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BackgroundThere are few data on the bronchodilatory effects of adding short-acting bronchodilators (SABA) to maintenance, long-acting bronchodilator therapy. This study assessed the additional bronchodilation and safety of adding supratherapeutic doses of salbutamol (SALB) or ipratropium bromide (IPR) to the novel bi-functional molecule (or dual pharmacophore) GSK961081 400 μg (MABA 400) or 1200 μg (MABA 1200).MethodsThis randomised, double-blind, complete, crossover study in 44 patients with moderate to severe COPD, evaluated 6 treatments with a washout of at least 7 days between treatments: single doses of MABA 400 or MABA 1200 followed by cumulative doses of either SALB (3× 200 μg at 20 min intervals), IPR (20 μg, 20 μg and 40 μg at 20 min intervals) or placebo (PLA) (three doses at 20 min intervals) at 1 h, 12 h and 24 h post-MABA dose. The primary endpoint was maximal increase in FEV1, from pre-dose bronchodilator (SABA/PLA), measured 15 min after each cumulative dose of SALB, IPR or PLA. Systemic pharmacodynamics (potassium, heart rate, glucose and QTc), adverse events and systemic pharmacokinetics were also assessed.ResultsThe additional bronchodilatory effects at 12 h and 24 h for both SALB and IPR were of a similar magnitude and statistically significant relative to PLA; mean differences (SE) (L) following MABA 400 dosing: 0.139 (0.023) after SALB at 12 h; 0.123 (0.022) after SALB at 24 h; 0.124 (0.023) after IPR at 12 h; 0.141 (0.021) after IPR at 24 h; and after MABA 1200 dosing: 0.091 (0.023) after SALB at 12 h; 0.126 (0.022) after SALB at 24 h; 0.055 (0.023) after IPR at 12 h; 0.122 (0.022) after IPR at 24 h. Any additional bronchodilator effects at 1 h were small and not clinically significantly different from PLA. There were small, non-clinically significant increases in mean heart rate after both MABA doses plus SALB, and decreased potassium levels in four patients after MABA 1200 plus SALB (×3) or PLA (×1) were observed but overall all treatments were well tolerated and raised no significant safety signals.ConclusionThe additional bronchodilation achieved following supratherapeutic doses of SALB and IPR on top of single doses of MABA 400 or 1200 was comparable for the two agents and neither were associated with any clinically relevant systemic pharmacodynamic effects other than the small transient hypokalemic effect in a 3 out of 41 patients receiving additional high dose salbutamol and MABA 1200. Either short-acting bronchodilator could potentially be used as rescue medication on top of MABA therapy. 相似文献
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P. Ambery T. W. Donner N. Biswas J. Donaldson J. Parkin C. M. Dayan 《Diabetic medicine》2014,31(4):399-402
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Eric D. Bateman Oliver Kornmann Claire Ambery Virginia Norris 《Pulmonary pharmacology & therapeutics》2013,26(5):581-587
GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β2-agonism (MABA) properties.This randomised, double-blind, double-dummy, crossover study evaluated 14 days treatment with the MABA GSK961081 400 μg and 1200 μg once daily and tiotropium 18 μg once daily plus salmeterol 50 μg twice daily (TIO + SAL), versus placebo in 50 patients with moderate COPD. The primary endpoint was forced expiratory volume in 1 s (FEV1) at 24 h on Days 1 and 14.MABA 400 (n = 29), MABA 1200 (n = 32) and TIO + SAL (n = 41) resulted in significant increases in FEV1 over 24 h. Mean (95% CI) 24 h trough FEV1 (L) values relative to placebo (n = 43) were, for Day 1, MABA 400: 0.141 (0.060, 0.222); MABA 1200: 0.184 (0.105, 0.263); TIO + SAL: 0.162 (0.092, 0.231); for Day 14, MABA 400: 0.115 (0.024, 0.205); MABA 1200: 0.168 (0.080, 0.255); TIO + SAL: 0.103 (0.026, 0.180). Onset of bronchodilation was faster for both MABA doses versus TIO + SAL. No clinically relevant systemic pharmacodynamic effects were observed. Adverse events were similar across groups; however tremor (n = 2, MABA 1200), dysgeusia (n = 2, MABA 1200; n = 2, MABA 400) and dry mouth (n = 1, MABA 1200) were reported after GSK961081 only.GSK961081 demonstrated sustained bronchodilation similar to TIO + SAL, but with a more rapid onset, and was well tolerated at the tested doses. 相似文献
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致编辑:葛兰素史克对最近美国糖尿病学会和欧洲糖尿病研究学会共识声明中不推荐2型糖尿病使用罗格列酮治疗的建议[1]表示遗憾,因为这有悖于科学证据. 相似文献
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Open‐label randomized non‐inferiority trial of a fixed‐dose combination of glimepiride and atorvastatin for the treatment of people whose Type 2 diabetes is uncontrolled on metformin
