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At least 19 recordsLinked to original sources
PubMed2000

[(3)H]-trimetazidine mitochondrial binding sites: regulation by cations, effect of trimetazidine derivatives and other agents and interaction with an endogenous substance.

Trimetazidine, an antiischaemic drug, has been shown to restore impaired mitochondrial functions. Specific binding sites for [(3)H]-trimetazidine have been previously detected in liver mitochondria. In the present study we confirm this observation and provide additional evidence for the involvement of these sites in the pharmacological effects of the drug. Inhibition experiments using a series of trimetazidine derivatives revealed the presence of three classes of binding sites. An N-benzyl substituted analogue of trimetazidine exhibited a very high affinity (K(i)=7 nM) for one of these classes of sites. Compounds from different pharmacological classes were evaluated for their ability to inhibit [(3)H]-trimetazidine binding. Among the drugs tested pentazocine, ifenprodil, opipramol, perphenazine, haloperidol, and to a lower extent prenylamine, carbetapentane and dextromethorphan competed with high affinity, suggesting a similarity of high affinity [(3)H]-trimetazidine sites with sigma receptors. [(3)H]-Trimetazidine binding was modulated by pH. Neutral trimetazidine had about 10 fold higher affinity than protonated trimetazidine for its mitochondrial binding sites. Various cations also affected [(3)H]-trimetazidine binding. Ca(2+) was the most potent inhibitor and totally suppressed the binding of [(3)H]-trimetazidine to the sites of medium affinity. An endogenous cytosolic ligand was able to displace [(3)H]-trimetazidine from its binding sites. Its activity was not affected by boiling for 15 min, suggesting a non-protein compound. These data suggest that mitochondrial [(3)H]-trimetazidine binding sites could have a physiological relevance and be involved in the antiischaemic effects of the drug.

Algorithms↗
PubMed2001

Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand.

AIMS: To assess the antiischaemic efficacy and tolerability of the metabolic agent trimetazidine in combination with metoprolol in patients with stable effort angina. METHODS: This was a randomized, multicentre, double-blind, placebo-controlled parallel group study. A total of 426 male and female patients with stable, effort-induced angina and documented coronary artery disease received either placebo or trimetazidine 20 mg three times daily in addition to metoprolol 50 mg twice daily. Treadmill exercise tests were performed at weeks (-1), 0, 4 and 12. RESULTS: After 12 weeks, there were significantly greater improvements in the metoprolol + trimetazidine group than in the metoprolol + placebo group in: time to 1 mm ST segment depression, total workload, time to onset of angina, maximum ST segment depression, mean weekly number of angina attacks, mean weekly nitrate consumption, and grade of anginal pain. There was no evidence of any development of tolerance to trimetazidine. The tolerability of trimetazidine was excellent. CONCLUSIONS: Therapy with trimetazidine plus metoprolol produced significant improvements in exercise stress tests and the symptoms of angina relative to metoprolol alone. With its metabolic effect, devoid of any haemodynamic action, trimetazidine is useful for combination therapy in patients with stable angina insufficiently controlled by monotherapy with a beta-blocker.

Administration, Oral↗
PubMed1994

Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group.

1. Trimetazidine has a direct anti-ischaemic effect on the myocardium without altering the rate x pressure product or coronary blood flow. 2. The effects of trimetazidine (20 mg three times daily) were compared with those of propranolol (40 mg three times daily) in a double-blind parallel group multicentre study in 149 men with stable angina. 3. Reproducibility of exercise performance was verified during a 3 week run-in placebo washout period. All patients had > 1 mm ST-depression on exercise test. 4. After 3 months, similar anti-anginal efficacy was observed between the trimetazidine (n = 71) and propranolol (n = 78) groups. No significant differences were observed between trimetazidine and propranolol as regards anginal attack rate per week (mean difference P-TMZ: 2; 95% CI: -4.4, 0.5) and exercise duration (mean difference P-TMZ: 0 s; 95% CI: -33, 34) or time to 1 mm ST segment depression (mean difference P-TMZ: 13 s; 95% CI: -24, 51). Heart rate and rate x pressure product at rest and at peak exercise remained unchanged in the trimetazidine group but significantly decreased with propranolol (P < 0.001 in all cases). With both drugs there was a trend to decreased ischaemic episodes in the 46% patients who experienced ambulatory ischaemia on Holter monitoring. Six patients stopped trimetazidine and 12 propranolol. Of these, five in each group were withdrawn because of deterioration in cardiovascular status. 5. The results suggest that trimetazidine and propranolol at the doses studied have similar efficacy in patients with stable angina pectoris.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed2004

Comparison of the effects of trimetazidine and diltiazem on exercise performance in patients with coronary heart disease. The Turkish trimetazidine study (TTS).

