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)

First developed for clinical use in the late 1980s, the phosphodiesterase inhibitors were found to increase the levels of the ubiquitous second messenger cyclic adenosine monophosphate and could effect changes in vascular tone, cardiac function, and other cellular events. After several early studies using high doses of phosphodiesterase inhibitors in patients with severe heart failure suggested adverse consequences, they fell out of favor. However, recent investigations of phosphodiesterase inhibitors in patients with intermittent claudication have demonstrated profound benefits. Furthermore, these agents have proven useful in prevention of cerebral infarction and coronary restenosis, and their use in the treatment of heart failure is being reevaluated. The reemergence of phosphodiesterase inhibitors can be attributed to a better understanding of dosing and drug-specific pharmacology, the use of concomitant medications, and a recognition of unique ancillary properties; however, their use still requires caution.
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PMID:Reevaluating the role of phosphodiesterase inhibitors in the treatment of cardiovascular disease. 1205 87

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

Diabetes is associated with considerably higher risks of developing peripheral arterial disease (PAD) which, when it occurs, is more severe and progresses more rapidly than in nondiabetics. Early detection of PAD in the diabetic patient is therefore important, but may be complicated by the presence of neuropathy and calcification of the arteries such that ischaemic symptoms are not felt by the patient and ankle pressures are not reduced. Toe pressures are an alternative diagnostic tool in these patients. Good glycaemic control, while an essential part of diabetes management, does not appear to bring more than modest benefits in preventing the peripheral vascular complications of diabetes. Therefore, attention to other risk factors is needed. Treatment with the phosphodiesterase III inhibitor, cilostazol, has been shown to improve walking distances significantly in diabetes patients with intermittent claudication and also appears to improve plasma lipid profiles. Further, cilostazol has an antiplatelet action, which may prove to be of benefit in diabetes because hyperglycaemia is associated with increased platelet aggregability. Revascularization in diabetes patients with critical leg ischaemia is complex and associated with poorer outcomes than in non-diabetes patients. While surgical revascularization has better patency rates, in patients at high risk of surgical complications, percutaneous transluminal angioplasty may be a better option.
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PMID:Treating peripheral arterial disease in patients with diabetes. 1218 Mar 55

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

In contradistinction to chronic critical limb ischemia, the peripheral arterial disease patient with intermittent claudication is at relatively low risk for limb loss. As a result, initial claudication management should employ non-interventional therapies rather than immediate catheter-based or surgical revascularization. Although exercise therapy is the most efficacious conservative treatment for claudication, supervised exercise programs are not widely available at present. Consequently, a pharmacologic agent can be utilized to lessen the symptoms and improve the function of the claudicant. This manuscript provides a comprehensive review of the various pharmacotherapies that have been investigated for improving walking distance in the setting of intermittent claudication. Cilostazol, a phosphodiesterase III inhibitor, appears to provide the greatest benefit, significantly improving not only walking distance but quality of life as well. Early trials indicate that propionyl-L-carnitine, oral prostaglandins, L-arginine, and therapeutic angiogenesis may eventually yield significant benefit in lessening the symptoms of intermittent claudication.
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PMID:Pharmacologic treatment for intermittent claudication. 1271 Aug 46

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

Pharmacotherapy is limited for the relief of intermittent claudication (IC), a common manifestation of peripheral arterial disease (PAD). Pentoxyfylline, the only current pharmacological therapy for IC, has been shown to have similar efficacy as placebo. Cilostazol, a new phosphodiesterase III (PDE III) inhibitor, is a potent inhibitor of platelet aggregation with vasodilatory, antithrombotic, antiproliferative and positive lipid-altering effects. To evaluate the efficacy and safety of cilostazol for the treatment of IC in Indian patients, 123 patients were selected from 6 centres in India. The patients, aged 58-73 years, with the diagnosis of stable moderate-to-severe IC received cilostazol 100/50 mg twice daily for a period of 12 weeks. Primary efficacy measures included initial claudication distance (ICD) and absolute walking distance (ACD) by treadmill testing and ankle-brachial index (ABI) using Doppler ultrasonography-measured systolic pressures. Secondary efficacy outcomes included subjective assessment of symptom improvement by patient and investigator and estimation of lipid values. Adverse events were monitored throughout the study. Laboratory investigations were carried out at baseline and end of study. At the end of week 12 of cilostazol therapy, there was a significant improvement in the raw walking distances (ICD and ACD). Percentage change in ICD and ACD was 46.77% and 64.5%, respectively, at the end of study. There was a significant increase (32.7%) in the ABI by the end of study period. According to patient and investigator assessment of symptoms, 58-60% of the subjects showed significant improvement to complete resolution of claudication symptoms by the end of 12 weeks of therapy. In addition, there was a significant increase of 20.24% in the mean plasma HDL-cholesterol levels and a decrease of 29.55% in the mean plasma triglyceride concentrations by the end of study period. Headache, diarrhoea, palpitation and dizziness were the commonly reported adverse effects during the study. No adverse effect led to discontinuation of therapy. The present study suggests that cilostazol is an effective therapeutic option with an acceptable tolerability profile for the treatment of IC in patients with PAD.
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PMID:Efficacy and safety of cilostazol, a novel phosphodiesterase inhibitor in patients with intermittent claudication. 1516 99

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

The US FDA has approved two drugs for the management of intermittent claudication: pentoxifylline and cilostazol. The mechanism of action that provides symptom relief with pentoxifylline is poorly understood but is thought to involve red blood cell deformability as well as a reduction in fibrinogen concentration, platelet adhesiveness and whole blood viscosity. The recommended dose of pentoxifylline is 400 mg three times daily with meals. Cilostazol is a potent, reversible, phosphodiesterase III inhibitor. The inhibition of phosphodiesterase allows for the increased availability of cyclic adenosine monophosphate (cAMP). cAMP mediates many agonist-induced platelet inhibitory, vasodilatory and vascular antiproliferative responses. Cilostazol, at a dose of 100 mg twice daily, is recommended to be taken 30 minutes before or 2 hours after breakfast and dinner. In addition to pentoxifylline and cilostazol, clinical trials indicate many other drugs may relieve the symptoms of intermittent claudication. Ginkgo biloba, available as an over-the-counter extract, provides symptom relief comparable to pentoxifylline. Two European agents, naftidrofuryl and buflomedil, also have efficacy that is reported to be similar to pentoxifylline. Policosanol is a mixture of fatty alcohols derived from honeybee wax which, according to very limited data, reduces symptoms of claudication. Amino acids, certain peptides and prostaglandins may have a therapeutic role. Finally, novel approaches including angiogenesis mediated by growth factors, are currently under investigation.
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PMID:Drug treatment of intermittent claudication. 1525 27

Cilostazol is a selective inhibitor of phosphodiesterase III with anti-platelet-aggregatory and vasodilating properties. Randomised, double-blind, placebo-controlled trials in 2702 patients with intermittent claudication demonstrated that cilostazol significantly increased walking distances compared with placebo. Furthermore, the agent has beneficial effects on the serum lipid profile and fatty acid composition in plasma. Consequently, cilostazol may be useful to prevent atherosclerosis from progressing by ameliorating lipid and fatty acid metabolism.
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PMID:Effects of cilostazol on lipid and fatty acid metabolism. 1575 Jul 63


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