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In vivo antithrombotic activity of depogen
Vol. 65, Sup@. 1
ABSTRACTS OF 12TH INTNAT’L CONGRESS
P310 IN VIVO ANTITHROMBOTIC ACTlVlTY OF DEPOGEN J. Peter&i, K. Boer, L. Tardos, 1. Hetmecz, 2. Kapui CHINOIN Pharm. and Chem. Works Ltd, Research Centre, Budapest, H Trental-Pentoxifilline is an orally active agent for the treatment of peripheral vascular disease, cerebrovascuiar disease and a number of other conditions involving a defective regional microcirculation. The primary mechanism by which it increases blood flow appears to be related to an overall improvement in haemorheological characteristics such as erythrocyte deformability, blood viscosity and plasma fibrinogen concentration. Our compound drotaverine-acephyllinate (Depogen) has similar effect of pentoxyfnline on the basis of earlier experiments. According to our earlier experiments, De.pogen inhibits the aggregation of rabbit and human platelets in a dose dependent manner. In this study we examined the ex vivo antiaggregatory effect and in vivo antithrombotic effect of Depogen on anaesthetised rabbits. The intravenously administered Depogen doses between 1 mglkg and 8 mg/kg showed dose dependent ex vivo antiaggregatory effect. The ED(s value of the Depogen was 7 mg/kg (table 1). Depogen iv. dose (mg/kg) 2.5 mg/kg 5 mg/kg 7.5 mg/kg
inhibition (%) of ex vivo aggr. in vivo thrombus formation 30*4 45&S 55+6 I. table
-
25*3 45Ir5 60+7 -
In this work we examined the antithrombotic activity of Depogen and its effect on plasma PGl(si)2 level after intravenously injection. Depogen doses between 1 and 5 mg/kg significantly increased the plasma PGl(si)2 level. In similar dose range we studied the antithrombotic effect of Depogen on anaesthetised rabbits with the help of arterial-venous shunt method. Depogen doses between 2.5 mg/kg and 7.5 mg/kg dose dependently inhibits the thrombus formation, prevented the sticking of platelets to the surface of cotton (table 1).
P311 ORAL VENOUS ANTITHROMBOTIC ACTIVITY OF NAROPARClL (LF 9.0055) IN EXPERiMENTAL THROMBOSIS J. Millet, J. Theveniaux, M. Vaillot and N.L. Brown Laboratoires Fourier, Recherche et Developpement, Daix, F The venous antithrombotic activity of LF 135 1 has previously been demonstrated in the rat following oral administration (l), but this compound was devoid of action in the rabbit. Further chemical modification gave rise to naroparcil (LF 9.0055) alias [4-(4-cyanobenzoyl)-phenyl]-l.5-dithio-B-D-xylopyranoside. Naroparcil produced a dose-related antithrombotic effect 4 hours after oral administration to rats in a Wessler type model of venous thrombosis employing factor Xa (2) as a thrombogenic challenge, the ED, being 8.5 (7.3,9.6) mg/kg (mean and 95% confidence limits). A similar effect was seen, two hours after i.v. administration, the ED, being 4.6 (3.6,5.8) mg/kg. Naroparcil, in contrast to LF 135 1, produced an antithrombotic effect in the rabbit - in a Wbssler/Xa model -giving an ED.50 36.0 (24.5, 44.9) mg/kg 4 hours after oral administration and 24.9 (1 I. 1, 37.6) mg/kg 2 hours after i.v. admmrstration. After single oral administration of 60 mg/kg (the approximate ED& the antithrombotic effect was maintained for 8 hours, there being no residual activity after 16 hours. Similarly in the rat, the antithrombotic effect persisted for 6 hours following oral administration of 12.5 mg/kg (ED&. In both animal species, the venous antithrombotic activity was not accompanied by detectable anticoagulant effects. In rats, even at 50 mg/kg p.o., naroparcil did not affect APTT, whilst the sensitized thrombin time (to about 40 set) was significantly increased by 40%. Similarly in the rabbit, naroparcil at 400 mg/kg p.o. (4 times the antithrombotic ED,,,& did not induce a significant increase in APTT but significantly prolonged thrombin time by 35%. (I) Millet J. et al., Thromb. Haemostas. 1992; 67, 176-179. (2) Fareed J. et al., Sem. Thromb. Haemostas. 1985; 1 I. 155-175.
