Pronounced Effects of the Combination of a New Thromboxane Antagonist (GR32191) and Heparin on Bleeding Time in Man

Summary

Potential pharmacokinetic and pharmacodynamic interactions between two oral doses of GR32191 (40 and 80 mg), a new thromboxane antagonist, and heparin (5,000 IU bolus + 1,000 IU/h for 3 h) were studied in eighteen healthy male volunteers using two separate double-blind, randomised, placebo-controlled, cross-over studies.

Mean (range) bleeding time values were 8.4 min (7.5–9.7) during heparin/placebo, 12.1 min (9.2–18.6) (GR32191/placebo) and 16.3 min (11.5–21.4) (GR32191/heparin) in the 40 mg study, while these values were 8.7 min (5.5–15.5), 16.0 min (9.3 – >36.0) and 23.8 min (10.7 – >36.0), respectively in the 80 mg study. Compared to screening values, the combination of 80 mg of GR 32191 and heparin had a greater effect on the bleeding time than the sum of the prolongations after the separate treatments (p = 0.05). In the 40 mg study this was not the case. Pharmacokinetics of heparin (as assessed by plasma anti-Xa and antithrombin activity) and GR32191 were unaltered during coadministration of the two drugs. GR32191 did not influence the effects of heparin on APTT. Heparin slightly diminished the inhibition of collagen induced platelet aggregation by 80 mg of GR32191 and the U-46619 (thromboxane A₂-mimetic) induced platelet aggregation remained unchanged. Overall fibrinolytic activity (as evaluated by the fibrin plate test) was similar during all three treatments in the study with 80 mg.

The combination of 80 mg of GR32191 and heparin caused a prolongation of the bleeding time which was more than expected on the basis of their individual effects.

