BACKGROUND & AIMS Patients infected with hepatitis C virus (HCV) genotype 1, body weight ≥85 kg, and high baseline viral load respond poorly to standard doses of pegylated interferon (peginterferon) and ribavirin. We evaluated intensified therapy with peginterferon alfa-2a plus ribavirin. METHODS This double-blind randomized trial included HCV genotype 1-infected outpatients from hepatology clinics with body weight ≥85 kg and HCV RNA titer ≥400,000 IU/mL. Patients were randomized to 180 μg/wk peginterferon alfa-2a for 48 weeks plus 1200 mg/day ribavirin (standard of care)(group A, n = 191) or 1400/1600 mg/day ribavirin (group B, n = 189). Additional groups included 360 μg/wk peginterferon alfa-2a for 12 weeks then 180 μg/wk peginterferon alfa-2a for 36 weeks plus 1200 mg/day ribavirin (group C, n = 382) or 1400/1600 mg/day ribavirin (group D, n = 383). Follow-up lasted 24 weeks after treatment. RESULTS Sustained virologic response rates (HCV RNA level <15 IU/mL at end of follow-up) in groups A, B, C, and D were 38%, 43%, 44%, and 41%, respectively. There were no significant differences among the 4 groups or between pooled peginterferon alfa-2a regimens (A + B vs C + D: odds ratio [OR], 1.08; 95% confidence interval [CI], 0.83-1.39; P =.584) or pooled ribavirin regimens (A + C vs B + D: OR, 1.00; 95% CI, 0.79-1.28; P =.974). CONCLUSIONS In patients infected with HCV genotype 1 who are difficult to treat (high viral load, body weight ≥85 kg), a 12-week induction regimen of peginterferon alfa-2a and/or higher-dose ribavirin is not more effective than the standard regimen.

BACKGROUND: Despite previous reports of potential adverse cardiovascular effects of peroxisome proliferator-activated receptor (PPAR) agonists, the promise for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes is of continued interest. The SYNCHRONY study aimed to establish the glucose-lowering and lipid-modifying effects, and safety profile, of the dual PPAR-alpha and PPAR-gamma agonist aleglitazar. METHODS: In this double-blind study, patients with type 2 diabetes (either drug-naive or pre-treated with </=two oral agents) were enrolled from 47 sites in seven countries. After a single-blind, 4-5-week placebo run-in period, 332 patients were randomised double-blind (via an interactive voice-response system) to 16 weeks' treatment with aleglitazar at once-daily doses of 50 mug, 150 mug, 300 mug, or 600 mug, or matching placebo (n=55 in each group), or to open-label pioglitazone 45 mg once daily (n=57) as a reference. The primary efficacy endpoint was the change in glycosylated haemoglobin (HbA(1c)) concentration from baseline to the end of treatment. Patients who received at least one dose of study drug and had at least one evaluable post-baseline HbA(1c) measurement were included in the efficacy analysis. This study is registered with ClinicalTrials.gov, number NCT00388518. FINDINGS: The efficacy analysis excluded six patients (n=0 in pioglitazone group; n=1 in each of placebo, 50 mug, 150 mug, and 600 mug aleglitazar groups; and n=2 in 300 mug aleglitazar group). Aleglitazar significantly reduced baseline HbA(1c) versus placebo in a dose-dependent manner, from -0.36%(95% CI 0.00 to -0.70, p=0.048) with 50 mug to -1.35%(-0.99 to -1.70, p<0.0001) with 600 mug. The trend of changes over time suggests that the maximum effect of aleglitazar on HbA(1c) concentration was not yet reached after 16 weeks of treatment. Oedema, haemodilution, and weight gain occurred in a dose-dependent manner. However, at aleglitazar doses less than 300 mug, no patients had congestive heart failure, frequency of oedema was similar to placebo (one case at 50 mug, two at 150 mug, and three with placebo) and less than with pioglitazone (four cases), and bodyweight gain was less than with pioglitazone (0.52 kg at 150 mug vs 1.06 kg). INTERPRETATION: The favourable balance in the safety and efficacy profile of aleglitazar represents encouraging short-term clinical data for this agent and provides good evidence to enter phase III investigation. FUNDING: F Hoffmann-La Roche AG (Switzerland).

OBJECTIVE: To determine the efficacy and safety of pamapimod in adult patients with active rheumatoid arthritis (RA) who had an inadequate clinical response to methotrexate (MTX). METHODS:/B> Patients receiving stable doses of MTX were randomized to one of six dose groups and received 12 weeks of double-blind pamapimod (up to 300 mg once daily [qd]) or matching placebo. The primary efficacy measure was the proportion of patients with >/= 20% improvement in RA based on the American College of Rheumatology criteria (ACR20) at 12 weeks. Secondary measures were ACR50, DAS/EULAR response, and individual ACR core set of parameters. Safety measures included adverse events (AEs), laboratory testing, and immunology assessments. RESULTS:/B> On a background of MTX, the percentage of patients with an ACR20 response at week 12 in the pamapimod groups (31-43%) was not significantly different from placebo (34%). Secondary efficacy end points showed a similar pattern. AEs were typically mild and included infections, gastrointestinal disturbances, dizziness and rashes; AEs resulting in discontinuation of study drug were primarily attributed to infections. CONCLUSION: In patients with active RA receiving stable doses of MTX, pamapimod showed non-significant improvement in efficacy outcomes compared to placebo.

