Effect of ezetimibe and/or simvastatin on coenzyme Q10 levels in plasma: a randomised trial.

BACKGROUND: HMG-CoA reductase inhibitors ('statins') have been associated with a decrease in ubidecarenone (ubiquinone) levels, a lipophilic enzyme also known as coenzyme Q10 (CoQ10), due to inhibition of mevalonate synthesis. There is speculation that a decrease in CoQ10 levels may be associated with statin-induced myopathy. The cholesterol absorption inhibitor ezetimibe increases endogenous cholesterol synthesis. The purpose of this study was to examine (i) the effects of ezetimibe and simvastatin on plasma CoQ10 levels and (ii) whether ezetimibe coadministered with simvastatin abrogates the suggested statin-induced decrease in the CoQ10 plasma levels. METHODS: Seventy-two healthy male subjects were enrolled in a single-centre, randomised, parallel-group study with three arms. Subjects received ezetimibe 10 mg/day, simvastatin 40 mg/day or the combination of ezetimibe 10 mg/day plus simvastatin 40 mg/day for 14 days. RESULTS: Baseline CoQ10 (0.99 +/- 0.30 mg/L) levels for the combined groups remained unchanged in the ezetimibe group (0.95 +/- 0.24 mg/L), and significantly decreased in the simvastatin and combination groups (0.82 +/- 0.18 mg/L, p = 0.0002 and 0.7 +/- 0.22 mg/L, p < 0.0001, respectively). There was a correlation between the percentage change in the levels of low-density lipoprotein-cholesterol (LDL-C) and the percentage change in CoQ10 levels in all treatment groups (correlation coefficient [R] = 0.67, p < 0.0001). The ratios of CoQ10 levels to LDL-C levels were significantly increased in all treatment groups (p < 0.0001). CoQ10 level was independent of cholesterol synthesis or absorption markers. CONCLUSIONS: Simvastatin and the combination of simvastatin and ezetimibe significantly decrease plasma CoQ10 levels whereas ezetimibe monotherapy does not. There is a significant correlation between the CoQ10 level decrease and the decrease in total and LDL-C levels in all three treatment groups, suggesting that the CoQ10 decrease may reflect the decrease in the levels of its lipoprotein carriers and might not be statin-specific. The statin-associated CoQ10 reduction is not abrogated through ezetimibe coadministration. Changes of CoQ10 levels are independent of cholesterol synthesis and absorption.     

Reduced mitochondrial coenzyme Q10 levels in HepG2 cells treated with high-dose simvastatin: a possible role in statin-induced hepatotoxicity?

Lowering of low-density lipoprotein cholesterol is well achieved by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). Statins inhibit the conversion of HMG-CoA to mevalonate, a precursor for cholesterol and coenzyme Q10 (CoQ10). In HepG2 cells, simvastatin decreased mitochondrial CoQ10 levels, and at higher concentrations was associated with a moderately higher degree of cell death, increased DNA oxidative damage and a reduction in ATP synthesis. Supplementation of CoQ10, reduced cell death and DNA oxidative stress, and increased ATP synthesis. It is suggested that CoQ10 deficiency plays an important role in statin-induced hepatopathy, and that CoQ10 supplementation protects HepG2 cells from this complication.     

The effect of HMG-CoA reductase inhibitors on coenzyme Q10: possible biochemical/clinical implications.

The HMG-CoA reductase inhibitors, also known as statins, have an enviable safety profile; however, myotoxicity and to a lesser extent hepatotoxicity have been noted in some patients following treatment. Statins target several tissues, depending upon their lipophilicity, where they competitively inhibit HMG-CoA reductase, the rate-limiting enzyme for mevalonic acid synthesis and subsequently cholesterol biosynthesis. HMG-CoA reductase is also the first committed rate-limiting step for the synthesis of a range of other compounds including steroid hormones and ubidecarenone (ubiquinone), otherwise known as coenzyme Q(10) (CoQ(10)). Recent interest has focused on the possible role CoQ(10) deficiency may have in the pathophysiology of the rare adverse effects of statin treatment. Currently, there is insufficient evidence from human studies to link statin therapy unequivocally to pathologically significantly decreased tissue CoQ(10) levels. Although statin treatment has been reported to lower plasma/serum CoQ(10) status, few human studies have assessed tissue CoQ(10) status. The plasma/serum CoQ(10) level is influenced by a number of physiological factors and, therefore, has limited value as a means of assessing intracellular CoQ(10) status. In those limited studies that have assessed the effect of statin treatment upon tissue CoQ(10) levels, none have shown evidence of a fall in CoQ(10) levels. This may reflect the doses of statins used, since many appear to have been used at doses below those recommended for their maximum therapeutic effects. Moreover, the poor bioavailability in those peripheral tissues tested may not reflect the effects the agents are having in liver and muscle, the tissues commonly affected in those patients who do not tolerate statins. This article reviews the biochemistry of CoQ(10), its role in cellular metabolism and the available evidence linking possible CoQ(10) deficiency to statin therapy.     