• References

• 1 UK-TIA Study Group United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: interim results. Br Med J 1988 296. 316-320
• 2 Lewis Jr HD, Davis HW, Archibald DG, Steinke WE, Smitherman TC, Soherty JE, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Sabharwal SC, Chesler E, Demots H. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. N Engl J Med 1983; 309: 396-403
• 3 ISIS-2 Collaborative Group Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected myocardial infarction: ISI-2. Lancet 1988 i. 349-360
• 4 Preston FE, Whipps S, Jackson CA, French AJ, Wyld PJ, Stoddard CJ. Inhibition of prostacyclin and thromboxane A₂ after low-dose aspirin. N Engl J Med 1981; 304: 76-79
• 5 Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (New Biol) 1971; 231: 232-235
• 6 Patrono C. Aspirin and human platelets: from clinical trials to acetylation of cyclooxygenase and back. TIPS 1989; 10: 453-458
• 7 Ritter JM. Thromboxane and prostacyclin in platelet/blood vessel interaction: a commentary. Long-Term Management of Patients after Myocardial Infarction. Martinus Nijhoff Publishing; Boston, IL: 1986: 233-244
• 8 Ritter JM. Cockkroft HS, Doktor HS, Beacham J, Barrow SE. Differential effect of aspirin on thromboxane and prostaglandin biosynthesis in man. Br J Clin Pharmacol 1989; 28: 573-579
• 9 Hornby EJ, Foster MR, McCabe PJ, Stratton LE. The inhibitory effect of GR32191, a thromboxane receptor blocking drug, on human platelet aggregation, adhesion and secretion. Thromb Haemostas 1989; 61: 429-436
• 10 Thomas M, Lumley P, Ballard P, O’Brien JR. Initial studies in man with a novel thromboxane receptor blocking drug GR32191. Thromb Haemostas 1987; 58: 181 (Abstr 668)
• 11 Kaplan K. Role of heparin after intravenous thrombolytic therapy for acute myocardial infarction. Am J Cardiol 1987; 59: 241-244
• 12 Heiden D, Rodvien R, Miehlke CH. Heparin bleeding, platelet dysfunction and Aspirin. JAMA 1981; 246: 330-331
• 13 Mikhailidis DP, Fonseca VA, Barradas MA, Jeremy JY, Dandona P. Platelet activation following intravenous injection of a conventional heparin: absence of effect with low molecular weight heparinoid (Org 10172). Br J Clin Pharmac 1987; 24: 415-424
• 14 Agnelli G, Borm J, Cosmi B, Levi M, Ten Cate JW. Effects of standard heparin and a low molecular weight heparin (Kabi 2165) on fibrinolysis. Thromb Haemostas 1988; 60: 311-313
• 15 Bjornsson ThD, Berger H. Aspirin acetylates fibrinogen and enhances fibrinolyis in vivo. Fibrinolytic effect is independent of changes in plasminogen activator levels. Thromb Haemostas 1987; 58: 38 (Abstr)
• 16 Yett HS, Skillman JJ, Salzman EW. The hazards of aspirin plus heparin. N Engl J Med 1978; 29: 1092
• 17 Teien AN, Lie M. Evaluation of an amidolytic heparin assay method: increased sensitivity by adding purified antithrombin III. Thromb Res 1977; 10: 399-410
• 18 Larsen ML. Abildgaard U, Teien AN, Gjesdal K. Assay of plasma heparin using thrombin and the chromogenic substrate H-D-Phe-Pip-Arg-pNA (S-2238). Thromb Res 1978; 13: 285-288
• 19 Marder VJ. A simple technique for the measurement of plasma heparin concentration during anticoagulant therapy. Thromb Diath Haemorrh 1970; 24: 230-239
• 20 Lumley P, Humphrey PA. A method for quantitating platelet aggregation and analyzing drug-rezeptor interactions on platelets in whole blood in vitro. J Pharmacol Meth 1981; 6: 153-166
• 21 Mielke CH, Kaneshiro MM, Maher IA. The standardised normal Ivy bleeding and its prolongation by aspirin. Blood 1969; 34: 204-215
• 22 Haverkate F, Brakman P. Fibrin plate assay. In: Progress in Chemical Fibrinolysis and Thrombolysis, Vol 1.. Raven Press; New York: 1975: 151
• 23 Kluft C, Brakman P, Veldhuyzen-Stolk EC. Screening of fibrinolytic activity in plasma euglobulin fractions on the fibrin plate. In: Progress in Chemical Fibrinolysis and Thrombolysis, Vol 2. Raven Press; New York: 1975: 88
• 24 Amrein PC, Ellman L, Harris WH. Aspirin-induced prolongation of bleeding time and pre-operative blood loss. JAMA 1981; 245: 1825-1828
• 25 Walker AM, Jick H. Predictors of bleeding during heparin therapy. JAMA 1980; 244: 1209-1212
• 26 Théroux P, Ouimet H, McCans J, Latour JG, Joly P, Lévy G, Pelletier E, Juneau M, Stasiak J, de Guise P, Pelletier GB, Rinzler D, Waters DD. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988; 319: 1105-1111
• 27 Moelker HCT. Heparins and platelet function. Prog Pharmacol 1982; 4: 99-133
• 28 Rosenberg RD. Actions and interactions of antithrombin and heparin. N Engl J Med 1975; 292: 146-151
• 29 Eyster ME, Gordon RA, Ballard JO. The bleeding time is longer than normal in haemophilia. Blood 1981; 58: 719-723
• 30 De Boer A, Danhof M, Cohen AF, Magnani HN, Breimer DD. Interaction study between Org 10172, a low molecular weight heparinoid, and acetylsalicylic acid in healthy male volunteers. Thromb Haemostas 1991; 66: 202-207
• 31 Takahara K, Murray R, Fitzgerald GA, Fitzgerald DJ. The response to thromboxane A₂ analogues in human platelets. J Biol Chem 1990; 265: 6836-6844
• 32 Armstrong RA, Lumley P, Humphrey PPA. Characteristics of [³H]-GR32191 binding to the thromboxane (TP) receptor of human platelets. Br J Pharmacol 1989; 98: 843 (Abstr)