Prolongation of Rat Tail Bleeding Time Caused by Oral Doses of a Thromboxane Synthetase Inhibitor Which Have Little Effect on Platelet Aggregation

Butler, K.D.; Maguire, E.D.; Smith, J. F.; Turnbull, AK; Wallis, Robert B.; White, Aprilfawn

doi:10.1055/s-0038-1657122

Cited by 36 publications

(16 citation statements)

References 10 publications

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“…In this extracorporeal shunt thrombosis model, cyclo-oxygenase inhibitors are marginally effective in that they inhibit thrombus formation by about 20 to 30% (Smith & White, 1982); CGS 12970 had no such effect.…”

Section: Thrombocytopenia Induced By the Forssman Reaction In Vivo (Gmentioning

confidence: 81%

“…Thrombus formation on a cotton thread in an arteriovenous shunt in the rat in vivo was measured as the wet weight of the thrombus after 15 min of blood flow (Smith & White, 1982 (PEG 400) for oral administration to laboratory animals. Platelet activating factor was synthetic l-0-hexadecyl-2-0-acetyl-snglyceryl-3-phosphorylcholine from CIBA-GEIGY Ltd, Basle, Switzerland and was prepared for use as previously described (Ambler & Wallis, 1983).…”

Section: Animal Modelsmentioning

confidence: 99%

“…The property of all thromboxane synthetase inhibitors to prolong the tail arteriolar bleeding time (transection method) in rats (Butler et al, 1982) is also shared by CGS 12970, although weaker in extent. In clinical studies, however, most thromboxane synthetase inhibitors were not shown to affect the capillary bleeding time in man (Tyler et al, 1981;MacNab et al, 1984).…”

Section: Thrombocytopenia Induced By the Forssman Reaction In Vivo (Gmentioning

confidence: 99%

“…In so much that the effect is demonstrable in rats, the drug action of CGS 12970 must be mediated through the changes in relative concentrations of TXA2 and PGI2. The bleeding time prolongation is most likely a consequence of the effect exerted on the diameter of the cut vessels (vasodilation) rather than through an action on platelet aggregation itself (Butler et al, 1982).…”

Section: Thrombocytopenia Induced By the Forssman Reaction In Vivo (Gmentioning

confidence: 99%

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CGS 12970: a novel, long acting thromboxane synthetase inhibitor

Ambler

Butler

Ku³

et al. 1985

British J Pharmacology

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1 CGS 12970 is a potent selective inhibitor of human platelet thromboxane synthestase in vitro (IC50 = 12 nM). It is four orders of magnitude less potent as an inhibitor of sheep seminal vesicle cyclooxygenase, bovine aorta prostacyclin synthetase and human leucocyte 15-lipoxygenase. 2 The compound inhibited collagen-induced thromboxane B2 production by human platelets in vitro without an effect on the accompanying platelet aggregation induced by collagen, ADP, platelet activating factor, thrombin, arachidonic acid or the prostaglandin mimetic, U 46619. 3 Administration of CGS 12970 to rats inhibited collagen-induced thromboxane B2 production but had no effect on platelet aggregation ex vivo. It also had no effect on platelet aggregation induced by thrombin or on plasma clotting times. 4 A single oral dose of 1 or 3 mg kg-' to rabbits inhibited thromboxane B2 production in clotting blood ex vivo for 12 or 24 h respectively. 5 CGS 12970 inhibited thromboxane B2 production in vivo induced by intravenous administration of collagen to rats or calcium ionophore to guinea-pigs. In both cases there was a concomitant elevation of immunoreactive 6-keto-prostaglandin Flr. but no effect on the induced thrombocytopenia.6 As with other thromboxane synthetase inhibitors, CGS 12970 prolonged tail bleeding time in the rat. However, CGS 12970 was not as potent as other thromboxane synthetase inhibitors in this test. 7 In addition to these usual effects of thromboxane synthetase inhibitors, CGS 12970 inhibited the thrombocytopenia induced by the Forssman reaction or ADP administration. In these tests the effect of the compound was of short duration. 8 CGS 12970 had no effect on the thrombocytopenia associated with the Arthus reaction which distinguishes it from cyclo-oxygenase inhibitors. It also had no effect on thrombus formation on a cotton thread in an arteriovenous shunt in the rat.

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Section: Thrombocytopenia Induced By the Forssman Reaction In Vivo (Gmentioning

confidence: 81%

Section: Animal Modelsmentioning

confidence: 99%

Section: Thrombocytopenia Induced By the Forssman Reaction In Vivo (Gmentioning

confidence: 99%

Section: Thrombocytopenia Induced By the Forssman Reaction In Vivo (Gmentioning

confidence: 99%

See 2 more Smart Citations

CGS 12970: a novel, long acting thromboxane synthetase inhibitor

Ambler

Butler

Ku³

et al. 1985

British J Pharmacology

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show abstract

“…Previous groups have failed to demonstrate a consistent effect of imidazole-analogue thromboxane synthase inhibitors on platelet aggregation ex vivo (10,13,16). Indeed, the aggregation response of human platelets to arachidonic acid, ADP, and collagen in vitro is often preserved, despite inhibition of thromboxane formation by such drugs (10,15,16,26). This may result from a direct, thromboxane-independent, proaggregatory action of the drug in vitro.…”

Section: Discussionmentioning

confidence: 99%

Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man.

FitzGerald¹,

Brash²,

Oates³

et al. 1983

J. Clin. Invest.

136

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A B S T R A C T The consequences of inhibiting the metabolism of prostaglandin G2 to thromboxane A2 in man were studied by using an inhibitor of thromboxane synthase, 4-[2-(IH-imidazol-1-yl)ethoxy] benzoic acid hydrochloride (dazoxiben). Single doses of 25, 50, 100, and 200 mg of dazoxiben were administered to healthy volunteers at 2-wk intervals in a randomized, placebo-controlled, double-blind manner. Serum thromboxane B2 and aggregation studies in whole blood and platelet-rich plasma were measured before dosing and at 1, 4, 6, 8, and 24 h after dosing. Both serum thromboxane B2 and the platelet aggregation response to arachidonic acid (1.33 mM) were reversibly inhibited in a dose-dependent manner. Aggregation induced by 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (0.4 and 4.0 ,uM) in platelet-rich plasma as well as both aggregation and nucleotide release induced by collagen (95 Zg/ml) in platelet-rich plasma and whole blood were unaltered by dazoxiben. Additional evidence for a platelet-inhibitory effect of the compound was a significant prolongation of the bleeding time at 1 h after administration of the highest dose (200 mg) of dazoxiben. Endogenous prostacyclin biosynthesis was assessed by measurement of the major urinary metabolite of prostacyclin, 2,3-dinor-6-ketoPGFia (PGI-M). PGI-M excretion was increased by

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Safety Pharmacology of Blood Constituents

Mousa

2006

Drug Discovery and Evaluation

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Prolongation of Rat Tail Bleeding Time Caused by Oral Doses of a Thromboxane Synthetase Inhibitor Which Have Little Effect on Platelet Aggregation

Cited by 36 publications

References 10 publications

CGS 12970: a novel, long acting thromboxane synthetase inhibitor

CGS 12970: a novel, long acting thromboxane synthetase inhibitor

Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man.

Safety Pharmacology of Blood Constituents

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