Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis.

Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.

Alanine transaminase is predominantly increased in the active phase of anti-HMGCR myopathy.

Autoantibodies against 3­hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and the signal recognition particle (SRP) are representative antibodies causing immune-mediated necrotizing myopathies (IMNM), called as anti-HMGCR and anti-SRP myopathies, respectively. Here, we analyzed the differences in routine blood test results between 56 anti-HMGCR and 77 anti-SRP myopathy patients. A higher alanine transaminase (ALT) level and a lower aspartate transaminase (AST)/ALT ratio were observed in anti-HMGCR myopathy patients [ALT, 265.7 ±â€¯213.3 U/L (mean ± standard deviation); AST/ALT ratio, 0.88 ±â€¯0.32] than in anti-SRP-myopathy patients (ALT, 179.3 ±â€¯111.2 U/L, p < 0.05; AST/ALT ratio, 1.28 ±â€¯0.40, p < 0.01). In the active phase, anti-HMGCR myopathy often showed ALT predominance, whereas anti-SRP myopathy often showed AST predominance. In addition, there were differences in erythrocyte sedimentation rate (ESR), total cholesterol (TChol) level, and high-density lipoprotein (HDL) level between anti-HMGCR and anti-SRP myopathies (ESR: HMGCR, 24.4 ±â€¯20.8 mm/1 h; SRP, 35.7 ±â€¯26.7 mm/1 h, p = 0.0334; TChol: HMGCR, 226.7 ±â€¯36.6 mg/dL; SRP, 207.6 ±â€¯40.8 mg/dL, p = 0.0163; HDL: HMGCR, 58.4 ±â€¯13.9 mg/dL; SRP, 46.2 ±â€¯17.3 mg/dL, p < 0.01). Additional studies on the differences in routine blood test results may further reveal the pathomechanisms of IMNM.

Statin-associated anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy: Imaging findings on thigh-muscle magnetic resonance imaging (MRI) in six patients.

INTRODUCTION/AIMS: Anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy is a rare but serious complication of statin use. The aim of this study was to describe the imaging features of statin-associated anti-HMGCR myopathy on thigh muscle magnetic resonance imaging (MRI). METHODS: Thigh muscle MRI images of six patients with statin-associated anti-HMGCR myopathy were reviewed for muscle edema, fatty replacement, and fascial edema in four compartments of each thigh: gluteal, anterior, medial, and posterior. Signal intensity ratio (SIR) was calculated in 17 muscles in both thighs on T2-weighted fat-suppressed images. Intracompartmental comparison of T2 SIRs of different muscles were performed. RESULTS: All patients demonstrated bilateral symmetrical pan-compartmental muscle edema. Three patients had fatty infiltration, involving gluteal and/or posterior compartments. In the anterior compartment, rectus femoris and vastus lateralis most frequently demonstrated the highest T2 SIR. In the posterior compartment, semimembranosus most frequently demonstrated the highest T2 SIR. The long head of the biceps femoris always had a higher T2 SIR than the short head. DISCUSSION: Statin-associated anti-HMGCR myopathy commonly demonstrates bilateral symmetrical pan-compartmental edema on thigh muscle MRI, with anterolateral predilection in the anterior compartment, and greater involvement of the semimembranosus with relative sparing of the short head of the biceps femoris in the posterior compartment. These observations can contribute to the diagnosis of statin-associated anti-HMGCR myopathy.

Association of statin induced reduction in serum coenzyme Q10 level and conduction deficits in motor and sensory nerves: An observational cross-sectional study.

OBJECTIVE: The reduction of Coenzyme Q10 (CoQ10) levels following statin use has been linked to cause peripheral neuropathy. Hence, this study was planned to explore the effect of statin on the serum HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase), serum CoQ10 levels and nerve conduction and their correlation. PATIENTS AND METHODS: In an open labelled, cross-sectional, observational study, estimation of serum HMGCR and CoQ10 levels was performed in 50 atorvastatin/rosuvastatin users and 50 normal healthy volunteers (NHV). Statin users were also subjected to nerve conduction studies (NCS). RESULTS: Mean serum HMGCR level in NHV was higher (73.58 ± 7.64 ng/ml; p = 0.003) than that in statin users (49.11 ± 1.98 ng/ml). Similarly, mean serum CoQ10 levels was also lower (30.54 ± 2.03 ng/ml, p < 0.0001) in statin users than in NHV (49.43 ± 3.23 ng/ml). Amongst the 50 statin users, 29 had impaired NCS in sural, tibial and common peroneal nerve with lower mean serum CoQ10 levels (24.05 ± 1.96 ng/ml; p < 0.0001). Significant negative correlation was observed between onset time of action potential (AP) of the sural nerve and serum CoQ10 (r=-0.32) and HMGCR (r=-0.43) levels. There was significant positive correlation of conduction velocity of sural (r = 0.38) and tibial (r = 0.31) nerves with serum CoQ10 level. While conduction velocity in sural (r = 0.37) and common peroneal (r = 0.34) nerves positively correlated with serum HMGCR levels. The amplitude of the AP of the common peroneal nerve positively correlated with both serum CoQ10 (r = 0.52) and HMGCR (r = 0.46) levels. CONCLUSION: Statin users had lower serum CoQ10 and HMGCR levels associated with nerve conduction deficits suggesting a role of CoQ10 in the occurrence of the neurological adverse effects.

