Amocarzine investigated as oral onchocercacidal drug in 272 adult male patients from Guatemala / Amocarzina investigada con droga oral antioncercosa 272 adultos pacientes hombres de Guatemala

ABSTRACT

The clinical investigations with three types of a three days regimen of amocarzine permitted to adjust the fixed dosing to the body weight related dosing and subsequently the adminstration of amocarzine from fasting state to drug intake after food. The main objective to reach a dose woth predictable and sustained absorption was achieved, and this in turn proved to be onchocercacidal and safe. A combined clinicopharmacokinetic study showed enhancement and consistency of amocarzine absorption after food. Quantitative assessment of the urinary excretion confirmed presence of the N-oxide metabolite, which qualitatively was visible by a urine colorimetry. This assay proved useful for drug monitoring. Ultrasonography of onchocercal skin nodules detected changes within the nodules following amocarzine therapy. Histology agter nodul-ectomy at four months post-therapy showed thal 57% of the female worms were dead, 24% necrobiotic, and 19% alive; male worms were more necrobiotic. Skin microfilariae were reduced within one week to about 10% of the initial level and after one year they remained at about 20%. Skin punch biopsies on day 5 showed that most microfilariae were dead or moribund. Ocular reduction of microfilariae was also observed, althought it was slower than in the skin. The visual acuity improved within the one year's observation time. Ocular and clinical tolerability was good, with one exception of neurological disturbance, which was fully reversible. Se quential testing of the liver function showed average values within the normal range. In conclusion, a repeat low dose regimen of amocarzine (3 mg/Kg twice daily postprandially for three consecutive days) was well absorbed with predictable plasma levels, macro-and microfilaricidal with good local and systemic tolerability in patients with moderate to heavy onchocerciasis. Amorcarzine is recommended for further clinical investigations, particularly inf emales and juveniles. Urine colorimetry and nodular ultrasonography are recommended for optional monitoring of amocarzine