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PubMed1996

Simvastatin inhibits myointimal hyperplasia following carotid artery injury in cholesterol-fed rabbits.

The effect of simvastatin, a potent inhibitor of 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) was evaluated in an experimental model of myointimal hyperplasia in cholesterol-fed rabbits. Myointimal hyperplasia was induced by an air-drying injury of the left carotid artery followed by a 2%-cholesterol diet for 14 days. A 2-week oral treatment with simvastatin (6 mg/kg/day, p.o.) significantly lowered the circulating levels of cholesterol and triglycerides (41% and 49% inhibition respectively) as well as the low density lipoprotein (LDL)-cholesterol and high density lipoprotein (HDL)-cholesterol levels. Simvastatin also strongly affected the uptake of cholesterol in the arteries occurring as a consequence of vascular injury (44% inhibition, P < 0.001). Morphometric analysis revealed that both the intima and the media areas increased substantially 2 weeks after the lesion and showed a considerable smooth muscle cell accumulation in the neointima together with the presence of numerous foam cells. A 16-day oral treatment with simvastatin strongly reduced smooth muscle cells hyperplasia occurring in both the media and the intima following deendothelialization (19% and 60% inhibition respectively) suggesting that simvastatin may be a useful inhibitor of restenosis which occurs following vascular injury.

Animals↗
PubMed2004

Simvastatin enhances the regeneration of endothelial cells via VEGF secretion in injured arteries.

The search for a novel therapy for endothelial regenerating is an area of intensive investigation. Recent experimental and clinical evidence strongly suggests that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have several physiological effects independent of low-density lipoprotein cholesterol reduction. We here report that the carotid arterial blood flow after endothelial injury in hamsters treated with simvastatin was restored, in contrast to the situation in nontreated hamsters. Histologic observations showed a prompt recovery of endothelial cells with a much higher DNA synthesis index in repaired endothelium of hamsters treated with simvastatin. The amount of secreted vascular endothelial cell growth factor (VEGF) by cultured vascular smooth muscle cells from hamsters treated with simvastatin was significantly increased. Mevalonate reduced the amount of VEGF secretion by simvastatin in vitro. Finally, an injection of either an anti-VEGF antibody or an anti-VEGF receptor-1 (Flt-1) antibody, but not anti-VEGF receptor-2 (Flk-1), reduced the prompt endothelial healing. Simvastatin regulates endothelial regenerating by an over-release of VEGF and by this may result in prompt endothelial healing after vascular injury. Our results provide new insights into the role of statin and VEGF in the pathogenesis of vascular diseases.

Animals↗
PubMed2003

The significance of femoral intima-media thickness and plaque scoring in the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) study.

BACKGROUND: Measurement of intima-media thickness (IMT) is a well established surrogate marker for cardiovascular endpoints. We studied the long-term effects of statins on femoral IMT and plaque scoring in the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) study. METHODS AND RESULTS: Three hundred and twenty-five patients with familial hypercholesterolaemia were randomized to either atorvastatin 80 mg/day or simvastatin 40 mg/day. IMT was measured at baseline and at 2 years. At baseline, femoral IMT was 1.69 mm in the atorvastatin group and 1.61 mm in the simvastatin group; at 2 years, IMT increased by 0.06 mm (P=0.24) and 0.15 mm (P=0.012), respectively. No significant differences were obvious between these two treatment arms (P=0.26). Femoral plaques were present in 64.7% in the atorvastatin group and 56.1% in the simvastatin group at baseline; after 2 years, these proportions rose to 66.0% (P=0.47) and 67.3% (P=0.02), respectively (P=0.87 between treatment arms). Carotid plaques were present in 6.3% versus 4.9%; after 2 years, these percentages were 5.0% (P=0.48) versus 5.5% (P=0.71), respectively (P=0.90 between treatment arms). CONCLUSION: Our study indicates increased efficacy of atorvastatin 80 mg in retarding progression of atherosclerosis in the femoral artery compared with simvastatin 40 mg. Interestingly, in the carotid arteries these statins influenced IMT to a greater extent, whereas in the femoral artery the effects were more pronounced on plaque frequency. These findings underscore the generalized effects of lipid lowering on atherosclerosis.

