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Biomedical subjects

K A Fox

Publications and source records attributed to K A Fox.

At least 127 records · Page 7Linked to original sources
PubMed1990

Thrombolysis: adjuvant therapy and the role of complement.

A possible role for adjuvant therapy following thrombolysis exists in the context of reperfusion injury and post-ischaemic dysfunction, or so-called 'stunned myocardium'. The question that arises is whether the extent of myocardial stunning, or the ultimate extent of necrosis, can be reduced by preventing reperfusion injury and the impairment of reflow. Essential to any attempted intervention is an understanding of the mechanisms underlying myocardial damage following ischaemia and reperfusion. Certain mediators responsible for injury and repair have been identified, and their effects modified in experimental preparations; the role of complement, in particular, is central to these phenomena. Lysis of coronary artery thrombus is only the initiator of a sequence of events involving vascular endothelium and an intravascular response to tissue injury. The challenge is whether reperfusion injury may be modified and whether such intervention will favourably alter clinical outcome.

Complement System Proteins↗
PubMed1990

A randomized dose-ranging study of rt-PA in acute myocardial infarction. Effects on coronary patency and fibrinolytic parameters.

This study was designed to examine the relationships between dose of Wellcome two-chain recombinant tissue type-plasminogen activator (BW rt-PA) and coronary patency and fibrinolytic parameters in acute myocardial infarction (AMI). In an open randomized study, patients with AMI (determined by ECG) and symptoms of less than 4 h duration without contraindications for fibrinolytic therapy were treated with rt-PA in nominal doses of 20 (7.7 MU), 50 (14.8-29.6 MU) or 100 mg (29.6-48.2 MU) administered over 90 min followed by intravenous heparin. Coronary patency was determined by coronary arteriography of the infarct-related artery and haematological parameters (fibrinogen, plasminogen, alpha 2-antiplasmin and fibrin(ogen) degradation products) measured at 90 min. Coronary patency increased in a dose-related manner to 53% (95% C.I. 37-69%) in the 100 mg/90 min group. Logistic regression demonstrated a relationship between dose (in MU kg-1) and coronary patency. Fibrinogen at 90 m was reduced to 74 (61.5-86.4%) of the pooled plasma standard in the nominal 100 mg group. Patients with a higher predose fibrinogen had higher reductions of fibrinogen. Serious bleeding occurred in three (3%) patients, and no intracranial bleeds were reported. BW rt-PA produces dose-related patency of the coronary arteries with moderate, dose-related reduction in fibrinogen.

Aged↗
PubMed1989

Extensive aortic valve ring abscess formation: a rare complication of Q fever endocarditis.

We report the successful management and 2 year follow up of a young patient with Q fever endocarditis on a congenitally bicuspid aortic valve complicated by extensive abscess formation in the aortic valve ring and interventricular septum. Aortic root abscess formation complicating Q fever endocarditis has been reported in only one previous patient. Serological tests may thus be indicated in patients with aortic abscesses. Despite extensive aortic and intramyocardial abscess formation it proved possible to control the progression of disease by open drainage of the abscess and aortic valve replacement. Although the requirement for aortic root replacement was anticipated in this patient, it has not been required.

Abscess↗
PubMed1987

Metabolism of beta-methyl[1-11C]heptadecanoic acid in canine myocardium.

To assess the contributions of metabolism to CO2 and back-diffusion of nonmetabolized tracer to total clearance of beta-methyl[1-11C]heptadecanoic acid ([1-11C]BMHDA) from myocardium and its distribution into lipid pools, 10-15 mCi of [1-11C]BMHDA were rapidly infused into the circumflex coronary artery of seven open-chest dogs. Externally detected clearance of myocardial 11C-activity was protracted (t1/2 = 41 +/- 18 min) with over 50% of extracted tracer retained in tissue after 20 min. Efflux of extracted [1-11C]BMHDA between 5 and 20 min was comprised of both 11CO2 (16.5 +/- 15.2%) and nonmetabolized [11C]BMHDA (24.6 +/- 11.5%). At 20 min, 11C-activity in lipid was distributed primarily between triglyceride (47 +/- 16% of total) and phospholipid (39 +/- 17%) pools. Partial oxidation to 11CO2 and partitioning into more than one lipid pool are likely to hinder evaluation of fatty acid metabolism based on residue detection of [1-11C]BMHDA with tomography.

Animals↗
PubMed1987

Intramuscular administration of human tissue-type plasminogen activator in rabbits and dogs and its implications for coronary thrombolysis.

