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Sample records for chloroquine

  1. Chloroquine Is a Zinc Ionophore

    OpenAIRE

    Jing Xue; Amanda Moyer; Bing Peng; Jinchang Wu; Hannafon, Bethany N.; Wei-Qun Ding

    2014-01-01

    Chloroquine is an established antimalarial agent that has been recently tested in clinical trials for its anticancer activity. The favorable effect of chloroquine appears to be due to its ability to sensitize cancerous cells to chemotherapy, radiation therapy, and induce apoptosis. The present study investigated the interaction of zinc ions with chloroquine in a human ovarian cancer cell line (A2780). Chloroquine enhanced zinc uptake by A2780 cells in a concentration-dependent manner, as assa...

  2. Chloroquine Phosphate Oral

    Science.gov (United States)

    ... as a tablet to take by mouth. For prevention of malaria in adults, one dose is usually taken once ... a day for the next 2 days.For prevention and treatment of malaria in infants and children, the amount of chloroquine ...

  3. Chloroquine is a zinc ionophore.

    Directory of Open Access Journals (Sweden)

    Jing Xue

    Full Text Available Chloroquine is an established antimalarial agent that has been recently tested in clinical trials for its anticancer activity. The favorable effect of chloroquine appears to be due to its ability to sensitize cancerous cells to chemotherapy, radiation therapy, and induce apoptosis. The present study investigated the interaction of zinc ions with chloroquine in a human ovarian cancer cell line (A2780. Chloroquine enhanced zinc uptake by A2780 cells in a concentration-dependent manner, as assayed using a fluorescent zinc probe. This enhancement was attenuated by TPEN, a high affinity metal-binding compound, indicating the specificity of the zinc uptake. Furthermore, addition of copper or iron ions had no effect on chloroquine-induced zinc uptake. Fluorescent microscopic examination of intracellular zinc distribution demonstrated that free zinc ions are more concentrated in the lysosomes after addition of chloroquine, which is consistent with previous reports showing that chloroquine inhibits lysosome function. The combination of chloroquine with zinc enhanced chloroquine's cytotoxicity and induced apoptosis in A2780 cells. Thus chloroquine is a zinc ionophore, a property that may contribute to chloroquine's anticancer activity.

  4. Chloroquine-induced pruritus

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    Aghahowa S

    2010-01-01

    Full Text Available Chloroquine-induced pruritus remains one of the most common side-effects in the use of chloroquine in the prophylaxis and treatment of uncomplicated malaria before the advent of artemisinin-based combination therapies. It has been reported to vary from a tolerable to intolerable intensity among susceptible individuals resulting in disruption of treatment and development of resistance to the drug thus leading to therapeutic failures as reported. This scourge is quite challenging due to the complex physiologic mechanism that has not been fully elucidated. Factors observed to be responsible in the induction of pruritus such as age, race, heredity, density of parasitaemia; impurities in formulations, plasmodial specie, dosage form and metabolites have been discussed in this review. Efforts to ameliorate this burden have necessitated the use of drugs of diverse pharmacological classes such as antihistamines, corticosteroids and multivitamins either alone or as a combination. This review is to look into the use of chloroquine retrospectively, and consider its re-introduction due to its safety. Efficacy can be attained if the pruritic effect is resolved.

  5. Effect of chloroquine on human lymphocyte proliferation

    DEFF Research Database (Denmark)

    Bygbjerg, Ib Christian; Flachs, H

    1986-01-01

    The effect of chloroquine on human blood mononuclear cells was studied. High concentrations of chloroquine in vitro profoundly suppressed the proliferation of mitogen- and antigen-stimulated cells, as indicated by decreased 14C-thymidine incorporation. Lower concentrations of chloroquine increase...

  6. 3-Halo Chloroquine Derivatives Overcome Plasmodium falciparum Chloroquine Resistance Transporter-Mediated Drug Resistance in P. falciparum.

    Science.gov (United States)

    Edaye, Sonia; Tazoo, Dagobert; Bohle, D Scott; Georges, Elias

    2015-12-01

    Polymorphism in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistant P. falciparum. All three derivatives inhibited the proliferation of P. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant P. falciparum.

  7. Determination of chloroquine and monodesethylchloroquine in hair.

    Science.gov (United States)

    Viala, A; Deturmeny, E; Aubert, C; Estadieu, M; Durand, A; Cano, J P; Delmont, J

    1983-10-01

    Using thin-layer and gas chromatography and mass spectrometry, chloroquine and its major metabolite (monodesethylchloroquine) were identified in hair samples of numerous patients who received this antimalarial drug for several months. In two patients the amounts of chloroquine were, respectively, 310 and 145 mg/kg hair and those of the monodesethylchloroquine 23 and 11 mg/kg. The respective proportions (93 and 7%) are the same in the two subjects. The chloroquine percentage was near those in the spleen or stomach wall after poisoning. Other metabolites in hair are being identified. Hair analysis may provide a good toxicologic and forensic science complement to the blood, urine, and tissues. It may be useful for the control of chloroquine therapy. PMID:6631371

  8. Chloroquine use improves dengue-related symptoms

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    Marcos Carvalho Borges

    2013-08-01

    Full Text Available Dengue is the most important arboviral disease in the world. As chloroquine, an antimalarial agent, has shown some antiviral effects, this study evaluated its effect in patients with dengue. A randomised, double-blind study was performed by administering chloroquine or placebo for three days to 129 patients with dengue-related symptoms. Of these patients, 37 were confirmed as having dengue and completed the study; in total, 19 dengue patients received chloroquine and 18 received placebo. There was no significant difference in the duration of the disease or the degree and days of fever. However, 12 patients (63% with confirmed dengue reported a substantial decrease in pain intensity and a great improvement in their ability to perform daily activities (p = 0.0004 while on the medication and the symptoms returned immediately after these patients stopped taking the medication. The same effect was not observed in patients with diseases other than dengue. Therefore, this study shows that patients with dengue treated with chloroquine had an improvement in their quality of life and were able to resume their daily activities. However, as chloroquine did not alter the duration of the disease or the intensity and days of fever, further studies are necessary to confirm the clinical effects and to assess the side effects of chloroquine in dengue patients.

  9. In-vitro antimalarial activity of azithromycin against chloroquine sensitive and chloroquine resistant Plasmodium falciparum.

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    Biswas S

    2001-10-01

    Full Text Available BAKGROUND: The spread of drug resistance in Plasmodium falciparum has made the situation essential to look into new effective therapeutic agents like antibiotics. Azithromycin is a potential, chemotherapeutic agent which possesses antimalarial activity and favourable pharmacokinetic properties. It is an azalide microbiocide derived semi-synthetically from macrolide erythromycin. Like other antibiotics, the azalide azithromycin has ability to inhibit protein synthesis on 70S ribosomes. SETTINGS: Experimental study. SUBJECTS AND METHODS: The parasiticidal profile was studied in five chloroquine sensitive and five chloroquine resistant P. falciparum isolates obtained from various places of India. The antimalarial activity was evaluated in P. falciparum schizont maturation by short term culture for 24 hours and by exposing the parasites to the drug for 96 hours. Parasites synchronized at ring stage were put for culture with various concentrations of azithromycin dihydrate (0.01-40 micro/ml. RESULTS: At highest concentration (40 micro/ml, parasite growth was inhibited totally in all 10 isolates. Antimalarial activity at 96 hours was greater than at 24 hours in both chloroquine sensitive and resistant parasites, which may indicate that the inhibition of parasite growth may occur at clinically achievable concentration of the drug when parasites were exposed for several asexual cycles. CONCLUSION: Azithromycin shows a potential for eventual use alone or in combination in the treatment of chloroquine sensitive and resistant P. falciparum malaria.

  10. High-Dose Chloroquine for Treatment of Chloroquine-Resistant Plasmodium falciparum Malaria

    DEFF Research Database (Denmark)

    Ursing, Johan; Rombo, Lars; Bergqvist, Yngve;

    2016-01-01

    BACKGROUND:  Due to development of multidrug-resistant Plasmodium falciparum new antimalarial therapies are needed. In Guinea-Bissau, routinely used triple standard-dose chloroquine remained effective for decades despite the existence of "chloroquine-resistant" P. falciparum. This study aimed to...

  11. Reported side effects to chloroquine, chloroquine plus proguanil, and mefloquine as chemoprophylaxis against malaria in Danish travelers

    DEFF Research Database (Denmark)

    Petersen, E; Ronne, T; Ronn, A;

    2000-01-01

    BACKGROUND: The aim of the study was to provide data on the relative frequency of reported symptoms in travelers using chloroquine, chloroquine plus proguanil, and mefloquine. METHOD: The study was an open, nonrandomized study recording self-reported events in travelers recruited consecutively from...... two travel clinics in Copenhagen, Denmark. The main outcome measures were the relative proportion of travelers reporting particular symptoms in the three prophylaxis groups, compliance, hospitalization and premature termination of the travel. RESULTS: From May 1996 to April 1998 5, 446 travelers were...... included and 4,158 questionnaires (76.3%) returned. Compliance was significantly better in mefloquine users with 83.3% of short term travelers compared to 76.3% in chloroquine plus proguanil users. Also, 84.8%, 59.3% and 69.5% using chloroquine, chloroquine plus proguanil, and mefloquine respectively...

  12. Development of in-vitro radiometric assay for the rapid assessment of chloroquine resistant plasmodium vivax

    International Nuclear Information System (INIS)

    Previously, resistance of malaria parasite to chloroquine has been restricted only to Plasmodium falciparum. Recently, there have been many reports of chloroquine-resistant Plasmodium vivax. One of the mechanisms of chloroquine resistance is the decreased uptake of chloroquine or rapid efflux of the drug from the food vacuole of the parasite. In this study, we have measured the rapid efflux of IH-chloroquine in fifty blood samples from patients with P Vivax infection. All 50 patients were hospitalised for 28 days for the standard treatment with chloroquine. It was found that seven patients who did not respond to the standard regimen of chloroquine have parasites with rapid effluxes of IH-chloroquine. Since rapid effluxes of IH-chloroquine in the resistant parasites showed strong correlation with in vivo 28 days clinical trial, this assay could be used as rapid assessment of chloroquine resistance in patients with P vivax infection

  13. Hair analysis of an unusual case of Chloroquine intoxication.

    Science.gov (United States)

    Imran, Muhammad; Ashiq, Muhammad Zar; Shafi, Humera; Usman, Hafiz Faisal; Wattoo, Sardar Ali; Sarwar, Muhammad; Tahir, Muhammad Ashraf

    2016-03-01

    A dead body of middle aged man was exhumed from 6.5 month earth-grave. Autopsy findings were non-specific as the body was completely putrefied. Deceased's scalp hair and kidney was sent for toxicological analysis. Hair sample (50mg) was incubated with 1M NaOH (2 ml). Chloroquine was detected in hair and kidney during basic drug screen performed on GC/MS. For confirmation and quantitation, chloroquine was extracted using Hypersep verify CX SPE cartridges while mass detector was operated in SIM mode using the ions of m/z 245.0, 290.1, 319.0 for chloroquine while ions of m/z 260 and 455 were monitored for nalorphine (internal standard). Chloroquine was present in high concentration in hair (211 ng/mg) as well as in kidney (37.3mg/kg). Moreover, chloroquine was not detected in the wash solvents, suggesting ingestion of the drug rather than an external contamination of hair. These findings strongly suggested the acute exposure of higher doses of chloroquine to the deceased before death. PMID:26980246

  14. On the mechanism of chloroquine resistance in Plasmodium falciparum.

    KAUST Repository

    Chinappi, Mauro

    2010-11-19

    Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.

  15. Chloroquine mediated modulation of Anopheles gambiae gene expression.

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    Patrícia Abrantes

    Full Text Available BACKGROUND: Plasmodium development in the mosquito is crucial for malaria transmission and depends on the parasite's interaction with a variety of cell types and specific mosquito factors that have both positive and negative effects on infection. Whereas the defensive response of the mosquito contributes to a decrease in parasite numbers during these stages, some components of the blood meal are known to favor infection, potentiating the risk of increased transmission. The presence of the antimalarial drug chloroquine in the mosquito's blood meal has been associated with an increase in Plasmodium infectivity for the mosquito, which is possibly caused by chloroquine interfering with the capacity of the mosquito to defend against the infection. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we report a detailed survey of the Anopheles gambiae genes that are differentially regulated by the presence of chloroquine in the blood meal, using an A. gambiae cDNA microarray. The effect of chloroquine on transcript abundance was evaluated separately for non-infected and Plasmodium berghei-infected mosquitoes. Chloroquine was found to affect the abundance of transcripts that encode proteins involved in a variety of processes, including immunity, apoptosis, cytoskeleton and the response to oxidative stress. This pattern of differential gene expression may explain the weakened mosquito defense response which accounts for the increased infectivity observed in chloroquine-treated mosquitoes. CONCLUSIONS/SIGNIFICANCE: The results of the present study suggest that chloroquine can interfere with several putative mosquito mechanisms of defense against Plasmodium at the level of gene expression and highlight the need for a better understanding of the impacts of antimalarial agents on parasite transmission.

  16. Multifocal Electroretinography after High Dose Chloroquine Therapy for Malaria

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    Aline Correa de Carvalho

    2013-01-01

    Full Text Available Purpose: To investigate changes in multifocal electroretinography (mfERG parameters associated with high dose chloroquine therapy for treatment of malaria in the Amazonia region of Brazil. Methods: Forty-eight subjects who had received chloroquine treatment for single or multiple malaria infections with a cumulative dose ranging from 1,050 to 27,000mg were included. The control group consisted of 37 healthy aged-matched subjects. Data was collected on amplitude and implicit time of the N1, P1 and N2 waves in the central macular hexagon (R1 and in five concentric rings at different retinal eccentricities (R2-R6. Results: No significant difference was observed in any mfERG parameter between chloroquine treated patients and control subjects. A comparison with previous data obtained from patients with rheumatologic disorders in the same region of Brazil who had received larger cumulative doses of chloroquine and had displayed mfERG changes, indicated that retinal toxicity seems to be dependent on cumulative dose. Conclusion: Lack of mfERG changes in the current study suggests that intensive high dose chloroquine therapy for treatment of malaria is not associated with retinal toxicity.

  17. Chloroquine is grossly overdosed and overused but well tolerated in Guinea-Bissau

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia;

    2009-01-01

    High chloroquine doses are commonly prescribed in Guinea-Bissau. Double dose chloroquine has been shown to be more efficacious (92% efficacy) than the standard dose (80% efficacy). However, chloroquine is toxic when overdosed and it is not known if the high doses prescribed in Guinea-Bissau are...... recorded. Chloroquine intake and adverse events were assessed by questioning. Chloroquine concentrations were measured in whole blood. The median total chloroquine dose prescribed and that reportedly taken was 81 and 77 mgkg(-1) respectively. The total dose was usually split into 2-3 daily doses of 6.......6 mgkg(-1) each. These were taken unsupervised for median of 5 days. Forty percent of the study children had chloroquine concentrations in the same range as those found in a previous study in which double the normal dose (50mgkg(-1)) of chloroquine was taken. Only 3/102 children had P. falciparum in the...

  18. In vivo confocal microscopy in chloroquine-induced keratopathy

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    Iacopo Paladini

    2013-01-01

    Full Text Available In vivo confocal microscopy is becoming a mandatory examination to study corneal abnormalities such as drug deposits in systemic disease. A female diagnosed with fibromyalgia on systemic chloroquine for 9 months presented for an ophthalmic examination. Confocal microscopy was performed using the Confoscan 4 (Nidek Co. Ltd., Gamagori, Japan and multiple highly reflective deposits in the epithelial basal cells were found, that were consistent with choloquine. Deposits were also present in the wing cell layer. In the anterior stroma these deposits were rare. Atypically shaped and branched nerves were also present in the anterior stroma. Corneal deposits of chloroquine can be evaluated by confocal microscopy. Confocal microscopy provides information on corneal metabolism and physiology. Chloroquine keratopathy can affect the anterior stroma in addition to the epithelium.

  19. An investigation into the suitability of amidated pectin hydrogel beads as a delivery matrix for chloroquine.

    Science.gov (United States)

    Munjeri, O; Hodza, P; Osim, E E; Musabayane, C T

    1998-08-01

    The aim of the present study was to delay the release of chloroquine to distal parts of the gastrointestinal tract by using a multiparticulate hydrogel formulation. Amidated pectin chloroquine beads (PC) with varying pectin-to-chloroquine ratios (PC) w/w loadings of 4:1, 2:1, and 1:1 in the dried beads were prepared by the gelation of drug-loaded pectin solutions in the presence of calcium. In vitro release studies of chloroquine from pectin-chloroquine hydrogel beads and chloroquine diphosphate powder were carried out in simulated gastric and intestinal fluids. The total release of the entrapped chloroquine from the hydrogel beads was achieved between 4 and 7 h in simulated intestinal fluid, but total release was not achieved in simulated gastric fluid. However, total release from chloroquine diphosphate powder was achieved by 1.5 and 2 h in gastric and intestinal fluids, respectively. The plasma pharmacokinetics of chloroquine from pectin hydrogel beads and chloroquine diphosphate solution following single or repeated dosing were compared in male Sprague-Dawley rats over a period of 60 h. Oral administration of the hyrogel beads to rats produced maximum plasma concentrations by 7 h, but highest plasma concentrations following chloroquine solution administration were observed by 2 h. The dissolution data and appearance of significant plasma concentrations of chloroquine 2 to 4 h after oral administration suggests release in duodenum, jejunum, or ileum.

  20. Tritium labelling and characterization of the antimalarial drug (+/-)-chloroquine by several methods

    Energy Technology Data Exchange (ETDEWEB)

    Egan, J.A.Judith A.; Laseter, Anne G.; Filer, C.N.Crist N. E-mail: crist.filer@perkinelmer.com

    2002-09-01

    To study its mechanism of antimalarial action, a tritium labelled analogue of (+/-)-chloroquine was required at high specific activity. Two synthetic methods were successfully employed. [3-{sup 3}H] (+/-)-Chloroquine 2 was prepared by the catalytic tritium dehalogenation of an iodo precursor and [N-ethyl-{sup 3}H] (+/-)-chloroquine 4 was synthesized by the alkylation of (+/-)-desethylchloroquine with [{sup 3}H] ethyl iodide.

  1. 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...... 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...... chloroquine with proguanil hydrochloride and three taking chloroquine with sulfadoxine-pyrimethamine developed falciparum malaria, which was verified microscopically. Side effects were reported by 36 subjects taking chloroquine phosphate with proguanil hydrochloride and 55 taking the other regimen (p = 0...

  2. Effects of chloroquine on the adrenocortical function. II. Histological, histochemical and biochemical changes in the suprarenal gland of rats on long-term administration of chloroquine.

    Science.gov (United States)

    Grundmann, M; Bayer, A

    1976-01-01

    White female Wistar rats were used in order to study the influence of long-term oral application of 7-chloro-4-(4-diethylamino-1-methylbutylamino) quinoline (chloroquine) in doses of 30, 40 and 80 mg of base/kg upon the suprarenal gland. Histological, histochemical and biochemical findings give evidence of adrenocortical activation induced by chloroquine at all dose levels tested. The differences between the signs of adrenocortical activation as observed after the various doses were only those of quantity and time onset. The results indicate that the stimulation of the suprarenal cortex produced by repeated administration of chloroquine is not solely a manifestation of toxic action of chloroquine.

  3. Enhancement of naked FIX minigene expression by chloroquine in mice

    Institute of Scientific and Technical Information of China (English)

    Hong-yan CHEN; Huan-zhang ZHU; Bin LU; Xuan XU; Ji-hua YAO; Qi SHEN; Jing-lun XUE

    2004-01-01

    AIM: To study the effect of chloroquine on the expression of human clotting factor IX (hFIX) in mice. METHODS:Hydrodynamics-based naked DNA plasmid administration was performed by tail vein injection of 10 μg of pCMVhFIX and chloroquine (0, 100, 200, and 500 μmol/L) in 2.2 mL of Ringer' solution within 6-7 s, the level and stability of hFIX expression, liver damage and toxicity were then examined. RESULTS: The maximum expression of hFIX level was 4.4±-1.8 mg/L at 8 h after injection, 9.7±1.6 mg/L at 24 h only existed in 200 μmol/L chloroquinetreated animals, which is 3-4 fold higher than that of control (P<0.01). There is no significant difference observed among all the treated groups, 3 d later. Transaminase level and liver histological study showed the damage of liver was not related to chloroquine (P>0.05). CONCLUSION: Chloroquine can enhance and sustain exogenous gene expression in vivo without side effect under our experimental conditions.

  4. In vitro evaluation of marketed antimalarial chloroquine phosphate tablets

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    Amit K. Patel, Bhupendra G. Prajapati, Rubina S. Moria & Chhaganbhai N. Patel

    2005-12-01

    Full Text Available Background & objectives: The aim of the present study is to investigate the physicochemicalequivalence of seven brands of tablets containing chloroquine phosphate, an antimalarial purchasedfrom different retail pharmacy outlets.Methods: The quality and physicochemical equivalence of seven different brands of chloroquinephosphate tablets were assessed. The assessment included the evaluation of uniformity of weight,friability, crushing strength, disintegration and dissolution tests as well as chemical assay of thetablets.Results: All the seven brands of the tablets passed the British Pharmacopoeia (BP standards foruniformity of weight, disintegration and crushing strength. One of seven brands failed the friabilitytest. One of the brands did not comply with the standard assay of content of active ingredients.Dissolution test passes the pharmacopoeial standards for chloroquine phosphate tablets. There wereno significant differences in the amounts of chloroquine phosphate released from the different brands.Interpretation & conclusion: Out of the seven brands of anti-malarial chloroquine phosphate tabletsonly one brand fails to meet BP quality specifications which shows constant market monitoring ofnew products to ascertain their equivalency to pharmacopoeial standards.

  5. Chloroquine treatment of severe malaria in children. Pharmacokinetics, toxicity, and new dosage recommendations.

    Science.gov (United States)

    White, N J; Miller, K D; Churchill, F C; Berry, C; Brown, J; Williams, S B; Greenwood, B M

    1988-12-01

    Although empirical regimens of parenteral chloroquine have been used extensively to treat severe malaria for 40 years, recent recommendations state that parenteral chloroquine should no longer be used because of potential toxicity. We studied prospectively the pharmacokinetics and toxicity of seven chloroquine regimens in 58 Gambian children with severe chloroquine-sensitive falciparum malaria. In all regimens the total cumulative dose was 25 mg of chloroquine base per kilogram of body weight. Chloroquine was rapidly absorbed after either intramuscular or subcutaneous administration (5 mg of base per kilogram every 12 hours), producing high peak blood concentrations but transient hypotension in 5 of 18 patients (28 percent). Intermittent intravenous infusion (5 mg of base per kilogram over 4 hours, repeated every 12 hours) also produced wide fluctuations in chloroquine levels, suggesting incomplete distribution from a small central compartment. Continuous infusion (0.83 mg of base per kilogram per hour for 30 hours) and smaller, more frequent intramuscular or subcutaneous injections of chloroquine (3.5 mg of base per kilogram every 6 hours) produced smoother blood-concentration profiles with lower early peak levels and no adverse cardiovascular or neurologic effects. Chloroquine given by nasogastric tube (initial dose, 10 mg of base per kilogram) was absorbed well, even in comatose children. We conclude that simple alterations in dosage and frequency of administration can give parenteral chloroquine an acceptable therapeutic ratio and reinstate it as the treatment of choice for severe malaria in areas where chloroquine resistance is not a major problem.

  6. Effect of chloroquine on feline infectious peritonitis virus infection in vitro and in vivo.

    Science.gov (United States)

    Takano, Tomomi; Katoh, Yasuichiroh; Doki, Tomoyoshi; Hohdatsu, Tsutomu

    2013-08-01

    Feline infectious peritonitis (FIP) is a feline coronavirus-induced fatal disease in domestic and wild cats. Several studies have investigated potential treatments for FIP. However, there have been no reports on agents that have exhibited a therapeutic effect. Recently, chloroquine has been reported to antiviral effect. We investigated whether chloroquine can be used to treat FIP in vitro and in vivo. It was demonstrated that chloroquine has inhibitory effect against the replication of FIPV and anti-inflammatory effect in vitro. In vivo study using cats with experimentally induced FIP, the clinical score of chloroquine-treatment groups were better than in chloroquine-untreated group. However, alanine aminotransferase levels increased in the chloroquine-treated groups. It will be necessary to further investigate the possibility of FIP treatment with a combination of chloroquine and other agents.

  7. 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

  8. Transdermal delivery of chloroquine by amidated pectin hydrogel matrix patch in the rat.

    Science.gov (United States)

    Musabayane, C T; Munjeri, O; Matavire, T P

    2003-07-01

    The aim of the present study was to investigate the suitability of amidated pectin matrix patch for transdermal chloroquine delivery in an effort to mask the bitter taste when orally administered. Chloroquine has easily measurable outputs that are linked to increased renal Na+ excretion. We thus monitored urinary Na+ output in separate groups intravenously administered chloroquine or topically applied pectin hydrogel chloroquine matrix patch. Male groups of anesthetized Sprague-Dawley rats were placed on a continuous jugular infusion of 0.077 M NaCl at 150 microL min(-1). After 3 h equilibration period, consecutive 20 min urine collections were made over the subsequent 4 h of 1 h control, 1 h 20 min treatment, and 1 h 40 min recovery periods for measurements of urine flow and Na+ and K+ excretion rates. The effects of intravenous chloroquine infusion or topical application of pectin hydrogel chloroquine matrix patch were examined in rats in which the drug was added to the infusate or patch applied onto the shaved area during the 1 h 20 min treatment period. The animals were switched back to the infusate alone for the final 1 h 40 min recovery period. Vehicle infused animals acted as controls. Trunk blood was collected after the treatment period from parallel groups for chloroquine measurements. The plasma chloroquine concentrations following iv chloroquine or application of pectin chloroquine hydrogel matrix patch were 9.3 +/- 0.8 mg L(-1) and 7.3 +/- 1.1 mg L(-1) respectively (n = 7 in both groups). Chloroquine infusion and pectin chloroquine patch significantly (p pectin chloroquine patch matrix preparation has potential applications for transdermal delivery of chloroquine and perhaps in the management of malaria.

  9. Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine

    OpenAIRE

    Islahudin, Farida; Khozoie, Combiz; Bates, Steven; Ting, Kang-Nee; Pleass, Richard J.; Avery, Simon V.

    2013-01-01

    Chloroquine (CQ) has been a mainstay of antimalarial drug treatment for several decades. Additional therapeutic actions of CQ have been described, including some reports of fungal inhibition. Here we investigated the action of CQ in fungi, including the yeast model Saccharomyces cerevisiae. A genomewide yeast deletion strain collection was screened against CQ, revealing that bck1Δ and slt2Δ mutants of the cell wall integrity pathway are CQ hypersensitive. This phenotype was rescued with sorbi...

  10. Chloroquine is grossly under dosed in young children with malaria

    DEFF Research Database (Denmark)

    Ursing, Johan; Eksborg, Staffan; Rombo, Lars;

    2014-01-01

    BACKGROUND: Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy....../l. Adverse events were not age/concentration dependent. CONCLUSIONS: CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged

  11. Evaluation of Sensitivity of Plasmodium vivax to Chloroquine

    Directory of Open Access Journals (Sweden)

    Nateghpour M

    2007-09-01

    Full Text Available "nBackground: To monitor the current response of P. vivax to chloroquine in South and Southeast Iran."nMethods: The study was undertaken from August 2004 until August 2005 at the Bandar- Abbas, Iranshahr, Nikshahr and Chabahar districts. A total of 195 patients out of 225 parasitologically positive P. vivax cases completed the study .The patients were given a standard 3- day regimen of chloroquine and followed-up clinically and parasitologically accord­ing to the world Health Organization guideline with some modifications. Results of study were addressed as mean of parasite clearance time (MPCT. "nResults: The patients responded to the regimen of chloroquine within 24-120 hours. The MPCTs of P. vivax for Ban­dar- Abbas, Iranshahr, Nikshahr and Chabahar districts were 63.05(±15.37, 56(± 21.7, 70.92 (±6.51 and 58(±14 hours, respectively and for the whole study area (South and South East of Iran was 63.50(±15.84 hours. The results of the whole studied areas indicate that difference of MPCT between male and female patients is marginally significant (P=0.05."nConclusion: Although, parasite clearance time for a number of cases occurred within 96 and 120 hours, no P. vivax para­sites had reappeared in considered patients after day five within 28 days follow- up, reflecting that chloroquine is still an efficacious drug for the treatment of vivax malaria in the studied districts. Higher MPCT in Nikshahr district than the other districts indicating this could be an early sign for reduced susceptibility of the parasite to the drug.

  12. A thirteen-year analysis of Plasmodium falciparum populations reveals high conservation of the mutant pfcrt haplotype despite the withdrawal of chloroquine from national treatment guidelines in Gabon

    NARCIS (Netherlands)

    M. Frank; N. Lehners; P.I. Mayengue; J. Gabor; M. Dal-Bianco; D.U. Kombila; G.M. Ngoma; C. Supan; B. Lell; F. Ntoumi; M.P. Grobusch; K. Dietz; P.G. Kremsner

    2011-01-01

    Chloroquine resistance (CR) decreased after the removal of chloroquine from national treatment guidelines in Malawi, Kenia and Tanzania. In this investigation the prevalence of the chloroquine resistance (CQR) conferring mutant pfcrt allele and its associated chromosomal haplotype were determined be

  13. In vitro inhibition of human influenza A virus replication by chloroquine

    OpenAIRE

    Loh Jin; Chew Janet; Ooi Eng; Chua Robert CS

    2006-01-01

    Abstract Chloroquine is a 9-aminoquinolone with well-known anti-malarial effects. It has biochemical properties that could be applied to inhibit viral replication. We report here that chloroquine is able to inhibit influenza A virus replication, in vitro, and the IC50s of chloroquine against influenza A viruses H1N1 and H3N2 are lower than the plasma concentrations reached during treatment of acute malaria. The potential of chloroquine to be added to the limited range of anti-influenza drugs ...

  14. In vitro inhibition of human influenza A virus replication by chloroquine

    Directory of Open Access Journals (Sweden)

    Loh Jin

    2006-05-01

    Full Text Available Abstract Chloroquine is a 9-aminoquinolone with well-known anti-malarial effects. It has biochemical properties that could be applied to inhibit viral replication. We report here that chloroquine is able to inhibit influenza A virus replication, in vitro, and the IC50s of chloroquine against influenza A viruses H1N1 and H3N2 are lower than the plasma concentrations reached during treatment of acute malaria. The potential of chloroquine to be added to the limited range of anti-influenza drugs should be explored further, particularly since antiviral drugs play a vital role in influenza pandemic preparedness.

  15. 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

  16. Comparison of chloroquine with artesunate in the treatment of cerebral malaria in Ghanaian children

    DEFF Research Database (Denmark)

    Goka, B Q; Adabayeri, V; Ofori-Adjei, E;

    2001-01-01

    and neurological deficits were documented. There was no difference in mortality rates (chloroquine, 16.7 per cent; artesunate, 21.7 per cent; p = 0.6), neurological deficit at day 14 (chloroquine, 0 per cent; artesunate, 4.3 per cent; p = 0.3), resolution of fever (p = 0.55), and coma recovery time (p = 0...

  17. Chloroquine-Resistant Malaria in Travelers Returning from Haiti after 2010 Earthquake

    OpenAIRE

    Gharbi, Myriam; Dylan R Pillai; Lau, Rachel; Hubert, Véronique; Khairnar, Krishna; Existe, Alexandre; Kendjo, Eric; Dahlström, Sabina; Guérin, Philippe J; Le Bras, Jacques; ,

    2012-01-01

    We investigated chloroquine sensitivity to Plasmodium falciparum in travelers returning to France and Canada from Haiti during a 23-year period. Two of 19 isolates obtained after the 2010 earthquake showed mixed pfcrt 76K+T genotype and high 50% inhibitory concentration. Physicians treating malaria acquired in Haiti should be aware of possible chloroquine resistance.

  18. Chloroquine-resistant malaria in travelers returning from Haiti after 2010 earthquake.

    Science.gov (United States)

    Gharbi, Myriam; Pillai, Dylan R; Lau, Rachel; Hubert, Véronique; Khairnar, Krishna; Existe, Alexandre; Kendjo, Eric; Dahlström, Sabina; Guérin, Philippe J; Le Bras, Jacques

    2012-08-01

    We investigated chloroquine sensitivity to Plasmodium falciparum in travelers returning to France and Canada from Haiti during a 23-year period. Two of 19 isolates obtained after the 2010 earthquake showed mixed pfcrt 76K+T genotype and high 50% inhibitory concentration. Physicians treating malaria acquired in Haiti should be aware of possible chloroquine resistance. PMID:22840888

  19. Synergistic activity of chloroquine with fluconazole against fluconazole-resistant isolates of Candida species.

    Science.gov (United States)

    Li, Yali; Wan, Zhe; Liu, Wei; Li, Ruoyu

    2015-02-01

    The in vitro activity of chloroquine and the interactions of chloroquine combined with fluconazole against 37 Candida isolates were tested using the broth microdilution, disk diffusion, and Etest susceptibility tests. Synergistic effect was detected with 6 of 9 fluconazole-resistant Candida albicans isolates, with Candida krusei ATCC 6258, and with all 12 fluconazole-resistant Candida tropicalis isolates.

  20. Chloroquine inhibits accessory cell presentation of soluble natural and synthetic protein antigens

    DEFF Research Database (Denmark)

    Buus, S; Werdelin, O

    1984-01-01

    We have studied the in vitro effect of the lysosomotrophic agent, chloroquine, on the presentation of soluble protein antigens by guinea pig accessory cells. Chloroquine inhibited the capacity of antigen-pulsed accessory cells to stimulate proliferation in appropriately primed T cells. The effect...

  1. Optical coherence tomography in a patient with chloroquine-induced maculopathy

    Directory of Open Access Journals (Sweden)

    Korah Sanita

    2008-01-01

    Full Text Available We herein report the optical coherence tomography (OCT findings in a case of chloroquine-induced macular toxicity, which to our knowledge, has so far not been reported. A 53-year-old lady on chloroquine for treatment of rheumatoid arthritis developed decrease in vision 36 months after initiation of the treatment. Clinical examination revealed evidence of retinal pigment epithelial (RPE disturbances. Humphrey field analyzer (HFA, fundus fluorescein angiography (FFA and OCT for retinal thickness and volume measurements at the parafoveal region were done. The HFA revealed bilateral superior paracentral scotomas, FFA demonstrated RPE loss and OCT revealed anatomical evidence of loss of ganglion cell layers, causing marked thinning of the macula and parafoveal region. Parafoveal retinal thickness and volume measurements may be early evidence of chloroquine toxicity, and OCT measurements as a part of chloroquine toxicity screening may be useful in early detection of chloroquine maculopathy.

  2. Overcoming chloroquine resistance in malaria: Design, synthesis and structure-activity relationships of novel chemoreversal agents.

    Science.gov (United States)

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois; Dymock, Brian W; Tan, Kevin S W

    2016-08-25

    Malaria remains a significant infectious disease with even artemisinin-based therapies now facing resistance in the field. Development of new therapies is urgently needed, either by finding new compounds with unique modes of action, or by reversing resistance towards known drugs with 'chemosensitizers' or 'chemoreversal' agents (CRA). Concerning the latter, we have focused on the resistance mechanisms developed against chloroquine (CQ). We have synthesized a series of compounds related to previously identified CRAs, and found promising novel compounds. These compounds show encouraging results in a coumarin labeled chloroquine uptake assay, exhibiting a dose response in resensitising parasites to the antimalarial effects of chloroquine. Selected compounds show consistent potency across a panel of chloroquine and artemisinin sensitive and resistant parasites, and a wide therapeutic window. This data supports further study of CRAs in the treatment of malaria and, ultimately, their use in chloroquine-based combination therapies. PMID:27173385

  3. Plasmodium falciparum genotypes associated with chloroquine and amodiaquine resistance in Guinea-Bissau

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia;

    2007-01-01

    infections. The pfcrt 72-76 haplotypes were CVIET and CVMNK. The pfcrt 76T prevalence was 23% at day 0 and 96%, 83% and 100% at recrudescence following treatment with 25 mg/kg and 50 mg/kg of chloroquine and 15 mg/kg of amodiaquine respectively. When treating pfcrt 76T carrying P. falciparum the efficacy...... of 50 mg/kg and 25 mg/kg of chloroquine was 78% and 34% respectively (P = 0.007). The genetic basis of chloroquine resistance is probably the same in Guinea-Bissau as in the rest of Africa. The low pfcrt 76T prevalence suggests that resistance to normal dose chloroquine does not confer a major advantage...... to falciparum in Bissau and could be a result of treatment with high-dose chloroquine....

  4. Chloroquine Transport in Plasmodium falciparum II: Analysis of PfCRT Mediated Drug Transport Using Proteoliposomes and a Fluorescent Chloroquine Probe

    OpenAIRE

    Paguio, Michelle F.; Cabrera, Mynthia; Roepe, Paul D.

    2009-01-01

    Mutations in the PfCRT protein cause chloroquine resistance (CQR) and earlier studies from our laboratory using plasma membrane inside-out vesicles (ISOV) prepared from yeast expressing recombinant PfCRT [Zhang, H., et al. (2004) Biochemistry 43, 8290–8296] suggested that the putative transporter mediates downhill facilitated diffusion of charged chloroquine (CQ). However, more recent experiments with a fluorescent CQ probe (NBD-CQ) presented in the accompanying paper [Cabrera, M., et al. (20...

  5. Use of pre-packaged chloroquine for the home management of presumed malaria in Malagasy children

    Directory of Open Access Journals (Sweden)

    Malvy Denis

    2006-09-01

    Full Text Available Abstract Objective The main objective of this study was to assess the quality of home malaria management with pre-packaged chloroquine in two areas in the Moramanga district of Madagascar. The knowledge, attitude and practices of care providers in terms of home treatment options were evaluated and compared. The availability of treatment options by studying retailers and community-based service providers was also investigated. Methods A cross-sectional investigation in two communities, in the hamlets and villages located close to carers, retailers, community-based service providers and primary health centres was carried out. Results Carers in the two districts were equally well aware of the use of pre-packaged chloroquine. Their first response to the onset of fever was to treat children with this antimalarial drug at home. The dose administered and treatment compliance were entirely satisfactory (100% with pre-packaged chloroquine and rarely satisfactory (1.6% to 4.5% with non pre-packaged chloroquine. In cases of treatment failure, the carers took patients to health centres. Chloroquine was supplied principally by private pharmacies and travelling salesmen selling unpackaged chloroquine tablets. Non pre-packaged chloroquine was the most common drug used at health centres. The frequency of positive rapid malaria tests (P = 0.01 was significantly higher in children treated with non pre-packaged chloroquine (38% than in children treated with pre-packaged chloroquine (1.3%. Conclusion Home malaria management should be improved in Madagascar. Efforts should focus on communication, the training of community-based service providers, access to pre-packaged drugs and the gradual withdrawal of pre-packaged chloroquine and its replacement by pre-packaged artemisinin-based combination therapies.

  6. Evaluation of chloroquine therapy for vivax and falciparum malaria in southern Sumatra, western Indonesia

    Directory of Open Access Journals (Sweden)

    Laihad Ferdinand

    2010-02-01

    Full Text Available Abstract Background Chloroquine was used as first-line treatment for Plasmodium falciparum or Plasmodium vivax in Indonesia before the initial launch of artemisinin combination therapy in 2004. A study to evaluate efficacies of chloroquine against P. falciparum and P. vivax was undertaken at Lampung in southern Sumatra, western Indonesia in 2002. Methods Patients infected by P. falciparum or P. vivax were treated with 25 mg/kg chloroquine base in three daily doses over 48 hr. Finger prick blood was collected on Days 0, 2, 3, 7, 14, 21 and 28 after starting drug administration. Whole blood chloroquine and its desethyl metabolite were measured on Days-0, -3 and -28, or on the day of recurrent parasitaemia. Results 42 patients infected by P. falciparum were enrolled, and 38 fullfilled criteria for per protocol analysis. Only six of 38 (16% showed a response consistent with senstivity to chloroquine. 25 of 32 failures were confirmed resistant by demonstrating chloroquine levels on day of recurrence exceeding the minimally effective concentration (200 ng/mL whole blood. The 28-day cumulative incidence of resistance in P. falciparum was 68% (95% CI: 0.5260 - 0.8306. Thirty one patients infected by P. vivax were enrolled, and 23 were evaluable for per protocol analysis. 15 out of 23 (65% subjects had persistent or recurrent parasitaemia. Measurement of chloroquine levels confirmed all treatment failures prior to Day-15 as resistant. Beyond Day-15, 4 of 7 recurrences also had drug levels above 100 ng/mL and were classified as resistant. The 28-day cumulative incidence of chloroquine resistance in P. vivax was 43% (95% CI: 0.2715 - 0.6384. Conclusion These findings confirm persistantly high levels of resistance to chloroquine by P. falciparum in southern Sumatra, and suggest that high-grade and frequent resistance to chloroquine by P. vivax may be spreading westward in the Indonesia archipelago.

  7. 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...

  8. Color vision loss in patients treated with chloroquine

    Directory of Open Access Journals (Sweden)

    Ventura Dora F.

    2003-01-01

    Full Text Available Patients that make use of chloroquine or hydroxychloroquine, drugs which are frequently administered for treatment of rheumatoid arthritis, lupus erithromatosus or malaria, may suffer alterations in color vision and in contrast sensitivity. The present work evaluates the visual function of these patients in a joint study of the University of São Paulo (USP, in São Paulo, and of the Federal University of Pará (UFPA, in Belém. Thirty two chloroquine user patients without alterations in the eye fundus exam were evaluated in São Paulo (n=10; aged 38 to 71 years; mean=55,8 years and in Belém (n=22; aged 20 to 67; mean=40 years. The prescribed accumulated chloroquine dose was 45 to 430 g (mean=213 g; sd = 152 g for the São Paulo group, and 36 to 540 g (mean=174 g; sd=183 g for the Belém group. Tests were performed monocularly with corrected eye refractive state. Color discrimination was evaluated using the Cambridge Colour Test (CCT: the color discrimination threshold was measured first in the protan, deutan and tritan axes and, in succession, three MacAdam's ellipses were determined. The patient's color vision was also evaluated with color arrangement tests: the Farnsworth-Munsell 100 Hue (FM100, the Farnsworth-Munsell D15, and the Lanthony Desaturated (D15d tests. We also measured the contrast sensitivity for black-and-white sine wave grating of twenty two patients. The results were compared with controls without ophthalmologic or neuro-ophthalmologic pathologies. Twenty four patients presented acquired dyschromatopsia. There were cases of selective loss (11 patients and of diffuse loss (13 patients. Although losses were present in the FM100 there was no correlation between the FM100 error score and the ellipse area measured by the CCT. Moreover, three patients that scored normal in the FM100, failed to reach normal threshold in the CCT. The Lanthony test was less sensitive than the other two tests, since it failed to indicate loss in about

  9. 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...... at the molecular level in selected sites in Senegal, because the scientific community is interested in using CQ again. Finger prick blood samples were collected from Plasmodium falciparum-positive children below the age of 10 years (N = 474) during cross-sectional surveys conducted in two study sites in Senegal...... with different malaria transmission levels. One site is in central Senegal, and the other site is in the southern part of the country. All samples were analyzed for single nucleotide polymorphisms (SNPs) in the P. falciparum CQ resistance transporter gene (Pfcrt; codons 72-76) using polymerase chain reaction...

  10. Chitosan conjugated chloroquine: proficient to protect the induction of liver apoptosis during malaria.

    Science.gov (United States)

    Tripathy, Satyajit; Chattopadhyay, Sourav; Dash, Sandeep Kumar; Chowdhuri, Angshuman Ray; Das, Sabyasachi; Sahu, Sumanta Kumar; Majumdar, Subrata; Roy, Somenath

    2015-03-01

    Chitosan has impelled continuous motion by its unique physicochemical and biological characteristics. In our study, chitosan-tripolyphosphate (CS-TPP) particles was conjugated with an undervalued antimalarial drug, chloroquine to find out the proficiency against ROS mediated caspase activation and apoptosis in liver during Plasmodium berghei NK65 infection. The transmission electron microscopic image illustrated the size range of particle was less than 50 nm and the particle showed the blood compatibility. ROS generation, mitochondrial membrane potential, anti apoptotic and pro apoptotic protein level of CS-TPP conjugated chloroquine treated group revealed that CS-TPP conjugation amplified the protective capability of chloroquine. FACS study by annexin v-FITC and PI staining reveals chloroquine treatment reduces significantly (Pnanoparticles to portray defense possessions against malarial damage.

  11. Pretreatment blood concentrations of chloroquine in patients with malaria infection: relation to response to treatment

    DEFF Research Database (Denmark)

    Quashie, Neils Ben; Akanmori, Bartholomew D; Goka, Bamenla Q;

    2005-01-01

    Resistance of Plasmodium falciparum to chloroquine has been reported in many areas in Ghana. Most of these reports, which are from hospital-based studies, indicate RI and RII rather than RIII type of resistance. Since high pretreatment levels of chloroquine have also been measured in patients...... with malaria infection in Ghana, we hypothesized that the 'added effect' of the pretreatment ingested drug to the full dose given at the hospital may be responsible for the low proportion of RIII type of resistance observed. To ascertain this, pretreatment blood levels of chloroquine were correlated...... and day 0 parasitaemia. Two hundred and seven patients (89.6 per cent) had parasites that were sensitive to chloroquine whilst 24 (10.4 per cent) had resistant parasites. Of the latter group 17, six, and one patients had P. falciparum parasites, which were resistant at RI, RII and RIII levels...

  12. Chloroquine mediated molecular tuning of astrocytes for enhanced permissiveness to HIV infection

    OpenAIRE

    Vijaykumar, Theophilus S.; Nath, Avindra; Chauhan, Ashok

    2008-01-01

    We report in this study that minimum productive HIV infection in astrocytes (a predominant cell type in brain and persists for the entire life) occurs through endocytosis. The lysosomotropic agent chloroquine enhanced permissiveness of astrocytes to HIV infection possibly by circumventing degradation of endosome-entrapped viral particles. In particular, chloroquine may promote establishment of a stable long term viral reservoir in astrocytes and may eventually facilitate early onset of neurol...

  13. Binding of chloroquine to ionic micelles: Effect of pH and micellar surface charge

    Energy Technology Data Exchange (ETDEWEB)

    Souza Santos, Marcela de, E-mail: marcelafarmausp77@gmail.com [Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, São Paulo 14040-903 (Brazil); Perpétua Freire de Morais Del Lama, Maria, E-mail: mpemdel@fcfrp.usp.br [Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, São Paulo 14040-903 (Brazil); Instituto Nacional de Ciência e Tecnologia de Bioanalítica, Departamento de Química Analítica, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, s/n, Campinas, São Paulo 13083-970 (Brazil); Siuiti Ito, Amando, E-mail: amandosi@ffclrp.usp.br [Departamento de Física, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo 14040-901 (Brazil); and others

    2014-03-15

    The pharmacological action of chloroquine relies on its ability to cross biological membranes in order to accumulate inside lysosomes. The present work aimed at understanding the basis for the interaction between different chloroquine species and ionic micelles of opposite charges, the latter used as a simple membrane model. The sensitivity of absorbance and fluorescence of chloroquine to changes in its local environment was used to probe its interaction with cetyltrimethylammonium micelles presenting bromide (CTAB) and sulfate (CTAS) as counterions, in addition to dodecyl sulfate micelles bearing sodium (SDS) and tetramethylammonium (TMADS) counterions. Counterion exchange was shown to have little effect on drug–micelle interaction. Chloroquine first dissociation constant (pKa{sub 1}) shifted to opposite directions when anionic and cationic micelles were compared. Chloroquine binding constants (K{sub b}) revealed that electrostatic forces mediate charged drug–micelle association, whereas hydrophobic interactions allowed neutral chloroquine to associate with anionic and cationic micelles. Fluorescence quenching studies indicated that monoprotonated chloroquine is inserted deeper into the micelle surface of anionic micelles than its neutral form, the latter being less exposed to the aqueous phase when associated with cationic over anionic assemblies. The findings provide further evidence that chloroquine–micelle interaction is driven by a tight interplay between the drug form and the micellar surface charge, which can have a major effect on the drug biological activity. -- Highlights: • Chloroquine (CQ) pKa{sub 1} increased for SDS micelles and decreased for CTAB micelles. • CQ is solubilized to the surface of both CTAB and SDS micelles. • Monoprotonated CQ is buried deeper into SDS micelles than neutral CQ. • Neutral CQ is less exposed to aqueous phase in CTAB over SDS micelles. • Local pH and micellar surface charge mediate interaction of CQ with

  14. Effect of Crocus sativus Stigma (saffron alone or in combination with chloroquine on chloroquine sensitive strain of Plasmodium berghei in mice

    Directory of Open Access Journals (Sweden)

    Pestechian Nader

    2015-10-01

    Full Text Available Introduction: In malaria treatment protocols, treatment failure or drug resistance of synthesized drugs like alkaloids related to quinine, and aminoquinolines are the main problems now. Therefore, discovering efficient drugs or combination therapy of blood schizonticidal drugs with different mechanisms or different targets in the parasite is a crucial effort to solve this problem. In this study, the effectiveness of Crocus sativus Stigma (saffron individually and in combination with chloroquine, was considered against chloroquine–sensitive strain of Plasmodium berghei.Methods: At the first stage, using 4 day suppressive Peter’s test in mice, ED50 and survival times of saffron methanol extract, and its aqueous and ethyl acetate fractions and chloroquine on P. berghei were calculated. Then, based on the toxicity and survival time results, combination therapy was conducted with the best saffron fraction and chloroquine against the parasite.Results: The saffron extract, aqueous and ethyl acetate fractions resulted in suppression of parasitemia with ED50 values of 587.0 ± 78.7, 323.7 ± 37.2, and 508.7 ± 35.6 mg/kg, respectively. Combination of ethyl acetate fraction with chloroquine, potentiated the antimalarial property and the survived percent of the treated mice on days 7, 14, and 28 significantly more than chloroquine or ethyl acetate fraction alone.Conclusion: Saffron and its fractions individually can be effective in reducing the parasitemia in mice. The outcome of combination of ethyl acetate fraction with chloroquine on the mice showed synergistic effect on the chloroquine–sensitive strain of parasite.

  15. Antimalarial activity of Ageratum conyzoides in combination with chloroquine and artesunate

    Institute of Scientific and Technical Information of China (English)

    Ukwe Chinwe V; Ekwunife Obinna I; Epueke Ebele A; Ubaka Chukwuemeka M

    2010-01-01

    Objective: To determine the suppressive and curative activity of aqueous leaf extract of Ageratum conyzoides (A. conyzoides) in combination with chloroquine and artesunate, respectively against Plasmodium berghei infection in mice. Methods: Using malaria (Plasmodium berghei) infected albino mice of both sexes, aqueous extracts of A. conyzoides in combination with chloroquine and artesunate were tested for antimalarial activity, respectively. Four-day suppressive test and Rane's curative test were carried out. Results: Suppressive tests showed significant dose dependent reduction in parasitemia level produced by the extract-chloroquine and extract-artesunate combinations. Suppressive activities of both extract-drug combinations were greater than the individual drugs alone. Extract-chloroquine (100:5) produced the highest suppressive effect (98% suppression). Curative tests showed absolute survival in two extract-drug combinations. Two extract-drug combinations produced higher curative effects than the individual drugs alone. The highest dose combinations of extract-chloroquine (100:5) and extract-artesunate (100:5) produced absolute parasitemia clearance (cure) in the infected mice. Conclusions: The study indicated that aqueous extract of A. conyzoides had the ability to potentiate the antimalarial activity of chloroquine and artesunate against induced plasmodiasis in mice. It contributes a lot in the malaria endemic and poverty stricken tropics.

  16. Chloroquine resistant P. falciparum prevalence is low and unchanged between 1990 and 2005 in Guinea-Bissau

    DEFF Research Database (Denmark)

    Ursing, Johan; Schmidt, Berit Aydin; Lebbad, Marianne;

    2007-01-01

    and other genetic polymorphisms in samples from 1992, 1993, 1995, 2004 and 2005. We have also monitored drug prescriptions for febrile illnesses. The mean proportion of in vitro tests indicating chloroquine resistance was 33% (range 14-54%) with the exception of an outlying value year 2000. The proportion...... of chloroquine resistant P. falciparum detected by in vitro testing did not increase over time. Pfcrt 76T was associated with chloroquine resistance but pfmdr1 86Y was not. The mean pfcrt 76T prevalence varied between 13% and 38%. The prevalence of SNPs at Pfcrt positions 76, 271, 326 and pfmdr1 position 86 did...... of chloroquine resistant P. falciparum has not gradually increased between 1990 and 2005 in Guinea-Bissau. Chloroquine is commonly prescribed at more than double the normal dose in Guinea Bissau. It has previously been hypothesized that treatment with high doses of chloroquine may be effective. We discuss...

  17. Maculopatia tóxica por cloroquina Chloroquine toxic maculopathy

    Directory of Open Access Journals (Sweden)

    Nikias Alves da Silva

    2009-06-01

    Full Text Available O fosfato de cloroquina é uma droga largamente utilizada no tratamento de doenças crônicas de autoagressão, mais comumente no controle da artrite reumatóide, do lupus eritematoso discóide ou disseminado, da porfiria cutânea, da urticária solar e outras afecções dermatológicas. Embora a incidência de toxicidade retiniana por esta droga seja baixa, mesmo com o emprego da dose máxima recomendada, sua ocorrência tem grande relevância por acometer a região macular com importante e irreversível comprometimento visual. Trata-se no presente caso de uma paciente de 44 anos, portadora de artrite reumatóide há 19 anos, que fez uso de fosfato de cloroquina na dose de 250 mg/dia durante dois períodos de 4 e 3 anos, intercalados por um período de 8 anos em que usou methotrexate. Ao final do segundo período de uso da cloroquina, foi observada a maculopatia, a partir de quando a droga foi definitivamente substituída por methotrexate e prednisona. Por seu caráter típico e conspícuo, a maculopatia em questão se presta muito bem para ilustrar os achados dos principais métodos propedêuticos que devem ser empregados para caracterizá-la, inclusive a tomografia de coerência óptica.Chloroquine phosphate is widely used for the treatment of chronic autoimune diseases, most commonly rheumatoid arthritis, discoid or disseminated lupus erythematous, light sensitivity eruptions as well as other dermatologic affections. Although the incidence of retinal toxicity by this drug is low even with the maximally recomended dose, its occurrence is relevant because it damages the macula with an important and irreversible visual impairment. A 44-year-old white female patient who had suffered from rheumatoid arthritis for about 19 years had been under treatment with chloroquine phosphate in the daily dose of 250 mg during two periods of 4 and 3 years, intercalated by an 8-year period of methotrexate usage. At the end of the 3-year period, a maculopathy

  18. Chloroquine Improves Survival and Hematopoietic Recovery After Lethal Low-Dose-Rate Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Lim Yiting [Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Hedayati, Mohammad; Merchant, Akil A.; Zhang Yonggang; Yu, Hsiang-Hsuan M. [Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Kastan, Michael B. [Department of Oncology, St. Jude Children' s Research Hospital, Memphis, Tennessee (United States); Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina (United States); Matsui, William, E-mail: matsuwi@jhmi.edu [Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); DeWeese, Theodore L., E-mail: deweete@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

    2012-11-01

    Purpose: We have previously shown that the antimalarial agent chloroquine can abrogate the lethal cellular effects of low-dose-rate (LDR) radiation in vitro, most likely by activating the ataxia-telangiectasia mutated (ATM) protein. Here, we demonstrate that chloroquine treatment also protects against lethal doses of LDR radiation in vivo. Methods and Materials: C57BL/6 mice were irradiated with a total of 12.8 Gy delivered at 9.4 cGy/hour. ATM null mice from the same background were used to determine the influence of ATM. Chloroquine was administered by two intraperitoneal injections of 59.4 {mu}g per 17 g of body weight, 24 hours and 4 hours before irradiation. Bone marrow cells isolated from tibia, fibula, and vertebral bones were transplanted into lethally irradiated CD45 congenic recipient mice by retroorbital injection. Chimerism was assessed by flow cytometry. In vitro methylcellulose colony-forming assay of whole bone marrow cells and fluorescence activated cell sorting analysis of lineage depleted cells were used to assess the effect of chloroquine on progenitor cells. Results: Mice pretreated with chloroquine before radiation exhibited a significantly higher survival rate than did mice treated with radiation alone (80% vs. 31%, p = 0.0026). Chloroquine administration before radiation did not affect the survival of ATM null mice (p = 0.86). Chloroquine also had a significant effect on the early engraftment of bone marrow cells from the irradiated donor mice 6 weeks after transplantation (4.2% vs. 0.4%, p = 0.015). Conclusion: Chloroquine administration before radiation had a significant effect on the survival of normal but not ATM null mice, strongly suggesting that the in vivo effect, like the in vitro effect, is also ATM dependent. Chloroquine improved the early engraftment of bone marrow cells from LDR-irradiated mice, presumably by protecting the progenitor cells from radiation injury. Chloroquine thus could serve as a very useful drug for protection

  19. Polycyclic amines as chloroquine resistance modulating agents in Plasmodium falciparum.

    Science.gov (United States)

    Joubert, Jacques; Kapp, Erika; Taylor, Dale; Smith, Peter J; Malan, Sarel F

    2016-02-15

    Pentacycloundecylamines (PCUs) and adamantane amines, such as NGP1-01 (1) and amantadine, have shown significant channel blocking activities. They are postulated to act as chemosensitizers and circumvent the resistance of the plasmodia parasite against chloroquine (CQ) by inhibiting the p-glycoprotein efflux pump and enabling the accumulation of CQ inside the parasite digestive vacuole. Twelve polycyclic amines containing either a PCU or adamantane amine moiety conjugated to different aromatic functionalities through various tethered linkers were selected based on their channel blocking abilities and evaluated as potential chemosensitizers. Compounds 2, 4, 5 and 10 showed significant voltage-gated calcium channel (VGCC) blocking ability (IC50=0.27-35 μM) and were able to alter the CQ IC50 in differing degrees (45-81%) in the multidrug resistant Plasmodium falciparum Dd2 isolate. Among them, the PCU-dansyl amine compound (4) displayed the best potential to act as a chemosensitizer against the Dd2 strain at a 1 μM concentration (RMI=0.19) while displaying moderate antiplasmodial activity (Dd2 IC50=6.25 μM) and low in vitro cytotoxicity against a mammalian cell line (CHO, IC50=119 μM). Compounds 2 and 10 also showed some promising chemosensitizing abilities (RMI=0.36 and 0.35 respectively). A direct correlation was found between the VGCC blocking ability of these polycyclic amines and their capacity to act as CQ resistance modulating agents. PMID:26832222

  20. Polymorphism in the Plasmodium falciparum chloroquine-resistance transporter protein links verapamil enhancement of chloroquine sensitivity with the clinical efficacy of amodiaquine

    Directory of Open Access Journals (Sweden)

    Warhurst David C

    2003-09-01

    Full Text Available Abstract Background Chloroquine accumulates in the acidic digestive vacuole of the intraerythrocytic malaria parasite, and prevents the detoxication of haematin released during haemoglobin digestion. Changes in protein PfCRT in the digestive vacuole membrane of growing intra-erythrocytic stages of Plasmodium falciparum are crucial for resistance. Expressed in yeast, PfCRT resembles an anion channel. Depressed anion channel function could increase intralysosomal pH to reduce entry of basic drug, or enhanced function could reduce drug interaction with target haematin. The most important resistance-associated change is from positively-charged lysine-76 to neutral threonine which could facilitate drug efflux through a putative channel. It has been proposed that the resistance-reversing effect of verapamil is due to hydrophobic binding to the mutated PfCRT protein, and replacement of the lost positive charge, which repels the access of 4-aminoquinoline cations, thus partially restoring sensitivity. Desethylamodiaquine, the active metabolite of amodiaquine, which has significant activity in chloroquine-resistance, may also act similarly on its own. Methods Changes in physicochemical parameters in different CQ-resistant PfCRT sequences are analysed, and correlations with drug activity on lines transfected with different alleles of the pfcrt gene are examined. Results and conclusions The results support the idea that PfCRT is a channel which, in resistant parasites, can allow efflux of chloroquine from the digestive vacuole. Activity of the chloroquine/verapamil combination and of desethylamodiaquine both correlate with the mean hydrophobicity of PfCRT residues 72-76. This may partly explain clinical-resistance to amodiaquine found in the first chloroquine-resistant malaria cases from South America and enables tentative prediction of amodiaquine's clinical activity against novel haplotypes of PfCRT.

  1. Chloroquine Engages the Immune System to Eradicate Irradiated Breast Tumors in Mice

    International Nuclear Information System (INIS)

    Purpose: This study used chloroquine to direct radiation-induced tumor cell death pathways to harness the antitumor activity of the immune system. Methods and Materials: Chloroquine given immediately after tumor irradiation increased the cure rate of MCaK breast cancer in C3H mice. Chloroquine blocked radiation-induced autophagy and drove MCaK cells into a more rapid apoptotic and more immunogenic form of cell death. Results: Chloroquine treatment made irradiated tumor vaccines superior at inducing strong interferon gamma-associated immune responses in vivo and protecting mice from further tumor challenge. In vitro, chloroquine slowed antigen uptake and degradation by dendritic cells, although T-cell stimulation was unaffected. Conclusions: This study illustrates a novel approach to improve the efficacy of breast cancer radiation therapy by blocking endosomal pathways, which enhances radiation-induced cell death within the field and drives antitumor immunity to assist therapeutic cure. The study illuminates and merges seemingly disparate concepts regarding the importance of autophagy in cancer therapy

  2. Chloroquine Engages the Immune System to Eradicate Irradiated Breast Tumors in Mice

    Energy Technology Data Exchange (ETDEWEB)

    Ratikan, Josephine Anna [Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California (United States); Sayre, James William [Public Health Biostatistics/Radiology at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, California (United States); Schaue, Dörthe, E-mail: dschaue@mednet.ucla.edu [Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California (United States)

    2013-11-15

    Purpose: This study used chloroquine to direct radiation-induced tumor cell death pathways to harness the antitumor activity of the immune system. Methods and Materials: Chloroquine given immediately after tumor irradiation increased the cure rate of MCaK breast cancer in C3H mice. Chloroquine blocked radiation-induced autophagy and drove MCaK cells into a more rapid apoptotic and more immunogenic form of cell death. Results: Chloroquine treatment made irradiated tumor vaccines superior at inducing strong interferon gamma-associated immune responses in vivo and protecting mice from further tumor challenge. In vitro, chloroquine slowed antigen uptake and degradation by dendritic cells, although T-cell stimulation was unaffected. Conclusions: This study illustrates a novel approach to improve the efficacy of breast cancer radiation therapy by blocking endosomal pathways, which enhances radiation-induced cell death within the field and drives antitumor immunity to assist therapeutic cure. The study illuminates and merges seemingly disparate concepts regarding the importance of autophagy in cancer therapy.

  3. A Case Report of Suicide with Chloroquine Overdose and Review of Literature

    Directory of Open Access Journals (Sweden)

    Maryam Hosseini

    2016-09-01

    Full Text Available Background & Objective: Suicide is considered as the tenth cause of death worldwide. There are several suicide reports consist in the use of certain unusual drugs, such as chloroquine. Case report: The cadaver of a 25-year-old single woman was found dead in her home and with suspect to using toxins or drugs was brought to Fars Province Forensic administration. She had history of psychiatric problems for which had referred to psychologist several times. Results: After the autopsy, there was no observation of pathologic lesions in her samples of liver, kidney, or heart. In bile samples, using Thin Layer Chromatography (TLC and High Performance Liquid Chromatography (HPLC methods, chloroquine was detected. In visceral and gut samples, chloroquine was found using TLC as +4 reactions and it was confirmed by HPLC and Gas Chromatography Mass Spectrometry (GC-MS. After examining all the aspects, eventually chloroquine overdose and its complications was determined as the cause of the death. Conclusion: Due to the high incidence of suicide in depressed patients and according to family and previous positive experience, preventive strategies based on the recognition and the treatment of depressed patients and also teaching the families to diagnose the illness in addition to the limitation of the free access to chloroquine and similar drugs is suggested to reduce overdose complications or suicide.

  4. Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds.

    Science.gov (United States)

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois; Dymock, Brian W; Tan, Kevin S W

    2016-05-01

    Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria.

  5. Apoptosis of erythrocytic stage parasites of Plasmodium berghei chloroquine-resistant strain

    Institute of Scientific and Technical Information of China (English)

    CHEN Ke-qiang; SONG Guan-hong

    2002-01-01

    Objective: To explore the characteristics of crisis state at erythrocytic stage of Plasmodium berghei chloroquine-resistant (RC) strain. Methods: Agarose electrophoresis, optical and transmission electron microscopes were used. Patterns of genomic DNA structures and ultra-structures of the erythrocytic parasites were observed in ICA mice (infected with the RC strain) during rising and declining of parasitemia. Results: During the declining parasitemia, the erythrocytic stage parasites of the RC strain showed round or oval appearance with intact plasma membrane and shrank nuclei with no metabolic window, mitochondria or other membranaceous structures. Their DNA electrophoretogram revealed a ladder pattern which evidently differed from the parasites of the RC strain in the rising parasitemia and the chloroquine-sensitive (N) strain.Conclusion: The crisis state of the erythrocytic stage parasites of the P. berghei chloroquine-resistant (RC)strain is characterized by apoptosis.

  6. EFFECT OF SINGLE DOSE OF MINOCYCLINE ON A CHLOROQUINE RESISTANT FALCIPARUM INFECTION FROM BALIKPAPAN, KALIMANTAN

    Directory of Open Access Journals (Sweden)

    J. Verdrager

    2012-09-01

    Full Text Available Selain 3 kasus P. falciparum yang resistent terhadap chloroquine dari Samarinda (Verdrager & Arwati, 1974 baru-baru ini ditemukan lagi satu kasus juga dari Kalimantan Timur, tetapi dari daerah yang lain (Balikpapan. Terhadap kasus yang terakhir ini dilaksanakan sensitivity test sesuai dengan standar WHO. Disamping test tersebut, kepada penderita diberikan pula sensitivity test dengan 300 mg minocycline secara single dose. Minocycline yang merupakan derivat dari tetracyclin mempunyai khasiat anti malaria. Pengobatan radical dapat dicapai (pada 9 penderita sukarela yang menderita malaria strain tdari Vietnam sesudah 7 hari pengobatan. Dengan pemberian 300 mg minocycline base secara single dose, bentuk asexual dari parasite menghilang untuk jangka waktu 2 minggu. Effek ini sama dengan effek pemberian 1.500 mg chloroquine base, hanya hilangnya parasit bentuk asexual lebih lambat. Pemberian pengobatan dengan minocycline dengan jangka yang lebih lama sebagai yang dikemukakan oleh WHO (1975 mungkin dapat mengobati radikal strain P. falciparum yang resistent terhadap chloroquine.

  7. RESPONSE OF FALCIPARUM MALARIA TO A STANDARD REGIMEN OF CHLOROQUINE IN JAYAPURA, IRIAN JAYA

    Directory of Open Access Journals (Sweden)

    J. Verdrager

    2012-09-01

    Full Text Available Untuk pertama kalinya di Indonesia, resistensi chloroquine terhadap Plasmodium falciparum telah dilaporkan oleh J. Verdrager dan Arwati pada tahun 1974. Distribusi yang pasti tentang adanya resistensi chloroquine terhadap P. falciparum di Asia Tenggara, khususnya di Indonesia, belumlah begitu jelas. Akan tetapi kelihatannya resistensi ini terdapat di daerah-daerah dimana A. balabacensis sebagai vector. Faktor-faktor lain yang mempengaruhi resistensi ini ialah intensitas transmisi dan penggunaan obat-obat anti malaria yang meluas, terutama pada penduduk yang tak mempunyai kekebalan. Keadaan seperti digambarkan diatas terutama tentang intensitas transmisi yang cukup tinggi terdapat di Irian Jaya dimana vector utama adalah A. punctulatus group. Dari 35 penderita yang di-follow-up, diperoleh 7 orang yang resisten tingkat RI. Seorang diantaranya timbul bentuk asexual dari parasit pada hari ke-9, dan ke-enam lainnya pada hari ke-21 setelah makan obat chloroquine dengan dosis sesuai dengan standard WHO.

