The effects of three phosphodiesterase type 5 inhibitors on ejaculation latency time in lifelong premature ejaculators: a double-blind laboratory setting study

Study Type – Therapy (RCT)
Level of Evidence 1b What’s known on the subject? and What does the study add? Several authors have reported their experience with PDE5 inhibitors alone or in combination with selective serotonin re‐uptake inhibitors for treating premature ejaculation. However, to our knowledge, this is the first laboratory design study to evaluate the effects of three PDE5 inhibitors throughout the ejaculation process in men with lifelong premature ejaculation. In this laboratory setting study PDE5 inhibitors seem to prolong ELT but the difference from placebo is significant only in vardenafil. The quality of penile rigidity is better with PDE5 inhibitors in the post‐ejaculatory period but the difference is significant only in sildenafil and vardenafil.

OBJECTIVE

? To evaluate the effects of three phosphodiesterase type 5 (PDE5) inhibitors on the ejaculation process in men with lifelong premature ejaculation using a double‐blind laboratory setting.

PATIENTS AND METHODS

? Eighty men with lifelong premature ejaculation, 20 in each group, received placebo, vardenafil (10 mg), sildenafil (50 mg) or tadalafil (20 mg) in a double‐blind study design. Placebo or PDE5 inhibitor was ingested after at least 2 h fasting and non‐smoking. The subjects were placed in a silent room immediately and real‐time penile rigidity and tumescence was monitored. ? Subjects read some magazines or newspapers without any sexually stimulating material for 1.5 h. At the end of this period audiovisual sexual stimulation began with a video film and after the 8th minute the subject began vibratory stimulation to the frenular area. ? At the beginning of ejaculation the patient stopped stimulation. When the patient began and stopped stimulation, the light near the observer turned on and off and the observer calculated the ejaculation period with a chronometer. The elapsed time was the ejaculation latency time (ELT) in seconds. ? There was no interaction between subjects and observer during the test. The ELT, and the qualities of base and tip rigidities during ELT and after ejaculation were calculated.

RESULTS

? Median age of patients was 29 (range 22–39) years and median duration of premature ejaculation was 60 (range 7–180) months and there was no significant difference between groups. Median duration of vibratory stimulation (ELT) of subjects who received placebo was 48.5 s: 53.5 s for sildenafil, 70.0 s for tadalafil and 82.5 s for vardenafil. Compared with the placebo group, ELT was significantly longer only in subjects receiving vardenafil (P = 0.019). ? In the post‐ejaculatory refractory period, times to last recorded base rigidities were significantly longer than placebo in vardenafil and sildenafil groups with better erection quality (P < 0.01 for each).

CONCLUSIONS

? The PDE5 inhibitors seem to prolong ELT and the quality of penile rigidity is better with PDE5 inhibitors in post‐ejaculatory period. ? These findings suggest that PDE5 inhibitors might have some beneficial effects in men with lifelong premature ejaculation.     

Long-term treatment of erectile dysfunction with a phosphodiesterase-5 inhibitor and dose optimization based on nocturnal penile tumescence

Associate Editor Michael G. Wyllie Editorial Board Ian Eardley, UK Jean Fourcroy, USA Sidney Glina, Brazil Julia Heiman, USA Chris McMahon, Australia Bob Millar, UK Alvaro Morales, Canada Michael Perelman, USA Marcel Waldinger, Netherlands

OBJECTIVE

To test the hypothesis that a variable dosage of the oral phosphodiesterase type 5 (PDE5) inhibitor sildenafil (25, 50, 100 mg) or vardenafil (5, 10, 25 mg) determined according to results obtained from nocturnal penile tumescence and rigidity (NPTR, RigiScan), given nightly for 1 year, can improve spontaneous erectile function (EF) in men with mild‐to‐moderate arteriogenic erectile dysfunction (ED); this regimen was compared with a fixed daily dosage of sildenafil 25 mg or vardenafil 5 mg.

PATIENTS AND METHODS

In a prospective open‐label, parallel‐group trial 154 men with ED were randomized either to fixed low‐dose sildenafil 25 mg or vardenafil 5 mg (group 1) or to the lowest erectile dosage of sildenafil (25, 50 or 100 mg) or vardenafil (5, 10 or 20 mg) (group 2) provoking an erectile event as measured by NPTR nightly for 1 year. The EF domain of the International Index of Erectile Function (IIEF) was assessed before and 1 year after the beginning of treatment, and at 4 weeks after ending treatment.

