Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cilostazol, a cyclic AMP phosphodiesterase inhibitor, has been used as an antiplatelet agent. In the present study, we investigated the in vitro effect of cilostazol on DNA synthesis in rat aortic arterial smooth muscle cells (SMCs) in culture stimulated with fetal calf serum (FCS), platelet-derived growth factor (PDGF), insulin, or insulin-like growth factor-I (IGF-I). Micromolar concentrations of cilostazol inhibited [3H]thymidine incorporation into DNA and cell growth as determined by cell number and protein concentration. Treatment with cilostazol increased the intracellular concentration of cyclic AMP, suggesting that the inhibition of SMC proliferation by cilostazol may be mediated through increased levels of cyclic AMP. The results suggested that cilostazol, by interfering with the proliferation of arterial SMCs, may have potential to prevent initiation and progression of atherosclerosis.
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PMID:Effect of cilostazol, a cyclic AMP phosphodiesterase inhibitor, on the proliferation of rat aortic smooth muscle cells in culture. 128 92

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

Cilostazol, a selective type III phosphodiesterase inhibitor, has antiplatelet and vasodilating effects. In this study, the effects of cilostazol on lipid metabolism and lipoprotein lipase (LPL) activity were studied in rats. Cilostazol was administered orally at doses of 30 or 100 mg/kg twice a day for 1-2 weeks to rats. Cilostazol decreased the serum triglyceride level in normolipidemic rats. The serum triglyceride level was reduced and HDL cholesterol level was increased by cilostazol in streptozotocin (STZ)-induced diabetic rats. The disappearance of exogenous triglyceride was accelerated by cilostazol in normolipidemic rats. Cilostazol increased post-heparin plasma LPL activity but had no effect on hepatic triglyceride lipase activity in STZ-induced diabetic rats. Cilostazol also increased LPL activity in the heart in STZ-induced diabetic rats. These findings suggest that an increase in LPL activity is responsible for the serum triglyceride lowering and HDL cholesterol elevating effects of cilostazol in rats.
Atherosclerosis 2000 Oct
PMID:Cilostazol, a selective type III phosphodiesterase inhibitor, decreases triglyceride and increases HDL cholesterol levels by increasing lipoprotein lipase activity in rats. 1099 57

The pathophysiology of intermittent claudication (IC) and the role of pentoxifylline and cilostazol for treating IC are discussed. IC, a result of inadequate blood flow to the musculature, is the primary symptom of occlusive peripheral vascular disease (PVD). Patients with IC often have a decreased quality of life because of mobility limitations. PVD is a sign of generalized atherosclerosis and increases the risk of cardiac morbidity and mortality. Smoking, hypertension, diabetes mellitus, and increasing age may hasten the progression of PVD. Strategies for treating IC are aimed at improving symptoms and reducing the progression of atherosclerosis and include risk-factor modification, exercise, and antiplatelet therapy. Cilostazol and pentoxifylline are the only two drugs with FDA-approved labeling for use in treating IC. Both drugs have been shown to increase pain-free walking time and total distance walked, although there is some conflicting evidence for pentoxifylline. Cilostazol and pentoxi-fylline are fairly well tolerated; the most common adverse effects involve the gastrointestinal tract and central nervous system. Inhibitors of cytochrome P-450 isoenzymes 3A4 and 2C19 should be used cautiously in patients taking cilostazol, and this drug is contraindicated in patients with congestive heart failure. Cilostazol is more costly than pentoxifylline. Initiation of therapy with either pentoxifylline or cilostazol may be reasonable if risk-factor modifications, lifestyle changes, and antiplatelet therapy are not effective. The mainstays of therapy for IC are risk-factor modification, exercise, and antiplatelet therapy. If these prove inadequate, treatment with pentoxifylline or cilostazol may be reasonable.
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PMID:Treatment of intermittent claudication with pentoxifylline and cilostazol. 1181 75

