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Biomedical subjects

K A Stringer

Publications and source records attributed to K A Stringer.

At least 19 recordsLinked to original sources
PubMed2001

An institution-specific heparin titration nomogram: development, validation, and assessment of compliance.

STUDY OBJECTIVE: To develop, validate, and assess compliance with a heparin titration nomogram. DESIGN: Prospective, open-label trial. SETTING: University teaching hospital. SUBJECTS: Patients admitted with heart failure who required therapy with intravenous unfractionated heparin. Intervention. An in vitro concentration-response was determined by measuring activated partial thromboplastin times (aPTTs) on normal pooled plasma containing known concentrations of heparin. The therapeutic aPTT range was determined from the concentration-response by using the therapeutic heparin concentration range of 0.2-0.4 U/ml (protamine neutralization). Patients were consecutively enrolled, and therapy was managed by using the heparin titration nomogram. Paired aPTT-heparin concentrations were obtained, and nomogram validation was performed by comparing the in vitro and the ex vivo concentration-responses with use of linear regression. Nomogram compliance also was assessed. MEASUREMENTS AND MAIN RESULTS: The therapeutic aPTT ranges based on in vitro and ex vivo data were determined to be 45-72 seconds and 47-61 seconds, respectively. The ranges were significantly different (p<0.001). Overall compliance with the nomogram was 88%. CONCLUSION: These results confirm that, even in a relatively homogeneous disease-state patient population, in vitro data do not accurately predict ex vivo data. If in vitro data are used to develop an institution-specific nomogram, a validation procedure should be used to ensure accuracy. Although 100% compliance to a nomogram may not be attainable, it should be expected. Therefore, a compliance rate of 88% is concerning and suggests a need for increased nursing and physician education.

Anticoagulants↗
PubMed2000

Prevention of venous thromboembolism: adherence to the 1995 American College of Chest Physicians consensus guidelines for surgical patients.

BACKGROUND: The American College of Chest Physicians addressed the dilemma of identifying optimal therapy for venous thromboembolism (VTE) prophylaxis and published their Fourth Consensus Conference on Antithrombotic Therapy in 1995, with recommendations for prophylactic therapy. Despite these recommendations, appropriate VTE prophylactic therapy is underused. OBJECTIVES: To examine routine practices in the prevention of VTE in high-risk surgical patients and to determine the extent of adoption of grade A prophylactic therapies as recommended by the American College of Chest Physicians. METHODS: Retrospective medical record review in 10 teaching or community-based hospitals located in the United States. Medical charts of 1907 patients were randomly selected for review from the population of patients who underwent high-risk major abdominal surgery, total hip replacement, hip fracture repair, or total knee replacement between January 1, 1996, and February 28, 1997. RESULTS: Of 1907 patients, VTE prophylaxis was used in 89.3%; use was 93.7% in each of the 3 orthopedic surgery groups and 75.2% in the high-risk major abdominal surgery group. The percentage of patients receiving grade A therapy was highest in the hip replacement group (84.3%) vs. the other groups (knee replacement, 75.9%; hip fracture repair, 45.2%; abdominal surgery, 50.3%). CONCLUSIONS: The use of grade A prophylaxis was related to the type of surgery, with the highest use seen in total hip replacement and the lowest in hip fracture repair. One in 4 patients who underwent high-risk major abdominal surgeries failed to receive any form of VTE prophylaxis. Publication of consensus statements alone may be insufficient to ensure the incorporation of important new clinical information into routine practice.

Adult↗
PubMed2000

Tissue plasminogen activator inhibits reactive oxygen species production by macrophages.

STUDY OBJECTIVE: To determine whether tissue plasminogen activator (tPA) alters macrophage reactive oxygen species (ROS) production. INTERVENTION: Cultured macrophages were exposed to either phorbol myristate acetate (PMA) or zymosan (ZMA) after a 1-hour incubation with either tPA 100 microg/ml or L-arginine 3.5 mg/ml, an excipient used in the formulation of tPA. MEASUREMENTS AND MAIN RESULTS: Production of ROS was measured using chemiluminescence (CL). Tissue plasminogen activator reduced the mean peak CL of macrophages exposed to PMA or ZMA by 20% and 36%, respectively (p=0.0008 and p=0.028, analysis of variance). L-arginine had no effect on either PMA- or ZMA-induced macrophage CL. CONCLUSION: Our results suggest that tPA has broad inhibitory effects on inflammatory cell ROS production. In diseases such as atherosclerosis and acute respiratory distress syndrome, these data suggest the possible utility of exogenous tPA as an antiinflammatory agent and a physiologic role for endogenous tPA that goes beyond maintenance of homeostasis.