Total coenzyme Q10 concentrations in Asian men following multiple oral 50-mg doses administered as coenzyme Q10 sustained release tablets or regular tablets

Coenzyme Q(10) (CoQ(10)), a highly lipophilic compound present in the inner mitochondrial membrane, is essential for production of cellular energy in the form of ATP. CoQ(10) is used as a dietary supplement and for treatment of various cardiovascular disorders. Our goal was to compare the CoQ(10) levels in Asians following multiple oral doses administered as sustained release or regular tablets. Twenty healthy male volunteers (19-23 years old) were divided into two equal groups. Each subject in Group I received 50 mg oral doses of coenzyme Q(10) as sustained release tablets once a day for fifteen days, while subject in Group II received 50 mg doses of coenzyme Q(10) regular tablets. The CoQ(10) levels were measured by HPLC-UV (reverse phase ODS column, 10 microm, 250 x 4.6 mm; oven temperature 30 degrees C). Mobile phase was constituted by methanol-ethanol 9 : 1 v/v. Flow rate was 1.5 ml/min and UV detection was carried out at 275 nm. Coenzyme Q(9) was used as an internal standard. CoQ(10) baseline in the morning was 0.88+/-0.48 mg/l. Following 1 week 50 mg/d dosing of CoQ(10), plasma CoQ(10) concentrations increased to 1.85+/-1.03 mg/l for sustained release tablets and up to 1.37+/-0.74mg/l for regular tablets. The net increment proportion in AUC for sustained release and regular tablets were 148.26+/-176.56%, 102.57+/-130.00%, respectively. Both preparations significantly increased the systemic exposure when compared to endogenous baseline.     

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin and the human lens. Clinical results of a 3-year follow-up.

Simavastatin (MK-733, Zocor, CAS 79902-63-9), a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, was administered for a period of at least 3 years to 21 patients suffering from primary hypercholesterolemia. Significant decreases were noted for plasma cholesterol (30%), low density lipoprotein cholesterol (40%), whereas an increase in plasma high density lipoprotein cholesterol (11%) was observed. The drug therapy was well tolerated and clinical examinations revealed no adverse effects. No development of cataracts or other ocular side effects have been observed during this 3-year follow-up period.     

Effect of simvastatin on trioleylglycerol hydrolysis and transacylation with cholesterol in serum of outpatients with coronary heart disease

At present, the most effective drugs in treating hypercholesterolemia and atherosclerosis are the statins, which are potent inhibitors of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Serum triacylglycerol (TAG) levels associate positively with the risk for coronary heart disease (CHD). Triacylglycerols are mainly hydrolyzed by the enzyme lipase (glycerol ester hydrolase [GEH], EC 3.1.1.3) but can also be transformed by transacylation with cholesterol (glycerol ester:cholesterol acyltransferase [GECAT], EC 2.3.1.43). We evaluated the effect of a 3-month treatment with simvastatin (10 mg/day) on GEH and GECAT activity in the serum of 26 outpatients with CHD. The activity of both GEH and GECAT was reduced in the CHD group compared with that in the control group: 5.9 +/- 0.9 mU/mg vs. 7.5 +/- 1.8 mU/mg and 11.1 +/- 1.4 mU/mg vs. 19.3 +/- 3.3 mU/mg, respectively (p < or = 0.05). In addition to the well known effect of reducing total cholesterol and low-density lipoprotein cholesterol in patients with CHD, we observed two other results of simvastatin treatment. First, GEH activity increased to values similar to those found in healthy subjects and, simultaneously, GECAT activity decreased. Trioleylglycerol transacylation with cholesterol amounted to 72% and hydrolysis to 28% in the control group and to 65% and 35% in the CHD group, respectively. After simvastatin treatment, transacylation with cholesterol and hydrolysis amounted to 51% and 49%, respectively. In conclusion, by increasing GEH and reducing GECAT, simvastatin seems not only to affect cholesterol synthesis but also to alter triacylglycerol metabolism. Further studies are needed to determine the physiological significance of these changes and their relationship with the development of atherosclerosis.     

