Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phosphodiesterase inhibitor, milrinone is used to treat low cardiac output syndrome, especially after cardiac surgery. But there were few reports about the precise hemodynamic effects at separation from cardiopulmonary bypass (CPB). We examined the hemodynamic effects of milrinone in 24 patients undergoing elective coronary artery bypass graft (CABG). Patients were assigned to the milrinone group (n = 12) and the control group (n = 12). Before separation from CPB, milrinone was administered as a loading dose of 50 micrograms.kg-1 into the reservoir of CPB at rectal temperature 33.5 degrees C and simultaneously a continuous infusion of 0.5 microgram.kg-1.min-1 was started. In addition, dopamine and nitroglycerine were administered in both groups. Hemodynamic measurements were performed before CPB, just after the weaning from CPB, 15, 30, 60 minutes after the weaning from CPB. Cardiac index increased significantly (P < 0.01) in the milrinone group as compared with the control group. Systemic vascular resistance index and mean arterial pressure decreased significantly (P < 0.0001, P < 0.05, respectively) in the milrinone group as compared with the control group. There were no significant differences in heart rate, mean pulmonary arterial pressure, pulmonary artery occlusion pressure, mean right atrial pressure, stroke volume index, and pulmonary vascular resistance index between the two groups. These hemodynamic effects showed that milrinone supported cardiac performance after CPB for CABG.
 ...
PMID:[The effects of milrinone on hemodynamics in patients undergoing cardiac surgery]. 1134 46

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.
 ...
PMID:Medical management of peripheral arterial disease. 1140 4

Cilostazol, a type III phosphodiesterase inhibitor, was approved in the United States in 1999 for the reduction of the symptoms of intermittent claudication. This article summarizes the safety data from 8 cilostazol phase 3 controlled clinical trials, involving 2,702 patients: 1,374 receiving cilostazol, 973 assigned to placebo, and 355 taking pentoxifylline. The trials ranged from 12 to 24 weeks in duration. There were a total of 475 patient-exposure years on cilostazol, 357 patient-exposure years on placebo, and 135 patient-exposure years on pentoxifylline. Headache, diarrhea, and other gastrointestinal complaints were seen more often in cilostazol-treated than placebo-treated patients; pharyngitis and nausea were more common in pentoxifylline-treated than placebo-treated patients. Headache requiring discontinuation occurred in 1.3% of patients taking cilostazol 50 mg bid and 3.7% of those receiving cilostazol 100 mg bid, compared with 0.3% of placebo-treated patients. Discontinuations due to diarrhea, palpitations, or myocardial infarction were similar in cilostazol-, placebo-, and pentoxifylline-treated patients. The rate of serious cardiovascular events was similar in all 3 treatment groups. Myocardial infarction occurred in 1.0% of cilostazol-treated, 0.8% of placebo-treated, and 1.1% of pentoxifylline-treated patients. The incidence of stroke was 0.5% in both cilostazol- and placebo-treated patients and 1.1% in pentoxifylline-treated patients. Total cardiovascular morbidity and all-cause mortality was 6.5% for cilostazol 100 mg bid, 6.3% for cilostazol 50 mg bid, and 7.7% for placebo. There were 16 deaths occurring in 0.6%, 0.5%, and 0.6% of cilostazol-, placebo-, and pentoxifylline-treated patients, respectively. The evaluations showed no trend toward increased cardiovascular morbidity or mortality risk in patients receiving cilostazol. In addition, postmarketing surveillance in the United States, representing 70,430 patient-years of cilostazol exposure, has shown minimal accounts of myocardial infarction, stroke, or death. The safety profile of cilostazol in doses of 50 mg bid and 100 mg bid appears to offer an acceptable risk-benefit ratio in patients with intermittent claudication.
 ...
PMID:Analysis of the cilostazol safety database. 1143 97

