Cardiovascular parameter changes in patients with Erectile Dysfunction using pde-5 inhibitors: a study withSildenafil Citrate (Viagra) and vardenafil.

Sildenafil is the most prescribed oral agent for patients with Erectile Dysfunction (ED). Vardenafil is a new phosphodiesterase type 5 (Pde-5) inhibitor that was approved by the US Food and Drug Administration last year to treat patients with ED of various causes. Both of these Pde-5 inhibitors have vasodilating properties and effects on blood pressure (BP), and like nitrates, they work through the nitric oxide cyclic guanosine monophosphate pathway. The aim of this study was to investigate the influence of these Pde-5 inhibitors on BP and heart rate (HR) in normotensive men with ED by a crossover comparison. Thirty-five patients with ED were enrolled to evaluate and compare the effect ofSildenafil Citrate (Viagra) (50 mg) and vardenafil (10 mg) on BP and HR. At the screening (baseline [B]) visit, sitting systolic blood pressure (B-SBP), diastolic blood pressure (B-DBP), and HR were measured. We performed a multiple administration for both drugs and, therefore, multiple measurements of BP and HR changes, 3 doses a week, on alternate days, late in the afternoon, and on an empty stomach. B-SBP, B-DBP, and HR were recorded before each 50-mgSildenafil Citrate (Viagra) dosing and after 30, 60, 120, and 240 minutes. Data were averaged over the 4 time points and compared with the baseline values obtained before each dosing. After a 3-week wash-out period, patients were crossed over to vardenafil (10 mg) with the same study design. After administration of both drugs, we observed a statistically significant decrease of BP and an increase of HR. On average,Sildenafil Citrate (Viagra) caused a decrease of SBP ranging from 5.1 +/- 3.9 mm Hg during the first dosing to 4.7 +/- 4.2 mm Hg during the third dosing, DBP ranged from 4.4 +/- 4.9 to 4 +/- 4.1 mm Hg, and HR increased 1.8 +/- 2.0 bpm (first dose) and 1.2 +/- 0.9 bpm (third dose). With vardenafil, we recorded a greater variation for SBP and DBP. SBP decreased from 8.02 +/- 8.0 mm Hg during the first dosing to 5.4 +/- 5.5 mm Hg during the third dosing, whereas DBP decreased from 6.6 +/- 7.2 to 5.0 +/- 5.3 mm Hg, respectively. Recorded HR showed an increase of 3.1 +/- 3.2 bpm (first dose) and 2.4 +/- 2.3 bpm (third dose). After the first vardenafil administration, we recorded fainting episodes in 3 patients because of a decrease in BP greater than 20 mm Hg. Two of the patients were in therapy with doxazosin for benign prostatic hyperplasia (BPH). Cardiovascular response was not significantly different after the first dose between the 2 treatments. Vardenafil demonstrated clinically significant differences (fainting) with respect toSildenafil Citrate (Viagra) only during the first doses. We suggest that before starting therapies with Pde-5 inhibitors, particularly with the newer ones, that baseline cardiovascular parameters are measured and monitored, especially during the first dose, because of the presence of a "first dose effect." Moreover, it is necessary to pay particular attention to those patients in treatment with other drugs that could have a synergistic hypotensive effect as a result of vasodilation potentiation

Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa.

By real-time RT-PCR and Western blot analysis, we found that phosphodiesterase type 5 (PDE5) mRNA and protein abundance was several fold higher in human male than in female reproductive tracts. The highest mRNA level (>1 x 10(7) molecules/microg total RNA) was detected in human corpora cavernosa (CC), where PDE5 protein was immunolocalized in both muscular and endothelial compartment. The possible role of androgens in regulating PDE5 expression was studied using a previously established rabbit model of hypogonadotropic hypogonadism. In this model, hypogonadism reduced, and testosterone (T) supplementation restored, CC PDE5 gene and protein expression. In addition, T supplementation completely rescued and even enhanced cyclic GMP conversion to metabolites, without changing IC(50) forSildenafil Citrate (Viagra) (IC(50) = 2.16 +/- 0.62 nm). In control CC strips,Sildenafil Citrate (Viagra) dose-dependently increased relaxation induced by electrical field stimulation, with EC(50) = 3.42 +/- 1.7 nm. Hypogonadism reduced, and T increased,Sildenafil Citrate (Viagra) effect on electrical field stimulation, again without changing their relative EC(50) values. CC sensitivity to the NO-donor NCX4040 was greater in hypogonadal rabbit strips than in control or T-treated counterparts. Moreover,Sildenafil Citrate (Viagra) enhanced NCX4040 effect in eugonadal rabbit strips but not in hypogonadal ones. This suggests that androgens up-regulate PDE5 in rabbit penis. We also measured PDE5 gene expression and metabolic activity in human CC from male-to-female transsexual individuals, chronically treated with estrogens and cyproterone acetate. Comparing the observed values vs. eugonadal controls, PDE5 mRNA, protein, and functional activity were significantly reduced. In conclusion, we demonstrated, for the first time, that androgens positively regulate PDE5, thus providing a possible explanation about the highest abundance of this enzyme in male genital tract

Sildenafil increases diclofenac antinociception in the formalin test.