Animals↗
PubMed1999

The evolving role of platelet glycoprotein IIb/IIIa inhibitors in the management of acute coronary syndromes.

OBJECTIVE: To briefly discuss the pathophysiology of acute coronary syndromes (ACS) and to present the clinical data currently available regarding the use of platelet glycoprotein (GP) IIb/IIIa inhibitors in the management of ACS. DATA SOURCES: Literature on antithrombotic therapy in ACS was identified using a MEDLINE search (January 1988-September 1998), along with the Agency on Health Care Policy and Research guidelines for the management of unstable angina. Abstracts from recent scientific meetings were also reviewed. STUDY SELECTION: Review articles from the cardiology literature (pathophysiology) and randomized, controlled clinical trials of currently approved platelet GP IIb/IIIa inhibitors in ACS were evaluated. Ex vivo platelet aggregation studies and pharmacology literature were also included. Abstract data were included to illustrate specific points when published literature was not available. DATA EXTRACTION: Study data were evaluated based on study design, outcome parameters, and adverse drug reactions. Clinical information from review articles was evaluated based on applicability to the treatment of ACS. DATA SYNTHESIS: Platelet adhesion and aggregation are pivotal events in the pathophysiology of ACS. The GP IIb/IIIa inhibitors represent a new and unique class of drugs that block fibrinogen and von Willebrand factor-mediated platelet aggregation, the common end point of all biologic pathways of platelet aggregation. Three agents are currently approved by the Food and Drug Administration: abciximab, a monoclonal antibody; eptifibatide, a synthetic peptide; and tirofiban, a synthetic nonpeptide. CONCLUSIONS: Clinical trial data demonstrate efficacy of all three GP IIb/IIIa inhibitors in reducing the combined end point of morbidity and mortality in patients undergoing angioplasty. Eptifibatide and tirofiban also reduce the combined end point of morbidity and mortality in patients with unstable angina. These data expand the present role of platelet GP IIb/IIIa inhibitors by providing evidence for their effectiveness in the medical treatment of ACS. However, the specific role that these agents will have in the management of ACS is yet to be fully defined.

Acute Disease↗
PubMed1999

Emergence of low-molecular-weight heparins in cardiology.

Drug therapy for the management of acute coronary syndromes is rapidly expanding. Over the past few years, a number of new antithrombotic agents have been introduced, including low-molecular-weight heparins. The epidemiology and pathophysiology of acute coronary syndromes are discussed, with a historical perspective on the use of antithrombotic therapy.

Acute Disease↗
PubMed1998

Tissue plasminogen activator (tPA) inhibits interleukin-1 induced acute lung leak.

Because plasminogen activators (PA) may participate in the inflammatory process associated with the acute respiratory distress syndrome (ARDS), we measured the effect of tissue plasminogen activator (tPA) on inflammation and acute lung leak caused by intratracheal instillation of IL-1alpha (50 ng) into male (300-400 g) Sprague-Dawley rats. Lung leak, lung myeloperoxidase (MPO) activity, and lung lavage neutrophil counts were increased in rats given IL-1 intratracheally compared to control rats that were given saline intratracheally. Giving tPA (12 mg/kg) intraperitoneally increased lung tPA concentration and reduced acute lung leak in rats given IL-1 intratracheally (p < .01; lung leak index for sham-treated rats: 0.040 + 0.001, n=6; IL-1: 0.10 + 0.01, n=10; tPA + IL-1: 0.050 + 0.002, n=6). In contrast, administering tPA did not change IL-1-induced increases in lung lavage neutrophils or lung MPO activity (sham: 0.003 x 106 + 0.001 x 10(6) cells; IL-1: 2.9 x 10(6) + 0.4 x 10(6) cells; tPA + IL-1: 2.7 x 10(6) + 0.4 x 10(6) cells; and sham: 0.6 + 0.2 U/g lung; IL-1: 11.2 + 2.9 U/g lung, tPA + IL-1: 11.1 + 1.6 U/g lung, respectively). Our results suggest that intraperitoneal tPA administration increases lung tissue tPA levels and decreases acute lung leak without reducing lung neutrophil infiltration in rats given IL-1alpha intratracheally. This work suggests that tPA may suppress neutrophil activation in vivo and accordingly have anti-inflammatory effects.

