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PubMed1999

Trimetazidine prevents cochlear lesions induced by intraperitoneal and perilymphatic administration of kainic acid.

The protective activity of trimetazidine (TMZ) against cochlear neurotoxicity induced by intraperitoneal and intracochlear administration of kainic acid (KA) has been analyzed. The amplitude of the CAP N1 wave was significantly higher in KA rats pretreated with TMZ, independently of the administration route, than in those only treated with KA. However, CAP N1 amplitude of both TMZ pretreated and non-pretreated animals was always lesser than the N1 wave amplitude observed in the control group. The CAP N1 latency did not show any significant difference between KA and TMZ+KA groups except at high intensities of 8 and 12 kHz. As a complementary control, we have demonstrated that the intraperitoneal administration of TMZ (5 mg/kg) alone did not affect either the electrophysiological activity or the morphology of the auditory nerve. Morphological results fit well with electrophysiology. Some isolated swollen afferent fibers were observed in TMZ+KA cochleae, the swollen dendrites being sparser than in the KA only treated animals. In TMZ+KA animals, the cochlear apical coils were less affected than the basal coils. Our results are in agreement with recent clinical studies and suggest that TMZ could be an active drug on cochlear impairment linked to hypoxic-ischaemic syndromes.

Animals↗
PubMed2002

Acute effects of heparin administration on the ischemic threshold of patients with coronary artery disease: evaluation of the protective role of the metabolic modulator trimetazidine.

OBJECTIVES: We sought to assess the effects of heparin and the potential protective effects of trimetazidine (TMZ) on exercise performance, plasma nitric oxide (NO), endothelin-1 (ET-1) and free fatty acid (FFA) release in patients with stable coronary artery disease (CAD). BACKGROUND: Heparin has been shown to reduce the ischemic threshold in patients with CAD. Trimetazidine may affect myocardial substrate utilization by shifting energy production from FFA to glucose oxidation. METHODS: In four consecutive days, nine patients with CAD each received one of the following four regimens: 1) one tablet of placebo the evening before and at 8 AM and 4 PM on the day of the study, 10 ml of saline in a bolus 10 min before exercise, followed by an infusion of the same preparation; 2) placebo at the same times as in the first regimen, 5,000 IU of heparin 10 min before exercise, followed by 1,000 IU/h; 3) 20 mg TMZ at the same times as in the first regimen, 5,000 IU of heparin 10 min before exercise, followed by 1,000 IU/h; or 4) TMZ at the same times as in the first regimen, 10 ml of saline 10 min before exercise, followed by an infusion of the same preparation. RESULTS: During placebo (test 2), heparin reduced the time to 1-mm ST-segment depression and prolonged the recovery time, as compared with the results of test 1. When heparin was administered after TMZ (test 3), the time to 1-mm ST-segment depression and the recovery time were similar to those recorded during saline (test 1). Finally, compared with all study phases, TMZ during saline (test 4) prolonged the time to 1 mm. No changes in NO release were found, whereas ET-1 was decreased at peak exercise and during recovery, when the patients were receiving TMZ (tests 3 and 4). Free fatty acids increased after heparin, both with placebo and TMZ. CONCLUSIONS: In patients with CAD, heparin reduces the ischemic threshold. Trimetazidine reduces the effects of heparin, probably by inhibiting FFA oxidation and enhancing glucose metabolism. The concomitant novel observation of reduced ET-1 release is likely to be also dependent on TMZ-induced improvement of endothelial metabolism or reduction of myocardial ischemia.

Aged↗
PubMed2000

Influence of cold-storage conditions on renal function of autotransplanted large pig kidneys.

