In vitro multistage malaria transmission blocking activity of selected malaria box compounds

Purpose: Continuous efforts into the discovery and development of new antimalarials are required to face the emerging resistance of the parasite to available treatments. Thus, new effective drugs, ideally able to inhibit the Plasmodium life-cycle stages that cause the disease as well as those responsible for its transmission, are needed. Eight compounds from the Medicines for Malaria Venture (MMV) Malaria Box, potentially interfering with the parasite polyamine biosynthesis were selected and assessed in vitro for activity against malaria transmissible stages, namely mature gametocytes and early sporogonic stages. Methods: Compound activity against asexual blood stages of chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains of Plasmodium falciparum was tested measuring the parasite lactate dehydrogenase activity. The gametocytocidal effect was determined against the P. falciparum 3D7elo1-pfs16-CBG99 strain with a luminescent method. The murine P. berghei CTRP.GFP strain was employed to assess compounds activities against early sporogonic stage development in an in vitro assay simulating mosquito midgut conditions. Results: Among the eight tested molecules, MMV000642, MMV000662 and MMV006429, containing a 1,2,3,4-tetrahydroisoquinoline-4-carboxamide chemical skeleton substituted at N-2, C-3 and C-4, displayed multi-stage activity. Activity against asexual blood stages of both strains was confirmed with values of IC50 (50% inhibitory concentration) in the range of 0.07\u20130.13 \ub5M. They were also active against mature stage V gametocytes with IC50 values below 5 \ub5M (range: 3.43\u20134.42 \ub5M). These molecules exhibited moderate effects on early sporogonic stage development, displaying IC50 values between 20 and 40 \ub5M. Conclusion: Given the multi-stage, transmission-blocking profiles of MMV000642, MMV000662, MMV006429, and their chemical characteristics, these compounds can be considered worthy for further optimisation toward a TCP5 or TCP6 target product profile proposed by MMV for transmission-blocking antimalarials

A simple technique for the detection of anti-malarial drug formulations and their presence in human urine

A simple, sensitive, specific assay technique for the detection and semi-quantification of chloroquine, amodiaquine, quinine, primaquine, sulfadoxine and pyrimethamine in formulations and in human urine by using thin layer chromatography (TLC) was developed and tested in the laboratory. The method involved developing test samples spotted on TLC chromatogram by diethylamine-toluene-isopropanol (1:4:5 v/v/v) as the eluting solvent. The solvent system diethylamine-toluene-isopropanol (1:4:5 v/v/v) enabled the elution and detection of all the tested antimalarial drugs in solution and those spiked in human urine. Detection limits for chloroquine, amodiaquine, quinine and primaquine were the lowest at 0.00025 mg/ml. Sulfadoxine exhibited a detection limit of 0.0005 mg/ml whereas that of pyrimethamine was 0.001 mg/ml. The results indicate the suitability of this technique in antimalarial drug quality and bioavailability studies. It is envisaged that this technique will adequately address the role of drug absorption and excretion in the chemotherapy of malaria as well as to detect types of antimalarial drugs commonly used in the community

Biological and haematological safety profile of oral amodiaquine and chloroquine in healthy volunteers with or without Plasmodium falciparum infection in northeast Tanzania

Amodiaquine (AQ), an effective antimalarial drug for uncomplicated malaria, has been greatly restricted after cases of life-threatening agranulocytosis and hepatic toxicity during prophylactic use. We conducted a hospital based open-label randomised clinical trial in 40 indigenous semi-immune healthy adult male volunteers with and without malaria parasites. The objective was to collect data on biological and haematological safety, tolerability, and parasitological efficacy to serve as baseline in the evaluation of the effectiveness of AQ preventive intermittent treatment against malaria morbidity in infants. Volunteers were stratified according to parasitaemia status and randomly assigned 20 participants each arm to three days treatment with either AQ or chloroquine (CQ). The level of difference of selected haematological and hepatological values pre-and post-trial were marginal and within the normal limits. Clinical adverse effects mostly mild and transient were noticed in 33.3% CQ treated-aparasitaemic, 23.8% of CQ treated-parasitaemic, 28.6% of AQ-treated parasitaemic and 14.3% of aparasitaemic receiving AQ. Amodiaquine attained 100% parasitological clearance rate versus 70% in CQ-treated volunteers. The findings indicate that there was no agranulocytosis or hepatic toxicity suggesting that AQ may pose no public health risk in its wide therapeutic dosage uses. Larger studies are needed to exclude rare adverse effects

Analysis of cost impact of HIV/AIDS on health service provision in nine regions, Tanzania: methodological challenges and lessons for policy

Tanzania is one of African countries that have since 1983 been facing the human immuno-deficiency virus-acquired immune-deficiency syndrome (HIV-AIDS) pandemic, thereby, drawing attention to the general public, the governmental and non-governmental organizations and government's partner development agencies. Due to few socioeconomic studies done so far to evaluate the impact this pandemic, a study was designed and undertaken in 2001 to analyse how this disease had impacted on health service provision in Tanzania from a cost perspective. The study involved a review of health service management information documents at selected health facilities in nine regions within mainland Tanzania, interviews with health service workers (HWs) at selected health facilities and health managers at district and regional levels as well as focus group discussions with people living with HIV/AIDS (PLWA). We noted that on average, HIV/AIDS caused 72% of all the deaths recorded at the study hospitals. The health management information system (HMIS) missed some data in relation to HIV/AIDS services, including the costs of such services which limited the investigators??? ability to determine the actual costs impact. Using their experience, health managers and HWs reported substantial amounts of funds, labour time, supplies and other resources to have been spent on HIV/AIDS preventive and curative services. The frontline HWs reported to face a problem of identifying the PLWA among those who presented multiple illness conditions at HF levels which means sometimes the services given to such people could not be separated for easy costing from services delivered to other categories of the patients. Such respondents and their superiors (i.e. Health managers) testified that PLWA were being screened and receiving treatment. HWs were concerned with spending much time on counselling PLWA, attending home-based care, sick-leaves and funeral ceremonies either after their relatives or co-staff have died of AIDS, lowering time for delivering services to other patients. HWs together with their superiors at district and regional levels reported increasing shortages of essential supplies, office-working space and other facilities at HF levels, although actual costs of such items were not documented. The cost impact of HIV/AIDS to the health sector is undoubtedly high even though it is not easy to establish the cost of each service delivered to PLWA in Tanzania. As adopted in the present study, designers of methods for analysing impacts of diseases like this should consider a mixture of both quantitative and qualitative techniques. Meanwhile concerted measures are needed to improve health service record keeping so as enhancing data usability for research and rational management decision-making purposes.