Anticholesteremic Agents↗
PubMed1995

A comparison of the effects of simvastatin and pravastatin monotherapy on muscle histology and permeability in hypercholesterolaemic patients.

1. In this double-blind, placebo controlled, prospective study, it was assessed whether simvastatin or pravastatin monotherapy have adverse effects on muscle histology and muscle membrane permeability in hypercholesterolaemic patients. 2. Twenty-four patients, seven females and 17 males, with primary hypercholesterolaemia (LDL cholesterol levels > or = 4.14 mmol l-1) were selected from the outpatient lipid clinic of a 650 bed academic medical centre. 3. After a 6-week lipid lowering diet and placebo period, patients were randomized into two groups of 12 subjects with similar characteristics, to receive either simvastatin or pravastatin in dosages of 10-40 mg day-1 for three periods of 6 weeks. After each 3-week period the dose was adjusted to LDL cholesterol to aim for equipotent dosage. 4. All subjects performed a 45 min, lean body mass standardized bicycle ergometer test, before and after 18 weeks of treatment. As parameter for muscle damage, the exercise-induced rise of the muscle proteins, creatine kinase (CK) and myoglobin (Mb), relative to pre-exercise levels, were determined 1 and 8 h after the test. Forty-eight hours after each test a biopsy was taken from the quadriceps muscle and histology was judged by three independent observers. 5. Eighteen weeks of monotherapy with simvastatin and pravastatin did not affect the exercise induced release of CK and Mb, neither were any differences observed in muscle histology before and after treatment with either of the drugs. 6. Although simvastatin doses were lower than pravastatin, reductions in total- and LDL-cholesterol were greater in the simvastatin treated patients than in the pravastatin treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Enhanced cellular metabolism of very low density lipoprotein by simvastatin. A novel mechanism of action of HMG-CoA reductase inhibitors.

To test the possibility that HMG-CoA reductase inhibitors reduce LDL mass by an increased VLDL catabolism, we determined the effect of simvastatin therapy on cellular metabolism of VLDL in 18 patients with primary hypercholesterolaemia. Six months of simvastatin therapy was followed by 26%, 31% and 21% reduction of plasma total cholesterol, LDL-cholesterol and plasma triglyceride levels, respectively. Before therapy, patients' VLDL metabolism in cultured human normal skin fibroblasts was similar to control VLDL. Six months after therapy was initiated, a remarkable 2-5-fold increase in VLDL cell metabolism was found. These effects were even more marked when the VLDL was enriched with exogenous recombinant apo E-3. A comparison of the metabolism of the patients' VLDL to control VLDL and LDL, revealed that simvastatin increased metabolic ratios of 60-70% and 45-95%, respectively. Simvastatin therapy was associated with a decrease of VLDL cholesteryl ester content of 19% and increase of the phospholipid content of 13%. The data strongly indicate that simvastatin therapy stimulates VLDL: cell interactions and catabolism, possibly reflecting alterations of the physico-chemical properties of the particle. It is proposed that in addition to other previously described pathways, HMG-CoA reductase inhibitors decrease LDL mass through a novel mechanism of enhanced VLDL catabolism prior to the conversion to LDL.

Adult↗
PubMed2005

Effects of simvastatin on blood lipids, vitamin E, coenzyme Q10 levels and left ventricular function in humans.

