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

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

Amocarzine investigated as oral onchocercacidal drug in 272 adult male patients from Guatemala. Results from three dose regimens spread over three days.

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 administration of amocarzine from fasting state to drug intake after food. The main objective to reach a dose with 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 the 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 after nodul-ectomy at four months post-therapy showed that 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, although 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. Sequential 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 post-prandially 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 in females and juveniles. Urine colorimetry and nodular ultrasonography are recommended for optional monitoring of amocarzine.

Use of an ophthalmologic ultrasoundscanner in human onchocercal skin nodules for non-invasive sequential assessment during a macrofilaricidal trial with amocarzine in Guatemala. The first experiences.

Ultrasonography of onchocercal skin nodules was performed with an ophthalmologic real time linear scanner with a B probe of 10 MHz. A clinical trial in Guatemala with amocarzine (CGP 6140)--a new oral macrofilaricidal compound--investigated three repeat dose regimens and one placebo control group, each group consisting of six patients. Onchocercal nodules were scanned before treatment and on day 10, 30 and 60 after start of amocarzine. A total of 28 treated and 8 additional untreated nodules were analysed and compared with the histologic findings following nodulectomy at day 60. Of the 28 treated nodules, 21 were of onchocercal origin and seven were lymph nodes. The correlation between ultrasonography and histology was good in 25 patients, but did not match in three. In 20 out of 21 treated nodules a progressive ultrasonographic change over two months was seen. Of the eight additional untreated nodules, five were of onchocercal origin, one was a lymph node, one an epidermoid cyst and in one only fibrous tissue was detected. The ultrasonography correlated well to histology in seven nodules but not in one. In five onchocercal nodules no change was observed over two months. For initial control purposes six nodules were excised around day 10, four were of onchocercal origin and two were lymph nodes. The correlation was good in four. The present results indicate that an ophthalmologic real time linear scanner can be used in the bidimensional mode as a non-invasive method to assess sequentially the events in superficial onchocercal nodules following chemotherapy with amocarzine. This is the first objective non-invasive method permitting sequential assessment of the content of onchocercal nodules and it is far superior than subjective sequential manual palpation.

Onchocercacidal effects of amocarzine (CGP 6140) in Latin America.

An open clinical trial of amocarzine was carried out in onchocerciasis patients in Ecuador and Guatemala. Administration after food was more effective than that during fasting. The most effective and best tolerated regimen, 3 mg/kg twice daily after food for 3 days (in 312 patients), killed 73% of 1477 female worms at nodulectomy 4 months after treatment. The mean microfilarial skin count was greatly reduced within a week (6-11% Of day 0 value on day 8) and it remained low at least 6 months (14-18% on day 180). Follow-up of a higher dose 3 day regimen taken while fasting showed microfilaridermia of 7-9% of the day 0 value 2 years after treatment.

The Onchocerca volvulus micro- and macrofilarial responses in onchocerciasis patients to increased dosage of diethylcarbamazine.

The response of 45 severely infected onchocerciasis patients to relatively high doses of diethylcarbamazine citrate (DEC-C) has been determined. The treatment comprised two sequential phases; the first phase comprised the topical applications of a DEC-C lotion and of the anti-inflammatory steroid betamethasone. The second phase comprised the daily oral administration of high doses of DEC-C (30 mg/kg body wt) for seven days. Onchocerca volvulus microfilarial (o.v.mf.) counts in skin snips of the 45 patients decreased by 96 +/- 1.5% after 5 days of treatment with topical DEC-C lotion. Following the administration of oral DEC, the average O.v.mf. counts in the skin snips at days 51, 97, and 143 remained decreased by 85 to 93%. The mean O.v.mf. counts in 10 nodules excised from 5 treated patients at day 77 had decreased by 93% compared to the mean O.v.mf. counts in 11 nodules taken from 5 untreated patients with similar initial O.v.mf. infection. No visual loss resulted from the treatment.

Chemotherapy of onchocerciasis: a controlled clinical trial of topical diethylcarbamazine (DEC) in Guatemala.

A double-masked, controlled clinical trial was conducted in Guatemala to assess the safety and efficacy of diethylcarbamazine (DEC) lotion as compared to placebo lotion in the treatment of onchocerciasis. One hundred eighty-seven people were enrolled in this study and were followed for two months. Lotion was applied daily for seven days, then weekly for seven weeks. The decrease in mean microfilarial counts per skin snip was significantly greater in those receiving DEC lotion than for those receiving placebo lotion. The proportionate reduction in microfilarial counts was similar for people with light, moderate, or heavy microfilarial loads. Side effects were mainly related to skin changes, fever, and malaise, and occurred in nearly one-third of the people receiving DEC lotion. These reactions occurred almost as commonly in those people who were lightly infected as in those who had moderate or heavy infections.