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At least 55 records · Page 3Linked to original sources
PubMed2004

Can we afford to add chemotherapy to radiotherapy for glioblastoma multiforme? Cost-identification analysis of concomitant and adjuvant treatment with temozolomide until patient death.

BACKGROUND: Adding temozolomide (TMZ) to standard radiotherapy as a first-line therapy for glioma may increase costs to a disproportionate degree compared with the resulting survival benefits. METHODS: Forty-six consecutive patients (28 males and 18 females; median age, 52 years; age range, 24-70 years) received concomitant TMZ with radiotherapy for 6 weeks followed by adjuvant TMZ for 6 cycles, and they were followed until disease recurrence and then until death. The authors assessed the costs associated with the four phases of treatment from a hospital-centered perspective. RESULTS: Treatment was discontinued early in 3 patients, 9 patients, and 15 patients during concomitant TMZ, before adjuvant TMZ, and during adjuvant TMZ, respectively. Karnofsky index values varied between 85% (at the beginning of treatment) and 76% (at the end of treatment). The nature of care after disease recurrence was diverse. Overall survival ranged from 1.4 months to 64.3 months (median, 15.8 months) and was better if surgical debulking could be carried out before treatment. Global costs amounted to Euros 39,092 +/- Euros 21,948 (concomitant TMZ, Euros 14,539 +/- Euros 4998; adjuvant TMZ, Euros 13,651 +/- Euros 4320; follow-up, Euros 6363 +/- Euros 6917; and recurrence, Euros 12,344 +/- Euros 18,327), with 53% of these costs being related to the acquisition of TMZ; this represented an eightfold increase in cost compared with radiotherapy alone. CONCLUSIONS: TMZ may be an effective but costly adjuvant outpatient therapy for patients with glioblastoma multiforme. Definite cost-effectiveness/utility must be assessed in a randomized Phase III trial.

Adult↗
PubMed2006

Effect of free fatty acid inhibition on silent and symptomatic myocardial ischemia in diabetic patients with coronary artery disease.

OBJECTIVE: Free fatty acid inhibition with trimetazidine (TMZ) improves myocardial metabolism and myocardial ischemia in patients with coronary artery disease (CAD). Because of its effect on myocardial glucose utilization TMZ may represent a therapeutic option in diabetic patients with CAD. Aim of the present study was to evaluate whether the metabolic effect of TMZ may improve episodes of myocardial ischemia in diabetic patients with CAD. RESEARCH DESIGN AND METHODS: We assessed the effect of TMZ on 24 h ambulatory ECG monitoring (AEM) in 30 patients (22 males and 8 females, mean (SE) age 67+/-6.5 years) with NIDDM and ischemic cardiomyopathy. Patients were randomized to receive on top of standard therapy either TMZ (20 mg, tds) or placebo (tds) and were evaluated at baseline and after 6 months. RESULTS: Patients randomized to TMZ or placebo were comparable regarding demographic data, distribution of CAD, and glicated haemoglobin levels. TMZ significantly reduced the number of episodes of transient myocardial ischemia (-24% compared to baseline, p<0.01; -27% compared to placebo, p<0.01), and Total Ischemic Burden (-28% compared to baseline, p<0.01; -29% compared to placebo, p<0.01). TMZ also significantly reduced the number of silent episodes of myocardial ischemia (-42% compared to baseline and -39% compared to placebo, p<0.01) and the time of silent myocardial ischemia/24 h (-37% compared to baseline and -35% compared to placebo, p<0.01). No significant changes in heart rate were detected between baseline, placebo and TMZ evaluations. CONCLUSIONS: TMZ is effective in reducing silent and symptomatic episodes of transient myocardial ischemia in diabetic patients with CAD on standard anti-anginal therapy.

Aged↗
PubMed2001

Temozolomide enhances herpes simplex virus thymidine kinase/ganciclovir therapy of malignant glioma.

