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)

Sexual problems are highly prevalent in both men and women and are affected by, among other factors, mood state, interpersonal functioning, and psychotropic medications. The incidence of antidepressant-induced sexual dysfunction is difficult to estimate because of the potentially confounding effects of the illness itself, social and interpersonal comorbidities, medication effects, and design and assessment problems in most studies. Estimates of sexual dysfunction vary from a small percentage to more than 80%. This article reviews current evidence regarding sexual side effects of selective serotonin reuptake inhibitors (SSRIs). Among the sexual side effects most commonly associated with SSRIs are delayed ejaculation and absent or delayed orgasm. Sexual desire (libido) and arousal difficulties are also frequently reported, although the specific association of these disorders to SSRI use has not been consistently shown. The effects of SSRIs on sexual functioning seem strongly dose-related and may vary among the group according to serotonin and dopamine reuptake mechanisms, induction of prolactin release, anticholinergic effects, inhibition of nitric oxide synthetase, and propensity for accumulation over time. A variety of strategies have been reported in the management of SSRI-induced sexual dysfunction, including waiting for tolerance to develop, dosage reduction, drug holidays, substitution of another antidepressant drug, and various augmentation strategies with 5-hydroxytryptamine-2 (5-HT2), 5-HT3, and alpha2 adrenergic receptor antagonists, 5-HT1A and dopamine receptor agonists, and phosphodiesterase (PDE5) enzyme inhibitors. Sexual side effects of SSRIs should not be viewed as entirely negative; some studies have shown improved control of premature ejaculation in men. The impacts of sexual side effects of SSRIs on treatment compliance and on patients' quality of life are important clinical considerations.
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PMID:Effects of SSRIs on sexual function: a critical review. 1127 Sep 25

The role of phosphodiesterase type 5 inhibition in the modulation of female sexual dysfunction was investigated by assessing its effects on in vitro relaxation of rabbit clitoris. Stimulation of the non-adrenergic, non-cholinergic neurons of the clitorus elicited a frequency-dependent relaxation response. Inhibition of NO synthase with L-NAME (100 microM) or inhibition of soluble guanylate cyclase with ODQ (1.0 microM) almost completely abolished the electrical field stimulation-induced relaxation of clitorus suggesting that NO-cGMP pathway mediates the relaxation response to electrical field stimulation. Similarly, tetrodotoxin, a neuronal sodium channel blocker abolished the electrical field stimulation-induced clitoral relaxation implying a neuronal release of NO contributes to the electrical field stimulation elicited relaxation. Pretreatment of the clitoral corpus cavernosum strips with sildenafil (100 nM) enhanced the electrical field stimulation-induced relaxations both in magnitude and duration. The results suggest that sildenafil enhances electrical field stimulation elicited clitoral relaxation by a NO-cGMP dependent pathway. These data also imply that sildenafil may be useful to treat female sexual dysfunction.
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PMID:Sildenafil relaxes rabbit clitoral corpus cavernosum. 1089 25

The past few years have witnessed major developments in the management of male sexual dysfunction. The introduction of the first efficacious and safe oral medication (sildenafil) resulted in the expansion of the patient base and, the change in health care delivery, with erectile dysfunction (ED) entering the primary care physician's practice. New guidelines for the diagnosis and treatment of ED have been developed, including the Process of Care in the USA and the 1st International Consultation on ED sponsored by the World Health Organization. Well-defined algorithms for diagnosis and treatment have been adopted. These recent developments have brought up challenging issues, including the cardiovascular safety of sexual activity, societal changes, internet prescriptions, definition of the patient, expansion of clinical and laboratory research, rise of interest in female sexual dysfunction, and a significant economic impact. The recent developments in male sexual dysfunction continue with the study of new oral medications. Some of these new medications, such as sublingual apomorphine, have a central mode of action, whereas others, such as the phosphodiesterase inhibitor IC351, have a selective peripheral vasodilation-enhancing action.
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PMID:Recent developments in male sexual dysfunction. 1112 55

Phosphodiesterase 5 terminates the cellular actions of the second messenger molecule cyclic GMP; inhibitors of phosphodiesterase 5 will therefore increase and prolong the actions of endogenous substances that signal via the cyclic GMP pathway, including nitric oxide released as a neurotransmitter from nitrergic nerves. To date, the most widely used phosphodiesterase 5 inhibitors, zaprinast and sildenafil, have proved vital in the elucidation of the widespread role of cyclic GMP in nitrergic transmission and, specifically in the case of sildenafil, have provided a major breakthrough in the treatment of erectile dysfunction in men. Although still a matter of debate, early evidence indicates that sildenafil may also be of benefit in some forms of sexual dysfunction in women. The remarkable clinical success of sildenafil has prompted the search for further novel phosphodiesterase 5 inhibitors which might be used to enhance nitrergic function in other disease states.
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PMID:Phosphodiesterase 5 inhibitors and nitrergic transmission-from zaprinast to sildenafil. 1113 52

