The safety, tolerability and pharmacokinetics of levamisole alone, levamisole plus ivermectin, and levamisole plus albendazole, and their efficacy against Onchocerca volvulus.

Two randomized, double-blind, placebo-controlled trials, in which levamisole (2.5 mg/kg) was given alone or co-administered with ivermectin (200 microg/kg) or albendazole (400 mg), were conducted. In Trial 1, safety and drug-drug interaction were explored in 42 healthy male volunteers. During Trial 2, the safety of the same treatment regimens and their efficacy against the adult worms and microfilariae of Onchocerca volvulus were investigated in 66 infected subjects of both sexes. Safety was determined from the results of detailed clinical and laboratory examinations before treatment, during hospitalization and on day 30. The pharmacokinetic parameters for levamisole alone and the combinations were determined in Trial 1 and then compared with historical data for ivermectin and albendazole, given as single agents, to determine if drug-drug interaction had occurred. The level of efficacy against the adult worms was determined by the examination of histology sections of nodules excised 6 months posttreatment and from the changes seen in the levels of microfilaridermia within a year of treatment. Microfilaricidal efficacy was estimated from the reductions in the levels of microfilaridermia between day 0 (1 day pre-treatment) and day 30. Although the regimens were generally well tolerated, there were unexpected adverse effects in both healthy volunteers and infected subjects. Clinically significant drug-drug interactions resulted in an increase in the bio-availability of ivermectin but a reduction in that of albendazole when these drugs were co-administered with levamisole. Levamisole given alone or with albendazole had little effect on O. volvulus. The combination of levamisole with ivermectin was neither macrofilaricidal nor more effective against the microfilariae and the adult worms than ivermectin alone. The pathogenesis of the adverse events and the drug-drug interactions are discussed.

Thirty-month follow-up of sub-optimal responders to multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana.

The pathogenesis of the sub-optimal response of Onchocerca volvulus to ivermectin was investigated in a 30-month follow-up of 28 individuals who, in a previous study, had been found to show a sub-optimal (N = 15) or adequate response (N = 13) to multiple treatments with the drug. Verbal informed consent was obtained before each subject was given a general clinical and ocular examination. Skin snips were taken from both iliac crests and both calves. Seventeen nodule carriers were hospitalized for nodulectomy. Adult worms were harvested, embryogrammes were constructed and all developmental stages were counted; degenerate, stretched microfilariae were noted separately. All the subjects were in good general health and all except one had received at least one additional treatment with ivermectin since the earlier study. A large proportion of the adult female worms in 10 out of the 11 sub-optimal responders who were nodule carriers were in full embryonic production but most of the stretched microfilariae they carried were degenerate. This picture is similar to that found in adult worms exposed to the first dose of ivermectin. In one subject who had no viable worms in his nodules, the existence of occult but actively reproductive worms was inferred from the high level of microfilaridermia observed less than 12 months after treatment. These observations confirm the existence of populations of adult female O. volvulus that respond poorly to repeated doses of ivermectin. The use of suramin in the treatment of the sub-optimal responders is discussed.

An investigation of persistent microfilaridermias despite multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana.

If ivermectin-based programmes for the control of human onchocerciasis are to be successful, the drug must remain effective for as long as necessary. In an open, case-control study, an attempt was made to determine if the persistent, significant, Onchocerca volvulus microfilaridermias seen in some individuals who had received at least nine treatments with ivermectin were the result of the development of drug resistance in the parasite. Twenty-one of these 'sub-optimal' responders (cases) were matched, by age, weight, number of treatments, locality and skin microfilarial counts, with seven amicrofilaridermic responders and 14 ivermectin-naive subjects. The number of treatments taken, any potential drug interactions and significant underlying disease were determined from detailed clinical and laboratory studies. Each subject was treated with ivermectin during the study, so that plasma concentrations of the drug could be determined for 72 h from the time of dosage. The microfilarial and adult-worm responses to this treatment were assessed from skin microfilarial counts (obtained before the treatment and at days 8, 90 and 365 post-treatment), day-90 embryogrammes, and the results of fly-feeding experiments. Parasite-sensitivity criteria for various time-points were derived from earlier data on skin microfilaridermias and the effects of ivermectin on the adult worms. The results indicate that the significant microfilaridermias that persist despite multiple treatments with ivermectin are mainly attributable to the non-response of the adult female worms and not to inadequate drug exposure or other factors. The possibility that some adult female worms have developed resistance to ivermectin cannot be excluded. These results justify the routine monitoring of treatment efficacy in any ivermectin-based programme of disease control.

The co-administration of ivermectin and albendazole--safety, pharmacokinetics and efficacy against Onchocerca volvulus.

