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Biomedical subjects

A Nehra

Publications and source records attributed to A Nehra.

At least 19 recordsLinked to original sources
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↗
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↗
PubMed2000

Predicting the survival of bladder carcinoma patients treated with radical cystectomy.

BACKGROUND: Clinical outcomes vary for patients treated with radical cystectomy. The authors sought to identify factors associated with the survival of patients treated with radical cystectomy for urothelial carcinoma of the urinary bladder. METHODS: The authors studied 218 patients treated with radical cystectomy for urothelial carcinoma between 1980 to 1984. Patient ages ranged from 41 to 78 years (mean, 64 years). Using the 1997 TNM system, T classifications were Ta (17 patients), T1 (44), T2 (71), T3a (42), T3b (14), T4a (28), and T4b (2). Thirty-two patients had lymph node metastasis at the time of surgery. Histologic grade was determined according to the newly proposed World Health Organization and International Society of Urological Pathology grading system; tumor was low grade in 43 patients and high grade in 175. The male-to-female ratio was 4.9 to 1. The mean follow-up of patients still alive was 13.1 years (median, 13.8 years; range, 30 days to 18 years). Cox proportional hazards models were used to determine the impact of numerous clinical and pathologic findings on survival. RESULTS: Ten-year local recurrence free, distant metastasis free, cancer specific, and all-cause survival were 71%, 73%, 67%, and 41%, respectively. In univariate analysis, cancer size, T classification, and lymph node status were associated with distant metastasis free, cancer specific, and all-cause survival. Histologic grade and surgical margin status were significantly associated with worse cancer specific and all-cause survival, but not with distant metastasis free survival. In multivariate analysis, cancer size, margin status, T classification, and lymph node status were identified as significantly associated with cancer specific survival after adjustment for age and gender. CONCLUSIONS: Long term survival is achieved in a significant number of patients treated with radical cystectomy. In this study, patients with organ-confined (< or = pT2) and small size (< or = 3 cm) cancer had favorable 10-year distant metastasis free (93%) and cancer specific survival (88%) after cystectomy. Tumor size, margin status, extravesical involvement, and lymph node metastasis are important pathologic factors and should be considered as stratification variables in identifying patients for whom adjuvant chemotherapy should be evaluated in clinical trials.

Adult↗
PubMed2000

Cancer heterogeneity and its biologic implications in the grading of urothelial carcinoma.

BACKGROUND: Urothelial carcinoma of the bladder often contains areas with different histologic grades. The influence of cancer heterogeneity on grading and its relation to patient outcome is uncertain. METHODS: The study group consisted of 164 patients with Ta urothelial carcinoma diagnosed at the Mayo Clinic between 1985 and 1986. None had previous or coexistent urothelial carcinoma in situ or invasive carcinoma. The primary (most common) and secondary (second most common if at least 5% of the cancer) patterns of cancer growth were graded by the newly proposed World Health Organization and International Society of Urological Pathology (WHO/ISUP) grading system. Scores of 1, 2, and 3 were assigned to urothelial neoplasms of low malignant potential (LMP), low grade urothelial carcinoma, and high grade urothelial carcinoma, respectively. The mean follow-up was 7.7 years (range, 0-13.3 years; median, 9.2 years). Progression was defined as the development of invasive carcinoma, distant metastasis, or death due to bladder carcinoma. RESULTS: Patient ages ranged from 36 to 96 years (mean, 69 years), and the male-to-female ratio was 4:1. Disease progression developed in 32 patients during a mean follow-up of 7.7 years. The mean interval from diagnosis to progression was 3.1 years (range, 0.01-8.7 years). Progression free survival was 82%, 77%, and 76% at 5, 7, and 10 years, respectively. Primary and secondary grades were different for 52 patients (32%). Based on the worst grade, 19 patients (12%) had urothelial neoplasms of low malignant potential (LMP), 92 (56%) had low grade carcinoma, and 53 (32%) had high grade carcinoma. Histologic grades based on worst, primary, secondary, and combined primary and secondary grades were all significant for predicting progression (P = 0.0009, 0.0004, 0.001, and 0.0001, respectively). Seven-year progression free survival rates for patients with LMP, low grade, and high grade carcinoma (based on worst grade) were 93%, 82%, and 61%, respectively; for patients with combined scores of 2, 3, 4, 5, and 6, survival rates were 93%, 80%, 82%, 68%, and 40%, respectively. The difference between patients with combined scores of 5 or 6 was statistically significant (P = 0.02). CONCLUSIONS: Histologic grade of urothelial carcinoma based on the newly proposed WHO/ISUP grading system stratifies patients into prognostically significant groups. Grading should also take cancer heterogeneity into consideration, and prognostic accuracy appears to be increased when the combined primary and secondary grades are applied. [See editorial counterpoint on pages 1509-12 and reply to counterpoint on pages 1513-6, this issue.]

