PubMed Health⌕ Search

Biomedical subjects

A Nehra

Publications and source records attributed to A Nehra.

At least 19 recordsLinked to original sources
PubMed2004

The 'effectiveness' scale--therapeutic outcome of pharmacologic therapies for ED: an international consensus panel report.

Despite availability of outcome measures and scales for assessing erectile dysfunction (ED) treatment efficacy, guidelines are not available for assessing broader therapeutic outcomes or defining treatment failure in ED. An International Consensus Advisory Panel was convened to develop guidelines, definitions and a new algorithm for evaluating treatment effectiveness in ED. These new guidelines are recommended for use in both research and clinical practice. A multidisciplinary, international panel, consisting of 11 senior researchers and clinicians, was convened to address pertinent issues concerning therapeutic outcome assessment for ED. The panel utilized a modified Delphi method of consensus development and proposed a new model for outcomes assessment. This model is inherently testable, using existing instruments and current methods of assessment. Following a comprehensive literature review and discussion, the Panel recommended adoption of a new treatment effectiveness conceptual framework or theoretical model for assessing therapeutic outcomes in ED. Treatment effectiveness is presumed to be a combined function of two other factors, treatment response and treatment satisfaction. Treatment response is based on the combined assessment of efficacy and tolerability, and treatment satisfaction on the combined assessment of patient and partner satisfaction. Taken together, these two domains define an overall domain of treatment effectiveness. This therapeutic index would be derived by independently assessing treatment efficacy and satisfaction by means of event logs, questionnaires or the more typical patient interview methods. In conclusion, the Ad Hoc Advisory Consensus Panel recommends adoption of a new framework or conceptual model for conducting ED outcome trials or clinical research. The concept of 'treatment effectiveness' is proposed as a new 'umbrella concept' or distal outcome to be evaluated.

Consensus Statements as Topic↗
PubMed2003

Lower extremity above-knee prosthesis-associated erectile dysfunction.

Blunt pelvic and perineal trauma has been previously reported to result in site-specific veno-occlusive dysfunction and/or site-specific cavernosal artery insufficiency. We herein describe a case of erectile dysfunction in a young previously potent amputee. We postulate that the erectile dysfunction is associated with a newly described form of blunt trauma, that is, site-specific compression from a perineal weight-bearing lower extremity above-knee prosthetic device. It is hypothesized that when the force exerted by the above-knee prosthesis is directed medially towards the ischiopubic ramus, the penile crura and common penile arterial blood supply become susceptible to crush-like injury, since they are in fixed anatomic locations in the perineum sandwiched between the compressive force and the bone. Clinical evaluation of the erectile dysfunction in this patient revealed site-specific corporal veno-occlusive dysfunction and site-specific common penile arterial occlusive pathology in the precise region of the contact of the above-knee prosthesis with the perineum. Further research is needed in above-knee prosthesis design to prevent erectile dysfunction.

Adult↗
PubMed2003

Functional prostaglandin E (EP) receptors in human penile corpus cavernosum.

In this study, we have characterized functional EP receptors in human corpus cavernosum (HCC) tissue and in HCC smooth muscle cells (SMC). Using RNase protection assays, we determined expression of EP2, EP3I and EP3II receptor mRNA. In organ bath preparations of HCC tissue strips, PGE1 caused dose-dependent relaxation at concentrations below 300 nM. At concentrations greater than 300 nM, PGE1 caused contraction. Addition of the EP1/EP2/EP3 receptor antagonist AH6809 inhibited this contraction and facilitated further relaxation through concentrations above 1 microM of PGE1. The EP1/EP3 receptor selective agonist 17-phenyltrinor-PGE2 caused dose-dependent contraction that was partially attenuated by SC51322, an EP1 selective antagonist. In cultures of HCC SMC, PGE1 stimulated cAMP accumulation in a dose-dependent manner. Interestingly, AH6809 significantly attenuated PGE1-induced cAMP accumulation. Sulprostone, a selective EP3 receptor agonist, induced weak contractions in HCC tissue strips but augmented forskolin-induced cAMP synthesis in HCC SMC. The data in this study suggest that HCC and cultured smooth muscle cells express EP1, EP2 and EP3 receptors. These receptors mediate their responses via different biochemical pathways and are expected to have different responses in regulating smooth muscle tone. Thus, we suggest that the ultimate response in erectile tissue to various prostanoids is the integration of responses elicited by individual EP receptor subtypes to a given ligand.

