The effect of trimetazidine on contrast-induced nephropathy in patients undergoing coronary angiography and/or percutaneous coronary intervention - A systematic review and meta-analysis.

OBJECTIVE: In this study, we aimed to evaluate whether the trimetazidine administration before CAG and/or PCI reduces the incidence of contrast-induced nephropathy (CIN). We also aimed to evaluate the factors affecting the effect and the certainty of the evidence. MATERIALS AND METHODS: A systematic literature search was performed to obtain studies that assess trimetazidine's effect on the incidence of CIN in CAG/PCI patients up until 21 January 2021 through PubMed, Embase, and Scopus. The main outcome is CIN, defined as the increase in serum creatinine level ≥ 0.5 mg/dL (44.2 mmol/L) or > 25% of the baseline value 48-72 h after contrast media (CM) administration. RESULTS: This systematic review and meta-analysis includes seven studies involving a total of 1590 patients. The prevalence of CIN was 11% [8%, 14%]. CIN's prevalence was 6% [4%, 8%] in the trimetazidine group and 16% [12%, 20%] in the control group. Trimetazidine use is associated with a lower incidence of CIN (RR 0.46 [0.34, 0.63], p<0.001; I2: 0%) with a high certainty of evidence, with an absolute risk reduction of 78 fewer per 1000. Subgroup analysis in patients with renal insufficiency showed that trimetazidine lowers the risk of CIN (RR 0.40 [0.26, 0.61], p<0.001; I2: 0%). The CIN reducing effect of trimetazidine was not significantly influenced by the age (p=0.960), body mass index (p=0.816), hypertension (p=0.595), diabetes (p=0.362), ejection fraction (p=0.261), baseline serum creatinine (0.579), and contrast media volume (p=0.958). CONCLUSIONS: Trimetazidine administration decreases the risk of CIN in patients undergoing CAG/PCI.

Trimetazidine improves hepatic lipogenesis and steatosis in non­alcoholic fatty liver disease via AMPK­ChREBP pathway.

Clinical studies have demonstrated that trimetazidine (TMZ) possesses a synergistic hypolipidemic effect together with statins, but the underlying mechanism remains to be elucidated. The present study aimed to investigate the role of TMZ in non­alcoholic fatty liver disease (NAFLD). By investigating the TMZ treatment of NAFLD, it was identified that high­fat diet (HFD) mice exhibit significant changes in several physiologic indices, including body weight, plasma lipids and glucose tolerance. Notably, hepatocyte bullous steatosis and fibrosis in HFD mice are greatly attenuated by 8 weeks of TMZ treatments. The results of the present study also indicated that the expression of carbohydrate­responsive element­binding protein (ChREBP), fatty acid synthase and acetyl­CoA carboxylase were all significantly reduced in the HFD + TMZ group compared with the HFD group. In order to confirm the hypothesis in vitro, the palmitate­treated liver cancer cell line (HepG2) was employed and similar results were obtained in TMZ­treated HepG2 cells. Furthermore, TMZ markedly upregulated the AMP­activated protein kinase (AMPK) signaling pathway and reduced the expression of forkhead box O1 (FOXO1) in the cells, while these effects controlled by TMZ were abolished by the AMPK inhibitor Compound C. The present study reported that knockdown of FOXO1 expression by FOXO1 small interfering RNA resulted in a reduction of ChREBP protein expression and post­transcriptional activity. In summary, for the first time, to the best of the authors' knowledge, the present study revealed a novel role of TMZ in hepatic steatosis; TMZ ameliorated ChREBP­induced de novo lipogenesis by activating the AMPK­FOXO1 pathway.

Metformin and trimetazidine ameliorate diabetes-induced cognitive impediment in status epileptic rats.

Patients with diabetes and epilepsy are more prone to cognitive impairment, dementia, and even Alzheimer's disease. Diabetes-induced inflammatory process is one of the main contributing factors; however, the impact on seizure is not clear. The current study is aimed to examine the role of metformin and trimetazidine in the reduction of neuronal damage caused by inflammatory mediators and apoptotic factors in diabetic epileptic rodent model. Diabetic epileptic rats received orally either metformin (100 mg/kg) or trimetazidine (10 mg/kg) for 3 weeks exhibited reduced cognitive function and ameliorated the disturbed brain neurotransmission. Besides, they improved both the inflammatory status and the histopathologic alterations. Administration of metformin or trimetazidine ameliorated the deterioration in cognitive function in Morris water maze (MWM) and reduced seizure score. Furthermore, brain neurotransmitters glutamate and γ-aminobutyric acid (GABA) were reverted back to their normal values. Both treatments reduced the rise in inflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), apoptotic markers nuclear factor-κB (NF-κB) and caspase-3, and improved the pathological photomicrograph of the hippocampus of diabetic epileptic rats. Such effects were closely correlated to the observed increase in the adenosine triphosphate and adenosine diphosphate (ATP/ADP) ratio and reduction of death-associated protein (DAP) and mammalian target of rapamycin (mTOR). In conclusion, the current study shed light on the potential neuroprotective role of metformin and trimetazidine in the amelioration of cognitive function via hindering inflammatory processes in diabetic epileptic rats.

