Linked Life Data

10087043

Source:http://linkedlifedata.com/resource/pubmed/id/10087043

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1999-4-21
pubmed:abstractText
The small molecule direct thrombin inhibitor L-374,087 was characterized across species in an in vitro activated partial thromboplastin clotting time (aPTT) assay and in vivo in rhesus monkey and dog thrombosis models. In vitro in rhesus, dog, and human plasma, L-374,087 concentrations eliciting 2-fold increases in aPTT were 0.25, 1.9, and 0.28 microM, respectively. In anesthetized rhesus monkeys, 300 microgram/kg bolus plus 12 microgram/kg/min and 300 microgram/kg bolus plus 30 microgram/kg/min L-374,087 i.v. infusions significantly reduced jugular vein thrombus extension, with both regimens limiting venous thrombus extension to 2-fold that of baseline thrombus mass compared with a 5-fold extension observed in the vehicle control group. Antithrombotic efficacy in the rhesus with the lower-dose regimen was achieved with 2.3- to 2.4-fold increases in aPTT and prothrombin time. In a conscious instrumented dog model of electrolytic vessel injury, the oral administration of two 10 mg/kg L-374,087 doses 12 h apart significantly reduced jugular vein thrombus mass, reduced the incidence of and delayed time to occlusive coronary artery thrombosis, and significantly reduced coronary artery thrombus mass and ensuing posterolateral myocardial infarct size. Antithrombotic efficacy in the dog was achieved with 1.6- to 2.0-fold increases in aPTT at 1 to 6 h after oral dosing with L-374,087. These results indicate significant antithrombotic efficacy against both venous and coronary arterial thrombosis with L-374,087 with only moderate elevations in aPTT or prothrombin time. The oral efficacy of L-374,087 characterizes this compound as a prototype for the further development of orally active direct thrombin inhibitors.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
289
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
503-10
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:10087043-Administration, Oral, pubmed-meshheading:10087043-Anesthesia, pubmed-meshheading:10087043-Animals, pubmed-meshheading:10087043-Bleeding Time, pubmed-meshheading:10087043-Blood Coagulation, pubmed-meshheading:10087043-Coronary Thrombosis, pubmed-meshheading:10087043-Dogs, pubmed-meshheading:10087043-Female, pubmed-meshheading:10087043-Fibrinolytic Agents, pubmed-meshheading:10087043-Hematocrit, pubmed-meshheading:10087043-Hemoglobins, pubmed-meshheading:10087043-Humans, pubmed-meshheading:10087043-Injections, Intravenous, pubmed-meshheading:10087043-Jugular Veins, pubmed-meshheading:10087043-Macaca mulatta, pubmed-meshheading:10087043-Male, pubmed-meshheading:10087043-Partial Thromboplastin Time, pubmed-meshheading:10087043-Platelet Count, pubmed-meshheading:10087043-Pyridones, pubmed-meshheading:10087043-Sulfonamides, pubmed-meshheading:10087043-Thrombin, pubmed-meshheading:10087043-Venous Thrombosis
pubmed:year
1999
pubmed:articleTitle
Antithrombotic efficacy of thrombin inhibitor L-374,087: intravenous activity in a primate model of venous thrombus extension and oral activity in a canine model of primary venous and coronary artery thrombosis.
pubmed:affiliation
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
pubmed:publicationType
Journal Article, In Vitro