Gemfibrozil Treatment Research Articles

Ameliorative role of gemfibrozil against partial abdominal aortic constriction-induced cardiac hypertrophy in rats.

Fibrates are peroxisome proliferator-activated receptor-α agonists and are clinically used for treatment of dyslipidemia and hypertriglyceridemia. Fenofibrate is reported as a cardioprotective agent in various models of cardiac dysfunction; however, limited literature is available regarding the role of gemfibrozil as a possible cardioprotective agent, especially in a non-obese model of cardiac remodelling. The present study investigated the role of gemfibrozil against partial abdominal aortic constriction-induced cardiac hypertrophy in rats. Cardiac hypertrophy was induced by partial abdominal aortic constriction in rats and they survived for 4 weeks. The cardiac hypertrophy was assessed by measuring left ventricular weight to body weight ratio, left ventricular wall thickness, and protein and collagen content. The oxidative stress in the cardiac tissues was assessed by measuring thiobarbituric acid-reactive substances, superoxide anion generation, and reduced glutathione level. The haematoxylin-eosin and picrosirius red staining was used to observe cardiomyocyte diameter and collagen deposition, respectively. Moreover, serum levels of cholesterol, high-density lipoproteins, triglycerides, and glucose were also measured. Gemfibrozil (30 mg/kg, p.o.) was administered since the first day of partial abdominal aortic constriction and continued for 4 weeks. The partial abdominal aortic constriction-induced cardiac oxidative stress and hypertrophy are indicated by significant change in various parameters used in the present study that were ameliorated with gemfibrozil treatment in rats. No significant change in serum parameters was observed between various groups used in the present study. It is concluded that gemfibrozil ameliorates partial abdominal aortic constriction-induced cardiac oxidative stress and hypertrophy and in rats.

Exploring Avenues for Raising HDL Cholesterol

Exploring Avenues for Raising HDL Cholesterol

Gemfibrozil treatment prolongs the life span of mouse model of late infantile neuronal ceroid lipofuscinosis

Gemfibrozil treatment prolongs the life span of mouse model of late infantile neuronal ceroid lipofuscinosis

Gemfibrozil, a Lipid-lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-activated Receptor-β

An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis. Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identified another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (myelin basic protein, myelin oligodendrocyte glycoprotein, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, and proteolipid protein (PLP)) in primary human oligodendrocytes, mixed glial cells, and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-α (PPAR-α), we were unable to detect PPAR-α in either gemfibrozil-treated or untreated human oligodendrocytes, and gemfibrozil increased the expression of myelin genes in oligodendrocytes isolated from both wild type and PPAR-α(-/-) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-β but not PPAR-γ. Consistently, antisense knockdown of PPAR-β, but not PPAR-γ, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not up-regulate myelin genes in oligodendroglia isolated from PPAR-β(-/-) mice. Chromatin immunoprecipitation analysis showed that gemfibrozil induced the recruitment of PPAR-β to the promoter of PLP and myelin oligodendrocyte glycoprotein genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-β to the PLP promoter in vivo in the spinal cord of experimental autoimmune encephalomyelitis mice and suppression of experimental autoimmune encephalomyelitis symptoms in PLP-T cell receptor transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-β and that gemfibrozil, a prescribed drug for humans, may find further therapeutic use in demyelinating diseases.

The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice

Peroxisome Proliferator Activated Receptor (PPAR)-α is a key regulator of lipid metabolism and recent studies reveal it also regulates inflammation in several different disease models. Gemfibrozil, an agonist of PPAR-α, is a FDA approved drug for hyperlipidemia and has been shown to inhibit clinical signs in a rodent model of multiple sclerosis. Since many studies have shown improved outcome from spinal cord injury (SCI) by anti-inflammatory and neuroprotective agents, we tested the efficacy of oral gemfibrozil given before or after SCI for promoting tissue preservation and behavioral recovery after spinal contusion injury in mice. Unfortunately, the results were contrary to our hypothesis; in our first attempt, gemfibrozil treatment exacerbated locomotor deficits and increased tissue pathology after SCI. In subsequent experiments, the behavioral effects were not replicated but histological outcomes again were worse. We also tested the efficacy of a different PPAR-α agonist, fenofibrate, which also modulates immune responses and is beneficial in several neurodegenerative disease models. Fenofibrate treatment did not improve recovery, although there was a slight trend for a modest increase in histological tissue sparing. Based on our results, we conclude that PPAR-α agonists yield either no effect or worsen recovery from spinal cord injury, at least at the doses and the time points of drug delivery tested here. Further, patients sustaining spinal cord injury while taking gemfibrozil might be prone to exacerbated tissue damage.

