Transplantation therapies
Inventors
Alexander, Jonathan Steven • Carpenter, April C. • Castor, Trevor Percival
Assignees
Aphios Corp • Louisiana State University
Publication Number
US-9994585-B2
Publication Date
2018-06-12
Expiration Date
2028-12-31
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Abstract
Embodiments of the present invention are directed to methods and dosage forms for treating inflammation and rejection in transplantation injuries with Bryostatin-1, Bryostatin-1 analogs and pharmaceutically acceptable salts thereof.
Core Innovation
The invention is directed to methods and dosage forms for treating inflammation and rejection in transplantation injuries using Bryostatin-1, Bryostatin-1 analogs, or pharmaceutically acceptable salts thereof. The core approach involves administering an effective amount of these compounds, formulated in a suitable dosage form, to reduce or prevent neutrophil trans endothelial migration, a key step in transplantation-mediated organ stress and rejection.
The problem addressed by the invention is the leukocyte-dependent injury that contributes significantly to both acute and chronic inflammatory diseases associated with transplantation, particularly due to neutrophil infiltration into transplanted organs and tissues. There is a need for therapies capable of reducing neutrophil migration to limit inflammation and organ rejection following transplantation.
The invention provides specific dosage forms, including oral and parenteral formulations, wherein Bryostatin-1 or its analogs are dispersed or dissolved in polyalkylene glycol glycerides. One method features a solid oral dosage form, and another features a pharmaceutical parenteral formulation, with defined concentrations to achieve effective plasma levels necessary for inhibiting neutrophil trans endothelial migration. The therapy can be employed as a pre- or co-treatment to stabilize the vasculature against leukocyte penetration via PKC-δ activation, thereby reducing transplantation injury.
Claims Coverage
The independent claims present one main inventive feature relating to methods for treating transplantation injury using specific compounds and formulations.
Method of treating transplantation injury with Bryostatin-1 compounds in polyalkylene glycol glyceride dosage form
The invention features administering to a subject in need an effective amount of Bryostatin-1, Bryostatin-1 analog, or a pharmaceutically acceptable salt thereof to reduce or prevent induced neutrophil trans endothelial migration. - The effective amount is contained in a dosage form. - The dosage form comprises polyalkylene glycol glyceride. Further dependent claims specify: - Use in organ preservation solution at 20 to 1000 nanograms per milliliter. - Amounts sufficient to achieve plasma concentrations of 10−7 M in the treated individual, tissue, or organ. - Oral dosage forms, including solid oral forms, and parenteral formulations. - Dosage forms may use polyalkylene glycol glyceride mixtures (polyalkylene esters of 8 to 18 carbon saturated fatty acids with glycerol), with polyethylene glycol component (molecular weight 1000–2000, preferably 1400–1600 daltons). - Bryostatin-1 or its analogs present in oral dosage forms at 1–30% by weight, preferably 10–20%, or parenteral at 1–30%, 10–20% by weight, or as aqueous dispersions (0.0005–0.5%).
The claim coverage centers on the use of dosage forms comprising Bryostatin-1, its analogs, or pharmaceutically acceptable salts in polyalkylene glycol glyceride formulations for reducing or preventing neutrophil trans endothelial migration in transplantation injury.
Stated Advantages
Provides a potent, lasting, and non-invasive means of tissue protection for transplantation injuries.
Allows for rapid and economical treatment of transplantation-mediated organ stress and rejection.
Bryostatin-1 treatment can protect against neutrophil infiltration for at least 48 hours after administration without persistent drug presence.
Bryostatin-1 therapy has reported no adverse cardiovascular effects or edema at dosing levels cited in clinical use.
Documented Applications
Treatment and prevention of transplantation injury by reducing or preventing neutrophil trans endothelial migration.
Use in organ or tissue perfusion solutions for organ transplantation to protect organs from leukocyte infiltration.
Suppression of graft-versus-host disease (GVHD) following bone marrow or stem cell transplantation.
Limiting neutrophil chemotaxis and extravasation in inflammatory scenarios associated with transplantation.
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