Metabolic study of trimetazidine using ultra-high performance liquid chromatography-tandem mass spectrometry

Abstract In the present study, the application of ultra-high performance liquid chromatography-tandem mass spectrometry allowed us to study of known-as well as hitherto unknown-trimetazidine (TMZ) metabolites in human urine and to propose their renal excretion profiles. Urine samples from a healthy volunteer were analyzed at baseline and at 0-4 h, 4-8 h, 8-12 h, and 12-24 h after a single dose of TMZ. A dilute-and-shoot procedure was used as sample treatment before separation. Full-scan spectra of possible metabolites were acquired. Additionally, product ion scan spectra of precursor ions of interest were also acquired at two collision energies. Intact TMZ was a major excretion product, with a maximum concentration at 4-8 h after administration. Moreover, five minor metabolites were observed, namely trimetazidine-N-oxide (M1), N-formyl trimetazidine (M2), desmethyl-trimetazidine O-sulfate (M3), desmethyl-trimetazidine O-glucuronide (M4), and desmethyl-trimetazidine-N-oxide-O-glucuronide (M5). Metabolite M5 has not previously been reported. Excretion curves were constructed based on the chromatographic peak areas of specific mass transitions (precursor ion > product ion) related to each of the detected metabolites

A new combination of naringin and trimetazidine protect kidney Mitochondria dysfunction induced by renal Ischemia / Reperfusion injury in rat

Abstract Ischemia/reperfusion (IR) injury leads to overproduction of Reactive Oxygen Species (ROS), and disrupts membrane potential that contributes to cell death. The aim of this study was to determine if naringin (NAR), trimetazidine (TMZ) or their combination, protect the kidney mitochondrial from IR injury. Forty rats were randomly allocated into five groups, harboring eight rats each: Sham, IR, NAR (100 mg/kg), TMZ (5 mg/kg) and NAR plus TMZ. Ischemia was induced by obstructing both renal pedicles for 45 min, followed by reperfusion for 4 hours. The mitochondria were isolated to examine the ROS, Malondialdehyde (MDA), Glutathione (GSH), mitochondrial membrane potential (MMP) and mitochondrial viability (MTT). Our findings indicated that IR injury resulted in excessive ROS production, increased MDA levels and decreased GSH, MMP and MMT levels. However, NAR, TMZ or their combination reversed these changes. Interestingly, a higher protection was noted with the combination of both, compared to each drug alone. We speculate that this combination demonstrates a promising process for controlling renal failure, especially with the poor clinical outcome, acquired with NAR alone. This study revealed that pretreatment their combination serves as a promising compound against oxidative stress, leading to suppression of mitochondrial stress pathway and elevation of GSH level.

Naringin and trimetazidine improve baroreflex sensitivity and nucleus tractus solitarius electrical activity in renal ischemia-reperfusion injury / Naringin and trimetazidine improve baroreflex sensitivity and nucleus tractus solitarius electrical activity in renal ischemia-reperfusion injury

