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Antimalarial Drugs (antimalarial + drug)
Selected AbstractsTrends in Antimalarial Drugs Prescribed in New Zealand 1993 to 1998JOURNAL OF TRAVEL MEDICINE, Issue 3 2003FACTM, Peter A. Leggat FAFPHM No abstract is available for this article. [source] Current status of malaria chemotherapy and the role of pharmacology in antimalarial drug research and developmentFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2009Kesara Na-Bangchang Abstract Antimalarial drugs have played a mainstream role in controlling the spread of malaria through the treatment of patients infected with the plasmodial parasites and controlling its transmissibility. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to currently used antimalarials, and the lack of affordable new drugs are the limiting factors in the fight against malaria. In addition, other problems with some existing agents include unfavorable pharmacokinetic properties and adverse effects/toxicity. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. In recent years, major advances have been made in the pharmacology of several antimalarial drugs both in pharmacokinetics and pharmacodynamics aspects. These include the design, development, and optimization of appropriate dosage regimens of antimalarials, basic knowledge in metabolic pathways of key antimalarials, as well as the elucidation of mechanisms of action and resistance of antimalarials. Pharmacologists have been working in close collaboration with scientists in other disciplines of science/biomedical sciences for more understanding on the biology of the parasite, host, in order to exploit rational design of drugs. Multiple general approaches to the identification of new antimalarials are being pursued at this time. All should be implemented in parallel with focus on the rational development of new agents directed against newly identified parasite targets. With major advances in our understanding of malaria parasite biology coupled with the completion of the malaria genome, has presented exciting opportunities for target-based antimalarial drug discovery. [source] Antimalarial treatment may have a time-dependent effect on lupus survival: Data from a multinational Latin American inception cohortARTHRITIS & RHEUMATISM, Issue 3 2010Samuel K. Shinjo Objective To evaluate the beneficial effect of antimalarial treatment on lupus survival in a large, multiethnic, international longitudinal inception cohort. Methods Socioeconomic and demographic characteristics, clinical manifestations, classification criteria, laboratory findings, and treatment variables were examined in patients with systemic lupus erythematosus (SLE) from the Grupo Latino Americano de Estudio del Lupus Eritematoso (GLADEL) cohort. The diagnosis of SLE, according to the American College of Rheumatology criteria, was assessed within 2 years of cohort entry. Cause of death was classified as active disease, infection, cardiovascular complications, thrombosis, malignancy, or other cause. Patients were subdivided by antimalarial use, grouped according to those who had received antimalarial drugs for at least 6 consecutive months (user) and those who had received antimalarial drugs for <6 consecutive months or who had never received antimalarial drugs (nonuser). Results Of the 1,480 patients included in the GLADEL cohort, 1,141 (77%) were considered antimalarial users, with a mean duration of drug exposure of 48.5 months (range 6,98 months). Death occurred in 89 patients (6.0%). A lower mortality rate was observed in antimalarial users compared with nonusers (4.4% versus 11.5%; P< 0.001). Seventy patients (6.1%) had received antimalarial drugs for 6,11 months, 146 (12.8%) for 1,2 years, and 925 (81.1%) for >2 years. Mortality rates among users by duration of antimalarial treatment (per 1,000 person-months of followup) were 3.85 (95% confidence interval [95% CI] 1.41,8.37), 2.7 (95% CI 1.41,4.76), and 0.54 (95% CI 0.37,0.77), respectively, while for nonusers, the mortality rate was 3.07 (95% CI 2.18,4.20) (P for trend < 0.001). After adjustment for potential confounders in a Cox regression model, antimalarial use was associated with a 38% reduction in the mortality rate (hazard ratio 0.62, 95% CI 0.39,0.99). Conclusion Antimalarial drugs were shown to have a protective effect, possibly in a time-dependent manner, on SLE survival. These results suggest that the use of antimalarial treatment should be recommended for patients with lupus. [source] Antimalarial drugs , host targets (re)visitedBIOTECHNOLOGY JOURNAL, Issue 3 2006Margarida Cunha-Rodrigues Abstract Every year, forty percent of the world population is at risk of contracting malaria. Hopes for the erradication of this disease during the 20th century were dashed by the ability of Plasmodium falciparum, its most deadly causative agent, to develop resistance to available drugs. Efforts to produce an effective vaccine have so far been unsuccessful, enhancing the need to develop novel antimalarial drugs. In this review, we summarize our knowledge concerning existing antimalarials, mechanisms of drug-resistance development, the use of drug combination strategies and the quest for novel anti-plasmodial compounds. We emphasize the potential role of host genes and molecules as novel targets for newly developed drugs. Recent results from our laboratory have shown Hepatocyte Growth Factor/MET signaling to be essential for the establishment of infection in hepatocytes. We discuss the potential use of this pathway in the