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PubMed1999

Differential effects of pravastatin, simvastatin, and atorvastatin on Ca2+ release and vascular reactivity.

The direct effects of the cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors, on vascular smooth muscle responsiveness were examined by incubation of isolated aorta from normocholesterolemic rats with simvastatin, atorvastatin, or pravastatin. The smooth muscle contractions caused by phenylephrine were progressively inhibited with increasing concentrations of simvastatin. Similarly, atorvastatin at the higher concentration caused decreased responses to phenylephrine. In contrast, incubation with pravastatin had no significant effect at all concentrations studied. In Ca2+-free buffer, the transient contraction caused by phenylephrine, which results from intracellular release of Ca2+, also was inhibited by simvastatin and atorvastatin but not by pravastatin. In cultured rat aortic smooth muscle cells loaded with fura-2, increases in intracellular free-Ca2+ concentration ([Ca2+]i) induced by angiotensin II were markedly inhibited in cells incubated with simvastatin and atorvastatin but not pravastatin. The inhibitory effects of simvastatin and atorvastatin were reversed by mevalonate. These findings demonstrate that inhibition of HMG CoA reductase by using simvastatin and atorvastatin, but not pravastatin, has effects on vascular smooth muscle cell responsiveness that involve alteration of Ca2+ homeostasis through a mevalonate-dependent pathway.

Animals↗

PubMed2000

Simvastatin acts synergistically with ACE inhibitors or amlodipine to decrease oxygen consumption in rat hearts.

Statin drugs, which are cholesterol-lowering agents, can upregulate endothelial nitric oxide synthase (eNOS) in isolated endothelial cells independent of lipid lowering. We investigated the effect of short-term simvastatin administration on NO-mediated regulation of myocardial oxygen consumption (MV(O2)) in tissue from rat hearts. Male Wistar rats were divided into (a) control group (n = 14), and (b) simvastatin group (n = 10, 20 mg/kg/day by oral gavage). After 2 weeks, left ventricular myocardium was isolated to measure MV(O2) using a Clark-type oxygen electrode, and aortic plasma nitrates and nitrites (NOx) were measured. Baseline plasma NOx levels (19+/-2.6 in control vs. 20+/-2.5 microM/L in simvastatin) and baseline MV(O2) (288+/-23 in control vs. 252+/-11 nmol/g/min; p = 0.09) were not significantly different between the two groups. NO-dependent regulation of MV(O2) in response to bradykinin, ramipril, or amlodipine was augmented in simvastatin rats compared with controls (p < 0.05). Decrease of MV(O2) from baseline in response to highest doses in control versus simvastatin groups was as follows-bradykinin, -28+/-5% vs. -44+/-6%; ramipril, -35+/-5% vs. -50+/-8%; and amlodipine, -32+/-9% vs. -42+/-3%. Response to highest dose of NO donor S-nitroso N-acetyl penicillamine (SNAP) was not significantly different in the two groups (-55+/-5% vs. -52+/-7%). Treatment with Nw-nitro-L-arginine methyl ester, inhibitor of NO synthesis, attenuated the effect of bradykinin, ramipril, and amlodipine on MV(O2) (p < 0.05). In conclusion, short-term administration of simvastatin in rats potentiates the ability of angiotensin-converting enzyme (ACE) inhibitors and amlodipine to cause NO-mediated regulation of MV(O2).

Amlodipine↗

PubMed1997

Rhabdomyolysis associated with simvastatin-gemfibrozil therapy.

Simvastatin is a potent inhibitor of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase intended for use as a hypocholesterolemic agent. The long-term clinical experience with simvastatin indicates that it is a safe, effective, and well-tolerated hypolipidemic agent. Laboratory adverse events involving elevations of serum transaminase levels and serum creatine kinase (CK) levels to more than three times the upper limit of normal range have been seen in 1.5% and 3.4% of cases, respectively. We describe a case of severe myopathy and rhabdomyolysis associated with concomitant use of simvastatin and gemfibrozil. Seven days after discontinuing administration of gemfibrozil and simvastatin, the patient's condition improved and she was discharged home. Although this is the first report to indicate an association between myopathy and concomitant use of simvastatin and gemfibrozil, we strongly recommend caution and careful monitoring if simvastatin is given to patients receiving gemfibrozil.

