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Biomedical subjects

H S Mueller

Publications and source records attributed to H S Mueller.

At least 37 records · Page 2Linked to original sources
PubMed1989

Thrombolytic therapy in acute myocardial infarction: Part II--rt-PA.

Thrombolysis with pharmacologic agents is a valuable modality for treatment of acute myocardial infarction. The results of several clinical studies indicate that early recanalization can be elicited with intravenous agents and that it is associated with substantial reductions of infarct size, improvement of ventricular function, and reduction in mortality. The recently introduced fibrin-selective agent, rt-PA, appears to represent a significant pharmacologic advance. Its use intravenously elicits high recanalization rates without marked derangements of the coagulation system, reflecting its relative fibrin selectivity. The efficacy of thrombolysis with any drug given by any route, unfortunately, is not 100 per cent. Bleeding remains an important risk. The optimal approach to management of residual stenosis after thrombolysis has not yet been delineated. Currently available information appears to justify the following conclusions: 1. Transmural myocardial infarction usually is caused by an acute obstructing coronary thrombus superimposed on a chronic atherosclerotic lesion. Myocardial necrosis following interruption of blood flow generally is complete within several hours. 2. The thrombus can be lysed and blood flow can be restored with intravenous agents that activate plasminogen. Intravenous rt-PA, a relatively fibrin-specific agent, elicits recanalization in 70 to 75 per cent of infarct-related arteries. 3. Recombinant t-PA evokes only modest depletion of fibrinogen (16 to 36 per cent reduction from baseline). 4. Early reperfusion preserves myocardium and ventricular function and reduces mortality. 5. The extent of benefit after pharmacologic reperfusion is correlated strongly with the brevity of myocardial ischemia prior to initiation of therapy. The greatest benefit is realized in patients treated within the first few hours of onset of acute myocardial infarction. 6. The incidence and optimal means of prevention of reocclusion and reinfarction following successful pharmacologic reperfusion are not yet entirely clear. Mechanical recanalization with PTCA in conjunction with thrombolysis is promising, but its routine immediate use on an emergency basis does not appear to be beneficial. Vigorous educational efforts are needed to heighten the awareness of prospective patients and all members of the health care team to the value of prompt diagnosis of incipient or evolving infarction so that prompt implementation of thrombolysis in appropriate candidates can be facilitated.

Heart↗
PubMed1988

Specificity of oxygen radical scavengers and assessment of free radical scavenger efficiency using luminol enhanced chemiluminescence.

The selective scavenging capacities of 19 important oxygen radical scavengers were determined by adding them individually to each of the four oxy radical standards, (superoxide, hydroxy, alkoxy and hydroperoxy, and singlet O2), calculating the percent chemiluminescence inhibited, and extrapolating O2 equivalents neutralized from baseline. The sensitivity (0.01 nm/ml) and selectivity of this method not only allows identification of individual oxygen free radical species but also quantitates the efficiency of free radical scavengers.

Benzofurans↗
PubMed1988

Thrombolytic therapy in acute myocardial infarction: Part I.

