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PubMed2005

[Observation on effect of compound danshen droplet-pill combined with trimetazidine in treating senile unstable angina pectoris].

OBJECTIVE: To investigate the effect of compound Danshen Droplet-pill (DS) combined with trimetazidine (TMZ) in treating senile unstable angina pectoris (SUAP). METHODS: One hundred and twenty patients with SUAP were eaually and randomly divided into 2 groups, the treated group and the control group. Changes of angina, occurrence of arrhythmia, myocardial infarction and sudden death, myocardial ischemia in ECG and partial indexes of heart function were observed. RESULTS: The total effective rate in the treated group was 78.3%, while that in the control group was 53.3%, comparison of the two groups showed significant difference (P < 0.05). The incidence rate of arrhythmia in the two groups was 18.2% and 30.0% respectively and that of acute myocardial infarction and sudden death was 0 and 5.0% respectively, also showed significant difference between them (P < 0.05). Condition of myocardial ischemia revealed in ECG and partial indexes of heart function in the treated group were all improved to certain extent. Conclusion DS combined with TMZ is superior in treating SUAP.

Aged↗
PubMed2005

The role of chemotherapy in the treatment of low-grade glioma. A review of the literature.

Low-grade gliomas (LGG) are a group of uncommon neuroglial tumors of the central nervous system. They are characterized by a grade I or II according to the WHO classification. Grade I tumors are non-invasive and amenable to surgical resection with curative intent. Diffuse infiltrating LGG (WHO grade II) are tumors with a highly variable prognosis. Curative resection can only rarely be achieved and progression is characterized by transformation into a high-grade glioma (WHO grade III-IV). There are only limited evidence-based treatment recommendations for the management of progressive LGG because of a lack of data from prospective randomized trials. Most often radiotherapy is offered to patients with symptomatic and/or progressive disease. Three randomized trials have failed to demonstrate a survival improvement with either early versus delayed radiation or with a higher dose of radiation. The potential role of chemotherapy for the treatment of LGG has only been addressed in phase II trials. The PCV-chemotherapy regimen is associated with considerable toxicity that limits its applicability. The results with temozolomide (TMZ) chemotherapy have been more promising. Patients with chemosensitive LGG as predicted by heterozygotic loss of chromosomal arms Ip and 19q or methylation of the promoter of the MGMT-gene in the genome of the glioma cells respond to TMZ. Radiotherapy will be compared to chemotherapy asfirst line treatment for LGG in two phase III studies that are planned for by the brain tumor group of the European Organization for Research and Treatment of Cancer (BTG-EORTC) and Radiation Therapy Oncology Group (RTOG).

Antineoplastic Agents↗
PubMed2005

[Therapeutic value of trimetazidine in patients with coronary heart disease and left ventricular dysfunction].

OBJECTIVE: Trimetazidine has been shown to have anti-ischemic properties by improving exercise tolerance without haemodynamic effects and direct cyto-protective effects on the myocardium. The aim of this study was to assess the effect of trimetazidine on the treatment of patients with ischemic cardiomyopathy, and to assess the anti-angina efficacy and the clinical tolerance of TMZ. METHODS: 60 ischemic cardiomyopathy patients on conventional therapy were enrolled in this open multiple center clinical trial and received TMZ (20 mg 3 times per day) for six months. Patients were followed up for six months and assessments included clinical evaluation, electrocardiography and echocardiography. RESULTS: All patients tolerated 60 mg of trimetazidine for six months, left ventricular ejection fraction (LVEF) was increased from 32.4 +/- 6.3% to 41.8 +/- 10.8% (P < 0.0001). Stage of NYHA classification was improved in most patients (P < 0.0001). Attack of angina was relieved and consumption of nitroglycerin reduced (both P < 0.001). CONCLUSION: Trimetazidine seems to improve clinical status and ejection fraction, and reduce angina onsets without adverse effects in patients with ischemic cardiomyopathy.