BACKGROUND: The consequences of ischemia/reperfusion injury (IRI) on delayed graft function (DGF) and graft survival for kidney recipients remain a matter of debate. Several strategies have been proposed to reduce IRI. We have shown that adding the anti-ischemic drug trimetazidine (TMZ) to different preservation solutions had beneficial effects on the function of reperfused rat and pig kidneys. METHODS: We analyzed the renal parameters of reperfused, autotransplanted large pigs following transplantation. The left kidneys were first removed and cold flushed with Euro-Collins (EC) and University of Wisconsin (UW) solutions (with or without 10-6 mol/L TMZ) and were stored for 48 hours at 4 degrees C. The kidney was then autotransplanted, and the contralateral kidneys were removed. Creatinine clearance, natriuresis, proteinuria, the degree of interstitial fibrosis, the number of CD4, CD8, and macrophage-positive cells, and the amount of vascular cell adhesion molecule-1 were analyzed on kidney biopsies taken at 2, 4 to 5, and 10 to 12 weeks after surgery. RESULTS: The functions of the transplanted kidneys were better preserved after cold flushing with TMZ-supplemented solutions than with TMZ-free solutions. Creatinine clearance was higher, and proteinuria was lower in animals transplanted with kidneys cold flushed with TMZ-supplemented solutions than with TMZ-free solutions. The cytoprotective action of TMZ also reduced interstitial fibrosis and the numbers of infiltrating CD4- and CD8-positive cells. CONCLUSION: These results indicate that the condition of cold preservation may influence long-term kidney graft functions and suggest that, to a certain extent, TMZ reduces the degree of interstitial fibrosis.

Animals↗
PubMed2000

A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.

Adult↗
PubMed1990

Therapeutic value of a cardioprotective agent in patients with severe ischaemic cardiomyopathy.

Trimetazidine (TMZ) has been shown to have anti-ischaemic properties improving exercise tolerance without haemodynamic effects. A 6-month double-blind placebo-controlled study was carried out in 20 patients, mean age 59 +/- 6 years, to examine the benefit of adding 60 mg of TMZ vs placebo to the classical therapy, excluding those previously treated with calcium-antagonists, conversion enzyme inhibitors, vasodilators and antiplatelet agents. All patients had severe ischaemic cardiomyopathy, confirmed by coronary angiography; six were in NYHA class IV; 14 in NYHA class III; four had mild recurrent angina pectoris. assessment included clinical and biological evaluation, electrocardiography (ECG), 24-h ECG monitoring, cardiac volume evaluation with chest X-ray, left ventricular fractional shortening by echocardiography, left ventricular ejection fraction by radionuclide angiography. Baseline characteristics were similar in placebo (11 patients) and TMZ (nine patients) groups. Eighteen patients (nine in each group) were followed up for 6 months. In eight patients of the placebo group, treatment had to be modified (addition of calcium antagonists: four patients, conversion enzyme inhibitors: two patients; digitalics: one patient; diuretics: one patient). In the TMZ group, digitalic therapy was withdrawn in one patient and added in one patient (P less than 0.01). At 6 months, all TMZ group patients were free from angina; dyspnoea was improved in all TMZ patients and in only one placebo patient (P less than 0.001). Ejection fraction, increased by 9.3% in the TMZ group and decreased by 15.6% in the placebo group (P less than 0.018), CV decreased by 7% with TMZ, increased by 4% with placebo. (P = 0.034).(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1997

Trimetazidine prevents renal injury in the isolated perfused pig kidney exposed to prolonged cold ischemia.

BACKGROUND: Ischemia caused by cold storage (CS) and reperfusion of the kidney is often responsible for delayed graft function after transplantation. Significant attention has been focused on the cascade of events involved in ischemia-reperfusion injury, with the objective of identifying drugs to ameliorate the functional damage that occurs. METHODS: The purpose of this study was to evaluate the renal function of isolated perfused pig kidneys after 48 hr of CS with Euro-Collins (EC) solution plus trimetazidine (EC+TMZ), standard EC solution, or University of Wisconsin (UW) solution. Normothermic isolated perfused pig kidneys were randomized into five experimental groups: (A) control group (cold flush with cold heparinized saline and immediately reperfused; n=6); (B) cold flush with cold heparinized saline with TMZ (10(-6) M), n=6; (C) 48 hr of CS with EC and reperfusion (n=8); (D) 48 hr of CS with EC+TMZ alone and reperfusion (n=8); (E) 48 hr of CS with UW and reperfusion (n=8). Proton nuclear magnetic resonance spectroscopy and biochemical studies were performed for the functional evaluation during reperfusion. Lipid peroxidation was also determined. Histological examination (optical and electron microscopy) was performed after CS and reperfusion. RESULTS: Using TMZ, the renal perfusate flow rate as well as the glomerular filtration rate and proximal tubular function were significantly improved. This improvement of renal function during reperfusion was correlated with a less significant cellular and interstitial edema. In addition, tubular injury markers were significantly lower in the group preserved with EC+TMZ, and TMZ reduced lipid peroxidation dramatically during reperfusion. CONCLUSIONS: The addition of TMZ to the EC solution increased the preservation quality and renal tubular function, and gave protection from reperfusion injury better than EC alone or UW. These results strongly suggest that TMZ has a cytoprotective effect and may therefore be useful for kidney preservation.

