Methods and Compositions for Reducing Side Effects in Chemotherapeutic Treatments

Abstract

The present invention relates to a method of preventing or reducing dermatological side effects of the therapeutic agents in a subject without substantial loss in efficacy, where the therapeutic agents would otherwise have significant effects. In particular, this beneficial effect is achieved by using an alpha-2 adrenergic agonist to isolate body areas from pharmacological effects of the therapeutic agents, such as a chemotherapeutic agent, and to prevent or reduce inflammatory processes.

We claim: 
     
         1 . A method of preventing or reducing an unwanted dermatological side effect of a chemotherapeutic agent in a skin body part of a human subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising an alpha-2 adrenergic agonist having more affinity for an alpha-2 adrenoreceptor than for an alpha-1 adrenoreceptor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         2 . The method according to  claim 1 , wherein the skin body part is selected from the group consisting of: scalp, face, neck, shoulders, back, torso, belly, genitals, arms, forearms, legs, hands, and feet. 
     
     
         3 . The method of  claim 1 , wherein the pharmaceutical composition further comprises an avermectin. 
     
     
         4 . The method of  claim 3 , wherein the avermectin is emamectin or ivermectin. 
     
     
         5 . The method of  claim 1 , wherein the pharmaceutical composition is topically administered to the skin body part of the human subject. 
     
     
         6 . The method of  claim 1 , wherein the pharmaceutical composition is administered before administration of the chemotherapeutic agent. 
     
     
         7 . The method of  claim 1 , wherein the pharmaceutical composition is administered during administration of the chemotherapeutic agent. 
     
     
         8 . The method of  claim 1 , wherein the pharmaceutically acceptable carrier comprises a gelling agent and a polyol. 
     
     
         9 . A method of  claim 1 , further comprising administration of the pharmaceutical composition without dosing interruptions of the chemotherapeutic agent for at least 12 weeks. 
     
     
         10 . The method of  claim 1 , further comprising administration of the pharmaceutical composition without the administration of an antibiotic or a corticosteroid to the skin body part of the human subject for at least 12 weeks. 
     
     
         11 . The method of  claim 1 , wherein the pharmaceutical composition comprises brimonidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         12 . The method of  claim 11 , wherein the brimonidine or a pharmaceutically acceptable salt thereof is about 0.1% (w/w) to about 0.6% (w/w) of the pharmaceutical composition. 
     
     
         13 . The method of  claim 1 , wherein the pharmaceutical composition comprises brimonidine tartrate and a pharmaceutically acceptable carrier. 
     
     
         14 . The method of  claim 12 , wherein the brimonidine tartrate is about 0.1% (w/w) to about 10.0% (w/w) of the pharmaceutical composition. 
     
     
         15 . A method of preventing or reducing dermatological side effects of in a skin body part of a human subject induced by a chemotherapeutic agent, comprising administering to the subject an effective amount of a pharmaceutical composition comprising an alpha-2 adrenergic agonist having more affinity for the alpha-2 adrenoreceptor than for an alpha-1 adrenoreceptor, or a pharmaceutically acceptable salt thereof;
 wherein the chemotherapeutic agent is selected from the group consisting of: an anti-EGFR compound, an MEK inhibitor compound, and an mTOR inhibitor compound.   
     
     
         16 . The method according to  claim 15 , wherein the chemotherapeutic agent is an anti-EGFR compound selected from the group consisting of: cetuximab, gefitinib, erlotinib, necitumumab, neratinib, panitumumab, vandetanib, osimertinib, and lapatinib. 
     
     
         17 . The method according to  claim 15 , wherein the chemotherapeutic agent is an MEK inhibitor compound selected from the group consisting of: trametinib, selumetinib, binimetinib, refametinib, pimasertib, and cobimetinib. 
     
     
         18 . The method according to  claim 15 , wherein the chemotherapeutic agent is an mTOR inhibitor compound selected from the group consisting of: rapamycin (sirolimus), temsirolimus, everomilus, ridaforolimus, dactolisib (NVP-BEZ235), GSK2126458, XL765, AZD8055, sapanisertib (INK128), OS1027, and rapalink-1. 
     
     
         19 . The method of  claim 15 , wherein the pharmaceutical composition comprises brimonidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         20 . The method of  claim 15 , wherein the pharmaceutical composition comprises brimonidine tartrate and a pharmaceutically acceptable carrier. 
     
     
         21 . The method of  claim 1 , wherein the dermatological side effect is one of papulopustular rash, dry skin, flushing, hyperpigmentation, unwanted nail changes and photosensitivity.