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Comparison of the sensitivity of different geographical isolates of Onchocerca volvulus microfilariae to ivermectin: effects of exposure to drug on development in the blackfly Simulium ornatum.

Four geographical isolates (Ghana forest, Ghana savannah, Cameroon forest, Guatemala) of Onchocerca volvulus microfilariae (mf) and O. lienalis mf (UK) were examined for their sensitivity to ivermectin by incubation in vitro in drug followed by assessing their ability to develop in the blackfly Simulium ornatum after intrathoracic injection. Parasites were incubated for 30 min in ivermectin (10(-6) to 10(-9) M), which resulted in a concentration dependent decrease in the numbers of parasites surviving and developing in the insect; there were significant reductions in parasite recoveries from all isolates in the 10(-6) M to 5 x 10(-8) M ivermectin groups, but no significant effect was seen following incubation in concentrations of 10(-8) M and below. Experiments consistently demonstrated that the 4 isolates of O. volvulus were similarly sensitive to ivermectin (in the 10(-7) M ivermectin groups there was a reduction of 76.3% to 85.1% in numbers of infective larvae, and 60.9% to 85.5% in numbers of all larval stages, compared to controls); O. lienalis mf were significantly more sensitive (100% reduction in infective larvae, 98.7% reduction in all larval stages). This baseline information on drug sensitivity and techniques should prove useful for examining populations of O. volvulus for possible development of drug resistance in the future.

Animals↗

The effect of ivermectin treatment on the antibody response to antigens of Onchocerca volvulus.

The effect of the microfilaricidal drug ivermectin on the antibody response to a detergent extract of adult Onchocerca volvulus (OvAg) and a number of specific recombinant peptides was examined. Three of the peptides were combined in a serodiagnostic 'cocktail' and the effect of ivermectin on the diagnostic performance of this assay was assessed. Immunoglobulin (Ig) G1 serum levels in response to OvAg significantly decreased following ivermectin treatment. The antibody response to only one recombinant peptide (OvMBP29) was significantly affected, with IgG levels decreasing following treatment. Levels of total IgE increased following treatment. No correlation was observed between initial antibody level (or change in antibody level) and any adverse reaction to treatment. The serodiagnostic 'cocktail' was 100% sensitive before and after the use of ivermectin. A serodiagnostic assay using specific recombinant peptides can be used to evaluate infection in the absence of dermal microfilariae in areas where ivermectin is used.

Adolescent↗

Comparison of the sensitivity of different geographical races of Onchocerca volvulus microfilariae to ivermectin: studies in vitro.

This study was designed to provide baseline information on the sensitivity of 4 geographical isolates of Onchocerca volvulus microfilariae (mf) (Ghana forest, Ghana savanna, Cameroon forest and Guatemala) to ivermectin, and to develop an in vitro system with which to examine parasites for the possible development of drug resistance. Drug effects were best visualized in the presence of monkey kidney (LLCMK2) feeder cells in the culture system (MEM medium+20% serum), since mf maintained in the absence of cells declined in condition rapidly. Incubation of Ghana forest mf (+cells) in ivermectin (10(-5)-10(-10) M) caused a decrease in motility index (MI) scores in a concentration-dependent fashion; drug effects could be observed as early as 6 h, but cultures maintained for up to 8 d showed greater differences between control and drug groups with increasing time. All 4 O. volvulus isolates and O. lienalis (bovine) were compared for their response to ivermectin (10(-7) M): O. lienalis mf were significantly more sensitive (78%) reduction in MI scores on day 8) than the O. volvulus isolates (33.4-47.7% reduction). O. volvulus microfilariae ex utero generally displayed lower levels of motility and were slightly less inhibited by ivermectin than were skin mf. The in vitro system described can distinguish between the populations of mf studied on the basis of differing MI responses to ivermectin and, when combined with assays to test the infectivity of mf to blackflies following exposure to drug, will provide methods with which to examine parasites for the possible development of resistance.

