S 35171 exerts protective effects in spontaneously hypertensive stroke-prone rats by preserving mitochondrial function.

S 35171 is one of a family of compounds that have been designed to protect mitochondrial function. We tested the hypothesis that S 35171 exerts protective effects in spontaneously hypertensive stroke-prone rats (SHRSPs), an animal model developing spontaneous brain damage preceded by proteinuria and systemic inflammation revealed by the urinary accumulation of acute-phase proteins (APPs) originating in the liver. Male SHRSPs fed a permissive diet received vehicle or S 35171 (10 mg/kg/day) started simultaneously with a high-sodium diet (group A) or after the establishment of proteinuria (group B). The drug delayed urinary APPs accumulation and the appearance of magnetic resonance imaging (MRI)-monitored brain lesions (after 62+/-3 days in group A, and 51+/-2 days in controls, P<0.01). The delay was more pronounced in group B as 30% of the animals survived the entire 90-day experimental period without brain abnormality. Proteomic analysis showed no significant alteration in the expression pattern of brain mitochondrial proteins, but the liver mitochondrial levels of carbamoylphosphate synthase I (CPS-I), an enzyme involved in urea metabolism) and the antioxidant peroxiredoxin-3 spot were affected by hypertension and S 35171. Stress reduces CPS-I and induces the peroxiredoxin-3 spot, whereas S 35171 brought about normal CPS-I expression and a 12-fold higher level of the peroxiredoxin-3 spot. As both enzymes are involved in maintaining mitochondrial functions, their increased expression after S 35171 treatment may be responsible for delaying the pathological condition that leads to the development of brain damage in SHRSPs.

[Effect of combination therapy with preduktal and prestarium on the left ventricular function in the postinfarction period].

The aim of the study was to estimate the efficiency of combination therapy with Preductal and Prestarium after MI. We investigated 152 patients with acute MI of anterior wall (Q wave) and Heart Failure (II-III class by NYHA). I group included 92 p, which were treated by Preductal (60 mg daily) on the background of the standard therapy. II group (60 p) treated by standard therapy. (ACE inhibitor, diuretic, beta-blocks). We divided the patients in 2 subgroups, with EF>45% and EF<45%. Echo investigation was performed after 1,3,6.12 months from the beginning of MI. We estimated LV EDV and ESV, EF, FS, SV and diastolic function. 12 month after myocardial infarction decreases of average heart failure and angina classes. After 6,12 months was noted decreased EDV and ESV, increased EF, FS,SV in both groups confidence, but spatially in the I gr. Patients, who had EF<45% and were treated with Preductal improved EF with 30,1%(p<0,05) confidence, which was 1,5 times more then in the control gr, also increased FS and SV by 32,7%, 13,6% p<0,05. At the same time was observed diastolic function improvement, particular decreased Ve, Ve/Va, and increased Va specially in the Preductal group more intensive and confidence. The treatment with Preductal during 12 months indicates his positive influence on the LV systolic and diastolic function, which is most significant in the patients with low EF.

Structure-activity studies on the protection of Trimetazidine derivatives modified with nitroxides and their precursors from myocardial ischemia-reperfusion injury.

Trimetazidine, the known anti-anginal and anti-ischemic drug, was modified by pyrroline and tetrahydropyridine nitroxides and their hydroxylamine and sterically hindered secondary amine precursors. The synthesized new compounds proved to be better superoxide scavenger molecules compared to the parent Trimetazidine in an in vitro experiment. This reactive oxygen species (ROS) scavenging activity was further supported by ischemia/reperfusion (I/R) studies on Langendorff-perfused rat hearts pretreated with Trimetazidine and with the modified Trimetazidine derivatives before ischemia. Two of the investigated compounds, containing 2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole and 4-phenyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole substituents on the piperazine ring, provided significant protection from the cardiac dysfunction caused by I/R. The protective effect could be attributed to the combined anti-ischemic and antioxidant effects.

Determination of trimetazidine dihydrochloride in the presence of its acid-induced degradation products.

Three methods are presented for the determination of trimetazidine dihydrochloride in the presence of its acid-induced degradation products. The first method was based on measurement of first-derivative D1 value of trimetazidine dihydrochloride at 282 nm over a concentration range of 8.00-56.00 microg/mL with mean percentage accuracy of 99.80+/-1.17. The second method was based on first derivative of the ratio spectra DD1 at 282 nm over the same concentration range with the percentage accuracy of 99.14+/-0.68. The third method was based on separation of trimetazidine dihydrochloride from its acid-induced degradation products followed by densitometric measurement of the spots at 215 nm. The separation was performed on silica gel 60 F254 using methanol-ammonia (100+/-1.5, v/v) as mobile phase. This method was applicable for determination of the intact drug in the presence of its degradation products over a concentration range of 2.00-9.00 microg/spot with mean percentage accuracy of 99.86+/-0.92. The proposed methods were successfully applied for the determination of trimetazidine dihydrochloride in bulk powder, laboratory-prepared mixtures containing different percentages of degradation products, and pharmaceutical dosage forms. The validity of results was assessed by applying the standard addition technique. The results obtained agreed statistically with those obtained by the reported method.

