Biomedical subjects

David J Ralph

Publications and source records attributed to David J Ralph.

21 records · Page 2Linked to original sources

PubMed2004

A novel therapy with testosterone and sildenafil for erectile dysfunction in patients on renal dialysis or after renal transplantation.

BACKGROUND: We undertook a prospective pilot study in a small cohort of patients with renal replacement therapy to determine the cause of erectile dysfunction (ED) and evaluate the role of testosterone replacement therapy and sildenafil. METHODS: We investigated 12 patients (eight post-transplant and four on haemodialysis) who presented with ED for hypogonadism and cavernosal insufficiency. We assessed sexual performance before and after treatment by a questionnaire method based on the modified International Index of Erectile Function (IIEF) and National Institutes of Health (NIH) rating. Patients received 250 mg intramuscular monthly injections of testosterone cypionate and 50-100 mg sildenafil orally once or twice weekly for 12 months. Therapeutic response was considered good if the patient could maintain an erection adequate for successful sexual intercourse (NIH criteria) and had a marked improvement in the overall sexual performance (IIEF scoring). RESULTS: Before treatment all patients had severe ED with a poor IIEF score while 11 also had diminished libido. Eleven patients had diminished testicular volume and six had elevated follicle-stimulating hormone levels suggestive of germ cell damage. All patients had a good response to the therapeutic trial of testosterone and sildenafil. CONCLUSIONS: Therapy with testosterone and sildenafil may be indicated for those with both cavernosal arterial insufficiency and reproductive hormone abnormalities. Further longer-term data are needed to determine the safety and efficacy of this novel regimen.

Adult↗

PubMed2003

BAY41-2272, a novel nitric oxide independent soluble guanylate cyclase activator, relaxes human and rabbit corpus cavernosum in vitro.

PURPOSE: In cavernous smooth muscle nitric oxide (NO) activates soluble guanylate cyclase, which catalyzes the synthesis of cyclic guanosine 3',5'-monophosphate, leading to smooth muscle relaxation, increased blood flow and penile erection. The pyrazolopyridine derivative BAY41-2272 (5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4ylamine) was identified and found to stimulate soluble guanylate cyclase in a NO independent manner. We investigated the effect of BAY41-2272 on human and rabbit corpus cavernosum. MATERIALS AND METHODS: We investigated the effect of BAY41-2272 on the tone and nitrergic relaxation responses of human and rabbit cavernous strips in the absence and presence of the soluble guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4-3a]quinoxalin-1-one) or the NO synthase inhibitor L-NAME (N-nitro-L-arginine-methyl ester HCl). The potency of BAY41-2272 was compared to that of another soluble guanylate cyclase activator YC-1, and the NO releasing compound spermine NONOate (N-2-aminoethyl-N-2-hydroxy-2-nitrosohydroazino-1,2-ethylenediamine). RESULTS: BAY41-2272 resulted in concentration dependent relaxation of human and rabbit cavernosum (mean EC50 +/- SEM 489.1 +/- 22.5 and 406.3 +/- 21.5 nM., respectively). The compound was 32 times more potent than YC-1 and twice as potent as spermine-NONOate. ODQ decreased the potency of BAY41-2272, such that in the presence of 30 microM. ODQ the EC50 of BAY41-2272 induced relaxation was 1,407.3 +/- 158.0 and 1,902.7 +/- 11.0 nM. in human and rabbit tissues, respectively. L-NAME also inhibited relaxations elicited by BAY41-2272 in rabbit tissue. In the presence of 500 microM. L-NAME the EC50 of BAY41-2272 induced responses was 836.7 +/- 46.7 nM. BAY41-2272 at subthreshold concentrations of 30 to 50 nM. potentiated nitrergic responses. Moreover, the inhibition of nitrergic responses by L-NAME was reversed by 0.3 to 3 microM. BAY41-2272. CONCLUSIONS: We report that a nonNO based soluble guanylate cyclase activator relaxes human and rabbit corpus cavernosum, and potentiates nitrergic responses.

Animals↗

PubMed2003

Y-27632, a Rho-kinase inhibitor, inhibits proliferation and adrenergic contraction of prostatic smooth muscle cells.

PURPOSE: Benign prostatic hyperplasia (BPH) causes mechanical urinary flow obstruction by 2 components, namely an enlarged prostate (static component) and elevated smooth muscle tone (dynamic component). Currently available treatments for BPH aim to inhibit the proliferation of prostatic cells or decrease the elevated tone. To our knowledge no single agent that can achieve these 2 ends has yet been identified. A specific inhibitor of Rho-kinase, Y-27632 ((+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride), has been demonstrated to cause smooth muscle relaxation and inhibit smooth muscle cell proliferation. Therefore, we investigated the effect of Y-27632 on prostatic smooth muscle proliferation and tone. MATERIALS AND METHODS: Rho-kinase expression was investigated by immunocytochemistry and immunoblotting in smooth muscle cells obtained from rat and human prostates. The effect of Y-27632 was examined on the proliferation of these cells and on the contractions elicited by electrical field stimulation and exogenous phenylephrine in rat prostatic strips. RESULTS: Immunoblot and immunofluorescence analysis showed that Rho-kinase is present in the cytosol and located in the perinuclear region in human and rat prostatic smooth muscle cells. Y-27632 decreased the proliferation of human and rat prostatic smooth muscle cells, and inhibited noradrenergic contractions elicited by electrical field stimulation and exogenous phenylephrine in rat prostatic strips (EC50 17.8 +/- 4.8 and 7.8 +/- 2.1 microM, respectively). CONCLUSIONS: To our knowledge we report the first demonstration of the presence of Rho-kinase in prostatic smooth muscle cells, and of the relaxant and antiproliferative effect of a Rho-kinase inhibitor. We suggest a novel use for Rho-kinase inhibitors in the treatment of BPH as a single agent with dual action.

Adrenergic alpha-Agonists↗