Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

On the basis of vascular involvement, an open clinical trial was performed to determine whether or not the antithrombotic drug cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2(1H)-quinolinone, OPC-13013, Pletaal, CAS 73963-72-1) applied as a single 100 mg tablet increases peripheral blood flow and prevents diabetic neuropathy in 30 patients with non-insulin dependent diabetes mellitus. The hemodynamic effects of this drug on the a. dorsalis pedis were examined using a new real-time two-dimensional Doppler echography. 1 h after oral administration of cilostazol, the cross-sectional area of the a. dorsalis pedis significantly increased from 2.2 +/- 0.2 to 2.9 +/- 0.3 mm2 (p less than 0.05). Also, the a. dorsalis pedis blood flow index significantly increased from 16 +/- 1 to 31 +/- 4 (p less than 0.05). Cilostazol did not affect plasma glucose level (from 213 +/- 14 to 198 +/- 15 mg/dl), but slightly plasma ratio of 6-keto PGF1a to TXB2 (from 0.71 +/- 0.09 to 0.83 +/- 0.12). These effects of cilostazol might ameliorate diabetic neuropathy by improving blood flow and preventing nerve tissue ischemia.
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PMID:Hemodynamic effects of cilostazol on peripheral artery in patients with diabetic neuropathy. 164 79

Cilostazol (Pletal), a quinolinone derivative with a cyclic nucleotide phosphodiesterase type 3 (PDE3) inhibitory activity, was recently approved by the Food and Drug Administration for treatment of symptoms of intermittent claudication (IC). However, the underlying mechanisms of action are not entirely clear. In this study, we showed that cilostazol inhibited adenosine uptake into cardiac ventricular myocytes, coronary artery smooth muscle, and endothelial cells with a median effective concentration (EC50) approximately 10 microM. In vivo, cilostazol increased cardiac interstitial adenosine levels after a 2-min ischemia in rabbit hearts (329 +/- 92% increase vs. 102 +/- 29% ischemia alone). The combination of cilostazol and 2-min ischemia reduced infarction from subsequent 30-min regional ischemia and 3 h of reperfusion (infarct size was 18 +/- 4% vs. 53 +/- 3% in the hearts with 2-min ischemia alone or 48 +/- 2% in the hearts treated with cilostazol alone). In contrast, milrinone had no effect on either adenosine uptake or interstitial adenosine levels. These data show that cilostazol, unlike milrinone, inhibits adenosine uptake, and thus potentiates adenosine accumulation from a 2-min ischemia. Future studies are needed to investigate the role of adenosine in the treatment of IC by cilostazol.
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PMID:Inhibition of adenosine uptake and augmentation of ischemia-induced increase of interstitial adenosine by cilostazol, an agent to treat intermittent claudication. 1097 93

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

During exercise, patients with intermittent claudication (IC) have decreased limb arterial blood pressure that recovers during rest. A novel method for assessing dynamic recovery of function is measurement of the hemodynamic response after exercise. Cilostazol (Pletal), a new agent for the treatment of IC, increases walking distance and may decrease ischemic burden. The objective of this study was to assess the effect of cilostazol versus placebo on hemodynamic measurements after exercise-induced ischemia in patients with IC. Two double-blind, placebo-controlled studies with similar inclusion/exclusion criteria and duration (24 weeks) were pooled. Patients walked on a treadmill at 2.0 miles/h (3.2 km/h) on a 12.5% grade until the claudication-limited maximal walking distance (MWD) was reached. Anterior and posterior tibial pressures were measured with Doppler ultrasound at baseline and at 1, 5, and 9 min during recovery. Area under the curve (AUC), a measure of the time course of recovery of systolic pressure after exercise-induced ischemia, and ankle-brachial index (ABI) were calculated and compared using analysis of variance (ANOVA). All three treatment groups (308 patients randomized to cilostazol 100 mg bid, 303 to cilostazol 50 mg bid, and 299 to placebo) had similar baseline characteristics. Mean post-exercise AUC for cilostazol 100 mg and 50 mg bid versus placebo increased by 0.31 (p = 0.001) and 0.26 (p = 0.004), respectively. Mean resting ABI increased by 0.03 (p = 0.0039) and 0.04 (p = 0.0001) in the cilostazol 100 mg and 50 mg bid groups, respectively. In conclusion, following 24 weeks of treatment, cilostazol increased the ABI at rest and improved the recovery time of ankle pressures post-exercise.
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PMID:Effects of cilostazol on resting ankle pressures and exercise-induced ischemia in patients with intermittent claudication. 1178 69