Resumo Fundamento: O núcleo do trato solitário (NTS) é uma área do cérebro que desempenha um papel fundamental na regulação renal e cardiovascular através dos impulsos dos barorreceptores. Objetivos: O objetivo deste estudo foi avaliar o efeito da Naringina (NAR) e trimetazidina (TMZ), isoladamente e combinadas, na atividade elétrica do NTS e na sensibilidade barorreflexa (SBR) na lesão de isquemia e reperfusão (I/R) renal. Métodos: Foram utilizados quarenta ratos machos Sprague-Dawley (200-250 g), alocados em 5 grupos com 8 ratos cada. Grupos: 1) Sham; 2) I/R; 3) TMZ 5 mg/kg; 4) NAR 100 mg/kg; e 5) TMZ5 + NAR100. A veia femoral esquerda foi canulada para infundir a solução salina ou droga e avaliar a SBR. A I/R foi induzida por oclusão dos pedículos renais por 45 min, seguida de reperfusão de 4 horas. O eletroencefalograma local do NTS foi registrado antes, durante a isquemia e durante a reperfusão. A fenilefrina foi injetada por via intravenosa para avaliar a SBR ao final do tempo de reperfusão. Os dados foram analisados por ANOVA de duas vias com medidas repetidas seguida pelo teste post hoc de Tukey. Um valor de p<0,05 foi considerado como significativo. Resultados: As ondas elétricas do NTS não se alteraram durante o tempo de isquemia, mas diminuíram significativamente durante todos os tempos de reperfusão. A atividade elétrica do NTS e a SBR foram reduzidas drasticamente em ratos com lesão I/R; no entanto, a administração de NAR e TMZ, isoladamente e combinadas, melhorou significativamente essas alterações em ratos com lesão I/R. Conclusões: Os resultados mostraram que a lesão de I/R leva à redução da atividade elétrica da SBR e do NTS, e pode haver uma ligação entre a I/R e a diminuição da SBR. Além disso, a NAR e a TMZ são agentes promissores para tratar complicações de I/R.

Abstract Background: Nucleus tractus solitarius (NTS) is a brain area that plays a key role in kidney and cardiovascular regulation via baroreceptors impulses. Objectives: The aim of this study was to evaluate the effect of naringin (NAR) and trimetazidine (TMZ) alone and their combination on NTS electrical activity and baroreceptor sensitivity (BRS) in renal ischemia- reperfusion (I/R) injury. Methods: Forty male Sprague-Dawley rats (200- 250 g) were allocated into 5 groups with 8 in each. 1) Sham; 2) I/R; 3) TMZ 5 mg/kg; 4) NAR 100 mg/kg; and 5) TMZ5+ NAR100. The left femoral vein was cannulated to infuse saline solution or drug and the BRS was evaluated. I/R was induced by occlusion of renal pedicles for 45 min, followed by 4 hours of reperfusion. The NTS local electroencephalogram (EEG) was recorded before, during ischemia and throughout the reperfusion. Phenylephrine was injected intravenously to evaluate BRS at the end of reperfusion time. The data were analyzed by two-way repeated measurement ANOVA followed by Tukey's post hoc test. A p-value <0.05 was considered significant. Results: NTS electrical waves did not change during ischemia time, while they significantly decreased during the entire reperfusion time. NTS electrical activity and BRS dramatically reduced in rats with I/R injury; however, administration of NAR, TMZ alone or their combination significantly improved these changes in rats with I/R injury. Conclusions: The results showed that I/R injury leads to reduced BRS and NTS electrical activity and there may be an association between I/R and decreased BRS. In addition, NAR and TMZ are promising agents to treat I/R complications.

The Effects of Trimetazidine on QT-interval Prolongation and Cardiac Hypertrophy in Diabetic Rats / Os Efeitos da Trimetazidina no Prolongamento do Intervalo QT e na Hipertrofia Cardíaca em Ratos Diabéticos

Abstract Background: Trimetazidine (TMZ) is an anti-ischemic drug. In spite of its protective effects on cardiovascular system, there is no scientific study on the usefulness of TMZ treatment for prolonged QT interval and cardiac hypertrophy induced by diabetes. Objectives: To evaluate the effects of TMZ on QT interval prolongation and cardiac hypertrophy in the diabetic rats. Methods: Twenty-four male Sprague-Dawley rats (200-250 g) were randomly assigned into three groups (n = 8) by simple random sampling method. Control (C), diabetic (D), and diabetic administrated with TMZ at 10 mg/kg (T10). TMZ was administrated for 8 weeks. The echocardiogram was recorded before isolating the hearts and transfer to a Langendorff apparatus. Hemodynamic parameters, QT and corrected QT interval (QTc) intervals, heart rate and antioxidant enzymes were measured. The hypertrophy index was calculated. The results were evaluated by one-way ANOVA and paired t-test using SPSS (version 16) and p < 0.05 was regarded as significant. Results: The diabetic rats significantly indicated increased hypertrophy, QT and QTc intervals and decreased Left ventricular systolic pressure (LVSP), Left ventricular developed pressure (LVDP), rate pressure product (RPP), Max dp/dt, and min dp/dt (±dp/dt max), heart rate, superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase in the heart. Treatment with TMZ in the diabetic animals was significantly improved these parameters in comparison to the untreated diabetic group. Conclusions: TMZ improves QTc interval prolongation and cardiac hypertrophy in diabetes.

