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Sample records for antimalarial combination formulations

  1. Antimalarial drug resistance and combination chemotherapy.

    OpenAIRE

    White, N.

    1999-01-01

    Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the cha...

  2. High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations.

    Science.gov (United States)

    Mott, Bryan T; Eastman, Richard T; Guha, Rajarshi; Sherlach, Katy S; Siriwardana, Amila; Shinn, Paul; McKnight, Crystal; Michael, Sam; Lacerda-Queiroz, Norinne; Patel, Paresma R; Khine, Pwint; Sun, Hongmao; Kasbekar, Monica; Aghdam, Nima; Fontaine, Shaun D; Liu, Dongbo; Mierzwa, Tim; Mathews-Griner, Lesley A; Ferrer, Marc; Renslo, Adam R; Inglese, James; Yuan, Jing; Roepe, Paul D; Su, Xin-Zhuan; Thomas, Craig J

    2015-01-01

    Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy. PMID:26403635

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

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    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.

  4. Determination of artemether and lumefantrine in anti-malarial fixed-dose combination tablets by microemulsion electrokinetic chromatography with short-end injection procedure

    OpenAIRE

    Amin, N’Cho Christophe; Fabre, Huguette; Blanchin, Marie-Dominique; Montels, Jérôme; Aké, Michèle

    2013-01-01

    Background Artemether-lumefantrine (AL) combination therapy is now the most used anti-malarial treatment in the world. Quality control of AL formulations is still a major challenge in developing countries. Until now, only liquid chromatographic methods have been reported in the literature for their analysis. Capillary electrophoretic methods, which present various advantages (low price of capillary, low volumes of electrolyte consumption), may be an alternative to liquid chromatography method...

  5. Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combination with curcumin

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    Swain Bijay K

    2009-02-01

    Full Text Available Abstract Background Herbal extracts of Andrographis paniculata (AP and Hedyotis corymbosa (HC are known as hepato-protective and fever-reducing drugs since ancient time and they have been used regularly by the people in the south Asian sub-continent. Methanolic extracts of these two plants were tested in vitro on choloroquine sensitive (MRC-pf-20 and resistant (MRC-pf-303 strains of Plasmodium falciparum for their anti-malarial activity. Methods Growth inhibition was determined using different concentrations of these plant extracts on synchronized P. falciparum cultures at the ring stage. The interactions between these two plant extracts and individually with curcumin were studied in vitro. The performance of these two herbal extracts in isolation and combination were further evaluated in vivo on Balb/c mice infected with Plasmodium berghei ANKA and their efficacy was compared with that of curcumin. The in vivo toxicity of the plant derived compounds as well as their parasite stage-specificity was studied. Results The 50% inhibitory concentration (IC50 of AP (7.2 μg/ml was found better than HC (10.8 μg/ml. Combination of these two herbal drugs showed substantial enhancement in their anti-malarial activity. Combinatorial effect of each of these with curcumin also revealed anti-malarial effect. Additive interaction between the plant extracts (AP + HC and their individual synergism with curcumin (AP+CUR, HC+CUR were evident from this study. Increased in vivo potency was also observed with the combination of plant extracts over the individual extracts and curcumin. Both the plant extracts were found to inhibit the ring stage of the parasite and did not show any in vivo toxicity, whether used in isolation or in combination. Conclusion Both these two plant extracts in combination with curcumin could be an effective, alternative source of herbal anti-malarial drugs.

  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. 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.

  8. A Quantitative Documentation of the Composition of Two Powdered Herbal Formulations (Antimalarial and Haematinic Using Ethnomedicinal Information from Ogbomoso, Nigeria

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    Adepoju Tunde Joseph Ogunkunle

    2014-01-01

    Full Text Available The safety of many African traditional herbal remedies is doubtful due to lack of standardization. This study therefore attempted to standardize two polyherbal formulations from Ogbomoso, Oyo State, Nigeria, with respect to the relative proportions (weight-for-weight of their botanical constituents. Information supplied by 41 local herbal practitioners was statistically screened for consistency and then used to quantify the composition of antimalarial (Maloff-HB and haematinic (Haematol-B powdered herbal formulations with nine and ten herbs, respectively. Maloff-HB contained the stem bark of Enantia chlorantha Oliv. (30.0, Alstonia boonei De Wild (20.0, Mangifera indica L. (10.0, Okoubaka aubrevillei Phelleg & Nomand (8.0, Pterocarpus osun Craib (4.0, root bark of Calliandra haematocephala Hassk (10.0, Sarcocephalus latifolius (J. E. Smith E. A. Bruce (8.0, Parquetina nigrescens (Afz. Bullock (6.0, and the vines of Cassytha filiformis L. (4.0, while Haematol-B was composed of the leaf sheath of Sorghum bicolor Moench (30.0, fruit calyx of Hibiscus sabdariffa L. (20.0, stem bark of Theobroma cacao L. (10.0, Khaya senegalensis (Desr. A. Juss (5.5, Mangifera indica (5.5, root of Aristolochia ringens Vahl. (7.0, root bark of Sarcocephalus latifolius (5.5, Uvaria chamae P. Beauv. (5.5, Zanthoxylum zanthoxyloides (Lam. Zepern & Timler (5.5, and seed of Garcinia kola Heckel (5.5. In pursuance of their general acceptability, the two herbal formulations are recommended for their pharmaceutical, phytochemical, and microbial qualities.

  9. A quantitative documentation of the composition of two powdered herbal formulations (antimalarial and haematinic) using ethnomedicinal information from ogbomoso, Nigeria.

    Science.gov (United States)

    Ogunkunle, Adepoju Tunde Joseph; Oyelakin, Tosin Mathew; Enitan, Abosede Oluwaseyi; Oyewole, Funmilayo Elizabeth

    2014-01-01

    The safety of many African traditional herbal remedies is doubtful due to lack of standardization. This study therefore attempted to standardize two polyherbal formulations from Ogbomoso, Oyo State, Nigeria, with respect to the relative proportions (weight-for-weight) of their botanical constituents. Information supplied by 41 local herbal practitioners was statistically screened for consistency and then used to quantify the composition of antimalarial (Maloff-HB) and haematinic (Haematol-B) powdered herbal formulations with nine and ten herbs, respectively. Maloff-HB contained the stem bark of Enantia chlorantha Oliv. (30.0), Alstonia boonei De Wild (20.0), Mangifera indica L. (10.0), Okoubaka aubrevillei Phelleg & Nomand (8.0), Pterocarpus osun Craib (4.0), root bark of Calliandra haematocephala Hassk (10.0), Sarcocephalus latifolius (J. E. Smith) E. A. Bruce (8.0), Parquetina nigrescens (Afz.) Bullock (6.0), and the vines of Cassytha filiformis L. (4.0), while Haematol-B was composed of the leaf sheath of Sorghum bicolor Moench (30.0), fruit calyx of Hibiscus sabdariffa L. (20.0), stem bark of Theobroma cacao L. (10.0), Khaya senegalensis (Desr.) A. Juss (5.5), Mangifera indica (5.5), root of Aristolochia ringens Vahl. (7.0), root bark of Sarcocephalus latifolius (5.5), Uvaria chamae P. Beauv. (5.5), Zanthoxylum zanthoxyloides (Lam.) Zepern & Timler (5.5), and seed of Garcinia kola Heckel (5.5). In pursuance of their general acceptability, the two herbal formulations are recommended for their pharmaceutical, phytochemical, and microbial qualities. PMID:24701246

  10. In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

    Science.gov (United States)

    Crumb, William; Pace, Silvia; Ubben, David; Wible, Barb; Yan, Gan-Xin; Funck-Brentano, Christian

    2012-01-01

    The in vitro cardiac properties of dihydroartemisinin (DHA) plus piperaquine phosphate (PQP) were compared with those of other antimalarial compounds. Results with antimalarial drugs, chosen on the basis of their free therapeutic maximum concentration in plasma (Cmax), were expressed as the fold of that particular effect with respect to their Cmax. The following tests were used at 37°C: hERG (human ether-à-go-go-related gene) blockade and trafficking, rabbit heart ventricular preparations, and sodium and slow potassium ion current interference (INa and IKs, respectively). Chloroquine, halofantrine, mefloquine, and lumefantrine were tested in the hERG studies, but only chloroquine, dofetilide, lumefantrine, and the combination of artemether-lumefantrine were used in the rabbit heart ventricular preparations, hERG trafficking studies, and INa and IKs analyses. A proper reference was used in each test. In hERG studies, the high 50% inhibitory concentration (IC50) of halofantrine, which was lower than its Cmax, was confirmed. All the other compounds blocked hERG, with IC50s ranging from 3- to 30-fold their Cmaxs. In hERG trafficking studies, the facilitative effects of chloroquine at about 30-fold its Cmax were confirmed and DHA blocked it at a concentration about 300-fold its Cmax. In rabbit heart ventricular preparations, dofetilide, used as a positive control, revealed a high risk of torsades de pointes, whereas chloroquine showed a medium risk. Neither DHA-PQP nor artemether-lumefantrine displayed an in vitro signal for a significant proarrhythmic risk. Only chloroquine blocked the INa ion current and did so at about 30-fold its Cmax. No effect on IKs was detected. In conclusion, despite significant hERG blockade, DHA-PQP and artemether-lumefantrine do not appear to induce potential torsadogenic effects in vitro, affect hERG trafficking, or block sodium and slow potassium ion currents. PMID:22391528

  11. Development of hot melt co-formulated antimalarial solid dispersion system in fixed dose form (ARLUMELT): Evaluating amorphous state and in vivo performance.

    Science.gov (United States)

    Fule, Ritesh; Dhamecha, Dinesh; Maniruzzaman, Mohammed; Khale, Anubha; Amin, Purnima

    2015-12-30

    The aim of this study was to investigate the industrial feasibility of developing a co-formulated solid dispersion (SD) containing two antimalarial drugs artemether (ARTM) and lumefantrine (LUMF). Soluplus(®) (polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer) was used as primary carrier matrices via hot-melt extrusion processing to improve solubility profile and the oral bioavailability of the combination. Based on the preliminary screening, the optimized quantities of PEG 400, Lutrol F127 and Lutrol F68 were incorporated as surfactant with soluplus in different ratios to improve extrudability, increase wettability and the melt viscosity of the HME process. Soluplus(®) was proved to successfully stabilize both the drugs inside its polymeric network during extrusion via forming a stable solid dispersion. Physicochemical properties of the APIs and the SDs characterized by thermo-gravimetric analysis (TGA), differential scanning calorimetry (DSC), MDSC, FTIR spectroscopy and X-ray diffractometry (XRD) revealed the amorphous existence of the drug in all SDs developed. Molecular level morphology of solid dispersion characterized by using advanced physicochemical characterization techniques such as Raman spectroscopy, atomic force microscopy (AFM) and 2D NMR showed the transformation of the crystalline drugs to its stable amorphous state. All manufactured SDs retained their amorphicity even after a stability study conducted in accelerated condition over 6 months. The solubility and in vitro dissolution performance of both drugs in SD formulations was improved significantly when compared with pure drugs and marketed product while the in vivo studies revealed the same.The pharmacokinetic studies in rats revealed that the SD (AL1) shows a 44.12-65.24 folds increase in the AUC(0-72) and 42.87-172.61 folds increase in Cmax compared to that of pure drugs and a better bioavailability than that of commercial product. PMID:26471056

  12. Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal

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    Faye Oumar

    2007-06-01

    Full Text Available Abstract Background In view of the high level of chloroquine resistance in many countries, WHO has recommended the use of combination therapy with artemisinin derivatives in the treatment of uncomplicated malaria due to Plasmodium falciparum. Four antimalarial drug combinations, artesunate plus amodiaquine (Arsucam®, artesunate plus mefloquine (Artequin®, artemether plus lumefantrine (Coartem®; four doses and six doses, and amodiaquine plus sulphadoxine-pyrimethamine, were studied in five health districts in Senegal. Methods This is a descriptive, analytical, open, randomized study to evaluate the efficacy and tolerability of these four antimalarial combinations in the treatment of uncomplicated falciparum malaria using the 2002 WHO protocol. Results All drug combinations demonstrated good efficacy. On day 28, all combinations resulted in an excellent clinical and parasitological response rate of 100% after correction for PCR results, except for the four-dose artemether-lumefantrine regimen (96.4%. Follow-up of approximately 10% of each treatment group on day 42 demonstrated an efficacy of 100%. The combinations were well tolerated clinically and biologically. No unexpected side-effect was observed and all side-effects disappeared at the end of treatment. No serious side-effect requiring premature termination of treatment was observed. Conclusion The four combinations are effective and well-tolerated.

  13. Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in African Children with Malaria

    OpenAIRE

    Salman, Sam; Bendel, Daryl; Lee, Toong C.; Templeton, David; Davis, Timothy M. E.

    2015-01-01

    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using establis...

  14. Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in African Children with Malaria

    Science.gov (United States)

    Salman, Sam; Bendel, Daryl; Lee, Toong C.; Templeton, David

    2015-01-01

    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using established population compartmental pharmacokinetic models. Parasite clearance was prompt (median parasite clearance time, 24 h), and there were no serious adverse events. Consistent with studies in healthy adults (S. Salman, D. Bendel, T. C. Lee, D. Templeton, and T. M. E. Davis, Antimicrob Agents Chemother 59:3197–3207, 2015, http://dx.doi.org/10.1128/AAC.05013-14), the absorption of sublingual artemether was biphasic, and multiple dosing was associated with the autoinduction of the metabolism of artemether to DHA (which itself has potent antimalarial activity). In contrast to studies using healthy volunteers, pharmacokinetic modeling indicated that the first absorption phase did not avoid first-pass metabolism, suggesting that the drug is transferred to the upper intestine through postdose fluid/food intake. Simulations using the present data and those from an earlier study in older Melanesian children with uncomplicated malaria treated with artemether-lumefantrine tablets suggested that the bioavailability of sublingual artemether was at least equivalent to that after conventional oral artemether-lumefantrine (median [interquartile range] areas under the concentration-time curve for artemether, 3,403 [2,471 to 4,771] versus 3,063 [2,358 to 4,514] μg · h/liter, respectively; and for DHA, 2,958 [2,146 to 4,278] versus 2,839 [1,812 to 3,488] μg · h/liter, respectively; P ≥ 0.42). These findings suggest that sublingual artemether could be used as prereferral treatment for sick

  15. 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

  16. 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...

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

    Science.gov (United States)

    Rajan, Aswathy; Bagai, Upma

    2013-01-01

    Homeopathy is a therapeutic method based on the application of similia principle, utilizing ultra-low doses of medicinal substances made from natural products. The present study has been designed to evaluate the efficacy of Cinchona officinalis (Chin.) 30C and Chelidonium majus (Chel.) 30C in combination therapy against lethal murine malaria. Five groups having twelve BALB/c mice each were administered orally with 0.2 ml/mouse/day of different drugs, and their antimalarial potential was evaluated by Peter's 4-day test. The combination of Chin. 30 and Chel. 30 exhibited complete parasite clearance by the 28th day post-inoculation which was similar to the positive control [artesunate (4 mg/kg)+sulphadoxine-primethamine (1.2 mg/kg)] group. Both the groups exhibited enhanced mean survival time (MST) 28±0 days,whereas, the mice of infected control group survived up to 7.6±0.4 days only. The preventive and curative activities of the combination in comparison to the positive controls [pyrimethamine (1.2 mg/Kg) and chloroquine (20 mg/Kg), respectively] were also evaluated. The combination had a significant preventive activity (p<0.0005), with 89.2% chemosuppression which was higher than the standard drug, pyrimethamine (83.8%). It also showed a moderate curative activity with complete clearance of parasite in 50% of surviving mice, and enhancing the MST of mice up to 26.8±2.8 days. These findings point to the significant antiplasmodial efficacy of the combination of these homeopathic drugs against Plasmodium berghei. PMID:23652641

  18. Saleability of anti-malarials in private drug shops in Muheza, Tanzania: a baseline study in an era of assumed artemisinin combination therapy (ACT)

    OpenAIRE

    Ringsted Frank M; Massawe Isolide S; Lemnge Martha M; Bygbjerg Ib C

    2011-01-01

    Abstract Background Artemether-lumefantrine (ALu) replaced sulphadoxine-pymimethamine (SP) as the official first-line anti-malarial in Tanzania in November 2006. So far, artemisinin combination therapy (ACT) is contra-indicated during pregnancy by the national malaria treatment guidelines, and pregnant women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may u...

  19. 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.

  20. 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....

  1. Antagonistic antimalarial properties of pawpaw leaf aqueous extract in combination with artesunic acid in Plasmodium berghei-infected mice

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    L.O. Onaku, A.A. Attama, V.C. Okore, A.Y. Tijani, A.A. Ngene & C.O. Esimone

    2011-06-01

    Full Text Available Background & objectives: Artemisinins, the main stay in the treatment of malaria are used in combinationswith other antimalarials to forestall resistance, as artemisinin-combination therapies (ACTs. However, ACTsare expensive and some of the non-artemisinin components are not well-tolerated by patients. There areseveral folkloric and scientific proofs of the efficacy of herbal remedies for malaria. Mature leaves of Caricapapaya is widely used to treat malaria in several African countries. An ACT involving a medicinal herb extractor its active constituent(s will provide an indigenous alternative/herbal ACT.Methods: Mature fresh leaves of Carica papaya were grounded and macerated in cold distilled water for 24 hand the extract (PCE was stored in the refrigerator for seven days. Fresh extracts were made as needed. Theantiplasmodial activity of PCE and/or artesunic acid were determined by using the Peter’s 4-day suppressivetest in Plasmodium berghei-infected mice. The ED50 and ED90 were calculated from the dose-responserelationships.Results: The combination of 50 mg/kg of PCE and 15 mg/kg of artesunic acid produced a significant reductionof parasitemia (81.25%, compared to 50 mg/kg PCE alone (37.7%. The mean survival time of the combinationsof PCE and 15 mg/kg of artesunic acid, and PCE alone followed a dose-dependent manner. The ED50 of PCEshowed that it has a very good activity. The isobolar equivalent (IE calculated from the ED90 of PCE incombination with artesunic acid showed that the interaction was antagonistic.Interpretation & conclusion: Although pawpaw alone was found to have a very good activity, its combinationwith artesunic acid is antagonistic. Combinations of artemisinins and pawpaw show little promise forcombination therapy development.

  2. Saleability of anti-malarials in private drug shops in Muheza, Tanzania: a baseline study in an era of assumed artemisinin combination therapy (ACT

    Directory of Open Access Journals (Sweden)

    Ringsted Frank M

    2011-08-01

    Full Text Available Abstract Background Artemether-lumefantrine (ALu replaced sulphadoxine-pymimethamine (SP as the official first-line anti-malarial in Tanzania in November 2006. So far, artemisinin combination therapy (ACT is contra-indicated during pregnancy by the national malaria treatment guidelines, and pregnant women depend on SP for Intermittent Preventive Treatment (IPTp during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform a baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. Methods All drug shops selling prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. Results All surveyed drug shops illicitly sold SP and quinine (QN, and legally amodiaquine (AQ. Calculated monthly sale was 4,041 doses, in a town with a population of 15,000 people. Local brands of SP accounted for 74% of sales volume, compared to AQ (13%, QN (11% and ACT (2%. Conclusions In community practice, the saleability of ACT was negligible. SP was best-selling, and use was not reserved for IPTp, as stipulated in the national anti-malarial policy. It is a major reason for concern that such drug-pressure in the community equals de facto intermittent presumptive treatment. In an area where SP drug resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp

  3. Cost-effectiveness study of three antimalarial drug combinations in Tanzania.

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    Virginia Wiseman

    2006-10-01

    Full Text Available BACKGROUND: As a result of rising levels of drug resistance to conventional monotherapy, the World Health Organization (WHO and other international organisations have recommended that malaria endemic countries move to combination therapy, ideally with artemisinin-based combinations (ACTs. Cost is a major barrier to deployment. There is little evidence from field trials on the cost-effectiveness of these new combinations. METHODS AND FINDINGS: An economic evaluation of drug combinations was designed around a randomised effectiveness trial of combinations recommended by the WHO, used to treat Tanzanian children with non-severe slide-proven malaria. Drug combinations were: amodiaquine (AQ, AQ with sulfadoxine-pyrimethamine (AQ+SP, AQ with artesunate (AQ+AS, and artemether-lumefantrine (AL in a six-dose regimen. Effectiveness was measured in terms of resource savings and cases of malaria averted (based on parasitological failure rates at days 14 and 28. All costs to providers and to patients and their families were estimated and uncertain variables were subjected to univariate sensitivity analysis. Incremental analysis comparing each combination to monotherapy (AQ revealed that from a societal perspective AL was most cost-effective at day 14. At day 28 the difference between AL and AQ+AS was negligible; both resulted in a gross savings of approximately US1.70 dollars or a net saving of US22.40 dollars per case averted. Varying the accuracy of diagnosis and the subsistence wage rate used to value unpaid work had a significant effect on the number of cases averted and on programme costs, respectively, but this did not change the finding that AL and AQ+AS dominate monotherapy. CONCLUSIONS: In an area of high drug resistance, there is evidence that AL and AQ+AS are the most cost-effective drugs despite being the most expensive, because they are significantly more effective than other options and therefore reduce the need for further treatment. This is

  4. Estimating antimalarial drugs consumption in Africa before the switch to artemisinin-based combination therapies (ACTs

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    Vreeke Ed

    2007-07-01

    Full Text Available Abstract Background Having reliable forecasts is critical now for producers, malaria-endemic countries and agencies in order to adapt production and procurement of the artemisinin-based combination treatments (ACTs, the new first-line treatments of malaria. There is no ideal method to quantify drug requirements for malaria. Morbidity data give uncertain estimations. This study uses drug consumption to provide elements to help estimate quantities and financial requirements of ACTs. Methods The consumption of chloroquine, sulphadoxine/pyrimethamine and quinine both through the private and public sector was assessed in five sub-Saharan Africa countries with different epidemiological patterns (Senegal, Rwanda, Tanzania, Malawi, Zimbabwe. From these data the number of adult treatments per capita was calculated and the volumes and financial implications derived for the whole of Africa. Results Identifying and obtaining data from the private sector was difficult. The quality of information on drug supply and distribution in countries must be improved. The number of adult treatments per capita and per year in the five countries ranged from 0.18 to 0.50. Current adult treatment prices for ACTs range US$ 1–1.8. Taking the upper range for both volumes and costs, the highest number of adult treatments consumed for Africa was estimated at 314.5 million, corresponding to an overall maximum annual need for financing ACT procurement of US$ 566.1 million. In reality, both the number of cases treated and the cost of treatment are likely to be lower (projections for the lowest consumption estimate with the least expensive ACT would require US $ 113 million per annum. There were substantial variations in the market share between public and private sources among these countries (the public sector share ranging from 98% in Rwanda to 33% in Tanzania. Conclusion Additional studies are required to build a more robust methodology, and to assess current consumptions

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

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    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.

  6. Artemisinin combination therapies price disparity between government and private health sectors and its implication on antimalarial drug consumption pattern in Morogoro Urban District, Tanzania

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    Malisa Allen

    2012-03-01

    Full Text Available Abstract Background Universal access to effective treatments is a goal of the Roll Back Malaria Partnership. However, despite official commitments and substantial increases in financing, this objective remains elusive, as development assistance continue to be routed largely through government channels, leaving the much needed highly effective treatments inaccessible or unaffordable to those seeking services in the private sector. Methods To quantify the effect of price disparity between the government and private health systems, this study have audited 92 government and private Drug Selling Units (DSUs in Morogoro urban district in Tanzania to determine the levels, trend and consumption pattern of antimalarial drugs in the two health systems. A combination of observation, interviews and questionnaire administered to the service providers of the randomly selected DSUs were used to collect data. Results ALU was the most selling antimalarial drug in the government health system at a subsidized price of 300 TShs (0.18 US$. By contrast, ALU that was available in the private sector (coartem was being sold at a price of about 10,000 TShs (5.9 US$, the price that was by far unaffordable, prompting people to resort to cheap but failed drugs. As a result, metakelfin (the phased out drug was the most selling drug in the private health system at a price ranging from 500 to 2,000 TShs (0.29–1.18 US$. Conclusions In order for the prompt diagnosis and treatment with effective drugs intervention to have big impact on malaria in mostly low socioeconomic malaria-endemic areas of Africa, inequities in affordability and access to effective treatment must be eliminated. For this to be ensued, subsidized drugs should be made available in both government and private health sectors to promote a universal access to effective safe and affordable life saving antimalarial drugs.

  7. Pharmacologic inhibition of CXCL10 in combination with anti-malarial therapy eliminates mortality associated with murine model of cerebral malaria.

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    Nana O Wilson

    Full Text Available Despite appropriate anti-malarial treatment, cerebral malaria (CM-associated mortalities remain as high as 30%. Thus, adjunctive therapies are urgently needed to prevent or reduce such mortalities. Overproduction of CXCL10 in a subset of CM patients has been shown to be tightly associated with fatal human CM. Mice with deleted CXCL10 gene are partially protected against experimental cerebral malaria (ECM mortality indicating the importance of CXCL10 in the pathogenesis of CM. However, the direct effect of increased CXCL10 production on brain cells is unknown. We assessed apoptotic effects of CXCL10 on human brain microvascular endothelial cells (HBVECs and neuroglia cells in vitro. We tested the hypothesis that reducing overexpression of CXCL10 with a synthetic drug during CM pathogenesis will increase survival and reduce mortality. We utilized atorvastatin, a widely used synthetic blood cholesterol-lowering drug that specifically targets and reduces plasma CXCL10 levels in humans, to determine the effects of atorvastatin and artemether combination therapy on murine ECM outcome. We assessed effects of atorvastatin treatment on immune determinants of severity, survival, and parasitemia in ECM mice receiving a combination therapy from onset of ECM (day 6 through 9 post-infection and compared results with controls. The results indicate that CXCL10 induces apoptosis in HBVECs and neuroglia cells in a dose-dependent manner suggesting that increased levels of CXCL10 in CM patients may play a role in vasculopathy, neuropathogenesis, and brain injury during CM pathogenesis. Treatment of ECM in mice with atorvastatin significantly reduced systemic and brain inflammation by reducing the levels of the anti-angiogenic and apoptotic factor (CXCL10 and increasing angiogenic factor (VEGF production. Treatment with a combination of atorvastatin and artemether improved survival (100% when compared with artemether monotherapy (70%, p<0.05. Thus, adjunctively

  8. Expanding the Antimalarial Drug Arsenal—Now, But How?

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    Rajeev K. Mehlotra

    2011-04-01

    Full Text Available The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/dhps, and others, have led to widespread resistance to all known classes of antimalarial compounds. Unfortunately, malaria parasites have started to exhibit some level of resistance in Southeast Asia even to the most recently introduced class of drugs, artemisinins. While there is much need, the antimalarial drug development pipeline remains woefully thin, with little chemical diversity, and there is currently no alternative to the precious artemisinins. It is difficult to predict where the next generation of antimalarial drugs will come from; however, there are six major approaches: (i re-optimizing the use of existing antimalarials by either replacement/rotation or combination approach; (ii repurposing drugs that are currently used to treat other infections or diseases; (iii chemically modifying existing antimalarial compounds; (iv exploring natural sources; (v large-scale screening of diverse chemical libraries; and (vi through parasite genome-based (“targeted” discoveries. When any newly discovered effective antimalarial treatment is used by the populus, we must maintain constant vigilance for both parasite-specific and human-related factors that are likely to hamper its success. This article is neither comprehensive nor conclusive. Our purpose is to provide an overview of antimalarial drug resistance, associated parasite genetic factors (1. Introduction; 2. Emergence of artemisinin resistance in P. falciparum, and the antimalarial drug development pipeline (3. Overview of the global pipeline of antimalarial drugs, and highlight some examples of the aforementioned approaches to future antimalarial treatment. These approaches can be categorized into “short term” (4. Feasible options for now and “long term” (5. Next generation of

  9. On peroxide antimalarials

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    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.

  10. Incidence of malaria and efficacy of combination antimalarial therapies over 4 years in an urban cohort of Ugandan children.

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    Tamara D Clark

    Full Text Available BACKGROUND: Combination therapies are now recommended to treat uncomplicated malaria. We used a longitudinal design to assess the incidence of malaria and compare the efficacies of 3 combination regimens in Kampala, Uganda. METHODOLOGY/PRINCIPAL FINDINGS: Children aged 1-10 years were enrolled from randomly selected households in 2004-05 and 2007, and were followed at least monthly through 2008. Insecticide-treated bednets (ITNs were provided in 2006. Children were randomized upon their first episode, and then treated for all episodes of uncomplicated malaria with amodiaquine/sulfadoxine-pyrimethamine (AQ/SP, artesunate/amodiaquine (AS/AQ, or artemether/lumefantrine (AL. Risks of parasitological failure were determined for each episode of uncomplicated malaria and clinical parameters were followed. A total of 690 children experienced 1464 episodes of malaria. 96% of these episodes were uncomplicated malaria and treated with study drugs; 94% were due to Plasmodium falciparum. The rank order of treatment efficacy was AL > AS/AQ > AQ/SP. Failure rates increased over time for AQ/SP, but not the artemisinin-based regimens. Over the 4-year course of the study the prevalence of asymptomatic parasitemia decreased from 11.8% to 1.4%, the incidence of malaria decreased from 1.55 to 0.32 per person year, and the prevalence of anemia (hemoglobin <10 gm/dL decreased from 5.9% to 1.0%. No episodes of severe malaria (based on WHO criteria and no deaths were seen. CONCLUSIONS/SIGNIFICANCE: With ready access to combination therapies and distribution of ITNs, responses were excellent for artemisinin-containing regimens, severe malaria was not seen, and the incidence of malaria and prevalence of parasitemia and anemia decreased steadily over time. TRIAL REGISTRATION: isrctn.org ISRCTN37517549.

  11. Tyrosine kinase inhibitors: New class of antimalarials on the horizon?

    Science.gov (United States)

    Pathak, Vrushali; Colah, Roshan; Ghosh, Kanjaksha

    2015-08-01

    Development of the antimalarial drug resistant strains has currently become a major public health challenge. There is an urgent need to develop new antimalarial drugs. Tyrosine kinase inhibitors (TKIs) are receiving increasing attention as anticancer therapy. It has revolutionarised the management of CML to say the least. TKIs are also increasingly being implicated in complicated but vital life cycle of malaria parasite. Hence we tested two commonly used but different classes of TKIs (imatinib and sorafenib) in-vitro for their antimalarial activity and possible synergistic activity with existing antimalarial drug. Antimalarial activity was tested with the help of modified WHO microtest technique in-vitro for five different Plasmodium falciparum laboratory strains (3D7, Dd2, 7G8, MRC2, PKL9). Imatinib and sorafenib showed a promising antimalarial activity with all the strains. These compounds caused dose dependent inhibition of parasite maturation. The isobologram analysis of the interactions of these TKIs with standard antimalarial drug, artesunate revealed distinct patterns of synergism, additivity and antagonism at different ratios. Imatinib showed worthwhile synergism with artesunate indicating imatinib and other tyrosine kinase inhibitors may have significant antimalarial activity and can be used in combination therapy. PMID:26142327

  12. Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combination with curcumin

    OpenAIRE

    Swain Bijay K; Dash Aditya P; Mishra Kirti; Dey Nrisingha

    2009-01-01

    Abstract Background Herbal extracts of Andrographis paniculata (AP) and Hedyotis corymbosa (HC) are known as hepato-protective and fever-reducing drugs since ancient time and they have been used regularly by the people in the south Asian sub-continent. Methanolic extracts of these two plants were tested in vitro on choloroquine sensitive (MRC-pf-20) and resistant (MRC-pf-303) strains of Plasmodium falciparum for their anti-malarial activity. Methods Growth inhibition was determined using diff...

  13. Benefits of Combinations of Vitamin A, C and E Derivatives in the Stability of Cosmetic Formulations

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    Patrícia Maria Berardo Gonçalves Maia Campos

    2012-02-01

    Full Text Available Chemically stable ester derivatives of vitamins A, C and E have become a focus of interest for their role in the satisfactory results in skin aging treatments. Accordingly, the aim of this study was to evaluate the physical and chemical stability of a cosmetic formulation containing 1% retinyl palmitate, ascorbyl tetraisopalmitate and tocopheryl acetate, alone or in combination. In the studies of physical stability, a Brookfield rheometer was used to determine rheological behavior of formulations containing the vitamins. Chemical stability was determined by HPLC on a Shimadzu system with UV detection. Results showed that formulations had pseudoplastic behavior and that vitamins did not alter their apparent viscosity and thixotropy. In the chemical stability studies, first-order reaction equations were used for determinations of the shelf-life of vitamins derivatives considering a remaining concentration of 85%. Combined vitamins in a single formulation had a slightly lower degradation rate as compared to different preparations containing only one of the vitamins. Considering that many cosmetic formulations contain vitamin combinations it is suggested that the present study may contribute to the development of more stable formulations containing liposoluble vitamins.

  14. Investigation of dielectric properties of different cake formulations during microwave and infrared-microwave combination baking.

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    Sakiyan, Ozge; Sumnu, Gulum; Sahin, Serpil; Meda, Venkatesh

    2007-05-01

    Dielectric properties can be used to understand the behavior of food materials during microwave processing. Dielectric properties influence the level of interaction between food and high frequency electromagnetic energy. Dielectric properties are, therefore, important in the design of foods intended for microwave preparation. In this study, it was aimed to determine the variation of dielectric properties of different cake formulations during baking in microwave and infrared-microwave combination oven. In addition, the effects of formulation and temperature on dielectric properties of cake batter were examined. Dielectric constant and loss factor of cake samples were shown to be dependent on formulation, baking time, and temperature. The increase in baking time and temperature decreased dielectric constant and loss factor of all formulations. Fat content was shown to increase dielectric constant and loss factor of cakes. PMID:17995773

  15. In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids

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    Birgit Viira

    2016-06-01

    Full Text Available Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery.

  16. Development of a new formulation combining calcipotriol and betamethasone dipropionate in an ointment vehicle

    DEFF Research Database (Denmark)

    Simonsen, Lene; Høy, Gert; Didriksen, Erik;

    2004-01-01

    Calcipotriol and betamethasone dipropionate are widely used effective treatments for psoriasis. Combined therapy is known to be superior to monotherapy, but current formulations do not permit simultaneous application as the drug substances will degrade when mixed. The purpose of the study was to ...

  17. Antimalarial Synergy of Cysteine and Aspartic Protease Inhibitors

    OpenAIRE

    Semenov, Andrey; Olson, Jed E.; Rosenthal, Philip J.

    1998-01-01

    It has been proposed that the Plasmodium falciparum cysteine protease falcipain and aspartic proteases plasmepsin I and plasmepsin II act cooperatively to hydrolyze hemoglobin as a source of amino acids for erythrocytic parasites. Inhibitors of each of these proteases have potent antimalarial effects. We have now evaluated the antimalarial effects of combinations of cysteine and aspartic protease inhibitors. When incubated with cultured P. falciparum parasites, cysteine and aspartic protease ...

  18. Antimalarial drug resistance: An overview

    OpenAIRE

    Antony, Hiasindh Ashmi; Parija, Subhash Chandra

    2016-01-01

    Malaria is a major public health burden throughout the world. Resistance to the antimalarial drugs has increased the mortality and morbidity rate that is achieved so far through the malaria control program. Monitoring the drug resistance to the available antimalarial drugs helps to implement effective drug policy, through the in vivo efficacy studies, in vitro drug susceptibility tests and detection of molecular markers. It is important to understand the mechanism of the antimalarial drugs, a...

  19. Formulation of a Combined Transportation and Inventory Optimization Model with Multiple Time Periods

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    G.Krishnakumari,

    2016-03-01

    Full Text Available Most distribution network design models existing in the literature have focused on minimizing the costs of inventory and transportation. During the analysis of supply chain of currency management problem it is observed that the transportation of currency from various sources to various destinations and the required inventory to be maintained to meet the emerging demands requires formulation of a combined problem. This framework aims to support the coordination of inventory and transportation activities to properly manage the inventory profiles and currency flows between source locations and distribution centers. This paper considers a multi-period inventory and transportation model for a single commodity. The key contribution of this paper is, a mathematical programming formulation of transportation cum inventory problem is proposed and an algorithm for this new formulation as a multi period decision process is intended. A numerical example of currency transportation cum inventory is presented to illustrate the proposed algorithm

  20. Benefits of Combinations of Vitamin A, C and E Derivatives in the Stability of Cosmetic Formulations

    OpenAIRE

    Patrícia Maria Berardo Gonçalves Maia Campos; Lorena Rigo Gaspar; Mirela Donato Gianeti; Flávio Bueno de Camargo Júnior

    2012-01-01

    Chemically stable ester derivatives of vitamins A, C and E have become a focus of interest for their role in the satisfactory results in skin aging treatments. Accordingly, the aim of this study was to evaluate the physical and chemical stability of a cosmetic formulation containing 1% retinyl palmitate, ascorbyl tetraisopalmitate and tocopheryl acetate, alone or in combination. In the studies of physical stability, a Brookfield rheometer was used to determine rheological behavior of formulat...

  1. Improved efficacy of cisplatin in combination with a nano-formulation of pentacyclic triterpenediol.

    Science.gov (United States)

    Alam, Noor; Qayum, Arem; Kumar, Ashok; Khare, Vaibhav; Sharma, Parduman Raj; Andotra, Samar Singh; Singh, Shashank K; Koul, Surinder; Gupta, Prem N

    2016-11-01

    Cisplatin is widely used for the treatment of various cancers including cervical, ovarian, lung and head and neck, however, its clinical success is limited owing to the dose-dependent adverse effects, mainly nephrotoxicity and neurotoxicity. In order to address this limitation, the present study was undertaken to investigate growth inhibitory effect of cisplatin in combination with a triterpenediol (3a, 24-dihydroxyurs-12-ene and 3a, 24-dihydroxyolean-12-ene, TPD) on human ovarian cancer cell line. Poly(dl-lactic-co-glycolic) acid nanoparticles loaded with TPD (TPD-PLGA-NPs) were successfully developed by emulsion solvent evaporation method. The TPD-PLGA-NPs were characterized for size distribution and zeta potential which was in order of 152.56±3.01nm and -17.36±0.37mV respectively. The morphological evaluation was carried out by transmission electron microscopy and the formulation was also characterized using Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The drug loading of the optimized formulation was 51.03±1.52μg/mg and the formulation exhibited sustained drug release profile. The in vitro cellular uptake study of coumarin-6 loaded PLGA nanoparticles in OVCAR-5 cells demonstrated a time dependent increase in uptake efficiency. Further, growth inhibitory effect of cisplatin was investigated in combination with TPD-PLGA-NPs. The combination index (CI) was <1, indicating a synergistic interaction. Further, at 75% of cell growth inhibition (ED75) the dose of cisplatin was reduced to 3.8 folds using this combination. The results indicated the potential of cisplatin and TPD-PLGA-NPs combination in order to reduce to dose limiting toxicities of the former. PMID:27524002

  2. Fixed-dose combinations of drugs versus single-drug formulations for treating pulmonary tuberculosis

    Science.gov (United States)

    Gallardo, Carmen R; Rigau Comas, David; Valderrama Rodríguez, Angélica; Roqué i Figuls, Marta; Parker, Lucy Anne; Caylà, Joan; Bonfill Cosp, Xavier

    2016-01-01

    Background People who are newly diagnosed with pulmonary tuberculosis (TB) typically receive a standard first-line treatment regimen that consists of two months of isoniazid, rifampicin, pyrazinamide, and ethambutol followed by four months of isoniazid and rifampicin. Fixed-dose combinations (FDCs) of these drugs are widely recommended. Objectives To compare the efficacy, safety, and acceptability of anti-tuberculosis regimens given as fixed-dose combinations compared to single-drug formulations for treating people with newly diagnosed pulmonary tuberculosis. Search methods We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL, published in the Cochrane Library, Issue 11 2015); MEDLINE (1966 to 20 November 2015); EMBASE (1980 to 20 November 2015); LILACS (1982 to 20 November 2015); the metaRegister of Controlled Trials; and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), without language restrictions, up to 20 November 2015. Selection criteria Randomized controlled trials that compared the use of FDCs with single-drug formulations in adults (aged 15 years or more) newly diagnosed with pulmonary TB. Data collection and analysis Two review authors independently assessed studies for inclusion, and assessed the risk of bias and extracted data from the included trials. We used risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data with 95% confidence intervals (CIs). We attempted to assess the effect of treatment for time-to-event measures with hazard ratios and their 95% CIs. We used the Cochrane 'Risk of bias' assessment tool to determine the risk of bias in included trials. We used the fixed-effect model when there was little heterogeneity and the random-effects model with moderate heterogeneity. We used an I² statistic value of 75% or greater to denote significant heterogeneity, in which case we did not perform a

  3. Antimalarial drug resistance: An overview.

    Science.gov (United States)

    Antony, Hiasindh Ashmi; Parija, Subhash Chandra

    2016-01-01

    Malaria is a major public health burden throughout the world. Resistance to the antimalarial drugs has increased the mortality and morbidity rate that is achieved so far through the malaria control program. Monitoring the drug resistance to the available antimalarial drugs helps to implement effective drug policy, through the in vivo efficacy studies, in vitro drug susceptibility tests and detection of molecular markers. It is important to understand the mechanism of the antimalarial drugs, as it is one of the key factors in the emergence and spread of drug resistance. This review summarizes the commonly used antimalarial drugs, their mechanism of action and the genetic markers validated so far for the detection of drug-resistant parasites. PMID:26998432

  4. Antimalarial Activity of Azadipeptide Nitriles

    OpenAIRE

    Löser, Reik; Gut, Jiri; Rosenthal, Philip J.; Frizler, Maxim; Gütschow, Michael; Andrews, Katherine T.

    2009-01-01

    Azadipeptide nitriles – novel cysteine protease inhibitors – display structure-dependent antimalarial activity against both chloroquine-sensitive and chloroquine-resistant lines of cultured Plasmodium falciparum malaria parasites. Inhibition of parasite’s haemoglobin-degrading cysteine proteases was also investigated, revealing the azadipeptide nitriles as potent inhibitors of falcipain-2 and -3. A correlation between the cysteine protease-inhibiting activity and the antimalarial potential of...

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

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    Sow Diarietou

    2009-06-01

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

  6. Chitosan-based nanocarriers for antimalarials

    Science.gov (United States)

    Dreve, Simina; Kacso, Iren; Popa, Adriana; Raita, Oana; Bende, A.; Borodi, Gh.; Bratu, I.

    2012-02-01

    The objective of this research was to synthesize and characterize chitosan-based liquid and solid materials with unique absorptive and mechanical properties as carriers for quinine - one of the most used antimalarial drug. The use of chitosan (CTS) as base in polyelectrolyte complex systems, to prepare solid release systems as sponges is presented. The preparation by double emulsification of CTS hydrogels carrying quinine as anti-malarial drug is reported. The concentration of quinine in the CTS hydrogel was 0.08 mmol. Chitosan - drug loaded hydrogel was used to generate solid sponges by freeze-drying at -610°C and 0.09 atm. Structural investigations of the solid formulations were done by Fourier-transformed infrared spectroscopy (FTIR), ultraviolet-visible spectroscopy (UV-VIS), spectrofluorimetry, differential scanning calorimetry (DSC) and X-ray diffractometry. The results indicated that the drug molecule is forming temporary chelates in CTS hydrogels and sponges. Electron paramagnetic resonance (EPR) demonstrates the presence of free radicals in a wide range and the antioxidant activity for chitosan - drug supramolecular cross-linked assemblies.

  7. Cajachalcone: An Antimalarial Compound from Cajanus cajan Leaf Extract

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    E. O. Ajaiyeoba

    2013-01-01

    Full Text Available Cajanus cajan L, a member of the family Fabaceae, was identified from the Nigerian antimalarial ethnobotany as possessing antimalarial properties. The bioassay-guided fractionation of the crude methanol extract of C. cajan leaves was done in vitro using the multiresistant strain of Plasmodium falciparum (K1 in the parasite lactate dehydrogenase assay. Isolation of compound was achieved by a combination of chromatographic techniques, while the structure of the compound was elucidated by spectroscopy. This led to the identification of a cajachalcone, 2′,6′-dihydroxy-4-methoxy chalcone, as the biologically active constituent from the ethyl acetate fraction. Cajachalcone had an IC50 value of 2.0 μg/mL (7.4 μM and could be a lead for anti-malarial drug discovery.

  8. From hybrid compounds to targeted drug delivery in antimalarial therapy.

    Science.gov (United States)

    Oliveira, Rudi; Miranda, Daniela; Magalhães, Joana; Capela, Rita; Perry, Maria J; O'Neill, Paul M; Moreira, Rui; Lopes, Francisca

    2015-08-15

    The discovery of new drugs to treat malaria is a continuous effort for medicinal chemists due to the emergence and spread of resistant strains of Plasmodium falciparum to nearly all used antimalarials. The rapid adaptation of the malaria parasite remains a major limitation to disease control. Development of hybrid antimalarial agents has been actively pursued as a promising strategy to overcome the emergence of resistant parasite strains. This review presents the journey that started with simple combinations of two active moieties into one chemical entity and progressed into a delivery/targeted system based on major antimalarial classes of drugs. The rationale for providing different mechanisms of action against a single or additional targets involved in the multiple stages of the parasite's life-cycle is highlighted. Finally, a perspective for this polypharmacologic approach is presented. PMID:25913864

  9. Comparison of the safety and efficacy of a fixed-dose combination regimen and separate formulations for pulmonary tuberculosis treatment

    Directory of Open Access Journals (Sweden)

    Jiun-Ting Wu

    2015-06-01

    Full Text Available OBJECTIVES: Fixed-dose combination formulations, which simplify the administration of drugs and prevent the development of drug resistance, have been recommended as a standard anti-tuberculosis treatment regimen. However, the composition and dosage recommendations for fixed-dose combination formulations differ from those for separate formulations. Thus, questions about the effectiveness and side effects of combination formulations remain. The aim of this study was to compare the safety and efficacy of these two types of anti-tuberculosis regimens for pulmonary tuberculosis treatment. METHOD: A prospective, randomized controlled study was conducted using the directly observed treatment short-course strategy. Patients were randomly allocated to one of two short-course regimens. One year after completing the treatment, these patients’ outcomes were analyzed. ClinicalTrials.gov: NCT00979290. RESULTS: A total of 161 patients were enrolled, 142 of whom were evaluable for safety assessment. The two regimens had a similar incidence of adverse effects. In the per-protocol population, serum bilirubin concentrations at the peak level, at week 4, and at week 8 were significantly higher for the fixed-dose combination formulation than for the separate formulations. All patients had negative sputum cultures at the end of the treatment, and no relapse occurred after one year of follow-up. CONCLUSIONS: In this randomized study, transient higher serum bilirubin levels were noted for the fixed-dose combination regimen compared with the separate formulations during treatment. However, no significant difference in safety or efficacy was found between the groups when the directly observed treatment short-course strategy was used.

  10. The interaction of x-rays and antimalarials

    International Nuclear Information System (INIS)

    Full text: The radiation sensitivity of malaria parasites has three potential clinical applications, namely i) to prevent the transmission of malaria by blood transfusion, ii) as adjunctive therapy when a radioactive isotope is complexed to a conventional antimalarial drug, and iii) to attenuate the pathogenicity of specific parasite stages as part of the development of a vaccine. In the first two applications, detailed information relating to parasite radiosensitivity and the interaction of ionising radiation with antimalarials is of vital importance because dosimetry must allow for the exposure of normal cells. Malaria parasite cultures (Plasmodium falciparum) were exposed to a logarithmic series of concentrations of antimalarial agents and irradiated using a Siemens Stabilipan orthovoltage radiotherapy unit. The irradiation was performed at room temperature and ambient oxygen concentration. Control samples were also irradiated. The DNA synthesis in each culture was measured 48 hours post irradiation by using a 3H-hypoxanthine incorporation assay. The antimalarials studied are: artesunate, quinine, retinol and chloroquine. The radiosensitivity of Plasmodium falciparum is not dependent on the strain of parasite with the dose required to inhibit 50% of DNA synthesis (ID50) equal to 24.7 ± 3.0 Gy. This applies equally for the drug resistant and drug sensitive strains studied. Because the measured radiosensitivity is dependent on the sera oxygen concentration, the reported value for the ID50 may not apply in hypoxic situations. The interaction of ionising radiation with the antimalarials shows synergy with retinol and choloquine, additivity with quinine and slight antagonism with artesunate. Radionuclide therapy may emerge as a novel treatment for malaria. If this does occur, then, although all strains appear to be equally radiosensitive, care must be taken when combining ionising radiation with existing antimalarials for the treatment of malaria. Copyright (2001

  11. Efficacy Evaluation of a Multifunctional Cosmetic Formulation: The Benefits of a Combination of Active Antioxidant Substances

    OpenAIRE

    Mirela D. Gianeti; Patrícia M. B. G. Maia Campos

    2014-01-01

    This study presents the association of active antioxidants substances in a multifunctional cosmetic formulation with established efficacy against signs of aging. A multifunctional cosmetic formulation containing an association of UV filters and antioxidant substances (liposoluble vitamins A, C and E, Ginkgo biloba and Phorphyra umbilicalis extracts) was evaluated. This formulation was submitted to a clinical efficacy study using biophysics techniques and skin images analysis (digital photogr...

  12. Efficacy Evaluation of a Multifunctional Cosmetic Formulation: The Benefits of a Combination of Active Antioxidant Substances

    Directory of Open Access Journals (Sweden)

    Mirela D. Gianeti

    2014-11-01

    Full Text Available This study presents the association of active antioxidants substances in a multifunctional cosmetic formulation with established efficacy against signs of aging. A multifunctional cosmetic formulation containing an association of UV filters and antioxidant substances (liposoluble vitamins A, C and E, Ginkgo biloba and Phorphyra umbilicalis extracts was evaluated. This formulation was submitted to a clinical efficacy study using biophysics techniques and skin images analysis (digital photography imaging systems, 20 MHz ultrasound, and reflectance confocal microscopy. The volunteers applied the formulation containing the UV filters and antioxidant substances during the day and the formulation with antioxidant substances and without the UV filters at night, for 90 days. The formulation increased the hydration and protected the skin barrier function after a single application. At the long term assessment the formulation provided an improvement in skin barrier function and skin hydration to the deeper layers of the epidermis, leading to an improvement in skin appearance by reducing wrinkles and skin roughness. The multifunctional cosmetic formulation studied can be suggested to preventing signs of aging and improving skin conditions. In addition, this study presents the benefits of associating different active antioxidants substances in a single cosmetic formulation to prevent skin aging.

  13. Combinational enhancing effects of formulation and encapsulation on digestive stability and intestinal transport of green tea catechins.

    Science.gov (United States)

    Son, Yu-Ra; Chung, Jae-Hwan; Ko, Sanghoon; Shim, Soon-Mi

    2016-01-01

    The hypothesis was that green tea catechins (GTCs) formulated with vitamin C and xylitol followed by enteric coating with hydroxypropyl methyl cellulose phthalate (HPMCP) or encapsulated into γ-cyclodextrin (γ-CD) could enhance intestinal absorption of GTCs. Surface morphology and size obtained by SEM were different. Digestive stability of GTCs encapsulated into γ-CD or coated with HPMCP was enhanced up to 65.56% or 57.63%, respectively. When GTCs were formulated, the digestive stability was greater than the one not formulated. Formulated GTCs followed by encapsulation into γ-CD significantly increased intestinal transport. Absorption of GTCs was 2.8%, 9.64%, 11.97%, 8.41% and 14.36% for only GTCs, GTCs encapsulated into γ-CD, formulated GTCs encapsulated into γ-CD, GTCs coated with HPMCP and formulated GTCs coated with HPMCP, respectively. This study suggests that GTCs, formulated with vitamin C and xylitol followed by γ-CD encapsulation or HPMCP enteric coating, provide combinational effect to increase bioavailability of GTCs. PMID:26878684

  14. A rapid stability-indicating, fused-core HPLC method for simultaneous determination of β-artemether and lumefantrine in anti-malarial fixed dose combination products

    OpenAIRE

    Wega, Sultan Suleman; Vandercruyssen, Kirsten; Wynendaele, Evelien; D'Hondt, Matthias; Bracke, Nathalie; Duchateau, Luc; Burvenich, Christian; Peremans, Kathelijne; De Spiegeleer, Bart

    2013-01-01

    Background: Artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However, the current artemisinin FDC products, such as beta-artemether and lumefantrine, are inherently unstable and require controlled distribution and storage conditions, which are not always available in resource-limited settings. Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and s...

  15. Metabolite identification of the antimalarial piperaquine in vivo using liquid chromatography-high-resolution mass spectrometry in combination with multiple data-mining tools in tandem.

    Science.gov (United States)

    Yang, Aijuan; Zang, Meitong; Liu, Huixiang; Fan, Peihong; Xing, Jie

    2016-08-01

    Artemisinin-based combination therapy is widely used for the treatment of uncomplicated Plasmodium falciparum malaria, and piperaquine (PQ) is one of important partner drugs. The pharmacokinetics of PQ is characterized by a low clearance and a large volume of distribution; however, metabolism of PQ has not been thoroughly investigated. In this work, the metabolite profiling of PQ in human and rat was studied using liquid chromatography tandem high-resolution LTQ-Orbitrap mass spectrometry (HRMS). The biological samples were pretreated by solid-phase extraction. Data processes were carried out using multiple data-mining techniques in tandem, i.e., isotope pattern filter followed by mass defect filter. A total of six metabolites (M1-M6) were identified for PQ in human (plasma and urine) and rat (plasma, urine and bile). Three reported metabolites were also found in this study, which included N-oxidation (M1, M2) and carboxylic products (M3). The subsequent N-oxidation of M3 resulted in a new metabolite M4 detected in urine and bile samples. A new metabolic pathway N-dealkylation was found for PQ in human and rat, leading to two new metabolites (M5 and M6). This study demonstrated that LC-HRMS(n) in combination with multiple data-mining techniques in tandem can be a valuable analytical strategy for rapid metabolite profiling of drugs. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26821381

  16. Antimalarial qinghaosu/artemisinin: The therapy worthy of a Nobel Prize

    OpenAIRE

    Jerapan Krungkrai; Sudaratana Rochanakij Krungkrai

    2016-01-01

    Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu (Chinese name) and its derivatives are highly potent, rapidly acting antimalarial drugs. Art...

  17. Poor quality vital anti-malarials in Africa - an urgent neglected public health priority.

    OpenAIRE

    Newton Paul N; Green Michael D; Mildenhall Dallas C; Plançon Aline; Nettey Henry; Nyadong Leonard; Hostetler Dana M; Swamidoss Isabel; Harris Glenn A; Powell Kristen; Timmermans Ans E; Amin Abdinasir A; Opuni Stephen K; Barbereau Serge; Faurant Claude

    2011-01-01

    Abstract Background Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. Methods Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African coun...

  18. 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

  19. Review of pyronaridine anti-malarial properties and product characteristics

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    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.

  20. Anti-Malarial Plants of Jonai, India: an Ethnobotanical Approach

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    Tonlong WANGPAN

    2016-03-01

    Full Text Available North-East India represents a unique ecosystem with treasured medicinal plant wealth closely related with Folk medicines. A large number of plants having medicinal properties and their folk uses have remained confined to the natives of this region. The tribal community of Jonai, Assam was explored to expose the indigenous herbal remedy for malaria. Sixteen antimalarial plants belonging to 13 families were reported. The analysis revealed highest fidelity level (FL value for Ajuga integrifolia (100% followed by Ricinus communis (94%, Alstonia scholaris (88%, Oroxylum indicum (86% and Achyranthes aspera (82%. The percentage of respondent’s knowledge (PRK about anti-malarial plants showed Alstonia scholaris as the most commonly known antimalarial species (53% within this region. Preference ranking (PR unveiled eight species to be very effective against malarial parasite, which includes Allium sativum, Artemisia indica, Azadirachta indica, Carica papaya, Clerodendrum glandulosum, Ocimum tenuiflorum, Oroxylum indicum, Piper longum and Piper nigrum. All medicine preparations are made using water as the medium and are orally administered in the form of crude extract, powder, juice and decoction. Overall analysis suggested Ajuga integrifolia, Achyranthes aspera, Alstonia scholaris, Artemisia indica, Oroxylum indicum and Ricinus communis to be used for the development of novel, economical, effective and ecofriendly herbal formulations for healthcare management.

  1. Ketotifen Fumarate and Salbutamol Sulphate Combined Transdermal Patch Formulations: In vitro release and Ex vivo Permeation Studies.

    Science.gov (United States)

    Yousuf, M; Ahmad, M; Usman, M; Ali, I

    2013-09-01

    The present work was performed to develop and evaluate transdermal patches of combined antiasthmatic drugs (salbutamol sulphate and ketotifen fumarate). Polyvinyl alcohol membrane was used as backing membrane and eudragit RL-100 was used as matrix material to suspend the drugs in the continuous thickness of the patch. Methanol was solvent and propylene glycol was used as plasticizer. Tween 20, isopropyl myristate, eucalyptus oil, castor oil and span-20 were used as permeability enhancers. Thickness, weight variation and drug uniformity were investigated. The patch formulations were also subjected to drug release in dissolution media and permeation through rabbit skin. Effects of different enhancers were evaluated on release and permeation of drugs. F3 formulations having isopropyl myristate as permeation enhancer, showed maximum amounts of drugs release (88.11% of salbutamol sulphate and 88.33% of ketotifen fumarate) at the end of 24 h dissolution study. F3 also showed maximum permeation of both drugs (4.235 mg salbutamol sulphate and 1.057 mg ketotifen fumarate) after 24 h permeation study through rabbit skin mounted in Franz cell. The patches having no enhancer in the formulation also showed some drug release and permeation due to the presence of plasticizer. The results of the study suggested that new controlled release transdermal formulations of combined antiasthmatic drugs can be suitably developed as an alternate to conventional dosage forms. PMID:24403658

  2. Ketotifen fumarate and salbutamol sulphate combined transdermal patch formulations: In vitro release and Ex vivo permeation studies

    Directory of Open Access Journals (Sweden)

    M Yousuf

    2013-01-01

    Full Text Available The present work was performed to develop and evaluate transdermal patches of combined antiasthmatic drugs (salbutamol sulphate and ketotifen fumarate. Polyvinyl alcohol membrane was used as backing membrane and eudragit RL-100 was used as matrix material to suspend the drugs in the continuous thickness of the patch. Methanol was solvent and propylene glycol was used as plasticizer. Tween 20, isopropyl myristate, eucalyptus oil, castor oil and span-20 were used as permeability enhancers. Thickness, weight variation and drug uniformity were investigated. The patch formulations were also subjected to drug release in dissolution media and permeation through rabbit skin. Effects of different enhancers were evaluated on release and permeation of drugs. F3 formulations having isopropyl myristate as permeation enhancer, showed maximum amounts of drugs release (88.11% of salbutamol sulphate and 88.33% of ketotifen fumarate at the end of 24 h dissolution study. F3 also showed maximum permeation of both drugs (4.235 mg salbutamol sulphate and 1.057 mg ketotifen fumarate after 24 h permeation study through rabbit skin mounted in Franz cell. The patches having no enhancer in the formulation also showed some drug release and permeation due to the presence of plasticizer. The results of the study suggested that new controlled release transdermal formulations of combined antiasthmatic drugs can be suitably developed as an alternate to conventional dosage forms.

  3. Formulation and evaluation of starch acetate matrix tablets in combination with surfactants for controlled release”

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    Mahesh Kumar Vishwanadha

    2015-04-01

    Full Text Available In the present study, an attempt has been made to evaluate starch acetate in combination with surfactant for the controlled release profile of drug from matrix system. Ibuprofen was used as a model drug to evaluate its release characteristics from different matrices. Starch acetate was synthesized, characterized and then employed in the matrix tablets as a hydrophobic polymer in different ratios in combination with SLS. Formulated tablets were characterized for parameters like thickness, weight variation, drug content uniformity, hardness, friability and in-vitro release rate profile and the release data were analysed as per various kinetic models. From the data it was found that the release was following first order kinetics for all the formulationsexcept F8 release profile of which followed zero order and the mechanism of release was found to be Non-fickian diffusion for all the formulations.

  4. Potential antimalarials from African natural products: a review

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    Bashir Lawal

    2015-12-01

    Full Text Available Ethnopharmacological relevance: Malaria remains an overwhelming infectious disease with significant health challenges in African and other endemic countries globally. Resistance to antimalarial drugs has become one of the most momentous challenges to human health and thus has necessitated the hunt for new and effective drugs. Consequently, few decades have witnessed a surfeit of research geared to validate the effectiveness of commonly used traditionally medicines against malaria fever. The present review work focuses on documenting natural products from African whose activity has been reported in-vivo or invi-tro against malaria parasite. Methods: Literature was collected using electronic search of published articles (Google Scholar, PubMed, Medline, Sciencedirect, Science domain that report on antiplasmodial activity of natural products from differernts Africa region. Results: A Total of 652 plant taxa from 146 families, 134 isolated antimalarial compounds from 39 plants species, 2 herbal formulations and 4 insect/products were found to be reported in literature from 1996 to 2015. Plants species from family Asteraceae (11.04%, Fababceae (8.128%, Euphorbiaceae (5.52%, Rubiaceas (5.52% and Apocyanaceae (5.214%, have received more scientific validation than others. Conclusion: African natural products possess remarkable healing properties as revealed in the various citations as promising antimalarial agents. Some of these natural products from Africa demonstrate high, promising or low activities against plasmodium parasite. This study also shows that natural products from Africa have a huge amount of novel antimalarial compounds that could serve as a leads for the development of new and effective antiplasmodial drugs. However, in a view of bridging the gap in knowledge, clinical validation of these natural products is of paramount importance. [J Intercult Ethnopharmacol 2015; 4(4.000: 318-343

  5. Natural products as starting points for future anti-malarial therapies: going back to our roots?

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    Wells Timothy NC

    2011-03-01

    Full Text Available Abstract Background The discovery and development of new anti-malarials are at a crossroads. Fixed dose artemisinin combination therapy is now being used to treat a hundred million children each year, with a cost as low as 30 cents per child, with cure rates of over 95%. However, as with all anti-infective strategies, this triumph brings with it the seeds of its own downfall, the emergence of resistance. It takes ten years to develop a new medicine. New classes of medicines to combat malaria, as a result of infection by Plasmodium falciparum and Plasmodium vivax are urgently needed. Results Natural product scaffolds have been the basis of the majority of current anti-malarial medicines. Molecules such as quinine, lapachol and artemisinin were originally isolated from herbal medicinal products. After improvement with medicinal chemistry and formulation technologies, and combination with other active ingredients, they now make up the current armamentarium of medicines. In recent years advances in screening technologies have allowed testing of millions of compounds from pharmaceutical diversity for anti-malarial activity in cellular assays. These initiatives have resulted in thousands of new sub-micromolar active compounds – starting points for new drug discovery programmes. Against this backdrop, the paucity of potent natural products identified has been disappointing. Now is a good time to reflect on the current approach to screening herbal medicinal products and suggest revisions. Nearly sixty years ago, the Chinese doctor Chen Guofu, suggested natural products should be approached by dao-xing-ni-shi or ‘acting in the reversed order’, starting with observational clinical studies. Natural products based on herbal remedies are in use in the community, and have the potential unique advantage that clinical observational data exist, or can be generated. The first step should be the confirmation and definition of the clinical activity of herbal

  6. STUDIES ON FORMULATION AND EVALUATION OF GLIPIZIDE AND PARECOXIB COMBINATION MUCOADHESIVE TABLETS

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    Narasimha Reddy D

    2011-02-01

    Full Text Available The main purpose of present investigation is to extend the release of drug from the dosage form at a particular site and controlling the release of drug from the dosage form and achieving controlled plasma level of the drug as well as improving bioavailability. The study was performed by selecting Glipizide and Parecoxib drugs. The mucoadhesive tablets were prepared to achieve controlled plasma level of the drug which is especially in diabetes mellitus patients with pain therapy. The tablets were prepared by direct compression technique. Both the drugs were found compatible with the excipient used. All the formulations were found to have good pre compression and post compression parameters. The optimized formulation was subjected to accelerated stability studies.

  7. Antimalarial natural products: a review

    Directory of Open Access Journals (Sweden)

    Faraz Mojab

    2012-03-01

    Results and Conclusion: There is an urgent need for the development of new treatments for malaria. Many countries have a vast precedence in the use of medicinal plants and the required knowledge spans many centuries. Although malaria is controlled in Iran, some researchers tend to study malaria and related subjects. In vitro biological tests for the detection of antimalarial activities in plant extracts are currently available. It is vital that the efficacy and safety of traditional medicines be validated and their active constituents be identified in order to establish reliable quality control measures.

  8. Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network.

    Science.gov (United States)

    Cui, Liwang; Mharakurwa, Sungano; Ndiaye, Daouda; Rathod, Pradipsinh K; Rosenthal, Philip J

    2015-09-01

    Antimalarial drugs are key tools for the control and elimination of malaria. Recent decreases in the global malaria burden are likely due, in part, to the deployment of artemisinin-based combination therapies. Therefore, the emergence and potential spread of artemisinin-resistant parasites in southeast Asia and changes in sensitivities to artemisinin partner drugs have raised concerns. In recognition of this urgent threat, the International Centers of Excellence for Malaria Research (ICEMRs) are closely monitoring antimalarial drug efficacy and studying the mechanisms underlying drug resistance. At multiple sentinel sites of the global ICEMR network, research activities include clinical studies to track the efficacies of antimalarial drugs, ex vivo/in vitro assays to measure drug susceptibilities of parasite isolates, and characterization of resistance-mediating parasite polymorphisms. Taken together, these efforts offer an increasingly comprehensive assessment of the efficacies of antimalarial therapies, and enable us to predict the emergence of drug resistance and to guide local antimalarial drug policies. Here we briefly review worldwide antimalarial drug resistance concerns, summarize research activities of the ICEMRs related to drug resistance, and assess the global impacts of the ICEMR programs. PMID:26259943

  9. Development of a combined solution formulation of atropine sulfate and obidoxime chloride for autoinjector and evaluation of its stability.

