If ivermectin-based programmes for the control of human onchocerciasis are to be successful, the drug must remain effective for as long as necessary. In an open, case-control study, an attempt was made to determine if the persistent, significant, Onchocerca volvulus microfilaridermias seen in some individuals who had received at least nine treatments with ivermectin were the result of the development of drug resistance in the parasite. Twenty-one of these 'sub-optimal' responders (cases) were matched, by age, weight, number of treatments, locality and skin microfilarial counts, with seven amicrofilaridermic responders and 14 ivermectin-naive subjects. The number of treatments taken, any potential drug interactions and significant underlying disease were determined from detailed clinical and laboratory studies. Each subject was treated with ivermectin during the study, so that plasma concentrations of the drug could be determined for 72 h from the time of dosage. The microfilarial and adult-worm responses to this treatment were assessed from skin microfilarial counts (obtained before the treatment and at days 8, 90 and 365 post-treatment), day-90 embryogrammes, and the results of fly-feeding experiments. Parasite-sensitivity criteria for various time-points were derived from earlier data on skin microfilaridermias and the effects of ivermectin on the adult worms. The results indicate that the significant microfilaridermias that persist despite multiple treatments with ivermectin are mainly attributable to the non-response of the adult female worms and not to inadequate drug exposure or other factors. The possibility that some adult female worms have developed resistance to ivermectin cannot be excluded. These results justify the routine monitoring of treatment efficacy in any ivermectin-based programme of disease control.

A method is described for the simultaneous determination of the carboxylic acid and N‐acetyl‐derivatives of primaquine, in plasma and urine. After oral administration of 45 mg primaquine, to five healthy volunteers, absorption was rapid, with peak primaquine levels of 153.3 +/‐ 23.5 ng/ml at 3 +/‐ 1 h, followed by an elimination half‐life of 7.1 +/‐ 1.6 h, systemic clearance of 21.1 +/‐ 7.1 l/h, volume of distribution of 205 +/‐ 371 and cumulative urinary excretion of 1.3 +/‐ 0.9% of the dose. Primaquine underwent rapid conversion to the carboxylic acid metabolite of primaquine, which achieved peak levels of 1427 +/‐ 307 ng/ml at 7 +/‐ 4 h. Levels of this metabolite were sustained in excess of 1000 ng/ml for the 24 h study period, and no carboxyprimaquine was recovered in urine. N‐acetyl primaquine was not detected in plasma or urine. Following [14C]‐primaquine administration to one subject, plasma radioactivity levels rapidly exceeded primaquine concentrations. Plasma radioactivity was accounted for mainly as carboxyprimaquine . Though 64% of the dose was recovered over 143 h, as [14C]‐radioactivity in urine, only 3.6% was due to primaquine. As neither carboxyprimaquine nor N‐ acetylprimaquine were detected in urine, the remaining radioactivity was due to unidentified metabolites.

ABSTRACT:The aim of this study was to elucidate the metabolic pathways for dihydroartemisinin (DHA), the active metabolite of the artemisinin derivative artesunate (ARTS). Urine was collected from 17 Vietnamese adults with falciparum malaria who had received 120 mg of ARTS i.v., and metabolites were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). ) but not with UGT1A1 or UGT1A6. There was no significant metabolism of DHA by cytochrome-P450 oxidation or by cytosolic sulfotransferases. We conclude that ␣-DHA-G is an important metabolite of DHA in humans and that its formation is catalyzed by UGT1A9 and UGT2B7.

The pathogenesis of the sub-optimal response of Onchocerca volvulus to ivermectin was investigated in a 30-month follow-up of 28 individuals who, in a previous study, had been found to show a sub-optimal (N = 15) or adequate response (N = 13) to multiple treatments with the drug. Verbal informed consent was obtained before each subject was given a general clinical and ocular examination. Skin snips were taken from both iliac crests and both calves. Seventeen nodule carriers were hospitalized for nodulectomy. Adult worms were harvested, embryogrammes were constructed and all developmental stages were counted; degenerate, stretched microfilariae were noted separately. All the subjects were in good general health and all except one had received at least one additional treatment with ivermectin since the earlier study. A large proportion of the adult female worms in 10 out of the 11 sub-optimal responders who were nodule carriers were in full embryonic production but most of the stretched microfilariae they carried were degenerate. This picture is similar to that found in adult worms exposed to the first dose of ivermectin. In one subject who had no viable worms in his nodules, the existence of occult but actively reproductive worms was inferred from the high level of microfilaridermia observed less than 12 months after treatment. These observations confirm the existence of populations of adult female O. volvulus that respond poorly to repeated doses of ivermectin. The use of suramin in the treatment of the sub-optimal responders is discussed.