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PubMed2001

The effect of trimetazidine on C-reactive protein, cytokines and adhesion molecules in the course of acute myocardial infarction.

The aim of this randomised, double-blind, placebo controlled, parallel group study was to assess the effect of trimetazidine (TMZ), a potent antiischaemic drug, on plasma C-reactive protein (C-RP), cytokine and adhesion molecule levels. The study population consists of 18 patients (16 males, 2 females, average age 56.45 +/- 10.97 years) with acute myocardial infarction admitted within 6 hours after onset of symptoms and treated with streptokinase. Blood samples were taken at 3-hour intervals during the time of treatment. All patients were randomised blindly using a centralised randomisation process, between trimetazidine (40 mg bolus i.v. then 60 mg per day for 48 hours intravenously in glucose infusion) or placebo group. Plasma C-RP level was significantly lower in TMZ group (39.5 mg/ml +/- 9.7 mg/ml) as compared to placebo (75.7 +/- 29.4 mg/ml, p < or = 0.001) and peaked 28 hours later in TMZ group. Plasma interleukin 6 (IL 6) level showed a sharp peak 9 hours after the onset of the symptoms in TMZ group (116.9 +/- 180.2 pg/ml vs. 45.4 +/- 37.9 pg/ml) and was increased up to 30 hours after the onset of the symptoms. Plasma interleukin 1 beta (IL 1 beta) was also higher in TMZ group notably 21 hours after the onset of symptoms (26.4 +/- 9.3 pg/ml vs. 16.2 +/- 2.4 pg/ml). TMZ group showed lower plasma E-selectin levels. Plasma IL 8, TNF alpha and ICAM 1 levels were without statistical significant differences. The present study demonstrates a significant reduction of plasma C-reactive protein level in the course of acute myocardial infarction treated with streptokinase and intravenous trimetazidine infusion compared with the group of patients without trimetazidine treatment.

C-Reactive Protein↗
PubMedDate not supplied

The effect of oxidative stress inhibition with trimetazidine on the peritoneal alterations induced by hypertonic peritoneal dialysis solution.

BACKGROUND: Chronic peritoneal dialysis (PD) can result in several peritoneal alterations of varying degree, which lead to progressive reduction in dialytic efficacy. Although its pathogenesis has not been clarified yet, it has been proposed that high glucose induced oxidative stress generation within the peritoneal membrane plays an important role in leading to membrane alterations. The aim of this study was to investigate the effect of oxidative stress inhibition on peritoneal alterations induced by hypertonic PD solutions in rats. METHODS: The rats were divided into three groups receiving no treatment (the control group), hypertonic PD solution intraperitoneally (ip) only (the hypertonic dextrose group) and hypertonic PD solution ip plus trimetazidine (TMZ) orally (TMZ group). After 4 weeks, a one-hour peritoneal equilibration test (PET) was performed. Dialysate-to-plasma urea ratio (D/P urea), glucose reabsorption (D(1)/D(0) glucose), ultrafiltration volume (UF) and the level of dialysate protein were determined. The levels of malondialdehyde (MDA), vascular endothelial growth factor (VEGF) and the activity of glutathione peroxidase (GPx) were investigated in the peritoneal tissue lysates. The peritoneal membrane was evaluated histologically by light microscopy. RESULTS: Compared to the control group, peritoneal function tests (UF: 3.6 +/- 0.4 vs. 1.2 +/- 0.6 mL, D/P urea: 0.57 +/- 0.03 vs. 0.76 +/- 0.04, D(1)/D(0) glucose: 0.46 +/- 0.02 vs. 0.33 +/- 0.05) and morphology (thickness: 4.4 +/- 0.5 vs. 61 +/- 14 micro m and neovascularisation: 0.2 +/- 0.4 vs 2.4 +/- 0.8 number/field) were dramatically altered in the hypertonic PD solution-treated rats. Likewise, higher levels of VEGF, MDA and decreased activity of GPx were determined in the hypertonic PD solution-treated rats. Although peritoneal thickness (37 +/- 17 micro m) was not completely decreased, peritoneal functions were protected in the TMZ group (UF: 4.0 +/- 0.4 mL, D/P urea: 0.62 +/- 0.06, D(1)/D(0) glucose: 0.43 +/- 0.02). In the TMZ group, MDA and VEGF levels and neoangiogenesis were significantly less than those of the hypertonic dextrose group. In addition, GPx activity significantly increased in the TMZ group. CONCLUSIONS: These data demonstrated that not only generating oxidative stress but also attenuating antioxidative system and high glucose concentration can cause structural and functional alterations within the peritoneal membrane. TMZ can preserve these alterations by inhibiting the oxidative stress within the peritoneal membrane.