Relation of Increased Prebeta-1 High-Density Lipoprotein Levels to Risk of Coronary Heart Disease

Preβ-1 high-density lipoprotein (HDL) plays a key role in reverse cholesterol transport by promoting cholesterol efflux. Our aims were (1) to test previous associations between preβ-1 HDL and coronary heart disease (CHD) and (2) to investigate whether preβ-1 HDL levels also are associated with risk of myocardial infarction (MI). Plasma preβ-1 HDL was measured by an ultrafiltration-isotope dilution technique in 1,255 subjects recruited from the University of California-San Francisco Lipid and Cardiovascular Clinics and collaborating cardiologists. Preβ-1 HDL was significantly and positively associated with CHD and MI even after adjustment for established risk factors. Inclusion of preβ-1 HDL in a multivariable model for CHD led to a modest improvement in reclassification of subjects (net reclassification index 0.15, p = 0.01; integrated discrimination improvement 0.003, p = 0.2). In contrast, incorporation of preβ-1 HDL into a risk model of MI alone significantly improved reclassification of subjects (net reclassification index 0.21, p = 0.008; integrated discrimination improvement 0.01, p = 0.02), suggesting that preβ-1 HDL has more discriminatory power for MI than for CHD in our study population. In conclusion, these results confirm previous associations between preβ-1 HDL and CHD in a large well-characterized clinical cohort. Also, this is the first study in which preβ-1 HDL was identified as a novel and independent predictor of MI above and beyond traditional CHD risk factors.

The Influence of Gemfibrozil on Malondialdehyde Level and Paraoxonase 1 Activity in Wistar and Fisher Rats

There are diverse experimental data about the influence of gemfibrozil (GEM) on the production of hydrogen peroxide (H(2)O(2)) and antioxidant enzymes. We investigated the influence of GEM treatment on the production of malondialdehyde (MDA) level in tissues of normolipidaemic Wistar and Fisher rats which is an index of lipid peroxidation. Because serum paraoxonase 1 (PON1) is an important enzyme with specific protective function on metabolism of lipid peroxides, we examined the influence of GEM on PON1 activity in liver and serum. MDA level and enzyme activities were also determined 10 days after withdrawal of GEM treatment. The significantly increased levels of MDA in liver, kidney and heart of both rat strains were obtained after 3 weeks of GEM treatment. We propose two possibilities for the increase of MDA levels caused by GEM, induction of peroxisome proliferation and activities of enzymes that participated in occurrence of H(2)O(2) and possible reduction of enzyme activities including in H(2)O(2) metabolism. Ten days after withdrawal of GEM treatment, MDA levels in all tissue levels of both rat strains were less in comparison with GEM treatment. GEM caused a significant drop of PON1 activity in serum and liver of Fisher rats, and in liver of Wistar rats. We suggest that GEM, through induction of lipid peroxidation, caused the damage of hepatocytes with consequent reduction of PON1 synthesis. The increase in PON1 activity in serum and tissues of both rat strains 10 days after withdrawal of GEM treatment shows the fast recovery of enzyme synthesis.

The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout

Gemfibrozil (GEM) is a fibrate drug consistently found in effluents from sewage treatment plants. This study characterizes the pharmacological effects of GEM on the plasma lipoproteins of rainbow trout ( Oncorhynchus mykiss). Our goals were to quantify the impact of the drug on: 1) lipid constituents of lipoproteins (phospholipids (PL), triacylglycerol (TAG), and cholesterol), 2) lipoprotein classes (high, low and very low density lipoproteins), and 3) fatty acid composition of lipoproteins. Potential mechanisms of GEM action were investigated by measuring lipoprotein lipase activity (LPL) and the hepatic gene expression of LPL and of the peroxisome proliferator-activated receptor (PPAR) α, β, and γ isoforms. GEM treatment resulted in decreased plasma lipoprotein levels (− 29%) and a reduced size of all lipoprotein classes (lower PL:TAG ratios). However, the increase in HDL-cholesterol elicited by GEM in humans failed to be observed in trout. Therefore, HDL-cholesterol cannot be used to assess the impact of the drug on fish. GEM also modified lipoprotein composition by reducing the abundance of long-chain n−3 fatty acids, thereby potentially reducing the nutritional quality of exposed fish. The relative gene expression of LPL was increased, but the activity of the enzyme was not, and we found no evidence for the activation of PPAR pathways. The depressing effects of GEM on fish lipoproteins demonstrated here may be a concern in view of the widespread presence of fibrates in aquatic environments. Work is needed to test whether exposure to environmental concentrations of these drugs jeopardizes the capacity of fish for reproduction, temperature acclimation or migratory behaviors.

