Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent reports to the U.S. Food and Drug Administration Adverse Event Reporting System implicate sildenafil citrate in adverse emotional and aggressive behaviors. Sildenafil citrate (Viagra) is widely prescribed for erectile dysfunction and acts by inhibiting phosphodiesterase Type-5, resulting in accumulation of cyclic-guanosine monophosphate (cGMP). Cyclic-GMP is synthesized by guanylyl cyclase that is directly activated by the messenger molecule, nitric oxide (NO), formed throughout the CNS by the enzyme nitric oxide synthase (NOS). Elevated concentrations of cGMP have been associated with increased aggressive behavior. In addition, the potential effect of cGMP accumulation on NO-mediated behavioral and neuroendocrine function through possible feedback mechanisms remains unspecified; however, neuronal NOS (nNOS) inhibition by pharmacologic agents or ablation of the gene encoding nNOS increases aggressive behavior in male mice. We tested the hypothesis that sildenafil citrate may increase aggression via its actions on cGMP and potential feedback inhibition of NO concentrations. Male C57BL/6 mice were injected with saline vehicle (0), 2, 5, 8, or 10 mg/kg of sildenafil citrate thrice weekly for 4 weeks. Latency to display aggressive behavior, frequency, and duration of aggressive behavior were recorded during neutral-arena aggression tests. No change in agonistic behavior was observed in mice during treatment with sildenafil citrate. However, sildenafil-treated mice given the highest dose were generally more aggressive 1 week post-cessation of drug treatment as compared to vehicle-treated mice. Additional investigation into potential withdrawal effects or abuse doses seems warranted.
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PMID:Aggressive behavior increases after termination of chronic sildenafil treatment in mice. 1563 52

1. Sildenafil citrate (Viagratrade mark; Pfizer, Sandwich, Kent, UK), a phosphodiesterase 5 inhibitor, rises cGMP levels in smooth muscle cells. It relaxes both vascular and visceral smooth muscle. In order to assess the intestinal effects of sildenafil, we decided to investigate its actions on rat duodenal motor activity in vitro. 2. In isolated duodenal segments maintained in Tyrode's solution, sildenafil exhibited a concentration-dependent antispasmodic effect on acetylcholine (ACh)-induced phasic contractions, with an IC50 value of 26.7 micromol/L (95% confidence interval (CI) 2.0-55.3 micromol/L). 3. Sildenafil also relaxed the carbamylcholine (CCh)-induced sustained contraction with an IC(50) of 16.2 micromol/L (95% CI 9.5-27.6 micromol/L). Sildenafil produced significant additional relaxation of 25.2 +/- 8.1% of the CCh-induced contraction, beyond basal tone. 4. Sildenafil reduced the amplitude of spontaneous duodenal contractions with an EC50 of 9.6 micromol/L (95% CI 5.7-16.2 micromol/L). This effect was significantly more potent than the effects of zaprinast and papaverine, which also reduced duodenal contractions with EC50 values of 91.6 micromol/L (95% CI 46.0-182.2 micromol/L) and 78.5 micromol/L (95% CI 37.1-166.3 micromol/L), respectively. 5. In preparations treated previously with methylene blue (10 micromol/L) or 1H-[1,2,4]oxadiazolo(4,3-a)quinoxalin-1-one (ODQ; 10 micromol/L), the EC50 values for the sildenafil effect were significantly increased to 39.0 micromol/L (95% CI 23.9-63.4 micromol/L) and 43.8 micromol/L (95% CI 24.5-78.3 micromol/L), respectively. These values were significantly greater than those obtained with sildenafil alone. 6. In conclusion, sildenafil has myorelaxant and antispasmodic effects on rat duodenal segments in vitro. The contractile inhibitory effect of sildenafil on rat isolated duodenum is probably due to intracellular cGMP accumulation as a result of its decreased degradation.
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PMID:Inhibitory effect of sildenafil on rat duodenal contractility in vitro: putative cGMP involvement. 1574 2

