(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Body-Weight

Statins can reduce reproductive damage induced by obesity or high-fat diet (HFD), but the specific regulatory mechanisms are largely unknown. Since mTOR/p70s6k sinaling promotes spermatogonia proliferation and spermatogenesis, we hypothesized that this pathway will be involved in the protective effects of statin in HFD-induced reproductive dysfunction.. Male Sprague Dawley rats (3 weeks old) were randomly divided into a control group (standard diet), HFD group, and a fluvastatin group (HFD + fluvastatin at 6mg/kg, once daily by oral gavage). After 8 weeks, body weight was obtain and rats were sacrificed. Weights of the testes, gross morphology, sperm parameters, circulating levels of sex hormones, lipid levels, and tissue mTOR, p-P70s6k were measured. Another set of male rats were treated with rapamycin or vehicle. Flow cytometry was used to detect the spermatogonia marker c-kit and cell cycle. p-P70s6k expression was analyzed by Western blot.. HFD not only results in rat obesity but also leads to spermatogenetic damage and fluvastatin was able to partially block the effects of HFD. Fluvastatin also partially reversed the suppression of mTOR and p-p70s6k expresson.. Our data suggest that fluvastatin has protective effects on reproductive function in obese male rats most probably through enhanced signaling of mTOR.

Topics: Animals; Body Weight; Cells, Cultured; Diet, High-Fat; Estradiol; Fatty Acids, Monounsaturated; Fluvastatin; Indoles; Lipids; Luteinizing Hormone; Male; Obesity; Protective Agents; Proto-Oncogene Proteins c-kit; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Spermatogenesis; Spermatogonia; Testis; Testosterone; TOR Serine-Threonine Kinases

A possible neuroprotective role has been recently suggested for 3H3MGCoA reductase inhibitors (statins). Here, we sought to determine neuroprotective effect of statins in quinolinic acid induced neurotoxicity in rats. Rats were surgically administered quinolinic acid and treated with Atorvastatin (10, 20 mg/kg), simvastatin (15, 30 mg/kg) and fluvastatin (5, 10 mg/kg) once daily up to 3 weeks. Atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) treatment significantly attenuated the quinolinic acid induced behavioral (locomotor activity, rotarod performance and beam walk test), biochemical (lipid peroxidation, nitrite concentration, SOD and catalase), mitochondrial enzyme complex alterations in rats suggesting their free radical scavenging potential. Additionally, atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) significantly decrease the TNF-α level and striatal lesion volume in quinolinic acid treated animals indicating their anti-inflammatory effects. In comparing the protective effect of different statins, atorvastatin is effective at both the doses while simvastatin and fluvastatins at respective lower doses were not able to produce the protective effect in quinolinic acid treated animals. These modulations can account, at least partly, for the beneficial effect of statins in our rodent model of striatal degeneration. Our findings show that statins could be explored as possible neuroprotective agents for neurodegenerative disorders such as HD.

Topics: Analysis of Variance; Animals; Atorvastatin; Behavior, Animal; Body Weight; Corpus Striatum; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipid Peroxidation; Male; Mitochondria; Motor Activity; Neuroprotective Agents; Neurotoxicity Syndromes; Nitrites; Oxidative Stress; Pyrroles; Quinolinic Acid; Rats; Rats, Wistar; Rotarod Performance Test; Simvastatin; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Statins have pleiotropic vascular protective effects that are independent of their cholesterol-lowering effects. The aim of the present study was to determine if statins have anti-flushing actions in an animal model of forced exercise-induced temperature dysregulation in menopausal hot flushes, and to clarify the critical role of statins in regulating vascular reactivity in the tail arteries of ovariectomized rats. Administration of fluvastatin or pravastatin (3mg/kg/day for 7days, p.o.) significantly ameliorated the flushing of tail skin in ovariectomized mice, and the effect of each statin was comparable with that of estrogen replacement (1mg/kg/week for 3weeks, i.m.). In phenylephrine-pre-contracted rat-tail arteries, ovariectomy inhibited acetylcholine-induced relaxation, but augmented sodium nitroprusside-induced relaxation. These ovariectomy-altered vasodilator responses were restored by fluvastatin treatment as well as by estrogen replacement. Nitrite/nitrate levels in the plasma of ovariectomized animals showed significantly lower values than those in sham-operated animals; this ovariectomy-reduced production of nitric oxide was improved by fluvastatin treatment. These data provide the first experimental evidence that statins such as fluvastatin and pravastatin exert anti-flushing effects by improving vasomotor dysfunction through nitric oxide-mediated mechanisms in ovariectomized animals. Thus, therapeutic methods that target improvement of vasomotor dysfunction could be novel strategies for reducing menopausal hot flushes.