Analysis of Variance↗
PubMed2005

Brain distribution and efficacy as chemosensitizer of an oral formulation of PARP-1 inhibitor GPI 15427 in experimental models of CNS tumors.

We previously demonstrated that intravenous or intra-cerebral administration of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors increases the antitumor activity of temozolomide (TMZ), an oral anticancer drug used for the treatment of malignant melanoma and primary or secondary brain tumors. Since the oral route has a number of advantages in terms of safety and convenience with respect to intravenous injection, in this study we tested whether administration per os of the novel PARP-1 inhibitor GPI 15427 allows sufficient absorption of the compound and achievement of brain concentrations capable of enhancing the efficacy of TMZ against tumors growing at the CNS. Pharmacokinetics analysis of GPI 15427 levels in plasma and brain was assessed in Sprague-Dawley rats after oral dosing, by liquid chromatography and tandem mass spectrometry. Antitumor activity of oral GPI 15427 in association with TMZ was evaluated in BD2F1 mice injected intracranially with B16 melanoma or L5178Y lymphoma. Pharmacokinetics studies revealed that GPI 15427 possesses a substantial oral bioavailability (plasma Cmax after a single dose of 40 mg/kg: 1041+/-516 ng/ml). Moreover, the brain levels and brain/plasma ratios of GPI 15427 (3.37 at 0.5 h and 3.19 at 1 h) indicated that the compound readily penetrates the blood-brain barrier. GPI 15427 (10 or 40 mg/kg/per os) was then administered for five days, 1 h before TMZ (100 mg/kg/i.p.), to tumor-bearing mice. The results indicated that GPI 15427+TMZ was well tolerated and significantly increased life-span of the animals with respect to TMZ. In conclusion, PARP-1 inhibitor GPI 15427 is efficacious as chemosensitizer for the treatment of tumors located at the CNS site when it is administered by oral route.

Administration, Oral↗
PubMedDate not supplied

Temozolomide and cisplatin in avdanced malignant melanoma.

BACKGROUND: Temozolomide (TMZ) is an oral alkylating agent; it produces DNA methyl adducts, which are removed by the DNA repair enzyme AGAT. In vitro studies suggest that CDDP may enhance the antitumor activity of TMZ due to the ability of cisplatin (CDDP) to down-regulate AGAT activity. In a previous phase I study, the combination of TMZ and CDDP was tested, and the recommended dose for each drug was defined. On the basis of these results, we designed a phase II study to evaluate the activity and safety profile of the TMZ-CDDP association in patients with advanced melanoma. PATIENTS AND METHODS: From March 2001 to March 2002, 37 patients with metastatic melanoma, not amenable to surgery, were enrolled in this study. All eligible patients were treated with the combination of CDDP 75 mg/m2 i.v. d 1, TMZ 200 mg/m2 p.o. days 1-5 recycled every 4 weeks. Interferon alpha2b (IFN alpha2b) was administered at the end of chemotherapy to responsive patients at the dose of 5 M.I. U s.c. 3 times a week for 1 year. RESULTS: A total of 174 courses were administered, with a median number of 4 courses/patient (range 1-10). After chemotherapy, 9 CRs and 9 PRs were observed for an overall response rate of 48.6% (95% C.I., 31.9%-65.6%). One of 5 patients with initial brain metastases showed a complete response to the therapy. Five out of 9 CR patients were still with no evidence of recurrence, ranging from 28+ to 82+ weeks. The median survival time was 48 weeks. The schedule was well tolerated, with the most frequent adverse events reported being nausea and vomiting (59%), alopecia (14%) and fatigue (11%), all well controlled by supportive therapy. Haemotological toxicities were mild to moderate. Side-effects attributable to IFN alpha2b were also mild and manageable. CONCLUSION: The combination of TMZ and CDDP seems to be active in untreated patients with advanced melanoma. Absence of recurrence in the majority (5/9; 56%) of CR patients seems to indicate that IFN may act on the duration of the response to chemotherapy. The schedule was well tolerated, with nausea and vomiting as the most frequent adverse events.