Adenosine↗
PubMed2004

Phase 1 study of 28-day, low-dose temozolomide and BCNU in the treatment of malignant gliomas after radiation therapy.

We conducted a study to determine the dose-limiting toxicity of an extended dosing schedule of temozolomide (TMZ) when used with a fixed dose of BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine), taking advantage of TMZ's ability to deplete O6-alkylguanine-DNA-alkyltransferase and the synergistic activity of these two agents. Patients with malignant gliomas who had undergone radiation therapy were eligible. Patients were treated with TMZ for 28 days, followed by a 28-day rest (1 cycle). The TMZ was started at 50 mg/m2 and increased in 10-mg/m2 increments; a fixed dose of BCNU (150 mg/m2) was given within 72 h of starting TMZ. A standard phase 1 dose-escalation scheme was used with 3 patients per cohort. Fourteen glioblastoma patients and 10 anaplastic astrocytoma patients were treated. The dose-limiting toxicity was myelosuppression at 90 mg/m2 of TMZ. The total number of cycles given was 73 (median number was 2). Six patients (25%) required a dose reduction in BCNU, and six were removed from study for hematologic toxicity after cycle 1; three patients overlapped. The median time to progression and overall survival were, respectively, 82 and 132 weeks for anaplastic astrocytomas and 14 and 69 weeks for glioblastomas. We conclude that the combination of BCNU and the extended dosing schedule of TMZ is feasible and that the maximal tolerated dose of a 28-day course of TMZ is 80 mg/m2 when combined with a fixed dose of BCNU at 150 mg/m2. This is the recommended dose for phase 2, but myelosuppression after cycle 1 suggests that long-term treatment may be difficult.

Adult↗
PubMed1999

O(6)-benzylguanine enhances the in vitro immunotoxic activity of temozolomide on natural or antigen-dependent immunity.

Temozolomide (TMZ) is a new cytotoxic triazene compound of clinical interest that is able to generate methyl adducts at the O(6)-guanine of DNA, which can be repaired by O(6)-alkylguanine-DNA alkyltransferase (OGAT). It was previously found that triazene compounds are highly immunosuppressive in mice. In the present study, we investigate whether TMZ could affect immune functions of human competent cells and whether methylation of O(6)-guanine could be involved in the immunosuppressive activity of the drug. Mononuclear cells (MNCs) obtained from peripheral blood of healthy donors were tested for OGAT activity and treated with TMZ alone or combined with the OGAT inhibitor O(6)-benzylguanine. Control or drug-treated MNCs were then assayed for natural killer activity and for the ability to proliferate and to generate cytotoxic effector cells in response to interleukin-2 or allogeneic MT-2 tumor cells. The results show that TMZ inhibited both proliferation and induction of lytic activity in response to interleukin-2 or allogeneic MT-2 cells. Moreover, an inverse correlation was found between the OGAT activity of MNCs and their sensitivity to TMZ. The involvement of O(6)-guanine methylation in the immunosuppressive effects of TMZ was further confirmed by the finding that O(6)-benzylguanine increased the activity of the drug. On the other hand, the natural killer activity of MNCs was only moderately affected by TMZ, and no relationship was observed between OGAT levels and sensitivity to the drug. These data suggest that in patients with tumors who are undergoing TMZ treatment, the drug may impair immune responses involving cell proliferation, depending on OGAT levels of MNCs, and that O(6)-benzylguanine may potentiate this activity.

Antibody-Dependent Cell Cytotoxicity↗
PubMed2003

Systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma.