    Science.gov (United States)

    Ettehadi, Hossein Ali; Ghalandari, Rouhollah; Shafaati, Alireza; Foroutan, Seyed Mohsen

    2013-01-01

    Atropine (AT) and oximes, alone or in combination, have been proven greatly valuable therapeutics in the treatment of organophosphates intoxications. An injectable mixture of AT and obidoxime (OB) was formulated for the administration by automatic self-injector. The aqueous single dose solution contained 275 mg obidoxime chloride and 2.5 mg atropine sulfate per 1 mL (220 mg and 2 mg per 0.8 effective dose, respectively). The final solution was sterilized by filtration through a 0.22 μm pore size filter. This more concentrated solution allowed to use a smaller size and lighter weight cartridge. Quality control tests, including assay of the two major compounds were performed separately, using reversed-phase HPLC methods. Besides, the stability test was carried out according to ICH guideline for the accelerated test. The obtained results showed that the proposed formulation is stable over a period of 2 years after preparation. PMID:24250669

  10. Quality of Artemisinin-Based Combination Formulations for Malaria Treatment: Prevalence and Risk Factors for Poor Quality Medicines in Public Facilities and Private Sector Drug Outlets in Enugu, Nigeria

    OpenAIRE

    Harparkash Kaur; Elizabeth Louise Allan; Ibrahim Mamadu; Zoe Hall; Ogochukwu Ibe; Mohamed El Sherbiny; Albert van Wyk; Shunmay Yeung; Isabel Swamidoss; Green, Michael D.; Prabha Dwivedi; Maria Julia Culzoni; Siân Clarke; David Schellenberg; Fernández, Facundo M.

    2015-01-01

    Background Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO) as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artem...

  11. Efficacy of Combined Formulations of Fungicides with Different Modes of Action in Controlling Botrytis Gray Mold Disease in Chickpea

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    M. H. Rashid

    2014-01-01

    Full Text Available Botrytis gray mold (BGM caused by Botrytis cinerea Pers. Ex. Fr. is an extremely devastating disease of chickpea (Cicer arietinum L. and has a regional as well as an international perspective. Unfortunately, nonchemical methods for its control are weak and ineffective. In order to identify an effective control measure, six fungicides with different modes of action were evaluated on a BGM susceptible chickpea variety BARIchhola-1 at a high BGM incidence location (Madaripur in Bangladesh for three years (2008, 2009, and 2010. Among the six fungicides tested, one was protectant [Vondozeb 42SC, a.i. mancozeb (0.2%], two systemic [Bavistin 50 WP, a.i. carbendazim (0.2%, and Protaf 250EC, propiconazole (0.05%], and three combination formulations [Acrobat MZ690, dimethomorph 9% + mancozeb 60%, (0.2%; Secure 600 WG, phenomadone + mancozeb (0.2%; and Companion, mancozeb 63% + carbendazim 12% (0.2%]. The results showed superiority of combination formulations involving both protectant and systemic fungicides over the sole application of either fungicide separately. Among the combination fungicides, Companion was most effective, resulting in the lowest disease severity (3.33 score on 1–9 scale and the highest increase (38% of grain yield in chickpea. Therefore, this product could be preferred over the sole application of either solo protectant or systemic fungicides to reduce yield losses and avoid fungicide resistance.

  12. Fast Disintegrating Combination Tablet of Taste Masked Levocetrizine Dihydrochloride and Montelukast Sodium: Formulation Design, Development, and Characterization

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    M. M. Gupta

    2014-01-01

    Full Text Available The aim of this study was to prepare fast disintegrating combination tablet of taste masked Levocetrizine dihydrochloride and Montelukast sodium by using direct compression method. To prevent bitter taste and unacceptable odour of the Levocetrizine dihydrochloride drug, the drug was taste masked with ion exchange resins like Kyron-T-104 and Tulsion-412. Among the two resins, Kyron-T-104 was selected for further studies because of high drug loading capacity, low cost, and better drug release profile. An ion exchange resin complex was prepared by the batch technique and various parameters; namely, resin activation, drug: resin ratio, pH, temperature, and stirring time, and swelling time were optimized to successfully formulate the tasteless drug resin complex (DRC. The tablets were prepared using microcrystalline cellulose (MCC PH 102 as diluent along with crospovidone (CP, croscarmellose sodium (CCM, and sodium starch glycolate (SSG as a superdisintegrants. The tablets were evaluated for weight variation, hardness, friability, wetting time, water absorption ratio, disintegration time (DT, and dissolution study and it was concluded that the tablet formulation prepared with 2% SSG + CCS showed better disintegration time in comparison with other formulation and good drug release. The stability studies were carried out for the optimized batch for three months and it showed acceptable results.

  13. Fast Disintegrating Combination Tablet of Taste Masked Levocetrizine Dihydrochloride and Montelukast Sodium: Formulation Design, Development, and Characterization.

    Science.gov (United States)

    Gupta, M M; Gupta, Niraj; Chauhan, Bhupendra S; Pandey, Shweta

    2014-01-01

    The aim of this study was to prepare fast disintegrating combination tablet of taste masked Levocetrizine dihydrochloride and Montelukast sodium by using direct compression method. To prevent bitter taste and unacceptable odour of the Levocetrizine dihydrochloride drug, the drug was taste masked with ion exchange resins like Kyron-T-104 and Tulsion-412. Among the two resins, Kyron-T-104 was selected for further studies because of high drug loading capacity, low cost, and better drug release profile. An ion exchange resin complex was prepared by the batch technique and various parameters; namely, resin activation, drug: resin ratio, pH, temperature, and stirring time, and swelling time were optimized to successfully formulate the tasteless drug resin complex (DRC). The tablets were prepared using microcrystalline cellulose (MCC) PH 102 as diluent along with crospovidone (CP), croscarmellose sodium (CCM), and sodium starch glycolate (SSG) as a superdisintegrants. The tablets were evaluated for weight variation, hardness, friability, wetting time, water absorption ratio, disintegration time (DT), and dissolution study and it was concluded that the tablet formulation prepared with 2% SSG + CCS showed better disintegration time in comparison with other formulation and good drug release. The stability studies were carried out for the optimized batch for three months and it showed acceptable results. PMID:26556198

  14. A database of antimalarial drug resistance

    Directory of Open Access Journals (Sweden)

    Ringwald Pascal

    2006-06-01

    Full Text Available Abstract A large investment is required to develop, license and deploy a new antimalarial drug. Too often, that investment has been rapidly devalued by the selection of parasite populations resistant to the drug action. To understand the mechanisms of selection, detailed information on the patterns of drug use in a variety of environments, and the geographic and temporal patterns of resistance is needed. Currently, there is no publically-accessible central database that contains information on the levels of resistance to antimalaria drugs. This paper outlines the resources that are available and the steps that might be taken to create a dynamic, open access database that would include current and historical data on clinical efficacy, in vitro responses and molecular markers related to drug resistance in Plasmodium falciparum and Plasmodium vivax. The goal is to include historical and current data on resistance to commonly used drugs, like chloroquine and sulfadoxine-pyrimethamine, and on the many combinations that are now being tested in different settings. The database will be accessible to all on the Web. The information in such a database will inform optimal utilization of current drugs and sustain the longest possible therapeutic life of newly introduced drugs and combinations. The database will protect the valuable investment represented by the development and deployment of novel therapies for malaria.

  15. Formulation and in vitro evaluation of nifedipine-controlled release tablet: Influence of combination of hydrophylic and hydrophobic matrix forms

    Directory of Open Access Journals (Sweden)

    Derakhshandeh Katayoun

    2010-01-01

    Full Text Available The aim of the present work was to develop controlled release matrix formulation of nifedipine and investigate the effects of both hydrophilic and hydrophobic polymers on in vitro drug release. Matrix tablets were prepared by wet granulation technique using different concentration of hydroxy propyl methyl cellulose (HPMC, ethyl cellulose (EC, compressible Eudragits (RSpo and RLpo and their combination in different ratios to examine their influence on tablet properties and drug release profile. Tablets were evaluated by measurement of hardness, friability, content uniformity, weight variation and drug release pattern. Release studies were carried out using USP type II apparatus in 900 ml of sodium phosphate buffer (pH 7.4 with 0.5% (w/v SDS. The amount of drug released was determined at 238 nm by UV-visible spectrophotometer.In vitro dissolution studies indicated that hydrophobic polymers significantly reduced the rate of drug release compared to hydrophilic ones in 12 hrs and combination of both polymers exhibited the best release profile to sustain the drug release for prolong period of time. As a result, the tablet containing HPMC:EC in ratio of 0.75:1 showed better controlled release pattern over a period of 12 hrs. In selected formulation, the calculated regression coefficients for release models fitted best to zero-order models.

  16. 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...

  17. Comparative Study of Different Combinational Mucoadhesive Formulations of Sumatriptan-Metoclopramide

    OpenAIRE

    Mitra Jelvehgari; Hadi Valizadeh; Sanam Ziapour; Mahdieh Rahmani; Seyed Hassan Montazam; Saieede Soltani

    2016-01-01

    Purpose: Sumatriptan succinate (Sum) is a Serotonin 5- HT1 receptor agonist, used in the treatment of migraine. It is absorbed rapidly but incompletely when taken orally and underwent first - pass metabolism, resulting in a low bioavailability of about 15%. The aim was to design mucoadhesive buccal discs and sublingual films of Sum and metoclopramide (Met) combined to improve their bioavailability. Methods: In the current study, the microparticles and films were prepared ...

  18. Monoclonal Antibodies That Recognize the Alkylation Signature of Antimalarial Ozonides OZ277 (Arterolane) and OZ439 (Artefenomel)

    OpenAIRE

    Jourdan, Joëlle; Matile, Hugues; Reift, Ellen; Biehlmaier, Oliver; Dong, Yuxiang; Wang, Xiaofang; Mäser, Pascal; Vennerstrom, Jonathan L.; Wittlin, Sergio

    2015-01-01

    The singular structure of artemisinin, with its embedded 1,2,4-trioxane heterocycle, has inspired the discovery of numerous semisynthetic artemisinin and structurally diverse synthetic peroxide antimalarials, including ozonides OZ277 (arterolane) and OZ439 (artefenomel). Despite the critical importance of artemisinin combination therapies (ACTs), the precise mode of action of peroxidic antimalarials is not fully understood. However, it has long been proposed that the peroxide bond in artemisi...

  19. Optimization of formulation of soy-cakes baked in infrared-microwave combination oven by response surface methodology.

    Science.gov (United States)

    Şakıyan, Özge

    2015-05-01

    The aim of present work is to optimize the formulation of a functional cake (soy-cake) to be baked in infrared-microwave combination oven. For this optimization process response surface methodology was utilized. It was also aimed to optimize the processing conditions of the combination baking. The independent variables were the baking time (8, 9, 10 min), the soy flour concentration (30, 40, 50 %) and the DATEM (diacetyltartaric acid esters of monoglycerides) concentration (0.4, 0.6 and 0.8 %). The quality parameters that were examined in the study were specific volume, weight loss, total color change and firmness of the cake samples. The results were analyzed by multiple regression; and the significant linear, quadratic, and interaction terms were used in the second order mathematical model. The optimum baking time, soy-flour concentration and DATEM concentration were found as 9.5 min, 30 and 0.72 %, respectively. The corresponding responses of the optimum points were almost comparable with those of conventionally baked soy-cakes. So it may be declared that it is possible to produce high quality soy cakes in a very short time by using infrared-microwave combination oven. PMID:25892790

  20. Formulation and evaluation of a topical niosomal gel containing a combination of benzoyl peroxide and tretinoin for antiacne activity

    Directory of Open Access Journals (Sweden)

    Gupta A

    2014-12-01

    Full Text Available Ankush Gupta,1,* Sima Singh,1,* Niranjan G Kotla,1 Thomas J Webster2,3 1Department of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India; 2Department of Chemical Engineering, Northeastern University, Boston, MA, USA; 3Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia *These authors contributed equally to this work Abstract: A skin disease, like acne, is very common and normally happens to everyone at least once in their lifetime. The structure of the stratum corneum is often compared with a brick wall, with corneocytes surrounded by the mortar of the intercellular lipid lamellae. One of the best options for successful drug delivery to the affected area of skin is the use of elastic vesicles (niosomes which can be transported through the skin through channel-like structures. In this study, a combination of tretinoin (keratolytic agent and benzoyl peroxide (BPO (a potent antibacterial was given by using niosomes as promising carriers for the effective treatment of acne by acting on a pathogenic site. In this section, niosomal gel formulation encapsulated drugs have been evaluated for in vitro, ex vivo, and in vivo, for their predetermined characteristics; and finally the stability of the niosome gel was tested at different temperature conditions for understanding of the storage conditions required for maintaining the quality of formulation attributes. The prepared niosome was found to be in the range of 531 nm with a zeta potential of -43 mV; the entrapment efficiencies of tretinoin (TRA and BPO niosomes were found to be 96.25%±0.56% and 98.75%±1.25%, respectively. The permeated amount of TRA and BPO from the niosomal gel after 24 hours was calculated as 6.25±0.14 µg/cm2 and 5.04±0.014 µg/cm2, respectively. A comparative drug retention study in Wistar rat skin using cream, an alcoholic solution, and a niosomal gel showed 11.54 µg, 2.68 µg, and 15.54 µg

  1. Recent developments in naturally derived antimalarials: cryptolepine analogues.

    Science.gov (United States)

    Wright, Colin W

    2007-06-01

    Increasing resistance of Plasmodium falciparum to commonly used antimalarial drugs has made the need for new agents increasingly urgent. In this paper, the potential of cryptolepine, an alkaloid from the West African shrub Cryptolepis sanguinolenta, as a lead towards new antimalarial agents is discussed. Several cryptolepine analogues have been synthesized that have promising in-vitro and in-vivo antimalarial activity. Studies on the antimalarial modes of action of these analogues indicate that they may have different or additional modes of action to the parent compound. Elucidation of the mode of action may facilitate the development of more potent antimalarial cryptolepine analogues. PMID:17637183

  2. Probing the antimalarial mechanism of artemisinin and OZ277 (arterolane) with nonperoxidic isosteres and nitroxyl radicals.

    Science.gov (United States)

    Fügi, Matthias A; Wittlin, Sergio; Dong, Yuxiang; Vennerstrom, Jonathan L

    2010-03-01

    Peroxidic antimalarials such as the semisynthetic artemisinins are critically important in the treatment of drug-resistant malaria. Nevertheless, their peroxide bond-dependent mode of action is still not well understood. Using combination experiments with cultured Plasmodium falciparum cells, we investigated the interactions of the nitroxide radical spin trap, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and four of its analogs with artemisinin and the ozonide drug development candidate OZ277. The antagonism observed for combinations of artemisinin or OZ277 with the TEMPO analogs supports the hypothesis that the formation of carbon-centered radicals is critical for the activity of these two antimalarial peroxides. The TEMPO analogs showed a trend toward greater antagonism with artemisinin than they did with OZ277, an observation that can be explained by the greater tendency of artemisinin-derived carbon-centered radicals to undergo internal self-quenching reactions, resulting in a lower proportion of radicals available for subsequent chemical reactions such as the alkylation of heme and parasite proteins. In a further mechanistic experiment, we tested both artemisinin and OZ277 in combination with their nonperoxidic analogs. The latter had no effect on the antimalarial activities of the former. These data indicate that the antimalarial properties of peroxides do not derive from reversible interactions with parasite targets. PMID:20028825

  3. Fake anti-malarials: start with the facts.

    Science.gov (United States)

    Kaur, Harparkash; Clarke, Siȃn; Lalani, Mirza; Phanouvong, Souly; Guérin, Philippe; McLoughlin, Andrew; Wilson, Benjamin K; Deats, Michael; Plançon, Aline; Hopkins, Heidi; Miranda, Debora; Schellenberg, David

    2016-01-01

    This meeting report presents the key findings and discussion points of a 1-day meeting entitled 'Fake anti-malarials: start with the facts' held on 28th May 2015, in Geneva, Switzerland, to disseminate the findings of the artemisinin combination therapy consortium's drug quality programme. The teams purchased over 10,000 samples, using representative sampling approaches, from six malaria endemic countries: Equatorial Guinea (Bioko Island), Cambodia, Ghana, Nigeria, Rwanda and Tanzania. Laboratory analyses of these samples showed that falsified anti-malarials (<8 %) were found in just two of the countries, whilst substandard artemisinin-based combinations were present in all six countries and, artemisinin-based monotherapy tablets are still available in some places despite the fact that the WHO has urged regulatory authorities in malaria-endemic countries to take measures to halt the production and marketing of these oral monotherapies since 2007. This report summarizes the presentations that reviewed the public health impact of falsified and substandard drugs, sampling strategies, techniques for drug quality analysis, approaches to strengthen health systems capacity for the surveillance of drug quality, and the ensuing discussion points from the dissemination meeting. PMID:26873700

  4. Case management of malaria fever in Cambodia: results from national anti-malarial outlet and household surveys

    Directory of Open Access Journals (Sweden)

    Littrell Megan

    2011-10-01

    Full Text Available Abstract Background Continued progress towards global reduction in morbidity and mortality due to malaria requires scale-up of effective case management with artemisinin-combination therapy (ACT. The first case of artemisinin resistance in Plasmodium falciparum was documented in western Cambodia. Spread of artemisinin resistance would threaten recent gains in global malaria control. As such, the anti-malarial market and malaria case management practices in Cambodia have global significance. Methods Nationally-representative household and outlet surveys were conducted in 2009 among areas in Cambodia with malaria risk. An anti-malarial audit was conducted among all public and private outlets with the potential to sell anti-malarials. Indicators on availability, price and relative volumes sold/distributed were calculated across types of anti-malarials and outlets. The household survey collected information about management of recent "malaria fevers." Case management in the public versus private sector, and anti-malarial treatment based on malaria diagnostic testing were examined. Results Most public outlets (85% and nearly half of private pharmacies, clinics and drug stores stock ACT. Oral artemisinin monotherapy was found in pharmacies/clinics (9%, drug stores (14%, mobile providers (4% and grocery stores (2%. Among total anti-malarial volumes sold/distributed nationally, 6% are artemisinin monotherapies and 72% are ACT. Only 45% of people with recent "malaria fever" reportedly receive a diagnostic test, and the most common treatment acquired is a drug cocktail containing no identifiable anti-malarial. A self-reported positive diagnostic test, particularly when received in the public sector, improves likelihood of receiving anti-malarial treatment. Nonetheless, anti-malarial treatment of reportedly positive cases is low among people who seek treatment exclusively in the public (61% and private (42% sectors. Conclusions While data on the anti-malarial

  5. Monitoring antimalarial safety and tolerability in clinical trials: A case study from Uganda

    Directory of Open Access Journals (Sweden)

    Mpimbaza Arthur

    2008-06-01

    Full Text Available Abstract Background New antimalarial regimens, including artemisinin-based combination therapies (ACTs, have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials. Case description Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity. Discussion and evaluation Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported. Conclusion Although the World Health Organization has supported the development of

  6. Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies

    Directory of Open Access Journals (Sweden)

    Dondorp Arjen M

    2008-11-01

    Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with

  7. Optimization of operation for combined heat and power plants - CHP plants - with heat accumulators using a MILP formulation

    Energy Technology Data Exchange (ETDEWEB)

    Grue, Jeppe; Bach, Inger [Aalborg Univ. (Denmark). Inst. of Energy Technology]. E-mails: jeg@iet.auc.dk; ib@iet.auc.dk

    2000-07-01

    The power generation system in Denmark is extensively based on small combined heat and power plants (CHP plants), producing both electricity and district heating. This project deals with smaller plants spread throughout the country. Often a heat accumulator is used to enable electricity production, even when the heat demand is low. This system forms a very complex problem, both for sizing, designing and operation of CHP plants. The objective of the work is the development of a tool for optimisation of the operation of CHP plants, and to even considering the design of the plant. The problem is formulated as a MILP-problem. An actual case is being tested, involving CHP producing units to cover the demand. The results from this project show that it is of major importance to consider the operation of the plant in detail already in the design phase. It is of major importance to consider the optimisation of the plant operation, even at the design stage, as it may cause the contribution margin to rise significantly, if the plant is designed on the basis of a de-tailed knowledge of the expected operation. (author)

  8. Improving the controlled delivery formulations of caffeine in alginate hydrogel beads combined with pectin, carrageenan, chitosan and psyllium.

    Science.gov (United States)

    Belščak-Cvitanović, Ana; Komes, Draženka; Karlović, Sven; Djaković, Senka; Spoljarić, Igor; Mršić, Gordan; Ježek, Damir

    2015-01-15

    Alginate-based blends consisting of carrageenan, pectin, chitosan or psyllium husk powder were prepared for assessment of the best formulation aimed at encapsulation of caffeine. Alginate-pectin blend exhibited the lowest viscosity and provided the smallest beads. Alginate-psyllium husk blend was characterised with higher viscosity, yielding the largest bead size and the highest caffeine encapsulation efficiency (83.6%). The release kinetics of caffeine indicated that the porosity of alginate hydrogel was not reduced sufficiently to retard the diffusion of caffeine from the beads. Chitosan coated alginate beads provided the most retarded release of caffeine in water. Morphological characteristics of beads encapsulating caffeine were adversely affected by freeze drying. Bitterness intensity of caffeine-containing beads in water was the lowest for alginate-psyllium beads and chitosan coated alginate beads. Higher sodium alginate concentration (3%) for production of hydrogel beads in combination with psyllium or chitosan coating would present the most favourable carrier systems for immobilization of caffeine. PMID:25149001

  9. DEVELOPMENT AND VALIDATION OF SPECTROPHOTOMETRIC METHODS FOR SIMULTANEOUS ESTIMATION OF METOPROLOL SUCCINATE AND TELMISARTAN IN COMBINED PHARMACEUTICAL FORMULATION

    Directory of Open Access Journals (Sweden)

    Mayur Modi*, Rikin Shah and R.C. Mashru

    2012-05-01

    Full Text Available Four simple, rapid, precise, economical and accurate spectrophotometric methods have been developed for simultaneous analysis of Metoprolol succinate and Telmisartan in their combined dosage form. Method 1, First derivative simultaneous equation method (Vierodt’s method. It employs formation and solving of simultaneous equation using two wavelengths 230.2 nm (λmax of Metoprolol succinate and 237 nm (λmax of Telmisartan in first derivative spectra. Method 2, First derivative Q-Absorbance equation method. It involves, formation of Q-absorbance equation at 231.8 nm (isoabsorptive point and 237 nm (λmax of Telmisartan in first derivative spectra. Method 3, Absorbance correction method, involves measurement of absorbance at 296.6 nm for estimation of TEL and measurement of corrected absorbance at 223 nm for estimation of MET. Method 4, Combination of First derivative dual wavelength ,which uses the difference in absorbance at 282.4 nm and 284.6 nm for estimation of MET and zero crossing first derivative spectrophotometry involves measurement of amplitudes at 330 nm for estimation of TEL in first derivative spectra. Developed methods were validated according to ICH guidelines. The calibration graph follows Beer’s law in the range of 3-20 µg/ml for MET and 4-16 µg/ml for TEL with R square value greater than 0.999. Accuracy of all methods was determined by recovery studies and showed % recovery between 99 to 101%. Intraday and interday precision was checked for all methods and mean %RSD was found to be less than 2 for all the methods. The methods were successfully applied for estimation of MET and TEL in marketed formulation.

  10. Study of the effect of formulation variables on the characteristics of combination tablets containing enalapril maleate and indapamide as active substances using experimental design

    Directory of Open Access Journals (Sweden)

    Szabó Zoltán-István

    2016-06-01

    Full Text Available To evaluate the influence of different variables on tablet formulations containing enalapril maleate and indapamide as active substances, two separate experimental designs were employed: one for evaluating powder properties and the other for tablet characteristics. Because of the low active pharmaceutical ingredient content, it was hypothesized that both powder and tablet properties could be determined only by the characteristics of excipients. In order to test this assumption, both experimental designs were done with placebo mixtures. The optimized formulation was then evaluated both with and without APIs. Results indicated that filler and lubricant percentage, along with compression force, were the most important variables during the formulation study. The optimized formulation showed similar characteristics in both cases for all responses, except for angle of repose and friability where only minor differences were observed. The combination of the applied approaches (using placebo composition and fractional experimental design proved to be efficient, cost effective and time saving.

  11. Study of the effect of formulation variables on the characteristics of combination tablets containing enalapril maleate and indapamide as active substances using experimental design.

    Science.gov (United States)

    Szabó, Zoltán-István; Székely-Szentmiklósi, Blanka; Deák, Boglárka; Székely-Szentmiklósi, István; Kovács, Béla; Zöldi, Katalin; Sipos, Emese

    2016-06-01

    To evaluate the influence of different variables on tablet formulations containing enalapril maleate and indapamide as active substances, two separate experimental designs were employed: one for evaluating powder properties and the other for tablet characteristics. Because of the low active pharmaceutical ingredient content, it was hypothesized that both powder and tablet properties could be determined only by the characteristics of excipients. In order to test this assumption, both experimental designs were done with placebo mixtures. The optimized formulation was then evaluated both with and without APIs. Results indicated that filler and lubricant percentage, along with compression force, were the most important variables during the formulation study. The optimized formulation showed similar characteristics in both cases for all responses, except for angle of repose and friability where only minor differences were observed. The combination of the applied approaches (using placebo composition and fractional experimental design) proved to be efficient, cost effective and time saving. PMID:27279063

  12. Substandard anti-malarial drugs in Burkina Faso

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    Sie Ali

    2008-05-01

    Full Text Available Abstract Background There is concern about an increasing infiltration of markets by substandard and fake medications against life-threatening diseases in developing countries. This is particularly worrying with regard to the increasing resistance development of Plasmodium falciparum against affordable anti-malarial medications, which has led to a change to more expensive drugs in most endemic countries. Methods A representative sample of modern anti-malarial medications from licensed (public and private pharmacies, community health workers and illicit (market and street vendors, shops sources has been collected in the Nouna Health District in north-western Burkina Faso in 2006. All drugs were tested for their quality with the standard procedures of the German Pharma Health Fund-Minilab. Detected low standard drugs were re-tested with European Pharmacopoeia 2.9.1 standards for disintegration and ultraviolet-visible spectroscopy at the laboratory of the Heidelberg University for confirmation. Results Overall, 86 anti-malarial drug samples were collected, of which 77 samples have been included in the final analysis. The sample consisted of 39/77 (50% chloroquine, 10/77 (13% pyrimethamine-sulphadoxine, 9/77 (12% quinine, 6/77 (8% amodiaquine, 9/77 (12% artesunate, and 4/77 (5% artemether-lumefantrine. 32/77 (42% drug samples were found to be of poor quality, of which 28 samples failed the visual inspection, nine samples had substandard concentrations of the active ingredient, four samples showed poor disintegration, and one sample contained non of the stated active ingredient. The licensed and the illicit market contributed 5/47 (10.6% and 27/30 (90.0% samples of substandard drugs respectively. Conclusion These findings provide further evidence for the wide-spread existence of substandard anti-malarial medications in Africa and call for strengthening of the regulatory and quality control capacity of affected countries, particularly in view of the

  13. The ACTwatch project: methods to describe anti-malarial markets in seven countries

    Directory of Open Access Journals (Sweden)

    Chapman Steven

    2011-10-01

    Full Text Available Abstract Background Policy makers, governments and donors are faced with an information gap when considering ways to improve access to artemisinin-based combination therapy (ACT and malaria diagnostics including rapid diagnostic tests (RDTs. To help address some of these gaps, a five-year multi-country research project called ACTwatch was launched. The project is designed to provide a comprehensive picture of the anti-malarial market to inform national and international anti-malarial drug policy decision-making. Methods The project is being conducted in seven malaria-endemic countries: Benin, Cambodia, the Democratic Republic of Congo, Madagascar, Nigeria, Uganda and Zambia from 2008 to 2012. ACTwatch measures which anti-malarials are available, where they are available and at what price and who they are used by. These indicators are measured over time and across countries through three study components: outlet surveys, supply chain studies and household surveys. Nationally representative outlet surveys examine the market share of different anti-malarials passing through public facilities and private retail outlets. Supply chain research provides a picture of the supply chain serving drug outlets, and measures mark-ups at each supply chain level. On the demand side, nationally representative household surveys capture treatment seeking patterns and use of anti-malarial drugs, as well as respondent knowledge of anti-malarials. Discussion The research project provides findings on both the demand and supply side determinants of anti-malarial access. There are four key features of ACTwatch. First is the overlap of the three study components where nationally representative data are collected over similar periods, using a common sampling approach. A second feature is the number and diversity of countries that are studied which allows for cross-country comparisons. Another distinguishing feature is its ability to measure trends over time. Finally, the

  14. Antimalarial qinghaosu/artemisinin: The therapy worthy of a Nobel Prize

    Directory of Open Access Journals (Sweden)

    Jerapan Krungkrai

    2016-05-01

    Full Text Available Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu (Chinese name and its derivatives are highly potent, rapidly acting antimalarial drugs. Artemisinin was discovered in 1971 by a Chinese medical scientist Youyou Tu, who was awarded the Nobel Prize in 2015 on her discovering the antimalarial properties of qinghaosu from the traditional Chinese qinghao plant. Nevertheless, artemisinin resistance in falciparum malaria patients has first emerged on the Thai-Cambodian border in 2009, which is now prevalent across mainland Southeast Asia from Vietnam to Myanmar. Here, we reviewed malaria disease severity, history of artemisinin discovery, chemical structure, mechanism of drug action, artemisinin-based combination therapies, emergence and spread of drug resistance, including the recent findings on mechanism of resistance in the falciparum malaria parasite. This poses a serious threat to global malaria control and prompts renewed efforts for the urgent development of new antimalarial drugs.

  15. Antimalarial qinghaosu/artemisinin:The therapy worthy of a Nobel Prize

    Institute of Scientific and Technical Information of China (English)

    Jerapan Krungkrai

    2016-01-01

    Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu (Chinese name) and its derivatives are highly potent, rapidly acting antimalarial drugs. Artemisinin was discovered in 1971 by a Chinese medical scientist Youyou Tu, who was awarded the Nobel Prize in 2015 on her discovering the antimalarial properties of qinghaosu from the traditional Chinese qinghao plant. Nevertheless, artemisinin resistance in falciparum malaria patients has first emerged on the Thai-Cambodian border in 2009, which is now prevalent across mainland Southeast Asia from Vietnam to Myanmar. Here, we reviewed malaria disease severity, history of artemisinin discovery, chemical structure, mechanism of drug action, artemisinin-based combination therapies, emergence and spread of drug resistance, including the recent findings on mechanism of resistance in the falciparum malaria parasite. This poses a serious threat to global malaria control and prompts renewed efforts for the urgent development of new antimalarial drugs.

  16. Deployment of ACT antimalarials for treatment of malaria: challenges and opportunities

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    Leslie Toby

    2008-12-01

    Full Text Available Abstract Following a long period when the effectiveness of existing mono-therapies for antimalarials was steadily declining with no clear alternative, most malaria-endemic countries in Africa and Asia have adopted artemisinin combination therapy (ACT as antimalarial drug policy. Several ACT drugs exist and others are in the pipeline. If properly targeted, they have the potential to reduce mortality from malaria substantially. The major challenge now is to get the drugs to the right people. Current evidence suggests that most of those who need the drugs do not get them. Simultaneously, a high proportion of those who are given antimalarials do not in fact have malaria. Financial and other barriers mean that, in many settings, the majority of those with malaria, particularly the poorest, do not access formal healthcare, so the provision of free antimalarials via this route has only limited impact. The higher cost of ACT creates a market for fake drugs. Addressing these problems is now a priority. This review outlines current evidence, possible solutions and research priorities.

  17. Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance

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    Lee Sue J

    2009-11-01

    Full Text Available Abstract Background Preventing the emergence of anti-malarial drug resistance is critical for the success of current malaria elimination efforts. Prevention strategies have focused predominantly on qualitative factors, such as choice of drugs, use of combinations and deployment of multiple first-line treatments. The importance of anti-malarial treatment dosing has been underappreciated. Treatment recommendations are often for the lowest doses that produce "satisfactory" results. Methods The probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed. Results Recrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission. Conclusion Current dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women. Patients with

  18. In vitro antioxidant, collagenase inhibition, and in vivo anti-wrinkle effects of combined formulation containing Punica granatum, Ginkgo biloba, Ficus carica, and Morus alba fruits extract

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    Ghimeray AK

    2015-07-01

    Full Text Available Amal Kumar Ghimeray,1 Un Sun Jung,1,2 Ha Youn Lee,1 Young Hoon Kim,1 Eun Kyung Ryu,1 Moon Sik Chang11R&D Center, Natural Solution Co., Ltd, Gojan-dong, Namdong-gu, Incheon, Republic of Korea; 2Department of Horticultural Biotechnology, Kyung Hee University, Yongin, Republic of KoreaBackground: In phytotherapy, the therapeutic potential is based on the combined action of different herbal drugs. Our objective was to evaluate the antioxidant, anti-collagenase (in vitro, and anti-wrinkle (in vivo effect of combined formulation containing Ginkgo biloba, Punica granatum, Ficus carica, and Morus alba fruits extract.Methods: Antioxidant evaluation was based on the scavenging activity of free radicals (1,1-diphenyl-2-picrylhydrazyl, H2O2, and O2- and the anti-collagenase activity was based on the reduction of collagenase enzyme in vitro. In an in vivo study, 21 female subjects were examined in a placebo-controlled trail. Facial wrinkle, especially the crow's feet region of eyes, was treated with topical formulated 2% cream for 56 days and compared with the placebo.Results: In the in vitro study, the combination of fruits extract showed a higher antioxidant activity which was comparable with the positive standard (ascorbic acid, butylated hydroxyanisole, and Trolox. The data also showed a dose-dependent inhibition of collagenase. In the in vivo study, treatment with 2% formulated cream for 56 days significantly reduced the percentage of wrinkle depth, length, and area with 11.5, 10.07, and 29.55, respectively.Conclusion: The combined formulation of fruit extracts showed excellent antioxidative and anti-collagenase activity as well as a significant effect on anti-wrinkle activity on human skin.Keywords: antioxidant, anti-collagenase, anti-wrinkle, fruits, topical formulation

  19. [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

  20. Plasmodium falciparum susceptibility to anti-malarial drugs in Dakar, Senegal, in 2010: an ex vivo and drug resistance molecular markers study

    OpenAIRE

    Fall, Bécaye; Pascual, Aurélie; Sarr, Fatoumata; Wurtz, Nathalie; Richard, Vincent; Baret, Eric; Diémé, Yaya; Briolant, Sébastien; Bercion, Raymond; Wade, Boubacar; Tall, Adama; Pradines, Bruno

    2013-01-01

    BACKGROUND: In 2006, the Senegalese National Malaria Control Programme recommended artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. Since the introduction of ACT, there have been very few reports on the level of resistance of P. falciparum to anti-malarial drugs. To determine whether parasite susceptibility has been affected by the new anti-malarial policies, an ex vivo susceptibility and drug resistance molecular marker study was conducted on...

  1. The antimalarial ferroquine: from bench to clinic

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    Biot C.

    2011-08-01

    Full Text Available Ferroquine (FQ, SSR97193 is currently the most advanced organometallic drug candidate and about to complete phase II clinical trials as a treatment for uncomplicated malaria. This ferrocenecontaining compound is active against both chloroquine-susceptible and chloroquine-resistant Plasmodium falciparum and P. vivax strains and/or isolates. This article focuses on the discovery of FQ, its antimalarial activity, the hypothesis of its mode of action, the current absence of resistance in vitro and recent clinical trials.

  2. Potential antimalarial activity of indole alkaloids

    OpenAIRE

    Frederich, Michel; Tits, Monique; Angenot, Luc

    2008-01-01

    New antimalarial treatments are now urgently required, following the emergence of resistance to the most used drugs. Natural products contribute greatly to the therapeutic arsenal in this area, including artemisinin and quinine (and atovaquone, semi-synthetic). Among the natural products, indole alkaloids represent an interesting class of compounds. Screening carried out to date has revealed several substances active in vitro under the micromolar range and with a good selectivity index. This ...

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

    Science.gov (United States)

    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 as half of antimalarials distributed in many developing countries. Use of antimalarials through the health services is often poor; drug shortages are common and overprescription and overuse of injections are significant problems. Anxiety over drug costs may prevent patients from getting the necessary treatment for malaria, especially because of the seasonal appearance of this disease when people's cash reserves are very low. The high costs may lead them to unofficial sources, which will sell a single tablet instead of a complete course of treatment, and subsequently to increased, often irrational demand for more drugs and more injections. Increasingly people are resorting to self-medication for malaria, which may cause delays in seeking proper treatment in cases of failure, especially in areas where chloroquine resistance has increased rapidly. Self-medication is now widespread, and measures to restrict the illicit sale of drugs have been unsuccessful. The "unofficial" channels thus represent an unacknowledged extension of the health services in many countries; suggestions are advanced to encourage better self-medication by increasing the knowledge base among the population at large (mothers, schoolchildren, market sellers, and shopkeepers), with an emphasis on correct dosing and on the importance of seeking further treatment without delay, if necessary. PMID:1893512

  4. 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...

  5. Poor quality vital anti-malarials in Africa - an urgent neglected public health priority

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    Newton Paul N

    2011-12-01

    Full Text Available Abstract Background Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. Methods Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis and botanical investigations were performed. Results Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA containing paracetamol (acetaminophen, counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. Conclusions Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.

  6. Linking Murine and Human Plasmodium falciparum Challenge Models in a Translational Path for Antimalarial Drug Development.

    Science.gov (United States)

    McCarthy, James S; Marquart, Louise; Sekuloski, Silvana; Trenholme, Katharine; Elliott, Suzanne; Griffin, Paul; Rockett, Rebecca; O'Rourke, Peter; Sloots, Theo; Angulo-Barturen, Iñigo; Ferrer, Santiago; Jiménez-Díaz, María Belén; Martínez, María-Santos; Hooft van Huijsduijnen, Rob; Duparc, Stephan; Leroy, Didier; Wells, Timothy N C; Baker, Mark; Möhrle, Jörg J

    2016-06-01

    Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ(-/-) (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stage Plasmodium falciparum challenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n = 8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems. In vivo 50% inhibitory concentrations (IC50s) were estimated at 2.0 μg/ml and 1.8 μg/ml in the NSG and IBSM models, respectively, aligning with 1.8 μg/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations. (This trial was registered at the Australian New Zealand Clinical Trials Registry [http://anzctr.org.au] under registration number ACTRN12612000323820.). PMID:27044554

  7. Dispersible formulation of artemether/lumefantrine: specifically developed for infants and young children

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    Sagara Issaka

    2009-10-01

    Full Text Available Abstract Infants and children under five years of age are the most vulnerable to malaria with over 1,700 deaths per day from malaria in this group. However, until recently, there were no WHO-endorsed paediatric anti-malarial formulations available. Artemisinin-based combination therapy is the current standard of care for patients with uncomplicated falciparum malaria in Africa. Artemether/lumefantrine (AL meets WHO pre-qualification criteria for efficacy, safety and quality. Coartem®, a fixed dose combination of artemether and lumefantrine, has consistently achieved cure rates of >95% in clinical trials. However, AL tablets are inconvenient for caregivers to administer as they need to be crushed and mixed with water or food for infants and young children. Further, in common with other anti-malarials, they have a bitter taste, which may result in children spitting the medicine out and not receiving the full therapeutic dose. There was a clear unmet medical need for a formulation of AL specifically designed for children. Ahead of a call from WHO for child-friendly medicines, Novartis, working in partnership with Medicines for Malaria Venture (MMV, started the development of a new formulation of AL for infants and young children: Coartem® Dispersible. The excellent efficacy, safety and tolerability already demonstrated by AL tablets were confirmed with dispersible AL in a large trial comparing the crushed tablets with dispersible tablets in 899 African children with falciparum malaria. In the evaluable population, 28-day PCR-corrected cure rates of >96% were achieved. Further, its sweet taste means that it is palatable for children, and the dispersible formulation makes it easier for caregivers to administer than bitter crushed tablets. Easing administration may foster compliance, hence improving therapeutic outcomes in infants and young children and helping to preserve the efficacy of ACT.

  8. Complex polymorphisms in the Plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response.

    Science.gov (United States)

    Veiga, Maria Isabel; Osório, Nuno S; Ferreira, Pedro Eduardo; Franzén, Oscar; Dahlstrom, Sabina; Lum, J Koji; Nosten, Francois; Gil, José Pedro

    2014-12-01

    Plasmodium falciparum has the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters: Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studied Pfmrp2. The role of Pfmrp2 polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of the Pfmrp2 genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found that Pfmrp2 harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identified Pfmrp2 polymorphisms with altered in vitro susceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggested Pfmrp2 polymorphisms modulate the parasite's in vitro response to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association with in vivo parasite clearance. In conclusion, our study reveals that the Pfmrp2 gene is the most diverse ABC transporter known in P. falciparum with a potential role in antimalarial drug resistance. PMID:25267670

  9. Two-stage in vitro digestibility assay, a tool for formulating non-starch polysaccharide degrading enzyme combinations for commonly used feed ingredients of poultry rations

    OpenAIRE

    Y. Ramana Reddy; D. Nagalakshmi; J. Narasimha; S. T. Viroji Rao

    2013-01-01

    Aim: An attempt was made to assess the effect of pure enzyme combinations with the objective of formulating customized enzyme mixtures based on sugar release when subjected to two-stage in vitro digestion assay. Materials and Methods: A two-stage in vitro digestibility assay was carried out for commonly used feed ingredients for poultry viz., maize, soy bean meal, sunflower cake, and de-oiled rice bran supplemented with three concentrations of xylanase (5000; 7500 and 10000 IU/kg), cellulase ...

  10. Two novel spectrophotometric methods for determinat ion of ternary mixture used as antihypertensive therapy in combined tablet dosage formulation

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    Trupti Solanki

    2015-03-01

    Full Text Available Aim: To develop and validate two novel spectrophotometric methods for the simultaneous determination of ternary mixture of Olmesartan medoxomil, Amlodipine besylate and Hydrochlorothiazide. Methods: The proposed methods, successive ratio derivative method and double divisor method involved treatment of normal absorption spectra of ternary mixture in UV probe software for the simultaneous determination of Olmesartan medoxomil, Amlodipine besylate and Hydrochlorothiazide in bulk and tablet dosage formulation without prior separation. Results: All the drugs exhibited good linearity over the reported concentration range with acceptable correlation coefficient. The method was validated according to ICH guidelines for evaluation of accuracy, repeatability, reproducibility, sensitivity showing acceptable percent relative standard deviation of less than 2. Conclusion: The proposed methods demonstrated that these are simple, rapid, accurate and precise methods and can be used for routine analysis of bulk and tablet dosage formulation in quality control laboratories eliminating the need of prior separation of the pharmaceutical mixtures.

  11. Two novel spectrophotometric methods for determinat ion of ternary mixture used as antihypertensive therapy in combined tablet dosage formulation

    Directory of Open Access Journals (Sweden)

    Trupti Solanki

    2015-03-01

    Full Text Available Aim: To develop and validate two novel spectrophotometric methods for the simultaneous determination of ternary mixture of Olmesartan medoxomil, Amlodipine besylate and Hydrochlorothiazide. Methods: The proposed methods, successive ratio derivative method and double divisor method involved treatment of normal absorption spectra of ternary mixture in UV probe software for the simultaneous determination of Olmesartan medoxomil, Amlodipine besylate and Hydrochlorothiazide in bulk and tablet dosage formulation without prior separation. Results: All the drugs exhibited good linearity over the reported concentration range with acceptable correlation coefficient. The method was validated according to ICH guidelines for evaluation of accuracy, repeatability, reproducibility, sensitivity showing acceptable percent relative standard deviation of less than 2.Conclusion: The proposed methods demonstrated that these are simple, rapid, accurate and precise methods and can be used for routine analysis of bulk and tablet dosage formulation in quality control laboratories eliminating the need of prior separation of the pharmaceutical mixtures.

  12. Prospective strategies to delay the evolution of anti-malarial drug resistance: weighing the uncertainty

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    McKenzie F Ellis

    2010-07-01

    Full Text Available Abstract Background The evolution of drug resistance in malaria parasites highlights a need to identify and evaluate strategies that could extend the useful therapeutic life of anti-malarial drugs. Such strategies are deployed to best effect before resistance has emerged, under conditions of great uncertainty. Methods Here, the emergence and spread of resistance was modelled using a hybrid framework to evaluate prospective strategies, estimate the time to drug failure, and weigh uncertainty. The waiting time to appearance was estimated as the product of low mutation rates, drug pressure, and parasite population sizes during treatment. Stochastic persistence and the waiting time to establishment were simulated as an evolving branching process. The subsequent spread of resistance was simulated in simple epidemiological models. Results Using this framework, the waiting time to the failure of artemisinin combination therapy (ACT for malaria was estimated, and a policy of multiple first-line therapies (MFTs was evaluated. The models quantify the effects of reducing drug pressure in delaying appearance, reducing the chances of establishment, and slowing spread. By using two first-line therapies in a population, it is possible to reduce drug pressure while still treating the full complement of cases. Conclusions At a global scale, because of uncertainty about the time to the emergence of ACT resistance, there was a strong case for MFTs to guard against early failure. Our study recommends developing operationally feasible strategies for implementing MFTs, such as distributing different ACTs at the clinic and for home-based care, or formulating different ACTs for children and adults.

  13. Anticancer properties of distinct antimalarial drug classes.

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    Rob Hooft van Huijsduijnen

    Full Text Available We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor, emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.

  14. Antimalarial Activity of Ultra-Short Peptides

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    María Yolanda Rios

    2009-12-01

    Full Text Available Ultra-short peptides 1-9 were designed and synthesized with phenylalanine, ornithine and proline amino acid residues and their effect on antimalarial activity was analyzed. On the basis of the IC50 data for these compounds, the effects of nature, polarity, and amino acid sequence on Plasmodium berghei schizont cultures were analyzed too. Tetrapeptides Phe-Orn-Phe-Orn (4 and Lys-Phe-Phe-Orn (5 showed a very important activity with IC50 values of 3.31 and 2.57 μM, respectively. These two tetrapeptides are candidates for subsequent in vivo assays and SARS investigations.

  15. Understanding Private Sector Antimalarial Distribution Chains: A Cross-Sectional Mixed Methods Study in Six Malaria-Endemic Countries

    Science.gov (United States)

    Palafox, Benjamin; Patouillard, Edith; Tougher, Sarah; Goodman, Catherine; Hanson, Kara; Kleinschmidt, Immo; Rueda, Sergio Torres; Kiefer, Sabine; O’Connell, Kathryn A.; Zinsou, Cyprien; Phok, Sochea; Akulayi, Louis; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Chavasse, Desmond

    2014-01-01

    Background Private for-profit outlets are important treatment sources for malaria in most endemic countries. However, these outlets constitute only the last link in a chain of businesses that includes manufacturers, importers and wholesalers, all of which influence the availability, price and quality of antimalarials patients can access. We present evidence on the composition, characteristics and operation of these distribution chains and of the businesses that comprise them in six endemic countries (Benin, Cambodia, Democratic Republic of Congo, Nigeria, Uganda and Zambia). Methods and Findings We conducted nationally representative surveys of antimalarial wholesalers during 2009–2010 using an innovative sampling approach that captured registered and unregistered distribution channels, complemented by in-depth interviews with a range of stakeholders. Antimalarial distribution chains were pyramidal in shape, with antimalarials passing through a maximum of 4–6 steps between manufacturer and retailer; however, most likely pass through 2–3 steps. Less efficacious non-artemisinin therapies (e.g. chloroquine) dominated weekly sales volumes among African wholesalers, while volumes for more efficacious artemisinin-based combination therapies (ACTs) were many times smaller. ACT sales predominated only in Cambodia. In all countries, consumer demand was the principal consideration when selecting products to stock. Selling prices and reputation were key considerations regarding supplier choice. Business practices varied across countries, with large differences in the proportions of wholesalers offering credit and delivery services to customers, and the types of distribution models adopted by businesses. Regulatory compliance also varied across countries, particularly with respect to licensing. The proportion of wholesalers possessing any up-to-date licence from national regulators was lowest in Benin and Nigeria, where vendors in traditional markets are important

  16. Understanding private sector antimalarial distribution chains: a cross-sectional mixed methods study in six malaria-endemic countries.

    Directory of Open Access Journals (Sweden)

    Benjamin Palafox

    Full Text Available BACKGROUND: Private for-profit outlets are important treatment sources for malaria in most endemic countries. However, these outlets constitute only the last link in a chain of businesses that includes manufacturers, importers and wholesalers, all of which influence the availability, price and quality of antimalarials patients can access. We present evidence on the composition, characteristics and operation of these distribution chains and of the businesses that comprise them in six endemic countries (Benin, Cambodia, Democratic Republic of Congo, Nigeria, Uganda and Zambia. METHODS AND FINDINGS: We conducted nationally representative surveys of antimalarial wholesalers during 2009-2010 using an innovative sampling approach that captured registered and unregistered distribution channels, complemented by in-depth interviews with a range of stakeholders. Antimalarial distribution chains were pyramidal in shape, with antimalarials passing through a maximum of 4-6 steps between manufacturer and retailer; however, most likely pass through 2-3 steps. Less efficacious non-artemisinin therapies (e.g. chloroquine dominated weekly sales volumes among African wholesalers, while volumes for more efficacious artemisinin-based combination therapies (ACTs were many times smaller. ACT sales predominated only in Cambodia. In all countries, consumer demand was the principal consideration when selecting products to stock. Selling prices and reputation were key considerations regarding supplier choice. Business practices varied across countries, with large differences in the proportions of wholesalers offering credit and delivery services to customers, and the types of distribution models adopted by businesses. Regulatory compliance also varied across countries, particularly with respect to licensing. The proportion of wholesalers possessing any up-to-date licence from national regulators was lowest in Benin and Nigeria, where vendors in traditional markets are

  17. Two-stage in vitro digestibility assay, a tool for formulating non-starch polysaccharide degrading enzyme combinations for commonly used feed ingredients of poultry rations

    Directory of Open Access Journals (Sweden)

    Y. Ramana Reddy

    2013-05-01

    Full Text Available Aim: An attempt was made to assess the effect of pure enzyme combinations with the objective of formulating customized enzyme mixtures based on sugar release when subjected to two-stage in vitro digestion assay. Materials and Methods: A two-stage in vitro digestibility assay was carried out for commonly used feed ingredients for poultry viz., maize, soy bean meal, sunflower cake, and de-oiled rice bran supplemented with three concentrations of xylanase (5000; 7500 and 10000 IU/kg, cellulase (50; 100 and 400 IU/kg and â-D-glucanase (100; 200 and 400 IU/kg were used to formulate various NSP enzymes combinations. In total 27 NSP enzyme combinations (3x3x3 were formulated and the sugar released due to NSP digestion was quantified by phenol sulphuric acid method. Results: The total sugar release was significantly (P<0.05 higher with supplementation of various enzymes combinations for maize, sunflower cake and de-oiled rice bran where as no significant (P<0.05 interaction of various NSP enzymes combinations was observed for soy bean meal. The NSP digestibility was highest in combination (xylanase-5000, cellulase-50 and â-D-glucanase-400 IU/kg, (xylanase-10000, cellulase-50 and â-D-glucanase-200 IU/kg and (xylanase-7500, cellulase- 100 and â-D-glucanase-100 IU/kg for maize, sunflower cake and de-oiled rice bran respectively. In case of sunflower cake, significant (P<0.01 three way interaction was observed among the xylanase, cellulose, and â-D-glucanase enzymes and the two-way interactions between the enzymes were also significant (P<0.01. Conclusion: It is concluded that 'n' number of non-starch Polysaccharide enzymes combinations can be screened for their efficiency to digest non-starch Polysaccharides present in various feed ingredients commonly used in poultry rations by employing two-stage in vitro digestibility assay as a tool. [Vet World 2013; 6(8.000: 525-529

  18. Clinical utility and development of the fluticasone/formoterol combination formulation (Flutiform® for the treatment of asthma

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    Tan RA

    2014-09-01

    Full Text Available Ricardo Antonio Tan,1 Jonathan Corren2 1California Allergy and Asthma Medical Group, 2David Geffen School of Medicine at UCLA, Los Angeles, CA, USAAbstract: Pharmacologic treatment of asthma should be done with a stepwise approach recommended in treatment guidelines. If inhaled corticosteroids (ICSs alone are not adequate, ICSs in combination with long-acting β-agonists (LABAs are now established and widely used as the next step in effective controller therapy. Fixed-dose ICS/LABA combinations in a single device are the preferred form of delivery and improve compliance by enabling patients to get symptom relief from the LABA while receiving the anti-inflammatory benefits of ICSs. Fluticasone propionate/formoterol fumarate is one of the newest fixed-dose combinations. It has been in use in Europe in 2012, but is still under regulatory review in the US. Fluticasone is a synthetic ICS with potent anti-inflammatory effects, while formoterol is a selective β2-adrenergic receptor agonist with a rapid onset of bronchodilation within 5–10 minutes and a 12-hour duration of action. Fluticasone/formoterol has shown superior efficacy when compared to fluticasone or formoterol alone in multiple well-designed studies. The combination has shown comparable or “noninferior” benefits in lung function, clinical symptoms, and asthma control when compared with fluticasone and formoterol administered concurrently in separate inhalers. Fluticasone/formoterol provides similar efficacy with fluticasone/salmeterol, but with more rapid symptom relief. It has been compared directly with budesonide/formoterol with comparable results. Fluticasone/formoterol is well tolerated, with no unusual or increased safety concerns versus each individual component or other available ICS/LABA combinations. Fluticasone/formoterol is the latest entry into a relatively crowded market of branded fixed-dose preparations. Upcoming generic fixed-dose combinations and once-daily agents

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

    Directory of Open Access Journals (Sweden)

    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.

  20. The contribution of microscopy to targeting antimalarial treatment in a low transmission area of Tanzania

    Directory of Open Access Journals (Sweden)

    Mwerinde Ombeni

    2006-01-01

    Full Text Available Abstract Background There is a need for improved targeting of antimalarial treatment if artemisinin combination therapy is to be successfully introduced in Africa. This study aimed to explore why malaria slides are requested and how their results guide treatment decisions in an area of low transmission of P. falciparum. Methods Outpatients attending a district hospital in a highland area of Tanzania were studied over a 3-week period. Clinical and social data were collected from patients who had been prescribed an antimalarial or sent for a malaria slide. Hospital slides were re-read later by research methods. Results Of 1,273 consultations 132(10% were treated presumptively for malaria and 214(17% were sent for a malaria slide; only 13(6% of these were reported positive for P. falciparum but 96(48% of the 201 slide-negative cases were treated for malaria anyway. In a logistic regression model, adults (OR 3.86, P Conclusion Progress in targeting of antimalarials in low malaria transmission settings is likely to depend on consistent use of malaria microscopy and on the willingness of health workers to be guided by negative slide results. Further studies are needed to identify how this can be achieved.

  1. Quality of Artemisinin-Based Combination Formulations for Malaria Treatment: Prevalence and Risk Factors for Poor Quality Medicines in Public Facilities and Private Sector Drug Outlets in Enugu, Nigeria

    Science.gov (United States)

    Kaur, Harparkash; Allan, Elizabeth Louise; Mamadu, Ibrahim; Hall, Zoe; Ibe, Ogochukwu; El Sherbiny, Mohamed; van Wyk, Albert; Yeung, Shunmay; Swamidoss, Isabel; Green, Michael D.; Dwivedi, Prabha; Culzoni, Maria Julia; Clarke, Siân; Schellenberg, David; Fernández, Facundo M.; Onwujekwe, Obinna

    2015-01-01

    Background Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO) as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artemisinin-containing antimalarials (ACAs) in Enugu metropolis, Nigeria, and compared the resulting quality estimates. Methods ACAs were purchased using three sampling approaches - convenience, mystery clients and overt, within a defined area and sampling frame in Enugu metropolis. The active pharmaceutical ingredients were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories. Results were expressed as percentage of APIs stated on the packaging and used to categorise each sample as acceptable quality, substandard, degraded, or falsified. Results Content analysis of 3024 samples purchased from 421 outlets using convenience (n=200), mystery (n=1,919) and overt (n=905) approaches, showed overall 90.8% ACAs to be of acceptable quality, 6.8% substandard, 1.3% degraded and 1.2% falsified. Convenience sampling yielded a significantly higher prevalence of poor quality ACAs, but was not evident by the mystery and overt sampling strategies both of which yielded results that were comparable between each other. Artesunate (n=135; 4 falsified) and dihydroartemisinin (n=14) monotherapy tablets, not recommended by WHO, were also identified. Conclusion Randomised sampling identified fewer falsified ACAs than previously reported by convenience approaches. Our findings emphasise the need for specific consideration to be given to sampling frame and sampling approach if representative information on drug quality is to be obtained

  2. Quality of artemisinin-based combination formulations for malaria treatment: prevalence and risk factors for poor quality medicines in public facilities and private sector drug outlets in Enugu, Nigeria.

    Directory of Open Access Journals (Sweden)

    Harparkash Kaur

    Full Text Available Artemisinin-based combination therapies are recommended by the World Health Organisation (WHO as first-line treatment for Plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. A recent meta-analysis reported 35% (796/2,296 of antimalarial drug samples from 21 Sub-Saharan African countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. We used three sampling strategies to purchase artemisinin-containing antimalarials (ACAs in Enugu metropolis, Nigeria, and compared the resulting quality estimates.ACAs were purchased using three sampling approaches--convenience, mystery clients and overt, within a defined area and sampling frame in Enugu metropolis. The active pharmaceutical ingredients were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories. Results were expressed as percentage of APIs stated on the packaging and used to categorise each sample as acceptable quality, substandard, degraded, or falsified.Content analysis of 3024 samples purchased from 421 outlets using convenience (n=200, mystery (n=1,919 and overt (n=905 approaches, showed overall 90.8% ACAs to be of acceptable quality, 6.8% substandard, 1.3% degraded and 1.2% falsified. Convenience sampling yielded a significantly higher prevalence of poor quality ACAs, but was not evident by the mystery and overt sampling strategies both of which yielded results that were comparable between each other. Artesunate (n=135; 4 falsified and dihydroartemisinin (n=14 monotherapy tablets, not recommended by WHO, were also identified.Randomised sampling identified fewer falsified ACAs than previously reported by convenience approaches. Our findings emphasise the need for specific consideration to be given to sampling frame and sampling approach if representative information on drug quality is to be obtained.

  3. Ketotifen fumarate and salbutamol sulphate combined transdermal patch formulations: In vitro release and Ex vivo permeation studies

    OpenAIRE

    M Yousuf; Ahmad, M.; M. Usman; Ali, I

    2013-01-01

    The present work was performed to develop and evaluate transdermal patches of combined antiasthmatic drugs (salbutamol sulphate and ketotifen fumarate). Polyvinyl alcohol membrane was used as backing membrane and eudragit RL-100 was used as matrix material to suspend the drugs in the continuous thickness of the patch. Methanol was solvent and propylene glycol was used as plasticizer. Tween 20, isopropyl myristate, eucalyptus oil, castor oil and span-20 were used as permeability enhancers. Thi...

  4. Clinical utility and development of the fluticasone/formoterol combination formulation (Flutiform®) for the treatment of asthma

    OpenAIRE

    Tan RA; Corren J

    2014-01-01

    Ricardo Antonio Tan,1 Jonathan Corren2 1California Allergy and Asthma Medical Group, 2David Geffen School of Medicine at UCLA, Los Angeles, CA, USAAbstract: Pharmacologic treatment of asthma should be done with a stepwise approach recommended in treatment guidelines. If inhaled corticosteroids (ICSs) alone are not adequate, ICSs in combination with long-acting β-agonists (LABAs) are now established and widely used as the next step in effective controller therapy. Fixed-dose ICS/LABA comb...

  5. Clinical utility and development of the fluticasone/formoterol combination formulation (Flutiform®) for the treatment of asthma

    OpenAIRE

    Corren, Jonathan

    2014-01-01

    Ricardo Antonio Tan,1 Jonathan Corren2 1California Allergy and Asthma Medical Group, 2David Geffen School of Medicine at UCLA, Los Angeles, CA, USAAbstract: Pharmacologic treatment of asthma should be done with a stepwise approach recommended in treatment guidelines. If inhaled corticosteroids (ICSs) alone are not adequate, ICSs in combination with long-acting β-agonists (LABAs) are now established and widely used as the next step in effective controller therapy. Fixed-dose ICS/LABA ...

  6. RAPID RP-HPLC METHOD FOR SIMULTANEOUS SEPARATION AND ESTIMATION OF METOPROLOL AND AMLODIPINE IN COMBINATION TABLET FORMULATION

    OpenAIRE

    JastiVasavi; Murukutla Vijaya Lakshmi; Nekkalapu Satya Sundari

    2013-01-01

    The aim of the present work was to develop a RP-HPLC method for simultaneous separation of Metoprolol and Amlodipine and validate the developed method for quantitative determination of the above said drugs in combination tablet dosage form. A simple, rapid, validated chromatographic method was developed for separation and determination of metoprolol and amlodipine in tablet preparations. The anti-hypertensive agents were separated using Welchrom RP-C18 Column (4.6 mm X 250 mm, 5 µ), Shimadzu ...

  7. DEVELOPMENT AND VALIDATION OF SPECTROPHOTOMETRIC METHODS FOR SIMULTANEOUS ESTIMATION OF METOPROLOL SUCCINATE AND TELMISARTAN IN COMBINED PHARMACEUTICAL FORMULATION

    OpenAIRE

    Mayur Modi*, Rikin Shah and R.C. Mashru

    2012-01-01

    Four simple, rapid, precise, economical and accurate spectrophotometric methods have been developed for simultaneous analysis of Metoprolol succinate and Telmisartan in their combined dosage form. Method 1, First derivative simultaneous equation method (Vierodt’s method). It employs formation and solving of simultaneous equation using two wavelengths 230.2 nm (λmax of Metoprolol succinate) and 237 nm (λmax of Telmisartan) in first derivative spectra. Method 2, First derivative Q-Absorbance eq...

  8. Fast Disintegrating Combination Tablet of Taste Masked Levocetrizine Dihydrochloride and Montelukast Sodium: Formulation Design, Development, and Characterization

    OpenAIRE

    M. M. Gupta; Niraj Gupta; Chauhan, Bhupendra S.; Shweta Pandey

    2014-01-01

    The aim of this study was to prepare fast disintegrating combination tablet of taste masked Levocetrizine dihydrochloride and Montelukast sodium by using direct compression method. To prevent bitter taste and unacceptable odour of the Levocetrizine dihydrochloride drug, the drug was taste masked with ion exchange resins like Kyron-T-104 and Tulsion-412. Among the two resins, Kyron-T-104 was selected for further studies because of high drug loading capacity, low cost, and better drug release p...

  9. Artemisinin anti-malarial drugs in China.

    Science.gov (United States)

    Guo, Zongru

    2016-03-01

    Discovered by Youyou Tu, one of the 2015 Nobel Prize winners in Physiology or Medicine, together with many other Chinese scientists, artemisinin, artemether and artesunate, as well as other artemisinins, have brought the global anti-malarial treatment to a new era, saving millions of lives all around the world for the past 40 years. The discoveries of artemisinins were carried out beginning from the 1970s, a special period in China, by hundreds of scientists all together under the "whole nation" system. This article focusing on medicinal chemistry research, briefly introduced the discovery and invention course of the scientists according to the published papers, and highlighted their academic contribution and achievements. PMID:27006895

  10. Synthesis and evaluation of antimalarial activity of curcumin derivatives

    International Nuclear Information System (INIS)

    ne of the main challenges in the development of new antimalarial drugs is to achieve a viable lead candidate with good pharmacokinetic properties. Curcumin has a broad range of biological activities, including antimalarial activity. Herein, we report the antimalarial activity of six curcumin derivatives (6-12) and an initial analysis of their pharmacokinetic properties. Five compounds have demonstrated potent activity against the P. falciparum in vitro (IC50 values ranging from 1.7 to 15.2 μg mL-1), with moderate or low cytotoxicity against the HeLa cell line. The substitution of the carbonyl group in 6 by a 2,4-dinitrophenylhydrazone group (to afford 11) increases the Selective Index. These preliminary results indicate curcumin derivatives as potential antimalarial compounds. (author)

  11. Antimalarial activity of plumbagin in vitro and in animal models

    OpenAIRE

    Sumsakul, Wiriyaporn; Plengsuriyakarn, Tullayakorn; Chaijaroenkul, Wanna; Viyanant, Vithoon; Karbwang, Juntra; Na-Bangchang, Kesara

    2014-01-01

    Background Plumbagin is the major active constituent in several plants including Plumbago indica Linn. (root). This compound has been shown to exhibit a wide spectrum of biological and pharmacological activities. The present study aimed to evaluate the in vitro and in vivo antimalarial activity of plumbagin including its acute and subacute toxicity in mice. Methods In vitro antimalarial activity of plumbagin against K1 and 3D7 Plasmodium falciparum clones were assessed using SYBR Green I base...

  12. Towards optimal design of anti-malarial pharmacokinetic studies.

    OpenAIRE

    White Nicholas J; Price Ric N; Jamsen Kris M; Simpson Julie A; Lindegardh Niklas; Tarning Joel; Duffull Stephen B

    2009-01-01

    Abstract Background Characterization of anti-malarial drug concentration profiles is necessary to optimize dosing, and thereby optimize cure rates and reduce both toxicity and the emergence of resistance. Population pharmacokinetic studies determine the drug concentration time profiles in the target patient populations, including children who have limited sampling options. Currently, population pharmacokinetic studies of anti-malarial drugs are designed based on logistical, financial and ethi...

  13. The role of anti-malarial drugs in eliminating malaria.

    OpenAIRE

    White, NJ

    2008-01-01

    Effective anti-malarial drug treatment reduces malaria transmission. This alone can reduce the incidence and prevalence of malaria, although the effects are greater in areas of low transmission where a greater proportion of the infectious reservoir is symptomatic and receives anti-malarial treatment. Effective treatment has greater effects on the transmission of falciparum malaria, where gametocytogenesis is delayed, compared with the other human malarias in which peak gametocytaemia and tran...

  14. The role of anti-malarial drugs in eliminating malaria

    OpenAIRE

    White Nicholas J

    2008-01-01

    Abstract Effective anti-malarial drug treatment reduces malaria transmission. This alone can reduce the incidence and prevalence of malaria, although the effects are greater in areas of low transmission where a greater proportion of the infectious reservoir is symptomatic and receives anti-malarial treatment. Effective treatment has greater effects on the transmission of falciparum malaria, where gametocytogenesis is delayed, compared with the other human malarias in which peak gametocytaemia...