The antinociceptive activity of an inhibitor of phosphodiesterase 5, alone or combined with diclofenac, was assessed in the formalin test. Local administration of diclofenac produced a significant antinociception in both phases of the formalin test in female Wistar rats. In contrast, 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [3,4-d]pyrimidin-5-yl)phenylsulfonyl]-4-methyl piperazine (sildenafil, an inhibitor of phosphodiesterase 5) produced significant antinociception, only during the second phase of the formalin test. Non-effective doses ofSildenafil Citrate (Viagra) (25-100 microg/paw) significantly increased the antinociceptive effect of an inactive dose of diclofenac (25 microg) in both phases of the test. The antinociception produced by the drugs alone or the combination was due to a local action, as its administration in the contralateral paw was ineffective. SinceSildenafil Citrate (Viagra) is a potent and selective inhibitor of phosphodiesterase 5, our results suggest that this drug produced its antinociceptive activity, and increased that of diclofenac, probably through the inhibition of cyclic GMP degradation

Oxidative stress and antioxidant therapy: their impact in diabetes-associated Erectile Dysfunction.

Oxidative stress is believed to affect the development of diabetic-associated vasculopathy, endothelial dysfunction, and neuropathy within erectile tissue. Our hypothesis is that, given adequate concentrations of the oxygen free radical scavenger vitamin E, enhanced levels of circulating nitric oxide (NO) should improve erectile function with the potential for a synergistic effect with a phosphodiesterase type 5 (PDE5) inhibitor. Twenty adult male Sprague-Dawley streptozotocin-induced (60 mg/kg intraperitoneally) diabetic rats were placed in 4 therapeutic groups (n = 5 per group) as follows: 1) peanut oil only (diabetic control), 2) 20 IU of vitamin E per day, 3) 5 mg/kg ofSildenafil Citrate (Viagra) per day, and 4) vitamin E plusSildenafil Citrate (Viagra) using oral gavage for 3 weeks. In addition, 5 age-matched rats served as normal nondiabetic controls (normal). Erectile function was assessed by measuring the rise in intracavernous pressure (ICP) following cavernous nerve electrostimulation. Penile tissue was evaluated for neuronal NO synthase (nNOS), smooth muscle alpha-actin, nitrotyrosine, and endothelial cell integrity. Urine nitrite and nitrate (NOx) concentration was quantified, and electrolytes were tested by a serum biochemistry panel. A significant decrease in ICP was recorded in the diabetic animals, with improvement measured in the animals receiving PDE5 inhibitors either with or without vitamin E; the controls had a pressure of 54.8 +/- 5.3 cm H2O, the vitamin E group had a pressure of 73.5 +/- 6.6 cm H2O, theSildenafil Citrate (Viagra) group had a pressure of 78.4 +/- 10.77 cm H2O, and the vitamin E plusSildenafil Citrate (Viagra) group had a pressure of 87.9 +/- 5.5 cm H2O (P <.05), compared with the normal cohorts at 103.0 +/- 4.8 cm H2O. Histoexaminations showed improved nNOS, endothelial cell, and smooth muscle cell staining in the vitamin E plusSildenafil Citrate (Viagra) group compared to the control animals. Urine NOx increased significantly in all the diabetic groups but was blunted in the vitamin E and vitamin E plusSildenafil Citrate (Viagra) groups. A significant increase in positive staining for nitrotyrosine was observed in the vitamin E plusSildenafil Citrate (Viagra) group. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in this study, supporting the potential use of oxygen free radical scavengers in salvaging erectile function in diabetic patients

Coronary artery flow reserve in diabetics with Erectile Dysfunction using sildenafil.

BACKGROUND: Diabetics with Erectile Dysfunction have a high prevalence of microvascular disturbance of the coronary circuit as measured by coronary flow reserve (CFR). PURPOSE: We aimed to evaluate the effects of the phosphodiesterase 5 inhibitorSildenafil Citrate (Viagra) on CFR in diabetics with Erectile Dysfunction. METHODS: Diabetics seeking diabetes refinement therapy were screened for vascular or neurogenic Erectile Dysfunction which was confirmed in 43 patients. No ischemic ECG changes were found in any of the ECG stress tests at the 100 W level. Cardiologic examinations raised suspicion of coronary artery disease in 16 patients; coronary angiography confirmed severe coronary artery lesions in 12, who were excluded from further analysis. CFR measurements were not possible in 10 participants. The 21 diabetics eligible for CFR measurements aged 60 years (50-69) had known diabetes for 11 years (3-30) and a BMI of 27 kg/m2 (24-36). CFR of the left anterior descending artery was assessed at baseline and 1 hour after 50 mg sildenafil, using transthoracic Doppler echocardiography. RESULTS: Baseline CFR was at the lower level of the normal range (median 245%, range 210 - 490%). AfterSildenafil Citrate (Viagra) administration, CFR decreased insignificantly (DeltaCFR -10%, p = 0.3). Patients with a BMI > 25 kg/m2 and left ventricular hypertrophy exhibited the highest reduction of CFR after sildenafil. No decrease of CFR below 200 % was observed. Systemic blood pressure dropped from 130/80 mmHg to 120/72 mmHg (p < 0.002). CONCLUSIONS: Diabetics with Erectile Dysfunction exhibit a CFR in the lower normal range indicating severe microvascular disturbance.Sildenafil Citrate (Viagra) did not alter CFR in those patients. A high prevalence of severe coronary macroangiopathy was identified in asymptomatic diabetic patients screened for contraindications forSildenafil Citrate (Viagra)