prophylaxis of malaria infection. [source] Electrocatalytic and Analytical Response of Cobalt Phthalocyanine Modified Carbon Paste Electrodes Towards Antimalarial Endoperoxide ArtemisininELECTROANALYSIS, Issue 3-5 2009Chhanda Debnath Abstract A cobalt phthalocyanine modified carbon paste electrode was constructed for the analysis of artemisinin in Artemisia annua plant. Artemisinin, a sesquiterpene endoperoxide, is a novel, important antimalarial drug and is used in the therapy against Plasmodium falciparum. The developed cobalt phthalocyanine modified electrode exhibited a significant electrocatalytic activity in presence of artemisinin when using cyclic and differential pulse voltammetry. Under optimized conditions in phosphate buffer of pH,7 a well defined voltammetric peak appeared at about ,500,mV vs. Ag/AgCl. The differential pulse voltammetric peak current of artemisinin was increased linearly with the concentration range of 2.1×10,5 to 5.3×10,4 M (R=0.9997). The limit of detection (LOD) was found to be 6.5×10,6 M. The modified electrode was successfully tested for detecting artemisinin in complex plant materials. [source] Dissolution of artemisinin/polymer composite nanoparticles fabricated by evaporative precipitation of nanosuspensionJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2010Mitali Kakran Abstract Objectives An evaporative precipitation of nanosuspension (EPN) method was used to fabricate composite particles of a poorly water-soluble antimalarial drug, artemisinin, with a hydrophilic polymer, polyethylene glycol (PEG), with the aim of enhancing the dissolution rate of artemisinin. We investigated the effect of polymer concentration on the physical, morphological and dissolution properties of the EPN-prepared artemisinin/PEG composites. Methods The original artemisinin powder, EPN-prepared artemisinin nanoparticles and artemisinin/PEG composites were characterised by scanning electron microscopy, Fourier-transform infrared spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), dissolution testing and HPLC. The percentage dissolution efficiency, relative dissolution, time to 75% dissolution and mean dissolution time were calculated. The experimental drug dissolution data were fitted to various mathematical models (Weibull, first-order, Korsemeyer,Peppas, Hixson,Crowell cube root and Higuchi models) in order to analyse the release mechanism. Key findings The DSC and XRD studies suggest that the crystallinity of the EPN-prepared artemisinin decreased with increasing polymer concentration. The phase-solubility studies revealed an AL -type curve, indicating a linear increase in drug solubility with PEG concentration. The dissolution rate of the EPN-prepared artemisinin and artemisinin/PEG composites increased markedly compared with the original artemisinin powder. Conclusions EPN can be used to prepare artemisinin nanoparticles and artemisinin/PEG composite particles that have a significantly enhanced dissolution rate. The mechanism of drug release involved diffusion and erosion. [source] Lysosomal trapping of amodiaquine: impact on transport across intestinal epithelia modelsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2008Rose Hayeshi Abstract The lipophilic weak base amodiaquine is an antimalarial drug that has been in use for over 40 years. Little is known of amodiaquine's mechanism of transport across membranes. Transport experiments of amodiaquine in Caco-2 cells showed a low recovery of 30% and rapid disappearance from the apical chamber. Compounds structurally similar to amodiaquine, and those affecting non-specific binding of amodiaquine or the pH of the system, were tested to unravel the mechanism behind these observations. Chloroquine and ammonium chloride increased the transmonolayer permeability of amodiaquine and decreased its accumulation in Caco-2 cells, whereas BSA had no effect. Chloroquine and BSA decreased plastic binding whereas ammonium chloride had no effect. This suggests that amodiaquine is trapped in acidic cell compartments such as lysosomes. Amodiaquine was also trapped in rat intestinal tissue. In addition, permeability from the apical to basolateral direction was significantly higher, suggesting an active uptake over the apical membrane of the rat tissue. It can be concluded that amodiaquine is trapped in acidic cell compartments due to its base properties and recovery may be improved by the use of ammonium chloride rather than BSA in transport experiments. Further studies are required to confirm whether amodiaquine is actively absorbed in the intestine. Copyright © 2008 John Wiley & Sons, Ltd. [source] Stereoselective halofantrine and desbutylhalofantrine disposition in the rat: cardiac and plasma concentrations and plasma protein bindingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2002Dion R. Brocks Abstract Halofantrine (HF) is a chiral antimalarial drug known to cause cardiac arrhythmias in susceptible patients. In this study, the cardiac uptake and plasma protein binding of HF and desbutylhalofantrine (DHF) enantiomers were examined in the rat. Rats were given 2 mg/kg of either HF HCl or DHF HCl intravenously, then sacrificed at various times after dosing. Specimens were assayed using stereospecific methods. Uptake of HF and DHF enantiomers into heart was rapid. Substantial concentrations of both HF and DHF enantiomers were observed in rat heart, with stereoselectivity being noted for both in plasma and heart. Stereoselectivity was more pronounced for HF (AUC (+):(,) ratio= 1.58) than DHF (AUC (+):(,) ratio =1.16) in heart tissue. Heart:plasma AUC ratios of 6.8,8.0, and 9.3,21, were observed for HF and DHF enantiomers, respectively, indicating that DHF has greater cardiac uptake than HF itself. Plasma protein binding was extensive for both HF and DHF (>99.95%), and was stereoselective for DHF, with a 38% higher unbound fraction for (,)-DHF than antipode. In contrast, binding of HF enantiomers was nonstereoselective. The lower degree of stereoselectivity for DHF in heart tissues was attributable to its greater stereoselectivity in plasma protein binding. Copyright © 2002 John Wiley & Sons, Ltd. [source] Proarrhythmic potential of halofantrine, terfenadine and clofilium in a modified in vivo model of torsade de pointesBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2002Andrew J Batey This study was designed to compare the proarrhythmic activity of the antimalarial drug, halofantrine and the antihistamine, terfenadine, with that of clofilium a K+ channel blocking drug that can induce torsade de pointes. Experiments were performed in pentobarbitone-anaesthetized, open-chest rabbits. Each rabbit received intermittent, rising dose i.v. infusions of the ,-adrenoceptor agonist phenylephrine. During these infusions rabbits also received increasing i.v. doses of clofilium (20, 60 and 200 nmol kg,1 min,1), terfenadine (75, 250 and 750 nmol kg,1 min,1), halofantrine (6, 20 and 60 ,mol kg,1) or vehicle. Clofilium and halofantrine caused dose-dependent increases in the rate-corrected QT interval (QTc), whereas terfenadine prolonged PR and QRS intervals rather than prolonging cardiac repolarization. Progressive bradycardia occurred in all groups. After administration of the highest dose of each drug halofantrine caused a modest decrease in blood pressure, but terfenadine had profound hypotensive effects resulting in death of most rabbits. The total number of ventricular premature beats was highest in the clofilium group. Torsade de pointes occurred in 6 out of 8 clofilium-treated rabbits and 4 out of 6 of those which received halofantrine, but was not seen in any of the seven terfenadine-treated rabbits. These results show that, like clofilium, halofantrine can cause torsade de pointes in a modified anaesthetized rabbit model whereas the primary adverse effect of terfenadine was cardiac contractile failure. British Journal of Pharmacology (2002) 135, 1003,1012; doi:10.1038/sj.bjp.0704550 [source] Current status of malaria chemotherapy and the role of pharmacology in antimalarial drug research and developmentFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2009Kesara Na-Bangchang Abstract Antimalarial drugs have played a mainstream role in controlling the spread of malaria through the treatment of patients infected with the plasmodial parasites and controlling its transmissibility. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to currently used antimalarials, and the lack of affordable new drugs are the limiting factors in the fight against malaria. In addition, other problems with some existing agents include unfavorable pharmacokinetic properties and adverse effects/toxicity. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. In recent years, major advances have been made in the pharmacology of several antimalarial drugs both in pharmacokinetics and pharmacodynamics aspects. These include the design, development, and optimization of appropriate dosage regimens of antimalarials, basic knowledge in metabolic pathways of key antimalarials, as well as the elucidation of mechanisms of action and resistance of antimalarials. Pharmacologists have been working in close collaboration with scientists in other disciplines of science/biomedical sciences for more understanding on the biology of the parasite, host, in order to exploit rational design of drugs. Multiple general approaches to the identification of new antimalarials are being pursued at this time. All should be implemented in parallel with focus on the rational development of new agents directed against newly identified parasite targets. With major advances in our understanding of malaria parasite biology coupled with the completion of the malaria genome, has presented exciting opportunities for target-based antimalarial drug discovery. [source] The mechanisms of resistance to antimalarial drugs in Plasmodium falciparumFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 2 2003Jacques Le Bras Abstract Drug-resistant malaria is primarily caused by Plasmodium falciparum, a species highly prevalent in tropical Africa, the Amazon region and South-east Asia. It causes severe fever or anaemia that leads to more than a million deaths each year. The emergence of chloroquine resistance has been associated with a dramatic increase in malaria mortality among inhabitants of some endemic regions. The rationale for chemoprophylaxis is weakening as multiple-drug resistance develops against well-tolerated drugs. Plasmodium falciparum drug-resistant malaria originates from chromosome mutations. Analysis by molecular, genetic and biochemical approaches has shown that (i) impaired chloroquine uptake by the parasite vacuole is a common characteristic of resistant strains, and this phenotype is correlated with mutations of the Pfmdr1, Pfcg2 and Pfcrt genes; (ii) one to four point mutations of dihydrofolate reductase (DHFR), the enzyme target of antifolates (pyrimethamine and proguanil) produce a moderate to high level of resistance to these drugs; (iii) the mechanism of resistance to sulfonamides and sulfones involves mutations of