLURP but the reverse observation was noticed for MSP1-19. Cytophilic and non-cytophilic antibodies were significantly associated with protection against all three antigens, except for IgG4 to MSP1-19 and GLURP. Conclusion Acquired anti-malarial antibodies may play an important role in the efficacy of anti-malarial drugs in younger children more susceptible to the disease.

  16. Efficacies of artesunate plus either sulfadoxine-pyrimethamine or amodiaquine, for the treatment of uncomplicated, Plasmodium falciparum malaria in eastern Sudan

    DEFF Research Database (Denmark)

    Ibrahium, A M; Kheir, M M; Osman, M E

    2007-01-01

    the follow-up and, although mild adverse effects (nausea, vomiting, abdominal pain, dizziness and/or rash) were detected in 14 patients, they occurred at the same frequency in each treatment arm. It therefore appears that the AS-SP and AS-AQ combinations were both effective and safe for the treatment...

  17. Prevalence of Plasmodium falciparum resistance markers to sulfadoxine-pyrimethamine among pregnant women receiving intermittent preventive treatment for malaria in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Birungi, Josephine; Yanow, Stephanie K;

    2015-01-01

    there was insufficient statistical power to test whether there was a true rise in the prevalence of this allele. The overall high frequency of Pfdhfr and Pfdhps quintuple mutations throughout pregnancy excluded further analyses of possible associations between certain haplotypes and the risk of lower birth weight...... and anemia. However, women infected with P. falciparum had 1.3-g/dl-lower hemoglobin levels (P = 0.001) and delivered babies with a 400-g-lower birth weight (P = 0.001) compared to nonparasitemic women. Despite this, 44 women who were P. falciparum positive at baseline became negative after one or two doses...

  18. Dihydrofolate reductase and dihydropteroate synthase genotypes associated with in vitro resistance of Plasmodium falciparum to pyrimethamine, trimethoprim, sulfadoxine, and sulfamethoxazole

    DEFF Research Database (Denmark)

    Khalil, Insaf; Rønn, Anita M; Alifrangis, Michael;

    2003-01-01

    with PYR and TRM drug responses (r = 0.93 and 0.85). Isolates with wild-type alleles showed mean half inhibitory concentrations (IC50 +/- SD) of 0.10 +/- 0.10 and 0.15 +/- 0.06 microg/100 microl for PYR and TRM. Parasites with mutations at codons 108 and 51 alone or combined with codon 59 have IC50 of 11.......46 +/- 0.86 (PYR) and 2.90 +/- 0.59 microg/100 microl (TRM). For both drugs, the differences in the mean IC50 between wild and mutant parasites were statistically significant (P

  19. Intermittent preventive sulfadoxine-pyrimethamine treatment of primigravidae reduces levels of plasma immunoglobulin G, which protects against pregnancy-associated Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Staalsoe, Trine; Shulman, Caroline E; Dorman, Edgar K;

    2004-01-01

    Pregnancy-associated malaria (PAM) is an important cause of maternal and neonatal suffering. It is caused by Plasmodium falciparum capable of inhabiting the placenta through expression of particular variant surface antigens (VSA) with affinity for proteoglycans such as chondroitin sulfate A....... Protective immunity to PAM develops following exposure to parasites inhabiting the placenta, and primigravidae are therefore particularly susceptible to PAM. The adverse consequences of PAM in primigravidae are preventable by intermittent preventive treatment (IPTp), where women are given antimalarials...

  20. Effect of antimalarial drugs on stimulation and interleukin 2 production of human lymphocytes

    DEFF Research Database (Denmark)

    Bygbjerg, I C; Svenson, M; Theander, T G

    1987-01-01

    Effect of pyrimethamine, an antimalarial antifolate, and of mefloquine, chloroquine, and quinine, which belong to the quinoline group of antimalarials, on proliferation and interleukin 2 (IL-2) production of human lymphocytes was studied in vitro. Pyrimethamine at concentrations above therapeutic...

  1. Sulfadoxine-Pyrimethamine-Based Intermittent Preventive Treatment, Bed Net Use, and Antenatal Care during Pregnancy: Demographic Trends and Impact on the Health of Newborns in the Kassena Nankana District, Northeastern Ghana

    Science.gov (United States)

    2010-01-01

    Hyg 77: 209-213. 17. Shulman CE, Graham WI, Iilo H, Lowe BS, New L, Obiero I, Snow RW, Marsh K, 1998. Malaria is an important cause of anaemia in...Trap Med Parasitol93: S25-s33. 26. Brabin BJ, Kalanda BF, Verhoef! FH, Chimsuku LH, Broadhead RL, 2004. Risk factors for foetal anaemia in a...Obstetrics 10: 2-7. 28. Brabin BJ,1992. Fetal anaemia in malarious areas: its causes and significance. Ann Trap Paediatr 12: 303--310.

  2. Increasing prevalence of wildtypes in the dihydrofolate reductase gene of Plasmodium falciparum in an area with high levels of sulfadoxine/pyrimethamine resistance after introduction of treated bed nets

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Lemnge, Martha M; Rønn, Anita M

    2003-01-01

    years old living in the villages from 1998 to 2000. In 2000, after two years of bed net use, the prevalence of wild types in codon 51, 59, and 108 of dhfr increased significantly in Magoda compared with previous years. Furthermore, the prevalence of dhfr wild types was significantly higher in Magoda...

  3. High frequency of Plasmodium falciparum CICNI/SGEAA and CVIET haplotypes without association with resistance to sulfadoxine/pyrimethamine and chloroquine combination in the Daraweesh area, in Sudan

    DEFF Research Database (Denmark)

    A-Elbasit, I E; Khalil, I F; Elbashir, M I

    2008-01-01

    , 50%; TF 55%) were not associated with TF. In contrast to other studies in Africa, the triple 51I/59R/108N mutation was rare (0.6%). In addition, the pfcrt CVIET haplotype (93%) was found to be associated with the CICNI/SGEAA haplotype. Finally, these data represent a baseline for SP resistance...

  4. Risks of hemolysis in glucose-6-phosphate dehydrogenase deficient infants exposed to chlorproguanil-dapsone, mefloquine and sulfadoxine-pyrimethamine as part of intermittent presumptive treatment of malaria in infants

    DEFF Research Database (Denmark)

    Poirot, Eugenie; Vittinghoff, Eric; Ishengoma, Deus;

    2015-01-01

    BACKGROUND: Chlorproguanil-dapsone (CD) has been linked to hemolysis in symptomatic glucose-6-phosphate dehydrogenase deficient (G6PDd) children. Few studies have explored the effects of G6PD status on hemolysis in children treated with Intermittent Preventive Treatment in infants (IPTi) antimala......BACKGROUND: Chlorproguanil-dapsone (CD) has been linked to hemolysis in symptomatic glucose-6-phosphate dehydrogenase deficient (G6PDd) children. Few studies have explored the effects of G6PD status on hemolysis in children treated with Intermittent Preventive Treatment in infants (IPTi...

  5. The association of parasitic infections in pregnancy and maternal and fetal anemia: a cohort study in coastal Kenya

    National Research Council Canada - National Science Library

    McClure, Elizabeth M; Meshnick, Steven R; Mungai, Peter; Malhotra, Indu; King, Christopher L; Goldenberg, Robert L; Hudgens, Michael G; Siega-Riz, Anna Maria; Dent, Arlene E

    2014-01-01

    .... All women enrolled in the study received presumptive treatment with sulfadoxine-pyrimethamine, iron and multi-vitamins and women diagnosed with helminthic infections were treated with albendazole...

  6. [Nature of cytogenetic and morphologic disorders in rat oogenesis and embryogenesis induced by chloridin and 2,4,5-trichlorophenoxyacetic acid during the preovulatory phase of meiosis].

    Science.gov (United States)

    Chebotar', N A

    1980-01-01

    The effect of pyrimethamine (chloridine) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) on embryo survival, cleavage rate and frequency of chromosome aberrations when injected into female rats just before ovulation was studied. Pyrimethamine induced 70% of embryonic death at a dose of 5 mg/kg and 27%--at a dose of 2 mg/kg. 200 mg/kg of 2,4,5-T had no embryotoxic effect, while 400 mg/kg increased the embryo loss up to 48%. Pyrimethamine (5 mg/kg) and 2,4,5-T (400 mg/kg), injected intragastrically just before ovulation, significantly affected the cleavage rate in the four day rat embryos. The frequency of chromosome aberrations in ovulated oocytes at metaphase, II subjected to pyrimethamine and 2,4,5-T, reached 6--8% and exceeded the control value in 5--10 times.

  7. Submicroscopic gametocytes and the transmission of antifolate-resistant Plasmodium falciparum in Western Kenya.

    NARCIS (Netherlands)

    Oesterholt, M.J.A.M.; Alifrangis, M.; Sutherland, C.J.; Omar, S.A.; Sawa, P.; Howitt, C.; Gouagna, L.C.; Sauerwein, R.W.; Bousema, T.

    2009-01-01

    BACKGROUND: Single nucleotide polymorphisms (SNPs) in the dhfr and dhps genes are associated with sulphadoxine-pyrimethamine (SP) treatment failure and gametocyte carriage. This may result in enhanced transmission of mutant malaria parasites, as previously shown for chloroquine resistant parasites.

  8. HUBUNGAN SENSISTIVITAS PLASMODIUM FALCIPARUM TERHADAP KOMBINASI PIRIMETAMIN/SULFADOKSIN DAN KLOROKUIN SECARA IN VITRO

    Directory of Open Access Journals (Sweden)

    Sahat Ompusunggu

    2012-09-01

    Full Text Available An in vitro sensitivity test was conducted to study the sensitivity of Plasmodium falciparum against chloroquine and pyrimethamine/sulphadoxine combination. The relationship between sensitivity of the parasite to the two drugs was also studied. A total of 72 patients from five localities were examined during 1984-1985. Test against chloroquine was conduc­ted according to WHO method, while against pyrimethamine/sulphadoxine combination, a modified method of Nguyen Dinh and Payne and Eastham and Rieckmann was used. The results showed that there is no relationship between the sensitivity of P. falciparum against pyrimethamine/ sulphadoxine combination and chloroquine. It can be concluded that in case of chloroquine resistant P. falciparum, pyrimethamine/sulphadoxine combination could be applied as an alternative chemotherapy.

  9. Feasibility and coverage of implementing intermittent preventive treatment of malaria in pregnant women contacting private or public clinics in Tanzania

    DEFF Research Database (Denmark)

    Mubyazi, Godfrey M; Magnussen, Pascal; Byskov, Jens;

    2013-01-01

    Evidence on healthcare managers' experience on operational feasibility of malaria intermittent preventive treatment for malaria during pregnancy (IPTp) using sulphadoxine-pyrimethamine (SP) in Africa is systematically inadequate. This paper elucidates the perspectives of District Council Health...

  10. Intermittent preventive treatment of malaria in pregnancy

    DEFF Research Database (Denmark)

    Mbonye, A.K.; Bygbjerg, Ib Christian; Magnussen, Pascal

    2008-01-01

    , still births, and maternal and child deaths were secondary endpoints. FINDINGS: 1404 (67.5%) of 2081 with the new delivery system received two doses of sulfadoxine-pyrimethamine versus 281 (39.9%) of 704 with health units (P

  11. Lindane

    Science.gov (United States)

    ... and your skin should be clean, dry, and free of other oils, lotions, or creams. If you ... Demerol); methocarbamol (Robaxin); neostigmine (Prostigmin); pyridostigmine (Mestinon, Regonol); pyrimethamine (Daraprim); radiographic dyes; sedatives; sleeping pills; tacrine (Cognex); ...

  12. Seasonal distribution of anti-malarial drug resistance alleles on the island of Sumba, Indonesia

    NARCIS (Netherlands)

    Asih, P.B.; Rogers, W.O.; Susanti, A.I.; Rahmat, A.; Rozi, I.E.; Kusumaningtyas, M.A.; Dewi, R.M.; Coutrier, F.N.; Sutamihardja, A.; Ven, A.J.A.M. van der; Sauerwein, R.W.; Syafruddin, D.

    2009-01-01

    BACKGROUND: Drug resistant malaria poses an increasing public health problem in Indonesia, especially eastern Indonesia, where malaria is highly endemic. Widespread chloroquine (CQ) resistance and increasing sulphadoxine-pyrimethamine (SP) resistance prompted Indonesia to adopt artemisinin-based com

  13. Chemotherapy of Rodent Malaria. Evaluation of Drug Action against Normal and Resistant Strains including Exo-Erythrocytic Stages.

    Science.gov (United States)

    1979-10-01

    transmissible PYR Highly resistant to pyrimethamine B highly resistant to proguanil and cycloguanil ORA highly resistant to sulphonamides V., P moderately...action of pyrimethamine (up to 10 months in polymer) and various sulphonamides . Silastic implants so far have proved less effective than polymers. -- 4...with a sulphonamide or sulphone proved successful. (4, 5, 9, 21, 23) In addition, however, several unexpected types of drug potentiation were

  14. The evolution of drug-resistant malaria

    OpenAIRE

    Plowe, Christopher V.

    2008-01-01

    Molecular epidemiological investigations have uncovered the patterns of emergence and global spread of Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine. Malaria parasites highly resistant to chloroquine and pyrimethamine spread from Asian origins to Africa, at great cost to human health and life. If artemisinin-resistant falciparum malaria follows the same pattern, renewed efforts to eliminate and eradicate malaria will be gravely threatened. This paper, adapted f...

  15. Methylene blue inhibits lumefantrine-resistant Plasmodium berghei.

    Science.gov (United States)

    Mwangi, Victor Irungu; Mumo, Ruth Mwende; Kiboi, Daniel Muthui; Omar, Sabah Ahmed; Ng'ang'a, Zipporah Waithera; Ozwara, Hastings Suba

    2016-06-30

    Chemotherapy still is the most effective way to control malaria, a major public health problem in sub-Saharan Africa. The large-scale use of the combination therapy artemether-lumefantrine for malaria treatment in Africa predisposes lumefantrine to emergence of resistance. There is need to identify drugs that can be used as substitutes to lumefantrine for use in combination therapy. Methylene blue, a synthetic anti-methemoglobinemia drug, has been shown to contain antimalarial properties, making it a candidate for drug repurposing. The present study sought to determine antiplasmodial effects of methylene blue against lumefantrine- and pyrimethamine-resistant strains of P. berghei. Activity of methylene blue was assessed using the classical four-day test on mice infected with lumefantrine-resistant and pyrimethamine-resistant P. berghei. A dose of 45 mg/kg/day was effective for testing ED90. Parasitemia and mice survival was determined. At 45 mg/kg/day, methylene blue sustained significant parasite inhibition, over 99%, for at least 6 days post-treatment against lumefantrine-resistant and pyrimethamine-resistant P. berghei (p = 0.0086 and p = 0.0191, respectively). No serious adverse effects were observed. Our results indicate that methylene blue at a concentration of 45 mg/kg/day confers over 99% inhibition against lumefantrine- and pyrimethamine-resistant P. berghei for six days. This shows the potential use methylene blue in the development of antimalarials against lumefantrine- and pyrimethamine-resistant parasites.

  16. In vitro biological evaluation of biguanides and dihydrotriazines against Brugia malayi and folate reversal studies.

    Science.gov (United States)

    Bag, Seema; Tawari, Nilesh R; Sharma, Richa; Goswami, Kalyan; Reddy, M V R; Degani, Mariam S

    2010-01-01

    Dihydrofolate reductase (DHFR) is a well-known target for antibacterial and anticancer therapy. DHFR inhibitors are useful for protozoan parasites, but are yet to be explored against metazoan species; hence the present work was designed to evaluate the efficacy of DHFR inhibitors against filariasis, one of the major neglected tropical diseases. Molecules from our in-house library of synthetic antifolate agents (biguanide and dihydrotriazine derivatives) were evaluated along with the antimalarial drug pyrimethamine and the antibacterial drug trimethoprim in an in vitro model against Brugia malayi microfilariae (Mf). Three biguanides and two dihydrotriazines were more potent than trimethoprim and pyrimethamine against B. malayi Mf. Trimethoprim, pyrimethamine and four of the five compounds active against Mf were also active against adult worms. To probe the mechanism of action of the compounds, reversal of activity of active compounds by folic acid and folinic acid was studied. In conclusion, DHFR inhibitors could be used as leads for new antifilarial drugs.

  17. Antibiotics for human toxoplasmosis: a systematic review of randomized trials.

    Science.gov (United States)

    Rajapakse, Senaka; Chrishan Shivanthan, Mitrakrishnan; Samaranayake, Nilakshi; Rodrigo, Chaturaka; Deepika Fernando, Sumadhya

    2013-06-01

    The efficacy of different treatment regimens in clinical syndromes of toxoplasmosis were assessed by conducting a systematic review of published randomized clinical trials through extensive searches in MEDLINE, EMBASE, and SCOPUS with no date limits, as well as manual review of journals. Outcome measures varied depending on the clinical entity of toxoplasmosis. Risk of bias was evaluated and quality of evidence was graded. Fourteen randomized trials were included of which one was a non-comparative study. One well-designed trial showed that trimethoprim-sulphamethoxazole was more effective than placebo for clinical recovery of toxoplasmic lymphadenopathy in immunocompetent hosts. For toxoplasmic encephalopathy, efficacy of pyrimethamine+sulphadiazine and trimethoprim+sulphamethoxazole were similar, whereas pyrimethamine+sulphadiazine versus pyrimathamine+clindamycin showed no difference, irrespective of the outcome. Intravitreal clindamycin+dexamethasone and conventional treatment with oral pyrimethamine+sulphadiazine had similar efficacy with regard to all outcome measures in ocular toxoplasmosis, and intravitreal therapy was found to be safe. Adverse effects seemed more common with pyrimethamine+sulphadiazine. Most trials for encephalitis and ocular manifestations had a high risk of bias and were of poor methodological quality. There were no trials evaluating drugs for toxoplasmosis in pregnancy, or for congenital toxoplasmosis. Pyrimethamine+sulphadiazine is an effective therapy for treatment of toxoplasmic encephalitis; trimethoprim+sulphamethoxazole and pyrimethamine+clindamycin are possible alternatives. Treatment with either oral or intravitreal antibiotics seems reasonable for ocular toxoplasmosis. Overall, trial evidence for the efficacy of these drugs for toxoplasmosis is poor, and further well-designed trials are needed.

  18. Antibiotics for human toxoplasmosis: a systematic review of randomized trials

    Science.gov (United States)

    Rajapakse, Senaka; Chrishan Shivanthan, Mitrakrishnan; Samaranayake, Nilakshi; Rodrigo, Chaturaka; Deepika Fernando, Sumadhya

    2013-01-01

    The efficacy of different treatment regimens in clinical syndromes of toxoplasmosis were assessed by conducting a systematic review of published randomized clinical trials through extensive searches in MEDLINE, EMBASE, and SCOPUS with no date limits, as well as manual review of journals. Outcome measures varied depending on the clinical entity of toxoplasmosis. Risk of bias was evaluated and quality of evidence was graded. Fourteen randomized trials were included of which one was a non-comparative study. One well-designed trial showed that trimethoprim-sulphamethoxazole was more effective than placebo for clinical recovery of toxoplasmic lymphadenopathy in immunocompetent hosts. For toxoplasmic encephalopathy, efficacy of pyrimethamine+sulphadiazine and trimethoprim+sulphamethoxazole were similar, whereas pyrimethamine+sulphadiazine versus pyrimathamine+clindamycin showed no difference, irrespective of the outcome. Intravitreal clindamycin+dexamethasone and conventional treatment with oral pyrimethamine+sulphadiazine had similar efficacy with regard to all outcome measures in ocular toxoplasmosis, and intravitreal therapy was found to be safe. Adverse effects seemed more common with pyrimethamine+sulphadiazine. Most trials for encephalitis and ocular manifestations had a high risk of bias and were of poor methodological quality. There were no trials evaluating drugs for toxoplasmosis in pregnancy, or for congenital toxoplasmosis. Pyrimethamine+sulphadiazine is an effective therapy for treatment of toxoplasmic encephalitis; trimethoprim+sulphamethoxazole and pyrimethamine+clindamycin are possible alternatives. Treatment with either oral or intravitreal antibiotics seems reasonable for ocular toxoplasmosis. Overall, trial evidence for the efficacy of these drugs for toxoplasmosis is poor, and further well-designed trials are needed. PMID:23816507

  19. Pyrimidines in antimalarial drug design

    CSIR Research Space (South Africa)

    Moleele, SS

    2008-09-01

    Full Text Available .0. Of the initial series of pyrimethamine analogues 3 screened in silico, 3a-c scored well in the docking experiments (Figure 2), with the majority of the compounds scoring better than pyrimethamine 1. In each case, the flexible linker allows for the aromatic... to 1, which is a rigid molecule, is thought to arise from steric clashes with mutant amino acid residues within the PfDHFR active site. In comparison, WR99210 2, which contains a flexible linker between the two rings, maintains binding affinity to all...

  20. Screening for congenital toxoplasmosis: accuracy of immunoglobulin M and immunoglobulin A tests after birth

    DEFF Research Database (Denmark)

    Gilbert, Ruth E; Thalib, Lukman; Tan, Hooi Kuan;

    2007-01-01

    with pyrimethamine-sulphonamide did not significantly reduce IgM or IgA sensitivity. Sensitivity was lowest for the immunofluorescence (IF) IgM test (10%) and the enzyme-linked immunosorbent assay (ELISA) IgM test (29%), but similar for the immunosorbent agglutination assay (ISAGA) IgM (54%), ISAGA IgA (58...

  1. Biguanide-Atovaquone Synergy against Plasmodium falciparum In Vitro

    OpenAIRE

    2002-01-01

    The synergistic potential of a range of biguanides, their triazine metabolites, tetracyclines, and pyrimethamine in combination with atovaquone has been assessed. All five biguanides tested interacted synergistically with atovaquone against Plasmodium falciparum in vitro. All of the other compounds tested were either additive or antagonistic.

  2. Prescription patterns and drug use among pregnant women with febrile illnesses in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Birungi, Josephine; Yanow, Stephanie;

    2013-01-01

    -pyrimethamine (SP) resistance in pregnancy, a sample of pregnant women presenting with fever in out-patient clinics was studied. The main objective was to assess prescription patterns and drug use in pregnancy especially SP; and draw implications on the efficacy of SP for intermittent preventive treatment...

  3. Molecular surveillance of the antifolate-resistant mutation I164L in imported African isolates of Plasmodium falciparum in Europe: sentinel data from TropNetEurop

    DEFF Research Database (Denmark)

    Wichmann, Ole; Jelinek, Tomas; Peyerl-Hoffmann, Gabriele;

    2003-01-01

    BACKGROUND: Malaria parasites that carry the DHFR-mutation I164L are not only highly resistant to sulfadoxine-pyrimethamine but also to the new antimalarial drug chlorproguanil-dapsone. The spread of this mutation in Africa would result in a public health disaster since there is a lack of effective...

  4. Five-year surveillance of molecular markers of Plasmodium falciparum antimalarial drug resistance in Korogwe District, Tanzania: accumulation of the 581G mutation in the em>P. falciparum dihydropteroate synthase gene

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Lusingu, John P; Mmbando, Bruno;

    2009-01-01

    In January 2007, Tanzania replaced sulfadoxine-pyrimethamine (SP) with artemether-lumefantrine for treatment of uncomplicated malaria. This study examined the impact of widespread SP use on molecular markers of Plasmodium falciparum drug resistance in blood samples from persons living in two vill...

  5. Efficacy of artemisinin-based combination therapy for treatment of persons with uncomplicated Plasmodium falciparum malaria in West Sumba District, East Nusa Tenggara Province, Indonesia, and genotypic profiles of the parasite.

    NARCIS (Netherlands)

    Asih, P.B.; Dewi, R.M.; Tuti, S.; Sadikin, M.; Sumarto, W.; Sinaga, B.; Ven, A.J.A.M. van der; Sauerwein, R.W.; Syafruddin, D.

    2009-01-01

    Reports on treatment failures associated with the use of first-and second-line antimalarial drugs chloroquine and sulfadoxine-pyrimethamine have recently increased in many parts of Indonesia. The present study evaluated artemisinin-based combination therapy for treatment of persons with

  6. A modified Plasmodium falciparum growth inhibition assay (GIA) to assess activity of plasma from malaria endemic areas.

    Science.gov (United States)

    Mlambo, Godfree; Kumar, Nirbhay

    2007-02-01

    Plasma samples from patients undergoing treatment in malaria endemic countries often contain anti-malaria drugs, that may overstate effects of specific antibodies in growth inhibition assays (GIA). We describe a modified assay that uses drug resistant P. falciparum parasites (W2) that circumvents the requirement for dialyzing samples that may likely contain drugs such as chloroquine and sulfadoxine/pyrimethamine (SP).

  7. Independent origin of Plasmodium falciparum antifolate super-resistance, Uganda, Tanzania, and Ethiopia

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Nag, Sidsel; Schousboe, Mette L

    2014-01-01

    Super-resistant Plasmodium falciparum threatens the effectiveness of sulfadoxine-pyrimethamine in intermittent preventive treatment for malaria during pregnancy. It is characterized by the A581G Pfdhps mutation on a background of the double-mutant Pfdhps and the triple-mutant Pfdhfr. Using sample...

  8. Distinguishing Plasmodium falciparum treatment failures from re-infections by using polymerase chain reaction genotyping in a holoendemic area in northeastern Tanzania

    DEFF Research Database (Denmark)

    Magesa, S M; Mdira, K Y; Farnert, A

    2001-01-01

    susceptibility to a combination of sulfadoxine/pyrimethamine (Fansidar; F. Hoffmann La Roche, Basel, Switzerland). Blood samples were collected before treatment and on days 7, 14, or 28 post-treatment in 51 asymptomatic children, of which 26 could not clear parasitemia within seven days post-treatment. Among...

  9. Efficacy of artemisinin-based combination therapy for treatment of persons with uncomplicated Plasmodium falciparum malaria in West Sumba District, East Nusa Tenggara Province, Indonesia, and genotypic profiles of the parasite.

    NARCIS (Netherlands)

    Asih, P.B.; Dewi, R.M.; Tuti, S.; Sadikin, M.; Sumarto, W.; Sinaga, B.; Ven, A.J.A.M. van der; Sauerwein, R.W.; Syafruddin, D.

    2009-01-01

    Reports on treatment failures associated with the use of first-and second-line antimalarial drugs chloroquine and sulfadoxine-pyrimethamine have recently increased in many parts of Indonesia. The present study evaluated artemisinin-based combination therapy for treatment of persons with uncomplicate

  10. Treatment of Plasmodium falciparum malaria with mefloquine alone or in combination with i.v. quinine at the Department of Communicable and Tropical Diseases, Rigshospitalet, Copenhagen 1982-1988

    DEFF Research Database (Denmark)

    Magnussen, P; Bygbjerg, Ib Christian

    1990-01-01

    At the Department of Communicable and Tropical Diseases, Rigshospitalet, Denmark, mefloquine has been used since 1982 for the treatment of patients with suspected or verified chloroquine and sulfadoxine-pyrimethamine resistant P. falciparum malaria. Eighty-one patients treated with mefloquine are...

  11. Maloprim malaria prophylaxis in children living in a holoendemic village in north-eastern Tanzania

    DEFF Research Database (Denmark)

    Lemnge, M M; Msangeni, H A; Rønn, A M;

    1997-01-01

    A randomized, double-'blind', placebo-controlled trial of weekly Maloprim (dapsone-pyrimethamine, D-P) for malaria prophylaxis was conducted at Magoda village in north-eastern Tanzania. The effect of D-P on the incidence of clinical malaria, Plasmodium falciparum prevalence and density, splenomeg...

  12. A new strategy and its effect on adherence to intermittent preventive treatment of malaria in pregnancy in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Yanow, Stephanie; Birungi, Josephine;

    2013-01-01

    Few women in Uganda access intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP). Previous studies have shown that high costs, frequent stock-out of drugs, supplies and poor quality of care are the greatest hindrance for women to access health services...

  13. Therapeutic efficacy test in malaria falciparum in Antioquia, Colombia

    Directory of Open Access Journals (Sweden)

    Álvarez Tania

    2006-02-01

    Full Text Available Abstract Objective Evaluate the frequency of failure of eight treatments for non-complicated malaria caused by Plasmodium falciparum in patients from Turbo (Urabá region, El Bagre and Zaragoza (Bajo Cauca region, applying the 1998 protocol of the World Health Organization (WHO. Monotherapies using chloroquine (CQ, amodiaquine (AQ, mefloquine (MQ and sulphadoxine-pyrimethamine (SP, and combinations using chloroquine-sulphadoxine-pyrimethamine (CQ-SP, amodiaquine-sulphadoxine-pyrimethamine (AQ-SP, mefloquine-sulphadoxine-pyrimethamine (MQ-SP and artesunate-sulphadoxine-pyrimethamine (AS-SP, were examined. Methodology A balanced experimental design with eight groups. Samples were selected based on statistical and epidemiological criteria. Patients were followed for 21 to 28 days, including seven or eight parasitological and clinical evaluations, with an active search for defaulting patients. A non-blinded evaluation of the antimalarial treatment response (early failure, late failure, adequate response was performed. Results Initially, the loss of patients to follow-up was higher than 40%, but the immediate active search for the cases and the monetary help for transportation expenses of patients, reduced the loss to 6%. The treatment failure was: CQ 82%, AQ 30%, MQ 4%, SP 24%, CQ-SP 17%, AQ-SP 2%, MQ-S-P 0%, AS-SP 3%. Conclusion The characteristics of an optimal epidemiological monitoring system of antimalarial treatment response in Colombia are discussed. It is proposed to focus this on early failure detection, by applying a screening test every two to three years, based on a seven to 14-day follow-up. Clinical and parasitological assessment would be carried out by a general physician and a field microscopist from the local hospital, with active measures to search for defaulter patients at follow-up.

  14. Susceptibility of Thai isolates of Plasmodium falciparum to artemisinine (qinghaosu) and artemether

    Science.gov (United States)

    Thaithong, Sodsri; Beale, G. H.

    1985-01-01

    Eleven Thai isolates and one West African isolate of Plasmodium falciparum were tested for their susceptibility to the Chinese antimalarial drugs artemisinine (qinghaosu) and artemether. The isolates were cultivated by the Trager—Jensen candle-jar technique and exposed to the action of the drugs for 36-48 hours. Artemisinine inhibited growth of most isolates at 10-7-10-8 mol/litre and artemether at 10-8 mol/litre (with an initial parasitaemia of 0.5-1.0%). Slight variation in the sensitivity of different isolates was found, but there was no correlation between sensitivity to artemisinine or artemether and sensitivity to pyrimethamine, pyrimethamine/sulfadoxine, or chloroquine. The action of artemisinine and artemether was reduced when the initial parasitaemia of the treated cultures was raised. PMID:3899399

  15. [Toxoplasmosis in pregnancy: prevention, prenatal diagnosis and treatment].

    Science.gov (United States)

    Hohlfeld, P; Biedermann, K; Extermann, P; Gyr, T

    1995-01-01

    Maternal infection with Toxoplasma gondii acquired during pregnancy occurs in more than 500 women per year in Switzerland. Systematic screening at the beginning of pregnancy allows the introduction of health education programs. The screening during pregnancy is performed to diagnose primary maternal infections and to propose prenatal diagnosis and treatment. The administration of specific antibiotherapy during pregnancy (spiramycine or the association of pyrimethamine and sulfonamides) significantly reduces the risk of fetal infection. Prenatal diagnosis of congenital toxoplasmosis is possible and reliable. It avoids unnecessary termination of pregnancy when the fetus is not infected and specific therapy in case of infection (association of pyrimethamine and sulfonamides). Prenatal treatment may be proposed without prenatal diagnosis as of the 16th week of gestation. In any case, prenatal treatment seems to reduce the incidence of severe congenital toxoplasmosis.

  16. Molecular diagnosis of resistance to antimalarial drugs during epidemics and in war zones.

    Science.gov (United States)

    Djimdé, Abdoulaye A; Dolo, Amagana; Ouattara, Amed; Diakité, Sira; Plowe, Christopher V; Doumbo, Ogobara K

    2004-08-15

    Plasmodium falciparum mutations pfcrt K76T and the dhfr/dhps "quintuple mutant" are molecular markers of resistance to chloroquine and sulfadoxine-pyrimethamine, respectively. During an epidemic of P. falciparum malaria in an area of political unrest in northern Mali, where standard efficacy studies have been impossible, we measured the prevalence of these markers in a cross-sectional survey. In 80% of cases of infection, pfcrt K76T was detected, but none of the cases carried the dhfr/dhps quintuple mutant. On the basis of these results, chloroquine was replaced by sulfadoxine-pyrimethamine in control efforts. This example illustrates how molecular markers for drug resistance can provide timely data that inform malaria-control policy during epidemics and other emergency situations.

  17. [Mutant alleles associated to chloroquine and sulfadoxine-pyrimethanime resistance in Plasmodium falciparum of the Ecuador-Peru and Ecuador-Colombia borders].

    Science.gov (United States)

    Arróspide, Nancy; Hijar-Guerra, Gisely; de Mora, Doménica; Diaz-Cortéz, César Eduardo; Veloz-Perez, Raúl; Gutierrez, Sonia; Cabezas-Sánchez, César

    2014-04-01

    The frequency of mutations in pfCRT and DHFR/DHPS genes of Plasmodium falciparum associated with resistance to chloroquine and sulfadoxine-pyrimethamine was evaluated in 83 strains from the districts of Esmeralda and Machala, located on the borders of Ecuador-Peru and Ecuador-Colombia in 2002. Polymerase chain reaction (PCR), conventional and its variants, was used. Mutations in the pfCRT gene were found in more than 90% of the samples from Esmeralda and Machala. For the DHFR gene, 90% of the strains were mutant samples from Esmeralda, 3 were double mutations and 1 was a triple mutation. In Machala, 25% were simple mutant forms and 75% mixed mutant forms (wild forms/mutant). In conclusion, resistance to chloroquine has been fixed in strains carrying K76T pfCRT mutation, whereas genetic imprinting for resistance to pyrimethamine is evolving, particularly in the district of Esmeralda.

  18. Evaluation of Chemotherapeutic Agents Against Malaria, Drugs, Diet, and Biological Response Modifiers.

    Science.gov (United States)

    1991-10-29

    observed between WR 238417, the putative biguanide precursor of a triazine (WR 99210), and both sulfadiazine and pyrime- thamine against pyrimethamine...bisquinolines (BM 03821) was more active and less toxic than BL 57511. Synergistic activity was observed between WR 238417, the putative biguanide ...intervals until day 60 postinfection. Survival times were also monitored for this 60 day period. In experiment 680 WR 250417, the putative biguanide

  19. A transgenic Neospora caninum strain based on mutations of the dihydrofolate reductase-thymidylate synthase gene.

    Science.gov (United States)

    Pereira, Luiz Miguel; Baroni, Luciana; Yatsuda, Ana Patrícia

    2014-03-01

    Neospora caninum is an Apicomplexa parasite related to abortion and losses of fertility in cattle. The amenability of Toxoplasma gondii and Plasmodium to genetic manipulation offers several tools to determine the invasion and replication processes, which support posterior strategies related to the combat of these diseases. For Plasmodium the use of pyrimethamine as an auxiliary drug on malaria treatment has been affected by the rise of resistant strains and the analyses on Dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene indicated several point mutations. In this work we developed a method for stable insertion of genes based on resistance to pyrimethamine. For that, the coding sequence of NcDHFR-TS (Dihydrofolate reductase-thymidylate synthase) was point mutated in two amino acids, generating DHFRM2M3. The DHFRM2M3 flanked by the promoter and 3'UTR of Ncdhfr-ts (Ncdhfr-DHFRM2M3) conferred resistance to pyrimethamine after transfection. For illustration of stability and expression, the cassette Ncdhfr-DHFRM2M3 was ligated to the reporter gene Lac-Z (β-galactosidase enzyme) controlled by the N. caninum tubulin promoter and was transfected and selected in N. caninum. The cassette was integrated into the genome and the selected tachyzoites expressed Lac-Z, allowing the detection of tachyzoites by the CPRG reaction and X-gal precipitation. The obtainment of transgenic N. caninum resistant to pyrimethamine confirms the effects on DHFR-TS among the Apicomplexa members and will support future approaches on pholate inhibitors for N. caninum prophylaxis. The construction of stable tachyzoites based on vectors with N. caninum promoters initiates the molecular manipulation of this parasite independently of T. gondii.

  20. Prevalence of Single Nucleotide Polymorphisms in the Plasmodium falciparum Multidrug Resistance Gene (Pfmdr-1) in Korogwe District in Tanzania Before and After Introduction of Artemisinin-Based Combination Therapy

    DEFF Research Database (Denmark)

    Thomsen, Thomas T; Ishengoma, Deus S; Mmbando, Bruno P;

    2011-01-01

    Abstract. Tanzania implemented artemether-lumefantrine (AL) as the first-line treatment for uncomplicated malaria in November of 2006 because of resistance to sulfadoxine-pyrimethamine. AL remains highly efficacious, but widespread use may soon facilitate emergence of artemisinin tolerance/resist.......9). The observed changes may be because of introduction of AL, and if so, this finding gives cause for concern and argues for continued surveillance of these molecular markers....

  1. Functional expression of parasite drug targets and their human orthologs in yeast.

    Directory of Open Access Journals (Sweden)

    Elizabeth Bilsland

    2011-10-01

    Full Text Available BACKGROUND: The exacting nutritional requirements and complicated life cycles of parasites mean that they are not always amenable to high-throughput drug screening using automated procedures. Therefore, we have engineered the yeast Saccharomyces cerevisiae to act as a surrogate for expressing anti-parasitic targets from a range of biomedically important pathogens, to facilitate the rapid identification of new therapeutic agents. METHODOLOGY/PRINCIPAL FINDINGS: Using pyrimethamine/dihydrofolate reductase (DHFR as a model parasite drug/drug target system, we explore the potential of engineered yeast strains (expressing DHFR enzymes from Plasmodium falciparum, P. vivax, Homo sapiens, Schistosoma mansoni, Leishmania major, Trypanosoma brucei and T. cruzi to exhibit appropriate differential sensitivity to pyrimethamine. Here, we demonstrate that yeast strains (lacking the major drug efflux pump, Pdr5p expressing yeast ((ScDFR1, human ((HsDHFR, Schistosoma ((SmDHFR, and Trypanosoma ((TbDHFR and (TcDHFR DHFRs are insensitive to pyrimethamine treatment, whereas yeast strains producing Plasmodium ((PfDHFR and (PvDHFR DHFRs are hypersensitive. Reassuringly, yeast strains expressing field-verified, drug-resistant mutants of P. falciparum DHFR ((Pfdhfr(51I,59R,108N are completely insensitive to pyrimethamine, further validating our approach to drug screening. We further show the versatility of the approach by replacing yeast essential genes with other potential drug targets, namely phosphoglycerate kinases (PGKs and N-myristoyl transferases (NMTs. CONCLUSIONS/SIGNIFICANCE: We have generated a number of yeast strains that can be successfully harnessed for the rapid and selective identification of urgently needed anti-parasitic agents.

  2. Cardiac toxoplasmosis after heart transplantation diagnosed by endomyocardial biopsy.

    Science.gov (United States)

    Petty, L A; Qamar, S; Ananthanarayanan, V; Husain, A N; Murks, C; Potter, L; Kim, G; Pursell, K; Fedson, S

    2015-10-01

    We describe a case of cardiac toxoplasmosis diagnosed by routine endomyocardial biopsy in a patient with trimethoprim-sulfamethoxazole (TMP-SMX) intolerance on atovaquone prophylaxis. Data are not available on the efficacy of atovaquone as Toxoplasma gondii prophylaxis after heart transplantation. In heart transplant patients in whom TMP-SMX is not an option, other strategies may be considered, including the addition of pyrimethamine to atovaquone.

  3. Editing the Plasmodium vivax Genome, Using Zinc-Finger Nucleases

    OpenAIRE

    Moraes Barros, Roberto R.; Straimer, Judith; Sa, Juliana M; Salzman, Rebecca E.; Melendez-Muniz, Viviana A.; Mu, Jianbing; David A Fidock; Thomas E. Wellems

    2014-01-01

    Plasmodium vivax is a major cause of malaria morbidity worldwide yet has remained genetically intractable. To stably modify this organism, we used zinc-finger nucleases (ZFNs), which take advantage of homology-directed DNA repair mechanisms at the site of nuclease action. Using ZFNs specific to the gene encoding P. vivax dihydrofolate reductase (pvdhfr), we transfected blood specimens from Saimiri boliviensis monkeys infected with the pyrimethamine (Pyr)–susceptible Chesson strain with a ZFN ...

  4. Adherence of community caretakers of children to pre-packaged antimalarial medicines (HOMAPAK®) among internally displaced people in Gulu district, Uganda

    OpenAIRE

    Jan H Kolaczinski; Ojok, Naptalis; Opwonya, John; Meek, Sylvia; Collins, Andrew

    2006-01-01

    Abstract Background In 2002, home-based management of fever (HBMF) was introduced in Uganda, to improve access to prompt, effective antimalarial treatment of all fevers in children under 5 years. Implementation is through community drug distributors (CDDs) who distribute pre-packaged chloroquine plus sulfadoxine-pyrimethamine (HOMAPAK®) free of charge to caretakers of febrile children. Adherence of caretakers to this regimen has not been studied. Methods A questionnaire-based survey combined ...

  5. In vivo assessment of antimicrobial agents against Toxoplasma gondii by quantification of parasites in the blood, lungs, and brain of infected mice.

    Science.gov (United States)

    Piketty, C; Derouin, F; Rouveix, B; Pocidalo, J J

    1990-01-01

    The in vivo effects of antimicrobial agents against Toxoplasma gondii were evaluated in mice that were infected intraperitoneally with 10(4) tachyzoites of the RH strain by determination of survival rates and study of the kinetics of growth of T. gondii in infected mice. At various intervals after infection, subcultures of serial dilutions of blood, lung, and brain homogenates were performed in fibroblast tissue cultures for determination of parasitic loads. Pyrimethamine (18.5 mg/kg per day), sulfadiazine (375 mg/kg per day), and clindamycin (300 mg/kg per day) were administered for 10 days from day 1 or day 4 after infection. Untreated control mice died within 9 days and showed early and predominant lung involvement. All mice treated with sulfadiazine administered from day 1 survived and were apparently healthy; parasitic loads decreased early after treatment, but a relapse was observed 5 days after the cessation of therapy. When pyrimethamine was administered from day 1, 7 of 11 mice died within 25 days; by determination of parasitic loads, the effect of pyrimethamine was only demonstrable from day 6, and a relapse was constantly observed after the cessation of therapy. When pyrimethamine and sulfadiazine were administered in combination, 100% of mice survived; when therapy was started at day 1, parasites remained undetectable; in mice treated from day 4, parasites were eradicated by day 8 but infection relapsed 8 days after the cessation of therapy. All mice treated with clindamycin from day 1 or day 4 died within 10 days, but parasitemia was always undetectable. These results indicate that study of the kinetics of parasitic loads in blood and organs may provide additional information on the effect of antimicrobial agents against T. gondii in regard to the evolution of the infection and may represent a reliable basis for the determination of therapeutic regimens in humans. PMID:2221854

  6. Treatment of Plasmodium falciparum malaria with mefloquine alone or in combination with i.v. quinine at the Department of Communicable and Tropical Diseases, Rigshospitalet, Copenhagen 1982-1988

    DEFF Research Database (Denmark)

    Magnussen, P; Bygbjerg, Ib Christian

    1990-01-01

    At the Department of Communicable and Tropical Diseases, Rigshospitalet, Denmark, mefloquine has been used since 1982 for the treatment of patients with suspected or verified chloroquine and sulfadoxine-pyrimethamine resistant P. falciparum malaria. Eighty-one patients treated with mefloquine...... and effective for the treatment of P. falciparum malaria and is recommended for treatment of worldwide acquired P. falciparum malaria, although patients should be monitored closely to disclose resistance....

  7. In vitro antiplasmodial activity of extracts of Argentinian plants.

    Science.gov (United States)

    Debenedetti, S; Muschietti, L; van Baren, C; Clavin, M; Broussalis, A; Martino, V; Houghton, P J; Warhurst, D; Steele, J

    2002-05-01

    Fifteen extracts from nine selected Argentine medicinal plants were tested for their antiplasmodial activity in vitro by assessing their ability to inhibit the uptake of [3H]-hypoxanthine into the Plasmodium falciparum K1 pyrimethamine/chloroquine resistant strain. The methanol extract of Satureja parvifolia showed good antiplasmodial activity (IC(50) 3 microg/ml). Inhibition of the growth of P. falciparum was also observed with aqueous extracts of Buddleja globosa and S. parvifolia.

  8. Off-patent drugs at brand-name prices: a puzzle for policymakers

    OpenAIRE

    Tallapragada, Naren P.

    2016-01-01

    In August 2015, Turing Pharmaceuticals acquired the marketing rights to Daraprim (pyrimethamine), a drug used to treat parasitic infections like malaria and toxoplasmosis. Soon after, Turing caused an uproar when it announced that it would raise the price per tablet of Daraprim from \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\...

  9. EFFECT OF IMMUNOMODULATOR DARAPRIM ON POTENTIATION OF VACCINE PROTECTION OF LEISHMANIA MAJOR IN BALB/c MICE

    OpenAIRE

    M. Keshavarzi; Z.M. Hassan

    2003-01-01

    In this study, a crude leishmanial antigen, was prepared by sonicating Leishmania major promastigotes used to induce immunity in BALB/c mice against cutaneous leishmaniasis. Correlation between the route of antigen injection and the efficacy of induced protection was examined. To enhance the effectiveness of the antigen, an immunostimulant drug, daraprim (pyrimethamine), was administered simultaneously with the antigen. The experiment demonstrated that simultaneous intraperitoneal injection o...

  10. Tracking Origins and Spread of Sulfadoxine-Resistant Plasmodium falciparum dhps Alleles in Thailand▿

    OpenAIRE

    Alam, Md Tauqeer; Vinayak, Sumiti; Congpuong, Kanungnit; Wongsrichanalai, Chansuda; Satimai, Wichai; Slutsker, Laurence; Escalante, Ananias A.; Barnwell, John W.; Udhayakumar, Venkatachalam

    2010-01-01

    The emergence and spread of drug-resistant Plasmodium falciparum have been a major impediment for the control of malaria worldwide. Earlier studies have shown that similar to chloroquine (CQ) resistance, high levels of pyrimethamine resistance in P. falciparum originated independently 4 to 5 times globally, including one origin at the Thailand-Cambodia border. In this study we describe the origins and spread of sulfadoxine-resistance-conferring dihydropteroate synthase (dhps) alleles in Thail...

  11. High prevalence of drug-resistance mutations in Plasmodium falciparum and Plasmodium vivax in southern Ethiopia

    OpenAIRE

    Schunk, Mirjam; Kumma, Wondimagegn P.; Barreto Miranda, Isabel; Maha E. Osman; Roewer, Susanne; Alano, Abraham; Loescher, Thomas; Bienzle, Ulrich; Mockenhaupt, Frank P

    2006-01-01

    Background: In Ethiopia, malaria is caused by both Plasmodium falciparum and Plasmodium vivax. Drug resistance of P. falciparum to sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) is frequent and intense in some areas. Methods: In 100 patients with uncomplicated malaria from Dilla, southern Ethiopia, P. falciparum dhfr and dhps mutations as well as P. vivax dhfr polymorphisms associated with resistance to SP and P. falciparum pfcrt and pfmdr1 mutations conferring CQ resistance were assesse...

  12. Antimalarial drug prescribing practice in private and public health facilities in South-east Nigeria: a descriptive study

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    Okebe Joseph

    2007-05-01

    Full Text Available Abstract Background Nigeria's national standard has recently moved to artemisinin combination treatments for malaria. As clinicians in the private sector are responsible for attending a large proportion of the population ill with malaria, this study compared prescribing in the private and public sector in one State in Nigeria prior to promoting ACTs. Objective To assess prescribing for uncomplicated malaria in government and private health facilities in Cross River State. Method Audit of 665 patient records at six private and seven government health facilities in 2003. Results Clinicians in the private sector were less likely to record history or physical examination than those in public facilities, but otherwise practice and prescribing were similar. Overall, 45% of patients had a diagnostic blood slides; 77% were prescribed monotherapy, either chloroquine (30.2%, sulphadoxine-pyrimethamine (22.7% or artemisinin derivatives alone (15.8%. Some 20.8% were prescribed combination therapy; the commonest was chloroquine with sulphadoxine-pyrimethamine. A few patients (3.5% were prescribed sulphadoxine-pyrimethamine-mefloquine in the private sector, and only 3.0% patients were prescribed artemisinin combination treatments. Conclusion Malaria treatments were varied, but there were not large differences between the public and private sector. Very few are following current WHO guidelines. Monotherapy with artemisinin derivatives is relatively common.

  13. Malaria prevention in travellers from the United Kingdom. Report of meetings convened by the Ross Institute.

    Science.gov (United States)

    1981-01-01

    Malaria prophylaxis is relative, not absolute, but can provide much protection. Travellers must take prophylactics regularly while in malarious areas and for one month thereafter; despite doing so, they may still develop malaria. For areas without chloroquine-resistant malaria, chloroquine, 300 mg base weekly, or proguanil, 100-200 mg daily, are preferred. In areas of chloroquine sensitivity there may be places with resistance to proguanil and pyrimethamine, but these places are not delineated. The risk of breakthrough of malaria is, therefore, least with chloroquine, but problems of potential side effects and regular medication are fewer with proguanil than chloroquine. Proguanil is preferred for long-term prophylaxis. Malaria poses a greater hazard for pregnant women and infants than do prophylactics. Pyrimethamine/sulphadoxine (Fansidar) or pyrimethamine/diaminodiphenyl sulphone (maloprim) are the preferred drugs for areas with prevalent chloroquine-resistant plasmodium falciparum. Fansidar is taken once a week and Maloprim also is usually recommended to be taken once a week. PMID:6789972

  14. Further antiplasmodial effects of the aqueous extract of cym-bopogon citratus stapf (lemon grass) against plasmodium berghei in Swiss albino mice

    Institute of Scientific and Technical Information of China (English)

    DV Dapper; IMSiminialayi; OO Ebong

    2008-01-01

    Lemon grass (Cymbopogon citratus Stapf)is a popular alternative to western medicines for a number of condi-tions,including fevers,muscle soreness and superficial infections in Nigeria.In addition to its already reported suppressive effects against P.berghei infection,this study sought to determine its repository and blood schizon-ticidal activities in established P.berghei infection using Swiss albino mice as models.Mice weighing on aver-age,between 15 and 25g were given 103mg/kg,155mg/kg and 310mg/kg/day of the crude aqueous extract of cymbopogon citratus stapf,in the 4-day test,24-hour Rane test and 72-hour Rane test.The effects of these do-ses of the extract were then compared with chloroquine (5mg/kg/day)and sulphadoxine /pyrimethamine (3mg/kg/day).We report an average percentage suppressive repository activity of 65.8% for the extract at a dose of 310mg/kg and a blood schizonticidal activity that increased from 68.33% in the 24-hour Rane test to 92% in the 72-hour Rane test for the same dose of extract.The crude aqueous extract of C.citratus stapf thus has significant repository and blood schizonticidal activities against established P.berghei infection in Swiss al-bino mice compare to that of pyrimethamine and sulphadoxine /pyrimethamine respectively.

  15. Successful Treatment of Cerebral Toxoplasmosis with Clindamycin: A Case Report

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    Deepak Madi

    2012-09-01

    Full Text Available Toxoplasmosis is caused by infection with the obligate intracellular parasite Toxoplasma gondii. Toxoplasmosis is generally a late complication of HIV infection and usually occurs in patients with CD4 + T-cell counts below 200/μl. Co-trimoxazole (trimethoprim plus sulfamethoxazole is the most common drug used in India for the treatment of AIDS-associated cerebral toxoplasmosis. Other alternative drugs used for the treatment of cerebral toxoplasmosis are clindamycin plus pyrimethamine and clarithromycin with pyrimethamine.A 30-year-old male known case of retroviral disease presented to Kasturba Medical College, India, with complaints of fever, headache and vomiting. Computed tomography scan of his brain showed irregular ring enhancing lesion in the right basal ganglia. Toxoplasma serology revealed raised IgG antibody levels. Based on the CT features and serology, diagnosis of cerebral toxoplasmosis was made. He was treated with clindamycin alone as he had historyof sulfonamide allergy. The patient was symptomatically better after 48 hours. After 21 days, repeat CT of brain was done which was normal. The patient showed good clinical improvement within 48 hours and the lesion resolved completely within 3 weeks. The authors recommend using clindamycin without pyrimethamine in resource poor settings and in patients who do not tolerate sulfa drugs.

  16. Treatment of falciparum malaria in the age of drug resistance

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    Shanks G

    2006-01-01

    Full Text Available The growing problem of drug resistance has greatly complicated the treatment for falciparum malaria. Whereaschloroquine and sulfadoxine/pyrimethamine could once cure most infections, this is no longer true and requiresexamination of alternative regimens. Not all treatment failures are drug resistant and other issues such asexpired antimalarials and patient compliance need to be considered. Continuation of a failing treatment policyafter drug resistance is established suppresses infections rather than curing them, leading to increasedtransmission of malaria, promotion of epidemics and loss of public confidence in malaria control programs.Antifolate drug resistance (i.e. pyrimethamine means that new combinations are urgently needed particularlybecause addition of a single drug to an already failing regimen is rarely effective for very long. Atovaquone/proguanil and mefloquine have been used against multiple drug resistant falciparum malaria with resistance toeach having been documented soon after drug introduction. Drug combinations delay further transmission ofresistant parasites by increasing cure rates and inhibiting formation of gametocytes. Most currentlyrecommended drug combinations for falciparum malaria are variants of artemisinin combination therapy wherea rapidly acting artemisinin compound is combined with a longer half-life drug of a different class. Artemisininsused include dihydroartemisinin, artesunate, artemether and companion drugs include mefloquine, amodiaquine,sulfadoxine/pyrimethamine, lumefantrine, piperaquine, pyronaridine, chlorproguanil/dapsone. The standard ofcare must be to cure malaria by killing the last parasite. Combination antimalarial treatment is vital not only tothe successful treatment of individual patients but also for public health control of malaria.

  17. Claritromicina associada com pirímetamina na toxoplasmose cerebral - relato de dois casos

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    Marcos Olivicr Dalston

    1995-12-01

    Full Text Available Os autores relatam a resposta terapêutica da claritromicina associada com pirímetamina em dois casos de toxoplasmose cerebral ocorridos em pacientes com Síndrome de Imunodeficiência Adquirida (SIDA. Nos dois casos o diagnóstico foi presuntivo, baseando-se nas manifestações clínicas e na presença de lesões expansivas hipercaptantes detectadas na tomografia computadorizada (TC de crânio. Em ambos os casos, observou-se exantema com o uso da sulfadiazina e da clindamicina, razão pela qual tais medicamentos foram substituídos pela claritromicina (1,5 a 2g/dia associada à pirímetamina (25mg/dia. A resposta terapêutica foi favorável nos dois casos com melhora das manifestações neurológicas e dos achados neurorradiológicos. Os autores sugerem que a associação claritromicina com pirímetamina pode ser útil como opção terapêutica na toxoplasmose cerebral em pacientes com SIDA que apresentam intolerância ou outra contra-indicação ao emprego das sulfonamidas.The authors report the use and tbe outcome of claritromycin associated with pyrimethamine in the treatment of toxoplasma encephalites in two patients with AIDS. Both patients had the diagnosis stablished on clinical grounds, positive sorology (IgG for toxoplasmosis and computed-tomographic (CT scan of the brain showing lesions consistent with T. gondii encephalitis. The two patients were initially treated with pyrimethamine and sulfadiazme, which was changed to clindamycin due to allergic reactions. These reactions (skin rash occurred with clindamycin as well and the patients were treated with claritromycin and pyrimethamine. The scheduled regimens were 1.5 to 2g of clarithromycin plus 25mg of pyrimethamine. The clinical response was very good in both cases with regression of neurologic signs and encephalitic abnormalities observed on CT scan. The authors suggest that clarithromycin associated with pyrimethamine may be an alternative treatment for toxoplasmosis in AIDS

  18. In vitro action of antiparasitic drugs, especially artesunate, against Toxoplasma gondii

    Directory of Open Access Journals (Sweden)

    Thaís Cobellis Gomes

    2012-08-01

    Full Text Available INTRODUCTION: Toxoplasmosis is usually a benign infection, except in the event of ocular, central nervous system (CNS, or congenital disease and particularly when the patient is immunocompromised. Treatment consists of drugs that frequently cause adverse effects; thus, newer, more effective drugs are needed. In this study, the possible activity of artesunate, a drug successfully being used for the treatment of malaria, on Toxoplasma gondii growth in cell culture is evaluated and compared with the action of drugs that are already being used against this parasite. METHODS: LLC-MK2 cells were cultivated in RPMI medium, kept in disposable plastic bottles, and incubated at 36ºC with 5% CO2. Tachyzoites of the RH strain were used. The following drugs were tested: artesunate, cotrimoxazole, pentamidine, pyrimethamine, quinine, and trimethoprim. The effects of these drugs on tachyzoites and LLC-MK2 cells were analyzed using nonlinear regression analysis with Prism 3.0 software. RESULTS: Artesunate showed a mean tachyzoite inhibitory concentration (IC50 of 0.075µM and an LLC MK2 toxicity of 2.003µM. Pyrimethamine was effective at an IC50 of 0.482µM and a toxicity of 11.178µM. Trimethoprim alone was effective against the in vitro parasite. Cotrimoxazole also was effective against the parasite but at higher concentrations than those observed for artesunate and pyrimethamine. Pentamidine and quinine had no inhibitory effect over tachyzoites. CONCLUSIONS: Artesunate is proven in vitro to be a useful alternative for the treatment of toxoplasmosis, implying a subsequent in vivo effect and suggesting the mechanism of this drug against the parasite.

  19. Monitoring the drug-sensitivity of Plasmodium falciparum in coastal towns in Madagascar by use of in vitro chemosensitivity and mutation detection tests

    Directory of Open Access Journals (Sweden)

    Rason M.A.

