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Nikolaos Tzoumas Tariq E. Farrah Neeraj Dhaun David J. Webb 《British journal of pharmacology》2020,177(24):5467
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.
Abbreviations
- 6MWD
- 6‐min walking distance
- ACEI
- ACE inhibitor
- ARB
- angiotensin receptor blocker
- BPS
- British Pharmacological Society
- CCB
- calcium channel blocker
- CKD
- chronic kidney disease
- Cmax
- maximum plasma/serum concentration
- CTEPH
- chronic thromboembolic pulmonary hypertension
- CVD
- cardiovascular disease
- CYP2C19
- cytochrome P450, family 2, subfamily C, polypeptide 19
- CYP2C9
- cytochrome P450, family 2, subfamily C, polypeptide 9
- CYP2D6
- cytochrome P450, family 2, subfamily D, polypeptide 6
- CYP3A
- cytochrome P450, family 3, subfamily A
- CYP3A4
- cytochrome P450, family 3, subfamily A, polypeptide 4
- CYP450
- cytochrome P450 enzyme family
- DN
- diabetic nephropathy
- ED
- erectile dysfunction
- eGFR
- estimated GFR
- ERA
- endothelin receptor antagonist
- ET
- endothelin
- ET‐1
- endothelin‐1
- FGR
- fetal growth restriction
- GSK3B
- glycogen synthase kinase 3 β
- HbA1c
- glycated Hb
- HFpEF
- heart failure with preserved ejection fraction
- HFrEF
- heart failure with reduced ejection fraction
- IC50
- half maximal inhibitory concentration
- IUPHAR
- International Union of Basic and Clinical Pharmacology
- MI
- myocardial infarction
- mitoKATP
- mitochondrial ATP‐sensitive potassium channels
- NAION
- nonarteritic anterior ischaemic optic neuropathy
- Na+/K+‐ATPase
- sodium–potassium pump
- NOS1
- neuronal NOS
- NOS2
- inducible NOS
- NOS3
- endothelial NOS
- PAH
- pulmonary arterial hypertension
- PDE5I
- PDE type 5 inhibitor
- PH
- pulmonary hypertension
- PPHN
- persistent pulmonary hypertension of the newborn
- RCT
- randomised controlled trial
- RHTN
- treatment‐resistant hypertension
- RP
- Raynaud''s phenomenon
- sGC
- soluble GC
- SGLT2
- sodium–glucose cotransporter 2
- Tmax
- time taken to reach the maximum plasma concentration
- T2DM
- type 2 diabetes mellitus
- UACR
- urinary albumin/creatinine ratio
- V/Q
- ventilation/perfusion
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Immunohistochemical and molecular analysis of PI3K/AKT/mTOR pathway in esophageal carcinoma 下载免费PDF全文
Georgia Levidou Dimitrios Theodorou Nikolaos V. Michalopoulos Efstratios Patsouris Angelica A. Saetta 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2015,123(8):639-647
Among the numerous signaling pathways involved in tumorigenesis, PI3K‐AKT‐mTOR is a key one that regulates diverse cellular functions. However, its prognostic value in esophageal carcinoma remains unclear. In our study, we examined the immunohistochemical expression of phosphorylated (p‐) AKT, mTOR, p70S6K and 4E‐BP1 along with the mutational status of PIK3CA and AKT1 genes by High Resolution Melting Analysis and Pyrosequencing in 44 esophageal carcinomas. The results were correlated with the clinicopathological characteristics of the patients in an effort to define their possible prognostic significance. Total p‐mTOR cytoplasmic expression, assessed in 10 random areas, was positively correlated with tumor stage (Kruskal–Wallis ANOVA, I/II vs III/IV, p = 0.0500). Μoreover, maximum p‐mTOR cytoplasmic immunoexpression, estimated in hot spot areas, was positively associated with tumor grade (Mann–Whitney U test, I/II vs III, p = 0.0565). Interestingly, p‐4E‐BP1 immunoreactivity was negatively correlated with tumor histological grade (Mann–Whitney U test, I/II vs III, p = 0.0427). No mutation was observed in exons 9 and 20 of PIK3CA gene and in exon 4 of AKT1 gene. In conclusion, our findings depict the presence of activated PI3K/AKT/mTOR pathway in esophageal cancer bringing forward p‐mTOR and p‐4E‐BP1 for their potential role in esophageal carcinogenesis. Additional studies are warranted to validate our findings. 相似文献
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Anand Dayama Nikolaos Tsilimparis Stephen Kolakowski Nathaniel M. Matolo Misty D. Humphries 《Journal of vascular surgery》2019,69(1):156-163.e1
Background
Chronic limb-threatening ischemia (CLTI), defined as ischemic rest pain or tissue loss secondary to arterial insufficiency, is caused by multilevel arterial disease with frequent, severe infrageniculate disease. The rise in CLTI is in part the result of increasing worldwide prevalence of diabetes, renal insufficiency, and advanced aging of the population. The aim of this study was to compare a bypass-first with an endovascular-first revascularization strategy in patients with CLTI due to infrageniculate arterial disease.Methods
