Administration to Man of Uk-37,248-01, a Selective Inhibitor of Thromboxane Synthetase

Tyler, H. M.; Saxton, CraigA.P.D.; Parry, M. J.

doi:10.1016/s0140-6736(81)91551-8

Cited by 159 publications

(49 citation statements)

References 5 publications

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“…OKY-1581 is a pyridine derivative which inhibits TxA2 production in vitro (39) and in vivo (40). UK-38485, an imidazole compound, is also a potent TxA2 inhibitor (41). Neither drug inhibits cyclooxygenase at doses necessary to decrease TxA2 (39-41).…”

Section: Methodsmentioning

confidence: 99%

Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. Effects on renal hemodynamics.

Lianos¹,

Andres²,

Dünn³

1983

J. Clin. Invest.

226

103

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Section: Methodsmentioning

confidence: 99%

Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. Effects on renal hemodynamics.

Lianos¹,

Andres²,

Dünn³

1983

J. Clin. Invest.

226

103

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“…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). 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.…”

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

confidence: 98%

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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“…Evidence has accumulated which implicates it in However, the beneficial inhibition of TxA2 formation with the pathophysiology of thromboembolic diseases such as aspirin may be compromised by the concomitant reduction in unstable angina, atherosclerosis and pulmonary embolism the formation of the anti-aggregatory prostaglandins (PG)D2 (Green & Vesterqvist, 1986;Fitzgerald et al, 1987;Catella et Ltd, 1991Ltd, al., 1981. Dazoxiben (Tyler et al, 1981), an example of this class of drug, as a result of preventing TxA2 formation, redirects PGH2 metabolism towards increased formation of PGI2 and PGD2 (Defreyn et al, 1982;Orchard et al, 1985;Gresele et al, 1987). It is now recognised, however, that thromboxane synthase inhibition causes the accumulation of PGH2, which is equipotent with TxA2 at platelet TPreceptors (Le Breton et al, 1979;Hornberger & Patscheke, 1989) and can itself produce platelet aggregation and granule secretion (Bertele et al, 1981;Hornby & Skidmore, 1982).…”

Section: Introductionmentioning

confidence: 99%

Thromboxane (Tx) A₂ receptor blockade and TxA₂ synthase inhibition alone and in combination: comparison of anti‐aggregatory efficacy in human platelets

Watts¹,

Wharton²,

White³

et al. 1991

British J Pharmacology

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The present study has compared the relative anti‐aggregatory effect of various compounds which interfere with thromboxane (Tx) A2‐dependent aggregation of human platelets in whole blood in vitro. These included the cyclo‐oxygenase inhibitor aspirin, the TxA2 synthase inhibitor dazoxiben, the TxA2 (TP‐) receptor blocking drug GR32191 and two compounds, R.68070 ((E)‐5‐[[[(3‐pyridinyl) [3‐(trifluoromethyl)phenyl]‐methylen] amino]oxy] pentanoic acid) and CV‐4151 ((E)‐7‐phenyl‐7‐(3‐pyridyl)‐6‐heptenoic acid), which possess both TP‐receptor blocking and TxA2 synthase inhibitory activities in the same molecule. GR32191, R.68070 and CV‐4151 all antagonized aggregation to the TxA2 mimetic U‐46619, with pA2 values of approximately 8.2, 5.4 and 4.8 respectively. This effect was specific, platelet aggregation induced by adenosine 5′‐diphosphate (ADP) being unaffected by concentrations up to 10, 1000 and 300 μm respectively. In contrast, neither aspirin nor dazoxiben exhibited any measurable TP‐receptor blocking activity. The rank order of potency (pIC50)for inhibition of TxA2 formation in serum was R.68070 (7.4) > CV‐4151 (6.9) > dazoxiben (5.7) > aspirin (5.3). In addition, all four drugs abolished collagen‐induced platelet TxA2 formation. In contrast, GR32191 produced no consistent inhibition of TxA2 formation in either system up to concentrations of 10–30 μm. The specificity of R.68070, CV‐4151 and dazoxiben for TxA2 synthase was indicated by their ability to increase serum levels of prostaglandin E2 (PGE2) and PGD2 in parallel with decreases in TxA2 formation. This profile was not observed with aspirin or GR32191. However, high concentrations of R.68070 (100 μm) and CV‐4151 (1000 μm) necessary for maximum TP‐receptor blocking activity, produced substantially smaller increases in PGE2 and PGD2, consistent with an aspirin‐like effect of these compounds upon cyclo‐oxygenase. With dazoxiben (1000 μm), PGE2 and PGD2 levels remained elevated. Aspirin inhibited collagen‐induced platelet aggregation, the effect correlating with inhibition of TxA2 formation. Dazoxiben, whilst also achieving maximal inhibition of TxA2 formation, produced significantly less inhibition of aggregation than aspirin. In contrast, GR32191 (0.1–10 μm), at concentrations specific for TP‐receptor blockade, produced a significantly greater antagonism of collagen‐induced platelet aggregation than aspirin. This additional effect of GR32191 was absent in platelets pretreated with aspirin, indicating the probable involvement of an endogenous anti‐aggregatory cyclo‐oxygenase product in response to collagen stimulation. R.68070 and CV‐4151 also inhibited collagen‐induced aggregation, with very high concentrations of R.68070 (100 μm) producing an effect equivalent to that of GR32191. In contrast, the combination of GR32191 with either dazoxiben, R.68070 or CV‐4151, at concentrations specific for TxA2 synthase, produced a synergistic inhibitory effect upon collagen‐induced platelet aggregation which was greater than that achieved with either aspirin or any of the ...

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Administration to Man of Uk-37,248-01, a Selective Inhibitor of Thromboxane Synthetase

Cited by 159 publications

References 5 publications

Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. Effects on renal hemodynamics.

Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. Effects on renal hemodynamics.

CGS 12970: a novel, long acting thromboxane synthetase inhibitor

Thromboxane (Tx) A₂ receptor blockade and TxA₂ synthase inhibition alone and in combination: comparison of anti‐aggregatory efficacy in human platelets

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Administration to Man of Uk-37,248-01, a Selective Inhibitor of Thromboxane Synthetase

Cited by 159 publications

References 5 publications

Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. Effects on renal hemodynamics.

Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. Effects on renal hemodynamics.

CGS 12970: a novel, long acting thromboxane synthetase inhibitor

Thromboxane (Tx) A2 receptor blockade and TxA2 synthase inhibition alone and in combination: comparison of anti‐aggregatory efficacy in human platelets

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Thromboxane (Tx) A₂ receptor blockade and TxA₂ synthase inhibition alone and in combination: comparison of anti‐aggregatory efficacy in human platelets