BACKGROUNDThere is currently considerable interest in the potential value of selective inhibitors of cyclic nucleotide phosphodiesterase 4 in the treatment of asthma. However, whether they influence eosinophilic airway inflammation-associated cough remains unclear. The objective of this study was to investigate the effects of selective phosphodiesterase 4 inhibitor SB207499 on cough response and airway inflammation in guinea pigs sensitized and challenged with ovalbumin.

METHODSForty sensitized guinea pigs were randomly divided into four groups: control (n = 10), challenge (n = 10), SB207499 (n = 10) and aminophylline (n = 10), then challenged with aerosol of 1% ovalbumin or saline. Two hours later, animals were intraperitoneally injected with either saline, 25 mg/kg of SB207499 or aminophylline. At the 24th hour, the injection was repeated with 2.5 mg/kg and 25 mg/kg SB207499 or aminophylline, then cough response to inhaled capsaicin and airway responsiveness to methacholine inducing a 150% of the peak airway pressure to the baseline (PC150) was measured. Finally, total cell number and differentials in bronchoalveolar lavage fluid were analysed.

RESULTSThe cough frequency per 3 minutes and PC150 in the challenge group were (22 +/- 4) times/3 minutes and (198 +/- 54) microg/ml, which were significantly different from (6 +/- 2) times/3 minutes and (691 +/- 81) microg/ml in the control group (P < 0.05, respectively). The injection of 25 mg/kg SB207499 significantly inhibited the increased cough response and airway hyperresponsiveness, the cough frequency and PC150 in guinea pigs were (13 +/- 2) times/3 minutes and (680 +/- 81) microg/ml (P < 0.05), which differed significantly from (18 +/- 2) times/3 minutes and (400 +/- 86) microg/ml after the administration of the same dose of aminophylline (P < 0.05). The inhibition of SB207499 on cough response was dose-dependent. Similarly, SB207499 decreased the total cell number and percentage of eosinophils in bronchoalveolar lavage fluid to (2.1 +/- 0.5) x 10(6)/ml and (20 +/- 5)% respectively, which were significantly different from (3.2 +/- 0.5) x 10(6)/ml and (29 +/- 5)% in the aminophylline group (P < 0.05, respectively) or (4.2 +/- 0.7) x 10(6)/ml and (35 +/- 4)% in the challenge group (P < 0.05, respectively).

CONCLUSIONPhosphodiesterase 4 inhibitor may be more useful than aminophylline for cough associated with eosinophilic airway inflammation via inhibiting airway inflammation and airway hyperresponsiveness.

3',5'-Cyclic-AMP Phosphodiesterases ; antagonists & inhibitors ; Animals ; Bronchial Hyperreactivity ; drug therapy ; Bronchoalveolar Lavage Fluid ; cytology ; Cough ; drug therapy ; Cyclic AMP ; biosynthesis ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Cyclohexanecarboxylic Acids ; therapeutic use ; Dose-Response Relationship, Drug ; Guinea Pigs ; Male ; Nitriles ; Ovalbumin ; immunology ; Phosphodiesterase Inhibitors ; therapeutic use

DA-8159, a selective inhibitor of phosphodiesterase type 5, was developed as a new drug for erectile dysfunction. The effect of DA-8159 on the electroretinogram (ERG) and the retinal histopathology were evaluated in rabbits. The ERG was performed prior to, and 1 and 5 hr after DA-8159 (5 to 30 mg/kg) administration. The plasma concentration of DA-8159 was determined at each time point, and retinal microscopic examination was also performed. There was no statistically significant ERG change at any dose or at any time. Though the 30 Hz flicker showed a prolongation of the implicit time at 5 hr after the administration of either DA-8159 15 mg or 30 mg/kg (p<0.05), but concurrent amplitude decreases were not statistically significant. At a dose of 5 mg/kg, no test drug was detected in the blood after either 1 or 5 hr. At either 15 mg/kg or 30 mg/kg, there was a dose-dependent increase in the blood concentration after 1 hr of drug administration, which decreased with time. In light and electron microscopic examinations of the retina, there was no remarkable change at any dose. These results suggest DA-8159 has a low risk potential to the retina, but further evaluation on the visual functions in human is needed.
3',5'-Cyclic-GMP Phosphodiesterase/*antagonists & inhibitors ; Animals ; Dose-Response Relationship, Drug ; Electroretinography/*drug effects ; Humans ; Male ; Phosphodiesterase Inhibitors/blood/*pharmacology ; Pyrimidines/blood/*pharmacology ; Rabbits ; Retina/*cytology/*drug effects

Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a variety of physiological and pathophysiological processes by mediating the hydrolysis of intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate. In recent years, a series of researches suggest that PDE inhibitors such as several PDE4 inhibitors, PDE5 inhibitors (sildenafil, tadalafil and vardenafil), PDE3 inhibitors (cilostazol), PDE9 inhibitor (PF-04447943) and PDE3/PDE4 double inhibitor (pumafentrine) have ameliorating effect on experimental colitis in animals. In clinical trials, PDE4 inhibitor apremilast showed more therapeutic advantage than tetomilast. This article reviews the recent research progress of PDE inhibitors in treatment of inflammatory bowel disease.
Animals ; Colitis ; Inflammatory Bowel Diseases/drug therapy* ; Phosphodiesterase 4 Inhibitors

PURPOSE: To compare the clinical efficacy and safety of three phosphodiesterase type 5 (PDE5) inhibitors in the treatment of mele erectile dysfunction according to patient preference. MATERIALS AND METHODS: Between January 2004 and August 2005, 113 male erectile dysfunctional patients were enrolled to this randomized, prospective, comparative, open-label, triple-crossover study of three PDE5 inhibitors. Patients were assigned to one of six medication schedules, and were prescribed a full dose of the drugs for 8 weeks, with a week of washout period prior to the next drug cycle. The International Index of Erectile Function (IIEF) scores and side effects related with each medication were obtained at the end of study. 48 patients finished all the medications, and completed the study with a global assessment questionnaire on their drug preference and reasons for that preference. RESULTS: The mean age of the patients was 54.6 (33-73) years. The mean pre-treatment IIEF and EF domain scores (+/-S.D.) were 28.2+/-14.7 and 10.6+/-6.6, respectively. The scores were significantly improved, to 47.9+/-14.6 and 19.9+/-6.6 with sildenafil, to 49.7+/-12.3 and 21.3+/-5.8 with vardenafil, and to 47.9+/-14.9 and 19.8+/-7.2 with tadalafil (p < 0.01). There were no significant differences in the scores or frequencies of side effects between the drugs. The preference percentages were 29.2, 29.2 and 35.4% for sildenafil, vardenafil and tadalafil, respectively. Patient preference was mainly due to improvement in erectile function (70.9%), such as rigid erection, prolonged erection and fast erection, and not to the infrequent rate of side effects (20.8%). CONCLISIONS: There were no significant differences of the efficacy and safety among the three PDE5 inhibitors. The preference for a drug for the treatment of erectile dysfunction was mainly related to the efficacy on the improvement of erectile function rather than the less frequent side effects.
Appointments and Schedules ; Erectile Dysfunction* ; Humans ; Male ; Patient Preference* ; Phosphodiesterase 5 Inhibitors* ; Phosphodiesterase Inhibitors ; Prospective Studies ; Questionnaires

In February 2011, the Korean Society for Sexual Medicine and Andrology (KSSMA) realized the necessity of developing a guideline on erectile dysfunction (ED) appropriate for the local context, and established a committee for the development of a guideline on ED. As many international guidelines based on objective evidence are available, the committee decided to adapt these guidelines for local needs instead of developing a new guideline. Considering the extensive research activities on ED in Korea, data with a high level of evidence among those reported by Korean researchers have been collected and included in the guideline development process. The latest KSSMA guideline on ED has been developed for urologists. The KSSMA hopes that this guideline will help urologists in clinical practice.
Andrology ; Erectile Dysfunction ; Korea ; Male ; Phosphodiesterase 5 Inhibitors

A multi-center, randomized, double-blind, placebo-controlled study was conducted with 158 subjects who were randomized to placebo or avanafil 50, 100, and 200 mg on demand for 8 weeks to evaluate the safety, tolerability, and efficacy of avanafil in the treatment of erectile dysfunction (ED) in Korean men. The primary outcome was the erectile function (EF) domain score of the International Index of Erectile Function (IIEF) questionnaire. Secondary outcomes included changes in the scores of IIEF questions 3 and 4 (IIEF Q3, Q4) from baseline, changes in all domain scores in the IIEF from baseline, Sexual Encounter Profile questions 2–5 (SEP2–5), the Global Efficacy Assessment Question (GEAQ), and the number of subjects whose EF domain score at the 8th week visit was ≥ 26. After 8 weeks of treatment, the dose groups except avanafil 50 mg scored significantly higher on the IIEF-EF domain from baseline than the placebo group. The changes from baseline in the avanafil group in IIEF Q3 (all doses) and Q4 (200 mg alone) were higher than the placebo group. The differences between avanafil and placebo groups were significant in SEP2 (100 and 200 mg) and SEP3–5 (200 mg). The differences in the GEAQ “Yes” response were also significant in the avanafil 100 and 200 mg groups. Regarding the ratio of normal EF at the end of the study, avanafil 200 mg differed significantly from the placebo. Most treatment-associated adverse events were mild and resolved spontaneously. This is a clinical trial study and was registered at www.ClinicalTrials.gov (Identifier: NCT02477436).
Erectile Dysfunction* ; Humans ; Male ; Penile Erection ; Phosphodiesterase 5 Inhibitors