Aged↗
PubMed2002

Rationale for combination therapy of intraurethral prostaglandin E(1) and sildenafil in the salvage of erectile dysfunction patients desiring noninvasive therapy.

Corpus cavernosum smooth muscle relaxation and hence penile erection are regulated in part by increases in smooth muscle synthesis of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). The object of this study was to determine 30-month follow-up results in motivated patients desiring noninvasive medical therapy using sildenafil citrate (Viagra) in combination with intraurethral prostaglandin E(1) (PGE(1)) (Medicated Urethral System for Erection [MUSE]). Twenty-eight patients (mean +/- s.d. age, 59 +/-7.3 y; 17 who had undergone radical prostatectomy and 11 who had a diagnosis of organic erectile dysfunction) were included in this study. Detailed history taking and physical examinations were performed and vascular risk factors noted. In these patients, treatment with either 100 mg of sildenafil citrate and/or 1000 microg of MUSE had failed. None of these patients desired intracavernosal injection. Duplex Doppler ultrasonography after redosing was carried out on all patients. Dynamic infusion corpus cavernosography/cavernosometry was obtained in 17 of 28 patients, and combination therapy was initiated using 100 mg of sildenafil citrate orally 60 min before intercourse and 500 microg of MUSE intraurethrally immediately before intercourse. Independently, either 100 mg of sildenafil citrate or 1000 microg of MUSE was not efficacious in inducing an erection sufficient for vaginal penetration in any of the 28 patients. After initiating a combination therapy, at 30 months, all 28 patients were reporting erections sufficient for vaginal penetration, with 3.6 intercourse episodes per month. None of the patients crossed over to intracavernosal therapy or penile prosthesis. During therapy, eight of 28 patients reduced the dose of sildenafil citrate to 50 mg. Combination therapy with MUSE and sildenafil may be more efficacious in the salvage of patients who desire noninvasive therapy but in whom single-treatment modalities fail. Although both cAMP- and cGMP-mediated vasodilation can lead to penile erection, combining therapies that incorporate both pathways may succeed when single therapies fail.

Aged↗
PubMed2002

Pathophysiology of Peyronie's disease.

Peyronie's disease is an inflammatory condition characterized by the formation of fibrous, noncompliant nodules in the tunica albuginea which can impede tunical expansion during penile erection, leading to deformity and bending. While the cause of this disease is thought to be due to microvascular trauma and abnormal wound healing, other hypotheses include genetic predisposition. In this review the pathophysiology of Peyronie's disease is discussed as well as current hypotheses regarding its origin.

Blood Vessels↗
PubMed2002

Expression of functional prostaglandin D (DP) receptors in human corpus cavernosum smooth muscle.

Prostaglandin D(2) (PGD(2)) binds to specific G-protein coupled receptors (DP) and induces smooth muscle relaxation by stimulating the synthesis of intracellular cAMP. In this study, we examined the role of PGD(2) and DP receptors in regulating human penile smooth muscle contractility. We determined that human corpus cavernosum tissue and smooth muscle cells in culture expressed functional DP receptor and lipocalin-like prostaglandin D synthase by reverse-transcribed polymerase chain reaction (RT-PCR). Functional PGD synthase activity was confirmed by the synthesis of PGD(2) in human corpus cavernosum smooth muscle cells upon addition of exogenous arachidonic acid. Organ bath preparations of human corpus cavernosum tissue strips, contracted with phenylephrine, relaxed in a dose-dependent fashion to either PGD(2) or the DP selective agonist BW245C. Cultures of human corpus cavernosum smooth muscle cells treated with BW245C showed a two-fold increase in cAMP synthesis. These data are consistent with the expression of functional DP receptors in human corpus cavernosum. This suggests the presence of an intact prostanoid autocrine system that may play a role in regulating penile erectile function.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed2001

Sildenafil citrate, a selective phosphodiesterase type 5 inhibitor: urologic and cardiovascular implications.