To determine whether sustained plasma concentration of human tissue-type plasminogen activator (t-PA) can be induced promptly after intramuscular injection with enhancers of absorption devoid of deleterious local and systemic effects, we studied 250 rabbits and 13 dogs. In rabbits with t-PA injected directly into exposed muscle followed by local electrical stimulation at the site, early absorption was increased markedly by addition of 0.63M methylamine plus 0.079M hydroxylamine to the excipient. Elevations peaked within 5 min and increased with dose of t-PA, concentration of methylamine, and volume of injection medium. The enhancers were effective with percutaneous injections in the absence of local electrical stimulation as well. They did not elicit any obviously deleterious local or systemic effects. In separate experiments in rats, intramuscular injections of 0.63M methylamine plus 0.079M hydroxylamine induced local egress of intravascular radiolabeled albumin within the injection site and endothelial gaps in venules detected with colloidal carbon--changes consistent with direct effects on vascular permeability. In dogs, percutaneous intramuscular injection of t-PA in excipient without enhancers did not lead to early elevations of human t-PA in plasma, although late elevations were seen. When the enhancers were used, early elevations occurred as well, with functional activity documented by fibrin plate assays of serially obtained plasma samples and by sequential coronary angiography delineating thrombolysis after experimentally induced coronary thrombosis. The results indicate that intramuscular administration of t-PA with selected enhancers of absorption is a feasible approach for rapid induction of fibrinolysis.

Absorption↗
PubMed1987

Radiation therapy salvage of Hodgkin's disease following chemotherapy failure.

Between 1972 and 1984, 17 patients with advanced Hodgkin's disease failing intensive combination chemotherapy in previously unirradiated nodal and/or pulmonary sites were treated with salvage radiotherapy. Treatment consisted of comprehensive wide field radiotherapy to all known areas of disease. Doses administered to these fields ranged from 1,700 to 5,000 rad, with only three patients (18%) receiving less than 3,000 rad to any field. With a median follow-up of over 4 years, 88% achieved a complete response, with median actuarial disease-free survival (DFS) of 19 months (range, 4 to 61+). Actuarial median survival was 64 months, with a range of 4 to 134+ months. Nine patients (53%) are currently alive with three (18%) in continuous complete remission (CR) for 24, 30, and 61 months. In addition, four patients relapsing after salvage radiotherapy are now in CR following additional therapy. Patients younger than 35 years of age had a significantly increased overall survival when compared with older patients (P less than .005). An initial complete response to chemotherapy lasting 12 or more months appeared to be a favorable prognostic factor, although small patient numbers preclude statistical significance. Comprehensive salvage radiotherapy is of significant benefit in patients with advanced Hodgkin's disease relapsing after combination chemotherapy in nodal and/or pulmonary sites.

Actuarial Analysis↗
PubMed1987

Determinants of salvage of jeopardized myocardium after coronary thrombolysis.

Coronary thrombolysis is an attractive approach for salvaging jeopardized, ischemic myocardium. The advent of second- and third-generation clot-selective thrombolytic agents will make this approach safer and more widely applicable in the future. However, residual stenoses and reocclusion are common after the thrombolytic therapy. In addition to thrombolysis, future management of coronary thrombosis may include adjunctive pharmacologic therapy such as calcium-channel antagonists, beta-blockers, or oxygen free radical scavengers, and/or mechanical interventions such as balloon or laser angioplasty, or bypass surgery.

Angioplasty, Balloon↗
PubMed1987

The temporal pattern of recovery of myocardial perfusion and metabolism delineated by positron emission tomography after coronary thrombolysis.