Current available treatment options for erectile dysfunction (ED) are effective but not without failure and/or side effects. Although the development of phosphodiesterase type 5 (PDE5) inhibitors (i.e. sildenafil, tadalafil and vardenafil) has revolutionized the treatment of ED, these oral medications require on-demand access and are not as effective in treating ED related to diabetic, post-prostatectomy and severe veno-occlusive disease states. Improvement in the treatment of ED is dependent on understanding the regulation of human corporal smooth muscle tone and on the identification of relevant molecular targets. Future ED therapies might consider the application of molecular technologies such as gene therapy. As a potential therapeutic tool, gene therapy might provide an effective and specific means for altering intracavernous pressure "on demand" without affecting resting penile function. However, the safety of gene therapy remains a major hurdle to overcome before being accepted as a mainstream treatment for ED. Gene therapy aims to cure the underlying conditions in ED, including fibrosis. Furthermore, gene therapy might help prolong the efficacy of the PDE5 inhibitors by improving penile nitric oxide bioactivity. It is feasible to apply gene therapy to the penis because of its location and accessibility, low penile circulatory flow in the flaccid state and the presence of endothelial lined (lacunar) spaces. This review provides a brief insight of the current role of gene therapy in the management of ED.
3',5'-Cyclic-GMP Phosphodiesterases ; antagonists & inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Erectile Dysfunction ; drug therapy ; genetics ; therapy ; Gene Transfer Techniques ; Genetic Therapy ; adverse effects ; Humans ; Male ; Phosphodiesterase Inhibitors ; therapeutic use ; Vasodilator Agents ; therapeutic use

Phosphodiesterase type 5 (PDE5) inhibitors are used most commonly in the treatment of penile erectile dysfunction (ED). Recent studies show that PDE5 inhibitors are ideal drugs for treating ischemia-reperfusion injury. This review focuses on the results of basic and clinical researches on PDE5 inhibitors for the treatment of ischemia-reperfusion injury and provides some theoretical evidence for clinical options of the drugs.
Erectile Dysfunction ; drug therapy ; Humans ; Male ; Phosphodiesterase 5 Inhibitors ; therapeutic use ; Phosphodiesterase Inhibitors ; therapeutic use ; Reperfusion Injury ; drug therapy

OBJECTIVETo observe and compare the effects and adverse events of the three phosphodiesterase type 5 (PDE-5) inhibitors sildenafil, vardenafil and tadalafil used in the same period for the treatment of erectile dysfunction (ED).

METHODSA total of 311 ED patients were treated with the three PDE-5 inhibitors in the same period, 134 with sildenafil, 109 with vardenafil and 88 with tadalafil, and followed up for 2-11 months. Their effects were compared.

RESULTSSildenafil produced satisfactory effect in 72 patients (79.12%), vardenafil in 63 (81.81%) and tadalafil in 52 (78.78%), respectively. And the efficacy rates of sildenafil, vardenafil and tadalafil in the treatment of ED with premature ejaculation were 55.56%, 44.44% and 42.3%, respectively. Our study also showed that the young and the newly married preferred vardenafil, the middle-aged chose tadalafil and the older and long-term users tend to take sildenafil. The main reasons for discontinuing the use of the three inhibitors were their high price, incomplete effect and the patients' worry about their adverse action.

CONCLUSIONThe three PDE-5 inhibitors can produce basically similar effects on ED, all with safety and few mild adverse events.

Adult ; Erectile Dysfunction ; drug therapy ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Phosphodiesterase 5 Inhibitors ; Phosphodiesterase Inhibitors ; administration & dosage

Phosphodiesterase (PDE) 4 inhibitors have been shown to induce the cAMP-mediated signaling pathway by inhibiting cAMP hydrolysis. This study investigated the effect of a PDE4 inhibitor on the expression of the inducible cAMP early repressor (ICER), which is an endogenous inhibitor of CRE- mediated transcription, in osteoblastic cells. RT-PCR analysis revealed that rolipram, a PDE4 inhibitor, stimulates the ICER mRNA in a dose dependent manner. The induction of ICER mRNA expression by rolipram was suppressed by the inhibitors of protein kinase A (PKA) and p38 MAPK, suggesting the involvement of PKA and p38 MAPK activation in ICER expression by rolipram. It was previously shown that rolipram induced the expression of TNF-related activation-induced cytokine (TRANCE, also known as RANKL, ODF, or OPGL) in osteoblasts. This paper provides evidences that a transcriptional repressor like ICER might modulate TRANCE mRNA expression by rolipram in osteoblasts.
3', 5'-Cyclic-Nucleotide Phosphodiesterase/*antagonists & inhibitors ; Animals ; Animals, Outbred Strains ; Cyclic AMP-Dependent Protein Kinases/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Gene Expression/drug effects ; Mice ; Osteoblasts/*drug effects/metabolism ; Phosphodiesterase Inhibitors/*pharmacology ; Research Support, Non-U.S. Gov't ; Rolipram/*pharmacology ; Transcription Factors/genetics/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism