Evaluation of ultrasonography for the detection of drug-induced changes in onchocercal nodules.

Clinical trials of macrofilaricidal drugs against Onchocerca volvulus are impeded due to the lack of means for assessing in vivo drug-induced changes in the onchocercomas. The application of ultrasonography in the sequential monitoring of morphologic alterations of onchocercal nodules after six weeks of suramin therapy was evaluated in 20 male patients from Ghana with a total of 64 nodule sites. After each follow-up session, a number of onchocercal nodules were extirpated so that by the end of one year, all nodules had been removed for histologic examination. The sonomorphologic changes observed and their time of appearance correlated well with the histologic findings of the onchocercomas. Eighty-three percent of the onchocercal nodules became hyperechogenic and 22% developed echo-free areas at the end of the follow-up period. Absence of the lateral acoustic shadow increased by more than 30% and the lack of differentiation of the worm center from the capsule and the nodule from its surrounding tissue increased by the end of one-year posttreatment to 100% and 91%, respectively. A mean reduction of nodule size of 27% was also documented. The histologic studies revealed that the proportion of the dead female worms increased from 17% at the end of the suramin therapy to 48% six months later and reached 61% at one year. It is concluded that ultrasonographic monitoring of onchocercomas can provide essential information on drug effects and facilitate clinical trials of macrofilaricidal drugs, limiting histologic evaluation to a few objectively selected onchocercomas.

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.

The black disease of Arabia, Sowda-onchocerciasis. New findings.

Sowda, the localized asymmetrical lesion of onchocerciasis endemic in Yemen and Southern Saudi Arabia, is characterized by hyperpigmented lichenified papular lesions on one leg with intense pruritus. There is enlargement of femoral and inguinal lymph glands. In our study, even the long standing cases do not show elephantiasis of the leg or genitalia. Microfilaria appeared to be scarce and adult worms could not be detected clinically, as well as by ultrasonography (except in one case). There was no significant lymphatic obstruction; such cases were studied by contrast lymphangiography and isotope lymphangiography.

Ultrasonographical investigations of onchocerciasis in Liberia.

The efficiency of ultrasonography (US) for the diagnosis and clinical characterization of onchocerciasis was evaluated. US was performed on 120 probands in Liberia. Ninety-two patients had generalized onchocerciasis, 21 patients suffered from the chronic hyperreactive form of onchocerciasis (sowda), and 7 probands served as controls. Patients were examined by US with linear (7.5 MHz and 5 MHz) and sector (3.5 MHz) scanners. US results were evaluated by examination of extirpated nodules. The US structure of nodules revealed a typical pattern consisting of a homogeneous echogenicity with small echodense particles and a lateral acoustic shadow, and differentiation from lymph nodes, lipoma, or fibroma was achieved. Within the onchocercomata, calcifications or fluid were identified. Regarding the estimation of the worm burden, it is important to note that in 24 patients, additional nodules not previously palpated were found by US. Also, the number of worm centers in palpable conglomerate nodules were determined more exactly by US than by palpation. In 4 of 16 sowda patients, impalpable nodules were found by US. In 13 patients with positive microfilaria counts, no nodules could be detected. The highly characteristic ultrasonographical pattern of onchocercomata may serve as a basis for further US investigations in onchocerciasis.

[Lymphographic and morphological studies of the conjunctiva in onchocerciasis patients in Liberia]. / Lymphographische und morphologische Untersuchung der Bindehaut von Onchozerkosepatienten in Liberia.

Conjunctival lymphographies in patients infected with Onchocerca volvulus in Liberia showed normal or only slightly dilated lymphatics. The light-microscopical studies of conjunctival specimens revealed microfilariae predominantly in edematous dilated interstitial channels. Microfilariae in lymphatics and interstitial channels without endothelium of the conjunctivae were demonstrated by scanning and transmission electron microscopy. No signs of inflammatory cellular reaction were found in the vicinity of the parasites. In conclusion, the dilatation of lymphatics and interstitial channels as well as the pathways along which the microfilarial penetrated the cornea and the anterior segments of the eye are discussed.

[Results of lymphography in 13 cases of onchocerciasis]. / Intéret de la lymphographie dans 13 cas d'onchocercose.

Systematic lymphographic studies in 13 cases of infection with Onchocerca volvulus have enabled a "lymphographic diagram" to be made for each infected patient. The images obtained are similar to those observed in wuchereriasis. The microfilariae in onchocerciasis, however, are not transmitted in the lymphatic system, and the lesions, which vary according to the degree of infestation, show little progression. They are found mainly in the inguino-crural ganglia which are the first main ganglionic relay system for the lower limbs.