  8. Chloroquine resistance and Plasmodium falciparum in Punjab, Pakistan during 2000-2001.

    Science.gov (United States)

    Rana, Muhammad Saleem; Tanveer, Akhtar

    2004-06-01

    During the years 2000-2001, the rural populations of 5 districts in Punjab were examined for malarial parasites. The incidence of Plasmodium falciparum was more than double (8.98%) that of P. vivax (4.06%). The incidence was higher among male subjects (53.5%) than females (46.9%). The largest number of infected male subjects was found in Sheikhupura district (77.78%). Chloroquine resistance was only checked in the subjects harboring P. falciparum, using in vivo techniques. Overall chloroquine sensitivity was 63.8%. Overall frequency of chloroquine resistance in the 5 Punjabi districts was 35%, with 30.6% RI and 4.4% RII. It is important that RIII was not found in the present study. Among the five districts, maximum RI (35.1%) and RII (5.4%) were noted in Multan. By age, maximum chloroquine resistance was noted in the 1-5 year age group (ie RI, 41%; RII 8%). A similar RI value (41%) was noted for the 6-14 age group, but with a low RII (3%) value. Although, the present finding is an outcome of a survey conducted in only 5 districts of Punjab, it reflects an alarming situation, as not only RI and RII resistance against chloroquine is increasing, but at the same time the incidence of P. falciparum is increasing two-fold that of P. vivax. The findings warrant that top priority be given to determining the exact status of chloroquine resistance among P. falciparum in this region, which is now hosting a heavy influx of refugees from Afghanistan, a country endemic for P. falciparum. PMID:15691126

  9. Sensitivity of Plasmodium falciparum to chloroquine and sulfadoxine/pyrimethamine in Nigerian children.

    OpenAIRE

    Ekanem, O. J.; Weisfeld, J. S.; Salako, L A; Nahlen, B. L.; Ezedinachi, E. N.; Walker, O.; Breman, J. G.; Laoye, O. J.; Hedberg, K.

    1990-01-01

    The in vivo sensitivity of Plasmodium falciparum to chloroquine and sulfadoxine/pyrimethamine was evaluated in children under 5 years of age in two areas of southern Nigeria in 1987. A modification of the WHO Standard Field and Extended Tests (in vivo) was used, with follow-up on days, 2, 3, 7, and 14 after treatment with 25 mg chloroquine per kg body weight given over 3 days, or with standard doses of sulfadoxine/pyrimethamine. Clinical and parasitological evaluations were performed. At Igbo...

  10. Characterization of the commercially-available fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a marker for chloroquine resistance and uptake in a 96-well plate assay.

    Directory of Open Access Journals (Sweden)

    Cheryl C Y Loh

    Full Text Available Chloroquine was a cheap, extremely effective drug against Plasmodium falciparum until resistance arose. One approach to reversing resistance is the inhibition of chloroquine efflux from its site of action, the parasite digestive vacuole. Chloroquine accumulation studies have traditionally relied on radiolabelled chloroquine, which poses several challenges. There is a need for development of a safe and biologically relevant substitute. We report here a commercially-available green fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a proxy for chloroquine accumulation. This compound localized to the digestive vacuole of the parasite as observed under confocal microscopy, and inhibited growth of chloroquine-sensitive strain 3D7 more extensively than in the resistant strains 7G8 and K1. Microplate reader measurements indicated suppression of LynxTag-CQGREEN efflux after pretreatment of parasites with known reversal agents. Microsomes carrying either sensitive- or resistant-type PfCRT were assayed for uptake; resistant-type PfCRT exhibited increased accumulation of LynxTag-CQGREEN, which was suppressed by pretreatment with known chemosensitizers. Eight laboratory strains and twelve clinical isolates were sequenced for PfCRT and Pgh1 haplotypes previously reported to contribute to drug resistance, and pfmdr1 copy number and chloroquine IC50s were determined. These data were compared with LynxTag-CQGREEN uptake/fluorescence by multiple linear regression to identify genetic correlates of uptake. Uptake of the compound correlated with the logIC50 of chloroquine and, more weakly, a mutation in Pgh1, F1226Y.

  11. Distribution pattern of Plasmodium falciparum chloroquine transporter (pfcrt) gene haplotypes in Sri Lanka 1996-2006

    DEFF Research Database (Denmark)

    Zhang, Jenny J; Senaratne, Tharanga N; Daniels, Rachel;

    2011-01-01

    Abstract. Widespread antimalarial resistance has been a barrier to malaria elimination efforts in Sri Lanka. Analysis of genetic markers in historic parasites may uncover trends in the spread of resistance. We examined the frequency of Plasmodium falciparum chloroquine transporter (pfcrt; codons 72...

  12. Neuronal monoamine reuptake inhibitors enhance in vitro susceptibility to chloroquine in resistant Plasmodium falciparum.

    OpenAIRE

    Coutaux, A F; Mooney, J. J.; Wirth, D. F.

    1994-01-01

    Chloroquine resistance in Plasmodium falciparum was reversed in vitro by the neuronal monoamine reuptake inhibitors and antidepressants desipramine, sertraline, fluoxetine, and norfluoxetine but not by carbamazepine, an antiseizure and mood-stabilizing tricyclic drug resembling desipramine which only weakly inhibits neuronal monoamine reuptake. These findings have important clinical implications for drug combination therapy.

  13. 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

  14. Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter.

    Science.gov (United States)

    Petersen, Ines; Gabryszewski, Stanislaw J; Johnston, Geoffrey L; Dhingra, Satish K; Ecker, Andrea; Lewis, Rebecca E; de Almeida, Mariana Justino; Straimer, Judith; Henrich, Philipp P; Palatulan, Eugene; Johnson, David J; Coburn-Flynn, Olivia; Sanchez, Cecilia; Lehane, Adele M; Lanzer, Michael; Fidock, David A

    2015-07-01

    The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria.

  15. Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities.

    Science.gov (United States)

    Pulcini, Serena; Staines, Henry M; Lee, Andrew H; Shafik, Sarah H; Bouyer, Guillaume; Moore, Catherine M; Daley, Daniel A; Hoke, Matthew J; Altenhofen, Lindsey M; Painter, Heather J; Mu, Jianbing; Ferguson, David J P; Llinás, Manuel; Martin, Rowena E; Fidock, David A; Cooper, Roland A; Krishna, Sanjeev

    2015-01-01

    Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs.

  16. Chloroquine clinical failures in P. falciparum malaria are associated with mutant Pfmdr-1, not Pfcrt in Madagascar.

    Directory of Open Access Journals (Sweden)

    Valérie Andriantsoanirina

    Full Text Available Molecular studies have demonstrated that mutations in the Plasmodium falciparum chloroquine resistance transporter gene (Pfcrt play a major role in chloroquine resistance, while mutations in P. falciparum multidrug resistance gene (Pfmdr-1 act as modulator. In Madagascar, the high rate of chloroquine treatment failure (44% appears disconnected from the overall level of in vitro CQ susceptibility (prevalence of CQ-resistant parasites 60% of isolates, but did not explore their association with P. falciparum chloroquine resistance. To document the association of Pfmdr-1 alleles with chloroquine resistance in Madagascar, 249 P. falciparum samples collected from patients enrolled in a chloroquine in vivo efficacy study were genotyped in Pfcrt/Pfmdr-1 genes as well as the estimation of the Pfmdr-1 copy number. Except 2 isolates, all samples displayed a wild-type Pfcrt allele without Pfmdr-1 amplification. Chloroquine treatment failures were significantly associated with Pfmdr-1 86Y mutant codon (OR = 4.6. The cumulative incidence of recurrence of patients carrying the Pfmdr-1 86Y mutation at day 0 (21 days was shorter than patients carrying Pfmdr-1 86N wild type codon (28 days. In an independent set of 90 selected isolates, in vitro susceptibility to chloroquine was not associated with Pfmdr-1 polymorphisms. Analysis of two microsatellites flanking Pfmdr-1 allele showed that mutations occurred on multiple genetic backgrounds. In Madagascar, Pfmdr-1 polymorphism is associated with late chloroquine clinical failures and unrelated with in vitro susceptibility or Pfcrt genotype. These results highlight the limits of the current in vitro tests routinely used to monitor CQ drug resistance in this unique context. Gaining insight about the mechanisms that regulate polymorphism in Pfmdr1 remains important, particularly regarding the evolution and spread of Pfmdr-1 alleles in P. falciparum populations under changing drug pressure which may have important

  17. Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells

    International Nuclear Information System (INIS)

    Highlights: ► Chloroquine synergistically killed LNCaP cells during androgen deprivation treatment. ► Chloroquine inhibited the function of autolysosomes and decreases the cytosolic ATP. ► Chloroquine induced nuclear and DNA fragmentation in androgen deprived LNCaP. ► Chloroquine may be an useful adjuvant in hormone ablation therapy in PCa patients. -- Abstract: Modulation of autophagy is a new paradigm in cancer therapeutics. Recently a novel function of chloroquine (CLQ) in inhibiting degradation of autophagic vesicles has been revealed, which raises the question whether CLQ can be used as an adjuvant in targeting autophagic pro-survival mechanism in prostate cancer (PCa). We previously showed that autophagy played a protective role during hormone ablation therapy, in part, by consuming lipid droplets in PCa cells. In addition, blocking autophagy by genetic and pharmacological means in the presence of androgen deprivation caused cell death in PCa cells. To further investigate the importance of autophagy in PCa survival and dissect the role of CLQ in PCa death, we treated hormone responsive LNCaP cells with CLQ in combination with androgen deprivation. We observed that CLQ synergistically killed LNCaP cells during androgen deprivation in a dose- and time-dependent manner. We further confirmed that CLQ inhibited the maturation of autophagic vesicles and decreased the cytosolic ATP. Moreover, CLQ induced nuclear condensation and DNA fragmentation, a hallmark of apoptosis, in androgen deprived LNCaP cells. Taken together, our finding suggests that CLQ may be an useful adjuvant in hormone ablation therapy to improve the therapeutic efficacy.

  18. Assessment of proarrhythmic activity of chloroquine in in vivo and ex vivo rabbit models

    Directory of Open Access Journals (Sweden)

    Shailaja B Khobragade

    2013-01-01

    Full Text Available Objectives: To evaluate the prolongation of ventricular repolarization and proarrhythmic activity of antimalarial drug chloroquine in two rabbit proarrhythmia models viz., in vivo α1 adrenoceptor-stimulated anesthetized rabbit and ex vivo isolated Langendorff rabbit heart using clofilium as standard proarrhythmic agent. Materials and Methods: In the in vivo model, three groups of rabbits, anesthetized by pentobarbitone sodium and α-chloralose, sensitized with α1 agonist methoxamine followed by either continuous infusion of saline (control or clofilium (3 mg/kg or chloroquine (21 mg/kg for 30 min. In ex vivo model, rabbit hearts were perfused with clofilium (10 μM or chloroquine (300 μM continuously after priming along with methoxamine, acetylcholine chloride and propranolol hydrochloride. Results: In these models, prolongation of repolarization during α1 -adrenoceptor stimulation produced early after depolarization (EAD and Torsade de pointes (TdP. Saline infusion did not induce any abnormality in the animals. Clofilium caused expected changes in the electrocardiogram in both the models including TdP (50.0% in in vivo and 66.67% in ex vivo. Chloroquine caused decrease in heart rate and increase in the corrected QT (QTc interval in both the models. Further, apart from different stages of arrhythmia, TdP was evident in 33.33% in ex vivo model, whereas no TdP was observed in in vivo model. Conclusions: The results indicated that proarrhythmic potential of chloroquine and clofilium was well evaluated in both the models; moreover, both the models can be used to assess the proarrhythmic potential of the new drug candidates.

  19. Chloroquine treatment enhances regulatory T cells and reduces the severity of experimental autoimmune encephalomyelitis.

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    Rodolfo Thomé

    Full Text Available BACKGROUND: The modulation of inflammatory processes is a necessary step, mostly orchestrated by regulatory T (Treg cells and suppressive Dendritic Cells (DCs, to prevent the development of deleterious responses and autoimmune diseases. Therapies that focused on adoptive transfer of Treg cells or their expansion in vivo achieved great success in controlling inflammation in several experimental models. Chloroquine (CQ, an anti-malarial drug, was shown to reduce inflammation, although the mechanisms are still obscure. In this context, we aimed to access whether chloroquine treatment alters the frequency of Treg cells and DCs in normal mice. In addition, the effects of the prophylactic and therapeutic treatment with CQ on Experimental Autoimmune Encephalomyelitis (EAE, an experimental model for human Multiple Sclerosis, was investigated as well. METHODOLOGY/PRINCIPAL FINDINGS: EAE was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG35-55 peptide. C57BL/6 mice were intraperitoneally treated with chloroquine. Results show that the CQ treatment provoked an increase in Treg cells frequency as well as a decrease in DCs. We next evaluated whether prophylactic CQ administration is capable of reducing the clinical and histopathological signs of EAE. Our results demonstrated that CQ-treated mice developed mild EAE compared to controls that was associated with lower infiltration of inflammatory cells in the central nervous system CNS and increased frequency of Treg cells. Also, proliferation of MOG35-55-reactive T cells was significantly inhibited by chloroquine treatment. Similar results were observed when chloroquine was administrated after disease onset. CONCLUSION: We show for the first time that CQ treatment promotes the expansion of Treg cells, corroborating previous reports indicating that chloroquine has immunomodulatory properties. Our results also show that CQ treatment suppress the inflammation in the CNS of

  20. Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt.

    OpenAIRE

    Pelleau, Stéphane; Moss, Eli L; Dhingra, Satish K.; Volney, Béatrice; Casteras, Jessica; Gabryszewski, Stanislaw J.; Volkman, Sarah K.; Wirth, Dyann F.; Legrand, Eric; David A Fidock; Neafsey, Daniel E; Musset, Lise

    2015-01-01

    International audience; In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations ...

  1. The detection of pfcrt and pfmdr1 point mutations as molecular markers of chloroquine drug resistance, Pahang, Malaysia

    OpenAIRE

    Atroosh Wahib M; Al-Mekhlafi Hesham M; Mahdy Mohammed AK; Surin Johari

    2012-01-01

    Abstract Background Malaria is still a public health problem in Malaysia with chloroquine (CQ) being the first-line drug in the treatment policy of uncomplicated malaria. There is a scarcity in information about the magnitude of Plasmodium falciparum CQ resistance. This study aims to investigate the presence of single point mutations in the P. falciparum chloroquine-resistance transporter gene (pfcrt) at codons 76, 271, 326, 356 and 371 and in P. falciparum multi-drug resistance-1 gene (pfmdr...

  2. COMPARATIVE STUDY OF EFFECTIVENESS AND RESISTANCE PROFILE OF CHLOROQUINE AND SULFADOXINE - PYRIMETHAMINE IN UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA IN KOLKATA

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    Ayan

    2014-01-01

    Full Text Available Malaria is one of the major public health problems of the country. Factors responsible for re - emergence of malaria in India was due to emergence and spread of chloroquine resistant Plasmodium falciparum strains across the country coupled with steady rise in insecticide resistance of the vector mosquitoes. Very little is known about the drug resistance status of P. falciparum in India. As per National Vector Borne Diseases Control Programme (NVBDCP , chloroquine is the drug of choice for uncomplicated P. falciparum cases and the combination of Artesunate and Sulfadoxine - Pyrimethamine(SP is being used to treat the documented chloroquine resistant uncomplicated cases. To evaluate the comparative effecti veness and resistance profile of Chloroquine vis - à - vis Sulfadoxine - Pyrimethamine (SP in uncomplicated Plasmodium falciparum cases as the first line therapy a study was undertaken at the Malaria Clinic of School of Tropical Medicine , Kolkata during the per iod from July 2008 to January 2009 under Ward no. 44 of Kolkata Municipal Corporation. Following WHO protocol 2003 and WHO guideline 2006 , a total of 100 parasitologically confirmed Plasmodium falciparum cases were recruited as per the recruitment criteria . Among them , 50 patients were given Chloroquine and another 50 patients were given SP. Eight patients were excluded or lost to follow - up during the follow - up period because of failure to follow the protocol .It was observed that in the chloroquine group ou t of 50 patients , 30 (60% showed Adequate Clinical and Parasitological Response (ACPR , 15 (30% had Late Treatment Failure (LTF and remaining 5 (10% were lost during the follow up period (LFU. On the other hand in the SP group out of 50 patients , 46 ( 92% showed ACPR and only one (2% had LTF and 3 patients were LFU. The difference of LTF in Chloroquine and Sulfadoxine - pyrimethamine groups was statistically significant (p value 10% , Sulfadoxine - Pyrimethamine ca n be

  3. Chloroquine Interference with Hemoglobin Endocytic Trafficking Suppresses Adaptive Heme and Iron Homeostasis in Macrophages: The Paradox of an Antimalarial Agent

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    Christian A. Schaer

    2013-01-01

    Full Text Available The CD163 scavenger receptor pathway for Hb:Hp complexes is an essential mechanism of protection against the toxicity of extracellular hemoglobin (Hb, which can accumulate in the vasculature and within tissues during hemolysis. Chloroquine is a lysosomotropic agent, which has been extensively used as an antimalarial drug in the past, before parasite resistance started to limit its efficacy in most parts of the world. More recent use of chloroquine is related to its immunomodulatory activity in patients with autoimmune diseases, which may also involve hemolytic disease components. In this study we examined the effects of chloroquine on the human Hb clearance pathway. For this purpose we developed a new mass-spectrometry-based method to specifically quantify intracellular Hb peptides within the endosomal-lysosomal compartment by single reaction monitoring (SRM. We found that chloroquine exposure impairs trafficking of Hb:Hp complexes through the endosomal-lysosomal compartment after internalization by CD163. Relative quantification of intracellular Hb peptides by SRM confirmed that chloroquine blocked cellular Hb:Hp catabolism. This effect suppressed the cellular heme-oxygenase-1 (HO-1 response and shifted macrophage iron homeostasis towards inappropriately high expression of the transferrin receptor with concurrent inhibition of ferroportin expression. A functional deficiency of Hb detoxification and heme-iron recycling may therefore be an adverse consequence of chloroquine treatment during hemolysis.

  4. Binding Reaction of Hemin with Chloroquine, Quinine and Quinidine in Water-propylene Glycol Mixture

    Institute of Scientific and Technical Information of China (English)

    MAVAKALA,B.K; NLANDU,B.B.; MPIANA,P.T.; GUSHIMANA,Z.Y.; 尉志武

    2003-01-01

    the interaction of hemin with chloroquine,quinine and quinidine was investigated in 50% water-propylene glycol mixture at pH=9,8.1,7.4 and 6.8using a spectrophotometric method.The data could be well fitted into a model consistent with the formation of a 1:1 complex between the reacting partners.In addition,the results indicated that hemin complexed more strongly with quinidine than with chloroquine and quinine,and the binding constants were pH-dependent.Moreover,it was proved that the water-propylene glycol mixture is well suitable to the study of the systems containing hemin and quinolinebased drugs.

  5. Current understanding of the molecular basis of chloroquine-resistance in Plasmodium falciparum

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    Jiang H

    2006-01-01

    Full Text Available Chloroquine (CQ is the most successful antimalarial drug ever discovered. Unfortunately, parasites resistant to the drug eventually emerged after its large scale use and are now widespread. Although great progress in our understanding of the mechanisms of CQ action and CQ resistance (CQR has been achieved over the past two decades, including the identification of the molecules responsible for CQR (e.g., Plasmodium falciparum chloroquine resistant transporter, PfCRT many questions remain unanswered. Here we highlight recent advances in our understanding of the genetics and molecular mechanisms of CQR, with particular emphasis on the role of genes such as pfcrt and pfmdr1 in the resistance to CQ and other drugs. New drug development and applications will undoubtedly benefit from a better understanding of CQR, eventually leading to more effective malaria control measures.

  6. 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

  7. EFFECT OF CHLOROQUINE ON BLOOD GLUCOSE LEVELS IN PATIENTS WITH NON INSULIN DEPENDENT DIABETES MELLITUS

    OpenAIRE

    H. Mostafavi

    1998-01-01

    77irty six patients with non insulin dependent diabetes mellitus, whose blood sugar was not controlled with maximal doses of oral hypoglycemic agents and did not accept insulin treatment, were selected for this study. The patients were randomly divided into two groups, the treatment group and the control group. The treatment group received oral hypoglycemic agent and chloroquine (150 mg twice daily) and the control group received oral hypoglycemic agent and placebo for a period of six months....

  8. Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes

    OpenAIRE

    Gao MH; Xu YZ; Qiu LY

    2015-01-01

    Menghua Gao,1 Yuzhen Xu,1 Liyan Qiu2,3 1College of Pharmaceutical Sciences, 2Ministry of Education (MOE) Key Laboratory of Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 3Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract: A novel composite liposomal system co-encapsulating paclitaxel (PTX) with chloroquine phosphate (CQ) was d...

  9. Fundus auto fluorescence and spectral domain ocular coherence tomography in the early detection of chloroquine retinopathy

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    Megan B. Goodman

    2015-03-01

    Full Text Available Purpose: To determine the sensitivity of spectral domain ocular coherence tomography (SD-OCT and fundus auto fluorescence (FAF images as a screening test to detect early changes in the retina prior to the onset of chloroquine retinopathy.Method: The study was conducted using patients taking chloroquine (CQ, referred by the Rheumatology Department to the Ophthalmology Department at Tygerberg Academic Hospital. Group A consisted of 59 patients on CQ for less than 5 years, and Group B consisted of 53 patients on CQ for more than 5 years. A 200 × 200 macula thickness map, 5-line raster SD-OCT on a Carl Zeiss Meditec Cirrus HD-OCT and FAF images on a Carl Zeiss Meditec Visucam 500 were recorded for 223 eyes. Images were reviewed independently, and then those of Groups A and B compared.Results: There were no statistically significant differences between Groups A and B. The criteria included the internal limiting membrane and the retinal pigment epithelium (ILM-RPE thickness, interdigitation zone integrity (p = 0.891, df = 1, χ² = 0.1876, ellipsoid zone integrity (p = 0.095, df = 2, χ² = 4.699 and FAF image irregularities (p = 0.479, df = 1, χ²= 4995978.Conclusion: The inclusion of SD-OCT and FAF as objective tests into the prescribed screening guidelines does not appear to simplify the detection of subclinical injury in patients on chloroquine treatment.

  10. Comparative study of chloroquine and quinine on malaria rodents and their effects on the mouse testis

    Institute of Scientific and Technical Information of China (English)

    Esmail Abolghasemi; Seyed Hassan Moosa-Kazemi; Maryam Davoudi; Ahmad Reisi; Mohammad Taghi Satvat

    2012-01-01

    Objective: To evaluate the effects of quinine and chloroquine against male mice infected withPlasmodium berghei and their adverse effects on the mice testes. Methods: In this study, 48 adult male mice, (20-25 g), aged 8 to 12 weeks were divided into four groups. This study was carried out from December 2009 until May 2010 in the School of Public Health, Tehran University of Medical Sciences. Results: The results showed that 58.33% of mice treated with chloroquine were completely recovered. Parasitemia was 4% on day 8 when compared to that on day 0, whereas it was 9% on day 9. There was no orchitis found in this group. The mortality of mice after exposing to quinine on day 5 was 8.3%, whereas from day 10 to day 14 it was 91.7%. We found 75% orchitis occurred in quinine treated group. There was a significant difference between quinine and chloroquine effects on the parasite and also mice testes (P<0.05). Conclusions: In this study, It can be concluded that male mice have full resistance to the quinine. Quinine does not only make male mice recover completely, but also cause inflammation on mice testicles tissue.

  11. Similar Efficacy and Tolerability of Double-Dose Chloroquine and Artemether-Lumefantrine for Treatment of Plasmodium falciparum Infection in Guinea-Bissau: A Randomized Trial

    OpenAIRE

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia; Blessborn, Daniel; Thoft-Nielsen, Rikke; Björkman, Anders; Rombo, Lars

    2011-01-01

    Background. In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele, was routinely used. The present study compared the efficacy and tolerability of a double standard dose of chloroquine with the efficacy and tolerability of artemether-lumefantrine.

  12. No Genetic Bottleneck in Plasmodium falciparum Wild-Type Pfcrt Alleles Reemerging in Hainan Island, China, following High-Level Chloroquine Resistance▿

    OpenAIRE

    Chen, Nanhua; Gao, Qi; Wang, Shanqing; Wang, Guangze; Gatton, Michelle; Cheng, Qin

    2007-01-01

    Chloroquine-resistant Plasmodium falciparum was highly prevalent in Hainan, China, in the 1970s. Twenty-five years after cessation of chloroquine therapy, the prevalence of P. falciparum wild-type Pfcrt alleles has risen to 36% (95% confidence interval, 22.1 to 52.4%). The diverse origins of wild-type alleles indicate that there was no genetic bottleneck caused by high chloroquine resistance.

  13. Chloroquine Increases Glucose Uptake via Enhancing GLUT4 Translocation and Fusion with the Plasma Membrane in L6 Cells

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    Qi Zhou

    2016-05-01

    Full Text Available Background/Aims: Chloroquine can induce an increase in the cellular uptake of glucose; however, the underlying mechanism is unclear. Methods: In this study, translocation of GLUT4 and intracellular Ca2+ changes were simultaneously observed by confocal microscope in L6 cells stably over-expressing IRAP-mOrange. The GLUT4 fusion with the plasma membrane (PM was traced using HA-GLUT4-GFP. Glucose uptake was measured using a cell-based glucose uptake assay. GLUT4 protein was detected by Western blotting and mRNA level was detected by RT-PCR. Results: We found that chloroquine induced significant increases in glucose uptake, glucose transporter GLUT4 translocation to the plasma membrane (GTPM, GLUT4 fusion with the PM, and intracellular Ca2+ in L6 muscle cells. Chloroquine-induced increases of GTPM and intracellular Ca2+ were inhibited by Gallein (Gβγ inhibitor and U73122 (PLC inhibitor. However, 2-APB (IP3R blocker only blocked the increase in intracellular Ca2+ but did not inhibit GTPM increase. These results indicate that chloroquine, via the Gβγ-PLC-IP3-IP3R pathway, induces elevation of Ca2+, and this Ca2+ increase does not play a role in chloroqui-ne-evoked GTPM increase. However, GLUT4 fusion with the PM and glucose uptake were significantly inhibited with BAPTA-AM. This suggests that Ca2+ enhances GLUT4 fusion with the PM resulting in glucose uptake increase. Conclusion: Our data indicate that chloroquine via Gβγ-PLC-IP3-IP3R induces Ca2+ elevation, which in turn promotes GLUT4 fusion with the PM. Moreover, chloroquine can enhance GLUT4 trafficking to the PM. These mechanisms eventually result in glucose uptake increase in control and insulin-resistant L6 cells. These findings suggest that chloroquine might be a potential drug for improving insulin tolerance in diabetic patients.

  14. 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.

  15. Chloroquine Analog Interaction with C2- and Iota-Toxin in Vitro and in Living Cells

    Science.gov (United States)

    Kronhardt, Angelika; Beitzinger, Christoph; Barth, Holger; Benz, Roland

    2016-01-01

    C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the target cells. The enzymatic subunits are in both cases actin ADP-ribosyltransferases that modify R177 of globular actin finally leading to cell death. Following their binding to host cells’ receptors and internalization, the two binding components form heptameric channels in endosomal membranes which mediate the translocation of the enzymatic components Iota a and C2I from endosomes into the cytosol of the target cells. The binding components form ion-permeable channels in artificial and biological membranes. Chloroquine and related 4-aminoquinolines were able to block channel formation in vitro and intoxication of living cells. In this study, we extended our previous work to the use of different chloroquine analogs and demonstrate that positively charged aminoquinolinium salts are able to block channels formed in lipid bilayer membranes by the binding components of C2- and Iota-toxin. Similarly, these molecules protect cultured mammalian cells from intoxication with C2- and Iota-toxin. The aminoquinolinium salts did presumably not interfere with actin ADP-ribosylation or receptor binding but blocked the pores formed by C2IIa and Iota b in living cells and in vitro. The blocking efficiency of pores formed by Iota b and C2IIa by the chloroquine analogs showed interesting differences indicating structural variations between the types of protein-conducting nanochannels formed by Iota b and C2IIa. PMID:27517960

  16. Chloroquine Analog Interaction with C2- and Iota-Toxin in Vitro and in Living Cells.

    Science.gov (United States)

    Kronhardt, Angelika; Beitzinger, Christoph; Barth, Holger; Benz, Roland

    2016-01-01

    C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the target cells. The enzymatic subunits are in both cases actin ADP-ribosyltransferases that modify R177 of globular actin finally leading to cell death. Following their binding to host cells' receptors and internalization, the two binding components form heptameric channels in endosomal membranes which mediate the translocation of the enzymatic components Iota a and C2I from endosomes into the cytosol of the target cells. The binding components form ion-permeable channels in artificial and biological membranes. Chloroquine and related 4-aminoquinolines were able to block channel formation in vitro and intoxication of living cells. In this study, we extended our previous work to the use of different chloroquine analogs and demonstrate that positively charged aminoquinolinium salts are able to block channels formed in lipid bilayer membranes by the binding components of C2- and Iota-toxin. Similarly, these molecules protect cultured mammalian cells from intoxication with C2- and Iota-toxin. The aminoquinolinium salts did presumably not interfere with actin ADP-ribosylation or receptor binding but blocked the pores formed by C2IIa and Iota b in living cells and in vitro. The blocking efficiency of pores formed by Iota b and C2IIa by the chloroquine analogs showed interesting differences indicating structural variations between the types of protein-conducting nanochannels formed by Iota b and C2IIa. PMID:27517960

  17. Macrofilaricidal effects of chloroquine on adult Onchocerca volvulus by local infiltration of palpable onchocercal nodules

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    Ronald H. Guderian

    1997-12-01

    Full Text Available The macrofilaricidal effects of local infiltration of high concentrations of chloroquine into the capsule of onchocercal nodules on adult worms of Onchocerca volvulus was determined. Six weeks post infiltration, histological examination of single nodules showed all adult worms to be dead. With nodule conglomerates, there was localized action of chloroquine only on the adult worms in the infiltrated nodule, with no diffusion of the drug to adjacent nodules. Chloroquine infiltration of young, recently formed nodules to reduce the adult worm load of infected individuals may be an alternative method to costly nodulectomy.O efeito macrofilaricida da infiltração local, com uma alta concentração de cloroquina, dentro da cápsula do nódulo oncocercótico sobre o verme adulto de Onchocerca volvulus foi determinado. Seis semanas depois da infiltração, estudos histopatológicos de nódulos simple demonstraram todos os vermes adultos mortos. Em conglomerados de nódulos a ação da cloroquina foi só sobre os vermes adultos do nódulo infiltrado, não acontecendo a difusão da droga aos nódulos adjacentes. A infiltração de cloroquina a nódulos novos ou de recente formação reduz a carga de vermes adultos dos indivíduos parasitados e pode ser uma alternativa para os altos custos das nodulectomias.

  18. Similar efficacy and tolerability of double-dose chloroquine and artemether-lumefantrine for treatment of Plasmodium falciparum infection in Guinea-Bissau: a randomized trial

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia;

    2011-01-01

    In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele...

  19. The Association of K76T Mutation in Pfcrt Gene and Chloroquine Treatment Failure in Uncomplicated Plasmodium falciparum Malaria in a Cohort of Nigerian Children

    Science.gov (United States)

    Umar, R. A.; Hassan, S. W.; Ladan, M. J.; Nma Jiya, M.; Abubakar, M. K.; Nata`Ala, U.

    The aim of this study was to evaluate the association of K76T mutation in Pfcrt gene and chloroquine treatment failure following reports that the efficacy of chloroquine in the treatment of uncomplicated falciparum malaria in Africa is seriously compromised by high levels of drug resistance. The occurrence of mutation on codon 76 of Plasmodium falciparum chloroquine resistance transporter (Pfcrt) gene has been associated with development of resistance to chloroquine. We investigated the association of K76T mutation in Pfcrt gene in malaria-infected blood samples from a cohort of Nigerian children with uncomplicated falciparum malaria treated with chloroquine and its association with clinical (in vivo) resistance. The Pfcrt T76 allele was very significantly associated with resistance to chloroquine (Fischer exact test: p = 0.0001). We conclude that K76T mutation in Pfcrt gene is significantly associated with chloroquine resistance and that it could be used as a population marker for chloroquine resistance in this part of the country

  20. Biosynthesis of intestinal microvillar proteins. Surface expression of aminopeptidase N is not affected by chloroquine

    DEFF Research Database (Denmark)

    Danielsen, E M; Sjöström, H; Norén, Ove

    1985-01-01

    The effect of chloroquine on the biosynthesis of pig intestinal aminopeptidase N (EC 3.4.11.2) was studied by labelling with [35S]methionine in organ cultured mucosal explants. The lysosomotropic agent did not alter the molecular size of either the transient or the mature form of the enzyme and d...... no consequence on the intracellular transport of the newly synthesized microvillar enzyme. This suggests that the acidic compartments are not involved in the post-Golgi transport and that this, in turn, probably occurs via a constitutive rather than a regulated pathway....

  1. A four-year surveillance program for detection of Plasmodium falciparum chloroquine resistance in Honduras

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    Gustavo A Fontecha

    2014-07-01

    Full Text Available Countries could use the monitoring of drug resistance in malaria parasites as an effective early warning system to develop the timely response mechanisms that are required to avert the further spread of malaria. Drug resistance surveillance is essential in areas where no drug resistance has been reported, especially if neighbouring countries have previously reported resistance. Here, we present the results of a four-year surveillance program based on the sequencing of the pfcrt gene of Plasmodium falciparum populations from endemic areas of Honduras. All isolates were susceptible to chloroquine, as revealed by the pfcrt “CVMNK” genotype in codons 72-76.

  2. A four-year surveillance program for detection of Plasmodium falciparum chloroquine resistance in Honduras.

    Science.gov (United States)

    Fontecha, Gustavo A; Sanchez, Ana L; Mendoza, Meisy; Banegas, Engels; Mejía-Torres, Rosa E

    2014-07-01

    Countries could use the monitoring of drug resistance in malaria parasites as an effective early warning system to develop the timely response mechanisms that are required to avert the further spread of malaria. Drug resistance surveillance is essential in areas where no drug resistance has been reported, especially if neighbouring countries have previously reported resistance. Here, we present the results of a four-year surveillance program based on the sequencing of the pfcrt gene of Plasmodium falciparum populations from endemic areas of Honduras. All isolates were susceptible to chloroquine, as revealed by the pfcrt "CVMNK" genotype in codons 72-76.

  3. Effects of chloroquine, mefloquine and quinine on natural killer cell activity in vitro. An analysis of the inhibitory mechanism

    DEFF Research Database (Denmark)

    Pedersen, B K; Bygbjerg, I C; Theander, T G;

    1986-01-01

    Natural killer (NK) cell activity against K 562 target cells was inhibited by pharmacological concentrations of chloroquine, mefloquine and quinine. The most potent were mefloquine and quinine. The drug-induced inhibition of the NK cell activity was abolished by addition of alpha-interferon (IF...... NK cell enriched populations in a single cell agarose assay, it was shown that the inhibitory effects of mefloquine, but not of chloroquine and quinine were due to an inhibition of the formation of effector/target cell conjugates....

  4. Multiple Drugs Compete for Transport via the Plasmodium falciparum Chloroquine Resistance Transporter at Distinct but Interdependent Sites*

    OpenAIRE

    Bellanca, Sebastiano; Summers, Robert L.; Meyrath, Max; Dave, Anurag; Nash, Megan N.; Dittmer, Martin; Sanchez, Cecilia P.; Stein, Wilfred D; Martin, Rowena E.; Lanzer, Michael

    2014-01-01

    Mutations in the “chloroquine resistance transporter” (PfCRT) are a major determinant of drug resistance in the malaria parasite Plasmodium falciparum. We have previously shown that mutant PfCRT transports the antimalarial drug chloroquine away from its target, whereas the wild-type form of PfCRT does not. However, little is understood about the transport of other drugs via PfCRT or the mechanism by which PfCRT recognizes different substrates. Here we show that mutant PfCRT also transports qu...

  5. Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes

    Directory of Open Access Journals (Sweden)

    Gao MH

    2015-10-01

    Full Text Available Menghua Gao,1 Yuzhen Xu,1 Liyan Qiu2,3 1College of Pharmaceutical Sciences, 2Ministry of Education (MOE Key Laboratory of Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 3Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract: A novel composite liposomal system co-encapsulating paclitaxel (PTX with chloroquine phosphate (CQ was designed for treating PTX-resistant carcinoma. It was confirmed that liposomal CQ can sensitize PTX by means of autophagy inhibition and competitively binding with multidrug-resistance transporters. Furthermore, according to the in vitro cytotoxicity and apoptosis assay, real-time observation of cellular uptake, and in vivo tissue distribution study, co-encapsulation of PTX and CQ in liposomes was validated as superior to the mixture of PTX liposome plus CQ liposome due to the simultaneous delivery and synergetic effect of the two drugs. Consequently, this composite liposome achieved significantly stronger anticancer efficacy in vivo than the PTX liposome plus CQ liposome mixture. This study helps to guide and enlighten ongoing and future clinical trials about the optimal administration modes for drug combination therapy. Keywords: paclitaxel, chloroquine, liposome, drug resistance, combination therapy

  6. In Vivo Susceptibility of Plasmodium Vivax to Chloroquine in Southeastern Iran

    Directory of Open Access Journals (Sweden)

    S Dittrich

    2012-06-01

    Full Text Available Background: Plasmodium vivax is the predominant species causes of malaria with about 90% total annual reported malaria in Iran. This study conducted to determine the susceptibility of Plasmodium vivax isolates to chloroquine in Sistan and Balochistan Province, southeastern Iran.Methods: A total 270 subjects with symptomatic malaria and confirmed P. vivax infection completed the designed 28-day in vivo study. The thick and thin film blood smears were screened for malaria parasites by microscopy. The nested PCR was applied using the Plasmodium 18 subunit ribosomal ribonu­cleic (Ssr RNA genes for detecting mixed infections and diagnosis of parasites in the samples with low parasite on days 0, 5, 6, 7, and 28. Results: P. vivax was cleared in 15%, 50%, 95%, and 100% of patients on days 1, 2, 3, 4 respectively by microscopy assessment. Six patients were exhibited specific P. vivax band in nested PCR on day 5. No recurrence was observed on days 7, 14 and 28. Mean (±standard deviation parasite clearance time was 2.41 (±0.8 days. Conclusion: P. vivax is still susceptible to chloroquine in Southeatern Iran. This finding is compati­ble with results of neighboring countries Pakistan and Afghanistan.

  7. Regulation of autophagy and chloroquine sensitivity by oncogenic RAS in vitro is context-dependent.

    Science.gov (United States)

    Morgan, Michael J; Gamez, Graciela; Menke, Christina; Hernandez, Ariel; Thorburn, Jacqueline; Gidan, Freddi; Staskiewicz, Leah; Morgan, Shellie; Cummings, Christopher; Maycotte, Paola; Thorburn, Andrew

    2014-10-01

    Chloroquine (CQ) is an antimalarial drug and late-stage inhibitor of autophagy currently FDA-approved for use in the treatment of rheumatoid arthritis and other autoimmune diseases. Based primarily on its ability to inhibit autophagy, CQ and its derivative, hydroxychloroquine, are currently being investigated as primary or adjuvant therapy in multiple clinical trials for cancer treatment. Oncogenic RAS has previously been shown to regulate autophagic flux, and cancers with high incidence of RAS mutations, such as pancreatic cancer, have been described in the literature as being particularly susceptible to CQ treatment, leading to the hypothesis that oncogenic RAS makes cancer cells dependent on autophagy. This autophagy "addiction" suggests that the mutation status of RAS in tumors could identify patients who would be more likely to benefit from CQ therapy. Here we show that RAS mutation status itself is unlikely to be beneficial in such a patient selection because oncogenic RAS does not always promote autophagy addiction. Moreover, oncogenic RAS can have opposite effects on both autophagic flux and CQ sensitivity in different cells. Finally, for any given cell type, the positive or negative effect of oncogenic RAS on autophagy does not necessarily predict whether RAS will promote or inhibit CQ-mediated toxicity. Thus, although our results confirm that different tumor cell lines display marked differences in how they respond to autophagy inhibition, these differences can occur irrespective of RAS mutation status and, in different contexts, can either promote or reduce chloroquine sensitivity of tumor cells.

  8. Transcriptomic Analysis of Chloroquine-Sensitive and Chloroquine-Resistant Strains of Plasmodium falciparum: Toward Malaria Diagnostics and Therapeutics for Global Health.

    Science.gov (United States)

    Antony, Hiasindh Ashmi; Pathak, Vrushali; Parija, Subhash Chandra; Ghosh, Kanjaksha; Bhattacherjee, Amrita

    2016-07-01

    Increasing drug resistance in Plasmodium falciparum is an important global health burden because it reverses the malarial control achieved so far. Hence, understanding the molecular mechanisms of drug resistance is the epicenter of the development agenda for novel diagnostic and therapeutic (drugs/vaccines) targets for malaria. In this study, we report global comparative transcriptome profiling (RNA-Seq) to characterize the difference in the transcriptome between 48-h intraerythrocytic stage of chloroquine-sensitive and chloroquine-resistant P. falciparum (3D7 and Dd2) strains. The two P. falciparum 3D7 and Dd2 strains have distant geographical origin, the Netherlands and Indochina, respectively. The strains were cultured by an in vitro method and harvested at the 48-h intraerythrocytic stage having 5% parasitemia. The whole transcriptome sequencing was performed using Illumina HiSeq 2500 platform with paired-end reads. The reads were aligned with the reference P. falciparum genome. The alignment percentages for 3D7, Dd2, and Dd2 w/CQ strains were 85.40%, 89.13%, and 84%, respectively. Nearly 40% of the transcripts had known gene function, whereas the remaining genes (about 60%) had unknown function. The genes involved in immune evasion showed a significant difference between the strains. The differential gene expression between the sensitive and resistant strains was measured using the cuffdiff program with the p-value cutoff ≤0.05. Collectively, this study identified differentially expressed genes between 3D7 and Dd2 strains, where we found 89 genes to be upregulated and 227 to be downregulated. On the contrary, for 3D7 and Dd2 w/CQ strains, 45 genes were upregulated and 409 were downregulated. These differentially regulated genes code, by and large, for surface antigens involved in invasion, pathogenesis, and host-parasite interactions, among others. The exhibition of transcriptional differences between these strains of P. falciparum contributes to our

  9. Transcriptomic Analysis of Chloroquine-Sensitive and Chloroquine-Resistant Strains of Plasmodium falciparum: Toward Malaria Diagnostics and Therapeutics for Global Health.

    Science.gov (United States)

    Antony, Hiasindh Ashmi; Pathak, Vrushali; Parija, Subhash Chandra; Ghosh, Kanjaksha; Bhattacherjee, Amrita

    2016-07-01

    Increasing drug resistance in Plasmodium falciparum is an important global health burden because it reverses the malarial control achieved so far. Hence, understanding the molecular mechanisms of drug resistance is the epicenter of the development agenda for novel diagnostic and therapeutic (drugs/vaccines) targets for malaria. In this study, we report global comparative transcriptome profiling (RNA-Seq) to characterize the difference in the transcriptome between 48-h intraerythrocytic stage of chloroquine-sensitive and chloroquine-resistant P. falciparum (3D7 and Dd2) strains. The two P. falciparum 3D7 and Dd2 strains have distant geographical origin, the Netherlands and Indochina, respectively. The strains were cultured by an in vitro method and harvested at the 48-h intraerythrocytic stage having 5% parasitemia. The whole transcriptome sequencing was performed using Illumina HiSeq 2500 platform with paired-end reads. The reads were aligned with the reference P. falciparum genome. The alignment percentages for 3D7, Dd2, and Dd2 w/CQ strains were 85.40%, 89.13%, and 84%, respectively. Nearly 40% of the transcripts had known gene function, whereas the remaining genes (about 60%) had unknown function. The genes involved in immune evasion showed a significant difference between the strains. The differential gene expression between the sensitive and resistant strains was measured using the cuffdiff program with the p-value cutoff ≤0.05. Collectively, this study identified differentially expressed genes between 3D7 and Dd2 strains, where we found 89 genes to be upregulated and 227 to be downregulated. On the contrary, for 3D7 and Dd2 w/CQ strains, 45 genes were upregulated and 409 were downregulated. These differentially regulated genes code, by and large, for surface antigens involved in invasion, pathogenesis, and host-parasite interactions, among others. The exhibition of transcriptional differences between these strains of P. falciparum contributes to our

  10. Chloroquine causes similar electroretinogram modifications, neuronal phospholipidosis and marked impairment of synaptic vesicle transport in Albino and Pigmented Rats

    International Nuclear Information System (INIS)

    Retinal toxicity of chloroquine has been known for several years, but the mechanism(s) of toxicity remain controversial; some author support the idea that the binding of chloroquine to melanin pigments in the retinal pigmented epithelium (RPE) play a major toxic role by concentrating the drug in the eye. In our study, 12 albinos Sprague-Dawley (SD) and 12 pigmented Brown Norway (BN) rats were treated orally for 3 months with chloroquine to compare functional and pathological findings. On Flash electroretinograms (ERG) performed in scotopic conditions, similar and progressive (time-dependent) delayed onset and decreased amplitudes of oscillatory potentials (from Day 71) and b-waves (on Day 92) were identified in both BN and SD rats. In both strains, identical morphological changes consisted of neuronal phospholipidosis associated with UV auto-fluorescence without evidence of retinal degeneration and gliosis; the RPE did not show any morphological lesions or autofluorescence. IHC analyses demonstrated a decrease in GABA expression in the inner nuclear layer. In addition, a marked accumulation of synaptic vesicles coupled with a marked disruption of neurofilaments in the optic nerve fibers was identified. In conclusion, ERG observations were very similar to those described in humans. Comparable ERG modifications, histopathology and immunohistochemistry findings were observed in the retina of both rat strains suggesting that melanin pigment is unlikely involved. chloroquine-induced impairment of synaptic vesicle transport, likely related to disruption of neurofilaments was identified and non-previously reported. This new mechanism of toxicity may also be responsible for the burry vision described in humans chronically treated with chloroquine

  11. Emerging Plasmodium vivax resistance to chloroquine in South America: an overview

    Directory of Open Access Journals (Sweden)

    Lígia Antunes Gonçalves

    2014-08-01

    Full Text Available The global emergence of Plasmodium vivax strains resistant to chloroquine (CQ since the late 1980s is complicating the current international efforts for malaria control and elimination. Furthermore, CQ-resistant vivax malaria has already reached an alarming prevalence in Indonesia, East Timor and Papua New Guinea. More recently, in vivo studies have documented CQ-resistant P. vivax infections in Guyana, Peru and Brazil. Here, we summarise the available data on CQ resistance across P. vivax-endemic areas of Latin America by combining published in vivo and in vitro studies. We also review the current knowledge regarding the molecular mechanisms of CQ resistance in P. vivax and the prospects for developing and standardising reliable molecular markers of drug resistance. Finally, we discuss how the Worldwide Antimalarial Resistance Network, an international collaborative effort involving malaria experts from all continents, might contribute to the current regional efforts to map CQ-resistant vivax malaria in South America.

  12. Efficacy of Chloroquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Honduras

    Science.gov (United States)

    Torres, Rosa Elena Mejia; Banegas, Engels Ilich; Mendoza, Meisy; Diaz, Cesar; Bucheli, Sandra Tamara Mancero; Fontecha, Gustavo A.; Alam, Md Tauqeer; Goldman, Ira; Udhayakumar, Venkatachalam; Zambrano, Jose Orlinder Nicolas

    2013-01-01

    Chloroquine (CQ) is officially used for the primary treatment of Plasmodium falciparum malaria in Honduras. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated P. falciparum malaria in the municipality of Puerto Lempira, Gracias a Dios, Honduras was evaluated using the Pan American Health Organization—World Health Organization protocol with a follow-up of 28 days. Sixty-eight patients from 6 months to 60 years of age microscopically diagnosed with uncomplicated P. falciparum malaria were included in the final analysis. All patients who were treated with CQ (25 mg/kg over 3 days) cleared parasitemia by day 3 and acquired no new P. falciparum infection within 28 days of follow-up. All the parasite samples sequenced for CQ resistance mutations (pfcrt) showed only the CQ-sensitive genotype (CVMNK). This finding shows that CQ remains highly efficacious for the treatment of uncomplicated P. falciparum malaria in Gracias a Dios, Honduras. PMID:23458957

  13. 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.

  14. Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling

    DEFF Research Database (Denmark)

    Balic, Anamaria; Sørensen, Morten Dræby; Trabulo, Sara Maria;

    2014-01-01

    Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs...... as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts...... in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more...

  15. Membrane fusion inducers, chloroquine and spermidine increase lipoplex-mediated gene transfection

    Energy Technology Data Exchange (ETDEWEB)

    Wong-Baeza, Carlos; Bustos, Israel; Serna, Manuel; Tescucano, Alonso; Alcantara-Farfan, Veronica; Ibanez, Miguel [Biochemistry Department, National Polytechnic Institute (IPN), Mexico City 11340 (Mexico); Montanez, Cecilia [Department of Genetics and Molecular Biology, Centre for Research and Advanced Studies (CINVESTAV), IPN, Mexico City 07360 (Mexico); Wong, Carlos [Biochemistry Department, National Polytechnic Institute (IPN), Mexico City 11340 (Mexico); Baeza, Isabel, E-mail: ibaeza@encb.ipn.mx [Biochemistry Department, National Polytechnic Institute (IPN), Mexico City 11340 (Mexico)

    2010-05-28

    Gene transfection into mammalian cells can be achieved with viral and non-viral vectors. Non-viral vectors, such as cationic lipids that form lipoplexes with DNA, are safer and more stable than viral vectors, but their transfection efficiencies are lower. Here we describe that the simultaneous treatment with a membrane fusion inducer (chlorpromazine or procainamide) plus the lysosomotropic agent chloroquine increases lipoplex-mediated gene transfection in human (HEK293 and C-33 A) and rat (PC12) cell lines (up to 9.2-fold), as well as in situ in BALB/c mice spleens and livers (up to 6-fold); and that the polyamine spermidine increases lipoplex-mediated gene transfection and expression in cell cultures. The use of these four drugs provides a novel, safe and relatively inexpensive way to considerably increase lipoplex-mediated gene transfection efficiency.

  16. The pH dependent toxicity and bioaccumulation of chloroquine tested on S. viminalis (basket willow)

    DEFF Research Database (Denmark)

    Rendal, Cecilie; Trapp, Stefan; Legind, Charlotte Nielsen

    2010-01-01

    divalent weak base) on S. viminalis (basket willow). The transpiration of sprouted S. viminalis cuttings was monitored under the exposure of increasing concentrations (1, 10, 20, and 40 mg/L) of chloroquine at pH levels of 6, 7, 8, and 9. Solutions were buffered with phosphate (pH 6 and 7) and TRIS...... (hydroxymethyl) – aminomethane (pH 8 and 9). Concentrations were determined with spectrophotometer. Toxicity was derived from calculations of normalized transpiration over time, and RCF (root concentration factor) values were calculated. Increasing BCF values were found for increasing pH levels, and the toxicity......It is known that the uptake and accumulation of electrolytes is very sensitive to pH owing to the slower diffusion of charged compounds across membranes, and other factors such as the Nernst effect and the ion trap effect. However, the significance of pH to the bioaccumulation of electrolytes has...

  17. Low level genotypic chloroquine resistance near Malawi's northern border with Tanzania.

    Science.gov (United States)

    Bridges, Daniel J; Molyneux, Malcolm; Nkhoma, Standwell

    2009-09-01

    We conducted a prevalence study of mutations in Plasmodium falciparum that are associated with antimalarial drug resistance at a rural site in Karonga near Malawi's northern border with Tanzania. We found a higher prevalence of the key chloroquine resistance-conferring mutation in the pfcrt gene (K76T) at this site in comparison with the prevalence in Blantyre, a city in the south of Malawi, far from an international border (9%vs. 0%; P Malawi was recently reported to be over 50%. Our findings suggest a considerable 'leakage' of parasite antimalarial drug resistance across the border between two countries with different national malaria control policies and with different levels of resistance. Neighbouring countries should consider implementing common regional rather than national malaria treatment policies to prevent the spread of antimalarial drug resistance alleles across their borders.

  18. Efficacy of chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in Honduras.

    Science.gov (United States)

    Mejia Torres, Rosa Elena; Banegas, Engels Ilich; Mendoza, Meisy; Diaz, Cesar; Bucheli, Sandra Tamara Mancero; Fontecha, Gustavo A; Alam, Md Tauqeer; Goldman, Ira; Udhayakumar, Venkatachalam; Zambrano, Jose Orlinder Nicolas

    2013-05-01

    Chloroquine (CQ) is officially used for the primary treatment of Plasmodium falciparum malaria in Honduras. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated P. falciparum malaria in the municipality of Puerto Lempira, Gracias a Dios, Honduras was evaluated using the Pan American Health Organization-World Health Organization protocol with a follow-up of 28 days. Sixty-eight patients from 6 months to 60 years of age microscopically diagnosed with uncomplicated P. falciparum malaria were included in the final analysis. All patients who were treated with CQ (25 mg/kg over 3 days) cleared parasitemia by day 3 and acquired no new P. falciparum infection within 28 days of follow-up. All the parasite samples sequenced for CQ resistance mutations (pfcrt) showed only the CQ-sensitive genotype (CVMNK). This finding shows that CQ remains highly efficacious for the treatment of uncomplicated P. falciparum malaria in Gracias a Dios, Honduras.

  19. Inhibition of Autophagy by Chloroquine Enhances the Antitumor Efficacy of Sorafenib in Glioblastoma.

    Science.gov (United States)

    Liu, Xiangyu; Sun, Kangjian; Wang, Handong; Dai, Yuyuan

    2016-10-01

    Glioblastoma multiforme (GBM) is the most aggressive and common brain tumor in adults. Sorafenib, a multi-kinase inhibitor, has been shown to inhibit cell proliferation and induce apoptosis through inhibition of STAT3 signaling in glioblastoma cells and in intracranial gliomas. However, sorafenib also induces cell autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the therapeutic effect of sorafenib on glioblastoma is uncertain. Here, we combined sorafenib treatment in GBM cells (U373 and LN229) and tumors with the autophagy inhibitor chloroquine. We found that blockage of autophagy further inhibited cell proliferation and migration and induced cell apoptosis in vitro and in vivo. These findings suggest the possibility of combination treatment with sorafenib and autophagy inhibitors for GBM. PMID:26971793

  20. Chloroquine-induced bilateral anterior shoulder dislocation: a unique aetiology for a rare clinical problem.

    Science.gov (United States)

    Martin, Alexander Nicholas; Tsekes, Dimitris; White, William James; Rossouw, Dan

    2016-01-01

    Bilateral anterior shoulder dislocation is a rare clinical entity with few case reports and limited series published in the literature. Bilateral shoulder dislocations are rare and of them, most are posterior. We present a highly unusual case of bilateral, atraumatic, anterior shoulder dislocation with concomitant comminuted greater tuberosity fracture on the right side, secondary to seizure, in a patient without known epilepsy, induced by oral chloroquine medication. We demonstrate the treatment approach that led to a satisfactory clinical outcome, evidenced by radiological union, clinical assessment and Patient Reported Outcome Measure data, following non-operative management of both shoulders. The unusual mechanism for anterior shoulder dislocation, the asymmetric dislocation pattern and peculiar precipitant for the causative seizure all provide interesting learning points from this case. PMID:27005796

  1. Safety, Immunogenicity, and Protective Efficacy of Intradermal Immunization with Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites in Volunteers Under Chloroquine Prophylaxis : A Randomized Controlled Trial

    NARCIS (Netherlands)

    G.J.H. Baestians (Guido); M.P.A. van Meer (Maurits); A. Scholzen (Anja); J.M. Obiero (Joshua); M. Vatanshenassan (Mansoureh); T. van Grinsven (Tim); B.K.L. Sim (B. Kim Lee); P.F. Billingsley (Peter); E.R. James (Eric); A. Gunasekera (Anusha); E.M. Bijker (Else); G-J. van Gemert (Geert-Jan); M. van de Vegte-Bolmer (Magda); W. Graumans (Wouter); C.C. Hermsen (Cornelus); Q. de Mast (Quirijn); A.J.A.M. van der Ven (André); S.L. Hoffman (Stephen); R.W. Sauerwein (Robert)

    2015-01-01

    markdownabstractImmunization of volunteers under chloroquine prophylaxis by bites of *Plasmodium falciparum* sporozoite (PfSPZ)–infected mosquitoes induces > 90% protection against controlled human malaria infection (CHMI). We studied intradermal immunization with cryopreserved, infectious PfSPZ in

  2. Effects of Chloroquine on GFAP, PCNA and Cyclin D1 in Hippocampus and Cerebral Cortex of Rats with Seizures Induced by Pentylenetetrazole

    Institute of Scientific and Technical Information of China (English)

    ZHANG Shuhua; ZHU Changgeng; LIU Qingying; WANG Wei

    2005-01-01

    The effects of chloroquine on glial fibrillary acidic protein (GFAP), proliferation cell nuclear antigen (PCNA) and Cyclin D1 in hippocampus and cerebral cortex of rats with seizures induced by pentylenetetrazole (PTZ) were observed in the present study. Forty-eight male adult Sprague-Dawley (SD) rats were randomly divided into control group, chloroquine intervening group, and PTZ group. The behavior and electroencephalogram (EEG) were observed and recor ded. GFAP and PCNA were examined with immunohistochemistry. The content of Cyclin D1 in hippocampus and cerebral cortex was inspected with Western blot. The results showed no seizure activity in the control group, severe seizure activity in the PTZ group (Ⅳ-Ⅴ degree), and slight seizure activity ( Ⅰ - Ⅲ degree) in the chloroquine intervening group (P<0. 05). EEG recordings showed no epileptic spikes in the control group, high amplitude with fast frequency in the PTZ group, low-amplitude and slow frequency in the chloroquine intervening group. The expression of GFAP and the positive index of PCNA in the PTZ group were higher than those of control group (P <0.05 and P<0.01, respectively). No differences in GFAP expression and PCNA index were observed between chloroquine intervening and control groups (P>0.05). The content of Cyclin D1 in hippocampus and cerebral cortex was significantly higher in the PTZ group than in control and chloroquine intervening groups (P< 0.05). Therefore, it is considered that chloroquine, by inhibiting the functions and proliferation of glial cells in the hippocampus and cerebral cortex, can alleviate the seizure activities. These results suggest that chloroquine may be an ideal anticonvulsant in preventing and treating epilepsy.

  3. Rapid selection of Plasmodium falciparum chloroquine resistance transporter gene and multidrug resistance gene-1 haplotypes associated with past chloroquine and present artemether-lumefantrine use in Inhambane District, southern Mozambique

    DEFF Research Database (Denmark)

    Thomsen, Thomas T; Madsen, Laura B; Hansson, Helle H;

    2013-01-01

    Chloroquine (CQ) use in Mozambique was stopped in 2002 and artemether-lumefantrine (AL) was implemented in 2008. In light of no use of CQ and extensive use of AL, we determined the frequency of molecular markers of Plasmodium falciparum drug resistance/tolerance to CQ and AL in persons living...... in Linga-Linga, an isolated peninsula and in Furvela village, which is located 8 km inland. The P. falciparum chloroquine resistance transporter gene CVMNK wild type increased in frequency from 43.9% in 2009 to 66.4% in 2010 (P = 0.001), and combined P. falciparum multidrug resistance gene 1 N86-184F-D1246...... haplotype increased significantly between years (P = 0.039). The combination of P. falciparum chloroquine resistance transporter gene CVMNK and P. falciparum multidrug resistance gene NFD increased from 24.3% (2009) to 45.3% in (2010, P = 0.017). The rapid changes observed may largely be caused by decreased...

  4. Discordant patterns of genetic variation at two chloroquine resistance loci in worldwide populations of the malaria parasite Plasmodium falciparum

    DEFF Research Database (Denmark)

    Mehlotra, Rajeev K; Mattera, Gabriel; Bockarie, Moses J;

    2008-01-01

    Mutations in the chloroquine resistance (CQR) transporter gene of Plasmodium falciparum (Pfcrt; chromosome 7) play a key role in CQR, while mutations in the multidrug resistance gene (Pfmdr1; chromosome 5) play a significant role in the parasite's resistance to a variety of antimalarials and also...... different mechanisms. Since Pfmdr1 mutations may be associated with resistance to artemisinin combination therapies that are replacing CQ, particularly in Africa, it is important to determine if, and how, the genetic characteristics of this locus change over time.......Mutations in the chloroquine resistance (CQR) transporter gene of Plasmodium falciparum (Pfcrt; chromosome 7) play a key role in CQR, while mutations in the multidrug resistance gene (Pfmdr1; chromosome 5) play a significant role in the parasite's resistance to a variety of antimalarials and also...

  5. Role of Pfmdr1 in In Vitro Plasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

    OpenAIRE

    Wurtz, Nathalie; Fall, Bécaye; Pascual, Aurélie; Fall, Mansour; Baret, Eric; Camara, Cheikhou; Nakoulima, Aminata; Diatta, Bakary; Fall, Khadidiatou Ba; Mbaye, Pape Saliou; Diémé, Yaya; Bercion, Raymond; Wade, Boubacar; Pradines, Bruno

    2014-01-01

    The involvement of Pfmdr1 (Plasmodium falciparum multidrug resistance 1) polymorphisms in antimalarial drug resistance is still debated. Here, we evaluate the association between polymorphisms in Pfmdr1 (N86Y, Y184F, S1034C, N1042D, and D1246Y) and Pfcrt (K76T) and in vitro responses to chloroquine (CQ), mefloquine (MQ), lumefantrine (LMF), quinine (QN), monodesethylamodiaquine (MDAQ), and dihydroartemisinin (DHA) in 174 Plasmodium falciparum isolates from Dakar, Senegal. The Pfmdr1 86Y mutat...

  6. In vitro and in vivo anti-malarial activity of tigecycline, a glycylcycline antibiotic, in combination with chloroquine

    OpenAIRE

    Sahu, Rajnish; Walker, Larry A.; Tekwani, Babu L.

    2014-01-01

    Background Several antibiotics have shown promising anti-malarial effects and have been useful for malarial chemotherapy, particularly in combination with standard anti-malarial drugs. Tigecycline, a semi-synthetic derivative of minocycline with a unique and novel mechanism of action, is the first clinically available drug in a new class of glycylcycline antibiotics. Methods Tigecycline was tested in vitro against chloroquine (CQ)-sensitive (D6) and resistant strains (W2) of Plasmodium falcip...

  7. Effects of chloroquine and cytochalasin B on the infection of cells by Sindbis virus and vesicular stomatitis virus.

    OpenAIRE

    Coombs, K; Mann, E; Edwards, J; Brown, D T

    1981-01-01

    The effects of cytochalasin B and chloroquine on the process of endocytosis of Sindbis virus particles and polystyrene spheres were determined by electron microscopy. The effects of these agents on the process of infection (attachment, penetration, and uncoating) of BHK-21 cells by Sindbis virus and vesicular stomatitis virus were also determined. Cytochalasin B completely blocked ingestion of Sindbis virus particles or latex spheres by BHK cells but had no effect on the ability of Sindbis vi...

  8. Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine

    OpenAIRE

    Mikus Gerd; Walter-Sack Ingeborg; Jahn Albrecht; Schiek Wolfgang; Rengelshausen Jens; Mansmann Ulrich; Tapsoba Théophile; Witte Steffen; Coulibaly Boubacar; Mandi Germain; Meissner Peter E; Burhenne Jürgen; Riedel Klaus-Dieter; Schirmer R Heiner; Kouyaté Bocar

    2006-01-01

    Abstract The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical ...

  9. Dynamics of pfcrt alleles CVMNK and CVIET in chloroquine-treated Sudanese patients infected with Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Warhurst David C

    2010-03-01

    Full Text Available Abstract Background Parasite resistance to the anti-malarial drug chloroquine is common in eastern Sudan. Dynamic within-host changes in the relative abundance of both sensitive and resistant Plasmodium falciparum parasites were examined in a cohort of chloroquine-treated patients presenting with uncomplicated falciparum malaria, using a novel allele-specific quantitative approach. Methods Treatment outcomes were determined for 93 patients of all ages in a per protocol cohort using a modified 14-day WHO protocol. Parasite DNA samples at days 0, 1, 2, 3, 7 and 14 following treatment were analysed using real-time quantitative PCR methods that distinguished resistant and sensitive genotypes at amino acids 72 - 76 of the pfcrt locus. Results Chloroquine treatment was not efficacious, and of 93 assessable patients, only 10 individuals (10.7%; 95% C.I. 4.34 - 17.2% enjoyed an adequate clinical and parasitological response. Resistant parasites with the haplotype CVIET at codons 72-76 of the pfcrt locus were dominant in the starting population. Chloroquine sensitive parasites with the haplotype CVMNK were detected in 19 individuals prior to treatment (20.43%; 95% C.I. 5.14 - 18.5%. In these patients, CQ treatment rapidly selected CVIET parasites, and this haplotype overwhelmingly dominated the parasite population in each individual by day 2 after treatment. Conclusions Such rapid intra-host selection of particular genotypes after the introduction of drug will cause frequent misidentification of parasite genotypes present in the starting population. This will have a potentially serious confounding effect on clinical trials which employ PCR-corrected estimates of treatment failure, as resistant parasites below the detection threshold in the pre-treatment sample can be erroneously classified as "new" infections during follow-up, over-estimating drug efficacy.