OBJECTIVE: A multicentre, double-blind comparative study was performed to compare the effects of trimetazidine with diltiazem on exercise performance in patients with stable angina pectoris. METHODS AND RESULTS: A total of 116 male patients with documented coronary artery disease at 11 centres were randomized into trimetazidine and diltiazem groups both including 58 men (mean age 55.1+/-8.6 years and 54.9+/-6.6 years, respectively) in a prospective, multicentre, double-blind active treatment trial. The study consisted of a two-week placebo washout period and a four-week active treatment phase. Clinical examinations and exercise tests were performed at the beginning (D0) and at the end (D28) of the active treatment. Laboratory investigations were also performed at the beginning of the washout period (D-14) and at D28. Holter recordings were done in the mid of the washout period (D-7) and D28. Both trimetazidine and diltiazem decreased the number of anginal attacks per week (p < 0.0001 for both drugs) and weekly nitrate consumption (p = 0.0008 and p < 0.0001, respectively). Both trimetazidine and diltiazem improved the recovery of anginal pain (p = 0.0188 and p = 0.0079, respectively) and maximal ST-segment depression (p = 0.0134 and p = 0.0214, respectively) but none of the drugs significantly changed the time to 1 mm ST-segment depression and ST recovery time on exercise test. Diltiazem caused a slight prolongation of PR and QRS durations (p = 0.039) on ambulatory ECG whereas trimetazidine did not change these parameters significantly. CONCLUSION: This study suggests that trimetazidine is an effective and safe alternative for diltiazem in the treatment of patients with stable angina pectoris. Although several other trials have shown that this drug can be used in combination with other antianginal drugs or instead of beta blockers or nifedipine in the symptomatic treatment of stable anginal syndromes, this study suggests that trimetazidine can be used instead of diltiazem, a well-known powerful antianginal drug.

Adolescent↗
PubMed2006

[Trimetazidine in the treatment of stable angina pectoris TRIADA-(trimetazidine in stable angina twice daily)].

The primary objective of the national study TRIADA was to evaluate the efficacy and tolerability of Preductal MR (trimetazidine) at a dose of 35 mg twice daily which was added to current therapy involving the maximum of two antianginal drugs. The outcome was evaluated after 12 weeks of therapy and compared with baseline data. The study included 74 patients with stable exertional angina pectoris (AP) and positive exercise testing results. Trimetazidine (Preductal MR) at a dose of 35 mg twice daily was added to their current therapy involving two drugs at most. TRIADA confirmed that the use of trimetazidine in a new pharmacological form is effective and well tolerated in the treatment of angina pectoris. The study also confirmed a beneficial effect of trimetazidine on the incidence of angina pectoris paroxysms and objective manifestations of ischaemia during exercise testing. Holter monitoring clearly showed that metabolic therapy added to standard antianginal therapy would reduce the incidence of symptomatic and asymptomatic ischaemia. In addition, 12-week therapy with trimetazidine helped improve all end points of quality of life of AP patients evaluated using a questionnaire for AP patients (The Seattle Angina Questionnaire).

Angina Pectoris↗
PubMedDate not supplied

Trimetazidine in Angina Combination Therapy--the TACT study: trimetazidine versus conventional treatment in patients with stable angina pectoris in a randomized, placebo-controlled, multicenter study.

The aim of this study was to assess the efficacy and acceptability of trimetazidine (TMZ) in combination with hemodynamic agents (beta-blockers or long-acting nitrates) in 177 stable angina patients. In this randomized, placebo-controlled study (TACT: Trimetazidine in Angina Combination Therapy), stable angina patients resistant to nitrates or beta-blockers were selected. After a 1-week selection period (W0), patients who had a difference of <10% in duration between 2 positive exercise tests, defined as 1-mm ST-segment depression (STD) 80 milliseconds after J point with angina pain or 1.5 mm without pain were randomly treated with TMZ (20 mg t.i.d., n = 90) or placebo (Pbo t.i.d., n = 87) orally. A final exercise test was performed after 12 weeks of treatment (W12). The efficacy was assessed by exercise test duration, time to 1-mm STD, time to angina onset, mean number of angina attacks, mean short-acting nitrate consumption, and rate-pressure product. Differences (W12 - W0) in these parameters were analyzed using the Student t test. All statistical tests were conducted at the 5% significance level. At inclusion and during the study, 52% of patients received long-acting nitrates, and 48% were treated with a beta-blocker as monotherapy. At the beginning of the study, the TMZ and Pbo groups were statistically homogeneous with respect to all analyzed characteristics (demographic characteristics, characteristics of anamnesis, characteristics used for evaluation of antianginal therapy efficacy). For various reasons, 11 patients (7 from the Pbo group and 4 from the TMZ group) were excluded from the trial. A total of 166 patients (80 from the Pbo group and 86 from the TMZ group) completed the study in full compliance with the protocol. After 12 weeks of therapy, exercise test duration increased from 417.7 +/- 14.2 (W0) to 506.8 +/- 17.7 seconds (W12) in the TMZ group versus 435.3 +/- 14.8 (W0) to 458.9 +/- 16.2 seconds (W12) in the Pbo group (P < 0.05). Time to 1-mm STD increased from 389.0 +/- 15.3 (W0) to 479.6 +/- 18.6 seconds (W12) in the TMZ group versus 411.8 +/- 15.2 (W0) to 428.5 +/- 17.3 seconds (W12) in the Pbo group (P < 0.05). Time to onset of anginal pain increased from 417.0 +/- 16.9 (W0) to 517.3 +/- 21.0 seconds (W12) in the TMZ group versus 415.1 +/- 16.5 (W0) to 436.4 +/- 18.5 seconds (W12) in the Pbo group (P < 0.005). The mean number of anginal attacks per week decreased from 5.6 +/- 0.6 to 2.7 +/- 0.5 in the TMZ group versus 6.8 +/- 0.7 to 5.1 +/- 0.7 in the Pbo group (P < 0.05), mean consumption short-acting nitrates per week decreased from 5.2 +/- 0.9 to 2.8 +/- 0.8 in the TMZ group versus 5.5 +/- 0.8 to 4.1 +/- 0.9 in the Pbo group (NS). No change in the rate-pressure product was seen in both. The combination of trimetazidine with beta-blockers or long-acting nitrates significantly improves exercise stress test parameters and angina symptoms compared with placebo. Due to its metabolic effect, free of any hemodynamic action, trimetazidine has proven to be beneficial for combination in patients with stable angina.

