Safety of moxidectin in avermectin-sensitive Collies

Paul, Allan; Tranquilli, William J.; Hutchens, Douglas E.

doi:10.2460/ajvr.2000.61.482

Cited by 55 publications

(43 citation statements)

References 3 publications

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“…This result is consistent with previous work reporting an IVM LD 50 of 0.6–0.8 µmol/kg bw in Mdr1a-deficient mice which had been mutated on only the abcb1a gene and had a compensatory increase in expression of the abcb1b gene [3]. Further, our results in the Mdr1ab−/− mice are consistent with observations that MOX did not induce any signs of toxicosis in IVM-sensitive dogs, which are P-gp-deficient [17], [19].…”

Section: Discussionsupporting

confidence: 93%

“…However, in dogs sensitive to 120 µg/kg IVM administered orally, a similar molar dose rate of MOX given by the same route did not produce any toxicological signs [17]. In another study, P-gp-deficient dogs that were sensitive to 120 µg/ml of IVM (20× the therapeutic dose rate (6 µg/kg) for IVM as a monthly heartworm preventative) did not produce signs of toxicosis following exposure to MOX at 100 µg/kg (more than the molar equivalent to 120 µg/ml IVM, and 33-fold the therapeutic dose rate (3 µg/kg) for MOX as a monthly heartworm preventative) given daily for 7 days [18].…”

Section: Introductionmentioning

confidence: 89%

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Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (−/−) Mice and Effects on Mammalian GABA(A) Channel Activity

et al. 2012

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The anthelmintics ivermectin (IVM) and moxidectin (MOX) display differences in toxicity in several host species. Entrance into the brain is restricted by the P-glycoprotein (P-gp) efflux transporter, while toxicity is mediated through the brain GABA(A) receptors. This study compared the toxicity of IVM and MOX in vivo and their interaction with GABA(A) receptors in vitro. Drug toxicity was assessed in Mdr1ab(−/−) mice P-gp-deficient after subcutaneous administration of increasing doses (0.11–2.0 and 0.23–12.9 µmol/kg for IVM and MOX in P-gp-deficient mice and half lethal doses (LD50) in wild-type mice). Survival was evaluated over 14-days. In Mdr1ab(−/−) mice, LD50 was 0.46 and 2.3 µmol/kg for IVM and MOX, respectively, demonstrating that MOX was less toxic than IVM. In P-gp-deficient mice, MOX had a lower brain-to-plasma concentration ratio and entered into the brain more slowly than IVM. The brain sublethal drug concentrations determined after administration of doses close to LD50 were, in Mdr1ab(−/−) and wild-type mice, respectively, 270 and 210 pmol/g for IVM and 830 and 740–1380 pmol/g for MOX, indicating that higher brain concentrations are required for MOX toxicity than IVM. In rat α1β2γ2 GABA channels expressed in Xenopus oocytes, IVM and MOX were both allosteric activators of the GABA-induced response. The Hill coefficient was 1.52±0.45 for IVM and 0.34±0.56 for MOX (p<0.001), while the maximum potentiation caused by IVM and MOX relative to GABA alone was 413.7±66.1 and 257.4±40.6%, respectively (p<0.05), showing that IVM causes a greater potentiation of GABA action on this receptor. Differences in the accumulation of IVM and MOX in the brain and in the interaction of IVM and MOX with GABA(A) receptors account for differences in neurotoxicity seen in intact and Mdr1-deficient animals. These differences in neurotoxicity of IVM and MOX are important in considering their use in humans.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 89%

Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (−/−) Mice and Effects on Mammalian GABA(A) Channel Activity

et al. 2012

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“…Thus, vertebrates (mostly mammals) are normally protected from the effects of avermectins by the blood-brain barrier [90]. However, although signs of toxicosis have not been observed in collie dogs treated repeatedly with IVM at doses ≤ 60 µg kg -1 of body weight, certain genetic lines of collies (approximately 35% of all collies treated with 120 µg IVM kg -1 ) develop mild to moderate signs of toxicosis [91-92]. Radio-labelled IVM has been detected also in the brain of Atlantic salmon ( Salmo salar ) administered with IVM at normal treatment doses [93].…”

Section: Chemistry and Mode Of Action Of Macrocyclic Lactonesmentioning

confidence: 99%

A Review on the Toxicity and Non-Target Effects of Macrocyclic Lactones in Terrestrial and Aquatic Environments