Differential effects of gemfibrozil and fenofibrate on reverse cholesterol transport from macrophages to feces in vivo

Gemfibrozil and fenofibrate, two of the fibrates most used in clinical practice, raise HDL cholesterol (HDLc) and are thought to reduce the risk of atherosclerotic cardiovascular disease. These drugs act as PPARα agonists and upregulate the expression of genes crucial in reverse cholesterol transport (RCT). In the present study, we determined the effects of these two fibrates on RCT from macrophages to feces in vivo in human apoA-I transgenic (hApoA-ITg) mice. [3H]cholesterol-labeled mouse macrophages were injected intraperitoneally into hApoA-ITg mice treated with intragastric doses of fenofibrate, gemfibrozil or a vehicle solution for 17days, and radioactivity was determined in plasma, liver and feces. Fenofibrate, but not gemfibrozil, enhanced [3H]cholesterol flux to plasma and feces of female hApoA-ITg mice. Fenofibrate significantly increased plasma HDLc, HDL phospholipids, hApoA-I levels and phospholipid transfer protein activity, whereas these parameters were not altered by gemfibrozil treatment. Unlike gemfibrozil, fenofibrate also induced the generation of larger HDL particles, which were more enriched in cholesteryl esters, together with higher potential to generate preβ-HDL formation and caused a significant increase in [3H]cholesterol efflux to plasma. Our findings demonstrate that fenofibrate promotes RCT from macrophages to feces in vivo and, thus, highlight a differential action of this fibrate on HDL.

Impact of obesity on hypertension-induced cardiac remodeling: role of oxidative stress and its modulation by gemfibrozil treatment in rats

This study investigated the possible synergistic role of obesity in hypertension-induced cardiac remodeling and its modulation by gemfibrozil treatment in rats. Male Wistar rats were fed a high-fat diet (HFD) for 90 days. Normal rats were subjected to hypertension by partial abdominal aortic constriction (PAAC) for 28 days. In the HFD + PAAC control group, rats on HFD were subjected to PAAC on the 62nd day and were sacrificed on the 90th day. HFD and PAAC individually resulted in significant cardiac hypertrophy and fibrosis along with increased oxidative stress and mean arterial blood pressure (MABP) in rats as evidenced by various morphological, biochemical, and histological parameters. Moreover, the HFD + PAAC control group showed marked cardiac remodeling compared to rats subjected to HFD or PAAC alone. The HFD + gemfibrozil and HFD + PAAC + gemfibrozil groups showed significant reduction in cardiac remodeling along with reduction in oxidative stress and MABP. Hence, it may be concluded that oxidative stress plays a key role in obesity-mediated synergistic effects on induction and progression of PAAC-induced cardiac remodeling, and its deleterious effects could be reversed by gemfibrozil treatment in rats through its antioxidant activity.

Effects of gemfibrozil treatment on vascular reactivity of streptozotocin-diabetic rat aorta.

The effects of gemfibrozil treatment on plasma lipids, lipid peroxides and vascular reactivity of aorta were investigated in diabetic rats. Rats were divided randomly into two groups: control and diabetic. Diabetes was induced by a single intraperitoneal injection of streptozotocin (45 mg kg(-1)). Twelve weeks after the induction of diabetes, some of the control and diabetic rats were started treatment with gemfibrozil (100 mg kg(-1) daily; gavage) for 2 weeks. Blood glucose, plasma triglyceride, cholesterol, low-density lipoprotein (LDL) cholesterol and thiobarbituric acid reactive substances (TBARS) levels were markedly increased and gemfibrozil treatment restored these parameters in diabetic rats. However high-density lipoprotein (HDL) cholesterol levels did not differ in all experimental groups. In diabetic rats, the endothelium-dependent relaxations to acetylcholine were decreased when compared with control rats. Gemfibrozil treatment restored the endothelium-dependent responses to acetylcholine in diabetic rats. The endothelium-independent relaxation responses to sodium nitroprusside were not altered in all groups. These findings suggest that gemfibrozil treatment has beneficial effects against cardiovascular and metabolic complications of diabetes via its hypolipidaemic and antioxidant properties.