    2002-09-01

    Full Text Available The dissemination of mutant and resistant strains of Plasmodium falciparum makes a considerable contribution to the spread of drug-resistant malaria. Populations around harbours and airports could be particularly exposed to Plasmodium isolates introduced with imported cases of malaria. The use of chloroquine as well as the use of and sulfadoxine/pyrimethamine is currently an effective method for treating uncomplicated cases of malaria in Madagascar. As part of a monitoring programme, in vitro methods were used to assess the sensitivity of P. falciparum isolates in two coastal towns in Madagascar: Mahajanga on the west coast and Toamasina on the east coast. All of the isolates from both sites were sensitive to amodiaquine, quinine, pyrimethamine and cycloguanil. All of the isolates from Mahajanga were sensitive to chloroquine (n = 25; mean IC50 = 22.6 nM, 95 % confidence interval: 16.8-28.7 nM, whereas three of the isolates from Toamasina were resistant to chloroquine (n = 18; mean IC50 = 66.3 nM; 95 % confidence interval : 42.6-90 nM, The frequency of the Pfcrt Thr-76 and the dhfr Asn- 108 mutations was estimated by PCR/RFLP. The 43 P. falciparum isolates examined, including the three in vitro chloroquine-resistant isolates from Toamasina were all wild-type (Lys-76. Phenotyping and genotyping studies suggested that the prevalence of chloroquine- and pyrimethamine-resistant isolates and of mutant strains of P. falciparum is very low. These results showed that in vitro test and genotyping of resistance markers approaches could be successfully used to monitor the emergence of drug-resistant malaria and to try to alleviate the lack of medical teams able to carry out in vivo test. The possible hazard/risk associated with imported cases of malaria is discussed.

  20. Brands, costs and registration status of antimalarial drugs in the Kenyan retail sector

    Directory of Open Access Journals (Sweden)

    Snow Robert W

    2005-07-01

    Full Text Available Abstract Background Although an important source of treatment for fevers, little is known about the structure of the retail sector in Africa with regard to antimalarial drugs. This study aimed to assess the range, costs, sources and registration of antimalarial drugs in the Kenyan retail sector. Methods In 2002, antimalarial drug registration and trade prices were established by triangulating national registration lists, government gazettes and trade price indices. Data on registration status and trade prices were compared with similar data generated through a retail audit undertaken among 880 randomly sampled retailers in four districts of Kenya. Results Two hundred and eighteen antimalarial drugs were in circulation in Kenya in 2002. These included 65 "sulfur"-pyrimethamine (sulfadoxine-pyrimethamine and sulfalene-pyrimethamine (SP, the first-line recommended drug in 2002 and 33 amodiaquine (AQ, the second-line recommended drug preparations. Only half of SP and AQ products were registered with the Pharmacy and Poisons Board. Of SP and AQ brands at district level, 40% and 44% were officially within legal registration requirements. 29% of retailers at district level stocked SP and 95% stocked AQ. The retail price of adult doses of SP and AQ were on average 0.38 and 0.76 US dollars, 100% and 347% higher than trade prices from manufacturers and importers. Artemether-lumefantrine, the newly announced first-line recommended antimalarial drug in 2004, was found in less than 1% of all retail outlets at a median cost of 7.6 US dollars. Conclusion There is a need to ensure that all antimalarial drugs are registered with the Pharmacy and Poisons Board to facilitate a more stringent post-marketing surveillance system to ensure drugs are safe and of good quality post-registration.

  1. The quality of antimalarials available in Yemen.

    Science.gov (United States)

    Abdo-Rabbo, Ahmed; Bassili, Amal; Atta, Hoda

    2005-06-29

    Malaria has always been a major public health problem in Yemen. Several studies in developing countries have demonstrated ineffective and poor quality drugs including antimalarials. Therefore, quality assessment of antimalarial drugs is of crucial importance. This study aimed to assess the quality of antimalarials (chloroquine and sulfadoxine/pyrimethamine) available in Yemen and to determine whether the quality of these products was related to the level of the distribution chain at which the samples were collected or related to the manufacturers. Four samples from each antimalarial product were collected from each of the various levels of the distribution chain. One sample was kept with the research team. Two were tested at Sana'a and Aden Drug Quality Control Laboratories. The fourth was sent to the Centre for Quality Assurance of Medicines in Potchefstroom, South Africa, for analysis. Quality indicators measured were the content of the active ingredient and dissolution rate (for tablets only) in comparison to standard specifications for these products in the relevant pharmacopoeia. The results identified several problems of sub-standard products within the drug distribution chain. They included high and low failures in ingredient content for chloroquine tablets and chloroquine syrup. There was some dissolution failure for chloroquine tablets, and high sulfadoxine/pyrimethamine tablets dissolution failures. Failures with the dissolution of the pyrimethamine were found at most of the collection points. No clear relationship neither between the quality products and the level of the distribution chain, nor between locally manufactured and imported products was observed. There are sub-standard antimalarial products circulating within the drug distribution chains in the country, which will have serious implications on the reduced therapeutic effectiveness and on the development of drug resistance. This appears to be due to non-compliance with Good Manufacturing

  2. Dihydrofolate-Reductase Mutations in Plasmodium knowlesi Appear Unrelated to Selective Drug Pressure from Putative Human-To-Human Transmission in Sabah, Malaysia.

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    Matthew J Grigg

    Full Text Available Malaria caused by zoonotic Plasmodium knowlesi is an emerging threat in Eastern Malaysia. Despite demonstrated vector competency, it is unknown whether human-to-human (H-H transmission is occurring naturally. We sought evidence of drug selection pressure from the antimalarial sulfadoxine-pyrimethamine (SP as a potential marker of H-H transmission.The P. knowlesi dihdyrofolate-reductase (pkdhfr gene was sequenced from 449 P. knowlesi malaria cases from Sabah (Malaysian Borneo and genotypes evaluated for association with clinical and epidemiological factors. Homology modelling using the pvdhfr template was used to assess the effect of pkdhfr mutations on the pyrimethamine binding pocket.Fourteen non-synonymous mutations were detected, with the most common being at codon T91P (10.2% and R34L (10.0%, resulting in 21 different genotypes, including the wild-type, 14 single mutants, and six double mutants. One third of the P. knowlesi infections were with pkdhfr mutants; 145 (32% patients had single mutants and 14 (3% had double-mutants. In contrast, among the 47 P. falciparum isolates sequenced, three pfdhfr genotypes were found, with the double mutant 108N+59R being fixed and the triple mutants 108N+59R+51I and 108N+59R+164L occurring with frequencies of 4% and 8%, respectively. Two non-random spatio-temporal clusters were identified with pkdhfr genotypes. There was no association between pkdhfr mutations and hyperparasitaemia or malaria severity, both hypothesized to be indicators of H-H transmission. The orthologous loci associated with resistance in P. falciparum were not mutated in pkdhfr. Subsequent homology modelling of pkdhfr revealed gene loci 13, 53, 120, and 173 as being critical for pyrimethamine binding, however, there were no mutations at these sites among the 449 P. knowlesi isolates.Although moderate diversity was observed in pkdhfr in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans.

  3. The quality of antimalarials available in Yemen

    Directory of Open Access Journals (Sweden)

    Atta Hoda

    2005-06-01

    Full Text Available Abstract Background Malaria has always been a major public health problem in Yemen. Several studies in developing countries have demonstrated ineffective and poor quality drugs including antimalarials. Therefore, quality assessment of antimalarial drugs is of crucial importance. This study aimed to assess the quality of antimalarials (chloroquine and sulfadoxine/pyrimethamine available in Yemen and to determine whether the quality of these products was related to the level of the distribution chain at which the samples were collected or related to the manufacturers. Methods Four samples from each antimalarial product were collected from each of the various levels of the distribution chain. One sample was kept with the research team. Two were tested at Sana'a and Aden Drug Quality Control Laboratories. The fourth was sent to the Centre for Quality Assurance of Medicines in Potchefstroom, South Africa, for analysis. Quality indicators measured were the content of the active ingredient and dissolution rate (for tablets only in comparison to standard specifications for these products in the relevant pharmacopoeia. Results The results identified several problems of sub-standard products within the drug distribution chain. They included high and low failures in ingredient content for chloroquine tablets and chloroquine syrup. There was some dissolution failure for chloroquine tablets, and high sulfadoxine/pyrimethamine tablets dissolution failures. Failures with the dissolution of the pyrimethamine were found at most of the collection points. No clear relationship neither between the quality products and the level of the distribution chain, nor between locally manufactured and imported products was observed. Conclusion There are sub-standard antimalarial products circulating within the drug distribution chains in the country, which will have serious implications on the reduced therapeutic effectiveness and on the development of drug resistance. This

  4. Multiple origins of Plasmodium falciparum dihydropteroate synthetase mutant alleles associated with sulfadoxine resistance in India.

    Science.gov (United States)

    Lumb, Vanshika; Das, Manoj K; Singh, Neeru; Dev, Vas; Khan, Wajihullah; Sharma, Yagya D

    2011-06-01

    With the spread of chloroquine (CQ)-resistant malaria in India, sulfadoxine-pyrimethamine (SP) alone or in combination with artesunate is used as an alternative antimalarial drug. Due to continuous drug pressure, the Plasmodium falciparum parasite is exhibiting resistance to antifolates because of mutations in candidate genes dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps). Our earlier study on flanking microsatellite markers of dhfr mutant alleles from India had shown a single origin of the pyrimethamine resistance and some minor haplotypes which shared haplotypes with Southeast Asian (Thailand) strains. In the present study, we have analyzed 193 of these Indian P. falciparum isolates for 15 microsatellite loci around dhps to investigate the genetic lineages of the mutant dhps alleles in different parts of the country. Eighty-one of these samples had mutant dhps alleles, of which 62 were from Andaman and Nicobar Islands and the remaining 19 were from mainland India. Of 112 isolates with a wild-type dhps allele, 109 were from mainland India and only 3 were from Andaman and Nicobar Islands. Consistent with the model of selection, the mean expected heterozygosity (H(e)) around mutant dhps alleles (H(e) = 0.55; n = 81) associated with sulfadoxine resistance was lower (P ≤ 0.05) than the mean H(e) around the wild-type dhps allele (H(e) = 0.80; n = 112). There was more genetic diversity in flanking microsatellites of dhps than dhfr among these isolates, which confirms the assertion that dhps mutations are at a very early stage of fixation in the parasite population. Microsatellite haplotypes around various mutant dhps alleles suggest that the resistant dhps alleles have multiple independent origins in India, especially in Andaman and Nicobar Islands. Determining the genetic lineages of the resistant dhps alleles on Andaman and Nicobar Islands and mainland India is significant, given the role of Asia in the intercontinental spread of chloroquine

  5. Monitoring antifolate resistance in intermittent preventive therapy for malaria

    DEFF Research Database (Denmark)

    Venkatesan, Meera; Alifrangis, Michael; Roper, Cally;

    2013-01-01

    Mutations in the Plasmodium falciparum genes Pfdhfr and Pfdhps have rendered sulfadoxine-pyrimethamine (SP) ineffective for malaria treatment in most regions of the world. Yet, SP is efficacious as intermittent preventive therapy in pregnant women (IPTp) and infants (IPTi) and as seasonal malaria...... control in children (SMC). SP-IPTp is being widely implemented in sub-Saharan Africa. SP-IPTi is recommended where the prevalence of SP-resistant malaria parasites is low, whereas SMC is recommended for areas of intense seasonal malaria transmission. The continuing success of these interventions depends...

  6. Recent acquisitions on chemotherapy and chemoprophylaxis of malaria.

    Science.gov (United States)

    Onori, E; Majori, G

    1989-01-01

    The most recent acquisitions on chemotherapy and chemoprophylaxis of malaria are reviewed. With regard to chemotherapy, candidate antimalarial compounds have been divided into four groups, according to their stages of development. Mefloquine and the combination of mefloquine with sulfadoxine/pyrimethamine belong to the first group: they have completed clinical trials and have been registered in several countries for routine clinical use. The second group is characterized by chemical compounds which are in an advanced stage of development, including clinical trials. The compounds considered in this group are: a) the 9-phenanthrenemethanols, among which halofantrine is the most promising one; b) the sesquiterpene lactones such as Qinghaosu, artemether, artesunate, artesunic acid and arteether which must be further tested in order to find more effective drug regimens capable of eliminating recrudescences and for the completion of toxicity studies; c) pyronaridine, which appears to be a promising antimalarial, effective also against chloroquine-resistant P. falciparum, but still requiring further investigations on resistance and cross-resistance, as well as its pharmacokinetics, tolerability and bioavailability; d) enpiroline, another promising compound, which needs to be further studied in Phase II and Phase III investigations with naturally acquired malaria. The third group is composed of seven chemical classes of compounds that are in an advanced pre-clinical development, namely: the 4-aminoquinolines, such as dabechin, piperaquine, hydroxypiperaquine, tripiperaquine, dichlor-quinazine and the Mannich base compounds, the 8-aminoquinolines, the 4-quinolinemethanols, the quinolones, the naphthoquinones, the quinazolines and the dihydrotriazines. Among the many antimalarial compounds of interest, which can be considered at the moment as leads for further studies, only the acridandione derivatives such as floxacrine, the antibiotics, antifungal agents or their

  7. The implication of dihydrofolate reductase and dihydropteroate synthetase gene mutations in modification of Plasmodium falciparum characteristics

    DEFF Research Database (Denmark)

    A-Elbasit, Ishraga E; Alifrangis, Michael; Khalil, Insaf F

    2007-01-01

    the effects of dhfr/dhps mutations on parasite characteristics other than SP resistance. METHOD: Parasite infections obtained from 153 Sudanese patients with uncomplicated falciparum malaria treated with SP or SP + chloroquine, were successfully genotyped at nine codons in the dhfr/dhps genes by PCR......BACKGROUND: The Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) are enzymes of central importance in parasite metabolism. The dhfr and dhps gene mutations are known to be associated with sulphadoxine/pyrimethamine (SP) resistance. OBJECTIVE: To investigate...

  8. Effect of oral proguanil on human lymphocyte proliferation

    DEFF Research Database (Denmark)

    Bygbjerg, Ib Christian; Flachs, H

    1986-01-01

    In vitro studies have indicated that the antifolates pyrimethamine [4, 6] and cycloguanil (the active metabolite of proguanil) suppress the proliferation of stimulated human lymphocytes; proguanil has no effect [2]. During the early growth phase of the cells, 14C-thymidine (14C-TdR) incorporation...... on human lymphocytes, the present study was undertaken. Little information is available about the serum levels of proguanil and cycloguanil following ingestion of prophylactic doses [8]. Therefore, the serum concentrations of proguanil and cycloguanil were estimated, to allow comparison with previous...

  9. The influence of Maloprim chemoprophylaxis on cellular and humoral immune responses to Plasmodium falciparum asexual blood stage antigens in schoolchildren living in a malaria endemic area of Mozambique

    DEFF Research Database (Denmark)

    Hogh, B; Thompson, R; Lobo, V;

    1994-01-01

    antigens. The study was carried out in the Escola Primária de Lingamo, a primary school in a suburban area of Maputo, Mozambique. A cohort of 392 schoolchildren (aged 7-12 years) was randomly allocated to two equal groups, one receiving chemoprophylaxis with dapsone/pyrimethamine (Maloprim), the other...... assays in vitro. Anti-GLURP and anti-Pf155/RESA antibodies were detected by enzyme-linked immunosorbent assay (ELISA) and erythrocyte membrane immunofluorescence (EMIF), and total anti-P. falciparum antibodies were measured by indirect fluorescent antibody test (IFAT). Immunological reactivities were...

  10. Transgenic Plasmodium parasites stably expressing Plasmodium vivax dihydrofolate reductase-thymidylate synthase as in vitro and in vivo models for antifolate screening

    Directory of Open Access Journals (Sweden)

    Yuthavong Yongyuth

    2011-10-01

    Full Text Available Abstract Background Plasmodium vivax is the most prevalent cause of human malaria in tropical regions outside the African continent. The lack of a routine continuous in vitro culture of this parasite makes it difficult to develop specific drugs for this disease. To facilitate the development of anti-P. vivax drugs, bacterial and yeast surrogate models expressing the validated P. vivax target dihydrofolate reductase-thymidylate synthase (DHFR-TS have been generated; however, they can only be used as primary screening models because of significant differences in enzyme expression level and in vivo drug metabolism between the surrogate models and P. vivax parasites. Methods Plasmodium falciparum and Plasmodium berghei parasites were transfected with DNA constructs bearing P. vivax dhfr-ts pyrimethamine sensitive (wild-type and pyrimethamine resistant (mutant alleles. Double crossover homologous recombination was used to replace the endogenous dhfr-ts of P. falciparum and P. berghei parasites with P. vivax homologous genes. The integration of Pvdhfr-ts genes via allelic replacement was verified by Southern analysis and the transgenic parasites lines validated as models by standard drug screening assays. Results Transgenic P. falciparum and P. berghei lines stably expressing PvDHFR-TS replacing the endogenous parasite DHFR-TS were obtained. Anti-malarial drug screening assays showed that transgenic parasites expressing wild-type PvDHFR-TS were pyrimethamine-sensitive, whereas transgenic parasites expressing mutant PvDHFR-TS were pyrimethamine-resistant. The growth and sensitivity to other types of anti-malarial drugs in the transgenic parasites were otherwise indistinguishable from the parental parasites. Conclusion With the permanent integration of Pvdhfr-ts gene in the genome, the transgenic Plasmodium lines expressing PvDHFR-TS are genetically stable and will be useful for screening anti-P. vivax compounds targeting PvDHFR-TS. A similar approach

  11. In Vivo Antiplasmodial, Anti-Inflammatory, and Analgesic Properties, and Safety Profile of Root Extracts of Haematostaphis barteri Hook F. (Anacardiaceae)

    OpenAIRE

    Johnson Nyarko Boampong

    2015-01-01

    Malaria is an endemic disease globally and the conundrum of drug resistance has led to the search for newer antimalarial agents. The root extract of H. barteri was evaluated for antimalarial, analgesic, and anti-inflammatory properties. The prophylactic effect of H. barteri on P. berghei was determined by pretreating mice with aqueous root extract of H. barteri (30–300 mg/kg), saline, and 1.2 mg/kg sulfadoxine/pyrimethamine for three days followed by 1 × 106 P. berghei inoculation. Parasite d...

  12. Successful treatment of malaria tropica with acute renal failure and cerebral involvement by plasmapheresis and hemodialysis.

    Science.gov (United States)

    Stuby, U; Kaiser, W; Biesenbach, G; Zazgornik, J

    1988-01-01

    A non-immune, 31-year-old woman developed an acute infection with Plasmodium falciparum after travelling to Kenia. The parasites proved resistant to chloroquine and sulfadoxine/pyrimethamine. The course of the disease was complicated by acute renal failure, hepatocellular damage, disorders of blood coagulation, thrombocytopenia, hemolysis and cerebral involvement. Despite a very high level of parasitemia (50% parasitized erythrocytes) a rapid clinical improvement was achieved by plasmapheresis and hemodialysis. Our experience shows that plasmapheresis and hemodialysis are excellent additive methods which rapidly improve clinical symptoms and may reduce morbidity and mortality in severe malaria tropica.

  13. Treatment of infants with congenital toxoplasmosis

    DEFF Research Database (Denmark)

    Schmidt, Dorte Remmer; Hogh, Birthe; Andersen, Ole;

    2006-01-01

    /kg, and folinic acid 7.5 mg was administered twice weekly. Blood cell counts and body weight were recorded during follow-up. The plasma concentrations of pyrimethamine and sulfadiazine were analysed in a subgroup of seven children, using high performance liquid chromatography with ultraviolet and mass...... efficacy is still a concern, since progression of eye lesions was observed in three eyes during the follow-up period. We concluded that the treatment was well tolerated in 86% (25/29) of the children. The drugs did not affect their weight gain. Drugs given in the recommended doses led to concentrations...

  14. Plasmodium falciparum mutant haplotype infection during pregnancy associated with reduced birthweight, Tanzania

    DEFF Research Database (Denmark)

    Minja, Daniel T R; Schmiegelow, Christentze; Mmbando, Bruno;

    2013-01-01

    Intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is a key strategy in the control of pregnancy-associated malaria. However, this strategy is compromised by widespread drug resistance from single-nucleotide polymorphisms in the Plasmodium falciparum...... dihydrofolate reductase and dihydropteroate synthetase genes. During September 2008-October 2010, we monitored a cohort of 924 pregnant women in an area of Tanzania with declining malaria transmission. P. falciparum parasites were genotyped, and the effect of infecting haplotypes on birthweight was assessed...

  15. Trends in chloroquine resistance marker, Pfcrt-K76T mutation ten years after chloroquine withdrawal in Tanzania

    DEFF Research Database (Denmark)

    Mohammed, Asia; Ndaro, Arnold; Kalinga, Akili;

    2013-01-01

    , continued to be used in intermittent preventive treatment of malaria in pregnancy (IPTp) despite reports of high levels of resistance to SP due to the lack of alternatives to SP for IPTp. Recent reports have indicated recovery of CQ-susceptibility in Malawi, Kenya, Mozambique, and Tanzania based......Plasmodium falciparum resistance to anti-malarial drugs remains a major obstacle to the control of malaria. In 2001 Tanzania replaced chloroquine (CQ) with sulphadoxine-pyrimethamine (SP) as first-line drug, which in turn was replaced by artemisinin combination therapy in 2006. SP has however...

  16. Assessment of the molecular marker of Plasmodium falciparum chloroquine resistance (Pfcrt) in Senegal after several years of chloroquine withdrawal

    DEFF Research Database (Denmark)

    Ndiaye, Magatte; Faye, Babacar; Tine, Roger

    2012-01-01

    Abstract. As a result of widespread antimalarial drug resistance, all African countries with endemic malaria have, in recent years, changed their malaria treatment policy. In Senegal, the health authorities changed from chloroquine (CQ) to a combination of sulfadoxine-pyrimethamine (SP) plus...... susceptibility in many African countries, it may be possible to reintroduce CQ in the near future in a drug combination; it could possibly be given to non-vulnerable groups, but it demands close monitoring of possible reemergence of CQ resistance development....

  17. Characterisation of pvmdr1 and pvdhfr genes associated with chemoresistance in Brazilian Plasmodium vivax isolates

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    Bianca Ervatti Gama

    2009-11-01

    Full Text Available Plasmodium vivax control is now being hampered by drug resistance. Orthologous Plasmodium falciparum genes linked to chloroquine or sulfadoxine-pyrimethamine chemoresistance have been identified in P. vivax parasites, but few studies have been performed. The goal of the present work is to characterise pvmdr1 and pvdhfr genes in parasite isolates from a Brazilian endemic area where no molecular investigation had been previously conducted. The pvmdr1 analysis revealed the existence of single (85.7% and double (14.3% mutant haplotypes, while the pvdhfr examination showed the presence of double (57.2% and triple (42.8% mutant haplotypes. The implications of these findings are discussed.

  18. Island-wide diversity in single nucleotide polymorphisms of the Plasmodium vivax dihydrofolate reductase and dihydropteroate synthetase genes in Sri Lanka

    DEFF Research Database (Denmark)

    Schousboe, Mette L; Rajakaruna, Rupika S; Salanti, Ali;

    2007-01-01

    BACKGROUND: Single nucleotide polymorphisms (SNPs) in the Plasmodium vivax dihydrofolate reductase (Pfdhfr) and dihydropteroate synthetase (Pvdhps) genes cause parasite resistance to the antifolate drug combination, sulphadoxine/pyrimethamine (SP). Monitoring these SNPs provide insights...... into the level of drug pressure caused by SP use and presumably other antifolate drugs. In Sri Lanka, chloroquine (CQ) with primaquine (PQ) and SP with PQ is used as first and second line treatment, respectively, against uncomplicated Plasmodium falciparum and/or P. vivax infections. CQ/PQ is still efficacious...... and diversity of Pvdhfr mutations was unexpected indicating the emergence of drug resistant parasites despite a low level of SP drug pressure....

  19. A REVIEW OF THE MALARIA SITUATION IN IRIAN JAYA

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    Suriadi Gunawan

    2012-09-01

    Full Text Available Karangan ini merupakan tinjauan mengenai situasi malaria di Irian Jaya hingga tahun 1980. Malaria merupakan masalah kesehatan masyarakat yang penting karena menyebabkan 14% dari kematian di rumah sakit dan 20% dari kunjungan ke fasilitas kesehatan. Malaria adalah hiper sampai mesoendemik di daerah pantai dan dataran rendah, sedangkan di dae­rah pegunungan sampai ketinggian 1700 m malaria tidak stabil dan potensial epidemik. Yang menjadi vektor ialah kelompok Anopheles punctulatus yang exo atau endophagik secara fakultatif serta bersifat exofilik. Program pemberantasan malaria yang didasarkan pada penyemprotan rumah dengan DDT melin­dungi sekitar 300.000 penduduk di 15 lokasi. Di semua lokasi penyemprotan angka parasit memang turun, kecuali di daerah Genyem (Nimboran di mana dicurigai adanya resistensi nyamuk terhadap DDT, tetapi transmisi malaria masih berjalan terus. Pembagian obat secara massal (chloroquin dan pyrimethamin juga tidak menghasilkan penurunan penu­laran yang diharapkan. Pemberantasan malaria di Irian Jaya menghadapi berbagai hambatan yang sangat besar. Selain ma­salah operasional, keuangan dan perilaku manusia, terdapat pula masalah teknis seperti berkembangnya resistensi P. falciparum terhadap pyrimethamin dan proguanil (1959, chloroquin (1973 dan sulfadoxin/ fansidar (1979 serta kemungkinan berkembangnya resistensi vektor terhadap DDT. Pemberantasan malaria di Irian Jaya perlu dievaluasi secara menyeluruh dan penelitian yang ber­sifat operasional perlu dilaksanakan untuk menyusun suatu program yang lebih rasional dan sesuai de­ngan kondisi setempat. Meningkatnya malaria akan menghambat pembangunan, maka penanggulangannya mutlak dilak­sanakan untuk menjamin berhasilnya proyek-proyek pembangunan sosial-ekonomi di propinsi tersebut.

  20. Seasonal intermittent preventive treatment for the prevention of anaemia and malaria in Ghanaian children: a randomized, placebo controlled trial.

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    Margaret Kweku

    Full Text Available BACKGROUND: Malaria and anaemia are the leading causes of morbidity and mortality in children in sub-Saharan Africa. We have investigated the effect of intermittent preventive treatment with sulphadoxine-pyrimethamine or artesunate plus amodiaquine on anaemia and malaria in children in an area of intense, prolonged, seasonal malaria transmission in Ghana. METHODS: 2451 children aged 3-59 months from 30 villages were individually randomised to receive placebo or artesunate plus amodiaquine (AS+AQ monthly or bimonthly, or sulphadoxine-pyrimethamine (SP bimonthly over a period of six months. The primary outcome measures were episodes of anaemia (Hb1 year old when they received IPTc compared to the placebo group. However the incidence of malaria in the post intervention period was higher in children who were <1 year old when they received AS+AQ monthly compared to the placebo group. INTERPRETATION: IPTc is safe and efficacious in reducing the burden of malaria in an area of Ghana with a prolonged, intense malaria transmission season. TRIAL REGISTRATION: ClinicalTrials.gov NCT00119132.

  1. Patterns of case management and chemoprevention for malaria-in-pregnancy by public and private sector health providers in Enugu state, Nigeria

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    Onwujekwe Ogochukwu C

    2012-07-01

    Full Text Available Abstract Background Malaria in pregnancy (MIP is a major disease burden in Nigeria and has adverse consequences on the health of the mother, the foetus and the newborn. Information is required on how to improve its prevention and treatment from both the providers’ and consumers’ perspectives. Methods The study sites were two public and two private hospitals in Enugu, southeast Nigeria. Data was collected using a pre-tested structured questionnaire. The respondents were healthcare providers (doctors, pharmacists and nurses providing ante-natal care (ANC services. They consisted of 32 respondents from the public facilities and 20 from the private facilities. The questionnaire elicited information on their: knowledge about malaria, attitude, chemotherapy and chemoprophylaxis using pyrimethamine, chloroquine proguanil as well as IPTp with sulphadoxine-pyrimethamine (SP. The data was collected from May to June 2010. Results Not many providers recognized maternal and neonatal deaths as potential consequences of MIP. The public sector providers provided more appropriate treatment for the pregnant women, but the private sector providers found IPTp more acceptable and provided it more rationally than public sector providers (p  Conclusions There is sub-optimal level of knowledge about current best practices for treatment and chemoprophylaxis for MIP especially in the private sector. Also, IPTp was hardly used in the public sector. Interventions are required to improve providers’ knowledge and practices with regards to management of MIP.

  2. Early diagnosis and successful treatment of disseminated toxoplasmosis after cord blood transplantation.

    Science.gov (United States)

    Kurihara, Taro; Sumi, Masahiko; Kaiume, Hiroko; Takeda, Wataru; Kirihara, Takehiko; Sato, Keijiro; Ueki, Toshimitsu; Hiroshima, Yuki; Ueno, Mayumi; Ichikawa, Naoaki; Kaneko, Yumi; Hikosaka, Kenji; Norose, Kazumi; Kobayashi, Hikaru

    2016-06-01

    A 66-year-old woman with refractory angioimmunoblastic T-cell lymphoma underwent cord blood transplantation. Prior to transplantation, a serological test for Toxoplasma gondii-specific IgG antibodies was positive. On day 96, she exhibited fever and dry cough. Chest CT showed diffuse centrilobular ground glass opacities in both lungs. The reactivation of T. gondii was identified by the presence of parasite DNA in peripheral blood and bronchoalveolar lavage fluid. Moreover, brain MRI revealed a space occupying lesion in the right occipital lobe. Therefore, disseminated toxoplasmosis was diagnosed. She received pyrimethamine and sulfadiazine from day 99. The lung and brain lesions both showed improvement but the PCR assay for T. gondii DNA in peripheral blood was positive on day 133. On day 146, she developed blurred vision and reduced visual acuity, and a tentative diagnosis of toxoplasmic retinochoroiditis was made based on ophthalmic examination results. As agranulocytosis developed on day 158, we decided to discontinue pyrimethamine and sulfadiazine and the treatment was thus switched to atovaquone. Moreover, we added spiramycin to atovaquone therapy from day 174, and her ocular condition gradually improved. In general, the prognosis of disseminated toxoplasmosis after hematopoietic stem cell transplantation (HSCT) is extremely poor. However, early diagnosis and treatment may contribute to improvement of the fundamentally dismal prognosis of disseminated toxoplasmosis after HSCT.

  3. Clinical trials of chemotherapy for falciparum malaria.

    Science.gov (United States)

    Winstanley, P; Olliaro, P

    1998-02-01

    Plasmodium falciparum remains one of the World's most prevalent and devastating pathogens. Mainly for economic reasons, the parasite's ability to develop resistance to drugs has not been matched by the rate at which new compounds are developed. Even so, there are new drugs (or new combinations of old drugs) currently under investigation, or in the process of development (at the moment): Pyronaridine, a well-tolerated, synthetic drug that may have utility for multi-resistant falciparum malaria in many parts of the world; however,problems remain over the formulation of this drug (which is a major determinant of its bioavailability) and its eventual cost. Chlorproguanil-dapsone (lap dap) is being studied as a possible low-cost'successor' to pyrimethamine-sulfadoxine; the utility of chlorproguanil-dapsone as 'salvage' therapy for clinical cases of pyrimethamine-sulfadoxine failure has yet to be tested in clinical trials. Atovaquone-proguanil (malarone) has utility against multi-resistant parasites; however, it is likely to be expensive (but is currently being provided free-of-charge in certain areas of Africa). Artemether-benflumetol (coartemether) combines the advantages of artemether (a rapid reduction in parasite load) with a second drug that reduces the risk of recrudescence; the cost of this combination is unclear. Rectal artesunate is being studied as an intervention to reduce the proportion of children with falciparum malaria who deteriorate to severe disease; the formulation is appropriate for use in rural health centres.

  4. Artemisinin-based combination therapies for uncomplicated malaria.

    Science.gov (United States)

    Davis, Timothy M E; Karunajeewa, Harin A; Ilett, Kenneth F

    2005-02-21

    There has been a relentless increase in resistance of malaria parasites to conventional antimalarial drugs, including chloroquine, sulfadoxine-pyrimethamine and mefloquine. In response to this situation, short-course artemisinin-based combination therapies (ACTs) have been developed. The World Health Organization has endorsed ACT as first-line treatment where the potentially life-threatening parasite Plasmodium falciparum is the predominant infecting species. ACTs combine the rapid schizontocidal activity of an artemisinin derivative (artesunate, artemether or dihydroartemisinin) with a longer-half-life partner drug. Although the use of chloroquine and sulfadoxine-pyrimethamine as partners in ACT improves their efficacy, this may only have value as a short-term measure in patients with a degree of immunity to malaria. Alternative currently available partner drugs include mefloquine, lumefantrine and piperaquine. Artesunate-mefloquine is highly effective but is expensive and side effects (mainly neurotoxicity) can be problematic. Artemether-lumefantrine, the only ACT available in Australia, appears less effective than artesunate-mefloquine and needs to be administered with food to ensure adequate bioavailability. Dihydroartemisinin-piperaquine is highly effective, well tolerated and relatively inexpensive. The goal of potent, safe, easy-to-administer and inexpensive ACTs may see trioxolanes in place of artemisinin derivatives, as well as novel partner drugs such as pyronaridine or naphthoquine, in the future.

  5. Resistência in vivo do Plasmodium falciparum às 4-aminoquinoleínas e à associação sulfadoxina-pirimetamina: II - estudo de imperatriz, Maranhão, 1983-1984

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    Afonso Dinis Costa Passos

    1987-06-01

    Full Text Available Através da prova de 7 dias foram estudadas as respostas terapêuticas de 96 pacientes com malária falciparum não grave atendidos pela SUCAM em Imperatriz, Maranhão. Esses pacientes foram distribuídos aleatoriamente em três grupos de estudo, tendo o primeiro recebido cloroquina, o segundo amodiaquina e o terceiro a associação sulfadoxina-pirimetamina. Mesmo sem evidenciar significância estatística ao nível de 5% de probabilidade, as diferenças observadas nas respostas as 3 drogas apontam para a associação sulfadoxina-pirimetamina como a que produziu melhores resultados terapêuticos. Recomenda-se a monitorização contínua da resistência nas áreas malarígenas criticas.The in vivo drug response of 96 patients with falciparum malaria was studied to chloroquine, amodiaquine or the combination of sulfadoxine and pyrimethamine, in Imperatriz, State of Maranhão, Brasil. The patients were randomly assigned to the three study groups and followed for seven days. Better results were obtained with the association sulfadoxine-pyrimethamine, although no statistically significant differences were observed. The need of continous surveillance of P. falciparum drug resistance in areas of high levels of transmission is emphasised.

  6. Antimalarial drug resistance in Bangladesh, 1996-2012.

    Science.gov (United States)

    Haque, Ubydul; Glass, Gregory E; Haque, Waziul; Islam, Nazrul; Roy, Shyamal; Karim, Jahirul; Noedl, Harald

    2013-12-01

    Malaria remains an important health problem in Bangladesh, with approximately 14 million people at risk. Antimalarial drug resistance is a major obstacle to the control of malaria in endemic countries. In 2012, Bangladesh reported an estimated 29 522 malaria episodes, of which 94% were reported as being caused by Plasmodium falciparum. In this study, we reviewed and summarized antimalarial drug resistance data from Bangladesh published until June 2013. We searched published sources for data referring to any type of P. falciparum drug resistance (in vivo, in vitro, or molecular) and found 169 articles published in peer-reviewed journals. Of these, 143 articles were excluded because they did not meet our inclusion criteria. After detailed review of the remaining 26 articles, 14 were selected for evaluation. Published studies indicate that P. falciparum shows varying levels of resistance to chloroquine, mefloquine and sulfadoxine-pyrimethamine. Combination therapy of chloroquine and primaquine has proven ineffective and combinations of sulfadoxine-pyrimethamine with either quinine or chloroquine have also shown poor efficacy. Recent studies indicate that artemisinin derivatives, such as artesunate, remain highly efficacious in treating P. falciparum malaria. Available data suggest that artemisinins, quinine, doxycyline, mefloquine-artesunate and azithromycin-artesunate combination therapy remain efficacious in the treatment of P. falciparum malaria in Bangladesh.

  7. On the effects of malaria treatment on parasite drug resistance--probability modelling of genotyped malaria infections.

    Science.gov (United States)

    Kum, Cletus Kwa; Thorburn, Daniel; Ghilagaber, Gebrenegus; Gil, Pedro; Björkman, Anders

    2013-10-12

    We compare the frequency of resistant genes of malaria parasites before treatment and at first malaria incidence after treatment. The data come from a clinical trial at two health facilities in Tanzania and concerns single nucleotide polymorphisms (SNPs) at three positions believed to be related to resistance to malaria treatment. A problem is that mixed infections are common, which both obscures the underlying frequency of alleles at each locus as well as the associations between loci in samples where alleles are mixed. We use combinatorics and quite involved probability methods to handle multiple infections and multiple haplotypes. The infection with the different haplotypes seemed to be independent of each other. We showed that at two of the three studied SNPs, the proportion of resistant genes had increased after treatment with sulfadoxine-pyrimethamine alone but when treated in combination with artesunate, no effect was noticed. First recurrences of malaria associated more with sulfadoxine-pyrimethamine alone as treatment than when in combination with artesunate. We also found that the recruited children had two different ongoing malaria infections where the parasites had different gene types.

  8. A REVIEW OF THE MALARIA SITUATION IN IRIAN JAYA

    Directory of Open Access Journals (Sweden)

    Suriadi Gunawan

    2012-09-01

    Full Text Available Karangan ini merupakan tinjauan mengenai situasi malaria di Irian Jaya hingga tahun 1980. Malaria merupakan masalah kesehatan masyarakat yang penting karena menyebabkan 14% dari kematian di rumah sakit dan 20% dari kunjungan ke fasilitas kesehatan. Malaria adalah hiper sampai mesoendemik di daerah pantai dan dataran rendah, sedangkan di dae­rah pegunungan sampai ketinggian 1700 m malaria tidak stabil dan potensial epidemik. Yang menjadi vektor ialah kelompok Anopheles punctulatus yang exo atau endophagik secara fakultatif serta bersifat exofilik. Program pemberantasan malaria yang didasarkan pada penyemprotan rumah dengan DDT melin­dungi sekitar 300.000 penduduk di 15 lokasi. Di semua lokasi penyemprotan angka parasit memang turun, kecuali di daerah Genyem (Nimboran di mana dicurigai adanya resistensi nyamuk terhadap DDT, tetapi transmisi malaria masih berjalan terus. Pembagian obat secara massal (chloroquin dan pyrimethamin juga tidak menghasilkan penurunan penu­laran yang diharapkan. Pemberantasan malaria di Irian Jaya menghadapi berbagai hambatan yang sangat besar. Selain ma­salah operasional, keuangan dan perilaku manusia, terdapat pula masalah teknis seperti berkembangnya resistensi P. falciparum terhadap pyrimethamin dan proguanil (1959, chloroquin (1973 dan sulfadoxin/ fansidar (1979 serta kemungkinan berkembangnya resistensi vektor terhadap DDT. Pemberantasan malaria di Irian Jaya perlu dievaluasi secara menyeluruh dan penelitian yang ber­sifat operasional perlu dilaksanakan untuk menyusun suatu program yang lebih rasional dan sesuai de­ngan kondisi setempat. Meningkatnya malaria akan menghambat pembangunan, maka penanggulangannya mutlak dilak­sanakan untuk menjamin berhasilnya proyek-proyek pembangunan sosial-ekonomi di propinsi tersebut.

  9. Mutations in the Antifolate-Resistance-Associated Genes Dihydrofolate Reductase and Dihydropteroate Synthase in Plasmodium vivax Isolates from Malaria-Endemic Countries

    Science.gov (United States)

    Lu, Feng; Lim, Chae Seung; Nam, Deok Hwa; Kim, Kwonkee; Lin, Khin; Kim, Tong-Soo; Lee, Hyeong-Woo; Chen, Jun-Hu; Wang, Yue; Sattabongkot, Jetsumon; Han, Eun-Taek

    2010-01-01

    Parasite dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) are known target enzymes of antifolate drugs used for the treatment and prophylaxis of persons with malaria. We sequenced the Plasmodium vivax dihydrofolate reductase (pvdhfr) and dihydropteroate synthase (pvdhps) genes to examine the prevalence and extent of point mutations in isolates from malaria-endemic countries. Double mutations (S58R and S117N) or quadruple mutations (F57L/I, S58R, T61M, and S117T) in the pvdhfr gene were found in isolates from Thailand (96.4%) and Myanmar (71.4%), but in only one isolate (1.0%) from Korea, where sulfadoxine-pyrimethamine has never been used. The pvdhfr point mutations correlated strongly with the pvdhps point mutations and ranged from single to triple mutations (S382A, A383G, and A553G), among isolates from Thailand, Myanmar, and Korea. These findings suggests that the prevalence of mutations in pvdhfr and pvdhps in P. vivax isolates from different malaria-endemic countries is associated with selection pressure imposed by sulfadoxine-pyrimethamine. PMID:20810806

  10. Randomized clinical trial of artemisinin versus non-artemisinin combination therapy for uncomplicated falciparum malaria in Madagascar

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    Ratsimbasoa Arsène

    2007-05-01

    Full Text Available Abstract Background Data concerning antimalarial combination treatment for uncomplicated malaria in Madagascar are largely lacking. Randomized clinical trial was designed to assess therapeutic efficacies of chloroquine (CQ, amodiaquine (AQ, sulphadoxine-pyrimethamine (SP, amodiaquine plus sulphadoxine-pyrimethamine combination (AQ+SP and artesunate plus amodiaquine combination (AQ+AS. Methods 287 children between 6 months and 15 years of age, with uncomplicated falciparum malaria, were enrolled in the study. Primary endpoints were the day-14 and day-28 risks of parasitological failure, either unadjusted or adjusted by genotyping. Results All treatment regimens, except for CQ treatment, gave clinical cure rates above 97% by day-14 and 92% by day-28 (PCR-corrected. AQ+SP was as effective as AQ+AS. The risk of new infection within the month after therapy was generally higher for AQ+AS than AQ+SP. Conclusion These findings show that the inexpensive and widely available combination AQ+SP may be valuable in for the treatment of uncomplicated malaria in Madagascar and could have an important role in this country, where much of the drugs administered go to patients who do not have malaria.

  11. Antiplasmodial effects of the aqueous ethanolic seed extract of Ziziphus mauritiana against Plasmodium berghei in Swiss albino mice

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    Tulika Mishra

    2014-08-01

    Full Text Available Ziziphus mauritiana is a fruit tree used traditionally since long back for wound healing, immunepotentiator, asthma, sedative, stomachic, styptic, as tonic etc. The present study determines the antiplasmodial effect of aqueous ethanolic seed extract against Chloroquine sensitive Plasmodium berghei berghei nk65 infection in Swiss albino mice. Based upon the acute toxicity data three different doses (100, 200, 400 mg/kg body weight of the plant extract was chosen to study the blood schizonticidal activity in early infection and in established infection and was compared with chloroquine. The Prophylactic activity was also assessed and compared with pyrimethamine. No mortality was observed in acute toxicity study however, above the dose of 1000 mg/kg animals showed the lethargic behaviour. In early infection, and in established infection the doses (100-400 mg/kg b.wt was found to cause significant (P<0.001 suppression of infection in a dose dependent manner as compared to control. Although, the activity was lower than standard chloroquine. Similarly, the extract at all the doses caused the suppression in repository activity but was lower than pyrimethamine. The mean survival time was also increased in mice by 14 and 17 days at the doses of 200 and 400 mg/kg respectively, whereas the control group sustained only for 7 days. Thus, the seed extract showed the effectiveness against plasmodium infection.

  12. MOLECULAR SURVEILLANCE OF Plasmodium vivax AND Plasmodium falciparum DHFR MUTATIONS IN ISOLATES FROM SOUTHERN IRAN.

    Science.gov (United States)

    Sharifi-Sarasiabi, Khojasteh; Haghighi, Ali; Kazemi, Bahram; Taghipour, Niloofar; Mojarad, Ehsan Nazemalhosseini; Gachkar, Latif

    2016-01-01

    In Iran, both Plasmodium vivax and P. falciparum malaria have been detected, but P. vivax is the predominant species. Point mutations in dihydrofolate reductase (dhfr) gene in both Plasmodia are the major mechanisms of pyrimethamine resistance. From April 2007 to June 2009, a total of 134 blood samples in two endemic areas of southern Iran were collected from patients infected with P. vivax and P. falciparum. The isolates were analyzed for P. vivax dihydrofolate reductase (pvdhfr) and P. falciparum dihydrofolate reductase (pfdhfr) point mutations using various PCR-based methods. The majority of the isolates (72.9%) had wild type amino acids at five codons of pvdhfr. Amongst mutant isolates, the most common pvdhfr alleles were double mutant in 58 and 117 amino acids (58R-117N). Triple mutation in 57, 58, and 117 amino acids (57L/58R/117N) was identified for the first time in the pvdhfr gene of Iranian P. vivax isolates. All the P. falciparumsamples analyzed (n = 16) possessed a double mutant pfdhfrallele (59R/108N) and retained a wild-type mutation at position 51. This may be attributed to the fact that the falciparum malaria patients were treated using sulfadoxine-pyrimethamine (SP) in Iran. The presence of mutant haplotypes in P. vivax is worrying, but has not yet reached an alarming threshold regarding drugs such as SP. The results of this study reinforce the importance of performing a molecular surveillance by means of a continuous chemoresistance assessment.

  13. Real-time PCR/MCA assay using fluorescence resonance energy transfer for the genotyping of resistance related DHPS-540 mutations in Plasmodium falciparum

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    Dujardin Jean-Claude

    2008-03-01

    Full Text Available Abstract Background Sulphadoxine-pyrimethamine has been abandoned as first- or second-line treatment by most African malaria endemic countries in favour of artemisinin-based combination treatments, but the drug is still used as intermittent preventive treatment during pregnancy. However, resistance to sulphadoxine-pyrimethamine has been increasing in the past few years and, although the link between molecular markers and treatment failure has not been firmly established, at least for pregnant women, it is important to monitor such markers. Methods This paper reports a novel sensitive, semi-quantitative and specific real-time PCR and melting curve analysis (MCA assay using fluorescence resonance energy transfer (FRET for the detection of DHPS-540, an important predictor for SP resistance. FRET/MCA was evaluated using 78 clinical samples from malaria patients and compared to PCR-RFLP. Results Sixty-two samples were in perfect agreement between both assays. One sample showed a small wild type signal with FRET/MCA that indicates a polyclonal infection. Four samples were not able to generate enough material in both assays to distinguish mutant from wild-type infection, six samples gave no signal in PCR-RFLP and five samples gave no amplification in FRET/MCA. Conclusion FRET/MCA is an effective tool for the identification of SNPs in drug studies and epidemiological surveys on resistance markers in general and DHPS-540 mutation in particular.

  14. Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum.

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    Marna S Costanzo

    Full Text Available BACKGROUND: Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness. METHODOLOGY/PRINCIPAL FINDINGS: We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possible public health implications of these findings are discussed.

  15. Prevalence of molecular markers of Plasmodium falciparum drug resistance in Dakar, Senegal

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    Wurtz Nathalie

    2012-06-01

    Full Text Available Abstract Background As a result of the widespread resistance to chloroquine and sulphadoxine-pyrimethamine, artemisinin-based combination therapy (ACT (including artemether-lumefantrine and artesunate-amodiaquine has been recommended as a first-line anti-malarial regimen in Senegal since 2006. Intermittent preventive treatments with anti-malarial drugs based on sulphadoxine-pyrimethamine are also given to children or pregnant women once per month during the transmission season. Since 2006, there have been very few reports on the susceptibility of Plasmodium falciparum to anti-malarial drugs. To estimate the prevalence of resistance to several anti-malarial drugs since the introduction of the widespread use of ACT, the presence of molecular markers associated with resistance to chloroquine and sulphadoxine-pyrimethamine was assessed in local isolates at the military hospital of Dakar. Methods The prevalence of genetic polymorphisms in genes associated with anti-malarial drug resistance, i.e., Pfcrt, Pfdhfr, Pfdhps and Pfmdr1, and the copy number of Pfmdr1 were evaluated for a panel of 174 isolates collected from patients recruited at the military hospital of Dakar from 14 October 2009 to 19 January 2010. Results The Pfcrt 76T mutation was identified in 37.2% of the samples. The Pfmdr1 86Y and 184F mutations were found in 16.6% and 67.6% of the tested samples, respectively. Twenty-eight of the 29 isolates with the 86Y mutation were also mutated at codon 184. Only one isolate (0.6% had two copies of Pfmdr1. The Pfdhfr 108N/T, 51I and 59R mutations were identified in 82.4%, 83.5% and 74.1% of the samples, respectively. The double mutant (108N and 51I was detected in 83.5% of the isolates, and the triple mutant (108N, 51I and 59R was detected in 75.3%. The Pfdhps 437G, 436F/A and 613S mutations were found in 40.2%, 35.1% and 1.8% of the samples, respectively. There was no double mutant (437G and 540E or no quintuple mutant (Pfdhfr 108N, 51I and 59R

  16. Impact of Chloroquine on Viral Load in Breast Milk

    Science.gov (United States)

    Semrau, Katherine; Kuhn, Louise; Kasonde, Prisca; Sinkala, Moses; Kankasa, Chipepo; Shutes, Erin; Vwalika, Cheswa; Ghosh, Mrinal; Aldrovandi, Grace; Thea, Donald M.

    2006-01-01

    Summary The anti-malarial agent chloroquine has activity against HIV. We compared the effect of chloroquine (n = 18) to an anti-malarial agent without known anti-HIV-activity, sulfadoxine-pyrimethamine (n = 12), on breast milk HIV RNA levels among HIV-infected breastfeeding women in Zambia. After adjusting for CD4 count and plasma viral load, chloroquine was associated with a trend towards lower levels of HIV RNA in breast milk compared with sulfadoxine-pyrimethamine (P 0.05). Higher breastmilk viral load was also observed among women receiving presumptive treatment = for symptomatic malaria compared with asymptomatic controls and among controls reporting fever in the prior week. Further research is needed to determine the potential role of chloroquine in prevention of HIV transmission through breastfeeding. Impacte de la chloroquine sur la charge virale dans le lait maternelle La chloroquine, agent antimalarique, a une activité contre le VIH. Nous avons comparé l’effet de la chloroquine à celui d’un autre agent antimalarique, la sulfadoxine-pyrimethamine, dont l’activité sur le VIH n’est pas connue, en mesurant les taux d’ARN de VIH dans le lait maternel de femmes allaitantes infectées par le VIH en Zambie. Après ajustement pour les taux de CD4 et la charge virale dans le plasma, la chloroquine comparée à la sulfadoxine pyrimethamine était associée à une tendance vers des teneurs plus bas en ARN de VIH dans le lait maternel (P = 0,05). Des charges virales plus élevées dans le lait maternel étaient aussi observées chez des femmes recevant un traitement présomptif pour des symptômes de malaria par rapport aux contrôles asymptomatiques et par rapport à des contrôles rapportant de la fièvre durant la première semaine. Des études supplémentaires sont nécessaires pour déterminer le rôle potentiel de la chloroquine dans la prévention de la transmission du VIH par l’allaitement maternel. mots clésVIH, malaria, allaitement maternel

  17. A simple cost-effective high performance liquid chromatographic assay of sulphadoxine in whole blood spotted on filter paper for field studies

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    Sijuade Abayomi O

    2009-10-01

    Full Text Available Abstract Background Artesunate plus sulphadoxine-pyrimethamine is one of the four artemisinin-based combination therapies currently recommended by WHO as first-line treatment for falciparum malaria. Sulphadoxine-pyrimethamine is also used for intermittent preventive treatment for malaria in pregnancy. Drug use patterns and drug pharmacokinetics are important factors impacting the spread of drug resistant parasites hence it is imperative to monitor the effect of pharmacokinetic variability on therapeutic efficacy. Unfortunately, information on the pharmacokinetics of sulphadoxine in children and pregnant women with malaria is very limited. Methods for the assay of sulphadoxine-pyrimethamine have been previously reported, but they are not cost-effective and practicable in analytical laboratories in low resource areas where malaria is endemic. Efforts in this study were thus devoted to development and evaluation of a simple, cost-effective and sensitive method for quantification of sulphadoxine in small capillary samples of whole blood dried on filter paper. Methods Sulphadoxine was determined in whole blood by reversed-phase high performance liquid chromatography with UV detection at 340 nm. Sulisoxazole (SLX was used as internal standard. Chromatographic separation was achieved using a Beckman Coulter ODS C18 and a mobile phase consisting of 0.05 M phosphate buffer-methanol-acetonitrile (70:17:13 V/V/V containing 1% triethylamine solution. Results Standard curves from sulphadoxine-spiked blood added to filter paper were linear over the concentration range studied. Linear regression analysis yielded correlation coefficient r2 > 0.99 (n = 6. Extraction recoveries were about 82-85%. The limit of quantification was 120 ng/ml while the within and between assay coefficient of variations were Conclusion The recovery and accuracy of determination of SDX from whole blood filter paper samples using the method described in this study is satisfactory, thus

  18. Malaria prevalence in Nias District, North Sumatra Province, Indonesia

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    Laowo Idaman

    2007-08-01

    Full Text Available Abstract Background The Nias district of the North Sumatra Province of Indonesia has long been known to be endemic for malaria. Following the economic crisis at the end of 1998 and the subsequent tsunami and earthquake, in December 2004 and March 2005, respectively, the malaria control programme in the area deteriorated. The present study aims to provide baseline data for the establishment of a suitable malaria control programme in the area and to analyse the frequency distribution of drug resistance alleles associated with resistance to chloroquine and sulphadoxine-pyrimethamine. Methods Malariometric and entomology surveys were performed in three subdistricts. Thin and thick blood smears were stained with Giemsa and examined under binocular light microscopy. Blood blots on filter paper were also prepared for isolation of parasite and host DNA to be used for molecular analysis of band 3 (SAO, pfcrt, pfmdr1, dhfr, and dhps. In addition, haemoglobin measurement was performed in the second and third surveys for the subjects less than 10 years old. Results Results of the three surveys revealed an average slide positivity rate of 8.13%, with a relatively higher rate in certain foci. Host genetic analysis, to identify the Band 3 deletion associated with Southeast Asian Ovalocytosis (SAO, revealed an overall frequency of 1.0% among the 1,484 samples examined. One hundred six Plasmodium falciparum isolates from three sub-districts were successfully analysed. Alleles of the dhfr and dhps genes associated with resistance to sulphadoxine-pyrimethamine, dhfr C59R and S108N, and dhps A437G and K540E, were present at frequencies of 52.2%, 82.5%, 1.18% and 1.18%, respectively. The pfmdr1 alleles N86Y and N1042D, putatively associated with mefloquine resistance, were present at 31.4% and 2%, respectively. All but one sample carried the pfcrt 76T allele associated with chloroquine resistance. Entomologic surveys identified three potential anopheline vectors in

  19. Development of behaviour change communication strategy for a vaccination-linked malaria control tool in southern Tanzania.

    Science.gov (United States)

    Mushi, Adiel K; Schellenberg, Joanna; Mrisho, Mwifadhi; Manzi, Fatuma; Mbuya, Conrad; Mponda, Haji; Mshinda, Hassan; Tanner, Marcel; Alonso, Pedro; Pool, Robert; Schellenberg, David

    2008-09-29

    Intermittent preventive treatment of malaria in infants (IPTi) using sulphadoxine-pyrimethamine and linked to the expanded programme on immunization (EPI) is a promising strategy for malaria control in young children. As evidence grows on the efficacy of IPTi as public health strategy, information is needed so that this novel control tool can be put into practice promptly, once a policy recommendation is made to implement it. This paper describes the development of a behaviour change communication strategy to support implementation of IPTi by the routine health services in southern Tanzania, in the context of a five-year research programme evaluating the community effectiveness of IPTi. Mixed methods including a rapid qualitative assessment and quantitative health facility survey were used to investigate communities' and providers' knowledge and practices relating to malaria, EPI, sulphadoxine-pyrimethamine and existing health posters. Results were applied to develop an appropriate behaviour change communication strategy for IPTi involving personal communication between mothers and health staff, supported by a brand name and two posters. Malaria in young children was considered to be a nuisance because it causes sleepless nights. Vaccination services were well accepted and their use was considered the mother's responsibility. Babies were generally taken for vaccination despite complaints about fevers and swellings after the injections. Sulphadoxine-pyrimethamine was widely used for malaria treatment and intermittent preventive treatment of malaria in pregnancy, despite widespread rumours of adverse reactions based on hearsay and newspaper reports. Almost all health providers said that they or their spouse were ready to take SP in pregnancy (96%, 223/242). A brand name, key messages and images were developed and pre-tested as behaviour change communication materials. The posters contained public health messages, which explained the intervention itself, how and when

  20. Assessment of Markers of Antimalarial Drug Resistance in Plasmodium falciparum Isolates from Pregnant Women in Lagos, Nigeria.

