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)

Inhibitors of phosphodiesterases 3 and 4, the main cyclic AMP (cAMP) degrading enzymes in arteries, may have therapeutic potential in cerebrovascular disorders. We analysed the effects of such phosphodiesterases in guinea pig cerebral arteries with organ bath technique and cyclic nucleotide assays. Guinea pig and human cerebral arteries were used for phosphodiesterase assays. Cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone), a phosphodiesterase 3 inhibitor, was compared to conventional phosphodiesterase 3 and 4 inhibitors. Phosphodiesterases 3 and 4 were the major contributors to total cAMP hydrolysis in the arteries examined. The phosphodiesterase 3 inhibitors additionally attenuated cyclic GMP (cGMP) hydrolysis, but relaxant responses were not dependent on an intact endothelium or on the nitric oxide-cGMP pathway. Conversely, the phosphodiesterase 4 inhibitor used was endothelium-dependent and affected by cGMP levels. This suggests that phosphodiesterase 3 inhibitors are still effective under conditions with possible dysfunctional nitric oxide-cGMP pathway, such as in ischemic stroke or cerebral vasospasm.
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PMID:Analysis of the effects of phosphodiesterase type 3 and 4 inhibitors in cerebral arteries. 1506 60

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

We have investigated the effects of cilostazol, a type III phosphodiesterase inhibitor, on the electrical responses of smooth muscle tissue isolated from the guinea-pig stomach antrum. Cilostazol (10(-5) M) inhibited slow waves recorded from circular muscle cells, but did not significantly alter the pacemaker potentials and follower potentials recorded from myenteric interstitial cells and longitudinal muscle cells respectively. Slow potentials generated in isolated circular muscle bundles without attached myenteric interstitial cells were inhibited by cilostazol (>10(-7) M), while all membrane activities were abolished by 10(-5) M cilostazol. In circular muscle bundles, the input resistance of smooth muscle cells and the refractory period for the generation of slow potentials were not altered during the inhibition of spontaneous activity with cilostazol. While cilostazol at 10(-7) and 10(-6) M did not elevate the tissue content of cyclic AMP, at 10(-5) M cyclic AMP was elevated by about 30%. A similar elevation was also produced by 10(-7) M forskolin. The content of cyclic AMP was not significantly increased in preparations stimulated with 10(-3) M caffeine. The potency for inhibiting slow waves was in the order caffeine (10(-3) M) > forskolin (10(-7) M) > cilostazol (10(-5) M). The frequency of slow waves was decreased by caffeine or forskolin but not by cilostazol, while the duration was reduced by caffeine but not by cilostazol or forskolin. Follower potentials were modulated by caffeine and forskolin, but not by cilostazol: the duration was reduced by caffeine, the frequency was reduced by caffeine or forskolin, and the amplitude was not significantly altered by any of them. The results indicate that cilostazol has high selectivity in inhibiting the activity of circular muscle much more than that of longitudinal muscle or pacemaker cells, with no causal relation to the tissue content of cyclic AMP as appears to be the case for the inhibitory actions of caffeine and forskolin.
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PMID:Inhibitory actions of cilostazol on electrical responses of smooth muscle isolated from the guinea-pig stomach antrum. 1535 65

We evaluated association between hyperinsulinemia/insulin resistance and microalbuminuria in the insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rat. OLETF rats showed glomerular hyperfiltration (an increase in creatinine clearance and a decrease in fractional excretion of Na) and microalbuminuria at the insulin-resistant prediabetic stage, and both were related to expression of transforming growth factor (TGF)-beta(1) and extracellular matrix protein such as fibronectin and collagen (a(1)) IV. Cilostazol, a selective type III cyclic nucleotide phosphodiesterase (PDE) inhibitor, normalized glomerular hyperfiltration and microalbuminuria with a parallel decline of TGF-beta(1) and extracellular matrix protein mRNA expression. Cilostazol may be beneficial to lessen early glomerular nephropathy in a state of hyperinsulinemia/insulin resistance.
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PMID:Cilostazol, a phosphodiesterase inhibitor, reduces microalbuminuria in the insulin-resistant Otsuka Long-Evans Tokushima Fatty rat. 1553 93

