A randomized double-blind trial of intravenous trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction.

BACKGROUND: Despite high patency rates, primary angioplasty for myocardial infarction does not necessarily result in optimal myocardial reperfusion and limitation of infarct size. Experimentally, trimetazidine limits infarct size, decreases platelet aggregation, and reduces leukocyte influx into the infarct zone. To assess trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction a prospective, double-blind, placebo-controlled pilot trial was performed. METHODS: 94 patients with acute myocardial infarction were randomized to receive trimetazidine (40 mg bolus followed by 60 mg/day intravenously for 48 h) (n=44) or placebo (n=50), starting before recanalization of the infarct vessel by primary angioplasty. Patients underwent continuous ST-segment monitoring to assess return of ST-segment deviation to baseline and presence of ST-segment exacerbation at the time of vessel recanalization. Infarct size was measured enzymatically from serial myoglobin measurements. Left ventricular angiography was performed before treatment and repeated at day 14. RESULTS: Blinded ST segment analysis showed that despite higher initial ST deviation from baseline in the trimetazidine group (355 (32) vs. 278 (29) microV, P=0.07), there was an earlier and more marked return towards baseline within the first 6 h than in the placebo group (P=0.014) (change: 245 (30) vs. 156 (31) microV respectively, P=0.044). There was a trend towards less frequent exacerbation of ST deviation at the time of recanalization in the trimetazidine group (23.3 vs. 42.2%, P=0.11). There was no difference in left ventricular wall motion at day 14, or in enzymatic infarct size. There was no side effect from treatment. Clinical outcomes were similar between groups. CONCLUSION: Trimetazidine was safe and led to earlier resolution of ST-segment elevation in patients treated by primary angioplasty for acute myocardial infarction.

Case-control study of the risk factors for age related macular degeneration. France-DMLA Study Group.

AIM: A case-control study was initiated to determine the risk factors for the development of age related macular degeneration (AMD). METHODS: Study participants, who were all white, aged 50-85 years, and were recruited from private ophthalmology practices. Each practitioner enrolled patients with bilateral AMD, who were then matched with controls for sex and age. Environmental factors and systemic and ocular histories were screened. All patients had bilateral red-free fundus photographs and fluorescein angiography. Photographs were classified into pigment epithelium alterations, drusen, geographic atrophy, and exudative AMD. Statistical analysis included the identification of risk factors for AMD. A multivariate analysis was performed at the end of the study. Analysis included the entire study population and was carried out for each stage of AMD. RESULTS: 1844 controls were compared with 1844 patients with AMD. Mean age was 71 years for controls and 72 for cases. Logistic regression identified six major risk factors for AMD (whole population): arterial hypertension (odds ratio (OR) = 1.28), coronary disease (OR = 1.31), hyperopia (OR = 1.33), light coloured irises (OR = 1.22), and lens opacities or previous cataract surgery (OR = 1.55). The significance of vascular risk factors was increased for late stages of AMD, especially the atrophic forms (coronary disease, OR = 3.19). CONCLUSIONS: This large case-control study confirms some of the risk factors previously identified and may contribute to the determination of methods for prevention of AMD.

Permutation distribution estimation applied to the comparison of the profile of the activity of two antianginal drugs.

The comparison of the anti-ischemic activity of trimetazidine and propranolol was evaluated by multiple end points (clinical, exercise test, and ambulatory electrocardiogram [ECG] monitoring criteria) in 149 male patients with effort angina who received either trimetazidine 20 mg tid or propranolol 40 mg tid during a period of 3 months. The distribution of the standardized differences between the two treatments for each variable was obtained by a permutation method. The medians (estimation of the actual difference between the two treatments) and the 5, 25, 75 and 95% quantiles were represented on the same diagram for all end points. The pattern of the standardized distribution of the differences showed a similar activity of both drugs on symptoms and nitrates consumption, on exercise tolerance and increase in ischemic threshold at exercise, and on ischemia recorded at ambulatory ECG monitoring. Conversely, only propranolol decreased heart rate and rate pressure product at rest as well as at exercise, underlining the difference in the mode of action of the two drugs. This descriptive technique is an attractive method to evaluate the differences between drugs considering multiple criteria favouring the estimation of these differences together with their variability.

Lack of effects of trimetazidine on systemic hemodynamics in patients with coronary artery disease: a placebo-controlled study.