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    Chimere Obiora Agomo

    Full Text Available The use of antimalarial drugs for prevention and treatment is a major strategy in the prevention of malaria in pregnancy. Although sulphadoxine-pyrimethamine (SP is currently recommended for intermittent preventive treatment of malaria during pregnancy in Nigeria, previously used drugs for prophylaxis such as chloroquine (CQ and pyrimethamine are accessible as they are purchased over the counter. This study describes the markers of absence or presence of resistance to quinoline (Pfcrt and Pfmdr 1 and type 1 antifolate antimalarial medicines (Pfdhfr.Plasmodium falciparum-positive dried blood spots from pregnant women attending antenatal clinics for the first time during current pregnancy were investigated for the presence of mutations at codons 72-76 of Plasmodium falciparum chloroquine resistance transporter (Pfcrt gene by real time polymerase chain reaction (PCR using haplotype-specific probes. PCR followed by sequence analysis was used to identify mutations at codons 86, 184, 1034, 1042 and 1246 of P. falciparum multi-drug resistance-1 (Pfmdr1 gene; and codons 16, 50, 51, 59, 108, 140 and 164 of Pfdhfr gene.Two haplotypes of Pfcrt (n = 54 were observed: CVMNK 13(24.2% and CVIET 41 (75.9% of the samples. The SVMNT haplotype was absent in this population. The Pfmdr1 (n = 28 haplotypes were NYSND 15(53.6%, YYSND 5(17.9%, NFSND 6(21.4% and YFSND 2(7.1%. The Pfdhfr (n = 15 were ACNCSVI 4(26.7%, and ACICNSVI 1(6.7% and ACIRNVI 10 (66.7%. The rate of occurrence of Pfcrt 76T, Pfdhfr108N, Pfmdr186Y and 184F were 75.9%, 73.3%, 25% and 28.1% respectively. The Pfmdr1 86Y was associated with low parasitaemia (median = 71 parasites/μl, P = 0.024 while Pfcrt 76T was associated with young maternal age (mean 24.1 ± 4.5 years; P = 0.006. The median parasitaemia were similar (P>0.05 in wild and mutant strains of Pfcrt 76, Pfmdr1 184 and Pfdhfr 108. There was no association between gravidity or gestational age of the women and presence of mutations in the Pfcrt

  1. Development of behaviour change communication strategy for a vaccination-linked malaria control tool in southern Tanzania

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    Mshinda Hassan

    2008-09-01

    Full Text Available Abstract Background Intermittent preventive treatment of malaria in infants (IPTi using sulphadoxine-pyrimethamine and linked to the expanded programme on immunization (EPI is a promising strategy for malaria control in young children. As evidence grows on the efficacy of IPTi as public health strategy, information is needed so that this novel control tool can be put into practice promptly, once a policy recommendation is made to implement it. This paper describes the development of a behaviour change communication strategy to support implementation of IPTi by the routine health services in southern Tanzania, in the context of a five-year research programme evaluating the community effectiveness of IPTi. Methods Mixed methods including a rapid qualitative assessment and quantitative health facility survey were used to investigate communities' and providers' knowledge and practices relating to malaria, EPI, sulphadoxine-pyrimethamine and existing health posters. Results were applied to develop an appropriate behaviour change communication strategy for IPTi involving personal communication between mothers and health staff, supported by a brand name and two posters. Results Malaria in young children was considered to be a nuisance because it causes sleepless nights. Vaccination services were well accepted and their use was considered the mother's responsibility. Babies were generally taken for vaccination despite complaints about fevers and swellings after the injections. Sulphadoxine-pyrimethamine was widely used for malaria treatment and intermittent preventive treatment of malaria in pregnancy, despite widespread rumours of adverse reactions based on hearsay and newspaper reports. Almost all health providers said that they or their spouse were ready to take SP in pregnancy (96%, 223/242. A brand name, key messages and images were developed and pre-tested as behaviour change communication materials. The posters contained public health messages

  2. A non-inferiority, individually randomized trial of intermittent screening and treatment versus intermittent preventive treatment in the control of malaria in pregnancy

    DEFF Research Database (Denmark)

    Tagbor, Harry; Cairns, Matthew; Bojang, Kalifa

    2015-01-01

    BACKGROUND: The efficacy of intermittent preventive treatment for malaria with sulfadoxine-pyrimethamine (IPTp-SP) in pregnancy is threatened in parts of Africa by the emergence and spread of resistance to SP. Intermittent screening with a rapid diagnostic test (RDT) and treatment of positive women...... (ISTp) is an alternative approach. METHODS AND FINDINGS: An open, individually randomized, non-inferiority trial of IPTp-SP versus ISTp was conducted in 5,354 primi- or secundigravidae in four West African countries with a low prevalence of resistance to SP (The Gambia, Mali, Burkina Faso and Ghana......-AL performed as well as IPTp-SP. In the absence of an effective alternative medication to SP for IPTp, ISTp-AL is a potential alternative to IPTp in areas where SP resistance is high. It may also have a role in areas where malaria transmission is low and for the prevention of malaria in HIV positive women...

  3. Efficacy comparison between anti-malarial drugs in Africans presenting with mild malaria in the Central Republic of Africa: a preliminary study

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    Nambei W.S.

    2005-03-01

    Full Text Available Drug resistance to Plasmodium falciparum contributes to major health problems in central Africa and, as a consequence, poverty. We have analyzed the efficacy of three currently available antimalarial drugs to treat symptomatic, uncomplicated P. falciparum malaria in semiimmune adults living in Bangui, Central Republic of Africa. 210 consecutive individuals were enrolled in the survey, of which 45 were excluded. Those having received dihydroartemisin proved significantly less parasitemic than those having received quinine per os or sulfadoxin-pyrimethamin (χ2 = 16.93 ; p < 0.05, and 75 % recovered in two days compared to 57 and 44 %, respectively. The 25 % who did not recover benefited from a second cure with dihydroartemisin, which proved 100 % efficient. The most accurate protocol remains to be established by analyzing clinical and parasitological data and taking into account the economics of the country.

  4. A community-based delivery system of intermittent preventive treatment of malaria in pregnancy and its effect on use of essential maternity care at health units in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Bygbjerg, I C; Magnussen, Pascal

    2007-01-01

    Community delivery of intermittent preventive treatment of malaria in pregnancy (IPTp) is one potential option that could mitigate malaria in pregnancy. However, there is concern that this approach may lead to complacency among women with low access to essential care at health units. A non...... approaches. Data on care-seeking practices before and after the intervention were collected. The majority of women with the new approaches accessed IPTp in the second trimester and adhered to two doses of sulfadoxine/pyrimethamine (SP) (1404/2081; 67.5%). Antenatal care (four recommended visits) increased...... from 3.4% (27/805) to 56.8% (558/983) (Pcare for malaria at health units increased from 16.7% (128/767) to 36.0% (146/405) (P

  5. Toxoplasmic encephalitis in an HIV infected pregnant woman: successful outcome for both mother and child

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    Susie Andries Nogueira

    Full Text Available This report describes a case of Toxoplasma encephalitis during pregnancy of an HIV infected woman who was severely immunosuppressed (CD4: 17 cells/mm3, had a high viral load (RNA PCR:230,000 copies/ml, was treated with sulfadiazine, pyrimethamine and folinic acid for toxoplasmosis and was being treated with highly potent antiretroviral drugs (AZT, 3TC and nelfinavir for HIV infection. The newborn was born through an elective C-section, received six weeks of AZT according to the 076 protocol and was clinically normal at birth. Subsequently he had two RNA PCR negatives for HIV, seroreverted and had no clinical or laboratory evidence of congenital toxoplasmosis. Despite the concerns of the use of these combined therapies on the foetus during pregnancy, their efficacy illustrates that keeping the mother alive and in good health is an important strategy to protect the unborn child from acquiring these two infections.

  6. Microbial hara-kiri: Exploiting lysosomal cell death in malaria parasites

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    Jun-Hong Ch’ng

    2015-01-01

    Full Text Available The antimalarial drug chloroquine (CQ has been sidelined in the fight against falciparum malaria due to wide-spread CQ resistance. Replacement drugs like sulfadoxine, pyrimethamine and mefloquine have also since been surpassed with the evolution of multi-drug resistant parasites. Even the currently recommended artemisinin-based combination therapies show signs of compromise due to the recent spread of artemisinin delayed-clearance parasites. Though there have been promising breakthroughs in the pursuit of new effective antimalarials, the development and strategic deployment of such novel chemical entities takes time. We therefore argue that there is a crucial need to re-examine the usefulness of ‘outdated’ drugs like chloroquine, and explore if they might be effective alternative therapies in the interim. We suggest that a novel parasite cell death (pCD pathway may be exploited through the reformulation of CQ to address this need.

  7. [Plasmodium falciparum malaria: epidemiology and clinical features at Tarapoto Hospital].

    Science.gov (United States)

    Calderon, J; Rodriguez, J; Romero, D

    1997-01-01

    A retrospective study was conducted of the clinical records of 41 patients discharged from a hospital in Tarapoto, Peru, between August 1992 and June 1996 following treatment for Plasmodium falciparum malaria. Patients ranged in age from 18 to 65 years; 25 were male. The cases were uniformly distributed throughout the year. The duration of illness averaged 11 days. At admission, 40 patients had fever, 36 had shaking chills, 29 had headache, 21 had nausea and vomiting, 21 had hyporexia, 15 had pallor, and 13 had splenomegaly. 3 of the 16 women were pregnant. 7 patients reported a history of malaria. The admission diagnosis was malaria in 33 cases. 31 patients were treated with chloroquine; 18 were subsequently treated with pyrimethamine-sulfadoxin and 1 received doxycycline. No cases of grave illness or death occurred. The increasing presence of Plasmodium falciparum malaria in the Peruvian lowlands should promote review of the adequacy of control programs.

  8. Molecular Epidemiology of Plasmodium falciparum Malaria Outbreak, Tumbes, Peru, 2010-2012.

    Science.gov (United States)

    Baldeviano, G Christian; Okoth, Sheila Akinyi; Arrospide, Nancy; Gonzalez, Rommell V; Sánchez, Juan F; Macedo, Silvia; Conde, Silvia; Tapia, L Lorena; Salas, Carola; Gamboa, Dionicia; Herrera, Yeni; Edgel, Kimberly A; Udhayakumar, Venkatachalam; Lescano, Andrés G

    2015-05-01

    During 2010-2012, an outbreak of 210 cases of malaria occurred in Tumbes, in the northern coast of Peru, where no Plasmodium falciparum malaria case had been reported since 2006. To identify the source of the parasite causing this outbreak, we conducted a molecular epidemiology investigation. Microsatellite typing showed an identical genotype in all 54 available isolates. This genotype was also identical to that of parasites isolated in 2010 in the Loreto region of the Peruvian Amazon and closely related to clonet B, a parasite lineage previously reported in the Amazon during 1998-2000. These findings are consistent with travel history of index case-patients. DNA sequencing revealed mutations in the Pfdhfr, Pfdhps, Pfcrt, and Pfmdr1 loci, which are strongly associated with resistance to chloroquine and sulfadoxine/pyrimethamine, and deletion of the Pfhrp2 gene. These results highlight the need for timely molecular epidemiology investigations to trace the parasite source during malaria reintroduction events.

  9. Origins and spread of pfdhfr mutant alleles in Plasmodium falciparum.

    Science.gov (United States)

    Mita, Toshihiro

    2010-06-01

    The emergence and spread of Plasmodium falciparum parasite resistant to sulfadoxine and pyrimethamine (SP) poses a serious public health problem. Resistance is caused by point mutations in dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps), the two key enzymes in the folate biosynthetic pathway. The use of microsatellite markers flanking pfdhfr has recently shown that the invasion of limited resistant lineages may explain the widespread SP resistance in many endemic regions. In Africa, however, multiple indigenous origins of pfdhfr triple mutants have been demonstrated. More new independent lineages and routes of geographical spread of resistance may be found by further molecular evolutionary analyses using samples from various endemic regions. Here, I review recent studies about the history of SP usage and the evolution and spread of resistant lineages while addressing the technical issue of microsatellite analysis.

  10. Intermittent preventive treatment of malaria in pregnancy: a community-based delivery system and its effect on parasitemia, anemia and low birth weight in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Bygbjerg, Ib; Magnussen, Pascal

    2008-01-01

    OBJECTIVE: The main objective of the study was to assess the impact of a community-based delivery system of intermittent preventive treatment (IPT) for malaria in pregnancy with sulfadoxine-pyrimethamine (SP) on access, parasitemia, anemia and low birth weight as primary outcome measures. METHODS.......0001). At both health units and the community-based approaches, IPT increased mean hemoglobin by 6.7% (panemia from 5.7% to 3.1% (p.... This intervention was acceptable to 89.6% of the women at the community-based approaches intending to use IPT in the future, while 48.1% of them had recommended it to other women. CONCLUSIONS: The community-based approaches increased access and adherence to IPT with an effect on anemia, severe anemia, parasitemia...

  11. [Toxoplasmosis in immunocompromised patients].

    Science.gov (United States)

    Machala, L; Kodym, P; Malý, M; Geleneky, M; Beran, O; Jilich, D

    2015-06-01

    In humans, toxoplasmosis mostly occurs as a latent infection, but in immunocompromised individuals, the agent may reactivate and cause severe to life-threatening disease. HIV positive individuals and transplant recipients, in particular hematopoietic stem cell transplant and heart transplant recipients, are at highest risk. The disease most often affects the central nervous system but can involve any organ. Because of the alteration of the immune response in these patients, the serodiagnosis is not reliable and direct detection of the causative agent is needed--namely by microscopy and DNA PCR. If inadequately treated or left untreated, toxoplasmosis generally has a fatal prognosis in immunocompromised patients and therefore, the treatment must be started as early and energetically as possible. The gold standard both in the treatment of reactivation and secondary prophylaxis is the pyrimethamine-sulfadiazine combination while co-trimoxazole can be used in the primary prophylaxis for high-risk patients.

  12. Congenital toxoplasmosis from a mother with type 2 diabetes mellitus: a case report.

    Science.gov (United States)

    Sato, Shimpei; Nishida, Masakazu; Nasu, Kaei; Narahara, Hisashi; Norose, Kazumi; Aosai, Fumie

    2014-11-01

    A 33-year-old woman with type 2 diabetes mellitus (DM) was suspected of being primarily infected with Toxoplasma gondii at 12 weeks of gestation (GW). Although acetylspiramycin was started at 17 GW, the T. gondii DNA gene was detected in the amniotic fluid at 18 GW. Chemotherapy was changed to pyrimethamine plus sulfadiazine from 20 GW, but was changed back to acetylspiramycin after 2 weeks because of vomiting. Acetylspiramycin was continued until her delivery. DM was controlled well during the pregnancy. An asymptomatic male baby was born by cesarean section at 37 GW, and was treated with acetylspiramycin for 4 weeks because the polymerase chain reaction results of umbilical cord blood were positive. He has developed normally until the present, that is, 6 months of age. Herein, we describe a case report in which symptomatic congenital toxoplasmosis was avoided in a pregnant woman with an immunosuppressive risk due to prompt chemotherapy.

  13. [Fever and lymphadenopathy: acute toxoplasmosis in an immunocompetent patient].

    Science.gov (United States)

    Kaparos, Nikolaos; Favrat, Bernard; D'Acremont, Valérie

    2014-11-26

    Toxoplasmosis is an infectious disease caused by the intracellular parasite Toxoplasma gondii. In Switzerland about a third of the population has antibodies against this pathogen and has thus already been in contact with the parasite or has contracted the disease. Immunocompetent patients are usually asymptomatic (80-90%) during primary infection. The most common symptom is neck or occipital lymphadenopathy. Serology is the diagnostic gold standard in immunocompetent individuals. The presence of IgM antibodies is however not sufficient to make a definite diagnosis of acute toxoplasmosis. Distinction between acute and chronic toxoplasmosis requires additional serological tests (IgG avidity test). If required, the most used and probably most effective treatment is the combination of pyrimethamine and sulfadiazine, with folinic acid.

  14. The national neonatal screening programme for congenital toxoplasmosis in Denmark: results from the initial four years, 1999-2002

    DEFF Research Database (Denmark)

    Schmidt, Dorte Remmer; Høgh, Birthe; Andersen, O;

    2006-01-01

    AIMS: To describe the outcome of four years' nationwide neonatal screening for congenital toxoplasmosis in liveborn newborns. METHODS: Congenital toxoplasmosis was diagnosed if specific Toxoplasma gondii IgM antibodies were detected in eluate from the PKU Guthrie filter paper card from a child....... Infants diagnosed with congenital toxoplasmosis were examined for intracranial and retinal lesions and treated for three months with sulphadiazine, pyrimethamine, and folinic acid continuously. RESULTS: Eluates from PKU-cards from 262 912 newborns were analysed. The birth prevalence of congenital...... toxoplasma infection was 2.1 per 10 000 liveborns. Congenital toxoplasmosis was suspected in 96 infants and confirmed in 55. Forty seven children were examined for intracranial and retinal lesions soon after birth; 12 had clinical signs at this first examination. Of these, 5 had intracranial calcifications...

  15. Cutaneous Manifestations of Toxoplasmosis: a Case Report

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    Marina Sonya

    2014-09-01

    Full Text Available Although toxoplasmosis is one of the most widely spread infections in the world, types that involve the skin are extremely rare. However, skin lesions are not specific; moreover, they are quite diverse, which makes the diagnosis of cutaneous toxoplasmosis rather difficult. Thus, differential diagnosis should include a number of other diseases. We present a case of a 43-year-old immunocompetent man with multiple livid erythematous papules and nodules with yellowish discharge that involved the skin of the body and the extremities. By using electro-chemiluminescence immunoassay, immunoglobulin G antibodies to Toxoplasma gondii were detected in the serum, confirming the diagnosis of toxoplasmosis. The treatment with pyrimethamine and trimethoprim-sulfamethoxazole led to complete resolution of skin lesions. In conclusion, although rare in the dermatological practice, cutaneous toxoplasmosis should be considered in all patients presenting with lymphadenopathy, non-specific skin eruptions, especially nodular and colliquative, blood eosinophilia and histological findigs revealing abundant eosinophilic inflitrations.

  16. Toxoplasmic encephalitis in an HIV infected pregnant woman: successful outcome for both mother and child

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    Susie Andries Nogueira

    2002-08-01

    Full Text Available This report describes a case of Toxoplasma encephalitis during pregnancy of an HIV infected woman who was severely immunosuppressed (CD4: 17 cells/mm3, had a high viral load (RNA PCR:230,000 copies/ml, was treated with sulfadiazine, pyrimethamine and folinic acid for toxoplasmosis and was being treated with highly potent antiretroviral drugs (AZT, 3TC and nelfinavir for HIV infection. The newborn was born through an elective C-section, received six weeks of AZT according to the 076 protocol and was clinically normal at birth. Subsequently he had two RNA PCR negatives for HIV, seroreverted and had no clinical or laboratory evidence of congenital toxoplasmosis. Despite the concerns of the use of these combined therapies on the foetus during pregnancy, their efficacy illustrates that keeping the mother alive and in good health is an important strategy to protect the unborn child from acquiring these two infections.

  17. Malaria Treatment Policy Change and Implementation: The Case of Uganda

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    Miriam Nanyunja

    2011-01-01

    Full Text Available Malaria due to P. falciparum is the number one cause of morbidity and mortality in Uganda where it is highly endemic in 95% of the country. The use of efficacious and effective antimalarial medicines is one of the key strategies for malaria control. Until 2000, Chloroquine (CQ was the first-line drug for treatment of uncomplicated malaria in Uganda. Due to progressive resistance to CQ and to a combination of CQ with Sulfadoxine-Pyrimethamine, Uganda in 2004 adopted the use of ACTs as first-line drug for treating uncomplicated malaria. A review of the drug policy change process and postimplementation reports highlight the importance of managing the policy change process, generating evidence for policy decisions and availability of adequate and predictable funding for effective policy roll-out. These and other lessons learnt can be used to guide countries that are considering anti-malarial drug change in future.

  18. Malaria treatment policy change and implementation: the case of Uganda.

    Science.gov (United States)

    Nanyunja, Miriam; Nabyonga Orem, Juliet; Kato, Frederick; Kaggwa, Mugagga; Katureebe, Charles; Saweka, Joaquim

    2011-01-01

    Malaria due to P. falciparum is the number one cause of morbidity and mortality in Uganda where it is highly endemic in 95% of the country. The use of efficacious and effective antimalarial medicines is one of the key strategies for malaria control. Until 2000, Chloroquine (CQ) was the first-line drug for treatment of uncomplicated malaria in Uganda. Due to progressive resistance to CQ and to a combination of CQ with Sulfadoxine-Pyrimethamine, Uganda in 2004 adopted the use of ACTs as first-line drug for treating uncomplicated malaria. A review of the drug policy change process and postimplementation reports highlight the importance of managing the policy change process, generating evidence for policy decisions and availability of adequate and predictable funding for effective policy roll-out. These and other lessons learnt can be used to guide countries that are considering anti-malarial drug change in future.

  19. Editing the Plasmodium vivax genome, using zinc-finger nucleases.

    Science.gov (United States)

    Moraes Barros, Roberto R; Straimer, Judith; Sa, Juliana M; Salzman, Rebecca E; Melendez-Muniz, Viviana A; Mu, Jianbing; Fidock, David A; Wellems, Thomas E

    2015-01-01

    Plasmodium vivax is a major cause of malaria morbidity worldwide yet has remained genetically intractable. To stably modify this organism, we used zinc-finger nucleases (ZFNs), which take advantage of homology-directed DNA repair mechanisms at the site of nuclease action. Using ZFNs specific to the gene encoding P. vivax dihydrofolate reductase (pvdhfr), we transfected blood specimens from Saimiri boliviensis monkeys infected with the pyrimethamine (Pyr)-susceptible Chesson strain with a ZFN plasmid carrying a Pyr-resistant mutant pvdhfr sequence. We obtained Pyr-resistant parasites in vivo that carried mutant pvdhfr and additional silent mutations designed to confirm editing. These results herald the era of stable P. vivax genetic modifications.

  20. Bilateral macular hemorrhage as a complication of drug-induced anemia: a case report

    Directory of Open Access Journals (Sweden)

    Belfort Rubens N

    2009-01-01

    Full Text Available Abstract Introduction Bilateral macular hemorrhage is a rare ocular finding and to the best of our knowledge, this is the first report of such hemorrhages as a presentation of drug-induced anemia. Case presentation We describe the case of a 14-year-old Caucasian boy who presented with a toxoplasmic retinochoroiditis and was treated with sulfadiazine and pyrimethamine. Three months later, he presented with a bilateral macular hemorrhage as a complication of a toxic induced anemia. Conclusion Our patient presented with toxic anemia secondary to the treatment of a very common disease, ocular toxoplasmosis. Prophylactic use of folinic acid could prevent such complications but in many cases, it is not prescribed owing to its cost or is mistakenly substituted with folic acid, which does not present as a valid substitute.

  1. [Historical overview of antimalarials used in Venezuela].

    Science.gov (United States)

    Zerpa de Artiles, N

    1993-06-01

    A historical review of antimalarials used in Venezuela is presented from the time when the bark of quina was used until the massive distribution of quinine and metoquine by the Dirección de Malariología y Saneamiento Ambiental. The utility of chloroquine and primaquine against sensible parasite isolates and of sulfadoxine-pyrimethamine and quinine, currently used against P. falciparum resistant strains, is thoroughly discussed. The author suggests use of artemisimine and its derivatives as a very promising antimalarial drug. She also stresses the possibility of the application of new antimalaria vaccine against P. falciparum blood states, presently assayed in the country as an additional tool in malaria control programs.

  2. Molecular Epidemiology of Plasmodium falciparum Malaria Outbreak, Tumbes, Peru, 2010–2012

    Science.gov (United States)

    Okoth, Sheila Akinyi; Arrospide, Nancy; Gonzalez, Rommell V.; Sánchez, Juan F.; Macedo, Silvia; Conde, Silvia; Tapia, L. Lorena; Salas, Carola; Gamboa, Dionicia; Herrera, Yeni; Edgel, Kimberly A.; Udhayakumar, Venkatachalam; Lescano, Andrés G.

    2015-01-01

    During 2010–2012, an outbreak of 210 cases of malaria occurred in Tumbes, in the northern coast of Peru, where no Plasmodium falciparum malaria case had been reported since 2006. To identify the source of the parasite causing this outbreak, we conducted a molecular epidemiology investigation. Microsatellite typing showed an identical genotype in all 54 available isolates. This genotype was also identical to that of parasites isolated in 2010 in the Loreto region of the Peruvian Amazon and closely related to clonet B, a parasite lineage previously reported in the Amazon during 1998–2000. These findings are consistent with travel history of index case-patients. DNA sequencing revealed mutations in the Pfdhfr, Pfdhps, Pfcrt, and Pfmdr1 loci, which are strongly associated with resistance to chloroquine and sulfadoxine/pyrimethamine, and deletion of the Pfhrp2 gene. These results highlight the need for timely molecular epidemiology investigations to trace the parasite source during malaria reintroduction events. PMID:25897626

  3. Molecular Characterization of a Cluster of Imported Malaria Cases in Puerto Rico.

    Science.gov (United States)

    Chenet, Stella M; Silva-Flannery, Luciana; Lucchi, Naomi W; Dragan, Ljolje; Dirlikov, Emilio; Mace, Kimberly; Rivera-García, Brenda; Arguin, Paul M; Udhayakumar, Venkatachalam

    2017-09-01

    The Caribbean island of Hispaniola is targeted for malaria elimination. Currently, this is the only island with ongoing transmission of malaria in the Caribbean. In 2015, six patients from Puerto Rico and one from Massachusetts, who traveled to Punta Cana, Dominican Republic, were confirmed to be infected with Plasmodium falciparum. Additional molecular analysis was performed at the Centers for Disease Control and Prevention to characterize the drug-resistant alleles and Plasmodium population genetic markers. All specimens carried wildtype genotypes for chloroquine, sulfadoxine-pyrimethamine, and artemisinin resistance genetic markers. A mutation in codon 184 (Y/F) of Pfmdr-1 gene was observed in all samples and they shared an identical genetic lineage as determined by microsatellite analysis. This genetic profile was similar to one previously reported from Hispaniola suggesting that a clonal P. falciparum residual parasite population present in Punta Cana is the source population for these imported malaria cases.

  4. Sulfadiazine-related obstructive urinary tract lithiasis: an unusual cause of acute renal failure after kidney transplantation.

    Science.gov (United States)

    Guitard, J; Kamar, N; Mouzin, M; Borde, J S; Tran-Van, T; Durand, D; Rostaing, L

    2005-05-01

    We report on the first case of acute renal failure related to obstructive urinary tract lithiasis involving sulfadiazine crystals in a kidney transplant recipient. This patient had disseminated toxoplasmosis which was treated by sulfadiazine (4 g/day) and pyrimethamine (50 mg/day). In the fourth week of anti-toxoplasmosis therapy, he presented with obstructive acute renal failure: the plasma creatinine level increased from 220 micromol/l to 547 micromol/l. Apercutaneous pyelography was conducted showing the presence of a lithiasis located at the junction between the graft ureter and the bladder. Six days later, he underwent surgery to retrieve an orange-colored, friable stone. Its spectrophotometric analysis confirmed that the stone consisted of N-acetyl sulfadiazine crystals.

  5. Perspective for the reproduction of antimalarial drugs in Brazil

    Directory of Open Access Journals (Sweden)

    Benjamin Gilbert

    1992-01-01

    Full Text Available The appears to be no chemical manufacture of antimalarial drugs is Brazil. Technology at laboratory process level has been developed for chloroquine, mefloquine, pyrimethamine and cycloquanil, but not perfected nor scaled-up, largely for economic reasons and market uncertainty. Development of primaquine has been contracted but it will run into the same difficulty. Manufacturing capacity for sulfadoxine was registred in the SDI by Roche. A project to produce artemisinine and its derivates is under way at UNICAMP-CPQBA but is hampered by low content in the plant. Proguanil could be produced easily, but apparently no attempt has been made to do so. Quinine is imported on a large scale mostly for softdrink production. Since malarial treatment falls largely within responsability of the Government health authorities, manufacture of drugs in Brazil will depend on an assured medium-term purchase order made to a potential local manufacturer, since competition in the world market is scarcelyviable at the present moment.

  6. Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients.

    Science.gov (United States)

    Rodriguez, Martin; Fishman, Jay A

    2004-10-01

    Pneumocystis infection in humans was originally described in 1942. The organism was initially thought to be a protozoan, but more recent data suggest that it is more closely related to the fungi. Patients with cellular immune deficiencies are at risk for the development of symptomatic Pneumocystis infection. Populations at risk also include patients with hematologic and nonhematologic malignancies, hematopoietic stem cell transplant recipients, solid-organ recipients, and patients receiving immunosuppressive therapies for connective tissue disorders and vasculitides. Trimethoprim-sulfamethoxazole is the agent of choice for prophylaxis against Pneumocystis unless a clear contraindication is identified. Other options include pentamidine, dapsone, dapsone-pyrimethamine, and atovaquone. The risk for PCP varies based on individual immune defects, regional differences, and immunosuppressive regimens. Prophylactic strategies must be linked to an ongoing assessment of the patient's risk for disease.

  7. Blood schizontocidal activity of methylene blue in combination with antimalarials against Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Garavito G.

    2007-06-01

    Full Text Available Methylene blue (MB is the oldest synthetic antimalarial. It is not used anymore as antimalarial but should be reconsidered. For this purpose we have measured its impact on both chloroquine sensitive and resistant Plasmodium strains. We showed that around 5 nM of MB were able to inhibit 50% of the parasite growth in vitro and that late rings and early trophozoites were the most sensitive stages; while early rings, late trophozoites and schizonts were less sensitive. Drug interaction study following fractional inhibitory concentrations (FIC method showed antagonism with amodiaquine, atovaquone, doxycycline, pyrimethamine; additivity with artemether, chloroquine, mefloquine, primaquine and synergy with quinine. These results confirmed the interest of MB that could be integrated in a new low cost antimalarial combination therapy.

  8. Asymptomatic Malaria Correlates with Anaemia in Pregnant Women at Ouagadougou, Burkina Faso

    Directory of Open Access Journals (Sweden)

    Zoenabo Douamba

    2012-01-01

    Full Text Available Sub-Saharan Africa records each year about thirty-two million pregnant women living in areas of high transmission of Plasmodium falciparum causing malaria. The aim of this study was to carve out the prevalence of asymptomatic malaria among pregnant women and to emphasize its influence on haematological markers. The prevalence of Plasmodium falciparum asymptomatic infection among pregnant women was 30% and 24% with rapid detection test (RDT and microscopy, respectively. The prevalence of P. falciparum asymptomatic malaria was reduced among pregnant women using sulfadoxine-pyrimethamine's intermittent preventive treatment and 61% of them were anaemic. Anaemia was significantly more common in women infected with P. falciparum compared with the uninfected pregnant women. Most of the women had normal levels of homocysteine and low levels of folate, respectively. Therefore, the systematic diagnosis of malaria should be introduced to pregnant women as a part of the antenatal care.

  9. Intermittent preventive treatment of malaria in pregnancy: the incremental cost-effectiveness of a new delivery system in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony; Hansen, Kristian Schultz; Bygbjerg, Ib

    2008-01-01

    The main objective of this study was to assess whether traditional birth attendants, drug-shop vendors, community reproductive health workers and adolescent peer mobilisers could administer intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) to pregnant women. The study...... was implemented in 21 community clusters (intervention) and four clusters where health centres provided routine IPTp (control). The primary outcome measures were the proportion of women who completed two doses of SP; the effect on anaemia, parasitaemia and low birth weight; and the incremental cost......-effectiveness of the intervention. The study enrolled 2785 pregnant women. The majority, 1404/2081 (67.5%) receiving community-based care, received SP early and adhered to the two recommended doses compared with 281/704 (39.9%) at health centres (Pwomen receiving community-based care had fewer episodes...

  10. Drug resistant falciparum malaria and the use of artesunate-based combinations : focus on clinical trials sponsored by TDR

    Directory of Open Access Journals (Sweden)

    Walter R.J. Taylor, Jean Rigal & Piero L. Olliaro

    2003-09-01

    Full Text Available Antimalarial drug resistance has now become a serious global challenge and is the principal reasonfor the decline in antimalarial drug efficacy. Malaria endemic countries need inexpensive and efficaciousdrugs. Preserving the life spans of antimalarial drugs is a key part of the strategy for rollingback malaria. Artemisinin-based combinations offer a new and potentially highly effective way tocounter drug resistance. Clinical trials conducted in African children have attested to the good tolerabilityof oral artesunate when combined with standard antimalarial drugs. The cure rates of thedifferent combinations were generally dependent on the degree of resistance to the companiondrug. They were high for amodiaquine-artesunate, variable for sulfadoxine/pyrimethamine-artesunate,and poor for chloroquine-artesunate.

  11. Prevalence and prevention of malaria in pregnancy in Edo State, Nigeria.

    Science.gov (United States)

    Wagbatsoma, V A; Omoike, B I

    2008-12-01

    The observational/longitudinal study was undertaken in Igueben Local Government Area (LGA), Edo State, Nigeria. The objective of the study was to determine the effect of prevention on the prevalence of malaria during pregnancy. The study population comprised 4 groups viz; Group l, had 100 women protected with Insecticide Treated bed Nets (ITNs); Group 2, another 100 treated with Sulphadoxine - pyrimethamine (SP); Group 3, 100 protected with both ITN and SP, while Group 4, were 100 unprotected others who served as control. Venous blood was collected 7 days to expected date of delivery while placental blood was collected after delivery from the subjects for parasitaemia determination. Findings showed that all protective devices used were effective against malaria. Prevention used against malaria in pregnancy is a sure safe guard against maternal morbidity/mortality and should be encouraged. It is therefore, recommended that pregnant women should be health educated to appreciate the need for malaria prevention.

  12. Selection of antimalarial drug resistance after intermittent preventive treatment of infants and children (IPTi/c) in Senegal

    DEFF Research Database (Denmark)

    Ndiaye, Magatte; Tine, Roger; Faye, Babacar

    2013-01-01

    Senegal has since 2003 used sulphadoxine-pyrimethamine (SP) for Intermittent Preventive Treatment (IPT) of malaria in risk groups. However, the large-scale IPT strategy may result in increasing drug resistance. Our study investigated the possible impact of SP-IPT given to infants and children...... on the prevalence of SP-resistant haplotypes in the Plasmodium falciparum genes Pfdhfr and Pfdhps, comparing sites with and without IPTi/c. P. falciparum positives samples (n=352) were collected from children under 5years of age during two cross-sectional surveys in 2010 and 2011 in three health districts (two...... on IPTi/c and one without IPTi/c intervention) located in the southern part of Senegal. The prevalence of SP-resistance-related haplotypes in Pfdhfr and Pfdhps was determined by nested PCR followed by sequence-specific oligonucleotide probe (SSOP)-ELISA. The prevalence of the Pfdhfr double mutant...

  13. Prevalence of molecular markers of anti-malarial drug resistance in Plasmodium vivax and Plasmodium falciparum in two districts of Nepal

    DEFF Research Database (Denmark)

    Ranjitkar, Samir; Schousboe, Mette L; Thomsen, Thomas

    2011-01-01

    ABSTRACT: BACKGROUND: Sulphadoxine-pyrimethamine (SP) and chloroquine (CQ) have been used in treatment of falciparum and vivax malaria in Nepal. Recently, resistance to both drugs have necessitated a change towards artemisinin combination therapy (ACT) against Plasmodium falciparum in highly...... endemic areas. However, SP is still used against P. falciparum infections in low endemic areas while CQ is used in suspected cases in areas with lack of diagnostic facilities. This study examines the prevalence of molecular markers of P. falciparum and Plasmodium vivax CQ and SP resistance to determine...... if high levels of in vivo resistance are reflected at molecular level as well. METHODS: Finger prick blood samples (n=189) were collected from malaria positive patients from two high endemic districts and analysed for single nucleotide polymorphisms (SNPs) in the resistance related genes of P. falciparum...

  14. Intermittent preventive treatment of malaria in pregnancy: the incremental cost-effectiveness of a new delivery system in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony; Hansen, Kristian Schultz; Bygbjerg, Ib

    2008-01-01

    The main objective of this study was to assess whether traditional birth attendants, drug-shop vendors, community reproductive health workers and adolescent peer mobilisers could administer intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) to pregnant women. The study...... was implemented in 21 community clusters (intervention) and four clusters where health centres provided routine IPTp (control). The primary outcome measures were the proportion of women who completed two doses of SP; the effect on anaemia, parasitaemia and low birth weight; and the incremental cost...... of anaemia or severe anaemia and fewer low birth weight babies. The cost per woman receiving the full course of IPTp was, however, higher when delivered via community care at US$2.60 compared with US$2.30 at health centres, due to the additional training costs. The incremental cost-effectiveness ratio...

  15. How is childhood development of immunity to Plasmodium falciparum enhanced by certain antimalarial interventions?

    Directory of Open Access Journals (Sweden)

    Schellenberg David

    2007-12-01

    Full Text Available Abstract The development of acquired protective immunity to Plasmodium falciparum infection in young African children is considered in the context of three current strategies for malaria prevention: insecticide-impregnated bed nets or curtains, anti-sporozoite vaccines and intermittent preventive therapy. Evidence is presented that each of these measures may permit attenuated P. falciparum blood-stage infections, which do not cause clinical malaria but can act as an effective blood-stage "vaccine". It is proposed that the extended serum half-life, and rarely considered liver-stage prophylaxis provided by the anti-folate combination sulphadoxine-pyrimethamine frequently lead to such attenuated infections in high transmission areas, and thus contribute to the sustained protection from malaria observed among children receiving the combination as intermittent preventative therapy or for parasite clearance in vaccine trials.

  16. Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design.

    Science.gov (United States)

    Welsch, Matthew E; Zhou, Jian; Gao, Yueqiang; Yan, Yunqing; Porter, Gene; Agnihotri, Gautam; Li, Yingjie; Lu, Henry; Chen, Zhongguo; Thomas, Stephen B

    2016-12-08

    Current treatment of toxoplasmosis targets the parasite's folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and human DHFR. Computational analysis of biochemical differences between Toxoplasma gondii and human DHFR enabled the design of inhibitors with both improved potency and selectivity. The approach described herein yielded TRC-19, a promising lead with an IC50 of 9 nM and 89-fold selectivity in favor of Toxoplasma gondii DHFR, as well as crystallographic data to substantiate in silico methodology. Overall, 50% of synthesized in silico designs met hit threshold criteria of IC50 2-fold selectivity favoring Toxoplasma gondii, further demonstrating the efficiency of our structure-based drug design approach.

  17. The molecular basis of antifolate resistance in Plasmodium falciparum: looking beyond point mutations.

    Science.gov (United States)

    Heinberg, Adina; Kirkman, Laura

    2015-04-01

    Drugs that target the folate-synthesis pathway have a long history of effectiveness against a variety of pathogens. As antimalarials, the antifolates were safe and well tolerated, but resistance emerged quickly and has persisted even with decreased drug pressure. The primary determinants of resistance in Plasmodium falciparum are well-described point mutations in the enzymes dihydropteroate synthase and dihydrofolate reductase targeted by the combination sulfadoxine-pyrimethamine. Recent work has highlighted the contributions of additional parasite adaptation to antifolate resistance. In fact, the evolution of antifolate-resistant parasites is multifaceted and complex. Gene amplification of the first enzyme in the parasite folate synthesis pathway, GTP-cyclohydrolase, is strongly associated with resistant parasites and potentially contributes to persistence of resistant parasites. Further understanding of how parasites adjust flux through the folate pathway is important to the further development of alternative agents targeting this crucial synthesis pathway.

  18. Toxoplasmosis with chorioretinitis in an HIV-infected child with no visual complaints-importance of fundus examination.

    Science.gov (United States)

    Pereira, Noella Maria Delia; Shah, Ira; Lala, Mamatha

    2017-01-01

    Central nervous system lesions are common in HIV-infected patients. In the combination anti-retroviral therapy (ART) era, Toxoplasma reactivation has been observed only in patients with unrecognized HIV infection or refusing therapy. We present the case of 10-year-old girl with AIDS who initially presented with pneumonia. She was treated for pneumonia and thereafter started on ART as her CD4 count was low. However, 5 days after starting ART she presented with left ptosis and right-sided monoparesis. She was diagnosed with neurotoxoplasmosis and responded successfully to pyrimethamine-sulfadoxine therapy. Though she had no vision difficulties, her fundus examination revealed chorioretinitis during the hospital stay. We emphasize the importance of routine fundus examination prior to starting ART to rule out chorioretinitis even in an older child with no visual complaints.

  19. Micronucleus test and metaphase analyses in mice exposed to known and suspected spindle poisons.

    Science.gov (United States)

    Marrazzini, A; Betti, C; Bernacchi, F; Barrai, I; Barale, R

    1994-11-01

    Micronucleus (Mn) and metaphase chromosome analyses were performed in mouse bone marrow cells with two known and eight suspected mitotic spindle poisons. Polychromatic (PCEs) and normochromatic (NCEs) erythrocytes were scored for presence of Mn, while structural (CAs) and numerical chromosome aberrations (NCAs), i.e. hyperploid cells, were evaluated by metaphase analysis. CAs were scored in first, and NCAs in the second metaphases, identified by BrdUrd differential staining. Hydroquinone induced Mn, NCAs and CAs; colchicine, vinblastine and, to a lesser extent, chloral hydrate, diazepam and econazole induced both Mn and NCAs; cadmium chloride and thimerosal induced Mn and CAs, while pyrimethamine and thiabendazole induced Mn only. The proposed stepwise protocol allowed satisfactory statistical evaluation of the effects induced with a reduction in the number of animals killed. An acceptable agreement was found between induction of Mn and NCAs, suggesting a possible use of the Mn test for revealing compounds with aneugenic properties.

  20. Implementing intermittent preventive treatment for malaria in pregnancy

    DEFF Research Database (Denmark)

    Mubyazi, Godfrey Martin; Magnussen, Pascal; Goodman, Catherine;

    2008-01-01

    INTRODUCTION: Implementing Intermittent Preventive Treatment for malaria in Pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) through antenatal care (ANC) clinics is recommended for malaria endemic countries. Vast biomedical literature on malaria prevention focuses more on the epidemiological...... of the recommended interventions. OBJECTIVE: To review literature on policy advances, achievements, constraints and challenges to malaria IPTp implementation, emphasising on its operational feasibility in the context of health-care financing, provision and uptake, resource constraints and psychosocial factors...... and other discriminatory socio-cultural values on pregnancy; target users, perceptions and attitudes towards SP, malaria, and quality of ANC; supply and cost of SP at health facilities; understaffing and demoralised staff; ambiguity and impracticability of user-fee exemption policy guidelines on essential...

  1. Lessons learnt from 20 years surveillance of malaria drug resistance prior to the policy change in Burkina Faso.

    Science.gov (United States)

    Tinto, Halidou; Valea, Innocent; Ouédraogo, Jean-Bosco; Guiguemdé, Tinga Robert

    2016-01-01

    The history of drug resistance to the previous antimalarial drugs, and the potential for resistance to evolve to Artemisinin-based combination therapies, demonstrates the necessity to set-up a good surveillance system in order to provide early warning of the development of resistance. Here we report a review summarizing the history of the surveillance of drug resistance that led to the policy change in Burkina Faso. The first Plasmodium falciparum Chloroquine-Resistance strain identified in Burkina Faso was detected by an in vitro test carried out in Koudougou in 1983. Nevertheless, no further cases were reported until 1987, suggesting that resistant strains had been circulating at a low prevalence before the beginning of the systematic surveillance system from 1984. We observed a marked increase of Chloroquine-Resistance in 2002-2003 probably due to the length of follow-up as the follow-up duration was 7 or 14 days before 2002 and 28 days from 2002 onwards. Therefore, pre-2002 studies have probably under-estimated the real prevalence of Chloroquine-Resistance by not detecting the late recrudescence. With a rate of 8.2% treatment failure reported in 2003, Sulfadoxine-Pyrimethamine was still efficacious for the treatment of uncomplicated malaria in Burkina Faso but this rate might rapidly increase as the result of its spreading from neighboring countries and due to its current use for both the Intermittent Preventive Treatment in pregnant women and Seasonal Malaria Chemoprophylaxis. The current strategy for the surveillance of the Artemisinin-based combination treatments resistance should build on lessons learnt under the previous period of 20 years surveillance of Chloroquine and Sulfadoxine-Pyrimethamine resistance (1994-2004). The most important aspect being to extend the number of sentinel sites so that data would be less patchy and could help understanding the dynamic of the resistance.

  2. Malaria prevention practices among mothers delivering in an urban hospital in southwest Nigeria

    Directory of Open Access Journals (Sweden)

    O.B. Yusuf

    2008-08-01

    Full Text Available Background & objectives: The pregnant woman is more prone to malaria than her non-pregnant counterpart with grave consequences for both mother and baby. This study aims at determining the malaria prevention practices among pregnant women in an area hyper-endemic for malaria. Methods: For the study 983 parturient mothers were enrolled in Ibadan, southwest Nigeria. Information was collected on sociodemographic characteristics, use of malaria chemoprophylaxis, use of anti-vector measures, and malaria parasitaemia. Results: Most mothers [956/972 (98.4%] reported the use of anti-vector measures for malaria prevention. These include, window screens (78.9%, insecticides spray (69.9%, mosquito coils (25.3%, untreated bednets (2.5%, and insecticide-treated nets (1.1%. Most mothers used anti-vector measures either singly or in combination. About 86% (840/972 of the mothers used drugs for chemoprophylaxis. Thirteen (1.3% mothers used chemoprophylaxis alone (CP, 135 (13.9% used anti-vector measures alone (AV while 820 (84.4% used chemoprophylaxis plus anti-vector (CPAV. Weekly dose of pyrimethamine [214 (25%] and intermittent preventive treatment with sulphadoxine-pyrimethamine [598 (71.2%] were the widely used chemoprophylactic drugs. The prevalence of patent parasitaemia at delivery was 7.7% (1/13, 12.1% (99/820 and 16.3% (22/135 among CP, CPAV and AV groups respectively. Geometric mean parasite densities among the respective groups were 7840/ul, 1228/ul and 8936/ul. Conclusion: Window screens and insecticide sprays were widely used for malaria prevention while the use of ITN was very low among enrolled mothers. There is a need to pay concerted efforts to improve ITN usage rate in Nigeria.

  3. Antimalarial potential of China 30 and Chelidonium 30 in combination therapy against lethal rodent malaria parasite: Plasmodium berghei.

    Science.gov (United States)

    Rajan, Aswathy; Bagai, Upma

    2013-05-07

    Homeopathy is a therapeutic method based on the application of similia principle, utilizing ultra-low doses of medicinal substances made from natural products. The present study has been designed to evaluate the efficacy of Cinchona officinalis (Chin.) 30C and Chelidonium majus (Chel.) 30C in combination therapy against lethal murine malaria. Five groups having twelve BALB/c mice each were administered orally with 0.2 ml/mouse/day of different drugs, and their antimalarial potential was evaluated by Peter's 4-day test. The combination of Chin. 30 and Chel. 30 exhibited complete parasite clearance by the 28th day post-inoculation which was similar to the positive control [artesunate (4 mg/kg)+sulphadoxine-primethamine (1.2 mg/kg)] group. Both the groups exhibited enhanced mean survival time (MST) 28±0 days,whereas, the mice of infected control group survived up to 7.6±0.4 days only. The preventive and curative activities of the combination in comparison to the positive controls [pyrimethamine (1.2 mg/Kg) and chloroquine (20 mg/Kg), respectively] were also evaluated. The combination had a significant preventive activity (p<0.0005), with 89.2% chemosuppression which was higher than the standard drug, pyrimethamine (83.8%). It also showed a moderate curative activity with complete clearance of parasite in 50% of surviving mice, and enhancing the MST of mice up to 26.8±2.8 days. These findings point to the significant antiplasmodial efficacy of the combination of these homeopathic drugs against Plasmodium berghei.

  4. Effect of Nigella sativa oil on experimental toxoplasmosis.

    Science.gov (United States)

    Mady, Rasha F; El-Hadidy, Wessam; Elachy, Samar

    2016-01-01

    Toxoplasmosis is a parasitic infection caused by Toxoplasma gondii protozoon. It is most commonly treated by pyrimethamine (PYR); however, this was intolerable by many patients. The aim of this study was to assess therapeutic effects of Nigella sativa oil (NSO) alone and combined with pyrimethamine (PYR) compared to a previous combination of clindamycin (CLN) and (PYR). One hundred Albino mice were used in the current study and were equally divided into five groups: normal (I), infected untreated control (II); infected, treated with NSO-only (III); infected, treated with NSO + PYR (IV); and infected, treated with CLN + PYR (V). The virulent RH Toxoplasma strain was used in infection survival rates estimation, impression smears from liver and spleen, and histopathological and ultrastructural studies were done. Liver malondialdehyde (MDA) level and total antioxidant capacity (TAC) were determined. Interferon-γ and specific IgM were also measured in sera by ELISA. Results showed that NSO alone has no direct anti-Toxoplasma effect, whereas its combination with PYR produced potent effect that is comparable to CLN + PYR. It significantly increased the survival rate and decreased the parasite density and pathological insult in both liver and spleen. Also, significant increase in interferon-γ level denotes stimulation of cellular immunity. NSO + PYR combination markedly improved the antioxidant capacity of Toxoplasma infected mice compared to the infected untreated ones and to CLN/PYR. In conclusion, although NSO, if administered alone, has significant immunostimulant and antioxidant properties, it failed to decrease tachyzoite counts. Combination of NSO and PYR had synergistic effect in treatment of toxoplasmosis.

  5. Antiplasmodial and antiulcer activities of Melanthera scadens

    Institute of Scientific and Technical Information of China (English)

    Jude E Okokon; Ette O Etebong; John A Udobang; Jackson Obot

    2012-01-01

    Objective: To evaluate the antimalarial and antiulcerogenic activities of leaf extract and fractions of Melanthera scandens (M. scandens). Methods: The crude leaf extract (37-111 mg/kg) and fractions (chloroform, ethylacetate and methanol; 78 mg/kg) of M. scadens were investigated for antiplasmodial activity against chloroquine-sensitive Plasmodium berghei infections in mice and for antiulcer activity against experimentally-induced ulcers. The antimalarial activity during early and established infections as well as prophylactic was investigated. Artesunate (5 mg/kg) and pyrimethamine (1.2 mg/kg) were used as positive controls. Thin films made from tail blood of each mouse were used to assess the level of parasitaemia of the mice. Antiulcer activity of the crude extract was also evaluated against indomethacin, ethanol and histamine induced ulcers.Results:The extract and its fractions dose-dependently reduced parasitaemia induced by chloroquine-sensitive Plasmodium berghei infection in prophylactic, suppressive and curative models in mice. These reductions were statistically significant (P<0.001). They also improved the mean survival time (MST) from 9.28 to 17.73 days as compared with the control (P<0.01 - 0.001). The activities of extract/fractions were incomparable to that of the standard drugs i.e. artesunate and pyrimethamine. On experimentally-induced ulcers, the extract inhibited indomethacin, ethanol and histamine induced ulcers. These inhibitions were statistically significant (P<0.001) and in a dose-dependent fashion. Conclusions: The antiplasmodial and antiulcerogenic effects of this plant may in part be mediated through the chemical constituents of the plant.

  6. Efficacy of non-artemisinin- and artemisinin-based combination therapies for uncomplicated falciparum malaria in Cameroon

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    Thalabard Jean-Christophe

    2010-02-01

    Full Text Available Abstract Background The use of drug combinations, including non-artemisinin-based and artemisinin-based combination therapy (ACT, is a novel strategy that enhances therapeutic efficacy and delays the emergence of multidrug-resistant Plasmodium falciparum. Its use is strongly recommended in most sub-Saharan African countries, namely Cameroon, where resistance to chloroquine is widespread and antifolate resistance is emerging. Methods Studies were conducted in Cameroonian children with acute uncomplicated P. falciparum malaria according to the standard World Health Organization protocol at four sentinel sites between 2003 and 2007. A total of 1,401 children were enrolled, of whom 1,337 were assigned to randomized studies and 64 were included in a single non-randomized study. The proportions of adequate clinical and parasitological response (PCR-uncorrected on day 14 and PCR-corrected on day 28 were the primary endpoints to evaluate treatment efficacy on day 14 and day 28. The relative effectiveness of drug combinations was compared by a multi-treatment Bayesian random-effect meta-analysis. Findings The results based on the meta-analysis suggested that artesunate-amodiaquine (AS-AQ is as effective as other drugs (artesunate-sulphadoxine-pyrimethamine [AS-SP], artesunate-chlorproguanil-dapsone [AS-CD], artesunate-mefloquine [AS-MQ], dihydroartemisinin-piperaquine [DH-PP], artemether-lumefantrine [AM-LM], amodiaquine, and amodiaquine-sulphadoxine-pyrimethamine [AQ-SP]. AM-LM appeared to be the most effective with no treatment failure due to recrudescence, closely followed by DH-PP. Conclusion Although AM-LM requires six doses, rather than three doses for other artemisinin-based combinations, it has potential advantages over other forms of ACT. Further studies are needed to evaluate the clinical efficacy and tolerance of these combinations in different epidemiological context.

  7. Antimalarial and analgesic activities of ethanolic leaf extract of Panicum maximum

    Institute of Scientific and Technical Information of China (English)

    JudeEOkokon; PaulANwafor; UkemeEAndrew

    2011-01-01

    Objective: To evaluate antiplasmodial and analgesic activities of ethanolic leaf extract/fractions of Panicum maximum. Methods:The crude leaf extract (47-190 mg/kg) and fractions (chloroform, ethyl acqeous and methanol; 96 mg/kg) of Panicum maximum were investigated for antiplasmodial activity against chloroquine sensitive Plasmodium berghei infections in mice and for analgesic activity against chemical and heat-induced pains. The antiplasmodial activity during early and established infections as well as prophylactic were investigated. Artesunate at 5 mg/kg and pyrimethamine at 1.2 mg/kg were used as positive controls. Analgesic activity of the crude extract/fractions was also evaluated against acetic acid, formalin and heat-induced pains. Results:The extract and its fractions dose-dependently reduced parasitaemia induced by chloroquine sensitive Plasmodium berghei infection in prophylactic, suppressive and curative models in mice. These reductions were statistically significant (P<0.001). They also improved the mean survival time from 13 to 28 days compared with control (P<0.001).The activities of extract/fractions were incomparable to that of the standard drugs (Artesunate and pyrimethamine). On chemically and thermally-induced pains,the extract inhibited acetic acid and formalin-induced inflammation as well as hot plate-induced pain in mice. These inhibitions were statistically significant (P<0.001) and in a dose-dependent fashion. Conclusions:Panicum maximum leaf extract has antiplasmodial and analgesic activities which may in part be mediated through the chemical constituents of the plant.

  8. Decline of placental malaria in southern Ghana after the implementation of intermittent preventive treatment in pregnancy

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    Eggelte Teunis A

    2007-11-01

    Full Text Available Abstract Background Intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine (IPTp-SP has been adopted as policy by many countries in sub-Saharan Africa. However, data on the post-implementation effectiveness of this measure are scarce. Methods Clinical and parasitological parameters were assessed among women delivering at a district hospital in rural southern Ghana in the year 2000 when pyrimethamine chemoprophylaxis was recommended (n = 839 and in 2006 (n = 226, approximately one year after the implementation of IPTp-SP. Examinations were performed in an identical manner in 2000 and 2006 including the detection of placental Plasmodium falciparum infection by microscopy, histidine-rich protein 2, and PCR. Results In 2006, 77% of the women reported to have taken IPTp-SP at least once (26%, twice; 24%, thrice. In 2006 as compared to 2000, placental P. falciparum infection was reduced by 43–57% (P P = 0.0009, and median birth weight was 130 g higher (P = 0.02. In 2006, likewise, women who had taken ≥ 1 dose of IPTp-SP revealed less infection and anaemia and their children tended to have higher birth weights as compared to women who had not used IPTp-SP. However, placental P. falciparum infection was still observed in 11% (microscopy to 26% (PCR of those women who had taken three doses of IPTp-SP. Conclusion In southern Ghana, placental malaria and maternal anaemia have declined substantially and birth weight has increased after the implementation of IPTp-SP. Likely, these effects can further be increased by improving IPTp-SP coverage and adherence. However, the remnant prevalence of infection in women having taken three doses of IPTp-SP suggests that additional antimalarial measures are needed to prevent malaria in pregnancy in this region.

  9. Plasmodium falciparum Polymorphisms associated with ex vivo drug susceptibility and clinical effectiveness of artemisinin-based combination therapies in Benin.

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    Dahlström, Sabina; Aubouy, Agnès; Maïga-Ascofaré, Oumou; Faucher, Jean-François; Wakpo, Abel; Ezinmègnon, Sèm; Massougbodji, Achille; Houzé, Pascal; Kendjo, Eric; Deloron, Philippe; Le Bras, Jacques; Houzé, Sandrine

    2014-01-01

    Artemisinin-based combination therapies (ACTs) are the main option to treat malaria, and their efficacy and susceptibility must be closely monitored to avoid resistance. We assessed the association of Plasmodium falciparum polymorphisms and ex vivo drug susceptibility with clinical effectiveness. Patients enrolled in an effectiveness trial comparing artemether-lumefantrine (n = 96), fixed-dose artesunate-amodiaquine (n = 96), and sulfadoxine-pyrimethamine (n = 48) for the treatment of uncomplicated malaria 2007 in Benin were assessed. pfcrt, pfmdr1, pfmrp1, pfdhfr, and pfdhps polymorphisms were analyzed pretreatment and in recurrent infections. Drug susceptibility was determined in fresh baseline isolates by Plasmodium lactate dehydrogenase enzyme-linked immunosorbent assay (ELISA). A majority had 50% inhibitory concentration (IC50) estimates (the concentration required for 50% growth inhibition) lower than those of the 3D7 reference clone for desethylamodiaquine, lumefantrine, mefloquine, and quinine and was considered to be susceptible, while dihydroartemisinin and pyrimethamine IC50s were higher. No association was found between susceptibility to the ACT compounds and treatment outcome. Selection was observed for the pfmdr1 N86 allele in artemether-lumefantrine recrudescences (recurring infections) (4/7 [57.1%] versus 36/195 [18.5%]), and of the opposite allele, 86Y, in artesunate-amodiaquine reinfections (new infections) (20/22 [90.9%] versus 137/195 [70.3%]) compared to baseline infections. The importance of pfmdr1 N86 in lumefantrine tolerance was emphasized by its association with elevated lumefantrine IC50s. Genetic linkage between N86 and Y184 was observed, which together with the low frequency of 1246Y may explain regional differences in selection of pfmdr1 loci. Selection of opposite alleles in artemether-lumefantrine and artesunate-amodiaquine recurrent infections supports the strategy of multiple first-line treatment. Surveillance based on clinical, ex

  10. Disagreement in genotyping results of drug resistance alleles of the Plasmodium falciparum dihydrofolate reductase (Pfdhfr) gene by allele-specific PCR (ASPCR) assays and Sanger sequencing.