Adult↗
PubMed2005

Evaluation of the effect of trimetazidine on Tc-99m methoxyisobutyl isonitrile gated scintigraphy in patients with coronary artery ectasia.

OBJECTIVE: Coronary artery ectasia (CAE) is the abnormal dilatation of a segment of the coronary artery to a diameter of at least 1.5 times that of normal adjacent segments. Symptoms are variable, and its prognosis and treatment modalities are unclear. The aim of this study is to evaluate the effect of trimetazidine (TMZ) on ischemic left ventricular function by rest-stress Tc-99m methoxyisobutyl isonitrile (Tc-99m MIBI) myocardial scintigraphy in symptomatic patients with CAE. METHODS: We included patients with ectasia admitted to our Cardiology Department, Turkey, between 2003 and 2004 in this study. All patients underwent coronary angiography and diagnosed with CAE, before and 4 weeks after TMZ administration. Seventeen patients (9 men, 8 women) underwent gated single-proton emission tomographic (SPECT) using Tc-99m MIBI. We performed quantitative global and regional ventricular functional analysis using quantitative gated SPECT software. RESULTS: The global ejection fraction increased from 59.9%+/-8.9% to 62.6%+/-8.3% after therapy (p=0.033). In addition, the end systolic volume and the end diastolic volume decreased after therapy (101.7+/-23.5 ml to 95.1+/-22.9 ml, p=0.002; from 41.1+/-14.3 to 36.4+/-13.6, p=002). In all segments, we observed significant post-therapy increases in relative tracer uptake. Percentage of MIBI uptake was 71.2+/-15.3 at baseline stress and 73.2+/-15 post-TMZ (p=0.001). As global function parameters, the total wall motion normal areas changed significantly (67-74% p=0.01) after therapy, but the total wall thickness did not changed significantly(49-45%, p=0.21). CONCLUSION: The results of this study demonstrate that TMZ improves myocardial function by rest-stress Tc-99m MIBI gated SPECT during stress-induced ischemia in patients with CAE. Also, the outcomes revealed improvement in functional parameters, and percentage of MIBI uptake post TMZ administration. We can use this procedure to monitor the effect of TMZ in CAE patients.

Adult↗
PubMed1989

[Value of trimetazidine in the long-term treatment of cardiomyopathies of ischemic origin].

The effect of a cellular anti-ischemic, trimetazidine (TMZ) in ischemic cardiomyopathies, was evaluated in a double-blind versus-placebo (P) trial, over a period of six months. 20 patients, mean age: 59.5 years, with advanced ischemic cardiomyopathy, demonstrated by left catheterization and coronary angiography, with a past history of myocardial infarction, received either 60 mg per day of TMZ (nine patients) or the placebo (eleven patients) in addition to a basic treatment of digitalis, diuretics and nitrated medications. A complete, clinical, biological and paraclinical evaluation, including chest X-ray, ultrasonography, isotopic ventriculography and 24 h-ECG, was performed upon inclusion in the study; and after three and six months of treatment. Two patients from the placebo group were not reevaluated at six months. The clinical condition, according to the NYHA classification, improved in all patients from the TMZ group, deteriorated in eight on nine patients from the placebo group (p less than 0.001). The isotopic stroke volume is preserved with TMZ, deteriorated with P. The cardiac volume decreases with TMZ, increasing with P. TMZ is beneficial clinically and functionally in advanced ischemic cardiomyopathies.

