A 24-week study to evaluate the efficacy and safety of once-weekly dulaglutide added on to glimepiride in type 2 diabetes (AWARD-8).

AIMS: To evaluate the safety and efficacy of once-weekly dulaglutide 1.5 mg, a long-acting glucagon-like peptide-1 receptor agonist, compared with placebo in patients with type 2 diabetes (T2D) on glimepiride monotherapy. METHODS: This phase III, randomized (4 : 1; dulaglutide:placebo), double-blind, placebo-controlled, 24-week study compared the safety and efficacy of once-weekly dulaglutide 1.5 mg with placebo in sulphonylurea-treated (≥half-maximal dose, stable ≥3 months) patients (N = 300) with T2D and inadequate glycaemic control [glycated haemoglobin (HbA1c) ≥7.5 and ≤9.5% (≥58 mmol/mol and ≤80 mmol/mol)]. Analysis was carried out according to intention-to-treat. RESULTS: At baseline, the mean participant age was 58 years; mean HbA1c was 8.4% (68 mmol/mol) and mean weight was 85.5 kg. Dulaglutide 1.5 mg was superior to placebo at 24 weeks for HbA1c reduction from baseline with a between-group HbA1c difference of -1.3% [95% confidence interval (CI) -1.6, -1.0] or -14 mmol/mol (95% CI -17, -11); p < 0.001. A greater proportion of participants in the dulaglutide group reached an HbA1c level of <7.0% (53 mmol/mol) compared with placebo (55.3% vs 18.9%; p < 0.001). Dulaglutide significantly decreased fasting serum glucose from baseline compared with placebo (between-group difference -1.86 mmol/l (95% CI -2.58, -1.14) or -33.54 mg/dl (95% CI -46.55, -20.53); p < 0.001. Weight was decreased significantly from baseline in the dulaglutide group (p < 0.001); the between-group difference was not significant. The most common treatment-emergent adverse events for dulaglutide 1.5 mg were gastrointestinal: nausea (10.5%), diarrhoea (8.4%) and eructation (5.9%). Total hypoglycaemia was higher with dulaglutide 1.5 mg vs placebo (2.37 and 0.07 events/participant/year, respectively; p = 0.025). No severe hypoglycaemia was reported. CONCLUSIONS: Once-weekly dulaglutide 1.5 mg had a favourable benefit/risk profile when added to glimepiride monotherapy.

Achieving the composite endpoint of glycated haemoglobin <7.0%, no weight gain and no hypoglycaemia in the once-weekly dulaglutide AWARD programme.

AIM: To compare the effectiveness of dulaglutide 1.5 and 0.75 mg with active comparators and placebo with regard to a composite endpoint of glycated haemoglobin (HbA1c), weight and hypoglycaemia, using post hoc analyses. METHODS: A logistic regression analysis was performed on the intention-to-treat population, using data from the last observation carried forward, and the composite endpoint of HbA1c <7.0% (53 mmol/mol), no weight gain (≤0 kg) and no hypoglycaemia (glucose <3.0 mmol/l or severe hypoglycaemia) after 26 weeks for each trial in the AWARD programme separately. RESULTS: At 26 weeks, within each study, 37-58% of patients on dulaglutide 1.5 mg, 27-49% of patients on dulaglutide 0.75 mg, and 9-61% of patients on active comparators achieved the composite endpoint. Significantly more patients reached the composite endpoint with dulaglutide 1.5 mg than with metformin, sitagliptin, exenatide twice daily or insulin glargine: odds ratio (OR) 1.5 [95% confidence interval (CI) 1.0, 2.2; p < 0.05], OR 4.5 (95% CI 3.0, 6.6; p < 0.001), OR 2.6 (95% CI 1.8, 3.7; p < 0.001) and OR 7.4 (95% CI 4.4, 12.6; p < 0.001), respectively, with no difference between dulaglutide 1.5 mg and liraglutide 1.8 mg. In addition, significantly more patients reached the composite endpoint with dulaglutide 0.75 mg than with sitagliptin or insulin glargine: OR 3.3 (95% CI 2.2, 4.8; p < 0.001) and OR 4.5 (95% CI 2.7, 7.8; p < 0.001), respectively. CONCLUSIONS: Dulaglutide is an effective treatment option, resulting in a similar or greater proportion of patients reaching the HbA1c target of <7.0% (53 mmol/mol), without weight gain or hypoglycaemia compared with active comparators.

