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PubMed2006

Efficacy of ivermectin treatment of cutaneous gnathostomiasis evaluated by placebo-controlled trial.

Previous studies have revealed that ivermectin treatment for gnathostomiasis can reduce parasitic loads in animals and make recurrent subcutaneous swelling subside in 76% of patients. Our study aimed to evaluate the efficacy of ivermectin for cutaneous gnathostomiasis treatment in a placebo-controlled trial. This study was a prospective randomized placebo-controlled study performed at The Bangkok Hospital for Tropical Diseases, Mahidol University, Thailand. Thirty patients with a serologically confirmed diagnosis of cutaneous gnathostomiasis were enrolled. Seventeen patients in the ivermectin treated group received a single dose of 12 mg ivermectin (200 microg/kg bodyweight), while 13 patients in the control group received a single dose of 40 mg of vitamin B1. The follow-up period was 1 year. Of the 17 patients, 7 (41.2%) responded to ivermectin, while no patient responded to placebo. The mean (95% Cl) time to the first recurrence of subcutaneous swelling with ivermectin and in the placebo groups were 257 (184-331) and 146 (42-250) days, respectively, (p=0.102). Although this study revealed no significant difference in the mean time to first recurrence of swelling between the ivermectin and placebo groups, there was a trend towards ivermectin efficacy against gnathostomiasis in previous animal and human studies. Further studies with different doses of ivermectin and larger sample sizes, and close monitoring for ivermectin tolerability and treatment response are necessary to confirm an efficacy of ivermectin.

Adult↗
PubMed1995

The effect of diethylene glycol monoethyl ether as a vehicle for topical delivery of ivermectin.

The effect of diethylene glycol monoethyl ether (DGME; Transcutol) on the permeation of ivermectin, a broad-spectrum antiparasitic agent, through bovine skin was evaluated by in vitro permeation experiments followed by serial sectioning of the skin to assess the amount of ivermectin retained in the skin. Ivermectin permeation through bovine skin was enhanced by DGME and this enhancement was DGME-concentration-dependent. Permeation of ivermectin was effectively enhanced in vehicles with low proportions of DGME, but the magnitude of permeation enhancement decreased as the proportion of DGME increased. The permeation was accompanied by the formation of cutaneous depots of ivermectin. Furthermore, the data indicated that the flux and the cutaneous accumulation of ivermectin were sensitive to the concentration gradient of DGME across the skin. This suggested that ivermectin was permeating with DGME, in which it is very soluble. Hence, the enhancing mechanism involves solubilization of the ivermectin by DGME and the transport of DGME itself across the skin. Based on these results, DGME appears to be a potential vehicle for topical delivery of ivermectin by transport through the skin and through formation of cutaneous depots of ivermectin.

Administration, Topical↗
PubMedDate not supplied

A community trial of ivermectin for onchocerciasis in Sierra Leone: adverse reactions after the first five treatment rounds.

We have studied the adverse reactions reported after ivermectin in 1745 villagers in southern Sierra Leone, allocated at random to receive ivermectin or placebo and treated 'double-blind' with 4 doses at six-monthly intervals. Six months after the fourth dose all eligible villagers received ivermectin regardless of their previous treatment. At the first treatment round more adverse reactions were reported by villagers treated with ivermectin than by those who received placebo. Reactions occurred most often on the second day after treatment. There were significant correlations between an individual's skin microfilarial load and the risk of developing adverse reactions. On re-treatment there was no significant excess of reported adverse reactions in the ivermectin group compared to the placebo group. Unlike other adverse reactions, the risk of cutaneous reactions after the first dose of ivermectin was not correlated with skin microfilarial load. In addition, after re-treatment with ivermectin, cutaneous reactions were reported significantly more often than with placebo. We confirm that ivermectin is safe for mass distribution, but adverse reactions should be monitored and treated after the first dose. Throughout this study ivermectin was well tolerated, with significantly more villagers returning for re-treatment after ivermectin than placebo, and all adverse reactions were self-limiting or successfully managed with symptomatic treatment. We question whether strict clinical monitoring should be routine at re-treatment, when only cutaneous reactions were consistently reported. If clinical monitoring could be used more selectively, distribution campaigns might be easier to manage and more cost-effective.

Adolescent↗
PubMed2005

A comparison of genetic polymorphism in populations of Onchocerca volvulus from untreated- and ivermectin-treated patients.