Erectile dysfunction (ED) occurs in varying degrees in an estimated 20 to 30 million American men and is associated with adverse effects on quality of life; particularly personal well-being, family and social interrelationships. Research into ED has focused primarily on the physiologic mechanisms of corpus cavernosum smooth muscle relaxation, and penile erection as the end result of smooth muscle relaxation. These processes are mediated by cholinergic, nonadrenergic, noncholinergic (NANC, e.g., nitric oxide), vasoactive intestinal peptide (VIP), and potentially calcitonin gene-related peptide (CGRP) containing nerves. Release of nitric oxide following sexual stimulation from non-adrenergic, non cholinergic nerves and vascular endothelium activates guanylyl cyclase and induces intracellular cGMP synthesis. In turn, cGMP results in lowering intracellular concentrations, inhibits contractility of the penile smooth muscle, and induces an erectile response. Phosphodiesterase type 5 (PDE 5) is the predominant enzyme responsible for cGMP hydrolysis in trabecular smooth muscle. Activation of PDE 5 terminates NO-induced, cGMP-mediated smooth muscle relaxation, and subsequent penile flaccidity. Sildenafil citrate is a potent PDE type 5 reversible and selective inhibitor which blocks cGMP hydrolysis effectively. FDA approval of sildenafil citrate as the first oral agent for ED in males has resulted in significant interest. We discuss the clinical and pharmacologic properties of sildenafil citrate as well as the urologic and cardiac implications.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

Intracavernosal therapy: when oral agents fail.

Erectile dysfunction is a common problem in men older than 40 years, and the incidence increases markedly with age. Approximately one fourth of impotent men use intracavernosal injections as a primary treatment. Since its original description in the early 1980s, injection therapy has been used safely and successfully by many men and their partners. Intraurethral and oral agents for the treatment of erectile dysfunction have been introduced over the last few years, but early reports of patient satisfaction and reproducibility of erectile rigidity have not matched those of intracavernosal therapy. Thus, injection therapy remains on the forefront of treatment options.

Administration, Oral↗
PubMed2001

Cyclin-dependent kinase 5 is expressed in both Sertoli cells and metaphase spermatocytes.

OBJECTIVE: To gain insight into the function of cyclin-dependent kinase 5 (Cdk5) in spermatogenesis. DESIGN: The expression of the Cdk5 protein was determined with the use of immunohistochemical and immunoblot analysis. SETTING: Academic research laboratory. ANIMAL(S): Adult mouse and archival human testicular tissue were used for the immunohistochemical analysis. Adult mice were used as the source of tissues for the immunoblot analysis. INTERVENTION(S): The immunohistochemical analysis was performed with an anti-Cdk5 antibody. The double immunohistochemical analysis was performed with anti-Cdk5 and alpha-tubulin antibodies. Immunoblotting was used to examine multiple mouse tissues for Cdk5 expression. MAIN OUTCOME MEASURE(S): Analysis of Cdk5 protein distribution. RESULT(S): Cdk5 was localized specifically within the cytoplasm of Sertoli cells and meiotic metaphase germ cells. The double immunohistochemistry analysis demonstrated the co-localization of Cdk5 and alpha-tubulin within the Sertoli cells. Western blot analysis revealed a high level of expression of Cdk5 in the testicular lysate. CONCLUSION(S): The cyclin-dependent kinases are known regulators of the cell cycle; however, Cdk5 expression previously has been described in terminally differentiated cells of the brain. The present evidence of an association between Cdk5 and microfilaments of Sertoli cells and meiotic metaphase germ cells suggests a role of Cdk5 in both seminiferous tubule function and meiosis.

Animals↗
PubMed2001

Neurologic erectile dysfunction.

Neurologic erectile dysfunction presents a diagnostic and treatment challenge to the internist and urologist. Multiple chronic disease modalities and traumatic etiologies exist. Education regarding these conditions and a detailed and thorough history and office work-up are the best resources for the clinician. Treatment can follow the model of proceeding from the least to most invasive procedure (process of care), taking into account patient and partner satisfaction. Because the psychology of grief and loss may enter into treatment of some neurologic conditions (e.g., erectile dysfunction after radical retropubic prostatectomy, spinal cord injury, or chronic diseases), a whole-patient approach encompassing psychotherapy is warranted.

Chronic Disease↗
PubMed2001

Report of the American Foundation for Urologic Disease (AFUD) Thought Leader Panel for evaluation and treatment of priapism.

