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Protective efficacy of doramectin and ivermectin against Cochliomyia hominivorax.

Two studies were conducted in Brazil using induced infestations of the New World screwworm, Cochliomyia hominivorax, to investigate: a) the comparative prophylactic efficacy of doramectin and ivermectin at their recommended use levels (200 micrograms kg-1 s.c.), and b) the duration of protection of a single injection of doramectin. In the comparative efficacy study, two groups of six animals each were treated with ivermectin or doramectin. Two hours after treatment, four incisions were made. Each incision was infested with 30 first instar C. hominivorax larvae and their status evaluated daily for 7 days post-treatment (p.t.). Doramectin treatment was 100% effective in prevention of C. hominivorax infestations whereas ivermectin efficacy was incomplete. First instar larvae were eliminated in doramectin-treated calves by 48 h p.t., while in the ivermectin group, C. hominivorax developed in over 29% of the incisions. Healing began in wounds of doramectin-treated animals at 24 h p.t. and was in progress in 100% of all wounds at 2 days p.t., while 50% of ivermectin-treated calves showed incisions with active lesions. In the duration of protection study, 24 calves were allocated to six groups (T1-T6) of four animals each. Three groups (T1, T3 and T5) were treated with saline and three groups (T2, T4 and T6) with doramectin. Animals were infested as described previously according to the following schedule: T1 and T2 at day 14, T3 and T4 at day 21, and T5 and T6 at day 28 p.t. Incisions were evaluated daily for 8 days post-infestation. Screwworm infestations and viable third-instar larvae developed of all incisions of saline-treated calves, while doramectin was 100% effective preventing development of C. hominivorax for 21 days p.t. and showed partial activity at 28 days p.t.

Animals↗

Persistent efficacy of doramectin and ivermectin against experimental infestations of Sarcoptes scabiei var. suis in swine.

Two studies were performed to compare the persistent efficacy of doramectin and ivermectin in swine experimentally infested with Sarcoptes scabiei var. suis. In the Study 1, 84 pigs were treated with doramectin, ivermectin, or saline solution on Day 0. Pigs were then challenged with mites on Days 0, 7, 14, 21, 28, 35, or 42. Weekly evaluations were performed for 5 weeks following challenge with mites. Weekly evaluations included physical examination for clinical signs of sarcoptic mange and collection of skin scrapings for determination of mite counts. In the Study 2, 80 pigs were treated with doramectin, ivermectin, or saline solution on Day 0, and challenged with mites on Days 3, 6, 9, 12, 15, 18, 21, 24, or 27. Weekly evaluations were performed for 6 weeks after challenge exposure. All negative-control (saline-treated) animals in both studies developed evidence of mite infestation. In the Study 1, doramectin prevented mite infestations 7 days longer than ivermectin. Results from the Study 2 indicated that the persistent efficacy of doramectin was 18 days on the basis of mite recovery. This was twice as long as the persistent efficacy of ivermectin, which was 9 days on the basis of mite recovery.

Animals↗

Ivermectin for Sarcoptes scabiei hyperinfestation.

OBJECTIVES: Crusted (Norwegian) scabies is an unusual variant of scabies caused by hyperinfestation with Sarcoptes scabiei. It has high morbidity, and secondary bacterial skin sepsis may result in life-threatening bacteremia. An open label study of oral ivermectin was carried out in patients with crusted scabies refractory to topical therapy. METHODS: Patients with refractory crusted scabies were prescribed oral ivermectin, one to three doses of 200 mg/kg at 14-day intervals, combined with topical scabicide and keratolytic therapy. RESULTS: Of the 20 patients who received ivermectin, 8 had a complete initial clinical response, a partial response was achieved in 9, and minimal improvement occurred in 3. Three doses of ivermectin were curative for 8 of 10 cases, but recurrence of scabies from presumed reinfestation occurred in at least half of these. CONCLUSION: The authors conclude that ivermectin is effective for crusted scabies; however, multiple doses may be required to achieve a cure, and recurrence 6 or more weeks after completing treatment is common.

Administration, Oral↗

Effect of ivermectin on infection with gastro-intestinal nematodes in Sierra Leone.

