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Platelet antiaggregating effects of acute and repeated oral administration of beraprost sodium in healthy volunteers
Vol. 65, Suppl. 1
ABSTRACTS OF 12TH INTNAT’L CONGRESS
s149
P292 PLATELET ANTIAGGREGATING EFFECTS OF ACUTE AND REPEATED ORAL ADMINISTRATION BERAPROST SODlUM 1N HEALTHY VOLUNTEERS
OF
A. Robert’, J.L. Demolis, C. Girault, M.N. Coueille, P, Jaillon Unite de Pharmacologic Clinique and Laboratoire d’titmatologie’, Hbp,pita]Saint-Antoine,Paris,F Beraprost sodium (BPS) is an orally stable analogue of prostacyclin. In order to determine &e duration and intensity of platelet anti-aggregating effects of BPS, 12 healthy male caucasian volunteers participated in a double blind, randomized, placeb*controlled, cross-over study. In 2 consecutive sessions, after overnight fasting, they absorbed: I) Single oral doses of BPS (20.40.60 pg and placebo); 2) Repeated oral doses of BPS (20,40,60 pg and placebo tid for 3 days). In vitro platelet aggregation in response to 5 pM ADP was measured in platelet rich titrated plasma. Results were normalized to placebo at simultaneous times during 8 hours). AK~-A~CREGAIING ~mcr (a~> man f scm p p < 0.05 “I plucbo) **p.udd#“kiud”
0
1
2
0
1
“u) _ 1o
2
BPS 40 and 60 pg significantly decreased ADP-induced platelet aggregation I h after single doses (-15.2 2 4.5% and -23.3-+ 7.0% respectively, p ~0.05). and 0.5 h (-23.0? 6.3%, -31.6 2 7.0% respectively, p <0.05) and 1 h (-20.0 2 6.3%. -25.02 5.0% respectively. p-z 0.05) after repeated doses (fig.). BPS 20 pg had no significant effect. sOme subj.-c&
complained
of mbderate
post-drug
absorption
headaches
(7112 after
single
and 8/12 after
repeated
doses) and flushes (6/l 2 and 7/l 2, respectively). These data suggest that single and repeated oral doses of BPS (40 or 60 ,,g) exe~ an antiaggregating action maximal between 30 mu and 1 h, in healthy v~luntte~~.
P293 MECHANISM OF IN VITRO ANTIAGGREGATORY ACTIVITY OF DEPOGEN Z. Kapui, K. Bokr, J. Petervti, L. Tardos, I. Hermecz CHINOIN
Pharm.
and Chem. Works
Ltd., Research
Centre,
Budapest,
H
Trental-Penloxifylhne is an orally active agent for the treatment of peripheral vascular number of other conditions involving a defective regional microcirculation. The primary
disease, cerebrovascular disease and a mechanism by which it increases blood
flow appears to be related to an overall improvement in haemorheological characteristicssuch aserythmcyte deformability, blood viscosity and plasma fibrinogen concentration. Our compound drotaverineacephyllinate (Depogen) has similar effect filline on the basis of earlier experiments. According to earlier experiments, Depogen inhibits the aggregation of rabbit and human platelets in a dose dependent this study we have compared the antiaggreqtory effect of papaverine, drotaverine, pentoxifylline and Depogen. We their platelet CAMP phosphodiesterase inhibitory effect too. Rabbit platelet aggregation was induced by arachidonic collagen, ADP and A-23 187 Ca ionophore. The phosphodiesterase enzyme was prepared from rabbit platelets.
Compound papaverine Depogen drotaverine pentoxifylline
PDE inhibition 7.5 24.8 62.0 190.0
Antiaggregatory AA 130 240 810 1870
collagen 270 140 580 2050
effect IC,, ADP 190 247 740 2660
of pentoxymanner. In determined acid (AA),
(urn) A 23187 1060 228 840 2770
We have found a good correlation between the phosphodiesterase inhibitory effect and the antiaggregatory effect of these compounds. These results suggest, that the phosphodiesterase inhibitory effect of these compounds constitutes the basis of their antiaggregatory effect. Depogen inhibits the PAF and U 46619 induced rabbit platelet aggregation and PAF induced SHidroxytriptamine release from rabbit platelet at a 10-1000 rM/l concentration range. In this work we examined the PGI, releasing effect of Depogen in a wide concentration range (0.1-100 &ml). We observed that the maximal PGI, releasing effect of Depogen appeared between l-5 !&ml. These experiments show, that the concentration which exerts the PGI, release and the concentration which has antiaggregatory effect are very close to each other.