Resumo Fundamento: A trimetazidina (TMZ) é uma droga anti-isquêmica. Apesar de seus efeitos protetores sobre o sistema cardiovascular, não há estudos científicos sobre a utilidade do tratamento com TMZ para o intervalo QT prolongado e a hipertrofia cardíaca induzida pelo diabetes. Objetivo: Avaliar os efeitos da TMZ no prolongamento do intervalo QT e na hipertrofia cardíaca em ratos diabéticos. Métodos: Vinte e quatro ratos machos Sprague-Dawley (200-250 g) foram distribuídos aleatoriamente em três grupos (n = 8) pelo método de amostragem aleatória simples. Controle (C), diabético (D) e diabético administrado com TMZ a 10 mg/kg (T10). A TMZ foi administrada por 8 semanas. O ecocardiograma foi registrado antes de isolar os corações e transferir para um aparelho de Langendorff. Foram medidos os parâmetros hemodinâmicos, intervalo QT e intervalo QT corrigido (QTc), frequência cardíaca e enzimas antioxidantes. O índice de hipertrofia foi calculado. Os resultados foram avaliados pelo one-way ANOVA e pelo teste t pareado pelo SPSS (versão 16) e p < 0,05 foi considerado significativo. Resultados: Os ratos diabéticos indicaram hipertrofia aumentada, intervalos QT e QTc e diminuição da pressão sistólica no ventrículo esquerdo (PSVE), pressão desenvolvida no ventrículo esquerdo (PDVE), duplo produto (DP), Max dp/dt e min dp/dt (± dp/dt max), frequência cardíaca, superóxido dismutase (SOD), glutationa peroxidase (GPx) e catalase no coração. O tratamento com TMZ nos animais diabéticos melhorou significativamente esses parâmetros em comparação com o grupo diabético não tratado. Conclusões: A TMZ melhora o prolongamento do intervalo QTc e a hipertrofia cardíaca no diabetes.

Effect of trimetazidine on cardiac function and exercise tolerance in hypertension patients with diabetic / 浙江大学学报·医学版

OBJECTIVE@#To determine the effect of trimetazidine on cardiac function and exercise tolerance in primary hypertension patients with type 2 diabetic.@*METHODS@#In this randomized, double-blind, placebo-controlled prospective study, 60 primary hypertensive patients with diabetic were equally assigned into two groups, patients received trimetazidine (20 mg, 3 times a day) or placebo for 1 year. Echocardiography, cardiopulmonary exercise testing were performed; and the plasma N terminal pro B type natriuretic peptide (NT-ProBNP), hr-CRP, TNF-α, angiotensin Ⅱ and endothelin concentration were determined before and after treatment.@*RESULTS@#In trimetazidine group, the left ventricular mass index, the mitral flow velocity E wave to A wave ratio (E/A), the peak early diastolic velocity (V) to late diastolic velocity (V) ratio (V/V) and the peak systolic velocity (Vs) were significantly improved, the plasma NT-ProBNP level was significantly decreased, and the exercise time, metabolic equivalent, maximal oxygen uptake and anaerobic threshold were significantly increased (all 0.05). No severe adverse reaction was observed in both groups.@*CONCLUSIONS@#For patients with both hypertension and diabetes, trimetazidine can improve cardiac function and increase exercise tolerance.