Functional anatomy of the human penis involves various parameters: cavernous tissue, covering integument, prepuce foreskin, corpora cavernosa, corpus spongiosum, glans, facia, arterial supply, venous drainage, lymph drainage, musculature, and nerve supply. Several factors affect the expression/degree of erectile dysfunction (ED) endocrine profile, aging/senescence, demyelinating diseases, and surgery. Risk factors of ED are: age, vascular factors, metabolic diseases (diabetes mellitus), neurologic diseases, and HIV/AIDS. Several drugs are associated with ED: antiandrogenic, anticholinergic, antidepressants, antihypertensive, major tranquilizers, anxiolytics, and certain medicines/metabolites. The International Index of Erectile Function (IIEF) is a multidimensional scale for assessment of erectile dysfunction. The main structures mediating erection are the corpora cavernosa or "erectile bodies," which are fused distally for approximately three-quarters of their length. They separate proximally to fuse with each ischial tuberosity of the pelvis. On their ventral surface lies the corpus spongiosum, which surrounds the urethra. Coital dysfunction is classified into "erectile dysfunction" (psychosexual and endocrine/neuro-endocrine) and "ejaculatory dysfunction" (psychosexual, and genitourinary surgery). Vasculogenic impotence was evaluated by high-resolution ultrasonography and pulsed Doppler spectrum analysis. Cavernosal, alpha-blockade is a technique used to evaluate and treat ED. Another diagnostic procedure for ED involves color floro and spectural Doppler imaging after papaverine-induced erection in impotent men. Color Doppler and duplex ultrasonography are used to evaluate Peyronie's disease. Sildenafil cilrate (Viagra) is an effective therapy of ED in men. Vardenavil is a highly selective phosphodiesterase 5 (PDE5) inhibitor which improved ED. Prostagland E1, vasoactive intestinal polypeptide (VIP), and phentolamine mesylate (administered by autoinjectors) have been applied to treat ED in patients resistant to other intracavernosal agents. Clinical trials were conducted on self-injection of vasoactive drugs, apomorphine SL, and tadalafil in diabetic men. Medical therapy of ED includes: medicated urethral system for erection (MUSE), intravenous pharmacotherapy, arterial revascularization, vacuum devices, two- and three-component inflatable penile prosthesis, semi-rigid penile prosthesis in situ, and inflatable one-piece penile prosthesis. Surgical therapy include procedures to correct Peyronie's penile deformity and penile deformity, procedures to avoid inevitable shortening accompanying Nesbit's disease, and for penile lengthening.
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PMID:Erectile dysfunction: anatomical parameters, etiology, diagnosis, and therapy. 1576 14

Our laboratories have developed several technologies to accelerate drug discovery process on the basis of structural chemoproteomics. They include SPS technology for the efficient determination of protein structures, SCP technology for the rapid lead generation and SDF technology for the productive lead optimization. Using these technologies, we could determine many 3D structures of target proteins bound with biologically active chemicals including the structure of phosphodiesterase 5/Viagra complex and obtain highly potent compounds in animal models of obesity, diabetes, cancer and inflammation. In this paper, we will discuss concepts and applications of structural chemoproteomics for drug discovery.
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PMID:Structural chemoproteomics and drug discovery. 1581 88

