A randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritis

OBJECTIVE: To evaluate the gastrointestinal safety and efficacy of the COX inhibiting nitric oxide donator AZD3582 in patients with hip or knee osteoarthritis. METHODS: 970 patients were randomised (7:7:2) to AZD3582 750 mg twice daily, naproxen 500 mg twice daily, or placebo twice daily in a double blind study. The primary end point was the six week incidence of endoscopic gastroduodenal ulcers (diameter > or =3 mm). Overall damage measured on the Lanza scale was a secondary end point. Safety and tolerability assessments included endoscopic upper gastrointestinal erosions and the gastrointestinal symptom rating scale (GSRS). Efficacy was primarily assessed by WOMAC. RESULTS: The incidence of ulcers with AZD3582 was 9.7% and with naproxen 13.7% (p = 0.07, NS), v 0% on placebo. The incidence of Lanza scores >2 was higher with naproxen (43.7%) than with AZD3582 (32.2%) (p<0.001). Compared with baseline, significantly fewer ulcers and erosions developed in stomach and stomach/duodenum combined, and fewer erosions developed in stomach, duodenum, and both combined on AZD3582 than on naproxen. GSRS reflux and abdominal pain subscale scores were lower for AZD3582 than for naproxen but there was no difference for indigestion, constipation, and diarrhoea. AZD3582 was as effective as naproxen at improving WOMAC scores. Both agents were well tolerated, with no significant effects on blood pressure. CONCLUSIONS: At doses with similar efficacy in relieving osteoarthritis symptoms, the primary end point of six week endoscopic gastroduodenal ulcer incidence was not significantly different between AZD3582 and naproxen. Most secondary endoscopic gastrointestinal end points favoured AZD3582.     

Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes

The stimulation of insulin vs. inhibition of glucagon secretion in relation to the antidiabetic action of glucagon-like peptide-1 (GLP-1) is not established. Here, the influence of a 4-wk increase in circulating GLP-1 by inhibition of dipeptidyl peptidase-4 (DPP-4) on 24-h glucose and insulin and glucagon responses to breakfast was studied in subjects with dietary controlled diabetes [age: 65 +/- 8 yr (SD), body mass index: 27.3 +/- 3.3 kg/m(2), fasting plasma glucose: 9.0 +/- 1.3 mmol/liter]. Compared with placebo (n = 19), a specific DPP-4 inhibitor [(1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine) (LAF237); 100 mg daily, n = 18] reduced fasting glucose by 0.70 mmol/liter (P = 0.037), 4-h prandial glucose excursion by 1.45 mmol/liter (P < 0.001), and mean 24-h glucose by 0.93 mmol/liter (P < 0.001). Baseline and postprandial active GLP-1 were increased by LAF237. The glucagon response to breakfast was reduced by LAF237 (glucagon levels at 60 min were 88 +/- 8 pg/ml before treatment vs. 77 +/- 5 pg/ml after; P = 0.001). In contrast, the overall insulin levels were not altered. The 4-wk reduction in glucagon correlated with the reduction in 2-h glucose (r = 0.61; P = 0.008). No such association was observed for insulin. Thus, improved metabolic control by DPP-4 inhibition in type 2 diabetes is seen in association with reduced glucagon levels and, despite the lower glycemia, unaltered insulin levels.     

Psychoeducation against depression,anxiety, alexithymia and fibromyalgia: a pilot study in primary care for patients on sick leave

Objectives: Feasibility testing of a psychoeducational method -The Affect School and Script Analyses (ASSA) – in a Swedish primary care setting. Exploring associations between psychological, and medically unexplained physical symptoms (MUPS).

Design: Pilot study.

Setting: Three Swedish primary care centers serving 20,000 people.

Intervention: 8 weekly 2-hour sessions with a 5–7 participant group led by two instructors - followed by 10 individual hour-long sessions.

Subjects: Thirty-six patients, 29 women (81%), on sick-leave due to depression, anxiety, or fibromyalgia.

Outcome measures: Feasibility in terms of participation rates and expected improvements of psychological symptoms and MUPS, assessed by self-report instruments pre-, one-week post-, and 18 months post-intervention. Regression coefficients between psychological symptoms and MUPS.

Results: The entire 26-hour psychoeducational intervention was completed by 30 patients (83%), and 33 patients (92%) completed the 16-hour Affect School. One-week post-intervention median test score changes were significantly favorable for 27 respondents, with p?Conclusions: A psychoeducational method previously untested in primary care for mostly women patients on sick-leave due to depression, anxiety, or fibromyalgia had?>80% participation rates, and clear improvements of self-assessed psychological symptoms and MUPS. The ASSA intervention thus showed adequate feasibility in a Swedish primary care setting.

• Key Points

• ?A pilot study of a psychoeducational intervention – The Affect School and Script Analyses (ASSA) – was performed in primary care

• ??The intervention showed feasibility for patients on sick-leave due to depression, anxiety, or fibromyalgia

• ??92% completed the 8 weeks/16?hours Affect School and 83% completed the entire 26-hour ASSA intervention

• ??9 of 11 self-reported measures improved significantly one-week post intervention

• ??7 of 11 self-reported measures improved significantly 18 months post-intervention

     

The Willingness to Pay for a Quality Adjusted Life Year: A Review of the Empirical Literature

There has been a rapid increase in the use of cost‐effectiveness analysis, with quality adjusted life years (QALYs) as an outcome measure, in evaluating both medical technologies and public health interventions. Alongside, there is a growing literature on the monetary value of a QALY based on estimates of the willingness to pay (WTP). This paper conducts a review of the literature on the WTP for a QALY. In total, 24 studies containing 383 unique estimates of the WTP for a QALY are identified. Trimmed mean and median estimates amount to 74,159 and 24,226 Euros (2010 price level), respectively. In regression analyses, the results indicate that the WTP for a QALY is significantly higher if the QALY gain comes from life extension rather than quality of life improvements. The results also show that the WTP for a QALY is dependent on the size of the QALY gain valued. Copyright © 2014 John Wiley & Sons, Ltd.     

Reduction of androstenedione by skin in vitro and serum levels of gonadotrophins and androgens in men with hypospadias

The reduction of 4-[1,2-3H]androstene-3,17-dione (androstenedione) in vitro by scrotal skin was measured in samples from nine men (16--34 years old) with hypospadias and from ten male control subjects. The reduction of androstenedione was also studied in axillary and upper arm skin of seven control subjects. Androstenedione was reduced to material with chromatographic characteristics of 5 alpha-androstane-3,17-dione and to 3 alpha- and 3 beta-hydroxy-5 alpha-androstan-17-one. No difference in 5 alpha-reductase activity (defined as the sum of these three metabolites formed) was found in scrotal skin from hypospadic and control men. The mean concentration of 5 alpha-dihydrotestosterone in serum from men with hypospadias was lower than that in serum from control subjects (P less than 0.01). The mean ratio of the serum concentrations of testosterone and 5 alpha-dihydrotestosterone was higher in hypospadic men than in control subjects (P less than 0.05). No differences between the two groups were found in the mean serum concentrations of LH, FSH, prolactin, dehydroepiandrosterone, androstenedione, testosterone or testosterone-binding globulin.