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)

Antithrombin III (AT III) supplementation has proven to be effective in the treatment of disseminated intravascular coagulation. Administration of AT III is also useful for prevention of organ failure in animals challenged with endotoxin or bacteria and it increases the survival rate of such animals. Since inhibition of coagulation abnormalities failed to prevent organ failure in animals given bacteria, AT III may exert a therapeutic effect independent of its anticoagulant effect. This therapeutic mechanism of AT III has been explored using an animal model of septicemia. AT III prevented pulmonary vascular injury by inhibiting leukocyte activation in rats given endotoxin. This effect is mediated by the promotion of endothelial release of prostacyclin which inhibits leukocyte activation. Interaction of AT III with heparin-like glycosaminoglycans (GAGs) on the endothelial cell surface appears to be important for this effect. Heparin inhibits these therapeutic effects of AT III by preventing AT III from interacting with the cell surface heparin-like GAGs. This activity of AT III may explain why AT III prevents organ failure as well as coagulation abnormalities in patients with sepsis. This antiinflammatory activity of AT III may be useful for the treatment of organ failure such as in ischemia/reperfusion-induced organ dysfunction, in which activated leukocytes play a critical role.
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PMID:The anti-inflammatory properties of antithrombin III: new therapeutic implications. 951 77

Thrombin has been suggested as one of the main pharmacologic targets in unstable coronary syndromes. Electrocardiographic signs of ischemia during continuous monitoring convey prognostic information in these patients. This study assessed the anti-ischemic and clinical effects of the novel low-molecular weight thrombin inhibitor inogatran in patients with unstable angina and non-Q-wave infarction without persistent ST-segment elevation on hospital admission. Within 24 hours of the last episode of chest pain, 324 patients were randomized to 72 hours of treatment with inogatran or heparin. Continuous ST-segment analysis with computerized vectorcardiography was used to monitor ischemia for 24 hours. The occurrence of cardiac events during the first 7 days were studied and compared with ischemic episodes during the initial 24 hours. The heparin-treated patients had less episodes of ischemia (ST vector magnitude [ST-VM]: 1 +/- 2.6 vs 2 +/- 4.5, p < 0.001 and ST change vector magnitude [STC-VM]: 3 +/- 4.7 vs 6 +/- 7.6, p < 0.001) than the patients receiving inogatran. This was paralleled by a lower incidence of the combined end point of death, nonfatal infarction, refractory or recurrent angina during the first 7 days for the heparin-treated patients (35%) compared with the inogatran-treated patients (50%) (p < 0.05). Patients who had episodes of ischemia in spite of anti-ischemic therapy were at increased risk of all events studied. Heparin is more effective than inogatran in suppressing myocardial ischemia and clinical events at short-term follow-up. Continuous ST-segment monitoring with vectorcardiography identifies nonresponders who are at an increased level of risk.
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PMID:Heparin is more effective than inogatran, a low-molecular weight thrombin inhibitor in suppressing ischemia and recurrent angina in unstable coronary disease. Thrombin Inhibition in Myocardial Ischemia (TRIM) Study Group. 957 50

We studied the presence of collagen degrading enzymes (matrix metalloproteinases, MMPs) in porcine myocardium following ischemia and late reperfusion. In nine pigs, left anterior descending coronary artery was occluded for 6 h followed by reperfusion for 3 h. Six pigs without coronary occlusion served as controls. After the reperfusion period, transmural biopsies from the anterior (ischemic zone) and posterior wall (non-ischemic myocardium) in the left ventricle were obtained and extracted. Heparin-Sepharose isolated components in extracts were analysed for collagenase (triple-helical collagen degradation) and gelatinase activity (zymography). Immunohistochemistry using anti-human (MMP-1, MMP-2, MMP-9, and fibronectin) antibodies was performed on additional biopsies. Collagenase (MMP-1) and gelatinases (MMP-2, MMP-9) could be demonstrated in the extracts of non-ischemic myocardium from ischemic/reperfused as well as control pigs and MMP-1 and MMP-9 activity was found to be increased in ischemic/reperfused myocardium compared with non-ischemic myocardium. In ischemic/reperfused myocardium from live pigs investigated, myocyte necrosis could be confirmed by fibronectin immunoreaction in myocytes and MMP-1 and MMP-9 immunoreactions were increased. MMP-9 was present in cells likely to be infiltrating leukocytes in a patchy distribution throughout the ischemic myocardium. Quite coincident with MMP-9 positive cells, MMP-1 immunoreaction appeared in necrotic myocytes, in addition to reactions observed in vessel walls, endo- and epicardium, and extracellular matrix in non-ischemic myocardium. Thus, the results showed increased amounts of collagenase (MMP-1) and gelatinase (MMP-9) in ischemic/ reperfused myocardium, indicating the appearance of increased amounts of collagen degrading enzymes very early following ischemia and late reperfusion.
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PMID:Increased amounts of collagenase and gelatinase in porcine myocardium following ischemia and reperfusion. 971 Aug 10