PURPOSE: Patients with priapism often develop permanent erectile dysfunction and personal sexual distress. This report is intended to help educate the public by reviewing the varied definitions and classifications of priapism and limited literature reports of pathophysiology, diagnosis and treatment outcomes of priapism. The AUA priapism guidelines committee is responsible for creating consensus as to appropriate individual patient management of priapism by physicians. MATERIALS AND METHODS: A multidisciplinary panel, consisting of 19 thought leaders in priapism, was convened by the Sexual Function Health Council of the American Foundation for Urologic Disease to address pertinent issues concerning the role of the urologist, primary care providers and other health care professionals in the education of the public regarding management of men with priapism. The panel utilized a modified Delphi method and built upon the peer review literature on priapism. RESULTS: The Thought Leader Panel recommended adoption of the definition of priapism as a pathological condition of a penile erection that persists beyond or is unrelated to sexual stimulation. Priapism is stressed to be an important medical condition that requires evaluation and may require emergency management. The classification system is categorized into ischemic and non-ischemic priapism. Essential elements of the ischemic classification are the inclusion of: (i) clinical characteristics of pain and rigidity; (ii) diagnostic characteristics of absence of cavernosal arterial blood flow; (iii) pathophysiological characteristics of a closed compartment syndrome; (iv) a time limit of 4 h prior to emergent medical care; and (v) a description of the potential consequences of delayed treatment. Essential elements of the non-ischemic classification are the inclusion of: (i) clinical characteristics of absence of pain and presence of partial rigidity; (ii) diagnostic and pathophysiological characteristics of unregulated cavernosal arterial inflow; and (iii) the need for evaluation but emphasizing the lack of a medical emergency. The panel recommended adoption of a rational management algorithm for the assessment and treatment of priapism where the cornerstone of initial assessment includes a careful clinical history, a focused physical examination and selected laboratory and/or radiologic tests. The panel recommended that specific criteria and clinical profiles requiring specialist referral should be identified. The panel further recommended that patient (and partner) needs and education concerning priapism should be addressed prior to therapeutic intervention, however only in the case of chronic management or post acute presentation evaluation should this delay intervention. Treatment goals to be discussed include management of the priapism with concomitant prevention of permanent and irreversible erectile dysfunction and associated psychosocial consequences. The panel recommended that when specific therapies for priapism are required, a step-care treatment approach based upon reversibility and invasiveness should be followed. CONCLUSIONS: The Thought Leader Panel calls for research to expand our understanding of the prevalence and diagnosis of priapism and education to create awareness among the public of the potential urgency of this condition. Critical areas to be addressed include the multiple pathophysiologies of priapism as well as multi-institutional trials to objectively assess safety and efficacy in the various treatment modalities.

Humans↗
PubMed2001

New advances in Peyronie's disease.

The formation of Peyronie's disease plaques is a process that seems to involve a cascade of genetic, structural and immunologic events. Clinical manifestations include penile deformity and possible erectile dysfunction. Rational strategies have been forthcoming, with both minimally invasive and surgical treatments of Peyronie's disease available. This article reviews and updates current scientific and clinical advances in Peyronie's disease.

Humans↗
PubMed2001

Corporeal structural and vascular micro architecture with X-ray micro computerized tomography in normal and diabetic rabbits: histopathological correlation.

PURPOSE: The pathophysiology of diabetes mellitus induced erectile dysfunction is poorly understood. In patients with diffuse venous leakage structural changes in the corpora cavernosa have correlated with failure of the veno-occlusive mechanism. Three-dimensional (D) micro computerized tomography (CT) has proved to be an important imaging technique for the intact kidney, heart, liver and bone. We examined control and diabetic rabbit penises by 3-D micro CT and quantified any structural changes. MATERIALS AND METHODS: Male white New Zealand rabbits were treated with alloxan to induce diabetes or used as normal controls. Via aortic access at laparotomy the penile vascular tree was vasodilated with papaverine and perfused with radiopaque silicone rubber. X-ray micro CT was then performed at 21 microm. resolution and images were analyzed in 3-D using custom software. RESULTS: Nine diabetic rabbits with blood glucose greater than 400 mg./dl. and 9 control animals were used for micro CT analysis. Significant decreases (p <0.05) were observed in the mean sinusoidal and vascular volume fraction plus or minus standard error of mean of the corpus cavernosum in the diabetic (323.7 +/- 43.1 mm.3 and 37.9 +/- 2.0%, respectively) and control (510.1 +/- 47.4 mm.3 and 53.1 +/- 3.80%, respectively) groups. Also, the mean left and right cavernous artery luminal cross-sectional area in diabetics (0.15 +/- 0.02 and 0.16 +/- 0.01 mm.2, respectively) versus controls (0.2 +/- 0.01 and 0.2 +/- 0.01 mm.2, respectively) was significantly decreased (p <0.05). Furthermore, the mean left and right total cavernous artery luminal volume in diabetics (0.4 +/- 0.07 and 0.4 +/- 0.09 mm.3, respectively) versus controls (1.0 +/- 0.13 and 0.9 +/- 0.11 mm.3, respectively) was significantly decreased (p <0.05). CONCLUSIONS: Diabetic rabbit penises showed a significant decrease in corporeal vascular volume as well as decreased cavernous artery diameter and luminal volume compared to controls. This finding correlated well with the mean decrease in trabecular smooth muscle in control and severely diabetic rabbits on histopathological studies (42.2% +/- 1.5% versus 35.8% +/- 1.5%). This combination of potential arterial insufficiency as well as an increase in diffuse connective tissue may contribute to the overall pathophysiology of diabetic erectile dysfunction. These results suggest that 3-D x-ray micro CT with molecular analysis may be a powerful tool for examining the pathophysiology of diabetic erectile dysfunction.