PURPOSE: Temozolomide (TMZ) is a DNA methylating agent that has shown promising antitumor activity in recent clinical trials against high grade gliomas, metastatic melanoma, and brain lymphoma. In this study, we tested whether systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase (PARP-1) inhibitor capable of crossing the blood-brain barrier, could enhance the efficacy of TMZ against metastatic melanoma, glioblastoma multiforme, and lymphoma growing in the brain. EXPERIMENTAL DESIGN: Murine B16 melanoma or L5178Y lymphoma cells were injected intracranially in syngeneic mice. An orthotopic xenograft of the human SJGBM2 glioblastoma multiforme was implanted in nude mice. Animals were treated with TMZ + GPI 15427 using a schedule of 40 mg/kg/i.v. GPI 15427 + 100 mg/kg/i.p. TMZ for 3 days. The efficacy of drug treatment was assessed by: (a) the increase of mouse survival and life span; and (b) the suppression of melanoma metastases to lung after i.v. injection of B16 cells. RESULTS: In all models, systemic administration of GPI 15427 shortly before TMZ significantly increased life span of tumor-bearing mice with respect to untreated controls or to groups treated with either GPI 15427 or TMZ only. Moreover, GPI 15427 increased the antimetastatic effect of TMZ. CONCLUSIONS: These data indicate that systemic administration of the poly(ADP-ribose) polymerase-1 inhibitor GPI 15427 significantly enhances TMZ antitumor efficacy against solid or hematological neoplasias even when located at the central nervous system site.

Animals↗
PubMed2006

Potentiation of antiglioma effect with combined temozolomide and interferon-beta.

Temozolomide (TMZ) is a DNA methylating agent that has shown promising antitumor activity against high grade glioma. Interferon-beta (IFN-beta) is known to have antiproliferative and antiangiogenic activities. The aim of this study was to elucidate whether an antiglioma effect could be potentiated by the combination of TMZ and IFN-beta. In vitro, the combination of these drugs suppressed the proliferative and migratory activities, as well as enhance of the apoptosis and cell cycle (S phase) arrest of U-87 cells more efficiently than TMZ or IFN-beta alone. IFN-beta exerted a potent inhibitory effect on the proliferation of human umbilical vein endothelial cells (HUVEC); however, no additive or synergistic effect was observed with the addition of TMZ. To determine in vivo effect, nude mice bearing intracerebral U-87 xenograft inoculation were treated with intraperitoneal administration of PBS, TMZ (15 mg/kg for 3 days), IFN-beta (2x10(5) IU for 15 days), and a TMZ + IFN-beta combination. The combined treatment (median 62.0+/-8.6 days, P=0.0005) was observed to significantly increase the survival of the animals compared to treatment with PBS (median 30.0+/-2.5 days), TMZ (median 41.0+/-3.5 days) or IFN-beta (mean 36.0+/-2.5 days). These results suggest that antiglioma activity can be enhanced by the combination of TMZ and IFN-beta, providing the possibility for a new strategy development in the management of malignant glioma.

Animals↗
PubMed1995

Trimetazidine effects on the damage to mitochondrial functions caused by ischemia and reperfusion.

Trimetazidine (TMZ) is an anti-ischemic compound whose precise mode of action is unknown, although several studies have suggested a metabolic effect, and there have been reports of protection of mitochondria against oxidative stress damage. Using a Langendorff rat heart model, we examined the effects of TMZ on the mitochondrial damage following 30 minutes of ischemia and 5 minutes of reperfusion. Mitochondrial respiration with succinate, glutamate-malate and ascorbate-N,N,N',N'-tetramethylphenylenediamine (TMPD) as substrates was significantly decreased following ischemia-reperfusion. Preperfusion with 10(-5) M TMZ had no effect on these rates in normoxic or ischemic hearts. However, 10(-3) M TMZ significantly decreased the glutamate-malate rate in mitochondria from normoxic hearts, and this rate was not further decreased following ischemia-reperfusion, and 10(-3) M TMZ also partially protected ascorbate-TMPD activity. The effect on glutamate-malate was probably due to an inhibition of complex I by TMZ, which specifically inhibited reduced nicotinamide-adenine-dinucleotide-cytochrome c reductase and complex I in lysed mitochondria. We also studied the effects of TMZ on the activity of pyruvate dehydrogenase (PDH) in normoxic and ischemic hearts perfused with 0.5 mM palmitate, which caused the enzyme to be almost completely inactivated. After short periods of ischemia (10-20 minutes) the PDH inactivation by palmitate was progressively lost. Preperfusion with 10(-5) M TMZ had a tendency to decrease lactate dehydrogenase release, accompanied by a maintenance of the inhibition of PDH by palmitate. This may allow the heart to oxidize fatty acids preferentially during reperfusion, hence removing possible toxic acyl esters.