Thrombosis is responsible for most of the acute manifestations of coronary artery disease, including unstable angina and non-Q-wave myocardial infarction. Antithrombotic therapy with antiplatelet agents and anticoagulants plays a major role in decreasing the risk of ischemic events in such patients. As thrombin generation plays a key role in the pathogenesis of thrombosis, recent studies have focused on thrombin inhibition in the management of acute ischemia. Heparin is the most widely used anticoagulant in the acute phase. Heparin given in therapeutic doses intravenously has been shown to be more effective than aspirin in decreasing the risk of death or myocardial infarction in patients with unstable angina. Low-molecular-weight heparin (LMWH) has improved pharmacologic and pharmacokinetic properties over standard heparin and this may provide greater efficacy and safety. LMWH may be given at fixed subcutaneous dose without monitoring and, therefore, is of greater clinical utility and is more cost-effective than standard heparin. Several LMWHs have been evaluated in the management of acute coronary syndromes and have shown equivalent or improved efficacy compared with standard heparin. As heparin in combination with aspirin is now the treatment of choice in acute unstable coronary syndromes, LMWH could potentially improve the outcome in such patients.
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PMID:Clinical potential of antithrombotic drugs in coronary syndromes. 973 74

Coronary angioplasty is used to treat coronary atherosclerotic disease in many patients. One problem with coronary angioplasty is the phenomenon of restenosis. Restenosis appears to be a universal response to arterial wall injury. The biological events that underlie restenosis are characterized by: platelet adhesion and aggregation at sites of damaged endothelium, and within dissections into the medial layers, release of platelet derived growth-promoting substances, inflammation of the injured medial zone, transformation, migration, and proliferation of smooth muscle cells of the media following their activation by growth-promoting substances, secretion of copious amounts of extracellular matrix material, and finally, termination of the growth process following regrowth of endothelium over the damaged area. More than a decade of research work has helped identify clinical correlates of restenosis after coronary angioplasty. Patient-related correlates include male gender, unstable angina, diabetes, and continued smoking after angioplasty. Lesion-related correlates include multilesion and multivessel procedures, higher post-angioplasty residual stenosis, proximal vessel location, location in the left anterior descending coronary artery, location in a vein graft, long lesions, and total occlusions. However, for the purposes of individual patient care, clinical correlates are not particularly helpful. No group of variables has predicted complete freedom from restenosis, and conversely no group of variables has reliably indicated its presence. All patients undergoing angioplasty will require some form of follow-up evaluation. Symptom status by itself has not been found to be useful for predicting restenosis. However, when symptom status is combined with exercise thallium-201 scintigraphy, performed 4-6 months after angioplasty, it is less than ideal, but has a negative predictive value of over 90%. This means that over 90% of patients who are asymptomatic and have no evidence of ischemia by thallium-201 scintigraphy, will not have angiographic restenosis. Numerous clinical trials have been performed in order to reduce or prevent restenosis. Almost all have been disappointing, while a few have been encouraging. Studies of antiplatelet agents such as aspirin, dipyridamole (Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA), and Ticlopidine (Syntex, Humgcao, Puerto Rico) have not shown efficacy, yet studies of an inhibitor of platelet-derived growth factor have been provocatively encouraging. No reduction in restenosis rates was found with the anticoagulants Coumadin (Du Pont Pharmaceuticals, Wilmington, DE, USA) and Heparin (Wyeth-Ayerst, Philadelphia, PA, USA). Fish oils (omega fatty acids) have been found in several clinical trials to provide modest, but encouraging, reductions in restenosis, but await further confirmation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Restenosis after coronary angioplasty. 1015 Oct 16