An analysis of the polymorphism of 16 genes from Onchocerca volvulus was undertaken, in two populations of worms from either ivermectin-naïve patients or patients who had been repeatedly treated with ivermectin, in Ghana. Six genes were selected for analysis because studies in other nematodes had suggested a possible association with ivermectin resistance. The other 10 genes were included as control genes and have not been associated with ivermectin resistance. Twelve of the 16 genes were polymorphic, including five of the candidate genes and seven of the control genes. In all of the control genes and four of the candidate genes, there were no differences in genetic polymorphism between the untreated and ivermectin treatment worms. However, there were statically significant differences (chi2=0.05) in allelic frequencies between the untreated and treatment derived worms for P-glycoprotein and beta-tubulin genes; both genes which have been previously associated with ivermectin resistance in other nematodes. These genes were in Hardy-Weinberg equilibrium in the untreated population. However, the P-glycoprotein alleles, in the worms from the patients under treatment were not in Hardy-Weinberg equilibrium, and analysis of the allele frequencies of beta-tubulin suggested that this gene may have also been under selection in the worms from the ivermectin-treated patients. This data provides evidence of genetic selection by ivermectin on O. volvulus and indicates that investigations should be made to determine whether ivermectin resistance is developing. The beta-tubulin and P-glycoprotein genes may prove useful for monitoring for possible development of ivermectin resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Ivermectin selection on beta-tubulin: evidence in Onchocerca volvulus and Haemonchus contortus.

Ivermectin resistance is common in trichostrongylid nematodes of livestock, such as Haemonchus contortus. This anthelmintic is the only drug approved for mass administration to control onchocerciasis caused by the nematode parasite, Onchocerca volvulus. In parts of West Africa up to 18 rounds of ivermectin treatment have been administered to communities and there are reports of poor parasitological responses to treatment. Understanding ivermectin resistance and ivermectin selection is an important step to reduce selection pressure for resistance, and to develop molecular markers which can be used to monitor the development of resistance and its spread. Here we report evidence that ivermectin selection changes the frequency of beta-tubulin alleles in both the sheep parasite, H. contortus, and the human parasite, O. volvulus. In O. volvulus we have been able to look at the frequency of beta-tubulin alleles in O. volvulus obtained before any ivermectin was used in humans in Africa, and following its widespread use. In H. contortus, we have been able to look at the frequency of beta-tubulin alleles in a strain which has not seen any anthelmintic selection and in an ivermectin selected strain derived from the unselected strain. We have found ivermectin selects on beta-tubulin in both of these nematode species. In the case of O. volvulus, we had previously reported that ivermectin selects for specific single nucleotide polymorphisms in the O. volvulus beta-tubulin gene. This polymorphism results in three amino acid changes in the H3 helix of beta-tubulin, as well as deletions in an associated intron. We report a simple PCR assay to detect the amplicon length polymorphism, resulting from these intronic deletions, which can be used to monitor the frequency of the beta-tubulin allele selected for by ivermectin in O. volvulus.

Africa, Western↗
PubMed2005

Influence of the route of administration on efficacy and tissue distribution of ivermectin in goat.

The tissue concentration and efficacy of ivermectin after per os and subcutaneous administration were compared in goats experimentally infected with Trichostrongylus colubriformis (ivermectin-susceptible strain, INRA). Infected goats (n = 24) were treated per os (n = 9) or subcutaneously (n = 9) with ivermectin, 0.2 mg/kg, or kept as not treated controls. The faecal egg counts and small intestine worm counts were determined. Ivermectin concentration was measured in the plasma, gastrointestinal tract, lung, skin or hair, liver and adipose tissues at 0, 2, 7 and 17 days post-treatment. The efficacy of ivermectin against T. colubriformis infection in goat was 98.7 and 99.9% for subcutaneous and oral administration, respectively. Ivermectin concentration declined with time and only residual concentration was measured at 17 days post-treatment in plasma and gastrointestinal tract. Ivermectin concentration was higher after subcutaneous compared to per os injection in most of the tissue examined. In skin, hair and subcutaneous adipose tissue ivermectin persisted at significant concentrations 17 days post-treatment for both routes of administration. In our experimental conditions, ivermectin provides similar efficacy against T. colubriformis after subcutaneous or per os administration in goat. However, the lower ivermectin levels in tissues after per os administration suggest that the lasting of efficacy may be shortened after per os compared to subcutaneous administration especially in animals with poor body condition in pasture where re-infection occurs quickly after anthelmintic treatment.

