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

Abstract

Background and Aim: Diphenhydramine is an H1-antihistamine that counteracts the toxic effects of organophosphate and carbamate insecticides that inhibit cholinesterase (ChE) activity. This meta-analysis aimed to investigate the effects of diphenhydramine on ChE inhibition induced by these insecticides in the plasma, erythrocytes, or whole brain of experimental animals. Materials and Methods: A data search was performed on erythrocyte, plasma, and brain ChE inhibition caused by organophosphate and carbamate insecticides in experimental animals (mice, rats, and chicks) treated with the antihistamine diphenhydramine in accordance with preferred reporting items for systematic reviews and meta-analysis, which was done by the two-group random-effects model meta-analysis. The meta-analysis included 18 records extracted from six studies that appeared from 1996 to 2022. Results: Using the random-effects model, a two-group meta-analysis revealed that the combined effect size (ChE inhibition) was significantly more favorable in the control group than in the diphenhydramine intervention, as shown by a forest plot. The combined effect size (standardized mean difference) was 0.67, with a standard error of 0.3, a lower limit of 0.04, and an upper limit of 1.29 (p = 0.025). The heterogeneity was moderate, as I2 of the combined effect size was 74%, with a significant Cochrane Q-test result (Q = 65, p < 0.0001). Subgroup analysis indicated that, with brain ChE inhibition, the heterogeneity (I2) became 5%, which was lower than ChE inhibition in plasma (84%) and erythrocytes (78%). No publication bias was identified using the funnel plot and Egger's test. Conclusion: This meta-analysis suggests that, in addition to its documented antidotal action against ChE-inhibiting insecticides, diphenhydramine can also reduce the extent of ChE inhibition, especially in the brain, which is the main site of toxicity of these insecticides. There is a need for additional studies to assess such enzyme inhibition in different parts of the brain.

Antidotal Effects of the Antihistamine Diphenhydramine Against Cholinesterase Inhibitor Poisoning: A Meta-Analysis of Median Lethal Doses in Experimental Animals

“…The present meta-analysis of LD50 values indicated that diphenhydramine unequivocally protected experimental animals (mice, rats, and chicks) from the acute toxicity of ChE inhibitors. This result is in agreement with a recent meta-analysis of the antidotal action of diphenhydramine against organophosphate and carbamate insecticides taking into consideration the acute toxidrome of these insecticides, but not their LD50 values [12]. LD50 values of toxicants are excellent indices of their acute toxicity, especially when conducted within 24 hours [31,36].…”

“…The mechanism of ameliorative action of diphenhydramine against ChE inhibitors' intoxication is most probably due to the potent antimuscarinic property of this antihistamine [10][11][12]. There is also a possibility of additional anti-nicotinic and anti-ChE (weak inhibition) actions of diphenhydramine that might contribute to this antidotal action [12,13].…”

“…Other antidotal agents such as the ChE reactivators oximes and benzodiazepines have been used too [8,9]. The H1 antihistamine diphenhydramine, with its potent antimuscarinic action, has been applied clinically in human beings and animals to antagonize organophosphate or carbamate poisoning in a manner similar to the standard antidote atropine [10][11][12][13]. The antagonistic actions of diphenhydramine against organophosphate or carbamate toxidrome of poisoning and lethality have been documented in experimental laboratory animals such as mice [14][15][16][17][18][19][20][21], rats [19,[22][23][24][25], and young chicks [26][27][28][29].…”

“…Additionally, one study reported the antidotal effect of diphenhydramine against imidocarb toxicosis in chicks [30]. A few review articles have delineated the antidotal properties of diphenhydramine against ChE inhibitors [10][11][12][13]. These review studies have focused either on the antidotal clinical use of diphenhydramine [10,11], ameliorative action on the cholinergic toxidrome in experimental animals [12], or the decrease in blood and brain ChE inhibition caused by organophosphates and carbamates [13], and one of the recent meta-analyses on diphenhydramine effects has demonstrated that this antihistamine significantly reduces the relative risks of organophosphate and carbamate pesticides by considering signs of poisoning and lethality in experimental laboratory animals [12].…”

“…A few review articles have delineated the antidotal properties of diphenhydramine against ChE inhibitors [10][11][12][13]. These review studies have focused either on the antidotal clinical use of diphenhydramine [10,11], ameliorative action on the cholinergic toxidrome in experimental animals [12], or the decrease in blood and brain ChE inhibition caused by organophosphates and carbamates [13], and one of the recent meta-analyses on diphenhydramine effects has demonstrated that this antihistamine significantly reduces the relative risks of organophosphate and carbamate pesticides by considering signs of poisoning and lethality in experimental laboratory animals [12]. However, none of the reviews cited above have considered analysis of the acute toxicity (median lethal dose, LD50) outcome of ChE inhibitors by the antidotal action of diphenhydramine [10][11][12][13], and we took this information gap for further meta-analytic exploration.…”