Intracoronary stenting has been shown to reduce acute closure and restenosis rate in patients treated with coronary angioplasty. The use of high inflation pressures and intravascular ultrasound guidance allowed the substitution of anticoagulants with antiplatelet agents but increased the cost. The aim of this study was to investigate the effectiveness, safety, and long-term outcome of the elective implantation of a relatively new type of stent (Micro-Stent II), without the use of quantitative coronary angiography or intravascular ultrasound guidance and without subsequent anticoagulation. The study included 361 patients who underwent elective microstent implantation. Stent expansion was performed at 8 atm followed by higher inflation pressure at 14-20 atm. Heparin was given intraarterially only once immediately after the arterial sheath insertion. Ticlopidine was started at least 48 hours before the procedure and continued for 1 month while aspirin was continued indefinitely. All patients were followed up for 12.9 +/- 3.6 months. Short term outcome (first month): Stent implantation was successfully achieved in 361 of 366 patients (98.6%). Seven patients (1.9%) were excluded from the study and received anticoagulants because of a suboptimal result. In total, 423 stents were implanted. There was no subacute thrombosis, but acute vessel closure occurred in one patient (0.3%). Non-Q wave myocardial infarction occurred in six patients (1.7%), Q wave myocardial infarction occurred in one patient (0.3%), and only one death (0.3%) of nonischemic origin was reported. No major peripheral vascular complications were observed. Late results: Q or non-Q wave infarction occurred in 13 patients (3.6%), 26 patients (7.2%) underwent a repeat angioplasty, eight patients (2.2%) underwent coronary artery bypass grafting, and four patients (1.1%) died. Overall, 284 patients (78.7%) were free of symptoms, while 77 (21.3%) had recurrent coronary ischemia. In conclusion, Micro-Stent II implantation without quantitative coronary angiography or intravascular ultrasound guidance and without anticoagulation was found to be effective, safe, and with good long-term outcome.
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PMID:Elective intracoronary Micro-Stent II implantation without quantitative coronary angiography or intravascular ultrasound guidance and without subsequent anticoagulation: short- and long-term results. 1034 26

A 30-year-old healthy woman was involved in a road traffic accident. She sustained a fracture dislocation of T11/12 with a complete Frankel A paraplegia below T11. She had no associated injuries. High Dose Methylprednisolone was administered according to the NASCIS III protocol (48 h) together with low molecular weight Heparin and gastroprotected medication. Complete transection of the spinal cord and an anterior haematoma from T11 to T12 were confirmed on X rays, CT's and MRI scans. Posterior surgical stabilisation was performed using Isola instrumentation, starting 8 h post injury. Her post surgical period was uneventful except for some episodes of low blood pressure (85/60 mmHg) from which she had no symptoms. On the 12th post operative day, while in the physiotherapy department, she complained of right scapular pain. This occurred every time she was sat up and was associated with paraesthesia of both upper limbs. Two days later she deteriorated neurologically and her level ascended initially to T8 and then to T3. MRI of the spine with and without gadolinium showed spinal cord oedema between C3 and T1. There was no evidence of haemorrhage or syringomyelia. The authors discussed this case making different hypotheses. They are mainly the following: (1) Gradually ascending ischaemia due to a vascular disorder; (2) Double spinal trauma; (3) Ischaemia related to repeated hypotensive episodes; (4) Low grade intramedullary tumour; and (5) Thrombus of the Radicularis Magna artery. The case has been recognised as being very rare and interesting. In the conclusions, the presenting author stresses the importance of adopting MRI-compatible instrumentation for the surgical stabilisation of the spine, and careful monitoring of blood pressure during the acute phase of spinal cord injury. Dr Aito agrees with Mr El Masry about the opportunity of forming a group of clinicians in order to discuss protocols to cope with this devastating complication.
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PMID:Ascending myelopathy in the early stage of spinal cord injury. 1049 Aug 52