  15. Antimalarial activity of Malaysian Plectranthus amboinicus against Plasmodium berghei

    OpenAIRE

    Ramli, Norazsida; Ahamed, Pakeer Oothuman Syed; Elhady, Hassan Mohamed; Taher, Muhammad

    2014-01-01

    Context: Malaria is a mosquito-borne disease caused by parasitic protozoa from the genus of Plasmodium. The protozoans have developed resistance against many of current drugs. It is urgent to find an alternative source of new antimalarial agent. In the effort to discover new antimalarial agents, this research has been conducted on Plectranthus amboinicus. Aims: This study was conducted to evaluate the toxicity and antiplasmodial properties of P. amboinicus. Materials and Methods: Acute oral t...

  16. Expanding the Antimalarial Drug Arsenal—Now, But How?

    OpenAIRE

    MEHLOTRA, RAJEEV K.; Grimberg, Brian T

    2011-01-01

    The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/dhps, and others, have led to widespread resistance to all known classes of antimalarial compounds. Unfortunately, malaria parasites have started to exhibit some level of resistance in Southeast Asia even to the most recently introduced class of drugs, artemisinins. While there is much need, th...

  17. In Vitro Antimalarial Activity of Novel Semisynthetic Nocathiacin I Antibiotics

    OpenAIRE

    Sharma, Indu; Sullivan, Margery; McCutchan, Thomas F.

    2015-01-01

    Presently, the arsenal of antimalarial drugs is limited and needs to be replenished. We evaluated the potential antimalarial activity of two water-soluble derivatives of nocathiacin (BMS461996 and BMS411886) against the asexual blood stages of Plasmodium falciparum. Nocathiacins are a thiazolyl peptide group of antibiotics, are structurally related to thiostrepton, have potent activity against a wide spectrum of multidrug-resistant Gram-positive bacteria, and inhibit protein synthesis. The in...

  18. RAPID RP-HPLC METHOD FOR SIMULTANEOUS SEPARATION AND ESTIMATION OF METOPROLOL AND AMLODIPINE IN COMBINATION TABLET FORMULATION

    Directory of Open Access Journals (Sweden)

    JastiVasavi

    2013-09-01

    Full Text Available The aim of the present work was to develop a RP-HPLC method for simultaneous separation of Metoprolol and Amlodipine and validate the developed method for quantitative determination of the above said drugs in combination tablet dosage form. A simple, rapid, validated chromatographic method was developed for separation and determination of metoprolol and amlodipine in tablet preparations. The anti-hypertensive agents were separated using Welchrom RP-C18 Column (4.6 mm X 250 mm, 5 µ, Shimadzu LC-20 AT Prominence Liquid Chromatograph and the mobile phase constituted of 10 mM Phosphate buffer (pH 3.0: acetonitrile (50:50, v/v. The flow rate was 1.0 mL/min and the analyses were performed using Shimadzu SPD-20A Prominence UV-Visible detector at 235 nm. The separation of the anti-hypertensive agents, Metoprolol and Amlodipine was achieved within 5 minutes. Metoprolol and Amlodipine eluted at retention times of 2.690 minutes and 3.797 minutes respectively. The drugs obeyed Beer’s law in the concentration range of 5 - 25 µg/mL for metoprolol and 1 - 5 µg/mL for amlodipine. The developed assay method was found to be selective, precise and accurate. The method has been successfully applied for determination of Metoprolol and Amlodipine in pharmaceutical combination tablet dosage form. This developed method is sensitive, fast, and simple with excellent peak symmetry and high resolution.

  19. Inhibition of cytochrome bc1 as a strategy for single-dose, multi-stage antimalarial therapy.

    Science.gov (United States)

    Stickles, Allison M; Ting, Li-Min; Morrisey, Joanne M; Li, Yuexin; Mather, Michael W; Meermeier, Erin; Pershing, April M; Forquer, Isaac P; Miley, Galen P; Pou, Sovitj; Winter, Rolf W; Hinrichs, David J; Kelly, Jane X; Kim, Kami; Vaidya, Akhil B; Riscoe, Michael K; Nilsen, Aaron

    2015-06-01

    Single-dose therapies for malaria have been proposed as a way to reduce the cost and increase the effectiveness of antimalarial treatment. However, no compound to date has shown single-dose activity against both the blood-stage Plasmodium parasites that cause disease and the liver-stage parasites that initiate malaria infection. Here, we describe a subset of cytochrome bc1 (cyt bc1) inhibitors, including the novel 4(1H)-quinolone ELQ-400, with single-dose activity against liver, blood, and transmission-stage parasites in mouse models of malaria. Although cyt bc1 inhibitors are generally classified as slow-onset antimalarials, we found that a single dose of ELQ-400 rapidly induced stasis in blood-stage parasites, which was associated with a rapid reduction in parasitemia in vivo. ELQ-400 also exhibited a low propensity for drug resistance and was active against atovaquone-resistant P. falciparum strains with point mutations in cyt bc1. Ultimately, ELQ-400 shows that cyt bc1 inhibitors can function as single-dose, blood-stage antimalarials and is the first compound to provide combined treatment, prophylaxis, and transmission blocking activity for malaria after a single oral administration. This remarkable multi-stage efficacy suggests that metabolic therapies, including cyt bc1 inhibitors, may be valuable additions to the collection of single-dose antimalarials in current development. PMID:25918204

  20. Quality of antimalarials at the epicenter of antimalarial drug resistance: results from an overt and mystery client survey in Cambodia.

    Science.gov (United States)

    Yeung, Shunmay; Lawford, Harriet L S; Tabernero, Patricia; Nguon, Chea; van Wyk, Albert; Malik, Naiela; DeSousa, Mikhael; Rada, Ouk; Boravann, Mam; Dwivedi, Prabha; Hostetler, Dana M; Swamidoss, Isabel; Green, Michael D; Fernandez, Facundo M; Kaur, Harparkash

    2015-06-01

    Widespread availability of monotherapies and falsified antimalarials is thought to have contributed to the historical development of multidrug-resistant malaria in Cambodia. This study aimed to document the quality of artemisinin-containing antimalarials (ACAs) and to compare two methods of collecting antimalarials from drug outlets: through open surveyors and mystery clients (MCs). Few oral artemisinin-based monotherapies and no suspected falsified medicines were found. All 291 samples contained the stated active pharmaceutical ingredient (API) of which 69% were considered good quality by chemical analysis. Overall, medicine quality did not differ by collection method, although open surveyors were less likely to obtain oral artemisinin-based monotherapies than MCs. The results are an encouraging indication of the positive impact of the country's efforts to tackle falsified antimalarials and artemisinin-based monotherapies. However, poor-quality medicines remain an ongoing challenge that demands sustained political will and investment of human and financial resources. PMID:25897063

  1. Effective control of Listeria monocytogenes by combination of nisin formulated and slowly released into a broth system.

    Science.gov (United States)

    Chi-Zhang, Yundong; Yam, Kit L; Chikindas, Michael L

    2004-01-01

    In order to identify conditions for efficient food preservation by nisin, the sensitivity of Listeria monocytogenes to this preservative was studied under the following three model conditions: (1) the instantaneous addition of nisin into broth medium to simulate the formation of nisin in foods, (2) the slow delivery of nisin solution into broth medium using a pump to simulate the slow release of nisin from packaging materials to foods, (3) a combination of the two delivery methods. Based on the following results, we conclude that the antimicrobial effectiveness of nisin strongly depends on its mode of delivery. The instantaneous and slow methods for adding nisin inhibited L. monocytogenes, but over time of exposure, L. monocytogenes developed tolerance to nisin. Our data indicate that cells treated with instantaneously added nisin developed resistance to higher concentrations of nisin (200 IU/ml), compared to cells treated with slowly added nisin at the same total amount of the antimicrobial. Further studies indicated that nisin-tolerant cells recovered from treatments in which 200 IU/ml nisin was added instantaneously were likely to be mutants, which became resistant to the bacteriocin. In contrast, when 200 IU/ml of the antimicrobial was added slowly to the cells, only a temporary tolerance was developed; these cells became nisin-sensitive after passage through nisin-free medium. Due to the development of nisin-resistant cells, excessive amounts of nisin in the model system did not further inhibit L. monocytogenes. These results signify that excess nisin in foods does not necessarily improve the efficiency of controlling L. monocytogenes. Our data suggest that the combination of packaging material containing nisin used in conjunction with nisin-containing foods will provide the most effective means of preventing L. monocytogenes growth. PMID:14672827

  2. Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc1 Inhibition Strategy for Malaria.

    Science.gov (United States)

    Stickles, Allison M; Smilkstein, Martin J; Morrisey, Joanne M; Li, Yuexin; Forquer, Isaac P; Kelly, Jane X; Pou, Sovitj; Winter, Rolf W; Nilsen, Aaron; Vaidya, Akhil B; Riscoe, Michael K

    2016-08-01

    Antimalarial combination therapies play a crucial role in preventing the emergence of drug-resistant Plasmodium parasites. Although artemisinin-based combination therapies (ACTs) comprise the majority of these formulations, inhibitors of the mitochondrial cytochrome bc1 complex (cyt bc1) are among the few compounds that are effective for both acute antimalarial treatment and prophylaxis. There are two known sites for inhibition within cyt bc1: atovaquone (ATV) blocks the quinol oxidase (Qo) site of cyt bc1, while some members of the endochin-like quinolone (ELQ) family, including preclinical candidate ELQ-300, inhibit the quinone reductase (Qi) site and retain full potency against ATV-resistant Plasmodium falciparum strains with Qo site mutations. Here, we provide the first in vivo comparison of ATV, ELQ-300, and combination therapy consisting of ATV plus ELQ-300 (ATV:ELQ-300), using P. yoelii murine models of malaria. In our monotherapy assessments, we found that ATV functioned as a single-dose curative compound in suppressive tests whereas ELQ-300 demonstrated a unique cumulative dosing effect that successfully blocked recrudescence even in a high-parasitemia acute infection model. ATV:ELQ-300 therapy was highly synergistic, and the combination was curative with a single combined dose of 1 mg/kg of body weight. Compared to the ATV:proguanil (Malarone) formulation, ATV:ELQ-300 was more efficacious in multiday, acute infection models and was equally effective at blocking the emergence of ATV-resistant parasites. Ultimately, our data suggest that dual-site inhibition of cyt bc1 is a valuable strategy for antimalarial combination therapy and that Qi site inhibitors such as ELQ-300 represent valuable partner drugs for the clinically successful Qo site inhibitor ATV. PMID:27270285

  3. Development of a Suitable Dissolution Method for the Combined Tablet Formulation of Atorvastatin and Ezetimibe by RP-LC Method.

    Science.gov (United States)

    Ozkan Cansel, Kose; Ozgur, Esim; Sevinc, Kurbanoglu; Ayhan, Savaser; Ozkan, Sibel A; Yalcin, Ozkan

    2016-01-01

    Pharmaceutical preparations of ezetimibe and atorvastatin are generally used to regulate the lipid level in blood. It decreases the secondary events for patients with high cholesterol and clinical cardiovascular disease such as non-fatal or fatal heart attack. There is no any pharmacopoeia method available for the dissolution testing recommended by the FDA. Development of dissolution tests method is very critical parameter especially for the pharmaceutical preparations that contain Class II drugs (slightly soluble, good permeable). In the proposed method, the effects of pH and surfactant on the dissolution of poorly water soluble combined drug therapy with a different pKa values in an in vitro environment is investigated. The content of our study was designed to answer these open-ended questions. The optimized test conditions achieved under sink conditions with USP apparatus 2 at a paddle rotation speed of 75 rpm and 900 ml in 0.01 M Acetate buffer (pH= 6.8) containing 0.45% SDS as a dissolution medium. Quantification of dissolution samples were analyzed with a new fully validated RP-LC method with UV detection at 242 nm. PMID:26638976

  4. Design and formulation of nanoemulsions using 2-(poly(hexafluoropropylene oxide)) perfluoropropyl benzene in combination with linear perfluoro(polyethylene glycol dimethyl ether).

    Science.gov (United States)

    Mountain, Gregory A; Jelier, Benson J; Bagia, Christina; Friesen, Chadron M; Janjic, Jelena M

    2014-06-01

    This is the first report where PFPAE aromatic conjugates and perfluoro(polyethylene glycol dimethyl ether) are combined and formulated as nanoemulsions with droplet size below 100 nm. A perfluoropolyalkylether (PFPAE) aromatic conjugate, 2-(poly(hexafluoropropylene oxide)) perfluoropropyl benzene, was used as fluorophilic-hydrophilic diblock (FLD) aimed at stabilizing perfluoro(polyethylene glycol dimethyl ether) nanoemulsions. Its effects on colloidal behaviors in triphasic (organic/fluorous/aqueous) nanoemulsions were studied. The addition of FLD construct to fluorous phase led to decrease in PFPAE nanoemulsion droplet size to as low as 85 nm. Prepared nanoemulsions showed high colloidal stability. Our results suggest that these materials represent viable novel approach to fluorous colloid systems design with potential for biomedical and synthetic applications. PMID:24976645

  5. Medicines informal market in Congo, Burundi and Angola: counterfeit and sub-standard antimalarials

    Directory of Open Access Journals (Sweden)

    Bertocchi Paola

    2007-02-01

    Full Text Available Abstract Background The presence of counterfeits and sub-standards in African medicines market is a dramatic problem that causes many deaths each year. The increase of the phenomenon of pharmaceutical counterfeiting is due to the rise of the illegal market and to the impossibility to purchase branded high cost medicines. Methods In this paper the results of a quality control on antimalarial tablet samples purchased in the informal market in Congo, Burundi and Angola are reported. The quality control consisted in the assay of active substance by means of validated liquid chromatographic methods, uniformity of mass determination, disintegration and dissolution tests. Moreover, a general evaluation on label and packaging characteristics was performed. Results The results obtained on thirty antimalarial tablet samples containing chloroquine, quinine, mefloquine, sulphadoxine and pyrimethamine showed the presence of different kinds of problems: a general problem concerning the packaging (loose tablets, packaging without Producer name, Producer Country and sometimes without expiry date; low content of active substance (in one sample; different, non-declared, active substance (in one sample; sub-standard technological properties and very low dissolution profiles (in about 50% of samples. This last property could affect the bioavailability and bioequivalence in comparison with branded products and could be related to the use of different excipients in formulation or bad storage conditions. Conclusion This paper evidences that the most common quality problem in the analysed samples appears to be the low dissolution profile. Here it is remarked that the presence of the right active substance in the right quantity is not a sufficient condition for a good quality drug. Dissolution test is not less important in a quality control and often evidences in vitro possible differences in therapeutic efficacy among drugs with the same active content. Dissolution

  6. The search for natural bioactive compounds through a multidisciplinary approach in Bolivia. Part II. Antimalarial activity of some plants used by Mosetene indians.

    Science.gov (United States)

    Muñoz, V; Sauvain, M; Bourdy, G; Callapa, J; Rojas, I; Vargas, L; Tae, A; Deharo, E

    2000-02-01

    Forty-six different species collected in the Mosetene ethnia, dwelling in the Andean Piedmont of Bolivia, were screened for antimalarial properties. Thirty-three extracts were screened for antimalarial activity in vitro on Plasmodium falciparum chloroquine resistant strain (Indo), and forty-seven extracts were evaluated in vivo on the rodent malaria P. vinckei petteri 279BY. Only two plants are specifically used in combination by the Mosetene against malaria attack (Hymenachne donacifolia and Tesseria integrifolia), but they did not display any activity in vivo at 1000 mg/kg. The in vivo most active extracts were Swietenia macrophylla bark, Trema micrantha bark and Triplaris americana bark, not all of them were used for antimalarial purposes by the Mosetene. The following extracts were moderately active: Jacaratia digitata inner bark and Momordica charantia aerial part (both traditionally used as febrifuge), Kalanchoe pinnate aerial part (used in inflammatory processes), Lunania parviflora twigs and leaves, Phyllanthus acuminatus (used as piscicide), Tynanthus schumannianus fruit (used against diarrhoea), Triumfetta semitrilobata (used as febrifuge, to alleviate kidney and gynecological pain) and finally Solanum mammosum fruit (used against scabies). We present here the results of this screening, emphazing on the in vivo antimalarial activity of the selected plants. The antimalarial in vivo activity of the selected species, in relation with their traditional Mosetene use is then discussed. PMID:10687870

  7. Antimalarial activity of some Colombian medicinal plants.

    Science.gov (United States)

    Garavito, G; Rincón, J; Arteaga, L; Hata, Y; Bourdy, G; Gimenez, A; Pinzón, R; Deharo, E

    2006-10-11

    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 grandifolia (Mart.) Sandwith (Menispermaceae) leaves, Acacia farnesiana (L.) Willd. (Mimosaceae) leaves, Acnistus arborescens (L.) Schltdl. (Solanaceae) aerial part, Croton leptostachyus Kunth (Euphorbiaceae) aerial part, Piper cumanense Kunth (Piperaceae) fruits and leaves, Piper holtonii C. DC. (Piperaceae) aerial part and Xylopia aromatica (Lam.) Mart. (Annonaceae) bark with IC(50) values ranging from <1 to 2.1 microg/ml, while in the in vivo model only Abuta grandifolia alkaloid crude extract exhibits activity, inhibiting 66% of the parasite growth at 250 mg/kg/day. In the FBIT model, five extracts were active (Abuta grandifolia, Croton leptostachyus, Piper cumanense fruit and leaves and Xylopia aromatica). PMID:16713157

  8. Use and quality of antimalarial drugs in the private sector in Viet Nam.

    OpenAIRE

    Cong, L D; Yen, P. T.; Nhu, T. V.; Binh, L N

    1998-01-01

    This study examines the use and quality of antimalarial drugs in the growing private sector of Viet Nam. The practices of drug vendors (called alternative treatment providers (ATPs)) as well as their stocks and the quality of drugs sold by them, and the local production and distribution of antimalarials were investigated. Antimalarials were sold by the vast majority of ATPs, almost all the common antimalarials being available for sale. The practices and indications for sale, however, varied. ...

  9. Prices and mark-ups on antimalarials: evidence from nationally representative studies in six malaria-endemic countries

    OpenAIRE

    Palafox, Benjamin; Patouillard, Edith; Tougher, Sarah; Goodman, Catherine; Hanson, Kara; Kleinschmidt, Immo; Torres Rueda, Sergio; Kiefer, Sabine; O’Connell, Kate; Zinsou, Cyprien; Phok, Sochea; Akulayi, Louis; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton

    2015-01-01

    The private for-profit sector is an important source of treatment for malaria. However, private patients face high prices for the recommended treatment for uncomplicated malaria, artemisinin combination therapies (ACTs), which makes them more likely to receive cheaper, less effective non-artemisinin therapies (nATs). This study seeks to better understand consumer antimalarial prices by documenting and exploring the pricing behaviour of retailers and wholesalers. Using data collected in 2009–1...

  10. Role of PfATP6 and pfMRP1 in Plasmodium falciparum resistance to antimalarial drugs

    OpenAIRE

    Dahlström, Sabina

    2009-01-01

    Half of the world s population live at risk for malaria and nearly one million people die from the disease every year. The malaria burden is greatest in children and pregnant women in sub-Saharan Africa. As effective treatment is crucial for malaria control, the spread of antimalarial drug resistance has contributed significantly to malaria attributed morbidity and mortality. The current cornerstones in malaria treatment are artemisininbased combination therapy (ACT) for tre...

  11. Probing the Antimalarial Mechanism of Artemisinin and OZ277 (Arterolane) with Nonperoxidic Isosteres and Nitroxyl Radicals ▿

    OpenAIRE

    Fügi, Matthias A.; Wittlin, Sergio; Dong, Yuxiang; Vennerstrom, Jonathan L.

    2009-01-01

    Peroxidic antimalarials such as the semisynthetic artemisinins are critically important in the treatment of drug-resistant malaria. Nevertheless, their peroxide bond-dependent mode of action is still not well understood. Using combination experiments with cultured Plasmodium falciparum cells, we investigated the interactions of the nitroxide radical spin trap, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and four of its analogs with artemisinin and the ozonide drug development candidate OZ27...

  12. Impact of extrafine formulations of inhaled corticosteroids/long-acting beta-2 agonist combinations on patient-related outcomes in asthma and COPD

    Directory of Open Access Journals (Sweden)

    Scichilone N

    2014-11-01

    Full Text Available Nicola Scichilone,1 Alida Benfante,1 Luca Morandi,2 Federico Bellini,2 Alberto Papi21Biomedical Department of Internal and Specialist Medicine, Section of Pulmonology, University of Palermo, Italy; 2Respiratory Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, ItalyAbstract: Asthma and chronic obstructive pulmonary disease (COPD are among the most common chronic diseases worldwide, characterized by a condition of variable degree of airway obstruction and chronic airway inflammation. A large body of evidence has demonstrated the importance of small airways as a pharmacological target in these clinical conditions. Despite a deeper understanding of the pathophysiological mechanisms, the epidemiological observations show that a significant proportion of asthmatic and COPD patients have a suboptimal (or lack of control of their diseases. Different factors could influence the effectiveness of inhaled treatment in chronic respiratory diseases: patient-related (eg, aging; disease-related (eg, comorbid conditions; and drug-related/formulation-related factors. The presence of multiple illnesses is common in the elderly patient as a result of two processes: the association between age and incidence of degenerative diseases; and the development over time of complications of the existing diseases. In addition, specific comorbidities may contribute to impair the ability to use inhalers, such as devices for efficient drug delivery in the respiratory system. The inability to reach and treat the peripheral airways may contribute to the lack of efficacy of inhaled treatments. The recent development of inhaled extrafine formulations allows a more uniform distribution of the inhaled treatment throughout the respiratory tree to include the peripheral airways. The beclomethasone/formoterol extrafine formulation is available for the treatment of asthma and COPD. Different biomarkers of peripheral airways are improved by beclomethasone

  13. Antimalarial Preclinical Drug Development: A Single Oral Dose of A 5-Carbon-linked Trioxane Dimer Plus Mefloquine Cures Malaria-Infected Mice.

    Science.gov (United States)

    Moon, Deuk Kyu; Singhal, Vandana; Kumar, Nirbhay; Shapiro, Theresa A; Posner, Gary H

    2009-01-01

    Three new 5-carbon-linked trioxane dimer carboxylate esters have been prepared from the natural trioxane, artemisinin in only 3-steps and 40-50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure. PMID:20686674

  14. Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

    Directory of Open Access Journals (Sweden)

    Avinaba Mukherjee

    2016-03-01

    Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

  15. Antimalarial activity of extracts of Malaysian medicinal plants.

    Science.gov (United States)

    Najib Nik A Rahman, N; Furuta, T; Kojima, S; Takane, K; Ali Mohd, M

    1999-03-01

    In vitro and in vivo studies revealed that Malaysian medicinal plants, Piper sarmentosum, Andrographis paniculata and Tinospora crispa produced considerable antimalarial effects. Chloroform extract in vitro did show better effect than the methanol extract. The chloroform extract showed complete parasite growth inhibition as low as 0.05 mg/ml drug dose within 24 h incubation period (Andrographis paniculata) as compared to methanol extract of drug dose of 2.5 mg/ml but under incubation time of 48 h of the same plant spesies. In vivo activity of Andrographis paniculata also demonstrated higher antimalarial effect than other two plant species. PMID:10363840

  16. Antimalarial medicine diversion: stock-outs and other public health problems

    Directory of Open Access Journals (Sweden)

    Roger Bate

    2010-09-01

    Full Text Available Roger Bate1,2, Kimberly Hess2, Lorraine Mooney31American Enterprise Institute, Washington, D.C., USA; 2Africa Fighting Malaria, Washington, D.C., USA; 3Africa Fighting Malaria, Cambridge, UKBackground: Antimalarial medicine diversion has been seen across numerous African markets and can lead to serious stock-outs in the public sector, which can be dangerous to countries with high burdens of disease. This study discusses the numbers of diverted antimalarial medicines from several samplings in Africa.Methods: A total of 894 samples of antimalarial medicines were covertly purchased from private pharmacies in 11 African cities from late 2007 to early 2010. All medicine packages were visually inspected for correctness, in line with the protocol established by the Global Pharma Health Fund e.V. Minilab®, as well as for signs of diversion.Results: Overall, 6.5% (58 out of 894 of collected antimalarial medicines were found to be diverted, comprising 2.4% (5/210 of medicines collected in 2007 from six African cities, all of which were artemisinin-based combination therapies (ACTs; 2.3% (3/129 of medicines collected in 2008 in Lagos, Nigeria, two of which were ACTs; and 9% (50/555 of medicines collected in 2010 in 10 African cities, 35 of which were ACTs. ACT was by far the most diverted treatment in this study: 15.6% (5/32 of ACTs collected in 2007, and 30.7% (35/114 of ACTs collected in 2010.Conclusion: The number of diverted ACTs over the 33 months covered by this study is probably related to the laudable provision of vast amounts of donated or low-priced ACTs across African nations and the actual increase in diversion of these medicines into the private sector. The small sample sizes in this study might exaggerate any problem, but a potentially serious problem may well exist. To the extent that diversion of medicines exacerbates stock-outs, this is a public health problem, and a perversion of donor intent, but there are other possible harms of

  17. Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance.

    Science.gov (United States)

    von Seidlein, Lorenz; Dondorp, Arjen

    2015-06-01

    The emergence and spread of antimalarial resistance has been a major liability for malaria control. The spread of chloroquine-resistant Plasmodium falciparum strains had catastrophic consequences for people in malaria-endemic regions, particularly in sub-Saharan Africa. The recent emergence of artemisinin-resistant P. falciparum strains is of highest concern. Current efforts to contain artemisinin resistance have yet to show success. In the absence of more promising plans, it has been suggested to eliminate falciparum malaria from foci of artemisinin resistance using a multipronged approach, including mass drug administrations. The use of mass drug administrations is controversial as it increases drug pressure. Based on current knowledge it is difficult to conceptualize how targeted malaria elimination could contribute to artemisinin resistance, provided a full treatment course is ensured. PMID:25831482

  18. Stress degradation studies and development of stability-indicating TLC-densitometry method for determination of prednisolone acetate and chloramphenicol in their individual and combined pharmaceutical formulations

    Directory of Open Access Journals (Sweden)

    Musharraf Syed

    2012-01-01

    Full Text Available Abstract A rapid and reproducible stability indicating TLC method was developed for the determination of prednisolone acetate and chloramphenicol in presence of their degraded products. Uniform degradation conditions were maintained by refluxing sixteen reaction mixtures for two hours at 80°C using parallel synthesizer including acidic, alkaline and neutral hydrolysis, oxidation and wet heating degradation. Oxidation at room temperature, photochemical and dry heating degradation studies were also carried out. Separation was done on TLC glass plates, pre-coated with silica gel 60F-254 using chloroform: methanol (14:1 v/v. Spots at Rf 0.21 ± 0.02 and Rf 0.41 ± 0.03 were recognized as chloramphenicol and prednisolone acetate, respectively. Quantitative analysis was done through densitometric measurements at multiwavelength (243 nm, λmax of prednisolone acetate and 278 nm, λmax of chloramphenicol, simultaneously. The developed method was optimized and validated as per ICH guidelines. Method was found linear over the concentration range of 200-6000 ng/spot with the correlation coefficient (r2 ± S.D. of 0.9976 ± 3.5 and 0.9920 ± 2.5 for prednisolone acetate and chloramphenicol, respectively. The developed TLC method can be applied for routine analysis of prednisolone acetate and chloramphenicol in presence of their degraded products in their individual and combined pharmaceutical formulations.

  19. Synchronized separation of seven medications representing most commonly prescribed antihypertensive classes by using reversed-phase liquid chromatography: Application for analysis in their combined formulations.

    Science.gov (United States)

    Ebeid, Walid M; Elkady, Ehab F; El-Zaher, Asmaa A; El-Bagary, Ramzia I; Patonay, Gabor

    2014-04-01

    A reversed-phase high-performance liquid chromatography method was developed for the simultaneous determination of the diuretic, hydrochlorothiazide, along with six drugs representing the most commonly prescribed antihypertensive pharmacological classes such as atenolol, a selective β1 blocker, amlodipine besylate, a calcium channel blocker, moexipril hydrochloride, an angiotensin-converting-enzyme inhibitor, valsartan and candesartan cilexetil, which are angiotensin II receptor blockers, and aliskiren hemifumarate, a renin inhibitor, using irbesartan as an internal standard. The chromatographic separation was achieved using acetonitrile/sodium phosphate dibasic buffer (0.02 M, pH 5.5) at a flow rate of 1 mL/min in gradient elution mode at ambient temperature on a stationary phase composed of an Eclipse XDB-C18 (4.6 × 150 mm, 5 μm) column. UV detection was carried out at 220 nm. The method was validated according to ICH guidelines. Linearity, accuracy, and precision were satisfactory over the concentration ranges of 2-40 μg/mL for hydrochlorothiazide and candesartan cilexetil, 20-120, 10-160, 5-40, 20-250, and 5-50 μg/mL for atenolol, valsartan, moexipril hydrochloride, aliskiren hemifumarate, and amlodipine besylate, respectively. The method was successfully applied for the determination of each of the studied drugs in their combined formulations with hydrochlorothiazide. The developed method is suitable for the quality control and routine analysis of the cited drugs in their pharmaceutical dosage forms. PMID:24482404

  20. In vitro Potentiation of Antimalarial Activities by Daphnetin Derivatives Against Plasmodium falciparum

    Institute of Scientific and Technical Information of China (English)

    FANG HUANG; LIN-HUA TANG; LIN-QIAN YU; YI-CHANG NI; QIN-MEI WANG; FA-JUN NAN

    2006-01-01

    Objective To screen the antimalarial compounds of daphnetin derivatives against Plasmodium falciparum in vitro. Method Plasmodium faciparum (FCC1) was cultured in vitro by a modified method of Trager and Jensen. Antimalarial compounds were screened by microscopy-based assay and microfluorimetric method. Results DA79 and DA78 showed potent antimalarial activity against Plasmodium falciparum cultured in vitro. Conclusion Though the relationship between the structures of daphnetin derivatives and their antimalarial activities has not been clarified yet, this study may provide a new direction for discovery of more potential antimalarial compounds.

  1. Andrographolide: A Novel Antimalarial Diterpene Lactone Compound from Andrographis paniculata and Its Interaction with Curcumin and Artesunate

    Directory of Open Access Journals (Sweden)

    Kirti Mishra

    2011-01-01

    Full Text Available Andrographolide (AND, the diterpene lactone compound, was purified by HPLC from the methanolic fraction of the plant Andrographis paniculata. The compound was found to have potent antiplasmodial activity when tested in isolation and in combination with curcumin and artesunate against the erythrocytic stages of Plasmodium falciparum in vitro and Plasmodium berghei ANKA in vivo. IC50s for artesunate (AS, andrographolide (AND, and curcumin (CUR were found to be 0.05, 9.1 and 17.4 μM, respectively. The compound (AND was found synergistic with curcumin (CUR and addictively interactive with artesunate (AS. In vivo, andrographolide-curcumin exhibited better antimalarial activity, not only by reducing parasitemia (29%, compared to the control (81%, but also by extending the life span by 2-3 folds. Being nontoxic to the in vivo system this agent can be used as template molecule for designing new derivatives with improved antimalarial properties.

  2. Molecular Farming in Artemisia annua, a Promising Approach to Improve Anti-malarial Drug Production.

    Science.gov (United States)

    Pulice, Giuseppe; Pelaz, Soraya; Matías-Hernández, Luis

    2016-01-01

    Malaria is a parasite infection affecting millions of people worldwide. Even though progress has been made in prevention and treatment of the disease; an estimated 214 million cases of malaria occurred in 2015, resulting in 438,000 estimated deaths; most of them occurring in Africa among children under the age of five. This article aims to review the epidemiology, future risk factors and current treatments of malaria, with particular focus on the promising potential of molecular farming that uses metabolic engineering in plants as an effective anti-malarial solution. Malaria represents an example of how a health problem may, on one hand, influence the proper development of a country, due to its burden of the disease. On the other hand, it constitutes an opportunity for lucrative business of diverse stakeholders. In contrast, plant biofarming is proposed here as a sustainable, promising, alternative for the production, not only of natural herbal repellents for malaria prevention but also for the production of sustainable anti-malarial drugs, like artemisinin (AN), used for primary parasite infection treatments. AN, a sesquiterpene lactone, is a natural anti-malarial compound that can be found in Artemisia annua. However, the low concentration of AN in the plant makes this molecule relatively expensive and difficult to produce in order to meet the current worldwide demand of Artemisinin Combination Therapies (ACTs), especially for economically disadvantaged people in developing countries. The biosynthetic pathway of AN, a process that takes place only in glandular secretory trichomes of A. annua, is relatively well elucidated. Significant efforts have been made using plant genetic engineering to increase production of this compound. These include diverse genetic manipulation approaches, such as studies on diverse transcription factors which have been shown to regulate the AN genetic pathway and other biological processes. Results look promising; however, further

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

    OpenAIRE

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

    2003-01-01

    Antimalarial drug resistance has now become a serious global challenge and is the principal reasonfor the decline in antimalarial drug efficacy. Malaria endemic countries need inexpensive and efficaciousdrugs. Preserving the life spans of antimalarial drugs is a key part of the strategy for rollingback malaria. Artemisinin-based combinations offer a new and potentially highly effective way tocounter drug resistance. Clinical trials conducted in African children have attested to the good toler...

  4. Detecting Counterfeit Antimalarial Tablets by Near-Infrared Spectroscopy

    Science.gov (United States)

    Counterfeit antimalarial drugs are found in many developing countries, but it is challenging to differentiate between genuine and fakes due to their increasing sophistication. Near-infrared spectroscopy (NIRS) is a powerful tool in pharmaceutical forensics, and we tested this technique for discrim...

  5. In vitro antimalarial activity of novel semisynthetic nocathiacin I antibiotics.

    Science.gov (United States)

    Sharma, Indu; Sullivan, Margery; McCutchan, Thomas F

    2015-01-01

    Presently, the arsenal of antimalarial drugs is limited and needs to be replenished. We evaluated the potential antimalarial activity of two water-soluble derivatives of nocathiacin (BMS461996 and BMS411886) against the asexual blood stages of Plasmodium falciparum. Nocathiacins are a thiazolyl peptide group of antibiotics, are structurally related to thiostrepton, have potent activity against a wide spectrum of multidrug-resistant Gram-positive bacteria, and inhibit protein synthesis. The in vitro growth inhibition assay was done using three laboratory strains of P. falciparum displaying various levels of chloroquine (CQ) susceptibility. Our results indicate that BMS461996 has potent antimalarial activity and inhibits parasite growth with mean 50% inhibitory concentrations (IC50s) of 51.55 nM for P. falciparum 3D7 (CQ susceptible), 85.67 nM for P. falciparum Dd2 (accelerated resistance to multiple drugs [ARMD]), and 99.44 nM for P. falciparum K1 (resistant to CQ, pyrimethamine, and sulfadoxine). Similar results at approximately 7-fold higher IC50s were obtained with BMS411886 than with BMS461996. We also tested the effect of BMS491996 on gametocytes; our results show that at a 20-fold excess of the mean IC50, gametocytes were deformed with a pyknotic nucleus and growth of stage I to IV gametocytes was arrested. This preliminary study shows a significant potential for nocathiacin analogues to be developed as antimalarial drug candidates and to warrant further investigation. PMID:25779576

  6. The antimalarial drug quinine interferes with serotonin biosynthesis and action

    DEFF Research Database (Denmark)

    Islahudin, Farida; Tindall, Sarah M.; Mellor, Ian R.;

    2014-01-01

    The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmit...

  7. Quality of anti-malarials collected in the private and informal sectors in Guyana and Suriname

    Directory of Open Access Journals (Sweden)

    Evans Lawrence

    2012-06-01

    Full Text Available Abstract Background Despite a significant reduction in the number of malaria cases in Guyana and Suriname, this disease remains a major problem in the interior of both countries, especially in areas with gold mining and logging operations, where malaria is endemic. National malaria control programmes in these countries provide treatment to patients with medicines that are procured and distributed through regulated processes in the public sector. However, availability to medicines in licensed facilities (private sector and unlicensed facilities (informal sector is common, posing the risk of access to and use of non-recommended treatments and/or poor quality products. Methods To assess the quality of circulating anti-malarial medicines, samples were purchased in the private and informal sectors of Guyana and Suriname in 2009. The sampling sites were selected based on epidemiological data and/or distance from health facilities. Samples were analysed for identity, content, dissolution or disintegration, impurities, and uniformity of dosage units or weight variation according to manufacturer, pharmacopeial, or other validated method. Results Quality issues were observed in 45 of 77 (58% anti-malarial medicines sampled in Guyana of which 30 failed visual & physical inspection and 18 failed quality control tests. The proportion of monotherapy and ACT medicines failing quality control tests was 43% (13/30 and 11% (5/47 respectively. A higher proportion of medicines sampled from the private sector 34% (11/32 failed quality control tests versus 16% (7/45 in the informal sector. In Suriname, 58 medicines were sampled, of which 50 (86% were Artecom®, the fixed-dose combination of piperaquine-dihydroartemisinin-trimethoprim co-blistered with a primaquine phosphate tablet. All Artecom samples were found to lack a label claim for primaquine, thus failing visual and physical inspection. Conclusions The findings of the studies in both countries point to

  8. Anti-malarial market and policy surveys in sub-Saharan Africa

    Directory of Open Access Journals (Sweden)

    Sevcsik Ann-Marie

    2010-04-01

    Full Text Available Abstract At a recent meeting (Sept 18, 2009 in which reasons for the limited access to artemisinin-based combination therapy (ACT in sub-Saharan Africa were discussed, policy and market surveys on anti-malarial drug availability and accessibility in Burundi and Sierra Leone were presented in a highly interactive brainstorming session among key stakeholders across private, public, and not-for-profit sectors. The surveys, the conduct of which directly involved the national malaria control programme managers of the two countries, provides the groundwork for evidence-based policy implementation. The results of the surveys could be extrapolated to other countries with similar socio-demographic and malaria profiles. The meeting resulted in recommendations on key actions to be taken at the global, national, and community level for better ACT accessibility. At the global level, both public and private sectors have actions to take to strengthen policies that lead to the replacement of loose blister packs with fixed-dose ACT products, develop strategies to ban inappropriate anti-malarials and regulate those bans, and facilitate technology and knowledge transfer to scale up production of fixed-dose ACT products, which should be readily available and affordable to those patients who are in the greatest need of these medicines. At the national level, policies that regulate the anti-malarial medicines market should be enacted and enforced. The public sector, including funding donors, should participate in ensuring that the private sector is engaged in the ACT implementation process. Research similar to the surveys discussed is important for other countries to develop and evaluate the right incentives at a local level. At the community level, community outreach and education about appropriate preventive and treatment measures must continue and be strengthened, with service delivery systems developed within both public and private sectors, among other measures

  9. Combining Two-Dimensional Diffusion-Ordered Nuclear Magnetic Resonance Spectroscopy, Imaging Desorption Electrospray Ionization Mass Spectrometry, and Direct Analysis in Real-Time Mass Spectrometry for the Integral Investigation of Counterfeit Pharmaceuticals

    Science.gov (United States)

    Nyadong, Leonard; Harris, Glenn A.; Balayssac, Stéphane; Galhena, Asiri S.; Malet-Martino, Myriam; Martino, Robert; Parry, R. Mitchell; Wang, May Dongmei; Fernández, Facundo M.; Gilard, Véronique

    2016-01-01

    During the past decade, there has been a marked increase in the number of reported cases involving counterfeit medicines in developing and developed countries. Particularly, artesunate-based antimalarial drugs have been targeted, because of their high demand and cost. Counterfeit antimalarials can cause death and can contribute to the growing problem of drug resistance, particularly in southeast Asia. In this study, the complementarity of two-dimensional diffusion-ordered 1H nuclear magnetic resonance spectroscopy (2D DOSY 1H NMR) with direct analysis in real-time mass spectrometry (DART MS) and desorption electrospray ionization mass spectrometry (DESI MS) was assessed for pharmaceutical forensic purposes. Fourteen different artesunate tablets, representative of what can be purchased from informal sources in southeast Asia, were investigated with these techniques. The expected active pharmaceutical ingredient was detected in only five formulations via both nuclear magnetic resonance (NMR) and mass spectrometry (MS) methods. Common organic excipients such as sucrose, lactose, stearate, dextrin, and starch were also detected. The graphical representation of DOSY 1H NMR results proved very useful for establishing similarities among groups of samples, enabling counterfeit drug “chemotyping”. In addition to bulk- and surface-average analyses, spatially resolved information on the surface composition of counterfeit and genuine antimalarial formulations was obtained using DESI MS that was performed in the imaging mode, which enabled one to visualize the homogeneity of both genuine and counterfeit drug samples. Overall, this study suggests that 2D DOSY 1H NMR, combined with ambient MS, comprises a powerful suite of instrumental analysis methodologies for the integral characterization of counterfeit antimalarials. PMID:19453162

  10. Gas chromatographic method for the determination of lumefantrine in antimalarial finished pharmaceutical products

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    Sultan Suleman

    2015-09-01

    Full Text Available A simple method has been developed and validated for quantitative determination of lumefantrine in antimalarial finished pharmaceutical products using gas chromatography coupled to flame ionization detector. Lumefantrine was silylated with N,O–bis(trimethyl-silyltrifluoro-acetamide at 70°C for 30 minutes, and chromatographic separation was conducted on a fused silica capillary (HP-5, 30 m length × 0.32 mm i.d., 0.25 μm film thickness column. Evaluation of the method within analytical quality-by-design principles, including a central composite face-centered design for the sample derivatization process and Plackett–Burman robustness verification of the chromatographic conditions, indicated that the method has acceptable specificity toward excipients and degradants, accuracy [mean recovery = 99.5%, relative standard deviation (RSD = 1.0%], linearity (=0.9986, precision (intraday = 96.1% of the label claim, RSD = 0.9%; interday = 96.3% label claim, RSD = 0.9%, and high sensitivity with detection limits of 0.01 μg/mL. The developed method was successfully applied to analyze the lumefantrine content of marketed fixed-dose combination antimalarial finished pharmaceutical products.

  11. Virtual Screening and Docking Studies of Synthesized Chalcones: Potent Anti-Malarial Drug

    Directory of Open Access Journals (Sweden)

    Prashant Singh

    2016-03-01

    Full Text Available A novel series of Chalcones were synthesized targets asexual blood stages of Plasmodium falciparum has been analyzed by utilizing a combination of molecular modeling techniques. Statistically significant structure-based quantitative structure activity relationships models were generated and validated through acceptable predictive ability to support internal and external set of compounds. Screening of most valuable drug among of pre-synthesized drug on the basis of binding efficiency to target receptor was carried out by docking view. Prior this pre-computed Mean IC50 and MIC value were also taken in consideration. The most effective compound on the basis all consideration was found. Previous studies have suggested that Ca2+-ATPase (PfATP6 of P. falciparum is the target of many anti-malarial drugs. However, the mechanism of inhibition of Ca2+- ATPase (PfATP6 is not known. Here we address this issue using bioinformatics tools. We generated a molecular model of Ca2+-ATPase (PfATP6 of P. falciparum and performed molecular docking of all chalcones. Molecular docking programme Glide iGEMDock was used to determine binding feasibility of 52 analogues of chalcones. The comparison of docking parameters showed, more than 5 analogues are better ligands of PfATP6. The binding of chalocones to PFATP6 is mediated by both hydrogen bonding, hydrophobic and polar interactions. Our results suggest that chalcones analogues are promising lead compounds for the development of anti-malarial drugs

  12. Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

    Science.gov (United States)

    Wright, Megan H.; Clough, Barbara; Rackham, Mark D.; Rangachari, Kaveri; Brannigan, James A.; Grainger, Munira; Moss, David K.; Bottrill, Andrew R.; Heal, William P.; Broncel, Malgorzata; Serwa, Remigiusz A.; Brady, Declan; Mann, David J.; Leatherbarrow, Robin J.; Tewari, Rita; Wilkinson, Anthony J.; Holder, Anthony A.; Tate, Edward W.

    2014-02-01

    Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase.

  13. High-content live cell imaging with RNA probes: advancements in high-throughput antimalarial drug discovery

    Science.gov (United States)

    Cervantes, Serena; Prudhomme, Jacques; Carter, David; Gopi, Krishna G; Li, Qian; Chang, Young-Tae; Le Roch, Karine G

    2009-01-01

    Background Malaria, a major public health issue in developing nations, is responsible for more than one million deaths a year. The most lethal species, Plasmodium falciparum, causes up to 90% of fatalities. Drug resistant strains to common therapies have emerged worldwide and recent artemisinin-based combination therapy failures hasten the need for new antimalarial drugs. Discovering novel compounds to be used as antimalarials is expedited by the use of a high-throughput screen (HTS) to detect parasite growth and proliferation. Fluorescent dyes that bind to DNA have replaced expensive traditional radioisotope incorporation for HTS growth assays, but do not give additional information regarding the parasite stage affected by the drug and a better indication of the drug's mode of action. Live cell imaging with RNA dyes, which correlates with cell growth and proliferation, has been limited by the availability of successful commercial dyes. Results After screening a library of newly synthesized stryrl dyes, we discovered three RNA binding dyes that provide morphological details of live parasites. Utilizing an inverted confocal imaging platform, live cell imaging of parasites increases parasite detection, improves the spatial and temporal resolution of the parasite under drug treatments, and can resolve morphological changes in individual cells. Conclusion This simple one-step technique is suitable for automation in a microplate format for novel antimalarial compound HTS. We have developed a new P. falciparum RNA high-content imaging growth inhibition assay that is robust with time and energy efficiency. PMID:19515257

  14. New quinoline derivatives demonstrate a promising antimalarial activity against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.

    Science.gov (United States)

    Soares, Roberta Reis; da Silva, José Marcio Fernandes; Carlos, Bianca Cecheto; da Fonseca, Camila Campos; de Souza, Laila Salomé Araújo; Lopes, Fernanda Valério; de Paula Dias, Rafael Mafra; Moreira, Paulo Otávio Lourenço; Abramo, Clarice; Viana, Gustavo Henrique Ribeiro; de Pila Varotti, Fernando; da Silva, Adilson David; Scopel, Kézia Katiani Gorza

    2015-06-01

    Malaria continues to be an important public health problem in the world. Nowadays, the widespread parasite resistance to many drugs used in antimalarial therapy has made the effective treatment of cases and control of the disease a constant challenge. Therefore, the discovery of new molecules with good antimalarial activity and tolerance to human use can be really important in the further treatment of the disease. In this study we have investigated the antiplasmodial activity of 10 synthetic compounds derived from quinoline, five of them combined to sulfonamide and five to the hydrazine or hydrazide group. The compounds were evaluated according to their cytotoxicity against HepG2 and HeLa cell lines, their antimalarial activity against CQ-sensitive and CQ-resistant Plasmodium falciparum strains and, finally, their schizonticide blood action in mice infected with Plasmodium berghei NK65. The compounds exhibited no cytotoxic action in HepG2 and HeLa cell lines when tested up to a concentration of 100 μg/mL. In addition, the hydrazine or hydrazide derivative compounds were less cytotoxic against cell lines and more active against CQ-sensitive and CQ-resistant P. falciparum strains, showing high SI (>1000 when SI was calculated using the CC50 from the 3D7 strain as reference). When tested in vivo, the hydrazine derivative 1f compound showed activity against the development of blood parasites similar to that observed with CQ, the reference drug. Interestingly, the 1f compound demonstrated the best LipE value (4.84) among all those tested in vivo. Considering the in vitro and in vivo activities of the compounds studied here and the LipE values, we believe the 1f compound to be the most promising molecule for further studies in antimalarial chemotherapy. PMID:25920564

  15. The popular herbal antimalarial, extract of Cryptolepis sanguinolenta, is potently cytotoxic.

    Science.gov (United States)

    Ansah, Charles; Gooderham, Nigel J

    2002-12-01

    The aqueous root extract of Cryptolepis sanguinolenta (CSE) is a popular antimalarial in West African ethnomedicine. Cryptolepine (CLP), the major alkaloid of the plant, is a cytotoxic DNA intercalator that has promise as an anticancer agent. To date the aqueous root extract, the traditional antimalarial formulation, has not been evaluated for toxicity. In this study, we have examined the in vitro toxicity of CSE and CLP using V79 cells, a Chinese hamster lung fibroblast frequently used to assess genetic toxicity, and a number of organ-specific human cancer cell lines. CSE and CLP caused a dose- and time-dependent reduction in viability of the V79 cell line. Flow cytometric analysis of CSE- and CLP-treated (24 h) asynchronously growing V79 cells using propidium iodide (PI) staining revealed an accumulation of cells (up to 55%) in the sub-G1 phase of the cell cycle, indicative of cell death. The V79 cells and almost all the organ-specific human cancer cell lines exposed to CSE and CLP were profoundly growth inhibited, as measured in a clonogenicity assay. In a V79 cell mutation assay (hprt gene), CSE (5-50 microg/ml) only induced mutation at the highest dose employed (mutation frequency approximately 4 and 38 mutant clones per 10(6) cells for control and CSE, respectively), but CLP (0.5-5.0 microM) was not mutagenic. These results indicate that CSE and CLP are very cytotoxic and may be weak mammalian mutagens and/or clastogens. The poor genotoxicity of CSE and CLP coupled with their potent cytotoxic action support their anticancer potential. PMID:12441369

  16. Discovery and optimisation studies of antimalarial phenotypic hits

    Science.gov (United States)

    Mital, Alka; Murugesan, Dinakaran; Kaiser, Marcel; Yeates, Clive; Gilbert, Ian H.

    2015-01-01

    There is an urgent need for the development of new antimalarial compounds. As a result of a phenotypic screen, several compounds with potent activity against the parasite Plasmodium falciparum were identified. Characterization of these compounds is discussed, along with approaches to optimise the physicochemical properties. The in vitro antimalarial activity of these compounds against P. falciparum K1 had EC50 values in the range of 0.09–29 μM, and generally good selectivity (typically >100-fold) compared to a mammalian cell line (L6). One example showed no significant activity against a rodent model of malaria, and more work is needed to optimise these compounds. PMID:26408453

  17. Drug resistance genomics of the antimalarial drug artemisinin

    OpenAIRE

    Elizabeth A Winzeler; Manary, Micah J

    2014-01-01

    Across the globe, over 200 million annual malaria infections result in up to 660,000 deaths, 77% of which occur in children under the age of five years. Although prevention is important, malaria deaths are typically prevented by using antimalarial drugs that eliminate symptoms and clear parasites from the blood. Artemisinins are one of the few remaining compound classes that can be used to cure multidrug-resistant Plasmodium falciparum infections. Unfortunately, clinical trials from Southeast...

  18. Antimicrobial peptides: a new class of antimalarial drugs?

    Directory of Open Access Journals (Sweden)

    Nuno eVale

    2014-12-01

    Full Text Available A range of antimicrobial peptides (AMP exhibit activity on malaria parasites, Plasmodium spp, in their blood or mosquito stages, or both. These peptides include a diverse array of both natural and synthetic molecules varying greatly in size, charge, hydrophobicity and secondary structure features. Along with an overview of relevant literature reports regarding AMP that display antiplasmodial activity, this review makes a few considerations about those molecules as a potential new class of antimalarial drugs.

  19. Antimalarial drug resistance in Africa: key lessons for the future

    OpenAIRE

    Takala-Harrison, Shannon; Laufer, Miriam K

    2015-01-01

    Drug-resistant parasites repeatedly arise as a result of widespread use of antimalarial drugs and have contributed significantly to the failure to control and eradicate malaria throughout the world. In this review, we describe the spread of resistance to chloroquine and sulfadoxine–pyrimethamine, two old drugs that are no longer used owing to high rates of resistance, and examine the effect of the removal of drug pressure on the survival of resistant parasites. Artemisinin-resistant malaria i...

  20. Intermittent Preventive Antimalarial Treatment for Children with Anaemia.

    OpenAIRE

    Athuman, Mwaka; Kabanywanyi, Abdunoor M; Rohwer, Anke C

    2015-01-01

    Background Anaemia is a global public health problem. Children under five years of age living in developing countries (mostly Africa and South-East Asia) are highly affected. Although the causes for anaemia are multifactorial, malaria has been linked to anaemia in children living in malaria-endemic areas. Administering intermittent preventive antimalarial treatment (IPT) to children might reduce anaemia, since it could protect children from new Plasmodium parasite infection (the parasites tha...

  1. 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...

  2. 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.

  3. Antimalarials and the fight against malaria in Brazil

    Directory of Open Access Journals (Sweden)

    Luiz MA Carmargo

    2009-04-01

    Full Text Available Luiz MA Carmargo1, Saulo de Oliveira2, Sergio Basano3, Célia RS Garcia21ICBV-USP, Monte Negro, Rondônia, Brasil; 2Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, SP, Brazil; 3CEMETRON, Porto Velho, Guaporé, BrazilAbstract: Malaria, known as the “fevers,” has been treated for over three thousand years in China with extracts of plants of the genus Artemisia (including Artemisia annua, A. opiacea, and A. lancea from which the active compound is artemisin, a sesquiterpene that is highly effective in the treatment of the disease, especially against young forms of the parasite. South American Indians in the seventeenth century already used an extract of the bark of chinchona tree, commonly named “Jesuits’ powder.” Its active compound was isolated in 1820 and its use spread all over the world being used as a prophylactic drug during the construction of the Madeira–Mamoré railroad in the beginning of the twentieth century. During the 1920s to the 1940s, new antimalarial drugs were synthesized to increase the arsenal against this parasite. However, the parasite has presented systematic resistence to conventional antimalarial drugs, driving researchers to find new strategies to treat the disease. In the present review we discuss how Brazil treats Plasmodium-infected patients.Keywords: Plasmodium falciparum, malaria, antimalarials, calcium

  4. 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...... action on human mononuclear cells of the various antimalarial drugs and the potential adverse effects of antimalarial chemotherapy are discussed....... at concentrations twice as high as those required to suppress lymphocyte proliferation. Addition of exogenous IL-2 only partially reversed the suppressive effect on lymphocyte proliferation. Delayed addition of the quinolines decreased their suppressive effect, but not completely. The mechanisms of...

  5. Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in Healthy Adults

    Science.gov (United States)

    Salman, Sam; Bendel, Daryl; Lee, Toong C.; Templeton, David

    2015-01-01

    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in two open-label studies. In study 1, 16 healthy males were randomized to each of four single-dose treatments administered in random order: (i) 15.0 mg of sublingual artemether (5 × 3.0 actuations), (ii) 30.0 mg of sublingual artemether (10 × 3.0 mg), (iii) 30.0 mg of sublingual artemether (5 × 6.0 mg), and (iv) 30.0 mg of artemether in tablet form. In study 2, 16 healthy males were randomized to eight 30.0-mg doses of sublingual artemether given over 5 days as either 10 3.0-mg or 5 6.0-mg actuations. Frequent blood samples were drawn postdose. Plasma artemether and dihydroartemisinin levels were measured using liquid chromatography-mass spectrometry. Population compartmental pharmacokinetic models were developed. In study 1, sublingual artemether absorption was biphasic, with both rate constants being greater than that of the artemether tablets (1.46 and 1.66 versus 0.43/h, respectively). Relative to the tablets, sublingual artemether had greater bioavailability (≥1.24), with the greatest relative bioavailability occurring in the 30.0-mg dose groups (≥1.58). In study 2, there was evidence that the first absorption phase accounted for between 32% and 69% of the total dose and avoided first-pass (FP) metabolism, with an increase in FP metabolism occurring in later versus earlier doses but with no difference in bioavailability between the dose actuations. Sublingual artemether is more rapidly and completely absorbed than are equivalent doses of artemether tablets in healthy adults. Its disposition appears to be complex, with two absorption phases, the first representing pregastrointestinal absorption, as well as dose-dependent bioavailability and autoinduction of metabolism with multiple dosing. PMID:25801553

  6. Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in Healthy Adults

    OpenAIRE

    Salman, Sam; Bendel, Daryl; Lee, Toong C.; Templeton, David; Davis, Timothy M. E.

    2015-01-01

    The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in two open-label studies. In study 1, 16 healthy males were randomized to each of four single-dose treatments administered in random order: (i) 15.0 mg of sublingual artemether (5 × 3.0 actuations), (ii) 30.0 mg of sublingual artemether (10 × 3.0 mg), (iii) 30.0 mg of sublingual artemether (5 × 6.0 mg), and (iv) 30.0 mg of artemether in tablet form. In study 2, 16 healthy males were randomized to eight 30.0-mg doses of...

  7. Efficacy and safety of a nano-emulsion gel formulation of adapalene 0.1% and clindamycin 1% combination in acne vulgaris: A randomized, open label, active-controlled, multicentric, phase IV clinical trial

    Directory of Open Access Journals (Sweden)

    Siva Prasad

    2012-01-01

    Full Text Available Background: Acne vulgaris is a very common skin disease with a significant detrimental effect on the quality of life of the patients. Aims: To assess the comparative efficacy and safety of a nano-emulsion gel formulation of adapalene and clindamycin combination with its conventional formulation in the treatment of acne vulgaris of the face. It was a prospective, randomized, open label, active-controlled, multicentric, clinical trial. Methods: Eligible patients suffering from acne vulgaris of the face were randomized to receive once-daily treatment with a nano-emulsion gel or conventional gel formulation of adapalene 0.1% and clindamycin (as phosphate 1% combination for 12 weeks. Total, inflammatory and noninflammatory lesion counts, with grading of acne severity were carried out on a monthly basis. Safety assessments were done to determine the comparative local and systemic tolerability. Two-tailed significance testing was carried out with appropriate statistical tests, and P-values < 0.05 were considered as significant. Results: 209/212 patients enrolled in the study were eligible for efficacy and safety assessments in both nano-emulsion gel (118/119 patients and conventional gel (91/93 patients groups. Significantly better reductions in total (79.7% vs. 62.7%, inflammatory (88.7% vs. 71.4% and noninflammatory (74.9% vs. 58.4% lesions were reported with the nano-emulsion gel as compared to the conventional gel (P < 0.001 for all. Mean acne severity score also reduced significantly more with the nano-emulsion formulation (1.9 ± 0.9 vs. 1.4 ± 1.0; P < 0.001 than the comparator. Significantly lower incidence and lesser intensity of adverse events like local irritation (4.2% vs. 19.8%; P < 0.05 and erythema (0.8% vs. 9.9%; P < 0.05 were recorded with the nano-emulsion gel. Conclusions: The nano-emulsion gel formulation of adapalene and clindamycin combination appears to be more efficacious and better tolerated than the conventional formulation

  8. Cost-effectiveness of a fixed-dose combination of solifenacin and oral controlled adsorption system formulation of tamsulosin in men with lower urinary tract symptoms associated with benign prostatic hyperplasia

    OpenAIRE

    Nazir, Jameel; Heemstra, Lars; van Engen, Anke; Hakimi, Zalmai; Ivanescu, Cristina

    2015-01-01

    Background Storage symptoms, associated with benign prostatic hyperplasia (BPH), often co-exist with voiding symptoms in men with lower urinary tract symptoms (LUTS). Storage symptoms are likely to be most bothersome, and may not be adequately resolved by treatment with α-blocker or antimuscarinic monotherapy. A recent randomised controlled phase 3 trial (NEPTUNE) demonstrated that a fixed-dose combination (FDC) of solifenacin 6 mg plus an oral controlled absorption system (OCAS™) formulation...

  9. Got ACTs? Availability, price, market share and provider knowledge of anti-malarial medicines in public and private sector outlets in six malaria-endemic countries

    Directory of Open Access Journals (Sweden)

    O'Connell Kathryn A

    2011-10-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC, Madagascar, Nigeria, Uganda and Zambia. Methods Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. Results 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets as compared to first-line quality-assured ACT ( Conclusions These standardized, nationally representative results demonstrate the typically low availability, low market share and high prices of ACT, in the private sector where most anti-malarials are accessed, with some exceptions. The results confirm that there is substantial room to improve availability and affordability of ACT treatment in the surveyed countries. The data will also be useful for monitoring the impact of interventions such as the Affordable Medicines Facility for malaria.

  10. Antimalarial activity and toxicity of Garcinia mangostana Linn.

    Institute of Scientific and Technical Information of China (English)

    Ratchanu; Bunyong; Wanna; Chaijaroenkul; Tullayakorn; Plengsuriyakarn; Kesara; Na-Bangchang

    2014-01-01

    Objective:To investigate the antimalarial activity and toxicity of the crude ethanolic extract of its pericarp both in vitro and in vim.Methods:The antimalarial activity of Gareinja mangostana(G.mangostana)Linn.extract against 3D7 and Kl Plasmodium falciparum(P.falciparum)clone were assessed using SYBR green I-based assay.A 4-day suppressive test of Plasmodium berghei{P.berghei)infected mouse was performed to investigate in vivo antimalarial activity.Results:The in vitro antimalarial activity was seleclive(SI>5?and classified as weak and good lo moderate activity against both 3D7 and K1 P.falciparum,clones with median IC50(range)values of 11.12(10.94-11.29)and 7.54(6.80-7.68)μg/mL,respectively.The extract was considered nontoxic to mice.The maximum tolerated doses for acute and subacute toxicity in mice were 5 000and 2 000 mg/kg,respectively.Median(range)parasite density on day 4 of the negative control group(25%Tween-80),mice treated with 250,500,1000,and 2 000 mg/kg body weight of the extract,and 10 mg/kg body weight of chloroquine for 14 d were 12.8(12.2-13.7),11.4(9.49-13.8),11.6(9.9-12.5),11.7(10.6-12.8),10.9(9.4-11.6)and 0(0-0)%respectively.Parasite density on day 4in the control group treated with Tween-80 was higher than the groups treated with chloroquine and all dose levels of the extract.Conclusions:G.mangostana linn,showed weak antimalarial activity of the extract both in vitro and in vivo could be due to limitation of absorption of the active compounds.

  11. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation.

    Science.gov (United States)

    Senarathna, S M D K Ganga; Page-Sharp, Madhu; Crowe, Andrew

    2016-01-01

    The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10-6 cm/sec, followed by amodiaquine around 20 x 10-6 cm/sec; both mefloquine and artesunate were around 10 x 10-6 cm/sec. Methylene blue was between 2 and 6 x 10-6 cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine. PMID:27045516

  12. A versatile in vitro ELISA test for quantification and quality testing of infectious, inactivated and formulated rabies virus used in veterinary monovalent or combination vaccine.

    Science.gov (United States)

    Sigoillot-Claude, Cécile; Battaglio, Myriam; Fiorucci, Marc; Gillet, Delphine; Vimort, Anne-Sophie; Giraud, Yves; Laurent, Sonia; Vaganay, Alain; Poulet, Hervé

    2015-07-31

    Regulatory potency test for rabies vaccines requires mice vaccination followed by challenge with a live virus via intracerebral route. An alternative in vitro test, consistent with the "3R's" (Reduce, Replace, Refine) was designed to quantify active glycoprotein G using seroneutralizing monoclonal antibodies. This versatile ELISA targets well conformed neutralizing epitopes. Therefore, it quantifies only the trimeric pre-fusion form of glycoprotein G known to elicits the production of viral neutralizing antibodies. The ELISA makes it possible to quantify the rabies antigen during all steps of the product cycle (i.e. viral cultivation, downstream process, formulation and product stability in the presence of aluminum gel or other vaccine valence). Moreover, the batch-to-batch consistency of our active ingredients and formulated products could be demonstrated. PMID:26144898

  13. The challenge to avoid anti-malarial medicine stock-outs in an era of funding partners: the case of Tanzania

    OpenAIRE

    Mikkelsen-Lopez, Inez; Shango, Winna; Barrington, Jim; Ziegler, Rene; Smith, Tom; de Savigny, Don

    2014-01-01

    Background Between 2007 and 2013, the Tanzanian public sector received 93.1 million doses of first-line anti-malarial artemisinin-based combination therapy (ACT) in the form of artemether-lumefantrine entirely supplied by funding partners. The introduction of a health facility ACT stock monitoring system using SMS technology by the National Malaria Control Programme in mid 2011 revealed a high frequency of stock-outs of ACT in primary care public health facilities. The objective of this study...

  14. 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 ...

  15. Stability profiling of anti-malarial drug piperaquine phosphate and impurities by HPLC-UV, TOF-MS, ESI-MS and NMR

    OpenAIRE

    Yan, Fang; Liu, Jie; Zeng, Xuefang; Zhang, Yuan; Hang, Taijun

    2014-01-01

    Background Piperaquine, 1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]-propane, is an anti-malarial compound belonging to the 4-aminoquinolines, which has received renewed interest in treatment of drug resistant falciparum malaria in artemisinin-based combination therapy with dihydroartemisinin. The impurity profile of this drug product is paid an ever-increasing attention. However, there were few published studies of the complete characterization of related products or impurities in piperaqu...

  16. The use of paediatric artemisinin combinations in sub-Saharan Africa: a snapshot questionnaire survey of health care personnel

    Directory of Open Access Journals (Sweden)

    Agnandji Selidji T

    2011-12-01

    Full Text Available Abstract Background Paediatric drug formulations for artemisinin combination therapy (P-ACT have been developed over the past few years and have been shown to improve the therapeutic management of young children with uncomplicated falciparum malaria. This process was however not equally paralleled by a timely adoption of P-ACT in national and international treatment recommendations. National malaria programmes in sub-Saharan Africa have not yet widely embraced this new therapeutic tool. To which extent P-ACT is used in the field in sub-Saharan Africa is not known to date. Methods This snapshot questionnaire survey aimed to provide an overview on the current routine practices for the availability and use of P-ACT as anti-malarial treatment for young children in sub-Saharan Africa. Health care personnel in seven countries in West-, Central, and East-Africa were invited to answer a structured questionnaire assessing use and availability of P-ACT. Results A total of 71 respondents including doctors, nurses and pharmacy personnel responsible for the anti-malarial treatment of young children were interviewed. P-ACT was used by 83% (95% confidence interval: 73-90%; n = 59 as first-line treatment for young children. Use of 15 different P-ACT products was reported among which only two have received WHO prequalification status and approval by a stringent registration authority. Use of a specific P-ACT product was not linked to consumer prices or availability of supporting clinical trial data, but may depend more on the marketing capacity of the manufacturer. Major differences in frequency and dosing of anti-malarial regimens with identical anti-malarial compounds and the marketing of loose combinations were recorded. Conclusion Paediatric ACT is widely used for the treatment of uncomplicated malaria in young children. However, the majority of P-ACT formulations in use do not meet highest international quality standards evoking concerns for patients

  17. First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials

    OpenAIRE

    Moehrle, Joerg J; Duparc, Stephan; Siethoff, Christoph; van Giersbergen, Paul L M; Craft, J Carl; Arbe-Barnes, Sarah; Charman, Susan A; Gutierrez, Maria; Wittlin, Sergio; Vennerstrom, Jonathan L.