BACKGROUND: As statin therapy has been reported to reduce antioxidants such as vitamin E and coenzyme Q10 and there are indications that this reduction may cause impairment of left ventricular function (LVF), we studied the influence of simvastatin on LVF and serum vitamin E and coenzyme Q10 levels in humans. MATERIAL AND METHODS: We assessed the effect of simvastatin on left ventricular function and coenzyme Q10 levels in 21 (11 male, 10 female) hypercholesterolaemic subjects (mean age = 56 years) with normal LVF, over a period of 6 months. Subjects were re-tested after a 1-month wash-out period (7 months). Echocardiography was performed on all subjects before commencement of simvastatin (20 mg day(-1)), and at 1, 3, 6 and 7 months after initiation of treatment. Fasting blood samples were also collected at these intervals to assess lipids, apoproteins, vitamin E and coenzyme Q10. RESULTS: Serum lipids showed the expected reductions. Plasma vitamin E and coenzyme Q10 levels were reduced by 17 +/- 4% (P < 0.01) and 12 +/- 4% (P < 0.03) at 6 months. However, the coenzyme Q10/LDL-cholesterol ratio and vitamin E/LDL-cholesterol ratio increased significantly. Left ventricular ejection fraction (EF) decreased transiently after 1 month, while no significant change was observed at 3 and 6 months. Other markers of left ventricular function did not change significantly at any time point. CONCLUSION: Despite reduced plasma vitamin E and coenzyme Q10, 20 mg of simvastatin therapy is associated with a significantly increased coenzyme Q10/LDL-cholesterol ratio and vitamin E/LDL-cholesterol ratio. Simvastatin treatment is not associated with impairment in left ventricular systolic or diastolic function in hypercholesterolaemic subjects after 6 months of treatment.

Adult↗
PubMed2005

Long term efficacy of simvastatin in renal transplant recipients treated with cyclosporine or tacrolimus.

BACKGROUND: Hyperlipidemia is frequently developed following renal transplantation and results in worsening of the patient's prognosis. METHODS: In this study, 14 patients who had hypercholesterolemia [total cholesterol (TC) >200 mg/dL] and hypertriglyceridemia [triglyceride (TG) >150 mg/dL] 1 month after renal transplantation (post-transplantation), seven patients each under the treatment with immunosuppressant, either cyclosporine or tacrolimus started simvastatin treatment of 5-10 mg/d and continued the treatment for 4 yr. The effect of simvastatin treatment was assessed by comparison in serum lipid levels (TC, TG, cholesterol in lipoprotein fractions, and apolipoproteins) and the lipid metabolism related enzyme activities for post-transplantation, after 6-month and 4-yr simvastatin treatment. RESULTS: Simvastatin treatment of 4 yr significantly decreased the elevated levels of serum TC from 234.5 +/- 30.8 to 186.3 +/- 20.5 mg/dL (p < 0.001), low density lipoprotein cholesterol (LDL-C) from 116.7 +/- 22.5 to 82.7 +/- 16.6 mg/dL (p < 0.05) and TG from 200.3 +/- 109.2 to 97.0 +/- 45.2 mg/dL (p < 0.001). In addition, there were significant decreases in elevated serum very-low-density lipoprotein cholesterol (VLDL-C) from 47.8 +/- 18.4 to 28.6 +/- 9.5 mg/dL (p < 0.001) and LDL2 cholesterol (LDL2-C) from 20.8 +/- 8.2 to 5.7 +/- 1.8 mg/dL (p < 0.001). CONCLUSION: The results indicate that 4-yr treatment of simvastatin improves profiles of the atherogenic lipids in renal transplant patients with immunosuppressant caused hypercholesterolemia and hypertriglyceridemia treated either cyclosporine or tacrolimus in similar manner.

Adult↗
PubMed1990

The use of simvastatin, an HMG CoA reductase inhibitor, in older patients with hypercholesterolemia and atherosclerosis.

Epidemiological evidence suggests that elevated serum cholesterol, especially the low density lipoprotein (LDL) fraction, the total/high density lipoprotein (HDL)-cholesterol ratio, and the LDL/HDL-cholesterol ratio, remains a risk factor for atheromatous disease up to the age of 79 years. We studied the efficacy and tolerability of simvastatin, an HMG CoA reductase inhibitor, in 20 patients aged 65 to 75 years with clinical evidence of atheromatous disease. After four weeks of treatment, there was a 29% fall in LDL-cholesterol levels (P less than .01 vs placebo) with low dose simvastatin and a 38% fall with high dose simvastatin (P less than .001 vs placebo). Similar falls were seen in total cholesterol levels and the LDL/HDL-cholesterol and total/HDL-cholesterol ratios. Apoprotein B levels decreased by approximately 20% with both doses (P less than .05 vs placebo). In an open extension of the study, the decreases in lipid parameters were sustained for a further 48 weeks of treatment with doses of simvastatin ranging from 10 to 40 mg. Two patients required the addition of cholestyramine. Although a small study like this cannot establish safety and tolerance, side effects were minor and did not require stopping therapy in any patient. Simvastatin is an effective cholesterol lowering agent in older patients.

