The effect of Sildenafil, a phosphodiesterase-5 inhibitor, on tendon healing: an experimental study in rat model of achilles tendon injury.

INTRODUCTION: Sildenafil Citrate has various effects on the body, including widening blood vessels, inhibiting platelet aggregation, promoting the growth of blood vessels, stimulating apoptosis and adhesion of fibroblasts, and reducing inflammation. This research aims to explore how Sildenafil Citrate affects surgically treated Achilles tendons, both in terms of tissue structure and mechanical properties. MATERIALS AND METHODS: Forty-eight Wistar-albino rats weighing 350-400 g were randomly divided into groups, 6 in each group, as the study group was given Sildenafil Citrate and the control group given saline, respectively. The Achilles tendon rupture model was created under ketamine and xylazine anesthesia. During the entire experiment, rats were housed in eight separate cages, six of them each. The study group and control group of the first group were sacrificed at the end of 1 week, and Achilles tendon samples were taken. After that, Achilles tendon samples were taken after sacrificing the second group at 14 days, the third group at 21 days, and the fourth group at 28 days, respectively. Neovascularization, inflammation, fibrosis and fibroblastic activities of the harvested Achilles tendons were evaluated histopathologically. Biomechanically, stretching was applied to the Achilles tendons and continued until the tendon ruptured. the maximum force values at the moment of rupture were calculated. RESULTS: The mean maximum strength value of group T21, which was given sildenafil citrate for 21 days, was 31.1 ± 4.36 N, and the mean maximum strength value of group C21, which was the control group, was 20.56 ± 6.92 N. A significant difference was observed between the groups (p: 0.008). Group T28 (45.17 ± 5.54 N) also demonstrated greater strength than group C28 (34.62 ± 3.21 N) in the comparison (p: 0.004). The study also noted significant differences between the groups in neovascularization, in the first week, 1 mild, 3 moderate and 2 prominent neovascularization was observed in group T7, in group T28, moderate neovascularization was observed in 4 specimens and prominent neovascularization was observed in 2 specimens (p: 0.001). Furthermore, the groups showed significant differences in their levels of fibrosis, inflammation and fibroblastic proliferation (p: 0.017, p: 0.036, (p: 0.035) respectively). CONCLUSIONS: Study has demonstrated that sildenafil citrate can enhance the biomechanical and histopathological aspects of tendon healing, resulting in a stronger tendon.

Effect of phosphodiesterase-5 inhibition on SystEmic Right VEntricular size and function. A multicentre, double-blind, randomized, placebo-controlled trial: SERVE.

AIMS: In adults with congenital heart disease and systemic right ventricles, progressive right ventricular systolic dysfunction is common and is associated with adverse outcomes. Our aim was to assess the impact of the phosphodiesterase-5-inhibitor tadalafil on right ventricular systolic function. METHODS AND RESULTS: This was a double-blind, randomized, placebo-controlled, multicentre superiority trial (NCT03049540) involving 100 adults with systemic right ventricles (33 women, mean age: 40.7 ± 10.7 years), comparing tadalafil 20 mg once daily versus placebo (1:1 ratio). The primary endpoint was the change in right ventricular end-systolic volume after 3 years of therapy. Secondary endpoints were changes in right ventricular ejection fraction, exercise capacity and N-terminal pro-B-type natriuretic peptide concentration. Primary endpoint assessment by intention to treat analysis at 3 years of follow-up was possible in 83 patients (42 patients in the tadalafil group and 41 patients in the placebo group). No significant changes over time in right ventricular end-systolic volumes were observed in the tadalafil and the placebo group, and no significant differences between treatment groups (3.4 ml, 95% confidence interval -4.3 to 11.0, p = 0.39). No significant changes over time were observed for the pre-specified secondary endpoints for the entire study population, without differences between the tadalafil and the placebo group. CONCLUSIONS: In this trial in adults with systemic right ventricles, right ventricular systolic function, exercise capacity and neuro-hormonal activation remained stable over a 3-year follow-up period. No significant treatment effect of tadalafil was observed. Further research is needed to find effective treatment for improvement of ventricular function in adults with systemic right ventricles.

Effects of tadalafil on skeletal muscle tissue: exploring interactions and novel mechanisms of action.

