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)

Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor and is predominantly used in the treatment of erectile dysfunction. While maintaining an excellent safety and tolerability profile in the management of erectile dysfunction, sildenafil also provides a prolonged benefit in various other diseases. Sildenafil has been shown to have a potential therapeutic efficacy for disorders related to the central nervous system and pulmonary system. In the central nervous system, it exerts its neuroprotective effects in multiple sclerosis and has a significant memory enhancing action. Sildenafil also significantly enhances neurogenesis. Several lines of evidence indicate that targeting PDE5 with sildenafil offers novel strategies in the treatment of age-related memory impairment. Guanylate cyclase/cGMP/protein kinase G pathway or glutamate/nitric oxide/cGMP pathway appears to mediate memory enhancing effects. Some of the positive cognitive features of sildenafil therapy are likely attributable to the mechanisms reviewed here. Sildenafil has been shown to reduce pulmonary hypertension and alleviate pain in animals and humans. The present review primarily focuses on the various pharmacological effects of sildenafil with regard to its influence on the nervous and pulmonary system.
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PMID:Versatile effects of sildenafil: recent pharmacological applications. 1755 93

Female sexual dysfunction can be founded by disorders of sexual desire, arousal, orgasm, and sexual pain. Physiologic sexual dysfunction can, in many cases, be the result of impaired neurovascular tone to the clitoris and vagina. The vagina and clitoris both contain erectile tissue and phosphodiesterase type 5 (PDE5). Accordingly, the use of sildenafil, a PDE5 inhibitor, has been studied in relation to neurogenic female sexual dysfunction. The present case report addresses neurogenic female sexual dysfunction from the result of a ruptured L5-S1 intervertebral disk. The patient was treated with sildenafil, and her symptoms were recorded using a Female Sexual Function Index score. Discussion of the use of sildenafil in women, with an emphasis on female neurovascular sexual physiology and function, is reviewed.
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PMID:Success of sildenafil treatment in neurogenic female sexual dysfunction caused by L5-S1 intervertebral disk rupture: a case report. 1759 8

The treatment of neuropathic pain is a major unresolved medical challenge. Present pharmacotherapies only have modest efficacy and numerous side effects. The use of opioid analgesics is additionally coupled with dependence and withdrawal syndromes. Ibudilast (AV-411) is a non-selective phosphodiesterase inhibitor that is also known to suppress glial cell activation. It has been used clinically for other indications with a good safety profile. As glial cell activation is considered to crucially contribute to neuropathic pain as well as opioid dependence and withdrawal, the authors conceived that ibudilast may be useful for treating these conditions. Preclinical data indicate that ibudilast crosses the blood-brain barrier, is well tolerated, is active on oral administration, reduces glial activation and attenuates pain symptoms in diverse rat models of neuropathic pain. In addition, it enhances acute morphine analgesia and attenuates morphine tolerance and withdrawal. Thus ibudilast may improve opioid efficacy and is a promising therapeutic candidate for neuropathic pain, with a novel mechanism of action.
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PMID:Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. 1759 81

