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      Established and emerging therapeutic uses of PDE type 5 inhibitors in cardiovascular disease

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          Abstract

          PDE type 5 inhibitors (PDE5Is), such as sildenafil, tadalafil and vardenafil, are a class of drugs used to prolong the physiological effects of NO/cGMP signalling in tissues through the inhibition of cGMP degradation. Although these agents were originally developed for the treatment of hypertension and angina, unanticipated side effects led to advances in the treatment of erectile dysfunction and, later, pulmonary arterial hypertension. In the last decade, accumulating evidence suggests that PDE5Is may confer a wider range of clinical benefits than was previously recognised. This has led to a broader interest in the cardiovascular therapeutic potential of PDE5Is, in conditions such as hypertension, myocardial infarction, stroke, peripheral arterial disease, chronic kidney disease and diabetes mellitus. Here, we review the pharmacological properties and established licensed uses of this class of drug, along with emerging therapeutic developments and possible future indications.

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          Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

          Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.
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            Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.

            End-stage renal disease substantially increases the risks of death, cardiovascular disease, and use of specialized health care, but the effects of less severe kidney dysfunction on these outcomes are less well defined. We estimated the longitudinal glomerular filtration rate (GFR) among 1,120,295 adults within a large, integrated system of health care delivery in whom serum creatinine had been measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation. We examined the multivariable association between the estimated GFR and the risks of death, cardiovascular events, and hospitalization. The median follow-up was 2.84 years, the mean age was 52 years, and 55 percent of the group were women. After adjustment, the risk of death increased as the GFR decreased below 60 ml per minute per 1.73 m2 of body-surface area: the adjusted hazard ratio for death was 1.2 with an estimated GFR of 45 to 59 ml per minute per 1.73 m2 (95 percent confidence interval, 1.1 to 1.2), 1.8 with an estimated GFR of 30 to 44 ml per minute per 1.73 m2 (95 percent confidence interval, 1.7 to 1.9), 3.2 with an estimated GFR of 15 to 29 ml per minute per 1.73 m2 (95 percent confidence interval, 3.1 to 3.4), and 5.9 with an estimated GFR of less than 15 ml per minute per 1.73 m2 (95 percent confidence interval, 5.4 to 6.5). The adjusted hazard ratio for cardiovascular events also increased inversely with the estimated GFR: 1.4 (95 percent confidence interval, 1.4 to 1.5), 2.0 (95 percent confidence interval, 1.9 to 2.1), 2.8 (95 percent confidence interval, 2.6 to 2.9), and 3.4 (95 percent confidence interval, 3.1 to 3.8), respectively. The adjusted risk of hospitalization with a reduced estimated GFR followed a similar pattern. An independent, graded association was observed between a reduced estimated GFR and the risk of death, cardiovascular events, and hospitalization in a large, community-based population. These findings highlight the clinical and public health importance of chronic renal insufficiency. Copyright 2004 Massachusetts Medical Society
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              Haemodynamic definitions and updated clinical classification of pulmonary hypertension

              Since the 1st World Symposium on Pulmonary Hypertension (WSPH) in 1973, pulmonary hypertension (PH) has been arbitrarily defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest, measured by right heart catheterisation. Recent data from normal subjects has shown that normal mPAP was 14.0±3.3 mmHg. Two standard deviations above this mean value would suggest mPAP >20 mmHg as above the upper limit of normal (above the 97.5th percentile). This definition is no longer arbitrary, but based on a scientific approach. However, this abnormal elevation of mPAP is not sufficient to define pulmonary vascular disease as it can be due to an increase in cardiac output or pulmonary arterial wedge pressure. Thus, this 6th WSPH Task Force proposes to include pulmonary vascular resistance ≥3 Wood Units in the definition of all forms of pre-capillary PH associated with mPAP >20 mmHg. Prospective trials are required to determine whether this PH population might benefit from specific management. Regarding clinical classification, the main Task Force changes were the inclusion in group 1 of a subgroup “pulmonary arterial hypertension (PAH) long-term responders to calcium channel blockers”, due to the specific prognostic and management of these patients, and a subgroup “PAH with overt features of venous/capillaries (pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis) involvement”, due to evidence suggesting a continuum between arterial, capillary and vein involvement in PAH.
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                Author and article information

                Contributors
                d.j.webb@ed.ac.uk
                Journal
                Br J Pharmacol
                Br J Pharmacol
                10.1111/(ISSN)1476-5381
                BPH
                British Journal of Pharmacology
                John Wiley and Sons Inc. (Hoboken )
                0007-1188
                1476-5381
                04 February 2020
                December 2020
                04 February 2020
                : 177
                : 24 ( doiID: 10.1111/bph.v177.24 )
                : 5467-5488
                Affiliations
                [ 1 ] British Heart Foundation/University Centre for Cardiovascular Science, Queen's Medical Research Institute University of Edinburgh Edinburgh UK
                [ 2 ] Institute of Genetic Medicine Newcastle University Newcastle Upon Tyne UK
                Author notes
                [*] [* ] Correspondence

                David J. Webb, British Heart Foundation/University Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Room E3.22, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.

                Email: d.j.webb@ 123456ed.ac.uk

                Author information
                https://orcid.org/0000-0003-2081-6042
                Article
                BPH14920 2019-BJP-0645-RCT-G.R2
                10.1111/bph.14920
                7707100
                31721165
                023fd5ff-03bc-4644-a194-a769c591f301
                © 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 July 2019
                : 15 October 2019
                : 21 October 2019
                Page count
                Figures: 2, Tables: 3, Pages: 22, Words: 19371
                Funding
                Funded by: MRC Clinical Research Training Fellowship
                Award ID: MR/R017840/1
                Funded by: BHF Intermediate Clinical Research Fellowship
                Award ID: FS/13/30/29994
                Funded by: British Heart Foundation (BHF) Centre of Research Excellence Award
                Award ID: RE/08/001/23904
                Categories
                Review Article
                TARGETING THE NITRIC OXIDE (NO)‐cGMP PATHWAY: THERAPEUTIC OPPORTUNITIES IN THE 21ST CENTURY
                Custom metadata
                2.0
                December 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.4 mode:remove_FC converted:01.12.2020

                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine

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