Ranolazine 2HCl

Antianginal agent with antiarrhythmic properties that acts as a partial fatty acid oxidation inhibitor. Activates pyruvate dehydrogenase in ischemic myocytes to promote glucose oxidation, switching substrate utilization from fatty acids to glucose. Also s

Inhibition of late sodium current to reduce electrical and mechanical dysfunction of ischaemic myocardium.[Pubmed:18071302]

Br J Pharmacol. 2008 Mar;153(6):1128-32.

This commentary on the review by DA Saint in the current issue of the British Journal of Pharmacology focuses on the pathological role of late I(Na) in the heart, the evidence supporting inhibition of late I(Na) as a therapeutic target in ischaemic heart disease, and the therapeutic applications and challenges for development of new late I(Na) inhibitors. Recent reports from a large clinical outcome trial (MERLIN) of ranolazine, a drug known to inhibit late I(Na), indicated that it was safe and reduced recurrent ischaemia and arrhythmic activity. In combination with other results indicating that inhibition of late I(Na) reduces ischaemia, myocardial Ca(2+) overload, and electrical and mechanical dysfunction when late I(Na) is increased, the new clinical trial results suggest that reduction of cardiac late I(Na) is safe and therapeutically beneficial.

Antitorsadogenic effects of ({+/-})-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-pipera zine (ranolazine) in anesthetized rabbits.[Pubmed:18322148]

J Pharmacol Exp Ther. 2008 Jun;325(3):875-81.

Ranolazine [Ranexa; (+/-)-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazi ne] is novel anti-ischemic agent that has been shown to inhibit late I(Na) and I(Kr) and to have antiarrhythmic effects in various preclinical in vitro models. This study was undertaken to investigate the effects of ranolazine on drug-induced Torsade de Pointes (TdP) in vivo. TdP was induced by an I(Kr) blocker, clofilium, in anesthetized, alpha(1)-agonist-sensitized rabbits. Clofilium prolonged QT interval corrected for heart rate (QTc) (52 +/- 9%) and monophasic action potential duration (MAPD)(90) (56 +/- 9%) and caused TdP in eight of eight rabbits. Pretreatment with ranolazine (480 microg/kg/min) or lidocaine (200 microg/kg/min) reduced the clofilium-induced prolongation of QTc (15 +/- 3 and 19 +/- 3%, respectively, p < 0.001 versus vehicle) and MAPD(90) (21 +/- 4 and 20 +/- 2%, respectively, p < 0.001 versus vehicle) and prevented the occurrence of TdP (zero of eight and zero of eight, respectively). Administration of ranolazine after the first episode of TdP terminated TdP and prevented its recurrence (zero of four versus vehicle, four of four). To rule out an alpha(1)-adrenoceptor antagonistic activity of ranolazine, we compared the effects of ranolazine on blood pressure with those of the alpha(1)-antagonist, prazosin. Although prazosin (10 microg/kg/min) markedly shifted the phenylephrine (alpha(1)-agonist) dose-response curve to the right, it did not have any effect on clofilium-induced prolongation of QTc and MAPD(90) (43 +/- 7 and 53 +/- 9%, respectively) or the occurrence of TdP (seven of eight). In contrast, ranolazine completely suppressed TdP but did not cause any shift in the phenylephrine dose-response curve at the highest dose tested (480 microg/kg/min). We conclude that ranolazine antagonizes the ventricular repolarization changes caused by clofilium and suppresses clofilium-induced TdP in rabbits.

Ranolazine, a partial fatty acid oxidation inhibitor, reduces myocardial infarct size and cardiac troponin T release in the rat.[Pubmed:11334871]

Eur J Pharmacol. 2001 Apr 20;418(1-2):105-10.

Ranolazine reduces cellular acetyl-CoA content via inhibition of fatty acid beta-oxidation and activates pyruvate dehydrogenase. This metabolic switch increases ATP production per mole of oxygen consumed, reduces the rise in lactic acid and acidosis, and maintains myocardial function under conditions of reduced myocardial oxygen delivery. It is still unclear whether ranolazine causes a reduction of (i) infarct size and (ii) cardiac troponin T release, in a male Wistar rat model of left anterior descending coronary artery occlusion (25 min) and reperfusion (2 h). Rats were subjected to saline infusion (n=12) or ranolazine (bolus injection: 10 mg/kg plus infusion: 9.6 mg/kg/h, n=12), 30 min prior to left anterior descending coronary artery occlusion-reperfusion, respectively. Ranolazine caused a significant reduction in myocardial infarct size of approximately 33% compared to saline control (P<0.05). In addition, infusion of ranolazine significantly attenuated the release of cardiac troponin T into the plasma from 65+/-14 (controls) to 12+/-2 ng/ml. This study demonstrates for the first time that ranolazine significantly reduces (i) infarct size and (ii) cardiac troponin T release in rats subjected to left anterior descending coronary artery occlusion-reperfusion.

Ranolazine dihydrochloride (CVT 303 dihydrochloride) is an anti-angina drug that achieves its effects by inhibiting the late phase of inward sodium current (INa and IKr with IC50 values of 6 μM and 12 μM, respectively) without affecting heart rate or blood pressure (BP). Ranolazine dihydrochloride is also a partial fatty acid oxidation inhibitor.

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