In a multicenter clinical monitoring study (observation of use investigation according to 67.6 of the German Drug Law), which was conducted between 2003 and 2005 in 105 urological practices in 314 patients with organic erectile dysfunction (ED), efficacy, safety, convenience and acceptance of intraurethral administered alprostadil (CAS 745-65-3; MUSE - Medicated Urethral System for Erection) was studied. 306 patients could statistically be evaluated. The patients were 61.3 +/- 9.2 years old (median+/- SD) (181 patients between 60 and 80 y). The time of ED was from 2 to 120 months with a mean duration of 21.5 +/- 22 months (median+/-SD. Genesis of the ED was in 55 % of the patients a local damage, which followed in 42.8 % a prostate cancer surgery. 46 % of the patients had vascular, 28 % metabolic diseases including diabetes and 11% neural damages. In 51.3% of the patients drugs, which were known to induce ED, were suspected to have caused or partially caused the impairment. The degree of the disturbance was in 93 % of the cases moderate to severe. Alprostadil (MUSE) was applicated three times in doses of 250, 500 or 1000 microg. The dosage of 1000 microg was used for the third application by 65 % of the patients. Very good and good efficacy increased from 45.8% of the patients after the first through 63.7 % after the second to 69.3 % after the third application. In patients after surgery because of prostate cancer very good and good efficacy improved in comparison to the first application about 20% and concerned 53.9 % of the patients after the third application. Sexual intercourse was possible by 67% of the patients after the first, 83 % after the second and 87 % after the third use. Tolerability of alprostadil (MUSE) was very good and good in 90% of the patients. 81.1% intended to continue the treatment. The handling of alprostadil (MUSE) was assessed very good and good by 75%, the acceptance was very good and good in 96% of the patients. In a retrospective comparison with other drugs for the treatment of ED intracavernosal alprostadil ("SKAT") was slightly more effective than intraurethral alprostadil (MUSE) (32.1% vs 25 %), but alprostadil (MUSE) was assessed more useful by 82.1% and preferred by 78.6% of the patients. In comparison to phosphodiesterase-5- (PDE-5)-inhibitors alprostadil (MUSE) was more effective in 77.7 %, and 79.6 % of the patients preferred it. In comparison to apomorphin 94.1% preferred alprostadil (MUSE). 98 % of the patients reported better efficacy of alprostadil (MUSE), and 94.1% preferred it. Five adverse events were reported (slight urethral pain). No patient dropped out. In this non-interventional investigation the good efficacy and tolerability of intraurethral applicated alprostadil (MUSE) as a second-line therapy after failure or minor efficacy of PDE-5 inhibitors and other oral drugs was comparable with the results of the clinical trials. The patients in the urological practices assessed handling and acceptance of the system high.
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PMID:[Intraurethrally applicated alprostadil for the treatment of organic erectile dysfunction in practice: a multicenter clinical monitoring study (noninterventional investigation)]. 1768 74

Recent years have seen great progress in the researches on the pharmacotherapy of female sexual dysfunction( FSD). Estrogen replacement therapy is effective on female sexual pain and dyspareunia; androgen can improve female hyposexuality; and a variety of drugs and medication forms are being studied for their efficacy on FSD, including the 5-phosphodiesterase inhibitor, dopamine receptor stimulant, prostaglandin E1, adrenergic receptor blocker, some traditional Chinese medicine, and so on, which have yielded lots of inspiring findings.
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PMID:[Progress in pharmacotherapy of female sexual dysfunction]. 1807 18

Controlling neuropathic pain is an unmet medical need and we set out to identify new therapeutic candidates. AV411 (ibudilast) is a relatively nonselective phosphodiesterase inhibitor that also suppresses glial-cell activation and can partition into the CNS. Recent data strongly implicate activated glial cells in the spinal cord in the development and maintenance of neuropathic pain. We hypothesized that AV411 might be effective in the treatment of neuropathic pain and, hence, tested whether it attenuates the mechanical allodynia induced in rats by chronic constriction injury (CCI) of the sciatic nerve, spinal nerve ligation (SNL) and the chemotherapeutic paclitaxel (Taxol). Twice-daily systemic administration of AV411 for multiple days resulted in a sustained attenuation of CCI-induced allodynia. Reversal of allodynia was of similar magnitude to that observed with gabapentin and enhanced efficacy was observed in combination. We further show that multi-day AV411 reduces SNL-induced allodynia, and reverses and prevents paclitaxel-induced allodynia. Also, AV411 cotreatment attenuates tolerance to morphine in nerve-injured rats. Safety pharmacology, pharmacokinetic and initial mechanistic analyses were also performed. Overall, the results indicate that AV411 is effective in diverse models of neuropathic pain and support further exploration of its potential as a therapeutic agent for the treatment of neuropathic pain.
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PMID:The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain. 1817 32