Animals↗
PubMed1996

Trimetazidine reverses calcium accumulation and impairment of phosphorylation induced by cyclosporine A in isolated rat liver mitochondria.

When applied to rat liver mitochondria in contact with Ca++, cyclosporine A (CsA) induced both an accumulation of this ion and a decrease in oxidative phosphorylation. Trimetazidine (TMZ) reversed both phenomena in a dose-dependent manner. These two effects were demonstrated in separate experiments. A decrease in oxidative phosphorylation was observed with succinate as substrate. V3 and P/O (ratio corresponds to the number of ADP molecules added in the medium per oxygen atom consumed during phosphorylation and represents the yield of ATP synthesis) were simultaneously decreased by CsA (1 microM) and restored by TMZ. Ca++ accumulation in mitochondria was observed when it was added to the mitochondrial suspension; its uptake was followed by a new equilibrium. CsA prolonged its duration, whereas TMZ reduced it in a dose-dependent manner. The same phenomenon was observed when ADP was used instead of CsA. Ca++ efflux from mitochondria could be induced by TMZ without the addition of CsA. It was immediate and always partial and followed by a reuptake process only observed at concentrations of TMZ of >1 microM. Compared with ruthenium red, which blocks Ca++ uniporter, TMZ seemed to act on Ca++ efflux mechanisms. Interestingly, low TMZ doses promote a Ca++ efflux process without activating reentry mechanism, which may explain the correction of deleterious effect of CsA on V3 and P/O. As nephrotoxicity observed in humans after CsA chronic administration is considered to be related, at least in part, to an alteration of Ca++ intracellular homeostasis, TMZ seems to be a candidate for alleviation of CsA nephrotoxic effects in humans.

Animals↗
PubMed1999

Simultaneous protection of G156A methylguanine DNA methyltransferase gene-transduced hematopoietic progenitors and sensitization of tumor cells using O6-benzylguanine and temozolomide.

O6-Benzylguanine (BG) potentiates temozolomide (TMZ) cytotoxicity in tumors by inactivating O6-alkylguanine DNA alkyltransferase but also increases toxicity in hematopoietic cells. To improve the hematopoietic cell tolerance to alkylating agents, we retrovirally transduced the BG-resistant mutant G156A methylguanine DNA methyltransferase gene (deltaMGMT) into hematopoietic progenitors and evaluated whether deltaMGMT expression in hematopoietic colony-forming units would result in greater drug resistance to TMZ. DeltaMGMT expression in human and mouse colony-forming units followed by BG treatment resulted in a >7.7-fold increase in the TMZ 90% inhibitory concentration (IC90) and a 5.6-fold increase in the 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) IC90 relative to untransduced cells. This degree of protection enabled deltaMGMT-transduced CD34 cells to become much more resistant to BG and TMZ than SW480 cells, which express high O6-alkylguanine DNA alkyltransferase and are normally resistant to TMZ or BCNU alone. DeltaMGMT-transduced long-term culture initiating cells were also resistant to the BG and TMZ combination, as were untransduced long-term culture initiating cells, suggesting that noncycling early progenitors may be partially protected from TMZ. These data indicate that retroviral transduction of deltaMGMT into hematopoietic progenitors followed by BG and TMZ treatment may selectively protect hematopoietic cells more efficiently than BCNU, allowing dose-intensive and repetitive therapy without the risk of cumulative myelosuppression.

Animals↗
PubMed2025

Circadian variation in MGMT promoter methylation and expression predicts sensitivity to temozolomide in glioblastoma.