Animals↗

Community based distribution of ivermectin in eastern Sudan: acceptability and early post-treatment reactions.

A study to monitor ivermectin acceptability and post-treatment reactions during mass community distribution was carried out in eastern Sudan, where severe reactive onchodermatitis is prevalent. Of 1081 individuals eligible for treatment, 1076 (99.5%) accepted the ivermectin. Post-treatment reactions were monitored by self reporting, 5 d after a single dose of about 150 micrograms/kg (range 103-200 micrograms/kg); 230 persons reported adverse events (21.4%). No reaction was rated as severe. The most common problem was itching with cutaneous papular eruptions (16.2%). Local oedematous swelling was the second most common and the most slowly resolving complaint (5.4%), followed by musculoskeletal pain. There was a high acceptance rate of the treatment and remarkable tolerance of the post-treatment effects, probably due to efforts made to prepare the community to expect reactions to ivermectin, widespread awareness of the beneficial effects of treatment by villagers who had participated in clinical trials previously, and the encouragement we gave to the population to become involved in improvement of their health care services. Single doses of ivermectin resulted in good clinical responses and created much goodwill among villagers. Improvements in physical fitness, ability to work, and freedom from musculoskeletal pain were reported at the 3 months' follow-up. We recommend that, during mass distribution of ivermectin, community involvement in planning overall health improvement should be included, since the treatment initiates the process well. In areas where sowda syndrome is prevalent, medical surveillance for 3 d or more should be considered.

Adolescent↗

Pregnancy outcome after inadvertent ivermectin treatment during community-based distribution.

Ivermectin is the drug of choice for community-based treatment of onchocerciasis. Since pregnancy testing during mass distribution campaigns is not feasible, the safety of ivermectin in pregnancy must be established. During a 3-year study, ivermectin was distributed to the population of a rubber plantation (14,000 people) in Liberia. Only 31% of women were aware of their pregnancy status during the first month; it was calculated that about half of women in the first trimester of pregnancy are likely to be treated inadvertently. 203 children born to women inadvertently treated during pregnancy were identified. In this limited sample, there was no significant difference in birth defects between treated and untreated mothers in the same population or compared with a reference population. Children of treated and untreated mothers showed no difference in developmental status or disease patterns. Further surveillance is necessary; however, since no major effects of ivermectin on pregnancy outcome were detected, there seems no need to change existing strategies of ivermectin distribution.

Abnormalities, Drug-Induced↗

Comparison of ivermectin and thiabendazole for treatment of naturally occurring nematode infections of goats in Kenya.

The anthelmintic activity of thiabendazole (TBZ) at 88 mg kg-1 and ivermectin at 0.2 mg kg-1 was examined in goats with naturally-acquired nematode infections. In one experiment, a herd of 450 does was treated with TBZ or ivermectin at 4-week intervals for 9 months and efficacy was measured by reduction in faecal egg counts after each treatment. In a second experiment, 100 kids were treated with ivermectin and effectiveness measured at 2 and 4 weeks after treatment by comparison of their egg counts with those of nontreated controls. In a third experiment, efficacy of treatment with TBZ and ivermectin was determined by recovery of parasites at necropsy in a controlled test with 15 kids. The results indicated that TBZ generally did not reduce egg counts and only removed 19% of Haemonchus contortus in the controlled test. The efficacy of ivermectin approached 100% for reduction in egg counts and elimination of H. contortus. Species of Ostertagia, Trichostrongylus, Nematodirus and Oesophagostomum also were present in some subjects, but not in sufficient numbers to evaluate effectiveness of treatment.

Animals↗

Effect of treatment with an ivermectin sustained-release bolus on productivity of stocker beef calves.

