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Ivermectin is a new drug for treatment of onchocerciasis. Experimental and clinical studies have shown that ivermectin is effective in the treatment of onchocerciasis when given as a single dose of 150 microgram/kilo bodyweight once a year. Ivermectin is registered as Mectizan and is at present supplied free of charge by Merck Sharp & Dohme for treatment programs in 11 developing countries.
Ivermectin (300 micrograms/kg of body weight) was given to swine subcutaneously in the neck to test its efficacy against the kidney worm, Stephanurus dentatus. Two separate field trials were conducted using 146 swine (40 males and 106 females). Urine was obtained before and after treatment and was examined for presence of S dentatus eggs. Stephanurus dentatus eggs were quantitated in positive samples. All treated swine positive for S dentatus eggs in the pretreatment urine samples (n = 54) were negative by 14 to 21 days after treatment with ivermectin. Adverse reactions caused by ivermectin injection were not noticed.
In the first of 2 separate trials, the efficacy of febantel, given at a dosage of 5 mg/kg of body weight, was assessed in calves with 60-day experimentally induced Bunostomum phlebotomum infection. Ten calves were given febantel paste, and 10 were given the vehicle only. All 20 calves were necropsied 7 days after cessation of treatment. Compared with untreated calves, febantel-treated calves harbored 99.4% fewer nematodes. In the second trial, the efficacy of ivermectin, given as a paste formulation at a dosage of 0.2 mg/kg, was assessed in calves with experimentally induced B phlebotomum infection. Ivermectin was given at 18 (n = 6) and 60 (n = 6) days after infection. At each treatment date, 3 additional calves were given vehicle only. At 67 days after infection, all calves were euthanatized. Efficacies of ivermectin against 18- and 60-day infections were 100 and 99.8%, respectively. Both anthelmintic preparations were easily administered, and adverse reactions were not observed.
In a double blind study Ivermectin has been compared to a placebo in 234 male and female with onchocerciasis who had more than 20 microfilariae per milligram of skin and moderate ocular involvement. Patient was randomized to receive a simple oral dose of Ivermectin 100, 150 and 200 micrograms/kg or placebo. The following was 12 months. The decrease of microfilarodermia since to the 3rd day was from 72.8 to 79.3% of initial rate. At six months it was more than 91% and more than 87% in 12 months. Ocular microfilariae, initially between 12 and 23 stay lower than 2 at 12 months. Punctuated keratitis disappear and did not recidive still 6 months in patients with persistent microfilariae. Ivermectin produce only few side effects. Negative waves have been observed on ECG but without any clinical signs. The Power efficient dose seen to be 100 micrograms/kg.
As ivermectin is supposed to have a paralyzing effect, the emergence of Onchocerca volvulus microfilariae from skin snips before and after treatment was examined. Before treatment 79.8% of the microfilariae emerged from the skin snips. Three days after treatment the microfilarial skin density had dropped to 83% (placebo), 28% (100 microgram/kg ivermectin), 19% (150 micrograms/kg) and 14% (200 micrograms/kg) of the pretreatment values but the microfilarial emergence was not altered distinctly. The majority of the remaining microfilariae were mobile and able to leave the biopsy. Only a slight, but significant, dose-dependent trend of reduced emergence could be shown. From our results no direct support is derived for the hypothesis that O. volvulus microfilariae are paralyzed or immobilized by ivermectin.
Twelve Holstein calves were used to determine the prophylactic efficacy of ivermectin against challenge exposure with gastrointestinal and pulmonary nematodes. Two groups of 6 calves (mean body weight, 205 kg) each were formed by restricted randomization according to body weight. Group-1 calves served as nonmedicated controls. Each calf of group 2 was orally given one prototype sustained-release bolus designed to deliver ivermectin at a continuous daily dose of 8 mg. Third-stage nematode infective larvae were given to the calves on posttreatment days 28 and 42. The calves were euthanatized 77 or 78 days after treatment. Ivermectin was 100% effective (P less than 0.05) in preventing the establishment of infection by Haemonchus placei, Ostertagia ostertagi, Cooperia spp (C punctata, C oncophora, C surnabada), Nematodirus helvetianus, Oesophagostomum radiatum, and Dictyocaulus viviparus and was greater than 99% effective against Trichostrongylus axei. Incidental infection by Trichuris spp was reduced by 94% (P = 0.08).
Ivermectin is a synthetic derivative of a macrocyclic lactone produced by an actinomycete Streptomyces avermitilis. It has a broad spectrum antiparasitic activity against nematodes and certain acarians in animals. The microfilaricide action of this product against horse and cattle onchocercosis led to the study of its effects in human onchocercosis against O. volvulus. Several trials performed mainly in endemic zones of Africa showed that this drug was more effective than the reference microfilaricide, diethylcarbamazine. A single oral dose of 200 micrograms/kg of Ivermectin reduces the dermal microfilaria population to nearly zero within a few days and the effect is maintained for at least 6 months. Secondary ocular or systemic effects are rare, negligible and transitory. The prolonged elimination of dermal microfilariasis caused by sequestration followed by degeneration of the microfilaria in the uterus of females raises the hope that Ivermectin used in a single annual or bi-annual dose will contribute to the interruption of the transmission of this serious parasitic disease.