The postoperative effects of use of trimetazidine before the coronary artery bypass graft surgery.

BACKGROUND: In this study, postoperative cardiac functions were observed in patients undergoing coronary artery bypass grafting (CABG) surgery following preoperative administration of the anti-ischemic drug trimetazidine. MATERIALS AND METHODS: The study included a total of 50 CABG patients; 25 were administered with trimetazidine preoperatively and 25 did not receive trimetazidine. A retrospective evaluation was made of the parameters of age, gender, preoperative echocardiography (ECHO) results, cross-clamping durations, postoperative inotropic requirements, and postoperative 4th-h troponin-I levels and the groups were compared. RESULTS: There was no statistically significant difference determined between the 2 groups in respect of the data of age, gender, comorbidity, preoperative ECHO signs [(ejection fraction (EF), left ventricle end systolic diameter (lvsd), left ventricle end diastolic diameter (lvdd), left atrium diameter (LA), and intraventricular septum thickness (IVS)], inotropic requirements, and postoperative troponin-I levels. In the control group, a positive correlation was determined between postoperative troponin-I levels and DM (r: 0.597, p: 0.002). There was no correlation determined in the trimetazidine group (r:-0.042, p: 0.844). CONCLUSION: The results of this study demonstrated a positive correlation between postoperative troponin-I levels and DM in the group not administered with trimetazidine. There was no such correlation determined in the group administered with trimetazidine. This result may suggest that DM may increase troponin-I levels in the absence of trimetazidine, and therefore that the drug may be cardioprotective in such cases. Further studies on more extensive patient populations are required to confirm these results.

The renoprotective effects of naringin and trimetazidine on renal ischemia/reperfusion injury in rats through inhibition of apoptosis and downregulation of micoRNA-10a.

Renal Ischemia-Reperfusion (IR) injury occurs due to circulatory shock and renal transplantation, leading to mortality and morbidity worldwide. The primary purpose of the current study was to evaluate the renoprotective effects of the naringin (NAR) and trimetazidine (TMZ) on IR injury, renal hemodynamics, antioxidant capacity, microRNA-10a, and expression of apoptosis factors. Forty rats were divided into five groups randomly: Sham, IR injury, (TMZ, 5 mg/kg), (NAR pretreatment, 100 mg/kg), and TMZ plus NAR. The sham group underwent the identical surgical procedure as the other groups, except for the application of clamps. After anesthesia, IR injury was induced by 45 min of ischemia, followed by reperfusion for 4 h. Tissue and blood samples were collected for evaluation of renal function, antioxidant activity and, biochemical and molecular parameters. Administration of the NAR, TMZ, and their combination decreased the plasma level of microRNA-10a, caspase-3, and Bcl-2 associated x protein (Bax) mRNA expression, but increased the B- cell lymphoma 2 (Bcl-2) mRNA expression in the kidney tissue. In addition, antioxidant activity, renal blood flow, creatinine clearance (CCr), and fractional excretion of sodium (FENa) were improved. The NAR, TMZ, and their combination can prevent renal I/R injury through promotion of the level of antioxidant enzymes, as well as decrease of microRNA-10a and anti-apoptosis properties. Our data also suggest that NAR, TMZ, or their combination might be beneficial as potent therapeutic factors against renal IR injury.

Ex vivo administration of trimetazidine improves post-transplant lung function in pig model.

OBJECTIVES: Ex vivo lung perfusion (EVLP) is not only used to assess marginal donor lungs but is also used as a platform to deliver therapeutic agents outside the body. We previously showed the beneficial effects of trimetazidine (TMZ) on ischaemia reperfusion (IR) injury in a rat model. This study evaluated the effects of TMZ in a pig EVLP transplant model. METHODS: Pig lungs were retrieved and stored for 24 h at 4°C, followed by 4 h of EVLP. Allografts were randomly allocated to 2 groups ( n = 5 each). TMZ (5 mg/kg) was added to the prime solution prior to EVLP. After EVLP, left lungs were transplanted and recipients were observed for 4 h. Allograft gas exchange function and lung mechanics were recorded hourly throughout reperfusion. Microscopic lung injury and inflammatory and biochemical parameters were assessed. RESULTS: There was a trend towards better oxygenation during EVLP in the TMZ group ( P = 0.06). After transplantation, pulmonary gas exchange was significantly better during the 4-h reperfusion period and after isolation of the allografts for 10 min ( P < 0.05). Tissue thiobarbituric acid levels, myeloperoxidase activity and protein concentrations in bronchoalveolar lavage samples were significantly lower in the TMZ group at the end of EVLP ( P < 0.05). CONCLUSIONS: Ex vivo treatment of donor lungs with TMZ significantly improved immediate post-transplant lung function. Further studies are warranted to understand the effect of this strategy on long-term lung function.

Effects of Trimetazidine on PDCD4/NF-κB/TNF-α Pathway in Coronary Microembolization.

