Pharmaceutical compositions and methods for countering chemotherapy induced cardiotoxicity
Inventors
Armstrong, Christopher G. • Kim, Kevin J. • Pham, Lisa Maria Lucia • PARK, Eunhye • Zhong, Zhong • Huang, Guanyi • Wu, Joseph C. • Elmer, Sidney Paul • Visuthikraisee, Viwat • Cadag, Eithon Michael G. • Freeman, Thomas Bernard • Lum, Pek Yee
Assignees
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Publication Number
US-10806716-B2
Publication Date
2020-10-20
Expiration Date
Abstract
This disclosure provides methods and pharmaceutical compositions for reducing or eliminating cardiotoxicity, particularly cardiotoxicity induced by a cancer treatment or other therapy. In some cases, the methods and compositions prevent or reduce cardiotoxicity caused by anthracycline treatment. The methods provided herein often comprise administering a protective agent such as myricetin, tricetin, robinetin, ficetin, vitexin, quercetin, dihydrorobinetin, kaempferol, 7,3′,4′,5′-tetrahydroxyflavone, and myricitrin in conjunction with the administration of a cancer drug or other treatment. They may comprise administering a protective agent in combination with dexrazoxane. The compositions provided herein include co-formulations of a protective agent with a different protective agent or with a cancer treatment (e.g., anthracycline drug).
Core Innovation
The invention relates to pharmaceutical compositions that include an anticancer agent and a protective agent myricetin. The anticancer agent is an anthracycline or a salt thereof, and the molar ratio of the protective agent to the anticancer agent is from about 1:1 to about 1000:1.
The disclosed subject matter is directed to preventing, reducing, or eliminating cancer therapy-induced cardiotoxicity, with particular emphasis on anthracycline-associated cardiotoxicity. The disclosure describes cardioprotection as preserving heart function and relates this to mitochondrial toxicity, apoptosis, QTc or electrophysiological dysfunction, and contractility or cardiac ejection fraction.
The protective agents are described as flavonoid protective agents, including myricetin and related flavonoids such as tricetin, robinetin, ficetin, vitexin, dihydrorobinetin, 7,3′,4′,5′-tetrahydroxyflavone, and myricitrin. The disclosure further describes that protective agents can be co-administered or co-formulated with anthracyclines and with other anticancer drugs, and that the compositions can optionally include dexrazoxane as an additional protective agent.
Claims Coverage
The provided claim set includes one independent claim covering a composition-level inventive concept defined by an anthracycline anticancer agent, myricetin as a protective agent, and a specified molar ratio range. Dependent claims refine cardiotoxicity-related language, constrain ratio bounds, specify particular anthracycline members, limit administration, or add dexrazoxane.
Myricetin with an anthracycline anticancer agent in a defined molar ratio
A pharmaceutical composition comprising an anticancer agent and a protective agent myricetin, wherein the anticancer agent is an anthracycline or salt thereof, and wherein the molar ratio of the protective agent to the anticancer agent is from about 1:1 to about 1000:1.
Cardiotoxicity mitigation by the protective agent
The protective agent prevents, reduces, or eliminates cardiotoxicity induced by the anticancer agent in an individual administered with the pharmaceutical composition.
Narrowed protective-agent to anticancer-agent molar ratio
The molar ratio of the protective agent to the anticancer agent is from about 1:1 to about 200:1.
Anthracycline members specified from a defined list
The anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin.
Intravenous administration acceptable for the composition
The pharmaceutical composition is acceptable for intravenous administration.
Optional second protective agent dexrazoxane
The second protective agent is dexrazoxane.
The claims cover a myricetin-protective pharmaceutical composition combined with an anthracycline anticancer agent at a defined molar ratio. Coverage includes cardiotoxicity mitigation and dependent refinements that narrow the ratio range, limit the anthracycline to listed members, constrain administration to intravenous, and optionally add dexrazoxane.
Stated Advantages
Provides cardioprotection against anthracycline-induced cardiotoxicity when used with the specified protective agent myricetin.
Protects iPSC-derived cardiomyocytes against death induced by epirubicin and idarubicin.
Protects against cardiotoxicity induced by sunitinib, sorafenib, and bortezomib.
Does not interfere with doxorubicin anti-cancer activity in MDA-MB-231 and A549 cancer assays.
Shows in vivo cardioprotection in mice against DOX-induced functional decline, with improved fractional shortening and ejection fraction.
Prevents, reduces, or eliminates cardiotoxicity induced by the anticancer agent.
Reduces anthracycline-induced cardiotoxicity, including via multiple endpoints such as mitochondrial toxicity, apoptosis, QTc or electrophysiological dysfunction, and contractility or ejection fraction.
Reduced risk of cardiotoxicity.
Documented Applications
Cardioprotection in iPSC-derived cardiomyocytes against epirubicin- and idarubicin-induced death.
Protection of cardiomyocytes against kinase/proteasome inhibitor-induced cardiotoxicity associated with sunitinib, sorafenib, and bortezomib.
Use in the context of maintaining doxorubicin anti-cancer activity in breast cancer cells (MDA-MB-231) and lung cancer cells (A549).
In vivo cardioprotection in mice against DOX-induced functional decline, with improved fractional shortening and ejection fraction.
Prevention, reduction, or elimination of cancer therapy-induced cardiotoxicity, particularly anthracycline-associated cardiotoxicity, in an individual administered with the pharmaceutical composition.
Use of a pharmaceutical composition containing a protective agent myricetin with an anthracycline anticancer agent for reducing anthracycline-induced cardiotoxicity in an individual.
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