The role of trimetazidine in ischemia/reperfusion damage treatment in an ovary torsion model experimentally induced in rats.

The aim of this experimental animal study was to investigate the histopathological and biochemical efficacy of trimetazidine (TMZ) in decreasing ovary damage in an ovary ischaemia/reperfusion (I/R) model in the rat. A total of 35 Wistar albino female rats were randomly separated into five groups, n = 7 per group: Group 1: Sham (S) was only given a laparotomy procedure. Group 2: Ischaemia (I) group with 2-hour ischaemia using a vascular sutur. Group 3: Ischaemia/Reperfusion (I/R) group with 2 hour ischaemia and 2-hour reperfusion. Group 4: Sham + 10 mg/kg orally TMZ (S + TMZ). Group 5: I/R + 10 mg/kg oral TMZ (I/R + TMZ) group with 2 hours ischaemia and 2 hours reperfusion after the administration orally 10 mg/kg oral TMZ. Two daily doses of TMZ were orally administered to Group 4 (S + TMZ) and Group 5 (I/R + TMZ) for three days. TMZ significantly decreased vascular congestion, haemorrhage, and polymorphonuclear leukocyte infiltration in group 5 compared to group 3 (p < .05). Despite TMZ decreased the malondialdehyde, total oxidant status, and oxidative stress index values, these decreases were not statistically significant (p > .05). TMZ which is an antioxidant agent can efficiently prevent in I/R damage in rat ovaries but further studies are necessary in order to implement it in the clinical settings.IMPACT STATEMENTWhat is already known on this subject? Adnexial torsion is the most common gynecological emergency and there are no specific clinical, laboratories, or radiological findings for adnexal torsion. Unfortunatelly, the currently accepted treatment is adnexal detorsion. Cytoprotective effects of Trimetazidine (TMZ), an antianginal drug, are well-defined and it has been demonstrated to improve oxidative stress markers and limits membrane damage induced by reactive oxygen species and protects tissues from free radicals with its antioxidant effects. The aim of this study is to investigate the effects of TMZ in experimentally induced adnexal torsion in rats and to investigate possible effects in maintaining ovarian reserve to prevent I/R damage or reperfusion damage.What do the results of this study add? Our study showed that TMZ significantly decreased vascular congestion, haemorrhage, and PMNL infiltration. TMZ decreased the malondialdehyde, total oxidant status, and the oxidative stress index values, but these decreases were not statistically significant.What are the implications of these findings for clinical practice and/or further research? Although various antioxidant drugs and chemicals have been used to protect the ovaries against I/R damage, they have not been demostrated to prevent it completely. TMZ, an antioxidant efficacy agent, has been shown to prevent ovarian I/R damage by suppressing inflammation in terms of histopathological parameters. Further studies involving a greater number of experimental animals are required before using TMZ for the treatment of humans with I/R damage in the clinical setting.

Trimetazidine can prevent the occurrence of contrast-induced nephropathy after percutaneous coronary intervention in elderly patients with renal insufficiency.

