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)

Sildenafil is the first orally administered available treatment for erectile dysfunction. It produces a selective vasodilatation of corpus carvernosum, mediated by the inhibition of phosphodiesterase 5, an enzyme that degrades GMPc. Its therapeutic efficacy has been demonstrated in organic as well as psychogenic or mixed erectile dysfunction. Most of its adverse effects, such as headache, flushing, gastroesophageal reflux and color vision disturbances, are related to the mechanism of action. Its interactions with other medications, can have severe adverse consequences. The concomitant use of sildenafil with drugs that release nitric oxide in their molecule, can produce severe hypotension. In patients with coronary heart disease or cardiac failure, this interaction can cause death. Sildenafil is metabolized in the liver through cytochrome P-450. This enzymatic system can be inhibited by cimetidine, ketoconazole or erythromycin. These drugs can increase plasma concentrations of sildenafil. We must identify the groups of patients that will have a better response to the drug and those in whom the drug will be useless. We must also know more about the security profile of the drug. With time, we will know the real role of sildenafil in the treatment of erectile dysfunction.
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PMID:[Sildenafil (viagra) at the time of warnings]. 1034 69

Authors survey the conservative treatment possibilities of erectile dysfunction. With the increase in interest, they estimate the new oral- and intracavernosal drugs, giving a review of their experiences with the treatment. A perspective prognosis is given of the important role of NO (nitric oxide) donors and PHD (phosphodiesterase) inhibitor drugs in the field of conservative therapy, while intracavernosal and intraurethral prostaglandin therapies are still important ingredients in the therapeutic arsenal, as is hormone substitution in indicated cases.
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PMID:Non-surgical treatment of erectile dysfunction. 1037 70

The hydrolysis of the second messenger cyclic AMP (cAMP) by phosphodiesterase 3 (PDE3) is known to play an important regulatory role in the context of relaxation of cavernous smooth muscle of the penis. Thus, we investigated the PDE3A isoform from penile cavernous tissues of male patients with and without symptoms of erectile dysfunction at the molecular biological level. As revealed by reverse transcriptase polymerase chain reaction, of all tissues of the urogenital tract analyzed the expression of the PDE3A gene was highest in the corpus cavernosum. However, significant differences in the levels of gene expression were not found between the two subgroups of patients. Also, the determined nucleotide sequences of the cloned penile PDE3A cDNAs of all patients were absolutely identical. Surprisingly, some deviations could be detected in the cDNA sequences of PDE3A from human myocard and platelets. The data obtained indicate that neither the expression levels nor the sequence deviations of PDE3A are the main reasons for erectile dysfunction in men.
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PMID:Molecular biological characterization of phosphodiesterase 3A from human corpus cavernosum. 1042 99

Erectile dysfunction (ED) is the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance. The disorder is age-associated, with estimated prevalence rates of 39% among men 40 years old and 67% among those 70 years old. ED is a common (2 to 3 million males in Italy) and multifactorial disease due to organic and/or psychological factors that strongly impair the quality of life in man. During the last decade many advances in the understanding of the pathophysiology of ED have been made and new therapeutic strategies have become available. It has been established that an insufficient production of nitric oxide by penile nerve terminals and/or vascular endothelium may result in an impaired erection or complete impotence. Nowadays, intracavernous injection of vasoactive drugs represents a standardised approach for the diagnosis and a treatment option for ED, but is not widely accepted by the patients. The possibility of treating ED with new oral agents (i.e. sildenafil, apomorphine, phentolamine) or intraurethral administration of prostaglandin-E1 made this therapy more acceptable. Vacuum erection devices and penile prostheses represent second-line treatments. Men with ED caused by endocrine disorders (i.e. hypogonadism, prolactinomas) should be treated appropriately (i.e. testosterone and dopaminergic agonists, respectively). Amongst new drugs, sildenafil is considered the most promising: it is a potent inhibitor of type-5 phosphodiesterase in the corpus cavernosum and therefore increases the penile response to sexual stimulation. Oral sildenafil (25-100 mg when needed) is an effective and well-tolerated treatment in impotent men suffering from ED of unknown etiology.
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PMID:[Erectile dysfunction]. 1042 21

The molecular mechanisms of the effects of sildenafil, a specific inhibitor of cyclic guanosine monophosphate (cGMP) phosphodiesterases are briefly reviewed. The second messenger cGMP as well as its molecular targets (with the exception of the photoreceptor signal transduction machinery) have long played an underdog role compared with cyclic adenosine monophosphate and other signalling molecules such as inositoltrisphosphate. The same holds for guanylyl cyclase, which, albeit being the main effector molecule of the gaseous neurotransmitters carbon monoxide and nitric oxide (NO), has received much less attention relative to its activators and their synthases. Stimulation of the arginine --> NO --> cGMP pathway by bypassing NO-synthase is a well-established pharmacological principle in the treatment of cardiovascular disorders. In contrast, local application of NO-donors or oral feeding of excessive amounts of precursor amino acid L-arginine to treat erectile dysfunction were met with variable success or failure. The advent of a new principle, amplification of the NO-signaling cascade by means of target organ selective phosphodiesterase inhibition, has renewed interest in phosphodiesterases and cGMP.
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PMID:Molecular mechanisms of the effects of sildenafil (VIAGRA). 1043 86

