Animal Models and Preclinical Studies

The novel antithrombotic agents were discovered, validated, and characterized through animal studies. Animal models provide a great deal of information regarding the mechanism, doses, and treatment options, as well as interaction among different thrombolytic agents. As there are many animal models only a few selected ones are discussed here.

Infused intravenous (i.v.)/intracoronary t-PA in the left anterior descending (LAD) coronary artery in an animal model induced a thrombus within 1-2 h. Coronary reperfusion, intermediary metabolism, and nutritional myocardial blood flow were restored within 10 min without inducing a systemic fibrinolytic state.22 Another study compared the thrombolytic effect of recombinant t-PA (rt-PA) with that of urokinase in dogs undergoing coronary occlusion for 1 h. Both agents were infused at the same rate. rt-PA elicited a faster reperfusion with less distal coronary embolization and systemic fibrinolysis as compared to urokinase.23

Dose and rate of infusion of rt-PA directly correlate to the degree of reperfusion of the coronary vessels. This was shown in open-chested, anesthetized dogs with induced thrombus in the LAD. Two hours after induction of the thrombus rt-PA was infused intravenously at different rates and doses. Lower rates of infusion and lower doses took longer to achieve coronary reperfusion when compared with higher doses, e.g., at 5 mgkg~ 1 min _ 1 time-to-reperfusion was greater than 40 min, while at 25 mgkg~1 min_ 1 lysis occurred within 13 min. Epicardial electrographic measurements showed a significant reduction in ST elevation in all reperfused hearts.24

Another important factor is the time of administration of the thrombolytic agent. Administration of rt-PA after 30-80 min in open-chested baboons showed a mean duration of reperfusion at 77 min and a decrease in infarct size by 38%. However, myocardial blood flow in the perfusion area of the LAD was only 70% of normal after 4h in spite of perfect angiographic refilling.25 From the above mentioned studies, it is concluded that t-PA i.v. may recanalize thrombosed coronary vessels without inducing a systemic fibrinolytic state. Timely reperfusion results in infarct sparing and restoration of nutritional blood flow.

Another comparative study was done using a canine model of coronary thrombosis; the aim of the study was to compare tissue plasminogen activator and urokinase. Urokinase was given in two doses, 15 000 (UK15) and 30 000 U kg"1 (UK30), and rt-PA was given in two doses, 0.25 (rtPA.25) and 0.75 mgkg"1 (rtPA.75). rtPA.75 showed a higher rate and extent of coronary thrombolysis; rtPA.25 was superior to UK15 but achieved the same results as UK30. Again, this study indicates that rt-PA is superior to urokinase.26

Platelet-rich coronary clot is resistant to thrombolytic therapy In order to investigate and overcome such a problem, investigators developed an animal model (dog) with platelet-rich coronary clot and investigated the effect of thrombolytic therapy combined with antiplatelet GP Ilb/IIIa antibody. The use of a reduced dose thrombolytic therapy with antiplatelet GP IIa/IIIa can overcome the resistant clot and restore perfusion. This study concluded that platelet-rich clot can be treated pharmacologically without the need for mechanical thrombolysis.27

A canine model of combined coronary arterial and femoral venous thrombosis was induced to compare intravenous bolus injection versus infusion of recombinant unglycosylated full-length single chain urokinase-type plasminogen activator (rscu-PA, saruplase). Coronary artery thrombosis and femoral vein clots were produced in five randomized blinded groups, each consisting of five dogs. rscu-PA was infused over 60min at 1 mgkg_ 1 and 0.5mgkg_ 1 (group I and III, respectively), and was given as a bolus at 1 mgkg_ 1 and 0.5 mgkg_ 1 (group II and IV, respectively). Group V was the control group. Four out of five dogs showed coronary recanalization in groups I and IV group I showed the highest percentage of clot lysis, while both groups I and II showed no coronary reocclusion Globally, this study proved that in both coronary and venous thrombolysis, intravenous bolus injection of rscu-PA is equipotent to an infusion over 60 min.28

Recent animal studies are now targeting inhibitors of PAI-1 or PAI-039. As noted above, PAI-1 functions to suppress t-PA and urokinase-type plasminogen activator (u-PA), so its inhibition should help in thrombolysis. Dogs were given PAI-039 orally and then subjected to coronary occlusion. Dogs treated with PAI-039 had more time for coronary reocclusion and thrombus weight was reduced compared to controls. Also the incidence of spontaneous reperfusion of the coronary artery was greater in dogs that received PAI-039 as compared to controls. Accordingly PAI-1 may be used as adjunctive therapy to lower the dose of thrombolytics and to increase their efficiency in clot lysis with fewer side effects such as cerebral hemorrhage and bleeding.29

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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