Adult↗
PubMed2000

Trimetazidine and the contractile response of dysfunctional myocardium in ischaemic cardiomyopathy.

BACKGROUND: The therapeutic effect of anti-ischemic compounds is related to their ability to improve the oxygen supply-demand balance of the ischemic myocardium by increasing myocardial blood flow (calcium-antagonists), by reducing regional myocardial oxygen consumption (verapamil, betablockers) and increasing peripheral pooling of blood (nitrates, nifedipine). All these actions are also accompanied by hemodynamic changes, as evidenced by a lower double product, reduced wall stress, lower pulmonary wedge pressure, and lower systemic arterial pressure. In general, it was found that the combination of a betablocker with nifedipine improved the antianginal effect by further reducing the number and duration of ischemic events. The combination of a nitrate with a beta-blocker is particularly useful because it reduces the risk of heart failure by lowering left ventricular end-diastolic pressure and volume and by attenuating the negative inotropic effect of the betablocker. Although a combination therapy demonstrated benefits in comparison with drug treatment alone, it is associated with a higher incidence of untoward events. Trimetazidine (2, 3, 4 trimethoxybenzyl-piperazine dihydrochloride) is a novel anti-ischemic compound with a peculiar mechanism of action. Its anti-ischemic properties are unrelated to changes in myocardial oxygen supply-to-demand ratio, as shown by no significant effects on heart rate, blood pressure or rate-pressure product both at rest and during dynamic exercise. There are several possible mechanisms of action by which trimetazidine promotes preservation of membrane structures and cellular function: limitation of intracellular acidosis, correction of disturbances of transmembrane ion exchange leading to calcium overload, prevention of an excessive production of free radicals, inhibition of the inflammatory reaction and an antiplatelet effect. These documented actions cooperate to increase the rate of resynthesis of high-energy phosphates within myocardial cells after episodes of ischemia. In several trials, trimetazidine has been tested as an antianginal agent, both as monotherapy and combined with "classical" anti-ischemic compounds. In comparison with nifedipine, trimetazidine had similar efficacy in reducing the number of weekly anginal attacks and in increasing the ischemic threshold in a group of 39 patients with stable angina. However, the incidence of side effects was significantly higher with nifedipine (5 vs 20), and affected 5 patients with trimetazidine and 13 patients with nifedipine (p = 0.03). In a relatively large European study involving 149 patients (Trimetazidine European Multicenter Study, TEMS), trimetazidine (20 mg t.i.d.) was compared with propranolol (40 mg t.i.d.) in patients with stable angina pectoris and documented significant coronary artery stenoses. The number of anginal attacks was reduced equally by both drugs and exercise duration was increased by both treatments. However, in contrast with propranolol trimetazidine did not alter the rate pressure product. In patients already treated with nifedipine or beta-blockers, the addition of trimetazidine (20 mg t.i.d.) was able to reduce the number and the duration of anginal attacks and improved also the exercise capacity. Trimetazidine is generally well tolerated and only minor side effects have been reported (drowsiness, sedation, diarrhea). The improvement in cardiac energy metabolism should theoretically translate into enhancement in mechanical efficiency. This hypothesis has been object of recent investigations in patients with ischemic heart disease with and without left ventricular dysfunction. Brottier, et al. demonstrated that patients with ischemic cardiomyopathy treated with trimetazidine had a higher ejection fraction (measured by radionuclide angiography) than control patients who received a placebo after 6 months of therapy (p < 0.018). The group of Chierchia demonstrated that trimetazidine improved ischemic regional myocardial dysfunction at rest and during stress-induced ischemia in 15 patients with chronic coronary artery disease without affecting the hemodynamic determinants of myocardial oxygen consumption. There is recent demonstration that trimetazidine improves the contractile response of left ventricular hibernating myocardium in patients with ischemic heart disease. Belardinelli et al. showed that trimetazidine improved the contractile response of dysfunctional myocardial to low-dose dobutamine in patients with ischemic heart disease and left ventricular function. Twenty-two patients with prior anterior myocardial infarction and injection fraction < 35% (33 +/- 7%) were randomized into 2 groups. A group (= 11) received trimetazidine (20 mg tid) for 2 months, while another group (= 11) received a placebo. The usual medications were not altered during the study. (ABSTRACT TRUNCATED)

Humans↗
PubMed2004

Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease.

