A Strategy for Optimizing the Combination of Active Components Based on Chinese Medicinal Formula Sheng-Mai-San for Myocardial Ischemia.

BACKGROUND/AIMS: Traditional Chinese medicine (TCM) has been used in clinical practice for thousands of years and has accumulated considerable knowledge concerning the in vivo efficacy of targeting complicated diseases. TCM formulae are a mixture of hundreds of chemical components with multiple potential targets, essentially acting as a combination therapy of multi-component drugs. However, the obscure substances and the unclear molecular mechanisms are obstacles to their further development and internationalization. Therefore, it is necessary to develop new modern drugs based on the combination of effective components in TCM with exact clinical efficacy. In present study, we aimed to detect optimal ratio of the combination of effective components based on Sheng-Mai-San for myocardial ischemia. METHODS: On the basis of preliminary studies and references of relevant literature about Sheng-Mai-San for myocardial ischemia, we chose three representative components (ginsenoside Rb1 (G), ruscogenin (R) and schisandrin (S)) for the optimization design studies. First, the proper proportion of the combination was explored in different myocardial ischemia mice induced by isoproterenol and pituitrin based on orthogonal design. Then, the different proportion combinations were further optimized through uniform design in a multi-model and multi-index mode. Finally, the protective effect of combination was verified in three models of myocardial ischemia injured by ischemia/reperfusion, chronic intermittent hypoxia and acute infarction. RESULTS: The optimized combination GRS (G: 6 mg/kg, R: 0.75 mg/kg, S: 6 mg/kg) obtained by experimental screening exhibited a significant protective effect on myocardial ischemia injury, as evidenced by decreased myocardium infarct size, ameliorated histological features, decreased myocardial myeloperoxidase (MPO) and malondiadehyde (MDA), calcium overload, and decreased serum lactate dehydrogenase (LDH), creatine kinase MB isoenzyme (CK-MB), cardiac troponin I (cTn-I) activity. In addition, the interactions of three components in combination GRS were also investigated. The combination, compared to G, R and S, could significantly reduce the concentration of serum CK-MB and cTn-I, and decrease myocardial infarct size, which demonstrated the advantages of this combination for myocardial ischemia. CONCLUSION: Our results demonstrated that the optimized combination GRS could exert significant cardioprotection against myocardial ischemia injury with similar effect compared to Sheng Mai preparations, which might provide some pharmacological evidences for further development of new modern Chinese drug for cardiovascular diseases basing on traditional Chinese formula with affirmative therapeutic effect.

[Effect of cavinton on the indices of carbohydrate metabolism in the blood vessel wall]. / Vliianie kavintona na pokazateli uglevodnogo obmena v stenke krovenosnykh sosudov.

Effect of cavinton on contents of pyruvic and lactic acids in the walls of the femoral and carotid arteries as well as the abdominal aorta and its arch was studied at administration for 3, 5 and 7 days to rabbits. Cavinton was shown to contribute to general aerobization of carbohydrate catabolism in the vessel wall. The femoral and carotid arteries were found to be the most reactive vessels. In experimental pituitrine-induced pathology a general decrease of carbohydrate catabolism was observed.

[Effect of lithium oxybutyrate on lipid metabolic changes in pituitrin-induced pulmonary edema]. / Vliianie oksibutirata litiia na izmeneniia lipidnogo obmena pri pituitrinovom oteke legkikh.

The experiments on white rats have confirmed that the development of lung edema following pituitrin infusion is characterized by considerable changes in phospholipid and cholesterol lung metabolism and cholesterol blood metabolism. Lithium hydroxybutyrate preinjection at a dose of 400 mg/kg prevented a decrease in cholesterol lung content and an increase in cholesterol blood plasma level which was accompanied by less prominent lung edema.

[Effect of heparin and fepromaron on the kallikrein-kinin system in pituitrin-induced hypertension]. / Vliianie geparina i fepromarona na kallikrein-kininovuiu sistemu pri pituitrinovoi gipertenzii.

A study was made of the effects of heparin and sodium fepromaron on prekallikrein (PK); kallikrein inhibitors (KI), initial esterase activity (IEA) of rat blood in health and pituitrin hypertension. Pituitrin hypertension was associated with IEA increase and KI decrease. A single administration of heparin raised IEA; if administered for 3 days, heparin reduced IEA. After pituitrin administration heparin decreased IEA if administered once or for 3 days. Administration of fepromaron in courses following pituitrin also reduced. IEA, with that reduction being preserved for not less than 4 days after drug discontinuation. Similarity of the effects of heparin and fepromaron on hemocoagulation and the tone of blood vessels suggests the common mechanisms of their action on the blood kinin system.

[Effect of vasodilator preparations on the ATPase activity of the erythrocyte membranes of rabbits with experimental vascular pathology]. / Vliianie sosudorasshiriaiushchikh preparatov na ATFaznuiu aktivnost' membran éritrotsitov krolikov s éksperimental'noi sosudistoi patologiei.

Experiments on rabbits with pituitrin hypertension have demonstrated activation of Na+, K+-ATPase of red cell membranes. Meanwhile ATPase activity declined in vasorenal hypertension. The vasodilatory drugs (papaverine, pentamine, euphylline, nicotinic acid) administered in courses normalized both the activity of transport ATPases of cell membranes and carbohydrate metabolism of blood vessels, which was disturbed in experimental vascular pathology.

[Metabolic effects of nicotinic acid in different types of experimental vascular pathology in rabbits]. / Metabolicheskie éffekty nikotinovoi kisloty pri razlichnykh vidakh éksperimental'noi sosudistoi patologii u krolikov.

In experiments on rabbits with pituitrin and vasorenal hypertension, the 7-day administration of nicotinic acid (4 mg/kg) produced distinct changes in carbohydrate-energy metabolism in blood vessels of different functions. The metabolic effects of nicotinic acid were dependent on the type of vascular pathology and functional features of blood vessels.

[Bioelectrical, biochemical and histomorphological changes in the ocular tissues in pituitrin hypertension and the use of euphylline and papaverine]. / Bioélektricheskie, biokhimicheskie i gistomorfologicheskie izmeneniia v tkaniakh glaza pri pituitrinovoi gipertenzii i primenenii éufillina i papaverina.

Experimental study on rabbits of bioelectric and biochemical characteristics of eye tissues during pituitrin hypertension and application of euphylline and papaverine as well as comparison of the data obtained indicate that during pituitrin hypertension, transtissue potential difference and density of short-circuit current in the lens are considerably increased whereas the level of tissue respiration in the eye is reduced. Administration of euphylline or papaverine during pituitrin hypertension aggravates hemodynamic disorders in eye tissues, deteriorates the bioelectric and biochemical characteristics in both hypertensive and control animals.