RESULTS

After 1 year, 27 of 63 (64%) evaluable men in group 1 had an EF domain score in the normal range, vs 46 of 61 (75%) men in group 2. After the subsequent 4‐week wash‐out phase, both groups continued to have improved EF domain scores; 22 of 63 (35%) men in group 1 still had a score in the normal range, whereas 38 of 61 (62%) in group 2 had a normal score. The EF domain score in group 1 and 2 improved significantly after 1 year of treatment, from 13.6 to 18.9, and 15.1 to 23.9, respectively (P < 0.01). After the subsequent 4‐week wash‐out phase, men from both groups maintained this significant level of EF, at 17.1 and 22.4, respectively (P < 0.05).

CONCLUSION

Nightly PDE5‐inhibitor treatment 1 year in a dosage determined by NPTR measurements results in better EF than giving a fixed dosage of sildenafil (25 mg) or vardenafil (5 mg). This improvement persisted for >4 weeks beyond the end of treatment. The results from this open‐label, randomized trial warrant verification under double‐blind, placebo‐controlled conditions.     

Efficacy and satisfaction rates of oral PDE5is in the treatment of erectile dysfunction secondary to spinal cord injury: a review of literature

Concept

Decreased sexual function is a major concern of men with spinal cord injuries (SCIs). Treatment of erectile dysfunction (ED) through oral pharmacotherapies has been proven to be an effective way to address and treat this concern.

Objective

To find an efficacious and satisfactory treatment ED secondary to SCI through the compilation of studies that utilized the International Index of Erectile Function (IIEF) when testing phosphodiesterase V inhibitors (PDE5i).

Method

Ten articles, which used the IIEF to study satisfaction and/or efficacy of PDE5is sildenafil, tadalafil, and vardenafil in the treatment of ED were reviewed and analyzed. Through the use of a self-made grading scale the value of each article was determined for this research.

Results

Sildenafil, tadalafil, and vardenafil all have been proven to be effective in treating ED in men with SCI. While sildenafil is the most thoroughly studied ED treatment for patients with SCI, tadalafil has a longer time duration effectiveness, which allows for more spontaneity in the sexual experience. Minimal adverse effects have been noted in patients with SCI using these medications; headache, flushing, and mild hypotension are the most common. In articles that study satisfaction, patients show great improvement over baseline with the use of these medications.

Conclusion

Although there is a need for further research on the safety in long-term use of tadalafil and vardenafil, comparative studies done on all three medications show no statistically significant difference in effectiveness or satisfaction. New medications and treatment options, such as avanafil, are being studied in hope of continued improvement of sexual function in men with SCI.     

An open-label, multicentre, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in men naïve to phosphodiesterase 5 inhibitor therapy

Associate Editor Michael G. Wylie Editorial Board Ian Eardley, UK Jean Fourcroy, USA Sidney Glina, Brazil Julia Heiman, USA Chris McMahon, Australia Bob Millar, UK Alvaro Morales, Canada Michael Perelman, USA Marcel Waldinger, Netherlands

OBJECTIVES

To compare treatment preference, efficacy, and tolerability of sildenafil citrate (sildenafil) and tadalafil for treating erectile dysfunction (ED) in men naïve to phosphodiesterase 5 (PDE5) inhibitor therapy.

PATIENTS AND METHODS

This was an open‐label, crossover study of sildenafil and tadalafil (taken as needed). After a 4‐week baseline assessment, 367 men with ED (mean age 54 years) were randomized to receive sildenafil for 12 weeks followed by tadalafil for 12 weeks or vice versa (8‐week dose optimization and 4‐week assessment phases). During dose optimization, patients started taking 25‐ or 50‐mg sildenafil or 10‐mg tadalafil and could titrate to find their optimum dose (25‐, 50‐ or 100‐mg sildenafil; 10‐ or 20‐mg tadalafil). After completing both 12‐week periods, patients chose which treatment to continue during an 8‐week extension. Efficacy was measured with the International Index of Erectile Function (IIEF) and Sexual Encounter Profile (SEP) diary.

