Potentiation of the antimalarial activity of atovaquone by doxycycline against Plasmodium falciparum in vitro

The effect of doxycycline, obtained from human volunteers administered doxycycline, on the minimum inhibitory concentration (MIC) of atovaquone was determined against the K1 and FC27 isolates of Plasmodium falciparum in vitro. Doxycycline concentrations ranging from 0.10-1.18 mu g/ml added to atovaquone produced MIC ratios [atovaquone + doxycycline/atovaquone alone] ranging from 0.38 to 0.70. These results suggest that the antimalarial activity of atovaquone is potentiated by doxycycline. Additionally, these drugs may be rational partners for the treatment and prophylaxis of falciparum malaria

Ex vivo antimalarial activity of proguanil combined with dapsone against cycloguanil-resistant plasmodium falciparum isolates

The ex vivo antimalarial activity of plasma samples obtained from 20 healthy Caucasian volunteers following daily proguanil (200 mg) plus dapsone (8 mg) for malaria chemoprophylaxis inhibited five cycloguanil-resistant Thai isolates of Plasmodium falciparum. All volunteers were phenotyped as extensive metabolisers (EMs) of proguanil. Three of the five isolates were obtained from Thai soldiers who had failed malaria prophylaxis on daily proguanil (200 mg) plus dapsone (4.0 or 12.5 mg). The Thai soldiers were also classified as EMs, but had relatively lower plasma cycloguanil concentrations compared to values reported in the literature for Caucasians and black Kenyans. Although the high level of parasite resistance to cycloguanil was the most likely explanation for the Thai soldiers failing prophylaxis on proguanil plus dapsone, their low cycloguanil concentrations may have also contributed to their lack of protection. However, in areas where parasites are more susceptible to cycloguanil, such as in certain regions of Africa, proguanil plus dapsone may still be an effective chemoprophylactic drug combination. (C) 1997 Elsevier Science B.V

Oxidative activation of proguanil and dapsone acetylation in Thai soldiers

The prevalence of putative poor metaboliser (PM) phenotypes of proguanil oxidation in Caucasian populations is 3-10%. The PM frequency in Oriental populations is unknown. In this study the plasma metabolic ratios of proguanil and dapsone to their principal metabolites cycloguanil and monoacetyldapsone were determined in Thai soldiers receiving antifolate drug combinations for malaria prophylaxis. The distribution ratio of proguanil to cycloguanil (PROG/CYC) was highly skewed with no evidence of bimodality. Assuming subjects with a PROG/CYC ratio greater than 10 are PMs from studies in Caucasians, the incidence of PMs in the soldiers would be 18% (30 of 170). The mean PROG/CYC ratio for PMs in the Thai soldiers was 31.2 +/- 28.9 (n = 30) compared with 25.5 +/- 2.5 (n = 3) in a study of Caucasians. The corresponding values for putative EMs were 5.4 +/- 2.1 (n = 140) and 2.4 +/- 0.2 (n = 134). Similar to other Oriental populations, Thais were found to be predominantly (76%, 173 of 228) rapid acetylators of dapsone

Gender differences in gastrointestinal disturbances and plasma concentrations of tafenoquine in healthy volunteers after tafenoquine administration for post-exposure vivax malaria prophylaxis

In an open-label sequential cohort study, we compared gastrointestinal (GI) disturbances and plasma tafenoquine concentrations after administration of single-dose (400 mg daily x 3 days; n=76 males, 11 females) and split-dose (200 mg twice daily x 3 days; n=73 males, 13 females) tafenoquine regimens in healthy Australian Defence Force volunteers for post-exposure malaria prophylaxis. The female and male volunteers had comparable demographic characteristics (age, weight, height) in the single- and split-dose treatment groups. GI disturbances were generally mild and self-limiting for both groups. The frequency of nausea and abdominal distress was over two-fold higher in females than in males for both treatment groups. Reporting of GI disturbances in the single-dose group differed significantly between males and females, but this gender difference was not seen for the split-dose group. In those volunteers who experienced GI disturbances, the mean plasma tafenoquine concentrations 12 h after the last dose of tafenoquine were approximately 1.3-fold higher in females than in males (means +/- SD: 737 +/- 118 ng/ml vs. 581 +/- 113 ng/ml). These preliminary findings suggest that further studies are required in a larger number of females to determine whether there is a need to reduce the dose of tafenoquine to minimise GI disturbances in females. Crown Copyrigh (c) 2006 Published by Elsevier Ltd on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved

Avaliação da resposta do Plasmodium falciparum à cloroquina, quinino e mefloquina

Nosso estudo envolveu a análise de cepas de Plasmodium falciparum provenientes da Região Amazônica Brasileira, coletadas no Laboratório de Malária da SUCEN. Os estudos "in vitro" foram efetuados com a cloroquina (46 ensaios), quinino (42 ensaios) e mefloquina (51 ensaios). Os resultados mostraram resistência de 100% em relação à cloroquina, 2,4% ao quinino e 31,4% à mefloquina, na análise "in vitro". Sete pacientes foram tratados com quinino isolado e nove com a associação mefloquina + pirimetamina-sulfadoxina, não mostrando correlação com os testes "in vitro"

Assessment of chloroquine single dose treatment of malaria due to Plasmodium vivax in Brazilian Amazon Cloroquina em dose simples no tratamento da malária por Plasmodium vivax na Amazônia brasileira

Malaria regions of the Amazon basin have been characterized by difficult access and non-compliance of the patients to treatment. In an attempt to assess the schizonticide efficacy of chloroquine in a single dose of 600 mg, the authors realized a double-blind, placebo-controlled trial in 132 outpatients with vivax malaria. Patients were distributed into two groups: group CPLA, given chloroquine 600 mg (single dose) on the first day of treatment, and two doses of placebo on second and third days. Group CHLO, given chloroquine 600 mg on first day and 450 mg on second and third day. Geometric means of the parasite density during the follow-up was similar in both groups. No differences were observed in the parasitological cure between the two groups (p = 0.442). There was clinical and parasitological efficacy in treatment of patients given a single-dose of chloroquine. This suggests that its restricted use could be indicated in remote areas of Brazilian Amazon Region, nevertheless the inadequate response of three patients indicates the need for further studies.<br>As regiões malarígenas da Amazônia brasileira têm se caracterizado por dificuldades no acesso ao tratamento e não aceitação das drogas pelos doentes. Com objetivos de avaliar a eficácia da cloroquina em dose simples de 600 mg, os autores realizaram um ensaio clínico duplo cego, placebo controlado em 132 pacientes portadores de malária por P. vivax. Os pacientes foram distribuídos em dois grupos: grupo CPLA que recebia 600 mg de cloroquina em dose simples no primeiro dia de tratamento e duas doses de placebo no segundo e terceiro dias de tratamento. Grupo CLO que recebia 600 mg de cloroquina no primeiro dia e 450 mg no segundo e terceiro dias. A média geométrica da densidade parasitária durante o seguimento foi similar em ambos os grupos. Não houve diferenças de cura parasitológica em ambos os grupos (p = 0,442). Observou-se eficácia clínica e parasitológica nos indivíduos que receberam dose simples de cloroquina, indicando a possibilidade de uso restrito a algumas áreas da Amazônia brasileira, contudo, a resposta inadequada de três pacientes sugere a necessidade de outros estudos