Thrombolytic therapy with pharmacologic agents is an exciting approach to the treatment of myocardial infarction. The results of several clinical studies indicate that perfusion can be restored with intravenous therapy and may be associated with a reduction in infarct size and improved left ventricular function. In a trial involving more than 11,000 patients, thrombolytic therapy reduced acute and long term mortality. Pharmacologic thrombolysis, however, is not without problems. When administered intravenously, the agents currently available, streptokinase and urokinase, are associated with a relatively low recanalization rate as well as a risk of adverse effects, most commonly a systemic lytic state and risk of bleeding complications. Although intracoronary administration is associated with a higher rate of recanalization, the need for cardiac catheterization limits its applicability and results in a delay in the initiation of thrombolytic therapy (which diminishes salvage of myocardium). The trials assessing the existing agents have shown that time is a critical variable in the success of thrombolytic therapy. This had led investigators to focus more attention on intravenous agents that can be administered rapidly. The newer agents now under investigation, acylated streptokinase and single-chain urokinase, may represent improvements of currently available products and may offer potentially increased benefits. A fibrinogen-sparing agent, such as t-PA, in addition to being highly effective, may offer advantages through minimizing the systemic lytic effect. Additional randomized, controlled clinical trials currently are underway to determine the effect on mortality of this "fibrinolytic" therapy as part of a total treatment regimen. The current status of our knowledge concerning thrombolytic therapy in acute myocardial infarction can be summarized as follows: 1. Transmural (that is, Q wave) myocardial infarction usually is caused by an obstructing coronary thrombus. 2. The thrombus can be lysed with intravenous therapy in the majority of cases, particularly with newer, well-tolerated fibrin-specific agents. 3. There is considerable evidence suggesting that reperfusion reduces the acute morbidity and mortality when therapy is administered successfully within the initial 3 to 4 hours (and possibly up to 6 hours) after onset of symptoms. 4. Data on long term prognosis after thrombolysis are very encouraging, although limited. 5. Conventional agents lead to significant fibrinogen depletion and therefore an increased risk of bleeding; the new fibrin-selected agents cause less fibrinogen degradation and may reduce the risk of hemorrhagic complications.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiomyopathies↗
PubMed1988

Thrombolysis in myocardial infarction (TIMI): update 1987.

The "Thrombolysis in Myocardial Infarction" (TIMI) Trial, sponsored by the National Heart, Lung and Blood Institute, has evaluated the efficacy of coronary recanalization in acute myocardial infarction in different phases. TIMI Phase I compared the efficacy of recombinant tissue-type plasminogen activator (rt-PA) with that of streptokinase (SK) in a randomized double blind trial, using 80 mg rt-PA or 1.5 million units SK within 7 hours of clinical onset of infarction. rt-PA recanalized infarct related arteries in 62% compared to 31% with streptokinase. Bleeding complications were similar in both treatment groups and mainly related to vascular puncture sites during heart catheterization. The pharmacological dose of rt-PA, applied, caused a moderate effect on the proteins of the fibrinolytic system, but by far less than streptokinase. TIMI Phase 1.5 compared two preparations of rt-PA, the early formulation in liquid excipient ("old" rt-PA) and the new lyophilized form ("new" rt-PA). With equal dosage regimens of 80 mg, coronary recanalization rates at 90 minutes of infusion were 62% (old rt-PA) and 45% (new rt-PA). The lower recanalization potency of the new rt-PA is related to its shorter plasma half life. Three dosage regimens were evaluated with the new rt-PA, using 80 mg, 100 mg and 150 mg. Coronary recanalization rates were 45%, 71% and 76%, respectively. The dosage of 150 mg achieved the highest recanalization rates at 30 minutes of infusion, 42%. A linear trend test indicated a significant relation (p less than 0.001) between the dose of rt-PA and effects of the proteins of the fibrinolytic system.(ABSTRACT TRUNCATED AT 250 WORDS)

Double-Blind Method↗
PubMed1987

Thrombolysis in myocardial infarction (TIMI): comparative studies of coronary reperfusion and systemic fibrinogenolysis with two forms of recombinant tissue-type plasminogen activator.

Coronary recanalization rates and changes in plasma proteins of the fibrinolytic system were evaluated with two preparations of recombinant tissue-type plasminogen activator (rt-PA): the early formulation in liquid excipient ("old" rt-PA) and the later lyophilized form ("new" rt-PA). The dose dependency of coronary recanalization and of effects on plasma proteins was evaluated for the new rt-PA. Four groups of patients were studied: Study 1, 80 mg old rt-PA infused intravenously over 3 hours (n = 113); Study A, 80 mg new rt-PA over 3 hours (n = 47); Study B, 100 mg new rt-PA over 3 hours (n = 83); and Study C, 150 mg new rt-PA over 6 hours (n = 62). With equal doses of 80 mg, coronary recanalization rates at 90 minutes of infusion, determined angiographically, averaged 62% (Study 1) and 45% (Study A) with no overlap of 95% confidence limits. Increasing the dose of the new rt-PA to 100 mg, recanalization rates at 90 minutes averaged 71% (Study B), similar to those observed in Study 1. An increase to 150 mg resulted in higher recanalization rates at 30 minutes of infusion, 42% compared with 24% in Study 1 with no overlap of 95% confidence limits, and comparable rates at 90 minutes, 76 versus 62%. A linear trend test indicated a significant relation (p less than 0.01) between the dose of the new rt-PA and the rate of coronary recanalization at 30, 60 and 90 minutes of infusion. The new rt-PA affected plasma proteins of the fibrinolytic system less than the old form. There was a dose-dependent relation (p less than 0.001) in the effect of the new rt-PA on the plasma proteins. The frequency of bleeding complications was similar in the four study groups. These results indicate that the new rt-PA is less potent than the old rt-PA, in relation to both coronary reperfusion and systemic fibrinogenolysis. A higher and longer dosage regimen caused more rapid recanalization with similar effects on fibrinogenolysis.

