Interspecies and intergender differences in acute toxicity of K-oximes drug candidates

Area of Science:

• Pharmacology and Toxicology
• Drug Development
• Neuroscience

Background:

• K-oximes are developed as modern drug candidates for acetylcholinesterase (AChE) reactivation.
• Understanding interspecies and intergender differences in toxicity is crucial for drug development.

Purpose of the Study:

• To investigate interspecies and intergender differences in the toxicity of selected K-oxime acetylcholinesterase reactivators.
• To determine the median lethal dose (LD50) for asoxime, obidoxime, K027, K048, and K075 in Wistar rats and Swiss mice.

Main Methods:

• Administration of increasing doses of K-oximes (asoxime, obidoxime, K027, K048, K075) to male and female Wistar rats and Swiss mice.
• Calculation of the median lethal dose (LD50) after 24-hour observation period.
• Intramuscular route of administration used for toxicity assessment.

Main Results:

• Asoxime and K027 exhibited the least toxicity in female rats and mice, with LD50 values ranging from 565.74 to 686.08 mg/kg.
• Asoxime and K027 were significantly less acutely toxic (3-8 times) than K048, obidoxime, and K075.
• K075 displayed the highest toxicity in male rats and mice, with LD50 values of 81.53 mg/kg and 57.34 mg/kg, respectively.

Conclusions:

• Results provide insights into the comparative toxicity of different K-oximes across species and genders.
• Findings can aid in predicting adverse effects, identifying target organs, and establishing risk categories for human overexposure.
• Data is valuable for dose selection in initial repeated dose toxicity tests for these oxime reactivators.