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Use of electrophilic compounds for inducing platelet production or maintaining platelet function

a technology of electrophilic compounds and platelets, which is applied in the direction of elcosanoid active ingredients, antibody medical ingredients, extracellular fluid disorders, etc., can solve the problems of increasing the risk of inflammation and disease transmission, increasing the cost and difficulty of platelet transfusion, and many victims without treatment. , to achieve the effect of promoting platelet formation, enhancing platelet production, and promoting platelet formation

Inactive Publication Date: 2015-09-24
UNIV OF ROCHESTER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent is about a method of increasing the life-span of platelets and improving their quality. This is important because platelet transfusion is the current treatment for thrombocytopenia, but it has limitations and can cause allergic reactions. The patent proposes using small molecules called electrophilic compounds that can stimulate platelet production. Two types of electrophilic compounds, prostaglandins and tri-terpenoids, are described as effective in increasing platelet formation. Further analysis of the molecules involved in platelet formation suggests that reactive oxygen species play a crucial role in this process. The patent proposes that small molecule treatments could offer a safer, more effective way to treat thrombocytopenia and improve platelet production.

Problems solved by technology

However, platelet transfusions increase the risk of inflammation and disease transmission, are costly and not always readily available (Blumberg et al., “An Association of Soluble CD40 Ligand (CD154) with Adverse Reactions to Platelet Transfusions,”Transfusion 46:1813-1821 (2006); Kaufman et al., “Release of Biologically Active CD154 During Collection and Storage of Platelet Concentrates Prepared for Transfusion,”J Thromb Haemost 5:788-796 (2007)).
A catastrophic event such as mass radiation exposure would leave many victims without treatment.

Method used

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  • Use of electrophilic compounds for inducing platelet production or maintaining platelet function
  • Use of electrophilic compounds for inducing platelet production or maintaining platelet function
  • Use of electrophilic compounds for inducing platelet production or maintaining platelet function

Examples

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example 1

Small Electrophilic Molecules Induce Platelet Formation

[0132]Initial studies demonstrated that three well-described megakaryocytic cell lines (Meg-01, M07e, Dami) all increased platelet production after exposure for 24 h to 15d-PGJ2 (FIG. 1A). Further studies were completed on Meg-01 cells, as this cell produces platelets similar in structure and function to freshly isolated human platelets (Takeuchi et al., “Production of Platelet-like Particles by a Human Megakaryoblastic Leukemia Cell Line (MEG-01),”Exp Cell Res 193:223-226 (1991), which is hereby incorporated by reference in its entirety. Treatment of Meg-01 cells with increasing concentrations of 15d-PGJ2 caused a dose-dependent increase in platelet production (FIG. 1 B). However, not every type of prostaglandin enhanced platelet production. For example, PGE2, PGI2 and PGF2α failed to enhance platelet production (FIG. 1B). Platelets derived from Meg-01 cells express the platelet marker CD61 (glycoprotein IIIa, FIG. 1C).

[0133]It...

example 2

15d-PGJ2 Promotes Platelet Production from Cultured Mouse Megakaryocytes

[0135]To evaluate whether 15d-PGJ2 affects platelet production from normal mouse megakaryocytes, primary mouse bone marrow cells were cultured for 5 days with rhTPO to promote megakaryocyte enrichment and maturation. Following culture, bone marrow cells were treated with 15d-PGJ2 for 24 h. 15d-PGJ2 increased the percentage of CD61+ platelets in culture by ˜14% (FIG. 2A). These mouse bone marrow-derived platelets exhibited normal responses to collagen, as they changed shape (decrease in size and increase in granularity) and increased their surface expression of CD41 (GPIIb, FIGS. 2B-C). Geometric mean fluorescence intensity increased from 9 to 20 after collagen treatment. Mouse bone marrow culture-derived platelets show functionality, as they spread in response to fibrinogen (FIG. 2D). 15d-PGJ2 also induced the appearance of ruffled edges on the megakaryocytes, commonly observed during membrane blebbing of platel...

example 3

15d-PGJ2 Promotes Platelet Production from Cultured Human Megakaryocytes

[0136]Cord blood-derived CD34+ cells (99% pure) were cultured for 14 days with rhTPO, at which time more than 90% of the cells expressed CD61. The cultures consisted of a mixed population of both immature and mature megakaryocytes as determined by ploidy observed by Diff-Quik staining These CD61+ cells were then treated with 15d-PGJ2 (10 μM) for 24 h and platelet production was assessed by flow cytometry. Treatment with 15d-PGJ2 doubled the number of platelets generated from these human megakaryocytes as determined by presence of the platelet marker CD61 and the absence of DNA (FIG. 3A). Flow cytometric data showed that human culture-derived platelets exhibited normal responses to collagen, as they changed shape (decrease in size and increase in granularity) and increased their surface expression of CD61 (FIGS. 3B-C). Geometric mean fluorescence intensity increased from 5 to 20 after collagen treatment. In addit...

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Abstract

The present invention is directed to a method of inducing platelet production that includes contacting a megakaryocyte with an electrophilic compound under conditions effective to induce platelet production by the contacting megakaryocyte. Methods of treating a patient for low platelet levels, increasing the circulating half-life of platelets, and improving the quality (activity) of platelets are also disclosed herein, which involve administering the electrophilic compound to a patient an effective amount to achieve the desired effect. Pharmaceutical compositions and therapeutic systems are also disclosed for carrying out these therapeutic treatments.

Description

[0001]This application is a divisional application of U.S. patent application Ser. No. 12 / 738,949, which is a national stage application under 35 U.S.C. 371 of PCT / US2008 / 081565, filed Oct. 29, 2008, and claims the priority benefit of U.S. Provisional Patent Application Ser. No. 60 / 983,352, filed Oct. 29, 2007, which is hereby incorporated by reference in its entirety.[0002]This invention was made with government support under grant HL 078604 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention is directed to the use of electrophilic compounds for inducing platelet production or maintaining platelet function, and therapeutic compositions, systems, and treatments for conditions invention involving low platelet counts (thrombocytopenia).BACKGROUND OF THE INVENTION[0004]Platelets initiate clot formation and have important roles in both innate and adaptive immunity (Henn et al., “CD40 Ligand on...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5575A61K31/277A61K31/19A61K45/06A61K31/215
CPCA61K31/5575A61K45/06A61K31/277A61K31/19A61K31/215A61K31/557A61K31/56A61P7/04
Inventor PHIPPS, RICHARD P.BERNARD, JAMIE J.
Owner UNIV OF ROCHESTER
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