Three groups of 30 crossbred beef steers, 8-10 months of age and ranging in weight from 158 to 320 kg, were used to compare effects of treatment with an ivermectin sustained-release bolus or two ivermectin injectable treatments on parasite control and productivity in relation to untreated controls during a 168 day winter-spring grazing period. Each group of 30 consisted of five cattle on each of six separate 1.6 ha pastures. Treatments on Day 0 (12 December) were: Group 1: untreated controls; Group 2: ivermectin injectable at 200 micrograms kg-1 bodyweight, s.c., on Day 0 and Day 56; Group 3: ivermectin sustained-release bolus to deliver ivermectin at 12 mg day-1 over approximately 135 days. All cattle were weighed at 28 day intervals and fecal samples were collected for egg per gram counts (EPG). Geometric mean EPG for Group 3 remained consistently less than 1.0 after Day 0 and were highest (2.4) on Day 168. All group EPG were significantly different (P < 0.01) by Day 56, and EPG of Group 2 had increased to 10.5 following initial treatment and to 42.8 on Day 112. With the exception of a low mean EPG of 6.8 for Group 1 on Day 112, EPG of the group were consistently highest (range 24.9-36.0) to the end of the experiment. Ostertagia ostertagi was predominant, along with smaller proportions of Haemonchus placei and Cooperia spp. Throughout the experiment Group 3 had highest liveweights and gains that were most often different from those of Group 1 at P < 0.01 or greater.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The effect of faecally excreted ivermectin and fenbendazole on the insect colonisation of cattle dung following the oral administration of sustained-release boluses.

The effects of faecal drug residues following the administration of anthelmintics in the form of sustained-release boluses, on dung-colonising Coleoptera and Diptera are reported. In blind field trials, pats of standard weight and size were prepared from the dung of cattle treated with an ivermectin (Ivomec SR Bolus, MSD Agvet) or a fenbendazole (Panacur Bolus, Hoechst) sustained-release bolus, and from a third control group of cattle that received no treatment. Pats were recovered after 7, 14, 21 and 42 days in the field and searched for invertebrates. There were no differences in the numbers of adult beetles found in the pats from the three treatment groups. Pats made from the dung of ivermectin-treated animals contained no larval Diptera Cyclorrhapha and significantly fewer larval Scarabaeidae than pats made from the dung of the other two groups. Furthermore, larval Scarabaeidae in the ivermectin pats were inhibited in their development. The pats from fenbendazole-treated animals contained similar numbers of larval Scarabaeidae and Diptera to the pats from untreated animals throughout the trial. At 42 days, the solid matter of the control and fenbendazole-containing cow pats were reduced to a crumbling, granular texture, while the pats from the ivermectin-treated animals were solid and compacted. Pitfall trapping, using traps baited with dung from the three groups, showed no significant difference between the numbers of adult Scarabaeidae attracted, though a trend towards higher numbers attracted to the dung of both anthelmintic-treated groups was evident. The results provide evidence of the toxic effects of excreted ivermectin on key dung-colonising families of insects, and show that fenbendazole lacks such toxic effects.

Administration, Oral↗

Efficacy of an in-feed formulation of ivermectin against adult worms and somatic larvae of Strongyloides ransomi.

The efficacy of an in-feed formulation (IVOMEC premix) containing 0.6% ivermectin was tested against Strongyloides ransomi in swine. The efficacy of ivermectin against patent infections of S. ransomi when given via the feed at 2 ppm for 7 days (Days 0-7) to provide 100 mcg ivermectin kg-1 body weight day-1 was evaluated in a study with 16 3-month-old male castrated piglets. Seven days prior to treatment each piglet was infected subcutaneously with 2500 infective larvae of S. ransomi. Fecal egg counts were carried out on Days -7, 0, 7 and 14, and worm counts on Day 14. Efficacy was 100% in all treated piglets. Two trials involving 40 pregnant gilts were carried out to evaluate the efficacy of ivermectin against the somatic larval stages of S. ransomi when given at a daily dose of 100 mcg kg-1 body weight for 7 days starting on Days 66, 78, 92 or 103 of pregnancy. The gilts were each experimentally infected with three subcutaneous injections of 250,000 infective larvae, with the last infection given between 12 and 30 days prior to commencement of treatment. Gilts were confirmed free of pre-existing intestinal stages of S. ransomi prior to ivermectin treatment. Fecal nematode egg counts were carried out in gilts/sows and piglets subsequently born. The Strongyloides larvae present in sow milk 1, 2 and 7 days post partum were counted. Fourteen days post natum, worm counts were performed in four randomly selected piglets for each litter. IVOMEC premix given to pregnant gilts prevented shedding of larvae in sow milk, egg output in feces and the establishment of S. ransomi in piglets.

