Allopurinol versus Trimetazidine for the Treatment of Angina: A Randomized Clinical Trial. / Alopurinol Versus Trimetazidina para o Tratamento da Angina: Ensaio Clínico Randomizado.

BACKGROUND: Recently, it was demonstrated that allopurinol, a xanthine oxidase inhibitor, has cardiovascular and anti-ischaemic properties and may be a metabolic antianginal agent option.Objective: The objective of this study was to evaluate the antianginal effect of allopurinol as a third drug for patients with stable coronary artery disease (CAD). METHODS: This was a randomized clinical trial between 2018 and 2020 including patients with CAD who maintained angina despite initial optimization with beta-blockers and calcium channel blockers. The individuals were randomized 1:1 to 300 mg of allopurinol twice daily or 35 mg of trimetazidine twice daily. The main outcome was the difference in the angina frequency domain of the Seattle Angina Questionnaire (SAQ-AF). A probability (p) value < 0.05 was considered statistically significant. RESULTS: A hundred and eight patients were included in the randomization phase, with 54 (50%) in the allopurinol group and 54 (50%) in the trimetazidine group. Six (5.6%) individuals, 3 from each group, were lost to follow-up for the primary outcome. In the allopurinol and trimetazidine groups, the median SAQ-AF scores were 50 (30.0 to 70.0) and 50 (21.3 to 78.3), respectively. In both groups, the SAQ-AF score improved, but the median of the difference compared to baseline was lower in the allopurinol group (10 [0 to 30] versus 20 [10 to 40]; p < 0.001), as was the mean of the difference in the total SAQ score (12.8 ± 17.8 versus 21.2 ± 15.9; p = 0.014). CONCLUSION: Both allopurinol and trimetazidine improved the control of angina symptoms; however, trimetazidine presented a greater gain compared to baseline. Brazilian Registry of Clinical Trials - Registration Number RBR-5kh98y.

FUNDAMENTO: Recentemente, foi demonstrado que o alopurinol, um inibidor da xantina oxidase, possui propriedades cardiovasculares e anti-isquêmicas e pode ser uma opção de agente antianginoso metabólico. OBJETIVO: O objetivo do presente estudo foi avaliar o efeito antianginoso do alopurinol como terceiro medicamento para pacientes com doença arterial coronariana (DAC) estável. MÉTODOS: Trata-se de um ensaio clínico randomizado entre 2018 e 2020 incluindo pacientes com DAC que mantiveram angina apesar da otimização inicial com betabloqueadores e bloqueadores dos canais de cálcio. Os indivíduos foram randomizados 1:1 para 300 mg de alopurinol 2 vezes ao dia ou 35 mg de trimetazidina 2 vezes ao dia. O desfecho principal foi a diferença no domínio da frequência da angina do Questionário de Angina de Seattle (QAS-FA). Foram considerados estatisticamente significativos valores de probabilidade (p) < 0,05. RESULTADOS: Foram incluídos 108 pacientes na fase de randomização, com 54 (50%) no grupo alopurinol e 54 (50%) no grupo trimetazidina. Seis (5,6%) indivíduos, 3 de cada grupo, foram perdidos no seguimento para o desfecho primário. Nos grupos de alopurinol e trimetazidina, as pontuações medianas do QAS-FA foram 50 (30,0 a 70,0) e 50 (21,3 a 78,3), respectivamente. Em ambos os grupos, a pontuação do QAS-FA melhorou, mas a mediana da diferença em relação à linha de base foi menor no grupo alopurinol (10 [0 a 30] versus 20 [10 a 40]; p < 0,001), assim como a média da diferença na pontuação total do QAS (12,8 ± 17,8 versus 21,2 ± 15,9; p = 0,014). CONCLUSÃO: Tanto o alopurinol quanto a trimetazidina melhoraram o controle dos sintomas de angina; no entanto, a trimetazidina apresentou um ganho maior em relação à linha de base. Registro Brasileiro de Ensaios Clínicos ­ Número de Registro RBR-5kh98y.

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

BAPST. A Combo of Common Use Drugs as Metabolic Therapy for Cancer: A Theoretical Proposal.

Cancer therapy advances have yet to impact global cancer mortality. One of the factors limiting mortality burden reduction is the high cost of cancer drugs. Cancer drug repurposing has already failed to meet expectations in terms of drug affordability. The three FDA-approved cancer drugs developed under repurposing: all-trans-retinoic acid, arsenic trioxide, and thalidomide do not differ in price from other drugs developed under the classical model. Though additional factors affect the whole process from inception to commercialization, the repurposing of widely used, commercially available, and cheap drugs may help. This work reviews the concept of the malignant metabolic phenotype and its exploitation by simultaneously blocking key metabolic processes altered in cancer. We elaborate on a combination called BAPST, which stands for the following drugs and pathways they inhibit: Benserazide (glycolysis), Apomorphine (glutaminolysis), Pantoprazole (Fatty-acid synthesis), Simvastatin (mevalonate pathway), and Trimetazidine (Fatty-acid oxidation). Their respective primary indications are: • Parkinson's disease (benserazide and apomorphine). • Peptic ulcer disease (pantoprazole). • Hypercholesterolemia (simvastatin). • Ischemic heart disease (trimetazidine). When used for their primary indication, the literature review on each of these drugs shows that they have a good safety profile and lack predicted pharmacokinetic interaction among them. Based on that, we propose that the BAPST regimen merits preclinical testing.