Aged↗
PubMed1990

Biochemical changes and morphological alterations of the liver in guinea-pigs after administration of simvastatin (HMG CoA reductase-inhibitor).

Simvastatin is a potent competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) which is the rate-limiting enzyme of cholesterol synthesis. In guinea-pigs, administration of a high oral dose of simvastatin (125 mg/kg/day at the beginning of the study) during 18 days had a major hepatotoxic effect whereas a lower oral dose (30 mg/kg/day) did not seem to cause any liver damage. A significant reduction in microsomal Cyt P 450 content was only observed on a high dose of simvastatin whereas HMG CoA reductase activity was reduced in the group with the low simvastatin dose. The hepatic microsomal aminopyrine N-demethylase activity remained unchanged in all groups. The liver lesion was hepatocellular necrosis accompanied in some animals by a biliary duct proliferation. It was associated with a 10-fold elevation in serum aspartate and alanine aminotransferase activities, as well as a great reduction in daily food intake and body weight (28%). The hepatotoxicity of simvastatin could result from the low basal content of HMG-CoA reductase in guinea-pig liver, the prolonged inhibition of mevalonate synthesis and probably, from the absence of HMG-CoA reductase enzyme de novo synthesis.

Aminopyrine N-Demethylase↗
PubMed2005

Brain cholesterol synthesis in mice is affected by high dose of simvastatin but not of pravastatin.

On a global scale, there is an increasing tendency for a more aggressive treatment of hypercholesterolemia. Minor effects of statins on brain cholesterol metabolism have been reported in some in vivo animal studies, and it seems that this is due to a local effect of the drug. We treated male mice of the inbred strain C57/BL6 with a high daily dose of lipophilic simvastatin (100 mg/kg b.wt.) or hydrophilic pravastatin (200 mg/kg b.wt.) or vehicle (controls) by oral gavage for 3 days. To compare the impact of both statins on brain cholesterol synthesis and degradation, levels of cholesterol, its precursor lathosterol, and its brain metabolite 24(S)-hydroxycholesterol as well as statin concentrations were determined in whole-brain lipid extracts using mass spectrometry. The expression of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase mRNA and of other target genes were evaluated using real-time reverse transcription-polymerase chain reaction. In addition, analysis of liver and serum samples was performed. Similar levels of simvastatin and pravastatin were detected in whole-brain homogenates. Cholesterol contents in the brain, liver, and serum were not affected by high-dose statin treatment. Whereas brain cholesterol precursor levels were reduced in simvastatin-treated animals only, no effect was observed on the formation of the brain cholesterol metabolite, 24(S)-hydroxycholesterol. Polymerase chain reaction analysis revealed that mRNA expression of HMG-CoA reductase and ATP-binding cassette transporter A1 in the brain was significantly up-regulated in simvastatin-treated animals compared with pravastatin-treated or control animals. We conclude that, under the present experimental conditions, brain cholesterol synthesis is significantly affected by short-term treatment with high doses of lipophilic simvastatin, whereas whole-brain cholesterol turnover is not disturbed.

Animals↗
PubMed1995

Absence of effect of simvastatin on the progression of lens opacities in a randomised placebo controlled study. Oxford Cholesterol Study Group.