Animals↗
PubMed1997

Clinical trials in thrombolytic therapy, Part 1: Outcome markers that go beyond mortality reduction.

The use of outcome markers other than mortality reduction alone for evaluating thrombolytic agents in patients with acute myocardial infarction (AMI) is discussed. Mortality has been a primary endpoint in clinical trials evaluating thrombolytic agents for treatment of AMI. However, differences in mortality rates among thrombolytics are 1% or less and require tens of thousands of patients to detect. Broadening the endpoints studied will allow for more extensive data collection and more comprehensive cost-effectiveness analysis, enabling clinicians to make better decisions. The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial measured not only mortality but issues related to the patency of the infarct-related artery and complications. Other potentially important outcome markers after AMI are left ventricular function; markers of reperfusion, such as early resolution of ST-segment elevation; and resolution of chest pain. Available long-term data show that the mortality benefit from alteplase is sustained over time and is correlated with enzymatically determined infarct size, left ventricular function, the number of diseased vessels, and Thrombolysis in Myocardial Infarction flow grade at the time of discharge from the hospital. Clinicians must also consider risk factors for stroke. Outcome measures other than mortality alone may help in determining which thrombolytic agent is most effective clinically and in financial decision-making without requiring large, expensive trials.

Cerebrovascular Disorders↗
PubMed1997

Pharmacokinetics of pirmenol enantiomers and pharmacodynamics of pirmenol racemate in patients with premature ventricular contractions.

The pharmacokinetics and pharmacodynamics of pirmenol were investigated in 12 patients with premature ventricular contractions (PVCs) after oral administration of racemic pirmenol, 100 mg and 200 mg every 12 hours. Holter monitoring was performed and serial blood samples were collected after the seventh doses. Plasma concentrations of pirmenol enantiomer were determined using a stereospecific liquid chromatographic assay. Clearance of total (-)-pirmenol was 20% higher than that of total (+)-pirmenol, and the difference in unbound clearance was 45% between enantiomers. Total pirmenol showed a smaller difference because of stereoselective protein binding, with 25% (100-mg dose) or 27% (200-mg dose) higher fraction unbound for (+)-pirmenol than for (-)-pirmenol. Distribution volume was similar for both enantiomers. Dose-dependent clearance was observed for unbound pirmenol enantiomers, as both enantiomers showed 20% lower unbound clearance at the higher dose. Antiarrhythmic effect (% reduction in PVCs from baseline) was correlated with plasma concentrations of pirmenol using a sigmoid maximum drug effect model, and patients showed a large variability in their antiarrhythmic response to plasma concentrations of pirmenol. The median value for minimum effective plasma concentration of racemic pirmenol was 1.5 micrograms/mL.

Adult↗
PubMed1997

Antiinflammatory activity of tissue plasminogen activator in the carrageenan rat footpad model.

Exogenous plasminogen activators (PAs), such as streptokinase (SK) and tissue plasminogen activator (tPA), have been shown to significantly improve the mortality of patients with acute myocardial infarction. However, reperfusion of the myocardium is associated with neutrophil activation and infiltration into the infarct region. Plasminogen activators influence neutrophil function in vitro, but no data exists regarding the effect of exogenous PAs on inflammation in vivo. Therefore, we evaluated the effect of PAs on inflammation using the carrageenan-induced rat footpad inflammation model. The magnitude of carrageenan-induced inflammation was determined by water-displacement and neutrophil infiltration, following administration of either tPA or SK to Sprague-Dawley rats. tPA (12 mg/kg) inhibited carrageenan-induced inflammation (p < .01). In contrast, administration of SK (40,000 U/kg) enhanced inflammation. These results suggest that exogenous PAs influence the inflammatory process but specific PAs differ in their actions. Ultimately, these differences may influence the efficacy of these agents in the management of acute myocardial infarction and lead to further evaluation of tPA in other inflammatory diseases such as acute respiratory distress syndrome (ARDS) and rheumatoid arthritis (RA), in which neutrophil-mediated injury is likely.