PURPOSE: Recent studies show that glioblastoma (GBM) is more sensitive to temozolomide (TMZ) in the morning. In cells, inhibiting O6-Methylguanine-DNA-Methyltransferase (MGMT) abolished time-dependent TMZ efficacy, suggesting that circadian regulation of this DNA repair enzyme underlies daily TMZ sensitivity. Here, we tested the hypotheses that MGMT promoter methylation and protein abundance vary with time-of-day in GBM, resulting in daily rhythms in TMZ efficacy. METHODS: We assessed daily rhythms in MGMT promoter methylation in GBM in vitro and retrospectively analyzed MGMT methylation status in human GBM biopsies collected at different times of day. Next, we measured MGMT and BMAL1 protein abundances in GBM cells collected at four-hour intervals. To understand the therapeutic implications of circadian variations in MGMT, we incorporated its daily rhythms into an in vitro mathematical model capturing interactions between MGMT, TMZ, and GBM DNA. RESULTS: We found daily rhythms in MGMT promoter methylation and protein levels in GBM in vitro, and in patient biopsies peaking at midday. Further, MGMT protein levels peaked at CT4, corresponding to the time of maximal TMZ efficacy in vitro. When we incorporated cell-intrinsic circadian rhythms in MGMT protein into a mathematical model for GBM chemotherapy, we found that dosing when daily MGMT levels peaked and began to decline produced maximum DNA damage. CONCLUSION: Our findings suggest that the likelihood of diagnosis of MGMT promoter methylation may vary with time of biopsy in GBM. Furthermore, theoretical modeling predicts that efforts to deliver TMZ after the daily peak of MGMT activity, with exact time being dose-dependent, may significantly enhance its therapeutic efficacy.

Humans↗
PubMed2003

Temozolomide in combination with interferon alpha-2b in patients with metastatic melanoma: a phase I dose-escalation study.

BACKGROUND: Metastatic melanoma (MM) is associated with a high risk of central nervous system (CNS) metastases, and current chemotherapy does not adequately treat or protect patients with MM against CNS metastases. Therefore, the authors initiated a Phase I study to determine the pharmacokinetics and safety profile of temozolomide (TMZ), a novel oral alkylating agent known to cross the blood-brain barrier, in combination with interferon alpha-2b (IFN-alpha2b). METHODS: Twenty-three patients with MM were enrolled in this single-center, open-label study. Patients with CNS metastasis were excluded. One cohort (n = 6 patients) received oral TMZ (200 mg/m(2) per day) for 5 days every 28-day cycle plus subcutaneous IFN-alpha2b (5 million International Units [MIU]/m(2) per day, 3 times per week). A second cohort (n = 17 patients) received TMZ 150 mg/m(2) per day on the same schedule plus escalating doses of IFN-alpha2b (5.0 MIU/m(2) per day, 7.5 MIU/m(2) per day, and 10 MIU/m(2) per day 3 times per week). RESULTS: The most common adverse events were fatigue, fever, nausea/emesis, anxiety, and diarrhea. Most toxicity was mild to moderate in severity. The primary dose-limiting toxicity was thrombocytopenia. The maximum tolerated dose was either TMZ 150 mg/m(2) plus IFN-alpha2b 7.5 MIU/m(2) or TMZ 200 mg/m(2) plus IFN-alpha2b 5.0 MIU/m(2). Four patients (17%) had objective responses (one complete response and three partial responses), and four patients had stable disease. The median survival was 9 months. The pharmacokinetics of TMZ were not affected by coadministration of IFN-alpha2b. CONCLUSIONS: TMZ can be combined safely with IFN-alpha2b. This regimen demonstrated clinical activity in patients with MM and merits further investigation to define its effect on the incidence of brain metastases.

Adult↗
PubMed2006

The anti-ischemic effect of trimetazidine in patients with postprandial myocardial ischemia is unrelated to meal composition.