Cilostazol, a selective phosphodiesterase type III inhibitor, has vasodilatory, antiplatelet, and antithrombotic actions, as well as being the first-choice drug for the intermittent claudication due to peripheral vascular disease. Main researches have demonstrated significant improvement for this situation, including patients with diabetes mellitus, concerning pain-free walking distance and quality-of-life, not rising the bleeding event risk. It does not affect the glucose metabolism even in patients suffering from diabetes. This paper aims to present a review on the discoveries of various studies, most of them experimental, on the prevention and treatment of diabetes mellitus complications, such as nephropathy and neuropathy, through the use of cilostazol, which demonstrated satisfactory results on the improvement in neural blood flow, on sodium-potassium ATPase activity, on insulin resistance, and microalbuminuria. However, strict controlling of glucose plasma levels, hypertension, and smoking habits, as well as more extended investigations on the matter are required to the better comprehension.
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PMID:[Potential therapeutic approaches for prevention and treatment of diabetic nephropathy and neuropathy: evidences of cilostazol]. 1820 97

Anandamide (AEA) is an endogenous ligand of cannabinoid receptors and a well characterized mediator of many physiological processes including inflammation, pain, and appetite. The biosynthetic pathway(s) for anandamide and its N-acyl ethanolamine (NAE) congeners remain enigmatic. Previously, we proposed an enzymatic route for producing NAEs that involves the double-O-deacylation of N-acyl phosphatidylethanolamines (NAPEs) by alpha/beta-hydrolase 4 (ABDH4 or Abh4) to form glycerophospho (GP)-NAEs, followed by conversion of these intermediates to NAEs by an unidentified phosphodiesterase. Here, we report the detection and measurement of GP-NAEs, including the anandamide precursor glycerophospho-N-arachidonoylethanolamine (GP-NArE), as endogenous constituents of mouse brain tissue. Inhibition of the phosphodiesterase-mediated degradation of GP-NAEs ex vivo resulted in a striking accumulation of these lipids in brain extracts, suggesting a rapid endogenous flux through this pathway. Furthermore, we identify the glycerophosphodiesterase GDE1, also known as MIR16, as a broadly expressed membrane enzyme with robust GP-NAE phosphodiesterase activity. Together, these data provide evidence for a multistep pathway for the production of anandamide in the nervous system by the sequential actions of Abh4 and GDE1.
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PMID:Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection of glycerophospho-N-acyl ethanolamine precursors in mouse brain. 1822 59

Functional urology knows more and more a marked development. Regarding benign prostatic hyperplasia, combined treatments are used often and new molecules such as inhibitor of phosphodiesterase of type 5 are appearing. The gold standard treatment of urinary incontinence with sphincteric deficiency remains the artificial urinary sphincter, in men and in women, where the rate of success is nearly of 95 %. The use of botulinic toxin in neurogenic bladder and especially in overactive bladder is growing remarkably, notably in patients of whom quality of life is improve against a very low toxicity. However, the effect of the molecules becomes blurred within a few months. The CT diagnosis of urinary lithiasis is about to provide nowadays the main component of each calculi. Peyronie's disease remains scarce in which verapamil's injections are strongly suggested to amend pain but not the curve during erection.
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PMID:[Functional urology: synopsis of the 101st Congress of the French Association of Urology]. 1845 79

Recently, it has been known that the antinociception of sildenafil, a phosphodiesterase 5 inhibitor, is mediated through the opioid receptors. There are common three types of opioid receptors mu, delta, and kappa. We characterized the role of subtypes of opioid receptor for the antinociception of sildenafil at the spinal level. Intrathecal catheters were placed for drug delivery and formalin solution (5%, 50 microl) was injected for induction of nociception within male SD rats. The effect of mu opioid receptor antagonist (CTOP), delta opioid receptor antagonist (naltrindole), and kappa opioid receptor antagonist (GNTI) on the activity of sildenafil was examined. Intrathecal sildenafil decreased the flinching responses during phases 1 and 2 in the formalin test. Intrathecal CTOP and naltrindole reversed the antinociception of sildenafil during both phases in the formalin test. Intrathecal GNTI reversed the effect of sildenafil during phase 2, but not phase 1. These results suggest that sildenafil is effective to acute pain and the facilitated pain state at the spinal level. Both mu and delta opioid receptors are involved. However, it seems that kappa opioid receptors play in the effect of sildenafil.
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PMID:Roles of opioid receptor subtypes on the antinociceptive effect of intrathecal sildenafil in the formalin test of rats. 1858 61


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