THELETTERATURA US A20170296525A1 TUTTIA UTOMATION ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2017/ 0296525 A1 Moran et al. ( 43 ) Pub . Date : Oct. 19 , 2017 ( 54 ) USE OF COTININE IN TREATING OR (60 ) Provisional application No . 62 /073 ,339 , filed on Oct . PREVENTING NEUROGENESIS DEFICITS 31 , 2014 . AND ENHANCING NEUROGENESIS (71 ) Applicants : Department of Veterans Affairs , Publication Classification Washington , DC (US ) ; University of (51 ) Int . Ci. South Florida , Tampa, FL (US ) A61K 31/ 454 (2006 .01 ) A6IK 31 /55 (2006 . 01 ) (72 ) Inventors : Valentina Echeverria Moran , Largo , A61K 31 / 444 ( 2006 .01 ) FL (US ) ; Doreen Appunn , Tampa , FL .) U . S . CI. (US ) CPC .. .. .. A61K 31/ 454 ( 2013 .01 ) ; A61K 31/ 444 (2013 .01 ) ; A61K 31/ 55 (2013 .01 ) (21 ) Appl. No. : 15 /583 ,937 ( 22 ) Filed : May 1, 2017 (57 ) ABSTRACT A method of inhibiting or treating chemotherapy - induced Related U . S . Application Data cognitive dysfunction comprising administering a therapeu (63 ) Continuation - in - part of application No . PCT/ US15 / tically effective amount of cotinine to a cancer patient 58625 , filed on Nov . 2 , 2015 . experiencing chemotherapy - induced cognitive dysfunction . Percent of Neurogenesis Genes Changed by Cotinine in Forced Swimming Stress 64 % 36 % W Down Up Patent Application Publication Oct. 19 , 2017 Sheet 1 of 10 US 2017 /0296525 A1 Percent of Inflammation and Autoimmunity Genes Changed By Contine in Forced Swimming Stress 39 % n Down Up A 61% Figure 1 . Patent Application Publication Oct. 19 , 2017 Sheet 2 of 10 US 2017 /0296525 A1 Percent of Neurogenesis Genes Changed by Cotinine in Forced Swimming Stress 64 % 36 % A Down Q Up Figure 2 . Patent Application Publication Oct. 19 , 2017 Sheet 3 of 10 US 2017 /0296525 A1 ACH a7nACAR { ? ??? PI3K ? Akt Ser473 . Ser473 Promotes AKD synaptic plasticity , GSK3 Synaptophysiques and mood GSK3P CREB SmartophysinPSD95 stability Impaired synaptic plasticity and depression Figure 3 . Patent Application Publication Oct. 19 , 2017 Sheet 4 of 10 US 2017 /0296525 A1 Tubulin B Tuan NES s NES + Cot= 5 Figure 4 . Patent Application Publication Oct. 19 , 2017 Sheet 5 of 10 US 2017 /0296525 A1 VEGF DNES + Veh DONES - Cot 5 § NormalizedVEGFlevels(%control) q Figure 5 . Patent Application Publication Oct. 19 , 2017 Sheet 6 of 10 US 2017 /0296525 A1 VEGF ** * * Tubulin B NES FS + Veh FS + Cot 5 Figure 6 . Patent Application Publication Oct. 19 , 2017 Sheet 7 of 10 US 2017 /0296525 A1 VEGF recommend NES 0 FS * Veh . FS * Cot 5 CA NormalizedVEGFlevels (%control) * * * Figure 7 . Patent Application Publication Oct. 19 , 2017 Sheet 8 of 10 US 2017 /0296525 A1 NOS2 VEGFA . ERBB2 . EGE CCRZ FOS CCL2 " XXXXX CCL3 CCR4 * * * * * down - regulation · up - regulation regulation coexpression chemicalmodification physical interaction predicted protein interaction Figure 8 . Patent Application Publication Oct. 19 , 2017 Sheet 9 of 10 US 2017 /0296525 A1 Figure 9A - D Fig . 9A Groups Weeks 1 - 2 Weeks 3 - 4 Week 5 CHEMO + Veh CMF Rest Behav . Test - - Veh M oh the others to the team with the CHEMO + Cot 5 CMF Rest Behav . Test Cot 5 Veh + Veh Rest Behav . Test - - - - one that Veb - - - - - - - - - - - - - Veh + Cot 5 Ven Rest Behav. Test Cot 5 Fig . 9B 325 CMF or VehCot 5 or Veh - Veheth Veh H Vehicle Cot 5 For Veh CMF Veh CMF or Ven - CMF + Cot 5 ** * Weight(g) 250 RE Food Supplement 225 _ 5 10 15 20 25 30 days Fig . 9 C Fig . 9 D * * * Rotarod Porsolt' s test moc med 2009 Veh + Veh et nsen ns Veh + Cot 5 * * * * CMF + Veh qowwKill! (sec) CMF Cot 5 Latencytofall (sec) Patent Application Publication Oct. 19 , 2017 Sheet 10 of 10 US 2017 /0296525 A1 Figure 10A - B Fig . 10 A Familiarization ns Vehi Veh Veh Cot 5 CMF Veh DiscriminationIndex CMF + Cot 5 Fig . 10 B Novel Location Recognition ns Veh + Veh O Veh + Cot 5 CMF + Veh DiscriminationIndex Za CMF 4 Cot 5 o US 2017 /0296525 A1 Oct . 19, 2017 USE OF COTININE IN TREATING OR [ 0007 ] These side effects negatively impact their quality of PREVENTING NEUROGENESIS DEFICITS life , impairing home, educational and occupational activities AND ENHANCING NEUROGENESIS and unnecessarily extend disease - related disabilities (Har rington CB , Hansen JA , Moskowitz M , Todd BL , Feuer [ 0001] This application is an 111a application of PCT / stein M (2010 ) It ' s not over when it ' s over : long - term US2015 /058625 , filed Nov. 2 , 2015 , which claims the ben symptoms in cancer survivors a systematic review . Int J efit of U . S . Provisional Application No. 62 /073 , 339, filed on Psychiatry Med 40 ( 2 ) : 163 - 181) . In addition to cognitive Oct . 