Topics: Animals; Arteries; Body Weight; Estrogen Replacement Therapy; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hot Flashes; Indoles; Menopause; Mice; Nitric Oxide; Organ Size; Ovariectomy; Physical Conditioning, Animal; Pravastatin; Rats; Skin; Uterus; Vasoconstriction; Vasodilation; Vasomotor System

Oleanolic acid (OA) is a plant triterpenoid steroid with potentially antiatherogenic properties. We investigated whether OA affected atherosclerosis development and vascular function in apolipoprotein E knockout (ApoE(-/-)) mice. ApoE(-/-) mice were fed a high cholesterol Western-type diet in combination with OA (100 mg/kg/day), fluvastatin (5 mg/kg/day) or vehicle, with wild type (WT) mice serving as controls. After 8 weeks of treatment atherosclerotic plaque areas in the aortic arch and plasma lipid concentrations were determined. Vasoconstriction and relaxation of the proximal part of aorta were investigated in vitro. Inducible nitric oxide synthase (iNOS) was visualized using immunoblotting. As opposed to WT and fluvastatin- and vehicle-treated mice, OA-fed ApoE(-/-) mice gained no weight during the treatment period. Plasma concentrations of total-cholesterol and triglyceride were not significantly reduced by OA- or fluvastatin treatment. Plaque area of vehicle-treated mice was 25%, but only 14% in OA- and 19% in fluvastatin-treated mice. As compared to WT, vasoconstriction to phenylephrine was attenuated in ApoE(-/-) mice. The NOS inhibitor asymmetric dimethylarginine (ADMA) enhanced phenylephrine constriction, but significantly more so in vehicle- and fluvastatin-treated than in OA-treated and WT mice. Relaxation to acetylcholine was only slightly attenuated in ApoE(-/-) mice and not affected by OA or fluvastatin treatment. ADMA abolished acetylcholine relaxation almost completely. In ApoE(-/-) mice iNOS expression was reduced by OA treatment. In conclusion OA exerts potent antiatherogenic effects independent of plasma lipid levels and without major changes in eNOS-mediated acetylcholine relaxation. However, OA reduced iNOS expression possibly altering vascular reactivity to phenylephrine.

Topics: Acetylcholine; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Body Weight; Cholesterol; Eating; Fatty Acids, Monounsaturated; Fluvastatin; Gene Knockout Techniques; Indoles; Male; Mice; Mice, Inbred C57BL; Oleanolic Acid; Phenylephrine; S-Nitroso-N-Acetylpenicillamine; Time Factors; Vasodilation

The present study was designed to investigate whether fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, would attenuate the acute myocardial infarction in isoproterenol-treated rat model via maintaining activities of endogenous antioxidant enzymes. Hemodynamic and electrocardiograph parameters were monitored and recorded continuously, cardiac marker enzymes and antioxidative parameters of plasma and heart tissues were measured, and histopathological examination of heart tissues was performed. Isoproterenol-treated rats showed lower of left-ventricular systolic pressure (LVSP), maximum (LVdP/dtmax) and minimum rate of developed left ventricular pressure (LVdP/dtmin), and higher of left ventricular end-diastolic pressure (LVEDP), in addition, a significant rise in ST-segment and increase in content of lactate dehydrogenase, glutamic oxalacetic transaminase, creatine kinase and malondialdehyde, as well as fall in activities of glutathione peroxidase, superoxide dismutase and catalase were observed. Oral administration of fluvastatin (5, 10 and 20 mg/kg, respectively) significantly prevented almost all the parameters of isoproterenol-induced heart failure and myocardial injury that mentioned above. The protective role of fluvastatin on isoproterenol-induced myocardial damage was further confirmed by histopathological examination. There was no significant change in heart rate in all experimental groups. Compared with control group, any indexes in sham rats treated with fluvastatin (20 mg/kg) alone were unaltered (all P>0.05). Our results suggest that fluvastatin has a significant effect on the protection of heart against isoproterenol-induced myocardial infarction through maintaining endogenous antioxidant enzyme activities.

