Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Early reperfusion of occluded coronary arteries offers great promise as a method for minimizing myocardial damage after acute myocardial infarction. Such reperfusion is usually attempted via administration of fibrinolytic agents. Urokinase may hold marginal advantages over streptokinase, especially in patients with high preexisting titers of antistreptokinase antibodies. These minor differences, however, pale in comparison to important advantages demonstrated by the newly developed agent, tissue plasminogen activator (t-PA). The advantages of t-PA derive primarily from its property of binding to, and being activated by, fibrin. Consequently the generated plasmin is also fibrin-bound, the bound plasmin is protected from circulating antiplasmin and therefore more efficiently utilized, and circulating fibrinogen is spared. Preliminary clinical experience indicates that the frequency of favorable response after intravenous administration of t-PA is considerably greater than after SK. A major determinant of clinical benefit after reperfusion is the brevity of ischemia. Selective intracoronary infusion of fibrinolytic agent produces faster lysis than does intravenous infusion, and rate of lysis may be further accelerated by transcatheter disruption of clot and intrathrombic injections of highly concentrated urokinase or t-PA. Even maximally accelerated lysis, however, cannot fully compensate for the inherent delay imposed by catheterization. For that reason, prompt intravenous infusion of fibrinolytic agents, presumably t-PA, seems preferable to the intracoronary route. In the effort to initiate fibrinolytic therapy at the earliest feasible time after infarction, administration by paramedics, or even home administration after training, is a program worthy of exploration.
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PMID:Streptokinase, urokinase, and tissue plasminogen activator: pharmacokinetics, relative advantages, and methods for maximizing rates and consistency of lysis. 310 38

Thrombolytic agents may be useful in the treatment of cerebral ischemia caused by arterial thrombosis or embolic occlusion. A trial of intravenous human tissue-type plasminogen activator (rt-PA) was carried out in seven male Sprague-Dawley rats subjected to embolic cerebral ischemia, with eight control animals. One-hour-old autogenous blood clot was injected into the internal carotid artery. A 30-minute infusion of 10 micrograms/kg/minute of rt-PA or saline followed. Areas of ischemia at two hours post-embolization were assessed by digital image processing of serial iodo-14C-antipyrine autoradiographic images. The volumes of "no-flow" (NF) and "low-flow" (LF) regions were calculated. One animal in each group suffered no detectable ischemia; the remainder had well-defined regions of middle and posterior cerebral artery ischemia. No animal sustained a hemorrhagic lesion. Treatment produced no noticeable effect on the patency of cervical vessels. Total NF and LF volumes were less for the treated group but did not reach statistical significance by t-test. In middle cerebral distribution sections, however, LF volume was significantly less (p less than 0.05) for treated animals (150 vs. 191 mm3), primarily due to a more significant decrease in LF volume in the anterior-middle cerebral overlap zone (47 vs. 90 mm3; p less than 0.025). Fibrinogen levels were not altered by drug treatment (p greater than 0.30).
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PMID:The effect of intravenous tissue-type plasminogen activator in a rat model of embolic cerebral ischemia. 311 Nov 8

Investigators have tried to limit ischemic cerebral infarct size by pharmacologic and surgical means with mixed results. Thrombolytic (fibrinolytic) therapy has been used in the past with unfavorable outcome. With advances in clinical and radiologic assessment and new knowledge of the pathophysiology of brain ischemia, thrombolytic therapy has now become a feasible pharmacologic intervention in acute stroke. Central nervous system hemorrhage, the most dreaded complication of fibrinolytic therapy, is rare in patients with acute myocardial infarction favorably treated with these agents. Risk of hemorrhagic transformation of ischemic cerebral infarcts is related to size, location, and age of patient. Anticoagulation therapy may increase its size, but not its likelihood. The development of clot-specific agents, such as tissue-type plasminogen activator, and careful patient selection make fibrinolytic therapy safe and potentially effective in acute stroke.
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PMID:Thrombolysis and stroke. Past and future. 329 8