    2012-01-01

    Aims To assess the safety and pharmacokinetics of a new synthetic ozonide antimalarial, OZ439, in a first-in-man, double-blind study in healthy volunteers. Methods OZ439 was administered as single oral daily doses of a capsule formulation (50–1200 mg) or an oral dispersion (400–1600 mg, fed and fasted states) and for up to 3 days as an oral dispersion (200–800 mg day−1). Plasma concentrations of OZ439 and its metabolites were measured by LC-MS. Results The pharmacokinetic (PK) profile of OZ43...

  18. In vivo antimalarial activity of extracts of Tanzanian medicinal plants used for the treatment of malaria.

    Science.gov (United States)

    Nondo, Ramadhani S O; Erasto, Paul; Moshi, Mainen J; Zacharia, Abdallah; Masimba, Pax J; Kidukuli, Abdul W

    2016-01-01

    Plants used in traditional medicine have been the source of a number of currently used antimalarial medicines and continue to be a promising resource for the discovery of new classes of antimalarial compounds. The aim of this study was to evaluate in vivo antimalarial activity of four plants; Erythrina schliebenii Harms, Holarrhena pubescens Buch-Ham, Phyllanthus nummulariifolius Poir, and Caesalpinia bonducella (L.) Flem used for treatment of malaria in Tanzania. In vivo antimalarial activity was assessed using the 4-day suppressive antimalarial assay. Mice were infected by injection via tail vein with 2 × 10(7) erythrocytes infected with Plasmodium berghei ANKA. Extracts were administered orally, once daily, for a total of four daily doses from the day of infection. Chloroquine (10 mg/kg/day) and solvent (5 mL/kg/day) were used as positive and negative controls, respectively. The extracts of C. bonducella, E. schliebenii, H. pubescens, and P. nummulariifolius exhibited dose-dependent suppression of parasite growth in vivo in mice, with the highest suppression being by C. bonducella extract. While each of the plant extracts has potential to yield useful antimalarial compounds, the dichloromethane root extract of C. bonducella seems to be the most promising for isolation of active antimalarial compound(s). In vivo antimalarial activity presented in this study supports traditional uses of C. bonducella roots, E. schliebenii stem barks, H. pubescens roots, and P. nummulariifolius for treatment of malaria. PMID:27144154

  19. Formulation development and evaluation of fast disintegrating tablets of salbutamol sulphate, cetirizine hydrochloride in combined pharmaceutical dosage form: a new era in novel drug delivery for pediatrics and geriatrics.

    Science.gov (United States)

    Sharma, Deepak; Singh, Gurmeet; Kumar, Dinesh; Singh, Mankaran

    2015-01-01

    The objective of the present study was to prepare the fast disintegrating tablet of Salbutamol Sulphate, Cetirizine Hydrochloride in combined tablet dosage form for respiratory disorders such as bronchitis, asthma, and coughing for pediatrics and geriatrics. The tablets were prepared by direct compression technique. Superdisintegrant such as Sodium Starch Glycolate was optimized as 4% on the basis of least disintegration time. Different binders such as MCC and PVP K-30 were optimized along with optimized superdisintegrant concentration. 1% MCC was selected as optimum binder concentration on the basis of least disintegration time. The tablets were evaluated for hardness, friability, weight variation, wetting time, disintegration time, and drug content uniformity. Optimized formulation was further evaluated by in vitro dissolution test, drug-excipient compatibility, and accelerated stability study. Percent weight variation and content uniformity were within the acceptable limit. The friability was less than 1%. The wetting time and disintegration time were practically good for all formulations. FTIR studies and accelerated stability study showed that there was no interaction between the drug and excipients. It was concluded that, by employing commonly available pharmaceutical excipients such as superdisintegrants, hydrophilic and swellable excipients and proper filler, a fast disintegrating tablet of Salbutamol Sulphate, Cetirizine Hydrochloride in combined tablet dosage form, were formulated successfully with desired characteristics. PMID:25810924

  20. Malaria: Antimalarial resistance and policy ramificationsand challenges

    Directory of Open Access Journals (Sweden)

    Kshirsagar N

    2006-01-01

    Full Text Available ′The National health Policy 2002" of India and the "Roll Back Malaria" policy makers have set up an ambitious goal of reducing malaria mortality and morbidity by 25% by 2007, and by 50% by 2010. To achieve these goals, problems should be identified, available evidence analyzed and policy should be changed early. Infection with drug resistant malarial parasites has a tremendous impact on health (prolonged recurrent illness, increased hospital admissions and death, health system (higher cost of treatment and socioeconomics of the region. In view of the evidence of the economic burden of malaria, it has been suggested that second line treatment could be considered at 10% failure instead of 25%. Effective schizonticidal drugs will not only reduce morbidity and mortality but will also reduce transmission. Studies have shown that prevalence of viable (as tested by exflagellation test gametocytes is considerably more after the Chloroquine or Chloroquine + Sulphadoxine-Pyrimethamine treatment compared to Quinine. Unfortunately, the only gametocytocidal drug for Plasmodium falciparum, primaquine, is also loosing its efficacy. 45 mg Primaquine reduces gametocyte prevalence by 50% while a new drug, 75 mg bulaquine or 60 mg primaquine reduces it by 90%. Plasmodium vivax forms 60-70% of malaria cases in India. Relapses which occur in 10-20% of cases adds to the burden. Efficacy, as confirmed by Polymerase Chain Reaction-Single Strand Conformational Polymorphism (PCRSSCP to differentiate relapse and re-infection, of standard dose of primaquine (15 mg/day for 5 days, even 15 mg/day for 14 days for vivax malaria is reducing. Fourteen day treatment is also impractical as compliance is poor. Newer drugs, newer drug delivery systems are thus needed. Slow release formulations with blood levels maintained for one week may be useful. Rationale of giving primaquine in higher doses and different timing need to be considered. The genome of Plasmodium falciparum and

  1. Vaccine Adjuvants in Fish Vaccines Make a Difference: Comparing Three Adjuvants (Montanide ISA763A Oil, CpG/Poly I:C Combo and VHSV Glycoprotein) Alone or in Combination Formulated with an Inactivated Whole Salmonid Alphavirus Antigen.

    Science.gov (United States)

    Thim, Hanna L; Villoing, Stéphane; McLoughlin, Marian; Christie, Karen Elina; Grove, Søren; Frost, Petter; Jørgensen, Jorunn B

    2014-01-01

    Most commercial vaccines offered to the aquaculture industry include inactivated antigens (Ag) formulated in oil adjuvants. Safety concerns are related to the use of oil adjuvants in multivalent vaccines for fish, since adverse side effects (e.g., adhesions) can appear. Therefore, there is a request for vaccine formulations for which protection will be maintained or improved, while the risk of side effects is reduced. Here, by using an inactivated salmonid alphavirus (SAV) as the test Ag, the combined use of two Toll-like receptor (TLR) ligand adjuvants, CpG oligonucleotides (ODNs) and poly I:C, as well as a genetic adjuvant consisting of a DNA plasmid vector expressing the viral haemorrhagic septicaemia virus (VHSV) glycoprotein (G) was explored. VHSV-G DNA vaccine was intramuscularly injected in combination with intraperitoneal injection of either SAV Ag alone or combined with the oil adjuvant, Montanide ISA763, or the CpG/polyI:C combo. Adjuvant formulations were evaluated for their ability to boost immune responses and induce protection against SAV in Atlantic salmon, following cohabitation challenge. It was observed that CpG/polyI:C-based formulations generated the highest neutralizing antibody titres (nAbs) before challenge, which endured post challenge. nAb responses for VHSV G-DNA- and oil-adjuvanted formulations were marginal compared to the CpG/poly I:C treatment. Interestingly, heat-inactivated sera showed reduced nAb titres compared to their non-heated counterparts, which suggests a role of complement-mediated neutralization against SAV. Consistently elevated levels of innate antiviral immune genes in the CpG/polyI:C injected groups suggested a role of IFN-mediated responses. Co-delivery of the VHSV-G DNA construct with either CpG/polyI:C or oil-adjuvanted SAV vaccine generated higher CD4 responses in head kidney at 48 h compared to injection of this vector or SAV Ag alone. The results demonstrate that a combination of pattern recognizing receptor (PRR

  2. Vaccine Adjuvants in Fish Vaccines Make a Difference: Comparing Three Adjuvants (Montanide ISA763A Oil, CpG/Poly I:C Combo and VHSV Glycoprotein Alone or in Combination Formulated with an Inactivated Whole Salmonid Alphavirus Antigen

    Directory of Open Access Journals (Sweden)

    Hanna L. Thim

    2014-03-01

    Full Text Available Most commercial vaccines offered to the aquaculture industry include inactivated antigens (Ag formulated in oil adjuvants. Safety concerns are related to the use of oil adjuvants in multivalent vaccines for fish, since adverse side effects (e.g., adhesions can appear. Therefore, there is a request for vaccine formulations for which protection will be maintained or improved, while the risk of side effects is reduced. Here, by using an inactivated salmonid alphavirus (SAV as the test Ag, the combined use of two Toll-like receptor (TLR ligand adjuvants, CpG oligonucleotides (ODNs and poly I:C, as well as a genetic adjuvant consisting of a DNA plasmid vector expressing the viral haemorrhagic septicaemia virus (VHSV glycoprotein (G was explored. VHSV-G DNA vaccine was intramuscularly injected in combination with intraperitoneal injection of either SAV Ag alone or combined with the oil adjuvant, Montanide ISA763, or the CpG/polyI:C combo. Adjuvant formulations were evaluated for their ability to boost immune responses and induce protection against SAV in Atlantic salmon, following cohabitation challenge. It was observed that CpG/polyI:C-based formulations generated the highest neutralizing antibody titres (nAbs before challenge, which endured post challenge. nAb responses for VHSV G-DNA- and oil-adjuvanted formulations were marginal compared to the CpG/poly I:C treatment. Interestingly, heat-inactivated sera showed reduced nAb titres compared to their non-heated counterparts, which suggests a role of complement-mediated neutralization against SAV. Consistently elevated levels of innate antiviral immune genes in the CpG/polyI:C injected groups suggested a role of IFN-mediated responses. Co-delivery of the VHSV-G DNA construct with either CpG/polyI:C or oil-adjuvanted SAV vaccine generated higher CD4 responses in head kidney at 48 h compared to injection of this vector or SAV Ag alone. The results demonstrate that a combination of pattern recognizing

  3. Antiretroviral Choice for HIV Impacts Antimalarial Exposure and Treatment Outcomes in Ugandan Children

    Science.gov (United States)

    Parikh, Sunil; Kajubi, Richard; Huang, Liusheng; Ssebuliba, Joshua; Kiconco, Sylvia; Gao, Qin; Li, Fangyong; Were, Moses; Kakuru, Abel; Achan, Jane; Mwebaza, Norah; Aweeka, Francesca T.

    2016-01-01

    Background. The optimal treatment of malaria in human immunodeficiency virus (HIV)–infected children requires consideration of critical drug–drug interactions in coinfected children, as these may significantly impact drug exposure and clinical outcomes. Methods. We conducted an intensive and sparse pharmacokinetic/pharmacodynamic study in Uganda of the most widely adopted artemisinin-based combination therapy, artemether-lumefantrine. HIV-infected children on 3 different first-line antiretroviral therapy (ART) regimens were compared to HIV-uninfected children not on ART, all of whom required treatment for Plasmodium falciparum malaria. Pharmacokinetic sampling for artemether, dihydroartemisinin, and lumefantrine exposure was conducted through day 21, and associations between drug exposure and outcomes through day 42 were investigated. Results. One hundred forty-five and 225 children were included in the intensive and sparse pharmacokinetic analyses, respectively. Compared with no ART, efavirenz (EFV) reduced exposure to all antimalarial components by 2.1- to 3.4-fold; lopinavir/ritonavir (LPV/r) increased lumefantrine exposure by 2.1-fold; and nevirapine reduced artemether exposure only. Day 7 concentrations of lumefantrine were 10-fold lower in children on EFV vs LPV/r-based ART, changes that were associated with an approximate 4-fold higher odds of recurrent malaria by day 28 in those on EFV vs LPV/r-based ART. Conclusions. The choice of ART in children living in a malaria-endemic region has highly significant impacts on the pharmacokinetics and pharmacodynamics of artemether-lumefantrine treatment. EFV-based ART reduces all antimalarial components and is associated with the highest risk of recurrent malaria following treatment. For those on EFV, close clinical follow-up for recurrent malaria following artemether-lumefantrine treatment, along with the study of modified dosing regimens that provide higher exposure, is warranted. PMID:27143666

  4. Antimalarial activity of Malaysian Plectranthus amboinicus against Plasmodium berghei

    Directory of Open Access Journals (Sweden)

    Norazsida Ramli

    2014-01-01

    Full Text Available Context: Malaria is a mosquito-borne disease caused by parasitic protozoa from the genus of Plasmodium. The protozoans have developed resistance against many of current drugs. It is urgent to find an alternative source of new antimalarial agent. In the effort to discover new antimalarial agents, this research has been conducted on Plectranthus amboinicus. Aims: This study was conducted to evaluate the toxicity and antiplasmodial properties of P. amboinicus. Materials and Methods: Acute oral toxicity dose at 5000 mg/kg was conducted to evaluate the safety of this extract. Twenty mice were divided into control and experimental group. All the mice were observed for signs of toxicity, mortality, weight changes and histopathological changes. Antimalarial activity of different extract doses of 50, 200, 400 and 1000 mg/kg were tested in vivo against Plasmodium berghei infections in mice (five mice for each group during early, established and residual infections. Results: The acute oral toxicity test revealed that no mortality or evidence of adverse effects was seen in the treated mice. The extract significantly reduced the parasitemia by the 50 (P = 0.000, 200 (P = 0.000 and 400 mg/kg doses (P = 0.000 in the in vivo prophylactic assay. The percentage chemo-suppression was calculated as 83.33% for 50 mg/kg dose, 75.62% for 200 mg/kg dose and 90.74% for 400 mg/kg dose. Body weight of all treated groups; T1, T2, T3 and T4 also showed enhancement after 7 days posttreatment. Statistically no reduction of parasitemia calculated for curative and suppressive test. Conclusion: Thus, this extract may give a promising agent to be used as a prophylactic agent of P. berghei infection.

  5. Combination of argan oil and phospholipids for the development of an effective liposome-like formulation able to improve skin hydration and allantoin dermal delivery.

    Science.gov (United States)

    Manca, Maria Letizia; Matricardi, Pietro; Cencetti, Claudia; Peris, Josè Esteban; Melis, Virginia; Carbone, Claudia; Escribano, Elvira; Zaru, Marco; Fadda, Anna Maria; Manconi, Maria

    2016-05-30

    Allantoin is traditionally employed in the treatment of skin ulcers and hypertrophic scars. In the present work, to improve its local deposition in the skin and deeper tissues, allantoin was incorporated in conventional liposomes and in new argan oil enriched liposomes. In both cases, obtained vesicles were unilamellar, as confirmed by cryo-TEM observation, but the addition of argan oil allowed a slight increase of the mean diameter (∼130nm versus ∼85nm). The formulations, especially those containing argan oil, favoured the allantoin accumulation in the skin, in particular in the dermis (∼8.7μg/cm(2)), and its permeation through the skin (∼33μg/cm(2)). The performances of vesicles as skin delivery systems were compared with those obtained by water dispersion of allantoin and the commercial gel, Sameplast(®). Moreover, in this work, for the first time, the elastic and viscous moduli of the skin were measured, underlining the different hydrating/moisturizing effects of the formulations. The application of ARG liposomes seems to provide a softening and relaxing effect on the skin, thus facilitating the drug accumulation and passage into and trough it. PMID:27063848

  6. Proteomics analysis of antimalarial targets of Garcinia mangostana Linn.

    OpenAIRE

    Wanna Chaijaroenkul; Artitiya Thiengsusuk; Kanchana Rungsihirunrat; Stephen Andrew Ward; Kesara Na-Bangchang

    2014-01-01

    Objective: To investigate possible protein targets for antimalarial activity of Garcinia mangostana Linn. (G. mangostana) (pericarp) in 3D7 Plasmodium falciparum clone using 2-dimensional electrophoresis and liquid chromatography mass-spectrometry (LC/MS/MS). Methods: 3D7 Plasmodium falciparum was exposed to the crude ethanolic extract of G. mangostana Linn. (pericarp) at the concentrations of 12μg/mL (IC50 level: concentration that inhibits parasite growth by 50%) and 30 μg/mL (IC90 level...

  7. Home treatment of febrile children with antimalarial drugs in Togo.

    OpenAIRE

    Deming, M. S.; Gayibor, A.; Murphy, K; Jones, T. S.; Karsa, T.

    1989-01-01

    In Togo, the principal strategy for preventing death from malaria in children is prompt treatment of fever with antimalarial drugs. A household survey was conducted in a rural area of south-central Togo in which information was collected from mothers on the treatment received by 507 children under 5 years of age who, according to their mothers, had recently had fever. Altogether, 20% of the children (95% confidence interval (Cl): 15-25%) were seen at a health centre during their illness, whil...

  8. 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.

  9. Mono- and bis-thiazolium salts have potent antimalarial activity.

    Science.gov (United States)

    Hamzé, Abdallah; Rubi, Eric; Arnal, Pascal; Boisbrun, Michel; Carcel, Carole; Salom-Roig, Xavier; Maynadier, Marjorie; Wein, Sharon; Vial, Henri; Calas, Michèle

    2005-05-19

    Three new series comprising 24 novel cationic choline analogues and consisting of mono- or bis (N or C-5-duplicated) thiazolium salts have been synthesized. Bis-thiazolium salts showed potent antimalarial activity (much superior to monothiazoliums). Among them, bis-thiazolium salts 12 and 13 exhibited IC(50) values of 2.25 nM and 0.65 nM, respectively, against P. falciparum in vitro. These compounds also demonstrated good in vivo activity (ED(50)

  10. Cloroquine – miscellaneous properties of the antimalarial drug

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    Robert Jarzyna

    2002-06-01

    Full Text Available Chloroquine is a drug with over 60 years of safe clinical use in the treatment of malaria. The multiple mechanisms of chloroquine action have appeared to be useful in the therapy of many miscellaneous disorders well beyond its original antimalarial purposes. This paper is focused on the application of chloroquine for the treatment of malaria, porphyria cutanea tarda, rheumatoid arthritis, palindromic rheumatism and lupus. The possibility of the use of chloroquine in the therapy of other disorders such as diabetes mellitus, AIDS, hyperlipidemia, sarcoidosis, hypercalcemia, and melanoma is reviewed. Mechanisms of action of the drug as well as side effects on metabolism are discussed in view of recent discoveries.

  11. Artemisinin-Naphthoquine Combination (ARCO®: An Overview of the Progress

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    Qingyun Huang

    2010-12-01

    Full Text Available With the rapidly spreading resistance of Plasmodium falciparum to available non-artemisinin antimalarial drugs, new and novel pharmaceuticals are needed. ARCO® is a new generation ACT, one of several artemisinin-based combinations developed in China to counter antimalarial drug resistance. ARCO® is a derivative of two independently developed antimalarials, artemisinin and naphthoquine phosphate, which were combined to form the artemisinin-naphthoquine combination. Both artemisinin and naphthoquine drugs have proven to be efficacious, safe and well tolerated as monotherapies. The artemisinin-naphthoquine combination offers a novel advantage over existing ACTs: it can be administered as a single oral dose (or a 1-day treatment. Several therapeutic studies conducted recently indicate that a single oral dose administration of artemisinin-naphthoquine combination is equally effective and safe as the 3-day treatment with artemether-lumefantrine combination and other existing ACTs. This would make ARCO® the next generation ACT for the treatment of uncomplicated falciparum malaria.

  12. In vitro interaction of artemisinin derivatives or the fully synthetic peroxidic anti-malarial OZ277 with thapsigargin in Plasmodium falciparum strains

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    Abiodun Oyindamola O

    2013-01-01

    Full Text Available Abstract Background Semi-synthetic artemisinin derivatives are powerful peroxidic drugs in artemisinin-based combination therapy (ACT recommended as first-line treatment of Plasmodium falciparum malaria in disease-endemic countries. Studies by Eckstein-Ludwig and co-workers showed both thapsigargin and artemisinin specifically inhibit the sarcoplasmic reticulum Ca2+−ATPase of Plasmodium falciparum (PfATP6. In the present study the type of interaction between thapsigargin and artemisinin derivatives as well as the ozonide OZ277 (RBx11160 or arterolane was evaluated in parasite cultures. The latter compound is an adamantane-based peroxide and the first fully synthetic clinical candidate recently registered in India by Ranbaxy Laboratories Ltd. for anti-malarial combination therapy. Methods Drug interaction studies were performed using a previously described fixed ratio method and anti-malarial activity measured using the [3H] hypoxanthine incorporation assay. Results The sum 50% and 90% fractional inhibitory concentration (∑FIC50, 90 of the interaction of thapsigargin with OZ277, artemether or artesunate, against NF54 and K1 strains of P. falciparum ranged from 0.9 to 1.4. Conclusion The interaction of thapsigargin with OZ277, artesunate or artemether was additive, data consistent with previous observations indicating that activity of anti-malarial peroxides does not derive from reversible interactions with parasite targets.

  13. Proteomics analysis of antimalarial targets of Garcinia mangostana Linn.

    Institute of Scientific and Technical Information of China (English)

    Wanna Chaijaroenkul; Artitiya Thiengsusuk; Kanchana Rungsihirunrat; Stephen Andrew Ward; Kesara Na-Bangchang

    2014-01-01

    Objective: To investigate possible protein targets for antimalarial activity of Garcinia mangostana Linn. (G. mangostana) (pericarp) in 3D7 Plasmodium falciparum clone using 2-dimensional electrophoresis and liquid chromatography mass-spectrometry (LC/MS/MS). Methods: 3D7 Plasmodium falciparum was exposed to the crude ethanolic extract of G.mangostana Linn. (pericarp) at the concentrations of 12µg/mL (IC50 level: concentration that inhibits parasite growth by 50%) and 30 µg/mL (IC90 level: concentration that inhibits parasite growth by 90%) for 12 h. Parasite proteins were separated by 2-dimensional electrophoresis and identified by LC/MS/MS.Results:At the IC50 concentration, about 82% of the expressed parasite proteins were matched with the control (non-exposed), while at the IC90 concentration, only 15% matched proteins were found. The selected protein spots from parasite exposed to the plant extract at the concentration of 12 µg/mL were identified as enzymes that play role in glycolysis pathway, i.e., phosphoglycerate mutase putative, L-lactate dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase, and fructose-bisphosphate aldolase/phosphoglycerate kinase. The proteosome was found in parasite exposed to 30 µg/mL of the extract.Conclusions:Results suggest that proteins involved in the glycolysis pathway may be the targets for antimalarial activity of G. mangostana Linn. (pericarp).

  14. Proteomics analysis of antimalarial targets of Garcinia mangostana Linn.

    Institute of Scientific and Technical Information of China (English)

    Wanna; Chaijaroenkul; Artitiya; Thiengsusuk; Kanchana; Rungsihirunrat; Stephen; Andrew; Ward; Kesara; Na-Bangchang

    2014-01-01

    Objective:To investigate possible protein targets for antimalarial activity of Garcina mangostana Linn.(G.mangostana)(pericarp)in 3D7 Plasmodium falciparum clone using 2-dimensional electrophoresis and liquid chromatography mass-spectrometry(LC/MS/MS).Methods:3D7 Plasmodium falciparum was exposed to the crude ethanolic extract of G.mangostana Linn.(pericarp)at the concentrations of 12μg/mL(1C50level:concentration that inhibits parasite growth by 50%)and 30μg/mL(1C90level:concentration that inhibits parasite growth by 90%)for 12 h.Parasite proteins were separated by 2-dimensional electrophoresis and identified by LC/MS/MS.Results:At the IC50concentration,about 82%of the expressed parasite proteins were matched with the control(non-exposed),while at the IC90concentration,only 15%matched proteins were found.The selected protein spots from parasite exposed to the plant extract at the concentration of 12μg/mL were identified as eneymes that play role in glycolysis pathway,i.e.,phosphoglyeerate mutase putative,L-lactate dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase,and fruetose-bisphosphate aldolase/phosphoglyeerate kinase.The proteosome was found in parasite exposed to 30μg/mL of the extract.Conclusions:Results suggest that proteins involved in the glycolysis pathway may be the targets for antimalarial activity of G.mangostana Linn.(pericarp).

  15. Antimalarials and the fight against malaria in Brazil.

    Science.gov (United States)

    Carmargo, Luiz Ma; de Oliveira, Saulo; Basano, Sergio; Garcia, Célia Rs

    2009-08-01

    Malaria, known as the "fevers," has been treated for over three thousand years in China with extracts of plants of the genus Artemisia (including Artemisia annua, A. opiacea, and A. lancea) from which the active compound is artemisin, a sesquiterpene that is highly effective in the treatment of the disease, especially against young forms of the parasite. South American Indians in the seventeenth century already used an extract of the bark of chinchona tree, commonly named "Jesuits' powder." Its active compound was isolated in 1820 and its use spread all over the world being used as a prophylactic drug during the construction of the Madeira-Mamoré railroad in the beginning of the twentieth century. During the 1920s to the 1940s, new antimalarial drugs were synthesized to increase the arsenal against this parasite. However, the parasite has presented systematic resistence to conventional antimalarial drugs, driving researchers to find new strategies to treat the disease. In the present review we discuss how Brazil treats Plasmodium-infected patients. PMID:19753125

  16. A retrospective analysis of the change in anti-malarial treatment policy: Peru

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    Vincent-Mark Arlene

    2009-04-01

    Full Text Available Abstract Background National malaria control programmes must deal with the complex process of changing national malaria treatment guidelines, often without guidance on the process of change. Selecting a replacement drug is only one issue in this process. There is a paucity of literature describing successful malaria treatment policy changes to help guide control programs through this process. Objectives To understand the wider context in which national malaria treatment guidelines were formulated in a specific country (Peru. Methods Using qualitative methods (individual and focus group interviews, stakeholder analysis and a review of documents, a retrospective analysis of the process of change in Peru's anti-malarial treatment policy from the early 1990's to 2003 was completed. Results The decision to change Peru's policies resulted from increasing levels of anti-malarial drug resistance, as well as complaints from providers that the drugs were no longer working. The context of the change occurred in a time in which Peru was changing national governments, which created extreme challenges in moving the change process forward. Peru utilized a number of key strategies successfully to ensure that policy change would occur. This included a having the process directed by a group who shared a common interest in malaria and who had long-established social and professional networks among themselves, b engaging in collaborative teamwork among nationals and between nationals and international collaborators, c respect for and inclusion of district-level staff in all phases of the process, d reliance on high levels of technical and scientific knowledge, e use of standardized protocols to collect data, and f transparency. Conclusion Although not perfectly or fully implemented by 2003, the change in malaria treatment policy in Peru occurred very quickly, as compared to other countries. They identified a problem, collected the data necessary to justify the

  17. Discovery of potent, novel, non-toxic anti-malarial compounds via quantum modelling, virtual screening and in vitro experimental validation

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    Kaludov Nikola

    2011-09-01

    Full Text Available Abstract Background Developing resistance towards existing anti-malarial therapies emphasize the urgent need for new therapeutic options. Additionally, many malaria drugs in use today have high toxicity and low therapeutic indices. Gradient Biomodeling, LLC has developed a quantum-model search technology that uses quantum similarity and does not depend explicitly on chemical structure, as molecules are rigorously described in fundamental quantum attributes related to individual pharmacological properties. Therapeutic activity, as well as toxicity and other essential properties can be analysed and optimized simultaneously, independently of one another. Such methodology is suitable for a search of novel, non-toxic, active anti-malarial compounds. Methods A set of innovative algorithms is used for the fast calculation and interpretation of electron-density attributes of molecular structures at the quantum level for rapid discovery of prospective pharmaceuticals. Potency and efficacy, as well as additional physicochemical, metabolic, pharmacokinetic, safety, permeability and other properties were characterized by the procedure. Once quantum models are developed and experimentally validated, the methodology provides a straightforward implementation for lead discovery, compound optimizzation and de novo molecular design. Results Starting with a diverse training set of 26 well-known anti-malarial agents combined with 1730 moderately active and inactive molecules, novel compounds that have strong anti-malarial activity, low cytotoxicity and structural dissimilarity from the training set were discovered and experimentally validated. Twelve compounds were identified in silico and tested in vitro; eight of them showed anti-malarial activity (IC50 ≤ 10 μM, with six being very effective (IC50 ≤ 1 μM, and four exhibiting low nanomolar potency. The most active compounds were also tested for mammalian cytotoxicity and found to be non-toxic, with a

  18. Prices and mark-ups on antimalarials: evidence from nationally representative studies in six malaria-endemic countries.

    Science.gov (United States)

    Palafox, Benjamin; Patouillard, Edith; Tougher, Sarah; Goodman, Catherine; Hanson, Kara; Kleinschmidt, Immo; Torres Rueda, Sergio; Kiefer, Sabine; O'Connell, Kate; Zinsou, Cyprien; Phok, Sochea; Akulayi, Louis; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Poyer, Stephen; Chavasse, Desmond

    2016-03-01

    The private for-profit sector is an important source of treatment for malaria. However, private patients face high prices for the recommended treatment for uncomplicated malaria, artemisinin combination therapies (ACTs), which makes them more likely to receive cheaper, less effective non-artemisinin therapies (nATs). This study seeks to better understand consumer antimalarial prices by documenting and exploring the pricing behaviour of retailers and wholesalers. Using data collected in 2009-10, we present survey estimates of antimalarial retail prices, and wholesale- and retail-level price mark-ups from six countries (Benin, Cambodia, the Democratic Republic of Congo, Nigeria, Uganda and Zambia), along with qualitative findings on factors affecting pricing decisions. Retail prices were lowest for nATs, followed by ACTs and artemisinin monotherapies (AMTs). Retailers applied the highest percentage mark-ups on nATs (range: 40% in Nigeria to 100% in Cambodia and Zambia), whereas mark-ups on ACTs (range: 22% in Nigeria to 71% in Zambia) and AMTs (range: 22% in Nigeria to 50% in Uganda) were similar in magnitude, but lower than those applied to nATs. Wholesale mark-ups were generally lower than those at retail level, and were similar across antimalarial categories in most countries. When setting prices wholesalers and retailers commonly considered supplier prices, prevailing market prices, product availability, product characteristics and the costs related to transporting goods, staff salaries and maintaining a property. Price discounts were regularly used to encourage sales and were sometimes used by wholesalers to reward long-term customers. Pricing constraints existed only in Benin where wholesaler and retailer mark-ups are regulated; however, unlicensed drug vendors based in open-air markets did not adhere to the pricing regime. These findings indicate that mark-ups on antimalarials are reasonable. Therefore, improving ACT affordability would be most readily

  19. Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development

    Directory of Open Access Journals (Sweden)

    Zaloumis Sophie

    2012-08-01

    Full Text Available Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50, derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle. The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i

  20. The respiratory syncytial virus fusion protein formulated with a novel combination adjuvant induces balanced immune responses in lambs with maternal antibodies.

    Science.gov (United States)

    Garg, R; Latimer, L; Gerdts, V; Potter, A; van Drunen Littel-van den Hurk, S

    2015-03-10

    Respiratory syncytial virus (RSV) causes severe respiratory illness in infants. There are no licensed vaccines to prevent RSV infection. The neonate receives short-term protection from maternally derived antibodies, which, however, can also interfere with the active response to vaccination. A RSV vaccine consisting of a truncated version of the fusion protein formulated with polyI:C, innate defense regulator peptide and polyphosphazene (ΔF/TriAdj), was evaluated in two to three week-old lambs. When delivered intrapulmonary, ΔF/TriAdj elicited IgA production in the lung in addition to a robust systemic response similar to that induced by intramuscular immunization. To investigate potential interference by maternal antibodies, pregnant ewes were vaccinated with ΔF/TriAdj. Lambs born to RSV F-immune or non-immune ewes were then given three vaccinations with ΔF/TriAdj at 3 days, 4 weeks and 8 weeks post-birth. Lambs immunized intramuscularly with ΔF/TriAdj vaccine developed high-affinity ΔF-specific serum IgG and virus neutralizing antibodies, and displayed an increase in the frequency of IFN-γ-secreting cells by in vitro restimulated peripheral blood mononuclear cells. Maternal antibodies did not interfere with the development of an immune response to ΔF/TriAdj in the newborn lambs. These results indicate that immunization of neonates with ΔF/TriAdj is effective even in the face of maternal antibodies. PMID:25637860

  1. The performance of a target-controlled infusion of propofol in combination with remifentanil : A clinical investigation with two propofol formulations

    NARCIS (Netherlands)

    Wietasch, JKG; Scholz, M; Zinserling, J; Kiefer, N; Frenkel, C; Knufermann, P; Brauer, U; Hoeft, A

    2006-01-01

    Target-controlled infusion (TCI) incorporates the pharmacokinetic variables of an IV drug to facilitate safe and reliable administration. In this clinical study we investigated the performance of propofol TCI in combination with remifentanil. Fifty-four adult patients scheduled for general surgery l

  2. Using Food Grade Lye “omushelekha” in the Formulation of Health Products from Commonly Consumed African Indigenous Vegetables and Vegetable Combinations

    Directory of Open Access Journals (Sweden)

    Florence O Habwe

    2011-05-01

    Full Text Available Background: Lye, sodium hydroxide and potassium hydroxide has been used over the years in food preparation including the preparation of vegetables and dried meat products, washing or chemical peeling of fruits and vegetables, cocoa processing, caramel production, poultry scalding and cooking among others. Lye is believed to improve the organoleptic properties and also enhances the nutritional value to the products.Objective: To assess the effect of food grade lye on the levels of copper and iron in the raw, boiled and boiled-fried single vegetables and vegetable combinations treated with and without food grade lye.Methods: Single vegetables, Crotalaria occroleuca, Solanum scabrum, Vigna unguiculata and Amaranthus blitum and their combinations were cooled and kept in the fridge at 4oCs. Elemental analysis was done for the raw, boiled and boiled-fried samples using Atomic Absorption Spectrophotometry (AAS under standard conditions using wavelengths of 248.3nm for iron and 324.2nm for copper. Paired t-test was used to compare the iron and copper levels of the boiled and boiled-fried vegetables while the independent t-test was done to assess the levels of iron and copper in the raw, boiled and boiled fried samples.Results: Boiled-fried samples recorded higher content of iron and copper than the boiled ones. A combination of Amaranthus blitum-Crotolaria occloreuca boiled without lye boiled-fried with lye, and boiled-fried without lye had the highest copper contents of 1.66mg/100gram, 4.56mg/100gram, and 4.56mg/100gram respectively, compared to Amaranthus blitum aloneFunctional Foods in Heals and Disease 2011; 5:189-197(3.48mg/100gram and Crotolaria occloreuca (0.42mg/100gram. A combination of Amaranthus blitum-Crotolaria occloreuca boiled in non-lye water, and those boiled-fried with and without lye had the highest extractable iron of 557mg/100g, 859.2mg/100g, and 859.2mg/100g respectively. Iron content was high in the Solanum scabrum (281.1mg/100g

  3. Development and evaluation of a solid oral dosage form for an artesunate and mefloquine drug combination / Abel Hermanus van der Watt

    OpenAIRE

    Van der Watt, Abel Hermanus

    2014-01-01

    Malaria affects about forty percent of the world’s population. Annually more than 1.5 million fatalities due to malaria occur and parasite resistance to existing antimalarial drugs such as mefloquine has already reached disturbingly high levels in South-East Asia and on the African continent. Consequently, there is a dire need for new drugs or formulations in the prophylaxis and treatment of malaria. Artesunate, an artemisinin derivative, represents a new category of antimalarials that is eff...

  4. Immunoprotective activity of a Salmonid Alphavirus Vaccine: comparison of the immune responses induced by inactivated whole virus antigen formulations based on CpG class B oligonucleotides and poly I:C alone or combined with an oil adjuvant.

    Science.gov (United States)

    Thim, Hanna L; Iliev, Dimitar B; Christie, Karen E; Villoing, Stéphane; McLoughlin, Marian F; Strandskog, Guro; Jørgensen, Jorunn B

    2012-07-01

    CpG oligonucleotides and polyinosinic:polycytidylic acid (poly I:C) are toll-like receptor (TLR) agonists that mimic the immunostimulatory properties of bacterial DNA and double-stranded viral RNA respectively, and which have exhibited potential to serve as vaccine adjuvants in previous experiments. Here, a combination of CpGs and poly I:C together with water- or oil-formulated Salmonid Alphavirus (SAV) antigen preparations has been used for a vaccine in Atlantic salmon and tested for protection in SAV challenge trial. The results demonstrate that vaccination with a high dose of the SAV antigen induced protection against challenge with SAV which correlated with production of neutralizing antibodies (NAbs). As the high antigen dose alone induced full protection, no beneficial effect from the addition of CpG and poly I:C could be observed. Nevertheless, these TLR ligands significantly enhanced the levels of NAbs in serum of vaccinated fish. Interestingly, gene expression analysis demonstrated that while addition of oil suppressed the CpG/poly I:C-induced expression of IFN-γ, the upregulation of IFNa1 was substantially enhanced. A low dose of the SAV antigen combined with oil did not induce any detectable levels of NAbs either with or without TLR ligands present, however the addition of CpG and poly I:C to the low SAV antigen dose formulation significantly enhanced the protection against SAV suggesting that CpG/poly I:C may have enhanced a cytotoxic response - a process which is dependent on the up-regulation of type I IFN. These results highlight the immunostimulatory properties of the tested TLR ligands and will serve as a ground for further, more detailed studies aimed to investigate their capacity to serve as adjuvants in vaccine formulations for Atlantic salmon. PMID:22634299

  5. Low-fat frankfurters formulated with a healthier lipid combination as functional ingredient: Microstructure, lipid oxidation, nitrite content, microbiological changes and biogenic amine formation

    OpenAIRE

    Delgado Pando, G.; Cofrades, Susana; Ruiz-Capillas, C.; Solas, M. Teresa; Triki, M.; Jiménez Colmenero, Francisco

    2011-01-01

    Oil (healthier lipid combination of olive, linseed and fish oils)-in-water emulsions stabilized with different protein systems (prepared with sodium caseinate (SC), soy protein isolate (SPI), and microbial transglutaminase (MTG)) were used as pork backfat replacers in low-fat frankfurters. Microstructure, lipid oxidation, nitrite content, microbiological changes and biogenic amine formation of frankfurters were analyzed and found to be affected by the type of oil-in-water emulsion and by chil...

  6. Analysis of the electrochemical reactivity of natural hemozoin and β-hemozoin in the presence of antimalarial drugs

    International Nuclear Information System (INIS)

    We report an evaluation of the reactivity of hemozoin (HZ) and β-hemozoin (β-HZ) obtained from the Triatoma Meccus longipennis, alone and in combination with quinine and amodiaquine. Using cyclic voltammetry and carbon paste electrodes, the redox processes that these compounds undergo were analysed. The results indicated that the atom Fe presence, the substance concentration, the drugs existence and the nature of the electrolytic medium are important in the redox processes. The strongest reactivity was for β-HZ from Triatoma, which suggests that cellular molecules are embedded in an oxidising environment due to the presence of β-HZ and indicates that like HZ, β-HZ could be associate with phospholipid bilayers and interfere with their physical and chemical integrity, contributing to membrane breakdown and hyper-oxidation of molecules. It was further observed that when measuring the reactivity of HZ and β-HZ with quinine and amodiaquine, a more oxidative stress was generated between the second one and the β-HZ, which could explain the effectiveness of amodiaquine as a better antimalarial drug. Finally, it was concluded that electrochemical evaluation may be a convenient tool in determining the efficiency of antimalarial drugs and the identification of their redox processes.

  7. In vitro antioxidant, collagenase inhibition, and in vivo anti-wrinkle effects of combined formulation containing Punica granatum, Ginkgo biloba, Ficus carica, and Morus alba fruits extract

    OpenAIRE

    Ghimeray AK; Jung US; Lee HY; Kim YH; Ryu EK; Chang MS

    2015-01-01

    Amal Kumar Ghimeray,1 Un Sun Jung,1,2 Ha Youn Lee,1 Young Hoon Kim,1 Eun Kyung Ryu,1 Moon Sik Chang11R&D Center, Natural Solution Co., Ltd, Gojan-dong, Namdong-gu, Incheon, Republic of Korea; 2Department of Horticultural Biotechnology, Kyung Hee University, Yongin, Republic of KoreaBackground: In phytotherapy, the therapeutic potential is based on the combined action of different herbal drugs. Our objective was to evaluate the antioxidant, anti-collagenase (in vitro), and anti-wrinkle (in...

  8. In vitro antioxidant, collagenase inhibition, and in vivo anti-wrinkle effects of combined formulation containing Punica granatum, Ginkgo biloba, Ficus carica, and Morus alba fruits extract

    OpenAIRE

    Ghimeray, Amal

    2015-01-01

    Amal Kumar Ghimeray,1 Un Sun Jung,1,2 Ha Youn Lee,1 Young Hoon Kim,1 Eun Kyung Ryu,1 Moon Sik Chang11R&D Center, Natural Solution Co., Ltd, Gojan-dong, Namdong-gu, Incheon, Republic of Korea; 2Department of Horticultural Biotechnology, Kyung Hee University, Yongin, Republic of KoreaBackground: In phytotherapy, the therapeutic potential is based on the combined action of different herbal drugs. Our objective was to evaluate the antioxidant, anti-collagenase (in vitro), and anti-wrinkle...

  9. Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials.

    Science.gov (United States)

    Norcross, Neil R; Baragaña, Beatriz; Wilson, Caroline; Hallyburton, Irene; Osuna-Cabello, Maria; Norval, Suzanne; Riley, Jennifer; Stojanovski, Laste; Simeons, Frederick R C; Porzelle, Achim; Grimaldi, Raffaella; Wittlin, Sergio; Duffy, Sandra; Avery, Vicky M; Meister, Stephan; Sanz, Laura; Jiménez-Díaz, Belén; Angulo-Barturen, Iñigo; Ferrer, Santiago; Martínez, María Santos; Gamo, Francisco Javier; Frearson, Julie A; Gray, David W; Fairlamb, Alan H; Winzeler, Elizabeth A; Waterson, David; Campbell, Simon F; Willis, Paul; Read, Kevin D; Gilbert, Ian H

    2016-07-14

    In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting. PMID:27314305

  10. Drug resistance genomics of the antimalarial drug artemisinin.

    Science.gov (United States)

    Winzeler, Elizabeth A; Manary, Micah J

    2014-01-01

    Across the globe, over 200 million annual malaria infections result in up to 660,000 deaths, 77% of which occur in children under the age of five years. Although prevention is important, malaria deaths are typically prevented by using antimalarial drugs that eliminate symptoms and clear parasites from the blood. Artemisinins are one of the few remaining compound classes that can be used to cure multidrug-resistant Plasmodium falciparum infections. Unfortunately, clinical trials from Southeast Asia are showing that artemisinin-based treatments are beginning to lose their effectiveness, adding renewed urgency to the search for the genetic determinants of parasite resistance to this important drug class. We review the genetic and genomic approaches that have led to an improved understanding of artemisinin resistance, including the identification of resistance-conferring mutations in the P. falciparum kelch13 gene. PMID:25470531

  11. New 1-Aryl-3-Substituted Propanol Derivatives as Antimalarial Agents

    Directory of Open Access Journals (Sweden)

    Antonio Monge

    2009-10-01

    Full Text Available This paper describes the synthesis and in vitro antimalarial activity against a P. falciparum 3D7 strain of some new 1-aryl-3-substituted propanol derivatives. Twelve of the tested compounds showed an IC50 lower than 1 μM. These compounds were also tested for cytotoxicity in murine J774 macrophages. The most active compounds were evaluated for in vivo activity against P. berghei in a 4-day suppressive test. Compound 12 inhibited more than 50% of parasite growth at a dose of 50 mg/kg/day. In addition, an FBIT test was performed to measure the ability to inhibit ferriprotoporphyrin biocrystallization. This data indicates that 1-aryl-3-substituted propanol derivatives hold promise as a new therapeutic option for the treatment of malaria.

  12. Screening Mangrove Endophytic Fungi for Antimalarial Natural Products

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    Laurent Calcul

    2013-12-01

    Full Text Available We conducted a screening campaign to investigate fungi as a source for new antimalarial compounds. A subset of our fungal collection comprising Chinese mangrove endophytes provided over 5000 lipophilic extracts. We developed an accelerated discovery program based on small-scale cultivation for crude extract screening and a high-throughput malaria assay. Criteria for hits were developed and high priority hits were subjected to scale-up cultivation. Extracts from large scale cultivation were fractionated and these fractions subjected to both in vitro malaria and cytotoxicity screening. Criteria for advancing fractions to purification were developed, including the introduction of a selectivity index and by dereplication of known metabolites. From the Chinese mangrove endophytes, four new compounds (14–16, 18 were isolated including a new dimeric tetrahydroxanthone, dicerandrol D (14, which was found to display the most favorable bioactivity profile.

  13. Triterpenes from Minquartia guianensis (Olacaceae) and in vitro antimalarial activity

    Energy Technology Data Exchange (ETDEWEB)

    Cursino, Lorena Mayara de Carvalho; Nunez, Cecilia Veronica [Instituto Nacional de Pesquisas da Amazonia (INPA), Manaus, AM (Brazil). Lab. de Bioprospeccao e Biotecnologia; Paula, Renata Cristina de; Nascimento, Maria Fernanda Alves do [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Fac. de Farmacia. Dept. de Produtos Farmaceuticos; Santos, Pierre Alexandre dos, E-mail: cecilia@inpa.gov.br [Universidade Federal do Amazonas (UFAM), Manaus, AM (Brazil). Fac. de Ciencias Farmaceuticas

    2012-07-01

    Minquartia guianensis, popularly known as acariquara, was phytochemically investigated. The following triterpenes were isolated from the dichloromethane extract of leaves: lupen-3-one (1), taraxer-3-one (2) and oleanolic acid (3). The dichloromethane extract of branches yielded the triterpene 3{beta}-methoxy-lup-20(29)-ene (4). The chemical structures were characterized by NMR data. Plant extracts, substance 3, squalene (5) and taraxerol (6), (5 and 6 previously isolated), were evaluated by in vitro assay against chloroquine resistant Plasmodium falciparum. The dichloromethane extract of leaves and the three triterpenes assayed have shown partial activity. Thus, these results demonstrated that new potential antimalarial natural products can be found even in partially active extracts. (author)

  14. Epidemiological models for the spread of anti-malarial resistance

    Directory of Open Access Journals (Sweden)

    Antia R

    2003-02-01

    Full Text Available Abstract Background The spread of drug resistance is making malaria control increasingly difficult. Mathematical models for the transmission dynamics of drug sensitive and resistant strains can be a useful tool to help to understand the factors that influence the spread of drug resistance, and they can therefore help in the design of rational strategies for the control of drug resistance. Methods We present an epidemiological framework to investigate the spread of anti-malarial resistance. Several mathematical models, based on the familiar Macdonald-Ross model of malaria transmission, enable us to examine the processes and parameters that are critical in determining the spread of resistance. Results In our simplest model, resistance does not spread if the fraction of infected individuals treated is less than a threshold value; if drug treatment exceeds this threshold, resistance will eventually become fixed in the population. The threshold value is determined only by the rates of infection and the infectious periods of resistant and sensitive parasites in untreated and treated hosts, whereas the intensity of transmission has no influence on the threshold value. In more complex models, where hosts can be infected by multiple parasite strains or where treatment varies spatially, resistance is generally not fixed, but rather some level of sensitivity is often maintained in the population. Conclusions The models developed in this paper are a first step in understanding the epidemiology of anti-malarial resistance and evaluating strategies to reduce the spread of resistance. However, specific recommendations for the management of resistance need to wait until we have more data on the critical parameters underlying the spread of resistance: drug use, spatial variability of treatment and parasite migration among areas, and perhaps most importantly, cost of resistance.

  15. Discovery of Novel Liver-Stage Antimalarials through Quantum Similarity.

    Directory of Open Access Journals (Sweden)

    David J Sullivan

    Full Text Available Without quantum theory any understanding of molecular interactions is incomplete. In principal, chemistry, and even biology, can be fully derived from non-relativistic quantum mechanics. In practice, conventional quantum chemical calculations are computationally too intensive and time consuming to be useful for drug discovery on more than a limited basis. A previously described, original, quantum-based computational process for drug discovery and design bridges this gap between theory and practice, and allows the application of quantum methods to large-scale in silico identification of active compounds. Here, we show the results of this quantum-similarity approach applied to the discovery of novel liver-stage antimalarials. Testing of only five of the model-predicted compounds in vitro and in vivo hepatic stage drug inhibition assays with P. berghei identified four novel chemical structures representing three separate quantum classes of liver-stage antimalarials. All four compounds inhibited liver-stage Plasmodium as a single oral dose in the quantitative PCR mouse liver-stage sporozoites-challenge model. One of the newly identified compounds, cethromycin [ABT-773], a macrolide-quinoline hybrid, is a drug with an extensive (over 5,000 people safety profile warranting its exploitation as a new weapon for the current effort of malaria eradication. The results of our molecular modeling exceed current state-of-the-art computational methods. Drug discovery through quantum similarity is data-driven, agnostic to any particular target or disease process that can evaluate multiple phenotypic, target-specific, or co-crystal structural data. This allows the incorporation of additional pharmacological requirements, as well as rapid exploration of novel chemical spaces for therapeutic applications.

  16. Distillation Time as Tool for Improved Antimalarial Activity and Differential Oil Composition of Cumin Seed Oil

    Science.gov (United States)

    A steam distillation extraction kinetics experiment was conducted to estimate essential oil yield, composition, antimalarial, and antioxidant capacity of cumin (Cuminum cyminum L.) seed (fruits). Furthermore, regression models were developed to predict essential oil yield and composition for a given...

  17. Quality of anti-malarial drugs provided by public and private healthcare providers in south-east Nigeria

    Directory of Open Access Journals (Sweden)

    Uzochukwu Benjamin

    2009-02-01

    Full Text Available Abstract Background There is little existing knowledge about actual quality of drugs provided by different providers in Nigeria and in many sub-Saharan African countries. Such information is important for improving malaria treatment that will help in the development and implementation of actions designed to improve the quality of treatment. The objective of the study was to determine the quality of drugs used for the treatment of malaria in a broad spectrum of public and private healthcare providers. Methods The study was undertaken in six towns (three urban and three rural in Anambra state, south-east Nigeria. Anti-malarials (225 samples, which included artesunate, dihydroartemisinin, sulphadoxine-pyrimethamine (SP, quinine, and chloroquine, were either purchased or collected from randomly selected providers. The quality of these drugs was assessed by laboratory analysis of the dissolution profile using published pharmacopoeial monograms and measuring the amount of active ingredient using high performance liquid chromatography (HPLC. Findings It was found that 60 (37% of the anti-malarials tested did not meet the United States Pharmacopoeia (USP specifications for the amount of active ingredients, with the suspect drugs either lacking the active ingredients or containing suboptimal quantities of the active ingredients. Quinine (46% and SP formulations (39% were among drugs that did not satisfy the tolerance limits published in USP monograms. A total of 78% of the suspect drugs were from private facilities, mostly low-level providers, such as patent medicine dealers (vendors. Conclusion This study found that there was a high prevalence of poor quality drugs. The findings provide areas for public intervention to improve the quality of malaria treatment services. There should be enforced checks and regulation of drug supply management as well as stiffer penalties for people stocking substandard and counterfeit drugs.

  18. In vitro genotoxicity of the West African anti-malarial herbal Cryptolepis sanguinolenta and its major alkaloid cryptolepine.

    Science.gov (United States)

    Ansah, Charles; Khan, Ayesha; Gooderham, Nigel J

    2005-03-01

    Cryptolepine (CLP), the major alkaloid of the West African anti-malarial herbal Cryptolepis sanguinolenta (Periplocaceae) is a DNA intercalator that exhibits potent toxicity to a variety of mammalian cells in vitro. We have hypothesized that the DNA intercalating properties of cryptolepine could trigger genetic damage in mammalian cells. The objective of the present study was therefore to assess the ability of both cryptolepine (CLP) and the traditional anti-malarial formulation, the aqueous extract from the roots (CSE) to induce mutation at the hprt locus and micronuclei (MN) formation in V79, a Chinese hamster fibroblast cell line commonly used in genetic toxicity studies. CSE at a high concentration (50 microg/ml) induced an apparent significant ten fold increase in mutant frequency compared to vehicle control (mean of 38 versus 4 mutant clones/10(6) surviving cells) but, this concentration of CSE was very toxic (<15% cell survival). CLP did not appear to be mutagenic in the dosage range used (up to 2.5 microM, equivalent to 1.1 microg/ml). However, after 24h treatment of V79 cells both CSE and CLP induced a dose-dependent increase in micronuclei of 4.15% and 6.43% (25 microg/ml CSE and 2.5 microM, equivalent to 1.1 microg/ml CLP, respectively) compared to 0.36% in vehicle control. These results show that treatment of mammalian cells with CSE and CLP can lead to DNA damage and we suggest that the routine use of CSE and the potential use of CLP derivatives in malaria chemotherapy could carry a genotoxic risk. PMID:15664441

  19. Post-marketing surveillance of anti-malarial medicines used in Malawi

    OpenAIRE

    Chikowe, Ibrahim; Osei-Safo, Dorcas; Harrison, Jerry JEK; Konadu, Daniel Y; Addae-Mensah, Ivan

    2015-01-01

    Background The growing concern over the extent of anti-malarial medicine resistance in sub-Saharan Africa, driven largely by administration of sub-therapeutic doses derived from falsified and substandard medicines necessitates regular monitoring of the quality of these medicines to avert any potential public health disaster. This study aimed at determining the active pharmaceutical ingredient (API) content of anti-malarial medicines available in Malawi with respect to the manufacturers’ label...

  20. Self-Medication with Antibiotics and Antimalarials in the Community of Silte Zone, South Ethiopia

    OpenAIRE

    Nasir Tajure Wabe; Dargicho Ahmed; Mulugeta Tarekegn Angamo

    2012-01-01

    AIM: Self-medication with antibiotics and antimalarials occurs among the population in Ethiopian. We studied to estimate the prevalence of self-medication with antibiotics and antimalarials in Ethiopia and evaluate factors associated with self-medications. METHODS: A cross-sectional study was conducted on 405 households, selected from Silte Zone in South Ethiopia, using a random sampling technique by employing a pretested questionnaire. Data were analyzed using SPSS for windows version 16.0. ...

  1. Public Awareness and Identification of Counterfeit Drugs in Tanzania: A View on Antimalarial Drugs

    OpenAIRE

    Mhando, Linus; Jande, Mary B.; Liwa, Anthony; Mwita, Stanley; Marwa, Karol J.

    2016-01-01

    Background. The illicit trade in counterfeit antimalarial drugs is a major setback to the fight against malaria. Information on public awareness and ability to identify counterfeit drugs is scanty. Aim. Therefore, the present study aimed at assessing public awareness and the ability to identify counterfeit antimalarial drugs based on simple observations such as appearance of the drugs, packaging, labelling, and leaflets. Methodology. A cross-sectional study was conducted using interviewer adm...

  2. In vitro antimalarial activity of different extracts of Eremostachys macrophylla Montbr. & Auch.

    OpenAIRE

    Solmaz Asnaashari; Fariba Heshmati Afshar; Atefeh Ebrahimi; Sedigheh Bamdad Moghaddam; Abbas Delazar

    2015-01-01

    Introduction: The risk of drug resistance and the use of medicinal plants in malaria prevention and treatment have led to the search for new antimalarial compounds with natural origin. Methods: In the current study, six extracts with different polarity from aerial parts and rhizomes of Eremostachys macrophylla Montbr. & Auch., were screened for their antimalarial properties by cell-free beta-hematin formation assay. Results: Dichloromethane (DCM) extracts of both parts of plant showed s...

  3. Evaluation of plants used for antimalarial treatment by the Maasai of Kenya.

    Science.gov (United States)

    Koch, A; Tamez, P; Pezzuto, J; Soejarto, D

    2005-10-01

    Semi-structured interviews with three Maasai herbalists led to the identification and collection of 21 species of plants used to treat malaria. Extracts were evaluated using in vitro antimalarial and cytotoxicity assays. Of the species tested, over half were antiplasmodial (IC5020 microg/ml) against cultured KB cells. The results of this preliminary investigation support the traditional knowledge of Maasai herbalists and justify ethnomedical inquiry as a promising method, specifically, in antimalarial therapy, to yield leads for drug discovery. PMID:15878245

  4. Insights following change in drug policy: A descriptive study for antimalarial prescription practices in children of public sector health facilities in Jharkhand state of India

    Directory of Open Access Journals (Sweden)

    Neelima Mishra

    2013-12-01

    Full Text Available Background & objectives: Widespread resistance to chloroquine was the mainstay to implement artemisininbased combination therapy (ACT in the year 2007 in few malaria endemic states in India including Jharkhand as the first line of treatment for uncomplicated Plasmodium falciparum malaria. This study was conducted in Jharkhand state of the country just after the implementation of ACT to assess the prevailing antimalarial drug prescribing practices, availability of antimalarial drugs and the acceptability of the new policy by the health professionals for the treatment of uncomplicated P. falciparum malaria patients particularly in children ≤15 yr of age. Methods: This is a cross-sectional study in children aged ≤15 yr with malaria or to whom antimalarial drug was prescribed. Main outcome measure was prescription of recommended ACT in children aged ≤15 yr with malaria in the selected areas of Jharkhand. Results: In the year 2008, artemisinin-based combination therapy (ACT was implemented in 12 districts of the studied state; however, the availability of ACT was confirmed only in five districts. Antimalarial prescription was prevalent amongst the undiagnosed (8.4%, malaria negative (64.3% and unknown blood test result (1.2% suggesting the prevalence of irrational treatment practices. ACT prescription was very low with only 3.2% of confirmed falciparum malaria patients receiving it while others received either non-artesunate (NA treatment (88.1% including chloroquine (CQ alone, CQ + Primaquine (PQ/other drugs, sulphadoxine-pyrimethamine (SP alone, SP + other drugs or artemisinin monotherapy (AM treatment (6.3%. Still others were given nonantimalarial treatment (NM in both malaria positive (0.3% and malaria negative (2.1% cases. Interpretation & conclusion: Despite the change in drug policy in the studied state the availability and implementation of ACT was a major concern. Nevertheless, the non-availability of blister packs for children aged

  5. Study of the antimalarial properties of hydroxyethylamine derivatives using green fluorescent protein transformed Plasmodium berghei

    Directory of Open Access Journals (Sweden)

    Mariana Conceição Souza

    2015-06-01

    Full Text Available A rapid decrease in parasitaemia remains the major goal for new antimalarial drugs and thus, in vivo models must provide precise results concerning parasitaemia modulation. Hydroxyethylamine comprise an important group of alkanolamine compounds that exhibit pharmacological properties as proteases inhibitors that has already been proposed as a new class of antimalarial drugs. Herein, it was tested the antimalarial property of new nine different hydroxyethylamine derivatives using the green fluorescent protein (GFP-expressing Plasmodium berghei strain. By comparing flow cytometry and microscopic analysis to evaluate parasitaemia recrudescence, it was observed that flow cytometry was a more sensitive methodology. The nine hydroxyethylamine derivatives were obtained by inserting one of the following radical in the para position: H, 4Cl, 4-Br, 4-F, 4-CH3, 4-OCH3, 4-NO2, 4-NH2 and 3-Br. The antimalarial test showed that the compound that received the methyl group (4-CH3 inhibited 70% of parasite growth. Our results suggest that GFP-transfected P. berghei is a useful tool to study the recrudescence of novel antimalarial drugs through parasitaemia examination by flow cytometry. Furthermore, it was demonstrated that the insertion of a methyl group at the para position of the sulfonamide ring appears to be critical for the antimalarial activity of this class of compounds.

  6. Chemical interactions study of antiretroviral drugs efavirenz and lamivudine concerning the development of stable fixed-dose combination formulations for AIDS treatment

    International Nuclear Information System (INIS)

    Lamivudine and efavirenz are among the most worldwide used drugs for acquired immune deficiency syndrome (AIDS) treatment. Solid state nuclear magnetic resonance (ssNMR), Fourier-transformed infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermo-optical analysis (TOA) were used to study possible interactions between these drugs, aiming the development of a fixed-dose drug combination. DSC and TOA have evidenced significant shifts on the melting points of both drugs in the mixture, which may be due to interaction between them. Although DSC and TOA results indicated incompatibility between the drugs, FTIR spectra were mostly unmodified due to overlapping peaks. The ssNMR analyses showed significant changes in chemical shifts values of the mixture when compared with spectra of pure drugs, especially in the signals relating to the deficient electron carbon atoms of both drugs. These results confirm the interactions suggested by DSC and TOA, which is probably due to acid-base interactions between electronegative and deficient electron atoms of both lamivudine and efavirenz. (author)

  7. Chemical interactions study of antiretroviral drugs efavirenz and lamivudine concerning the development of stable fixed-dose combination formulations for AIDS treatment

    Energy Technology Data Exchange (ETDEWEB)

    Gomes, Elionai C. de L.; Mussel, Wagner N.; Resende, Jarbas M.; Yoshida, Maria I., E-mail: mirene@ufmg.br [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Instituto de Ciencias Exatas. Departamento de Quimica; Fialho, Silvia L.; Barbosa, Jamile; Fialho, Silvia L. [Fundacao Ezequiel Dias, Belo Horizonte, MG (Brazil)

    2013-04-15

    Lamivudine and efavirenz are among the most worldwide used drugs for acquired immune deficiency syndrome (AIDS) treatment. Solid state nuclear magnetic resonance (ssNMR), Fourier-transformed infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermo-optical analysis (TOA) were used to study possible interactions between these drugs, aiming the development of a fixed-dose drug combination. DSC and TOA have evidenced significant shifts on the melting points of both drugs in the mixture, which may be due to interaction between them. Although DSC and TOA results indicated incompatibility between the drugs, FTIR spectra were mostly unmodified due to overlapping peaks. The ssNMR analyses showed significant changes in chemical shifts values of the mixture when compared with spectra of pure drugs, especially in the signals relating to the deficient electron carbon atoms of both drugs. These results confirm the interactions suggested by DSC and TOA, which is probably due to acid-base interactions between electronegative and deficient electron atoms of both lamivudine and efavirenz. (author)

  8. Does anti-malarial drug knowledge predict anti-malarial dispensing practice in drug outlets? A survey of medicine retailers in western Kenya

    Directory of Open Access Journals (Sweden)

    Rusk Andria

    2012-08-01

    Full Text Available Abstract Background Malaria is a major cause of morbidity and mortality in Kenya, where it is the fifth leading cause of death in both children and adults. Effectively managing malaria is dependent upon appropriate treatment. In Kenya, between 17 to 83 percent of febrile individuals first seek treatment for febrile illness over the counter from medicine retailers. Understanding medicine retailer knowledge and behaviour in treating suspected malaria and dispensing anti-malarials is crucial. Methods To investigate medicine retailer knowledge about anti-malarials and their dispensing practices, a survey was conducted of all retail drug outlets that sell anti-malarial medications and serve residents of the Webuye Health and Demographic Surveillance Site in the Bungoma East District of western Kenya. Results Most of the medicine retailers surveyed (65% were able to identify artemether-lumefantrine (AL as the Kenyan Ministry of Health recommended first-line anti-malarial therapy for uncomplicated malaria. Retailers who correctly identified this treatment were also more likely to recommend AL to adult and paediatric customers. However, the proportion of medicine retailers who recommend the correct treatment is disappointingly low. Only 48% would recommend AL to adults, and 37% would recommend it to children. It was discovered that customer demand has an influence on retailer behaviour. Retailer training and education were found to be correlated with anti-malarial drug knowledge, which in turn is correlated with dispensing practices. Medicine retailer behaviour, including patient referral practice and dispensing practices, are also correlated with knowledge of the first-line anti-malarial medication. The Kenya Ministry of Health guidelines were found to influence retailer drug stocking and dispensing behaviours. Conclusion Most medicine retailers could identify the recommended first-line treatment for uncomplicated malaria, but the percentage that could

  9. Crystallization Formulation Lab

    Data.gov (United States)

    Federal Laboratory Consortium — The Crystallization Formulation Lab fills a critical need in the process development and optimization of current and new explosives and energetic formulations. The...

  10. Assessment of Malaria In Vitro Drug Combination Screening and Mixed-Strain Infections Using the Malaria Sybr Green I-Based Fluorescence Assay▿

    OpenAIRE

    Co, Edgie-Mark A.; Dennull, Richard A.; Reinbold, Drew D.; Waters, Norman C; Johnson, Jacob D.

    2009-01-01

    Several drug development strategies, including optimization of new antimalarial drug combinations, have been used to counter malaria drug resistance. We evaluated the malaria Sybr green I-based fluorescence (MSF) assay for its use in in vitro drug combination sensitivity assays. Drug combinations of previously published synergistic (atovaquone and proguanil), indifferent (chloroquine and azithromycin), and antagonistic (chloroquine and atovaquone) antimalarial drug interactions were tested ag...

  11. Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery

    OpenAIRE

    Sara E. McCarty; Amanda Schellenberger; Douglas C. Goodwin; Ngolui Rene Fuanta; Tekwani, Babu L.; Calderón, Angela I.

    2015-01-01

    The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR), an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences...