Analysis of Variance↗
PubMed1996

Uptake of temozolomide in a rat glioma model in the presence and absence of the angiogenesis inhibitor TNP-470.

The angiogenic phenotype is associated with hyperpermeable capillaries. Through treatment with angiogenesis inhibitors capillary permeability may be reduced, and it can be anticipated that cytotoxic agents coadministered may be adversely affected. The current investigation examined this possibility for the combination of TNP-470, an angiogenesis inhibitor, and temozolomide (TMZ), a DNA-alkylating agent with demonstrated activity in brain tumors. TNP-470 (30 mg/kg) was given s.c. on days 6, 8, 10, 12, and 14 following s.c. implantation of rat C6 glioma cells in Sprague-Dawley rats. On the 15th day following tumor implantation, control (no TNP-470) and treated rats received 40 mg/kg of TMZ intraarterially. Prior to dosing, a linear microdialysis probe was placed in the tumor to collect interstitial fluid. Plasma and interstitial fluid samples were collected for 8 h and measured for TMZ by a high-performance liquid chromatography assay. Pharmacokinetic parameters for TMZ were calculated by noncompartmental methods. Total systemic clearance (39.8 +/- 7 versus 44.2 +/- 14 ml min(-1) kg(-1)) and volume of distribution (5.4 +/- 2 versus 5.2 +/- 0.8 L kg(-1)) were not significantly different in control and TNP-470-treated animals. However, the mean TMZ area under the interstitial fluid concentration-time curve was reduced by 25% in the TNP-470-treated group compared to the control (5450 +/- 1892 versus 4120 +/- 1790 micrograms min ml(-1); P < 0.05). It appears that TNP-470 caused this reduction in the tumor uptake of TMZ by its pharmacodynamic action on the tumor vasculature. Since combination regimens using angiogenesis inhibitors and cytotoxic drugs will be needed to determine how such combinations can be used effectively. The current animal model, which utilized tumor microdialysis, can serve as a model to further analyze combination chemotherapy.

Animals↗
PubMed1996

Inhibition of rat cerebral mitochondrial respiration by cyclosporins A, D, and G and restoration with trimetazidine.

The aim of this work was to investigate possible inhibitory effects of Ca+ and different cyclosporins (Cs) on the rat brain mitochondrial respiratory control ratio (RCR) and whether or not these effects could be antagonized by trimetazidine (TMZ). The RCR was evaluated as the state 3/state 4 ratio of oxidative phosphorylation. CsA, D, and G inhibited about 10% of RCR in a concentration-dependent manner with EC50 of 57, 19 and 7 nM, respectively, whereas CsH did not modify RCR. TMZ was able to fully antagonize this inhibitory effect in a concentration-dependent manner with EC50 of 5,200, 180, and 1 nM, respectively. The Ca2+ added to the mitochondrial preparation decreased RCR in a concentration-dependent manner with a maximal effect of 46% obtained with 100 microM Ca2+. In the presence of TMZ (100 microM), the inhibitory effect of Ca2+ was partly reversed (9%). TMZ alone showed no inhibitory or stimulant effect on RCR. These results show that restoration of RCR by TMZ is due to a Ca(2+)-dependent mechanism, promoting Ca2+ efflux from the mitochondrial matrix. However, Ca2+ efflux is only partial in case of Ca2+ overload. These data suggest that TMZ may restore ATP synthesis in circumstances where neither Ca2+ overload, nor a prooxidant have generated a RCR decrease.

Analysis of Variance↗
PubMed1998

Efficiency of trimetazidine in renal dysfunction secondary to cold ischemia-reperfusion injury: a proposed addition to University of Wisconsin solution.