Trimetazidine has been shown to improve anginal symptoms and exercise tolerance in patients with coronary artery disease (CAD). To determine the hemodynamic effects of trimetazidine, systemic hemodynamics were studied in 15 patients suffering from CAD (12 male, 3 female, mean age +/- SEM = 58.6 +/- 1.8 years). Cardiac index was determined by thermodilution method. Left ventricular and aortic pressures were measured using micromanometers (Miller Instruments). After basal measurements, patients were randomly given either placebo (n = 5) or one of two therapeutic doses of trimetazidine 1 mg.kg-1 (n = 5) or trimetazidine 1.5 mg.kg-1 (n = 5) in a double-blind procedure. Data were recorded 5, 10 and 20 min after intravenous drug bolus. Throughout the procedure, the evolution of systemic hemodynamic parameters was not statistically different between the three groups, in particular heart rate, cardiac index, systolic, diastolic and mean aortic pressures, end-diastolic ventricular pressure, mean capillary wedge pressure, pulmonary artery pressures or systemic vascular resistances. We conclude that, unlike other antianginal drugs (particularly beta-blockers, nitrates and calcium-channel inhibitors), trimetazidine does not modify systemic hemodynamics in patients with CAD. These results are consistent with a direct effect of trimetazidine on the ischemic myocardial cell previously reported.

[Granulometry and measurement of a aerosol drug deposit (fusafungine) in normal and pathological airways]. / Granulométrie et mesure du dépôt d'un aérosol médicamenteux (fusafungine) dans les voies aériennes normales et pathologiques.

We measured with a laser velocimeter granulometric deposit of an aerosol anti-infectious agent, fusafungin, administered with a controlled inhalator. Total drug deposit was determined on the basis of a granulometric spectrum of the polydispered aerosol (mass mean aerodynamic diameter (MMAD) = 2.8 +/- 1.7 microns) and dispersion in the airways was estimated using the Stahlhofen model. We first compared deposits obtained with oral inhalation in 19 normal subjects and 20 patients with chronic obstructive lung disease. Total deposit in the airways of patients with chronic obstructive lung disease (82%) was not significantly different from that in normal subjects (85%). Estimated dispersion in normal airways was 27% in the alveoles, 8.4% in the tracheobronchic region and 23.5% in the extrathoracic regions. We then compared deposits after nasal inhalation in 22 normal subjects and 21 patients with rhinitis: nasal deposit was significantly greater in patients with rhinitis (54.5%) than in controls (44.7%). We conclude that such an inhalator can be adapted for local treatment of ENT infections and upper respiratory infections. Deposit is not modified in case of obstructive bronchopathy.

Improvement of long-term preservation of isolated arrested rat heart: beneficial effect of the antiischemic agent trimetazidine.

Rat hearts, arrested in situ after intracaval injection of a simple mineral cardioplegic solution (St. Thomas), were preserved for 15 h at 4 degrees C either by simple immersion in the cardioplegic solution or low-flow perfusion by the same liquid (0.3 ml/min). Trimetazidine (TMZ) was added to the cardioplegic solution at a concentration of 10(-6) M in two additional groups corresponding to both preservation conditions. The biochemically determined ventricular ATP content was increased in immersed hearts by TMZ (+ 78%). The [ATP]/[Pi] ratio, as calculated from 31P nuclear magnetic resonance (NMR) spectroscopy, was significantly increased in both preservation conditions by TMZ: 0.08 +/- 0.03 versus 0.04 +/- 0.01 in immersed hearts and 0.53 +/- 0.13 versus 0.26 +/- 0.16 in perfused hearts (mean +/- SD). Intracellular pH was increased when TMZ was administered in perfused hearts (7.02 +/- 0.14 vs. 6.67 +/- 0.14, mean +/- SD). Functional recovery, estimated by the pressure developed by the left ventricle (intraventricular isovolumic balloon) when hearts were reperfused with a physiologic solution, was improved by TMZ in both preservation conditions: +137% in immersed hearts and +54% in perfused hearts. These results demonstrate that both the bioenergetic status of the myocardial cell and the functional capabilities of isolated, arrested, stored rat heart can be significantly improved by addition of the antiischemic drug TMZ to the preservation solution.

Evolution of free radical formation during low-flow ischemia and reperfusion in isolated rat heart.