Trimetazidine in angina and poor muscle function: protocol for a randomized controlled study / 中华医学杂志(英文版)

BACKGROUND@#Low handgrip strength (HS) and declining gait speed (GS) are increasingly obvious with aging, requiring effective, and safe medication for treatment. Trimetazidine (TMZ) modified release tablets, a common anti-angina drug, has potential benefits for alleviating the condition, but this has not yet been fully studied and therefore is the aim of this study.@*METHODS@#This is a prospective randomized controlled study. Fifty-eight eligible patients will be randomly assigned to one of two study groups: TMZ group or control group. For the TMZ group, a dose of 35 mg of oral TMZ will be administered with a meal twice a day for 3 months, in addition to any conventional treatments for angina. Only conventional treatments for angina will be administrated in the control group. The primary outcome will be the 6-min walking distance and the secondary outcomes will be: muscle strength (HS and pinch strength), GS, muscle endurance (five times sit-to-stand test), balance maintenance (tandem standing test), and the frequency of angina per week. Additionally, body mass index, circumferences (biceps, waist, hip, and calf), albumin levels, and the score on a five-question scale for sarcopenia will be obtained during the study.@*DISCUSSION@#This study aims to evaluate the usefulness of TMZ in a population with poor muscle function. The results may provide an effective and safe medical treatment to people with low muscle strength or physical performance.@*TRIAL REGISTRATION@#Chinese Clinical Trial Registry, ChiCTR1800015000; www.chictr.org.cn/showproj.aspx?proj=25445.

Custo-efetividade de trimetazidina no tratamento de angina estável em pacientes diabéticos não respondedores a betabloqueadores, nitratos e bloqueadores do canal de cálcio / Cost-effectiveness of trimetazidine for stable angina treatment in non-responder diabetics after beta blockers, nitrates and calcium channel blockers

Objetivo: Avaliar o custo-efetividade da trimetazidina (TMZ) associada ao tratamento convencional (diurético, ácido acetilsalicílico [AAS], betabloqueador, inibidores da enzima de conversão da angiotensina (IECA), nitrato, estatina, digitálico e antagonista dos canais de cálcio) versus tratamento convencional isolado no tratamento de pacientes diabéticos com angina estável não respondedores a betabloqueadores, nitratos e bloqueadores do canal de cálcio sob a perspectiva do Sistema Público de Saúde (SUS). Métodos: Foi elaborado um modelo de Markov, com ciclos de 1 ano, que acompanhou os pacientes ao longo do curso natural da doença até o final de suas vidas. Dados clínicos foram obtidos a partir de revisão da literatura. Custos unitários foram extraídos de bases de dados oficiais. Apenas custos médicos diretos foram contemplados. Custos e benefícios foram descontados a uma taxa de 5% ao ano. Desfecho clínico foi expresso como episódio de hospitalização por angina pectoris (EHAP) evitado. Análise de sensibilidade univariada foi realizada para determinar os parâmetros de maior influência nos resultados, variando-os em mais ou menos 20% comparado ao cenário base. Resultados: O tratamento com TMZ mostrou maior benefício comparado ao tratamento convencional e gerou uma Razão de Custo-Efetividade Incremental de R$ 7.344,96 por EHAP evitado. O parâmetro de maior impacto no resultado foi o número de episódios de angina pectoris. Apesar do alto impacto, este não alterou o resultado da análise, mantendo-o custo-efetivo. Conclusão: TMZ associada ao tratamento convencional mostrou ser uma alternativa eficaz, segura e custo-efetiva para o tratamento de pacientes diabéticos com angina estável não respondedores a betabloqueadores, nitratos e bloqueadores do canal de cálcio.