dihydropteroate synthase (DHPS), their enzyme target; (iv) treatment with sulphadoxine,pyrimethamine selects for DHFR variants Ile(51), Arg(59), and Asn(108) and for DHPS variants Ser(436), Gly(437), and Glu(540); (v) clones that were resistant to some traditional antimalarial agents acquire resistance to new ones at a high frequency (accelerated resistance to multiple drugs, ARMD). The mechanisms of resistance for amino-alcohols (quinine, mefloquine and halofantrine) are still unclear. Epidemiological studies have established that the frequency of chloroquine resistant mutants varies among isolated parasite populations, while resistance to antifolates is highly prevalent in most malarial endemic countries. Established and strong drug pressure combined with low antiparasitic immunity probably explains the multidrug-resistance encountered in the forests of South-east Asia and South America. In Africa, frequent genetic recombinations in Plasmodium originate from a high level of malaria transmission, and falciparum chloroquine-resistant prevalence seems to stabilize at the same level as chloroquine-sensitive malaria. Nevertheless, resistance levels may differ according to place and time. In vivo and in vitro tests do not provide an adequate accurate map of resistance. Biochemical tools at a low cost are urgently needed for prospective monitoring of resistance. [source] A Chemical Approach Towards Understanding the Mechanism and Reversal of Drug Resistance in Plasmodium falciparum: Is it Viable?IUBMB LIFE, Issue 4-5 2002Kelly Chibale Abstract Genetic and biochemical approaches to studies of drug resistance mechanisms in Plasmodium falciparum have raised controversies and contradictions over the past several years. A different and novel chemical approach to this important problem is desirable at this point in time. Recently, the molecular basis of drug resistance in P. falciparum has been associated with mutations in the resistance genes, Chloroquine Resistance Transporter (PfCRT) and the P-glycoprotein homologue (Pgh1). Although not the determinant of chloroquine resistance in P. falciparum, mutations in Pgh1 have important implications for resistance to other antimalarial drugs. Because it is mutations in the aforementioned resistance genes rather than overexpression that has been associated with drug resistance in malaria, studies on mechanisms of drug resistance and its reversal by chemosensitisers should benefit from a chemical approach. Target-oriented organic synthesis of chemosensitisers against proteins implicated in drug resistance in malaria should shed light on mechanism of drug resistance and its reversal in this area. The effect of structurally diverse chemosensitisers should be examined on several putative resistance genes in P. falciparum to deal with antimalarial drug resistance in the broadest sense. Therefore, generating random mutations of these resistance proteins and subsequent screening in search of a specific phenotype followed by a search for mutations and/or chemosensitisers that affect a specific drug resistance pathway might be a viable strategy. This diversity-oriented organic synthesis approach should offer the means to simultaneously identify resistance proteins that can serve as targets for therapeutic intervention (therapeutic target validation) and chemosensitisers that modulate the functions of these proteins (chemical target validation). [source] Antimalarial drug quality in AfricaJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2007A. A. Amin PhD Abstract Background and objective: There are several reports of sub-standard and counterfeit antimalarial drugs circulating in the markets of developing countries; we aimed to review the literature for the African continent. Methods: A search was conducted in PubMed in English using the medical subject headings (MeSH) terms: ,Antimalarials/analysis'[MeSH] OR ,Antimalarials/standards'[MeSH] AND ,Africa'[MeSH]' to include articles published up to and including 26 February 2007. Data were augmented with reports on the quality of antimalarial drugs in Africa obtained from colleagues in the World Health Organization. We summarized the data under the following themes: content and dissolution; relative bioavailability of antimalarial products; antimalarial stability and shelf life; general tests on pharmaceutical dosage forms; and the presence of degradation or unidentifiable impurities in formulations. Results and discussion: The search yielded 21 relevant peer-reviewed articles and three reports on the quality of antimalarial drugs in Africa. The literature was varied in the quality and breadth of data presented, with most bioavailability studies poorly designed and executed. The review highlights the common finding in drug quality studies that (i) most antimalarial products pass the basic tests for pharmaceutical dosage forms, such as the uniformity of weight for tablets, (ii) most antimalarial drugs pass the content test and (iii) in vitro product dissolution is the main problem area where most drugs fail to meet required pharmacopoeial specifications, especially with regard to sulfadoxine,pyrimethamine products. In addition, there are worryingly high quality failure rates for artemisinin monotherapies such as dihydroartemisinin (DHA); for instance all five DHA sampled products in one study in Nairobi, Kenya, were reported to have failed the requisite tests. Conclusions: There is an urgent need to strengthen pharmaceutical management systems such as post-marketing surveillance and the broader health systems