Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trimetazidine (1-[2,3,4-trimethoxybenzyl] piperazine) (TMZ) is a cellular anti-ischemic agent able to prevent intracellular ATP decrease, limit intracellular acidosis, protect against oxygen-free radical-induced toxicity and inhibit neutrophil infiltration. However, its definitive mechanism of action had not been identified. Recent studies showed the existence of an endogenous mechanism of cellular protection against ischemia, defined as 'ischemic preconditioning'. This mechanism was related mainly to cellular liberation of adenosine, a nucleoside with protective effects in myocardial ischemia. Since TMZ acts by increasing cell tolerance to ischemia and adenosine is the mediator of ischemic preconditioning, in this study we investigated a possible interaction between TMZ and adenosine. Two groups of patients affected by angina pectoris, were admitted to the study. They received a single oral dose of TMZ. One group was treated, during different sessions, with TMZ 10 and 20 mg, the other group with TMZ 40 and 80 mg. After a 3 day wash-out from drug administration, each group received a placebo. Blood samples were collected at baseline (time 0) and 1, 2, 3, 4, 6, 8 h after drug administration, in order to detect plasma levels of adenosine by a high-performance liquid chromatography method. We observed that the administration of TMZ at doses of 10, 20, 40 and 80 mg induced an increase of adenosine plasma levels of 19, 50, 62 and 62%, respectively. We hypothesized that the activity of TMZ could depend, at least in part, on adenosine mediation and this interaction opens a new interpretation of the drug antischemic effect.
 ...
PMID:Increase of adenosine plasma levels after oral trimetazidine: a pharmacological preconditioning? 1182 Aug 65

In the present study a series of trimetazidine (1-(2,3,4-trimethoxybenzyl)piperazine, CAS 5011-34-7) derivatives is subjected to quantitative structure-activity relationship (QSAR) analysis aiming at establishing the relationship between molecular structure and the binding affinity of the compounds to the respective receptor sites in the cells. Trimetazidine is used in the therapy of ischaemic heart disease. Literature data for the biological effect of the compounds are used. The derivatives studied include compounds with different substituents at the fourth position of the piperazine ring and a variation between the ortho-methoxy and ortho-hydroxy group in the benzyl residue. A statistically significant correlation between the Van der Waals volume of the substituents and the binding affinity of the respective compounds was found.
 ...
PMID:Quantitative structure-activity relationship analysis of the substituent effects on the binding affinity of derivatives of trimetazidine. 1497 3

Ranolazine (Ranexa), a piperazine derivative, is a new antianginal agent approved for the treatment of chronic stable angina pectoris for use as combination therapy when angina is not adequately controlled with other antianginal agents. While the exact mechanism of action of ranolazine is not known, its antianginal and anti-ischaemic effects do not appear to depend upon changes in blood pressure or heart rate. An extended-release (ER) oral formulation of ranolazine has been developed to facilitate twice-daily administration whilst maintaining therapeutically effective plasma concentrations. In patients with chronic stable angina, ranolazine ER monotherapy was shown to improve exercise duration at trough plasma drug concentration in a dose-dependent manner compared with placebo. The drug was effective as adjunctive therapy in patients with chronic stable angina whose condition was not controlled adequately with conventional antianginal therapy. 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 (QTc) interval (but no torsades de pointes). Importantly, the efficacy and tolerability of ranolazine ER were not affected by comorbid conditions, including old age, heart failure (HF) or diabetes mellitus. 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. Nevertheless, ranolazine ER may well prove to be a useful alternative and adjunct to conventional haemodynamic antianginal therapy in the treatment of chronic stable angina.
 ...
PMID:Ranolazine: a review of its use in chronic stable angina pectoris. 1662 Jan 47

Ranolazine (Ranexa), a piperazine derivative, is a new antianginal agent approved for the treatment of chronic stable angina pectoris for use as combination therapy when angina is not adequately controlled with other antianginal agents. While the exact mechanism of action of ranolazine is not known, its antianginal and anti-ischemic effects do not appear to depend upon changes in BP or heart rate. An extended-release (ER) oral formulation of ranolazine has been developed to facilitate twice-daily administration whilst maintaining therapeutically effective plasma concentrations. In patients with chronic stable angina, ranolazine ER monotherapy was shown to improve exercise duration at trough plasma drug concentration in a dose-dependent manner compared with placebo. The drug was effective as adjunctive therapy in patients with chronic stable angina whose condition was not controlled adequately with conventional antianginal therapy. In randomized clinical trials, ranolazine ER was well tolerated, with no overt effects on cardiovascular hemodynamics or conduction, apart from a modest increase in corrected QT interval (but no torsades de pointes). Importantly, the efficacy and tolerability of ranolazine ER were not affected by old age and co-morbid conditions (heart failure or diabetes mellitus). Comparative trials of ranolazine ER with other antianginal agents and trials examining its effects on long-term morbidity and mortality in patients with ischemic heart disease are required to determine with greater certainty the place of the drug in current antianginal therapy. Nevertheless, ranolazine ER may well prove to be a useful alternative and adjunct to conventional hemodynamic antianginal therapy in the treatment of chronic stable angina.
 ...
PMID:Spotlight on ranolazine in chronic stable angina pectoris. 1708 71

Nitric oxide (NO) is a potent vasodilator and inhibitor of platelet activation. Its donors, organic nitrates, are still a main group of drugs administered in ischaemic heart disease. The aim of this study was to investigate the effect of a new NO-donor analogue, 1-(3-piperidinepropionyl)-4-(2-nitrooxy-3-piperidinepropyl) piperazine trihydrochloride (NO-P), on platelet activity. Its influence on the main mechanisms of human platelet activation (adhesion, shape change, secretion and aggregation) was evaluated with the use of a pharmacological model produced on the basis of known platelet activation measuring methods and our computer program. Our experiments revealed that the new NO derivative of piperazine favourably influences platelet activity, and decreases adhesion (spontaneous and induced by ADP) and aggregation. NO-P shows the same direction of action as nitroglycerin (used as a model compound), and is even stronger in the case of ADP-induced and collagen-induced aggregation. These findings broaden the possibility of using NO-P in cardiovascular diseases. Furthermore, our computer program, used to evaluate kinetic parameters of platelet aggregation, shape change, and the adhesion measuring method, provides a simple and accessible experimental model. This model can be useful in in-vitro screening studies, estimating the influence of new compounds (potential drugs) on platelet activity.
 ...
PMID:A new nitrate derivative of piperazine: its influence on platelet activity. 1728 32

Premature ventricular complexes (PVCs) are a frequent occurrence in the presence of ischemic heart disease. A very high PVC load can be symptomatic or occasionally result in a cardiomyopathy (CMP). Treatment options include pharmacologic agents and radiofrequency ablation (RFA). RFA has been successful in treating PVCs in symptomatic patients or in the presence of unexplained CMP. Ranolazine is a piperazine derivative used for treating chronic stable angina. It also has antiarrhythmic properties. We report a patient with ischemic CMP, symptomatic PVCs, and monomorphic ventricular tachycardia (VT) despite attempts to control symptoms with two antiarrhythmic drugs. Initiation of ranolazine led to marked reduction in PVCs along with control of VT and symptoms.
 ...
PMID:Ranolazine--treatment of ventricular tachycardia and symptomatic ventricular premature beats in ischemic cardiomyopathy. 2034 26

Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.
 ...
PMID:Identification of a potent sodium hydrogen exchanger isoform 1 (NHE1) inhibitor with a suitable profile for chronic dosing and demonstrated cardioprotective effects in a preclinical model of myocardial infarction in the rat. 2280 59