Plasma and urine carnitine concentrations in well-trained athletes at rest and after exercise. Influence of L-carnitine intake.

L-carnitine is essential to cellular energy production mainly because of its acyl- and acetyl-carrier properties. Athletes commonly take L-carnitine, which is thought to improve exercise performance. There are no reports on carnitine plasma concentrations and carnitine excretion in short-duration maximal exercise in well-trained athletes taking this substance. We measured plasma and urine carnitine concentrations before and 10 min after maximal treadmill ergometry in nine well-trained sportsmen with and without oral supplementation with 1 g L-carnitine. In athletes without L-carnitine intake, plasma free carnitine concentration decreased significantly from 45.2 +/- 5.3 to 41.6 +/- 5.0 mumol/l (mean +/- SD, p < 0.001) 10 min after exercise compared with baseline. In athletes with oral L-carnitine supplementation, plasma free carnitine concentration at baseline was 71.3 +/- 10.2 mumol/l and did not change after maximal exercise (71.8 mumol/l +/- 10.7 mumol/l). The elevated plasma concentration of free carnitine without decrease after maximal exercise in well-trained athletes taking L-carnitine could be important in view of the newly postulated direct vascular effects of L-carnitine in improving skeletal muscle performance.     

Effect of troglitazone on endothelial function in type 2 diabetic patients

Lysophosphatidylcholine (lysoPC), a component of oxidized low-density lipoprotein cholesterol (LDL-C), has been reported to impair nitric oxide production and endothelium-dependent vasorelaxation. The effects of troglitazone (CAS 97322-87-7), which is an antidiabetic agent with antioxidant properties, on serum levels of lysoPC and nitrite/nitrate (NOx) have been studied. Eight patients with Type 2 diabetes (non-insulin dependent diabetes mellitus, NIDDM) were studied (age: 61.5 +/- 2.8 years; diabetes duration: 10.2 +/- 1.6 years). They were additionally given troglitazone (200 mg once daily) since their fasting plasma glucose (FPG) and HbA1c levels had been increased in spite of conventional medications. Before and after 12 weeks of treatment with troglitazone their blood pressure, FPG, HbA1c, lipid profiles and NOx were measured. Troglitazone treatment had a slight depressor effect (decreasing the blood pressure from 133 +/- 5/72 +/- 3 to 127 +/- 4/68 +/- 1 mmHg; p < 0.05). FPG and HbA1c were significantly decreased with the therapy (181 +/- 10 to 160 +/- 10 mg/dl; p < 0.05 and 9.1 +/- 0.6 to 8.1 +/- 0.5%; p < 0.05, respectively). In contrast, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and LDL-C were maintained within normal limits throughout the study. Although lysoPC and NOx levels were not altered, a negative correlation between lysoPC and NOx levels was observed. These results suggest that troglitazone is a beneficial agent improving FPG and HbA1c levels in NIDDM patients, while its effects on serum lysoPC and NOx levels, at least for 12 weeks, seem to be minimal.     

Clinical efficacy of pitavastatin,a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor,in patients with hyperlipidemia. Dose-finding study using the double-blind,three-group parallel comparison

Pitavastatin (CAS 147526-32-7, NK-104), the first totally synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor discovered in Japan, was examined. Pitavastatin significantly decreased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) at doses of 1 mg/day or more, and significant dose-dependence of the effect of this drug was observed within the dose range from 1 mg/day to 4 mg/day. It also significantly decreased the serum levels of triglycerides (TG) within this dose range. There was no dose-dependence of the incidence of adverse reactions to pitavastatin.     

Isotachophoretic evidence for energy-preservating effect of coenzyme Q10 on isolated guinea-pig cardiac muscle

Effects of coenzyme Q10 (CoQ10) on hypoxia-induced changes in ATP, NAD and NADH levels were studied in the isolated atrial and ventricular muscles of guinea-pigs. Guinea-pigs were pretreated with CoQ10 (60 mg/kg/day, i.p.) or the solvent for 3 consecutive days before initiation of study. The concentrations of ATP, NAD and NADH were determined by isotachophoresis. The concentrations of ATP and NAD contained in the atrial or ventricular muscle decreased with increasing incubation time with hypoxic Tyrode's solution (pO2 not equal to 160 mmHG), but that of NADH increased. However, the ATP and NAD concentrations of atrial and ventricular muscles from CoQ10-pretreated animals tended to be higher than those from solvent-pretreated ones. Moreover, the increase in NADH concentration during hypoxia tended to be less in the CoQ10-pretreated preparation than in the solvent-pretreated one. These results suggest that the pretreatment with CoQ10 leads to the increase in CoQ10 content in mitochondria of heart muscle, thereby permitting the improvement of oxidative phosphorylation in the mitochondria during hypoxia.     

Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.     

Time-of-intake (morning versus evening) of extended-release fluvastatin in hyperlipemic patients is without influence on the pharmacodynamics (mevalonic acid excretion) and pharmacokinetics

OBJECTIVE: Statins inhibit the rate-limiting step in cholesterol biosynthesis, the conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate by HMG-CoA reductase. Statins are usually taken in the evening as the HMG-CoA reductase activity is high during the night. This recommendation might not apply if statins are given as extended-release (ER) formulations. The present study investigated the influence of time of intake of fluvastatin 80 mg ER on cholesterol biosynthesis. Main objectives were to measure the change in 24-hour urinary mevalonic acid excretion, to determine plasma concentrations of mevalonic acid and fluvastatin and to monitor triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol. METHODS: This was a randomized, 2-period crossover study in 26 hypercholesterolemic patients who received a single daily dose of fluvastatin both in the morning and in the evening. RESULTS: At baseline, the amount of mevalonic acid was 204.9 +/- 68.1 microg/g creatinine. After a single dose of fluvastatin mean urine values of mevalonate were significantly reduced to 129.8 +/- 66.2 micro/g (evening) and to 118.7 +/-34.3 microg/g (morning; n.s. between groups), thus representing a reduction of about 39%. Compared to baseline, plasma mevalonate concentrations were decreased by fluvastatin resulting in similar 24-hour profiles after the morning and the evening dosage. The pharmacokinetics of fluvastatin were similar in both periods of the study, with higher plasma concentrations for several hours following the evening dosage. CONCLUSION: This study demonstrates that fluvastatin ER is equally effective in inhibiting cholesterol biosynthesis when given once daily in the morning and once daily in the evening.     

The effect of pravastatin in relation to low density lipoprotein receptor activity

Pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, suppresses new synthesis of cholesterol via HMG-CoA in hepatocytes. As a result, low density lipoprotein (LDL) receptor activity in the liver is enhanced, which leads to lowering of plasma cholesterol. Inhibitors are shown to be effective in heterozygous familial hypercholesterolaemia (FH). Although FH heterozygotes are defined genetically as possessing half the normal LDL receptor activity, some heterogeneity of LDL receptor activity is observed in these patients. To see whether the effect of an inhibitor is related to LDL receptor activity in each patient, pravastatin was administered to 7 FH heterozygotes for 3 months at a daily dose of 10 mg; their mean LDL receptor activities measured before the therapy were 45.0 +/- 9.9% of the normal control. After medication, mean serum total cholesterol decreased from 349.0 to 279.7 mg/dl (p less than 0.05), and LDL-cholesterol decreased from 272.6 to 207.7 mg/dl (p less than 0.05). A significant correlation between the initial LDL receptor activity and the effect of pravastatin was not proved. However, the pre-treatment level of LDL-cholesterol was positively correlated (r = 0.795) with the absolute decrement of LDL-cholesterol after 3 months (p less than 0.05). This implies that the more LDL-cholesterol was elevated, the more pravastatin was effective.     

Regional permeability of coenzyme Q10 in isolated rat gastrointestinal tracts

The objective of the study was to identify the region with the maximum permeability for low bioavailable coenzyme Q10 (CoQ) in the gastrointestinal tract. To evaluate the regional differences in permeability, male Sprague-Dawley rats, 250-300 g, were anesthetized and the gastrointestinal segments were isolated. Stomach, duodenum, jejunum, ileum and colon tissues were mounted on a Navicyte side-by-side diffusion apparatus. Radiolabeled CoQ (1 microM in DMEM, pH 7.4, 37 degrees C was added to the donor side and the samples withdrawn from the receiver compartment at predetermined time intervals were analyzed using a scintillation counter. Membrane integrity was monitored by 14C-mannitol permeability. The apical to basal permeability coefficients (Papp x 10(-6), cm/s) were 0.32 +/- 0.13, 3.14 +/- 0.89, 1.36 +/- 1.4, 0.83 +/- 0.40, and 1.59 +/- 0.13, for CoQ through rat stomach, duodenum, jejunum, ileum, and colon tissues respectively. The basolateral to apical permeability coefficients (Papp x 10(-6), cm/s) were 1.6 +/- 0.2, 2.2 +/- 1.2, 0.88 +/- 0.12, 1.6 +/- 0.42, and 1.9 +/- 0.41 respectively. Therefore the region of maximum CoQ permeability is duodenum followed by colon and ileum. Jejunum and stomach regions also have fairly high permeability. Therefore CoQ formulations should be made with an aim to target the duodenum to get maximum dosage effect.     