AIMS: A detailed assessment of ophthalmic effects of an HMG CoA reductase inhibitor, simvastatin, was performed. METHODS: Six hundred and twenty one individuals considered to be at increased risk of coronary heart disease were randomised, following an 8 week placebo 'run in' period, to receive 40 mg daily simvastatin, 20 mg daily simvastatin, or matching placebo. Patients with a baseline corrected visual acuity better than 6/24 and without a history of cataract were eligible for detailed ophthalmic assessment at 6 months (539 patients assessed) and at 18 months (474 patients assessed). RESULTS: No significant differences between the treatment groups were detected at the 6 month or 18 month visit in the refractive condition of the eye or in the mean intraocular pressure. Nor were there clear differences in the Oxford grading system scores for various measures of the major types of cataract (cortical spokes, posterior subcapsular cataract, nuclear brunescence, white scatter) or for other morphological features visible within the lens (fibre folds or focal dots). Scheimpflug slit image photographs and retroillumination analysis of the percentage of cataract within a defined region of the lens were also performed at each visit, with no clear differences observed between the treatment groups. CONCLUSION: This single centre double blind study found no good evidence of any adverse effects of 18 months of simvastatin treatment on lens opacity formation, using a variety of validated techniques to assess cataract development. Routine clinic follow up of visual symptoms and admission to hospital for ophthalmic procedures over 5 years of treatment was also reassuring, with no excess adverse outcomes observed with simvastatin.

Adult↗
PubMed1995

Effects of simvastatin and cholestyramine on bile lipid composition and gall bladder motility in patients with hypercholesterolaemia.

Although the effects of 3-hydroxy, 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and bile acid sequestrants on bile lipid composition have been studied separately, no data are available on combination therapy of these drugs. Moreover, the effects of prolonged (four weeks) administration of these drugs on gall bladder motility, an important determinant of cholesterol gall stone formation, have not been studied so far. A prospective study was therefore performed with eight patients who had hypercholesterolaemia (age 53 (5) (SEM), body mass index 27.4 (1.1) kg m-2, low density lipoprotein cholesterol 5.9 (0.3) mmol/l). They received treatment during three periods of four weeks with simvastatin 20 mg/day, cholestyramine 4 g twice daily, and a combination of both in random order, each treatment period separated by a two week wash out period. Before treatment and after each treatment period, postprandial gall bladder motility was studied with ultrasound, followed by duodenal bile sampling. Serum cholesterol decreased in all subjects in any treatment period illustrating good compliance. Molar percentages in duodenal bile of cholesterol, phospholipids, and bile salts were unchanged during simvastatin and cholestyramine treatment. During combined therapy percentage bile salts was lower (72.5 (2.9)% v 77.8 (1.7)% at baseline, p < 0.05) whereas phospholipids were higher (21.2 (2.4)% v 16.4 (1.3)% at baseline, p < 0.05). As a result cholesterol saturation index (CSI) did not change in any treatment period. No cholesterol crystals were detected in any bile sample, taken at baseline and after each treatment period. Bile salt hydrophobicity index during cholestyramine (0.19 (0.02)) and combined treatment (0.22 (0.01)) decreased strongly compared with baseline (0.34 (0.01), p < 0.001, p < 0.01, respectively), resulting from increased proportions of glycocholate (59.4 (3.9)% (cholestyramine), 55.6 (2.4)% (combination), and 28.2 (2.2) (baseline), p < 0.001)) and decreased proportions of deoxycholic acid and chenodeoxycholic acid. Fasting gall bladder volume was increased during simvastatin (28.7 (2.8) ml) v baseline (23.2 (2.3) ml, p < 0.01) whereas, residual volume did not differ (5.7 (0.9) ml (simvastatin) v 5.9 (0.7) (baseline). During cholestyramine and combined treatment, no significant differences in gall bladder motility were seen. In conclusion, this study suggests that HMG-CoA reductase inhibitors alone and combined with cholestyramine do not affect major determinants of cholesterol gall stone formation, for example, CSI and gall bladder emptying. In addition cholestyramine alone and combined with simvastatin leads to a strong decrease of bile salt hydrophobicity, which may be beneficial in the prevention of nucleation of cholesterol crystals.

Anticholesteremic Agents↗
PubMed2003

Attenuation of chronic hypoxic pulmonary hypertension by simvastatin.