Gene therapy for malignant glioma with the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system is already in the stage of clinical trials, but still needs major improvement to achieve greater clinical efficacy. The aim of this study was to determine whether combining HSV-tk/GCV gene therapy with temozolomide (TMZ), an alkylating drug clinically proven to be efficient in recurrent high-grade gliomas, would result in enhanced antitumor effect in malignant glioma in culture and in vivo. Human U87MG glioblastoma (GBM) cells with or without expression of HSV-tk were treated with different concentrations of GCV, TMZ, or both drugs. Cell viability was accessed by an automated microplate assay (MTT). The isobologram method and the combination index (CI) method of Chou-Talalay were used to measure the interactions between the two drugs when applied simultaneously. U87-tk and control U87 cells (5x10(6) each) were implanted in the flanks of nude mice, and animals were treated with GCV or TMZ or with both drugs. All tumors were measured and weighed at specified time points. IC(50) for GCV was 511 microM in control U87 cells and 14.3 microM in U87-tk cells, resulting in 35.7-fold increase of toxicity in the HSV-tk-expressing cells. TMZ had an IC(50) of 20.2 mM in control cells and 2.35 mM in U87-tk cells, resulting in 8.6-fold increase in sensitivity of the HSV-tk-expressing cells. TMZ and HSV-tk/GCV actions were synergistic (CI<1) in both control and U87-tk cells with higher synergism in U87-tk cells at high effect levels. Tumors expressing HSV-tk and treated with TMZ and GCV were significantly smaller than those treated by TMZ, but not by GCV. There was also a significant difference between the weight of HSV-tk expressing versus control tumors treated with TMZ, with GCV, or with both drugs. These data demonstrate synergism between HSV-tk/GCV and TMZ and higher sensitivity against TMZ in HSV-tk-expressing GBM cells. The potential importance for clinical studies combining both local tumor gene therapy and systemic chemotherapy should be explored further.

Animals↗
PubMed1996

Myocardial protection during coronary artery bypass graft surgery: a randomized, double-blind, placebo-controlled study with trimetazidine.

We conducted a randomized, double-blind, placebo-controlled study to assess the cardioprotective effects of trimetazidine (TMZ), an antiischemic drug, on left ventricular function using transesophageal echocardiography (TEE) after coronary artery bypass grafting (CABG). Forty patients undergoing elective CABG received either TMZ or a placebo (PCB). The primary measures of efficacy were serial measurements of fractional area change (FAC), percent of systolic wall thickening (SWT), and malonedialdehyde (MDA) production. The two groups were similar for the following variables: number of vessels revascularized (2.5 +/- 0.2 in the TMZ group and 2.8 +/- 0.1 in the PCB group), duration of aortic clamping (46 +/- 4 min in the TMZ group and 48 +/- 3 min in the PCB group), and bypass time (63 +/- 4 min in the TMZ group and 70 +/- 4 min in the PCB group). FAC increased by 12% in both groups 20 min after aortic unclamping (P < 0.05) and remained above the initial value at the sixth postoperative hour. SWT was 23.8% +/- 1.6%, 25.4% +/- 1.9%, then 21.6% +/- 1.5% in the TMZ group and 22.8% +/- 1.6%, 23.8% +/- 1.4%, then 22.3% +/- 1.6 % in the PCB group, after induction of anesthesia and 1 and 6 h after aortic unclamping (not significant). MDA increased by 24% in the PCB group and 25% in the TMZ group 20 min after aortic unclamping (P < 0.01). Lactate levels were lower in the TMZ group (P < 0.05) and patients from the TMZ group received less intravenous calcium before aortic clamping (P < 0.02) and less calcium channel entry blocking drugs in the early phase after aortic unclamping (P < 0.01) compared to the PCB group. We conclude that in patients with good preoperative ejection fraction undergoing CABG, TMZ as administered did not demonstrate clinically significant cardioprotective effects on left ventricular performance and lipid peroxidation compared to PCB.

Coronary Artery Bypass↗
PubMedDate not supplied

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

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

Adult↗
PubMed2003

Inhibition of DNA repair for sensitizing resistant glioma cells to temozolomide.