1. We have already shown that the left ventricular (LV) end-systolic pressure-volume relationship (ESPVR) of rat hearts in situ is an upward convex curve and that LV end- systolic pressure (ESP(mLVV)) and the systolic pressure-volume area (PVA(mLVV)) at a mid-range LV volume (mLVV) sensitively reflect acute changes in LV contractility and work capability. Milrinone is a non-glycosidic, non-sympathomimetic drug that increases myocardial cAMP concentrations by selective inhibition of cardiac phosphodiesterase III. Therefore, milrinone could act on the entire cardiovascular system and cause an increase in inotropy, arterial vasodilatation and venodilatation. The aim of the present study was to investigate whether the approach we have recently instituted is able to detect the effects of milrinone on the entire cardiovascular system. 2. We measured simultaneously, in anaesthetized rats, continuous LV pressure using a catheter-tip micromanometer and LV volume by LV volumetry using a conductance catheter. We obtained steady state LV pressure-volume loops and intermittently obtained the LV ESPVR by gradual occlusion of the ascending aorta. We then evaluated LV function by assessing milrinone-induced changes in the ESPVR (i.e. ESP(mLVV) and PVA(mLVV)) and vasodilator actions by assessing milrinone-induced changes in ESP(ESV) and effective arterial elastance (Ea), defined as the ESP(ESV)/stroke volume ratio. 3. Milrinone (total dose 49.5 microg; infusion rate 3.3-6.7 microg/min, 7-10 microg/kg per min; blood concentration 53.9 ng/mL) largely shifted the ESPVR upwards and, thus, significantly increased end-systolic pressure (ESP(0.08)) and the systolic pressure-volume area (PVA(0.08)) at a mid-range LV volume (= 0.08 mL/g myocardium). Milrinone also significantly decreased LV ESP(ESV) and decreased Ea, although these decreases were not significant. 4. The results of the present study suggest that our own recently instituted approach to evaluate LV function by measuring LV pressure-volume loops and ESPVR succeeded in detecting a cardiotonic action of milrinone with arterial vasodilatation in normal rat hearts.
 ...
PMID:Effects of milrinone on left ventricular end-systolic pressure-volume relationship of rat hearts in situ. 1155 33

1. It is unknown how cardiac stimulation by Ca(2+) sensitization modulates the cardiovascular response to exercise when left ventricular (LV) function is chronically depressed following a myocardial infarction. We therefore investigated the effects of EMD 57033 at rest and during exercise and compared these to those of the mixed Ca(2+)-sensitizer/phosphodiesterase-III inhibitor pimobendan. 2. Pigs were chronically instrumented for measurement of cardiovascular performance. At the time of instrumentation, infarction was produced by coronary artery ligation (MI, n=12). Studies in MI were performed in the awake state, 2 - 3 weeks after infarction. 3. MI were characterized by a lower resting cardiac output (18%), stroke volume (30%) and LVdP/dt(max) (18%), and a doubling of LV end-diastolic pressure, compared to normal pigs (N, n=13). 4. In 11 resting MI, intravenous EMD 57033 (0.2 - 0.8 mg kg(-1) min(-1)) increased LVdP/dt(max) (57+/-5%) and stroke volume (26+/-6%) with no effect on heart rate, LV filling pressure, and myocardial O(2)-consumption, similar to N. 5. In MI, the effects of EMD 57033 (0.4 mg kg(-1) min(-1), IV) on stroke volume and LVdP/dt(max) were maintained during treadmill exercise up to 85% of maximal heart rate, while heart rate was lower compared to control exercise (all P<0.05). In contrast, the effects of EMD57033 gradually waned in N at increasing intensity of exercise. 6. Compared to N, the cardiostimulatory effects of pimobendan (20 microg kg(-1) min(-1), IV) were blunted in MI both at rest and during exercise compared to N. 7. In conclusion, the positive inotropic actions of the Ca(2+) sensitizer EMD 57033 are unmitigated in resting and exercising MI compared to N, while those of the mixed Ca(2+)-sensitizer/phosphodiesterase-III inhibitor pimobendan are blunted.
 ...
PMID:Beneficial effects of the Ca2+ sensitizer EMD 57033 in exercising pigs with infarction-induced chronic left ventricular dysfunction. 1158 9

Ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It is widely used in Japan for improving prognosis and relieving symptoms in patients suffering from ischemic stroke or bronchial asthma. These clinical applications are based on the properties of ibudilast that inhibit platelet aggregation, improve cerebral blood flow and attenuate allergic reactions. The inhibition of platelet aggregation and vasodilatation by ibudilast may be due to synergistic elevation of intracellular cyclic nucleotides and release of nitric oxide (NO) or prostacyclin from endothelium, rather than direct inhibition of PDE5 or PDE3. Another important property of ibudilast is its antiinflammatory activity possibly associated with potent inhibition of PDE4. Combined with its relaxing effects on bronchial smooth muscle, antiinflammatory activity of ibudilast could favorably influence pathophysiology of asthma by antagonizing chemical mediators triggering asthmatic attacks. Ibudilast was also reported to significantly attenuate inflammatory cell infiltration in the lumbar spinal cord in an animal model of encephalomyelitis. Future investigations should include effects of ibudilast on inflammatory reactions between endothelium and blood cells, which may initiate the development of atherosclerosis.
 ...
PMID:Ibudilast: a non-selective PDE inhibitor with multiple actions on blood cells and the vascular wall. 1160 39