Topics: Adrenergic beta-Agonists; Animals; Antioxidants; Body Weight; Electrocardiography; Fatty Acids, Monounsaturated; Fluvastatin; Heart Function Tests; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Indoles; Isoproterenol; Male; Myocardial Infarction; Myocardium; Oxidative Stress; Rats; Rats, Sprague-Dawley

Skeletal muscle injury by hypolipidemic drugs is not fully understood. An extensive analysis of the effect of chronic treatment with fluvastatin (5 mgkg(-1) and 20 mgkg(-1)), atorvastatin (10 mgkg(-1)) and fenofibrate (60 mgkg(-1)) on rat skeletal muscle was undertaken.. Myoglobinemia as sign of muscle damage was measured by enzymatic assay. Histological and immunohistochemical techniques were used to estimate muscle integrity and the presence of aquaporin-4, a protein controlling water homeostasis. Electrophysiological evaluation of muscle Cl(-) conductance (gCl) and mechanical threshold (MT) for contraction, index of intracellular calcium homeostasis, was performed by the two-intracellular microelectrodes technique.. Fluvastatin (20 mgkg(-1)) increased myoglobinemia. The lower dose of fluvastatin did not modify myoglobinemia, but reduced urinary electrolytes, suggesting direct effects on renal function. Atorvastatin also increased myoglobinemia, with slight effects on urinary parameters. No treatment caused any histological damage to muscle or modification in the number of fibres expressing aquaporin-4. Either fluvastatin (at both doses) or atorvastatin reduced sarcolemma gCl and changed MT. Both statins produced slight effects on total cholesterol, suggesting that the observed modifications occur independently of HMGCoA-reductase inhibition. Fenofibrate increased myoglobinemia and decreased muscle gCl, whereas it did not change the MT, suggesting a different mechanism of action from the statins.. This study identifies muscle gCl and MT as early targets of drugs action that may contribute to milder symptoms of myotoxicity, such as muscle cramps, while the increase of myoglobinemia is a later phenomenon.

Topics: Action Potentials; Animals; Aquaporin 4; Atorvastatin; Body Weight; Chloride Channels; Dose-Response Relationship, Drug; Eating; Fatty Acids, Monounsaturated; Fenofibrate; Fluvastatin; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Indoles; Kidney Diseases; Lipids; Male; Membrane Potentials; Muscle Contraction; Muscle Fibers, Fast-Twitch; Muscle, Skeletal; Muscular Diseases; Myosin Heavy Chains; Organ Size; Pyrroles; Rats; Rats, Wistar; Rhabdomyolysis; Time Factors

Statins, the 3-hydroxy-3-methylglutaryl-cooenzyme A (HMG-CoA) reductase inhibitors, have been shown to inhibit the migration of macrophages and smooth muscle cell proliferation leading to an antiproliferative effect. Although this beneficial effect of statins has been suggested to be independent of lipid lowering properties, the possible mechanisms responsible for this action is largely unknown. Gap junctions, which serve as channels for direct intercellular exchange of ions, secondary messengers, and small signaling molecules, play an important role in tissue homeostasis and regulation of growth, differentiation, and development. This study was designed to test the hypothesis that expression of the component proteins of gap junctions, connexins 40 and 43 (Cx40 and Cx43), is upregulated in arteries subjected to balloon injury and that this upregulation can be suppressed by statin therapy. Male New Zealand white rabbits were subjected to injury in which an angioplasty catheter was introduced into the right iliac artery from the femoral artery under fluoroscopic guidance. Five groups of rabbits (n = 6 to 7) were treated for 2 weeks with one of the following: balloon injury (BL); BL+lovastatin (BL+L, 10 mg/kg/day); BL+fluvastatin (BL+F, 10 mg/kg/day); sham operation (Sham); and control (Con). Immunohistochemistry studies showed that Cx40 and Cx43 were expressed in normal smooth muscle cells (SMC) throughout the media. Reverse transcription-polymerase chain reaction and Western blot analysis showed that Cx40 and Cx43 mRNA and protein expression was elevated after injury (P < .001 for both proteins and both assays), and these elevations were suppressed by lovastatin and fluvastatin to a similar degree (P < .05 for both drugs and both assays). Immunostaining of Cx40 and Cx43 was consistently enhanced in the neointimal area after injury and lovastatin and fluvastatin reduced staining of these proteins in the lessened neointimal layer. Transmission electron microscopy revealed that there were abundant gap junctions between neointimal SMC as well as fewer and smaller gap junctions after statin treatment. Therefore, balloon injury causes upregulation of Cx40 and Cx43 in neointimal SMC. Lovastatin and fluvastatin suppress upregulated Cx40 and Cx43 expression and reduce neointimal proliferation, suggesting that Cx40 and Cx43 may play a role in statin-induced antiproliferative effect.

