CYP2C19 genetics in fatal carisoprodol intoxications

Introduction

Carisoprodol, a frequently used muscle relaxant, can cause potentially fatal intoxications. Conversion to its active metabolite meprobamate is almost solely mediated by cytochrome P450 2C19 (CYP2C19), and mutations in this enzyme could have significant effects on serum concentrations. The objective of this study was to investigate the role of CYP2C19 genetics in mortalities due to carisoprodol intoxication.

Methods

The frequencies of CYP2C19 variant alleles were compared between the study group (n?=?75) and two control groups, i.e. (1) deaths where carisoprodol was detected in the blood of the deceased, but intoxication was not the cause of death (control group A, n?=?38), and (2) a healthy population not using carisoprodol (control group B, n?=?185). In the study group and control A, the concentrations of carisoprodol and meprobamate were compared between the different genotype subgroups.

Results

The variant allele frequencies of CYP2C19 did not differ significantly between the study group and control groups. Moreover, no statistically significant difference in the concentrations of carisoprodol and meprobamate between the different genotype subgroups was found.

Conclusions

This study finds no evidence for an important association between CYP2C19 genetics and mortality risk of carisoprodol. Other factors, such as co-administration with other drugs, likely play a more important role.     

Comparison of sequential rosuvastatin doses in hypercholesterolaemia: a meta-analysis of randomised controlled trials

Abstract

Background:

Rosuvastatin is an effective treatment for patients with hypercholesterolaemia. However, the incremental benefit and risk of increasing through the licensed dose range have not been comprehensively assessed across all available clinical trials.     

The CYP2C19 genotype and the use of oral contraceptives influence the pharmacokinetics of carisoprodol in healthy human subjects

AIMS: The aim of the present study was to investigate if subjects with one normal and one non-functional CYP2C19 allele (intermediate metabolizers; IMs) metabolized carisoprodol differently than individuals with two normal CYP2C19 alleles (extensive metabolizers; EMs) We also wanted to investigate whether the use of oral contraceptives influences the metabolism of carisoprodol in EMs and IMs. Impairing effects on psychomotor coordination and feelings of sedation were studied by comparing IMs with EMs following their ingestion of a single dose of 700 mg carisoprodol. METHODS: Thirty-seven healthy Caucasian volunteers participated in the study, of whom 25 were not using any drugs known to interact with CYP2C19, including two poor metabolizers (PMs) (CYP2C19 *2/*2 or CYP2C19 *2 /*4), 11 IMs (CYP2C19 *1/*2 or CYP2C19 *1/*4) and 12 EMs (CYP2C19 *1/*1); the remaining 12 participants were six EMs and six IMs using oral contraceptives. A single oral dose of 700 mg of carisoprodol was given, and blood drug concentrations were followed for 11 h and 45 min. During this time period, different pharmacodynamic measurements were made. RESULTS: IMs had a longer elimination half life (T_&frac;) (127 min; 95% confidence interval (CI) 95, 159) than EMs (96 min; 95% CI 84, 107) and a larger area under the concentration-time curve from 0 to infinity (AUC_0-) for carisoprodol (16.3 g h ml^–1 ; 95% CI 11.9, 20.7) than EMs (11.3 g h ml^–1 ; 95% CI 7.8, 14.8). The use of oral contraceptives was accompanied by larger AUC_0- for carisoprodol in both EMs (18.5 g h ml^–1; 95% CI 10.7, 26.3) and IMs (26.0 g h ml^–1 ; 95% CI 18.8, 33.2). EMs using oral contraceptives also had a longer T_&frac; (117 min; 95% CI 92, 143) and higher maximum carisoprodol concentration than EMs not using oral contraceptives. No significant differences in pharmacodynamic parameters were found between subjects in the different genotype groups or between users and non-users of oral contraceptives. CONCLUSIONS: Subsequent to a single-dose administration of carisoprodol, the carisoprodol AUC was approximately 45% larger in CYP2C19 IMs than in EMs. The use of oral contraceptives increased the AUC by approximately 60% in both EMs and IMs. Despite these pharmacokinetic effects, no significant differences with respect to the CYP2C19 IM and EM genotypes were observed in the acute impairing effects of a single dose of carisoprodol.     

Further assessment of the clinically effective dose range of etoricoxib: a randomized,double-blinded,placebo-controlled trial in rheumatoid arthritis

Abstract

Objective:

To further assess the clinically active dose range of etoricoxib, a COX-2 selective inhibitor, in rheumatoid arthritis (RA).     

A randomized trial in primary biliary cirrhosis comparing ursodeoxycholic acid in daily doses of either 10 mg/kg or 20 mg/kg

Background:

Ursodeoxycholic acid (UDCA) prolongs transplantation-free survival in primary biliary cirrhosis (PBC). However, the optimal therapeutic dose has not been established.

Aim:

To compare the effects of UDCA administered in daily doses of 10 vs. 20 mg/kg on symptoms, liver biochemistry and biliary UDCA enrichment.

Methods:

A 6-month multicentre randomized open controlled trial was conducted to assess the effects of an increase in the dose of UDCA to 20 mg/kg/day vs. continuation of 10 mg/kg/day for patients who had not achieved biochemical normalization during treatment for at least 6 months with the 10 mg/kg dose. Clinical and laboratory evaluations were performed at entry and at 3-month intervals. The percentage UDCA in duodenal bile was assessed at entry and at 6 months.