Angiography↗
PubMed2001

Potassium outward currents in freshly dissociated rabbit corpus cavernosum myocytes.

PURPOSE: Cavernous smooth muscle cells have a key role in the control of penile erection and detumescence. In this study the types of smooth muscle cells and currents present in isolated rabbit corpus cavernosum myocytes were characterized. MATERIALS AND METHODS: Immunohistochemical methods were used to identify cavernous smooth muscle cells. Currents were recorded from freshly dissociated myocytes using the whole cell and amphotericin perforated patch clamp techniques. RESULTS: Cavernous myocytes were identified by alpha-smooth muscle actin and smooth muscle myosin immunoreactivity. Based on electrical properties at least 2 types of myocytes were present. Type I cells showed more depolarized membrane potentials, lower capacitance, higher input resistance and increased current densities at positive potentials than type II cells. In types I and II cells at voltages positive to 30 mV, maxi K+ channel (Ca2+ activated large conductance K+ channel or BK) blockade with iberiotoxin or charybdotoxin reduced outward currents by approximately 40% to 80% at 80 mV. Maxi K+ channel blocking did not affect cell membrane potential. Type II cells showed delayed rectifier K+ channel-type outward currents that were not detected in type I cells. Delayed rectifier K+ channel-type currents were resistant to iberiotoxin or charybdotoxin, activated at approximately -50 to -40 mV. and inactivated weakly. CONCLUSIONS: The data suggest that cavernous smooth muscle cells are heterogeneous with at least 2 subtypes identified based on membrane potential, capacitance, input resistance, current density and delayed rectifier K+ channel expression. The activation threshold suggests that delayed rectifier K+ channels are open at the resting membrane potential and, therefore, contribute to control and regulation of the cavernous myocyte excitability.

Animals↗
PubMed2000

Effects of sildenafil citrate (Viagra) combined with nitrate on the heart.

BACKGROUND: Sildenafil citrate (Viagra) is indicated for the treatment of erectile dysfunction. Large and sudden decreases in systemic blood pressure were reported in a substantial number of patients taking sildenafil citrate combined with nitroglycerin. We studied the effect of sildenafil citrate on the relationship between changes in systemic blood pressure and coronary blood flow. METHODS AND RESULTS: Healthy male beagles were used to assess systemic blood pressure, pulmonary arterial pressure, and flow in the left circumflex artery (in which a critical stenosis was established) and left anterior descending coronary artery. After measurement of the hemodynamic variables, 2 mg/kg sildenafil citrate was administered via a nasogastric tube. Hemodynamic changes were monitored for 1 hour. Subsequently, the acute effect of nitrate combined with sildenafil citrate was studied by the bolus injection of 0.2 mg isosorbide dinitrate before and after sildenafil citrate. Systemic blood and pulmonary arterial pressures and circumflex flow did not change during this study; however, left anterior descending coronary arterial flow increased from 16.0+/-5.8 to 24.6+/-8.7 mL/min 1 hour after administration of sildenafil citrate. The prolongation of systemic blood pressure decrease and the circumflex flow decrement induced by isosorbide dinitrate after sildenafil citrate were significantly larger and longer than those before sildenafil citrate. CONCLUSIONS: Sildenafil citrate had the effect of vasodilation in a normal coronary artery; however, a combined effect with nitrate resulted in large and protracted decreases in systemic blood pressure and coronary blood flow in vessels with critical stenosis.

Administration, Oral↗