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 (EC50=50.18 μM) and contraction amplitude (EC50=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.

Parascaris sp. is the only ascarid parasitic nematode in equids and one of the most threatening infectious organisms in horses. Only a limited number of compounds are available for treatment of horse helminthiasis, and Parascaris sp. worms have developed resistance to the three major anthelmintic families. In order to overcome the appearance of resistance, there is an urgent need for new therapeutic strategies. The active ingredients of herbal essential oils are potentially effective antiparasitic drugs. Carvacrol is one of the principal chemicals of essential oil from Origanum, Thymus, Coridothymus, Thymbra, Satureja and Lippia herbs. However, the antiparasitic mode of action of carvacrol is poorly understood. Here, the objective of the work was to characterize the activity of carvacrol on Parascaris sp. nicotinic acetylcholine receptor (nAChR) function both in vivo with the use of worm neuromuscular flap preparations and in vitro with two-electrode voltage-clamp electrophysiology on nAChRs expressed in Xenopus oocytes. We developed a neuromuscular contraction assay for Parascaris body flaps and obtained acetylcholine concentration-dependent contraction responses. Strikingly, we observed that 300 µM carvacrol fully and irreversibly abolished Parascaris sp. muscle contractions elicited by acetylcholine. Similarly, carvacrol antagonized acetylcholine-induced currents from both the nicotine-sensitive AChR and the morantel-sensitive AChR subtypes. Thus, we show for the first time that body muscle flap preparation is a tractable approach to investigating the pharmacology of Parascaris sp. neuromuscular system. Our results suggest an intriguing mode of action for carvacrol, being a potent antagonist of muscle nAChRs of Parascaris sp. worms, which may account for its antiparasitic potency.

Background: The objective of this study was to evaluate the efficacy of modified clinoptilolite (Minazel Plus^®, MZ) as a mycotoxin adsorbent for preventing the negative the effects of ochratoxin A (OTA) on performance, pathohistological changes, and OTA residue in the eggs of laying hens. Methods: Forty eight (n = 48) laying hens (27 weeks old) were equally divided into six groups and depending on the type of addition were allocated to the following experimental treatments for 7 weeks: E-I group-1 mg/kg OTA; E-II group 0.25 mg/kg OTA; E-III group 1 mg/kg OTA + 0.2% of MZ; E-IV group 0.25 mg/kg OTA + 0.2% of MZ; MZ group supplemented with 0.2% of the adsorbent; and control (K, without feed additive). Results: Overall, the addition of 0.2% MZ to laying hen feed mitigated the harmful effects of OTA on target organs and reduced the presence of OTA residue in eggs. The groups that received 0.2% of MZ achieved better production results in terms of body weight, number of eggs, and feed consumption, compared to the other treatments. Conclusions: The current findings confirm the efficacy of MZ in preventing performance losses in laying hens exposed to OTA, as well as for improving the welfare and health of food producing animals.