Peripheral arterial disease affects approximately 8-10 million people in the United States. Approximately one-third to one-half of these individuals are symptomatic. The risk factors that contribute to peripheral arterial disease are similar to those associated with other forms of atherosclerosis, including diabetes mellitus, cigarette smoking, hypercholesterolemia, high blood pressure, and hyperhomocysteinemia. Of these, diabetes and cigarette smoking pose the greatest risk for developing peripheral arterial disease. The prognosis of patients with these risk factors is limited because of their greater risks for myocardial infarction, stroke, and cardiovascular death. Cardiovascular mortality correlates inversely with the ankle/brachial index, and the risk of death is greatest in those with the most severe peripheral arterial disease. Treatment regimens to reduce cardiovascular morbidity and mortality in patients with peripheral arterial disease should include risk factor modification and antiplatelet therapy. The cardinal symptoms of peripheral arterial disease include intermittent claudication and rest pain, with the latter being indicative of critical limb ischemia. Therapeutic strategies that focus on improving the patient's quality of life, reducing the severity of claudication, and improving limb viability include supervised exercise training, pharmacotherapy, and revascularization. Two drugs-pentoxifylline and cilostazol-currently are approved by the Food and Drug Administration for the treatment of patients with claudication. Meta-analyses have suggested that, compared with placebo, pentoxifylline improves maximal walking distance by approximately 20-25%. Cilostazol is a phosphodiesterase type 3 inhibitor. In clinical trials, cilostazol has consistently improved maximal walking distance as compared with placebo, with the range of improvement being approximately 40-60%. Drugs that are currently under investigation include propionyl-L-carnitine, vasodilator prostaglandins, L-arginine, and the angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factors.
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PMID:Medical management of peripheral arterial disease. 1140 4

Intermittent claudication (IC), most often characterized by a reproducible, painful aching or cramping in muscle groups of the leg caused by walking and relieved by rest, is a common, lifestyle-limiting symptom of lower-extremity peripheral arterial occlusive disease. Because IC is usually indicative of systemic atherosclerosis, active investigation and treatment are recommended. Positive outcomes have been shown with a treatment regimen including risk-factor modification, particularly smoking cessation and control of diabetes, exercise, and pharmacotherapy. Pentoxifylline has been used since 1984 for the treatment of IC with indifferent results. Recently, clinical trials with cilostazol, a drug approved for use in the United States, have shown significant effectiveness in IC patients, generally doubling their maximal walking distance at 24 weeks of treatment. Cilostazol has also been shown to be significantly more effective than pentoxifylline in improving pain-free and maximal walking distance. Other classes of drugs, such as platelet antiaggregants, are being studied for the treatment of IC, but little efficacy has been shown. Arterial revascularization by endovascular or surgical methods is an additional option but must be considered on an individual basis depending on severity of symptoms and disability in each patient.
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PMID:Intermittent claudication: effective medical management of a common circulatory problem. 1143 95

Cilostazol is an antiplatelet drug, which has beneficial effects in treatment of intermittent claudication and decreases serum triacyiglycerol level in these patients. In this study, we examined adipogenic potency of cilostazol using 3T3-L1 preadipocyte cell line because cilostazol is one of the tissue specific phosphodiesterase (PDE) inhibitors. Addition of cilostazol into the differentiation medium including insulin and dexamethasone, induced the adipocyte differentiation without isobutyl methylxanthine (IBMX). Compared with the cells incubated with vehicle, the cells treated with cilostazol contain much more lipid droplets in the cells 6 days after induction of differentiation. Adipocyte specific gene like stearoyl-CoA desaturase was strongly induced after addition of cilostazol. C/EBPbeta, which is induced by IBMX was also induced by cilostazol. These findings suggest a possibility that adipogenic effect of cilostazol is one of the mechanisms, by which this agent decreases blood triacylglycerol level in the intermittent claudication patients.
Atherosclerosis 2001 Sep
PMID:Antiplatelet agent cilostazol potentiates adipocyte differentiation of 3T3-L1 cells. 1150 Jan 70

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.
Atherosclerosis 2001 Sep
PMID:Cilostazol represses vascular cell adhesion molecule-1 gene transcription via inhibiting NF-kappaB binding to its recognition sequence. 1150 Jan 82