Anticholesteremic Agents↗

PubMed1996

Effects of simvastatin and ciprofibrate alone and in combination on lipid profile, plasma fibrinogen and low density lipoprotein particle structure and distribution in patients with familial combined hyperlipidaemia and coronary artery disease.

BACKGROUND: Hypolipidaemic agents do not usually normalize all of the multiple lipoprotein abnormalities in patients with familial combined hyperlipidaemia (FCHL). The effect of the simvastatin-ciprofibrate combination in comparison with each drug alone on the lipoprotein abnormality patterns was studied in patients with FCHL and coronary artery disease (CAD). METHODS: Sixty patients (53 men and seven women), mean age 52 years (range 36-60 years), were studied. After a 4-week placebo period, patients were randomly assigned to three groups. The first group (n = 20) received simvastatin (20 mg daily), the second group (n = 20) ciprofibrate (100 mg daily) and the third group (n = 20) the combination of both drugs for a 12-week period. Parameters measured were as follows: plasma fibrinogen, total cholesterol, triglycerides, low density lipoprotein (LDL), very low density lipoprotein, intermediate density lipoprotein, and high density lipoprotein cholesterol, as well as LDL subfraction distribution and structure by density gradient ultracentrifugation. Apoproteins (apo) B and AI were assessed by immunoturbidometry. RESULTS: At baseline, apoB, LDL cholesterol and triglycerides were increased, whereas LDL particles were small and dense. ApoB was significantly reduced by all three interventions. Drug combination and ciprofibrate significantly reduced plasma fibrinogen (-24 and -25%, respectively; P < 0.001) and triglycerides (-51 and -49%, respectively; P < 0.001). Drug combination and simvastatin significantly reduced LDL cholesterol (-25 and -22%, respectively; P < 0.001) compared with ciprofibrate (-10%; P < 0.01). Ciprofibrate and drug combination increased LDL particle size (parameter K -0.24 versus -0.61 and -0.30 versus -0.62, respectively; P < 0.001), whereas simvastatin had no significant effect on LDL particle size. The cholesterol content of LDL particles was reduced with ciprofibrate and the drug combination only in the dense LDL particles (LDL3-5) and increased in the light (LDL1-2) subfractions, whereas simvastatin reduced the cholesterol content of all LDL subfractions except LDL2. Ciprofibrate and drug combination reduced the triglyceride content of all LDL subfractions. CONCLUSION: Combined treatment with simvastatin and ciprofibrate effectively reduced plasma fibrinogen, triglycerides, total and LDL cholesterol and increased LDL particle size in patients with FCHL and CAD. These effects might induce a clinical benefit for these patients.

Adult↗

PubMed2004

Simvastatin-induced myocardial protection against ischemia-reperfusion injury is mediated by activation of ATP-sensitive K+ channels.

OBJECTIVES: Previous studies have suggested that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors attenuate ischemia-reperfusion injury. We investigated whether pretreatment with simvastatin reduces myocardial infarct size and whether glyburide, a non-selective inhibitor of the ATP-sensitive K channels, abrogates this infarct size-limiting effect. METHODS: Sprague-Dawley rats were treated with either simvastatin (20 mg/kg per day) or saline alone for 3 days. Additional groups of rats were treated as above and on the fourth day they received intravenous glyburide (0.3 mg/kg). All rats underwent 30 min of coronary artery occlusion followed by 180 min of reperfusion. Ischemic myocardium at risk was assessed with blue dye and infarct size with triphenyltetrazolium chloride. RESULTS: Infarct size, expressed as a percentage of the myocardium at risk, was significantly smaller in the simvastatin group (n = 8, 20.8 +/- 3.4%) than in the placebo group (n = 6, 40.1 +/- 2.7%) (P = 0.001). Glyburide abolished the protective effect of simvastatin with infarct size being 34.2 +/- 6.9% and 29.7 +/- 3.9% of the area at risk in the simvastatin group (n = 7) and placebo (n = 7) group, respectively (P = 0.58). CONCLUSIONS: Simvastatin significantly reduced myocardial infarct size. The protective effect was completely abrogated by glyburide, strongly suggesting that this protective effect is mediated via activation of the ATP-sensitive K channels.

ATP-Binding Cassette Transporters↗

PubMed2006

Effect of simvastatin on coronary flow reserve in patients with atherosclerosis and hypercholesterolemia: an intracoronary Doppler study.