This study examined the protective effects of cilostazol on cerebral infarcts produced by subjecting rats to 2-h occlusion of the left middle cerebral artery followed by 24-h reperfusion. The ischemic cerebral infarct consistently involved the cortex and striatum. The infarct size was significantly reduced, when rats received 10 mg/kg cilostazol intravenously 5 min or 1 h after the completion of 2-h ischemia. Cyclic AMP level was significantly elevated in the cortex of 4- and 12-h reperfusion (P < 0.01) following treatment with cilostazol (10 mg/kg, 5 min after 2-h ischemia) accompanied by decreased tumor necrosis factor-alpha level. Samples from the regions corresponding to the penumbra showed markedly reduced Bcl-2 protein level and, in contrast, high levels of Bax protein and cytochrome c release. Cilostazol decreased Bax protein and cytochrome c release and increased the levels of Bcl-2 protein. Cilostazol (10(-7)-10(-5) M) potently and concentration dependently scavenged hydroxyl and peroxyl radicals. In conclusion, cilostazol treatment decreases ischemic brain infarction in association with inhibition of apoptotic and oxidative cell death.
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PMID:Neuroprotective effect of cilostazol against focal cerebral ischemia via antiapoptotic action in rats. 1186 82

Three patients were evaluated for refractory digital ischemia. The first patient presented with chronic, post-traumatic, unremitting, cold, painful, right fourth and fifth fingers. The symptoms had failed to improve despite topical nitroglycerin and a calcium channel blocker. Baseline digital plethysmography documented impaired perfusion within the affected digits. Cilostazol (Pletal) was added to the medical regimen and at the 8-week follow-up the fourth and fifth fingers were warm with repeat plethysmography displaying normal perfusion. A second patient had CREST syndrome-associated painful bilateral index finger ulcerations that had evolved despite taking a calcium channel blocker. Consequently the patient was started on cilostazol and within 4 weeks the digital ulcerations and pain had resolved. The third patient with traumatic right fifth digital arterial thrombosis was seen for persistent pain and cyanosis in spite of undergoing thrombolysis and subsequent anticoagulation with vasodilator therapy. Digital plethysmography established fixed ischemia within the fifth finger; subsequently, cilostazol was prescribed. Four weeks later the digital pain and cyanosis had essentially resolved. A follow-up plethysmographic waveform documented restored perfusion. Although approved for the treatment of intermittent claudication, cilostazol was successfully utilized in the setting of severe digital ischemia.
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PMID:Three cases of digital ischemia successfully treated with cilostazol. 1195 91

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

This study shows the in vivo neuroprotective effect of cilostazol against cerebral ischemic injury evoked by subjecting rats to 2-h occlusion of middle cerebral artery (MCAO) followed by 24-h reperfusion. We observed the signaling pathway by which cilostazol suppressed MCAO-induced increased phosphorylation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) and apoptosis via increased phosphorylation of casein kinase 2 (CK2). When rats received 30 mg/kg cilostazol orally two times at 5 min and 4 h after the completion of ischemia, the infarct area was significantly reduced in the cortex and striatum with improvement of neurological deterioration. Increased DNA fragmentation in the penumbral zone was significantly reduced by cilostazol. Cilostazol significantly elevated phosphorylation levels of CK2, Akt, and cyclic AMP response element-binding protein (CREB) in association with increased Bcl-2 in the ischemic area, whereas the elevated PTEN phosphorylation was significantly reduced, all of which were antagonized by iberiotoxin, a maxi-K channel blocker, administered intracisternally 30 min before ischemia. In conclusion, cilostazol ameliorates the neuronal damage by suppression of apoptotic cell death via the maxi-K channel opening-coupled up-regulation of CK2 phosphorylation and down-regulation of PTEN phosphorylation with resultant increase in the Akt and CREB phosphorylation and increased Bcl-2 protein.
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PMID:Cilostazol prevents focal cerebral ischemic injury by enhancing casein kinase 2 phosphorylation and suppression of phosphatase and tensin homolog deleted from chromosome 10 phosphorylation in rats. 1463 32