OBJECT: Temozolomide (TMZ) is a DNA alkylating agent currently used as adjuvant treatment for anaplastic astrocytomas. Its use in managing glioblastoma multiforme has been halted because of the lack of therapeutic effects due to cell resistance. Note that O6-alkylguanine-DNA alkyltranferase (AGT) is a DNA repair enzyme that limits the efficacy of TMZ. In this study the authors investigated the ability of O6-benzylguanine (BG), an AGT inhibitor, to sensitize a glioblastoma cell line resistant to TMZ. METHODS: The effects of TMZ alone (100 microg) and after exposure to BG (50 microg) were assessed in two glioblastoma cell lines, U373-MG and T98G, respectively, sensitive and resistant to TMZ. Cell viability was assessed using trypan blue; cell cycle analysis by fluorescence-activated cell sorter; and apoptosis and autophagy by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and acridine orange staining, respectively. Furthermore, the involvement of an autophagy marker, microtubule-associated light chain 3 (LC3), was assessed. Temozolomide suppressed the growth of and caused cell cycle arrest in the G2-M phase of U373-MG cells but not T98G cells. Exposure to BG prior to TMZ resulted in a significant decrease in cell viability as well as cell cycle arrest in the G2-M phase in T98G cells (p < 0.05). Although apoptosis was not detected on TUNEL staining, programmed cell death Type II (autophagy) was detected after exposure to BG and TMZ in T98G cells. CONCLUSIONS: These results indicate that inhibition of AGT by BG can render previously resistant glioma cells sensitive to TMZ treatment. The mechanism of cell demise following BG-TMZ treatment seems to be autophagy and not apoptosis. Combination therapy involving TMZ and an AGT inhibitor may be an effective strategy to treat resistant gliomas.

Antineoplastic Agents, Alkylating↗
PubMed1999

Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer.

The purpose of this study is to characterize the absorption, metabolism, and excretion of carbon 14-labeled temozolomide (14C-TMZ) administered p.o. to adult patients with advanced solid malignancies. On day 1 of cycle 1, six patients received a single oral 200-mg dose of 14C-TMZ (70.2 microCi). Whole blood, plasma, urine, and feces were collected from days 1-8 and on day 14 of cycle 1. Total radioactivity was measured in all samples. TMZ, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), and 4-amino-5-imidazole-carboxamide (AIC) concentrations were determined in plasma, and urine and plasma samples were profiled for metabolite/degradation products. Maximum TMZ plasma concentrations were achieved between 0.33 to 2 h (mean, 1.2 h), and half-life, apparent volume of distribution, and oral clearance values averaged 1.9 h, 17 liters/m2, and 104 ml/min/m2, respectively. A first-order absorption, one-compartment linear model, which included first-order formation of MTIC from TMZ and elimination of MTIC via degradation to AIC, and a peripheral distribution compartment for AIC, adequately described the plasma TMZ, MTIC, and AIC concentrations. MTIC systemic clearance was estimated to be 5384 ml/min/m2, and the half-life was calculated to be 2.5 min. Metabolite profiles of plasma at 1 and 4 h after treatment showed that 14C-derived radioactivity was primarily associated with TMZ, and a smaller amount was attributed to AIC. Profiles of urine samples from 0-24 h revealed that 14C-TMZ-derived urinary radioactivity was primarily associated with unchanged drug (5.6%), AIC (12%), or 3-methyl-2,3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxyl ic acid (2.3%). The recovered radioactive dose (39%) was principally eliminated in the urine (38%), and a small amount (0.8%) was excreted in the feces. TMZ exhibits rapid oral absorption and high systemic availability. The primary elimination pathway for TMZ is by pH-dependent degradation to MTIC and further degradation to AIC. Incomplete recovery of radioactivity may be explained by the incorporation of AIC into nucleic acids.

Absorption↗
PubMed2001

Temozolomide: the effect of once- and twice-a-day dosing on tumor tissue levels of the DNA repair protein O(6)-alkylguanine-DNA-alkyltransferase.