BACKGROUND: Early stages of coronary atherosclerosis are accompanied by a functional impairment of coronary vasodilator capacity and endothelial dysfunction. Reduced coronary flow reserve has been reported in patients with hypercholesterolemia, despite angiographically normal coronary arteries. The aim of the study was to evaluate the effect of simvastatin on coronary flow reserve. METHODS: The study was an open non-placebo-controlled serial investigation in which every patient acted as his own control: 36 male patients with hypercholesterolemia and a non-significant coronary artery lesion in a not previously revascularized coronary artery. Intracoronary Doppler measurements were performed. Coronary flow reserve, relative coronary flow reserve and average peak velocity were performed at baseline, after 3 months on a lipid-lowering diet (control period), and after another 12 months of simvastatin 40 mg/day. In the same patient cohort, significant reduction in lesion plaque plus media has been demonstrated by intravascular ultrasound. RESULTS: Changes in coronary flow reserve were not influenced by either diet or simvastatin (2.5+/-0.6 vs. 2.6+/-0.5 vs. 2.6+/-0.6, P=ns). Maximum hyperemic flow (34.8+/-12.2 vs. 36.7+/-12.5 vs. 42.5+/-13.1, P<0.001) as well as resting flow (14.3+/-5.3 vs. 14.5+/-4.4 vs. 16.6+/-4.6, P<0.001) increased significantly after 12 months simvastatin therapy. CONCLUSION: Despite plaque plus media, regression simvastatin therapy for 12 months does not affect coronary flow reserve obtained using serial intracoronary Doppler studies. Simvastatin, however, increases the hyperemic flow velocity.

Blood Flow Velocity↗

PubMed2003

Simvastatin inhibits interleukin-6 release in human monocytes stimulated by C-reactive protein and lipopolysaccharide.

BACKGROUND: The accumulating evidence suggests that C-reactive protein (CRP) may have direct inflammatory effects on the vascular wall and that statin therapy may have important non-lipid anti-inflammatory effects confirmed by decreasing serum inflammatory markers, such as CRP. However, the effect of simvastatin on interleukin-6 (IL-6) release in cultured human monocytes was not investigated. DESIGN A prospective, human monocyte culture, simvastatin intervention study. METHODS: Monocytes were isolated from blood of healthy volunteers by the Ficoll density gradient and stimulated by broad concentrations of CRP (1-20 microg/ml) and lipopolysaccharide (LPS, 1-10 ng/ml) at indicated time points (0, 2, 4, 8, 16 and 24 h). Also 10-8-10-6 mol/l simvastatin was coincubated with cells in the presence of CRP and LPS. Measurements of IL-6 were performed from supernatants of cultured medium in duplicate, using a commercial assay kit. RESULTS: CRP and LPS induced the rapid release of IL-6, with significantly elevated levels in cultured supernatants at 4 h in the CRP group and at 2 h in the LPS group. The effects of CRP and LPS on IL-6 release of monocytes were dose and time dependent. A greater than 11-fold increase of IL-6 in the CRP group (20 microg/ml) and a greater than 26-fold increase in the LPS group (10 ng/ml) were observed at 24 h compared with the control group (945.7+/-98.3 pg/ml compared with 94.3+/-12.4 pg/ml and 1720.4+/-690.1 pg/ml compared with 70.1+/-16.7 pg/ml, P<0.001, respectively). However, 10-8-10-6 mol/l simvastatin inhibited significantly the production of IL-6 in monocytes stimulated by CRP and LPS in a dose-dependent manner, with the maximal inhibiting effect at a concentration of 10-6 mol/l (945.7+/-98.3 pg/ml compared with 180.9+/-31.2 pg/ml and 1720.4+/-690.1 pg/ml compared with 824.0+/-206.2 pg/ml, P<0.001 respectively). CONCLUSIONS: CRP and LPS could induce IL-6 release in human monocytes and simvastatin could inhibit this response in a dose-dependent manner, which may provide an insight into the mechanisms of anti-inflammatory or anti-atherosclerotic actions of simvastatin.

C-Reactive Protein↗

PubMed2004

Superoxide anion overproduction in sepsis: effects of vitamin e and simvastatin.

