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)

Effects of cilostazol (OPC-13013, CAS 73963-72-1), a selective inhibitor of platelet cAMP-phosphodiesterase, on peripheral vascular disease in diabetes mellitus were studied. Cilostazol in a dose of 200 to 300 mg/d was administered to 5 diabetic patients with arteriosclerosis obliterans. Skin temperature of the finger and the toe, which reflects blood flow to the tissue, was selected as an objective index of cilostazol effects and measured by infra-red thermography at a constant temperature of 26 degrees C. Before administration, digital skin temperatures were low in 9 limbs of 5 patients. 200 mg/d of cilostazol significantly (p less than 0.001) increased the digital skin temperatures of 8 limbs, the increase (mean +/- SD) ranging from 29.9 +/- 1.4 degrees C to 33.2 degrees C +/- 1.2 degrees C for the average skin temperatures and from 28.7 +/- 2.1 degrees C to 33.1 +/- 1.5 degrees C for the lowest ones. An increase in the dose to 300 mg/d resulted in further elevation of skin temperatures of the digits. Cilostazol constantly elicited an increase in blood flow to the digits within the range of its therapeutic dose. This effect was observed about 1 month after initiation of administration and persisted while administration was continued. The measurement of digital skin temperatures by infrared thermography provided a noninvasive means to individualize the dosage of cilostazol and to monitor the cilostazol effect and patient complicance during long-term administration. It is concluded that cilostazol exerts a potent and steady vasodilatory effect on peripheral circulation in patients with diabetes mellitus.
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PMID:Effects of the anti-platelet agent cilostazol on peripheral vascular disease in patients with diabetes mellitus. 149 93

The effects of cilostazol (OPC-13013, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quin olinone) on cyclic nucleotide metabolism and Ca2+-induced contraction of intact and skinned rabbit arterial smooth muscles were investigated. The concentrations of cilostazol producing 50% inhibition of cyclic adenosine monophosphate phosphodiesterase and Ca2+-dependent cyclic nucleotide phosphodiesterase were 0.4 microM and above 100 microM, respectively. This compound has no significant effect on adenylate cyclase in concentrations of up to 100 microM. Addition of cilostazol increased significantly the cAMP content without significant effect on cyclic guanosine monophosphate level of rabbit thoracic aorta in the presence of forskolin. Moreover, the ED50 value of cilostazol in relaxation of rabbit mesenteric arterial strips was decreased selectively by addition of 0.01 microM forskolin, which alone at this concentration has no effect on vascular contraction. Cilostazol of up to 30 microM did not suppress the Ca2+-induced contraction of the chemically skinned rabbit mesenteric artery. Therefore, cilostazol may produce the relaxation of intact vascular smooth muscle by its inhibition of cyclic adenosine monophosphate hydrolysis.
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PMID:Effects of cilostazol, a selective cAMP phosphodiesterase inhibitor on the contraction of vascular smooth muscle. 284 93

We studied the effect of cilostazol, a cyclic nucleotide phosphodiesterase (PDE) III inhibitor, on a substance P (SP)-induced increase in lung resistance and in airway microvascular leakage in guinea pigs in vivo. Four minutes after intravenous (i.v.) administration of cilostazol (1.5 and 5 mg/kg) or vehicle, Evans blue dye (20 mg/kg) was given i.v. One minute later, 30 nmol/kg SP was administered i.v. The SP-induced increase in lung resistance was measured for 6 min. Following the measurement of lung resistance, microvascular leakage at the trachea, main bronchi and intrapulmonary airways was also examined. Cilostazol attenuated the SP-induced increase in lung resistance, with a significant inhibition at the concentration of 5 mg/kg. Five milligrams per kilogram cilostazol also significantly inhibited SP-induced Evans blue dye extravasation at the trachea and main bronchi. These results suggest that cilostazol might reduce airflow obstruction which is seen in diseases such as asthma through attenuation of bronchoconstriction and, possibly, airway edema resulting from airway microvascular leakage in man.
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PMID:Effects of cilostazol, a cyclic nucleotide phosphodiesterase III inhibitor, on substance P-induced airflow obstruction and airway microvascular leakage in guinea pigs. 751 49