Temozolomide (TMZ) is a methylating agent of the imidotetrazine class, whose cytotoxic product is O(6)-methylguanine DNA adducts, which initiate a futile recycling of the mismatch repair pathway causing DNA strand breaks and apoptotic cell death in mismatch repair proficient cells. The DNA repair protein O(6)-alkylguanine DNA alkyltransferase (AGT) repairs these adducts in a suicide manner and reduces the cytotoxic action of TMZ. An antitumor threshold is reached when sufficient adducts are formed by TMZ to inactivate AGT. In this study, we evaluated the relation between TMZ dosing and AGT depletion in patients with deep visceral tumors and in peripheral blood mononuclear cells (PBMCs) to determine whether the dose of TMZ was sufficient to inactivate AGT and lead to therapeutic efficacy. To do so, we compared single dose therapy with a novel twice daily regimen in a laboratory correlate-driven Phase I dose escalation study. p.o. bolus dose TMZ 200 mg/m(2) daily times five was compared with the same bolus on day 1 followed by nine doses at 12-h intervals of 50, 75, 90, or 100 mg/m(2). Dose-limiting toxicity in the bid regimen (grade IV thrombocytopenia and neutropenia) was seen at 100 mg/m(2), cumulative dose 1100 mg/m(2), and the maximum tolerated dose was 1010 mg/m(2). The degree of tumor tissue AGT activity depletion measured in biopsies before and on day 5 of therapy varied widely, between 0 (in 3 patients) and 99% (in 1), with the majority of patients (10 of 15) having 52-84% tumor AGT depletion. In contrast, AGT activity in PBMCs fell rapidly during TMZ administration to undetectable levels in all dosage groups on day 5 but did not correlate with tumor AGT depletion. TMZ pharmacokinetics were dose proportional; no accumulation occurred >5-day period in the bid regimen. Two partial responses were seen, lasting 3 and 4 months. Five additional patients achieved prolonged stabilization of disease for 4-6 monthly cycles. This is the first study to document that at maximum tolerated doses, TMZ depletes PBMC AGT but only partially and variably depletes visceral tumor AGT in most patients, even during twice daily dosing. Drug combinations or schedules designed to maximally deplete tumor AGT might improve TMZ efficacy.

Adult↗
PubMed2002

Multifaceted resistance of gliomas to temozolomide.

PURPOSE AND EXPERIMENTAL DESIGN: The contributions of O6-methylguanine-DNA-methyltransferase(MGMT), p53 status, mismatch repair, and apoptotic response to the resistance of glial tumors to temozolomide (TMZ) were tested using seven established human glial tumor cell lines in culture and xenografts in athymic mice. RESULTS: Resistance to TMZ was only marginally dependent on MGMT activity, because subtoxic doses of TMZ easily eliminated MGMT reserves for at least 18 h after treatment. Resistance to TMZ varied most notably with the p53 status of the tumor. Tumors with wild-type (wt) p53 and a functional p53 response to DNA damage (SWB40 and SWB61) were most sensitive. The p21-related cell cycle arrest was intimately linked to TMZ toxicity because tumors with wt p53 but lacking a robust increase in p21 protein level (D-54) were resistant to TMZ. In contrast, tumors with a dysfunctional p53 cycle and a weak cell cycle response to DNA damage (SWB39 and SWB77) were extremely unresponsive to treatment even with the aid of MGMT inactivators. Notable exceptions to the above were observed with the p53 mutated tumors SWB33 and SWB95, which were arrested by TMZ in G1-S and consequently underwent apoptosis despite their failure to express p21. CONCLUSIONS: By testing a limited number of glial tumors in cell culture and also as xenografts, we have shown that mobilization of the p53 in response to TMZ damage is likely to induce a cell cycle arrest and apoptosis in glial tumors. Additional pathways linking cell cycle arrest and apoptosis contribute to the efficacy of TMZ against p53 mutated glial tumors. The unusual resistance of tumors, of which the cell cycle was not arrested in response to TMZ treatment, was associated with allelic losses during regrowth of treated tumors. Nevertheless such resistance was not related to dysfunctional mismatch repair.

Alleles↗
PubMed2003

Formation of DNA adducts and induction of lacI mutations in Big Blue Rat-2 cells treated with temozolomide: implications for the treatment of low-grade adult and pediatric brain tumors.

