In vivo toxic and lethal cardiorespiratory effects of a synthetic quaternary ammonium salt derivative of haloperidol in mice

Background: To investigate the toxicity of N-n-butyl haloperidol iodide (F2), a quaternary ammonium salt derivative of haloperidol, in mice for potential therapeutic purposes.

Methods: The acute median lethal dose (LD₅₀) of F2 was determined using the Bliss method following intravenous administration in mice. Routine surface electrocardiograms (ECGs) and arterial blood pressures (aBPs) were recorded under general anesthesia in untreated and pharmacologically vagotomized mice injected with F2. Sublethal doses of F2 were tested for their effects on aBP, heart rate, and biochemical parameters such as lactate dehydrogenase (LDH), blood urea nitrogen (BUN), and serum lactate levels. Histopathological changes in the heart, lungs, liver, and kidneys were evaluated after F2 administration.

Results: The acute LD₅₀ of F2 was determined to be 5.11 mg/kg. A 10 mg/kg dose of F2 caused severe hypotension, second-degree atrioventricular block, progressive prolongation of Pmurr intervals, and death due to cardiac asystole. Similar ECG and aBP changes were observed in atropine-pretreated mice, indicating that cholinergic effects do not play a major role in F2-induced toxicity. Sublethal doses of F2 (1.2 and 2.4 mg/kg) caused dose-dependent decreases in aBP and increases in heart rate. F2 induced significant, dose-dependent increases in LDH, BUN, and serum lactate levels. Histopathological analysis revealed acute lung lesions at 10 mg/kg, with no significant changes observed in the heart, liver, or kidneys.

Conclusion: Acute intravenous injection of F2 exhibits dose-dependent cardiopulmonary toxicity, characterized by severe hypotension, arrhythmias, and biochemical changes. These findings highlight the potential risks of F2 and the need for further evaluation of its safety profile for therapeutic use.