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-10874633-B2
Publication Date
2020-12-29
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 and methods for reducing or eliminating cardiotoxicity associated with cancer therapy. The problem addressed is cardiotoxicity induced by an anticancer agent in a subject, particularly cardiotoxicity caused by anthracyclines or salts thereof. The invention frames cardiotoxicity in terms of cardiac tissue damage and electrophysiological dysfunction, including QT/QTc prolongation, as well as mitochondrial toxicity, apoptosis, contractility dysfunction, and oxidative stress.
The core inventive concept is co-administration of a protective agent with the anticancer agent, where the protective agent is myricetin. The protective agent is administered prior to or simultaneously with the anticancer agent, with the protective agent preventing, reducing, or eliminating cardiotoxicity induced by the anticancer agent in the subject. A treatment method is also described for treating cancer while administering the anticancer agent together with the protective agent in this prior-or-simultaneous manner.
The disclosure further supports the protective-agent concept through specified protective-agent chemical scope and example flavonoids. The protective agent myricetin is described alongside flavonoids and derivatives, including myricitrin and dihydrorobinetin and derivatives or salts, and the invention contemplates formulation approaches that combine the protective agent and anticancer agent as a co-formulation. The cardiotoxicity is also described as a multi-endpoint phenomenon, including mitochondrial toxicity, apoptosis, electrophysiological dysfunction such as QTc prolongation, and contractility dysfunction as measured by ejection fraction and fractional shortening.
Claims Coverage
The document includes two independent claims that focus on preventing, reducing, or eliminating cardiotoxicity induced by an anticancer agent using myricetin administered prior to or simultaneously with the anticancer agent. Across the independent claims, the inventive coverage includes the anticancer agent being an anthracycline or salt thereof and the protective agent being myricetin.
Protective-agent co-administration with anthracycline for cardiotoxicity prevention
Administering an effective amount of a protective agent prior to or simultaneously with an anticancer agent to prevent, reduce, or eliminate cardiotoxicity induced by the anticancer agent in a subject, wherein the anticancer agent is an anthracycline or salt thereof, and wherein the protective agent is myricetin.
Cancer treatment with myricetin preventing anthracycline cardiotoxicity
Treating cancer by administering an effective amount of an anticancer agent and administering an effective amount of a protective agent prior to or simultaneously with the anticancer agent, wherein the protective agent prevents, reduces, or eliminates cardiotoxicity induced by the anticancer agent in the subject, wherein the anticancer agent is an anthracycline or salt thereof, and wherein the protective agent is myricetin.
Both independent claims cover administering myricetin prior to or simultaneously with an anthracycline or anthracycline salt to prevent, reduce, or eliminate anticancer-induced cardiotoxicity, while one claim additionally frames the method as treating cancer.
Stated Advantages
Prevents, reduces, or eliminates cardiotoxicity induced by an anticancer agent.
Provides cardioprotection against cardiotoxic phenotypes including mitochondrial toxicity, apoptosis, electrophysiological dysfunction such as QTc prolongation, and contractility dysfunction as measured by EF and FS.
Documented Applications
Preventing, reducing, or eliminating cardiotoxicity induced by anthracycline anticancer agents, including doxorubicin, in a subject.
Treating cancer in a subject by administering an anthracycline anticancer agent together with myricetin to prevent, reduce, or eliminate anticancer-induced cardiotoxicity.
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