The long-acting antianginal drug molsidomine has been shown experimentally to reduce myocardial infarct size when administered prior to or after cardiac insult. This is due to several drug actions. Dilation of postcapillary capacitance vessels diminishes venous return, preload, heart dimensions, and myocardial oxygen consumption. Relaxation of stenosed conductive coronary arteries increases the perfusion of myocardial areas at risk of infarction due to enhanced collateral circulation. Increased regional blood supply nourishes predominantly subendocardial cardiac muscles as a result of reduction of extravascular coronary pressure, and resistance. The stable heart rate and cardiac contractility favor improved heart performance. The inhibition of platelet aggregation in vivo by molsidomine or its active metabolites, SIN-1 and SIN-1A, is linked to the stimulation of prostacyclin synthesis, inhibition of thromboxane release with induction of thrombosis and vasoconstriction, and enhanced concentrations of cyclic guanosine monophosphate. Dilation of coronary arteries after intracoronary administration of SIN-1, with inhibition of platelet aggregation by restrained release of adenosine diphosphate and stabilization of platelet membranes, facilitates the recanalization of stenosed arteries and reduces coronary muscle tone at the site of thrombosis. Activation of the human fibrinolytic system and drug-induced release of a plasminogen activator favor dysaggregatory effects. The drug's inhibiting actions on lipoxygenase products of arachidonate (e.g., 12-hydroperoxy-eicosatetraenoic acid and leukotrienes) may shift prostaglandin catabolism to cyclooxygenase products (e.g., prostacyclin) that protect against the expansion of ischemia and the induction of coronary spasm. Experimentally, the hemodynamic effectiveness of molsidomine can be antagonized by catecholamines (afterload effects) and dihydroergotamine (preload and afterload effects) respectively. Further clinical investigations will clarify the application of these mechanisms for the therapeutic success of the drug in human myocardial infarction.
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PMID:Molsidomine: alternative approaches to treat myocardial ischemia. 355 58

Human arteries and veins contract with hypoxia and deprivation of substrate provoked by increasing calcium inflow into the cell and reduced energy. Such spasm may be eliminated by phosphoenolpyruvate which loads up the cell's energy, blocking glycogen reduction at the same time. Reperfusion will then guarantee a sufficient energy stroke. Therapy should pursue the following steps: 1. Phosphoenolpyruvate infusion (1 X 10(-6) up to 1 X 10(-3) gm/ml in tyrodes solution pH 7.3) into the arterial branch, proximal and distal to the injury. 2. Subsequent treatment with vasodilating drugs and rheologically active substances. 3. Failed therapy after more than three hours warm ischemia could be due to autolytic processes and requires resection of the affected vessel. 4. The imbalance of the thrombolytic system with the so-called no reflow phenomenon could be due to a plasminogen activator's inhibitor released during hypoxia. Such cases may reasonably be treated by urokinase or by streptokinase plasminogen complex.
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PMID:[Vascular spasms in microsurgery]. 362 68

Yucatan miniature swine were the experimental model used to examine the effect of ischemia-injury on post-ischemic monocyte (MO) and immune function. Monocyte plasminogen activator (PA) was depressed while MO tissue factor activity was increased. The ability of porcine monocytes to generate a primary in vitro antibody forming cell (AFC) response to sheep red blood cells (SRBC) also was depressed by ischemic injury. The mechanism by which ischemic injury modulated immunosuppression appeared to be through generation of immunosuppressive serum substances.
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PMID:Post-ischemia immunosuppression in a miniature swine model. 377 45

Conventional activators of the fibrinolytic system used for coronary thrombolysis entail unavoidable delay, risk of bleeding, or both in contrast to tissue-type plasminogen activator (t-PA). Because the potential benefit of coronary thrombolysis is inversely related to the duration of antecedent ischemia, this study was performed to develop an approach for facilitated absorption of intramuscularly injected t-PA potentially adaptable for prompt, self-medication. In rabbits, absorption was markedly potentiated by hydroxylamine hydrochloride and electrical stimulation at the injection site. Intramuscular administration of t-PA in doses of 1 mg/kg of body weight, comparable to amounts given intravenously to patients (0.5-0.75 mg/kg), elicited peak blood levels of 431 +/- 52 (SEM) ng/ml 5 min after injection, well within the therapeutic range. In dogs, absorption facilitated by hydroxylamine promptly elicited angiographically documented coronary thrombolysis as well. The approach developed should ultimately permit prompt coronary thrombolysis and enhanced salvage of jeopardized ischemic myocardium in patients with life-threatening coronary thrombi.
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PMID:Coronary thrombolysis with facilitated absorption of intramuscularly injected tissue-type plasminogen activator. 385 78

