Discovery and repurposing of artemisinin / 医学前沿

Malaria is an ancient infectious disease that threatens millions of lives globally even today. The discovery of artemisinin, inspired by traditional Chinese medicine (TCM), has brought in a paradigm shift and been recognized as the "best hope for the treatment of malaria" by World Health Organization. With its high potency and low toxicity, the wide use of artemisinin effectively treats the otherwise drug-resistant parasites and helps many countries, including China, to eventually eradicate malaria. Here, we will first review the initial discovery of artemisinin, an extraordinary journey that was in stark contrast with many drugs in western medicine. We will then discuss how artemisinin and its derivatives could be repurposed to treat cancer, inflammation, immunoregulation-related diseases, and COVID-19. Finally, we will discuss the implications of the "artemisinin story" and how that can better guide the development of TCM today. We believe that artemisinin is just a starting point and TCM will play an even bigger role in healthcare in the 21st century.

Reasearch on lipid metabolism of Plasmodium and antimalarial mechanism of artemisinin / 中国中药杂志

As a unicellular organism, Plasmodium displays a panoply of lipid metabolism pathways that are seldom found together in a unicellular organism. These pathways mostly involve the Plasmodium-encoded enzymatic machinery and meet the requirements of membrane synthesis during the rapid cell growth and division throughout the life cycle. Different lipids have varied synthesis and meta-bolism pathways. For example, the major phospholipids are synthesized via CDP-diacylglycerol-dependent pathway in prokaryotes and de novo pathway in eukaryotes, and fatty acids are synthesized mainly via type Ⅱ fatty acid synthesis pathway. The available studies have demonstrated the impacts of artemisinin and its derivatives, the front-line compounds against malaria, on the lipid metabolism of Plasmodium. Therefore, this article reviewed the known lipid metabolism pathways and the effects of artemisinin and its derivatives on these pathways, aiming to deepen the understanding of lipid synthesis and metabolism in Plasmodium and provide a theoretical basis for the research on the mechanisms and drug resistance of artemisinin and other anti-malarial drugs.

Effect of artemisinin-piperaquine treatment on the electrocardiogram of malaria patients

Abstract INTRODUCTION: Concern regarding the cardiotoxicity of antimalarials has been renewed because of their potential to cause QT/QTc interval prolongation related to torsade de pointes (TdP). Artemisinin-piperaquine (AP) is considered an effective artemisinin-based combination therapy (ACT) for malaria. METHODS: This study involved a retrospective analysis of clinical data of 93 hospitalized malaria patients who had received AP orally. Electrocardiograms (ECGs) were obtained at specific time points in the original study. RESULTS: Some cases of QT prolongation were observed. However, no TdP was found. CONCLUSIONS: AP may cause QT interval prolongation in some malaria patients but may not lead to TdP.

Prescripción de antipalúdicos en hospitales centrales y provinciales de Angola / Antimalarials prescription in central and provincial hospitals in Angola

Introducción: La malaria constituye la primera causa de morbilidad y mortalidad en Angola y se desconocen las características de la prescripción de antipalúdicos en los hospitales. Objetivo: Caracterizar la prescripción de antipalúdicos en pacientes internados en hospitales centrales y provinciales de Angola. Método: Estudio de Utilización de Medicamentos, tipo indicación-prescripción, con elementos de esquema terapéutico. La muestra fue de 2 634 pacientes. La variable principal: evaluación de la prescripción, se operacionalizó como adecuada o no en función de la indicación, pauta terapéutica y contraindicaciones. Resultados: Predominó la malaria complicada (66,6 por ciento) y el sexo femenino en niños (51,7 por ciento) y adultos (51,0 por ciento). Se indicaron 4 518 prescripciones. La quinina endovenosa (20,4 por ciento) fue el tratamiento más utilizado en la malaria complicada y la quinina tabletas (26,5 por ciento) en la malaria simple. El 94,8 por ciento de las prescripciones no presentaron contraindicaciones, mientras que el 69,0 por ciento fueron adecuadas en su selección y el 65,1 por ciento en la pauta terapéutica. La evaluación de la prescripción resultó ser adecuada (55,0 por ciento). La malaria complicada presentó mayor número de prescripciones no adecuadas (47,5 por ciento). Conclusiones: Existe prescripción irracional de antipalúdicos, con mayor repercusión en la malaria complicada. Persiste una baja utilización de derivados de la artemisina, por lo que se incumple lo establecido en la Guía de Tratamiento de la Malaria(AU)