BACKGROUND/AIMS: The local inflammatory response caused by coronary microembolization (CME) is the primary cause of progressive cardiac dysfunction. The PDCD4/NF-κB/TNF-α signaling pathway plays a significant role in CME-induced myocardial Inflammation. Trimetazidine (TMZ) reduces myocardial injury, caused by percutaneous coronary intervention, through relieving the CME-induced myocardial systolic dysfunction. Therefore, the present study investigated the role of TMZ pre-treatment in the protection of myocardium after CME and PDCD4/NF-κB/TNF-α in mini pigs. METHODS: 20 Bama mini pigs were randomized into sham operation (sham), microembolization (CME), TMZ, and siRNA-PDCD4 groups (n = 5). The CME model was established by injecting polyethylene microspheres via microcatheter into the left anterior descending coronary artery. The TMZ group was injected 2.5 mg/kg drug via ear vein 30 min before CME; whereas, the siRNA-PDCD4 group was transfected with PDCD4 siRNA at the left anterior descending coronary artery via microcatheter 72h before CME. Cardiac function indexes were measured using cardiac echocardiography. The mRNA expression of PDCD4 and TNF-α in the myocardium was detected by quantitative fluorescence PCR, and the protein expression of PDCD4, NF-κB (p65), and TNF-α by Western blot. RESULTS: Echocardiographic parameters showed lower cardiac function and higher serum cTnI level in the CME group than sham, which was manifested as reduced left ventricular ejection fraction (LVEF), left ventricular fractional shortening (FS), cardiac output (CO), and increased left ventricular diastolic diameter (LVEDd). Compared to the CME group, the CME-induced cardiac function injury was reduced, and the serum cTnI level was decreased in the TMZ and siRNA-PDCD4 groups. The expressions of PDCD4, NF-κB (p65), and TNF-α were significantly increased in the CME than the sham groups (P < 0.05), and significantly decreased in the TMZ and siRNA-PDCD4 groups than the CME group (P < 0.05). CONCLUSION: TMZ pretreatment effectively reduced the myocardial damage caused by CME via inhibiting the PDCD4/NF-κB/ TNF-α pathway in cardiomyocytes.

Trimetazidine protects against cardiac ischemia/reperfusion injury via effects on cardiac miRNA­21 expression, Akt and the Bcl­2/Bax pathway.

Trimetazidine is a piperazine-derived metabolic agent, which exerts cell protective effects and has been reported to be efficient in the treatment of chronic stable angina pectoris. In addition, it has been shown to exert protection against acute myocardial infarction. The present study aimed to investigate whether trimetazidine protects against cardiac ischemia/reperfusion (I/R) injury, and to determine whether its curative effects are associated with microRNA (miRNA)­21 expression, Akt, and the B­cell lymphoma 2 (Bcl­2)/Bcl­2­associated X protein (Bax) pathway. Cardiac I/R injury was induced by ligating the left anterior descending coronary artery in adult rats. Subsequently, cardiac function was evaluated, and the expression levels of miRNA­21, Bcl­2, Bax and phosphorylated­Akt were detected using quantitative polymerase chain reaction and western blotting. The results indicated that trimetazidine was able to significantly protect cardiac function and reduce infarct size in rats following cardiac I/R injury. Furthermore, trimetazidine significantly promoted miRNA­21 expression and phosphorylated­Akt protein expression, and reduced the Bcl­2/Bax ratio in rats following cardiac I/R injury. Knockdown of miRNA­21 using anti­miR­21 plasmids was able to reverse the protective effects of trimetazidine against cardiac I/R injury. These results indicated that miRNA­21 serves a protective role in cardiac I/R injury via Akt and the Bcl­2/Bax pathway. In addition, trimetazidine exerts protective effects against cardiac I/R injury through cardiac miRNA­21 expression, Akt, and the Bcl­2/Bax pathway. Therefore, the present study provided evidence regarding the protective effects of miRNA­21 on cardiac I/R injury following treatment with trimetazidine in vivo.

Trimetazidine attenuates the acute inflammatory response induced by Novolimus eluting bioresorbable coronary scaffold implantation.

BACKGROUND: This study aims to investigate the inflammatory response in Novolimus bioresorbable coronary scaffold implantation after a course treatment with trimetazidine (35mg tablet/twice daily for 4days). METHODS: This was a randomized single blind study. Forty diabetic patients with critical coronary stenosis were subjected to elective coronary scaffold implantation in Al-Najaf Center for Cardiac Surgery and Trans-Catheter Therapy, Najaf, Iraq, between January and July 2015. All patients were informed about the nature of the study and they signed the consent form before they included in the study. Patients were randomly allocated into the two study groups: Group 1 included 20 patients who did the elective coronary scaffold implementation without trimetazidine medication. Group 2 included 20 patients who did the elective coronary scaffold implementation with a course of the trimetazidine (35mg tablet/twice daily for 4days). RESULTS: There were significant reduction in the levels of the interleukin-6 and cardiac troponin-I in the trimetazidine-treated group (group 2) compared to the control group (group 1) (P<0.001), after 12h and 24h post-operative. This was associated with a significant rise in the levels of interleukin 10 in group 2 compared to group 1 (P<0.001). Pentraxin-3 was significantly reduced in group 2 but only 24h post-operative (P<0.006). CONCLUSION: Our study concluded that trimetazidine minimizes the acute inflammatory response occurred due to systemic release of inflammatory markers into blood in diabetic patients undergoing elective Novolimus bioresorbable coronary scaffold implementation.

