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[The role of pharmacological preconditioning in renal ischemic and reperfusion injury].
Kostina, DA, Pokrovskaya, TG, Olefir, YV, Yavorskii, AN, Elagin, VV
Urologiia (Moscow, Russia : 1999). 2017;(5):139-144
Abstract
Renal ischemic and reperfusion injury resulting in acute renal failure is a multidisciplinary problem at the junction of pathophysiology, transplantology, urology, nephrology, cardiac surgery and pharmacology. One of renal protection strategies is using the phenomenon of preconditioning. Preconditioning is one of the ways to adopt a tissue to repeated short-term effects of damaging factors to induce an enhanced tolerance to the long period of hypoxia and/or ischemia. There are multiple cellular and molecular mechanisms of the renal protective effects of preconditioning stimuli, but the key effectors and signaling molecules are ATP-dependent potassium channels, nitric oxide synthase, nitric oxide, and mitochondrial pore. Contradictory data on the protective effect of ischemic preconditioning allow searching for approaches to pharmacological correction of ischemic and reperfusion injuries. The article provides data on possible ways of using erythropoietin, darbepoetin and phosphodiesterase 5 inhibitors.
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Evaluation and Management of Erectile Dysfunction in the Hypertensive Patient.
Patel, JP, Lee, EH, Mena-Hurtado, CI, Walker, CN
Current cardiology reports. 2017;(9):89
Abstract
PURPOSE OF REVIEW The prevalence of hypertension and erectile dysfunction has steadily increased, and greater than 40% of men with erectile dysfunction concurrently share a diagnosis of hypertension. The treatment of the patient with both diseases poses a clinical challenge as both are closely correlated and share multiple overlapping risk factors.To address the recognized knowledge gap among clinicians who care for these patients, we will review the current literature on the diagnosis and treatment of erectile dysfunction in the hypertensive patient and will provide recommendations for the management of this challenging patient population. RECENT FINDINGS The pharmacological treatment of hypertension may adversely affect sexual function, and certain treatments for erectile dysfunction are contraindicated or cautioned against with certain antihypertensive agents. In review of the literature, we find that the clinician should opt to use an angiotensin-receptor blocker followed by an angiotensin-converting enzyme inhibitor or calcium channel blocker for the treatment of hypertension in patients with erectile dysfunction. Other agents require careful consideration for adverse effects on sexual function. Men with erectile dysfunction should be assessed for cardiovascular fitness for sexual activity, and PDE-5 inhibitors remain the first-line treatment for erectile dysfunction.
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A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management.
Grossmann, M, Matsumoto, AM
The Journal of clinical endocrinology and metabolism. 2017;(3):1067-1075
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CONTEXT Middle-aged and older men (≥50 years), especially those who are obese and suffer from comorbidities, not uncommonly present with clinical features consistent with androgen deficiency and modestly reduced testosterone levels. Commonly, such men do not demonstrate anatomical hypothalamic-pituitary-testicular axis pathology but have functional hypogonadism that is potentially reversible. EVIDENCE ACQUISITION Literature review from 1970 to October 2016. EVIDENCE SYNTHESIS Although definitive randomized controlled trials are lacking, evidence suggests that in such men, lifestyle measures to achieve weight loss and optimization of comorbidities, including discontinuation of offending medications, lead to clinical improvement and a modest increase in testosterone. Also, androgen deficiency-like symptoms and end-organ deficits respond to targeted treatments (such as phosphodiesterase-5 inhibitors for erectile dysfunction) without evidence that hypogonadal men are refractory. Unfortunately, lifestyle interventions remain difficult and may be insufficient even if successful. Testosterone therapy should be considered primarily for men who have significant clinical features of androgen deficiency and unequivocally low testosterone levels. Testosterone should be initiated either concomitantly with a trial of lifestyle measures, or after such a trial fails, after a tailored diagnostic work-up, exclusion of contraindications, and appropriate counseling. CONCLUSIONS There is modest evidence that functional hypogonadism responds to lifestyle measures and optimization of comorbidities. If achievable, these interventions may have demonstrable health benefits beyond the potential for increasing testosterone levels. Therefore, treatment of underlying causes of functional hypogonadism and of symptoms should be used either as an initial or adjunctive approach to testosterone therapy.