Objective: To assess the cost-effectiveness analysis of trimetazidine (TMZ) associated with conventional treatment (diuretic, acetylsalicylic acid [ASA], beta blocker, angiotensin converting enzyme inhibitor (ACEI), nitrate, statine, digitalis and calcium channel antagonist) versus conventional treatment alone in the treatment of diabetic patients with stable angina non-responders to beta blockers, nitrates and calcium channel blockers from the perspective of the Public Health System (SUS). Methods: A Markov model was developed, with one year cycles, to follow the patients along the natural course of disease until the end of your lifes. Clinical data were obtained from the literature review. Unit costs were extracted from official databases. Only direct medical costs were included. Costs and benefits were discounted at a rate of 5% per year. Outcome were expressed as hospitalization due to angina pectoris (HAP) avoided. Univariate sensitivity analysis was performed to determine the parameters of greatest influence on the results, varying them by plus or minus 20% compared to the baseline scenario. Results: Treatment with TMZ showed greater benefit compared to conventional treatment and generated an Incremental Cost-Effectiveness Ratio of USD 2,225.75 per HAP avoided (1USD = 3.30BRL). The parameter with the greatest impact on outcome was the number of angina pectoris episodes. Despite the high impact, it did not change the result, keeping it cost-effective. Conclusion: TMZ associated with conventional treatment has been shown to be an effective, safe and cost-effective alternative for the treatment of diabetic patients with stable angina non-responders to beta blockers, nitrates and calcium channel blockers.

The efficacy of oral trimetazidine in preventing contrast-induced nephropathy among patients undergoing elective coronary procedures: A meta-analysis of randomized controlled trials

INTRODUCTION: Contrast-induced nephropathy (CIN) is a serious but preventable complication of coronary procedures. Trimetazidine (TMZ) has recently been explored for use in preventing post-procedural CIN due to its cellular anti-ischemic and antioxidant properties. The objective is to assess the efficacy of oral TMZ in the prevention of contrast induced nephropathy during elective coronary angiography and PCI among patients with renal impairment. METHODS: We conducted a systematic search of the Cochrane Central Register of Controlled Trials, Pubmed/ MEDLINE, EMBASE, clinicaltrials.gov for articles published until June 2016 for randomized controlled trials examining the effects of adding oral TMZ to standard therapy in preventing CIN. Outcome measures were incidence of CIN, defined as a 0.5 mg/dl or ?25% increase in serum creatinine 48-72 hours after contrast exposure, and incidence of dialysisrequiring CIN. Validity of studies was assessed through a risk assessment tool available from Cochrane. Treatment effect was estimated by calculating the Mantel-Haenszelweighted risk ratio (RR) using a fixed-effects model available from RevMan 5.3. RESULTS: A total of four studies comprising 714 patients (TMZ group=352, Control group=362) were included in the final analysis. Pooled results revealed the TMZ group was associated with significantly fewer incidences of CIN compared to control (RR 0.33, 95% confidence interval [CI], 0.20, 0.53; P CONCLUSION: The addition of oral TMZ to standard hydration confers a significant benefit in preventing CIN after coronary procedures among patients with mild to moderate renal impairment. We recommend the addition of TMZ to standard prevention strategies. However, a large well-designed trial should be conducted to determine its effect on other outcomes such as prevention of dialysis-requiring CIN and mortality. 

The efficacy of oral trimetazidine in preventing contrast-induced nephropathy among patients undergoing elective coronary procedures: A meta-analysis of randomized controlled trials

