[Molecular mechanisms of the cytoprotector cramizol effect in the experimental dyslipidemia model]. / Molekuliarnye mekhanizmy gipolipidemicheskogo deistviia tsitoprotektora kramizola pri éksperimental'noi dislipidemii.

The tested drug cramizol exhibits lipid-lowering and anti-atherogenic effects. Cramizol reduces blood cholesterol and triglycerides. It also increases HDL and reduces the atherogenic index in rats with the chronic dyslipidemia model induced by a hypercholesterol diet. Cramizol is effective as a hypolipidemic agent and its efficiency is comparable with the reference drug, phenofibrate. Cramizol increases expression of the ApoA1 and ApoC2 genes, and also reduces expression of the Scarb1 gene in rats with experimentally induced hyperlipidemia. These mechanisms could be the basis of its hypolipidemic and anti-atherogenic actions.

The mechanisms of action of water-soluble aminohexanoic and malonic adducts of fullerene C60 with hexamethonium on model lipid membranes.

In an attempt to understand the possibility of applications of the fullerene-based systems for transporting various polar compounds like hexamethonium through the blood-brain barrier, we studied the influence of a series of derivatives of fullerene C60 in the form of salts with hexamethonium bis-anion, namely the adducts of fullerenols with 6-aminohexanoic acid (IEM-2197), and two bis-adduct malonic acid derivatives of fullerene with addents bound in two hemispheres (IEM-2143) and in equatorial positions (IEM-2144), on model membranes. We showed that IEM-2197 induced the disintegration of the bilayers composed of DOPC at the concentrations more than 2 mg/ml. IEM-2144 and IEM-2143-induced ion-permeable pores at concentrations of 0.3 and 0.02 mg/ml, respectively; herewith, IEM-2143 was characterized by the greater efficiency than IEM-2144. IEM-2197 did not significantly affect the phase behavior of DPPC, while the melting temperature significantly decreased with addition of IEM-2144 and IEM-2143. The increase in the half-width of the main transition peaks by more than 2.0 °C in the presence of IEM-2144 and IEM-2143 was observed, along with the pronounced peak deconvolution. We proposed that the immersion of IEM-2144 and IEM-2143 into the polar region of the DOPC or DPPC bilayers led to an increase in the relative mobility of tails and formation of ion-permeable defects. IEM-2197 demonstrated the more pronounced effects on the melting and ion permeability of PG- and PS-containing bilayers compared to PC-enriched membranes. These results indicated that IEM-2197 preferentially interacts with the negatively charged lipids compared to neutral species.

[Effects of сramizol on expression of the ApoA1 gene in rats with experimental hyperlipidemia]. / Vliianie kramizola na ékspressiiu gena apolipoproteina A1 (ApoA1) v pecheni krys pri éksperimental'no indutsirovannoi giperlipidemii.

An imidazole derivative cramizol, has lipid-lowering and anti-atherogenic effects. Cramizol reduces blood levels of cholesterol and triglycerides, and also reduces the atherogenic index in animals with acute hyperlipidemia induced by Triton WR-1339. Cramizol and the lipid-lowering drug fenofibrate exhibited similar effectiveness as hypolipidemic agents. Cramizol also restores the expression of the Apoa1 gene in rats with experimentally induced hyperlipidemia to normal values. This may be a basis of its hypolipidemic and anti-atherogenic action.

Enhanced brain penetration of hexamethonium in complexes with derivatives of fullerene C60.

The present report describes development of hexamethonium complexes based on fullerene C60. Hexamethonium has a limited penetration into CNS and therefore can antagonize central effects of nicotine only when given at high doses. In the present studies conducted in laboratory rodents, intraperitoneal administration of hexamethonium-fullerene complexes blocked effects of nicotine (convulsions and locomotor stimulation). When compared to equimolar doses of hexamethonium, complexes of hexamethonium with derivatives of fullerene C60 were 40 times more potent indicating an enhanced ability to interact with central nicotine receptors. Thus, fullerene C60 derivatives should be explored further as potential carrier systems for polar drug delivery into CNS.

The biodegradation of fullerene C60 by myeloperoxidase.

It is shown for the first time that the mammalian enzymes can cause the degradation of the C60 fullerene molecules. This biodegradation is caused by the action of а hypochlorite generated neutrophil enzyme myeloperoxidase of fullerene molecule and leads to the loss of the topology of the fullerene core.

Disposition of ethimizol, a xanthine-related nootropic drug, in perfused rat liver and isolated hepatocytes.

Ethimizol, 4,5-di(methylcarbamoyl)-1-ethyl-imidazole, was metabolized into at least six metabolites in an isolated perfused rat liver preparation. Based on TLC and mass spectrometry, 4-carbamoyl-5-methylcarbamoyl-1-ethyl-imidazole and 4,5-di(methylcarbamoyl)-imidazole were identified as the primary metabolites of ethimizol. These undergo further biotransformation: both can form 4(5)-carbamoyl-5(4)-methylcarbamoyl-imidazole, and, moreover, the former can be hydroxylated. Besides the identified metabolites, two polar ones of unknown structure were detected. Dose-dependent elimination of ethimizol was observed when the drug was added to the liver perfusion recirculating medium in initial reservoir concentrations of 39, 48, 85, 165, and 240 microM. The observed nonlinearity appeared to be a result of a competitive product inhibition. Similar to the parent drug, ethimizol primary metabolites were formed and eliminated in a dose-dependent manner. The uptake of ethimizol by isolated hepatocytes was extremely rapid, independent of drug concentration, over the range 0 to 250 microM, unaffected by inhibitors and independent of temperature.

The effect of enzyme induction and inhibition on the disposition of the xanthine-related nootropic drug ethimizol in perfused liver and hepatocytes of rats.

The once-through perfused (18 ml/min) rat liver preparations from vehicle-, phenobarbital (PB)-, and 3-methylcholanthrene (3-MC)-treated rats were used for the study of 14C-ethimizol [4,5-di(methylcarbamoyl)-1-ethyl-imidazole] elimination after input concentrations of 5, 25, 50, and 100 microM. The steady state hepatic extraction ratios decreased with increasing ethimizol inputs and were (mean +/- SD): for vehicle-treated rats, 0.361 +/- 0.038, 0.193 +/- 0.018, 0.141 +/- 0.010, and 0.100 +/- 0.011; for PB-treated rats, 0.578 +/- 0.093, 0.393 +/- 0.039, 0.302 +/- 0.028, and 0.236 +/- 0.032; and for 3-MC-treated rats, 0.913 +/- 0.057, 0.783 +/- 0.130, 0.619 +/- 0.097, and 0.447 +/- 0.053, for the respective concentrations. In recirculating experiments both PB and 3-MC increased ethimizol elimination, but the effect of the latter was considerably greater. 3-MC was also more effective than PB in enhancing the rate of formation and subsequent biotransformation of the primarily formed ethimizol metabolites, 4-carbamoyl-1-ethyl-5-methylcarbamoyl-imidazole and 4,5-di(methylcarbamoyl)-imidazole. Elimination of ethimizol was inhibited in suspension of rat hepatocytes by SKF 525-A at concentrations of 10 and 100 microM by 63% and 60%, respectively, and by alpha-naphthoflavone, at the same concentrations, by 71% and 85%, respectively. Their simultaneous addition almost completely inhibited ethimizol biotransformation. An increase of the ethimizol elimination rate in single-pass rat liver perfusion by 55% was observed in preparations from rats treated by ethimizol in their drinking water, whereas the liver/body weight ratio, microsomal protein, and cytochrome P-450 content remained unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)