Background: Both obesity and type 2 diabetes are associated with increased morbidity and mortality. Published data suggest that orlistat 120 mg, a lipase inhibitor used to treat obesity, may improve glycaemic parameters through weight loss-independent effects. Aim: To investigate the effect of orlistat 120 mg on weight loss, and assess whether changes in glycaemic parameters [fasting plasma glucose (FPG) and haemoglobin A(1c)(HbA(1c))] are independent of weight loss. Methods: This retrospective analysis of pooled data from seven multicentre, double-blind, placebo-controlled studies involved overweight or obese patients with type 2 diabetes (aged 18-70 years). Patients were required to have a body mass index of 27-43 kg/m(2), HbA(1c) of 6.5 to <13%, and stable weight for >/=3 months. Subjects received orlistat 120 mg tid or placebo for 6 or 12 months. Results: A total of 2550 overweight or obese patients with type 2 diabetes were enrolled and randomized to treatment with orlistat 120 mg tid (n = 1279) or placebo (n = 1271). For the whole population, patients treated with orlistat 120 mg had significantly greater mean decreases in FPG compared with placebo-treated patients (-1.39 mmol/l vs.-0.47 mmol/l; p < 0.0001). In addition, orlistat 120 mg provided significantly larger mean decreases in HbA(1c) compared with placebo (-0.74% vs.-0.31%; p < 0.0001). For patients with minimal weight loss (</=1% of baseline body weight), orlistat 120 mg still provided a significantly greater decrease in the least squares mean value for both FPG (-0.83 mmol/l vs.+/-0.02 mmol/l; p = 0.0052) and HbA(1c)-0.29% vs.+/-0.14%; p = 0.0008). This suggested that the improvement of glycaemic control with orlistat 120 mg was independent of weight loss. Using linear regression analysis, improvement in glycaemic control (FPG and HbA(1c)) with orlistat 120 mg was less strongly correlated with weight loss than for placebo. Conclusion: Orlistat 120 mg appears to improve glycaemic control more than would be predicted by weight loss alone in overweight or obese patients with type 2 diabetes. Postulated mechanisms underlying this effect include an improvement of insulin sensitivity, a slower and incomplete digestion of dietary fat, reduction of postprandial plasma non-esterified fatty acids, decreased visceral adipose tissue, and stimulation of glucagon-like peptide-1 secretion in the lower small intestine.

A retrospective pharmacogenetic study was conducted to identify possible genetic susceptibility factors in patients in whom the administration of the anti-Parkinson drug, tolcapone (TASMAR), was associated with hepatic toxicity. We studied 135 cases of patients with elevated liver transaminase levels (ELT) of >/=1.5 times above the upper limit of normal, in comparison with matched controls that had also received the drug but had not experienced ELT. DNA samples were genotyped for 30 previously described or newly characterized bi-allelic single nucleotide polymorphisms (SNPs), representing 12 candidate genes selected based on the known metabolic pathways involved in the tolcapone elimination. SNPs located within the UDP-glucuronosyl transferase 1A gene complex, which codes for the enzymes involved in the main elimination pathway of the drug, were found to be significantly associated with the occurrence of tolcapone-associated ELTs.

Background and Purpose: To determine the changes in haemodynamics, tolerability and pharmacokinetics that may occur when a combination of tolcapone and levodopa/carbidopa are given with desipramine. Methods: In a crossover study, 22 healthy subjects received desipramine during two 13-day treatment periods (25 mg t.i.d. for 3 days and 50 mg t.i.d. for 10 days), with a washout period of 10-15 days. Subjects received levodopa/carbidopa (100 mg/25 mg t.i.d. for 5 days, days 9-13) and concomitant, double-blind, randomized treatment with either tolcapone (200 mg t.i.d.) or placebo. Results: No significant pharmacodynamic and pharmacokinetic interactions occurred between tolcapone and desipramine. Adverse events were predictable based on the known effects of the individual drugs. Conclusions: Tolcapone can be combined with levodopa/carbidopa and desipramine in patients with Parkinson's disease.

The effect and clinical significance of tolcapone withdrawal on erythrocyte catechol-O-methyltransferase (COMT) activity, levodopa pharmacokinetics, and levodopa requirements were investigated in 59 patients with fluctuating parkinsonism who were randomized to receive placebo or tolcapone 100 or 200 mg three times daily for 6 weeks. Tolcapone withdrawal caused a transient elevation in COMT activity by 64% in patients receiving 100 mg three times daily and by 128% in those receiving 200 mg three times daily at approximately 1-2 weeks after discontinuation of drug. Thereafter, COMT activity was declining but did not reach baseline values by the 12-week study endpoint. However, this had no effect on plasma levodopa and 3-O-methyldopa (3-OMD) concentrations or on levodopa requirements. During treatment, tolcapone increased "on" time and decreased "off" time; after discontinuation of study medication and levodopa dose adjustment, on and off times were similar to baseline. Withdrawal was generally well tolerated; no patients withdrew from the trial during the posttreatment period, and no serious adverse events were observed. In conclusion, the transient increase in erythrocyte COMT activity observed after discontinuation oftolcapone is not associated with changes in peripheral levodopa metabolism and therefore has no significant clinical consequences in terms of levodopa requirements, clinical symptoms, or adverse events.