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)

This study examined the effects of dopamine D1 and D2 receptor agonists and antagonists on the spontaneous and calcium-dependent, K+-induced release of gamma-[3H]aminobutyric acid [( 3H]GABA) accumulated by slices of rat substantia nigra. SKF 38393 (D1 agonist) and dopamine (dual D1/D2 agonist) were without effect on [3H]GABA efflux by themselves (1-40 microM), or in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) (0.5 mM), but potentiated evoked release in the presence of forskolin (0.5 microM), an adenylate cyclase activator. These increases in release were prevented by the D1 antagonist SCH 23390 (0.5 microM), but not by the D2 antagonist metoclopramide (0.5 microM). Higher concentrations of forskolin (10-40 microM) augmented stimulus-evoked [3H]GABA release directly, whereas dibutyryl cyclic AMP (100-200 microM) depressed it. Apomorphine, noradrenaline, and 5-hydroxytryptamine (1-40 microM) had no effect. The D2 stimulants lisuride, RU 24213, LY 171555, and bromocriptine dose-dependently inhibited depolarisation-induced but not basal [3H]GABA outflow. These inhibitory responses were not modified by the additional presence of SKF 38393 (10 microM) or SCH 23390 (1 microM), or by injection of 6-hydroxydopamine into the medial forebrain bundle 42 days earlier, but were attenuated by metoclopramide (0.5 microM). Higher amounts (10 microM) of SCH 23390, metoclopramide, or other D2 antagonists (loxapine, haloperidol) reduced evoked GABA release by themselves, probably by nonspecific mechanisms. These results suggest D1 and D2 receptors may have opposing effects on nigral GABA output and could explain the variable effects of mixed D1/D2 dopaminomimetics in earlier release and electrophysiological experiments.
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PMID:Opposing roles of dopamine D1 and D2 receptors in nigral gamma-[3H]aminobutyric acid release? 295 68

Rats were trained to discriminate between the stimulus properties of intraperitoneal 0.16 mg/kg apomorphine and saline in a two-lever, food-motivated operant task. Apomorphine, at doses different than the training dose, produced a dose-response relationship, whereas, caffeine (7.5-30 mg/kg) produced saline-like responding. However, co-administered of 15 mg/kg caffeine with 0.01, 0.02 or 0.04 mg/kg apomorphine potentiated the discriminative stimulus properties of these low apomorphine doses. This potentiation was antagonized by pretreatment with 0.25 mg/kg haloperidol. The results are consistent with the idea that caffeine, by virtue of being a phosphodiesterase inhibitor, may increase post-synaptic cyclic-AMP and this, in turn, may supersensitize the dopamine receptors and result in the potentiation of the apomorphine-induced dopaminergic responses.
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PMID:Caffeine potentiation of apomorphine discrimination. 625 84

Contractions evoked by noradrenaline (1 microM) or a depolarizing solution of 60 mM KCl were concentration dependently depressed by the aporphine alkaloids (S)-boldine and (R)-apomorphine in rat aorta. Both drugs had a greater inhibitory potency on the contraction elicited by noradrenaline. Dose-response curves for noradrenaline were shifted to the right in presence of (S)-boldine. (R)-Apomorphine acted by a complex mechanism at alpha 1-adrenoceptors and its inhibitory effect was irreversible. The conformational features of these alkaloids may explain their different behaviour at alpha 1-adrenoceptors. In Ca(2+)-free solution, the alkaloids inhibited the contraction evoked by noradrenaline but did not modify (apomorphine) or increase (boldine) the contractile response induced by caffeine. Both alkaloids interacted with [3H]prazosin binding and with the benzothiazepine binding site of the Ca2+ entry receptor complex but had no effect at the dihydropyridine binding site in the rat cerebral cortex. Both drugs showed some selectivity as inhibitors of [3H]prazosin binding as opposed to [3H]d-cis diltiazem binding. (R)-Apomorphine slightly inhibited one of the two forms of the Ca(2+)-independent, low Km cyclic AMP-phosphodiesterase (type IV), whereas it did not have a significant effect on the other phosphodiesterase forms. (S)-Boldine had negligible inhibitory effects on all phosphodiesterase forms. The present study provides evidence that (S)-boldine and (R)-apomorphine have interesting properties as Ca2+ entry blockers (through the benzothiazepine receptor site in the Ca2+ channel) and at alpha 1-adrenoceptors.
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PMID:Selective action of two aporphines at alpha 1-adrenoceptors and potential-operated Ca2+ channels. 838 12