Introduction: The characteristics of the prescription of antimalarials in hospitals, where malaria is the first cause of mortality and morbidity, are unknown. Objective: To characterize the prescription of antimalarials in patients admitted to central and provincial hospitals in Angola. Methods: A Study of Drug's Use was made, type indication-prescription, with elements of a therapeutic scheme. The sample was of 2 634 patients. The main variable (evaluation of the prescription) was operationalized in adequate or not according to the indication, therapeutic guideline and contraindications. Absolute frequency and percentage were used as summary measures. Results: The most represented patients were adults (54.1 percent) and those admitted in general hospitals (82.6 percent). Complicated malaria was predominant (66.6 percent) and female sex in children (51.7 percent) and adults (51.0 percent). There were 4 518 prescriptions. Intravenous quinine (20.4 percent) was the most used treatment in complicated malaria and quinine tablets (26.5 percent) in simple malaria. 94.8 percent of the prescriptions had no contraindications, while 69.0 percent were adequate in their selection and 65.1 percent in the therapeutic regimen. The evaluation of the prescription was adequate (55.0 percent). Complicated malaria had a greater number of inappropriate prescriptions (47.5 percent). Conclusions: The existence of irrational prescription of antimalarials is evidenced with more repercussion in complicated malaria. There is still a low use of artemisinin derivatives, in breach of the Guide for Malaria's Treatment(AU)

Desinvestimento do medicamento artemeter para o tratamento de Malária Grave / Disinvestment of the drug artemether for the treatment of Serious Malaria

CONTEXTO: A malária é uma doença parasitária infecciosa aguda causada por protozoários do gênero Plasmodium e representa um grave problema de saúde pública. No Brasil, há três espécies associadas à malária em seres humanos: P. falciparum, P. vivax e P. malariae. O demandante solicitou o desinvestimento do medicamento artemeter 80 mg/ml, mantendo apenas o artesunato 60 mg/ml como opção de tratamento injetável com derivado de artemisinina para malária grave. A recomendação de retirada do artemeter fundamenta-se em orientação do guia de tratamento da Organização Mundial de Saúde (OMS), publicado em 2015, que orienta que o tratamento de adultos e crianças com malária grave (incluindo as gestantes em todos os trimestres e mulheres lactantes) deve ser feito, preferencialmente, com artesunato intravenoso ou intramuscular. TECNOLOGIA SOLICITADA PARA DESINVESTIMENTO: Artemeter 80 mg/ml.: Tratamento da malária grave. EVIDÊNCIAS CIENTÍFICAS: Com o objetivo de avaliar se artesunato injetável é uma melhor opção terapêutica que o artemeter injetável para o tratamento da malária grave, em termos de eficácia, efetividade e segurança, foram pesquisadas evidências científicas comparando os dois medicamentos. Foi selecionada uma revisão sistemática da Cochrane que mostrou que o risco de mortalidade por todas as causas foi significativamente menor com o artesunato do que com o artemeter. O artesunato reduziu o risco de hipoglicemia, como evento adverso aos tratamentos, em relação ao artemeter. Não houve diferenças significativas entre os tratamentos na resolução do coma, no tempo para clearance do parasita e no tempo para desaparecimento da febre. IMPACTO ORÇAMENTÁRIO: Embora o custo de tratamento com artesunato 60 mg/mL seja maior do que com o artemeter 80 mg/ml, o demandante informou que não vai aumentar a quantidade de artesunato comprada, visto que os casos de malária grave estão diminuindo. RECOMENDAÇÃO DA CONITEC: Pelo exposto, os membros do Plenário da CONITEC, presentes na 56ª reunião ordinária, deliberaram que o tema fosse submetido à consulta pública com recomendação preliminar favorável ao desinvestimento do artemeter para tratamento da malária grave. CONSULTA PÚBLICA: Foi recebida somente 1 contribuição sobre experiência de profissional de saúde que concordou totalmente com a recomendação da CONITEC. : Os membros da CONITEC deliberaram por recomendar a exclusão do medicamento artemeter para o tratamento de malária grave. DECISÃO: A Portaria nº 42, de 9 de outubro de 2017, tornou pública a decisão de excluir o medicamento artemeter para o tratamento de Malária Grave, no âmbito do Sistema Único de Saúde ­ SUS.(AU)