Animals↗
PubMed1997

Tissue plasminogen activator (tPA) inhibits human neutrophil superoxide anion production in vitro.

Because neutrophils contribute to reperfusion injury associated with acute myocardial infarction (MI), and because tissue plasminogen activator (tPA) is often used in the management of MI, we evaluated the effect of tPA on superoxide (O2.-) production by human neutrophils in vitro. We found that adding increasing amounts of tPA significantly (r = 0.89, P < 0.025) and progressively reduced O2.- generation by neutrophils treated with phorbol myristate acetate (PMA) in vitro. Furthermore, adding tPA that had been previously treated with the protease inhibitor, D-Phe-Pro-Arg-chloromethyl ketone HCl (PPACK), also decreased neutrophil O2.- generation in vitro (P < 0.05). In contrast, adding L-arginine, a component of the tPA preparation and a precursor of nitric oxide (NO), did not inhibit PMA-induced neutrophil O2.- production. Also, adding increasing concentrations of tPA did not reduce (P > 0.05) the concentrations of O2.- produced by xanthine oxidase (XO) in vitro. Our findings suggest that tPA reduces neutrophil O2.- generation by a mechanism that is not related to L-arginine, is not dependent on tPA proteolytic activity, and is not a function of direct scavenging. This property may account for some of the effectiveness of tPA in the treatment of MI and/or make tPA valuable for treating acute respiratory distress syndrome (ARDS) or other inflammatory disorders involving neutrophil O2.- production.

Amino Acid Chloromethyl Ketones↗
PubMed1994

Intravenous torsemide as adjunctive therapy in patients with acute pulmonary edema.

The safety and efficacy of intravenous (i.v.) torsemide as adjunctive therapy for acute cardiogenic pulmonary edema was evaluated. Thirteen patients were treated with i.v. torsemide and six patients, with i.v. furosemide, as a positive control. Doses of torsemide, 20 mg or 40 mg, and furosemide, 40 mg or 80 mg, were administered initially. The dose was titrated as necessary over the next 24 hours. In patients who received i.v. torsemide, median fractional sodium excretion significantly increased from 2.88% (0.04-10.1%) at baseline to 6.76% (0.71-11.6%) at peak (P = 0.0342). Hourly urine volume increased from 134 mL (25-400 mL) to 375 mL (145-790 mL) (P = 0.0034). Torsemide administration resulted in a significant improvement in both pulmonary rales and orthopnea. None of the patients experienced serious adverse events or required withdrawal from the study. These results suggest that i.v. torsemide is an effective and well-tolerated diuretic in patients with acute cardiogenic pulmonary edema.

Acute Disease↗
PubMed1994

Beyond thrombolysis: other effects of thrombolytic drugs.

OBJECTIVE: To review the effects of plasminogen activators (tissue plasminogen activator, streptokinase, and anistreplase) on fibrinogen and thrombin, platelets, complement, blood rheology, and neutrophils. DATA SOURCES: A MEDLINE search, as well as a review of recent scientific abstracts, was conducted to identify pertinent literature. STUDY SELECTION: Focus was placed on studies conducted in humans. However, many in vitro studies have been performed to fully elucidate the effect of plasminogen activators on different aspects of hemostasis and on the fibrinolytic and immune systems. DATA EXTRACTION: Data from in vitro, human, and animal studies were evaluated. DATA SYNTHESIS: There is a discrepancy between 90-minute patency and mortality in acute myocardial infarction patients treated with thrombolytic drugs. This could be caused, in part, by other hematologic and immunologic effects of thrombolytic drugs. Though the emphasis of clinical trials has been infarct-related artery patency, left ventricular function, and mortality, some studies have evaluated the effect of thrombolytic agents on fibrinogen and thrombin, platelets, blood rheology, complement, and neutrophils. This review discusses the alteration of systemic hematologic and immunologic parameters by thrombolytic drugs and the possible clinical implications of these effects. CONCLUSIONS: Although the interactions between thrombolytic drugs, hemostasis, and the fibrinolytic and immune systems are complex and still not fully understood, it appears that these drugs differ in their effects on these systems. A greater understanding of these properties and their clinical implications may ultimately enhance the care and outcome of acute myocardial infarction patients treated with thrombolytic therapy.