Sexual dysfunction is highly prevalent in both sexes. Considerable progress has been made in the development of new pharmacologic treatments since the approval of sildenafil in 1998. A variety of oral erectogenic agents are available or are in late-phase development, including centrally active dopamine agonists (e.g., sublingual apomorphine), peripheral nonselective alpha-blockers (e.g., oral phentolamine), and other phosphodiesterase type-5 inhibitors (e.g., vardenafil). These drugs have recently been evaluated for the treatment of female sexual arousal disorder, although results to date have been inconclusive. Pharmacologic therapies have also been proposed for the treatment of premature ejaculation and hypoactive sexual desire disorder. Strong evidence exists for the value of serotonergic drugs (e.g., selective serotonin reuptake inhibitors) in the treatment of premature ejaculation. Further research is needed, particularly on the effects of these drugs on female sexual dysfunction.
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PMID:Sexual pharmacology in the 21st century. 1125 55

Cyclic nucleotide second messengers (cAMP and cGMP) play a central role in signal transduction and regulation of physiologic responses. Their intracellular levels are controlled by the complex superfamily of cyclic nucleotide phosphodiesterase (PDE) enzymes. Continuing advances in our understanding of the molecular pharmacology of these enzymes has led to the development of selective inhibitors as therapeutic agents for disease states ranging from cancer and heart failure to depression and sexual dysfunction. Several PDE types have been identified as therapeutic targets for immune/inflammatory diseases. This article briefly reviews the available in vitro, preclinical, and clinical data supporting the potential for selective PDE inhibitors as immunomodulatory agents.
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PMID:Cyclic nucleotide phosphodiesterases. 1169 87

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

A high incidence of sexual dysfunction among women is reported in the clinical literature. Little experimental investigation has been initiated on the ability of phosphodiesterase (PDE) inhibitors to overcome deficits in sexual functioning because of selective serotonin reuptake inhibitors (SSRIs). The effects of fluoxetine, an SSRI, and zaprinast, a PDE-5 inhibitor, on the lateral displacement response (used as a measure of sensitivity to reproductively relevant stimuli) of hamsters in behavioral estrus were investigated. In Experiment 1, hamsters that were maximally sensitive to reproductively relevant stimuli because they were at the peak of behavioral estrus were administered fluoxetine (10 mg/kg, i.p.); they had significantly decreased lateral displacement responses compared to vehicle-administered hamsters. In Experiment 2, hamsters that were relatively less sensitive to sexual stimuli because they were at the termination of behavioral estrus were administered zaprinast (3 mg/kg; i.p.); they had significantly enhanced lateral displacement responses compared to responses seen following vehicle administration. In Experiment 3, fluoxetine-induced deficits in the lateral displacement of hamsters at the peak of behavioral estrus were overcome by the coadministration of zaprinast. These data confirm previous findings that sexual dysfunction can be induced by SSRIs and extend the current knowledge to suggest that administration of a PDE-5 inhibitor can override SSRI-induced deficits in sexual functioning.
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PMID:Zaprinast, a phosphodiesterase 5 inhibitor, overcomes sexual dysfunction produced by fluoxetine, a selective serotonin reuptake inhibitor in hamsters. 1258 84

Sexual dysfunction related to antidepressants, particularly serotonin reuptake inhibitors is a major cause of premature treatment discontinuation. This places patients at increased risk for recurrence, relapse, chronicity, and mortality (eg, suicide). The clinical assessment requires a comprehensive evaluation of sexual function, including libido, arousal, orgasm, and resolution prior to affective disorder, disturbances associated with the emergence of depression, and changes or dysfunctions associated with antidepressant treatment. Other factors to be included for evaluating sexual dysfunction include inquiry for concurrent medical conditions, somatic treatments, lifestyle risk factors, and response to antidepressants. Current treatment approaches to antidepressant-associated sexual dysfunction have relied on open-label reports, literature reviews, and clinical wisdom. Without double-blind, placebo-controlled studies to support them, too much non-evidence-based treatment may be offered to patients. Advances into nonadrenergic-noncholinergic novel signal transduction, specifically phosphodiesterase type-5 inhibitors, offer new opportunities for developing evidence-based treatments for this side effect and improving depression disease management outcomes.
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PMID:Selective phosphodiesterase type-5 inhibitor treatment of serotonergic reuptake inhibitor antidepressant-associated sexual dysfunction: a review of diagnosis, treatment, and relevance. 1259 14

Inhibitors of phosphodiesterase type 5 are playing a large role in the revolution in the treatment of sexual dysfunction that has taken place in recent years. The revolution was launched in 1998 with the introduction of a phosphodiesterase type 5 inhibitor, sildenafil, which opened up new avenues of investigation and greater recognition of the prevalence and various characteristics of these conditions. As more treatments with this and other mechanisms of action reach advanced stages of development and international markets, clinicians and patients alike are gaining confidence in the idea that sexual dysfunction can be successfully treated, and this, in turn inspires further research. While the efficacy of sildenafil has been striking, the drug is not effective and agreeable for all patients. Researchers have naturally sought to exploit this drug's mechanism of action in the hope that other agents can be found that are more selective, potent and tolerable. The etiology of sexual dysfunction is variable, as are its manifestations and the requirements patients have for therapy, and it is therefore likely that numerous treatments will be used to enhance sexual satisfaction in this population. Vardenafil, a new phosphodiesterase type 5 inhibitor, is an agent which has shown promise at each stage of development. The drug is currently in the third phase of clinical testing for the treatment of erectile dysfunction.
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PMID:Effective treatment of erectile dysfunction with vardenafil. 1266 8


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