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THR-18 is believed to potentially extend tPA’s therapeutic time window from three to nine hours, allowing treatment of about 85% of embolic stroke patients. A short (18-mer) peptide, THR-18 binds to the modulatory docking site for PAI-1 on the tPA molecule, rather than the molecule’s catalytic site. This modifies the tPA molecule by preventing chemical interaction, which trigger harmful side-effects, between tPA and some of its non-embolic targets, thus making it possible for the drug to dissolve blood clots without causing bleeding in the brain.
The resulting structural change in the tPA enzyme has been shown in rat models to remarkably reduce tPA’s harmful side effects. In addition, these models have established that THR-18 can attenuate neurotoxicity induced by tPA, which activates harmful excitatory pathways. It has also been found that THR-18 prevents the deleterious opening of the blood brain barrier following tPA administration, which causes swelling of the brain and damage to the nerves.
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Finally, the experiments revealed that in some thromboembolic models THR-18 significantly improved the clot dissolution properties of tPA. Clot dissolution results in recanalization and renewed blood flow, which in turn allows improved neurological performance in patients.
Once the clot has been dissolved by the combined action of tPA and THR-18, blood flow is restored to the brain or other organ in which the clot had formed. Then oxygen-rich blood can speedily be restored to the tissue and revitalize it. This makes it possible to reverse some of the damage to the tissue, or at least minimize it. |
Efficacy in Large Animal - Neuroprotective Effect
Brain Edema - Pig Traumatic Brain injury Model
PAI-1 derived peptide provided neuroprotection in a traumatic brain damage
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In vitro: Inhibition of tPA-induced vasorelaxation of aortic rings – potentially preventing steal phenomena from penumbra
EC50 of phenylephrin - induced contraction
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In vivo: inhibition of Blood-Brain Barrier opening by tPA
OD of Evans-blue in brain extracts.
t MCAO- transient Middle Cerebral Artery Occlusion model.
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THR-18 is not only intended for treatment of acute ischemic stroke. It may also be effective against heart attacks (myocardial infarctions in which a blood clot in the heart prevents oxygen from reaching cells and thereby kills muscle tissue); neurodegenerative diseases; lung embolisms; occluded arteries and veins in the legs and arms; and traumatic brain injuries resulting from road accidents, falls and other incidents.
Diagram of a myocardial infarction (2) of the tip of the anterior wall
of the heart
(an apical infarct) after occlusion (1) of a branch of the
left coronary artery
(LCA, right coronary artery = RCA)
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