Administration, Oral↗
PubMed2001

Effect of ivermectin on activities of cytochrome P450 isoenzymes in mouflon (Ovis musimon) and fallow deer (Dama dama).

Ivermectin is an antiparasitic drug widely used in veterinary and human medicine. We have found earlier that repeated treatments of rats with high doses of this drug led to significant increase of cytochrome P450-dependent 7-methoxyresorufin O-demethylase (MROD) and 7-ethoxyresorufin O-deethylase (EROD) activities in hepatic microsomes. In the present study, the effects of ivermectin on cytochrome P450 (CYP) activities were investigated in mouflon (Ovis musimon) and fallow deer (Dama dama). This study was conducted also to point out general lack of information on both basal levels of CYP enzymes and their inducibilities by veterinary drugs in wild ruminants. Liver microsomes were prepared from control animals, mouflons, after single or repeated (six doses in six consecutive days) treatments with therapeutic doses of ivermectin (0.5 mg kg(-1) of body weight), and fallow deer exposed to repeated doses of ivermectin under the same conditions. Alkyloxyresorufins, testosterone and chlorzoxazone were used as the specific substrate probes of activities of the CYP isoenzymes. A single therapeutic dose of ivermectin significantly induced (300-400% of the control group) the activities of all alkyloxyresorufin dealkylases tested in mouflon liver microsomes. Repeated doses of ivermectin also caused an increase of these activities, but due to fair inter-individual differences, this increase was not significant. The administration of ivermectin led to an induction (170-210% of the control) of the testosterone 6beta- and 16alpha-hydroxylase activities in mouflon liver but no significant modulation of chlorzoxazone hydroxylase (CZXOH) activity was found in mouflon liver. CYP-dependent activities in hepatic microsomes were generally higher in fallow deer than in mouflons. However, with the exception of slight increase in the 7-benzyloxyresorufin O-dealkylase (BROD) activities, no significant modulation of the other activities was observed. The induction of CYP3A-like isoenzyme was confirmed by immunoblotting only in the microsomes from mouflons administered with repeated doses of ivermectin; however, no significant increase of CYP1A isoenzymes was observed due to a weak cross-reactivity of anti-rat CYP1A1/2 polyclonal antibodies used in the study. The results indicate that ivermectin should be considered as an inducer of several cytochrome P450 isoenzymes, including CYP1A, 2B and 3A subfamilies, in mouflons. The comparison of induction effect of ivermectin in rat, mouflon and fallow deer also demonstrates the inter-species differences in inducibility of CYP enzymes.

Animals↗
PubMedDate not supplied

[Ivermectin].

Ivermectin is a semi-synthetic derivative of a macrocyclic lactone. It causes paralysis in many nematodes and arthropodes because of its effect on ion-channels in cell membranes. Ivermectin was first used in veterinary medicine. In man, it was shown to be microfilaricid against Onchocerca volvulus. Most of the adverse reactions following treatment were mild, without the systemic and ocular side effects usually complicating diethylcarbamazine therapy. In endemic areas after repeated administration of ivermectin, a dramatic reduction in dermal microfilarial load was observed, resulting in a decrease in transmission. There was a significant decrease in the prevalence of anterior segment lesions in the eyes and acute onchocercal skin disease. Moreover, ivermectin also exhibited microfilaricidal activity against Wuchereria bancrofti and Brugia malayi. Annual mass treatment with a single dose of diethylcarbamazine alone, or associated with ivermectin, was initiated in endemic areas for lymphatic filariasis. The preliminary results showed a decrease in the reservoir of microfilariae and rate of transmission, a reduction in the frequency of clinical lymphatic abnormalities due to bancroftan filariasis. In Loa loa infections ivermectin decreases microfilaremia, but serious adverse events such as encephalopathy can be induced in patients with high rate of microfilaremia. Ivermectin appears to be the drug of choice in Strongyloides stercoralis infections, a single dose is highly effective with less frequent side effects than thiabendazole. Oral ivermectin is an alternative to topical scabicides, it appears as effective as local treatment for common scabies, but there are few comparative studies. The best indications for ivermectin in this ectoparasitic infection could be the outbreak in institutions and crusty scabies, but in association with topical treatment. The precise position of this agent in the treatment of scabies remains to be specified. Ivermectin is also affective in the treatment of ascariasis and cutaneous larva migrans. It could also be a promising treatment for head lice.

