[Determination of simvastatin in human plasma by high performance liquid chromatography]

[Article in Chinese]

Ling SS.

Department of Clinical Pharmacology, General Hospital of Nanjing PLA, Nanjing 210002, China.

Simvastatin is widely used in the treatment of hypercholestero-lemia. Recently, it was reported that it is also effective in reducing lethality in coronary heart disease. A simple and sensitive reversed-phase liquid chromatographic method has been developed and validated for the analysis of simvastatin in human plasma. Simvastatin and internal standard lovastatin in plasma were extracted with cyclohexane-dichloromethane (3.5:1, V/V), and then measured by HPLC using a Lichrospher C18 column as stationary phase and an acetonitrile-water (70:30, V/V) mixture as mobile phase. The flow rate was 1.2 mL/min. Simvastatin was quantified by UV at 237 nm. The calibration curve showed a good linearity in the mass concentration range of 0.25-50.0 micrograms/L. The regression equation is: Y = 0.0364 rho + 0.00583, r = 0.9998. Intra-day and inter-day coefficients of variation of assay for simvastatin in plasma < 7.94% and < 8.58%, respectively. The recoveries of simvastatin were > 93.3%. The method has been used to determine simvastatin in plasma from 12 healthy male volunteers.

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[Simvastatin induced apoptosis and its effect on apoptosis-related gene expression in rat vascular smooth muscle cell]

[Article in Chinese]

Shi YP.

The Second Affiliated Hospital, College of Medical Sciences, Zhejiang University, Hangzhou 310009, China.

OBJECTIVE: To observe the influence of simvastatin on the apoptosis of vascular smooth muscle cells (VSMC) and its effects on the expression of apoptosis-related genes. METHODS: The presence of apoptosis was detected by electron microscope and flow cytometry assessment of PI/Annexin V stain; The protein levels of Bax, Bel-2 and activation of caspase-3 were examined using Western blot technique. RESULTS: After treatment with 30 &mgr;mol/L simvastatin for 24 h, apoptosis were identified with electron microscope in VSMC and flow cytometry showed that rate of apoptosis in simvastatin group (35.5+/-5.8)% was singificantly higher than that in control group (15.1+/-5.0)%. Western blot analyses revealed that the apoptosis process was associated with upregulation of Bax protein and activation of caspase-3, but not with Bel-2 expression. CONCLUSION: Simvastatin can induce apoptosis in VSMC in associated with induction of bax and activation of caspase-3.

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Rapid spectrophotometric method for quantitative determination of simvastatin and fluvastatin in human serum and pharmaceutical formulations.

Erk N.

Department of Analytical Chemistry, Faculty of Pharmacy, University of Ankara, Turkey. erk pharmacy.ankara.edu.tr

A spectrophotometric method has been developed and applied to the determination of simvastatin and fluvastatin in human serum and in tablets. Simvastatine and fluvastatin were determined by measurement of their first derivative signals at 241.6, 245.9, 249.1 nm (for simvastatin) and 259.6 nm (for fluvastatin), respectively. Calibration curves were linear and the ranges of quantification were 12.0-28.0 micrograms.ml-1 for simvastatin and 10.0-28.0 micrograms.ml-1 for fluvastatin. The procedure was successfully applied to the determination of these compounds in pharmaceutical formulations as well as in human serum with a high percentage of recovery, good accuracy and precision, and without measurable interference by the excipients.

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Effect of simvastatin on endothelium-dependent vaso-relaxation and endogenous nitric oxide synthase inhibitor.

Li YJ.

Department of Pharmacology, School of Pharmaceutic Sciences, Central South University, Changsha 410078, China.