Aged↗
PubMed1986

Platelet hyperactivity in acute myocardial infarction in man--effects of prostacyclin.

There is increasing evidence that platelets play an important role in the pathogenesis of acute ischemic heart disease. Therefore, an understanding of factors which impact on platelet performance is important. The present study was undertaken 1. to characterize during evolving myocardial infarction (MI) platelet activity in the peripheral circulation and across the ischemic/infarcting myocardial compartment, the locus of presumed platelet hyperactivity, and 2. to evaluate the effects of prostacyclin (PGI2), a most potent antiplatelet agent and vasodilator. A total of 59 patients with evolving MI were studied. 22 patients were instrumented with arterial and coronary sinus catheters and received intravenous infusion of PGI2, 13 +/- 4.5 ng/kg/min (mean +/- SD), for 90 minutes. In 15 of these patients, who had an anterior MI, transcardiac platelet function and response to PGI2 were studied. The results are as follows: Plasma levels of beta-thromboglobulin (beta-TG) and of thromboxane B2 (TxB2), in vivo measures of platelet activity, are elevated three and ten fold. 6-keto-prostaglandin F1 alpha, the stable end product of PGI2, is less than 10 pg/ml, reflecting a leftward shift of the TxB2/PGI2 ratio. Platelets, circulating during evolving MI ("ischemic platelets") are hyperaggregable in response to adenosine diphosphate and relatively resistent to PGI2, both in vivo and in vitro. Concentrations of platelet cyclic adenosine monophosphate and the cAMP response to PGI2 are diminished. The platelet hyper-reactivity is most intense early during infarct evolution and decreases with time. Transcardiac measurements indicate that thromboxane is produced across the ischemic/infarcting compartment in ten of 15 patients with anterior MI. The antiplatelet effect of PGI2 is greatly diminished. In summary, the data define an abnormal pattern of platelet behavior during evolving MI characterized by a pro-aggregatory environment, heightened platelet re-activity, both in the peripheral and coronary circulation, and relative resistance to PGI2. The clinical consequence of the data are that the infarct patient in the acute phase may benefit from platelet function suppression and requires significantly greater doses of prostacyclin than normal subjects. The data also suggest future directions for therapeutic manipulation of platelet hyper-reactivity in the setting of acute myocardial ischemia.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Sub-aggregatory doses of catecholamines prevent prostacyclin-induced inhibition of platelet aggregation.

To assess the effect of subaggregatory concentrations of catecholamines on the antiaggregatory effect of prostacyclin (PGI2), platelets from normal human volunteers were exposed sequentially in vitro to epinephrine (less than or equal to 50 nM)- or norepinephrine (less than or equal to 1 microM) followed by PGI2 and adenosine diphosphate (ADP). Platelets thus pretreated did not manifest the normal inhibitory response to PGI2, aggregating to a similar extent as platelets exposed to ADP alone. This effect was unaffected by aspirin but was abolished by exposure to phentolamine. Catecholamine pretreatment similarly blocked the PGI2-induced increase in intracellular cyclic AMP, an effect which was also reversed by phentolamine. These data suggest that platelets exposed in vivo to elevated catecholamine concentrations, such as are seen clinically during myocardial infarction, might be similarly unresponsive to endogenous PGI2.