Oxidative stress during sepsis induces tissue damage, leading to organ dysfunction and high mortality. The antioxidant effects of vitamin E have been reported in several diseases, but not in sepsis. Statins have cholesterol-independent anti-inflammatory effects that are related to a decrease of isoprenoid proteins and oxidative stress. Therefore, we evaluated superoxide anion (O2- degree) production and ex vivo effects of vitamin E and simvastatin in sepsis. Fourteen healthy volunteers, 14 intensive care unit (ICU) nonseptic, and 14 ICU patients with sepsis were included in this prospective study. Plasma cholesterol, triglyceride, and vitamin E levels were determined by routine laboratory tests. Superoxide anion production was measured in the venous blood by chemiluminescence technique after phorbol myristate acetate stimulation. Effects of vitamin E and simvastatin on O2- degree production was investigated ex vivo. Luminescence was indexed to the leukocyte count. We also investigated the in vitro effect of simvastatin on translocation of NADPH oxidase p21 Rac2 subunit in THP-1 monocytic cell line. The ratio of vitamin E/cholesterol + triglycerides was significantly decreased in septic as compared with nonseptic patients and volunteers. The O2- degree production was significantly higher in the group of septic patients than in the others, regardless of the polymorphonuclear leukocyte count. Vitamin E and simvastatin induced ex vivo an inhibition of O2- degree production of 20% and 40% respectively. In vitro, simvastatin inhibited phorbol myristate acetate-induced- O2- degree production by monocytes through NADPH oxidase inactivation. We conclude that sepsis is associated with a significant decrease in vitamin E and an overproduction of O2- degree. Vitamin E and simvastatin lessen this phenomenon through NADPH oxidase inactivation.

APACHE↗

PubMed2005

Treatment with simvastatin suppresses the development of experimental abdominal aortic aneurysms in normal and hypercholesterolemic mice.

OBJECTIVE: To determine if treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) can influence the development of experimental abdominal aortic aneurysms (AAAs). SUMMARY BACKGROUND DATA: AAAs are associated with atherosclerosis, chronic inflammation, and matrix metalloproteinase (MMP)-mediated connective tissue destruction. Because statins exert antiinflammatory activities independent of their lipid-lowering effects, these agents may help suppress aneurysmal degeneration. METHODS: C57Bl/6 wild-type and hypercholesterolemic apoE-deficient mice underwent transient perfusion of the aorta with elastase followed by subcutaneous treatment with either 2 mg/kg simvastatin per day or vehicle. Aortic diameter (AD) was measured before and 14 days after elastase perfusion. The extent of aortic dilatation (DeltaAD) was determined with AAAs defined as DeltaAD >100%. RESULTS: Wild-type mice treated with simvastatin exhibited a 21% reduction in DeltaAD and a 33% reduction in AAAs compared with vehicle-treated controls. Suppression of AAAs in simvastatin-treated mice was associated with preservation of medial elastin and vascular smooth muscle cells, as well as a relative reduction in aortic wall expression of MMP-9 and a relative increase in expression of TIMP-1. In hypercholesterolemic apoE-deficient mice, treatment with simvastatin was associated with a 26% reduction in DeltaAD and a 30% reduction in AAAs. Treatment with simvastatin had no effect on serum cholesterol levels in either normal or hypercholesterolemic mice. CONCLUSIONS: Treatment with simvastatin suppresses the development of experimental AAAs in both normal and hypercholesterolemic mice. The mechanisms of this effect are independent of lipid-lowering and include preservation of medial elastin and smooth muscle cells, as well as altered aortic wall expression of MMPs and their inhibitors.

Animals↗

PubMed2004

Simvastatin decreases nitric oxide overproduction and reverts the impaired vascular responsiveness induced by endotoxic shock in rats.

