Beneficial effects of combined thromboxane synthase inhibition/receptor blockade with CGS 22652 in a canine model of coronary thrombosis

Olson, Richard W.; Dotson, Ronald; Mathis, J.; Cohen, David S.; Webb, Randy L.

doi:10.1016/0014-2999(93)90229-b

Cited by 5 publications

(7 citation statements)

References 34 publications

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“…Possible mechanisms of platelet activation in this setting in clude an action of plasmin directly on the platelet, generation of throm bin in plasma or through the release of clot-bound thrombin, and the release of pro-aggregatory substances from the platelet, such as throm boxane A2, serotonin and ADP (25). Consistent with this prothrom botic role for platelets are a number of studies demonstrating improved thrombolysis with thrombin inhibitors (13)(14)(15), thromboxane A2-receptor antagonists (6,7), and antagonists of the platelet glycoprotein Ilb/IIIa (10)(11)(12)(13)(14). Results of the present study indicate that the anti thrombotic action of acadesine confers effects on thrombolysis which are qualitatively similar to those agents previously tested.…”

Section: Discussionmentioning

confidence: 91%

“…However, the benefits of thrombolytic agents such as tissue plas minogen activator (t-PA) and streptokinase are limited by unsuccessful or incomplete coronary reperfusion, or by acute reocclusion of the recanalized vessel. Clinical studies demonstrating improved coronary patency with adjunctive antiplatelet therapy (3,4) implicate activated platelets in acute reocclusion, and substantial evidence exists that platelets are activated during thrombolytic therapy by a number of mechanisms (5)(6)(7)(8)(9)). Yet despite antiplatelet therapy, the rate of post thrombolytic coronary reocclusion remains between 5 and 20%, prompting extensive investigation into alternative agents which inhibit platelet aggregation and improve coronary thrombolysis, including inhibitors of the platelet GP Ilb/IIIa receptor (10)(11)(12), and thrombin or Xa inhibitors (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

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Acadesine Reduces the Frequency of Coronary Artery Reocclusion Following rt-PA Induced Thrombolysis in the Dog

et al. 1995

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SummaryAcadesine is a ribose-substituted imidazole with antithrombotic properties mediated by adenosine. In view of the beneficial effects of antiplatelet agents on thrombolysis and post-thrombolytic reocclusion, we studied the effects of acadesine on t-PA induced coronary reperfusion and continued patency in anesthetized dogs with electrically-induced coronary artery thrombosis. In 4 groups of dogs we examined the effects of saline and 3 doses of acadesine (0.5,1.0,2.0 mg/kg/min, i.v.) on time to reperfusion, and incidence and time to reocclusion following infusion of t-PA (10 μg/kg/min, i.v.). Acadesine had no effect on time to reperfusion, but significantly (p <0.05) reduced the incidence of reocclusion and prolonged the time to reocclusion at the highest dose tested. In saline treated animals vessels reoccluded in 6 of 7 animals (86%) at 33 ± 6 min after reperfusion. With the lowest dose of acadesine (0.5 mg/kg/min) vessels reoccluded in 3 of 3 animals (100%) at 18 ± 7 min. In animals treated with 1.0 mg/kg/min acadesine, the incidence of reocclusion was reduced, but not significantly (p<0.1) to 2 of 6 (33%), and time to reocclusion was prolonged to 59 ± 11 min (p<0.1). At the highest dose (2.0 mg/kg/min) of acadesine, only 2 of 8 (25%) animals reoccluded (p<0.05), and time to occlusion was prolonged to 80 ± 13 min (p<0.05). Acadesine had no effect on hemodynamics. These results suggest that acadesine might prove beneficial in clinical settings of platelet activation and prothrombotic conditions, such as occur during thrombolysis with t-PA.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Acadesine Reduces the Frequency of Coronary Artery Reocclusion Following rt-PA Induced Thrombolysis in the Dog

et al. 1995

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“…On the other hand, the TXA2-receptor an tagonist, but not the TX synthetase inhibitor, antagonizes TXA2 and PGH2, both of which exhibit a potent proag gregatory action (35,36). Recently, the combined treat ment with a TXA2 receptor antagonist and a TX syn thetase inhibitor has been recommended (37,38). The combined treatment seems to be theoretically preferable, since it can lead to the inhibition of PGH2 as well as TXA2 and, moreover, to locally increased PGI2 at the site of thrombus.…”

Section: Discussionmentioning

confidence: 99%

Effects of a Thromboxane A2-Receptor Antagonist, a Thromboxane Synthetase Inhibitor and Aspirin on Prostaglandin I2 Production in Endothelium-Intact and -Injured Aorta of Guinea Pigs

