Some basic facts on combination therapy

What are the problems with malaria? • The disease • The drugs • The policies • The finance COMBINATION THERAPY: DEFINITION • CT is the simultaneous use of two or more blood schizonticidal drugs with independent modes of action and different biochemical targets in the parasites • • CTs can be either fixed ratio combinations or multiple-drug therapy, in which components are co-administered in separate tablets or capsules

Molecular monitoring of the Leu-164 mutation of dihydrofolate reductase in a highly sulfadoxine/pyrimethamine-resistant area in Africa

The selection of point mutation at codon 164 (from isoleucine to leucine) of the dihydrofolate reductase (DHFR) enzyme in Plasmodium falciparum is associated with high sulfadoxine /pyrimethamine (SP) resistance. Using the yeast expression system that allows the detection of dhfr allele present at low level, the presence of this mutation had previously been reported between 1998–1999 in Muheza, Tanzania, an area of high SP resistance. Eighty five P. falciparum isolates, obtained from the same area between 2002 and 2003, were analysed for the presence of Leu-164 mutation, using standard protocol based on PCR-RFLP. None of the isolates had the Leu-164 mutation

Better Board Education for Better Leadership and Management in the Health Sectors of Low and Middle Income Countries

Board member education must be elevated within the curricula of leadership development programming in Low and Middle Income Countries (LMICs) across the globe. When properly trained and supported, the community, business, and health sector leaders serving on these boards can create the conditions within which those who deliver and manage health services are more likely to successfully achieve the mission of their organizations. The importance of incorporating education for governing body members into health sector leadership development programming, and three strategies for board development, are defined in in this article

Chloroquine-resistant Plasmodium vivax malaria in Debre Zeit, Ethiopia

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium vivax </it>accounts for about 40% of all malaria infection in Ethiopia. Chloroquine (CQ) is the first line treatment for confirmed <it>P. vivax </it>malaria in the country. The first report of CQ treatment failure in <it>P. vivax </it>was from Debre Zeit, which suggested the presence of chloroquine resistance.</p> <p>Methods</p> <p>An <it>in vivo </it>drug efficacy study was conducted in Debre Zeit from June to August 2006. Eighty-seven patients with microscopically confirmed <it>P. vivax </it>malaria, aged between 8 months and 52 years, were recruited and treated under supervision with CQ (25 mg/kg over three days). Clinical and parasitological parameters were assessed during the 28 day follow-up period. CQ and desethylchloroquine (DCQ) blood and serum concentrations were determined with high performance liquid chromatography (HPLC) in patients who showed recurrent parasitaemia.</p> <p>Results</p> <p>Of the 87 patients recruited in the study, one was lost to follow-up and three were excluded due to <it>P. falciparum </it>infection during follow-up. A total of 83 (95%) of the study participants completed the follow-up. On enrolment, 39.8% had documented fever and 60.2% had a history of fever. The geometric mean parasite density of the patients was 7045 parasites/μl. Among these, four patients had recurrent parasitaemia on Day 28. The blood CQ plus DCQ concentrations of these four patients were all above the minimal effective concentration (> 100 ng/ml).</p> <p>Conclusion</p> <p>Chloroquine-resistant <it>P. vivax </it>parasites are emerging in Debre Zeit, Ethiopia. A multi-centre national survey is needed to better understand the extent of <it>P. vivax </it>resistance to CQ in Ethiopia.</p

Chloroquine resistance before and after its withdrawal in Kenya

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Paromomycin for the Treatment of Visceral Leishmaniasis in Sudan: A Randomized, Open-Label, Dose-Finding Study

Visceral leishmaniasis (VL) is a parasitic disease transmitted through the bite of sandflies. The WHO estimates 500,000 new cases of VL each year, with more than 90% of cases occurring in Southeast Asia, East Africa, and South America. If left untreated, VL can be fatal. We had previously conducted a large multi-center study in Sudan, East Africa, to assess the efficacy of paromomycin (PM) alone or in combination with sodium stibogluconate. Clinical studies in India have shown that 15 mg/kg/day PM for 21 days was an effective cure. However, the same treatment regimen was not efficacious in two study sites in Sudan. Here, our aim was to assess two high-dose regimens of PM in Sudan: 15 mg/kg/day for 28 days and 20 mg/kg/day for 21 days. The results suggest that, at these total doses, PM is more efficacious than when given daily at 15 mg/kg for 21 days, and that high doses are required to treat VL in Sudan. Efficacy of 20 mg/kg/day PM for 21 days is currently being evaluated in a prospective, comparative phase III trial in East Africa

A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers

<p>Abstract</p> <p>Background</p> <p>Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers.</p> <p>Methods</p> <p>Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days.</p> <p>Results</p> <p>The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (C_max) was 160-200 nM and after 6 hours, the effective concentration (C_eff) was <150 nM.</p> <p>Conclusion</p> <p>Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable C_effof 250-400-nM required to clear malaria infection <it>in vivo</it>. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.</p

Understanding the pharmacokinetics of Coartem®

Artemether and lumefantrine (AL), the active constituents of Coartem® exhibit complementary pharmacokinetic profiles. Artemether is absorbed quickly; peak concentrations of artemether and its main active metabolite, dihydroartemisinin (DHA) occur at approximately two hours post-dose, leading to a rapid reduction in asexual parasite mass and a prompt resolution of symptoms. Lumefantrine is absorbed and cleared more slowly (terminal elimination half-life 3-4 days in malaria patients), and accumulates with successive doses, acting to prevent recrudescence by destroying any residual parasites that remain after artemether and DHA have been cleared from the body. Food intake significantly enhances the bioavailability of both artemether and lumefantrine, an effect which is more apparent for the highly lipophilic lumefantrine. However, a meal with only a small amount of fat (1.6 g) is considered sufficient to achieve adequate exposure to lumefantrine. The pharmacokinetics of artemether or lumefantrine are similar in children, when dosed according to their body weight, compared with adults. No randomized study has compared the pharmacokinetics of either agent in pregnant versus non-pregnant women. Studies in healthy volunteers and in children with malaria have confirmed that the pharmacokinetic characteristics of crushed standard AL tablets and the newly-developed Coartem® Dispersible tablet formulation are similar. Studies to date in healthy volunteers have not identified any clinically relevant drug-drug interactions; data relating to concomitant administration of HIV therapies are limited. While dose-response analyses are difficult to undertake because of the low rate of treatment failures under AL, it appears that artemether and DHA exposure impact on parasite clearance time while lumefantrine exposure is associated with cure rate, consistent with their respective modes of action. In conclusion, knowledge of the pharmacokinetic profiles of artemether and lumefantrine is increasing within a range of settings, including infants and children. However, additional data would be warranted to better characterize artemether and lumefantrine pharmacokinetics in patients with hepatic impairment, in pregnant women, and in patients undergoing HIV/AIDS chemotherapy

Ongoing challenges in the management of malaria

This article gives an overview of some of the ongoing challenges that are faced in the prevention, diagnosis and treatment of malaria

Guidelines for Field Surveys of the Quality of Medicines: A Proposal

Paul Newton and colleagues propose guidelines for conducting and reporting field surveys of the quality of medicines