The efficacy of sustained-release ivermectin was evaluated against challenge infestations of gastro-intestinal nematodes in a laboratory study involving 12 treated and 12 untreated control cattle. A weighted, orally administered osmotically activated device designed to lodge in the rumeno-reticulum and to deliver ivermectin at a dosage rate of approximately 8 mg/day for a 120-day period, was administered to treated cattle. Animals were challenged with infective larvae of Bunostomum phlebotomum and Oesophagostomum radiatum approximately 4 weeks, and with Haemonchus placei, Ostertagia ostertagi, Trichostrongylus axei and Cooperia pectinata approximately 4 and 6 weeks after bolus administration. No parasites were recovered from ivermectin-treated animals, representing 100% efficacy (p less than 0.01) against challenge infestations with larvae of all of the above species. Efficacy against an incidental infestation of Trichuris spp was 92% (p less than 0.01).
The eighth generation of adult Haemonchus contortus, selected by subjecting infected pairs of sheep to suboptimal ivermectin treatment once per generation from parent (P; BBH isolate) through F7 (IV-A; selected isolate), required an approximate 4-fold increase in the ivermectin dose to produce 95% efficacy compared with its contemporary parent isolate. In a dose titration experiment the dose-response curve of the drug pressure-derived isolate, IV-A, was significantly (0.02 less than P less than 0.05) less steep than was the response curve of the parent, BBH, isolate. Potency estimates based upon these nonparallel dose-response curves would not remain constant over a range of efficacy levels but would decrease rapidly at efficacies greater than 95%. Passage of a closed population of the F8 generation of IV-A sequentially through pairs of sheep for an additional 11 generations (F8A-F8K) without additional drug pressure being applied produced no reversion to sensitivity to ivermectin relative to the F7 generation, thus suggesting that the selected "resistance" was stable.
A sensitive and specific high performance liquid chromatographic technique is described for the determination of ivermectin in milk. Milk samples (1 ml) were extracted with organic solvent (iso-octane and acetonitrile) and then chromatographed using reversed phase system. Specificity of the assay was confirmed by the use of mass spectrometry. After an subcutaneous administration of ivermectin (0.2 mg/kg) in a cow, ivermectin was detected in milk for about three weeks and over this period milk and plasma concentration were of the same order of magnitude.
At concentrations of 0.1-100 ng/ml ivermectin inhibited L3-L4 molting by Onchocerca lienalis in vitro. The degree of inhibition was dose-dependent with a significant effect apparent at 0.1 ng/ml and complete inhibition occurring at 100 ng/ml. The ED50 for molt inhibition was 0.19 ng/ml. Molt-inhibiting levels of the drug were not acutely toxic to the worms. In the presence of 10 ng/ml, a concentration giving 95% molt inhibition, motility at day 7 postinoculation was 71% of that seen in nontreated controls. A more pronounced effect on motility was apparent in larvae under long-term cultivation in the presence of ivermectin. Kinetic studies indicated that the majority of the larvae respond irreversibly to the drug within the first 2 hr of exposure. Twenty-four hours of exposure were required for a maximal response. The inhibitory effects of ivermectin were less pronounced if larvae were allowed to develop under normal culture conditions for 24 or more hours prior to the initiation of drug treatment.
Anthelmintic efficacies of dichlorvos, fenbendazole, and ivermectin were compared in specific-pathogen-free crossbred weanling pigs inoculated with Ascaris suum, Trichuris suis, and Oesophagostomum dentatum. On postinoculation day (PID) 50, 24 pigs in each treatment group were treated orally with 43 mg of dichlorvos/kg of body weight, 3 X 3 mg of fenbendazole/kg, or 300 micrograms of ivermectin/kg, SC. Twenty-four pigs were not treated. On posttreatment day 7 (PID 57), 12 pigs from each treatment group (phase I) were slaughtered, and the anthelmintic efficacy of each treatment was determined. Efficacies against A suum, T suis, and O dentatum, respectively, were: dichlorvos, 100%, 99.9%, and 100%; fenbendazole, 100%, 99.8%, and 100%; and ivermectin, 98.7%, 53.9%, and 87.6%. Weight gains and feed conversions of the remaining pigs were monitored until they reached market weight (phase II). The average weight gains (kg) and feed conversions (kg of feed/kg of gain) at posttreatment day 81 (PID 131), respectively, were: 73.6 and 3.44 for nontreated controls, 78.9 and 3.31 for dichlorvos-treated pigs, 72.1 and 3.36 for fenbendazole-treated pigs, and 74 and 3.48 for ivermectin-treated pigs. Differences in average weight gains and feed conversions were not significant (P greater than 0.05).
One oral dose of ivermectin successfully rid a dog of Capillaria aerophila that were infecting the nasal passages. Diagnosis was made by finding the eggs in the feces and in the nasal discharge, and or finding the worms in a biopsy specimen taken from the nasal passage. Ivermectin was chosen because of ease of administration, expected efficacy, and minimal expense. Although this dog did not show any of the adverse CNS effects associated with the use of ivermectin, these potential side-effects should be kept in mind any time this anthelmintic is used in dogs.