Candidate for laser cooling of a negative ion: observations of bound-bound transitions in La(-).

Despite the tremendous advances in laser cooling of neutral atoms and positive ions, no negatively charged ion has been directly laser cooled. The negative ion of lanthanum, La(-), has been proposed as the best candidate for laser cooling of any atomic anion [ and , Phys. Rev. A 81, 032503 (2010)]. Tunable infrared laser photodetachment spectroscopy is used to measure the bound-state structure of La(-), revealing a spectrum of unprecedented richness with multiple bound-bound electric dipole transitions. The potential laser-cooling transition ((3)F(2)(e)→(3)D(1)(o)) is identified and its excitation energy is measured. The results confirm that La^{-} is a very promising negative ion for laser-cooling applications.

Effect of the approach to insulin therapy on glycaemic fluctuations and autonomic tone in hospitalized patients with diabetes.

AIMS: Glycaemic variability (GV) is associated with mortality in acutely ill patients, but the mechanism is unknown. The objective of this study is to determine whether common approaches to insulin therapy have distinct effects on GV and autonomic tone. METHODS: Hospitalized patients with diabetes were randomized to short-term intravenous (IV) or physiologic subcutaneous (SQ) insulin. Heart rate variability (HRV) and cardiac impedance (pre-ejection period, PEP) were used to estimate parasympathetic and sympathetic tone, respectively. GV was measured using a continuous glucose monitor. RESULTS: Mean glucose tended to be lower initially in the SQ group (N = 16) compared with the IV group (N = 17) on day 1 (10.5 vs. 8.6 mmol/l, p = 0.05), but became non-significant during the transition off of the infusion. There was no difference in glycaemic lability index (GLI), continuous overlapping net glycaemic action (CONGA) or coefficient of variation (CV) on day 1, but by day 2, these measures were higher in the IV group (p < 0.05 for all). PEP was higher in the SQ group during (110 vs. 123 ms, p = 0.02) and after the intervention (104 vs. 126 ms, p = 0.004). Hypoglycaemia was similar in both groups. There were only small differences in HRV. Post-treatment PEP was inversely correlated with log GLI (r = -0.41, p = 0.03) but not other measures. CONCLUSIONS: Short-term IV insulin is associated with an increase in multiple GV measures compared with optimal SQ insulin. However, GLI was the only predictor of PEP. Further research is needed to determine if interventions that minimize GV improve outcomes in the hospital.

Differential response between diabetes and stress-induced hyperglycaemia to algorithmic use of detemir and flexible mealtime aspart among stable postcardiac surgery patients requiring intravenous insulin.

AIM: To determine whether an insulin algorithm could be used in a similar manner in the setting of diabetes and stress hyperglycaemia following cessation of intravenous (IV) insulin after cardiac surgery. METHODS: Subjects who were clinically stable, requiring ≥ 1 unit/h of IV insulin 48 h after surgery, were randomized to once daily detemir at 50, 65 or 80% of IV insulin requirements and received aspart according to carbohydrate intake. Diabetes was defined as any history of diabetes or preoperative HbA1c 6.5%. RESULTS: The morning glucose in patients with diabetes was 143 mg/dl (n = 61) vs. 124 mg/dl in those with stress hyperglycaemia (n = 21,p = 0.05) on day 1 and 127 vs. 110 mg/dl over 72 h (p = 0.01). This was unaffected by adjustment for initial dosing group. At 72 h, 56% of patients with stress hyperglycaemia reached AM (80-130 mg/dl) and 87% reached overall (80-180 mg/dl) glucose targets, compared to 90 and 100% of patients with stress hyperglycaemia, respectively. There was no difference in hypoglycaemia in patients with stress hyperglycaemia or diabetes. The percentage of patients with diabetes receiving insulin was 46% on admission and 77% at discharge, compared to 0 and 42% of patients with stress hyperglycaemia. CONCLUSIONS: Following cardiac surgery, patients with stress hyperglycaemia may be converted from IV insulin to detemir with a 50% conversion factor, while patients with diabetes may require a higher conversion factor. Stress hyperglycaemia may be prolonged; the intensity and duration of insulin therapy required for optimal outcomes warrants further examination.

