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)

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

According to a pathogenetic concept originally presented by Moncada in 1977 a therapeutic combination of a low-dose cyclooxygenase inhibitor with a phosphodiesterase inhibitor might help in restoring a disturbed hemostatic balance, as thromboxane synthesis in the platelets should be inhibited to a greater extent than the prostacyclin synthesis of the endothelium. Therefore, we evaluated the influence of a therapeutic combination of cyclooxygenase inhibitors in different dosages (sulfinpyrazone, acetylsalicylic acid) with a phosphodiesterase inhibitor (dipyridamole) on platelet sensitivity and plasma factor in comparison to placebo treatment. We examined 76 males with peripheral vascular disease (PVD) stage IIa according to Fontaine in a double-blind randomized study over a 3 months period. Patients were divided into 4 groups and the different drugs were randomized as follows: I. 75 mg sulfinpyrazone and 75 mg dipyridamole, II. 150 mg ASA and 75 mg dipyridamole, III. 330 mg ASA and 75 mg dipyridamole, IV. placebo. Clinical symptoms as well as the plasma factor and the diminished platelet sensitivity to prostacyclin in patients with PVD remained unchanged throughout the whole observation period. Our findings suggest that no improvement in hemostatic dysregulation can be obtained by this combined treatment.
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PMID:Plasma factor and platelet sensitivity to prostacyclin in patients with peripheral vascular disease before and after treatment with a combination of a cyclooxygenase and a phosphodiesterase inhibitor. 643 32

Pentoxifylline (PTX) is a phosphodiesterase inhibitor used in the treatment of peripheral vascular disease, and this agent can suppress inflammatory vascular damage. Inflammation has been implicated in vascular lesion formation, and we examined the effects of PTX in a model of arterial injury. Sprague-Dawley rats were treated with intraperitoneal PTX (75 mg/kg/day) or saline starting 3 days before carotid balloon injury, and killed 24 h or 14 days later. Carotid arteries were analyzed by cross-sectional morphometry, immunostaining for proliferating cell nuclear antigen (PCNA) and subjected to terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL). Moreover, the effects of PTX on vascular smooth-muscle cell (VSMC) migration and production of collagen types I, IV, and VI were examined in vitro. At 14 days after balloon injury, PTX reduced the neointimal area (0.074+/-0.001 vs. 0.172+/-0.003 mm2; p<0.001), media area (0.143+/-0.001 vs. 0.176+/-0.001 mm2; p<0.01), intima/media ratio (0.50+/-0.02 vs. 0.99+/-0.12; p<0.001), and total vessel area (0.601+/-0.010 vs. 0.744+/-0.011 mm2; p<0.01). The lumen area, PCNA expression, and TUNEL were similar in the two treatment groups, whereas the neointimal cell density was increased by PTX (3,476+/-504 cells/mm2 vs. 2,215+/-232 cells/mm2; p<0.05). In vitro, PTX inhibited VSMC production of collagen type I in a concentration-dependent manner and did not influence VSMC migration. We conclude that PTX inhibits neointimal formation and induces constrictive vascular remodeling in the rat model of balloon injury by mechanisms involving decreased VSMC collagen type I production.
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PMID:Pentoxifylline inhibits neointimal formation and stimulates constrictive vascular remodeling after arterial injury. 1054 84

Cilostazol is a specific inhibitor of cAMP phosphodiesterase, which is used for treatment of ischemic symptoms of peripheral vascular disease. Although cilostazol has antiplatelet and vasodilator properties, its effect on the expression of adhesion molecules in vascular endothelium is not known. In the present investigation, we examined the effect of cilostazol on the expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured vascular endothelial cells. Cilostazol strongly inhibited tumor necrosis factor (TNF)-alpha-induced expression of VCAM-1 protein and its mRNA. In addition, cilostazol reduced TNF-alpha-induced U937 cell adhesion to the vascular endothelial cells. In transient transfection studies, cilostazol inhibited TNF-alpha-induced transcriptional activation of VCAM-1 promoter. Electrophoretic mobility shift assays revealed that cilostazol repressed TNF-alpha-induced increase in binding of the transcription nuclear factor-kappaB (NF-kappaB) to its recognition site of VCAM-1 promoter. Cilostazol, however, failed to prevent nuclear translocation of the NF-kappaB p65 protein. These data indicate that cilostazol repressed VCAM-1 gene transcription in cultured vascular endothelial cells, via inhibiting NF-kappaB binding to its recognition sequence. Since the expression of the adhesion molecule is one of the earliest events occurred in atherogenic process, cilostazol might have the potential to prevent atherosclerosis at least via inhibition of the expression of the adhesion molecule.
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PMID:Cilostazol represses vascular cell adhesion molecule-1 gene transcription via inhibiting NF-kappaB binding to its recognition sequence. 1150 Jan 82

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

Peripheral neuropathy is the most common complication of diabetes. This paper reviews the case histories of five patients with diabetic peripheral neuropathy or severe peripheral vascular disease who reported improvement in their symptoms when treated with regular or daily dosing with phosphodiesterase type 5 inhibitors (PDE5Is). These patients had been previously treated with PDE5Is for erectile dysfunction (ED) and not responded to on-demand therapy with a PDE5I at maximal recommended dose. This improvement is likely to be due to the known benefit of these drugs on endothelial dysfunction via an improvement of blood supply to the vasa nervorum. These cases suggest that further research is indicated to evaluate the potential use of PDE5Is in the treatment and prevention of diabetic peripheral neuropathy, particularly as these drugs are already licensed to treat ED, which occurs in around 50% of male diabetics.
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PMID:PDE5 inhibitors in diabetic peripheral neuropathy. 1693 41

