Darkovska-Serafimovska Marija, Janevik-Ivanovska Emilija, Djorgoski Icko, Arsova-Sarafinovska Zorica, Zdravkovska Milka, Balkanov Trajan, Ugresic Nenad
Department of Pharmacy, Faculty of Medical Sciences, Goce Delcev University, Stip; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
Department of Pharmacy, Faculty of Medical Sciences, Goce Delcev University, Stip.
Drug Des Devel Ther. 2016 Sep 21;10:2989-2996. doi: 10.2147/DDDT.S112366. eCollection 2016.
The aim of this study was to investigate the possibility of using technetium (Tc)-labeled tirofiban (a reversible antagonist of glycoprotein IIb/IIIa) for detection of deep venous thrombosis (DVT) in rats without causing an antiplatelet effect.
The ability of in vitro tirofiban to inhibit adenosine 5'-diphosphate (ADP)-induced platelet aggregation was evaluated using optical aggregometer. Binding of Tc-tirofiban to platelets was evaluated. Serum levels of unlabeled (a validated high performance liquid chromatography method) and Tc-tirofiban after single intravenous injection were evaluated in male Wistar rats with or without induced DVT (femoral vein ligation model), and the rats were also subjected to whole body scintigraphy.
Tirofiban in vitro inhibits ADP-induced aggregation of human platelets in a dose- and concentration-dependent manner (10 nM to 2 μM), but only if it is added before ADP and not after ADP. Tc labeling did not affect the ability of tirofiban to bind to either human or rat platelets, nor did it affect tirofiban pharmacokinetics in intact rats or in animals with induced DVT. When Tc-tirofiban was injected to rats after induction of DVT, at a molar dose lower than the one showing only a weak antiaggregatory effect in vitro, whole body scintigraphy indicated localization of Tc-tirofiban around the place of the induced DVT.
Tc labeling of tirofiban does not affect its ability to bind to glycoprotein IIb/IIIa or its in vivo pharmacokinetics in rats, either intact or with DVT. A low, nonantiaggregatory dose of Tc-tirofiban may be used to visualize DVT at an early stage.
本研究旨在探讨使用锝（Tc）标记的替罗非班（一种糖蛋白IIb/IIIa可逆拮抗剂）检测大鼠深静脉血栓形成（DVT）且不产生抗血小板作用的可能性。
使用光学聚集仪评估替罗非班体外抑制腺苷5'-二磷酸（ADP）诱导的血小板聚集的能力。评估Tc-替罗非班与血小板的结合情况。在有或无诱导性DVT（股静脉结扎模型）的雄性Wistar大鼠中，单次静脉注射后评估未标记的（一种经过验证的高效液相色谱法）和Tc-替罗非班的血清水平，并且对大鼠进行全身闪烁扫描。
替罗非班在体外以剂量和浓度依赖性方式（10 nM至2 μM）抑制ADP诱导的人血小板聚集，但前提是在ADP之前而非之后添加。Tc标记不影响替罗非班与人或大鼠血小板结合的能力，也不影响替罗非班在完整大鼠或诱导性DVT动物中的药代动力学。在诱导DVT后给大鼠注射Tc-替罗非班，当摩尔剂量低于在体外仅显示微弱抗聚集作用的剂量时，全身闪烁扫描表明Tc-替罗非班定位于诱导性DVT部位周围。
替罗非班的Tc标记不影响其与糖蛋白IIb/IIIa结合的能力或其在完整或患有DVT的大鼠体内的药代动力学。低剂量、无抗聚集作用的Tc-替罗非班可用于早期可视化DVT。
