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(Circulation Research. 1996;78:643-649.)
© 1996 American Heart Association, Inc.

Articles

Inhibitory Effects of TA-993, a New 1,5-Benzothiazepine Derivative, on Platelet Aggregation

Akio Odawara, Kohei Kikkawa, Makoto Katoh, Hiromi Toryu, Tamotu Shimazaki, Yasuhiko Sasaki

From the Pharmacological Research Laboratory, Tanabe Seiyaku Co, Ltd, Toda, Japan.

Correspondence to Dr Akio Odawara, Pharmacological Research Laboratory, Tanabe Seiyaku Co, Ltd, 2-2-50 Kawagishi, Toda, Saitama 335, Japan.

Abstract TA-993, an l-cis 4',8-dimethyl derivative of the Ca²⁺ antagonist diltiazem, and some of its metabolites inhibited platelet aggregation induced by collagen, ADP, epinephrine, platelet activating factor, arachidonic acid, and U-46619 in human platelets in vitro. Among the metabolites, MB3 was the most potent (IC₅₀, <1 µmol/L; several hundred times more potent than the parent compound). The d isomer of MB3 was >100 times less potent than the l isomer. Unlike acetylsalicylic acid (ASA), TA-993 inhibited both primary and secondary phases of ADP-induced platelet aggregation and also exhibited a disaggregating effect on human platelet aggregates. The inhibitory effect of TA-993 was enhanced when used in combination with ASA. In ex vivo studies involving rats, TA-993 (0.3 to 100 mg/kg PO) dose-dependently inhibited collagen-induced platelet aggregation (ED₅₀, 3 mg/kg PO). In the whole-blood platelet aggregation system in rats, orally administered TA-993 was also inhibitory in single (3 to 30 mg/kg) or repeated daily (10 mg/kg per day for 10 days) dosage. Orally administered TA-993 dose-dependently inhibited ADP-induced platelet aggregation ex vivo in dogs (0.3 to 10 mg/kg), significantly protected mice against collagen+epinephrine–induced thromboembolic death (10 mg/kg), and inhibited thrombus formation in an arteriovenous shunt in rats (30 mg/kg). The Ca²⁺-antagonistic action of TA-993 was very weak in depolarized canine basilar arteries: the potency was 1/10 that of diltiazem (d-cis) and d-TA-993. These results suggest that antiplatelet action is more characteristic of the l-cis than the d-cis 1,5-benzothiazepine structure and that TA-993 may become a clinically useful antiplatelet agent of this structure series.

Key Words: TA-993 • antiplatelet effect • ticlopidine • acetylsalicylic acid • diltiazem

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