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    Sharma, Divya; Lather, Manila; Dykes, Cherry L; Dang, Amita S; Adak, Tridibes; Singh, Om P

    2016-01-01

    The rapid spread of antimalarial drug resistance in Plasmodium falciparum over the past few decades has necessitated intensive monitoring of such resistance for an effective malaria control strategy. P. falciparum dihydropteroate synthase (Pfdhps) and P. falciparum dihydrofolate reductase (Pfdhfr) genes act as molecular markers for resistance against the antimalarial drugs sulphadoxine and pyrimethamine, respectively. Resistance to pyrimethamine which is used as a partner drug in artemisinin combination therapy (ACT) is associated with several mutations in the Pfdhfr gene, namely A16V, N51I, C59R, S108N/T and I164L. Therefore, routine monitoring of Pfdhfr-drug-resistant alleles in a population may help in effective drug resistance management. Allele-specific PCR (ASPCR) is one of the commonly used methods for molecular genotyping of these alleles. In this study, we genotyped 55 samples of P. falciparum for allele discrimination at four codons of Pfdhfr (N51, C59, S108 and I164) by ASPCR using published methods and by Sanger's DNA sequencing method. We found that the ASPCR identified a significantly higher number of mutant alleles as compared to the DNA sequencing method. Such discrepancies arise due to the non-specificity of some of the allele-specific primer sets and due to the lack of sensitivity of Sanger's DNA sequencing method to detect minor alleles present in multiple clone infections. This study reveals the need of a highly specific and sensitive method for genotyping and detecting minor drug-resistant alleles present in multiple clonal infections.

  11. Coverage, adherence and costs of intermittent preventive treatment of malaria in children employing different delivery strategies in Jasikan, Ghana.

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    Edith Patouillard

    Full Text Available BACKGROUND: Intermittent preventive treatment of malaria in children (IPTc involves the administration of a course of anti-malarial drugs at specified time intervals to children at risk of malaria regardless of whether or not they are known to be infected. IPTc provides a high level of protection against uncomplicated and severe malaria, with monthly sulphadoxine-pyrimethamine plus amodiaquine (SP&AQ and sulphadoxine-pyrimethamine plus piperaquine being the most efficacious regimens. A key challenge is the identification of a cost-effective delivery strategy. METHODS: A community randomized trial was undertaken in Jasikan district, Ghana to assess IPTc effectiveness and costs using SP&AQ delivered in three different ways. Twelve villages were randomly selected to receive IPTc from village health workers (VHWs or facility-based nurses working at health centres' outpatient departments (OPD or EPI outreach clinics. Children aged 3 to 59 months-old received one IPT course (three doses in May, June, September and October. Effectiveness was measured in terms of children covered and adherent to a course and delivery costs were calculated in financial and economic terms using an ingredient approach from the provider perspective. RESULTS: The economic cost per child receiving at least the first dose of all 4 courses was US$4.58 when IPTc was delivered by VHWs, US$4.93 by OPD nurses and US$ 5.65 by EPI nurses. The unit economic cost of receiving all 3 doses of all 4 courses was US$7.56 and US$8.51 when IPTc was delivered by VHWs or facility-based nurses respectively. The main cost driver for the VHW delivery was supervision, reflecting resources used for travelling to more remote communities rather than more intense supervision, and for OPD and EPI delivery, it was the opportunity cost of the time spent by nurses in dispensing IPTc. CONCLUSIONS: VHWs achieve higher IPTc coverage and adherence at lower costs than facility-based nurses in Jasikan district

  12. Anti-malarial effect of semi-synthetic drug amitozyn.

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    Tcherniuk, Sergey O; Chesnokova, Olga; Oleinikov, Irina V; Potopalsky, Anatoly I; Oleinikov, Andrew V

    2015-10-29

    Malaria caused by Plasmodium falciparum is the most virulent form of malaria, leading to approximately a half million deaths per year. Chemotherapy continues to be a key approach in malaria prevention and treatment. Due to widespread parasite drug resistance, identification and development of new anti-malarial compounds remains an important task of malarial parasitology. The semi-synthetic drug amitozyn, obtained through alkylation of major celandine (Chelidonium majus) alkaloids with N,N'N'-triethylenethiophosphoramide (ThioTEPA), is a widely used Eastern European folk medicine for the treatment of various tumours. However, its anti-malarial effect has never been studied. The anti-malarial effects of amitozyn alone and in combination with chloroquine, pyrimethamine and artemisinin on the blood stages of P. falciparum were analysed. The cytostatic effects of amitozyn on parasites and various cancerous and non-cancerous human cells were compared and their toxic effects on unparasitized human red blood cells were analysed. Obtained results demonstrate that amitozyn effectively inhibits the growth of blood-stage parasites with IC50 9.6 ± 2, 11.3 ± 2.8 and 10.8 ± 1.8 μg/mL using CS2, 3G8 and NF54 parasite lines, respectively. The median IC50 for 14 tested human cell lines was 33-152 μg/mL. Treatment of uninfected red blood cells with a high dose of amitozyn (500 μg/mL) did not change cell morphology, demonstrating its non-toxicity for erythrocytes. The synergistic impact of the amitozyn/chloroquine combination was observed at growth inhibition levels of 10-80 %, while demonstrating a nearly additive effect at a growth inhibition level of 90 %. The combination of amitozyn with pyrimethamine has a synergistic effect at growth inhibition levels of 10-70 % and a nearly additive effect at a growth inhibition level of 90 %. The synergistic anti-malarial effect of the amitozyn/artemisinin combination was observed at growth inhibition levels of 10-40 % and a nearly

  13. CLINICAL PROFILE OF CEREBRAL TOXOPLASMOSIS IN HIV INFECTED PATIENTS ADMITTED TO THE BOWRING AND VICTORIA HOSPITAL DURING THE PERIOD SEPTEMBER 2007 TO SEPTEMBER 2009

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    Hareesh

    2015-10-01

    Full Text Available BACKGROUND : TE was the frequent CNS opportunistic infection in AIDS in the pre - HAART era. It occurred in 10% of the patients or more depending on the geographic origin, in areas where HAART is not used widely and where AIDS patients are not on appropriate anti - paras itic prophylaxis. Cerebral toxoplasmosis in AIDS almost always occurs from recrudescence of previously acquired infection. It usually occurs in patients with CD4 counts less than 100/μ L. Most recently the incidence of cerebral toxoplasmosis has further decreased in the HAART era. The clinical profile of Cerebral toxoplasmosis is as similar to other neuro infection, but differs radiologically and treatment response. OBJECTIVES: The present study is taken up with respect to its c linical manifestations, diagnostic features, response to therapy and outcome. METHODS : We carried out a prospective observational study in 30 patients of cerebral toxoplasmosis who were HIV Seropositive, at Bowring & Victoria Hospitals attached to Bangalor e Medical College and Research Institute, Bangalore from September 2007 to September 2009. RESULTS : Out of 30 patients studied, the mean age was35.7±9.3 years. Prevalence of TE was more in males ( Ratio was 2.01. Headache and altered sensorium were more co mmon presentation 73.3% each. Mean CD4 count was 59.57± 5.32 (4:14 cells/ μ L. 22(73.3% were positive for serum antitoxoplasma IgG antibodies. Majority of the TE patients 76.7% showed bilateral multiple ring enhancing hypodense lesion, 20% of the patients s howed solitary lesions. Among the 30 patients, clinical outcome was good with 18(60% improved to combination therapy of pyrimethamine plus sulfadiazine for a period of 14±2 days with minimum toxicity and 6 (20%patients died during the therapy and 6(20% patients lost follow up. CONCLUSION : TE was the AIDS defining illness in 50% of our patients. In patients with AIDS, TE is usually a presumptive diagnosis. CT scan brain, was found to be the

  14. Prescription practices and availability of artemisinin monotherapy in India: where do we stand?

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    Mishra Neelima

    2011-12-01

    Full Text Available Abstract Background The World Health Organization has urged all member states to deploy artemisinin-based combination therapy and progressively withdraw oral artemisinin monotherapies from the market due to their high recrudescence rates and to reduce the risk of drug resistance. Prescription practices by physicians and the availability of oral artemisinin monotherapies with pharmacists directly affect the pattern of their use. Thus, treatment practices for malaria, with special reference to artemisinin monotherapy prescription, in selected states of India were evaluated. Methods Structured, tested questionnaires were used to conduct convenience surveys of physicians and pharmacists in eleven purposively selected districts across six states in 2008. In addition, exit interviews of patients with a diagnosis of uncomplicated malaria or a prescription for an anti-malarial drug were also performed. Logistic regression was used to determine patient clinical care, and institutional factors associated with artemisinin monotherapy prescription. Results Five hundred and eleven physicians from 196 health facilities, 530 pharmacists, and 1, 832 patients were interviewed. Artemisinin monotherapy was available in 72.6% of pharmacies and was prescribed by physicians for uncomplicated malaria in all study states. Exit interviews among patients confirmed the high rate of use of artemisinin monotherapy with 14.8% receiving such a prescription. Case management, i.e. method of diagnosis and overall treatment, varied by state and public or private sector. Treatment in the private sector (OR 8.0, 95%CI: 3.8, 17 was the strongest predictor of artemisinin monotherapy prescription when accounting for other factors. Use of the combination therapy recommended by the national drug policy, artesunate + sulphadoxine-pyrimethamine, was minimal (4.9%, with the exception of one state. Conclusions Artemisinin monotherapy use was widespread across India in 2008. The accessible

  15. A retrospective evaluation of the quality of malaria case management at twelve health facilities in four districts in Zambia

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    Pascalina Chanda-Kapata; Emmanuel Chanda; Freddie Masaninga; Annette Habluetzel; Felix Masiye; Ibrahima Soce Fall

    2014-01-01

    Objective: To establish the appropriateness of malaria case management at health facility level in four districts in Zambia. Methods: This study was a retrospective evaluation of the quality of malaria case management at health facilities in four districts conveniently sampled to represent both urban and rural settings in different epidemiological zones and health facility coverage. The review period was from January to December 2008. The sample included twelve lower level health facilities from four districts. The Pearson Chi-square test was used to identify characteristics which affected the quality of case management.Results:Out of 4891 suspected malaria cases recorded at the 12 health facilities, more than 80% of the patients had a temperature taken to establish their fever status. About 67% (CI95 66.1-68.7) were tested for parasitemia by either rapid diagnostic test or microscopy, whereas the remaining 22.5% (CI95 21.3.1-23.7) were not subjected to any malaria test. Of the 2247 malaria cases reported (complicated and uncomplicated), 71% were parasitologically confirmed while 29% were clinically diagnosed (unconfirmed). About 56% (CI95 53.9-58.1) of the malaria cases reported were treated with artemether-lumefantrine (AL), 35% (CI95 33.1-37.0) with sulphadoxine-pyrimethamine, 8% (CI95 6.9-9.2) with quinine and 1% did not receive any anti-malarial. Approximately 30% of patients WHO were found negative for malaria parasites were still prescribed an anti-malarial, contrary to the guidelines. There were marked inter-district variations in the proportion of patients in WHOm a diagnostic tool was used, and in the choice of anti-malarials for the treatment of malaria confirmed cases. Association between health worker characteristics and quality of case malaria management showed that nurses performed better than environmental health technicians and clinical officers on the decision whether to use the rapid diagnostic test or not. Gender, in service training on malaria

  16. Characterization of Plasmodium falciparum genes associated with drug resistance in Hodh Elgharbi, a malaria hotspot near Malian-Mauritanian border.

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    Ould Ahmedou Salem, Mohamed Salem; Mint Lekweiry, Khadijetou; Bouchiba, Houssem; Pascual, Aurelie; Pradines, Bruno; Ould Mohamed Salem Boukhary, Ali; Briolant, Sébastien; Basco, Leonardo K; Bogreau, Hervé

    2017-04-05

    A malaria hotspot in the southeastern region of Mauritania, near the Malian border, may hamper malaria control strategies. The objectives were to estimate the prevalence of genetic polymorphisms associated with drug resistance in Plasmodium falciparum isolates and establish baseline data. The study was conducted in two malaria-endemic areas in Hodh Elgharbi, situated in the Malian-Mauritanian border area. Blood samples were collected from symptomatic patients. Single nucleotide polymorphisms in Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps were genotyped using PCR-restriction fragment length polymorphism, DNA sequencing and primer extension. The Pfmdr1 gene copy number was determined by real-time PCR. Of 280 P. falciparum-infected patients, 193 (68.9%) carried the Pfcrt 76T mutant allele. The Pfmdr1 86Y and 184F mutations were found in 61 (23.1%) of 264 isolates and 167 (67.6%) of 247 samples that were successfully genotyped, respectively. Pfmdr1 mutant alleles 1034C, 1042D and 1246Y were rarely observed. Of 102 P. falciparum isolates analysed, ten (9.8%) had more than one copy of Pfmdr1 gene. The prevalence of isolates harbouring at least triple mutant Pfdhfr 51I, 59R, 108 N/T was 42% (112/268), of which 42 (37.5%) had an additional Pfdhps 437G mutation. The Pfdhps 540E mutation was observed in four isolates (1.5%), including three associated with Pfdhfr triple mutant. Only two quintuple mutants (Pfdhfr-51I-59R-108N Pfdhps-437G-540E) were observed. The observed mutations in Pfdhfr, Pfdhps, Pfmdr1, and Pfcrt may jeopardize the future of seasonal malaria chemoprevention based on amodiaquine-sulfadoxine-pyrimethamine, intermittent preventive treatment for pregnant women using sulfadoxine-pyrimethamine, and treatment with artesunate-amodiaquine. Complementary studies should be carried out to document the distribution, origin and circulation of P. falciparum populations in this region and more widely in the country to assess the risk of the spread of resistance.

  17. The drug sensitivity and transmission dynamics of human malaria on Nias Island, North Sumatra, Indonesia.

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    Fryauff, D J; Leksana, B; Masbar, S; Wiady, I; Sismadi, P; Susanti, A I; Nagesha, H S; Syafruddin; Atmosoedjono, S; Bangs, M J; Baird, J K

    2002-07-01

    Nias Island, off the north-western coast of Sumatra, Indonesia, was one of the first locations in which chloroquine-resistant Plasmodium vivax malaria was reported. This resistance is of particular concern because its ancient megalithic culture and the outstanding surfing conditions make the island a popular tourist destination. International travel to and from the island could rapidly spread chloroquine-resistant strains of P. vivax across the planet. The threat posed by such strains, locally and internationally, has led to the routine and periodic re-assessment of the efficacy of antimalarial drugs and transmission potential on the island. Active case detection identified malaria in 124 (17%) of 710 local residents whereas passive case detection, at the central health clinic, confirmed malaria in 77 (44%) of 173 cases of presumed 'clinical malaria'. Informed consenting volunteers who had malarial parasitaemias were treated, according to the Indonesian Ministry of Health's recommendations, with sulfadoxine-pyrimethamine (SP) on day 0 (for P. falciparum) or with chloroquine (CQ) on days 0, 1 and 2 (for P. vivax). Each volunteer was then monitored for clinical and parasite response until day 28. Recurrent parasitaemia by day 28 treatment was seen in 29 (83%) of the 35 P. falciparum cases given SP (14, 11 and four cases showing RI, RII and RIII resistance, respectively). Recurrent parasitaemia was also observed, between day 11 and day 21, in six (21%) of the 28 P. vivax cases given CQ. Although the results of quantitative analysis confirmed only low prevalences of CQ-resistant P. vivax malaria, the prevalence of SP resistance among the P. falciparum cases was among the highest seen in Indonesia. When the parasites present in the volunteers with P. falciparum infections were genotyped, mutations associated with pyrimethamine resistance were found at high frequency in the dhfr gene but there was no evidence of selection for sulfadoxine resistance in the dhps gene

  18. Drug resistance and genetic diversity of Plasmodium falciparum parasites from suriname.

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    Peek, Ron; VAN Gool, Tom; Panchoe, Daynand; Greve, Sophie; Bus, Ellen; Resida, Lesley

    2005-11-01

    Plasmodium falciparum in Suriname was studied for the presence of drug resistance and genetic variation in blood samples of 86 patients with symptomatic malaria. Drug resistance was predicted by determining point mutations in the chloroquine resistance marker of the P. falciparum chloroquine resistance transporter (pfcrt) gene (codon 76) and the pyrimethamine-sulfadoxine resistance markers in the dihydrofolate reductase (dhfr) gene (codons 16, 51, 59, 108, and 164) and dihydropteroate synthase (dhps) gene (codons 436, 437, 540, 581, and 613). Genetic variability was determined by sequence analysis of the polymorphic segments of the merozoite surface protein 2 (msp-2) and glutamate-rich protein (glurp) genes. Mutations in the pfcrt, dhps, and dhfr genes were found in all samples tested, suggesting that resistance to chloroquine and antifolate drugs is present at a high frequency. A low number of alleles was found for the msp-2 and glurp genes. This indicates limited genetic diversity and, based on geographic data, a genetically homogeneous P. falciparum population in Suriname.

  19. A country on the verge of malaria elimination--the Kingdom of Saudi Arabia.

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    Michael Coleman

    Full Text Available Significant headway has been made in the global fight against malaria in the past decade and as more countries enter the elimination phase, attention is now focused on identifying effective strategies to shrink the malaria map. Saudi Arabia experienced an outbreak of malaria in 1998, but is now on the brink of malaria elimination, with just 82 autochthonous cases reported in 2012. A review of published and grey literature was performed to identify the control strategies that have contributed to this achievement. The number of autochthonous malaria cases in Saudi Arabia decreased by 99.8% between 1998 and 2012. The initial steep decline in malaria cases coincided with a rapid scaling up of vector control measures. Incidence continued to be reported at low levels (between 0.01 and 0.1 per 1,000 of the population until the adoption of artesunate plus sulfadoxine-pyrimethamine as first line treatment and the establishment of a regional partnership for a malaria-free Arabian Peninsula, both of which occurred in 2007. Since 2007, incidence has decreased by nearly an order of magnitude. Malaria incidence is now very low, but a high proportion of imported cases, continued potential for autochthonous transmission, and an increased proportion of cases attributable to Plasmodium vivax all present challenges to Saudi Arabia as they work toward elimination by 2015.

  20. Evaluation of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: Implications for schizophrenia

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    Notarangelo, F. M.; Wilson, E. H.; Horning, K. J.; Thomas, M. A. R.; Harris, T. H.; Fang, Q.; Hunter, C. A.; Schwarcz, R.

    2014-01-01

    Toxoplasma gondii, an intracellular protozoan parasite, is a major cause of opportunistic infectious disease affecting the brain and has been linked to an increased incidence of schizophrenia. In murine hosts, infection with T. gondii stimulates tryptophan degradation along the kynurenine pathway (KP), which contains several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA). As these endogenous compounds may provide a mechanistic connection between T. gondii and the pathophysiology of schizophrenia, we measured KP metabolites in both brain and periphery of T. gondii-treated C57BL/6 mice 8 and 28 days post-infection. Infected mice showed early decreases in the levels of tryptophan in brain and serum, but not in the liver. These reductions were associated with elevated levels of kynurenine, KYNA, 3-HK and QUIN in the brain. In quantitative terms, the most significant increases in these KP metabolites were observed in the brain at 28 days post-infection. Notably, the anti-parasitic drugs pyrimethamine and sulfadiazine, a standard treatment of toxoplasmosis, significantly reduced 3-HK and KYNA levels in the brain of infected mice when applied between 28 and 56 days post-infection. In summary, T. gondii infection, probably by activating microglia and astrocytes, enhances the production of KP metabolites in the brain. However, during the first two months after infection, the KP changes in these mice do not reliably duplicate abnormalities seen in the brain of individuals with schizophrenia. PMID:24345671

  1. Analyzing Thiol-Dependent Redox Networks in the Presence of Methylene Blue and Other Antimalarial Agents with RT-PCR-Supported in silico Modeling

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    Zirkel, J.; Cecil, A.; Schäfer, F.; Rahlfs, S.; Ouedraogo, A.; Xiao, K.; Sawadogo, S.; Coulibaly, B.; Becker, K.; Dandekar, T.

    2012-01-01

    Background In the face of growing resistance in malaria parasites to drugs, pharmacological combination therapies are important. There is accumulating evidence that methylene blue (MB) is an effective drug against malaria. Here we explore the biological effects of both MB alone and in combination therapy using modeling and experimental data. Results We built a model of the central metabolic pathways in P. falciparum. Metabolic flux modes and their changes under MB were calculated by integrating experimental data (RT-PCR data on mRNAs for redox enzymes) as constraints and results from the YANA software package for metabolic pathway calculations. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, chloroquine resistance based on pfmdr/and pfcrt transporters, as well as pyrimethamine/sulfadoxine resistance (by mutations in DHF/DHPS), were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs. Conclusions Theoretical and experimental results support that methylene blue should, because of its resistance-breaking potential, be further tested as a key component in drug combination therapy efforts in holoendemic areas. PMID:23236254

  2. Herbicidal properties of antimalarial drugs.

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    Corral, Maxime G; Leroux, Julie; Stubbs, Keith A; Mylne, Joshua S

    2017-03-31

    The evolutionary relationship between plants and the malarial parasite Plasmodium falciparum is well established and underscored by the P. falciparum apicoplast, an essential chloroplast-like organelle. As a result of this relationship, studies have demonstrated that herbicides active against plants are also active against P. falciparum and thus could act as antimalarial drug leads. Here we show the converse is also true; many antimalarial compounds developed for human use are highly herbicidal. We found that human antimalarial drugs (e.g. sulfadiazine, sulfadoxine, pyrimethamine, cycloguanil) were lethal to the model plant Arabidopsis thaliana at similar concentrations to market herbicides glufosinate and glyphosate. Furthermore, the physicochemical properties of these herbicidal antimalarial compounds were similar to commercially used herbicides. The implications of this finding that many antimalarial compounds are herbicidal proffers two novel applications: (i) using the genetically tractable A. thaliana to reveal mode-of-action for understudied antimalarial drugs, and (ii) co-opting antimalarial compounds as a new source for much needed herbicide lead molecules.

  3. Molecular genetic transfection of the coccidian parasite Sarcocystis neurona.

    Science.gov (United States)

    Gaji, Rajshekhar Y; Zhang, Deqing; Breathnach, Cormac C; Vaishnava, Shipra; Striepen, Boris; Howe, Daniel K

    2006-11-01

    Sarcocystis neurona is an apicomplexan parasite that is the major cause of equine protozoal myeloencephalitis (EPM). The biology of this pathogen remains poorly understood in part due to unavailability of molecular genetic tools. Hence, with an objective to develop DNA transfection capabilities for S. neurona, the 5' flanking region of the SnSAG1 gene was isolated from a genomic library and used to construct expression plasmids. In transient assays, the reporter molecules beta-galactosidase (beta-gal) and yellow fluorescent protein (YFP) could be detected in electroporated S. neurona, thereby confirming the feasibility of transgene expression in this organism. Stable transformation of S. neurona was achieved using a mutant dihydrofolate reductase thymidylate synthase (DHFR-TS) gene of Toxoplasma gondii that confers resistance to pyrimethamine. This selection system was used to create transgenic S. neurona that stably express beta-gal and YFP. As shown in this study, these transgenic clones can be useful for analyzing growth rate of parasites in vitro and for assessing drug sensitivities. More importantly, the DNA transfection methods described herein should greatly facilitate studies examining intracellular parasitism by this important coccidian pathogen.

  4. Aneuploidy in mammalian somatic cells in vivo.

    Science.gov (United States)

    Cimino, M C; Tice, R R; Liang, J C

    1986-01-01

    Aneuploidy is an important potential source of human disease and of reproductive failure. Nevertheless, the ability of chemical agents to induce aneuploidy has been investigated only sporadically in intact (whole-animal) mammalian systems. A search of the available literature from the EMCT Aneuploidy File (for years 1970-1983) provided 112 papers that dealt with aneuploidy in mammalian somatic cells in vivo. 59 of these papers did not meet minimal criteria for analysis and were rejected from subsequent review. Of the remaining 53 papers that dealt with aneuploidy induction by chemical agents in mammalian somatic cells in vivo, only 3 (6%) contained data that were considered to be supported conclusively by adequate study designs, execution, and reporting. These 3 papers dealt with 2 chemicals, one of which, mercury, was negative for aneuploidy induction in humans, and the other, pyrimethamine, was positive in an experimental rodent study. The majority of papers (94%) were considered inconclusive for a variety of reasons. The most common reasons for calling a study inconclusive were (a) combining data on hyperploidy with those on hypoploidy and/or polyploidy, (b) an inadequate or unspecified number of animals and/or cells per animal scored per treatment group, and (c) poor data presentation such that animal-to-animal variability could not be assessed. Suggestions for protocol development are made, and the future directions of research into aneuploidy induction are discussed.

  5. HIV-related movement disorders: epidemiology, pathogenesis and management.

    Science.gov (United States)

    Cardoso, Francisco

    2002-01-01

    Clinically relevant movement disorders are identified in 3% of patients with HIV infection seen at tertiary referral centres. In the same setting, prospective follow-up shows that 50% of patients with AIDS develop tremor, parkinsonism or other extrapyramidal features. Hemiballism-hemichorea and tremor are the most common hyperkinesias seen in patients who are HIV positive, but other movement disorders diagnosed in these patients include dystonia, chorea, myoclonus, tics, paroxysmal dyskinesias and parkinsonism. Patients with movement disorders usually present with other clinical features such as peripheral neuropathy, seizures, myelopathy and dementia. In the vast majority of patients, hyperkinesias result from lesions caused by opportunistic infections, particularly toxoplasmosis, which damage the basal ganglia connections. On the other hand, parkinsonism and tremor can result from dopaminergic dysfunction resulting from HIV itself or the use of antidopaminergic drugs. The management of patients who are HIV positive who present with movement disorders involves recognition and treatment of opportunistic infections, symptomatic treatment of the movement disorder and the use of highly active antiretroviral therapy (HAART). The most effective treatment of cerebral toxoplasmosis in patients with HIV infection is the combination of sulfadiazine and pyrimethamine. Symptomatic treatment of the movement disorder is often disappointing: hemiballism improves with antipsychotics, but tremor, parkinsonism and other phenomena usually fail to respond to available therapies. Preliminary data suggest that HAART may be helpful in the symptomatic control as well as prevention of movement disorders in patients who are HIV positive.

  6. A cohort study of Plasmodium falciparum malaria in pregnancy and associations with uteroplacental blood flow and fetal anthropometrics in Kenya.

    Science.gov (United States)

    McClure, Elizabeth M; Meshnick, Steven R; Lazebnik, Noam; Mungai, Peter; King, Christopher L; Hudgens, Michael; Goldenberg, Robert L; Siega-Riz, Anna-Maria; Dent, Arlene E

    2014-07-01

    To use ultrasound to explore the impact of malaria in pregnancy on fetal growth and newborn outcomes among a cohort of women enrolled in an intermittent presumptive treatment in pregnancy (IPTp) with sulfadoxine/pyrimethamine (SP) program in coastal Kenya. Enrolled women were tested for malaria at first prenatal care visit, and physical and ultrasound examinations were performed. In total, 477 women who had term, live births had malaria tested at delivery and their birth outcomes assessed, and were included in the study. Peripheral malaria was detected via polymerase chain reaction among 10.9% (n=87) at first prenatal care visit and 8.8% (n=36) at delivery. Insecticide-treated bed nets (ITNs) were used by 73.6% (n=583) and were associated with decreased malaria risk. There was a trend for impaired fetal growth and placental blood flow in malaria-infected women in the second trimester, but not later in pregnancy. Among women with low body mass index (BMI), malaria was associated with reduced birth weight (P=0.04); anthropometric measures were similar otherwise. With IPTp-SP and ITNs, malaria in pregnancy was associated with transient differences in utero, and reduced birth weight was restricted to those with low BMI. Copyright © 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

  7. Sequential synthesis of amino-1,4-naphthoquinone-appended triazoles and triazole-chromene hybrids and their antimycobacterial evaluation.

    Science.gov (United States)

    Devi Bala, Balasubramanian; Muthusaravanan, Sivasubramanian; Choon, Tan Soo; Ashraf Ali, Mohamed; Perumal, Subbu

    2014-10-06

    A general method for the synthesis of a library of hitherto unreported amino-1,4-naphthoquinone-appended triazoles was accomplished via a sequential three-component reaction of substituted N-propargylaminonaphthoquinones with variously substituted alkyl bromides/2-bromonaphthalene-1,4-dione and sodium azide in the presence of Et3N/CuI in water. Aminonaphthoquinone-appended iminochromene-triazole hybrid heterocycles were also synthesized from the amino-1,4-naphthoquinone-appended-1,2,3-triazolylacetonitriles. All the triazole hybrids were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB). Among the triazoles, 2-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)(4-(trifluoromethyl)phenyl)amino)naphthalene-1,4-dione (7d) emerged as the most active one with IC50 = 1.87 μM, being more potent than the anti-TB drugs, cycloserine (6 times), pyrimethamine (20 times) and equipotent as the drug ethambutol (IC50 < 1.56 μM). Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  8. Mother-to-Children Plasmodium falciparum Asymptomatic Malaria Transmission at Saint Camille Medical Centre in Ouagadougou, Burkina Faso

    Science.gov (United States)

    Douamba, Zoenabo; Dao, Nangnéré Ginette Laure; Zohoncon, Théodora Mahoukédé; Bisseye, Cyrille; Compaoré, Tegwindé Rebeca; Kafando, Jacques Gilbert; Sombie, Bavouma Charles; Ouermi, Djeneba; Djigma, Florencia W.; Ouedraogo, Paul; Ghilat, Nadine; Colizzi, Vittorio; Simpore, Jacques

    2014-01-01

    Background. Malaria's prevalence during pregnancy varies widely in parts of sub-Saharan Africa, including Burkina Faso. The objective of this study was to evaluate the incidence of mother-to-child malaria transmission during childbirth at St. Camille Medical Centre in the city of Ouagadougou. Methods. Two hundred and thirty-eight (238) women and their newborns were included in the study. Women consenting to participate in this study responded to a questionnaire that identified their demographic characteristics. Asymptomatic malaria infection was assessed by rapid detection test Acon (Acon Malaria Pf, San Diego, USA) and by microscopic examination of Giemsa-stained thick and thin smears from peripheral, placental, and umbilical cord blood. Birth weights were recorded and the biological analyses of mothers and newborns' blood were also performed. Results. The utilization of long-lasting insecticidal nets (LLINs) and intermittent preventive treatment with sulfadoxine-pyrimethamine (SP) were 86.6% and 84.4%, respectively. The parasitic infection rates of 9.5%, 8.9%, and 2.8% were recorded, respectively, for the peripheral, placental, and umbilical cord blood. Placental infection was strongly associated with the presence of parasites in the maternal peripheral blood and a parasite density of >1000 parasites/µL. Conclusion. The prevalence of congenital malaria was reduced but was associated with a high rate of mother-to-child malaria transmission. PMID:25506464

  9. [Clinical and developmental aspects of care-related tetanus in the reference service of the teaching hospital of Abidjan].

    Science.gov (United States)

    Aba, T; Kra, O; Ehui, E; Tanon, K A; Kacou, A R; Ouatara, B; Bissagnéné, E; Kadio, A

    2011-02-01

    A cross-sectional descriptive study was conducted from medical data of inpatients with tetanus in the Department of Infectious and Tropical Diseases of the University Hospital of Treichville in Abidjan from January 2003 to December 2007. In five years, 221 cases of tetanus have been hospitalized. The tetanus gateway was found in 188 patients (85%). Tetanus gateway linked to care was found in 22 patients (11.7%). Acts of care in question were intramuscular injections (10 cases) and operative procedures (12 cases). Concerning medical care by intramuscular injection, quinine (four cases), sulfadoxine-pyrimethamine (one case), and long-acting penicillin (one case) were the identified drugs. The operative procedures mainly involved were skin sutures (nine cases), cures of hernia (two cases), and flattening of Fournier's gangrene (one case). The average incubation period was 9.5 days. The invasion lasted for an average of 1.8 days. On admission, tetanus was immediately generalized for all patients with the presence of paroxysms in 20 patients (90.9%). The lethality of tetanus related care was 54.5%. The death rate in the first 48 hours of hospitalization was estimated at 83.3%. The average length of hospital stay was 14.6 days. Health workers should be involved in the prevention of tetanus in improving the quality of care and especially in reducing intramuscular injections. Also, any patient not immunized against tetanus should receive anti-tetanus serum and an update of its tetanus vaccine before any invasive procedures.

  10. Effects of Extracts from Thai Piperaceae Plants against Infection with Toxoplasma gondii

    Science.gov (United States)

    Leesombun, Arpron; Boonmasawai, Sookruetai; Shimoda, Naomi; Nishikawa, Yoshifumi

    2016-01-01

    Herbal medicines and natural herb extracts are widely used as alternative treatments for various parasitic diseases, and such extracts may also have potential to decrease the side effects of the standard regimen drugs used to treat toxoplasmosis (sulfadiazine-pyrimethamine combination). We evaluated how effective the Thai piperaceae plants Piper betle, P. nigrum and P. sarmentosum are against Toxoplasma gondii infection in vitro and in vivo. Individually, we extracted the piperaceae plants with ethanol, passed them through a rotary evaporator and then lyophilized them to obtain crude extracts for each one. The in vitro study indicated that the P. betle extract was the most effective extract at inhibiting parasite growth in HFF cells (IC50 on RH-GFP: 23.2 μg/mL, IC50 on PLK-GFP: 21.4 μg/mL). Furthermore, treatment of experimental mice with the P. betle extract for 7 days after infection with 1,000 tachyzoites of the T. gondii PLK strain increased their survival (survival rates: 100% in 400 mg/kg-treated, 83.3% in 100 mg/kg-treated, 33.3% in 25 mg/kg-treated, 33.3% in untreated mice). Furthermore, treatment with 400 mg/kg of the P. betle extract resulted in 100% mouse survival following infection with 100,000 tachyzoites. The present study shows that P. betle extract has the potential to act as a medical plant for the treatment of toxoplasmosis. PMID:27213575

  11. In vivo antiplasmodial potentials of the combinations of four nigerian antimalarial plants.

    Science.gov (United States)

    Adebajo, Adeleke Clement; Odediran, Samuel Akintunde; Aliyu, Fatimah Abosede; Nwafor, Paul Alozie; Nwoko, Ndifreke Thomas; Umana, Usenobong Samuel

    2014-08-26

    Various combinations of Nauclea latifolia root, Artocarpus altilis stem bark, Murraya koenigii leaf and Enantia chlorantha stem bark used in African ethnomedicine as decoctions for malaria and fevers, and combinations with standard drugs, were investigated for antiplasmodial activities using Plasmodium berghei berghei-infected mice. The respective prophylactic and curative ED50 values of 189.4 and 174.5 mg/kg for N. latifolia and chemosuppressive ED50 value of 227.2 mg/kg for A. altilis showed that they were the best antimalarial herbal drugs. A 1.6-fold increase of the survival time given by the negative control was elicited by M. koenigii, thereby confirming its curative activity. Pyrimethamine with an ED50 of 0.5 ± 0.1 mg/kg for the prophylactic, and chloroquine with ED50 = 2.2 ± 0.1 and 2.2 ± 0.0 mg/kg for the chemosuppressive and curative tests, respectively, were significantly (p altilis or N. latifolia enhanced their respective prophylactic or curative activities, making these combinations most beneficial against malaria infections. Combinations of three and four extracts gave varied activities. Hence, the results justified the combinations of ethnomedicinal plants in antimalarial herbal remedies and showed the importance of the three in vivo models in establishing antimalarial activity.

  12. [Retrospective study of the implementation of the qualitative PCR technique in biological samples for monitoring toxoplasmosis in pediatric patients receiving hematopoietic stem cell transplantation].

    Science.gov (United States)

    Nigro, Mónica G; Figueroa, Carlos; Ledesma, Bibiana A

    2014-01-01

    Toxoplasmosis is an opportunistic infection caused by the parasite Toxoplasma gondii. The infection is severe and difficult to diagnose in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twelve patients receiving HSCT were monitored post-transplant, by qualitative PCR at the Children's Hospital S.A.M.I.C. "Prof. Dr. Juan P. Garrahan". The monitoring of these patients was defined by a history of positive serology for toxoplasmosis in the donor or recipient and because their hematologic condition did not allow the use of trimethoprim-sulfamethoxazole for prophylaxis. During the patients' monitoring, two of them with positive PCR results showed signs of illness by T. gondii and were treated with pyrimethamine-clindamycin. In two other patients, toxoplasmosis was the cause of death and an autopsy finding, showing negative PCR results. Four patients without clinical manifestations received treatment for toxoplasmosis because of positive PCR detection. In four patients there were no signs of toxoplasmosis disease and negative PCR results during follow-up. The qualitative PCR technique proved useful for the detection of toxoplasmosis reactivation in HSCT recipients, but has limitations in monitoring and making clinical decisions due to the persistence of positive PCR over time and manifestations of toxicity caused by the treatment.

  13. Multiresidue method for the determination of pharmacologically active substances in egg and honey using a continuous solid-phase extraction system and gas chromatography-mass spectrometry.

    Science.gov (United States)

    Azzouz, Abdelmonaim; Ballesteros, Evaristo

    2015-07-01

    A sensitive, selective, efficient gas chromatography-mass spectrometry method for the simultaneous determination of 22 pharmacologically active substances (antibacterials, nonsteroidal antiinflammatories, antiseptics, antiepileptics, lipid regulators, β-blockers and hormones) in eggs and honey was developed. The sample pretreatment includes precipitation of proteins and lipids with acetonitrile:water (3:2, v/v), centrifugation and continuous solid-phase extraction for cleanup and preconcentration. The proposed method was validated with quite good analytical results including limits of detection of 0.4-3.3 ng/kg for 2g of sample and good linearity (r(2)>0.995) throughout the studied concentration ranges. The recoveries of analytes from real honey and egg samples spiked at concentrations of 15-2,000 ng/kg fell in the range 87-102%, with relative standard deviations from 2.6% to 7.0%. The method was successfully used to determine the target compounds in various types of eggs (hen, quail and duck) and honey samples (flower, forest, acacia, sunflower, clover and pine tree). Two samples of hen eggs bought at supermarkets and one of quail eggs were found to contain florfenicol, pyrimethamine, estrone and 17β-estradiol at levels from 0.095 to 2.7 μg/kg.

  14. Development and validation of a generic liquid chromatographic method for the simultaneous determination of five commonly used antimalarial drugs: Application to pharmaceutical formulations and human plasma.

    Science.gov (United States)

    Mannemala, Sai Sandeep; Nagarajan, Janaki Sankarachari Krishnan

    2015-05-01

    A simple, sensitive, and rapid liquid chromatographic method was developed and validated using diode array detection for the determination of five commonly used antimalarial drugs in pharmaceutical formulations and in human plasma. Chromatographic separation of antimalarial drugs and internal standard (ibuprofen) was achieved on a C18 column with a mobile phase composed of 10 mM dipotassium orthophosphate at pH 3.0, methanol, and acetonitrile in a ratio of 20:38:42 v/v, at a flow rate of 1 mL/min. The analytes were monitored at 220 nm and separated in ˂10 min. The method was validated for linearity, accuracy, precision, limit of quantification, and robustness. Both intra- and interday precisions (in terms of %RSD) were lower than 3% and accuracy ranged from 98.1 to 104.5%. Extraction recoveries were ≥96% in plasma. The limits of quantitation for artemether, lumefantrine, pyrimethamine, sulfadoxine, and mefloquine were 0.3, 0.03, 0.06, 0.15, and 0.15 μg/mL in human plasma. Stability under various conditions was also investigated. The method was successfully applied for quantification of antimalarial drugs in marketed formulations and in spiked human plasma. The method can be employed for routine QC purposes and in pharmacokinetic investigations.

  15. Risk of drug resistance in Plasmodium falciparum malaria therapy-a systematic review and meta-analysis.

    Science.gov (United States)

    Zhou, Li-Juan; Xia, Jing; Wei, Hai-Xia; Liu, Xiao-Jun; Peng, Hong-Juan

    2017-02-01

    Plasmodium falciparum is responsible for the vast majority of the morbidity and mortality associated with malaria infection globally. Although a number of studies have reported the emergence of drug resistance in different therapies for P. falciparum infection, the degree of the drug resistance in different antimalarials is still unclear. This research investigated the risk of drug resistance in the therapies with different medications based on meta-analyses. Relevant original randomized control trials (RCTs) were searched in all available electronic databases. Pooled relative risks (RRs) with 95% confidence intervals (95% CIs) were used to evaluate the risk of drug resistance resulting from different treatments. Seventy-eight studies were included in the meta-analysis to compare drug resistance in the treatment of P. falciparum infections and yielded the following results: chloroquine (CQ) > sulfadoxine-pyrimethamine (SP) (RR = 3.67, p  artemether + lumefantrine (AL) (RR = 2.94, p  artemisinin-based combination therapies (ACTs) (RR = 1.93, p < 0.001); no significant difference was found in amodiaquine (AQ) vs. SP, AS + AQ vs. AS + SP, AS + AQ vs. AL, or AS + MQ vs. AL. These results presented a global view for the current status of antimalarial drug resistance and provided a guidance for choice of antimalarials for efficient treatment and prolonging the life span of the current effective antimalarial drugs.

  16. Safety, efficacy and population pharmacokinetics of fixed-dose combination of artesunate-mefloquine in the treatment of acute uncomplicated Plasmodium falciparum malaria in India.

    Science.gov (United States)

    Valecha, Neena; Srivastava, Bina; Dubhashi, N G; Rao, B H Krishnamoorthy; Kumar, Ashwani; Ghosh, S K; Singh, Jai Prakash Narayan; Kiechel, J R; Sharma, Bhawna; Jullien, V; Dash, A P; Taylor, W R J; Anvikar, Anupkumar R

    2013-12-01

    India has switched over to artemisinin-based combination therapy (ACT) for the treatment of acute uncomplicated Plasmodium falciparum malaria and the ACT used in the national programme is artesunate + sulphadoxine-pyrimethamine. Since the efficacy of ACT is dependent also on the partner drug, there is a need to evaluate and deploy multiple ACTs. This multicentre, single-arm, open-label clinical trial was carried out to assess the efficacy, safety and population pharmacokinetics of a fixed dose combination (FDC) artesunate mefloquine (ASMQ) in P. falciparum infected, Indian adults at Panjim, Goa, and Mangalore, Karnataka between December 2007 and November 2008. A total of 77 patients (males 74) were screened and enrolled: 42 at Goa and 35 at Mangalore with a median age of 25 yr (range 18-55 yr). One patient failed in treatment on D53, a PCR proven new infection, seven developed recurrent vivax parasitaemia and 11 did not have a parasitological endpoint. By per protocol analysis, the D63 cure rate was 58/59 (98.3; 95% C.I. 90.9-99.9%), and 58/58, with PCR correction. ASMQ was well-tolerated and no serious adverse events were reported. The study showed that the ASMQ FDC was efficacious and well-tolerated for the treatment of acute, uncomplicated P. falciparum malaria in highly endemic, chloroquine resistant areas of Goa and Mangalore. It is a viable option for India.

  17. [Clinical problems in medical mycology: Problem number 49].

    Science.gov (United States)

    Negroni, Ricardo; Depardo, Roxana; Messina, Fernando; García, Julián; Santiso, Gabriela; Mingrone, Verónica; Marin, Emmanuel; Arechavala, Alicia

    2016-01-01

    The case of a 59-year-old female born in Buenos Aires (Argentina) is presented. She had been diagnosed with HIV in 2007 and received highly active antiretroviral therapy until 2011; she also suffered from diabetes type 2. She had received empirical treatment (pyrimethamine-clindamycin) for cerebral toxoplasmosis. Fifteen days later she suffered a drug-induced skin disorder and was treated in the Dermatology Service of the Hospital Muñiz with corticosteroids. After five weeks she was readmitted to the Infectious Disease Unit due to asthenia, weight loss, left hip pain and weakness in all four limbs. Septic arthritis and aseptic hip necrosis were ruled out. Blood cultures were positive for Staphylococcus aureus and Escherichia coli. The patient received intravenous antibiotics, but before being discharged Acinetobacter baumannii was isolated from blood, catheter and urine cultures, and a new series of antibiotics were prescribed. On the 3rd day she presented encephalic facies, changes of behaviour and disorientation, without nuchal rigidity, Kernig and Brudzinski signs or focal signs. An X-ray computed tomography did not show parenchymal lesions. A yeast identified as Candida albicans was isolated in a cerebrospinal fluid culture. The same yeast was recovered in a new cerebrospinal fluid sample. The isolate was susceptible to amphotericin B and susceptible dose dependent to fluconazole. The patient was treated with amphotericin B (0.7mg/kg plus 800mg fluconazole daily). Three weeks later, new cerebrospinal fluid cultures were negative. Unfortunately, the patient died soon afterwards.

  18. Anti-malarial effect of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one and green tea extract on erythrocyte-stage Plasmodium berghei in mice

    Institute of Scientific and Technical Information of China (English)

    Phitsinee; Thipubon; Wachiraporn; Tipsuwan; Chairat; Uthaipibull; Sineenart; Santitherakul; Somdet; Srichiratanakool

    2015-01-01

    Objective: To examine the efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one(CM1) iron chelator and green tea extract(GTE) as anti-malarial activity in Plasmodium berghei(P. berghei) infected mice.Methods: The CM1(0–100 mg/kg/day) and GTE(0–100 mg(-)-epigallocatechin 3-gallate equivalent/kg/day) were orally administered to P. berghei infected mice for consecutive 4 days. Parasitized red blood cells(PRBC) were enumerated by using Giemsa staining microscopic method.Results: CM1 lowered percentage of PRBC in dose-dependent manner with an ED50 value of 56.91 mg/kg, when compared with pyrimethamine(PYR)(ED50= 0.76 mg/kg).GTE treatment did not show any inhibition of the malaria parasite growth. In combined treatment, CM1 along with 0.6 mg/kg PYR significantly inhibited the growth of P. berghei in mice while GTE did not enhance the PYR anti-malarial activity.Conclusions: CM1 would be effective per se and synergize with PYR in inhibiting growth of murine malaria parasites, possibly by limiting iron supply from plasma transferrin and host PRBC cytoplasm, and chelating catalytic iron cstitutive in parasites’ mitochondrial cytochromes and cytoplasmic ribonucleotide reductase. CM1 would be a promising adjuvant to enhance PYR anti-malarial activity and minimize the drug resistance.

  19. Anti-malarial effect of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one and green tea extract on erythrocyte-stage Plasmodium berghei in mice

    Institute of Scientific and Technical Information of China (English)

    Phitsinee Thipubon; Wachiraporn Tipsuwan; Chairat Uthaipibull; Sineenart Santitherakul; Somdet Srichiratanakool

    2015-01-01

    Objective:To examine the efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) iron chelator and green tea extract (GTE) as anti-malarial activity in Plasmodium berghei (P. berghei ) infected mice. Methods:The CM1 (0–100 mg/kg/day) and GTE (0–100 mg (-)-epigallocatechin 3-gallate equivalent/kg/day) were orally administered to P. berghei infected mice for consecutive 4 days. Parasitized red blood cells (PRBC) were enumerated by using Giemsa staining microscopic method. Results: CM1 lowered percentage of PRBC in dose-dependent manner with an ED50 value of 56.91 mg/kg, when compared with pyrimethamine (PYR) (ED50=0.76 mg/kg). GTE treatment did not show any inhibition of the malaria parasite growth. In combined treatment, CM1 along with 0.6 mg/kg PYR significantly inhibited the growth of P. berghei in mice while GTE did not enhance the PYR anti-malarial activity. Conclusions: CM1 would be effective per se and synergize with PYR in inhibiting growth of murine malaria parasites, possibly by limiting iron supply from plasma transferrin and host PRBC cytoplasm, and chelating catalytic iron constitutive in parasites’ mitochondrial cytochromes and cytoplasmic ribonucleotide reductase. CM1 would be a promising adjuvant to enhance PYR anti-malarial activity and minimize the drug resistance.

  20. Whole Genome Sequencing of Field Isolates Reveals Extensive Genetic Diversity in Plasmodium vivax from Colombia.

    Science.gov (United States)

    Winter, David J; Pacheco, M Andreína; Vallejo, Andres F; Schwartz, Rachel S; Arevalo-Herrera, Myriam; Herrera, Socrates; Cartwright, Reed A; Escalante, Ananias A

    2015-12-01

    Plasmodium vivax is the most prevalent malarial species in South America and exerts a substantial burden on the populations it affects. The control and eventual elimination of P. vivax are global health priorities. Genomic research contributes to this objective by improving our understanding of the biology of P. vivax and through the development of new genetic markers that can be used to monitor efforts to reduce malaria transmission. Here we analyze whole-genome data from eight field samples from a region in Cordóba, Colombia where malaria is endemic. We find considerable genetic diversity within this population, a result that contrasts with earlier studies suggesting that P. vivax had limited diversity in the Americas. We also identify a selective sweep around a substitution known to confer resistance to sulphadoxine-pyrimethamine (SP). This is the first observation of a selective sweep for SP resistance in this species. These results indicate that P. vivax has been exposed to SP pressure even when the drug is not in use as a first line treatment for patients afflicted by this parasite. We identify multiple non-synonymous substitutions in three other genes known to be involved with drug resistance in Plasmodium species. Finally, we found extensive microsatellite polymorphisms. Using this information we developed 18 polymorphic and easy to score microsatellite loci that can be used in epidemiological investigations in South America.

  1. Clindamycin in the treatment of toxoplasmic retinochoroiditis.

    Science.gov (United States)

    Lakhanpal, V; Schocket, S S; Nirankari, V S

    1983-05-01

    We treated 26 patients with acute toxoplasmic retinochoroiditis with clindamycin between 1974 and 1982. Four patients were treated with clindamycin alone and 17 with clindamycin and prednisolone. Five patients received clindamycin and prednisolone, sulfadiazine, pyrimethamine, or cryocoagulation, or a combination of these. All patients with the acute disease had the characteristic foci and a positive titer on the Sabin-Feldman dye test of at least 1:16. Other causes of retinochoroiditis were excluded. All but two patients, who developed diarrhea after two weeks, received clindamycin for a minimum of three weeks. All patients improved after two weeks of treatment, but two patients with lesions larger than 2 disk diameters required an additional six weeks of treatment to heal completely. During follow-up periods ranging from 18 months to seven years (mean, three years) there have been only two recurrences (7.7%). Complications with clindamycin treatment were limited to gastrointestinal upsets, diarrhea, and skin rash. There were no cases of pseudomembranous colitis, the most serious reported complication of clindamycin use.

  2. Burden of Placental Malaria among Pregnant Women Who Use or Do Not Use Intermittent Preventive Treatment at Mulago Hospital, Kampala

    Directory of Open Access Journals (Sweden)

    Charles Okot Odongo

    2016-01-01

    Full Text Available Intermittent preventive treatment of malaria in pregnancy with sulphadoxine-pyrimethamine (SP-IPTp is widely used to reduce the incidence of adverse pregnancy outcomes. As a monitor for continued effectiveness of this intervention amidst SP resistance, we aimed to assess malaria burden among pregnant women who use or do not use SP-IPTp. In a descriptive cohort study at Mulago Hospital, Kampala, 87 women who received two supervised doses of SP-IPTp were followed up until delivery. Controls were pregnant women presenting in early labour without history of SP-IPTp. Histopathological investigation for placental malaria (PM was performed using the Bulmer classification criterion. Thirty-eight of the 87 women returned for delivery and 33 placentas were successfully collected and processed along with 33 placentas from SP nonusers. Overall, 12% (4/33 of the users had evidence of PM compared to 48% (16/33 of nonusers. Among nonusers, 17/33, 8/33, 2/33, and 6/33 had no placental infection, active infection, active-chronic infection, and past-chronic infection, respectively. Among users, respective proportions were 29/33, 2/33, 0/33, and 2/33. No difference in birth weights was apparent between the two groups, probably due to a higher proportion of infections occurring later in pregnancy. Histological evidence here suggests that SP continues to offer substantial benefit as IPTp.

  3. Off-patent drugs at brand-name prices: a puzzle for policymakers.

    Science.gov (United States)

    Tallapragada, Naren P

    2016-04-01

    In August 2015, Turing Pharmaceuticals acquired the marketing rights to Daraprim (pyrimethamine), a drug used to treat parasitic infections like malaria and toxoplasmosis. Soon after, Turing caused an uproar when it announced that it would raise the price per tablet of Daraprim from [Formula: see text], a 5500% price hike for a drug that has been on the market for over 60 years and off patent since the 1970s. Old, off-patent drugs are becoming increasingly expensive; Daraprim is the archetypal example. Turing had the power to set a high price for Daraprim because the drug's limited patient population, the absence of competing manufacturers, and a lack of therapeutic alternatives all created an effective monopoly. Similar forces have driven up the prices of other off-patent drugs that treat diseases as diverse as heart failure and multi-drug-resistant tuberculosis. Thus, policymakers will have to consider how the high cost of off-patent drugs impacts public health as well as public spending. In this Note I outline the extent of the high-cost off-patent drug problem, drawing special attention to the problem's negative effects on both health outcomes and government budgets. After discussing some of the problem's underlying causes, I present several solutions to the problem that policymakers could consider, with a focus on proposals like reference pricing and expanded compounding that have received relatively little media attention.

  4. A novel flow cytometric hemozoin detection assay for real-time sensitivity testing of Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Maria Rebelo

    Full Text Available Resistance of Plasmodium falciparum to almost all antimalarial drugs, including the first-line treatment with artemisinins, has been described, representing an obvious threat to malaria control. In vitro antimalarial sensitivity testing is crucial to detect and monitor drug resistance. Current assays have been successfully used to detect drug effects on parasites. However, they have some limitations, such as the use of radioactive or expensive reagents or long incubation times. Here we describe a novel assay to detect antimalarial drug effects, based on flow cytometric detection of hemozoin (Hz, which is rapid and does not require any additional reagents. Hz is an optimal parasite maturation indicator since its amount increases as the parasite matures. Due to its physical property of birefringence, Hz depolarizes light, hence it can be detected using optical methods such as flow cytometry. A common flow cytometer was adapted to detect light depolarization caused by Hz. Synchronized in vitro cultures of P. falciparum were incubated for 48 hours with several antimalarial drugs. Analysis of depolarizing events, corresponding to parasitized red blood cells containing Hz, allowed the detection of parasite maturation. Moreover, chloroquine resistance and the inhibitory effect of all antimalarial drugs tested, except for pyrimethamine, could be determined as early as 18 to 24 hours of incubation. At 24 hours incubation, 50% inhibitory concentrations (IC50 were comparable to previously reported values. These results indicate that the reagent-free, real-time Hz detection assay could become a novel assay for the detection of drug effects on Plasmodium falciparum.

  5. Morphologic and molecular study of hemoparasites in wild corvids and evidence of sequence identity with Plasmodium DNA detected in captive black-footed penguins (Spheniscus demersus).

    Science.gov (United States)

    Leclerc, Antoine; Chavatte, Jean-Marc; Landau, Irène; Snounou, Georges; Petit, Thierry

    2014-09-01

    A morphologic and molecular epidemiologic investigation was conducted on a captive African black-footed penguin (Spheniscus demersus) colony with a history of Plasmodium infections at La Palmyre Zoo (France). Each penguin received 12.5 mg of pyrimethamine twice a week as a prophylaxis every year from April to November. Although Plasmodium parasites were not detected in blood smears and tissues collected from the penguins, various blood parasites were recorded in blood smears from wild Eurasian magpies (Pica pica) and carrion crows (Corvus corone) sampled at the same time in the study area. These parasites consisted of several Plasmodium spp. (P. lenoblei, P. dorsti, P bioccai, P. relictum, P. dherteae, P. beaucournui, P. maior, P. tranieri, and P. snounoui), Parahaemoproteus spp., Trypanosoma spp., and Leucocytozoon spp. On the other hand, nested polymerase chain reaction enabled detection of Plasmodium DNA in 28/44 (64%) penguins, 15/25 (60%) magpies, and 4/9 (44%) crows. Sequencing and phylogenetic analyses indicated that the parasite DNA amplified from the penguins, magpies, and crows were similar. Magpies and crows could therefore act as a reservoir for penguin Plasmodium infections, which may be more prevalent than previously thought. Morphologic characterization of the Plasmodium spp. detected in the penguins, as well as further biological and epidemiologic studies, are needed to fully understand the transmission of Plasmodium parasites to captive penguins.

  6. Disseminated toxoplasmosis in an immunocompetent patient from Peruvian Amazon Toxoplasmosis diseminada en un paciente inmunocompetente procedente de la Amazonía peruana

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    Juan Nunura

    2010-04-01

    Full Text Available We report a case of severe toxoplasmosis in an immunocompetent patient, characterized by pneumonia, retinochoroiditis, hepatitis and myositis. Diagnosis was confirmed by serology, T. gondii in thick blood smear and presence of bradyzoites in muscle biopsy. Treatment with pyrimethamine plus sulfadoxine was successful but visual acuity and hip extension were partially recovered. This is the first case report of severe toxoplasmosis in an immunocompetent patient from Peru.Reportamos un caso de toxoplasmosis severa en un paciente inmunocompetente caracterizado por neumonía, retinocoroiditis, hepatitis y miositis. El diagnóstico fue confirmado por serología, el hallazgo de T. gondii en gota gruesa y la presencia de bradizoitos en biopsia muscular. El tratamiento con pirimetamina mas sulfadoxina fue exitoso pero solo hubo una parcial recuperación de la agudeza visual y de la capacidad de extensión de la cadera. Este es el primer reporte de un caso de toxoplasmosis severa en el Perú.

  7. Mefloquine gap junction blockade and risk of pregnancy loss.

    Science.gov (United States)

    Nevin, Remington Lee

    2012-09-01

    Obstetric use of the antimalarial drug mefloquine has historically been discouraged during the first trimester and immediately before conception owing to concerns of potential fetal harm. With the rise of resistance to the antimalarial drug sulfadoxine-pyrimethamine (SP), mefloquine is now being considered as a replacement for SP for universal antenatal administration to women from malaria-endemic regions. Recent recommendations have also suggested that mefloquine may be used cautiously among pregnant travelers who cannot otherwise avoid visiting these areas. Mefloquine has been demonstrated to cause blockade of gap junction protein alpha 1 (GJA1) gap junction intercellular communication (GJIC), and recent evidence suggests that GJA1 GJIC is critical to successful embryonic implantation and early placental development. During routine use, mefloquine accumulates in organ and peripheral tissue, crosses the blood-placental barrier, and may plausibly accumulate in developing decidua and trophoblast at concentrations sufficient to interfere with GJA1 GJIC and, thus, cause deleterious effects on fetal outcomes. This conclusion is supported by epidemiological evidence that demonstrates use of the drug during early development is associated with an increased risk of miscarriage and stillbirth. Confirmatory studies are pending, but the available experimental and epidemiological evidence support renewed adherence, where feasible, to existing mefloquine package insert guidance that women avoid the drug during the periconceptional period.