Newly developed sildenafil citrate (SC), a selective inhibitor of cyclic guanosine monophosphate (c-GMP) specific phosphodiesterase type 5 (PDE 5) in the corpus cavernosum is used for the oral treatment of erectile dysfunction. A convenient, sensitive and simple method for the determination of sildenafil in human plasma is presented. The analytical technique was based on reversed-phase high-performance liquid chromatography coupled with UV detector set at 295 nm. Rofecoxib was used as internal standard (I.S). Liquid-liquid extraction using diethyl ether was performed to recover sildenafil and rofecoxib. The retention time of I.S and sildenafil were 5.5 minutes and 7.2 minutes respectively. The method was validated over a linear range of 10 to 1000 ng/ml from plasma. Separate stability study showed that sildenafil is stable under conditions of analysis. The extraction efficiency from plasma varied from 79.69% to 81.13 %. The minimum quantifiable concentration was set at 10 ng/ml. (%o CV<12.5%). The method was used for Bioequivalence Study of Two Brands of Sildenafil citrate 50 mg tablets in healthy human volunteers. All pharmacokinetic parameter were calculated along with statistical evaluation.
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PMID:Bioequivalence study of sildenafil citrate tablets in healthy human volunteers. 1588 13

More than 30 million men are estimated to have erectile dysfunction (ED) in the United States. Worldwide, ED is estimated to affect more than 150 million men, and that number is expected to exceed 300 million men by the year 2025. The prevalence of ED ranges from 7% in men aged 18-29 years to 85% in men aged 76-85 years. In addition, a recent report showed that 68% of patients with ED aged 18 years and older have at least one comorbid diagnosis of hypertension, hyperlipidaemia, diabetes or depression, and research suggests that ED may be an early indicator of systemic vascular disease. Viagra (sildenafil citrate), the first-in-class phosphodiesterase type 5 (PDE5) inhibitor, was introduced in 1998 for the treatment of ED. In the 7 years since its market launch, more than 750,000 physicians have prescribed sildenafil to more than 23 million men, helping establish an excellent safety and efficacy record. Clinical studies have demonstrated that sildenafil successfully treats ED of varied organic, psychogenic or mixed aetiology, and is effective in men with ED and comorbidities such as hypertension, hyperlipidaemia, diabetes or depression. Sildenafil was a breakthrough medication that addressed a previously unfulfilled medical need. The impact of sildenafil has stimulated academic, clinical and industrial research to better understand the nature of sexual function and develop better treatment and management for sexual dysfunctions such as ED. With the advent of other erectogenic therapies for the treatment of ED, this 7-year update will focus on the unique history and development of sildenafil, its current use and applications and its future directions and indications. Special emphasis is placed on the impact of sildenafil on our understanding of sexual health and on the extensive safety and efficacy data that have been amassed from numerous clinical trials.
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PMID:Past, present, and future: a 7-year update of Viagra (sildenafil citrate). 1592 97

Sildenafil citrate is a potent inhibitor of specific phosphodiesterase-5, which mediates metabolism of intracellular second message -- cGMP. Sildenafil citrate has been widely used for erectile dysfunction in men. Moreover, it is known that men with liver diseases have higher rate of erectile dysfunction. Furthermore, it has been demonstrated that nitric oxide plays an important role in liver function and regeneration. The present study evaluates effects of sildenafil citrate on hepatic function and regeneration in normal and alcohol-fed rats. In normal rats sildenafil citrate has a trend to improve hepatic function after partial hepatectomy (PHx). Moreover, sildenafil citrate significantly reduces hepatic regenerative activity at the concentration of 5 mg/kg body weight. However, sildenafil had no effects on hepatic function and regeneration of alcohol-fed rats. In general, sildenafil citrate did not induce significant changes in hepatic function and regenerative activity after PHx in normal and alcohol-fed rats, except at concentration of 5 mg/kg sildenafil citrate significantly inhibit hepatic regeneration in normal rats.
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PMID:Effects of sildenafil citrate on hepatic function and regeneration in normal and alcohol-fed rats. 1599 44