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Postprandial effects of the phosphodiesterase-5 inhibitor tadalafil in people with well-controlled Type 2 diabetes mellitus: a randomized controlled trial.
Sjögren, L, Olausson, J, Strindberg, L, Mobini, R, Fogelstrand, P, Mattsson Hultén, L, Jansson, PA
Diabetic medicine : a journal of the British Diabetic Association. 2016;(9):1299-301
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A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition.
Shibao, CA, Celedonio, JE, Ramirez, CE, Love-Gregory, L, Arnold, AC, Choi, L, Okamoto, LE, Gamboa, A, Biaggioni, I, Abumrad, NN, et al
The Journal of clinical endocrinology and metabolism. 2016;(7):2751-8
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CONTEXT The scavenger receptor CD36 influences the endothelial nitric oxide-cGMP pathway in vitro. Genetic variants that alter CD36 level are common in African Americans (AAs), a population at high risk of endothelial dysfunction. OBJECTIVE To examine if the minor allele (G) of coding CD36 variant rs3211938 (G/T) which reduces CD36 level by approximately 50% influences endothelial function, insulin sensitivity (IS), and the response to treatment with the nitric oxide-cGMP potentiator sildenafil. DESIGN IS (frequently sampled iv glucose tolerance) and endothelial function (flow mediated dilation [FMD]) were determined in age- and body mass index-matched obese AA women with or without the G allele of rs3211938 (protocol 1). Effect of chronic sildenafil treatment on IS and FMD was tested in AA women with metabolic syndrome and with/without the CD36 variant, using a randomized, placebo-controlled trial (protocol 2). SETTING Two-center study. PARTICIPANTS Obese AA women. INTERVENTION A total of 20-mg sildenafil citrate or placebo thrice daily for 4 weeks. MAIN OUTCOME IS, FMD. RESULTS G allele carriers have lower FMD (P = .03) and cGMP levels (P = .01) than noncarriers. Sildenafil did not improve IS, mean difference 0.12 (95% confidence interval [CI], -0.33 to 0.58; P = .550). However, there was a significant interaction between FMD response to sildenafil and rs3211938 (P = .018). FMD tended to improve in G carriers, 2.9 (95% CI, -0.9 to 6.8; P = .126), whereas it deteriorated in noncarriers, -2.6 (95% CI, -5.1 to -0.1; P = .04). CONCLUSIONS The data document influence of a common genetic variant on susceptibility to endothelial dysfunction and its response to sildenafil treatment.
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Recognizing and treating Raynaud phenomenon.
Thoelen, K, Maiers, K, Bondi, KA, Covino, J
JAAPA : official journal of the American Academy of Physician Assistants. 2015;(11):40-4
Abstract
Raynaud phenomenon is an episodic ischemia caused by cold, emotional stimuli, or rheumatologic disorders, and is more common in women than men. This article describes the clinical presentation of Raynaud phenomenon and how to diagnose and appropriately treat patients and prevent complications. Research on the use of different pharmacologic interventions for Raynaud phenomenon is ongoing and treatment options are expanding.
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Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus.
Assadi, F, Sharbaf, FG
American journal of nephrology. 2015;(1):65-9
Abstract
BACKGROUND Congenital nephrogenic diabetes insipidus (NDI) is characterized by massive polyuria and polydipsia due to defects in the vasopressin-sensitive signaling system expression of the acuaporin-2 (AQP2) water channel of the kidney collecting duct principal cells. Current conventional treatment regimen including hydration, diuretics and nonsteroidal anti-inflammatory drugs can only partially reduce polyuria. Recent experimental studies have suggested that treatment with sildenafil, a selective phosphodiesterase inhibitor, may enhance cyclic guanosine monophosphate (cGMP)-mediated apical trafficking of AQP2 and may be effective in increasing water reabsorption in patients with congenital NDI. PATIENT AND METHODS A 4-year old boy with X-linked NDI resistant to conventional therapy was treated with sildenafil for 10 days after a 2-day washout period between the 2 treatment regimens. Aliquots of the 24-hour urine collections before and after treatment were analyzed for urine volume, osmolality, cGMP and AQP2 determinations. Blood samples were also obtained for sodium and osmolality measurements. The primary endpoint was 24-hour urine volume after 10 days of sildenafil and conventional treatments. RESULTS Compared to conventional therapy, treatment with sildenafil resulted in substantial reduction in 24-hour urine volume (1,764 vs. 950 ml) and serum sodium (148 vs. 139) mEq/l, and increased urine osmolality (104 vs. 215 mOsm/l), and AQP2 excretion (5 vs. 26 fmol/mg creatinine). The patient tolerated sildenafil well and experienced no adverse effects. CONCLUSIONS Sildenafil citrate should be considered an alternative agent in the treatment of X-linked NDI resistant to conventional therapy.