Beside its mechanical roles in controlling posture and locomotion, skeletal muscle system, the largest insulin and steroid hormones target tissue, plays a key role in influencing thermoregulation, secondary sexual characteristics, hormones metabolism, and glucose uptake and storage, as well as energetic metabolism. Indeed, in addition to insulin, several hormones influence the skeletal muscle metabolism/function and/or are influenced by skeletal muscles activity (i.e., physical exercise). Particularly, steroid hormones play a key role in modulating many biological processes in muscles, essential for overall muscle's function and homeostasis, both at rest and during all physical activities (i.e., physical exercise, muscular work). Phosphodiesterase type 5 (PDE5) is the enzyme engaged to hydrolyze cyclic guanosine monophosphate (cGMP) in inactive 5'-GMP form. Therefore, through the inhibition of this enzyme, the intracellular level of cGMP increases, and the cGMP-related cellular responses are prolonged. Different drugs inhibiting PDE5 (PDE5i) exist, and the commercially available PDE5i are sildenafil, vardenafil, tadalafil, and avanafil. The PDE5i tadalafil may influence cellular physiology and endocrine-metabolic pathways in skeletal muscles and exerts its functions both by activating the cell signaling linked to the insulin-related metabolic pathways and modulating the endocrine responses, protein catabolism and hormone-related anabolism/catabolism during and after physical exercise-related stress. Based on recent in-vivo and in-vitro findings, in this narrative review the aim was to summarize the available evidence describing the interactions between the PDE5i tadalafil and steroid hormones in skeletal muscle tissue and physical exercise adaptation, focusing our interest on their possible synergistic or competitive action(s) on muscle metabolism and function.

The NO/cGMP/PKG pathway in platelets: The therapeutic potential of PDE5 inhibitors in platelet disorders.

Platelets are the "guardians" of the blood circulatory system. At sites of vessel injury, they ensure hemostasis and promote immunity and vessel repair. However, their uncontrolled activation is one of the main drivers of thrombosis. To keep circulating platelets in a quiescent state, the endothelium releases platelet antagonists including nitric oxide (NO) that acts by stimulating the intracellular receptor guanylyl cyclase (GC). The latter produces the second messenger cyclic guanosine-3',5'-monophosphate (cGMP) that inhibits platelet activation by stimulating protein kinase G, which phosphorylates hundreds of intracellular targets. Intracellular cGMP pools are tightly regulated by a fine balance between GC and phosphodiesterases (PDEs) that are responsible for the hydrolysis of cyclic nucleotides. Phosphodiesterase type 5 (PDE5) is a cGMP-specific PDE, broadly expressed in most tissues in humans and rodents. In clinical practice, PDE5 inhibitors (PDE5i) are used as first-line therapy for erectile dysfunction, pulmonary artery hypertension, and lower urinary tract symptoms. However, several studies have shown that PDE5i may ameliorate the outcome of various other conditions, like heart failure and stroke. Interestingly, NO donors and cGMP analogs increase the capacity of anti-platelet drugs targeting the purinergic receptor type Y, subtype 12 (P2Y12) receptor to block platelet aggregation, and preclinical studies have shown that PDE5i inhibits platelet functions. This review summarizes the molecular mechanisms underlying the effect of PDE5i on platelet activation and aggregation focusing on the therapeutic potential of PDE5i in platelet disorders, and the outcomes of a combined therapy with PDE5i and NO donors to inhibit platelet activation.

Topically delivered nitric oxide acts synergistically with an orally administered PDE5 inhibitor in eliciting an erectile response in a rat model of radical prostatectomy.