Temozolomide (TMZ) is a chemotherapeutic agent used in the treatment of high-grade brain tumors. Treatment of patients with alkylating chemotherapeutic agents has been established to increase their risk for acute myelogenous leukemia. The formation of DNA adducts and induction of mutations are likely to play a role in the etiology of therapy-related acute myeloid leukemia. To evaluate this issue for TMZ, we have measured the formation of DNA adducts and induction of lacI mutations in Big Blue Rat-2 cells treated with TMZ. Treatment of Big Blue Rat-2 cells with either 0, 0.5, or 1 mM TMZ resulted in lacI mutant frequencies of 9.1 +/- 2.9 x 10(-5), 48.9 +/- 12 x 10(-5), and 89.7 +/- 40.3 x 10(-5), respectively. Comparison of the mutant frequencies demonstrated that 0.5 and 1 mM TMZ treatments increased the mutant frequencies by 5.3- and 9.8-fold and that this increase was significant (P < 0.001). Sequence analysis of the lacI mutants from the TMZ treatment group demonstrated that they were GC-->AT transitions at non-CpG sites, which is significantly different from the mutation spectrum observed in the control treatment group. Treatment of Big Blue Rat-2 cells with various concentrations of TMZ produced a linear increase in the levels of N7-methylguanine and O(6)-methylguanine. The lacI mutation spectrum induced by TMZ treatment is consistent with these mutations being produced by O(6)-MeG. This study establishes TMZ has significant mutagenic potential and suggests that careful consideration in the use of TMZ for the treatment of low-grade adult and pediatric brain tumors should be given.

Alkylation↗
PubMed2005

The effects of trimetazidine on heart rate variability in patients with slow coronary artery flow.

OBJECTIVE: We sought to examine the effect of trimetazidine (TMZ) on heart rate variability (HRV), endothelin-1 (ET-1), NO, and anginal symptoms in patients with slow coronary artery flow (SCAF). METHODS: The 48 patients with SCAF (29 women and 19 men; mean age, 52 +/- 9 years) were included in the study. Twenty milligrams TMZ 3 times a day or matched placebo were given randomly in a double-blinded fashion for 4 weeks. Patients were divided into 4 groups as follows: exercise-positive, TMZ-given group (group A, n = 12); exercise-positive, placebo-given group (group B, n = 12); exercise-negative, TMZ-given group (group C, n = 12); and exercise-negative, placebo-given group (group D, n = 12). RESULTS: After TMZ treatment, HRV parameters, including SD of the all R-R intervals, SD of the averages of R-R intervals in all 5-minute segments of the entire recording, percentage of R-R intervals with more than 50-millisecond variation, and the square root of the mean of the sum of the squares of differences between adjacent R-R intervals, significantly improved both in exercise-positive and exercise-negative groups when compared with baseline. After TMZ treatment, ET-1 and NO levels significantly altered both in exercise-positive and exercise-negative groups when compared with baseline (17.7 +/- 2.7 vs 13.9 +/- 2.8 pg/mL [P = .01] and 18.1 +/- 3.8 vs 14.2 +/- 2.6 pg/mL [P = .01], respectively). After TMZ treatment, NO levels significantly increased in both exercise-positive and exercise-negative groups when compared with baseline (36.4 +/- 5.4 vs 43.3 +/- 6.8 micromol/L [P = .01] and 36.8 +/- 7.8 vs 43.3 +/- 4.8 micromol/L [P = .01], respectively). However, in placebo group, neither HRV parameters nor ET-1 and NO levels altered when compared with baseline. Also, after treatment, a significant correlation was detected between HRV parameters, including SD of the averages of R-R intervals in all 5-minute segments of the entire recording, SD of the all R-R intervals, percentage of R-R intervals with more than 50-millisecond variation, and the square root of the mean of the sum of the squares of differences between adjacent R-R intervals, and NO and ET-1 levels in TMZ group but not placebo. CONCLUSION: Short-term TMZ therapy improved HRV parameters and endothelial products such as ET-1 and NO as well as anginal symptom in patients with SCAF. Improvement in HRV parameters was correlated with ET-1 and NO levels.

Blood Flow Velocity↗
PubMed2003

A mechanistic mathematical model of temozolomide myelosuppression in children with high-grade gliomas.

Temozolomide (TMZ) is currently being evaluated for the treatment of high-grade gliomas in children. Myelosuppression (the suppression of bone marrow activity) is the dose-limiting toxicity for TMZ in adults and children. Empirical methods (i.e. relations between the percent change in absolute neutrophil count (ANC) and the area under the plasma concentration curve (AUC) of TMZ or its active metabolite MTIC) showed poor results when attempting to describe myelosuppression from serial data derived during TMZ therapy in a Phase II study of children with high-grade glioma. Therefore, to improve our understanding of the myelosuppressive effects of TMZ and MTIC in children we developed a mechanistic mathematical model. The model describes the progression of neutrophils from their production in the bone marrow to their release in the plasma. Included in the model are the feedback effects of granulocyte colony stimulating factor (G-CSF), which stimulates neutrophil production when there is a decrease in circulating neutrophils. The model is fit to serial ANC measurements obtained after TMZ dosing and it is able to explain, among other things, the lag in ANC reduction following a dose of TMZ, the ANC nadir, and the 'rebound effect' observed where the ANC recovers to levels greater than that observed pre-TMZ dose. This model will be useful for the prospective design of clinical trials of TMZ in children with cancer.

Adolescent↗
PubMed2006

Trimetazidine improves post-ischemic recovery by preserving endothelial nitric oxide synthase expression in isolated working rat hearts.

OBJECTIVE: Previous investigations have consistently shown that the piperazine derivative trimetazidine (TMZ, 1-[2,3,4-trimethoxybenzil] piperazine, dihydrocloride) has cardioprotective effects in the experimental ischemia-reperfusion model. We tested the hypothesis that cardioprotective effect of TMZ is partly mediated by preservation of the endothelial barrier of the coronary microcirculation. METHODS: Isolated Wistar rat (250-300 g) hearts were subjected to a 15 min period of global ischemia and 180 min reperfusion in the presence or absence of 1 microM TMZ. Hemodynamic parameters, heart weight, creatinekinase (CK) release and microvascular permeability (FITC-albumin extravasation) were evaluated. In addition, eNOS gene expression was estimated by rt-PCR, and eNOS protein levels were assessed by Western analysis. In order to confirm the involvement of NO in mediating the cardioprotective effects of TMZ, 30 microM N(omega)-nitro-l-arginine methylester (L-NAME), a specific inhibitor of nitric oxide synthase, was used. RESULTS: After ischemia and reperfusion, TMZ produced a significant improvement of mechanical function associated with a reduction of CK release and FITC-albumin diffusion (P<0.001); the agent also resulted in improvement in coronary flow (at 45 min+27% vs control). The eNOS mRNA and protein levels were significantly higher in TMZ-treated hearts compared to controls. The addition of L-NAME significantly reduced the beneficial effects of TMZ on contractile function, CK release and FITC-albumin diffusion. CONCLUSIONS: in the isolated rat heart, TMZ exerts a relevant, NO-dependent, cardioprotection against ischemia-reperfusion injury and preserves the endothelial barrier of the coronary circulation. This could contribute to explain the cardioprotective action of TMZ following ischemia and reperfusion.

Animals↗
PubMed2005

Trimetazidine inhibits mitochondrial permeability transition pore opening and prevents lethal ischemia-reperfusion injury.

Trimetazidine (TMZ) affects mitochondrial function during ischemia. Mitochondrial permeability transition is a pivotal event in cardiomyocyte death following acute ischemia. The aim of the present study was to determine whether the anti-ischemic agent TMZ might modulate mitochondrial permeability transition pore (mPTP) opening and limit lethal ischemia-reperfusion injury. Anesthetized NZW rabbits underwent 30 min of coronary artery occlusion followed by 4 hours of reperfusion. Prior to this, they underwent either no intervention (control, C), ischemic preconditioning (PC), or an IV injection of 5 mg kg(-1) TMZ 10 min before ischemia (TMZ). Additional rabbits (Sham group) underwent no ischemia/reperfusion throughout the experiment. Infarct size was assessed by triphenyltetrazolium staining, and apoptosis via measurement of caspase 3 activity. Ca(2+)-induced mPTP opening was assessed in mitochondria isolated from ischemic myocardium. TMZ and PC significantly reduced infarct size that averaged 34 +/- 4% and 21 +/- 4% of the risk region respectively, versus 63 +/- 6% in controls (P<0.005). Caspase 3 activity was reduced in both TMZ and PC groups: 37 +/- 11 and 29 +/- 7 respectively, versus 68 +/- 9 nmol min(-1) mg(-1) mitochondrial protein in controls (P=0.01 versus TMZ and PC). In controls, Ca(2+) load required for mPTP opening averaged 11 +/- 4 microM mg(-1) mitochondrial protein versus 116 +/- 6 in shams (P<0.0001). Pre-treatment by TMZ or PC attenuated this, with Ca(2+) loads averaging 45 +/- 4 and 46 +/- 4 microM mg(-1) mitochondrial proteins, respectively (P<0.005 versus C). These data suggest that TMZ inhibits mPTP opening and protects the rabbit heart from prolonged ischemia-reperfusion injury.