in Africa to ensure populations in the continent have access to antimalarial drugs that are safe, of the highest quality standards and that retain their integrity throughout the distribution chain through adequate enforcement of existing legislation and enactment of new ones if necessary, and provision of the necessary resources for drug quality assurance. [source] Antimalarial compounds isolated from plants used in traditional medicineJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2009Joanne Bero Abstract Objectives This review covers the compounds with antiplasmodial activity isolated from plants published from 2005 to the end of 2008, organized according to their phytochemical classes. Details are given for substances with IC50 values , 11 ,M. Key findings Malaria is a major parasitic disease in many tropical and subtropical regions and is responsible for more than 1 million deaths each year in Africa. The rapid spread of resistance encourages the search for new active compounds. Nature and particularly plants used in traditional medicine are a potential source of new antimalarial drugs as they contain molecules with a great variety of structures and pharmacological activities. Summary A large number of antimalarial compounds with a wide variety of structures have been isolated from plants and can play a role in the development of new antimalarial drugs. Ethnopharmacological approaches appear to be a promising way to find plant metabolites that could be used as templates for designing new derivatives with improved properties. [source] Recent advances in antimalarial drug developmentMEDICINAL RESEARCH REVIEWS, Issue 1 2007Suryanaryana Vangapandu Abstract Malaria caused by protozoa of the genus Plasmodium, because of its prevalence, virulence, and drug resistance, is the most serious and widespread parasitic disease encountered by mankind. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to commonly used drugs such as chloroquine, and the lack of affordable new drugs are the limiting factors in the fight against malaria. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. This review provides an in-depth look at the most significant progress made during the past 10 years in antimalarial drug development. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 1, 65,107, 2007 [source] Plasmepsins as potential targets for new antimalarial therapyMEDICINAL RESEARCH REVIEWS, Issue 5 2006Karolina Ersmark Abstract Malaria is one of the major diseases in the world. Due to the rapid spread of parasite resistance to available antimalarial drugs there is an urgent need for new antimalarials with novel mechanisms of action. Several promising targets for drug intervention have been revealed in recent years. This review addresses the parasitic aspartic proteases termed plasmepsins (Plms) that are involved in the hemoglobin catabolism that occurs during the erythrocytic stage of the malarial parasite life cycle. Four Plasmodium species are responsible for human malaria; P. vivax, P. ovale, P. malariae, and P. falciparum. This review focuses on inhibitors of the haemoglobin-degrading plasmepsins of the most lethal species, P. falciparum; Plm I, Plm II, Plm IV, and histo-aspartic protease (HAP). Previously, Plm II has attracted the most attention. With the identification and characterization of new plasmepsins and the results from recent plasmepsin knockout studies, it now seems clear that in order to achieve high-antiparasitic activities in P. falciparum -infected erythrocytes it is necessary to inhibit several of the haemoglobin-degrading plasmepsins. Herein we summarize the structure,activity relationships of the Plm I, II, IV, and HAP inhibitors. These inhibitors represent all classes which, to the best of our knowledge, have been disclosed in journal articles to date. The 3D structures of inhibitor/plasmepsin II complexes available in the protein data bank are briefly discussed and compared. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 5, 626,666, 2006 [source] Chloroquine resistance in the malarial parasite, Plasmodium falciparumMEDICINAL RESEARCH REVIEWS, Issue 5 2002Lyann M.B. Ursos Abstract Malarial parasites remain a health problem of staggering proportions. Worldwide, they infect about 500 million, incapacitate tens of millions, and kill approximately 2.5 million (mostly children) annually. Four species infect humans, but most deaths are caused by one particular species, Plasmodium falciparum. The rising number of malarial deaths is due in part to increased drug resistance in P. falciparum. There are many varieties of antimalarial drug resistance, and there may very well be several molecular level contributions to each variety. This is because there are a number of different drugs with different mechanisms of action in use, and more than one molecular event may sometimes be relevant for resistance to any one class of drugs. Thus, "multidrug" resistance in a clinical setting likely entails complex combinations of overlapping resistance pathways, each specific for one class of drug, that then add together to confer the particular multidrug resistance phenotype. Nonetheless, rapid progress has been made in recent years in elucidating mechanisms of resistance to specific classes of antimalarial drugs. As one example, resistance to the antimalarial drug chloroquine, which has been the mainstay therapy for decades, is becoming well understood. This article focuses on recent advances in determining the molecular mechanism of chloroquine resistance, with particular