  10. Arguments against Chemoprophylaxis in Areas at Low Risk for Chloroquine-Resistant Plasmodium falciparum.

    Science.gov (United States)

    Armengaud

    1995-03-01

    Chemoprophylaxis of malaria prevents the disease not the infection (suppressive chemoprophylaxis) with "high levels of confusion and low levels of compliance." The magnitude of danger of contracting malaria for travelers varies in several endemic zones. In West Africa, without prophylaxis, malaria is estimated to have an incidence of 1.4% per person per month. In South and Central America, the incidence is 0.05 and 0.01% per month, respectively. In Asia, the transmission and percentage of infection due to Plasmodium falciparum is much lower. The dangers of chemoprophylaxis in an area at low risk for chloroquine resistant P. falciparum are a reality. Incompletely active drugs change clinical manifestations, and changes in clinical manifestations delay the establishment of a correct diagnosis. The rate of adverse events is 15-20%, and hospitalization due to side effects of prophylaxis occurs in one in 10,000 travelers. Neuropsychiatric side effects have been reported with both mefloquine and chloroquine. A false sense of security can hinder a physician practicing in a nonendemic area from thinking of malaria when a traveler returns with fever. To complicate the picture, in many countries, there is an emerging drug resistance in P. falciparum as well as an emerging chloroquine resistance in P. vivax strains (20% in New Guinea and Irian Jaya). In short, no available chemoprophylaxis is free from toxicity, and its efficacy is never 100%. Alternatives to conventional chemoprophylaxis are encouraged in areas of low morbidity of malaria. In areas where P. vivax occurs primarily, and when the risk of serious side effects from chemoprophylaxis outweighs the risk of life threatening P. falciparum infection, there are four alternative strategies.2,3 The first strategy is that the traveler avoid mosquito bites. With a compulsive attitude, a high degree of protection can be realized with the proper use of pyrethrum-impregnated mosquito netting, topical DEET-containing insect

  11. The behavior of chloroquine (a synthesized anti-malaria drug) labeled with 14C in healthy and malarious animals

    International Nuclear Information System (INIS)

    The distribution of 14C labeled chloroquine is identical in healthy and malarious animals. Fixation (by order of intensity) takes place in the liver, spleen, lungs, lacrimal glands, cerebrospinal fluid, bones, thyroid, and intestinal walls. This was confirmed from quantitative studies and demonstrates the traversing of the blood-brain barrier and the intestinal elimination after biliary excretion. Pharmaco-kinetic studies were undertaken with healthy animals and those afflicted with malaria. After a phase, in which the distribution of chloroquine is identical for both types of animal, a more rapid decrease in the blood level is observed with the malarious animals. The leucocytes contained distinctly more of the tracer than the normal or malarious red corpuscles or the blood plasma. Examination of the urinary elimination revealed a mono-exponential function; nevertheless, the urinary elimination was less regular with the malarious rats. This elimination corresponds to the excretion of unchanged chloroquine accompanied by two metabolites. A third metabolite appeared after a delay period. (author)

  12. The anti-malarial chloroquine overcomes Primary resistance and restores sensitivity to Trastuzumab in HER2-positive breast cancer

    Science.gov (United States)

    Cufí, Sílvia; Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Corominas-Faja, Bruna; Cuyàs, Elisabet; López-Bonet, Eugeni; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A.

    2013-01-01

    Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein—a finding that correlates with increased numbers of autophagosomes—and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are in a state of “autophagy addiction” because genetic ablation of autophagy-specific genes (ATG8, ATG5, ATG12) notably reduces intrinsic refractoriness to trastuzumab. When the anti-malarial lysosomotropic drug chloroquine impedes autophagic resolution of the accumulation of autophagolysosomes formed in the presence of trastuzumab, cells commit to die by apoptosis. Accordingly, combination treatment with trastuzumab and chloroquine radically suppresses tumor growth by > 90% in a tumor xenograft completely refractory to trastuzumab. Adding chloroquine to trastuzumab-based regimens may therefore improve outcomes among women with autophagy-addicted HER2-positive breast cancer. PMID:23965851

  13. Sequence and gene expression of chloroquine resistance transporter (pfcrt in the association of in vitro drugs resistance of Plasmodium falciparum

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    Bray Patrick G

    2011-02-01

    Full Text Available Abstract Background Plasmodium falciparum chloroquine resistance (CQR transporter protein (PfCRT is known to be the important key of CQR. Recent studies have definitively demonstrated a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Although these mutations are predictive of chloroquine resistance, they are not quantitatively predictive of the degree of resistance. Methods In this study, a total of 95 recently adapted P. falciparum isolates from Thailand were included in the analysis. Parasites were characterized for their drug susceptibility phenotypes and genotypes with respect to pfcrt. From the original 95 isolates, 20 were selected for complete pfcrt sequence analysis. Results Almost all of the parasites characterized carried the previously reported mutations K76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at K76A and E198K. There was a suggestion that parasites carrying E198K were less resistant than those that did not. In addition, pfcrt and pfmdr1 gene expression were investigated by real-time PCR. No relationship between the expression level of either of these genes and response to drug was observed. Conclusion Data from the present study suggest that other genes must contribute to the degree of resistance once the resistance phenotype is established through mutations in pfcrt.

  14. Genotyping of chloroquine resistant Plasmodium falciparum in wild caught Anopheles minimus mosquitoes in a malaria endemic area of Assam, India.

    Science.gov (United States)

    Sarma, D K; Mohapatra, P K; Bhattacharyya, D R; Mahanta, J; Prakash, A

    2014-09-01

    We validated the feasibility of using Plasmodium falciparum, the human malaria parasite, DNA present in wild caught vector mosquitoes for the characterization of chloroquine resistance status. House frequenting mosquitoes belonging to Anopheles minimus complex were collected from human dwellings in a malaria endemic area of Assam, Northeast India and DNA was extracted from the head-thorax region of individual mosquitoes. Anopheles minimus complex mosquitoes were identified to species level and screened for the presence of Plasmodium sp. using molecular tools. Nested PCR-RFLP method was used for genotyping of P. falciparum based on K76T mutation in the chloroquine resistance transporter (pfcrt) gene. Three of the 27 wild caught An. minimus mosquitoes were harbouring P. falciparum sporozoites (positivity 11.1%) and all 3 were had 76T mutation in the pfcrt gene, indicating chloroquine resistance. The approach of characterizing antimalarial resistance of malaria parasite in vector mosquitoes can potentially be used as a surveillance tool for monitoring transmission of antimalarial drug resistant parasite strains in the community.

  15. Effects of Low Dose of Ketotifen and Chloroquine Combination on the Ultrastructure of Chloroquine Resistant Strain of Plasmodium Yoelii%低剂量氯喹和酮替酚联合作用下疟原虫的超微结构研究

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    46 inbred NIH mice were infected by chloroquine resistant strain of Plasmodium yoelii. The ultrastructure changes were observed under the administration of ketotifen(10mg· kg- 1· d- 1 ) and chloroquine( 10mg. kg-1 · d- 1 ) combination and one after another respectively. The effect of taking ketotifen and chloroquine combination showed that parasites died rapidly with a few of intermittent membranes and vacuoles. The effect of taking two kinds of drugs one after another showed that there were exceedingly rich membranes, concentric arrangement structures similar to rough endo-reticulum and conspiciously blocking of the formation of food vacuoles.

  16. 3-Iodo-4-aminoquinoline derivative sensitises resistant strains of Plasmodium falciparum to chloroquine.

    Science.gov (United States)

    Edaye, Sonia; Tazoo, Dagobert; Bohle, D Scott; Georges, Elias

    2016-06-01

    Chloroquine (CQ), the first cost-effective synthetic antimalarial, is rendered ineffective in malaria-endemic regions owing to the rise and spread of CQ-resistant Plasmodium falciparum. In this report, we show that a halogen derivative of CQ, namely 3-iodo-CQ, inhibits the proliferation of CQ-sensitive and -resistant P. falciparum in a verapamil-insensitive manner. Similar to CQ, the antimalarial activity of 3-iodo-CQ is likely due to its inhibition of β-haematin formation. Interestingly, the presence of non-inhibitory concentrations of 3-iodo-CQ potentiated the antiproliferative activity of CQ against CQ-resistant strains or P. falciparum transfectants expressing wild-type or mutant P. falciparum CQ resistance transporter (PfCRT) (C2(GC03) or C4(Dd2), respectively). These findings demonstrate that halogenation of the third position of 4-aminoquinoline, with a simple one-step reaction from CQ, generates a novel derivative that is active against CQ-sensitive and -resistant P. falciparum, possibly by inhibiting the activity of mutant PfCRT. PMID:27211211

  17. Surface and micellar properties of Chloroquine Diphosphate and its interactions with surfactants and Human Serum Albumin

    International Nuclear Information System (INIS)

    Highlights: ► Free energy of adsorption is more negative than free energy of micellization. ► Shifts in UV/Visible spectra in presence of SDS indicated interaction of CLQ with SDS. ► The decrease in fluorescence intensity of HSA by CLQ shows its binding with HSA. -- Abstract: This manuscript addresses the physicochemical behavior of an antimalarial drug Chloroquine Diphosphate (CLQ) as well as its interaction with anionic surfactants and Human Serum Albumin (HSA). Surface tension and specific conductivity were employed to detect the critical micelle concentration (CMC) and thus its surface and thermodynamic parameters were calculated. Solubilization of this drug within micelles of anionic surfactant sodium dodecyl sulfate (SDS) has also been studied. UV/Visible spectroscopy was used to calculate partition coefficient (Kx), free energy of partition and number of drug molecules per micelle. The complexation of drug with HSA at physiological conditions (pH 7.4) has also been analyzed by using UV/Visible and fluorescence spectroscopy. The values of drug-protein binding constant, number of binding sites and free energy of binding were calculated

  18. Synthesis, Antiplasmodial Activity, and β-Hematin Inhibition of Hydroxypyridone-Chloroquine Hybrids.

    Science.gov (United States)

    Andayi, Warren A; Egan, Timothy J; Gut, Jiri; Rosenthal, Philip J; Chibale, Kelly

    2013-07-11

    A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor N-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of Plasmodium falciparum. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were 8c (0.13, 0.004, and 0.1 μM); 8d (0.08, 0.01, and 0.02 μM); and 7g (0.07, 0.03, and 0.08 μM). PMID:24900724

  19. The efficacy of chloroquine treatment against naturally occuring Giardia duodenalis infection in lambs

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    Umit Karademir

    2016-05-01

    Full Text Available Objective. The aim of the present study was to determine the efficacy of Chloroquine (Cq, an antimalarial medicine, administered at a dose of 2.5 mg/kg, orally, during 5 consecutive days, in Sakiz and Merino lambs naturally infected with Giardia duodenalis. Materials and methods. To this extent weaned 10 weeks of aged lambs were enrolled and randomly assigned into two groups based on treatment (group C, n=18 lambs treated with Cq and placebo (group P, n=8 untreated control animals. Diagnosis was based on detection of trophozoit and/or cysts on fecal flotation. Cyst count per gram feces (days 0, 3, 7 and 10 was analyzed among groups. Results. During the trial, regarding the efficacy of Cq on days 3., 7., and 10. There was significant (p<0.01 reduction in cyst excretion; whereas evaluation of mean geometric cyst excretion revealed 100% reduction. Conclusions. There was a very high (100% reduction in cyst excretion in the Cq treatment group compared to the positive untreated control group on days 3, 7 and 10, resulting in a significant (p<0.001 reduction, making Cq, safety, and thus highly effective treatment option of lambs with naturally occuring giardiasis.

  20. Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic mice

    Science.gov (United States)

    Yuan, Xun; Xiao, Yi-Chuan; Zhang, Gui-Ping; Hou, Ning; Wu, Xiao-Qian; Chen, Wen-Liang; Luo, Jian-Dong; Zhang, Gen-Shui

    2016-01-01

    Diabetes is a potent risk factor for heart failure with preserved ejection fraction (HFpEF). Autophagy can be activated under pathological conditions, including diabetic cardiomyopathy. The therapeutic effects of chloroquine (CQ), an autophagy inhibitor, on left ventricle function in streptozotocin (STZ)-induced diabetic mice were investigated. The cardiac function, light chain 3 (LC3)-II/LC3-I ratio, p62, beclin 1, reactive oxygen species, apoptosis, and fibrosis were measured 14 days after CQ (ip 60 mg/kg/d) administration. In STZ-induced mice, cardiac diastolic function was decreased significantly with normal ejection fraction. CQ significantly ameliorated cardiac diastolic function in diabetic mice with HFpEF. In addition, CQ decreased the autophagolysosomes, cardiomyocyte apoptosis, and cardiac fibrosis but increased LC3-II and p62 expressions. These results suggested that CQ improved the cardiac diastolic function by inhibiting autophagy in STZ-induced HFpEF mice. Autophagic inhibitor CQ might be a potential therapeutic agent for HFpEF. PMID:27621594

  1. Chitosan/Sterculia striata polysaccharides nanocomplex as a potential chloroquine drug release device.

    Science.gov (United States)

    Magalhães, Guilherme A; Moura Neto, Erico; Sombra, Venícios G; Richter, Ana R; Abreu, Clara M W S; Feitosa, Judith P A; Paula, Haroldo C B; Goycoolea, Francisco M; de Paula, Regina C M

    2016-07-01

    Nanoparticles are produced by means of polyelectrolyte complexation (PEC) of oppositely charged polycationic chitosan (CH) with polyanionic polysaccharide extracted from Sterculia striata exudates (rhamnogalacturonoglycan (RG)-type polysaccharide). The nanoparticles formed with low-molar-mass CH are larger than those formed with high-molar-mass CH. This behavior is in contrast with that previously observed for other systems and may be attributed to different mechanisms related to the association of CH with RG of higher persistence length chain than that of CH. Nanoparticles harnessed with a charge ratio (n(+)/n(-)) of <1 are smaller than particles with an excess of polycations. Particles with hydrodynamic sizes smaller than 100nm are achieved using a polyelectrolyte concentration of 10(-4)gmL(-1) and charge ratio (n(+)/n(-)) of <1. The CH/RG nanoparticles are associated with chloroquine (CQ) with an efficiency of 28% and release it for up to ∼60% within ∼10h, whereas in the latter, only ∼40% of the CQ was released after 24h. The main factor that influenced drug release rate is the nanoparticle charge ratio.

  2. Powder properties of binary mixtures of chloroquine phosphate with lactose and dicalcium phosphate

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    Michael Ayodele Odeniyi

    2010-09-01

    Full Text Available A study was conducted on the packing and cohesive properties of chloroquine phosphate in binary mixtures with lactose and dicalcium phosphate powders. The maximum volume reduction due to packing as expressed by the Kawakita constant, a, and the angle of internal flow, θ, were the assessment parameters. The individual powders were characterized for their particle size and shape using an optical microscope. Binary mixtures of various proportions of chloroquine phosphate with lactose and dicalcium phosphate powders were prepared. The bulk and tapped densities, angles of repose and internal flow, as well as compressibility index of the materials were determined using appropriate parameters. The calculated and determined values of maximum volume reduction for the binary mixtures were found to differ significantly (PRealizou-se estudo das propriedades de empacotamento e de coesão do fosfato de cloroquina em misturas binárias com lactose e fosfato dicálcico em pó. O volume máximo de redução devido ao empacotamento, segundo expresso pela constante de Kawakita, a, e o ângulo de fluxo interno, θ, foram os parâmetros de avaliação. Os pós individuais foram caracterizados por seu tamanho e forma de partículas, utilizando microscópio óptico. Prepararam-se misturas binárias de várias proporções de fosfato de cloroquine e lactose e fosfato dicálcico em pó. As densidades de bulk and tapped, os ângulos de repouso e de fluxo interno e o índice de compressibilidade dos materiais foram determinados utilizando-se parâmetros apropriados. Os valores calculados e determinados do volume máximo de redução para as misturas binárias mostraram-se significativamente diferentes (P< 0,05, sendo o traçado de Kawakita mais confiável na determinação das propriedades de empacotamento. O tipo de diluente influenciou as propriedades de fluxo das misturas com fosfato dicálcico, dando resultados previsíveis, enquanto as misturas contendo lactose

  3. FORMULATION AND EVALUATION OF TASTE MASKED DISPERSIBLE TABLETS OF CHLOROQUINE PHOSPHATE

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    Moon Rajkumar Sukdeo

    2012-09-01

    Full Text Available The primary aim of present work was to formulate and evaluate taste masked dispersible tablets of Chloroquine phosphate, an antimalarial drug, using ion exchange resins like INDION 294 and TULSION 339 as a taste masking agent and superdisintegrating agents like crospovidone and sodium starch glycolate in different concentrations. Characterization of drug was done by melting point determination, FT-IR spectroscopy and UV-spectroscopy. Drug-resin complexes were prepared by batch method using the resins in different ratios. Drug loading study was carried at different pH. INDION 294 showed highest drug loading (93.31%. Hence, further studies were done using INDION 294. The drug-resin complexes were studied for micromeritic properties, in vitro drug release and taste masking ability by determining threshold bitterness concentration of the drug. The complexes were characterized by drug content, FTIR and DSC studies. Powder blends were prepared and evaluated for various physical properties. Dispersible tablets of drug-resin complex (DRC were prepared by wet granulation method using crospovidone and sodium starch glycolate in different concentrations as superdisintegrants. Tablets were evaluated for thickness, hardness, friability, uniformity of weight, dispersion time, uniformity of dispersion, disintegration time, wetting time, wetting volume, content of active ingredient and dissolution studies. All the formulations showed the evaluated parameters within the acceptable limits for dispersible tablets. Finally, formulation F3 was taken as an optimized formulation which was containing 3% of crospovidone and showed the least in vitro disintegration time and an excellent drug release. Stability study was also conducted on the optimized batch F3 which showed good results.

  4. Assessment of therapeutic efficacy of chloroquine and sulphadoxine-pyrimethamine in uncomplicated falciparum malaria

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    Sukla Biswas, Neena Valecha, Prajesh K. Tyagi, Shobhan Phookan, Vas Dev ,Surya K. Sharma & Sarala K. Subbarao

    2003-09-01

    Full Text Available A standardised protocol has been developed by World Health Organization (CDS/RBM/2002 toassess the efficacy of common antimalarials in the treatment of clinically manifested infection withuncomplicated P. falciparum malaria for areas with low to moderate transmission. The therapeuticefficacy protocol is based on clinical and parasitological responses of the patients and it has thepurpose of determining the practical efficacy of the drug regimen in study areas with the ultimateobjective of ascertaining its continued usefulness or the necessity for replacing it in the routinetreatment. Present study has been conducted at seven sites—Kathiatali and Simonabasti of DistrictNowgaon, Assam; Sonapur and Boko of District Kamrup, Assam; Keonjhar Town, Padampur andBasudebpur of District Keonjhar, Orissa. In order to reduce the patient recruitment time, health centreclose to well-defined community was identified to conduct the activities at peak malaria seasonby selecting local pockets and organising mobile clinics. Microscopically confirmed cases of P. falciparumwere enrolled according to the criteria for inclusion and exclusion. Treatment with recommendeddrug was given under supervision and a follow-up schedule at various intervals for 28days was maintained. In chloroquine (CQ study areas, wherever patients showed treatment failure,they were treated with second line drug—sulphadoxine-pyrimethamine (SP combination and thenfollowed-up as per study protocol. It was observed that 30% cases showed treatment failure to CQin District Nowgaon, where revised drug policy has already been introduced. In Kamrup district,treatment failure with CQ was found to be less than 25%, which denotes the said regimen is still effective.Almost all the patients from Padampur and Basudebpur of District Keonjhar responded toCQ, treatment failure was noticed only in two patients (3%. The antifolate combination found to befully effective as second line and also as first line

  5. Chloroquine and its derivatives exacerbate B19V-associated anemia by promoting viral replication.

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    Claudia Bönsch

    Full Text Available BACKGROUND: An unexpectedly high seroprevalence and pathogenic potential of human parvovirus B19 (B19V have been observed in certain malaria-endemic countries in parallel with local use of chloroquine (CQ as first-line treatment for malaria. The aims of this study were to assess the effect of CQ and other common antimalarial drugs on B19V infection in vitro and the possible epidemiological consequences for children from Papua New Guinea (PNG. METHODOLOGY/PRINCIPAL FINDINGS: Viral RNA, DNA and proteins were analyzed in different cell types following infection with B19V in the presence of a range of antimalarial drugs. Relationships between B19V infection status, prior 4-aminoquinoline use and anemia were assessed in 200 PNG children <10 years of age participating in a case-control study of severe infections. In CQ-treated cells, the synthesis of viral RNA, DNA and proteins was significantly higher and occurred earlier than in control cells. CQ facilitates B19V infection by minimizing intracellular degradation of incoming particles. Only amodiaquine amongst other antimalarial drugs had a similar effect. B19V IgM seropositivity was more frequent in 111 children with severe anemia (hemoglobin <50 g/L than in 89 healthy controls (15.3% vs 3.4%; P = 0.008. In children who were either B19V IgM or PCR positive, 4-aminoquinoline use was associated with a significantly lower admission hemoglobin concentration. CONCLUSIONS/SIGNIFICANCE: Our data strongly suggest that 4-aminoquinoline drugs and their metabolites exacerbate B19V-associated anemia by promoting B19V replication. Consideration should be given for choosing a non-4-aminoquinoline drug to partner artemisinin compounds in combination antimalarial therapy.

  6. Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance.

    Science.gov (United States)

    Warhurst, David C; Craig, John C; Raheem, K Saki

    2016-01-01

    Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p-aminopyridine (pAP) basic aromatic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol substituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logResistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications. PMID:27483471

  7. Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum.

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    Stephanie G Valderramos

    2010-05-01

    Full Text Available Mutant forms of the Plasmodium falciparum transporter PfCRT constitute the key determinant of parasite resistance to chloroquine (CQ, the former first-line antimalarial, and are ubiquitous to infections that fail CQ treatment. However, treatment can often be successful in individuals harboring mutant pfcrt alleles, raising questions about the role of host immunity or pharmacokinetics vs. the parasite genetic background in contributing to treatment outcomes. To examine whether the parasite genetic background dictates the degree of mutant pfcrt-mediated CQ resistance, we replaced the wild type pfcrt allele in three CQ-sensitive strains with mutant pfcrt of the 7G8 allelic type prevalent in South America, the Oceanic region and India. Recombinant clones exhibited strain-dependent CQ responses that ranged from high-level resistance to an incremental shift that did not meet CQ resistance criteria. Nonetheless, even in the most susceptible clones, 7G8 mutant pfcrt enabled parasites to tolerate CQ pressure and recrudesce in vitro after treatment with high concentrations of CQ. 7G8 mutant pfcrt was found to significantly impact parasite responses to other antimalarials used in artemisinin-based combination therapies, in a strain-dependent manner. We also report clinical isolates from French Guiana that harbor mutant pfcrt, identical or related to the 7G8 haplotype, and manifest a CQ tolerance phenotype. One isolate, H209, harbored a novel PfCRT C350R mutation and demonstrated reduced quinine and artemisinin susceptibility. Our data: 1 suggest that high-level CQR is a complex biological process dependent on the presence of mutant pfcrt; 2 implicate a role for variant pfcrt alleles in modulating parasite susceptibility to other clinically important antimalarials; and 3 uncover the existence of a phenotype of CQ tolerance in some strains harboring mutant pfcrt.

  8. Chloroquine stimulates Cl- secretion by Ca2+ activated Cl- channels in rat ileum.

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    Ning Yang

    Full Text Available Chloroquine (CQ, a bitter tasting drug widely used in treatment of malaria, is associated gastrointestinal side effects including nausea or diarrhea. In the present study, we investigated the effect of CQ on electrolyte transport in rat ileum using the Ussing chamber technique. The results showed that CQ evoked an increase in short circuit current (ISC in rat ileum at lower concentration (≤5×10(-4 M but induced a decrease at higher concentrations (≥10(-3 M. These responses were not affected by tetrodotoxin (TTX. Other bitter compounds, such as denatoniumbenzoate and quinine, exhibited similar effects. CQ-evoked increase in ISC was partly reduced by amiloride(10(-4 M, a blocker of epithelial Na(+ channels. Furosemide (10(-4 M, an inhibitor of Na(+-K(+-2Cl(- co-transporter, also inhibited the increased ISC response to CQ, whereas another Cl(- channel inhibitor, CFTR(inh-172(10(-5 M, had no effect. Intriguingly, CQ-evoked increases were almost completely abolished by niflumic acid (10(-4 M, a relatively specific Ca(2+-activated Cl(- channel (CaCC inhibitor. Furthermore, other CaCC inhibitors, such as DIDS and NPPB, also exhibited similar effects. CQ-induced increases in ISC were also abolished by thapsigargin(10(-6 M, a Ca(2+ pump inhibitor and in the absence of either Cl(- or Ca(2+ from bathing solutions. Further studies demonstrated that T2R and CaCC-TMEM16A were colocalized in small intestinal epithelial cells and the T2R agonist CQ evoked an increase of intracelluar Ca(2+ in small intestinal epithelial cells. Taken together, these results demonstrate that CQ induces Cl(- secretion in rat ileum through CaCC at low concentrations, suggesting a novel explanation for CQ-associated gastrointestinal side-effects during the treatment of malaria.

  9. Survey of chloroquine-resistant mutations in the Plasmodium falciparum pfcrt and pfmdr-1 genes in Hadhramout, Yemen.

    Science.gov (United States)

    Bamaga, Omar A A; Mahdy, Mohammed A K; Lim, Yvonne A L

    2015-09-01

    Malaria is still a major public health problem in Yemen. More than 95% of the malaria cases are due to Plasmodium ‎falciparum‎. Recently in Yemen, the antimalarial treatment policy was changed from chloroquine (CQ) to artemisinin combination therapy (ACTs). However, CQ is still available and prescribed in the Yemeni market. The persistence of CQ resistance will be prolonged if the shift to ACT and the simultaneous withdrawal of CQ are not rigorously implemented. The aim of the current survey is to detect chloroquine-resistant mutations in P. falciparum chloroquine-resistance transporter (pfcrt) and P. falciparum multi-drug resistance-1 (pfmdr1) genes. These data will be important for future monitoring and assessment of antimalarial drug policy in Yemen. Blood specimens were collected from 735 individuals from different districts of the Hadhramout province, Yemen by house-to-house visit. Mutation-specific nested polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP) methods were used to investigate the mutations in the pfmdr1(codons 86 and 1246) and pfcrt (codons 76, 271, 326, 356 and 371) genes. The overall prevalence of pfcrt mutations at codons 76, 271, 326 and 371 were 50.4%, 58.7%, 54.3% and 44.9%, respectively. All isolates had wild-type pfcrt 356 allele. The majority of pfmdr1 86 alleles (83.3%) and all pfmdr1 1246 alleles were wild type. There was no association between pfcrt mutations and symptomatology, gender and age groups. In conclusion, point mutations in codons 76, 271, 326 and 371 of pfcrt of P. falciparum are high suggesting a sustained high CQ resistance even after 4 years of shifting to ACTs. These findings warrant complete withdrawal of CQ use from the Yemeni market for P. falciparum and careful usage of CQ for treating Plasmodium vivax.

  10. In vitro effect of chloroquine, mefloquine and quinine on human lymphocyte proliferative responses to malaria antigens and other antigens/mitogens

    DEFF Research Database (Denmark)

    Bygbjerg, I C; Theander, T G; Andersen, B J;

    1986-01-01

    The effect of 3 antimalarial quinoline derivatives, chloroquine, mefloquine and quinine on human blood mononuclear cells in vitro was studied. High concentrations profoundly suppressed the proliferation of mitogen- and antigen-stimulated lymphocytes, as indicated by decreased 14C-thymidine incorp......The effect of 3 antimalarial quinoline derivatives, chloroquine, mefloquine and quinine on human blood mononuclear cells in vitro was studied. High concentrations profoundly suppressed the proliferation of mitogen- and antigen-stimulated lymphocytes, as indicated by decreased 14C......-thymidine incorporation. On a weight base, the most potent drug was mefloquine. At clinically relevant doses, chloroquine and mefloquine did not affect the response to malaria antigens, but mefloquine decreased the response to phytohaemagglutinin; quinine suppressed the response to all mitogens (with the exception...

  11. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine in Guinea-Bissau between 2003 and 2012

    DEFF Research Database (Denmark)

    Jovel, Irina Tatiana; Kofoed, Poul-Erik; Rombo, Lars;

    2015-01-01

    BACKGROUND: Guinea-Bissau, West-Africa introduced artemether-lumefantrine in 2008 but quinine has also been commonly prescribed for treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes...... of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine are described. METHODS: Pfcrt K76T, pfmdr1 gene copy numbers, N86Y, Y184F and 1034-1246 sequences were determined using PCR-based methods. Blood samples came from virtually all (n=1806) children aged.......001). CONCLUSIONS: Following the discontinuation of an effective chloroquine regimen highly artemether-lumefantrine susceptible P. falciparum (with pfcrt 76T) accumulated possibly due to suboptimal use of quinine and despite a fitness cost linked to 76T....

  12. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine in Guinea-Bissau between 2003 and 2012.

    Science.gov (United States)

    Jovel, Irina Tatiana; Kofoed, Poul-Erik; Rombo, Lars; Rodrigues, Amabelia; Ursing, Johan

    2015-02-01

    In 2008, artemether-lumefantrine was introduced in Guinea-Bissau, West Africa, but quinine has also been commonly prescribed for the treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine have been described. P. falciparum chloroquine resistance transporter (pfcrt) K76T, pfmdr1 gene copy numbers, pfmdr1 polymorphisms N86Y and Y184F, and pfmdr1 sequences 1034 to 1246 were determined using PCR-based methods. Blood samples came from virtually all (n=1,806) childrenquinine and despite a fitness cost linked to pfcrt 76T. (The studies reported here were registered at ClinicalTrials.gov under registration no. NCT00137514 [PSB-2001-chl-amo], NCT00137566 [PSB-2004-paracetamol], NCT00426439 [PSB-2006-coartem], NCT01157689 [AL-eff 2010], and NCT01704508 [Eurartesim 2012].).

  13. Different doses of amodiaquine and chloroquine for treatment of uncomplicated malaria in children in Guinea-Bissau

    DEFF Research Database (Denmark)

    Kofoed, Poul-Erik; Ursing, Johan; Poulsen, Anja;

    2007-01-01

    The aim of the present study was to compare different doses of chloroquine (CQ) and amodiaquine (AQ) for the treatment of falciparum malaria in children. Children with Plasmodium falciparum monoinfection were allocated by block randomisation to treatment with CQ 50/kg mg or 25 mg/kg or AQ 15 mg...... is not superior to treatment with CQ 50 mg/kg. However, 25 mg/kg of CQ is less efficient. As an interim option, Guinea-Bissau could change the recommended first-line treatment of uncomplicated malaria to CQ 50 mg/kg, reserving AQ as a partner drug for a future combination therapy....

  14. The effects of chloroquine and hydroxychloroquine on nitric oxide production in RAW 264.7 and bone marrow-derived macrophages.

    Science.gov (United States)

    Perečko, T; Kassab, R B; Vašíček, O; Pekarová, M; Jančinová, V; Lojek, A

    2014-01-01

    Chloroquine, an antimalarial drug, can also be used in the regulation of the immune system, e.g. it is used in the treatment of autoimmune diseases. In this study we investigated the effects of chloroquine and its hydroxy-derivative on nitric oxide (NO) production in two different cell types: (i) immortalized mouse macrophage cell line RAW 264.7 and (ii) mouse bone marrow-derived macrophages (BMDM). The cells were treated with different concentrations (1-100 μM) of chloroquine or hydroxychloroquine and stimulated with lipopolysaccharide for 24 h to induce NO production. Measurement of nitrites by the Griess reaction was used to evaluate the production of NO. Expression of inducible NO synthase was evaluated with Western blot and ATPcytotoxicity test was used to measure the viability of the cells. Our results showed that both chloroquine and its hydroxy-derivative inhibited NO production in both cell types. However, based on the results of LD50 these inhibitory effects of both derivatives were due to their cytotoxicity. The LD50 values for chloroquine were 24.77 μM (RAW 264.7) and 24.86 μM (BMDM), the LD50 for hydroxychloroquine were 13.28 μM (RAW 264.7) and 13.98 μM (BMDM). In conclusion, hydroxychloroquine was more cytotoxic than its parent molecule. Comparing the two cell types tested, our data suggest that there are no differences in cytotoxicity of chloroquine or hydroxychloroquine for primary cells (BMDM) or immortalized cell line (RAW 264.7). PMID:25369339

  15. Antiplasmodial activity-aided isolation and identification of quercetin-4'-methyl ether in Chromolaena odorata leaf fraction with high activity against chloroquine-resistant Plasmodium falciparum.

    Science.gov (United States)

    Ezenyi, I C; Salawu, O A; Kulkarni, R; Emeje, M

    2014-12-01

    The present study was undertaken to evaluate the antiplasmodial activity of Chromolaena odorata leaf extract and gradient fractions through in vivo and in vitro tests, aimed at identifying its antiplasmodial constituents. Sub-fractions obtained from the most active gradient fraction were further tested for cytotoxicity against THP-1 cells, chloroquine-sensitive (HB3) and chloroquine-resistant (FCM29) Plasmodium falciparum. Our results showed the dichloromethane gradient fraction was most effective, significantly (P odorata leaves, which exhibit potential for development as medicine against malaria. PMID:25199554

  16. Monitoring of clinical efficacy and in vitro sensitivity of Plasmodium vivax to chloroquine in area along Thai Myanmar border during 2009-2010

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    Rungsihirunrat Kanchana

    2011-02-01

    Full Text Available Abstract Background In Thailand, the proportion of Plasmodium vivax infection has become equal to Plasmodium falciparum. Reports of a trend of gradual decline of in vitro sensitivity of P. vivax to chloroquine in some areas of the country, together with accumulating evidences of chloroquine resistance P. vivax in other parts of the world, emphasize the need for closely and continuously monitoring clinical efficacy in conjunction with in vitro sensitivity of P. vivax isolates. Methods The study was conducted at Mae Tao clinic for migrant workers, Tak Province during March 2008 - August 2009. A total of 130 patients (17 Thais and 113 Burmeses; 64 males and 66 females with mono-infection of P. vivax malaria, aged between 15-60 years and weighing more than 40 kg, were included in the study. Patients received treatment with chloroquine (2,000 mg chloroquine phosphate over three days and the anti-relapse drug primaquine (15 mg for 14 days. In vitro sensitivity of P. vivax isolates was evaluated by schizont maturation inhibition assay. Results All patients showed satisfactory response to treatment. The cure rate was virtually 100% within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred during the investigation period. In vitro data showed a stable sensitivity of chloroquine in this area since 2006. Geometric mean and median (95% CI values of IC50 for chloroquine were 100.1 and 134.7 (1.1-264.9 nM, respectively. Conclusion In vivo results suggest that the standard regimen of chloroquine was still very effective for the treatment of blood infections with P. vivax in the Thai-Myanmar border area. In vitro sensitivity data however, raise the possibility of potential advent of resistance in the future. Regular monitoring of the chloroquine sensitivity of P. vivax is essential to facilitate the early recognition of treatment failures and to expedite the formulation of appropriate changes to

  17. Failure of Supervised Chloroquine and Primaquine Regimen for the Treatment of Plasmodium vivax in the Peruvian Amazon

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    Paul C. F. Graf

    2012-01-01

    Full Text Available The widespread use of primaquine (PQ and chloroquine (CQ, together, may be responsible for the relatively few, isolated cases of chloroquine-resistant P. vivax (CQRPV that have been reported from South America. We report here a case of P. vivax from the Amazon Basin of Peru that recurred against normally therapeutic blood levels of CQ. Four out of 540 patients treated with combination CQ and PQ had a symptomatic recurrence of P. vivax parasitemia within 35 days of treatment initiation, possibly indicating CQ failure. Whole blood total CQ level for one of these four subjects was 95 ng/ml on the day of recurrence. Based on published criteria that delineate CQRPV as a P. vivax parasitemia, either recrudescence or relapse, that appears against CQ blood levels >100 ng/mL, we document the occurrence of a P. vivax strain in Peru that had unusually high tolerance to the synergistic combination therapy of CQ + PQ that normally works quite well.

  18. Influence of ginger and banana starches on the mechanical and disintegration properties of chloroquine phosphate tab-lets

    Institute of Scientific and Technical Information of China (English)

    O.A.Odeku; M.A.Odeniyi; G.O.Ogunlowo

    2009-01-01

    Objective:The influence of two experimental starches -ginger starch obtained from Zingiber officinale and ba-nana starch from Musa sapientum -on the mechanical and disintegration properties of chloroquine tablets have been studied in comparison with the influence of official corn starch.Methods:Chloroquine tablets were for-mulated using various concentarions of the starches as binding agent.The mechanical properties of the tablets were assessed in terms of crushing strength and friability and the crushing strength-friability ratio (CSFR) while drug release properties were evaluated based on disintegration and the time of tablets.Results:The ranking for crushing strength and CSFR was corn >banana >ginger starch while the ranking was reverse for friability.The disintegration time increased with packing fraction and starch concentration in the rank order of formulations containing corn >banana >ginger starch.The CSFR/DT values increased with concentration of starch binder indicating an improved balance between binding and disintegrant properties of the starches.Sta-tistical analysis showed that there were significant (P <0.001)difference in the CSFR/DT for tablets contai-ning the various starch binders.Conclusion:The mechanical and disintegration properties of the experimental starches compared favorably with those of corn starch and ginger starch could be more useful when faster tablet disintegration is desired.

  19. Molecular interaction of selected phytochemicals under the charged environment of Plasmodium falciparum chloroquine resistance transporter (PfCRT) model.

    Science.gov (United States)

    Patel, Saumya K; Khedkar, Vijay M; Jha, Prakash C; Jasrai, Yogesh T; Pandya, Himanshu A; George, Linz-Buoy; Highland, Hyacinth N; Skelton, Adam A

    2016-01-01

    Phytochemicals of Catharanthus roseus Linn. and Tylophora indica have been known for their inhibition of malarial parasite, Plasmodium falciparum in cell culture. Resistance to chloroquine (CQ), a widely used antimalarial drug, is due to the CQ resistance transporter (CRT) system. The present study deals with computational modeling of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein and development of charged environment to mimic a condition of resistance. The model of PfCRT was developed using Protein homology/analogy engine (PHYRE ver 0.2) and was validated based on the results obtained using PSI-PRED. Subsequently, molecular interactions of selected phytochemicals extracted from C. roseus Linn. and T. indica were studied using multiple-iterated genetic algorithm-based docking protocol in order to investigate the translocation of these legends across the PfCRT protein. Further, molecular dynamics studies exhibiting interaction energy estimates of these compounds within the active site of the protein showed that compounds are more selective toward PfCRT. Clusters of conformations with the free energy of binding were estimated which clearly demonstrated the potential channel and by this means the translocation across the PfCRT is anticipated. PMID:25783783

  20. Characterization and evaluation of acid-modified starch of Dioscorea oppositifolia (Chinese yam as a binder in chloroquine phosphate tablets

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    Adenike Okunlola

    2013-12-01

    Full Text Available Chinese yam (Dioscorea oppositifolia starch modified by acid hydrolysis was characterized and compared with native starch as a binder in chloroquine phosphate tablet formulations. The physicochemical and compressional properties (using density measurements and the Heckel and Kawakita equations of modified Chinese yam starch were determined, and its quantitative effects as a binder on the mechanical and release properties of chloroquine phosphate were analyzed using a 2³ full factorial design. The nature (X1, concentration of starch (X2 and packing fraction (X3 were taken as independent variables and the crushing strength-friability ratio (CSFR, disintegration time (DT and dissolution time (t80 as dependent variables. Acid-modified Chinese yam starch showed a marked reduction (p<0.05 in amylose content and viscosity but increased swelling and water-binding properties. The modified starch had a faster onset and greater amount of plastic flow. Changing the binder from native to acid-modified form led to significant increases (p<0.05 in CSFR and DT but a decrease in t80. An increase in binder concentration and packing fraction gave similar results for CSFR and DT only. These results suggest that acid-modified Chinese yam starches may be useful as tablet binders when high bond strength and fast dissolution are required.

  1. Functional Comparison of 45 Naturally Occurring Isoforms of the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT).

    Science.gov (United States)

    Callaghan, Paul S; Hassett, Matthew R; Roepe, Paul D

    2015-08-18

    At least 53 distinct isoforms of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein are expressed in strains or isolates of P. falciparum malarial parasites from around the globe. These parasites exhibit a range of sensitivities to chloroquine (CQ) and other drugs. Mutant PfCRT is believed to confer cytostatic CQ resistance (CQR(CS)) by transporting CQ away from its DV target (free heme released upon hemoglobin digestion). One theory is that variable CQ transport catalyzed by these different PfCRT isoforms is responsible for the range of CQ sensitivities now found for P. falciparum. Alternatively, additional mutations in drug-selected parasites, or additional functions of PfCRT, might complement PfCRT-mediated CQ transport in conferring the range of observed resistance phenotypes. To distinguish between these possibilities, we recently optimized a convenient method for measuring PfCRT-mediated CQ transport, involving heterologous expression in Saccharomyces cerevisiae. Here, we use this method to quantify drug transport activity for 45 of 53 of the naturally occurring PfCRT isoforms. Data show that variable levels of CQR likely depend upon either additional PfCRT functions or additional genetic events, including perhaps changes that influence DV membrane potential. The data also suggest that the common K76T PfCRT mutation that is often used to distinguish a P. falciparum CQR phenotype is not, in and of itself, a fully reliable indicator of CQR status.

  2. Molecular interaction of selected phytochemicals under the charged environment of Plasmodium falciparum chloroquine resistance transporter (PfCRT) model.

    Science.gov (United States)

    Patel, Saumya K; Khedkar, Vijay M; Jha, Prakash C; Jasrai, Yogesh T; Pandya, Himanshu A; George, Linz-Buoy; Highland, Hyacinth N; Skelton, Adam A

    2016-01-01

    Phytochemicals of Catharanthus roseus Linn. and Tylophora indica have been known for their inhibition of malarial parasite, Plasmodium falciparum in cell culture. Resistance to chloroquine (CQ), a widely used antimalarial drug, is due to the CQ resistance transporter (CRT) system. The present study deals with computational modeling of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein and development of charged environment to mimic a condition of resistance. The model of PfCRT was developed using Protein homology/analogy engine (PHYRE ver 0.2) and was validated based on the results obtained using PSI-PRED. Subsequently, molecular interactions of selected phytochemicals extracted from C. roseus Linn. and T. indica were studied using multiple-iterated genetic algorithm-based docking protocol in order to investigate the translocation of these legends across the PfCRT protein. Further, molecular dynamics studies exhibiting interaction energy estimates of these compounds within the active site of the protein showed that compounds are more selective toward PfCRT. Clusters of conformations with the free energy of binding were estimated which clearly demonstrated the potential channel and by this means the translocation across the PfCRT is anticipated.

  3. Large-scale survey for novel genotypes of Plasmodium falciparum chloroquine-resistance gene pfcrt

    Directory of Open Access Journals (Sweden)

    Takahashi Nobuyuki

    2012-03-01

    Full Text Available Abstract Background In Plasmodium falciparum, resistance to chloroquine (CQ is conferred by a K to T mutation at amino acid position 76 (K76T in the P. falciparum CQ transporter (PfCRT. To date, at least 15 pfcrt genotypes, which are represented by combinations of five amino acids at positions 72-76, have been described in field isolates from various endemic regions. To identify novel mutant pfcrt genotypes and to reveal the genetic relatedness of pfcrt genotypes, a large-scale survey over a wide geographic area was performed. Methods Sequences for exon 2 in pfcrt, including known polymorphic sites at amino acid positions 72, 74, 75 and 76, were obtained from 256 P. falciparum isolates collected from eight endemic countries in Asia (Bangladesh, Cambodia, Lao P.D.R., the Philippines and Thailand, Melanesia (Papua New Guinea and Vanuatu and Africa (Ghana. A haplotype network was constructed based on six microsatellite markers located -29 kb to 24 kb from pfcrt in order to examine the genetic relatedness among mutant pfcrt genotypes. Results In addition to wild type (CVMNK at positions 72-76, four mutant pfcrt were identified; CVIET, CVIDT, SVMNT and CVMNT (mutated amino acids underlined. Haplotype network revealed that there were only three mutant pfcrt lineages, originating in Indochina, Philippines and Melanesia. Importantly, the Indochina lineage contained two mutant pfcrt genotypes, CVIET (n = 95 and CVIDT (n = 14, indicating that CVIDT shares a common origin with CVIET. Similarly, one major haplotype in the Melanesian lineage contained two pfcrt genotypes; SVMNT (n = 71 and CVMNT (n = 3. In Africa, all mutant pfcrt genotypes were the CVIET of the Indochina lineage, probably resulting from the intercontinental migration of CQ resistance from Southeast Asia. Conclusions The number of CQ-mutant lineages observed in this study was identical to that found in previous studies. This supports the hypothesis that the emergence of novel CQ resistance

  4. Are Long-Term Chloroquine or Hydroxychloroquine Users Being Checked Regularly for Toxic Maculopathy?

    Science.gov (United States)

    Nika, Melisa; Blachley, Taylor S.; Edwards, Paul; Lee, Paul P.; Stein, Joshua D.

    2014-01-01

    Importance According to evidence-based, expert recommendations, long-term users of chloroquine (CQ) or hydroxychloroquine (HCQ) should undergo regular visits to eye-care providers and diagnostic testing to check for maculopathy. Objective To determine whether patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) taking CQ or HCQ are regularly visiting eye-care providers and being screened for maculopathy. Setting, Design and Participants Patients with RA or SLE who were continuously enrolled in a particular managed-care network for ≥5 years during 2001-2011 were studied. Patients' amount of CQ/HCQ use in the 5 years since initial RA/SLE diagnosis was calculated, along with their number of eye-care visits and diagnostic tests for maculopathy. Those at high risk for maculopathy were identified. Visits to eye providers and diagnostic testing for maculopathy were assessed for each enrollee over the study period. Logistic regression was performed to assess potential factors associated with regular eye-care-provider visits (≥3 in 5 years) among CQ/HCQ users, including those at greatest risk for maculopathy. Main Outcome Measures Among CQ/HCQ users and those at high risk for toxic maculopathy, the proportions with regular eye-care visits and diagnostic testing, and the likelihood of regular eye-care visits (odds ratios [ORs] with 95% confidence intervals [CI]). Results Among 18,051 beneficiaries with RA or SLE, 6,339 (35.1%) had ≥1 record of HCQ/CQ use and 1,409 (7.8%) used HCQ/CQ for ≥4 years. Among those at high risk for maculopathy, 27.9% lacked regular eye-provider visits, 6.1% had no visits to eye providers, and 34.5% had no diagnostic testing for maculopathy during the 5-year period. Among high-risk patients, each additional month of HCQ/CQ use was associated with a 2.0%-increased likelihood of regular eye care (adjusted OR=1.02, CI=1.01-1.03). High-risk patients whose SLE/RA were managed by rheumatologists had a 77%-increased

  5. From chloroquine to artemether-lumefantrine: the process of drug policy change in Zambia

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    Snow Robert W

    2008-01-01

    Full Text Available Abstract Background Following the recognition that morbidity and mortality due to malaria had dramatically increased in the last three decades, in 2002 the government of Zambia reviewed its efforts to prevent and treat malaria. Convincing evidence of the failing efficacy of chloroquine resulted in the initiation of a process that eventually led to the development and implementation of a new national drug policy based on artemisinin-based combination therapy (ACT. Methods All published and unpublished documented evidence dealing with the antimalarial drug policy change was reviewed. These data were supplemented by the authors' observations of the policy change process. The information has been structured to capture the timing of events, the challenges encountered, and the resolutions reached in order to achieve implementation of the new treatment policy. Results A decision was made to change national drug policy to artemether-lumefantrine (AL in the first quarter of 2002, with a formal announcement made in October 2002. During this period, efforts were undertaken to identify funding for the procurement of AL and to develop new malaria treatment guidelines, training materials, and plans for implementation of the policy. In order to avoid a delay in implementation, the policy change decision required a formal adoption within existing legislation. Starting with donated drug, a phased deployment of AL began in January 2003 with initial use in seven districts followed by scaling up to 28 districts in the second half of 2003 and then to all 72 districts countrywide in early 2004. Conclusion Drug policy changes are not without difficulties and demand a sustained international financing strategy for them to succeed. The Zambian experience demonstrates the need for a harmonized national consensus among many stakeholders and a political commitment to ensure that new policies are translated into practice quickly. To guarantee effective policies requires

  6. Chloroquine enhances gefitinib cytotoxicity in gefitinib-resistant nonsmall cell lung cancer cells.

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    Mei-Chuan Tang

    Full Text Available Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs, including gefitinib, are effective for non-small cell lung cancer (NSCLC patients with EGFR mutations. However, these patients eventually develop resistance to EGFR-TKI. The goal of the present study was to investigate the involvement of autophagy in gefitinib resistance. We developed gefitinib-resistant cells (PC-9/gef from PC-9 cells (containing exon 19 deletion EGFR after long-term exposure in gefitinib. PC-9/gef cells (B4 and E3 were 200-fold more resistant to gefitinib than PC-9/wt cells. Compared with PC-9/wt cells, both PC-9/gefB4 and PC-9/gefE3 cells demonstrated higher basal LC3-II levels which were inhibited by 3-methyladenine (3-MA, an autophagy inhibitor and potentiated by chloroquine (CQ, an inhibitor of autophagolysosomes formation, indicating elevated autophagy in PC-9/gef cells. 3-MA and CQ concentration-dependently inhibited cell survival of both PC-9wt and PC-9/gef cells, suggesting that autophagy may be pro-survival. Furthermore, gefitinib increased LC3-II levels and autolysosome formation in both PC-9/wt cells and PC-9/gef cells. In PC-9/wt cells, CQ potentiated the cytotoxicity by low gefitinib (3 nM. Moreover, CQ overcame the acquired gefitinib resistance in PC-9/gef cells by enhancing gefitinib-induced cytotoxicity, activation of caspase 3 and poly (ADP-ribose polymerase cleavage. Using an in vivo model xenografting with PC-9/wt and PC-9/gefB4 cells, oral administration of gefitinib (50 mg/kg completely inhibited the tumor growth of PC-9/wt but not PC-9/gefB4cells. Combination of CQ (75 mg/kg, i.p. and gefitinib was more effective than gefitinib alone in reducing the tumor growth of PC-9/gefB4. Our data suggest that inhibition of autophagy may be a therapeutic strategy to overcome acquired resistance of gefitinib in EGFR mutation NSCLC patients.

  7. Occurrence of the Southeast Asian/South American SVMNT haplotype of the chloroquine-resistance transporter gene in Plasmodium falciparum in Tanzania

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Dalgaard, Michael B; Lusingu, John P;

    2006-01-01

    Two main haplotypes, CVIET and SVMNT, of the Plasmodium falciparum chloroquine-resistance transporter gene (Pfcrt) are linked to 4-aminoquinoline resistance. The CVIET haplotype has been reported in most malaria-endemic regions, whereas the SVMNT haplotype has only been found outside Africa. We i...

  8. Chloroquine improved carbon tetrachloride-induced liver fibrosis through its inhibition of the activation of hepatic stellate cells: role of autophagy.

    Science.gov (United States)

    He, Wei; Wang, Bin; Yang, Jing; Zhuang, Yun; Wang, Liangzhi; Huang, Xiaodan; Chen, Jianping

    2014-01-01

    Autophagy is involved in the activation of hepatic stellate cells (HSCs), which is the key process of liver fibrosis. We reasoned that chloroquine, based on its ability to inhibit autophagy, might exert beneficial effects in liver fibrosis. Liver fibrosis in rats was induced by carbon tetrachloride (CCl4). Rats were divided into three groups, a normal control group (N group), model group (M group), and chloroquine group (CQ group). Liver fibrosis in the rats was evaluated by hematoxyline-eosin (H&E) and Masson staining. The activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) were determined using an automated biochemistry analyzer. Total hepatic hydroxyproline levels were determined with a kit. The expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) were detected by immunofluorescence staining, and the expressions of LC3-II and p62 were determined by Western blotting. Compared with N group, M group showed impaired liver function, liver fibrosis, increased hydroxyproline content, up-regulated expressions of α-SMA and TGF-β1, which have been reported to be pro-fibrogenic genes in vivo, and increased autophagy flux as indicated by the accumulation of LC3-II and degradation of p62. These changes were attenuated by chloroquine treatment. Chloroquine exerts beneficial effects in CCl4-induced liver fibrosis. The mechanism of action includes inhibition of autophagy pathways and inhibition of activation of HSCs. PMID:25177034

  9. A thirteen-year analysis of Plasmodium falciparum populations reveals high conservation of the mutant pfcrt haplotype despite the withdrawal of chloroquine from national treatment guidelines in Gabon

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    Ngoma Ghyslain

    2011-10-01

    Full Text Available Abstract Background Chloroquine resistance (CR decreased after the removal of chloroquine from national treatment guidelines in Malawi, Kenia and Tanzania. In this investigation the prevalence of the chloroquine resistance (CQR conferring mutant pfcrt allele and its associated chromosomal haplotype were determined before and after the change in Gabonese national treatment guidelines from chloroquine (CQ to artesunate plus amodiaquine (AQ in 2003. Methods The prevalence of the wild type pfcrt allele was assessed in 144 isolates from the years 2005 - 07 by PCR fragment restriction digest and direct sequencing. For haplotype analysis of the chromosomal regions flanking the pfcrt locus, microsatellite analysis was done on a total of 145 isolates obtained in 1995/96 (43 isolates, 2002 (47 isolates and 2005 - 07 (55 isolates. Results The prevalence of the mutant pfcrt allele decreased from 100% in the years 1995/96 and 2002 to 97% in 2005 - 07. Haplotype analysis showed that in 1995/96 79% of the isolates carried the same microsatellite alleles in a chromosomal fragment spanning 39 kb surrounding the pfcrt locus. In 2002 and 2005 - 07 the prevalence of this haplotype was 62% and 58%, respectively. Pfcrt haplotype analysis showed that all wild type alleles were CVMNK. Conclusion Four years after the withdrawal of CQ from national treatment guidelines the prevalence of the mutant pfcrt allele remains at 97%. The data suggest that the combination of artesunate plus AQ may result in continued selection for the mutant pfcrt haplotype even after discontinuance of CQ usage.

  10. Spinal neurons that contain gastrin-releasing peptide seldom express Fos or phosphorylate extracellular signal-regulated kinases in response to intradermal chloroquine

    Science.gov (United States)

    Bell, Andrew M; Gutierrez-Mecinas, Maria; Polgár, Erika; Todd, Andrew J

    2016-01-01

    Background Gastrin-releasing peptide (GRP) is thought to play a role in the itch evoked by intradermal injection of chloroquine. Although some early studies suggested that GRP was expressed in pruriceptive primary afferents, it is now thought that GRP in the spinal cord is derived mainly from a population of excitatory interneurons in lamina II, and it has been suggested that these are involved in the itch pathway. To test this hypothesis, we used the transcription factor Fos and phosphorylation of extracellular signal-regulated kinases (ERK) to look for evidence that interneurons expressing GRP were activated following intradermal injection of chloroquine into the calf, in mice that express enhanced green fluorescent protein (EGFP) in these cells. Results Injection of chloroquine resulted in numerous Fos- or phospho-ERK (pERK) positive cells in the somatotopically appropriate part of the superficial dorsal horn. The proportion of all neurons in this region that showed Fos or pERK was 18% and 21%, respectively. However, among the GRP–EGFP, only 7% were Fos-positive and 3% were pERK-positive. As such, GRP–EGFP cells were significantly less likely than other neurons to express Fos or to phosphorylate ERK. Conclusions Both expression of Fos and phosphorylation of ERK can be used to identify dorsal horn neurons activated by chloroquine injection. However, these results do not support the hypothesis that interneurons expressing GRP are critical components in the itch pathway. PMID:27270268

  11. The synergistic effect of everolimus and chloroquine on endothelial cell number reduction is paralleled by increased apoptosis and reduced autophagy occurrence.

    Directory of Open Access Journals (Sweden)

    Anna Grimaldi

    Full Text Available Endothelial Progenitor Cells (EPCs, a minor subpopulation of the mononuclear cell fraction in peripheral blood, play a critical role in cancer development as they contribute to angiogenesis-mediated pathological neovascularization. In response to tumor cytokines, including VEGF, EPCs mobilize from the bone marrow into the peripheral circulation and move to the tumor bed where they incorporate into sprouting neovessels. In the present study, we evaluated the effects of everolimus (Afinitor, Novartis, a rapamycin analogue, alone or in combination with chloroquine, a 4-alkylamino substituted quinoline family member, one of the autophagy inhibitors, on EPCs biological functions. We found that either everolimus or chloroquine induce growth inhibition on EPCs in a dose-dependent manner after 72 h from the beginning of incubation. The combined administration of the two drugs to EPC was synergistic in inducing growth inhibition; in details, the maximal pharmacological synergism between everolimus and chloroquine in inducing growth inhibition on EPCs cells was recorded when chloroquine was administered 24 h before everolimus. Moreover, we have studied the mechanisms of cell death induced by the two agents alone or in combination on EPCs and we have found that the synergistic effect of combination on EPC growth inhibition was paralleled by increased apoptosis induction and reduced autophagy. These effects occurred together with biochemical features that are typical of reduced autophagic death such as increased co-immunoprecipitation between Beclin 1 and Bcl-2. Chloroquine antagonized the inhibition of the activity of Akt→4EBP1 axis mediated by everolimus and at the same time it blocked the feed-back activation of Erk-1/2 induced by RAD in EPCs. These data suggest a new strategy in order to block angiogenesis in tumours in which this process plays a key role in both the sustainment and spreading of cancer cells.

  12. Development of ELISA-based methods to measure the anti-malarial drug chloroquine in plasma and in pharmaceutical formulations

    DEFF Research Database (Denmark)

    Khalil, Insaf F; Alifrangis, Michael; Recke, Camilla;

    2011-01-01

    therapeutic agent. There is a dire need to continue monitoring quality of CQ as there is a major influx of substandard and fake formulations into malaria-endemic countries. The use of fake/substandard drugs will result in sub-therapeutic levels endangering the patient and possibly select for parasite......In Central and South America and Eastern and Southern Africa, Plasmodium vivax infections accounts for 71-81% and 5% of malaria cases, respectively. In these areas, chloroquine (CQ) remains the treatment of choice for P. vivax malaria. In addition, CQ has recently proven to be an effective HIV-1...... resistance. The aim of this study was to develop an inexpensive, simple antibody-based ELISA to measure CQ concentrations in tablets and in plasma....

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

    Science.gov (United States)

    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.

  14. 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.

  15. FET-PET-based reirradiation and chloroquine in patients with recurrent glioblastoma. First tolerability and feasibility results

    Energy Technology Data Exchange (ETDEWEB)

    Bilger, Angelika; Bittner, Martin-Immanuel; Grosu, Anca L.; Wiedenmann, Nicole; Firat, Elke; Niedermann, Gabriele; Milanovic, Dusan [University Medical Center Freiburg, Department of Radiation Oncology, Freiburg (Germany); Meyer, Philipp T. [University Medical Center Freiburg, Department of Nuclear Medicine, Freiburg (Germany); Weber, Wolfgang A. [University Medical Center Freiburg, Department of Nuclear Medicine, Freiburg (Germany); Memorial Sloan-Kettering Cancer Center, Molecular Imaging and Therapy Service, York Avenue, NY (United States)

    2014-10-15

    Treatment of recurrent glioblastoma (rGBM) remains an unsolved clinical problem. Reirradiation (re-RT) can be used to treat some patients with rGBM, but as a monotherapy it has only limited efficacy. Chloroquine (CQ) is an anti-malaria and immunomodulatory drug that may inhibit autophagy and increase the radiosensitivity of GBM. Between January 2012 and August 2013, we treated five patients with histologically confirmed rGBM with re-RT and 250 mg CQ daily. Treatment was very well tolerated; no CQ-related toxicity was observed. At the first follow-up 2 months after finishing re-RT, two patients achieved partial response (PR), one patient stable disease (SD), and one patient progressive disease (PD). One patient with reirradiated surgical cavity did not show any sign of PD. In this case series, we observed encouraging responses to CQ and re-RT. We plan to conduct a CQ dose escalation study combined with re-RT. (orig.) [German] Die Behandlung rezidivierter Glioblastome (rGBM) ist problematisch. Manche Patienten koennen erneut bestrahlt (re-RT) werden, jedoch nur mit begrenzter Wirksamkeit. Das Antimalariamittel Chloroquin (CQ) wirkt immunmodulatorisch, hemmt die Autophagie und kann die Radiosensibilitaet erhoehen. Zwischen Januar 2012 und August 2013 wurden 5 Patienten mit einem histologisch gesicherten rGBM mit re-RT und zusaetzlich taeglich 250 mg CQ behandelt. Diese Behandlung wurde sehr gut, ohne CQ-assoziierte Nebenwirkungen toleriert. Zum ersten Follow-up, 2 Monate nach der re-RT, fanden sich zwei partielle Remissionen (PR), ein stabiler Verlauf (SD) und ein Progress (PD). Ein zuvor operierter Patient war in anhaltender Remission. Diese Fallstudie zeigt ein ermutigendes Ansprechen von Patienten mit rGBM auf eine Behandlung mit CQ und re-RT. Eine Dosiseskalationsstudie CQ/re-RT ist geplant. (orig.)

  16. Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt.

    Science.gov (United States)

    Pelleau, Stéphane; Moss, Eli L; Dhingra, Satish K; Volney, Béatrice; Casteras, Jessica; Gabryszewski, Stanislaw J; Volkman, Sarah K; Wirth, Dyann F; Legrand, Eric; Fidock, David A; Neafsey, Daniel E; Musset, Lise

    2015-09-15

    In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance.

  17. The detection of pfcrt and pfmdr1 point mutations as molecular markers of chloroquine drug resistance, Pahang, Malaysia

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    Atroosh Wahib M

    2012-08-01

    Full Text Available Abstract Background Malaria is still a public health problem in Malaysia with chloroquine (CQ being the first-line drug in the treatment policy of uncomplicated malaria. There is a scarcity in information about the magnitude of Plasmodium falciparum CQ resistance. This study aims to investigate the presence of single point mutations in the P. falciparum chloroquine-resistance transporter gene (pfcrt at codons 76, 271, 326, 356 and 371 and in P. falciparum multi-drug resistance-1 gene (pfmdr1 at codons 86 and 1246, as molecular markers of CQ resistance. Methods A total of 75 P. falciparum blood samples were collected from different districts of Pahang state, Malaysia. Single nucleotide polymorphisms in pfcrt gene (codons 76, 271, 326, 356 and 371 and pfmdr1 gene (codons 86 and 1246 were analysed by using mutation-specific nested PCR and restriction fragment length polymorphism (PCR-RFLP methods. Results Mutations of pfcrt K76T and pfcrt R371I were the most prevalent among pfcrt gene mutations reported by this study; 52% and 77%, respectively. Other codons of the pfcrt gene and the positions 86 and 1246 of the pfmdr1 gene were found mostly of wild type. Significant associations of pfcrt K76T, pfcrt N326S and pfcrt I356T mutations with parasitaemia were also reported. Conclusion The high existence of mutant pfcrt T76 may indicate the low susceptibility of P. falciparum isolates to CQ in Peninsular Malaysia. The findings of this study establish baseline data on the molecular markers of P. falciparum CQ resistance, which may help in the surveillance of drug resistance in Peninsular Malaysia.

  18. Nonradioactive heteroduplex tracking assay for the detection of minority-variant chloroquine-resistant Plasmodium falciparum in Madagascar

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    Mwapasa Victor

    2009-03-01

    Full Text Available Abstract Background Strains of Plasmodium falciparum genetically resistant to chloroquine (CQ due to the presence of pfcrt 76T appear to have been recently introduced to the island of Madagascar. The prevalence of such resistant genotypes is reported to be low (P. falciparum isolates on the island. Previously, minority variant chloroquine resistant parasites were described in Malawian patients using an isotopic heteroduplex tracking assay (HTA, which can detect pfcrt 76T-bearing P. falciparum minority variants in individual patients that were undetectable by conventional PCR. However, as this assay required a radiolabeled probe, it could not be used in many resource-limited settings. Methods This study describes a digoxigenin (DIG-labeled chemiluminescent heteroduplex tracking assay (DIG-HTA to detect pfcrt 76T-bearing minority variant P. falciparum. This assay was compared to restriction fragment length polymorphism (RFLP analysis and to the isotopic HTA for detection of genetically CQ-resistant parasites in clinical samples. Results Thirty one clinical P. falciparum isolates (15 primary isolates and 16 recurrent isolates from 17 Malagasy children treated with CQ for uncomplicated malaria were genotyped for the pfcrt K76T mutation. Two (11.7% of 17 patients harboured genetically CQ-resistant P. falciparum strains after therapy as detected by HTA. RFLP analysis failed to detect any pfcrt K76T-bearing isolates. Conclusion These findings indicate that genetically CQ-resistant P. falciparum are more common than previously thought in Madagascar even though the fitness of the minority variant pfcrt 76T parasites remains unclear. In addition, HTAs for malaria drug resistance alleles are promising tools for the surveillance of anti-malarial resistance. The use of a non-radioactive label allows for the use of HTAs in malaria endemic countries.

  19. [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.

  20. The effect of prophylaxis with chloroquine and proguanil on delayed-type hypersensitivity and antibody production following vaccination with diphtheria, tetanus, polio, and pneumococcal vaccines

    DEFF Research Database (Denmark)

    Gyhrs, A; Pedersen, B K; Bygbjerg, I;

    1991-01-01

    (1,000 mg/week), or 4) proguanil hydrochloride (200 mg/day) for six weeks. Skin testing was performed on days 0 and 28. Vaccinations with diphtheria, tetanus, polio, and pneumococcal polysaccharide antigen vaccines were performed on day 28, and the presence of specific antibodies was determined...... dosages, does not induce any detectable suppression of delayed-type hypersensitivity or vaccination responses to diphtheria, tetanus, polio, or pneumococcal polysaccharide antigens....... with seven delayed-type common antigens (Multitest) and 2) humoral immunity by measurement of specific antibody response to vaccination. Sixty healthy young individuals were randomized into four groups and given 1) no treatment (controls), 2) chloroquine diphosphate (500 mg/week), 3) chloroquine diphosphate...

  1. Antiplasmodial properties of kaempferol-3-O-rhamnoside isolated from the leaves of Schima wallichii against chloroquine-resistant Plasmodium falciparum

    Science.gov (United States)

    BARLIANA, MELISA I.; SURADJI, EKA W.; ABDULAH, RIZKY; DIANTINI, AJENG; HATABU, TOSHIMITSU; NAKAJIMA-SHIMADA, JUNKO; SUBARNAS, ANAS; KOYAMA, HIROSHI

    2014-01-01

    Previous intervention studies have shown that the most effective agents used in the treatment of malaria were isolated from natural sources. Plants consumed by non-human primates serve as potential drug sources for human disease management due to the similarities in anatomy, physiology and disease characteristics. The present study investigated the antiplasmodial properties of the primate-consumed plant, Schima wallichii (S. wallichii) Korth. (family Theaceae), which has already been reported to have several biological activities. The ethanol extract of S. wallichii was fractionated based on polarity using n-hexane, ethyl acetate and water. The antiplasmodial activity was tested in vitro against chloroquine-resistant Plasmodium falciparum (P. falciparum) at 100 μg/ml for 72 h. The major compound of the most active ethyl acetate fraction was subsequently isolated using column chromatography and identified by nuclear magnetic resonance. The characterized compound was also tested against chloroquine-resistant P. falciparum in culture to evaluate its antiplasmodial activity. The ethanol extract of S. wallichii at 100 μg/ml exhibited a significant parasite shrinkage after 24 h of treatment. The ethyl acetate fraction at 100 μg/ml was the most active fraction against chloroquine-resistant P. falciparum. Based on the structural characterization, the major compound isolated from the ethyl acetate fraction was kaempferol-3-O-rhamnoside, which showed promising antiplasmodial activity against chloroquine-resistant P. falciparum with an IC50 of 106 μM after 24 h of treatment. The present study has provided a basis for the further investigation of kaempferol-3-O-rhamnoside as an active compound for potential antimalarial therapeutics. PMID:24944812

  2. Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso [ISRCTN27290841

    OpenAIRE

    Walter-Sack Ingeborg; Tapsoba Théophile; Sanon Mamadou; Jahn Albrecht; Schiek Wolfgang; Rengelshausen Jens; Mansmann Ulrich; Coulibaly Boubacar; Witte Steffen; Mandi Germain; Meissner Peter E; Mikus Gerd; Burhenne Jürgen; Riedel Klaus-Dieter; Schirmer Heiner

    2005-01-01

    Abstract Background Safe, effective and affordable drug combinations against falciparum malaria are urgently needed for the poor populations in malaria endemic countries. Methylene blue (MB) combined with chloroquine (CQ) has been considered as one promising new regimen. Objectives The primary objective of this study was to evaluate the safety of CQ-MB in African children with uncomplicated falciparum malaria. Secondary objectives were to assess the efficacy and the acceptance of CQ-MB in a r...

