TOMMUNICIUNUS009808444B2 CLOU UN TAI TAI MAN UNITED (12 ) United States Patent (10 ) Patent No. : US 9 ,808 , 444 B2 Arnou (45 ) Date of Patent : Nov. 7 , 2017 ( 54 ) METHODS FOR RESTORATION OF on Aug. 20 , 2013 , provisional application No . HISTAMINE BALANCE 62 / 002 ,613 , filed on May 23, 2014 . @(71 ) Applicant : BioHealthonomics Inc. , Santa Monica , ( ) Int. Cl. CA (US ) A61K 31/ 417 ( 2006 . 01 ) A61K 45 / 06 ( 2006 .01 ) @(72 ) Inventor : Cristian Arnou , Santa Monica , CA (52 ) U .S . CI. (US ) CPC .. .. A61K 31/ 417 ( 2013. 01 ); A61K 45/ 06 ( 2013 .01 ) @(73 ) Assignee : BioHealthonomics Inc. , Santa Monica , (58 ) Field of Classification Search CA (US ) USPC .. .. .. 514 / 400 See application file for complete search history . @( * ) Notice : Subject to any disclaimer , the term of this patent is extended or adjusted under 35 (56 ) U . S . C . 154 (b ) by 0 days . References Cited U . S . PATENT DOCUMENTS (21 ) Appl. No. : 15 /341 ,839 9 ,511 ,054 B2 * 12 /2016 Arnou .. .. A61K 31/ 417 ( 22 ) Filed : Nov . 2 , 2016 * cited by examiner (65 ) Prior Publication Data Primary Examiner — Rei - Tsang Shiao US 2017 /0266163 A1 Sep . 21 , 2017 (74 ) Attorney , Agent, or Firm — Knobbe Martens Olson & Bear LLP Related U . S . Application Data (63 ) Continuation of application No. 14 /684 , 174 , filed on (57 ) ABSTRACT Apr. 10 , 2015 , now Pat. No. 9 ,511 , 054 , which is a Several embodiments provided herein relate to histamine continuation of application No. 14 / 315 , 206 , filed on dosing regimens are and uses of such regimens in the Jun . 25 , 2014 , now Pat. No . 9 ,023 ,881 , which is a restoration of histamine balance in subjects suffering from , continuation - in -part of application No . for example , histapenia and /or histadelia . Several embodi ments also relate to the use of histamine dosing regimens for PCT/ US2013 / 046420 , filed on Jun . 18 , 2013 . the treatment and /or prevention of migraine headaches. (60 ) Provisional application No . 61/ 733 ,630 , filed on Dec. 5 , 2012 , provisional application No . 61 /867 , 966 , filed 18 Claims, 7 Drawing Sheets atent Nov . 7 , 2017 Sheet 1 of 7 US 9 ,808 , 444 B2 N NH2 Figure 1 atent Nov . 7 , 2017 Sheet 2 of 7 US 9 ,808 ,444 B2 Diarrhea Stomachache, cramps Contributiontothe regulationof bodytemperature, foodintake, locomotion, learning,memory Mastcellsecretion Leukocytes Meteorism (Gastrointestinum) 10- Gastricacid CAMP secretion panahonCircadianrhythm,arousal BoneMarrow CGMP Uterus H2 Smoothmuscleconstriction Dysmenorrhea 10.Regulationof 699601 H1 (hematopoiesis Estrogen H3 Nausea,vomitus HISTAMINE Mucus Bronchoconstriction,dyspnea release H12/( secretion Neurotransmitter H1/2 H1 mgasamasamangCentral nervoussystem tract Tachycardia, Endothelial permeability Respiratory Vasodilatation Arrhythmias Stimulationof nociceptive nervefibres Headache system Skin Congestionofthenose, rhinorrhea,sneezing Vertigo Hypotonia, Cardiovascular Hypertension Ana phylaxia Arrhythmia Pruritus Flush Urticaria FIG.2 atent Nov . 7 , 2017 Sheet 3 of 7 US 9 ,808 , 444 B2 Extracellular 7 1 A m 14 IntracellularIntracellular LLLLLLL 12* H1Ho+ Gay H3 and H4 " PLC AC PKC Ca ??? Biological Effects Figure 3 atent Nov . 7 , 2017 Sheet 4 of 7 US 9 ,808 , 444 B2 .! ! Dr.C !.4 A. Serum Histamine Levels During Symptom - Free . States . ! . ! . ! .! ! ! . W :/!. ! W (ng/mL) .! K W. U !: W SerumHistamingConcentration :. RSSITARIAMS:* : w .! : Healthy ( n =45 ) Migraine ( n = 28) Migraine + Allergy ! :/* ( n = 42 ) ! Figure 4 atent Nov . 7 , 2017 Sheet 5 of 7 US 9 ,808 , 444 B2 A :797 r .: !. : . : . Serum Histamine Levels During Migraine Events : .: . : : . 180 .: .: . *. :. 160 . : . * *. .: . : . : . : . : . .:* (10/8) : :. gooåo * . .: * : uonenju?buoyBurwers!HWnjas 3:. : : .: : : : .: : : :. moderne de porno con :. .: . : . .: .150: */:.! :. Healthy ( n = 45) Migraine ( n = 28 ) Migraine + : ! : Allergy ( n = 42 ) !. .* Figure 5 U. S. Patent atent Nov . 7 , 2017 Sheet 6 of 7 US 9 , 808, 444 B2 Brain Histamine Levels in Patients withi Parkinson ' s vs . Healthy Subjects S . Healthy ( N = 27) 2 . 2 Parkinson ' s Disease 4 2 1 . 58 BrainHistamineLevelspmol(/mg) ?? 1 . 25 1 : 06 1 0 . 66 Putam 1 retinte Substanta 3 Bilidus Externalpallidus ( p = 0 .0005 ) ( p = 0 .002 ) Figure 6 : Brain Histamine Levels in Patients with Parkinson ' s vs . Healthy Subjects Brain Histamine Concentration Sed5VS i Healthy ( N = 8 ) . Alzheimer' s ( N = 6 ). DU00 bile . stamine. PERU . du# PonsPo ) Motorcortex Postcentral(FoxA4 )cyrus (PCXA1Posterior ,2) paratal cortex ?.33?e?? ?34c3e425 Nucleus{?? }& cumbens Anterior(NAC ) thalamus Posterior(AT ) thaiamus (PT snidwesoddtw) )dra Medullaoblongata (MO ) Figure 7 : Brain Histamine Concentration in Patients with Alzheimer ' s Disease vs . Healthy Population U .S . Patentatent Nov . 