Therapeutic efficacy of alternative primaquine regimens to standard treatment in preventing relapses by Plasmodium vivax: A systematic review and meta-analysis / Eficacia terapéutica de esquemas de Primaquina usados como alternativa al tratamiento estándar en la prevención de recaídas por Plasmodium vivax: Una revisión sistemática y meta-análisis

Objective: To compare efficacy and safety of primaquine regimens currently used to prevent relapses by P. vivax. Methods: A systematic review was carried out to identify clinical trials evaluating efficacy and safety to prevent malaria recurrences by P. vivax of primaquine regimen 0.5 mg/kg/day for 7 or 14 days compared to standard regimen of 0.25 mg/kg/day for 14 days. Efficacy of primaquine according to cumulative incidence of recurrences after 28 days was determined. The overall relative risk with fixed-effects meta-analysis was estimated. Results: For the regimen 0.5 mg/kg/day/7 days were identified 7 studies, which showed an incidence of recurrence between 0% and 20% with follow-up 60-210 days; only 4 studies comparing with the standard regimen 0.25 mg/kg/day/14 days and no difference in recurrences between both regimens (RR= 0.977, 95% CI= 0.670 to 1.423) were found. 3 clinical trials using regimen 0.5 mg/kg/day/14 days with an incidence of recurrences between 1.8% and 18.0% during 330-365 days were identified; only one study comparing with the standard regimen (RR= 0.846, 95% CI= 0.484 to 1.477). High risk of bias and differences in handling of included studies were found. Conclusion: Available evidence is insufficient to determine whether currently PQ regimens used as alternative rather than standard treatment have better efficacy and safety in preventing relapse of P. vivax. Clinical trials are required to guide changes in treatment regimen of malaria vivax.

Objetivo: Comparar la eficacia y seguridad de los esquemas de primaquina actualmente usados para prevenir las recaídas de malaria por P. vivax. Métodos: A través de una revisión sistemática se identificaron ensayos clínicos que evaluaran la eficacia y seguridad para prevenir recurrencias por P. vivax del régimen de primaquina 0.5 mg/Kg/día por 7 o 14 días comparado al régimen estándar de 0.25 mg/Kg/día por 14 días. Se determinó la eficacia de primaquina con la incidencia acumulada de recurrencias posterior a 28 días. Se estimó el riesgo relativo global con un meta-análisis de efectos fijos. Resultados: Se identificaron 7 ensayos clínicos para el régimen 0.5 mg/Kg/día/7 días que mostraron una incidencia de recurrencias entre 0% y 20% con un seguimiento de 60 a 210 días; solo 4 estudios compararon con el régimen estándar y no se encontraron diferencias en las recurrencias entre ambos esquemas (RR= 0.977; IC 95%= 0.670-1.423). Se identificaron tres ensayos clínicos que usaron el esquema 0.5 mg/Kg/día/14 días con una incidencia de recurrencias entre 1.8% y 18.0% para 330 a 365 días; solo un estudio comparó con el régimen estándar (RR= 0.846; IC 95%= 0.484-1.477). Se encontró alto riesgo de sesgo y diferencias en la conducción de los estudios incluidos. Conclusión: No hay suficiente evidencia para determinar si los regímenes de primaquina usados como alternativas al tratamiento estándar tienen mejor eficacia para prevenir las recaídas de P. vivax. Se requieren ensayos clínicos para orientar los cambios en el esquema de tratamiento de este tipo de malaria.

