Scientific publications 2010

Antileishmanial High-Throughput Drug Screening Reveals Drug Candidates with New Scaffolds by Siqueira-Neto J L, Song O-R., Oh H, Sohn J-H, Yang G, Nam J, Jang J, Cechetto J, Lee C B, Moon S, Genovesio A, Chatelain E, Christophe T, Freitas-Junior L H. PLoS Neglected Tropical Diseases, 2010 May, Volume 4, Issue 5.
Drugs currently available for leishmaniasis treatment often show parasite resistance, highly toxic side effects and prohibitive costs commonly incompatible with patients from the tropical endemic countries. In this sense, there is an urgent need for new drugs as a treatment solution for this neglected disease. Here we show the development and implementation of an automated high-throughput viability screening assay for the discovery of new drugs against Leishmania. Assay validation was done with Leishmania promastigote forms, including the screening of 4,000 compounds with known pharmacological properties. In an attempt to find new compounds with leishmanicidal properties, 26,500 structurally diverse chemical compounds were screened. A cut-off of 70% growth inhibition in the primary screening led to the identification of 567 active compounds. Cellular toxicity and selectivity were responsible for the exclusion of 78% of the pre-selected compounds. The activity of the remaining 124 compounds was confirmed against the intramacrophagic amastigote form of the parasite. In vitro microsomal stability and cytochrome P450 (CYP) inhibition of the two most active compounds from this screening effort were assessed to obtain preliminary information on their metabolism in the host. The HTS approach employed here resulted in the discovery of two new antileishmanial compounds, bringing promising candidates to the leishmaniasis drug discovery pipeline.
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Pharmacokinetics and Comparative Bioavailability of Artesunate and Mefloquine Administered Separately or as a Fixed Combination Product to Healthy Volunteers and Patients with Uncomplicated Plasmodium falciparum Malaria by Olliaro P, Ramanathan S, Vaillant M, Reuter S, Evans A, Krudsood S, Looareesuwan S,
Kiechel J-R, Taylor W, and Navaratnam V. Journal of Bioequivalence & Bioavailability, 2010 May, Volume 2(3): 059-066.
The pharmacokinetics of artesunate, dihydroartemisinin, the artesunate metabolite and predominant species and mefloquine were assessed in a single-dose, randomised, crossover design study in healthy volunteers and in a multiple-dose, randomised, parallel group study in patients with uncomplicated falciparum malaria.
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Anti-malarial market and policy surveys in sub-Saharan Africa by Diap G, Amuasi J, Boakye I, Sevcsik A-M, and Pecoul B. Malaria Journal Supplement, BioMed Central 2010 April, 9(1):S1
Following the development by DNDi and the FACT partners of the ASAQ fixed-dose combination, according to WHO recommendations (easy to use, affordable, field adapted and non-patented), and despite the fact that ASAQ fixed-dose combination is registered and available in more than 25 African endemic countries and eligible for Global Fund and other international funding, general access to ACTs for patients is still inadequate.
At the recent meeting (Sept 18, 2009) on public and private market and policy survey: ‘Antimalarial market and policy surveys in sub-Saharan Africa’, a validated methodology for these surveys in two countries (Sierra Leone and Burundi) was discussed. Real-life data were presented in a highly interactive brainstorming session among key stakeholders, in a time when market issues for malaria are at the top of the international agendas.
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Population Pharmacokinetics and Pharmacodynamic considerations of Amodiaquine and Desethylamodiaquine in Kenyan Adults with uncomplicated malaria receiving the Artesunate-Amodiaquine combination therapy by Jullien V, Ogutu B, Juma E, Carn G, Obyono C, and Kiechel J-R. Antimicrobial Agents and Chemotherapy. 2010 April 5. 01496-09.
Amodiaquine (AQ) is an antimalarial drug that was frequently combined with artesunate (AS) for the treatment of uncomplicated malaria due to Plasmodium falciparum and is now available as a fixed dose combination. Despite its widespread use, the simultaneous  pharmacokinetics of AQ and its active metabolite, desethylamodiaquine (DAQ) were not characterized to date in patients. The pharmacokinetics of AQ and DAQ were therefore investigated in 54 adult patients receiving the AS/AQ combination by the use of a population approach. AQ followed a 1-compartment model with first-order absorption and elimination as well as a first-order and irreversible transformation  into DAQ, which in turn followed a 2-compartment model with first-order elimination from its central compartment. Mean AQ apparent clearance and distribution volume were 3410 L/h and 39200 L respectively. Mean terminal elimination half-life of DAQ was 211 h. Bodyweight was found to explain the interindividual variability of the apparent volume of distribution of AQ and the elimination rate constant of DAQ. A new dosage form consisting in a fixed dose combination of AS and AQ was found to have no effect on the pharmacokinetic parameters of AQ and DAQ. All patients achieved parasite clearance within 4 days following the initiation of the treatment, which prevented the investigation of the possible relationship between DAQ exposure and treatment outcome. This study provided the first simultaneous pharmacokinetic model for AQ and DAQ.
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In vitro and in vivo experimental models for drug screening and development for Chagas disease by Romanha A J, de Castro S L, de Nazaré Correia Soeiro M, Lannes-Vieira Ribeiro I, Talvani A, Bourdin B, Blum B, Olivieri B, Zani C, Spadafora C, Chiari E, Chatelain E, Chaves G, Calzada J E, Bustamante J M, Freitas-Junior L H, Romero L I, Bahia M T, Lotrowska M, Soares M, Andrade S G, Armstrong T, Degrave W, de Araújo Andrade Z. Mem Inst Oswaldo Cruz, 2010 March, Vol. 105 (2): 233-238
Although the occurrence of acute cases of Chagas disease has declined, there still remain serious challenges, including the maintenance of sustainable public policies for Chagas disease control and the urgent need for better drugs to treat chagasic patients. Since the introduction of benznidazole and nifurtimox approximately 40 years ago, many natural and synthetic compounds have been assayed against Trypanosoma cruzi, yet only a few compounds have advanced to clinical trials. The development of more effective drugs requires (i) the identification and validation of parasite targets, (ii) compounds to be screened against the targets or the whole parasite and (iii) a panel of minimum standardised procedures to advance leading compounds to clinical trials. This third aim was the topic of a workshop held in Rio de Janeiro, Brazil, in November 2008: the minimum steps, requirements and decision gates for the determination of the efficacy of novel drugs for T. cruzi control were evaluated by interdisciplinary experts and an in vitro and in vivo flowchart was designed to serve as a general and standardised protocol for screening potential drugs for the treatment of Chagas disease.
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Combination therapy for visceral leishmaniasis by van Griensven J, Balasegaram M, Meheus F, Alvar J, Lynen L, Boelaert M. In Lancet Infect Dis 2010; 10: 184–94
Combination therapy for the treatment of visceral leishmaniasis has increasingly been advocated as a way to increase treatment efficacy and tolerance, reduce treatment duration and cost, and limit the emergence of drug resistance. The authors reviewed the evidence and potential for combination therapy, and the criteria for the choice of drugs in such regimens.
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