Statin use in patients with non-HMGCR idiopathic inflammatory myopathies: A retrospective study.

BACKGROUND: Statins are the most widely used lipid lowering therapies which reduce cardiovascular risk, but are associated with muscular adverse events (AEs). Idiopathic inflammatory myopathies (IIM) are autoimmune diseases of the muscle with higher risk of cardiovascular disease. More data is needed regarding statin safety in patients with intrinsic muscle disease such as IIM. HYPOTHESIS: Statins are tolerated in patients with IIM without leading to significant increase in muscular AEs. METHODS: Statin use was retrospectively examined in a longitudinal IIM cohort. Safety analysis included assessment of muscular and nonmuscular AEs by chart review. IIM patients receiving a statin during the cohort follow-up period were matched to IIM patients not receiving a statin for comparative analysis of longitudinal outcomes. RESULTS: 33/214 patients had a history of statin use. 63% started for primary prevention, while others were started for clinical ASCVD events, vascular surgery, IIM related heart failure, and cardiac transplantation. A high intensity statin was used in nine patients with non-HMGCR myositis, and tolerated in 8/9 patients. Statin related muscular AE was noted in three patients. There were no cases of rhabdomyolysis, or statin related nonmuscular AEs in a median observation period of 5 years. In patients newly started on statins during cohort follow-up (n = 7) there was no change in disease activity after statin initiation. Long term outcomes were not different between statin and nonstatin IIM control groups. CONCLUSION: Statins were well tolerated in patients with non-HMGCR positive IIM. Given the accelerated atherosclerotic risk in IIM patients, further prospective studies of statin safety in IIM patients are warranted.

Prevalence of polymyalgia rheumatica in a cohort of patients with idiopathic inflammatory myopathy.

Polymyalgia rheumatica (PMR) is a common rheumatological condition occurring in adults aged over 50 years. The association of PMR with other autoimmune diseases such as rheumatoid arthritis is complex. There is a clear relationship with giant cell arteritis. We sought to determine whether there is any association between PMR and idiopathic inflammatory myopathy (IIM). We undertook a database study of adult patients with a diagnosis of IIM under the care of the Rheumatology Department of the Royal Adelaide Hospital, and retrospectively determined the frequency of PMR in this patient cohort. Patients were considered to have PMR if this had been diagnosed by a physician or if they satisfied all five of the following clinical criteria: (1) bilateral shoulder and/or pelvic girdle aching, (2) morning stiffness exceeding 45 min, (3) age greater than 50 years, (4) duration more than 2 weeks, and (5) evidence of an elevated erythrocyte sedimentation rate or C-reactive protein. Amongst 82 patients with IIM, seven (8.5%) were found to have PMR. There was a disproportionate representation of necrotizing autoimmune myopathy (NAM) in patients with IIM/PMR (5/7) compared with patients with IIM alone (19/75), p = 0.02. There was a high prevalence of antibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with IIM/PMR (4/7, 57%) compared with those with IIM alone (9/32, 28%), p = 0.19. The prevalence of PMR in our IIM cohort was much higher than the population prevalence 0.91-1.53% and it appears there is a specific association with NAM and anti-HMGCR antibodies. Further studies are required to confirm these findings and explore mechanisms of shared disease susceptibility.Key Points• Idiopathic inflammatory myositis, in particular, statin-associated necrotizing myositis and anti-HMG co-A reductase antibodies, may have a previously unrecognized association with polymyalgia rheumatica.

Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition.

Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.