Topics: Animals; Blotting, Western; Body Weight; Catheterization; Cell Proliferation; Cholesterol; Connexin 43; Connexins; Fatty Acids, Monounsaturated; Fluvastatin; Gap Junction alpha-5 Protein; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Iliac Artery; Indoles; Lovastatin; Male; Microscopy, Electron, Transmission; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tunica Intima; Tunica Media

The in vivo antioxidant effect of fluvastain, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, was investigated using Watanabe heritable hyperlipidemic (WHHL) rabbits subjected to nicotine-free cigarette smoke extracts as oxidative stress. Fluvastatin was given orally at doses of 10 and 30 mg/kg per day for 5 months. The cigarette smoke extracts were prepared by bubbling the gas phase of smoke into phosphate-buffered saline and was injected daily into the rabbit ear vein. The rabbits chronically treated with the cigarette smoke extracts showed an increase in plasma lipid peroxide levels, estimated as thiobarbituric acid-reactive substances. Oxidative modification of plasma low-density lipoprotein (LDL) was assessed by anion-exchange high-performance liquid chromatographic analysis, LDL susceptibility to oxidation, LDL incorporation into macrophages and thiobarbituric acid-reactive substances levels in LDL. Treatment with fluvastatin significantly reduced these effects induced by the cigarette smoke extracts in a dose-related manner and exerted a cholesterol-lowering effect. At the end of the experiment, the cigarette smoke extracts caused accumulation of cholesteryl ester in the thoracic aorta, while fluvastatin significantly prevented this accumulation. These results indicate that fluvastatin can exert an antioxidant effect in vivo, with a strong effect on oxidative stress such as smoking, a major risk factor of atherosclerosis.

Topics: Animals; Antioxidants; Aorta, Thoracic; Body Weight; Cholesterol; Cholesterol Esters; Cholesterol, LDL; Chromatography, High Pressure Liquid; Copper; Coronary Vessels; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hyperlipidemias; In Vitro Techniques; Indoles; Lipoproteins, LDL; Macrophages, Peritoneal; Male; Mice; Oxidation-Reduction; Oxidative Stress; Rabbits; Renal Artery; Thiobarbituric Acid Reactive Substances

Short-term administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, has been shown to attenuate ischemia-reperfusion injury. However, the effects of long-term administration of statins on left ventricular (LV) remodeling and failure after myocardial infarction remain unknown.. Mice were subjected to coronary artery ligation and were treated for 4 weeks with vehicle or fluvastatin (10 mg/kg per day PO). Fluvastatin increased survival (61% versus 86%; P<0.05) without affecting the infarct size (52+/-2% versus 49+/-3%; P=NS). Fluvastatin not only attenuated LV dilatation but also decreased LV end-diastolic pressure and lung weight. Furthermore, it reduced cardiac myocyte hypertrophy and interstitial fibrosis of the noninfarcted LV and also improved LV ejection performance. LV matrix metalloproteinase (MMP)-2 and MMP-13 were increased in myocardial infarction, which was attenuated in fluvastatin-treated mice.. Fluvastatin increased survival in a murine model of postinfarct heart failure, which was associated with the amelioration of LV structural remodeling and contractile failure. Moreover, these effects were associated with the attenuation of increased MMP activity. Thus, long-term treatment with fluvastatin might be beneficial also in patients with heart failure and might improve their long-term survival.

