Efficacy and factors associated with successful outcome of sildenafil citrate use for erectile dysfunction after radical prostatectomy.

Raina R, Lakin MM, Agarwal A, Mascha E, Montague DK, Klein E, Zippe CD.

Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

OBJECTIVES: To assess the efficacy and factors associated with successful treatment of sildenafil citrate for erectile dysfunction after radical prostatectomy (RP). METHODS: Of the 470 patients who underwent RP at our institution between July 1998 and January 2000, 227 (48%) sought treatment for erectile dysfunction, and 174 (37%) were prescribed sildenafil citrate. The starting dose was 50 mg, which was increased to 100 mg if the patient did not have a positive response. Of the 174 patients, 104 (59.8%) had undergone a bilateral nerve-sparing (NS) procedure, 28 (16.1%) had undergone a unilateral NS procedure, and 42 (24.1%) had undergone a non-NS procedure. Erectile function was assessed by the abridged five-item version of the International Index of Erectile Function questionnaire, referred to as the Sexual Health Inventory for Men (SHIM), at baseline and 1 year after sildenafil use. The patients' charts were retrospectively reviewed to find factors associated with a successful outcome, which was defined as successful vaginal intercourse. Association with success was assessed by chi-square analysis and the Cochran Armitage test for trend. Bonferroni correction for multiple comparisons was used, with an overall significance level of 0.05 for each factor assessed. RESULTS: The mean age was 60.1 +/- 6.25 years, and the mean interval from RP to drug use was 3 months. After treatment with sildenafil, 100 (57%) of 174 patients responded to the drug: 79 (76%) of 104 in the bilateral NS group, 15 (53.5%) of 28 in the unilateral NS group, and 6 (14.2%) of 42 in the non-NS group. SHIM analysis showed that the magnitude of the improvement was greater in the bilateral NS group (19.97 +/- 1.12) than in the unilateral NS (15.89 +/- 3.38) or non-NS (10.06 +/- 2.0) groups (P <0.020). Four factors were significantly associated statistically with a successful outcome: the presence of at least one neurovascular bundle, a preoperative SHIM score of 15 or greater, age 65 years old or younger, and interval from RP to drug use of more than 6 months (P <0.001). CONCLUSIONS: The efficacy of sildenafil citrate after RP correlated with the degree of neurovascular bundle preservation, preoperative erectile function status, age, and interval before starting treatment.

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Reasons for discontinuation of sildenafil citrate after successful restoration of erectile function.

Son H, Park K, Kim SW, Paick JS.

Department of Urology, Seoul National University Hospital, Yongun-dong, Jongro-gu, Seoul,110-744, Korea.

AIM: To investigate the reasons for discontinuations of sildenafil after the successful restoration of erectile function. METHODS: One hundred fifty six patients, whose scores of erectile function domain of the 15-item International Index of Erectile Function (IIEF) increased to 26 or more after sildenafil medication, were included in this study. Six-months after the first sildenafil prescription, compliance to medication and the reason for discontinuity were reviewed by chart or surveyed by telephone. RESULTS: Fifty-four (34.6 %) of the 156 successfully treated patients discontinued sildenafil medication. The reasons for discontinuance were shortcomings in the partners' or patients' emotional readiness for the restoration of sexual life after long-term abstinence (37.0 %), fear of possible side effects (18.5 %), recovery of spontaneous erection (14.8 %), postponement of ED treatment because of co-morbid disease treatment (11.1 %), unwillingness to accept drug-dependent erection (7.4 %), high drug cost (3.7 %), unacceptability of planned sexual activity (3.7 %) and lack of sexual interest (3.7 %). CONCLUSION: The reasons for discontinuing sildenafil medication were primarily emotional or relationship-oriented, which indicates that simple recovery of a rigid erection is insufficient to restore sexual activity. More education about the effects of drug and the counseling of both partners is recommended to promote the successful recovery of sexual activity.

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Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats.

Pauvert O, Bonnet S, Rousseau E, Marthan R, Savineau JP.