  3. Multiple Origins of Mutations in the mdr1 Gene--A Putative Marker of Chloroquine Resistance in P. vivax.

    Directory of Open Access Journals (Sweden)

    Mette L Schousboe

    2015-11-01

    Full Text Available Chloroquine combined with primaquine has been the recommended antimalarial treatment of Plasmodium vivax malaria infections for six decades but the efficacy of this treatment regimen is threatened by chloroquine resistance (CQR. Single nucleotide polymorphisms (SNPs in the multidrug resistance gene, Pvmdr1 are putative determinants of CQR but the extent of their emergence at population level remains to be explored.In this study we describe the prevalence of SNPs in the Pvmdr1 among samples collected in seven P. vivax endemic countries and we looked for molecular evidence of drug selection by characterising polymorphism at microsatellite (MS loci flanking the Pvmdr1 gene.We examined the prevalence of SNPs in the Pvmdr1 gene among 267 samples collected from Pakistan, Afghanistan, Sri Lanka, Nepal, Sudan, São Tomé and Ecuador. We measured and diversity in four microsatellite (MS markers flanking the Pvmdr1 gene to look evidence of selection on mutant alleles.SNP polymorphism in the Pvmdr1 gene was largely confined to codons T958M, Y976F and F1076L. Only 2.4% of samples were wildtype at all three codons (TYF, n = 5, 13.3% (n = 28 of the samples were single mutant MYF, 63.0% of samples (n = 133 were double mutant MYL, and 21.3% (n = 45 were triple mutant MFL. Clear geographic differences in the prevalence of these Pvmdr mutation combinations were observed. Significant linkage disequilibrium (LD between Pvmdr1 and MS alleles was found in populations sampled in Ecuador, Nepal and Sri Lanka, while significant LD between Pvmdr1 and the combined 4 MS locus haplotype was only seen in Ecuador and Sri Lanka. When combining the 5 loci, high level diversity, measured as expected heterozygosity (He, was seen in the complete sample set (He = 0.99, while He estimates for individual loci ranged from 0.00-0.93. Although Pvmdr1 haplotypes were not consistently associated with specific flanking MS alleles, there was significant differentiation between geographic

  4. Antiplasmodial activity of certain medicinal plants against chloroquine resistant Plasmodium berghei infected white albino BALB/c mice.

    Science.gov (United States)

    Rajendran, C; Begam, M; Kumar, Dharmendra; Baruah, Indra; Gogoi, H K; Srivastava, R B; Veer, Vijay

    2014-06-01

    In the present study of antimalarial efficacy, aqueous extracts of leaves and unripe fruits of Psidium guajava, leaves of Ocimum sanctum and leaves of Murraya koenigii are evaluated against Plasmodium berghei (chloroquine resistant NK65 strain) infected white albino BALB/c mice. A 7 days oral administration was adopted with different dosage viz., 350 mg, 750 mg and 1,000 mg/kg body weight as treatment schedule along with parasite (Group I) and drug control with Chloroquine, 50 mg/kg body weight (Group II). All the parts were extracted based on the decoction method, which is commonly seen among the villagers/tribes as their usual method of preparation of decoction for most of the ailments. The antimalarial activities were evaluated from the giemsa stained blood smears collected from different treated groups of mice used in this experiment. The antiplasmodial effect that is percent parasitaemia and percent suppression (values in parenthesis) showed by the treated groups of mice at 350 mg/kg b. wt. by the aqueous extracts of P. guajava leaves (Group III) was 19.8 ± 1.22 (73.7 %), P. guajava unripe fruits (Group IV) was 52.7 ± 2.19 (30.0 %), leaves of O. sanctum (Group V) was 64.0 ± 0.73 (15.1 %) and leaves of M. koenigii (Group VI) was 28.9 ± 0.81 (61.6 %) whereas at 750 mg/kg b. wt., it all showed 10.3 ± 0.7 (80.2 %), 26.3 ± 0.52 (65.1 %), 42.0 ± 0.47 (44.2 %) and 14.9 ± 0.46 (71.5 %) whereas at 1,000 mg/kg b. wt. dose, it all showed 9.2 ± 0.39 (85.8 %), 25.6 ± 0.40 (62.0 %), 41.8 ± 0.29 (35.5 %) and 14.0 ± 0.42 (76.9 %) respectively. PMID:24808642

  5. Microsatellite polymorphism within pfcrt provides evidence of continuing evolution of chloroquine-resistant alleles in Papua New Guinea

    Directory of Open Access Journals (Sweden)

    Sharma Yagya D

    2007-03-01

    Full Text Available Abstract Background Polymorphism in the pfcrt gene underlies Plasmodium falciparum chloroquine resistance (CQR, as sensitive strains consistently carry lysine (K, while CQR strains carry threonine (T at the codon 76. Previous studies have shown that microsatellite (MS haplotype variation can be used to study the evolution of CQR polymorphism and to characterize intra- and inter-population dispersal of CQR in Papua New Guinea (PNG. Methods Here, following identification of new polymorphic MS in introns 2 and 3 within the pfcrt gene (msint2 and msint3, respectively, locus-by-locus and haplotype heterozygosity (H analyses were performed to determine the distribution of this intronic polymorphism among pfcrt chloroquine-sensitive and CQR alleles. Results For MS flanking the pfcrt CQR allele, H ranged from 0.07 (B5M77, -18 kb to 0.094 (9B12, +2 kb suggesting that CQ selection pressure was responsible for strong homogenisation of this gene locus. In a survey of 206 pfcrt-SVMNT allele-containing field samples from malaria-endemic regions of PNG, H for msint2 was 0.201. This observation suggests that pfcrt msint2 exhibits a higher level of diversity than what is expected from the analyses of pfcrt flanking MS. Further analyses showed that one of the three haplotypes present in the early 1980's samples has become the predominant haplotype (frequency = 0.901 in CQR parasite populations collected after 1995 from three PNG sites, when CQR had spread throughout malaria-endemic regions of PNG. Apparent localized diversification of pfcrt haplotypes at each site was also observed among samples collected after 1995, where minor CQR-associated haplotypes were found to be unique to each site. Conclusion In this study, a higher level of diversity at MS loci within the pfcrt gene was observed when compared with the level of diversity at pfcrt flanking MS. While pfcrt (K76T and its immediate flanking region indicate homogenisation in PNG CQR parasite populations

  6. 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.

  7. [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)].

  8. Preparation and in vitro evaluation of liposomal chloroquine diphosphate loaded by a transmembrane pH-gradient method.

    Science.gov (United States)

    Qiu, Liyan; Jing, Na; Jin, Yi

    2008-09-01

    This study developed an active loading method for encapsulating chloroquine diphosphate (CQ) into liposomes. The effects of different formulation factors on the encapsulation efficiency (EE) and the size of CQ liposomes were investigated. These factors included the internal phase of liposomes, the external phase of liposomes, the ratio of drug to soybean phosphatidylcholine (drug/SPC), the ratio of cholesterol to soybean phosphatidylcholine (Chol/SPC), and the incubation temperature and time. The EE (93%) was obtained when using drug/SPC (1:50 mass ratio), SPC/Chol (1:5 mass ratio) at 0.10 M citrate-sodium citrate buffer (pH 3.6). As 5 mol% methoxypoly(ethylene glycol)(2,000) cholesteryl succinate (CHS-PEG(2000)) or distearoyl phosphatidylethanolamine-poly (ethylene glycol)(2,000) (DSPE-PEG(2000)) was added, the size of particle was reduced and the EE was improved. Freeze-drying with 5% trehalose as a cryoprotectant was carried out to achieve long-term stability. The drug release studies were performed in vitro simulating the desired application conditions, such as physiological fluids (pH 7.4), tumor tissues (pH 6.5) and endosomal compartments (pH 5.5). The release of CQ from the liposomes prepared via remote loading showed the significant pH-sensitivity and retention properties, which favored the application of liposomal CQ at tumor tissues and endosomal compartments.

  9. Low Prevalence of Pfcrt Resistance Alleles among Patients with Uncomplicated Falciparum Malaria in Niger Six Years after Chloroquine Withdrawal

    Directory of Open Access Journals (Sweden)

    Adamou Salissou

    2014-01-01

    Full Text Available Chloroquine (CQ resistance is widespread in Africa, but few data are available for Niger. Pfcrt haplotypes (aa 56–118 and ex vivo responses to CQ and amodiaquine were characterized for 26 isolates collected in South Niger from children under 15 years of age suffering from uncomplicated falciparum malaria, six years after the introduction of artemisinin-based combinations and the withdrawal of CQ. The wild-type Pfcrt haplotype CVMNK was found in 22 of the 26 isolates, with CVIET sequences observed in only three of the samples. We also describe for the first time a new CVINT haplotype. The ex vivo responses were better for CVMNK than for CVIET parasites. Pfcrt sequence data were compared with those obtained for 26 additional parasitized blood samples collected in Gabon, from an area of CQ resistance used as a control. Our findings suggest that there has been a significant decline in CQ-resistant genotypes since the previous estimates for Niger were obtained. No such decline in molecular resistance to CQ was observed in the subset of samples collected in similar conditions from Gabon. These results have important implications for public health and support the policy implemented in Niger since 2005, which aims to increase the efficacy and availability of antimalarial drugs whilst controlling the spread of resistance.

  10. Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine

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    Mikus Gerd

    2006-10-01

    Full Text Available Abstract The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB has a similar mode of action as chloroquine (CQ and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical failure rate in this area in 2003. Three serious adverse events (SAE occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%] and 24% [95% CI (19.4%, 28.3%], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa.

  11. Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine

    Science.gov (United States)

    Meissner, Peter E; Mandi, Germain; Coulibaly, Boubacar; Witte, Steffen; Tapsoba, Théophile; Mansmann, Ulrich; Rengelshausen, Jens; Schiek, Wolfgang; Jahn, Albrecht; Walter-Sack, Ingeborg; Mikus, Gerd; Burhenne, Jürgen; Riedel, Klaus-Dieter; Schirmer, R Heiner; Kouyaté, Bocar; Müller, Olaf

    2006-01-01

    The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical failure rate in this area in 2003). Three serious adverse events (SAE) occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%)] and 24% [95% CI (19.4%, 28.3%)], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa. PMID:17026773

  12. Assessment of Therapeutic Response of Plasmodium vivax and Plasmodium falciparum to Chloroquine in a Malaria Transmission Free Area in Colombia

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    Castillo Carmen Manuela

    2002-01-01

    Full Text Available In order to determine the frequency of therapeutic failures to chloroquine (CQ in patients with malaria due to either Plasmodium falciparum or P. vivax, and to explore the usefulness of a malaria-free city as a sentinel site to monitor the emergence of drug resistance, 53 patients (44 infected with P. vivax and 9 with P. falciparum were evaluated at the Laboratory of Parasitology, Universidad del Valle in Cali, Colombia. Patients received 25 mg/kg of CQ divided in three doses over 48 h; they were followed during 28 days according to WHO/PAHO protocols. While therapeutic failures to CQ in the P. vivax group were not detected, the proportion of therapeutic failures in the P. falciparum group was high (78% and consistent with the reports from endemic areas in Colombia. The diverse origin of cases presenting therapeutic failure confirmed that P. falciparum resistant to CQ is widespread in Colombia, and further supports the change in the national antimalarial drug scheme. Monitoring of drug resistance in malaria free areas would be useful to identify sites requiring efficacy evaluation, and in some situations could be the most appropriate alternative to collect information from endemic areas where therapeutic efficacy studies are not feasible.

  13. In vivo and in vitro Plasmodium falciparum Resistance to Chloroquine, Amodiaquine and Quinine in the Brazilian Amazon

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    Aluisio Augusto Cotrim SEGURADO

    1997-03-01

    Full Text Available In order to study the chemoresistance of Plasmodium falciparum to commonly used antimalarial drugs in Brazil the authors have studied ten patients with falciparum malaria, acquired in the Brazilian Amazon region. Patients were submitted to in vivo study of drug sensitivity, after chemotherapy with either 4-aminoquinolines (chloroquine or amodiaquine or quinine. Adequate drug absorption was confirmed by standard urine excretion tests for antimalarials. Eight patients could be followed up to 28 days. Among these in vivo resistance (R I and R II responses was seen in all patients who received 4-amino-quinolines. One patient treated with quinine exhibited a R III response. Peripheral blood samples of the same patients were submitted to in vitro microtests for sensitivity to antimalarials. Out of nine successful tests, resistance to chloroquine and amodiaquine was found in 100% and resistance to quinine in 11.11% of isolates. Probit analysis of log dose-response was used to determine effective concentrations EC50, EC90 and EC99 to the studied drugs. Good correlation between in vivo and in vitro results was seen in six patients. The results emphasize high levels of P. falciparum resistance to 4- aminoquinolines and suggest an increase in resistance to quinine in the Brazilian Amazon region, reinforcing the need for continuous monitoring of drug sensitivity to adequate chemotherapy according to the most efficacious drug regimensResistência in vivo e in vitro do Plasmodium falciparum à cloroquina, amodiaquina e quinino na Amazônia Brasileira. Com o propósito de avaliar a resistência do Plasmodium falciparum às drogas antimaláricas, rotineiramente empregadas no Brasil, os autores acompanharam dez pacientes com malária falciparum adquirida na Amazônia brasileira. Os pacientes foram submetidos a estudo in vivo de sensibilidade a drogas, após tratamento com derivados 4-aminoquinoleínicos (cloroquina e amodiaquina ou quinino. A absorção das

  14. Expression of Plasmodium vivax crt-o Is Related to Parasite Stage but Not Ex Vivo Chloroquine Susceptibility.

    Science.gov (United States)

    Pava, Zuleima; Handayuni, Irene; Wirjanata, Grennady; To, Sheren; Trianty, Leily; Noviyanti, Rintis; Poespoprodjo, Jeanne Rini; Auburn, Sarah; Price, Ric N; Marfurt, Jutta

    2015-11-02

    Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o (pvcrt-o) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5; P < 0.001). Twenty-nine isolates fulfilled the criteria for ex vivo drug susceptibility testing and showed high variability in CQ responses (median, 107.9 [range, 6.5 to 345.7] nM). After controlling for the parasite stage, we found that pvcrt-o expression levels did not correlate with the ex vivo response to CQ or with that to any of the other antimalarials tested. Our results highlight the importance of development-stage composition for measuring pvcrt-o expression and suggest that pvcrt-o transcription is not a primary determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivax drug resistance.

  15. Expression of Plasmodium vivax crt-o Is Related to Parasite Stage but Not Ex Vivo Chloroquine Susceptibility.

    Science.gov (United States)

    Pava, Zuleima; Handayuni, Irene; Wirjanata, Grennady; To, Sheren; Trianty, Leily; Noviyanti, Rintis; Poespoprodjo, Jeanne Rini; Auburn, Sarah; Price, Ric N; Marfurt, Jutta

    2016-01-01

    Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o (pvcrt-o) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5; P importance of development-stage composition for measuring pvcrt-o expression and suggest that pvcrt-o transcription is not a primary determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivax drug resistance. PMID:26525783

  16. 间日疟原虫氯喹抗性研究进展%Research progress on Plasmodium vivax chloroquine resistance

    Institute of Scientific and Technical Information of China (English)

    李江艳; 李倩; 方强

    2014-01-01

    Malaria remains a serious public health problem,especially in developing countries. With the deepening of the un-derstanding of vivax malaria,Plasmodium vivax is also attracting more and more attention. An effective drug treatment is the foun-dation of controlling or even eliminating malaria. In recent years,more and more reports of chloroquine-resistance Plasmodium vivax have been reported. Plasmodium vivax chloroquine resistance has been a focus problem in vivax malaria prevention and treat-ment. In this paper,the research progress on distribution situation,detection methods and molecular markers of Plasmodium vivax chloroquine resistance is summarized.%疟疾仍然是一个严重危害人类健康的公共卫生问题,尤其多见于发展中国家。随着认识的深入,间日疟也获得越来越多的重视。有效的药物治疗是控制疟疾甚至消除疟疾的基石,近年来已有越来越多的间日疟原虫氯喹抗性报道,间日疟原虫氯喹抗性已成为间日疟防治中一个备受关注的问题。本文就间日疟原虫氯喹抗性的分布现状、体内外检测方法和分子检测标志物研究进展进行初步总结。

  17. The single crystal X-ray structure of β-hematin DMSO solvate grown in the presence of chloroquine, a β-hematin growth-rate inhibitor

    Science.gov (United States)

    Gildenhuys, Johandie; le Roex, Tanya; Egan, Timothy J.; de Villiers, Katherine A.

    2012-01-01

    Single crystals of solvated β-hematin were grown from a DMSO solution containing the antimalarial drug chloroquine, a known inhibitor of β-hematin formation. In addition, a kinetics study employing biomimetic lipid-water emulsion conditions was undertaken to further investigate the effect of chloroquine and quinidine on the formation of β-hematin. Scanning electron microscopy shows that the external morphology of the β-hematin DMSO solvate crystals is almost indistinguishable from that of malaria pigment (hemozoin) and single crystal X-ray diffraction confirms the presence of μ-propionato coordination dimers of iron(III) protoporphyrin IX. The free propionic acid functional groups of adjacent dimers hydrogen bond to included DMSO molecules, rather than forming carboxylic acid dimers. The observed exponential kinetics were modeled using the Avrami equation, with an Avrami constant equal to 1. The decreased rate of β-hematin formation observed at low concentrations of both drugs could be accounted for by assuming a mechanism of drug adsorption to sites on the fastest growing face of β-hematin. This behavior was modeled using the Langmuir isotherm. Higher concentrations of drug resulted in decreased final yields of β-hematin, and an irreversible drug-induced precipitation of iron(III) protoporphyrin IX was postulated to account for this. The model permits determination of the equilibrium adsorption constant (Kads). The values for chloroquine (log Kads = 5.55 ± 0.03) and quinidine (log Kads = 4.92 ± 0.01) suggest that the approach may be useful as a relative probe of the mechanism of action of novel antimalarial compounds. PMID:23253048

  18. 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...

  19. Falciparum malaria in the north of Laos: the occurrence and implications of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene haplotype SVMNT

    DEFF Research Database (Denmark)

    Dittrich, Sabine; Alifrangis, Michael; Stohrer, Jörg M;

    2005-01-01

    OBJECTIVE: The Pfcrt-gene encodes a transmembrane protein located in the Plasmodium falciparum digestive vacuole. Chloroquine resistant (CQR) strains of African and Southeast Asian origin carry the Pfcrt-haplotype (c72-76) CVIET, whereas most South American and Papua New Guinean CQR stains carry...... the SVMNT haplotype. METHOD: Eighty-eight samples from an area with reported in vivo Chloroquine and in vitro Amodiaquine-resistance were screened for the K76T mutation and their Pfcrt-haplotype (c72-76) using a new SSOP-ELISA. RESULTS: Hundred percent of the analysed samples showed the K76T mutation which...... is highly associated with in vivo drug failure. This very high rate of a CQR-marker is alarming in an area were CQ is still used as first line drug. The distribution of the three main Pfcrt-haplotypes was as follows: 68% CVIET, 31% SVMNT, 0% CVMNT. CONCLUSIONS: These data show, for the first time, the South...

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

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    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

  1. Development of ELISA-based methods to measure the anti-malarial drug chloroquine in plasma and in pharmaceutical formulations

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    Ronn Anita

    2011-08-01

    Full Text Available Abstract Background In Central and South America and Eastern and Southern Africa, Plasmodium vivax infections accounts for 71-81% and 5% of malaria cases, respectively. In these areas, chloroquine (CQ remains the treatment of choice for P. vivax malaria. In addition, CQ has recently proven to be an effective HIV-1 therapeutic agent. There is a dire need to continue monitoring quality of CQ as there is a major influx of substandard and fake formulations into malaria-endemic countries. The use of fake/substandard drugs will result in sub-therapeutic levels endangering the patient and possibly select for parasite resistance. The aim of this study was to develop an inexpensive, simple antibody-based ELISA to measure CQ concentrations in tablets and in plasma. Methods A monoclonal antibody (MAb that reacts with the N-side chain of the CQ molecule was prepared by use of a CQ analogue. A specific and reliable ELISA for detection of CQ was developed. The developed assay was validated by measuring CQ in tablets sold in Denmark, India and Sudan. Furthermore, kinetics of CQ concentrations in plasma of four volunteers, who ingested two tablets of Malarex® containing, 250 mg CQ base, were measured before drug intake, three hours later and thereafter at days 1, 3, 7, 14, 21 and 28. The same plasma samples were simultaneously measured by high performance liquid chromatography (HPLC. Results The ELISA proved an easy-to-handle and very sensitive tool for the detection of CQ with a lower limit of detection at 3.9 ng/ml. ELISA levels of CQ in plasma showed high agreement with the levels obtained by HPLC (r = 0.98. The specificity in the negative control group was 100%. Conclusion The developed ELISA can be used for quality screening of CQ in pharmaceutical formulations and for drug monitoring in malaria and in other infectious diseases, such as HIV, where CQ proved to be an effective therapeutic agent. The methodology has been exploited to develop monoclonal

  2. Monitoring of malaria parasite resistance to chloroquine and sulphadoxine-pyrimethamine in the Solomon Islands by DNA microarray technology

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    Felger Ingrid

    2010-10-01

    Full Text Available Abstract Background Little information is available on resistance to anti-malarial drugs in the Solomon Islands (SI. The analysis of single nucleotide polymorphisms (SNPs in drug resistance associated parasite genes is a potential alternative to classical time- and resource-consuming in vivo studies to monitor drug resistance. Mutations in pfmdr1 and pfcrt were shown to indicate chloroquine (CQ resistance, mutations in pfdhfr and pfdhps indicate sulphadoxine-pyrimethamine (SP resistance, and mutations in pfATPase6 indicate resistance to artemisinin derivatives. Methods The relationship between the rate of treatment failure among 25 symptomatic Plasmodium falciparum-infected patients presenting at the clinic and the pattern of resistance-associated SNPs in P. falciparum infecting 76 asymptomatic individuals from the surrounding population was investigated. The study was conducted in the SI in 2004. Patients presenting at a local clinic with microscopically confirmed P. falciparum malaria were recruited and treated with CQ+SP. Rates of treatment failure were estimated during a 28-day follow-up period. In parallel, a DNA microarray technology was used to analyse mutations associated with CQ, SP, and artemisinin derivative resistance among samples from the asymptomatic community. Mutation and haplotype frequencies were determined, as well as the multiplicity of infection. Results The in vivo study showed an efficacy of 88% for CQ+SP to treat P. falciparum infections. DNA microarray analyses indicated a low diversity in the parasite population with one major haplotype present in 98.7% of the cases. It was composed of fixed mutations at position 86 in pfmdr1, positions 72, 75, 76, 220, 326 and 356 in pfcrt, and positions 59 and 108 in pfdhfr. No mutation was observed in pfdhps or in pfATPase6. The mean multiplicity of infection was 1.39. Conclusion This work provides the first insight into drug resistance markers of P. falciparum in the SI. The

  3. Functional characterization of the Plasmodium falciparum chloroquine-resistance transporter (PfCRT in transformed Dictyostelium discoideum vesicles.

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    Janni Papakrivos

    Full Text Available BACKGROUND: Chloroquine (CQ-resistant Plasmodium falciparum malaria has been a global health catastrophe, yet much about the CQ resistance (CQR mechanism remains unclear. Hallmarks of the CQR phenotype include reduced accumulation of protonated CQ as a weak base in the digestive vacuole of the erythrocyte-stage parasite, and chemosensitization of CQ-resistant (but not CQ-sensitive P. falciparum by agents such as verapamil. Mutations in the P. falciparum CQR transporter (PfCRT confer CQR; particularly important among these mutations is the charge-loss substitution K→T at position 76. Dictyostelium discoideum transformed with mutant PfCRT expresses key features of CQR including reduced drug accumulation and verapamil chemosensitization. METHODOLOGY AND FINDINGS: We describe the isolation and characterization of PfCRT-transformed, hematin-free vesicles from D. discoideum cells. These vesicles permit assessments of drug accumulation, pH, and membrane potential that are difficult or impossible with hematin-containing digestive vacuoles from P. falciparum-infected erythrocytes. Mutant PfCRT-transformed D. discoideum vesicles show features of the CQR phenotype, and manipulations of vesicle membrane potential by agents including ionophores produce large changes of CQ accumulation that are dissociated from vesicular pH. PfCRT in its native or mutant form blunts the ability of valinomycin to reduce CQ accumulation in transformed vesicles and decreases the ability of K(+ to reverse membrane potential hyperpolarization caused by valinomycin treatment. CONCLUSION: Isolated vesicles from mutant-PfCRT-transformed D. discoideum exhibit features of the CQR phenotype, consistent with evidence that the drug resistance mechanism operates at the P. falciparum digestive vacuole membrane in malaria. Membrane potential apart from pH has a major effect on the PfCRT-mediated CQR phenotype of D. discoideum vesicles. These results support a model of PfCRT as an

  4. Cytotoxicity of Ru(II) piano-stool complexes with chloroquine and chelating ligands against breast and lung tumor cells: Interactions with DNA and BSA.

    Science.gov (United States)

    Colina-Vegas, Legna; Villarreal, Wilmer; Navarro, Maribel; de Oliveira, Clayton Rodrigues; Graminha, Angélica E; Maia, Pedro Ivo da S; Deflon, Victor M; Ferreira, Antonio G; Cominetti, Marcia Regina; Batista, Alzir A

    2015-12-01

    The synthesis and spectroscopic characterization of nine π-arene piano-stool ruthenium (II) complexes with aromatic dinitrogen chelating ligands or containing chloroquine (CQ), are described in this study: [Ru(η(6)-C10H14)(phen)Cl]PF6 (1), [Ru(η(6)-C10H14)(dphphen)Cl]PF6 (2), [Ru(η(6)-C10H14)(bipy)Cl]PF6 (3), [Ru(η(6)-C10H14)(dmebipy)Cl]PF6 (4) and [Ru(η(6)-C10H14)(bdutbipy)Cl]PF6 (5), [Ru(η(6)-C10H14)(phen)CQ](PF6)2 (6), [Ru(η(6)-C10H14)(dphphen)CQ](PF6)2 (7), [Ru(η(6)-C10H14)(bipy)CQ](PF6)2 (8), [Ru(η(6)-C10H14)(dmebipy)CQ](PF6)2 (9): [1,10-phenanthroline (phen), 4,7-diphenyl-1,10-phenanthroline (dphphen), 2,2'-bipyridine (bipy), 5,5'-dimethyl-2,2'-bipyridine (dmebipy), and 4,4'-di-t-butyl-2,2'-bipyridine (dbutbipy)]. The solid state structures of five ruthenium complexes (1-5) were determined by X-ray crystallography. Electrochemical experiments were performed by cyclic voltammetry to estimate the redox potential of the Ru(II)/Ru(III) couple in each case. Their interactions with DNA and BSA, and activity against four cell lines (L929, A549, MDA-MB-231 and MCF-7) were evaluated. Compounds 2, 6 through 9, interact with DNA which was comparable to the one observed for free chloroquine. The results of fluorescence titration revealed that these complexes strongly quenched the intrinsic fluorescence of BSA following a static quenching procedure. Binding constants (Kb) and the number of binding sites (n~1) were calculated using modified Stern-Volmer equations. The thermodynamic parameters ΔG at different temperatures were calculated and subsequently the values of ΔH and ΔS were also calculated, which revealed that hydrophobic and electrostatic interactions play a major role in the BSA-complex association. The MTT assay results indicated that complexes 2, 5 and 7 showed cytostatic effects at appreciably lower concentrations than those needed for cisplatin, chloroquine and doxorubicin.

  5. Cytotoxicity of Ru(II) piano-stool complexes with chloroquine and chelating ligands against breast and lung tumor cells: Interactions with DNA and BSA.

    Science.gov (United States)

    Colina-Vegas, Legna; Villarreal, Wilmer; Navarro, Maribel; de Oliveira, Clayton Rodrigues; Graminha, Angélica E; Maia, Pedro Ivo da S; Deflon, Victor M; Ferreira, Antonio G; Cominetti, Marcia Regina; Batista, Alzir A

    2015-12-01

    The synthesis and spectroscopic characterization of nine π-arene piano-stool ruthenium (II) complexes with aromatic dinitrogen chelating ligands or containing chloroquine (CQ), are described in this study: [Ru(η(6)-C10H14)(phen)Cl]PF6 (1), [Ru(η(6)-C10H14)(dphphen)Cl]PF6 (2), [Ru(η(6)-C10H14)(bipy)Cl]PF6 (3), [Ru(η(6)-C10H14)(dmebipy)Cl]PF6 (4) and [Ru(η(6)-C10H14)(bdutbipy)Cl]PF6 (5), [Ru(η(6)-C10H14)(phen)CQ](PF6)2 (6), [Ru(η(6)-C10H14)(dphphen)CQ](PF6)2 (7), [Ru(η(6)-C10H14)(bipy)CQ](PF6)2 (8), [Ru(η(6)-C10H14)(dmebipy)CQ](PF6)2 (9): [1,10-phenanthroline (phen), 4,7-diphenyl-1,10-phenanthroline (dphphen), 2,2'-bipyridine (bipy), 5,5'-dimethyl-2,2'-bipyridine (dmebipy), and 4,4'-di-t-butyl-2,2'-bipyridine (dbutbipy)]. The solid state structures of five ruthenium complexes (1-5) were determined by X-ray crystallography. Electrochemical experiments were performed by cyclic voltammetry to estimate the redox potential of the Ru(II)/Ru(III) couple in each case. Their interactions with DNA and BSA, and activity against four cell lines (L929, A549, MDA-MB-231 and MCF-7) were evaluated. Compounds 2, 6 through 9, interact with DNA which was comparable to the one observed for free chloroquine. The results of fluorescence titration revealed that these complexes strongly quenched the intrinsic fluorescence of BSA following a static quenching procedure. Binding constants (Kb) and the number of binding sites (n~1) were calculated using modified Stern-Volmer equations. The thermodynamic parameters ΔG at different temperatures were calculated and subsequently the values of ΔH and ΔS were also calculated, which revealed that hydrophobic and electrostatic interactions play a major role in the BSA-complex association. The MTT assay results indicated that complexes 2, 5 and 7 showed cytostatic effects at appreciably lower concentrations than those needed for cisplatin, chloroquine and doxorubicin. PMID:26277415

  6. The effect of pH on the uptake and toxicity of the bivalent weak base chloroquine tested on Salix viminalis and Daphnia magna

    DEFF Research Database (Denmark)

    Rendal, Cecilie; Kusk, Kresten Ole; Trapp, Stefan

    2011-01-01

    The uptake and accumulation of most electrolytes will change with pH because of the different speciation states of these compounds at various pH. Non-ionized compounds will partition into fatty and organic phases (such as cell membranes) more readily than the corresponding charged compounds....... The toxicity of chloroquine was tested on Daphnia magna using the standard Organisation for Economic Co-operation and Development acute toxicity test modified to accommodate testing at pH levels of 7, 8, and 9. Increasing toxicity was seen at higher pH. The results of the current study confirm...... that the toxicity of weak bases with intermediate pKa values is higher at high pH levels....

  7. 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

    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......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...... vs. 60 h). SP plus CQ had a highly significantly shorter median survival time to fever clearance than SP alone (48 vs. 60 h) (P

  8. Malária falciparum resistente à cloroquina e ao Fansidar R tratada com minociclina Minocycline treatment of chloroquine-and Fansidar R-resistant falciparum malarial

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    José J. Ferraroni

    1983-08-01

    Full Text Available Em abril de 1978 uma infecção malárica causada por Plasinodium falciparum foi diagnosticada em um paciente adulto do sexo masculino, nativo da Amazônia brasileira. O parasito foi resistente in vitro à cloroquina e in vivo à associação pirimetamina + sulfadoxina (FansidarR. O paciente foi tratado com minociclina (MinomaxR; contudo, sua resposta imune ao parasito pode ter tido um importante papel na eficácia do tratamento com a minociclina.In April 1978, a Plasmodium falciparum infection was diagnosed in an adult male in Brazilian Amazonia. The parasite was resistant in vitro to chloroquine and resistent in vivo to pyrimethamine-sulfadoxine (FansidarR. The patient was successfully treated with minocycline (MinomaxR; however, his immune response to the parasite may have played an important role in the efficacy of the minocycline treatment.

  9. 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

    -malarial drug resistance. In this study, malaria patients treated with SP alone (60) and SP with CQ (194) had a total treatment failure (TF) of 35.4%, with no difference between the two arms. The polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA) method was used to identify polymorphisms......Estimation of the prevalence of the molecular markers of sulfadoxine/pyrimethamine (SP) and chloroquine (CQ) resistance and validation of the association of mutations with resistance in different settings is needed for local policy guidance and for contributing to a global map for anti......, 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...

  10. Dietary supplementation of chloroquine with nigella sativa seed and oil extracts in the treatment of malaria induced in mice with plasmodium berghei

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    Promise Madu Emeka

    2014-01-01

    Full Text Available Background: The aim of the study was to investigate the effects of dietary combination of Nigella sativa seed and oil extracts with chloroquine (CQ, and how these combinations enhance CQ efficacy in mice infected with Plasmodium berghei and their survival rates. Materials and Methods: Chloroquine sensitive P. berghei, NK65 strain was used for the study. This was passaged intraperitoneally into albino mice with a 0.2ml standard inoculum consisting of 10 6 parasitized erythrocyte suspension in phosphate buffer solution (PBS. Parasitaemia was ascertained by microscopical examination of blood films under oil immersion at X100 magnification. Results: Nigella sativa seed in feed (NSSF, NSSF + CQ on day 4, produced 86.1% and 86.0% suppression respectively, while Nigella sativa oil extract in feed (NSOF and in combination with CQ had 86.0% and 99.9% suppression respectively. The degree of suppression with the combination was significantly higher compared to CQ alone (P < 0.001 (36.1%. Complete parasitaemia clearance was obtained on the 20 th and 15 th day of treatment for NSSF, NSSF + CQ respectively, while that for NSOF and NSOF + CQ was on days 26 and 12 respectively. For CQ parasite clearance was 12 days with treatment. Also, the combinastion of 10 mg/kg Nigella sativa oil treatment injected intraperitoneally with oral CQ produced very significant parasite suppression (P < 0.0001 (93%. Survival rate in NSSF and NSOF and in combination with CQ groups was 100 and 60.0% for CQ alone. Conclusion : sThis study shows that the use of Nigella sativa seed and oil extract as dietary supplements in combination with CQ has a potential in enhancing the efficacy of CQ and could be of benefit in management of malaria.

  11. Dietary supplementation of chloroquine with nigella sativa seed and oil extracts in the treatment of malaria induced in mice with plasmodium berghei

    Science.gov (United States)

    Emeka, Promise Madu; Badger-Emeka, Lorina Ineta; Eneh, Chiamaka Maryann; Khan, Tahir Mahmood

    2014-01-01

    Background: The aim of the study was to investigate the effects of dietary combination of Nigella sativa seed and oil extracts with chloroquine (CQ), and how these combinations enhance CQ efficacy in mice infected with Plasmodium berghei and their survival rates. Materials and Methods: Chloroquine sensitive P. berghei, NK65 strain was used for the study. This was passaged intraperitoneally into albino mice with a 0.2ml standard inoculum consisting of 106 parasitized erythrocyte suspension in phosphate buffer solution (PBS). Parasitaemia was ascertained by microscopical examination of blood films under oil immersion at X100 magnification. Results: Nigella sativa seed in feed (NSSF), NSSF + CQ on day 4, produced 86.1% and 86.0% suppression respectively, while Nigella sativa oil extract in feed (NSOF) and in combination with CQ had 86.0% and 99.9% suppression respectively. The degree of suppression with the combination was significantly higher compared to CQ alone (P < 0.001) (36.1%). Complete parasitaemia clearance was obtained on the 20th and 15th day of treatment for NSSF, NSSF + CQ respectively, while that for NSOF and NSOF + CQ was on days 26 and 12 respectively. For CQ parasite clearance was 12 days with treatment. Also, the combinastion of 10 mg/kg Nigella sativa oil treatment injected intraperitoneally with oral CQ produced very significant parasite suppression (P < 0.0001) (93%). Survival rate in NSSF and NSOF and in combination with CQ groups was 100 and 60.0% for CQ alone. Conclusions: This study shows that the use of Nigella sativa seed and oil extract as dietary supplements in combination with CQ has a potential in enhancing the efficacy of CQ and could be of benefit in management of malaria. PMID:24991115

  12. Quinine dimers are potent inhibitors of the Plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum.

    Science.gov (United States)

    Hrycyna, Christine A; Summers, Robert L; Lehane, Adele M; Pires, Marcos M; Namanja, Hilda; Bohn, Kelsey; Kuriakose, Jerrin; Ferdig, Michael; Henrich, Philipp P; Fidock, David A; Kirk, Kiaran; Chmielewski, Jean; Martin, Rowena E

    2014-03-21

    Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the "chloroquine resistance transporter" (PfCRT). The resistance-conferring form of PfCRT (PfCRT(CQR)) mediates CQ resistance by effluxing the drug from the parasite's digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRT(CQR) can also decrease the parasite's susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRT(CQR) and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H(+) ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRT(CQR) reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRT(CQR) from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRT(CQR). This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.

  13. Factors associated with chloroquine induced pruritus during malaria treatment in Mozambican University students Factores asociados a la aparición de prurito por cloroquina durante el tratamiento de la malaria en estudiantes universitarios de Mozambique

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    Helena Gama

    2009-08-01

    Full Text Available Introduction: It has been suggested that reductions in chloroquine use may be followed by a resurgence of chloroquine-susceptible falciparum malaria, and chloroquine might once again be an effective treatment choice, which renews the importance of aspects related to its use and misuse. Therefore, we aimed to estimate the prevalence of chloroquine-induced pruritus and to identify risk factors for its occurrence in Mozambican University students. Methods: A cross-sectional study was conducted at a private University in Maputo. Students were approached in the classrooms to complete a self-administered questionnaire covering sociodemographic characteristics, number of previous malaria episodes, utilization of antimalarial drugs, and life prevalence of chloroquine induced pruritus. Results: Among 795 respondents, 77.4% (601/777 reported at least one malaria episode and 73.2% (542/740 had used chloroquine before. The life-prevalence of chloroquine-induced pruritus was 30.1% (158/525. Pruritus tended to be more frequent when chloroquine was used for treatment compared with prophylaxis only (31.2% vs. 10.3%, pIntroducción: Se ha sugerido que la reducción en el uso de la cloroquina puede derivar en el resurgimiento de la malaria falciparum sensible a la cloroquina, por lo que ésta puede volver a ser un tratamiento efectivo de elección, renovando la importancia de aspectos relacionados con su uso y su mal uso. Se pretende estimar la prevalencia de prurito inducido por cloroquina e identificar los factores de riesgo asociados a su ocurrencia en estudiantes universitarios de Mozambique. Métodos: Se realizó una encuesta transversal en una Universidad privada de Mozambique. Los estudiantes fueron abordados en las aulas para completar un cuestionario autoadministrado, que contenía datos sociodemográficos e información sobre el número de episodios previos de malaria, la utilización de fármacos antipalúdicos y la prevalencia de prurito inducido por

  14. Identification of chloroquine resistance Pfcrt-K76T and determination of Pfmdr1-N86Y copy number by SYBR Green I qPCR

    Institute of Scientific and Technical Information of China (English)

    Addimas; Tajebe; Mulugeta; Aemero; Kimani; Francis; Gabriel; Magoma

    2015-01-01

    Objective:To identify prevalence of chloroquine resistance point mutation at(Pfcrt,K76T)and(Pfindr1.N86Y) copy number variation.Methods:SYBR Green I based real time PCR was used.One hundred and thirty-three samples were analyzed for(Pfcrt,K76T) and(Pfmdr1.N86Y) copy number from dried blood spot.Parasite DNA was extracted using high pure DNA preparation kit.The amplification of DNA was done by using AccuPower 2* GreenStar ’’ qPCR Master mix.For quantification purpose a new primer pair was designed for 178 base pair template from complete genome sequence of Plasmodium falciparum strain 3D7 at NCBI.Absolute quantification method was used to determine the Pfmdr1-N86 Y copy number variations.Standard curve was built from strain3D7 gDNA since it has single copy of Pfindr1 per haploid genome.The known positive controls with single and multi-copy number of Pfindr1 gene were included in each experiment.The copy number ratio of the samples to the standard calibrator was made to obtain the fold difference among the samples with respect to copy number variation.Results:Out of 133 samples 73(54.89%) were confirmed as mutant(Pfcrt,76T) and the remaining 60(45.11%) were genotyped as wild type(Pfcrt,K76).The(Pfindr1.N86Y) copy number variation was determined for 133 clinical samples.Out of these samples 61(45.86%)had single copy and the remaining 72(54.14%) had multi-copy numbers higher than 1.5 copies per genome.Thirty-four(25.56%) multi-copies were between 1.5 and 2.5 copies per genome while 38(28.57%) were more than 2.5 copies per genome.The minimum and maximum copies per genome were 0.474 and 4.741.respectively.Conclusions:The study showed high prevalence level and fixation of Pfcrt.76 T mutation after chloroquine withdrawal.The prevalence of Pfindr1 copy number variant suggested that the presence of modulating factor for emergence of Plasmodium falciparum strains with higher copy numbers.However,the prevalence level was not statistically significant.

  15. Therapeutic Assessment of Chloroquine-Primaquine Combined Regimen in Adult Cohort of Plasmodium vivax Malaria from Primary Care Centres in Southwestern India

    Science.gov (United States)

    Saravu, Kavitha; Kumar, Rishikesh; Ashok, Herikudru; Kundapura, Premananda; Kamath, Veena; Kamath, Asha; Mukhopadhyay, Chiranjay

    2016-01-01

    Background Several reports of chloroquine treatment failure and resistance in Plasmodium vivax malaria from Southeast Asian countries have been published. Present study was undertaken to assess the efficacy of chloroquine-primaquine (CQ-PQ) combined regimen for the treatment of P. vivax malaria patients who were catered by the selected primary health centres (PHCs) of Udupi taluk, Udupi district, Karnataka, India. Method Five PHCs were selected within Udupi taluk based on probability proportional to size. In-vivo therapeutic efficacy assessment of CQ (1500 mg over three days) plus PQ (210 mg over 14 days) regimen was carried out in accordance with the World Health Organization’s protocol of 28 days follow-up among microscopically diagnosed monoinfection P. vivax cohort. Results In total, 161 participants were recruited in the study of which, 155 (96.3%) participants completed till day 28 follow-up, fully complied with the treatment regimen and showed adequate clinical and parasitological response. Loss to follow up was noted with 5 (3.1%) participants and non-compliance with treatment regimen occurred with one participant (0.6%). Glucose-6-phosphate dehydrogenase deficiency (G6PDd, <30% of normal mean activity) was noted among 5 (3.1%) participants and one of them did develop PQ induced dark-brown urination which subsided after PQ discontinuation. G6PDd patients were treated with PQ 45 mg/week for eight weeks while PQ was discontinued in one case with G6PD 1.4 U/g Hb due to complaint of reddish-brown coloured urine by 48 hours of PQ initiation. Nested polymerase chain reaction test revealed 45 (28%) cases as mixed (vivax and falciparum) malaria. Conclusions The CQ-PQ combined regimen remains outstandingly effective to treat uncomplicated P. vivax malaria in Udupi taluk and thus it should continue as first line regimen. For all P. vivax cases, G6PD screening before PQ administration must be mandatory and made available in all PHCs. PMID:27315280

  16. Therapeutic Assessment of Chloroquine-Primaquine Combined Regimen in Adult Cohort of Plasmodium vivax Malaria from Primary Care Centres in Southwestern India.

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    Kavitha Saravu

    Full Text Available Several reports of chloroquine treatment failure and resistance in Plasmodium vivax malaria from Southeast Asian countries have been published. Present study was undertaken to assess the efficacy of chloroquine-primaquine (CQ-PQ combined regimen for the treatment of P. vivax malaria patients who were catered by the selected primary health centres (PHCs of Udupi taluk, Udupi district, Karnataka, India.Five PHCs were selected within Udupi taluk based on probability proportional to size. In-vivo therapeutic efficacy assessment of CQ (1500 mg over three days plus PQ (210 mg over 14 days regimen was carried out in accordance with the World Health Organization's protocol of 28 days follow-up among microscopically diagnosed monoinfection P. vivax cohort.In total, 161 participants were recruited in the study of which, 155 (96.3% participants completed till day 28 follow-up, fully complied with the treatment regimen and showed adequate clinical and parasitological response. Loss to follow up was noted with 5 (3.1% participants and non-compliance with treatment regimen occurred with one participant (0.6%. Glucose-6-phosphate dehydrogenase deficiency (G6PDd, <30% of normal mean activity was noted among 5 (3.1% participants and one of them did develop PQ induced dark-brown urination which subsided after PQ discontinuation. G6PDd patients were treated with PQ 45 mg/week for eight weeks while PQ was discontinued in one case with G6PD 1.4 U/g Hb due to complaint of reddish-brown coloured urine by 48 hours of PQ initiation. Nested polymerase chain reaction test revealed 45 (28% cases as mixed (vivax and falciparum malaria.The CQ-PQ combined regimen remains outstandingly effective to treat uncomplicated P. vivax malaria in Udupi taluk and thus it should continue as first line regimen. For all P. vivax cases, G6PD screening before PQ administration must be mandatory and made available in all PHCs.

  17. Signaling of chloroquine-induced stress in the yeast Saccharomyces cerevisiae requires the Hog1 and Slt2 mitogen-activated protein kinase pathways.

    Science.gov (United States)

    Baranwal, Shivani; Azad, Gajendra Kumar; Singh, Vikash; Tomar, Raghuvir S

    2014-09-01

    Chloroquine (CQ) has been under clinical use for several decades, and yet little is known about CQ sensing and signaling mechanisms or about their impact on various biological pathways. We employed the budding yeast Saccharomyces cerevisiae as a model organism to study the pathways targeted by CQ. Our screening with yeast mutants revealed that it targets histone proteins and histone deacetylases (HDACs). Here, we also describe the novel role of mitogen-activated protein kinases Hog1 and Slt2, which aid in survival in the presence of CQ. Cells deficient in Hog1 or Slt2 are found to be CQ hypersensitive, and both proteins were phosphorylated in response to CQ exposure. CQ-activated Hog1p is translocated to the nucleus and facilitates the expression of GPD1 (glycerol-3-phosphate dehydrogenase), which is required for the synthesis of glycerol (one of the major osmolytes). Moreover, cells treated with CQ exhibited an increase in intracellular reactive oxygen species (ROS) levels and the effects were rescued by addition of reduced glutathione to the medium. The deletion of SOD1, the superoxide dismutase in yeast, resulted in hypersensitivity to CQ. We have also observed P38 as well as P42/44 phosphorylation in HEK293T human cells upon exposure to CQ, indicating that the kinds of responses generated in yeast and human cells are similar. In summary, our findings define the multiple biological pathways targeted by CQ that might be useful for understanding the toxicity modulated by this pharmacologically important molecule.

  18. Perception of chloroquine efficacy and alternative treatments for uncomplicated malaria in children in a holoendemic area of Tanzania: implications for the change of treatment policy

    DEFF Research Database (Denmark)

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

    2001-01-01

    of fever. It was hypothesized that the long experience with CQ and its antipyretic effect (lacking in S/P) might impede acceptance of S/P for wider use as first-line drug. Malarial fevers in children were most commonly treated with CQ (92.8%), followed by quinine (60.7%) and S/P (28.7%). A 63.2% knew......Prior to policy change from chloroquine (CQ) to sulphadoxine/pyrimethamine (S/P; Fansidar) we assessed the perception of CQ efficacy and the alternative treatment options for malaria in children among parents/guardians (N=527) of under-fives attending first level health facilities on account...... and proven CQ failures in first level health facilities and the district hospital. S/P was judged to be more effective than quinine, but too strong for children, and was the least known drug in the study area. All formulations of S/P cost more per dose for a child and an adult than CQ. The implications...

  19. Treatment of erythrocytes with the 2-cys peroxiredoxin inhibitor, Conoidin A, prevents the growth of Plasmodium falciparum and enhances parasite sensitivity to chloroquine.

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    Mariana Brizuela

    Full Text Available The human erythrocyte contains an abundance of the thiol-dependant peroxidase Peroxiredoxin-2 (Prx2, which protects the cell from the pro-oxidant environment it encounters during its 120 days of life in the blood stream. In malarial infections, the Plasmodium parasite invades red cells and imports Prx2 during intraerythrocytic development, presumably to supplement in its own degradation of peroxides generated during cell metabolism, especially hemoglobin (Hb digestion. Here we demonstrate that an irreversible Prx2 inhibitor, Conoidin A (2,3-bis(bromomethyl-1,4-dioxide-quinoxaline; BBMQ, has potent cytocidal activity against cultured P. falciparum. Parasite growth was also inhibited in red cells that were treated with BBMQ and then washed prior to parasite infection. These cells remained susceptible to merozoite invasion, but failed to support normal intraerythrocytic development. In addition the potency of chloroquine (CQ, an antimalarial drug that prevents the detoxification of Hb-derived heme, was significantly enhanced in the presence of BBMQ. CQ IC50 values decreased an order of magnitude when parasites were either co-incubated with BBMQ, or introduced into BBMQ-pretreated cells; these effects were equivalent for both drug-resistant and drug-sensitive parasite lines. Together these results indicate that treatment of red cells with BBMQ renders them incapable of supporting parasite growth and increases parasite sensitivity to CQ. We also propose that molecules such as BBMQ that target host cell proteins may constitute a novel host-directed therapeutic approach for treating malaria.

  20. Feasibility of amlodipine besylate, chloroquine phosphate, dapsone, phenytoin, pyridoxine hydrochloride, sulfadiazine, sulfasalazine, tetracycline hydrochloride, trimethoprim and zonisamide in SyrSpend(®) SF PH4 oral suspensions.

    Science.gov (United States)

    Ferreira, Anderson O; Polonini, Hudson C; Silva, Sharlene L; Patrício, Fernando B; Brandão, Marcos Antônio F; Raposo, Nádia R B

    2016-01-25

    The objective of this study was to evaluate the feasibility of 10 commonly used active pharmaceutical ingredients (APIs) compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend(®) SF PH4 liquid): (i) amlodipine, (as besylate) 1.0mg/mL; (ii) chloroquine phosphate,15.0 mg/mL; (iii) dapsone, 2.0 mg/mL; (iv) phenytoin, 15.0 mg/mL; (v) pyridoxine hydrochloride, 50.0 mg/mL; (vi) sulfadiazine, 100.0 mg/mL; (vii) sulfasalazine, 100.0 mg/mL; (viii) tetracycline hydrochloride, 25.0 mg/mL; (ix) trimethoprim, 10.0 mg/mL; and (x) zonisamide, 10.0 mg/mL. All suspensions were stored both at controlled refrigeration (2-8 °C) and controlled room temperature (20-25 °C). Feasibility was assessed by measuring the percent recovery at varying time points throughout a 90-day period. API quantification was performed by high-performance liquid chromatography (HPLC-UV), via a stability-indicating method. Given the percentage of recovery of the APIs within the suspensions, the expiration date of the final products (API+vehicle) was at least 90 days for all suspensions with regard to both the controlled temperatures. This suggests that the vehicle is stable for compounding APIs from different pharmacological classes.

  1. The zinc ionophore clioquinol reverses autophagy arrest in chloroquine-treated ARPE-19 cells and in APP/mutant presenilin-1-transfected Chinese hamster ovary cells.

    Science.gov (United States)

    Seo, Bo-Ra; Lee, Sook-Jeong; Cho, Kyung Sook; Yoon, Young Hee; Koh, Jae-Young

    2015-12-01

    Arrested autophagy may contribute to the pathogenesis of Alzheimer's disease. Because we found that chloroquine (CQ) causes arrested autophagy but clioquinol (ClioQ), a zinc ionophore, activates autophagic flux, in the present study, we examined whether ClioQ can overcome arrested autophagy induced by CQ or mutant presenilin-1 (mPS1). CQ induced vacuole formation and cell death in adult retinal pigment epithelial (ARPE-19) cells, but co-treatment with ClioQ attenuated CQ-associated toxicity in a zinc-dependent manner. Increases in lysosome dilation and blockage of autophagic flux by CQ were also markedly attenuated by ClioQ treatment. Interestingly, CQ increased lysosomal pH in amyloid precursor protein (APP)/mPS1-expressing Chinese hamster ovary 7WΔE9 (CHO-7WΔE9) cell line, and ClioQ partially re-acidified lysosomes. Furthermore, accumulation of amyloid-β (Aβ) oligomers in CHO-7WΔE9 cells was markedly attenuated by ClioQ. Moreover, intracellular accumulation of exogenously applied fluorescein isothiocyanate-conjugated Aβ(1-42) was also increased by CQ but was returned to control levels by ClioQ. These results suggest that modulation of lysosomal functions by manipulating lysosomal zinc levels may be a useful strategy for clearing intracellular Aβ oligomers. PMID:26453000

  2. Alteração da camada de fibras nervosas da retina em usuários crônicos de cloroquina Retinal nerve fiber layer alteration in chronic users of chloroquine

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    Daniela de Almeida Lyra Antunes

    2005-04-01

    Full Text Available OBJETIVOS: Avaliar a camada de fibras nervosas da retina (CFN por meio da polarimetria a laser, em pacientes em uso crônico de cloroquina. MÉTODOS: Foram estudados 44 olhos de 22 pacientes em uso de cloroquina por doenças reumatológicas, por pelo menos um ano. Como controle, foram incluídos vinte indivíduos sem uso de cloroquina com idade, gênero e raça similares. Foram excluídos os pacientes que apresentavam história familiar de hipertensão ocular ou glaucoma. Ambos os olhos foram submetidos à análise da camada de fibras nervosas da retina, com o aparelho GDx® Nerve Fiber Analyser, pelo mesmo examinador. RESULTADOS: Nos usuários crônicos de cloroquina, verificou-se alteração em mais de dois parâmetros do GDx em 28 olhos (63,6%. Ocorreu também alteração no gráfico "Deviation from normal" com perda de fibras nervosas em 11 olhos (25%. Quando comparado com o grupo controle, os parâmetros que demonstraram diferença estatisticamente significante foram: Superior Ratio, Inferior Ratio, Superior Nasal, Elipse Modulation, The Number, Superior Average e Superior Integral. Houve também associação estatisticamente significante entre o tempo de uso de cloroquina e perda da CFN. CONCLUSÕES: Comprovou-se a associação entre o uso crônico da cloroquina e a alteração da CFN detectada pelo GDx. Desta forma, esses resultados podem contribuir para o diagnóstico precoce da perda de fibras nervosas na retinopatia por cloroquina.PURPOSES: To evaluate the retina nerve fiber layer by laser polarimetry in patients in chronic use of chloroquine. METHODS: Forty-four eyes of twenty-two patients were studied. These were in use of chloroquine due to rheumatic diseases during at least one year. As a control group, twenty patients without use of chloroquine with similar characteristics (age, gender and race were included. Patients who had a family history of ocular hypertension or glaucoma were not included in this group. Both eyes were

  3. Complicações oculares da terapêutica com a cloroquina e derivados Ocular complications of chloroquine and derivatives therapy

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    Augusto Cézar Lacava

    2010-08-01

    gastrointestinal, nervous and skeletal muscular systems and the skin. Ocular adverse reactions are: photophobia, cornea verticillata, poliosis, cataract, extraocular muscle palsy, anterior uveitis, toxic maculopathy and optical neuritis. PURPOSE: Bibliography review of complications due to the use of chloroquine and its derivatives. To analyze the current practice and propedeutics' evolution. To suggest practical managements for early toxicity signs. METHODS: Bibliographic review through research on MEDLINE, PUBMED, LILACS and SciELO database. DISCUSSION: All exams that can be used to screen ocular adverse reactions are described, such as: complete ophthalmologic exam, with emphasis on biomicroscopy and indirect binocular ophthalmoscopy, computerized visual field, Amsler grid testing and color vision testing, electrophysiological exams, polarimetry and optical coherence tomography. A description of maculopathy is presented, focusing on epidemiology, risk factors, histopathology and propedeutics. Chemical structure and the differences between 4-aminoquinolone derivatives are described. CONCLUSION: All patients using chloroquine and its derivatives must be followed-up and documented since the beginning of the therapy until they reach a cumulative dose above 100 grams. The higher the cumulative dose, the more we must be concerned with patient follow-up.

  4. Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso [ISRCTN27290841

    Science.gov (United States)

    Meissner, Peter E; Mandi, Germain; Witte, Steffen; Coulibaly, Boubacar; Mansmann, Ulrich; Rengelshausen, Jens; Schiek, Wolfgang; Jahn, Albrecht; Sanon, Mamadou; Tapsoba, Théophile; Walter-Sack, Ingeborg; Mikus, Gerd; Burhenne, Jürgen; Riedel, Klaus-Dieter; Schirmer, Heiner; Kouyaté, Bocar; Müller, Olaf

    2005-01-01

    Background Safe, effective and affordable drug combinations against falciparum malaria are urgently needed for the poor populations in malaria endemic countries. Methylene blue (MB) combined with chloroquine (CQ) has been considered as one promising new regimen. Objectives The primary objective of this study was to evaluate the safety of CQ-MB in African children with uncomplicated falciparum malaria. Secondary objectives were to assess the efficacy and the acceptance of CQ-MB in a rural population of West Africa. Methods In this hospital-based randomized controlled trial, 226 children (6–59 months) with uncomplicated falciparum malaria were treated in Burkina Faso. The children were 4:1 randomized to CQ-MB (n = 181; 25 mg/kg CQ and 12 mg/kg MB over three days) or CQ (n = 45; 25 mg/kg over three days) respectively. The primary outcome was the incidence of severe haemolysis or other serious adverse events (SAEs). Efficacy outcomes were defined according to the WHO 2003 classification system. Patients were hospitalized for four days and followed up until day 14. Results No differences in the incidence of SAEs and other adverse events were observed between children treated with CQ-MB (including 24 cases of G6PD deficiency) compared to children treated with CQ. There was no case of severe haemolysis and also no significant difference in mean haemoglobin between study groups. Treatment failure rates were 53.7% (95% CI [37.4%; 69.3%]) in the CQ group compared to 44.0% (95% CI [36.3%; 51.9%]) in the CQ-MB group. Conclusion MB is safe for the treatment of uncomplicated falciparum malaria, even in G6PD deficient African children. However, the efficacy of the CQ-MB combination has not been sufficient at the MB dose used in this study. Future studies need to assess the efficacy of MB at higher doses and in combination with appropriate partner drugs. PMID:16179085

  5. In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity.

    Science.gov (United States)

    Lucchi, Naomi W; Komino, Franklin; Okoth, Sheila Akinyi; Goldman, Ira; Onyona, Philip; Wiegand, Ryan E; Juma, Elizabeth; Shi, Ya Ping; Barnwell, John W; Udhayakumar, Venkatachalam; Kariuki, Simon

    2015-12-01

    Malaria control is hindered by the evolution and spread of resistance to antimalarials, necessitating multiple changes to drug policies over time. A comprehensive antimalarial drug resistance surveillance program is vital for detecting the potential emergence of resistance to antimalarials, including current artemisinin-based combination therapies. An antimalarial drug resistance surveillance study involving 203 Plasmodium falciparum malaria-positive children was conducted in western Kenya between 2010 and 2013. Specimens from enrolled children were analyzed in vitro for sensitivity to chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), lumefantrine, and artemisinin derivatives (artesunate and dihydroartemisinin) and for drug resistance allele polymorphisms in P. falciparum crt (Pfcrt), Pfmdr-1, and the K13 propeller domain (K13). We observed a significant increase in the proportion of samples with the Pfcrt wild-type (CVMNK) genotype, from 61.2% in 2010 to 93.0% in 2013 (P < 0.0001), and higher proportions of parasites with elevated sensitivity to CQ in vitro. The majority of isolates harbored the wild-type N allele in Pfmdr-1 codon 86 (93.5%), with only 7 (3.50%) samples with the N86Y mutant allele (the mutant nucleotide is underlined). Likewise, most isolates harbored the wild-type Pfmdr-1 D1246 allele (79.8%), with only 12 (6.38%) specimens with the D1246Y mutant allele and 26 (13.8%) with mixed alleles. All the samples had a single copy of the Pfmdr-1 gene (mean of 0.907 ± 0.141 copies). None of the sequenced parasites had mutations in K13. Our results suggest that artemisinin is likely to remain highly efficacious and that CQ sensitivity appears to be on the rise in western Kenya.

  6. Chloroquine for the maintenance of remission of autoimmune hepatitis: results of a pilot study Cloroquina para manutenção da remissão da hepatite auto-imune: resultado de estudo piloto

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    Marcos Mucenic

    2005-12-01

    Full Text Available BACKGROUND: Due to the risks related to long-term treatment with prednisone and azathioprine, most clinicians try to withdraw these drugs when patients with autoimmune hepatitis are in remission. However, there is a high probability of relapse, and most patients end up receiving maintenance treatment. AIM: To evaluate the safety and efficacy of maintenance treatment with chloroquine in the prevention of autoimmune hepatitis relapses. METHODS: Classical treatment was stopped after achievement of biochemical and histological remission of autoimmune hepatitis. Chloroquine diphosphate, 250 mg daily, was given for at least 12 months or until the occurrence of relapses defined by levels of aminotransferases at least twice the upper normal values. RESULTS: Fourteen patients were consecutively treated and compared with 18 historical controls. There was a 6.49 (1.38-30.30 greater chance of relapse in the historical controls when compared with patients treated with chloroquine (72.2% x 23.5%; 0.031. CONCLUSIONS: The group treated with chloroquine had a lower frequency of relapses. Chloroquine was safe in patients with autoimmune hepatitis and hepatic cirrhosis without decompensation, on 250 mg daily up to 2 years. These preliminary results provide a basis for upcoming controlled studies comparing chloroquine with placebo or for maintenance treatment with prednisone and/or azathioprine for the prevention of autoimmune hepatitis relapses.RACIONAL: Em razão dos riscos relacionados ao tratamento prolongado com prednisona e azatioprina, tenta-se a retirada dessas drogas em pacientes com hepatite auto-imune em remissão. Como há alta taxa de recidiva, a maioria dos pacientes recebe tratamento por tempo indefinido. OBJETIVO: Avaliar a segurança e a eficácia do tratamento de manutenção com cloroquina na prevenção de recidiva da hepatite auto-imune. MÉTODOS: O tratamento convencional foi suspenso após obtenção de remissão bioquímica e histol

  7. Comparing histopathology of ICR mice infected with chloroquine-sensitive and chloroquine-resistant strains of Plasmodium berghei%伯氏疟原虫氯喹敏感株和抗性株感染ICR鼠病理变化的比较研究

    Institute of Scientific and Technical Information of China (English)

    陈克强; 宋关鸿

    2001-01-01

    目的:研究伯氏疟原虫(Plasmodium berghei)的抗药性与致病力的关系。方法:比较伯氏疟原虫氯喹敏感株(N)和抗性株(RC)感染ICR鼠的肝、脾、脑、心、肺、肾等重要脏器病理组织学的动态变化。结果:N株感染后,小鼠肝、脾有较多的疟色素沉着,肺脏呈郁血性水肿;脑微血管充血和阻塞;各脏器呈急性炎症的病理变化特点。RC株感染后,小鼠肝、脾脏的病理组织学改变与原虫血症的变化有关。肺脏呈间质性肺炎,各脏器呈慢性增生性炎症的病理变化特点。结论:N株致病力较强,感染后引起宿主死亡的主要原因是感染疟原虫的红细胞对脑微血管内皮细胞的粘附,造成微血管阻塞;RC株致病力较弱,宿主的应答反应在感染早期可能是CD4+Th1相关的迟发型超敏炎症反应,而感染后期是CD4+T h2辅助作用下的抗体依赖性的免疫应答,并在疟原虫的最后清除上起着关键性的作用。%Objective: To understand the relationship between chloroquine resistance and the virulence of Plasmodium berghei. Met hods: Dynamic changes of histopathologic features of livers, spleens, brains, hearts, lungs and kidneys of mice infected with the chloroquine-sensitive (N) and the chloroquine-resistant (RC) strains of P. berghei were compared. Results: In mice infected with the N strain, deposition of heavy hemoz oin in livers and spleens, congestive edema in lungs, and congestion and embolis m in the brain capillaries were observed. The histopathologic features revealed ac ute inflammatory reaction. In mice infected with the RC strain, histopathologic variations of livers and spleens were associated with changes of parasitemia. In terstitial pneumonia was displayed in lungs. There were chronic histopathologic changes of the organs in the mice infected with RC strain. Conclusion: The mice infected by the N strain with potent virulence die due to adher ence of

  8. Property-based design and synthesis of new chloroquine hybrids via simple incorporation of 2-imino-thiazolidine-4-one or 1h-pyrrol-2, 5-dione fragments on the 4-amino-7-chloroquinoline side chain

    Energy Technology Data Exchange (ETDEWEB)

    Rojas, Fernando A.; Kouznetsov, Vladimir V., E-mail: kouznet@uis.edu.co [Laboratorio de Quimica Organica y Biomolecular, Escuela de Quimica, Universidad Industrial de Santander, Bucaramanga (Colombia)

    2011-09-15

    In the present work, the syntheses of new 4-amino-7-chloroquinoline N-derivatives were performed by selective modification of the side chain amino group of N-(7-chloroquinoline-4-yl) alkyldiamines, basis framework of chloroquine (CQ) drug through the incorporation of heterocyclic 2-imino-thiazolidine-4-one and {sup 1}H-pyrrol-2,5-dione systems. These potential activity modulators were selected thanks to their characteristic properties, and evaluated by virtual screening employing the OSIRIS and Molinspirations platforms. Designed and synthesized quinolinic derivatives could increase the antimalarial activity of CQ analogues without affecting the lipophilicity as described in literature, suggesting them as candidates for further biological assessments. (author)

  9. Assessment of chloroquine single dose treatment of malaria due to Plasmodium vivax in Brazilian Amazon Cloroquina em dose simples no tratamento da malária por Plasmodium vivax na Amazônia brasileira

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    Ana Yecê das Neves Pinto

    2003-12-01

    Full Text Available Malaria regions of the Amazon basin have been characterized by difficult access and non-compliance of the patients to treatment. In an attempt to assess the schizonticide efficacy of chloroquine in a single dose of 600 mg, the authors realized a double-blind, placebo-controlled trial in 132 outpatients with vivax malaria. Patients were distributed into two groups: group CPLA, given chloroquine 600 mg (single dose on the first day of treatment, and two doses of placebo on second and third days. Group CHLO, given chloroquine 600 mg on first day and 450 mg on second and third day. Geometric means of the parasite density during the follow-up was similar in both groups. No differences were observed in the parasitological cure between the two groups (p = 0.442. There was clinical and parasitological efficacy in treatment of patients given a single-dose of chloroquine. This suggests that its restricted use could be indicated in remote areas of Brazilian Amazon Region, nevertheless the inadequate response of three patients indicates the need for further studies.As regiões malarígenas da Amazônia brasileira têm se caracterizado por dificuldades no acesso ao tratamento e não aceitação das drogas pelos doentes. Com objetivos de avaliar a eficácia da cloroquina em dose simples de 600 mg, os autores realizaram um ensaio clínico duplo cego, placebo controlado em 132 pacientes portadores de malária por P. vivax. Os pacientes foram distribuídos em dois grupos: grupo CPLA que recebia 600 mg de cloroquina em dose simples no primeiro dia de tratamento e duas doses de placebo no segundo e terceiro dias de tratamento. Grupo CLO que recebia 600 mg de cloroquina no primeiro dia e 450 mg no segundo e terceiro dias. A média geométrica da densidade parasitária durante o seguimento foi similar em ambos os grupos. Não houve diferenças de cura parasitológica em ambos os grupos (p = 0,442. Observou-se eficácia clínica e parasitológica nos indivíduos que

  10. Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases

    International Nuclear Information System (INIS)

    Chloroquine (CLQ), an antimalarial drug, has a lysosomotropic effect associated with increased radiationsensibility, which is mediated by the leakage of hydrolytic enzymes, increased apoptosis, autophagy and increased oxidative stress in vitro. In this phase II study, we evaluated the efficacy and safety of radiosensibilization using CLQ concomitant with 30 Gray (Gy) of whole-brain irradiation (WBI) to treat patients with brain metastases (BM) from solid tumors. Seventy-three eligible patients were randomized. Thirty-nine patients received WBI (30 Gy in 10 fractions over 2 weeks) concomitant with 150 mg of CLQ for 4 weeks (the CLQ arm). Thirty-four patients received the same schedule of WBI concomitant with a placebo for 4 weeks (the control arm). All the patients were evaluated for quality of life (QoL) using the EORTC Quality of Life (QoL) Questionnaire (EORTC QLQ-C30) (Mexican version) before beginning radiotherapy and one month later. The overall response rate (ORR) was 54% for the CLQ arm and 55% for the control arm (p=0.92). The progression-free survival of brain metastases (BMPFS) rates at one year were 83.9% (95% CI 69.4-98.4) for the CLQ arm and 55.1% (95% CI 33.6-77.6) for the control arm. Treatment with CLQ was independently associated with increased BMPFS (RR 0.31,95% CI [0.1-0.9], p=0.046).The only factor that was independently associated with increased overall survival (OS) was the presence of< 4 brain metastases (RR 1.9, 95% CI [1.12-3.3], p=0.017). WBI was associated with improvements in cognitive and emotional function but also with worsened nausea in both patients groups. No differences in QoL or toxicity were found between the study arms. Treatment with CLQ plus WBI improved the control of BM (compared with the control arm) with no increase in toxicity; however, CLQ did not improve the RR or OS. A phase III clinical trial is warranted to confirm these findings

  11. High frequency of Plasmodium falciparum chloroquine resistance marker (pfcrt T76 mutation in Yemen: An urgent need to re-examine malaria drug policy

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    Al-Mekhlafi Hesham M

    2011-05-01

    Full Text Available Abstract Background Malaria remains a significant health problem in Yemen with Plasmodium falciparum being the predominant species which is responsible for 90% of the malaria cases. Despite serious concerns regarding increasing drug resistance, chloroquine is still used for the prevention and treatment of malaria in Yemen. This study was carried out to determine the prevalence of choloroquine resistance (CQR of P. falciparum isolated from Yemen based on the pfcrt T76 mutation. Methods A cross-sectional study was carried out among 511 participants from four governorates in Yemen. Blood samples were screened using microscopic and species-specific nested PCR based on the 18S rRNA gene to detect and identify Plasmodium species. Blood samples positive for P. falciparum were used for detecting the pfcrt T76 mutation using nested-PCR. Results The prevalence of pfcrt T76 mutation was 81.5% (66 of 81 isolates. Coastal areas/foothills had higher prevalence of pfcrt T76 mutation compared to highland areas (90.5% vs 71.8% (p = 0.031. The pfcrt T76 mutation had a significant association with parasitaemia (p = 0.045. Univariate analysis shows a significant association of pfcrt T76 mutation with people aged > 10 years (OR = 9, 95% CI = 2.3 - 36.2, p = 0.001, low household income (OR = 5, 95% CI = 1.3 - 19.5, p = 0.027, no insecticide spray (OR = 3.7, 95% CI = 1.16 - 11.86, p = 0.025 and not sleeping under insecticide treated nets (ITNs (OR = 4.8, 95% CI = 1.38 - 16.78, p = 0.01. Logistic regression model confirmed age > 10 years and low household income as predictors of pfcrt T76 mutation in Yemen P. falciparum isolates. Conclusions The high prevalence of pfcrt T76 mutation in Yemen could be a predictive marker for the prevalence of P. falciparum CQR. This finding shows the necessity for an in-vivo therapeutic efficacy test for CQ. P. falciparum CQR should be addressed in the national strategy to control malaria.