  12. Molecular markers of anti-malarial drug resistance in Lahj Governorate, Yemen: baseline data and implications

    Directory of Open Access Journals (Sweden)

    Chance Michael L

    2011-08-01

    Full Text Available Abstract Background This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for Plasmodium falciparum resistance against CQ and sulphadoxine/pyrimethamine (SP. Methods Between 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for P. falciparum chloroquine resistance transporter gene (pfcrt-76 polymorphisms, mutation pfcrt-S163R and the antifolate resistance-associated mutations dihydrofolate reductase (dhfr-C59R and dihydropteroate synthase (dhps-K540E. Direct DNA sequencing of the pfcrt gene from three representative field samples was carried out after DNA amplification of the 13 exons of the pfcrt gene. Results Treatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant pfcrt T76 was 98% in 112 amplified pre-treatment samples. The presence of pfcrt T76 was poorly predictive of in vivo CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9. The prevalence of dhfr Arg-59 mutation in 99 amplified samples was 5%, while the dhps Glu-540 was not detected in any of 119 amplified samples. Sequencing the pfcrt gene confirmed that Yemeni CQ resistant P. falciparum carry the old world (Asian and African CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371. Conclusion This is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR P. falciparum

  13. The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin

    Directory of Open Access Journals (Sweden)

    Barik Sailen

    2003-09-01

    Full Text Available Abstract Background The naturally occurring benzoquinone ansamycin compound, geldanamycin (GA, is a specific inhibitor of heat shock protein 90 (Hsp90 and is a potential anticancer agent. Since Plasmodium falciparum has been reported to have an Hsp90 ortholog, we tested the possibility that GA might inhibit it and thereby display antiparasitic activity. Results We provide direct recombinant DNA evidence for the Hsp90 protein of Plasmodium falciparum, the causative agent of fatal malaria. While the mRNA of Hsp90 was mainly expressed in ring and trophozoite stages, the protein was found in all stages, although schizonts contained relatively lower amounts. In vitro the parasitic Hsp90 exhibited an ATP-binding activity that could be specifically inhibited by GA. Plasmodium growth in human erythrocyte culture was strongly inhibited by GA with an IC50 of 20 nM, compared to the IC50 of 15 nM for chloroquine (CQ under identical conditions. When used in combination, the two drugs acted synergistically. GA was equally effective against CQ-sensitive and CQ-resistant strains (3D7 and W2, respectively and on all erythrocytic stages of the parasite. Conclusions Together, these results suggest that an active and essential Hsp90 chaperone cycle exists in Plasmodium and that the ansamycin antibiotics will be an important tool to dissect its role in the parasite. Additionally, the favorable pharmacology of GA, reported in human trials, makes it a promising antimalarial drug.

  14. Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin

    International Nuclear Information System (INIS)

    We report that the antimalarial drug artemisinin inhibits hepatitis C virus (HCV) replicon replication in a dose-dependent manner in two replicon constructs at concentrations that have no effect on the proliferation of the exponentially growing host cells. The 50% effective concentration (EC5) for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by artemisinin was 78 ± 21 μM. Hemin, an iron donor, was recently reported to inhibit HCV replicon replication [mediated by inhibition of the viral polymerase (C. Fillebeen, A.M. Rivas-Estilla, M. Bisaillon, P. Ponka, M. Muckenthaler, M.W. Hentze, A.E. Koromilas, K. Pantopoulos, Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus, J. Biol. Chem. 280 (2005) 9049-9057.)] at a concentration that had no adverse effect on the host cells. When combined, artemisinin and hemin resulted, over a broad concentration range, in a pronounced synergistic antiviral activity. Also at a concentration (2 μM) that alone had no effect on HCV replication, hemin still potentiated the anti-HCV activity of artemisinin

  15. Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities.

    Science.gov (United States)

    Beteck, Richard M; Coertzen, Dina; Smit, Frans J; Birkholtz, Lyn-Marie; Haynes, Richard K; N'Da, David D

    2016-07-01

    As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones. PMID:27210430

  16. Accessibility, availability and affordability of anti-malarials in a rural district in Kenya after implementation of a national subsidy scheme

    Directory of Open Access Journals (Sweden)

    Simiyu Chrispinus

    2011-10-01

    Full Text Available Abstract Background Poor access to prompt and effective treatment for malaria contributes to high mortality and severe morbidity. In Kenya, it is estimated that only 12% of children receive anti-malarials for their fever within 24 hours. The first point of care for many fevers is a local medicine retailer, such as a pharmacy or chemist. The role of the medicine retailer as an important distribution point for malaria medicines has been recognized and several different strategies have been used to improve the services that these retailers provide. Despite these efforts, many mothers still purchase ineffective drugs because they are less expensive than effective artemisinin combination therapy (ACT. One strategy that is being piloted in several countries is an international subsidy targeted at anti-malarials supplied through the retail sector. The goal of this strategy is to make ACT as affordable as ineffective alternatives. The programme, called the Affordable Medicines Facility - malaria was rolled out in Kenya in August 2010. Methods In December 2010, the affordability and accessibility of malaria medicines in a rural district in Kenya were evaluated using a complete census of all public and private facilities, chemists, pharmacists, and other malaria medicine retailers within the Webuye Demographic Surveillance Area. Availability, types, and prices of anti-malarials were assessed. There are 13 public or mission facilities and 97 medicine retailers (registered and unregistered. Results The average distance from a home to the nearest public health facility is 2 km, but the average distance to the nearest medicine retailer is half that. Quinine is the most frequently stocked anti-malarial (61% of retailers. More medicine retailers stocked sulphadoxine-pyramethamine (SP; 57% than ACT (44%. Eleven percent of retailers stocked AMFm subsidized artemether-lumefantrine (AL. No retailers had chloroquine in stock and only five were selling artemisinin

  17. Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement.

    Science.gov (United States)

    Shen, Shuo; Liu, Shu-Zhi; Zhang, Yu-Shi; Du, Mao-Bo; Liang, Ai-Hua; Song, Li-Hua; Ye, Zu-Guang

    2015-01-01

    Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel compound antimalarial transdermal nanosystem-ethosomal cataplasm, to investigate its characteristics and efficiency, and to systematically explore the penetration-enhancing mechanisms of ethosomal cataplasm. Artesunate-loaded ethosomes and febrifugine-loaded ethosomes were prepared, and their characteristics were evaluated. Drug-loaded ethosomes were incorporated in the matrix of cataplasm to form the compound antimalarial ethosomal cataplasm. With the help of ethosomal technology, the accumulated permeation quantity of artesunate significantly increased at 8 hours after administration, which was 1.57 times as much as that of conventional cataplasm. Soon after administration, the ethosomal cataplasm could make a large quantity of antimalarial drug quickly penetrate through skin, then the remaining drug in the ethosomal cataplasm could be steadily released. These characteristics of ethosomal cataplasm are favorable for antimalarial drugs to kill Plasmodium spp. quickly and prevent the resurgence of Plasmodium spp. As expected, the ethosomal cataplasm showed good antimalarial efficiency in this experiment. The negative conversion rates were 100% and the recurrence rates were 0% at all dosages. The mechanism of penetration enhancement of the ethosomal cataplasm was systematically explored using an optics microscope, polarization microscope, and transmission electron microscopy. The microstructure, ultrastructure, and birefringent structure in skin were observed. Data obtained in this study showed that the application of ethosomal technology to antimalarial cataplasm could improve the transdermal delivery of drug, enhance the efficacy, and facilitate practical application in clinic. PMID:26170661

  18. Responding to the challenge of antimalarial drug resistance by routine monitoring to update national malaria treatment policies

    DEFF Research Database (Denmark)

    Vestergaard, Lasse S; Ringwald, Pascal

    2007-01-01

    of rational and updated malaria treatment policies, but defining and updating such policies requires a sufficient volume of high-quality drug-resistance data collected at national and regional levels. Three main tools are used for drug resistance monitoring, including therapeutic efficacy tests, in......Reduced sensitivity of Plasmodium falciparum to formerly recommended cheap and well-known antimalarial drugs places an increasing burden on malaria control programs and national health systems in endemic countries. The high costs of the new artemisinin-based combination treatments underline the use...... additional information about changing patterns of resistance. However, some of the tests are technically demanding, and thus there is a need for more resources for training and capacity building in endemic countries to be able to adequately respond to the challenge of drug resistance....

  19. Asthma control in patients receiving inhaled corticosteroid and long-acting beta2-agonist fixed combinations. A real-life study comparing dry powder inhalers and a pressurized metered dose inhaler extrafine formulation

    Directory of Open Access Journals (Sweden)

    Nicolini Gabriele

    2011-07-01

    Full Text Available Abstract Background Although patients have more problems using metered dose inhalers, clinical comparisons suggest they provide similar control to dry powder inhalers. Using real-life situations this study was designed to evaluate asthma control in outpatients with moderate to severe persistent asthma and to compare efficacy of fixed combinations of inhaled corticosteroids (ICS and long acting beta-agonists (LABA. Methods This real-life study had a cross-sectional design. Patients using fixed combinations of ICS and LABA had their asthma control and spirometry assessed during regular visits. Results 111 patients were analyzed: 53 (47.7% received maintenance therapy of extrafine beclomethasone-formoterol (BDP/F pressurized metered dose inhaler (pMDI, 25 (22.5% fluticasone-salmeterol (FP/S dry powder inhaler (DPI, and 33 (29.7% budesonide-formoterol (BUD/F DPI. Severity of asthma at time of diagnosis, assessed by the treating physician, was comparable among groups. Asthma control was achieved by 45.9% of patients; 38.7% were partially controlled and 15.3% were uncontrolled. In the extrafine BDF/F group, asthma control total score, daytime symptom score and rescue medication use score were significantly better than those using fixed DPI combinations (5.8 ± 6.2 vs. 8.5 ± 6.8; 1.4 ± 1.8 vs. 2.3 ± 2.1; 1.8 ± 2.2 vs. 2.6 ± 2.2; p = 0.0160; p = 0.012 and p = 0.025, respectively and the mean daily ICS dose were significantly lower. Conclusions pMDI extrafine BDP/F combination demonstrated better asthma control compared to DPIs formulated with larger particles. This could be due to the improved lung deposition of the dose or less reliance on the optimal inhalation technique or both.

  20. Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design.

    Science.gov (United States)

    Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Betancourt-Conde, Irene; Aguirre-Raudry, Miriam; Vázquez-Raygoza, Alejandra; Luevano-De la Cruz, Artemisa; Favela-Candia, Alejandro; Sarabia-Sanchez, Marie; Ríos-Soto, Lluvia; Méndez-Hernández, Edna; Cisneros-Martínez, Jorge; Palacio-Gastélum, Marcelo Gómez; Valdez-Solana, Mónica; Hernández-Rivera, Jessica; De Lira-Sánchez, Jaime; Campos-Almazán, Mara; Téllez-Valencia, Alfredo

    2016-01-01

    Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria. PMID:26983887

  1. Public Awareness and Identification of Counterfeit Drugs in Tanzania: A View on Antimalarial Drugs

    Directory of Open Access Journals (Sweden)

    Linus Mhando

    2016-01-01

    Full Text Available Background. The illicit trade in counterfeit antimalarial drugs is a major setback to the fight against malaria. Information on public awareness and ability to identify counterfeit drugs is scanty. Aim. Therefore, the present study aimed at assessing public awareness and the ability to identify counterfeit antimalarial drugs based on simple observations such as appearance of the drugs, packaging, labelling, and leaflets. Methodology. A cross-sectional study was conducted using interviewer administered structured questionnaire and a checklist. Respondents were required to spot the difference between genuine and counterfeit antimalarial drugs given to them. Data was analysed using SPSS version 20. Results. The majority of respondents, 163 (55.6%, were able to distinguish between genuine and counterfeit antimalarial drugs. Respondents with knowledge on health effects of counterfeit drugs were more likely to identify genuine and counterfeit drugs than their counterparts (P=0.003; OR = 2.95; 95% CI: 1.47–5.65. The majority of respondents, 190 (64.8%, perceived the presence of counterfeit drugs to be a big problem to the community. Conclusions. A substantial proportion of respondents were able to distinguish between genuine and counterfeit antimalarial drugs. Public empowerment in identifying counterfeit drugs by simple observations is a major step towards discouraging the market of counterfeit drugs.

  2. Targeting protein kinases in the malaria parasite: update of an antimalarial drug target.

    Science.gov (United States)

    Zhang, Veronica M; Chavchich, Marina; Waters, Norman C

    2012-01-01

    Millions of deaths each year are attributed to malaria worldwide. Transmitted through the bite of an Anopheles mosquito, infection and subsequent death from the Plasmodium species, most notably P. falciparum, can readily spread through a susceptible population. A malaria vaccine does not exist and resistance to virtually every antimalarial drug predicts that mortality and morbidity associated with this disease will increase. With only a few antimalarial drugs currently in the pipeline, new therapeutic options and novel chemotypes are desperately needed. Hit-to-Lead diversity may successfully provide novel inhibitory scaffolds when essential enzymes are targeted, for example, the plasmodial protein kinases. Throughout the entire life cycle of the malaria parasite, protein kinases are essential for growth and development. Ongoing efforts continue to characterize these kinases, while simultaneously pursuing them as antimalarial drug targets. A collection of structural data, inhibitory profiles and target validation has set the foundation and support for targeting the malarial kinome. Pursuing protein kinases as cancer drug targets has generated a wealth of information on the inhibitory strategies that can be useful for antimalarial drug discovery. In this review, progress on selected protein kinases is described. As the search for novel antimalarials continues, an understanding of the phosphor-regulatory pathways will not only validate protein kinase targets, but also will identify novel chemotypes to thwart malaria drug resistance. PMID:22242850

  3. Monitoring the efficacy of antimalarial medicines in India via sentinel sites: Outcomes and risk factors for treatment failure

    Directory of Open Access Journals (Sweden)

    Neelima Mishra

    2016-01-01

    Interpretation & conclusion: Till 2012, India′s national antimalarial drug resistance monitoring system proved highly efficacious and safe towards first-line antimalarials used in the country, except in Northeastern region where a decline in efficacy of AS+SP has been observed. This led to change in first-line treatment for P. falciparum to artemether-lumefantrine in Northeastern region.

  4. Reduction of transmission from malaria patients by artemisinin combination therapies: a pooled analysis of six randomized trials

    OpenAIRE

    Bousema Teun; Ghani Azra C; Drakeley Chris J; Okell Lucy C; Sutherland Colin J

    2008-01-01

    Abstract Background Artemisinin combination therapies (ACT), which are increasingly being introduced for treatment of Plasmodium falciparum malaria, are more effective against sexual stage parasites (gametocytes) than previous first-line antimalarials and therefore have the potential to reduce parasite transmission. The size of this effect is estimated in symptomatic P. falciparum infections. Methods Data on 3,174 patients were pooled from six antimalarial trials conducted in The Gambia and K...

  5. Collaborative health and enforcement operations on the quality of antimalarials and antibiotics in southeast Asia.

    Science.gov (United States)

    Yong, Yuk Lin; Plançon, Aline; Lau, Yen Hui; Hostetler, Dana M; Fernández, Facundo M; Green, Michael D; Sounvoravong, Sourisak; Nara, Suon; Boravann, Mam; Dumrong, Thitikornkovit; Bangsawan, Nurjaya; Low, Min Yong; Lim, Chin-Chin; Ai, Ruth Lee Choo; Newton, Paul N

    2015-06-01

    Counterfeit (or falsified) and substandard medicines pose a major public health risk. We describe the findings of Operation Storm I and II conducted in 2008-2009 to combat counterfeit medicines through partnership between national customs, Drug Regulatory Agencies (DRAs), and police in Cambodia, Indonesia, Laos, Myanmar, Singapore, Thailand, and Vietnam. Samples were obtained from seizures and market surveillance by national DRAs. Laboratory analysis using spectroscopic and chromatographic techniques and examination of packaging were performed. Ninety-three suspect antibiotics and 95 antimalarial samples were collected. Of the 93 antibiotics, 29 (31%) had % active pharmaceutical ingredient content (%API) 115% (including one counterfeit). Of the 95 antimalarials, 30 (32%) had %API 115% API (including one counterfeit). A significant minority of samples, antimalarials (13%) and antibiotics (15%), were collected in plastic bags with minimal or no labeling. Of 20 ampicillin samples, 13 (65%) contained medicines. PMID:25897069

  6. Influence of smoking on disease severity and antimalarial therapy in cutaneous lupus erythematosus

    DEFF Research Database (Denmark)

    Kuhn, A; Sigges, J; Biazar, C;

    2014-01-01

    BACKGROUND: In recent years it has been controversially discussed in the literature if smoking is associated with the activity of cutaneous lupus erythematosus (CLE) and the efficacy of antimalarial agents. OBJECTIVES: To investigate the influence of smoking on disease severity and antimalarial...... treatment in patients with CLE using the Core Set Questionnaire of the European Society of Cutaneous Lupus Erythematosus (EUSCLE). METHODS: A total of 1002 patients (768 female, 234 male) with different CLE subtypes were included in this cross-sectional study, which was performed in 14 different countries....... Smoking behaviour was assessed by the EUSCLE Core Set Questionnaire in 838 patients and statistically analysed using an SPSS database. The results were correlated with the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the efficacy of antimalarial treatment. RESULTS: A high...

  7. IT Supporting Strategy Formulation

    NARCIS (Netherlands)

    Achterbergh, J.M.I.M.

    2005-01-01

    This overview approaches information and communication technology (ICT) for competitive intelligence from the perspective of strategy formulation. It provides an ICT architecture for supporting the knowledge processes producing relevant knowledge for strategy formulation. To determine what this arch

  8. The impact of text message reminders on adherence to antimalarial treatment in northern Ghana: a randomized trial.

    Directory of Open Access Journals (Sweden)

    Julia R G Raifman

    Full Text Available BACKGROUND: Low rates of adherence to artemisinin-based combination therapy (ACT regimens increase the risk of treatment failure and may lead to drug resistance, threatening the sustainability of current anti-malarial efforts. We assessed the impact of text message reminders on adherence to ACT regimens. METHODS: Health workers at hospitals, clinics, pharmacies, and other stationary ACT distributors in Tamale, Ghana provided flyers advertising free mobile health information to individuals receiving malaria treatment. The messaging system automatically randomized self-enrolled individuals to the control group or the treatment group with equal probability; those in the treatment group were further randomly assigned to receive a simple text message reminder or the simple reminder plus an additional statement about adherence in 12-hour intervals. The main outcome was self-reported adherence based on follow-up interviews occurring three days after treatment initiation. We estimated the impact of the messages on treatment completion using logistic regression. RESULTS: 1140 individuals enrolled in both the study and the text reminder system. Among individuals in the control group, 61.5% took the full course of treatment. The simple text message reminders increased the odds of adherence (adjusted OR 1.45, 95% CI [1.03 to 2.04], p-value 0.028. Receiving an additional message did not result in a significant change in adherence (adjusted OR 0.77, 95% CI [0.50 to 1.20], p-value 0.252. CONCLUSION: The results of this study suggest that a simple text message reminder can increase adherence to antimalarial treatment and that additional information included in messages does not have a significant impact on completion of ACT treatment. Further research is needed to develop the most effective text message content and frequency. TRIAL REGISTRATION: ClinicalTrials.gov NCT01722734.

  9. IT Supporting Strategy Formulation

    OpenAIRE

    Achterbergh, J.M.I.M.

    2005-01-01

    This overview approaches information and communication technology (ICT) for competitive intelligence from the perspective of strategy formulation. It provides an ICT architecture for supporting the knowledge processes producing relevant knowledge for strategy formulation. To determine what this architecture looks like, we first examine the process of strategy formulation and determine the knowledge required in the process of strategy formulation. To this purpose, we use Beer’s viable system m...

  10. Investigation of Traditional Palestinian Medicinal Plant Inula viscosa as Potential Anti-malarial Agent

    Directory of Open Access Journals (Sweden)

    M. Akkawi

    2014-10-01

    Full Text Available Malaria is a life threatening parasitic disease which is prevalent mainly in developing countries; it is the main cause of global mortality and morbidity. Development and search of novel and effective anti-malarial agents to overcome chloroquine resistance have become a very important issue. Most anti-malarial drugs target the erythrocytic stage of malaria infection, where hemozoin synthesis takes place and is considered a crucial process for the parasite survival. Throughout last decades, natural products have been a significant source of chemotherapeutics especially against malaria. Inula viscosa, Inula viscosa , is a shrub that grows around the Mediterranean basin and considered as an important Palestinian traditional medicinal herb. In this research it was found that the Palestinian flora Inula viscosa alcoholic extract has a significant and promising anti-malarial effect in both in vitro and in vivo systems. The crude alcoholic extract of Inula viscosa has the capability to impede the formation of &beta-hematin in vitro; with an efficiency of about 93% when compared to the standard chloroquine which gave 94% at comparable concentrations. in vivo studies showed that this crude extract inhibited the growth of Plasmodium parasites in the red blood cells at a rate of about 96.6%, with an EC50 value of 0.55 ng/mL. Several secondary plant metabolites may be responsible for this anti-malarial activity; the effect also may be most probably due to the presence of high concentrations of nerolidol which has often been found at high concentrationsin this plant. Nerolidol shows a stronger inhibition of hypoxanthine incorporation than quinine. Its anti-malarial effect is potentiated by other essential oils. Nerolidol is also found in several Artemisia species and in Cymbopogon citratus (lemongrass and Virola surinamensis, all plants known for their anti-malarial properties.

  11. In vitro and in vivo assessment of the anti-malarial activity of Caesalpinia pluviosa

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    Eberlin Marcos N

    2011-05-01

    Full Text Available Abstract Background To overcome the problem of increasing drug resistance, traditional medicines are an important source for potential new anti-malarials. Caesalpinia pluviosa, commonly named "sibipiruna", originates from Brazil and possess multiple therapeutic properties, including anti-malarial activity. Methods Crude extract (CE was obtained from stem bark by purification using different solvents, resulting in seven fractions. An MTT assay was performed to evaluate cytotoxicity in MCF-7 cells. The CE and its fractions were tested in vitro against chloroquine-sensitive (3D7 and -resistant (S20 strains of Plasmodium falciparum and in vivo in Plasmodium chabaudi-infected mice. In vitro interaction with artesunate and the active C. pluviosa fractions was assessed, and mass spectrometry analyses were conducted. Results At non-toxic concentrations, the 100% ethanolic (F4 and 50% methanolic (F5 fractions possessed significant anti-malarial activity against both 3D7 and S20 strains. Drug interaction assays with artesunate showed a synergistic interaction with the F4. Four days of treatment with this fraction significantly inhibited parasitaemia in mice in a dose-dependent manner. Mass spectrometry analyses revealed the presence of an ion corresponding to m/z 303.0450, suggesting the presence of quercetin. However, a second set of analyses, with a quercetin standard, showed distinct ions of m/z 137 and 153. Conclusions The findings show that the F4 fraction of C. pluviosa exhibits anti-malarial activity in vitro at non-toxic concentrations, which was potentiated in the presence of artesunate. Moreover, this anti-malarial activity was also sustained in vivo after treatment of infected mice. Finally, mass spectrometry analyses suggest that a new compound, most likely an isomer of quercetin, is responsible for the anti-malarial activity of the F4.

  12. [Combination Chemotherapy Using Sorafenib and Hepatic Arterial Infusion with a Fine-Powder Formulation of Cisplatin for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis--A Case Report].

    Science.gov (United States)

    Tsukamoto, Tadashi; Kanazawa, Akishige; Shimizu, Sadatoshi; Murata, Akihiro; Sakae, Masayuki; Kurihara, Shigeaki; Tashima, Tetsuzo; Deguchi, Sota; Nakai, Takashi; Kawasaki, Yasuko; Kioka, Kiyohide

    2015-11-01

    Sorafenib has been a standard therapy for advanced hepatocellular carcinoma (HCC) with portal vein thrombosis. Hepatic arterial infusion chemotherapy (HAIC) is still preferably performed in Japan because of its relatively good tumor-shrinking effect. We report a case of advanced multiple HCC with portal thrombus that responded to combination chemotherapy with sorafenib and repeat hepatic arterial infusion with a fine-powder formulation of cisplatin (IA-call®). A 57-year-old man presented for the treatment of HCC with alcoholic cirrhosis. Multiple HCC were found to be rapidly progressing with portal thrombosis. HAIC with IA-call® was performed, but the tumors progressed. TAE was performed 3 times thereafter and the main tumor shrunk to some extent. A month after the last TAE, the HCC was found to progress again, and oral sorafenib was administered. A reservoir and catheter were placed and HAIC with low-dose 5-fluorouracil and cisplatin was performed for 3 cycles following 1 HAIC cycle with epirubicin and mitomycin C, which was not effective. For 10 months after initial therapy, HAIC using IA-call® has been performed once for 6 weeks. After performing HAIC with IA-call® 5 times, the serum levels of HCC tumor markers AFP and PIVKA-Ⅱdecreased, and the tumors continued to shrink and were not stained on enhanced CT scan. The patient has been alive for 23 months after the initial therapy and has maintained stable disease. PMID:26805203

  13. 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...

  14. 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...

  15. Availability of antimalarial drugs and evaluation of the attitude and practices for the treatment of uncomplicated malaria in bangui, central african republic.

    Science.gov (United States)

    Manirakiza, Alexandre; Njuimo, Siméon Pierre; Le Faou, Alain; Malvy, Denis; Millet, Pascal

    2010-01-01

    National malaria management policy is based upon the availability of effective and affordable antimalarial drugs. This study was undertaken to evaluate the quality of the treatment of uncomplicated malaria cases in Bangui, an area with multidrug-resistant parasites, at a time preceding implementation of a new therapeutic policy relying on the artemisinin derivative combined treatment artemether-lumefantrine. A cross-sectional study was carried out in Bangui city to assess availability of antimalarial drugs and the performances of health workers in the management of uncomplicated malaria. Availability of drugs was recorded in all drugs wholesalers (n = 3), all pharmacies in health facilities (n = 14), private drugstores (n = 15), and in 60 non-official drug shops randomly chosen in the city. Despite a limited efficacy at the time of the survey, chloroquine remained widely available in the official and nonofficial markets. Artemisinin derivatives used in monotherapy or in combination were commonly sold. In health care facilities, 93% of the uncomplicated malaria cases were treated in the absence of any laboratory confirmation and the officially recommended treatment, amodiaquine-sulfadoxine/pyrimethamine, was seldom prescribed. Thus, the national guidelines for the treatment of uncomplicated malaria are not followed by health professionals in Bangui. Its use should be implemented while a control of importation of drug has to be reinforced. PMID:20339579

  16. Mind the gaps - the epidemiology of poor-quality anti-malarials in the malarious world - analysis of the WorldWide Antimalarial Resistance Network database

    OpenAIRE

    Tabernero, Patricia; Facundo M Fernández; Green, Michael; Guerin, Philippe J; Newton, Paul N.

    2014-01-01

    Background Poor quality medicines threaten the lives of millions of patients and are alarmingly common in many parts of the world. Nevertheless, the global extent of the problem remains unknown. Accurate estimates of the epidemiology of poor quality medicines are sparse and are influenced by sampling methodology and diverse chemical analysis techniques. In order to understand the existing data, the Antimalarial Quality Scientific Group at WWARN built a comprehensive, open-access, global datab...

  17. Prioritization of anti-malarial hits from nature: chemo-informatic profiling of natural products with in vitro antiplasmodial activities and currently registered anti-malarial drugs

    OpenAIRE

    Egieyeh, Samuel Ayodele; Syce, James; Malan, Sarel F.; Christoffels, Alan

    2016-01-01

    Background A large number of natural products have shown in vitro antiplasmodial activities. Early identification and prioritization of these natural products with potential for novel mechanism of action, desirable pharmacokinetics and likelihood for development into drugs is advantageous. Chemo-informatic profiling of these natural products were conducted and compared to currently registered anti-malarial drugs (CRAD). Methods Natural products with in vitro antiplasmodial activities (NAA) we...

  18. Post-marketing assessment of content and efficacy of preservatives in artemisinin-derived antimalarial dry suspensions for paediatric use

    Directory of Open Access Journals (Sweden)

    Plaizier-Vercammen Jacqueline

    2007-01-01

    Full Text Available Abstract Background Artemisinin-derivative formulations are now widely used to treat falciparum malaria. However, the dry powder suspensions developed for children are few and/or are of poor quality. In addition to the active compound, the presence of a suitable preservative in these medicines is essential. In this study, an evaluation of the preservative content and efficacy in some dry suspensions available on the Kenyan market was performed. Method UV spectrophotometry was used to identify the preservatives in each sample while HPLC-UV was used for quantification. After reconstitution of the powders in water, the dissolution of the preservatives was followed for 7 days. Antimicrobial efficacy of the preservatives was assessed by conducting a preservative efficacy test (PET following the European pharmacopoeia standards. Results Four different preservatives were identified namely methylparahydroxybenzoate (MP, propylparahydroxybenzoate (PP, benzoic acid and sorbic acid. MP and PP were identified in Artesiane® (artemether 300 mg/100 ml, Alaxin® (dihydroartemisinin 160 mg/80 ml andGvither ® (artemether 300 mg/100 ml respectively. Sorbic acid was presentin Artenam® (artemether 180 mg/60 ml while benzoic acid was identified in Santecxin® (dihydroartemisinin 160 mg/80 ml andArtexin® (dihydroartemisinin 160 mg/80 ml respectively. Cotecxin® (dihydroartemisinin 160 mg/80 ml did not contain any of the above preservatives. After reconstitution in water, preservativesin 50%(3/6 of the products did not completely dissolve and the PET results revealed that only Artenam® and Gvither® met the requirements for antimicrobial efficacy. The other products did not conform. Conclusion These results show that paediatric antimalarial dry powder formulations on the market may contain ineffective or incorrect amounts of preservatives. This is a potential risk to the patient. Studies conducted on the dry powder suspensions should include the analysis of both

  19. A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity

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    Cleydson Breno R. Santos

    2013-12-01

    Full Text Available The Hartree-Fock method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with antimalarial activity. Maps of molecular electrostatic potential (MEPs and molecular docking were used to investigate the interaction between ligands and the receptor (heme. Principal component analysis and hierarchical cluster analysis were employed to select the most important descriptors related to activity. The correlation between biological activity and molecular properties was obtained using the partial least squares and principal component regression methods. The regression PLS and PCR models built in this study were also used to predict the antimalarial activity of 30 new artemisinin compounds with unknown activity. The models obtained showed not only statistical significance but also predictive ability. The significant molecular descriptors related to the compounds with antimalarial activity were the hydration energy (HE, the charge on the O11 oxygen atom (QO11, the torsion angle O1-O2-Fe-N2 (D2 and the maximum rate of R/Sanderson Electronegativity (RTe+. These variables led to a physical and structural explanation of the molecular properties that should be selected for when designing new ligands to be used as antimalarial agents.

  20. Amazonian Plant Natural Products: Perspectives for Discovery of New Antimalarial Drug Leads

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    Lucio H. Freitas-Junior

    2013-08-01

    Full Text Available Plasmodium falciparum and P. vivax malaria parasites are now resistant, or showing signs of resistance, to most drugs used in therapy. Novel chemical entities that exhibit new mechanisms of antiplasmodial action are needed. New antimalarials that block transmission of Plasmodium spp. from humans to Anopheles mosquito vectors are key to malaria eradication efforts. Although P. vivax causes a considerable number of malaria cases, its importance has for long been neglected. Vivax malaria can cause severe manifestations and death; hence there is a need for P. vivax-directed research. Plants used in traditional medicine, namely Artemisia annua and Cinchona spp. are the sources of the antimalarial natural products artemisinin and quinine, respectively. Based on these compounds, semi-synthetic artemisinin-derivatives and synthetic quinoline antimalarials have been developed and are the most important drugs in the current therapeutic arsenal for combating malaria. In the Amazon region, where P. vivax predominates, there is a local tradition of using plant-derived preparations to treat malaria. Here, we review the current P. falciparum and P. vivax drug-sensitivity assays, focusing on challenges and perspectives of drug discovery for P. vivax, including tests against hypnozoites. We also present the latest findings of our group and others on the antiplasmodial and antimalarial chemical components from Amazonian plants that may be potential drug leads against malaria.

  1. Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity

    OpenAIRE

    Rijpma, S.R.; Heuvel, J. J.; van de Velden, M.; Sauerwein, R. W.; Russel, F. G.; Koenderink, J.B.

    2014-01-01

    BACKGROUND: Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involved in drug deposition, as they are located at membranes of many uptake and excretory organs and at protective barriers, where they export endogenous and xenobiotic compounds, including pharmaceutica...

  2. New anti-HIV-1, antimalarial, and antifungal compounds from Terminalia bellerica

    DEFF Research Database (Denmark)

    Valsaraj, R; Pushpangadan, P; Smitt, U W;

    1997-01-01

    A bioactivity-guided fractionation of an extract of Terminalia bellerica fruit rind led to the isolation of two new lignans named termilignan (1) and thannilignan (2), together with 7-hydroxy-3',4'-(methylenedioxy)flavan (3) and anolignan B (4). All four compounds possessed demonstrable anti-HIV-......, antimalarial, and antifungal activity in vitro....

  3. Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement

    Directory of Open Access Journals (Sweden)

    Shen S

    2015-06-01

    Full Text Available Shuo Shen, Shu-Zhi Liu, Yu-Shi Zhang, Mao-Bo Du, Ai-Hua Liang, Li-Hua Song, Zu-Guang Ye Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China Abstract: Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel compound antimalarial transdermal nanosystem–ethosomal cataplasm, to investigate its characteristics and efficiency, and to systematically explore the penetration-enhancing mechanisms of ethosomal cataplasm. Artesunate-loaded ethosomes and febrifugine-loaded ethosomes were prepared, and their characteristics were evaluated. Drug-loaded ethosomes were incorporated in the matrix of cataplasm to form the compound antimalarial ethosomal cataplasm. With the help of ethosomal technology, the accumulated permeation quantity of artesunate significantly increased at 8 hours after administration, which was 1.57 times as much as that of conventional cataplasm. Soon after administration, the ethosomal cataplasm could make a large quantity of antimalarial drug quickly penetrate through skin, then the remaining drug in the ethosomal cataplasm could be steadily released. These characteristics of ethosomal cataplasm are favorable for antimalarial drugs to kill Plasmodium spp. quickly and prevent the resurgence of Plasmodium spp. As expected, the ethosomal cataplasm showed good antimalarial efficiency in this experiment. The negative conversion rates were 100% and the recurrence rates were 0% at all dosages. The mechanism of penetration enhancement of the ethosomal cataplasm was systematically explored using an optics microscope, polarization microscope, and transmission electron microscopy. The microstructure, ultrastructure, and birefringent structure in skin were observed. Data

  4. Subsidizing artemisinin-based combination therapies: a preliminary investigation of the Affordable Medicines Facility – malaria

    Directory of Open Access Journals (Sweden)

    Bate R

    2012-07-01

    Full Text Available Roger Bate,1,2 Kimberly Hess,2 Richard Tren,2 Lorraine Mooney,3 Franklin Cudjoe,4 Thompson Ayodele,5 Amir Attaran61American Enterprise Institute, Washington, DC, USA; 2Africa Fighting Malaria, Washington, DC, USA; 3Africa Fighting Malaria, Cambridge, United Kingdom; 4IMANI Center for Policy and Education, Accra, Ghana; 5Initiative for Public Policy Analysis, Lagos, Nigeria; 6University of Ottawa, Ottawa, ON, CanadaBackground: The Affordable Medicines Facility – malaria (AMFm is a subsidy mechanism to lower the price of, and hence increase access to, the best antimalarial medicines, artemisinin-based combination therapies (ACTs. While the AMFm stipulates that only quality-approved products are eligible for subsidy, it is not known whether those products, when actually supplied, are of good quality and comport with established pharmacopeial guidance on formulation and content of active ingredients. This study aimed to assess price and quality of AMFm ACTs, to compare AMFm ACTs with non-AMFm ACTs and artemisinin monotherapies, and to assess whether AMFm ACTs have been pilfered and diverted to a nearby country.Methods: In all, 140 artemisinin-based antimalarial drugs were acquired from 37 pharmacies in Lagos, Nigeria, and Accra, Ghana. An additional ten samples of AMFm ACTs were collected from Lomé, Togo (not participating in the AMFm. Samples were analyzed using high-performance liquid chromatography.Results: The AMFm ACTs were lower in price than many of the other drugs collected, but by less than anticipated or stipulated by the participating governments of Nigeria and Ghana. The quality of the AMFm ACTs was not universally good: overall, 7.7% had too little active pharmaceutical ingredient (API and none had too much – these results are not likely to be as a result of random chance. AMFm ACTs were also found to have been diverted, both to pharmacies in Lagos not participating in the AMFm and to a foreign city (Lomé where the AMFm is not

  5. Substandard artemisinin-based antimalarial medicines in licensed retail pharmaceutical outlets in Ghana

    Directory of Open Access Journals (Sweden)

    M. El-Duah & K. Ofori-Kwakye

    2012-09-01

    Full Text Available Background & objectives: The artemisinin-based antimalarial medicines are first line medicines in the treatmentof severe and uncomplicated falciparum malaria. Numerous brands of these medicines manufactured in variouscountries are available in the Ghanaian market. The study was aimed at evaluating the authenticity and qualityof selected brands of artemisinin-based antimalarial medicines marketed in Ghana.Methods: In all, 14 artemisinin-based antimalarial medicines were purchased from pharmacies (P and licensedchemical shops (LCSs in the Kumasi metropolis, Ghana. Simple field tests based on colorimetry and thin layerchromatography were employed in determining the authenticity of the samples. Important quality assessmenttests, namely uniformity of mass, crushing strength, disintegration time, and the percentage content of activepharmaceutical ingredients (APIs were determined.Results: All the brands tested contained the stipulated APIs. Artesunate tablet AT2 failed the uniformity of masstest while artesunate tablets AT3 & AT4 as well as amodiaquine tablets AM4 & AM6 failed the crushing strengthtest. All the six artemether-lumefantrine tablet brands passed the uniformity of mass, crushing strength anddisintegration tests. Only artemether-lumefantrine tablet brand AL1 contained the correct amount of the drugs.The other 13 artemisinin products contained either a lower (underdose or higher (overdose amount of thespecified drug. Artesunate monotherapy tablets were readily available in pharmacies and licensed chemicalshops.Interpretation & conclusion: All the artemisinin-based medicines tested (except AL1 were of substandardquality. The results demonstrate the need for continuous monitoring and evaluation of the quality of artemisininbased antimalarials in the Ghanaian market. Also, the practice of artemisinin antimalarial monotherapy is prevalentin Ghana. Determined efforts should, therefore, be made to eradicate the practice to prevent the development

  6. In vitro antimalarial activity of extracts of some plants from a biological reserve in Costa Rica.

    Science.gov (United States)

    Chinchilla, Misael; Valerio, Idalia; Sánchez, Ronald; Mora, Víctor; Bagnarello, Vanessa; Martínez, Laura; Gonzalez, Antonieta; Vanegas, Juan Carlos; Apestegui, Alvaro

    2012-06-01

    Treatment with the usual antimalarial drugs, have induced parasite resistance, reinforcing the need to finding natural antimalarial components that would be found on plants from the forest. Therefore, we decided to look for these components in Costa Rican plants from a protected forest area. Fresh and dry extracts of roots, bark, leaves, flowers and fruits of 25 plants from a biological reserve in Costa Rica, Reserva Biol6gica Alberto Manuel Brenes (REBAMB), were studied in vitro for the presence of substances with antimalarial activity. By studying the inhibition of P berghei schizogony, we assessed the antimalarial activity of several plant extracts: Aphelandra aurantiaca, A. tridentata (Acanthaceae); Xanthosoma undipes (Araceae); Iriartea deltoidea (Arecaceae); Neurolaena lobata (Asteraceae); Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae); Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae); Hampea appendiculata (Malvaceae); Ruagea glabra, Guarea glabra (Meliaceae); Psidium guajava (Myrtaceae); Bocconia frutescens (Papaveraceae); Piper friedrichsthalii (Piperaceae); Clematis dioica (Ranunculaceae); Prunus annularis (Rosaceae); Siparuna thecaphora (Siparunaceae); Solanum arboreum, Witheringia solanacea (Solanaceae); Ticodendrum incognitum (Ticodendraceae); Heliocarpus appendiculatus (Tiliaceae) and Myriocarpa longipes (Urticaceae). We used different parts of the plants as well as fresh and dried extracts for testing IC50. The solid content of the extracts ranged from 1-71.9 microg/mL. The fresh extracts showed stronger activity than the dry ones. Since the plants showing the strongest antimalarial activity are very common in Central America, and some similar genera of these plants have shown positives results in South America, we considered important to present these findings for discussion. On the other hand, this is the first systematic study of this kind ever realized in a circumscribed and protected area of

  7. Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

    OpenAIRE

    Ma, Yufan; Lu, Tingli; Zhao, Wen; Wang, Ying(School of Physics, Shandong University, Jinan, 250100, PR China); Chen, Ting; Mei, Qibing; Chen, Tao

    2014-01-01

    Artemether and lumefantrine (also known as benflumetol) are difficult to formulate for parenteral administration because of their low aqueous solubility. Cremophor EL as an emulsion excipient has been shown to cause serious side effects. This study reports a method of preparation and the therapeutic efficacies of novel lipid emulsion (LE) delivery systems with artemether, lumefantrine, or artemether in combination with lumefantrine, for parenteral administration. Their physical and chemical s...

  8. High School Students Are a Target Group for Fight against Self-Medication with Antimalarial Drugs: A Pilot Study in University of Kinshasa, Democratic Republic of Congo.

    Science.gov (United States)

    Kabongo Kamitalu, Ramsès; Aloni, Michel Ntetani

    2016-01-01

    Aim. To assess the self-medication against malaria infection in population of Congolese students in Kinshasa, Democratic Republic of Congo (DRC). Methods. A cross-sectional study was carried out in University of Kinshasa, Kinshasa, Democratic Republic of Congo. Medical records of all students with malaria admitted to Centre de Santé Universitaire of University of Kinshasa from January 1, 2008, to April 30, 2008, were reviewed retrospectively. Results. The median age of the patients was 25.4 years (range: from 18 to 36 years). The majority of them were male (67.9%). Artemisinin-based combination treatments (ACTs) was the most used self-prescribed antimalarial drugs. However, self-medication was associated with the ingestion of quinine in 19.9% of cases. No case of ingestion of artesunate/artemether in monotherapy was found. All the medicines taken were registered in DRC. In this series, self-prescribed antimalarial was very irrational in terms of dose and duration of treatment. Conclusion. This paper highlights self-medication by a group who should be aware of malaria treatment protocols. The level of self-prescribing quinine is relatively high among students and is disturbing for a molecule reserved for severe disease in Congolese health care policy in management of malaria. PMID:27340411

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

    Institute of Scientific and Technical Information of China (English)

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

    2015-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Rath Srikanta

    2011-05-01

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

  12. Synthesis and evaluation of antimalarial activity of curcumin derivatives; Sintese e avaliacao da atividade antimalarica de compostos derivados da curcumina

    Energy Technology Data Exchange (ETDEWEB)

    Gomes, Patricia Ramos; Miguel, Fabio Balbino; Almeida, Mauro Vieira de; Couri, Mara Rubia Costa [Universidade Federal de Juiz de Fora (UFSJ), MG (Brazil). Instituto de Ciencias Exatas. Departamento de Quimica; Oliveira, Michael Eder de; Ferreira, Vanessa Viana; Guimaraes, Daniel Silqueira Martins; Lima, Aline Brito de; Barbosa, Camila de Souza; Oliveira, Mariana Amorim de; Almeida, Mauro Vieira de; Viana, Gustavo Henrique Ribeiro; Varotti, Fernando de Pilla, E-mail: varotti@ufsj.edu.br [Universidade Federal de Sao Joao Del Rei (UFSJ), MG (Brazil). Centro de Ciencias da Saude; and others

    2014-05-15

    ne of the main challenges in the development of new antimalarial drugs is to achieve a viable lead candidate with good pharmacokinetic properties. Curcumin has a broad range of biological activities, including antimalarial activity. Herein, we report the antimalarial activity of six curcumin derivatives (6-12) and an initial analysis of their pharmacokinetic properties. Five compounds have demonstrated potent activity against the P. falciparum in vitro (IC{sub 50} values ranging from 1.7 to 15.2 μg mL{sup -1}), with moderate or low cytotoxicity against the HeLa cell line. The substitution of the carbonyl group in 6 by a 2,4-dinitrophenylhydrazone group (to afford 11) increases the Selective Index. These preliminary results indicate curcumin derivatives as potential antimalarial compounds. (author)

  13. Efficacy of a preservative-free formulation of fixed-combination bimatoprost and timolol (Ganfort PF in treatment-naïve patients vs previously treated patients

    Directory of Open Access Journals (Sweden)

    Cordeiro MF

    2015-08-01

    Full Text Available M Francesca Cordeiro,1 Ivan Goldberg,2 Rhett Schiffman,3 Paula Bernstein,3 Marina Bejanian31Western Eye Hospital, Imperial College Healthcare NHS Trust, London, UK; 2Discipline of Ophthalmology, University of Sydney, Sydney, NSW, Australia; 3Allergan, Inc., Irvine, CA, USAPurpose: To evaluate, using subgroup analysis, the effect of treatment status on the intraocular pressure (IOP-lowering efficacy of a preservative-free formulation of fixed-combination bimatoprost 0.03%/timolol 0.5% (FCBT PF.Methods: A primary, multicenter, randomized, double-masked, 12-week study compared the efficacy and safety of FCBT PF with preserved FCBT (Ganfort® in 561 patients diagnosed with glaucoma or ocular hypertension. For this analysis, eligible patients were treatment-naïve or had inadequate IOP lowering and underwent a washout of previous treatment. IOP (8 am, 10 am, and 4 pm was measured at baseline and weeks 2, 6, and 12. Subgroup analysis of the FCBT PF arm assessed changes in average eye IOP from baseline in treatment-naïve vs previously treated patients. To evaluate the effect of treatment status at baseline (treatment-naïve vs previously treated on IOP reduction in the FCBT PF treatment group, an analysis of covariance model was used with treatment status and investigator as fixed effects, and baseline average eye IOP, age, glaucoma diagnosis, and baseline average eye corneal thickness as covariates. P-values and the 95% confidence intervals were determined using the model.Results: In the FCBT PF arm, IOP mean changes from baseline ranged from -8.7 mmHg to -9.8 mmHg in treatment-naïve patients (N=50, compared with -7.3 mmHg to -8.5 mmHg in previously treated patients (N=228. Baseline IOP, age, glaucoma diagnosis, and corneal thickness significantly affected IOP reduction in the FCBT PF group. Adjusting for these covariates, FCBT PF had a greater IOP-lowering effect (0.8–1.7 mmHg in treatment-naïve patients than previously treated patients

  14. Gel versus capillary electrophoresis genotyping for categorizing treatment outcomes in two anti-malarial trials in Uganda

    OpenAIRE

    Hubbard Alan E; Dorsey Grant; Gupta Vinay; Rosenthal Philip J; Greenhouse Bryan

    2010-01-01

    Abstract Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure) or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary elec...

  15. Evaluation of antimalarial activity of leaves of Acokanthera schimperi and Croton macrostachyus against Plasmodium berghei in Swiss albino mice

    OpenAIRE

    Mohammed, Tigist; Erko, Berhanu; Giday, Mirutse

    2014-01-01

    Background Malaria is one of the most important tropical diseases and the greatest cause of hospitalization and death. Recurring problems of drug resistance are reinforcing the need for finding new antimalarial drugs. In this respect, natural plant products are the main sources of biologically active compounds and have potential for the development of novel antimalarial drugs. A study was conducted to evaluate extracts of the leaves of Croton macrostachyus and Acokanthera schimperi for their ...

  16. Development of a Specific Monoclonal Antibody-Based ELISA to Measure the Artemether Content of Antimalarial Drugs

    OpenAIRE

    Suqin Guo; Yongliang Cui; Lishan He; Liang Zhang; Zhen Cao; Wei Zhang; Rui Zhang; Guiyu Tan; Baomin Wang; Liwang Cui

    2013-01-01

    Artemether is one of the artemisinin derivatives that are active ingredients in antimalarial drugs. Counterfeit and substandard antimalarial drugs have become a serious problem, which demands reliable analytical tools and implementation of strict regulation of drug quality. Structural similarity among artemisinin analogs is a challenge to develop immunoassays that are specific to artemisinin derivatives. To produce specific antibodies to artemether, we used microbial fermentation of artemethe...

  17. Antimalarial potential of homeopathic medicines against schizont maturation of Plasmodium berghei in short-term in vitro culture

    OpenAIRE

    Upma Bagai; Aswathy Rajan

    2012-01-01

    In vitro assessment of antimalarial drug susceptibility of Plasmodium has been a major research success, which has paved the way for the understanding of parasite and rapid screening of antimalarial drugs for their effectiveness. In the present study a preliminary screening to check the antiplasmodial activity of mother tincture (ϕ) and various potencies (6C, 30C, 200C) of homeopathic medicines Cinchona officinalis/china (Chin.), Chelidonium majus (Chel.) and Arsenicum album (Ars.) were done ...

  18. Audits of radiopharmaceutical formulations

    International Nuclear Information System (INIS)

    A procedure for auditing radiopharmaceutical formulations is described. To meet FDA guidelines regarding the quality of radiopharmaceuticals, institutional radioactive drug research committees perform audits when such drugs are formulated away from an institutional pharmacy. All principal investigators who formulate drugs outside institutional pharmacies must pass these audits before they can obtain a radiopharmaceutical investigation permit. The audit team meets with the individual who performs the formulation at the site of drug preparation to verify that drug formulations meet identity, strength, quality, and purity standards; are uniform and reproducible; and are sterile and pyrogen free. This team must contain an expert knowledgeable in the preparation of radioactive drugs; a radiopharmacist is the most qualified person for this role. Problems that have been identified by audits include lack of sterility and apyrogenicity testing, formulations that are open to the laboratory environment, failure to use pharmaceutical-grade chemicals, inadequate quality control methods or records, inadequate training of the person preparing the drug, and improper unit dose preparation. Investigational radiopharmaceutical formulations, including nonradiolabeled drugs, must be audited before they are administered to humans. A properly trained pharmacist should be a member of the audit team

  19. Audits of radiopharmaceutical formulations.

    Science.gov (United States)

    Castronovo, F P

    1992-03-01

    A procedure for auditing radiopharmaceutical formulations is described. To meet FDA guidelines regarding the quality of radiopharmaceuticals, institutional radioactive drug research committees perform audits when such drugs are formulated away from an institutional pharmacy. All principal investigators who formulate drugs outside institutional pharmacies must pass these audits before they can obtain a radiopharmaceutical investigation permit. The audit team meets with the individual who performs the formulation at the site of drug preparation to verify that drug formulations meet identity, strength, quality, and purity standards; are uniform and reproducible; and are sterile and pyrogen free. This team must contain an expert knowledgeable in the preparation of radioactive drugs; a radiopharmacist is the most qualified person for this role. Problems that have been identified by audits include lack of sterility and apyrogenicity testing, formulations that are open to the laboratory environment, failure to use pharmaceutical-grade chemicals, inadequate quality control methods or records, inadequate training of the person preparing the drug, and improper unit dose preparation. Investigational radiopharmaceutical formulations, including nonradiolabeled drugs, must be audited before they are administered to humans. A properly trained pharmacist should be a member of the audit team. PMID:1598931

  20. An exact approach for aggregated formulations

    DEFF Research Database (Denmark)

    Gamst, Mette; Spoorendonk, Simon; Røpke, Stefan

    Aggregating formulations is a powerful approach for problems to take on tractable forms. Aggregation may lead to loss of information, i.e. the aggregated formulation may be an approximation of the original problem. In branch-and-bound context, aggregation can also complicate branching, e.g. when...... optimality cannot be guaranteed by branching on aggregated variables. We present a generic exact solution method to remedy the drawbacks of aggregation. It combines the original and aggregated formulations and applies Benders' decomposition. We apply the method to the Split Delivery Vehicle Routing Problem....

  1. Stage-specific activity of potential antimalarial compounds measured in vitro by flow cytometry in comparison to optical microscopy and hypoxanthine uptake

    Directory of Open Access Journals (Sweden)

    Carmen E Contreras

    2004-03-01

    Full Text Available The evaluation of new antimalarial agents using older methods of monitoring sensitivity to antimalarial drugs are laborious and poorly suited to discriminate stage-specific activity. We used flow cytometry to study the effect of established antimalarial compounds, cysteine protease inhibitors, and a quinolone against asexual stages of Plasmodium falciparum. Cultured P. falciparum parasites were treated for 48 h with different drug concentrations and the parasitemia was determined by flow cytometry methods after DNA staining with propidium iodide. P. falciparum erythrocytic life cycle stages were readily distinguished by flow cytometry. Activities of established and new antimalarial compounds measured by flow cytometry were equivalent to results obtained with microscopy and metabolite uptake assays. The antimalarial activity of all compounds was higher against P. falciparum trophozoite stages. Advantages of flow cytometry analysis over traditional assays included higher throughput for data collection, insight into the stage-specificity of antimalarial activity avoiding use of radioactive isotopes.

  2. Assessment of strategy formulation

    DEFF Research Database (Denmark)

    Acur, Nuran; Englyst, Linda

    2006-01-01

    Purpose – Today, industrial firms need to cope with competitive challenges related to innovation, dynamic responses, knowledge sharing, etc. by means of effective and dynamic strategy formulation. In light of these challenges, the purpose of the paper is to present and evaluate an assessment tool...... for strategy formulation processes that ensures high quality in process and outcome. Design/methodology/approach – A literature review was conducted to identify success criteria for strategy formulation processes. Then, a simple questionnaire and assessment tool was developed and used to test the...... three generic approaches to strategy assessment, namely the goal-centred, comparative and improvement approaches, as found in the literature. Furthermore, it encompasses three phases of strategy formulation processes: strategic thinking, strategic planning and embedding of strategy. The tool reflects...

  3. Preparation of radiopharmaceutical formulations

    International Nuclear Information System (INIS)

    Radiopharmaceutical formulations for complexes comprising at least one radionuclide complexed with a ligand, or its physiologically-acceptable salts thereof, especially 153samarium-ethylenediaminetetramethylenephosphonic acid, which optionally contains a divalent metal ion, e.g. calcium, and is frozen, thawed, and then administered by injection. Alternatively, the radiopharmaceutical formulations must contain the divalent metal and are frozen only if the time before administration is sufficiently long to cause concern for radiolysis of the ligand. 2 figs., 9 tabs

  4. CPP-ZFN: A potential DNA-targeting anti-malarial drug

    Directory of Open Access Journals (Sweden)

    Nain Vikrant

    2010-09-01

    Full Text Available Abstract Background Multidrug-resistant Plasmodium is of major concern today. Effective vaccines or successful applications of RNAi-based strategies for the treatment of malaria are currently unavailable. An unexplored area in the field of malaria research is the development of DNA-targeting drugs that can specifically interact with parasitic DNA and introduce deleterious changes, leading to loss of vital genome function and parasite death. Presentation of the hypothesis Advances in the development of zinc finger nuclease (ZFN with engineered DNA recognition domains allow us to design and develop nuclease of high target sequence specificity with a mega recognition site that typically occurs only once in the genome. Moreover, cell-penetrating peptides (CPP can cross the cell plasma membrane and deliver conjugated protein, nucleic acid, or any other cargo to the cytoplasm, nucleus, or mitochondria. This article proposes that a drug from the combination of the CPP and ZFN systems can effectively enter the intracellular parasite, introduce deleterious changes in its genome, and eliminate the parasite from the infected cells. Testing the hypothesis Availability of a DNA-binding motif for more than 45 triplets and its modular nature, with freedom to change number of fingers in a ZFN, makes development of customized ZFN against diverse target DNA sequence of any gene feasible. Since the Plasmodium genome is highly AT rich, there is considerable sequence site diversity even for the structurally and functionally conserved enzymes between Plasmodium and humans. CPP can be used to deliver ZFN to the intracellular nucleus of the parasite. Signal-peptide-based heterologous protein translocation to Plasmodium-infected RBCs (iRBCs and different Plasmodium organelles have been achieved. With successful fusion of CPP with mitochondrial- and nuclear-targeting peptides, fusion of CPP with 1 more Plasmodium cell membrane translocation peptide seems achievable

  5. Screening of the antimalarial activity of plants of the Cucurbitaceae family

    Directory of Open Access Journals (Sweden)

    Cláudia Zuany Amorim

    1991-01-01

    Full Text Available Crude ethanolic extracts (CEEs from two species of Cucurbitaceae, Cucurbita maxima and Momordica charantia (commonly called "abóbora moranga" and melão de São Caetano", respectively were assayed for antimalarial activity by the 4-d suppressive test. The CEE of dry C. maxima seeds showed strong antimalarial activity following oral administration (259 and 500 mg/kg, reducing by 50% the levels of parasistemia in Plasmodium berghey-infected mice. Treatment of normal animals with 500 mg/Kg of the extract three days before intravenous injection of P. berghei caused a significant 30% reduction in parasitemic levels. No effect was observed when the animals were treated with the CEE only on the day of inoculation. Oral administration of the CEE of dry M. charantia leaves adminstered orally was ineffective up to 500 mg/Kg in lowering the parasitemic levels of malarious mice.

  6. A novel multiple-stage antimalarial agent that inhibits protein synthesis

    Science.gov (United States)

    Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus C. S.; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana J.; Pradhan, Anupam; Porzelle, Achim; Martínez, María Santos; Bolscher, Judith M.; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Jiménez-Díaz, María Belén; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M.; Sauerwein, Robert W; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Iñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, Peter; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon; Fairlamb, Alan H.; Willis, Paul; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.

    2015-01-01

    Summary There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. We describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the parasite, with good pharmacokinetic properties, and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery. PMID:26085270

  7. Saleability of anti-malarials in private drug shops in Muheza, Tanzania

    DEFF Research Database (Denmark)

    Ringsted, Frank M; Massawe, Isolide S; Lemnge, Martha M;

    2011-01-01

    women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform a...... baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. Methods: All drug shops selling...... resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp strategy. Further studies are recommended to find out barriers for ACT utilization and preference for self-medication and to train private drug...

  8. A novel multiple-stage antimalarial agent that inhibits protein synthesis

    Science.gov (United States)

    Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus C. S.; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana J.; Pradhan, Anupam; Porzelle, Achim; Martínez, María Santos; Bolscher, Judith M.; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Jiménez-Díaz, María Belén; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M.; Sauerwein, Robert W.; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Iñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, Peter; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth A.; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon; Fairlamb, Alan H.; Willis, Paul A.; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.

    2015-06-01

    There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

  9. Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype.

    Science.gov (United States)

    Santos, Sofia A; Lukens, Amanda K; Coelho, Lis; Nogueira, Fátima; Wirth, Dyann F; Mazitschek, Ralph; Moreira, Rui; Paulo, Alexandra

    2015-09-18

    A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight compounds were obtained following a three-step synthetic approach and evaluated for anti-parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-resistant and sensitive strains (EC50 values ∼ 3 μM), selectivity for malaria parasite and no cross-resistance with chloroquine, thus representing a potential new chemotype for further optimization towards novel and affordable antimalarial drugs. PMID:26295174

  10. Detection of In Vitro Antimalarial Activity of Some Myanmar Medicinal Plants

    International Nuclear Information System (INIS)

    In order to find out the novel effective antimalarials. six medicinal plants, namely Erythrina stricta Roxb. (Kathit), Luffa acutangula Roxb. (Thabut - Kja), Cordia rothii Roem. and Schult. (Thanet), Tribulus terrestris Linn. (Sule). Zizphus oenoplia Mill. (Paung - pe) and Mimusops elengi Roxb. (Khaye) were selected and tested for their antimalarial activity by using in vitro microdilution technique. According to the in vitro test results, Erythrina stricta Roxb. (Kathit) was found to possess significant suppressive effect on Plasmodium falciparum. With the serially diluted extract dosage concentrations ranging from 1.250 ng/ml to 40,000 ng/ml, the schizont suppressive percentage of Eryhrina stricta Roxb. (Kathi) was observed to be 19.57%, 35.44%, 55.18%, 96.04%,100% and 100% respectively

  11. 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.

  12. Hallazgos complementarios sobre la actividad antimalarica del azul de metileno = Complementary findings on the antimalarial activity and toxicity of methylene blue

    OpenAIRE

    G. Garavito; Bertani, S; Deharo, Eric

    2008-01-01

    Methylene blue was reported as the first synthetic antimalarial by Ehrlich in 1881. It is currently no longer used for that purpose but it should be reconsidered since new economic alternatives are urgently needed in the arsenal of antimalarial drugs. The antimalarial activity of methylene blue is investigated here in vivo against rodent malaria parasites. 15 mg/kg daily dose of methylene blue inhibits 50% of the erythrocytic parasite growth of Plasmodium berghei and R yoelii nigeriensis, whi...

  13. Effect of Disposition of Mannich Antimalarial Agents on Their Pharmacology and Toxicology

    OpenAIRE

    Ruscoe, J. E.; Tingle, M. D.; O’Neill, P. M.; S.A. Ward; Park, B K

    1998-01-01

    The use of the antimalarial agent amodiaquine has been curtailed due to drug-induced idiosyncratic reactions. These have been attributed to the formation of a protein-reactive quinoneimine species via oxidation of the 4-aminophenol group. Therefore, the effects of chemical modifications on the disposition of amodiaquine in relation to its metabolism, distribution, and pharmacological activity have been investigated. The inclusion of a group at the C-5′ position of amodiaquine reduced or elimi...

  14. Novel Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Anti-malarial Activity in the Mouse Model*

    OpenAIRE

    Booker, Michael L.; Bastos, Cecilia M.; Kramer, Martin L.; Barker, Robert H.; Skerlj, Renato; Sidhu, Amar Bir; Deng, Xiaoyi; Celatka, Cassandra; Cortese, Joseph F.; Guerrero Bravo, Jose E.; Crespo Llado, Keila N.; Serrano, Adelfa E.; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Viera, Sara

    2010-01-01

    Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low ...

  15. Preliminary assessment of medicinal plants used as antimalarials in the southeastern Venezuelan Amazon

    Directory of Open Access Journals (Sweden)

    Caraballo Alejandro

    2004-01-01

    Full Text Available Eighteen species of medicinal plants used in the treatment of malaria in Bolívar State, Venezuela were recorded and they belonged to Compositae, Meliaceae, Anacardiaceae, Bixaceae, Boraginaceae, Caricaceae, Cucurbitaceae, Euphorbiaceae, Leguminosae, Myrtaceae, Phytolaccaceae, Plantaginaceae, Scrophulariaceae, Solanaceae and Verbenaceae families. Antimalarial plant activities have been linked to a range of compounds including anthroquinones, berberine, flavonoids, limonoids, naphthquinones, sesquiterpenes, quassinoids, indol and quinoline alkaloids.

  16. Medicines informal market in Congo, Burundi and Angola: counterfeit and sub-standard antimalarials

    OpenAIRE

    Bertocchi Paola; Antoniella Eleonora; Cocchieri Emilia; Di Maggio Anna; Gaudiano Maria; Alimonti Stefano; Valvo Luisa

    2007-01-01

    Abstract Background The presence of counterfeits and sub-standards in African medicines market is a dramatic problem that causes many deaths each year. The increase of the phenomenon of pharmaceutical counterfeiting is due to the rise of the illegal market and to the impossibility to purchase branded high cost medicines. Methods In this paper the results of a quality control on antimalarial tablet samples purchased in the informal market in Congo, Burundi and Angola are reported. The quality ...

  17. Antimalarial Chemotherapy: Natural Product Inspired Development of Preclinical and Clinical Candidates with Diverse Mechanisms of Action.

    Science.gov (United States)

    Fernández-Álvaro, Elena; Hong, W David; Nixon, Gemma L; O'Neill, Paul M; Calderón, Félix

    2016-06-23

    Natural products have played a pivotal role in malaria chemotherapy progressing from quinine and artemisinin to ozonide-based compounds. Many of these natural products have served as template for the design and development of antimalarial drugs currently in the clinic or in the development phase. In this review, we will detail those privileged scaffolds that have guided medicinal chemistry efforts yielding molecules that have reached the clinic. PMID:26791529

  18. 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...

  19. A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya.

    Directory of Open Access Journals (Sweden)

    Jason P Wendler

    Full Text Available BACKGROUND: Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. METHODS AND PRINCIPAL FINDINGS: Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. CONCLUSIONS/SIGNIFICANCE: Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.

  20. Anti-malarial drugs and the prevention of malaria in the population of malaria endemic areas

    OpenAIRE

    Greenwood Brian

    2010-01-01

    Abstract Anti-malarial drugs can make a significant contribution to the control of malaria in endemic areas when used for prevention as well as for treatment. Chemoprophylaxis is effective in preventing deaths and morbidity from malaria, but it is difficult to sustain for prolonged periods, may interfere with the development of naturally acquired immunity and will facilitate the emergence and spread of drug resistant strains if applied to a whole community. However, chemoprophylaxis targeted ...

  1. Synthesis and in vitro antimalarial activity of novel chalcone derivatives / Frans Johannes Smit

    OpenAIRE

    Smit, Frans Johannes

    2014-01-01

    Malaria is endemic in 106 countries worldwide. This disease is caused by a parasite from the genus Plasmodium. Of the five species that infect humans, Plasmodium falciparum is the most virulent, with over three billion people at risk and around 660 000 deaths reported in 2011. Of these deaths, 91% were in the African region, while 86% were children under the age of five. In light of the widespread development of resistance by malaria parasites against the classic antimalarial drugs, such as c...

  2. Amazonian plant natural products:perspectives for discovery of new antimalarial drug leads

    OpenAIRE

    Lucio H Freitas-Junior; Pedro Cravo; Marcus Vinícius Guimarães Lacerda; André Machado Siqueira; Carolina Borsoi Moraes; Gina Frausin; Luiz Francisco Rocha e Silva; Stefanie Costa Pinto Lopes; Renata Braga Souza Lima; Fabio Trindade Maranhão Costa; Adrian Martin Pohlit

    2013-01-01

    Plasmodium falciparum and P. vivax malaria parasites are now resistant, or showing signs of resistance, to most drugs used in therapy. Novel chemical entities that exhibit new mechanisms of antiplasmodial action are needed. New antimalarials that block transmission of Plasmodium spp. from humans to Anopheles mosquito vectors are key to malaria eradication efforts. Although P. vivax causes a considerable number of malaria cases, its importance has for long been neglected. Vivax malaria can cau...

