Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intermittent claudication (IC) is leg muscle pain, cramping and fatigue brought on by exercise and is the primary symptom of peripheral arterial disease. The goals of pharmacotherapy for IC are to increase the walking capacity/quality of life and to decrease rates of amputation. In 1988, pentoxifylline was the only drug that had reasonable supportive clinical trial evidence for being beneficial in IC. Since then a number of drugs have shown benefit or potential in IC. Cilostazol, a specific inhibitor of phosphodiesterase 3 and activator of lipoprotein lipase, clearly increases pain-free and absolute walking distances in claudicants. However, cilostazol does cause minor side effects including headache, diarrhoea, loose stools and flatulence. Naftidrofuryl, a serotonin (5-HT2) receptor antagonist and antiplatelet drug, is beneficial in claudicants. Inhibitors of platelet aggregation (including nitric oxide from L -arginine or glyceryl trinitrate) and anticoagulants (low molecular weight heparin, defibrotide) probably have both short and long-term benefits in IC. In addition, intravenous infusions of prostaglandins (PGs) PGE1 and PGI2 have an established role in severe peripheral arterial disease and the recent introduction of longer lasting and/or oral forms of the PGs makes them more likely to be useful in the IC associated with less severe forms of the disease. There are some exciting new approaches to the treatment of IC, including propionyl-L-carnitine and basic fibroblast growth factor (bFGF).
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PMID:Pharmacotherapy of intermittent claudication. 1182 12

Inflammatory bladder disorders such as interstitial cystitis (IC) deserve attention since a major problem of the disease is diagnosis. IC affects millions of women and is characterized by severe pain, increased frequency of micturition, and chronic inflammation. Characterizing the molecular fingerprint (gene profile) of IC will help elucidate the mechanisms involved and suggest further approaches for therapeutic intervention. Therefore, in the present study we used established animal models of cystitis to determine the time course of bladder inflammatory responses to antigen, Escherichia coli lipopolysaccharide (LPS), and substance P (SP) by morphological analysis and cDNA microarrays. The specific aim of the present study was to compare bladder inflammatory responses to antigen, LPS, and SP by morphological analysis and cDNA microarray profiling to determine whether bladder responses to inflammation elicit a specific universal gene expression response regardless of the stimulating agent. During acute bladder inflammation, there was a predominant infiltrate of polymorphonuclear neutrophils into the bladder. Time-course studies identified early, intermediate, and late genes that were commonly up-regulated by all three stimuli. These genes included: phosphodiesterase 1C, cAMP-dependent protein kinase, iNOS, beta-NGF, proenkephalin B and orphanin, corticotrophin-releasing factor (CRF) R, estrogen R, PAI2, and protease inhibitor 17, NFkB p105, c-fos, fos-B, basic transcription factors, and cytoskeleton and motility proteins. Another cluster indicated genes that were commonly down-regulated by all three stimuli and included HSF2, NF-kappa B p65, ICE, IGF-II and FGF-7, MMP2, MMP14, and presenilin 2. Furthermore, we determined gene profiles that identify the transition between acute and chronic inflammation. During chronic inflammation, the urinary bladder presented a predominance of monocyte/macrophage infiltrate and a concomitant increase in the expression of the following genes: 5-HT 1c, 5-HTR7, beta 2 adrenergic receptor, c-Fgr, collagen 10 alpha 1, mast cell factor, melanocyte-specific gene 2, neural cell adhesion molecule 2, potassium inwardly-rectifying channel, prostaglandin F receptor, and RXR-beta cis-11-retinoic acid receptor. We conclude that microarray analysis of genes expressed in the bladder during experimental inflammation may be predictive of outcome. Further characterization of the inflammation-induced gene expression profiles obtained here may identify novel biomarkers and shed light into the etiology of cystitis.
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PMID:Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. 1205 14

A 92-year-old woman with normal systolic function had recently begun using the newly approved phosphodiesterase III inhibitor cilostazol when she was admitted with lower-extremity pain. Cilostazol is indicated for patients with intermittent claudication and contraindicated for patients with congestive heart failure. Two days after admission, the patient developed ventricular tachycardia. Cilostazol was discontinued, and shortly thereafter the ventricular tachycardia subsided. In this case, cilostazol was apparently an important predisposing factor for ventricular tachycardia.
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PMID:Rapid ventricular tachycardias associated with cilostazol use. 1207 74

