Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of Na+/H+ exchanger (NHE) may have an important role in ischemic cell death by means of intracellular overload of Na(+) and Ca(2+). Recent evidence has suggested that inhibitors of NHE have protective effects on myocardial ischemia both in vivo and in vitro. In this study, we tested the hypothesis that FR183998, an inhibitor of NHE, reduces infarct volume produced by focal cerebral ischemia in rats. We used 20 male spontaneously hypertensive rats. Either FR183998 (1 mg/kg; n=10), or vehicle (n=10) was given intravenously to the rats and the distal middle cerebral artery of each animal was occluded using a photothrombotic technique. We measured regional cerebral blood flow using laser-Doppler flowmetry throughout the experiments. After 3 days, infarct volume was measured in each animal group. To estimate the brain edema, we also calculated the cortical volume in both hemispheres. The infarct volume in the FR183998-treated group (82+/-8 mm(3), mean+/-S.E.M.) was significantly smaller than that in the control group (115+/-12 mm(3)) (P=0.034). The cortical volume of the occluded side in the FR183998-treated group (359+/-7 mm(3)) tended to be smaller than that in the control group (378+/-9 mm(3)) (P=0.116). The regional cerebral blood flow and physiological variables during ischemia were not significantly different between the two groups throughout the experiments. These results suggest that inhibition of NHE by FR183998 may have beneficial effects in reducing infarct volume and brain edema during cerebral ischemia. Thus, NHE may play an important role in the development of neuronal damage during acute cerebral ischemia.
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PMID:Inhibition of Na+/H+ exchanger reduces infarct volume of focal cerebral ischemia in rats. 1174 53

Without a doubt PEG-SOD has been the enzyme most studied in PEGylation. One can say that it represents the preferred model to assess chemistries for PEG activation, analytical procedures suitable for conjugate characterization, the influence of PEG size in conjugate removal from circulation and elimination of immunogenicity and antigenicity, and the effect of route of administration. The effect of PEG conjugation was studied in vitro and in vivo models in comparison with the free enzyme and the following conclusions may be drawn: (1) At the blood vessel level, PEG-SOD has been shown to provide a greater resistance to oxidant stress, to improve endothelium relaxation and inhibit lipid oxidation. (2) In the heart, PEG-SOD proved to be at least as effective as native SOD in treatment of reperfusion-induced arrhythmias and myocardial ischemia. (3) In the lung, PEG-SOD appeared to be able to reduce oxygen toxicity and E. coli-induced lung injury, but not in the treatment of lung physiopathology associated with endotoxin-induced acute respiratory failure and in the reduction of asbestos-induced cell damage. (4) On cerebral ischemia/reperfusion injuries the effect of PEG-SOD was uncertain, also due to the difficulty of cerebral cell penetration. (5) In kidney and liver ischemia both enzyme forms were found to ameliorate reperfusion damage. In view of so much positive research on PEG-SOD, it is surprising that no approved application in human therapy has been established and approved.
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PMID:Polyethylene glycol-superoxide dismutase, a conjugate in search of exploitation. 1205 16

Free radicals appear to participate in the final common pathway of neuronal death in ischemia and may therefore be an adequate target for therapy. Tempol is a nitroxide antioxidant with proven protective efficacy in several animal models, including myocardial ischemia, that has not been previously tested in models of permanent cerebral ischemia. Spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO). Following dose-response and time-window-finding experiments rats were given vehicle or tempol (50 mg/kg) subcutaneously 1 h after PMCAO (n = 10/group). Five animals in each group were evaluated with a motor scale 24 h after the infarct and were then sacrificed and the injury volume was measured. The remaining animals were examined daily with the motor scale and also with a Morris water maze test on days 26-30 after PMCAO and sacrificed on day 30. Motor scores at all time points examined were significantly better in the tempol-treated animals (P < 0.05 for all). Significantly better performance in the water maze test for performance on days 26-30 was noted in the tempol group compared with the vehicle-treated group (P < 0.05). Injury volumes at days 1 and 30 were significantly reduced in the tempol group (9.83 +/- 1.05 vs 19.94 +/- 1.43% hemispheric volume, P = 0.0009, and 13.2 +/- 2.97 vs 24.4 +/- 2.38% hemispheric volume, P = 0.02, respectively). In conclusion, treatment with tempol led to significant motor and behavioral improvement and reduced injured tissue volumes both in the short and in the long term after stroke.
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PMID:The nitroxide antioxidant tempol is cerebroprotective against focal cerebral ischemia in spontaneously hypertensive rats. 1235 77