ABSTRACTS OF 12TH INTNAT’L CONGRESS
s149
P292 PLATELET ANTIAGGREGATING EFFECTS OF ACUTE AND REPEATED ORAL ADMINISTRATION BERAPROST SODlUM 1N HEALTHY VOLUNTEERS
OF
A. Robert’, J.L. Demolis, C. Girault, M.N. Coueille, P, Jaillon Unite de Pharmacologic Clinique and Laboratoire d’titmatologie’, Hbp,pita]Saint-Antoine,Paris,F Beraprost sodium (BPS) is an orally stable analogue of prostacyclin. In order to determine &e duration and intensity of platelet anti-aggregating effects of BPS, 12 healthy male caucasian volunteers participated in a double blind, randomized, placeb*controlled, cross-over study. In 2 consecutive sessions, after overnight fasting, they absorbed: I) Single oral doses of BPS (20.40.60 pg and placebo); 2) Repeated oral doses of BPS (20,40,60 pg and placebo tid for 3 days). In vitro platelet aggregation in response to 5 pM ADP was measured in platelet rich titrated plasma. Results were normalized to placebo at simultaneous times during 8 hours). AK~-A~CREGAIING ~mcr (a~> man f scm p p < 0.05 “I plucbo) **p.udd#“kiud”
0
1
2
0
1
“u) _ 1o
2
BPS 40 and 60 pg significantly decreased ADP-induced platelet aggregation I h after single doses (-15.2 2 4.5% and -23.3-+ 7.0% respectively, p ~0.05). and 0.5 h (-23.0? 6.3%, -31.6 2 7.0% respectively, p <0.05) and 1 h (-20.0 2 6.3%. -25.02 5.0% respectively. p-z 0.05) after repeated doses (fig.). BPS 20 pg had no significant effect. sOme subj.-c&
complained
of mbderate
post-drug
absorption
headaches
(7112 after
single
and 8/12 after
repeated
doses) and flushes (6/l 2 and 7/l 2, respectively). These data suggest that single and repeated oral doses of BPS (40 or 60 ,,g) exe~ an antiaggregating action maximal between 30 mu and 1 h, in healthy v~luntte~~.
P293 MECHANISM OF IN VITRO ANTIAGGREGATORY ACTIVITY OF DEPOGEN Z. Kapui, K. Bokr, J. Petervti, L. Tardos, I. Hermecz CHINOIN
Pharm.
and Chem. Works
Ltd., Research
Centre,
Budapest,
H
Trental-Penloxifylhne is an orally active agent for the treatment of peripheral vascular number of other conditions involving a defective regional microcirculation. The primary
disease, cerebrovascular disease and a mechanism by which it increases blood
flow appears to be related to an overall improvement in haemorheological characteristicssuch aserythmcyte deformability, blood viscosity and plasma fibrinogen concentration. Our compound drotaverineacephyllinate (Depogen) has similar effect filline on the basis of earlier experiments. According to earlier experiments, Depogen inhibits the aggregation of rabbit and human platelets in a dose dependent this study we have compared the antiaggreqtory effect of papaverine, drotaverine, pentoxifylline and Depogen. We their platelet CAMP phosphodiesterase inhibitory effect too. Rabbit platelet aggregation was induced by arachidonic collagen, ADP and A-23 187 Ca ionophore. The phosphodiesterase enzyme was prepared from rabbit platelets.
Compound papaverine Depogen drotaverine pentoxifylline
PDE inhibition 7.5 24.8 62.0 190.0
Antiaggregatory AA 130 240 810 1870
collagen 270 140 580 2050
effect IC,, ADP 190 247 740 2660
of pentoxymanner. In determined acid (AA),
(urn) A 23187 1060 228 840 2770
We have found a good correlation between the phosphodiesterase inhibitory effect and the antiaggregatory effect of these compounds. These results suggest, that the phosphodiesterase inhibitory effect of these compounds constitutes the basis of their antiaggregatory effect. Depogen inhibits the PAF and U 46619 induced rabbit platelet aggregation and PAF induced SHidroxytriptamine release from rabbit platelet at a 10-1000 rM/l concentration range. In this work we examined the PGI, releasing effect of Depogen in a wide concentration range (0.1-100 &ml). We observed that the maximal PGI, releasing effect of Depogen appeared between l-5 !&ml. These experiments show, that the concentration which exerts the PGI, release and the concentration which has antiaggregatory effect are very close to each other.