The d-Enantiomer Form of Indobufen Totally Accounts for the Anti-Cyclooxygenase and Antiplatelet Activity Ex Vivo and for the Increase in Bleeding Time by Indobufen in Man

Raffaele De Caterina; Rosa Sicari; An Yan; Walter Bernini; Daniela Giannessi; Guido Lazzerini; Costantin Efthymiopoulos; Margherita Strolin-Benedetti

doi:10.1055/s-0038-1648422

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1992; 67(02): 258-263
DOI: 10.1055/s-0038-1648422

Original Articles

Schattauer GmbH Stuttgart

The d-Enantiomer Form of Indobufen Totally Accounts for the Anti-Cyclooxygenase and Antiplatelet Activity Ex Vivo and for the Increase in Bleeding Time by Indobufen in Man

Raffaele De Caterina

The Laboratory for Thrombosis and Vascular Research, CNR Institute of Clinical Physiology, Pisa

,

Rosa Sicari

The Laboratory for Thrombosis and Vascular Research, CNR Institute of Clinical Physiology, Pisa

,

An Yan

The Laboratory for Thrombosis and Vascular Research, CNR Institute of Clinical Physiology, Pisa

,

Walter Bernini

The Laboratory for Thrombosis and Vascular Research, CNR Institute of Clinical Physiology, Pisa

,

Daniela Giannessi

The Laboratory for Thrombosis and Vascular Research, CNR Institute of Clinical Physiology, Pisa

,

Guido Lazzerini

The Laboratory for Thrombosis and Vascular Research, CNR Institute of Clinical Physiology, Pisa

,

Costantin Efthymiopoulos

^*The Department of Pharmacokinetics and Metabolism, Farmitalia Carlo Erba, Milan, Italy

,

Margherita Strolin-Benedetti

^*The Department of Pharmacokinetics and Metabolism, Farmitalia Carlo Erba, Milan, Italy

› Author Affiliations

Abstract

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Summary

Indobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean ± S.D., 58.7 ± 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B₂ generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB₂ production at 2 h from administration, with no statistical difference between the two treatments (97 ±3% for both treatments). At 12 h inhibition was 87 ± 6% for d-indobufen and 88 ± 6% for dl-indobufen (p = NS). Inhibition of TXB₂ production correlated significantly with plasma levels of the drugs. Maximum inhibitory effect on aggregation was seen in response to collagen 1.5 pg/ml (63 ± 44% for d-indobufen and 81 ± 22% for dl-indobufen) and arachidonic acid 0.5-2 mM (78 ± 34% for d-indobufen and 88 ± 24% for dl-indobufen) at 2 h after each administration. An effect of both treatments on platelet aggregation after 12 h was present only for adrenaline 2 μM (55 ± 41% for d-indobufen and 37 ± 54% for dl-indobufen), collagen 1.5 pg/ml (69 ± 30% for d-indobufen and 51 ± 61% for dl-indobufen), arachidonic acid 0.5-2 mM (56 ± 48% for d-indobufen and 35 ± 49% for dl-indobufen). The extent of inhibition of TX production and the extent of residual platelet aggregation were never significantly different between treatments. Bleeding time prolongation was similar in the two treatment groups without showing a pronounced and long lasting effect (from 7.0 ± 2.0 min to 10.0 ± 3.0 min at 2 h and 8.0 ± 2.0 min at 12 h for d-indobufen; from 6.0 ±1.0 min to 8.5 ± 2.0 min at 2 h and 8.0 ± 1.0 min at 12 h for dl-indobufen). These results demonstrate that the biological activity of dl-indobufen as an antiplatelet agent in vivo is totally accounted for by d-indobufen.