Levels of intestinal nematode infections were assessed six months after a two year trial of ivermectin for efficacy against onchocerciasis had ended. In the trial the inhabitants of six villages in Sierra Leone were offered treatment with ivermectin or placebo at six monthly intervals for four rounds in total. Quantitative faecal egg counts were carried out on stool samples provided by 202 subjects, all of whom had received all four rounds of treatment, in two of the villages (Dodo and Mogibisi). These data were analysed by a novel procedure in which a 3-way ANOVA with negative binomial errors enabled village and host gender influences on the outcome of treatment to be identified. Necator americanus was the most common species showing an overall prevalence of 90% but a higher intensity in Mogibisi relative to Dodo, particularly among male subjects. Neither prevalence nor intensity of infection were altered in ivermectin-treated compared with placebo-treated subjects. Trichuris trichiura was the least common species with a prevalence of 15%. It was concluded that there was no significant protection from infection with this species among the ivermectin relative to the placebo-treated subjects. Ascaris lumbricoides, with an overall prevalence of 39%, was more common among female (50%) compared with male (27%) villagers. Prevalence was not significantly affected by ivermectin but the intensity of infection declined by 91.3% in Dodo whilst in Mogibisi intensity was only reduced by 14.6%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Actions of the anthelmintic ivermectin on the pharyngeal muscle of the parasitic nematode, Ascaris suum.

The anthelmintic invermectin has a number of effects on nematodes which result in changes in behaviour, particularly locomotion, including paralysis and an inhibition of feeding. This paper describes the application of an in vitro pharmacological approach to further delineate the action of ivermectin on feeding behaviour. Contraction of Ascaris suum pharyngeal muscle was monitored using a modified pressure transducer system which detects changes in intrapharyngeal pressure and therefore contraction of the radial muscle of the pharynx. The pharynx did not contract spontaneously. However, serotonin (5-HT, 100 microM) stimulated rhythmic contractions and relaxations (pumping) at a frequency of 0.5 Hz. gamma-Aminobutyric acid (GABA) and glutamic acid inhibited the pumping elicited by 5-HT. The duration of inhibition was concentration dependent (1-1000 microM) with a threshold of 1 microM and 10 microM respectively (n = 8). Ivermectin also inhibited pharyngeal pumping (1-1000 nM). At lower concentrations, ivermectin (1-10 pM) potentiated the GABA and glutamate inhibition, so that inhibition occurred at concentrations which were below threshold in the absence of ivermectin. These data provide evidence that the pharynx is a site for the action of ivermectin. Thus interruption of pharyngeal processes such as, feeding, regulation of hydrostatic pressure and secretion may provide a new site of anthelmintic action.

Animals↗

Chemoprophylaxis of Onchocerca infections: in a controlled, prospective study ivermectin prevents calves becoming infected with O. ochengi.

Onchocerciasis ('River Blindness'), caused by the filarial nematode Onchocerca volvulus is of major public health importance in West Africa. Ivermectin, a drug originally developed for veterinary use, is now being incorporated in control strategies but whilst it has potent efficacy against L1 larvae (microfilariae), ivermectin is not lethal to adult (L5) O. volvulus, nor to adults of the related cattle parasite O. ochengi. We have exploited this model to determine if ivermectin has prophylactic activity against naturally transmitted, O. ochengi infections in a controlled, prospective study in northern Cameroon. Calves were treated monthly with ivermectin at either 200 micrograms/kg or 500 micrograms/kg for 21 months. None of 15 treated calves developed adult worm infection, whereas 5/6 untreated controls became infected (P < 0.001) with a total of 54 O. ochengi nodules, and all 5 developed patent microfilaridermia. These results have significant implications for the use of ivermectin in humans, and suggest that strategic chemotherapy at times of maximal transmission will confer prophylactic as well as therapeutic benefits.

Animals↗

Environmental consequences of treating cattle with the antiparasitic drug ivermectin.