7 , 2017 Sheet 7 of 7 US 9 , 808, 444 B2 Histamine Blood Concentration i 1 90 . 85 mL)BloodConcentration(ng/Histamine 79 . 5 44 . 87 Healthy ( n = 32 ) Stable Coronary Artery Acute Coronary Syndrome, Acute Coronary Syndrome, Disease ( SCAD , n = 28 ) Nonocclusive Type ( ACS UA , Occlusive Type ( ACS STEMI, m = 26 ) 37 ) Figure 8 : Histamine Blood Concentration in Patients with Coronary Disease vs . Healthy Population Plasma Histamine Level Myelogenous Leukemia Patients vs . Healthy 19 . 6 Vice 15 0 . 49 e . eusejd 7 . 6 O . Healthy ??? ?ye ?????? ?? ????? : 3 Cat????? ??y???? ???? ?ds tefker??ta ( N = 10 ) ( N - 13 ) Figure 9 : Plasma Histamine Levels in Patients with Myelogenous Leukemia vs. Healthy Population US 9 , 808 , 444 B2 METHODS FOR RESTORATION OF mine agonists and antagonists , naturally -occurring or syn HISTAMINE BALANCE thetic , are provided in several embodiments . For example , in one embodiment , titrated histamine dosing regimens are RELATED CASES used to restore normal histamine function . The dosing 5 regimens are useful, in several embodiments , for restoring This application is a continuation of U . S . patent applica - histamine function in patients having deficient or excessive tion Ser . No. 14 /684 , 174 , filed Apr. 10 , 2015 , which is a levels of histamine, and can be used to treat or prevent any continuation of U . S . patent application Ser. No . 14 /315 , 206 , disorders in which histamine imbalance plays a causative now U . S . Pat . No. 9 ,023 ,881 , filed Jun . 25 , 2014 , which is role . a continuation in part of International Application No. 10 Although histamine is used as the therapeutic agent in PCT/ US2013 /046420 , filed Jun . 18 , 2013 , which claims the many embodiments , the invention is not limited to the benefit of U . S . Provisional Application No . 61 / 733 ,630 , filed administration of histamine . For example , therapeutic agents Dec . 5 . 2012 . U . S . patent application Ser . No . 14 / 315 .206 thatmimic the effects of histamine are used in some embodi also claims the benefit of U . S . Provisional Application No . ments . Histamine agonists , antagonists , and other agents that 61 /867 , 966 , filed on Aug . 20 , 2013 and U . S . Provisional 15 interact or interfere with histamine receptors are used as Application No . 62 / 002, 613 , filed on May 23 , 2014 . The therapeutic agents in several embodiments . Therapeutic entire disclosure of each of the applications listed above is agents may , for example , provide stop the progression of incorporated by reference herein . symptoms, or may reduce or prevent the onset or severity of symptoms. A surprising versatile dosing regimen has been BACKGROUND 20 developed for the administration of histamine , or other therapeutic agent, that relies, in several embodiments , on Field sequential dosing segments . In several embodiments , each Several embodiments of the present invention relate gen segment includes a plurality of escalating doses. For erally to methods for the restoration of histamine balance . In example , in one embodiment, the regimen comprises a particular , several embodiments related restoring histamine 25 plurality of dosing segments, each comprising a plurality of levels to normal ranges in order to treat various illnesses or doses, wherein each segment is defined by the same volume disorders . for every dose and the same time interval between every Description of the Related Art dose , but concentrations of the therapeutic agent ( e . g . , Histamine , also referred to chemically as 2 - ( 1H - imidazol- histamine ) are increased from dose to dose , and each suc 4 - yl) ethanamine is composed of an imidazole ring and an 30 cessive segment is defined by a greater dosing volume than amino group connected by a chain of two carbon atoms ( see the previous segment and a longer time interval between FIG . 1 ) . Histamine is the decarboxylation product of the doses. The administration of histamine or other therapeutic amino acid histidine and is associated with local immune agent, as used herein , includes the administration of its responses to foreign pathogens . For example , the granules of pharmaceutically acceptable salt ( such as , for example , mast cells or white blood cells generate and / or store hista - 35 histamine phosphate , histamine dihydrochloride or any other mine which is released upon injury or exposure to allergens. histamine salt ) . Thus , references to the administration of Histamine also functions as a neurotransmitter and plays a histamine encompass the administration of pharmacologi role in the pathways of gastric acid secretion in the stomach . cally acceptable salts and forms in several embodiments . A histamine receptor activator includes but is not limited