BACKGROUND: Contrast-induced nephropathy (CIN) has become a common cause of hospital-acquired acute kidney injury in elderly patients. Trimetazidine (TMZ) is a type of anti-ischemic drug developed in recent years, which can reduce the incidence of CIN. This study aimed to evaluate the efficacy of TMZ in the prevention of contrast-induced nephropathy in elderly patients with renal insufficiency undergoing percutaneous coronary intervention (PCI) and to explore the mechanism of action. METHODS: A total of 310 elderly patients with renal insufficiency undergoing elective PCI were enrolled and randomly assigned to a control group (n = 155, hydration only) and a TMZ group (n = 155, 20 mg thrice daily orally 24 hours before and 72 hours after PCI). The primary endpoint of the study was the incidence of CIN, which was defined as an increase of 25% or more, or an absolute increase of 0.5 mg/dL or more in serum creatinine from baseline value, at 48 to 72 hours following the exposure to contrast media (CM). RESULTS: The incidence of CIN was significantly lower in the TMZ group than that in the control group (3.2% vs. 9.7%, p = 0.021). There was no difference regarding the incidence of major adverse events during hospitalization between the TMZ group and control group (1.9% vs. 2.6%, p = 1.000). Binary logistic regression results showed that TMZ was protective factors of CIN (OR = 0.274; 95% CI: 0.089-0.847; p = 0.025). CONCLUSION: Therefore, we came to the conclusion that prophylactic administration of TMZ can prevent the occurrence of CIN in elderly patients with renal insufficiency undergoing PCI and has a certain protective effect on the renal function of patients. According to the experimental results and the mechanism of TMZ on cardiomyocytes, we speculate that TMZ increases kidney glucose metabolism, reduces fatty acid oxidation, and also has a protective effect on kidney free radical damage and ischemia-reperfusion injury.

The effect of trimetazidine treatment in patients with type 2 diabetes undergoing percutaneous coronary intervention for AMI.

PURPOSE: Trimetazidine (TMZ) improves clinical outcomes in patients with chronic heart failure and stable coronary artery disease. No study has yet evaluated the efficacy of TMZ in type 2 diabetes patients with acute myocardial infarction (AMI) undergoing Percutaneous Coronary Intervention (PCI). We performed this study to evaluate the efficacy TMZ in DM patients with AMI undergoing PCI, such as the effect on reductions in myocardial enzyme, improvements in liver function, modulation of glucose levels, and improvement in cardiac function. METHODS: For this randomized study, we enrolled 173 AMI patients with type 2 diabetes undergoing PCI between January 1, 2014, and January 1, 2016. All patients received aspirin and ticagrelor upon admission and throughout their hospitalization. Patients in the experimental group were treated with a loading dose of 60mg TMZ at admission, and 20 mg TMZ three times a day thereafter. 89 patients were included in experimental group, and 84 patients were included in control group. All patients received PCI treatments. The endpoints evaluated were serum creatine kinase and its isoenzyme (CK and CK-MB), cardiac troponin I (cTNI), serum creatinine (Cr), serum urea, blood glucose, serum glutamic pyruvic transaminase (ALT), serum glutamic oxaloacetictransaminase (AST), left atrial dimension (LA), left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), and cardiac output (CO). FINDINGS: Compared with the control group, TMZ treatment significantly reduced CK and CK-MB on the second day in hospital ([797±582] vs. [1092±1114]; [80±60] vs. [105±100]; p=0.029, p=0.041, respectively), and cTNI after one and six days in hospital ([13.5±12.7] vs. [19.8±19.2]; [3.3±3.2] vs. [4.8±4.7]; two-tailed p=0.012). In addition, TMZ significantly lowered liver enzymes (ALT, AST) at 6days ([29.0±11.6] vs. [42.4±24.5]; [39.8±17.3] vs. [69.2±70.0]; two-tailed p=0.000), lowered glucose after 6days ([6.80±2.12] vs. [7.59±2.24]; p=0.019), and increased LVEF after ten to fourteen days ([58.4±8.6] vs. [54.9±8.4]; p=0.008). There were no significant effect on Cr and serum urea (p=0.988, p=0.569, respectively), nor on LA, LVEDD, and CO ([36.3±4.5] vs. [37.0±4.1], p=0.264; [52.0±4.9] vs. [53.1±4.6], p=0.128; [5.4±0.9] vs. [5.4±0.9], p=0.929, respectively). IMPLICATIONS: Among type 2 diabetic patients with AMI undergoing PCI, TMZ significantly reduces serum myocardial enzyme, improves liver function, adjusts blood glucose and improves cardiac function.

[Metabolic treatment of stable coronary artery disease ­ the present and perspectives].

