TItROMBOSIS
RESEARCH
Volume 10, Pngcs
BRIEF
525-530. Pcrgnmon
Press,
1977. P.
.ntcd in Gt. Uritnin.
COMMUNICATION
EFFEa OF SULOCl'IDIL ON BLEEDINGTIME AND IN VIVO PLATELETAGGREGATION IN RATS Giovanni de Gaetano and Anna Elisa Laboratory
of Cardiovascular
Clinical
Cavenaghi Pharmacology
Istituto di Ricerche Fannacologiche “Mario Negri” Via Eritrea,’ 62 - 20157 MILANO,Italy
(Received Received
24.12.‘1976. by Executive
Accepted Editorial
by Editor L. Roka. Office 22.1.1977)
Suloctidil (1-(4-isopropyl-thiophenyl)-2-n-octilaminopropanol, Contine tal Pharma, Belgiwn) is a new drug recently reported to inhibit platelet aggregation in human beings (1) and to possess antiplatelet aggregation and antithranbotic properties in several animal models (2,3). The drug has also been shown to inhibit serotonin uptake and to cause a specific loss of serotonin in human (4) and rat platelets (5). In the present study, the acute effect of suloctidil on bleeding time and on platelet aggregation induced in vivo by different stimuli was evaluated in rats. The-s used have been described previously (6-9). A total of 140 CD male rats (weighing 250-300 g) were obtained from Charles River, Italy and were randomly allocated to control (carboxymethyl-cellulose) or suloctidil-treated groups. Treatments were administered orally after a 15-h period of fasting. Platelet counts were made by phase contrast microscopy by the same “blind” reader. The results were analysed by the Paired Student’s t Test. From the results reported in Table 1 it appears that oral administration to rats of suloctidil (200 mg/kg b.w. or 400 mg/kg b.w.) one hour before the tests did not modify either the platelet count or bleeding time. In similar experimental conditions, acetylsalicylic acid (Bayer) and ditazole (Serono) tended to shorten the bleeding time to a degree which was statistically significant in some groups of animals (6,7). In contrast, both VK 774 and StI 869, two pyrimido-pyrimidine campounds (Karl Thomae) , markedly prolonged bleeding time (10). None of the above campounds affected the platelet count. These results seem to support the suggestion (1,3) that the mechanism of action of suloctidil in modifying platelet function differs from that of aspirin-like drugs and dipyridamole-like compounds. Figure 1 indicates that suloctidil (200 mg/kg b.w., orally, one hour before ADP injection) reduced platelet aggregation induced by i.v. injection of ADP. This inhibition was statistically significant (p < 0.001) at 30 set after ADP injection. Suloctidil did not have this inhibitory effect when administered at the same dosage two hours before the challenge with ADP. In previous experiments (7) it was found that previous oral administra tion of either acetylsalicylic acid or ditazole (400 mg/kgb.w.) did not 525
526
IN VIVO EFFECT OF SULOCTIDIL
Vol.lO,No.3
significantly modifyAt&'-induced in vivo plateletaggregation in rats: In contrast,SH 869(25mg/kg b.w.) significantly inhibitedaggregation when administered one but not two hoursbeforeADP injection(8,lO). TABLE1 Effectof suloctidilon plateletcount and bleedingtime in normalrats. Means + S.E. of 10 experimentsfor each groupof animals. Drug administered 1 h beyoretesting. Plateletsx 103/u1 Control Suloctidil (200mg/kg) Suloctidil (400mg/kg)
PragaBleedingTime (set)
840 -+ 34
146 -+ 10
868 + 32
150 + 13
892 2 90
136 + 10
/
30
90 5iziEZ TIME
( sec. 1 FIG. 1
Effectof suloctidilpretreatment on in vivo ADP-induced plateletaggregation in normalrats. ADP was aclminism.v. at a dose of 1 mg/kgb.w. (8). Means+ S.E. of 10 pairedexperiments.
Vol.lO,No.3
IN VIVO EFFECT OF SULOCTIDIL
0
/
90
30 TIME
(sec.
527
150 %zbo
1
FIG. 2 Effect of suloctidil pretreatment on in vivo collagen-induced platelet aggregation in normal rats. Collagen (SijjiiZj was administered i.v. at a dose of 2.6 mg/kg b.w. (7,9). Means + S.E. of 10 paired experiments.
I
30
TIME (sec.1
90
FIG. 3 Effect of suloctidil pretreatment on in vivo ADP-induced platelet aggregation in rats fed a fat-rich diet for IT)s (11,12). ADP was administered i.v. at a dose of 1 mg/kg b.w. (8). Means -+ S.E. of 10 paired experiments.
528
IN VIVO EFFECT OF SULOCTIDIL
Vol.lO,No.3
Figure 2 shms that suloctidii (200 mg/kg b.w., orally, one hour before i.v. collagen injection) reduced platelet aggregation induced by this Inhibition was statistically significant both at 30 set (p
RESEARCH
Volume 10, Pngcs
BRIEF
525-530. Pcrgnmon
Press,
1977. P.
.ntcd in Gt. Uritnin.