Oral drugs are a well-established, first-line therapy for erectile dysfunction. As a result of the success of sildenafil, a plethora of new drugs for erectile dysfunction are on the horizon. Apomorphine and IC351 are in late phase III development. Vardenafil (Bayer, New Haven, CT), a PDE5 inhibitor, and the combination of yohimbine and L-arginine (NitroMed, Boston, MA) are in early phase III development. Early clinical and preclinical studies are investigating new phosphodiesterase inhibitors, cyclic AMP activators, alpha-adrenergic antagonists, dopamine agonists, melanocyte-stimulating hormone, potassium channel modulators, endothelin antagonists, and new nitric oxide donors. The future is bright for this infant field of sexual pharmacotherapy.
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PMID:Oral drug therapy for erectile dysfunction. 1140 84

Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents, but also by visual, olfactory, and imaginary stimuli. The reflex involves both autonomic and somatic efferents and is modulated by supraspinal influences. Several central transmitters involved in the erectile control have been identified. Dopamine, acetylcholine, nitric oxide (NO), and peptides, such as oxytocin and adrenocorticotropic/alpha-melanocyte-stimulating hormone, seem to have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. Peripherally, the balance between contractant and relaxant factors controls the degree of contraction of the smooth muscle of the corpora cavernosa and determines the functional state of the penis. Noradrenaline contracts both corpus cavernosum and penile vessels via stimulation of alpha(1)-adrenoceptors. Neurogenic NO is considered the most important factor for relaxation of penile vessels and corpus cavernosum. The role of other mediators released from nerves or endothelium has not been definitely established. Erectile dysfunction (ED) may be due to inability of penile smooth muscles to relax. This inability can have multiple causes. However, patients with ED respond well to the pharmacological treatments that are currently available. The drugs used are able to substitute, partially or completely, the malfunctioning endogenous mechanisms that control penile erection. Most drugs have a direct action on penile tissue facilitating penile smooth muscle relaxation, including prostaglandin E(1), NO donors, phosphodiesterase inhibitors, and alpha-adrenoceptor antagonists. Dopamine receptors in central nervous centers participating in the initiation of erection have been targeted for the treatment of ED. Apomorphine, administered sublingually, is the first of such drugs.
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PMID:Pharmacology of penile erection. 1154 36

Erectile dysfunction (ED) is a common problem with a prevalence of approximately 50% in men aged 40 to 70. There are several etiologies for ED including vasculogenic, neurogenic, hormonal and/or psychogenic factors; one-fourth of ED cases can be drug-related. Penile erection involves a complex interaction between the CNS and local factors. It is a neurovascular event modulated by psychological and hormonal factors. Pharmacologically, neural modulation and endocrine status are very important to attaining penile erection. There have been several significant advances for the pharmacologic treatment of ED. Treatments include agents that are not only orally effective, but possess either local or central acting mechanisms of action. Apomorphine, a centrally-acting agent, is effective in the treatment of ED. Sildenafil, another orally effective agent, acts by inhibiting cyclic GMP-specific phosphodiesterase Type V. Testosterone can be effective transdermally. Non-orally active agents include alprostadil and papaverine. Phentolamine and trazodone are effective in selected cases. Some agents can interact with other medications. Several pharmacological agents, some with central-acting mechanisms and some with Iocally-acting vascular effects, are therapeutically useful in the treatment of ED.
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PMID:Pharmacological aspects of erectile dysfunction. 1212 Jul 51

Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men worldwide. Many drugs are now available for treating ED; oral pharmacotherapy represents the first-line option for most patients with ED. Sildenafil, an inhibitor of the enzyme phosphodiesterase type 5, is currently the most widely prescribed oral agent and has a very satisfactory efficacy-safety profile in all patient categories. Apomorphine SL is a dopamine D1- and D2-receptor agonist which has recently been approved for marketing in Europe. It is best selected for treating patients with mild to moderate ED. Vardenafil and tadalafil are new phosphodiesterase type 5 inhibitors which are expected to be approved this year. Both of them have significant positive efficacy-safety profiles. Patients who do not respond to oral pharmacotherapy or who cannot use it are good candidates for intracavernosal and intraurethral therapy. Alprostadil is the most widely used drug, both for injection therapy and for the intraurethral route. The efficacy of second-line treatment is high but the attrition rate remains significant.
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PMID:Pharmacological management of erectile dysfunction. 1260 96