Nonspecific injury in cadaveric renal transplants adversely affects early graft function and influences long-term graft survival after organ transplantation. Trimetazidine (TMZ) has been reported to exert a protective action against normothermic ischemia and reperfusion injury in several experimental and clinical studies. In an isolated perfused pig kidney model, we investigated the effects of TMZ added to University of Wisconsin solution (UW) during 48 or 72 h of cold storage (CS) and the consequence during reperfusion. Under all conditions tested renal perfusate flow rate (PFR), renal functions, and tubular injury markers were determined during a 120-min perfusion period. Lipid peroxidation and histological examination (optical and electron microscopy) were also determined after CS and reperfusion. The addition of TMZ (10(-6) M) to the UW solution improved dramatically the quality of preserved kidneys and consequently the functional recovery during reperfusion. TMZ + UW also significantly had a protecting role against reperfusion injury and lipid peroxidation when compared to UW alone. These results were correlated with both a better preservation of the proximal brush border membrane and reduced cellular and mitochondrial swelling. These results also suggested that the TMZ-induced renoprotection correlated well with the observed decrease membrane lipid peroxidation. Therefore, trimetazidine may be useful for clinical kidney graft preservation.

Adenosine↗
PubMed1998

Lipid peroxidation after cold storage and normothermic reperfusion: the effect of trimetazidine.

Ischemia reperfusion injury is still a leading cause of early graft dysfunction after transplantation. Trimetazidine (TMZ) has been postulated to be protective against renal damage from oxygen free radicals. The aim of this study was to assess the effect TMZ during cold storage (CS) and normothermic reperfusion in an isolated perfused pig kidney model. Three groups were studied: control group, immediately perfused (G0), 48 h CS in Euro-Collins solution (G1), and 48 h CS in Euro-Collins solution plus TMZ (G2). Glomerular filtration rate (GFR) and fractional sodium reabsorption (FRNa+) were calculated during reperfusion from urine and perfusate samples. Lipid peroxidation was determined by the renal tissue level of Schiff bases (SB) and malondialdehyde (MDA) after reperfusion. A histological evaluation was performed after reperfusion. Renal function was significantly improved and lipid peroxidation reduced after preservation in Euro-Collins solution plus TMZ. Functional data were closely related to histological damage. In conclusion, TMZ is a useful protective agent against renal damage induced by CS.

Animals↗
PubMed2006

Use of 11C-methionine PET to monitor the effects of temozolomide chemotherapy in malignant gliomas.

PURPOSE: The purpose of this study was to monitor the metabolic effects of temozolomide (TMZ) chemotherapy in malignant gliomas by means of repeated positron emission tomography (PET) with [(11)C]methionine (MET). METHODS: Fifteen patients with histologically proven malignant glioma were treated by TMZ chemotherapy. MET-PET studies were performed before and after the third cycle of TMZ chemotherapy in all patients, and in 12 patients also after the sixth cycle. Gadolinium-enhanced MRI studies were performed in 12 patients before the first and after the sixth cycle. Clinical status was assessed by the modified Rankin scale. Long-term outcome was assessed by calculating the time to progression (TTP) in months. RESULTS: Decline in MET uptake during therapy corresponded to a stable clinical status. The median TTP was significantly longer in patients with decline in MET uptake than in those with increasing MET uptake (23 vs 3.5 months; p=0.01, log rank test). There was no significant correlation between change in MET uptake and change in contrast enhancement during treatment for all patients. CONCLUSION: The present data demonstrate that clinical stability, which is often achieved under TMZ chemotherapy of malignant glioma, corresponds to a decline in or stability of tumour amino acid metabolism. Tumour responses can already be demonstrated with MET-PET after three cycles of chemotherapy, and absence of progression at that time indicates a high probability of further stability during the next three cycles. A reduction in MET uptake during TMZ treatment predicts a favourable clinical outcome. Molecular imaging of amino acid uptake by MET-PET offers a new method of measurement of the biological activity of recurrent glioma.