Nitric oxide (NO), a mediator involved in penile erection, is synthesized by the nitric oxide synthase (NOS) family of enzymes. It has been shown that NOS activity decreases with age. To determine whether adenoviral-mediated overexpression of endothelial NOS (eNOS) could enhance erectile responses, we administered a recombinant adenovirus containing the eNOS gene (AdCMVeNOS) into the corpora cavernosum of the aged rat. Adenoviral expression of the beta-galactosidase reporter gene was observed in cavernosal tissue 1 day after intracavernosal administration of AdCMVbetagal; 1 day after administration of AdCMVeNOS, transgene expression was confirmed by immunoblot staining of eNOS protein, and cGMP levels were increased. The increase in cavernosal pressure in response to cavernosal nerve stimulation was enhanced in animals transfected with eNOS, and erectile responses to acetylcholine and zaprinast were enhanced at a time when the erectile response to the NO donor sodium 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate was not altered. These results suggest that in vivo gene transfer of eNOS, alone or in combination with a type V phosphodiesterase inhibitor, may constitute a new therapeutic intervention for the treatment of erectile dysfunction.
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PMID:Gene transfer of endothelial nitric oxide synthase to the penis augments erectile responses in the aged rat. 1050 Feb 31

The recent introduction of sildenafil has revolutionized the treatment of erectile dysfunction (ED). The availability of sildenafil, the first effective oral agent for ED, has also expanded the field of sexual healthcare to include general and primary care practitioners and other nonurology specialists. A new process-of-care algorithm has been developed to facilitate the evaluation and treatment of ED in these nonurology settings. Sildenafil has been demonstrated to be safe and effective in randomized, double-blind, placebo-controlled trials involving >3,000 men ages 19-87 years. Sildenafil is effective across a broad range of etiologies including diabetes. For patients in whom first-line treatment with sildenafil fails or ceases to be effective, second-line interventions with intracavernosal self-injection therapy or transurethral alprostadil may be indicated. In addition to sildenafil, other oral agents such as oral phentolamine and sublingual apomorphine are now in clinical trials. Drugs under development include second-generation phosphodiesterase type 5 (PDE5) inhibitors, endothelin antagonists, and agents that offer specific molecular targeting. Clinical studies are also being planned to examine the efficacy of combination oral drug regimens for ED.
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PMID:A new era in the treatment of erectile dysfunction. 1050 72

At any one time, around 10% of men are unable to achieve and/or maintain an erection sufficient for satisfactory sexual activity, a condition known as erectile dysfunction. Several mechanical, surgical and medical approaches have been developed for the treatment of this problem but none are ideal. Sildenafil (Viagra-Pfizer), a selective phosphodiesterase inhibitor, is the first licensed oral drug treatment for erectile dysfunction. It was marketed in the UK in October 1998, at which time the Department of Health was advising doctors that they "should not prescribe sildenafil" and that health authorities should not "support the provision of sildenafil at NHS expense to patients requiring treatment for erectile dysfunction, other than in exceptional circumstances". Here we review sildenafil for the management of erectile dysfunction and discuss whether it should be available on the NHS.
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PMID:Sildenafil for erectile dysfunction. 1056 64

Penile erection follows relaxation of the corpus cavernosum in which nitric oxide (NO) released during sexual stimulation from non-adrenergic non-cholinergic nerve endings and from endothelial cells of the corpus cavernosum plays a crucial role. Sildenafil (VIAGRA) selectively inhibited phosphodiesterase type 5 (PDE5) activity in the human corpus cavernosum and increased cGMP concentrations in the rabbit cavernosum in the presence of NO. Sildenafil enhanced the NO-dependent relaxation of the isolated human corpus cavernosum and the intracavernosal pressure in the anesthetized dog without affecting systemic blood pressure and heart rate. In the patients with erectile dysfunction, an orally administered sildenafil enhanced the penile rigidity during visual sexual stimulation. Sildenafil did not affect the phenylephrine-induced contraction of the isolated rabbit aorta, but enhanced the relaxant effect of glyceryl trinitrate. The pharmacodynamic interaction with glyceryl trinitrate was also observed in human studies where sildenafil potentiated the hypotensive effect of the nitrate. These results indicate that sildenafil, which enhances the physiological process of penile erection during sexual arousal, is a novel orally effective treatment for erectile dysfunction. It should be noted, however, that sildenafil enhanced the hypotensive effect of glyceryl trinitrate, as a result of inhibition of PDE5 in vascular smooth muscle. Therefore, administration of sildenafil to patients who are using nitrates and NO donors is contraindicated.
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PMID:[Pharmacological profiles of sildenafil (VIAGRA) in the treatment of erectile dysfunction: efficacy and drug interaction with nitrate]. 1058 34

Sildenafil is a specific inhibitor of phosphodiesterase (PDE) type 5 and represents a powerful therapy for male erectile dysfunction (ED) of different aetiology. Recently, sildenafil has been shown to restore erections in temporary ED related to the need of semen collection for assisted reproductive techniques. In this study, we investigated whether sildenafil administration modifies seminal parameters and/or erectile function in normal healthy volunteers. In a double-blind, randomized, placebo-controlled, cross-over two period investigation we enrolled 20 healthy male volunteers (mean +/- SE age 32 +/- 0.5 years). Subjects were not using any medication for the 3 month period prior to the study and were engaged in a stable relationship with proven fertility. The effects of sildenafil (100 mg) on seminal parameters and erectile function after audiovisual sexual stimulation were evaluated by semen analysis and by colour-Duplex ultrasound (the Resistive Index) respectively. In all subjects, sildenafil caused no changes in seminal and erection parameters when compared to placebo. Interestingly, sildenafil administration led to a marked reduction of the post-ejaculatory refractory time (10.8 +/- 0.9 min versus 2.6 +/- 0.7 min for placebo and sildenafil respectively; P < 0.0001). These results indicate that in normal subjects acute sildenafil treatment does not modify semen characteristics and has a positive influence over the resumption of erections following ejaculation in the presence of a continuous erotic stimulus.
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PMID:Effects of sildenafil (Viagra) administration on seminal parameters and post-ejaculatory refractory time in normal males. 1061 Dec 1


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