Intermittent claudication (IC) is the symptomatic expression of peripheral arterial disease (PAD), which itself is a manifestation of systemic atherosclerosis. Like other forms of atherosclerosis, PAD is associated with elevated rates of cardiovascular and cerebrovascular morbidity and mortality. Until recently, therapeutic options for the treatment of the symptoms of IC have been limited, and the efficacy of available treatment has been questioned. Cilostazol, a selective phosphodiesterase III inhibitor with vasodilator, antiplatelet, and antiproliferative properties, has recently been approved for the treatment of IC symptoms in the United States. Cilostazol significantly improves maximal and pain-free walking distances. Clinical studies have also demonstrated that cilostazol favorably alters plasma lipids (elevates HDL-cholesterol, lowers triglycerides). These properties may contribute to the benefit of this drug in IC and in other diseases secondary to atherosclerosis.
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PMID:Clinical manifestation of atherosclerotic peripheral arterial disease and the role of cilostazol in treatment of intermittent claudication. 1246 22

We examined the effect of cilostazol, a type III phosphodiesterase inhibitor, on pain-free and maximal walking distance and quality of life measures. The present study examined adverse effects in 2,702 patients with stable, moderate to severe claudication enrolled in 8 randomized, double-blind, placebo-controlled trials. Treatment duration ranged from 12 to 24 weeks. Cilostazol therapy increased maximal and pain-free walking distances by 50% and 67%, respectively. In subgroup analysis, cilostazol increased pain-free and maximal walking distance similarly in men and women, in older (>/=65 years) and younger patients, and in patients with and without diabetes. Quality-of-life assessments revealed enhanced scores for physical well-being. Cilostazol-treated patients reported a higher incidence of headache, bowel complaints, and palpitations than patients given placebos. Cilostazol decreased triglycerides by 15.8% and increased high-density lipoprotein cholesterol by 12.8%, but there were no deleterious effects on any hematologic or serum markers. We conclude that cilostazol significantly increases walking distance and quality-of-life measures in patients with claudication without major adverse effects.
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PMID:Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. 1248 40

Various evidence has demonstrated a role of the nitric oxide (NO)/cGMP signaling pathway in the processing of nociception. The exact role of phosphodiesterase-5 (PDE-5) via the NO/cGMP pathway is not fully understood in pain response. The aim of the present study was to investigate the possible peripheral interaction between a PDE-5 inhibitor (sildenafil) and morphine. Carrageenan-induced hyperalgesia in rats and the acetic-acid-induced writhing test in mice were used as animal models. Local administration of sildenafil (50-200 microg/paw, i.pl.) exhibited a dose-dependent antinociceptive effect against the paw pressure test. Sildenafil also demonstrated an antinociceptive effect (1-10 mg/kg, i.p.) against in the writhing test. Co-administration of sildenafil (100 microg/paw, i.pl. and 2 mg/kg, i.p.) significantly enhanced the antinociceptive effect of morphine (2 microg/ paw, i.pl. and 2 mg/kg, i.p respectively). The antinociception produced by the drugs alone or combined was due to a local action, as its administration in the contralateral paws was ineffective. Pretreatment with N(G)-nitro-L-arginine methyl ester (an NO synthesis inhibitor), methylene blue (gunalyl cyclase inhibitor) or naloxone (opioid receptor antagonist) blocked the effect of a sildenafil-morphine combination in both tests. The results suggest that opioid receptor (NO and cGMP) mechanisms are involved in the combined antinociceptive effect. Further, sildenafil produced antinociception per se and increased the response of morphine, probably through the inhibition of cGMP degradation.
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PMID:Sildenafil, a phosphodiesterase-5 inhibitor, enhances the antinociceptive effect of morphine. 1257 11