Randomized controlled trial comparing the efficacy of daily and every other day atorvastatin therapy and its correlation with serum hydroxymethylglutaryl-CoA reductase enzyme levels in naïve dyslipidemic patients.

OBJECTIVE: Data regarding efficacy comparison of daily regimen (DR) versus every other day regimen (EODR) atorvastatin therapy is not validated by estimation of serum hydroxymethylglutaryl-CoA reductase (HMGCR) levels and HMGCR correlation with lipid indices. METHODS: In this randomized controlled trial, we compared the efficacy of DR versus EODR by measuring lipid indices and serum HMGCR levels at baseline and after 12 weeks of 10 mg atorvastatin therapy. Primary endpoint was comparison of mean change in serum HMGCR levels and lipid indices of both groups and their correlation with each other. Secondary endpoints were assessed by estimating serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase MM (CK-MM) levels and adverse drug reactions (ADRs). RESULTS: A total of 61 patients were enrolled of which 46 completed the study (24 in DR vs 22 in EODR group). The mean reduction in total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and non-high density lipoprotein-cholesterol (HDL-C) was significantly higher in DR group, whereas mean reduction in triglycerides (TG) and increase in HDL-C was similar in both the groups. Reduction in serum HMGCR levels was comparable in both the groups (31.17% vs 28.19%). Change in serum HMGCR levels correlated more with change in lipid indices of DR group. Also, safety parameters were similar between the two groups. CONCLUSION: Both the regimens achieved therapeutic goals, however DR was found to be superior as it achieved greater reduction in TC and LDL-C. Further, these findings are substantiated by correlation of lipid indices with serum HMGCR levels.

Semi-synthetic thymoquinone analogs: new prototypes as potential antihyperlipidemics in irradiated rats.

AIM: Thymoquinone (TQ), has been reported to possess strong antihyperlipidemic properties. However, a variety of serious side effects has been reported for TQ. The present study aimed to evaluate the potential antihyperlipidemic activity of newly synthesized TQ analogs. METHODS & RESULTS: first, novel TQ derivatives were studied against radiation-induced dyslipidemia in male rats. Second, the most promising sulfur derivatives (4-7), were further tested to elucidate their possible mechanism(s) of actions. Results showed that they possess Hydroxymethyl Glutaryl-Co A reductase inhibitory activity, as well as stimulatory effects on the activities of each of plasma Lecithin-Cholesterol Acyltransferase and lipoprotein lipase enzymes. CONCLUSION: TQ derivatives (4-7), could be considered as promising agents in pathologies implicating impaired lipid metabolism, preclinical evaluation is warranted. [Formula: see text].

Anti-3-hydroxy-3-methylglutaryl-coenzyme a reductase necrotizing myopathy masquerading as a muscular dystrophy in a child.

INTRODUCTION: Immune-mediated necrotizing myopathies (IMNMs) are characterized by progressive weakness, elevated serum creatine kinase levels, and necrotizing myopathic features on muscle biopsy. Presence of highly specific autoantibodies against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR) can aid in recognition and confirmation of IMNMs. METHODS: In this study we describe a boy with HMGCR-positive necrotizing myopathy and highlight the clinical features of the patient. RESULTS: In contrast to most adults, the patient described had a more indolent disease course, reminiscent of a muscular dystrophy. Intravenous immunoglobulin monotherapy resulted in a dramatic clinical response with return to normal strength. CONCLUSIONS: Systematic consideration of IMNMs and testing for relevant autoantibodies in children with suspected but genetically unconfirmed muscular dystrophy may help improve diagnostic accuracy and allow timely treatment with potentially highly effective immunotherapies. Muscle Nerve 56: 175-179, 2017.

Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase.

BACKGROUND: Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. OBJECTIVES: This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. METHODS: Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. RESULTS: Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R(2) = 0.94, slope 1.00 ± 0.03). CONCLUSIONS: Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms.

Clinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase in patients with immune-mediated myositis and necrotizing myopathy.