  12. Chloroquine aggravates Con A-induced autoimmune hepatitis%氯喹可加重Con A诱导的自身免疫性肝损伤

    Institute of Scientific and Technical Information of China (English)

    李延利; 王守杰; 唐媛; 张丽芸; 卢晓; 左大明; 陈政良

    2016-01-01

    氯喹(chloroquine,CQ)可抑制免疫反应,偶用于类风湿性关节炎、系统性红斑狼疮等自身免疫性疾病的治疗,但氯喹对自身免疫性肝炎的影响目前尚不明确.本研究拟探讨CQ对小鼠自身免疫性肝损伤的影响及可能机制.小鼠尾静脉注射Con A建立小鼠肝损伤模型,1h后,腹腔注射CQ或等体积PBS.观察小鼠生存状况,在不同时间点收集血清和肝组织,采用赖氏法检测血清谷丙转氨酶(GPT)水平;ELISA方法检测血清细胞因子IFN γ及TNF-α含量;HE染色观察肝脏病理损伤情况;免疫印迹检测小鼠肝脏自噬水平指标LC3-Ⅱ和P62.结果显示,Con A+CQ组小鼠血清中GPT水平显著高于Con A组,且病理切片染色显示Con A+CQ组肝脏损伤较Con A组更严重;Con A+CQ注射组小鼠的存活率明显低于仅注射Con A组(P<0.0001);Con A+CQ组小鼠血清中炎性细胞因子IFN-γ和TNF-α的分泌高于Con A组;CQ可抑制Con A刺激诱导的小鼠肝脏自噬水平升高.氯喹可加重Con A诱导的自身免疫性肝损伤,其机制可能是通过抑制肝脏自噬水平从而加剧小鼠肝脏损伤.

  13. Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso [ISRCTN27290841

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    Walter-Sack Ingeborg

    2005-09-01

    Full Text Available Abstract Background Safe, effective and affordable drug combinations against falciparum malaria are urgently needed for the poor populations in malaria endemic countries. Methylene blue (MB combined with chloroquine (CQ has been considered as one promising new regimen. Objectives The primary objective of this study was to evaluate the safety of CQ-MB in African children with uncomplicated falciparum malaria. Secondary objectives were to assess the efficacy and the acceptance of CQ-MB in a rural population of West Africa. Methods In this hospital-based randomized controlled trial, 226 children (6–59 months with uncomplicated falciparum malaria were treated in Burkina Faso. The children were 4:1 randomized to CQ-MB (n = 181; 25 mg/kg CQ and 12 mg/kg MB over three days or CQ (n = 45; 25 mg/kg over three days respectively. The primary outcome was the incidence of severe haemolysis or other serious adverse events (SAEs. Efficacy outcomes were defined according to the WHO 2003 classification system. Patients were hospitalized for four days and followed up until day 14. Results No differences in the incidence of SAEs and other adverse events were observed between children treated with CQ-MB (including 24 cases of G6PD deficiency compared to children treated with CQ. There was no case of severe haemolysis and also no significant difference in mean haemoglobin between study groups. Treatment failure rates were 53.7% (95% CI [37.4%; 69.3%] in the CQ group compared to 44.0% (95% CI [36.3%; 51.9%] in the CQ-MB group. Conclusion MB is safe for the treatment of uncomplicated falciparum malaria, even in G6PD deficient African children. However, the efficacy of the CQ-MB combination has not been sufficient at the MB dose used in this study. Future studies need to assess the efficacy of MB at higher doses and in combination with appropriate partner drugs.

  14. 复方地巴唑氢氯噻嗪胶囊中磷酸氯喹的杂质定性分析%The Qualitative Analysis of Impurities by Chloroquine Phosphate in Compound Bendazol and Hydrochlorothiazide Capsules

    Institute of Scientific and Technical Information of China (English)

    陈晓英

    2015-01-01

    The impurities of chloroquine phosphate in Compound bendazol and hydrochlorothiazide capsules, were identi⁃fied using high performance liquid chromatography(UV detector and two diode array detector)and mass spectrometry. Us⁃ing Luna C18 column with the mobile phase of methanol and acetic acid-2%,(υ/υ10∶90), with flow rate of 0.5 ml/min, col⁃umn temperature at room temperature,the injection volume was 20μl, the UV detection wavelength was 324nm and the DAD detection wavelength range was 200~400nm, by high performance liquid chromatography. In mass spectrometry, ESI electro⁃spray ionization was used, atomization gas pressure was 45 psi, with drying air flow rate 10 L/min and temperature 350℃and capillary voltage 3.5 kV, scaning MS. And then the second scan was carried out to the first target ion with voltage 20eV and collection range of 100-1000 m/z. UV detection results showed that the impurity peak in Compound bendazol and hydro⁃chlorothiazide capsules was similar to that in chloroquine phosphate. And the DAD detection result of the impuritie was simi⁃lar to chloroquine. The second mass scan result showed that the molecular fragments were similar to chloroquine. The impuri⁃ties generated by chloroquine phosphate in Compound bendazol and hydrochlorothiazide capsules is N-deethylation chloro⁃quine.%采用高效液相色谱法(HPLC)(紫外检测器UV和二级管阵列检测器DAD)和质谱法MS)对复方地巴唑氢氯噻嗪胶囊中磷酸氯喹所产生的杂质进行定性鉴别与归属.实验使用Luna C18色谱柱,以甲醇-2%醋酸(υ/υ10∶90)为流动相,流速0.5 mL/min,柱温为室温,进样量为20μl ,紫外检测波长为324 nm,DAD检测波长扫描范围为200~400 nm,进行高效液相色谱.质谱法则使用ESI电喷雾离子化源,雾化气压力为45 psi,干燥气流速为10 L/min,干燥气温度350℃,毛细管电压3.5 kV,扫描方式采用一级质谱全扫描,再对目标离子进

  15. 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

  16. Chloroquine sensitizes cisplatin cytotoxicity in human gastric cancer xenografts%抗疟药氯喹增强胃癌裸鼠移植瘤对顺铂的化疗敏感性

    Institute of Scientific and Technical Information of China (English)

    方念; 张慧卿; 刘小梅; 何波; 万以叶; 程海涛; 谢桂生

    2014-01-01

    Objective To investigate the enhanced effect of cisplatin on chloroquine in SGC7901 xenografts. Methods The models of SGC7901 xenograft on athymic mouse were established and randomized to four groups with intraperitoneal injection of different drugs: control, cisplatin(DDP), chloroquine(CQ) and DDP+CQ. Drugs were injected once every 3 days, 10 times in all. The tumor volume were measured during the process of drug therapy. The mice were sacrificed 3 days after the last injection,and then the weight of tumor were measured. Western Blot was performed to detect the expression of beclin-1, LC3Ⅱ/Ⅰ, Caspase3 and P-gp, RT-PCR was performed to detect the expression of MDR1 mRNA. Results Compared to group control,the growth of tumor were more slowly and the tumor volume were much smaller in group DDP, the inhibition of tumor rate was 47.6%;and the expression of Beclin1 and LC3 were up-regulated. After combined with CQ, the inhibition of tumor rate was increased to 84.7%(P<0.01), and the ratio between LC3Ⅱ/Ⅰ was decreased;the expression of MDR1 and P-gp were also down-regulated. Conclusion Chloroquine can enhance the anti-tumor effect of cisplatin on gastric cancer xenografts, inhibition of autophagy and down-regulation of MDR1/P-gp expression are possibly the related mechanisms.%目的:探讨抗疟药氯喹(CQ)增强顺铂(DDP)抑制胃癌SGC7901细胞裸鼠移植瘤生长的作用。方法建立胃癌SGC7901细胞裸鼠异位移植瘤模型,将24只荷瘤鼠随机分为对照组、DDP组、CQ组和CQ+DDP组。腹腔注射给药,给药后每3日测量肿瘤体积。给药结束时处死裸鼠,剥离移植瘤,称重。Western Blot检测肿瘤组织beclin-1、LC3Ⅱ/Ⅰcaspase3和P-gp表达,RT-PCR技术检测MDR1 mRNA水平。结果与对照组相比,DDP组移植瘤生长缓慢,体积较小,抑瘤率为47.6%,而且Beclin1和LC3表达增加,LCⅠ转换LCⅡ增多。联合氯喹后,抑瘤率提高至84.7%(P<0.01),LC3

  17. Métodos diagnósticos para retinopatia induzida pelo difosfato de cloroquina nos portadores de lúpus eritematoso sistêmico Diagnostic methods for chloroquine diphosphate induced retinopathy in systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Luciana Duarte Rodrigues

    2009-06-01

    Full Text Available OBJETIVOS: Avaliar diferentes métodos diagnósticos para a avaliação de pacientes portadores de lúpus eritematoso sistêmico, usuários crônicos do difosfato de cloroquina (DFC e, portanto, com alto risco para retinopatia tóxica. MÉTODOS: Foram analisados 72 olhos de 36 pacientes consecutivos, seguidos no Serviço de Reumatologia do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, de julho de 2007 a abril de 2008. Dados demográficos e clínicos foram avaliados com o intuito de estudar os fatores de alto risco e comparar os seguintes métodos oftalmológicos: acuidade visual, biomicroscopia da córnea, biomicroscopia do fundo, retinografia, angiofluoresceinografia da retina, campo visual macular com mira branca. RESULTADOS: Dos 36 pacientes, 34 (94,4% eram mulheres. A média de idade foi 39,9 ± 9,8 anos, com tempo de doença igual a 13,9 ± 6,6 anos. Além do uso crônico da cloroquina, os pacientes apresentaram altas doses diárias (>3 mg/kg e cumulativas. Não foi observada relação entre estes fatores de alto risco e maior prevalência de retinopatia. Foi encontrada prevalência de retinopatia igual a 38,9%, confirmada por alterações bilaterais, centrais ou paracentrais e reprodutíveis no exame de campo visual. Outros exames indicados para seguimento, como acuidade visual, biomicroscopia de fundo e angiofluoresceinografia não foram capazes de diagnosticar a maioria das alterações confirmadas pelo campo visual. CONCLUSÃO: Foi observada alta prevalência de retinopatia por cloroquina entre os pacientes com alto risco, usuários crônicos do DFC, segundo os achados do campo visual. A avaliação desses pacientes deve considerar a realização do exame de campo visual em intervalos menores que os propostos, mesmo quando não há suspeita clínica.PURPOSE: To evaluate different diagnostic methods for high risk chloroquine retinopathy due to prolonged use of chloroquine (more than 5 years by systemic

  18. How sulfadoxine-pyrimethamine (SP was perceived in some rural communities after phasing out chloroquine (CQ as a first-line drug for uncomplicated malaria in Tanzania: lessons to learn towards moving from monotherapy to fixed combination therapy

    Directory of Open Access Journals (Sweden)

    Nsimba Stephen ED

    2006-01-01

    Full Text Available Abstract Malaria is a leading cause of death in Sub-Saharan Africa. Tanzania changed its malaria treatment policy from chloroquine (CQ to Sulphadoxine-Pyrimethamine (SP as first line drug in August 2001. We wanted to assess the perception and behaviour about SP after phasing out chloroquine which was very popular, cheap, available, and was preferred by many people for self-medication in homes as it was considered to have minimal side effects. Focus Group Discussions (FGDs were carried out after one year of the anti-malarial drug treatment policy change in the country. The FGD themes were on malaria for under-five children and other age groups, anti-malarial drug use through self-medications, specific experiences people had about SP drug for both mothers/guardians, men in the communities and health workers. A total of twelve FGDs were performed with mothers/guardians, men and health workers in the selected public health care facilities in the district. In the FGDs people feared adverse reactions from SP; its slow ability of reducing fever and self-treatment in this case was less reported from the mothers/guardians groups. However, SP was reported by health workers to be administered using the direct observation approach under supervision in their health care facilities. This was done in order to increase compliance as there were worries that some mothers were throwing away the drug if they were instructed by health workers to go and administer SP to their sick children at home. Based on this information, it is obvious that fear and negative perceptions about SP drug was common in the study setting. As evidence of this, there was less reported home-stocking and self-medication in the discussions for this particular recommended new first-line anti-malarial. The public has demonstrated a lack of confidence in SP. Furthermore, some health workers expressed obvious fear and negative perceptions towards the drug despite the fact that some FGDs with

  19. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.

    Science.gov (United States)

    Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia; Dahal, Prabin; Nsanzabana, Christian; Moriera, Clarissa; Price, Ric N; Mårtensson, Andreas; Rosenthal, Philip J; Dorsey, Grant; Sutherland, Colin J; Guérin, Philippe; Davis, Timothy M E; Ménard, Didier; Adam, Ishag; Ademowo, George; Arze, Cesar; Baliraine, Frederick N; Berens-Riha, Nicole; Björkman, Anders; Borrmann, Steffen; Checchi, Francesco; Desai, Meghna; Dhorda, Mehul; Djimdé, Abdoulaye A; El-Sayed, Badria B; Eshetu, Teferi; Eyase, Frederick; Falade, Catherine; Faucher, Jean-François; Fröberg, Gabrielle; Grivoyannis, Anastasia; Hamour, Sally; Houzé, Sandrine; Johnson, Jacob; Kamugisha, Erasmus; Kariuki, Simon; Kiechel, Jean-René; Kironde, Fred; Kofoed, Poul-Erik; LeBras, Jacques; Malmberg, Maja; Mwai, Leah; Ngasala, Billy; Nosten, Francois; Nsobya, Samuel L; Nzila, Alexis; Oguike, Mary; Otienoburu, Sabina Dahlström; Ogutu, Bernhards; Ouédraogo, Jean-Bosco; Piola, Patrice; Rombo, Lars; Schramm, Birgit; Somé, A Fabrice; Thwing, Julie; Ursing, Johan; Wong, Rina P M; Zeynudin, Ahmed; Zongo, Issaka; Plowe, Christopher V; Sibley, Carol Hopkins

    2014-10-01

    Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

  20. Sensitized cytotoxic effects of dexamethasone or radiation on multiple myeloma cells by chloroquine%氯喹增敏地塞米松或辐射对多发性骨髓瘤细胞的杀伤作用

    Institute of Scientific and Technical Information of China (English)

    付慧; 陶玉龙; 倪敏; 李冬洁; 沈甫明

    2016-01-01

    目的 研究氯喹(chloroquine,CQ),及CQ是否增敏化疗药物地塞米松(dexamethasone,DEX)或辐射对多发性骨髓瘤细胞株U266细胞的杀伤作用,并探讨其可能机制.方法 用细胞活性检测试剂盒(cell counting kit-8,cck8)检测CQ单药,以及CQ联用DEX对U266细胞增殖的影响,运用中效原理软件评估两药相互作用;cck8及流式细胞术分别检测CQ处理条件下辐射对U266细胞增殖和凋亡作用的改变;Western blot检测CQ合用DEX,以及CQ联合辐射对U266细胞内B细胞淋巴瘤-2(B-cellymphoma-2,Bcl-2)蛋白表达变化.结果 CQ及DEX对U266细胞的增殖抑制作用呈浓度依赖性,且CQ(3.9μmol/L)能够增强DEX(125μmol/L)对U266细胞的杀伤作用,并增加DEX降低细胞内抗凋亡蛋白Bcl-2的表达水平;不同辐射剂量(5~25 Gy)对U266细胞的生长抑制作用并无差异;CQ(1.0μmol/L)可以增加辐射对U266细胞的敏感性,诱导细胞凋亡.结论 CQ能够增敏DEX或辐射对U266细胞的杀伤作用,CQ增敏DEX的作用机制可能与抑制Bcl-2蛋白表达相关.%Objective To investigate the role and possible mechanism of combination use of chloroquine (CQ) with either dexamethasone (DEX) or radiation on multiple myeloma (MM) cell line U266 .Methods Cell viability of U266 treated with CQ alone ,or CQ combined with either DEX or radiation was measured by cell counting kit-8 (cck8) .CalcuSyn method was used to assess effect of drugs interaction .Cell viability and apoptosis of U266 pre-treated with CQ were also measured by cck8 and flow cytometry after radiation .Expression of B-cellymphoma-2 (Bcl-2) in U266 cells treated by CQ combined with DEX or radiation was determined by Western blot analysis .Results Either CQ or DEX displayed a dose dependent cell proliferation in-hibitory effect on U266 cells .Cytotoxic effect of DEX (125 μmol/L) on U266 cells was enhanced and expression of Bcl-2 pro-tein in U266 cells was decreased by combining with CQ (3 .9 μmol/L) .U266 cells were

  1. An HPLC method with diode array detector for the simultaneous quantification of chloroquine and desethylchloroquine in plasma and whole blood samples from Plasmodium vivax patients in Vietnam, using quinine as an internal standard.

    Science.gov (United States)

    Van Pham, Toi; Pham Nguyen, Phuong; Nguyen Duc Khanh, Tho; Nguyen Thanh Thuy, Nhien; Nguyen Thuy Nha, Ca; Pouplin, Thomas; Farrar, Jeremy; Thwaites, Guy E; Tran Tinh, Hien

    2016-07-01

    A sensitive, simple method for quantification of chloroquine (CQ) and desethylchloroquine (MCQ) in whole blood and plasma from Plasmodium vivax patients has been developed using HPLC with diode array detection (DAD). Solid-phase extraction on Isolute-96-CBA was employed to process 100 μL of plasma/whole blood samples. CQ, MCQ and quinine were separated using a mobile phase of phosphate buffer 25 mm, pH 2.60-acetonitrile (88:12, v/v) with 2 mm sodium perchlorate on a Zorbax SB-CN 150 × 4.6 mm, 5 μm column at a flow rate of 1.2 mL/min, at ambient temperature in 10 min, with the DAD wavelength of 343 nm. The method was linear over the range of 10-5000 ng/mL for both CQ and MCQ in plasma and whole blood. The limit of detection was 4 ng/mL and limit of quantification was 10 ng/mL in both plasma and blood for CQ and MCQ. The intra-, inter- and total assay precision were <10% for CQ and MCQ in plasma and whole blood. In plasma, the accuracies varied between 101 and 103%, whereas in whole blood, the accuracies ranged from 97.0 to 102% for CQ and MCQ. The method is an ideal technique with simple facilities and instruments, bringing about good separation in comparison with previous methods. © 2016 The Authors Biomedical Chromatography Published by John Wiley & Sons Ltd. PMID:26578224

  2. On the molecular basis of the activity of the antimalarial drug chloroquine: EXAFS-assisted DFT evidence of a direct Fe-N bond with free heme in solution

    Science.gov (United States)

    Macetti, Giovanni; Rizzato, Silvia; Beghi, Fabio; Silvestrini, Lucia; Lo Presti, Leonardo

    2016-02-01

    4-aminoquinoline antiplasmodials interfere with the biocrystallization of the malaria pigment, a key step of the malaria parasite metabolism. It is commonly believed that these drugs set stacking π···π interactions with the Fe-protoporphyrin scaffold of the free heme, even though the details of the heme:drug recognition process remain elusive. In this work, the local coordination of Fe(III) ions in acidic solutions of hematin at room temperature was investigated by extended x-ray absorption fine structure (EXAFS) spectroscopy in the 4.0-5.5 pH range, both in the presence and in the absence of the antimalarial drug chloroquine. EXAFS results were complemented by DFT simulations in polarizable continuum media to model solvent effects. We found evidence that a complex where the drug quinoline nitrogen is coordinated with the iron center might coexist with formerly proposed adduct geometries, based on stacking interactions. Charge-assisted hydrogen bonds among lateral chains of the two molecules play a crucial role in stabilizing this complex, whose formation is favored by the presence of lipid micelles. The direct Fe-N bond could reversibly block the axial position in the Fe 1st coordination shell in free heme, acting as an inhibitor for the crystallization of the malaria pigment without permanently hampering the catalytic activity of the redox center. These findings are discussed in the light of possible implications on the engineering of drugs able to thwart the adaptability of the malaria parasite against classical aminoquinoline-based therapies.

  3. In Vitro Sensitivity of Plasmodium falciparum Isolates from China-Myanmar Border Region to Chloroquine,Piperaquine and Pyronaridine%中缅边境地区恶性疟原虫对氯喹、哌喹、咯萘啶敏感性的体外测定

    Institute of Scientific and Technical Information of China (English)

    张苍林; 周红宁; 王剑; 刘慧

    2012-01-01

    目的 了解中缅边境地区恶性疟原虫(Plasmodium falciparum)对氯喹、哌喹和咯萘啶敏感性的变化.方法 2009年9~12月在中缅边境的缅甸拉咱市采集了51份恶性疟血样,采用Rieckmann体外微量测定法进行药物敏感性测定. 结果 敏感性测定结果有效的42份血样中,其恶性疟原虫对氯喹、哌喹和咯萘啶的抗性率分别为95.2%、7.1%和54.8%,半数抑制量(ID50)分别为320.5、128.2和96.0 nmol/L.在抗咯萘啶的23份血样中,对氯喹和哌喹的交叉抗性率分别为91.3% (21/23)和13.0% (3/23);抗氯喹的40份血样中,对哌喹和咯萘啶的交叉抗性率分别为7.5% (3/40)和52.5% (21/40);抗哌喹的3份血样中,对氯喹和咯萘啶的交叉抗性率均为100%.结论 在缅甸拉咱市调查点流行的恶性疟原虫对氯喹已普遍产生抗性,约半数对咯萘啶具有抗性,多数对哌喹则敏感.%Objective To assess the in vitro sensitivity of Plasmodium falciparum to chloroquine, piperaquine and pyronaridine in China-Myanmar border area. Methods Fifty-one blood specimens of P. Falcipamm isolates were collected from Laza City of Myanmar during September to December in 2009, and the sensitivity of the parasites to the drugs was detected by Rieckmann's in vitro microtest. Results Among the 42 blood samples with valid results of sensitivity test, the resistance rate to chloroquine, piperaquine and pyronaridine was 95.2%, 7.1%, and 54.8%, with a corresponding 50% inhibition dose (ID50 ) of 320.5, 128.2, and 96.0nmol/L, respectively. Pyronaridine-resistant P. Falcipamm exhibited some degree of cross-resistance to chloroquine [91.3%(21/23)] and piperaquine [13.0% (3/23)], and chloroquine-resistant P. Falciparum showed cross-resistance to piperaquine [7.5%(3/40)] and pyronaridine [52.5%(21/40) ]. High level of cross-resistance was present to chloroquine (100%) and pyronaridine (100%) in piperaquineresistant P. Falciparum. Conclusion In Laza City, P. Falciparum

  4. In vitro sensitivity of chloroquine sensitive and resistant Plasmodium falciparum to artemisinin antimalarials%恶性疟原虫氯喹敏感株与抗性株对青蒿素类药物体外敏感性的研究

    Institute of Scientific and Technical Information of China (English)

    黄芳; 冯晓平; 周水森; 汤林华

    2008-01-01

    目的 测定恶性疟原虫氯喹敏感株与抗性株对青蒿素类药物的体外敏感性. 方法 运用体外微量法与酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)测定青蒿琥酯、蒿甲醚及双氢青蒿素等3种青蒿素类抗疟药物对体外培养的恶性疟原虫氯喹敏感株与氯喹抗性株的体外敏感性,并比较两种方法测定的IC50值. 结果 体外微量法测定的3种药物对恶性疟原虫氯喹敏感株的IC50值依次为3.12 nmol/L、4.30 nmol/L、2.18 nmol/L,对恶性疟原虫氯喹抗性株的IC50值依次为4.31nmol/L、3.90 nmol/L、3.17 nmol/L;同时,将体外微量法与ELISA法所获的结果进行相关性分析,两种方法结果基本一致(r2=0.93,P<0.001). 结论 恶性疟原虫氯喹抗性株对青蒿素类药物无明显的交叉抗性;ELISA法可用于恶性疟原虫对抗疟药物的体外敏感性检测.%Objective To test the sensitivity of chloroquine sensitive and resistant Plasmodium falciparum to artemisinin anfimalarials. Method The responses of chloroquine sensitive and resistant P.falciparum to artemisinin antimalarials including artesunate,artemether and dihydroartemisinin were determined with Rieckmann s in vitro micro-technique and enzyme-linked immunosorbent assay(ELISA).The values of 50%inhibition of parasitemia(IC50)were compared with above two methods. Results The IC50 of artemisinin antimalarials in chloroquine sensitive P.falciparum were 3.12 nmoL/L,4.30 nmol/L,2.18 nmol/L respectively,while that in chloroquine resistant P. falciparum were 4.31nmol/L,3.90 nmol/L,3.17 nmol/L.The results obtained with both techniques were similar or identical by correlation analysis(r2=0.93,P<0.001).Conclusions There were no apparent cross-resistance of chloroquine resistant P.falciparum to artemisinin antimalarials.The ELISA test would be suitable for testing antimalarial drugs sensitivitv in vitro.

  5. 滋阴润燥生津汤联合硫酸羟化氯喹治疗干燥综合征患者的临床疗效%Oneself can Nourish dry soup Combined Sulphuric acid Hydroxyl,the Clinical Curative effect Analysis of Chloroquine Treatment of Sjogren's Syndrome

    Institute of Scientific and Technical Information of China (English)

    张宝国

    2016-01-01

    Objective To study the oneself can nourish dry soup combined sulphuric acid hydroxyl chloroquine in effect in the treatment of sjogren's syndrome.Methods Choose 80 cases of patients with sjogren's syndrome,were randomly divided into control group and the treatment group,al 40 cases,the control group given sulfuric acid hydroxyl chloroquine treatment,the treatment group in the control group on the basis of joint oneself can nourish dry soup treatment,compared two groups of therapeutic effect.Results The treatment group effective rate was 95.0%,control group was 80.0%,the treatment group is significantly higher than control group(P<0.05).Conclusion For sjogren's syndrome using oneself can nourish dry soup combined sulphuric acid hydroxyl chloroquine treatment can improve symptoms, obvious effect,have clinical application value.%目的:探讨滋阴润燥生津汤联合硫酸羟化氯喹治疗干燥综合征患者的临床疗效。方法选取80例干燥综合征患者为研究对象,按随机数字表法分为对照组与试验组,各40例,对照组患者给予硫酸羟化氯喹治疗,试验组患者在对照组基础上联合滋阴润燥生津汤治疗,对比两组患者的治疗效果。结果试验组患者治疗总有效率为95.0%,对照组为80.0%,试验组明显高于对照组(P<0.05)。结论对于干燥综合征患者采用滋阴润燥生津汤联合硫酸羟化氯喹治疗能改善临床症状,效果显著。

  6. 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

  7. The roles of the pfcrt 76T and pfmdr1 86Y mutations, immunity and the initial level of parasitaemia, in predicting the outcome of chloroquine treatment in two areas with different transmission intensities

    DEFF Research Database (Denmark)

    Khalil, I F; Alifrangis, M; Tarimo, D S;

    2005-01-01

    , and the ability to clear P. falciparum parasites carrying the key chloroquine-resistance (CQR) mutations, pfcrt 76T and pfmdr1 86Y. Identical CQ-efficacy trials were performed in 51 young children (aged <5 years) from Kibaha, in north-western Tanzania, and 44 patients (aged 3-57 years) from Darawish......, in eastern Sudan. In both areas, all the CQ-treatment failures had infections with the 76T and 86Y alleles before treatment. Although the presence of these two alleles was significantly associated with treatment failure in Sudan (P=0.001), the corresponding association in Tanzania did not reach......-values of 0.05 in Tanzania and 0.01 in Sudan) and with age-- the best surrogate for protective immunity in endemic areas (with P-values of 0.02 in Tanzania and 0.001 in Sudan). These results confirm previous observations that indicated that the 76T and 86Y alleles play a role in the mechanism of CQR...

  8. In vitro evaluation of quinidine sensitivity in brazilian Plasmodium falciparum isolates: comparative analysis to quinine and chloroquine Avaliação da sensibilidade in vitro à quinidina em isolados brasileiros de Plasmodium falciparum: análise comparativa à quinina e à cloroquina

    Directory of Open Access Journals (Sweden)

    Carla M. S. MENEZES

    2001-08-01

    Full Text Available Falciparum malaria represents a serious and an increasing world public health problem due to the acquired parasite's resistance to the most available drugs. In some endemic areas, quinidine, a diastereoisomer of the antimalarial quinine, has been employed for replacing the latter. In order to evaluate the use of quinidine as an alternative to the increasing loss of quinine effectiveness in Brazilian P. falciparum strains, as has been observed in the Amazon area, we have assayed quinidine, quinine and chloroquine. The in vitro microtechnique was employed. All isolates showed to be highly resistant to chloroquine. Resistance to quinine was not noted although high MIC (minimal inhibitory concentration values have been observed. These data corroborate the decreasing sensitivity to quinine in strains from Brazil. Quinidine showed IC50 from 0.053 to 4.577 mumol/L of blood while IC50 from 0.053 to 8.132 mumol/L of blood was estimated for quinine. Moreover, clearance of the parasitemia was observed in concentrations lower than that used for quinidine in antiarrhythmic therapy, confirming our previous data. The results were similar to African isolate.Malária falciparum representa grave e crescente problema de saúde pública mundial, dada a resistência do parasito à maioria dos fármacos disponíveis. Em algumas áreas endêmicas, a quinidina, diastereoisômero do antimalárico quinina, vem sendo empregada em substituição a este último. Com o objetivo de avaliar o emprego da quinidina como alternativa à perda crescente de sensibilidade de cepas brasileiras de P. falciparum à quinina, como o observado na região Amazônica, realizamos ensaio comparativo entre quinidina, quinina e cloroquina. A técnica in vitro do microteste de sensibilidade foi utilizada. Todos os isolados mostraram-se altamente resistentes à cloroquina. Resistência à quinina não foi observada, embora altos valores de CMI (concentração mínima inibitória tenham sido

  9. Creation of cloned strains of chloroquine-resistant Plasmodium falciparum from Yunnan, China with resistance to dihydroartemisinin%云南省抗氯喹恶性疟原虫双氢青蒿素抗性株体外培育与单克隆品系的建立

    Institute of Scientific and Technical Information of China (English)

    杨亚明; 李雪平; 张苍林; 李奔福; 刘慧; 李丽

    2013-01-01

    目的 建立云南省恶性疟原虫抗双氢青蒿素的单克隆品系,为开展恶性疟原虫对青蒿素类的抗药性研究奠定基础. 方法 体外长期连续培养恶性疟原虫,采用体外间断双氢青蒿素药物刺激法对恶性疟原虫株进行抗药性培育,待达到一定抗药性后采用有限稀释法对虫株进行克隆,采用体外微量法测定克隆虫株对双氢青蒿素、青蒿素、氯喹的敏感性,并对其生物学特性进行鉴定. 结果 获得2个云南氯喹抗性恶性疟原虫对双氢青蒿素抗性的单克隆品系C10和H6,IC50值分别为39.01 nmol/L和26.91 nmol/L. 结论 经过8次体外间断药物刺激和筛选,获得2株恶性疟双氢青蒿素抗性单克隆品系,其药物耐受性水平与现场抗性株接近.%Objectives To establish monoclonal strains of Plasmodium falciparum from Yunnan Province with resistance to dihydroartemisinin and to lay the foundation for study of the resistance of P.falciparum to artemisinin-based drugs.Methods Strains of P.falciparum were cultured via long-term continuous in vitro culturing.Strains were intermittently challenged with dihydroartemisinin in vitro.After the strains developed a certain level of resistance to dihydroartemisinin according to a microtest assay,they were cloned using a limited dilution.Biological characteristics of sensitivity to dihydroartemisinin,artemisinin,and chloroquine in vitro were identified.Results Two monoclonal strains of dihydroartemisinin-resistant P.falciparum were obtained from chloroquine resistant P.falciparum originating in Yunnan.The IC50 of the C10 cloned strain was 39.01nmol/L and the IC50 of the H6 cloned strain was 26.91 nmol/L.Conclusion Two monoclonal strains of dihydroartemisinin-resistant P.falciparum were obtained after the parasites were intermittently challenged with 8 rounds of dihydroartemisinin in vitro.These strains had a level of drug resistance close to that of resistant strains from Yunnan.

  10. Effects of Low Dose of Ketotifen and Chloroquine Combination on the Ultras tructure of Chloroquine Resistant Strain of Plasmodium Yoelii

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    1 Introduction Thewidespreaddevelopmentofchloroquineresis tant (CR)strainofmalariahasresultedinsearchingforneweffectiveanti malariadrugs[1~ 4 ] .Ananti asthmaandanti malariadrugketotifen (K)hasbeenprovedtoshowstronganti malariaactionbyPanetal[5~ 7] .FurthermoreKhadstrongerreverseeffectonP .yoelii (CR)thanVerapmil[8] .TheultrastructurestudyhasrevealedthattheeffectofK ( 10mg·kg- 1·d- 1)onchloroquine sensitive(CS)strainofP .yoeliiandK ( 4 0mg/kg·d)onP .yoelii (CR)isdifferentfromotheranti malariadrugswiththecha...

  11. The measurement of hydroxyl free radical scavenging activity of melanin-binding hydroxyl chloroquine by an electron spin resonance spectroscopy%电子自旋共振捕捉技术测定与黑素结合的羟基氯喹对羟自由基的清除

    Institute of Scientific and Technical Information of China (English)

    陈俊佑; 刘小明; 史赢; 雷铁池

    2012-01-01

    Objective: To determine the scavenging effects of melanin-binding hydroxyl chloroquine (HCQ) on transient hydroxyl free radical generated via the Fenton reaction, it is helpful in better understanding the mechanisms of antimalarials behind anti-inflammation and anti-photosensitivity. Methods: Transient hydroxyl free radical was generated via the Fenton reaction and trapped by DMPO. DMPO (400 mmol/L), ferrous sulfate (0.4 mmol/L), H2O2 (0.1%) and varying concentrations of melanin-binding HCQ were mixed and incubated, then sucked into a quartz capillary for 30 sec and measured by electron spin resonance (ESR). The relative amount of the radicals was estimated from the peak height of the second peak of the DMPO-OH signals in typical ESR spectra. Results: The bacteria-derived melanin (b-melanin) ranging from 20 mg/L to 100 mg/L exhibited a potent scavenging activity against hydroxyl free radical in a dose-dependent manner. 100 mg/L of b-melanin could afford a maximum scavenging activity (92.5%) against hydroxyl free radical. HCQ showed a limited and dose-independent scavenging activity toward hydroxyl radical. 50 mol/L of HCQ had the maximum scavenging rate (43.72%) against hydroxyl free radicals. The melanin-binding with 10 p,mol/L HCQ, which was equivalent to a mean blood concentration of HCQ in SLE patients receiving 400 mg of HCQ daily, demonstrated an increased scavenging activity against the radicals to compare with that of HCQ alone (P<0.05). High scavenging activity of melanin-binding HCQ against free radical was failure to reach by an increased concentration of HCQ. Conclusion; The melanin achieves an enhanced scavenging activity against hydroxyl free radical by binding with HCQ at its physiological concentration (10 μmol/L) and thereby protects skin cells from oxidative damages, which likely contributes to anti-photosensitivity of antimalarials in the treatment of cutaneous lupus erythematosus.%目的:观察与黑素结合的羟基氯喹(HCQ)对Fenton反应

  12. Antiviral Activity of Chloroquine against Human Coronavirus OC43 Infection in Newborn Mice▿

    OpenAIRE

    Keyaerts, Els; Li, Sandra; Vijgen, Leen; Rysman, Evelien; Verbeeck, Jannick; Van Ranst, Marc; Maes, Piet

    2009-01-01

    Until recently, human coronaviruses (HCoVs), such as HCoV strain OC43 (HCoV-OC43), were mainly known to cause 15 to 30% of mild upper respiratory tract infections. In recent years, the identification of new HCoVs, including severe acute respiratory syndrome coronavirus, revealed that HCoVs can be highly pathogenic and can cause more severe upper and lower respiratory tract infections, including bronchiolitis and pneumonia. To date, no specific antiviral drugs to prevent or treat HCoV infectio...

  13. Analysis of chloroquine resistance transporter (CRT) isoforms and orthologues in S. cerevisiae yeast.

    Science.gov (United States)

    Baro, Nicholas K; Pooput, Chaya; Roepe, Paul D

    2011-08-01

    Previous work from our laboratory optimized MeOH-inducible expression of the P. falciparum malarial parasite transporter PfCRT in P. pastoris yeast. These strains are useful for many experiments but do not allow for inducible protein expression under ambient growth conditions. We have therefore optimized galactose-inducible expression of PfCRT in S. cerevisiae yeast. We find that expression of PfCRT confers CQ hypersensitivity to growing yeast and that this is due to plasma membrane localization of the transporter. We use quantitative analyses of growth rates to compare hypersensitivity for yeast expressing various PfCRT isoforms. We also report successful high level inducible expression of the P. vivax orthologue, PvCRT, and compare CQ hypersensitivity for PvCRT vs PfCRT expressing yeast. We test the hypothesis that hypersensitivity is due to increased transport of CQ into yeast expressing the transporters via direct (3)H-CQ transport experiments and analyze the effect that membrane potential has on transport. The data suggest important new tools for rapid functional screening of PfCRT and PvCRT isoforms and provide further evidence for a model wherein membrane potential promotes charged CQ transport by PfCRT. Data also support our previous conclusion that wild type PfCRT is capable of CQ transport and provide a basis for understanding the lack of correspondence between PvCRT mutations and resistance to CQ in the important malarial parasite P. vivax.

  14. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes

    DEFF Research Database (Denmark)

    Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia;

    2014-01-01

    with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized...

  15. 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

    of uncomplicated malaria, of three combinations: AQ + SP, artesunate (AR) + SP and AQ + AR. Based on the WHO (1996, WHO/MAL/96.1077) in vivo protocol, we conducted two open, randomized, clinical trials. Children aged 6-59 months with axillary body temperature > or = 37.5 degrees C and non-complicated malaria were......% 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....

  16. CHLOROQUINE SENSITIVITY OF PLASMODIUM FALCIPARUM IN BERAKIT, BINTAN ISLAND, SUMATRA, AFTER MASS CHEMOPROPHYLAXIS THROUGH COMMUNITY PARTICIPATION, AND ITS SOCIOLOGICAL STUDIES

    Directory of Open Access Journals (Sweden)

    Wita Pribadi

    2012-09-01

    Full Text Available Profilaksis minggguan dengan klorokuin yang dilakukan secara massal melalui peran serta masyarakat telah dilakukan pada penduduk RK I di desa Berakit, Bintan, Propinsi Riau, Sumatra selama dua tahun (¡983-1985. Delapan tahun kemudian (¡993, pemeriksaan sensitivitas Plasmodium falciparum terhadap klorokuin in vivo dan in vitro dilakukan di RK I untuk mengetahui apakah pemberian klorokuin setiap minggu pada penduduk secara massal selama 2 tahun mempunyai dampak terhadap timbulnya resistensi P. falciparum terhadap obat tersebut di RK I atau dapat menyebar­luaskan resistensi klorokuin. Penelitian sosial dilakukan untuk mendapatkan informasi melalui pemeriksaan pengetahuan, sikap dan perilaku (KAP tentang malaria pada penduduk RK II di desa Berakit. RK II letaknya bersebelahan dengan RK I yang penduduknya telah diwawancara dan diberi penyuluhan kesehatan dengan "learning module" tentang malaria, dan. apakah hal ini mempengaruhi situasi/keadaan malaria di RK II. Hasil penelitian malariometrik di RK I dan RK II menunjukkan angka limpa dan angka parasit menurun secara bermakna, bila dibandingkan dengan hasil pada tahun 1991 tetapi di RK I tidak berbeda bermakna dibandingkan dengan hasil tahun 1995. Dari pemeriksaan 644 sediaan darah dari RK I dan RK II untuk tes sensitivitas, prevalensi parasitnya adalah 8.2 % (53/644 dan 58.5 % kasus positif adalah P. falciparum dan infeksi campur, selebihnya adalah P. vivax (41.5 %. Sayang sekali, hanya satu infeksi P. falciparum yang memenuhi syarat untuk tes dengan hasil S/R I in vivo 7 hari yang disederhanakan. Tes mikro in vitro menunjukkan resistensi (R terhadap klorokuin dan masih sensitif (S terhadap obat malaria lain (kina, S-P, meftokuin.Hasil pemeriksaan sosiologis menunjukkan adanya pengaruh"learning module" mengenai penyakit malaria sebanyak 20 % responden di RK II yang mempunyai sikap dan perilaku yang positif, bila dibandingkan dengan penelitian di RK II tahun 1991 sebesar 27.9 % dan tahun 1995 sebesar 47.9%. Hal ini dapat tercermin pada hasil malariometrik di RK II . Walaupun demikian, masih diperlukan penyuluhan kesehatan tentang malaria untuk penduduk RK II. Perlu diketahui bahwa setelah penelitian selesai sampai dilakukan evaluasi tahun 1991 dan tahun 1993, di daerah ini tidak pernah dilakukan intervensi dalam bentuk apa pun kecuali satu kali penyemprotan pada tahun 1992

  17. Immunoglobulin G antibodies to merozoite surface antigens are associated with recovery from chloroquine-resistant Plasmodium falciparum in Gambian children.

    NARCIS (Netherlands)

    Pinder, M.; Sutherland, C.J.; Sisay-Joof, F.; Ismaili, J.; McCall, M.B.B.; Ord, R.; Hallett, R.; Holder, A.A.; Milligan, P.

    2006-01-01

    We examined the hypothesis that recovery from uncomplicated malaria in patients carrying drug-resistant Plasmodium falciparum is a measure of acquired functional immunity and may therefore be associated with humoral responses to candidate vaccine antigens. Gambian children with malaria were treated

  18. Multiple Origins of Mutations in the mdr1 Gene—A Putative Marker of Chloroquine Resistance in P. vivax

    DEFF Research Database (Denmark)

    Schousboe, Mette L; Ranjitkar, Samir; Rajakaruna, Rupika S;

    2015-01-01

    resistance gene, Pvmdr1 are putative determinants of CQR but the extent of their emergence at population level remains to be explored. OBJECTIVE: In this study we describe the prevalence of SNPs in the Pvmdr1 among samples collected in seven P. vivax endemic countries and we looked for molecular evidence...

  19. 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.

  20. 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...... 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......: Acquired anti-malarial antibodies may play an important role in the efficacy of anti-malarial drugs in younger children more susceptible to the disease....

  1. Antiplasmodial properties of kaempferol-3-O-rhamnoside isolated from the leaves of Schima wallichii against chloroquine-resistant Plasmodium falciparum

    OpenAIRE

    Melisa I. Barliana; SURADJI, EKA W.; ABDULAH, RIZKY; DIANTINI, AJENG; HATABU, TOSHIMITSU; Nakajima-Shimada, Junko; SUBARNAS, ANAS; Koyama, Hiroshi

    2014-01-01

    Previous intervention studies have shown that the most effective agents used in the treatment of malaria were isolated from natural sources. Plants consumed by non-human primates serve as potential drug sources for human disease management due to the similarities in anatomy, physiology and disease characteristics. The present study investigated the antiplasmodial properties of the primate-consumed plant, Schima wallichii (S. wallichii) Korth. (family Theaceae), which has already been reported...

  2. Biological and haematological safety profile of oral amodiaquine and chloroquine in healthy volunteers with or without Plasmodium falciparum infection in northeast Tanzania

    DEFF Research Database (Denmark)

    Massaga, J J; Lusingu, J P; Makunde, R;

    2008-01-01

    -immune healthy adult male volunteers with and without malaria parasites. The objective was to collect data on biological and haematological safety, tolerability, and parasitological efficacy to serve as baseline in the evaluation of the effectiveness of AQ preventive intermittent treatment against malaria......Amodiaquine (AQ), an effective antimalarial drug for uncomplicated malaria, has been greatly restricted after cases of life-threatening agranulocytosis and hepatic toxicity during prophylactic use. We conducted a hospital based open-label randomised clinical trial in 40 indigenous semi...

  3. REVERSAL OF HALOFANTRINE RESISTANCE IN PLASMODIUM FALCIPARUM BY PENFLURIDOL IN VITRO

    Directory of Open Access Journals (Sweden)

    M. Nateghpour

    1998-10-01

    Full Text Available Penfluridol, a neuroleptic drug, considerably reversed halofantrine resistance in T9.96HF halofantrine resistant strain of Plasmodium falicparum (originally chloroquine sensitive parasites, but not in K1HF halofantrine resistant strain (originally chloroquine resistant parasites

  4. Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from em>P. yoelii infection

    DEFF Research Database (Denmark)

    Chen, M; Theander, T G; Christensen, S B;

    1994-01-01

    Licochalcone A, isolated from Chinese licorice roots, inhibited the in vitro growth of both chloroquine-susceptible (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains in a [3H]hypoxanthine uptake assay. The growth inhibition of the chloroquine-resistant strain by licochalcone A w...

  5. A simple, high-throughput method to detect Plasmodium falciparum single nucleotide polymorphisms in the dihydrofolate reductase, dihydropteroate synthase, and P. falciparum chloroquine resistance transporter genes using polymerase chain reaction- and enzyme-linked immunosorbent

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Enosse, Sonia; Pearce, Richard;

    2005-01-01

    . However, to be a practical tool in the surveillance of drug resistance, simpler methods for high-throughput haplotyping are warranted. Here we describe a quick and simple technique that detects dhfr, dhps, and Pfcrt SNPs using polymerase chain reaction (PCR)- and enzyme-linked immunosorbent assay (ELISA......)-based technology. Biotinylated PCR products of dhfr, dhps, or Pfcrt were captured on streptavidin-coated microtiter plates and sequence-specific oligonucleotide probes (SSOPs) were hybridized with the PCR products. A stringent washing procedure enabled detection of remaining bound SSOPs and distinguished between...... the SNPs of dhfr, dhps, and Pfcrt with high specificity. The SSOP-ELISA compared well with a standard PCR-restriction fragment length polymorphism procedure, and gave identical positive results in more than 90% of the P. falciparum slide-positive samples tested. The SSOP-ELISA of all dhfr, dhps, or Pfcrt...

  6. Tinospora cordifolia as an adjuvant drug in the treatment of hyper-reactive malarious splenomegaly – case reports

    OpenAIRE

    Ranjan Kumar Singh

    2005-01-01

    Background & objectives: The effect of aqueous extract of Tinospora cordifolia, an immunomodulatorwith antimalarial activity along with chloroquine was studied in the treatment of three cases ofhyper-reactive malarious splenomegaly in District Hospital, Daltonganj town, Jharkhand, India. Thesecases were partial/slow responders to the conventional antimalarial drug chloroquine.Methods: Aqueous extract of T. cordifolia (500 mg) was added to chloroquine (CQ) base (300 mg)weekly and CQ prophylaxi...

  7. [Effect of anti-inflammatory preparations on the process of thermogenesis in blood erythrocytes].

    Science.gov (United States)

    Sigidin, Ia A; Taratuta, O V

    1975-04-01

    The authors studied the influence of the main antiphlogistic agents (prednisolone, acetylsalicylic acid, rheopyrine, chloroquine and indomethacine) on the thermal effect of the peripheral blood erythrocytes in man. It was found that only chloroquine possessed a significant inhibitory effect. This fact pointed to the inhibition by chloroquine of energy production in the process of glycolysis, which could be regarded as one of the factors of the therapeutic action of this preparation. PMID:1081413

  8. The novel oxygenated chalcone, 2,4-dimethoxy-4'-butoxychalcone, exhibits potent activity against human malaria parasite Plasmodium falciparum in vitro and rodent parasites Plasmodium berghei and Plasmodium yoelii in vivo

    DEFF Research Database (Denmark)

    Chen, M; Brøgger Christensen, S; Zhai, L;

    1997-01-01

    growth of both a chloroquine-susceptible (3D7) and a chloroquine-resistant (Dd2) strain of Plasmodium falciparum in a [3H]hypoxanthine uptake assay. The in vivo activity of 2,4mbc was tested in mice infected with Plasmodium berghei or Plasmodium yoelii and in rats infected with P. berghei. 2,4mbc...

  9. Drug: D07680 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07680 Drug Chloroquine sulfate; Nivaquine (TN) C18H26ClN3. H2SO4 417.1489 417.9506 D07680.gif Antiprotozoa...sification [BR:br08302] Antiparasitics Antiprotozoals Chloroquine D07680 Chloroqu

  10. Possible artefacts in the in vitro determination of antimalarial activity of natural products that incorporate into lipid bilayer

    DEFF Research Database (Denmark)

    Ziegler, Hanne Lindvig; Jensen, Thomas Høgh; Christensen, Jette;

    2002-01-01

    Dehydroabietinol isolated from Hyptis suaveolens (L.) Poit. was found to inhibit growth of chloroquine-sensitive as well as chloroquine-resistant strains of Plasmodium falciparum cultivated in erythrocytes in vitro (IC 50 26-27 microM). However, erythrocytes exposed to dehydroabietinol were...

  11. Carl Jung.

    Science.gov (United States)

    Kyle, R A; Shampo, M A

    1978-11-17

    Physicians should be prepared to provide prophylactic medications for travelers to malarious areas and to treat patients with malaria. Chloroquine hydrochloride is the suppressive agent of choice for treatment of mild infections due to all species of malaria except for those due to chloroquine-resistant strains of Plasmodium falciparum. For treatment of severe infections with P falciparum and for treatment of all infections due to chloroquine-resistant strains of P falciparum quinine is the suppressive agent of choice. Chloroquine is also the prophylactic agent of choice for most travelers. To prevent infection with P vivax or P ovale, primaquine must also be given. A RBC glucose-6-phosphate dehydrogenase level should be obtained before administration of primaquine. For prophylaxis of chloroquine-resistant strains of P falciparum, no completely satisfactory regime is presently available in the United States.

  12. Effect of chloroquine on hydrogen peroxide-induced apoptosis of smooth muscle cells via endoplasmic reticulum stress pathway%氯喹对过氧化氢诱导平滑肌细胞内质网应激途径凋亡的影响

    Institute of Scientific and Technical Information of China (English)

    李松岩; 郭敏; 王烟; 于洋; 刘师兵; 徐冶

    2015-01-01

    目的 探讨氯喹对过氧化氢诱导平滑肌细胞(SMC)内质网应激途径凋亡的影响.方法 体外培养主动脉SMC细胞,分别加入100、400和800μmol/L H2O2培养12h后,MTT法检测SMC细胞生存率.将细胞分为对照组、H2O2组、氯喹组、H2O2+氯喹组,培养12h后采用MTT法检测氯喹阻断自噬后SMC细胞的生存率,倒置相差显微镜观察H2O2对SMC细胞形态变化的影响,间接免疫荧光法检测自噬相关蛋白LC3和p62的表达,Western blotting检测Beclin-1、 LC3、GRP78、 CHOP、Caspase-3及Cleaved Caspase-3蛋白的表达.结果 MTT检测结果显示,100、400、800μmol/L H2O2作用12h后,SMC细胞存活率明显降低,IC50为447.4μmol/L;氯喹阻断自噬后,SMC细胞存活率明显降低(P<0.05).倒置相差显微镜观察结果显示,H2O2+氯喹组SMC收缩变圆,细胞密度明显下降.激光共聚焦显微镜观察显示,H2O2与氯喹联合作后,SMC细胞质中LC3和p62蛋白表达均明显增加,且有明显共定位现象.Western blotting检测结果表明,H2O2与氯喹联合作用后,SMC中内质网应激相关蛋白GRP78、CHOP和自噬相关蛋白Beclin-1、LC3Ⅱ/LC3 Ⅰ的表达明显增加(P<0.05, P<0.01),凋亡执行分子Caspase-3的裂解形式蛋白表达水平明显升高(P<0.01).结论 氯喹对过氧化氢诱导SMC通过内质网应激途径的凋亡具有促进作用.

  13. Exploring QSAR for Antimalarial Activities and Drug Distribution within Blood of a Series of 4-Aminoquinoline Drugs Using Genetic-MLR

    Directory of Open Access Journals (Sweden)

    Amir Najafi

    2013-01-01

    Full Text Available Malaria has been one of the most significant public health problems for centuries. QSAR modeling of the antimalarial activity and blood-to-plasma concentration ratio of Chloroquine and a new series of 4-aminoquinoline derivatives were developed using genetic algorithms with multiple linear regression (GA-MLR method. We obtained two different models against Chloroquine-sensitive (3D7 and Chloroquine-resistant (W2 strains of Plasmodium falciparum with good adjustment levels. Drug distribution in blood, defined as drug blood-to-plasma concentration ratio (Rb, is related to molecular descriptors. Leave-many-out (LMO and Y-randomization methods confirmed the models' robustness.

  14. 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.

  15. Effect of Combination Therapy on Joint Destruction in Rheumatoid Arthritis

    DEFF Research Database (Denmark)

    Graudal, N.; Hubeck-Graudal, T.; Tarp, S.;

    2014-01-01

    on progression of radiographic joint erosions in patients with rheumatoid arthritis (RA). Methods and Findings: The following combination drug therapies compared versus single DMARD were investigated: Double DMARD: 2 DMARDs (methotrexate, sulfasalazine, leflunomide, injectable gold, cyclosporine, chloroquine...

  16. Chemotherapy and drug resistance status of malaria parasite in northeast India

    Institute of Scientific and Technical Information of China (English)

    Diganta Goswami; Indra Baruah; Sunil Dhiman; Bipul Rabha; Vijay Veer; Lokendra Singh; Dhirendra Kumar Sharma

    2013-01-01

    India reports the highest number of malaria cases in Southeast Asia, of which Plasmodiumfalciparum contribute more than half of the cases every year. North eastern states of India contribute only 3.96% of country’s population but account for >10% of total reported malaria cases, 11% of Plasmodium falciparum cases and 20% of malaria related deaths annually. In India, chloroquine resistance was reported for the first time from northeast region and since then chloroquine treatment failure is being reported from many parts of the region. Increased chloroquine treatment failure has led to change of the drug policy to artemisinin combination therapy as first line of malaria treatment in the region. However, replacing chloroquine to artemisinin combination therapy has not shown significant difference in the overall malaria incidence in the region. The present review addresses the current malaria situation of northeastern region of India in the light of antimalarials drug resistance.

  17. Methemoglobinemia

    Science.gov (United States)

    ... benzocaine Benzene Certain antibiotics (including dapsone and chloroquine) Nitrites (used as additives to prevent meat from spoiling) The condition may also occur in infants who are very ill or who are fed too many vegetables containing nitrates (such as beets).

  18. 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

  19. Polymorphisms of the oxidant enzymes glutathione S-transferase and glutathione reductase and their association with resistance ofPlasmodium falciparum isolates to antimalarial drugs

    Institute of Scientific and Technical Information of China (English)

    Raewadee Wisedpanichkij; Wanna Chaicharoenkul; Poonuch Mahamad; Prapichaya Prompradit; Kesara Na-Bangchang

    2010-01-01

    Objective:To investigate the association between amplification of the two regulatory genes controlling glutathione(GSH)levels, glutathione reductase(PfGR)and glutathione S-transferase (PfGST) genes and sensitivity ofPlasmodium falciparum (P. falciparum)isolates collected from different malaria endemic areas of Thailand to standard antimalarial drugs.Methods: A total of70P. falciparum isolates were collected from endemic areas of multi-drug resistance (Tak, Chantaburi and Ranong Provinces) during the year2008-2009. The in vitro assessment of antimalarial activity ofP. falciparumclones (K1- and Dd2 chloroquine resistant and3D7-chloroquine sensitive) and isolates to chloroquine, quinine, mefloquine and arteusnate was performed based onSYBR Green modified assay.Results:68 (97.14%), 11 (15.71%) and28 (40%) isolates respectively were classified as chloroquine-, quinine- and mefloquine-resistant isolates. With this limited number ofP. falciparum isolates included in the analysis, no significant association between amplification ofPfGST gene and sensitivity of the parasite to chloroquine, quinine, mefloquine and quinine was found. Based onPCR analysis,Dd2, K1 and3D7clones all contained only one copy of thePfGST gene. All isolates (70) also carried only one copy number of PfGST gene. There appears to be an association between amplification ofPfGR gene and chloroquine resistance. The3D7and Dd2 clones were found to carry only onePfGR gene copy, whereas the K1 clone carried two gene copies.Conclusions: Chloroquine resistance is likely to be a consequence of multi-factors and enzymes in theGSH system may be partly involved. Larger number of parasite isolates are required to increase power of the hypothesis testing in order to confirm the involvement of both genes as well as other genes implicated in glutathione metabolism in conferring chloroquine resistance.

  20. Cyclopalladated organosilane-tethered thiosemicarbazones: novel strategies for improving antiplasmodial activity.

    Science.gov (United States)

    Adams, Muneebah; Barnard, Linley; de Kock, Carmen; Smith, Peter J; Wiesner, Lubbe; Chibale, Kelly; Smith, Gregory S

    2016-04-01

    Two series of ferrocenyl- and aryl-derived cyclopalladated organosilane thiosemicarbazone complexes were synthesised via C-H bond activation. Selected compounds were evaluated for in vitro antiplasmodial activity against the chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains of the human malaria parasite Plasmodium falciparum. Cyclopalladation of the thiosemicarbazones resulted in antiplasmodial activities in the low micromolar range. PMID:26911403

  1. Surveillance of antimalarial drug resistance in China in the 1980s–1990s

    OpenAIRE

    Liu, De-Quan

    2014-01-01

    Since the successful preparation of the microplates and the medium for field application, the resistance degree and its geographical distribution of chloroquine-resistant Plasmodium falciparum, the fluctuation of the resistance degree of P. falciparum to chloroquine, and the sensitivity of the parasite to commonly used antimalarial drugs were investigated between 1980 and 2003 by the in vitro microtest and the in vivo four-week test recommended by the World Health Organization (WHO). The resu...

  2. Diversity and utilization of antimalarial ethnophytotherapeutic remedies among the Kikuyus (Central Kenya)

    OpenAIRE

    Bussmann Rainer W; Njoroge Grace N

    2006-01-01

    Abstract Plants in Kenya are becoming increasingly important as sources of traditional medicines. The World Health Organization (WHO) has estimated that malaria kills about 2.7 million people every year, 90% of who are from Africa. Malaria continues to be a national concern in Kenya as it plays a major role in the high mortality rates being experienced currently. The use and miss-use of chloroquine to prevent and treat falciparium malaria has led to widespread appearance of chloroquine resist...

  3. Treatment of severe malaria.

    OpenAIRE

    Warrell, D. A.

    1989-01-01

    In the treatment of severe Plasmodium falciparum infection antimalarial drugs should, ideally, be given by controlled rate intravenous infusion until the patient is able to swallow tablets. In cases where infection has been acquired in a chloroquine resistant area, and where it has broken through chloroquine prophylaxis or where the geographical origin or species are uncertain, quinine is the treatment of choice. When access to parenteral quinine is likely to be delayed, parenteral quinidine ...

  4. Relapsing malaria infection acquired in Kenya.

    OpenAIRE

    Patterson, J E; Bia, F. J.; Miller, K.; McPhedran, P.

    1987-01-01

    An American physician-traveler to East Africa presented with manifestations of cerebral malaria and was treated with intravenous quinidine for chloroquine-resistant falciparum malaria. He later relapsed with Plasmodium ovale infection, despite previous primaquine therapy. Treatment of chloroquine-resistant malaria is discussed. The difficulty in diagnosing P. ovale infections and the predominance of this malaria species over P. vivax in East Africa are reviewed. Images FIG. 1 FIG. 2 FIG. 3

  5. Synthesis, in vitro antimalarial activity and cytotoxicity of novel 4-aminoquinolinyl-chalcone amides

    OpenAIRE

    Smit, Frans J; N'Da, David D.

    2014-01-01

    A series of 4-aminoquinolinyl-chalcone amides 11–19 were synthesized through condensation of carboxylic acid-functionalized chalcone with aminoquinolines, using 1,10-carbonyldiimidazole as coupling agent. These compounds were screened against the chloroquine sensitive (3D7) and chloroquine resistant (W2) strains of Plasmodium falciparum. Their cytotoxicity towards the WI-38 cell line of normal human fetal lung fibroblast was determined. All compounds were found active, with IC50 v...

  6. Anti-Plasmodial Activity of Aroylhydrazone and Thiosemicarbazone Iron Chelators: Effect on Erythrocyte Membrane Integrity, Parasite Development and the Intracellular Labile Iron Pool

    OpenAIRE

    Walcourt, Asikiya; Kurantsin-Mills, Joseph; Kwagyan, John; Adenuga, Babafemi B.; Kalinowski, Danuta S.; Lovejoy, David B.; Lane, Darius J.R.; Richardson, Des R.

    2013-01-01

    Iron chelators inhibit the growth of the malaria parasite, Plasmodium falciparum, in culture and in animal and human studies. We previously reported the anti-plasmodial activity of the chelators, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), 2-hydroxy-1-naphthylaldehyde 4-methyl-3-thiosemicarbazone (N4mT), and 2-hydroxy-1-naphthylaldehyde 4-phenyl-3-thiosemicarbazone (N4pT). In fact, these ligands showed greater growth inhibition of chloroquine-sensitive (3D7) and chloroquine-re...

  7. Protecting the malaria drug arsenal: halting the rise and spread of amodiaquine resistance by monitoring the PfCRT SVMNT type

    OpenAIRE

    Twu Olivia; Sa Juliana M

    2010-01-01

    Abstract The loss of chloroquine due to selection and spread of drug resistant Plasmodium falciparum parasites has greatly impacted malaria control, especially in highly endemic areas of Africa. Since chloroquine removal a decade ago, the guidelines to treat falciparum malaria suggest combination therapies, preferentially with an artemisinin derivative. One of the recommended partner drugs is amodiaquine, a pro-drug that relies on its active metabolite monodesethylamodiaquine, and is still ef...

  8. The novel oxygenated chalcone, 2,4-dimethoxy-4'-butoxychalcone, exhibits potent activity against human malaria parasite Plasmodium falciparum in vitro and rodent parasites Plasmodium berghei and Plasmodium yoelii in vivo

    DEFF Research Database (Denmark)

    Chen, M; Brøgger Christensen, S; Zhai, L;

    1997-01-01

    growth of both a chloroquine-susceptible (3D7) and a chloroquine-resistant (Dd2) strain of Plasmodium falciparum in a [3H]hypoxanthine uptake assay. The in vivo activity of 2,4mbc was tested in mice infected with Plasmodium berghei or Plasmodium yoelii and in rats infected with P. berghei. 2,4mbc...... activity and might be developed into a new antimalarial drug....

  9. 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...

  10. 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

  11. INDUCTION OF DRUG RESISTANCE IN PLASMODIUM FALCIPARUM: AN INTERMITTENT DRUG EXPOSURE METHOD

    Directory of Open Access Journals (Sweden)

    M.Nateghpour

    1998-03-01

    Full Text Available The production of experimentally induced drug resistance in the laboratory provides valuable opportunities for investigators to study the nature and genetics of drug resistance mechanisms to a given agent, patterns of cross resistance and the mode of action of drugs. At the beginning the continuous drug exposure was chosen as a standard procedure to produce drug— resistant strains of P. falciparum,.but later on some other methods were also applied. An intermittent drug exposure method as a novel procedure has been introduced in this study. Intermittent exposure of chloroquine resistant Kl and chloroquine sensitive T9.96 strains of P. falciparum to halofantrine culminated in a relatively rapid reduction in sensitivity to the drug. The response of halofantrifle - resistnat K1HF and T9.96 strains and parent parasites to halofantrifle, inefloquine, quinine and chloroquine was determined. The results indicated that the effectiveness of halofantrine to K1HF and T9.96HF strains decreased 9 and 3 folds respectively, compared to the parent parasites. Cross -resistance occurred among halofantrine. mefloquine and quinine. Halofantrine resistance was associated with enhanced chloroquine sensitivity in the strain derived from chloroquine - resistant K1 strain, hut not in the strain derived from chloroquine - sensitive T9.96 parasites.