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Phosphodiesterase type 5 inhibitors and kidney disease.
Afsar, B, Ortiz, A, Covic, A, Gaipov, A, Esen, T, Goldsmith, D, Kanbay, M
International urology and nephrology. 2015;(9):1521-8
Abstract
Chronic kidney disease (CKD) represents a worldwide health problem. Traditionally, the nephroprotective treatment for CKD aims to slow progression to end-stage renal disease and includes dietary protein restriction, correction of metabolic acidosis, and renin-angiotensin system blockers. However, current standard therapeutic options may not be enough for preventing CKD progression in a subset of patients making necessary to develop novel therapeutic options to further slow renal function loss. Phosphodiesterase type 5 (PDE5) inhibitors represent a class of drugs traditionally used to treat erectile dysfunction and pulmonary hypertension. However, recent evidence suggests that PDE5 inhibitors may have additional therapeutic effects, such as cardioprotection and cerebrovascular protection. In the current review, we summarize PDE5 inhibitors' utility in disease states and clinical conditions related to kidney disease such as systemic hypertension and acute and chronic kidney injury and discuss the mechanisms explaining possible kidney protective roles of PDE5 inhibitors. A recently completed phase 2 trials demonstrated that the long-acting PDE5 inhibitor PF-00489791 decreased albuminuria in patients with overt diabetic nephropathy when added on top of renin-angiotensin system blockade.
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Advances in the pathophysiology and treatment of heart failure with preserved ejection fraction.
Tannenbaum, S, Sayer, GT
Current opinion in cardiology. 2015;(3):250-8
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PURPOSE OF REVIEW With the failure of multiple trials to identify a successful therapy for heart failure with preserved ejection fraction (HFpEF), attention has shifted to defining specific phenotypes within the HFpEF spectrum in an effort to develop a targeted approach to treatment. Here we summarize the most recent studies investigating the pathophysiology and clinical features of HFpEF, and discuss recent clinical trials in the context of developing treatments that look toward the underlying cause of this disorder. RECENT FINDINGS Advances in basic science and clinical research have further characterized HFpEF, identifying multiple pathophysiological mechanisms that ultimately lead to exercise intolerance and volume overload. The success of small studies focused on specific subsets of the HFpEF population has promoted the concept that there may not be one treatment strategy that can universally be applied to HFpEF. SUMMARY HFpEF is associated with significant morbidity and mortality and accounts for approximately half of patients with chronic heart failure. HFpEF is a complex disease, encompassing a diverse cohort of patients and marked by the presence of multiple etiological mechanisms. The failure to develop successful therapies for the management of HFpEF may be because of inadequate standardization of the HFpEF diagnosis, overly broad inclusion criteria and inadequate differentiation of disease subtypes. Given the heterogeneity among patients with HFpEF, much of the current research is focused on understanding of pathophysiology and identifying disease phenotypes that may respond to a targeted treatment approach. Several newer approaches, including neprilysin inhibition and device therapy, offer promise for a new era of HFpEF treatment.
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Pulmonary hypertension and pregnancy: an overview.
Gei, A, Montúfar-Rueda, C
Clinical obstetrics and gynecology. 2014;(4):806-26
Abstract
Pulmonary hypertension is a syndrome infrequently associated with pregnancy. Despite advancements in therapy during the past 25 years and encouraging reports of improved outcomes, pulmonary arterial hypertension remains a devastating disease with a significantly reduced lifespan. This disorder should still be considered a contraindication to pregnancy. The decision of a patient to continue the pregnancy should be supported by an empathetic group of health care professionals who would optimize their treatment and hopefully their pregnancy outcomes and survival after delivery. We overview here different aspects of the diagnosis, evaluation, management, and counseling of patients suffering from pulmonary hypertension during pregnancy.