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Cellek S.,Cranfield University | Cameron N.E.,University of Aberdeen | Cotter M.A.,University of Aberdeen | Fry C.H.,University of Bristol | Ilo D.,Lilly UK
Nature Reviews Urology | Year: 2014

Benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS) and erectile dysfunction commonly coexist, and both respond to phosphodiesterase (PDE) 5 inhibitors, suggesting a shared pathophysiological mechanism. We propose that both BPH-LUTS and erectile dysfunction are caused by microvascular dysfunction within the pelvic organs, and we present an overview of preclinical and clinical studies supporting the hypothesis that, within both the penis and the lower urinary tract, a combination of endothelial and neural dysfunction leads to a vicious cycle of hypoxia, vasoconstriction, altered smooth muscle contractility, and degeneration of autonomic neurons and ganglia. This hypothesis explains much of the preclinical and clinical research relating to these two conditions, and provides a rationale for further investigation into the effects of PDE5 inhibitors on the pathophysiology and symptoms of BPH-LUTS. © 2014 Macmillan Publishers Limited. All rights reserved.

Ferrari F.D.,University of Glasgow | Pasqua A.E.,University of Glasgow | Ledgard A.J.,Lilly UK | Marquez R.,University of Glasgow
Organic and Biomolecular Chemistry | Year: 2013

The enantioselective synthesis of the oxa-pinnaic acid framework has been achieved through internal asymmetric induction. The synthetic strategy pursued illustrates the adaptability of the Achmatowicz oxidative rearrangement for the synthesis of complex spirocyclic pyrans starting from tertiary alcohols. This journal is © The Royal Society of Chemistry.

Blak B.T.,Cegedim Strategic Data Medical Research Ltd | Smith H.T.,Lilly UK | Hards M.,Cegedim Strategic Data Medical Research Ltd | Maguire A.,United Biosource Corporation | Gimeno V.,Lundbeck
Diabetic Medicine | Year: 2012

Diabet. Med. 29, e191-e198 (2012) Aims This study characterized UK primary care patients with Type 2 diabetes who initiated insulin treatment, and described the initial insulin regimens used, overall metabolic changes and health-care resource usage. Methods A retrospective cohort study was performed using quality-checked patient data from The Health Improvement Network database. Eligible patients who initiated insulin for the first time between 2004 and 2006 were grouped into four cohorts according to the type of insulin regimen initiated. Data on patient characteristics, metabolic and clinical outcomes and health-care resource use were collected at baseline and during 6months of follow-up. Results In total, 4045 eligible adults [2269 male, 1776 female; mean age 62.6±13.3years; mean baseline HbA 1c 82±22mmol/mol (9.6%±2.0%)] initiated insulin. Approximately half (52.4%) initiated insulin as basal insulin only, 41.6% as premixed only, 4.0% as basal-bolus and 2.1% as prandial insulin only. Among patients with ≥180days follow-up (n=3815), the initial insulin regimen was not changed during follow-up in 75.1% of patients, while 13.7% discontinued, 7.0% switched and 4.7% intensified insulin therapy. The mean change in HbA 1c was -14mmol/mol (-1.3%, n=2881), with 17.3% of patients achieving an HbA 1c of <53mmol/mol (7%, n=3024). The mean weight change was +0.9kg (n=2345). Conclusions Basal and premixed insulin were the most common types of insulin initiated and in most patients no changes were made to the initial regimen over 6months. However, few patients achieved glycemic control targets. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Blak B.T.,Cegedim Strategic Data Medical Research Ltd | Smith H.T.,Lilly UK | Hards M.,Cegedim Strategic Data Medical Research Ltd | Curtis B.H.,Lilly United States | Ivanyi T.,Lilly Hungary
Diabetic Medicine | Year: 2012

Aims To describe patients with Type 2 diabetes mellitus treated with basal insulin, with or without oral antidiabetics in UK primary care, and evaluate insulin treatment patterns and factors explaining changes in therapy. Methods Retrospective analysis of patients with Type 2 diabetes within The Health Improvement Network UK primary care database. Patients receiving basal insulin between January and June 2006 were followed until July 2009. Results Analysis included 3185 patients, mean age 65.6years [standard deviation (SD) 12.4], 50.9% men, median diabetes duration 9.6years, median basal insulin use 1.3years, 86.5% had received oral antidiabetics in the previous 12months. Mean follow-up was 2.9years (SD 1.0), 59.8% patients maintained basal insulin throughout follow-up with a mean HbA1C of 69mmol/mol (SD 19; 8.4%, SD 1.7) at baseline and 65mmol/mol (SD 17; 8.1%, SD 1.6) during follow-up. During follow-up, 6.9% of patients discontinued, 19.3% intensified with and 14.1% switched to prandial or premixed insulin. Patients who intensified (prandial) had a mean HbA1c of 77mmol/mol (SD 18; 9.2%, SD 1.6) before change and a mean HbA1c of 71mmol/mol (SD 21; 8.6%, SD 2.0) at the end of the study. Those switching to premixed insulin had a mean HbA1c of 80mmol/mol (SD 18; 9.5%, SD 1.7) before change and a mean HbA1c of 69mmol/mol (SD 17; 8.5%, SD 1.5) at the end of the study. Increasing HbA1c and longer diabetes duration explained intensification and switch. Conclusions The majority of patients had HbA1c above the 53mmol/mol (<7%) target at baseline and post-intensification/switch. The HbA1c levels were reduced by intensification/switch suggesting that insulin changes did have some impact. Most patients did not change insulin treatment despite having higher than recommended HbA1c levels. Reasons for not changing treatment in face of unsatisfactory clinical outcomes are unclear. Further research is warranted to explore barriers towards therapy change. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Mortensen M.,University College London | Ebert B.,Lundbeck | Wafford K.,Lilly UK | Smart T.G.,University College London
Journal of Physiology | Year: 2010

The activation characteristics of synaptic and extrasynaptic GABAA receptors are important for shaping the profile of phasic and tonic inhibition in the central nervous system, which will critically impact on the activity of neuronal networks. Here, we study in isolation the activity of three agonists, GABA, muscimol and 4,5,6,7-tetrahydoisoxazolo[5,4-c]pyridin-3(2H)-one (THIP), to further understand the activation profiles of α1β3γ2, α4β3γ2 and α4β3δ receptors that typify synaptic- and extrasynaptic-type receptors expressed in the hippocampus and thalamus. The agonists display an order of potency that is invariant between the three receptors, which is reliant mostly on the agonist dissociation constant. At δ subunit-containing extrasynaptic-type GABAA receptors, both THIP and muscimol additionally exhibited, to different degrees, superagonist behaviour. By comparing whole-cell and single channel currents induced by the agonists, we provide a molecular explanation for their different activation profiles. For THIP at high concentrations, the unusual superagonist behaviour on α4β3δ receptors is a consequence of its ability to increase the duration of longer channel openings and their frequency, resulting in longer burst durations. By contrast, for muscimol, moderate superagonist behaviour was caused by reduced desensitisation of the extrasynaptic-type receptors. The ability to specifically increase the efficacy of receptor activation, by selected exogenous agonists over that obtained with the natural transmitter, may prove to be of therapeutic benefit under circumstances when synaptic inhibition is compromised or dysfunctional. © 2010 The Authors. Journal compilation © 2010 The Physiological Society.

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