  3. ANTIMALARIAL DRUGS IN THERAPY OF SYSTEMIC LUPUS ERYTHEMATOSUS: PAST, PRESENT, FUTURE

    OpenAIRE

    Tatyana Andreyevna Lisitsyna; N. M. Kosheleva

    2010-01-01

    The data available in the literature on experience in using antimalarial drugs in the treatment of systemic lupus erythematosus are summarized. A major emphasis is placed on therapy with hydroxychlorochine (plaquenil) versus chlorine. Possible mechanisms of action of the drug and its effect on the course of the disease itself and concomitant abnormalities are described. Data on the toxicity of the drug and its safe use in pregnancy and lactation are also discussed

  4. ANTIMALARIAL DRUGS IN THERAPY OF SYSTEMIC LUPUS ERYTHEMATOSUS: PAST, PRESENT, FUTURE

    Directory of Open Access Journals (Sweden)

    Tatyana Andreyevna Lisitsyna

    2010-01-01

    Full Text Available The data available in the literature on experience in using antimalarial drugs in the treatment of systemic lupus erythematosus are summarized. A major emphasis is placed on therapy with hydroxychlorochine (plaquenil versus chlorine. Possible mechanisms of action of the drug and its effect on the course of the disease itself and concomitant abnormalities are described. Data on the toxicity of the drug and its safe use in pregnancy and lactation are also discussed

  5. Serine Proteases of Malaria Parasite Plasmodium falciparum: Potential as Antimalarial Drug Targets

    OpenAIRE

    Asrar Alam

    2014-01-01

    Malaria is a major global parasitic disease and a cause of enormous mortality and morbidity. Widespread drug resistance against currently available antimalarials warrants the identification of novel drug targets and development of new drugs. Malarial proteases are a group of molecules that serve as potential drug targets because of their essentiality for parasite life cycle stages and feasibility of designing specific inhibitors against them. Proteases belonging to various mechanistic classes...

  6. 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

  7. Altered plasmodial surface anion channel activity and in vitro resistance to permeating antimalarial compounds

    OpenAIRE

    Lisk, Godfrey; Pain, Margaret; Sellers, Morgan; Gurnev, Philip A.; Pillai, Ajay D.; Bezrukov, Sergey M.; Desai, Sanjay A.

    2010-01-01

    Erythrocytes infected with malaria parasites have increased permeability to various solutes. These changes may be mediated by an unusual small conductance ion channel known as the plasmodial surface anion channel (PSAC). While channel activity benefits the parasite by permitting nutrient acquisition, it can also be detrimental because water-soluble antimalarials may more readily access their parasite targets via this channel. Recently, two such toxins, blasticidin S and leupeptin, were used t...

  8. Natural polyhydroxyalkanoate–gold nanocomposite based biosensor for detection of antimalarial drug artemisinin

    International Nuclear Information System (INIS)

    The worrisome trend of antimalarial resistance has already highlighted the importance of artemisinin as a potent antimalarial agent. The current investigation aimed at fabricating a biosensor based on natural polymer polyhydroxyalkanoate–gold nanoparticle composite mounting on an indium-tin oxide glass plate for the analysis of artemisinin. The biosensor was fabricated using an adsorbing horse-radish peroxidase enzyme on the electrode surface for which cyclic voltammetry was used to monitor the electro-catalytic reduction of artemisinin under diffusion controlled conditions. Electrochemical interfacial properties and immobilization of enzyme onto a polyhydroxyalkanoate–gold nanoparticle film were evaluated, and confirmed by cyclic voltammetry, electrochemical impedance spectroscopy and scanning electron microscopy. The differential pulse voltammetric peak current for artemisinin was increased linearly (concentration range of 0.01–0.08 μg mL−1) with sensitivity of 0.26 μA μg mL−1. The greater sensitivity of the fabricated biosensor to artemisinin (optimum limits of detection were 0.0035 μg mL−1 and 0.0036 μg mL−1 in bulk and spiked human serum, respectively) could be of much aid in medical diagnosis. - Highlights: • Extraction of PHA from indigenously isolated Pseudomonas aeruginosa BPC2 • Developed PHA/AuNPs/HRP/ITO based biosensor without the use of chemical cross linker • Detection of antimalarial drug artemisinin using the nanocomposite based biosensor

  9. Safety, Tolerability, and Compliance with Long-Term Antimalarial Chemoprophylaxis in American Soldiers in Afghanistan.

    Science.gov (United States)

    Saunders, David L; Garges, Eric; Manning, Jessica E; Bennett, Kent; Schaffer, Sarah; Kosmowski, Andrew J; Magill, Alan J

    2015-09-01

    Long-term antimalarial chemoprophylaxis is currently used by deployed U.S. military personnel. Previous small, short-term efficacy studies have shown variable rates of side effects among patients taking various forms of chemoprophylaxis, though reliable safety and tolerability data on long-term use are limited. We conducted a survey of troops returning to Fort Drum, NY following a 12-month deployment to Operation Enduring Freedom, Afghanistan from 2006 to 2007. Of the 2,351 respondents, 95% reported taking at least one form of prophylaxis during their deployment, and 90% were deployed for > 10 months. Compliance with daily doxycycline was poor (60%) compared with 80% with weekly mefloquine (MQ). Adverse events (AEs) were reported by approximately 30% with both MQ and doxycycline, with 10% discontinuing doxycycline compared with 4% of MQ users. Only 6% and 31% of soldiers reported use of bed nets and skin repellents, respectively. Compliance with long-term malaria prophylaxis was poor, and there were substantial tolerability issues based on these anonymous survey results, though fewer with MQ than doxycycline. Given few long-term antimalarial chemoprophylaxis options, there is an unmet medical need for new antimalarials safe for long-term use. PMID:26123954

  10. Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum

    Science.gov (United States)

    Vaidya, Akhil B.; Morrisey, Joanne M.; Zhang, Zhongsheng; Das, Sudipta; Daly, Thomas M.; Otto, Thomas D.; Spillman, Natalie J.; Wyvratt, Matthew; Siegl, Peter; Marfurt, Jutta; Wirjanata, Grennady; Sebayang, Boni F.; Price, Ric N.; Chatterjee, Arnab; Nagle, Advait; Stasiak, Marcin; Charman, Susan A.; Angulo-Barturen, Iñigo; Ferrer, Santiago; Belén Jiménez-Díaz, María; Martínez, María Santos; Gamo, Francisco Javier; Avery, Vicky M.; Ruecker, Andrea; Delves, Michael; Kirk, Kiaran; Berriman, Matthew; Kortagere, Sandhya; Burrows, Jeremy; Fan, Erkang; Bergman, Lawrence W.

    2014-01-01

    The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na+ regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na+ homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na+ homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes. PMID:25422853

  11. Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum.

    Science.gov (United States)

    Vaidya, Akhil B; Morrisey, Joanne M; Zhang, Zhongsheng; Das, Sudipta; Daly, Thomas M; Otto, Thomas D; Spillman, Natalie J; Wyvratt, Matthew; Siegl, Peter; Marfurt, Jutta; Wirjanata, Grennady; Sebayang, Boni F; Price, Ric N; Chatterjee, Arnab; Nagle, Advait; Stasiak, Marcin; Charman, Susan A; Angulo-Barturen, Iñigo; Ferrer, Santiago; Belén Jiménez-Díaz, María; Martínez, María Santos; Gamo, Francisco Javier; Avery, Vicky M; Ruecker, Andrea; Delves, Michael; Kirk, Kiaran; Berriman, Matthew; Kortagere, Sandhya; Burrows, Jeremy; Fan, Erkang; Bergman, Lawrence W

    2014-01-01

    The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes. PMID:25422853

  12. Metabolic Dysregulation Induced in Plasmodium falciparum by Dihydroartemisinin and Other Front-Line Antimalarial Drugs.

    Science.gov (United States)

    Cobbold, Simon A; Chua, Hwa H; Nijagal, Brunda; Creek, Darren J; Ralph, Stuart A; McConville, Malcolm J

    2016-01-15

    Detailed information on the mode of action of antimalarial drugs can be used to improve existing drugs, identify new drug targets, and understand the basis of drug resistance. In this study we describe the use of a time-resolved, mass spectrometry (MS)-based metabolite profiling approach to map the metabolic perturbations induced by a panel of clinical antimalarial drugs and inhibitors on Plasmodium falciparum asexual blood stages. Drug-induced changes in metabolite levels in P. falciparum-infected erythrocytes were monitored over time using gas chromatography-MS and liquid chromatography-MS and changes in specific metabolic fluxes confirmed by nonstationary [(13)C]-glucose labeling. Dihydroartemisinin (DHA) was found to disrupt hemoglobin catabolism within 1 hour of exposure, resulting in a transient decrease in hemoglobin-derived peptides. Unexpectedly, it also disrupted pyrimidine biosynthesis, resulting in increased [(13)C]-glucose flux toward malate production, potentially explaining the susceptibility of P. falciparum to DHA during early blood-stage development. Unique metabolic signatures were also found for atovaquone, chloroquine, proguanil, cycloguanil and methylene blue. We also show that this approach can be used to identify the mode of action of novel antimalarials, such as the compound Torin 2, which inhibits hemoglobin catabolism. PMID:26150544

  13. Natural polyhydroxyalkanoate–gold nanocomposite based biosensor for detection of antimalarial drug artemisinin

    Energy Technology Data Exchange (ETDEWEB)

    Phukon, Pinkee [Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784028, Assam (India); Radhapyari, Keisham [Analytical Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam (India); Konwar, Bolin Kumar [Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784028, Assam (India); Nagaland University (Central), Lumami, Zunheboto, Nagaland 798627 (India); Khan, Raju, E-mail: khan.raju@gmail.com [Analytical Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam (India)

    2014-04-01

    The worrisome trend of antimalarial resistance has already highlighted the importance of artemisinin as a potent antimalarial agent. The current investigation aimed at fabricating a biosensor based on natural polymer polyhydroxyalkanoate–gold nanoparticle composite mounting on an indium-tin oxide glass plate for the analysis of artemisinin. The biosensor was fabricated using an adsorbing horse-radish peroxidase enzyme on the electrode surface for which cyclic voltammetry was used to monitor the electro-catalytic reduction of artemisinin under diffusion controlled conditions. Electrochemical interfacial properties and immobilization of enzyme onto a polyhydroxyalkanoate–gold nanoparticle film were evaluated, and confirmed by cyclic voltammetry, electrochemical impedance spectroscopy and scanning electron microscopy. The differential pulse voltammetric peak current for artemisinin was increased linearly (concentration range of 0.01–0.08 μg mL{sup −1}) with sensitivity of 0.26 μA μg mL{sup −1}. The greater sensitivity of the fabricated biosensor to artemisinin (optimum limits of detection were 0.0035 μg mL{sup −1} and 0.0036 μg mL{sup −1} in bulk and spiked human serum, respectively) could be of much aid in medical diagnosis. - Highlights: • Extraction of PHA from indigenously isolated Pseudomonas aeruginosa BPC2 • Developed PHA/AuNPs/HRP/ITO based biosensor without the use of chemical cross linker • Detection of antimalarial drug artemisinin using the nanocomposite based biosensor.

  14. EVALUATION OF NEPETA LEAVIGATA, NEPETA KURRAMENSIS AND RHYNCHOSIA RENIFORMIS ON ANTIMALARIAL AND ANTILEISHMANIAL ACTIVITIES

    Directory of Open Access Journals (Sweden)

    Memoona A, Amir MK, Sultan A, Razia P, Sumera P, Lal M, Nisar Ahmed*

    2012-10-01

    Full Text Available The pharmacological investigation of methanolic extracts and different fractions of the Nepeta leavigata, Nepeta kurramensis and Rhynchosia reniformis were designed to assess the antimalarial and antileishmanial screening of medicinal plants for development of drugs. Materials and Methods: The shade-dried whole plant material of Nepeta leavigata was soaked in methanol for 10 days. The powdered drug was extracted with 80 % methanol three times and filtered at room temperature. The filtrate was evaporated in rotary to get a dark-greenish residue (extract, which was further suspended in water and partitioned successively with n-hexane, chloroform, ethyl acetate and n-butanol to obtain n-hexane-soluble, chloroform-soluble, ethyl acetate-soluble, n-butanol-soluble and aqueous fractions, respectively (Khan, et al., 2010a. Same extraction and fractionation procedure was adopted for Nepeta kurramensis and Rhynchosia reniformis. The antimalarial / antileishmanial activity of crude extracts/fractions was determined through standard protocol (Kerharo & Adam, 1974/. Results: The crude extract, chloroform fraction of Nepeta leavigata and fractions chloroform and ethyl acetate of Nepeta kurramensis showed promising antileishmanial and antimalarial activity against parasites of leishmania and malaria (promistogetes and schizonts by observing 1 or 0 number of parasites on slide field where ≤ 1 level is significant, while all fractions of Rhynchosia reniformis did not showed any action against promistigotes and schizonts. Conclusions: The bioassays guided isolation and phytochemical screening of active fractions against these activities will further enhance research in the field of pharmacology.

  15. Natural and Semi synthetic Antimalarial Compounds: Emphasis on the Terpene Class.

    Science.gov (United States)

    Silva, G N S; Rezende, L C D; Emery, F S; Gosmann, G; Gnoatto, S C B

    2015-01-01

    Malaria is one of the most important tropical diseases since more than 40% of the world population is at risk. This disease is endemic to more than 100 nations and remains one of the main leading causes of death in children less than five years of age worldwide. Natural product-derived compounds have played a major role in drug discovery, often as prototypes to obtain more active semi synthetic derivatives. Antimalarial pharmacotherapy is a significant example of plant-derived medicines, such as quinine and artemisinin. This review highlights studies on terpenes and their semi synthetic derivatives from natural sources with antimalarial activity reported in the literature during eleven years (2002-2013). A total of 114 compounds are found among terpenes and their semi synthetic derivatives. Cytotoxicity of the compounds is also found in this review. Furthermore, the physicochemical properties of the terpenes addressed are discussed based on seven well established descriptors, which provide a useful source for the elaboration of a terpene library of antimalarial compounds. PMID:25553426

  16. A generalized anisotropic deformation formulation for geomaterials

    Science.gov (United States)

    Lei, Z.; Rougier, Esteban; Knight, E. E.; Munjiza, A.; Viswanathan, H.

    2016-04-01

    In this paper, the combined finite-discrete element method (FDEM) has been applied to analyze the deformation of anisotropic geomaterials. In the most general case geomaterials are both non-homogeneous and non-isotropic. With the aim of addressing anisotropic material problems, improved 2D FDEM formulations have been developed. These formulations feature the unified hypo-hyper elastic approach combined with a multiplicative decomposition-based selective integration for volumetric and shear deformation modes. This approach is significantly different from the co-rotational formulations typically encountered in finite element codes. Unlike the co-rotational formulation, the multiplicative decomposition-based formulation naturally decomposes deformation into translation, rotation, plastic stretches, elastic stretches, volumetric stretches, shear stretches, etc. This approach can be implemented for a whole family of finite elements from solids to shells and membranes. This novel 2D FDEM based material formulation was designed in such a way that the anisotropic properties of the solid can be specified in a cell by cell basis, therefore enabling the user to seed these anisotropic properties following any type of spatial variation, for example, following a curvilinear path. In addition, due to the selective integration, there are no problems with volumetric or shear locking with any type of finite element employed.

  17. Parenteral formulation of zopiclone

    Directory of Open Access Journals (Sweden)

    Swamy P

    2008-01-01

    Full Text Available The present study was undertaken with an intention to develop a stable and effective parenteral formulation, containing the drug zopiclone. Since zopiclone is a water insoluble drug, various methods such as co-solvency, pH control and hydrotrophy have been tried in order to enhance its solubility. When all these methods could not give adequate solubility enhancement of the drug, a hydrochloride salt was prepared, and it was found to be thermostable. Various batches of zopiclone hydrochloride injection formulation were prepared in order to assess the influence of light, atmospheric oxygen and antioxidant on the stability of the drug and the formulations were also subjected to accelerated stability testing in order to predict approximate shelf-life of the product.

  18. Granulated decontamination formulations

    Science.gov (United States)

    Tucker, Mark D.

    2007-10-02

    A decontamination formulation and method of making that neutralizes the adverse health effects of both chemical and biological compounds, especially chemical warfare (CW) and biological warfare (BW) agents, and toxic industrial chemicals. The formulation provides solubilizing compounds that serve to effectively render the chemical and biological compounds, particularly CW and BW compounds, susceptible to attack, and at least one reactive compound that serves to attack (and detoxify or kill) the compound. The formulation includes at least one solubilizing agent, a reactive compound, a sorbent additive, and water. A highly adsorbent sorbent additive (e.g., amorphous silica, sorbitol, mannitol, etc.) is used to "dry out" one or more liquid ingredients into a dry, free-flowing powder that has an extended shelf life, and is more convenient to handle and mix in the field.

  19. A review of age-old antimalarial drug to combat malaria:efficacy upgradation by nanotechnology based drug delivery

    Institute of Scientific and Technical Information of China (English)

    Satyajit; Tripathy; Somenath; Roy

    2014-01-01

    Malaria is uncontrolled burden in the world till now.Despite of different efforts to develop antimalarial drug for decades,any anti-malarial drug can able to eradicate completely till now.Many anti-malarial substances are practically ineffectual because of their physicochemical limitations,cytotoxicity,chemical instability and degradation,and limited activities against intracellular parasites.Taking into consideration,the amount of research is going to conduct in the field of nanoparticle based drug delivery systems,lead to new ways of improving the treatment of infectious diseases.The study has focused on the progress and advancement of research on nanotechnology based drug delivery to eradicate the malaria.We like to focus the efficacy of nanotechnology based drug application for the opening out of novel chemotherapeutics in laboratory research,which may show the way to better use with age-old antimalarial drug and may draw the attention of pharmaceutical industries for the improvement and designing of effective anti-malarial drugs in future.

  20. Closing the access barrier for effective anti-malarials in the private sector in rural Uganda: consortium for ACT private sector subsidy (CAPSS pilot study

    Directory of Open Access Journals (Sweden)

    Talisuna Ambrose O

    2012-10-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT, the treatment of choice for uncomplicated falciparum malaria, is unaffordable and generally inaccessible in the private sector, the first port of call for most malaria treatment across rural Africa. Between August 2007 and May 2010, the Uganda Ministry of Health and the Medicines for Malaria Venture conducted the Consortium for ACT Private Sector Subsidy (CAPSS pilot study to test whether access to ACT in the private sector could be improved through the provision of a high level supply chain subsidy. Methods Four intervention districts were purposefully selected to receive branded subsidized medicines - “ACT with a leaf”, while the fifth district acted as the control. Baseline and evaluation outlet exit surveys and retail audits were conducted at licensed and unlicensed drug outlets in the intervention and control districts. A survey-adjusted, multivariate logistic regression model was used to analyse the intervention’s impact on: ACT uptake and price; purchase of ACT within 24 hours of symptom onset; ACT availability and displacement of sub-optimal anti-malarial. Results At baseline, ACT accounted for less than 1% of anti-malarials purchased from licensed drug shops for children less than five years old. However, at evaluation, “ACT with a leaf” accounted for 69% of anti-malarial purchased in the interventions districts. Purchase of ACT within 24 hours of symptom onset for children under five years rose from 0.8% at baseline to 26.2% (95% CI: 23.2-29.2% at evaluation in the intervention districts. In the control district, it rose modestly from 1.8% to 5.6% (95% CI: 4.0-7.3%. The odds of purchasing ACT within 24 hours in the intervention districts compared to the control was 0.46 (95% CI: 0.08-2.68, p=0.4 at baseline and significant increased to 6.11 (95% CI: 4.32-8.62, p Conclusions These data demonstrate that a supply-side subsidy and an intensive communications campaign

  1. Algebraic formulation of duality

    International Nuclear Information System (INIS)

    Two dimensional lattice spin (chiral) models over (possibly non-abelian) compact groups are formulated in terms of a generalized Pauli algebra. Such models over cyclic groups are written in terms of the generalized Clifford algebra. An automorphism of this algebra is shown to exist and to lead to the duality transformation

  2. Deciphering the Late Biosynthetic Steps of Antimalarial Compound FR-900098

    OpenAIRE

    Johannes, Tyler W.; DeSieno, Matthew A.; Griffin, Benjamin M.; Thomas, Paul M.; Kelleher, Neil L.; Metcalf, William W.; Zhao, Huimin

    2010-01-01

    FR-900098 is a potent chemotherapeutic agent for the treatment of malaria. Here we report the heterologous production of this compound in E. coli by re-constructing the entire biosynthetic pathway using a three plasmid system. Based on this system, whole cell feeding assays in combination with in vitro enzymatic activity assays reveal an unprecedented functional role of nucleotide conjugation and lead to the complete elucidation of the previously unassigned late biosynthetic steps. These stud...

  3. In vitro solubility, dissolution and permeability studies combined with semi-mechanistic modeling to investigate the intestinal absorption of desvenlafaxine from an immediate- and extended release formulation

    DEFF Research Database (Denmark)

    Franek, F; Jarlfors, A; Larsen, F.;

    2015-01-01

    pH down the small intestine. Consequently, desvenlafaxine absorption from an IRF appears rate-limited by low Peff in the upper small intestine, which “delays” the predicted time to the maximal plasma concentration (tmax), consistent with clinical data. Conversely, desvenlafaxine absorption from the...... ERF appears rate-limited by dissolution due to the formulation, which tends to negate the influence of pH-dependent permeability on absorption. We suggest that desvenlafaxine Peff is mainly driven by transcellular diffusion of the unionized form. In the case of desvenlafaxine, poor metabolism does not...

  4. CRIMALDDI: a co-ordinated, rational, and integrated effort to set logical priorities in anti-malarial drug discovery initiatives

    Directory of Open Access Journals (Sweden)

    Doerig Christian

    2010-07-01

    Full Text Available Abstract Despite increasing efforts and support for anti-malarial drug R&D, globally anti-malarial drug discovery and development remains largely uncoordinated and fragmented. The current window of opportunity for large scale funding of R&D into malaria is likely to narrow in the coming decade due to a contraction in available resources caused by the current economic difficulties and new priorities (e.g. climate change. It is, therefore, essential that stakeholders are given well-articulated action plans and priorities to guide judgments on where resources can be best targeted. The CRIMALDDI Consortium (a European Union funded initiative has been set up to develop, through a process of stakeholder and expert consultations, such priorities and recommendations to address them. It is hoped that the recommendations will help to guide the priorities of the European anti-malarial research as well as the wider global discovery agenda in the coming decade.

  5. In vitro antimalarial activity and cytotoxicity of cochlospermum tinctorium and C. planchonii leaf extracts and essential oils.

    Science.gov (United States)

    Benoit-Vical, F; Valentin, A; Mallié, M; Bastide, J M; Bessière, J M

    1999-05-01

    The antimalarial and toxicological properties of Cochlospermum tinctorium and C. planchonii extracts and essential oils prepared from their leaves were studied. The oil components were extracted by hydrodistillation of the plant leaves and characterized by gas chromatography and mass spectrometry. Crude extracts and oils were tested for in vitro antimalarial activity on Plasmodium falciparum. The IC50 were evaluated after 24 and 72 h contact between the oils and the parasite culture, and ranged from 22 to 500 micrograms/ml. C. planchonii leaf oil yielded the best antimalarial effect (IC50: 22-35 micrograms/ml), while the most potent effect from crude leaf extracts was induced by C. tinctorium. The cytotoxicity of the leaf crude extracts and oils was assessed on the K562 cell line and showed IC50 values ranging between 33 and 2000 micrograms/ml. PMID:10364849

  6. Antimalarial activity of extracts and alkaloids isolated from six plants used in traditional medicine in Mali and Sao Tome.

    Science.gov (United States)

    Ancolio, C; Azas, N; Mahiou, V; Ollivier, E; Di Giorgio, C; Keita, A; Timon-David, P; Balansard, G

    2002-11-01

    Methanol and chloroform extracts were prepared from various parts of four plants collected in Mali: Guiera senegalensis (Gmel.) Combretaceae, Feretia apodanthera (Del.) Rubiaceae, Combretum micranthum (Don.) Combretaceae, Securidaca longepedunculata (Fres.) Polygalaceae and two plants -collected in Sao Tome: Pycnanthus angolensis (Welw.) Myristicaceae and Morinda citrifolia (Benth.) Rubiaceae were assessed for their in vitro antimalarial activity and their cytotoxic effects on human monocytes (THP1 cells) by flow cytometry. The methanol extract of leaves of Feretia apodanthera and the chloroform extract of roots of Guiera senegalensis exhibited a pronounced antimalarial activity. Two alkaloids isolated from the active extract of Guiera senegalensis, harman and tetrahydroharman, showed antimalarial activity (IC(50) lower than 4 microg/mL) and displayed low toxicity against THP1. Moreover, the decrease of THP1 cells in S phase of the cell cycle, after treatment with harman and tetrahydroharman, was probably due to an inhibition of total protein synthesis. PMID:12410545

  7. Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

    Directory of Open Access Journals (Sweden)

    Olliaro P

    2004-01-01

    Full Text Available The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent

  8. First Assessment in Humans of the Safety, Tolerability, Pharmacokinetics, and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative Artemisone▿

    Science.gov (United States)

    Nagelschmitz, Johannes; Voith, Barbara; Wensing, Georg; Roemer, Axel; Fugmann, Burkhard; Haynes, Richard K.; Kotecka, Barbara M.; Rieckmann, Karl H.; Edstein, Michael D.

    2008-01-01

    In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10- to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t1/2) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t1/2, its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t1/2 is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria. PMID:18559649

  9. First assessment in humans of the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of the new artemisinin derivative artemisone.

    Science.gov (United States)

    Nagelschmitz, Johannes; Voith, Barbara; Wensing, Georg; Roemer, Axel; Fugmann, Burkhard; Haynes, Richard K; Kotecka, Barbara M; Rieckmann, Karl H; Edstein, Michael D

    2008-09-01

    In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10- to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t(1/2)) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t(1/2), its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t(1/2) is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria. PMID:18559649

  10. Effect of selenium (Se) deficiency on the anti-malarial action of Qinghaosu (QHS) in mice

    Energy Technology Data Exchange (ETDEWEB)

    Levander, O.A.; Ager, A.L.; May, R.

    1986-03-01

    QHS is an endoperoxide, so it occurred to the authors that its anti-malarial action might be potentiated by low glutathione peroxidase (GSH-Px) activity. Weanling female mice were fed 1 of 4 diets: chow or a Torula yeast-based diet supplemented with 0, 0.1 or 0.5 ppm Se as Na/sub 2/SeO/sub 3/. After 6 weeks, mean hepatic GSH-Px activities and plasma Se levels in these 4 dietary groups were 17.3, 0.1, 5.4, and 14.5 munits/mg protein and 242, 4, 230, and 532 ng/ml, respectively. At this time, all mice were inoculated i.p. with asexual blood stages of Plasmodium yoelii. Then groups of 7 or 8 mice fed each diet were given 0, 4, 16, or 64 mg QHS/kg orally bid at 3, 4, and 5 days post inoculation. On the 6th day, blood films were taken and antimalarial activity was assessed by determining % parasitemia (% PARA). Mice given 0 or 4 mg QHS/kg averaged 47% PARA and this was not affected by diet. Mice receiving 64 mg QHS/kg averaged about 1% PARA irrespective of diet. However, mice given 16 mg QHS/kg had 25% PARA when fed chow but only 8 to 11% PARA when fed the Torula diet, regardless of Se intake. Thus, while Se status did not appear to influence the antimalarial potency of QHS, some factor(s) in the Torula diet enhanced its activity at intermediate doses vs. the chow diet.

  11. In vitro and in vivo characterization of the antimalarial lead compound SSJ-183 in Plasmodium models

    Directory of Open Access Journals (Sweden)

    Schleiferböck S

    2013-11-01

    Full Text Available Sarah Schleiferböck,1,2 Christian Scheurer,1,2 Masataka Ihara,3,4 Isamu Itoh,3,4 Ian Bathurst,5,† Jeremy N Burrows,5 Pascal Fantauzzi,5 Julie Lotharius,5 Susan A Charman,6 Julia Morizzi,6 David M Shackleford,6 Karen L White,6 Reto Brun,1,2 Sergio Wittlin1,21Swiss Tropical and Public Health Institute, Basel, 2University of Basel, Basel, Switzerland; 3Drug Discovery Science Research Center, Hoshi University, Shinagawa, Tokyo, Japan; 4Synstar Japan Co, Ltd, Odawara, Japan; 5Medicines for Malaria Venture, Geneva, Switzerland; 6Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia †Ian Bathurst passed away on 26 June 2011Abstract: The objective of this work was to characterize the in vitro (Plasmodium falciparum and in vivo (Plasmodium berghei activity profile of the recently discovered lead compound SSJ-183. The molecule showed in vitro a fast and strong inhibitory effect on growth of all P. falciparum blood stages, with a tendency to a more pronounced stage-specific action on ring forms at low concentrations. Furthermore, the compound appeared to be equally efficacious on drug-resistant and drug-sensitive parasite strains. In vivo, SSJ-183 showed a rapid onset of action, comparable to that seen for the antimalarial drug artesunate. SSJ-183 exhibited a half-life of about 10 hours and no significant differences in absorption or exposure between noninfected and infected mice. SSJ-183 appears to be a promising new lead compound with an attractive antimalarial profile.Keywords: antimalarial studies, cross-resistance, stage-specificity, Plasmodium falciparum

  12. Innovative public-private partnerships to maximize the delivery of anti-malarial medicines: lessons learned from the ASAQ Winthrop experience

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    Sebbag Robert

    2011-05-01

    Full Text Available Abstract Background This case study describes how a public-private partnership initiated to develop a new anti-malarial combination, ASAQ Winthrop, has evolved over time to address issues posed by its effective deployment in the field. Case description In 2002, DNDi created the FACT project to develop two fixed-dose combinations, artesunate-amodiaquine and artesunate-mefloquine, to meet the WHO anti-malarial treatment recommendations and international regulatory agencies approval standards. In 2002, Sanofi-aventis had started a development programme for a fixed-dose combination of artesunate and amodiaquine, to replace its co-blister combination. DNDi and sanofi-aventis joined forces in 2004, with the objective of developing within the shortest possible time frame a non-patented, affordable and easy to use fixed-dose combination of artesunate and amodiaquine adapted to the needs of patients, in particular, those of children. The partners developed Coarsucam®/Artesunate Amodiaquine Winthrop® ("ASAQ Winthrop" which was prequalified by the WHO in 2008. Additional partnerships have since been established by DNDi and sanofi-aventis to ensure: 1 the adoption of this new medicine by malaria-endemic countries, 2 its appropriate usage through a broad range of information tools, and 3 the monitoring of its safety and efficacy in the field through an innovative Risk Management Plan. Discussion and evaluation The partnership between DNDi and sanofi-aventis has enabled the development and pre-qualification of ASAQ Winthrop in a short timeframe. As a result of the multiple collaborations established by the two partners, as of late 2010, ASAQ Winthrop was registered in 30 sub-Saharan African countries and in India, with over 80 million treatments distributed in 21 countries. To date, 10 clinical studies, involving 3432 patients with ASAQ Winthrop were completed to document efficacy and safety issues identified in the Risk Management Plan. Conclusions The

  13. Evaluation of the ex vivo antimalarial activity of organotin (IV) ethylphenyldithiocarbamate on erythrocytes infected with Plasmodium berghei NK 65.

    Science.gov (United States)

    Awang, Normah; Jumat, Hafizah; Ishak, Shafariatul Akmar; Kamaludin, Nurul Farahana

    2014-06-01

    Malaria is the most destructive and dangerous parasitic disease. The commonness of this disease is getting worse mainly due to the increasing resistance of Plasmodium falciparum against antimalarial drugs. Therefore, the search for new antimalarial drug is urgently needed. This study was carried out to evaluate the effects of dibutyltin (IV) ethylphenyldithiocarbamate (DBEP), diphenyltin (IV) ethylphenyldithiocarbamate (DPEP) and triphenyltin (IV) ethylphenyldithiocarbamate (TPEP) compounds as antimalarial agents. These compounds were evaluated against erythrocytes infected with Plasmodium berghei NK65 via ex vivo. Organotin (IV) ethylphenyldithiocarbamate, [R(n)Sn(C9H10NS2)(4-n)] with R = C4H9 and C6H5 for n = 2; R = C6H5 for n = 3 is chemically synthesised for its potential activities. pLDH assay was employed for determination of the concentration that inhibited 50% of the Plasmodium's activity (IC50) after 24 h treatment at concentration range of 10-0.0000001 mg mL(-1). Plasmodium berghei NK65 was cultured in vitro to determine the different morphology of trophozoite and schizont. Only DPEP and TPEP compounds have antimalarial activity towards P. berghei NK65 at IC50 0.094±0.011 and 0.892±0.088 mg mL(-1), respectively. The IC50 of DPEP and TPEP were lowest at 30% parasitemia with IC50 0.001±0.00009 and 0.0009±0.0001 mg mL(-1), respectively. In vitro culture showed that TPEP was effective towards P. berghei NK65 in trophozoite and schizont morphology with IC50 0.0001±0.00005 and 0.00009±0.00003 μg mL(-1), respectively. In conclusion, DPEP and TPEP have antimalarial effect on erythrocytes infected with P. berghei NK65 and have potential as antimalarial and schizonticidal agents. PMID:26035957

  14. Formulation and evaluation of gliclazide loaded controlled release microspheres

    OpenAIRE

    Dey, Sanjay; Mohanta, Bibhash C.; Das Gupta, Sandipan; Mazumder, Bhaskar

    2011-01-01

    The aim of this study was to formulate gliclazide loaded controlled release microspheres. Microspheres were prepared by quasi emulsion solvent diffusion technique using eudragit RLPO, eudragit RSPO and with their various combinations. The effect of different formulation variables (drug-polymer ratio and polymer-polymer ratio) on percent yield, mean particle size, encapsulation efficiency and in vitro release of drug were evaluated. In vivo test of the optimized formulation was performed on st...

  15. Antibacterial, antimalarial and leishmanicidal activities of Cu (II) and nickel (II) complexes of diclofenac sodium

    International Nuclear Information System (INIS)

    Metal complexes are famous for a wide array of chemotherapeutic effects. The current study was designed to synthesize and evaluate unexplored chemotherapeutic effects of Cu (II) and Nickel (II) complexes of the non-steroidal anti-inflammatory drug diclofenac. Nickel complex exhibited significant leishmanicidal activity against Lieshmania major, while the copper complex was found to possess low activity against the same pathogen. Both of the complexes revealed low antibacterial activities and were interestingly failed to produce any considerable antimalarial activity against Plasmodium falciparum 3D7. Selective leishmanicidal activities of Nickel (II) complex of diclofenac needs further improvement to be developed as potential new metal-based leishmanicidal agent.(author)

  16. Targeting the Plasmodium vivax equilibrative nucleoside transporter 1 (PvENT1 for antimalarial drug development

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    Roman Deniskin

    2016-04-01

    Full Text Available Infection with Plasmodium falciparum and vivax cause most cases of malaria. Emerging resistance to current antimalarial medications makes new drug development imperative. Ideally a new antimalarial drug should treat both falciparum and vivax malaria. Because malaria parasites are purine auxotrophic, they rely on purines imported from the host erythrocyte via Equilibrative Nucleoside Transporters (ENTs. Thus, the purine import transporters represent a potential target for antimalarial drug development. For falciparum parasites the primary purine transporter is the P. falciparum Equilibrative Nucleoside Transporter Type 1 (PfENT1. Recently we identified potent PfENT1 inhibitors with nanomolar IC50 values using a robust, yeast-based high throughput screening assay. In the current work we characterized the Plasmodium vivax ENT1 (PvENT1 homologue and its sensitivity to the PfENT1 inhibitors. We expressed a yeast codon-optimized PvENT1 gene in Saccharomyces cerevisiae. PvENT1-expressing yeast imported both purines ([3H]adenosine and pyrimidines ([3H]uridine, whereas wild type (fui1Δ yeast did not. Based on radiolabel substrate uptake inhibition experiments, inosine had the lowest IC50 (3.8 μM, compared to guanosine (14.9 μM and adenosine (142 μM. For pyrimidines, thymidine had an IC50 of 183 μM (vs. cytidine and uridine; mM range. IC50 values were higher for nucleobases compared to the corresponding nucleosides; hypoxanthine had a 25-fold higher IC50 than inosine. The archetypal human ENT1 inhibitor 4-nitrobenzylthioinosine (NBMPR had no effect on PvENT1, whereas dipyridamole inhibited PvENT1, albeit with a 40 μM IC50, a 1000-fold less sensitive than human ENT1 (hENT1. The PfENT1 inhibitors blocked transport activity of PvENT1 and the five known naturally occurring non-synonymous single nucleotide polymorphisms (SNPs with similar IC50 values. Thus, the PfENT1 inhibitors also target PvENT1. This implies that development of novel

  17. Four-step synthesis of the antimalarial cardamom peroxide via an oxygen stitching strategy.

    Science.gov (United States)

    Hu, Xirui; Maimone, Thomas J

    2014-04-01

    A four-step synthesis of the antimalarial terpene cardamom peroxide, a 1,2-dioxepane-containing natural product, is reported from (-)-myrtenal and molecular oxygen. This highly concise route was guided by biosynthetic logic and enabled by an unusual manganese-catalyzed, tandem hydroperoxidation reaction. The absolute configuration of the cardamom peroxide is reported, and its mode of fragmentation following Fe(II)-mediated endoperoxide reduction is established. These studies reveal the generation of reactive intermediates distinct from previously studied endoperoxide natural products. PMID:24673099

  18. Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates.

    Science.gov (United States)

    Faidallah, Hassan M; Panda, Siva S; Serrano, Juan C; Girgis, Adel S; Khan, Khalid A; Alamry, Khalid A; Therathanakorn, Tanya; Meyers, Marvin J; Sverdrup, Francis M; Eickhoff, Christopher S; Getchell, Stephen G; Katritzky, Alan R

    2016-08-15

    Click chemistry technique led to novel 1,2,3-triazole-quinine conjugates 8a-g, 10a-o, 11a-h and 13 utilizing benzotriazole-mediated synthetic approach with excellent yields. Some of the synthesized analogs (11a, 11d-h) exhibited antimalarial properties against Plasmodium falciparum strain 3D7 with potency higher than that of quinine (standard reference used) through in vitro standard procedure bio-assay. Statistically significant BMLR-QSAR model describes the bio-properties, validates the observed biological observations and identifies the most important parameters governing bio-activity. PMID:27298002

  19. In vitro antimalarial drug susceptibility in Thai border areas from 1998–2003

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    Mungthin Mathirut

    2005-08-01

    Full Text Available Abstract Background The Thai-Myanmar and Thai-Cambodia borders have been historically linked with the emergence and spread of Plasmodium falciparum parasites resistant to antimalarial drugs. Indeed, the areas are often described as harbouring multi-drug resistant parasites. These areas of Thailand have experienced significant changes in antimalarial drug exposure patterns over the past decade. This study describes the in vitro antimalarial susceptibility patterns of 95 laboratory-adapted P. falciparum isolates, collected between 1998 and 2003,. Methods Ninety five P. falciparum isolates were collected from five sites in Thailand between 1998 and 2003. After laboratory adaptation to in vitro culture, the susceptibility of these parasites to a range of established antimalarial drugs (chloroquine [CQ], mefloquine [MQ], quinine [QN] and dihydroartemisinin [DHA] was determined by the isotopic microtest. Results Mefloquine (MQ sensitivity remained poorest in areas previously described as MQ-resistant areas. Sensitivity to MQ of parasites from this area was significantly lower than those from areas reported to harbour moderate (p = 0.002 of low level MQ resistance (p = 000001. Importantly for all drugs tested, there was a considerable range in absolute parasite sensitivities. There was a weak, but statistically positive correlation between parasite sensitivity to CQ and sensitivity to both QN and MQ and a positive correlation between MQ and QN. In terms of geographical distribution, parasites from the Thai-Cambodia were tended to be less sensitive to all drugs tested compared to the Thai-Myanmar border. Parasite sensitivity to all drugs was stable over the 6-year collection period with the exception of QN. Conclusion This study highlights the high degree of variability in parasite drug sensitivity in Thailand. There were geographical differences in the pattern of resistance which might reflect differences in drug usage in each area. In contrast to many

  20. Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement

    OpenAIRE

    Shen S; Liu SZ; Zhang YS; Du MB; Liang AH; Song LH; Ye ZG

    2015-01-01

    Shuo Shen, Shu-Zhi Liu, Yu-Shi Zhang, Mao-Bo Du, Ai-Hua Liang, Li-Hua Song, Zu-Guang Ye Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China Abstract: Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel ...

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

    OpenAIRE

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

    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...

  2. A new phloroglucinol derivative from Hypericum calycinum with antifungal and in vitro antimalarial activity.

    Science.gov (United States)

    Decosterd, L A; Hoffmann, E; Kyburz, R; Bray, D; Hostettmann, K

    1991-12-01

    The new phloroglucinol derivative 1 has been isolated from the light petroleum ether extract of the aerial parts of Hypericum calycinum. Its structure has been established by means of 1H- and 13C-NMR spectroscopy and by nOe, MHQC, and HMBC experiments on its monomethyl ether derivative 3. Compound 1 was fungicidal against Cladosporium cucumerinum in a TLC bioassay. In addition, this new phloroglucinol derivative was also found to exert an interesting antimalarial activity in an in vitro test system. PMID:1818346

  3. Liposomal formulations for inhalation.

    Science.gov (United States)

    Cipolla, David; Gonda, Igor; Chan, Hak-Kim

    2013-08-01

    No marketed inhaled products currently use sustained release formulations such as liposomes to enhance drug disposition in the lung, but that may soon change. This review focuses on the interaction between liposomal formulations and the inhalation technology used to deliver them as aerosols. There have been a number of dated reviews evaluating nebulization of liposomes. While the information they shared is still accurate, this paper incorporates data from more recent publications to review the factors that affect aerosol performance. Recent reviews have comprehensively covered the development of dry powder liposomes for aerosolization and only the key aspects of those technologies will be summarized. There are now at least two inhaled liposomal products in late-stage clinical development: ARIKACE(®) (Insmed, NJ, USA), a liposomal amikacin, and Pulmaquin™ (Aradigm Corp., CA, USA), a liposomal ciprofloxacin, both of which treat a variety of patient populations with lung infections. This review also highlights the safety of inhaled liposomes and summarizes the clinical experience with liposomal formulations for pulmonary application. PMID:23919478

  4. Priority setting for the implementation of artemisinin-based combination therapy policy in Tanzania: evaluation against the accountability for reasonableness framework

    Directory of Open Access Journals (Sweden)

    Mori Amani

    2012-03-01

    Full Text Available Abstract Background Priority setting for artemisinin-based antimalarial drugs has become an integral part of malaria treatment policy change in malaria-endemic countries. Although these drugs are more efficacious, they are also more costly than the failing drugs. When Tanzania changed its National Malaria Treatment Policy in 2006, priority setting was an inevitable challenge. Artemether-lumefantrine was prioritised as the first-line drug for the management of uncomplicated malaria to be available at a subsidized price at public and faith-based healthcare facilities. Methods This paper describes the priority-setting process, which involved the selection of a new first-line antimalarial drug in the implementation of artemisinin-based combination therapy policy. These descriptions were further evaluated against the four conditions of the accountability for reasonableness framework. According to this framework, fair decisions must satisfy a set of publicity, relevance, appeals, and revision and enforcement conditions. In-depth interviews were held with key informants using pretested interview guides, supplemented with a review of the treatment guideline. Purposeful sampling was used in order to explore the perceptions of people with different backgrounds and perspectives. The analysis followed an editing organising style. Results Publicity: The selection decision of artemether-lumefantrine but not the rationale behind it was publicised through radio, television, and newspaper channels in the national language, Swahili. Relevance: The decision was grounded on evidences of clinical efficacy, safety, affordability, and formulation profile. Stakeholders were not adequately involved. There was neither an appeals mechanism to challenge the decision nor enforcement mechanisms to guarantee fairness of the decision outcomes. Conclusions The priority-setting decision to use artemether-lumefantrine as the first-line antimalarial drug failed to satisfy the four

  5. Prediction of potential antimalarial targets of artemisinin based on protein information from whole genome of Plasmodium falciparum

    Institute of Scientific and Technical Information of China (English)

    HAN LiPing; HUANG Qiang; NAN Peng; ZHONG Yang

    2009-01-01

    On the basis of the genomic data and protein pathway information about Plasmodium falciparum clone 3D7 from the NCBI taxonomy database and the KEGG database,eight key protein enzymes in the signal pathways were selected to perform molecular docking with artemisinin.The binding modes obtained from the molecular docking suggested that purine nucleoside phosphorylase (pfPNP),peptide deformylase (pfPDF),and ribose 5-phosphate isomerase (pfRpiA) may be involved in the antimalarial mode of action of artemisinin.Artemisinin exhibited its antimalarial activity probably by interfering with the metabolic pathways of purine,pyrimidine,methionine,glyoxylate and dicarboxylate,or pentose phosphate.

  6. Stability-indicating HPLC-DAD/UV-ESI/MS impurity profiling of the anti-malarial drug lumefantrine

    Directory of Open Access Journals (Sweden)

    Duchateau Luc

    2011-02-01

    Full Text Available Abstract Background Lumefantrine (benflumetol is a fluorene derivative belonging to the aryl amino alcohol class of anti-malarial drugs and is commercially available in fixed combination products with β-artemether. Impurity characterization of such drugs, which are widely consumed in tropical countries for malaria control programmes, is of paramount importance. However, until now, no exhaustive impurity profile of lumefantrine has been established, encompassing process-related and degradation impurities in active pharmaceutical ingredients (APIs and finished pharmaceutical products (FPPs. Methods Using HPLC-DAD/UV-ESI/ion trap/MS, a comprehensive impurity profile was established based upon analysis of market samples as well as stress, accelerated and long-term stability results. In-silico toxicological predictions for these lumefantrine related impurities were made using Toxtree® and Derek®. Results Several new impurities are identified, of which the desbenzylketo derivative (DBK is proposed as a new specified degradant. DBK and the remaining unspecified lumefantrine related impurities are predicted, using Toxtree® and Derek®, to have a toxicity risk comparable to the toxicity risk of the API lumefantrine itself. Conclusions From unstressed, stressed and accelerated stability samples of lumefantrine API and FPPs, nine compounds were detected and characterized to be lumefantrine related impurities. One new lumefantrine related compound, DBK, was identified and characterized as a specified degradation impurity of lumefantrine in real market samples (FPPs. The in-silico toxicological investigation (Toxtree® and Derek® indicated overall a toxicity risk for lumefantrine related impurities comparable to that of the API lumefantrine itself.

  7. Phytochemical screening, antimalarial and histopathological studies of Allophylus africanus and Tragia benthamii

    Institute of Scientific and Technical Information of China (English)

    Oladosu I.A.; Balogun S.O.; Ademowo G.O.

    2013-01-01

    The anti-malarial potential of different parts ofAllophylus africanus P.Beauv and Tragia benthamii Baker were determined in vivo for suppressive,curative and cytotoxic activities in mice receiving 0.2 mL of a standard inoculum size of 1 × 107 infected erythrocytes of Plasmodium berghei (NK-65) intraperitoneally.The A.africanus extracts suppressed parasitaemia following administration to infected mice by 92.82%-97.81% on day 7 post-infection against 96.81% for chloroquine.The infected extract-treated animals had significantly moderate (P < 0.05) packed cell volume (PCV) compared with the infected,untreated animals.Phytochemical screening revealed a predominance of tannins,saponins,flavonoids and carbohydrates in all parts of A.africanus,and alkaloids instead of flavonoids in the extract of T.benthamii.The results suggest that the extract possesses considerable antimalarial activity.These results support further studies on A.africanus.

  8. Synthesis, Cytotoxic and Antimalarial Activities of Benzoyl Thiosemicarbazone Analogs of Isoquinoline and Related Compounds

    Directory of Open Access Journals (Sweden)

    Somsak Ruchirawat

    2010-02-01

    Full Text Available Thiosemicarbazone analogs of papaveraldine and related compounds 1–6 were synthesized and evaluated for cytotoxic and antimalarial activities. The cytotoxic activity was tested against HuCCA-1, HepG2, A549 and MOLT-3 human cancer cell lines. Thiosemicarbazones 1–5 displayed cytotoxicity toward all the tested cell lines, while compounds 2–5 selectively showed potent activity against the MOLT-3 cell lines. Significantly, N(4-phenyl-2-benzoylpyridine thiosemicarbazone 4 exhibited the most potent activity against HuCCA-1, HepG2, A549 and MOLT-3 cell lines with IC50 values of 0.03, 4.75, 0.04 and 0.004 µg/mL, respectively. In addition, 2-benzoylpyridine thio-semicarbazones 3 and 4 showed antimalarial activity against Plasmodium falciparum with IC50 of 10-7 to < 10-6 M. The study demonstrates the quite promising activity of analog 4 as a lead molecule for further development.

  9. Evaluation of the Quality of Artemisinin-Based Antimalarial Medicines Distributed in Ghana and Togo

    Directory of Open Access Journals (Sweden)

    Dorcas Osei-Safo

    2014-01-01

    Full Text Available This study, conducted as part of our overall goal of regular pharmacovigilance of antimalarial medicines, reports on the quality of 132 artemisinin-based antimalarial medicines distributed in Ghana and Togo. Three methods were employed in the quality evaluation—basic (colorimetric tests for establishing the identity of the requisite active pharmaceutical ingredients (APIs, semi-quantitative TLC assay for the identification and estimation of API content, and HPLC assay for a more accurate quantification of API content. From the basic tests, only one sample totally lacked API. The HPLC assay, however, showed that 83.7% of the ACTs and 57.9% of the artemisinin-based monotherapies failed to comply with international pharmacopoeia requirements due to insufficient API content. In most of the ACTs, the artemisinin component was usually the insufficient API. Generally, there was a good correlation between the HPLC and SQ-TLC assays. The overall failure rates for both locally manufactured (77.3% and imported medicines (77.5% were comparable. Similarly the unregistered medicines recorded a slightly higher overall failure rate (84.7% than registered medicines (70.8%. Only two instances of possible cross-border exchange of medicines were observed and there was little difference between the medicine quality of collections from border towns and those from inland parts of both countries.

  10. Investigation of Indolglyoxamide and Indolacetamide Analogues of Polyamines as Antimalarial and Antitrypanosomal Agents

    Directory of Open Access Journals (Sweden)

    Jiayi Wang

    2014-05-01

    Full Text Available Pure compound screening has previously identified the indolglyoxy lamidospermidine ascidian metabolites didemnidine A and B (2 and 3 to be weak growth inhibitors of Trypanosoma brucei rhodesiense (IC50 59 and 44 μM, respectively and Plasmodium falciparum (K1 dual drug resistant strain (IC50 41 and 15 μM, respectively, but lacking in selectivity (L6 rat myoblast, IC50 24 μM and 25 μM, respectively. To expand the structure–activity relationship of this compound class towards both parasites, we have prepared and biologically tested a library of analogues that includes indoleglyoxyl and indoleacetic “capping acids”, and polyamines including spermine (PA3-4-3 and extended analogues PA3-8-3 and PA3-12-3. 7-Methoxy substituted indoleglyoxylamides were typically found to exhibit the most potent antimalarial activity (IC50 10–92 nM but with varying degrees of selectivity versus the L6 rat myoblast cell line. A 6-methoxyindolglyoxylamide analogue was the most potent growth inhibitor of T. brucei (IC50 0.18 μM identified in the study: it, however, also exhibited poor selectivity (L6 IC50 6.0 μM. There was no apparent correlation between antimalarial and anti-T. brucei activity in the series. In vivo evaluation of one analogue against Plasmodium berghei was undertaken, demonstrating a modest 20.9% reduction in parasitaemia.

  11. Basigin is a druggable target for host-oriented antimalarial interventions.

    Science.gov (United States)

    Zenonos, Zenon A; Dummler, Sara K; Müller-Sienerth, Nicole; Chen, Jianzhu; Preiser, Peter R; Rayner, Julian C; Wright, Gavin J

    2015-07-27

    Plasmodium falciparum is the parasite responsible for the most lethal form of malaria, an infectious disease that causes a large proportion of childhood deaths and poses a significant barrier to socioeconomic development in many countries. Although antimalarial drugs exist, the repeated emergence and spread of drug-resistant parasites limit their useful lifespan. An alternative strategy that could limit the evolution of drug-resistant parasites is to target host factors that are essential and universally required for parasite growth. Host-targeted therapeutics have been successfully applied in other infectious diseases but have never been attempted for malaria. Here, we report the development of a recombinant chimeric antibody (Ab-1) against basigin, an erythrocyte receptor necessary for parasite invasion as a putative antimalarial therapeutic. Ab-1 inhibited the PfRH5-basigin interaction and potently blocked erythrocyte invasion by all parasite strains tested. Importantly, Ab-1 rapidly cleared an established P. falciparum blood-stage infection with no overt toxicity in an in vivo infection model. Collectively, our data demonstrate that antibodies or other therapeutics targeting host basigin could be an effective treatment for patients infected with multi-drug resistant P. falciparum. PMID:26195724

  12. 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.

  13. Antimalarial properties of Artemisia vulgaris L. ethanolic leaf extract in a Plasmodium berghei murine malaria model

    Directory of Open Access Journals (Sweden)

    Gayan S. Bamunuarachchi

    2013-12-01

    Full Text Available Background & objectives: Artemisinin isolated from Artemisia annua is the most potent antimalarial drug against chloroquine-resistant Plasmodium falciparum malaria. Artemisia vulgaris, an invasive weed, is the only Artemisia species available in Sri Lanka. A pilot study was undertaken to investigate the antiparasitic activity of an A. vulgaris ethanolic leaf extract (AVELE in a P. berghei ANKA murine malaria model that elicits pathogenesis similar to falciparum malaria. Methods: A 4-day suppressive and the curative assays determined the antiparasitic activity of AVELE using four doses (250, 500, 750 and 1000 mg/kg, Coartem® as the positive control and 5% ethanol as the negative control in male ICR mice infected with P. berghei. Results: The 500, 750 and 1000 mg/kg doses of AVELE significantly (p ≤0.01 inhibited parasitaemia by 79.3, 79.6 and 87.3% respectively, in the 4-day suppressive assay, but not in the curative assay. Chronic administration of the high dose of AVELE ruled out overt signs of toxicity and stress as well as hepatotoxicity, renotoxicity and haematotoxicity. Interpretation & conclusion: The oral administration of a crude ethonolic leaf extract of A. vulgaris is non-toxic and possesses potent antimalarial properties in terms of antiparasitic activity.

  14. Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis

    Directory of Open Access Journals (Sweden)

    Huthmacher Carola

    2010-08-01

    Full Text Available Abstract Background Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed. Results Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicted life cycle stage specific metabolism with the help of a flux balance approach that integrates gene expression data. Predicted metabolite exchanges between parasite and host were found to be in good accordance with experimental findings when the parasite's metabolic network was embedded into that of its host (erythrocyte. Knock-out simulations identified 307 indispensable metabolic reactions within the parasite. 35 out of 57 experimentally demonstrated essential enzymes were recovered and another 16 enzymes, if additionally the assumption was made that nutrient uptake from the host cell is limited and all reactions catalyzed by the inhibited enzyme are blocked. This predicted set of putative drug targets, shown to be enriched with true targets by a factor of at least 2.75, was further analyzed with respect to homology to human enzymes, functional similarity to therapeutic targets in other organisms and their predicted potency for prophylaxis and disease treatment. Conclusions The results suggest that the set of essential enzymes predicted by our flux balance approach represents a promising starting point for further drug development.

  15. An Alternative Paradigm for the Role of Antimalarial Plants in Africa

    Directory of Open Access Journals (Sweden)

    Steven Maranz

    2012-01-01

    Full Text Available Most investigations into the antimalarial activity of African plants are centered on finding an indigenous equivalent to artemisinin, the compound from which current frontline antimalarial drugs are synthesized. As a consequence, the standard practice in ethnopharmacological research is to use in vitro assays to identify compounds that inhibit parasites at nanomolar concentrations. This approach fails to take into consideration the high probability of acquisition of resistance to parasiticidal compounds since parasite populations are placed under direct selection for genetic that confers a survival advantage. Bearing in mind Africa's long exposure to malaria and extensive ethnobotanical experimentation with both therapies and diet, it is more likely that compounds not readily overcome by Plasmodium parasites would have been retained in the pharmacopeia and cuisine. Such compounds are characterized by acting primarily on the host rather than directly targeting the parasite and thus cannot be adequately explored in vitro. If Africa's long history with malaria has in fact produced effective plant therapies, their scientific elucidation will require a major emphasis on in vivo investigation.

  16. Automatic query formulations in information retrieval.

    Science.gov (United States)

    Salton, G; Buckley, C; Fox, E A

    1983-07-01

    Modern information retrieval systems are designed to supply relevant information in response to requests received from the user population. In most retrieval environments the search requests consist of keywords, or index terms, interrelated by appropriate Boolean operators. Since it is difficult for untrained users to generate effective Boolean search requests, trained search intermediaries are normally used to translate original statements of user need into useful Boolean search formulations. Methods are introduced in this study which reduce the role of the search intermediaries by making it possible to generate Boolean search formulations completely automatically from natural language statements provided by the system patrons. Frequency considerations are used automatically to generate appropriate term combinations as well as Boolean connectives relating the terms. Methods are covered to produce automatic query formulations both in a standard Boolean logic system, as well as in an extended Boolean system in which the strict interpretation of the connectives is relaxed. Experimental results are supplied to evaluate the effectiveness of the automatic query formulation process, and methods are described for applying the automatic query formulation process in practice. PMID:10299297

  17. Formulation and optimization of carbamazepine floating tablets

    Directory of Open Access Journals (Sweden)

    Patel D

    2007-01-01

    Full Text Available Floating tablets of carbamazepine were developed using melt granulation technique. Bees wax was used as a hydrophobic meltable material. Hydroxypropylmethylcellulose, sodium bicarbonate and ethyl cellulose were used as matrixing agent, gas-generating agent and floating enhancer, respectively. The tablets were evaluated for in vitro buoyancy and dissolution studies. A simplex lattice design was applied to investigate the combined effect of 3 formulation variables i.e. amount of hydroxypropyl methylcellulose ( X 1 , ethyl cellulose ( X 2 and sodium bicarbonate ( X 3 . The floating lag time (F lag , time required for 50% (t 50 and 80% drug dissolution (t 80 were taken as responses. Results of multiple regression analysis indicated that, low level of X 1 and X 2 , and high level of X 3 should be used to manufacture the tablet formulation with desired in vitro floating time and dissolution. Formulations developed using simplex lattice design were fitted to various kinetic models for drug release. Formulation S3 was selected as a promising formulation and was found stable at 40 o and 75% relative humidity for 3 months. Present study demonstrates the use of simplex lattice design in the development of floating tablets with minimum experimentation.

  18. Ether formulations of relativity

    Energy Technology Data Exchange (ETDEWEB)

    Duffy, M.C.

    1980-12-01

    Contemporary ether theories are surveyed and criticized, especially those formally identical to orthodox Relativity. The historical development of Relativity, Special and General, in terms of an ether, is briefly indicated. Classical interpretations of Generalized Relativity using ether are compared to Euclidean formulations using a background space. The history of a sub-group of theories, formulating a 'new' Relativity involving modified transforms, is outlined. According to the theory with which they agree, recent supposed detections of drift are classified and criticized. Cosmological evidence suggesting an ether is mentioned. Only ether theories formally identical to Relativity have been published in depth. They stand criticized as being contrary to the positivist spirit. The history of mechanical analogues is traced, from Hartley's representing gravitating matter as spherical standing waves, to recent suggestions that vortex-sponge might model electromagnetic, quantum, uncertainty and faster-than-light phenomena. Contemporary theories are particular physical theories, themselves 'second interpretations' of a primary mathematical model. Mechanical analogues are auxiliary, not necessary, to other theory, disclosing relationships between classical and non-classical descriptions of assemblies charging state. The ether-relativity polemic, part of a broader dispute about relativity, is founded on mistaken conceptions of the roles of mathematical and physical models, mechanical analogues; and a distored view of history, which indicates that ether theories have become relativistic. 103 references.

  19. Ether formulations of relativity

    International Nuclear Information System (INIS)

    Contemporary ether theories are surveyed and criticised, especially those formally identical to orthodox Relativity. The historical development of Relativity, Special and General, in terms of an ether, is briefly indicated. Classical interpretations of Generalized Relativity using ether are compared to Euclidean formulations using a background space. The history of a sub-group of theories, formulating a 'new' Relativity involving modified transforms, is outlined. According to the theory with which they agree, recent supposed detections of drift are classified and criticised. Cosmological evidence suggesting an ether is mentioned. Only ether theories formally identical to Relativity have been published in depth. They stand criticised as being contrary to the positivist spirit. The history of mechanical analogues is traced, from Hartley's representing gravitating matter as spherical standing waves, to recent suggestions that vortex-sponge might model electromagnetic, quantum, uncertainty and faster-than-light phenomena. Contemporary theories are particular physical theories, themselves 'second interpretations' of a primary mathematical model. Mechanical analogues are auxiliary, not necessary, to other theory, disclosing relationships between classical and non-classical descriptions of assemblies charging state. The ether-relativity polemic, part of a broader dispute about relativity, is founded on mistaken conceptions of the roles of mathematical and physical models, mechanical analogues; and a distored view of history, which indicates that ether theories have become relativistic. (author)

  20. Antimicrobial and antimalarial properties of medicinal plants used by the indigenous tribes of Andaman and Nicobar Islands, India.

    Science.gov (United States)

    Chander, M Punnam; Pillai, C R; Sunish, I P; Vijayachari, P

    2016-07-01

    In this study, methanol extracts of six medicinal plants (Alstonia macrophylla, Claoxylon indicum, Dillenia andamanica, Jasminum syringifolium, Miliusia andamanica and Pedilanthus tithymaloides) traditionally used by Nicobarese tribes of Andaman and Nicobar Islands were studied for antimicrobial and antimalarial activities as well as preliminary photochemical analysis. Plants were collected from Car Nicobar of Andaman and Nicobar Islands and the ethnobotanical data were gathered from traditional healers who inhabit the study area. The methanol extracts were obtained by cold percolation method and the antimicrobial activity was found using agar well diffusion method. Among the plants tested, J. syringifolium, D. andamanica, C. indicum were most active. The antimalarial activity was evaluated against Plasmodium falciparum chloroquine-sensitive MRC-2 isolate. The crude extract of M. andamanica showed excellent antimalarial activity followed by extracts of P. tithymaloides, J. syringifolium and D. andamanica. The chemical injury to erythrocytes was also carried out and it showed that, there were no morphological changes in erythrocytes by the methanol crude extracts. The in vitro antimicrobial and antimalarial activity might be due to the presence of alkaloids, flavonoids, triterpenes, sterols, tannins and saponins in the methanol extracts of tested plants. PMID:27174207

  1. A new class of anti-malarial therapeutics that inhibit nucleotide synthesis in Plasmodium falciparum and vivax

    Czech Academy of Sciences Publication Activity Database

    Keough, D. T.; Hocková, Dana; Holý, Antonín; Naesens, L.; Skinner-Adams, T. S.; de Jersey, J.; Guddat, L. W.

    Lorne : The University of Queensland, 2009. -. [Lorne Conference on Protein Structure and Function /34./. 08.02.2009-12.02.2009, Lorne] Institutional research plan: CEZ:AV0Z40550506 Keywords : Plasmodium falciparum * anti-malarial therapeutics * nucleotide synthesis Subject RIV: CC - Organic Chemistry

  2. Effect of antimalarial drug primaquine and its derivatives on the ionization potential of hemoglobin: A QM/MM study

    OpenAIRE

    Liu, Haining; Ding, Yuanqing; Walker, Larry A.; Doerksen, Robert J

    2013-01-01

    We used quantum mechanics/molecular mechanics calculations to test if antimalarial primaquine (PQ) and its derivatives aid the conversion of hemoglobin to methemoglobin by binding to hemoglobin and merely lowering hemoglobin’s ionization potential (IP). Our results showed that PQ and its derivatives do not significantly lower the hemoglobin IP, disproving the hypothesis.

  3. Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery.

    Science.gov (United States)

    McCarty, Sara E; Schellenberger, Amanda; Goodwin, Douglas C; Fuanta, Ngolui Rene; Tekwani, Babu L; Calderón, Angela I

    2015-01-01

    The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR), an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences between the thioredoxin reductases (TrxRs) of different Plasmodium species and the human forms of the enzyme, gives an overview of modeling Plasmodium infections in animals, and suggests the role of Trx functions in antimalarial drug resistance. TrxR of Plasmodium falciparum is a central focus of this paper since it is the only Plasmodium TrxR that has been crystallized and P. falciparum is the species that causes most malaria cases. It is anticipated that the information summarized here will give insight and stimulate new directions in which research might be most beneficial. PMID:26111176

  4. Plasmodium falciparum Thioredoxin Reductase (PfTrxR and Its Role as a Target for New Antimalarial Discovery

    Directory of Open Access Journals (Sweden)

    Sara E. McCarty

    2015-06-01

    Full Text Available The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR, an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences between the thioredoxin reductases (TrxRs of different Plasmodium species and the human forms of the enzyme, gives an overview of modeling Plasmodium infections in animals, and suggests the role of Trx functions in antimalarial drug resistance. TrxR of Plasmodium falciparum is a central focus of this paper since it is the only Plasmodium TrxR that has been crystallized and P. falciparum is the species that causes most malaria cases. It is anticipated that the information summarized here will give insight and stimulate new directions in which research might be most beneficial.

  5. Plant-Derived Antimalarial Agents: New Leads and Efficient Phytomedicines. Part II. Non-Alkaloidal Natural Products

    Directory of Open Access Journals (Sweden)

    Alaíde Braga de Oliveira

    2009-08-01

    Full Text Available Malaria is still the most destructive and dangerous parasitic infection in many tropical and subtropical countries. The burden of this disease is getting worse, mainly due to the increasing resistance of Plasmodium falciparum against the widely available antimalarial drugs. There is an urgent need for new, more affordable and accessible antimalarial agents possessing original modes of action. Natural products have played a dominant role in the discovery of leads for the development of drugs to treat human diseases, and this fact anticipates that new antimalarial leads may certainly emerge from tropical plant sources. This present review covers most of the recently-published non-alkaloidal natural compounds from plants with antiplasmodial and antimalarial properties, belonging to the classes of terpenes, limonoids, flavonoids, chromones, xanthones, anthraquinones, miscellaneous and related compounds, besides the majority of papers describing antiplasmodial crude extracts published in the last five years not reviewed before. In addition, some perspectives and remarks on the development of new drugs and phytomedicines for malaria are succinctly discussed.