Sildenafil is a cyclic guanosine-specific phosphodiesterase type 5 (PD-5) inhibitor that is widely used for erectile dysfunction. Potent and competitive inhibition of PD-5 enhances levels of cyclic guanosine monophosphate (cGMP). Fibrin glue-apart from tissue fixation-has been used for slow release of drugs. In this study, local delivery of Sildenafil citrate with fibrin glue was accomplished to improve random flap survival. Fifty Wistar rats were randomized into 5 groups, and a standardized dorsal random-pattern skin flap was elevated in each rat. In Group I (n = 10), the base of the flap was divided, making it a "graft" control to study the graft effect. In Group II (n = 10), a thin Silastic sheet was used to separate the flap from the underlying vascular bed, and no pharmacologic treatment was given. In Group III (n = 10), only 0.5 mL of fibrin glue was applied to the flap donor site. In Group IV (n = 10), 2.5 mg of sildenafil citrate mixed in 0.5 mL of fibrin glue was applied to donor site of the flap, whereas 10 mg of sildenafil citrate mixed in 0.5 mL of fibrin glue was applied in Group V (n = 10). Area of flap survival was evaluated on postoperative seventh day. Total necrosis of all of the flaps was observed in "graft" control group (Group I). Sildenafil and fibrin glue groups (Group IV and V) resulted in a statistically significant decrease in flap necrosis compared with Groups II and III (P < 0.0001). A statistically significant difference could not be documented between Group II and Group III (P > 0.0001). The decrease in skin necrosis was statistically significant in Group V compared with Group IV (P < 0.0001). Histologic examination revealed significantly increased vascular density in Groups IV and V compared with Groups II and III (P < 0.0001), whereas a significant difference could not be documented between Groups IV and V (P > 0.0001) and between Groups II and III (P > 0.0001). In view of these results, topical sildenafil application seems to improve flap survival in random-pattern skin flaps in dose-dependent manner.
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PMID:Improved flap viability with site-specific delivery of sildenafil citrate using fibrin glue. 1610 70

A 32-year-old male presented to our department for recurrent epistaxis during sexual intercourses. The patient controlled the bleeding each time with sponge packs and gauzes. During the consultation, he volunteered that the trigger for the epistaxis appeared to have been misuse of phosphodiesterase (PDE)-5 inhibitors, Viagra and Cialis. This first report of epistaxis after PDE-5 inhibitors in a young patient underline the possibility that in the next years the number of similar cases might increase due to the diffusion of PDE-5 inhibitor misuse in recreational settings.
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PMID:Epistaxis after PDE-5 inhibitors misuse. 1610 67

This meeting underscored advances in the exploitation of cyclic nucleotide phosphodiesterases (PDEs) as drug targets. One highlight of the meeting was the disclosure of a new PDE isozyme, bringing to 11 the total number of genetically distinct isozyme families thus far identified. Also reported was the phenotypic characterization of a PDE4D murine genetic knockout. With respect to drug discovery and development, the most encouraging information presented centered on advances in targeting PDE4 with therapeutically useful inhibitors. Historically, the therapeutic utility of isozyme-selective PDE4 inhibitors has been limited by class-associated side effects, namely nausea and dyspepsia. New PDE4 inhibitors are being designed with the specific intent of improving upon the therapeutic ratio of first-generation agents. The profiles of two second-generation PDE4 inhibitors, SB-207499 (Ariflo; Smithkline Beecham plc) and PD-189659, were presented. SB-207499 demonstrated marked efficacy in phase II clinical trials in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD), a disease of very high unmet medical need. PD-189659 has yet to enter clinical trials, but its preclinical profile indicates that this agent can produce substantial anti-inflammatory effects without producing class-associated side effects in animal models. A number of presentations were also given on the utility of PDE5 inhibitors in the treatment of male erectile dysfunction (MED). The widespread use of Viagra (sildenafil; Pfizer Inc) over the last year has reinforced the perception that PDE5 inhibitors are safe and effective agents for the treatment of MED. The overall tenor of the meeting was distinctly upbeat, with most participants believing that PDE isozymes are becoming ever more accessible as targets for drug discovery in a variety of therapeutic areas.
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PMID:PDE inhibitors--Second William Harvey Research Conference. Drugs with an expanding range of therapeutic uses. 1-3 December 1999, Nice, France. 1610 32


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