  8. Formulation, process development and evaluation of artemether and lumefantrine soft gelatin capsule

    Directory of Open Access Journals (Sweden)

    A Patel

    2012-01-01

    Full Text Available Artemether and Lumefantrine capsules are indicated for the treatment of P. falciparum malaria cases resistant to both chloroquine and sulphadoxine, pyrimethamine combination. Both artemether and lumefantrine act as blood schizontocides. Artemether is a sesquiterpene lactone derived from artemisinin. Artemisinin is a compound derived from the sweet wormwood plant and has been used for centuries in traditional Chinese medicine to treat fever. Lumefantrine is a synthetic aryl-amino alcohol antimalarial (quinine, mefloquine and halofantrine are members of the same group. Artemether is absorbed fairly rapidly with peak plasma concentrations reached about 2 hours after dosing. Absorption of lumefantrine, a highly lipophilic compound, starts after a lag period of up to 2 hours, with peak plasma concentration about 6-8 hours after dosing. In order to overcome this problem, we have observed that when the drug is given in the soft gelatin dosage form, the bioavailability of the drug is increased. Thus, increasing the absorption of the drug and peak plasma concentration is reached earlier then the conventional dosage form.

  9. Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal

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    Faye Oumar

    2007-06-01

    Full Text Available Abstract Background In view of the high level of chloroquine resistance in many countries, WHO has recommended the use of combination therapy with artemisinin derivatives in the treatment of uncomplicated malaria due to Plasmodium falciparum. Four antimalarial drug combinations, artesunate plus amodiaquine (Arsucam®, artesunate plus mefloquine (Artequin®, artemether plus lumefantrine (Coartem®; four doses and six doses, and amodiaquine plus sulphadoxine-pyrimethamine, were studied in five health districts in Senegal. Methods This is a descriptive, analytical, open, randomized study to evaluate the efficacy and tolerability of these four antimalarial combinations in the treatment of uncomplicated falciparum malaria using the 2002 WHO protocol. Results All drug combinations demonstrated good efficacy. On day 28, all combinations resulted in an excellent clinical and parasitological response rate of 100% after correction for PCR results, except for the four-dose artemether-lumefantrine regimen (96.4%. Follow-up of approximately 10% of each treatment group on day 42 demonstrated an efficacy of 100%. The combinations were well tolerated clinically and biologically. No unexpected side-effect was observed and all side-effects disappeared at the end of treatment. No serious side-effect requiring premature termination of treatment was observed. Conclusion The four combinations are effective and well-tolerated.

  10. Malarone-donation programme in Africa.

    Science.gov (United States)

    Bloland, P B; Kazembe, P N; Watkins, W M; Doumbo, O K; Nwanyanwu, O C; Ruebush, T K

    1997-11-29

    Glaxo Wellcome announced in November 1996 its intent to donate up to 1 million treatment courses per year of its new antimalarial drug, Malarone, to countries in Africa, Southeast Asia, and South America, where malaria is endemic. Because the effectiveness of the small number of available antimalarial drugs is threatened by the emergence of drug resistance, the advantages of introduction of this new drug to a given area should be given careful consideration. Chloroquine, for example, is nearing the end of its effectiveness as a first-line drug for the treatment of uncomplicated falciparum malaria in many areas of East and Central Africa. The lifespan of its replacement, sulfadoxine-pyrimethamine, is likely to be even shorter given its long half-life and the ease with which resistance-conferring mutations occur. In Southeast Asia and the Amazon basin of South America, where multidrug-resistant Plasmodium falciparum malaria is a serious problem, the advantages of Malarone introduction clearly outweigh any disadvantages. In sub-Saharan Africa, the premature distribution and increasing use of artemisinins may jeopardize their long-term effectiveness, however. Another factor complicating decisions to introduce Malarone is its required 3-day course of treatment, necessitating hospitalization if compliance is to be ensured. The donation project gives patients in developing countries access to an expensive drug that would otherwise be unavailable. Time must be taken, however, to fully debate the project's pros and cons, resolve inherent logistic problems, and establish guidelines for Malarone use in sub-Saharan Africa.

  11. Resistência "in vivo" do Plasmodium falciparum às 4-amino - quinoleínas e à associação sulfadoxina-pirimetamina: I - estudo de Porto Velho, Rondônia, 1983

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    Santiago Reyes

    1985-09-01

    Full Text Available Através da prova de 7 dias foi estudado o grau de resistência do Plasmodium falciparum à cloroquina, amodiaquina e sulfadoxina-pirimetamina em Porto Velho, Estado de Rondônia, Brasil. Não se observaram diferenças significativas nas médias de parasitas nos dias de seguimento e nas proporções de resistência entre os três medicamentos testados, fazendo com que os autores recomendem a manutenção das 4-aminoquinoleínas como drogas a serem usadas atualmente em infecções não graves por P. falciparum na área de Porto Velho.The authors studied the levei of resistance of Plasmodium falciparum malaria to chloroquine, amodiaquine and the combination of sulfadoxine and pyrimethamine in the City of Porto Velho, State Capital of Rondônia, Brazil. Using a seven day observation test they did not find signiftcant differences in the parasite count averages in the follow-up as well as in the proportions of resistance to the three drugs. Based upon theseflndings they recommend the maintenance of the 4-aminoquinolines in treating uncomplicated forms of falciparum malaria in the area of Porto Velho.

  12. Perspective for the production of antimalarial drugs in Brazil.

    Science.gov (United States)

    Gilbert, B

    1992-01-01

    There appears to be no chemical manufacture of antimalarial drugs in Brazil. Technology at the laboratory process level has been developed for chloroquine, mefloquine, pyrimethamine and cycloguanil, but not perfected nor scaled-up, largely for economic reasons and market uncertainty. Development of primaquine has been contracted but it will run into the same difficulty. Manufacturing capacity for sulfadoxine was registered in the SDI by Roche. A project to produce artemisinine and its derivatives is under way at UNICAMP-CPQBA but is hampered by low content in the plant. Proguanil could be produced easily, but apparently no attempt has been made to do so. Quinine is imported on a large scale mostly for soft-drink production. Since malarial treatment falls largely within the responsibility of the Government health authorities, manufacture of drugs in Brazil will depend on an assured medium-term purchase order made to a potential local manufacturer, since competition in the world market is scarcely viable at the present moment.

  13. Tracking origins and spread of sulfadoxine-resistant Plasmodium falciparum dhps alleles in Thailand.

    Science.gov (United States)

    Alam, Md Tauqeer; Vinayak, Sumiti; Congpuong, Kanungnit; Wongsrichanalai, Chansuda; Satimai, Wichai; Slutsker, Laurence; Escalante, Ananias A; Barnwell, John W; Udhayakumar, Venkatachalam

    2011-01-01

    The emergence and spread of drug-resistant Plasmodium falciparum have been a major impediment for the control of malaria worldwide. Earlier studies have shown that similar to chloroquine (CQ) resistance, high levels of pyrimethamine resistance in P. falciparum originated independently 4 to 5 times globally, including one origin at the Thailand-Cambodia border. In this study we describe the origins and spread of sulfadoxine-resistance-conferring dihydropteroate synthase (dhps) alleles in Thailand. The dhps mutations and flanking microsatellite loci were genotyped for P. falciparum isolates collected from 11 Thai provinces along the Burma, Cambodia, and Malaysia borders. Results indicated that resistant dhps alleles were fixed in Thailand, predominantly being the SGEGA, AGEAA, and SGNGA triple mutants and the AGKAA double mutant (mutated codons are underlined). These alleles had different geographical distributions. The SGEGA alleles were found mostly at the Burma border, while the SGNGA alleles occurred mainly at the Cambodia border and nearby provinces. Microsatellite data suggested that there were two major genetic lineages of the triple mutants in Thailand, one common for SGEGA/SGNGA alleles and another one independent for AGEAA. Importantly, the newly reported SGNGA alleles possibly originated at the Thailand-Cambodia border. All parasites in the Yala province (Malaysia border) had AGKAA alleles with almost identical flanking microsatellites haplotypes. They were also identical at putatively neutral loci on chromosomes 2 and 3, suggesting a clonal nature of the parasite population in Yala. In summary, this study suggests multiple and independent origins of resistant dhps alleles in Thailand.

  14. [11C]-Labeled Metformin Distribution in the Liver and Small Intestine Using Dynamic Positron Emission Tomography in Mice Demonstrates Tissue-Specific Transporter Dependency.

    Science.gov (United States)

    Jensen, Jonas B; Sundelin, Elias I; Jakobsen, Steen; Gormsen, Lars C; Munk, Ole L; Frøkiær, Jørgen; Jessen, Niels

    2016-06-01

    Metformin is the most commonly prescribed oral antidiabetic drug, with well-documented beneficial preventive effects on diabetic complications. Despite being in clinical use for almost 60 years, the underlying mechanisms for metformin action remain elusive. Organic cation transporters (OCT), including multidrug and toxin extrusion proteins (MATE), are essential for transport of metformin across membranes, but tissue-specific activity of these transporters in vivo is incompletely understood. Here, we use dynamic positron emission tomography with [(11)C]-labeled metformin ([(11)C]-metformin) in mice to investigate the role of OCT and MATE in a well-established target tissue, the liver, and a putative target of metformin, the small intestine. Ablation of OCT1 and OCT2 significantly reduced the distribution of metformin in the liver and small intestine. In contrast, inhibition of MATE1 with pyrimethamine caused accumulation of metformin in the liver but did not affect distribution in the small intestine. The demonstration of OCT-mediated transport into the small intestine provides evidence of direct effects of metformin in this tissue. OCT and MATE have important but separate roles in uptake and elimination of metformin in the liver, but this is not due to changes in biliary secretion. [(11)C]-Metformin holds great potential as a tool to determine the pharmacokinetic properties of metformin in clinical studies.

  15. A non-inferiority, individually randomized trial of intermittent screening and treatment versus intermittent preventive treatment in the control of malaria in pregnancy

    DEFF Research Database (Denmark)

    Tagbor, Harry; Cairns, Matthew; Bojang, Kalifa;

    2015-01-01

    BACKGROUND: The efficacy of intermittent preventive treatment for malaria with sulfadoxine-pyrimethamine (IPTp-SP) in pregnancy is threatened in parts of Africa by the emergence and spread of resistance to SP. Intermittent screening with a rapid diagnostic test (RDT) and treatment of positive women......). Women in the IPTp-SP group received SP on two or three occasions whilst women in the ISTp group were screened two or three times with a RDT and treated if positive for malaria with artemether-lumefantrine (AL). ISTp-AL was non-inferior to IPTp-SP in preventing low birth weight (LBW), anemia......-AL performed as well as IPTp-SP. In the absence of an effective alternative medication to SP for IPTp, ISTp-AL is a potential alternative to IPTp in areas where SP resistance is high. It may also have a role in areas where malaria transmission is low and for the prevention of malaria in HIV positive women...

  16. A database of antimalarial drug resistance

    Directory of Open Access Journals (Sweden)

    Ringwald Pascal

    2006-06-01

    Full Text Available Abstract A large investment is required to develop, license and deploy a new antimalarial drug. Too often, that investment has been rapidly devalued by the selection of parasite populations resistant to the drug action. To understand the mechanisms of selection, detailed information on the patterns of drug use in a variety of environments, and the geographic and temporal patterns of resistance is needed. Currently, there is no publically-accessible central database that contains information on the levels of resistance to antimalaria drugs. This paper outlines the resources that are available and the steps that might be taken to create a dynamic, open access database that would include current and historical data on clinical efficacy, in vitro responses and molecular markers related to drug resistance in Plasmodium falciparum and Plasmodium vivax. The goal is to include historical and current data on resistance to commonly used drugs, like chloroquine and sulfadoxine-pyrimethamine, and on the many combinations that are now being tested in different settings. The database will be accessible to all on the Web. The information in such a database will inform optimal utilization of current drugs and sustain the longest possible therapeutic life of newly introduced drugs and combinations. The database will protect the valuable investment represented by the development and deployment of novel therapies for malaria.

  17. Selection of antimalarial drug resistance after intermittent preventive treatment of infants and children (IPTi/c) in Senegal.

    Science.gov (United States)

    Ndiaye, Magatte; Tine, Roger; Faye, Babacar; Ndiaye, Jean L; Diouf, Ibrahima; Lo, Aminata C; Sylla, Khadime; Dieng, Yemou; Hallett, Rachel; Alifrangis, Michael; Gaye, Oumar

    2013-01-01

    Senegal has since 2003 used sulphadoxine-pyrimethamine (SP) for Intermittent Preventive Treatment (IPT) of malaria in risk groups. However, the large-scale IPT strategy may result in increasing drug resistance. Our study investigated the possible impact of SP-IPT given to infants and children on the prevalence of SP-resistant haplotypes in the Plasmodium falciparum genes Pfdhfr and Pfdhps, comparing sites with and without IPTi/c. P. falciparum positives samples (n=352) were collected from children under 5years of age during two cross-sectional surveys in 2010 and 2011 in three health districts (two on IPTi/c and one without IPTi/c intervention) located in the southern part of Senegal. The prevalence of SP-resistance-related haplotypes in Pfdhfr and Pfdhps was determined by nested PCR followed by sequence-specific oligonucleotide probe (SSOP)-ELISA. The prevalence of the Pfdhfr double mutant haplotypes (CNRN and CICN) was stable between years atSenegal according to WHO recommendations.

  18. Increased Prevalence of Mutant Allele Pfdhps 437G and Pfdhfr Triple Mutation in Plasmodium falciparum Isolates from a Rural Area of Gabon, Three Years after the Change of Malaria Treatment Policy

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    Jacques-Mari Ndong Ngomo

    2016-01-01

    Full Text Available In Gabon, sulfadoxine-pyrimethamine (SP is recommended for intermittent preventive treatment during pregnancy (IPTp-SP and for uncomplicated malaria treatment through ACTs drug. P. falciparum strains resistant to SP are frequent in areas where this drug is highly used and is associated with the occurrence of mutations on Plasmodium falciparum dihydrofolate reductase (Pfdhfr and dihydropteroate synthetase (Pfdhps genes. The aim of the study was to compare the proportion of mutations on Pfdhfr and Pfdhps genes in isolates collected at Oyem in northern Gabon, in 2005 at the time of IPTp-SP introduction and three years later. Point mutations were analyzed by nested PCR-RFLP method. Among 91 isolates, more than 90% carried Pfdhfr 108N and Pfdhfr 59R alleles. Frequencies of Pfdhfr 51I (98% and Pfdhps 437G (67.7% mutant alleles were higher in 2008. Mutations at codons 164, 540, and 581 were not detected. The proportion of the triple Pfdhfr mutation and quadruple mutation including A437G was high: 91.9% in 2008 and 64.8% in 2008, respectively. The present study highlights an elevated frequency of Pfdhfr and Pfdhps mutant alleles, although quintuple mutations were not found in north Gabon. These data suggest the need of a continuous monitoring of SP resistance in Gabon.

  19. Home-based management of fever in rural Uganda: community perceptions and provider opinions

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    Jesca-Nsungwa-Sabiiti

    2007-01-01

    Full Text Available Abstract Background Uganda was the first country to scale up Home Based Management of Fever/Malaria (HBM in 2002. Under HBM pre-packaged unit doses with a combination Sulphadoxine/Pyrimethamin (SP and Chloroquine (CQ called "HOMAPAK" are administered to all febrile children by community selected voluntary drug distributors (DDs. In this study, community perceptions, health worker and drug provider opinions about the community based distribution of HOMAPAK and its effect on the use of other antimalarials were assessed. Methods In 2004, four focus group discussions with mothers and 11 key informant interviews with drug sellers, drug distributors and health workers were conducted in Kasese district, western Uganda. This was complemented by three months of field observations. Results Caretakers concurred that they were benefiting from the programme. However, according to the information from the DDs and health workers, many caretakers perceived HOMAPAK as a drug of lower quality only meant for first aid. Caretakers also expressed need for other drugs to treat other childhood diseases. The introduction of HOMAPAKs was said not to affect the sale of other allopathic antimalarial drugs in the community. DDs expressed concerns about lack of incentives and facilitation such as torches, gumboots and diagnostic equipment to improve their performance. Conclusion HBM is well appreciated by the community. However, more efforts are needed to improve uptake of the strategy through systematic community sensitization and community dialogue. This study highlights the potential of community based volunteers if well trained, facilitated and integrated into a functioning local health system.

  20. Effect of methanol extracts of nony fruit on mice infected by RH strain of Toxoplasma gondii

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    Didik T Subekti

    2005-12-01

    Full Text Available Intraperitoneal infection of Type I Toxoplasma gondii on mice causes high mortality at a short time due to parasitic burden, immunosuppression, cell and tissue damage. The mice survival is increased after treated with drugs that reduce or destroy tachyzoite and modulate or recovered the immune system. Nony fruit (Morinda citrifolia is popular as immunomudulator and has antoxoplasma properties. The purpose of this experiment is to evaluate the effect of ethanol extract of nony fruit and Fansidar® (pyrimethamine-sulfadiazine to reduce tachyzoite and improve survival as well as immunomudulator on mice following toxoplasma infection. Mice was divided into six groups (10 mice respectively consist of infected-non treated groups, infected + Fansidar®, infected + ethanol extract of nony on several doses (100, 50, 25% and non infected-non treated groups. All mice on each groups were infected intraperitoneally by 5 x 106 and 2,5 x 103 RH strain of Toxoplasma gondii tachyzoite/mice respectively. The results have shown that Fansidar® was successfully to reduced tachyzoite and improved mice survival but the ethanol extract of nony fruit was failed.

  1. [Screening for toxoplasmosis in pregnancy--a pilot program in Northeast Germany].

    Science.gov (United States)

    Krausse, T; Straube, W; Wiersbitzky, S; Hitz, V; Kewitsch, A

    1993-09-01

    A general serological screening of pregnant women for toxoplasmosis was carried out by means of an IgG-ELISA in Greifswald and its surroundings from October 1986 to the end of 1990. Anti-toxoplasma gondii antibodies were detected in 72.8% of 4355 pregnant women. Since 1987, the prevalence of antibodies has decreased from 76% to 68%. The incidence of acquired toxoplasmosis in pregnancy was 2.53 per 1000. Seroconversion occurred in 11 women, but only 8 of them were treated with combined pyrimethamine and sulphamerazine. Despite treatment we observed 3 connatal infections. No newborn infant had clinical symptoms. With regard to the epidemiological situation, a toxoplasmosis screening is recommendable, at least in our area, from an ethical, moral, medical and economical point of view. To ensure, that toxoplasmosis screening is adequately effective, treatment of the pregnant women and their infants must be guaranteed both organisationally and professionally. It must also comprise health education measures, especially for non-immunised women to avoid the well-known main sources of infection.

  2. Identification of Pfdhfr mutant variants in Plasmodium berghei model

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    Chairat Uthaipibull

    2011-12-01

    Full Text Available Parasite resistance to antimalarials is a major burden in controlling malaria disease. Genetic mutations within the parasites are found to be the factor in conferring resistance to drugs. In this study, the power of random mutant library and transgenic parasite systems were employed to identify mutations on the antimalarial drug target, viz. Plasmodium falciparum dihydrofolate reductase (DHFR, which could contribute to resistance, and to elucidate the functionality of resistant mutant parasites in P. berghei. Using the moderate drug-resistant PfdhfrS108N gene as template, we generated a library of Pfdhfr mutants by error-prone PCR followed by transfection and selection in P. berghei. Two clones of transgenic P. berghei expressing PfDHFR of interest due to the position of mutations, i.e. PbPfDHFR3m1 (M55I+S108N+S189C and PbPfDHFR3m2 (C50Y+S108N+F116S, were selected for drug sensitivity test. Although these transgenic parasite clones showed similar reproducibility with the parental transgenic P. berghei, expressing PfDHFR with mutation at S108N (PbPfS108N in response to antifolate pyrimethamine, this study reconfirms that this P. berghei model is effective in predicting the evolution of Pfdhfr mutations in vivo. This approach can be applied during the development of new antifolates with better effective properties against drug resistant parasites.

  3. Apicoplast Biosynthetic Pathways as Possible Targetsfor Combination Therapy of Malaria

    Institute of Scientific and Technical Information of China (English)

    Solomon Tesfaye; Bhanu Prakash; Prati Pal Singh

    2015-01-01

    The emergence of malaria parasite strains resistant to practically all the antimalarial drugs in clinical use is now making itnecessary to discover and develop both new antimalarial drugs and treatments. Recent advances in molecular techniques along withthe availability of genome sequence ofPlasmodiumfalciparum may provide a wide range of novel targets in metabolic pathways likeisoprenoid biosynthesis, fatty acid biosynthesis and heme biosynthesis in the apicoplast of Plasmodiurn. On the other hand, thecombination therapy approach (currently used to retard the selection of parasite strains resistant to individual components of acombination of drugs) has proved to be a success in the combination of sulphadoxine and pyrimethamine, which targets two differentsteps in the folate pathway of malaria parasite. However, after the success of this therapeutic combination, the efficacy of othercombinations of drugs which target different enzymes in a particular metabolic pathway has, apparently, not been reported. Therefore,herein, we review various drug targets so far discovered in apicoplast-related anabolic pathways, especially, with a sharper focus onthe possibility to target more than one enzyme at a time in a particular metabolic pathway of malaria parasites.

  4. Homologous recombination and gene replacement at the dihydrofolate reductase-thymidylate synthase locus in Toxoplasma gondii.

    Science.gov (United States)

    Donald, R G; Roos, D S

    1994-02-01

    To investigate the feasibility of genomic transgene expression and gene targeting in Toxoplasma gondii, parasites have been transfected with constructs differing in the length of contiguous genomic sequence spanning the dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene. We have previously reported that vectors derived from a DHFR-TS cDNA 'minigene' containing mutations in the DHFR coding sequence confer pyrimethamine resistance to transfected parasites (Donald and Roos, 1993). Stably resistant parasite clones arise at high frequency, generally by virtue of transgene integration into parasite chromosomes at locations scattered throughout the genome. In contrast, using a vector which contains 8 kb of contiguous genomic sequence (vs. homologous recombination. Homologous recombination appears to occur at even higher frequency when a 16 kb genomic clone is used. Circular plasmids were more efficient than linearized molecules at producing homologous recombination in this system, integrating by reciprocal crossing-over to produce a duplication of the DHFR-TS locus. Double crossing-over (or gene conversion) was also observed at low frequency, resulting in complete allelic replacement in this haploid stage of the parasite. The ability to produce either homologous or non-homologous recombinants, by the selection of appropriate transformation constructs, has considerable genetic potential.

  5. In Vivo Antiplasmodial, Anti-Inflammatory, and Analgesic Properties, and Safety Profile of Root Extracts of Haematostaphis barteri Hook F. (Anacardiaceae).

    Science.gov (United States)

    Boampong, Johnson Nyarko

    2015-01-01

    Malaria is an endemic disease globally and the conundrum of drug resistance has led to the search for newer antimalarial agents. The root extract of H. barteri was evaluated for antimalarial, analgesic, and anti-inflammatory properties. The prophylactic effect of H. barteri on P. berghei was determined by pretreating mice with aqueous root extract of H. barteri (30-300 mg/kg), saline, and 1.2 mg/kg sulfadoxine/pyrimethamine for three days followed by 1 × 10(6) P. berghei inoculation. Parasite density was measured after 72 h. The curative antimalarial property of the extract was assessed by treating mice with extract, saline, and 1.14 : 6.9 mg/kg Artemether : Lumefantrine four days after 1 × 10(6) P. berghei inoculation. Selected organs were harvested for toxicity assessment. The anti-inflammatory and analgesic effect of the extract was determined in the carrageenan and thermal tail withdrawal tests, respectively. The extract significantly reduced the parasite density in the prophylactic but not the curative study. The anti-inflammatory and analgesic activities of the extract were significant (P analgesic property of the extract occurred at the highest doses used.

  6. In Vivo Antiplasmodial, Anti-Inflammatory, and Analgesic Properties, and Safety Profile of Root Extracts of Haematostaphis barteri Hook F. (Anacardiaceae

    Directory of Open Access Journals (Sweden)

    Johnson Nyarko Boampong

    2015-01-01

    Full Text Available Malaria is an endemic disease globally and the conundrum of drug resistance has led to the search for newer antimalarial agents. The root extract of H. barteri was evaluated for antimalarial, analgesic, and anti-inflammatory properties. The prophylactic effect of H. barteri on P. berghei was determined by pretreating mice with aqueous root extract of H. barteri (30–300 mg/kg, saline, and 1.2 mg/kg sulfadoxine/pyrimethamine for three days followed by 1 × 106 P. berghei inoculation. Parasite density was measured after 72 h. The curative antimalarial property of the extract was assessed by treating mice with extract, saline, and 1.14 : 6.9 mg/kg Artemether : Lumefantrine four days after 1 × 106 P. berghei inoculation. Selected organs were harvested for toxicity assessment. The anti-inflammatory and analgesic effect of the extract was determined in the carrageenan and thermal tail withdrawal tests, respectively. The extract significantly reduced the parasite density in the prophylactic but not the curative study. The anti-inflammatory and analgesic activities of the extract were significant (P<0.05 only at the highest doses employed. Regeneration of hepatocytes was also evident in the extract treated groups. The extract has prophylactic but not curative activity on P. berghei-induced malaria. The anti-inflammatory and analgesic property of the extract occurred at the highest doses used.

  7. Effects of Extracts from Thai Piperaceae Plants against Infection with Toxoplasma gondii.

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    Arpron Leesombun

    Full Text Available Herbal medicines and natural herb extracts are widely used as alternative treatments for various parasitic diseases, and such extracts may also have potential to decrease the side effects of the standard regimen drugs used to treat toxoplasmosis (sulfadiazine-pyrimethamine combination. We evaluated how effective the Thai piperaceae plants Piper betle, P. nigrum and P. sarmentosum are against Toxoplasma gondii infection in vitro and in vivo. Individually, we extracted the piperaceae plants with ethanol, passed them through a rotary evaporator and then lyophilized them to obtain crude extracts for each one. The in vitro study indicated that the P. betle extract was the most effective extract at inhibiting parasite growth in HFF cells (IC50 on RH-GFP: 23.2 μg/mL, IC50 on PLK-GFP: 21.4 μg/mL. Furthermore, treatment of experimental mice with the P. betle extract for 7 days after infection with 1,000 tachyzoites of the T. gondii PLK strain increased their survival (survival rates: 100% in 400 mg/kg-treated, 83.3% in 100 mg/kg-treated, 33.3% in 25 mg/kg-treated, 33.3% in untreated mice. Furthermore, treatment with 400 mg/kg of the P. betle extract resulted in 100% mouse survival following infection with 100,000 tachyzoites. The present study shows that P. betle extract has the potential to act as a medical plant for the treatment of toxoplasmosis.

  8. In vivo antiplasmodial activities of ethanolic exract and fractions of Eleucine indica

    Institute of Scientific and Technical Information of China (English)

    Ettebong EO; Nwafor PA; Okokon JE

    2012-01-01

    Objective:To evaluate the in vivo antiplasmodial activities of the extract and fractions(n-hexane, chloroform, ethylacetate, butanol, aqueous) of the whole plant inPlasmodium berghei berghei infected mice.Methods:Oral administrations of the extract(200,400, and600 mg/kg) ofEleucine indica and fractions(400 mg/kg) were screened in the4-day, repository and curative tests. Chloroquine(5 mg/kg), pyrimethamine(1.2 mg/kg) and artesunate(5 mg/kg) were used as controls. Results:The extract showed significant(P<0.05-0.001) dose-dependent, antiplasmodial activity in the4-day, repository and curative tests and increased the survival times of the infected mice. All the fractions exhibited significant antiplasmodial activity with the highest being ethylacetate fraction.Conclusions:Eleucine indica extract and fractions possess antimalarial activity which confirms the ethnobotanical use of this plant as a malarial remedy and opens a new highway to further investigate its potentials in the on-going fight against malaria.

  9. Antiplasmodial and analgesic activities ofClausena anisata

    Institute of Scientific and Technical Information of China (English)

    Jude E Okokon; Ette O Etebong; John A Udobang; Grace E Essien

    2012-01-01

    Objective:Antiplasmodial and analgesic activities of the leaf extract and fractions ofClausena anisata (C. anisata) were evaluated for antimalarial and analgesic activities.Methods:The crude leaf extract (39 - 117 mg/kg) and fractions (chloroform and acqeous; 78 mg/kg) ofC. anisata were investigated for antiplasmodial activity against chloroquine-sensitivePlasmodium berghei (P. berghei ) infections in mice using suppressive, prophylactic and curative models and analgesic activity against acetic acid, formalin and heat-induced pains. Artesunate,5 mg/kg and pyrimethamine,1.2 mg/kg were used as positive controls. Thin films made from tail blood of each mouse were used to assess the level of parasitaemia of the mice.Results: The extract and its fractions dose-dependently reduced parasitaemia induced by chloroquine-sensitive P. berghei in prophylactic, suppressive and curative models in mice. These reductions were statistically significant (P<0.001). They also improved the mean survival time (MST) from17 to21 days relative to control (P<0.01 - 0.001). On chemically and thermally- induced pains, the extract inhibited acetic acid and formalin-induced inflammation as well as hot plate-induced pain in mice. These inhibitions were statistically significant (P<0.001) and in a dose-dependent fashion. Conclusions: The antiplasmodial and analgesic effects of this plant may in part be mediated through its chemical constituents and it can be concluded that the C. anisata possess significant antimalarial and analgesic properties.

  10. Screening for inhibitors of dihydrofolate reductase using pulsed ultrafiltration mass spectrometry.

    Science.gov (United States)

    Nikolic, D; van Breemen, R B

    1998-04-01

    A method of screening combinatorial libraries for inhibitors of eukaryotic dihydrofolate reductase has been developed using pulsed ultra-filtration electrospray mass spectrometry, which is a continuous-flow affinity separation system for extracting and identifying high affinity ligands in combinatorial libraries. In this application, pulsed ultrafiltration conditions were optimized for the isolation and identification of inhibitors of dihydrofolate reductase from a 22 compound library containing six known inhibitors of the enzyme including trimethoprim, aminopterin, methotrexate, pyrimethamine, folic acid, and folinic acid, and 16 compounds without known affinity. In order to optimize the screening method, sources of non-specific binding were identified and minimized. A significant source of non-specific binding for this set of library compounds was hydrophobic interaction with the surfaces of the ultrafiltration chamber. After affinity separation of bound (high affinity) versus free (low affinity) library compounds during pulsed ultrafiltration, receptor-bound ligands were released and eluted using either organic solvent or acidified mobile phase. Although 80% methanol easily disrupted the receptor-ligand complexes, organic solvent had the undesirable effect of releasing non-specifically bound compounds from the chamber and thereby increasing the background noise. Interference from non-specific binding was minimized by releasing bound ligands using a low pH mobile phase eluent instead of organic solvent. Under the conditions used, pulsed ultrafiltration mass spectrometry selectively identified the two library compounds with the highest affinity for dihydrofolate reductase, methotrexate and aminopterin.

  11. Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design.

    Science.gov (United States)

    Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Betancourt-Conde, Irene; Aguirre-Raudry, Miriam; Vázquez-Raygoza, Alejandra; Luevano-De la Cruz, Artemisa; Favela-Candia, Alejandro; Sarabia-Sanchez, Marie; Ríos-Soto, Lluvia; Méndez-Hernández, Edna; Cisneros-Martínez, Jorge; Palacio-Gastélum, Marcelo Gómez; Valdez-Solana, Mónica; Hernández-Rivera, Jessica; De Lira-Sánchez, Jaime; Campos-Almazán, Mara; Téllez-Valencia, Alfredo

    2016-01-01

    Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria.

  12. The Role of Folate Transport in Antifolate Drug Action in Trypanosoma brucei*

    Science.gov (United States)

    Dewar, Simon; Sienkiewicz, Natasha; Ong, Han B.; Wall, Richard J.; Horn, David

    2016-01-01

    The aim of this study was to identify and characterize mechanisms of resistance to antifolate drugs in African trypanosomes. Genome-wide RNAi library screens were undertaken in bloodstream form Trypanosoma brucei exposed to the antifolates methotrexate and raltitrexed. In conjunction with drug susceptibility and folate transport studies, RNAi knockdown was used to validate the functions of the putative folate transporters. The transport kinetics of folate and methotrexate were further characterized in whole cells. RNA interference target sequencing experiments identified a tandem array of genes encoding a folate transporter family, TbFT1–3, as major contributors to antifolate drug uptake. RNAi knockdown of TbFT1–3 substantially reduced folate transport into trypanosomes and reduced the parasite's susceptibly to the classical antifolates methotrexate and raltitrexed. In contrast, knockdown of TbFT1–3 increased susceptibly to the non-classical antifolates pyrimethamine and nolatrexed. Both folate and methotrexate transport were inhibited by classical antifolates but not by non-classical antifolates or biopterin. Thus, TbFT1–3 mediates the uptake of folate and classical antifolates in trypanosomes, and TbFT1–3 loss-of-function is a mechanism of antifolate drug resistance. PMID:27703008

  13. Consumer survey of malaria fact card: an educational and communication tool in Tanzania.

    Science.gov (United States)

    Chambuso, M; Mugoyela, V; Kalala, W

    2007-10-01

    To determine the usefulness of the malaria fact card as a health educational and communication tool in Dar Es Salaam. A prospective consumer survey pilot study on the malaria fact card, a health educational and communication tool was carried out between January and February 2004 in Dar Es Salaam, Tanzania. Parameters studied include consumers' understanding of the malaria fact card, consumer behavioural responses and awareness of malaria prevention and treatment. A total of 131 respondents from 10 randomly selected community pharmacies in which malaria fact cards were distributed since 2003 participated in the study. Data were collected using structured and semi structured questionnaires. It was found that 95% of respondents reported that the fact card was easy to read and understand. The study revealed that 64.6% (n = 127) responses acknowledged getting new information on correct treatment of malaria using Sulphadoxine-Pyrimethamine (SP), while 8.6% acquired new information about prevention strategies. Only 33% of the consumers surveyed indicated to visit the pharmacies on regular basis. Further, results indicated that 84% of respondents asked the pharmacists for health information and/or advice when purchasing antimalarial medicines. Of all responses 38% (n = 179) related to prevention strategies and 26.8% related to correct use of SP medications. We conclude that the malaria fact card is useful as a health educational and communication tool . It is recommended that pharmacists should provide quality and educative information through use of communication tools such as updated malaria fact cards.

  14. In vivo drug resistance of falciparum malaria in mining areas of Venezuela.

    Science.gov (United States)

    Aché, A; Escorihuela, M; Vivas, E; Páez, E; Miranda, L; Matos, A; Pérez, W; Díaz, O; Izarra, E

    2002-09-01

    The Lot Quality Assurance Double-Sampling Plan (LQADSP) technique was used in three areas, Maripa, Kilómetro 88 and Ikabaru, to assess the efficacy of antimalarials used routinely by the Venezuelan Malaria Programme. The use of chloroquine (25 mg/kg), chloroquine (40 mg/kg) and the combination of sulfadoxine (500 mg) and pyrimethamine (25 mg) registered treatment failures above the threshold level of 25% in Maripa and Kilómertro 88. In Ikabaru the use of chloroquine (40 mg/kg) did not surpass that quality level and could possibly be less than 10%. Quinine (30 mg/kg) was totally effective in curing patients in all three areas. The use of this technique seems adequate for rapid field evaluations and in this case for providing appropriate information to assist this health programme. However, whilst being an ideal technique for surveying areas in which considerable variation may exist among lots and particularly for Plasmodium falciparum infections in these areas, repeated surveys should be carried out in the same areas over time to monitor changes in the susceptibility of this parasite to first-, second- and third-line drugs. In that way, national drug policies can be modified adequately.

  15. Consequences of gestational malaria on birth weight: finding the best timeframe for intermittent preventive treatment administration.

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    Bich-Tram Huynh

    Full Text Available To investigate the consequences of intermittent preventive treatment (IPTp timing on birth weight, we pooled data from two studies conducted in Benin between 2005 and 2010: a prospective cohort of 1037 pregnant women and a randomised trial comparing sulfadoxine-pyrimethamine (SP to mefloquine in 1601 women. A total of 1439 women (752 in the cohort and 687 in the SP arm of the randomised trial who delivered live singletons were analysed. We showed that an early intake of the first SP dose (4 months of gestation was associated with a lower risk of LBW compared to a late intake (6-7 months of gestation (aOR = 0.5 p = 0.01. We also found a borderline increased risk of placental infection when the first SP dose was administered early in pregnancy (aOR = 1.7 p = 0.1. This study is the first to investigate the timing of SP administration during pregnancy. We clearly demonstrated that women who had an early intake of the first SP dose were less at risk of LBW compared to those who had a late intake. Pregnant women should be encouraged to attend antenatal visits early to get their first SP dose and a third dose of SP could be recommended to cover the whole duration of pregnancy and to avoid late infections of the placenta.

  16. Synthesis and evaluation of naphthyl bearing 1,2,3-triazole analogs as antiplasmodial agents, cytotoxicity and docking studies.

    Science.gov (United States)

    Balabadra, Saikrishna; Kotni, MeenaKumari; Manga, Vijjulatha; Allanki, Aparna Devi; Prasad, Rajesh; Sijwali, Puran Singh

    2017-01-01

    Novel series of naphthyl bearing 1,2,3-triazoles (4a-t) were synthesized and evaluated for their in vitro antiplasmodial activity against pyrimethamine (Pyr)-sensitive and resistant strains of Plasmodium falciparum. The synthesized compounds were assessed for their cytotoxicity employing human embryonic kidney cell line (HEK-293), and none of them was found to be toxic. Among them 4j, 4k, 4l, 4m, 4n, 4t exhibited significant antiplasmodial activity in both strains, of which compounds 4m, 4n and 4t (∼3.0-fold) displayed superior activity to Pyr against resistant strain. Pyr and selected compounds (4n, 4p and 4t) that repressed parasite development also inhibited PfDHFR activity of the soluble parasite extract, suggesting that anti-parasitic activity of these compounds is a result of inhibition of the parasite DHFR. In silico studies suggest that activity of these compounds might be enhanced due to π-π stacking. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Malaria prevention and treatment in pregnancy: survey of current practice among private medical practitioners in Lagos, Nigeria.

    Science.gov (United States)

    Rabiu, Kabiru Afolarin; Davies, Nosimot Omolola; Nzeribe-Abangwu, Ugochi O; Adewunmi, Adeniyi Abiodun; Akinlusi, Fatimat Motunrayo; Akinola, Oluwarotimi Ireti; Ogundele, Sunday O

    2015-01-01

    We studied the practice of malaria prevention and treatment in pregnancy of 394 private medical practitioners in Lagos State, Nigeria using a self-administered pre-tested structured questionnaire. Only 39 (9.9%) respondents had correct knowledge of the World Health Organization (WHO) strategies. Malaria prophylaxis in pregnancy was offered by 336 (85.3%), but only 98 (24.9%) had correct knowledge of recommended chemoprophylaxis. Of these, 68 (17.3%) had correct knowledge of first trimester treatment, while only 41 (10.4%) had knowledge of second and third trimester treatment. Only 64 (16.2%) of respondents routinely recommended use of insecticide-treated bed nets. The most common anti-malarial drug prescribed for chemoprophylaxis was pyrimethamine (43.7%); chloroquine was the most common anti-malarial prescribed for both first trimester treatment (81.5%) and second and third trimester treatment (55.3%). The study showed that private medical practitioners have poor knowledge of malaria prophylaxis and treatment in pregnancy, and the practice of most do not conform to recommended guidelines.

  18. Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal

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    Mateusz Stoszko

    2016-01-01

    Full Text Available Persistence of latently infected cells in presence of Anti-Retroviral Therapy presents the main obstacle to HIV-1 eradication. Much effort is thus placed on identification of compounds capable of HIV-1 latency reversal in order to render infected cells susceptible to viral cytopathic effects and immune clearance. We identified the BAF chromatin remodeling complex as a key player required for maintenance of HIV-1 latency, highlighting its potential as a molecular target for inhibition in latency reversal. Here, we screened a recently identified panel of small molecule inhibitors of BAF (BAFi's for potential to activate latent HIV-1. Latency reversal was strongly induced by BAFi's Caffeic Acid Phenethyl Ester and Pyrimethamine, two molecules previously characterized for clinical application. BAFi's reversed HIV-1 latency in cell line based latency models, in two ex vivo infected primary cell models of latency, as well as in HIV-1 infected patient's CD4+ T cells, without inducing T cell proliferation or activation. BAFi-induced HIV-1 latency reversal was synergistically enhanced upon PKC pathway activation and HDAC-inhibition. Therefore BAFi's constitute a promising family of molecules for inclusion in therapeutic combinatorial HIV-1 latency reversal.

  19. Prevention and control of malaria in pregnancy - new threats, new opportunities?

    Science.gov (United States)

    Rogerson, Stephen J; Unger, Holger W

    2017-04-01

    Over 100 million women and their babies are at risk of malaria in pregnancy each year. Malaria prevention in pregnancy relies on long-lasting insecticidal nets (LLINs), and, in Africa, intermittent preventive treatment in pregnancy (IPTp). Increasing resistance of malaria parasites to sulfadoxine-pyrimethamine, the only drug endorsed for IPTp, and increasing mosquito resistance to pyrethroids used in LLINs, threaten the efficacy of these proven strategies, while operational challenges restrict their implementation in areas of great need. Areas Covered: This review summarizes strategies for malaria prevention in pregnancy (both currently used and those undergoing preclinical and clinical evaluation), primarily drawing on publications and study protocols from the last decade. Challenges associated with each strategy are discussed, including the particular problem of HIV and malaria in pregnancy, and areas of further research are highlighted. Expert Commentary: Alternative drugs for IPTp are needed. Dihydroartemisinin-piperaquine is particularly promising, but requires further evaluation, and might contribute to artemisinin resistance. Intermittent screening and treatment in pregnancy (ISTp) is an alternative to IPTp that could reduce unnecessary antenatal drug exposure and resistance risk, but it is not recommended with current, insensitive screening tests. Optimal strategies for areas of low or declining malaria transmission remain to be determined.

  20. Molecular epidemiology of drug-resistant malaria in western Kenya highlands

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    Menge David M

    2008-07-01

    Full Text Available Abstract Background Since the late 1980s a series of malaria epidemics has occurred in western Kenya highlands. Among the possible factors that may contribute to the highland malaria epidemics, parasite resistance to antimalarials has not been well investigated. Methods Using parasites from highland and lowland areas of western Kenya, we examined key mutations associated with Plasmodium falciparum resistance to sulfadoxine – pyrimethamine and chloroquine, including dihydrofolate reductase (pfdhfr and dihydropteroate synthetase (pfdhps, chloroquine resistance transporter gene (pfcrt, and multi-drug resistance gene 1 (pfmdr1. Results We found that >70% of samples harbored 76T pfcrt mutations and over 80% of samples harbored quintuple mutations (51I/59R/108N pfdhfr and 437G/540E pfdhps in both highland and lowland samples. Further, we did not detect significant difference in the frequencies of these mutations between symptomatic and asymptomatic malaria volunteers, and between highland and lowland samples. Conclusion These findings suggest that drug resistance of malaria parasites in the highlands could be contributed by the mutations and their high frequencies as found in the lowland. The results are discussed in terms of the role of drug resistance as a driving force for malaria outbreaks in the highlands.

  1. A Method for Amplicon Deep Sequencing of Drug Resistance Genes in Plasmodium falciparum Clinical Isolates from India.

    Science.gov (United States)

    Rao, Pavitra N; Uplekar, Swapna; Kayal, Sriti; Mallick, Prashant K; Bandyopadhyay, Nabamita; Kale, Sonal; Singh, Om P; Mohanty, Akshaya; Mohanty, Sanjib; Wassmer, Samuel C; Carlton, Jane M

    2016-06-01

    A major challenge to global malaria control and elimination is early detection and containment of emerging drug resistance. Next-generation sequencing (NGS) methods provide the resolution, scalability, and sensitivity required for high-throughput surveillance of molecular markers of drug resistance. We have developed an amplicon sequencing method on the Ion Torrent PGM platform for targeted resequencing of a panel of six Plasmodium falciparum genes implicated in resistance to first-line antimalarial therapy, including artemisinin combination therapy, chloroquine, and sulfadoxine-pyrimethamine. The protocol was optimized using 12 geographically diverse P. falciparum reference strains and successfully applied to multiplexed sequencing of 16 clinical isolates from India. The sequencing results from the reference strains showed 100% concordance with previously reported drug resistance-associated mutations. Single-nucleotide polymorphisms (SNPs) in clinical isolates revealed a number of known resistance-associated mutations and other nonsynonymous mutations that have not been implicated in drug resistance. SNP positions containing multiple allelic variants were used to identify three clinical samples containing mixed genotypes indicative of multiclonal infections. The amplicon sequencing protocol has been designed for the benchtop Ion Torrent PGM platform and can be operated with minimal bioinformatics infrastructure, making it ideal for use in countries that are endemic for the disease to facilitate routine large-scale surveillance of the emergence of drug resistance and to ensure continued success of the malaria treatment policy.

  2. [Drug-resistant malaria: problems with its definition and technical approaches].

    Science.gov (United States)

    Basco, L; Ringwald, P

    2000-01-01

    % inhibitory concentration IC50). The in vitro assay not only yields quantitative results, it also determines the phenotype of the parasite independently of the immune and physiopathological conditions of the host. However, this in vitro assay requires highly skilled personnel and laboratory equipment. In addition, parasites isolated from patients who have taken medication on their own initiative a few days before consultation usually do not grow in vitro and the interpretation of assay results for patients with multiple infections may be equivocal. One of the major problems with in vitro tests is the determination of the threshold IC50 values that distinguish susceptible from resistant parasites. There are currently no fully validated cut-off points for assessing in vitro resistance. Despite these shortcomings, in vitro tests are of value, particularly if performed in parallel with the in vivo test. Molecular biology has made a major contribution to our understanding of the mechanisms of drug resistance. Discrete point mutations in the genes encoding dihydrofolate reductase and dihydropteroate synthase are strongly associated with resistance in vitro to pyrimethamine and sulfadoxine, respectively. Preliminary results have also suggested that these mutations are responsible for the failure of sulfadoxine-pyrimethamine combination treatment. No causal relationship between discrete polymorphisms in the candidate genes and in vitro chloroquine resistance has yet been established. High-performance liquid chromatography is being increasingly used to determine the plasma concentrations of antimalarial drugs in patients with prophylactic or therapeutic failure, to check that the failure of the treatment is not due to inadequate levels of the drug in the patient. Taking into account all these aspects of resistance to antimalarial drugs we think that the WHO definition of drug resistance is now inadequate. (ABSTRACT TRUNCATED)

  3. Cost comparison of microscopy vs. empiric treatment for malaria in southwestern nigeria: a prospective study

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    Davidson Mario

    2010-12-01

    Full Text Available Abstract Background Presumptive treatment for malaria is common in resource-limited settings, yet controversial given the imprecision of clinical diagnosis. The researchers compared costs of diagnosis and drugs for two strategies: (1 empirical treatment of malaria via clinical diagnosis; and (2 empirical diagnosis followed by treatment only with Giemsa smear confirmation. Methods Patients with a diagnosis of clinical malaria were recruited from a mission/university teaching hospital in southwestern Nigeria. The patients underwent free Giemsa thick (diagnosis and thin (differentiation smears, but paid for all anti-malarial drugs. Clinical diagnosis was made on clinicians' judgments based on symptoms, including fever, diarrhoea, headache, and body aches. The paediatric regimen was artesunate (6-9 tablets of 3 mg/kg on day one and 1.5 mg/kg for the next four days plus amodiaquine (10 mg/kg day 1-2 and 5 mg/kg on day three in suspension. Adults were given two treatment options: option one (four and one-half 50 mg artesunate tablets on day one and nine tablets for the next four days, plus three 500 mg sulphadoxine/25 mg pyrimethamine tablets and option two (same artesunate regimen plus nine 200 mg tablets of amodiaquine at 10 mg/kg day 1-2 and 5 mg/kg on day three. The researchers calculated the costs of smears/drugs from standard hospital charges. Results Doctors diagnosed 304 patients (170 adults ages >16 years and 134 pediatric with clinical malaria, prescribing antimalarial drugs to all. Giemsa thick smears were positive in 115/304 (38%. The typical patient cost for a Giemsa smear was 550 Naira (US$3.74 in 2009. For children, the cost of testing all, but treating only Giemsa positives was N888 ($6.04/child; the cost of empiric treatment of all who were clinically diagnosed was lower, N660 ($4.49/child. For adults, the cost of testing all, but treating only Giemsa positives was N711 ($4.84/adult for treatment option one (artesunate and

  4. Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library

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    Jie Feng

    2015-09-01

    Full Text Available Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2–4 week antibiotic treatment, 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS. While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV, thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin, and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy

  5. Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model

    Science.gov (United States)

    Wargo, A.R.; Huijben, S.; De Roode, J. C.; Shepherd, J.; Read, A.F.

    2007-01-01

    Malaria infections frequently consist of mixtures of drug-resistant and drug-sensitive parasites. If crowding occurs, where clonal population densities are suppressed by the presence of coinfecting clones, removal of susceptible clones by drug treatment could allow resistant clones to expand into the newly vacated niche space within a host. Theoretical models show that, if such competitive release occurs, it can be a potent contributor to the strength of selection, greatly accelerating the rate at which resistance spreads in a population. A variety of correlational field data suggest that competitive release could occur in human malaria populations, but direct evidence cannot be ethically obtained from human infections. Here we show competitive release after pyrimethamine curative chemotherapy of acute infections of the rodent malaria Plasmodium chabaudi in laboratory mice. The expansion of resistant parasite numbers after treatment resulted in enhanced transmission-stage densities. After the elimination or near-elimination of sensitive parasites, the number of resistant parasites increased beyond that achieved when a competitor had never been present. Thus, a substantial competitive release occurred, markedly elevating the fitness advantages of drug resistance above those arising from survival alone. This finding may explain the rapid spread of drug resistance and the subsequently brief useful lifespans of some antimalarial drugs. In a second experiment, where subcurative chemotherapy was administered, the resistant clone was only partly released from competitive suppression and experienced a restriction in the size of its expansion after treatment. This finding raises the prospect of harnessing in-host ecology to slow the spread of drug resistance. ?? 2007 by The National Academy of Sciences of the USA.

  6. Revisiting the circulation time of Plasmodium falciparum gametocytes: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs

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    Sawa Patrick

    2010-05-01

    Full Text Available Abstract Background There is renewed acknowledgement that targeting gametocytes is essential for malaria control and elimination efforts. Simple mathematical models were fitted to data from clinical trials in order to determine the mean gametocyte circulation time and duration of gametocyte carriage in treated malaria patients. Methods Data were used from clinical trials from East Africa. The first trial compared non-artemisinin combination therapy (non-ACT: sulphadoxine-pyrimethamine (SP plus amodiaquine and artemisinin-based combination therapy (ACT: SP plus artesunate (AS or artemether-lumefantrine. The second trial compared ACT (SP+AS with ACT in combination with a single dose of primaquine (ACT-PQ: SP+AS+PQ. Mature gametocytes were quantified in peripheral blood samples by nucleic acid sequence based amplification. A simple deterministic compartmental model was fitted to gametocyte densities to estimate the circulation time per gametocyte; a similar model was fitted to gametocyte prevalences to estimate the duration of gametocyte carriage after efficacious treatment. Results The mean circulation time of gametocytes was 4.6-6.5 days. After non-ACT treatment, patients were estimated to carry gametocytes for an average of 55 days (95% CI 28.7 - 107.7. ACT reduced the duration of gametocyte carriage fourfold to 13.4 days (95% CI 10.2-17.5. Addition of PQ to ACT resulted in a further fourfold reduction of the duration of gametocyte carriage. Conclusions These findings confirm previous estimates of the circulation time of gametocytes, but indicate a much longer duration of (low density gametocyte carriage after apparently successful clearance of asexual parasites. ACT shortened the period of gametocyte carriage considerably, and had the most pronounced effect on mature gametocytes when combined with PQ.

  7. Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo.

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    Ernest J Mui

    Full Text Available BACKGROUND AND METHODOLOGY: Toxoplasma gondii causes substantial morbidity, mortality, and costs for healthcare in the developed and developing world. Current medicines are not well tolerated and cause hypersensitivity reactions. The dihydrotriazine JPC-2067-B (4, 6-diamino-1, 2-dihydro-2, 2-dimethyl-1-(3'(2-chloro-, 4-trifluoromethoxyphenoxypropyloxy-1, 3, 5-triazine, which inhibits dihydrofolate reductase (DHFR, is highly effective against Plasmodium falciparum, Plasmodium vivax, and apicomplexans related to T. gondii. JPC-2067-B is the primary metabolite of the orally active biguanide JPC-2056 1-(3'-(2-chloro-4-trifluoromethoxyphenyloxypropyl oxy- 5-isopropylbiguanide, which is being advanced to clinical trials for malaria. Efficacy of the prodrug JPC-2056 and the active metabolite JPC-2067-B against T. gondii and T. gondii DHFR as well as toxicity toward mammalian cells were tested. PRINCIPAL FINDINGS AND CONCLUSIONS: Herein, we found that JPC-2067-B is highly effective against T. gondii. We demonstrate that JPC-2067-B inhibits T. gondii growth in culture (IC50 20 nM, inhibits the purified enzyme (IC50 6.5 nM, is more efficacious than pyrimethamine, and is cidal in vitro. JPC-2067-B administered parenterally and the orally administered pro-drug (JPC-2056 are also effective against T. gondii tachyzoites in vivo. A molecular model of T. gondii DHFR-TS complexed with JPC-2067-B was developed. We found that the three main parasite clonal types and isolates from South and Central America, the United States, Canada, China, and Sri Lanka have the same amino acid sequences preserving key binding sites for the triazine. SIGNIFICANCE: JPC-2056/JPC-2067-B have potential to be more effective and possibly less toxic treatments for toxoplasmosis than currently available medicines.

  8. Ensuring sustained ACT production and reliable artemisinin supply

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    Olliaro Piero

    2007-09-01

    Full Text Available Abstract Introduction This paper reviews recent trends in the production, supply and price of the active ingredients as well as finished ACT products. Production and cost data provided in this paper are based on an ongoing project (Artepal. Stability data are derived from a development project on rectal artesunate. Discussion The artemisinin raw material and its derivatives appear to be very stable compared to the finished products. Supply of artemisinin changed in May 2004 when the Global Fund shifted financial support to qualified countries from chloroquine or sulphadoxine-pyrimethamine to an ACT for treatment of malaria. First, there was a sudden shortage of the starting material, and short term scarcity led to a steep rise in API price: it increased dramatically in 2004, from $350 per kg to more than $1000. Second, there was a parallel increase in the number of companies extracting artemisinin from 10 to 80 between 2003 and 2005 in China, and from 3 to 20 in Vietnam. Commercial cultivation began also in East Africa and Madagascar. A steady and predictable demand for the crop can eliminate such wide fluctuations and indirectly contribute to price stability of the herb, the API and ACT. With appropriate mechanisms to reduce those fluctuations, the cost of artemisinin might decrease sustainably to US$ 250–300 per kg. Conclusion Today the global health community is facing the risk of another cyclical swing with lower demand feeding into reduced planting of A. annua and, thereafter, a new shortage of the raw material and higher API prices. International donors, the largest purchasers for ACTs could better coordinate their activities, in order to guarantee purchase of ACTs and consequently of API with manufacturers. In parallel, the base of quality producers of APIs and finished ACT products needs to be broadened. While the ACT programme is still in its early stages, the consequences of another wave of artemisinin and ACT shortages would

  9. Polymorphism of Plasmodium Falciparum Dihydrofolate Reductase and Dihydropteroate Synthase Genes among Pregnant Women with Falciparum Malaria in Banjar District, South Kalimantan Province, Indonesia

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    Sukmawati Basuki

    2012-12-01

    Full Text Available Pregnant women are highly vulnerable to malaria infection in its endemic areas, particularly infection by Plasmodium falciparum that can cause premature, low birth weight, severe anemia in pregnant women, and death. Sulfadoxine-pyrimethamine (SP for Intermittent Preventive Treatment for pregnant (IPTp is used for malaria control in pregnancy recommended by the World Health Organization that has already been implemented in Africa. The P. falciparum resistance to SP has been reported in several malarial endemic areas, and mutations in the genes of Plasmodium falciparum Dihydrofolate Reductase (Pfdhfr and Dihydropteroate Synthase (Pfdhps are shown to be associated with parasite resistance to SP treatment. Genetic analysis of Pfdhfr and Pfdhps genes in pregnant women infected with P. falciparum has not yet been examined in Indonesia. The cross-sectional study was conducted at two subdistricts, Sungai Pinang and Peramasan, in Banjar district of South Kalimantan Province, where 127 pregnant women were recruited from 2008 to April 2010. Two important mutations in Pfdhfr gene (amino acid positions at N51 and S108 and three in Pfdhps gene (A437, K540 and A581 were analyzed by nested PCR-RFLP method. All of the seven pregnant women samples infected with P. falciparum presented PfDHFR 108N and PfDHPS 437G mutations. One of the samples had the additional mutation at PfDHPS 540, in which Lys is substituted by Glu. These results suggested that P. falciparum might present only some resistance to SP at Sungai Pinang and Peramasan subdistricts, Banjar District, South Kalimantan province, Indonesia. Although there were limited number of samples, this study showed only few mutations of Pfdhfr and Pfdhps genes in P. falciparum at Banjar district, South Kalimantan Province, that suggests SP might be effective for IPTp in this area. Thus, further analysis of the other mutation sites in Pfdhfr and Pfdhps genes and in vivo efficacy study of SP with more sufficient

  10. Reduction of Malaria Transmission to Anopheles Mosquitoes with a Six-Dose Regimen of Co-Artemether

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    Sutherland Colin J

    2005-01-01

    Full Text Available Background Resistance of malaria parasites to chloroquine (CQ and sulphadoxine-pyrimethamine (SP is increasing in prevalence in Africa. Combination therapy can both improve treatment and provide important public health benefits if it curbs the spread of parasites harbouring resistance genes. Thus, drug combinations must be identified which minimise gametocyte emergence in treated cases, and so prevent selective transmission of parasites resistant to any of the partner drugs. Methods and Findings In a randomised controlled trial, 497 children with uncomplicated falciparum malaria were treated with CQ and SP (three doses and one dose respectively; n = 91, or six doses of artemether in fixed combination with lumefantrine (co-artemether [Coartem, Riamet] (n = 406. Carriage rates of Plasmodium falciparum gametocytes and trophozoites were measured 7, 14, and 28 d after treatment. The infectiousness of venous blood from 29 children carrying P. falciparum gametocytes 7 d after treatment was tested by membrane-feeding of Anopheles mosquitoes. Children treated with co-artemether were significantly less likely to carry gametocytes within the 4 weeks following treatment than those receiving CQ/SP (30 of 378 [7.94%] versus 42 of 86 [48.8%]; p < 0.0001. Carriers in the co-artemether group harboured gametocytes at significantly lower densities, for shorter periods (0.3 d versus 4.2 d; p < 0.0001 and were less infectious to mosquitoes at day 7 (p < 0.001 than carriers who had received CQ/SP. Conclusions Co-artemether is highly effective at preventing post-treatment transmission of P. falciparum. Our results suggest that co-artemether has specific activity against immature sequestered gametocytes, and has the capacity to minimise transmission of drug-resistant parasites.