  12. Lysosomotropic agents as HCV entry inhibitors

    Directory of Open Access Journals (Sweden)

    Nawaz Zafar

    2011-04-01

    Full Text Available Abstract HCV has two envelop proteins named as E1 and E2 which play an important role in cell entry through two main pathways: direct fusion at the plasma membrane and receptor-mediated endocytosis. Fusion of the HCV envelope proteins is triggered by low pH within the endosome. Lysosomotropic agents (LA such as Chloroquine and Ammonium chloride (NH4Cl are the weak bases and penetrate in lysosome as protonated form and increase the intracellular pH. To investigate the antiviral effect of LA (Chloroquine and NH4Cl on pH dependent endocytosis, HCV pseudoparticles (HCVpp of 1a and 3a genotype were produced and used to infect liver cells. The toxicological effects of Chloroquine and NH4Cl were tested in liver cells through MTT cell proliferation assay. For antiviral screening of Chloroquine and NH4Cl, liver cells were infected with HCVpp of 3a and 1a genotype in the presence or absence of different concentrations of Chloroquine and NH4Cl and there luciferase activity was determined by using a luminometer. The results demonstrated that Chloroquine and NH4Cl showed more than 50% reduction of virus infectivity at 50 μM and 10 mM concentrations respectively. These results suggest that inhibition of HCV at fusion step by increasing the lysosomal pH will be better option to treat chronic HCV.

  13. Antimalarial therapy selection for quinolone resistance among Escherichia coli in the absence of quinolone exposure, in tropical South America.

    Directory of Open Access Journals (Sweden)

    Ross J Davidson

    Full Text Available BACKGROUND: Bacterial resistance to antibiotics is thought to develop only in the presence of antibiotic pressure. Here we show evidence to suggest that fluoroquinolone resistance in Escherichia coli has developed in the absence of fluoroquinolone use. METHODS: Over 4 years, outreach clinic attendees in one moderately remote and five very remote villages in rural Guyana were surveyed for the presence of rectal carriage of ciprofloxacin-resistant gram-negative bacilli (GNB. Drinking water was tested for the presence of resistant GNB by culture, and the presence of antibacterial agents and chloroquine by HPLC. The development of ciprofloxacin resistance in E. coli was examined after serial exposure to chloroquine. Patient and laboratory isolates of E. coli resistant to ciprofloxacin were assessed by PCR-sequencing for quinolone-resistance-determining-region (QRDR mutations. RESULTS: In the very remote villages, 4.8% of patients carried ciprofloxacin-resistant E. coli with QRDR mutations despite no local availability of quinolones. However, there had been extensive local use of chloroquine, with higher prevalence of resistance seen in the villages shortly after a Plasmodium vivax epidemic (p<0.01. Antibacterial agents were not found in the drinking water, but chloroquine was demonstrated to be present. Chloroquine was found to inhibit the growth of E. coli in vitro. Replica plating demonstrated that 2-step QRDR mutations could be induced in E. coli in response to chloroquine. CONCLUSIONS: In these remote communities, the heavy use of chloroquine to treat malaria likely selected for ciprofloxacin resistance in E. coli. This may be an important public health problem in malarious areas.

  14. Targeting protein translation, RNA splicing, and degradation by morpholino-based conjugates in Plasmodium falciparum.

    Science.gov (United States)

    Garg, Aprajita; Wesolowski, Donna; Alonso, Dulce; Deitsch, Kirk W; Ben Mamoun, Choukri; Altman, Sidney

    2015-09-22

    Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome.

  15. A cross-sectional survey of Plasmodium falciparum pfcrt mutant haplotypes in the Democratic Republic of Congo.

    Science.gov (United States)

    Antonia, Alejandro L; Taylor, Steve M; Janko, Mark; Emch, Michael; Tshefu, Antoinette K; Meshnick, Steven R

    2014-06-01

    In the Democratic Republic of the Congo (DRC), artesunate-amodiaquine is first-line therapy for falciparum malaria; little is known about the prevalence of molecular markers of parasite drug resistance. Across the DRC, we genotyped 166 parasites in Plasmodium falciparum chloroquine resistance transporter (pfcrt) using polymerase chain reaction (PCR) and sequencing. Of these parasites, 73 (44%) parasites were pure wild-type CVMNK, 55 (31%) parasites were chloroquine-resistant CVIET: , 35 (21.1%) parasites were mixed CVMNK and CVIET: , and 3 parasites were other genotypes. Ninety-two infections (55.4%) harbored the pfcrt K76T: substitution that is highly correlated with chloroquine failure. The amodiaquine-resistant S: VMNT: haplotype was absent. Geographically, pfcrt haplotypes were not clearly clustered. Chloroquine accounted for 19.4% of antimalarial use, and amodiaquine accounted for 15.3% of antimalarial use; there were no associations between drug use and mutant haplotype prevalence. In the DRC, our molecular survey indicates that resistance to chloroquine is substantial but that resistance to amodiaquine is absent. These contrasting findings highlight the need for molecular surveillance of drug resistance to inform malaria control policies.

  16. The Impact of Nanochloroquine on Restoration of Hepatic and Splenic Mitochondrial Damage against Rodent Malaria

    Directory of Open Access Journals (Sweden)

    Satyajit Tripathy

    2013-01-01

    Full Text Available The applications of nanotechnology to pharmacology are the potential appliance of biodegradable polymers and convection-enhanced drug delivery in the diagnostics and treatment of diseases. Chitosan is a natural polysaccharide that has attracted significant scientific interest during the last two decades. The present study was to evaluate the possible effects of chitosan tripolyphosphate conjugated nanochloroquine against Plasmodium berghei infection on select makers of oxidative damage and antioxidant status in mitochondria of liver and spleen. P. berghei infection was developed in Swiss mice by intraperitoneal injection of 200 µL of infected blood. Parasite-infected mice were treated with chloroquine and nanoconjugated chloroquine. Superoxide radical generation, nitrate level, and oxidized glutathione were increased significantly (P<0.05 in the mitochondria of infected group as compared to control group, and reduced glutathione level, activity of SOD, GPx, GR, and GST, and mitochondrial transmembrane potential were decreased significantly (P<0.05, which were increased or decreased significantly (P<0.05 near to normal in nanoconjugated chloroquine treated group than chloroquine treated group. So, the findings may suggest the advantageous role of nanoconjugated chloroquine against the P. berghei induced oxidative damage in hepatic and splenic mitochondria.

  17. Tinospora cordifolia as an adjuvant drug in the treatment of hyper-reactive malarious splenomegaly – case reports

    Directory of Open Access Journals (Sweden)

    Ranjan Kumar Singh

    2005-03-01

    Full Text Available Background & objectives: The effect of aqueous extract of Tinospora cordifolia, an immunomodulatorwith antimalarial activity along with chloroquine was studied in the treatment of three cases ofhyper-reactive malarious splenomegaly in District Hospital, Daltonganj town, Jharkhand, India. Thesecases were partial/slow responders to the conventional antimalarial drug chloroquine.Methods: Aqueous extract of T. cordifolia (500 mg was added to chloroquine (CQ base (300 mgweekly and CQ prophylaxis was observed up to six months. Improvement was gauzed by measuringspleen enlargement, Hb, serum IgM and well-being in three cases of hyper-reactive malarious splenomegaly.Results: Addition of extract of T. cordifolia for the first six weeks to chloroquine showed regressionof spleen by 37–50% after six weeks and 45–69% after six months from the start of treatment. Likewisedecrease in IgM and increase in Hb as well as wellbeing (Karnofsky performance scale were observed.Conclusion: The results of the present study paves a new sight in the treatment of hyper-reactivemalarious splenomegaly, however, large-scale trial is required to confirm the beneficial effect of T.cordifolia extract in combination with chloroquine.

  18. Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum.

    Science.gov (United States)

    Bushman, Mary; Morton, Lindsay; Duah, Nancy; Quashie, Neils; Abuaku, Benjamin; Koram, Kwadwo A; Dimbu, Pedro Rafael; Plucinski, Mateusz; Gutman, Julie; Lyaruu, Peter; Kachur, S Patrick; de Roode, Jacobus C; Udhayakumar, Venkatachalam

    2016-03-16

    Infections with the malaria parasite Plasmodium falciparum typically comprise multiple strains, especially in high-transmission areas where infectious mosquito bites occur frequently. However, little is known about the dynamics of mixed-strain infections, particularly whether strains sharing a host compete or grow independently. Competition between drug-sensitive and drug-resistant strains, if it occurs, could be a crucial determinant of the spread of resistance. We analysed 1341 P. falciparum infections in children from Angola, Ghana and Tanzania and found compelling evidence for competition in mixed-strain infections: overall parasite density did not increase with additional strains, and densities of individual chloroquine-sensitive (CQS) and chloroquine-resistant (CQR) strains were reduced in the presence of competitors. We also found that CQR strains exhibited low densities compared with CQS strains (in the absence of chloroquine), which may underlie observed declines of chloroquine resistance in many countries following retirement of chloroquine as a first-line therapy. Our observations support a key role for within-host competition in the evolution of drug-resistant malaria. Malaria control and resistance-management efforts in high-transmission regions may be significantly aided or hindered by the effects of competition in mixed-strain infections. Consideration of within-host dynamics may spur development of novel strategies to minimize resistance while maximizing the benefits of control measures.

  19. Synthesis, characterization, and antiplasmodial activity of polymer-incorporated aminoquinolines.

    Science.gov (United States)

    Aderibigbe, B A; Neuse, E W; Sadiku, E R; Ray, S Shina; Smith, P J

    2014-06-01

    In this research, aminoquinoline compounds were synthesized, characterized, and incorporated into water-soluble polymers to form conjugates. The conjugates were characterized by X-ray diffraction, thermal gravimetric analysis, scanning electron microscope, Fourier transform infrared spectroscopy, and nuclear magnetic resonance spectroscopy to confirm the successful incorporation of the aminoquinoline compound on to the polymer. The synthesized conjugates were screened for in vitro antiplasmodial activity in triplet test against chloroquine-sensitive strain of Plasmodium falciparum and chloroquine drug was used as a reference drug in all the experiments. A full dose-response was performed to determine the concentration inhibiting 50% of parasite growth (IC50 value). Polymeric conjugates containing 3-diethylamino-1-propylamine solubilizing units were found to be most active against the chloroquine-sensitive strain of P. falciparum.

  20. Imported malaria: a retrospective study in University Hospital, Kuala Lumpur, a ten-year experience.

    Science.gov (United States)

    Jamaiah, I; Anuar, A K; Najib, N A; Zurainee, M N

    1998-03-01

    Over a period of ten years (1983-1992), 134 malaria cases admitted to University Hospital, Kuala Lumpur (UHKL) were analysed. Malays constituted 27.6%, Chinese 29.8%, Indians 9.7%, Indonesians 16.4% and other foreigners 16.4%. Therefore, of the total number of cases, foreigners constituted 32.8% (44) of all the malaria cases admitted to UHKL. Fifteen of these foreigners had chloroquine-resistant strains of malarial parasites. Three species of malaria were reported of which Plasmodium falciparum constituted the most (46.3%) (80% of these developed resistance to chloroquine). Plasmodium vivax was confirmed in 44.8% (10% of these developed resistance to chloroquine) and there was only one case of Plasmodium malarie infection.

  1. Drug resistance associated genetic polymorphisms in Plasmodium falciparum and Plasmodium vivax collected in Honduras, Central America

    Directory of Open Access Journals (Sweden)

    Jovel Irina T

    2011-12-01

    Full Text Available Abstract Background In Honduras, chloroquine and primaquine are recommended and still appear to be effective for treatment of Plasmodium falciparum and Plasmodium vivax malaria. The aim of this study was to determine the proportion of resistance associated genetic polymorphisms in P. falciparum and P. vivax collected in Honduras. Methods Blood samples were collected from patients seeking medical attention at the Hospital Escuela in Tegucigalpa from 2004 to 2006 as well as three regional hospitals, two health centres and one regional laboratory during 2009. Single nucleotide polymorphisms in P. falciparum chloroquine resistance transporter (pfcrt, multidrug resistance 1 (pfmdr1, dihydrofolate reductase (pfdhfr and dihydropteroate synthase (pfdhps genes and in P. vivax multidrug resistance 1 (pvmdr1 and dihydrofolate reductase (pvdhfr genes were detected using PCR based methods. Results Thirty seven P. falciparum and 64 P. vivax samples were collected. All P. falciparum infections acquired in Honduras carried pfcrt, pfmdr1, pfdhps and pfdhfr alleles associated with chloroquine, amodiaquine and sulphadoxine-pyrimethamine sensitivity only. One patient with parasites acquired on a Pacific Island had pfcrt 76 T and pfmdr1 86Y alleles. That patient and a patient infected in West Africa had pfdhfr 51I, 59 R and 108 N alleles. Pvmdr1 976 F was found in 7/37 and two copies of pvmdr1 were found in 1/37 samples. Pvdhfr 57 L + 58 R was observed in 2/57 samples. Conclusion The results indicate that P. falciparum from Honduras remain sensitive to chloroquine and sulphadoxine-pyrimethamine. This suggests that chloroquine and sulphadoxine-pyrimethamine should be efficacious for treatment of uncomplicated P. falciparum malaria, supporting current national treatment guidelines. However, genetic polymorphisms associated with chloroquine and sulphadoxine-pyrimethamine tolerance were detected in local P. vivax and imported P. falciparum infections. Continuous

  2. On peroxide antimalarials

    Directory of Open Access Journals (Sweden)

    IGOR OPSENICA

    2007-12-01

    Full Text Available Several dicyclohexylidene tetraoxanes were prepared in order to gain a further insight into structure–activity relationship of this kind of antimalarials. The tetraoxanes 2–5, obtained as a cis/trans mixture, showed pronounced antimalarial activity against Plasmodium falciparum chloroquine susceptible D6, chloroquine resistant W2 and multidrug-resistant TM91C235 (Thailand strains. They have better than or similar activity to the corresponding desmethyl dicyclohexylidene derivatives. Two chimeric endoperoxides with superior antimalarial activity to the natural product ascaridole were also synthesized.

  3. Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands

    OpenAIRE

    Timothy J. Hubin; Amoyaw, Prince N. -A.; Roewe, Kimberly D.; Simpson, Natalie C.; Maples, Randall D.; Carder Freeman, TaRynn N.; Amy N. Cain; Le, Justin G.; Stephen J Archibald; Khan, Shabana I.; Tekwani, Babu L.; Khan, M. O. Faruk

    2014-01-01

    Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal comple...

  4. Characterization of PfTrxR inhibitors using antimalarial assays and in silico techniques

    OpenAIRE

    Munigunti, Ranjith; Gathiaka, Symon; Acevedo, Orlando; Sahu, Rajnish; Tekwani, Babu; Angela I. Calderón

    2013-01-01

    Background The compounds 1,4-napthoquinone (1,4-NQ), bis-(2,4-dinitrophenyl)sulfide (2,4-DNPS), 4-nitrobenzothiadiazole (4-NBT), 3-dimethylaminopropiophenone (3-DAP) and menadione (MD) were tested for antimalarial activity against both chloroquine (CQ)-sensitive (D6) and chloroquine (CQ)-resistant (W2) strains of Plasmodium falciparum through an in vitro assay and also for analysis of non-covalent interactions with P. falciparum thioredoxin reductase (PfTrxR) through in silico docking studies...

  5. In vitro activity of artemether against African isolates (Senegal) of Plasmodium falciparum in comparison with standard antimalarial drugs

    OpenAIRE

    Pradines, B; Rogier, C.; Fusai, T; Tall, A; Trape, Jean-François; Doury, J C

    1998-01-01

    The in vitro activity of artemether against 56 African isolates of #Plasmodium falciparum$ from Senegal was evaluated using an isotope-based drug susceptibility semi-microtest. The 50% inhibitory concentration (IC50) values for artemether were in narrow range from 0.8 to 15.2 nM (mean IC50 = 3.43 nM) and the 95% confidence interval (CI) was 2.50-4.36 nM. Artemether was equally effective on chloroquine-sensitive and chloroquine-resistant isolates (mean IC50 = 346 nM, 95% CI = 2.08-4.84 nM vers...

  6. Antiplasmodial and larvicidal compounds of Toddalia asiatica root bark

    Indian Academy of Sciences (India)

    T Nyahanga; J Isaac Jondiko; L Onyango Arot Manguro; J Atieno Orwa

    2013-09-01

    From the -hexane, ethyl acetate and methanol extracts of Toddalia asiatica root bark were isolated eight compounds (1-8) which were identified on the basis of both spectroscopic and physical data as well as comparison with already published results. The crude extracts and isolated compounds showed moderate in vitro antiplasmodial activity against D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) strains of Plasmodium falciparum. The extracts and isolates also exhibited larvicidal activities against Aedes aegypti and coumarins were identified as the active compounds.

  7. In vivo antimalarial activities of russelia equisetiformis in plasmodium berghei infected mice

    Directory of Open Access Journals (Sweden)

    O Ojurongbe

    2015-01-01

    Full Text Available The rising problem of resistance to most commonly used antimalarials remains a major challenge in the control of malaria suggesting the need for new antimalarial agents. This work explores the antiplasmodial potential of ethanol extract of Russelia equisetiformis in chloroquine Plasmodium berghei infected mice. Swiss albino mice were intraperitoneally infected with chloroquine-resistant P. berghei (ANKA. Experimental mice were treated for four days consecutively with graded doses of plant extracts and standard antimalarial drugs (artesunate and chloroquine at a dose of 10 mg/kg body weight used as control. The extract showed a dose-dependent activity in the chemosuppression of P. berghei parasites by 31.6, 44.7, 48.4 and 86.5% at doses of 100, 200, 400 and 800 mg/kg, while chloroquine (10 mg/kg and artesunate produced 59.4 and 68.4%, respectively. The extract showed a significant decrease in parasitaemia (P<0.05. The level of parasitemia and decrease in weight in all the treated groups was significantly lower (P<0.05 compared with the infected but untreated mice. The plant extract was devoid of toxicity at the highest dose tested (5000 mg/kg. The study concluded that the ethanol extract of R. equisetiformis possesses antimalarial effect, which supports the folk medicine claim of its use in the treatment of malaria.

  8. Pyronaridine for treatment of Plasmodium ovale and Plasmodium malariae infections.

    OpenAIRE

    Ringwald, P; Bickii, J; Same-Ekobo, A.; Basco, L K

    1997-01-01

    The clinical efficacy of oral pyronaridine was assessed in 22 symptomatic Cameroonian patients infected with Plasmodium ovale or Plasmodium malariae. All patients were cured on or before day 4. In vitro drug assays confirmed the sensitivity of P. ovale and P. malariae isolates to chloroquine and pyronaridine.

  9. A Solid Phase Synthesis of Chalcones by Claisen-Schmidt Condensations

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    In order to accelerate the development of relatively inexpensive antimalarials that are effective against chloroquine-resistant strains of Plasmodium falclparum, a methodology for the solid phase synthesis of chalcone (l, 3-diphenyl-2-propen-l-one) analogues in reasonably high yields has been developed.

  10. 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...

  11. High absolute bioavailability of methylene blue given as an aqueous oral formulation

    OpenAIRE

    Walter-Sack, Ingeborg; Rengelshausen, Jens; Oberwittler, Heike; Burhenne, Juergen; Mueller, Olaf; Meissner, Peter; Mikus, Gerd

    2008-01-01

    Abstract Purpose Methylene blue (MB) has recently been reevaluated for malaria treatment. With the aim of excluding treatment failures due to low bioavailability, we have investigated the absolute bioavailability of MB given as an aqueous oral formulation and its interaction with chloroquine (CQ). Methods A phase...

  12. Leishmanicidal, antiplasmodial and cytotoxic activity of indole alkaloids from Corynanthe pachyceras

    DEFF Research Database (Denmark)

    Staerk, D; Lemmich, E; Christensen, J;

    2000-01-01

    -NMR resonances by COSY and NOESY experiments. These and related alkaloids showed pronounced activity against Leishmania major promastigotes (IC50 at the micromolar level) but no significant in vitro antiplasmodial activity (against chloroquine-sensitive Plasmodium falciparum). Cytotoxicity assessed with drug...

  13. N-Terminal dual protein functionalization by strain-promoted alkyne-nitrone cycloaddition

    NARCIS (Netherlands)

    Temming, R.P.; Eggermont, L.J.; Eldijk, M.B. van; Hest, J.C. van; Delft, F.L. van

    2013-01-01

    Strain-promoted alkyne-nitrone cycloadditon (SPANC) was optimized as a versatile strategy for dual functionalization of peptides and proteins. The usefulness of the dual labeling protocol is first exemplified by the simultaneous introduction of a chloroquine and a stearyl moiety, two endosomal escap

  14. Antiplasmodial constituents of Cajanus cajan.

    Science.gov (United States)

    Duker-Eshun, George; Jaroszewski, Jerzy W; Asomaning, William A; Oppong-Boachie, Francis; Brøgger Christensen, S

    2004-02-01

    Bioactivity-guided fractionation of extracts of roots and leaves of Cajanus cajan afforded 8 compounds: betulinic acid, biochanin A, cajanol, genistein and 2'-hydroxygenistein, longistylin A and C, and pinostrobin. The two stilbenes, longistylin A and C, and betulinic acid showed a moderately high in vitro activity against the chloroquine-sensitive Plasmodium falciparum strain 3D7. PMID:15022164

  15. 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

  16. Interactions of Prednisolone and Other Immunosuppressants Used in Dual Treatment of Systemic Lupus Erythematosus in Lymphocyte Proliferation Assays

    OpenAIRE

    Kamal, Mohamed A.; Jusko, William J.

    2004-01-01

    Systemic lupus erythematosus is an autoimmune disease primarily affecting women. Currently, systemic lupus erythematosus therapy is suboptimal due to adverse effects of immunosuppressants, particularly corticosteroids. This study determines the single effects of prednisolone, dehydroepiandrosterone, bromocriptine, tamoxifen, mycophenolic acid, 2-chloro-2′-deoxyadenosine, azathioprine, and chloroquine on lectin-stimulated proliferation of human T lymphocytes, as well as determining whether the...

  17. Een belangrijke oorzaak van therapieontrouw : Pruritus sine materia als bijwerking van geneesmiddelen

    NARCIS (Netherlands)

    Heeringa, M.; Van Puijenbroek, E.P.

    1999-01-01

    Pruritus without cutaneous diseases can occur as a direct adverse drug reaction of a limited number of medicines, like opioids, chloroquine, hydroxyethyl starch, gold compounds, amlodipine and methoxsalen. The prevalence of this adverse drug reaction is often high. Pruritus may also be a symptom of

  18. Experimental Evaluations of Two Strategies to Improve Reading Achievement in Kenya: Enhanced Literacy Instruction and Treatment of Malaria

    Science.gov (United States)

    Jukes, Matthew; Dubeck, Margaret; Brooker, Simon; Wolf, Sharon

    2012-01-01

    There is less quality evidence on how malaria may affect cognitive abilities and educational achievement or on how schools can tackle the problem of malaria among school children. A randomised trial among Sri Lankan children showed that weekly malaria chemoprophylaxis with chloroquine can improve school examination scores. The Health and Literacy…

  19. Autophagy inhibitors as a potential antiamoebic treatment for Acanthamoeba keratitis.

    Science.gov (United States)

    Moon, Eun-Kyung; Kim, So-Hee; Hong, Yeonchul; Chung, Dong-Il; Goo, Youn-Kyoung; Kong, Hyun-Hee

    2015-07-01

    Acanthamoeba cysts are resistant to extreme physical and chemical conditions. Autophagy is an essential pathway for encystation of Acanthamoeba cells. To evaluate the possibility of an autophagic Acanthamoeba encystation mechanism, we evaluated autophagy inhibitors, such as 3-methyladenine (3MA), LY294002, wortmannin, bafilomycin A, and chloroquine. Among these autophagy inhibitors, the use of 3MA and chloroquine showed a significant reduction in the encystation ratio in Acanthamoeba cells. Wortmannin also inhibited the formation of mature cysts, while LY294002 and bafilomycin A did not affect the encystation of Acanthamoeba cells. Transmission electron microscopy revealed that 3MA and wortmannin inhibited autophagy formation and that chloroquine interfered with the formation of autolysosomes. Inhibition of autophagy or autolysosome formation resulted in a significant block in the encystation in Acanthamoeba cells. Clinical treatment with 0.02% polyhexamethylene biguanide (PHMB) showed high cytopathic effects on Acanthamoeba trophozoites and cysts; however, it also revealed high cytopathic effects on human corneal epithelial cells. In this study, we investigated effects of the combination of a low (0.00125%) concentration of PHMB with each of the autophagy inhibitors 3MA, wortmannin, and chloroquine on Acanthamoeba and human corneal epithelial cells. These new combination treatments showed low cytopathic effects on human corneal cells and high cytopathic effects on Acanthamoeba cells. Taken together, these results provide fundamental information for optimizing the treatment of Acanthamoeba keratitis.

  20. No hearing loss associated with the use of artemether-lumefantrine to treat experimental human malaria.

    NARCIS (Netherlands)

    McCall, M.B.B.; Beynon, A.J.; Mylanus, E.A.M.; Ven, A.J.A.M. van der; Sauerwein, R.W.

    2006-01-01

    Artemisinin derivatives are becoming the first-line treatment for uncomplicated malaria in areas with widespread resistance to chloroquine. Although generally safe and well tolerated, it has been suggested from animal experiments, and more recently from one human study with artemether-lumefantrine,

  1. Protecting the malaria drug arsenal: halting the rise and spread of amodiaquine resistance by monitoring the PfCRT SVMNT type

    Directory of Open Access Journals (Sweden)

    Twu Olivia

    2010-12-01

    Full Text Available Abstract The loss of chloroquine due to selection and spread of drug resistant Plasmodium falciparum parasites has greatly impacted malaria control, especially in highly endemic areas of Africa. Since chloroquine removal a decade ago, the guidelines to treat falciparum malaria suggest combination therapies, preferentially with an artemisinin derivative. One of the recommended partner drugs is amodiaquine, a pro-drug that relies on its active metabolite monodesethylamodiaquine, and is still effective in areas of Africa, but not in regions of South America. Genetic studies on P. falciparum parasites have shown that different pfcrt mutant haplotypes are linked to distinct levels of chloroquine and amodiaquine responses. The pfcrt haplotype SVMNT (termed after the amino acids from codon positions 72-76 is stably present in several areas where amodiaquine was introduced and widely used. Parasites with this haplotype are highly resistant to monodesethylamodiaquine and also resistant to chloroquine. The presence of this haplotype in Africa was found for the first time in 2004 in Tanzania and a role for amodiaquine in the selection of this haplotype was suggested. This commentary discusses the finding of a second site in Africa with high incidence of this haplotype. The >50% SVMNT haplotype prevalence in Angola represents a threat to the rise and spread of amodiaquine resistance. It is paramount to monitor pfcrt haplotypes in every country currently using amodiaquine and to re-evaluate current combination therapies in areas where SVMNT type parasites are prevalent.

  2. Treatment of Plasmodium chabaudi Parasites with Curcumin in Combination with Antimalarial Drugs: Drug Interactions and Implications on the Ubiquitin/Proteasome System

    Directory of Open Access Journals (Sweden)

    Zoraima Neto

    2013-01-01

    Full Text Available Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin against Plasmodium spp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS were analyzed. In vivo efficacy of curcumin was studied in BALB/c mice infected with Plasmodium chabaudi clones resistant to chloroquine and artemisinin, and drug interactions were analyzed by isobolograms. Subtherapeutic doses of curcumin, chloroquine, and artemisinin were administered to mice, and mRNA was collected following treatment for RT-PCR analysis of genes encoding deubiquitylating enzymes (DUBs. Curcumin was found be nontoxic in BALB/c mice. The combination of curcumin/chloroquine/piperine reduced parasitemia to 37% seven days after treatment versus the control group’s 65%, and an additive interaction was revealed. Curcumin/piperine/artemisinin combination did not show a favorable drug interaction in this murine model of malaria. Treatment of mice with subtherapeutic doses of the drugs resulted in a transient increase in genes encoding DUBs indicating UPS interference. If curcumin is to join the arsenal of available antimalarial drugs, future studies exploring suitable drug partners would be of interest.

  3. In vitro Antiplasmodial Activity of Some Medicinal Plants Used in Folk Medicine in Burkina Faso Against Malaria

    Directory of Open Access Journals (Sweden)

    Cheikna Zongo

    2011-05-01

    Full Text Available The aim of this study was to evaluate the in vitro antiplasmodial activities of four plants used in traditional medicine. Hydroethanolic extract, hydroacetonic extract and aqueous extract of Mitragyna inermis (Willd. O. Kuntze (Rubiaceae, Combretum sericeum G. Don (Combretaceae, Alternanthera pungens H.B. and K (Amaranthaceae and Ampelocissus grantii (Baker Planch (Vitaceae have been tested in vitro against chloroquine-resistant strain (K1 and chloroquine-sensitve strain (3D7 of Plasmodium falciparum using pLDH assay. Aqueous extracts exhibited the best results against K1 with the 50% inhibitory concentration (IC50 values of 0.54±0.18, 1.72±0.99, 1.54±0.04 μg/mL for respectively, M. inermis leaves, C. sericeum leaves and whole plant of A. pungens. Hydroethanolic extract from the leaves of M. inermis gave also IC50 value of 0.87±0.10 μg/mL with 3D7. Extracts showed antiplasmodial activity against both chloroquine-sensitive and chloroquine-resistant P. falciparum strains. Our study justifies the use of these plants in traditional medicine and leads to further investigations.

  4. Antimalarial activity of the bisquinoline trans-N1,N2-bis (7- chloroquinolin-4-yl)cyclohexane-1,2-diamine: Comparison of two stereoisomers and detailed evaluation of the S,S enantiomer, Ro 47-7737

    NARCIS (Netherlands)

    Ridley, R.G.; Matile, H.; Jaquet, C.; Dorn, A.; Hofheinz, W.; Leupin, W.; Masciadri, R.; Theil, F.P.; Richter, W.F.; Girometta, M.A.; Guenzi, A.; Urwyler, H.; Gocke, E.; Potthast, J.M.; Csato, M.; Thomas, A.; Peters, W.

    1997-01-01

    The S,S enantiomer of the bisquinoline trans-N1,N2-bis(7- chloroquinolin-4-yl)cyclohexane-1,2-diamine, Ro 47-7737, is significantly more potent against chloroquine-resistant Plasmodium falciparum than the R,R enantiomer and the previously described racemate. Both the enantiomers and the racemate are

  5. Epidemiology and resistance to chioroquine of Plasmodium falciparum and IPT research prowess.%恶性疟原虫对氯喹抗药性的流行病学及IPT的研究进展

    Institute of Scientific and Technical Information of China (English)

    刘若冰; 吴兰鸥; 杨照青

    2011-01-01

    Chloroquine,first discovered and used as the most effective antimalarial drug,in large-scale treatment for malaria,Hasmodium fcdciparum gradually give rise to resistance to chloroquine and resistant strains of insects spread rapidly around the world. In recent years, studies have shown that chloroquine can be used for periodic preventive treatment of malaria (intermittent preventive treatment,IPT). This article reviews the epidemiology of chloroquine resistance,drug resistance mechanisms and IPT of new progress.%氯喹作为最早发现和使用的最为有效的抗疟药物,在大规模用于疟疾治疗后,恶性疟原虫陆续对它产生抗药性,并且抗性虫株在全球范围迅速播散.近年来的研究显示氯喹可用于疟疾的周期性预防疗法.本文综述了氯喹抗药性流行病学的研究,抗药性产生的机制及周期性预防疗法(Intermittent preventive treatment,IPT)的研究新进展.

  6. Malaria Epidemic and Drug Resistance, Djibouti

    OpenAIRE

    Rogier, Christophe; Pradines, Bruno; Bogreau, H.; Koeck, Jean-Louis; Kamil, Mohamed-Ali; Mercereau-Puijalon, Odile

    2005-01-01

    Analysis of Plasmodium falciparum isolates collected before, during, and after a 1999 malaria epidemic in Djibouti shows that, despite a high prevalence of resistance to chloroquine, the epidemic cannot be attributed to a sudden increase in drug resistance of local parasite populations.

  7. A randomized, double-blind, placebo-controlled, clinical trial of the impact of malaria prevention on the educational attainment of school children.

    Science.gov (United States)

    Fernando, Deepika; de Silva, Damani; Carter, Richard; Mendis, Kamini N; Wickremasinghe, Rajitha

    2006-03-01

    A double-blind, placebo-controlled trial of nine months duration was carried out to investigate the impact of malaria and its prevention on the educational attainment of school children in a malaria-endemic area in southern Sri Lanka where both Plasmodium falciparum and P. vivax infections are prevalent. A total of 587 children attending grades 1-5 in four schools and resident in the area were randomly allocated to chloroquine (n = 295) and placebo (n = 292) arms. Language and mathematics scores of end-of-term school examinations for 1998 and 1999 and number of days absent and reasons for absenteeism during seven months pre-intervention and nine months of the intervention were recorded. The results indicate that there were no differences in language (95% confidence interval [CI] = 48.44-53.78 in chloroquine group and 50.43-55.81 in placebo group) and mathematics (95% CI = 49.24-54.38 in chloroquine group and 51.12-56.38 in placebo group) scores between the two groups prior to the intervention. During the intervention, the malaria incidence rate decreased by 55% (95% CI = 49-61%) and school absenteeism due to malaria was reduced by 62.5% (95% CI = 57-68%) in children who received chloroquine compared with the placebo group. Post-intervention, children who received chloroquine scored approximately 26% higher in both language (95% CI = 21-31%) and mathematics (95% CI = 23-33%) than children who received placebo. In a multivariate model, educational attainment was significantly associated with taking chloroquine prophylaxis and absenteeism due to malaria (P < 0.001 for both) but not due to health causes other than malaria or non-health causes. Language scores were associated with number of malaria attacks (P < 0.022). Educational attainment was significantly better among children whose compliance to chloroquine prophylaxis was higher (P < 0.001). The data suggest that malarial attacks have an adverse impact on the educational attainment of the school child and

  8. Assessment of in vitro sensitivity of Plasmodium vivax fresh isolates

    Institute of Scientific and Technical Information of China (English)

    Poonuch Muhamad; Wanna Chacharoenkul; Kanchana Rungsihirunrat; Ronnatrai Ruengweerayut; Kesara Na-Bangchang

    2011-01-01

    Objective: To compare the applicability of the SYBR Green-I assay with the standard schizont maturation assay, for determination of sensitivity of Plasmodium vivax (P. vivax) to chloroquine and a new antifolate WR 99210. Methods: The study was conducted at Mae Tao Clinic for migrant workers, Tak Province during April 2009 to July 2010. A total of 64 blood samples (1 mL blood collected into sodium heparinized plastic tube) were collected from patients with mono-infection with P. vivax malaria prior to treatment with standard regimen of a 3-day chloroquine.In vitro sensitivity of P. vivax isolates was evaluated by schizont maturation inhibition and SYBR Green-I assays. Results: A total of 30 out of 64 blood samples collected from patients withP. vivax malaria were successfully analyzed using both the microscopic schizont maturation inhibition and SYBR Green-I assays. The failure rates of the schizont maturation inhibition assay (50%) and the SYBR Green-I assay (54%) were similar (P=0.51). The median IC10s, IC50s and IC90s of both chloroquine and WR99210 were not significantly different from the clinical isolates of P. vivax tested. Based on the cut-off of 100 nM, the prevalences of chloroquine resistance determined by schizont maturation inhibition and SYBR Green-I assays were 19 and 11 isolates, respectively. The strength of agreement between the two methods was very poor for both chloroquine and WR99210. Conclusions: On the basis of this condition and its superior sensitivity, the microscopic method appears better than the SYBR Green-I Green assay for assessing in vitro sensitivity of fresh P. vivax isolates to antimalarial drugs.

  9. Assessment of in vitro sensitivity of Plasmodium vivax fresh isolates

    Institute of Scientific and Technical Information of China (English)

    Poonuch; Muhamad; Wanna; Chacharoenkul; Kanchana; Rungsihirunrat; Ronnatrai; Ruengweerayut; Kesara; NaBangchang

    2011-01-01

    Objective:To compare the applicability of the SYBK Grcen-Ⅰ assay with the standard schizont maturalion assay,for determination of sensitivity of Plasmodium vivax(P.vivax) to chloroquine and a new antifolale WR 99210.Methods:The study was conducted at Mae Tao Clinic for migrant workers,Tak Province during April 2009 to July 2010.A total of 64 blood samples(1 mL blood collected into sodium heparinized plastic tube) were collected from patients with monoinfection with P.vivax malaria prior to treatment with standard regimen of a 3-day chloroquine. In vitro sensitivity of P.vivax isolates was evaluated by schizont maturation inhibition and SYBR Green-Ⅰ assays.Results:A total of 30 out of 64 blood samples collected from patients with P.vivax malaria were successfully analyzed using both the microscopic schizont maturation inhibition and SYBR Green-I assays.The failure rates of the schizont maturation inhibition assay(50%) and the SYBR Green-I assay(54%) were similar(P=0.51).The median IC10s,IC50s and IC90s of both chloroquine and WR99210 were not significantly different from the clinical isolates of P.vivax tested.Based on the cut-off of 100 nM,the prevalences of chloroquine resistance determined by schizont maturation inhibition and SYBR Green-I assays were 19 and 11 isolates,respectively.The strength of agreement between the two methods was very poor for both chloroquine and WR992I0.Conclusions:On the basis of this condition and its superior sensitivity,the microscopic method appears better than the SYUK Green-I Green assay for assessing in vitro sensitivity of fresh P.vivax isolates to antimalarial drugs.

  10. Prescription pattern of anti-malarial drugs in a tertiary care hospital

    Institute of Scientific and Technical Information of China (English)

    Santoshkumar R Jeevangi; Manjunath S; Sharanabasappa M Awanti

    2010-01-01

    Objective:To evaluate the prescribing pattern of anti malarial drugs in a tertiary care hospital. Methods:A prospective cross-sectional study was conducted for 6 months of patients visiting in Basaveshwar Teaching and General Hospital, Gulbarga. Data were analyzed for various drug use indicators. Results: A total of 212 prescriptions were collected, with 136 (64.15%) male and 76 (35.85%) female. There were 128 (60.37%) Plasmodium vivax cases and 84 (39.63%) Plasmodium falciparum cases. All Plasmodium vivax cases were treated with chloroquine alone and among these 16 (12.5%) recieved radical treatment with primaquine along with chloroquine. Among 84 patients with Pasmodium falciparum, 40 patients received single drug such as quinine/mefloquinine/artesunate/arteether. Another 44 patients received multidrug regime like, quinine+artesunate (54.54%), quinine+mefloquine (27.27%) and quinine+arteether (18.18%). Chloroquine was not administered to any of the patients with Plasmodium falciparum malaria. The most common adverse effects with chloroquine were anorexia, nausea, vomiting and tinnitus in 9.37%of the cases. With quinine it was nausea and vomiting in 17.64%, tinnitus in 11.76%and hypoglycemia in 2.1%of cases. Conclusions: Our study found the perennial favorites like chloroquine for Plasmodium vivax and quinine for Plasmodium falciparum were the most effective drug. In the severe Plasmodium falciparum cases the artesunate derivatives and combination of artesunate with quinine/mefloquine were most effective with fewer incidences of side effects.

  11. 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.

  12. Plasmodium falciparum isolates from southern Ghana exhibit polymorphisms in the SERCA-type PfATPase6 though sensitive to artesunate in vitro

    Directory of Open Access Journals (Sweden)

    Ofori Michael F

    2011-07-01

    Full Text Available Abstract Background In 2005, Ghana replaced chloroquine with artemisinin-based combination therapy as the first-line treatment for uncomplicated malaria. The aim of this work was to determine for the first time, polymorphisms in the putative pfATPase6 and pftctp, pfmdr1, pfcrt genes in Ghanaian isolates, particularly at a time when there is no report on artemisinin resistance in malaria parasites from Ghana. The sensitivity of parasite isolates to anti-malaria drugs were also evaluated for a possible association with polymorphisms in these genes. Methods The prevalence of point mutations in the above Plasmodium falciparum genes were assessed from filter-paper blood blot samples by DNA sequencing. In vitro drug sensitivity test was carried out on some of the blood samples from volunteers visiting hospitals/clinics in southern Ghana using a modified version of the standard WHO Mark III micro-test. Results All successfully tested parasite isolates were sensitive to artesunate; while 19.4%, 29.0% and 51.6% were resistant to quinine, amodiaquine and chloroquine respectively. The geometric mean of IC50 value for artesunate was 0.73 nM (95% CI, 0.38-1.08, amodiaquine 30.69 nM (95% CI, 14.18-47.20 and chloroquine 58.73 nM (95% CI, 38.08-79.38. Twenty point mutations were observed in pfATPase6 gene, with no L263E and S769N. All mutations found were low in frequency, except D639G which was observed in about half of the isolates but was not associated with artesunate response (p = 0.42. The pftctp gene is highly conserved as no mutation was observed, while CVIET which is chloroquine-resistant genotype at codon 72-76 of the pfcrt gene was identified in about half of the isolates; this was consistent with chloroquine IC50 values (p = 0.001. Mutations were present in pfmdr1 gene but were not associated with artemisinin response (p = 1.00. Conclusion The pfATPase6 gene is highly polymorphic with D639G appearing to be fixed in Ghanaian isolates. These may just

  13. Comprehensive study of proteasome inhibitors against Plasmodium falciparum laboratory strains and field isolates from Gabon

    Directory of Open Access Journals (Sweden)

    Kremsner Peter G

    2008-09-01

    Full Text Available Abstract Background The emergence and spread of Plasmodium falciparum resistance to almost all available antimalarial drugs necessitates the search for new chemotherapeutic compounds. The ubiquitin/proteasome system plays a major role in overall protein turnover, especially in fast dividing eukaryotic cells including plasmodia. Previous studies show that the 20S proteasome is expressed and catalytically active in plasmodia and treatment with proteasome inhibitors arrests parasite growth. This is the first comprehensive screening of proteasome inhibitors with different chemical modes of action against laboratory strains of P. falciparum. Subsequently, a selection of inhibitors was tested in field isolates from Lambaréné, Gabon. Methods Epoxomicin, YU101, YU102, MG132, MG115, Z-L3-VS, Ada-Ahx3-L3-VS, lactacystin, bortezomib (Velcade®, gliotoxin, PR11 and PR39 were tested and compared to chloroquine- and artesunate-activities in a standardized in vitro drug susceptibility assay against P. falciparum laboratory strains 3D7, D10 and Dd2. Freshly obtained field isolates from Lambaréné, Gabon, were used to measure the activity of chloroquine, artesunate, epoxomicin, MG132, lactacystin and bortezomib. Parasite growth was detected through histidine-rich protein 2 (HRP2 production. Raw data were fitted by a four-parameter logistic model and individual inhibitory concentrations (50%, 90%, and 99% were calculated. Results Amongst all proteasome inhibitors tested, epoxomicin showed the highest activity in chloroquine-susceptible (IC50: 6.8 nM [3D7], 1.7 nM [D10] and in chloroquine-resistant laboratory strains (IC50: 10.4 nM [Dd2] as well as in field isolates (IC50: 8.5 nM. The comparator drug artesunate was even more active (IC50: 1.0 nM, whereas all strains were chloroquine-resistant (IC50: 113 nM. Conclusion The peptide α',β'-epoxyketone epoxomicin is highly active against P. falciparum regardless the grade of the parasite's chloroquine

  14. Screening of African medicinal plants for antimicrobial and enzyme inhibitory activity.

    Science.gov (United States)

    Tshibangu, Jeannette Ndaya; Chifundera, Kusamba; Kaminsky, Ronald; Wright, Anthony David; König, Gabriele Maria

    2002-04-01

    Seven plant species, belonging to different families, were collected in the eastern part of the Republic of Congo (Kivu) based on ethnopharmacological information. Their dichloromethane and methanolic extracts were tested for biological activity. Five of the seven collected plants exhibited antiplasmodial activity with IC(50) values ranging from 1.1 to 9.8 microg/ml. The methanolic extract of Cissampelos mucronata was the most active one showing activity against chloroquine sensitive (D6) and chloroquine resistant (W2) Plasmodium falciparum strains with IC(50) values of 1.5 and 1.1 microg/ml, respectively. Additionally, this extract significantly inhibited the enzyme tyrosine kinase p56(lck) (TK). The dichloromethane extract of Amorphophallus bequaertii inhibited the growth of Mycobacterium tuberculosis with a MIC of 100 microg/ml and the methanolic extract of Rubus rigidus inhibited the activity of both enzymes HIV1-reverse transcriptase (HIV1-RT) and TK p56(lck). PMID:11891084

  15. Screening of Kenyan medicinal plants for antimalarial effects on Plasmodium falciparum in vitror. Final report for the period 15 December 1993 - 31 December 1994

    International Nuclear Information System (INIS)

    The antimalarial activities of extracts of Albizia gummifera and Aspilia mossambicensis against culture adapted isolates of Plasmodium falciparum were evaluated using an in citro 3H-hypoxanthine uptake technique. Chloroquine was used as a standard antimalarial drug for comparison with the plant extracts. The plant extracts showed various levels of activities (expressed as 50% inhibitory concentration (IC50s) in ug/ml of test culture) against P. falciparum in vitro, with Al gummifera showing the highest activity (eman IC50 of 5.98 ± 2.9 SD, n=6), followed by A. mossambicensis (mean IC50 73.36 ± 59.3 SD, n=18). The mean antimalarial activity of chloroquine (in ug/ml) was 0.037 (± 0.04 SD, n=10), far higher than that of the plant extracts. (author). 5 refs, 2 tabs

  16. In vitro antiplasmodial activity and toxicity assessment of plant extracts used in traditional malaria therapy in the Lake Victoria Region

    Directory of Open Access Journals (Sweden)

    Teresa Akeng'a Ayuko

    2009-08-01

    Full Text Available As part of our program screening the flora of the Lake Victoria Region, a total of 54 organic extracts from seven plant families (8 species were individually tested for antiplasmodial activity against chloroquine-sensitive [Sierra Leone (D-6] and chloroquine-resistant [Vietnam (W-2] strains. Only 22% of these extracts exhibited very high in vitro antiplasmodial activity. Six methanol (MeOH extracts and one chloroform extract showed in vitro antiplasmodial activity against the D-6 Plasmodium falciparum strain, while only three MeOH extracts were active against the W-2 strain. All of the ethyl acetate extracts proved to be inactive against both strains of P. falciparum. A brine shrimp cytotoxicity assay was used to predict the potential toxicity of the extracts. The cytotoxicity to antiplasmodial ratios for the MeOH extracts were found to be greater than 100, which could indicate that the extracts are of low toxicity.

  17. Holographic analysis on deformation and restoration of malaria-infected red blood cells by antimalarial drug

    Science.gov (United States)

    Byeon, Hyeokjun; Ha, Young-Ran; Lee, Sang Joon

    2015-11-01

    Malaria parasites induce morphological, biochemical, and mechanical changes in red blood cells (RBCs). Mechanical variations are closely related to the deformability of individual RBCs. The deformation of various RBCs, including healthy and malaria-infected RBCs (iRBCs), can be directly observed through quantitative phase imaging (QPI). The effects of chloroquine treatment on the mechanical property variation of iRBCs were investigated using time-resolved holographic QPI of single live cells on a millisecond time scale. The deformabilities of healthy RBCs, iRBCs, and drug-treated iRBCs were compared, and the effect of chloroquine on iRBC restoration was experimentally examined. The present results are beneficial to elucidate the dynamic characteristics of iRBCs and the effect of the antimalarial drug on iRBCs.

  18. 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.

  19. Pathogenesis of drug induced acneform eruptions

    Directory of Open Access Journals (Sweden)

    Lobo Audrey

    1992-01-01

    Full Text Available To determine the pathogenesis of drug induced acneform eruption (DAE, 44 patients were evaluated clinically and representative samples histologically. INAH and corticosteroids were the main offenders in 38.6 percent and 36.4 percent patients respectively. Chloroquin precipitated lesions in 9.1 percent of the patients. There were significant differences in the duration of drug-intake before onset, morphology and severity of lesions. Histological differences with different drugs were also noted. Based on clinical and histological findings, pathogenesis of lesions caused by different drugs could be suggested. Keratinization of follicular epithelium was the main effect with corticosteroids and INAH. Suppuration of follicular epithelium was an additional early event with corticosteroids. Type III allergic reaction was responsible for iodine lesions and delayed hypersensitivity for chlorpromazine and chloroquine induced lesions.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Molecular surveillance of drug resistance through imported isolates of Plasmodium falciparum in Europe

    DEFF Research Database (Denmark)

    Jelinek, Tomas; Peyerl-Hoffmann, Gabriele; Mühlberger, Nikolai;

    2002-01-01

    BACKGROUND: Results from numerous studies point convincingly to correlations between mutations at selected genes and phenotypic resistance to antimalarials in Plasmodium falciparum isolates. In order to move molecular assays for point mutations on resistance-related genes into the realm of applied...... tools for surveillance, we investigated a selection of P. falciparum isolates that were imported during the year 2001 into Europe to study the prevalence of resistance-associated point mutations at relevant codons. In particular, we tested for parasites which were developing resistance to antifolates...... and chloroquine. The screening results were used to map the prevalence of mutations and, thus, levels of potential drug resistance in endemic areas world-wide. RESULTS: 337 isolates have been tested so far. Prevalence of mutations that are associated with resistance to chloroquine on the pfcrt and pfmdr genes...

  2. Audit of imported and domestic malaria cases at Kuala Lumpur Hospital.

    Science.gov (United States)

    Moore, C S; Cheong, I

    1995-01-01

    The clinical, haematological and biochemical profiles of all domestic and imported malaria cases admitted to the Hospital Kuala Lumpur were analysed. The most common malaria types were Plasmodium falciparum (39.5%) and Plasmodium vivax (42%). The most common patient type was men aged 29-40 years (reflecting the high mobility of this group, many of whom were illegal immigrants). Misdiagnosis on admission was frequently due to the variable clinical presentation of the disease and the difficulties of obtaining an accurate history. Associated haematological abnormalities were common. Chloroquine resistance was diagnosed in four P. falciparum patients and in one P. falciparum/vivax patient. Overall, imported malaria did not seem more severe than domestic. The three patients with cerebral malaria survived. One patient died of acute liver failure. The large influx of illegal immigrants to Malaysia has resulted in a surge in malaria infection; illegal immigrants remain a source of chloroquine resistance.

  3. Antiplasmodial benzophenone derivatives from the root barks of Symphonia globulifera (Clusiaceae)

    OpenAIRE

    Marti, G; Eparvier, V.; Moretti, Christian; Prado, S.; Grellier, P; Hue, N.; Thoison, O.; Delpech, B; Gueritte, F.; Litaudon, M.

    2010-01-01

    In an effort to find antimalarial drugs, a systematic in vitro evaluation on a chloroquine-resistant strain of Plasmodium falciparum (FcB1) was undertaken on sixty plant extracts collected in French Guiana. The ethyl acetate extract obtained from the root barks of Symphonia globulifera exhibited a strong antiplasmodial activity (97% at 10 mu g/ml). The phytochemical investigation of this extract led to the isolation of nine polycyclic polyprenylated acylphloroglucinol (PPAPs) compounds and tw...

  4. Rationalization of Symptomatic Drug Administration to Malaria Patients in Arso Timur Public Health Center, Keerom Regency

    OpenAIRE

    Oktliana Pasangka; A. L. Rantetampang; B. Sandjaja

    2016-01-01

    Malaria Eradication Program began using ACT to replace Chloroquine which already resistant. To overcome the adverse effects of malaria medicine and to reduce the clinical symptoms of malaria disease along with clinical symptoms of comorbidities, the health personnel will provide symptomatic medication or other drugs in addition to malaria drugs. Drug administration is sometimes not just one type of drugs but a combination of several types of drugs. The rationale for the use of the drug can be...

  5. The calcium-dependent myoblast adhesion that precedes cell fusion is mediated by glycoproteins

    OpenAIRE

    1985-01-01

    Presumptive myoblasts from explants of chick embryo pectoral muscle proliferate, differentiate, and fuse to form multinucleate myotubes. One event critical to multinucleate cell formation is the specific adhesion of myoblasts before union of their membranes. In the studies reported here five known inhibitors of myotube formation-- trifluoperazine, sodium butyrate, chloroquine, 1,10 phenanthroline, and tunicamycin--were tested for their effect on the Ca++-dependent myoblast adhesion step. The ...

  6. Pricing, distribution, and use of antimalarial drugs.

    OpenAIRE

    Foster, S. D.

    1991-01-01

    Prices of new antimalarial drugs are targeted at the "travellers' market" in developed countries, which makes them unaffordable in malaria-endemic countries where the per capita annual drug expenditures are US$ 5 or less. Antimalarials are distributed through a variety of channels in both public and private sectors, the official malaria control programmes accounting for 25-30% of chloroquine distribution. The unofficial drug sellers in markets, streets, and village shops account for as much a...

  7. Pharmaco-Epidemiology of Artemisinin-Based Combination Therapy in the Context of Impact Evaluation of Artemether-Lumefantrine on Malaria Morbidity and Mortality During Programmatic Implementation in Rural Tanzania

    OpenAIRE

    Kabanywanyi, Abdunoor Mulokozi

    2012-01-01

    In sub-Saharan Africa previous efforts to control malaria have proved less successful mostly due to prolonged use of less efficacious mono-therapy drugs to which Plasmodium falciparum has developed drug resistance. In most parts of malaria endemic regions chloroquine (CQ) was found to be poorly effective for several decades but it was still being prescribed until recently. In Tanzania, for instance, P.falciparum was already resistant to CQ in more than 60% of all P. falciparum ...

  8. 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

  9. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch

    OpenAIRE

    Wilson, Sarah R.; Kristin A Gerhold; Bifolck-Fisher, Amber; Liu, Qin; Patel, Kush N.; Dong, Xinzhong; Bautista, Diana M.

    2011-01-01

    SUMMARY Itch, the unpleasant sensation that evokes a desire to scratch, accompanies numerous skin and nervous system disorders. In many cases, pathological itch is insensitive to antihistamine treatment. Recent studies have identified members of the Mas-related GPCR (Mrgpr) family that are activated by mast cell mediators and promote histamine-independent itch. MrgprA3 and MrgprC11 act as receptors for the pruritogens chloroquine and BAM8–22, respectively. However, the signaling pathways and ...

  10. Drug resistance associated genetic polymorphisms in Plasmodium falciparum and Plasmodium vivax collected in Honduras, Central America

    OpenAIRE

    Jovel Irina T; Mejía Rosa E; Banegas Engels; Piedade Rita; Alger Jackeline; Fontecha Gustavo; Ferreira Pedro E; Veiga Maria I; Enamorado Irma G; Bjorkman Anders; Ursing Johan

    2011-01-01

    Abstract Background In Honduras, chloroquine and primaquine are recommended and still appear to be effective for treatment of Plasmodium falciparum and Plasmodium vivax malaria. The aim of this study was to determine the proportion of resistance associated genetic polymorphisms in P. falciparum and P. vivax collected in Honduras. Methods Blood samples were collected from patients seeking medical attention at the Hospital Escuela in Tegucigalpa from 2004 to 2006 as well as three regional hospi...

  11. Vacuolin-1 potently and reversibly inhibits autophagosome-lysosome fusion by activating RAB5A

    OpenAIRE

    Lu, Yingying; Dong, Shichen; Hao, Baixia; Li, Chang; Zhu, Kaiyuan; Guo, Wenjing; Wang, Qian; Cheung, King-Ho; Wong, Connie WM; Wu, Wu-Tian; Markus, Huss; Yue, Jianbo

    2014-01-01

    Autophagy is a catabolic lysosomal degradation process essential for cellular homeostasis and cell survival. Dysfunctional autophagy has been associated with a wide range of human diseases, e.g., cancer and neurodegenerative diseases. A large number of small molecules that modulate autophagy have been widely used to dissect this process and some of them, e.g., chloroquine (CQ), might be ultimately applied to treat a variety of autophagy-associated human diseases. Here we found that vacuolin-1...

  12. 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...... levels suppressed the lymphocytes' proliferation, but not their IL-2 production. All three quinolines suppressed the proliferation of lymphocytes, but not equally, with mefloquine having the strongest effect. Quinine suppressed the growth at therapeutic concentrations. The IL-2 production was suppressed...

  13. Malaria in Kenya's Western Highlands

    OpenAIRE

    Shanks, G. Dennis; Simon I. Hay; Omumbo, Judy A.; Robert W Snow

    2005-01-01

    Records from tea estates in the Kericho district in Kenya show that malaria reemerged in the 1980s. Renewed epidemic activity coincided with the emergence of chloroquine-resistant Plasmodium falciparum malaria and may have been triggered by the failure of antimalarial drugs. Meteorologic changes, population movements, degradation of health services, and changes in Anopheles vector populations are possible contributing factors. The highland malaria epidemics of the 1940s were stopped largely b...

  14. Acute plasmodium vivax malaria presenting with pancytopenia secondary to hemophagocytic syndrome: Case report and literature review

    Directory of Open Access Journals (Sweden)

    Waleed Albaker

    2009-01-01

    Full Text Available Pancytopeni,a as an initial manifestation of acute plasmodium vivax malaria is extremely rare and mainly reported with plasmodium falciparum. We report a 37- year old Nepali patient who recently came to Saudi Arabia and presented with a three-week history of intermittent fever, chills and rigor. She was found to have spleenomegaly, pancytopenia, hyperferrtinemia, and hypofibronogenemia with positive peripheral blood smear for plasmodium vivax. The patient had a full recovery from pancytopenia with oral chloroquine.

  15. Biochemical and ultrastructural processing of [125I]epidermal growth factor in rat epidermis and hair follicles: accumulation of nuclear label

    DEFF Research Database (Denmark)

    Green, M R; Mycock, C; Smith, C G;

    1987-01-01

    . Sodium azide inhibited internalization of label, whereas a series of lysosomal inhibitors (chloroquine, monensin, and iodoacetamide) caused a slight increase in silver grains associated with lysosomal vesicles and a decrease in nuclear label. Biochemical analysis indicated that greater than 35......-linked with low efficiency to a protein having the molecular weight of the EGF receptor. These data are discussed in the light of the effects of EGF on epithelial cell proliferation in skin....

  16. Regulation of lipoprotein lipase in primary cultures of isolated human adipocytes.

    OpenAIRE

    Kern, P A; Marshall, S; Eckel, R H

    1985-01-01

    To study the regulation of adipose tissue lipoprotein lipase (LPL) in human adipocytes, omental adipose tissue was obtained from healthy subjects and digested in collagenase. The isolated adipocytes thus obtained were suspended in Medium 199 and cultured at 37 degrees C. Cell viability was demonstrated in adipocytes cultured for up to 72 h by constancy of cell number, cell size, trypan-blue exclusion, and specific 125I-insulin binding. In addition, chloroquine induced an increase in cell-asso...

  17. A case of SLE with acute, subacute and chronic cutaneous lesions successfully treated with Dapsone.

    Science.gov (United States)

    Neri, R; Mosca, M; Bernacchi, E; Bombardieri, S

    1999-01-01

    We describe a patient with systemic lupus erythematosus (SLE) who exhibited severe cutaneous involvement characterized by the simultaneous presence of acute, subacute and discoid lesions in association with anti-S1 antibodies. After she failed to respond to chloroquine, medium to low dose steroids, steroid pulses, retinoids and cyclophosphamide, the patient was treated with Dapsone and a dramatic improvement in the cutaneous lesions was seen after only one month. PMID:10342718

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

    OpenAIRE

    Wurtz Nathalie; Fall Bécaye; Pascual Aurélie; Diawara Silmane; Sow Kowry; Baret Eric; Diatta Bakary; Fall Khadidiatou B; Mbaye Pape S; Fall Fatou; Diémé Yaya; Rogier Christophe; Bercion Raymond; Briolant Sébastien; Wade Boubacar

    2012-01-01

    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, ...

  19. Antimalarial activity of some Colombian medicinal plants

    OpenAIRE

    Garavito, G. (G.); Rincon, J.; Arteaga, L.; Hata, Y; Bourdy, Geneviève; Gimenez, A.; Pinzon, R.; Deharo, Eric

    2006-01-01

    Antimalarial activity of 10 vegetal extracts (9 ethanolic extracts and 1 crude alkaloid extract), obtained from eight species traditionally used in Colombia to treat malaria symptoms, was evaluated in culture using Plasmodium falciparum chloroquine resistant (FcB2) strain and in vivo on rodent malaria Plasmodium berghei. The activity on ferriprotoporphyrin biomineralization inhibition test (FBIT) was also assessed. Against Plasmodium falciparum, eight extracts displayed good activity Abuta gr...

  20. Doxycycline for Malaria Chemoprophylaxis and Treatment: Report from the CDC Expert Meeting on Malaria Chemoprophylaxis

    OpenAIRE

    Tan, Kathrine R.; Magill, Alan J; Parise, Monica E.; Arguin, Paul M

    2011-01-01

    Doxycycline, a synthetically derived tetracycline, is a partially efficacious causal prophylactic (liver stage of Plasmodium) drug and a slow acting blood schizontocidal agent highly effective for the prevention of malaria. When used in conjunction with a fast acting schizontocidal agent, it is also highly effective for malaria treatment. Doxycycline is especially useful as a prophylaxis in areas with chloroquine and multidrug-resistant Plasmodium falciparum malaria. Although not recommended ...

  1. Fatal falciparum malaria in Canadian travellers

    OpenAIRE

    Humar, A.; Sharma, S.; Zoutman, D; Kain, K. C.

    1997-01-01

    The authors report 2 cases of severe falciparum malaria in Canadians that had fatal outcomes. In the first case a man presented to a local hospital shortly after returning from Africa, but a diagnosis of malaria was not considered. He was transferred to a secondary and then to a tertiary care facility, where he subsequently died. Intravenous quinidine therapy, the treatment of choice, was unavailable at all 3 hospitals. In the second case, a woman taking chloroquine prophylaxis while visiting...

  2. Exploring malaria case mangement of underfive children at households and public primary health care facilities in Kibaha district, Tanzania

    OpenAIRE

    Nsimba, Stephen ED

    2003-01-01

    Background: Chloroquine (CQ) was the first line drug for treating malaria in Tanzania until 2001 when it was replaced with sulfadoxine/pyrimethamine (SP). The first four studies (I -IV) were conducted before the policy change, and the last one (V) after. Aim: To explore different aspects of malaria case management of underfives in households and at primary health care facilities in the Kibaha district. Materials and methods: Four cross-sectional studies (I, II, IV & V) we...

  3. Naphthylisoquinoline Alkaloids : Structural Elucidation, Metabolism and Functional Analysis of their Bioactivities

    OpenAIRE

    Faber, Johan Henrik

    2007-01-01

    This thesis deals with the isolation and structural elucidation of bioactive naphthylisoquinoline alkaloids and related analogs. The mode of action of the antiplasmodial activity exhibited by the naphthylisoquinoline alkaloids was explored and compared to that of the antimalarial drug chloroquine. Furthermore, the phase 1 and 2 metabolism of dioncophyllines A and C and dioncopeltine A were investigated. In detail the following results have been obtained: • From the leaves of the recently disc...

  4. Characterization of pruriceptive trigeminothalamic tract neurons in rats

    OpenAIRE

    Moser, Hannah R.; Giesler, Glenn J.

    2014-01-01

    Rodent models of facial itch and pain provide a valuable tool for distinguishing between behaviors related to each sensation. In rats, pruritogens applied to the face elicit scratching using the hindlimb while algogens elicit wiping using the forelimb. We wished to determine the role of trigeminothalamic tract (VTT) neurons in carrying information regarding facial itch and pain to the forebrain. We have characterized responses to facially applied pruritogens (serotonin, BAM8–22, chloroquine, ...

  5. 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.

  6. Situs inversus totalis with azoospermia in a patient presenting with liver abscess

    Directory of Open Access Journals (Sweden)

    P. Mohan Rao

    2014-04-01

    Full Text Available Situs inversus with dextrocardia is a rare congenital anomaly. Azoospermia and situs inversus may be encountered in ciliary dyskinesia syndromes. We report the case of a 30-year-old male who manifested situs inversus totalis, dextrocardia and azoospermia with maturation arrest at primary spermatogenesis who presented with liver abscess. The patient responded well to treatment with i.v. metronidazole and oral chloroquine.

  7. Antimalarial and cytotoxic properties of Chukrasia tabularis A. Juss and Turraea vogelii Hook F. Ex. Benth.

    Science.gov (United States)

    Ogbole, Omonike O; Saka, Yusuf A; Fasinu, Pius S; Fadare, Adenike A; Ajaiyeoba, Edith O

    2016-04-01

    Malaria, caused by plasmodium parasite, is at the moment the highest cause of morbidity and mortality in the tropics. Recently, there is increasing efforts to develop more potent antimalarials from plant sources that will have little or no adverse effects. This study is aimed at investigating the in vivo mice antimalarial and in vitro antiplasmodial effects of two Meliaceae plants commonly used in Nigerian ethnomedicine as part of recipe for treating malaria infection: Chukrasia tabularis and Turraea vogelii. Hot water decoction and methanol extract of both plants were evaluated for their antimalarial activity in vivo using the mice model assay and in vitro using the parasite lactate dehydrogenase (pLDH) assay. The extracts were also assessed for toxicity with brine shrimp lethality assay and in mammalian cell lines using the neural red assay. The in vivo mice model antimalarial study showed that the methanol extract of the stem bark of C. tabularis exhibited the highest % chemosuppression (83.65 ± 0.66) at the highest dosage administered (800 mg/kg) when compared with chloroquine diphosphate, the standard reference drug which had a % suppression of 90.36 ± 0.04 (p < 0.05). The in vitro antiplasmodial study indicated that the aqueous extract of the stem bark of C. tabularis displayed good activity against Plasmodium falciparum chloroquine-sensitive (D6) strain (IC50 of 10.739 μg/mL) and chloroquine-resistant (W2) strain. Chloroquine and artemisinin had <0.163 and <0.0264, respectively. PMID:26911147

  8. Malaria treatment policies and drug efficacy in Haiti from 1955-2012

    OpenAIRE

    von Fricken, Michael E; Weppelmann, Thomas A.; Hosford, Jennifer D.; Existe, Alexander; Okech, Bernard A

    2013-01-01

    Objectives Chloroquine (CQ), after 67 years of use in Haiti, is still part of the official treatment policy for malaria. Several countries around the world have used CQ in the past due to its low incidence of adverse events, therapeutic efficacy, and affordability, but were forced to switch treatment policy due to the development of widespread CQ resistance. The purpose of this paper was to compile literature on malaria treatment policies and antimalarial drug efficacy in Haiti over 67-year p...

  9. Dosagem de artemisinina em Artemisia annua L. por cromatografia líquida de alta eficiência com detecção por índice de refração

    Directory of Open Access Journals (Sweden)

    Vera Lúcia Garcia Rehder

    2002-01-01

    Full Text Available Artemisinin is a sesquiterpene lactone used in treatment of chloroquine-resistant malaria. This paper presents high-performance liquid chromatographic assay for artemisinin in leaves of A. annua using differential refractometer detector and a single step of clean-up in a silica cartridge. The average of recoveries were 95% and the limit of quantification was 0,21% p/p using 200 mg of the leaves. This method was found to be simple, robust and relatively rapid.

  10. Anti-plasmodial polyvalent interactions in Artemisia annua L. aqueous extract--possible synergistic and resistance mechanisms.

