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

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

Antiphospholipid syndrome is a disorder characterized by arterial and venous thromboses, thrombocytopaenia and stroke. Acute myocardial infarction is rarely associated with this syndrome. The treatment of these patients is a clinical challenge. This report is about a patient with antiphospholipid syndrome presenting with an acute myocardial infarction after an exercise test. The infarct-related coronary artery was successfully revascularized by primary angioplasty and stenting without any major bleeding complications. We think that the physical exertion could have favoured acute coronary thrombosis in this particular setting.
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PMID:Successful treatment of post-exertion acute myocardial infarction by primary angioplasty and stenting in a patient with antiphospholipid antibody syndrome. 1516 50

When mitochondria are exposed to high Ca2+ concentrations, especially when accompanied by oxidative stress and adenine nucleotide depletion, they undergo massive swelling and become uncoupled. This occurs as a result of the opening of a non-specific pore in the inner mitochondrial membrane, known as the MPTP (mitochondrial permeability transition pore). If the pore remains open, cells cannot maintain their ATP levels and this will lead to cell death by necrosis. This article briefly reviews what is known of the molecular mechanism of the MPTP and its role in causing the necrotic cell death of the heart and brain that occurs during reperfusion after a long period of ischaemia. Such reperfusion injury is a major problem during cardiac surgery and in the treatment of coronary thrombosis and stroke. Prevention of MPTP opening either directly, using agents such as cyclosporin A, or indirectly by reducing oxidative stress or Ca2+ overload, provides a protective strategy against reperfusion injury. Furthermore, mice in which a component of the MPTP, CyP-D (cyclophilin D), has been knocked out are protected against heart and brain ischaemia/reperfusion. When cells experience a less severe insult, the MPTP may open transiently. The resulting mitochondrial swelling may be sufficient to cause release of cytochrome c and activation of the apoptotic pathway rather than necrosis. However, the CyP-D-knockout mice develop normally and show no protection against a range of apoptotic stimuli, suggesting that the MPTP does not play a role in most forms of apoptosis.
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PMID:Calcium, mitochondria and reperfusion injury: a pore way to die. 1654 83

Atherosclerosis is a multifocal, smoldering, immunoinflammatory disease of medium-sized and large arteries fuelled by lipids. Endothelial cells, leukocytes, and intimal smooth muscle cells are the major players in the development of this disease. The most devastating consequences of atherosclerosis, such as heart attack and stroke, are caused by superimposed thrombosis. Therefore, the vital question is not why atherosclerosis develops but rather why atherosclerosis, after years of indolent growth, suddenly becomes complicated with luminal thrombosis. If thrombosis-prone plaques could be detected and thrombosis averted, atherosclerosis would be a much more benign disease. Approximately 76% of all fatal coronary thrombi are precipitated by plaque rupture. Plaque rupture is a more frequent cause of coronary thrombosis in men (approximately 80%) than in women (approximately 60%). Ruptured plaques are characterized by a large lipid-rich core, a thin fibrous cap that contains few smooth muscle cells and many macrophages, angiogenesis, adventitial inflammation, and outward remodeling. Plaque rupture is the most common cause of coronary thrombosis. Ruptured plaques and, by inference, rupture-prone plaques have characteristic pathoanatomical features that might be useful for their detection in vivo by imaging. This article describes the pathogenesis of atherosclerosis, how it begets thrombosis, and the possibility to detect thrombosis-prone plaques and prevent heart attack.
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PMID:Pathogenesis of atherosclerosis. 1663 13

Platelets are essential for the maintenance of vascular integrity and control of bleeding at sites of injury, but they are also implicated in the progression of atherosclerotic lesions and arterial vascular thrombosis. The use of antiplatelet drugs for the primary and secondary prevention of cardiovascular and cerebrovascular thromboses in adult populations has been extensively evaluated, resulting in defined management strategies. Much less is known about the appropriate use of antiplatelet drugs (primarily aspirin) in infants and children for secondary prevention in ischemic stroke, for prevention of coronary artery thrombosis in Kawasaki disease, or for prevention of thromboembolism following surgery for congenital cardiac disease. Additional studies will be required to evaluate the relative benefits of aspirin and anticoagulants in these settings. A role for newer antiplatelet drugs in the management of pediatric arterial thrombosis is as yet unexplored.
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PMID:Antiplatelet therapy in children. 1670 76