Adult↗
PubMed2003

Combined effects of temozolomide and the ribonucleotide reductase inhibitors didox and trimidox in malignant brain tumor cells.

PURPOSE: Temozolomide (TMZ), an oral alkylating agent with good penetration of the blood-brain barrier, has shown efficacy in the treatment of malignant brain tumors. Ribonucleotide reductase (RR), the rate-limiting enzyme of DNA synthesis, seems to be a complementary target for combination chemotherapy of brain tumors. Trimidox (TX) and didox (DX) are two recently synthesized specific inhibitors of RR. The combinations of TMZ with TX or DX as a basis for synergistic chemotherapy protocols were tested in this study. METHODS: The effects of the single drugs TMZ, DX, and TX, and the combinations TMZ/DX and TMZ/TX were evaluated in the human malignant glioma cell lines U87MG, T98G, LNZ308, and wt1119. In the latter, experiments were carried out in the presence or absence of wild-type p53 protein expressed under the control of a tetracycline-responsive transgene system. Cytotoxicity was evaluated by MTT assays. The isobologram and combination index (CI) method of Chou-Talalay were used to evaluate interactions between drugs. RESULTS: All drugs demonstrated cytotoxicity in brain tumor cells. Synergistic cytotoxic effects (CI<1) for TMZ and TX or DX at different dose levels were demonstrated in most of the examined cell lines. In some instances, however, drug combinations resulted in additive or even antagonistic effects. Toxicity of the single agents and synergy of the combinations did not correlate with wild-type p53 expression in the tumor cells. CONCLUSION: The tumor toxicity of TMZ as a single agent may be modified by combinations with the novel RR inhibitors DX and TX, and is synergistically enhanced in most cases. Depending on the combination ratio, the doses for each drug for a given degree of effect in the combination may be drastically reduced.

Antineoplastic Agents, Alkylating↗
PubMed2006

Adverse effects of free fatty acid associated with increased oxidative stress in postischemic isolated rat hearts.

The mechanisms of the adverse effects of free fatty acids on the ischemic-reperfused myocardium are not fully understood. Long-chain fatty acids, including palmitate, uncouple oxidative phosphorylation and should therefore promote the formation of oxygen-derived free radicals, with consequent adverse effects. Conversely, the antianginal agent trimetazidine (TMZ), known to inhibit cardiac fatty acid oxidation, could hypothetically lessen the formation of reactive oxygen species (ROS) and thus improve reperfusion mechanical function. Isolated perfused rat hearts underwent 30 min of total global ischemia followed by 30 min of reperfusion. Hearts were perfused with glucose 5.5 mmol/l or palmitate 1.5 mmol/l with or without TMZ (100 micromol/l). Ascorbyl free radical (AFR) release during perfusion periods was measured by electron spin resonance as a marker of oxidative stress. Post-ischemic recovery in the palmitate group of heart was lower than in the glucose group with a marked rise in diastolic tension and reduction in left ventricular developed pressure (Glucose: 85 +/- 11 mmHg; Palmitate: 10 +/- 6 mmHg; p < 0.001). TMZ decreased diastolic tension in both glucose- and in palmitate-perfused hearts. Release of AFR within the first minute of reperfusion was greater in palmitate-perfused hearts and in hearts perfused with either substrate, this marker of oxidative stress was decreased by TMZ (expressed in arbitrary units/ml; respectively: 8.49 +/- 1.24 vs. 1.06 +/- 0.70 p < 0.05; 12.47 +/- 2.49 vs. 3.37 +/- 1.29 p < 0.05). Palmitate increased the formation of ROS and reperfusion contracture. TMZ, a potential inhibitor of palmitate-induced mitochondrial uncoupling, decreased the formation of free radicals and improved postischemic mechanical dysfunction. The novel conclusion is that adverse effects of fatty acids on ischemic-reperfusion injury may be mediated, at least in part, by oxygen-derived free radicals.