Two proposed mechanisms of diabetic neuropathy are microvascular ischaemia and a reduction in Na,K-ATPase activity. We evaluated the effect of cilostazol, a drug that is both a potent phosphodiesterase inhibitor that normalizes nerve Na,K-AT-Pase and a vasodilator, on nerve blood flow (NBF) to determine whether it would improve experimental diabetic neuropathy. We examined whether epineurally applied cilostazol acted as a vasodilator on the peripheral nerve of normal and diabetic rats, and whether feeding the rats a cilostazol-supplemented diet could improve diabetic neuropathy. Cilostazol increased nerve blood flow (NBF) in a dose-dependent fashion with an EC50 of 10(-5.74) mol/l. Cilostazol also normalized NBF in experimental diabetic neuropathy with a 10(-4) mol/l local application on the sciatic nerve. In diabetic neuropathy, a cilostazol-supplemented diet improved both NBF and nerve conduction in a dose- and time-dependent fashion. Potential mechanisms of action of cilostazol on the nerve include its effect on NBF, Na, K-ATPase, and restoration of the thromboxane:prostacyclin ratio. Cilostazol may have potential in the treatment of diabetic neuropathy.
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PMID:Effect of cilostazol on experimental diabetic neuropathy in the rat. 758 76

Cilostazol is a selective orally active phosphodiesterase (PDE) III inhibitor. This study was conducted to evaluate whether inhibition of PDE subtype III can reduce bronchial responsiveness. We examined the effects of cilostazol on bronchial responsiveness to methacholine in eight normal subjects by a single-blinded, crossover study. Each subject received 200 mg of cilostazol or placebo in random order. The subjects underwent methacholine challenge test 3 h after administration of each drug on two occasions separated by 5 d or more. The geometric mean value of provocative concentration of methacholine causing a 20% fall in FEV1 (PC20-FEV1) and the mean value (+/- SEM) of maximum expiratory flow on partial flow-volume curve at isovolume of 40% FVC above residual volume (PEF40) after administration of cilostazol were 25.3 (geometric standard error of the mean [GSEM], 1.35) mg/ml and 3.78 +/- 0.31 L/s, which were significantly (p < 0.02 and p < 0.05) greater than those after the placebo administration (6.81 [GSEM, 1.42] mg/ml and 2.71 +/- 0.39 L/s). All subjects complained of mild to severe headache when cilostazol was given. These findings suggest that PDE III inhibitors such as cilostazol have bronchodilator and bronchoprotective effects in humans. Further studies regarding smaller oral dosing of or aerosol administration of cilostazol or the other PDE III inhibitors are needed to determine clinical usefulness.
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PMID:Bronchodilator and bronchoprotective effects of cilostazol in humans in vivo. 781 59

Cilostazol (Cls) is a inhibitor of phosphodiesterase and increases cyclic AMP (cAMP) in platelets and also raises the vascular smooth muscle cell cAMP level causing vasodilation. Therefore, it was expected to increase local blood flow in the skin. Topical application of Cls may improve local blood flow without systemic effects in clinical situations. In this paper the effect of Cls lotion on skin blood flow was assessed in animal experiments. Application of this lotion allowed skin blood flow to remain at increased levels for about 60-90 min. Tissue assay of the Cls content revealed that Cls is absorbed percutaneously and retained, even in the inner tissue layer, for at least 180 min.
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PMID:Effects of cilostazol lotion on blood flow in rabbit skin. 806 Sep 17

Microalbuminuria is characteristic in diabetic nephropathy and is thought to be influenced by renal hemodynamics, especially by the metabolism of prostaglandins (PGs) in glomruli. To reduce urinary albumin excretion in patients with non-insulin-dependent diabetes mellitus (NIDDM), we administered 100 mg of cilostazol, a phosphodiesterase inhibitor, daily for 3 months. The urinary albumin index (UAI: microgram albumin/mg creatinine) decreased significantly after 3 months of administering cilostazol. Urinary excretions of thromboxane B2 (TXB2), a stable metabolite of thromboxane A2, decreased significantly after treatment. However, it had no effects on urinary excretions of PGE2 and 6-keto PGF1 alpha (6KF), a stable metabolite of prostacyclin. The ratio 6KF/TXB2 has been known to reflect the renal metabolism of PGs. In this study, urinary 6KF/TXB2 ratio increased significantly in parallel with a significant reduction of UAI. Cilostazol had no adverse effects on the control of blood glucose and lipids. In conclusion, cilostazol has a beneficial effect on UAI in patients with NIDDM by reducing renal production of TXB2., which increases 6KF/TXB2 ratio.
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PMID:Effects of cilostazol, a phosphodiesterase inhibitor, on urinary excretion of albumin and prostaglandins in non-insulin-dependent diabetic patients. 813 17