Sildenafil is widely used as a primary pharmacological treatment of erectile dysfunction in men with and without underlying cardiovascular disease. Although initial reports of adverse cardiac events were reported soon after Food and Drug Administration approval of this agent, a large body of data suggests that sildenafil does not significantly increase the risk of nonfatal myocardial infarction, stroke, or cardiovascular deaths in patients with preexisting ischemic heart disease. We report the case of a 66-year-old man who developed thrombotic occlusion of the left anterior descending artery and presented with acute myocardial infarction after the use of sildenafil. The patient had presented with chest pain syndrome and borderline elevation of serum troponin I levels 1 week before sildenafil use, and a coronary angiogram had demonstrated normal coronary arteries. This case emphasizes the potential of precipitating coronary thrombosis in patients with unstable plaque after sildenafil use, even in patients with angiographically normal coronary arteries.
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PMID:Sildenafil-associated coronary thrombosis in a patient with angiographically normal coronary arteries: a case report with review of literature. 1685 76

Metabolic syndrome is characterized by the clustering of a number of metabolic abnormalities in the presence of underlying insulin resistance with a strong association with diabetes and cardiovascular disease morbidity and mortality. The disorder is defined in different ways, but the pathophysiology is attributable to insulin resistance. An increased release of free fatty acids (FFAs) from adipocytes block insulin signal transduction pathway, induce endothelial dysfunction due to increased reactive oxygen species (ROS) generation and oxidative stress. Dyslipidemia, associated with high levels of triglycerides and low concentrations of high density lipoproteins (HDLs), contributes to a proinflammatory state. Inflammation, the key pathogenic component of atherosclerosis, promotes thrombosis, a process that underlies acute coronary event and stroke. Tissue factor, a potent trigger of the coagulation cascade, is increased in diabetes with poor glycemic control. Therapeutic lifestyle changes (weight loss and physical activity) along with pharmacological interventions are recommended to prevent the complications of metabolic syndrome. In addition to statins, metformin, blood pressure lowering medications, interventions to increase HDLs are other important approaches to decrease the risk of cardiovascular disease. Furthermore, the peroxisome proliferator activated receptor (PPAR)-alpha and gamma agonists are potent anti-inflammatory and anti-atherogenic agents that could both improve insulin sensitivity and the long-term cardiovascular risk. In this review we focus on the molecular and pathophysiological basis of metabolic syndrome, which augments diabetes (insulin resistance) and the contribution of neovascularization in the plaque progression in diabetes, leading to rupture and coronary thrombosis.
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PMID:Metabolic syndrome and diabetic atherothrombosis: implications in vascular complications. 1691 71

Coronary thrombosis is a pivotal event in the pathogenesis of acute coronary syndromes and ischemic complications resulting from coronary intervention. Activation of the platelet glycoprotein (GP) IIb/IIIa receptor is the final common pathway leading to platelet aggregation, coronary thrombus formation, and myocardial ischemia. Inhibitors of platelet GP IIb/IIIa are potent agents to prevent progression to myocardial infarction and death. We prospectively surveyed the indications, frequency, and complications associated with the use of GP IIb/IIIa inhibitors in percutaneous coronary intervention in a tertiary center setting. A total of 170 patients underwent screening over a period of 6 weeks. One hundred four (61%) had coronary intervention, out of which eight (8%) had failed intervention. Glycoprotein IIb/IIIa inhibitors were used in 57 (55%) patients; 47 (45%) did not have any agent periprocedure. Eptifibatide was the most commonly used agent in 35 (33%), followed by abciximab in 19 (18%) and tirofiban in 3 (3%). Out of 57 patients in whom GP IIb/IIIa agents were used, 22 (38%) had visible intracoronary thrombus, 22 (38%) had diffuse disease, 8 (14%) had complex intervention, and 5 (9%) had diabetes. The overall incidence of complications was not increased by the use of GP IIb/IIIa inhibitors; serious complications were rare with the use of GP IIb/IIIa agents; no stroke, thrombocytopenia, gastrointestinal bleed, or death was recorded. The overall use in emergency settings was not associated with increased complications. Bradycardia and vomiting were more common with abciximab group, whereas puncture site pain was commoner in eptifibatide group.
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PMID:An audit of the use and complications of glycoprotein IIb/IIIa inhibitors in percutaneous coronary intervention against national UK standards. 1717 71