RESULTS

Of the 291 men who completed both treatments, 85 (29%) chose sildenafil and 206 (71%) chose tadalafil (P < 0.001) for the 8‐week extension. The IIEF erectile function domain scores were 14.2 at baseline, 23.9 at endpoint on sildenafil, and 24.3 at endpoint on tadalafil (P = 0.08, sildenafil vs tadalafil). The mean per patient percentage success scores for SEP2 (penetration) were: baseline (46%), sildenafil (post‐baseline 82%) and tadalafil (post‐baseline 85%; P = 0.06, sildenafil vs tadalafil), and for SEP3 (successful intercourse) were: baseline (19%), sildenafil (post‐baseline 72%), and tadalafil (post‐baseline 77%; P = 0.003, sildenafil vs tadalafil). The only treatment‐emergent adverse events that were reported by >5% of men were headache and flushing.

CONCLUSIONS

In men with ED who were naïve to PDE5 inhibitor therapy, sildenafil and tadalafil were both effective and well tolerated. After treatment with sildenafil and tadalafil, 29% of men chose sildenafil and 71% chose tadalafil for ED therapy during an 8‐week extension.

     

cDNA microarray analysis of differentially expressed genes in penile tissue after treatment with tadalafil

OBJECTIVE

To evaluate differential gene expression in penile tissue after treatment with the phosphodiesterase 5 (PDE5) inhibitor tadalafil, as of the three clinically available PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) used for the treatment of erectile dysfunction (ED), tadalafil has a long half‐life and low incidence of side‐effects.

MATERIALS AND METHODS

In all, 32 adult rats were divided into two groups. The control group received 0.5 mL of drinking water alone, while the tadalafil group was treated with tadalafil at a dose of 0.27 mg/kg. At 4 h after treatment with water or tadalafil the rats were killed and the penile tissue was removed. The total RNA was isolated from the penile tissue from both groups and differentially expressed genes were identified by cDNA microarray analysis. To validate the expression data from the microarray analysis, quantitative real‐time polymerase chain reaction (PCR) and immunohistochemistry were used.

RESULTS

In all, 153 genes were differentially expressed between the control group and the tadalafil group. We validated the microarray results by quantitative PCR for the insulin‐like growth factor binding protein 6 (IGFBP‐6) gene and the neuronal calcium sensor 1 (NCS‐1) gene, both of which were up‐regulated in the tadalafil group, and for the natriuretic peptide receptor 1 (NPR‐1) gene that was down‐regulated in this group. Immunohistochemistry showed localization of the NCS‐1 protein in sinusoid trabeculae of the corpus cavernosum in control and tadalafil‐treated rats.

CONCLUSIONS

There was differential expression in 153 genes after tadalafil treatment. Some of these genes such as IGFBP‐6, NPR‐1 and NCS‐1, might result in new targets in the treatment of ED.     

Comparative Effectiveness and Safety of Oral Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction: A Systematic Review and Network Meta-analysis

Context

Phosphodiesterase type 5 inhibitors (PDE5-Is) are currently the first-line therapy for erectile dysfunction (ED), but available studies investigating the comparative effects of different PDE5-Is are limited.

Objective

To compare the efficacy and safety of different classes of oral PDE5-Is for ED.

Evidence acquisition

A systematic search was performed in PubMed, Cochrane Library, and Embase to identify randomized controlled trials that compared different PDE5-Is or PDE5-Is with a placebo for ED. The methodological quality of included studies was appraised with the Cochrane Collaboration bias appraisal tool, and the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation system.

Evidence synthesis

A total of 118 trials (31 195 individuals) were included. There was no major difference in the results between the traditional meta-analysis and the network meta-analysis. Network meta-analysis demonstrated that PDE5-Is were superior to placebo to improve erectile function. Compared with tadalafil (relative risk [RR]: 0.61; 95% confidence interval [CI], 0.33–0.90) and vardenafil (RR: 0.63; 95% CI, 0.35–0.92), avanafil was less effective on Global Assessment Questionnaire question 1. Tadalafil was more effective than vardenafil (mean difference [MD]: 1.49; 95% CI, 0.50–2.50) and udenafil (MD: −1.84; 95% CI, −3.31 to −0.33) as measured by the erectile function domain of the International Index of Erectile Function. For all efficacy outcomes, the absolute effects and the rank tests indicated that tadalafil and vardenafil were the most effective agents. After adjusting for dosage, the conclusion remained the same. Safety analysis showed there was no major difference among different agents.

Conclusions

In recommended doses, oral PDE5-Is are more effective than placebo for ED, and tadalafil seems to be the most effective agent, followed by vardenafil. PDE5-Is are generally safe and well tolerated, and there is no major difference on the safety profile.     