Results:

Sixty-one patients were enrolled. No side-effects of UDCA were observed. Within the 20 mg/kg/day group significant decreases were found for alkaline phosphatase (? 8%; P = 0.003), aspartate aminotransferase (? 11%; P = 0.01), alanine aminotransferase (? 17%; P < 0.001), γ-glutamyl transferase?(? 34%; P < 0.001), immunoglobulin M (? 11%; P = 0.002) and cholesterol (? 8.1%; P < 0.001). In the 10 mg/kg group none of these parameters differed significantly from baseline. No significant differences between dose groups for symptom scores or serum bilirubin were found. Biliary enrichment with UDCA increased from 37% to 46% in the 20 mg/kg group (P = 0.02) while remaining stable in the 10 mg/kg group.

Conclusions:

Liver biochemistry improved in PBC patients receiving UDCA 20 mg/kg/day compared to a dose of 10 mg/kg/day. Both doses were equally well tolerated. These results indicate that UDCA 10 mg/kg/day is a suboptimal dose for treating PBC.

     

Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolaemia: systematic review and meta-analysis

Abstract

Objective:

To systematically review and analyse evidence for cholesterol-lowering efficacy of at least 4 weeks of add-on ezetimibe vs doubling statin dose, in adults with primary hypercholesterolaemia.     

Average daily dose,medication adherence,and healthcare costs among commercially-insured patients with fibromyalgia treated with duloxetine

Abstract

Objective:

What is the relationship between average daily dose (ADD) of duloxetine, adherence to therapy, and healthcare costs among patients with fibromyalgia?     

Effects of saxagliptin added to sub-maximal doses of metformin compared with uptitration of metformin in type 2 diabetes: the PROMPT study

Abstract

Objective:

The PROMPT study compared efficacy and tolerability of two treatment intensification strategies: adding saxagliptin or uptitrating metformin monotherapy, in patients with type 2 diabetes (T2D) and inadequate glycaemic control on a sub-maximal metformin dose.     

Dosing fentanyl buccal tablet for breakthrough cancer pain: dose titration versus proportional doses

Abstract

Objectives:

The aim of this study was to compare the efficacy and safety of doses of fentanyl buccal tablet (FBT) proportional to doses of opioids used for background analgesia versus dose titration starting with the minimal dose for the management of breakthrough cancer pain (BTcP).     

Findings of clinical trials that evaluate the impact of medical therapies on progression of atherosclerosis

Abstract

Background:

Arterial wall imaging has been increasingly employed in clinical trials to evaluate the impact of medical therapies on progression of atherosclerosis.     

Association between hypoglycemia and inpatient mortality and length of hospital stay in hospitalized,insulin-treated patients

Abstract

Objective:

To assess the impact of hypoglycemia on clinical outcomes among hospitalized, insulin-treated patients.     

Aripiprazole in patients with bipolar mania and beyond: an update of practical guidance

Abstract

Background:

Aripiprazole is an atypical antipsychotic with a pharmacological and clinical profile distinct from other atypical antipsychotics.     

Evaluation of a new safety peripheral IV catheter designed to reduce mucocutaneous blood exposure

Abstract

Objectives:

We evaluated performance and clinical acceptability of a new peripheral intravenous catheter (PIVC) designed to reduce blood exposure.     

Colesevelam in the treatment of hypercholesterolemia and hyperglycemia: a retrospective analysis from an ambulatory care medical network

Abstract

Objective:

To examine outcomes associated with colesevelam treatment among patients with hypercholesterolemia in real-world clinical practice.     

An evaluation of patient and physician satisfaction with controlled-release oxybutynin 15 mg as a one-step daily dose in elderly and non-elderly patients with overactive bladder: results of the STOP study

Abstract

Objective:

Evaluate patient and physician satisfaction with a novel formulation of a once-daily controlled-release (CR) oxybutynin (Uromax ) 15-mg tablet as both the initial and maintenance dose in elderly and non-elderly patients with overactive bladder (OAB).     

Exenatide bid observational study (ExOS): baseline population characteristics of a prospective research study to evaluate the clinical effectiveness of exenatide bid use in patients with type 2 diabetes in a real-world setting

Abstract

Objectives:

To describe the Exenatide Observational Study (ExOS) and patients initiating exenatide therapy in a real-world clinical practice setting.     

Exenatide BID Observational Study (ExOS): results for primary and secondary endpoints of a prospective research study to evaluate the clinical effectiveness of exenatide BID use in patients with type 2 diabetes in a real-world setting

Abstract

Objective:

The Exenatide BID Observational Study (ExOS) was designed to evaluate the clinical effectiveness of exenatide BID use in patients with type 2 diabetes (T2D) in a real-world clinical practice setting in the United States.     

Long-term clinical and economic outcomes associated with angiotensin II receptor blocker use in hypertensive patients

Abstract

Objective:

To examine clinical and economic outcomes associated with angiotensin II receptor blockers (ARB).     

Effects of alendronate plus alfacalcidol in osteoporosis patients with a high risk of fracture: the Japanese Osteoporosis Intervention Trial (JOINT) – 02

Abstract

Objectives:

The authors conducted a randomized controlled trial to clarify the efficacy and safety of alendronate plus alfacalcidol versus alendronate alone in a clinical setting.     

The effects of statin on atrial fibrillation: a meta-analysis of published data from randomized controlled trials

Abstract

Background:

Some clinical and experimental studies have shown the use of statins could protect against AF, but there are not adequate data at present.