AIM: Elderly patients have an increased incidence of ischaemic dilated cardiomyopathy often related to diffuse coronary artery disease. Trimetazidine protects ischaemic myocardium by improving the myocardial energy utilisation during myocardial ischaemia. Aim of the present study was to evaluate the effects of trimetazidine on left ventricular (LV) function in elderly patients with ischaemic heart disease and reduced LV function. METHODS: Forty seven elderly patients (40 males and 7 females, mean age 78+/-3 years) were randomised to receive, in addition to standard therapy, either trimetazidine or placebo and were evaluated by echocardiography at baseline and after 6 months. RESULTS: Trimetazidine and placebo had no effect on either blood pressure or heart rate (SBP 2+/-5 vs 4+/-6 mmHg, DBP -1+/-6 vs 3+/-4 mmHg, HR -3+/-7 vs 5+/-9 bpm, trimetazidine and placebo compared to baseline, respectively). At the end of the study patients randomised to trimetazidine showed a significant greater left ventricular function and smaller left ventricular diastolic and systolic diameters and volume indices compared to patients receiving placebo (LVEF: 34.4+/-2.3% vs 27+/-2.8%, p<0.0001; LVEDD: 58.6+/-1.9 mm vs 64+/-1.7 mm, p<0.0001; LVESD: 44.5+/-1.1 vs 50+/-0.8 mm, p<0.0001). A significant smaller wall motion score index was detected in trimetazidine-treated patients compared to those allocated to placebo (1.24+/-0.12 vs 1.45+/-0.19, p<0.01), the percentage change in LVEF compared to baseline was also significantly greater in trimetazidine-treated patients. Diastolic function significantly improved in the trimetazidine group while it remained unchanged in the placebo group. At follow-up evaluation, patients receiving trimetazidine showed a greater improvement in angina and NYHA class than patients allocated to placebo. Quality of life significantly improved in all patients treated with trimetazidine while remained unchanged in those allocated to placebo. CONCLUSION: In elderly patients with ischaemic cardiomyopathy trimetazidine in addition to standard medical therapy has a beneficial effect on LV systolic and diastolic function, and improves quality of life.

Aged↗
PubMed2005

Trimetazidine for stable angina.

BACKGROUND: Patients with stable angina not controlled by monotherapy with nitrates, beta blockers, or calcium channel blockers are often treated with combinations of these drugs. There may be adverse effects from, or contraindications to, the use of combinations. In low risk groups, medical treatment appears to be as good an option as percutaneous transluminal coronary angioplasty in terms of averting myocardial infarction, death, or subsequent revascularization. Revascularization procedures are too costly or inaccessible for many patients in developing countries therefore effective and safe medical treatment is needed. Trimetazidine is a less well known anti-anginal drug that controls myocardial ischaemia through intracellular metabolic changes. Trimetazidine has been reported, in some studies, to be better tolerated than combined anti-anginal therapy; however it is not considered in published guidelines. OBJECTIVES: To determine the efficacy and tolerability of trimetazidine in patients with stable angina. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, LILACS and SCISEARCH, without language restriction, from inception to October 2003. Experts in the field were contacted to locate unpublished studies. SELECTION CRITERIA: Randomised studies comparing trimetazidine with placebo, or other anti-angina drug in adults with stable angina. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria, assessed trial quality and extracted data. MAIN RESULTS: Twenty-three studies (1378 patients) met the inclusion criteria. There was a paucity of information about mortality, cardiovascular events and quality of life. Trimetazidine, compared with placebo, reduced the number of weekly angina attacks ( mean difference -1.44, 95% CI -2.10 to -0.79; P < 0.0001), reduced weekly nitroglycerin tablet consumption (95% CI -1.47 to -2.20, -0.73; P < 0.0001) and improved exercise time to 1 mm segment depression (P=0.0002). Four small trials (263 patients) compared trimetazidine against other anti-anginal agents. One favoured trimetazidine over nitrates. Three tended to favour alternative regimens but with confidence intervals consistent with both major increases and decreases in frequency of angina episodes. In this subgroup, adverse events were considered in 5 trials (448 patients) and totals of 2 versus 12 drop outs due to adverse events were observed in the trimetazidine and alternative regimens respectively, but this was mostly driven by a single trial. AUTHORS' CONCLUSIONS: Trimetazidine is effective in the treatment of stable angina compared with placebo, alone or combined with conventional anti-anginal agents. Trimetazidine may result in fewer dropouts due to adverse events. Large, long term trials comparing trimetazidine with other anti-anginal drugs assessing clinically relevant important outcomes are required to establish its role in clinical management.