In vivo and in vitro response of corpus cavernosum to phosphodiesterase-5 inhibition in the hypercholesterolaemic rabbit

OBJECTIVE

To investigate the effects of hypercholesterolaemia (HC) on rabbit corpus cavernosa in vivo and in vitro, and evaluate the efficacy of vardenafil and sildenafil in normal and HC rabbits, as the phosphodiesterase‐5 (PDE‐5) inhibitors vardenafil and sildenafil are widely used for treating erectile dysfunction (ED) and most organic causes of ED are associated with vascular risk factors like HC.

MATERIALS AND METHODS

Male New Zealand White rabbits were randomly divided into two groups; 11 HC rabbits were fed a 2% cholesterol diet, and 12 age‐matched control rabbits received a regular diet. After 12–14 weeks, erectile responses to intravenous sodium nitroprusside (SNP) and PDE‐5 inhibitors were evaluated for 2 h in conscious rabbits. Penile length was measured and the area under the curve calculated. Relaxant responses of corpus cavernosal strips to electrical‐field stimulation (EFS) were measured before and after exposure to PDE‐5 inhibitors and the nitric oxide synthase inhibitor N′‐nitro‐ l ‐arginine methyl ester.

RESULTS

HC rabbits had a lower erectile response to SNP than controls; in both control and HC rabbits there was a greater erectile response after simultaneous exposure to SNP and vardenafil, or SNP and sildenafil. However, the responses of the HC rabbits were still significantly less than those of the controls. Corpora from control rabbits responded to EFS with greater relaxations at all frequencies, except 1 Hz. Corpora from both HC and control rabbits had greater responses to EFS after exposure to vardenafil and sildenafil; N′‐nitro‐ l ‐arginine methyl ester diminished the response to EFS.

CONCLUSIONS

There was a significantly lower in vivo and in vitro erectile response in HC rabbits than in controls; erectile function measured in conscious rabbits can be used to assess quantitatively the efficacy of different agents, e.g. sildenafil and vardenafil, in pathological animals. In addition, both agents improve in vitro responses of erectile tissue from HC rabbits to EFS.

     

Phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction in patients with diabetes mellitus

Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has become a first-line therapy for diabetic patients with erectile dysfunction (ED). The efficacy in this subgroup, based on the Global Efficacy Question, is 56% vs 84% in a selected group of non-diabetic men with ED. Two novel PDE5 inhibitors, tadalafil (Lilly ICOS) and vardenafil (Bayer), have recently completed efficacy and safety clinical trials in 'general' and diabetic study populations and are now candidates for US FDA approval. A summary analysis of the phase three clinical trials of sildenafil, tadalafil and vardenafil in both study populations is presented to provide a foundation on which the evaluation of the role of the individual PDE5 inhibitors for the treatment of patients with ED and DM can be built.     

Evidence for contamination of herbal erectile dysfunction products with phosphodiesterase type 5 inhibitors

PURPOSE: We determined if pharmacological dosages of phosphodiesterase type 5 inhibitors (PDE5) inhibitors were present within a group of natural products marketed for the treatment of erectile dysfunction. MATERIALS AND METHODS: Seven herbal products marketed for the treatment of erectile dysfunction were purchased via the Internet or at local health food stores. Specimens were batched, relabeled and blindly analyzed for contamination with PDE5 inhibitors. High performance liquid chromatography and mass spectrometry were used to detect evidence of contamination with sildenafil, tadalafil or vardenafil. RESULTS: Of the 7 tested products 2 contained pharmacological dosages of sildenafil and tadalafil. Contamination with vardenafil was not identified. Mean dosages of sildenafil and tadalafil were 30.2 and 19.7 mg, respectively. CONCLUSIONS: A significant proportion of natural products marketed for erectile dysfunction contains PDE5 inhibitors. Although marketed as natural products devoid of adverse effects, these agents are known to have potentially fatal drug interactions with nitrates. Better regulation of the natural health products industry is urged.     

Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study

Study Type – Therapy (cohort)
Level of Evidence 2b What’s known on the subject? and What does the study add? Phosphodiesterase type‐5 (PDE5) inhibitors (tadalafil, vardenafil, and sildenafil) are well‐known treatment options for men with erectile dysfunction and should be taken before anticipated sexual activity. Tadalafil is also approved for once daily use in men with erectile dysfunction. Recent 12‐week studies in men with benign prostatic hyperplasia (BPH) have shown once daily use of tadalafil significantly reduced their urinary symptoms. This article is the first to report the long‐term safety and maintenance of efficacy for once‐daily use of tadalafil in men with urinary symptoms secondary to BPH.