Ivermectin (22,23-dihydroavermectin B1) is a recently discovered, persistent, broad-spectrum, antiparasitic drug of unpredecented potency which is now routinely administered to cattle, horses, sheep and pigs in many countries. In cattle, it is an efficient control for parasitic gastrointestinal and respiratory tract nematodes, warble fly, mites, lice and ticks. However, most of the ivermectin dose is ultimately eliminated in the faeces of the treated animals where it has been shown to have an insecticidal effect on the larvae of economically important, dung-breeding, haematophagous Diptera. Nevertheless, the effects of excreted ivermectin on the cowpat fauna as a whole and the wider consequences of such effects have not previously been considered. In field trials reported here, the faeces of calves fitted with rumenal boluses delivering ivermectin at 40 micrograms per kg per day, failed to degrade in the normal way and this failure was associated with the absence of dung-degrading insects. Faeces from placebo-treated controls contained a characteristic dung-degrading invertebrate community and were largely degraded within 100 days. These results indicate that the increasing widespread use of ivermectin may have important environmental consequences for pastureland.

Animals↗

Protein binding and ivermectin estimations in patients with onchocerciasis.

We measured ivermectin in plasma, urine, and saliva of nine patients with onchocerciasis. The aim was to establish pharmacokinetic parameters and to assess the most facile medium for use in monitoring compliance. Binding of ivermectin to plasma proteins in vitro was also investigated. The mean (+/- SEM) plasma values for the nine subjects were as follows: weight, 66.3 +/- 2.8 kg; dose, 11.11 +/- 0.4 mg; half-life, 56.50 +/- 7.01 hours; clearance, 142.5 +/- 22.6 L/kg; volume of distribution, 9.91 +/- 2.67 L/kg; area under the plasma concentration-time curve, 1545.3 +/- 190.5 ng/ml.hr; time to reach maximum concentration, 4.7 +/- 0.5 hours; and maximum concentration, 38.2 +/- 5.8 ng/ml. Ivermectin was not detected in the urine of any of the nine subjects. Low levels were found in saliva. Blood specimens remain the only reliable biologic fluid for assessment of compliance after ivermectin oral administration. Ivermectin binds specifically to human serum albumin.

Administration, Oral↗

Specific interaction of ivermectin with retinol-binding protein from filarial parasites.

Specific cellular binding proteins for retinol and retinoic acid from mammalian and avian species may mediate the action of retinoids in the control of epithelial differentiation, growth and tumorigenesis. Parasite retinol-binding protein (PRBP) and parasite retinoic acid-binding protein (PRABP) isolated and characterized from parasitic worms of the family Filarioidea might be involved in some possible action of vitamin A compounds in these parasites. Ivermectin, a potent and widely used anti-parasitic drug, competes efficiently with retinol for retinol-binding sites on PRBP, but not for the host-tissue retinol-binding-protein sites. The drug has no affinity for retinoic acid-binding proteins from either parasite or host tissues. Binding studies using radiolabelled ivermectin and retinol reveal that ivermectin has a higher affinity than retinol for PRBP. A correlation exists between the binding affinities of ivermectin analogues and their anti-parasitic activities. A binding-protein-mediated interrelationship may exist between the actions of retinol and ivermectin in the parasites, but not in the host tissues.

Animals↗

Involvement and performance of women in community-directed treatment with ivermectin for onchocerciasis control in Rukungiri District, Uganda.