Adult↗
PubMed1998

Evidence for the existence of [3H]-trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore.

1. Trimetazidine is an anti-ischaemic drug effective in different experimental models but its mechanism of action is not fully understood. Data indicate that mitochondria could be the main target of this drug. The aim of this work was to investigate the binding of [3H]-trimetazidine on a purified preparation of rat liver mitochondria. 2. [3H]-trimetazidine binds to two populations of mitochondrial binding sites with Kd values of 0.96 and 84 microM. The total concentration of binding sites is 113 pmol mg(-1) protein. Trimetazidine binding sites are differently distributed. The high-affinity ones are located on the outer membranes and represent only a small part (4%) of total binding sites, whereas the low-affinity ones are located on the inner membranes and are more abundant (96%) with a Bmax=108 pmol mg(-1) protein. 3. Drug displacement studies with pharmacological markers for different mitochondrial targets showed that [3H]-trimetazidine binding sites are different from previously described mitochondrial sites. 4. The possible involvement of [3H]-trimetazidine binding sites in the regulation of the mitochondrial permeability transition pore (MTP), a voltage-dependent channel sensitive to cyclosporin A, was investigated with mitochondrial swelling experiments. Trimetazidine inhibited the mitochondrial swelling induced by Ca2+ plus tert-butylhydroperoxide (t-BH). This effect was concentration-dependent with an IC50 value of 200 microM. 5. Assuming that trimetazidine effectiveness may be related to its structure as an amphiphilic cation, we compared it with other compounds exhibiting the same chemical characteristic both for their ability to inhibit MTP opening and to displace [3H]-trimetazidine bound to mitochondria. Selected compounds were drugs known to interact with various biological membranes. 6. A strong correlation between swelling inhibition potency and low-affinity [3H]-trimetazidine binding sites was observed: r=0.907 (n=24; P<0.001). 7. These data suggest that mitochondrial sites labelled with [3H]-trimetazidine may be involved in the MTP inhibiton.

Animals↗
PubMed2000

The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.

Trimetazidine is a clinically effective antianginal agent that has no negative inotropic or vasodilator properties. Although it is thought to have direct cytoprotective actions on the myocardium, the mechanism(s) by which this occurs is as yet undefined. In this study, we determined what effects trimetazidine has on both fatty acid and glucose metabolism in isolated working rat hearts and on the activities of various enzymes involved in fatty acid oxidation. Hearts were perfused with Krebs-Henseleit solution containing 100 microU/mL insulin, 3% albumin, 5 mmol/L glucose, and fatty acids of different chain lengths. Both glucose and fatty acids were appropriately radiolabeled with either (3)H or (14)C for measurement of glycolysis, glucose oxidation, and fatty acid oxidation. Trimetazidine had no effect on myocardial oxygen consumption or cardiac work under any aerobic perfusion condition used. In hearts perfused with 5 mmol/L glucose and 0.4 mmol/L palmitate, trimetazidine decreased the rate of palmitate oxidation from 488+/-24 to 408+/-15 nmol x g dry weight(-1) x minute(-1) (P<0.05), whereas it increased rates of glucose oxidation from 1889+/-119 to 2378+/-166 nmol x g dry weight(-1) x minute(-1) (P<0.05). In hearts subjected to low-flow ischemia, trimetazidine resulted in a 210% increase in glucose oxidation rates. In both aerobic and ischemic hearts, glycolytic rates were unaltered by trimetazidine. The effects of trimetazidine on glucose oxidation were accompanied by a 37% increase in the active form of pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation. No effect of trimetazidine was observed on glycolysis, glucose oxidation, fatty acid oxidation, or active pyruvate dehydrogenase when palmitate was substituted with 0.8 mmol/L octanoate or 1.6 mmol/L butyrate, suggesting that trimetazidine directly inhibits long-chain fatty acid oxidation. This reduction in fatty acid oxidation was accompanied by a significant decrease in the activity of the long-chain isoform of the last enzyme involved in fatty acid beta-oxidation, 3-ketoacyl coenzyme A (CoA) thiolase activity (IC(50) of 75 nmol/L). In contrast, concentrations of trimetazidine in excess of 10 and 100 micromol/L were needed to inhibit the medium- and short-chain forms of 3-ketoacyl CoA thiolase, respectively. Previous studies have shown that inhibition of fatty acid oxidation and stimulation of glucose oxidation can protect the ischemic heart. Therefore, our data suggest that the antianginal effects of trimetazidine may occur because of an inhibition of long-chain 3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid oxidation and a stimulation of glucose oxidation.

Angina Pectoris↗
PubMedDate not supplied

Cardioprotective effect of trimetazidine during coronary artery graft surgery.