Recovery of mechanical function by ischemic myocardium is dependent on the restoration of nutritive blood flow and oxidative metabolism subsequent to reperfusion. To characterize the time course and extent of recovery of perfusion and metabolism, we used positron emission tomography with 15O-labeled water and 11C-labeled palmitate to sequentially study six dogs after 2 hr of ischemia followed by reperfusion for 4 wk. Myocardial blood flow in the ischemic region increased from 15 +/- 8% of normal during coronary occlusion to 82 +/- 25% 1 hr after reperfusion. Despite maintained coronary patency documented angiographically, flow was reduced after 24 hr to 37 +/- 16% of normal. This decrease was temporary, with flow returning to 66 +/- 11%, 62 +/- 7%, and 64 +/- 18% of normal after 1, 2, and 4 wk of reperfusion, respectively. Uptake of 11C-labeled palmitate paralleled alterations in perfusion during ischemia and early reperfusion, averaging 32 +/- 15% of normal during ischemia, and 67 +/- 22% and 36 +/- 10% after 1 and 24 hr of reperfusion. After that, palmitate uptake was more variable. Flow and fatty acid uptake after 4 wk of reperfusion were not related to collateral flow during ischemia or the extent of initial reperfusion. However, uptake of palmitate 1 hr after reperfusion was a strong predictor of the uptake of palmitate 4 wk after reperfusion (r = 0.86, p less than 0.03). The results indicate that positron emission tomography with 15O-labeled water and 11C-labeled palmitate may be useful for assessing the success of recanalization in restoring nutritive perfusion and fatty acid metabolism and that the uptake of [11C]palmitate early after reperfusion predicts the ultimate salvage of myocardium.

Animals↗
PubMed1987

Metabolic fate of radiolabeled palmitate in ischemic canine myocardium: implications for positron emission tomography.

Interpretation of dynamic and integrated myocardial tomograms requires elucidation of the biochemical fate of the tracer and characterization of its tissue distribution and rate of efflux. The fate of [1-11C] and [1-14C]palmitate was studied in 13 open-chest dogs during control or ischemic extracorporeal perfusion of the left circumflex coronary artery. Residue detection of myocardial radioactivity, and radio-biochemical analyses of sequential transmural biopsies and arterial and coronary venous effluent were performed for 30 min after intracoronary bolus administration of tracer. In control hearts, 10.3% of initially extracted tracer was retained in tissue (2.9% in triglyceride, 3.5% in phospholipid, and 3.9% in other lipid and aqueous fractions), 73.7% was oxidized, and 16.1% back-diffused unaltered. With ischemia (pump flow 10% of normal), 28.1% was retained (18% in triglyceride, 6.0% in phospholipid, and 4.1% in other lipid and aqueous fractions), 27.2% was oxidized, and 44.4% back diffused (p less than 0.05 compared to control). Throughout the 30-min study interval, triglyceride, diglyceride, and nonesterified fatty acid comprised a significantly greater fraction of initially extracted radioactivity in ischemic than in control hearts. Thus, during ischemia externally detected clearance rates cannot be used as a direct measure of fatty acid metabolism because of marked influences on efflux of nonmetabolized radiolabeled palmitate and the distribution of tracer retained in tissue. Quantitative measurements of specific metabolic processes by tomography will require development and validation of tracers confined to individual metabolic pathways or pools.

Animals↗
PubMed1987

Pathophysiology of myocardial reperfusion.

The feasibility of myocardial reperfusion is established. However, restoring patency to epicardial coronary arteries does not necessarily signify restoration of tissue perfusion or restoration of biochemical or mechanical function to the heart muscle previously supplied by the occluded vessel. This review examines the biochemical, functional, and histopathologic changes associated with myocardial reperfusion in an attempt to define the constraints within which reperfusion may lead to optimal recovery of myocardium, and to explore future possibilities for maximizing benefits of reperfusion while minimizing potential reperfusion injury.

Animals↗
PubMed1986

Enhancement of salvage of reperfused ischemic myocardium by diltiazem.

Concomitant use of pharmacologic agents may be required for maximal salvage of ischemic myocardium by reperfusion. Accordingly, in dogs with induced thrombotic coronary occlusion, the effects of intravenous diltiazem given 30 minutes before administration of streptokinase on myocardial blood flow and myocardial salvage were evaluated. Two independent types of end points were employed. Positron emission tomography was utilized for noninvasive assessment of myocardial perfusion and infarct extent. Direct measurements included quantification of myocardial infarction by assay of creatine kinase activity in myocardial homogenates. Infarct extent averaged 27.9 +/- 11.4% of left ventricular weight in 10 control dogs in which coronary occlusion was maintained for 24 hours. In eight dogs given streptokinase alone, the infarct extent averaged 16.7 +/- 10.0% of left ventricular mass (p less than 0.05 versus control). In nine other dogs given diltiazem (15 micrograms/kg per min continuously until death was induced) beginning 30 minutes before streptokinase, infarct extent averaged 9.4 +/- 6.7% of left ventricular mass (p less than 0.05 compared with reperfusion alone). At the dose administered, diltiazem did not alter blood flow, heart rate or mean arterial pressure after coronary occlusion or thrombolysis. The region at risk, determined in 16 dogs from perfusion images obtained with positron tomography and oxygen-15-labeled water after coronary occlusion, was similar in the three groups (30.6 +/- 7.3% of the left ventricle in six control dogs, 31.8 +/- 4.5% in five dogs with reperfusion alone and 30.5 +/- 11.6% in five dogs with reperfusion plus diltiazem). Infarct size quantified in terms of the extent of myocardium exhibiting less than 50% of peak carbon-11-labeled palmitate uptake 24 hours after occlusion and expressed as the percent of the region at risk averaged 89.6 +/- 11.4% in control dogs, was significantly reduced to 45.1 +/- 29.8% in dogs with reperfusion alone and was reduced further to 22.3 +/- 16.4% in dogs given diltiazem and reperfusion. Thus, concomitant treatment with diltiazem markedly enhances salvage of reperfused myocardium after coronary thrombolysis.