Gemfibrozil-Induced Myositis in a Patient with Normal Renal Function

To describe a case of gemfibrozil monotherapy-induced myositis in a patient with normal renal function A 68-year-old white man presented to his primary care clinic complaining of a 6-month history of total body pain. His past medical history was significant for hypertension, diabetes mellitus, hyperlipidemia, gastroesophageal reflux disease, benign prostatic hypertrophy, arthritis, impotence, and pancreatic cancer that required excision of part of his pancreas. His home drug regimen included bupropion 75 mg twice daily, gemfibrozil 600 mg twice daily for the past 8 months, glimiperide 1 mg daily, insulin glargine 5 units at bedtime, insulin aspart 5 units in the evening, lisinopril 10 mg daily, omeprazole 40 mg daily, pregabalin 100 mg daily, and sildenafil 100 mg as needed. Laboratory test results were significant for elevated aspartate aminotransferase (AST) 78 U/L (reference range 15-46 U/L), alanine aminotransferase (ALT) 83 U/L (13-69 U/L), and creatine kinase (CK) 3495 U/L (55-170 U/L). Serum creatinine was normal at 1.19 mg/dL. The physician determined that the elevated CK indicated myositis secondary to gemfibrozil use, and gemfibrozil was subsequently discontinued. The patient returned 1 week later to repeat the laboratory tests. Results were CK 220 U/L, AST 26 U/L, ALT 43 U/L, and serum creatinine 1.28 mg/dL. The patient was asked to return in 3 weeks to repeat the laboratory tests. At that time, CK had continued to decrease to 142 U/L, and the AST and ALT had returned to normal, at 22 and 29 U/L, respectively. The patient reported complete resolution of total body pain 3 weeks after discontinuation of gemfibrozil. Follow-up 5 weeks after discontinuation revealed no change compared to the 3-week follow-up. Myositis most often produces weakness and elevated CK levels more than 10 times the upper limit of normal. The risk of developing myositis, myopathy, or rhabdomyolysis is low (1%) when fibrates such as gemfibrozil are used as monotherapy. Evaluation of the literature revealed one case of gemfibrozil-related myositis in a patient with chronic renal failure. There is also one report of myopathy associated with gemfibrozil monotherapy in a patient with normal renal function. The present case is the first documented case of gemfibrozil monotherapy-induced myositis in a patient with normal renal function. The Naranjo probability scale indicated a probable relationship between gemfibrozil treatment and the onset of myositis in our patient. Other potential causes of myositis were ruled out by patient interview and chart review. Although the risk of myositis appears to be low with gemfibrozil monotherapy, clinicians should be aware of the potential for this adverse event. For patients taking gemfibrozil monotherapy who present with myalgia, discontinuation of the medication may be necessary for the alleviation of pain.

CYP2C8 Activity Recovers within 96 Hours after Gemfibrozil Dosing: Estimation of CYP2C8 Half-Life Using Repaglinide as an in Vivo Probe

Gemfibrozil 1-O-beta-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8. We studied the recovery of CYP2C8 activity after discontinuation of gemfibrozil treatment using repaglinide as a probe drug, to estimate the in vivo turnover half-life of CYP2C8. In a randomized five-phase crossover study, nine healthy volunteers ingested 0.25 mg of repaglinide alone or after different time intervals after a 3-day treatment with 600 mg of gemfibrozil twice daily. The area under the plasma concentration-time curve (AUC) from time 0 to infinity of repaglinide was 7.6-, 2.9-, 1.4- and 1.0-fold compared with the control phase when it was administered 1, 24, 48, or 96 h after the last gemfibrozil dose, respectively (P < 0.001 versus control for 1, 24, and 48 h after gemfibrozil). Thus, a strong CYP2C8 inhibitory effect persisted even after gemfibrozil and gemfibrozil 1-O-beta-glucuronide concentrations had decreased to less than 1% of their maximum (24-h dosing interval). In addition, the metabolite to repaglinide AUC ratios indicated that significant (P < 0.05) inhibition of repaglinide metabolism continued up to 48 h after gemfibrozil administration. Based on the recovery of repaglinide oral clearance, the in vivo turnover half-life of CYP2C8 was estimated to average 22 +/- 6 h (mean +/- S.D.). In summary, CYP2C8 activity is recovered gradually during days 1 to 4 after gemfibrozil discontinuation, which should be considered when CYP2C8 substrate dosing is planned. The estimated CYP2C8 half-life will be useful for in vitro-in vivo extrapolations of drug-drug interactions involving induction or mechanism-based inhibition of CYP2C8.