Eficacia y seguridad de trimetazidina 35mg en pacientes adultos con cardiopatia isquemica refractaria y no tributarios a revascularización miocárdica percutánea o quirúrgica / Efficacy and safety of trimetazidine 35mg in adult patients with refractory ischemic heart disease and non-tributary to percutaneous or surgical myocardial revascularization

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología sanitaria acerca de la eficacia y seguridad del medicamento Trimetazidina 35mg para el tratamiento de pacientes con cardiopatía isquémica refractaria y no tributarios a revascularización miocárdica percutánea o quirúrgica. Aspectos Generales: La angina pectoris estable es un síndrome clínico de dolor, presión o molestia temporal en el pecho pudiéndose extender a la mandíbula, hombro, espalda o brazo. Es la manifestación clínica más común de la cardiopatía isquémica, la cual es la principal causa de muerte en los Estados Unidos. Los factores pronósticos más importantes de la angina pectoris son la función sistólica ventricular y clase funcional además de co-morbilidades como la diabetes mellitus y la enfermedad vascular periférica. Tecnología Sanitaria de Interés: El medicamento Trimetazidina (Vastarel®, Laboratorios Servier) es un anti-angínico, inhibidor parcial de la oxidación de ácidos grasos, con fórmula química Trimetazidina-1-(2,3,4 trimetoxi benzil)-piperazina dihidroclorido, que inhibe la enzima [3-Ketoacil-CoA tiolasa, la cual forma parte del proceso de oxidación de ácidos grasos en las células. METODOLOGIA: Estrategia de Busqueda: Se realizó una estrategia de búsqueda sistemática de la evidencia científica con respecto a la eficacia y seguridad de TMZ 35mg en pacientes con angina estable sintomática severa que han recibido terapia óptima con nitratos, calcio - antagonistas y beta bloqueadores en dosis máximas tolerables y no son tributarios de ser beneficiarios mediante revascularización miocárdica percutánea o quirúrgica. Para la búsqueda primaria se revisó la información disponible por entes reguladoras y normativas como la Administración de Drogas y Alimentos (FDA), la EMA y la DIGEMID. Posteriormente se buscaron Guías de Práctica Clínica a través de los metabuscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline), The National Guideline of Clearinghouse, y Health Systems Evidence. Finalmente, se realizó una búsqueda dentro de la información generada por grupos internacionales que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica, tales como The Cochrane Library, The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH), The Scottish Medicines Consortium (SMC), que a su vez fue complementada con una búsqueda en www.clinicaltrials.gov, para identificar estudios primarios en elaboración o que no hayan sido publicados aún. RESULTADOS: Tras la búsqueda bibliográfica se encontró evidencia que sustenta la eficacia y seguridad de TMZ 35mg en pacientes con angina estable sintomática severa que han recibido terapia óptima con nitratos, calcio ­ antagonistas y beta bloqueadores a dosis máximas tolerables y no son tributarios de ser beneficiarios mediante revascularización miocárdica percutánea o quirúrgica. Sinopsis de la Evidencia: Se encontró evidencia acerca de la eficacia y seguridad de TMZ 35mg en pacientes con angina estable sintomática severa que han recibido terapia óptima con nitratos, calcio - antagonistas y beta bloqueadores a dosis máximas tolerables y no son tributarios de ser beneficiarios mediante revascularización miocárdica percutánea o quirúrgica. CONCLUSIONES: En la presente evaluación de tecnología sanitaria se ha encontrado evidencia acerca de la eficacia y seguridad de TMZ en pacientes con cardiopatía isquémica refractaria y que no son tributarios de ser beneficiarios mediante revascularización miocárdica percutánea o quirúrgica. Los resultados de las revisiones sistemáticas de ensayos clínicos aleatorizados evidencian que TMZ no ha demostrado ser superior a otros agentes anti-angínicos como monoterapia de primera línea. Sin embargo, se encontraron resultados de eficacia muy limitada para el tratamiento con TMZ como medicamento concomitante a otras terapias óptimas como beta-bloqueadores, calcio-antagonistas y nitratos en pacientes cuya condición clínica no haya sido controlada adecuadamente por los mismos o que sean intolerantes a ellas. Se encontró que la eficacia mínima de TMZ en terapia combinada, fue evaluada para desenlaces secundarios y no relevantes para la evaluación establecida en el presente Dictamen. No existen en la actualidad estudios que evalúen desenlaces duros y clínicamente importantes desde la perspectiva del paciente. El Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI, no aprueba el uso de Trimetazidina MR 35mg BID para el tratamiento de pacientes con cardiopatía isquémica refractaria y que no son tributarios a revascularización miocárdica percutánea o quirúrgica. El presente Dictamen Preliminar tiene vigencia de dos años a partir de la fecha de su publicación.