  11. Therapeutic and prophylactic effect of intermittent preventive anti-malarial treatment in infants (IPTi from Ghana and Gabon

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    Kreuels Benno

    2008-10-01

    Full Text Available Abstract Background Intermittent preventive treatment in infants (IPTi with sulphadoxine-pyrimethamine (SP reduces the incidence of malaria episodes in young children. The exact mechanism by which the protective effect is mediated needs to be defined. This study aimed to investigate therapeutic, prophylactic, and possible exceeding effects of SP-based IPTi in two clinical trials. Methods Protective efficacies from two IPTi trials performed in Kumasi, Ghana, and Lambaréné, Gabon, were assessed for overlapping time series of 61 days. For six-months periods after each of three IPTi doses a multivariate Poisson regression model with the respective cohort as co-variate was generated and effect modification of protective efficacy with time strata was evaluated by log-likelihood tests. Results Protective efficacies were not significantly different between the two study cohorts. Study-cohort corrected protective efficacy was highest for the first 61 days after each IPTi application and decreased continuously. For the first 61 days after IPTi-1, IPTi-2, and IPTi-3 the protective efficacy was 71%, 44%, and 43%, respectively. A reduction of the malaria incidence rate was detectable for the first 60, 30 and 40 days after IPTi-1, IPTi-2 and IPTi-3 drug application, respectively. After IPTi-3 a higher risk for malaria could be seen after day 60. This effect was mainly based on the overwhelming influence of the Kumasi cohort. Conclusion The results suggest that SP-based IPTi mainly works through a therapeutic and prophylactic effect over 30 to 60 days after drug application and that a sustained effect beyond post-treatment prophylaxis might be very low. Trial registration Data analysis from clinical trials NCT ID # 00206739 (Kumasi Trial and NCT ID # 00167843 (Lambaréné Trial, http://www.clinicaltrials.gov.

  12. Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance.

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    C Brandon Ogbunugafor

    2016-01-01

    Full Text Available The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance. A major barrier to applications of these concepts is a lack of detail concerning how the environment affects adaptive landscape topography, and consequently, the outcome of drug treatment. Here we combine empirical data, evolutionary theory, and computer simulations towards dissecting adaptive landscape by environment interactions for the evolution of drug resistance in two dimensions-drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR to two related inhibitors-pyrimethamine and cycloguanil-across a breadth of drug concentrations. We first examine whether the adaptive landscapes for the two drugs are consistent with common definitions of cross-resistance. We then reconstruct all accessible pathways across the landscape, observing how their structure changes with drug environment. We offer a mechanism for non-linearity in the topography of accessible pathways by calculating of the interaction between mutation effects and drug environment, which reveals rampant patterns of epistasis. We then simulate evolution in several different drug environments to observe how these individual mutation effects (and patterns of epistasis influence paths taken at evolutionary "forks in the road" that dictate adaptive dynamics in silico. In doing so, we reveal how classic metrics like the IC50 and minimal inhibitory concentration (MIC are dubious proxies for understanding how evolution will occur across drug environments. We also consider how the findings reveal ambiguities in the cross-resistance concept, as subtle differences in adaptive landscape topography between otherwise equivalent drugs can drive drastically different evolutionary outcomes. Summarizing, we discuss the results with

  13. Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance.

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    Ogbunugafor, C Brandon; Wylie, C Scott; Diakite, Ibrahim; Weinreich, Daniel M; Hartl, Daniel L

    2016-01-01

    The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance. A major barrier to applications of these concepts is a lack of detail concerning how the environment affects adaptive landscape topography, and consequently, the outcome of drug treatment. Here we combine empirical data, evolutionary theory, and computer simulations towards dissecting adaptive landscape by environment interactions for the evolution of drug resistance in two dimensions-drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR) to two related inhibitors-pyrimethamine and cycloguanil-across a breadth of drug concentrations. We first examine whether the adaptive landscapes for the two drugs are consistent with common definitions of cross-resistance. We then reconstruct all accessible pathways across the landscape, observing how their structure changes with drug environment. We offer a mechanism for non-linearity in the topography of accessible pathways by calculating of the interaction between mutation effects and drug environment, which reveals rampant patterns of epistasis. We then simulate evolution in several different drug environments to observe how these individual mutation effects (and patterns of epistasis) influence paths taken at evolutionary "forks in the road" that dictate adaptive dynamics in silico. In doing so, we reveal how classic metrics like the IC50 and minimal inhibitory concentration (MIC) are dubious proxies for understanding how evolution will occur across drug environments. We also consider how the findings reveal ambiguities in the cross-resistance concept, as subtle differences in adaptive landscape topography between otherwise equivalent drugs can drive drastically different evolutionary outcomes. Summarizing, we discuss the results with regards to their

  14. Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance

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    Ogbunugafor, C. Brandon; Wylie, C. Scott; Diakite, Ibrahim; Weinreich, Daniel M.; Hartl, Daniel L.

    2016-01-01

    The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance. A major barrier to applications of these concepts is a lack of detail concerning how the environment affects adaptive landscape topography, and consequently, the outcome of drug treatment. Here we combine empirical data, evolutionary theory, and computer simulations towards dissecting adaptive landscape by environment interactions for the evolution of drug resistance in two dimensions—drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR) to two related inhibitors—pyrimethamine and cycloguanil—across a breadth of drug concentrations. We first examine whether the adaptive landscapes for the two drugs are consistent with common definitions of cross-resistance. We then reconstruct all accessible pathways across the landscape, observing how their structure changes with drug environment. We offer a mechanism for non-linearity in the topography of accessible pathways by calculating of the interaction between mutation effects and drug environment, which reveals rampant patterns of epistasis. We then simulate evolution in several different drug environments to observe how these individual mutation effects (and patterns of epistasis) influence paths taken at evolutionary “forks in the road” that dictate adaptive dynamics in silico. In doing so, we reveal how classic metrics like the IC50 and minimal inhibitory concentration (MIC) are dubious proxies for understanding how evolution will occur across drug environments. We also consider how the findings reveal ambiguities in the cross-resistance concept, as subtle differences in adaptive landscape topography between otherwise equivalent drugs can drive drastically different evolutionary outcomes. Summarizing, we discuss the results with

  15. Poor quality vital anti-malarials in Africa - an urgent neglected public health priority

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    Newton Paul N

    2011-12-01

    Full Text Available Abstract Background Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. Methods Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis and botanical investigations were performed. Results Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA containing paracetamol (acetaminophen, counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. Conclusions Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.

  16. Medicines informal market in Congo, Burundi and Angola: counterfeit and sub-standard antimalarials

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    Bertocchi Paola

    2007-02-01

    Full Text Available Abstract Background The presence of counterfeits and sub-standards in African medicines market is a dramatic problem that causes many deaths each year. The increase of the phenomenon of pharmaceutical counterfeiting is due to the rise of the illegal market and to the impossibility to purchase branded high cost medicines. Methods In this paper the results of a quality control on antimalarial tablet samples purchased in the informal market in Congo, Burundi and Angola are reported. The quality control consisted in the assay of active substance by means of validated liquid chromatographic methods, uniformity of mass determination, disintegration and dissolution tests. Moreover, a general evaluation on label and packaging characteristics was performed. Results The results obtained on thirty antimalarial tablet samples containing chloroquine, quinine, mefloquine, sulphadoxine and pyrimethamine showed the presence of different kinds of problems: a general problem concerning the packaging (loose tablets, packaging without Producer name, Producer Country and sometimes without expiry date; low content of active substance (in one sample; different, non-declared, active substance (in one sample; sub-standard technological properties and very low dissolution profiles (in about 50% of samples. This last property could affect the bioavailability and bioequivalence in comparison with branded products and could be related to the use of different excipients in formulation or bad storage conditions. Conclusion This paper evidences that the most common quality problem in the analysed samples appears to be the low dissolution profile. Here it is remarked that the presence of the right active substance in the right quantity is not a sufficient condition for a good quality drug. Dissolution test is not less important in a quality control and often evidences in vitro possible differences in therapeutic efficacy among drugs with the same active content. Dissolution

  17. Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi.

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    Joseph D Planer

    2014-07-01

    Full Text Available An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA-approved drugs (described in this paper have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC50's in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC50 of 0.4 µM, a selective serotonin reuptake inhibitor (fluoxetine, EC50 of 4.4 µM, and an antifolate drug (pyrimethamine, EC50 of 3.8 µM and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease.

  18. Concurrence of Plasmodium falciparum dhfr and crt mutations in northern Ghana

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    Otchwemah Rowland N

    2005-09-01

    Full Text Available Abstract Background Both chloroquine (CQ and sulfadoxine-pyrimethamine (SP are failing drugs in much of sub-Saharan Africa. Previous findings suggest an association between resistance to CQ and to SP in vivo, in vitro, and on the molecular level. Methods In 126 Ghanaian children with uncomplicated malaria, associations between mutations conferring resistance in the Plasmodium falciparum dihydrofolate reductase (dhfr; SP and chloroquine resistance transporter (crt; CQ genes, concentrations of residual antimalarial drugs, and gametocyte carriage were examined. Results Mutant dhfr alleles and the CQ-resistance allele crt T76 were strongly associated with each other. Isolates exhibiting the dhfr triple mutation seven times more likely also contained crt T76 parasites as compared to isolates without the dhfr triple variant (P = 0.0001. Moreover, both, isolates with the dhfr triple mutation (adjusted OR, 3.2 (95%CI, 1.0–10.4 and with crt T76 (adjusted OR, 14.5 (1.4–150.8 were associated with an increased likelihood of pre-treatment gametocytaemia. However, crt T76 did not correlate with gametocytaemia following SP treatment and no selection of crt T76 in SP treatment failure isolates was observed. Conclusion These results confirm an association between CQ and SP resistance markers in isolates from northern Ghana. This could indicate accelerated development of resistance to SP if CQ resistance is already present, or vice versa. Considering the enhanced transmission potential as reflected by the increased proportion of isolates containing gametocytes when resistant parasites are present, co-resistance can be expected to spread in this area. However, the underlying mechanism leading to this constellation remains obscure.

  19. Do health workers’ preferences influence their practices? Assessment of providers’ attitude and personal use of new treatment recommendations for management of uncomplicated malaria, Tanzania

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    Masanja Irene M

    2012-11-01

    Full Text Available Abstract Background Due to growing antimalarial drug resistance, Tanzania changed malaria treatment policies twice within a decade. First in 2001 chloroquine (CQ was replaced by sulfadoxine-pyrimethamine (SP for management of uncomplicated malaria and by late 2006, SP was replaced by artemether-lumefantrine (AL. We assessed health workers’ attitudes and personal practices following the first treatment policy change, at six months post-change and two years later. Methods Two cross-sectional surveys were conducted in 2002 and 2004 among healthcare workers in three districts in South-East Tanzania using semi-structured questionnaires. Attitudes were assessed by enquiring which antimalarial was considered most suitable for the management of uncomplicated malaria for the three patient categories: i children below 5; ii older children and adults; and iii pregnant women. Practice was ascertained by asking which antimalarial was used in the last malaria episode by the health worker him/herself and/or dependants. Univariate and multivariate logistic regression was used to identify factors associated with reported attitudes and practices towards the new treatment recommendations. Results A total of 400 health workers were interviewed; 254 and 146 in the first and second surveys, respectively. SP was less preferred antimalarial in hospitals and private health facilities (p Conclusion Following changes in malaria treatment recommendations, most health workers did not prefer the new antimalarial drug, and their preferences worsened over time. However, many of them still used the newly recommended drug for management of their own or family members’ malaria episode. This indicates that, other factors than providers’ attitude may have more influence in their personal treatment practices.

  20. Estimating antimalarial drugs consumption in Africa before the switch to artemisinin-based combination therapies (ACTs

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    Vreeke Ed

    2007-07-01

    Full Text Available Abstract Background Having reliable forecasts is critical now for producers, malaria-endemic countries and agencies in order to adapt production and procurement of the artemisinin-based combination treatments (ACTs, the new first-line treatments of malaria. There is no ideal method to quantify drug requirements for malaria. Morbidity data give uncertain estimations. This study uses drug consumption to provide elements to help estimate quantities and financial requirements of ACTs. Methods The consumption of chloroquine, sulphadoxine/pyrimethamine and quinine both through the private and public sector was assessed in five sub-Saharan Africa countries with different epidemiological patterns (Senegal, Rwanda, Tanzania, Malawi, Zimbabwe. From these data the number of adult treatments per capita was calculated and the volumes and financial implications derived for the whole of Africa. Results Identifying and obtaining data from the private sector was difficult. The quality of information on drug supply and distribution in countries must be improved. The number of adult treatments per capita and per year in the five countries ranged from 0.18 to 0.50. Current adult treatment prices for ACTs range US$ 1–1.8. Taking the upper range for both volumes and costs, the highest number of adult treatments consumed for Africa was estimated at 314.5 million, corresponding to an overall maximum annual need for financing ACT procurement of US$ 566.1 million. In reality, both the number of cases treated and the cost of treatment are likely to be lower (projections for the lowest consumption estimate with the least expensive ACT would require US $ 113 million per annum. There were substantial variations in the market share between public and private sources among these countries (the public sector share ranging from 98% in Rwanda to 33% in Tanzania. Conclusion Additional studies are required to build a more robust methodology, and to assess current consumptions

  1. Malaria prevention with IPTp during pregnancy reduces neonatal mortality.

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    Clara Menéndez

    Full Text Available BACKGROUND: In the global context of a reduction of under-five mortality, neonatal mortality is an increasingly relevant component of this mortality. Malaria in pregnancy may affect neonatal survival, though no strong evidence exists to support this association. METHODS: In the context of a randomised, placebo-controlled trial of intermittent preventive treatment (IPTp with sulphadoxine-pyrimethamine (SP in 1030 Mozambican pregnant women, 997 newborns were followed up until 12 months of age. There were 500 live borns to women who received placebo and 497 to those who received SP. FINDINGS: There were 58 infant deaths; 60.4% occurred in children born to women who received placebo and 39.6% to women who received IPTp (p = 0.136. There were 25 neonatal deaths; 72% occurred in the placebo group and 28% in the IPTp group (p = 0.041. Of the 20 deaths that occurred in the first week of life, 75% were babies born to women in the placebo group and 25% to those in the IPTp group (p = 0.039. IPTp reduced neonatal mortality by 61.3% (95% CI 7.4%, 83.8%; p = 0.024]. CONCLUSIONS: Malaria prevention with SP in pregnancy can reduce neonatal mortality. Mechanisms associated with increased malaria infection at the end of pregnancy may explain the excess mortality in the malaria less protected group. Alternatively, SP may have reduced the risk of neonatal infections. These findings are of relevance to promote the implementation of IPTp with SP, and provide insights into the understanding of the pathophysiological mechanisms through which maternal malaria affects fetal and neonatal health. TRIAL REGISTRATION: ClinicalTrials.gov NCT00209781.

  2. Evaluation of malaria prevention strategies during pregnancy in Ndola, Zambia

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    Mulamba, Mwamba

    2010-01-01

    ABSTRACT Background Malaria in pregnancy is associated with many negative outcomes for the woman, foetus and neonate. Intermittent preventive treatment during pregnancy (IPTp) using three doses of sulfadoxine/pyrimethamine (SP), insecticide-treated mosquito nets (ITNs) and indoor residual spray (IRS), constitute the main strategies used to prevent malaria. The aim of this study is to evaluate the effectiveness of these strategies for the reduction of malaria prevalence in pregnant women. Methods A questionnaire on socio-demographic information, history of malaria during current pregnancy and prevention strategies used was administered to 450 consecutive patients admitted into labour wards at three local clinics. From the antenatal cards, information was collected on the last menstrual period, date of each dose of SP taken, gravidity, and HIV status. A blood slide to detect Plasmodium was then collected from each woman after consent. Results Of the participants in the study, 2.4% had a positive blood slide at term and 15.8% reported malaria during pregnancy. All the participants took at least one dose of SP with 87.6% completing the stipulated three doses. The mean gestational ages for each dose were 22.1 (SD 4.6), 29.1 (SD 4.4) and 34.4 (SD 3.9) weeks for the first, second and third dose respectively. With regard to ITNs, 79.5% had one, but only 74.1% used it regularly. IRS was completed in all three of the clinics’ catchment areas. Only 23.4% used commercial insecticide. Conclusion The measured prevalence of malaria at term in Ndola was remarkably low, although the self-reported rate during pregnancy was still high. The national targets for accessing IPTp were exceeded, although the timing of each dose needs to be improved. Access to ITNs was high, but usage needs to increase.

  3. Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

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    Olliaro P

    2004-01-01

    Full Text Available The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent

  4. Nonlinear mixed effects modeling of gametocyte carriage in patients with uncomplicated malaria

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    Little Francesca

    2010-02-01

    Full Text Available Abstract Background Gametocytes are the sexual form of the malaria parasite and the main agents of transmission. While there are several factors that influence host infectivity, the density of gametocytes appears to be the best single measure that is related to the human host's infectivity to mosquitoes. Despite the obviously important role that gametocytes play in the transmission of malaria and spread of anti-malarial resistance, it is common to estimate gametocyte carriage indirectly based on asexual parasite measurements. The objective of this research was to directly model observed gametocyte densities over time, during the primary infection. Methods Of 447 patients enrolled in sulphadoxine-pyrimethamine therapeutic efficacy studies in South Africa and Mozambique, a subset of 103 patients who had no gametocytes pre-treatment and who had at least three non-zero gametocyte densities over the 42-day follow up period were included in this analysis. Results A variety of different functions were examined. A modified version of the critical exponential function was selected for the final model given its robustness across different datasets and its flexibility in assuming a variety of different shapes. Age, site, initial asexual parasite density (logged to the base 10, and an empirical patient category were the co-variates that were found to improve the model. Conclusions A population nonlinear modeling approach seems promising and produced a flexible function whose estimates were stable across various different datasets. Surprisingly, dihydrofolate reductase and dihydropteroate synthetase mutation prevalence did not enter the model. This is probably related to a lack of power (quintuple mutations n = 12, and informative censoring; treatment failures were withdrawn from the study and given rescue treatment, usually prior to completion of follow up.

  5. Quality of anti-malarial drugs provided by public and private healthcare providers in south-east Nigeria

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    Uzochukwu Benjamin

    2009-02-01

    Full Text Available Abstract Background There is little existing knowledge about actual quality of drugs provided by different providers in Nigeria and in many sub-Saharan African countries. Such information is important for improving malaria treatment that will help in the development and implementation of actions designed to improve the quality of treatment. The objective of the study was to determine the quality of drugs used for the treatment of malaria in a broad spectrum of public and private healthcare providers. Methods The study was undertaken in six towns (three urban and three rural in Anambra state, south-east Nigeria. Anti-malarials (225 samples, which included artesunate, dihydroartemisinin, sulphadoxine-pyrimethamine (SP, quinine, and chloroquine, were either purchased or collected from randomly selected providers. The quality of these drugs was assessed by laboratory analysis of the dissolution profile using published pharmacopoeial monograms and measuring the amount of active ingredient using high performance liquid chromatography (HPLC. Findings It was found that 60 (37% of the anti-malarials tested did not meet the United States Pharmacopoeia (USP specifications for the amount of active ingredients, with the suspect drugs either lacking the active ingredients or containing suboptimal quantities of the active ingredients. Quinine (46% and SP formulations (39% were among drugs that did not satisfy the tolerance limits published in USP monograms. A total of 78% of the suspect drugs were from private facilities, mostly low-level providers, such as patent medicine dealers (vendors. Conclusion This study found that there was a high prevalence of poor quality drugs. The findings provide areas for public intervention to improve the quality of malaria treatment services. There should be enforced checks and regulation of drug supply management as well as stiffer penalties for people stocking substandard and counterfeit drugs.

  6. Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library

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    Feng, Jie; Weitner, Megan; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Zhang, Ying

    2015-01-01

    Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2–4 week antibiotic treatment, 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and

  7. Knowledge and Adherence to the National Guidelines for Malaria Case Management in Pregnancy among Healthcare Providers and Drug Outlet Dispensers in Rural, Western Kenya.

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    Christina Riley

    Full Text Available Although prompt, effective treatment is a cornerstone of malaria control, information on provider adherence to malaria in pregnancy (MIP treatment guidelines is limited. Incorrect or sub-optimal treatment can adversely affect the mother and fetus. This study assessed provider knowledge of and adherence to national case management guidelines for uncomplicated MIP.We conducted a cross-sectional study from September to November 2013, in 51 health facilities (HF and a randomly-selected sample of 39 drug outlets (DO in the KEMRI/CDC Health and Demographic Surveillance System area in western Kenya. Provider knowledge of national treatment guidelines was assessed with standardized questionnaires. Correct practice required adequate diagnosis, pregnancy assessment, and treatment with correct drug and dosage. In HF, we conducted exit interviews in all women of childbearing age assessed for fever. In DO, simulated clients posing as first trimester pregnant women or as relatives of third trimester pregnant women collected standardized information.Correct MIP case management knowledge and practice were observed in 45% and 31% of HF and 0% and 3% of DO encounters, respectively. The correct drug and dosage for pregnancy trimester was prescribed in 62% of HF and 42% of DO encounters; correct prescription occurred less often in first than in second/ third trimesters (HF: 24% vs. 65%, p<0.01; DO: 0% vs. 40%, p<0.01. Sulfadoxine-pyrimethamine, which is not recommended for malaria treatment, was prescribed in 3% of HF and 18% of DO encounters. Exposure to artemether-lumefantrine in first trimester, which is contraindicated, occurred in 29% and 49% of HF and DO encounters, respectively.This study highlights knowledge inadequacies and incorrect prescribing practices in the treatment of MIP. Particularly concerning is the prescription of contraindicated medications in the first trimester. These issues should be addressed through comprehensive trainings and increased

  8. Got ACTs? Availability, price, market share and provider knowledge of anti-malarial medicines in public and private sector outlets in six malaria-endemic countries

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    O'Connell Kathryn A

    2011-10-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC, Madagascar, Nigeria, Uganda and Zambia. Methods Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. Results 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets as compared to first-line quality-assured ACT ( Conclusions These standardized, nationally representative results demonstrate the typically low availability, low market share and high prices of ACT, in the private sector where most anti-malarials are accessed, with some exceptions. The results confirm that there is substantial room to improve availability and affordability of ACT treatment in the surveyed countries. The data will also be useful for monitoring the impact of interventions such as the Affordable Medicines Facility for malaria.

  9. Fixed drug eruption at a dermatology clinic in Lagos, Nigeria

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    Olusola Olabisi Ayanlowo

    2015-01-01

    Full Text Available Background: Fixed drug eruption (FDE is common cutaneous drug eruption characterized by the development of one or more annular, oval, erythematous, and hyperpigmented patches as a result of systemic exposure to a drug. Drugs causing FDE vary with prevailing diseases and prescription pattern in different parts of the world. This study is aimed at reviewing cases of FDE seen at the dermatology outpatient clinic of Lagos University Teaching Hospital (LUTH over a 9-year period, highlighting the spectrum of drugs implicated and the clinical characteristics. Materials and Methods: Data were obtained from the clinic records and patients' case notes. These included the demographic details, duration of presentation, drugs implicated, and clinical characteristics. Results: FDE was diagnosed in 1.8% (295/16,160 of patients seen. There was a slight female preponderance. Antimalarials were the commonest group of medications implicated (51.0% followed by antibiotics (27.9%; analgesics (10.2%, herbal toothpaste (6.1%, and oral hypoglycemic agents (4.1%. Sulfonamides were the commonest group of drugs found in 78 patients (53.1% predominantly as sulfadoxine/pyrimethamine antimalarials and trimethoprim/sulfamethoxazole antibiotics (co-trimoxazole. Conclusion: Concerted efforts are needed to discourage over-the-counter sales and purchase of nonprescription sulfonamide-based medications. A change in prescription pattern from sulfonamides to other classes of antimalarials and antibiotics is desirable and/or recommended. Patients should inform their caregivers at any point of care about their reaction to drugs. It is advised that they have a list of common implicating drugs and they wear a medic alert or carry an ID card bearing this information.

  10. In Vivo Antiplasmodial Potentials of the Combinations of Four Nigerian Antimalarial Plants

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    Adeleke Clement Adebajo

    2014-08-01

    Full Text Available Various combinations of Nauclea latifolia root, Artocarpus altilis stem bark, Murraya koenigii leaf and Enantia chlorantha stem bark used in African ethnomedicine as decoctions for malaria and fevers, and combinations with standard drugs, were investigated for antiplasmodial activities using Plasmodium berghei berghei-infected mice. The respective prophylactic and curative ED50 values of 189.4 and 174.5 mg/kg for N. latifolia and chemosuppressive ED50 value of 227.2 mg/kg for A. altilis showed that they were the best antimalarial herbal drugs. A 1.6-fold increase of the survival time given by the negative control was elicited by M. koenigii, thereby confirming its curative activity. Pyrimethamine with an ED50 of 0.5 ± 0.1 mg/kg for the prophylactic, and chloroquine with ED50 = 2.2 ± 0.1 and 2.2 ± 0.0 mg/kg for the chemosuppressive and curative tests, respectively, were significantly (p < 0.05 more active. Co-administrations of N. latifolia with the standard drugs significantly reduced their prophylactic, chemosuppressive and curative actions, possibly increasing the parasites’ resistance. Binary combinations of N. latifolia or M. koenigii with any of the other plants significantly increased the prophylactic and suppressive activities of their individual plants, respectively. Also, E. chlorantha with A. altilis or N. latifolia enhanced their respective prophylactic or curative activities, making these combinations most beneficial against malaria infections. Combinations of three and four extracts gave varied activities. Hence, the results justified the combinations of ethnomedicinal plants in antimalarial herbal remedies and showed the importance of the three in vivo models in establishing antimalarial activity.

  11. Congenital toxoplasmosis in a reference center of Paraná, Southern Brazil

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    Jaqueline Dario Capobiango

    2014-08-01

    Full Text Available This study describes the characteristics of 31 children with congenital toxoplasmosis children admitted to the University Hospital of Londrina, Southern Brazil, from 2000 to 2010. In total, 23 (85.2% of the mothers received prenatal care but only four (13.0% were treated for toxoplasmosis. Birth weight was <2500 g in 37.9% of the infants. During the first month of life, physical examination was normal in 34.5%, and for those with clinical signs and symptoms, the main manifestations were hepatomegaly and/or splenomegaly (62.1%, jaundice (13.8%, and microcephaly (6.9%. During ophthalmic examination, 74.2% of the children exhibited injuries, 58.1% chorioretinitis, 32.3% strabismus, 19.4% microphthalmia, and 16.2% vitreitis. Anti-Toxoplasma gondii IgM antibodies were detected in 48.3% of the children. Imaging brain evaluation was normal in 44.8%; brain calcifications, hydrocephaly, or both conditions were observed in 27.6%, 10.3%, and 17.2%, respectively, of the patients. Patients with cerebrospinal fluid protein ≥ 200 mg/dL presented more brain calcifications (p = 0.0325. Other sequelae were visual impairment (55.2% of the cases, developmental delay (31.0%, motor deficit (13.8%, convulsion (27.5%, and attention deficit (10.3%. All patients were treated with sulfadiazine, pyrimethamine, and folinic acid, and 55.2% of them exhibited adverse effects. The results demonstrate the significance of the early diagnosis and treatment of toxoplasmosis during pregnancy to reduce congenital toxoplasmosis and its consequences.

  12. Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo.

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    Mui, Ernest J; Schiehser, Guy A; Milhous, Wilbur K; Hsu, Honghue; Roberts, Craig W; Kirisits, Michael; Muench, Stephen; Rice, David; Dubey, J P; Fowble, Joseph W; Rathod, Pradipsinh K; Queener, Sherry F; Liu, Susan R; Jacobus, David P; McLeod, Rima

    2008-03-05

    Toxoplasma gondii causes substantial morbidity, mortality, and costs for healthcare in the developed and developing world. Current medicines are not well tolerated and cause hypersensitivity reactions. The dihydrotriazine JPC-2067-B (4, 6-diamino-1, 2-dihydro-2, 2-dimethyl-1-(3'(2-chloro-, 4-trifluoromethoxyphenoxy)propyloxy)-1, 3, 5-triazine), which inhibits dihydrofolate reductase (DHFR), is highly effective against Plasmodium falciparum, Plasmodium vivax, and apicomplexans related to T. gondii. JPC-2067-B is the primary metabolite of the orally active biguanide JPC-2056 1-(3'-(2-chloro-4-trifluoromethoxyphenyloxy)propyl oxy)- 5-isopropylbiguanide, which is being advanced to clinical trials for malaria. Efficacy of the prodrug JPC-2056 and the active metabolite JPC-2067-B against T. gondii and T. gondii DHFR as well as toxicity toward mammalian cells were tested. Herein, we found that JPC-2067-B is highly effective against T. gondii. We demonstrate that JPC-2067-B inhibits T. gondii growth in culture (IC50 20 nM), inhibits the purified enzyme (IC50 6.5 nM), is more efficacious than pyrimethamine, and is cidal in vitro. JPC-2067-B administered parenterally and the orally administered pro-drug (JPC-2056) are also effective against T. gondii tachyzoites in vivo. A molecular model of T. gondii DHFR-TS complexed with JPC-2067-B was developed. We found that the three main parasite clonal types and isolates from South and Central America, the United States, Canada, China, and Sri Lanka have the same amino acid sequences preserving key binding sites for the triazine. JPC-2056/JPC-2067-B have potential to be more effective and possibly less toxic treatments for toxoplasmosis than currently available medicines.

  13. Cotrimoxazole prophylactic treatment prevents malaria in children in sub-Saharan Africa: systematic review and meta-analysis.

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    Mbeye, Nyanyiwe M; ter Kuile, Feiko O; Davies, Mary-Ann; Phiri, Kamija S; Egger, Matthias; Wandeler, Gilles

    2014-09-01

    Cotrimoxazole prophylactic treatment (CPT) prevents opportunistic infections in HIV-infected or HIV-exposed children, but estimates of the effectiveness in preventing malaria vary. We reviewed studies that examined the effect of CPT on incidence of malaria in children in sub-Saharan Africa. We searched PubMed and EMBASE for randomised controlled trials (RCTs) and cohort studies on the effect of CPT on incidence of malaria and mortality in children and extracted data on the prevalence of sulphadoxine-pyrimethamine resistance-conferring point mutations. Incidence rate ratios (IRR) from individual studies were combined using random effects meta-analysis; confounder-adjusted estimates were used for cohort studies. The importance of resistance was examined in meta-regression analyses. Three RCTs and four cohort studies with 5039 children (1692 HIV-exposed; 2800 HIV-uninfected; 1486 HIV-infected) were included. Children on CPT were less likely to develop clinical malaria episodes than those without prophylaxis (combined IRR 0.37, 95% confidence interval: 0.21-0.66), but there was substantial between-study heterogeneity (I-squared = 94%, P < 0.001). The protective efficacy of CPT was highest in an RCT from Mali, where the prevalence of antifolate resistant plasmodia was low. In meta-regression analyses, there was some evidence that the efficacy of CPT declined with increasing levels of resistance. Mortality was reduced with CPT in an RCT from Zambia, but not in a cohort study from Côte d'Ivoire. Cotrimoxazole prophylactic treatment reduces incidence of malaria and mortality in children in sub-Saharan Africa, but study designs, settings and results were heterogeneous. CPT appears to be beneficial for HIV-infected and HIV-exposed as well as HIV-uninfected children. © 2014 John Wiley & Sons Ltd.

  14. [Pediatric management of sickle cell disease: experience at the Charles de Gaulle University Children's Hospital in Ouagadougou (Burkina Faso)].

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    Yé, Diarra; Kouéta, Fla; Dao, Lassina; Kaboret, Sonia; Sawadogo, Alphonse

    2008-01-01

    Sickle cell disease is a genetic disease most common in blacks. We retrospectively collected records for patients with sickle cell disease who were seen from January 2002 through September 2006 to assess the care provided for this disease at Charles de Gaulle University Children's Hospital of Ouagadougou. In all, 88 patients were monitored quarterly at outpatient visits for sickle cell disease, in the absence of any crisis. Their age ranged from 6 months to 16 years, with an average age of 7. There were more boys than girls, with a sex ratio of 1.44. The distribution according to sickle cell genotype showed that SC accounted for 62% of cases, while SS forms were more frequent until the age of 5. All children have received the immunizations in the standard Expanded Programme on Immunization (EPI) [diphtheria, tetanus, pertussis, polio, measles and yellow fever]. The immunization rates for non-EPI vaccines including hepatitis B, Haemophilus influenzae B, Salmonella typhi, meningitis, pneumonia and the combined vaccine against measles, mumps and rubella ranged from 94 to 100%. A prophylactic anti-anaemic agent was made with folic acid often associated with iron. In addition, patients receive malaria chemoprophylaxis. Chloroquine was initially provided, and since 2006, children have been receiving sulfadoxine-pyrimethamine. Our encouraging results deserve reinforcement in the short-term - at the local level by neonatal screening, the creation of an immunization unit, and the systematization of antibiotic prophylaxis, and in the medium-term by implementation of a National sickle cell disease programme to help meet the objective of a 40% reduction in mortality among affected children younger than 5 years by 2015, set by the Sickle Cell Disease International Organization.

  15. The impact of prenatal exposure to parasitic infections and to anthelminthic treatment on antibody responses to routine immunisations given in infancy: Secondary analysis of a randomised controlled trial

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    Mentzer, Alexander J.; Lule, Swaib A.; Kizito, Dennison; Smits, Gaby; van der Klis, Fiona R. M.; Elliott, Alison M.

    2017-01-01

    Background Chronic parasitic infections are associated with active immunomodulation which may include by-stander effects on unrelated antigens. It has been suggested that pre-natal exposure to parasitic infections in the mother impacts immunological development in the fetus and hence the offspring’s response to vaccines, and that control of parasitic infection among pregnant women will therefore be beneficial. Methodology/Principal findings We used new data from the Entebbe Mother and Baby Study, a trial of anthelminthic treatment during pregnancy conducted in Uganda, to further investigate this hypothesis. 2705 mothers were investigated for parasitic infections and then randomised to albendazole (400mg) versus placebo and praziquantel (40mg/kg) during pregnancy in a factorial design. All mothers received sulfadoxine/pyrimethamine for presumptive treatment of malaria. Offspring received Expanded Programme on Immunisation vaccines at birth, six, 10 and 14 weeks. New data on antibody levels to diphtheria toxin, three pertussis antigens, Haemophilus influenzae type B (HiB) and Hepatitis B, measured at one year (April 2004 –May 2007) from 1379 infants were analysed for this report. Additional observational analyses relating maternal infections to infant vaccine responses were also conducted. Helminth infections were highly prevalent amongst mothers (hookworm 43.1%, Mansonella 20.9%, Schistosoma mansoni 17.3%, Strongyloides 11.7%, Trichuris 8.1%) and 9.4% had malaria at enrolment. In the trial analysis we found no overall effect of either anthelminthic intervention on the measured infant vaccine responses. In observational analyses, no species was associated with suppressed responses. Strongyloidiasis was associated with enhanced responses to pertussis toxin, HiB and Hep B vaccine antigens. Conclusions/Significance Our results do not support the hypothesis that routine anthelminthic treatment during pregnancy has a benefit for the infant’s vaccine response, or

  16. Effect of artemether-lumefantrine policy and improved vector control on malaria burden in KwaZulu-Natal, South Africa.

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    Karen I Barnes

    2005-11-01

    Full Text Available Between 1995 and 2000, KwaZulu-Natal province, South Africa, experienced a marked increase in Plasmodium falciparum malaria, fuelled by pyrethroid and sulfadoxine-pyrimethamine resistance. In response, vector control was strengthened and artemether-lumefantrine (AL was deployed in the first Ministry of Health artemisinin-based combination treatment policy in Africa. In South Africa, effective vector and parasite control had historically ensured low-intensity malaria transmission. Malaria is diagnosed definitively and treatment is provided free of charge in reasonably accessible public-sector health-care facilities.We reviewed four years of malaria morbidity and mortality data at four sentinel health-care facilities within KwaZulu-Natal's malaria-endemic area. In the year following improved vector control and implementation of AL treatment, malaria-related admissions and deaths both declined by 89%, and outpatient visits decreased by 85% at the sentinel facilities. By 2003, malaria-related outpatient cases and admissions had fallen by 99%, and malaria-related deaths had decreased by 97%. There was a concomitant marked and sustained decline in notified malaria throughout the province. No serious adverse events were associated causally with AL treatment in an active sentinel pharmacovigilance survey. In a prospective study with 42 d follow up, AL cured 97/98 (99% and prevented gametocyte developing in all patients. Consistent with the findings of focus group discussions, a household survey found self-reported adherence to the six-dose AL regimen was 96%.Together with concurrent strengthening of vector control measures, the antimalarial treatment policy change to AL in KwaZulu-Natal contributed to a marked and sustained decrease in malaria cases, admissions, and deaths, by greatly improving clinical and parasitological cure rates and reducing gametocyte carriage.

  17. Reduction of malaria transmission to Anopheles mosquitoes with a six-dose regimen of co-artemether.

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    Colin J Sutherland

    2005-04-01

    Full Text Available Resistance of malaria parasites to chloroquine (CQ and sulphadoxine-pyrimethamine (SP is increasing in prevalence in Africa. Combination therapy can both improve treatment and provide important public health benefits if it curbs the spread of parasites harbouring resistance genes. Thus, drug combinations must be identified which minimise gametocyte emergence in treated cases, and so prevent selective transmission of parasites resistant to any of the partner drugs.In a randomised controlled trial, 497 children with uncomplicated falciparum malaria were treated with CQ and SP (three doses and one dose respectively; n = 91, or six doses of artemether in fixed combination with lumefantrine (co-artemether [Coartem, Riamet] (n = 406. Carriage rates of Plasmodium falciparum gametocytes and trophozoites were measured 7, 14, and 28 d after treatment. The infectiousness of venous blood from 29 children carrying P. falciparum gametocytes 7 d after treatment was tested by membrane-feeding of Anopheles mosquitoes. Children treated with co-artemether were significantly less likely to carry gametocytes within the 4 weeks following treatment than those receiving CQ/SP (30 of 378 [7.94%] versus 42 of 86 [48.8%]; p < 0.0001. Carriers in the co-artemether group harboured gametocytes at significantly lower densities, for shorter periods (0.3 d versus 4.2 d; p < 0.0001 and were less infectious to mosquitoes at day 7 (p < 0.001 than carriers who had received CQ/SP.Co-artemether is highly effective at preventing post-treatment transmission of P. falciparum. Our results suggest that co-artemether has specific activity against immature sequestered gametocytes, and has the capacity to minimise transmission of drug-resistant parasites.

  18. Artemisinin-Resistant Plasmodium falciparum Malaria.

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    Fairhurst, Rick M; Dondorp, Arjen M

    2016-06-01

    For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins, the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs)-the first-line treatments for malaria-are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in vitro, genomics, and transcriptomics studies in SEA have defined in vivo and in vitro phenotypes of artemisinin resistance, identified its causal genetic determinant, explored its molecular mechanism, and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early-ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's K13 gene, is associated with an upregulated "unfolded protein response" pathway that may antagonize the pro-oxidant activity of artemisinins, and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent, test whether new combinations of currently available drugs cure ACT failures, and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest.

  19. Combating multidrug-resistant Plasmodium falciparum malaria.

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    Thu, Aung Myint; Phyo, Aung Pyae; Landier, Jordi; Parker, Daniel M; Nosten, François H

    2017-08-01

    Over the past 50 years, Plasmodium falciparum has developed resistance against all antimalarial drugs used against it: chloroquine, sulphadoxine-pyrimethamine, quinine, piperaquine and mefloquine. More recently, resistance to the artemisinin derivatives and the resulting failure of artemisinin-based combination therapy (ACT) are threatening all major gains made in malaria control. Each time resistance has developed progressively, with delayed clearance of parasites first emerging only in a few regions, increasing in prevalence and geographic range, and then ultimately resulting in the complete failure of that antimalarial. Drawing from this repeated historical chain of events, this article presents context-specific approaches for combating drug-resistant P. falciparum malaria. The approaches begin with a context of drug-sensitive parasites and focus on the prevention of the emergence of drug resistance. Next, the approaches address a scenario in which resistance has emerged and is increasing in prevalence and geographic extent, with interventions focused on disrupting transmission through vector control, early diagnosis and treatment, and the use of new combination therapies. Elimination is also presented as an approach for addressing the imminent failure of all available antimalarials. The final drug resistance context presented is one in which all available antimalarials have failed; leaving only personal protection and the use of new antimalarials (or new combinations of antimalarials) as a viable strategy for dealing with complete resistance. All effective strategies and contexts require a multipronged, holistic approach. © 2017 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

  20. FATAL DISSEMINATED CRYPTOCOCCOSIS WITH RENAL INVOLVEMENT IN AN HIV-INFECTED PATIENT

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    Elizabeth De Francesco DAHER

    2015-08-01

    Full Text Available SUMMARY Introduction: We present a fatal case of disseminated cryptococcosis in a young man whose diagnosis of HIV infection was made at the time of admission to the emergency room. Case report: The patient was a twenty-three-year-old man, with a history of daily fever during one month associated with diarrhea, weight loss, headache, vomiting and generalized seizures. He also had a history of diabetes mellitus, alcoholism and drug addiction. Upon physical examination the patient was pale, disoriented and had periods of agitation. White blood cells count was 3,440/mm3 (5% lymphocytes, hemoglobin was 10g/dL, platelets were 83,000/ mm3. Creatinine was 0.7 mg/dL; urea 19 mg/dL; Na, K, and liver enzymes were within normal limits. Lactic dehydrogenase was 494 IU/L. Cerebrospinal fluid (CSF analysis revealed 10 white blood cells/mm3 (58% neutrophils, 31% lymphocytes, 11% monocytes and 2 red blood cells/mm3. India ink test revealed six Cryptococcus yeasts/mm3. CSF glucose was 122 mg/dL and protein was 36 mg/ dL. VDRL test was negative and anti-HIV test was positive. Intravenous hydration, insulin, phenytoin, fluconazole, pyrimethamine, sulfadiazine, folinic acid, and amphotericin B were started. The patient did not improve and became obtunded and hypotensive. He was intubated and put on mechanical respiration. He received vasoactive drugs and died less than 24 hours after admission. A postmortem examination was performed and revealed disseminated cryptococcosis, with severe involvement of the kidneys. Conclusion: Cryptococcosis, as a rule, is a systemic disease that affects mostly immunocompromised individuals, especially patients with AIDS. When diagnosed late in its course it has a very high mortality.

  1. Antenatal and delivery care in rural western Kenya: the effect of training health care workers to provide "focused antenatal care"

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    Odhiambo Frank O

    2010-04-01

    Full Text Available Abstract Background Maternal mortality remains high in developing countries and data to monitor indicators of progress in maternal care is needed. We examined the status of maternal care before and after health care worker (HCW training in WHO recommended Focused Antenatal Care. Methods An initial cross-sectional survey was conducted in 2002 in Asembo and Gem in western Kenya among a representative sample of women with a recent birth. HCW training was performed in 2003 in Asembo, and a repeat survey was conducted in 2005 in both areas. Results Antenatal clinic (ANC attendance was similar in both areas (86% in 2005 and not significantly different from 2002 (90%. There was no difference in place of delivery between the areas or over time. However, in 2005, more women in Asembo were delivered by a skilled assistant compared to Gem (30% vs.23%, P = 0.04, and this proportion increased compared to 2002 (17.6% and 16.1%, respectively. Provision of iron (82.4%, folic acid (72.0%, sulfadoxine-pyrimethamine (61.7%, and anthelminths (12.7% had increased in Asembo compared to 2002 (2002: 53.3%, 52.8%, 20.3%, and 4.6%, respectively, and was significantly higher than in Gem in 2005 (Gem 2005: 69.7%, 47.8%, 19.8%, and 4.1%, respectively (P Conclusions We observed improvements in some ANC services in the area where HCWs were trained. However, since our evaluation was carried out 2 years after three-day training, we consider any significant, sustained improvement to be remarkable.

  2. In vivo antiplasmodial and in vitro antioxidant property of stem bark extracts of Haematostaphis barteri

    Institute of Scientific and Technical Information of China (English)

    Johnson; Nyarko; Boampong; Akua; Afryie; Karikari; Elvis; Ofori; Ameyaw

    2015-01-01

    Objective: To evaluate the antimalarial and antioxidant properties of stem bark extracts of Haematostaphis barteri(H. barteri).Methods: The prophylactic activity of the plant was performed by dosing mice with sulfadoxine-pyrimethamine(1.2 mg/kg), aqueous extract(30, 100, 300 mg/kg) and dichloromethane/methanol(D/M)(30, 100, 300 mg/kg) extracts of H. barteri for 3 days. On the 4th day, the mice were inoculated with Plasmodium berghei. The parasite density was estimated for each mouse 72 h post-parasite inoculation. The curative activity of the plant was also performed by inoculating mice with Plasmodium berghei. Three days later, they were treated with artemether-lumefantrine(4 mg/kg), aqueous and D/M extracts of H. barteri stem bark for 5 days. The in vitro antioxidant property of the aqueous extract was determined by using the reducing power, nitric oxide and total antioxidant capacity assays. Results: The aqueous extract exerted significant(P < 0.05) curative and prophylactic antimalarial activities. The D/M extract exhibited significant curative(P < 0.05) but not prophylactic antiplasmodial ef ect. The aqueous extract exhibited in vitro antioxidant property with IC50’s of(0.930 ± 0.021) mg/mL,(0.800 ± 0.001) mg/mL and(0.22 ± 0.05) mg/mL in the total antioxidant capacity, reducing power and nitric oxide assays. Histological assessment of the liver of aqueous and D/M treated animals did not reveal any sign of toxicity.Conclusions: H. barteri is not toxic which exerted significant curative antiplasmodial ef ects but the prophylactic property was however fraction dependent. The mechanism of the antiplasmodial activity of H. barteri may partly be mediated by its antioxidant property.

  3. Ozonation of pyridine and other N-heterocyclic aromatic compounds: Kinetics, stoichiometry, identification of products and elucidation of pathways.

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    Tekle-Röttering, Agnes; Reisz, Erika; Jewell, Kevin S; Lutze, Holger V; Ternes, Thomas A; Schmidt, Winfried; Schmidt, Torsten C

    2016-10-01

    Pyridine, pyridazine, pyrimidine and pyrazine were investigated in their reaction with ozone. These compounds are archetypes for heterocyclic aromatic amines, a structural unit that is often present in pharmaceuticals, pesticides and dyestuffs (e.g., enoxacin, pyrazineamide or pyrimethamine). The investigated target compounds react with ozone with rate constants ranging from 0.37 to 57 M(-1) s(-1), hampering their degradation during ozonation. In OH radical scavenged systems the reaction of ozone with pyridine and pyridazine is characterized by high transformation (per ozone consumed) of 55 and 54%, respectively. In non scavenged system the transformation drops to 52 and 12%, respectively. However, in the reaction of pyrimidine and pyrazine with ozone this is reversed. Here, in an OH radical scavenged system the compound transformation is much lower (2.1 and 14%, respectively) than in non scavenged one (22 and 25%, respectively). This is confirmed by corresponding high N-oxide formation in the ozonation of pyridine and pyridazine, but probably low formation in the reaction of pyrimidine and pyrazine with ozone. With respect to reaction mechanisms, it is suggested that ozone adduct formation at nitrogen is the primary step in the ozonation of pyridine and pyridazine. On the contrary, ozone adduct formation to the aromatic ring seems to occur especially in the ozonation of pyrimidine as inferred from hydrogen peroxide yield. However, also OH radical reactions are supposed processes in the case of pyrimidine and in particular for pyrazine, albeit negligible OH radical yields are obtained. The low compound transformation in OH radical scavenged system can prove this. As a result of negligible OH radical yields in all cases (less than 6%) electron transfer as primary reaction pathway plays a subordinate role.

  4. [Pharmaceutical development concerning diseases predominating in tropical regions: the concept of indigent drugs].

    Science.gov (United States)

    Trouiller, P; Rey, J L; Bouscharain, P

    2000-01-01

    When the WHO certified the eradication of smallpox in 1981, there was a general impression that the fight against infectious diseases which began with Jenner and Pasteur was entering a phase of achievement: poliomyelitis, dracunculasis, leprosy, Chagas' disease and neonatal tetanus were also responding to eradication campaigns. However, in 1995, infectious diseases are still an important cause of mortality and morbidity and the rising incidence of emerging or re-emerging diseases remains a matter of great concern. Although this situation can be explained, at least partly, by the deterioration of health care systems and diverse socio-economic and ecological disorders, important changes occurring in the drug industry since 1980 have also played a role due to changes in pharmaco-epidemiology and new policies of drug development. Among the 1061 new drugs developed from 1975 to 1994, less than 2.7% concern tropical diseases. Since praziquantel, novel drugs have issued from veterinary medicine (ivermectin), military research (halofantrine, mefloquine) or fortuitous analysis of pharmacopoeia (artesunate). The cost of investments and the lack of market potential and market security in developing countries have dampened interest in developing drugs for tropical diseases. Observing the combined effect of deficient pharmaceutical development, drug wear due to chemoresistance (chloroquine, sulfadoxine-pyrimethamine, aminopenicillins), the cost barrier (second generation molecules) and the potential abandon of major drugs (eflornithine, melarsoprol) has led us to establish a classification of these "indigent" drugs (in opposition to "orphan" drugs) into five classes: true indigent drugs (eflornithine), indigent drugs by indication (pentamidine), indigent drugs by function (ceftriaxone), indigent drugs by formulation (melarsoprol) and indigent drugs by default (suramin). This analysis can serve as a basis for a search for solutions (regulatory, administrative and financial

  5. TINJAUAN HASIL UJI COBA PENGOBATAN DAN PENCEGAHAN MALARIA DI BEBERAPA TEMPAT INDONESIA, 1986- 1995

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    Emiliana Tjitra

    2012-09-01

    Full Text Available In Indonesia, only antimalarials chloroquine, sulfadoxine/ sulfalene-pyrimethamine, quinine, and primaquine are available. The development of chloroquine and multidrug resistance poses a therapeutic challenge. In order to obtain alternative antimalarial drugs, trials were conducted of malaria treatment and prophylaxis in several chloroquine or multidrug resistance areas. The objective of these trials was to assess the efficacy and safety of the alternative antimalarial drugs. All the trials were mostly open studies in the fields and hospitals. These were collaboration studies between Communicable Disease Research Center, Communicable Disease Control and Environmental Health, Faculty of Medicine of the University of Indonesia, NAMRU-2, and local health staff. The patients were selected according to the WHO criteria for in-vivo antimalarial drug sensitivity testing. They should sign the informed consent form and they were followed up during the study, for 2 weeks - 4 months. In chloroquine and multidrug resistance areas, mefloquine, halofantrine, and artemether are effective and safe for treatment of uncomplicated falciparum malaria. While artesunate was noted effective and safe only in the first 14 days. Halofantrine was also documented effective and safe for vivax malaria treatment. Intramuscular artemether was effective and safe for treatment of severe and complicated falciparum malaria, particularly in remote areas lacking hospitals and the capability for intravenous infusion. Primaquine, doxycycline and mefloquine are effective and safe for malaria prophylaxis. Since the new antimalarials are not yet available in Indonesia, the improvement of efficacy of antimalarial drugs currently available should be studied. Prophylactic drugs which are effective and safe for children, pregnant and lactating women should also be studied.

  6. Estudo sobre malária e parasitoses intestinais em indígenas da tribo Nadëb-Maku, Estado do Amazonas, Brasil A study of malaria and intestinal parasites among the Nadëb-Maku Indians of Amazonas State-Brazil

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    Odair Genaro

    1984-04-01

    Full Text Available Em março de 1983 detectou-se uma epidemia de malária por Plasmodium falciparum na tribu indígena Nadëb-Maku localizada às margens do Rio Uneiuxi, alto Rio Negro, no Estado do Amazonas (Brasil. Foram obtidas e examinadas para hematozoários amostras de sangue periférico de 76 indígenas. Vinte e sete (35,5% dessas amostras estavam positivas para plasmódios. A infecção malárica foi tratada com Fansidar® (pirimetamina + sulfadoxina, mefloquina e/ou primaquina. A única espécie de anofelino coletada na aldeia durante o período da epidemia foi Anopheles mediopunctatus. Amostras de fezes obtidas de 49 indígenas foram examinadas para parasitas intestinais e 100% delas estavam positivas. A maioria dos indígenas estavam parasitada por mais de uma espécie de parasita.In March, 1983, a falciparum malaria outbreak occurred in the Nadëb-Maku Indian tribe in Amazonas State, Brazil. Seventy six blood samples were obtained and examined for hematozoa with 27 (35.5% positive for Plasmodium falciparum. Malaria infections were treated with Fansidar® (Pyrimethamine plus sulfadoxine, mefloquine and/or primaquine. The only Anopheles species collected in the Indian tribe during the outbreak period was Anopheles mediopunctatus. All 49 stool samples obtained from the Indians were positive when examined for intestinal parasites.

  7. Army Malaria Institute – its Evolution and Achievements – Third Decade (1st half: 1985-1990

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    Karl H Rieckmann

    2012-11-01

    Full Text Available The first half of the third decade (1985-1990 after the establishment of the Malaria Research Unit was characterised by a substantial increase in laboratory and field activities. Various new procedures were developed to discover and counter the increasing problem of parasite resistance to established antimalarial drug regimens. After early findings that the currently-used pyrimethamine/dapsone (Maloprim® prophylaxis was no longer effective against Plasmodium falciparum malaria, in vitro, ex vivo and pharmacological investigations were undertaken with proguanil and a low dose of dapsone. This led to a field study in Papua New Guinea (PNG which indicated that such a drug combination might be more effective than Maloprim®. Before the effectiveness of this combination could be determined further, it became obvious that Maloprim®/chloroquine had become inadequate for the protection of ADF soldiers on exercises in PNG. During one of these exercises, the landmark discovery that P. vivax had developed resistance to chloroquine was the first documented evidence that this previously successful standard medication had lost its efficacy against vivax malaria. These findings in 1988/1989 led to the evaluation of mefloquine and doxycycline as alternative prophylactic regimens for ADF personnel serving in malarious areas. In efforts to identify and assess other potential antimalarial drugs, in vitro studies were continued with various strains of P. falciparum. These studies were supplemented by investigations with P. falciparum and P. vivax in non-human primates and by malaria transmission studies with Anopheles farauti mosquitoes. The survey of anopheline mosquitoes in northern Australia indicated the widespread presence of three isomorphic species of An. farauti and the ever-present possibility of re-introducing malaria into northern Australia. Investigations relating to the biological control of mosquitoes were gradually phased out and emphasis was given

  8. The impact of prenatal exposure to parasitic infections and to anthelminthic treatment on antibody responses to routine immunisations given in infancy: Secondary analysis of a randomised controlled trial.

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    Stephen Nash

    2017-02-01

    Full Text Available Chronic parasitic infections are associated with active immunomodulation which may include by-stander effects on unrelated antigens. It has been suggested that pre-natal exposure to parasitic infections in the mother impacts immunological development in the fetus and hence the offspring's response to vaccines, and that control of parasitic infection among pregnant women will therefore be beneficial.We used new data from the Entebbe Mother and Baby Study, a trial of anthelminthic treatment during pregnancy conducted in Uganda, to further investigate this hypothesis. 2705 mothers were investigated for parasitic infections and then randomised to albendazole (400mg versus placebo and praziquantel (40mg/kg during pregnancy in a factorial design. All mothers received sulfadoxine/pyrimethamine for presumptive treatment of malaria. Offspring received Expanded Programme on Immunisation vaccines at birth, six, 10 and 14 weeks. New data on antibody levels to diphtheria toxin, three pertussis antigens, Haemophilus influenzae type B (HiB and Hepatitis B, measured at one year (April 2004 -May 2007 from 1379 infants were analysed for this report. Additional observational analyses relating maternal infections to infant vaccine responses were also conducted. Helminth infections were highly prevalent amongst mothers (hookworm 43.1%, Mansonella 20.9%, Schistosoma mansoni 17.3%, Strongyloides 11.7%, Trichuris 8.1% and 9.4% had malaria at enrolment. In the trial analysis we found no overall effect of either anthelminthic intervention on the measured infant vaccine responses. In observational analyses, no species was associated with suppressed responses. Strongyloidiasis was associated with enhanced responses to pertussis toxin, HiB and Hep B vaccine antigens.Our results do not support the hypothesis that routine anthelminthic treatment during pregnancy has a benefit for the infant's vaccine response, or that maternal helminth infection has a net suppressive effect

  9. Incidence of malaria and efficacy of combination antimalarial therapies over 4 years in an urban cohort of Ugandan children.