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References

References
1 Vinazzer H, Fuccella LA. Clinical pharmacology studies with indobu-fen (K3920), inhibitor of platelet aggregation. J Clin Pharmacol 1980; 20: 316-325
2 Patrignani P, Volpi D, Ferrario R, Romanzini L. Effects of racemic, S- and R-indobufen of cyclooxygenase and lipooxygenase activities in human whole blood. Eur J Pharmacol 1990; 191: 83-88
3 Mannucci L, Maderna P, Colli S, Lavezzari M, Sirtori CR, Tremoli E. Indobufen is a potent inhibitor of whole blood aggregation in patients with a high atherosclerotic risk. Thromb Res 1987; 48: 417-426
4 Cattaneo M, Bevilacqua C, Lecchi A, Mannucci PM. In vitro and ex vivo effects of indobufen on human platelet aggregation, the release reaction and thromboxane B₂ production. Haemostasis 1987; 17: 293-300
5 Pinto S, Abbate R, Favilla S, Paneta A, Gensini GF, Neri Serneri GG. Ex vivo and in vitro study of the effects of indobufen on endogenous and exogenous arachidonic acid metabolism by platelets. Curr Ther Res 1987; 42: 243-252
6 Salter MCP, Mayor P, Crow MJ, Rajah SM, Davison AM. Microthrombus formation on hemodialysis membranes: A placebo-controlled randomized trial of two doses of indobufen. Clin Nephrol 1985; 24: 31-36
7 Italian Multicenter Study Group Long-term antiplatelet activity and safety of indobufen on patients with cardiovascular disease. Int J Pharmacol Ther Toxicol 1985; 23: 439-446
8 Signorini GP, Salmistraro G, Maraglino G. Efficacy of indobufen in the treatment of intermittent claudication. Angiology 1988; 39: 742-746
9 Di Minno G, Silver MJ. Mouse antithrombotic assay: A simple method for the evaluation of antithrombotic agents in vivo. Potentiation of antithrombotic activity by ethyl alcohol. J Pharmacol Exp Ther 1983; 225: 57-60
10 Peters SHA, Jonker JJC, Boer AC, Den Ottolander GJH. The incidence of deep venous thrombosis in patients with an acute myocardial infarction treated with acenocoumarol or indobufen. Thromb Haemostas 1982; 4: 222-225
11 Fornaro G, Rossi P, Mantica PG, Caccia M, Aralda D, Lavezzari M, Milanesi G. Indobufen in the prevention of thromboembolic complications in patients with cardiac disease. A pilot study. Eur Heart J 1990; 11: 168 P850 (Abstract)
12 Strolin Benedetti M, Moro E, Frigerio E, Jannuzzo MG, Roncucci R, Caldwell J. The dispositional enantioselectivity of indobufen in rat and mouse. Biochem Pharmacol 1990; 40: 1719-1723
13 Gibaldi M, Perrier D. Pharmacokinetics. 2nd Edition. Marcel Dekker Inc; New York: 1982. pp 409-417
14 Giannessi D, De Caterina R, Gazzetti P, Bernini W, Masini S, Zucchelli GC. Methodological assessment and applications of a radioimmunoassay for thromboxane (TX) B₂ release by platelets. J Nucl Med All Sci 1982; 26: 25-33
15 De Caterina R, Giannessi D, Bernini W, Gazzetti P, Michelassi C, L’Abbate A, Donato L, Patrignani P, Filabozzi P, Patrono C. Low-dose aspirin in patients recovering from myocardial infarction. Evidence for a selective inhibition of thromboxane-related platelet function. Eur Heart J 1985; 6: 409-417
16 Mielke CH, Rodvien R. Bleeding time procedures. In: Clinical Laboratory Science. Section 1: Hematology. Seligsohn D, Schmidt RM. (eds). CRC Press Inc.; Boca Raton, FL: 1979. 1 369-380
17 Strolin Benedetti M, Frigerio E, Tamassia V, Noseda G, Grubb N, Caldwell J. Pharmacokinetic and metabolism of the enantiomers of indobufen in man. Biochem Pharmacol. in press
18 Cerletti C, Manarini S, Colombo M, Tavani A. The (+)-enantiomer is responsible for the antiplatelet and anti-inflammatory activity of (+)(—)-indobufen. J Pharm Pharmacol 1990; 42: 885-887