Effects of bezafibrate on hepatic cholesterol metabolism

Summary The influence of bezafibrate treatment on hepatic cholesterol metabolism was studied in rats and in humans. The activities of the three key enzymes involved in cholesterol metabolism [3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7 -hydroxylase, and acyl-coenzyme A: cholesterol acyltransferase (ACAT)] were suppressed by bezafibrate treatment in rats, but only the ACAT activity was significantly decreased when the activity was related to total liver weight. In humans, HMG-CoA reductase activity was increased about twice in the treated normolipidemic gallstone patients. In contrast, the concentration of lathosterol in serum decreased, indicating depression of the cholesterol synthesis. The increase in HMG-CoA reductase activity may be a compensatory effect of an inhibition of some other enzymes in the synthesis of cholesterol, as in vitro study on liver microsomes excluded a direct inhibitory effect of bezafibrate on HMG-CoA reductase. The ACAT activity was not significantly changed, and the cholesterol 7 a-hydroxylase activity was decreased by 55–60% compared with controls. The LDL-receptor-binding activity was unaffected by bezafibrate treatment.     

Combined effects of coenzyme Q(10) and Vitamin E in cadmium induced alterations of antioxidant defense system in the rat heart

Our study investigated the possible protective effects of coenzyme Q(10) (CoQ(10)) and Vitamin E (Vit E) alone or in combination against cadmium (Cd) induced alterations of antioxidant defense system in the rat heart. Male Wistar rats were injected with a single dose of CdCl(2) (0.4mg Cd/kg BW i.p.), CoQ(10) (20mg CoQ(10)/kg BW i.m.) and Vit E (20IU Vit E/kg BW i.m.), alone or in combination. Acute intoxication of rats with Cd were followed by significantly increased activity of antioxidant defense enzymes (CuZn SOD, GSH-Px, GST and GR), while the activity of Mn SOD was decreased in the heart. The treatment with Cd significantly decreased Vit C and Vit E concentrations. Treatment with CoQ(10) and Vit E reversed Cd-induced alterations of antioxidant defense system. The obtained results support the assumption that CoQ(10) and Vit E functions cooperatively with endogenous antioxidants and diminished toxic effects of Cd in rat heart.     

Effects of insulin-oral hypoglycemic agents combined therapy in outpatients with type 2 diabetes

To evaluate the efficacy of combined insulin-OHAs therapy in subjects with NIDDM who received treatment with OHAs and insulin alone, we selected 60 outpatients divided in two groups: Group A: 36 subjects treated with OHAs therapy that received insulin treatment for secondary failure; Group B: 24 subjects in which OHAs therapy was added to insulin regimen to avoid the effects of hyperinsulinization. In the group A body weight increased significantly (+1.94 +/- 2.80 kg, p < 0.001 vs baseline), while in group B no gain of body weight was observed. Both groups showed a similar improvement of glycemic control. For the group A, the FPG and HbA1c decreased, respectively, from 14.64 +/- 3.76 to 8.72 +/- 2.92 mmol/l and from 9.10 +/- 0.30 to 7.20 +/- 0.53% at 6 months (p < 0.001). For the group B FPG and HbA1c decreased, respectively, from 12.05 +/- 3.49 to 8.24 +/- 3.01 mmol/l and from 8.3 +/- 0.1 to 6.8 +/- 0.13% (p < 0.001). Plasma cholesterol, triglycerides and uric acid concentrations did not show significant changes in either group. Insulin requirement in group A was 0.21 +/- 0.13 U/Kg/day. Despite of improvement of glycemia, total insulin requirement decreased in Group B from 0.53 +/- 0.25 to 0.34 +/- 0.2 U/Kg/day after OHAs therapy (p < 0.001). In the group A the bedtime insulin administration was prevalent (52.68%), while the most patients of group B needed a second or a third daily insulin injection (83.33%). In conclusion, in type 2 diabetic patients, therapy with combination of OHAs and insulin was associated with lower insulin doses and less weight gain.     