  6. Why Hospital Pharmacists Have Failed to Manage Antimalarial Drugs Stock-Outs in Pakistan? A Qualitative Insight

    Directory of Open Access Journals (Sweden)

    Madeeha Malik

    2013-01-01

    Full Text Available Purpose. This study aimed to explore the perceptions of hospital pharmacists towards drug management and reasons underlying stock-outs of antimalarial drugs in Pakistan. Methods. A qualitative study was designed to explore the perceptions of hospital pharmacists regarding drug management and irrational use of antimalarial drugs in two major cities of Pakistan, namely, Islamabad (national capital and Rawalpindi (twin city. Semistructured interviews were conducted with 16 hospital pharmacists using indepth interview guides at a place and time convenient for the respondents. Interviews, which were audiotaped and transcribed verbatim, were evaluated by thematic content analysis and by other authors’ analysis. Results. Most of the respondents were of the view that financial constraints, inappropriate drug management, and inadequate funding were the factors contributing toward the problem of antimalarial drug stock-outs in healthcare facilities of Pakistan. The pharmacists anticipated that prescribing by nonproprietary names, training of health professionals, accepted role of hospital pharmacist in drug management, implementation of essential drug list and standard treatment guidelines for malaria in the healthcare system can minimize the problem of drug stock outs in healthcare system of Pakistan. Conclusion. The current study showed that all the respondents in the two cities agreed that hospital pharmacist has failed to play an effective role in efficient management of anti-malarial drugs stock-outs.

  7. [Optimization of formulations for dietetic pastry products].

    Science.gov (United States)

    Villarroel, M; Uquiche, E; Brito, G; Cancino, M

    2000-03-01

    Optimized formulations of dietetic pastry products such as cake and sponge cake premixes were formulated using the surface response methodology. % Emulsifier agent and baking time were the selected independent variables for cake, as well as % emulsifier agent % chlorinated flour the variables selected for sponge cake. Three different level of each variable summing up thirteen experimental formulae of each product were assessed to optimize the variables that could have some influence in the sensory characteristics of these dietetic products. The total sensory quality was determined for both dietetic products using the composite scoring test and a panel of 18 trained judges. Looking at the contour graphic and considering economic aspects the best combination of variables for cake formulation was 2% emulsifier agent and 48 minutes for baking time, With respect to sponge cake, the best combination was 6% emulsifier agent and 48% chlorinated flour. Shelf life studies showed that both dietetic formulations remained stable during storage conditions of 75 days at 30 degrees C. During this period, significant differences in sensory characteristics were not found (p < 0.05). Data of peroxide values were kept under the critical value reported for detection of organoleptic rancidity. Reported values of hedonic test showed that these dietetics pastry products had good acceptability, and open up marketing opportunities for new products with potential health benefits to consumers. PMID:11048573

  8. Screening of mucoadhesive vaginal gel formulations

    Directory of Open Access Journals (Sweden)

    Ana Ochoa Andrade

    2014-12-01

    Full Text Available Rational design of vaginal drug delivery formulations requires special attention to vehicle properties that optimize vaginal coating and retention. The aim of the present work was to perform a screening of mucoadhesive vaginal gels formulated with carbomer or carrageenan in binary combination with a second polymer (carbomer, guar or xanthan gum. The gels were characterised using in vitroadhesion, spreadability and leakage potential studies, as well as rheological measurements (stress and frequency sweep tests and the effect of dilution with simulated vaginal fluid (SVF on spreadability. Results were analysed using analysis of variance and multiple factor analysis. The combination of polymers enhanced adhesion of both primary gelling agents, carbomer and carrageenan. From the rheological point of view all formulations presented a similar behaviour, prevalently elastic and characterised by loss tangent values well below 1. No correlation between rheological and adhesion behaviour was found. Carbomer and carrageenan gels containing the highest percentage of xanthan gum displayed good in vitro mucoadhesion and spreadability, minimal leakage potential and high resistance to dilution. The positive results obtained with carrageenan-xanthan gum-based gels can encourage the use of natural biocompatible adjuvants in the composition of vaginal products, a formulation field that is currently under the synthetic domain.

  9. Acceptability by community health workers in Senegal of combining community case management of malaria and seasonal malaria chemoprevention

    DEFF Research Database (Denmark)

    Tine, Roger Ck; Ndiaye, Pascal; Ndour, Cheikh T;

    2013-01-01

    Community case management of malaria (CCMm) and seasonal malaria chemoprevention (SMC) are anti-malarial interventions that can lead to substantial reduction in malaria burden acting in synergy. However, little is known about the social acceptability of these interventions. A study was undertaken...... to assess whether combining the interventions would be an acceptable approach to malaria control for community health workers (CHWs)....

  10. Food formulation comprising spent coffee grounds

    OpenAIRE

    Castillo, M. Dolores del; Martínez Sáez, Nuria; Ullate, Mónica

    2014-01-01

    [EN] The invention relates to a novel food formulation comprising a combination of spent coffee grounds as a source of antioxidant insoluble dietary fibre and a source of proteins, together with other additional ingredients, used to make healthy solid food for bakeries, pastry shops, and confectioner's, including bread, pastries, biscuits, breakfast cereals and appetisers, for the general population and for people with special nutritional requirements.

  11. MOUTH DISSOLVING TABLETS OF LOSARTAN POTASSIUM: FORMULATION AND EVALUATION

    Directory of Open Access Journals (Sweden)

    Dr. Satyabrata Bhanja et al

    2012-09-01

    Full Text Available Losartan potassium is an angiotention receptor antagonist, used in the management of hypertension. The objective of the proposed research work is to prepare and evaluate the mouth dissolving/disintegrating tablets (MDTs of losartan Potassium, which avoid the first-pass metabolism, improved the dissolution rate and enhance the bioavailability. Mouth dissolving tablets (MDTs were prepared by direct compression method by using combination of superdisintegrant like Ac-Di-Sol and Polyplasdone-xl (1%,2%,3%&4% and evaluated for physico-chemical evaluation parameter such as hardness, friability, weight variation, drug content uniformity, water absorption ratio, wetting time, in-vitro and in-vivo disintegration time, in-vitro dissolution studies. The control tablet (without superdisintegrant was formulated and evaluated. The twelve formulations, B1to B8 were formulated and among these formulations, B8 was optimized. The hardness, friability, weight variation and drug content were found to be within pharmacopeias limits. The water absorption ratio, wetting time, in-vitro and in-vivo disintegration time of optimized formulation, B8 was found to be 86.1%, 8secs, 18secs and 25secs respectively. The formulation, B8 was considered to best formulation, which released up to 99.21% in 2 minutes. The comparison of dissolution rate profile of marketed formulation of Losartan potassium (Losacar tablet with best formulation, B8 was conducted. The result showed that the formulation, B8showed complete drug release within 2 minutes and marketed formulation showed complete drug release in 5 minutes. The stability study was also conducted the best formulation, B8 and it indicates that there was no significant change in any parameters. Hence the formulation A4 was considered to be highly stable.

  12. Antimalarial drug quality in the most severely malarious parts of Africa - a six country study.

    Directory of Open Access Journals (Sweden)

    Roger Bate

    Full Text Available A range of antimalarial drugs were procured from private pharmacies in urban and peri-urban areas in the major cities of six African countries, situated in the part of that continent and the world that is most highly endemic for malaria. Semi-quantitative thin-layer chromatography (TLC and dissolution testing were used to measure active pharmaceutical ingredient content against internationally acceptable standards. 35% of all samples tested failed either or both tests, and were substandard. Further, 33% of treatments collected were artemisinin monotherapies, most of which (78% were manufactured in disobservance of an appeal by the World Health Organisation (WHO to withdraw these clinically inappropriate medicines from the market. The high persistence of substandard drugs and clinically inappropriate artemisinin monotherapies in the private sector risks patient safety and, through drug resistance, places the future of malaria treatment at risk globally.

  13. Structural Basis for Binding and Selectivity of Antimalarial and Anticancer Ethylenediamine Inhibitors to Protein Farnesyltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Hast, Michael A.; Fletcher, Steven; Cummings, Christopher G.; Pusateri, Erin E.; Blaskovich, Michelle A.; Rivas, Kasey; Gelb, Michael H.; Voorhis, Wesley C.Van; Sebti, Said M.; Hamilton, Andrew D.; Beese, Lorena S. ((Yale)); ((USF)); ((UWASH)); ((Duke))

    2009-03-20

    Protein farnesyltransferase (FTase) catalyzes an essential posttranslational lipid modification of more than 60 proteins involved in intracellular signal transduction networks. FTase inhibitors have emerged as a significant target for development of anticancer therapeutics and, more recently, for the treatment of parasitic diseases caused by protozoan pathogens, including malaria (Plasmodium falciparum). We present the X-ray crystallographic structures of complexes of mammalian FTase with five inhibitors based on an ethylenediamine scaffold, two of which exhibit over 1000-fold selective inhibition of P. falciparum FTase. These structures reveal the dominant determinants in both the inhibitor and enzyme that control binding and selectivity. Comparison to a homology model constructed for the P. falciparum FTase suggests opportunities for further improving selectivity of a new generation of antimalarial inhibitors.

  14. 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.

  15. Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes.

    Science.gov (United States)

    Goodman, Christopher D; Siregar, Josephine E; Mollard, Vanessa; Vega-Rodríguez, Joel; Syafruddin, Din; Matsuoka, Hiroyuki; Matsuzaki, Motomichi; Toyama, Tomoko; Sturm, Angelika; Cozijnsen, Anton; Jacobs-Lorena, Marcelo; Kita, Kiyoshi; Marzuki, Sangkot; McFadden, Geoffrey I

    2016-04-15

    Drug resistance compromises control of malaria. Here, we show that resistance to a commonly used antimalarial medication, atovaquone, is apparently unable to spread. Atovaquone pressure selects parasites with mutations in cytochrome b, a respiratory protein with low but essential activity in the mammalian blood phase of the parasite life cycle. Resistance mutations rescue parasites from the drug but later prove lethal in the mosquito phase, where parasites require full respiration. Unable to respire efficiently, resistant parasites fail to complete mosquito development, arresting their life cycle. Because cytochrome b is encoded by the maternally inherited parasite mitochondrion, even outcrossing with wild-type strains cannot facilitate spread of resistance. Lack of transmission suggests that resistance will be unable to spread in the field, greatly enhancing the utility of atovaquone in malaria control. PMID:27081071

  16. Distillation Time as Tool for Improved Antimalarial Activity and Differential Oil Composition of Cumin Seed Oil.

    Science.gov (United States)

    Zheljazkov, Valtcho D; Gawde, Archana; Cantrell, Charles L; Astatkie, Tess; Schlegel, Vicki

    2015-01-01

    A steam distillation extraction kinetics experiment was conducted to estimate essential oil yield, composition, antimalarial, and antioxidant capacity of cumin (Cuminum cyminum L.) seed (fruits). Furthermore, regression models were developed to predict essential oil yield and composition for a given duration of the steam distillation time (DT). Ten DT durations were tested in this study: 5, 7.5, 15, 30, 60, 120, 240, 360, 480, and 600 min. Oil yields increased with an increase in the DT. Maximum oil yield (content, 2.3 g/100 seed), was achieved at 480 min; longer DT did not increase oil yields. The concentrations of the major oil constituents α-pinene (0.14-0.5% concentration range), β-pinene (3.7-10.3% range), γ-cymene (5-7.3% range), γ-terpinene (1.8-7.2% range), cumin aldehyde (50-66% range), α-terpinen-7-al (3.8-16% range), and β-terpinen-7-al (12-20% range) varied as a function of the DT. The concentrations of α-pinene, β-pinene, γ-cymene, γ-terpinene in the oil increased with the increase of the duration of the DT; α-pinene was highest in the oil obtained at 600 min DT, β-pinene and γ-terpinene reached maximum concentrations in the oil at 360 min DT; γ-cymene reached a maximum in the oil at 60 min DT, cumin aldehyde was high in the oils obtained at 5-60 min DT, and low in the oils obtained at 240-600 min DT, α-terpinen-7-al reached maximum in the oils obtained at 480 or 600 min DT, whereas β-terpinen-7-al reached a maximum concentration in the oil at 60 min DT. The yield of individual oil constituents (calculated from the oil yields and the concentration of a given compound at a particular DT) increased and reached a maximum at 480 or 600 min DT. The antimalarial activity of the cumin seed oil obtained during the 0-5 and at 5-7.5 min DT timeframes was twice higher than the antimalarial activity of the oils obtained at the other DT. This study opens the possibility for distinct marketing and utilization for these improved oils. The antioxidant

  17. Plutonium Immobilization Project Baseline Formulation

    Energy Technology Data Exchange (ETDEWEB)

    Ebbinghaus, B.

    1999-02-01

    A key milestone for the Immobilization Project (AOP Milestone 3.2a) in Fiscal Year 1998 (FY98) is the definition of the baseline composition or formulation for the plutonium ceramic form. The baseline formulation for the plutonium ceramic product must be finalized before the repository- and plant-related process specifications can be determined. The baseline formulation that is currently specified is given in Table 1.1. In addition to the baseline formulation specification, this report provides specifications for two alternative formulations, related compositional specifications (e.g., precursor compositions and mixing recipes), and other preliminary form and process specifications that are linked to the baseline formulation. The preliminary specifications, when finalized, are not expected to vary tremendously from the preliminary values given.

  18. Combating poor-quality anti-malarial medicines: a call to action.

    Science.gov (United States)

    Bassat, Quique; Tanner, Marcel; Guerin, Philippe J; Stricker, Kirstin; Hamed, Kamal

    2016-01-01

    The circulation of poor-quality medicines continues to undermine the fight against many life-threatening diseases. Anti-malarial medicines appear to have been particularly compromised and present a major public health threat in malaria-endemic countries, negatively affecting individuals and their communities. Concerted collaborative efforts are required from global, regional and national organizations, involving the public and private sectors, to address the problem. While many initiatives are underway, a number of unmet needs deserve urgent and increased multisector attention. At the global level, there is a need for an international public health legal framework or treaty on poor-quality medicines, with statutes suitable for integration into national laws. In addition, increased international efforts are required to strengthen the governance of global supply chains and enhance cooperation between national medicine regulation authorities and law enforcement bodies. Increased investment is needed in innovative technologies that will enable healthcare teams to detect poor-quality medicines at all levels of the supply chain. At the regional level, a number of initiatives would be beneficial-key areas are standardization, simplification, and reciprocal recognition of registration processes and development of quality control capacity in regional centres of excellence that are better aligned with public health needs; improved surveillance methods and creation of a framework for compulsory and transparent reporting of poor-quality medicines; additional support for national medicine regulation authorities and other national partner authorities; and an increase in support for regional laboratories to boost their capabilities in detecting poor-quality medicines. It is vital that all stakeholders involved in efforts against poor-quality anti-malarial medicines extend and strengthen their actions in these critical areas and thus effectively support global health development

  19. 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

  20. 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.

  1. Malaria healthcare policy change in Kenya: Implications on sales and marketing of antimalarials

    Directory of Open Access Journals (Sweden)

    Peter K. Ngure , Lorraine Nyaoke & David Minja

    2012-03-01

    Full Text Available Background & objectives: Malaria healthcare policy change in Kenya aimed at improving the control of malariabut faced a number of challenges in implementation related to marketing of the drugs. This research investigatedthe effect of the change of the national malaria policy on drug sales and strategic marketing responses ofantimalarial pharmaceutical companies in Kenya.Study design: A descriptive cross-sectional design was employed to describe the existing state of antimalarialsmarket in Kenya after the change of the malaria healthcare policy.Results & conclusion: Policy change did result in an increase in the sales of Coartem®. Novartis Pharma recordeda 97% growth in sales of Coartem® between 2003 and 2004. However, this increase was not experienced by allthe companies. Further, SPs (which had been replaced as first-line therapy for malaria registered good sales. Inmost cases, these sales were higher than the sales of Coartem®. Generally, the sales contribution of SPs andgeneric antimalarial medicines exceeded that of Coartem® for most distributors. The most common changemade to marketing strategies by distributors (62.5% was to increase imports of antimalarials. A total of 40% ofthe manufacturers preferred to increase their budgetary allocation for marketing activities. In view of the factthat continued sale of SP drugs and limited availability of AL poses the risk of increasing the incidence ofmalaria in Kenya, it is therefore, recommended that pharmacy surveillance systems be strengthened to ensuredrugs that have been rendered non-viable or that prescription-only medicines are not sold contrary to the nationalguidelines.

  2. In Vivo Antimalarial Activity of Annona muricata Leaf Extract in Mice Infected with Plasmodium berghei.

    Science.gov (United States)

    Somsak, Voravuth; Polwiang, Natsuda; Chachiyo, Sukanya

    2016-01-01

    Malaria is one of the most important infectious diseases in the world. The choice for the treatment is highly limited due to drug resistance. Hence, finding the new compounds to treat malaria is urgently needed. The present study was attempted to evaluate the antimalarial activity of the Annona muricata aqueous leaf extract in Plasmodium berghei infected mice. Aqueous leaf extract of A. muricata was prepared and tested for acute toxicity in mice. For efficacy test in vivo, standard 4-day suppressive test was carried out. ICR mice were inoculated with 10(7) parasitized erythrocytes of P. berghei ANKA by intraperitoneal injection. The extracts (100, 500, and 1000 mg/kg) were then given orally by gavage once a day for 4 consecutive days. Parasitemia, percentage of inhibition, and packed cell volume were subsequently calculated. Chloroquine (10 mg/kg) was given to infected mice as positive control while untreated control was given only distilled water. It was found that A. muricata aqueous leaf extract at doses of 100, 500, and 1000 mg/kg resulted in dose dependent parasitemia inhibition of 38.03%, 75.25%, and 85.61%, respectively. Survival time was prolonged in infected mice treated with the extract. Moreover, no mortality to mice was observed with this extract up to a dose of 4000 mg/kg. In conclusion, the A. muricata aqueous leaf extract exerted significant antimalarial activity with no toxicity and prolonged survival time. Therefore, this extract might contain potential lead molecule for the development of a new drug for malaria treatment. PMID:27092277

  3. Ligand based validated comparative chemometric modeling and pharmacophore mapping of aurone derivatives as antimalarial agents.

    Science.gov (United States)

    Adhikari, Nilanjan; Halder, Amit Kumar; Mondal, Chanchal; Jha, Tarun

    2013-09-01

    Chloroquine resistance is nowadays a great problem. Aurone derivatives are effective against chloroquine resistant parasite. Ligand based validated comparative chemometric modeling through 2D-QSAR and kNN-MFA 3DQSAR studies as well as common feature 3D pharmacophore mapping were done on thirtyfive aurone derivatives having antimalarial activity. Statistically significant 2D-QSAR models were generated on unsplitted as well as splitted dataset by MLR and PLS technique. The MLR model of the unsplitted method was validated by two-deep cross validation and 10 fold cross validation for determining the predictive ability. The PLS technique of the unsplitted method was done to compare the significance of these methods. In the splitted method, model was developed on the training set by Y-based ranking method by using the same descriptors and was validated on fifty pairs of the test and the training sets by k-MCA technique. These models generated by using the same descriptors were well validated irrespective of MLR as well as PLS analysis of unsplitted as well as splitted methods and are showing similar results. Therefore, these descriptors and model generated were reliable and robust. The kNN-MFA 3D-QSAR models were generated by three variable selection methods: genetic algorithm, simulated annealing and stepwise regression. The kNN-MFA 3D-QSAR results support the 2D QSAR data and in turn validate the earlier observed SAR results. Common feature 3D-pharmacophore generation was performed on these compounds to validate both 2D and 3D-QSAR studies as well as the earlier observed SAR data. The work highlights the required structural features for the higher antimalarial activity. PMID:24010937

  4. Compatibility assessment of thermoplastic formulations

    OpenAIRE

    D. McAteer; Weaver, M.; Blair, L H; Flood, N; Gaulter, S E

    2016-01-01

    Prior to the large-scale preparation of any new chemical formulation an assessment of the potential reactivity between the components must be carried out. This practice, which is common to many fields including pharmaceutical science, is particularly essential in the case of energetic formulations whose chemical incompatibility may result in an unexpected and potentially explosive decomposition. The common method used to investigate incompatibility is to heat 1:1 (w/w) formulations and eva...

  5. Explosive Formulation Code Naming SOP

    Energy Technology Data Exchange (ETDEWEB)

    Martz, H. E. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2014-09-19

    The purpose of this SOP is to provide a procedure for giving individual HME formulations code names. A code name for an individual HME formulation consists of an explosive family code, given by the classified guide, followed by a dash, -, and a number. If the formulation requires preparation such as packing or aging, these add additional groups of symbols to the X-ray specimen name.

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

    Directory of Open Access Journals (Sweden)

    Opwonya John

    2006-05-01

    Full Text Available 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 with inspection of blister packaging was conducted to investigate caretakers' adherence to HOMAPAK®. The population surveyed consisted of internally displaced people (IDPs from eight camps. Results A total of 241 caretakers were interviewed. 95.0% (CI: 93.3% – 98.4% of their children had received the correct dose for their age and 52.3% of caretakers had retained the blister pack. Assuming correct self-reporting, the overall adherence was 96.3% (CI: 93.9% – 98.7%. The nine caretakers who had not adhered had done so because the child had improved, had vomited, did not like the taste of the tablets, or because they forgot to administer the treatment. For 85.5% of cases treatment had been sought within 24 hours. Blister packaging was considered useful by virtually all respondents, mainly because it kept the drugs clean and dry. Information provided on, and inside, the package was of limited use, because most respondents were illiterate. However, CDDs had often told caretakers how to administer the treatment. For 39.4% of respondents consultation with the CDD was their reported first action when their child has fever and 52.7% stated that they consult her/him if the child does not get better. Conclusion In IDP camps, the HBMF strategy forms an important component of medical care for young children. In case of febrile illness, most caretakers obtain prompt and adequate antimalarial treatment, and adhere to it. A large proportion of malaria episodes are thus

  7. Baseline LAW Glass Formulation Testing

    Energy Technology Data Exchange (ETDEWEB)

    Kruger, Albert A. [USDOE Office of River Protection, Richland, WA (United States); Mooers, Cavin [The Catholic University of America, Washington, DC (United States). Vitreous State Lab.; Bazemore, Gina [The Catholic University of America, Washington, DC (United States). Vitreous State Lab; Pegg, Ian L. [The Catholic University of America, Washington, DC (United States). Vitreous State Lab; Hight, Kenneth [The Catholic University of America, Washington, DC (United States). Vitreous State Lab; Lai, Shan Tao [The Catholic University of America, Washington, DC (United States). Vitreous State Lab; Buechele, Andrew [The Catholic University of America, Washington, DC (United States). Vitreous State Lab; Rielley, Elizabeth [The Catholic University of America, Washington, DC (United States). Vitreous State Lab; Gan, Hao [The Catholic University of America, Washington, DC (United States). Vitreous State Lab; Muller, Isabelle S. [The Catholic University of America, Washington, DC (United States). Vitreous State Lab; Cecil, Richard [The Catholic University of America, Washington, DC (United States). Vitreous State Lab

    2013-06-13

    The major objective of the baseline glass formulation work was to develop and select glass formulations that are compliant with contractual and processing requirements for each of the LAW waste streams. Other objectives of the work included preparation and characterization of glasses with respect to the properties of interest, optimization of sulfate loading in the glasses, evaluation of ability to achieve waste loading limits, testing to demonstrate compatibility of glass melts with melter materials of construction, development of glass formulations to support ILAW qualification activities, and identification of glass formulation issues with respect to contract specifications and processing requirements.

  8. Pharmacokinetics and bioavailability of oxycodone and acetaminophen following single-dose administration of MNK-795, a dual-layer biphasic IR/ER combination formulation, under fed and fasted conditions

    Directory of Open Access Journals (Sweden)

    Devarakonda K

    2014-08-01

    Full Text Available Krishna Devarakonda,1 Terri Morton,1 Rachel Margulis,2 Michael Giuliani,3 Thomas Barrett4 1Clinical Pharmacology and Pharmacokinetics, 2Clinical Operations, 3Research and Development, 4Clinical Affairs, Mallinckrodt Inc., Hazelwood, MO, USA Background: XARTEMIS™ XR (formerly MNK-795 is a combination oxycodone (OC and acetaminophen (APAP analgesic with both immediate-release and extended-release (ER components (ER OC/APAP. The tablets are designed with gastric-retentive ER oral delivery technology that releases the ER component at a controlled rate in the upper gastrointestinal tract. Because consumption of food has demonstrated an impact on the pharmacokinetics (PK of some marketed products using gastric-retentive ER oral delivery technology, a characterization of the effects of fed (high- and low-fat diets versus fasted conditions on the PK of ER OC/APAP was performed. Methods: This Phase I study used an open-label randomized single-dose three-period six-sequence crossover single-center design. Healthy adult participants (n=48 were randomized to receive two tablets of ER OC/APAP under three conditions: following a high-fat meal; following a low-fat meal; and fasted. Plasma concentration versus time data from predose throughout designated times up to 48 hours postdose was used to estimate the PK parameters of oxycodone and APAP. Results: Thirty-one participants completed all three treatment periods. Both oxycodone and APAP were rapidly absorbed under fasted conditions. Total oxycodone and APAP exposures (area under the plasma drug concentration-time curve [AUC] from ER OC/APAP were not significantly affected by food, and minimal changes to maximum observed plasma concentration for oxycodone and APAP were also noted. However, food marginally delayed the time to maximum observed plasma concentration of oxycodone and APAP. There was no indication that tolerability was affected by food. Conclusion: The findings from this study suggest that ER OC

  9. A Chemical Proteomics Approach for the Search of Pharmacological Targets of the Antimalarial Clinical Candidate Albitiazolium in Plasmodium falciparum Using Photocrosslinking and Click Chemistry

    OpenAIRE

    Diana Marcela Penarete-Vargas; Anaïs Boisson; Serge Urbach; Hervé Chantelauze; Suzanne Peyrottes; Laurent Fraisse; Vial, Henri J

    2014-01-01

    Plasmodium falciparum is responsible for severe malaria which is one of the most prevalent and deadly infectious diseases in the world. The antimalarial therapeutic arsenal is hampered by the onset of resistance to all known pharmacological classes of compounds, so new drugs with novel mechanisms of action are critically needed. Albitiazolium is a clinical antimalarial candidate from a series of choline analogs designed to inhibit plasmodial phospholipid metabolism. Here we developed an origi...

  10. Development of a TaqMan Allelic Discrimination Assay for detection of Single Nucleotides Polymorphisms associated with anti-malarial drug resistance

    Directory of Open Access Journals (Sweden)

    Kamau Edwin

    2012-01-01

    Full Text Available Abstract Background Anti-malarial drug resistance poses a threat to current global efforts towards control and elimination of malaria. Several methods are used in monitoring anti-malarial drug resistance. Molecular markers such as single nucleotide polymorphism (SNP for example are increasingly being used to identify genetic mutations related to anti-malarial drug resistance. Several methods are currently being used in analysis of SNP associated with anti-malarial drug resistance and although each one of these methods has unique strengths and shortcoming, there is still need to improve and/or develop new methods that will close the gap found in the current methods. Methods TaqMan Allelic Discrimination assays for detection of SNPs associated with anti-malarial drug resistance were designed for analysis on Applied Biosystems PCR platform. These assays were designed by submitting SNP sequences associated with anti-malarial drug resistance to Applied Biosystems website. Eleven SNPs associated with resistance to anti-malarial drugs were selected and tested. The performance of each SNP assay was tested by creating plasmid DNAs carrying codons of interests and analysing them for analysis. To test the sensitivity and specificity of each SNP assay, 12 clinical samples were sequenced at codons of interest and used in the analysis. Plasmid DNAs were used to establish the Limit of Detection (LoD for each assay. Results Data from genetic profiles of the Plasmodium falciparum laboratory strains and sequence data from 12 clinical samples was used as the reference method with which the performance of the SNP assays were compared to. The sensitivity and specificity of each SNP assay was establish at 100%. LoD for each assay was established at 2 GE, equivalent to less than 1 parasite/μL. SNP assays performed well in detecting mixed infection and analysis of clinical samples. Conclusion TaqMan Allelic Discrimination assay provides a good alternative tool in

  11. Formulation and Evaluation of Coprocessed Excipient for Mouth Dissolving Formulation

    Directory of Open Access Journals (Sweden)

    Gandhi PP and Mundada AS

    2016-03-01

    Full Text Available In the present study an attempt has been made to evaluate Ocimum bascilium mucilage coprocessed with Mannitol as a novel super disintegrant. Coprocessed excipients were prepared by solvent evaporation method and evaluated in the formulation of mouth dissolving tablets of Terbutaline sulphate. Formulated mouth dissolving tablets were characterised for physicochemical parameters like hardness, friability, weight variation, disintegration time, drug content and in vitro drug release behaviour. The outcomes of physicochemical evaluation of formulations showed that all developed formulations had desirable features. The coprocessed mucilage (Mannitol: Mucilage exhibited disintegration within 8 sec at the concentration of 1 gm: 65 mg as compared to the coprocessed Mannitol: SSG which disintegrated within 11 sec at the concentration of 1 gm: 85 mg. The developed excipient showed improvement in parent excipient functionalities and proving coprocessed mucilage of Ocimum bascilium to be an excellent novel superdisintegrant in mouth dissolving formulation and thus it can be exploited commercially.

  12. Increasing use of artemisinin-based combination therapy for treatment of malaria infection in Nigerian hospitals

    Directory of Open Access Journals (Sweden)

    Igboeli NU

    2010-12-01

    Full Text Available Objectives: This study aimed at describing the pattern of outpatient antimalarial drug prescribing in a secondary and a tertiary hospital, and to assess adherence to the National Antimalarial Treatment Guideline (ATG. Methods: An audit of antimalarial prescription files from the two health facilities for a period of six months in 2008 was conducted. Semi structured questionnaires were used to collect information from the doctors and pharmacists on their awareness and knowledge of the National Antimalarial Treatment Guideline. Results: Artemisinin-based combination therapies (ACTs were the most prescribed antimalarials. Overall, 81.4% of the total prescriptions contained ACTs, out of which 56.8% were artemether-lumefantrine. However, adherence to the drugs indicated by national guideline within the DU90% was 38.5% for the tertiary and 66.7 % for the secondary hospital. The standard practice of prescribing with generic name was still not adhered to as evidenced in the understudied hospitals. The percentage of health care providers that were aware of the ATG was 88.2% for doctors and 85.1% for pharmacists. However, 13.3% and 52.2% of doctors and pharmacists respectively could not properly list the drugs specified in the guideline. Amodiaquine was the most commonly preferred option for managing children aged 0 – 3 months with malaria infection against the indicated oral quinine.Conclusion: This study showed an increased use of artemisinin-based combination therapy for the treatment of uncomplicated malaria compared previous reports in Nigeria. This study also highlights the need for periodic in-service quality assurance among health professionals with monitoring of adherence to and assessment of knowledge of clinical guidelines to ensure the practice of evidence based medicine.

  13. Saltstone Clean Cap Formulation

    Energy Technology Data Exchange (ETDEWEB)

    Langton, C

    2005-04-22

    The current operation strategy for using Saltstone Vault 4 to receive 0.2 Ci/gallon salt solution waste involves pouring a clean grout layer over the radioactive grout prior to initiating pour into another cell. This will minimize the radiating surface area and reduce the dose rate at the vault and surrounding area. The Clean Cap will be used to shield about four feet of Saltstone poured into a Z-Area vault cell prior to moving to another cell. The minimum thickness of the Clean Cap layer will be determined by the cesium concentration and resulting dose levels and it is expected to be about one foot thick based on current calculations for 0.1 Ci Saltstone that is produced in the Saltstone process by stabilization of 0.2 Ci salt solution. This report documents experiments performed to identify a formulation for the Clean Cap. Thermal transient calculations, adiabatic temperature rise measurements, pour height, time between pour calculations and shielding calculations were beyond the scope and time limitations of this study. However, data required for shielding calculations (composition and specific gravity) are provided for shielding calculations. The approach used to design a Clean Cap formulation was to produce a slurry from the reference premix (10/45/45 weight percent cement/slag/fly ash) and domestic water that resembled as closely as possible the properties of the Saltstone slurry. In addition, options were investigated that may offer advantages such as less bleed water and less heat generation. The options with less bleed water required addition of dispersants. The options with lower heat contained more fly ash and less slag. A mix containing 10/45/45 weight percent cement/slag/fly ash with a water to premix ratio of 0.60 is recommended for the Clean Cap. Although this mix may generate more than 3 volume percent standing water (bleed water), it has rheological, mixing and flow properties that are similar to previously processed Saltstone. The recommended

  14. Saltstone Clean Cap Formulation

    International Nuclear Information System (INIS)

    The current operation strategy for using Saltstone Vault 4 to receive 0.2 Ci/gallon salt solution waste involves pouring a clean grout layer over the radioactive grout prior to initiating pour into another cell. This will minimize the radiating surface area and reduce the dose rate at the vault and surrounding area. The Clean Cap will be used to shield about four feet of Saltstone poured into a Z-Area vault cell prior to moving to another cell. The minimum thickness of the Clean Cap layer will be determined by the cesium concentration and resulting dose levels and it is expected to be about one foot thick based on current calculations for 0.1 Ci Saltstone that is produced in the Saltstone process by stabilization of 0.2 Ci salt solution. This report documents experiments performed to identify a formulation for the Clean Cap. Thermal transient calculations, adiabatic temperature rise measurements, pour height, time between pour calculations and shielding calculations were beyond the scope and time limitations of this study. However, data required for shielding calculations (composition and specific gravity) are provided for shielding calculations. The approach used to design a Clean Cap formulation was to produce a slurry from the reference premix (10/45/45 weight percent cement/slag/fly ash) and domestic water that resembled as closely as possible the properties of the Saltstone slurry. In addition, options were investigated that may offer advantages such as less bleed water and less heat generation. The options with less bleed water required addition of dispersants. The options with lower heat contained more fly ash and less slag. A mix containing 10/45/45 weight percent cement/slag/fly ash with a water to premix ratio of 0.60 is recommended for the Clean Cap. Although this mix may generate more than 3 volume percent standing water (bleed water), it has rheological, mixing and flow properties that are similar to previously processed Saltstone. The recommended

  15. Biopsychosocial Formulation: Recognizing Educational Shortcomings

    Science.gov (United States)

    McClain, Tina; O'Sullivan, Patricia S.; Clardy, James A.

    2004-01-01

    Objective: Since Engel introduced the biopsychosocial model, it has been extensively examined. The authors expect psychiatrists to formulate cases using the biopsychosocial model. However, resident psychiatrists' ability to generate formulations using this model has received little attention. Methods: The authors evaluated resident biopsychosocial…

  16. Formulation and evaluation of Rizatriptan Benzoate Orally Disintegrating Tablets

    Directory of Open Access Journals (Sweden)

    Mothilal. M

    2012-06-01

    Full Text Available Formulation research is oriented towards safety, efficacy and quick onset of action of existing drug molecule through novel concepts of drug delivery. Orally disintegrating tablets of Rizatriptan benzoate were prepared by direct compression method to provide faster relief from pain to migraine sufferers. About twelve formulations for the present study were carried out based on 2 level 2 factor full factorial design for each set of superdisintegrants. Croscarmellose sodium, Crospovidone and Sodium starch glycolate (SSG were used as superdisintegrants, while microcrystalline cellulose was used as diluent. The prepared batches of tablets were evaluated for weight variation, hardness, friability, wetting time, invitro dispersion time, drug content and invitro dissolution studies. The formulation containing combination of Croscarmellose sodium and Sodium starch glycolate showed rapid invitro dispersion time as compared to other formulations. The optimized formulation dispersed in 8 seconds. It also showed a higher water absorption ratio and 99.58% of drug is released within 2 minutes.

  17. Effects of mometasone furoate/formoterol fumarate fixed-dose combination formulation on chronic obstructive pulmonary disease (COPD: results from a 52-week Phase III trial in subjects with moderate-to-very severe COPD

    Directory of Open Access Journals (Sweden)

    Doherty DE

    2012-02-01

    Full Text Available Dennis E Doherty1, Donald P Tashkin2, Edward Kerwin3, Barbara A Knorr4, Tulin Shekar4, Sibabrata Banerjee4, Heribert Staudinger41Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky, Lexington, KY, 2David Geffen School of Medicine at UCLA, Los Angeles, CA, 3Clinical Research Institute of Southern Oregon, Medford, OR, 4Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USARationale: The purpose of this study was to investigate the clinical efficacy and safety of a fixed-dose combination of mometasone furoate/formoterol fumarate (MF/F administered via a metered-dose inhaler in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD.Methods: This multicenter, double-blind, placebo-controlled trial had a 26-week treatment period and a 26-week safety extension. Subjects (n = 1196, at least 40 years old, were current or ex-smokers randomized to twice-daily inhaled MF/F 400/10 µg, MF/F 200/10 µg, MF 400 µg, F 10 µg, or placebo. The trial’s co-primary endpoints were mean changes from baseline, as area under the curve (AUC, in forced expiratory volume (FEV1 over 0–12 hours (AUC0-12 h FEV1 with MF/F versus MF, and in morning (AM pre-dose (trough FEV1 with MF/F versus F after 13 weeks of treatment. Key secondary endpoints were the effects of MF/F on respiratory health status using the Saint George’s Respiratory Questionnaire (SGRQ, symptom-free nights, partly stable COPD at 26 weeks, and time to first COPD exacerbation.Results: The largest improvements in AUC0-12 h FEV1 were observed with MF/F 400/10 µg and MF/F 200/10 µg. Serial spirometry results demonstrated that bronchodilator effects with MF/F occurred rapidly (within 5 minutes, persisted for 12 hours after dosing, and were sustained over the 26-week treatment period. Similar findings were observed for AM pre-dose FEV1, for which effects were further investigated, excluding subjects whose AM FEV1 data were incorrectly collected after 2

  18. Vector incrimination and effects of antimalarial drugs on malaria transmission and control in the Amazon Basin of Brazil

    Directory of Open Access Journals (Sweden)

    T. A. Klein

    1992-01-01

    Full Text Available World ecosystems differ significantly and a multidisciplinary malaria control approach must be adjusted to meet these requirements. These include a comprehensive understanding of the malaria vectors, their behavior, seasonal distribution and abundance, susceptibility to insecticides (physiological and behavioral, methods to reduce the numbers of human gametocyte carriers through effective health care systems and antimalarial drug treatment, urban malaria transmission versus rural or forest malaria transmission, and the impact of vaccine development. Many malaria vectors are members of species complexes and individual relationship to malaria transmission, seasonal distribution, bitting behavior, etc. is poorly understood. Additionaly, malaria patients are not examined for circulating gametocytes and both falciparum and vivax malaria patients may be highly infective to mosquitoes after treatment with currently used antimalarial drugs. Studies on the physiological and behavioral effects of DDT and other insecticides are inconclusive and need to be evalusted.

  19. Towards a methodology to formulate sustainable diets for livestock: accounting for environmental impact in diet formulation.

    Science.gov (United States)

    Mackenzie, S G; Leinonen, I; Ferguson, N; Kyriazakis, I

    2016-05-28

    The objective of this study was to develop a novel methodology that enables pig diets to be formulated explicitly for environmental impact objectives using a Life Cycle Assessment (LCA) approach. To achieve this, the following methodological issues had to be addressed: (1) account for environmental impacts caused by both ingredient choice and nutrient excretion, (2) formulate diets for multiple environmental impact objectives and (3) allow flexibility to identify the optimal nutritional composition for each environmental impact objective. An LCA model based on Canadian pig farms was integrated into a diet formulation tool to compare the use of different ingredients in Eastern and Western Canada. By allowing the feed energy content to vary, it was possible to identify the optimum energy density for different environmental impact objectives, while accounting for the expected effect of energy density on feed intake. A least-cost diet was compared with diets formulated to minimise the following objectives: non-renewable resource use, acidification potential, eutrophication potential, global warming potential and a combined environmental impact score (using these four categories). The resulting environmental impacts were compared using parallel Monte Carlo simulations to account for shared uncertainty. When optimising diets to minimise a single environmental impact category, reductions in the said category were observed in all cases. However, this was at the expense of increasing the impact in other categories and higher dietary costs. The methodology can identify nutritional strategies to minimise environmental impacts, such as increasing the nutritional density of the diets, compared with the least-cost formulation. PMID:26987378

  20. Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs

    OpenAIRE

    Mu, Jianbing; Myers, Rachel A.; Jiang, Hongying; Liu, Shengfa; Ricklefs, Stacy; Waisberg, Michael; Chotivanich, Kesinee; Wilairata, Polrat; Krudsood, Srivicha; White, Nicholas J; Udomsangpetch, Rachanee; Cui, Liwang; Ho, May; Ou, Fengzheng; Li, Haibo

    2010-01-01

    Antimalarial drugs impose strong pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome 1,2. Search for signals of selection may lead to genes encoding drug or immune targets 3. The lack of high-throughput genotyping methods, inadequate knowledge of parasite population history, and time-consuming adaptations of parasites to in vitro culture have hampered genome-wide association studies (GWAS) of parasite traits. Here we report genotyping of DNA fr...

  1. Activity of clinically relevant antimalarial drugs on Plasmodium falciparum mature gametocytes in an ATP bioluminescence "transmission blocking" assay.

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    Joël Lelièvre

    Full Text Available BACKGROUND: Current anti-malarial drugs have been selected on the basis of their activity against the symptom-causing asexual blood stage of the parasite. Which of these drugs also target gametocytes, in the sexual stage responsible for disease transmission, remains unknown. Blocking transmission is one of the main strategies in the eradication agenda and requires the identification of new molecules that are active against gametocytes. However, to date, the main limitation for measuring the effect of molecules against mature gametocytes on a large scale is the lack of a standardized and reliable method. Here we provide an efficient method to produce and purify mature gametocytes in vitro. Based on this new procedure, we developed a robust, affordable, and sensitive ATP bioluminescence-based assay. We then assessed the activity of 17 gold-standard anti-malarial drugs on Plasmodium late stage gametocytes. METHODS AND FINDINGS: Difficulties in producing large amounts of gametocytes have limited progress in the development of malaria transmission blocking assays. We improved the method established by Ifediba and Vanderberg to obtain viable, mature gametocytes en masse, whatever the strain used. We designed an assay to determine the activity of antimalarial drugs based on the intracellular ATP content of purified stage IV-V gametocytes after 48 h of drug exposure in 96/384-well microplates. Measurements of drug activity on asexual stages and cytotoxicity on HepG2 cells were also obtained to estimate the specificity of the active drugs. CONCLUSIONS: The work described here represents another significant step towards determination of the activity of new molecules on mature gametocytes of any strain with an automated assay suitable for medium/high-throughput screening. Considering that the biology of the forms involved in the sexual and asexual stages is very different, a screen of our 2 million-compound library may allow us to discover novel anti-malarial

  2. Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

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    Mullié Catherine

    2012-03-01

    Full Text Available Abstract Background A better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ (+- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs. Results The (S-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R -enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S and (R-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ. Conclusions The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro.

  3. Anti-malarial activity and toxicity assessment of Himatanthus articulatus, a plant used to treat malaria in the Brazilian Amazon

    OpenAIRE

    Vale, Valdicley V; Thyago C. Vilhena; Trindade, Rafaela C Santos; Ferreira, Márlia Regina C; Percário, Sandro; Soares, Luciana F; Pereira, Washington Luiz A; Geraldo C. Brandão; Oliveira, Alaíde B; Dolabela, Maria F; De Vasconcelos, Flávio

    2015-01-01

    Background Plasmodium falciparum has become resistant to some of the available drugs. Several plant species are used for the treatment of malaria, such as Himatanthus articulatus in parts of Brazil. The present paper reports the phyto-chemistry, the anti-plasmodial and anti-malarial activity, as well as the toxicity of H. articulatus. Methods Ethanol and dichloromethane extracts were obtained from the powder of stem barks of H. articulatus and later fractionated and analysed. The anti-plasmod...

  4. From Supersaturated Drug Delivery Systems to the Rising Era of Pediatric Formulations

    OpenAIRE

    Charkoftaki, G.; Valsami, G.; Macheras, P.

    2012-01-01

    The number of options available to drug discovery scientists to enhance the solubility of poorly soluble compounds by conventional formulation approaches is limited. In most cases, drug formulation is oriented toward the creation of a supersaturated solution upon contact with aqueous environment, often combined with solubilizing agents and precipitation inhibitors. The most popular formulations for achieving this target are the lipid-based formulations called self-emulsifying and self-micr...

  5. Development of a specific monoclonal antibody-based ELISA to measure the artemether content of antimalarial drugs.

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    Suqin Guo

    Full Text Available Artemether is one of the artemisinin derivatives that are active ingredients in antimalarial drugs. Counterfeit and substandard antimalarial drugs have become a serious problem, which demands reliable analytical tools and implementation of strict regulation of drug quality. Structural similarity among artemisinin analogs is a challenge to develop immunoassays that are specific to artemisinin derivatives. To produce specific antibodies to artemether, we used microbial fermentation of artemether to obtain 9-hydroxyartemether, which was subsequently used to prepare a 9-O-succinylartemether hapten for conjugation with ovalbumin as the immunogen. A monoclonal antibody (mAb, designated as 2G12E1, was produced with high specificity to artemether. 2G12E1 showed low cross reactivities to dihydroartemisinin, artemisinin, artesunate and other major antimalarial drugs. An indirect competitive enzyme linked immunosorbent assay (icELISA developed showed a concentration causing 50% of inhibition for artemether as 3.7 ng mL⁻¹ and a working range of 0.7-19 ng mL⁻¹. The icELISA was applied for determination of artemether content in different commercial drugs and the results were comparable to those determined by high-performance liquid chromatography analysis. In comparison with reported broad cross activity of anti-artemisinin mAbs, the most notable advantage of the 2G12E1-based ELISA is its high specificity to artemether only.

  6. The use of genotyping in antimalarial clinical trials: a systematic review of published studies from 1995–2005

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    Rosenthal Philip J

    2006-12-01

    Full Text Available Abstract Background The use of genotyping to distinguish recrudescent from new infections is currently recommended for all clinical antimalarial efficacy trials by the World Health Organization. However, genotyping-adjusted drug efficacy estimates may vary between trials due to the use of different genotyping methods and to the different settings in which these methods are applied. Methods A systematic review of all clinical antimalarial efficacy trials published from 1995–2005 was performed to characterize the use of genotyping, including the methods used and the effect of these methods on estimates of drug efficacy. Results In a multivariate analysis, the method of interpretation of genotyping results, the studied therapy, the location of the trial, and the duration of study follow-up all had statistically significant effects on the percent of genotyped outcomes classified as new infections. Conclusion Criteria for defining appropriate, standardized genotyping methods for use in different settings are needed to enable more accurate estimates of antimalarial drug efficacy and better comparison between trials. The advantages and disadvantages of different genotyping methods and their potential impact in various settings are discussed.

  7. Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum.

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    Daria Van Tyne

    2011-04-01

    Full Text Available The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (∼ 1 SNP/kb, and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS, searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.

  8. Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor.

    Science.gov (United States)

    Goldgof, Gregory M; Durrant, Jacob D; Ottilie, Sabine; Vigil, Edgar; Allen, Kenneth E; Gunawan, Felicia; Kostylev, Maxim; Henderson, Kiersten A; Yang, Jennifer; Schenken, Jake; LaMonte, Gregory M; Manary, Micah J; Murao, Ayako; Nachon, Marie; Stanhope, Rebecca; Prescott, Maximo; McNamara, Case W; Slayman, Carolyn W; Amaro, Rommie E; Suzuki, Yo; Winzeler, Elizabeth A

    2016-01-01

    The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in ScPMA1 do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace ScPma1p from the plasma membrane. Using an in vitro cell-free assay, we demonstrate that KAE609 directly inhibits ScPma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a ScPma1p homology model identifies a binding mode that supports genetic resistance determinants and in vitro experimental structure-activity relationships in both P. falciparum and S. cerevisiae. This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity. PMID:27291296

  9. Formulation and evaluation of buccoadhesive quetiapine fumarate tablets

    OpenAIRE

    Appa Rao Potu; Naresh Pujari; Shashidher Burra; Prabhakar Reddy Veerareddy

    2012-01-01

    The aim of present study was to develop and evaluate buccoadhesive Quetiapine Fumarate (QF) tablets, which is extensively metabolised by liver. Buccoadhesive tablets of QF were prepared using HPMC K4M, HPMC K15M and combination of carbopol and HPC as mucoadhesive polymers by direct compression method. Sodium deoxycholate was added to formulation to improve the permeation of drug. The formulations were tested for bioadhesion strength, ex vivo residence time, swelling time and in vitro dissolut...

  10. Novel Formulations for Antimicrobial Peptides

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    Ana Maria Carmona-Ribeiro

    2014-10-01

    Full Text Available Peptides in general hold much promise as a major ingredient in novel supramolecular assemblies. They may become essential in vaccine design, antimicrobial chemotherapy, cancer immunotherapy, food preservation, organs transplants, design of novel materials for dentistry, formulations against diabetes and other important strategical applications. This review discusses how novel formulations may improve the therapeutic index of antimicrobial peptides by protecting their activity and improving their bioavailability. The diversity of novel formulations using lipids, liposomes, nanoparticles, polymers, micelles, etc., within the limits of nanotechnology may also provide novel applications going beyond antimicrobial chemotherapy.

  11. G6PD Deficiency and Antimalarial Efficacy for Uncomplicated Malaria in Bangladesh: A Prospective Observational Study

    Science.gov (United States)

    Ley, Benedikt; Alam, Mohammad Shafiul; Thriemer, Kamala; Hossain, Mohammad Sharif; Kibria, Mohammad Golam; Auburn, Sarah; Poirot, Eugenie; Price, Ric N.; Khan, Wasif Ali

    2016-01-01

    Background The Bangladeshi national treatment guidelines for uncomplicated malaria follow WHO recommendations but without G6PD testing prior to primaquine administration. A prospective observational study was conducted to assess the efficacy of the current antimalarial policy. Methods Patients with uncomplicated malaria, confirmed by microscopy, attending a health care facility in the Chittagong Hill Tracts, Bangladesh, were treated with artemether-lumefantrine (days 0–2) plus single dose primaquine (0.75mg/kg on day2) for P. falciparum infections, or with chloroquine (days 0–2) plus 14 days primaquine (3.5mg/kg total over 14 days) for P. vivax infections. Hb was measured on days 0, 2 and 9 in all patients and also on days 16 and 30 in patients with P. vivax infection. Participants were followed for 30 days. The study was registered with the clinical trials website (NCT02389374). Results Between September 2014 and February 2015 a total of 181 patients were enrolled (64% P. falciparum, 30% P. vivax and 6% mixed infections). Median parasite clearance times were 22.0 (Interquartile Range, IQR: 15.2–27.3) hours for P. falciparum, 20.0 (IQR: 9.5–22.7) hours for P. vivax and 16.6 (IQR: 10.0–46.0) hours for mixed infections. All participants were afebrile within 48 hours, two patients with P. falciparum infection remained parasitemic at 48 hours. No patient had recurrent parasitaemia within 30 days. Adjusted male median G6PD activity was 7.82U/gHb. One male participant (1/174) had severe G6PD deficiency (<10% activity), five participants (5/174) had mild G6PD deficiency (10–60% activity). The Hb nadir occurred on day 2 prior to primaquine treatment in P. falciparum and P. vivax infected patients; mean fractional fall in Hb was -8.8% (95%CI -6.7% to -11.0%) and -7.4% (95%CI: -4.5 to -10.4%) respectively. Conclusion The current antimalarial policy remains effective. The prevalence of G6PD deficiency was low. Main contribution to haemolysis in G6PD normal

  12. G6PD Deficiency and Antimalarial Efficacy for Uncomplicated Malaria in Bangladesh: A Prospective Observational Study.

    Directory of Open Access Journals (Sweden)

    Benedikt Ley

    Full Text Available The Bangladeshi national treatment guidelines for uncomplicated malaria follow WHO recommendations but without G6PD testing prior to primaquine administration. A prospective observational study was conducted to assess the efficacy of the current antimalarial policy.Patients with uncomplicated malaria, confirmed by microscopy, attending a health care facility in the Chittagong Hill Tracts, Bangladesh, were treated with artemether-lumefantrine (days 0-2 plus single dose primaquine (0.75mg/kg on day2 for P. falciparum infections, or with chloroquine (days 0-2 plus 14 days primaquine (3.5mg/kg total over 14 days for P. vivax infections. Hb was measured on days 0, 2 and 9 in all patients and also on days 16 and 30 in patients with P. vivax infection. Participants were followed for 30 days. The study was registered with the clinical trials website (NCT02389374.Between September 2014 and February 2015 a total of 181 patients were enrolled (64% P. falciparum, 30% P. vivax and 6% mixed infections. Median parasite clearance times were 22.0 (Interquartile Range, IQR: 15.2-27.3 hours for P. falciparum, 20.0 (IQR: 9.5-22.7 hours for P. vivax and 16.6 (IQR: 10.0-46.0 hours for mixed infections. All participants were afebrile within 48 hours, two patients with P. falciparum infection remained parasitemic at 48 hours. No patient had recurrent parasitaemia within 30 days. Adjusted male median G6PD activity was 7.82U/gHb. One male participant (1/174 had severe G6PD deficiency (<10% activity, five participants (5/174 had mild G6PD deficiency (10-60% activity. The Hb nadir occurred on day 2 prior to primaquine treatment in P. falciparum and P. vivax infected patients; mean fractional fall in Hb was -8.8% (95%CI -6.7% to -11.0% and -7.4% (95%CI: -4.5 to -10.4% respectively.The current antimalarial policy remains effective. The prevalence of G6PD deficiency was low. Main contribution to haemolysis in G6PD normal individuals was attributable to acute malaria rather

  13. Cytotoxicity of antimalarial plant extracts from Kenyan biodiversity to the brine shrimp, Artemia salina L. (Artemiidae

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    Joseph Mwanzia Nguta

    2012-07-01

    Full Text Available Artemia salina (Artemiidae, the brine shrimp larva, is an invertebrate used in the alternative test to determine toxicity of chemicals and natural products. In this study the medium lethal concentration fifty (LC50 values of 45 antimalarial plant extracts and positive controls, cyclophosphamide and etoposide were determined using Artemia salina (Artemiidae. Out of the 45 organic extracts screened for activity against Artemia salina larvae, 23 (51% of the crude extracts demonstrated activity at or below 100 μg/mL, and were categorized as having strong cytotoxic activity, 18 (40% of the crude extracts had LC50 values between 100 μg/mL and 500 μg/mL, and were categorized as having moderate cytotoxicity, 2 (4.5% of the crude extracts had LC50 values between 500 μg/mL and 1000 μg/mL, and were considered to have weak cytotoxic activity, while 2 (4.5% of the crude extracts had LC50 values greater than 1000 μg/mL and were considered to be non toxic. Approximately 20% (9 of the aqueous extracts demonstrated activity at or below 100 g/mL and were considered to have strong cytotoxic activity, 40% (18 of the screened aqueous crude extracts had LC50 values between 100 μg/mL and 500 μg/mL and were considered to be moderately cytotoxic, 16% (7 of the crude extracts had LC50 values between 500 μg/mL and 1000 μg/mL and were considered to have weak cytotoxic activity while 24% (11 of the aqueous extracts had LC50 values greater than 1000μg/mL and were categorized as non toxic The positive controls, cyclophosphamide and etoposide exhibited strong cytotoxicity with LC50 values of 95 μg/mL and 6 μg/mL respectively in a 24 hour lethality study, validating their use as anticancer agents. In the current study, 95.5% of all the screened organic extracts and 76% of the investigated aqueous extracts demonstrated LC50 values <1000 g/mL, indicating that these plants could not make safe anti-malarial treatments. This calls for dose adjustment amongst the

  14. Malaria Control Dynamics in Rural Tanzania: Evaluation of implementation of Artemisinin based Anti-malarial Combination Therapy

    OpenAIRE

    Khatib, Rashid Ali

    2010-01-01

    Malaria is the most important parasitic disease caused by protozoans of the genus plasmodia that are transmitted by female anophelene mosquitoes. Plasmodium falciparum is the most important species owing to its distribution, virulence and pathogenicity. World-wide some 500 million infections, 200-300 million episodes and about 1 million malaria-related deaths occur every year amounting to a burden of some 45 million DALYs (Disability Adjusted Life Years) [1]. At least 80% of this intolerable ...

  15. Malaria control dynamics in rural Tanzania : evaluation of implementation of artemisinin based anti-malarial combination therapy

    OpenAIRE

    Khatib, Rashid Ali

    2010-01-01

    Malaria is the most important parasitic disease caused by protozoans of the genus plasmodia that are transmitted by female anophelene mosquitoes. Plasmodium falciparum is the most important species owing to its distribution, virulence and pathogenicity. World-wide some 500 million infections, 200-300 million episodes and about 1 million malaria-related deaths occur every year amounting to a burden of some 45 million DALYs (Disability Adjusted Life Years) [1]. At least 80% of...

  16. SMS for Life: a pilot project to improve anti-malarial drug supply management in rural Tanzania using standard technology

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    Mwafongo Winfred

    2010-10-01

    Full Text Available Abstract Background Maintaining adequate supplies of anti-malarial medicines at the health facility level in rural sub-Saharan Africa is a major barrier to effective management of the disease. Lack of visibility of anti-malarial stock levels at the health facility level is an important contributor to this problem. Methods A 21-week pilot study, 'SMS for Life', was undertaken during 2009-2010 in three districts of rural Tanzania, involving 129 health facilities. Undertaken through a collaborative partnership of public and private institutions, SMS for Life used mobile telephones, SMS messages and electronic mapping technology to facilitate provision of comprehensive and accurate stock counts from all health facilities to each district management team on a weekly basis. The system covered stocks of the four different dosage packs of artemether-lumefantrine (AL and quinine injectable. Results Stock count data was provided in 95% of cases, on average. A high response rate (≥ 93% was maintained throughout the pilot. The error rate for composition of SMS responses averaged 7.5% throughout the study; almost all errors were corrected and messages re-sent. Data accuracy, based on surveillance visits to health facilities, was 94%. District stock reports were accessed on average once a day. The proportion of health facilities with no stock of one or more anti-malarial medicine (i.e. any of the four dosages of AL or quinine injectable fell from 78% at week 1 to 26% at week 21. In Lindi Rural district, stock-outs were eliminated by week 8 with virtually no stock-outs thereafter. During the study, AL stocks increased by 64% and quinine stock increased 36% across the three districts. Conclusions The SMS for Life pilot provided visibility of anti-malarial stock levels to support more efficient stock management using simple and widely available SMS technology, via a public-private partnership model that worked highly effectively. The SMS for Life system has

  17. Relativistic formulation of quark model

    International Nuclear Information System (INIS)

    A relativistic model, which describes spin-orbital excitations of quark-antiquark bound system, is proposed. A formulation of the model provides the meson classification established in frame of the nonrelativistic quark model. 3 refs

  18. Formulation Optimization of Arecoline Patches

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    Pao-Chu Wu

    2014-01-01

    Full Text Available The response surface methodology (RSM including polynomial equations has been used to design an optimal patch formulation with appropriate adhesion and flux. The patch formulations were composed of different polymers, including Eudragit RS 100 (ERS, Eudragit RL 100 (ERL and polyvinylpyrrolidone K30 (PVP, plasticizers (PEG 400, and drug. In addition, using terpenes as enhancers could increase the flux of the drug. Menthol showed the highest enhancement effect on the flux of arecoline.

  19. Niosomal Formulation Of Orlistat: Formulation And In-Vitro Evaluation

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    SAMYUKTHA RANI. B

    2011-06-01

    Full Text Available The purpose of the research was to prepare Orlistat niosomes from proniosome to improve its poor and variable oral bioavailability. The non-ionic surfactant vesicles are prepared by the reverse phase evaporation technique (slurry method. The slurry of - Cyclodextrin and Span 60 was dried to form a free flowing powder in rotary flash evaporator which could be rehydrated by addition of buffer (0.5% NaCl with 3% SLS at pH 6.0. The lipid mixture consisted of cholesterol, Span 60 and - Cyclodextrin carrier in molar ratios of (0.1:0.9:1 to 0.9:0.1:1 respectively. The niosomal formulations were evaluated for particle size, entrapment efficiency, in-vitro drug release, release kinetics, Interactions and compatibility (FT-IR, surface morphology (SEM, stability studies, conductivity and sedimentation rate, pH density, viscosity. The formulation OT9 which showed higher entrapment efficiency of 44.09% and invitro releases of 94.59% at the end of 12hrs was found to be best among all the 9 formulations. Release was best fitted with Hixson kinetics and it shows that the drug release may follow diffusion mechanism. FT-IR data revealed that, compatible and there were no interactions between the drug and excipients added in the formulation. SEM images of niosomes with various magnifications revealed the mean size of the niosomes were 100 nm with smooth surface. Niosome formulation has showed appropriate stability for 90 days by storing the formulation at room temperature. Thus the niosomal formulations could be a promising delivery system for Orlistat with improved oral bioavailability, stability and for sustained drug release.

  20. Pyrrolidine-Acridine hybrid in Artemisinin-based combination: a pharmacodynamic study.

    Science.gov (United States)

    Pandey, Swaroop Kumar; Biswas, Subhasish; Gunjan, Sarika; Chauhan, Bhavana Singh; Singh, Sunil Kumar; Srivastava, Kumkum; Singh, Sarika; Batra, Sanjay; Tripathi, Renu

    2016-09-01

    Aiming to develop new artemisinin-based combination therapy (ACT) for malaria, antimalarial effect of a new series of pyrrolidine-acridine hybrid in combination with artemisinin derivatives was investigated. Synthesis, antimalarial and cytotoxic evaluation of a series of hybrid of 2-(3-(substitutedbenzyl)pyrrolidin-1-yl)alkanamines and acridine were performed and mode of action of the lead compound was investigated. In vivo pharmacodynamic properties (parasite clearance time, parasite reduction ratio, dose and regimen determination) against multidrug resistant (MDR) rodent malaria parasite and toxicological parameters (median lethal dose, liver function test, kidney function test) were also investigated. 6-Chloro-N-(4-(3-(3,4-dimethoxybenzyl)pyrrolidin-1-yl)butyl)-2-methoxyacridin-9-amine (15c) has shown a dose dependent haem bio-mineralization inhibition and was found to be the most effective and safe compound against MDR malaria parasite in Swiss mice model. It displayed best antimalarial potential with artemether (AM) in vitro as well as in vivo. The combination also showed favourable pharmacodynamic properties and therapeutic response in mice with established MDR malaria infection and all mice were cured at the determined doses. The combination did not show toxicity at the doses administered to the Swiss mice. Taken together, our findings suggest that compound 15c is a potential partner with AM for the ACT and could be explored for further development. PMID:27230403

  1. Novel morpholinoquinoline nucleus clubbed with pyrazoline scaffolds: Synthesis, antibacterial, antitubercular and antimalarial activities.

    Science.gov (United States)

    Karad, Sharad C; Purohit, Vishal B; Thakor, Parth; Thakkar, Vasudev R; Raval, Dipak K

    2016-04-13

    A series of novel morpholinoquinoline based conjugates with pyrazoline moiety were synthesized under microwave irradiation. The newly synthesized compounds were screened for their preliminary in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi, antituberculosis activity against Mycobacterium tuberculosis H37Rv and antimalarial activity against Plasmodium falciparum. Most of them exhibited significant antibacterial activity as compared to the first line drugs. Compounds 6a and 9d were found to possess excellent antibacterial activity potency as compared to ampicillin (286 μM), chloramphenicol (154 μM) and ciprofloxacin (150 μM). In antifungal screening, against Candida albicans, compounds 6c, 7c, 8a, 8b, 8c and 9b showed significant activity as compared to griseofulvin (1147 μM). Compounds 8b, 6b, 9d, 6a, 9b, 7b and 8a displayed brilliant activity against P. falciparum strain as compared to chloroquine (IC50 0.062 μM) as well as quinine (IC50 0.826 μM). Compounds 6d, 7b, 8b, 9c and 9d exhibited superior antitubercular activity. Among them 8b was found to be equipotent to rifampicin with 95% inhibition. The cytotoxicity of the synthesized compounds was tested using bioassay of Schizosaccharomyces pombe cells at cellular level. PMID:26900659

  2. Reverse pharmacology for developing an anti-malarial phytomedicine. The example of Argemone mexicana

    Directory of Open Access Journals (Sweden)

    Claudia Simoes-Pires

    2014-12-01

    Reverse pharmacology, also called bedside-to-bench, is a research approach based on the traditional knowledge and relates to reversing the classical laboratory to clinic pathway to a clinic to laboratory practice. It is a trans-disciplinary approach focused on traditional knowledge, experimental observations and clinical experiences. This paper is an overview of the reverse pharmacology approach applied to the decoction of Argemone mexicana, used as an antimalarial traditional medicine in Mali. A. mexicana appeared as the most effective traditional medicine for the treatment of uncomplicated falciparum malaria in Mali, and the clinical efficacy of the decoction was comparable to artesunate–amodiaquine as previously published. Four stages of the reverse pharmacology process will be described here with a special emphasis on the results for stage 4. Briefly, allocryptopine, protopine and berberine were isolated through bioguided fractionation, and had their identity confirmed by spectroscopic analysis. The three alkaloids showed antiparasitic activity in vitro, of which allocryptopine and protopine were selective towards Plasmodium falciparum. Furthermore, the amount of the three active alkaloids in the decoction was determined by quantitative NMR, and preliminary in vivo assays were conducted. On the basis of these results, the reverse pharmacology approach is discussed and further pharmacokinetic studies appear to be necessary in order to determine whether these alkaloids can be considered as phytochemical markers for quality control and standardization of an improved traditional medicine made with this plant.