Quantitative structure-activity relationship analysis of the substituent effects on the binding affinity of derivatives of trimetazidine.

In the present study a series of trimetazidine (1-(2,3,4-trimethoxybenzyl)piperazine, CAS 5011-34-7) derivatives is subjected to quantitative structure-activity relationship (QSAR) analysis aiming at establishing the relationship between molecular structure and the binding affinity of the compounds to the respective receptor sites in the cells. Trimetazidine is used in the therapy of ischaemic heart disease. Literature data for the biological effect of the compounds are used. The derivatives studied include compounds with different substituents at the fourth position of the piperazine ring and a variation between the ortho-methoxy and ortho-hydroxy group in the benzyl residue. A statistically significant correlation between the Van der Waals volume of the substituents and the binding affinity of the respective compounds was found.

S15176 and S16950 interaction with Cyclosporin A antiproliferative effect on cultured human lymphocytes.

S15176 and S16950 are trimetazidine derivatives that antagonize more strongly than the parent drug mitochondrial toxicity, which leads to cellular hypoxia and nephrotoxicity in kidneys experimentally exposed to cyclosporin A. We have investigated whether every derivative might interact or not with the inhibitory effect of Cyclosporin A on the proliferation of cultured human lymphocytes. S15176 significantly increased the antilymphoproliferative effect of Cyclosporin A, whereas S15176 by itself neither displayed any antilymphoproliferative effect, nor did it induce any apoptotic process in cultured human lymphocytes. The effect of S16950 was not significant.

[(3)H]-trimetazidine mitochondrial binding sites: regulation by cations, effect of trimetazidine derivatives and other agents and interaction with an endogenous substance.

Trimetazidine, an antiischaemic drug, has been shown to restore impaired mitochondrial functions. Specific binding sites for [(3)H]-trimetazidine have been previously detected in liver mitochondria. In the present study we confirm this observation and provide additional evidence for the involvement of these sites in the pharmacological effects of the drug. Inhibition experiments using a series of trimetazidine derivatives revealed the presence of three classes of binding sites. An N-benzyl substituted analogue of trimetazidine exhibited a very high affinity (K(i)=7 nM) for one of these classes of sites. Compounds from different pharmacological classes were evaluated for their ability to inhibit [(3)H]-trimetazidine binding. Among the drugs tested pentazocine, ifenprodil, opipramol, perphenazine, haloperidol, and to a lower extent prenylamine, carbetapentane and dextromethorphan competed with high affinity, suggesting a similarity of high affinity [(3)H]-trimetazidine sites with sigma receptors. [(3)H]-Trimetazidine binding was modulated by pH. Neutral trimetazidine had about 10 fold higher affinity than protonated trimetazidine for its mitochondrial binding sites. Various cations also affected [(3)H]-trimetazidine binding. Ca(2+) was the most potent inhibitor and totally suppressed the binding of [(3)H]-trimetazidine to the sites of medium affinity. An endogenous cytosolic ligand was able to displace [(3)H]-trimetazidine from its binding sites. Its activity was not affected by boiling for 15 min, suggesting a non-protein compound. These data suggest that mitochondrial [(3)H]-trimetazidine binding sites could have a physiological relevance and be involved in the antiischaemic effects of the drug.

Structure-property relationships of trimetazidine derivatives and model compounds as potential antioxidants.

Twenty-five compounds (trimetazidine derivatives and other compounds, mostly having a free phenolic group) were examined for their radical scavenging and antioxidant properties. Their reaction with DPPH (2,2-diphenyl-1-picrylhydrazyl) as a measure of radical scavenging capacity was assessed by two parameters, namely EC50 (the concentration of antioxidant decreasing DPPH by 50%), and log Z, a kinetic parameter proposed here and derived from initial second-order rate constants and antioxidant/DPPH ratios. Antioxidant activities were determined by the inhibition of lipid peroxidation and albumin oxidation. The most active compounds were derivatives having a trolox or hydroquinone moiety. Physicochemical and structural properties were determined by molecular modeling as lipophilicity (virtual log P calculations) and H-Surf (solvent-accessible surface of hydroxyl hydrogen) and by quantum mechanical calculations (deltaH(ox) = oxidation enthalpy; deltaH(abs) = enthalpy of hydrogen abstraction). QSAR models were derived to identify molecular mechanisms responsible for the reactivity toward the DPPH radical and for the inhibition of lipid peroxidation. A useful prediction of antioxidant capacity could be achieved from calculated molecular properties and the kinetic parameter developed here.