1. When a cerebral aneurysm ruptures, bleeding and clot formation occur around the surface of the brain, including several major blood vessels. The resulting condition, known as subarachnoid haemorrhage (SAH), often results in death or severe disability and is a significant cause of stroke. Delayed cerebral vasospasm and impaired vasodilatation are critical clinical complications that occur after SAH. Mechanisms contributing to the development of vasospasm and abnormal reactivity of cerebral arteries after SAH have been intensively investigated in recent years. The present short review briefly decribes recent advances in our knowledge of two relatively novel aspects of the mechanism(s) underlying the vascular abnormalities following SAH. 2. Cerebral arteries are depolarized after SAH, possibly due to decreased activity of potassium channels in vascular muscle. Decreased basal activation of potassium channels may be due to several mechanisms, including impaired activity of nitric oxide (NO). Vasodilator drugs that produce hyperpolarization, such as potassium channel openers, appear to be particularly effective for dilating cerebral arteries after experimental SAH. 3. Subarachnoid haemorrhage often involves decreased responsiveness of cerebral arteries to NO. This could be due to impaired activity of soluble guanylate cyclase, resulting in reduced basal levels of cGMP in cerebral vessels. However, an alternative explanation is that there may be an increased rate of cGMP hydrolysis by phosphodiesterase (PDE)-V in the cerebral vascular wall and that this abnormality contributes substantially to the impairment of NO-mediated cerebral vasodilatation after SAH. In support of this proposal, vasodilator responses to NO are reported to be normalized when coadministered with a PDE-V inhibitor following experimental SAH. 4. Thus, in cerebral vascular muscle after SAH, abnormalities of vasodilator mechanisms involving potassium channel function and also NO/cGMP activity may contribute to cerebral vascular dysfunction. These mechanisms may also represent useful and novel therapeutic targets for the treatment of vasospasm.
 ...
PMID:Cerebrovascular dysfunction after subarachnoid haemorrhage: novel mechanisms and directions for therapy. 1170 98

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.
 ...
PMID:Cilostazol (pletal): a dual inhibitor of cyclic nucleotide phosphodiesterase type 3 and adenosine uptake. 1183 Jul 53

Cilostazol, a novel cyclic adenosine monophosphate phosphodiesterase type III inhibitor, has been developed as an antiplatelet drug with a vasodilating action on peripheral arteries. The present study was designed to test, in humans, whether cilostazol can dilate the epicardial coronary arteries and what are its hemodynamic effects. Eight patients with chest pain syndrome were subjected to serial quantitative coronary arteriography immediately before and at 30, 60 and 150min after a single oral dose of cilostazol (200mg). Luminal cross-sectional areas (mm2) at the proximal and distal sites of major coronary arteries (6 segments at each sampling time) were significantly increased at 150 min after taking the drug. The percent increases relative to the baseline values were 25+/-7 (6.8+/-0.8-->8.3+/-1.0*) and 42+/-7% (2.1+/-0.3-->3.0+/-0.4*) in the right coronary artery, 24+/-5 (5.1+/-0.7-->6.1+/-0.8*) and 28+/-10% (1.6+/-0.31-->9+/-0.3*) in the left anterior descending artery, and 14+/-6 (5.9+/-0.9-->6.6+/-0.9*) and 24+/-10% (1.3+/-0.2-->1.5+/-0.2*) in the left circumflex artery, respectively (*p<0.05 vs baseline). This action, relative to that of nitroglycerine, was between 27% and 54%. Moreover, small but sustained decreases in systolic pulmonary pressure and stroke work index were observed. Thus, cilostazol has a mild coronary vasodilating action with minimal hemodynamic effects, thereby giving it a possible role in the treatment of coronary artery disease.
 ...
PMID:Effects of a single oral dose of cilostazol on epicardial coronary arteries and hemodynamics in humans. 1192 71

Platelet aggregation plays a key role in the pathogenesis of thromboembolic diseases such as myocardial infarction, stroke, unstable angina and peripheral artery disease. Until recently, aspirin was the only antiplatelet agent available to prevent or treat these events. Over the past several years, there has been a substantial expansion in the antiplatelet armamentarium as well as in the understanding of the clinical importance of antiplatelet therapy in limiting the complications of thrombosis. Aspirin was one of the first agents to be adopted and it remains as the standard therapy with the higher amount of available clinical information. Following aspirin, ADP receptor antagonists like ticlopidine and clopidogrel as well as phosphodiesterase inhibitors dipyridamole and cilostazol have been introduced. Glycoprotein (GP) IIb/IIIa receptor antagonists like eptifibatide, tirofiban and abciximab are the newer antiplatelet agents which act at the end of the common pathway of platelet aggregation. Although results of clinical studies with the first oral GPIIb/IIIa antagonists were disappointing, agents of the new generation might expand the potential application of GPIIb/IIIa targeted therapy. This review will highlight recent advances in the development of aspirin, phosphodiesterase inhibitors, ADP receptor antagonists and the platelet glycoprotein IIb/IIIa inhibitors. The emphasis of this paper has been placed on the chemical aspects of these agents.
 ...
PMID:Recent advances in antiplatelet agents. 1194 25


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>