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We report the clinical and parasitological effects of a modified treatment regimen for suramin. Twenty adult males received up to 5 g (72.5 to 84.7 mg/kg) of suramin over 36 days. Detailed clinical and laboratory examinations were done before treatment and then at intervals over 2 years. Nodules were removed at 6, 13, 26 and 52 weeks for histology. Systemic tolerance was good. Anterior segment inflammation was however common and 2 patients required intervention to prevent posterior synechiae. No new posterior segment lesions developed; a rare improvement occurred in one patient with papillitis. Proteinuria, mostly mild, occurred in nearly all patients. Previously unreported renal glycosuria was documented in one patient. Microfilariae in the skin and anterior chamber did not change significantly for 5 or more weeks after which rapid reductions occurred. Ocular parasites were absent at 2 years and skin microfilariae were near zero. Peripheral blood eosinophil counts fell in parallel with those of microfilariae in the skin and anterior chamber and were normal at one and two years. These findings at 2 years may provide indirect evidence of a macrofilaricidal or a permanent chemosterilant effect on the adult worms. Nodule examination revealed an embryotoxic effect from week 6, a lethal effect on the male worms from month 3 and on the female worms from month 6 after treatment started. At one year 34% of the female worms examined were alive. Thus total doses of suramin in the range 72.5 to 84.7 mg/kg have only a modest lethal effect on the female worms. Suramin remains a restricted drug and a suitable replacement is urgently needed.

Peripheral blood leukocytes from chimpanzees experimentally infected with third stage larvae, or with nodular microfilaria (mf) of Onchocerca volvulus, were evaluated for their ability to kill nodular mf in vitro. Inoculation of chimpanzees with third stage larvae, and prospective follow up, permitted each animal to be classified as patent, infected but not patent, or post-patent. Neither lymphocytes nor monocytes significantly adhered to, immobilized, or killed mf. However, neutrophils or eosinophils killed mf effectively in the presence of immune serum. Neutrophil and eosinophil enriched cell preparations from control animals were able to kill mf with serum from infected animals, but to a significantly lesser degree than when both cells and serum were taken from infected animals. Chimpanzees inoculated with mf showed a progressive increase in cellular killing of mf after a second inoculation which surpassed that seen with animals inoculated with third stage larvae. Antibody-mediated killing of mf by neutrophils and eosinophils may be important in the termination of patency in this infection.

Microfilariae of Onchocerca volvulus were found in the cerebrospinal fluid (CSF) of 5/8 heavily infected onchocerciasis patients. During treatment with diethylcarbamazine citrate 10/11 patients showed increased numbers of 0. volvulus microfilariae in the CSF. Patients with concentrations of 8-31 mf/ml CSF developed severe vertigo, and some other neurological manifestations, during treatment. A hypothesis is put forward to account for this clinical piciture, and its importance in relation to the treatment of onchocerciasis is discussed.

During treatment with suramin the numbers of O. volvulus microfilariae in the blood, urine, sputum, and anterior chambers of the eye fell before those in the skin. When diethylcarbamazine (DEC) was given after suramin, increased numbers of microfilariae appeared in the blood, urine, cerebrospinal fluid (CSF) and sputum, but the increase in the blood was less marked, and of shorter duration, than in similar patients receiving DEC without previous suramin. Microfilariae are thought to enter the urine, sputum and CSF directly from the blood by penetrating the capillary walls in the glomeruli, pulmonary alveoli, and choroid plexuses. Those in the aqueous humour do not appear to come directly from the bloodstream. The total numbers of microfilariae in the skin of some heavily infected onchocerciasis patients are estimated, as are the total numbers moving into the blood-stream under the influence of DEC and the proportion which escape into the urine, sputum and CSF. It is concluded that the majority of the microfilariae which appear in the blood during DEC therapy must be destroyed in the body, probably in the liver.

The effect of various substances on the output of Onchocerca volvulus microfilariae in the urine was investigated in volunteers infected with the Cameroon forest and Sudan-savanna strains of the parasite. Output of microfilariae in the urine tended to be higher during periods of normal activity than during sleep. During waking hours, the rate of output remained generally steady, but in some patients occasional showers of microfilariae appeared in the urine, possibly associated with the intake of food and drink. Drinking 1.2-2.5 litres water produced a shower of microfilariae in the urine of some subjects. This began within an hour of drinking and its onset preceeded that of the diuresis. Thiazide diuretics, acting on the convoluted tubules, produced no increase in microfilaruria. In savanna subjects intravenous injection of DT TAB vaccine caused pyrexia, and simultaneously large numbers of microfilariae appeared in the urine. There was no associated diuresis, and no increase in the concentration of microfilariae in the venous blood. In forest subjects DT TAB caused no increase in microfilaruria. In all subjects 25-50 mg diethylcarbamazine (DEC) caused large numbers of microfilariae to appear in the urine on day 0, within a few hours of the first dose; and there was an increased output of urine over the first 24 hours. Microfilaruria declined sharply on day 1 of treatment, but in subjects developing a high microfilaraemia, it rose again on day 2, and declined more slowly thereafter. Betamethazone, given in conjunction with DEC, appeared to slow the rate of destruction of microfilariae in the skin and lymph glands, and to prolong the duration of microfilaraemia and microfilaruria. The findings suggest that there is a reservoir of microfilariae in the glomerular capillaries, which fills slowly by accumulating microfilariae from the circulating blood. The microfilariae probably enter the urine by penetrating the glomerular capillary.