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P. Ambery A. Stylianou G. Atkinson C. Dott L. Baylor Curtis N. Haque K. LaCroix K. W. Min 《Diabetic medicine》2016,33(8):1084-1093
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Borges JL Bilezikian JP Jones-Leone AR Acusta AP Ambery PD Nino AJ Grosse M Fitzpatrick LA Cobitz AR 《Diabetes, obesity & metabolism》2011,13(11):1036-1046
Aim: The purpose of this study was to evaluate if superior glycaemic control could be achieved with Avandamet® (rosiglitazone/metformin/AVM) compared with metformin (MET) monotherapy, and if glycaemic effects attained with AVM are durable over 18 months of treatment. Bone mineral density (BMD) and bone biomarkers were evaluated in a subgroup of patients. Methods: This was a phase IV, randomized, double‐blind, multi‐centre study in 688, drug naÏve, male and female patients who had an established clinical diagnosis of type 2 diabetes mellitus (T2DM). Patients were randomized in a 1 : 1 ratio either to AVM or MET. Results: As initial therapy in patients with T2DM, AVM was superior to MET in achieving statistically significant reductions in glycated haemoglobin (HbA1c) (p < 0.0001) and fasting plasma glucose (FPG) (p < 0.001), with more patients reaching recommended HbA1c and FPG targets for intensive glycaemic control. The glycaemic effects attained with AVM compared to MET monotherapy were durable over 18 months of treatment. In the bone substudy, AVM was associated with a significantly lower BMD in comparison with MET at week 80 in the lumbar spine and total hip (p < 0.0012 and p = 0.0005, respectively). Between‐treatment differences were not statistically significant for distal one‐third of radius BMD, femoral neck BMD or total BMD. Conclusion: Superior glycaemic control was achieved with AVM compared with MET monotherapy. The superior glycaemic effects were shown to be durable over 18 months of treatment. AVM was associated with a significantly reduced BMD in comparison with MET at week 80 in the lumbar spine and total hip. 相似文献
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Gretchen Bain Christopher D. King Kevin Schaab Melissa Rewolinski Virginia Norris Claire Ambery Jane Bentley Masanori Yamada Angelina M. Santini Jeroen van de Wetering de Rooij Nicholas Stock Jasmine Zunic John H. Hutchinson Jilly F. Evans 《British journal of clinical pharmacology》2013,75(3):779-790
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To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5‐lipoxygenase‐activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations.Method
Western European subjects received single (50–1000 mg) or multiple (10–450 mg) oral doses of GSK2190915 or placebo in a dose‐escalating manner. Japanese subjects received three of four GSK2190915 doses (10–200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B4 and leukotriene E4, respectively, as pharmacodynamic markers of drug activity.Results
There was no clear difference in adverse events between placebo and active drug‐treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose‐related manner and mean half‐life values ranged from 16–34 h. Dose‐dependent inhibition of blood leukotriene B4 production was observed and near complete inhibition of urinary leukotriene E4 excretion was shown at all doses except the lowest dose. The EC50 values for inhibition of LTB4 were 85 nm and 89 nm in the Western European and Japanese studies, respectively.Conclusion
GSK2190915 is well‐tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E4 at 24 h post‐dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB4. 相似文献10.
Page LA Daly E Schmitz N Simmons A Toal F Deeley Q Ambery F McAlonan GM Murphy KC Murphy DG 《The American journal of psychiatry》2006,163(12):2189-2192
OBJECTIVE: The neural basis for autistic spectrum disorders is unclear, but abnormalities in the development of limbic areas and of glutamate have been suggested. Proton magnetic resonance spectroscopy ((1)H-MRS) can be used to measure the concentration of brain metabolites. However, the concentration of glutamate/glutamine in brain regions implicated in autistic spectrum disorders has not yet been examined in vivo. METHOD: The authors used (1)H-MRS to investigate the neuronal integrity of the amygdala-hippocampal complex and a parietal control region in adults with autistic spectrum disorders and healthy subjects. RESULTS: People with autistic spectrum disorders had a significantly higher concentration of glutamate/glutamine and creatine/phosphocreatine in the amygdala-hippocampal region but not in the parietal region. CONCLUSIONS: Abnormalities in glutamate/glutamine may partially underpin the pathophysiology of autistic spectrum disorders, and the authors confirm earlier reports that limbic areas are metabolically aberrant in these disorders. 相似文献