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PubMed2002

High-level ivermectin resistance in a field isolate of Haemonchus contortus associated with a low level of resistance in the larval stage: implications for resistance detection.

The IVPro isolate of Haemonchus contortus was isolated in 1999 after significant numbers of the parasite survived an ivermectin capsule treatment of grazing sheep acquiring a natural infection at Prospect, NSW, Australia. The isolate shows high-level resistance to ivermectin (faecal egg count is unaffected by ivermectin oral treatment at 0.2mg kg(-1)). The larval LC(50), as assessed by larval development assays (LDAs), is only approximately two-fold higher than several susceptible isolates, making it difficult to detect the resistance using larval LC(50) as an indicator. However, the isolate shows the presence of a small proportion of the population (<20%) able to develop at significantly higher drug concentrations than the susceptible isolates. Hence, if the IVPro and susceptible isolates are compared at the LC(99) level, the IVPro isolate is readily identifiable as resistant. This degree of distinction at the LC(99) allows the IVPro isolate to be identified as resistant by simply observing the highest drug concentration in the development assay at which some larvae develop relative to the susceptible isolates. Assessing the development assay using this criterion allows a distinction between IVPro and the susceptible isolates equivalent to 10-fold differences in drug concentration, greatly increasing the likelihood of detecting the resistant isolate in routine resistance tests. This study highlights the need to examine this aspect of LDAs in order to detect the type of resistance displayed by IVPro H. contortus.

Animals↗
PubMed1996

Control of Filaroides hirthi infections in Beagle dogs by ivermectin.

The efficacy of ivermectin against Filaroides hirthi was evaluated in a series of three trials using Beagle dogs of a breeding colony known to be endemically infected with this lungworm. Ivermectin was subcutaneously given at a dosage of 1 mg kg-1 bodyweight once to 40 (group A) or, at a one week interval, twice to 32 dogs (group B) 14-15 weeks prior to necropsy; another 40 dogs (group C) remained untreated. All animals were necropsied and lungs were digested using the pepsin-hydrochloride method and qualitatively examined for Filaroides spp. stages. A 44.8% and 74.1% reduction of the prevalence of lungworm infection as well as a 87.5% and 94.8% reduction of the proportion of dogs harbouring first-stage Filaroides spp. larvae were found in groups A and B, respectively, as compared to group C. These results suggest that repeated treatments of breeding dogs with ivermectin might reduce the transmission of F. hirthi infection to their offspring.

Animals↗
PubMed1997

Prophylactic use of ivermectin against cattle myiasis caused by Cochliomyia hominivorax (Coquerel, 1858).

The prophylactic efficacy of ivermectin against navel or scrotal myiasis in calves was evaluated in eight trials in Argentina and Brazil. In two trials, calves were injected subcutaneously with ivermectin at a dosage of at least 200 microg kg(-1) within 24 h of birth. In the other six trials, two with two-month-old calves and four with four-month-old or older calves, all calves were treated with ivermectin at a dosage of at least 200 microg kg(-1) immediately after castration. In all trials, calves were maintained together on pasture and naturally exposed to Cochliomyia hominivorax. Navel and scrotal wounds were examined for myiasis daily for at least 14 days. Incidence of navel and scrotal myiasis was significantly lower (P < 0.01) in treated calves than in control calves.

Animals↗
PubMed1997

Comparative curative and preventive efficacies of ivermectin and closantel on Oestrus ovis (Linné 1758) in naturally infected sheep.

A field trial was undertaken to assess the efficacy of each of two formulations of ivermectin and of closantel in prevention and treatment of Oestrus ovis in a naturally infected flock grazing on the foothills of the Pyrenees mountains, in south-western France. Within the flock, 875 sheep were randomly divided into four groups, and treated twice during the fly season, with an interval of 60 days between treatments. Group 1 sheep were treated with albendazole (ABZ) at a dose rate of 3.8 mg/kg to maintain control of trichostrongylid parasites without affecting O. ovis; Group 2 received closantel at a dose rate of 10 mg/kg because of its known persistent activity against O. Ovis; Groups 3 and 4 received ivermectin at a dose rate of 200 mcg/kg bodyweight by subcutaneous injection (Isc) and orally (Io), respectively. All sheep were managed as a single group throughout the study. In order to assess the prophylactic effect of each product, immediately prior to the scheduled second treatment on Day 60 (D60), five sheep from each group were chosen at random and necropsied. Similarly, to assess the therapeutic effect, another five sheep from each group were selected on D70 and necropsied for parasite counts. During the 120 days of the trial, a significant number of animals from each group were regularly individually examined to assess their clinical status with regard to O. Ovis infection. Clinical signs of infection had significantly declined in Groups 2, 3 and 4 by 10 days after treatment reaching their lowest level at D30. In the control group during this period, clinical signs increased. Ten days after the second treatment, (D70), there was also evidence of a significant response to treatment. Finally the between-treatment differences in clinical scores of the closantel and ivermectin groups were small, although scores in Group 1 sheep was suggestive of a higher challenge in the second half of the study. On the basis of the postmortem counts and arithmetic means, prophylactic efficacies for the treatments relative to ABZ treated group, were 97.7, 62.5 and 0%, for the closantel, Isc and Io groups respectively. Therapeutic efficacies for the closantel, Isc and Io were 100, 100 and 98% respectively.