Laboratoire de Physiologie Cellulaire Respiratoire, INSERM (E 356 and IFR 4 Universite Bordeaux 2, 146 rue Leo Saignat, 33076 Bordeaux, France.

Sildenafil, a potent type 5 nucleotide-dependent phosphodiesterase (PDE) inhibitor, has been recently proposed as a therapeutic tool to treat or prevent pulmonary artery hypertension (PAHT). We thus studied the effect of sildenafil on both the calcium signaling of isolated pulmonary artery smooth muscle cells (PASMCs) and the reactivity of pulmonary artery (PA) obtained from chronic hypoxia (CH)-induced pulmonary hypertensive rats compared with control (normoxic) rats. CH rats were maintained in an hypobaric chamber (50.5 kPa) for 3 wk leading to full development of PAHT. Intracellular calcium concentration ([Ca2+]i) was measured in PASMCs loaded with the calcium fluorophore indo 1. Unlike in control rats, sildenafil (10-100 nM) decreased the resting [Ca2+]i value in PASMCs obtained from CH rats. In PASMCs from both control and CH rats, sildenafil concentration dependently inhibited the [Ca2+]i response induced by G-coupled membrane receptor agonists such as angiotensin II and phenylephrine but had no effect on the amplitude of the [Ca2+]i response induced by caffeine. Sildenafil (0.1 nM-1 microM) concentration dependently reduced basal PA tone that is present in CH rats and relaxed PA rings precontracted with phenylephrine in both control and CH rats. These data show that sildenafil is a potent pulmonary artery relaxant in CH rats and that it normalizes CH-induced increases in resting [Ca2+]i and basal tone. Consequently, pharmacological inhibition of sildenafil-sensitive PDE5 downregulates the Ca2+ signaling pathway involved in this model of pulmonary hypertension.

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Adenosine receptor, protein kinase G, and p38 mitogen-activated protein kinase-dependent up-regulation of serotonin transporters involves both transporter trafficking and activation.

Zhu CB, Hewlett WA, Feoktistov I, Biaggioni I, Blakely RD.

Department of Psychiatry, Vanderbilt School of Medicine, Nashville, Tennessee 37232-8548, USA.

Serotonin (5-hydroxytryptamine; 5-HT) transporters (SERTs) are critical determinants of synaptic 5-HT inactivation and the targets for multiple drugs used to treat psychiatric disorders. In support of prior studies, we found that short-term (5-30 min) application of the adenosine receptor (AR) agonist 5'-N-ethylcarboxamidoadenosine (NECA) induces an increase in 5-HT uptake Vmax in rat basophilic leukemia 2H3 cells that is enhanced by pretreatment with the cGMP phosphodiesterase inhibitor sildenafil. NECA stimulation is blocked by the A3 AR antagonist 3-ethyl-5-benzyl-2-methyl-phenylethynyl-6-phenyl-1,4(+/-)dihydropyridine-3,5-dicarboxylate (MRS1191), by the phospholipase C inhibitor 1-(6-[[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl] amino]hexyl)-1H-pyrrole-2,5-dione (U73122), by the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, and by the guanyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Hydroxylamine, a nitric-oxide donor, and 8-bromo-cGMP, a membrane-permeant analog of cGMP, mimic the effects of NECA on 5-HT uptake, whereas the protein kinase G (PKG) inhibitor N-[2-(methylamino)ethy]-5-isoquinoline-sulfonamide (H8) blocks NECA, hydroxylamine, and 8-bromo-cGMP effects. NECA stimulation activates p38 mitogen-activated protein kinase (MAPK), whereas p38 MAPK inhibitors block NECA stimulation of SERT activity, as does the protein phosphatase 2A (PP2A) inhibitor calyculin A. 5-HT-displaceable [125I]3beta-(4-iodophenyl)-tropane-2beta-carboxylic acid methylester tartrate (RTI-55) whole-cell binding is increased by NECA or sildenafil, and both surface binding and cell surface SERT protein are elevated after NECA or sildenafil stimulation of AR/SERT-cotransfected Chinese hamster ovary cells. Whereas p38 MAPK inhibition blocks NECA stimulation of 5-HT activity, it fails to blunt stimulation of SERT surface density. Moreover, inactivation of existing surface SERTs fails to eliminate NECA stimulation of SERT. Together, these results reveal two PKG-dependent pathways supporting rapid SERT regulation by A3 ARs, one leading to enhanced SERT surface trafficking, and a separate, p38 MAPK-dependent process augmenting SERT intrinsic activity.

