Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The generation of nitric oxide (NO) in penile erectile tissue and the subsequent elevation of cyclic GMP (cGMP) levels are important for normal penile erection. Current treatments of erectile dysfunction elevate either cGMP levels by blocking cGMP degrading phosphodiesterase 5 or cyclic AMP (cAMP) levels by intrapenile injection of prostaglandin E1. The molecular target or targets of cGMP in erectile tissue and the role of cAMP for normal penile erection are not known. Herein, we report that mice lacking cGMP-dependent kinase I (cGKI) have a very low ability to reproduce and that their corpora cavernosa fail to relax on activation of the NO/cGMP signaling cascade. Elevation of cAMP by forskolin, however, induces similar relaxation in normal and cGKI-null corpus cavernosum. In addition, sperm derived from cGKI-null mice is normal, can undergo acrosomal reactions, and can efficiently fertilize eggs. Altogether, these data identify cGKI as the downstream target of cGMP in erectile tissue and provide evidence that cAMP signaling cannot compensate for the absence of the cGMP/cGKI signaling cascade in vivo.
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PMID:Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. 1068 76

Sildenafil is a selective and by oral administration potent type-5 phosphodiesterase (PDE 5) inhibitor, which increases the erection by corpus cavernosum smooth muscle relaxation. In a non-placebo controlled study, 134 patients with erectile dysfunction were treated with oral sildenafil. The aim of the study was to estimate the efficacy and adverse effects of this treatment. 51 patients (38%) had psychogenic, and 83 (62%) organic origin of the erectile dysfunction. 73 of them have already had some treatment for this problem before. The effective dose was 50 mg for 84 patients (63%), 100 mg for 32 (24%) and 25 mg for 4 patients. The treatment was effective for 120 patients (90%). The most common adverse effect was flushing in 18 (13%) and headache in 9 (7%) cases, two patients had headache and flushing together. Nasal congestion and visual disturbances were complained by two patients. Two patients reported prolonged (max. 2h) erections. Cardiological investigation was performed for cardiovascular patients and for patients with risk factors. Exact criteria of the cardiological opinion of sildenafil treatment are reviewed. Cardial or other serious adverse effects were not observed. It was not necessary to stop the treatment because of the adverse effects. The authors found, that sildenafil is an effective and safe treatment for the erectile dysfunction.
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PMID:[Effectiveness and adverse effects of sildenafil in erectile dysfunction]. 1069 32

Erectile disfunction (E. D.) is more common in older men but may affect younger men too. Diabetes mellitus, coronary heart disease and hypertension are often associated with E. D. The majority of the patients are treated medically for erectile dysfunction and, recently, oral therapy has become most important since Viagra has been approved. New phosphodiesterase blockers are in preclinical evaluation since then. Phentolamine and apomorphine will become available soon for the treatment of E. D. It is important to know about the etiology of E. D. as well as the mechanisms by which drugs may improve erection in order to decide which drug is appropriate for a particular patient.
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PMID:[Oral therapy of erectile dysfunction]. 1074 89

Sildenafil citrate (Viagra) is a phosphodiesterase type V inhibitor used to treat erectile dysfunction. Ten men with idiopathic Parkinson's disease (PD) and erectile dysfunction were prescribed 50-100 mg sildenafil citrate to use in eight sexual encounters over a 2-month period. Patients underwent Unified Parkinson's Disease Rating Scale (UPDRS) evaluations and completed a Beck's Depression Inventory (BDI) and a Sexual Health Inventory-M version (SHI-M) at baseline and after 8 weeks. There was statistically significant improvement in total SHI-M scores (23.8 +/- 2.0 vs 16.6 +/- 2.8; p = 0.01), overall sexual satisfaction (p = 0.03), satisfaction with sexual desire (p = 0.04), ability to achieve erection (p = 0.02), ability to maintain erection (p = 0.03), and ability to reach orgasm (p = 0.04) with use of sildenafil citrate. UPDRS and BDI scores were not significantly changed. Side effects included headache in one patient during three sexual encounters. In this open-label study, sildenafil citrate significantly improved sexual function in men with PD and erectile dysfunction.
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PMID:Sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men with Parkinson's disease. 1075 81