    Directory of Open Access Journals (Sweden)

    John O Suberu

    Full Text Available Artemisia annua hot water infusion (tea has been used in in vitro experiments against P. falciparum malaria parasites to test potency relative to equivalent pure artemisinin. High performance liquid chromatography (HPLC and mass spectrometric analyses were employed to determine the metabolite profile of tea including the concentrations of artemisinin (47.5±0.8 mg L(-1, dihydroartemisinic acid (70.0±0.3 mg L(-1, arteannuin B (1.3±0.0 mg L(-1, isovitexin (105.0±7.2 mg L(-1 and a range of polyphenolic acids. The tea extract, purified compounds from the extract, and the combination of artemisinin with the purified compounds were tested against chloroquine sensitive and chloroquine resistant strains of P. falciparum using the DNA-intercalative SYBR Green I assay. The results of these in vitro tests and of isobologram analyses of combination effects showed mild to strong antagonistic interactions between artemisinin and the compounds (9-epi-artemisinin and artemisitene extracted from A. annua with significant (IC50 <1 μM anti-plasmodial activities for the combination range evaluated. Mono-caffeoylquinic acids, tri-caffeoylquinic acid, artemisinic acid and arteannuin B showed additive interaction while rosmarinic acid showed synergistic interaction with artemisinin in the chloroquine sensitive strain at a combination ratio of 1:3 (artemisinin to purified compound. In the chloroquine resistant parasite, using the same ratio, these compounds strongly antagonised artemisinin anti-plasmodial activity with the exception of arteannuin B, which was synergistic. This result would suggest a mechanism targeting parasite resistance defenses for arteannuin B's potentiation of artemisinin.

  11. Whole transcriptome expression analysis and comparison of two different strains of Plasmodium falciparum using RNA-Seq

    OpenAIRE

    Antony, Hiasindh Ashmi; Pathak, Vrushali; Parija, Subhash Chandra; Ghosh, Kanjaksha; Bhattacherjee, Amrita

    2016-01-01

    The emergence and distribution of drug resistance in malaria are serious public health concerns in tropical and subtropical regions of the world. However, the molecular mechanism of drug resistance remains unclear. In the present study, we performed a high-throughput RNA-Seq to identify and characterize the differentially expressed genes between the chloroquine (CQ) sensitive (3D7) and resistant (Dd2) strains of Plasmodium falciparum. The parasite cells were cultured in the presence and absen...

  12. Harnessing evolutionary fitness in Plasmodium falciparum for drug discovery and suppressing resistance

    OpenAIRE

    Lukens, Amanda Kathleen; Ross, L. S.; Heidebrecht, Richard W; Javier Gamo, F.; Lafuente-Monasterio, M. J.; Booker, M. L.; Hartl, Daniel L.; Wiegand, R C; Wirth, Dyann F

    2013-01-01

    Drug resistance emerges in an ecological context where fitness costs restrict the diversity of escape pathways. These pathways are targets for drug discovery, and here we demonstrate that we can identify small-molecule inhibitors that differentially target resistant parasites. Combining wild-type and mutant-type inhibitors may prevent the emergence of competitively viable resistance. We tested this hypothesis with a clinically derived chloroquine-resistant (CQr) malaria parasite and with para...

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

    OpenAIRE

    Opwonya John; Ojok Naptalis; Kolaczinski Jan H; 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 ...

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

    OpenAIRE

    Rath Srikanta; Singh Prabhat; Mishra Shrawan

    2011-01-01

    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 e...

  15. Quantitative gait analysis as a method to assess mechanical hyperalgesia modulated by disease-modifying antirheumatoid drugs in the adjuvant-induced arthritic rat

    Science.gov (United States)

    Simjee, Shabana Usman; Jawed, Huma; Quadri, Javeria; Saeed, Sheikh Arshad

    2007-01-01

    In the present study, azothioprine, chloroquine, D-penicillamine, methotrexate and sodium aurothiomalate (gold salt) were evaluated for possible disease-modifying effects in the adjuvant-induced arthritis model of human rheumatoid arthritis in rats. Gait analysis was used to examine the role of disease-modifying antirheumatic drugs in the development of pain. Body weights were also measured to monitor the progression of disease and the systemic antiarthritic effects of the test compounds used in this study, as well as their systemic toxicity. Our results showed that azothioprine (5 mg/kg/day), chloroquine (12.5 mg/kg/day), sodium aurothiomalate (2.5 mg/kg/day) and methotrexate (1 mg/kg/week) not only inhibited the macroscopic changes such as erythema and swelling of limbs, but also exhibited significant reversal of gait deficits seen in the untreated or saline-treated arthritic rats. No reduction in the body weights were observed in the arthritic rats treated with azothioprine, chloroquine, sodium aurothiomalate and methotrexate. D-Penicillamine (12.5 mg/kg/day), however, showed a significant reduction (P < 0.03) in the body weights of the arthritic rats over a period of 22 days; furthermore, it was unable to show any reduction in arthritic score (P < 0.1). In earlier experiments, chloroquine and methotrexate failed to suppress carageenan-induced edema, suggesting that the mode of antiarthritic action may be different from those of nonsteroidal anti-inflammatory agents. Since these disease-modifying antirheumatic drugs are reported to have an immunomodulatory role, especially the gold salt, which influences the monocyte–macrophage system, it is suggested that the observed antiarthritic effects of disease-modifying antirheumatic drugs may be partly attributed to their immunomodulatory activity. PMID:17848187

  16. Reduction of Malaria Transmission to Anopheles Mosquitoes with a Six-Dose Regimen of Co-Artemether.

    OpenAIRE

    Sutherland, Colin J.; Rosalynn Ord; Sam Dunyo; Musa Jawara; Drakeley, Christopher J; Neal Alexander; Rosalind Coleman; Margaret Pinder; Gijs Walraven; Targett, Geoffrey A. T

    2005-01-01

    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 FI...

  17. Formulation, process development and evaluation of artemether and lumefantrine soft gelatin capsule

    OpenAIRE

    Patel, A; Lodha, A.; Chaudhuri, J.; P Jadia; Joshi, T.; Dalal, J.

    2012-01-01

    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 antim...

  18. Aberrarone: A Gorgonian-Derived Diterpene from Pseudopterogorgia elisabethae

    Science.gov (United States)

    Rodríguez, Ileana I.; Rodríguez, Abimael D.; Zhao, Hong

    2009-01-01

    A marine metabolite based on a previously undescribed carbon skeleton, aberrarone (1), is reported as a natural product from the Caribbean sea whip, Pseudopterogorgia elisabethae. The molecular structure of the crystalline metabolite was established by spectral analysis and subsequently confirmed by X-ray crystallographic analysis. Aberrarone shows in vitro antimalarial activity against a chloroquine-resistant strain of the protozoan parasite Plasmodium falciparum. PMID:19736920

  19. Treatment of Plasmodium chabaudi Parasites with Curcumin in Combination with Antimalarial Drugs: Drug Interactions and Implications on the Ubiquitin/Proteasome System

    OpenAIRE

    Zoraima Neto; Marta Machado; Ana Lindeza; Virgílio do Rosário; Gazarini, Marcos L.; Dinora Lopes

    2013-01-01

    Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT) is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin against Plasmodium spp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS) were analyzed. In vivo...

  20. Effect of membrane filtration of antimalarial drug solutions on in vitro activity against Plasmodium falciparum*

    OpenAIRE

    Baird, J K; Lambros, C.

    1984-01-01

    Antimalarial activities of chloroquine, mefloquine, amodiaquine, and quinine in vitro against Plasmodium falciparum were diminished as a consequence of membrane filtration. Filtered drug solutions gave ID50 values up to 25-fold greater than those of non-filtered (ethanol-sterilized) drug solutions. Loss of activity by filtration was overcome by increasing the drug concentration prior to filtration. Water solutions filtered through Millex-GS filter units consistently showed an absorbance maxim...

  1. MICROBIAL ASSESSMENT OF SOME SYRUP SOLD IN PATENT MEDICINE STORES IN MINNA METROPOLIS, NIGERIA

    OpenAIRE

    Daniyan S .Y.; Sangodere T.A.

    2011-01-01

    The microbiological quality of eighteen different brands of syrups comprising of Paracetamol, Chloroquine phosphate and Vitamin C syrups purchased from different patent medicine stores in Minna metropolis was assessed. The microbial load was determined using the viable cell count method; the resulting contaminant microorganisms were isolated and characterized by standard methods. The results revealed the contamination in four of six; five of six and four of six, Vitamin C. Paracetamol and Chl...

  2. Bovine Viral Diarrhea Virus Entry Is Dependent on Clathrin-Mediated Endocytosis

    OpenAIRE

    Lecot, Steve; Belouzard, Sandrine; Dubuisson, Jean; Rouillé, Yves

    2005-01-01

    Cellular mechanisms of bovine viral diarrhea virus (BVDV) entry in MDBK cells were investigated. Chloroquine, bafilomycin A1, or ammonium chloride inhibited BVDV infection, indicating that an acidic endosomal pH is required for BVDV entry. The tyrosine kinase inhibitor genistein partially inhibited BVDV infection at a postentry step, whereas BVDV entry was strongly inhibited by chlorpromazine or by the overexpression of a dominant-negative form of EPS15, a protein essential for the formation ...

  3. 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...

  4. Plasmodium falciparum drug resistance in Angola

    OpenAIRE

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-01-01

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information ...

  5. Canonical autophagy does not contribute to cellular radioresistance

    International Nuclear Information System (INIS)

    Background: (Pre)clinical studies indicate that autophagy inhibition increases response to anti-cancer therapies. Although promising, due to contradicting reports, it remains unclear if radiation therapy changes autophagy activity and if autophagy inhibition changes the cellular intrinsic radiosensitivity. Discrepancies may result from different assays and models through off-target effects and influencing other signaling routes. In this study, we directly compared the effects of genetic and pharmacological inhibition of autophagy after irradiation in human cancer cell lines. Materials and methods: Changes in autophagy activity after ionizing radiation (IR) were assessed by flux analysis in eight cell lines. Clonogenic survival, DNA damage (COMET-assay) and H2AX phosphorylation were assessed after chloroquine or 3-methyladenine pretreatment and after ATG7 or LC3b knockdown. Results: IR failed to induce autophagy and chloroquine failed to change intrinsic radiosensitivity of cells. Interestingly, 3-methyladenine and ATG7- or LC3b-deficiency sensitized cancer cells to irradiation. Surprisingly, the radiosensitizing effect of 3-methyladenine was also observed in ATG7 and LC3b deficient cells and was associated with attenuated γ-H2AX formation and DNA damage repair. Conclusion: Our data demonstrate that the anti-tumor effects of chloroquine are independent of changes in intrinsic radioresistance. Furthermore, ATG7 and LC3b support radioresistance independent of canonical autophagy that involves lysosomal degradation

  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. Effects ofPlasmodium falciparum-infected erythrocytes on matrix metalloproteinase-9 regulation in human microvascular endothelial cells

    Institute of Scientific and Technical Information of China (English)

    Sarah D Alessandro; Nicoletta Basilico; Mauro Prato

    2013-01-01

    Objective:To investigate the regulation of matrix metalloproteinases(MMPs) and tissue inhibitors of metalloproteinases(TIMPs) in human microvascular endothelium(HMEC-1) exposed to erythrocytes infected by different strains ofPlasmodium falciparum (P. falciparum).Methods:HMEC-1 cells were co-incubated for72 h with erythrocytes infected by late stage trophozoite of D10(chloroquine-sensitive) orW2(chloroquine-resistant)P. falciparum strains.Cell supernatants were then collected and the levels of pro- or active gelatinasesMMP-9 andMMP-2 were evaluated by gelatin zymography and densitometry.The release of pro-MMP-9,MMP-3,MMP-1 andTIMP-1 proteins was analyzed by western blotting and densitometry.Results:Infected erythrocytes inducedde novo proMMP-9 andMMP-9 release.Neither basal levels of proMMP-2 were altered, nor activeMMP-2 was found.MMP-3 andMMP-1 secretion was significantly enhanced, whereas basalTIMP-1 was unaffected.All effects were similar for both strains. Conclusions:P. falciparum parasites, either chloroquine-sensitive or -resistant, induce the release of activeMMP-9 protein from human microvascular endothelium, by impairing balances between proMMP-9 and its inhibitor, and by enhancing the levels of its activators.This work provides new evidence onMMP involvement in malaria, pointing atMMP-9 as a possible target in adjuvant therapy.

  8. Metabolic stress in infected cells may represent a therapeutic target for human immunodeficiency virus infection.

    Science.gov (United States)

    Alonso-Villaverde, Carlos; Menéndez, Javier A; Joven, Jorge

    2013-07-01

    Worldwide, there are thousands of new cases of human immunodeficiency virus-1 (HIV-1) infection per day. The effectiveness of current combination antiretroviral therapy (ART) is relative; to prioritize finding vaccines and/or cure-oriented initiatives should be reinforced because there is little room, if any, for procrastination. Basic and clinical findings on HIV-1 reservoirs suggest that disruption of virus latency is feasible. Because the goal is curing HIV-1 infection, we should be aware that the challenge is to eradicate the viruses of every single infected cell and consequently acting upon virus latency is necessary but not sufficient. The large majority of the virus reservoir, CD4(+) T lymphocytes, is readily accessible but other minor reservoirs, where ART does not diffuse, require innovative strategies. The situation closely resembles that currently faced in the treatment of cancer. Exploiting the fact that histone deacetylase inhibitors, mainly vorinostat, may disrupt the latency of HIV-1, we propose to supplement this effect with a programmed interference in the metabolic stress of infected cells. Metformin and chloroquine are cheap and accessible modulators of pro-survival mechanisms to which viruses are constantly confronted to generate alternative energy sources and maximize virus production. Metformin restrains the use of the usurped cellular biosynthetic machinery by viral genes and chloroquine contributes to death of infected cells. We suggest that the combination of vorinostat, chloroquine and metformin should be combined with ART to pursue viral eradication in infected cells. PMID:23639282

  9. Trafficking of. cap alpha. -L-fucosidase in lymphoid cells

    Energy Technology Data Exchange (ETDEWEB)

    DiCioccio, R.A.; Brown, K.S.

    1987-05-01

    The quantity of ..cap alpha..-L-fucosidase in human serum is determined by heredity. The mechanism controlling levels of the enzyme in serum is unknown. To investigate this, lymphoid cell lines derived from individuals with either low, intermediate or high ..cap alpha..-L-fucosidase in serum were established. Steady state levels of extracellular ..cap alpha..-L-fucosidase protein and activity overlapped among the cell lines. Thus, in vivo serum phenotypes of ..cap alpha..-L-fucosidase are not adequately expressed in this system. ..cap alpha..-L-Fucosidase was also metabolically labelled with /sup 35/S-methionine, immunoprecipitated, and examined by SDS-PAGE. Cells pulse-labelled from 0.25-2 h had a major intracellular form of enzyme (Mr = 58,000). Cells pulsed for 1.5 h and chased for 21 h with unlabeled methionine had an intracellular form of Mr = 60,000 and an extracellular form of Mr = 62,000. Cells treated with chloroquine had only the 58,000-form both intra- and extra-cellularly. Moreover, chloroquine did not effect the quantitative distribution of ..cap alpha..-L-fucosidase between cells and medium. In fibroblasts, chloroquine enhanced the secretion of newly made lysosomal enzymes and blocked the processing of intercellular enzyme forms from a higher to a lower molecular mass. Thus, there are trafficking differences between ..cap alpha..-L-fucosidase in lymphoid cells and lysosomal enzymes in fibroblasts. This suggests that alternative targeting mechanisms for lysosomal enzymes exist in these cells.

  10. In vitro susceptibility of Plasmodium vivax to antimalarials in Colombia.

    Science.gov (United States)

    Fernández, Diana; Segura, César; Arboleda, Margarita; Garavito, Giovanny; Blair, Silvia; Pabón, Adriana

    2014-11-01

    The in vitro susceptibilities of 30 isolates of Plasmodium vivax to a number of antimalarials (chloroquine [CQ], mefloquine, amodiaquine, quinine, and artesunate [AS]) were evaluated. The isolates came from the region of Urabá in Colombia, in which malaria is endemic, and were evaluated by the schizont maturation test. The 50% inhibitory concentration (IC50) was 0.6 nM (95% confidence interval [CI], 0.3 to 1.0 nM) for artesunate, 8.5 nM (95% CI, 5.6 to 13.0 nM) for amodiaquine, 23.3 nM (95% CI, 12.4 to 44.1 nM) for chloroquine, 55.6 nM (95% CI, 36.8 to 84.1 nM) for mefloquine, and 115.3 nM (95% CI, 57.7 to 230.5 nM) for quinine. The isolates were classified according to whether the initial parasites were mature or immature trophozoites (Tfz). It was found that the IC50s for chloroquine and artesunate were significantly different in the two aforementioned groups (P Colombia, P. vivax continues to be susceptible to antimalarials. This is the first report, to our knowledge, showing in vitro susceptibilities of P. vivax isolates to antimalarials in Colombia.

  11. Low antiplasmodial activity of alkaloids and amides from the stem bark of Zanthoxylum rubescens (Rutaceae

    Directory of Open Access Journals (Sweden)

    Penali L.

    2007-06-01

    Full Text Available The stem bark of Zanthoxylum rubescens (syn. Fagara rubescens is used for treating fevers associated with malaria in the Ivory Coast. Three alkaloids: N-nornitidine, 7,9-dimethoxy-2,3- methylenedioxybenzophenanthridine, and bis[6-(5,6- dihydrochelerythrinyl] ether; and two amides: zanthomamide and lemairamide, were isolated from the stem bark of this plant. These compounds were screened in vitro against the chloroquine-sensitive 3D7 strain and the chloroquine-resistant FCM29 strain of P. falciparum. N-nornitidine was found to be inactive. 7,9- dimethoxy-2,3-methylenedioxybenzophenanthridine, lemairamide and zanthomamide showed weak activity with average IC50 values ranging from 45.6 μM to 149.9 μM. Bis[6-(5,6- dihydrochelerythrinyl] ether was the most active of the tested compounds with mean IC50s of 14.9 ± 1.4 μM in FCM29 strain and 15.3 ± 3.4 μM in 3D7 strain (~ 58 to ~ 1130 times less active than chloroquine respectively. The anti-Plasmodium activities of the tested alkaloids of Z. rubescens were low; and do not encourage the use of this plant as antimalarial.

  12. Trafficking of α-L-fucosidase in lymphoid cells

    International Nuclear Information System (INIS)

    The quantity of α-L-fucosidase in human serum is determined by heredity. The mechanism controlling levels of the enzyme in serum is unknown. To investigate this, lymphoid cell lines derived from individuals with either low, intermediate or high α-L-fucosidase in serum were established. Steady state levels of extracellular α-L-fucosidase protein and activity overlapped among the cell lines. Thus, in vivo serum phenotypes of α-L-fucosidase are not adequately expressed in this system. α-L-Fucosidase was also metabolically labelled with 35S-methionine, immunoprecipitated, and examined by SDS-PAGE. Cells pulse-labelled from 0.25-2 h had a major intracellular form of enzyme (Mr = 58,000). Cells pulsed for 1.5 h and chased for 21 h with unlabeled methionine had an intracellular form of Mr = 60,000 and an extracellular form of Mr = 62,000. Cells treated with chloroquine had only the 58,000-form both intra- and extra-cellularly. Moreover, chloroquine did not effect the quantitative distribution of α-L-fucosidase between cells and medium. In fibroblasts, chloroquine enhanced the secretion of newly made lysosomal enzymes and blocked the processing of intercellular enzyme forms from a higher to a lower molecular mass. Thus, there are trafficking differences between α-L-fucosidase in lymphoid cells and lysosomal enzymes in fibroblasts. This suggests that alternative targeting mechanisms for lysosomal enzymes exist in these cells

  13. Review of pyronaridine anti-malarial properties and product characteristics

    Directory of Open Access Journals (Sweden)

    Croft Simon L

    2012-08-01

    Full Text Available Abstract Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.

  14. MICROBIAL ASSESSMENT OF SOME SYRUP SOLD IN PATENT MEDICINE STORES IN MINNA METROPOLIS, NIGERIA

    Directory of Open Access Journals (Sweden)

    Daniyan S.Y.

    2011-08-01

    Full Text Available The microbiological quality of eighteen different brands of syrups comprising of Paracetamol, Chloroquine phosphate and Vitamin C syrups purchased from different patent medicine stores in Minna metropolis was assessed. The microbial load was determined using the viable cell count method; the resulting contaminant microorganisms were isolated and characterized by standard methods. The results revealed the contamination in four of six; five of six and four of six, Vitamin C. Paracetamol and Chloroquine phosphate syrups respectively exceeding the tolerance limit of permissible microorganisms specified officially for syrups. The contaminant organisms isolated from analyzed syrups include bacteria: Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and fungal isolates include: Aspergillus niger, Aspergillus fumigatus, Penicillum notatum, Aspergillus flavus and Mucor specie. Bacilus subtilis were found to be most predominant bacterial isolates while Aspergillus niger was the predominant fungal isolate. The pH values of the analyzed syrups ranged from 2.71-3.94 with the exception of Paracetamol syrups,brands of Vitamin C and Chloroquine phosphate syrups which had pH range of 5.28-7.11, 5.30-5.32 and 4.83-4.88 respectively. The susceptibility patterns of each bacterial isolates to antimicrobial agents showed resistance to Nalixidic acid,Ampicillin,Rocephin,Ampiclox and Amoxacillin, with high sensitivity to Pefloxacin,Ciprofloxacin, Streptomycin and Septrin.

  15. Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta

    Directory of Open Access Journals (Sweden)

    Kenworthy David

    2011-07-01

    Full Text Available Abstract Background Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD deficiency is a concern. Combination with other antimalarials may mitigate these concerns. Methods In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD. In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans. Results The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg than for monotherapy. This regimen (1.8 mg/kg was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg appears to be biologically

  16. 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.

    Science.gov (United States)

    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

  17. Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy.

    Directory of Open Access Journals (Sweden)

    Patricia A Reis

    Full Text Available Neurological impairments are frequently detected in children surviving cerebral malaria (CM, the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. In the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatment. Infection of C57BL/6 and Swiss (SW mice with Plasmodium berghei ANKA (PbA or a lethal strain of Plasmodium yoelii XL (PyXL, respectively, resulted in documented CM and sustained persistent cognitive damage detected by a battery of behavioral tests after cure of the acute parasitic disease with chloroquine therapy. Strikingly, cognitive impairment was still present 30 days after the initial infection. In contrast, BALB/c mice infected with PbA, C57BL6 infected with Plasmodium chabaudi chabaudi and SW infected with non lethal Plasmodium yoelii NXL (PyNXL did not develop signs of CM, were cured of the acute parasitic infection by chloroquine, and showed no persistent cognitive impairment. Reactive oxygen species have been reported to mediate neurological injury in CM. Increased production of malondialdehyde (MDA and conjugated dienes was detected in the brains of PbA-infected C57BL/6 mice with CM, indicating high oxidative stress. Treatment of PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage. These studies provide new insights into the natural history of cognitive dysfunction after rescue therapy for CM that may have clinical relevance, and may also be relevant to cerebral sequelae of sepsis and other disorders.

  18. Thermoluminescence as a complementary technique for the toxicological evaluation of chemicals in photosynthetic organisms

    International Nuclear Information System (INIS)

    Highlights: • There are very few toxicological applications of thermoluminescence. • It is a luminescence emission induced by heating the sample in the dark. • It is useful for study the photosystem II function and the level of lipid peroxidation. - Abstract: Thermoluminescence is a simple technique very useful for studying electron transfer reactions on photosystem II (standard thermoluminescence) or the level of lipid peroxidation in membranes (high temperature thermoluminescence) in photosynthetic organisms. Both techniques were used to investigate the effects produced on Chlorella vulgaris cells by six compounds: the chemical intermediates bromobenzene and diethanolamine, the antioxidant propyl gallate, the semiconductor indium nitrate, the pesticide sodium monofluoroacetate and the antimalarial drug chloroquine. Electron transfer activity of the photosystem II significantly decreased after the exposure of Chlorella cells to all the six chemicals used. Lipid peroxidation was slightly decreased by the antioxidant propyl gallate, not changed by indium nitrate and very potently stimulated by diethanolamine, chloroquine, sodium monofluoroacetate and bromobenzene. For five of the chemicals studied (not bromobenzene) there is a very good correlation between the cytotoxic effects in Chlorella cells measured by the algal growth inhibition test, and the inhibition of photosystem II activity. The results suggest that one very important effect of these chemicals in Chlorella cells is the inhibition of photosynthetic metabolism by the blocking of photosystem II functionality. In the case of sodium monofluoroacetate, diethanolamine and chloroquine this inhibition seems to be related with the induction of high level of lipid peroxidation in cells that may alter the stability of photosystem II. The results obtained by both techniques supply information that can be used as a supplement to the growth inhibition test and allows a more complete assessment of the effects of

  19. Thermoluminescence as a complementary technique for the toxicological evaluation of chemicals in photosynthetic organisms

    Energy Technology Data Exchange (ETDEWEB)

    Repetto, Guillermo, E-mail: grepkuh@upo.es [Departamento de Biología Molecular e Ingeniería Bioquímica, Área de Toxicología, Universidad Pablo de Olavide, Carretera de Utrera km. 1, 41013 Seville (Spain); Zurita, Jorge L. [Departamento de Biología Molecular e Ingeniería Bioquímica, Área de Toxicología, Universidad Pablo de Olavide, Carretera de Utrera km. 1, 41013 Seville (Spain); Roncel, Mercedes; Ortega, José M. [Instituto de Bioquímica Vegetal y Fotosíntesis, Universidad de Sevilla-CSIC, Américo Vespucio 49, 41092 Seville (Spain)

    2015-01-15

    Highlights: • There are very few toxicological applications of thermoluminescence. • It is a luminescence emission induced by heating the sample in the dark. • It is useful for study the photosystem II function and the level of lipid peroxidation. - Abstract: Thermoluminescence is a simple technique very useful for studying electron transfer reactions on photosystem II (standard thermoluminescence) or the level of lipid peroxidation in membranes (high temperature thermoluminescence) in photosynthetic organisms. Both techniques were used to investigate the effects produced on Chlorella vulgaris cells by six compounds: the chemical intermediates bromobenzene and diethanolamine, the antioxidant propyl gallate, the semiconductor indium nitrate, the pesticide sodium monofluoroacetate and the antimalarial drug chloroquine. Electron transfer activity of the photosystem II significantly decreased after the exposure of Chlorella cells to all the six chemicals used. Lipid peroxidation was slightly decreased by the antioxidant propyl gallate, not changed by indium nitrate and very potently stimulated by diethanolamine, chloroquine, sodium monofluoroacetate and bromobenzene. For five of the chemicals studied (not bromobenzene) there is a very good correlation between the cytotoxic effects in Chlorella cells measured by the algal growth inhibition test, and the inhibition of photosystem II activity. The results suggest that one very important effect of these chemicals in Chlorella cells is the inhibition of photosynthetic metabolism by the blocking of photosystem II functionality. In the case of sodium monofluoroacetate, diethanolamine and chloroquine this inhibition seems to be related with the induction of high level of lipid peroxidation in cells that may alter the stability of photosystem II. The results obtained by both techniques supply information that can be used as a supplement to the growth inhibition test and allows a more complete assessment of the effects of

  20. Copper(ii) mixed-ligand polypyridyl complexes with doxycycline - structures and biological evaluation.

    Science.gov (United States)

    Abosede, Olufunso O; Vyas, Nilima A; Singh, Sushma B; Kumbhar, Avinash S; Kate, Anup; Kumbhar, Anupa A; Khan, Ayesha; Erxleben, Andrea; Smith, Peter; de Kock, Carmen; Hoffmann, Frank; Obaleye, Joshua A

    2016-02-21

    Mixed-ligand Cu(ii) complexes of the type [Cu(doxycycline)(L)(H2O)2](NO3)2, where doxycycline = [4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide] and L = 2,2'-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 3) and dipyrido[3,2-a:2',3'-c]phenazine (dppz, 4) have been synthesised and characterised by structural, analytical, and spectral methods. The single-crystal X-ray structures of 1 and 2 exhibited two different geometries, distorted square-pyramidal and octahedral respectively as well as different coordination modes of doxycycline. Complexes 2-4 exhibit prominent plasmid DNA cleavage at significantly low concentrations probably by an oxidative mechanism. Matrix Metalloproteinase (MMP-2) inhibition studies revealed that all complexes inhibit MMP-2 similar to doxycycline which is a well-known MMP inhibitor with 3 being the most potent. IC50 values of doxycycline and 1-4 against MCF-7 (human breast cancer) and HeLa cell lines were almost equal in which 3 showed the highest efficiency (IC50 = 0.46 ± 0.05 μM), being consistent with its increased MMP inhibition potency. The antimalarial activities of these complexes against the chloroquine-sensitive Plasmodium falciparum NF54 and chloroquine-resistant Plasmodium falciparum Dd2 strains reveal that complex 3 exhibited a higher activity than artesunate drug against the chloroquine-resistant Dd2 strain.

  1. Diversity and utilization of antimalarial ethnophytotherapeutic remedies among the Kikuyus (Central Kenya

    Directory of Open Access Journals (Sweden)

    Bussmann Rainer W

    2006-02-01

    Full Text Available Abstract Plants in Kenya are becoming increasingly important as sources of traditional medicines. The World Health Organization (WHO has estimated that malaria kills about 2.7 million people every year, 90% of who are from Africa. Malaria continues to be a national concern in Kenya as it plays a major role in the high mortality rates being experienced currently. The use and miss-use of chloroquine to prevent and treat falciparium malaria has led to widespread appearance of chloroquine resistant parasites in Kenya and other tropical countries. These factors and the rising costs of non-chloroquine drugs have made the local people to turn to traditional remedies for management of this menace. This paper examines the current utilization of traditional plant medicines in managing malaria menace in Central Kenya. The results show both indigenous and introduced species are in use indicating traditional medicinal practices in this region are dynamic. In total 58 species in 54 genera and 33 families were identified. The family Rubiaceae was found to have the highest number of reported species. Use of the various taxa is compared between five districts within Central Province of Kenya. The commonest species in this pharmacopoeia are: Caesalpinia volkensii Harms, Strychnos henningsii Gilg, Ajuga remota Benth., Warbugia ugandensis Sprague and Olea europaea L. The first three species are used in all the five districts while the others are restricted in some of the districts. In 74% of the anti-malarial plant species reported in this study, the remedies are obtained in destructive manner and may need conservation measures to ensure sustainable utilization. The results of this study become a basis for selecting plants for further pharmacological and phytochemical studies in developing new and locally relevant anti-malarial agents.

  2. Salvianolic acid B inhibits autophagy and protects starving cardiac myocytes

    Institute of Scientific and Technical Information of China (English)

    Xiao HAN; Jian-xun LIU; Xin-zhi LI

    2011-01-01

    Aim: To investigate the protective or lethal role of autophagy and the effects of Salvianolic acid B (Sal B) on autophagy in starving myocytes.Methods: Cardiac myocytes were incubated under starvation conditions (GD) for O, 1, 2, 3, and 6 h. Autophagic flux in starving cells was measured via chloroquine (3 μmol/L). After myocytes were treated with Sat B (50 μmol/L) in the presence or absence of chloro-quine (3 μmol/L) under GD 3 h, the amount of LC3-11, the abundance of LC3-positive fluorescent dots in cells, cell viability and cellular ATP levels were determined using immunoblotting, immunofluorescence microscopy, MTT assay and luminometer, respectively. More-over, electron microscopy (EM) and immunofluorescent duel labeling of LC3 and Caspase-8 were used to examine the characteristics of autophagy and apoptosis.Results: Immunoblot analysis showed that the amount of LC3-11 in starving cells increased in a time-dependent manner accompanied by increased LC3-positive fluorescence and decreased cell viability and ATP content. Sal B (50 μmol/L) inhibited the increase in LC3-11, reduced the abundance of LC3 immunofluorescence and intensity of Caspase-8 fluorescence, and enhanced cellular viability and ATP levels in myocytes under GD 3 h, regardless of whether chloroquine was present.Conclusion: Autophagy induced by starvation for 3 h led to cell injury. Sal B protected starving cells by blocking the early stage of autophagic flux and inhibiting apoptosis that occurred during autophagy.

  3. ISOLASI DAN IDENTIFIKASI ARTEMISININ DARI HERBA Artemisia annua L .

    Directory of Open Access Journals (Sweden)

    Sukmayati Alegantina

    2012-07-01

    Full Text Available Abstract. Malaria is still a major problem in Indonesia, because mortality in patients with severe malaria remains high. Many cases are occurs in endemic areas (e.g. Papua,Kalimantan, Bali and Sulawesi. Chloroquin is the most common antimalarial drug which is widely used since 1934. Plasmodium falciparum resistant to chloroquine was reported in some countries (e.g. Thailand, Vietnam, Indonesia, and Bangladesh. To delay the development of resistance, WHO recommended antimalarial combination therapy. Artemisinin and its derivatives (artesunate, artemether, dihydroartemisin produce rapid clearance of parasitemia and rapid resolution of symptoms compare with chloroquine. Artemisinin is obtained from Artemisia annua L. Even though there are some research produced a chemical synthetic of artemisinin, but it is not efficient and notstable. Our purposes are to conduct a preliminary research to obtain a method of isolation and identification of artemisinin which is the first step to develop a raw material of artemisinin as antimalarial drug in Indonesia.The first step of isolation is extraction from herb Artemisia annua L with n-hexane thatproduced n-hexane extract, this process is well-known as soxhletation. The second step isidentification of chemical substances from n-hexane extract. The third step is to obtain isolate from n-hexane extract by fractionation with acetonitril and separation with column chromatography. The last step is chemical and physical identification of isolateby TLC (Thin Layer (Chromatography and FT-IR.The result from n-hexane extract measurement is 4.33 % and from acetonitril fraction is2. 40 %. Chemical identification of n-hexan extract found there are terpenoid, phenol, flavonoid, fatty acid, atsiri oil and saponin. Organoleptic identification of isolate is white crystal, monosubstrate, odorless and bitter. Identification of isolate with TLC and FT-IR confirmed that the isolate is artemisinin.Keywords: artemisinin, Artemisia

  4. Factors influencing the clearance rates of colloidal particles from the rabbit knee joint

    International Nuclear Information System (INIS)

    Three aspects of colloidal drug delivery are examined. (a) Interaction of liposomes, containing the anti-inflammatory agent chloroquine with sinovial fluid. Changes in the surface charge of particles in the presence of sinovial fluid, and changes in viscosity are examined. (b) Influence of liposome concentration, drug concentration and surface change on the rate of macrophage uptake. (c) Use of gamma scintigraphy to determine clearance kinetics of various types of particles, influence of particle size, charge and chemical composition on uptake. (U.K.)

  5. Lupus miliaris disseminatus faciei report of 4 cases

    Directory of Open Access Journals (Sweden)

    Sule R

    1992-01-01

    Full Text Available Lupus miliaris disseminatus faciei is an uncommon disease affecting face. Previously lupus miliaris disseminatus faciei was thought to be a tuberculid; but now it is considered as a granulomatuous variant fo acne rosacea. We report 4 cases; each having lesions on face but in 1 also on body. The cases had erythematous tiny popular lesions of varying chronicity of 4 months to 1 year. Investigations for tuberculosis were negative. Histopathology revealed tuberculoid granuloma. All patients responded to Erythromycin; except 1 required Chloroquine.

  6. A natural product based DOS library of hybrid systems.

    Science.gov (United States)

    Prabhu, Ganesh; Agarwal, Shalini; Sharma, Vijeta; Madurkar, Sanjay M; Munshi, Parthapratim; Singh, Shailja; Sen, Subhabrata

    2015-05-01

    Here we described a natural product inspired modular DOS strategy for the synthesis of a library of hybrid systems that are structurally and stereochemically disparate. The main scaffold is a pyrroloisoquinoline motif, that is synthesized from tandem Pictet-Spengler lactamization. The structural diversity is generated via "privileged scaffolds" that are attached at the appropriate site of the motif. Screening of the library compounds for their antiplasmodial activity against chloroquine sensitive 3D7 cells indicated few compounds with moderate activity (20-50 μM). A systematic comparison of structural intricacy between the library members and a natural product dataset obtained from ZINC(®) revealed comparable complexity. PMID:25794788

  7. Assessment of the therapeutic efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in northern KwaZulu-Natal: an observational cohort study

    Directory of Open Access Journals (Sweden)

    Vaughan-Williams Charles H

    2012-12-01

    Full Text Available Abstract Background Recent malaria epidemics in KwaZulu-Natal indicate that effective anti-malarial therapy is essential for malaria control. Although artemether-lumefantrine has been used as first-line treatment for uncomplicated Plasmodium falciparum malaria in northern KwaZulu-Natal since 2001, its efficacy has not been assessed since 2002. The objectives of this study were to quantify the proportion of patients treated for uncomplicated P. falciparum malaria with artemether-lumefantrine who failed treatment after 28 days, and to determine the prevalence of molecular markers associated with artemether-lumefantrine and chloroquine resistance. Methods An observational cohort of 49 symptomatic patients, diagnosed with uncomplicated P. falciparum malaria by rapid diagnostic test, had blood taken for malaria blood films and P. falciparum DNA polymerase chain reaction (PCR. Following diagnosis, patients were treated with artemether-lumefantrine (Coartem® and invited to return to the health facility after 28 days for repeat blood film and PCR. All PCR P. falciparum positive samples were analysed for molecular markers of lumefantrine and chloroquine resistance. Results Of 49 patients recruited on the basis of a positive rapid diagnostic test, only 16 were confirmed to have P. falciparum by PCR. At follow-up, 14 were PCR-negative for malaria, one was lost to follow-up and one blood specimen had insufficient blood for a PCR analysis. All 16 with PCR-confirmed malaria carried a single copy of the multi-drug resistant (mdr1 gene, and the wild type asparagine allele mdr1 codon 86 (mdr1 86N. Ten of the 16 samples carried the wild type haplotype (CVMNK at codons 72-76 of the chloroquine resistance transporter gene (pfcrt; three samples carried the resistant CVIET allele; one carried both the resistant and wild type, and in two samples the allele could not be analysed. Conclusions The absence of mdr1 gene copy number variation detected in this study

  8. In vitro susceptibility of Plasmodium falciparum Welch field isolates to infusions prepared from Artemisia annua L. cultivated in the Brazilian Amazon

    OpenAIRE

    Luiz Francisco Rocha e Silva; Pedro Melillo de Magalhães; Mônica Regina Farias Costa; Maria das Graças Costa Alecrim; Francisco Célio Maia Chaves; Ari de Freitas Hidalgo; Adrian Martin Pohlit; Pedro Paulo Ribeiro Vieira

    2012-01-01

    Artemisinin is the active antimalarial compound obtained from the leaves of Artemisia annua L. Artemisinin, and its semi-synthetic derivatives, are the main drugs used to treat multi-drug-resistant Plasmodium falciparum (one of the human malaria parasite species). The in vitro susceptibility of P. falciparum K1 and 3d7 strains and field isolates from the state of Amazonas, Brazil, to A. annua infusions (5 g dry leaves in 1 L of boiling water) and the drug standards chloroquine, quinine and ar...

  9. Autophagic flux data in differentiated C2C12 myotubes following exposure to acetylcholine and caffeine

    Directory of Open Access Journals (Sweden)

    Darin Bloemberg

    2016-06-01

    Full Text Available The C2C12 line of mouse myoblasts is a useful cell culture model in which to conduct in vitro analyses related to skeletal muscle. Here we present data regarding the autophagic response induced by two chemicals known to influence calcium release and contraction in skeletal muscles and C2C12 cells: acetylcholine and caffeine. More specifically, by concurrently administering acetylcholine or caffeine along with chloroquine to differentiated myotubes for various amounts of time and assessing the protein expression of LC3 and p62, we report data on the relative level of autophagic flux induced by these two calcium- and contraction-regulating chemicals.

  10. Guidelines for malaria prevention in travellers from the United Kingdom for 2003.

    Science.gov (United States)

    Bradley, D J; Bannister, B

    2003-09-01

    This updated guidance from the Advisory Committee on Malaria Prevention for UK Travellers provides the essential information for healthcare workers who advise travellers. The many personal, visit and location-specific factors that need to be taken into account are discussed. Tables include the available antimalarials for prophylaxis and for standby treatment, appropriate choices of regimen by region and country for malarious areas, and the adjustments needed for children and in concomitant disease. There is greater emphasis on mefloquine, doxycycline and atovaquone/proguanil as the three options for highly chloroquine-resistant falciparum malarious areas, and changes in emergency standby medication.

  11. Antiplasmodial activity of compounds from the surface exudates of Senecio roseiflorus.

    Science.gov (United States)

    Kerubo, Leonidah Omosa; Midiwo, Jacob Ogweno; Derese, Solomon; Langat, Moses K; Akala, Hosea M; Waters, Norman C; Peter, Martin; Heydenreich, Matthias

    2013-02-01

    From the surface exudates of Senecio roseiflorus fourteen known methylated flavonoids and one phenol were isolated and characterized. The structures of these compounds were determined on the basis of their spectroscopic analysis. The surface exudate and the flavonoids isolated showed moderate to good antiplasmodial activity with 5,4'-dihydroxy-7-dimethoxyflavanone having the highest activity against chloroquine-sensitive (D6) and resistant (W2) strains of Plasmodium falciparum, with IC50 values of 3.2 +/- 0.8 and 4.4 +/- 0.01 microg/mL respectively. PMID:23513721

  12. Absence of lipofuscin in motor neurons of SOD1-linked ALS mice

    OpenAIRE

    Bandyopadhyay, Urmi; Nagy, Maria; Fenton, Wayne A.; Horwich, Arthur L.

    2014-01-01

    This is the first report, to our knowledge, of the absence of lipofuscin, “aging pigment,” in a setting of motor neuron neurodegenerative disease, mutant SOD1-linked ALS. Although the initial hypothesis was that this must be due to a block in the autophagy/lysosome pathway, instead studies of autophagy markers and of ALS mice treated with chloroquine suggest the opposite, that there is hyperactivity of the autophagy/lysosome pathway, at least in part mediated through MTORC1.

  13. Treatment of severe active systemic lupus erythematosus by PMC therapy combined Langchuang Fuzheng Jiedu capsule: a clinical observation

    Institute of Scientific and Technical Information of China (English)

    宋欣伟

    2013-01-01

    Objective To evaluate the efficacy and safety of PMC therapy (Prednisone,Methotrexate,Chloroquine) combined Langchuang Fuzheng Jiedu Capsule (LFJC) ,thus choosing a better therapy of integrative medicine for SLE in the period of glucocorticoid use.Methods Sixty active SLE patients were randomly assigned to two groups,the control group and the treatment group.Those in the control group received PMC therapy (As for Prednisone,it was given at the daily dose of 1 mg/kg till 2weeks after the condition being stable or after 8 weeks of

  14. Problemer med primakin-recidivprofylakse hos malariapatienter

    DEFF Research Database (Denmark)

    Rønn, A M; Bygbjerg, Ib Christian

    1993-01-01

    Standard treatment of P. ovale and P. vivax malaria is 1500 mg of chloroquine base given over three days followed by 15 mg of primaquine base daily for 14 days. At the Department of Infectious Diseases, Rigshospitalet, Copenhagen an increasing number of cases of relative by primaquine-resistant...... malaria have been observed. The side effects of primaquine are mainly gastrointestinal. Primaquine may also cause serious toxic side effects, including methaemoglobin formation and haemolytic anaemia, especially in individuals with erythrocyte glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. We...

  15. Bioactive acridone alkaloids from Swinglea glutinosa.

    Science.gov (United States)

    Weniger, B; Um, B H; Valentin, A; Estrada, A; Lobstein, A; Anton, R; Maillé, M; Sauvain, M

    2001-09-01

    A new prenylated acridone alkaloid, 1,3,5-trihydroxy-2,8-bis(3-methylbut-2-enyl)-10-methyl-9-acridone (1), was isolated from the stembark of Swinglea glutinosa, along with three known acridone alkaloids, 5-hydroxynoracronycine (2), 1,3,5-trihydroxy-4-methoxy-2-(3-methylbut-2-enyl)-10-methyl-9-acridone (3), and 1,3,5-trihydroxy-4-methoxy-10-methylacridone (4). The isolated alkaloids were assessed in vitro against chloroquine-sensitive and -resistant Plasmodium falciparum strains and for cytotoxicity using HeLa cells. PMID:11575960

  16. Antibiotics for prophylaxis of Plasmodium falciparum infections : in vitro activity of doxycycline against Senegalese isolates

    OpenAIRE

    Pradines, B; Spiegel, A.; Rogier, C; Tall, A; Mosnier, J.; Fusai, T.; Trape, Jean-François; Parzy, D

    2000-01-01

    The in vitro acivities of doxycycline, chloroquine, quinine, amodiaquine, artemether, pyrimethamine, and cycloguanil were evaluated against #Plasmodium falciparum$ isolates from Senegal (Dielmo and Ndiop), using an isotopic, micro, drug susceptibility test. The 71 50% inhibitory concentration (IC50) values for doxycycline ranged from 0.7 to 108.0 microMol and the geometric mean IC50 for the 71 isolates was 11.3 microMol (95% confidence interval = 9.5-13.4 microM). The activity of doxycycline ...

  17. Evaluation of the effect of pyrimethamine, an anti-malarial drug, on HIV-1 replication

    OpenAIRE

    Oguariri, Raphael M.; Joseph W Adelsberger; Michael W Baseler; Imamichi, Tomozumi

    2010-01-01

    Co-infection of human immunodeficiency virus (HIV) with malaria is one of the pandemic problems in Africa and parts of Asia. Here we investigated the impact of PYR and two other clinical anti-malarial drugs (chloroquine [CQ] or artemisinin [ART]) on HIV-1 replication. Peripheral blood mononuclear cells (PBMCs) or MT-2 cells were infected with HIVNL4.3 strain and treated with different concentrations of the anti-malarial drugs. HIV-1 replication was measured using p24 ELISA. We show that 10 μM...

  18. In vivo antimalarial activity of leaves of Plectranthus amboinicus (lour) spreng on Plasmodium berghei yoelii.

    Science.gov (United States)

    Periyanayagam, K; Nirmala Devi, K; Suseela, L; Uma, A; Ismail, M

    2008-06-01

    An invivo study of aqueous extract of the leaves of Plectranthus amboinicus on Plasmodium berghei yoelii was conducted on laboratory infected albino mice and compared with standard drug chloroquine. Reduction of parasitemia at 250 mg/kg and 500 mg/kg of aqueous extract for 24 hrs, 48 hrs, 72 hrs and 96 hrs were determined. The reduction of parasitemia after 96 hrs was 100%, 67.9% and 76.2% for standard, 250 mg/kg and 500 mg/kg of aqueous extract respectively. The isolation of active principle responsible for the reduction of parasitemia may give a promising drug molecule. PMID:19301696

  19. Comparative Cytotoxicity of Artemisinin and Cisplatin and Their Interactions with Chlorogenic Acids in MCF7 Breast Cancer Cells

    OpenAIRE

    Suberu, John O.; Romero-Canel?n, Isolda; Sullivan, Neil; Lapkin, Alexei A.; Barker, Guy C

    2014-01-01

    In parts of Africa and Asia, self-medication with a hot water infusion of Artemisia annua (Artemisia tea) is a common practice for a number of ailments including malaria and cancer. In our earlier work, such an extract showed better potency than artemisinin alone against both chloroquine-sensitive and -resistant parasites. In this study, in vitro tests of the infusion in MCF7 cells showed high IC50 values (>200 μm). The combination of artemisinin and 3-caffeoylquinic acid (3CA), two major com...

  20. Drug accumulation in the presence of the multidrug resistance pump

    DEFF Research Database (Denmark)

    Ayesh, S; Litman, Thomas; Stein, W D

    1997-01-01

    We studied the interaction between the multidrug transporter, P-glycoprotein, and two compounds that interact with it: vinblastine, a classical substrate of the pump, and verapamil, a classical reverser. Steady-state levels of accumulation of these two drugs were determined in a multidrug resistant...... P388 leukemia cell line, P388/ADR. The time course of accumulation of these drugs, and the effect of energy starvation and the presence of chloroquine on the level of their steady-state accumulation were quite disparate. Vinblastine inhibited the accumulation of verapamil whereas it enhanced...

  1. Synthesis and biological evaluation of febrifugine analogues.

    Science.gov (United States)

    Mai, Huong Doan Thi; Thanh, Giang Vo; Tran, Van Hieu; Vu, Van Nam; Vu, Van Loi; Le, Cong Vinh; Nguyen, Thuy Linh; Phi, Thi Dao; Truong, Bich Ngan; Chau, Van Minh; Pham, Van Cuong

    2014-12-01

    A series of febrifugine analogues were designed and synthesized. Antimalarial activity evaluation of the synthetic compounds indicated that these derivatives had a strong inhibition against both chloroquine-sensitive and -resistant Plasmodium falciparum parasites. Many of them were found to be more active than febrifugine hydrochloride. The tested analogues had also a significant cytotoxicity against four cancer cell lines (KB, MCF7, LU1 and HepG2). Among the synthetic analogues, two compounds 17b and 17h displayed a moderate cytotoxicity while they exhibited a remarkable antimalarial activity. PMID:25632466

  2. Diphtheria toxin entry into cells is facilitated by low pH

    OpenAIRE

    1980-01-01

    At neutral pH, NH4Cl and chloroquine protected cells against diphtheria toxin. A brief exposure of the cells to low pH (4.5-5.5) at 37 degrees completely abolished this protection. When, to cells preincubated with diphtheria toxin and NH4Cl, neutralizing amounts of anti-diphtheria toxin were added before the pH was lowered, the toxic effect was considerably reduced, but it was not completely abolished. A much stronger toxic effect was seen when antibodies were added immediately after incubati...

  3. [Juvenile chronic arthritis: therapeutic strategy 1990].

    Science.gov (United States)

    Gerber, N J; Sauvain, M J

    1991-04-27

    Therapeutic strategies based on experience with 119 patients with juvenile chronic arthritis are reviewed. Therapeutic goals are formulated and the means of attaining them (NSAIDs, the so-called disease modifying drugs gold, chloroquine and penicillamine, the antimetabolite methotrexate, intra-articular and systemic corticosteroids, physio- and ergotherapy, technical and orthopedic measures, as well as vocational and medicosocial aspects) are discussed. As the individual prognosis normally depends less on drugs than on preventive and rehabilitative measures, the outcome is largely determined by the quality of a well-coordinated inter-disciplinary team approach. PMID:2047820

  4. Thymus size at 6 months of age and subsequent child mortality

    DEFF Research Database (Denmark)

    Garly, M.L.; Trautner, S.L.; Marx, C.;

    2008-01-01

    with BCG in the preceding 4 weeks before inclusion into the study had larger thymuses. Children who had malaria or had been treated with chloroquine or Quinimax in the previous week before inclusion had smaller thymuses. Controlled for background factors associated with thymus size and mortality, small...... thymus size remained a strong and independent risk factor for mortality (hazard ratio = 0.31; 95% confidence interval = 0.18 to 0.52). CONCLUSIONS: Small thymus size at age 6 months is a strong risk factor for mortality. To prevent unnecessary deaths, it is important to identify preventable factors...

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Neuropsychiatric manifestations after mefloquine therapy for Plasmodium falciparum malaria: comparing a retrospective and a prospective study

    DEFF Research Database (Denmark)

    Rønn, A M; Rønne-Rasmussen, J; Gøtzsche, P C;

    1998-01-01

    . Neuropsychiatric adverse drug reactions are now well documented. We compared an open prospective 3 year study including all patients with P. falciparum treated with mefloquine with an earlier published, retrospective study on a comparable population from our department covering the period up to 1989......Mefloquine has been increasingly used for treatment of chloroquine-resistant malaria since its introduction in the late 1970s. In 1987 the first case of toxic encephalopathy was published, and in 1989 the WHO initiated reporting and investigation of neuropsychiatric adverse reactions of mefloquine...

  7. Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

    Directory of Open Access Journals (Sweden)

    Dea Shahinas

    2013-02-01

    Full Text Available Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.

  8. 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....

  9. Antimalarial drug resistance of Plasmodium falciparum in India: changes over time and space

    OpenAIRE

    Shah, Naman K.; Dhillon, Gajender P S; Dash, Adtiya P; Arora, Usha; Meshnick, Steven R.; Valecha, Neena

    2011-01-01

    After the launch of the National Malaria Control Programme in 1953, the number of malaria cases reported in India fell to an all-time low of 0·1 million in 1965. However, the initial success could not be maintained and a resurgence of malaria began in the late 1960s. Resistance of Plasmodium falciparum to chloroquine was first reported in 1973 and increases in antimalarial resistance, along with rapid urbanisation and labour migration, complicated the challenge that India’s large geographical...

  10. Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies.

    Science.gov (United States)

    Veiga, M Isabel; Dhingra, Satish K; Henrich, Philipp P; Straimer, Judith; Gnädig, Nina; Uhlemann, Anne-Catrin; Martin, Rowena E; Lehane, Adele M; Fidock, David A

    2016-01-01

    Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine. In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin. The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT. Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated haemoglobin degradation. Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes. PMID:27189525

  11. Study of antimalarial activity of chemical constituents from Diospyros quaesita.

    Science.gov (United States)

    Ma, Cui-Ying; Musoke, Sebisubi Fred; Tan, Ghee Teng; Sydara, Kongmany; Bouamanivong, Somsanith; Southavong, Bounhoong; Soejarto, D Doel; Fong, Harry H S; Zhang, Hong-Jie

    2008-11-01

    Bioassay-directed fractionation led to the isolation of seven compounds from a sample of the dried leaves, twigs, and branches of Diospyros quaesita Thw. (Ebenaceae). One of the isolates, betulinic acid 3-caffeate (1), showed in vitro antimalarial activity against Plasmodium falciparum clones D(6) (chloroquine-sensitive) and W(2) (chloroquine-resistant) with IC(50) values of 1.40 and 0.98 microM, respectively. Evaluation of compound 1 in the human oral epidermoid (KB) cancer cell line revealed cytotoxicity at ED(50) of 4.0 microM. In an attempt to reduce the cytotoxicity of 1, the acetylated derivative 1a and betulinic acid (1b) were prepared. Of the seven isolates, diospyrosin (2) was determined to be a new neolignan. In addition to 1, other known compounds isolated in this study were pinoresinol, lariciresinol, N-benzoyl-L-phenylalaninol, scopoletin, and poriferast-5-en-3beta,7alpha-diol. The structure of 2 was elucidated based on spectroscopic data analysis including 1D- and 2D-NMR, and HR-ESI-MS. PMID:19035573

  12. Antiplasmodial and Cytotoxic Activities of Toad Venoms from Southern Amazon, Brazil.

    Science.gov (United States)

    Banfi, Felipe Finger; Guedes, Karla de Sena; Andrighetti, Carla Regina; Aguiar, Ana Carolina; Debiasi, Bryan Wender; Noronha, Janaina da Costa; Rodrigues, Domingos de Jesus; Júnior, Gerardo Magela Vieira; Sanchez, Bruno Antonio Marinho

    2016-08-01

    The drug-resistance of malaria parasites is the main problem in the disease control. The huge Brazilian biodiversity promotes the search for new compounds, where the animal kingdom is proving to be a promising source of bioactive compounds. The main objective of this study was to evaluate the antiplasmodial and cytotoxic activity of the compounds obtained from the toad venoms of Brazilian Amazon. Toad venoms were collected from the secretion of Rhinella marina and Rhaebo guttatus in Mato Grosso State, Brazil. The powder was extracted at room temperature, yielding 2 extracts (RG and RM) and a substance ('1') identified as a bufadienolide, named telocinobufagin. Growth inhibition, intraerythrocytic development, and parasite morphology were evaluated in culture by microscopic observations of Giemsa-stained thin blood films. Cytotoxicity was determined against HepG2 and BGM cells by MTT and neutral red assays. The 2 extracts and the pure substance ('1') tested were active against chloroquine-resistant Plasmodium falciparum strain, demonstrating lower IC50 values. In cytotoxic tests, the 2 extracts and substance '1' showed pronounced lethal effects on chloroquine-resistant P. faciparum strain and low cytotoxic effect, highlighting toad parotoid gland secretions as a promising source of novel lead antiplasmodial compounds. PMID:27658592

  13. Antimalarial effect of agmatine on Plasmodium berghei K173 strain

    Institute of Scientific and Technical Information of China (English)

    SURui-Bin; WEIXiao-Li; LIUYin; LIJin

    2003-01-01

    AIM: To study the antimalarial effect of agmatine (Agm) on chloroquine-susceptible Plasmodium berghei K173strain (S strain) and the P berghei K173 resistant strain (R strain). METHODS: The antimalarial effects of Agm onP berghei K173 S strain and R strain were evaluated by Peters 4-d suppression test in mice. RESULTS: Agm(12.5-200 mg/kg,ig,daily) decreased the parasitemia for both P berghei K173 S strain (IC50=139 mg/kg) and Rstrain (IC50=126mg/kg) in mice. Subcutaneous injection (sc) of Agm (5-40mg/kg,tid) showed relatively strongerantimalarial effect than intragastric gavage (IC50=30 mg/kg) in P berghei K 173 S strain. Spermidine antagonized theantimalarial effect of Agm for P berghei K173 S strain and R strain. Agm did not reverse the chloroquine resistanceof P berghei K173 S strain, dl-α-Difluoromethylornithine (DFMO, sc) decreased the parasitemia of P BergheiK173 S strain and this effect was antagonized by spermidine. CONCLUSION: Agm has an antimalarial effect andthe mechanism is related to its inhibition of polyamine synthesis.

  14. Report of treatment of a patient with a mixed infection of Plasmodium vivax and Plasmodium falciparum malaria%间日疟、恶性疟混合感染1例治疗报告

    Institute of Scientific and Technical Information of China (English)

    温卫珊; 魏荣英

    2011-01-01

    2009年龙岩市报告1例间日疟、恶性疟混合感染病例,患者在国外感染、发病,曾接受过治疗,回国后再次发病.在国内经3个疗程青蒿琥酯(1 800mg)和4个疗程的氯伯8 d疗法(氯喹4 800 mg、伯氨喹720 mg)治疗后痊愈.%The City of Longyan reported a case of a mixed infection of Plasmodium vivax and Plasmodium falciparum malaria in 2009. The patient had been infected abroad, developed malaria, been treated, returned home, and developed malaria again. In China, the patient received an 8-day-treatment with 3 courses of artesunate (1 800 mg) and 4 courses of chloroquine+primaquine (chloroquine, 4 800 mg, primaquine 720 mg). Afterwards, the patient recovered.

  15. A combination of the leaves and tuber of Icacina senegalensis A. Juss (Icacinaceae improves the antimalarial activity of the plant in mice

    Directory of Open Access Journals (Sweden)

    Esien David-Oku

    2015-10-01

    Full Text Available Objective: To investigate the possibility of increased antimalarial activity of Icacina senegalensis A. Juss (Icacinaceae upon a combination of its leaves and tubers against Plasmodium berghei malaria in mice. Methods: Chloroquine sensitive ANKA clones of Plasmodium berghei were used to develop experimental models based on intraperitoneal injection of 107 parasitized erythrocytes in phosphate buffer saline (pH 7.2 and subsequent development of parasitemia. The models were employed to investigate prophylactic and curative anti-malarial activities of tuber and tuberleaf methanol extracts of the plant at selected dosages (25, 50 and 100 mg/kg body weight. Chloroquine with a curative dosage of 10 mg/kg body weight was used as positive control in both studies. Results: Tuber and tuber-leaf extracts produced a dose-dependent chemosuppression of the parasites, with higher activity and mean survival time exhibited by the combined extract. Conclusions: Anti-plasmodia activity has been discovered in methanol extract of Icacina senegalensis tuber extract. The observed optimization of the antimalarial actions of the plant upon a combination of its leaf and tuber opens a new area of medicinal plant research.

  16. Identification and characterisation of small molecule inhibitors of feline coronavirus replication.

    Science.gov (United States)

    McDonagh, Phillip; Sheehy, Paul A; Norris, Jacqueline M

    2014-12-01

    Feline infectious peritonitis (FIP), a feline coronavirus (FCoV) induced disease, is almost invariably fatal with median life expectancy measured in days. Current treatment options are, at best, palliative. The objectives of this study were to evaluate a panel of nineteen candidate compounds for antiviral activity against FCoV in vitro to determine viable candidates for therapy. A resazurin-based cytopathic effect inhibition assay, which detects viable cells through their reduction of the substrate resazurin to fluorescent resorufin, was developed for screening compounds for antiviral efficacy against FCoV. Plaque reduction and virus yield reduction assays were performed to confirm antiviral effects of candidate compounds identified during screening, and the possible antiviral mechanisms of action of these compounds were investigated using virucidal suspension assays and CPE inhibition and IFA-based time of addition assays. Three compounds, chloroquine, mefloquine, and hexamethylene amiloride demonstrated marked inhibition of virus induced CPE at low micromolar concentrations. Orthogonal assays confirmed inhibition of CPE was associated with significant reductions in viral replication. Selectivity indices calculated based on in vitro cytotoxicity screening and reductions in extracellular viral titre were 217, 24, and 20 for chloroquine, mefloquine, and hexamethylene amiloride respectively. Preliminary experiments performed to inform the antiviral mechanism of the compounds demonstrated all three acted at an early stage of viral replication. These results suggest that these direct acting antiviral compounds, or their derivatives, warrant further investigation for clinical use in cats with FIP.

  17. Improved antiparasitic activity by incorporation of organosilane entities into half-sandwich ruthenium(II) and rhodium(III) thiosemicarbazone complexes.

    Science.gov (United States)

    Adams, Muneebah; de Kock, Carmen; Smith, Peter J; Land, Kirkwood M; Liu, Nicole; Hopper, Melissa; Hsiao, Allyson; Burgoyne, Andrew R; Stringer, Tameryn; Meyer, Mervin; Wiesner, Lubbe; Chibale, Kelly; Smith, Gregory S

    2015-02-01

    A series of ferrocenyl- and aryl-functionalised organosilane thiosemicarbazone compounds was obtained via a nucleophilic substitution reaction with an amine-terminated organosilane. The thiosemicarbazone (TSC) ligands were further reacted with either a ruthenium dimer [(η(6-i)PrC6H4Me)Ru(μ-Cl)Cl]2 or a rhodium dimer [(Cp*)Rh(μ-Cl)Cl]2 to yield a series of cationic mono- and binuclear complexes. The thiosemicarbazone ligands, as well as their metal complexes, were characterised using NMR and IR spectroscopy, and mass spectrometry. The molecular structure of the binuclear ruthenium(ii) complex was determined by single-crystal X-ray diffraction analysis. The thiosemicarbazones and their complexes were evaluated for their in vitro antiplasmodial activities against the chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) Plasmodium falciparum strains, displaying activities in the low micromolar range. Selected compounds were screened for potential β-haematin inhibition activity, and it was found that two Rh(iii) complexes exhibited moderate to good inhibition. Furthermore, the compounds were screened for their antitrichomonal activities against the G3 Trichomonas vaginalis strain, revealing a higher percentage of growth inhibition for the ruthenium and rhodium complexes over their corresponding ligand. PMID:25559246

  18. EVALUATION OF MORINGA OLEIFERA GUM AS A BINDER IN TABLET FORMULATION

    Directory of Open Access Journals (Sweden)

    Patil Basawaraj S.

    2010-12-01

    Full Text Available Various plant gums have been used as binders in tablet formulations. But still finding novel binder for the manufacture of tablets, in pharmaceutical industry. The Moringa oleifera gum was found its binding property. In the present study Moringa oleifera gum was employed as a binding agent in Chloroquine phosphate tablets at concentrations of 4.0, 6.0 and 8.0 % w/w, in comparison with potato starch. The properties of Moringa oleifera gum were evaluated for angle of repose, bulk density, tapped density, carr’s compressibility index and hausner’s ratio. The granules were evaluated for moisture content, angle of repose, bulk and tapped densities. The tablets were evaluated for thickness, weight variation, hardness, friability, disintegration time and dissolution profiles. Studies showed that increase in binding concentration of Moringa oleifera gum, increases the hardness, increases the disintegration time, decreases the percentage friability and decreases % cumulative release. Results obtained indicated that Moringa oleifera gum performed as good as potato starch as a binder to Chloroquine phosphate tablets.

  19. Imaging the intracellular distribution of tyrosine kinase inhibitors in living cells with quantitative hyperspectral stimulated Raman scattering

    Science.gov (United States)

    Fu, Dan; Zhou, Jing; Zhu, Wenjing Suzanne; Manley, Paul W.; Wang, Y. Karen; Hood, Tami; Wylie, Andrew; Xie, X. Sunney

    2014-07-01

    ABL1 tyrosine-kinase inhibitors (TKI) are front-line therapy for chronic myelogenous leukaemia and are among the best-known examples of targeted cancer therapeutics. However, the dynamic uptake into cells of TKIs of low molecular weight and their intracellular behaviour is unknown because of the difficulty of observing non-fluorescent small molecules at subcellular resolution. Here we report the direct label-free visualization and quantification of two TKI drugs (imatinib and nilotinib) inside living cells using hyperspectral stimulated Raman scattering imaging. Concentrations of both drugs were enriched over 1,000-fold in lysosomes as a result of their lysosomotropic properties. In addition, low solubility appeared to contribute significantly to the surprisingly large accumulation of nilotinib. We further show that the lysosomal trapping of imatinib was reduced more than tenfold when chloroquine is used simultaneously, which suggests that chloroquine may increase the efficacy of TKIs through lysosome-mediated drug-drug interaction in addition to the commonly proposed autophagy-inhibition mechanism.

  20. Resistência in vitro de cepas do Plasmodium falciparum isoladas no sul do estado do Pará, em diferentes períodos: emergência de casos de multirresistência

    Directory of Open Access Journals (Sweden)

    A. A. Couto

    1993-03-01

    Full Text Available O presente estudo avalia a resposta de cepas de Plasmodium falciparum às drogas antimaláricas, através de testes in vitro, isoladas em 7 municípios do sul do Estado do Pará. Foram efetuados 69 testes para cloroquina e mefloquina, 62 para amodiaquina e 61 para quinino. Os resultados mostram elevada resistência para cloroquina (71%, relativamente baixa resistência para amodiaquina com (25,8% e para o quinino apenas 8,2%. Mefloquina revela ampla sensibilidade (100%, mas, demonstrando perda da mesma quando comparada em dois períodos distintos. Evidenciou-se também cepas multirresistentes em dois dos municípios estudados.The responses of Plasmodium falciparum to antimalarial drugs were evaluated through the in vitro test using blood sample collected from patients of 7 municipalities of the south of Pará State. Sixty nine microtests for chloroquine and mefloquine, 62 for amodiaquine and 61 for quinine were pet formed. The results showed a high resistance for chloroquine (71%, a relatively low resistance level for amodiaquine (25.8% and little resistance to quinine (8.2%. For mefloquine 100% of sensitivity was found.

  1. Inhibition of autophagy enhances heat-induced apoptosis in human non-small cell lung cancer cells through ER stress pathways.

    Science.gov (United States)

    Xie, Wen-Yue; Zhou, Xiang-Dong; Yang, Juan; Chen, Ling-Xiu; Ran, Dan-Hua

    2016-10-01

    The occurrence and mechanisms of autophagy induced by heat stress are not well known in lung cancer cells. Here, we have demonstrated that heat stress induces autophagy in A549 and NCI-H460 cells through morphological and biochemical analyses. The inhibition of autophagy by chloroquine, 3-methyladenine and Beclin 1 siRNA enhanced heat-induced apoptosis. Moreover, the combination of chloroquine and heat stress inhibited tumor growth and enhanced apoptosis in vivo experiments. In addition, heat-induced autophagy involved the ER stress pathway (PERK- or IRE1-dependent). Further, heat treatment led to the increased phosphorylation of AMPK and the decreased phosphorylation of mTOR in vitro and in vivo. Knockdown of GRP78 inhibited the AMPK-mTOR pathway, and the AMPK inhibitor compound C decreased heat-induced autophagy, suggesting that activation of ER stress was involved in autophagy induction and promotion of the AMPK-mTOR pathway. In conclusion, our data suggested that the heat treatment of lung cancer cells triggered protective autophagy, as mediated by ER stress. Thus, inhibition of autophagy can be a promising strategy to enhance hyperthermia in the treatment of lung cancer patients.