Clomiphene citrate–induced severe hypertriglyceridemia

To report a case of severe hypertriglyceridemia associated with clomiphene citrate (CC) treatment. Case report. A patient referred to an endocrinology clinic of a state hospital. A 29-year-old, overweight woman with a history of polycystic ovary syndrome who had been given clomiphene citrate (CC) for ovulation induction and presented with severe hypertriglyceridemia. She had a family history of type 2 diabetes and hyperlipidemia. Clomiphene citrate treatment was discontinued, and gemfibrozil treatment at a dose of 1,200 mg/d was started. Serum lipid levels. With the discontinuation of CC treatment and start of a specific lipid-lowering agent, the patient's lipid profile improved. After 3 months, CC therapy was restarted, and again severe hypertriglyceridemia developed, which resolved with the previous treatment strategies. Clomiphene citrate should be used cautiously in women having risk factors for dyslipidemia, and, even in the presence of a normal lipid profile, lipid levels should be closely monitored when CC treatment is instituted.

Effect of Combination Nicotinic Acid and Gemfibrozil Treatment on Intermediate Density Lipoprotein, and Subclasses of Low Density Lipoprotein and High Density Lipoprotein in Patients With Combined Hyperlipidemia

The goal of this study was to determine, using analytic ultracentrifugation, the effect of nicotinic acid alone or nicotinic acid added to gemfibrozil on lipoprotein subclass distribution, including intermediate-density lipoprotein (IDL; low-density to very low density flotation rate [S(f)] 12 to 20); low-density lipoprotein (LDL) subfractions LDL-I (S(f) 7 to 12), LDL-II (S(f) 5 to 7), LDL-III (S(f) 3 to 5), and LDL-IV (S(f) 0 to 3); and high-density lipoprotein (HDL) subfractions HDL(2) (high-density flotation rate 3.5 to 9.0) and HDL(3) (high-density flotation rate 0 to 3.5). Patients with combined hyperlipidemia were randomized to nicotinic acid (1,500 mg/day) plus placebo or nicotinic acid plus gemfibrozil (1,200 mg/d) for 12 weeks. Baseline characteristics were similar between the 2 groups, and mean LDL cholesterol (180 +/- 33 mg/dl) and triglycerides (310 +/- 126 mg/dl) were typical for patients with combined hyperlipidemia. Treatment with nicotinic acid resulted in a reduction in dense LDL (S(f) 5 to 7; p = 0.02), which was counterbalanced by an increase in buoyant LDL (S(f) 7 to 12; p = 0.03) that resulted in no significant LDL mass or LDL cholesterol change. IDL was reduced (p = 0.005) and HDL(2) increased by 143% (p = 0.004). The combination of nicotinic acid and gemfibrozil resulted in a further 17.8% reduction in apolipoprotein B (p = 0.06), a further 33.8% reduction in IDL (p = 0.06), and a greater reduction in the apolipoprotein B/apolipoprotein A-I ratio (p = 0.02). The combination of nicotinic acid and gemfibrozil reduced atherogenic by IDL 71%, dense LDL-III by 52%, and apolipoprotein B by 37% and increased protective HDL(2) by 90%. In conclusion, this investigation revealed that a combination of a fibric acid derivative and nicotinic acid offers greater improvement in detailed lipoprotein subclass distribution and apolipoprotein ratios than monotherapy.