Reperfusion injury remains the most uncontrolled phenomenon during cardiac surgery. Potential myocardial protection by trimetazidine was tested in a double blind placebo controlled study on 19 patients undergoing aorto-coronary bypass surgery. The trimetazidine group was composed of 10 patients and the placebo group of 9 patients. Pretreatment was started three weeks before surgery with 1 tablet (trimetazidine 20 mg) t.i.d. and the same drug was added to the cardioplegic solutions (trimetazidine: 10(-6) M). The cross clamping time was 41.1 +/- 3.8 minutes in the trimetazidine group and 39.8 +/- 2.3 minutes in the placebo group. Metabolic measurements showed that the increase of malondialdehyde measured in the coronary sinus 20 minutes after reperfusion was significantly (p = 0.014) less in the trimetazidine group (from 1.60 +/- 0.11 to 1.79 +/- 0.2 mumol/L-1) than in the placebo group (from 1.17 +/- 0.11 to 2.84 +/- 0.58 mumol/L-1). Myosin was present 4 hours after surgery in all patients in the placebo group and in 5 of the 10 of the trimetazidine group (p = 0.036). Haemodynamic measurements showed that patients pretreated with trimetazidine had a better ventricular function, as assessed by the stroke work index (SWI) significantly (p = 0.01) higher in the trimetazidine group (0.0391 +/- 0.0029 g/min/m2/beta) than in the placebo group (0.0282 +/- 0.0026 g/min/m2/beat), the evolution of SWI during surgery was not significantly different between the two groups. Thus trimetazidine seems to reduce ischaemia-reperfusion damage during cardiac surgery; moreover pretreatment with trimetazidine allows the patient to face the operation with better ventricular function.

Blood Transfusion, Autologous↗
PubMed1998

Is the cytoprotective effect of trimetazidine associated with lipid metabolism?

Trimetazidine is an anti-ischemic compound devoid of hemodynamic effect, which was recently suspected to induce cardioprotection at the cellular level by a mechanism involving lipid metabolism. The effect on trimetazidine was evaluated in vivo by determination of rat cardiac fatty acid composition, and in vitro by investigation of the phospholipid metabolism in cultured rat cardiomyocytes. In rats, a 4-week trimetazidine treatment induced a significant decrease in the phospholipid content in linoleic acid, balanced by a small increase in oleic and stearic acids. These changes were not correlated with similar alterations in plasma fatty acid composition. In isolated cells, the time-dependent incorporation of labeled precursors of membrane phospholipid ([3H]inositol, [14C]ethanolamine, [14C]choline, [3H]glycerol, [14C]arachidonic acid, and [14C]linoleic acid 10 micromol/L) was compared in trimetazidine-treated cells and control cells. In trimetazidine-treated cells, arachidonic acid incorporation was increased in the phospholipid, but not in other lipid fractions. This enhanced fatty acid utilization elicited a net increase in the total arachidonic acid uptake. The incorporation of [14C] inositol in phosphatidylinositol was strongly stimulated by trimetazidine, although the uptake of inositol was not altered. The difference was significant within 30 minutes, and reached +70%(in trimetazidine-treated cells) after 150 minutes. A similar result was obtained with ethanolamine as phosphatidylethanolamine precursor, where turnover increased by 50% in trimetazidine-treated cells. Conversely, the incorporation of choline in phosphatidylcholine was not significantly affected by the presence of trimetazidine. In conclusion, trimetazidine appears to interfere with the metabolism of phospholipids in cardiac myocytes in a manner that could indicate an increased phosphatidylinositol turnover and a redirection of cytidine triphosphate (CTP) utilization toward phosphatidylethanolamine instead of phosphatidylcholine turnover. This overall phospholipid turnover increase may contribute to a reorganization of the fatty acid utilization balance in the heart, which could lead to a lowered availability of fatty acids for energy production.

Animals↗
PubMed2005

Pharmacological investigation of trimetazidine in models of inflammation, pain and gastric injury in rodents.

The antinociceptive, anti-inflammatory and gastric effects of trimetazidine (2,3,4-trimethoxybenzyl-piperazine dihydrochloride), a novel anti-ischaemic compound, were evaluated in various animal models. In acute pain models, namely acetic acid-induced writhing, hot-plate assay, tail electric stimulation test, capsaicin-induced pain and the formalin test, trimetazidine (1.8-7.2 mg/kg, i.p.) showed marked antinociceptive effects. Trimetazidine did not produce any behavioural impairment as revealed by the mouse rotarod. The inhibition of writhing response by trimetazidine was reduced by yohimbine, theophylline (and to a certain extent by sulpiride) but not by prazosin, guanethidine, naloxone, atropine, propranolol, haloperidol, domperidone, clozapine, glibenclamide or caffeine. The carrageenan-evoked acute paw oedema was reduced by 19.2-21.2 and 17-18.6% by 3.6 and 7.2 mg/kg trimetazidine, respectively. The drug did not alter the oedema-suppressive effect of indomethacin or dexamethasone, but reduced that of rofecoxib. Trimetazidine at 7.2 mg/kg reduced immobility time in Porsolt's forced-swimming test by 28.9%. The acute gastric mucosal lesions evoked by indomethacin in the rat were inhibited in a dose-dependent manner by co-administration of trimetazidine. In anesthetized rats, trimetazidine potentiated the gastric acid secretory response. This study indicates that trimetazidine possesses antinociceptive and gastric protective properties. The antinociceptive properties of trimetazidine are likely to be centrally mediated, but do not involve opioid pathways.