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to improve multiple normal endothelial cell functions and inhibit vascular wall cell proliferation. We hypothesized that one such agent, simvastatin, would attenuate chronic hypoxic pulmonary hypertension. Male adult Sprague-Dawley rats were exposed (14 days) to normoxia (N), normoxia plus once-a-day administered simvastatin (20 mg/kg ip) (NS), hypoxia (10% inspired O2 fraction) (H), or hypoxia plus simvastatin (HS). Mean pulmonary artery pressure, measured in anesthetized, ventilated rats with an open-chest method, was reduced from 25 +/- 2 mmHg in H to 18 +/- 1 in HS (P < 0.001) but did not reach normoxic values (12 +/- 1 mmHg). Similarly, right ventricular/left ventricular plus interventricular septal weight was reduced from 0.53 +/- 0.02 in the H group to 0.36 +/- 0.02 in the HS group (P < 0.001). The increased hematocrit in H (0.65 +/- 0.02) was prevented by simvastatin treatment (0.51 +/- 0.01, P < 0.001). Hematocrit was similar in N versus NS. Alveolar vessel muscularization and medial thickening of vessels 50-200 microM in diameter induced by hypoxia were also significantly attenuated in the HS animals. Lung endothelial nitric oxide synthase (eNOS) protein expression in the HS group was less than H (P < 0.01) but was similar in N versus NS. We conclude that simvastatin treatment potently attenuates chronic hypoxic pulmonary hypertension and polycythemia in rats and inhibits vascular remodeling. Enhancement of lung eNOS expression does not appear to be involved in mediating this effect.

Animals↗
PubMed1999

In vitro effects of simvastatin on tubulointerstitial cells in a human model of cyclosporin nephrotoxicity.

To investigate the possibility that 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase inhibitors ameliorate renal disease via direct effects on the tubulointerstitium, primary cultures of human proximal tubule cells (PTC) and renal cortical fibroblasts (CF) were exposed for 24 h to simvastatin (0.1-10 micromol/l) under basal conditions and in the presence of 1,000 ng/ml of cyclosporin (CsA), which we have previously shown to promote in vitro interstitial matrix accumulation at least partially via activation of local cytokine networks. Simvastatin, in micromolar concentrations, engendered cholesterol-independent inhibition of CF and PTC thymidine incorporation and cholesterol-dependent suppression of PTC apical Na+/H+ exchange (NHE) (ethylisopropylamiloride-sensitive apical 22Na+ uptake). Similarly, CF secretion of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 were depressed, whereas CF collagen synthesis ([3H]proline incorporation) and PTC secretion of the fibrogenic cytokines, transforming growth factor-beta1, and platelet-derived growth factor were unaffected. A lower concentration (0.1 micromol/l) of simvastatin did not affect any of the above parameters under basal conditions but completely prevented CsA-stimulated CF collagen synthesis (control, 6.6 +/- 0.6; CsA, 8.3 +/- 0.6; CsA+simvastatin, 6.2 +/- 0.5%; P < 0.05) and IGF-I secretion (89.5 +/- 16.6, 204.7 +/- 57.0, and 94.6 +/- 22.3 ng. mg protein-1. day-1, respectively; P < 0.05). The results suggest that simvastatin exerts direct cholesterol-dependent and -independent effects on the human kidney tubulointerstitium. HMGCoA reductase inhibitors may ameliorate interstitial fibrosis complicating CsA therapy via direct actions on human renal cortical fibroblasts.

Aged↗
PubMed2001

Simvastatin reverses impaired regulation of renal oxygen consumption in congestive heart failure.

Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) regulates renal O(2) consumption. This mechanism is impaired in heart and kidney of dogs with heart failure (CHF). Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, increases eNOS expression in the endothelium. Therefore, we studied whether simvastatin treatment could restore the regulation of renal O(2) consumption by stimulators of NO production in dogs with CHF. Renal O(2) consumption was measured after stimulation of NO production with bradykinin, ramiprilat, or amlodipine or the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Simvastatin delayed the time to euthanasia in dogs with CHF (35 +/- 1.0 vs. 29 +/- 1.2 days; P < 0.01). In normal dogs, bradykinin (10(-4) M), ramiprilat (10(-4) M), amlodipine (10(-5) M), and SNAP (10(-4) M) significantly reduced O(2) consumption in the renal cortex (-31.8 +/- 0.9, -30.3 +/- 1.1, -30.1 +/- 2.0, -46.9 +/- 1.0%) and renal medulla (-29.7 +/- 2.1, -33.0 +/- 2.7, -30.8 +/- 2.2, -46.8 +/- 1.1%). Responses to bradykinin, ramiprilat, and amlodipine were significantly attenuated in CHF but were partially or completely restored by simvastatin. Responses to SNAP were unaffected. These data demonstrate that treatment with simvastatin improves renal production of NO in CHF, restoring the normal regulation of renal O(2) consumption by NO.