The prevalence of peripheral arterial disease (PAD) increases with age. PAD in elderly persons may be asymptomatic, may be associated with intermittent claudication, or may be associated with critical limb ischemia. Other atherosclerotic vascular disorders, especially coronary artery disease (CAD), may coexist with PAD. Elderly persons with PAD are at increased risk for all-cause mortality, cardiovascular mortality, and mortality from CAD. Modifiable risk factors should be treated in persons with PAD such as cessation of cigarette smoking and control of hypertension, dyslipidemia, and diabetes. Statins have been shown to reduce the incidence of intermittent claudication and to improve treadmill exercise duration until the onset of intermittent claudication in persons with PAD and hypercholesterolemia. Antiplatelet drugs such as aspirin or clopidogrel, especially clopidogrel, should be administered to all persons with PAD. Persons with PAD should be treated with angiotensin-converting enzyme inhibitors and also with beta blockers if CAD is present. Cilostazol should be given to persons with intermittent claudication to improve exercise capacity unless heart failure is present. Exercise rehabilitation programs improve exercise time until claudication. Indications for lower extremity angioplasty, preferably with stenting, or bypass surgery are 1) incapacitating claudication in persons interfering with work or lifestyle; 2) limb salvage in persons with limb-threatening ischemia as manifested by rest pain, nonhealing ulcers, and/or infection or gangrene; and 3) vasculogenic impotence. However, amputation should be performed if tissue loss has progressed beyond the point of salvage, if surgery is too risky, if life expectancy is very low, or if functional limitations obviate the benefit of limb salvage.
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PMID:Management of peripheral arterial disease of the lower extremities in elderly patients. 1499 33

Cilostazol was developed as a selective inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3). The anti-platelet and vasodilator properties of cilostazol have been extensively characterized and considered to contribute to the variety of clinical effects such as intermittent claudication and recurrent stroke. In this review, the novel action mechanism (s) of cilostazol are overviewed with the focus on the action of cilostazol in in vitro and in vivo studies as a maxi-K channel opener targeting anti-apoptotic signaling pathways. Under treatment with cilostazol (10 mg/kg intravenously or 30 mg/kg orally), a significant reduction in cerebral infarct area was evident in rats subjected to ischemia/reperfusion. Increase in cyclic AMP and decrease in TNF-alpha levels were identified in the ipsilateral cortex under treatment with cilostazol accompanied by decreased Bax formation and cytochrome c release with increased Bcl-2 production in the penumbral area as well as in the in vitro human umbilical endothelial cells. Cilostazol suppressed TNF-alpha-induced decrease in viability of SK-N-SH (human neuroblastoma) cells and HCN-1A (human cortical neuron) cells in association with decrease in PTEN phosphorylation and increase in Akt/CREB phosphorylation with suppression of DNA fragmentation, all of which were antagonized by iberiotoxin, a maxi-K(+) channel blocker. Further, cilostazol prevented TNF-alpha-induced PTEN phosphorylation and apoptotic cell death via increased CK2 phosphorylation in the SK-N-SH cells. Cilostazol increased K(+) current in SK-N-SH cells by opening the maxi-K channels. Thus, it was suggested that the action of cilostazol to promote cell survival was ascribed to the maxi-K channel opening-coupled upregulation of CK2 phosphorylation and downregulation of PTEN phosphorylation with resultant increased phosphorylation of Akt and CREB. These in vitro data were confirmed in the in vivo results of rats subjected to focal transient ischemic damage.
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PMID:Cilostazol: therapeutic potential against focal cerebral ischemic damage. 1647 48


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