Paraherquamide is a novel natural anthelmintic product with a mode of action that is incompletely characterized. Nicotine and cholinergic-anthelmintic agonists of different chemical classes were used to produce contraction in Ascaris muscle strips. Paraherquamide and a semisynthetic derivative, 2-deoxy-paraherquamide, antagonized these responses. Analysis of the actions of the antagonists was made using the simple competitive model and nonlinear regression to estimate the pK B values of the antagonists. The analysis was tested using Clark plots. The pK B values for paraherquamide were: nicotine, 5.86 Ϯ 0.14; levamisole, 6.61 Ϯ 0.19; pyrantel, 6.50 Ϯ 0.11; and bephenium, 6.75 Ϯ 0.15. The pK B of nicotine was significantly different from the pK B values for levamisole, pyrantel, and bephenium, showing that paraherquamide can distinguish a subtype of cholinergic receptors sensitive to nicotine and a subtype of cholinergic receptors sensitive to levamisole, pyrantel, and bephenium. The pK B values for 2-deoxy-paraherquamide were: levamisole, 5.31 Ϯ 0.13; pyrantel, 5.63 Ϯ 0.10; and bephenium, 6.07 Ϯ 0.13. The Clark plots of the antagonism illustrated the degree of fit to the competitive model for 2-deoxy-paraherquamide. 2-Deoxy-paraherquamide selectively antagonized the effects of bephenium; the pK B values of levamisole and pyrantel were significantly different from the pK B of bephenium. Paraherquamide and 2-deoxy-paraherquamide are selective competitive cholinergic antagonists that distinguish subtypes of cholinergic receptor in Ascaris muscle corresponding to nicotine-, levamisole-, and bephenium-sensitive receptors.Nematode parasite infections of humans and animals cause disease with loss of productivity, debility, and occasionally death. Ascariasis and hookworm infections are carried by 1.6 billion people throughout the world and in 2% of cases cause loss of life. The use of therapeutic compounds forms a major component of control, and the development of novel therapeutic agents is required to deal with the increasing levels of resistance to existing drugs.Paraherquamide (Fig. 1) is a novel anthelmintic (Yamazaki et al., 1981) that is an alkaloid fermentation product originally isolated from Penicillium paraherquii. The anthelmintic property of paraherquamide was first identified using jirds infected with Trichostrongylus colubriformis (Ostlind et al., 1990). Paraherquamide produces paralysis of parasitic nematodes in culture, without an effect on ATP, suggesting that it does not act as a metabolic poison (Thompson et al., 1996). Interestingly, one of the toxic effects of paraherquamide in the dog (Shoop et al., 1990) is a prolapsed nictitating membrane, an effect that suggests antagonism of neuronal nicotinic receptors (nAChRs). Recently, it has been reported (E.

No abstract

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 M) and contraction amplitude (EC 50 =59.32 M) 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.

No abstract

Essential plant oils (or their active principles) are safe to use and a potentially attractive alternative to current antiparasitic drugs. In the present study, we tested the effects of carvacrol on the isolated tissues of Ascaris suum and investigated potential interactions with other antiparasitic drugs. We used somatic muscle flaps for contraction assays, as well as for electrophysiological investigations. Carvacrol 300 μM highly significantly inhibited contractions caused by 1, 3, 10, 30, and 100 μM of ACh (p=0.0023, p=0.0002, p=0.0002, p<0.0001, and p<0.0001). The control EC50 for acetylcholine was 8.87 μM (log EC50=0.95±0.26), while Rmax was 2.53±0.24 g. The EC50 of acetylcholine in the presence of 300 μM of carvacrol was 27.71 μM (log EC50=1.44±0.28) and the Rmax decreased to 1.63±0.32 g. Furthermore, carvacrol highly significant potentiates inhibitory effect of GABA and piperazine on the contractions induced by ACh. However, carvacrol (100 and 300 μM), did not produce any changes in the membrane potential or conductance of the A. suum muscle cell. While, 300 μM of carvacrol showed a significant inhibitory effect on ACh-induced depolarization response. The mean control depolarization was 13.58±0.66 mV and decreased in presence of carvacrol to 4.50±1.02 mV (p<0.0001). Mean control Δg was 0.168±0.017 μS, while in the presence of 300 μM of carvacrol, Δg significantly decreased to 0.060±0.018 ΔS (p=0.0017). The inhibitory effect on contractions may be the explanation of the antinematodal potential of carvacrol. Moreover, inhibition of depolarizations caused by ACh and reduction of conductance changes directly points to an interaction with the nAChR in A. suum.