Animals↗
PubMed1985

Coronary thrombolysis with facilitated absorption of intramuscularly injected tissue-type plasminogen activator.

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.

Animals↗
PubMed1985

Pathophysiology of myocardial reperfusion.

The feasibility of myocardial reperfusion induced by coronary thrombolysis stimulated marked changes in the management of patients with acute myocardial infarction. Despite the demonstrable successful recanalization achieved in many patients, effective tissue reperfusion has not necessarily been achieved. Furthermore, factors defining the risk/benefit relationships of reperfusion, the extent to which salutary effects on jeopardized myocardium can be anticipated, and the ultimate long-term benefit conferred on the patient all require further definition. Widespread implementation of interventions utilized to induce myocardial reperfusion should be based on thorough characterization of the functional and metabolic responses of the heart to reperfusion. This selective review considers reperfusion within the context of an extensive body of information pertinent to the pathophysiological mechanisms underlying ischemic injury and discusses the potential favorable and unfavorable responses to reperfusion.

Acute Disease↗
PubMed1985

Characterization of the functional significance of subcritical coronary stenoses with H(2)15O and positron-emission tomography.

We have previously developed a method employing cardiac positron-emission tomography (PET) with 15O (half-life 2.1 min)-labeled water (H2(15)O) and blood pool subtraction with C15O for assessment of myocardial perfusion. This study was performed to determine whether the method developed permits detection of the differences in blood flow, induced by vasodilator stress, indicative of functionally significant subcritical coronary stenosis despite normal perfusion at rest. Coronary stenoses were induced with a small Teflon cylinder placed in the left anterior descending coronary artery of the closed-chest dog. Regional myocardial blood flow was assessed tomographically with H(2)15O given intravenously and C15O given inhalation. Blood flow distal to the stenoses was normal under conditions of rest. However, significant reductions in the hyperemic response to dipyridamole were detected consistently in regions distal to 50% to 70% diameter stenoses. Flow distal to stenoses more than doubled in absolute terms in response to dipyridamole but was only 43 +/- 9% of the increased flow in normal regions in the same dogs or in corresponding anterior regions in normal dogs. Relative myocardial blood flow measured noninvasively with PET correlated closely with the distribution of radiolabeled microspheres measured in vitro (r = .88). Thus, assessment of myocardial blood flow with H(2)15O and PET in dogs at rest and during vasodilator-induced stress permits detection of physiologically significant coronary stenoses. The procedure should therefore prove useful diagnostically for the detection of coronary insufficiency in patients as well as for the assessment of clinical interventions designed to augment regional perfusion.

Animals↗
PubMed1985

Prevention of coronary thrombosis with subthrombolytic doses of tissue-type plasminogen activator.

To determine whether tissue-type plasminogen activator (t-PA) may prevent coronary thrombosis or accelerate the lysis of clot formed under conditions in which increased concentration of the activator is present before thrombosis, clot lysis studies were undertaken in vitro and in vivo. In vitro, exogenous t-PA (6 to 100,000 ng/ml) accelerated the lysis of clot in a dose-dependent fashion when the clot was formed either from whole plasma or from euglobulin fractions (n = 316 determinations). Adding t-PA before clot formation shortened the time to lysis by at least threefold with euglobulin fractions and by at least 10-fold with whole plasma clots, which is consistent with the presence of inhibitors of fibrinolysis in whole plasma and with the binding of t-PA to nascent fibrin. In an intact dog preparation of coronary thrombosis (n = 25), occlusive thrombus formation was prevented when t-PA was present in subthrombolytic concentrations (430 to 1200 ng/ml, n = 5). Occlusive thrombus formation occurred after only discontinuation of the t-PA infusion and clearance of t-PA. Lower concentrations of t-PA (147 to 427 ng/ml, n = 6) significantly delayed occlusion (26 +/- 6.5 vs 7.8 +/- 2.8 min for controls). In animals with t-PA concentrations of less than 140 ng/ml (n = 4), the time to occlusion was unaltered (7.7 +/- 4.5 min). The present study demonstrates that t-PA present before clot formation inhibits thrombosis or accelerates thrombolysis depending on concentration, and that subthrombolytic doses of t-PA can prevent thrombus formation in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Efflux of metabolized and nonmetabolized fatty acid from canine myocardium. Implications for quantifying myocardial metabolism tomographically.

