Recognition and Assessment of Antidotal Effects of Diphenhydramine against Acute Carbaryl Insecticide Poisoning in a Chick Model

Abstract

Diphenhydramine antagonizes poisoning produced by cholinesterase (ChE) inhibiting insecticides. This study examines the effects of diphenhydramine against acute poisoning induced by the carbamate insecticide carbaryl in a chick model. The effects of diphenhydramine on the 24 h median Lethal Dose (LD50), and acute toxicity of carbaryl were assessed in chicks (7-15 days old). The plasma and whole brain ChE activities were measured electrometrically in vitro and in vivo. Diphenhydramine at 10mg/Kg Body wt. administered intramuscularly 15 min before carbaryl dosing increased the oral LD50 value of carbaryl (207 mg/Kg Body wt.) by 62%. Carbaryl at 250 mg/Kg Body wt. has orally produced toxidrome of cholinergic poisoning with 100% lethality in 24 h. Diphenhydramine (10mg/ Kg Body wt.) used 15 min before carbaryl (250mg/Kg Body wt., orally) was the most effective dose (vs 5 and 20mg/Kg Body wt.) in delaying carbaryl-toxicity and increasing survivals in chicks. The intramuscular median effective dose (ED50) of diphenhydramine which prevented 24 h carbaryl-death in chicks was 8.6mg/ Kg Body wt. The antidotal response to diphenhydramine was similar to that of the standard antidote atropine sulfate. Diphenhydramine at 10mg/Kg Body wt., given immediately after carbaryl (200mg/Kg Body wt.), reduced the percentages of plasma and whole brain ChE inhibitions in vivo by 12- and 13%, respectively. Carbaryl (10μmol/L) in vitro inhibited ChE activities in the plasma and brain by 53 and 77%, respectively; these inhibitions were reduced by 13- and 14%, respectively, when diphenhydramine (10μmol/L) was added to in vitro reactions. Diphenhydramine exerted antidotal action against a model of acute and lethal carbaryl intoxication in chicks.

First meta-analysis study of cholinesterase inhibition in experimental animals by organophosphate or carbamate insecticides under the influence of diphenhydramine

“…However, other sources of heterogeneity could be the types of insecticides used, since they variably and differentially inhibit ChEs, and the species of experimental animals, since they inherently possess ChEs of various physiological activities in the blood or brain [43,44]. In support of our meta-analysis, which was conducted on blood and brain ChEs in vivo (mice, rats, and chicks), in vitro studies on human PChE and EChE [30] and chick PChE and BChE [21,22] suggested that diphenhydramine might partially protect the enzyme from additional inhibition induced by OP or CA insecticides. However, at the current stage, we cautiously draw such a conclusion, since the prediction of a future study by the drapery plot suggested the possibility of a shift of the point of effect size toward the diphenhydramine intervention.…”

“…Studies in humans [23,24] and animals [9,25] have demonstrated that diphenhydramine can be used as an alternative, but not a substitute, antidote against poisoning induced by ChE-inhibiting OP or CA insecticides. The antidotal effects of diphenhydramine against poisoning by OP or CA insecticides in experimental animals have been well documented [11][12][13][14][15][16][17][18][19][20][21][22]. Regarding the proposed mechanism behind the antidotal action of diphenhydramine, this has been attributed to its potent antimuscarinic [9][10][11] and possibly antinicotinic effects [23].…”

“…Regarding the proposed mechanism behind the antidotal action of diphenhydramine, this has been attributed to its potent antimuscarinic [9][10][11] and possibly antinicotinic effects [23]. However, despite the variations in the effects of diphenhydramine on PChE, EChE, or BChE activities in different animal species intoxicated with OP or CA insecticides [14,15,[20][21][22]31], some studies have suggested that diphenhydramine might protect the enzyme from further inhibition by the insecticides [20][21][22]. The suggested weak inhibitory action of diphenhydramine on ChE activity [32] might contribute to its antidotal property [21,22,30].…”

“…Meanwhile, diphenhydramine alone was reported to exhibit inhibitory effects on PChE and BChE in vivo in chicks [32]. These findings raised the possibility that diphenhydramine could weakly inhibit OP-induced ChE inhibition [21,22,30], as found with other weak ChE inhibitors [33,34].…”

“…Several studies in mice [ 11 – 13 ], rats [ 14 – 19 ], and chicks [ 20 – 22 ] have clearly demonstrated that diphenhydramine, similar to the standard antidote atropine, reduced the toxicity of these insecticides. The antidotal or preventive actions of diphenhydramine against these insecticides involved increasing the median lethal insecticide dose, decreasing the occurrence of cholinergic toxidrome with reductions in toxicity scores, delaying the latency to poisoning onset and death, and increasing the survival rate [ 11 – 13 , 16 , 21 , 22 ]. It has also been reported that diphenhydramine reduced OP-induced injuries in the pancreas [ 18 ] and heart [ 19 ] of laboratory rats.…”