Adult↗
PubMed2000

Squamous papilloma of the urinary tract is unrelated to condyloma acuminata.

BACKGROUND: To the authors' knowledge, there is no previous report of squamous papilloma of the urinary tract. It is uncertain whether there is a correlation between squamous papilloma, condyloma acuminatum, and verrucous carcinoma. METHODS: The authors evaluated the clinical and pathologic features of squamous papilloma (5 of the bladder, 2 of the urethra), condyloma acuminatum (3 cases), and verrucous carcinoma (3 cases) of the urinary bladder and performed human papillomavirus (HPV) DNA in situ hybridization studies to determine whether HPV was a common feature shared by these lesions. In addition, DNA ploidy evaluation by image cytometry and p53 immunohistochemical staining were performed. RESULTS: Squamous papilloma of the urinary tract occurred in elderly women and followed a benign clinical course with infrequent recurrence. All squamous papillomas were HPV DNA negative and DNA diploid with no or minimal p53 nuclear accumulation. Condyloma acuminata of the bladder contained HPV DNA, increased p53 protein expression, and aneuploid DNA content. All three cases of condyloma acuminata were associated with coexistent condylomata of the external genitalia, and two required pelvic exenteration for uncontrolled expansile growth. Verrucous carcinoma of the bladder occurred in elderly patients. All three cases of verrucous carcinoma were negative for HPV DNA and DNA aneuploid, and they exhibited consistent p53 expression. CONCLUSIONS: These data indicate that squamous papilloma is a distinct entity not related to condyloma or verrucous carcinoma. These lesions are benign, HPV DNA negative, DNA diploid, and they lack p53 overaccumulation.

Adult↗
PubMed2000

Misoprostol induces relaxation of human corpus cavernosum smooth muscle: comparison to prostaglandin E1.

Prostaglandin E1 (PGE1) relaxes trabecular smooth muscle by interacting with specific G-protein coupled receptors on human corpus cavernosum smooth muscle and increasing intracellular synthesis of cAMP. Misoprostol (Cytotec), is an oral prostaglandin E analogue. The purpose of this study was to compare the functional activity of misoprostol with PGE1 in human corpus cavernosum and cultured human corpus cavernosum smooth muscle cells. Misoprostol, misoprostol free acid or PGE1 induced dose-dependent relaxations in strips of human corpus cavernosum. At concentrations greater than 10(-6) M, tissue recontraction was observed with all three agents. This was abrogated by pretreatment with the thromboxane A2 receptor antagonist SQ29,548. From these observations, we conclude that misoprostol is activated by human corpus cavernosum in situ and relaxes phenylephrine-precontrated tissue strips in vitro. This relaxation response is mediated by the increased cAMP synthesis by these agents.

Alprostadil↗
PubMed2000

Medical and surgical advances in the radical prostatectomy patient.

Maintaining the quality of life after surgery in the radical prostatectomy patient is of paramount importance. One of the major dilemmas in surgical management of radical retropubic prostatectomy (RRP) is preservation of the neurovascular bundle and, hence, erectile function and the continence mechanism. This manuscript addresses anatomical considerations for the surgeon and discusses the following issues with regard to medical and surgical therapies: (1) incidence of erectile dysfunction solely due to complications during RRP; (2) nerve damage during RRP; (3) vascular damage during RRP; (4) current medical and surgical therapies for restoring or maintaining potency; and (5) new advances on the horizon for management of the prostatectomy patient. International Journal of Impotence Research (2000) 12, Suppl 4, S47-S52.

Blood Vessels↗