Animals↗
PubMed1989

Effect of phenazine methosulfate on electrophysiological activity of the semicircular canal: antioxidant properties of trimetazidine.

Ischemia strokes appear to be the main source of cochleo-vestibular dysfunctions of peripheral origin. The present study aimed to investigate the action of oxygen free radicals on the bioelectric activity of the labyrinthine epithelium, using the frog semicircular canal as an in vitro preparation. We also examined the possible effect of the antianginal drug, trimetazidine (TMZ), under physiological conditions and during the administration of phenazine methosulfate (PMS). The model allows the ionic composition of endolymphatic and perilymphatic fluids bathing the semicircular canal to be dealt with separately. Spontaneous afferent vestibular nerve activity and the endolymphatic potential were recorded under resting conditions. Three additional parameters were investigated during mechanical displacement of the endolymphatic fluid: the ampullar direct current, the nerve direct current and the frequency of the evoked afferent spikes. Addition of TMZ (10(-6) and 10(-5) M, 50 min) into the perilymphatic compartment did not induce significant modifications of the different bioelectrical signals. Generation of oxygen free radicals, through administration of PMS (10(-5) M, 15 min) into the perilymphatic compartment, caused an impairment of all bioelectrical signals, except the ampullar direct current. The spontaneous activity, nerve direct current and frequency of afferent evoked spikes signals were significantly reduced 75 min after the start of PMS administration (-64, -17 and -32%, respectively). In contrast, there was a marked increase of the endolymphatic potential signal (+51%). Addition of TMZ (10(-6) or 10(-5) M) into the perilymph solution reversed the effect of PMS on all bioelectrical signals. These results indicate that TMZ acts as an antioxidant molecule which is capable of protecting the labyrinthine epithelium from the deleterious effect of oxygen radicals. Our data suggest that the protective effect of TMZ on ischemia-induced cochleo-vestibular dysfunctions may be accounted for by the antioxidant properties of this antianginal drug.

Animals↗
PubMed2005

Poly(ADP-ribose) glycohydrolase inhibitor as chemosensitiser of malignant melanoma for temozolomide.

Disruption of poly(ADP-ribose) polymerase (PARP) pathways by inhibitors of PARP catalytic domain has been shown to increase the anti-tumour activity of temozolomide (TMZ). Since PARP is inhibited by poly(ADP)ribosylation, herein we tested whether inhibition of poly(ADP-ribose) glycohydrolase (PARG) might enhance TMZ efficacy. The PARG inhibitor N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide (GPI 16552) was administered in combination with TMZ to mice injected subcutaneously or intracranially with B16 melanoma cells. The ability of treatment to reduce melanoma metastatic spreading and invasion of the extracellular matrix was also tested. The results indicated that combined treatment with GPI 16552 and TMZ significantly reduced melanoma growth, increased life-span of mice bearing tumour at the CNS site, and decreased the ability of melanoma cells to form lung metastases and to invade the extracellular matrix. In conclusion, PARG inhibition represents an alternative strategy to enhance TMZ efficacy against melanoma in peripheral as well as at CNS site.

Animals↗
PubMed2005

A phase II study of concurrent temozolomide and cis-retinoic acid with radiation for adult patients with newly diagnosed supratentorial glioblastoma.

PURPOSE: This Phase II study was designed to determine the median survival time of adults with supratentorial glioblastoma treated with a combination of temozolomide (TMZ) and 13-cis-retinoic acid (cRA) given daily with conventional radiation therapy (XRT). METHODS AND MATERIALS: This was a single arm, open-labeled, Phase II study. Patients were treated with XRT in conjunction with cRA and TMZ. Both drugs were administered starting on Day 1 of XRT, and chemotherapy cycles continued after the completion of XRT to a maximum of 1 year. RESULTS: Sixty-one patients were enrolled in the study. Time to progression was known for 55 patients and 6 were censored. The estimated 6-month progression-free survival was 38% and the estimated 1-year progression-free survival was 15%. Median time to progression was estimated as 21 weeks. The estimated 1-year survival was 57%. The median survival was 57 weeks. CONCLUSIONS: The combined therapy was relatively well tolerated, but there was no survival advantage compared with historical studies using XRT either with adjuvant nitrosourea chemotherapy, with TMZ alone, or with the combination of TMZ and thalidomide. Based on this study, cRA does not seem to add a significant synergistic effect to TMZ and XRT.