Control of hypertension is a well-established goal of the primary and secondary prevention of stroke. However, management of blood pressure in the setting of acute brain ischemia is complicated by the possible effect of blood pressure changes on cerebral perfusion. In acute stroke, patients may have an ischemic penumbra of brain tissue, which has impaired perfusion but which is not irreversibly damaged. The ischemic penumbra may be salvaged with reperfusion. Lowering of blood pressure in this setting, however, would hasten the progression of the penumbra to infarction. With the exception of patients treated with thrombolytic agents, blood pressure reduction is not recommended in acute ischemic stroke for this reason. Preliminary studies suggest that there may be a role for interventions to elevate blood pressure as a treatment for acute stroke patients. Despite interest in induced hypertension as a treatment of stroke dating back to the 1950s, this practice has not achieved widespread use owing to concerns about potential adverse effects such as intracerebral hemorrhage, cerebral edema, and myocardial ischemia. It is commonly used, however, to treat patients with threatened cerebral ischemia due to vasospasm after subarachnoid hemorrhage. Until future studies clarify the effectiveness of induced hypertension in stroke treatment, maintaining adequate blood pressure and fluid volume is recommended for patients with acute ischemic stroke, particularly if the neurologic deficits are fluctuating or the patient has persistent large-vessel occlusive disease.
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PMID:Hypoperfusion and Its Augmentation in Patients with Brain Ischemia. 1277 97

RSR13 binds to hemoglobin (Hb), reduces oxygen (O2) binding affinity, and enhances O2 unloading from Hb to hypoxic tissue. Tissue hypoxia is common to cancer, surgery, myocardial ischemia, and stroke. RSR13 increases tumor pO2, reduces tumor hypoxic fraction and because O2 is necessary to maximize the effectiveness of radiation therapy, RSR13 enhances the efficacy of radiation therapy. Patients with brain metastases or glioblastoma multiforme receiving RSR13 and radiation therapy have improved median survival, compared to matched historical controls. Myocardial and cerebral hypoxia can be complications to cardiopulmonary bypass (CPB) surgery. RSR13 improves myocardial oxidative metabolism and contractile function in models of myocardial ischemia, including CPB. In CPB patients, RSR13 improved cardiac contractile function and reduced blood product use. In animals, RSR13 increased brain pO2 and reduced neuronal cell death following cerebral ischemia, alone or in combination with excitotoxic neurotransmitter inhibition. Allosteric modification of Hb by RSR13 represents a unique therapeutic strategy.
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PMID:Allosteric modification of hemoglobin by RSR13 as a therapeutic strategy. 1456 22

The most important adaptive responses from a physiological stance involved the cardiovascular system, consisting in particular of elevation of the cardiac output and its redistribution to favor the coronary and cerebral circulations, at the expense of the splanchnic vascular beds. The evidence regarding these physiological responses, especially in experimental studies that permit the control of many variables, is particularly powerful and convincing. On the other hand, there is a remarkable lack, in quality and quantity, of clinical studies addressing how normal physiological adaptive responses may be affected by a variety of diseases and conditions that often accompany and may complicate anemia, and interactions with other such compounding variables as age and different patient populations. For these reasons, it is not possible to offer guidelines on how to increase, maintain, or even to determine optimal DO2 in high-risk patients and how best transfusion strategies might be used under these conditions. From the brief review of physiological principles and the strong consensus in the literature, it is evident that cardiac function must be a central consideration in decisions regarding transfusion in anemia, because of the critical role it plays in assuring adequate oxygen supply of all vital tissues. Particular attention should be paid to the possible presence of CAD or incipient or cardiac failure, as these conditions may require careful transfusions to improve DO2 at levels that may not necessitate such interventions when cardiac disease is absent. Although the cerebral circulation also serves an obligate aerobic organ unable to tolerate significant hypoxia, there is little convincing evidence to support the notion that cerebral ischemia is aggravated by anemia and that this can be prevented by improved DO2 through rapid correction of anemia. Consequently, the arguments favoring transfusions in the presence of ischemic heart disease do not appear to apply to occlusive cerebrovascular disease. Because firm evidence is lacking on the interactions of concurrent diseases and anemia in various patient populations, understanding of the physiological consequences of anemia, and of the diseases concerned, is useful but not fully sufficient to provide firm and rational guidance to transfusion practice in specific complex clinical instances. A good deal of clinical and experimental investigation is required to support fully rational and comprehensive guidelines. In the meantime, prudent and conservative management, based on awareness of risks and sound understanding of the normal and pathological physiology, must remain the guiding principle.
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PMID:Physiologic aspects of anemia. 1513 60

Cerebral oxygenation (rSO(2)) in the region of sagittal sinus and main hemodynamic parameters were measured in 112 patients with ischemic heart disease and class II-III angina. Four groups of patients were distinguished according to degree of rSO(2) lowering. Hemodynamics and oxygen transport function of the blood were proportionally related to degree of rSO(2) lowering. Normal rSO(2) (>70%) and degree lower (70-61%) was associated with predicted (desirable) cerebral blood flow. Lower rSO(2) values (60-50%) were accompanied with increased oxygen utilization (by 20-25%). Critical rSO(2) lowering (below 50%) was associated with>/=75% rise of oxygen utilization what was indicative of decreased brain blood flow and cerebral ischemia.
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PMID:[The study of cerebral oxygenation and central hemodynamics in patients with ischemic heart disease at rest and during physical effort.]. 1547 72

