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Biomedical subjects

D J Ralph

Publications and source records attributed to D J Ralph.

At least 19 recordsLinked to original sources
PubMed2004

NCX-911, a novel nitric oxide-releasing PDE5 inhibitor relaxes rabbit corpus cavernosum in the absence of endogenous nitric oxide.

Phosphodiesterase type 5 (PDE5) inhibitors have reduced efficacy in treating erectile dysfunction (ED) in conditions where there is a lack of endogenous nitric oxide (NO). Therefore, NO-releasing PDE5 inhibitors have been developed. Here we report the effect of such a compound, NCX-911, on the tone and nitrergic relaxations of rabbit corpus cavernosum in the absence or presence of a NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 500 microM). NCX-911 was found to be as potent as sildenafil at inducing relaxation of rabbit cavernosum (EC(50) values 997.8+/-195.7 and 1000.5+/-140.8 nM, respectively). The potency of NCX-911 was not altered, but that of sildenafil decreased five-fold in the presence of L-NAME (EC(50) values 1281.2+/-268.3 and 4959.1+/-882.1, nM respectively, P<0.001 for sildenafil). Both compounds potentiated nitrergic relaxations with similar potencies. These results suggest that NO-releasing PDE5 inhibitors could potentially be more useful than PDE5 inhibitors in the treatment of ED in conditions where there is a lack of endogenous NO.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

The management of Peyronie's disease.

Peyronie's disease has no known cause; recent understanding of the molecular mechanisms involved and the development of an animal model will aid the medical management of early disease. The medical management of chronic disease is futile as the delicate tunical architecture cannot regenerate. Surgical correction of the penile deformity is required in a minority of patients, and a choice lies between a Nesbit operation and a plaque incision and venous patch in patients who are concerned with penile shortening.

4-Aminobenzoic Acid↗
PubMed2003

Cialis (tadalafil): a new treatment for erectile dysfunction.

Oral phosphodiesterase inhibitors have become the mainstay of treatment for erectile dysfunction. A novel and potent phosphodiesterase inhibitor, tadalafil, known as Cialis, has been introduced in the UK as an alternative to the other currently available phosphodiesterase inhibitors for the treatment of erectile dysfunction.

Carbolines↗
PubMed2003

Oral agents for erectile dysfunction.

Erectile dysfunction is a common disease affecting the lives of millions of men worldwide. Sildenafil was the first oral treatment licensed for male erectile dysfunction. However, there are now a number of other options available. In this article the currently available oral treatments are reviewed.

Administration, Oral↗
PubMed2002

Human and rabbit cavernosal smooth muscle cells express Rho-kinase.

Rho-kinase is an enzyme involved in the Ca2+-sensitizing pathway in smooth muscle cells. Inhibition of this enzyme has been recently demonstrated to elicit penile erection by relaxing cavernosal smooth muscle. We aimed to investigate the presence and activity of Rho-kinase in human cavernosal smooth muscle. Primary culture of smooth muscle cells from human and rabbit penile corpus cavernosum was developed, and cells showed characteristic myocyte morphology and alpha-actin immunoreactivity. The presence of Rho-kinase was demonstrated by indirect immunofluorescence and Western blotting. A specific inhibitor of Rho-kinase, Y-27632, inhibited in a concentration-dependent manner the kinase activity of the protein immunoprecipitated with anti-Rho-kinase antibody. These results demonstrate for the first time expression and activity of Rho-kinase in human penile cavernosal smooth muscle cells and suggest that these cells can provide a cellular model for the study of enzymes involved in Ca2+-sensitizing pathways.

Actins↗
PubMed2002

Clinical presentations of Peyronie's disease.

Patients with Peyronie's disease usually present soon after the onset of the disease with penile pain and deformity when they develop an erection. They are middle-aged men and a palpable plaque is usually present. A good clinical history and examination are all that are necessary to manage most patients with Peyronie's disease. Further investigation is only required in those men with erectile dysfunction or where surgery is indicated.

Erectile Dysfunction↗
PubMed2002

A shared care approach to the management of erectile dysfunction in the community.

Erectile dysfunction (ED) affects men of all ages and results in considerable distress and impact on quality of life for those who suffer from it. As ED is associated with a wide variety of under-lying conditions and cardiovascular co-morbidities, there is a requirement for diversity of treatment options and several factors must be considered to customise and optimise therapy. In the ideal holistic approach to management of the ED patient, both primary care and specialist physicians have an important role to play. This article reports on a sequential approach for the diagnosis and treatment of ED, with an emphasis on 'shared care'. The deliberations are based on a pan-European inter-disciplinary group that met at the Lygon Arms, UK on 22 February 2002.