@#<p style="text-align: justify;"><strong>INTRODUCTION:</strong> Contrast-induced nephropathy (CIN) is a serious but preventable complication of coronary procedures. Trimetazidine (TMZ) has recently been explored for use in preventing post-procedural CIN due to its cellular anti-ischemic and antioxidant properties. The objective is to assess the efficacy of oral TMZ in the prevention of contrast induced nephropathy during elective coronary angiography and PCI among patients with renal impairment.</p><p style="text-align: justify;"><strong>METHODS:</strong> We conducted a systematic search of the Cochrane Central Register of Controlled Trials, Pubmed/ MEDLINE, EMBASE, clinicaltrials.gov for articles published until June 2016 for randomized controlled trials examining the effects of adding oral TMZ to standard therapy in preventing CIN. Outcome measures were incidence of CIN, defined as a 0.5 mg/dl or ?25% increase in serum creatinine 48-72 hours after contrast exposure, and incidence of dialysisrequiring CIN. Validity of studies was assessed through a risk assessment tool available from Cochrane. Treatment effect was estimated by calculating the Mantel-Haenszelweighted risk ratio (RR) using a fixed-effects model available from RevMan 5.3.</p><p style="text-align: justify;"><strong>RESULTS:</strong> A total of four studies comprising 714 patients (TMZ group=352, Control group=362) were included in the final analysis. Pooled results revealed the TMZ group was associated with significantly fewer incidences of CIN compared to control (RR 0.33, 95% confidence interval [CI], 0.20, 0.53; P<.00001), with a relative risk reduction of 67% and an absolute risk reduction of 11.04% (NNT=nine). No dialysis-requiring CIN was observed in the included studies.</p><p style="text-align: justify;"><strong>CONCLUSION:</strong> The addition of oral TMZ to standard hydration confers a significant benefit in preventing CIN after coronary procedures among patients with mild to moderate renal impairment. We recommend the addition of TMZ to standard prevention strategies. However, a large well-designed trial should be conducted to determine its effect on other outcomes such as prevention of dialysis-requiring CIN and mortality. </p>

The efficacy of oral trimetazidine in preventing contrast-induced nephropathy among patients undergoing elective coronary procedures: A meta-analysis of randomized controlled trials

INTRODUCTION: Contrast-induced nephropathy (CIN) is a serious but preventable complication of coronary procedures. Trimetazidine (TMZ) has recently been explored for use in preventing post-procedural CIN due to its cellular anti-ischemic and antioxidant properties. The objective is to assess the efficacy of oral TMZ in the prevention of contrast induced nephropathy during elective coronary angiography and PCI among patients with renal impairment.METHODS: We conducted a systematic search of the Cochrane Central Register of Controlled Trials, Pubmed/ MEDLINE, EMBASE, clinicaltrials.gov for articles published until June 2016 for randomized controlled trials examining the effects of adding oral TMZ to standard therapy in preventing CIN. Outcome measures were incidence of CIN, defined as a 0.5 mg/dl or ?25% increase in serum creatinine 48-72 hours after contrast exposure, and incidence of dialysisrequiring CIN. Validity of studies was assessed through a risk assessment tool available from Cochrane. Treatment effect was estimated by calculating the Mantel-Haenszelweighted risk ratio (RR) using a fixed-effects model available from RevMan 5.3.RESULTS: A total of four studies comprising 714 patients (TMZ group=352, Control group=362) were included in the final analysis. Pooled results revealed the TMZ group was associated with significantly fewer incidences of CIN compared to control (RR 0.33, 95% confidence interval [CI], 0.20, 0.53; PCONCLUSION: The addition of oral TMZ to standard hydration confers a significant benefit in preventing CIN after coronary procedures among patients with mild to moderate renal impairment. We recommend the addition of TMZ to standard prevention strategies. However, a large well-designed trial should be conducted to determine its effect on other outcomes such as prevention of dialysis-requiring CIN and mortality. 

Nuevos enfoques farmacológicos en el manejo de la angina de pecho estable / New pharmacological approaches in the management of stable angina