Trimetazidine does not alter metabolic substrate oxidation in cardiac mitochondria of target patient population.

BACKGROUND AND PURPOSE: Trimetazidine, known as a metabolic modulator, is an anti-anginal drug used for treatment of stable coronary artery disease (CAD). It is proposed to act via modulation of cardiac metabolism, shifting the mitochondrial substrate utilization towards carbohydrates, thus increasing the efficiency of ATP production. This mechanism was recently challenged; however, these studies used indirect approaches and animal models, which made their conclusions questionable. The goal of the current study was to assess the effect of trimetazidine on mitochondrial substrate oxidation directly in left ventricular myocardium from CAD patients. EXPERIMENTAL APPROACH: Mitochondrial fatty acid (palmitoylcarnitine) and carbohydrate (pyruvate) oxidation were measured in permeabilized left ventricular fibres obtained during coronary artery bypass grafting surgery from CAD patients, which either had trimetazidine included in their therapy (TMZ group) or not (Control). KEY RESULTS: There was no difference between the two groups in the oxidation of either palmitoylcarnitine or pyruvate, and in the ratio of carbohydrate to fatty acid oxidation. Activity and expression of pyruvate dehydrogenase, the key regulator of carbohydrate metabolism, were also not different. Lastly, acute in vitro exposure of myocardial tissue to different concentrations of trimetazidine did not affect myocardial oxidation of fatty acid. CONCLUSION AND IMPLICATIONS: Using myocardial tissue from CAD patients, we found that trimetazidine (applied chronically in vivo or acutely in vitro) had no effect on cardiac fatty acid and carbohydrate oxidation, suggesting that the clinical effects of trimetazidine are unlikely to be due to its metabolic effects, but rather to an as yet unidentified intracardiac mechanism.

Effects of atorvastatin combined with trimetazidine on myocardial injury and inflammatory mediator in unstable angina patients during perioperative of percutaneous coronary intervention.

OBJECTIVE: To investigate the effects of atorvastatin combined with trimetazidine on periprocedural myocardial injury and serum inflammatory mediators in unstable angina pectoris (UAP) patients following percutaneous coronary intervention (PCI) treatment. PATIENTS AND METHODS: 90 patients with UAP treated with conventional medications and PCI were recruited and were randomly divided into the control group and the experimental group. The control group had 42 patients were treated with atorvastatin alone, while the experimental group had 48 cases treated with atorvastatin combined with trimetazidine. All the patients were checked the preoperative 24h and postoperative 24h PCI concentrations of cardiac troponin I (cTnI), hypersensitive C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), serum interferon-γ (IFN-γ) and interlukin-10 (IL-10). RESULTS: At the pre-PCI stage, every serum factors was no significant difference. 24 hours after the PCI intervention, the occurence of abnormal cTnI level in the experimental group was remarkable reduced than the control group. In the experimental group, the serum levels of TNF-α and IFN-γ significantly decreased (p < 0.05); while IL-10 was increased. In the control group, all the mediators were increased significantly except the hs-CRP (p < 0.05). CONCLUSIONS: No unexpected symptom was found in patients with large dose atorvastatin combined with large dose trimetazidine. The administration of conventional medications together with the atorvastatin plus trimetazidine were able to reduce the prevalence of postoperative myocardial injury.

[Pharmacological therapy of age-related macular degeneration based on etiopathogenesis]. / Adalékok az idoskori maculadegeneráció - etiopatogenezisébol fakadó - gyógyszeres intervenciójához.

It is of great therapeutic significance that disordered function of the vascular endothelium which supply the affected ocular structures plays a major role in the pathogenesis and development of age-related macular degeneration. Chronic inflammation is closely linked to diseases associated with endothelial dysfunction, and age-related macular degeneration is accompanied by a general inflammatory response. According to current concept, age-related macular degeneration is a local manifestation of systemic vascular disease. This recognition could have therapeutic implications because restoration of endothelial dysfunction can restabilize the condition of chronic vascular disease including age-related macular degeneration as well. Restoration of endothelial dysfunction by pharmaacological or non pharmacological interventions may prevent the development or improve endothelial dysfunction, which result in prevention or improvement of age related macular degeneration as well. Medicines including inhibitors of the renin-angiotensin system (converting enzyme inhibitors, angiotensin-receptor blockers and renin inhibitors), statins, acetylsalicylic acid, trimetazidin, third generation beta-blockers, peroxisome proliferator-activated receptor gamma agonists, folate, vitamin D, melatonin, advanced glycation end-product crosslink breaker alagebrium, endothelin-receptor antagonist bosentan, coenzyme Q10; "causal" antioxidant vitamins, N-acetyl-cysteine, resveratrol, L-arginine, serotonin receptor agonists, tumor necrosis factor-alpha blockers, specific inhibitor of the complement alternative pathway, curcumin and doxycyclin all have beneficial effects on endothelial dysfunction. Restoration of endothelial dysfunction can restabilize chronic vascular disease including age-related macular degeneration as well. Considering that the human vascular system is consubstantial, medicines listed above should be given to patients (1) who have no macular degeneration but have risk factors for the disease and are older than 50 years; (2) who have been diagnosed with unilateral age-related macular degeneration in order to prevent damage of the contralateral eye; (3) who have bilateral age-related macular degeneration in order to avert deterioration and in the hope of a potential improvement. However, randomised prospective clinical trials are still needed to elucidate the potential role of these drug treatments in the prevention and treatment of age-related macular degeneration.