ABSTRACTS OF 12TH INTNAT’L CONGRESS
P310 IN VIVO ANTITHROMBOTIC ACTlVlTY OF DEPOGEN J. Peter&i, K. Boer, L. Tardos, 1. Hetmecz, 2. Kapui CHINOIN Pharm. and Chem. Works Ltd, Research Centre, Budapest, H Trental-Pentoxifilline is an orally active agent for the treatment of peripheral vascular disease, cerebrovascuiar disease and a number of other conditions involving a defective regional microcirculation. The primary mechanism by which it increases blood flow appears to be related to an overall improvement in haemorheological characteristics such as erythrocyte deformability, blood viscosity and plasma fibrinogen concentration. Our compound drotaverine-acephyllinate (Depogen) has similar effect of pentoxyfnline on the basis of earlier experiments. According to our earlier experiments, De.pogen inhibits the aggregation of rabbit and human platelets in a dose dependent manner. In this study we examined the ex vivo antiaggregatory effect and in vivo antithrombotic effect of Depogen on anaesthetised rabbits. The intravenously administered Depogen doses between 1 mglkg and 8 mg/kg showed dose dependent ex vivo antiaggregatory effect. The ED(s value of the Depogen was 7 mg/kg (table 1). Depogen iv. dose (mg/kg) 2.5 mg/kg 5 mg/kg 7.5 mg/kg
inhibition (%) of ex vivo aggr. in vivo thrombus formation 30*4 45&S 55+6 I. table
-
25*3 45Ir5 60+7 -
In this work we examined the antithrombotic activity of Depogen and its effect on plasma PGl(si)2 level after intravenously injection. Depogen doses between 1 and 5 mg/kg significantly increased the plasma PGl(si)2 level. In similar dose range we studied the antithrombotic effect of Depogen on anaesthetised rabbits with the help of arterial-venous shunt method. Depogen doses between 2.5 mg/kg and 7.5 mg/kg dose dependently inhibits the thrombus formation, prevented the sticking of platelets to the surface of cotton (table 1).
P311 ORAL VENOUS ANTITHROMBOTIC ACTIVITY OF NAROPARClL (LF 9.0055) IN EXPERiMENTAL THROMBOSIS J. Millet, J. Theveniaux, M. Vaillot and N.L. Brown Laboratoires Fourier, Recherche et Developpement, Daix, F The venous antithrombotic activity of LF 135 1 has previously been demonstrated in the rat following oral administration (l), but this compound was devoid of action in the rabbit. Further chemical modification gave rise to naroparcil (LF 9.0055) alias [4-(4-cyanobenzoyl)-phenyl]-l.5-dithio-B-D-xylopyranoside. Naroparcil produced a dose-related antithrombotic effect 4 hours after oral administration to rats in a Wessler type model of venous thrombosis employing factor Xa (2) as a thrombogenic challenge, the ED, being 8.5 (7.3,9.6) mg/kg (mean and 95% confidence limits). A similar effect was seen, two hours after i.v. administration, the ED, being 4.6 (3.6,5.8) mg/kg. Naroparcil, in contrast to LF 135 1, produced an antithrombotic effect in the rabbit - in a Wbssler/Xa model -giving an ED.50 36.0 (24.5, 44.9) mg/kg 4 hours after oral administration and 24.9 (1 I. 1, 37.6) mg/kg 2 hours after i.v. admmrstration. After single oral administration of 60 mg/kg (the approximate ED& the antithrombotic effect was maintained for 8 hours, there being no residual activity after 16 hours. Similarly in the rat, the antithrombotic effect persisted for 6 hours following oral administration of 12.5 mg/kg (ED&. In both animal species, the venous antithrombotic activity was not accompanied by detectable anticoagulant effects. In rats, even at 50 mg/kg p.o., naroparcil did not affect APTT, whilst the sensitized thrombin time (to about 40 set) was significantly increased by 40%. Similarly in the rabbit, naroparcil at 400 mg/kg p.o. (4 times the antithrombotic ED,,,& did not induce a significant increase in APTT but significantly prolonged thrombin time by 35%. (I) Millet J. et al., Thromb. Haemostas. 1992; 67, 176-179. (2) Fareed J. et al., Sem. Thromb. Haemostas. 1985; 1 I. 155-175.