Acute arterial thrombosis in rabbits: Reduced platelet accumulation after treatment with thromboxane synthetase inhibitor dazoxiben hydrochloride, (UK-37,248-01)

Randall, Michael J.; Wilding, R. I. R.

doi:10.1016/0049-3848(82)90152-9

Cited by 19 publications

(4 citation statements)

References 13 publications

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“…Although , zt the intravenous doses of each agonist we employed for drug inhibition studies, thrombin caused smaller increases in plasma thromboxane 82 than collagen (Fig.3), thrombin is also recognised as a potent stimulant of prostacyclin formation in vascular endothelial cells (35)(36)(37). Consequently, an intravenous dose of thrombin in the presence of a selective thromboxane Az synthase inhibitor might cause both accumulation of platelet derived PGH2 as potential substrate, and direct stimulation of local prostacyclin formation in the vasculature, with resultant attenuation of the aggregatory respense as previously postulated in other rabbit models (38,39). Additional studies are in progress to further elucidate this possibility.…”

Section: Discussionsupporting

confidence: 54%

Effect of Indomethacin and Dazoxiben on Intravascular Platelet Aggregation in the Anaesthetized Rabbit

Honey¹,

Lad²,

Tuffin³

1986

Thromb Haemost

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Summary Collagen (10-40 μg kg−1), thrombin (1-10 units kg−1), adenosine diphosphate (ADP; 3-300 pμ kg−1), 1-0-hexadecyl Paf-acether and 1-0-octadecyl Paf-acether (1-300 ng kg−1) administered by bolus intravenous injection each caused dose-dependent thrombocytopoenia accompanied by marked hypotension in anaesthetized rabbits. Responses to ADP and the Paf-acether derivatives were transient in nature (3-8 min) whereas those induced by collagen and thrombin were always of longer duration (5-20 min) and frequently fatal at high doses. Responses to collagen, thrombin, and the Paf-acether derivatives were invariably accompanied by substantial, dose-related increases in plasma levels of thromboxane B2 in samples obtained 30 s after agonist administration, whereas following ADP, no change in plasma thromboxane B2 was detected at any dose level. Indomethacin (3.0 mg kg−1 by infusion) had no effect on responses to thrombin or Paf-acether, partially inhibited collagen-induced thrombocytopenia, and potentiated responses to ADP. In contrast, dazoxiben (10 mg kg−1 by infusion) partially but significantly inhibited responses to thrombin, whereas those induced by collagen, Paf-acether or ADP were unchanged. These results indicate that in this model of intravascular aggregation, whilst platelet responses to collagen and thrombin appear partially dependent on intact cyclic endoperoxide and thromboxane A2 synthetic capacity respectively, responses to ADP and Paf-acether are independent of arachidonate metabolism via cyclo-oxygenase despite measurably increased TXB2 formation in the latter case.

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Section: Discussionsupporting

confidence: 54%

Effect of Indomethacin and Dazoxiben on Intravascular Platelet Aggregation in the Anaesthetized Rabbit

Honey¹,

Lad²,

Tuffin³

1986

Thromb Haemost

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“…Given the pivotal role of platelets in the process of aggregation after antiplatelet therapy. Thromboxane A2 endothelial injury, antiplatelet drugs such as aspirin, synthetase inhibitors have been shown to reduce radiodipyridamole, heparin, and selective thromboxane A2 active indium-labeled platelet accumulation both at sites synthetase inhibitors have been tested, both experimen-of electrically induced rabbit carotid artery injury (Rantally and clinically, in an attempt to modify platelet dall and Wilding, 1983) and at sites of deendothelialized accumulation on injured endothelium. Experimentally, rabbit abdominal aorta (Hall et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

Pathological changes in cerebral arteries following experimental subarachnoid hemorrhage: Role of blood platelets

Clower¹,

Yoshioka²,

Honma³

et al. 1988

Anat. Rec.

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The role of blood platelets in producing early intimal changes in cerebral arteries following subarachnoid hemorrhage (SAH) was examined by using 18 cats. Experimental SAH was produced by a rupture of the proximal portion of the right middle cerebral artery. Following SAH, the scanning electron microscope revealed that structural alterations in the intimal layer of major cerebral arteries occurred as early as 2 hours and became more severe by 48 hours. Vascular alterations, which were predominantly detected in the ruptured vessel, consisted of endothelial cell corrugation, detachment, crater formation, intimal adhesion of platelets and red blood cells, intimal thrombi, and reendothelialization. When cats were pretreated prior to SAH with an anti-platelet-aggregating agent, OKY-1581, the intimal blood elements and thrombi were clearly reduced, and reendothelialization was not observed. However, endothelial cell changes in the OKY-1581-treated group were very similar to those occurring in the nontreated group. While these results suggest that bioactive substances contained within blood platelets, such as growth factors, serotonin, and norepinephrine, have little effect on producing endothelial cell injury, platelets may be important in the initiation of reendothelialization following vessel injury.

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“…The endoperoxide is further transformed through thromboxane synthase into thromboxane A 2 , which is inactivated by rapid (t 1/2 30 sec) decomposition into thromboxane B 2 . Regulation of thromboxane formation is important in thromboembolic diseases as in septic shock and thrombosis [27][28][29][30][31][32]. Although NSAIDs such as aspirin are useful in controlling platelet aggregation, they act at an early stage through inhibition of cyclooxygenase within the platelet and depending on the dose.…”

Section: Anti-thrombotic Actionsmentioning

confidence: 99%

Hepoxilin Analogs, Potential New Therapeutics in Disease

Pace-Asciak

Li²,

Qiao³

et al. 2006

CPD

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We have chemically synthesized several stable analogs of the naturally occurring hepoxilins, 12-LO products derived from arachidonic acid, which we found to have promising actions in a variety of test systems of disease. The analogs, PBTs, afford chemical and biological stability to the hepoxilin molecule. This article reviews some of our latest observations with the PBTs in the areas of inflammation (inhibition of the bleomycin-evoked lung fibrosis in mice in vivo), platelet aggregation (antagonism of the thromboxane receptor in human platelets in vitro) and thrombosis (inhibitors in vivo), and cancer (apoptosis of the human leukemia cell line, K562 in vitro and in vivo). The demonstration that the PBTs are active in vivo suggests that they can serve as a platform for their further development as novel therapeutics in disease.

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Acute arterial thrombosis in rabbits: Reduced platelet accumulation after treatment with thromboxane synthetase inhibitor dazoxiben hydrochloride, (UK-37,248-01)

Cited by 19 publications

References 13 publications

Effect of Indomethacin and Dazoxiben on Intravascular Platelet Aggregation in the Anaesthetized Rabbit

Effect of Indomethacin and Dazoxiben on Intravascular Platelet Aggregation in the Anaesthetized Rabbit

Pathological changes in cerebral arteries following experimental subarachnoid hemorrhage: Role of blood platelets

Hepoxilin Analogs, Potential New Therapeutics in Disease

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