The present study aimed: (1) to assess and improve the level of women's involvement in a strategy to control onchocerciasis by community-directed treatment with ivermectin (CDTI) in three parishes of Rukungiri District, Uganda; (2) to measure the performance of female community-directed health workers (CDHWs) in comparison with males; and (3) to identify culturally acceptable means of enhancing women's involvement in community-directed healthcare. Health education sessions were used to instruct community members to select female CDHWs in Masya Parish and to stress their potential importance in Karangara Parish; this subject was not raised in Mukono Parish. In all, 403 mature women who were randomly selected from the three parishes were interviewed as to their: (1) knowledge of the classes of people not eligible to take ivermectin; (2) knowledge and beliefs about the benefits of ivermectin; (3) participation in decision-making; and (4) attitudes on the performance of female CDHWs. For analysis, the respondees were divided into: (1) those who had or had not taken ivermectin treatment during the previous year; and (2) those who had or had not attended health education sessions. During the period when face-to-face interviews with women in randomly selected households were being carried out, participatory evaluation meetings (PEMs) were conducted in selected communities from the same parishes in order to reach a consensus on issues which could not easily be included in individual face-to-face interviews. Participant observations were also made regarding: how communities selected their CDHWs; how the CDHWs organised the distribution exercise and treated community members; and how the CDHWs kept records in order to understand issues which were deliberately hidden from the researchers during face-to-face interviews and PEMs. Significantly, the women who had been treated or health educated in Masya Parish were: (1) more knowledgeable on the groups which were not supposed to be treated; (2) aware of women's involvement in mobilisation of other community members; (3) involved in CDTI decision-making; and (4) had a better attitude towards female CDHWs' performance compared with males when compared with those from Karangara and Mukono parishes. There were no differences between the attitude of women in Karangara and Mukono parishes towards performance of female CDHWs. Face-to-face interviews and records from all parishes indicated that female CDHWs achieved as good a coverage as their male counterparts, and sometimes better, in about the same time. Health education increased the number of female CDHWs from nine to 52 in Masya Parish, from 7 to 22 in Karangara Parish and from 6 to 20 in Mukono Parish. Health education improved the attitude of women towards female CDHWs, but the actual experience of having and observing female CDHWs in action in Masya Parish had a more significant positive impact on the womenfolk, as well as on the rest of the community members, and created an impetus for more of them to become actively involved in actual ivermectin distribution. The present authors conclude that recruiting more female CDHWs and supervisors would reduce the current male domination of the health delivery services, greatly strengthening the activities of CDTI programmes.

Community Health Services↗

Ivermectin influence on the mast cell activity in nodules of onchocerciasis patients.

Onchocercal nodules were stained immunohistochemically using antibodies specific for human mast cells and IgE to elucidate the localization and frequency of mast cells after a single oral dose of 150 microg/kg ivermectin. Tryptase-and chymase-positive mast cells occurred predominantly in mixed inflammatory infiltrates and perivascularly, and never adhered to adult worms or microfilariae. Up to three days after ivermectin, mast cells and IgE-positive cells were markedly increased in the capsular area of nodules containing female worms with embryos and microfilariae compared to untreated nodules. In the centre of these nodules, around the adult Onchocerca volvulus, we found many tryptase-positive cells. More mast cells were IgE-positive than in untreated nodules, equalling the number of tryptase-positive mast cells. There was a clear correlation between the appearance of mast cells and the attacks on damaged microfilariae by eosinophils and macrophages and in the vicinity of adult worms by neutrophils that occur soon after ivermectin treatment. Onchocercomata harbouring female worms with oocytes only revealed, after all treatment intervals, the same mast cell numbers as untreated nodules. In conclusion, during the first three days after administration, ivermectin produces increased numbers of mast cells in nodules harbouring females with embryos and microfilariae, probably as part of an allergic reaction to the attacked microfilariae. Four to 19 days after ivermectin the number of mast cells in the entire nodule is no longer elevated.

Animals↗

The effects of ivermectin on onchocercal skin disease and severe itching: results of a multicentre trial.

OBJECTIVE: To determine the effects of ivermectin in annual, 3-monthly and 6-monthly doses on onchocercal skin p6isease (OSD) and severe itching. METHOD: A multicentre, double-blind placebo controlled trial was conducted among 4072 residents of rural communities in Ghana, Nigeria and Uganda. Baseline clinical examination categorized reactive skin lesions as acute papular onchodermatitis, chronic papular onchodermatitis and lichenified onchodermatitis. Presence and severity of itching was determined by open-ended and probing questions. Clinical examination and interview took place at baseline and each of 5 subsequent 3-monthly follow-up visits. RESULTS: While prevalence and severity of reactive lesions decreased for all 4 arms, those receiving ivermectin maintained a greater decrease in prevalence and severity over time. The difference between ivermectin and placebo groups was significant for prevalence at 9 months and for severity at 3 months. Differences between placebo and ivermectin groups were much more pronounced for itching. From 6 months onward, the prevalence of severe itching was reduced by 40-50% among those receiving ivermectin compared to the trend in the placebo group. CONCLUSION: This is an important effect on disease burden as severe itching is for the affected people the most troubling complication of onchocerciasis. The difference among regimens was not significant, and the recommended regimen of annual treatment for the control of ocular onchocerciasis appears also the most appropriate for onchocerciasis control in areas where the skin manifestations predominate. The final determination of the effect on skin lesions requires a longer period of study.