OBJECTIVE

? To evaluate the 1‐year safety of 5 mg of tadalafil once daily in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH‐LUTS); efficacy measures were included to evaluate the maintenance of efficacy after an additional year of treatment.

PATIENTS AND METHODS

? In total, 427 men who completed a 12‐week, placebo‐controlled, dose‐ finding study assessing once‐daily tadalafil (2.5, 5, 10 or 20 mg) or placebo elected to continue into the open‐label extension period. Safety and efficacy parameters were assessed after 1 month and every 3 months.

RESULTS

? In total, 299 patients (69.9%) completed the 1‐year, open‐label extension period. Treatment‐emergent adverse events (TEAEs) were reported by 57.6% of patients, with most TEAEs being mild (44%) or moderate (45%) in severity; the most common TEAEs (≥2%) were dyspepsia, gastro‐oesophageal reflux disease, back pain, headache, sinusitis, hypertension and cough. Twenty‐two patients (5.2%) discontinued as a result of AEs. During the open‐label extension period, mean prostate‐specific antigen increased from 1.6 ± 1.3 ng/mL to 1.8 ± 1.4 ng/mL. ? Mean post‐void residual volume was 61.1 ± 60.4 mL at study entry and 42.2 ± 64.1 mL after the open‐label extension period. Changes in the total International Prostate Symptom Score (IPSS), IPSS irritative and obstructive subscores, IPSS health‐related quality of life and BPH Impact Index were maintained after 1 year. In sexually‐active patients with erectile dysfunction, improvements in the International Index of Erectile Function–Erectile Function domain were maintained after 1 year.

CONCLUSION

? In men with BPH‐LUTS, 5 mg of tadalafil once daily during 1 year of treatment was well tolerated and efficacy changes were maintained.     

Molecular pharmacotherapeutic targeting of PDE5 for preservation of penile health

The molecular science of erection physiology has established that phosphodiesterase 5 (PDE5) serves an important biological role in the penis. Current research in the field has revealed this molecular effector to be relevant for penile erection, controlling the erectile response by degrading the second messenger product of the erection mediatory nitric oxide (NO) signaling pathway, 3', 5'-cyclic guanosine monophosphate. Accordingly, PDE5 has been targeted for sexual medicine purposes, and orally administered PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil comprise a foremost intervention for erectile dysfunction (ED). New investigation of PDE5 regulation in the penis has suggested alternative roles for the enzyme and new therapeutic opportunities involving its molecular interactions. In particular, PDE5 function is altered under derangements of androgen deficiency, decreased NO bioactivity, and oxidative stress-associated inflammatory changes, thus contributing to an assortment of erectile disorders including hypogonadism-associated ED, recurrent ischemic priapism, penile vasculopathy, and penile fibrosis. This review provides a critical examination of the multifaceted role of the PDE5 regulatory system in the penis and its relevance for applying existing and emerging therapeutic strategies for erectile disorders.     

Bedeutung von Phosphodiesteraseisoenzymen in der Kontrolle der humanen Detrusormuskulatur

Objectives

The use of inhibitors of phosphodiesterase (PDE) isoenzymes 1 and 5 to treat overactive bladder has been suggested. To further evaluate the significance of PDE isoenzymes in detrusor smooth muscle relaxation, we investigated the effects of selective PDE inhibitors on the tension induced by carbachol of isolated human detrusor tissue. Using immunohistochemical methods, the expression of PDE1, PDE4, and PDE5 in human detrusor was also investigated.

Material and Methods

The expression of PDE1, PDE4, and PDE5 was evaluated by means of conventional immunohistochemistry (IHC). Using the organ bath technique, the effects of the PDE inhibitors vinpocetine, rolipram, sildenafil, tadalafil, and vardenafil on the tension induced by the muscarinic agonist carbachol (1 µM) were investigated.

Results

The tension induced by carbachol was dose-dependently reversed by the PDE inhibitors; the maximum reversal of tension ranged from 7% (tadalafil) to 34% (vardenafil). IHC revealed that the expression of PDE isoenzymes was limited to the smooth musculature of the detrusor. While there was prominent expression of PDE4 and PDE5, immunoreactions indicating the presence of PDE1 were less abundant.

