Search

Arterolane (RBx 11160) maleate is a novel, rapidly acting synthetic trioxolane antimalarial compound being developed by Ranbaxy Research Laboratories (Haryana, India). It is presently under phase III in combination with piperaquine phosphate. The present work reports the relationship between pharmacokinetic (PK) parameter (AUC0-8h on day 0/day 6) and indices of pharmacodynamic (PD) response (50% parasite clearance [PC50], 90% parasite clearance [PC90], parasite clearance time [PCT], recrudescence) from a phase II, double-blind, multicenter, randomized, parallel-group, dose-ranging trial. Patients with acute uncomplicated P. falciparum malaria were randomized to 1 of 3 arterolane maleate (50, 100, and 200 mg) doses for 7 consecutive days. Plasma concentration data were available from 78, 76, and 75 patients receiving a 50-, 100-, and 200-mg dose, respectively. Based on PD modeling, its limitations and assumptions, minimum 150-mg dose arterolane maleate was recommended to optimize the probability of maximum therapeutic benefits for an adult. Doses higher than 100 mg are unlikely to reduce the probability of recrudescence. This study re-stresses the need of combining short and long-acting drugs to prevent resistance development and minimize recrudescence. [ABSTRACT FROM PUBLISHER]

Several mutations have been identified in Plasmodium falciparum that cause, or contribute to, drug resistance. It is relatively easy to measure their prevalence in human blood samples, so they are often used to infer drug failure rates, clinical and parasitological, that will occur in the human population. One current method of making this inference is through the use of genotypic resistance and genotypic failure indices. These indices are rather sensitive to background drug failures rates (i.e. failures not caused by the mutation), to mutation prevalence, and to the genetic background in which the marker occurs. Extreme care should therefore be taken in the construction and interpretation of these indices. [ABSTRACT FROM AUTHOR]

Between 1998 and 2001, Kenya, Uganda, Tanzania, Zanzibar, Rwanda and Burundi changed antimalarial drug policy, in the face of widespread chloroquine resistance. The new first-line treatment is either sulphadoxine-pyrimethamine (SP) monotherapy, or a combination of SP with either chloroquine or amodiaquine. Two national malaria control programmes, Burundi and Zanzibar, have decided upon amodiaquine-artesunate as their first-line treatment, although SP will continue to fill this role until the new policy can be implemented. Given the broad uniformity of parasite chemoresistance in the six countries, The East African Network for Monitoring Antimalarial Treatment (EANMAT) has focused attention on, and worked towards, a sub-regional antimalarial drug policy, where the evidence base would be the entire portfolio of network in vivo test results. Currently, there are several different antimalarial drug policies within the EANMAT area: the intention is to eventually replace this plethora of policies with a single, sub-regional policy based upon combination therapy. Currently, successful malaria treatment depends primarily upon the efficacy of SP, and of amodiaquine, which is either a component of first-line treatment, or the second line drug. This report addresses the results of WHO in vivo tests on these two monotherapies within the network. Results are analysed to assess the evidence for change in parasite susceptibility over time; the range of susceptibility to each drug within countries, and the implications of test results on policy. [ABSTRACT FROM AUTHOR]

Since 1994, the Peruvian Malaria Control Program has used a simplified operational approach for monitoring antimalarial drug efficacy, in which blood smears are taken 7 and 14 days after treatment from all patients diagnosed with malaria at Ministry of Health facilities. The proportion of patients with parasitaemia on one of their return visits provides an indication of the efficacy of the drug being administered. We compared this approach for antimalarial drug resistance monitoring to the more labour-intensive and expensive World Health Organization (WHO) 14-day in vivo efficacy trial at six sites in the Amazon Basin and the north coast of Peru. Although the proportion of treatment failures at 7 and 14 days identified by the operational monitoring system was considerably lower than the results of the WHO in vivo efficacy test, the operational approach did accurately reflect the overall efficacy or lack of efficacy of the drugs being evaluated. Differences in the results of the two methods were greatest in the Peruvian Amazon region, where fully supervised treatment and patient follow-up is very difficult due to the widely dispersed population. While the operational approach cannot be considered an alternative to WHO in vivo testing for evaluating the efficacy of antimalarial drugs or for recommending changes in malaria treatment policy, if treatment is supervised and follow-up blood smears taken as scheduled, this method could serve as a simple, inexpensive and sustainable early warning system for reduced drug efficacy. [ABSTRACT FROM AUTHOR]

Since 1993 sulphadoxine/pyrimethamine (SP) has been used as the first-line drug for uncomplicated Plasmodium falciparum malaria in Malawi. To investigate the current efficacy of SP and other antimalarial drug resistance, we studied in vivo and in vitro responses to SP, chloroquine (CQ), mefloquine (MF), quinine (QN), and halofantrine (HF) in Salima, central Malawi. In a follow-up of 14 days, nine (13.8%) of 65 children under five showed RII/RIII parasitological resistance, and in in vitro microtests 18 (62.1%) of 29 isolates showed < 90% inhibition of schizont maturation at pyrimethamine 75 nmol/l blood medium mixture, indicating resistance. The discrepancy between in vivo and in vitro results might be partially explained by acquired immunity in this holoendemic area. In vitro one (3.4%) of 29 isolates failed schizont inhibition at 1.6 micromol/l blood of CQ, indicating resistance. Compared with an in vitro study conducted in 1988 in another region of Malawi using the same cut-off point, the proportion of resistant isolates had decreased significantly (P < 0.01). Although 31% of isolates were borderline, showing schizont maturation at 0.8 micromol/l blood but no schizonts at 1.6 micromol/l in our study, the results suggest possible recovery of CQ sensitivity after long-term absence of drug pressure. Resistance remains a major problem in malaria control. Monitoring resistance patterns in vitro provides early warning signs of impending loss of therapeutic efficacy of the standard treatment, and may detect changing patterns in alternative drug resistance. [ABSTRACT FROM AUTHOR]