A pilot study in the efficacy and safety of gemfibrozil in a pediatric population

Gemfibrozil reduces plasma triglycerides and raises high-density lipoprotein cholesterol (HDL-C) in adults and also reduces the incidence of cardiovascular endpoints in adults. Its efficacy in improving lipid abnormalities has not been evaluated in children. Our purpose was to investigate whether gemfibrozil would lower triglycerides and raise HDL-C with minimal adverse effects in a pediatric population with metabolic syndrome. We conducted a retrospective study of 47 pediatric patients with metabolic syndrome who started gemfibrozil treatment, 1200 mg/day because of failure or lack of interest in therapeutic lifestyle changes. Eligibility required patients to be younger than 21 years of age, and have pretreatment and on-treatment fasting lipid profiles. Data recorded included age at start of treatment, blood pressure, body mass index, waist circumference, percent body fat, total plasma cholesterol, HDL, low-density lipoprotein, triglycerides, alanine aminotransferase, and aspartate aminotransferase. Treatment duration was elapsed time between starting gemfibrozil and the last clinic visit. Average age of the study cohort was 14 years and mean duration on medication was 249 days. Those patients who had pretreatment and on-treatment plasma lipid data (33 of 47) were included in an analysis for efficacy. All 47 patients were monitored for safety. Mean triglycerides decreased by 57%: 426 (standard error of mean = 33.6) to 184 mg/dL (standard error of mean = 19) (P < 0.0001). Mean HDL increased by 20%: 35 to 42 mg/dL (P < 0.001). Body composition changes were insignificant, indicating that the lipid changes can be attributed to gemfibrozil. Two of forty-seven patients reported muscle pain from the drug, one of whom was considered to have had a possible adverse effect from the medication as indicated by muscle pain. Gemfibrozil significantly lowers triglycerides and raises HDL with reasonable safety in a pediatric population with metabolic syndrome.

Relation of gemfibrozil treatment and high-density lipoprotein subpopulation profile with cardiovascular events in the Veterans Affairs High-Density Lipoprotein Intervention Trial

The significant cardiovascular disease (CVD) event reduction in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) could not be fully explained by the 6% increase in high-density lipoprotein (HDL) cholesterol with the fibrate gemfibrozil. We examined whether measurement of HDL subpopulations provided additional information relative to CVD risk reduction. The HDL subpopulations were characterized by 2-dimensional gel electrophoresis in subjects who were treated with gemfibrozil (n = 754) or placebo (n = 741). In this study, samples obtained at the 3-month visit were used; and data were analyzed prospectively using CVD events (coronary heart disease death, myocardial infarction, or stroke) during the 5.1 years of follow-up. Analyses in the gemfibrozil arm showed that subjects with recurrent CVD events had significantly higher pre β-1 and had significantly lower α-1 and α-2 HDL levels than those without such events. Pre β-1 level was a significant positive predictor; α-1 and α-2 levels were significant negative risk factors for future CVD events. α-2 level was superior to HDL cholesterol level in CVD-risk assessment after adjustment for established risk factors. Gemfibrozil treatment was associated with 3% to 6% decreases in the small, lipid-poor pre β-1 HDL and in the large, lipid-rich α-1 and α-2 HDL and with increases in the small α-3 (3%) and pre α-3 (16%) HDLs. Although the use of gemfibrozil has been associated with reduction in CVD events in VA-HIT, HDL subpopulation analysis indicates that gemfibrozil-mediated improvement in CVD risk might not be the result of its effects on HDL. It is quite possible that much of the cardiovascular benefits of gemfibrozil are due to a much wider spectrum of effects on metabolic processes that is not reflected by changes in blood lipids and HDL subpopulations.

Gemfibrozil Ameliorates Relapsing-Remitting Experimental Autoimmune Encephalomyelitis Independent of Peroxisome Proliferator-Activated Receptor-α