Administration, Oral↗
PubMed1997

Duration of anthelmintic efficacy of doramectin and ivermectin injectable solutions against naturally acquired nematode infections of cattle.

A comparison of persistent efficacy of doramectin injectable (D) and ivermectin injectable (I) was investigated under field conditions with treated permanent principal (PP) and interval-grazed principal (IGP) calves. The experiment was initiated on October 13, 1992 (day 0). Cattle used were crossbred beef heifers of 185 kg average weight and 8 to 10 months old. By random allotment, 66 calves were divided into two groups of 15 PP-D and PP-I calves for each treatment and two groups of 15 IGP-D and IGP-I calves for each treatment. Three extra or replacement calves were allotted for each group. Permanent principal calves in three replicates of five cattle per treatment grazed continuously on nematode-contaminated replicate pastures from day 0 to day 70. At 2-week intervals, i.e., days 0 to 14, 14 to 28, 28 to 42, 42 to 56 and 56 to 70, one IGP-D and one IGP-I calf was grazed with each of the respective PP-D and PP-I calf replicates and necropsied 21 days after removal from pasture. All respective PP calves and IGP calves were treated with doramectin at 200 micrograms kg-1 or ivermectin at 200 micrograms kg-1 by s.c. injection on day 0. After the day 0-14 interval, all IGP-D calves had zero egg counts. From the day 14-28 interval through the next three grazing intervals, the arithmetic mean egg counts of IGP-D calves were 18, 90, 281 and 31; those of IGP-I calves were 30, 226, 74 and 185. This suggested a persistence effect of approximately 2 to 4 weeks. In PP-D calves, egg counts reached a mean maximum at day 56 of only five eggs per gram, while counts of PP-I calves reached a peak of 40 on day 42. From the day 14-28 interval and through all subsequent intervals, arithmetic mean total worm counts from IGP-I calves were 58 to 73% greater than those in IGP-D tracers. A maximal total worm count of 4159 was observed in IGP-D calves of the day 42-56 interval; total worm counts in IGP-I calves from the day 14-28 interval through the day 42-56 interval were: 5420, 6739 and 9979, respectively. Haemonchus and Cooperia were higher in prevalence than Ostertagia in both treatments. Results of PP-D egg counts and total worm burdens in IGP-I calves indicated a high level of doramectin persistent activity for approximately 4 to 5 weeks and an advantage over persistence activity of ivermectin.

Animal Feed↗
PubMed1997

Comparative persistent efficacy of doramectin, ivermectin and fenbendazole against natural nematode infections in cattle.

A study was conducted in Argentina, to investigate the period of protection of a single injection of doramectin administered subcutaneously (s.c.) at 200 micrograms kg-1 (1 ml/50 kg) compared with single treatments of ivermectin (200 micrograms kg-1 s.c.) and fenbendazole (5 mg kg-1 p.o.), against field infections of gastrointestinal parasites of cattle. Eighty-three animals were selected and ranked on the basis of serial fecal egg counts (e.p.g.'s). From this group, three animals were slaughtered before treatment and their lungs, abomasum, small and large intestines, were processed for parasite counts and identification. The remaining 80 animals were allocated in ranked groups of four to a control or one of three treated groups. Animals of the four groups were grazed together in the same pasture for the duration of the study. Treatments were administered on Day 0. Individual fecal samples were collected at weekly intervals for the first 49 days post-treatment and twice a week from Day 52 to Day 84 (end of study). At each collection day fecal samples were pooled for coprocultures. On Day 28 and 56, two animals from each group, previously identified on Day 0, were killed and their parasite burdens determined. The duration of protection of a single injection of doramectin was longer than ivermectin or fenbendazole treatment. On Day 56, the total number of parasites found in doramectin-treated animals was significantly (P < 0.05) lower than parasite burdens found in either ivermectin- or fenbendazole-treated animals. The longer persistent activity of doramectin was expressed by the lower number of adults and L4 stages of Ostertagia ostertagi. Data from this experiment demonstrated the limitations of using fecal egg counts to evaluate the persistent efficacy of anthelmintics. The duration of activity of doramectin was demonstrated more accurately by parasite counts in cattle from each group since decreasing e.p.g.'s were seen in non-medicated animals without changes in total parasite burdens.

