Browsing by Author "K. H. Rieckmann"

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    Disposition of proguanil in Thai patients with uncomplicated falciparum malaria
    (1997-01-01) M. D. Edstein; S. Looareesuwan; P. Wilairatana; S. Vanijanonta; D. E. Kyle; K. H. Rieckmann; Australian Army Malaria Institute; Mahidol University; Walter Reed Army Institute of Research
    The objective of this study was to examine the disposition of proguanil in malaria-infected Thai patients with acute uncomplicated falciparum malaria. Eleven patients were administered 500 mg of proguanil twice a day for three days (total dose = 3,000 mg). Four patients were tentatively classified as extensive metabolizers (EMs) and seven as poor metabolizers (PMs). The mean plasma clearances of proguanil for EMs and PMs were 1.31 and 1.10 L/hr/kg, respectively. The mean elimination half-life of proguanil was statistically longer in PMs than EMs (19.6 hr versus 16.1 hr; P = 0.01). Plasma clearance and elimination half-life of proguanil in the malaria patients were comparable with those reported in the literature for healthy Thai volunteers. In contrast to other ethnic groups, Thai EM patients had relatively low plasma concentrations of cycloguanil, the active metabolite of proguanil. None of the 11 patients treated with proguanil were cured of malaria and their phenotypic status did not affect the treatment outcome. Although high levels of parasite resistance to cycloguanil were probably responsible for the poor response to proguanil treatment, the inability of Thai EM and PM patients to produce cycloguanil may have also contributed to the treatment outcome.
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    Proguanil polymorphism does not affect the antimalarial activity of proguanil combined with atovaquone in vitro
    (1996-01-01) M. D. Edstein; A. E.T. Yeo; D. E. Kyle; S. Looareesuwan; P. Wilairatana; K. H. Rieckmann; Australian Army Malaria Institute; Walter Reed Army Institute of Research; Mahidol University
    Clinical studies have shown proguanil (PROG) combined with atovaquone (ATQ) to be an effective and safe antimalarial combination for the treatment of multidrug-resistant falciparum malaria. PROG is a prodrug, which undergoes hepatic metabolism to its pharmacologically active metabolite cycloguanil (CYC). Individuals exhibit genetic polymorphism with respect to PROG, and can be phenotyped as either extensive metabolizers (EMs) or poor metabolizers (PMs) by measuring their PROG/CYC concentration ratio in plasma following PROG/ATQ administration. PMs produce lower plasma concentrations of CYC than EMs and thus may be more susceptible to prophylaxis or treatment failure. Both FROG and CYC potentiate the activity of ATQ in vitro. The antimalarial activity ex vivo of Thai patients' plasma samples obtained from EMs and PMs given concurrent PROG and ATQ was studied using the K1 isolate of Plasmodium falciparum This isolate is resistant to PROG and CYC, but sensitive to ATQ. Maximum inhibitory dilution profiles of the patients' plasma samples containing PROG and ATQ from EMs and PMs were similar. These findings indicate that differences in plasma drug concentrations between EMs and PMs did not alter the antimalarial activity in vitro against the K1 isolate. The phenotypic status of individuals is not an important issue in the treatment of patients with PROG/ATQ.