Lipopolysaccharides (LPS) can be used to induce experimental endotoxic shock, which is characterized by a significant decrease in mean arterial pressure (MAP) and a decreased vasoconstrictor response that have been attributed to excessive nitric oxide production. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), in addition to lowering serum cholesterol levels, exert many pleiotropic effects, including anti-inflammatory action. In the present study, we investigated the effect of simvastatin, an HMG-CoA reductase inhibitor, on the production of nitric oxide and the cardiovascular response to LPS. Male Wistar rats were pretreated with different doses of simvastatin (10, 20, 40, and 80 mg/kg, i.p.) or saline 20 min before i.v. injection of LPS (1.5 mg/kg) or saline (control). MAP was continuously recorded and nitrate plasma concentration was determined during the 6-h experimental session at 1-h intervals. The pressor response to phenylephrine (1 microg/kg) was evaluated before and 6 h after LPS administration. In the LPS-treated group, there was a time-dependent increase in nitrate plasma concentration (P<0.001), and this response was decreased in simvastatin pretreated rats (P<0.001). We also observed that LPS decreased the pressor response to phenylephrine (P<0.001), an effect that was reverted by simvastatin pretreatment (P<0.05). However, simvastatin did not modify the decrease of MAP induced by LPS. We concluded that simvastatin decreases nitrate plasma concentration in response to LPS and recovers vascular responsiveness during an experimental endotoxic shock. These data suggest the potential use of HMG-CoA reductase inhibitors as a coadjuvant in the treatment of septic shock.

Animals↗

PubMed2006

Short-term simvastatin treatment has no effect on plasma cytokine response in a human in vivo model of low-grade inflammation.

Statins reduce plasma cholesterol, but clinical trials and in vitro studies indicate that they might also possess anti-inflammatory properties. The effect of simvastatin on circulating cytokines and leucocytes was evaluated in a human in vivo model of low-grade inflammation. Thirty young healthy male participants received an injection of the bacterial cell wall product endotoxin (0.06 ng/kg) to induce systemic inflammation. Participants were then randomized into a control and a simvastatin group. The simvastatin group received simvastatin 20 mg daily for 14 days. All participants returned after 14 days to receive a second endotoxin injection. Plasma concentrations of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-1 receptor antagonist were measured by enzyme-linked immunosorbent assay (ELISA) before and hourly for 6 hours after endotoxin administration. Plasma cytokines as well as total leucocyte counts increased in all participants upon endotoxin challenge but were not affected by simvastatin treatment. Tolerance to endotoxin was observed in both groups after 14 days. Short-term treatment with simvastatin (20 mg/day) did not influence circulating cytokine levels during endotoxaemia in this human in vivo study.

Adult↗

PubMed1990

The effects of simvastatin on plasma lipoproteins and cholesterol homeostasis in patients with heterozygous familial hypercholesterolaemia.

We have examined the influence of simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase on plasma concentrations of lipids and lipoproteins, the rates of cholesterol biosynthesis and degradation of 125I-labelled LDL by freshly isolated mononuclear leucocytes and the 24 h urinary excretion of mevalonic acid in patients with heterozygous familial hypercholesterolaemia. Patients were treated with progressively increasing doses of simvastatin (20, 40, and 80 mg day-1) taken in a twice-daily dosage for a period of 6 weeks on each dose. Plasma concentrations of LDL cholesterol decreased by 36.6%, 45.6% and 47.1% respectively on the three doses. High-affinity degradation of 125I-LDL by freshly isolated mononuclear leucocytes increased significantly on the 20 mg day-1 dosage but no further increase was observed on doses of 40 and 80 mg of simvastatin per day. Rates of 2-14C acetate incorporation into cholesterol by freshly isolated mononuclear leucocytes (obtained 12-15 h after the last dose of simvastatin) increased by 62%, 71% and 29% in cells isolated from patients on 20, 40, and 80 mg day-1 of simvastatin compared with values at baseline. In contrast, the 24 h excretion of mevalonic acid in the urine fell by 16.9%, 31.4% and 31.9% respectively on these three doses. Our results indicate that the potent hypocholesterolaemic effects of simvastatin are accompanied by increases in high-affinity LDL receptor-mediated degradation of LDL and a compensatory increase in cholesterol biosynthesis in freshly isolated mononuclear leucocytes but that rates of mevalonic acid excretion in the urine decrease.

Adult↗

PubMed1989

Simvastatin and cholestyramine in the long-term treatment of hypercholesterolaemia.