Inhibitors of cyclic nucleotide phosphodiesterase hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate are known to inhibit platelet aggregation, which plays an important role in acute reocclusion after thrombolysis in acute myocardial infarction. In the present study of a canine preparation of coronary artery thrombosis superimposed on high-grade stenosis, we tested whether the antithrombotic agent cilostazol, an inhibitor of cAMP phosphodiesterase, could prevent acute reocclusion or sustain coronary blood flow after thrombolysis when used with recombinant tissue-type plasminogen activator (rt-PA) and heparin. Intravenous infusion of rt-PA (0.5 mg/kg body wt for 30 minutes) and heparin (a 150 IU/kg body wt i.v. bolus and then 25 IU/kg body wt per hour i.v.) was combined with cilostazol (0.6 or 1.8 mg/kg body wt for 60 minutes). Without cilostazol, reperfusion was observed in seven of eight dogs, but reocclusion occurred in six of these seven dogs after 9 +/- 2 minutes. After administration of 1.8 mg/kg body wt cilostazol (group B-2; a 120-minute observation after the start of rt-PA infusion), reperfusion occurred in all seven dogs (p < 0.05 versus control group), and brief cyclic reocclusion was observed in only one dog 63 minutes after reperfusion. At the same dose of cilostazol (group B-2L; a 240-minute observation after the start of rt-PA infusion), reperfusion occurred in all five dogs (p < 0.05 versus control group), and coronary blood flow was well maintained except for one short reocclusion in one dog. Cilostazol inhibited cyclic flow reduction in a dose-dependent fashion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cilostazol, a novel cyclic AMP phosphodiesterase inhibitor, prevents reocclusion after coronary arterial thrombolysis with recombinant tissue-type plasminogen activator. 838 80

In platelets, an increase in cAMP levels potently inhibits aggregation and release reactions. Cilostazol is an antiplatelet agent that increases intracellular cAMP levels by selective Type III phosphodiesterase (PDE) inhibition. The characteristics of cilostazol are presented in this review. Adenylate cyclase potentiator also shows strong inhibitory actions on platelet functions, but a number of reports suggest that the continuous use of an adenylate cyclase potentiator may lead to a reduction of drug efficacy. On the other hand, such an action has not been seen with cilostazol even after continuous administration of cilostazol (100 mg/kg) for two weeks in rats, which may be due to a feature of this drug, namely, inhibitory actions on PDE. Inhibitory actions of cilostazol on PDE are specific: strong inhibition (IC50 = 0.19 microM) against Type III PDE that comprises most of the PDE activities in platelets and weak inhibition against Type IV PDE that comprises most of the PDE activities in endothelial cells (ECs). This fact (i.e., specificity of cilostazol) brought about important results when the drug reacted in the presence of both platelets and blood vessels. A non-specific PDE inhibitor such as IBMX increases cAMP and decreases PGI2 synthesis in ECs, but such a phenomenon was not seen with cilostazol. The inhibitory actions of cilostazol on platelet functions were potently enhanced in the presence of PGI2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Selective type III phosphodiesterase inhibitor as an antithrombotic agent]. 852 65

Heparin-binding EGF-like growth factor (HB-EGF) is a mitogen for smooth muscle cells (SMC) and is detected in SMC and macrophages in atherosclerotic plaques, suggesting that HB-EGF may be associated with the pathogenesis of atherosclerosis. The present study indicates that cilostazol, a phosphodiesterase III inhibitor, suppresses the expression of HB-EGF in rat aortic SMC and in U-937 cells, a macrophage-like cell line, stimulated by lipopolysaccharide. Further, cilostazol diminished the induction of HB-EGF mRNA by methylglyoxsal, which is a reactive dicarbonyl metabolite produced as the result of a glycation reaction and which might be associated with macroangiopathy caused by hyperglycemia. Cilostazol suppressed the production of HB-EGF protein in the conditioned medium of SMC. These data suggest that cilostazol might act by suppressing the progression of atherogenesis by means of suppressing the expression of HB-EGF in SMC and macrophages.
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PMID:The effect of cilostazol, a cyclic nucleotide phosphodiesterase III inhibitor, on heparin-binding EGF-like growth factor expression in macrophages and vascular smooth muscle cells. 929 35


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