Sildenafil citrate is the first oral agent approved for the treatment of erectile dysfunction (ED); other oral agents are in the process of development. Because the mechanism of action of many of these agents involves vasodilation, there is a potential for interaction with the cardiovascular system. Sildenafil inhibits phosphodiesterase-5 (PDE-5) which is found in the corpus cavernosum and in the systemic vasculature. Sildenafil causes a mild decrease in systemic arterial pressure ( approximately -8/-5.5 mm Hg); it causes a synergistic and often major decrease in systemic arterial pressure in the presence of organic nitrates (nitric oxide donors). Sildenafil is therefore contraindicated in patients taking organic nitrates. A review was made of clinical trials in populations of men with (1) erectile dysfunction; (2) chronic stable ischemic heart disease and erectile dysfunction; and (3) hypertension and erectile dysfunction. This review showed that sildenafil was effective and not associated with an increase in serious cardiovascular adverse events, myocardial infarction (MI), or death compared with placebo. Although there have been spontaneous reports of death among men using sildenafil, there are limitations to spontaneous-event reporting. In addition. the numbers of such reports are well below the expected numbers of deaths when considering the number of men who have received prescriptions for sildenafil and their age and cardiovascular risk factor profile. Because there is a small but finite risk of having a cardiac event with sexual activity, physicians should discuss with their cardiac patients the risks of sexual activity before prescribing any treatment for ED. In addition, they should evaluate their patients' cardiac status when considering the safety of administering any ED treatment that may have systemic vasodilatory properties and can potentially lower blood pressure. In some cases, exercise treadmill testing may be warranted to determine whether ED patients with coronary artery disease can achieve the physiologic workload (4-6 metabolic equivalents) associated with sexual intercourse.
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PMID:Cardiovascular risk and sildenafil. 1089 81

Research on penile smooth muscle physiology has increased the number of drugs available for treating erectile dysfunction (ED). Penile erection involves the relaxation of smooth muscle in the corpus cavernosum. The key mediator of smooth muscle relaxation is nitric oxide (NO), which acts by increasing the cellular level of cGMP. Another cyclic nucleotide, cAMP, is involved in smooth muscle cell relaxation; cAMP formation is stimulated by a number of compounds, such as alprostadil. An increase in cAMP and/or cGMP levels can also be induced by inhibition of phosphodiesterases (PDEs), the enzymes involved in cyclic nucleotide breakdown. Both papaverine and sildenafil are PDE inhibitors. Papaverine is a non-specific inhibitor of these enzymes; sildenafil is an orally active, potent and selective inhibitor of GMP-specific PDE5, the predominant isoenzyme metabolizing cGMP in the cells of the corpus cavernosum. Penile smooth muscle contraction, induced by adrenergic fibers through alpha(1) adrenoceptors, produces detumescence, thus making alpha adrenoceptor antagonists suitable for maintenance of penile erection. The orally active drug yohimbine is a mixed alpha(1)-alpha(2) adrenoceptor antagonist that works by a dual mechanism; it facilitates sexual arousal by acting on alpha(2) adrenoceptors in the central nervous system and blocks adrenergic influences at peripheral level.
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PMID:Erectile dysfunction: from biochemical pharmacology to advances in medical therapy. 1091 32

We examined the mechanism underlying the potentiation of penile tumescence by methyl 2-(4-aminophenyl)-1, 2dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4, 5-trimethoxyphenyl)3-isoquinoline carboxylate sulfate (T-1032), a new potent and selective phosphodiesterase type V inhibitor. In vivo, pelvic nerve stimulation induced a penile tumescence together with increase of total nitric oxide metabolite levels within the corpus cavernosa of anesthetized dogs. Intravenous (1-100 microg/kg) and intraduodenal (3, 30, 300 microg/kg) treatment with T-1032 dose dependently potentiated the tumescence. The potency of T-1032 was equivalent to that of sildenafil. T-1032 did not influence the intracavernous pressure when the pelvic nerve stimulation was absent. The potentiation of tumescence was more pronounced by intracavernous than i.v. injection. Intracavernous N(G)-nitro-L-arginine, a nitric-oxide synthase inhibitor, but not N(G)-nitro-D-arginine diminished the effects of T-1032 on the tumescence. Furthermore, i.v. T-1032 augmented the tumescence induced by sodium nitroprusside (SNP) but not by vasoactive intestinal polypeptide (VIP). In vitro, in isolated preparations of canine corpus cavernosum precontracted with phenylephrine, SNP (0. 01-100 microM) and VIP (0.01-1 microM) produced a dose-dependent relaxation accompanied by an increase in cGMP and cAMP levels, respectively. T-1032 augmented the relaxation induced by SNP but not by VIP. These data suggest that oral treatment with T-1032 has potential to improve erectile dysfunction through the inhibition of phosphodiesterase type V in the smooth muscles of corpus cavernosa.
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PMID:Potentiation of penile tumescence by T-1032, a new potent and specific phosphodiesterase type V inhibitor, in dogs. 1094 35

