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PubMed2000

Technical assessment of the affymetrix yeast expression GeneChip YE6100 platform in a heterologous model of genes that confer resistance to antimalarial drugs in yeast.

The advent of high-density gene array technology has revolutionized approaches to drug design, development, and characterization. At the laboratory level, the efficient, consistent, and dependable exploitation of this complex technology requires the stringent standardization of protocols and data analysis platforms. The Affymetrix YE6100 expression GeneChip platform was evaluated for its performance in the analysis of both global (6,000 yeast genes) and targeted (three pleiotropic multidrug resistance genes of the ATP binding cassette transporter family) gene expression in a heterologous yeast model system in the presence and absence of the antimalarial drug chloroquine. Critical to the generation of consistent data from this platform are issues involving the preparation of the specimen, use of appropriate controls, accurate assessment of experiment variance, strict adherence to optimized enzymatic and hybridization protocols, and use of sophisticated bioinformatics tools for data analysis.

ATP-Binding Cassette Transporters↗
PubMed1992

Severity of imported falciparum malaria: effect of taking antimalarial prophylaxis.

OBJECTIVE: To investigate the effects of antimalarial chemoprophylaxis and other variables on the severity of falciparum malaria. DESIGN: Review of consecutive malaria cases between 1987 and 1991. SETTING: The Hospital for Tropical Diseases, London. SUBJECTS: 250 consecutive cases of mild and 51 consecutive cases of severe falciparum malaria. RESULTS: Prophylaxis was taken in 52.4% (131/250) of the cases of mild malaria and 21.6% (11/51) of cases of severe malaria. Severe malaria was more common in white patients than in those of African origin and was also seen more commonly in people returning from central, southern, and east Africa than in those returning from west Africa. Patients with severe malaria presented sooner than patients with mild malaria. CONCLUSIONS: Prior chemoprophylaxis led to a reduction in the severity of falciparum malaria. Ethnic origin, time to presentation, and sex were also associated with the severity of malaria.

Adult↗
PubMed1999

In vitro biotransformation of a novel antimalarial cysteine protease inhibitor in human liver microsomes.

4-Dimethylamino-4'-(imidazol-1-yl)chalcone (RL3142) is a newly developed antimalarial cysteine protease inhibitor. Four metabolites (M1-M4) were found in human liver microsomes and their structures were identified by LC/MS/MS. Two primary metabolites, M2 (minor) and M4 (major), were determined to be the N-demethylated product (M2) and the product (M4) resulting from 1,2-hydrogenation of the alpha, beta-unsaturated ketone moiety of the parent compound. A combined approach utilizing selective P450 inhibitors, immunoinhibition with CYP3A and NADPH P450 reductase antibodies, and cDNA expressed human CYP3A4 and NADPH P450 reductase, was used for identification of enzymes responsible for the biotransformation. For formation of M2, both a rabbit CYP3A polyclonal antibody (110 microliter/mg microsomal protein) and ketoconazole (2 micromol/l), a CYP3A inhibitor, showed about 50% inhibitory effects; other specific inhibitors of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 showed no significant effects. For formation of M4, neither CYP3A antibody nor the above mentioned CYP inhibitors exhibited inhibitory effects. Anti-rat NADPH P450 reductase serum (50 microliter/100 microgram microsomal protein) exhibited 70 and 58% inhibitory effects on M2 and M4 formation, respectively. Incubation of RL3142 with cDNA expressed human NADPH P450 reductase yielded formation of M4, but not M2. Carbon monoxide inhibited formation of M2 and M1 (the reduced product of M2), but had no effect on M4 and M3 (the reduced product of M4) formation. Collectively, NADPH P450 reductase solely catalyzed reduction of RL3142 to M4, whereas CYP3A contributed in part to formation of M2.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Iron chelators: mode of action as antimalarials.