Colesevelam

Colesevelam, a bile acid sequestrant used in the treatment of patients with hypercholesterolemia, is a lipid-lowering polymer that has high affinity for bile acids. In animals colesevelam was not systemically absorbed after oral administration and was rapidly eliminated via the gastrointestinal tract. Colesevelam did not alter the serum concentrations or pharmacokinetic properties of drugs from several different classes in healthy volunteers. Colesevelam administered orally in patients with primary hypercholesterolemia significantly reduced serum levels of low density lipoprotein (LDL)-cholesterol and total cholesterol. This lipid-lowering activity was sustained during short (6 weeks) and longer term (24 weeks) treatment. Combination therapy with colesevelam plus hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (lovastatin, simvastatin or atorvastatin) was associated with additive reductions in serum levels of LDL-cholesterol and total cholesterol, relative to either agent alone. Colesevelam treatment was well tolerated and lacked severe gastrointestinal adverse events typical of other bile acid sequestrants (bloating, flatulence, heartburn and nausea). The most frequently reported adverse events were constipation and dyspepsia. In humans colesevelam did not induce clinically significant changes in serum levels of vitamins, coagulation parameters or liver enzymes.     

Anti-oxidant effects of coenzyme Q10 on experimental viral myocarditis in mice

We studied the effects of coenzyme Q10 (CoQ10) on mice with acute myocarditis inoculated with the encephalomyocarditis (EMC) virus with the analysis of indices of effects of oxidative injury and DNA damage in the myocardium. The mice were treated as follows: CoQ10 group (n = 118); CoQ10 1.0 mg (0.1 mL) x 2/d (0.1 mg/g/d), control group (n = 128); sham-liquid 0.1 mL x 2/d. The mice were injected intraperitoneally 1 day before and daily for 12 days after EMC virus inoculation. The expression of thioredoxin, a marker of oxidative stress overload, as well as 8-hydroxy-2'-deoxyguanosine, an established marker of DNA damage, in the myocardium was investigated. The survival rate was significantly higher (P < 0.01) in the CoQ10 group (46.8%, 29/62) than in the control group (14.3%, 10/70). There were significant increases of CoQ9 and CoQ10 in the heart, which are the biologically active forms of CoQ in mice, and significant decrease of serum creatine kinase (CK)-MB in the CoQ10 group as compared with the control group. Histologic examination showed that the severity of myocarditis was less severe (P < 0.01) in the CoQ10 group than in the control group. In addition, the up-regulation of myocardial thioredoxin with DNA damage, which was induced by the inflammatory stimuli by the virus, was suppressed by the CoQ10 treatment, which may reflect the anti-oxidant effects of CoQ10 treatment. Thus, pretreatment with CoQ10 may reduce the severity of viral myocarditis in mice associated with decreasing oxidative stress in the condition.     

Effect of HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors on the concentration of insulin-like growth factor-1 (IGF-1) in hypercholesterolemic patients

Studies have shown that HMG-CoA reductase inhibitors (statins) play an important role in the prevention and treatment of atherosclerosis and hyperlipidemia. The aim of this study was to investigate the effect of 3-month treatment with simvastatin on serum levels of Insulin-Like Growth Factor-1 (IGF-1) in patients with diagnosed hypercholesterolemia. In total, 156 patients with hypercholesterolemia were recruited for the study. The inclusion criteria for this study were designed to allow the enrollment of a representative group of patients for cytokine studies. The patients were divided into two groups: (1) patients with a mild-tomoderate risk of heart disease, who had total cholesterol (TC)  <  300 mg/dl (7.8 mmol/l), LDL-cholesterol > 210 mg/dl (5.4 mmol/l), and who lacked risk factors for coronary artery disease (CAD) after treatment with a diet for 3 months; (2) patients with a high-to very high risk of CAD, who had TC > 300 mg/dl (7.8 mmol/l), LDL-cholesterol > 210 mg/dl (5.4 mmol/l), and at least two risk factors for CAD after treatment with a diet and administration of simvastatin (20 mg/day) for a three month period. The control group consisted often healthy volunteers who each had a normal lipid profile. Total cholesterol, LDL-cholesterol and IGF-1 concentrations were measured at baseline and either after six months of dietary supplementation (first group) or after three months of dietary supplementation and three months of simvastatin treatment (second group). Conclusions: In patients with mild-tomoderate risk of CAD, a decreased serum concentration of IGF-1 was observed three months after beginning a low-fat diet. However, no changes in the serum concentration of IGF-1 were noted in patients with high-to-very high risk of CAD. Additional three-month treatment with simvastatin decreased the serum concentration of IGF-1.