Trimetazidine Prevention of Contrast-Induced Nephropathy in Coronary Angiography.

BACKGROUND: Contrast-induced nephropathy (CIN) after coronary angiography is frequently observed in patients with chronic renal insufficiency and no effective measures have been developed for prevention of CIN. There is evidence showing that trimetazidine (TMZ) has renoprotective effect on CIN. This study was to evaluate the role of TMZ in the prevention of CIN in renal dysfunction patients undergoing coronary angiography. METHODS: A total of 132 patients with renal dysfunction who underwent coronary angiography were enrolled in our study and divided into control group (n = 70) and TMZ group (n = 62). Standard hydration was administered in all the patients. In TMZ group, patients were administered TMZ orally for 48 hours before and 24 hours after coronary angiography. Serum creatinine (SCr) and cystatin (CysC) were detected before and after contrast media injection, and the incidence of CIN was evaluated according to the elevation of SCr. Adverse events were observed in 12 months. RESULTS: In both groups, CysC and SCr increased significantly after coronary angiography and peaked at 24 and 48 hours, respectively. CysC and SCr were significantly lower in TMZ group than in control group after coronary angiography. The incidence of CIN and adverse events was reduced in TMZ group when compared with control group (P = 0.034 and P = 0.043, respectively). CONCLUSIONS: TMZ in combination with standard hydration is more effective than isotonic saline alone in protecting renal function in patients with renal dysfunction who undergo coronary angiography and can reduce the adverse events within 12 months.

Effective inhibition of cardiomyocyte apoptosis through the combination of trimetazidine and N-acetylcysteine in a rat model of myocardial ischemia and reperfusion injury.

OBJECTIVE: Apoptosis is the early and predominant form of cell death in infarcted myocardia. The aim of the study was to investigate the effects of trimetazidine (TMZ) and N-acetylcysteine (NAC), used alone or in combination, on oxidative stress, infarct size, and ischemia-reperfusion (IR)-induced cardiomyocyte apoptosis in a rat model of myocardial IR. METHODS AND RESULTS: Myocardial IR was established by ligating an area under the left main coronary artery for 30 min followed by 3 h of reperfusion. Saline (1 ml/kg), NAC (50, 150 mg/kg), or TMZ (3, 5 mg/kg) was intravenously injected during the middle of the ischemic period. At the end of the reperfusion, blood samples were collected from the animals to measure serum M30 and M65 levels, which are markers of cell death, the S100b level, which is a marker of inflammation, and the malondialdehyde (MDA) level, which is a marker of oxidative stress. The infarct size was evaluated as the ratio of the infarct area to the risk area. Apoptotic activation was assessed by caspase-3 immunostaining and a TUNEL assay. TMZ and NAC, either alone or in combination, significantly reduced serum MDA levels, infarct area and apoptotic activity compared to those observed in saline group. Interestingly, the infarct area was more smaller in TMZ (3 and 5 mg/kg) injected groups (9.72 ± 1.3% and 9.96 ± 2.3%) than those observed in NAC (50 and 150 mg/kg) (16.1 ± 2.5% and 19.1 ± 2.14%) or TMZ (5 mg/kg)- NAC (150 mg/kg) combination groups (16.9 ± 1.6%). However, the apoptotic activity was reduced more significantly in the combination of TMZ (5 mg/kg)-NAC (50 mg/kg) compared to TMZ-only group. Neither TMZ or NAC treatments nor the combination of the drugs significantly affected serum M30, M65 and S100B levels. CONCLUSION: Intravenous NAC and TMZ administration decreased oxidative stress, infarct area and apoptotic activity in a rat model of IR. Although the combination treatment was more effective in reducing the apoptotic activity than either treatment groups alone, TMZ treatment was more successful in reducing the infarct area than NAC or combination treatments. Present results suggest that, in addition to mechanical attempts to secure myocardial reperfusion, the use of TMZ and NAC may help to reduce IR injury.