Trimetazidine, a piperazine analogue, is a metabolic agent that selectively inhibits beta-oxidation. The effect of trimetazidine is to block fatty free acids and subsequently to enhance glucose oxidation. The results of both experimental and clinical researches provided evidences for antianginal effects and for improvement of coronary flow reserve with trimetazidine treatment. The current European Cardiac Society Guidelines on stable coronary artery disease suggest that trimetazidine be used as second-line treatment. Recent study indicate for beneficial effects of trimetazidine treatment in the population of patients after coronary revascularization (reduction of restenosis rate, improvement of left ventricle systolic function, reduction of angina episodes). However the results of currently ongoing large randomized trials are required to confirm this findings.

Efficacy of medical therapy in the prevention of residual dizziness after successful repositioning maneuvers for Benign Paroxysmal Positional Vertigo (BPPV).

OBJECTIVES: The aim of this study was to investigate the efficacy of trimetazidine, betahistine, and ginkgo biloba extract in the treatment of residual dizziness after successful repositioning maneuvers for benign paroxysmal positional vertigo. METHODOLOGY: This was a randomized controlled clinical trial. Complete clinical data were analyzed from 100 patients (27 men and 73 women; mean age 52.16 ± 13.2 years, range 11-80 years) with BPPV who underwent succcessful repositioning maneuvers and then received betahistine, trimetazidine, gingko biloba extract, or no medication (n = 25 for each group) for 1 week. On days 1, 3, and 5 after the repositioning maneuver, scores obtained from the Dizziness Handicap Inventory (DHI) questionnaire were compared. RESULTS: There were no statistically significant differences in the premedication DHI scores of patients with residual dizziness among the four groups (p > 0.005). After 3 and 5 days of treatment, the mean DHI scores of the groups receiving medication did not differ significantly from the the mean DHI score of the control group (p > 0.005). CONCLUSIONS: Our study results suggest that betahistine, trimetazidine, and gingko biloba extract do not alleviate residual dizziness after successful repositioning maneuvers.

[Metabolic therapy for heart failure]. / Terapia metabolica per l'insufficienza cardiaca.

Heart failure may promote metabolic changes such as insulin resistance, in part through neurohumoral activation, and determining an increased utilization of non-carbohydrate substrates for energy production. In fact, fasting blood ketone bodies as well as fat oxidation have been shown to be increased in patients with heart failure. The result is depletion of myocardial ATP, phosphocreatine and creatine kinase with decreased efficiency of mechanical work. A direct approach to manipulate cardiac energy metabolism consists in modifying substrate utilization by the failing heart. To date, the most effective metabolic treatments include several pharmacological agents that directly inhibit fatty acid oxidation. The results of current research are supporting the concept that shifting the energy substrate preference away from fatty acid metabolism and toward glucose metabolism could be an effective adjunctive treatment in patients with heart failure. Trimetazidine is the most studied drug in this context. Several small studies have evidenced the usefulness of such additional therapeutic tools for heart failure. More specifically, recent meta-analyses and a multicenter retrospective study have shown that additional use of trimetazidine in patients with heart failure, along with symptoms and cardiac function improvement, also provides a significant protective effect on all-cause mortality, cardiovascular events and hospitalization due to cardiac causes. Nevertheless, the exact role of metabolic therapy in heart failure is yet to be established, and a large multicenter randomized trial is necessary.

[Clinical aspects of the use of trimetazidine in the prevention and treatment of myocardial diseases]. / Kliniczne aspekty zastosowania trimetazydyny w prewencji i terapii chorób miesnia sercowego.