Antiparasitic Agents↗
PubMed1998

Ivermectin resistance in nematodes may be caused by alteration of P-glycoprotein homolog.

Resistance to ivermectin and related drugs is an increasing problem for parasite control. The mechanism of ivermectin resistance in nematode parasites is currently unknown. Some P-glycoproteins and multidrug resistance proteins have been found to act as membrane transporters which pump drugs from the cell. A disruption of the mdrla gene, which encodes a P-glycoprotein in mice, results in hypersensitivity to ivermectin. Genes encoding members of the P-glycoprotein family are known to exist in nematodes but the involvement of P-glycoprotein in nematode ivermectin-resistance has not been described. Our data suggest that a P-glycoprotein may play a role in ivermectin resistance in the sheep nematode parasite Haemonchus contortus. A full length P-glycoprotein cDNA from H. contortus has been cloned and sequenced. Analysis of the sequence showed 61-65% homology to other P-glycoprotein/multidrug resistant protein sequences, such as mice, human and Caenorhabditis elegans. Expression of P-glycoprotein mRNA was higher in ivermectin-selected than unselected strains of H. contortus. An alteration in the restriction pattern was also found for the genomic locus of P-glycoprotein derived from ivermectin-selected strains of H. contortus compared with unselected strains. P-glycoprotein gene structure and/or its transcription are altered in ivermectin-selected H. contortus. The multidrug resistance reversing agent, verapamil, increased the efficacy of ivermectin and moxidectin against a moxidectin-selected strain of this nematode in jirds (Meriones unguiculatus). These data indicate that a P-glycoprotein may be involved in resistance to ivermectin and other macrocyclic lactones in H. contortus.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Comparison of pharmacokinetic profiles of doramectin and ivermectin pour-on formulations in cattle.

The plasma pharmacokinetics of doramectin and invermectin after topical administration (500 microg kg(-1)) were compared over a 50-day period in 24 young beef cattle. Observed maximum concentration (Cmax) and time to maximum concentration (Tmax) were determined directly from plasma concentrations for each animal. The area under the plasma concentration-time curve (AUC) and mean residence time (MRT) were calculated as indices of drug exposure and persistence. The Cmax of doramectin (12.2+/-4.8 ng ml(-1)) and ivermectin (12.2+/-6.0 ng ml(-1)) and Tmax of doramectin (4.3+/-1.6 days) and ivermectin (3.4+/-0.8 days) were not significantly different (p > 0.05). In contrast, the AUC of doramectin (168.0+/-41.7 ng day ml(-1)) was significantly greater than that of ivermectin (115.5+/-43.0 ng day ml(-1)). Furthermore, the range of AUC values calculated for ivermectin was wider than that obtained for doramectin, extending from 51.3 to 182.3 ng day ml(-1) for ivermectin versus 104.3-228.7 ng day ml(-1) for doramectin. The MRT was significantly greater for doramectin (12.8+/-1.9 days) than for ivermectin (8.4+/-1.5 days). It was concluded that a 500 microg kg(-1) pour-on administration of doramectin and ivermectin led to an overall exposure as reflected by the mean AUC, that was 45% higher for doramectin compared to ivermectin and that the relative inter-individual variability was less for doramectin than for ivermectin. Possible therapeutic consequences of these differences between doramectin and ivermectin pour-on formulations are discussed.

Administration, Topical↗
PubMed2003

Pharmacological effects of ivermectin, an antiparasitic agent for intestinal strongyloidiasis: its mode of action and clinical efficacy.