Efectividad y seguridad de trimetazidina en pacientes con angina estable / Effectiveness and safety of trimetazidine in patients with stable angina

Introducción: La angina de pecho es el dolor causado por la isquemia miocárdica que por lo general es debida a enfermedad coronaria. Los antianginosos recomendados para el tratamiento inicial son los betabloqueadores y los calcioantagonistas y por lo general se requiere combinarlos con un nitrato para aliviar los episodios de dolor. Cuando los medicamentos de primera línea no son bien tolerados, están contraindicados, o no logran controlar los síntomas es necesario utilizar otros como la trimetazidina (TMZ). Objetivos: Evaluar la evidencia científica sobre los beneficios y riesgos del uso de TMZ para el tratamiento de pacientes con angina estable (AE), como uno de los criterios para informar la toma de decisiones relacionada con la posible inclusión de tecnologías en el Plan Obligatorio de Salud, en el marco de su actualización ordinaria para el año 2015. Métodos: Se buscaron estudios en los que se hubiera probado el uso de TMZ en pacientes con AE. Los comparadores podían ser placebo u otros antianginosos como calcioantagonistas, betabloqueadores, nitratos o ivabradina. No se usaron límites de tiempo y solamente se incluyeron estudios en inglés o español. Resultados: No se encontró evidencia de que el tratamiento con TMZ tenga efecto sobre la mortalidad y los eventos cardiovasculares en pacientes con AE. La capacidad funcional como tal no fue evaluada en ninguno de los estudios encontrados. Un estudio primario de baja calidad metodológica demostró que la TMZ mejora la calidad de vida al comparar con el estado basal. Evidencia de buena calidad demostró que el medicamento disminuye los episodios semanales de angina cuando se compara con placebo, pero evidencia de moderada calidad demostró que no hay diferencias al comparar con otros antianginosos. No se observaron diferencias en la frecuencia de eventos adversos al comparar con placebo. Conclusiones: En pacientes con AE el tratamiento con TMZ no tiene impacto sobre la muerte y los eventos cardiovasculares, no se conoce el efecto sobre la capacidad funcional. El medicamento disminuye el número de ataques semanales de angina cuando se compara con placebo y podría mejorar la calidad de vida pero se necesitan más estudios para demostrarlo.(AU)

Impact of trimetazidine on incidence of myocardial injury and contrast-induced nephropathy in diabetic patients with renal dysfunction undergoing elective percutaneous coronary intervention.

Trimetazidine is an anti-ischemic agent with antioxidant activity. This study evaluated the effect of periprocedural administration of trimetazidine on the incidence of percutaneous coronary intervention (PCI)-induced myocardial injury and contrast-induced nephropathy (CIN) in diabetic patients with mild-to-moderate renal dysfunction. One hundred patients with a mean glomerular filtration rate of 48 ± 16 (ml/min/1.73 m(2)) were prospectively enrolled, then randomly assigned to receive (50 patients; trimetazidine group) or not receive (50 patients; control group) periprocedural trimetazidine (70 mg/day) for 72 hours. The serum creatinine level was measured pre-PCI, 72 hours, and 10 days thereafter. An increase in the serum creatinine level by >0.5 mg/dl or 0.25% of the baseline value is considered as CIN. Cardiac troponin I levels were measured before and 6, 12, and 24 hours after PCI. Mean age of the study cohort was 59 ± 6 years (men 68%). The serum creatinine level in the control group increased significantly 3 days after PCI and decreased on the tenth day. However, it showed no significant change in the trimetazidine group. Incidence of CIN was 12% in the trimetazidine group and 28% in the control group (p <0.05). Cardiac troponin I levels were significantly reduced in the trimetazidine group (6 hours: 8 ± 0.3 vs 16 ± 0.2 pg/ml, 12 hours: 13 ± 0.9 vs 24 ± 0.8 pg/ml, 24 hours: 7 ± 0.7 vs 14 ± 0.3 pg/ml, p <0.001). In conclusion, trimetazidine intake before elective PCI in diabetic patients with mild-to-moderate renal dysfunction is associated with decreased incidence of CIN and myocardial injury.

Trimetazidine protects umbilical cord mesenchymal stem cells against hypoxia and serum deprivation induced apoptosis by activation of Akt.

BACKGROUND: Mesenchymal stem cell (MSC) transplantation is a promising therapy for cardiac repair. However, the efficacy is limited by the poor viability of MSCs in the infarcted heart. Recent findings have implicated that trimetazidine (TMZ) enhanced the survival of the stem cells under various conditions. However, as the stem cells in these studies were animal-derived, little information is available about the effects of TMZ on human MSCs. Herein, we propose that TMZ may protect human MSCs against apoptosis induced by Hypoxia/Serum deprivation (H/SD). METHODS: Human umbilical cord MSCs (UC-MSCs) from Wharton's jelly were pretreated with 10µM TMZ of H/SD with or without the Akt inhibitor LY294002. The morphological changes were assessed using Hoechst 33342. Apoptosis was evaluated via Annexin V/PI staining; and apoptosis-related proteins were detected using Western-blot. Protein chip technology was used to screen for differences between the cell supernatants. RESULTS: TMZ had a significant protective effect against H/SD-induced apoptosis, accompanied by an increase in Bcl-2 and p-Akt. The TMZ-mediated anti-apoptotic effect on MSCs could be attenuated by treatment with LY294002. Moreover, protein chip assays showed that TMZ treatment increased the paracrine functions of MSCs. CONCLUSION: Trimetazidine protects human UC-MSCs from H/SD-induced apoptosis via the Akt pathway and may therefore be a potentially useful therapeutic adjunct for transplanting MSCs into damaged heart after myocardial infarction.