This pilot study was designed to determine whether the low molecular weight heparin, enoxaparin, could be used for elective percutaneous coronary intervention (PCI) to provide antithrombotic effects without the full systemic anticoagulation that occurs with the use of unfractionated heparin. Sixty patients were randomized to receive intravenous enoxaparin (1 mg/kg bolus dose) or unfractionated heparin at the time of coronary intervention. Laboratory testing was performed at baseline, 5 minutes, and 4 hours after study drug to test if a single bolus dose of intravenous enoxaparin can consistently achieve therapeutic antithrombotic effect, thus eliminating the need for multiple doses of heparin and closely monitoring levels of anticoagulation during PCI. Thirty percent of patients who received unfractionated heparin required a second bolus of intravenous heparin to achieve the target-activated clotting time of 300 seconds before PCI. Enoxaparin showed antithrombotic properties comparable to that of unfractionated heparin as measured by anti-Xa levels, with less inhibition of thrombin (factor IIa) at the time points measured (p <0.0001). Angioplasty success rates, in-hospital ischemia, bleeding, and vascular complications were similar in both groups. Thus, intravenous enoxaparin has predictable and effective antithrombotic effects during elective PCI. Although the level of anticoagulation attained with enoxaparin is significantly lower than that after unfractionated heparin, no increase in ischemic complications were noted. The use of a single bolus of intravenous enoxaparin, without the need for measuring the activated clotting time or titrating heparin anticoagulation, has the potential for simplifying the performance and perhaps enhancing the safety of PCI.
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PMID:Usefulness of intravenous enoxaparin for percutaneous coronary intervention in stable angina pectoris. 1060 10

BACKGROUND: We determined if a single administration of heparin or nonanticoagulant N-acetylheparin could reduce myocardial injury resulting from a 90-minute occlusion of the left circumflex coronary artery (LCX) and 6 hours of reperfusion in the anesthetized canine. METHODS AND RESULTS: Heparin (2 mg/kg), N-acetylheparin (2 mg/kg), or vehicle, 0.9% sodium chloride (control), was administered intravenously to separate groups of animals 2 hours before LCX occlusion. To ensure parity of LCX ischemia, only animals with ischemic zone regional blood flow < 0.16 mL/min/g tissue were included in the final analysis. Hemodynamics did not differ among the three study groups. Infarct size as a percentage of the left ventricular area at risk was obtained for each group. Myocardial infarct size was 43.0 +/- 3.9% in the vehicle, 28.8 +/- 5.8% in the heparin (P <.05 vs vehicle) and 24.7 +/- 4.6% (P <.05 vs vehicle) in the N-acetylheparin-treated animals. CONCLUSIONS: Pretreatment with heparin or its nonanticoagulant derivative, N-acetylheparin, provides significant protection to the regionally ischemic and reperfused canine myocardium independent of either plasma glycosaminoglycan concentration or alterations in the coagulation system.
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PMID:Reduction of Myocardial Necrosis After Glycosaminoglycan Administration: Effects of a Single Intravenous Administration of Heparin or N-Acetylheparin 2 Hours Before Regional Ischemia and Reperfusion. 1068 20

Heparin reduces ischemia-reperfusion injury to myocardium. This effect has been attributed to complement inhibition, but heparin also has other activities that might diminish ischemia-reperfusion. To further probe these mechanisms, we compared heparin or an o-desulfated nonanticoagulant heparin with greatly reduced anticomplement activity. When given at the time of coronary artery reperfusion in a canine model of myocardial infarction, heparin or o-desulfated heparin equally reduced neutrophil adherence to ischemic-reperfused coronary artery endothelium, influx of neutrophils into ischemic-reperfused myocardium, myocardial necrosis, and release of creatine kinase into plasma. Heparin or o-desulfated heparin also prevented dysfunction of endothelial-dependent coronary relaxation following ischemic injury. In addition, heparin and o-desulfated heparin inhibited translocation of the transcription nuclear factor-kappaB (NF-kappaB) from the cytoplasm to the nucleus in human endothelial cells and decreased NF-kappaB DNA binding in human endothelium and ischemic-reperfused rat myocardium. Thus heparin and nonanticoagulant heparin decrease ischemia-reperfusion injury by disrupting multiple levels of the inflammatory cascade, including the novel observation that heparins inhibit activation of the proinflammatory transcription factor NF-kappaB.
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PMID:Nonanticoagulant heparin inhibits NF-kappaB activation and attenuates myocardial reperfusion injury. 1084 8


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