AIM: To investigate the effect of simvastatin on endothelium-dependent vasorelaxation and endogenous nitric oxide synthesis inhibitor asymmetric dimethylarginine (ADMA) in rats and cultured ECV304 cells. METHODS: Endothelial injury was induced by a single injection of low density lipoprotein (LDL) (4 mg/kg, 48 h) in rats or incubation with LDL (300 mg/L) or oxidative-modified LDL (100 mg/L) in cultured ECV304 cells, and vasodilator responses to acetylcholine (ACh) in the aortic rings and the level of ADMA, nitrite/nitrate (NO) and tumor necrosis factor-alpha (TNF-alpha) in the serum or cultured medium were determined. And the adhesion of the monocytes to endothelial cells and the activity of dimethylarginine dimethylaminohydrolase (DDAH) in the cultured ECV304 cells were measured. RESULTS: A single injection of LDL decreased endothelium-dependent relaxation to ACh, markedly increased the serum level of endogenous ADMA and TNF-alpha, and reduced serum level of NO. Pretreatment with simvastatin (30 or 60 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, the increased level of TNF-alpha and the decreased level of NO by LDL, but no effect on serum concentration of endogenous ADMA. In cultured ECV304 cells, LDL or ox-LDL markedly increased the level of ADMA and TNF-alpha and potentiated the adhesion of monocytes to endothelial cells, concomitantly with a significantly decrease in the activity of DDAH and serum level of NO. Pretreatment with simvastatin (0.1, 0.5, or 2.5 micromol/L) markedly decreased the level of TNF-alpha and the adhesion of monocytes to endothelial cells, but did not affect the concentration of endogenous ADMA and the activity of DDAH. CONCLUSION: Simvastatin protect the vascular endothelium against the damages induced by LDL or ox-LDL in rats or cultured ECV304 cells, and the beneficial effects of simvastatin may be related to the reduction of inflammatory cytokine TNF-alpha level.

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Simvastatin and markers of endothelial function in patients undergoing continuous ambulatory peritoneal dialysis.

Mysliwiec M.

Department of Nephrology and Internal Medicine, Medical Academy, Bialystok, Poland. jolmal poczta.onet.pl

Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are prone to dyslipidemia and have a high risk of cardiovascular death. The aim of this study was to assess the effects of a 6-month treatment with simvastatin (10 mg at bedtime) on markers of endothelial cell injury in 12 hypercholesterolemic CAPD patients. Cholesterol and low-density lipoprotein cholesterol fell significantly after 1 month of therapy. Simvastatin treatment significantly decreased concentrations of vascular cell adhesion molecule and intracellular adhesion molecule after 3 and 6 months of the therapy, respectively. Thrombomodulin decreased significantly after 6 months of the treatment, whereas von Willebrand's factor, P-selectin and E-selectin remained unaltered during simvastatin therapy. Simvastatin, an effective hypolipemic agent, favorably affects endothelial function and may potentially slow the progression of atherosclerosis and confer protection from thrombotic complications in patients with hypercholesterolemia undergoing CAPD.

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Lipid-lowering-independent effects of simvastatin on the kidney in experimental hypercholesterolaemia.

Lerman LO.

Division of Hypertension, Mayo Clinic, Rochester, MN 55905, USA.

BACKGROUND: Hypercholesterolaemia (HC), an independent risk factor for renal injury, is associated with formation of oxidized low-density-lipoprotein (ox-LDL), increased oxidative-stress and renal inflammation. HMG-CoA-reductase inhibitors are commonly used in HC, but their effects on renal haemodynamics and function in HC are poorly understood. METHODS: Pigs were studied after a 12-week normal diet, a 2% high-cholesterol diet (HC) or an HC diet supplemented with simvastatin (HC+simvastatin, 80 mg/day) (n=6-8 each group). Renal haemodynamics and function were quantified in vivo with electron-beam computed tomography (EBCT). Shock-frozen renal tissue was subsequently studied using immunohistochemistry. RESULTS: LDL cholesterol was similarly increased in HC and HC+simvastatin. Simvastatin-treated animals showed increased expression of endothelial nitric-oxide-synthase (eNOS), and decreased expression of the ox-LDL receptor LOX-1 in renal endothelial cells. Simvastatin also decreased tubular immunoreactivity of inducible-NOS, nitrotyrosine, nuclear-factor-kappaB, and tubuloglomerular trichrome staining. These were associated with a significant increase in cortical (6.1+/-0.1 vs 5.0+/-0.3 and 5.0+/-0.1 ml/min/cc, respectively, P<0.001) and medullary perfusion in HC+simvastatin compared to normal and HC. CONCLUSIONS: Simvastatin attenuated the inflammatory and pro-oxidative environment as well as fibrosis in kidneys in pigs with diet-induced HC, in association with enhanced renal perfusion. These cholesterol-lowering-independent changes imply novel renoprotective effects of statins in the setting of HC and atherosclerosis.

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