Administration, Oral↗

Effects of perinatal ivermectin exposure on behavioral development of rats.

The antiparasitic agent ivermectin was administered to pregnant rats from days 6 to 20 of gestation and 2 to 20 of lactation at 1, 2 or 4 mg/kg/day. Reproductive performance and behavior of offspring in the preweaning period were observed. Ivermectin had no effect on reproductive performance and dams' growth. The highest dose induced 100% pup mortality. Later on, ivermectin at 4 mg/kg was administered only during gestation. At that dose, the drug induced 22% mortality and affected temporarily cliff avoidance, locomotion, negative geotaxis and swimming development. At 2 mg/kg, the drug induced offspring mortality (31%), retarded growth and delayed eye opening, cliff avoidance and surface righting reflex, negative geotaxis, locomotion and swimming development. Ivermectin at 1 mg/kg had no effect on mortality and growth but cliff avoidance and locomotion were retarded. Data suggest that newborn rats were highly susceptible to the neurotoxic action of ivermectin. Whether its effects were prenatal or by acute intoxication via mother's milk are discussed.

Animals↗

Ivermectin: concentration-dependent effects on adenosine triphosphatases in adult worms of Onchocerca volvulus.

The effect of increasing concentrations of ivermectin on adenosine triphosphatase (ATPase) activity was investigated in adult worms of Onchocerca volvulus. Mean Mg- and Na,K-ATPase activities decreased significantly (F ratio = 29.82, P < 0.01 and F ratio = 28.54, P < 0.01, respectively) with increasing concentrations of ivermectin (0-100 ng/ml) in the female worms. When male and female worms were mixed with equal amounts of proteins from each, only the Na,K-ATPase activity was significantly decreased (F ratio = 56.61, P < 0.01) over a similar range of ivermectin concentrations. Since ivermectin exhibits concentration-dependent effects on both ATPases in female adult worms, this might provide an insight into other effects of the drug. However, the adjustment of the dose of ivermectin to obtain a nodular concentration of at least 40 ng/ml is therefore recommended in the complete chemotherapy of onchocerciasis.

Adenosine Triphosphatases↗

The efficacy of ivermectin against laboratory strains of Heligmosomoides polygyrus (Nematoda).

A susceptible strain of Heligmosomoides polygyrus was selected for 15 generations with increasing doses of ivermectin (0-6 mg/kg). A passage strain was developed, parallel with the ivermectin-selected strain, to control for changes due to rapid passage from mouse to mouse. The LD50s of the 8th and 15th generations of the ivermectin-selected strain were 1.5 times that of the susceptible strain. The LD50 of the passage strain at generations 8 and 15 remained similar to that of the susceptible strain. Ivermectin efficacy was lower against the LA stage than against the adult stage in the susceptible strain, the Ivermectin-selected strain and the passage strain at generation 8.

Animals↗

Single-dose treatment of Wuchereria bancrofti infections with ivermectin and albendazole alone or in combination: evaluation of the potential for control at 12 months after treatment.