Malaria parasites growing inside human erythrocytes differ from mammalian cells in their mode of acquisition of bioavailable iron and in their susceptibility to the antiproliferative action of iron chelators. We have assessed here three major properties associated with these phenomena: (a) the stage-dependent nature of parasite iron mobilization from the host and its integration into parasite proteins; (b) the differential permeability of the plasma membrane to iron chelators, and (c) the in situ generation of toxic chelator-metal complexes in the intracellular milieu of infected cells. We have used a combination of synthetic and natural iron chelators with similar iron-binding properties but markedly different capacities to permeate membranes. The profiles of action of these agents on the in vitro growth of Plasmodium falciparum were assessed in terms of inhibitory concentrations, speed of action, stage dependence and reversibility of effects. These profiles provided the basis for a working model of chelator action on parasitized cells. The model allowed us to predict major improvements in the antimalarial performance of iron chelators when used in appropriate combinations of slow-and fast-permeating substances. The synergistic actions found in vitro for various combinations of iron chelators are in accordance with the model and have implications for the design of therapeutic schemes.

Animals↗
PubMed1978

Antimalarial activity of saccharidic polymers of dapsone and sulfadimethoxine.

With the purpose of obtaining pro-drugs of dapsone and sulfadimethoxine, those chemotherapeutic agents were attached through covalent bonding to starch polymeric dialdehyde (Sumstar-190). The antimalarial activity of the two resulting compounds - the dapsone saccharidic polymer (PS6) and the sulfadimethoxine saccharidic polymer (PS7) - in mice experimentally inoculated with Plasmodium berghei was significantly increased with this molecular modification. Mice infected with malaria and kept without treatment together with others which received different doses of PS6 and PS7 were also partially or totally cured, possibly due to the ingestion of excrements containing the parent chemotherapeutic agents.

Animals↗
PubMed1987

Single-dose investigation of possible interactions between the components of the antimalarial combination Fansimef.

Fansimef is a new oral schizonticide which contains pyrimethamine (P), sulfadoxine (S) and mefloquine (M) in a weight ratio of 1:20:10. This antimalarial combination is highly active against multi-resistant Plasmodium falciparum and in vitro studies showed that the resistance development by plasmodia against this combination is considerably delayed. The single-dose pharmacokinetics of the three Fansimef components were investigated in 10 Caucasian volunteers with special emphasis on possible mutual kinetic interactions. For this reason the same subjects received successively tablets of Fansimef (P + S + M), Fansidar (P + S) and mefloquine alone. Following administration of Fansimef all three components revealed long elimination half-lives (P = 88 h, S = 183 h, M = 437 h) and high binding to plasma proteins (P = 92.5%, S = 87.6%, M = 97.6%). The apparent volume of distribution in the postdistributive phase (VD beta/F) was small for S (0.13 l/kg) but amounted to 2.1 l/kg for P and reached even 11.8 l/kg in the case of M. The systemic clearance (ClTS/F) showed almost identical values for P and M, namely approximately equal to 19 ml/h/kg, while sulfadoxine reached only a value of 0.5 ml/h/kg. Almost identical pharmacokinetic parameters (p greater than 0.05) were found after administration of Fansidar or M alone. Therefore one can exclude any significant interaction between the single components of the Fansimef combination. In addition, animal studies showed that synergism of the toxicity of the three combination partners can be excluded.

Adult↗
PubMed1989

Spectrum of the antimalarial activity of a new macrolide antibiotic midecamycin in mice and monkeys.

The antimalarial activity of a new macrolide antibiotic, midecamycin, has been evaluated against a sensitive strain of Plasmodium berghei, a chloroquine-resistant strain of P. yoelii nigeriensis and a simian parasite, P. cynomolgi B. The ED50 and ED90 values of this antibiotic administered in two divided daily doses were found to be 37.15 +/- 3.51 and 100.84 +/- 7.54 mg/kg, respectively, against P. berghei and 362.34 +/- 85.33 and 878.04 +/- 10.02 mg/kg, respectively, against P. yoelii nigeriensis. Doses above 45 mg/kg for 4 days significantly extended the mean survival time of treated mice infected with either of the two parasites. However, no appreciable blood schizontocidal (at 100 mg/kg X 7 days), anti-relapse (at 100 mg/kg X 7 days) or causal prophylactic activities (at 200 mg/kg X 3 days) were observed against P. cynomolgi infection in rhesus monkeys.

Animals↗
PubMedDate not supplied

Susceptibility of Malaysian Plasmodium falciparum isolates to antimalarial drugs after cryopreservation and 12 months of continuous in vitro culture.

