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

Abstract

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. 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. 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. 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.