INTRODUCTION: Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) with statins may trigger idiopathic inflammatory myositis (IIM) or immune-mediated necrotizing myopathy (IMNM). Anti-HMGCR antibodies have been detected in patients with IIM/IMNM. We aimed to determine the associations of anti-HMGCR in IIM/IMNM. METHODS: Anti-HMGCR antibodies were detected by ELISA in sera from patients with IIM/IMNM. RESULTS: Anti-HMGCR antibodies were detected in 19 of 207 patients with IIM/IMNM, and there was a trend toward an association with male gender (P = 0.079). Anti-HMGCR antibodies were associated strongly with statin exposure (OR = 39, P = 0.0001) and HLA-DRB1*11 (OR = 50, P < 0.0001). The highest risk for development of anti-HMGCR antibodies was among HLA-DR11 carriers exposed to statins. Univariate analysis showed a strong association of anti-HMGCR antibodies with diabetes mellitus (P = 0.008), which was not confirmed by multiple regression. Among anti-HMGCR(+) patients there was a trend toward increased malignancy (P = 0.15). CONCLUSIONS: Anti-HMGCR antibodies are seen in all subtypes of IIM and IMNM and are associated strongly with statin use and HLA-DR11. Muscle Nerve 52: 196-203, 2015.

The flavonoid morin restores blood pressure and lipid metabolism in DOCA-salt hypertensive rats.

OBJECTIVE: This study was undertaken to investigate the antihypertensive and antihyperlipedimic potential of morin against deoxycorticosterone acetate (DOCA)-salt hypertensive rats. METHODS: Hypertension was induced in uninephrectomized rats (UNX) by weekly twice subcutaneous injection of DOCA (25 mg/kg) and 1% NaCl in the drinking water for six consecutive weeks. Morin (50 mg/kg) was administered to DOCA-salt rats orally using an intragastric tube daily for a period of 6 weeks. RESULTS: The DOCA-salt hypertensive rats showed significant elevation in mean arterial pressure (MAP), heart rate (HR) and reduction in body weight. A significant increase in the concentrations of plasma and tissue (liver, kidney, heart, and aorta) lipids such as total cholesterol, triglycerides, free fatty acids, phospholipids, plasma low-density and very low-density lipoproteins cholesterol, and a decrease in the concentration of high-density lipoprotein cholesterol were noticed in DOCA-salt hypertensive rats. Also, the levels of urinary protein and the activity of 3-hydroxy 3-methylglutaryl coenzyme A reductase in the plasma and tissues were increased, and lecithin cholesterol acyl transferase activity in the plasma was decreased in DOCA-salt rats. Morin supplementation (50 mg/kg) throughout the experimental period restored all the above parameters significantly. CONCLUSION: Morin has a potential role in attenuating severe hypertension and hyperlipedimia.

[Cholesterol homeostasis and cardiovascular risk]. / Cholesterinhomöostase und kardiovaskuläres Risiko.

Hypercholesterolemia is a major risk factor for cardiovascular diseases. Serumcholesterol concentrations are regulated by enteral absorption and hepatic synthesis. Statins inhibit the rate-limiting enzyme of endogenous cholesterol synthesis, HMG-CoA-reductase and reduce serum cholesterol concentrations as well as cardiovascular morbidity. Indirect evidence from smaller studies shows, that patients with high baseline cholesterol absorption may show only a small response to statin treatment in terms of cholesterol lowering. Moreover, evidence from recent clinical studies suggests that increased cholesterol absorption and decreased hepatic cholesterol synthesis is associated with an increased cardiovascular risk. This article reviews the current literature on this issue and suggests prospective clinical studies to analyze whether determination of the baseline relation of cholesterol synthesis and absorption may facilitate an individualized lipid lowering therapy to further reduce cardiovascular risk.

2,4,5-trimethoxycinnamic acid: the major metabolite of alpha-asarone, retains most of the pharmacological properties of alpha-asarone.

2,4,5-trimethoxycinnamic acid (TMC), the major and non toxic metabolite of alpha-asarone (2,4,5-trimethoxy-1-propenyl benzene), retains most of the pharmacological properties of alpha-asarone, since both substances, administered to hypercholesterolemic rats at 80 mg/kg body wt, decreased total serum cholesterol, lowered LDL-cholesterol levels and kept unaffected HDL-cholesterol levels. In addition, both substances increased bile flow, especially in hypercholesterolemic rats, by rising the secretion of bile salts, phospholipids and bile cholesterol. These drugs also reduced cholesterol levels of gallbladder bile, whereas phospholipids and bile salts concentrations were increased, decreasing the cholesterol saturation index (CSI). We also found that alpha-asarone was 20 times better inhibitor of HMG-CoA reductase than TMC. This effect on HMG-CoA reductase was the only property highly reduced in TMC in comparison with alpha-asarone, while the other pharmacological properties of alpha-asarone were retained by TMC. These experiments strongly suggest that TMC can be further studied as a possible hypocholesterolemic and cholelitholytic agent.

