Enhancement by Ticlopidine of the Inhibitory Effect on In Vitro Platelet Aggregation of the Glycoprotein IIb/IIIa Inhibitor Tirofiban

Summary

We determined the effects of combining the glycoprotein IIb/IIIa inhibitor tirofiban (MK-383, Aggrastat) and ticlopidine on inhibition of ADP-induced platelet aggregation, inhibition of collagen-induced platelet aggregation, and prolongation of bleeding time in 5 healthy male volunteers. The study consisted of 2 periods. In period 1, tirofiban was administered intravenously as a bolus injection at a dose of 5.0 µg/kg for 5 min, then as a continuous infusion at a rate of 0.05 µg/kg/min for 5 h 55 min. In period 2, ticlopidine was given orally at a dose of 200 mg once daily for 4 days, after which tirofiban was administered in the same manner as in period 1, starting 2 h after the last dose of ticlopidine. The percent inhibition of platelet aggregation induced by ADP 5 µM at the end of tirofiban infusion in periods 1 and 2 was 73.6 ± 2.6 and 87.1 ± 5.7% (mean ± SD), respectively. The corresponding values for inhibition of platelet aggregation induced by collagen 2 µg/ml were 45.4 ± 36.1 and 82.8 ± 27.0%, respectively. In contrast, the percent inhibition of platelet aggregation induced by ADP and collagen after treatment with ticlopidine alone was 15.8 ± 20.2 and p ± 4.8%, respectively. Compared with tirofiban alone, the combination of tirofiban and ticlopidine significantly enhanced inhibition of platelet aggregation induced by both ADP and collagen (p <0.02 and p <0.012, respectively). The inhibitory effects of ticlopidine alone were not statistically significant. Tirofiban prolonged bleeding time both in period 1 and in period 2. However, tirofiban and ticlopidine combined did not affect bleeding time. Ticlopidine administration did not alter the pharmacokinetics of tirofiban. In conclusion, at the doses of tirofiban and ticlopidine used in this study, the combination of the two drugs enhanced inhibition of platelet aggregation but did not prolong bleeding time, suggesting that appropriate doses of tirofiban can be used concomitantly with ticlopidine with no further safety concerns but with potential additional clinical effects.

• References

• 1 Topol EJ, Califf RM, Weisman HF, Elli SG, Tcheng JE, Worley S, Ivanhoe R, George BS, Fintel D, Weston M, Sigmon K, Anderson KM, Lee KL. Willerson JT on behalf of the EPIC investigators. Randomized trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet 1994; 343: 881-886
• 2 The EPIC investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Eng J Med 1994; 330: 956-961
• 3 Rothrock JF, Hart RG. Antithrombotic therapy in cerebrovascular disease. Ann Inter Med 1991; 115: 885-895
• 4 Kubo Y, Sasajima T, Goh K, Inaba M, Izumi Y, Azuma N. Arterial reconstruction of the lower extremities: Modem vascular surgery. Springer-Ver-lag; New York: 1994
• 5 Sanchez LA, Gupta SK, Veith FJ, Goldsmith J, Lyon RT, Wengerter KR, Panetta TF, Marin ML, Cynamon J, Berdejo G, Sprayregen S, Cynamon J. A ten-year experience with one hundred fifty failing or threatened vein and polytetrafluoroethylene arterial bypass grafts. J Vase Surgery 1991; 14: 729-736
• 6 Bennett JS, Villaire G. Exposure of platelet fibrinogen receptors by ADP and epinephrine. J Clin Invest 1979; 64: 1393-1401
• 7 Marguerie GA, Edgington TS, Plow EF. Interaction of fibrinogen with its platelet receptor as part of a multistep reaction in ADP-induced platelet aggregation. J Biol Chem 1980; 255: 154-161
• 8 Kereiakes DJ, Kleiman NS, Ambrose J, Cohen M, Rodriguez S, Palabri T, Herrmann HC, Sutton JM, Weaver WD, McKee DB, Fitzpatrick V, Sax FL. Randomized, double-blind, placebo-controlled dose-ranging study of tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients undergoing coronary angioplasty. J Am Coll Cardiol 1996; 27: 536-542
• 9 Barrett JS, Murphy G, Peerlinck K, De Lepeleire I, Gould RJ, Panebianco D, Hand E, Deckmyn H, Vermylen J, Amout J. Pharmacokinetics and pharmacodynamics of MK-383, a selective non-peptide platelet glycoprotein-IIb/IIIa receptor antagonist, in healthy men. Clin Pharmacol Ther 1994; 56: 377-388
• 10 Peerlinck K, De Lepeleire I, Goldberg M, Farrell D, Barrett J, Hand E, Panebianco D, Deckmyn H, Vermylen J, Amout J. MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man. Circulation 1993; 88: 1512-1517
• 11 Hall P, Nakamura S, Maiello L, Itoh A, Blengino S, Martini G, Ferraro M, Colombo A. A randomized comparison of combined ticlopidine and aspirin therapy versus aspirin therapy alone after successful intravascular ultrasound-guided stent implantation. Circulation 1996; 93: 215-222
• 12 Lynch Jr JJ, Cook JJ, Sitko GR, Holahan MA, Ramjit DR, Mellott MJ, Stranieri MT, Stabilito II, Zhang G, Lynch RJ, Manno PD, Chang CTC, Egbertson MS, Halczenko W, Duggan ME, Laswell WL, Vassallo LM, Shafer JA, Anderson PS, Friedman PA, Hartman GD, Gould RJ. Nonpeptide glycoprotein IIb/IIIa inhibitors. 5. Antithrombotic effects of MK-0383. J Pharmacol Exp Ther 1995; 272: 20-32
• 13 Hartman GD, Egbertson MS, Halczenko W, Laswell WL, Duggan ME, Smith RL, Naylor AM, Manno PD, Lynch RJ, Zhang G, Chang CTC, Gould R. Non-peptide fibrinogen receptor antagonists. 1. Discovery and design of exosite inhibitors. J Med Chem 1992; 35: 4640-4642
• 14 Hand EL, Gilbert JD, Yuan AS, Olah TV, Hichens M. Determination of MK-383, a non-peptide fibrinogen receptor antagonist, in human plasma and urine by radioimmunoassay. J Pharm Biomed Anal 1994; 12: 1047-1053
• 15 Perrier D, Mayersohn M. Noncompartmental determination of the steady- state volume of distribution for any mode of administration. J Pharm Sci 1982; 71: 372-373
• 16 Gachet C, Cattaneo M, Ohlmann P, Hechler B, Lecchi A, Chevalier J, Cassel D, Mannucci PM, Cazenave JP. Purinoceptors on blood platelets: further pharmacological and clinical evidence to suggest the presence of two ADP receptors. Brit J Haematology 1995; 91: 434-444
• 17 Hardisty RM, Powling MJ, Nokes TJ. The action of ticlopidine on human platelets. Studies on aggregation, secretion, calcium mobilization and membrane glycoproteins. Thromb Haemost 1990; 64: 150-155
• 18 FitzGerald DJ, Wright F, FitzGerald GA. Increased thromboxane biosynthesis during coronary thrombolysis. Evidence that platelet activation and thromboxane A₂ modulate the response to tissue-type plasminogen activator in vivo. Cir Res 1989; 65: 83-94
• 19 Nishiyama H, Umemura K, Wada K, Nakashima M. Antithrombotic effect of a new glycoprotein IIb/IIIa antagonist, SC-52012A: Studies in two guinea pig thrombosis models. Platelets 1995; 6: 283-287