Comparación de las biodisponibilidades in vitro de Artesunato tabletas de diferentes procedências / Comparación de las bioavailability in vitro Artesunate tablets from different sources

En las décadas pasadas se incrementó los casos de malaria en los países de la cuenca amazónica, inclu-yendo la aparición de P. falciparum y la resistencia a los medicamentos de primera línea; Cloroquina y Sulfadoxina / Pirimetamina, adicionalmente en estudios recientes se reportaron deficiencias en la calidad de los medicamentos antimalaricos43. Por lo que Perú cambió su esquema de tratamiento para P. falcipa-rum no complicada: con Mefloquina más Artesunato en la selva y Sulfadoxina / Pirimetamina en la costa norte. En el esquema de tratamiento de Perú, se utiliza un medicamento genérico nacional (multifuente) que no ha demostrado ser intercambiable con el medicamento original, debido a que la regulación actual no ha implementado este requisito; aunque en la Ley 29459, ya se señale como parte de los requisitos del Registro Sanitario y que se espere entre en vigencia gradualmente. Objetivo: comparar las disponibilida-des in vitro de las tabletas de Artesunato usadas por la estrategia sanitaria de malaria en Perú, con las tabletas de Artesunato fabricadas en empresas precalificadas por la Organización Mundial de la Salud (OMS) en Brasil y Ghana. Metodología: para los ensayos de control de calidad y pruebas de cinética de disolución se utilizó la Farmacopea Non Standard de Los Estados Unidos, las guías de FDA y OMS...

Malaria cases have increased in the countries of the Amazon basin in the past decades, including the ap-pearance of P. falciparum and resistance to first-line drugs; Chloroquine and Sulfadoxine / Pyrimethamine. In recent studies were reported deficiencies in the quality of antimalarial drugs, because of that Peru changed the treatment scheme for uncomplicated P. falciparum, and begin to use Mefloquine plus Arte-sunate for Amazon Area and Sulfadoxine / Pyrimethamine on the North coast. In Peruvian treatment scheme, is used a national generic drug (multisource), which one did not demonstrate to be interchangea-ble with the innovator, because, this is not yet a requirement to get the Sanitary Register, according to Law 29459, and hopefully it will be implemented gradually. Objective: compare the in vitro availability of Artesunate tablets used by the health strategy against malaria in Peru, with Artesunate tablets manufac-tured by WHO prequalified manufactures from Brazil and Ghana. Methodology: testing and dissolution kinetics tests were performed with Non Standard Pharmacopoeia of the United States, FDA and WHO guidelines...

Plasmodium falciparum Genotype Diversity in Artemisinin Derivatives Treatment Failure Patients along the Thai-Myanmar Border

