Ranolazine a Potential New Therapeutic Application

• Status: Withdrawn
• Trial end date: 2020-10-01
• Target enrollment: 0
• Participant gender: All

Summary

Despite surgical and medical innovation have reduced mortality rates in cardiac surgery, the disease severity and operative procedural complexity have increased and morbidity rate is still high. Ischemia-reperfusion (I/R) injury, redefined in cardiac surgery "post-cardioplegic injury" (2) as a whole of ischemia-reperfusion, cardiopulmonary bypass and surgical trauma, has been recognized as a significant contributor to mortality and morbidity. I/R injury is classified as reversible or irreversible. Reversible injury includes arrhythmias, edema, vascular dysfunction and contractile stunning expressed as low output syndrome without cell death and without apparent signs of infarction or other serum injury markers. Irreversible reperfusion injury includes apoptosis and necrosis. I/R injury is a complex process associated with increase of radical, oxidant and cytokines production, complement and neutrophil activation and endothelial activation leading to microvascular dysfunction and deterioration of coronary flow reserve. In the hypoxic heart increase anaerobic lactate production, K+ efflux and membrane depolarization. The intracellular Na+ concentration rises as a consequence of slow Na+ channels inactivation and the induction of voltage-gated Na+ channel late current component (late INA). Intracellular Na++ accumulation enhanced activity of reversed-mode Na+-Ca++ exchanger causing intracellular Ca++ overload and ventricular dysfunction. Therefore inhibition of late INA has been shown to be cardioprotective. Ranolazine, an FDA-approval antianginal and anti-ischemic agent, high selective blocker of late INA, inhibits the late sodium current in myocardial ischemia, decreases Na+ and Ca2+ overload and improves left ventricular function in experimental animal models. For this reason it was also adjuncted to cardioplegia improving diastolic function in isolate Langerdoff-perfused rat hearts. The authors test the hypothesis that ranolazine improve myocardical protection in patients undergoing coronary artery surgery with cardiopulmonary by-pass (CPB).

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS; Policlinico Universitario Agostino Gemelli
• Treatments: Ranolazine

Criteria

Inclusion Criteria:

• age ≥ 18 years

• sinus rhythm, heart rate (FC) ≥ 50 bpm at rest;

• NYHA class I, II, III (CCS I, II, III);

Exclusion Criteria:

• drugs intolerance or hypersensitivity;

• cardiogenic shock;ejection fraction (FE ) ≤ 50 % ;

• NYHA class IV (CCS IV);

• II or III atrioventricular block;

• a resting heart rate (HR) < 50 bpm or sick sinus syndrome;

• rate-corrected QT interval (QTc) greater than 500 ms;

• age <18 years;

• symptomatic hypotension or uncontrolled hypertension (systolic blood pressure at rest ≥ 180 mmHg or diastolic blood pressure ≥ 100 mmHg);

• severe liver disease

• severe renal impairment (creatinine clearance ≤ 30 ml/min);

• from moderate to severe electrolyte disorders (potassium concentration < 2,5 or > 6 mmol/L; calcium concentration < 8 or > 11 mg/dl; magnesium < 1,8 or > 2,5 mg/dl);

• pregnancy;

• concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone)

• concomitant administration of Class Ia (e.g. quinidine) or Class III (e.g. dofetilide, sotalol) antiarrhythmics other than amiodarone;

• previous cardiac interventions