Animals↗
PubMed2003

Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy.

BACKGROUND: Trimetazidine (TMZ) has been shown to partially inhibit free fatty acid oxidation by shifting substrate utilization from fatty acid to glucose. The aim of this study was to assess the effects of TMZ in patients with diabetes and ischemic cardiomyopathy. METHODS: Sixteen patients with diabetes and ischemic hypokinetic cardiomyopathy (all males) on conventional therapy were randomized to receive either placebo or TMZ (20 mg 3 times per day), each arm lasting 15 days, and then again to receive either placebo or TMZ for 2 additional 6-month periods, according to a double-blind, crossover design. At the end of each period, all patients underwent exercise testing, 2-dimensional echocardiography, and hyperinsulinemic/euglycemic clamp. Among the others, New York Heart Association class, ejection fraction, exercise time, fasting blood glucose, end-clamp M value (index of total body glucose disposal) and endothelin-1 levels were evaluated. RESULTS: Both in the short and long term (completed by 13 patients), on TMZ compared to placebo, ejection fraction (47 +/- 7 vs 41 +/- 9 and 45 +/- 8 vs 36 +/- 8%, P <.001 for both) and M value (4.0 +/- 1.8 vs 3.3 +/- 1.6, P =.003, and 3.5 +/- 1.5 vs 2.7 +/- 1.6 mg/kg body weight/min, P <.01) increased, while fasting blood glucose (121 +/- 30 vs 136 +/- 40, P =.02 and 125 +/- 36 vs 140 +/- 43, P =.19) and endothelin-1 (8.8 +/- 3.8 vs 10.9 +/- 3.8, P <.001 and 6.2 +/- 2.4 vs 9.2 +/- 4.3 pg/mL, P =.03) decreased. In the short term, 10 patients decreased 1 class on the NYHA scale during treatment with TMZ (P =.019 vs placebo). Eight patients decreased 1 NYHA class while on long-term TMZ treatment, while on placebo 1 patient increased 1 NYHA class and none improved (P =.018 vs placebo). CONCLUSIONS: In a short series of patients with diabetes and ischemic cardiomyopathy, TMZ improved left ventricular function, symptoms, glucose metabolism, and endothelial function. Shifting energy substrate preference away from fatty acid metabolism and toward glucose metabolism by TMZ appears an effective adjunctive treatment in patients with diabetes with postischemic cardiomyopathy.

Aged↗
PubMed2004

The acute administration of trimetazidine modified myocardial perfusion and left ventricular function in 31 patients with ischaemic ventricular dysfunction.

UNLABELLED: Trimetazidine (TMZ) increases the mithocondrial oxidative metabolism and improves Tc-99m sestamibi uptake in myocardial single photon emission tomography (SPECT). The aim of this study was to evaluate whether the acute administration of TMZ improved myocardial perfusion and modified left ventricular ejection fraction (LVEF) in ischaemic left ventricular impairment. METHODS: Thirty-one patients (23 males, age 66 years) with prior myocardial infarction (>6 months) and echocardiographic LVEF < or = 45% underwent coronary angiography, rest basal myocardial SPECT (after 3-day placebo administration) and rest TMZ myocardial SPECT [after 3-day TMZ administration (60mg/die)]. The left ventricle was analysed in 16 segments. The summed placebo score (SPS) and the summed TMZ score (STS) were calculated with a 5-point scale (from 0 = normal uptake to 4 = absent uptake) by two blinded operators. The GATED Tc-99m SPECT was always provided. RESULTS: After TMZ administration GATED LVEF improved from 26.5+/-9.7% to 29.1+/-11.3% (p = 0.04) and left ventricular end-systolic volume (LVESV) was reduced from 90.2+/-40.7 to 85.6+/-39.2 ml/mq (p = 0.006). Similarly the addition of TMZ to myocardial SPECT significantly reduced the STS compared to SPS (21.5+/-11 vs. 26.6+/-10.5 p = 0.0001). Eleven patients (35.5%) had an echocardiographic LVEF < or = 30%; in these patients who had severe ventricular dysfunction, GATED LVEF and LVESV did not change after TMZ (20.2+/-5.7% vs. 21+/-6.9% p =0.6; 116.7+/-35.3 ml vs. 112.6+/-32.3 ml p = 0.08, respectively). CONCLUSION: In comparison with placebo, the addition of TMZ to myocardial Tc-99m tetrofosmin SPECT improved myocardial perfusion and LVEF, reducing LVESV. These effects were lost in patients with more severe ventricular dysfunction.