Lumaret

Errouissi²,

Floate³

et al. 2012

CPB

292

215

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The avermectins, milbemycins and spinosyns are collectively referred to as macrocyclic lactones (MLs) which comprise several classes of chemicals derived from cultures of soil micro-organisms. These compounds are extensively and increasingly used in veterinary medicine and agriculture. Due to their potential effects on non-target organisms, large amounts of information on their impact in the environment has been compiled in recent years, mainly caused by legal requirements related to their marketing authorization or registration. The main objective of this paper is to critically review the present knowledge about the acute and chronic ecotoxicological effects of MLs on organisms, mainly invertebrates, in the terrestrial and aquatic environment. Detailed information is presented on the mode-of-action as well as the ecotoxicity of the most important compounds representing the three groups of MLs. This information, based on more than 360 references, is mainly provided in nine tables, presenting the effects of abamectin, ivermectin, eprinomectin, doramectin, emamectin, moxidectin, and spinosad on individual species of terrestrial and aquatic invertebrates as well as plants and algae. Since dung dwelling organisms are particularly important non-targets, as they are exposed via dung from treated animals over their whole life-cycle, the information on the effects of MLs on dung communities is compiled in an additional table. The results of this review clearly demonstrate that regarding environmental impacts many macrocyclic lactones are substances of high concern particularly with larval instars of invertebrates. Recent studies have also shown that susceptibility varies with life cycle stage and impacts can be mitigated by using MLs when these stages are not present. However information on the environmental impact of the MLs is scattered across a wide range of specialised scientific journals with research focusing mainly on ivermectin and to a lesser extent on abamectin doramectin and moxidectin. By comparison, information on compounds such as eprinomectin, emamectin and selamectin is still relatively scarce.

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“…The individuals evaluating each Collie were masked to treatment, genotype, and phenotype. A predefined four-level scoring system for depression, ataxia, mydriasis, and salivation was employed to assess the clinical impact of loperamide administration (Fassler et al, 1991;Paul et al, 2000). The scoring criteria for each parameter ranged from normal (0) through severe (3), with narrative descriptions included for each scoring category and parameter.…”

Section: Loperamide Administrationmentioning

confidence: 99%

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

Myers

Martinez

et al. 2015

Drug Metab Dispos

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Thirty-three Collies (14 male and 19 female) were used in a doseescalation study to determine the impact of ABCB1 genotype on loperamide pharmacokinetics (PK) and pharmacodynamics (PD). Loperamide was orally administered in four ascending doses (0.01, 0.05, 0.1, or 0.2 mg/kg) over a 4-wk period to fasted Collies. Comparisons were made within each dose to genotype, phenotype, and whether Collies received three (3D) or four (4D) loperamide doses. The 3D and 4D groupings had statistically significant differences in systemic drug exposure (defined by the area under the concentration-versus-time profile estimated from time zero to the last quantifiable drug concentration, AUC 0-last ). In contrast, statistical differences in AUC 0-last only occurred in the comparison between wild-type (WT) Collies versus homozygous mutant (Mut) Collies administered 0.1 mg/kg. Statistical differences in the proportionality relationship were observed when comparing 3D to 4D Collies, and the WT to Mut Collies. Intersubject variability in drug exposure tended to be twice as high between Mut and WT Collies. Associations were observed between systemic drug exposure and ataxia or depression but not between systemic drug exposure and mydriasis or salivation. Thus, Collies expressing the greatest sensitivity to CNS-associated effects of loperamide (Mut) tended to have higher drug exposure compared with those less sensitive to the adverse effects of loperamide. Genotype and phenotype only partially explained differences in loperamide PK and PD, suggesting this relationship may not be straightforward and that other factors need to be considered. Accordingly, the PD and PK of one P-glycoprotein substrate only partially predicted the likelihood of adverse responses to unrelated substrates.

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Safety of moxidectin in avermectin-sensitive Collies

Abstract: The moxidectin formulation used in the study reported here appears to have a wider margin of safety than ivermectin or milbemycin in avermectin-sensitive Collies.

Cited by 55 publications

References 3 publications

Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (−/−) Mice and Effects on Mammalian GABA(A) Channel Activity

Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (−/−) Mice and Effects on Mammalian GABA(A) Channel Activity

A Review on the Toxicity and Non-Target Effects of Macrocyclic Lactones in Terrestrial and Aquatic Environments

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

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