31 , 2014 , the contents of all of which are incorporated deterioration , people treated with chemotherapy may have herein by reference in their entireties into the present appli higher risk of developing depression due to physical suffer cation . ing or as a complication of therapy itself. For example , [ 0002 ] This invention was made with government support long - term prophylaxis with tamoxifen , a selective estrogen by the United States Department of Veterans Affairs . The receptor modulator commonly used for the hormone recep government has certain rights in the invention . tor- positive breast cancer , has been associated with a higher [0003 ] Throughout this application various publications risk of developing depressive symptoms and cognitive dys are referenced . The disclosures of these publications in their function (Seliktar N , Polek C , Brooks A , Hardie T (2015 ) entireties are hereby incorporated by reference into this Cognition in breast cancer survivors : hormones versus application in order to more fully describe the state of the art depression . Psychooncology 24 ( 4 ) : 402 -407 ) . Currently , to which this invention pertains. there are no completely safe and effective treatments against these side effects ( Joly F , Rigal O , Noal S , Giffard B ( 2011 ) FIELD OF THE INVENTION Cognitive dysfunction and cancer : which consequences in terms of disease management ? Psychooncology 20 ( 12 ) : [0004 ] This invention relates to treatment of chemo 1251 - 1258 ) . Most memory enhancers currently available therapy or stress - related side effects . More specifically, the have significant side effects or limited efficacy in cancer present invention provides therapeutic methods and compo patients . For example , donepezil, a pro - cholinergic drug , has sitions for treating chemotherapy treatment or reducing been studied at the preclinical level , but the attempts to show stress - related neuro - inflammation . efficacy in humans have been unsuccessful ( Fardell J E , Vardy J , Johnston IN , Winocur G ( 2011 ) Chemotherapy and BACKGROUND OF THE INVENTION cognitive impairment: treatment options . Clin Pharmacol [0005 ] Cancer is a group of diseases characterized by Ther 90 ( 3 ) : 366 - 376 ) . uncontrolled growth and dissemination of abnormal cells . It [0008 ] One of the main concerns when selecting an anti was estimated that in 2008 there were 12 . 7 million new depressant is the potential effect that the drug can have on cancer cases worldwide (Belcher E C -GK , Desantis C , the effectiveness or toxicity of the chemotherapeutic regime. Edwards B , Ferlay J , Forman D , Grey N , Harford J , Kramer For example , treatment of depression in a patient treated J , McMikel A , McNeal B , O 'Brien M , Pace L , Parkin M , with tamoxifen can be complicated by drug interactions. Robbins A , Sankaranarayanan R , Sitas F , Slona R , Sullivan Tamoxifen is a mainly inactive pro - drug, necessitating K , Wagner D , Ward E ( 2011 ) Global cancer facts and metabolism by the cytochrome P450 (CYP ) pathway, into its Figures , 2nd edn . American Cancer Society , Atlanta ) . For active metabolites , 4 - hydroxytamoxifen and endoxifen , to many patients afflicted with malignancies , chemotherapy achieve its therapeutic effect. Some antidepressants such as offers the best options for disease control. Though chemo the selective serotonin reuptake inhibitors (SSRI ) paroxetine therapy is an effective way to treat many types of cancer, it and fluoxetine affect the chemotherapy effectiveness by also carries negative side effects . Patients treated with che inhibiting the CYPD6 enzyme which metabolizes tamoxifen motherapy are at an increased risk of altered brain structure to its more active metabolites ( Brauch H , Miirdter T E , and function (de Ruiter M B , Reneman L , Boogerd W , Eichelbaum M , Schwab M ( 2009 ) Pharmacogenomics of Veltman DJ, van Dam F S , Nederveen AJ, Boven E , tamoxifen therapy. Clin Chem 55 ( 10 ) : 1770 - 1782 ) . Schagen S B (2011 ) Cerebral hyporesponsiveness and cog [0009 ] Brain magnetic resonance imaging (MRI ) analysis nitive impairment 10 years after chemotherapy for breast in patients treated with high -dose chemotherapy showed cancer . Hum Brain Mapp 32 ( 8 ) : 1206 - 1219 ) . Neurological white matter lesions that correlated with greater neurocog abnormalities after chemotherapy might result from chemi nitive decline (Fouladi M , Chintagumpala M , Laningham F cal neurotoxicity , indirect oxidative damage, inflammation H , Ashley D , Kellie S J , Langston J W , McCluggage CW , or a type of autoimmune response . Clinical studies indicated Woo S , Kocak M , Krull K , Kun L E , Mulhern RK , Gajjar that up to 70 % of cancer patients who received chemo A (2004 ) White matter lesions detected by magnetic reso therapy experience cognitive impairment and other symp nance imaging after radiotherapy and high - dose chemo toms such as fatigue