The cardiac sodium-calcium exchanger (NCX) plays an important role in calcium homeostasis. It is the primary mechanism for removing calcium ions that enter myocytes through L-type calcium channels on a beat-to-beat basis. Its direction of transport is determined by the membrane potential and the ionic concentrations of Na+ and Ca2+, with the forward (or Ca2+-efflux) mode of transport being the dominant mode under physiological conditions. In contrast, the Ca2+-influx mode (or reverse mode) of NCX becomes important in certain pathophysiological conditions, such as myocardial ischemia and reperfusion. Recent discovery of compounds that inhibit the Ca2+-influx mode (or reverse mode) of NCX has generated intense research interest in the pharmacology of NCX. Among the newer NCX inhibitors described to date, 2-[4-[(2,5-difluorophenyl)methoxy]-phenoxy]-5-ethoxyaniline (SEA0400) appears particularly promising in attenuating cardiac, renal, and cerebral ischemia/reperfusion injuries in various experimental models. Moreover, the mixed results that have emerged from clinical trials evaluating the efficacy and safety of inhibitors of the sodium-hydrogen exchanger (an upstream target in relation to the sodium-calcium exchanger) in myocardial protection stimulated interest in evaluating NCX as an alternative therapeutic target. This article reviews the pharmacological profile of SEA0400, as presented in the published literature, and discusses the therapeutic potential of this compound in attenuating myocardial ischemia/reperfusion injury.
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PMID:SEA0400: a novel sodium-calcium exchange inhibitor with cardioprotective properties. 1559 78

Owing to the selective inhibition of PGI2 synthesis, treatment with COX-2 inhibitors constitutes a potential risk for the increased occurrence of thrombotic cardiovascular incidents and of the first-time occurrence or a deterioration in pre-existing heart failure. Elderly patients, particularly those with a history of ischemic heart disease, hypertension or heart failure, are at risk. One key indication for selective COX-2 inhibitors is the chronic treatment of patients suffering from rheumatoid arthritis or osteoarthritis. However, these patients have an excess cardiovascular mortality, which relates particularly to cardiovascular incidents or heart failure. The use of nonselective antiphlogistic drugs and COX-2 inhibitors is associated with a higher potential risk in these patient groups. In essence, more than 80 million patients worldwide were treated with rofecoxib up to its voluntary withdrawal. The high number of patients who are still being treated with COX-2 inhibitors or for whom the use of COX-2 inhibitors is planned justifies the use of a biochemical marker which, as a screening instrument, is initially designed to recognize the patients who are "ill" despite the lack of symptoms. In asymptomatic patients with NT-proBNP levels below the cut-off, high-risk patients require further work-up. Recognition of these risk factors is easily accomplished considering the case history and the results of an established cardiovascular risk score (e.g. PROCAM score). These risk patients should then also be referred for intensive diagnostic work-up. On the other hand, symptomatic patients or those with high NT-proBNP levels should primarily be referred for more extensive cardiovascular diagnosis before a decision is taken concerning the use of COX-2 inhibitors. As an integral part of this extensive work-up the determination of NT-proBNP can help to improve the accuracy of diagnosis and prognostic assessment. With the exception of patients showing symptoms of an unstable coronary heart disease, imminent cerebral ischemia, uncontrolled arterial hypertension or decompensated heart failure, the use of a COX-2 inhibitor is possible provided special caution is exercised. Termination of treatment is advisable if there is a clinical deterioration of specific symptoms or signs in those patients (product information). Follow-up with NT-proBNP (monitoring) can be helpful in detecting imminent cardiac decompensation at an earlier stage in order to take suitable countermeasures.
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PMID:Rationale for testing the cardiovascular risk for patients with COX-2 inhibitors on the basis of biomarker NT-proBNP. 1571 8

Dyslipemia is a clear risk factor (RF) for ischemic heart disease and peripheral artery disease, but its relation with ischemic stroke (IS) is not so clear. HMG-CoA reductase inhibitor drugs or statins (simvastatin, atorvastatin, pravastatin) reduce the relative risk of IS by between 18 and 51% in patients with IHD, in patients with high vascular disease risk and in hypertensive patients with other RFs, acute coronary syndrome, and type 2 diabetes mellitus. According to the guidelines for use, statins are indicated in the majority of patients with IS since the risk is equivalent to that of IHD or high vascular disease risk. In view of the existing clinical evidence of benefit, it would not seem unreasonable to proceed with treatment of patients using statins while awaiting specific studies justifying their use. The non-lipid-lowering mechanisms of the statins and results of studies, such as the Heart Protection Study, provide evidence for widening the indications of statins beyond the prevention of dyslipemia, as a new therapeutic approach in the prevention of IS in patients with plasma levels of total cholesterol or low density lipoproteins currently considered within the normal distribution. The neuroprotective role, which these drugs may play in the acute phase of cerebral ischemia, remains to be clarified, but very recent evidence suggests that such patients may also benefit.
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PMID:Lipids and stroke: the opportunity of lipid-lowering treatment. 1632 54


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