Animals↗
PubMed1992

Effect of cimetidine administration on the pharmacokinetics of pirmenol.

The potential for a drug-drug interaction between pirmenol, an extensively metabolized antiarrhythmic agent, and cimetidine, an inhibitor of hepatic drug-metabolizing enzymes, was evaluated in eight healthy adults. A single 150-mg oral dose of pirmenol was administered on study days 1 and 8 and oral cimetidine, 300-mg QID, was administered on study days 4 through 11. Plasma and urine samples were collected after each pirmenol dose for determination of pirmenol concentration. Mean pirmenol concentration-time curves and pharmacokinetic parameters, including elimination rate constant, were not significantly altered by concomitant administration of cimetidine.

Administration, Oral↗
PubMed1992

The effect of three different oral doses of verapamil on the disposition of theophylline.

Results of previous studies suggest that the theophylline-verapamil drug interaction may be dependent on verapamil dose. Therefore, in a randomized four-way cross over study, 12 healthy males received theophylline, as a single intravenous dose of aminophylline, alone (phase I) and after a four day regimen of oral verapamil 40 mg (phase II), 80 mg (phase III), and 120 mg (phase IV) every 8 h. Serial blood samples were collected over a 24 hour period for determination of serum theophylline concentration and subsequent pharmacokinetic analysis. Mean theophylline AUC for phase I-IV was 93.6, 105.6, 110.8, 120.1 mg.h.l-1, respectively. Mean theophylline clearance for phase I-IV was 3.89, 3.59, 3.35, and 3.20 l.h-1, respectively. The changes in AUC, clearance, and lambda z were linearly correlated to verapamil dose. These results suggest that the inhibitory effect of verapamil on the pharmacokinetic disposition of theophylline is directly related to verapamil dose.

Administration, Oral↗
PubMed1992

Hirudins: antithrombin anticoagulants.

OBJECTIVE: To review the chemistry, pharmacology, available clinical data, and adverse effects of the hirudin anticoagulants. DATA SOURCES: A MEDLINE search and a review of recent scientific abstracts was conducted to identify pertinent literature. STUDY SELECTION: Focus was placed on studies conducted in humans. Because hirudin is still an investigational agent, however, relevant animal data, particularly pharmacokinetic studies and studies of preclinical efficacy, were also selected. DATA EXTRACTION: Data from both human and animal studies were evaluated; emphasis was placed on human trials. DATA SYNTHESIS: Hirudin has demonstrated potent anticoagulant effects. Although hirudin could have a significant impact on the therapeutic management of patients requiring anticoagulant therapy, only a limited number of human studies have been published to date. Trials comparing hirudin and heparin in specific patient populations are still ongoing. CONCLUSIONS: Although still in clinical trials, hirudin is a unique agent that may represent a breakthrough in anticoagulant therapy. The specific role that this agent will play in the management of patients has yet to be determined.

Amino Acid Sequence↗
PubMed1992

Disposition of oral dipyridamole in patients undergoing thallium 201 myocardial imaging.

Oral dipyridamole has been used in conjunction with thallium 201 imaging to diagnose coronary artery disease in patients unable to exercise. However, the pharmacokinetic disposition of high-dose dipyridamole, particularly the time to maximum drug concentration, has not been described in patients undergoing oral dipyridamole-thallium 201 scanning. Therefore, we measured serial concentrations in 20 outpatients undergoing thallium 201 testing after a single 400-mg oral dose of dipyridamole. In patients with positive thallium scans (group A), concentrations were slightly higher than in those with negative scans (group B). The variability in concentrations for both groups ranged from 3-118%. The area under the dipyridamole concentration-time curve from 0-4 hours ranged from 2.9-2.3 microgram.hr/ml. The time to peak plasma level for dipyridamole ranged from 0.5-2.5 hours, with two patients having undetectable levels at the time of thallium 201 injection. Dipyridamole concentrations did not correlate with changes in diastolic or systolic blood pressure, or heart rate. Although it is unknown what concentration is required to produce changes in coronary flow velocity, use of oral dipyridamole in this setting resulted in highly variable concentrations. In addition, these data suggest that a small percentage of patients will not have detectable concentrations at the time of the first thallium 201 scan, possibly limiting the usefulness of this agent in conjunction with thallium scintigraphy in some patients.

Administration, Oral↗