Diphenhydramine as a Protective Agent in a Rat Model of Acute, Lethal Organophosphate Poisoning

Abstract

Objective: To evaluate the effects of diphenhydramine chloride (DPH) on mortality in a rat model of acute, severe organophosphate poisoning (OP). Methods: Wistar rats (n = 40) were randomized to pretreatment with either normal saline (controls), 5 mg/kg atropine, 3 mg/kg DPH, 15 mg/kg DPH, or 30 mg/kg DPH given as a single intramuscular injection 5 minutes prior to a subcutaneous injection of 25 mg/kg dichlorvos (n = 8 per group). The primary endpoint was 10-minute survival. Survival at 24 hours was a secondary endpoint. Comparison of survival rates between groups was carried out by ANOVA and the Student-Newman-Keuls test. Results: Dichlorvos exposure resulted in profound fasciculations within 2 minutes of injection in all cohorts. In controls, fasciculations were followed by respiratory arrest within 10 minutes (0% survival). The rats receiving atropine pre-treatment exhibited similar fasciculations (nicotinic effects) without subsequent respiratory arrest, resulting in a significant improvement in survival (88%, p < 0.001). The DPH-treated rats exhibited a significant dose-dependent reduction in mortality, with the 3 mg/kg, 15 mg/kg, and 30 mg/kg groups demonstrating 0%, 25%, and 100% survival, respectively. There was no additional mortality between 10 minutes and 24 hours in any group. There was no significant difference in survival between the high-dose DPH and the atropine groups. Conclusions: Diphenhydramine chloride significantly reduced mortality in rats with acute, severe dichlorvos exposure.

Pretreating Rats with Parenteral Ophthalmic Antimuscarinic Agents Decreases Mortality from Lethal Organophosphate Poisoning

“…9 In addition, glycopyrrolate bromide, scopolamine, diphenhydramine, and jimson weed extract have been studied. 6,7,10 Despite demonstrating some efficacy, these agents all share limitations in availability, in ease of administration, or in both. We believe that the consideration of ophthalmic antimuscarinic products may provide a more natural, convenient, and logical approach to a mass casualty event.…”

“…Other studies using 24 hours as an endpoint discovered that if rats lived beyond 30 minutes, they survived for 24 hours. 6,7 In light of this, a two hour endpoint was sufficient to decrease any unnecessary suffering by the animals. In addition, those animals that survived the duration of the two hour observation after experimentation appeared healthy and vibrant after a short period of fasciculations and lethargy.…”

“…A total of 70 adult male Sprague-Dawley rats (mean weight = 255 g) were used in a pretreatment model, as described elsewhere. 6,7 Atropine sulfate (Sigma-Aldrich, St. Louis, MO), ophthalmic atropine sulfate (Alcon Laboratories, Inc., Fort Worth, TX), or ophthalmic homatropine (Alcon Laboratories, Inc.) was mixed in sterile normal saline and administered via the intraperitoneal (IP) route.…”

Enzymes and bioscavengers for prophylaxis and treatment of organophosphate poisoning

“…Four therapeutic goals exist when treating a patient poisoned with OP compounds: 1) decreasing the amount of OP present in, or on, a patient through the use of skin decontamination, gastric decontamination, or bioscavengers, (5); 2) reversing the effects of muscarinic stimulation via anti-muscarinic agents such as atropine, ipratroprium, or diphenhydramine (6)(7)(8); 3) regeneration of the inhibited acetylcholinesterase (AChE) via oxime use (9); and 4) mitigating central nervous system toxicity by use of benzodiazepines (10,11). While the goals of treatment are straightforward, the management of severe OP poisoning remains challenging.…”

New Coumarinic Azo-Derivatives of Metoclopramide and Diphenhydramine: Synthesis and In Vitro Testing for Cholinesterase Inhibitory Effect and Protection Ability Against Chlorpyrifos

“…13,14 Diphenhydramine inhibits in vitro human ChE 15 and in vivo in experimental animals like mice and horse. 13,14,16 Coumarin is a phytochemical (benzopyrone); a toxin found in many plants, having vanilla like flavor. It has a sweet scent and has been used in perfumes since 1882, and it used for centuries in traditional medicine.…”