Azimilide

Inhibitory effect of azimilide on Na+/Ca2+ exchange current in guinea-pig cardiac myocytes.[Pubmed:20710119]

J Pharmacol Sci. 2010;114(1):111-4. Epub 2010 Aug 11.

We examined the effect of Azimilide, a class III antiarrhythmic drug, on Na(+)/Ca(2+) exchange current (I(NCX)) in guinea-pig cardiac single ventricular cells. External application of Azimilide suppressed bi-directional I(NCX) in a concentration-dependent manner. IC(50) values for outward and inward I(NCX) were 45 and 40 microM, respectively, with Hill coefficients of 1. Azimilide attenuated I(NCX) in the presence of trypsin in the patch pipette, indicating that Azimilide is a trypsin-insensitive NCX inhibitor. Delayed afterdepolarization induced by electrical stimulation with ouabain disappeared in the presence of 30 microM Azimilide. We conclude that Azimilide inhibits NCX at supratherapeutic concentrations.

Results of a curtailed randomized controlled trial, evaluating the efficacy and safety of azimilide in patients with implantable cardioverter-defibrillators: The SHIELD-2 trial.[Pubmed:28267474]

Am Heart J. 2017 Mar;185:43-51.

BACKGROUND: Frequent hospital attendances in patients with implantable cardioverter-defibrillators (ICDs) result in significant morbidity and health care costs. Current drugs to reduce ICD shocks and hospital visits have limited efficacy and considerable toxicity. We evaluated the efficacy and safety of Azimilide, a novel oral class III antiarrhythmic, for use in ICD patients. METHODS: A total of 240 patients were enrolled in a prospective, randomized, double-blind, placebo-controlled trial to evaluate the effect of oral Azimilide 75 mg daily in ICD patients with previously documented ventricular tachycardia or ventricular fibrillation, and a left ventricular ejection fraction Azimilide demonstrated numerical but statistically nonsignificant reductions in the primary composite outcome (odds ratio [OR] 0.79, 95% CI 0.44-1.44), unplanned CV hospitalizations (OR 0.75, 95% CI 0.41-1.38), ED visits (OR 0.68, 95% CI 0.35-1.31), and all-cause shocks (OR 0.58, 95% CI 0.32-1.05). The incidence of adverse events was lower in the Azimilide group. Neutropenia was not observed (absolute neutrophil count <1000 mu/L), and there was one possible torsade de pointes case that led to a successful ICD discharge. CONCLUSION: The SHIELD-2 trial was statistically underpowered due to early trial termination and did not meet its primary objective. Despite this limitation, Azimilide showed promise as a safe and effective drug in reducing all-cause shocks, unplanned hospitalizations, and ED visits in ICD patients.

CPUY11018, an azimilide derivative, ameliorates isoproterenol-induced cardiac insufficiency through relieving dysfunctional mitochondria and endoplasmic reticulum.[Pubmed:25828246]

J Pharm Pharmacol. 2015 Aug;67(8):1029-41.

OBJECTIVES: Deterioration of cardiac performance under stress may be partly mediated by dysfunctional mitochondria and endoplasmic reticulum (ER) that is likely related to an activation of NADPH oxidase (NOX) and an increase in pro-inflammatory factors. We investigated if a new compound CPUY11018 (CPUY) derived from Azimilide could ameliorate the stress impaired cardiac performance. METHODS: Forty-eight male Sprague Dawley rats were randomly divided into six groups and were injected with isoproterenol (ISO, 1 ml/kg, s.c.) for 10 days. Cardiac myocytes and fibroblasts from neonate rats were incubated with ISO. CPUY was employed and compared with apocynin (APO) - an inhibitor of NOX. KEY FINDINGS: In ISO-treated group, the compromised haemodynamics and cardiac remodelling were significant with dysfunctional mitochondria indicated by decreased MnSOD and mitochondrial membrane potential, and an enhanced reactive oxygen species genesis. Downregulation of FKBP12.6, CASQ2 and SERCA2a was also remarkable in vivo and in vitro implying an abnormal ER. Upregulated Nox4, p22(phox) and p47(phox) were significant, associated with upregulation of Src, IkappaBbeta and NFkappaB, and downregulation of pAMPK/AMPK and Cx40 in vivo and in vitro. These abnormalities were relieved by CPUY and APO. CONCLUSIONS: CPUY is potential in managing cardiac insufficiency through normalizing mitochondria and ER in the affected heart.