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Biomedical subjects

Richard C Becker

Publications and source records attributed to Richard C Becker.

61 records · Page 4Linked to original sources
PubMed2002

First experience with direct factor Xa inhibition in patients with stable coronary disease: a pharmacokinetic and pharmacodynamic evaluation.

BACKGROUND: Thrombin generation is critical to the formation of an arterial thrombus after rupture of an atherosclerotic plaque. In patients with stable coronary disease receiving standard medical therapy, we evaluated the pharmacokinetics, pharmacodynamics, and safety profile of DX-9065a, a novel small-molecule anticoagulant that directly, selectively, and reversibly inhibits factor Xa. METHODS AND RESULTS: In a double-blind trial, 73 patients (median age, 63 years; 29% women) were randomly assigned to receive a fixed-dose intravenous bolus, followed by a 72-hour infusion of placebo or 1 of 4 weight-adjusted regimens of DX-9065a. Plasma samples were collected during infusion and a 24-hour elimination period. Only minor bleeding occurred, predominantly ecchymoses at infusion sites, and its incidence did not differ significantly among the groups, including placebo. Median hemoglobin, platelet count, serum creatinine level, and liver function tests did not change significantly from baseline during infusion or elimination. Significant predictors of pharmacokinetic response included infusion dose and weight. At 60 hours into the DX-9065a infusion, plasma drug levels correlated strongly with anti-factor Xa activity (r=0.97), prothrombin time (r=0.77), and international normalized ratio (r=0.72) but less so with activated partial thromboplastin time (r=0.56; all P<0.001). CONCLUSIONS: This is the first study of a selective, reversible, and direct small-molecule factor Xa inhibitor in patients with stable coronary disease. These data lay the foundation for further investigation of factor Xa inhibitors in the treatment of patients with coronary atherothrombosis.

Adrenergic beta-Antagonists↗
PubMed2002

Choice of agents to limit the coagulation cascade in acute coronary syndromes.

Arterial thrombosis, the predominant event in acute coronary syndromes (ACS), is the end-result of endothelial cell dysfunction, impaired vascular thromboresistance, and sudden atheromatous plaque disruption, each occurring amid a backdrop of inflammation and inflammatory mediators. Because the contribution of individual coagulation proteins to coronary arterial thrombosis varies from modest to marked, selective pharmacologic targeting is both pathobiologically sound and clinically preferred. The development of second-generation anticoagulants with broadened therapeutic windows represents an advance in the management of ACS.

Acute Disease↗
PubMed2002

Intramural hematoma of the thoracic aorta in a woman with neurofibromatosis.

The natural history and preferred approach to patients with intramural hematoma of the aorta remains controversial. We describe herein the management of the case of a 45-year-old woman with acute onset of chest pain, intramural hematoma of the arch and proximal descending aorta, and left pleural effusion. In this particular case, a nonsurgical approach led to complete recovery of the patient and documented resolution of the hematoma.

Aorta, Thoracic↗
PubMed2002

Comparative effects of unfractionated heparin and low molecular weight heparin on vascular endothelial cell tissue factor pathway inhibitor release: a model for assessing intrinsic thromboresistance.

OBJECTIVES: The purpose of our study was to characterize tissue factor pathway inhibitor (TFPI) release from human vascular endothelial cells following daily exposure to varying concentrations of unfractionated heparin (UFH) and low molecular weight heparin (LMWH). BACKGROUND: A "rebound" increase in ischemic/thrombotic events, including myocardial infarction and cardiovascular death, has been observed after the abrupt cessation of UFH. In a single center pilot study of patients with acute coronary syndromes (ACS) we reported that thrombin generation was evident within one (1) hour of UFH cessation, increased progressively over the subsequent 24 hours, correlated directly with factor VII activity and inversely with TFPI (concentration and activity). METHODS: Human umbilical vein endothelial cells were grown to confluence and incubated with varying concentrations of UFH or dalteparin, a low molecular weight haparin, for up to 144 hours. Daily samples of the cells supernatant were obtained and assayed for TFPI. Cellular reserve and responsiveness to recombinant endothelial cell growth factor (rEGF) stimulation were determined at 168 hours. RESULTS: In low concentrations (0.5 U/mL) UFH caused a progressive rise in TFPI concentration with a peak level of 6.36 +/- 0.5 ng/10(5) cells at 24 hours. By 72 hours of daily exposure, the levels declined to below control values and TFPI release following rEGF stimulation was reduced by approximately 60% compared to control (1.93 +/- 0.42 vs 4.3 +/- 0.78 ng/10(5) cells; p = 0.001). Initial endothelial cell release and rate of decline were more robust with high concentrations of UFH (5.0 U/ml). TFPI levels were above control values at each sampling time point up to 120 hours and cellular responsiveness to stimulation was preserved with dalteparin (compared to UFH) (p < 0.001). CONCLUSIONS: Thrombin generation and clinical events that occur during treatment with UFH and following its abrupt cessation may represent an acquired state of transiently impaired thromboresistance to the tissue factor-VIIa complex. The differing effects of UFH and LMWH on vascular endothelial cell TFPI synthesis, release and reserve with prolonged administration require further investigation.

