Chlorproguanil/dapsone for uncomplicated Plasmodium falciparum malaria in young children: pharmacokinetics and therapeutic range.

The disposition of chlorproguanil/dapsone (one daily dose for 3 d of 1.2 and 2.4 mg/kg respectively) has been studied in young children with Plasmodium falciparum malaria, to provide data complementary to a clinical trial of this drug combination. Unbound concentrations of chlorcycloguanil (the active metabolite of chlorproguanil) and dapsone in clinical samples have been related to the unbound drug concentrations which produced defined outcomes in tests in vitro of drug efficacy and toxicity. Twelve children with uncomplicated malaria were treated: all cleared parasitaemia within 72 h and made uneventful recoveries. After the first dose of chlorproguanil/dapsone the maximum unbound chlorcycloguanil concentration in clinical samples (19 ng/mL [about 60 nM]) was 2 orders of magnitude above the 50% inhibitory concentration (IC50) value for this drug against the K39 stain of P. falciparum, while falling 2 orders of magnitude below its IC50 against human bone marrow cells; the maximum unbound dapsone concentration in clinical samples (160 ng/mL [about 645 nM]) was 10-fold higher than its IC50 against the K39 strain. However, because of the rapid elimination of chlorproguanil from the body (half-life 12.6 +/- 6.3 h), the minimum fractional inhibitory concentrations of unbound chlorcycloguanil/dapsone against the K39 strain were probably exceeded for no more than 6 d. These data, together with the clinical trial, will be helpful in deciding whether current chlorproguanil/dapsone doses are optimal for the treatment of falciparum malaria.

Marked variation in pyrimethamine disposition in AIDS patients treated for cerebral toxoplasmosis.

We have characterized the disposition of pyrimethamine in 20 adults with advanced AIDS. After the first dose, the area under concentration versus time curves (corrected for dose-size) varied 13-fold. This marked variation in drug levels was also noted during accumulation towards steady-state: pyrimethamine levels were consistently below the suggested lower end of the therapeutic range (750 mg/L) in three severely ill patients with perturbed consciousness (two of whom received the drug by nasogastric tube). Possible mechanisms for these observations are discussed. Pyrimethamine levels may be an important determinant of the rate of response to treatment by AIDS patients with toxoplasmosis: therapeutic drug monitoring may have a role.

Cardiac complications of halofantrine: a prospective study of 20 patients.

Halofantrine, increasingly used for treatment of Plasmodium falciparum malaria, is a normally well-tolerated amino-alcohol with very few side-effects, but torsades de pointes ventricular tachycardia due to halofantrine has been reported in a few patients with a congenital long QT interval (Romano-Ward syndrome). We performed a prospective study of the cardiac effect of halofantrine in 20 patients with 48 h ambulatory electrocardiographic (ECG) monitoring; the halofantrine levels in their serum were also determined. Minimal ECG changes were noted, with lengthening of the QT interval without clinical symptoms. This effect was dose-dependent and can be very severe in cases of pre-existing cardiopathy; it also occurs in patients without any pre-existing cardiopathy. In order to reduce the likelihood of such incidents, which are admittedly rare, we suggest performing electrocardiography on all patients before initiating treatment with halofantrine.