Conclusion

Despite the fact that inhibitors of PDE1, PDE4, and PDE5 exerted only a weak relaxant response on detrusor strips precontracted by carbachol, our findings indicate that both the cAMP and cGMP pathways might be involved in the relaxation mechanism of human detrusor smooth muscle.     

Oral Agents: First-Line Therapy for Erectile Dysfunction

Oral agents are relatively non-invasive, reversible, readily administered and well tolerated; hence, they are emerging as first-line treatments for patients with erectile dysfunction. Two medications have been licensed in Europe: the dopamine agonist sublingual apomorphine, which influences central regulatory mechanisms, and the phosphodiesterase type 5 (PDE5) inhibitor sildenafil citrate, which affects local regulation of erectile function by potentiating the effects of nitric oxide. Two other potent, selective, reversible PDE5 inhibitors (tadalafil and vardenafil) are under regulatory review in Europe, the United States and other countries. In double-blind, placebo-controlled trials, these compounds significantly enhanced erectile function and increased the likelihood of successful sexual intercourse largely irrespective of etiology or severity of erectile insufficiency. Apomorphine and PDE5 inhibitors also significantly improved scores in the erectile function, orgasmic function, intercourse satisfaction and overall satisfaction domains of the International Index of Erectile Function. Oral agents were well tolerated; adverse events were generally mild or moderate, prompting premature treatment discontinuation in a small minority of patients. The chief adverse effects with apomorphine were nausea and headache, and with PDE5 inhibitors, headache, dyspepsia and flushing. Because of a potential pharmacodynamic interaction between PDE5 inhibitors and nitrates or nitric oxide donors that has been associated with hypotension, concomitant nitrate use is an absolute contraindication. However, the actual incidences of myocardial infarction in sildenafil and tadalafil patients are similar to those in placebo controls.     

Effects of the recreational use of PDE5 inhibitors on the corpus cavernosum of young,healthy rats

Purpose

PDE5 inhibitors are widely used for the treatment of erectile dysfunction. However, these drugs have recently become popular among men without erectile dysfunction as a means of enhancing sexual performance and improving sexual desire. The aim of this study was to investigate the histopathological and ultrastructural effects of PDE5 inhibitors on the corpus cavernosum in young, healthy male rats.

Methods

Twenty-four 4-month-old male rats were divided into four groups: group 1 was the control group, group 2 rats received sildenafil citrate, group 3 rats received vardenafil hydrochloride, and group 4 rats received tadalafil. All drugs were administered for 4 weeks. Penile tissue was collected for electron microscopy and tissue collagen measurements. Electron microscopic analysis indicated that the number of active fibroblasts and macrophages and the synthesis of new collagen fibers increased in treated rats.

Results

Cavernous tissue collagen levels were significantly higher in the sildenafil-, vardenafil-, and tadalafil-treated groups than in controls (46.16 ± 4.9, 42.06 ± 2.4, 41.07 ± 2.4, and 29.20 ± 3.3, respectively) (p < 0.001).

Conclusions

Young men who use these drugs to enhance performance in the absence of erectile dysfunction may experience irreversible damage to the cavernosal tissue. However, more studies are needed to evaluate the molecular mechanisms by which PDE5 inhibitors affect the corpus cavernosum.     

Sildenafil improves nocturnal penile erections in organic impotence.

We studied the effects of sildenafil on nocturnal penile erections. We prospectively evaluated 36 patients with organic or psychogenic impotence and 5 normal, potent men. All patients completed 3 sessions of consecutive nights using the RigiScan Plus device. The first two nights the patients were asked to take placebo before the session and to take 50 mg of sildenafil before the third session. In the organic impotence group the use of sildenafil induced a significant improvement in time of rigidity 60-100%, rigidity and tumescence activity unit values and rigidity and tumescence activity unit values per hour in the tip and base. In the psychogenic impotence group it caused significant improvement only in rigidity activity unit per hour in the tip. In the potent men, changes were statistically insignificant. Sildenafil improves nocturnal penile erectile activity in organic impotence. Our study shows that phosphodiesterase inhibitors can improve penile erections not induced by sexual stimulation.     

Differences in side‐effect duration and related bother levels between phosphodiesterase type 5 inhibitors

OBJECTIVE

To assess whether the longer half‐life of tadalafil is associated with longer lasting or more severe side‐effects than the other phosphodiesterase type 5 inhibitors (PDE‐5Is), as clinical trials have shown that the efficacy and safety of the three available are similar, but tadalafil has a half‐life four times longer than the other two drugs.

