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

Sct Ii LLC • Auransa Inc

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 provides methods for preventing, reducing, or eliminating cardiotoxicity induced by an anthracycline or salt thereof in a subject. The methods include administering to the subject an effective amount of a protective agent prior to or simultaneously with the anthracycline or salt thereof, and the protective agent provides an effective amount of myricetin in the subject.

The invention also provides a method of treating cancer in a subject without inducing cardiotoxicity or with reduced cardiotoxicity. In this approach, an effective amount of an anthracycline or salt thereof is administered to the subject, and the subject has an effective amount of myricetin, thereby preventing, reducing, or eliminating the cardiotoxicity induced by the anthracycline or salt thereof.

The described cardiotoxicity endpoints include cardiac tissue damage, electrophysiological dysfunction, contractile dysfunction, mitochondrial toxicity, apoptosis, and oxidative stress. Electrophysiological dysfunction includes QT prolongation and/or QTc prolongation, and contractile dysfunction includes reduced ejection fraction and/or reduced fractional shortening.

The document also describes structure-activity relationship findings for flavone/flavonol scaffolds, emphasizing that B-ring hydroxyl substitution patterns correlate with TOPOIIα/β inhibition and cardioprotective activity, and that B-ring absence or methoxy substitution often reduces potency or increases cytotoxicity. Representative compounds and analogs include myricetin and related analogs such as robinetin, tricetin, dihydromyricetin, and dihydrorobinetin, with Formula 1 and Formula 2 chemical scaffolds defined by variable substituent definitions and illustrative structures.

Claims Coverage

The document includes two independent claims centered on using myricetin to prevent, reduce, or eliminate anthracycline-induced cardiotoxicity. The inventive features are directed to administration timing and to achieving an effective amount of myricetin in the subject in connection with anthracycline administration.

Across the independent claims, the core inventive coverage is achieved by ensuring an effective amount of myricetin in the subject in connection with anthracycline administration, using either prior or simultaneous protective-agent administration or administering anthracycline while the subject has an effective amount of myricetin.

Stated Advantages

Documented Applications