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. / Naringina e Trimetazidina Melhoram a Sensibilidade Barorreflexa e a Atividade Elétrica do Trato Solitário do Núcleo na Lesão de Isquemia-Reperfusão Renal.

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.

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.

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.

Trimetazidine Protects from Mercury-Induced Kidney Injury.

INTRODUCTION: The presence of mercury in the environment is a worldwide concern. Inorganic mercury is present in industrial materials, is employed in medical devices, is widely used in batteries, is a component of fluorescent light bulbs, and it has been associated with human poisoning in gold mining areas. The nephrotoxicity induced by inorganic mercury is a relevant health problem mainly in developing countries. The primary mechanism of mercury toxicity is oxidative stress. Trimetazidine (TMZ) is an anti-ischemic drug, which inhibits cellular oxidative stress, eliminates oxygen-free radicals, and improves lipid metabolism. The aim of this study was to evaluate whether the administration of TMZ protects against mercuric chloride (HgCl2) kidney damage. METHODS: Adult male Wistar rats received only HgCl2 (4 mg/kg bw, sc) (Hg group, n = 5) or TMZ (3 mg/kg bw, ip) 30 min before HgCl2 administration (4 mg/kg bw, sc) (TMZHg group, n = 7). Simultaneously, a control group of rats (n = 4) was studied. After 4 days of HgCl2 injection, urinary flow, urea and creatinine (Cr) plasma levels, Cr clearance, urinary glucose, and sodium-dicarboxylate cotransporter 1 (NaDC1) in urine were determined. Lipid peroxidation (MDA) and glutathione (GSH) levels were measured in kidney homogenates. RESULTS: Rats only treated with HgCl2 showed an increase in urea and Cr plasma levels, urinary flow, fractional excretion of water, glucosuria, and NaDC1 urinary excretion as compared with the control group and a decrease in Cr clearance. TMZHg group showed a decrease in urea and Cr plasma levels, urinary flow, fractional excretion of water, glucosuria, NaDC1 urinary excretion, and an increase in Cr clearance when compared to the Hg group. Moreover, MDA and GSH levels observed in Hg groups were decreased and increased, respectively, by TMZ pretreatment. CONCLUSION: TMZ exerted a renoprotective action against HgCl2-induced renal injury, which might be mediated by the reduction of oxidative stress. Considering the absence of toxicity of TMZ, its clinical application against oxidative damage due to HgCl2-induced renal injury should be considered. The fact that TMZ is commercially available should simplify and accelerate the translation of the present data "from bench to bedside." In this context, TMZ become an interesting new example of drug repurposing.

Efficacy and safety of trimetazidine after percutaneous coronary intervention (ATPCI): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Angina might persist or reoccur despite successful revascularisation with percutaneous coronary intervention (PCI) and antianginal therapy. Additionally, PCI in stable patients has not been shown to improve survival compared with optimal medical therapy. Trimetazidine is an antianginal agent that improves energy metabolism of the ischaemic myocardium and might improve outcomes and symptoms of patients who recently had a PCI. In this study, we aimed to assess the long-term potential benefits and safety of trimetazidine added to standard evidence-based medical treatment in patients who had a recent successful PCI. METHODS: We did a randomised, double-blind, placebo-controlled, event-driven trial of trimetazidine added to standard background therapy in patients who had undergone successful PCI at 365 centres in 27 countries across Europe, South America, Asia, and north Africa. Eligible patients were aged 21-85 years and had had either elective PCI for stable angina or urgent PCI for unstable angina or non-ST segment elevation myocardial infarction less than 30 days before randomisation. Patients were randomly assigned by an interactive web response system to oral trimetazidine 35 mg modified-release twice daily or matching placebo. Participants, study investigators, and all study staff were masked to treatment allocation. The primary efficacy endpoint was a composite of cardiac death; hospital admission for a cardiac event; recurrence or persistence of angina requiring an addition, switch, or increase of the dose of at least one antianginal drug; or recurrence or persistence of angina requiring a coronary angiography. Efficacy analyses were done according to the intention-to-treat principle. Safety was assessed in all patients who had at least one dose of study drug. This study is registered with the EU Clinical Trials Register (EudraCT 2010-022134-89). FINDINGS: From Sept 17, 2014, to June 15, 2016, 6007 patients were enrolled and randomly assigned to receive either trimetazidine (n=2998) or placebo (n=3009). After a median follow-up of 47·5 months (IQR 42·3-53·3), incidence of primary endpoint events was not significantly different between the trimetazidine group (700 [23·3%] patients) and the placebo group (714 [23·7%]; hazard ratio 0·98 [95% CI 0·88-1·09], p=0·73). When analysed individually, there were no significant differences in the incidence of the components of the primary endpoint between the treatment groups. Similar results were obtained when patients were categorised according to whether they had an elective or urgent PCI. 1219 (40·9%) of 2983 patients in the trimetazidine group and 1230 (41·1%) of 2990 patients in the placebo group had serious treatment-emergent adverse events. Frequencies of adverse events of interest were similar between the groups. INTERPRETATION: Our results show that the routine use of oral trimetazidine 35 mg twice daily over several years in patients receiving optimal medical therapy, after successful PCI, does not influence the recurrence of angina or the outcome; these findings should be taken into account when considering the place of trimetazidine in clinical practice. However, the long-term prescription of this treatment does not appear to be associated with any statistically significant safety concerns in the population studied. FUNDING: Servier.

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.

The Effects of Trimetazidine on QT-interval Prolongation and Cardiac Hypertrophy in Diabetic Rats.

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.

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.

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.