Ivermectin is an oral semi-synthetic lactone anthelmintic agent derived from avermectins isolated from fermentation products of Streptomyces avermitilis. Ivermectin showed a concentration-dependent inhibitory effect on motility of a free-living nematode, Caenorhabditis elegans (C. elegans). There exist specific binding sites having a high affinity for ivermectin in the membrane fraction of C. elegans, and a strong positive correlation was detected between the affinity for these binding sites and the suppressive effect on motility of C. elegans in several ivermectin-related substances. These results suggested that the binding to these binding sites is important for the nematocidal activity of ivermectin. In oocytes of Xenopus laevis injected with the Poly (A)(+) RNA of C. elegans, expression of a chloride channel, which is irreversibly activated by ivermectin, was recognized. The pharmacological properties of this channel suggest that the ivermectin-sensitive channel is a glutamate-activated chloride channel. As to the glutamate-activated chloride channel, two subtypes (GluCl-alpha and GluCl-beta) were cloned, suggesting these subtypes constitute the glutamate-activated chloride channel. These findings suggest that ivermectin binds to glutamate-activated chloride channels existing in nerve or muscle cells of nematode with a specific and high affinity, causing hyperpolarization of nerve or muscle cells by increasing permeability of chloride ion through the cell membrane, and as a result, the parasites are paralyzed to death. In experimental infections in sheep and cattle, ivermectin exhibited potent dose-dependent anthelmintic effects on Haemonchus, Ostertagia, Trichostrongylus, Cooperia, Oesphagostomum, and Dictyocaulus. Anthelmintic effects were reported also in dogs, horses, and humans infected with Strongyloides. In the clinical Phase III trial in Japan, 50 patients infected with Strongyloides stercoralis were administered approx. 200 microg/kg of ivermectin to be given orally twice at an interval of 2 weeks. As a result, the Strongyloides stercoralis-eradicating rate was 98.0% (49/50).

Animals↗
PubMed2001

Behavioral effects of ivermectin in a freshwater oligochaete, Lumbriculus variegatus.

Ivermectin is a potent antiparasitic drug against nematode and arthropod parasites. In this study, we examined the lethal and sublethal effects of ivermectin in a freshwater oligochaete, Lumbriculus variegatus. The median lethal concentration (LC50) at 72 h after ivermectin exposure was 560 nM. Sublethal endpoints focused on several stimulus-evoked locomotor behaviors: escape reflexes controlled by giant interneuron pathways, swimming and reversal, and crawling. Swimming, reversal, and crawling are controlled by nongiant interneuron pathways. Ivermectin inhibited swimming, reversal, crawling frequency, and crawling speed in a time- and concentration-dependent manner with a mean inhibitory concentration (IC50) at 3 h of 1.1, 16, 91, and 51 nM, respectively. Ivermectin at 0.3 nM also significantly decreased the frequency of helical swimming waves. Picrotoxin, a Cl- channel blocker, antagonized the ivermectin-induced decrease in swimming frequency, crawling frequency, and crawling speed. There were no adverse effects on escape reflex 3 h after exposure to 300 nM ivermectin. Electrophysiological recordings showed that ivermectin had no effects on the conduction velocity of giant fiber systems. The results indicated that locomotor behaviors controlled by nongiant locomotor pathways were more sensitive to ivermectin than pathways controlled by giant interneurons and that Cl- channels may be involved in mediating ivermectin's inhibitory effects.

Animals↗
PubMed2002

Efficacy of a new long-acting formulation of ivermectin and other injectable avermectins against induced Psoroptes ovis infestations in cattle.

Two studies describe the therapeutic and protective efficacy of commercially available, injectable avermectins against Psoroptes ovis infestations. In each study, six untreated calves were compared to groups of six calves each treated with ivermectin long-acting injectable (LAI) 3.15% w/v solution, generic long-acting (LA) ivermectin 1% w/v solution or 1% w/v doramectin solution. Treatments were carried out according to the manufacturer's instructions at 1 ml/50 kg body weight. Live mites in skin scrapings were counted prior to treatment and at weekly intervals for 8 weeks thereafter in the therapeutic study, or at 15, 21 and 28 days after P. ovis challenge which occurred 28 days post-treatment in the study to compare protective efficacy. P. ovis infested calves treated with ivermectin LAI had significantly ( P<0.05) fewer mites than did the untreated controls from 1 week after treatment. They also had significantly fewer mites at 7 and 8 weeks after treatment than did the calves treated with generic LA ivermectin and at 8 weeks after treatment than the calves treated with doramectin. No mites were counted on the animals treated with ivermectin LAI from 4 weeks after treatment through to the end of the study; however, five of the six calves from each of the groups treated with generic LA ivermectin or doramectin were infested with P. ovis at 8 weeks after treatment. No P. ovis mites were recorded on the calves treated prophylactically with ivermectin LAI. In contrast, five or all of the six calves treated prophylactically with generic LA ivermectin or doramectin, respectively, were positive for P. ovis mites at the end of the study. Calves treated prophylactically with ivermectin LAI gained significantly more weight than the untreated controls.

