Methods for improved endovascular thrombectomy using 3,3′-diindolylmethane
Inventors
Zeligs, Michael A. • Jacobs, Irwin C.
Assignees
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Publication Number
US-11980604-B2
Publication Date
2024-05-14
Expiration Date
Abstract
Provided herein are methods of enhancing mechanical thrombectomy during endovascular therapy for acute thrombosis using 3,3′-diindolylmethane.
Core Innovation
The patent describes compositions comprising 3,3′-diindolylmethane (DIM) or DIM analogs for treating acute ischemic stroke and large vessel occlusion, and for treating acute myocardial infarction. The treatment is directed to inhibiting neutrophil extracellular trap (NET) formation and propagation (NETosis) by neutrophils/PMNs, thereby modulating NET-associated thrombotic mechanisms.
The patent further links NET activity to endovascular therapy and mechanical thrombectomy outcomes by associating NETs with device passes, prolonged recanalization time, failed thrombectomy, fibrin/leukocyte-rich thrombus formation, and vascular adhesion. By inhibiting NETosis and/or NET propagation, DIM or DIM analogs are presented as improving or facilitating endovascular therapy/mechanical thrombectomy outcomes and addressing tPA resistance.
The document states that DIM can be formulated for oral and intravenous administration, including oral SMEDDS (such as BR-9001) and an IV injectable microparticle/premix (such as BR-2022 IV). It also describes combination approaches with other NET inhibitors, including recombinant DNase I and anti-IL1β and IL-8 antibodies, and includes tPA co-administration in the described treatment context.
Claims Coverage
The independent claim provides a single, specific pharmaceutical composition defined by a set of weight percentages, including DIM and a defined ethanol/lipid/surfactant excipient system. Dependent claims refine this composition by adding an additional active ingredient and by defining injectable formulations via combination with sterile 0.9% normal saline under specified mixing constraints.
Specific DIM composition with an ethanol and surfactant excipient system
A composition comprising about 2 wt % DIM, about 45 wt % anhydrous ethanol, about 10 wt % medium chain triglycerides of caprylic (C8) and capric (C10) acids, about 8 wt % phosphatidyl choline, about 15 wt % polyoxyl 15 hydroxystearate, about 8 wt % of poloxamer 188, and about 12 wt % of poloxamer 407.
Addition of all-trans retinoic acid to the DIM composition
A composition that further includes all-trans retinoic acid.
Injectable pharmaceutical composition via combination with sterile 0.9% normal saline
A pharmaceutical composition made by combining the composition with sterile 0.9% normal saline for injection.
Specified mixing ratio of composition to sterile 0.9% normal saline
The pharmaceutical composition of the composition combined with sterile 0.9% normal saline for injection in a ratio of about 1:10.
Specified amounts for preparing the saline combination
A pharmaceutical composition made by combining 5 g of the composition with 50 cc of sterile 0.9% normal saline for injection.
Overall, the claims cover a defined DIM-containing composition in specific weight percentages, optional inclusion of all-trans retinoic acid, and injectable formulations created by combining the composition with sterile 0.9% normal saline either by ratio or fixed amounts.
Stated Advantages
Improving or facilitating endovascular therapy/mechanical thrombectomy outcomes.
Addressing tPA resistance.
Documented Applications
Treatment of acute ischemic stroke/large vessel occlusion in the context of endovascular therapy and mechanical thrombectomy.
Treatment of acute myocardial infarction.
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