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)

We describe the pharmacological characteristics of a novel phosphodiesterase type 5 inhibitor FR226807, N-(3,4-dimethoxybenzyl)-2-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-nitrobenzamide. FR226807 inhibited phosphodiesterase type 5 isolated from human platelets with an IC(50) value of 1.1 nM. FR226807 also inhibited phosphodiesterase type 6 with an IC(50) of 20 nM; however, the IC(50) value for phosphodiesterase type 6 was 18-fold higher than that for phosphodiesterase type 5. The IC(50) values of FR226807 for other phosphodiesterases (phosphodiesterase type 1, phosphodiesterase type 2, phosphodiesterase type 3, and phosphodiesterase type 4) were 1000-fold higher than that for phosphodiesterase type 5. FR226807 increased the cyclic guanosine monophosphate (cGMP) content in corpus cavernosum isolated from rabbit, an effect associated with relaxation of the muscle. FR226807 enhanced the relaxation response induced by electrical field stimulation of corpus cavernosum isolated from the rabbit. In an anesthetized dog model for the evaluation of erectile function, intravenous administration of FR226807 prolonged the time to return to 75% of maximal intracavernosal pressure after cessation of electrical stimulation of the pelvic nerve. In summary, FR226807 is a potent and highly selective phosphodiesterase type 5 inhibitor with an augmentative effect on penile erection and will be useful for the treatment of erectile dysfunction.
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PMID:FR226807: a potent and selective phosphodiesterase type 5 inhibitor. 1167 48

Pharmacotherapy for men experiencing erectile dysfunction has undergone dramatic advances over the past 5 years with the introduction of an effective oral agent. Sildenafil has increased the pool of couples seeking treatment for this important health issue as well as expanding the numbers of physicians treating it. Research into the growing field of erectile dysfunction is expanding at a rapid pace. Independent investigators worldwide now regularly contribute to our body of scientific knowledge. Novel oral therapies targeted at specific points along the erectile cascade are undergoing pre-clinical and early phase registration trials with the promise of rapid action, extended duration of responsiveness and an improved side effect profile. In this review, we have highlighted recent information on the next generation of phosphodiesterase inhibitors and summarized the evolving research into centrally acting agents, which may lead to effective combination therapy.
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PMID:Modern pharmacotherapy for erectile dysfunction: evolving concepts with central and peripheral acting agents. 1173

Anticholinergic drugs are currently the therapy of choice to treat urgency and urge incontinence. However, muscarinergic receptor blockers with adequate selectivity for detrusor smooth muscle are not available. Also, in contrast to the normal detrusor, the unstable detrusor neurotransmission seems to be at least partially regulated by non-cholinergic (NANC) pathways. These factors may explain the common side effects and the limited clinical efficacy of these compounds. Specific modulation of intracellular second messenger pathways offers the possibility of organ selective manipulation of tissue function, specifically contraction and relaxation of smooth musculature. Because of their central role in the intracellular regulation of smooth muscle tone phosphodiesterases (PDEs) are an attractive pharmacological targets. The PDE 5 specific inhibitor sildenafil (Viagra) has revolutionized the treatment of patients with erectile dysfunction. Numerous other PDE inhibitors are currently under investigation for the treatment of various disorders. We investigated the role of PDEs in human detrusor smooth muscle. Our data demonstrate the presence of five PDE isoenzymes in human detrusor and suggest, for the first time, that the cAMP pathway and the calcium/calmodulin-stimulated PDE (PDE 1) are of functional importance in the intracellular regulation in this tissue in vitro. In addition. initial clinical data with the PDE 1 inhibitor vinpocetine in patients not responding to standard anticholinergic therapy indicate a possible role for vinpocetine in the treatment of urgency, urge incontinence and, possibly, low compliance bladder and interstitial cystitis. The results of a larger randomized, double-blind, placebo-controlled, multicenter trial with vinpocetine show a tendency in favor of vinpocetine over placebo; however, statistically significant results were documented for one parameter only. This might be due to the rather low dosage chosen and the small sample size. Further studies are necessary and currently underway to delineate the optimal dosage, indications and patient population. Modulation of intracellular key enzymes effecting second messenger metabolism, i.e. isoenzyme-selective PDE inhibition is a novel approach which possibly avoids the limitations of anticholinergic therapy in patients with lower urinary tract dysfunction.
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PMID:Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: from bench to bedside. 1176 Jul 83