During the last decade, the cellular pathways involved in excitation-contraction coupling have been identified and explained. The key event in the initiation of the contraction is the rise in sarcoplasmic free calcium. Inositol 1,4,5-triphosphate (IP3) and cyclic nucleotides (cAMP, cGMP) have been demonstrated to be the second messengers associated with stimulation of smooth muscle selective receptor-subtypes (cholinergic, adrenergic, non adrenergic-non cholinergic) by specific neuromodulators. Furthermore, activation of voltage-gated L type- or receptor operated calcium channels is involved in the sarcoplasmic free calcium changes. KCa and KATP-channels play an important role in smooth muscle hyperpolarization; KATP-openers excite great interest as therapeutic agents for the detrusor instability. The specificity of different receptor subtypes and their transductional pathways has increased the number of targets for drug treatment of urinary bladder disorders and erectile dysfunction. As the level of intracellular nucleotide second messengers can be modulated by tissue-specific phosphodiesterase (PDE) isoenzymes, PDEs selective inhibitors have the potential to exert organ-specific therapeutic effects. So, PDE I selective inhibitor vinpocetine has been proposed for the symptomatic treatment of detrusor instability; PDE V selective inhibitor sildenafil, enhancing the NO-cGMP pathway-mediated cavernosal smooth muscle relaxation, is an effective drug to treat erectile dysfunction.
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PMID:[Bladder and cavernous contractility and relaxation among intracellular messengers, changes in sarcoplasmatic free calcium and phosphodiesterase activity]. 1095 93

The research programme that started in 1985 led to the approval of Sildenafil (Viagra), in 1998, as the first oral treatment for male erectile dysfunction. The initial project objective was the design and synthesis of novel inhibitors of phosphodiesterase that would increase tissue levels of cGMP, and that could be beneficial for the treatment of cardiovascular conditions. Starting from zaprinast, a weak phosphodiesterase inhibitor, computer modelling guided rational medicinal chemistry to achieve significant increases in potency and selectivity for the 5-isoenzyme within a novel series of pyrazolopyrimidinones. Optimization of structure-activity relationships and pharmacokinetic properties led to sildenafil, which proved essentially devoid of cardiovascular activity in clinical trials. However, the emerging role of nitric oxide and cGMP in controlling blood flow in the penis suggested that sildenafil would have a beneficial effect on erectile function. This hypothesis was confirmed by extensive clinical trials in nearly 5000 patients and the Food and Drug Administration approved sildenafil in March 1998 for male erectile dysfunction. Sildenafil is now available in over 100 countries and more than 150 million tablets have been dispensed worldwide. The sildenafil research programme reflects a traditional approach to drug discovery, but pressures to improve productivity have prompted major investments in genome sciences and new technologies. The impact of these initiatives on the drug discovery paradigm will be discussed, particularly with respect to shortening time scales between identifying gene sequences and submitting innovative products for regulatory approval.
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PMID:Science, art and drug discovery: a personal perspective. 1099 89

The long-term efficacy and safety of oral Viagra (sildenafil citrate), a selective phosphodiesterase 5 inhibitor, and the effect of withdrawing treatment were evaluated in men with erectile dysfunction (ED). In 233 men with ED of psychogenic or mixed organic/psychogenic aetiology, 16 weeks of open-label, flexible-dose sildenafil treatment (10-100 mg) was followed by eight weeks of double-blind, fixed-dose, randomised withdrawal to placebo or continued treatment with sildenafil. Sildenafil was taken as needed (not more than once daily) approximately 1 h prior to sexual activity. The main outcome measures were a global efficacy question, a sexual function questionnaire, an event log of erections, and adverse event recording. In the open-label phase, 200 of 216 patients (93%) reported improved erections with sildenafil; 28 patients (12%) discontinued treatment. In the double-blind phase, the significant improvements in the frequency and duration of erections were maintained in the sildenafil group but returned to pre-treatment values in patients on placebo (P values < 0.0001 versus placebo). The most frequent adverse events in the sildenafil group during the double-blind phase were flushing (7%), headache (6%), and dyspepsia (5%). Of the 192 patients enrolled in the 1-y extension, 90% completed the study; only two patients (1%) were withdrawn due to lack of efficacy. In men with ED of psychogenic or mixed aetiology, oral sildenafil is effective and well-tolerated both at the initiation of therapy and during long-term treatment. For most patients, sildenafil treatment must be continued for improvements in erectile function to be maintained.
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PMID:Long-term efficacy and safety of oral Viagra (sildenafil citrate) in men with erectile dysfunction and the effect of randomised treatment withdrawal. 1104 12


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