attention to the biochemistry and biophysics of the P. falciparum digestive vacuole, wherein changes in pH have recently been found to be associated with chloroquine resistance. © 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 5, 465,491, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.10016 [source] Antimalarial activities of gedunin and 7-methoxygedunin and synergistic activity with dillapiolANNALS OF APPLIED BIOLOGY, Issue 2 2003S OMAR Summary Gedunin from Cedrela odorata (Meliaceae), a potent in vitro antimalarial agent, was investigated for its in vivo efficacy in CD-1 mice infected with Plasmodium berghei. When orally administered at 50 mg kg-1 day-1 for 4 days, gedunin was able to suppress the parasitaemia level by 44%. However, no clear dose-response effects were observed in the 0,100 mg kg-1 day-1 dose range. Preliminary pharmacokinetics in Sprague-Dawley rats showed poor absorption. However, a binary treatment of 50 mg kg-1 day-1 gedunin with 25 mg kg-1 day-1 dillapiol, a cytochrome P450 inhibitor, increased parasitaemia clearance in mice to 75%. A clear dose-response was observed in the 0,50 mg kg-1 day-1 gedunin dose range when administration was combined with 25 mg kg-1 day-1 dillapiol. In addition, 7-methoxygedunin, a semi-synthetic derivative which is more stable to degradation than gedunin, suppressed the level in mice by 67% at 50 mg kg-1 day-1. When administered at this dose in combination with 25 mg kg-1 day-1 dillapiol, clearance increased to 80%. These results demonstrate the potentialefficacy of antimalarial drugs and phytomedicines based on gedunin and the value of the combination therapy. [source] Antimalarial treatment may have a time-dependent effect on lupus survival: Data from a multinational Latin American inception cohortARTHRITIS & RHEUMATISM, Issue 3 2010Samuel K. Shinjo Objective To evaluate the beneficial effect of antimalarial treatment on lupus survival in a large, multiethnic, international longitudinal inception cohort. Methods Socioeconomic and demographic characteristics, clinical manifestations, classification criteria, laboratory findings, and treatment variables were examined in patients with systemic lupus erythematosus (SLE) from the Grupo Latino Americano de Estudio del Lupus Eritematoso (GLADEL) cohort. The diagnosis of SLE, according to the American College of Rheumatology criteria, was assessed within 2 years of cohort entry. Cause of death was classified as active disease, infection, cardiovascular complications, thrombosis, malignancy, or other cause. Patients were subdivided by antimalarial use, grouped according to those who had received antimalarial drugs for at least 6 consecutive months (user) and those who had received antimalarial drugs for <6 consecutive months or who had never received antimalarial drugs (nonuser). Results Of the 1,480 patients included in the GLADEL cohort, 1,141 (77%) were considered antimalarial users, with a mean duration of drug exposure of 48.5 months (range 6,98 months). Death occurred in 89 patients (6.0%). A lower mortality rate was observed in antimalarial users compared with nonusers (4.4% versus 11.5%; P< 0.001). Seventy patients (6.1%) had received antimalarial drugs for 6,11 months, 146 (12.8%) for 1,2 years, and 925 (81.1%) for >2 years. Mortality rates among users by duration of antimalarial treatment (per 1,000 person-months of followup) were 3.85 (95% confidence interval [95% CI] 1.41,8.37), 2.7 (95% CI 1.41,4.76), and 0.54 (95% CI 0.37,0.77), respectively, while for nonusers, the mortality rate was 3.07 (95% CI 2.18,4.20) (P for trend < 0.001). After adjustment for potential confounders in a Cox regression model, antimalarial use was associated with a 38% reduction in the mortality rate (hazard ratio 0.62, 95% CI 0.39,0.99). Conclusion Antimalarial drugs were shown to have a protective effect, possibly in a time-dependent manner, on SLE survival. These results suggest that the use of antimalarial treatment should be recommended for patients with lupus. [source] The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 3 2010Hyejung Jung Objective The antimalarial medication hydroxychloroquine has been proposed as a thromboprotective agent in systemic lupus erythematosus (SLE), but studies thus far have been limited by the possibility of confounding by indication. This study was conducted to assess whether exposure to antimalarial drugs is associated with a decrease in thrombovascular events (TEs) in patients with SLE. Methods The study was designed as a nested case,control study embedded in an inception cohort of patients with SLE, which allowed adjustments for possible confounding by calendar year, duration of disease, duration of observation, and severity of lupus. After controlling for the possible confounding variables in conditional logistic regression models, the use of antimalarial drugs was assessed for its effects on the development of TEs in lupus patients. Results Fifty-four cases of TE were identified, and these were matched with 108 control subjects (lupus patients without TEs). Univariate analyses identified older age (odds ratio [OR] 1.04, 95% confidence interval [95%CI] 1.01,1.07) or being older than age 50 years (OR 3.5, 95% CI 1.4,8.6) and ever having hypertension (OR 2.5, 95% CI 1.0,5.8) as being associated with an increased risk of TEs, whereas use of antimalarial drugs (OR 0.31, 95% CI 0.13,0.71) was associated with a decreased risk of TEs. Separate analyses were done for arterial and venous TEs, which yielded similar results. In multivariate