Higo

Karasawa

1994

Japanese Journal of Pharmacology

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ABSTRACT-We examined the effects of KW-3635, a thromboxane (TX) A2-receptor antagonist, and OKY-046, a TX synthetase inhibitor, on the prostaglandin (PG) 12 production in endothelium-intact and -in jured guinea pig aorta and compared them with those of aspirin. In the endothelium-intact aorta, both the low (3 mg/kg) and the high (100 mg/kg) dose of aspirin similarly reduced the PGI2 production, as measured ex vivo 1 hr after the injury. In contrast, neither KW-3635 (10 mg/kg) nor OKY-046 (30 mg/kg) inhibited the PGI2 production. The endothelial injury, induced by balloon catheterization, caused a reduction of PGI2 production in the aorta and decline of plasma PGI2/TXA2 ratio. In the endothelium-injured animals, the high dose of aspirin further reduced the PGI2 production in the aorta, whereas KW-3635 and OKY-046 did not affect it. KW-3635 and OKY-046 also ameliorated the reduced ratio of PGI2/TXA2 in the plasma. The present results demonstrate that aspirin, but not KW-3635 or OKY-046, reduces the PGI2 production in the aorta either in the endothelium-intact or -injured state. It is thus suggested that the TXA2-receptor an tagonist and the TX synthetase inhibitor have some advantages over aspirin when used for the prevention of acute thrombosis after percutaneous transluminal angioplasty.

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“…A total of 47 articles were considered relevant to the PICO question, including 20 studies suggesting that protocolized aspirin therapy is more effective, or safer than, no aspirin therapy, or other thromboprophylaxis protocols. Twenty‐five studies were considered neutral to the question . The majority of the published literature regarding the administration of aspirin in dogs involves experimental (laboratory) studies (LOE 3) of arterial thrombosis, fewer studies evaluated venous thrombosis .…”

Section: Pico Question: Aspirin Therapymentioning

confidence: 99%

“…The majority of studies were designed to model the treatment of human diseases including coronary artery disease and arterial grafting. Models included coronary angioplasty and endarterectomy‐induced endothelial injury, as well as evaluations of the effect of thromboprophylaxis on the rate of coronary arterial reocclusion after thrombolysis . Most of these models are not directly applicable to veterinary clinical medicine.…”

Section: Pico Question: Aspirin Therapymentioning

confidence: 99%

Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 3—Defining antithrombotic protocols

Blais

Bianco

Goggs

et al. 2019

J Vet Emergen Crit Care

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Objectives:To systematically examine the evidence for use of a specific protocol (dose, frequency, route) of selected antithrombotic drugs, in comparisons to no therapy or to other antithrombotic therapies, to reduce the risk of complications or improve outcomes in dogs and cats at risk for thrombosis. Design: Standardized, systematic evaluation of the literature, categorization of relevant articles according to level of evidence (LOE) and quality (Good, Fair, or Poor), and development of consensus on conclusions via a Delphi-style survey for application of the concepts to clinical practice. Settings: Academic and referral veterinary medical centers. Results: Databases searched included Medline via PubMed and CAB abstracts. Eight different antithrombotic drugs were investigated using a standardized Patient, Intervention, Comparison, Outcome (PICO) question format both for dogs and cats, including aspirin, clopidogrel, warfarin, unfractionated heparin (UFH), dalteparin, enoxaparin, fondaparinux, and rivaroxaban, generating a total of 16 worksheets. Most studies identified were experimental controlled laboratory studies in companion animals (LOE 3) with only four randomized controlled clinical trials in companion animals (LOE 1). Conclusions:Overall, evidence-based recommendations concerning specific protocols could not be formulated for most antithrombotic drugs evaluated, either because of the wide range of dosage reported (eg, aspirin in dogs) or the lack of evidence in the current literature. However, clopidogrel administration in dogs and cats at risk of arterial thrombosis, notably in cats at risk of cardiogenic thromboembolism, is supported by the literature, and specific protocols were recommended. Comparably, aspirin should not be used as a sole antithrombotic in cats with cardiomyopathy. Using the available safety profile information contained in the literature, the panel reached consensus on suggested dosage schemes for most antithrombotics. Significant knowledge gaps were highlighted, which will hopefully drive novel research.

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Beneficial effects of combined thromboxane synthase inhibition/receptor blockade with CGS 22652 in a canine model of coronary thrombosis

Cited by 5 publications

References 34 publications

Acadesine Reduces the Frequency of Coronary Artery Reocclusion Following rt-PA Induced Thrombolysis in the Dog

Acadesine Reduces the Frequency of Coronary Artery Reocclusion Following rt-PA Induced Thrombolysis in the Dog

Effects of a Thromboxane A2-Receptor Antagonist, a Thromboxane Synthetase Inhibitor and Aspirin on Prostaglandin I2 Production in Endothelium-Intact and -Injured Aorta of Guinea Pigs

Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 3—Defining antithrombotic protocols

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