It has generally been assumed, from assessment of myocardial metabolism with [1(-11)C]palmitate and positron emission tomography, that clearance of the radiolabel from the myocardium is attributable solely to efflux of the products of oxidative metabolism. However, interpretations would differ if this assumption were unfulfilled. Furthermore, efflux of metabolized and nonmetabolized tracer has not been quantified. Accordingly, in this study, myocardium was perfused extracorporeally in 21 open-chest anesthetized dogs, and the extraction and clearance of [1(-11)C]palmitate were characterized under baseline conditions (normoxia, n = 21), and, again, with ischemia (n = 6), with hypoxia (n = 9), or under control conditions (n = 6). After intracoronary bolus injection of [1(-11)C]palmitate, myocardial time activity curves were measured with a beta-probe, and the products of oxidative metabolism (11CO2) and efflux of extracted but nonmetabolized fatty acid ("back-diffusion" of [1(-11)C]palmitate) were measured directly from analysis of arterial and regional coronary venous blood. Under control conditions, 45.2 +/- 3.8% (mean +/- SD) of initially extracted [1(-11)C]palmitate was metabolized to 11CO2, whereas 6.2 +/- 2.6% back-diffused in unaltered form in 1-10 minutes. In contrast, with ischemia (perfusion of 26% of baseline), only 16.9 +/- 9.8% of administered tracer evolved as 11CO2 (P less than 0.001 compared with control) but 15.6 +/- 8.9% (i.e., almost half of the total amount cleared) evolved unaltered as [1(-11)C]palmitate (P less than 0.05). Similarly, with hypoxia, 15.1 +/- 8.4% evolved as 11CO2 (P less than 0.0001) and 18.8 +/- 11.7% back-diffused (P less than 0.001). Overall, from 1-40 minutes after intracoronary injection of tracer, back-diffusion of [1(-11)C]palmitate contributed 40.6% of total radioactivity in the effluent with ischemia, 48.7% with hypoxia, but only 8.9% under control conditions. Despite the increased back-diffusion of [1(-11)C]palmitate seen with ischemia and hypoxia, the overall residue of 11C activity in myocardium increased, consistent with the diminished clearance observed in the myocardial time-activity curves and the increase in the tissue content of triglyceride and nonesterified fatty acid. Our results indicate that estimates of oxidative metabolism based upon clearance of radiolabeled fatty acid must take into account the efflux of initially extracted but nonmetabolized fatty acid. The findings apply to external determination of oxidative metabolism of the heart with any imaging modality that delineates retention and clearance of labeled fatty acids or their analogs.

Animals↗
PubMed1985

Gallium-68 1,1,1-tris (5-methoxysalicylaldiminomethyl) ethane: a potential tracer for evaluation of regional myocardial blood flow.

Reaction of tris(acetylacetonato)gallium(III) with 1,1,1-tris(5-methoxysalicladiminomethyl)ethane, H3[(5-MeOsal)3 TAME], affords a neutral six-coordinate complex, Ga[5-MeOsal)3 TAME], for which the x-ray crystal structure is reported. The 67Ga and 68Ga complexes of H3[(5-MeOsal)3 TAME] and the bis(salicylaldimine) of triethylenetetramine were prepared and characterized by paper chromatography and electrophoresis. The biodistribution of lipophilic 68Ga[(5-MeOsal)3 TAME] was determined following intravenous injection in rats. Myocardial images obtained by positron emission tomography from three dogs injected with 68Ga[(5-MeOsal)3 TAME] show a correlation between 68Ga uptake and regional myocardial blood flow. Single-pass coronary extraction studies in open-chest dogs indicate that 68Ga[(5-MeOsal)3 TAME] behaves neither as a freely diffusible tracer nor as a microsphere analog.

Animals↗