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The effect of selective phosphodiesterase inhibitors, alone and in combination, on a murine model of allergic asthma.

Clayton RA, Dick CA, Mackenzie A, Nagasawa M, Galbraith D, Hastings SF, MacKenzie SJ.

Scottish Biomedical, West of Scotland Science Park, Todd Campus, Glasgow, Scotland, G20 OXA, UK. rob.clayton Scottish-biomedical.com

BACKGROUND: The anti-inflammatory effects of the selective phosphodiesterase (PDE) inhibitors cilostazol (PDE 3), RO 20-1724 (PDE 4) and sildenafil (PDE 5) were examined in a murine model of allergic asthma. These compounds were used alone and in combination to determine any potential synergism, with dexamethasone included as a positive control. METHODS: Control and ovalbumin sensitised Balb/C mice were administered orally with each of the possible combinations of drugs at a dose of 3 mg/Kg for 10 days. RESULTS: When used alone, RO 20-1724 significantly reduced eosinophil influx into lungs and lowered tumour necrosis factor-alpha, interleukin-4 and interleukin-5 levels in the bronchoalveolar lavage fluid when compared to untreated mice. Treatment with cilostazol or sildenafil did not significantly inhibit any markers of inflammation measured. Combining any of these PDE inhibitors produced no additive or synergistic effects. Indeed, the anti-inflammatory effects of RO 20-1724 were attenuated by co-administration of either cilostazol or sildenafil. CONCLUSIONS: These results suggest that concurrent treatment with a PDE 3 and/or PDE 5 inhibitor will reduce the anti-inflammatory effectiveness of a PDE 4 inhibitor.

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Cardiovascular effects of sildenafil in hypertensive men with erectile dysfunction and different alleles of the type 5 cGMP-specific phosphodiesterase (PDE5).

Salvi F, Sarzani R, Giorgi R, Donatelli G, Pietrucci F, Micheli A, Baldoni M, Minaroli D, Dessi-Fulgheri P, Polito M, Muzzonigro G, Rappelli A.

Department of Internal Medicine, Polytechnical University of Marche, Ancona, Italy. fbidlv libero.it

Erectile dysfunction (ED) is frequent in patients with essential hypertension (EH); a likely common pathogenetic pathway could be a reduced ability of arteriolar vascular smooth muscle (VSM) to relax. Increasing intracellular levels of cGMP reduce the contractile status of VSM; on the contrary, type 5 cGMP-specific phosphodiesterase (PDE5, codified by PDE5A gene) regulates cGMP levels through its clearance. The PDE5A gene represents a good candidate for the intermediate phenotype EH/ED: genetic variants of the PDE5A may predispose to EH and ED and could affect the local and systemic response to sildenafil administration. Thus, a functionally relevant portion of PDE5 5'-flanking promoter region was analyzed by PCR and direct sequencing in patients with EH and idiopathic ED. The sequences obtained showed a T/G polymorphism at position -1142, near an AP1 regulatory element, that was not apparently associated with the intermediate phenotype. We also studied the relationship between this polymorphism and the effects of oral sildenafil on blood pressure (BP) and heart rate (HR) in men with ED. Sildenafil caused a significant decrease of BP, but had no effects on HR; statistical analysis showed no differences in BP and HR variations among PDE5A genotypes. In conclusion, our data showed no correlations of a novel polymorphism of the PDE5A promoter gene with the intermediate phenotype EH/ED and the BP and HR response to sildenafil administration. Further studies are necessary to define the role of this polymorphism and to study the genetic predisposition for EH with ED.

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