Animals↗
PubMed1997

Effect of early treatment with ivermectin and doramectin on the dynamics of antibody response in cattle naturally infested by Hypoderma lineatum and H. bovis.

The field efficacy of two avermectins (ivermectin and doramectin) and the subsequent development of the antibody response were assessed in cows naturally infested with first-instar larvae (L-1) of Hypoderma sp. Twenty-eight Frisian cows were randomly divided into three groups while the first-instar larvae were still in migration: Group 1 (G-C) untreated control; Group 2 (G-Iv), treated with ivermectin injectable (0.2 mg kg-1 body weight) and Group 3 (G-Dor), which received doramectin injectable (0.2 mg kg-1 body weight). Serum antibody response was studied by an indirect ELISA test using, as antigen, the hypodermin C obtained from L-1 of H. lineatum. In treated animals no grubs were present on the back at any time during the trial, whereas a variable number of nodules were found in untreated animals. Both avermectins showed total efficacy against L-1 of Hypoderma sp., and there were no local or general reactions. In ivermectin-treated cattle serum antibody levels declined from one month p.t., while in those treated with doramectin they started to fall two weeks later, but no differences were found among both groups. On the other hand, G-C antibody levels progressively increased and remained high until December, when the first grubs became detectable on the back; after that, they began to decline. Early treatments against Hypoderma sp. have an influence on the results of ELISA, so they must be considered to determine the most suitable time for blood sampling.

Animals↗
PubMed2000

Persistent activity of doramectin and ivermectin in the prevention of cutaneous myiasis in cattle experimentally infested with Cochliomyia hominivorax.

A study was conducted to evaluate the activity of a single administration of doramectin or ivermectin against severe, induced infestations of Cochliomyia hominivorax. Twenty-four Holstein bull calves were allocated to four groups of six animals each and treated either with saline, doramectin 1%, or either one of two formulations of ivermectin 1% at a dose rate of 200 microg/kg. On Day 12 after treatment, each calf was anesthetized and two wounds were created on the left side of the shoulder and rump of each calf and 2 h later, each wound was implanted with 100 newly hatched larvae of C. hominivorax. On Day 15 after treatment, the procedure was repeated on the right side of each calf. Wounds were examined daily for 5 days and evidence of live larvae was recorded. Doramectin provided reduction in myiasis of 90.9 and 83.3% at 12 and 15 days after treatment, respectively, compared to the saline control treatment (P < 0.0001). In contrast, there were no significant differences in the number of calves with myiasis between those treated with either of the ivermectin formulations and the saline control.

Animals↗
PubMed2003

Development and validation of an automated extraction method (accelerated solvent extraction) and a reverse-phase HPLC analysis method for assay of ivermectin in a meat-based chewable formulation.

A new method for monitoring ivermectin content in HEARTGARD CHEWABLES has been developed and validated. The method consists of the automated extraction of ivermectin from the meat-based formulation under conditions of elevated temperature and pressure (accelerated solvent extraction, ASE, and determination of the active by reverse-phase high performance liquid chromatography (HPLC). The method resolves both active species of ivermectin (components H(2)B(1a) and H(2)B(1b)) from the formulation matrix.

Animals↗
PubMed2003

Ivermectin.

Ivermectin is a potent antiparasitic drug and the first commercially available member of a new class of drugs (macrocyclic lactones) that has been approved for human use. Ivermectin has already proven to be highly effective in the elimination of river blindness as a public health burden. Side effects have been minor, and patient acceptance is good. Promising results in off-label applications for ectoparasitic infestations are increasingly important as resistance to topical therapy becomes more prevalent Ivermectin represents an advance in the therapeutic armamentarium and should be considered in appropriate cases.