Adult↗
PubMedDate not supplied

Differences in the development of tolerance to various benzodiazepines.

Anticonvulsant, sedative and anxiolytic effects of the following benzodiazepines, administered chronically by the intraperitoneal route, were assessed: nitrazepam (NTZ), diazepam (DZ), oxazepam (OXZ), chlordiazepoxide (CDX) and temazepam (TMZ). The action of NTZ in tests for sedative, anticonvulsant and anxiolytic effects rapidly changed upon a repeated daily treatment, which suggests development of tolerance, while no tolerance developed to such effects of OXZ. The stimulating effect of DZ was found not earlier than after 5 weeks of chronic treatment, but no tolerance to the anxiolytic action was observed, and the anticonvulsant action was even potentiated. The stimulating action and tolerance to the anxiolytic effects of CDX and TMZ developed rapidly, but was accompanied with an only slight decrease in the anticonvulsant effect.

Animals↗
PubMed1986

[Current concepts in cellular ischemia: role of trimetazidine].

Comparative clinical trials have already enabled to appreciate the clinical efficacy of trimetazidine (TMZ) during chronic coronary angina. Two recent controlled studies have been done in patients with chronic stable angina, and conducted in double blind versus placebo, with randomized assignment of the treatments. They showed that TMZ administered either in a single dose (60 mg), or for one month at a daily dose of 60 mg, enabled on the one hand an improvement of the stress ability: increase of the total work (respectively 31 and 38 per cent), and of the duration of the stress (17 per cent in an average), and on the other hand, the recession of the myocardial ischemic threshold: increase in the time of appearance of a 1 mm sub-shift of ST (respectively 7 and 17 per cent). The absence of alteration, in each of the placebo and trimetazidine groups, of the cardiac frequency and systolic arterial blood pressure at rest and the double product on exertion, suggested a different mechanism of action from the usual anti-angina medications. Many experimental works have been able to show that trimetazidine has an intra-cellular "anti-ischemic" activity and a cardioprotective effect which would be present during ischemic phases. The anti-ischemic activity would counteract the harmful effects of hypoxia by maintaining cellular energetic reserves, and by decreasing the deadly membrane effects of the free radicals, particularly passive permeability to potassium. In the same experimental conditions of ischemia, the cardioprotective effect is demonstrated by the decrease of the creatine kinase leakage and the upholding or the rapid recovery of the myocardial electric activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1980

Cutaneous microcirculatory effects of various vasodilator agents on the conscious rabbit, with special regard to changes in the rhythmic property of vasomotion.

Microcirculatory effects of intravenous administrations in the appropriate doses of phenoxybenzamine (POBA), phentolamine (PTA), nicotinic acid (NAc), trimetazidine (TMZ), dilazep (DZ), cepharanthine (CT), alpha-tocopheryl acetate (TP-A), and alpha-tocopheryl nicotinate (TP-N) as vasodilator agents were investigated in the subcutaneous tissue within a transparent ear chamber of the normal conscious rabbit. The intra-vital microscopic findings obtained following administration of the drugs were as follows: POBA, a marked and long-lasting vasodilatation without vasomotion (more than 1 hour); PTA, a quite brief vasodilatation followed by a marked and long-lasting vasoconstriction without vasomotion (more than 1 hour); NAc, a short-lasting vasodilatation with slightly blunted vasomotion (less than 10 minutes); TMZ, DZ, CT, TP-A, and TP-N, a similar notable and transient vasodilatation with vasomotion (about 1 hour or more). Some physiological implications on the microcirculatory changes induced by administrations of the drugs were discussed especially in relation to the significance of sustaining the rhythmic fluctuations of blood flow due to vasomotion.

Animals↗
PubMed2002

Effect of O6-(4-bromothenyl)guanine on different temozolomide schedules in a human melanoma xenograft model.