The effect of single-dose ivermectin (150-200 micrograms/kg) and albendazole (400 mg) treatment alone and in combination on Wuchereria bancrofti microfilaraemia, antigenaemia and clinical manifestations was compared 12 months after treatment in a double-blind placebo-controlled field trial carried out in Ghana in 1996-98, to evaluate the potential of these treatments for control. Both ivermectin and combination treatments resulted in pronounced reductions in microfilaraemia among individuals who were microfilaria positive before treatment. Among individuals who were positive for circulating filarial antigen before treatment, antigen levels increased considerably over the 1-year period after treatment in the placebo group, whereas they decreased in the ivermectin and combination groups. However, the post-treatment difference reached statistical significance in neither microfilaraemia nor antigenaemia between the ivermectin and the combination groups. Albendazole treatment alone showed only a minor effect on microfilaraemia and antigenaemia. No effect of the treatments on the incidence of new cases of microfilaraemia or antigenaemia, or on clinical manifestations, was observed. Both ivermectin and combination treatment thus appeared effective for control of W. bancrofti infections, but the difference in efficacy between the 2 treatments after 12 months appeared to be minimal.

Adolescent↗

A clinical trial to evaluate the effects of flumethrin or ivermectin treatment on hemoparasites, gastrointestinal parasites, conception and daily weight gain in a dairy farm in Japan.

A clinical trial was performed to compare the effects of flumethrin and ivermectin treatments of grazing heifers at one farm in central Japan. 64 heifers were randomly allocated into two groups. Flumethrin (1 mg/kg pour on) was applied approximately once every 3 weeks to heifers in one group and heifers in the second group were injected approximately once every month with ivermectin (200 microg/kg; id). Between groups, no significant differences were detected in the proportions of animals that showed parasitemia of Theileria sergenti and conception risks. Significantly lower average log-transformed nematode-egg counts and higher average daily weight gain were observed in the ivermectin-treated group. Animals with higher body weight at the start of grazing and lower log-transformed total nematode-egg and coccidia-oocyst counts had higher odds of conceiving. Animals with ivermectin treatment, lower body weight at the start of grazing and lower log-transformed coccidia-oocyst count had higher daily weight gain. Ivermectin may be more useful in this farm because of the higher productivity for cattle and lower cost for its usage.

Administration, Cutaneous↗

Ivermectin and piperazine toxicoses in dogs and cats.

Review of all reports involving anthelmintics in dogs and cats to the IAPIC between January 1, 1986 and August 10, 1988, revealed that ivermectin (extra-label use) and piperazine accounted for over 50% of the calls assessed as toxicoses and suspected toxicoses. Both ivermectin and piperazine are gamma-aminobutyric acid (GABA) agonists and their major effects appear to be on the central nervous system. Ivermectin toxicoses at estimated doses of greater than or equal to 100-less than 500 micrograms/kg were reported more than once only in the collies (n = 25) and Australian shepherds (n = 10); these two breeds accounted for 46% (69 of 150) of the toxicoses and suspected toxicoses calls in dogs. Ataxia, behavioral disturbances, tremors, mydriasis, weakness/recumbency, apparent blindness, hypersalivation/drooling (dogs only), and coma were the most commonly reported clinical signs in dogs and cats with suspected ivermectin toxicoses. Shock, dyspnea, vomiting, and ataxia were the most common clinical signs attributed to the microfilaricidal activity of ivermectin. Piperazine was the anthelmintic with the greatest number of reports of toxicoses and suspected toxicoses in cats. Piperazine neurotoxicity in cats and dogs usually was manifested by muscle tremors, ataxia, and/or behavioral disturbances within 24 hours after estimated daily dose(s) between 20 and 110 mg/kg.

Animals↗

Community-perceived benefits of ivermectin treatment in northeastern Nigeria.

A 3-step approach involving focus group discussion, structured interviews and informal conversations with key individuals was used to investigate community usage and perceived benefits of ivermectin in nine Nigerian villages participating in a WHO-sponsored investigation of community-directed treatment with ivermectin (CDTI). Only 27% of 284 persons interviewed had received treatment. An under-estimation of the district's ivermectin needs led to inadequate supply of ivermectin to the communities, which was cited as the main reason (65%) for non-treatment. All those treated (N=76) were further interviewed using questionnaires. Worm expulsion (80%) and blindness prevention (68%) were the most frequently stated benefits. Other perceived benefits were an increase in vitality (68%), sexual drive and performance (29%). The sudden relief from a heavy burden of worms, which had built up over a long period, may have indirect effect on all aspects of an individual's health and account for the diverse experiences. The feeling of vitality, good appetite and general health following ivermectin treatment is an animating experience to many communities. Health planners face the challenge of preparing communities for fewer 'sensational' experiences and preventing a possible feeling of disappointment that may result from frequent usage.