Erectile Dysfunction↗
PubMed2002

Comparison of a needle-free high-pressure injection system with needle-tipped injection of intracavernosal alprostadil for erectile dysfunction.

Patients identified from hospital records as using alprostadil injections for erectile dysfunction were invited to take part in this open crossover study. On alternate weeks eight patients were given intracavernosal needle injections and transdermal needle-free injection of alprostadil in a randomized order. Efficacy of injection and associated pain were assessed and compared for the two methods. Pain produced during injection was significantly greater with the needle-free system than with the needle-tipped injection whilst efficacy was significantly less. Bruising was reported in all except one patient following needle-free injection only. Patient ratings of the needle-free injector were significantly lower than ratings for needle-tipped alprostadil delivery and when asked to express a preference, every patient chose the needle-tipped injection over the needle-free device.

Adult↗
PubMed2002

The Lue procedure: an analysis of the outcome in Peyronie's disease.

OBJECTIVE: To assess the Lue procedure (plaque incision and venous grafting) for correcting the penile deformity of Peyronie's disease (which can cause penile shortening and erectile dysfunction) as an alternative to the Nesbit procedure (which can worsen the shortening). PATIENTS AND METHODS: Fifty-one patients (mean age 51 years, range 27-68) with Peyronie's disease had their penile deformity corrected by plaque incision and saphenous vein grafting. All patients had stable Peyronie's disease and a mean (range) penile deformity of 57 (20-90). The vein graft was taken from the long saphenous vein at the ankle or groin and several sites grafted in 14 patients. The mean follow-up was 16 months. RESULTS: An excellent or satisfactory result was obtained in 47 patients (92%); the penis was completely straightened in 42 (82%). Four patients (8%) developed postoperative erectile dysfunction. Eighteen men (35%) had some degree of penile shortening (> 1 cm in eight), among whom intercourse was affected to a variable extent in six (12%). CONCLUSION: The Lue procedure is an effective option in the surgical management of Peyronie's disease, but penile shortening after surgery remains a risk.

Adult↗
PubMed2002

The management of low-flow priapism with the immediate insertion of a penile prosthesis.

OBJECTIVE: To evaluate the outcome of patients undergoing the immediate insertion of a penile prosthesis as a treatment for acute low-flow priapism. PATIENTS AND METHODS: Eight patients presenting with low-flow priapism with a mean duration of 91 h (range 32-192) were prospectively evaluated. All had failed conservative management with the instillation of alpha-adrenergic agents, and four had already undergone shunt procedures elsewhere. Immediate management consisted of the insertion of a malleable prosthesis in six patients and an inflatable prosthesis in two. One of the malleable prostheses was subsequently changed to an inflatable device. RESULTS: There were no early complications, with all patients being satisfied with the end result, and seven having sexual intercourse. One patient developed a penile deformity after surgery, cause by fibrosis around one inflatable cylinder. All patients have maintained their penile length. CONCLUSIONS: Prolonged low-flow priapism results in a variable degree of cavernosal fibrosis and a subsequent loss of penile length. The delayed insertion of a penile prosthesis can be difficult, with high complication rates. The immediate insertion of a penile prosthesis in patients with prolonged low-flow priapism is simple and maintains penile length. This should always be offered to the patient at initial presentation, as the complication rate is low and the subsequent outcome excellent.

Adult↗
PubMed2002

Ontogeny of human fetal testicular apoptosis during first, second, and third trimesters of pregnancy.