In vitro effects of beta adrenoceptor agonists and antagonists on the rat ovarian suspensory ligament.

The mesovarian suspensory ligament of the rat was used to compare the activities of beta adrenoceptor agonists and antagonists. The following beta adrenoceptor agonists, in descending order of potency, inhibited spontaneous activity in a dose-related manner: zinterol greater than isoproterenol much greater than dobutamine. Several noncardioselective, beta-2 adrenoceptor antagonists with intrinsic sympathomimetic activity (ISA) also inhibited the activity of the ligament: pindolol greater than alprenolol = bucindolol = oxprenolol greater than labetalol. Maximal relaxation induced by the antagonists was equivalent to that caused by the beta receptor agonists. Two cardioselective, beta adrenoceptor antagonists with ISA, acebutolol and practolol, did not inhibit the activity of the suspensory ligament but did increase the rate of the isolated right atrium of the rat. The maximal increases in atrial rate evoked by the antagonists were significantly less than those induced by the beta adrenoceptor agonists. Studies with ICI 118,551 or atenolol as beta-2 or beta-1 selective adrenoceptor blockers, respectively, suggest that the beta adrenoceptors of the suspensory ligament are predominantly of the beta-2 subtype. The possible relevance of these results to the induction of mesovarian leiomyomas in rats by noncardioselective beta adrenoceptor agonists and antagonists with ISA is discussed.

Selected immunologic properties of tiprinast, a non-steroidal antiallergy agent.

Tiprinast [(3,4-dihydro-5-methyl-6-(2-methylpropyl)-4-oxothieno[2,3-d]- pyrimidine-2-carboxylic acid] is a new antiallergy compound which shares many of the pharmacological actions of disodium cromoglycate (DSCG). Both compounds inhibit passive cutaneous anaphylaxis in the rat, histamine release from rat peritoneal mast cells and nasal constriction due to antigen in the rat. In all cases tiprinast is more potent than DSCG and also longer acting.

Antiallergics: 3-(1H-tetrazol-5-yl)-4H-pyrimido[2,1-b]benzothiazol-4-ones.

A short series of the title compounds was prepared and evaluated for both antiallergic and bronchodilator activity. Members of the series exhibit good oral activity in the rat PCA test, the most potent being the parent compound, 3-(1H-tetrazol-5-yl)-4H-pyrimido[2,1-b]benzothiazol-4-one, and its 8-chloro derivative. The latter two compounds are considerably more potent than either disodium chromoglycate or theophylline as antiallergic agents and also show significant bronchodilator activity.

Substituted 6,7-dihydroimidazo[1,2-a]purin-9(4H)-ones.

The synthesis of a series of substituted 6,7-dihydroimidazo[1,2-a]purin-9(4H)-ones is described. Several members of the series exhibit enhanced antiallergic and bronchodilator activity and reduced side effects as compared to theophylline. Structure-activity relationships and metabolic considerations are discussed for the series. Analogues substituted with a 4-(4-chlorobenzyl) moiety, such as 33 and 40, shown an optimal balance of antiallergic and bronchodilator activity and are of particular interest. Compound 33 is significantly more potent than theophylline against both metacholine- and antigen-induced bronchospasms, does not affect spontaneous motor activity, and shows minimal cardiovascular effects in the rat.

Specific hypotensive and antihypertensive ocular effects of d-isoproterenol in rabbits.

d-Isoproterenol (ISO) applied topically to the rabbit eye specifically lowered intraocular pressure. Thus, it effectively reduced normal intraocular pressure and inhibited intraocular pressure elevation induced by water load without causing other obvious local or systemic pharmacologic effects. By comparison, dl-ISO was pharmacologically nonspecific in that amounts required to reduce intraocular pressure also produced significant and marked tachycardia. Furthermore, maximal intraocular pressure reduction was less with dl-than with d-ISO. Accordingly, and in consideration of reported clinical experience with dl-ISO in glaucomatous man, the d-isomer should be the preferred form of ISO for treating glaucoma. d-ISO should offer advantages over any other topical medication used currently in the treatment of this condition. Toxicity studies employing large, topical doses of drug in rabbit eyes showed that d-ISO was free from ocular irritation as well as systemic toxicologic effects and should be safe for controlled studies in man.