The DNA repair protein O(6)-alkylguanine DNA alkyltransferase (ATase) is a major component of resistance to treatment with methylating agents and nitrosoureas. Inactivation of the protein, via the administration of pseudosubstrates, prior to chemotherapy has been shown to improve the latter's therapeutic index in animal models of human tumours. We have also shown that rational scheduling of temozolomide, so that drug is administered at the ATase nadir after the preceding dose, increases tumour growth delay in these models. We now report the results of combining these two approaches. Nude mice bearing A375M human melanoma xenografts were treated with vehicle or 100 mg/kg temozolomide ip for 5 doses spaced 4, 12 or 24 hr apart. Each dose was preceded by the injection of vehicle or 20 mg/kg 4BTG. All treatments resulted in significant delays in tumour quintupling time compared with controls: by 6.2, 5.9 and 16.8 days, respectively, for 24-, 12- and 4-hourly temozolomide alone and by 22.3, 21.3 and 22.1 days, respectively, in combination with 4BTG. Weight loss due to TMZ was unaffected by the presence of 4BTG. This was of the order of 6.2-10.6% with 24- and 12-hourly administration and 17.4-20.1% (p < 0.0001) with 4-hourly treatment. In our model, combining daily temozolomide with 4-BTG confers increased antitumour activity equivalent to that achieved by compressing the temozolomide schedule but with less toxicity. Using temozolomide schedule compression with 4-BTG does not improve on this result, suggesting that ATase inactivation with pseudosubstrates is a more promising means of enhancing the activity of temozolomide than compressed scheduling.

Adenosine Triphosphatases↗
PubMed2005

Artificial tumor model suitable for monitoring 31P and 13C NMR spectroscopic changes during chemotherapy-induced apoptosis in human glioma cells.

An artificial tumor method was developed to study cells inside the sensitive volume of an NMR spectrometer during growth and apoptosis. The tumor was composed of a 50:50 mixture of tightly packed porous-collagen and nonporous-polystyrene microspheres. The porous collagen served as a growth surface for the tumor cells, and the nonporous polystyrene served as a structural support to limit compression of the packed bed during perfusion. The microspheres were held between two porous polyethylene discs that were tightly sealed inside the NMR perfusion chamber. The new method was evaluated with two cell types: a mouse mammary tumor line (EMT6/SF) and a human glioma line (SF188). The results indicate that for both lines, approximately 10(9) metabolically active cells could be sustained for at least 1 week in the 12-cm(3) artificial tumor. Further, cells undergoing chemotherapy-induced apoptosis (which is known to cause detachment of cells from their surroundings) were retained in the artificial tumor. In preliminary 31P NMR studies, glioma cells treated with temozolomide (TMZ) exhibited reduced phosphocholine (PCh) levels relative to glycerophosphocholine (GPC) and diphosphodiester (DPDE) levels. They also exhibited sharply reduced oxygen consumption and TCA cycle 13C labeling, while they retained glycolytic activity. These metabolic changes are consistent with those that would be expected during mitochondrially-mediated apoptosis.

Animals↗
PubMed2006

Temozolomide for recurrent or progressive high-grade malignant glioma: results of an Austrian multicenter observational study.

BACKGROUND: The use of chemotherapy in patients with malignant gliomas has remained a controversial issue even after the publication of favorable study data and a meta-analysis. The present study was initiated to support the use of chemotherapy in patients with relapsed high-grade gliomas (HGG). PATIENTS AND METHODS: Six Austrian centers recruited 43 patients with histologically confirmed HGG at first recurrence. Twelve chemotherapy-naïve patients received oral temozolomide at a dose of 200 mg/m(2) once a day for five consecutive days and 26 patients a dose of 150 mg/m(2) also for five days after various first-line chemotherapies. TMZ treatment was repeated every four weeks for a total of six cycles. RESULTS: Twenty-one patients (52.5 %) received at least six cycles of therapy. Two patients experienced complete remission and eight patients a partial response. Twenty patients survived at one year after enrolment in the study; eight patients survived beyond three years of follow-up. Hematological toxicities consisted of three thrombocytopenias G4 and 35 lymphocytopenias G3 and G4; these did not cause interstitial pneumonia or require inpatient treatment. Non-hematological toxicities were rare and without clinical relevance. Patients' quality of life was maintained during treatment. CONCLUSION: The study data confirm the feasibility and efficacy of chemotherapy with temozolomide in patients with relapsed/progressive HGG.