analyses, use of antimalarial drugs (OR 0.32, 95% CI 0.14,0.74) and older age (OR 1.04, 95% CI 1.01,1.07) were the only 2 variables that remained significant. Conclusion The results from this nested case,control study demonstrate that, after accounting for the effects of disease severity, disease duration, and calendar year, antimalarial drugs were found to be thromboprotective, being associated with a 68% reduction in the risk of all TEs, with a range of risk reduction of at least 26% up to as high as 86%. [source] Crystallization and preliminary X-ray crystallographic study of 1-deoxy- d -xylulose 5-phosphate reductoisomerase from Plasmodium falciparumACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2010Tomonobu Umeda The nonmevalonate pathway of isoprenoid biosynthesis present in Plasmodium falciparum is known to be an effective target for antimalarial drugs. The second enzyme of the nonmevalonate pathway, 1-deoxy- d -xylulose 5-phosphate reductoisomerase (DXR), catalyzes the transformation of 1-deoxy- d -xylulose 5-phosphate (DXP) to 2- C -methyl- d -erythritol 4-phosphate (MEP). For crystallographic studies, DXR from the human malaria parasite P. falciparum (PfDXR) was overproduced in Escherichia coli, purified and crystallized using the hanging-drop vapour-diffusion method in the presence of NADPH. X-ray diffraction data to 1.85,Å resolution were collected from a monoclinic crystal form belonging to space group C2 with unit-cell parameters a = 168.89, b = 59.65, c = 86.58,Å, , = 117.8°. Structural analysis by molecular replacement is in progress. [source] Development and validation of a simple thin layer chromatographic method for the analysis of artemisinin in Artemisia annua L. plant extractsBIOMEDICAL CHROMATOGRAPHY, Issue 5 2008Els Marchand Abstract Owing to the development of parasite resistance to standard antimalarial treatments like chloroquine and sulfadoxine,pyrimethamine, the demand for Artemisia annua, a key ingredient for new and highly effective antimalarial drugs, is huge. Therefore selective and precise methods to determine the content of artemisinin in dry plant material and in raw impure extracts are needed. In this work a method is described for the clear separation and extraction of artemisinin from other plant components in the Artemisia annua L. plant by thin-layer chromatography (TLC). To obtain optimal extraction and recovery efficiency, several parameters were evaluted, including choice of extraction solvent, TLC plate type and sensitivity between UV and visible light. Method validation was performed on both the dry plant material and non-purified plant extracts. Toluene presented the highest extraction efficiency compared with petroleum ether, hexane and methanol. Reversed-phase plates showed more concentrated spots than normal-phase plates, while the sensitivity of the analysis in UV was comparable to that in visible light but less precise. The impure plant extracts were analyzed by both TLC and HPLC-UV at 215 nm and both methods met the requirements for linearity, selectivity, precision and accuracy. Hence, the proposed TLC method can easily be used for both qualitative and quantitative control of the raw plant extract in areas where advanced methods are scarce. Copyright © 2007 John Wiley & Sons, Ltd. [source] Antimalarial drugs , host targets (re)visitedBIOTECHNOLOGY JOURNAL, Issue 3 2006Margarida Cunha-Rodrigues Abstract Every year, forty percent of the world population is at risk of contracting malaria. Hopes for the erradication of this disease during the 20th century were dashed by the ability of Plasmodium falciparum, its most deadly causative agent, to develop resistance to available drugs. Efforts to produce an effective vaccine have so far been unsuccessful, enhancing the need to develop novel antimalarial drugs. In this review, we summarize our knowledge concerning existing antimalarials, mechanisms of drug-resistance development, the use of drug combination strategies and the quest for novel anti-plasmodial compounds. We emphasize the potential role of host genes and molecules as novel targets for newly developed drugs. Recent results from our laboratory have shown Hepatocyte Growth Factor/MET signaling to be essential for the establishment of infection in hepatocytes. We discuss the potential use of this pathway in the prophylaxis of malaria infection. [source] REVIEW: Malaria in pregnancyBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 9 2005Christopher J.M. Whitty Malaria in pregnancy is one of the major causes of maternal morbidity worldwide, and leads to poor birth outcomes. There is a complex interaction between pregnancy and parasite,all favour the parasite and disadvantage the pregnant woman. Women who are semi-immune lose much of that immunity. They may present with placental malaria but with no parasites in their peripheral blood. A non-immune pregnant women and her fetus are at serious risk from falciparum malaria. The diagnosis and management of malaria in pregnancy, including the safety of antimalarial drugs and interactions of malaria with HIV in pregnancy are reviewed. [source] Fluorinated Quinine Alkaloids: Synthesis, X-ray Structure Analysis and Antimalarial Parasite ChemotherapyCHEMISTRY - A EUROPEAN JOURNAL, Issue 31 2009Christoph Bucher Abstract Herein we report the synthesis of a series of C9-fluorinated quinine alkaloids by direct nucleophilic deoxyfluorination. This transformation gives rise to products bearing both S - and R -configured monofluoromethylene functionalities, consistent with an SN1-like