Adenosine Diphosphate↗
PubMed1985

Evaluation of a rat model for assessing interventions to salvage ischaemic myocardium: effects of ibuprofen and verapamil.

Coronary ligated rats were administered intraperitoneal injections of 6.24, 12.52, and 25.00 mg . kg-1 ibuprofen and 5.00 and 10.00 mg . kg-1 verapamil 1 h before ligation, 1 h after ligation, and then every 8 h for 48 h. Ibuprofen at 50.00 mg . kg-1 was administered 1 h before ligation, 1 h after ligation and 5 h after ligation. Infarct size was determined either by weighing the stained excised infarcted area or by measuring the creatine kinase activity from the excised left ventricle. Ibuprofen and verapamil treatment resulted in less myocardial damage after 48 h than placebo treatment but the differences were generally not statistically significant. The reduction in infarct size was greater in the ibuprofen treated animals compared with verapamil treated rats. In addition, there was a lower mortality with ibuprofen treatment than for either verapamil or placebo. This rat model was useful as a screening tool for the initial evolution of therapeutic interventions to reduce myocardial infarct size. It required substantially less time than large animal models and can be used to examine a variety of treatment doses. These experiments also demonstrated the importance of randomisation to treatment and control groups because of the possibility of disproportionate mortality affecting infarct size.

Animals↗
PubMed1985

Systemic and transcardiac platelet activity in acute myocardial infarction in man: resistance to prostacyclin.

There is increasing evidence that platelets play an important role in the pathogenesis of acute ischemic heart disease. Therefore an understanding of factors that influence platelet performance is important. This study was undertaken (1) to characterize during evolving myocardial infarction platelet activity in the peripheral circulation and across the ischemic/infarcting myocardial compartment, the locus of presumed platelet hyperactivity, and (2) to evaluate the effects of prostacyclin (PGI2), a most potent antiplatelet agent and vasodilator. A total of 59 patients with evolving myocardial infarction were studied. Twenty-two patients were instrumented with arterial and coronary sinus catheters and received intravenous infusion of PGI2, 13 +/- 4.5 ng/kg/min (mean +/- SD), for 90 min. In 15 patients with anterior myocardial infarction, transcardiac platelet function and response to PGI2 were studied. Plasma levels of beta-thromboglobulin (beta-TG) and of thromboxane B2 (TxB2), in vivo measures of platelet activity, were elevated three- and 10-fold. 6-Keto-prostaglandin F 1 alpha, the stable end product of PGI2, was less than 10 pg/ml, reflecting a leftward shift of the TxB2/PGI2 ratio. Platelets circulating during evolving myocardial infarction ("ischemic platelets") were hyperaggregable in response to ADP and relatively resistant to PGI2, both in vivo and in vitro. Concentrations of platelet cyclic AMP and the cyclic AMP response to PGI2 were diminished. The platelet hyperreactivity, expressed by plasma beta-TG, platelet aggregation, and PGI2-induced inhibition of aggregation, was most intense early during infarct evolution and decreased with time. The increased platelet performance resulted in "platelet fatigue," indicated by decreased contents of beta-TG of the ischemic platelet and decreased TxA2 production in response to collagen. However, the ischemic platelet produced twice normal TxA2 in response to arachidonic acid (stimulus and substrate), demonstrating a heightened metabolic capacity. TxA2 was produced across the ischemic/infarcting compartment in 10 of 15 patients with anterior myocardial infarction. The antiplatelet effect of PGI2 was greatly diminished. In summary, the data define an abnormal pattern of platelet behavior during evolving myocardial infarction, characterized by a proaggregatory environment, heightened platelet reactivity in both the peripheral and coronary circulation, and relative resistance to PGI2. The clinical consequences of the data are that the patient in the acute phase of myocardial infarction may benefit from suppression of platelet function and requires significantly greater doses of PGI2 than normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1983

Production of free radicals and lipid peroxides in early experimental myocardial ischemia.