Adult↗

A health club for a community school in south-eastern Nigeria: influence on adult perception of onchocerciasis and compliance with community-based ivermectin therapy.

The impact of a school health club on adult perception of onchocerciasis and compliance with ivermectin was evaluated in an onchocerciasis-endemic community in southeastern Nigeria. Venous blood was collected from each of 26, 32 and 124 randomly selected subjects during ivermectin distribution programmes in 1995 1996 and 1997 respectively. Ivermectin concentrations were measured in the samples. Data was also collected from 334 and 319 randomly selected household heads or their representatives (aged 24 to 65 years) before and after health talks by schoolchildren, using interviewer-administered questionnaires. There was an increasing number of subjects who participated in control programmes (116 in 1995, 437 in 1996 and 2055 in 1997). Compliance with ivermectin treatment was low (53.9%) in 1995 but increased dramatically (90.1%) in 1997. A significant proportion (chi2 = 108.7, df = 1, P < 0.0001) of respondents knew about onchocerciasis after health education, predominantly from health workers (64.5%) before the tests and children (92.3%) after. Knowledge and beliefs about causative agents (chi2 = 266.4, df = 5, P < 0.0001), diagnostic method (chi2 = 207.4, df = 3, P < 0.0001), prevention (chi2 = 67.0, df = 4, P < 0.0001) of onchocerciasis and the effectiveness of ivermectin (chi2 = 40.4, df = 1, P < 0.0001) also differed significantly between the periods before and after tests. The school health club increased adult knowledge about onchocerciasis and its treatment. Schoolchildren could therefore supplement the information, education and communication (IEC) aspect of health care delivery in a community through such health clubs.

Adult↗

Variation in incidence of serious adverse events after onchocerciasis treatment with ivermectin in areas of Cameroon co-endemic for loiasis.

OBJECTIVE: To determine the incidence of serious adverse events (SAEs) after mass treatment with ivermectin in areas co-endemic for loiasis and onchocerciasis, and to identify potential risk factors associated with the development of these SAEs, in particular encephalopathic SAEs. METHODS: We retrospectively analysed SAEs reported to have occurred between 1 December 1998 and 30 November 1999 in central-southern Cameroon by chart review, interview and examination of a subset of patients. RESULTS: The overall incidence of SAEs for the three provinces studied was 6 per 100,000. However, for Central Province alone the incidence of SAEs was 2.7 per 10,000 overall, and 1.9 per 10,000 for encephalopathic SAEs associated with Loa loa microfilaremia (PLERM). The corresponding rates for the most severely affected district within Central Province (Okola) were 10.5 per 10,000 and 9.2 per 10,000 respectively. Symptoms began within the first 24-48 h of ivermectin administration but there was a delay of approximately 48-84 h in seeking help after the onset of symptoms. First-time exposure to ivermectin was associated with development of PLERM. CONCLUSION: In Cameroon, the incidence of SAEs following ivermectin administration in general, and PLERM cases in particular, varies substantially by district within the areas co-endemic for loiasis and onchocerciasis. More intense surveillance and monitoring in the first 2 days after mass distribution in ivermectin-naïve populations would assist in early recognition, referral and management of these cases. The increased reporting of SAEs from Okola is unexpected and warrants further investigation. Research is urgently needed to find a reliable screening tool to exclude individuals (rather than communities) at risk of PLERM from the mass treatment program.

Adolescent↗

Study of the nematode putative GABA type-A receptor subunits: evidence for modulation by ivermectin.

Two alleles of the HG1 gene, which encodes a putative GABA receptor alpha/gamma subunit, were isolated from Haemonchus contortus. These two alleles were shown previously to be associated with ivermectin susceptibility (HG1A) and resistance (HG1E), respectively. Sequence analysis indicates that they differ in four amino acids. To explore the functional properties of the two alleles, a full-length cDNA encoding the beta subunit, a key functional component of the GABA receptor, was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank locus ZC482.1) and coexpressed in Xenopus oocytes with the HG1 alleles. When gab-1 was coexpressed with either the HG1A allele or the HG1E allele in Xenopus oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different sensitivity to the agonist were formed. The effects of ivermectin on the hetero-oligomeric receptors were determined. Application of ivermectin alone had no effect on the receptors. However, when coapplied with 10 micro m GABA, ivermectin potentiated the GABA-evoked current of the GAB-1/HG1A receptor, but attenuated the GABA response of the GAB-1/HG1E receptor. We demonstrated that the coexpressed HG1 and GAB-1 receptors are GABA-responsive, and provide evidence for the possible involvement of GABA receptors in the mechanism of ivermectin resistance.

