9 research outputs found
Pharmacokinetics/Pharmacodynamics findings after repeated Administration of ARTESUNATE thermostable suppositories (RECTOCAPS) in Vietnamese patients with uncomplicated malaria
Summary: In recent years, Artemisinin and particularly one of its derivatives — Artesunate (ART — has become an essential alternative for treatment of both uncomplicated and severe falciparum malaria in Asia and Africa as well. Therefore, these compounds are still and inccreasingly in the focus of interest because of quick acting of this drug, is able to help even unconscious to overcome the malaria attack, when administered by injection. As an alternative, RECTOCAPS have been developed and their use is meanwhile well established. From earlier studies in children, suffering from Plasmodium falciparum malaria, we obtained a high level of DHART in the blood, but as expected also a rapid decline in the levels of both DHART and ART. A second administration of ART was additionally applied 4 hours after the first administration. DHART and ART plasma levels were found to last longer on an assumed therapeutic level than those obtained after one administration only. The fever clearance and the parasitemia reduction rates were found to be effective according to this dosing regimen. In view of these findings, we decided to conduct the actual described study by administering 200 mg of ART every 3 hours (0, 3, 6 and 9 h) by the rectal route. Soft geiatine capsules (RECTOCAPS) containing 200 mg of ART GMP — type each (Artesunic acid) were administered by rectal route. Each patient received four RECTOCAPS capsules (4×200 mg of ART) over a 3 h period. 12 adult patients with uncomplicated malaria were selected. Age, weight, height, body temperature, parasite counts before treatment and their evolution until 96 h are determined. Blood samples were taken at short time intervals after starting with the first medication: 0, 30 min, 60 min, 3 h, 6 h, 9 h, 12 h, 24 h, 36 h, 48 h, 60 h, 72 h, 84 h, 96 h and 108 h. The aliquots of all the blood samples were used for performing parasite counts. Plasma obtained following the traditional procedure was kept at −40°C until analysis. HPLC technique with electrochemical detector was used for quantification of ART and DHART. From the blood concentration values of ART and DHART, the following observation can be derived: the onset of action is observed within the first half hours, therapeutic levels of the drug obtained (89 μg/ml ART compared to 84 μg/ml DHART). The DHART levels are somewhat higher than those of ART (a peak concentration after 6 h starting medication of 151 μg/ml ART as compared to 276 μg/ml DHART). The variations as a function of frequency of DHART uptake are much less marked than those observed for ART. Another finding is that after the administration, some sort of a plateau of DHART and ART is built up, lasting at least from 9 to 12 hours with DHART level of about 190 μg/ml and ART of 90 μg/ml. In the case of single-dose administration, the levels of both compounds were below the detection threshold after three hours. With regard to the parasite counts, although there were inter-individual variations, it should be noted that after 48 hours a high proportion of the patients (8 out of 12) was completely clear of parasites. Similar results were observed with regard to the body temperature (7 out of 12 returned to normal temperature 36 hours after starting the therapy). The findings of the study support the RECTOCAPS application principle resulting in effectiveness both for the velocity of drug uptake as well as for the height of plasma levels. Repeated administration of ART can extend the duration of therapeutic plasma levels of the dru
Combination of drug level measurement and parasite genotyping data for improved assessment of amodiaquine and sulfadoxine-pyrimethamine efficacies in treating Plasmodium falciparum malaria in Gabonese children
Molecular epidemiology of malaria in Cameroon : 9. Characteristics of recrudescent and persistent Plasmodium falciparum infections after chloroquine or amodiaquine treatment in children
Sequence variations in the genes encoding dihydropteroate synthase and dihydrofolate reductase and clinical response to sulfadoxine-pyrimethamine in patients with acute uncomplicated falciparum malaria
Mutations in dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) are associated with in vitro resistance to sulfadoxine and pyrimethamine, respectively. The response of 75 patients to sulfadoxine-pyrimethamine was determined, and the genes of the corresponding #Plasmodium falsiparum$ isolates were sequenced. Of 12 different unmixed allelic combinations, the triple dhfr mutation Asn-108/Arg-59/Ile-51 was observed in all patients responding with early treatment failure. Some, but not all, patients with an adequate clinical response also harbored isolates with the triple dhfr mutation. Higher initial parasitemia and fever distinguished these 2 patient groups. The dhps genotype apparently had no influence on the clinical outcome. The other dhfr alleles with 1 or 2 mutations and the wild-type allele were found in patients with an adequate clinical response. The triple dhfr mutation is one of the genetic determinants associated with in vivo resistance to sulfadoxine-pyrimethamine. (Résumé d'auteur
Chimiorésistance de P. falciparum en milieu urbain à Yaoundé, Cameroun : 2. Evaluation de l'efficacité de l'amodiaquine et de l'association sulfadoxine-pyriméthamine pour le traitement de l'accès palustre simple à Plasmodium falciparum à Yaoundé, Cameroun