IC351 (tadalafil, trade name Cialis) is a new representative compound of the second generation of selective phosphodiesterase 5 (PDE-5) inhibitors. The selectivity ratio vs PDE-5 is more than 10 000 for PDE-1 through PDE-4 and PDE-7 through PDE-10 and 780 for PDE-6. In the European daily-dosing trial, the efficacy rates were up to 93% for successful intercourses with completion in the 50-mg dose in patients with mild to moderate erectile dysfunction (ED). In two different dose-ranging studies with 2-25 mg taken as needed, efficacy rates of up to 88% improvement in erections and up to 73% successful intercourses with completion were achieved. In a placebo-controlled, fixed-dose (10- and 20-mg) trial in diabetic patients, improved erections of 56% and 64% were reported compared with 25% after placebo. Drug-related adverse effects, with headache in up to 23% of patients (placebo, up to 17%), dyspepsia in up to 11% (placebo, up to 7%), back pain in up to 4.7% (placebo, 0%), and myalgia in up to 4.1% (placebo, up to 2.4%), were mostly mild to moderate. Neither drug-related serious cardiovascular adverse events nor color vision disturbances were encountered. The long half-life (>17 h), with a comfortably long window of opportunity, releases couples from the need to plan sexual activities and therefore provides the highest amount of spontaneity for sexual activities.
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PMID:IC351 (tadalafil, Cialis): update on clinical experience. 1185 Jul 37

Vardenafil, a potent and selective phosphodiesterase 5 inhibitor, has entered phase 3 clinical trials. Pharmacodynamic studies showed that the maximum plasma concentration after oral administration of 20-40 mg of vardenafil occurred in 0.7-0.9 h, the half-life was 4-5 h, and negligible amounts remained in the circulation after 24 h. The efficacy of vardenafil compared with placebo was shown in RigiScan studies, a phase 2 study involving 601 men with mild-to-severe erectile dysfunction for at least 6 months, and a phase 3 study involving 452 diabetic men. Adverse effects were not severe and tended to decrease with time.
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PMID:Vardenafil: update on clinical experience. 1185 Jul 38

Research in the field of erectile function and dysfunction has continued to expand rapidly. Based on the information available, some directions for future erectile dysfunction therapies can be identified. The first direction is improvement of current therapeutic principles. A second generation of orally active phosphodiesterase (PDE) inhibitors is being introduced, and further developments within this field can be expected. The recent introduction of apomorphine has opened the way for new dopamine receptor agonists. The second direction is combinations of existing therapeutic principles. Combinations of apomorphine and sildenafil and apomorphine and alpha(1)-adrenoceptor (AR) antagonists, for example, seem attractive and may have a therapeutic potential in patients not responding satisfactorily to single-drug treatment. Nitrosylated alpha(1)-AR antagonists, combining nitric oxide donation and alpha(1)- or alpha(2)-AR antagonism, are currently being evaluated. The third direction is new targets within the central nervous system. Melanocortin receptor agonists have shown promise not only in animal models, but also in preliminary studies in humans. Other possible targets, such as growth hormone-releasing peptide receptors, are being explored. The fourth direction is new peripheral targets. Rho-kinase antagonism and non-nitric oxide-mediated stimulation of soluble guanylyl cyclase have been suggested as possible new principles for drug development. The fourth direction is gene therapy. Progress has been made in intracavernosal somatic gene therapy and will probably continue. Still, problems remain, and advantages over conventional pharmacological therapies have to be demonstrated. The final direction is prevention strategies. Strategies to prevent cavernosal degeneration and/or to restore cavernosal function will be one of the most exciting challenges for future research.
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PMID:New directions for erectile dysfunction therapies. 1185 Jul 40

In vascular tissues including the corpus cavernosum, the organ function is reciprocally regulated by noradrenergic and non-adrenergic, non-cholinergic (NANC) nerves. NANC nerves innervating the corpus cavernosum is thought to be nitroxidergic (nitrergic) nerves which liberate nitric oxide (NO) produced by neuronal NO synthase, and liberated NO activates soluble guanylate cyclase (sGC) in cavernous smooth muscle cells. Intracellular increase in cyclic (c) GMP by activation of sGC dilates cavernous smooth muscle and then induces penile erection. Nitroxidergic (nitrergic) vasodilator nerves also innervate cavernous arteries and veins which regulate the blood volume in the corpus cavernosum. The order of potency of nitroxidergic nerve functions in these tissues (cavernosum > artery >> vein) may be suitable for producing the erection. Therefore, obstruction of the arteries and impairment of nitroxidergic (nitrergic) nerve function are speculated to be one of the causes for erectile dysfunction (ED). On the other hand, NO derived from the cavernous endothelium may partly contribute to erectile function. Sildenafil (Viagra) is one of the potent therapeutics for ED. The agent is a selective phosphodiesterase type 5 (PDE-V) inhibitor that inhibits degradation of cGMP elevated by NO mainly derived from the nerves. To develop more selective and safer therapeutics for ED, further systematic investigations are required.
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PMID:[Nitroxidergic (nitrergic) nerve and erectile dysfunction]. 1186 53