Cilostazol, an inhibitor of phosphodiesterase (PDE) type 3, is used clinically in peripheral artery disease. PDE3 inhibitors may be clinically useful in the treatment of delayed cerebral vasospasm after subarachnoid hemorrhage. The authors present the first results on the effect of cilostazol on cerebral hemodynamics in normal participants. In this double-blind, randomized, crossover study, 200 mg cilostazol or placebo was administered orally to 12 healthy participants. Cerebral blood flow was measured using 133Xe inhalation and single photon emission computerized tomography. Mean flow velocity in the middle cerebral arteries (VMCA) was measured with transcranial Doppler, and the superficial temporal and radial arteries diameters were measured with ultrasonography. During the 4-hour observation period, there was no effect on systolic blood pressure (P = 0.28), but diastolic blood pressure decreased slightly compared with placebo (P = 0.04). VMCA decreased 21.5 +/- 5.7% after cilostazol and 5.5 +/- 12.2% after placebo (P = 0.02, vs. placebo), without any change in global or regional cerebral blood flow. The superficial temporal artery diameter increased 17.6 +/- 12.3% (P < 0.001 vs. baseline) and radial artery diameter increased 12.6 +/- 8.6% (P < 0.001 vs. baseline). Adverse events, especially headache, were common. The findings suggest that cilostazol is an interesting candidate for future clinical trials of delayed cerebral vasospasm.
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PMID:The phosphodiesterase 3 inhibitor cilostazol dilates large cerebral arteries in humans without affecting regional cerebral blood flow. 1562 9

Neointimal formation, the leading cause of restenosis, is caused by proliferation of vascular smooth muscle cells (VSMCs). Patients with diabetes mellitus have higher restenosis rates after coronary angioplasty than nondiabetic patients. Cilostazol, a selective type 3 phosphodiesterase inhibitor, is currently used to treat patients with diabetic vascular complications. Cilostazol is a potent antiplatelet agent that inhibits VSMC proliferation. In the present study, we examine whether the antiproliferative effect of cilostazol on VSMCs is mediated by inhibition of an important cell cycle transcription factor, E2F. Cilostazol inhibited the proliferation of human VSMCs in response to high glucose in vitro and virtually abolished neointimal formation in rats subjected to carotid artery injury in vivo. Moreover, the compound suppressed high-glucose-induced E2F-DNA binding activity, and the expression of E2F1, E2F2, cyclin A, and PCNA proteins. These data suggest that the beneficial effects of cilostazol on high-glucose-stimulated proliferation of VSMCs are mediated by the downregulation of E2F activity and expression of its downstream target genes, including E2F1, E2F2, cyclin A, and PCNA.
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PMID:Cilostazol inhibits vascular smooth muscle cell growth by downregulation of the transcription factor E2F. 1572 65

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

The Cilostazol for RESTenosis (CREST) clinical trial was initiated to evaluate the efficacy of cilostazol, an antiplatelet drug, in inhibiting restenosis after stent implantation in a native coronary artery as evaluated by quantitative coronary angiography. Preliminary results suggest that cilostazol reduces restenosis by 36% over standard therapy alone. Restenosis after coronary stenting is primarily attributed to neointimal formation. Cilostazol decreases the activity of phosphodiesterase type 3, leading to the accumulation of cyclic adenosine monophosphate, which initiates a cascade of events including upregulation of anti-oncogenes p53 and p21 and upregulation of hepatocyte growth factor (HGF). The increase in p53 protein blocks cell cycle progression and induces apoptosis in vascular smooth muscle cells (VSMCs), leading to an antiproliferative effect. Upregulation of local HGF stimulates rapid regeneration of endothelial cells, which inhibits neointimal formation via two mechanisms: inhibition of abnormal VSMC growth and improvement of endothelial function. These mechanisms may be responsible for the improvement in restenosis shown in the CREST trial and a number of other trials in patients who underwent percutaneous transluminal coronary angioplasty. These effects, in addition to antithrombotic and vasodilatory attributes of cilostazol, make it a potentially viable treatment option for preventing restenosis following coronary stenting.
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PMID:A scientific rationale for the CREST trial results: evidence for the mechanism of action of cilostazol in restenosis. 1627 67


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