After 6 weeks on a lipid-lowering diet, 20 outpatients with type II hyperlipoproteinaemia (18 type IIa) were randomized to treatment with cholestyramine 12 g b.i.d. (5 patients) or simvastatin (a new HMG-CoA reductase inhibitor) 40 mg q.p.m. (15 patients) for 12 weeks. From week 13 to week 20 nine patients in the simvastatin group and all patients in the cholestyramine group were treated with the combination of the two drugs. From week 21 to week 52 all patients were on monotherapy with simvastatin. Simvastatin treatment reduced low-density lipoprotein (LDL) cholesterol by 40% after 12 weeks, compared with 33% in the cholestyramine group. This difference was not significant. The total reductions of LDL-cholesterol on combination therapy were respectively 60% and 56% in each group. After 52 weeks LDL-cholesterol was still reduced by 36% (P less than 0.001) on monotherapy with simvastatin. Simvastatin also reduced triglycerides (TG) by 17% (P less than 0.05) and high-density lipoprotein (HDL) cholesterol was increased by 19% (P less than 0.01). No serious side effects were observed, and the new HMG-CoA reductase inhibitors may offer a new approach to the treatment of hypercholesterolaemia.

Adult↗

PubMed1997

Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study.

The Scandinavian Simvastatin Survival Study (4S) was a double-blind, randomized placebo-controlled multi-centre clinical trial of long-term Simvastatin therapy in patients with coronary heart disease who had total cholesterol levels between 5.5 and 8.0 mmol/l, comprising 4444 patients, equally distributed to a Simvastatin and a placebo group. Patients achieved a significant 30% relative reduction in overall mortality with Simvastatin therapy through a 42% relative reduction in coronary heart disease mortality. Lp(a) lipoprotein levels in Scandinavian coronary heart disease patients were strikingly higher than in healthy controls. Numbers of deaths in the Simvastatin group differed significantly between quartiles of Lp(a) lipoprotein levels, the reduction in deaths being most pronounced in the second (next to lowest) quartile. Subjects with major coronary events had significantly higher Lp(a) lipoprotein levels than subjects without such events, in all groups. The relationship between Lp(a) lipoprotein level and total mortality as well as between Lp(a) lipoprotein level and major coronary events was significantly different from zero, in logistic regression analyses. The findings show that Lp(a) lipoprotein predicts major coronary events as well as death in secondary prevention with Simvastatin. This prospective study provides independent confirmation that a high Lp(a) lipoprotein level is a significant coronary heart disease risk factor.

Adult↗

PubMed2006

Simvastatin causes changes in affective processes in elderly volunteers.

OBJECTIVES: To test for simvastatin-induced changes in affect and affective processes in elderly volunteers. DESIGN: Randomized, clinical trial. SETTING: The Geriatric Behavioral Psychopharmacology Laboratory at the University of Pennsylvania. PARTICIPANTS: Eighty older volunteers, average age 70, with high normal/mildly elevated serum cholesterol. INTERVENTION: Simvastatin up to 20 mg/d or placebo for 15 weeks. MEASUREMENTS: Daily diary records of positive and negative affects and of events and biweekly measures of depressive symptoms. Affect ratings were obtained using the Lawton positive and negative affect scales; independent raters coded the valences of events. RESULTS: Thirty-one of 39 subjects assigned to placebo and 33 of 41 receiving simvastatin completed the study. During biweekly assessments, four subjects on simvastatin and one on placebo experienced depressive symptoms, as manifest by Center for Epidemiological Studies Depression scale scores greater than 16 (exact P=.36). Diary data demonstrated significant effects on affective processes. For positive affect, there was a significant medication-by-time interaction that reflected decreases in positive affect in subjects receiving simvastatin, greatest in those patients whose final total cholesterol levels were below 148 mg/dL. For negative affect, there were significant medication-by-event, and medication-by-event-by-time interactions, reflecting a time-limited increase in the apparent effect of negative events. CONCLUSION: Simvastatin has statistically significant effects on affect and affective processes in elderly volunteers. The decrease in positive affect may be significant clinically and relevant to the quality of life of many patients.

Affect↗

PubMed2001

Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are effective agents in lowering cholesterol and triglycerides and are being used by human immunodeficiency virus-positive patients to treat the lipid elevation that may be associated with antiretroviral therapy. Many HMG-CoA reductase inhibitors and protease inhibitors are metabolized by the same cytochrome P450 enzyme 3A4 (CYP3A4). In addition, many protease inhibitors are potent inhibitors of CYP3A4. Therefore, coadministration of these two classes of drugs may cause significant drug interactions. This open-label, multiple-dose study was performed to determine the interactions between nelfinavir, a protease inhibitor, and two HMG-CoA reductase inhibitors, atorvastatin and simvastatin, in healthy volunteers. Thirty-two healthy subjects received either atorvastatin calcium (10 mg once a day) or simvastatin (20 mg once a day) for the first 14 days of the study. Nelfinavir (1,250 mg twice a day) was added on days 15 to 28. Pharmacokinetic assessment was performed on days 14 and 28. The study drugs were well tolerated. Nelfinavir increased the steady-state area under the plasma concentration-time curve during one dosing period (AUC(tau)) of atorvastatin 74% and the maximum concentration (C(max)) of atorvastatin 122% and increased the AUC(tau) of simvastatin 505% and the C(max) of simvastatin 517%. Neither atorvastatin nor simvastatin appeared to alter the pharmacokinetics of nelfinavir. It is recommended that coadministration of simvastatin with nelfinavir should be avoided, whereas atorvastatin should be used with nelfinavir with caution.