RESUMEN En años recientes han sido introducidos nuevos antianginosos al mercado con mecanismos de acción novedosos, complementarios a los del arsenal farmacoterapéutico existente. Aunque el tratamiento de primera línea continúan siendo los betabloqueadores, antagonistas de canales de calcio y nitratos, el descubrimientos de nuevos aspectos fisiopatológicos de la enfermedad permitieron el desarrollo de blancos terapéuticos innovadores a nivel celular y molecular. El nicorandil, la trimetazidina, la ivabradina y la ranolazina se consideran nuevos fármacos antianginosos y constituyen la segunda línea de tratamiento de la angina de pecho estable; están indicados en pacientes que persisten sintomáticos a pesar del manejo de primera línea o en aquellos que presentan intolerancia o contraindicación a los betabloqueadores o antagonistas de canales de calcio. La trimetazidina, a través de su mecanismo de acción metabólico, mejora la tolerancia al ejercicio y puede ser útil en pacientes con falla cardíaca y contraindicación al uso de digitales; la ivabradina tiene un efecto cronotrópico negativo sin afectar el inotropismo ni la tensión arterial por lo que se puede usar en pacientes con taquiarritmias o falla cardíaca concomitante; en contraste, la ranolazina no afecta el cronotropismo por lo que se usa en pacientes con bradiarritmias aunque puede generar prolongación del intervalo QTc. La elección de alguno de estos medicamentos antianginosos de primera o segunda línea debe ser individualizado para cada paciente y se basa en las comorbilidades, contraindicaciones y preferencias del paciente. MÉD.UIS. 2016;29(3):79-93.

ABSTRACT In recent years, new antianginal agents with novel mechanisms of action have been launched to the market, as a complement to the existing therapeutic arsenal. Even though the beta-blockers, calcium channel blockers and nitrates continue to be the first line of treatment, recent discoveries of pathophysiological aspects of the disease led to the development of innovative therapeutic targets on both cellular and molecular level. Nicorandil, trimetazidine, ivabradine and ranolazine are novel antianginal drugs and constitute the second line of treatment of stable angina; these drugs are indicated for those patients who persist symptomatic despite treatment with first line agents or in those with contraindication or intolerance to beta-blockers o calcium channel blockers. Trimetazidine, through its metabolic mechanism of action, improves exercise tolerance and might be useful in patients with concomitant heart failure and contraindication to digitalis; ivabradine can be used in patients with concomitant tachyarrhythmias due to its negative chronotropic effect without affecting inotropism or blood pressure; in contrast, ranolazine doesn't affect chronotropism and can be used in patients with bradyarrhythmias, however, it might cause prolongation of the QTc interval. The choice of treatment with either of the first line or second line antianginal agents must be individualized for each patient and based on comorbidities, contraindications and patient's preference. MÉD.UIS. 2016;29(3):79-93.

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.

A Systematic Review on Drug Safety for Molsidomine, Nicorandil and Trimetazidine

BACKGROUND: Ischemic heart disease is the most common type of heart disease and an important cause of death in Korea. Among marketed anti-anginal medications, molsidomine, nicorandil, and trimetazidine are approved in Korea with unique mechanism of actions. As these drugs are not approved by the US Food and Drug Administration, the access to the up-to-dated and comprehensive safety-related information has been less than optimal from drug information resources used by Korean pharmacists. METHODS: A systematic review was conducted using Embase and Korean manuscripts to compile safety updates for these medications. Out of 418 articles from keyword searches, 52 studies were reviewed in full to compare adverse effects (AEs) with the approved package inserts (PI). RESULTS: Molsidomine related adverse effects were mostly mild or moderate, but anxiety, palpitation, epigastric pain, and sexual potency reduction were additional AEs found from the review not listed in PI. Although PI has included ulceration in oral cavity and gastrointestinal tracts including anus by nicorandil, the Korea FDA recently recommended adding corneal, genital, and skin ulcers to the approved PI. Trimetazidine induced Parkinsonism, worsening of the symptoms for patients diagnosed with Parkinson's disease, gastrointestinal burning, and muscle cramps were additionally identified AEs not listed in PI for trimetazidine. CONCLUSION: Continuous evaluations of the safety profile of these agents are needed to balance the risks and benefits to provide evidence-based safety counseling to the patients. In addition, more focused efforts on spontaneous reporting are warranted by healthcare professionals to safeguard patients against AEs.