Amlodipine↗
PubMedDate not supplied

Simvastatin-induced rhabdomyolysis in a patient with chronic renal failure.

Simvastatin belongs to a class of lipid-lowering drugs which completely inhibit 3-hydroxy-3-methylglutaryl co-enzyme A (HMG CoA) reductase. The commonest adverse effects of therapy with simvastatin HMG CoA reductase inhibitors are gastro-intestinal disturbance, myositis and myopathy. Rhabdomyolysis leading to renal failure has been reported, but it appears to be very rare, except in patients also receiving cyclosporin, nicotinic acid or gemfibrozil. Here we report the case of an elderly lady who was known to have chronic renal failure, but who developed rhabdomyolysis following simvastatin therapy. Her symptoms of muscle pain, fatigue, myoglobulinuria, oliguria and pulmonary oedema appeared 48 h after the first dose of simvastatin. Simvastatin was immediately stopped, and the patient was dialysed for 1 week. Her renal function improved and came back. We suggest that extreme care should be exercised in prescribing this drug, particularly for the elderly with renal impairment.

Acute Kidney Injury↗
PubMed2005

Regulation of vascular tone from spontaneously hypertensive rats by the HMG-CoA reductase inhibitor, simvastatin.

The acute effect of simvastatin on aortic rings from spontaneously hypertensive rats (SHRs) was identified. Simvastatin-evoked relaxations of both depolarized and phenylephrine-precontracted arteries were independent of the presence of endothelium. This effect was inhibited by diltiazem and mevalonate, but not by the Rho-kinase inhibitor, Y-27632. Simvastatin prevented contraction induced by phenylephrine, calcium ionophore A-23187 and CaCl2 in Ca2+-free medium. Y-27632 decreased the effect of simvastatin. On the contrary, contraction induced by noradrenaline in Ca2+-free medium was not affected. These results suggest that simvastatin elicited an effect on vascular smooth muscle cells from SHRs that may involve blockade of extracellular calcium entry and decrease vascular contraction by affecting Rho-kinase.

Amides↗
PubMed1990

Lovastatin and simvastatin--inhibitors of HMG CoA reductase and cholesterol biosynthesis.

The microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is a key rate-controlling step early in the cholesterol biosynthetic pathway that catalyzes the conversion of HMG CoA to mevalonic acid. Since this enzyme plays a significant role in regulating cholesterol synthesis, it is a rational target for pharmacologic intervention. The first potent, specific inhibitor of HMG CoA was mevastatin (compactin, ML-236B), which was discovered in 1976 by Endo et al. [J Antibiot 1976:29:1346-1348]. Subsequently, lovastatin, a novel, more active fungal metabolite was isolated from a strain of Aspergillus terreus. Lovastatin, the first of this class of agents to be approved for clinical use, was chemically modified to form simvastatin. Simvastatin is superior to lovastatin in intrinsic inhibitory potency. Both are inactive lactone prodrugs that must be converted to their respective dihydroxy open-acid forms to elicit inhibitory activity. Pharmacologic characterization of lovastatin and simvastatin has demonstrated that these potent inhibitors of HMG CoA reductase specifically inhibit cholesterol synthesis in animal cells, as well as in vivo after oral administration of the agents. Oral administration of either lovastatin or simvastatin to dogs in the presence or absence of the bile acid sequestrant cholestyramine results in a marked, sustained lowering of plasma cholesterol. Associated with the cholesterol lowering is a decrease in urinary and plasma levels of mevalonic acid, the end product of the HMG CoA reductase reaction. The target organ for inhibitors of HMG CoA reductase is the liver, the primary site of cholesterol biosynthesis. Both lovastatin and simvastatin are preferentially extracted by this organ.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