mechanism. Furthermore, a series of ring-expanded 1-azabicyclo[3.2.2]nonane systems were generated by a skeletal rearrangement of the quinuclidine core. The modified alkaloids were converted to the corresponding hydrochloride salts and characterised by single-crystal X-ray diffraction analysis. The preference of the benzylic fluorine atom to adopt a gauche conformation relative to the protonated quinuclidine nitrogen atom was consistently observed throughout the cage-conserved compounds. Conversely, the molecular architecture of the 1-azabicyclo[3.2.2]nonane systems enforced an anti relationship between the fluorine atom and the protonated tertiary amine. This constitutes the first X-ray evidence of a vicinal fluorine atom at a stereogenic centre positioned anti to a substituted ammonium cation. The pharmacological efficacy of these compounds was assessed in vitro against the NF54 strain of Plasmodium falciparum (sensitive to all known antimalarial drugs). IC50 values of as low as 267,nM were observed; this highlights the potential of these materials in developing novel agents for parasite chemotherapy. [source] Facile Oxidation of Leucomethylene Blue and Dihydroflavins by Artemisinins: Relationship with Flavoenzyme Function and Antimalarial Mechanism of ActionCHEMMEDCHEM, Issue 8 2010Richard Abstract The antimalarial drug methylene blue (MB) affects the redox behaviour of parasite flavin-dependent disulfide reductases such as glutathione reductase (GR) that control oxidative stress in the malaria parasite. The reduced flavin adenine dinucleotide cofactor FADH2 initiates reduction to leucomethylene blue (LMB), which is oxidised by oxygen to generate reactive oxygen species (ROS) and MB. MB then acts as a subversive substrate for NADPH normally required to regenerate FADH2 for enzyme function. The synergism between MB and the peroxidic antimalarial artemisinin derivative artesunate suggests that artemisinins have a complementary mode of action. We find that artemisinins are transformed by LMB generated from MB and ascorbic acid (AA) or N -benzyldihydronicotinamide (BNAH) in,situ in aqueous buffer at physiological pH into single electron transfer (SET) rearrangement products or two-electron reduction products, the latter of which dominates with BNAH. Neither AA nor BNAH alone affects the artemisinins. The AA,MB SET reactions are enhanced under aerobic conditions, and the major products obtained here are structurally closely related to one such product already reported to form in an intracellular medium. A ketyl arising via SET with the artemisinin is invoked to explain their formation. Dihydroflavins generated from riboflavin (RF) and FAD by pretreatment with sodium dithionite are rapidly oxidised by artemisinin to the parent flavins. When catalytic amounts of RF, FAD, and other flavins are reduced in,situ by excess BNAH or NAD(P)H in the presence of the artemisinins in the aqueous buffer, they are rapidly oxidised to the parent flavins with concomitant formation of two-electron reduction products from the artemisinins; regeneration of the reduced flavin by excess reductant maintains a catalytic cycle until the artemisinin is consumed. In preliminary experiments, we show that NADPH consumption in yeast GR with redox behaviour similar to that of parasite GR is enhanced by artemisinins, especially under aerobic conditions. Recombinant human GR is not affected. Artemisinins thus may act as antimalarial drugs by perturbing the redox balance within the malaria parasite, both by oxidising FADH2 in parasite GR or other parasite flavoenzymes, and by initiating autoxidation of the dihydroflavin by oxygen with generation of ROS. Reduction of the artemisinin is proposed to occur via hydride transfer from LMB or the dihydroflavin to O1 of the peroxide. This hitherto unrecorded reactivity profile conforms with known structure,activity relationships of artemisinins, is consistent with their known ability to generate ROS in,vivo, and explains the synergism between artemisinins and redox-active antimalarial drugs such as MB and doxorubicin. As the artemisinins appear to be relatively inert towards human GR, a putative model that accounts for the selective potency of artemisinins towards the malaria parasite also becomes apparent. Decisively, ferrous iron or carbon-centered free radicals cannot be involved, and the reactivity described herein reconciles disparate observations that are incompatible with the ferrous iron,carbon radical hypothesis for antimalarial mechanism of action. Finally, the urgent enquiry into the emerging resistance of the malaria parasite to artemisinins may now in one part address the possibilities either of structural changes taking place in parasite flavoenzymes that render the flavin cofactor less accessible to artemisinins or of an enhancement in the ability to use intra-erythrocytic human disulfide reductases required for maintenance of parasite redox balance. [source] In,vitro Effects of Plasmodium falciparum Dihydrofolate Reductase Inhibitors on Normal and Cancer Cell ProliferationCHEMMEDCHEM, Issue 3 2008Tiziana Rossi Prof. Toxicological evaluations were performed on two novel Plasmodium falciparum dihydrofolate reductase inhibitors and other known antimalarial drugs. Cytotoxicity tests were performed on Vero and MCF-7 cells and apoptotic and/or proliferative markers p21 and p53 and A, B1, D1, and D2 cyclines. The results are discussed and show that this molecule can be considered an interesting new candidate for further development. [source] | ||||||||||||||||