Erectile dysfunction is a medical condition that influences the sexual life of millions of men and women worldwide. Due to a large number of currently available drugs, the therapy of erectile dysfunction has changed profoundly during the last decades. The pharmacologic options are divided into initiators versus conditioners and central- or peripheral-acting drugs. Besides intraurethral and intracavernous application of prostaglandin E(1) (PGE(1), peripheral initiator)--a transdermal application is still in clinical testing--there are drugs for oral application. PGE(1), the vasoactive drug mainly used, was replaced by sildenafil in first-line-therapy. PGE(1), administered intracavernosally or intraurethrally, is highly effective with success rates up to 90%, but the attrition rate due to personal inconvenience remains significant. Yohimbine is known as a central amplifier of erection and is useful in psychogenic and mild organic erectile dysfunction. Apomorphine, a central initiator of erection, amplifies erectile response as a central dopamine agonist in mild and moderate erectile dysfunction and starts acting 15-20 min after sublingual application. The phosphodiesterase type 5 (PDE-5) inhibitors sildenafil, vardenafil, and taldalafil are peripheral conditioners. Sildenafil, the most distributed oral agent worldwide, should be taken orally 60 min before sexual intercourse in combination with sexual stimulation. Sildenafil shows a high efficacy-safety profile with success rates for all etiologies between 50-80%. Paralleling nitrate-containing medication is an absolute contraindication. Vardenafil, another selective PDE-5 inhibitor with potentially higher selectivity and efficacy compared to sildenafil was just approved. The data from the clinical trials show the same adverse events and success rates as sildenafil. Tadalafil, just launched as well, amplifies erectile function for up to 24 h, allowing the patient to engage in sexual activity for this period. Adverse events and success rates resemble those of the other two substances. If medical treatment fails, there are nonpharmacologic options such as the vacuum constriction device and penile implants. The vacuum device is a safe and effective option for well-selected patients. Penile implants, especially the inflatable ones, completely imitate the physiologic erection. Due to recent research, infection rates and mechanical failures were minimized. Therefore penile implant surgery is well accepted by the patients and their partners. Despite this wide variety of options, therapy of erectile dysfunction should be performed in an individually adapted way. The patient's exact history, physical examination, collaboration of medical disciplines and choice of therapy will offer all patients the possibility to achieve or regain a satisfying sexual life.
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PMID:[New treatment options for erectile dysfunction. Pharmacologic and nonpharmacologic options]. 1282 47

Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men worldwide. Many drugs are now available for the treatment of ED, with oral pharmacotherapy representing the first-line option for most patients. Sildenafil citrate, an inhibitor of the enzyme phosphodiesterase type 5 (PDE5), is the most widely prescribed oral agent and has a very satisfactory efficacy-safety profile in all patient categories. Tadalafil (Cialis; Eli Lilly & Co., ICOS) and vardenafil (Levitra; Bayer Pharmaceuticals, GlaxoSmithKline) are new PDE5 inhibitors that have recently been approved worldwide. Both have been associated with significant positive efficacy-safety profiles. Apomorphine sublingual is a dopamine D1 and D2 receptor agonist, which has been approved for marketing in Europe. It is best selected for treating patients with mild-to-moderate ED, but it is seldom used in clinical practice due to its limited efficacy and side effects, particularly nausea. Patients who do not respond to oral pharmacotherapy or who are unable to use it are appropriate candidates for intracavernosal and intraurethral therapy. The efficacy of second-line treatment is high, but the attrition rate remains significant. For the purpose of this review, clinical and pharmacological analysis focuses on the recent advances in the field of oral therapy, including PDE5 inhibitors and sublingual apomorphine.
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PMID:Emerging oral drugs for erectile dysfunction. 1515 43

In 1998, we concluded that sildenafil (Viagra--fizer Ltd), a selective phosphodiesterase type 5 inhibitor, appeared to offer advantages over other medical approaches for erectile dysfunction in terms of ease of administration and cost. Oral drug treatment is now widely advocated as first-line therapy for erectile dysfunction, except where the cause is clearly psychological. In the past 4 years, three more oral preparations have been licensed in the UK for the treatment of men with erectile dysfunction. A sublingual preparation of the dopaminergic agonist apomorphine (Uprima--Abbott Laboratories Ltd) is the first centrally acting drug to be licensed. Tadalafil (Cialis--Eli-Lilly) and vardenafil (Levitra--Bayer PLC) are phosphodiesterase type 5 inhibitors. Here we review the place of these preparations for men with erectile dysfunction.
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PMID:New oral drugs for erectile dysfunction. 1527 71


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