Ipazilide fumarate

Ipazilide fumarate (WIN 54177-4) is a chemically novel antiarrhythmic agent that prolongs ventricular refractoriness and possesses antiectopic activity. The compound is being developed as oral and iv therapy for ventricular and supraventricular arrhythmias. Since ipazilide therapy may require long-term use, a 1-year oral gavage study (daily dosages of 20, 80, or 160 mg/kg) was conducted in rats. Controls received the purified water vehicle. Treatment-related clinical signs were limited to post-dosing salivation. Increased relative liver weight (females, at 80 and 160 mg/kg) was correlated with centrilobular hypertrophy, but was not associated with significant increased serum liver enzymes activities. These liver weight changes were interpreted as an adaptive metabolic response and were not considered toxicologically significant. An increased incidence of centrilobular hepatocellular vacuolation representing lipid accumulation over that observed for male controls occurred for males in all ipazilide-treated groups. This observation, however, was not correlated with elevated hepatic enzyme activities. Hepatocellular basophilic foci were observed for females only (80 and 160 mg/kg groups); however, the significance of this lesion is unclear. Transient dosage-related duodenal villous atrophy/sloughing was observed for males from the 80 and 160 mg/kg groups. Mild increases in hemoglobin, hematocrit, urea, and creatinine (160 mg/kg), attributed to treatment, were considered of minor toxicologic importance. Likewise, no clinical or anatomical pathologic observations that may indicate cardiac toxicity were determined. It is concluded that a dosage of 20 mg/kg (two to three times the clinical efficacious dosage) was considered a no-effect dosage level since it did not produce any effects of toxicological significance.

Ipazilide fumarate (Win 54, 177-4) is a chemically novel antiarrhythmic agent that prolongs ventricular refractoriness and possesses antiectopic activity. Subchronic (29 days) nonclinical safety evaluation of ipazilide was conducted following oral and iv administration in Sprague-Dawley rats (20-320 mg/kg oral and 1.25-10 mg/kg iv) and 14 and 28 days in beagle dogs (3-30 mg/kg oral and 2.5-20 mg/kg iv). The pharmacokinetic parameters of ipazilide indicate that ipazilide is absorbed (tmax less than or equal to 1 hr) in fasted rats and dogs following single and repeated oral administrations. The apparent elimination half-life in the two species is approximately 1 hr (except in rats at a dosage of 320 mg/kg), suggesting rapid clearance. Increases in liver weights (rats 320 mg/kg) accompanied by the observation of centrilobular hypertrophy of hepatocytes were considered an expression of an adaptive metabolic response of the liver to ipazilide and may be associated with the induction of microsomal enzymes. Duodenal villous atrophy and epithelial hyperplasia (rats, 80 and 320 mg/kg) were interpreted to represent an irritant response to the drug. Local irritation was also observed at the injection site in rats and dogs. Dogs tolerated the oral and the iv administration of ipazilide at dosages of up to 30 and 20 mg/kg, respectively. Despite emesis (oral dogs), which was reduced in frequency following repeated treatment over several weeks, plasma levels in treated dogs (i.e., Cmax 4-5 micrograms/ml) were approximately twice that required to convert spontaneous arrhythmias in the conscious dog model 24 hr after myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)