Adult↗

PubMed2004

Simvastatin reduces MMP-3 level in interleukin 1beta stimulated human chondrocyte culture.

OBJECTIVES: Matrix metalloproteinases (MMPs) produced by chondrocytes play a role in the development of cartilage degradation in joint diseases. Moreover, inhibition of MMP secretion by macrophages accumulating in arteriosclerotic plaques would account for the plaque stabilising activity of statins in cardiovascular patients. Recently, simvastatin has been shown to inhibit both developing and established collagen induced arthritis in a murine model. We thus decided to investigate the effect of simvastatin on the production of MMP-3 from cultured interleukin (IL)1 stimulated human chondrocytes. METHODS: Cells from human cartilage, obtained from eight subjects with osteoarthritis undergoing surgery for total hip prostheses, were cultured in the presence of different concentrations of simvastatin (5, 10, and 50 micromol/l) with and without IL1beta (5 ng/ml). MMP-3 level was measured in the culture medium after 48 h of incubation. RESULTS: IL1beta stimulation of chondrocytes increased MMP-3 concentration in the cultures (from 0.69 (0.09) to 1.94 (0.12) ng/microg protein). Incubation with simvastatin was associated with a dose dependent reduction in MMP-3 increase, both in the presence (-15%, -17%, and -26% with 5, 10, and 50 micromol/l, respectively) and in the absence (-32% with 50 micromol/l) of IL1beta. The inhibiting effect of simvastatin was completely reversed by the addition of mevalonate (100 micromol/l) or farnesol (10 micromol/l). CONCLUSIONS: Our data show that simvastatin, by blocking HMGCoA-reductase and interfering in the prenylation processes, is able to inhibit MMP-3 production from cultured human chondrocytes that have been either unstimulated or stimulated with IL1beta, thus suggesting a possible additional mechanism for statins in counteracting chronic joint disease related cartilage damage.

Aged↗

PubMed1999

Effect of long term simvastatin administration as an adjunct to ursodeoxycholic acid: evidence for a synergistic effect on biliary bile acid composition but not on serum lipids in humans.

BACKGROUND: Stimulated bile acid synthesis preferentially utilises newly synthesised cholesterol, raising the possibility that combination of simvastatin (an inhibitor of cholesterol synthesis) with ursodeoxycholic acid (UDCA; a stimulator of bile acid synthesis) may result in reduced bile acid synthesis and greater enrichment of the pool with UDCA than that achieved with UDCA treatment alone. AIMS: To investigate the effect of simvastatin and UDCA given alone and in combination on serum and biliary lipid and biliary bile acid composition. METHODS: Eighteen patients with primary non-familial hypercholesterolaemia were studied during treatment with simvastatin 20 mg/day, UDCA 10 mg/kg/day, and a combination of the two drugs. Each regimen was given in random order for three months following a three month lead in period. RESULTS: Simvastatin significantly reduced serum low density lipoprotein (LDL) cholesterol but biliary cholesterol concentration remained unchanged. Combination of the two drugs had no synergistic effect on serum cholesterol concentration, but significantly increased the proportion of UDCA in the bile acid pool from 35% during UDCA to 48% during combination treatment (p<0.04). CONCLUSIONS: Results showed that: (1) simvastatin reduces serum LDL cholesterol but has no effect on biliary cholesterol concentration, supporting the concept that newly synthesised cholesterol is not the preferential source for biliary cholesterol; and (2) combination of simvastatin with UDCA has the predicted effect of enhancing the proportion of UDCA in the pool. This effect may be of benefit in the treatment of cholestatic liver diseases.

Adult↗