Peripheral vascular disease (PVD) is generally accepted to result in the failure of skeletal muscle blood flow to increase adequately at the onset of muscular work. There are currently no routine pharmacological interventions towards the treatment of PVD, however, recent Phase III trials in the USA have demonstrated the clinical potential of the phosphodiesterase III inhibitor Cilostazol for pain-free and maximal walking distances in patients with intermittent claudication. PVD is characterized by a marked reliance on oxygen-independent routes of ATP regeneration (phosphocreatine hydrolysis and glycolysis) in skeletal muscle during contraction and the rapid onset of muscular pain and fatigue. The accumulation of metabolic by-products of oxygen-independent ATP production (hydrogen and lactate ions and inorganic phosphate) has long been associated with an inhibition in contractile function in both healthy volunteers and PVD patients. Therefore, any strategy that could reduce the reliance upon ATP re-synthesis from oxygen-independent routes, and increase the contribution of oxygen-dependent (mitochondrial) ATP re-synthesis, particularly at the onset of exercise, might be expected to improve functional capacity and be of considerable therapeutic value. Historically, the increased contribution of oxygen-independent ATP re-synthesis to total ATP generation at the onset of exercise has been attributed to a lag in muscle blood flow limiting oxygen delivery during this period. However, recent evidence suggests that limited inertia is present at the level of oxygen delivery, whilst considerable inertia exists at the level of mitochondrial enzyme activation and substrate supply. In support of this latter hypothesis, we have reported on a number of occasions that activation of the pyruvate dehydrogenase complex, using pharmacological interventions, can markedly reduce the dependence on ATP re-synthesis from oxygen-independent routes at the onset of muscle contraction. This review will focus on these findings and will highlight the pyruvate dehydrogenase complex as a novel therapeutic target towards the treatment of peripheral vascular disease, or any other disease state where premature muscular fatigue is prevalent due to metabolite accumulation.
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PMID:Metabolic inertia in contracting skeletal muscle: a novel approach for pharmacological intervention in peripheral vascular disease. 1499 19

Intermittent claudication is a common, disabling symptom of peripheral arterial disease that limits walking distance and is associated with an increased cardiovascular risk of acute limb- or life-threatening complications. Very few patients with intermittent claudication (<7%) are suitable candidates for surgical revascularization, yet in contrast to the treatment of stable angina, few effective medical therapies (apart from exercise) are available for the symptomatic relief of intermittent claudication. The phosphodiesterase-3 inhibitor, cilostazol (Pletal, Otsuka Pharmaceuticals Ltd), is the first symptom-relieving treatment for intermittent claudication that has been evaluated successfully in large multicenter placebo-controlled, double-blind clinical trials (involving >2000 patients). A meta-analysis of the eight major efficacy studies with cilostazol has shown significant improvements in pain-free and maximum walking distance, and a good overall safety and tolerability profile. Thus, in the UK, USA and Japan, cilostazol administered at 100 mg twice daily is licensed for symptom relief in patients with stable, moderate-to-severe intermittent claudication, as an adjunct to nonpharmacological approaches such as exercise.
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PMID:Cilostazol: improving walking distance in patients with intermittent claudication. 1522 10

New drugs for pulmonary arterial hypertension have shown efficacy in randomized controlled trials. Endothelin receptor antagonists (ERA) and prostanoids are most important for clinical practice. Bosentan represents the first approved orally active therapy for PAH. Besides its hepatotoxicity it is mostly well tolerated. The first approved prostanoid, epoprostenol, is currently first choice only for decompensated right heart failure in PAH. It has to be delivered continuously intravenously and is prone to complications, side effects and very high costs. Alternatively, subcutaneous treprostinil can be applied. It is less risky and expensive but may cause local pain at the infusion site. Inhaled iloprost combines the features of a prostanoid with pulmonary and intrapulmonary selectivity. Alternatively, iloprost is being used as continuous intravenous infusion. The phosphodiesterase-5 inhibitor sildenafil was effective in two randomized controlled trials but has not been approved for PAH therapy.
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PMID:[Therapy of pulmonary arterial hypertension]. 1570 89

The local peripheral (subcutaneous) injection of phosphodiesterase 3 inhibitor trequinsin dose-dependently enhanced formalin-evoked flinching during late second phase of this test. Treatment with the nitric oxide synthase inhibitor N-L-nitro-arginine methyl ester or guanylyl cyclase inhibitor 1-H-[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one significantly reversed trequinsin-induced pronociceptive effect. Results suggest that the peripheral phosphodiesterase 3 may play an important physiologic role on inflammatory pain by controlling cyclic AMP levels and therefore the nociceptor threshold.
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PMID:Peripheral participation of the phosphodiesterase 3 on formalin-evoked nociception. 1611 78


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