Acute Disease↗
PubMed2002

Trimetazidine limits the effects of myocardial ischaemia during percutaneous coronary angioplasty.

This open-label, randomised, controlled study is aimed at assessing the effect of pre-treatment with the metabolic agent trimetazidine on the degree of ischaemia during percutaneous transluminal coronary angioplasty (PTCA). Overall 44 patients with one-vessel coronary artery stenosis (> 70%) in the medial part of the left anterior descending artery were included. One group (n = 22) was pre-treated with oral trimetazidine. The other group (n = 22) was the control. All patients (n = 44) were administered aspirin and conventional treatment. All patients underwent PTCA; stents were implanted in 11 trimetazidine patients and in seven control patients. The mean ST-segment elevation during all balloon inflations was significantly lower in the trimetazidine group than in the control group (-1.66 +/- 1.50 mm vs. 3.29 +/- 1.59 mm, p = 0.001). Maximal ST-segment elevations and mean ST elevation values during sequential balloon inflations were also significantly lower with trimetazidine (p = 0.018). The mean amplitude of the T-wave alterations during all balloon inflations was significantly lower with trimetazidine (3.09 +/- 2.39 mm vs. 6.83 +/- 4.31 mm; p = 0.001). Similarly, the maximal amplitude of the T-wave alterations was 4.50 +/- 2.90 mm with trimetazidine vs. 9.25 +/- 4.97 mm in control patients (p = 0.0005). Angina and rhythm disturbances were more frequent in the control group. Time from balloon inflation to onset of angina was 50 +/- 26.2 s with trimetazidine vs. 32 +/- 15.0 s, for control group (p = 0.03). The time to pain relief after deflation was 19.3 +/- 11.4 s with trimetazidine vs. 28.2 +/- 16.8 s (p = 0.001). Trimetazidine administered a few days before PTCA appears to be a cardioprotective agent for the prevention of myocardial ischaemia.

Angioplasty, Balloon, Coronary↗
PubMed1999

Trimetazidine. A review of its use in stable angina pectoris and other coronary conditions.

UNLABELLED: The orally administered antianginal agent trimetazidine increases cell tolerance to ischaemia by maintaining cellular homeostasis. In theory, this cytoprotective activity should limit myocyte loss during ischaemia in patients with angina pectoris. Data from studies in patients with coronary artery disease indicate that, unlike the effects of other antianginals, the anti-ischaemic effects of trimetazidine 20 mg are not associated with alterations in haemodynamic determinants of myocardial oxygen consumption such as heart rate, systolic blood pressure and the rate-pressure product. Furthermore, limited evidence suggests trimetazidine may improve left ventricular function in patients with chronic coronary artery disease or ischaemic cardiomyopathy and in patients experiencing acute periods of ischaemia when undergoing percutaneous transluminal coronary angioplasty. Clinical studies have shown that oral trimetazidine 20 mg 3 times daily reduces the frequency of anginal attacks and nitroglycerin use and increases exercise capacity when used as monotherapy in patients with angina pectoris. Its clinical effects are broadly similar to those of nifedipine 40 mg/day and propranolol 120 to 160 mg/day but, unlike these agents, trimetazidine does not affect the rate-pressure product during peak exercise or at rest. Adjunctive trimetazidine 60 mg/day reduces the frequency of anginal attacks and nitroglycerin use and improves exercise capacity in patients with angina pectoris not sufficiently controlled by conventional antianginal agents. Furthermore, the drug appears to be more effective than isosorbide dinitrate 30 mg/day when used adjunctively in patients with angina pectoris poorly controlled by propranolol 120 mg/day. The tolerability profile of trimetazidine 60 mg/day was similar to that of placebo when used as add-on therapy in patients with angina pectoris insufficiently controlled by other antianginal agents and was superior to that of either nifedipine 40 mg/day or propranolol 120 to 160 mg/day when used as monotherapy. The most frequently reported adverse events in trimetazidine recipients were gastrointestinal disorders, although the incidence of these events was low. CONCLUSIONS: Trimetazidine is an effective and well tolerated anti-ischaemic agent which, in addition to providing symptom relief and functional improvement in patients with angina pectoris, has a cytoprotective action during ischaemia. The drug is suitable for initial use as monotherapy in patients with angina pectoris and, because of its different mechanism of action, as adjunctive therapy in those with symptoms not sufficiently controlled by nitrates, beta-blockers or calcium antagonists. The role of trimetazidine in other coronary conditions has yet to be clearly established.