  3. Inhibition of Plasmodium falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-carbazoles.

    Science.gov (United States)

    Wang, Tai; Mäser, Pascal; Picard, Didier

    2016-07-14

    Malaria caused by the protozoan parasite Plasmodium falciparum (Pf) remains a major public health problem throughout the developing world. One molecular target that should receive more attention is the molecular chaperone Hsp90. It is essential and highly conserved in all eukaryotes, including in protozoan parasites. We have identified an amino-alcohol carbazole (N-CBZ) as a PfHsp90-selective inhibitor by virtually docking a large set of antimalarial compounds, previously found in a phenotypic screen, into a PfHsp90-specific pocket. By correlating the ability of 30 additional N-CBZ derivatives to bind directly to PfHsp90 with their Pf-inhibitory activity, we found that these types of compounds are more likely to inhibit Pf growth if they bind PfHsp90. For plausible targets such as PfHsp90, our workflow may help identifying the molecular target for compounds found by screening large chemical libraries for a desired biological effect and, conversely, ensuring biological effectiveness for compounds affecting a particular target. PMID:27312008

  4. Assessment of Antimalarial Activity against Plasmodium falciparum and Phytochemical Screening of Some Yemeni Medicinal Plants

    Directory of Open Access Journals (Sweden)

    Mohammed A. Alshawsh

    2009-01-01

    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. In the present study, six selected plants (Acalypha fruticosa, Azadirachta indica, Cissus rotundifolia, Echium rauwalfii, Dendrosicyos socotrana and Boswellia elongata commonly used in Yemen by traditional healers for the treatment of malaria as well as other diseases, were collected from different localities of Yemen, dried and extracted with methanol and water successfully. The antiplasmodial activity of the extracts was evaluated against fresh clinical isolates of Plasmodium falciparum. The selectivity parameters to evaluate the efficacy of these medicinal plants were measured by in vitro micro test (Mark III according to World Health Organization (WHO 1996 & WHO 2001 protocols of antimalarial drug tests. Among the investigated 12 extracts, three were found to have significant antiplasmodial activity with IC50 values less than 4 µg/ml, namely the water extracts of A. fruticosa, A. indica and D. socotrana. Six extracts showed moderate activity with IC50 values ranging from 10 to 30 µg/ml and three appeared to be inactive with IC50 values more than 30 µg/ml. In addition, preliminary phytochemical screening of the methanolic and aqueous extracts indicated the presence of saponins, tannins, flavonoids, terpenoids, polysaccharides and peptides.

  5. Antimalarial activity of selected Sudanese medicinal plants with emphasis to Maytenus senegalensis

    International Nuclear Information System (INIS)

    The aim of the present study is to identify and characterize the antimalrial agents from traitional Sudanese medicinal plants. 49 plants parts representing 26 species from 15 families were extracted and screened for their in vitro antimalrial activity using P. falciparum strain 3D7 which is chloroquine sensitive and Dd2 strain which is chloroquine resistant and pyrimethamine sensitive.The plant species investigated exhibited diverse botanical families. They includes Annonaceae, Aristolochiaceae, Asteraceae, Balantiaceae, Caesalpiniceae, Celasteraceae, Cucurbitaceae, Fabaceae, Graminae, Meliaceae, Myrtaceae, Polygonaceae, Rubiaceae, Rutaceae, and simaroubaceae. The evaluation of these plants for their antimalarial activity and their effect on lymphocyte proliferation was carried out. 57 extracts were tested on the chloroquine sensitive strain (3D7). Where 34 extracts (59%) exhibited significant activity against 3D7 with IC50 values ≤ 50 μ g/ml. While 21 extracts (57%) showed antimalrial activities with IC50 values ≤ 50 μ g/ml on Dd2. 13 extracts (22%) and ten extracts (18%) only showed an activity with IC50 values ≤ 5 μ g/ml on 3 D7 and Dd2, respectively. The activities of some plant extracts, which affected 3D7 strain, were measured using the radiolabelled (3H) hypoxanthine method and microscopical count. 15 plant extracts (48%) from 32 showed IC50 values ≤ 50 μ g/ml against 3D7 strain using the radiolabelled hypoxanthine methods and only 5 extracts (16%) showed IC50 values ≤ 5 μ g/ml against 3D7. Most of the extracts screened had a low effect on lymphocyte proliferation (IC50 values >100 μ g/ml), where as Sonochous cornatus, Balanites aegyptiaca, Tamarindus indica, Acacia nilotica, Annona squamosa, Eucalyptus globulus and Cassia tora enhanced lymphocyte proliferation. liquid-liquid partition of methanolic preparation of Acacia nilotica seeds and husk showed that the ethylacetate phase possessed the highest activity against both 3D7 and Dd2 strains

  6. Chemogenomic profiling of Plasmodium falciparum as a tool to aid antimalarial drug discovery

    Science.gov (United States)

    Pradhan, Anupam; Siwo, Geoffrey H.; Singh, Naresh; Martens, Brian; Balu, Bharath; Button-Simons, Katrina A.; Tan, Asako; Zhang, Min; Udenze, Kenneth O.; Jiang, Rays H.Y.; Ferdig, Michael T.; Adams, John H.; Kyle, Dennis E.

    2015-01-01

    The spread of Plasmodium falciparum multidrug resistance highlights the urgency to discover new targets and chemical scaffolds. Unfortunately, lack of experimentally validated functional information about most P. falciparum genes remains a strategic hurdle. Chemogenomic profiling is an established tool for classification of drugs with similar mechanisms of action by comparing drug fitness profiles in a collection of mutants. Inferences of drug mechanisms of action and targets can be obtained by associations between shifts in drug fitness and specific genetic changes in the mutants. In this screen, P. falciparum, piggyBac single insertion mutants were profiled for altered responses to antimalarial drugs and metabolic inhibitors to create chemogenomic profiles. Drugs targeting the same pathway shared similar response profiles and multiple pairwise correlations of the chemogenomic profiles revealed novel insights into drugs’ mechanisms of action. A mutant of the artemisinin resistance candidate gene - “K13-propeller” gene (PF3D7_1343700) exhibited increased susceptibility to artemisinin drugs and identified a cluster of 7 mutants based on similar enhanced responses to the drugs tested. Our approach of chemogenomic profiling reveals artemisinin functional activity, linked by the unexpected drug-gene relationships of these mutants, to signal transduction and cell cycle regulation pathways. PMID:26541648

  7. Novel Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Anti-malarial Activity in the Mouse Model

    Energy Technology Data Exchange (ETDEWEB)

    Booker, Michael L.; Bastos, Cecilia M.; Kramer, Martin L.; Barker, Jr., Robert H.; Skerlj, Renato; Sidhu, Amar Bir; Deng, Xiaoyi; Celatka, Cassandra; Cortese, Joseph F.; Guerrero Bravo, Jose E.; Crespo Llado, Keila N.; Serrano, Adelfa E.; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Viera, Sara; Garuti, Helen; Wittlin, Sergio; Papastogiannidis, Petros; Lin, Jing-wen; Janse, Chris J.; Khan, Shahid M.; Duraisingh, Manoj; Coleman, Bradley; Goldsmith, Elizabeth J.; Phillips, Margaret A.; Munoz, Benito; Wirth, Dyann F.; Klinger, Jeffrey D.; Wiegand, Roger; Sybertz, Edmund (Leiden-MC); (Puerto Rico); (STPHI); (Harvard); (GSK); (Genzyme); (UTSMC)

    2010-11-22

    Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED{sub 50} values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.

  8. Antimalarial Evaluation of the Chemical Constituents of Hairy Root Culture of Bixa orellana L.

    Directory of Open Access Journals (Sweden)

    Bo Zhai

    2014-01-01

    Full Text Available Over 216 million malaria cases are reported annually worldwide and about a third of these cases, primarily children under the age of five years old, will not survive the infection. Despite this significant world health impact, only a limited number of therapeutic agents are currently available. The lack of scaffold diversity poses a threat in the event that multi-drug–resistant strains emerge. Terrestrial natural products have provided a major source of chemical diversity for starting materials in many FDA approved drugs over the past century. Bixa orellana L. is a popular plant used in South America for the treatment of malaria. In search of new potential therapeutic agents, the chemical constituents of a selected hairy root culture line of Bixa orellana L. were characterized utilizing NMR and mass spectrometry methods, followed by its biological evaluation against malaria strains 3D7 and K1. The crude extract and its isolated compounds demonstrated EC50 values in the micromolar range. Herein, we report our findings on the chemical constituents of Bixa orellana L. from hairy roots responsible for the observed antimalarial activity.

  9. Thermodynamic Studies of Antimalarial Drugs and Their Interaction with Myoglobin, Hemoglobin and Phospholipid Model Membranes

    Directory of Open Access Journals (Sweden)

    Samira A. Barghouthi

    2005-01-01

    Full Text Available In this research we present binding studies of some selected antimalarial drugs such as primaquine and quinacrine with biomolecules. Ultraviolet-visible spectrophotometry and fluorescence spectrophotometry along with equilibrium dialysis techniques were used to monitor the interaction of these drugs with myoglobin, hemoglobin albumin and with phospholipid unilamellar vesicles. Fluorescence spectrophotometry, UV-visible difference spectrophotometry and equilibrium dialysis showed no evidence of any binding of these drugs to myoglobin or hemoglobin. However, binding to albumin was evident from a blue shift in UV-Vis absorption spectra. Both primaquine and quinacrine were found to bind to phospholipid vesicles with binding constants of 2.7 ± 0.4x102 and 8.1 ± 0.8x104, respectively. As for the number of molecules per binding site, we found that eight molecules of primaquine occupies ten binding sites and in case of quinacrine two drug molecule for each ten binding sites. Physical parameters for primaquine are determined via UV-Vis absorption at a wavelength of 350 nm. In case of quinacrine fluorescence intensity was employed to measure concentrations with an excitation wavelength of 425 nm and an emission wavelength at 497 nm.

  10. Resistance of Plamodium falciparum to Antimalarial Drugs in Zaragoza (Antioquia, Colombia, 1998

    Directory of Open Access Journals (Sweden)

    Silvia Blair-Trujillo

    2002-04-01

    Full Text Available Plasmodium falciparum sensitivity to chloroquine (CHL, amodiaquine (AMO and sulfadoxine/pyrimethamine (SDX/PYR was assessed in vivo and in vitro in a representative sample from the population of Zaragoza in El Bajo Cauca region (Antioquia-Colombia. There were 94 patients with P. falciparum evaluated. For the in vivo test the patients were followed by clinical examination and microscopy, during 7 days. The in vitro test was performed following the recommendations of the World Health Organization. The in vivo prevalence of resistance to CHL was 67%, to AMO 3% and to SDX/PYR 9%. The in vitro test showed sensitivity to all antimalarials evaluated. Concordance for CHL between the in vivo and in vitro tests was 33%. For AMO and SDX/PYR, the concordance was 100%. We conclude that a high percentage of patients are resistant to CHL (in vivo. A high rate of intestinal parasitism might explain in part, the differences observed between the in vivo and the in vitro results. Therefore, new policies and treatment regimens should be proposed for the treatment of the infection in the region. Nationwide studies assessing the degree of resistance are needed.

  11. Cytotoxic and Antimalarial Amaryllidaceae Alkaloids from the Bulbs of Lycoris radiata

    Directory of Open Access Journals (Sweden)

    Bin Hao

    2013-02-01

    Full Text Available Phytochemical investigation of the 80% ethanol extract of the bulbs of Lycoris radiata resulted in the isolation of five new Amaryllidaceae alkaloids: (+-5,6-dehydrolycorine (1, (+-3α,6β-diacetyl-bulbispermine (2, (+-3α-hydroxy-6β-acetyl- bulbispermine (3, (+-8,9-methylenedioxylhomolycorine-N-oxide (5, and 5,6-dihydro-5- methyl-2-hydroxyphenanthridine (7, together with two known compounds, (+-3α-methoxy- 6β-acetylbulbispermine (4 and (+-homolycorine- N-oxide (6. Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC NMR spectroscopy, in addition to high resolution mass spectrometry. Alkaloid 1 showed potent cytotoxicity against astrocytoma and glioma cell lines (CCF-STTG1, CHG-5, SHG-44, and U251, as well as HL-60, SMMC-7721, and W480 cell lines with IC50 values of 9.4–11.6 μM. Additonally, compound 1 exhibited antimalarial activity with IC50 values of 2.3 μM for D-6 strain and 1.9 μM for W-2 strain of Plasmodium falciparum.

  12. Antimalarial Drug Resistance: Surveillance and Molecular Methods for National Malaria Control Programmes

    Directory of Open Access Journals (Sweden)

    Umberto D'Alessandro

    1998-09-01

    Full Text Available National malaria control programmes have the responsibility to develop a policy for malaria disease management based on a set of defined criteria as efficacy, side effects, costs and compliance. These will fluctuate over time and national guidelines will require periodic re-assessment and revision. Changing a drug policy is a major undertaking that can take several years before being fully operational. The standard methods on which a decision can be taken are the in vivo and the in vitro tests. The latter allow a quantitative measurement of the drug response and the assessment of several drugs at once. However, in terms of drug policy change its results might be difficult to interpret although they may be used as an early warning system for 2nd or 3rd line drugs. The new WHO 14-days in vivo test addresses mainly the problem of treatment failure and of haematological parameters changes in sick children. It gives valuable information on whether a drug still `works'. None of these methods are well suited for large-scale studies. Molecular methods based on detection of mutations in parasite molecules targeted by antimalarial drugs could be attractive tools for surveillance. However, their relationship with in vivo test results needs to be established

  13. Four formulations of noncommutative quantum mechanics

    CERN Document Server

    Gouba, Laure

    2016-01-01

    Four formulations of noncommutative quantum mechanics are reviewed. These are the canonical, path-integral, Weyl-Wigner and systematic formulations. The four formulations are charaterized by a deformed Heisenberg algebra but differ in mathematical and conceptual overview.

  14. Combination Therapy Counteracts the Enhanced Transmission of Drug-Resistant Malaria Parasites to Mosquitoes

    OpenAIRE

    Hallett, Rachel L; Colin J Sutherland; Alexander, Neal; Ord, Rosalynn; Jawara, Musa; Drakeley, Chris J.; Pinder, Margaret; Walraven, Gijs; Geoffrey A T Targett; Alloueche, Ali

    2004-01-01

    Malaria parasites carrying genes conferring resistance to antimalarials are thought to have a selective advantage which leads to higher rates of transmissibility from the drug-treated host. This is a likely mechanism for the increasing prevalence of parasites with resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine in sub-Saharan Africa. Combination therapy is the key strategy being implemented to reduce the impact of resistance, but its effect on the transmission of genetically resi...

  15. A review of age-old antimalarial drug to combat malaria:efficacy up-gradation by nanotechnology based drug delivery

    Institute of Scientific and Technical Information of China (English)

    Satyajit Tripathy; Somenath Roy

    2014-01-01

    Malaria is uncontrolled burden in the world till now.Despite of different efforts to develop antimalarial drug for decades, any anti-malarial drug can able to eradicate completely till now. Many anti-malarial substances are practically ineffectual because of their physicochemical limitations, cytotoxicity, chemical instability and degradation, and limited activities against intracellular parasites.Taking into consideration, the amount of research is going to conduct in the field of nanoparticle based drug delivery systems, lead to new ways of improving the treatment of infectious diseases.The study has focused on the progress and advancement of research on nanotechnology based drug delivery to eradicate the malaria.We like to focus the efficacy of nanotechnology based drug applicationfor the opening out of novel chemotherapeutics in laboratory research, which may show the way to better use with age-old antimalarial drug and may draw the attention of pharmaceutical industries for the improvement and designing of effective anti-malarial drugs in future.

  16. Feasibility, safety and effectiveness of combining home based malaria management and seasonal malaria chemoprevention in children less than 10 years in Senegal

    DEFF Research Database (Denmark)

    Tine, Roger C K; Ndour, Cheikh T; Faye, Babacar;

    2014-01-01

    Home-based management of malaria (HMM) may improve access to diagnostic testing and treatment with artemisinin combination therapy (ACT). In the Sahel region, seasonal malaria chemoprevention (SMC) is now recommended for the prevention of malaria in children. It is likely that combinations of...... antimalarial interventions can reduce the malaria burden. This study assessed the feasibility, effectiveness and safety of combining SMC and HMM delivered by community health workers (CHWs)....

  17. Pharmacognostical Characterization of an Anti-Diabe tic Polyherbal Formulation

    Directory of Open Access Journals (Sweden)

    P P JOHN

    2015-03-01

    Full Text Available Standardization of drugs and formulation is one theessential parameter in today’s drug discovery. Current study includes pharmacognostic study of a polyherbal formulation which comprise of six crude powdered drugs i.e.Acacia catechu, Phyllanthus embellica, Pterocarpus marsupium, Salacia reticulata, Tinospora cordifoliaand Vetiveria zizanioides, which is used locally for diabetes. Morphological, microscopical and physico-chemical studies were done to standardize the plant ingredients and also for the formulation. Current study includes lycopodium spore method, which is one of the most important methods for standardization of individual powder drug and powdered formulations. When combined with various parameters like linearity, specificity, precision, repeatability and accuracy, the method become a powerful tool to uncover and check even a very small amount of adulteration in a large extent. Mean value for the identifying characters in the mixture was near to one-sixth as compared to the drug when they were individually studied, vindicating our assumption that after mixing the ratio remained intact in the formulation. Thus, this method can be used for finding the exact ratio of drugs in any formulation in near future. All the result of the study could be useful in setting some diagnostic indices for the identification and preparation of a monograph of the drugs. The developed technique will be useful for standardization of different formulations also.

  18. Molecular monitoring of plasmodium falciparum drug susceptibility at the time of the introduction of artemisinin-based combination therapy in Yaoundé, Cameroon: Implications for the future

    Directory of Open Access Journals (Sweden)

    Menard Sandie

    2012-04-01

    Full Text Available Abstract Background Regular monitoring of the levels of anti-malarial resistance of Plasmodium falciparum is an essential policy to adapt therapy and improve malaria control. This monitoring can be facilitated by using molecular tools, which are easier to implement than the classical determination of the resistance phenotype. In Cameroon, chloroquine (CQ, previously the first-line therapy for uncomplicated malaria was officially withdrawn in 2002 and replaced initially by amodiaquine (AQ monotherapy. Then, artemisinin-based combination therapy (ACT, notably artesunate-amodiaquine (AS-AQ or artemether-lumefantrine (AL, was gradually introduced in 2004. This situation raised the question of the evolution of P. falciparum resistance molecular markers in Yaoundé, a highly urbanized Cameroonian city. Methods The genotype of pfcrt 72 and 76 and pfmdr1 86 alleles and pfmdr1 copy number were determined using real-time PCR in 447 P. falciparum samples collected between 2005 and 2009. Results This study showed a high prevalence of parasites with mutant pfcrt 76 (83% and pfmdr1 86 (93% codons. On the contrary, no mutations in the pfcrt 72 codon and no samples with duplication of the pfmdr1 gene were observed. Conclusion The high prevalence of mutant pfcrt 76T and pfmdr1 86Y alleles might be due to the choice of alternative drugs (AQ and AS-AQ known to select such genotypes. Mutant pfcrt 72 codon was not detected despite the prolonged use of AQ either as monotherapy or combined with artesunate. The absence of pfmdr1 multicopies suggests that AL would still remain efficient. The limited use of mefloquine or the predominance of mutant pfmdr1 86Y codon could explain the lack of pfmdr1 amplification. Indeed, this mutant codon is rarely associated with duplication of pfmdr1 gene. In Cameroon, the changes of therapeutic strategies and the simultaneous use of several formulations of ACT or other anti-malarials that are not officially recommended result in a

  19. FORMULATION OF CLOTRIMAZOLE ORORETENTIVE JELLY

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    akshay sidharam javalgikar

    2016-03-01

    Full Text Available Objective: Patient compliance and ease of administration are of significant importance in the design of dosage forms. Dysphasia is common among all age groups, especially in elderly and pediatrics. There are dosage forms like tablets, syrups in the market but still there is a need for new dosage form which acts effectively and locally. Jellies can provide an attractive alternative formulation in the treatment of oral candidiasis. So the present investigation aims to design, prepare and evaluate Clotrimazole jellies using xanthan gum with different concentrations. The benefits of these prepared jellies are increased bioavailability by-passing first pass metabolism. Method: The sucrose based jellies were prepared by heating and congealing method. Physical characteristics, pH, syneresis, in vitro dissolution testing, drug release kinetics, IR Spectral analysis and stability studies were conducted. Result: The prepared formulations are free from gritty particles. Among the prepared formulations, formulation C3 containing 1.5% xanthan gum released 93.22% in 30min was found to be promising. Stability studies on the promising and other formulations indicated that there were no significant changes in the drug content and in vitro dissolution characteristics. IR spectroscopic studies indicated that there were no drug-excipient interactions. Anti-fungal studies revealed that there is no change in the molecular activity of the drug. Conclusion: The prepared jellies of Clotrimazole could stay in the mouth for a longer period of time, which indicates a potential use of jellies of Clotrimazole for treating oral candidiasis.

  20. 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.

  1. Relativistic Formulation of Reaction Theory

    CERN Document Server

    Polyzou, W N

    2014-01-01

    A relativistic formulation of reaction theory for nuclei with a dynamics given by a unitary representations of the Poincar\\'e group is developed. Relativistic dynamics is introduced by starting from a relativistic theory of free particles to which rotationally invariant interactions are added to the invariant mass operator. Poincar\\'e invariance is realized by requiring that simultaneous eigenstates of the mass and spin transform as irreducible representations of the Poincar\\'e group. A relativistic formulation of scattering theory is presented and approximations emphasizing dominant degrees of freedom that preserve unitarity, exact Poincar\\'e invariance and exchange symmetry are discussed. A Poincar\\'e invariant formulation of a (d,p) reaction as a three-body problem is given as an explicit example.

  2. Decontamination formulation with sorbent additive

    Science.gov (United States)

    Tucker; Mark D. , Comstock; Robert H.

    2007-10-16

    A decontamination formulation and method of making that neutralizes the adverse health effects of both chemical and biological compounds, especially chemical warfare (CW) and biological warfare (BW) agents, and toxic industrial chemicals. The formulation provides solubilizing compounds that serve to effectively render the chemical and biological compounds, particularly CW and BW compounds, susceptible to attack, and at least one reactive compound that serves to attack (and detoxify or kill) the compound. The formulation includes at least one solubilizing agent, a reactive compound, a bleaching activator, a sorbent additive, and water. The highly adsorbent, water-soluble sorbent additive (e.g., sorbitol or mannitol) is used to "dry out" one or more liquid ingredients, such as the liquid bleaching activator (e.g., propylene glycol diacetate or glycerol diacetate) and convert the activator into a dry, free-flowing powder that has an extended shelf life, and is more convenient to handle and mix in the field.

  3. A variational formulation of electrodynamics

    CERN Document Server

    De Nicola, Antonio

    2007-01-01

    We present a variational formulation of electrodynamics using de Rham even and odd differential forms. Our formulation relies on a variational principle more complete than the Hamilton principle and thus leads to field equations with external sources and permits the derivation of the constitutive relations. We interpret a domain in space-time as an odd de Rham 4-current. This permits a treatment of different types of boundary problems in an unified way. In particular we obtain a smooth transition to the infinitesimal version by using a current with a one point support.

  4. 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

  5. In Vivo Antimalarial Effects of Iranian Flora Artemisia khorassanica against Plasmodium berghei and Pharmacochemistry of its Natural Components

    Directory of Open Access Journals (Sweden)

    M Amini

    2010-02-01

    Full Text Available "nBackground: The aim of this study was to evaluate the antimalarial effects of Iranian flora Artemisia khorassanica against Plasmodium berghei in vivo and pharmacochemistry of its natural components."nMethods: The aerial parts of Iranian flora A. khorasanica were collected at flowering stage from Khorassan Province, northeastern Iran in 2008. They were air-dried at room temperature; powder was macerated in methanol and the extract defatted in refrigerator, filtered, diluted with water, then eluted with n-hexane and finally non-polar components were identified through Gas Chromatography and Mass Spectroscopy (GC-MS. Toxicity of herbal extracts was assessed on naïve NMRI mice, and its anti-malarial efficacy was investigated on infected Plasmodium berghei animals. This is the first ap­plication on A. khorssanica extract for treatment of murine malaria. The significance of differences was determined by Analysis of Variances (ANOVA and Student's t-test using Graph Pad Prism Software."nResults: The herbal extract was successfully tested in vivo for its anti-plasmodial activity through ar­temisin composition, which is widely used as a standard malaria treatment."nConclusion: Although, this study confirmed less anti-malarial effects of A. khorssanica against mur­ine malaria in vivo, how­ever there are some evidences on reducing pathophysiology by this medica­tion. In complementary assay, major components were detected by GC-MS analysis in herbal extract including chrysanthe­none (7.8%, palmitic acid (7.4% and cis-thujone (5.8%.  The most retention indices of the compo­nent are given as n-eicosane, palmitic acid and n-octadecane.

  6. Gel versus capillary electrophoresis genotyping for categorizing treatment outcomes in two anti-malarial trials in Uganda

    Directory of Open Access Journals (Sweden)

    Hubbard Alan E

    2010-01-01

    Full Text Available Abstract Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary electrophoresis from randomized trials of artemether-lumefantrine (AL vs. dihydroartemisinin-piperaquine (DP performed in two areas of Uganda: Kanungu, where transmission is moderate, and Apac, where transmission is very high. Both gel and capillary methods evaluated polymorphic regions of the merozoite surface protein 1 and 2 and glutamine rich protein genes. Results Capillary electrophoresis detected more alleles and provided higher discriminatory power than agarose gel electrophoresis at both study sites. There was only moderate agreement between classification of outcomes with the two methods in Kanungu (kappa = 0.66 and poor agreement in Apac (kappa = 0.24. Overall efficacy results were similar when using gel vs. capillary methods in Kanungu (42-day risk of treatment failure for AL: 6.9% vs. 5.5%, p = 0.4; DP 2.4% vs. 2.9%, p = 0.5. However, the measured risk of recrudescence was significantly higher when using gel vs. capillary electrophoresis in Apac (risk of treatment failure for AL: 17.0% vs. 10.7%, p = 0.02; DP: 8.5% vs. 3.4%, p = 0.03. Risk differences between AL and DP were not significantly different whether gel or capillary methods were used. Conclusions Genotyping with gel electrophoresis overestimates the risk of recrudescence in anti-malarial trials performed in areas of high transmission intensity. Capillary electrophoresis provides more accurate outcomes for such trials and should be performed when possible. In areas of moderate transmission

  7. Identification of β-hematin inhibitors in a high-throughput screening effort reveals scaffolds with in vitro antimalarial activity

    Directory of Open Access Journals (Sweden)

    Rebecca D. Sandlin

    2014-12-01

    Full Text Available The emergence of drug resistant strains of Plasmodium spp. creates a critical need for the development of novel antimalarials. Formation of hemozoin, a crystalline heme detoxification process vital to parasite survival serves as an important drug target. The quinoline antimalarials including chloroquine and amodiaquine owe their antimalarial activity to inhibition of hemozoin formation. Though in vivo formation of hemozoin occurs within the presence of neutral lipids, the lipophilic detergent NP-40 was previously shown to serve as a surrogate in the β-hematin (synthetic hemozoin formation process. Consequently, an NP-40 mediated β-hematin formation assay was developed for use in high-throughput screening. Here, the assay was utilized to screen 144,330 compounds for the identification of inhibitors of crystallization, resulting in 530 hits. To establish the effectiveness of these target-based β-hematin inhibitors against Plasmodium falciparum, each hit was further tested in cultures of parasitized red blood cells. This effort revealed that 171 of the β-hematin inhibitors are also active against the parasite. Dose–response data identified 73 of these β-hematin inhibitors have IC50 values ⩽5 μM, including 25 compounds with nanomolar activity against P. falciparum. A scaffold-based analysis of this data identified 14 primary scaffolds that represent 46% of the 530 total hits. Representative compounds from each of the classes were further assessed for hemozoin inhibitory activity in P. falciparum infected human erythrocytes. Each of the hit compounds tested were found to be positive inhibitors, while a negative control did not perturb this biological pathway in culture.

  8. A new double-antibody sandwich ELISA targeting Plasmodium falciparum aldolase to evaluate anti-malarial drug sensitivity

    Directory of Open Access Journals (Sweden)

    Brun Reto

    2009-10-01

    Full Text Available Abstract Background The standard in vitro test to assess anti-malarial activity of chemical compounds is the [3H]hypoxanthine incorporation assay. It is a radioactivity-based method to measure DNA replication of Plasmodium in red blood cells. The method is highly reproducible, however, the handling of radioactive material is costly, hazardous and requires the availability of appropriate technology and trained staff. Several other ways to evaluate in vitro anti-malarial activity do exist, all with their own assets and limitations. Methods The newly developed double-antibody sandwich ELISA described here is based on the properties of a non-overlapping pair of monoclonal antibodies directed against Plasmodium falciparum aldolase. This glycolytic enzyme possesses some unique nucleotide sequences compared to the human isoenzymes and has been highly conserved through evolution. Out of twenty possibilities, the most sensitive antibody pair was selected and used to quantitatively detect parasite aldolase in infected blood lysates. Results A total of 34 compounds with anti-malarial activity were tested side-by-side by ELISA and the [3H]hypoxanthine incorporation assay. The novel ELISA provided IC50s closely paralleling those from the radioactivity-based assay (R = 0.99, p Conclusion The newly developed ELISA presents several advantages over the comparative method, the [3H]hypoxanthine incorporation assay. The assay is highly reproducible, less hazardous (involves no radioactivity and requires little and cheap technical equipment. Relatively unskilled personnel can conduct this user-friendly assay. All this makes it attractive to be employed in resource-poor laboratories.

  9. Global gene expression profiling of Plasmodium falciparum in response to the anti-malarial drug pyronaridine

    Directory of Open Access Journals (Sweden)

    Chavalitshewinkoon-Petmitr Porntip

    2011-08-01

    Full Text Available Abstract Background Pyronaridine (PN and chloroquine (CQ are structurally related anti-malarial drugs with primarily the same mode of action. However, PN is effective against several multidrug-resistant lines of Plasmodium falciparum, including CQ resistant lines, suggestive of important operational differences between the two drugs. Methods Synchronized trophozoite stage cultures of P. falciparum strain K1 (CQ resistant were exposed to 50% inhibitory concentrations (IC50 of PN and CQ, and parasites were harvested from culture after 4 and 24 hours exposure. Global transcriptional changes effected by drug treatment were investigated using DNA microarrays. Results After a 4 h drug exposure, PN induced a greater degree of transcriptional perturbation (61 differentially expressed features than CQ (10 features. More genes were found to respond to 24 h treatments with both drugs, and 461 features were found to be significantly responsive to one or both drugs across all treatment conditions. Filtering was employed to remove features unrelated to primary drug action, specifically features representing genes developmentally regulated, secondary stress/death related processes and sexual stage development. The only significant gene ontologies represented among the 46 remaining features after filtering relate to host exported proteins from multi-gene families. Conclusions The malaria parasite's molecular responses to PN and CQ treatment are similar in terms of the genes and pathways affected. However, PN appears to exert a more rapid response than CQ. The faster action of PN may explain why PN is more efficacious than CQ, particularly against CQ resistant isolates. In agreement with several other microarray studies of drug action on the parasite, it is not possible, however, to discern mechanism of drug action from the drug-responsive genes.

  10. Evaporation and skin penetration characteristics of mosquito repellent formulations

    Energy Technology Data Exchange (ETDEWEB)

    Reifenrath, W.G.; Hawkins, G.S.; Kurtz, M.S.

    1989-03-01

    Formulations of the mosquito repellent N,N-diethyl-3-methylbenzamide (deet) in combination with a variety of additives were developed to control repellent evaporation and percutaneous penetration. Deet was also formulated with the repellent dimethyl phthalate to study the interaction of the two compounds on the skin. The evaporation and penetration processes were evaluated on whole and split-thickness pig skin using radiolabeled repellents with an in vitro apparatus. Under essentially still air and air flow conditions, one of the deet formulations resulted in significantly reduced total evaporation and percutaneous penetration of deet as compared to unformulated repellent. When deet and dimethyl phthalate were combined, neither repellent affected the total amount of evaporation and penetration of the other compound. However, initial percutaneous penetration and evaporation rates were slightly less and decayed less rapidly than when both chemicals were tested separately at the same dose. These results indicated a degree of competition of the two compounds for the same avenues of loss.

  11. Evaporation and skin penetration characteristics of mosquito repellent formulations

    International Nuclear Information System (INIS)

    Formulations of the mosquito repellent N,N-diethyl-3-methylbenzamide (deet) in combination with a variety of additives were developed to control repellent evaporation and percutaneous penetration. Deet was also formulated with the repellent dimethyl phthalate to study the interaction of the two compounds on the skin. The evaporation and penetration processes were evaluated on whole and split-thickness pig skin using radiolabeled repellents with an in vitro apparatus. Under essentially still air and air flow conditions, one of the deet formulations resulted in significantly reduced total evaporation and percutaneous penetration of deet as compared to unformulated repellent. When deet and dimethyl phthalate were combined, neither repellent affected the total amount of evaporation and penetration of the other compound. However, initial percutaneous penetration and evaporation rates were slightly less and decayed less rapidly than when both chemicals were tested separately at the same dose. These results indicated a degree of competition of the two compounds for the same avenues of loss

  12. Competing intermolecular interactions of artemisinin-type agents and aspirin with membrane phospholipids: Combined model mass spectrometry and quantum-chemical study

    International Nuclear Information System (INIS)

    Highlights: • Competitive binding of artemisinin agents and aspirin with phospholipids is shown. • Complexation between the antimalarial drugs and aspirin molecules is also found. • Energetically favorable structures of the model complexes are identified by DFT. • Membranotropic activity of the studied drugs can be modified under joint usage. - Abstract: Study of intermolecular interactions of antimalarial artemisinin-type drugs and aspirin with membrane phospholipids is important in term of elucidation of the drugs activity modification under their joint usage. Combined experimental and computational study of the interaction of dihydroartemisinin, α-artemether, and artesunate with aspirin (ASP) and dipalmitoylphosphatidylcholine (DPPC) is performed by electrospray ionization (ESI) mass spectrometry and by DFT B3LYP/aug-cc-pVDZ methods. The results of the ESI investigation of systems containing artemisinin-type agent, ASP and DPPC, reveal a competition between the antimalarial agents and ASP for binding with DPPC molecules. The complexation between the antimalarial drugs and ASP is also found. Observed phenomena suggest that membranotropic activity of artemisin-type agents and aspirin is modified under their combined usage. To elucidate structure-energy characteristics of the non-covalent complexes studied the model DFT calculations are performed for dihydroartemisinin · ASP complex and complexes of the each drug with phosphatidylcholine head of DPPC in neutral and cationized forms

  13. Competing intermolecular interactions of artemisinin-type agents and aspirin with membrane phospholipids: Combined model mass spectrometry and quantum-chemical study

    Energy Technology Data Exchange (ETDEWEB)

    Pashynska, Vlada, E-mail: vlada@vl.kharkov.ua [B.Verkin Institute for Low Temperature Physics and Engineering of the National Academy of Sciences of Ukraine, Lenin Ave., 47, 61103 Kharkov (Ukraine); Stepanian, Stepan [B.Verkin Institute for Low Temperature Physics and Engineering of the National Academy of Sciences of Ukraine, Lenin Ave., 47, 61103 Kharkov (Ukraine); Gömöry, Agnes; Vekey, Karoly [Institute of Organic Chemistry of Research Centre for Natural Sciences of the Hungarian Academy of Sciences, Magyar tudosok korutja, 2, Budapest H-1117 (Hungary); Adamowicz, Ludwik [University of Arizona, Department of Chemistry and Biochemistry, Tucson, AZ 85721 (United States)

    2015-07-09

    Highlights: • Competitive binding of artemisinin agents and aspirin with phospholipids is shown. • Complexation between the antimalarial drugs and aspirin molecules is also found. • Energetically favorable structures of the model complexes are identified by DFT. • Membranotropic activity of the studied drugs can be modified under joint usage. - Abstract: Study of intermolecular interactions of antimalarial artemisinin-type drugs and aspirin with membrane phospholipids is important in term of elucidation of the drugs activity modification under their joint usage. Combined experimental and computational study of the interaction of dihydroartemisinin, α-artemether, and artesunate with aspirin (ASP) and dipalmitoylphosphatidylcholine (DPPC) is performed by electrospray ionization (ESI) mass spectrometry and by DFT B3LYP/aug-cc-pVDZ methods. The results of the ESI investigation of systems containing artemisinin-type agent, ASP and DPPC, reveal a competition between the antimalarial agents and ASP for binding with DPPC molecules. The complexation between the antimalarial drugs and ASP is also found. Observed phenomena suggest that membranotropic activity of artemisin-type agents and aspirin is modified under their combined usage. To elucidate structure-energy characteristics of the non-covalent complexes studied the model DFT calculations are performed for dihydroartemisinin · ASP complex and complexes of the each drug with phosphatidylcholine head of DPPC in neutral and cationized forms.

  14. Mestizos with Systemic Lupus Erythematosus Develop Renal Disease Early while Antimalarials Retard its Appearance: Data from a Latin American Cohort

    Science.gov (United States)

    Pons-Estel, Guillermo J.; Alarcón, Graciela S.; Burgos, Paula I.; Hachuel, Leticia; Boggio, Gabriela; Wojdyla, Daniel; Nieto, Romina; Alvarellos, Alejandro; Catoggio, Luis J.; Guibert-Toledano, Marlene; Sarano, Judith; Massardo, Loreto; Vásquez, Gloria M.; Iglesias-Gamarra, Antonio; Lavras Costallat, Lilian T.; Da Silva, Nilzio A.; Alfaro, José L.; Abadi, Isaac; Segami, María I.; Huerta, Guillermo; Cardiel, Mario H.; Pons-Estel, Bernardo A.

    2014-01-01

    Objectives To assess the predictors of time-to-lupus renal disease in Latin American patients. Methods SLE patients (n=1480) from GLADEL’s (Grupo Latino Americano De Estudio de Lupus) longitudinal inception cohort were studied. Endpoint was ACR renal criterion development after SLE diagnosis (prevalent cases excluded). Renal disease predictors were examined by univariable and multivariable Cox proportional hazards regression analyses. Antimalarials were considered time-dependent in alternative analyses. Results Of the entire cohort, 265 patients (17.9%) developed renal disease after entering the cohort. Of them, 88 (33.2%) developed persistent proteinuria, 44 (16.6%) cellular casts and 133 (50.2%) both; 233 patients (87.9%) were women; mean (± SD) age at diagnosis was 28.0 (11.9) years; 12.8% were African-Latin Americans, 52.5% Mestizos, 34.7% Caucasians (p=0.0016). Mestizo ethnicity (HR 1.61, 95% CI 1.19–2.17), hypertension (HR 3.99, 95% CI 3.02–5.26) and SLEDAI at diagnosis (HR 1.04, 95% CI 1.01–1.06) were associated with a shorter time-to-renal disease occurrence; antimalarial use (HR 0.57, 95% CI 0.43–0.77), older age at onset (HR 0.90, 95% CI 0.85–0.95, for every 5 years) and photosensitivity (HR 0.74, 95% CI 0.56–0.98) were associated with a longer time. Alternative model results were consistent with the antimalarial protective effect (HR 0.70, 95% CI 0.50–0.99). Conclusions Our data strongly support the fact that Mestizo patients are at increased risk of developing renal disease early while antimalarials seem to delay the appearance of this SLE manifestation. These data have important implications for the treatment of these patients regardless of their geographic location. PMID:23857989

  15. Acyclic Nucleoside Phosphonates as Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: New Anti-Malarial Chemotherapy Leads

    Czech Academy of Sciences Publication Activity Database

    Hocková, Dana; Holý, Antonín; Česnek, Michal; Baszczyňski, Ondřej; Tichý, Tomáš; Krečmerová, Marcela; Janeba, Zlatko; Skinner-Adams, T. S.; Naesens, L.; Keough, D. T.; de Jersey, J.; Guddat, L. W.

    Praha : Institute of Organic Chemistry and Biochemistry AS CR, v. v. i., 2011 - (Hocek, M.), s. 171-174 ISBN 978-80-86241-37-1. - (Collection Symposium Series. 12). [Chemistry of Nucleic Acid Components /15./. Český Krumlov (CZ), 05.06.2011-10.06.2011] R&D Projects: GA MŠk 1M0508; GA ČR GAP207/11/0108 Institutional research plan: CEZ:AV0Z40550506 Keywords : ANPs * acyclic nucleoside phosphonates * anti-malarial * Plasmodium * HGXPRTase Subject RIV: CC - Organic Chemistry

  16. FORMULATION DEVELOPMENT AND EVALUATION OF CALCIPOTRIOL AND PREDNICARBATE FOR TOPICAL TREATMENT OF PSORIASIS

    Directory of Open Access Journals (Sweden)

    Jyoti Phatangare

    2014-09-01

    Full Text Available Calcipotriol and Prednicarbate are widely used effective treatments for psoriasis vulgaris. Combined therapy is known to be superior to monotherapy, but the drug substance degrades when mixed together. The purpose of the study was to develop a formulation which combines Calcipotriol and Prednicarbate in a single vehicle hereby with optimal drug delivery into the skin. As the two substances are incompatible in aqueous and alcoholic medias, different non-aqueous formulations were prepared with suitable solvents and antioxidants. Formulations based on DPPG had no overall effect on skin permeability. However, A 5% polyoxypropylene-15 stearyl ether (PSE formulation had a marked effect, resulted in a permeation rate comparable to the marketed combination product Diavobet (Calcipotriol and Betamethasone ointment. Thus, by using PSE as solvent, it was possible to combine Calcipotriol and Prednicarbate in a single formulation.

  17. Curcumin nanodisks: formulation and characterization

    OpenAIRE

    Ghosh, Mistuni; Singh, Amareshwar T.K.; Xu, Wenwei; Sulchek, Todd; Gordon, Leo I.; Ryan, Robert O.

    2010-01-01

    Nanodisks (ND) are nanoscale, disk-shaped phospholipid bilayers whose edge is stabilized by apolipoproteins. In the present study, ND were formulated with the bioactive polyphenol, curcumin, at a 6:1 phospholipid:curcumin molar ratio. Atomic force microscopy revealed that curcumin-ND are particles with diameters

  18. Hamiltonian formulation of bond graphs

    NARCIS (Netherlands)

    Golo, Goran; Schaft, van der Arjan; Breedveld, Peter C.; Maschke, Bernhard M.; Johansson, R.; Rantzer, A.

    2003-01-01

    This paper deals with the mathematical formulation of bond graphs. It is proven that the power continuous part of bond graphs, the junction structure, can be associated with a Dirac structure and that the equations describing a bond graph model correspond to a port Hamiltonian system. The conditions

  19. Hamiltonian formulation of the supermembrane

    International Nuclear Information System (INIS)

    The Hamiltonian formulation of the supermembrane theory in eleven dimensions is given. The covariant split of the first and second class constraints is exhibited, and their Dirac brackets are computed. Gauge conditions are imposed in such a way that the reparametrizations of the membrane with divergence free 2-vectors are unfixed. (author). 10 refs

  20. Reduction of anti-malarial consumption after rapid diagnostic tests implementation in Dar es Salaam: a before-after and cluster randomized controlled study

    Directory of Open Access Journals (Sweden)

    Swai Ndeniria

    2011-04-01

    Full Text Available Abstract Background Presumptive treatment of all febrile patients with anti-malarials leads to massive over-treatment. The aim was to assess the effect of implementing malaria rapid diagnostic tests (mRDTs on prescription of anti-malarials in urban Tanzania. Methods The design was a prospective collection of routine statistics from ledger books and cross-sectional surveys before and after intervention in randomly selected health facilities (HF in Dar es Salaam, Tanzania. The participants were all clinicians and their patients in the above health facilities. The intervention consisted of training and introduction of mRDTs in all three hospitals and in six HF. Three HF without mRDTs were selected as matched controls. The use of routine mRDT and treatment upon result was advised for all patients complaining of fever, including children under five years of age. The main outcome measures were: (1 anti-malarial consumption recorded from routine statistics in ledger books of all HF before and after intervention; (2 anti-malarial prescription recorded during observed consultations in cross-sectional surveys conducted in all HF before and 18 months after mRDT implementation. Results Based on routine statistics, the amount of artemether-lumefantrine blisters used post-intervention was reduced by 68% (95%CI 57-80 in intervention and 32% (9-54 in control HF. For quinine vials, the reduction was 63% (54-72 in intervention and an increase of 2.49 times (1.62-3.35 in control HF. Before-and-after cross-sectional surveys showed a similar decrease from 75% to 20% in the proportion of patients receiving anti-malarial treatment (Risk ratio 0.23, 95%CI 0.20-0.26. The cluster randomized analysis showed a considerable difference of anti-malarial prescription between intervention HF (22% and control HF (60% (Risk ratio 0.30, 95%CI 0.14-0.70. Adherence to test result was excellent since only 7% of negative patients received an anti-malarial. However, antibiotic

  1. Problem Formulation in Planning and Design

    OpenAIRE

    Volkema, Roger J.

    1983-01-01

    This paper deals with the role of problem formulation in planning and design, including: (a) the importance of problem formulation to planning and design; (b) problematic, physiological, psychological and environmental factors that can affect the formulation process; and (c) problem formulation heuristics. Two types of formulation heuristics are identified---problem reduction and problem expansion. Because the latter type has received little empirical research, an initial study of a problem e...

  2. A Comparison of Fick and Maxwell-Stefan Diffusion Formulations in PEMFC Cathode Gas Diffusion Layers

    CERN Document Server

    Lindstrom, Michael

    2013-01-01

    This paper explores the mathematical formulations of Fick and Maxwell-Stefan diffusion in the context of polymer electrolyte membrane fuel cell cathode gas diffusion layers. Formulations of diffusion combined with mass-averaged Darcy flow are considered for three component gases. Fick formulations can be considered as approximations of Maxwell-Stefan in a certain sense. For this application, the formulations can be compared computationally in a simple, one dimensional setting. We observe that the predictions of the formulations are very similar, despite their seemingly different structure. Analytic insight is given to the result. In addition, it is seen that for both formulations, diffusion laws are small perturbations from bulk flow. The work is also intended as a reference to multi-component gas diffusion formulations in the fuel cell setting.

  3. In-silico studies on DegP protein of Plasmodium falciparum in search of anti-malarials.

    Science.gov (United States)

    Sharma, Drista; Soni, Rani; Patel, Sachin; Joshi, Deepti; Bhatt, Tarun Kumar

    2016-09-01

    Despite encouraging progress over the past decade, malaria caused by the Plasmodium parasite continues to pose an enormous disease burden and is one of the major global health problems. The extreme challenge in malaria management is the resistance of parasites to traditional monochemotherapies like chloroquine and sulfadoxine-pyrimethamine. No vaccine is yet in sight, and the foregoing effective drugs are also losing ground against the disease due to the resistivity of parasites. New antimalarials with novel mechanisms of action are needed to circumvent existing or emerging drug resistance. DegP protein, secretory in nature has been shown to be involved in regulation of thermo-oxidative stress generated during asexual life cycle of Plasmodium, probably required for survival of parasite in host. Considering the significance of protein, in this study, we have generated a three-dimensional structure of PfDegP followed by validation of the modeled structure using several tools like RAMPAGE, ERRAT, and others. We also performed an in-silico screening of small molecule database against PfDegP using Glide. Furthermore, molecular dynamics simulation of protein and protein-ligand complex was carried out using GROMACS. This study substantiated potential drug-like molecules and provides the scope for development of novel antimalarial drugs. PMID:27491850

  4. De Novo transcriptome assembly (NGS of Curcuma longa L. rhizome reveals novel transcripts related to anticancer and antimalarial terpenoids.

    Directory of Open Access Journals (Sweden)

    Ramasamy S Annadurai

    Full Text Available Herbal remedies are increasingly being recognised in recent years as alternative medicine for a number of diseases including cancer. Curcuma longa L., commonly known as turmeric is used as a culinary spice in India and in many Asian countries has been attributed to lower incidences of gastrointestinal cancers. Curcumin, a secondary metabolite isolated from the rhizomes of this plant has been shown to have significant anticancer properties, in addition to antimalarial and antioxidant effects. We sequenced the transcriptome of the rhizome of the 3 varieties of Curcuma longa L. using Illumina reversible dye terminator sequencing followed by de novo transcriptome assembly. Multiple databases were used to obtain a comprehensive annotation and the transcripts were functionally classified using GO, KOG and PlantCyc. Special emphasis was given for annotating the secondary metabolite pathways and terpenoid biosynthesis pathways. We report for the first time, the presence of transcripts related to biosynthetic pathways of several anti-cancer compounds like taxol, curcumin, and vinblastine in addition to anti-malarial compounds like artemisinin and acridone alkaloids, emphasizing turmeric's importance as a highly potent phytochemical. Our data not only provides molecular signatures for several terpenoids but also a comprehensive molecular resource for facilitating deeper insights into the transcriptome of C. longa.

  5. 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

  6. Site-specific integration and expression of an anti-malarial gene in transgenic Anopheles gambiae significantly reduces Plasmodium infections.

    Directory of Open Access Journals (Sweden)

    Janet M Meredith

    Full Text Available Diseases transmitted by mosquitoes have a devastating impact on global health and this is worsening due to difficulties with existing control measures and climate change. Genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the delivery of novel control strategies. Historically the genetic modification of insects has relied upon transposable elements which have many limitations despite their successful use. To circumvent these limitations the Streptomyces phage phiC31 integrase system has been successfully adapted for site-specific transgene integration in insects. Here, we present the first site-specific transformation of Anopheles gambiae, the principal vector of human malaria. Mosquitoes were initially engineered to incorporate the phiC31 targeting site at a defined genomic location. A second phase of genetic modification then achieved site-specific integration of Vida3, a synthetic anti-malarial gene. Expression of Vida3, specifically in the midgut of bloodfed females, offered consistent and significant protection against Plasmodium yoelii nigeriensis, reducing average parasite intensity by 85%. Similar protection was observed against Plasmodium falciparum in some experiments, although protection was inconsistent. In the fight against malaria, it is imperative to establish a broad repertoire of both anti-malarial effector genes and tissue-specific promoters for their expression, enabling those offering maximum effect with minimum fitness cost to be identified. In the future, this technology will allow effective comparisons and informed choices to be made, potentially leading to complete transmission blockade.

  7. The search for new antimalarial drugs from plants used to treat fever and malaria or plants ramdomly selected: a review

    Directory of Open Access Journals (Sweden)

    Krettli Antoniana U

    2001-01-01

    Full Text Available In this review we discuss the ongoing situation of human malaria in the Brazilian Amazon, where it is endemic causing over 610,000 new acute cases yearly, a number which is on the increase. This is partly a result of drug resistant parasites and new antimalarial drugs are urgently needed. The approaches we have used in the search of new drugs during decades are now reviewed and include ethnopharmocology, plants randomly selected, extracts or isolated substances from plants shown to be active against the blood stage parasites in our previous studies. Emphasis is given on the medicinal plant Bidens pilosa, proven to be active against the parasite blood stages in tests using freshly prepared plant extracts. The anti-sporozoite activity of one plant used in the Brazilian endemic area to prevent malaria is also described, the so called "Indian beer" (Ampelozizyphus amazonicus, Rhamnaceae. Freshly prepared extracts from the roots of this plant were totally inactive against blood stage parasites, but active against sporozoites of Plasmodium gallinaceum or the primary exoerythrocytic stages reducing tissue parasitism in inoculated chickens. This result will be of practical importance if confirmed in mammalian malaria. Problems and perspectives in the search for antimalarial drugs are discussed as well as the toxicological and clinical trials to validate some of the active plants for public health use in Brazil.

  8. Phytochemical screening and in vivo antimalarial activity of extracts from three medicinal plants used in malaria treatment in Nigeria.

    Science.gov (United States)

    Bankole, A E; Adekunle, A A; Sowemimo, A A; Umebese, C E; Abiodun, O; Gbotosho, G O

    2016-01-01

    The use of plant to meet health-care needs has greatly increased worldwide in the recent times. The search for new plant-derived bioactive agents that can be explored for the treatment of drug-resistant malaria infection is urgently needed. Thus, we evaluated the antimalarial activity of three medicinal plants used in Nigerian folklore for the treatment of malaria infection. A modified Peter's 4-day suppressive test was used to evaluate the antimalarial activity of the plant extracts in a mouse model of chloroquine-resistant Plasmodium berghei ANKA strain. Animals were treated with 250, 500, or 800 mg/kg of aqueous extract. It was observed that of all the three plants studied, Markhamia tomentosa showed the highest chemosuppression of parasites of 73 % followed by Polyalthia longifolia (53 %) at day 4. All the doses tested were well tolerated. Percentage suppression of parasite growth on day 4 post-infection ranged from 1 to 73 % in mice infected with P. berghei and treated with extracts when compared with chloroquine diphosphate, the standard reference drug which had a chemosuppression of 90 %. The percentage survival of mice that received extract ranged from 0 to 60 % (increased as the dose increases to 800 mg/kg). Phytochemical analysis revealed the presence of tannins, saponins, and phenolic compounds in all the three plants tested. PMID:26391173

  9. Antimalarial potential of homeopathic medicines against schizont maturation of Plasmodium berghei in short-term in vitro culture

    Directory of Open Access Journals (Sweden)

    Upma Bagai

    2012-12-01

    Full Text Available In vitro assessment of antimalarial drug susceptibility of Plasmodium has been a major research success, which has paved the way for the understanding of parasite and rapid screening of antimalarial drugs for their effectiveness. In the present study a preliminary screening to check the antiplasmodial activity of mother tincture (ϕ and various potencies (6C, 30C, 200C of homeopathic medicines Cinchona officinalis/china (Chin., Chelidonium majus (Chel. and Arsenicum album (Ars. were done by assessing the in vitro schizont maturation inhibition assay. A significant reduction in the growth of intraerythrocytic stages of P. berghei was observed with decreasing dilution of ϕ and various potencies of Chin., Chel. and Ars. exhibiting a dose dependent effect. Maximum schizont maturation inhibition was observed by Chin. ϕ (1:1, Chin. 30 (1:1, 1:2 and Chel. 30 (1:1 i.e. 80%. The standard drug CQ at 10 µM concentration exhibited 95.4±1.6% inhibition of schizont maturation. Ars. 30 (1:1 also have been found to possess strong antiplasmodial efficacy with 75.5±2.6% schizont inhibition. The presence of free merozoites in Ars. 200 with weak schizonticidal inhibition activity (40-45% also pointed towards the ability of parasite to survive in the given drug pressure.

  10. Formulation of elastic multi-structures

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Based on the creative and groundbreaking work done by Feng and Shi, some further work has been carried out comprehensively by the first author on the formulation of elastic multi-structures. The main contribution of this paper can be summarized as follows: The work of Feng and Shi has been extended to an elastic multi-structures with nonlinear structural element: shell in both linear and nonlinear case. Three general combinations of multi-structures have been formulated, that is, Case 1: linear elements of 3-D body, 1-D bar/beam, 2-D plates and 2-D shell; Case 2: nonlinear elements of 3-D body, 1-D bar/beam, 2-D plates and 2-D shell; and Case 3: the linear-nonlinear mix problem of 3-D body (nonlinear), 1-D bar/beam (linear), 2-D plates (linear) and 2-D shell (linear). From the investigation, it has proved that the higher dimensional element will have a strong influence on the lower one with the inner linkage boundaries, and also proved that solution uniqueness of elastic multi-structures is different from a single 3-D body.

  11. Projecting India's energy requirements for policy formulation

    International Nuclear Information System (INIS)

    Energy policy has to have a long-term perspective. To formulate it one needs to know the contours of energy requirements and options. Different approaches have been followed in literature, each with their own problems. A top down econometric approach provides little guidance on policies, while a bottom up approval requires too much knowledge and too many assumptions. Using top-down econometric approach for aggregate overall benchmarking and a detailed activity analysis model, Integrated Energy System Model, for a few large sectors, provides a unique combination for easing the difficulties of policy formulation. The model is described in this paper. Eleven alternate scenarios are built, designed to map out extreme points of feasible options. Results show that even after employing all domestic energy resource to their full potential, there will be a continued rise of fossil fuel use, continued importance of coal, and continued rise of import dependence. Energy efficiency emerges as a major option with a potential to reduce energy requirement by as much as 17%. Scenario results point towards pushing for development of alternative sources.

  12. Projecting India's energy requirements for policy formulation

    International Nuclear Information System (INIS)

    Energy policy has to have a long-term perspective. To formulate it one needs to know the contours of energy requirements and options. Different approaches have been followed in literature, each with their own problems. A top down econometric approach provides little guidance on policies, while a bottom up approval requires too much knowledge and too many assumptions. Using top-down econometric approach for aggregate overall benchmarking and a detailed activity analysis model, Integrated Energy System Model, for a few large sectors, provides a unique combination for easing the difficulties of policy formulation. The model is described in this paper. Eleven alternate scenarios are built, designed to map out extreme points of feasible options. Results show that even after employing all domestic energy resource to their full potential, there will be a continued rise of fossil fuel use, continued importance of coal, and continued rise of import dependence. Energy efficiency emerges as a major option with a potential to reduce energy requirement by as much as 17%. Scenario results point towards pushing for development of alternative sources. (author)

  13. Formulation and evaluation of floating tablets of liquorice extract

    Directory of Open Access Journals (Sweden)

    H N Aswatha Ram

    2010-01-01

    Full Text Available Background: Floating tablets prolong the gastric residence time of drugs, improve bioavailability, and facilitate local drug delivery to the stomach. With this objective, floating tablets containing aqueous extract of liquorice as drug was prepared for the treatment of Helicobacter pylori and gastric ulcers. Methods: The aqueous extract of liquorice was standardized by HPTLC. Tablets containing HPMC K100M (hydrophilic polymer, liquorice extract, sodium bicarbonate (gas generating agent, talc, and magnesium stearate were prepared using direct compression method. The formulations were evaluated for physical parameters like diameter, thickness, hardness, friability, uniformity of weight, drug content, buoyancy time, dissolution, and drug release mechanism. The formulations were optimized on the basis of buoyancy time and in vitro drug release. Results: The diameter of all formulations was in the range 11.166-11.933 mm; thickness was in the range 4.02-4.086 mm. The hardness ranged from 3.1 to 3.5 kg/cm 2 . All formulations passed the USP requirements for friability and uniformity of weight. The buoyancy time of all tablet formulations was less than 5 min and tablet remained in floating condition throughout the study. All the tablet formulations followed zero-order kinetics and Korsemeyer-Peppas model in drug release. Conclusion: The optimized formulation was found to be F6 which released 98.3% of drug in 8 h in vitro, while the buoyancy time was 3.5 min. Formulations containing psyllium husk, sodium bicarbonate and HPMC K100M in combination can be a promising for gastroretentive drug delivery systems.

  14. Langevin formulation of quantum dynamics

    International Nuclear Information System (INIS)

    We first show that nonrelativistic quantum mechanics formulated at imaginary-(h/2 π) can formally be viewed as the Fokker-Planck description of a frictionless brownian motion, which occurs (in general) in an absorbing medium. We next offer a new formulation of quantum mechanics, which is basically the Langevin treatment of this brownian motion. Explicitly, we derive a noise-average representation for the transition probability W(X'',t''|X',t'), in terms of the solutions to a Langevin equation with a Gaussian white-noise. Upon analytic continuation back to real-(h/2 π),W(X'',t''|X',t') becomes the propagator of the original Schroedinger equation. Our approach allows for a straightforward application to quantum dynamical problems of the mathematical techniques of classical stochastic processes. Moreover, computer simulations of quantum mechanical systems can be carried out by using numerical programs based on the Langevin dynamics. (author). 19 refs, 1 tab

  15. Uncertainty formulations for multislit interferometry

    Science.gov (United States)

    Biniok, Johannes C. G.

    2014-12-01

    In the context of (far-field) multislit interferometry we investigate the utility of two formulations of uncertainty in accounting for the complementarity of spatial localization and fringe width. We begin with a characterization of the relevant observables and general considerations regarding the suitability of different types of measures. The detailed analysis shows that both of the discussed uncertainty formulations yield qualitatively similar results, confirming that they correctly capture the relevant tradeoff. One approach, based on an idea of Aharonov and co-workers, is intuitively appealing and relies on a modification of the Heisenberg uncertainty relation. The other approach, developed by Uffink and Hilgevoord for single- and double-slit experiments, is readily applied to multislits. However, it is found that one of the underlying concepts requires generalization and that the choice of the parameters requires more consideration than was known.

  16. Formulation of soy oil products

    OpenAIRE

    Woerfel, John B.

    1995-01-01

    The paper comments different formulations of soy oil products such as salad and cooking oils, margarine, shortenings, commercial shortenings, frying shortenings, and fluid shortenings. Hydrogenation and its influence on final products is also included.

    El trabajo presenta diferentes formulaciones a base de aceite de soja tales como aceites para ensalada y cocinado, margarina, grasas sólidas (shortenings), grasas sólidas comerciales, grasas sólidas para frituras y grasas flu...

  17. Nanoparticle formulations of cisplatin for cancer therapy.

    Science.gov (United States)

    Duan, Xiaopin; He, Chunbai; Kron, Stephen J; Lin, Wenbin

    2016-09-01

    The genotoxic agent cisplatin, used alone or in combination with radiation and/or other chemotherapeutic agents, is an important first-line chemotherapy for a broad range of cancers. The clinical utility of cisplatin is limited both by intrinsic and acquired resistance and dose-limiting normal tissue toxicity. That cisplatin shows little selectivity for tumor versus normal tissue may be a critical factor limiting its value. To overcome the low therapeutic ratio of the free drug, macromolecular, liposomal, and nanoparticle drug delivery systems have been explored toward leveraging the enhanced permeability and retention effect and promoting delivery of cisplatin to tumors. Here, we survey recent advances in nanoparticle formulations of cisplatin, focusing on agents that show promise in preclinical or clinical settings. WIREs Nanomed Nanobiotechnol 2016, 8:776-791. doi: 10.1002/wnan.1390 For further resources related to this article, please visit the WIREs website. PMID:26848041

  18. Produtividade do Sorgo granífero cv. sacarino e qualidade de produtos formulados isoladamente ou combinados ao caldo de cana-de-açúcar Yield of Sorghum bicolor cv. sacarino and quality of products formulated isolated or combined with sugar cane juice

    Directory of Open Access Journals (Sweden)

    Cassiara Camelo de Souza

    2005-09-01

    Full Text Available Este trabalho teve como objetivo avaliar o comportamento produtivo do Sorgo granífero (Sorghum bicolor L variedade IPA- 467, mediante condições de irrigação e adubação, bem como, a caracterização físico-química da farinha de diferentes tipos de grãos e de rapadura obtida a partir de combinações de caldo de sorgo (CS x caldo de cana (CC. O experimento resultou em uma produção de biomassa, sementes, colmo, caldo, melaço fino e melaço grosso, respectivamente, de: 64t/ha; 3,5t/ha; 46t/ha; 700L/t de colmo; 140L/t de colmo e 90L/t de colmo. A farinha obtida a partir de grãos de sorgo apresenta teor de açúcares totais inferior aos da farinha de trigo. As rapaduras em que o caldo de sorgo foi adicionado nas proporções de 10 e 20%, em associação com o caldo-de-cana, obtiveram maior nível de aceitação, quando comparada à rapadura obtida a partir de 100% de caldo de cana-de-açúcar. A aceitação de rapaduras formuladas a partir 30% de caldo sorgo e 70% de caldo de cana não diferiu de rapaduras obtidas de 100% de caldo de cana.The objective of this work was to evaluate the yield of Sorghum bicolor var. IPA-467, under irrigation and fertilizer conditions and the physical-chemical characterization of grain flours and 'rapadura' obtained from combinations of sorghum stem juice (SJ x sugar cane juice (CJ. The experiment resulted im biomass production, seeds, stem, juice, thick sugarcane syrup, respectively of 64t/ha; 3,5t/ha, 46t/ha, 700L/t of stem, 140L/t of stem and 90L/t of stem. The total sugars of sorghum grain flour were lower than results reported for wheat flour. 'Rapaduras' in which sorghum juice was used at 10 and 20, in combination of sugar cane juice, had higher acceptance scores, as compared with 'rapadura' obtaned from 100% sugar cane juice. The acceptance of 'rapaduras' formulated from 30% SJ x 70% CJ did not differ from those obtained from 100% CJ.

  19. Biomarkers and special features of oxidative stress in the anterior segment of the eye linked to lens cataract and the trabecular meshwork injury in primary open-angle glaucoma: challenges of dual combination therapy with N-acetylcarnosine lubricant eye drops and oral formulation of nonhydrolyzed carnosine.

    Science.gov (United States)

    Babizhayev, Mark A

    2012-02-01

    analogs, beta-blockers, or local carbonic anhydrase inhibitors, these effects were markedly reduced. Oxidative stress can induce characteristic glaucomatous TM changes, and these oxidative stress-induced TM changes can be minimized by the use of antioxidants and IOP-lowering substances. It is tempting to speculate that the prevention of oxidative stress exposure to the TM may help to reduce the progression of POAG. The author's laboratory has developed and patented the dual combination therapy with N-acetylcarnosine lubricant eye drops and oral formulation of nonhydrolyzed carnosine in ripe cataracts and POAG. The specific regimen for the treatment in each stage of age-related ophthalmic disease has been taken up. In the treatment of POAG, this dual therapy can be combined with conventional antiglaucoma therapy with beta-blocking and/or adrenergic agonist medicines providing the significant IOP-lowering effect and significant increase in outflow facility. The developed therapy is a prominent management care of the glaucomatous neurodegeneration. PMID:21883446

  20. Surface Integral Formulations for the Design of Plasmonic Nanostructures

    Science.gov (United States)

    Forestiere, Carlo; Iadarola, Giovanni; Rubinacci, Guglielmo; Tamburrino, Antonello; Dal Negro, Luca; Miano, Giovanni; Boston University Team; Universita'degli Studi di Napoli Federico Team, II; Universita'di Cassino e del Lazio Meridionale Team

    2013-03-01

    Numerical formulations based on surface integral equations (SIEs) provide an accurate and efficient framework for the solution of the electromagnetic scattering problem by three-dimensional plasmonic nanostructures in the frequency domain. In this work, we present a unified description of SIE formulations with both singular and nonsingular kernel and we study their accuracy in solving the scattering problem by metallic nanoparticles with spherical and nonspherical shape. In fact, the accuracy of the numerical solution, especially in the near zone, is of great importance in the analysis and design of plasmonic nanostructures, whose operation critically depends on the manipulation of electromagnetic hot spots. Four formulation types are considered: the N-combined region integral equations, the T-combined region integral equations, the combined field integral equations and the null field integral equations. A detailed comparison between their numerical solutions obtained for several nanoparticle shapes is performed by examining convergence rate and accuracy in both the far and near zone of the scatterer as a function of the number of degrees of freedom. A rigorous analysis of SIE formulations can have a high impact on the engineering of numerous nano-scale optical devices.