Animals↗
PubMed1994

Effect of ivermectin on gamma-aminobutyric acid-induced chloride currents in mouse hippocampal embryonic neurones.

The effect of ivermectin on gamma-aminobutyric acid (GABA)-induced Cl- currents was studied in embryonicse hippocampal cells in culture. When 0.1 microM ivermectin was applied to the perfusion medium, the responses to 2 microM GABA were enhanced to 273% within 60 s, and the GABA EC50 was reduced from 8.2 to 3.2 microM. Half-maximal potentiation of GABA responses was found with 17.8 nM ivermectin. The potentiating effect of ivermectin diminished to 146% within 10 min but the GABA EC50 did not change any further. At the same time, the maximal GABA-induced Cl- current decreased to 64%. Both the fast and slow desensitization time constants of GABA-activated membrane currents were shortened after ivermectin application. The final effect of ivermectin was irreversible. Modulation of the GABA responses by ivermectin did not interfere with the potentiation induced by diazepam and pentobarbital or with the sensitivity to blockade by bicuculline, picrotoxin and Zn2+. These results support the view that ivermectin binds to a novel site on the GABAA receptor and allosterically enhances the affinity of the GABA binding site. The more slowly occurring conformational changes in the ivermectin-GABAA receptor complex apparently accelerate the desensitization of the GABAA receptor, reducing the amplitude of maximal GABA-induced currents.

Animals↗
PubMed1991

Effects of repeated doses of ivermectin on ocular onchocerciasis: community-based trial in Sierra Leone.

Ivermectin seems to be a safe and effective treatment for onchocerciasis when given in a single dose, but less is known about the effects of repeated doses. Also, there seem to be differences in its effectiveness in anterior and posterior segment ocular disease. The ocular effects of ivermectin were studied in 586 villagers who were taking part in a double-blind, placebo-controlled, randomised trial in Sierra Leone. Only those who had received four doses, with 6-month intervals, of ivermectin or placebo were eligible. The 296 ivermectin-treated subjects and the 272 who received placebo were comparable with respect to age, sex, Onchocerca infection, blindness, and visual impairment before treatment. After treatment, the ivermectin group had less anterior segment disease than the placebo group, with significantly lower prevalences of microfilariae in the anterior chamber and cornea, and punctate keratitis (all p less than 0.001), and iritis (p less than 0.05). There was no significant difference in the prevalence of sclerosing keratitis, optic atrophy, or chorioretinitis between the groups. Visual acuities tended to be better in the ivermectin group, but the difference was not significant. There was a small but significant (p less than 0.01) excess of vascular sheathing in the ivermectin group. These differences persisted when subjects who were blind or visually impaired at baseline were excluded from analysis. The long-term effects of ivermectin, particularly on posterior segment disease, need further evaluation. In the mean time, the mass distribution of ivermectin should be promoted for all communities with hyperendemic onchocerciasis at risk of anterior segment disease.

Adolescent↗
PubMed2004

Cattle protected from onchocerciasis by ivermectin are highly susceptible to infection after drug withdrawal.

Ivermectin administration is now the major tool in the control of human onchocerciasis (caused by Onchocerca volvulus) based on its suppression of microfilariae and hence the prevention of disease. However, in Africa, transmission is not eliminated and treated populations continue to be exposed to infective larval (L(3)) challenge, albeit at reduced levels. We have investigated whether protective immunity might develop under such conditions using the analogous host-parasite system Onchocerca ochengi in cattle, based on our previous findings in cattle exposed to challenge, that in vivo ivermectin attenuates the development of adult infections and that irradiation-attenuated L(3) induce significant protection. In a two-phase prospective study over 4 years, groups of cattle were exposed to severe natural challenge. In the first phase, 38/40 animals treated either with ivermectin or with moxidectin at either monthly or 3-monthly intervals had not developed detectable infections after 22 months of exposure whereas, in a non-treated control group (n = 14) nodule prevalence was 78.6% and the geometric mean (range) nodule load was 4.8 (0-33). In the second phase, all drug treatments were withdrawn, a new control group (n = 8) introduced, and exposure continued at the same site. After 24 months, all groups had developed patent infections, with geometric mean (range) nodule loads of 17.4 (4-99), 38.4 (10-111), 50.7 (26-86), 14.3 (0-69) and 14.7 (0-55) for the control, monthly-ivermectin, 3-monthly ivermectin, monthly moxidectin and 3-monthly moxidectin groups, respectively. There was no evidence of protection-indeed the 3-monthly ivermectin group was significantly (P < 0.05) hyper-susceptible. In addition, microfilarial densities and the rate of increase in microfilarial load were significantly higher (P < 0.05) in the ivermectin-treated groups than in control animals. These results have important implications for ivermectin-based control of human onchocerciasis and suggest that humans exposed to ongoing transmission in endemic areas whilst receiving ivermectin are unlikely to develop immunity and will be highly susceptible should drug distribution cease.