Free radicals and lipid peroxides have recently been identified by us [1, 2, 3] as metabolic intermediates during acute myocardial ischemia. The mechanisms by which evolving myocardial ischemia initiates free radical production are not clear. Based on studies in vitro, it is feasible to consider the following possibilities: (a) dissociation of intramitochondrial electron support system and altered phospholipid integrity with inactivation of cytochrome oxidase, which results in release of ubisemiquinone, flavoprotein and superoxide radicals; (b) accumulation and increased release of intra/extracellular metabolites like NADH, lactate flavoproteins and catecholamines which react either with themselves or with O2 and ascorbic acid; (c) interaction of the metabolic product hypoxanthine with O2 in the presence of xanthine oxidase and (d) activation of phospholipase by calcium influx with enhanced arachidonic acid metabolism and superoxide radical production. Detailed in vitro radiobiological studies [4] have demonstrated that free radical reactions occur even at very low O2 tensions (83% of maximum rate of PO2 approximately 6 mmHg and 50% at PO2 approximately 1 mmHg), and Smith [5] has demonstrated that free radical peroxidation takes place quite rapidly in rat brain homogenates incubated in gas mixtures containing only 5% O2. Thus, the low oxygen tensions in ischemic tissue are adequate to support free radical reactions. The free radicals thus produced may initiate and enhance lipid peroxidation by attacking polyunsaturated membrane lipids.

Animals↗
PubMed1982

Enhanced transcardiac l-norepinephrine response during cold pressor test in obstructive coronary artery disease.

An increase in cardiac sympathetic activity can enhance coronary vasomotor tone and lower the ventricular fibrillation threshold. We compared the transcardiac l-norepinephrine responses during cold pressor test of 20 patients with normal coronary arteries with those of 23 patients with obstructive coronary artery disease. Baseline hemodynamic data did not differ in the 2 patient groups except for left ventricular end-diastolic pressures; mean values (+/- standard deviation [SD] were 10 +/- 3.7 and 15 +/- 4.5 mm Hg in patients with normal and abnormal coronary arteries (p less than 0.01). Baseline l-norepinephrine contents averaged 295 +/- 152 (normal coronary arteries) and 250 +/- 134 pg/ml (coronary artery disease) in the arterial blood, and 273 +/- 152 and 250 +/- 115 pg/ml, respectively, in the coronary sinus blood. Hemodynamic responses during cold stimulus were similar in both groups. Also, cold pressor-induced increases in arterial and coronary sinus l-norepinephrine contents were balanced in patients with normal coronary arteries, averaging 19 +/- 30 and 17 +/- 37%, respectively. In patients with coronary artery disease, however, a 26 +/- 58% increase in arterial l-norepinephrine contents was associated with a 58 +/- 62% increase in coronary sinus l-norepinephrine contents (p less than 0.02), suggesting myocardial l-norepinephrine net release. It is concluded that transcardiac l-norepinephrine responses during cold stimulus are enhanced in patients with obstructive coronary artery disease. This response to a relatively mild sympathetic stress, reproducible by a variety of analogous stressful situations during daily life, could present an increased risk for acute cardiac events.

Adult↗
PubMed1981

Interim report of multicenter double-blind, placebo-controlled studies of nifedipine in chronic stable angina.

Preliminary results from multicenter double-blind placebo-controlled studies involving crossover and parallel designs were analyzed in 32 and 34 patients with stable angina pectoris entered respectively into the two protocols. The frequency of anginal attacks and the intake of nitroglycerin were decreased about 50 percent in patients receiving nifedipine, and the difference from those on placebo was statistically significant. Similarly, exercise tolerance was significantly increased with nifedipine, as evidenced by several variables, and the degree of ischemia was believed decreased, as reflected by lesser ST segment depression at peak exercise. The heart rate-blood pressure product, an approximation of myocardial oxygen consumption, was slightly but significantly decreased at equivalent workloads, but was not significantly different from placebo at the onset of angina or at maximal exercise. Adverse reactions to nifedipine, although frequent, were generally benign and usually responded to dose adjustment or improved spontaneously. These results suggest that the calcium antagonist nifedipine is effective and safe in the treatment of chronic stable angina.

Angina Pectoris↗