Models of thrombosis

Non-peptide inhibitors of thrombin (obtained by random screening procedures) include compounds based around benzothiophene (e.g. 155) and other ring systems and cyclic and linear oligocarbamate derivatives (e.g. 156). The benzothiophene derivative 155 showed antithrombotic efficacy in a rat model of thrombosis after infusion (ED50 2.3 mg/kg/h). The cyclic oligocarbamate tetramer 156 inhibited thrombin with an apparent K[ of 31 nM. 

Santos, J. C, Mesquita, J. M. F., Belmiro, C. L. R., Carolina da Silveira, . M., Viskov, C., Mourier, P. A., and Pavao, M. S. G. (2007). Isolation and characterization of a heparin with low antithrombin activity from the body of Styela plicata (Chordata-Tunicata). Distinct effects on venous and arterial models of thrombosis. Thromb. Res. 121,213-222. 

Table 1 Factor Xa Inhibitors (TAP, Antistasin) in Experimental Models of Thrombosis Rat and rabbit models of venous thrombosis [25]...

Mousa SA, Abulencia JP, McCarty OJ et al. (2002) Comparative efficacy between glycoprotein Ilb/IIIa antagonists roxifiban and orbofiban in inhibiting platelet responses in flow models of thrombosis. J Cardiovasc Pharmacol 39 552-560... 

Abulencia JP, Tien N, McCarty OJT et al. (2001) Comparative antiplatelet efficacy of a novel, nonpeptide GPIIb/IIIa antagonist (XV454) and Abciximab (c7E3) in flow models of thrombosis. Arterioscler Thromb Vase Biol 21 149-156 McCarty OJ, Abulencia JP, Mousa SA, Konstantopoulos K (2004) Evaluation of platelet antagonists in in vitro flow models of thrombosis. Methods Mol Med 93 21-34... 

In most animal models of thrombosis, healthy animals are challenged with thrombogenic (pathophysiologic) stimuli and/or physical stimuli to produce thrombotic or occlusive conditions. These models are useful for the screening of antithrombotic drugs. 

Leadley RJ, Chi L, Rebello SS, Gagnon A (2000) Contribution of in vivo models of thrombosis to the discovery and development of novel antithrombotic agents. J Pharmacol Toxicol Methods 43 101-116... 

Harbauer (1984) first described a venous model of thrombosis induced by mechanical injury and stenosis of the jugular vein. In a modification, both arterial and venous thrombosis is produced in rabbits by stenosis of the carotid artery and the jugular vein with simultaneous mechanical damage of the endothelium. This activates platelets and the coagulation system and leads to changes in the bloodstream pattern. As a consequence, occluding thrombi are formed as detected by blood flow measurement. The dominant role of platelets in this model is shown by the inhibitory effect of an antiplatelet serum in both types of vessels (Just 1986). The test is used to evaluate the antithrombotic capacity of compounds in an in vivo model of arterial and venous thrombosis where thrombus formation is highly dependent on platelet activation. 

Best CH, Cowan C, MacLean DL (1938) Heparin and the formation of white thrombi. J Physiol 92 20-31 Chi L, Rebello S, Lucchesi BR (1999) In vivo models of thrombosis. In U Prichard ACG and Gallagher KP (eds) Anti-thrombotics. Springer-Verlag, Berlin Heidelberg, pp 101-127... 

Table 10 Animal models of thrombosis and their clinical correlates.

In view of the overwhelming evidence implicating thrombin as the primary mediator of arterial thrombosis (vide supra), numerous thrombin inhibitors have been evaluated in various experimental models of thrombosis [73,74] while hirudin and Hirulog have progressed to advanced stages of clinical development [75]. 

Using an arteriovenous shunt model of thrombosis in the rat, compounds 4 and 7 were evaluated for their ability to maintain patency of the extracorporeal circuit which serves as a thrombogenic surface [76]. Table 2 shows that on a gravimetric basis r-hirudin and inhibitor 4, were equipotent [r-hirudin EDis = 1.4 mg/kg 4 EDi5= 1.2 mg/kg i.v. bolus]. The thrombin inhibitor 7 was less effective in this assay having an EDi5= 6.3 mg/kg. 

Antithrombotic effect of r-hirudin, heparin and experimental compounds in various models of thrombosis in the rat... 

Despite the ubiquitous nature of serine proteases, it is possible to design specific thrombin inhibitors by taking advantage of the accessory regulatory binding sites on the enzyme surface. The inibitors are efficacious in several experimental models of thrombosis, and above all, illustrate the feasibility of low molecular weight protein mimetics. 

Whether endogenous prostacyclin modulates platelet activity in vivo is uncertain, but studies using cyclo-oxygenase and thromboxane synthase inhibitors in animal models of thrombosis support this hypothesis. Inhibition of platelet deposition on de-endothelialized rabbit abdominal aorta by aspirin is dose dependent, being less at higher doses at which coincident inhibition... 

TognoUni, M., V. Ballabeni, S. Bertoni, et al. 2007. Protective effect of Foeniculum vulgare essential oil and anethole in an experimental model of thrombosis. Pharmacol. Res. 56(3) 254-260. 

A number of reports on to vivo studies of the antithrombogenic properties of aspirin have appeared recently. In this regard, it is important to realize that the validity of animal models of thrombosis remains open to question. Platelets from aspirin treated rabbits were found to be morphologically normal, but did not aggregate in the presence of collagen to vitro.23 Thrombus formation induced in rats by typhosa endotoxin was inhibited by aspirin previously administered by stomach tube. 4 Platelets from these animals exhibited a reduced tendency to aggregate vitro and the prevention of thrombus formation could be... 

Antithrombotic EGb-761 In a rat model of thrombosis, the antithrombotic effects of EGb-761 combination therapy were more effective than with ticlopidine alone combinative therapy of G-B and cilostazol enhanced antithrombotic efficacies without increasing side effects [40,41]... 

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