A randomized, double-blind, placebo-controlled trial was conducted, to determine whether the co-administration of ivermectin with albendazole is safe and more effective against Onchocerca volvulus than ivermectin alone, and whether a significant pharmacokinetic interaction occurs. Forty-two male onchocerciasis patients received ivermectin (200 mug/kg) alone, albendazole (400 mg) alone or the combination. Safety was determined from the results of detailed clinical and laboratory examinations before treatment, during hospitalization and on day 30. Microfilaricidal efficacy was estimated from the reductions in skin counts between day 0 (pretreatment) and day 30. To determine efficacy against the adult worms, two independent observers examined histology slides prepared from nodules excised on day 180; changes in the skin counts of skin microfilariae between days 30 and 365 provided additional indicators of the level of adulticidal activity. Pharmacokinetic parameters for ivermectin and albendazole sulphoxide were defined over 72 h post-treatment. The co-administration of ivermectin with albendazole did not produce more severe adverse effects than ivermectin alone. Both nodule examiners found that the combination was not macrofilaricidal and that it was not clearly superior to ivermectin alone in the effects on reproductive activity; this was supported by the similar efficacy of the two regimens in the suppression of skin microfilariae. There was no significant pharmacokinetic interaction. Although the co-administration of ivermectin with albendazole appears safe, it offers no advantage over ivermectin alone in the control of onchocerciasis. The combination does not require an alteration in the dosage of either component.

The effects of high-dose ivermectin regimens on Onchocerca volvulus in onchocerciasis patients.

Ivermectin, at the standard dose of 150 micrograms/kg bodyweight, does not kill the adult worms of Onchocerca volvulus and does not disrupt embryogenesis or spermatogenesis. Repeated standard doses, if maintained, arrest microfilarial production but result in only a mild-to-modest macrofilaricidal effect. We investigated whether high doses would effectively kill the adult worms, and whether cessation of microfilarial production could be reproduced by an equivalent, single, high dose. One hundred men participated in a double-blind placebo-controlled trial and received increasing doses of ivermectin from 150 micrograms/kg to 1600 micrograms/kg bodyweight. Nodules were excised at day 180 and examined by histopathology. Total doses of ivermectin up to 1600 micrograms/kg were not significantly more effective than 150 micrograms/kg. Moreover, they did not reproduce the marked inhibitory effects of the repeat standard-dose regimens on embryogenesis, nor the modest effect on adult worm viability, at comparable total doses. These effects may be functions of multiplicities of dosages rather than of the total dose. Our findings also suggest that repeated high-dose regimens are unlikely to be more effective than a similar number of 150 micrograms/kg doses. This deficiency of ivermectin requires that the search for macrofilaricides remains a top priority.

The safety and efficacy of amocarzine in African onchocerciasis and the influence of ivermectin on the clinical and parasitological response to treatment.

The hundred men from a forest area of Ghana, without vector control or ivermectin distribution, were randomized to receive a single dose of ivermectin (150 micrograms/kg body weight) on day 1 followed by amocarzine (3 mg/kg twice daily after meals) on days 8, 9 and 10 (34 patients), the ivermectin alone (33 patients) or the amocarzine alone (33 patients). Detailed clinical and laboratory examinations were made before, during and after drug administration. On day 120, all palpable nodules were excised, fixed, sectioned, stained and examined by two blinded observers and the results compared with those for nodules from untreated controls. Mazzotti-type reactions, such as itching, rash, peripheral sensory phenomena and swellings, were more severe or frequent with amocarzine than ivermectin. Pretreatment with ivermectin markedly suppressed these reactions to amocarzine but did not affect other manifestations such as dizziness and gaze-evoked nystagmus. Ocular effects were minor in all groups. Ivermectin produced minor macrofilaricidal effects on the adult male worms, marked degeneration of intra-uterine embryos, and potent microfilaricidal effects and suppressed skin microfilariae. Amocarzine did not affect the male worms or the intra-uterine embryos, was a less potent microfilaricide and did not suppress skin microfilariae. The efficacy of ivermectin plus amocarzine was similar to that of ivermectin alone. The present results do not support the findings from the Americas and show that amocarzine has no role in the treatment of onchocerciasis in Africa.

The chemotherapy of onchocerciasis XX: ivermectin in combination with albendazole.

Ivermectin is a potent microfilaricide that also blocks microfilarial release while albendazole is toxic to all intrauterine stages. We investigated whether their combination would permanently sterilize the adult worms. In the first open phase, all 69 patients received 150 micrograms/kg of ivermectin. In the second double-blind phase one week later, 35 patients were randomized to receive 800 mg of albendazole with a fatty breakfast for three consecutive days while 34 patients received matching placebo tablets. Detailed clinical and laboratory examinations were done before treatment and were repeated at intervals over one year. Nodules were excised at three and six months. There was a rapid reduction in skin microfilariae, maximal at four weeks (99.9%). Counts increased subsequently and were between 11 and 18% of initial values at one year. Nodule histology showed no macrofilaricidal activity of the combination. A high proportion of the stretched intrauterine microfilariae were degenerate in both groups. Anterior chamber microfilarial counts were unchanged until day 18 and then fell successively. Low levels persisted in several patients at one year. Dead corneal microfilariae and corneal punctate opacities increased initially, fell with time and then disappeared in most patients. Systemic and ocular reactions were mild to moderate and biochemical abnormalities were minor. A pronounced posttreatment eosinophilia subsided by day 30. There was no significant difference between the two groups in clinical and laboratory tolerance or in alterations in skin and ocular parasites and no important differences in the effect on the adult worms. The combination of ivermectin with albendazole given one week apart is well tolerated but produces no additional effect against Onchocerca volvulus when compared to ivermectin given alone.