Trimetazidina e resposta inflamatória em cirurgia de revascularização do miocárdio / Trimetazidine and inflammatory response in coronary artery bypass grafting

FUNDAMENTO: A resposta inflamatória orgânica constitui um mecanismo fisiopatológico presente em todas as cirurgias de revascularização do miocárdio com circulação extracorpórea (CRVM-CEC), e a liberação de mediadores inflamatórios constitui um de seus mecanismos de defesa. OBJETIVO: Avaliar, em estudo prospectivo duplo-cego randomizado e controlado com placebo, os efeitos da trimetazidina (Tmz) sobre a resposta inflamatória, por meio da variação nas interleucinas 6 e 8; TNF-α; complementos C3 e C5, e na proteína C reativa ultrassensível (PCR-us), em dois momentos, pré e pós-operatório. MÉTODOS: Foram estudados 30 pacientes submetidos a CRVM-CEC utilizando cardioplegia hipotérmica intermitente, e com no máximo disfunção ventricular leve, divididos em dois grupos (placebo e Tmz), estratificados por ecocardiografia e recebendo medicação/placebo na dose de 60mg/dia. As amostras foram dosadas no pré-operatório sem medicação, no dia da cirurgia com 12 a 15 dias de medicação/placebo e, seguidamente, 5 min após o desclampeamento aórtico, 12 e 24h, para interleucinas e complementos, e 48h para PCR. RESULTADOS: Não ocorreram diferenças significativas entre os níveis de interleucina 8, Tnf-α, complementos C3 e C5, e PCR-us. No entanto, no grupo tratado, os níveis de interleucina 6 foram significativamente inferiores aos do grupo controle, em todos os momentos analisados. CONCLUSÃO: A trimetazidina mostrou-se eficaz apenas na redução da interleucina 6 nos pacientes submetidos à CRVM.

BACKGROUND: Organic inflammatory response is a pathophysiological mechanism present at every coronary artery bypass grafting with extracorporeal circulation (CABG-ECC), the release of inflammatory mediators being one of its defense mechanisms. OBJECTIVE: To assess, in a prospective double-blind randomized and placebo-controlled study, the effects of trimetazidine (Tmz) on the inflammatory response, by using the variation in interleukins 6 and 8, TNF-α, complements C3 and C5, and highly sensitive C-reactive protein (HS-CRP) levels in the pre- and post-operative periods. METHODS: This study assessed 30 patients undergoing CABG-ECC with intermittent hypothermic cardioplegia, and having, at most, mild ventricular dysfunction. The patients were divided into two groups (placebo and Tmz), stratified by echocardiography, and received drug/placebo at the dose of 60 mg/day. Measurements were taken as follows: in the pre-operative period with no drug; on the day of surgery, corresponding to 12 to 15 days on drug/placebo; five minutes after aortic unclamping; 12 and 24 hours after surgery, for interleukins and complements; and 48 hours after surgery, for HS-CRP. RESULTS: No significant difference between the levels of interleukin 8, TNF-α, C3 and C5, and HS-CRP was observed. However, the interleukin 6 levels were significantly lower in the group treated as compared with those in the control group at all time points assessed. CONCLUSION: Trimetazidine proved to be effective only for reducing interleukin 6 in patients undergoing CABG.

Trimetazidine and inflammatory response in coronary artery bypass grafting.

BACKGROUND: Organic inflammatory response is a pathophysiological mechanism present at every coronary artery bypass grafting with extracorporeal circulation (CABG-ECC), the release of inflammatory mediators being one of its defense mechanisms. OBJECTIVE: To assess, in a prospective double-blind randomized and placebo-controlled study, the effects of trimetazidine (Tmz) on the inflammatory response, by using the variation in interleukins 6 and 8, TNF-α, complements C3 and C5, and highly sensitive C-reactive protein (HS-CRP) levels in the pre- and post-operative periods. METHODS: This study assessed 30 patients undergoing CABG-ECC with intermittent hypothermic cardioplegia, and having, at most, mild ventricular dysfunction. The patients were divided into two groups (placebo and Tmz), stratified by echocardiography, and received drug/placebo at the dose of 60 mg/day. Measurements were taken as follows: in the pre-operative period with no drug; on the day of surgery, corresponding to 12 to 15 days on drug/placebo; five minutes after aortic unclamping; 12 and 24 hours after surgery, for interleukins and complements; and 48 hours after surgery, for HS-CRP. RESULTS: No significant difference between the levels of interleukin 8, TNF-α, C3 and C5, and HS-CRP was observed. However, the interleukin 6 levels were significantly lower in the group treated as compared with those in the control group at all time points assessed. CONCLUSION: Trimetazidine proved to be effective only for reducing interleukin 6 in patients undergoing CABG.