title: Central and peripheral neurotoxic effects of ivermectin in rats.
abstract: Ivermectin is considered a very safe drug; however, there are reports of toxic effects in particularly sensitive populations or due to accidental overdose. The aim of this study was (1) to further characterize the central and peripheral toxic effects of ivermectin in animals and (2) to determine possible therapeutic strategies for use in cases of ivermectin poisoning. We tested the effects of experimental doses of ivermectin previously reported to cause various intensities of CNS depression. However, in our study, ivermectin at 2.5, 5.0 and 7.5 mg/kg i.v. did not produce visible CNS depression in rats and 10 mg/kg resulted in sleepiness and staggering 10 to 40 min after application, while a dose of 15 mg/kg caused CNS depression very similar to general anesthesia. Ivermectin dose-dependently potentiates thiopentone-induced sleeping time in rats. Flumazenil (0.2 mg/kg), the benzodiazepine antagonist, did not affect the action of thiopentone; however, it significantly reduced sleeping time in rats treated with a combination of ivermectin (10 mg/kg) and thiopentone (25 mg/kg; from 189.86 ± 45.28 min to 83.13 ± 32.22 min; mean ± SD). Ivermectin causes an increase in the tonus (EC(50)=50.18 µM) and contraction amplitude (EC(50)=59.32 µM) of isolated guinea pig ileum, very similar to GABA, but without the initial relaxation period. These effects are dose-dependent and sensitive to atropine. Our results confirm the central and peripheral GABAergic properties of ivermectin in mammals and also indicate involvement of the cholinergic system in its toxicity. In addition, the results suggest that flumazenil and atropine have potential clinical roles in the treatment of ivermectin toxicity.
authors.affiliation: Faculty of Veterinary Medicine, Department of Pharmacology and Toxicology, University of Belgrade, Bulevar oslobodjenja 18, Belgrade 11000,Serbia. sasa@vet.bg.ac.rs
authors.forename: Sasa M
authors.initials: SM
authors.lastname: Trailovic
authors.forename: Jelena Trailovic
authors.initials: JT
authors.lastname: Nedeljkovic
mesh_terms: D000759:Adjuvants, Anesthesia / Q000494:pharmacology; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D000977:Antiparasitic Agents / Q000009:adverse effects*; D001285:Atropine / Q000494:pharmacology; D002493:Central Nervous System Diseases / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005442:Flumazenil / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D007559:Ivermectin / Q000009:adverse effects*; D008297:Male; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced*; D051381:Rats; D017208:Rats, Wistar; D013874:Thiopental / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000759:Adjuvants, Anesthesia; D000931:Antidotes; D000977:Antiparasitic Agents; D005442:Flumazenil; D007559:Ivermectin; D001285:Atropine; D013874:Thiopental