Trimetazidine, next to ranolazine and L-carnitine, belongs to cardioprotective drugs and as their main agent is used in experimental and clinical trials to evaluate its effect on modulation of cardiomyocytes metabolism. The blockade of fatty acid oxidation in ischemic myocardium and increase in the glucose utilization are the main mechanisms of trimetazidine action, which eventually lead to the reduction in intracellular acidosis. Recent studies concerning cardioprotective treatment encourage to continue the research on effectiveness, possible side effects, and clinical outcome which arise from "metabolic shift" toward the improvement of glucose metabolism. It has been demonstrated that trimetazidine not only ameliorate the quality of life by increasing physical tolerance, but also inhibits cardiac remodeling associated with long-standing diabetes or ischemia. Futhermore, trimetazidine exhibits antiarrhythmic properties and reduces myocardial damage associated with oxidative stress and inflammation after invasive procedures. In the light of these findings, trimetazidine seems to be an attractive therapeutic option andlor complementary therapy for treated conservatively patients with heart disease and with high risk of postreperfusal damage after cardiac invasive procedures. Moreover, particularly large benefits from introducing the metabolic treatment obtain patients with diabetes. The literature concerning trimetazidine function and treatment is broad. Therefore, the aim of this article is to summarize recent multicenter clinical trials on metabolic cardioprotection, showing its effectiveness or neutrality to the myocardial damaging factors.

The role of postoperative trimetazidine therapy in on-pump coronary artery bypass surgery.

INTRODUCTION: Coronary artery bypass surgery remains the gold standard in the treatment of patients with ischemic heart disease. However, the increased oxidative stress caused by the release of free radicals during the ischemia-reperfusion time is a well-known pathophysiological process during and after coronary revascularization procedures. It may lead to reversible and irreversible myocardial injury.

Trimetazidine in the prevention of contrast induced nephropathy after coronary angiogram.

This prospective randomized, controlled trial was done to evaluate the efficacy of trimetazidine in the prevention of contrast induced nephropathy in patients with raised serum creatinine levels undergoing coronary angiogram. This study was performed in the Department of Cardiology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh from April 2009 to March 2010. Contrast-induced nephropathy (CIN) is a serious complication of coronary angiography that is associated with considerably increased mortality and morbidity, including the need for short-term haemodialysis, extended hospitalisation and permanent impairment of renal function. Trimetazidine (TMZ) has been described as a cellular anti-ischaemic agent. This study was trial with 400 patients. Among them 200 patients treated with trimetazidine plus hydration with normal saline and 200 patients (control) given hydration by normal saline only. It was found that the incidence of CIN was significantly (p<0.05) reduced by trimetazidine administration with saline in comparison with saline alone in patients undergoing coronary angiogram (4% vs. 14%).

[Trimetazidine addition to antianginal therapy: effects on efficacy and quality of life in patients with stable angina treated outpatiently].

AIM: To compare effects of original trimetazidine versus its generics addition to antianginal treatment efficacy and quality of life in patients with stable angina (SA). MATERIAL AND METHODS: Twenty patients aged 37-74 years with SA of functional class (FC) II-III received standard SA treatment with addition of trimetazidine generics which were later changed for original trimetazidine. Original trimetazidine effects were examined by frequency of anginal attacks and use of short-acting nitrates, changes in anginal FC and chronic cardiac failure, in quality of the patients' life. RESULTS: SA treatment with hemodynamic drugs in combination with trimetazidine generics was insufficiently effective. Change of the generics for an original drug (preductal MB) raised antianginal treatment efficacy as shown by less frequent anginal attacks (reduction from 9.0 +/- 6.9 to 0.3 +/- 0.6 per a week) and by reduced need in short-acting nitrates (from 9.1 +/- 6.9 to 0.4 +/- 0.6 per week) and significant improvement of the patients' quality of life. CONCLUSION: In combined treatment of SA patients it is more effective to use preductal MB which is an original trimetazidine drug than trimetazidine generics.

The role of trimetazidine after acute myocardial infarction.

