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We studied the effect of a new indolinone derivative GRS on animal survival and on functioning and histological structure of the lungs in rats with experimental pneumonitis. The rats of experimental groups were intratracheally administered 0.5% aqueous solution of carrageenan under intramuscular anesthesia. Compound GRS (10 mg/kg; a suspension in 0.5% aqueous solution of carboxymethyl cellulose) was orally administered for 4 days starting from the day of carrageenan administration; another rat group received the aqueous solution of carboxymethyl cellulose alone. Control rats received intratracheally isotonic solution of sodium chloride. Animal mortality was registered over 5 days; on day 5, the respiratory parameters were measured, the lungs were weighed, pulmonary edema was evaluated, and histological structure of the lungs was studied. GRS compound improved survival of animals with modeled pneumonitis, restored the respiratory parameters to the level of control animals, and reduced pulmonary edema by 35% and the severity of histological damage score in the lungs by 17% (p<0.05). [ABSTRACT FROM AUTHOR]

We studied antihypertensive activity of an indolinone derivative (compound GRS), a soluble guanylate cyclase stimulator and a drug with previously proven antiaggregant effects. Contraction activity of isolated aorta segments of Wistar-Kyoto (WKY) rats was assessed in vitro using a mechanographic method. Addition of GRS (0.1-100 μМ) resulted in dose-dependent relaxation of endothelium-denuded aorta segments. Pretreatment of aorta smooth muscle segments with a specific inhibitor of soluble guanylate cyclase (ODQ, 1 μM) weakened the vasodilatory effect of GRS. Antihypertensive activity of the indolinone derivative GRS was studied in spontaneously hypertensive SHR rats. Single oral administration of 5 and 10 mg/kg GRS was followed by a significant dose-dependent reduction of systolic and diastolic BP in SHR rats. Antihypertensive effect of GRS in a dose of 5 mg/kg was more potent than that of the reference drug isosorbide dinitrate. GRS in a dose of 10 mg/kg did not affect systolic and diastolic BP in normotensive WKY rats. [ABSTRACT FROM AUTHOR]

Cytochrome p450-mediated metabolism of GRS (indolinone antiaggregant) and its effects on activities of cytochrome p450 isoenzymes were studied. Inhibition of 6 isomers of cytochrome p450 in human liver microsomes was studied with the use of specific substrates. It was found that human liver cytochrome p450 enzymes could not induce degradation of GRS and that GRS was not an inductor or inhibitor of cytochrome p450 family members 1A2, 2C9, 2C19, 2D6, 2C8, and 3A4. Hence, clinical use of the prospective antiaggregant would not involve the risk of uncontrolled fluctuations in GRS concentrations in the organism because of interactions between the drugs. [ABSTRACT FROM AUTHOR]

Objective. Specific activity of an antiplatelet drug of indolinone series (codenamed DI) was studied in vitro in a model of ADP-induced platelet aggregation in vitro and in vivo in a model of streptozotocininduced diabetes mellitus in rats. Material and Methods. Acetylsalicylic acid and dipyridamole were used as reference drugs. In vitro tests have demonstrated that DI exhibits antiplatelet activity in a wide range of concentrations (0,75×10-6 - 1.5×10-5 M, P<0,05), being comparable to acetylsalicylic acid and dipyridamole. In vivo tests have demonstrated dose-dependent antiplatelet activity of DI in doses of 2,5 - 20 mg/kg (21-14 %). Results and Discussion.Increasing the dose of DI above 10 mg/kg doesn't increase its antiplatelet activity. After multiple oral administration to rats with streptozotocin-induced diabetes mellitus in 10 mg/kg dose, DI has exhibited antiplatelet activity, reducing the platelet aggregation rate to that of the control group (P<0,05).Conclusion. Thus, DI isapromisingcompound for furtherdevelopmentof an antiplatelet drug with new mechanism of action [ABSTRACT FROM AUTHOR]