RESUMO
Twenty male patients from Guatemala infected with Onchocerca volvulus received a 3 mg/kg oral dose of amocarzine twice daily for three days. The patients were randomly assigned to the sequence fasting/non-fasting and non-fasting/fasting for the morning administration on days 1 and 3. All other doses were given after food intake. Blood samples on days 1 and 3 and urine fractions from days 3 to 5 were collected for the determination of the unchanged drug and of its N-oxide metabolite, CGP 13 231. The absorption of amocarzine and CGP 13 231 was slower and sustained for longer time in fed patients than in fasting ones. The mean AUC of amocarzine was significantly higher (about 20%) in fed patients. No significant difference was found for CGP 13 231. The relative improvement of bioavailability of amocarzine due to food was less prominent than previously obtained after a high dose of 1200 mg which demonstrated a bioavailability improvement of a factor of three. Therefore, saturable dose dependent absorption processes are likely to be involved for the administration in fasting conditions. Conversely, the concentrations of amocarzine in fed patients after 150 and 1200 mg were dose proportional, thus indicating linear kinetics. The cumulative urinary excretions of CGP 6140 ranged from 0.1 to 3.8% of the daily dose. Those of CGP 13 231 ranged from 31 to 64%. This total excretion was larger than that previously recorded in fasting patients after a single oral dose. The present results confirm the improvement of the bioavailability of the drug administered after food intake.
Assuntos
Filaricidas/farmacocinética , Alimentos , Piperazinas/farmacocinética , Absorção , Administração Oral , Adulto , Disponibilidade Biológica , Jejum/fisiologia , Filaricidas/administração & dosagem , Filaricidas/uso terapêutico , Guatemala , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/uso terapêuticoRESUMO
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.