Antiparasitic Agents↗
PubMed2002

Determination of ivermectin in bovine liver by optical immunobiosensor.

A rapid and sensitive biosensor immunoassay was developed for residues of the antiparasitic agent ivermectin in bovine liver. A detection limit of 19.1 ng g(-1) was achieved. The sensor employed was a Biacore optical instrument based on surface plasmon resonance. 5-O-succinoylivermectin-apo-transferrin conjugate was used to produce monoclonal antibody while a second derivative, ivermectin-oxime, was immobilised onto the surface of a sensor chip. A range of assay parameters (flow rate, injection time, temperature) and extraction techniques were investigated. In the final assay procedure, ivermectin was extracted with acetonitrile followed by C(8) SPE clean-up. Matrix effect was minimised by increasing the flow rate to 25 microl min(-1) and reducing the sample injection time to 2 min. The average value for liver samples spiked at 100 ng g(-1) (the MRL for the drug) and 50 ng g(-1) concentrations were 93.7 and 43.2 ng g(-1), respectively.

Animals↗
PubMed1985

Efficacy of ivermectin against Syphacia obvelata (Nematoda) in mice.

Ivermectin was evaluated against natural and artificial pinworm (Syphacia) infections in mice. Ivermectin given in the diet for 6 days at 0.0005% was 99% effective against both immature and adult worms. A diet level of 0.0004% reduced immature and mature pinworm by 99 and 75%, respectively but 0.0001% was inactive. One oral dose of 2.0 mg/kg was 100 and 97% effective against gravid females and immature worms, respectively. A dose of 1.0 mg/kg was 96 and 66% effective against the same parasitic stages. A similar effect was observed against adult male worms where 94 and 86% were removed by one oral dose of ivermectin at 2.0 and 1.0 mg/kg, respectively.

Animals↗
PubMed1989

In vitro effect of ivermectin on Pseudoterranova decipiens survival.

Third larval stages (L3) removed from fish fillets, fourth larval stages (L4) raised in in vitro culture, and adults of Pseudoterranova decipiens, collected from grey seal (Halichoerus grypus) stomachs, were exposed to the broad spectrum anthelmintic, ivermectin. L3 and L4 parasites were exposed, in vitro, to 500, 100, 50, 20, 5 and 1 micrograms/ml concentrations of the drug, in culture media. Adult P. decipiens were exposed in vitro to a concentration of 500 micrograms/ml ivermectin, only. Controls consisted of parasites placed in culture media alone or culture media plus drug vehicle. These three developmental stages of P. decipiens were all found to be susceptible to the effects of ivermectin.

Animals↗
PubMed1996

Genetic control of acquired resistance to Heligmosomoides polygyrus: overcoming genetically determined weak responder status by strategic immunization with ivermectin-abbreviated infections.

The induction of acquired resistance to H. polygyrus, following treatment of mice by a 6 day immunizing infection abbreviated with the anthelmintic drug ivermectin (6d I-AI), was investigated. Four worms were sufficient to elicit > 80% protection against challenge and immunizing infections > 50 worms generated > 95% protection in female NIH mice. A few worms were recovered during the second week from immunized challenged mice but these were rapidly expelled from the gut lumen. Treatment with hydrocortisone from day 10 postinfection, permitted worm burdens to accumulate over the following 2 weeks. The 6d I-AI protocol enabled females of strains previously designated as weak responders to develop potent acquired resistance to challenge (CBA mice showed > 90% protection), although weak responder strain male mice were not significantly protected. Delaying treatment with ivermectin by as little as 24 h resulted in poorer expression of acquired resistance. A positive correlation between the increasing interval from infection to treatment with ivermectin and worm burdens after challenge, and the negative correlation with IgGI antibody responses after challenge indicated that the immunodepressive activities of 7 day and older worms down-regulated local intestinal immune responses. Mice characterized by weak responder phenotype were significantly more sensitive to downregulation than mouse strains showing strong responder phenotype. In consequence, optimal timing of treatment with anthelmintics during exposure to the immunizing infection, intending to minimize exposure to the immunodepressive stages of the parasite, is sufficient to overcome reported genetic constraints on the development of resistance in this system.

Animals↗
PubMed2000

Ivermectin: effectiveness in lymphatic filariasis.