We reviewed the American College of Surgeons National Surgical Quality Improvement Program targeted lower extremity revascularization database from 2012 to 2015 to identify patients with CLTI and isolated infrageniculate arterial disease who underwent primary infrageniculate bypass or endovascular intervention. We excluded patients with a history of ipsilateral revascularization and proximal interventions. The end points were major adverse limb event (MALE), major adverse cardiovascular event (MACE), amputation at 30 days, reintervention, patency, and mortality. Multivariable logistic regression was used to determine the association of a bypass-first or an endovascular-first intervention with outcomes.Results
There were 1355 CLTI patients undergoing first-time revascularization to the infrageniculate arteries (821 endovascular-first revascularizations and 534 bypass-first revascularizations) identified. There was no significant difference in adjusted rate of 30-day MALE in the bypass-first vs endovascular-first revascularization cohort (9% vs 11.2%; odds ratio [OR], 0.73; 95% confidence interval [CI], 0.50-1.08). However, the incidence of transtibial or proximal amputation was lower in the bypass-first cohort (4.3% vs 7.4%; OR, 0.60; CI, 0.36-0.98). Patients with bypass-first revascularization had higher wound complication rates (9.7% vs 3.7%; OR, 2.75; CI, 1.71-4.42) compared with patients in the endovascular-first cohort. Compared with the endovascular-first cohort, the incidence of 30-day MACE was significantly higher in bypass-first patients (6.9% vs 2.6%; adjusted OR, 3.88; CI, 2.18-6.88), and 30-day mortality rates were 3.23% vs 1.8% (adjusted OR, 2.77; CI, 1.26-6.11). There was no difference in 30-day untreated loss of patency, reintervention of treated arterial segment, readmissions, and reoperations between the two cohorts. In subgroup analysis after exclusion of dialysis patients, there was also no significant difference in MALE or amputation between the bypass-first and endovascular-first cohorts.Conclusions
CLTI patients with isolated infrageniculate arterial disease treated by a bypass-first approach have a significantly lower 30-day amputation. However, this benefit was not observed when dialysis patients were excluded. The bypass-first cohort had a higher incidence of MACE compared with an endovascular-first strategy. These results reaffirm the need for randomized controlled trials, such as the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL-2) trial and Best Endovascular vs Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI), to provide level 1 evidence for the role of endovascular-first vs bypass-first revascularization strategies in the treatment of this population of challenging patients. 相似文献8.
George Kakavas Nikolaos Malliaropoulos Georgios Bikos Ricard Pruna Xavier Valle Panagiotis Tsaklis Nicola Maffulli 《Medical principles and practice》2021,30(2):101
More than 250,000 anterior cruciate ligament (ACL) injuries occur each year in the USA, and approximately 65% of these injuries undergo reconstructive surgery. Appropriate rehabilitation after ACL reconstruction can yield predictably good outcomes, with return to previous levels of activity and high knee function. At present, periodization is used at all levels of sports training. Whether conceptualized and directed by coaches, or by athletes themselves, competitors structure their training in a cyclic fashion, enabling athletes to best realize their performance goals. In practical application, sport physical therapists use periodization: postoperative “protocols” serve as rudimentary forms of periodization, albeit implemented over shorter time frames than that typically employed in preparation for competition. An ACL injury should not be considered a “simple” musculoskeletal pathology with only local mechanical or motor dysfunctions. Together with the psychological trauma and reduction in physical capacity, there is a cascade of events, including neurological insult to the central nervous system and reduction in afferences to the sensorimotor system. Rehabilitation should consider all these issues, and periodization would allow to better define and to plan aims and objectives to return athletes to their sport. Technological resources including advanced neuroimaging methods, virtual reality for injury risk screening and return to sport assessment, and interactive artificial reality-based neuromuscular training methods offer new approaches and tools to address this important biomedical problem. The cost and availability of many of these technologies will continue to decrease, providing greater availability, scientific rigor, and ultimately, utility for cost-effective and data-driven assessments. 相似文献
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Nikolaos G. Papadopoulos Adnan ustovi Michael D. Cabana Sharon D. Dell Antoine Deschildre Gunilla Hedlin Elham Hossny Peter Le Souëf Paolo M. Matricardi Antonio Nieto Wanda Phipatanakul Paulo M. Pitrez Petr Pohunek Marcela Gavornikova Xavier Jaumont David B. Price 《Pediatric allergy and immunology》2019,30(1):7-16
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