COMMUNICATION
EFFEa OF SULOCl'IDIL ON BLEEDINGTIME AND IN VIVO PLATELETAGGREGATION IN RATS Giovanni de Gaetano and Anna Elisa Laboratory
of Cardiovascular
Clinical
Cavenaghi Pharmacology
Istituto di Ricerche Fannacologiche “Mario Negri” Via Eritrea,’ 62 - 20157 MILANO,Italy
(Received Received
24.12.‘1976. by Executive
Accepted Editorial
by Editor L. Roka. Office 22.1.1977)
Suloctidil (1-(4-isopropyl-thiophenyl)-2-n-octilaminopropanol, Contine tal Pharma, Belgiwn) is a new drug recently reported to inhibit platelet aggregation in human beings (1) and to possess antiplatelet aggregation and antithranbotic properties in several animal models (2,3). The drug has also been shown to inhibit serotonin uptake and to cause a specific loss of serotonin in human (4) and rat platelets (5). In the present study, the acute effect of suloctidil on bleeding time and on platelet aggregation induced in vivo by different stimuli was evaluated in rats. The-s used have been described previously (6-9). A total of 140 CD male rats (weighing 250-300 g) were obtained from Charles River, Italy and were randomly allocated to control (carboxymethyl-cellulose) or suloctidil-treated groups. Treatments were administered orally after a 15-h period of fasting. Platelet counts were made by phase contrast microscopy by the same “blind” reader. The results were analysed by the Paired Student’s t Test. From the results reported in Table 1 it appears that oral administration to rats of suloctidil (200 mg/kg b.w. or 400 mg/kg b.w.) one hour before the tests did not modify either the platelet count or bleeding time. In similar experimental conditions, acetylsalicylic acid (Bayer) and ditazole (Serono) tended to shorten the bleeding time to a degree which was statistically significant in some groups of animals (6,7). In contrast, both VK 774 and StI 869, two pyrimido-pyrimidine campounds (Karl Thomae) , markedly prolonged bleeding time (10). None of the above campounds affected the platelet count. These results seem to support the suggestion (1,3) that the mechanism of action of suloctidil in modifying platelet function differs from that of aspirin-like drugs and dipyridamole-like compounds. Figure 1 indicates that suloctidil (200 mg/kg b.w., orally, one hour before ADP injection) reduced platelet aggregation induced by i.v. injection of ADP. This inhibition was statistically significant (p < 0.001) at 30 set after ADP injection. Suloctidil did not have this inhibitory effect when administered at the same dosage two hours before the challenge with ADP. In previous experiments (7) it was found that previous oral administra tion of either acetylsalicylic acid or ditazole (400 mg/kgb.w.) did not 525
526
IN VIVO EFFECT OF SULOCTIDIL
Vol.lO,No.3
significantly modifyAt&'-induced in vivo plateletaggregation in rats: In contrast,SH 869(25mg/kg b.w.) significantly inhibitedaggregation when administered one but not two hoursbeforeADP injection(8,lO). TABLE1 Effectof suloctidilon plateletcount and bleedingtime in normalrats. Means + S.E. of 10 experimentsfor each groupof animals. Drug administered 1 h beyoretesting. Plateletsx 103/u1 Control Suloctidil (200mg/kg) Suloctidil (400mg/kg)
PragaBleedingTime (set)
840 -+ 34
146 -+ 10
868 + 32
150 + 13
892 2 90
136 + 10
/
30
90 5iziEZ TIME
( sec. 1 FIG. 1
Effectof suloctidilpretreatment on in vivo ADP-induced plateletaggregation in normalrats. ADP was aclminism.v. at a dose of 1 mg/kgb.w. (8). Means+ S.E. of 10 pairedexperiments.
Vol.lO,No.3
IN VIVO EFFECT OF SULOCTIDIL
0
/
90
30 TIME
(sec.
527
150 %zbo
1
FIG. 2 Effect of suloctidil pretreatment on in vivo collagen-induced platelet aggregation in normal rats. Collagen (SijjiiZj was administered i.v. at a dose of 2.6 mg/kg b.w. (7,9). Means + S.E. of 10 paired experiments.
I
30
TIME (sec.1
90
FIG. 3 Effect of suloctidil pretreatment on in vivo ADP-induced platelet aggregation in rats fed a fat-rich diet for IT)s (11,12). ADP was administered i.v. at a dose of 1 mg/kg b.w. (8). Means -+ S.E. of 10 paired experiments.
528
IN VIVO EFFECT OF SULOCTIDIL
Vol.lO,No.3
Figure 2 shms that suloctidii (200 mg/kg b.w., orally, one hour before i.v. collagen injection) reduced platelet aggregation induced by this Inhibition was statistically significant both at 30 set (p