Adolescent↗
PubMed2005

Inhibition of beta-oxidative respiration is a therapeutic window associated with the cancer chemo-preventive activity of PPARgamma agonists.

We demonstrate expression and coordinate induction of PPARgamma and lipogenic enzymes (HMG-CoA synthase, HMG-CoA reductase and fatty acid synthase) in a murine lung alveolar carcinoma cell line (Line 1) treated with the PPARgamma agonist troglitazone (TRO) [0-100 microM]. We postulate that TRO induces a shift in cellular energy metabolism towards fatty acid oxidation (beta-oxidative respiration). Accordingly, co-treatment with TRO [30 microM] and increasing concentrations of trimetazidine (TMZ) [0.1-3 mM], an inhibitor of beta-oxidation, results in a dose dependent decrease cellular ATP levels and a dose dependent induction of apoptosis. These findings, suggest that inhibition of beta-oxidative respiration is a therapeutic window associated with the cancer chemo-preventive activity of PPARgamma agonists.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2004

Effect of trimetazidine on renal ischemia/reperfusion injury in rats.

There is increasing evidence to suggest that toxic oxygen radicals play a role in the pathogenesis of ischemia/reperfusion (I/R) injury in the kidney. This study was designed to investigate the effects of trimetazidine, in I/R induced renal failure in rats. The protective effect of trimetazidine (Tmz) against the damage inflicted by reactive oxygen species (ROS) during renal I/R was investigated in Sprague-Dawley rats using histopathological and biochemical parameters. In one set of experiments animals were unilaterally nephrectomized, and subjected to 45 min of left renal pedicle occlusion and in another set both the renal pedicles were occluded for 45 min followed by 24 h of reperfusion. Trimetazidine (3 mg kg(-1), i.p.) was administered 30 min prior to ischemia and repeated 12 h after the first dose. At the end of the reperfusion period, rats were sacrificed. Thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) levels, glutathione reductase (GR) catalase (CAT), and superoxide dismutase (SOD) activities were determined in renal tissue. Serum creatinine and blood urea nitrogen (BUN) concentrations were measured for the evaluation of renal function. Ischemic control animals demonstrated severe deterioration of renal function, renal morphology and a significant renal oxidative stress. Pretreatment of animals with trimetazidine markedly attenuated renal dysfunction, morphological alterations, reduced elevated TBARS levels and restored the depleted renal antioxidant enzymes. The findings imply that ROS play a causal role in I/R induced renal injury and trimetazidine exert renoprotective effects probably by the radical scavenging and antioxidant activities.

Animals↗
PubMed2002

Recognition forces involved in mitochondrial binding to a low-affinity trimetazidine binding site related to anti-ischemic activity.

A number of heterogeneous drugs previously shown to bind to trimetazidine (TMZ) binding sites on mitochondria and to inhibit mitochondrial swelling (Morin et al., Br J Pharmacol 1998;123:1385-94) were investigated here for their physicochemical properties. The molecular parameters measured were the partition coefficients of the neutral and monocationic forms in the n-octanol/water and dichloroethane/water systems, their distribution coefficients at pH 7.4 in these two solvent systems, as well as their distribution coefficients at pH 7.4 in a phosphatidylcholine (PhC) liposomes/water system (log D(lip)(7.4)). Most of these properties were not correlated with affinity to mitochondria or inhibition of mitochondrial swelling. In contrast, log D(lip)(7.4) showed a modest correlation with binding to the low-affinity site (r(2)=0.52) and a better correlation with anti-swelling activity (r(2)=0.69), itself well correlated with binding to the low-affinity sites (r(2)=0.83). Thus, these sites have recognition properties much like those of membranes, as they depend on lipophilicity-hydrophobicity (core binding) and ionic bonds (surface interactions).