This detailed review of the published studies underlying ivermectin's recent registration for use in lymphatic filariasis (LF) demonstrates the drug's single-dose efficacy (over the range of 20-400 microg/kg) in clearing microfilaraemia associated with both Wuchereria bancrofti and Brugia malayi infections of humans. While doses as low as 20 microg/kg could effect transient microfilarial (mf) clearance, higher dosages induced greater and more sustained mf reduction. The single dose of 400 microg/kg yielded maximal responses, but a number of practical considerations suggest that either 400 microg/kg or 200 microg/kg doses would be acceptable for use in LF control programmes. Associated safety assessments indicate that adverse events, which occur commonly following treatment of microfilaraemic individuals, develop not because of drug toxicity but because of host inflammatory responses to dying microfilariae killed by the ivermectin treatment. Ivermectin is, therefore, a highly effective and generally well tolerated microfilaricide that may soon become an essential component of many public health initiatives to interrupt transmission of lymphatic filarial infection in an effort to eliminate LF globally.

Anthelmintics↗
PubMed2004

Structure of the microfilarial reservoir of Loa loa in the human host and its implications for monitoring the progr,ammes of Community-Directed Treatment with Ivermectin carried out in Africa.

This paper describes the structure of the microfilarial reservoir of Loa loa in an endemic population of central Cameroon. The possible effects of age and sex on the prevalence and intensity of microfilaraemia have been explored. Logistic analysis showed that the prevalence of microfilaraemia increased significantly with age, reaching 60 % in the oldest males. This result suggests that the figure commonly reported, according to which only one third of the infected individuals were microfilaraemic, should be reconsidered; in addition, as part of surveys of loiasis, crude microfilaraemia prevalence values should be replaced by adjusted ones. The intensity of infection did not show any age-specific change. As a result, even if the oldest members of the male population are clearly the most at risk of developing post-ivermectin serious adverse reactions, especially Loa-encephalopathy, the other members of the population are not risk-free. Therefore, in those areas where the African Programme for Onchocerciasis Control is undertaking regular mass distributions of ivermectin for onchocerciasis control, and where loiasis is co-endemic, no subpopulation should be excluded from surveillance and monitoring during community directed treatments with ivermectin.

Adolescent↗
PubMed2005

Genetic polymorphism of the beta-tubulin gene of Onchocerca volvulus in ivermectin naïve patients from Cameroon, and its relationship with fertility of the worms.

Observations of low response of patients infected with Onchocerca volvulus to ivermectin suggest that the parasite may be under a selection process toward potential resistance. To limit the extension of this phenomenon, it is crucial to characterize the genes of O. volvulus that are involved. For this, O. volvulus adult worms collected before the introduction of ivermectin in an onchocerciasis endemic area of central Cameroon were genotyped for beta-tubulin. To derive a baseline to investigate the selective pressure of ivermectin, we analysed (1) the frequency distribution of the beta-tubulin alleles, and (2) the relationship between the different beta-tubulin related genotypes and the fertility status of the female worms. The frequency of allele b of the beta-tubulin gene was very low, as it was observed in West Africa. We observed a deficit of heterozygous female worms leading to Hardy Weinberg disequilibrium, which might be explained by a shorter life-span of these worms compared to the homozygous worms. Unexpectedly, our results also show that the heterozygous female worms were much less fertile than the homozygotes: more than two thirds of the homozygotes were fertile, whereas only 37% of the heterozygotes were fertile. These results will be further considered when analysing post-treatment data.

Adolescent↗
PubMed1999

Efficacy of ivermectin in the treatment of Wuchereria bancrofti infection: a model-based analysis of trial results.

Ivermectin is a promising drug for the treatment of lymphatic filariasis. A meta-analysis of trials investigating the effects of a single treatment suggested a dose-dependent effect on the production of microfilariae (mf) by adult Wuchereria bancrofti parasites. A mathematical model that describes the parasite dynamics in the human host and the impact of ivermectin treatment is presented and its outputs compared with these trials. The calculated trend in mf density after treatment appears to be particularly sensitive to the assumption about the mean life-span of mf. Adopting 0.5-2 years as a range of plausible values for this mf life-span, the model is used to estimate the impact of treatment on the parasite. It is found that irrespective of dosage, ivermectin eliminates 100% of the blood mf from a patient. Furthermore, at a dosage level of 400 micrograms/kg a single treatment irreversibly reduces the mf production of the adult parasites by at least 65%. For a dosage of 200 micrograms/kg this reduction is at least 35%. No such effect can be concluded from the results of trials using lower dosages.

Animals↗