Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of the study was to compare the efficacy and safety of liraglutide in type 2 diabetes mellitus vs placebo and insulin glargine (A21Gly,B31Arg,B32Arg human insulin), all in combination with metformin and glimepiride. METHODS: This randomised (using a telephone or web-based randomisation system), parallel-group, controlled 26 week trial of 581 patients with type 2 diabetes mellitus on prior monotherapy (HbA(1c) 7.5-10%) and combination therapy (7.0-10%) was conducted in 107 centres in 17 countries. The primary endpoint was HbA(1c). Patients were randomised (2:1:2) to liraglutide 1.8 mg once daily (n = 232), liraglutide placebo (n = 115) and open-label insulin glargine (n = 234), all in combination with metformin (1 g twice daily) and glimepiride (4 mg once daily). Investigators, participants and study monitors were blinded to the treatment status of the liraglutide and placebo groups at all times. RESULTS: The number of patients analysed as intention to treat were: liraglutide n = 230, placebo n = 114, insulin glargine n = 232. Liraglutide reduced HbA(1c) significantly vs glargine (1.33% vs 1.09%; -0.24% difference, 95% CI 0.08, 0.39; p = 0.0015) and placebo (-1.09% difference, 95% CI 0.90, 1.28; p < 0.0001). There was greater weight loss with liraglutide vs placebo (treatment difference -1.39 kg, 95% CI 2.10, 0.69; p = 0.0001), and vs glargine (treatment difference -3.43 kg, 95% CI 4.00, 2.86; p < 0.0001). Liraglutide reduced systolic BP (-4.0 mmHg) vs glargine (+0.5 mmHg; -4.5 mmHg difference, 95% CI 6.8, -2.2; p = 0.0001) but not vs placebo (p = 0.0791). Rates of hypoglycaemic episodes (major, minor and symptoms only, respectively) were 0.06, 1.2 and 1.0 events/patient/year, respectively, in the liraglutide group (vs 0, 1.3, 1.8 and 0, 1.0, 0.5 with glargine and placebo, respectively). A slightly higher number of adverse events (including nausea at 14%) were reported with liraglutide, but only 9.8% of participants in the group receiving liraglutide developed anti-liraglutide antibodies. CONCLUSIONS/INTERPRETATION: Liraglutide added to metformin and sulfonylurea produced significant improvement in glycaemic control and bodyweight compared with placebo and insulin glargine. The difference vs insulin glargine in HbA(1c) was within the predefined non-inferiority margin. TRIAL REGISTRATION: ClinicalTrials.gov NCT00331851. FUNDING: The study was funded by Novo Nordisk A/S.

Pharmacokinetics of oral diclofenac and acetaminophen in children after surgery.

BACKGROUND: Our aim was to study the pharmacokinetics and pain scores following administration of single oral doses of either diclofenac or high-dose acetaminophen (paracetamol). METHODS: In the morning, the day after tonsillectomy, children 5-15 years of age were randomized in a double-blind manner to receive either diclofenac 1-2 mg.kg-1 (n=11) or acetaminophen 22.5 mg.kg-1 (n=10). Postoperative pain was assessed by self-report and blood samples were drawn every 30 min for 4 h after medication. RESULTS: Large interindividual differences in maximum plasma diclofenac concentrations (Cmax) were found. Mean Cmax was 2.4+/-1.3 microg.ml-1 and mean tmax was 2+/-0.5 h. No significant reduction in pain score with diclofenac was seen at any of the assessments during the study period. Eight of 10 children achieved Cmax of acetaminophen within the 10-20 microg.ml-1 antipyretic range. Mean tabs was 0.7+/-0.3 h and mean Cmax and tmax were 12.7+/-3.8 microg ml-1 and 1.4+/-0.5 h, respectively. No significant reduction in pain score with acetaminophen was seen at any of the assessments during the study period. CONCLUSIONS: The achieved concentrations of diclofenac and acetaminophen were not able to significantly reduce the children's pain score during the 5 h postingestion study period. Analgesic plasma acetaminophen concentrations may be higher than those required for antipyresis.

Diclofenac or acetaminophen for analgesia in paediatric tonsillectomy outpatients.

BACKGROUND: In order to establish an effective drug regimen, we compared the analgesic efficacy of oral diclofenac and high-dose acetaminophen on pain after tonsillectomy. METHODS: In this randomised, double-blind study 48 children, 5 to 15 years of age, following tonsillectomy were assigned to receive either diclofenac 2-3 mg kg(-1) 24 h(-1) (n=24) or acetaminophen 90 mg kg(-1) 24 h(-1) (n=24) for the first three days after surgery. Postoperative pain was assessed by self-report each day before scheduled medication at 7 h, 12 h, 18 h and 23 h. RESULTS: The number of children rating severe pain was high in both the diclofenac group, 5-50%, and in the acetaminophen group, 12-58% during the three day study period. Pain scores in the diclofenac group were only significantly lower at 12 h on day 1-3 compared to pain scores in the acetaminophen group (P<0.05). None of the children in the diclofenac group experienced any episodes of nausea/vomiting compared to 9 children in the acetaminophen group on day 1. The incidences of nausea/vomiting increased with pain (P<0.05). None of the 48 children experienced any episodes of bleeding. CONCLUSIONS: This study indicates that diclofenac was no more effective than high-dose acetaminophen (90 mg vs. 60 mg kg(-1) 24 h(-1)) for analgesia, but resulted in a lower incidence of nausea and vomiting in patients following tonsillectomy.

Mycotoxin production by Penicillium expansum on blackcurrant and cherry juice.

The production of mycotoxins and other secondary metabolites by Penicillium expansum on blackcurrant and cherry juice has been studied at 10 degrees C and 25 degrees C under storage imitated conditions. P. expansum was able to synthesize extracellular patulin under all conditions, and together with extracellular chaetoglobosin A when unlimited oxygen was available. Patulin, the chaetoglobosins A and C, the communesins A and B and the expansolides A and B could be detected intracellularly depending on the conditions. The metabolites were detected using thin-layer chromatography and high-performance liquid chromatography with diode array detection by comparison to standards. A method to detect the expansolides A and B by TLC was developed.