Animals↗
PubMed2000

Health-related quality of life in patients with anaplastic astrocytoma during treatment with temozolomide.

One of the objectives of this phase II study was to determine whether temozolomide (TMZ) improved the health-related quality of life (HRQL) of patients with recurrent anaplastic astrocytoma (AA). HRQL was assessed at baseline (pretreatment) and every 4 weeks at each treatment cycle using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (version 2.0) and the Brain Cancer Module (BCM20). Changes from baseline in the scores of seven preselected HRQL domains (role and social functioning, global QL, visual disorder, motor dysfunction, communication deficit and drowsiness) were determined at 6 months as well as prior to, and at the time of, disease progression. The significance of the changes was assessed by calculating statistical significance, effect sizes and the proportions of patients with improvement in their HRQL scores (changes of >/=10 points). After 6 months of treatment, patients who were free of progression of disease reported either an improvement or maintenance of all the preselected HRQL domains scores. Patients with disease progression by 6 months usually experienced improvement in HRQL before progression, but there was a sharp decline in most of the preselected domains at progression. We conclude that treatment of recurrent AA with temozolomide is associated with significant HRQL benefits.

Adult↗
PubMed2002

Hematoprotection and enrichment of transduced cells in vivo after gene transfer of MGMT(P140K) into hematopoietic stem cells.

The overexpression of mutant forms of O(6)-methylguanine-DNA-methyltransferase (MGMT), resistant to the MGMT inhibitor O(6)-benzylguanine (BG), protects hematopoietic cells from the toxicity of combined BG plus O(6)-alkylating agent chemotherapy. To evaluate the feasibility of this approach for clinically relevant O(6)-alkylating agents, combined therapy with BG and two chloroethylnitrosourea-type drugs, ACNU or BCNU, or the triazene derivative temozolomide (TMZ) was investigated in a murine bone marrow transplant model allowing transgenic expression of the highly BG-resistant MGMT(P140K) mutant. Whereas 20/20 control animals transplanted with nontransduced cells died of progressive myelosuppression during therapy, nearly all animals transplanted with MGMT(P140K)-transduced cells survived treatment with BG/ACNU (12/15), BG/TMZ (10/10), or BG/BCNU (5/5). In surviving animals, hematological parameters improved during chemotherapy and pretreatment levels were reestablished during or shortly after therapy. All animals showed enrichment of transgenic granulocytes (range: 15- to 101-fold) and lymphocytes (range: 16- to 55-fold) in peripheral blood, bone marrow, and spleen. No significant differences were observed between individual treatment groups. Serial transplants demonstrated protection in secondary recipients and confirmed the transduction of transplantable stem cells. Thus, these data demonstrate efficient protection from hematotoxicity and substantial enrichment of transgenic cells following MGMT(P140K) gene transfer and treatment with different O(6)-alkylating drugs.

Animals↗
PubMed2000

Effect of 48-h intravenous trimetazidine on short- and long-term outcomes of patients with acute myocardial infarction, with and without thrombolytic therapy; A double-blind, placebo-controlled, randomized trial. The EMIP-FR Group. European Myocardial Infarction Project--Free Radicals.

