| Reference | 1. Thromb Haemost. 1993 Mar 1;69(3):268-71. <br />
<br />
Potentiating effect of clopidogrel and SR 46349, a novel 5-HT2 antagonist, on
streptokinase-induced thrombolysis in the rabbit. <br />
<br />
Herbert JM(1), Bernat A, Sainte-Marie M, Dol F, Rinaldi M. <br />
Author information: <br />
(1)Sanofi Recherche, Haemobiology Research Department, Toulouse, France. <br />
<br />
Current thrombolytic strategies have a number of important shortcomings including
resistance to recanalization and development of acute reocclusion. The purpose of
this study was to investigate whether the lysis of venous thrombi by
streptokinase could be enhanced by SR 46349, a novel 5-HT2 receptor antagonist,
or clopidogrel, an analogue of ticlopidine. The activity of these compounds was
evaluated by following the lysis of radiolabelled fibrin under a continuous
infusion of streptokinase (4,000 IU kg-1 h-1 over 4 h). Streptokinase alone
induced 42% thrombolysis when compared to saline. The i.v. co-administration of
SR 46349 or clopidogrel (10 mg/kg) enhanced significantly streptokinase-induced
thrombolysis. Thrombolysis measured by [125I]-fibrinogen lysis increased to 65
and 59% respectively. This efficacy was achieved without additional prolongation
of the template bleeding time observed with streptokinase alone. Thus, the
concomitant use of a 5-HT2 receptor antagonist or an anti-ADP agent during
streptokinase therapy may facilitate clot lysis. <br />
<br />
2. Thromb Haemost. 1993 Mar 1;69(3):262-7. <br />
<br />
Antithrombotic activity of SR 46349, a novel, potent and selective 5-HT2 receptor
antagonist. <br />
<br />
Herbert JM(1), Bernat A, Barthelemy G, Dol F, Rinaldi M. <br />
Author information: <br />
(1)Sanofi Recherche, Haemobiology Research Department, Toulouse, France. <br />
<br />
SR 46349 (trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-fluorophe nyl)
propen-1-yl] phenol, hemifumarate) is the first member of a newly-developed 5-HT2
antagonist series. SR 46349 potently inhibited serotonin-induced aggregation of
rabbit and human platelets (IC50 = 1 and 3.9 nM respectively) but had no effect
on the action of other platelet aggregating agents. SR 46349 was 118 and 25 times
more potent than ketanserin against 5-HT+epinephrine-induced aggregation of
rabbit and human platelets respectively. A single per os administration of SR
46349 (1 mg/kg) resulted in a strong inhibition of 5-HT+epinephrine-induced
platelet aggregation in the rabbit as measured ex vivo (67% inhibition, 6 h after
the administration). Intravenous or oral administration of SR 46346 inhibited in
a dose-dependent manner venous thrombosis induced by ligature of the jugular vein
of rabbits whose blood was made hypercoagulable by i.v. administration of tissue
thromboplastin. The doses of SR 46349 which inhibited 50% of thrombus formation
were 1.5 +/- 0.8 mg/kg and 17 +/- 0.5 mg/kg after i.v. or oral administration
respectively. When given i.v. to rabbits, SR 46349 exhibited a dose-dependent
antithrombotic effect in an arterio-venous shunt model. Significant increase of
the bleeding time was observed after the i.v. administration of 5 mg/kg of SR
46349 (3-fold increase). In dogs, SR 46349 inhibited cyclic coronary artery blood
flow variations, complete abolition of CFVs being achieved after the i.v.
administration of 0.5 mg/kg. In conclusion, SR 46349 is a highly potent,
selective antagonist of serotonin in vitro and is to be considered as a potent,
orally active antithrombotic agent. <br />
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