Adult↗

Evaluation of the persistent efficacy of doramectin and ivermectin injectable against Ostertagia ostertagi and Cooperia oncophora in cattle.

The persistent efficacy of doramectin and ivermectin injectable against moderate and high infection levels of Ostertagia ostertagi and Cooperia oncophora were evaluated in cattle. Calves were allocated to six groups of six animals. On Day 0 animals of Groups I1/I2 and D1/D2 were treated with 0.2mg/kg ivermectin and doramectin injectable, respectively. Animals of the C1, I1 and D1 groups received a daily (moderate) infection of 1000 L3 of O. ostertagi and 1000 L3 of C. oncophora, and animals of the C2, I2 and D2 groups received a daily (high) infection of 10,000 L3 of each species. The animals were infected for 21 days with both species, the infections with C. oncophora and O. ostertagi started from Days 8 and 15 post treatment, respectively. Animals were necropsied on Day 40. The calculation of the persistent activity of ivermectin and doramectin was based on the efficacy against the different developmental and adult stages of both parasites. The present study confirmed that infection levels may influence the duration of persistent efficacy of an anthelmintic. Doramectin had at the moderate infection level a persistent efficacy of at least 35 days against O. ostertagi and at least 28 days against C. oncophora; at the high infection dose persistent efficacy was somewhat shorter i.e. up to 33 days and approximately 28 days, respectively. The duration of persistent efficacy of ivermectin against O. ostertagi at the moderate infection level was between 14 and 25 days, at the high dose level up to 25 days. Persistent efficacy of ivermectin against C. oncophora could, at both infection doses, not be measured, with the present experimental design.

Animals↗

Re-evaluation of ivermectin efficacy against equine gastrointestinal parasites.

Two trials were conducted to confirm the efficacy of ivermectin paste against endoparasites of horses. In these trials, 20 ponies were treated with ivermectin oral paste at 200 mcg x kg body weight once on Day 0, and 20 ponies served as unmedicated controls. The animals carried naturally acquired parasite infections as confirmed by pretrial fecal examination. The animals were necropsied for worm recovery on Days 14, 15 or 16. Parasites recovered were identified to species. Horses treated with ivermectin had significantly (P<0.05) fewer (>99.0% reduction) adult small strongyles (Coronocyclus spp including C. coronatus, C. labiatus, C. labratus; Cyathostomum spp including C. catinatum, C. pateratum; Cylicocyclus spp including C. ashworthi, C. elongatus, C. insigne, C. leptostomum, C. nassatus, C. radiatus; Cylicodontophorus bicoronatus; Cylicostephanus spp including C. asymetricus, C. bidentatus, C. calicatus, C. goldi, C. longibursatus, C. minutus; Gyalocephalus capitatus; Parapoteriostomum spp including P. euproctus, P. mettami; Petrovinema poculatum; Poteriostomum spp including P. imparidentatum, P. ratzii) and adult large strongyles (Strongylus edentatus, S. vulgaris; Triodontophorus spp including T. brevicauda, T. serratus; Craterostomum acuticaudatum) than the controls. Ivermectin was also highly effective (94% to >99%, P<0.05-0.01) against Gasterophilus intestinalis larvae, Habronema spp., Oxyuris equi, Parascaris equorum. The data from these two trials confirm that ivermectin paste administered to horses orally at 200mcg x kg(-1) continues to be highly effective for treatment and control of a broad range of small and large strongyle species as well as other species of gastrointestinal parasites.

Administration, Oral↗