AIMS: To compare the effect of trimetazidine (TMZ) versus placebo administered during the acute phase of myocardial infarction on long- and short-term mortality. METHODS AND RESULTS: EMIP-FR (European Myocardial Infarction Project - Free Radicals) was a prospective, double-blind, European multicentre trial in which 19 725 patients, presenting symptoms of acute myocardial infarction within the previous 24 h were randomized. Stratification was according to thrombolytic therapy (56%) or not (44%). An intravenous bolus injection of trimetazidine (40 mg) was given just before or simultaneously with thrombolysis, followed by continuous infusion (60 mg. 24 h(-1)) for 48 h. Overall, no difference was found between trimetazidine and placebo for the main end-point, short-term (35-day) mortality, (P = 0.98) in an intention-to-treat analysis. This was the result of opposing trends in the two strata. Thrombolysed patients showed a tendency towards more short-term deaths with trimetazidine, compared to placebo (trimetazidine: 11.3%, placebo: 10.5%, P = 0.15) and non-thrombolysed patients the converse (trimetazidine: 14.0%, placebo: 15.1%, P = 0.14). In a per-protocol analysis the beneficial effect of trimetazidine for non-thrombolysed patients became statistically significant (trimetazidine: 13.3%, placebo: 15.1%, P = 0.027). CONCLUSION: Trimetazidine does not reduce mortality in patients undergoing thrombolytic therapy; however, it might have some beneficial effect for non-thrombolysed patients.

Adult↗
PubMed1990

Effects of calmodulin antagonists on radiation-induced lipid peroxidation in microsomes.

Rat liver microsomes were irradiated with gamma-rays at a dose rate of 1.31 Gys-1. The extent of lipid peroxidation, measured in terms of malondialdehyde (MDA) formed, increased with radiation dose. The presence of calmodulin antagonists during irradiation decreased lipid peroxidation. The order of their protective efficiency was: chlorpromazine (CPZ) greater than promethazine (PMZ) greater than trimeprazine (TMZ). Their protective effect was diminished in the presence of ferrous (Fe2+) ions and was restored on addition of EDTA. However, calmodulin antagonists considerably inhibited radiation-induced lipid peroxidation in the presence of ferric (Fe3+) ions. Calmodulin antagonists also decreased the cytochrome P-450 content of microsomes. These results are discussed with respect to their applicability to radiotherapy. A possible mechanism for the inhibition of radiation-induced lipid peroxidation is suggested.

Animals↗
PubMed1995

Inhibition of radiation-induced changes of glyoxalase I activity in mouse spleen and liver by phenothiazines.

Swiss albino mice (male) were irradiated with gamma-rays at a dose-rate of 0.05 Gy s-1, and the activities of glyoxalase I (GI) and glyoxalase II (GII) were determined after 24 h in the spleen and liver. Radiation up to 4 Gy increased the activity of GI and decreased that of GII. It was possible that the radiation-induced changes in the activity of the glyoxalase system, particularly that of GI, were suggestive of the regeneration status of the tissue. Phenothiazines such as chlorpromazine (CPZ), promethazine (PMZ) and trimeprazine (TMZ) inhibited the radiation-enhanced activity of GI in a concentration-dependent manner. On the other hand, almost no change in the activity of GII was observed using phenothiazines. The effect of phenothiazines on radiation-induced changes of glyoxalase activity were reversed in the presence of ferrous (Fe2+) ions. However, phenothiazines inhibited the radiation effect in the presence of ferric (Fe3+) ions. This combined effect was predominant in the liver. A possible mechanism for the modifying effect of phenothiazines is suggested.

Animals↗
PubMed1996

Feline immunodeficiency virus can infect a human cell line (MOLT-4) but establishes a state of latency in the cells.

Infectivity of feline immunodeficiency virus (FIV) in feline and human lymphoblastoid cell lines was examined using homogeneous populations of FIV derived from infectious molecular clones of strains TMZ and Petaluma, and two recombinant chimeric clones carrying gag, pol, vif and ORF-A from the heterologous virus. FIV from the clones with the env region of the Petaluma strain was shown to infect and establish provirus in a human lymphoid cell line (MOLT-4), although the FIV-infected cells did not produce any infectious viruses. By treatment of the infected MOLT-4 cells with a phorbol ester, infectious virus was rescued. To examine which stage of the life-cycle of FIV is blocked in these cells, we analysed transcription of FIV-14 in the cells by RT-PCR. FIV-specific RNA expression could not be detected. These results strongly suggest that latency of the virus in MOLT-4 cells is due to a failure in transcription.

Antigens, Viral↗