Angina Pectoris↗
PubMed2005

Effects of trimetazidine on myocardial perfusion and the contractile response of chronically dysfunctional myocardium in ischemic cardiomyopathy: a 24-month study.

OBJECTIVE: The aim was to assess the long-term effect of trimetazidine on myocardial perfusion, using gated single photon emission computerized tomography (SPECT). METHODS: 200 patients (aged 54.7 +/- 12 years) with ischemic left ventricular dysfunction (LVD) and multivessel coronary artery disease were randomized to receive trimetazidine 20mg three times daily or a placebo for 24 months. At baseline and after 24 months of treatment, all patients underwent a symptom-limited cardiopulmonary exercise test concluded by the injection of (99m)Tc-MIBI (technetium-99m methoxy-isobutyl-isonitrile). Imaging of post-stress gated SPECT and resting gated SPECT were performed. Standard antianginal therapy was interrupted for 48 hours (nitrates for 6 hours) before the exercise tests and resumed immediately after testing. RESULTS: On initial evaluation, summed stress and rest scores (SSS and SRS, respectively), systolic wall thickness (SWT), and wall motion score index (WMI), heart rate, SBP, and rate pressure product were similar at rest and peak exercise in both groups. After 24 months, 91% of patients in the trimetazidine group versus 22% in the placebo group showed a significant decrease of the frequency of anginal episodes per week (3.9 vs 5.7, p < 0.01). Weekly nitroglycerin (glyceryl trinitrate) tablet consumption was significantly lower with trimetazidine than with placebo at endpoint (2.3 +/- 0.8 vs 6.1 +/- 1.6, p < 0.01). This was supported by perfusion SPECT data. Compared with baseline values, SSS and SRS were significantly reduced with trimetazidine (from 19.8 +/- 7.7 to 11.2 +/- 6.1, p < 0.00001 and from 12.4 +/- 8.7 to 5.8 +/- 3.3, p < 0.00001, respectively). There was a nonsignificant decrease from baseline values in both SRS and SSS with placebo group (from 11.9 +/- 8.3 to 11.2 +/- 7.4 and 18.1 +/- 6.3 to 17.9 +/- 9.2, respectively). Duration of peak exercise increased significantly from baseline values with trimetazidine (from 4.6 to 5.8 minutes, p < 0.01) but not with placebo (from 5.4 to 5.8 minutes). Accordingly, mean maximum work at peak exercise improved by 1.2 metabolic equivalents with trimetazidine. This was proved by gated SPECT with an increase in SWT score of 89.5% (p < 0.00001) and in ejection fraction of 23% with trimetazidine (p < 0.001) without significant changes in hemodynamic parameters. CONCLUSION: Trimetazidine improves ischemic attacks in patients with ischemic cardiomyopathy, clinically and objectively as seen in gated SPECT myocardial perfusion. The improvement in myocardial function with trimetazidine was not accompanied by hemodynamic changes.

Aged↗
PubMedDate not supplied

Cardioprotective effect of trimetazidine and nifedipine in guinea-pig hearts subjected to ischaemia.

The cardioprotective effects of nifedipine and trimetazidine were evaluated in the Langendorff heart, the working heart and the heart-lung preparation of the guinea-pig. The effects of pretreatment with the drugs on cardiac function and on high energy phosphate content after global ischaemia were determined. Nifedipine was 1000-fold more active than trimetazidine in depressing cardiac functional parameters. In the Langendorff heart, nifedipine, but not trimetazidine, increased the coronary flow. With the exception of trimetazidine (4 x 10(-5) mol/l) in the Langendorff heart, nifedipine and trimetazidine markedly improved and in a similar fashion, the recovery of cardiac mechanical parameters in the three models of myocardial ischaemia. Pretreatment with nifedipine, but not with trimetazidine, resulted in slightly but statistically not significant higher ATP-levels after global ischaemia in the working heart and in the heart-lung preparation. After reperfusion, the cardioprotective effect of nifedipine was associated with increased ATP-levels, whereas that of trimetazidine was merely related to increased phosphocreatine (PCr) levels. In the pithed rat, trimetazidine did not influence the vasoconstrictor response to the selective alpha 1-adrenoceptor agonist cirazoline or to the selective alpha 2-adrenoceptor agonist B-HT 920. The latter response is known to be strongly dependent on the influx of extracellular calcium. Nifedipine caused a pronounced inhibition of vasoconstriction evoked by B-HT 920. These results indicate that trimetazidine is devoid of calcium entry blocking activity. The data obtained clearly show that trimetazidine exerts a pronounced beneficial effect on the ischaemic myocardium without influencing hemodynamic parameters. The mechanism of the cardioprotective activity of the drug is not related to calcium entry blockade or alpha-adrenoceptor antagonism, but rather caused by a mechanism at a cellular level, so far not known in detail.

Adenine Nucleotides↗