Genetic characteristics of Plasmodium falciparum may play a role in the treatment outcome of malaria infection. We have studied the association between diversity at the merozoite surface protein-1 (msp-1), msp-2, and glutamate-rich protein (glurp) loci and the treatment outcome of uncomplicated falciparum malaria patients along the Thai-Myanmar border who were treated with artemisinin derivatives combination therapy. P. falciparum isolates were collected prior to treatment from 3 groups of patients; 50 cases of treatment failures, 50 recrudescences, and 56 successful treatments. Genotyping of the 3 polymorphic markers was analyzed by nested PCR. The distribution of msp-1 alleles was significantly different among the 3 groups of patients but not the msp-2 and glurp alleles. The allelic frequencies of K1 and MAD20 alleles of msp1 gene were higher while RO33 allele was significantly lower in the successful treatment group. Treatment failure samples had a higher median number of alleles as compared to the successful treatment group. Specific genotypes of msp-1, msp-2, and glurp were significantly associated with the treatment outcomes. Three allelic size variants were significantly higher among the isolates from the treatment failure groups, i.e., K1270-290, 3D7610-630, G650-690, while 2 variants, K1150-170, and 3D7670-690 were significantly lower. In conclusion, the present study reports the differences in multiplicity of infection and distribution of specific alleles of msp-1, msp-2, and glurp genes in P. falciparum isolates obtained from treatment failure and successful treatment patients following artemisinin derivatives combination therapy.

Evidence of an increased incidence of day 3 parasitaemia in Suriname: an indicator of the emerging resistance of Plasmodium falciparum to artemether

The emerging resistance to artemisinin derivatives that has been reported in South-East Asia led us to assess the efficacy of artemether-lumefantrine as the first line therapy for uncomplicated Plasmodium falciparum infections in Suriname. This drug assessment was performed according to the recommendations of the World Health Organization in 2011. The decreasing number of malaria cases in Suriname, which are currently limited to migrating populations and gold miners, precludes any conclusions on artemether efficacy because adequate numbers of patients with 28-day follow-up data are difficult to obtain. Therefore, a comparison of day 3 parasitaemia in a 2011 study and in a 2005/2006 study was used to detect the emergence of resistance to artemether. The prevalence of day 3 parasitaemia was assessed in a study in 2011 and was compared to that in a study in 2005/2006. The same protocol was used in both studies and artemether-lumefantrine was the study drug. Of 48 evaluable patients in 2011, 15 (31%) still had parasitaemia on day 3 compared to one (2%) out of 45 evaluable patients in 2005/2006. Overall, 11 evaluable patients in the 2011 study who were followed up until day 28 had negative slides and similar findings were obtained in all 38 evaluable patients in the 2005/2006 study. The significantly increased incidence of parasite persistence on day 3 may be an indication of emerging resistance to artemether.

Schistogram changes after administration of antischistosomal drugs in mice at the early phase of Schistosoma mansoni infection

Mice infected with Schistosoma mansoni were treated with oxamniquine, praziquantel, artesunate at the pre-patent phase, aiming at observing schistogram alterations. Half of the animals were perfused five days post-treatment for counting and classification of immature worms, based on pre-established morphological criteria (schistogram); the remaining animals were evaluated 42 or 100 days after infection and perfusion of the portal-system was performed for collection and counting of adult worms and oogram. It was observed that oxamniquine and artesunate treatment administered at the pre-postural phase causes significant reduction in the number of immature and adult worms. However, there was little reduction with praziquantel when used at the dose of 400 mg/kg for treatments administered 14, 15, 21 or 23 days post-infection. Artesunate was responsible for significant alterations in development of young worms, as well as for a higher number of worms presenting intestinal damages. Immature adult worms were detected in mice treated with artesunate or oxamniquine at the pre-patent phase of infection and recovered by perfusion 100 days after infection. Schistogram proved to be a very useful tool for experimental evaluation of the activity of antischistosomal drugs and a good model to identify the most sensitive stages to drugs.