Effects of Trimetazidine on T Wave Alternans in Stable Coronary Artery Disease

BACKGROUND AND OBJECTIVES: Studies reveal that the microvolt T wave alternans (MTWA) test has a high negative predictive value for arrhythmic mortality among patients with ischemic or non-ischemic cardiomyopathy. In this study, we investigate the effects of trimetazidine treatment on MTWA and several echocardiographic parameters in patients with stable coronary artery disease. SUBJECTS AND METHODS: One hundred patients (23 females, mean age 55.6±9.2 years) with stable ischemic heart disease were included in the study group. Twenty-five age- and sex-matched patients with stable coronary artery disease formed the control group. All patients were stable with medical treatment, and had no active complaints. Trimetazidine, 60 mg/day, was added to their current treatment for a minimum three months in the study group and the control group received no additional treatment. Pre- and post-treatment MTWA values were measured by 24 hour Holter testing. Left ventricular systolic and diastolic functions were assessed by echocardiography. RESULTS: After trimetazidine treatment, several echocardiographic parameters related with diastolic dysfunction significantly improved. MTWA has been found to be significantly improved after trimethazidine treatment (63±8 µV vs. 53±7 µV, p<0.001). Abnormal MTWA was present in 29 and 11 patients pre- and post-treatment, respectively (p< 0.001). CONCLUSION: Trimetazidine improves MTWA, a non-invasive determinant of electrical instability. Moreover, several echocardiographic parameters related with left ventricular functions also improved. Thus, we can conclude that trimetazidine may be an effective agent to prevent arrhythmic complications and improve myocardial functions in patients with stable coronary artery disease.

Efficacy of Trimetazidine Dihydrochloride for Relieving Chronic Tinnitus: A Randomized Double-Blind Study

OBJECTIVES: To evaluate the efficacy of trimetazidine dihydrochloride as a treatment for chronic tinnitus. METHODS: A total of 97 chronic tinnitus patients were evaluated in this randomized, prospective, double-blind, placebo-controlled trial. After assessing for eligibility, 82 patients were randomly assigned into placebo or trimetazidine groups according to the medication. The trimetazidine group received 20×3 mg/day per oral trimetazidine dihydrochloride and the placebo group received 20×3 mg/day per oral placebo for 3 months. Tinnitus handicap inventory (THI), visual analogue scale (VAS) questionnaires and audiometric results were used to determine the effectiveness of trimetazidine treatment. RESULTS: The study group comprised 82 tinnitus subjects, 42 (51%) of whom received trimetazidine dihydrochloride and 40 (49%) who received placebo. There was no significant difference between placebo and trimetazidine groups in THI grade and VAS (both pre- and posttreatment scores) (P>0.05) and no significant improvement was observed in subjective loudness score in either group (P>0.05). Additionally there was no significant difference between groups in pre- and posttreatment pure tone hearing thresholds at all measured frequencies (P>0.05). CONCLUSION: Trimetazidine dihydrochloride therapy was ineffective for relieving chronic tinnitus.

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)

Tratamento medicamentoso atual / Current drug treatment

A elevada prevalência populacional de doença arterial coronária crônica propiciou a melhora dos métodos preventivos, diagnósticos e terapêuticos. A confirmação de isquemia, com ou sem sintomas, trouxe tratamento inovadores visando à redução de eventos agudos, melhora na qualidade de vida e aumento de sobrevida Estudos recentes comparam os resultados do tratamento clínico com outras intervenções e concluíram que o sucesso da intervenção clínica está embasado na otimização terapêutica. Definida a influência dos fatores de risco e os mecanismos fisiopatológicos da doença, o tratamento medicamentoso constitui a base e a sequência de todas as intervenções na doença arterial coronária crônica.

The high prevalence of patients with chronic coronary artery disease has led to the improvement of preventive, diagnostic and therapeutic methods. Confirmation of ischemia with or without symptoms, brought innovative treatment aimed at reducing acute events, improvement in quality of life and increased survival. Recent studies have compared the results of clinical treatment with other interventions and concluded that the success of clinical intervention is based on therapeutic optimization. Once established the inluence of risk factors and physiopathological mechanisms of the disease, drug treatment constitutes the basis and the sequence of all interventionns in chronic artery disease.