The present study underlines the importance of gemfibrozil, a lipid-lowering drug and an activator of peroxisome proliferator-activated receptor-alpha (PPAR-alpha), in inhibiting the disease process of adoptively transferred experimental allergic encephalomyelitis (EAE), an animal model of relapsing-remitting multiple sclerosis. Clinical symptoms of EAE, infiltration of mononuclear cells, and demyelination were significantly lower in SJL/J female mice receiving gemfibrozil through food chow than those without gemfibrozil. It is noteworthy that the drug was equally effective in treating EAE in PPAR-alpha wild-type as well as knockout mice. Gemfibrozil also inhibited the encephalitogenicity of MBP-primed T cells and switched the immune response from a Th1 to a Th2 profile independent of PPAR-alpha. Gemfibrozil consistently inhibited the expression and DNA-binding activity of T-bet, a key regulator of interferon-gamma (IFN-gamma) expression and stimulated the expression and DNA-binding activity of GATA3, a key regulator of IL-4. Gemfibrozil treatment decreased the number of T-bet-positive T cells and increased the number of GATA3-positive T cells in spleen of donor mice. The histological and immunohistochemical analyses also demonstrate the inhibitory effect of gemfibrozil on the invasion of T-bet-positive T cells into the spinal cord of EAE mice. Furthermore, we demonstrate that the differential effect of gemfibrozil on the expression of T-bet and GATA3 was due to its inhibitory effect on NO production. Although excess NO favored the expression of T-bet, scavenging of NO stimulated the expression of GATA-3. Taken together, our results suggest gemfibrozil, an approved drug for hyperlipidemia in humans, may find further therapeutic use in multiple sclerosis.

Increased Survival after Gemfibrozil Treatment of Severe Mouse Influenza

Gemfibrozil, an agent that inhibits production of proinflammatory cytokines in addition to its clinically useful lipid-lowering activity, increased survival in BALB/c mice that were already ill from infection by influenza virus A/Japan/305/57 (H2N2). Gemfibrozil was administered intraperitoneally once daily from days 4 to 10 after intranasal exposure to the virus. Survival increased from 26% in vehicle-treated mice (n = 50) to 52% in mice given gemfibrozil at 60 mg/kg/day (n = 46) (P = 0.0026). If this principle translates to patients, a drug already approved for human use, albeit by a different route for another purpose, might be adapted relatively fast for use against influenza, conceivably including human infection with a derivative of the avian H5N1 strain.

Safety of Rosuvastatin: Update on 16,876 Rosuvastatin-Treated Patients in a Multinational Clinical Trial Program

Background: The safety and tolerability of rosuvastatin were assessed using data from 16,876patients who received rosuvastatin 5–40 mg in a multinational phase II/III/IIIb/IV program, representing 25,670 patient-years of continuous exposure to rosuvastatin. Methods: An integrated database, consisting of 33 trials whose databases were locked up to and including September 16, 2005, was used to examine adverse events and laboratory data. Results: In placebo-controlled trials, adverse events irrespective of causality assessment occurred in 52.1% of patients receiving rosuvastatin 5–40 mg (n = 931) and 51.8% of patients receiving placebo (n = 483). In all controlled clinical trials with comparator statins, rosuvastatin 5–40 mg was associated with an adverse event profile similar to profiles for atorvastatin 10–80 mg, simvastatin 10–80 mg, and pravastatin 10–40 mg. Clinically significant elevations in alanine aminotransferase (>3 times the upper limit of normal [ULN] on at least 2 consecutive occasions) were uncommon (≤0.2%) in the rosuvastatin and comparator statin groups. Elevated creatine kinase >10 times ULN occurred in ≤0.3% of patients receiving rosuvastatin or other statins. Myopathy (creatine kinase >10 times ULN with muscle symptoms) possibly related to treatment occurred in 0.03% of patients taking rosuvastatin at doses ≤40 mg. The frequency of dipstick-positive proteinuria at rosuvastatin doses ≤20 mg was comparable to that seen with other statins, and the development of proteinuria was not predictive of acute or progressive renal disease. Both short- and long-term rosuvastatin treatment were associated with small increases in estimated glomerular filtration rate, with improvements appearing to be somewhat greater in those patients beginning treatment with greater renal impairment. In the phase II–IV program, no deaths were attributed to rosuvastatin; at doses of rosuvastatin ≤40 mg, 1 case of rhabdomyolysis occurred in a patient who received rosuvastatin 20 mg and concomitant gemfibrozil treatment. Conclusion: In summary, rosuvastatin was well tolerated by a broad range of patients with dyslipidemia, and its safety profile was similar to those of comparator statins investigated in the clinical program. (Nota bene: The clinical development program for rosuvastatin initially evaluated rosuvastatin doses up to 80 mg. Following completion of the phase III/IIIb program, a decision was made not to pursue marketing approval for the 80-mg dose because the additional lipid-modifying benefits of this dose did not justify the potential risks for use in the general population of patients with dyslipidemia.)