Plasmodium falciparum gametocyte carriage, sex ratios and asexual parasite rates in Nigerian children before and after a treatment protocol policy change instituting the use of artemisinin-based combination therapies

The effects of artemisinin-based combination therapies (ACTs) on transmission of Plasmodium falciparum were evaluated after a policy change instituting the use of ACTs in an endemic area. P. falciparum gametocyte carriage, sex ratios and inbreeding rates were examined in 2,585 children at presentation with acute falciparum malaria during a 10-year period from 2001-2010. Asexual parasite rates were also evaluated from 2003-2010 in 10,615 children before and after the policy change. Gametocyte carriage declined significantly from 12.4 percent in 2001 to 3.6 percent in 2010 (@@χ2 for trend = 44.3, p < 0.0001), but sex ratios and inbreeding rates remained unchanged. Additionally, overall parasite rates remained unchanged before and after the policy change (47.2 percent vs. 45.4 percent), but these rates declined significantly from 2003-2010 (@@χ2 for trend 35.4, p < 0.0001). Chloroquine (CQ) and artemether-lumefantrine (AL) were used as prototype drugs before and after the policy change, respectively. AL significantly shortened the duration of male gametocyte carriage in individual patients after treatment began compared with CQ (log rank statistic = 7.92, p = 0.005). ACTs reduced the rate of gametocyte carriage in children with acute falciparum infections at presentation and shortened the duration of male gametocyte carriage after treatment. However, parasite population sex ratios, inbreeding rates and overall parasite rate were unaffected.

In vitro and in vivo antileishmanial efficacy of a combination therapy of diminazene and artesunate against Leishmania donovani in BALB/c mice / Estudo in vitro e in vivo da eficácia anti leishmaniótica de terapêutica combinada de Diminazene e Artesunate contra Leishmania donovani em camundongos Balb/c

The in vitro and in vivo activity of diminazene (Dim), artesunate (Art) and combination of Dim and Art (Dim-Art) against Leishmania donovani was compared to reference drug; amphotericin B. IC50 of Dim-Art was found to be 2.28 ± 0.24 µg/mL while those of Dim and Art were 9.16 ± 0.3 µg/mL and 4.64 ± 0.48 µg/mL respectively. The IC50 for Amphot B was 0.16 ± 0.32 µg/mL against stationary-phase promastigotes. In vivo evaluation in the L. donovani BALB/c mice model indicated that treatments with the combined drug therapy at doses of 12.5 mg/kg for 28 consecutive days significantly (p < 0.001) reduced parasite burden in the spleen as compared to the single drug treatments given at the same dosages. Although parasite burden was slightly lower (p < 0.05) in the Amphot B group than in the Dim-Art treatment group, the present study demonstrates the positive advantage and the potential use of the combined therapy of Dim-Art over the constituent drugs, Dim or Art when used alone. Further evaluation is recommended to determine the most efficacious combination ratio of the two compounds.

A atividade in vitro e in vivo de Diminazene (Dim), Artezunate (Art) e a combinação Dim e Art (Dim-Art) contra Leishmania donovani foi comparada com a droga de referência Anfotericina B. IC50 da Dim-Art foi 2,28 ± 0,24 µg/mL enquanto aquelas de Dim e Art foram 9,16 ± 0,3 µg/mL e 4,64 ± 0,48 µg/mL respectivamente. O IC50 da Anfotericina B foi 0,16 ± 0,32 µg/mL contra a fase estacionária de promastigotas. A avaliação in vivo do modelo de L. donovani em camundongos Balb/c indicou que os tratamentos com a terapêutica de drogas combinadas em doses de 12,5 mg/kg por 28 dias consecutivos significantemente (p < 0,001) reduziu a carga parasitária no baço quando comparada a tratamentos com uma única droga dada nas mesmas dosagens. Embora a carga parasitária tenha sido levemente mais baixa (p < 0.05) no grupo Anfotericina B quando comparada com o grupo tratado Dim-Art, o estudo presente demonstra a vantagem positiva do uso potencial da terapêutica combinada Dim-Art sobre drogas como Dim ou Art quando usadas isoladamente. Posterior avaliação é recomendada para determinar a média de combinação mais eficaz dos dois compostos.

Rare presentation of a common disease of tropics.

A 19 years male presented with fever, oliguria and purpuric lesions involving both hands. The patient was diagnosed as a case of purpura fulminans with disseminated intravascular coagulation due to complicated falciparum malaria. The case is presented to sensitize the physicians to keep malaria as a differential in cases of fever with purpura fulminans.