Animals↗
PubMed2005

Liquid chromatographic assay of ivermectin in human plasma for application to clinical pharmacokinetic studies.

There is a need for an accurate, sensitive and selective high-performance liquid chromatography (HPLC) method for the quantitation of ivermectin in human plasma that separates the parent drug from metabolites. Ivermectin and the internal standard, moxidectin, were extracted from 0.2 ml of human plasma using Oasis HLB solid phase extraction cartridges. After extraction, fluorescent derivatives of ivermectin and moxidectin were made by reaction with trifluoroacetic anhydride and N-methylimidazole. Separation was achieved on a Alltech Ultrasphere C18 5mu column with a mobile phase composed of tetrahydrofuran-acetonitrile-water (40:38:22 v/v/v). Detection is by fluorescence, with an excitation of 365 nm and emission of 475 nm. The retention times of ivermectin and internal standard, moxidectin are approximately 24.5 and 12.5 min, respectively. The assay is linear over the concentration range of 0.2-200 ng/ml of ivermectin in human plasma (r = 0.9992, weighted by 1/concentration). Recoveries of ivermectin are greater than 80% at all concentrations. The analysis of quality control samples for ivermectin 0.2, 25, and 200 ng/ml demonstrated excellent precision with coefficient of variation of 6.1, 3.6 and 2.3%, respectively (n = 6). The method is accurate with all intra-day (n = 6) and interday (n = 12) mean concentration within 10% of nominal values at all quality control sample concentrations. Storage stability for 30 days at -80 degrees C and after three freeze-thaw cycles are within acceptable limits. The method separates ivermectin from multiple less and more polar unidentified metabolites. This method is robust and suitable for clinical pharmacokinetic studies. The analytical procedure has been applied to a pharmacokinetic study of ivermectin in healthy volunteers and to the analysis of plasma specimens from patients with disseminated strongyloidiasis.

Antiparasitic Agents↗
PubMed1999

Resistance of field isolates of Trichostrongylus colubriformis and Ostertagia circumcincta to ivermectin.

Twelve Romney lambs and 10 Angora goats were infected with 7000 infective third-stage larvae (89% Trichostrongylus, 11% Ostertagia) collected from goats suspected of harbouring ivermectin-resistant nematodes. On 28 days p.i., the lambs and goats were divided into treatment and control groups of six and five animals, respectively. The animals in the treatment groups were treated with ivermectin (0.2 mg/kg) and necropsied 35 days p.i. Faecal egg counts were estimated on days 28 and 35 p.i. and larval development assays (LDAs) were conducted on 22, 24, 26, 28, 30, 32, 34 and 35 days p.i. The ivermectin treatment reduced Trichostronglus colubriformis burdens by 39% and 13% and Ostertagia circumcincta by 33% and 0% in lambs and goats, respectively. When compared with a susceptible strain, the LDAs indicated a resistance factor before treatment in lambs for T. colubriformis of 2.6 and 1.5 with ivermectin and avermectin B2, respectively, which rose to 3.4 and 2.0 after treatment. The LD50 values of the two control groups were relatively constant throughout the experiment. Prior to ivermectin treatment the LD50 values of the treated groups were similar (P > 0.05) to the control groups but following ivermectin treatment their LD50 values increased steadily until the animals were killed on 35 days p.i. The LD50 values for ivermectin and avermectin B2 of sheep were always slightly higher and significantly different (P < 0.01) than those of goats indicating a host effect on this parameter. The greater reduction in worm counts in goats suggests a difference in the efficacy of ivermectin between lambs and goats. This is the first confirmed report of ivermectin resistance in a field strain of T. colubriformis.

Administration, Oral↗