L'extension de la chloroquino-résistance ou sa stabilisation à un niveau élevé nécessite une modification des stratégies thérapeutiques avec éventuellement le remplacement de la chloroquine. Nous avons évalué l'efficacité de l'amodiaquine comparée à celle de l'association sulfadoxine-pyriméthamine à Yaoundé. Parmi les 140 adultes et enfants de plus de cinq ans inclus, 59 dans le groupe amodiaquine et 58 dans le groupe sulfadoxine-pyriméthamine, ont été suivis à 14 jours. L'efficacité de l'amodiaquine a été de 100% alors que 12.1% (3.7% - 20.5%) d'échecs thérapeutiques précoces ont été dénombrés dans le groupe sulfadoxine-pyriméthamine. Les effets secondaires dans les deux groupes ont été mineurs et spontanément résolutifs. Cette étude a été complétée par des tests in vitro au monodéséthylamodiaquine (le métabolite actif de l'amodiaquine) et à la pyriméthamine, et par des dosages plasmatiques du monodéséthylamodiaquine, de la sulfadoxine et de la pyriméthamine. Les résultats du test in vitro ont confirmé les variations inter-individuelles. Contrairement à la chloroquine, les concentrations moyennes ne varient pas en fonction de l'âge. Il n'existe pas de différence significative entre les concentrations de sulfadoxine et de pyriméthamine chez les malades ayant présenté un succès ou un échec thérapeutique. L'amodiaquine présente plusieurs avantages par rapport à l'association sulfadoxine-pyriméthamine et peur être considérée comme un médicament efficace en zone de chloroquino-résistance modérée. (Résumé d'auteur
Chimiorésistance de P. falciparum en milieu urbain à Yaoundé, Cameroun : 1. Surveillance in vitro et in vivo de la résistance de Plasmodium falciparum à la chloroquine entre 1994 et 1999 à Yaoundé, Cameroun
La chloroquine reste le médicament de première intention dans la plupart des pays africains pour le traitement de l'accès palustre simple. Cependant, l'extension de la résistance de #Plasmodium falciparum$ à ce médicament nécessite une surveillance régulière. Nous avons évalué de 1994 à 1999, l'évolution de la chloroquino-résistance chez des adultes (supérieur à 15 ans) par des tests d'efficacité thérapeutique et par des tests in vitro. Le test in vivo a été effectué sur 14 jours et les résultats ont été exprimés selon les nouveaux critères de l'Organisation Mondiale de la Santé. Les résultats du semi-microtest et du microtest ont été exprimés en concentration inhibitrice 50% (CI50) et le seuil de résistance est fixé à CI50 supérieure à 100 nM. Sur l'ensemble de l'étude, le pourcentage d'échecs cliniques et parasitologiques est de 39.7% (31.3% - 48.1%) et 48.8% (40.2% - 57.4%), respectivement. Parallèlement, le pourcentage de résistance in vitro atteint 52.5% (48.1% - 56.9%) et la moyenne géométrique des CI50 variait au cours du suivi de 84.6 nM à 149.8nM. Les résultats des tests in vitro sont concordants avec les résultats des tests d'efficacité thérapeutique (coefficient de kappa égal à 0.69). Ces études ont été complétées par des dosages de la chloriquinémie dans les plasmas des sujets à j0, j3, j7 et j14. Ces dosages ont permis de mettre en évidence des variations inter-individuelles importantes et des concentrations moyennes de chloroquine supérieures chez les adultes par rapport aux enfants et ont démontré que certains accès palustres pouvaient être liés à des concentrations insuffisantes de la chloroquine. Ces résultats confirment le niveau élevé de résistance à la chloroquine à Yaoundé et suggèrent l'utilisation d'un autre antipaludique en première intention pour le traitement de l'accès simple. (Résumé d'auteur
Cardiac effects of amodiaquine and sulfadoxine-pyrimethamine in malaria-infected African patients
Chemosusceptibility analysis of Plasmodium falciparum imported from Comoros to Marseilles, France in 2001-2003
Objectives. - The aim of this work was to study the chemosensitivity of Plasmodium falciparum strains isolated from patients presenting with malaria after having returned from Comoros Islands in 2002-2003, and hospitalized at the North University Hospital, in Marseilles, France. Materials and methods. - In vitro drug susceptibility (for strains maintained in culture) and mutation-specific polymerase chain reaction (PCR) assays (for all strains) were performed. Results. - Out of 23 strains kept in culture, 50% were shown to be resistant in vitro to chloroquine, 50% were resistant to pyrimethamine, 40% to cycloguanil, 25% to atovaquone, and 7% to mefloquine. However all these strains were susceptible to quinine, halofantrine, and artemether. Moreover, 48 strains were tested by molecular methods. As a result, 69% were shown to have the Asp 108 mutation in the dihy-drofolate reductase gene (Pfdhfr), the basic mutation associated with antifolate resistance, and 54% had additional mutations Ile51 plus Arg59, associated with a high level of resistance. Furthermore, 90% of the 20 strains tested in 2003 were shown to have the point mutation Pfcrt76 in the R falciparum chloroquine resistance transporter (Pfcrt) gene recently proposed as a molecular marker of chloroquine-resistance. Conclusion. - Obtaining plasmodium strains from Comoros to be tested in Marseilles, where all laboratory facilities are available, is a unique opportunity to establish a surveillance of falciparum drug resistance in the Comoros islands. (c) 2005 Elsevier SAS. Tons droits reserves