Alleles↗

Topical ivermectin: a new successful treatment for scabies.

Ivermectin is the only one of the avermectins that has been widely used in humans, since it is recommended as the treatment of choice for onchocerciasis, a filariasis that produces "river blindness," a parasitic endemic infestation in countries of West Equatorial Africa and in some areas of Central and South America. Also, ivermectin has been used for treating human endo- and ectoparasites with effective results and with almost no side effects. To study the efficacy of ivermectin for scabies, which is very common in Colombia, a trial with this drug that could be easily administered, with fast application and high efficacy, was undertaken. For this purpose, six complete families with active scabies, consisting of 12 adults and 20 children ranging in age from 1 to 10 years, were treated with 1% ivermectin in a solution of propylene glycol applied topically to the affected skin. The dose employed was 400 microg/kg, repeated once the following week. All patients were cured, tolerated the medication well, and there were no side effects or signs of recurrence 2, 4, or 6 weeks after therapy. In addition to its efficacy, easy administration, and lack of side effects, ivermectin is a low-cost medication.

Administration, Cutaneous↗

Activity of albendazole-ivermectin combination and other filaricidal drugs against infective larvae, preadult, microfilariae and adult worms of Molinema dessetae in the rodent Proechimys oris.

The efficacy of albendazole-ivermectin combination was tested an adult and developing stages of Molinema dessetae in the rodent Proechimys oris. Albendazole and ivermectin, both given alone, suramin and diethylcarbamazine were used as reference compounds. The drug combination (albendazole at 10 mg/kg/ day x 5 days and Ivermectin at 0.04 mg/kg/day x 5 days) was effective against infective larvae and preadult worms, and substantially reduced the number of live adult worms. The known filaricidal agents, diethylcarbamazine (400 mg/kg twice daily x 5 days), ivermectin (0.2 mg/kg/day x 5 days), and suramin (40 mg/kg/day x 5 days), as well as albendazole (50 mg/kg/day x 5 days) were active on infective larvae, preadult worms, microfilariae and adult worms. All drugs had the same level of efficacity on infective larvae. Albendazole had the highest efficacy against adult and preadult worms and diethylcarbamazine was the most active on microfilariae. Although the drug combination was not as effective against preadult and adult worms as albendazole alone, the results indicate that albendazole-ivermectin combination at a low dose had prophylactic effect and suggest a possible macrofilaricidal activity.

Administration, Oral↗

A pharmacokinetic model to document the actual disposition of topical ivermectin in cattle.

Ivermectin is a worldwide-used antiparasitic drug largely administered to cattle as a topical formulation (pour-on). The actual plasma and faecal disposition of pour-on ivermectin in cattle was documented using an original pharmacokinetic model, and taking into account the oral ingestion of the topical drug following physiological licking as a secondary route of exposure. Six pairs of monozygotic twin cattle received successively one i.v. and two pour-on administrations of ivermectin at a 3-5-month interval. For one pour-on administration, the twins were separated into an unrestrained group and a group where self- and allo-licking were prevented. Ivermectin concentrations in the plasma and faeces were determined by HPLC. Licking resulted in a high intra-and inter-individual variability of systemic exposure after topical application. By the means of pharmacokinetic modelling, we showed that 58-87% of the pour-on dose was ingested, while only 10% was absorbed percutaneously. Approximately 72% of the ingested ivermectin transited directly into the faeces, resulting in a 7-fold higher faecal excretion of the parent drug than in the non-lickers. We conclude that topical administration does not guarantee a controlled drug delivery in cattle. More importantly, the simulations revealed that non-treated cattle could get easily contaminated by allo-licking, raising the public health problem of unexpected drug residues in edible tissues.

Administration, Topical↗