Ro 44-9883, a New Non-Peptidic GPIIb-GPIIIa Antagonist Prevents Platelet Loss in a Guinea Pig Model of Extracorporeal Circulation

Abstract

SummaryExtensive contact between blood and artificial surfaces causes platelet activation and depletion. The aim of the present study was to test the efficacy of Ro 44-9883, a potent and selective peptidomimetic GPIIb-IIIa antagonist, in preventing platelet loss in guinea pigs undergoing extracorporeal circulation (ECC) with bubble oxygenation. In 15 guinea pigs, an arterio-arterial shunt was created and perfused for 1 h from the aortic arch to the descending aorta. The guinea pigs were divided into three groups: A control group receiving only heparin as an i.v. bolus, a low dose-treated group and a high dose-treated group receiving in addition to heparin and before starting ECC, 1 or 7 mg/kg Ro 449883 as an i.v. bolus, respectively. In the control group, the platelet count at 30 and 60 min of ECC was dramatically decreased (35 ± 4% and 25 ± 3% of initial value). In the low dose-treated group, Ro 44-9883 partially prevented the drop in platelet count (69 ± 8% and 54 ± 9%; p <0.05) whereas in the high dose-treated group, the platelet count was normal at 30 min (97 ± 8%) and only slightly decreased at 60 min (80 ± 7%). Mean arterial pressure and hematocrit were not significantly different between groups during the experiment. We conclude that i) ECC in guinea pigs provides an interesting in-vivo model for studying platelet loss by contact activation and ii) Ro 44-9883 prevents platelet loss during ECC in a dose dependent manner.

Greater inhibition of platelet procoagulant activity by antibody‐derived glycoprotein IIb–IIIa inhibitors than by peptide and peptidomimetic inhibitors

“…These compounds include a chimaeric human/murine monoclonal antibody fragment (c7E3, abciximab; ReoPro) (Coller et al , 1995), peptide‐derived compounds based on the arg–gly–asp (RGD) sequence or its KGD analogue (e.g. eptifibatide, Integrilin) (Scarborough et al , 1993) and peptidomimetics such as MK‐383 (tirofiban, Aggrastat) (Egbertson et al , 1994) and RO44–9883 (Lamifiban) (Carteaux et al , 1993).…”

How not to discover a drug - integrins

“…Using a similar approach to synthesising RGDS-peptidomimetics [55] Roche discovered lamifiban, a non-peptide antagonist [56]. Despite its lack of oral activity they took it into clinical trials [57] although it was unsuccessful.…”

Synthetic Inhibitors of Platelet Glycoprotein IIb/IIIa in Clinical Development

“…1 In a Canadian study, lamifiban (1, 2, 4, and 5 g/min IV) protected 365 patients with unstable angina from severe ischemic events during a 2-to 5-day infusion (all doses combined 3.3% versus 8.1%, Pϭ0.04) and reduced the incidence of death and myocardial infarction at 1 month (3.7% versus 8.1%). 2 No clear dose-related incremental clinical benefit could be documented in this small study, but more major bleeding (2.9% versus 0.8%) and significantly more minor bleeding (11.1% versus 1.6%, Pϭ0.002) were noted in the high-dose lamifiban groups.…”