Three vehicle formulations for melagatran, a direct thrombin inhibitor, evaluated in a vena cava thrombosis model in the rat.
BACKGROUND
The objective of this study was to investigate whether the use of a depot formulation would enhance the antithrombotic effect of the direct thrombin inhibitor melagatran.


RESULTS
In a rat venous thrombosis model, animals were openly randomized to receive subcutaneously (s.c.) either vehicle (saline, cyclodextrin or poloxamer) or melagatran (0.5 microM/kg) dissolved in vehicle. An additional injection of cyclodextrin or poloxamer was given at another site to investigate whether the vehicle itself had any additional effect. All injections were given 30 min before induction of thrombus formation. Thrombus formation was induced by ferric chloride, together with stenosis of the caval vein, during a short period of inhalation anaesthesia. Five hours later the thrombi were harvested and their wet weight determined. Thrombus size was comparable across the vehicle-only groups. The antithrombotic effects of melagatran in saline or poloxamer were comparable while melagatran in cyclodextrin was less effective. The effects of melagatran in saline, cyclodextrin or poloxamer were not enhanced by additional cyclodextrin or poloxamer. Thrombin time (TT) and activated partial thromboplastin time (aPTT) at the end of the experiment were prolonged to a greater extent in the groups receiving melagatran in cyclodextrin or poloxamer compared with those receiving melagatran in saline.


CONCLUSIONS
In this vena cava thrombosis model, no enhanced antithrombotic effect was observed with melagatran given as a s.c. depot formulation in cyclodextrin or poloxamer compared with that in saline.
Elg
Margareta
M
Department of Integrative Pharmacology, AstraZeneca R and D, Mölndal, Sweden. Margareta.Elg@astrazeneca.com
Börjesson
Inger
I
Carlsson
Stefan
S
D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001384:Azetidines; D001596:Benzylamines; D002626:Chemistry, Pharmaceutical; D003251:Constriction, Pathologic; D003505:Cyclodextrins / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000293:injuries; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D007279:Injections, Subcutaneous; D008297:Male; D010314:Partial Thromboplastin Time; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D020442:Poloxamer / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012996:Solutions / Q000737:chemistry; D013548:Sweden; D013918:Thrombin Time; D014682:Vena Cava, Inferior / Q000293:injuries*; D020246:Venous Thrombosis / Q000139:chemically induced
D000991:Antithrombins; D001384:Azetidines; D001596:Benzylamines; D003505:Cyclodextrins; D003692:Delayed-Action Preparations; D014677:Pharmaceutical Vehicles; D012996:Solutions; D020442:Poloxamer; C109573:melagatran; D005998:Glycine