PATIENTS AND METHODS

Treatment‐naive men beginning PDE5‐I therapy were recruited from a specialist clinic. Data on the type and duration of drug‐associated side‐effects were collected prospectively. Levels of bother were assessed with a visual analogue scale (VAS). Differences in type, duration and bother of side‐effect were compared between drugs.

RESULTS

In all, 409 men provided data; there were no differences between drugs in the proportion of men responding, or the overall prevalence of side‐effects. The mean duration of side‐effects with tadalafil was 14.9 h, compared to 3.9 and 7.7 h for sildenafil and vardenafil. Of men taking tadalafil, 30% had side‐effects lasting >12 h. There were no differences in mean VAS scores between the drugs. Individual side‐effects caused similar levels of bother, except for facial flushing, which was less bothersome.

CONCLUSIONS

Men taking tadalafil are at risk of prolonged side‐effects, although levels of bother associated with these side‐effects are not significantly greater than those seen with short‐acting PDE5‐Is.     

Indirect comparison of interventions using published randomised trials: systematic review of PDE-5 inhibitors for erectile dysfunction

Background

There are no randomised and properly blinded trials directly comparing one PDE-5 inhibitor with another in a normal home setting. Valid indirect comparisons with a common comparator must examine equivalent doses, similar duration, similar populations, with the same outcomes reported in the same way.

Methods

Published randomised, double-blind trials of oral PDE-5 inhibitors for erectile dysfunction were sought from reference lists in previous reviews and electronic searching. Analyses of efficacy and harm were carried out for each treatment, and results compared where there was a common comparator and consistency of outcome reporting, using equivalent doses.

Results

Analysis was limited by differential reporting of outcomes. Sildenafil trials were clinically and geographically more diverse. Tadalafil and vardenafil trials tended to use enriched enrolment. Using all trials, the three interventions were similar for consistently reported efficacy outcomes. Rates of successful intercourse for sildenafil, tadalafil and vardenafil were 65%, 62%, and 59%, with placebo rates of 23–28%. The rates of improved erections were 76%, 75% and 71%, respectively, with placebo rates of 22–24%, and NNTs of 1.9 or 2.0. Reporting of withdrawals was less consistent, but all-cause withdrawals for sildenafil, tadalafil and vardenafil were 8% 13% and 20%. All three drugs were well tolerated, with headache being the most commonly reported event at 13–17%. There were few serious adverse events.

Conclusion

There were differences between trials in outcomes reported, limiting comparisons, and the most useful outcomes were not reported. For common outcomes there was similar efficacy between PDE-5 inhibitors.     

Erektile Dysfunktion

Erectile dysfunction (ED) tends to be associated with other diseases, the common basis of which is endothelial dysfunction. ED is also frequently combined with LUTS and the common basis for both conditions seems to be elevation of Rho-kinase activity and decrease of NO concentration. Because all three PDE 5 inhibitors sildenafil, tadalafil, and vardenafil have a common mode of action, i.e., inhibition of PDE 5, they are not different in terms of their efficacy and safety profile except for color vision disturbances which are more common after sildenafil and back pain/myalgia more often observed after tadalafil. The main differentiating characteristics among the three PDE 5 inhibitors are their pharmacokinetics. These are ultimately responsible for the observation that in head-to-head comparative trials depending on the respective study design the overwhelming majority of the patients opted either for tadalafil as the longest acting PDE 5 inhibitor (36 h) or for vardenafil as a relatively rapidly acting drug.All published studies so far have shown that in terms of the cardiovascular risk profile (myocardial infarction rate) all three PDE 5 inhibitors performed better than placebo although the results were not statistically significant. Without any exception it applies to all three PDE 5 inhibitors that they are absolutely contraindicated in patients taking nitrate- or molsidomine-containing medications and that they may interact in particular with non-uroselective alpha-adrenoceptor blockers. This is why their simultaneous application with PDE 5 inhibitors has to be avoided.In the near future chronic (daily) application of a PDE 5 inhibitor may show advantages, at least in those 50-60% of all patients in whom there is a high likelihood of endothelial dysfunction due to the diagnostic (penile duplex Doppler) outcome. Possible new developments in the management of ED with a time frame of 5-8 years until their market approval are guanylate cyclase activators, Rho-kinase inhibitors, melanocortin receptor agonists, gene therapy, and tissue engineering.