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)

Current pharmacological treatment modalities for urge incontinence and low compliance bladder are limited by a low clinical efficacy and the significant side effects of the standard drugs available. Previous in vitro studies indicated a possible functional relevance of the intracellular phosphodiesterase (PDE)-1 isoenzyme in the regulation of human detrusor smooth muscle contractility. We therefore investigated the effect of the PDE-1 inhibitor vinpocetine in nonresponders to standard pharmacological therapy. In 11/19 patients (57.9%) clinical symptoms and/or urodynamic parameters were improved. Although these initial data are preliminary, they represent the first evidence that isoenzyme-selective PDE inhibition may be a novel approach to the treatment of lower urinary tract disorders.
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PMID:Initial clinical experience with the selective phosphodiesterase-I isoenzyme inhibitor vinpocetine in the treatment of urge incontinence and low compliance bladder. 1120 66

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

Although patients with multiple sclerosis (MS) are likely to have problems with bladder, bowel and sexual function, these problems have often been neglected in the past. Bladder dysfunction produces symptoms of urgency, frequency and urge incontinence (due to bladder overactivity and incomplete emptying), and is found in up to 75% of patients with MS. The mainstay of drug treatment for neurogenic bladder overactivity is anticholinergic medication, although intravesical treatments have also been proposed, such as the vanilloids and botulinum toxin, as well as sublingual cannibanoids. There has been much progress with pro-erectile agents in recent years, notably the use of sildenafil citrate, which has been shown to be particularly efficacious in these patients. Other agents include apomorphine hydrochloride and newer phosphodiesterase 5 inhibitors; however, the efficacy of these drugs in patients with MS remains to be proven. Research in female sexual dysfunction is also progressing, although this aspect of patient well being has only recently been addressed; the reported development of a classification system for the condition is likely to help categorise future treatments. Unlike bladder and sexual dysfunction, there have been rather limited advances in the treatment of faecal incontinence and constipation specifically for patients with MS, despite a prevalence of up to 50%. This review highlights the strategies for these types dysfunction commonly seen in patients with MS, with report of recent pharmacological developments.
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PMID:Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies. 1251 63

Lower urinary tract disorders include disorders affecting continence (stress urinary incontinence, urge urinary incontinence, and benign prostatic hyperplasia) and male erectile dysfunction. Although none of these conditions are fatal, they affect overall quality of life. Throughout modern medicine the treatment of these conditions was limited to psychological counseling or surgical intervention. In recent years, research defining the physiological mechanisms of continence and male sexual function has aided in the pharmacologic design of approaches to these conditions. These agents can act both centrally or on the peripheral genitourinary smooth muscle to alleviate disease symptoms. Incontinence is primarily treated with agents that act directly on the bladder smooth muscle such as muscarinic antagonists. However, afferent blockade to attenuate the spinalbulbospinal reflex pathway including mixed norepinephrine/serotonin reuptake inhibitors may provide a key breakthrough. Erectile dysfunction treatment has been revolutionized via the discovery of the nitric oxide pathway and phosphodiesterase 5 inhibitors. New peripheral targets as well as centrally acting agents represent potential emerging therapies. In this review, the pharmacologic basis of treatment of these disorders is discussed with special emphasis on emerging new therapeutics.
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PMID:Emerging pharmacologic approaches for the treatment of lower urinary tract disorders. 1471 92

Autonomic pathways are important in the regulation of both lower urinary tract and sexual function, and their interruption in neurological pathologies predictably results in variable urogenital dysfunction, depending mainly on the level of the lesion. A normal neurological examination of a patient with urogenital complaints should exclude an underlying neurological pathology, and the neurologist should become involved in the management of symptoms. Electromyography can be of value in the diagnosis and management of cauda equina lesions and multiple system atrophy, but neurophysiological investigations are of no importance in the diagnosis of neurogenic sexual dysfunction. Urodynamic studies have proven helpful in determining the type and management of lower urinary tract dysfunction. Oral anticholinergics usually combined with clean intermittent catheterizations are the first-line treatment options for neurogenic lower urinary tract dysfunction, with intravesical treatments emerging as the main alternative in intractable incontinence. The availability of effective oral phosphodiesterase inhibitors has revolutionized the management of erectile dysfunction, but treatment of ejaculatory and orgasmic disorders as well as of female sexual dysfunction still remains problematic.
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PMID:Evaluation and treatment of autonomic disorders of the urogenital system. 1508 65

Cyclic nucleotide levels are controlled through their synthesis from nucleotide triphosphates by cyclases and their degradation to 5'-monophosphates by phosphodiesterases (PDEs). Components controlling cyclic AMP-induced relaxation in the urinary tract include receptors, inhibitory and stimulatory G-proteins, isoforms of adenylyl cyclase and PDEs. The responsiveness of PDEs to a variety of physiological challenges is related to the presence of multiple families of isoenzymes with specific localization within tissues and within cells. At least 11 families of PDEs encode more than 50 PDE proteins produced in mammalian cells. In the urinary tract, characterization of PDE isoforms has lagged behind other systems and much of the literature was published prior to identification of PDE7, 8, 9, 10, 11. Specific PDE inhibitors regulate smooth muscle function in the bladder, urethra, prostate and ureter. The pharmacological potential of these inhibitors may include treatment of urge incontinence and the low compliance bladder, and treatment of prostate cancer. G-proteins also regulate cyclic AMP production. Changes in specific G- protein isoforms with aging, most prominently Gialpha2, cause decreased relaxation response in the aging bladder. As we have seen here with aging and certainly in other disease processes, levels of the components of adenylyl cyclase/phosphodiesterase/protein kinase can change and thus affect the relaxation response. By exploitation of differences in PDE expression in disease, such as the overexpression of PDEs in cancer, treatment options may present themselves.
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PMID:Regulation of cyclic nucleotides in the urinary tract. 1585 36