The chemotherapy of onchocerciasis. XIX: The clinical and laboratory tolerance of high dose ivermectin.

Ivermectin is the drug of choice for the treatment of onchocerciasis. However at the recommended dose of 150 micrograms/kg, it neither kills nor permanently sterilises the adult worms. We investigated whether high doses given with and without a preceding 150 micrograms/kg 'clearing' dose would be tolerable as well as effective against the adult worms. Seventy-five healthy males with moderate to heavy infections with Onchocerca volvulus were enrolled in a double-blind trial to receive one of the following treatment regimens: 150 micrograms/kg followed by placebo (9 patients); 400 micrograms/kg with (9 patients) or without (16 patients) a clearing dose; 600 micrograms/kg with (8 patients) or without (16 patients) a clearing dose and 800 micrograms/kg with (8 patients) or without (9 patients) a clearing dose. Detailed examinations were conducted before and at various times after treatment. A preliminary report on the clinical and laboratory safety as at 30 days is presented. All the regimens were well tolerated. No clinical or laboratory drug related effects were observed. The overall severity of the Mazzotti reaction was similar in all groups. Ocular reactions were minimal and there were no changes in ocular function or in fluorescein angiograms. The groups were similar in the extent of microfilaricidal activity; there was however a suggestion that microfilariae were killed more rapidly at 400 micrograms/kg and 600 micrograms/kg but not at 800 micrograms/kg. This needs further study. Single doses of ivermectin up to 800 micrograms/kg are well tolerated; no special precautions for treatment monitoring are required and a 'clearing' dose is not necessary.

The chemotherapy of onchocerciasis XVIII. Aspects of treatment with suramin.

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.

The chemotherapy of onchocerciasis XVII. A clinical evaluation of albendazole in patients with onchocerciasis; effects of food and pretreatment with ivermectin on drug response and pharmacokinetics.

Three pharmacokinetic studies were conducted in Ghanaian patients in support of investigations of albendazole and its combination with ivermectin in the treatment of onchocerciasis. These included dose-finding studies, investigations into the influence of a fatty meal on the relative bioavailability of albendazole as assessed by the measurement of concentrations of albendazole sulphoxide and the effect of prior treatment with ivermectin on antiparasitic efficacy and plasma concentrations of albendazole suphoxide. Increasing the dose of albendazole from 800 mg x 3 daily to 1200 mg x 3 daily produced no additional antiparasitic effects although plasma concentrations of albendazole sulphoxide were increased in proportion to dose size. Moreover, the plasma concentration vs time profiles suggest that most of the effects observed may have been due to the first 800 mg dose. Administration of ivermectin had no effect on the pharmacokinetics of albendazole sulphoxide and there was no additive effect on the parasite. Albendazole was well tolerated and its administration 5-7 days after ivermectin produced little additional reaction. Although it is not macrofilaricidal, it does possess important chemosterilant properties which are enhanced by its administration with a fatty breakfast. Under these conditions, the relative bioavailability of albendazole is increased four-fold. These studies support further work with albendazole administered with food either as a single dose, as multiple single doses repeated at intervals of several months and its coadministration with ivermectin. They also encourage the belief that a more potent and bioavailable benzimidazole may be macrofilaricidal or a permanent chemosterilant for Onchocerca volvulus on single dosage.

A community trial of ivermectin in the onchocerciasis focus of Asubende, Ghana. II. Adverse reactions.

A community trial of the microfilaricide ivermectin undertaken in an hyperendemic focus of blinding onchocerciasis in Ghana. One objective was to investigate the safety of this new drug when used in mass treatments. 14,911 persons (61.5% of the census population) were treated with ivermectin. Of these, 15% reported with adverse reactions which were generally similar to those reported in the clinical trials. However, cutaneous reactions were relatively less frequent while brawny oedema of the limbs and inguinal gland pain were important. The severe reactions consisted of 37 cases of Severe Symptomatic Postural Hypotension (SSPH), 13 cases of severe fever and two cases of severe dyspnoea. The latter two cases represented life threatening situations, but there was no evidence that they were complications of ivermectin treatment. Only four of the SSPH cases required treatment. All severe adverse reactions were managed successfully and recovered within one day, usually within a few hours. The incidence of adverse reactions was highest the first day after treatment. Thirteen cases of delayed reactions were reported during a four-week follow-up. There was a highly significant relationship between incidence of adverse reactions and intensity of infection but no relation with ivermectin dosage within the range of 130-200 mcg/kg. The results suggest that ivermectin is sufficiently safe to be used in mass treatments. However, mass distribution of this drug should not be undertaken without adequate monitoring.