Mieux prescrire les derrives de l'artemisinine

N.A.

CD4 count, viral load and parasite density of HIV positive individuals undergoing malaria treatment with dihydroartemisinin in Benin City, Edo state, Nigeria.

BACKGROUND & OBJECTIVES: A prospective study on 72 HIV infected and 33 HIV negative individuals undergoing malaria treatment with dihydroartemisinin (Cotecxin) was undertaken to compare CD4 cells count, viral load and parasite density at two time-points, a baseline visit and a 9-day post-treatment visit. METHODS: CD4 count and viral load of the subjects were estimated using Dynabeads T4-T8 Quantification Protocol (Dyneal Biotech, Norway) and Amplicor HIV-1 Monitor Test respectively (Roche, United Kingdom). RESULTS: There was a significant decrease in CD4 count at 9-day post-treatment when compared with baseline value (p < 0.05) in HIV infected individuals with CD4 < or =200 cells/microl. Also, the 9-day post-treatment viral load value was statistically higher than the baseline value (p < 0.05). In HIV positive patients with CD4 >200 cells/microl, a marked significant increase was obtained when the mean viral load at baseline was compared to the 9-day post-treatment visit value (p <0.05). The mean parasite density in HIV positive subjects was statistically higher when compared to that of HIV negative individuals at baseline and 9-day post-treatment (p < 0.05). INTERPRETATION & CONCLUSION: The study as such may not confirm the impact of malaria infection on progression to AIDS, incorporating effective malaria control in HIV management programmes may improve tremendously the quality of life of HIV infected individuals.

Minor liver profile dysfunctions in Plasmodium vivax, P. malaria and P. ovale patients and normalization after treatment

Liver function tests were performed in 61 vivax, 54 malariae and 15 ovale malaria patients who were admitted to Bangkok Hospital for Tropical Diseases between 2001 and 2004. The objective of the study was to evaluate changes in hepatic biochemical indices before and after treatment with artemisinin derivatives. On admission and prior to treatment, hepatic dysfunction was found among the 3 groups. Serum liver function tests and physical examinations were performed weekly during the 28-day follow-up period. Initially elevated serum bilirubin and diminished albumin returned to normal within 2 weeks of treatment. Serum alkaline phosphatase and aminotransferases returned to within normal limits within 3 weeks. We conclude that patients with Plasmodium vivax, P. malariae and P. ovale infections had slightly elevated serum bilirubin, aminotransferase and alkaline phosphatase levels, and hypoalbuminemia. These minor abnormalities returned to normal within a few weeks after treatment with therapies based on artemisinin derivatives.

Studies on drug metabolizing enzymes during arteether treatment of Plasmodium yoelii nigeriensis infected mice cerebral microvessels.

Human cerebral malaria is caused by a protozoan parasitic with no cure till date. The isolation of brain capillaries i.e. microvessels has permitted the in vitro study related to cerebral function. Microvessels were isolated from normal and P. yoelii infected mice brain cortex and subjected to biochemical characterization by the following enzyme markers viz alkaline phosphatase, gamma-glutamyI transpeptidase and monoamine oxidase and electron microscopically. Limited studies have been carried out in relation to drug metabolizing enzymes in cerebral microvessels of rodents. The present studies have been carried out in relation to status of drug metabolizing enzymes during P. yoelii infection in cerebral microvessels of mice. The data obtained depicted a clear cut impairment of cytochrome P450 (a terminal monooxygenase) and related indices viz b5, benzopyrene hydroxylase, aminopyrene-n-demethylase, aniline hydroxylase except NADH cytochrome e reductase which increased during P. yoelii infection in mice as compared to normal. Further the oral drug administration (arteether) treatment brought back the altered MFO system normal a week alter cessation of drug treatment.