Free radicals have been implicated in several aspects of cellular injury, both during ischemia and reperfusion of the myocardium. In this study, formation of free radicals in the isolated rat heart was measured a) directly using electron paramagnetic resonance (EPR) spectroscopy and b) indirectly using the generation of thiobarbituric acid reactants as an index of lipid peroxidation. EPR spectra of frozen heart powder recorded at 100 degrees K show several lines and consist of different components separated by temperature studies: signal C disappears after warming the sample 1 minute at 190 degrees K and is suggestive of a triplet signal g = 2.001, aN = 25 Gauss; signal B g parallel = 2.034, g perpendicular = 2.007, disappears after 1 min at 240 degrees K, and is similar to those previously reported for oxygen alkylperoxyl free radical; the remaining signal, signal A with g = 2.004 is identical to that of a carbon-centered ubiquinone free radical. The total free radical concentration in isolated rat heart perfused at a constant flow rate of 12 ml/min was increased by 44% compared with control (p less than 0.05) after 10 minutes of normothermic global ischemia with a 10% residual flow, and by only 31% compared with control after 20 seconds of reflow with oxygenated perfusate (p less than 0.05). Compared with the reperfused group, trimetazidine 10(-5) M administered 15 minutes before the ischemic period decreased the free radical concentration (-20%). However, this free radical generation in heart was not associated with a concomitant increase of lipid peroxides.

[A cellular anti-ischemic agent, trimetazidine prevents the deleterious effects of oxygen free-radicals on the internal ear]. / Anti-ischémique cellulaire, la trimétazidine prévient les effets délétères des radicaux libres de l'oxygène sur l'oreille interne.

Improvement of cochleovestibular symptoms induced by trimetazidine (TMZ) has been evidenced by clinical studies. However, a poor knowledge of the physiopathology and the scarcity of experimental models contributed to making determination of the mode of action of the drugs difficult. We studied the effect, in vitro, of TMZ on the production of oxygen-derived free radicals using, as a biological model, the isolated semicircular canal of the frog. This model allows to exert separate control over the ionic composition of the endo- and perilymphatic fluids. The spontaneous activity of the afferent nerve fibers, as well as the endolymphatic potential, were recorded at rest. Three additional parameters were analyzed, while the semicircular canal was subjected to mechanical stimulation, i.e., ampulla potential, nerve potential and the evoked frequency of action potentials. Free radical generation induced by the administration of phenazine methosulfate (PMS, 10(-5) M, 15 min) into the perilymphatic compartment, leads to a deterioration of the production of endolymph and the release of this afferent neuromediator. Inversely, PMS has no influence whatsoever on the mechanisms of mechanical-electrical transduction. The addition of TMZ (10(-6) or 10(-5) M) in the perilymphatic compartment counteracts the harmful effects of free radicals on the various bioelectric activities. These results suggest that the beneficial action of TMZ observed during treatment of cochleovestibular disorders is due, at least in part, to the anti-oxidizing properties of the molecule of interest.

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.

[Importance of urinary enzymes as a marker of post-ischemic proximal tubular involvement in rat]. / Intérêt de l'enzymurie comme marqueur de l'atteinte tubulaire proximale post-ischémique chez le rat.

We have studied in rats the influence of renal ischemia on urinary excretion of three brush border membrane enzymes (gamma glutamyl transferase, alkaline phosphatase and leucine aminopeptidase) and of a lysosomal one (N-acetyl-B-D-glucosaminidase). Urines were collected over 24 hours periods during three days before and after a 45 minutes renal artery clamping. Urinary GGT, PAL and LAP excretion were significantly increased on the first day after renal ischemia, but returns to normal values on the second day. Urinary NAG activity increases on the first day, but contrary to the latter enzymes, reached to normal values only on the third day. Enzymuria seems to be a useful marker of tubular injury occurring after a temporary renal ischemia in the rat.

Effect of trimetazidine on membrane damage induced by oxygen free radicals in human red cells.

The effect of trimetazidine, 1-(2, 3, 4 trimethoxybenzyl)piperazine di-hydrochloride, on membrane damage induced by oxygen free radicals in red cells was studied in seven healthy volunteers after oral administration. Red cells collected prior to and after a 7 day treatment period with trimetazidine were incubated in the presence of phenazine methosulphate (an intracellular oxygen free radical generator) and diethyldithiocarbamate (a Cu-Zn superoxide dismutase inhibitor). The loss of intracellular K+ induced by oxygen free radicals and the membrane content of peroxidated lipids were significantly reduced in red cells collected after the period of treatment. These results indicate a potent antioxidant activity of trimetazidine which could explain its cardioprotective role during ischaemic and reperfusion phases in which oxygen free radicals are generated and probably implicated in the genesis of cardiac cell injury.