Background and purpose: Elevated plasma total homocysteine (tHcy) level has been established as an independent risk factor for cardiovascular diseases. Danshensu, an active ingredient of Salvia miltiorrhiza, shows wide cardiovascular benefit. However, in terms of its own methylation, danshensu could elevate tHcy level, which would act against its cardiovascular benefit, thus posing a 'therapeutic paradox'. As this paradox has not been fully assessed, we have evaluated the effects of danshensu on tHcy levels to uncover the underlying mechanisms. Experiment approach: We evaluated the influence of danshensu on homocysteine (Hcy) metabolism in rats with normal tHcy levels and in rat models of elevated tHcy (single intravenous methionine loading model and a hyperhomocysteinemic model after 3 weeks methionine dosing, with and without 3 weeks of danshensu treatment). We also quantified some metabolic intermediates (S-adenosyl methionine, S-adenosyl-l-homocysteine, cysteine and glutathione) relevant to Hcy metabolism in rat liver and kidney. Key results: Acute treatment with a single dose of danshensu in rats with normal tHcy did not change plasma tHcy. In contrast, danshensu significantly lowered tHcy in rats with elevated tHcy. The relatively higher cysteine and glutathione levels after treatment with danshensu indicated that its tHcy-lowering effect was via increased activity of the trans-sulphuration pathway. Conclusions and implications:Our results suggested that danshensu may act both acutely to increase trans-sulphuration and after chronic exposure to up-regulate the activity of the trans-sulphuration enzymes. The tHcy-lowering effect of danshensu is another cardiovascular benefit provided by S. miltiorrhiza and suggests a potential tHcy-lowering therapy.

Stem cell factor (SCF) is a recently described factor active in the early stages of hematopoiesis. It can exist in membrane-bound form and in proteolytically released soluble form. The levels and nature of SCF in human serum are described. As determined by an enzyme-linked immunosorbent assay performed for 257 samples, SCF level in serum averaged 3.3 +/- 1.1 ng/mL. The serum SCF was partially purified by immunoaffinity chromatography and analyzed by glycosidase treatments in conjunction with sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. The results show that the SCF has N- linked and O-linked carbohydrate and corresponds to the soluble form, at or about 165 amino acids in length. The findings suggest functional importance for soluble SCF in humans.

Pharmacokinetics of ranolazine (RAN) in both female and male rats was studied. RAN concentrations in plasma were determined after oral administration of 12.5, 25 and 50 mg/kg RAN. Concentrations in tissues, recoveries of RAN in urine and bile were also analyzed following oral dose of 25 mg/kg. It was found that plasma concentrations of RAN in female rats were significantly higher than those in male rats. Drug exposures based on Cmax and AUC in female rats were roughly 2-to 3-fold of those in male rats. Terminate half-life T1/2 and MRT in male rats were shorter than those in female rats. The recoveries in urine and bile of female rats were also markedly higher than those in male rats'. Tissue concentrations of RAN in female rats were also markedly higher than those in male rats. These results demonstrated existence of marked gender difference in RAN pharmacokinetics in rats.

The aim of this study was to investigate effects of type 2 diabetes on the pharmacokinetics of verapamil after intravenous administration. Diabetes mellitus (DM) rats were induced by combination of high-fat diet (HFD) and streptozotocin. Plasma concentrations of verapamil in DM rats, rats fed with HFD, and control (CON) rats were measured after intravenous administration of 1 mg/kg verapamil and corresponding pharmacokinetic parameters were estimated. Area under the plasma concentration in DM rats was significantly smaller than that in CON rats. In vitro microsomal study showed that intrinsic clearance of verapamil in DM rats was significantly higher than those in CON rats. Compared to CON rats, higher intrinsic clearance was also observed in HFD rats. Western blot results demonstrated higher levels of CYP3A2 in DM and HFD rats, which was in line to activity of CYP3A. All the results gave a conclusion that diabetes may enhance metabolism of verapamil in rat, and the enhancement may partly result from induction of CYP3A.

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