Prostate cancer is the leading malignancy in men in the United States and causes more than 60,000 deaths annually. Treatment of prostate cancer, whether it be with surgery, radiation therapy, cryotherapy, or medical treatment, is associated with significant life-altering morbidity. Incontinence and erectile dysfunction (ED) too often are sequelae of these treatment alternatives. ED can be a significant complication and can alter the life of the patient with prostate cancer and his partner. Newer modifications of the radical prostatectomy with nerve-sparing techniques are the cornerstone of erection preservation. Time following radical prostatectomy has been shown to increase erectile function such that more patients have functional erections at 3 years than 1 year after surgery. With the advent of phosphodiesterase-5 (PDE-5) inhibitors, many men can have improved functional erections and return to active coitus. Prevention of ED also is an important management technique. Evidence is gathering that prophylaxis with regular vasoactive injection or daily PDE-5 agents may be an integral part of preservation of corpus cavernosum smooth muscle function. Combination medical therapy and surgical penile prosthesis implantation also are options for patients who do not respond to oral PDE-5 inhibitors.
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PMID:Erectile dysfunction and treatment of carcinoma of the prostate. 1623 21

There are several conditions associated with dysfunction of the lower urinary tract or which result in a reduction in the ability to engage in satisfactory sexual function and result in significant bother to sufferers, partners and/or carers. This review describes some of the animal models that may be used to discover safe and effective medicines with which to treat them. While alpha adrenoceptor antagonists and 5-alpha-reductase inhibitors deliver improvement in symptom relief in benign prostatic hyperplasia sufferers, the availability of efficacious and well-tolerated medicines to treat incontinence is less well served. Stress urinary incontinence (SUI) has no approved medical therapy in the United States and overactive bladder (OAB) therapy is limited to treatment with muscarinic antagonists (anti-muscarinics). SUI and OAB are characterised by high prevalence, a growing ageing population and a strong desire from sufferers and physicians for more effective treatment options. High patient numbers with low presentation rates characterizes sexual dysfunction in men and women. The introduction of Viagra in 1998 for treating male erectile dysfunction and the success of the phosphodiesterase type 5 inhibitor class (PDE5 inhibitor) have indicated the willingness of sufferers to seek treatment when an effective alternative to injections and devices is available. The main value of preclinical models in discovering new medicines is to predict clinical outcomes. This translation can be established relatively easily in areas of medicine where there are a large number of drugs with different underlying pharmacological mechanisms in clinical usage. However, apart from, for example, the use of PDE5 inhibitors to treat male erectile dysfunction and the use of anti-muscarinics to treat OAB, this clinical information is limited. Therefore, current confidence in existing preclinical models is based on our understanding of the biochemical, physiological, pathophysiological and psychological mechanisms underlying the conditions in humans and how they are reflected in preclinical models. Confidence in both the models used and the pharmacological data generated is reinforced if different models of related aspects of the same disorder generate confirmatory data. However, these models will only be fully validated in retrospect once the pharmacological agents they have helped identify are tested in humans.
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PMID:Animal models in urological disease and sexual dysfunction. 1646 85

Radical prostatectomy (RP) is a commonly performed procedure for the management of prostate cancer. While documented oncologic outcome for early stage disease is excellent, functional impairments such as incontinence and erectile dysfunction (ED) are common after the procedure. Recent evidence has implicated cavernous nerve damage and subsequent corporal oxygen deprivation, as well as corporal inflammation, in the pathogenesis of post-RP ED. Targeted therapies such as oral phosphodiesterase-5 inhibitors, mechanical vacuum erection devices, local alprostadil delivery and testosterone replacement (for hypogonal patients) have demonstrated some efficacy in the management of post-RP ED. This review aggregates much of the recent data in support of these therapies and critically reviews them. The article then presents tools to assess patients and partner sexual function to aid in identifying and monitoring post-RP ED. Finally, the article describes a protocol in use at Baylor College of Medicine as a guide toward the development of a protocol for erectile preservation (EP). The purpose of this work is to educate clinicians on emerging concepts in EP and provide an implementable protocol for use in practice.
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PMID:Emerging concepts in erectile preservation following radical prostatectomy: a guide for clinicians. 2169 60

This summary of the American Cancer Society Prostate Cancer Survivorship Care Guidelines targets primary care physicians who coordinate care of prostate cancer survivors with subspecialists. Prostate cancer survivors should undergo prostate-specific antigen screening every six to 12 months and digital rectal examination annually. Surveillance of patients who choose watchful waiting for their prostate cancer should be conducted by a subspecialist. Any hematuria or rectal bleeding must be thoroughly evaluated. Prostate cancer survivors should be screened regularly for urinary incontinence and sexual dysfunction. Patients with predominant urge incontinence symptoms, which can occur after surgical and radiation treatments, may benefit from an anticholinergic agent. If there is difficulty with bladder emptying, a trial of an alpha blocker may be considered. A phosphodiesterase type 5 inhibitor can effectively treat sexual dysfunction following treatment for prostate cancer. Osteoporosis screening should occur before initiation of androgen deprivation therapy, and patients treated with androgen deprivation therapy should be monitored for anemia, metabolic syndrome, and vasomotor symptoms. Healthy lifestyle choices should be encouraged, including weight management, regular physical activity, proper nutrition, and smoking cessation. Primary care physicians should be vigilant for psychosocial distress, including depression, among prostate cancer survivors, as well as the potential impact of this distress on patients' family members and partners.
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PMID:Primary Care of the Prostate Cancer Survivor. 2717 54


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