Disease relevance of RANOLAZINE

• This study was conducted to evaluate the antianginal and anti-ischemic effects and safety of different doses of ranolazine administered three times daily (tid) compared with placebo in patients with stable angina pectoris [1].
• This concept of metabolic modulation has gained favor in coronary heart disease, and its efficacy currently is being investigated in stable angina using the new class of partial fatty acid oxidation inhibitors, including trimetazidine and ranolazine [2].
• In randomised clinical trials, ranolazine ER was well tolerated, with no overt effects on cardiovascular haemodynamics or conduction, apart from a modest increase in corrected QT (QT(c)) interval (but no torsades de pointes) [3].
• Comparative trials of ranolazine ER with other antianginal agents and trials examining its effects on long-term morbidity and mortality in patients with ischaemic heart disease are required to determine with greater certainty the place of the drug in current antianginal therapy [3].
• Importantly, the efficacy and tolerability of ranolazine ER were not affected by comorbid conditions, including old age, heart failure (HF) or diabetes mellitus [3].

High impact information on RANOLAZINE

• Effects of ranolazine on glucose and palmitate oxidation and glycolysis were assessed in isolated rat hearts [4].
• Insulin increased basal glucose oxidation and glycolysis but did not alter ranolazine responses [4].
• Compared with the baseline values, the number of anginal attacks per week and the number and duration of ischemic episodes per 48 hours during Holter monitoring decreased significantly by similar magnitudes in the placebo and ranolazine groups [1].
• Ranolazine had negligible effects on heart rate and blood pressure [5].
• Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes [6].

Chemical compound and disease context of RANOLAZINE

• The beneficial effects of ranolazine in reducing Ca(2+) overload and LV mechanical dysfunction during ischemia/reperfusion is consistent with the inhibition of late I(Na) mechanism of action [7].
• A Comparison between Ranolazine and CVT-4325, a Novel Inhibitor of Fatty Acid Oxidation, on Cardiac Metabolism and Left Ventricular Function in Rat Isolated Perfused Heart during Ischemia and Reperfusion [8].
• In conclusion, ranolazine therapy prolonged exercise duration and decreased exercise-induced ischemia and angina with quantitative effects equal to or greater than those with atenolol [9].
• The sildenafil-induced transient tachycardia (Delta change: 114 +/- 10 beats/min) was significantly (P < 0.05) blunted by either 4 (Delta change: 71 +/- 8 beats/min) or 8 (Delta change: 66 +/- 9 beats/min) microM ranolazine [10].
• The transient hypotension and tachycardia caused by isosorbide dinitrate were not altered by ranolazine [10].

Biological context of RANOLAZINE

• Effect of renal impairment on multiple-dose pharmacokinetics of extended-release ranolazine [11].
• Less than 7% of the administered dose was excreted unchanged in all groups, indicating that factors other than reduced glomerular filtration rate contributed to the increase in ranolazine concentrations in renal impairment [11].
• The anti-anginal effect of ranolazine does not depend on changes in heart rate or blood pressure [12].
• Digoxin AUC is increased 40-60% by ranolazine through P-glycoprotein inhibition [12].
• Ranolazine protein binding is about 61-64% over the therapeutic concentration range [12].

Anatomical context of RANOLAZINE

• Ten minutes before coronary artery occlusion (CAO), anesthetized rabbits were assigned to vehicle (n=15) or ranolazine (2 mg/kg i.v. bolus plus 60 microg/kg/min i.v. infusion; n=15) [13].
• Pretreatment of myocytes with ranolazine delayed and reduced the increases of APD, [Na+]i, and [Ca2+]i caused by H2O2 [14].
• Further studies using rat heart mitochondria in different energisation states (i.e. broken, uncoupled, or coupled) showed a 50-100-fold shift to greater potency of ranolazine in the broken compared to the coupled; with the uncoupled it was about 2-fold less potent than the broken [15].
• The antianginal agent ranolazine is a weak inhibitor of the respiratory complex I, but with greater potency in broken or uncoupled than in coupled mitochondria [15].
• Studies with radiolabelled ranolazine showed that it bound to mitochondrial membranes with greater affinity in the broken compared to the coupled or uncoupled conditions [15].

Associations of RANOLAZINE with other chemical compounds

• No substantial changes in glycolysis were noted with/without ranolazine; rates were approximately 10-fold glucose oxidation rates, suggesting that pyruvate supply was not limiting [4].
• This study was designed to test the hypothesis that an increased late sodium channel current (I(Na)) leads to Ca(2+) overload and left ventricular (LV) dysfunction, and thereby inhibition of late I(Na) (e.g., by ranolazine) improves Ca(2+) homeostasis and reduces LV dysfunction [7].
• With broken mitochondrial membranes or submitochondrial particles, ranolazine inhibited NADH but not succinate oxidation and with pIC50 values in the lower range of 3-50 microM [15].
• In perfusions where octanoate (+/- albumin) replaced palmitate, ranolazine still decreased acetyl CoA, but not when acetate replaced palmitate [16].
• In this trial, 158 patients who had symptom-limited exercise discontinued beta-blocker therapy and were randomized into a double-blind, 3-period, crossover study of 400 mg of immediate-release ranolazine 3 times daily, 100 mg/day of atenolol, or placebo, each administered for 1 week [9].

Gene context of RANOLAZINE

• Elimination occurs through parallel linear and saturable elimination pathways, where the saturable pathway is related to CYP2D6, which is partly inhibited by ranolazine [12].
• Ketoconazole increased ranolazine plasma concentrations and reduced the CYP3A4-mediated metabolic transformation of ranolazine, confirming that CYP3A4 is the primary metabolic pathway for ranolazine [17].
• AUC0-infinity for the CYP3A substrate midazolam administered as a single dose was significantly correlated with ranolazine AUC0-12 at steady state (r2 = .33, P < .001) [18].
• AIMS: The anti-anginal efficacy and safety of ranolazine in diabetic and non-diabetic patients included in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial (JAMA 2004;291:309) were studied [6].
• Activation of PDH by ranolazine and promotion of glucose oxidation offers a plausible means by which the drug may be anti-ischaemic nonhaemodynamically [16].

Analytical, diagnostic and therapeutic context of RANOLAZINE

• In reperfused ischemic working hearts, ranolazine significantly improved functional outcome, which was associated with significant increases in glucose oxidation, a reversal of the increased FA oxidation seen in control reperfusions (versus preischemic), and a smaller but significant increase in glycolysis [4].
• METHODS: Patients (n = 191) with angina-limited exercise discontinued anti-anginal medications and were randomized into a double-blind four-period crossover study of sustained-release ranolazine 500, 1,000, or 1,500 mg, or placebo, each administered twice daily for one week [5].
• After equilibration, hearts were treated with ranolazine (10 or 20 microM) or vehicle control for 10 min before exposure to a 30 min period of global ischaemia and 60 min reperfusion; a normoxic control group was also studied [19].
• The whole cell patch clamp technique was used to examine the action of ranolazine on basal calcium channel currents and those stimulated by activation at various steps in the PKA cascade [20].
• The characterization of the metabolites of ranolazine in man by liquid chromatography mass spectrometry [21].

References