Patients undergoing radical prostatectomy (RP) have a high incidence of postoperative erectile dysfunction (ED) refractory to treatment by oral phosphodiesterase-5 inhibitors (PDE5i). In the present studies, we investigated if a topically applied, nitric oxide microparticle delivery system (NO-MP) might act synergistically with an oral PDE5i (sildenafil) to improve erectile function outcomes in a rat model of RP. Thirty-five Sprague-Dawley rats underwent bilateral transection of the cavernous nerve (CN) for 1 week. After 1 week, animals were orally administered 0, 0.05, or 0.005 mg sildenafil/kg and the erectile response following topical application to the penile shaft of 250 or 100 mg NO-MP, or blank-MP, was monitored over a 2-h timeframe by recording the intracorporal pressure normalized to systemic blood pressure (ICP/BP, N = 5 animals/treatment group). Oral treatment with sildenafil by itself resulted in no observable erectile response. However, a combination of orally administered 0.05 sildenafil/kg with topical application of 250 mg NO-MP, compared to 250 mg NO-MP by itself, resulted in significantly more spontaneous erections (4.6 compared to 2 erections per hour, t-test; p value = 0.043), with a significantly faster onset for the first erectile response (11 compared to 22 min; t-test, p value = 0.041). Our results demonstrate a synergistic effect between orally administered PDE5i and topically applied NO-MP in eliciting an erectile response. Furthermore, they suggest a potential novel therapeutic approach to treat men with ED resulting from RP, through combination therapy of a topically applied NO-MP and an orally administered PDE5i.

Current Modulation of Guanylate Cyclase Pathway Activity-Mechanism and Clinical Implications.

For years, guanylate cyclase seemed to be homogenic and tissue nonspecific enzyme; however, in the last few years, in light of preclinical and clinical trials, it became an interesting target for pharmacological intervention. There are several possible options leading to an increase in cyclic guanosine monophosphate concentrations. The first one is related to the uses of analogues of natriuretic peptides. The second is related to increasing levels of natriuretic peptides by the inhibition of degradation. The third leads to an increase in cyclic guanosine monophosphate concentration by the inhibition of its degradation by the inhibition of phosphodiesterase type 5. The last option involves increasing the concentration of cyclic guanosine monophosphate by the additional direct activation of soluble guanylate cyclase. Treatment based on the modulation of guanylate cyclase function is one of the most promising technologies in pharmacology. Pharmacological intervention is stable, effective and safe. Especially interesting is the role of stimulators and activators of soluble guanylate cyclase, which are able to increase the enzymatic activity to generate cyclic guanosine monophosphate independently of nitric oxide. Moreover, most of these agents are effective in chronic treatment in heart failure patients and pulmonary hypertension, and have potential to be a first line option.

Phosphodiesterase-5 Inhibitor Use: An Under-Reported Cause of Profuse Nasal Bleeding.

BACKGROUND: Phosphodiesterase-5 (PDE-5) inhibitors enhance penile erection and have gained popularity not only for erectile dysfunction, but also in recreational settings. Nevertheless, adverse effects have been associated with their use, with nasal bleeding among them. PDE-5 inhibitor action is materialized through the inhibition of the cyclic guanosine monophosphate (cGMP) enzyme. cGMP is present at several sites of the human body in addition to the corpus cavernosum, leading to the adverse effects associated with its nonselective inhibition. CASE REPORTS: Two male patients with severe epistaxis who were taking PDE-5 inhibitors for erectile dysfunction or recreational purposes are discussed. Surgical intervention was required in both patients to control the nasal hemorrhage. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Nasal bleeding in patients who are taking PDE-5 inhibitors might represent an under-reported cause of epistaxis because of the unwillingness of most male patients to discuss issues pertaining their use without hesitation. Yet such episodes are rather profuse. This is especially true when the venous engorgement caused in the nasal mucosa by the smooth muscle relaxant effect of PDE-5 inhibitors is combined with a second event (e.g., specific drugs or blood dyscrasia). Emergency physicians should be also aware of the possibility that in the coming years the number of such cases might increase because of the increased use of these medications for erectile dysfunction or recreational purposes. It is likely that these patients could not be managed conservatively, but would rather require referral to an Ear, Nose, and Throat Department for surgical intervention.

Novel phosphodiesterase type 5 modulators: a patent survey (2008 - 2010).