"Metabolic treatment" involves the use of drugs to improve cardiomyocyte function. Trimetazidine is the most investigated drugs in this group. The ESC 2006 guidelines on the management of patients with stable angina mention the efficacy of metabolic treatment in improving physical efficiency and decreasing the recurrence of pain. The available data suggest that combined therapy of trimetazidine and haemodynamic drugs is an effective antianginal treatment that reduces the risk of pain recurrence (in as many as 64% of patients). The most recent studies also suggest that trimetazidine might be effective in patients with acute coronary syndromes, ischemic cardiomyopathy and heart failure. However, while trimetazidine has shown beneficial effects on surrogate endpoints in several small trials its effect on cardiovascular events is uncertain. Further large randomized studies are needed before its effects on cardiovascular events can be evaluated.

Clinical benefits of a metabolic approach with trimetazidine in revascularized patients with angina.

As patients with coronary artery disease live longer and more often reach the stage where further myocardial revascularization procedures can no longer be performed, efficacious and well-tolerated antianginal medications are needed. Metabolic agents offer the advantage of controlling symptoms without untoward hemodynamic effects. This article reviews the epidemiology of stable angina and the use of antianginal medications in patients who have undergone myocardial revascularization. It also describes the clinical data on the anti-ischemic effects of metabolic agents in patients undergoing coronary artery bypass surgery or angioplasty, the latter in the setting of acute myocardial infarction and elective procedures. Lastly, the effects of trimetazidine on exercise tests in previously revascularized patients treated with beta-blockers, such as documented in the subgroup analysis of the Second Trimetazidine in Poland (TRIMPOL II) trial, are reported. In all, metabolic agents are likely to be beneficial in revascularized patients, with a documented anti-ischemic effect during myocardial revascularization procedures and the ability to improve exercise tolerance and symptoms in patients with chronic stable angina, despite myocardial revascularization.

[Therapeutic value of trimetazidine in patients with coronary heart disease and left ventricular dysfunction].

OBJECTIVE: Trimetazidine has been shown to have anti-ischemic properties by improving exercise tolerance without haemodynamic effects and direct cyto-protective effects on the myocardium. The aim of this study was to assess the effect of trimetazidine on the treatment of patients with ischemic cardiomyopathy, and to assess the anti-angina efficacy and the clinical tolerance of TMZ. METHODS: 60 ischemic cardiomyopathy patients on conventional therapy were enrolled in this open multiple center clinical trial and received TMZ (20 mg 3 times per day) for six months. Patients were followed up for six months and assessments included clinical evaluation, electrocardiography and echocardiography. RESULTS: All patients tolerated 60 mg of trimetazidine for six months, left ventricular ejection fraction (LVEF) was increased from 32.4 +/- 6.3% to 41.8 +/- 10.8% (P < 0.0001). Stage of NYHA classification was improved in most patients (P < 0.0001). Attack of angina was relieved and consumption of nitroglycerin reduced (both P < 0.001). CONCLUSION: Trimetazidine seems to improve clinical status and ejection fraction, and reduce angina onsets without adverse effects in patients with ischemic cardiomyopathy.

[Trimetazidine prevents ischemia-reperfusion injury in hepatic surgery under vascular clamping]. / La trimétazidine prévient les lésions d'ischémie-reperfusion de la chirurgie hépatique sous clampage vasculaire.

Clamping the hepatic pedicle (or Pringle's manoeuvre) is frequently used to reduce blood loss during liver surgery. This induces a normothermic ischaemia of the overall liver. In this study we have investigated the anti-ischaemic effect of trimetazidine during surgery on hydatid cysts of the liver requiring vascular clamping of the hepatic pedicle. Seventy-six hepatic pericystectomies were performed under a 40 min normothermic ischaemia. Two randomized groups including 38 patients each received daily either trimetazidine (80 mg/kg, group 1) or placebo (group 2) for 5 days before surgery. The effect of trimetazidine was evaluated on different parameters, the macroscopic appearance of the tissue, the ATP content in liver biopsies obtained before and after 15, 30 and 60 min reperfusion, the activity of the aminotransferase in the plasma and the plasma concentrations of reduced and oxidized gluthatione. No mortality was observed. The duration of hospital stay was reduced for patients treated with trimetazidine (8 +/- 1 days compared with 11 +/- 1.5 days for patients in group 2; p < 0.05). Morbidity rate was lower in group 1 (11 per cent) than in group 2 (18.5 per cent) but the decrease was not significant. Trimetazidine treatment reduced cytolysis (p < 0.05 on day 1, day 3, day 5), increased liver ATP content and limited the increase of reduced and oxidized gluthatione in the plasma during reperfusion. These results suggest that trimetazidine alleviates ischaemia-reperfusion injury during liver surgery and may allow extension of the ischaemic period without damage to the liver.

[Therapeutic perspectives in the treatment of stable angina]. / Perspectives thérapeutiques dans le traitement de l'angor stable.

Five groups of drugs are presently available to reduce the symptoms associated with angina pectoris: beta-blockers, calcium channel antagonists, nitrates, potassium channel agonists and trimetazidine. beta-blockers remain the drugs of first strategy since they are unique in reducing major cardiac events. Angiogenesis and gene therapy are still in the field of research. The second therapeutic goal is to reduce cardiovascular morbi-mortality. Inhibitors of platelet aggregation, hypolipemic agents and converting enzyme inhibitors have proved their efficacy in these fields. Conversely, vitamins C, E and B, antibiotics against intra-cellular germs and substitutive hormonotherapy of post-menopausal women must yet prove their efficacy.

[Antiischemic efficacy of trimetazidine in patients with intermittent claudication and effort angina]. / Antiishemicheskaia éffektivnost' trimetazidina u bol'nykh s sochetaniem peremezhaiushcheisia khromoty i stenokardii napriazheniia.

Male patients (n=42) with atherosclerosis obliterans and stage IIA-III ischemia of lower extremities combined with class II-III angina pectoris were divided into 2 groups. Patients of group 1 (n=21) were given simvastatin (10-20 mg/day), clopidogrel (75 mg/day) and trimetazidine (60 mg/day) for 6 months, those of group 2 - simvastatin and clopidogrel also for 6 months. Statistically significant decreases of frequency of attacks of angina, nitroglycerine consumption and increases of walking distance occurred only in group 1.

[Effect of acetyl-CoA C-acyltransferase inhibitor trimetazidine on parameters of global and local systolic and diastolic functions of left ventricular myocardium in patients with combined postinfarction ischemic syndrome]. / Vliianie 3-KAT ingibitora trimetazidina na pokazateli global'noi i regional'noi sistolicheskoi i diastolicheskoi funktsii miokarda levogo zheludochka u bol'nykh s sochetannym postinfarktnym ishemicheskim sindromom.

AIM: To assess effect of trimetazidine on global and regional systolic and diastolic left ventricular function in patients with combined postinfarction ischemic syndrome. MATERIAL: Patients (n=32) with healed myocardial infarction and signs of global systolic (ejection fraction 38,5+/-2,7%) and diastolic (EIA=0,88+/-0,03) left ventricular dysfunction confirmed by Doppler echocardiography. METHODS: Regional systolic and diastolic function was assessed by dobutamine stress echocardiography with Doppler tissue imaging before and after 3 months during which the patients received 60 mg/day of trimetazidine. RESULTS: The segments with hibernating myocardium were found in every patient. These segments along with segments with scars displayed greatest degree of local systolic and diastolic dysfunction and because of their prevalence made significant contribution to the setting of global diastolic dysfunction. Improvement of global diastolic function at rest after trimetazidine was associated with decrease of total number of ischemic segments (from 80 to 67%) especially of those with hibernation (from 61 to 46%). CONCLUSION: The hibernating myocardium was most sensitive to metabolic intervention and its presence after myocardial infarction predicted improvement after drug treatment of not only systolic but also diastolic left ventricle dysfunction. Restoration of function of hibernating myocardium turned out to be possible not only after myocardial revascularization but also after medical therapy.