Adult↗
PubMed2005

Trimetazidine reduces the degree of fibrosis in alkali burns of the esophagus.

PURPOSE: The aim of this study was to investigate the efficacy of trimetazidine (TMZ), an antioxidant agent, on the prevention of stricture development after esophageal caustic injuries in rat. METHODS: Thirty rats were divided into 3 equal groups. A standard esophageal caustic burn was produced by application of 37.5% NaOH for a period of 90 seconds followed by water rinse. Group A (sham) animals were uninjured. Group B rats were injured but untreated. Group C rats were injured and received TMZ (5 mg/kg/d) via intraperitoneal route. Efficacy of the treatment was assessed in 28 days by measuring stenosis index and histopathologic damage score and by determining tissue hydroxyproline content. RESULTS: The stenosis index in the TMZ-treated group was significantly lower than the untreated group, similarly in the sham laparotomy group (stenosis index: 0.34 +/- 0.10, 0.94 +/- 0.21, 0.38 +/- 0.05, respectively; P < .05). The hydroxyproline level (microgram per milligram of wet tissue) was significantly lower in the TMZ-treated group compared with untreated group, similarly in the sham laparotomy group (1.06 +/- 0.14, 1.33 +/- 0.08, 0.68 +/- 0.15 microg/mg wet tissue, respectively; P < .05). In the untreated group, histopathologic damage score was significantly higher than TMZ-treated group (P < .05). CONCLUSIONS: Trimetazidine reduces the degree of fibrosis and ameliorates histopathologic damage in experimental model of corrosive esophagitis in rats.

Animals↗
PubMed2005

Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer: phase II study.

INTRODUCTION: The primary tumour type most likely to metastasize to the brain is lung cancer. In heavily pre-treated patients, limited therapeutic option is available and the results of availability therapies reported in literature are disappointing. The present phase II study was designed to assess the efficacy and safety of temozolomide (TMZ) as palliative treatment for brain metastases (BrM) in NSCLC patients pre-treated with WBRT and at least one line of chemotherapy for metastatic brain disease. MATERIAL AND METHODS: Temozolomide was administered orally at 150 mg/mq/day for five consecutive days for the first cycle, doses were increased to 200 mg/mq/day for 5 days every 28 days for subsequent cycles if no grade 3/4 haematological toxicity was observed. Eligibility criteria included cytological or histological confirmed NSCLC; BrM, recurrent or progressing after WBRT and at least one line of chemotherapy. A total of 30 consecutive patients entered the study and received the allocated treatment. RESULTS: Three patients (10%) achieved an objective response (OR) of BrM with two complete remission. Stable disease and progressive disease were achieved in 3 (10%) and 24 patients (80%), respectively. A correlation between response to TMZ and sensitivity to the previous first line chemotherapy was reported. Time to progression and overall survival were examined both for responder patients and for all included patients. For long-term survivors, we considered the patients who survived >12 months after the start of TMZ. According to this definition, three patients resulted long-term survivors: 2 with OR and 1 with stable brain disease. No grades 3 or 4 toxicity occurred. The total of treatment-related adverse events were mild or moderate (G1-2) in intensity. No patients discontinued TMZ as a result of treatment-related toxicity. DISCUSSION: The results of the present trial clearly demonstrates that TMZ is active and safe in BrM NSCLC patients previously treated with WBRT and at least one line of chemotherapy.

Administration, Oral↗