Topics: Administration, Oral; Animals; Blotting, Western; Body Weight; Dilatation, Pathologic; Disease Models, Animal; Echocardiography; Fatty Acids, Monounsaturated; Fluvastatin; Heart Failure; Hemodynamics; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lung; Male; Matrix Metalloproteinases; Mice; Myocardial Infarction; Myocardium; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Organ Size; Peptidyl-Dipeptidase A; Survival Rate; Ventricular Function, Left; Ventricular Remodeling

Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has recently been reported to have the antioxidative activity in vitro. However, it is still unclear whether chronic treatment with this drug actually leads to amelioration of the redox status in the body. In this study, we investigated the antioxidative effect of fluvastatin in vivo, using a vitamin E-deficient hamster model, an in vivo model of enhanced oxidative stress. After pre-treatment with a vitamin E-deficient diet for 2 months, fluvastatin, pravastatin or probucol was added to the diet for 1 month. Vitamin E deficiency caused a significant increase in the levels of plasma oxidative stress markers such as 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) and hydroperoxides. Furthermore, there was a significant increase in the oxidizability of plasma lipids in the vitamin E-deficient animals, indicating that the oxidative stress was increased in the circulation. Fluvastatin markedly depressed the above oxidative stress markers in plasma, and significantly decreased the oxidizability of plasma lipids without affecting their levels. Probucol, a reference antioxidant, also showed a similar effect while pravastatin, another HMG-CoA reductase inhibitor, showed only a weak improvement. We suggest that the treatment with fluvastatin leads to a reduction of oxidative stress in vivo, which is mainly derived from its antioxidative property rather than its lipid-lowering activity.

Topics: Animals; Body Weight; Chromatography, High Pressure Liquid; Cricetinae; Dinoprost; Eating; F2-Isoprostanes; Fatty Acids, Monounsaturated; Fluvastatin; Indoles; Lipid Peroxidation; Lipid Peroxides; Liver; Myocardium; Oxidation-Reduction; Oxidative Stress; Time Factors; Vitamin E; Vitamin E Deficiency

1. The effects of 11 week treatments with the new hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin on renal intrinsic anti-oxidant enzyme (AOE) activities and renal function were evaluated in streptozotocin (STZ)-induced diabetic rats. 2. Renal intrinsic AOE activities, creatinine clearance and urinary albumin excretion were examined in STZ-induced diabetic rats. The levels of total cholesterol (TC), triglyceride (TG) and phospholipid (PL) were also examined. 3. In general, renal AOE activities and function were lower in diabetic rats than in non-diabetic Sprague-Dawley rats. 4. Decreases in TC, TG and PL levels and urinary albumin excretion by the HMG-CoA reductase inhibitor fluvastatin improved renal function and produced a non-uniform alteration in renal AOE; only glutathione peroxidase (GSH-Px) activity increased significantly with fluvastatin treatment. 5. It appears that the improvement in renal function and albuminuria may be related to increases in GSH-Px activity, but there was no correlation between changes in renal function and changes in the activity of Mn-superoxide dismutase or catalase.

Topics: Animals; Body Weight; Catalase; Cholesterol; Creatinine; Diabetes Mellitus, Experimental; Fatty Acids, Monounsaturated; Fluvastatin; Glutathione Peroxidase; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Kidney; Kidney Function Tests; Male; Phospholipids; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase; Triglycerides

We determined the role of Fluvastatin: HMG-CoA reductase inhibitor on the regression of atherosclerosis following removal of dietary cholesterol. Male rabbits fed a 0.5% cholesterol diet for 12 weeks were divided into three groups: A1, hypercholesterolemic; A2, fed a regular diet for an 12 additional weeks; and A3, fed a regular diet with fluvastatin (2 mg/kg/day). Fluvastatin treatment (A3) did not affect serum lipid levels compared with A2. However, it decreased the atherosclerotic area in the aortic arch and decreased total and esterified cholesterol concentrations in the descending aorta. Tone-related basal NO release in the thoracic aorta was larger in A3 than in A2. eNOS mRNA in vessel was determined by competitive RT-PCR assay. It increased in A1, compared with normal aorta and decreased in A2; however, it did not decrease in A3. This is the first report of a decrease in eNOS mRNA in atherosclerosis after removal of dietary cholesterol and a reversal of it by a HMG-CoA reductase inhibitor, which may contribute to the regression of atherosclerosis.