Eleven Malaysian Plasmodium falciparum isolates were cultured in vitro and later subjected to antimalarial evaluations in 96-well microtiter plates. After cryopreservation, the IC50 (nM) for ST 195, ST 196, ST 197, ST 244 and ST 245 isolates were, respectively: 180.9, 198.7, 482.0, 580.0 and 690.1 for chloroquine; 3.4, 3.4, 9.2, 4.0 and 5.8 for mefloquine; 21.9, 10.5, 40.7, 40.1 and 48.7 for quinine; 136.7, 58.8, 116.4, 29.4 and 95.4 for cycloguanil, and 48.3, 57.5, 47.4, 61.5 and 37.8 for pyrimethamine. Before cryopreservation they were 172.5, 141.5, 453.2, 636.0 and 651.6 nM for chloroquine; 4.8, 2.6, 9.0, 6.9 and 5.8 nM for mefloquine; 21.3, 8.3, 41.9, 49.6 and 40.1 nM for quinine, 129.9, 47.3, 109.3, 30.6 and 95.4 nM for cycloguanil, and 45.4, 47.4, 40.2, 66.3 and 36.0 nM for pyrimethamine. IC50 (nM) for Gombak A, Gombak C, ST 9, ST 12, ST 85 and ST 148 isolates after 12 months of continuous in vitro culture were, respectively: 477.0, 492.3, 367.1, 809.4, 566.5 and 341.8 for chloroquine; 2.9, 11.1, 8.5, 16.9, 5.3 and 4.2 for mefloquine; 6.2, 58.3, 52.7, 36.7, 31.8 and 26.2 for quinine; 154.5, 57.2, 130.3, 94.2, 81.4 and 102.9 for cycloguanil, 26.9, 24.9, 43.8, 31.0, 14.1 and 56.7 for pyrimethamine. Before the 12-month culture they were 472.3, 452.9, 352.7, 773.7, 702.7 and 322.7 nM for chloroquine; 2.6, 13.2, 8.5, 17.2, 5.0 and 4.0 nM for mefloquine; 6.2, 85.4, 53.9, 38.5, 35.8 and 38.5 nM for quinine; 106.8, 74.3, 112.4, 89.8, 91.8 and 103.3 nM for cycloguanil, and 26.9, 31.4, 47.0, 28.1, 14.9 and 56.7 nM for pyrimethamine. Thus none of these isolates differed in their original susceptibilities after either of these procedures.

Animals↗
PubMed1989

An unusual combination of phototoxicity and Stevens-Johnson syndrome due to antimalarial therapy.

A 12-year-old boy developed a phototoxic rash with subsequent progression to Stevens-Johnson syndrome due to prophylactic ingestion of antimalarials (chloroquine and sulfadoxine-pyrimethamine; Fansidar). The patient recovered from his skin symptoms after 4 weeks during which he received systemic corticosteroids and antibiotics. This unusual combination of two different patterns of adverse cutaneous drug reactions was most probably caused by the sulfonamide component of Fansidar.

Antimalarials↗
PubMed1991

Antimalarial effects of peptide inhibitors of a Plasmodium falciparum cysteine proteinase.

We previously identified a Plasmodium falciparum trophozoite cysteine proteinase (TCP) and hypothesized that it is required for the degradation of host hemoglobin by intraerythrocytic malaria parasites. To test this hypothesis and to evaluate TCP as a chemotherapeutic target, we examined the antimalarial effects of a panel of peptide fluoromethyl ketone proteinase inhibitors. For each inhibitor, effectiveness at inhibiting the activity of TCP correlated with effectiveness at both blocking hemoglobin degradation and killing cultured parasites. Benzyloxycarbonyl (Z)-Phe-Arg-CH2F, the most potent inhibitor, inhibited TCP at picomolar concentrations and blocked hemoglobin degradation and killed parasites at nanomolar concentrations. Micromolar concentrations of the inhibitor were nontoxic to cultured mammalian cells. These results support the hypothesis that TCP is a necessary hemoglobinase and suggest that it is a promising chemotherapeutic target.

Animals↗
PubMed1993

The antimalarial action of desferal involves a direct access route to erythrocytic (Plasmodium falciparum) parasites.