During spermatogenesis in human adults, testicular germ cells proliferate, differentiate, and die by apoptosis. However, little is known about the temporal or spatial nature of this programmed cell death. Such information may be useful for understanding prenatal developmental biology as well as spermatogenesis during adulthood, particularly in the context of germ cell disorders. We undertook this study to determine 1) whether apoptosis occurred in a cell-specific fashion in the germ cell population and the supporting somatic cells; and 2) whether apoptosis varied with gestational age. We examined human fetal testicular tissues obtained from 17 karyotypically and structurally normal fetuses of mothers who underwent spontaneous or induced abortions. Three gestational ages were defined as follows: group A, 12-13 wk gestation (n = 5); group B, 20-22 wk gestation (n = 7); and group C, 37-40 wk gestation (n = 5). Morphology in conjunction with in situ end labeling was used to identify and quantify apoptotic nuclei in fetal gonadal tissues. The results of this study suggest that gonadal apoptosis occurred in germ cells, Sertoli cells, and Leydig cells at all gestational ages. Apoptotic death was highest in the Leydig cells, followed by germ cells and Sertoli cells. There was a significant positive correlation between the apoptosis of germ cells and Sertoli cells (P < 0.01) and a negative correlation between healthy germ cells and Sertoli cells (P < 0.001). There was also a negative correlation between the intratubular cell number and the gestational age. Specifically, the proportion of Sertoli cells decreased with gestational age, although there was no significant change in the germ cell in relation to gestational age. No such relationship was found in the Leydig cell population, all of which reside outside the seminiferous tubules. These results are the first to suggest that fetal testicular apoptosis begins in the first trimester, occurs in the three major cell types, and continues throughout pregnancy. Our data also suggest that in the fetal gonad, germ and Sertoli cell proliferation and death may be controlled by a genetic program distinct from that of the Leydig cells. This information is relevant to the understanding of abnormal spermatogenesis associated with infertility and to germ cell tumors in adult life.

Apoptosis↗
PubMed2002

Priapism: a medical emergency.

Priapism is defined as a prolonged penile erection that fails to subside despite orgasm. It is a medical emergency which should be diagnosed and treated early to preserve erectile function and avoid corporal fibrosis resulting from anoxia of the corporal tissue. Decompression is usually successful with no permanent damage if treatment is provided within 12 hours of onset.

Emergencies↗
PubMed2002

Current oral treatments for erectile dysfunction.

Erectile dysfunction (ED) is defined as the inability to achieve and maintain a penile erection adequate for satisfactory sexual intercourse. It is a significant male health problem of global dimensions affecting approximately 150 million men worldwide. A broad range of options are currently available for the management of ED. They include oral agents (phosphodiesterase 5 inhibitors, dopamine agonists and alpha-receptor blocking drugs), intracavernosal injection (papaverine, phentolamine, prostaglandin E1, vasoactive intestinal peptide), transurethral vasoactive agents (prostaglandin E1), vacuum erection devices, vascular surgery and penile prostheses. Here we review the physiology of penile erection and the currently available oral preparations. In addition, novel therapeutic strategies to improve erectile function are discussed.

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

Y-27632, an inhibitor of Rho-kinase, antagonizes noradrenergic contractions in the rabbit and human penile corpus cavernosum.

We have examined the effect of an inhibitor of Rho-kinase, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632), on the contractions elicited by noradrenergic nerve stimulation and by phenylephrine in the human and rabbit penile corpus cavernosum. In both tissues, after treatment with scopolamine (10 microM) and N(G)-nitro-L-arginine methyl ester (L-NAME; 300 microM), electrical field stimulation (EFS) elicited noradrenergic contractions. These contractions were inhibited by Y-27632 in a concentration-dependent manner. The compound caused concentration-dependent relaxation of phenylephrine-contracted tissues, which were treated with scopolamine (10 microM), guanethidine (10 microM) and L-NAME (300 microM). These results suggest that Rho-kinase is involved in noradrenergic contractile pathway in the cavernosal smooth muscle of the penis.

Amides↗
PubMed2001

The Nesbit operation for Peyronie's disease: an analysis of the failures.

OBJECTIVE: To analyse critically the reasons for a poor outcome of the Nesbit operation for Peyronie's disease in 51 patients over a 20-year period. PATIENTS AND METHODS: Fifty-one patients who were classified as having a poor result from the Nesbit operation were reviewed (mean age 53 years, mean follow-up 21 months). The factors responsible for a poor result were analysed and classified into three groups: (i) deformity > 30 degrees; (ii) penile shortening > 2 cm; and (iii) impaired erection. Patients with a recurrent deformity were further classified according to the interval from surgery to the presentation of the recurrence. RESULTS: Thirty-one patients had a deformity of > 30 degrees; this occurred immediately in three patients through surgical error, soon after surgery in eight patients because of suture failure and after 11 months in the remaining 20 patients because their Peyronie's disease progressed. Penile shortening of > 2 cm was present in 19 patients but this only affected coital function in four. Erection was impaired in 10 patients but this was present before surgery in most. CONCLUSION The results of the Nesbit operation for Peyronie's disease can be improved by a preoperative assessment of erectile function and the use of sutures of high tensile strength. Patients should be warned that the disease may progress and that some penile shortening should be expected, although this does not affect coital function.

Adult↗