BACKGROUND: Previous studies provide evidence for a significant reduction of coronary flow reserve after ingestion of meals of different compositions. A possible role of hyperinsulinemia and increased free fatty acid levels, which are deleterious during acute myocardial ischemia and reperfusion, has been hypothesized. We assessed in patients with stable coronary disease the effects of high-fat meals (HFMs) and high-carbohydrate meals (HCMs) on ischemic threshold and stress left ventricular function on placebo and after partial fatty acid inhibition by trimetazidine (TMZ). METHODS: Ten patients (9 men, age 68 +/- 7 years) were allocated to placebo and TMZ (40 mg TID), both administered in the 24 hours preceding testing, according to a randomized double-blind study design. All patients underwent stress (treadmill exercise testing according to the Bruce protocol) echocardiography after fasting (8 hours) and after an HFM and HCM (2 hours) either on placebo or on TMZ. Time to 1-mm ST-segment depression (time to 1 mm) and stress wall motion score index (WMSI) were evaluated. RESULTS: An HFM did not affect exercise variables compared with fasting, whereas an HCM resulted in a reduction of the ischemic threshold (time to 1 mm from 402 +/- 141 to 292 +/- 123 seconds, P = .025). Compared with placebo, TMZ improved time to 1 mm after fasting, HFM, and HCM (432 +/- 153 vs 402 +/- 141, 439 +/- 118 vs 380 +/- 107, 377 +/- 123 vs 292 +/- 123, F(1,9) = 26.91, P = .0006). Compared with placebo, on TMZ, stress WMSI decreased from 1.55 +/- 0.25 to 1.29 +/- 0.14 after fasting, from 1.57 +/- 0.10 to 1.39 +/- 0.28 after HFM, and from 1.64 +/- 0.21 to 1.39 +/- 0.21 after HCM (F(1,9) = 37.04, P = .0002). Interestingly, stress WMSI on TMZ was never different from rest WMSI on placebo. CONCLUSIONS: In patients with coronary disease, exercise testing after an HCM results in more severe myocardial ischemia compared with that after an HFM. The observed beneficial effects of the partial fatty acid inhibitor TMZ seem to be unrelated to meal composition and are possibly caused by the better glucose use induced by the drug.

Aged↗
PubMed2006

Placebo or trimetazidine (99m)Tc tetrofosmin myocardial SPECT and low-dose dobutamine echocardiography in hibernating myocardium.

BACKGROUND: Trimetazidine (TMZ) improves (99m)Tc sestamibi uptake in myocardial single photon emission tomography (SPECT). This study compared TMZ (99m)Tc tetrofosmin SPECT and low-dose dobutamine echocardiography (LDDE) as predictors of functional recovery of hibernating myocardium after coronary revascularization. METHODS: Thirty-one patients with prior myocardial infarction and left ventricular dysfunction underwent coronary angiography, LDDE, placebo SPECT and TMZ SPECT. Echocardiographic follow-up was obtained at 2/6 months; the clinical follow-up lasted 2 years. RESULTS: Twenty-three (74.2%) patients (195 dysfunctioning left ventricular segments) were revascularized. TMZ improved (99m)Tc tetrofosmin uptake (p = 0.0001) as well as LVEF at gated SPECT (p = 0.04). At 2-months, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated (LDDE 71.9, 78.7, 71, 79.5; placebo SPECT 66.2, 75.6, 65.4, 76.3; TMZ SPECT 79.2, 67.7, 61.6, 83.3, respectively). The specificity improved in placebo and TMZ SPECT (82.1 and 78.7%) at 6-months follow-up. Two patients (2/23) with hibernating myocardium treated with revascularization and three (3/4) treated medically died a cardiac death (p = 0.0016, log rank 12.89). None (0/4) without viability died during the 2-year follow-up (p = 0.6, log rank 0.28). CONCLUSIONS: The addition of TMZ to (99m)Tc tetrofosmin SPECT improved diagnostic accuracy. The importance of hibernating myocardium revascularization was confirmed.

Adult↗
PubMed2005

Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial.

PURPOSE: To evaluate the safety profile and efficacy of whole brain radiotherapy (WBRT) concomitantly with temozolomide (TMZ) in patients with brain metastases (BM). METHODS AND MATERIALS: Patients with BM were randomly assigned to 30 Gy of WBRT with or without concomitant TMZ (75 mg/m(2)/d) plus two cycles of TMZ (200 mg/m(2)/d for 5 days). The primary outcome was analysis of neurologic toxicity. The primary efficacy measures were 90-day progression-free survival of BM and the radiologic response at Days 30 and 90. RESULTS: We enrolled 82 patients. No neurologic acute toxicity was observed. Grade 3 or worse hematologic toxicity was seen in 3 patients and Grade 3 or worse vomiting in 1 patient of the WBRT plus TMZ arm. The objective response rate at 30 and 90 days and overall survival were similar in both arms. The percentage of patients with progression-free survival of BM at 90 days was 54% for WBRT vs. 72% for WBRT and TMZ (p = 0.03). Death from BM was greater in the WBRT arm (69% vs. 41%, p = 0.03). CONCLUSION: The concomitant use of RT with TMZ was well tolerated and resulted in significantly better progression-free survival of BM at 90 days. Although caution should be used, these results suggest TMZ could improve local control of BM.

Aged↗