Cilostazol, a novel oral phosphodiesterase inhibitor, has shown consistent improvement in exercise tolerance in patients with intermittent claudication (IC). In addition to this effect, cilostazol has previously been shown to have beneficial effects on the dyslipidemia, i.e., combination of high triglycerides with low high-density-lipoprotein cholesterol (HDL-C) levels. Interleukin-6 (IL-6) suppresses the activity of lipoprotein lipase, which modulates the metabolism of triglycerides and HDL-C. To determine whether a reduction of IL-6 contributes to the improvement of lipid profiles, we prospectively investigated the effect of cilostazol (n=16, 100 mg, twice daily) on the changes of lipid profiles and on the association with the changes of IL-6 compared with those of pentoxifylline (n=16, 400 mg, bid) in patients with IC. After eight weeks of administration of cilostazol to patients with IC, walking distances were increased, associated with a 29% decrease in plasma triglycerides and a 13% increase in HDL-C. No significant changes of lipid profiles in the pentoxifylline and placebo groups were observed although a similar improvement in walking distances was achieved in the pentoxifylline group. IL-6 levels were significantly reduced in patients receiving cilostazol as compared with those receiving placebo or pentoxifylline. The cilostazol-induced changes in the IL-6 were positively related to those of triglycerides in the cilostazol group (r=0.63, P<0.05) and negatively related to those of HDL-C (r=-0.55, P<0.05). These findings suggest that in addition to consistent improvement of exercise tolerance, cilostazol may improve lipid profiles by reducing IL-6 release. However, pentoxifylline did not affect lipid profiles although a similar improvement of maximal walking distance (MWD) was achieved.
Atherosclerosis 2001 Oct
PMID:Differential lipogenic effects of cilostazol and pentoxifylline in patients with intermittent claudication: potential role for interleukin-6. 1158 28

Cilostazol (Pletal), a quinolinone derivative, has been approved in the U.S. for the treatment of symptoms of intermittent claudication (IC) since 1999 and for related indications since 1988 in Japan and other Asian countries. The vasodilatory and antiplatelet actions of cilostazol are due mainly to the inhibition of phosphodiesterase 3 (PDE3) and subsequent elevation of intracellular cAMP levels. Recent preclinical studies have demonstrated that cilostazol also possesses the ability to inhibit adenosine uptake, a property that may distinguish it from other PDE3 inhibitors, such as milrinone. Elevation of interstitial and circulating adenosine levels by cilostazol has been found to potentiate the cAMP-elevating effect of PDE3 inhibition in platelets and smooth muscle, thereby augmenting antiplatelet and vasodilatory effects of the drug. In contrast, elevation of interstitial adenosine by cilostazol in the heart has been shown to reduce increases in cAMP caused by the PDE3-inhibitory action of cilostazol, thus attenuating the cardiotonic effects. Cilostazol has also been reported to inhibit smooth muscle cell proliferation in vitro and has been demonstrated in a clinical study to favorably alter plasma lipids: to decrease triglyceride and to increase HDL-cholesterol levels. One, or a combination of several of these effects may contribute to the clinical benefits and safety of this drug in IC and other disease conditions secondary to atherosclerosis. In eight double-blind randomized placebo-controlled trials, cilostazol significantly increased maximal walking distance, or absolute claudication distance on a treadmill. In addition, cilostazol improved quality of life indices as assessed by patient questionnaire. One large randomized, double-blinded, placebo-controlled, multicenter competitor trial demonstrated the superiority of cilostazol over pentoxifylline, the only other drug approved for IC. Cilostazol has been generally well-tolerated, with the most common adverse events being headache, diarrhea, abnormal stools and dizziness. Studies involving off-label use of cilostazol for prevention of coronary thrombosis/restenosis and stroke recurrence have also recently been reported.
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PMID:Cilostazol (pletal): a dual inhibitor of cyclic nucleotide phosphodiesterase type 3 and adenosine uptake. 1183 Jul 53


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