Antagonism of methomyl-induced toxicosis by diphenhydramine in rats

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Abstract

The efficacy of diphenhydramine in the prevention and treatment of methomyl-induced toxicosis was evaluated in female rats. Diphenhydramine at 10 and 20 mg/kg subcutaneously (s.c.) given immediately after methomyl increased the LD50 of methomyl (6.29 mg/kg intraperitoneally (i.p.)) in the rats by 71 and 75% respectively. Diphenhydramine at 20 mg/kg s.c. given immediately after methomyl (6 mg/kg i.p.) decreased the occurrence of cholinergic signs of toxicosis, and prevented convulsions, gasping and death by 100% in comparison with the control (methomyl-saline) group. Diphenhydramine administration at 2.5, 5 and 10 mg/kg s.c. 20 min before methomyl (8 mg/kg i.p.) significantly and dose-dependently decreased the number of convulsion episodes in rats in comparison with the control group. This effect was similar to those of atropine and diazepam pretreatments at 20 mg/kg s.c. Diphenhydramine and atropine at 20 mg/kg i.p. given 5 min after the methomyl administration (8 mg/kg i.p.) were close to each other in reducing the signs of cholinergic toxicity as well as the severity of toxicosis induced by methomyl in rats. Methomyl at 4 and 8 mg/kg i.p. significantly decreased erythrocyte (40 and 43%) and plasma (23 and 31%) cholinesterase activities in comparison with the control group. Diphenhydramine (10 mg/kg s.c.) injected 15 min before methomyl significantly decreased the inhibitory effect of methomyl (4 and 8 mg/kg i.p.) on erythrocyte cholinesterase to 17 and 27%, respectively. The inhibitory effect on plasma cholinesterase was not affected by the diphenhydramine pretreatment. The data suggest that diphenhydramine could be of therapeutic value in reducing the toxic effects of methomyl.

Introduction

Methomyl is a carbamate insecticide widely used in agriculture (WHO, 1996). It induces acute cholinergic poisoning in mammals by inhibiting acetylcholinesterase (AChE) activity reversibly with a subsequent accumulation of acetylcholine at peripheral and central nervous systems (Osweiler et al., 1985, Fikes, 1990, WHO, 1996). Atropine is the standard antidote used to control only the muscarinic signs of carbamate poisoning (Fikes, 1990, WHO, 1996).

The H1-receptor antagonist diphenhydramine was found to protect mice against physostigmine and neostigmine toxicosis and lethality (Mohammad et al., 1987). It also protects mice (Mohammad et al., 1989, Faris and Mohammad, 1997) and dogs (Clemmons et al., 1984, Fikes, 1990) against organophosphate insecticide-induced toxicosis. Diphenhydramine alleviates the muscarinic (Mohammad et al., 1987, Mohammad et al., 1989, Fikes, 1990, Faris and Mohammad, 1997) and nicotinic (Clemmons et al., 1984, Moody and Terp, 1988, Fikes, 1990) signs of poisoning produced by the AChE inhibitors. Furthermore, diphenhydramine inhibits the effects of acetylcholine at the neuromuscular junction (Katayama and Tasaka, 1985). However, diphenhydramine inhibits cholinesterases in vitro (Fernandez et al., 1975) and in vivo (Fernandez et al., 1975, Faris and Mohammad, 1996), but this effect apparently does not interfere with the antidotal action of diphenhydramine against poisoning produced by AChE inhibitors (Mohammad et al., 1987, Mohammad et al., 1989, Fikes, 1990, Faris and Mohammad, 1996).

The purpose of the present study was to further examine and expand the antidotal efficacy of diphenhydramine against methomyl-induced toxicosis in rats, since such information is not available in the literature. Atropine and diazepam were used in the present study as the standard antimuscarinic (WHO, 1986, Domino, 1987, Fikes, 1990) and anticonvulsant (Domino, 1987) agents, respectively.

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Animals

Female albino Wistar rats (Drug Control Center, Ministry of Health, Baghdad, Iraq) weighing 116–167 g were used. The rats were housed in rodent plastic cages (55×33×20 cm with wire mesh covers) (four or five per cage) with wood shavings as bedding. The housing quarter was maintained at a temperature of 23±2°C with a 14-h light, 10-h dark cycle. Pelleted rodent food (according to specifications of Rodent Laboratory Chow 5001, Ralston Purina, St. Louis, MO) and water were available ad libitum.

Determination of the median lethal dose (LD50) of methomyl

Effect of diphenhydramine on the LD50 value of methomyl

The 24-h LD50 value of methomyl in rats was 6.29 mg/kg (Table 1). The intoxicated rats showed signs of cholinergic overstimulation within 1–4 min. The signs were salivation, lacrimation, piloerection, tremors, straub tail, flat body appearance, muscle fasiculation, convulsions and gasping before death within 7–27 min. Subcutaneous injection of diphenhydramine at 10 and 20 mg/kg increased the LD50 value of methomyl by 71 and 75%, respectively (Table 1). Correspondingly, the protective ratios

Discussion

The signs of methomyl poisoning seen in the rats were characteristic of cholinergic toxicity in rodents (Buccafusco, 1982, Mohammad et al., 1987, Buccafusco et al., 1988, Mohammad et al., 1989, Faris and Mohammad, 1997). Carbamate insecticides reversibly inhibit AChE leading to accumulation of acetylcholine at the nerve endings and subsequently causing parasympathetic overstimulation (Fikes, 1990, WHO, 1996).

Diphenhydramine effectively protected and treated rats acutely intoxicated with

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  • This report represents a portion of a thesis submitted by the first author to the University of Mosul, Iraq as partial fulfillment of the requirements for MSc degree in Veterinary Pharmacology and Toxicology. Presented in part at the 6th Scientific and Professional Meeting of the Iraqi Veterinary Medical Association, Baghdad, Iraq, October 26–28, 1998.

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