Adult↗
PubMed2001

The effect of trimetazidine on the survival of rat island skin flaps subjected to ischemia-reperfusion injury.

The effect of trimetazidine (TMZ) on flap ischemia-reperfusion injury was investigated in rat inferior epigastric artery flaps. Twenty-six rats, divided into four experimental groups-nonischemic group (group 1, N = 5), ischemic control group (group 2, N = 7), preischemic TMZ-treated group (group 3, N = 7), and postischemic TMZ-treated group (group 4, N = 7)-were used. Rat inferior epigastric artery flaps were rendered ischemic by occluding the feeding femoral artery, and they were reperfused by releasing the clamps after 11 hours in groups 2 through 4. Group 3 rats were given TMZ (3 mg per kilogram, intravenously) diluted in saline before application of the clamp, and group 4 rats were given TMZ before clamp removal. Flap survival was scored on postoperative day 8. All flaps in the nonischemic control group (group 1) survived completely. The ischemic control group (group 2) demonstrated a 6.3 +/- 4.3% survival area. In the preischemic TMZ group (group 3) the mean survival area was 76.9 +/- 6.1%, and in the postischemic TMZ group (group 4) it was 76.8 +/- 5.6%. TMZ-treated flaps showed a significant increase in survival area regardless of the time of administration (p = 0.001, group 3 vs. group 2; p = 0.001, group 4 vs. group 2). This finding suggests that TMZ has a beneficial effect on the prevention or treatment of arterial ischemic flaps.

Animals↗
PubMed2000

Effect of trimetazidine on 99Tcm-tetrofosmin uptake in patients with coronary artery disease.

Myocardial uptake of 99Tcm-tetrofosmin in vivo is determined by a combination of flow and metabolic status of myocytes. The accumulation of tetrofosmin in the mitochondria is related to their ability to transduce metabolic energy into electronegative membrane potential. Trimetazidine (TMZ), an anti-ischaemic drug, appears to have a metabolic cytoprotective effect related to mitochondrial function, since it does not induce systemic or coronary haemodynamic changes. In this study, we evaluated the effects of TMZ on tetrofosmin uptake in hypoperfused myocardial regions in patients with coronary artery disease (CAD). Twenty-two patients, 14 with previous myocardial infarction (group A) and eight with a history of angina (group B), with angiographically documented CAD were studied. All patients underwent two tetrofosmin SPET studies at rest, before (baseline) and 1 week after TMZ administration (post-TMZ). On quantitative analysis, 131 segments showed less tetrofosmin uptake at baseline. In these segments, tetrofosmin uptake was 51 +/- 13% at baseline and 55 +/- 15% post-TMZ (P < 0.001 vs control). In the 86 hypoperfused segments of group A, tetrofosmin uptake was 48 +/- 14% at baseline and 52 +/- 17% post-TMZ (P < 0.001 vs control). In the 45 hypoperfused segments of group B, tetrofosmin uptake was 56 +/- 9% at baseline and 60 +/- 10% post-TMZ (P < 0.001 vs control). In the remaining 309 segments, no significant difference in tetrofosmin uptake before and after TMZ was observed. In conclusion, our results suggest that TMZ administration may increase myocardial uptake of tetrofosmin in hypoperfused regions at rest in patients with CAD, based on its metabolic effect.

Aged↗