Topics: Acyl Coenzyme A; Animals; Aorta; Arteriosclerosis; Body Weight; Cholesterol, Dietary; Endothelium, Vascular; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Fluvastatin; Gene Expression Regulation, Enzymologic; Hypercholesterolemia; Indoles; Lipids; Male; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Rabbits; RNA, Messenger; Superoxide Dismutase; Up-Regulation

The CD-1 male-mouse model was employed to evaluate comparatively the toxicity of four vastatins (VTS) currently used in clinical medicine: lovastatin (LVT), simvastatin (SVT), pravastatin (PVT) and fluvastatin (FVT). Each vastatin was used orally in doses of 500 mg/Kg body weight/day, in animals with a hypercholesterolemic diet (HD) 5 days, or with a control diet (CD) 30 days. The association of high doses of VTS + HD produced a significant increase in liver weight and liver weight to body weight ratio in animals with SVT and FVT. Cholesterol (Chol) and triacylglycerols (TAG) in the liver increased significantly with FVT but not with the other VTS; Chol increased and TAG decreased in serum very significantly with FVT and SVT. The serum aminotransferases increased quite significantly with FVT but not with other VTS. In the experiment with high doses of VTS + CD, the animals receiving SVT or FVT showed a moderate loss of body weight. Liver weight and liver weight to body weight ratios were similar among all groups. Liver Chol showed a significant decrease with all VTS. Serum Chol decreased moderately with LVT and FVT. TAG in serum and liver showed a moderate decrease with all VTS. The serum aminotransferases were not modified by any vastatin. Our results indicate that high doses of VTS in male mice with a hypercholesterolemic diet result in a decreasing toxicity as follows: FVT>SVT>LVT>PVT.

Topics: Animals; Anticholesteremic Agents; Body Weight; Cholesterol; Cholesterol, Dietary; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipids; Liver; Lovastatin; Male; Mice; Mice, Inbred Strains; Organ Size; Pravastatin; Simvastatin; Time Factors; Transaminases; Triglycerides

Fluvastatin is a potent synthetic competitive inhibitor of beta-hydroxy-beta-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the biosynthetic pathway for hepatic cholesterol synthesis. The therapeutic indication is reduction of elevated total and low-density lipoprotein cholesterol levels. Results from four toxicity studies in beagle dogs and one study in rhesus monkeys following oral administration of fluvastatin are reported. In two 26-week dog studies, doses were 0, 1, 8, or 48 mg/kg/day (reduced to 36 mg/kg/day in Week 7) and 0, 6, 24, or 36 mg/kg/day (reduced to 30 mg/kg/day in Week 2). In a 2-year dog study, doses were 0, 1, 8, or 16 mg/kg/day. Dose levels in the 26-week monkey study were 0, 0.6, 12, and 48 mg/kg/day (raised to 84 mg/kg/day in Week 17 and to 108 mg/kg/day in Week 22). In these studies, evaluations included clinical and physical examinations, body weight and food consumption, electrocardiography, ophthalmoscopy, hematology and clinical chemistries, urinalysis, blood drug concentration, and macroscopic and microscopic examinations of observed lesions and representative tissues. In the 26- and 52-week dog studies and the monkey study, lenticular biochemistry, the HMG-CoA reductase activity of liver microsomes, and serum lipid concentrations were investigated. The fourth dog study was a single-dose toxicokinetic study in which 48 mg/kg [3H]-fluvastatin was monitored for up to 2 weeks. Sampling was limited to ocular tissues for enzyme analysis. Doses of > or = 24 mg/kg/day were lethal in dogs. At lethal doses, ataxia, convulsions, fecal blood, multifocal congestion and hemorrhage, isolated foci of malacia in the medulla oblongata, and liver necrosis were observed. Reduced weight gain, emesis, cataracts, elevated liver enzymes, reduced cholesterol, and gallbladder inflammation with mucosal hyperplasia occurred at > or = 8 mg/kg/day. In contrast to other HMG-CoA reductase inhibitors, fluvastatin did not cause significant central nervous system hemorrhage or testicular changes in dogs. Monkeys tolerated exposure to fluvastatin well with only mild gallbladder changes observed. Reduced serum cholesterol and slight hyperplasia of the gallbladder mucosa occurred in the 12 and 48/84/108 mg/kg/day groups.

Topics: Administration, Oral; Animals; Body Weight; Cataract; Dogs; Eating; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lens, Crystalline; Lipids; Liver; Macaca mulatta; Male; Microsomes, Liver; Time Factors