We designed the N-methylanthranilic-desferrioxamine (MA-DFO) as a fluorescent iron (III) chelator with improved membrane permeation properties. Upon binding of iron (III), MA-DFO fluorescence is quenched, thus allowing traceability of drug-iron (III) interactions. MA-DFO is well tolerated by mammalian cells in culture. Its antimalarial activity is pronounced: IC50 values on in vitro (24-h) growth of Plasmodium falciparum were 3 +/- 1 microM for MA-DFO compared with 30 +/- 8 for DFO. The onset of growth inhibition of rings or trophozoites occurs 2-4 h after exposure to 13 microM MA-DFO. This effect is commensurate with MA-DFO permeation into infected cells. In a 24-h exposure to MA-DFO or DFO, trophozoites take up either compound to approximately 10% of the external concentration, rings to 5%, and noninfected cells to < 1%. Red cells encapsulated with millimolar concentrations of DFO or MA-DFO fully support parasite invasion and growth. We conclude that extracellular MA-DFO and DFO gain selective access into parasites by bypassing the host. The rate-limiting step is permeation through the parasite membrane, which MA-DFO accomplishes faster than DFO, in accordance with its higher hydrophobicity. These views are consistent with the proposed duct, which apparently provides parasitized cells with a window to the external medium.

Animals↗
PubMedDate not supplied

Antimalarial drugs and reduced incidence of dental plaque.

Known antimalarial compunds from several chemical classes were tested for their ability to inhibit in vitro growth of microorganisms causing dental plaque and to prevent the development of plaque in a hamster model. Approximately a third of the compounds tested inhibited in vitro growth; however, none prevented development of plaque.

Actinomyces↗
PubMed2002

The chemotherapy of rodent malaria. LX. The importance of formulation in evaluating the blood schizontocidal activity of some endoperoxide antimalarials.

The activities of artemisinin (QHS) and a number of its semi-synthetic analogues, as well as Fenozan B07 (B07), a synthetic 1,2,4-trioxane, and arteflene (ATF), a synthetic surrogate of yingzhaosu, were compared in mice infected with drug-sensitive Plasmodium berghei or chloroquine-resistant P. yoelii ssp. NS. The studies were stimulated by the observation that B07, in certain aqueous preparations, appears to be equipotent by the subcutaneous (sc) or oral (po) routes in the rodent model but not in a simian model. In the rodent model, B07 was found to undergo rapid alteration (with a half-life of <24h) in an aqueous stock solution prepared using dimethyl sulphoxide (DMSO) to pre-dissolve the drug. Therefore, for all later experiments with aqueous preparations, the test material was newly formulated each day. In a carboxymethylcellulose formulation used as a 'standard suspending vehicle' (SSV), B07 and dihydroartemisinin (DIHYD) were found to be, respectively, one sixth and one 10th as active po as when the drugs were pre-dissolved in DMSO and then diluted with water. ATF in DMSO given po was less than one 20th as active as when used sc in the rodent model, and this drug in SSV was almost inactive po. The relatively low oral activity of these three compounds (especially DIHYD and ATF) may be attributable to extensive first-pass metabolism in the mouse. Oral beta-artemether (AM) and beta-arteether (AE) were highly active when used in SSV. ATF has been found to have low activity in simian models and clinical trials because of its poor absolute bio-availability. In in-vivo studies of the blood schizontocidal action of anti-malarials, in rodent malaria models, the data collected on the structure-activity relationships (SAR) of the drugs must be viewed critically when selecting specific compounds from a chemical series for further development. A study of the influence of drug formulation on the activity of other, novel antimalarials is crucial to the evaluation of the drugs, and merits high priority.

Administration, Oral↗
PubMed2003

Methylene blue as an antimalarial agent.

Methylene blue has intrinsic antimalarial activity and it can act as a chloroquine sensitizer. In addition, methylene blue must be considered for preventing methemoglobinemia, a serious complication of malarial anemia. As an antiparasitic agent, methylene blue is pleiotropic: it interferes with hemoglobin and heme metabolism in digestive organelles, and it is a selective inhibitor of Plasmodium falciparum glutathione reductase. The latter effect results in glutathione depletion which sensitizes the parasite for chloroquine action. At the Centre de Recherche en Santé de Nouna in Burkina Faso, we study the combination of chloroquine with methylene blue (BlueCQ) as a possible medication for malaria in endemic regions. A pilot study with glucose-6-phosphate dehydrogenase-sufficient adult patients has been conducted recently.