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    Tamara D Clark

    Full Text Available BACKGROUND: Combination therapies are now recommended to treat uncomplicated malaria. We used a longitudinal design to assess the incidence of malaria and compare the efficacies of 3 combination regimens in Kampala, Uganda. METHODOLOGY/PRINCIPAL FINDINGS: Children aged 1-10 years were enrolled from randomly selected households in 2004-05 and 2007, and were followed at least monthly through 2008. Insecticide-treated bednets (ITNs were provided in 2006. Children were randomized upon their first episode, and then treated for all episodes of uncomplicated malaria with amodiaquine/sulfadoxine-pyrimethamine (AQ/SP, artesunate/amodiaquine (AS/AQ, or artemether/lumefantrine (AL. Risks of parasitological failure were determined for each episode of uncomplicated malaria and clinical parameters were followed. A total of 690 children experienced 1464 episodes of malaria. 96% of these episodes were uncomplicated malaria and treated with study drugs; 94% were due to Plasmodium falciparum. The rank order of treatment efficacy was AL > AS/AQ > AQ/SP. Failure rates increased over time for AQ/SP, but not the artemisinin-based regimens. Over the 4-year course of the study the prevalence of asymptomatic parasitemia decreased from 11.8% to 1.4%, the incidence of malaria decreased from 1.55 to 0.32 per person year, and the prevalence of anemia (hemoglobin <10 gm/dL decreased from 5.9% to 1.0%. No episodes of severe malaria (based on WHO criteria and no deaths were seen. CONCLUSIONS/SIGNIFICANCE: With ready access to combination therapies and distribution of ITNs, responses were excellent for artemisinin-containing regimens, severe malaria was not seen, and the incidence of malaria and prevalence of parasitemia and anemia decreased steadily over time. TRIAL REGISTRATION: isrctn.org ISRCTN37517549.

  10. Effect of transmission reduction by insecticide-treated bednets (ITNs on antimalarial drug resistance in western Kenya.

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    Monica Shah

    Full Text Available Despite the clear public health benefit of insecticide-treated bednets (ITNs, the impact of malaria transmission-reduction by vector control on the spread of drug resistance is not well understood. In the present study, the effect of sustained transmission reduction by ITNs on the prevalence of Plasmodium falciparum gene mutations associated with resistance to the antimalarial drugs sulfadoxine-pyrimethamine (SP and chloroquine (CQ in children under the age of five years was investigated during an ITN trial in Asembo area, western Kenya. During the ITN trial, the national first line antimalarial treatment changed from CQ to SP. Smear-positive samples collected from cross sectional surveys prior to ITN introduction (baseline, n = 250 and five years post-ITN intervention (year 5 survey, n = 242 were genotyped for single nucleotide polymorphisms (SNPs at dhfr-51, 59, 108, 164 and dhps-437, 540 (SP resistance, and pfcrt-76 and pfmdr1-86 (CQ resistance. The association between the drug resistance mutations and epidemiological variables was evaluated. There were significant increases in the prevalence of SP dhps mutations and the dhfr/dhps quintuple mutant, and a significant reduction in the proportion of mixed infections detected at dhfr-51, 59 and dhps-437, 540 SNPs from baseline to the year 5 survey. There was no change in the high prevalence of pfcrt-76 and pfmdr1-86 mutations. Multivariable regression analysis further showed that current antifolate use and year of survey were significantly associated with more SP drug resistance mutations. These results suggest that increased antifolate drug use due to drug policy change likely led to the high prevalence of SP mutations 5 years post-ITN intervention and reduced transmission had no apparent effect on the existing high prevalence of CQ mutations. There is no evidence from the current study that sustained transmission reduction by ITNs reduces the prevalence of genes associated with malaria

  11. Origin and evolution of sulfadoxine resistant Plasmodium falciparum.

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    Sumiti Vinayak

    2010-03-01

    Full Text Available The Thailand-Cambodia border is the epicenter for drug-resistant falciparum malaria. Previous studies have shown that chloroquine (CQ and pyrimethamine resistance originated in this region and eventually spread to other Asian countries and Africa. However, there is a dearth in understanding the origin and evolution of dhps alleles associated with sulfadoxine resistance. The present study was designed to reveal the origin(s of sulfadoxine resistance in Cambodia and its evolutionary relationship to African and South American dhps alleles. We sequenced 234 Cambodian Plasmodium falciparum isolates for the dhps codons S436A/F, A437G, K540E, A581G and A613S/T implicated in sulfadoxine resistance. We also genotyped 10 microsatellite loci around dhps to determine the genetic backgrounds of various alleles and compared them with the backgrounds of alleles prevalent in Africa and South America. In addition to previously known highly-resistant triple mutant dhps alleles SGEGA and AGEAA (codons 436, 437, 540, 581, 613 are sequentially indicated, a large proportion of the isolates (19.3% contained a 540N mutation in association with 437G/581G yielding a previously unreported triple mutant allele, SGNGA. Microsatellite data strongly suggest the strength of selection was greater on triple mutant dhps alleles followed by the double and single mutants. We provide evidence for at least three independent origins for the double mutants, one each for the SGKGA, AGKAA and SGEAA alleles. Our data suggest that the triple mutant allele SGEGA and the novel allele SGNGA have common origin on the SGKGA background, whereas the AGEAA triple mutant was derived from AGKAA on multiple, albeit limited, genetic backgrounds. The SGEAA did not share haplotypes with any of the triple mutants. Comparative analysis of the microsatellite haplotypes flanking dhps alleles from Cambodia, Kenya, Cameroon and Venezuela revealed an independent origin of sulfadoxine resistant alleles in each

  12. Origin and evolution of sulfadoxine resistant Plasmodium falciparum.

    Science.gov (United States)

    Vinayak, Sumiti; Alam, Md Tauqeer; Mixson-Hayden, Tonya; McCollum, Andrea M; Sem, Rithy; Shah, Naman K; Lim, Pharath; Muth, Sinuon; Rogers, William O; Fandeur, Thierry; Barnwell, John W; Escalante, Ananias A; Wongsrichanalai, Chansuda; Ariey, Frederick; Meshnick, Steven R; Udhayakumar, Venkatachalam

    2010-03-26

    The Thailand-Cambodia border is the epicenter for drug-resistant falciparum malaria. Previous studies have shown that chloroquine (CQ) and pyrimethamine resistance originated in this region and eventually spread to other Asian countries and Africa. However, there is a dearth in understanding the origin and evolution of dhps alleles associated with sulfadoxine resistance. The present study was designed to reveal the origin(s) of sulfadoxine resistance in Cambodia and its evolutionary relationship to African and South American dhps alleles. We sequenced 234 Cambodian Plasmodium falciparum isolates for the dhps codons S436A/F, A437G, K540E, A581G and A613S/T implicated in sulfadoxine resistance. We also genotyped 10 microsatellite loci around dhps to determine the genetic backgrounds of various alleles and compared them with the backgrounds of alleles prevalent in Africa and South America. In addition to previously known highly-resistant triple mutant dhps alleles SGEGA and AGEAA (codons 436, 437, 540, 581, 613 are sequentially indicated), a large proportion of the isolates (19.3%) contained a 540N mutation in association with 437G/581G yielding a previously unreported triple mutant allele, SGNGA. Microsatellite data strongly suggest the strength of selection was greater on triple mutant dhps alleles followed by the double and single mutants. We provide evidence for at least three independent origins for the double mutants, one each for the SGKGA, AGKAA and SGEAA alleles. Our data suggest that the triple mutant allele SGEGA and the novel allele SGNGA have common origin on the SGKGA background, whereas the AGEAA triple mutant was derived from AGKAA on multiple, albeit limited, genetic backgrounds. The SGEAA did not share haplotypes with any of the triple mutants. Comparative analysis of the microsatellite haplotypes flanking dhps alleles from Cambodia, Kenya, Cameroon and Venezuela revealed an independent origin of sulfadoxine resistant alleles in each of these regions.

  13. From chloroquine to artemisinin-based combination therapy: the Sudanese experience

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    Elhassan AH

    2006-07-01

    Full Text Available Abstract Background In Sudan, chloroquine (CQ remains the most frequently used drug for falciparum malaria for more than 40 years. The change to artemisinin-based combination therapy (ACT was initiated in 2004 using the co-blister of artesunate + sulfadoxine/pyrimethamine (AS+SP and artemether + lumefantrine (ART+LUM, as first- and second-line, respectively. This article describes the evidence-base, the process for policy change and it reflects the experience of one year implementation. Relevant published and unpublished documents were reviewed. Data and information obtained were compiled into a structured format. Case description Sudan has used evidence to update its malaria treatment to ACTs. The country moved without interim period and proceeded with country-wide implementation instead of a phased introduction of the new policy. The involvement of care providers and key stakeholders in a form of a technical advisory committee is considered the key issue in the process. Development and distribution of guidelines, training of care providers, communication to the public and provision of drugs were given great consideration. To ensure presence of high quality drugs, a system for post-marketing drugs surveillance was established. Currently, ACTs are chargeable and chiefly available in urban areas. With the input from the Global Fund to fight AIDs, Tuberculosis and Malaria, AS+SP is now available free of charge in 10 states. Conclusion Implementation of the new policy is affected by the limited availability of the drugs, their high cost and limited pre-qualified manufacturers. Substantial funding needs to be mobilized by all partners to increase patients' access for this life-saving intervention.

  14. Anticancer properties of distinct antimalarial drug classes.

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    Rob Hooft van Huijsduijnen

    Full Text Available We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor, emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.

  15. Systematic assessment of multi-gene predictors of pan-cancer cell line sensitivity to drugs exploiting gene expression data [version 1; referees: 2 approved

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    Linh Nguyen

    2016-12-01

    Full Text Available Background: Selected gene mutations are routinely used to guide the selection of cancer drugs for a given patient tumour. Large pharmacogenomic data sets were introduced to discover more of these single-gene markers of drug sensitivity. Very recently, machine learning regression has been used to investigate how well cancer cell line sensitivity to drugs is predicted depending on the type of molecular profile. The latter has revealed that gene expression data is the most predictive profile in the pan-cancer setting. However, no study to date has exploited GDSC data to systematically compare the performance of machine learning models based on multi-gene expression data against that of widely-used single-gene markers based on genomics data. Methods: Here we present this systematic comparison using Random Forest (RF classifiers exploiting the expression levels of 13,321 genes and an average of 501 tested cell lines per drug. To account for time-dependent batch effects in IC50 measurements, we employ independent test sets generated with more recent GDSC data than that used to train the predictors and show that this is a more realistic validation than K-fold cross-validation. Results and Discussion: Across 127 GDSC drugs, our results show that the single-gene markers unveiled by the MANOVA analysis tend to achieve higher precision than these RF-based multi-gene models, at the cost of generally having a poor recall (i.e. correctly detecting only a small part of the cell lines sensitive to the drug. Regarding overall classification performance, about two thirds of the drugs are better predicted by multi-gene RF classifiers. Among the drugs with the most predictive of these models, we found pyrimethamine, sunitinib and 17-AAG. Conclusions: We now know that this type of models can predict in vitro tumour response to these drugs. These models can thus be further investigated on in vivo tumour models.

  16. A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria during pregnancy

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    Manyando Christine

    2012-05-01

    Full Text Available Abstract Malaria during pregnancy, particularly Plasmodium falciparum malaria, has been linked to increased morbidity and mortality, which must be reduced by both preventive measures and effective case management. The World Health Organization (WHO recommends artemisinin-based combination therapy (ACT to treat uncomplicated falciparum malaria during the second and third trimesters of pregnancy, and quinine plus clindamycin during the first trimester. However, the national policies of many African countries currently recommend quinine throughout pregnancy. Therefore, the aim of this article is to provide a summary of the available data on the safety and efficacy of artemether-lumefantrine (AL in pregnancy. An English-language search identified 16 publications from 1989 to October 2011 with reports of artemether or AL exposure in pregnancy, including randomized clinical trials, observational studies and systematic reviews. Overall, there were 1,103 reports of AL use in pregnant women: 890 second/third trimester exposures; 212 first trimester exposures; and one case where the trimester of exposure was not reported. In the second and third trimesters, AL was not associated with increased adverse pregnancy outcomes as compared with quinine or sulphadoxine-pyrimethamine, showed improved tolerability relative to quinine, and its efficacy was non-inferior to quinine. There is evidence to suggest that the pharmacokinetics of anti-malarial drugs may change in pregnancy, although the impact on efficacy and safety needs to be studied further, especially since the majority of studies report high cure rates and adequate tolerability. As there are fewer reports of AL safety in the first trimester, additional data are required to assess the potential to use AL in the first trimester. Though the available safety and efficacy data support the use of AL in the second and third trimesters, there is still a need for further information. These findings reinforce the

  17. Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library.

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    Feng, Jie; Weitner, Megan; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Zhang, Ying

    2015-09-16

    Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2-4 week antibiotic treatment, 10%-20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and reactive

  18. Efficacy, safety, and tolerability of three regimens for prevention of malaria: a randomized, placebo-controlled trial in Ugandan schoolchildren.

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    Joaniter Nankabirwa

    Full Text Available BACKGROUND: Intermittent preventive treatment (IPT is a promising malaria control strategy; however, the optimal regimen remains unclear. We conducted a randomized, single-blinded, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of a single course of sulfadoxine-pyrimethamine (SP, amodiaquine + SP (AQ+SP or dihydroartemisinin-piperaquine (DP among schoolchildren to inform IPT. METHODS: Asymptomatic girls aged 8 to 12 years and boys aged 8 to 14 years enrolled in two primary schools in Tororo, Uganda were randomized to receive one of the study regimens or placebo, regardless of presence of parasitemia at enrollment, and followed for 42 days. The primary outcome was risk of parasitemia at 42 days. Survival analysis was used to assess differences between regimens. RESULTS: Of 780 enrolled participants, 769 (98.6% completed follow-up and were assigned a treatment outcome. The risk of parasitemia at 42 days varied significantly between DP (11.7% [95% confidence interval (CI: 7.9, 17.1], AQ+SP (44.3% [37.6, 51.5], and SP (79.7% [95% CI: 73.6, 85.2], p<0.001. The risk of parasitemia in SP-treated children was no different than in those receiving placebo (84.6% [95% CI: 79.1, 89.3], p = 0.22. No serious adverse events occurred, but AQ+SP was associated with increased risk of vomiting compared to placebo (13.0% [95% CI: 9.1, 18.5] vs. 4.7% [95% CI: 2.5, 8.8], respectively, p = 0.003. CONCLUSIONS: DP was the most efficacious and well-tolerated regimen tested, although AQ+SP appears to be a suitable alternative for IPT in schoolchildren. Use of SP for IPT may not be appropriate in areas with high-level SP resistance in Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT00852371.

  19. Tracing the origins and signatures of selection of antifolate resistance in island populations of Plasmodium falciparum

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    Pinto João

    2010-06-01

    Full Text Available Abstract Background Resistance of the malaria parasite Plasmodium falciparum to sulfadoxine-pyrimethamine (SP has evolved worldwide. In the archipelago of São Tomé and Principe (STP, West Africa, although SP resistance is highly prevalent the drug is still in use in particular circumstances. To address the evolutionary origins of SP resistance in these islands, we genotyped point mutations at P. falciparum dhfr and dhps genes and analysed microsatellites flanking those genes. Methods Blood samples were collected in July and December 2004 in three localities of São Tomé Island and one in Principe Island. Species-specific nested-PCR was used to identify P. falciparum infected samples. Subsequently, SNPs at the dhfr and dhps genes were identified through PCR-RFLP. Isolates were also analysed for three microsatellite loci flanking the dhfr gene, three loci flanking dhps and four loci located at putative neutral genomic regions. Results An increase of resistance-associated mutations at dhfr and dhps was observed, in particular for the dhfr/dhps quintuple mutant, associated with clinical SP failure. Analysis of flanking microsatellites suggests multiple independent introductions for dhfr and dhps mutant haplotypes, possibly from West Africa. A reduced genetic diversity and increased differentiation at flanking microsatellites when compared to neutral loci is consistent with a selective sweep for resistant alleles at both loci. Conclusions This study provides additional evidence for the crucial role of gene flow and drug selective pressures in the rapid spread of SP resistance in P. falciparum populations, from only a few mutation events giving rise to resistance-associated mutants. It also highlights the importance of human migration in the spread of drug resistant malaria parasites, as the distance between the islands and mainland is not consistent with mosquito-mediated parasite dispersal.

  20. The association of parasitic infections in pregnancy and maternal and fetal anemia: a cohort study in coastal Kenya.

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    Elizabeth M McClure

    2014-02-01

    Full Text Available Relative contribution of these infections on anemia in pregnancy is not certain. While measures to protect pregnant women against malaria have been scaling up, interventions against helminthes have received much less attention. In this study, we determine the relative impact of helminthes and malaria on maternal anemia.A prospective observational study was conducted in coastal Kenya among a cohort of pregnant women who were recruited at their first antenatal care (ANC visit and tested for malaria, hookworm, and other parasitic infections and anemia at enrollment. All women enrolled in the study received presumptive treatment with sulfadoxine-pyrimethamine, iron and multi-vitamins and women diagnosed with helminthic infections were treated with albendazole. Women delivering a live, term birth, were also tested for maternal anemia, fetal anemia and presence of infection at delivery.Of the 706 women studied, at the first ANC visit, 27% had moderate/severe anemia and 71% of women were anemic overall. The infections with highest prevalence were hookworm (24%, urogenital schistosomiasis (17%, trichuria (10%, and malaria (9%. In adjusted and unadjusted analyses, moderate/severe anemia at first ANC visit was associated with the higher intensities of hookworm and P. falciparum microscopy-malaria infections. At delivery, 34% of women had moderate/severe anemia and 18% of infants' cord hemoglobin was consistent with fetal anemia. While none of the maternal infections were significantly associated with fetal anemia, moderate/severe maternal anemia was associated with fetal anemia.More than one quarter of women receiving standard ANC with IPTp for malaria had moderate/severe anemia in pregnancy and high rates of parasitic infection. Thus, addressing the role of co-infections, such as hookworm, as well as under-nutrition, and their contribution to anemia is needed.

  1. Prenatal Iron Deficiency, Neonatal Ferritin, and Infant Cognitive Function.

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    Mireku, Michael O; Davidson, Leslie L; Boivin, Michael J; Zoumenou, Romeo; Massougbodji, Achille; Cot, Michel; Bodeau-Livinec, Florence

    2016-12-01

    To investigate the impact of prenatal maternal iron deficiency (ID) on cord blood serum ferritin (CBSF) concentration and infant cognitive and motor development. Our prospective cohort study included 636 mother-singleton child pairs from 828 eligible pregnant women who were enrolled during their first antenatal care (ANC) visit in Allada, Benin, into a clinical trial comparing the efficacy of mefloquine and sulfadoxine-pyrimethamine. Venous blood samples of women were assessed for ferritin and hemoglobin concentrations at the first and second ANC visits (occurring at least 1-month apart) and at delivery. Women were prescribed daily iron and folic acid supplements throughout pregnancy. Hematologic examinations were repeated for cord blood at birth. At age 1 year, cognitive and motor functions of children were assessed by using the Mullen Scales of Early Learning. The prevalence of prenatal ID at first and second ANC visits, and at delivery was 30.5%, 34.0%, and 28.4%, respectively. CBSF concentrations were similar between ID and non-ID pregnant women. Neither prenatal ID nor CBSF concentration was associated with poor cognitive or gross motor function of children at age 1 year. CBSF concentrations were lower among mothers who had ID anemia (IDA) at delivery compared with non-IDA pregnant women (adjusted mean difference: -0.2 [95% confidence interval: -0.4 to -0.0]). In a malaria-endemic region, ID in pregnancy in the context of iron supplementation is neither associated with CBSF concentration nor with infant cognitive and motor development. Prenatal IDA around the time of delivery is associated with lower CBSF concentrations. Copyright © 2016 by the American Academy of Pediatrics.

  2. Seasonal malaria chemoprevention in an area of extended seasonal transmission in Ashanti, Ghana: an individually randomised clinical trial.

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    Tagbor, Harry; Antwi, Gifty Dufie; Acheampong, Princess Ruhama; Bart Plange, Constance; Chandramohan, Daniel; Cairns, Matthew

    2016-02-01

    To investigate the effectiveness of seasonal malaria chemoprevention (SMC) and community case management with long-acting artemisinin-based combination therapies (ACTs) for the control of malaria in areas of extended seasonal malaria transmission. Individually randomised, placebo-controlled trial in the Ashanti Region of Ghana. A total of 2400 children aged 3-59 months received either: (i) a short-acting ACT for case management of malaria (artemether-lumefantrine, AL) plus placebo SMC, or (ii) a long-acting ACT (dihydroartemisinin-piperaquine, DP) for case management plus placebo SMC or (iii) AL for case management plus active SMC with sulphadoxine-pyrimethamine and amodiaquine. SMC or placebo was delivered on five occasions during the rainy season. Malaria cases were managed by community health workers, who used rapid diagnostic tests to confirm infection prior to treatment. The incidence of malaria was lower in children given SMC during the rainy season. Compared to those given placebo SMC and AL for case management, the adjusted hazard ratio (aHR) was 0.62 (95% CI: 0.41, 0.93), P = 0.020 by intention to treat and 0.53 (95% CI: 0.29, 0.95), P = 0.033 among children given five SMC courses. There were no major differences between groups given different ACTs for case management (aHR DP vs. AL 1.18 (95% CI 0.83, 1.67), P = 0.356). SMC may have an important public health impact in areas with a longer transmission season, but further optimisation of SMC schedules is needed to maximise its impact in such settings. © 2015 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.

  3. Evaluating the effectiveness of IPTi on malaria using routine health information from sentinel health centres in southern Tanzania

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    Mshinda Hassan

    2011-02-01

    Full Text Available Abstract Background Intermittent preventive treatment of malaria in infants (IPTi consists of the administration of a treatment dose of sulphadoxine-pyrimethamine (SP at the time of routine vaccinations. The use of routine Health Management and Information Services (HMIS data to investigate the effect of IPTi on malaria, anaemia, and all-cause attendance in children aged 2-11 months presenting to 11 health centres in southern Tanzania is described. Methods Clinical diagnosis of malaria was confirmed with a positive blood slide reading from a quality assurance laboratory. Anaemia was defined using two thresholds (mild [Hb Results Seventy two per cent of infants presenting in intervention areas received at least one dose of IPTi- 22% received all three. During March 2006 - April 2007, the incidence of all cause attendance was two attendances per person, per year (pppy, including 0.2 episodes pppy of malaria, 0.7 episodes of mild and 0.13 episodes of severe anaemia. Point estimates for the effect of IPTi on malaria varied between 18% and 52%, depending on the scope of the analysis, although adjustment for clustering rendered these not statistically significant. Conclusions The point estimate of the effect of IPTi on malaria is consistent with that from a large pooled analysis of randomized control trials. As such, it is plausible that the difference seen in health centre data is due to IPTi, even thought the effect did not reach statistical significance. Findings draw attention to the challenges of robust inference of effects of interventions based on routine health centre data. Analysis of routine health information can reassure that interventions are being made available and having desired effects, but unanticipated effects should trigger data collection from representative samples of the target population.

  4. Provider and user acceptability of intermittent screening and treatment for the control of malaria in pregnancy in Malawi.

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    Almond, Deborah; Madanitsa, Mwayi; Mwapasa, Victor; Kalilani-Phiri, Linda; Webster, Jayne; Ter Kuile, Feiko; Paintain, Lucy

    2016-11-28

    Malaria in pregnancy is a major cause of adverse maternal and fetal outcomes. Intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) is one of the control strategies promoted by WHO. In response to mounting resistance to SP, intermittent screening and treatment (ISTp) has been proposed as an alternative. The objective of this study was to explore the acceptability of ISTp for health workers and pregnant women. Semi-structured interviews of ten health workers and five focus group discussions of 38 women enrolled in an ongoing trial comparing IPTp-SP and ISTp with dihydroartemisinin-piperaquine (DP) were conducted at two antenatal clinics in rural Malawi. All transcripts were coded and themes were identified using a content analysis approach. Amongst health workers, there were contrasting opinions on the preference of blood sampling methods, and the influence of method on reliability of diagnosis. The perceived greater effectiveness of DP compared to SP was appreciated, however concerns of user compliance with the full dose of DP in non-trial settings were raised. Despite the discomfort of repeated finger pricks, pregnant women were generally accepting of ISTp, particularly the chance for regular blood tests to check for infections and the perceived greater effectiveness with fewer side effects of DP compared to SP. In the trial context, pregnant women tended to prefer ISTp-DP over IPTp-SP. Health workers were also accepting of ISTp-DP as an alternative to IPTp-SP in light of increasing SP resistance. However, reliability of stock, adherence to malaria test results and user adherence to the full course of DP may present barriers to successful routine implementation. Effective communication with health workers and between health workers, pregnant women and their communities will be essential for the acceptability of focused antenatal care, including the best malaria control measures available.

  5. Use of antenatal care, maternity services, intermittent presumptive treatment and insecticide treated bed nets by pregnant women in Luwero district, Uganda

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    Mufubenga Patrobas

    2008-03-01

    Full Text Available Abstract Background To reduce the intolerable burden of malaria in pregnancy, the Ministry of Health in Uganda improved the antenatal care package by including a strong commitment to increase distribution of insecticide-treated nets (ITNs and introduction of intermittent preventive treatment with sulphadoxine-pyrimethamine for pregnant women (IPTp-SP as a national policy in 2000. This study assessed uptake of both ITNs and IPTp-SP by pregnant women as well as antenatal and maternity care use with the aim of optimizing their delivery. Methods 769 post-partum women were recruited from a rural area of central Uganda with perennial malaria transmission through a cross-sectional, community-based household survey in May 2005. Results Of the 769 women interviewed, antenatal clinic (ANC attendance was high (94.4%; 417 (57.7% visiting initially during the 2nd trimester, 242 (33.5% during the 3rd trimester and 266 (37.1% reporting ≥ 4 ANC visits. About 537 (71% and 272 (35.8% received one or ≥ 2 IPTp-SP doses respectively. Only 85 (15.8% received the first dose of IPTp-SP in the 3rd trimester. ITNs were used by 239 (31.3% of women during pregnancy and 314 (40.8% delivered their most recent pregnancy outside a health facility. Post-partum women who lacked post-primary education were more likely not to have attended four or more ANC visits (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.2–9.3. Conclusion These findings illustrate the need to strengthen capacity of the district to further improve antenatal care and maternity services utilization and IPTp-SP uptake. More specific and effective community health strategies to improve effective ANC, maternity services utilization and IPTp-SP uptake in rural communities should be undertaken.

  6. Patterns of chloroquine use and resistance in sub-Saharan Africa: a systematic review of household survey and molecular data

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    Venkatesan Meera

    2011-05-01

    Full Text Available Abstract Background As a result of widespread chloroquine and sulphadoxine-pyrimethamine (SP resistance, 90% of sub-Saharan African countries had adopted policies of artemisinin-based combination therapy (ACT for treatment of uncomplicated malaria by 2007. In Malawi, cessation of chloroquine use was followed by the re-emergence of chloroquine-susceptible malaria. It was expected that introduction of ACT would lead to a return in chloroquine susceptibility throughout Africa, but this has not yet widely occurred. This observation suggests that there is continuing use of ineffective anti-malarials in Africa and that persistent chloroquine-resistant malaria is due to ongoing drug pressure despite national policy changes. Methods To estimate drug use on a national level, 2006-2007 Demographic Health Survey and Multiple Indicator Cluster Survey data from 21 African countries were analysed. Resistance data were compiled by systematic review of the published literature on the prevalence of the Plasmodium falciparum chloroquine resistance transporter polymorphism at codon 76, which causes chloroquine resistance. Results Chloroquine was the most common anti-malarial used according to surveys from 14 of 21 countries analysed, predominantly in West Africa. SP was most commonly reported in two of 21 countries. Among eight countries with longitudinal molecular resistance data, the four countries where the highest proportion of children treated for fever received chloroquine (Uganda, Burkina Faso, Guinea Bissau, and Mali also showed no significant declines in the prevalence of chloroquine-resistant infections. The three countries with low or decreasing chloroquine use among children who reported fever treatment (Malawi, Kenya, and Tanzania had statistically significant declines in the prevalence of chloroquine resistance. Conclusions This study demonstrates that in 2006-2007, chloroquine and SP continued to be used at high rates in many African countries. In

  7. Prenatal treatment for serious neurological sequelae of congenital toxoplasmosis: an observational prospective cohort study.

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    Mario Cortina-Borja

    2010-10-01

    Full Text Available BACKGROUND: The effectiveness of prenatal treatment to prevent serious neurological sequelae (SNSD of congenital toxoplasmosis is not known. METHODS AND FINDINGS: Congenital toxoplasmosis was prospectively identified by universal prenatal or neonatal screening in 14 European centres and children were followed for a median of 4 years. We evaluated determinants of postnatal death or SNSD defined by one or more of functional neurological abnormalities, severe bilateral visual impairment, or pregnancy termination for confirmed congenital toxoplasmosis. Two-thirds of the cohort received prenatal treatment (189/293; 65%. 23/293 (8% fetuses developed SNSD of which nine were pregnancy terminations. Prenatal treatment reduced the risk of SNSD. The odds ratio for prenatal treatment, adjusted for gestational age at maternal seroconversion, was 0.24 (95% Bayesian credible intervals 0.07-0.71. This effect was robust to most sensitivity analyses. The number of infected fetuses needed to be treated to prevent one case of SNSD was three (95% Bayesian credible intervals 2-15 after maternal seroconversion at 10 weeks, and 18 (9-75 at 30 weeks of gestation. Pyrimethamine-sulphonamide treatment did not reduce SNSD compared with spiramycin alone (adjusted odds ratio 0.78, 0.21-2.95. The proportion of live-born infants with intracranial lesions detected postnatally who developed SNSD was 31.0% (17.0%-38.1%. CONCLUSION: The finding that prenatal treatment reduced the risk of SNSD in infected fetuses should be interpreted with caution because of the low number of SNSD cases and uncertainty about the timing of maternal seroconversion. As these are observational data, policy decisions about screening require further evidence from a randomized trial of prenatal screening and from cost-effectiveness analyses that take into account the incidence and prevalence of maternal infection. Please see later in the article for the Editors' Summary.

  8. Prevalence of malaria and anaemia among HIV infected pregnant women receiving co-trimoxazole prophylaxis in Tanzania: a cross sectional study in Kinondoni Municipality.

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    Manyanga, Vicent P; Minzi, Omary; Ngasala, Billy

    2014-04-24

    HIV-infected pregnant women are particularly more susceptible to the deleterious effects of malaria infection particularly anaemia. In order to prevent opportunistic infections and malaria, a policy of daily co-trimoxazole prophylaxis without the standard Suphadoxine-Pyrimethamine intermittent preventive treatment (SP-IPT) was introduced to all HIV infected pregnant women in the year 2011. However, there is limited information about the effectiveness of this policy. This was a cross sectional study conducted among HIV-infected pregnant women receiving co-trimoxazole prophylaxis in eight public health facilities in Kinondoni Municipality from February to April 2013. Blood was tested for malaria infection and anaemia (haemoglobin anaemia. Pearson chi-square test, Fischer's exact test and multivariate logistic regression were used in the statistical analysis. This study enrolled 420 HIV infected pregnant women. The prevalence of malaria infection was 4.5%, while that of anaemia was 54%. The proportion of subjects with poor adherence to co-trimoxazole was 50.5%. As compared to HIV infected pregnant women with good adherence to co-trimoxazole prophylaxis, the poor adherents were more likely to have a malaria infection (Adjusted Odds Ratio, AOR = 6.81, 95% CI = 1.35-34.43, P = 0.02) or anaemia (AOR = 1.75, 95% CI = 1.03-2.98, P = 0.039). Other risk factors associated with anaemia were advanced WHO clinical stages, current malaria infection and history of episodes of malaria illness during the index pregnancy. The prevalence of malaria was low; however, a significant proportion of subjects had anaemia. Good adherence to co-trimoxazole prophylaxis was associated with reduction of both malaria infection and anaemia among HIV infected pregnant women.

  9. Intermittent preventive treatment using artemisinin-based combination therapy reduces malaria morbidity among school-aged children in Mali

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    Barger, Breanna; Maiga, Hamma; Traore, Oumar Bila; Tekete, Mamadou; Tembine, Intimbeye; Dara, Antoine; Traore, Zoumana Isaac; Gantt, Soren; Doumbo, Ogobara K.; Djimde, Abdoulaye A.

    2011-01-01

    Summary OBJECTIVE To assess the efficacy of intermittent preventive treatment (IPT) against malaria in school-aged children. METHODS This was an open randomized controlled trial of seasonal IPT among school children (IPTsc) aged 6–13 years in Kollé, Mali. The study began in September 2007 and completed follow-up in May 2008. Students were randomized to one of three study arms: Sulfadoxine–pyrimethamine plus artesunate (SP/AS), amodiaquine plus artesunate (AQ/AS) or vitamin C. All students received two full treatment doses, given 2 months apart during the season of high transmission from September to December. Groups were compared with respect to incidence of clinical malaria, asymptomatic parasitemia and haemoglobin concentration. RESULTS A total of 296 students were randomized, and retention in the study was 99.3%. Clinical malaria incidence in the SP/AS and AQ/AS arms was reduced by 66.6% and 46.5%, respectively, vs. vitamin C (P < 0.001). There were fewer clinic visits for any cause among the children receiving SP/AS or AQ/AS (P = 0.024). The prevalence of asymptomatic parasitemia was fivefold higher in the vitamin C arm than either SP/AS or AQ/AS at each post-treatment evaluation (P < 0.001). At the end of the transmission period, children treated with IPT had lower rates of anaemia (SP/AS, 17.7%; AQ/AS, 16.0%; vitamin C, 29.6%; P = 0.039). CONCLUSION IPT among school children reduced the rates of clinical malaria, all-cause acute clinic visits, asymptomatic parasitemia and anaemia among school-aged children. PMID:19497079

  10. An artesunate-containing antimalarial treatment regimen did not suppress cytomegalovirus viremia.

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    Gantt, Soren; Huang, Meei-Li; Magaret, Amalia; Bunts, Lisa; Selke, Stacy; Wald, Anna; Rosenthal, Philip J; Dorsey, Grant; Casper, Corey

    2013-09-01

    Additional drugs are needed for the treatment of cytomegalovirus (CMV) infection. Artesunate is an antimalarial drug that has activity against CMV in vitro and in a rodent model. Only a small number of case reports are available describing the clinical effects of artesunate on CMV infection, and these yielded inconsistent results. To evaluate the effect of artesunate on CMV infection, using blood samples collected from children who participated in malaria treatment trials. Quantitative CMV DNA PCR was performed on dried blood spots collected from 494 Ugandan children, who were randomized either to artesunate plus amodiaquine or sulfadoxine-pyrimethamine plus amodiaquine for acute malaria infection. Poisson regression was used to compare treatment regimens with respect to the change in the frequency and quantity of CMV detected that occurred before and after treatment. CMV was detected in 11.4% of children immediately prior to treatment and 10.7% 3 days later (p=0.70). The average quantity of CMV was 0.30 log10 copies per million cells higher on day 3 than at treatment initiation (95% CI 0.01-0.58, p=0.041). There was no measurable difference in either the frequency or quantity of CMV detected in blood between children randomized to the two treatment arms. A standard 3-day artesunate-containing antimalarial regimen had no detectable effect on CMV viremia in children with malaria. Longer treatment courses and/or higher doses of artesunate than those routinely used for malaria may be required for effective treatment of CMV infection. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones

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    Sarkar, Souvik; Siddiqui, Asim A.; Saha, Shubhra J.; De, Rudranil; Mazumder, Somnath; Banerjee, Chinmoy; Iqbal, Mohd S.; Nag, Shiladitya; Adhikari, Susanta

    2016-01-01

    We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite in vitro, as well as in vivo in a murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (KD [equilibrium dissociation constant] = 1.17 ± 0.8 μM), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structure-activity relationship studies indicated that a nitrogen- and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [3H]hypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity in vitro against a chloroquine/pyrimethamine-resistant strain of Plasmodium falciparum (K1). We also evaluated in vivo antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of Plasmodium yoelii was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During in vitro and in vivo toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria. PMID:27139466

  12. Artemether-lumefantrine versus artesunate plus amodiaquine for treating uncomplicated childhood malaria in Nigeria: randomized controlled trial

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    Nwachukwu Chukwuemeka

    2006-05-01

    Full Text Available Abstract Background The therapeutic efficacy of artesunate plus amodiaquine and artemether/lumefantrine were assessed in an area of Nigeria with high levels of Plasmodium falciparum resistance to chloroquine and sulphadoxine-pyrimethamine. Participants Children aged 6 to 59 months with uncomplicated P. falciparum infection and parasite density 1,000 to 200,000 parasites/μL enrolled following informed consent by parents. Methods Eligible children were randomly assigned to receive either a 3-day course of artesunate (4 mg/kg plus amodiaquine (10 mg/kg or 6-dose course of artemether/lumefantrine (20/120 mg tablets over three days. Patients were followed up with clinical and laboratory assessments until day 14 using standard WHO in-vivo antimalarial drug test protocol. Results A total 119 eligible children were enrolled but 111 completed the study. Adequate clinical and parasitological response (ACPR was 47 (87.0% and 47 (82.5% for artemether-lumefantrine (AL and artesunate+amodiaquine (AAMQ respectively (OR 0.7, 95% confidence interval 0.22 to 2.22. Early treatment failure (ETF occurred in one participant (1.8% treated with AAQ but in none of those with AL. Two (3.7% patients in the AL group and none in the AAQ group had late clinical failure. Late parasitological failure was observed in 9 (15.8 and 5 (9.3% of patients treated with AAQ and AL respectively. None of participants had a serious adverse event. Conclusion Artemether-lumenfantrine and artesunate plus amodiaquine have high and comparable cure rates and tolerability among under-five children in Calabar, Nigeria.

  13. Efficacy of two artemisinin combination therapies for uncomplicated falciparum malaria in children under 5 years, Malakal, Upper Nile, Sudan

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    Alemu Engudaye

    2005-02-01

    Full Text Available Abstract Background The treatment for Plasmodium falciparum malaria in Sudan has been in process of change since 2003. Preceding the change, this study aimed to determine which artemisinin-based combination therapies is more effective to treat uncomplicated malaria in Malakal, Upper Nile, Sudan. Methods Clinical trial to assess the efficacy of 2 antimalarial therapies to treat P. falciparum infections in children aged 6–59 months, in a period of 42 days after treatment. Results A total of 269 children were followed up to 42 days. Artesunate plus Sulfadoxine/Pyrimethamine (AS+SP and Artesunate plus Amodiaquine (AS+AQ were both found to be efficacious in curing malaria infections by rapid elimination of parasites and clearance of fever, in preventing recrudescence and suppressing gametocytaemia. The combination of AS+SP appeared slightly more efficacious than AS+AQ, with 4.4% (4/116 versus 15% (17/113 of patients returning with malaria during the 6-week period after treatment (RR = 0.9, 95% CI 0.81–0.96. PCR analysis identified only one recrudescence which, together with one other early treatment failure, gave efficacy rates of 99.0% for AS+AQ (96/97 and 99.1% for AS+SP (112/113. However, PCR results were incomplete and assuming part of the indeterminate samples were recrudescent infections leads to an estimated efficacy ranging 97–98% for AS+SP and 88–95% for AS+AQ. Conclusion These results lead to the recommendation of ACT, and specifically AS+SP, for the treatment of uncomplicated falciparum malaria in this area of Sudan. When implemented, ACT efficacy should be monitored in sentinel sites representing different areas of the country.

  14. Influences of intermittent preventive treatment and persistent multiclonal Plasmodium falciparum infections on clinical malaria risk.

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    Anne Liljander

    Full Text Available BACKGROUND: Intermittent preventive treatment (IPT of malaria involves administration of curative doses of antimalarials at specified time points to vulnerable populations in endemic areas, regardless whether a subject is known to be infected. The effect of this new intervention on the development and maintenance of protective immunity needs further understanding. We have investigated how seasonal IPT affects the genetic diversity of Plasmodium falciparum infections and the risk of subsequent clinical malaria. MATERIAL AND METHODS: The study included 2227 Ghanaian children (3-59 months who were given sulphadoxine-pyrimethamine (SP bimonthly, artesunate plus amodiaquine (AS+AQ monthly or bimonthly, or placebo monthly for six months spanning the malaria transmission season. Blood samples collected at three post-interventional surveys were analysed by genotyping of the polymorphic merozoite surface protein 2 gene. Malaria morbidity and anaemia was monitored during 12 months follow-up. RESULTS: Monthly IPT with AS+AQ resulted in a marked reduction in number of concurrent clones and only children parasite negative just after the intervention period developed clinical malaria during follow-up. In the placebo group, children without parasites as well as those infected with ≥2 clones had a reduced risk of subsequent malaria. The bimonthly SP or AS+AQ groups had similar number of clones as placebo after intervention; however, diversity and parasite negativity did not predict the risk of malaria. An interaction effect showed that multiclonal infections were only associated with protection in children without intermittent treatment. CONCLUSION: Molecular typing revealed effects of the intervention not detected by ordinary microscopy. Effective seasonal IPT temporarily reduced the prevalence and genetic diversity of P. falciparum infections. The reduced risk of malaria in children with multiclonal infections only seen in untreated children suggests that

  15. In vitro effects of four macrolides (roxithromycin, spiramycin, azithromycin (CP-62,993), and A-56268) on Toxoplasma gondii

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    Chang, H.R.; Pechere, J.C.

    1988-04-01

    The effect of four macrolides against intracellular Toxoplasma gondii was determined in three different in vitro systems. Unactivated murine peritoneal macrophages were infected with the virulent RH strain of T. gondii. The activity of the macrolides was first measured with (/sup 3/H)uracil, which is incorporated by the parasite but not the host cell. The 50% inhibitory concentrations (IC50s) and 95% confidence limits were calculated at 54 (38 to 73), 140 (98 to 201), 147 (101 to 214), and 246 (187 to 325) micron for roxithromycin, azithromycin (CP-62,993), A-56268, and spiramycin, respectively. Inhibition of Toxoplasma growth was confirmed by microscopic examination of the infected macrophages after treatment with roxithromycin. Compared with untreated controls, roxithromycin concentrations near the IC50s decreased the number of infected cells, the number of tachyzoites per vacuole, and the number of cells containing rosettes (i.e., clusters of more than eight tachyzoites). After treatment with the four macrolides, tachyzoites were released from the macrophages and subcultured in HeLa cells, which are nonprofessional phagocytes, to assess the viability of the remaining parasites. This showed that the macrolides at concentrations corresponding to four times their 90% inhibitory concentrations (IC90s) had no significant killing effect. At 8 times the IC90, roxithromycin showed an incomplete killing effect, similar to that of the combination of pyrimethamine (0.41 microM)-sulfadiazine (99.42 microM). All macrolides tested showed inhibitory effects against intracellular T. gondii, but amounts of azithromycin and A-56268 corresponding to the IC90 appeared to be toxic against the host macrophages, which might have had nonspecific activity against Toxoplasma metabolism.

  16. Tratamiento de la toxoplasmosis, observaciones en 112 pacientes

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    Francisco Biagi

    1978-12-01

    Full Text Available En los últimos 5 anos hemos tratado 112 casos de toxoplasmosis. La mayor parte presentaba abortos o coriorretinitis; algunos presentaban meningo-encefalitis, miocarditis y otras formas. Ocho por ciento de los pacientes presentaban dos cuadros anatomoclínicos de toxoplasmosis. Se administro en forma alterna pirimetamina, sulfametopirazina o espiramicina durante períodos prolongados, practicando reacción de Sabin y Feldman cada tres meses. La meta es negativizar la prueba serológica, la cual generalmente logramos. Clinicamente se aprecia curación al observar la desaparición de los fenômenos inflamatorios en el fondo del ojo, la desaparición de adenopatías u otros signos clínicos, ó el desarrollo de embarazos normales con productos normales en mujeres abortadoras. Considerando los graves problemas que hemos visto en hijos de madres con toxoplasmosis, preferimos tratar a éstas antes de nuevos embarazos.Along the last five years we have treated 112 cases of toxoplasmosis. The majority of them had abortion or corioretinitis; a few had meningo-encephalities, miocarditis or other forms: 8% o f the patients had two anatomoclinical pictures at the same time. The patients received pyrimethamine, sulphametopyrazine, or spiromycine on alternating periods for several months. A Sabin and Feldman test was repeated every three months. The target was obtaining negative serology, th is was accomplished on the majority of the cases. From the clinical stand point cure was supported by disapearance of inflamatory findings on the fundus, disappearing of adenopathy or other signs, as for the achievement of normal pregnancies with normal children in women with repeated abortion. Taking into account the serious secuelae that we have seen on children from mothers with toxoplasmosis, we prefer to treat the women before new pregnancies.

  17. In vitro antiprotozoal and cytotoxic activity of 33 ethonopharmacologically selected medicinal plants from Democratic Republic of Congo.

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    Musuyu Muganza, D; Fruth, B I; Nzunzu Lami, J; Mesia, G K; Kambu, O K; Tona, G L; Cimanga Kanyanga, R; Cos, P; Maes, L; Apers, S; Pieters, L

    2012-05-07

    The antiprotozoal and cytotoxic activity of the aqueous extracts from 33 medicinal plants, used by traditional healers for the treatment of various parasitic diseases and collected after an ethnopharmacological inventory conducted in the Bolongo area, Bandundu province in DR Congo, was evaluated. Decoctions were prepared, lyophilized and evaluated for in vitro antiprotozoal activity against Trypanosoma b. brucei, Trypanosoma cruzi, Leishmania infantum, and the chloroquine- and pyrimethamine-resistant K1 strain of Plasmodium falciparum. Cytotoxicity against MRC-5 cells was included to assess selectivity of activity. Most of the tested extracts exhibited pronounced (IC(50)≤5μg/ml) or good (5plant extracts inhibited Trypanosoma b. brucei, especially the extract from Isolona hexaloba stem bark (IC(50)=1.95μg/ml, SI=16.5); 8 plant extracts were active against Trypanosoma cruzi, the extracts from Enanatia chlorantha stem bark and Quassia africana root bark being the most active with IC(50) values of 1.87 and 1.88μg/ml, respectively (SI=3.0 and 3.3, respectively); 8 plant extracts showed activity against Leishmania infantum, with extracts from Napoleona vogelii stem bark and Quassia africana root bark as the most active with IC(50) values of 5.66 and 5.04μg/ml (SI=11.3 and 1.2). Finally, 9 plant extracts inhibited Plasmodium falciparum K1 with the extracts from Quassia africana (root bark and stem bark) being the most active ones with IC(50) values of 0.46 and 1.27μg/ml (SI=13.7 and 13.6). Extracts from Enantia chlorantha stem bark, Piptadeniastrum africanum stem bark and Quassia africana root bark were cytotoxic for MRC-5 cells (CC(50)plant species for the treatment of parasitic diseases. Copyright © 2012. Published by Elsevier Ireland Ltd.

  18. Treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in rural health facilities in southern Cameroon

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    Bley Daniel

    2009-07-01

    Full Text Available Abstract Background One year after the adoption of artesunate-amodiaquine (AS/AQ as first-line therapy for the treatment of uncomplicated malaria, this study was designed to assess the treatment practices regarding anti-malarial drugs at health facilities in four rural areas in southern Cameroon. Methods Between April and August 2005, information was collected by interviewing fifty-two health professionals from twelve rural health facilities, using a structured questionnaire. Results In 2005, only three anti-malarial drugs were used in rural health facilities, including: amodiaquine, quinine and sulphadoxine-pyrimethamine. Only 2.0% of the health professionals prescribed the recommended AS/AQ combination. After reading the treatment guidelines, 75.0% were in favour of the treatment protocol with the following limitations: lack of paediatric formulations, high cost and large number of tablets per day. Up to 21.0% of professionals did not prescribe AS/AQ because of the level of adverse events attributed to the use of amodiaquine as monotherapy. Conclusion The present study indicates that AS/AQ was not available in the public health facilities at the time of the study, and health practitioners were not informed about the new treatment guidelines. Results of qualitative analysis suggest that prescribers should be involved as soon as possible in projects related to the optimization of treatment guidelines and comply with new drugs. Adapted formulations should be made available at the international level and implemented locally before new drugs and treatments are proposed through a national control programme. This baseline information will be useful to monitor progresses in the implementation of artemisinin-based combination therapy in Cameroon.

  19. Evaluation of malaria prevention strategies during pregnancy in Ndola, Zambia

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    Mwamba Mulamba

    2010-03-01

    Full Text Available Background: Malaria in pregnancy is associated with many negative outcomes for the woman,foetus and neonate. Intermittent preventive treatment during pregnancy (IPTp using three doses of sulfadoxine/pyrimethamine (SP, insecticide-treated mosquito nets (ITNs and indoor residual spray (IRS, constitute the main strategies used to prevent malaria. The aim of this study is to evaluate the effectiveness of these strategies for the reduction of malaria prevalence in pregnant women.Methods: A questionnaire on socio-demographic information, history of malaria during current pregnancy and prevention strategies used was administered to 450 consecutive patients admitted into labour wards at three local clinics. From the antenatal cards, information was collected on the last menstrual period, date of each dose of SP taken, gravidity, and HIV status. A blood slide to detect Plasmodium was then collected from each woman after consent.Results: Of the participants in the study, 2.4% had a positive blood slide at term and 15.8% reported malaria during pregnancy. All the participants took at least one dose of SP with 87.6% completing the stipulated three doses. The mean gestational ages for each dose were 22.1 (SD 4.6, 29.1 (SD 4.4and 34.4 (SD 3.9 weeks for the first, second and third dose respectively. With regard to ITNs, 79.5% had one, but only 74.1% used it regularly. IRS was completed in all three of the clinics’ catchment areas. Only 23.4% used commercial insecticide.Conclusion: The measured prevalence of malaria at term in Ndola was remarkably low, although the self-reported rate during pregnancy was still high. The national targets for accessing IPTp were exceeded, although the timing of each dose needs to be improved. Access to ITNs was high, but usage needs to increase.

  20. Safety of artemether-lumefantrine in pregnant women with malaria: results of a prospective cohort study in Zambia

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    Manyando Christine

    2010-09-01

    Full Text Available Abstract Background Safety data regarding exposure to artemisinin-based combination therapy in pregnancy are limited. This prospective cohort study conducted in Zambia evaluated the safety of artemether-lumefantrine (AL in pregnant women with malaria. Methods Pregnant women attending antenatal clinics were assigned to groups based on the drug used to treat their most recent malaria episode (AL vs. sulphadoxine-pyrimethamine, SP. Safety was assessed using standard and pregnancy-specific parameters. Post-delivery follow-up was six weeks for mothers and 12 months for live births. Primary outcome was perinatal mortality (stillbirth or neonatal death within seven days after birth. Results Data from 1,001 pregnant women (AL n = 495; SP n = 506 and 933 newborns (AL n = 466; SP n = 467 showed: perinatal mortality (AL 4.2%; SP 5.0%, comprised of early neonatal mortality (each group 2.3%, stillbirths (AL 1.9%; SP 2.7%; preterm deliveries (AL 14.1%; SP 17.4% of foetuses; and gestational age-adjusted low birth weight (AL 9.0%; SP 7.7%. Infant birth defect incidence was 1.8% AL and 1.6% SP, excluding umbilical hernia. Abortions prior to antenatal care could not be determined: abortion occurred in 4.5% of women treated with AL during their first trimester; none were reported in the 133 women exposed to SP and/or quinine during their first trimester. Overall development (including neurological assessment was similar in both groups. Conclusions These data suggest that exposure to AL in pregnancy, including first trimester, is not associated with particular safety risks in terms of perinatal mortality, malformations, or developmental impairment. However, more data are required on AL use during the first trimester.

  1. Malaria risk factors in women on intermittent preventive treatment at delivery and their effects on pregnancy outcome in Sanaga-Maritime, Cameroon.

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    Calvin Tonga

    Full Text Available Malaria is known to have a negative impact on pregnant women and their foetuses. The efficacy of Sulfadoxine-Pyrimethamine (SP used for intermittent preventive treatment (IPT is being threatened by increasing levels of resistance. This study assessed malaria risk factors in women on intermittent preventive treatment with SP (IPTp-SP at delivery and their effects on pregnancy outcome in Sanaga-Maritime Division, Cameroon. Socio-economic and obstetrical data of mothers and neonate birth weights were documented. Peripheral blood from 201 mothers and newborns as well as placental and cord blood were used to prepare thick and thin blood films. Maternal haemoglobin concentration was measured. The overall malaria parasite prevalence was 22.9% and 6.0% in mothers and newborns respectively. Monthly income lower than 28000 FCFA and young age were significantly associated with higher prevalence of placental malaria infection (p = 0.0048 and p = 0.019 respectively. Maternal infection significantly increased the risk of infection in newborns (OR = 48.4; p<0.0001. Haemoglobin concentration and birth weight were lower in infected mothers, although not significant. HIV infection was recorded in 6.0% of mothers and increased by 5-folds the risk of malaria parasite infection (OR = 5.38, p = 0.007. Attendance at antenatal clinic and level of education significantly influenced the utilisation of IPTp-SP (p<0.0001 and p = 0.018 respectively. Use of SP and mosquito net resulted in improved pregnancy outcome especially in primiparous, though the difference was not significant. Malaria infection in pregnancy is common and increases the risk of neonatal malaria infection. Preventive strategies are poorly implemented and their utilization has overall reasonable effect on malaria infection and pregnancy outcome.

  2. Mitochondrial peroxidase TPx-2 is not essential in the blood and insect stages of Plasmodium berghei

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    Masuda-Suganuma Hirono

    2012-11-01

    Full Text Available Abstract Background Malaria parasites actively proliferate in the body of their vertebrate and insect hosts, and are subjected to the toxic effects of reactive oxygen species. The antioxidant defenses of malaria parasites are considered to play essential roles in their survival and are thus considered promising targets for intervention. We sought to identify the cellular function of thioredoxin peroxidase-2 (TPx-2, which is expressed in the mitochondria, by disrupting the TPx-2 gene (pbtpx-2 of the rodent malaria parasite Plasmodium berghei. Findings In three independent experiments, two disruptant populations (TPx-2 KO and three wild-type parasite populations with pyrimethamine resistance (dhfr-ts/mt at the DHFR-TS locus and intact pbtpx-2 (TPx-2 WT were obtained and cloned. Null expression of TPx-2 in the KO population was confirmed by RT-PCR and Western blot analyses. The TPx-2 KO parasite developed normally in mouse erythrocytes and multiplied at a rate similar to that of the TPx-2 WT parasite during the experimental period. The peak period of gametocytemia was delayed by 1 day in the TPx-2 KO compared with that of the TPx-2 WT and the parent parasite, however, the highest gametocyte number was comparable. The number of midgut oocysts in the TPx-2 KO at 14 days post feeding was comparable to that of the TPx-2 WT. Conclusions The present finding suggests that mitochondrial Prx TPx-2 is not essential for asexual and the insect stage development of the malaria parasite.

  3. PfHRP2 and PfLDH antigen detection for monitoring the efficacy of artemisinin-based combination therapy (ACT in the treatment of uncomplicated falciparum malaria

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    Deloron Philippe

    2009-09-01

    Full Text Available Abstract Background An assessment of the accuracy of two malaria rapid diagnostic tests (RDT for the detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP2 or Pf lactate dehydrogenase (PfLDH was undertaken in children aged between six and 59 months included in an anti-malarial efficacy study in Benin. Methods In Allada (Benin, 205 children aged 6-59 months with falciparum malaria received either artesunate-amodiaquine (ASAQ, artemether-lumefantrine (AL, or sulphadoxine-pyrimethamine (SP. Children included in the study were simultaneously followed by both RDT and high-quality microscopy for up to 42 days. Results At the time of inclusion, PfHRP2-based tests were positive in 203 children (99% and PfLDH-based tests were positive in 204 (99.5%. During follow-up, independent of the treatment received, only 17.3% (28/162 of children effectively cured were negative with the PfHRP2 RDT at day 3, with a gradual increase in specificity until day 42. The specificity of antigen detection with the PfLDH test was 87% (141/162 on day 3, and between 92% and 100% on days 7 to 42. A statistical difference was observed between the persistence of PfHRP2 and PfLDH antigenaemia during follow-up in children treated with artemisinin-based combination therapy (ACT but not with SP. Conclusion Although both RDTs are as sensitive as microscopy in detecting true malaria cases, the PfHRP2 RDT had very low specificity during follow-up until day 28. On the other hand, the PfLDH test could be used to detect failures and, therefore, to assess anti-malarial efficacy.

  4. 标准使用碳酸氢盐缓冲液进行恶性疟原虫培养和耐药性实验的研究%STANDARDISATION OF THE BICARBONATE BUFFER FORCULTIVATION OF PLASMODIUM FALCIPARUM AND EVALUATION OF DRUG RESISTANCE

    Institute of Scientific and Technical Information of China (English)

    何深一; 古钦民; 李瑛; 周怀瑜; 丛华; 赵群力

    2002-01-01

    目的变化使用碳酸氢盐缓冲液以探讨药物对恶性疟原虫的不同效果. 方法用[3H]次黄嘌呤摄取法检测抗疟药物效果. 结果不同二氧化碳浓度引起的pH变化对氯喹抑制恶性疟原虫的效果差异显著,而乙胺嘧啶抑制恶性疟原虫的效果,受二氧化碳浓度的影响不大. 结论进行恶性疟原虫培养和耐药性实验时应根据二氧化碳的使用浓度而选择适当的碳酸氢钠浓度.%Objective To investigate the differential effects of drugs on Plasmodium falciparum by changes in using bicarbonate buffer. Methods Effects of antimalarial drugs on parasite growth were assayed by monitoring uptake of [3H]hypoxanthine. Results The inhibitory effect of chloroquine, on P. falciparum (K1 strain) is affected by pH differences caused by various CO2 concentrations in the presence of a constant NaHCO3 concentration. In contrast, inhibition by pyrimethamine on the growth of the K1 strain was unaffected by different CO2 concentrations. Conclusion Conventional medium for P. falciparum culture should be modified with constant NaHCO3 according to the CO2 concentration to evaluate drug resistance of P. falciparum.

