[The study of vasodilative and antiischemic function of nicorandil in regional ischemia and reperfusion of rat heart in vivo].

Aim of the work was to study effect of nicorandil [N-(2-nitrooxiethyl) nicotinamide, SG75] on blood pressure (BP), heart rate (HR) and rhythm disturbances during regional ischemia and reperfusion of the heart in rats in vivo and its ability to limit acute myocardial infarction (MI). Nicorandil was obtained by nitrating nicotinamide ethanol using produced by industry ethylnicotinate. MI in Wistar rats was modeled by 40-min occlusion of anterior descending coronary artery (ADCA) and subsequent 60-min reperfusion. Nicorandil (3,2 mmol/kg) was administered intravenously before occlusion. Nitroglycerine was used as preparation of comparison; it was administered in the same dose. MI area and zone at risk (ZR) were measured by computer planimetry after staining of left ventricular sections with 2, 3, 5-triphenyltetrazolium chloride. Lowering of mean BP under influence of nicorandil during ADCA occlusion and subsequent reperfusion were deeper and longer than under influence of nitroglycerine. Contrary to nitroglycerine administration of nicorandil did not cause decrease of HR. Administration of both drugs postponed origination of rhythm disturbances during ischemia but did not affect their duration. MI dimension assessed by MI/ZR ratio after administration of nicorandil and nitroglycerine was significantly lowered down to 22 +/- 4 and 32 +/- 3%, respectively, compared with 47 +/- 3% in control. The results obtained evidence that in this model of ischemic and reperfusion damage of the heart vasodilating properties of nicorandil combined with decrease of postischemic loss of cardiomyocytes in ZR are comparable with effects of nitroglycerine.

[Nitric oxide donor increases the effectiveness of cytostatic therapy and inhibits the development of drug resistance]. / Donor oksida azota povyshaet éffektivnost' tsitostaticheskoi terapii i zaderzhivaet razvitie lekarstvennoi rezistentnosti.

The investigation has established a potential of low-dosage chemotherapy with cytostatics when used in combination with nitric oxide (NO) donor. Such regimen resulted in more animals being cured of leukemias P388 and L1210 and longer survival. Similar effect was reported with transplantable intracerebral leukemia P388 in which case mean survival after cyclophosphamide plus NO-donor was three times as high as that after cyclophosphamide alone. Combination therapy also promoted animetastatic effect: melanoma B16 inhibition by cyclophosphamide alone was 50% vs. 80% after cyclophosphamide plus NO-donor. NO-donor inhibited development of drug resistance to cyclophosphamide.

Nitric oxide donor increases the efficiency of cytostatic therapy and retards the development of drug resistance.

The potentiality to increase the chemotherapeutic effectiveness of some cytostatics in low, subtherapeutic doses in combination with nitric oxide (NO) donor has been shown. This type of combined therapy results in significant increase in life span and number of survivors among mice bearing leukemias P388 and L-1210. A similar effect was observed for intracerebral leukemia P388 transplantation. In this case the life span of mice treated with cyclophosphamide and NO donor increased by three times in comparison to therapy with cyclophosphamide alone. The coinjection of nitric oxide donor and cytostatics improved the antimetastatic activity of the cytostatics: the index of melanoma B16 metastasis inhibition at the cyclophosphamide monotherapy is 50%; on addition of NO donor the index is over 80%. Comparative studies of NO donor (organic nitrate) and a similar compound in which ONO(2) moieties were replaced by OH groups demonstrated that the presence of NO(2) is required for adjuvant activity of compounds and confirmed that nitric oxide modifies the antitumor effects of cytostatics. It is shown also that nitric oxide donor retards the development of drug resistance to cyclophosphamide.

NMR study on the interaction of 1,4-cubanedicarboxylic acid and its esters with elemental fluorine. The synthesis of dimethyl 2-fluorocubane-1,4-dicarboxylate.

Elemental fluorine can be successfully used for fluorination of cubane derivatives. The nature of the products depends on the fluorination conditions: in CH3CN at -20 to -30 degrees C, dimethyl 2-fluorocubane-1,4-dicarboxylate was obtained from dimethyl ester of 1,4-cubanedicarboxylic acid; in CF3COOH at -12 to -15 degrees C in the presence of alkali metal acetates, 1,4-cubanedicarboxylic acid and its dimethyl and diethyl esters gave complex mixtures of fluorinated cubane products. Our investigation by 1H and 19F NMR spectroscopy and spectra computer simulation revealed production of mono- and difluorinated cubanes. Fluorine-containing cubane derivatives were also found with extra substituents in other than 1 and 4 positions.