Animals↗
PubMed2004

Characterization of the choline carrier of Plasmodium falciparum: a route for the selective delivery of novel antimalarial drugs.

New drugs are urgently needed to combat the growing problem of drug resistance in Plasmodium falciparum malaria. The infected erythrocyte is a multicompartmental system, and its transporters are of interest as drug targets in their own right and as potential routes for the delivery of antimalarial drugs. Choline is an important nutrient that penetrates infected erythrocyte membranes through the endogenous carrier and through parasite-induced permeability pathways, but nothing is known about its transport into the intracellular parasite. Here we present the first characterization of choline transport across the parasite membrane. Transport exhibits Michaelis-Menten kinetics with an apparent K(m) of 25.0 +/- 3.5 muM for choline. The carrier is inhibitor-sensitive, temperature-dependent, and Na(+)-independent, and it is driven by the proton-motive force. Highly active bis-amidine and bis-quaternary ammonium compounds are also known to penetrate the host erythrocyte membrane through parasite-induced permeability pathways. Here, we demonstrate that the parasite choline transporter mediates the delivery of these compounds to the intracellular parasite. Thus, the induced permeability pathways in the host erythrocyte membrane and the parasite choline transporter described here form a cooperative transport system that shows great promise for the selective targeting of new agents for the chemotherapy of malaria.

Animals↗
PubMed2003

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

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.

Adenosine Triphosphate↗
PubMed2005

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

INTRODUCTION: Research is an essential tool in facing the challenges of scaling up interventions and improving access to services. As in many other countries, the translation of research evidence into drug policy action in Tanzania is often constrained by poor communication between researchers and policy decision-makers, individual perceptions or attitudes towards the drug and hesitation by some policy decision-makers to approve change when they anticipate possible undesirable repercussions should the policy change as proposed. Internationally, literature on the role of researchers on national antimalarial drug policy change is limited. OBJECTIVES: To describe the (a) role of researchers in producing evidence that influenced the Tanzanian government replace chloroquine (CQ) with sulfadoxine-pyrimethamine (SP) as the first-line drug and the challenges faced in convincing policy-makers, general practitioners, pharmaceutical industry and the general public on the need for change (b) challenges ahead before a new drug combination treatment policy is introduced in Tanzania. METHODS: In-depth interviews were held with national-level policy-makers, malaria control programme managers, pharmaceutical officers, general medical practitioners, medical research library and publications officers, university academicians, heads of medical research institutions and district and regional medical officers. Additional data were obtained through a review of malaria drug policy documents and participant observations were also done. RESULTS: In year 2001, the Tanzanian Government officially changed its malaria treatment policy guidelines whereby CQ--the first-line drug for a long time was replaced with SP. This policy decision was supported by research evidence indicating parasite resistance to CQ and clinical CQ treatment failure rates to have reached intolerable levels as compared to SP and amodiaquine (AQ). Research also indicated that since SP was also facing rising resistance trend, the need for a more effective drug was indispensable but for an interim 5-10 year period it was justifiable to recommend SP that was relatively more cost-effective than CQ and AQ. The government launched the policy change considering that studies (ethically approved by the Ministry of Health) on therapeutic efficacy and cost-effectiveness of artemisinin drug combination therapies were underway. Nevertheless, the process of communicating research results and recommendations to policy-making authorities involved critical debates between policy makers and researchers, among the researchers themselves and between the researchers and general practitioners, the speculative media reports on SP side-effects and reservations by the general public concerning the rationale for policy change, when to change, and to which drug of choice. CONCLUSION: Changing national drug policy will remain a sensitive issue that cannot be done overnight. However, to ensure that research findings are recognised and the recommendations emanating from such findings are effectively utilized, a systematic involvement of all the key stakeholders (including policy-makers, drug manufacturers, media, practitioners and the general public) at all stages of research is crucial. It also matters how and when research information is communicated to the stakeholders. Professional organizations such as the East African Network on Malaria Treatment have potential to bring together malaria researchers, policy-makers and other stakeholders in the research-to-drug policy change interface.

Animals↗
PubMed2006

A database of antimalarial drug resistance.

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.

Animals↗