Comparative evaluation of the hypolipidemic effects of coconut water and lovastatin in rats fed fat-cholesterol enriched diet.

The coconut water presents a series of nutritional and therapeutic properties, being a natural, acid and sterile solution, which contains several biologically active components, l-arginine, ascorbic acid, minerals such as calcium, magnesium and potassium, which have beneficial effects on lipid levels. Recent studies in our laboratory showed that both tender and mature coconut water feeding significantly (P<0.05) reduced hyperlipidemia in cholesterol fed rats [Sandhya, V.G., Rajamohan, T., 2006. Beneficial effects of coconut water feeding on lipid metabolism in cholesterol fed rats. J. Med. Food 9, 400-407]. The current study evaluated the hypolipidemic effect of coconut water (4ml/100g body weight) with a lipid lowering drug, lovastatin (0.1/100g diet) in rats fed fat-cholesterol enriched diet ad libitum for 45 days. Coconut water or lovastatin supplementation lowered the levels of serum total cholesterol, VLDL+LDL cholesterol, triglycerides and increased HDL cholesterol in experimental rats (P<0.05). Coconut water feeding decreased activities of hepatic lipogenic enzymes and increased HMG CoA reductase and lipoprotein lipase activity (P<0.05). Incorporation of radioactive acetate into free and ester cholesterol in the liver were higher in coconut water treated rats. Coconut water supplementation increased hepatic bile acid and fecal bile acids and neutral sterols (P<0.05). Coconut water has lipid lowering effect similar to the drug lovastatin in rats fed fat-cholesterol enriched diet.

Development and validation of a liquid chromatography-tandem mass spectrometric assay for pitavastatin and its lactone in human plasma and urine.

A rapid, selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with electrospray ionization (ESI) was developed and validated for the simultaneous determination of pitavastatin and its lactone in human plasma and urine. Following a liquid-liquid extraction, both the analytes and internal standard racemic i-prolact were separated on a BDS Hypersil C(8) column, using methanol-0.2% acetic acid in water (70: 30, v/v) as the mobile phase. The mass spectrometer was operated in multiple reaction monitoring (MRM) mode using the transition m/z 422.4-->m/z 290.3 for pitavastatin, m/z 404.3-->m/z 290.3 for pitavastatin lactone and m/z 406.3-->m/z 318.3 for the internal standard, respectively. Linear calibration curves of pitavastatin and its lactone were obtained in the concentration range of 1-200 ng/ml, with a lower limit of quantitation of 1 ng/ml. The intra- and inter-day precision values were less than 4.2%, and accuracies were between -8.1 and 3.5% for both analytes. The proposed method was utilized to support clinical pharmacokinetic studies of pitavastatin in healthy subjects following oral administration.

Evaluation of the potential for steady-state pharmacokinetic interaction between vildagliptin and simvastatin in healthy subjects.

BACKGROUND: Vildagliptin is an orally active, potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), the enzyme responsible for the degradation of incretin hormones. By enhancing prandial levels of incretin hormones, vildagliptin improves glycemic control in type 2 diabetes. Co-administration of vildagliptin and simva statin, an HMG-CoA-reductase inhibitor may be required to treat patients with diabetes and dyslipidemia. There fore, this study was conducted to determine the potential for pharmacokinetic drug-drug interaction between vildagliptin and simvastatin at steady-state. METHODS: An open label, single center, multiple dose, three period, crossover study was conducted in 24 healthy subjects. All subjects received once daily doses of either vildagliptin 100 mg or simvastatin 80 mg or the combination for 7 days with an inter-period washout of 7 days. Plasma levels of vildagliptin, simvastatin, and its active metabolite, simvastatin beta-hydroxy acid (major active metabolite of simvastatin) were determined using validated LC/MS/MS methods. Pharmacokinetic and statistical analyses were performed using WinNonlin and SAS, respectively. RESULTS: The 90% confidence intervals of C(max) and AUC(tau) of vildagliptin, simvastatin, and simvastatin beta-hydroxy acid were between 80 and 125% (bioequivalence range) when vildagliptin and simvastatin were admin istered alone and in combination. These data indicate that the rate and extent of absorption of vildagliptin and simvastatin were not affected when co-administered, nor was the metabolic conversion of simvastatin to its active metabolite. All treatments were safe and well tolerated in this study. CONCLUSIONS: The pharmacokinetics of vildagliptin, simvastatin, and its active metabolite were not altered when vildagliptin and simvastatin were co-administered.