Nineteen patients from an area of vector control in the savanna region of Northern Ghana, all with moderate to heavy infections with Onchocerca volvulus and some with ocular involvement, were treated with 50, 100, 150 or 200 micrograms kg-1 of ivermectin. Detailed monitoring of clinical and ocular reactions and of alterations in skin microfilarial counts and laboratory indices were carried out during the first 28 days. Microfilarial counts in skin snips and detailed ocular examinations were then repeated at intervals over a period of nine months. Ivermectin slowly eliminated microfilariae from the skin and eye without serious adverse clinical or ocular reactions in all treated groups. There was little difference in efficacy between doses of 100, 150 and 200 micrograms kg-1, and these were more effective than the 50 micrograms kg-1 dose. Very low levels of skin microfilariae were maintained for nine months. Microfilariae were not eliminated from the eye for at least three months. The drug was neither macrofilaricidal nor embryotoxic. However, it produced a dose-dependent stimulation of embryogenesis manifest at one month and succeeded by a suppression of embryogenesis at three months after therapy. In areas where transmission of onchocerciasis has been interrupted, ivermectin may need not be given more often than once a year. The efficacy of the drug on single dosage and the mild adverse reactions produced, if confirmed in subsequent controlled studies, would greatly simplify the treatment of onchocerciasis and would reintroduce new concepts of the role of chemotherapy in the control of onchocerciasis.
A comparison was made of the efficacy of Ivermectin administered as an injection and as a paste. Fourteen horses which were naturally infected with small strongyles were divided into three groups. Animals of group 1 received an injection of 5 ml Ivermectin, equivalent to 500 kg bodyweight, horses of group 2 received one injector with Ivermectin as a paste (for 500 kg body weight), a third group remained untreated as a control. Faecal examinations and larval cultures on the day of treatment and 14, 28 and 42 days later showed that both injection and paste had a 100 percent efficacy against mature and immature small strongyles in these horses.
The efficacy of various formulations of ivermectin administered at the recommended dose rate of 200 micrograms/kg was evaluated in cattle infested with mange mites (Sarcoptes scabiei var. bovis.), lice (Linognathus vituli and Damalinia bovis) and ticks (Boophilus decoloratus, Amblyomma hebraeum, Rhipicephalus appendiculatus and Hyalomma spp.) in 8 trials conducted in South Africa. Mange mites (S. scabiei) were eliminated from animals treated subcutaneously, resulting in marked clinical recovery. Oral administration reduced the numbers of, but did not eliminate these mites. Sucking lice (L. vituli) were eliminated from animals treated orally or subcutaneously. Numbers of biting lice (D. bovis) were reduced but not eliminated, subcutaneous injection being more effective than oral drenching. Subcutaneous injection with ivermectin every 14 d over a period of 84 d significantly reduced numbers of engorged female R. appendiculatus and A. hebraeum. Numbers of Boophilus spp. and Hyalomma spp. were also reduced. A single subcutaneous injection resulted in significantly fewer engorged female B. decoloratus on treated animals for up to 28 d after treatment. In one trial significantly fewer A. hebraeum males occurred on treated animals for up to 28 d after treatment. Too few R. evertsi were present in these trials to evaluate the effect of ivermectin against this parasite.
The efficacy of ivermectin against later fourth-stage Strongylus vulgaris larvae was studied in pony foals at 14 and 35 days after treatment. These foals had been reared parasite-free, inoculated with 500 infective larvae and 56 days later given either ivermectin at 200 micrograms/kg or a placebo intramuscularly. At necropsy, foals were examined for lesions and larvae grossly and histologically. Ivermectin was found to be highly effective (98.6%) against later fourth-stage larvae in five foals which were examined at 35 days after treatment, but not in five others examined at 14 days (72.5%). In some foals larvae were found in the tunica media of the ileocolic arteries. The conformation of these larvae appeared normal, but there were degenerative changes which suggested that they were dying or dead. Questions as to how the larvae attained that site and the consequences of their presence there were raised.
Twelve dairy calves, naturally infected with lungworms and gastrointestinal parasites, were selected for a controlled test with single doses of ivermectin, administered subcutaneously, at the dose rate of 200 micrograms/kg. Specific interest was on efficacy of ivermectin against lungworms (Dictyocaulus viviparus), with ancillary interest directed on abomasal parasites. Ivermectin was administered to 6 calves, and the vehicle only, to 6 calves. At necropsy, 7 days after treatment, lungworms were not recovered from any of the treated calves; nontreated calves, given the vehicle only, were infected with 1 to 46 lungworms each. Removal efficacy against adult Ostertagia ostertagi was 99%. Fourth-stage Ostertagia spp and Trichostrongylus spp and mature Trichostrongylus axei, present in low numbers, were all removed. The fecal egg count for gastrointestinal parasites indicated all eggs, except for a few Nematodirus eggs, were cleared from treated calves. One treated calf showed signs of irritation of the neck at injection site for a short time after treatment and 1 treated calf had a slight indurated area at injection site at necropsy.