Sildenafil in the Treatment of SSRI-Induced Sexual Dysfunction: A Pilot Study.

BACKGROUND: Sexual dysfunction is a well-documented side effect of selective serotonin reuptake inhibitors (SSRIs). Commonly reported side effects include erectile impotence, anorgasmia, ejaculatory delay, pain, loss of sensation, and decreased pleasure. Early reports of the reversal of sexual dysfunction after usingSildenafil Citrate (Viagra) in male and female patients receiving various types and dosages of SSRIs are promising and prompted this study. Our aim was to evaluate the effects of oralSildenafil Citrate (Viagra) on reported secondary sexual dysfunction in patients concurrently treated with SSRIs. METHOD: Fourteen male patients who developed sexual dysfunction while receiving SSRIs were screened using the Arizona Sexual Experience (ASEX) scale. An electrocardiogram was obtained at the beginning and at the end of the study. Each patient was prescribedSildenafil Citrate (Viagra) tablets to be taken twice a week, 25-100 mg, prior to sexual activity and told to record the findings in a running diary which he was to keep during his treatment period. The patients were seen weekly and evaluated by clinical interview and ASEX scale. Patients were treated for a total of 8 weeks. RESULTS: All but 1 of the 14 patients experienced an improvement of sexual dysfunction, with 9 patients at the first dose of 25 mg and 4 at higher doses (3 at 50 mg and 1 at 75 mg). One patient required 100 mg to obtain minimal response. DISCUSSION:Sildenafil Citrate (Viagra) was shown to be helpful in the treatment of SSRI-induced sexual dysfunction. Three patients continued to experience ongoing positive effects after discontinuation of sildenafil; the other 10 patients relapsed

Sildenafil versus the vacuum erection device: patient preference.

PURPOSE: We evaluated the preference of patients with Erectile Dysfunction who had been effectively treated with a vacuum erection device and then switched to sildenafil. MATERIALS AND METHODS: A total of 52 patients with Erectile Dysfunction who achieved satisfactory erectile function according to the International Index of Erectile Function (IIEF) while using a vacuum erection device were switched to an increasing dose ofSildenafil Citrate (Viagra) (range 25 to 100 mg.) until satisfactory erection was maintained at least twice a week for at least 1 month. The 2 treatment methods were not used concomitantly. A total of 36 patients with a mean age of 59 years (range 35 to 77) who claimed to have achieved satisfactory erections with a vacuum erection device andSildenafil Citrate (Viagra) reported their preference to continueSildenafil Citrate (Viagra) or resume the use of a vacuum erection device, reasons for the choice and any adverse side effects. RESULTS: Of the 36 participants in whom the efficacy ofSildenafil Citrate (Viagra) was similar to that of a vacuum erection device according to the IIEF scores (mean plus or minus standard deviation 61.6 +/- 10.4 and 62.5 +/- 6, respectively), 12 (33.3%) decided to resume use of a vacuum erection device (group 1) while 24 (66.6%) preferred to continueSildenafil Citrate (Viagra) (group 2). There were no statistically significant differences between the groups regarding patient age or the etiology and duration of Erectile Dysfunction. The increase in the IIEF score while using a vacuum erection device was higher in group 1 than 2, with a mean of 66.75 versus 60.4, respectively (p = 0.002). The adverse side effects ofSildenafil Citrate (Viagra) were the main reasons for preferring a vacuum erection device. Fewer ejaculatory difficulties, efficacy, comfort and ease of use were the main reasons for choosing sildenafil. CONCLUSIONS: Even in an era of effective oral medication, the vacuum erection device remains a preferred treatment option for a substantial number of patients with Erectile Dysfunction

Sildenafil.

Case reports have documented the utility ofSildenafil Citrate (Viagra) for sexual dysfunction caused by selective serotonin-reuptake inhibitors (SSRIs) and have suggested its potential utility for women and men with various iatrogenic sexual dysfunctions. This brief review summarizes the psychopharmacology of sildenafil, discusses possible interactions with SSRIs, reviews side effects and risks, highlights the need for concomitant psychological counseling, reviews sildenafil's possible mechanisms of action for iatrogenic sexual dysfunctions, and suggests areas for future research