Argatroban for Prevention and Treatment of Thromboembolism in Heparin-Induced Thrombocytopenia

Kondo, Lisa; Wittkowsky, Ann K.

doi:10.1345/aph.10301

Cited by 47 publications

(24 citation statements)

References 31 publications

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“…Its elimination half-life is approximately 40-50 minutes, and it is primarily eliminated by hepatic metabolism and biliary secretion. Compared with historical controls, argatroban-treated patients with heparin-induced thrombocytopenia or heparin-induced thrombocytopenia with thrombosis experienced lower rates of the composite end point of death, amputation, and new thrombosis [9].…”

Section: Discussionmentioning

confidence: 85%

“…Also argatroban significantly decreased cerebral edema following severe forebrain ischemia in gerbil [17]. Argatroban is also a synthetic direct thrombin inhibitor indicated for parenteral use in the prevention and treatment of thromboembolism in patients with heparin-induced thrombocytopenia [9]. Its elimination half-life is approximately 40-50 minutes, and it is primarily eliminated by hepatic metabolism and biliary secretion.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of anti-coagulant treatment with argatroban on cardioembolic stroke

et al. 2007

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Argatroban, which is a thrombin inhibitor, has an indication as a treatment in the acute phase on atherosclerotic ischemic stroke in Japan. Howeve, in cardioembolic stroke, argatroban is considered to be contraindicated with the side effect of hemorrhage, though there is no clear clinical evidence to show that argatroban increases hemorrhagic compared with heparin. The efficacy of anticoagulant treatment with argatroban on cardioembolic stroke was evaluated retrospectively in this study. We identified 3,113 patients from the Japan Standard Stroke Registry Study who had had a cardioembolic ischemic stroke. We excluded patients with the anti-platelet treatment or the combination therapy of anticoagulation. Our analyses are therefore based on a cohort of 2,529 patients who were treated either with heparin, and argatroban, or with no anti-coagulation treatment. With multivariable regression, hemorrhagic it was shown that hemorrhage was significantly reduced in heparin and argatroban treatments in the patients with mild severity. There was no significant difference in the recurrence of ischemic stroke between the treatments. Both argatroban and heparin showed dramatic improvement compared with the no treatment standard, but only heparin achieved statistical significance for mortality and change in NIHSS score (admission to discharge) in the moderate stroke subgroup [NIHSS 11-22]. Both heparin and argatroban [more so than heparin alone] have a significantly reduced mortality risk. From the present study, it is suggested that argatroban may be useful on cardioembolic stroke, increasing the improvement of recovery of stroke severity without increasing the risk of hemorrhage. Further prospective studies are awaited for evaluating better the efficacy of argatroban on cardioembolic stroke.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Efficacy of anti-coagulant treatment with argatroban on cardioembolic stroke

et al. 2007

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“…Thus, it is surprising that short-term (4 weeks) thrombin inhibition with argatroban did not significantly impact body weight gain in obese hypercholesterolemic Ldlr 2/2 mice (Kassel et al, 2012). However, argatroban is a thrombin inhibitor of limited utility and potency due to poor pharmacokinetics (e.g., t 1/2 of only 50 minutes) (Kondo et al, 2001), a requirement of parenteral delivery and a complex drug formulation. It is conceivable that in the previous study the degree or duration of thrombin inhibition with argatroban was insufficient to impact body weight gain, despite the observed reduction in hepatic inflammation and correction of serum cholesterol in argatroban-treated mice (Kassel et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Thrombin Inhibition with Dabigatran Protects against High-Fat Diet–Induced Fatty Liver Disease in Mice

Kopec

Joshi

Towery

et al. 2014

J Pharmacol Exp Ther

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Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome. Robust coagulation cascade activation is common in obese patients with NAFLD. We identified a critical temporal relationship between thrombin generation and the manifestation of hepatic steatosis, inflammation, and injury in C57BL/6J mice fed a high-fat diet (HFD) for 1, 2, and 3 months. Mice fed a HFD exhibited dramatic increases in hepatocellular injury and inflammation over time. Hepatic fibrin deposition preceded an increase in serum alanine aminotransferase, and the most dramatic changes in liver histopathology occurred in conjunction with a detectable increase in plasma thrombin-antithrombin levels at 3 months. To directly determine whether thrombin activity promotes NAFLD pathogenesis, mice were fed a HFD and simultaneously treated with the direct thrombin inhibitor dabigatran etexilate for 3 months. Notably, dabigatran treatment significantly reduced hepatic fibrin deposition, hepatic inflammation, hepatocellular injury, and steatosis in mice fed a HFD. Of interest, dabigatran treatment also significantly attenuated HFD-induced body weight gain. Gene expression analysis suggested that thrombin potentially drives NAFLD pathogenesis by altering the expression of genes associated with lipid metabolism and bile acid synthesis. Collectively, the results suggest that thrombin activity is central to HFD-induced body weight gain, liver injury, and inflammation and provide the proof-of-principle evidence that pharmacological thrombin inhibition could be effective in limiting NAFLD and associated pathologies.

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“…Non-physiologic thrombin inhibitors include several univalent molecules that act directly against the active site such as argatroban and melagatran (Kondo et al, 2001;Wittkowsky, 2002;Gustafsson and Elg, 2003;Evans et al, 2004;Reiffel, 2004;Gurm and Bhatt, 2005). Argatroban is a synthetic heterocyclic peptide that binds with moderate high affinity to a site near of the thrombin catalytic site (Gurm and Bhatt, 2005).…”

Section: Review Looking Into a Serine Protease: Thrombinmentioning

confidence: 99%

Looking at the proteases from a simple perspective

Castro

Abreu

Geraldo

et al. 2011

J of Molecular Recognition

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Proteases have received enormous interest from the research and medical communities because of their significant roles in several human diseases. Some examples include the involvement of thrombin in thrombosis, HIV-1 protease in Acquired Immune Deficiency Syndrome, cruzain in Trypanosoma cruzi infection, and membrane-type 1 matrix metalloproteinase in tumor invasion and metastasis. Many efforts has been undertaken to design effective inhibitors featuring potent inhibitory activity, specificity, and metabolic stability to those proteases involved in such pathologies. Protease inhibitors usually target the active site, but some of them act by other inhibitory mechanisms. The understanding of the structure-function relationships of proteases and inhibitors has an impact on new inhibitor drugs designing. In this paper, the structures of four proteases (thrombin, HIV-protease, cruzain, and a matrix metalloproteinase) are briefly reviewed, and used as examples of the importance of proteases for the development of new treatment strategies, leading to a longer and healthier life.

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Argatroban for Prevention and Treatment of Thromboembolism in Heparin-Induced Thrombocytopenia

Cited by 47 publications

References 31 publications

Efficacy of anti-coagulant treatment with argatroban on cardioembolic stroke

Efficacy of anti-coagulant treatment with argatroban on cardioembolic stroke

Thrombin Inhibition with Dabigatran Protects against High-Fat Diet–Induced Fatty Liver Disease in Mice

Looking at the proteases from a simple perspective

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