Platelet activation and aggregation is an integral component of the pathophysiology that leads to thrombotic and ischemic diseases such as cerebral stroke, peripheral vascular disease and myocardial infarction. Anti-platelet agents (such as aspirin, ADP receptor antagonists, and GPIIb/IIIa antagonists), phosphodiesterase inhibitors and anti-coagulants are major part of the current treatment towards treating ischemic diseases. However, their limited efficacy in the setting of arterial thrombosis, unfavorable side effect profile and cost-to-benefit issues substantiate the need for the development of newer and more efficacious antithrombotic drugs. Various platelet agonists like adenosine diphosphate (ADP), thrombin and thromboxane A2 (TXA2) activate platelets by acting via their respective surface receptors, which couple to one or more distinct G-proteins belonging to either the G(i), G(q), G(12/13) or G(s) families. Upon activation, each of these G-proteins trigger a series of intracellular signaling cascades, causing the platelets to undergo shape change, secrete their granular contents, generate positive feedback mediators and form stable platelet aggregates. In addition, various G-protein-mediated signaling cascades act in synergy with one another to amplify the magnitude of the platelet responses. The significance of G-proteins as key mediators of the platelet function and normal hemostasis is further corroborated by extensive gene knockout studies. In this review we will limit our discussion to understanding the role of G-proteins in the process of platelet activation and discuss some of the anti-thrombotic drugs that mediate their beneficial effects by interfering with or preventing the initiation of the G-protein signaling pathway.
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PMID:G-protein dependent platelet signaling--perspectives for therapy. 1707 86

Cilostazol, a selective type III phosphodiesterase inhibitor, is widely used for treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The activation of inflammatory cells and pro-inflammatory cytokine production play critical roles in the pathogenesis of aspirin-induced gastric irritation. The aim of the present study was to determine whether cilostazol can ameliorate aspirin-induced gastric mucosal lesions in rats, reduce neutrophil accumulation, and reduce the production of pro-inflammatory cytokines. Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 N, 8.0 ml/kg). Cilostazol (1-10 mg/kg, IP) was injected 30 min before aspirin administration. Also, we measured the gastric mucosal concentrations of myeloperoxidase and interleukin-1 beta, tumor necrosis factor-alpha, and cytokine-induced neutrophil chemoattractants-1, as an index of neutrophil accumulation, and the pro-inflammatory cytokines. Cilostazol ameliorated the gastric mucosal lesions induced by aspirin administration (P<0.01). The gastric contents of myeloperoxidase and pro-inflammatory cytokines were all increased after aspirin administration and significantly reduced by cilostazol treatment. In this study, we demonstrated that a selective type III phosphodiesterase inhibitor, cilostazol, reduced aspirin-induced gastric inflammation and damage via suppression of the production of proinflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions induced by aspirin.
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PMID:Attenuation of gastric mucosal inflammation induced by aspirin through inhibition of selective type III phospshodiesterase in rats. 1737 21

Antiplatelet agents, sarpogrelate (SAR), a 5-HT(2A) receptor antagonist, and cilostazol (CIL), a phosphodiesterase III (PDE-III) inhibitor, are used for the treatment of peripheral vascular disease. We tested whether these agents affect cardiac function and subcellular remodelling in congestive heart failure (CHF) induced by myocardial infarction (MI). Three weeks after MI, rats were treated daily with 5 mg/kg SAR or CIL as well as vehicle for 5 weeks. Sham-operated animals served as controls. At end of the treatment period, haemodynamic measurements were performed and the left ventricle was processed for the determination of sarcoplasmic reticulum (SR) Ca(2+)-uptake and -release activities, and expression of SR Ca(2+)-pump, phospholamban and ryanodine receptors, as well as myofibrillar ATPase activities, expression of alpha- and beta-myosin heavy chain (MHC) isoforms, and phosphorylation of phospholamban and cardiac troponin-I (c Tn-I). Marked haemodynamic changes in the MI-induced CHF were associated with depressions in SR Ca (+)-uptake and -release activities as well as in protein content and gene expression for SR proteins. Furthermore, myofibrillar Ca(2+)-stimulated ATPase activity, as well as protein content and gene expression for alpha-MHC were decreased whereas those for beta-MHC were increased in the failing heart. Also, phosphorylation levels of phospholamban and cTn-I were reduced in failing hearts. The MI-associated changes in cardiac function, SR and myofibillar activities, as well as SR and myofibrillar protein and gene expression were attenuated by treatment with SAR or CIL. The results suggest that SAR and CIL improve cardiac function by ameliorating subcellular remodelling in the failing heart and indicate the potential therapy of CHF with antiplatelet agents.
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PMID:Antiplatelet therapy attenuates subcellular remodelling in congestive heart failure. 1808 89

Cilostazol, a selective phosphodiesterase type III inhibitor, has vasodilatory, antiplatelet, and antithrombotic actions, as well as being the first-choice drug for the intermittent claudication due to peripheral vascular disease. Main researches have demonstrated significant improvement for this situation, including patients with diabetes mellitus, concerning pain-free walking distance and quality-of-life, not rising the bleeding event risk. It does not affect the glucose metabolism even in patients suffering from diabetes. This paper aims to present a review on the discoveries of various studies, most of them experimental, on the prevention and treatment of diabetes mellitus complications, such as nephropathy and neuropathy, through the use of cilostazol, which demonstrated satisfactory results on the improvement in neural blood flow, on sodium-potassium ATPase activity, on insulin resistance, and microalbuminuria. However, strict controlling of glucose plasma levels, hypertension, and smoking habits, as well as more extended investigations on the matter are required to the better comprehension.
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PMID:[Potential therapeutic approaches for prevention and treatment of diabetic nephropathy and neuropathy: evidences of cilostazol]. 1820 97


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