Quantitation of drug levels and platelet receptor blockade caused by a thromboxane antagonist

Friedhoff, Lawrence; Manning, James A.; Funke, Phillip T.; Ivashkiv, Eugene; Tu, Jie; Cooper, Warren D.; Willard, David A.

doi:10.1038/clpt.1986.238

Cited by 18 publications

(12 citation statements)

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“…A study with a TP antagonist demonstrates that 494% blockade of the TP receptor results in an increased bleeding time, whereas lower levels of receptor blockade results in measurable effects on collagen-induced platelet aggregation or bleeding time. 15 For the U-46619-induced platelet aggregation assay, differences between laropiprant and placebo were observed for the multiple doses tested (30-450 mg). With data pooled from the multiple-dose studies, a sigmoid E max model was used to estimate the EC 50 for inhibition of U-46619-induced platelet aggregation (amplitude) as 0.762+0.125 mM (typical value+SE).…”

Section: Discussionmentioning

confidence: 95%

“…A similar degree of inhibition of the thromboxane pathway through receptor blockade is associated with prolongation of bleeding time. A study with a TP antagonist demonstrates that >94% blockade of the TP receptor results in an increased bleeding time, whereas lower levels of receptor blockade results in measurable effects on collagen‐induced platelet aggregation or bleeding time 15 …”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics, Pharmacodynamics, and Safety of a Prostaglandin D2 Receptor Antagonist

Lai

Wenning

Crumley

et al. 2007

Clin Pharmacol Ther

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Laropiprant is a selective antagonist of the prostaglandin D(2) (PGD(2)) receptor subtype 1 (DP1). Three double-blind, randomized, placebo-controlled studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of laropiprant in healthy male volunteers. Single doses up to 900 mg and multiple doses up to 450 mg were generally well tolerated. Laropiprant exhibited dose-proportional pharmacokinetics. Oral absorption is rapid (T(max)=0.8-2.0 h) and the terminal half-life is approximately 12-18 h. The pharmacokinetics of laropiprant was not affected by food. Single doses of 6 mg and higher were effective in suppressing PGD(2)-induced cyclic AMP accumulation in platelets, demonstrating laropiprant target engagement with DP1. Laropiprant has detectable off-target antagonist effects at the thromboxane A(2) receptor but no clinically significant effect on collagen-induced platelet aggregation or bleeding times with multiple doses up to 200 mg.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics, and Safety of a Prostaglandin D2 Receptor Antagonist

Lai

Wenning

Crumley

et al. 2007

Clin Pharmacol Ther

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“…unequal effect of this class of compounds on platelet aggregation (8) and for the discouraging results of the preliminary trials in clinical conditions (9). Thromboxane receptor antagonists have recently become available for use in man (10)(11)(12). These drugs have the potential advantage of impeding the action of TXA2 simultaneously at the platelet and vessel wall levels and of antagonizing the effects of PG endoperoxides that act on a common TXA2/PG endoperoxide receptor; moreover, they would not interfere with PG12 formation by the vessel wall.…”

Section: Introductionmentioning

confidence: 99%

Role of proaggregatory and antiaggregatory prostaglandins in hemostasis. Studies with combined thromboxane synthase inhibition and thromboxane receptor antagonism.

Gresele¹,

Arnout²,

Deckmyn³

et al. 1987

J. Clin. Invest.

122

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Thromboxane synthase inhibition can lead to two opposing effects: accumulation of proaggregatory cyclic endoperoxides and increased formation of antiaggregatory PGI2 and PGD2. The elimination of the effects of the cyclic endoperoxides by an endoperoxide-thromboxane A2 receptor antagonist should enhance the inhibition of hemostasis by thromboxane synthase blockers. We have carried out a series of double-blind, placebo-controlled, crossover studies in healthy volunteers to check if this hypothesis may be operative in vivo in man.In a first study, in 10 healthy male volunteers, the combined administration of the thromboxane receptor antagonist BM 13.177 and the thromboxane synthase inhibitor dazoxiben gave stronger inhibition of platelet aggregation and prolonged the bleeding time more than either drug alone. In a second study, in 10 different healthy male volunteers, complete inhibition of cyclooxygenase with indomethacin reduced the prolongation of the bleeding time by the combination BM 13.177 plus dazoxiben. In a third study, in five volunteers, selective cumulative inhibition of platelet TXA2 synthesis by low-dose aspirin inhibited platelet aggregation and prolonged the bleeding time less than the combination BM 13.177 plus dazoxiben.In vitro, in human platelet-rich plasma stimulated with arachidonic acid, the combination of BM 13.177 and dazoxiben increased intraplatelet cAMP while the single drugs did not affect it.Our results indicate that prostaglandin endoperoxides can partly substitute for the activity of TXA2 in vivo in man and that an increased formation of endogenous antiaggregatory and vasodilatory prostaglandins, as obtained with selective thromboxane synthase inhibitors, may contribute to the impairment of hemostasis.

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“…Toxicological studies showed that compound 5 (R = CH(CH 3 )Ph) was free of any over toxicity and was advanced to phase I clinical trials [35]. A more detailed pharmacology of the related compound can be found in Ref.…”

Section: -Synthesis and Biological Activity Of Heterocyclic Prostmentioning

confidence: 99%

Synthesis and Biological Activity of Prostaglandin Analogs Containing Heteroatoms in the Cyclopentane Ring

Biaggio¹,

Rufino²,

Zaim³

et al. 2005

COC

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Prostaglandins (PG's) are a very important class of naturally occurring physiologically active substances, which have been the subject of continuous attention by biologists, pharmacists and chemists since their discovery in the 1930s. Pharmacological studies have shown that prostaglandins exhibit an extremely broad spectrum of activity such as on the smooth muscles of various organs, their mediating role in the central and peripheral nervous systems, in inflammatory processes, and their hormone-like and antihormonal activities. Due to the diversified biological activity and rapid metabolism of the natural prostaglandins, a lot of effort has been done to synthesize prostaglandin analogs. Particularly interesting are the prostaglandin analogs containing heteroatoms in the cyclopentane ring which have received a great deal of attention in relation to their potential biological properties and diversified biological activity.This article is dedicated to Prof. Sune K. Bergstrom (in memoriam) for his milestone contributions to prostaglandin research.

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Quantitation of drug levels and platelet receptor blockade caused by a thromboxane antagonist

Cited by 18 publications

References 0 publications

Pharmacokinetics, Pharmacodynamics, and Safety of a Prostaglandin D2 Receptor Antagonist

Pharmacokinetics, Pharmacodynamics, and Safety of a Prostaglandin D2 Receptor Antagonist

Role of proaggregatory and antiaggregatory prostaglandins in hemostasis. Studies with combined thromboxane synthase inhibition and thromboxane receptor antagonism.

Synthesis and Biological Activity of Prostaglandin Analogs Containing Heteroatoms in the Cyclopentane Ring

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