INTRODUCTION: The inhibition of cyclic nucleotide PDE5 has been clinically validated as an effective treatment for erectile dysfunction and pulmonary arterial hypertension. There are three PDE5 inhibitors (sildenafil, vardenafil and tadalafil) approved worldwide and a further two agents (udenafil and mirodenafil) approved only in Korea. These first generation agents are perceived to have flaws in selectivity over other PDEs: slow onset, duration of action or CNS penetration, which has driven further research to identify optimal PDE5 inhibitors for the current pathologies. Several clinical trials have been reported to investigate the potential for PDE5 inhibitors to treat additional indications, which might require agents with different biological and/or pharmacokinetic profiles. AREAS COVERED: This review provides a summary of developments in the patent and open literature over the period 2008 - 2010. EXPERT OPINION: Avanafil, the first of a new generation of PDE5 inhibitors, has shown encouraging efficacy in clinical trials, and is likely to result in a new drug application filing during 2011, followed by a possible launch in 2012. Judging by the wealth of different structural series being claimed in patents, it seems that the selectivity and pharmacokinetic issues facing the first generation can be addressed through novel chemical matter.

Inhibitors of hyaluronan export from hops prevent osteoarthritic reactions.

SCOPE: An early reaction in osteoarthritic chondrocytes is hyaluronan overproduction followed by proteoglycan loss and collagen degradation. We recently found that hyaluronan is exported by the ATP-binding cassette transporter multidrug resistance associated protein 5 (MRP5) in competition with cGMP and that some phosphodiesterase 5 inhibitors also inhibited hyaluronan export. These inhibitors also prevented osteoarthritic reactions in cartilage. In an effort to identify the improved inhibitors directed primarily toward MRP5, we analyzed the flavonoids. METHODS AND RESULTS: Prenylflavonoids from hop xanthohumol, isoxanthohumol and 8-prenylnaringenin inhibited MRP5 export at lower concentrations than phosphodiesterase 5 activity. They were analyzed for their effect on IL-induced osteoarthritic reactions in bovine chondrocytes. Xanthohumol was the superior compound to inhibit hyaluronan export, as well as proteoglycan and collagen loss. It also prevented the shedding of metalloproteases into the culture medium. It directly inhibited MRP5, because it reduced the export of the MRP5 substrate fluorescein immediately and did not influence the hyaluronan synthase activity. CONCLUSIONS: Xanthohumol may be a natural compound to prevent hyaluronan overproduction and subsequent reactions in osteoarthritis.

Factors associated with phosphodiesterase type 5 inhibitor treatment satisfactions: results of patient interrogation.

INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitor therapy is an efficacious means of treatment for erectile dysfunction (ED). PDE5 inhibitors supply penile erection by inhibiting the hydrolysis of cGMP and therefore relaxing the corpus cavernosum. In this study, retrospective evaluation of those patients who were admitted to our clinic with the complaint of ED and who were recommended on PDE5 inhibitor treatment in terms of follow-up results and patient satisfaction were aimed. METHOD: The patients were called by phone and after informing about the study and taking the informed consent, patient satisfaction with the treatment, purposes of withdrawal, treatment alterations and partner satisfaction were investigated. RESULTS: Interviews were made with 345 patients, who accepted to enroll in the study and the mean patient age was 56 +/- 11.2 years. Of the patients 66.4% were learned to be satisfied with the treatment. It was determined that 10.7% of the patients have never used the medication and 50% could not continue because of high drug cost. It was recognised that 50.2% of the patients who are not satisfied with the treatment tried another PDE5 inhibitor. The success rate of the treatment was found to be higher in the followed-up group than those losses to follow-up. CONCLUSION: Therapy with PDE5 inhibitors is an effective means of ED treatment. The importance of doctor-patient communication should be considered, and the patient should be advised for adaptation to follow-up program. High drug cost is a significant predictor of patient compliance to treatment continuation.

Determination of mirodenafil and sildenafil in the plasma and corpus cavernous of SD male rats.

The purpose of the present study was to determine sildenafil and a novel PDE-5 inhibitor, mirodenafil in the plasma and corpus cavernosum tissue of rats to compare their pharmacokinetic properties. The concentrations of mirodenafil and sildenafil in the rat plasma and corpus cavernosum tissue samples were analyzed using LC-MS/MS after a single oral administration at a dose of 40mg/kg to rats. Although the T(max), Tlambda(1/2) and MRT were not different between mirodenafil and sildenafil, the C(max) and AUC of mirodenafil were significantly higher than those of sildenafil in the plasma and corpus cavernosum tissue. Consequently mirodenafil remained longer than sildenafil in the plasma and tissue. This may provide pharmacokinetic evidence for assessment of the in vivo efficacy of mirodenafil and sildenafil.