  2. PENGOBATAN PENDERITA MALARIA FALSIPARUM TANPA KOMPLIKASI DENGAN MEFLOKUIN DI DAERAH RESISTEN KLOROKUIN

    Directory of Open Access Journals (Sweden)

    Emiliana Tjitra

    2012-09-01

    Full Text Available Treatment with mefloquine of uncomplicated falciparum malaria patients was undertaken in ITCI Hospital, Balikpapan, East Kalimantan, Indonesia in 1991. This study was conducted to assess the efficacy and safety of mefloquine, and to assess in vitro sensitivity of P. falciparum to other antimalarials currently in use. A total of 16 falciparum malaria patients who had been selected according to WHO criteria for the drug sensitivity test were treated with 750 mg mefloquine single dose orally. All patients were hospitalized for 3-5 days and followed up on day 7, 14, 21 and 28. Clinical and parasitological examinations were carried out during the study, haematological and biochemical examinations were also performed before drug administration and when the patient was discharged from the hospital. The main presenting symptoms were chills, headache and fever. Cure rate was 100% with the mean fever clearance time and parasite clearance time was 9.3 ±_ 2.4 hours and 47.1 +_ 3.7 hours respectively. No significant drug-related changes were noted in hematological or biochemical parameters. Only nausea was observed as a side effect of mefloquine which was mild and disappeared without treatment. ITCI Hospital area is a highly chloroquine resistant area (90,9% and also as a multidrug resistant area (50%. This study shows that mefloquine is effective and safe for the treatment of uncomplicated falcipamm malaria resistant to chloroquine as well as for multidrug resistant cases.

  3. Piperaquine and Lumefantrine resistance in Plasmodium berghei ANKA associated with increased expression of Ca2+/H+ antiporter and glutathione associated enzymes.

    Science.gov (United States)

    Kiboi, Daniel; Irungu, Beatrice; Orwa, Jennifer; Kamau, Luna; Ochola-Oyier, Lynette Isabella; Ngángá, Joseph; Nzila, Alexis

    2014-12-01

    We investigated the mechanisms of resistance of two antimalarial drugs piperaquine (PQ) and lumefantrine (LM) using the rodent parasite Plasmodium berghei as a surrogate of the human parasite, Plasmodium falciparum. We analyzed the whole coding sequence of Plasmodium berghei chloroquine resistance transporter (Pbcrt) and Plasmodium berghei multidrug resistance gene 1(Pbmdr-1) for polymorphisms. These genes are associated with quinoline resistance in Plasmodium falciparum. No polymorphic changes were detected in the coding sequences of Pbcrt and Pbmdr1 or in the mRNA transcript levels of Pbmdr1. However, our data demonstrated that PQ and LM resistance is achieved by multiple mechanisms that include elevated mRNA transcript levels of V-type H(+) pumping pyrophosphatase (vp2), Ca(2+)/H(+) antiporter (vcx1), gamma glutamylcysteine synthetase (ggcs) and glutathione-S-transferase (gst) genes, mechanisms also known to contribute to chloroquine resistance in P. falciparum and rodent malaria parasites. The increase in ggcs and gst transcript levels was accompanied by high glutathione (GSH) levels and elevated activity of glutathione-S-transferase (GST) enzyme. Taken together, these results demonstrate that Pbcrt and Pbmdr1 are not associated with PQ and LM resistance in P. berghei ANKA, while vp2, vcx1, ggcs and gst may mediate resistance directly or modulate functional mutations in other unknown genes. PMID:25448357

  4. Temporal trends in prevalence of Plasmodium falciparum drug resistance alleles over two decades of changing antimalarial policy in coastal Kenya.

    Science.gov (United States)

    Okombo, John; Kamau, Alice W; Marsh, Kevin; Sutherland, Colin J; Ochola-Oyier, Lynette Isabella

    2014-12-01

    Molecular surveillance of drug resistance markers through time provides crucial information on genomic adaptations, especially in parasite populations exposed to changing drug pressures. To assess temporal trends of established genotypes associated with tolerance to clinically important antimalarials used in Kenya over the last two decades, we sequenced a region of the pfcrt locus encompassing codons 72-76 of the Plasmodium falciparum chloroquine resistance transporter, full-length pfmdr1 - encoding multi-drug resistance protein, P-glycoprotein homolog (Pgh1) and pfdhfr encoding dihydrofolate reductase, in 485 archived Plasmodium falciparum positive blood samples collected in coastal Kenya at four different time points between 1995 and 2013. Microsatellite loci were also analyzed to compare the genetic backgrounds of parasite populations circulating before and after the withdrawal of chloroquine and sulfadoxine/pyrimethamine. Our results reveal a significant increase in the prevalence of the pfcrt K76 wild-type allele between 1995 and 2013 from 38% to 81.7% (p drug in contrast to a selective sweep around the triple mutant pfdhfr allele, leading to a mono-allelic population at this locus. These findings highlight the importance of continual surveillance and characterization of parasite genotypes as indicators of the therapeutic efficacy of antimalarials, particularly in the context of changes in malaria treatment policy. PMID:25516825

  5. Schizonticidal effect of a combination of Amaranthus spinosus L. and Andrographis paniculata Burm. f./Nees extracts in Plasmodium berghei-infected mice

    Directory of Open Access Journals (Sweden)

    Tiwuk Susantiningsih

    2012-05-01

    Full Text Available Background: Amaranthus spinosus and Andrographis paniculata are traditionally used as antimalarial herbs, but the combination of both has not yet been tested. The aim of this study was to determine the schizonticidal anti-malaria effect of a combination in Plasmodium berghei-infected mice.Methods: Male mice (Balb/c strain weighing 28-30 g, 7-8 weeks old, were randomly devided into 5 groups of 4 animals each. Group A: controls (nil and 4 treatment groups (B, C, D, and E. Group B: Amarathus 10 mg/kgBW, group C: Andrographis 2 mg/kgBW, group D: combination of Amaranthus + Andrographis 10 mg + 2 mg/kgBW. All treatment with plant extracts was administered orally, once per day for 7 days. Group E was given chloroquine 10 mg/kgBW, once a day orally, for 3 days.Results: The body weigh increased only in group D, hemoglobin concentration increased significantly vs controls (p < 0.05 in treatment groups C, D, and E, and blood schizonticidal activity was seen in all treatment groups, highest at almost 90% in groups D and E. Survival rate was 100% in all groups.Conclusion: The combination of Amaranthus and Andrographis (10 mg + 2 mg/kgBW exerts the same blood schizonticidal activity as chloroquine 10 mg/kgBW. (Med J Indones. 2012;21:66-70Keywords: Amaranthus spinosus, Andrographis paniculata, Balb/c mice, Plasmodium berghei, schizonticidal effect

  6. Pharmacodynamic evaluation for antiplasmodial activity of Holarrhena antidysentrica (Kutaja) and Azadirachta indica (Neemb) in Plasmodium berghei infected mice model

    Institute of Scientific and Technical Information of China (English)

    Jadhav Priyanka; Lal Hingorani; Kshirsagar Nilima

    2013-01-01

    Objective: To investigate in-vivo anti-plasmodial activity of aqueous extracts of plants selected based on the symptomology mentioned in Ayurveda. Methods: The aqueous extracts of Holarrhena antidysentrica (H. antidysentrica) (Kutaja) and Azadirachta indica (A. indica) (Neemb) for their antiplasmodial potential in Plasmodium berghei (P. berghei) infected mice was assessed using Peters four day suppressive test. Both the extracts were administered at 2 dose levels, full dose (1 000 mg/d) and minimized dose (200 mg/d). 106 P. berghei infected RBCs were injected on day ’0’ and treated from day ’0’ till day ’3’ post-infection. Tail blood smears were collected, giemsa stained and analyzed. The mice were observed for survival and parasitemia was assessed till 50% of mice in control survived. Results: It was observed that the percentage of parasitemia increased gradually in all the groups, with maximum in control group (Day 3-35, Day 9-46.98) and minimum in Chloroquine arm (Day 3-14.06, Day 9-19.92). The percentage of parasitemia was compared using Mann-Whitney U test depicting that all test groups exhibited reduction in parasitemia as compared to control (P-value<0.002 for all groups). These groups showed similar percentage of survival as Chloroquine. Conclusions: The present investigation demonstrated the anti-plasmodial effects of H. antidysentrica and A. indica, which are two most commonly used medicinal plants in Ayurved for treatment of fever.

  7. In vitro and in vivo anti-malarial activity of Boerhavia elegans and Solanum surattense

    Directory of Open Access Journals (Sweden)

    Khodakarim Nastaran

    2010-05-01

    Full Text Available Abstract Background There is an urgent need to identify new anti-malarial drug targets for both prophylaxis and chemotherapy, due to the increasing problem of drug resistance to malaria parasites. In the present study, the aim was to discover novel, effective plant-based extracts for the activity against malaria. Methods Ten plants found in Iran were selected by ethnobotanical survey of medicinal plants. The crude ethanolic extracts were tested for in vitro anti-plasmodial activity against two strains of Plasmodium falciparum: K1 (chloroquine-resistant strain and CY27 (chloroquine-sensitive strain, using the parasite lactate dehydrogenase (pLDH assay. The anti-plasmodial activity of the extracts was also assessed in the 4-day suppressive anti-malarial assay in mice inoculated with Plasmodium berghei (ANKA strain. Crude ethanolic extracts showed good anti-plasmodial activity were further fractionated by partitioning in water and dichloromethane. Results Of 10 plant species assayed, three species: Boerhavia elegans (Choisy, Solanum surattense (Burm.f. and Prosopis juliflora (Sw. showed promising anti-plasmodial activity in vitro (IC50 ≤ 50 μg/ml and in vivo with no toxicity. The dichloromethane fraction of three extracts revealed stronger anti-plasmodial activity than the total extracts. Conclusion Anti-plasmodial activities of extracts of B. elegans and S. surattense are reported for the first time.

  8. A search for natural bioactive compounds in Bolivia through a multidisciplinary approach. Part IV. Is a new haem polymerisation inhibition test pertinent for the detection of antimalarial natural products?

    Science.gov (United States)

    Baelmans, R; Deharo, E; Bourdy, G; Muñoz, V; Quenevo, C; Sauvain, M; Ginsburg, H

    2000-11-01

    The search for new antimalarial agents in plant crude extracts using traditional screening tests is time-consuming and expensive. New in vitro alternative techniques, based on specific metabolic or enzymatic process, have recently been developed to circumvent testing of antimalarial activity in parasite culture. The haem polymerisation inhibition test (HPIA) was proposed as a possible routine in vitro assay for the detection of antimalarial activity in natural products. A total of 178 plant extracts from the Pharmacopeia of the Bolivian ethnia Tacana, were screened for their ability to inhibit the polymerisation of haematin. Five extracts from Aloysia virgata (Ruíz & Pavón) A.L. Jussieu (Verbenaceae), Bixa orellana L. (Bixaceae), Caesalpinia pluviosa D.C. (Caesalpiniaceae), Mascagnia stannea (Griseb) Nied. (Malpighiaceae) and Trichilia pleenea (Adr. Jussieu) (Meliaceae) demonstrated more than 70% inhibition of haematin polymerisation at 2.5 mg/ml. The extracts were also tested for antimalarial activity in culture against F32 strain (chloroquine-sensitive) and D2 strain (chloroquine-resistant) of Plasmodium falciparum and in vivo against P. berghei. The extract from Caesalpinia pluviosa was the only one that showed activity in HPIA and in the classical test in culture. The accuracy and pertinence of HPIA, applied to natural products is discussed. PMID:11025165

  9. Phytochemical Characterization and in-vivo Anti-Malaria Activity of Lantana camara Leaf Extract

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    Gabi Baba

    2011-12-01

    Full Text Available The characteristic multi-drug resistant strains of Plasmodium to the existing anti-malaria has increase the global threat of malaria, couple with the wide medicinal application of Lantana camara in different countries and the literature of its use as anti-microbial, antifungal and insecticidal agents, and the quest for alternative anti-malaria this work look into the phytochemical screening, characterization and the In-vivo anti-malaria activity of the Lantana camara leaf extracts. The leaf extracts from plant were screened for phytochemicals and further FTIR characterized to correlate the routine qualitative phytochemical screening. In-vivo anti-plasmodia screening was carried out using 24 Swiss albino mice under laboratory conditions. The effectiveness of the aqueous and ethanolic extracts from the plant (L. camara was compared with standard drug Chloroquine. The result indicated the presence of Alkaloids, Cardiac glycosides and Saponins in the Petroleum ether, aqueous and ethanolic extracts. Carbohydrate in both aqueous and ethanolic extracts, while Flavonoids and steroids in petroleum ether and ethanolic extracts. Tannins and terpenoids were present in aqueous and ethanolic extracts respectively. The identified phytochemicals correlate with FTIR spectral analysis from the identified characteristic functional groups. In-vivo study showed that Chloroquine was 83% effective in clearing the parasites, while aqueous and ethanolic extracts were 38 and 76% effective respectively. The curative capacity indicated possible concentration and time-dependency. The ethanolic extract showed higher level of anti-malaria potential and has indicated some level of protection.

  10. In Vitro Anti-Plasmodial Activity of Trigonella foenum–graecum L.

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    M. Palaniswamy

    2010-01-01

    Full Text Available Developing countries, where malaria is one of the most prevalent diseases, still rely on traditional medicine as a source for the treatment of this disease. For the present study, Trigonella foenum-graecum L. (fenugreek were collected from Coimbatore, Tamilnadu, India. The test plant has been used in India by traditional healers for the treatment of fever as well as other diseases. The active principle was extracted out in different solvent systems to assess the anti-plasmodial potential, with an aim that they can further be utilized to formulate drugs. In vitro anti-plasmodial assay of the extracted fractions of fenugreek leaves was carried out using laboratory adapted chloroquine sensitive and resistant Plasmodium falciparum isolates. Schizont maturation inhibition assay was adopted to analyze the potential of the extracts. Ethanol extract (50% seemed to possess profound anti-plasmodial activity with IC50 value of 8.75 ± 0.35 µg ml−1 and 10.25 ± 0.35 µg ml−1 against chloroquine sensitive and resistant P. falciparum isolates, respectively. Among the investigated six fractions of the plant extracts, two were found to have significant anti-plasmodial activity with IC50 values 85 µg ml−1. In addition, preliminary phytochemical screening of the various extracts indicated the presence of alkaloids, saponin, tannin like phenolic compounds, flavonoids and steroids.

  11. A combination of the leaves and tuber ofIcacina senegalensis A. Juss (Icacinaceae) improves the antimalarial activity of the plant in mice

    Institute of Scientific and Technical Information of China (English)

    Esien David-Oku; Juliet Ifeoma Obiajunwa-Otteh

    2015-01-01

    Objective:To investigate the possibility of increased antimalarial activity ofIcacina senegalensis A. Juss (Icacinaceae) upon a combination of its leaves and tubers against Plasmodium berghei malaria in mice. Methods: Chloroquine sensitiveANKA clones ofPlasmodium berghei were used to develop experimental models based on intraperitoneal injection of 107 parasitized erythrocytes in phosphate buffer saline (pH 7.2) and subsequent development of parasitemia. The models were employed to investigate prophylactic and curative anti-malarial activities of tuber and tuber-leaf methanol extracts of the plant at selected dosages (25, 50 and 100 mg/kg body weight). Chloroquine with a curative dosage of 10 mg/kg body weight was used as positive control in both studies. Results:Tuber and tuber-leaf extracts produced a dose-dependent chemosuppression of the parasites, with higher activity and mean survival time exhibited by the combined extract. Conclusions:Anti-plasmodia activity has been discovered in methanol extract ofIcacina senegalensis tuber extract. The observed optimization of the antimalarial actions of the plant upon a combination of its leaf and tuber opens a new area of medicinal plant research.

  12. 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.

  13. 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.

  14. In vitro susceptibility of Plasmodium falciparum Welch field isolates to infusions prepared from Artemisia annua L. cultivated in the Brazilian Amazon

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    Luiz Francisco Rocha e Silva

    2012-11-01

    Full Text Available Artemisinin is the active antimalarial compound obtained from the leaves of Artemisia annua L. Artemisinin, and its semi-synthetic derivatives, are the main drugs used to treat multi-drug-resistant Plasmodium falciparum (one of the human malaria parasite species. The in vitro susceptibility of P. falciparum K1 and 3d7 strains and field isolates from the state of Amazonas, Brazil, to A. annua infusions (5 g dry leaves in 1 L of boiling water and the drug standards chloroquine, quinine and artemisinin were evaluated. The A. annua used was cultivated in three Amazon ecosystems (várzea, terra preta de índio and terra firme and in the city of Paulínia, state of São Paulo, Brazil. Artemisinin levels in the A. annua leaves used were 0.90-1.13% (m/m. The concentration of artemisinin in the infusions was 40-46 mg/L. Field P. falciparum isolates were resistant to chloroquine and sensitive to quinine and artemisinin. The average 50% inhibition concentration values for A. annua infusions against field isolates were 0.11-0.14 μL/mL (these infusions exhibited artemisinin concentrations of 4.7-5.6 ng/mL and were active in vitro against P. falciparum due to their artemisinin concentration. No synergistic effect was observed for artemisinin in the infusions.

  15. In vitro susceptibility of Plasmodium falciparum Welch field isolates to infusions prepared from Artemisia annua L. cultivated in the Brazilian Amazon.

    Science.gov (United States)

    Silva, Luiz Francisco Rocha e; Magalhães, Pedro Melillo de; Costa, Mônica Regina Farias; Alecrim, Maria das Graças Costa; Chaves, Francisco Célio Maia; Hidalgo, Ari de Freitas; Pohlit, Adrian Martin; Vieira, Pedro Paulo Ribeiro

    2012-11-01

    Artemisinin is the active antimalarial compound obtained from the leaves of Artemisia annua L. Artemisinin, and its semi-synthetic derivatives, are the main drugs used to treat multi-drug-resistant Plasmodium falciparum (one of the human malaria parasite species). The in vitro susceptibility of P. falciparum K1 and 3d7 strains and field isolates from the state of Amazonas, Brazil, to A. annua infusions (5 g dry leaves in 1 L of boiling water) and the drug standards chloroquine, quinine and artemisinin were evaluated. The A. annua used was cultivated in three Amazon ecosystems (várzea, terra preta de índio and terra firme) and in the city of Paulínia, state of São Paulo, Brazil. Artemisinin levels in the A. annua leaves used were 0.90-1.13% (m/m). The concentration of artemisinin in the infusions was 40-46 mg/L. Field P. falciparum isolates were resistant to chloroquine and sensitive to quinine and artemisinin. The average 50% inhibition concentration values for A. annua infusions against field isolates were 0.11-0.14 μL/mL (these infusions exhibited artemisinin concentrations of 4.7-5.6 ng/mL) and were active in vitro against P. falciparum due to their artemisinin concentration. No synergistic effect was observed for artemisinin in the infusions. PMID:23147140

  16. Intracellular insulin-receptor dissociation and segregation in a rat fibroblast cell line transfected with a human insulin receptor gene

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    Levy, J.R.; Olefsky, J.M.

    1988-05-05

    The cellular processing of insulin and insulin receptors was studied using a rat fibroblast cell line that had been transfected with a normal human insulin receptor gene, expressing approximately 500 times the normal number of native fibroblasts insulin receptors. These cells bind and internalize insulin normally. Biochemically assays based on the selective precipitation by polyethylene glycol of intact insulin-receptor complexes but not of free intracellular insulin were developed to study the time course of intracellular insulin-receptor dissociation. Fibroblasts were incubated with radiolabeled insulin at 4/sup 0/C, and internalization of insulin-receptor complexes was initiated by warming the cells to 37/sup 0/C. Within 2 min, 90% of the internalized radioactivity was composed of intact insulin-receptor complexes. The dissociation of insulin from internalized insulin-receptor complexes was markedly inhibited by monensin and chloroquine. Furthermore, chloroquine markedly increased the number of cross-linkable intracellular insulin-receptor complexes, as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiography. These findings suggest that acidification of intracellular vesicles is responsible for insulin-receptor dissociation. Physical segregation of dissociated intracellular insulin from its receptor was monitored. The results are consistent with the view that segregation of insulin and receptor occurs 5-10 min after initiation of dissociation. These studies demonstrate the intracellular itinerary of insulin-receptor complexes, including internalization, dissociation of insulin from the internalized receptor within an acidified compartment, segregation of insulin from the receptor, and subsequent ligand degradation.

  17. Intracellular insulin-receptor dissociation and segregation in a rat fibroblast cell line transfected with a human insulin receptor gene

    International Nuclear Information System (INIS)

    The cellular processing of insulin and insulin receptors was studied using a rat fibroblast cell line that had been transfected with a normal human insulin receptor gene, expressing approximately 500 times the normal number of native fibroblasts insulin receptors. These cells bind and internalize insulin normally. Biochemically assays based on the selective precipitation by polyethylene glycol of intact insulin-receptor complexes but not of free intracellular insulin were developed to study the time course of intracellular insulin-receptor dissociation. Fibroblasts were incubated with radiolabeled insulin at 40C, and internalization of insulin-receptor complexes was initiated by warming the cells to 370C. Within 2 min, 90% of the internalized radioactivity was composed of intact insulin-receptor complexes. The dissociation of insulin from internalized insulin-receptor complexes was markedly inhibited by monensin and chloroquine. Furthermore, chloroquine markedly increased the number of cross-linkable intracellular insulin-receptor complexes, as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiography. These findings suggest that acidification of intracellular vesicles is responsible for insulin-receptor dissociation. Physical segregation of dissociated intracellular insulin from its receptor was monitored. The results are consistent with the view that segregation of insulin and receptor occurs 5-10 min after initiation of dissociation. These studies demonstrate the intracellular itinerary of insulin-receptor complexes, including internalization, dissociation of insulin from the internalized receptor within an acidified compartment, segregation of insulin from the receptor, and subsequent ligand degradation

  18. Albumin-bound nanoparticles of practically water-insoluble antimalarial lead greatly enhance its efficacy.

    Science.gov (United States)

    Ibrahim, Nehal; Ibrahim, Hany; Dormoi, Jerome; Briolant, Sébastien; Pradines, Bruno; Moreno, Alicia; Mazier, Dominique; Legrand, Philippe; Nepveu, Françoise

    2014-04-10

    We recently showed that the indolone-N-oxides can be promising candidates for the treatment of chloroquine-resistant malaria. However, the in vivo assays have been hampered by the very poor aqueous solubility of these compounds resulting in poor and variable activity. Here, we describe the preparation, characterization and in vivo evaluation of biodegradable albumin-bound indolone-N-oxide nanoparticles. Nanoparticles were prepared by precipitation followed by high-pressure homogenization and characterized by photon correlation spectroscopy, transmission electron microscopy, differential scanning calorimetry and X-ray powder diffraction. The process was optimized to yield nanoparticles of controllable diameter with narrow size distribution suitable for intravenous administration, which guarantees direct drug contact with parasitized erythrocytes. Stable nanoparticles showed greatly enhanced dissolution rate (complete drug release within 30 min compared to 1.5% of pure drug) preserving the rapid antimalarial activity. The formulation achieved complete cure of Plasmodium berghei-infected mice at 25mg/kg with parasitemia inhibition (99.1%) comparable to that of artesunate and chloroquine and was remarkably more effective in prolonging survival time and inhibiting recrudescence. In 'humanized' mice infected with Plasmodium falciparum, the same dose proved to be highly effective: with parasitemia reduced by 97.5% and the mean survival time prolonged. This formulation can help advance the preclinical trials of indolone-N-oxides. Albumin-bound nanoparticles represent a new strategic approach to use this most abundant plasma protein to target malaria-infected erythrocytes.

  19. Naghibione; A Novel Sesquiterpenoid with Antiplasmodial Effect from Dorema hyrcanum Koso-Pol. Root, a Plant Used in Traditional Medicine.

    Science.gov (United States)

    Naghibi, Farzaneh; Ghafari, Saeedeh; Esmaeili, Somayeh; Jenett-Siems, Kristina

    2015-01-01

    Some Dorema species are used in Persian traditional medicine. In the present study the total extract from the roots of Dorema hyrcanum Koso-Pol. was investigated for its in-vitro (pLDH assay) and in-vivo (Peters' 4-days suppressive test) antiplasmodial effects and assessed for cytotoxicity against the normal cell line MDBK (MTT test). The IC50 values for a chloroquine- sensitive (3D7) and a chloroquine- resistant (K1) strain of Plasmodium falciparum were 28.64 and 9.79 µg/mL, respectively. The inhibition percentage of the rodent parasite, Plasmodium berghei, on day 4 in mice was 77.9% and IC50 value on Madin-Darby bovine kidney cells (MDBK cells) was 59.84 µg/mL. The total extract was subjected to a bioassay-guided fractionation protocol based on the in-vivo model which resulted in the isolation of an acetophenon (compound 1), one new sesquiterpenoid; naghibione (compound 2) and two known sesquiterpenoid derivatives (compounds 3, 4). Their structures were elucidated by spectroscopic analysis, including 1D and 2D NMR experiments and ESI-MS. All compounds were evaluated for in-vivo antiplasmodial effect and the results revealed that naghibione showed good suppression activity, inhibiting 68.1 % of the parasite growth.

  20. Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents

    Science.gov (United States)

    Vanden Eynde, Jean J.; Mayence, Annie; Mottamal, Madhusoodanan; Bacchi, Cyrus J.; Yarlett, Nigel; Kaiser, Marcel; Brun, Reto; Huang, Tien L.

    2016-01-01

    A series of 15 alkanediamide-linked bisbenzamidines and related analogs was synthesized and tested in vitro against two Trypanosoma brucei (T.b.) subspecies: T.b. brucei and T.b. rhodesiense, Trypanosoma cruzi, Leishmania donovani and two Plasmodium falciparum subspecies: a chloroquine-sensitive strain (NF54) and a chloroquine-resistant strain (K1). The in vitro cytotoxicity was determined against rat myoblast cells (L6). Seven compounds (5, 6, 10, 11, 12, 14, 15) showed high potency against both strains of T. brucei and P. falciparum with the inhibitory concentrations for 50% (IC50) in the nanomolar range (IC50 = 1–96 nM). None of the tested derivatives was significantly active against T. cruzi or L. donovani. Three of the more potent compounds (5, 6, 11) were evaluated in vivo in mice infected with the drug-sensitive (Lab 110 EATRO and KETRI 2002) or drug-resistant (KETRI 2538 and KETRI 1992) clinical isolates of T. brucei. Compounds 5 and 6 were highly effective in curing mice infected with the drug-sensitive strains, including a drug-resistant strain KETRI 2538, but were ineffective against KETRI 1992. Thermal melting of DNA and molecular modeling studies indicate AT-rich DNA sequences as possible binding sites for these compounds. Several of the tested compounds are suitable leads for the development of improved antiparasitic agents. PMID:27104545

  1. Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents

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    Jean J. Vanden Eynde

    2016-04-01

    Full Text Available A series of 15 alkanediamide-linked bisbenzamidines and related analogs was synthesized and tested in vitro against two Trypanosoma brucei (T.b. subspecies: T.b. brucei and T.b. rhodesiense, Trypanosoma cruzi, Leishmania donovani and two Plasmodium falciparum subspecies: a chloroquine-sensitive strain (NF54 and a chloroquine-resistant strain (K1. The in vitro cytotoxicity was determined against rat myoblast cells (L6. Seven compounds (5, 6, 10, 11, 12, 14, 15 showed high potency against both strains of T. brucei and P. falciparum with the inhibitory concentrations for 50% (IC50 in the nanomolar range (IC50 = 1–96 nM. None of the tested derivatives was significantly active against T. cruzi or L. donovani. Three of the more potent compounds (5, 6, 11 were evaluated in vivo in mice infected with the drug-sensitive (Lab 110 EATRO and KETRI 2002 or drug-resistant (KETRI 2538 and KETRI 1992 clinical isolates of T. brucei. Compounds 5 and 6 were highly effective in curing mice infected with the drug-sensitive strains, including a drug-resistant strain KETRI 2538, but were ineffective against KETRI 1992. Thermal melting of DNA and molecular modeling studies indicate AT-rich DNA sequences as possible binding sites for these compounds. Several of the tested compounds are suitable leads for the development of improved antiparasitic agents.

  2. In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum.

    Science.gov (United States)

    Cabrera, Mynthia; Cui, Liwang

    2015-12-01

    Currently, the World Health Organization recommends addition of a 0.25-mg base/kg single dose of primaquine (PQ) to artemisinin combination therapies (ACTs) for Plasmodium falciparum malaria as a gametocytocidal agent for reducing transmission. Here, we investigated the potential interactions of PQ with the long-lasting components of the ACT drugs for eliminating the asexual blood stages and gametocytes of in vitro-cultured P. falciparum strains. Using the SYBR green I assay for asexual parasites and a flow cytometry-based assay for gametocytes, we determined the interactions of PQ with the schizonticides chloroquine, mefloquine, piperaquine, lumefantrine, and naphthoquine. With the sums of fractional inhibitory concentrations and isobolograms, we were able to determine mostly synergistic interactions for the various PQ and schizonticide combinations on the blood stages of P. falciparum laboratory strains. The synergism in inhibiting asexual stages and gametocytes was highly evident with PQ-naphthoquine, whereas synergism was moderate for the PQ-piperaquine, PQ-chloroquine, and PQ-mefloquine combinations. We have detected potentially antagonistic interactions between PQ and lumefantrine under certain drug combination ratios, suggesting that precautions might be needed when PQ is added as the gametocytocide to the artemether-lumefantrine ACT (Coartem). PMID:26416869

  3. Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents.

    Science.gov (United States)

    Vanden Eynde, Jean J; Mayence, Annie; Mottamal, Madhusoodanan; Bacchi, Cyrus J; Yarlett, Nigel; Kaiser, Marcel; Brun, Reto; Huang, Tien L

    2016-01-01

    A series of 15 alkanediamide-linked bisbenzamidines and related analogs was synthesized and tested in vitro against two Trypanosoma brucei (T.b.) subspecies: T.b. brucei and T.b. rhodesiense, Trypanosoma cruzi, Leishmania donovani and two Plasmodium falciparum subspecies: a chloroquine-sensitive strain (NF54) and a chloroquine-resistant strain (K1). The in vitro cytotoxicity was determined against rat myoblast cells (L6). Seven compounds (5, 6, 10, 11, 12, 14, 15) showed high potency against both strains of T. brucei and P. falciparum with the inhibitory concentrations for 50% (IC50) in the nanomolar range (IC50 = 1-96 nM). None of the tested derivatives was significantly active against T. cruzi or L. donovani. Three of the more potent compounds (5, 6, 11) were evaluated in vivo in mice infected with the drug-sensitive (Lab 110 EATRO and KETRI 2002) or drug-resistant (KETRI 2538 and KETRI 1992) clinical isolates of T. brucei. Compounds 5 and 6 were highly effective in curing mice infected with the drug-sensitive strains, including a drug-resistant strain KETRI 2538, but were ineffective against KETRI 1992. Thermal melting of DNA and molecular modeling studies indicate AT-rich DNA sequences as possible binding sites for these compounds. Several of the tested compounds are suitable leads for the development of improved antiparasitic agents. PMID:27104545

  4. Synthesis and Antiplasmodial Activity of 2-(4-Methoxyphenyl-4-Phenyl-1,10-Phenanthroline Derivative Compounds

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    Nazudin

    2012-08-01

    Full Text Available A unique of synthetic methods was employed to prepare 2-(4-methoxyphenyl-4-phenyl-1,10-phenanthroline (5 derivatives from 4-methoxy-benzaldehyde (1, acetophenone (2, and 8-aminoquinoline (4 with aldol condensation and cyclization reactions. The derivatives were tested through antiplasmodial test. The synthesis of derivatives compound 5 was conducted in three steps. The 3-(4-methoxyphenyl-1-phenylpropenone 3 was synthesized through aldol condensation of 1 and 2 which has a yield of 96.42%. The compound 5 was synthesized through cyclization of compound 4 and 3 with 84.55% yield. The derivative of compound 5 was synthesized from compound 5 using DMS and DES reagents which refluxed for 21 and 22 h, to produce (1-N-methyl-9-(4-methoxyphenyl-7-phenyl-1,10-phenanthrolinium sulfate (6 and (1-N-ethyl-9-(4-methoxyphenyl-7-phenyl-1,10-phenanthrolinium sulfate (7 with 91.42 and 86.36% yields, respectively. Results of in vitro testing of antiplasmodial activity of compound 5 derivatives (i.e., compound 6 and 7 against chloroquine-resistant P. falciparum FCR3 strain showed that compound 7 had higher antimalarial activity than compounds 5 and 6. Whereas, results of in vitro testing against chloroquine-sensitive P. falciparum D10 strain showed that compound 6 has higher antimalarial activity than compounds 5 and 7.

  5. Identification and deconvolution of cross-resistance signals from antimalarial compounds using multidrug-resistant Plasmodium falciparum strains.

    Science.gov (United States)

    Chugh, Monika; Scheurer, Christian; Sax, Sibylle; Bilsland, Elizabeth; van Schalkwyk, Donelly A; Wicht, Kathryn J; Hofmann, Natalie; Sharma, Anil; Bashyam, Sridevi; Singh, Shivendra; Oliver, Stephen G; Egan, Timothy J; Malhotra, Pawan; Sutherland, Colin J; Beck, Hans-Peter; Wittlin, Sergio; Spangenberg, Thomas; Ding, Xavier C

    2015-02-01

    Plasmodium falciparum, the most deadly agent of malaria, displays a wide variety of resistance mechanisms in the field. The ability of antimalarial compounds in development to overcome these must therefore be carefully evaluated to ensure uncompromised activity against real-life parasites. We report here on the selection and phenotypic as well as genotypic characterization of a panel of sensitive and multidrug-resistant P. falciparum strains that can be used to optimally identify and deconvolute the cross-resistance signals from an extended panel of investigational antimalarials. As a case study, the effectiveness of the selected panel of strains was demonstrated using the 1,2,4-oxadiazole series, a newly identified antimalarial series of compounds with in vitro activity against P. falciparum at nanomolar concentrations. This series of compounds was to be found inactive against several multidrug-resistant strains, and the deconvolution of this signal implicated pfcrt, the genetic determinant of chloroquine resistance. Targeted mode-of-action studies further suggested that this new chemical series might act as falcipain 2 inhibitors, substantiating the suggestion that these compounds have a site of action similar to that of chloroquine but a distinct mode of action. New antimalarials must overcome existing resistance and, ideally, prevent its de novo appearance. The panel of strains reported here, which includes recently collected as well as standard laboratory-adapted field isolates, is able to efficiently detect and precisely characterize cross-resistance and, as such, can contribute to the faster development of new, effective antimalarial drugs.

  6. 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.

  7. Assessment of Plasmodium falciparum resistance to ferroquine (SSR97193 in field isolates and in W2 strain under pressure

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    Pradines Bruno

    2006-02-01

    Full Text Available Abstract Background Ferroquine (FQ, or SSR97193, is a novel antimalarial drug currently in phase I clinical trials. FQ is a unique organometallic compound designed to overcome the chloroquine (CQ resistance problem. FQ revealed to be equally active on CQ-sensitive and CQ-resistant Plasmodium falciparum laboratory strains and field isolates. FQ is also curative on rodent malaria parasites. As FQ will be tested in patients, the potential for resistance to this drug was evaluated. Methods The relationship between CQ-resistant transporter gene genotype and susceptibility to FQ were studied in 33 Cambodian P. falciparum field isolates previously studied for their in vitro response to CQ. In parallel, the ability of the CQ-resistant strain W2, to become resistant to FQ under drug pressure was assessed. Results The IC50 values for FQ in field isolates were found to be unrelated to mutations occurring in the P. falciparum chloroquine resistance transporter (PfCRT or to the level of expression of the corresponding mRNA. In vitro, under a drug pressure of 100 nM of FQ, transient survival was observed in only one of two experiments. Conclusion Field isolates studies and experimental drug pressure experiments showed that FQ overcomes CQ resistance, which reinforces the potential of this compound as a new antimalarial drug.

  8. Antiplasmodial and Cytotoxic Activities of Toad Venoms from Southern Amazon, Brazil

    Science.gov (United States)

    Banfi, Felipe Finger; Guedes, Karla de Sena; Andrighetti, Carla Regina; Aguiar, Ana Carolina; Debiasi, Bryan Wender; Noronha, Janaina da Costa; Rodrigues, Domingos de Jesus; Júnior, Gerardo Magela Vieira; Sanchez, Bruno Antonio Marinho

    2016-01-01

    The drug-resistance of malaria parasites is the main problem in the disease control. The huge Brazilian biodiversity promotes the search for new compounds, where the animal kingdom is proving to be a promising source of bioactive compounds. The main objective of this study was to evaluate the antiplasmodial and cytotoxic activity of the compounds obtained from the toad venoms of Brazilian Amazon. Toad venoms were collected from the secretion of Rhinella marina and Rhaebo guttatus in Mato Grosso State, Brazil. The powder was extracted at room temperature, yielding 2 extracts (RG and RM) and a substance (‘1’) identified as a bufadienolide, named telocinobufagin. Growth inhibition, intraerythrocytic development, and parasite morphology were evaluated in culture by microscopic observations of Giemsa-stained thin blood films. Cytotoxicity was determined against HepG2 and BGM cells by MTT and neutral red assays. The 2 extracts and the pure substance (‘1’) tested were active against chloroquine-resistant Plasmodium falciparum strain, demonstrating lower IC50 values. In cytotoxic tests, the 2 extracts and substance ‘1’ showed pronounced lethal effects on chloroquine-resistant P. faciparum strain and low cytotoxic effect, highlighting toad parotoid gland secretions as a promising source of novel lead antiplasmodial compounds. PMID:27658592

  9. Effect of Farnesyltransferase Inhibitor R115777 on Mitochondria of Plasmodium falciparum.

    Science.gov (United States)

    Ha, Young Ran; Hwang, Bae-Geun; Hong, Yeonchul; Yang, Hye-Won; Lee, Sang Joon

    2015-08-01

    The parasite Plasmodium falciparum causes severe malaria and is the most dangerous to humans. However, it exhibits resistance to their drugs. Farnesyltransferase has been identified in pathogenic protozoa of the genera Plasmodium and the target of farnesyltransferase includes Ras family. Therefore, the inhibition of farnesyltransferase has been suggested as a new strategy for the treatment of malaria. However, the exact functional mechanism of this agent is still unknown. In addition, the effect of farnesyltransferase inhibitor (FTIs) on mitochondrial level of malaria parasites is not fully understood. In this study, therefore, the effect of a FTI R115777 on the function of mitochondria of P. falciparum was investigated experimentally. As a result, FTI R115777 was found to suppress the infection rate of malaria parasites under in vitro condition. It also reduces the copy number of mtDNA-encoded cytochrome c oxidase III. In addition, the mitochondrial membrane potential (ΔΨm) and the green fluorescence intensity of MitoTracker were decreased by FTI R115777. Chloroquine and atovaquone were measured by the mtDNA copy number as mitochondrial non-specific or specific inhibitor, respectively. Chloroquine did not affect the copy number of mtDNA-encoded cytochrome c oxidase III, while atovaquone induced to change the mtDNA copy number. These results suggest that FTI R115777 has strong influence on the mitochondrial function of P. falciparum. It may have therapeutic potential for malaria by targeting the mitochondria of parasites.

  10. Antimalarial activity of cedronin.

    Science.gov (United States)

    Moretti, C; Deharo, E; Sauvain, M; Jardel, C; David, P T; Gasquet, M

    1994-06-01

    Cedronin was isolated from Simaba cedron Planchon (Simaroubaceae), a species popularly believed in South America to have antimalarial properties. It was examined for in vitro and in vivo antimalarial activities and for cytotoxicity against KB cells. Experimental results showed that cedronin was active against chloroquine-sensitive and resistant strain, with an IC50 of 0.25 micrograms/ml (0.65 mumol/ml). It was also found to be active in vivo against Plasmodium vinkei with an IC50 of 1.8 mg/kg (4.7 nM/kg) in the classic 4-day test. Cedronin belongs to the small group of quassinoids with a C19 basic skeleton and shows a rather low cytotoxicity against KB cells (IC50 = 4 micrograms/ml, 10.4 microM) as compared with C20 biologically active quassinoids; however its toxic/therapeutic ratio (10/1.8) remains lower than chloroquine (10/0.5).

  11. Do health care providers adhere to the revised malaria control guidelines? '

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    Sujoy Ray

    2011-10-01

    Full Text Available Introduction: Malaria is a public health problem worldwide with India contributing to 77% cases in the South East Asian region of World Health Organization (WHO. Karnataka is one of the project states under World Bank with API>2. Statistics from the district of Udupi, which is the setting for this study, shows a rise in malaria cases from January-May 2009. There were a total of 1189 malaria cases reported of which 103 were positive for P. falciparum. The National Programme to control malaria has recently revised its strategies, thus involved personnel need to be aware of it for the programme to be effective.Objectives: Keeping in mind the emergence of Choloroquine resistant malaria, The National Malaria Control Programme has revised its strategy. This cross-sectional study was conducted to assess the awareness and practice of National Guidelines for malaria among health care providers in Urban Udupi, Karnataka (which is one of the project states under the World Bank for malaria control and the problems in implementation of these guidelines.Settings and design: Cross sectional study, Udupi district.Methods: Data was collected by personal interview (structured questionnaire after obtaining due consent.Statistical analysis used: Data was analyzed by SPSS software.ObservationsResults: Most respondents were from both Manipal and Udupi and had been practicing for over 5 years. Chills and headache were used as main guiding symptoms for diagnosis, all insisted on lab diagnosis with QBC being the most preferred test followed by smear. Cases were treated on pure clinical diagnosis in case of typical signs, unresponsiveness to other therapy, unwillingness or non-affordability of tests. Both species of Plasmodium were prevalent, Chloroquine being first line treatment for P. Vivax and Artemisinin compounds for Falciparum. Clinical failure was encountered against Falciparum due to chloroquine resistance and quinine was mainly used to combat it. Medical

  12. Genotyping of Plasmodium falciparum using antigenic polymorphic markers and to study anti-malarial drug resistance markers in malaria endemic areas of Bangladesh

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    Akter Jasmin

    2012-11-01

    Full Text Available Abstract Background In the past many regions of Bangladesh were hyperendemic for malaria. Malaria control in the 1960s to 1970s eliminated malaria from the plains but in the Chittagong Hill Tracts remained a difficult to control reservoir. The Chittagong Hill Tracts have areas with between 1 and 10% annual malaria rates, predominately 90-95% Plasmodium falciparum. In Southeast Asia, multiplicity of infection for hypo-endemic regions has been approximately 1.5. Few studies on the genetic diversity of P. falciparum have been performed in Bangladesh. Anderson et al. performed a study in Khagrachari, northern Chittagong Hill Tracts in 2002 on 203 patients and found that parasites had a multiplicity of infection of 1.3 by MSP-1, MSP-2 and GLURP genotyping. A total of 94% of the isolates had the K76T Pfcrt chloroquine resistant genotype, and 70% showed the N86Y Pfmdr1 genotype. Antifolate drug resistant genotypes were high with 99% and 73% of parasites having two or more mutations at the dhfr or dhps loci. Methods Nested and real-time polymerase chain reaction (PCR methods were used to genotype P. falciparum using antigenic polymorphic markers and to study anti-malarial drug resistance markers in malaria endemic areas of Bangladesh. Results The analysis of polymorphic and drug resistant genotype on 33 paired recrudescent infections after drug treatment in the period 2004 to 2008 in the Chittagong Hill Tracts, which is just prior to countrywide provision of artemisinin combination therapy. Overall the multiplicity of infection for MSP-1 was 2.7 with a slightly smaller parasite diversity post-treatment. The 13 monoclonal infections by both GLURP and MSP-1 were evenly divided between pre- and post-treatment. The MSP-1 MAD block was most frequent in 66 of the samples. The prevalence of the K76T PfCRT chloroquine resistant allele was approximately 82% of the samples, while the resistant Pfmdr1 N86Y was present in 33% of the samples. Interestingly, the post

  13. Altered regulation of Akt signaling with murine cerebral malaria, effects on long-term neuro-cognitive function, restoration with lithium treatment.

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    Minxian Dai

    Full Text Available Neurological and cognitive impairment persist in more than 20% of cerebral malaria (CM patients long after successful anti-parasitic treatment. We recently reported that long term memory and motor coordination deficits are also present in our experimental cerebral malaria model (ECM. We also documented, in a murine model, a lack of obvious pathology or inflammation after parasite elimination, suggesting that the long-term negative neurological outcomes result from potentially reversible biochemical and physiological changes in brains of ECM mice, subsequent to acute ischemic and inflammatory processes. Here, we demonstrate for the first time that acute ECM results in significantly reduced activation of protein kinase B (PKB or Akt leading to decreased Akt phosphorylation and inhibition of the glycogen kinase synthase (GSK3β in the brains of mice infected with Plasmodium berghei ANKA (PbA compared to uninfected controls and to mice infected with the non-neurotrophic P. berghei NK65 (PbN. Though Akt activation improved to control levels after chloroquine treatment in PbA-infected mice, the addition of lithium chloride, a compound which inhibits GSK3β activity and stimulates Akt activation, induced a modest, but significant activation of Akt in the brains of infected mice when compared to uninfected controls treated with chloroquine with and without lithium. In addition, lithium significantly reversed the long-term spatial and visual memory impairment as well as the motor coordination deficits which persisted after successful anti-parasitic treatment. GSK3β inhibition was significantly increased after chloroquine treatment, both in lithium and non-lithium treated PbA-infected mice. These data indicate that acute ECM is associated with abnormalities in cell survival pathways that result in neuronal damage. Regulation of Akt/GSK3β with lithium reduces neuronal degeneration and may have neuroprotective effects in ECM. Aberrant regulation of Akt

  14. Synthesis and evaluation of the antiplasmodial activity of tryptanthrin derivatives

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    Liliane Abodo Onambele

    2015-08-01

    Full Text Available Malaria remains one of the most deadly diseases threatening humankind and is still affecting a significant proportion of the world population, especially in Africa. Chemotherapy is a vital component of the fight against the disease and new antimalarial agents are urgently needed to curb the spread of malaria parasites that are resistant to existing drugs. The natural product tryptanthrin is known for its wide range of activities, including antiplasmodial activity, but its poor solubility has undermined its development as potent antimicrobial and antiprotozoan agent. The aim of this work was to synthesize analogues of tryptanthrin and to evaluate their antiplasmodial activity against the asexual and sexual blood stages of Plasmodium falciparum. Our results suggest that most tryptanthrin analogues retained their antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant malaria parasites in the nanomolar range (30–100 nM. The antiplasmodial activity of the most active compound NT1 (IC50: 30 nM; SI: 155.9 was similar in both strains and close to that of chloroquine (IC50: 20 nM on the sensitive strain. The antiplasmodial activity was improved with derivatization, thus pointing out the necessity to explore tryptanthrin using medicinal chemistry approaches. Ten (10 of the tested derivatives met the criteria, allowing for advancement to animal testing, i.e., SI > 100 and IC50 < 100 nM. In addition to their activity on the asexual stages, tryptanthrin and two selected derivatives (NT1 and T8 prevented the maturation of gametocytes at their IC90 concentrations, indicating a transmission-blocking potential. Moreover, NT1 was able to impair gametogenesis by reducing the exflagellation of microgametes by 20% at IC90, while tryptanthrin and T8 had no influence on exflagellation. The results of this study confirm that tryptanthrin and its derivatives are potential antimalarial candidates with abilities to kill the

  15. 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

  16. 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

  17. Antiplasmodial benzophenone derivatives from the root barks of Symphonia globulifera (Clusiaceae).

    Science.gov (United States)

    Marti, Guillaume; Eparvier, Véronique; Moretti, Christian; Prado, Soizic; Grellier, Philippe; Hue, Nathalie; Thoison, Odile; Delpech, Bernard; Guéritte, Françoise; Litaudon, Marc

    2010-06-01

    In an effort to find antimalarial drugs, a systematic in vitro evaluation on a chloroquine-resistant strain of Plasmodium falciparum (FcB1) was undertaken on sixty plant extracts collected in French Guiana. The ethyl acetate extract obtained from the root barks of Symphonia globulifera exhibited a strong antiplasmodial activity (97% at 10 microg/ml). The phytochemical investigation of this extract led to the isolation of nine polycyclic polyprenylated acylphloroglucinol (PPAPs) compounds and two oxidized derivatives. All compounds showed antiplasmodial activity with IC(50)s ranged from 2.1 to 10.1 microM. A LC/ESI-MS(n) study performed on polyprenylated benzophenones previously isolated from Moronobea coccinea provided a reliable method for their detection in the extract and structural elucidation. PMID:20356612

  18. Review: Malaria chemoprophylaxis for travelers to Latin America.

    Science.gov (United States)

    Steinhardt, Laura C; Magill, Alan J; Arguin, Paul M

    2011-12-01

    Because of recent declining malaria transmission in Latin America, some authorities have recommended against chemoprophylaxis for most travelers to this region. However, the predominant parasite species in Latin America, Plasmodium vivax, can form hypnozoites sequestered in the liver, causing malaria relapses. Additionally, new evidence shows the potential severity of vivax infections, warranting continued consideration of prophylaxis for travel to Latin America. Individualized travel risk assessments are recommended and should consider travel locations, type, length, and season, as well as probability of itinerary changes. Travel recommendations might include no precautions, mosquito avoidance only, or mosquito avoidance and chemoprophylaxis. There are a range of good options for chemoprophylaxis in Latin America, including atovaquone-proguanil, doxycycline, mefloquine, and--in selected areas--chloroquine. Primaquine should be strongly considered for nonpregnant, G6PD-nondeficient patients traveling to vivax-endemic areas of Latin America, and it has the added benefit of being the only drug to protect against malaria relapses.

  19. [Epidemiology and prevention of malaria in the southwestern islands of the Indian Ocean].

    Science.gov (United States)

    Tchen, J; Ouledi, A; Lepère, J F; Ferrandiz, D; Yvin, J L

    2006-06-01

    Malaria epidemiology differs greatly in the geographically close islands of the southwestern Indian Ocean. In Madagascar and the Comoros Union malaria is still a major public health problem. In Mayotte indigenous transmission resumed in 1995 and is currently high in some communities. In the Mascarene Islands (Reunion and Mauritius), indigenous transmission has been eradicated (Reunion) or become rare (Mauritius). The Seychelles Islands are malaria-free since local conditions are unfavorable for Anopheles mosquitoes. The level of resistance to antimalarials also differs from one island to another. Resistance to chloroquine ranges from moderate in Madagascar to high in the Comoros Union. Health recommendations for travelers must be adapted to the epidemiological features on each island. PMID:16924826

  20. Modification of solid phase red cell adherence assay for the detection of platelet antibodies in patients with thrombocytopenia.

    Science.gov (United States)

    Vongchan, Preeyanat; Nawarawong, Weerasak; Linhardt, Robert J

    2008-09-01

    Platelet refractoriness is caused by HLA antibodies and platelet-specific antibodies. Current methods used to detect antiplatelet antibodies have limitations. Solid phase red cell adherence (SPRCA) lacks sensitivity and requires a second assay using chloroquine-treated intact platelets to specify the response due to anti-HLA. We modified SPRCA by using 2 types of antihuman platelet antibodies with different specificities toward platelet lysate and tested samples from 361 patients (69 with unexplained thrombocytopenia and 292 with poor response to platelet transfusions not explicable by alloimmunization or the clinical situation) and 50 from healthy volunteers. Our method compared favorably with platelet suspension direct immunofluorescence. All samples from healthy volunteers were negative; of the samples from the patient population, 240 were positive (147 samples had only antiplatelet and 3 samples had only anti-HLA antibodies). This modified technique had a sensitivity of 98% and a specificity of 91%.

  1. [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.

  2. 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.

  3. Site-specific genome editing in Plasmodium falciparum using engineered zinc-finger nucleases.

    Science.gov (United States)

    Straimer, Judith; Lee, Marcus C S; Lee, Andrew H; Zeitler, Bryan; Williams, April E; Pearl, Jocelynn R; Zhang, Lei; Rebar, Edward J; Gregory, Philip D; Llinás, Manuel; Urnov, Fyodor D; Fidock, David A

    2012-10-01

    Malaria afflicts over 200 million people worldwide, and its most lethal etiologic agent, Plasmodium falciparum, is evolving to resist even the latest-generation therapeutics. Efficient tools for genome-directed investigations of P. falciparum-induced pathogenesis, including drug-resistance mechanisms, are clearly required. Here we report rapid and targeted genetic engineering of this parasite using zinc-finger nucleases (ZFNs) that produce a double-strand break in a user-defined locus and trigger homology-directed repair. Targeting an integrated egfp locus, we obtained gene-deletion parasites with unprecedented speed (2 weeks), both with and without direct selection. ZFNs engineered against the parasite gene pfcrt, responsible for escape under chloroquine treatment, rapidly produced parasites that carried either an allelic replacement or a panel of specified point mutations. This method will enable a diverse array of genome-editing approaches to interrogate this human pathogen.

  4. A short history of anti-rheumatic therapy - VI. Rheumatoid arthritis drugs

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    G. Pasero

    2011-09-01

    Full Text Available The treatment of rheumatoid arthritis traditionally includes symptomatic drugs, showing a prompt action on pain and infl ammation, but without any infl uence on disease progression, and other drugs that could modify the disease course and occasionally induce clinical remission (DMARDs or disease modifying anti-rheumatic drugs. This review describes the historical steps that led to the use of the main DMARDs in rheumatoid arthritis, such as gold salts, sulphasalazine, chloroquine and hydroxychloroquine, D-penicillamine, and other immunoactive drugs, including methotrexate, azathioprine, cyclosporin and lefl unomide. The historical evolution of use of these drugs is then discussed, including the strategy of progressive (“therapeutic pyramid” or of more aggressive treatment, through the simultaneous use of two or more DMARDs (“combination therapy”.

  5. Targeting autophagy to sensitive glioma to temozolomide treatment.

    Science.gov (United States)

    Yan, Yuanliang; Xu, Zhijie; Dai, Shuang; Qian, Long; Sun, Lunquan; Gong, Zhicheng

    2016-02-02

    Temozolomide (TMZ), an alkylating agent, is widely used for treating primary and recurrent high-grade gliomas. However, the efficacy of TMZ is often limited by the development of resistance. Recently, studies have found that TMZ treatment could induce autophagy, which contributes to therapy resistance in glioma. To enhance the benefit of TMZ in the treatment of glioblastomas, effective combination strategies are needed to sensitize glioblastoma cells to TMZ. In this regard, as autophagy could promote cell survival or autophagic cell death, modulating autophagy using a pharmacological inhibitor, such as chloroquine, or an inducer, such as rapamycin, has received considerably more attention. To understand the effectiveness of regulating autophagy in glioblastoma treatment, this review summarizes reports on glioblastoma treatments with TMZ and autophagic modulators from in vitro and in vivo studies, as well as clinical trials. Additionally, we discuss the possibility of using autophagy regulatory compounds that can sensitive TMZ treatment as a chemotherapy for glioma treatment.

  6. Highly active ozonides selected against drug resistant malaria

    Science.gov (United States)

    Lobo, Lis; de Sousa, Bruno; Cabral, Lília; Cristiano, Maria LS; Nogueira, Fátima

    2016-01-01

    Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites. PMID:27276364

  7. The effects of DNA intercalators on chromatin of chicken red blood cells——differential extraction on nonhistone proteins

    Institute of Scientific and Technical Information of China (English)

    WangFan; ZhuJingde

    1990-01-01

    Taking advantage of the effects on DNA secondary structure of two DNA-intercalators,ethidium bromide and chloroquine,we used each of them to treat nuclei from both mature erythrocytes and reticulocytes of chicken,as an alternative approach to study the relationships between DNA secondary structure,nuclear proteins and chromatin structure.We presented results of differential extraction of nuclear proteins from nuclei with DNA-intercalators,as well as preliminary characterization of these proteins.A 45kd protein is the major component in fractions extracted by both intercalators from nuclei from either mature erythrocytes or reticulocytes and seems to be a DNA-binding protein.Furthermore,from current concepts of functional aspects of DNA conformation and structural heterogeneity in chromatin and nuclear proteins,we have discussed both the significance of our results as well as technical aspects of this approach.

  8. Internalization, lysosomal degradation and new synthesis of surface membrane CD4 in phorbol ester-activated T-lymphocytes and U-937 cells

    DEFF Research Database (Denmark)

    Petersen, C M; Christensen, E I; Andresen, B S;

    1992-01-01

    degradation was low in resting cells. Endocytosis and/or degradation of anti-CD4 mAb was suppressed by H7, and by inhibitors of membrane traffic (Monensin) and lysosome function (methylamine, chloroquine). Immunocytochemistry localized CD4 to the surface of unstimulated T-cells. Upon PMA stimulation...... occasional labeling was seen in endosomes but whole cell CD4 decreased dramatically. However, methylamine-treated PMA blasts showed accumulation of CD4 in lysosomes and accordingly, pulse-chase experiments in biolabeled cell cultures suggested a manifest reduction of CD4 half-life in response to PMA. Despite...... lysosomal degradation of membrane CD4. Transport of CD4 to the cell surface and CD4 synthesis is unaffected by activation....

  9. The efficacy of artemether in the treatment of Plasmodium falciparum malaria in Sudan

    DEFF Research Database (Denmark)

    Elhassan, I M; Satti, G H; Ali, A E;

    1994-01-01

    The efficacy of artemether (a qinghaosu derivative) administered intramuscularly for the treatment of Plasmodium falciparum malaria was compared to quinine in an open randomized trial including 54 patients in eastern Sudan, where chloroquine resistance is common. The artemether treatment (5 d...... intramuscular regimen) was effective and the drug was well tolerated. All patients had cleared the parasitaemia and were free of symptoms 48 h after initiation of treatment. The parasite clearance time was comparable in patients receiving artemether and quinine. No side effect was reported by patients receiving...... artemether. No recrudescence was seen in 21 patients treated with artemether who completed 28 d follow-up. In the quinine group 3 of 18 patients had recrudescences, or possibly reinfections, on days 14, 21 and 28....

  10. In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

    Directory of Open Access Journals (Sweden)

    Valter F de Andrade-Neto

    2007-06-01

    Full Text Available In the present study, a quassinoid, neosergeolide, isolated from the roots and stems of Picrolemma sprucei (Simaroubaceae, the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and A. desmanthum (Apocynaceae, respectively, and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae, all presented significant in vitro inhibition (more active than quinine and chloroquine of the multi-drug resistant K1 strain of Plasmodium falciparum. Neosergeolide presented activity in the nanomolar range. This is the first report on the antimalarial activity of these known, natural compounds. This is also the first report on the isolation of aspidocarpine from A. desmanthum. These compounds are good candidates for pre-clinical tests as novel lead structures with the aim of finding new antimalarial prototypes and lend support to the traditional use of the plants from which these compounds are derived.

  11. Quinine conjugates and quinine analogues as potential antimalarial agents.

    Science.gov (United States)

    Jones, Rachel A; Panda, Siva S; Hall, C Dennis

    2015-06-01

    Malaria is a tropical disease, prevalent in Southeast Asia and Africa, resulting in over half a million deaths annually; efforts to develop new antimalarial agents are therefore particularly important. Quinine continues to play a role in the fight against malaria, but quinoline derivatives are more widely used. Drugs based on the quinoline scaffold include chloroquine and primaquine, which are able to act against the blood and liver stages of the parasite's life cycle. The purpose of this review is to discuss reported biologically active compounds based on either the quinine or quinoline scaffold that may have enhanced antimalarial activity. The review emphasises hybrid molecules, and covers advances made in the last five years. The review is divided into three sections: modifications to the quinine scaffold, modifications to aminoquinolines and finally metal-containing antimalarial compounds.

  12. Dermatological medication effects on male fertility.

    Science.gov (United States)

    Millsop, Jillian Wong; Heller, Misha M; Eliason, Mark J; Murase, Jenny E

    2013-01-01

    Many drugs have been reported to impair semen parameters, leading to temporary or persistent infertility. Therefore, potential fathers may be concerned about the effect of medications on fertility. We searched the MEDLINE database of articles in English combining key terms including "male infertility," "spermatogenesis," "fertility," "drug effects," and "dermatology." Administration of methotrexate and finasteride has resulted in severe oligospermia and reversible infertility. Ketoconazole has had negative effects on sperm motility and testosterone production. Few individual case reports and a limited number of studies have demonstrated negative effects of tetracyclines, erythromycin, chloroquine, glucocorticoids, spironolactone, and antihistamines on fertility. It is important to counsel male patients when appropriate about the reversible negative effect on fertility when taking methotrexate and finasteride, and the adverse effect of ketoconazole. Patients may be reassured that taking oral retinoids, cyclosporine, azathioprine, and tumor necrosis factor alpha inhibitors should not affect their fertility. PMID:23914891

  13. The Expanding Role of NMR in Drug Discovery and Development

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    @@ The role of NMR in the pharmaceutical industry has changed dramatically over the last decade. Once thought of as an analytical technique used primarily to support synthetic chemistry, NMR now has an important role in the investigation of biochemical changes involved in clinical diseases and drug toxicity. It is also used extensively to elucidate the structures of drug metabolites. Data obtained using LC NMR MS and 19F NMR will be used to illustrate the utility of hyphenated methods in identifying xenobiotic metabolites as part of a drug development program. The application of NMR to the study of potential drug toxicity will also be described using the cationic, amphiphilic drugs chloroquine and amiodarone. These drugs are known to induce phospholipidosis characterized by lysosomal lamellar bodies and drug accumulation. Using a metabonomic approach, NMR spectroscopy of urine allowed the identification of a combination of urinary biomarkers of phospholipidosis.

  14. Complex Membrane Channel Blockade: A Unifying Hypothesis for the Prodromal and Acute Neuropsychiatric Sequelae Resulting from Exposure to the Antimalarial Drug Mefloquine

    Directory of Open Access Journals (Sweden)

    Jane C. Quinn

    2015-01-01

    Full Text Available The alkaloid toxin quinine and its derivative compounds have been used for many centuries as effective medications for the prevention and treatment of malaria. More recently, synthetic derivatives, such as the quinoline derivative mefloquine (bis(trifluoromethyl-(2-piperidyl-4-quinolinemethanol, have been widely used to combat disease caused by chloroquine-resistant strains of the malaria parasite, Plasmodium falciparum. However, the parent compound quinine, as well as its more recent counterparts, suffers from an incidence of adverse neuropsychiatric side effects ranging from mild mood disturbances and anxiety to hallucinations, seizures, and psychosis. This review considers how the pharmacology, cellular neurobiology, and membrane channel kinetics of mefloquine could lead to the significant and sometimes life-threatening neurotoxicity associated with mefloquine exposure. A key role for mefloquine blockade of ATP-sensitive potassium channels and connexins in the substantia nigra is considered as a unifying hypothesis for the pathogenesis of severe neuropsychiatric events after mefloquine exposure in humans.

  15. [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. PMID:11640680

  16. In vivo and in vitro antiplasmodial activities of some plants traditionally used in Guatemala against malaria.

    Science.gov (United States)

    Franssen, F F; Smeijsters, L J; Berger, I; Medinilla Aldana, B E

    1997-07-01

    We present an evaluation of the antiplasmodial and cytotoxic effects of four plants commonly used in Guatemalan folk medicine against malaria. Methanol extracts of Simarouba glauca D. C., Sansevieria guineensis Willd, Croton guatemalensis Lotsy, and Neurolaena lobata (L.)R.Br. significantly reduced parasitemias in Plasmodium berghei-infected mice. Dichloromethane fractions were screened for their cytotoxicities on Artemia salina (brine shrimp) larvae, and 50% inhibitory concentrations were determined for Plasmodium falciparum in in vitro cultures. Both chloroquine-susceptible and -resistant strains of P. falciparum were significantly inhibited by these extracts. Of all dichloromethane extracts, only the S. glauca cortex extract was considered to be toxic to nauplii of A. salina in the brine shrimp test. PMID:9210673

  17. Toxicidad ocular medicamentosa Ocular toxicity induced by medication

    Directory of Open Access Journals (Sweden)

    A. Garralda

    2008-01-01

    Full Text Available En el presente trabajo se analiza la toxicidad ocular inducida por cuatro grupos de fármacos sistémicos: tamoxifeno, cloroquina y derivados, anticolinérgicos y tamsulosina. El objetivo principal es dar unas normas prácticas que sirvan para el manejo diario de los pacientes sometidos a estos tratamientos, más que profundizar en los mecanismos de acción de cada uno de ellos.This paper analyses ocular toxicity induced by four groups of systemic medicines: tamoxifen, chloroquine and derivatives, anticholinergics and tamsulosin. Our main aim is to provide some practical rules that will be of use in the everyday management of patients receiving these treatments, rather than to examine the mechanisms by which each of these medicines act.

  18. Chemical Inhibition of Autophagy

    DEFF Research Database (Denmark)

    Baek, Eric; Lin Kim, Che; Gyeom Kim, Mi;

    2016-01-01

    Chinese hamster ovary (CHO) cells activate and undergo apoptosis and autophagy for various environmental stresses. Unlike apoptosis, studies on increasing the production of therapeutic proteins in CHO cells by targeting the autophagy pathway are limited. In order to identify the effects of chemical...... autophagy inhibitors on the specific productivity (qp), nine chemical inhibitors that had been reported to target three different phases of autophagy (metformin, dorsomorphin, resveratrol, and SP600125 against initiation and nucleation; 3-MA, wortmannin, and LY294002 against elongation, and chloroquine...... significantly increased the qp of DG44-Fc and DUKX-Fc. In contrast, for DG44-Ab, only 3-MA significantly increased the qp. The autophagy-inhibiting activity of the nine chemical inhibitors on the rCHO cell lines was evaluated through Western blot analysis and flow cytometry. Unexpectedly, some chemical...

  19. Malaria control at the district level in Africa: the case of the muheza district in northeastern Tanzania

    DEFF Research Database (Denmark)

    Alilio, Martin S; Kitua, Andrew; Njunwa, Kato;

    2004-01-01

    An assessment was done in Tanzania to determine the extent to which the primary health care services have contributed to reducing the burden of malaria since the system was initiated in the 1980s. Seven descriptive processes and outcome indicators of effectiveness were used: changes of malaria...... transmission and incidence over time; use of facility-based care services for malaria; patients' access to professional advice; the trend of treatment failure over time of sulfadoxine-pyrimethamine and chloroquine; survival rates of severe cases at the district hospital; a district malaria control strategy......; number of malaria specific training for care providers; and the number of activities carried out on mosquito control measures. The data were collected from 1996 to 2003 in the Muheza district northeastern Tanzania. It covered household interviews with a stratified sample of 1,250 respondents, and in...

  20. PFAPA (Periodic fever, aphtous stomatitis, pharingitis, cervical adenitis or Marshall’s syndrome in children

    Directory of Open Access Journals (Sweden)

    N N Kuzmina

    2005-01-01

    Full Text Available PFAPA (periodic fever, aphtous stomatitis, pharingitis, cervical adenitis or Marshall’s syndrome is one of the rare periodic fever conditions appearing in children. Its cause is unknown. This syndrome may continue for several years. During interictal period the child is quite well, grows and develops normally. The disease should be differentiated from Behcet’s disease, cyclic neutropenia, familial Mediterranean fever, familial Ireland fever, hyperimmunoglobulinemia D syndrome, systemic juvenile idiopathic arthritis, chronic tonsillitis, some infectious diseases. Many drugs are used for the treatment of PFAPA syndrome: antibiotics, non-steroidal anti-inflammatory drugs, chloroquin, antiviral drugs, glucocorticoids, cimetidin. Tonsillectomy is used quite often. Analysis of the literature data shows that best results may be achieved with tonsillectomy (sometimes in combination with ade- notomy. PFAPA in a child of 2 years age diagnosed for the first time in Russian pediatric rheumatology is described.