This study was performed to measure the effects of sustained coronary flow reduction on lung lymph flow and protein clearance at normal and elevated lung microvascular pressures. Eleven halothane-anesthetized sheep were provided with lung lymph and carotid-to-left-anterior-descending coronary artery cannulas. Six sheep (ischemic group) were observed in a protocol of five periods, each of 2 hr duration: baseline, left atrial pressure (PLA) increased by mitral valve obstruction, return to baseline, reduced coronary flow, and reduced coronary flow plus increased PLA. Five sheep (control group) were studied in an identical protocol except that coronary flow was not reduced. PLAS were equal in the second and fifth periods. Lung lymph flow QL and protein clearance (QL times the lymph-to-plasma protein concentration ratio) normalized to second baseline were greater during ischemia than in the comparable control period, and clearance was also greater during the second increased-pressure period. We conclude that reduced coronary flow is related to sustained, significant increases in lung vascular transport at elevated as well as at normal vascular pressures.
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PMID:Lung vascular transport at controlled pressures with reduced coronary flow in sheep. 404 68

Postoperative abdominal adhesion formation can undo the reconstructive work of the infertility surgeon. Adhesions can form in as little as three hours after surgery. Most adhesions are transient and lyse spontaneously within 72 hours of surgery. Such factors as tissue trauma, anoxia and ischemia cause a reduction in plasminogen activator activity that is strongly correlated with the persistence and progression of postoperative adhesions. Adhesions can be prevented by a proper and meticulous surgical technique emphasizing preservation of tissue without abrasion, anoxia or ischemia. Dextran, antiprostaglandins, antibiotics, steroids, antihistamines, anticoagulants and enzymes have various roles. Our current regimen involves Hyskon, Motrin and deoxycycline.
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PMID:Formation and prevention of postoperative abdominal adhesions. 672 92

Early postinfarction angina implies an unfavorable prognosis. Most published information on this outcome represents data collected in the prethrombolytic era, in which definitions and populations differed considerably. Our purpose was to evaluate the incidence and importance of recurrent ischemia after administration of thrombolytic therapy. We studied patients enrolled in the Thrombolysis and Angioplasty in Myocardial Infarction studies. Patients were enrolled into 5 studies with similar entry criteria; 552 patients were treated with tissue plasminogen activator (t-PA), 293 were treated with urokinase, and 385 received both thrombolytic agents. Recurrent ischemia was defined as symptoms in association with electrocardiographic changes; reinfarction was defined as a reelevation of creatine kinase myocardial band isoenzyme in an appropriate clinical setting. Both recurrent ischemia and reinfarction occurred in 42 patients (3.4%), recurrent ischemia alone occurred in 226 (18%), whereas neither occurred in 964 (78%). Although baseline characteristics were similar among the 3 groups, in-hospital cardiac events (total 73 deaths, 253 heart failure episodes) were not: in-hospital mortality in patients with reinfarction was 21%; with recurrent ischemia, 11%; and with neither event, 4% (p < 0.0001). The in-hospital heart failure rate of patients with reinfarction was 50%; with recurrent ischemia alone, 31%; and with neither event, 17% (p < 0.0001). As expected, median in-hospital costs were highest in patients with reinfarction ($26,802), intermediate for those with recurrent ischemia alone ($18,422), and lowest in patients with neither event ($15,623). Recurrent myocardial ischemia after thrombolytic therapy is a frequent, important, and expensive adverse clinical outcome, making it a critical target for therapeutic intervention.
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PMID:Frequency, significance, and cost of recurrent ischemia after thrombolytic therapy for acute myocardial infarction. TAMI Study Group. 748 52


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