  5. Prevalence of resistance associated polymorphisms in Plasmodium falciparum field isolates from southern Pakistan

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    Beg Mohammad A

    2011-01-01

    Full Text Available Abstract Background Scarce data are available on Plasmodium falciparum anti-malarial drug resistance in Pakistan. The aim of this study was, therefore, to determine the prevalence of P. falciparum resistance associated polymorphisms in field isolates from southern Pakistan. Methods Blood samples from 244 patients with blood-slide confirmed P. falciparum mono-infections were collected between 2005-2007. Single nucleotide polymorphisms in the P. falciparum chloroquine resistance transporter (pfcrt K76T, multi drug resistance (pfmdr1 N86Y, dihydrofolate reductase (pfdhfr A16V, N51I, C59R, S108N, I164L and dihydropteroate synthetase (pfdhps A436S, G437A and E540K genes and pfmdr1 gene copy numbers were determined using PCR based methods. Results The prevalence of pfcrt 76T and pfmdr1 86Y was 93% and 57%, respectively. The prevalence of pfdhfr double mutations 59R + 108N/51R + 108N was 92%. The pfdhfr triple mutation (51I, 59R, 108N occurred in 3% of samples. The pfdhfr (51I, 59R, 108N and pfdhps (437G, 540E quintuple mutation was found in one isolate. Pfdhps 437G was observed in 51% and 540E in 1% of the isolates. One isolate had two pfmdr1 copies and carried the pfmdr1 86Y and pfcrt 76T alleles. Conclusions The results indicate high prevalence of in vivo resistance to chloroquine, whereas high grade resistance to sulphadoxine-pyrimethamine does not appear to be widespread among P. falciparum in southern Pakistan.

  6. 转基因技术在疟原虫药物抗性机制研究中的应用%Investigation of drug-resistant mechanism of malaria parasites by transfection technology

    Institute of Scientific and Technical Information of China (English)

    叶润; 张冬梅; 潘卫庆

    2010-01-01

    疟疾是世界上危害人类健康最严重的感染性疾病之一.随着抗疟药物的广泛使用,疟原虫抗药性问题日趋严重.开展疟原虫药物抗性机制的研究,有助于开发新的药物以及制定用药策略.采用疟原虫转基因的方法能够从分子水平证实抗性基因与药物敏感的相关性以及基因突变在药物抗性产生中所起的作用.该文综述了疟原虫转基因技术在氯喹和磺胺多辛-乙胺嘧啶药物抗性机制研究中的应用.%Malaria is one of the leading infectious diseases in the world. The acquisition and spread of drug-resistant parasite arose gradually since widely utilization of antimalarial drugs. Investigations of the drugresistant mechanisms of malaria parasites may have advantages in developing new drug and modifying chemotherapy strategy. Introduction of transfection technologies made it possible to prove the role of candidate genes responsible for drug resistance, and the contribution of specific mutations to the resistance phenotype. This review focused on the application of transfection technologies in both Plasmodium falciparum and P. vivax to dissect the mechanisms of antimalarial drug resistance including chloroquine and sulfadoxin-pyrimethamine.

  7. Potential impact of host immunity on malaria treatment outcome in Tanzanian children infected with Plasmodium falciparum

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    Theander Thor G

    2007-11-01

    Full Text Available Abstract Background In malaria endemic areas children may recover from malaria after chemotherapy in spite of harbouring genotypically drug-resistant Plasmodium falciparum. This phenomenon suggests that there is a synergy between drug treatment and acquired immunity. This hypothesis was examined in an area of moderately intense transmission of P. falciparum in Tanzania during a drug trail with sulphadoxine-pyrimethamine (SP or amodiaquine (AQ. Methods One hundred children with uncomplicated malaria were treated with either SP or AQ and followed for 28 days. Mutations in parasite genes related to SP and AQ-resistance as well as human sickle cell trait and alpha-thalassaemia were determined using PCR and sequence-specific oligonucleotide probes and enzyme-linked immunosorbent assay (SSOP-ELISA, and IgG antibody responses to a panel of P. falciparum antigens were assessed and related to treatment outcome. Results Parasitological or clinical treatment failure (TF was observed in 68% and 38% of children receiving SP or AQ, respectively. In those with adequate clinical and parasitological response (ACPR compared to children with TF, and for both treatment regimens, prevalence and levels of anti-Glutamate-rich Protein (GLURP-specific IgG antibodies were significantly higher (P Conclusion These findings suggest that GLURP-specific IgG antibodies in this setting contribute to clearance of drug-resistant infections and support the hypothesis that acquired immunity enhances the clinical efficacy of drug therapy. The results should be confirmed in larger scale with greater sample size and with variation in transmission intensity.

  8. Selection of drug resistance-mediating Plasmodium falciparum genetic polymorphisms by seasonal malaria chemoprevention in Burkina Faso.

    Science.gov (United States)

    Somé, Anyirékun Fabrice; Zongo, Issaka; Compaoré, Yves-Daniel; Sakandé, Souleymane; Nosten, François; Ouédraogo, Jean-Bosco; Rosenthal, Philip J

    2014-07-01

    Seasonal malaria chemoprevention (SMC), with regular use of amodiaquine plus sulfadoxine-pyrimethamine (AQ/SP) during the transmission season, is now a standard malaria control measure in the Sahel subregion of Africa. Another strategy under study is SMC with dihydroartemisinin plus piperaquine (DP). Plasmodium falciparum single nucleotide polymorphisms (SNPs) in P. falciparum crt (pfcrt), pfmdr1, pfdhfr, and pfdhps are associated with decreased response to aminoquinoline and antifolate antimalarials and are selected by use of these drugs. To characterize selection by SMC of key polymorphisms, we assessed 13 SNPs in P. falciparum isolated from children aged 3 to 59 months living in southwestern Burkina Faso and randomized to receive monthly DP or AQ/SP for 3 months in 2009. We compared SNP prevalence before the onset of SMC and 1 month after the third treatment in P. falciparum PCR-positive samples from 120 randomly selected children from each treatment arm and an additional 120 randomly selected children from a control group that did not receive SMC. The prevalence of relevant mutations was increased after SMC with AQ/SP. Significant selection was seen for pfcrt 76T (68.5% to 83.0%, P = 0.04), pfdhfr 59R (54.8% to 83.3%, P = 0.0002), and pfdhfr 108N (55.0% to 87.2%, P = 0.0001), with trends toward selection of pfmdr1 86Y, pfdhfr 51I, and pfdhps 437G. After SMC with DP, only borderline selection of wild-type pfmdr1 D1246 (mutant; 7.7% to 0%, P = 0.05) was seen. In contrast to AQ/SP, SMC with DP did not clearly select for known resistance-mediating polymorphisms. SMC with AQ/SP, but not DP, may hasten the development of resistance to components of this regimen. (This study has been registered at ClinicalTrials.gov under registration no. NCT00941785.).

  9. Imputation-based population genetics analysis of Plasmodium falciparum malaria parasites.

    Science.gov (United States)

    Samad, Hanif; Coll, Francesc; Preston, Mark D; Ocholla, Harold; Fairhurst, Rick M; Clark, Taane G

    2015-04-01

    Whole-genome sequencing technologies are being increasingly applied to Plasmodium falciparum clinical isolates to identify genetic determinants of malaria pathogenesis. However, genome-wide discovery methods, such as haplotype scans for signatures of natural selection, are hindered by missing genotypes in sequence data. Poor correlation between single nucleotide polymorphisms (SNPs) in the P. falciparum genome complicates efforts to apply established missing-genotype imputation methods that leverage off patterns of linkage disequilibrium (LD). The accuracy of state-of-the-art, LD-based imputation methods (IMPUTE, Beagle) was assessed by measuring allelic r2 for 459 P. falciparum samples from malaria patients in 4 countries: Thailand, Cambodia, Gambia, and Malawi. In restricting our analysis to 86 k high-quality SNPs across the populations, we found that the complete-case analysis was restricted to 21k SNPs (24.5%), despite no single SNP having more than 10% missing genotypes. The accuracy of Beagle in filling in missing genotypes was consistently high across all populations (allelic r2, 0.87-0.96), but the performance of IMPUTE was mixed (allelic r2, 0.34-0.99) depending on reference haplotypes and population. Positive selection analysis using Beagle-imputed haplotypes identified loci involved in resistance to chloroquine (crt) in Thailand, Cambodia, and Gambia, sulfadoxine-pyrimethamine (dhfr, dhps) in Cambodia, and artemisinin (kelch13) in Cambodia. Tajima's D-based analysis identified genes under balancing selection that encode well-characterized vaccine candidates: apical merozoite antigen 1 (ama1) and merozoite surface protein 1 (msp1). In contrast, the complete-case analysis failed to identify any well-validated drug resistance or candidate vaccine loci, except kelch13. In a setting of low LD and modest levels of missing genotypes, using Beagle to impute P. falciparum genotypes is a viable strategy for conducting accurate large-scale population genetics and

  10. Cluster-randomized study of intermittent preventive treatment for malaria in infants (IPTi in southern Tanzania: evaluation of impact on survival

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    Schellenberg Joanna

    2011-12-01

    Full Text Available Abstract Background Intermittent Preventive Treatment for malaria control in infants (IPTi consists of the administration of a treatment dose of an anti-malarial drug, usually sulphadoxine-pyrimethamine, at scheduled intervals, regardless of the presence of Plasmodium falciparum infection. A pooled analysis of individually randomized trials reported that IPTi reduced clinical episodes by 30%. This study evaluated the effect of IPTi on child survival in the context of a five-district implementation project in southern Tanzania. [Trial registration: clinical trials.gov NCT00152204]. Methods After baseline household and health facility surveys in 2004, five districts comprising 24 divisions were randomly assigned either to receive IPTi (n = 12 or not (n = 12. Implementation started in March 2005, led by routine health services with support from the research team. In 2007, a large household survey was undertaken to assess the impact of IPTi on survival in infants aged two-11 months through birth history interviews with all women aged 13-49 years. The analysis is based on an "intention-to-treat" ecological design, with survival outcomes analysed according to the cluster in which the mothers lived. Results Survival in infants aged two-11 months was comparable in IPTi and comparison areas at baseline. In intervention areas in 2007, 48% of children aged 12-23 months had documented evidence of receiving three doses of IPTi, compared to 2% in comparison areas (P P = 0.31. Conclusion The lack of evidence of an effect of IPTi on survival could be a false negative result due to a lack of power or imbalance of unmeasured confounders. Alternatively, there could be no mortality impact of IPTi due to low coverage, late administration, drug resistance, decreased malaria transmission or improvements in vector control and case management. This study raises important questions for programme evaluation design.

  11. Assessing the quality of anti-malarial drugs from Gabonese pharmacies using the MiniLab®: a field study.

    Science.gov (United States)

    Visser, Benjamin J; Meerveld-Gerrits, Janneke; Kroon, Daniëlle; Mougoula, Judith; Vingerling, Rieke; Bache, Emmanuel; Boersma, Jimmy; van Vugt, Michèle; Agnandji, Selidji T; Kaur, Harparkash; Grobusch, Martin P

    2015-07-15

    Recent studies alluded to the alarming scale of poor anti-malarial drug quality in malaria-endemic countries, but also illustrated the major geographical gaps in data on anti-malarial drug quality from endemic countries. Data are particularly scarce from Central Africa, although it carries the highest burden of malaria. The aim of this medicine quality field survey was to determine the prevalence of poor-quality anti-malarial drugs in Gabon. A field survey of the quality of anti-malarial drugs in Gabonese pharmacies was conducted using the Global Pharma Health Fund Minilab(®) tests, following the Medicine Quality Assessment Reporting Guidelines. Anti-malarial drugs were purchased randomly from selected pharmacies in Gabon. Semi-quantitative thin-layer chromatography (TLC) and disintegration testing were carried out to measure the concentration of active pharmaceutical ingredients (APIs). The samples failing the TLC test were analysed by high-performance liquid chromatography. Following the collection of anti-malarial drugs, a street survey was conducted to understand where people purchase their anti-malarial drugs. A total of 432 samples were purchased from 41 pharmacies in 11 cities/towns in Gabon. The prevalence of poor-quality anti-malarial drugs was 0.5% (95% CI 0.08-1.84%). Two out of 432 samples failed the MiniLab(®) semi-quantitative TLC test, of which a suspected artemether-lumefantrine (AL) sample was classified as falsified and one sulfadoxine-pyrimethamine (SP) sample as substandard. High performance liquid chromatography with ultraviolet photo diode array detection analysis confirmed the absence of APIs in the AL sample, and showed that the SP sample did contain the stated APIs but the amount was half the stated dose. Of the people interviewed, 92% (187/203) purchased their anti-malarial drugs at a pharmacy. Using the GPHF Minilab(®), the prevalence of poor-quality anti-malarial drugs is far lower than anticipated. The findings emphasize the need for

  12. Finding parasites and finding challenges: improved diagnostic access and trends in reported malaria and anti-malarial drug use in Livingstone district, Zambia

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    Masaninga Freddie

    2012-10-01

    Full Text Available Abstract Background Understanding the impact of malaria rapid diagnostic test (RDT use on management of acute febrile disease at a community level, and on the consumption of anti-malarial medicines, is critical to the planning and success of scale-up to universal parasite-based diagnosis by health systems in malaria-endemic countries. Methods A retrospective study of district-wide community-level RDT introduction was conducted in Livingstone District, Zambia, to assess the impact of this programmed on malaria reporting, incidence of mortality and on district anti-malarial consumption. Results Reported malaria declined from 12,186 cases in the quarter prior to RDT introduction in 2007 to an average of 12.25 confirmed and 294 unconfirmed malaria cases per quarter over the year to September 2009. Reported malaria-like fever also declined, with only 4,381 RDTs being consumed per quarter over the same year. Reported malaria mortality declined to zero in the year to September 2009, and all-cause mortality declined. Consumption of artemisinin-based combination therapy (ACT dropped dramatically, but remained above reported malaria, declining from 12,550 courses dispensed by the district office in the quarter prior to RDT implementation to an average of 822 per quarter over the last year. Quinine consumption in health centres also declined, with the district office ceasing to supply due to low usage, but requests for sulphadoxine-pyrimethamine (SP rose to well above previous levels, suggesting substitution of ACT with this drug in RDT-negative cases. Conclusions RDT introduction led to a large decline in reported malaria cases and in ACT consumption in Livingstone district. Reported malaria mortality declined to zero, indicating safety of the new diagnostic regime, although adherence and/or use of RDTs was still incomplete. However, a deficiency is apparent in management of non-malarial fever, with inappropriate use of a low-cost single dose drug, SP

  13. The cost-effectiveness of intermittent preventive treatment for malaria in infants in Sub-Saharan Africa.

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    Lesong Conteh

    Full Text Available BACKGROUND: Intermittent preventive treatment in infants (IPTi has been shown to decrease clinical malaria by approximately 30% in the first year of life and is a promising malaria control strategy for Sub-Saharan Africa which can be delivered alongside the Expanded Programme on Immunisation (EPI. To date, there have been limited data on the cost-effectiveness of this strategy using sulfadoxine pyrimethamine (SP and no published data on cost-effectiveness using other antimalarials. METHODS: We analysed data from 5 countries in sub-Saharan Africa using a total of 5 different IPTi drug regimens; SP, mefloquine (MQ, 3 days of chlorproguanil-dapsone (CD, SP plus 3 days of artesunate (SP-AS3 and 3 days of amodiaquine-artesunate (AQ3-AS3.The cost per malaria episode averted and cost per Disability-Adjusted Life-Year (DALY averted were modeled using both trial specific protective efficacy (PE for all IPTi drugs and a pooled PE for IPTi with SP, malaria incidence, an estimated malaria case fatality rate of 1.57%, IPTi delivery costs and country specific provider and household malaria treatment costs. FINDINGS: In sites where IPTi had a significant effect on reducing malaria, the cost per episode averted for IPTi-SP was very low, USD 1.36-4.03 based on trial specific data and USD 0.68-2.27 based on the pooled analysis. For IPTi using alternative antimalarials, the lowest cost per case averted was for AQ3-AS3 in western Kenya (USD 4.62 and the highest was for MQ in Korowge, Tanzania (USD 18.56. Where efficacious, based only on intervention costs, IPTi was shown to be cost effective in all the sites and highly cost-effective in all but one of the sites, ranging from USD 2.90 (Ifakara, Tanzania with SP to USD 39.63 (Korogwe, Tanzania with MQ per DALY averted. In addition, IPTi reduced health system costs and showed significant savings to households from malaria cases averted. A threshold analysis showed that there is room for the IPTi-efficacy to fall and

  14. The cost-effectiveness of intermittent preventive treatment for malaria in infants in Sub-Saharan Africa.

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    Conteh, Lesong; Sicuri, Elisa; Manzi, Fatuma; Hutton, Guy; Obonyo, Benson; Tediosi, Fabrizio; Biao, Prosper; Masika, Paul; Matovu, Fred; Otieno, Peter; Gosling, Roly D; Hamel, Mary; Odhiambo, Frank O; Grobusch, Martin P; Kremsner, Peter G; Chandramohan, Daniel; Aponte, John J; Egan, Andrea; Schellenberg, David; Macete, Eusebio; Slutsker, Laurence; Newman, Robert D; Alonso, Pedro; Menéndez, Clara; Tanner, Marcel

    2010-06-15

    Intermittent preventive treatment in infants (IPTi) has been shown to decrease clinical malaria by approximately 30% in the first year of life and is a promising malaria control strategy for Sub-Saharan Africa which can be delivered alongside the Expanded Programme on Immunisation (EPI). To date, there have been limited data on the cost-effectiveness of this strategy using sulfadoxine pyrimethamine (SP) and no published data on cost-effectiveness using other antimalarials. We analysed data from 5 countries in sub-Saharan Africa using a total of 5 different IPTi drug regimens; SP, mefloquine (MQ), 3 days of chlorproguanil-dapsone (CD), SP plus 3 days of artesunate (SP-AS3) and 3 days of amodiaquine-artesunate (AQ3-AS3).The cost per malaria episode averted and cost per Disability-Adjusted Life-Year (DALY) averted were modeled using both trial specific protective efficacy (PE) for all IPTi drugs and a pooled PE for IPTi with SP, malaria incidence, an estimated malaria case fatality rate of 1.57%, IPTi delivery costs and country specific provider and household malaria treatment costs. In sites where IPTi had a significant effect on reducing malaria, the cost per episode averted for IPTi-SP was very low, USD 1.36-4.03 based on trial specific data and USD 0.68-2.27 based on the pooled analysis. For IPTi using alternative antimalarials, the lowest cost per case averted was for AQ3-AS3 in western Kenya (USD 4.62) and the highest was for MQ in Korowge, Tanzania (USD 18.56). Where efficacious, based only on intervention costs, IPTi was shown to be cost effective in all the sites and highly cost-effective in all but one of the sites, ranging from USD 2.90 (Ifakara, Tanzania with SP) to USD 39.63 (Korogwe, Tanzania with MQ) per DALY averted. In addition, IPTi reduced health system costs and showed significant savings to households from malaria cases averted. A threshold analysis showed that there is room for the IPTi-efficacy to fall and still remain highly cost effective in

  15. Cost effectiveness of intermittent screening followed by treatment versus intermittent preventive treatment during pregnancy in West Africa: analysis and modelling of results from a non-inferiority trial.

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    Fernandes, Silke; Sicuri, Elisa; Halimatou, Diawara; Akazili, James; Boiang, Kalifa; Chandramohan, Daniel; Coulibaly, Sheikh; Diawara, Sory Ibrahim; Kayentao, Kassoum; Ter Kuile, Feiko; Magnussen, Pascal; Tagbor, Harry; Williams, John; Woukeu, Arouna; Cairns, Matthew; Greenwood, Brian; Hanson, Kara

    2016-09-23

    Emergence of high-grade sulfadoxine-pyrimethamine (SP) resistance in parts of Africa has led to growing concerns about the efficacy of intermittent preventive treatment of malaria during pregnancy (IPTp) with SP. The incremental cost-effectiveness of intermittent screening and treatment (ISTp) with artemether-lumefantrine (AL) as an alternative strategy to IPTp-SP was estimated followed by a simulation of the effects on cost-effectiveness of decreasing efficacy of IPTp-SP due to SP resistance. The analysis was based on results from a multi-centre, non-inferiority trial conducted in West Africa. A decision tree model was analysed from a health provider perspective. Model parameters for all trial countries with appropriate ranges and distributions were used in a probabilistic sensitivity analysis. Simulations were performed in hypothetical cohorts of 1000 pregnant women who received either ISTp-AL or IPTp-SP. In addition a cost-consequences analysis was conducted. Trial estimates were used to calculate disability-adjusted-life-years (DALYs) for low birth weight and severe/moderate anaemia (both shown to be non-inferior for ISTp-AL) and clinical malaria (inferior for ISTp-AL). Cost estimates were obtained from observational studies, health facility costings and public procurement databases. Results were calculated as incremental cost per DALY averted. Finally, the cost-effectiveness changes with decreasing SP efficacy were explored by simulation. Relative to IPTp-SP, delivering ISTp-AL to 1000 pregnant women cost US$ 4966.25 more (95 % CI US$ 3703.53; 6376.83) and led to a small excess of 28.36 DALYs (95 % CI -75.78; 134.18), with LBW contributing 81.3 % of this difference. The incremental cost-effectiveness ratio was -175.12 (95 % CI -1166.29; 1267.71) US$/DALY averted. Simulations show that cost-effectiveness of ISTp-AL increases as the efficacy of IPTp-SP decreases, though the specific threshold at which ISTp-AL becomes cost-effective depends on assumptions

  16. Health service providers in Somalia: their readiness to provide malaria case-management

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    Moonen Bruno

    2009-05-01

    Full Text Available Abstract Background Studies have highlighted the inadequacies of the public health sector in sub-Saharan African countries in providing appropriate malaria case management. The readiness of the public health sector to provide malaria case-management in Somalia, a country where there has been no functioning central government for almost two decades, was investigated. Methods Three districts were purposively sampled in each of the two self-declared states of Puntland and Somaliland and the south-central region of Somalia, in April-November 2007. A survey and mapping of all public and private health service providers was undertaken. Information was recorded on services provided, types of anti-malarial drugs used and stock, numbers and qualifications of staff, sources of financial support and presence of malaria diagnostic services, new treatment guidelines and job aides for malaria case-management. All settlements were mapped and a semi-quantitative approach was used to estimate their population size. Distances from settlements to public health services were computed. Results There were 45 public health facilities, 227 public health professionals, and 194 private pharmacies for approximately 0.6 million people in the three districts. The median distance to public health facilities was 6 km. 62.3% of public health facilities prescribed the nationally recommended anti-malarial drug and 37.7% prescribed chloroquine as first-line therapy. 66.7% of public facilities did not have in stock the recommended first-line malaria therapy. Diagnosis of malaria using rapid diagnostic tests (RDT or microscopy was performed routinely in over 90% of the recommended public facilities but only 50% of these had RDT in stock at the time of survey. National treatment guidelines were available in 31.3% of public health facilities recommended by the national strategy. Only 8.8% of the private pharmacies prescribed artesunate plus sulphadoxine/pyrimethamine, while 53

  17. Pravastatin and simvastatin inhibit the adhesion, replication and proliferation of Toxoplasma gondii (RH strain) in HeLa cells.

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    Sanfelice, Raquel Arruda; da Silva, Suelen Santos; Bosqui, Larissa Rodrigues; Miranda-Sapla, Milena Menegazzo; Barbosa, Bellisa Freitas; Silva, Rafaela José; Ferro, Eloísa A Vieira; Panagio, Luciano Aparecido; Navarro, Italmar Teodorico; Bordignon, Juliano; Conchon-Costa, Ivete; Pavanelli, Wander Rogerio; Almeida, Ricardo Sergio; Costa, Idessania Nazareth

    2017-03-01

    The conventional treatment for toxoplasmosis with pyrimethamine and sulfadiazine shows toxic effects to the host, and it is therefore necessary to search for new drugs. Some studies suggest the use of statins, which inhibit cholesterol synthesis in humans and also the initial processes of isoprenoid biosynthesis in the parasite. Thus, the objective of this study was to evaluate the activity of the statins pravastatin and simvastatin in HeLa cells infected in vitro with the RH strain of T. gondii. HeLa cells (1×10(5)) were infected with T. gondii tachyzoites (5×10(5)) following two different treatment protocols. In the first protocol, T. gondii tachyzoites were pretreated with pravastatin (50 and 100μg/mL) and simvastatin (1.56 and 3.125μg/mL) for 30min prior to infection. In the second, HeLa cells were first infected (5×10(5)) with tachyzoites and subsequently treated with pravastatin and simvastatin for 24h at the concentrations noted above. Initially, we evaluated the cytotoxicity of drugs by the MTT assay, number of tachyzoites adhered to cells, number of infected cells, and viability of tachyzoites by trypan blue exclusion. The supernatant of the cell cultures was collected post-treatment for determination of the pattern of Th1/Th2/Th17 cytokines by cytometric bead array. There was no cytotoxicity to HeLa cells with 50 and 100μg/mL pravastatin and 1.56 and 3.125μg/mL simvastatin. There was no change in the viability of tachyzoites that received pretreatment. Regarding the pre- and post-treatment of the cells with pravastatin and simvastatin alone, there was a reduction in adhesion, invasion and proliferation of cells to T. gondii. As for the production of cytokines, we found that IL-6 and IL-17 were significantly reduced in cells infected with T. gondii and treated with pravastatin and simvastatin, when compared to control. Based on these results, we can infer that pravastatin and simvastatin alone possess antiproliferative effects on tachyzoites forms

  18. Access to Artemisinin-Combination Therapy (ACT) and other Anti-Malarials: National Policy and Markets in Sierra Leone

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    Amuasi, John H.; Diap, Graciela; Nguah, Samuel Blay; Karikari, Patrick; Boakye, Isaac; Jambai, Amara; Lahai, Wani Kumba; Louie, Karly S.; Kiechel, Jean-Rene

    2012-01-01

    Malaria remains the leading burden of disease in post-conflict Sierra Leone. To overcome the challenge of anti-malarial drug resistance and improve effective treatment, Sierra Leone adopted artemisinin-combination therapy artesunate-amodiaquine (AS+AQ) as first-line treatment for uncomplicated P. falciparum malaria. Other national policy anti-malarials include artemether-lumefantrine (AL) as an alternative to AS+AQ, quinine and artemether for treatment of complicated malaria; and sulphadoxine-pyrimethamine (SP) for intermittent preventive treatment (IPTp). This study was conducted to evaluate access to national policy recommended anti-malarials. A cross-sectional survey of 127 medicine outlets (public, private and NGO) was conducted in urban and rural areas. The availability on the day of the survey, median prices, and affordability policy and available non-policy anti-malarials were calculated. Anti-malarials were stocked in 79% of all outlets surveyed. AS+AQ was widely available in public medicine outlets; AL was only available in the private and NGO sectors. Quinine was available in nearly two-thirds of public and NGO outlets and over one-third of private outlets. SP was widely available in all outlets. Non-policy anti-malarials were predominantly available in the private outlets. AS+AQ in the public sector was widely offered for free. Among the anti-malarials sold at a cost, the same median price of a course of AS+AQ (US$1.56), quinine tablets (US$0.63), were found in both the public and private sectors. Quinine injection had a median cost of US$0.31 in the public sector and US$0.47 in the private sector, while SP had a median cost of US$0.31 in the public sector compared to US$ 0.63 in the private sector. Non-policy anti-malarials were more affordable than first-line AS+AQ in all sectors. A course of AS+AQ was affordable at nearly two days’ worth of wages in both the public and private sectors. PMID:23133522

  19. Intermittent screening and treatment versus intermittent preventive treatment of malaria in pregnancy: provider knowledge and acceptability.

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    Lucy Smith Paintain

    Full Text Available Malaria in pregnancy (MiP is associated with increased risks of maternal and foetal complications. The WHO recommends a package of interventions including intermittent preventive treatment (IPT with sulphadoxine-pyrimethamine (SP, insecticide-treated nets and effective case management. However, with increasing SP resistance, the effectiveness of SP-IPT has been questioned. Intermittent screening and treatment (IST has recently been shown in Ghana to be as efficacious as SP-IPT. This study investigates two important requirements for effective delivery of IST and SP-IPT: antenatal care (ANC provider knowledge, and acceptance of the different strategies. Structured interviews with 134 ANC providers at 67 public health facilities in Ashanti Region, Ghana collected information on knowledge of the risks and preventative and curative interventions against MiP. Composite indicators of knowledge of SP-IPT, and case management of MiP were developed. Log binomial regression of predictors of provider knowledge was explored. Qualitative data were collected through in-depth interviews with fourteen ANC providers with some knowledge of IST to gain an indication of the factors influencing acceptance of the IST approach. 88.1% of providers knew all elements of the SP-IPT policy, compared to 20.1% and 41.8% who knew the treatment policy for malaria in the first or second/third trimesters, respectively. Workshop attendance was a univariate predictor of each knowledge indicator. Qualitative findings suggest preference for prevention over cure, and increased workload may be barriers to IST implementation. However, a change in strategy in the face of SP resistance is likely to be supported; health of pregnant women is a strong motivation for ANC provider practice. If IST was to be introduced as part of routine ANC activities, attention would need to be given to improving the knowledge and practices of ANC staff in relation to appropriate treatment of MiP. Health

  20. A randomised trial to compare the safety, tolerability and efficacy of three drug combinations for intermittent preventive treatment in children.

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    Kalifa Bojang

    Full Text Available BACKGROUND: Results from trials of intermittent preventive treatment (IPT in infants and children have shown that IPT provides significant protection against clinical malaria. Sulfadoxine-pyrimethamine (SP given alone or in combination with other drugs has been used for most IPT programmes. However, SP resistance is increasing in many parts of Africa. Thus, we have investigated whether SP plus AQ, SP plus piperaquine (PQ and dihydroartemisinin (DHA plus PQ might be equally safe and effective when used for IPT in children in an area of seasonal transmission. METHODS: During the 2007 malaria transmission season, 1008 Gambian children were individually randomized to receive SP plus amodiaquine (AQ, SP plus piperaquine (PQ or dihydroartemisinin (DHA plus PQ at monthly intervals on three occasions during the peak malaria transmission season. To determine the risk of side effects following drug administration, participants in each treatment group were visited at home three days after the start of each round of drug administration and a side effects questionnaire completed. To help establish whether adverse events were drug related, the same questionnaire was administered to 286 age matched control children recruited from adjacent villages. Morbidity was monitored throughout the malaria transmission season and study children were seen at the end of the malaria transmission season. RESULTS: All three treatment regimens showed good safety profiles. No severe adverse event related to IPT was reported. The most frequent adverse events reported were coughing, diarrhoea, vomiting, abdominal pain and loss of appetite. Cough was present in 15.2%, 15.4% and 18.7% of study subjects who received SP plus AQ, DHA plus PQ or SP plus PQ respectively, compared to 19.2% in a control group. The incidence of malaria in the DHA plus PQ, SP plus AQ and SP plus PQ groups were 0.10 cases per child year (95% CI: 0.05, 0.22, 0.06 (95% CI: 0.022, 0.16 and 0.06 (95% CI: 0.02, 0

  1. Impaired CD4-cell immune reconstitution upon HIV therapy in patients with toxoplasmic encephalitis compared to patients with pneumocystis pneumonia as AIDS indicating disease

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    Kastenbauer U

    2009-06-01

    Full Text Available Abstract Objectives There is only little data on immune reconstitution in antiretroviral naïve AIDS-patients with toxoplasmosis. The observation of several cases with reduced increase of CD4-cells upon start of antiretroviral treatment (ART prompted us to investigate the topic using the ClinSurv cohort. Methods 17 German HIV treatment centers contribute to ClinSurv, a multicentre observational cohort under the auspices of the Robert Koch Institute. We retrospectively selected all antiretroviral-naïve patients with toxoplasmic encephalitis (TE and -as comparator group -with pneumocystosis (PCP between January 1999 and December 2005. Results A total of 257 patients were included in the analysis, 61 with TE and 196 with PCP. Demographic baseline data showed differences with regard to gender, transmission group, and baseline CD4+ counts (60.9 vs. 44.7/μl, p = 0.022. After ART-initiation the increase in CD4+ lymphocytes was lower in the TE-versus the PCP-group in the first, second and fourth three-month-period (74.4 vs. 120.3/μl, p = 0.006; 96.6 vs. 136.2/μl, p = 0.021; 156.5 vs. 211.5/μl, p = 0.013. Viral load (VL was higher in the PCP-group at baseline (4.46 log10cop/ml vs. 5.00 log10cop/ml, p = 0.008, while virological success of ART was equal. Conclusions Our data show for the first time that the average CD4+ T-cell increase of patients with toxoplasmosis is impaired compared to PCP-patients. Most clinicians would not be prepared to discontinue follow-up TE-therapy unless CD4+ counts of 200/μl are reached. Explanation for our finding might be the myelosuppressive side effect of pyrimethamine, possible interactions of toxoplasmosis therapy with ART, or an unknown direct biological influence of toxoplasmosis on immune restoration.

  2. A Non-Inferiority, Individually Randomized Trial of Intermittent Screening and Treatment versus Intermittent Preventive Treatment in the Control of Malaria in Pregnancy.

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    Harry Tagbor

    Full Text Available The efficacy of intermittent preventive treatment for malaria with sulfadoxine-pyrimethamine (IPTp-SP in pregnancy is threatened in parts of Africa by the emergence and spread of resistance to SP. Intermittent screening with a rapid diagnostic test (RDT and treatment of positive women (ISTp is an alternative approach.An open, individually randomized, non-inferiority trial of IPTp-SP versus ISTp was conducted in 5,354 primi- or secundigravidae in four West African countries with a low prevalence of resistance to SP (The Gambia, Mali, Burkina Faso and Ghana. Women in the IPTp-SP group received SP on two or three occasions whilst women in the ISTp group were screened two or three times with a RDT and treated if positive for malaria with artemether-lumefantrine (AL. ISTp-AL was non-inferior to IPTp-SP in preventing low birth weight (LBW, anemia and placental malaria, the primary trial endpoints. The prevalence of LBW was 15.1% and 15.6% in the IPTp-SP and ISTp-AL groups respectively (OR = 1.03 [95% CI: 0.88, 1.22]. The mean hemoglobin concentration at the last clinic attendance before delivery was 10.97g/dL and 10.94g/dL in the IPTp-SP and ISTp-AL groups respectively (mean difference: -0.03 g/dL [95% CI: -0.13, +0.06]. Active malaria infection of the placenta was found in 24.5% and in 24.2% of women in the IPTp-SP and ISTp-AL groups respectively (OR = 0.95 [95% CI 0.81, 1.12]. More women in the ISTp-AL than in the IPTp-SP group presented with malaria parasitemia between routine antenatal clinics (310 vs 182 episodes, rate difference: 49.4 per 1,000 pregnancies [95% CI 30.5, 68.3], but the number of hospital admissions for malaria was similar in the two groups.Despite low levels of resistance to SP in the study areas, ISTp-AL performed as well as IPTp-SP. In the absence of an effective alternative medication to SP for IPTp, ISTp-AL is a potential alternative to IPTp in areas where SP resistance is high. It may also have a role in areas where malaria

  3. Toxoplasmosis retinochoroiditis after photodynamic therapy and intravitreal triamcinolone for a supposed choroidal neovascularization: a case report Retinocoroidite toxoplásmica após terapia fotodinâmica e triancinolona intravítrea em suposta neovascularização de coróide: relato de um caso

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    Mário Junqueira Nóbrega

    2007-02-01

    Full Text Available The purpose is to report a complication after photodynamic therapy (PDT and intravitreal triamcinolone for a presumed choroidal neovascularization in age-related macular degeneration. Photodynamic therapy and intravitreal triamcinolone were used in an 84-year-old man with choroidal neovascularization in the left eye. Forty-five days after therapy, the patient returned with a severe necrotizing uveitis in the posterior pole and vitritis. Laboratory investigation disclosed a high anti-Toxoplasma IgG titer. Therapy with pyrimethamine, sulfadiazine and folinic acid resulted in total lesion healing although central vision was lost. Intravitreal triamcinolone may have had an influence on the exacerbation of retinochoroiditis in the posterior pole of the patient. Although rare, this complication may not be disregarded in the cases that require intraocular corticosteroids for treatment of several conditions, especially in patients who had previously suffered from toxoplasmosis infection.O objetivo é relatar complicação após terapia fotodinâmica (PDT e triancinolona intravítrea para presumida neovascularização de coróide em degeneração macular relacionada à idade. A terapia fotodinâmica e triancinolona intravítrea foram utilizados em paciente de 84 anos, do sexo masculino, com neovascularização de coróide no olho esquerdo. Quarenta e cinco dias após o tratamento, o paciente retornou com grave retinite necrosante do pólo posterior e vitreíte. Investigação laboratorial indicou alto título de IgG anti-Toxoplasma. Tratamento com pirimetamina, sulfadiazina e ácido folínico levaram à total cicatrização da lesão embora a visão central tenha sido comprometida. Conclui-se que a triancinolona intravítrea pode ter influenciado na exacerbação da retinocoroidite no pólo posterior do paciente. Embora rara, esta complicação não pode ser descartada nos casos que necessitem corticóide intra-ocular para tratamento de várias doen

  4. Substandard anti-malarial drugs in Burkina Faso

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    Sie Ali

    2008-05-01

    Full Text Available Abstract Background There is concern about an increasing infiltration of markets by substandard and fake medications against life-threatening diseases in developing countries. This is particularly worrying with regard to the increasing resistance development of Plasmodium falciparum against affordable anti-malarial medications, which has led to a change to more expensive drugs in most endemic countries. Methods A representative sample of modern anti-malarial medications from licensed (public and private pharmacies, community health workers and illicit (market and street vendors, shops sources has been collected in the Nouna Health District in north-western Burkina Faso in 2006. All drugs were tested for their quality with the standard procedures of the German Pharma Health Fund-Minilab. Detected low standard drugs were re-tested with European Pharmacopoeia 2.9.1 standards for disintegration and ultraviolet-visible spectroscopy at the laboratory of the Heidelberg University for confirmation. Results Overall, 86 anti-malarial drug samples were collected, of which 77 samples have been included in the final analysis. The sample consisted of 39/77 (50% chloroquine, 10/77 (13% pyrimethamine-sulphadoxine, 9/77 (12% quinine, 6/77 (8% amodiaquine, 9/77 (12% artesunate, and 4/77 (5% artemether-lumefantrine. 32/77 (42% drug samples were found to be of poor quality, of which 28 samples failed the visual inspection, nine samples had substandard concentrations of the active ingredient, four samples showed poor disintegration, and one sample contained non of the stated active ingredient. The licensed and the illicit market contributed 5/47 (10.6% and 27/30 (90.0% samples of substandard drugs respectively. Conclusion These findings provide further evidence for the wide-spread existence of substandard anti-malarial medications in Africa and call for strengthening of the regulatory and quality control capacity of affected countries, particularly in view of the

  5. Exposure to anti-malarial drugs and monitoring of adverse drug reactions using toll-free mobile phone calls in private retail sector in Sagamu, Nigeria: implications for pharmacovigilance

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    Ogunwande Isiaka A

    2011-08-01

    Full Text Available Abstract Background Adverse drug reactions (ADRs contribute to ill-health or life-threatening outcomes of therapy during management of infectious diseases. The exposure to anti-malarial and use of mobile phone technology to report ADRs following drug exposures were investigated in Sagamu - a peri-urban community in Southwest Nigeria. Methods Purchase of medicines was actively monitored for 28 days in three Community Pharmacies (CP and four Patent and Proprietary Medicine Stores (PPMS in the community. Information on experience of ADRs was obtained by telephone from 100 volunteers who purchased anti-malarials during the 28-day period. Results and Discussion A total of 12,093 purchases were recorded during the period. Antibiotics, analgesics, vitamins and anti-malarials were the most frequently purchased medicines. A total of 1,500 complete courses of anti-malarials were purchased (12.4% of total purchases; of this number, purchases of sulphadoxine-pyrimethamine (SP and chloroquine (CQ were highest (39.3 and 25.2% respectiuvely. Other anti-malarials purchased were artesunate monotherapy (AS - 16.1%, artemether-lumefantrine (AL 10.0%, amodiaquine (AQ - 6.6%, quinine (QNN - 1.9%, halofantrine (HF - 0.2% and proguanil (PR - 0.2%. CQ was the cheapest (USD 0.3 and halofantrine the most expensive (USD 7.7. AL was 15.6 times ($4.68 more expensive than CQ. The response to mobile phone monitoring of ADRs was 57% in the first 24 hours (day 1 after purchase and decreased to 33% by day 4. Participants in this monitoring exercise were mostly with low level of education (54%. Conclusion The findings from this study indicate that ineffective anti-malaria medicines including monotherapies remain widely available and are frequently purchased in the study area. Cost may be a factor in the continued use of ineffective monotherapies. Availability of a toll-free telephone line may facilitate pharmacovigilance and follow up of response to medicines in a resource

  6. CLINICO - HAEMATOLOGICAL PROFILE AND OUTCOME OF CEREBRAL MALARIA IN A TEACHING HOSPITAL OF SOUTH EAST RAJASTHAN

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    Gautam Lal

    2015-05-01

    Full Text Available AIM: Evaluation of Clinico - hematological profile and outcome of cerebral malaria in semi urban hospital situated in endemic area. MATERIAL AND METHODS : A cross - sectional hospital - based study was conducted from August to November, 2014 at Department of Paediatrics SRG Zanana Hospital, Jhalawar Rajasthan. Every child, except who was previously abnormal neurologically, of the age of six month to 12 years, presented with a history of fever in the last 7 days, with o r without convulsion, and/or impaired consciousness, screened for malaria by peripheral blood smear examination and rapid diagnostic test for malaria parasite. On the basis of this screening examination, these children were classified definite cerebral mal aria where the peripheral smear was positive and probable cerebral malaria where the peripheral smear was negative. If the patients presented with fever, convulsion, and/or impaired level of consciousness, they were treated with Artesunate intravenously em pirically. Patients were followed - up regularly till they regained consciousness and when, they were able to swallow, treated with oral Artisunate and single dose of Sulphadoxine and Pyrimethamine combination is also given. RESULTS: Of the3332 admissions, 8 69 (26.08% were admitted for fever. Out of these 869 febrile patients 352 patients were having other obvious clinical diagnosis for fever. In remaining 517(59.49% cases were suspected to be suffering from malaria, but all of these children who were admit ted with the diagnosis of fever, were screened for malaria and 74(08.51%were found to be positive for malaria parasite either by peripheral blood smear or rapid diagnostic test or both. Cerebral malaria developed in 37 patients. Most cases were of age gro up of 2 - 5 years, 14children had definite cerebral malaria and 9 were labelled as suspected to have probable cerebral malaria. Neurological symptoms of altered sensorium, convulsion and abnormal behaviour ranged from 35

  7. Improvements in access to malaria treatment in Tanzania after switch to artemisinin combination therapy and the introduction of accredited drug dispensing outlets - a provider perspective

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    Dillip Angel

    2010-06-01

    Full Text Available Abstract Background To improve access to treatment in the private retail sector a new class of outlets known as accredited drug dispensing outlets (ADDO was created in Tanzania. Tanzania changed its first-line treatment for malaria from sulphadoxine-pyrimethamine (SP to artemether-lumefantrine (ALu in 2007. Subsidized ALu was made available in both health facilities and ADDOs. The effect of these interventions on access to malaria treatment was studied in rural Tanzania. Methods The study was carried out in the villages of Kilombero and Ulanga Demographic Surveillance System (DSS and in Ifakara town. Data collection consisted of: 1 yearly censuses of shops selling drugs; 2 collection of monthly data on availability of anti-malarials in public health facilities; and 3 retail audits to measure anti-malarial sales volumes in all public, mission and private outlets. The data were complemented with DSS population data. Results Between 2004 and 2008 access to malaria treatment greatly improved and the number of anti-malarial treatment doses dispensed increased by 78%. Particular improvements were observed in the availability (from 0.24 shops per 1,000 people in 2004 to 0.39 in 2008 and accessibility (from 71% of households within 5 km of a shop in 2004 to 87% in 2008 of drug shops. Despite no improvements in affordability this resulted in an increase of the market share from 49% of anti-malarial sales 2005 to 59% in 2008. The change of treatment policy from SP to ALu led to severe stock-outs of SP in health facilities in the months leading up to the introduction of ALu (only 40% months in stock, but these were compensated by the wide availability of SP in shops. After the introduction of ALu stock levels of the drug were relatively high in public health facilities (over 80% months in stock, but the drug could only be found in 30% of drug shops and in no general shops. This resulted in a low overall utilization of the drug (19% of all anti

  8. Systematic assessment of multi-gene predictors of pan-cancer cell line sensitivity to drugs exploiting gene expression data

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    Nguyen, Linh; Dang, Cuong C; Ballester, Pedro J.

    2017-01-01

    Background: Selected gene mutations are routinely used to guide the selection of cancer drugs for a given patient tumour. Large pharmacogenomic data sets, such as those by Genomics of Drug Sensitivity in Cancer (GDSC) consortium, were introduced to discover more of these single-gene markers of drug sensitivity. Very recently, machine learning regression has been used to investigate how well cancer cell line sensitivity to drugs is predicted depending on the type of molecular profile. The latter has revealed that gene expression data is the most predictive profile in the pan-cancer setting. However, no study to date has exploited GDSC data to systematically compare the performance of machine learning models based on multi-gene expression data against that of widely-used single-gene markers based on genomics data. Methods: Here we present this systematic comparison using Random Forest (RF) classifiers exploiting the expression levels of 13,321 genes and an average of 501 tested cell lines per drug. To account for time-dependent batch effects in IC 50 measurements, we employ independent test sets generated with more recent GDSC data than that used to train the predictors and show that this is a more realistic validation than standard k-fold cross-validation. Results and Discussion: Across 127 GDSC drugs, our results show that the single-gene markers unveiled by the MANOVA analysis tend to achieve higher precision than these RF-based multi-gene models, at the cost of generally having a poor recall (i.e. correctly detecting only a small part of the cell lines sensitive to the drug). Regarding overall classification performance, about two thirds of the drugs are better predicted by the multi-gene RF classifiers. Among the drugs with the most predictive of these models, we found pyrimethamine, sunitinib and 17-AAG. Conclusions: Thanks to this unbiased validation, we now know that this type of models can predict in vitro tumour response to some of these drugs. These models

  9. Drugs use pattern for uncomplicated malaria in medicine retail outlets in Enugu urban, southeast Nigeria: implications for malaria treatment policy.

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    Ezenduka, Charles C; Ogbonna, Brian O; Ekwunife, Obinna I; Okonta, Mathew J; Esimone, Charles O

    2014-06-24

    Malaria treatment policy recommends regular monitoring of drug utilization to generate information for ensuring effective use of anti-malarial drugs in Nigeria. This information is currently limited in the retail sector which constitutes a major source of malaria treatment in Nigeria, but are characterized by significant inappropriate use of drugs. This study analyzed the use pattern of anti-malarial drugs in medicine outlets to assess the current state of compliance to policy on the use of artemisinin-based combination therapy (ACT). A prospective cross-sectional survey of randomly selected medicine outlets in Enugu urban, southeast Nigeria, was conducted between May and August 2013, to determine the types, range, prices, and use pattern of anti-malarial drugs dispensed from pharmacies and patent medicine vendors (PMVs). Data were collected and analyzed for anti-malarial drugs dispensed for self-medication to patients, treatment by retail outlets and prescription from hospitals. A total of 1,321 anti-malarial drugs prescriptions were analyzed. ACT accounted for 72.7%, while monotherapy was 27.3%. Affordable Medicines Facility-malaria (AMFm) drugs contributed 33.9% (326/961) of ACT. Artemether-lumefantrine (AL), 668 (50.6%) was the most used anti-malarial drug, followed by monotherapy sulphadoxine-pyrimethamine (SP), 248 (18.8%). Median cost of ACT at $2.91 ($0.65-7.42) per dose, is about three times the median cost of monotherapy, $0.97 ($0.19-13.55). Total cost of medication (including co-medications) with ACT averaged $3.64 (95% CI; $3.53-3.75) per prescription, about twice the mean cost of treatment with monotherapy, $1.83 (95% CI; $1.57-2.1). Highest proportion 46.5% (614), of the anti-malarial drugs was dispensed to patients for self-treatment. Treatment by retail outlets accounted for 35.8% while 17.7% of the drugs were dispensed from hospital prescriptions. Self-medication, 82%, accounted for the highest source of monotherapy and a majority of prescriptions

  10. Isolation and identification of an antiparasitic triterpenoid estersaponin from the stem bark of Pittosporum mannii (Pittosporaceae

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    Kennedy D Nyongbela

    2013-10-01

    Full Text Available Objective: To screen for antiparasitic properties of Pittosporum mannii Hook (Pittosporaceae through in vitro bioassay tests and to identify the bioactive compound(s. Methods: The stem bark of Pittosporum mannii was harvested in Bali Nyonga in January 2007. The CH 2Cl2 and MeOH extracts were tested in vitro for antiparasitic activity. NF54 (an airport strain of unknown origin and sensitive to all known drugs and K1 (a clone originating from Thailand and resistant to chloroquine/pyrimethamine strains were used for the antiplasmodial screening while Leishmania donovani MHOM-ET-67/L82 was used for antileishmanial testing. 1H and 13C NMR spectra were recorded on a Bruker AMX-500 spectrometer using CDCl3 as solvent. EIMS were recorded on a double-focusing mass spectrometer (Varian MAT 311A while HREIMS were recorded on a JEOL HX 110 mass spectrometer. Results: The MeOH extract was active on both the chloroquine-resistant (K1 strain (IC50=4.3 μg/ mL and on the macrophages of Leishmania donovani (IC50=8.6 μg/mL. The CH2Cl2 extract was considered inactive on both parasites (IC50>5.0 μg/mL and 21.7 μg/mL respectively. Compound 1, a constituent that precipitated from the MeOH extract, showed pronounced activity on both Plasmodium falciparum and Leishmania donovani parasites (IC 50=1.02 and 1.80 μg/mL respectively with artemisinin and miltefosine included as reference drugs. Its structure was identified as 1-O-[apha-L-(Rhamnopyranosyl]-23-acetoxyimberbic acid 29-methyl ester, a pentacyclic triterpenoid estersaponin. Conclusions: The present study constitutes the first report on the antiparasitic activity of this plant and provides some support for the traditional use of the plant in the treatment of malaria. The plant has therefore been identified as a potential source for the discovery of antiparasitic lead compounds.

  11. The challenges of changing national malaria drug policy to artemisinin-based combinations in Kenya

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    Otieno Dorothy N

    2007-05-01

    Full Text Available Abstract Backgound Sulphadoxine/sulphalene-pyrimethamine (SP was adopted in Kenya as first line therapeutic for uncomplicated malaria in 1998. By the second half of 2003, there was convincing evidence that SP was failing and had to be replaced. Despite several descriptive investigations of policy change and implementation when countries moved from chloroquine to SP, the different constraints of moving to artemisinin-based combination therapy (ACT in Africa are less well documented. Methods A narrative description of the process of anti-malarial drug policy change, financing and implementation in Kenya is assembled from discussions with stakeholders, reports, newspaper articles, minutes of meetings and email correspondence between actors in the policy change process. The narrative has been structured to capture the timing of events, the difficulties and hurdles faced and the resolutions reached to the final implementation of a new treatment policy. Results Following a recognition that SP was failing there was a rapid technical appraisal of available data and replacement options resulting in a decision to adopt artemether-lumefantrine (AL as the recommended first-line therapy in Kenya, announced in April 2004. Funding requirements were approved by the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM and over 60 million US$ were agreed in principle in July 2004 to procure AL and implement the policy change. AL arrived in Kenya in May 2006, distribution to health facilities began in July 2006 coincidental with cascade in-service training in the revised national guidelines. Both training and drug distribution were almost complete by the end of 2006. The article examines why it took over 32 months from announcing a drug policy change to completing early implementation. Reasons included: lack of clarity on sustainable financing of an expensive therapeutic for a common disease, a delay in release of funding, a lack of comparative efficacy data

  12. A comparison of malaria prevalence, control and management strategies in irrigated and non-irrigated areas in eastern Kenya.

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    Muriuki, John Muthii; Kitala, Philip; Muchemi, Gerald; Njeru, Ian; Karanja, Joan; Bett, Bernard

    2016-08-11

    This study was conducted in Bura irrigation scheme in Tana River County and the pastoral area in Ijara, Garissa County in the eastern Kenya to establish the knowledge, attitude and practices on malaria transmission, control and management, and determine malaria prevalence and the associated risk factors. A cross sectional survey design that involved 493 randomly selected people from 334 households was used between November and December 2013. All the randomly selected people were screened for malaria parasites using rapid diagnostic test (RDT)-Carestart™ malaria HRP2 (pf) kit. A questionnaire was administered to determine potential risk factors and perceptions on malaria exposure within a period of 2 months prior to the survey. Two logistic regression models were fitted to the data; one used the RDT results while the other used data from the questionnaire survey. Using RDT, the prevalence of malaria was 4.68 % (95 % CI: 1.48-7.88 %) and 0.31 % (-0.30 to 0.92 %) in irrigated and non-irrigated areas, respectively. From the questionnaires, 14.62 % (9.27-19.97 %) and 23.91 % (19.23-28.60 %) of the participants perceived to have had malaria in the irrigated and pastoral areas, respectively. The main malaria control measure was the use of bed nets: average of three nets per household in Bura irrigation scheme and one in Ijara. Artemether-lumefantrine was the main drug of choice mainly in the irrigated area while sulfadoxine-pyrimethamine was likely to be used in the non-irrigated area. Households located >5 km from the nearest health facility had higher prevalence of Plasmodium infection than those located ≤5 km. The residents of Bura irrigation scheme were more likely to be infected compared to those living in the non-irrigated area of Ijara. However, those in the non-irrigated area were more likely to be treated or use over-the-counter medication for perceived malaria illnesses compared to those in the irrigated area. There is a need, therefore, to

  13. Costs and cost-effectiveness of delivering intermittent preventive treatment through schools in western Kenya

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    Jukes Matthew CH

    2008-09-01

    Full Text Available Abstract Background Awareness of the potential impact of malaria among school-age children has stimulated investigation into malaria interventions that can be delivered through schools. However, little evidence is available on the costs and cost-effectiveness of intervention options. This paper evaluates the costs and cost-effectiveness of intermittent preventive treatment (IPT as delivered by teachers in schools in western Kenya. Methods Information on actual drug and non-drug associated costs were collected from expenditure and salary records, government budgets and interviews with key district and national officials. Effectiveness data were derived from a cluster-randomised-controlled trial of IPT where a single dose of sulphadoxine-pyrimethamine and three daily doses of amodiaquine were provided three times in year (once termly. Both financial and economic costs were estimated from a provider perspective, and effectiveness was estimated in terms of anaemia cases averted. A sensitivity analysis was conducted to assess the impact of key assumptions on estimated cost-effectiveness. Results The delivery of IPT by teachers was estimated to cost US$ 1.88 per child treated per year, with drug and teacher training costs constituting the largest cost components. Set-up costs accounted for 13.2% of overall costs (equivalent to US$ 0.25 per child whilst recurrent costs accounted for 86.8% (US$ 1.63 per child per year. The estimated cost per anaemia case averted was US$ 29.84 and the cost per case of Plasmodium falciparum parasitaemia averted was US$ 5.36, respectively. The cost per case of anaemia averted ranged between US$ 24.60 and 40.32 when the prices of antimalarial drugs and delivery costs were varied. Cost-effectiveness was most influenced by effectiveness of IPT and the background prevalence of anaemia. In settings where 30% and 50% of schoolchildren were anaemic, cost-effectiveness ratios were US$ 12.53 and 7.52, respectively. Conclusion This

  14. A cross-sectional study of the availability and price of anti-malarial medicines and malaria rapid diagnostic tests in private sector retail drug outlets in rural Western Kenya, 2013.

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    Kioko, Urbanus; Riley, Christina; Dellicour, Stephanie; Were, Vincent; Ouma, Peter; Gutman, Julie; Kariuki, Simon; Omar, Ahmeddin; Desai, Meghna; Buff, Ann M

    2016-07-12

    Although anti-malarial medicines are free in Kenyan public health facilities, patients often seek treatment from private sector retail drug outlets. In mid-2010, the Affordable Medicines Facility-malaria (AMFm) was introduced to make quality-assured artemisinin-based combination therapy (ACT) accessible and affordable in private and public sectors. Private sector retail drug outlets stocking anti-malarial medications within a surveillance area of approximately 220,000 people in a malaria perennial high-transmission area in rural western Kenya were identified via a census in September 2013. A cross-sectional study was conducted in September-October 2013 to determine availability and price of anti-malarial medicines and malaria rapid diagnostic tests (RDTs) in drug outlets. A standardized questionnaire was administered to collect drug outlet and personnel characteristics and availability and price of anti-malarials and RDTs. Of 181 drug outlets identified, 179 (99 %) participated in the survey. Thirteen percent were registered pharmacies, 25 % informal drug shops, 46 % general shops, 13 % homesteads and 2 % other. One hundred sixty-five (92 %) had at least one ACT type: 162 (91 %) had recommended first-line artemether-lumefantrine (AL), 22 (12 %) had recommended second-line dihydroartemisinin-piperaquine (DHA-PPQ), 85 (48 %) had sulfadoxine-pyrimethamine (SP), 60 (34 %) had any quinine (QN) formulation, and 14 (8 %) had amodiaquine (AQ) monotherapy. The mean price (range) of an adult treatment course for AL was $1.01 ($0.35-4.71); DHA-PPQ was $4.39 ($0.71-7.06); QN tablets were $2.24 ($0.12-4.71); SP was $0.62 ($0.24-2.35); AQ monotherapy was $0.42 ($0.24-1.06). The mean AL price with or without the AMFm logo did not differ significantly ($1.01 and 1.07, respectively; p = 0.45). Only 17 (10 %) drug outlets had RDTs; 149 (84 %) never stocked RDTs. The mean RDT price was $0.92 ($0.24-2.35). Most outlets never stocked RDTs; therefore, testing prior to

  15. User and Provider Acceptability of Intermittent Screening and Treatment and Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine to Prevent Malaria in Pregnancy in Western Kenya.

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    Hill, Jenny; Hoyt, Jenna; Achieng, Florence; Ouma, Peter; L'lanziva, Anne; Kariuki, Simon; Desai, Meghna; Webster, Jayne

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