Atherosclerosis is a systemic disease responsible for strokes, myocardial infarction, renal hypertension, and intermittent claudication. Acute coronary syndromes (unstable angina, acute myocardial infarction, and sudden cardiac death) are the major causes of morbidity and mortality in developed countries. These acute manifestations of heart disease share a common pathophysiologic phenomenon: coronary thrombosis. Two principal mechanisms are responsible for coronary thrombosis: plaque disruption (75%) and plaque erosion (25%). Disrupted plaques exhibit a large lipid content, increased macrophages, and a thin fibrous cap. Hypercholesterolemia and diabetes are associated with plaque disruption. Eroded plaques are smooth muscle-cell rich with an intact fibrous cap. Cigarette smoking is associated with plaque erosion, most frequently in women with sudden death when they are younger than 50 years of age. Systemic inflammation is a novel, robust marker for future cardiovascular events, not only in patients with established atherosclerotic disease but also in apparently healthy individuals. Local inflammation at the plaque disruption site is documented by increased macrophage infiltration. Macrophages are responsible for plaque disruption, neovascularization, smooth muscle cell apoptosis, and plaque thrombogenicity. Experimental studies have identified the lipid core as the most thrombogenic substrate of the atherosclerotic plaque. Tissue factor, a cell membrane-bound protein, is crucial in thrombus formation. Tissue factor is expressed in apoptotic macrophages, suggesting that macrophages are not only responsible for plaque disruption but also pivotal in thrombus generation, the most important mechanism of acute coronary syndromes.
J Stroke Cerebrovasc Dis
PMID:Pathophysiology of plaque disruption and thrombosis in acute ischemic syndromes. 1790 43

The efficacy of clopidogrel, as an established anti-platelet agent for the acute coronary syndrome treatment and for the thrombotic complications prevention after percutaneous coronary angioplasty and coronary artery stenting has been supported by the evidence of several major randomized clinical trials. However, some patients treated with clopidogrel have a minor, but still a risk of coronary artery thrombosis and sudden death. Moreover, clopidogrel was not effective in patients after ischemic stroke, as well as it was not effective for the primary prevention of vascular events. Several authors proposed the theory of " clopidogrel-resistance " . However, this theory is based on a limited number of laboratory findings, and was not supported by the evidence of clinical studies. The phenomena of " clopidogrel-resistance " could be masked by the low patient compliance, while the rate of such patients could exceed 30% after one year of treatment. The offered methods for overcoming clopidogrel-resistance include doubling or tripling of the loading dose (600-900 mg vs. 300mg) or administration one or two more potent antiplatelet agents. However, such approach could not only increase the risk of major and fatal bleedings, but could have a potential to reduce patients compliance, and consequently increase the risk of thrombosis. Only multicenter randomized study with hard outcome or ideally survival endpoint, supported by comprehensive serial platelet assessment, strict compliance rules including measurement of clopidogrel metabolite(s) will determine whether " clopidogrel resistance " is a real danger (as suggested by the platelet biomarkers), or an artificial tool (as suggested by the randomized clinical evidence) introduced to help novel antiplatelet agents to gain the vascular market share.
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PMID:[Clopidogrel resistance: myth or reality]. 1826 Sep 49


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