Cells, Cultured↗
PubMed2002

Comparative efficacy of fibrinogen and platelet supplementation on the in vitro reversibility of competitive glycoprotein IIb/IIIa receptor-directed platelet inhibition.

BACKGROUND: Platelet surface glycoprotein IIb/IIIa (alphaIIb/beta3) receptor inhibition, with prevention of fibrinogen binding and platelet aggregation, concomitantly attenuates arterial thrombotic capacity and impairs protective hemostasis, 2 divergent platelet-dependent processes. PURPOSE: Because the currently available, Food and Drug Administration-approved small molecule glycoprotein IIb/IIIa receptor antagonists are considered "competitive" inhibitors and there is limited information on the reversibility of platelet inhibition with fibrinogen or platelet supplementation, the following series of in vitro experiments were performed. METHODS AND RESULTS: Washed platelets from 24 healthy volunteers were suspended in tyrodes buffer and incubated with achievable (in vivo) concentrations of either tirofiban or eptifibatide before activation with thrombin receptor agonist peptide (15 micromol/L). Platelet aggregation was inhibited by 40% to 50%, but reversal was achieved with fibrinogen supplementation in a concentration-dependent manner. In a separate series of in vitro experiments, platelet inhibition exceeding 90% was established with tirofiban (average concentration 9.28 microg/L) and eptifibatide (average concentration 95.4 microg/L). Recovery of platelet aggregation to at least 50% was achieved after the addition of fibrinogen (0.76-0.80 g/L), platelets (2.4 x 10(11)/L), or their combination. There was an inverse relationship between plasma baseline fibrinogen and the amount of supplemental fibrinogen needed to restore platelet aggregability (r = -0.60; P <.01). CONCLUSION: The reversibility of glycoprotein IIb/IIIa-directed platelet inhibition is influenced by cell surface receptor availability and intrinsic pharmacodynamic mechanism of action. Fibrinogen supplementation with fresh frozen plasma or cryoprecipitate either alone or in combination with platelet transfusion represents an important and readily available treatment consideration for restoring hemostatic potential and managing major hemorrhagic complications associated with the administration of small-molecule, competitive glycoprotein IIb/IIIa receptor antagonists.

Adult↗
PubMed2002

Influence of patient characteristics and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in non-ST-segment elevation acute coronary syndromes.

BACKGROUND: The current standard of care for patients with non-ST-segment elevation acute coronary syndromes (ACS) includes antithrombotic therapy with aspirin and heparin. Although emerging data suggest that low-molecular weight preparations offer distinct advantages over unfractionated heparin, limited information on patient-related factors that may influence dosing, safety, and efficacy is available. PURPOSE: The purpose of our study was the determination of the impact of patient age, sex, body weight, and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in patients with ACS. METHODS AND RESULTS: Patients enrolled in the TIMI 11A trial received a full complement of antiischemic therapy, aspirin, and enoxaparin (30 mg intravenously, followed by weight-adjusted doses of either 1 mg/kg or 1.25 mg/kg subcutaneously every 12 hours). Before and after the third and last doses, blood samples were obtained from 445 patients for measurement of anti-Xa activity. The mean apparent clearance, distribution volume, and plasma half-life were 0.733 L/h, 5.24 L, and 5 hours, respectively. Among a wide range of clinical and laboratory covariates, creatinine clearance emerged as the most influential factor on apparent clearance, area under the curve, and anti-Xa activity. Patients with marked renal impairment (creatinine clearance <40 mL/min) had higher trough and peak anti-Xa activity compared with those with normal renal function and were more likely to have major hemorrhagic events. CONCLUSION: The pharmacokinetic and pharmacodynamic profiles after enoxaparin administration are consistent across a broad range of patients with ACS. Dose adjustments or anti-Xa coagulation monitoring or both will be necessary rarely in routine clinical practice, with the exception of patients with severe renal insufficiency.

Age Factors↗