Diabetic men have a more than 3-fold increased prevalence of erectile dysfunction (ED) compared with nondiabetic men. Erectile function is primarily a vascular phenomenon, triggered by neurologic controls and facilitated by appropriate hormonal and psychological components. Recent advances in the understanding of the physiology of penile vasculature and its role in male sexual performance have influenced the clinical approach to ED. The pathophysiological alterations leading to impotence in diabetic men include vasculogenic, neurogenic, and hormonal etiologies. A clinical work-up, including a thorough history and physical examination, is an important aspect of ED management. Biochemical evaluations to rule out secondary causes like hypogonadism and thyroid abnormalities are suggested. Oral medications acting through phosphodiesterase inhibition in penile vasculature have revolutionized treatment of impotence in diabetic men. Because of a high success rate in treating ED of various etiologies, these agents are the treatment of choice for most patients. Safety and efficacy of vacuum-constriction devices, intraurethral suppositories, intracavernosal injections, and other therapies are discussed. A clinical algorithm for the evaluation and management of ED is provided for use in the primary care setting.
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PMID:Evaluation and treatment of erectile dysfunction in men with diabetes mellitus. 1188 32

We investigated the potency and the selectivity profile of vardenafil on phosphodiesterase (PDEs) enzymes, its ability to modify cGMP metabolism and cause relaxation of penile smooth muscle and its effect on erections in vivo under conditions of exogenous nitric oxide (NO) stimulation. PDE isozymes were extracted and purified from human platelets (PDE5) or bovine sources (PDEs 1, 2, 3, 4 and 6). The inhibition of these PDEs and of human recombinant PDEs by vardenafil was determined. The ability to potentiate NO-mediated relaxation and influence cGMP levels in human corpus cavernosum strips was measured in vitro, and erection-inducing activity was demonstrated in conscious rabbits after oral administration together with intravenous doses of sodium nitroprusside (SNP). The effects of vardenafil were compared with those of the well-recognized PDE5 inhibitor, sildenafil (values for sildenafil in brackets). Vardenafil specifically inhibited the hydrolysis of cGMP by PDE5 with an IC50 of 0.7 nM (6.6 nM). In contrast, the IC50 of vardenafil for PDE1 was 180 nM; for PDE6, 11 nM; for PDE2, PDE3 and PDE4, more than 1000 nM. Relative to PDE5, the ratios of the IC50 for PDE1 were 257 (60), for PDE6 16 (7.4). Vardenafil significantly enhanced the SNP-induced relaxation of human trabecular smooth muscle at 3 nM (10 nM). Vardenafil also significantly potentiated both ACh-induced and transmural electrical stimulation-induced relaxation of trabecular smooth muscle. The minimum concentration of vardenafil that significantly potentiated SNP-induced cGMP accumulation was 3 nM (30 nM). In vivo studies in rabbits showed that orally administered vardenafil dose-dependently potentiated erectile responses to intravenously administered SNP. The minimal effective dose that significantly potentiated erection was 0.1 mg/kg (1 mg/kg). The selectivity for PDE5, the potentiation of NO-induced relaxation and cGMP accumulation in human trabecular smooth muscle and the ability to enhance NO-induced erection in vivo indicate that vardenafil has the appropriate properties to be a potential compound for the treatment of erectile dysfunction. Vardenafil was more potent and selective than sildenafil on its inhibitory activity on PDE5.
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PMID:The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. 1189 May 15

Nitric oxide (NO) activates corpus cavernosum smooth muscle soluble guanylate cyclase (sGC) and increases the synthesis of cGMP that results in smooth muscle relaxation and ultimately, penile erection. To characterize sGC and define the potential synergy between NO and the allosteric activator YC-1 in corpus cavernosum, rat sGC was activated by either sodium nitroprusside (SNP) or YC-1, and YC-1 potentiated the effects of SNP with a 200-fold activation of sGC. Both SNP and YC-1 decreased the Km and increased the Vmax. ODQ significantly inhibited sGC activated by SNP with IC50 of 0.5 nM, but did not affect the sGC activated by YC-1 as well as basal sGC activity. SNP and YC-1 synergistically increased intracellular cGMP levels in rabbit corpus cavernosum smooth muscle cell cultures. YC-1 significantly relaxed rabbit cavernosum tissue strips in organ baths with an EC50 of 8.4 microM. In the presence of L-nitroarginine methyl ester to block endogenous NO production, co-administration of SNP shifted the dose response of YC-1 to the left, showing the synergism of SNP and YC-1 in tissue strips. In view of the clinical efficacy of phosphodiesterase-5 inhibitors, activation of sGC may provide an alternative means for enhancing the activity of neurally derived NO during sexual stimulation in the corpus cavernosum, representing a novel approach for the treatment of erectile dysfunction.
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PMID:Activation of soluble guanylate cyclase causes relaxation of corpus cavernosum tissue: synergism of nitric oxide and YC-1. 1197 28


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