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(12) Patent Application Publication (10) Pub. No.: US 2015/0209331 A1 Arnou (43) Pub US 20150209331A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0209331 A1 Arnou (43) Pub. Date: Jul. 30, 2015 (54) HISTAMINE BALANCE RESTORATION on Aug. 20, 2013, provisional application No. 62/002, METHODS 613, filed on May 23, 2014. (71) Applicant: BioHealthonomics Inc., Santa Monica, Publication Classification CA (US) (51) Int. Cl. (72) Inventor: Cristian Arnou, Santa Monica, CA (US) A613 L/47 (2006.01) A6II 45/06 (2006.01) (21) Appl. No.: 14/684,174 (52) U.S. Cl. CPC ............... A61K 31/417 (2013.01); A61K 45/06 Related U.S. Application Data (57) ABSTRACT (63) Continuation of application No. 14/315,206, filed O Several embodiments provided herein relate to histamine Jun. 25, 2014, now Pat. No. 9,023,881, which is a dosing regimens are and uses of Such regimens in the resto continuation-in-part of application No. PCT/US2013/ ration of histamine balance in Subjects Suffering from, for 046420, filed on Jun. 18, 2013. example, histapenia and/or histadelia. Several embodiments (60) Provisional application No. 61/733,630, filed on Dec. also relate to the use of histamine dosing regimens for the 5, 2012, provisional application No. 61/867,966, filed treatment and/or prevention of migraine headaches. Patent Application Publication Jul. 30, 2015 Sheet 1 of 7 US 2015/0209331 A1 HN NH2 Figure 1 Patent Application Publication US 2015/0209331 A1 '9?02UOBUJOS SduJeJOGae) Patent Application Publication Jul. 30, 2015 Sheet 3 of 7 US 2015/0209331 A1 Extracellular Intracellular PLC AC 4 N . PKC Ca PKA Biological Effects Figure 3 Patent Application Publication Jul. 30, 2015 Sheet 4 of 7 US 2015/0209331 A1 Serum Histamine Levels During Symptom-Free States 1OO 90 8O WO 6O SO AO 3O 2O 1O Migraine (n=28) Migraine + Allergy (n=42) Figure 4 Patent Application Publication Jul. 30, 2015 Sheet 5 of 7 US 2015/0209331 A1 Healthy (n=45) Migraine (n=28) Migraine + Allergy (n =42) Figure 5 Patent Application Publication Jul. 30, 2015 Sheet 6 of 7 US 2015/0209331 A1 Brait is airie Lewes in Patients with Parkinsor's wis, Healthy Subjects Healthy Na2. : Parkinson's Disease Na24 E s . Putary ps, Sustantia nigra pie. (3 literial pallicits Exter aii: p:0.0005) p:0.02 Figure 6: Brain Histamine Levels in Patients with Parkinson's vs, Healthy Subjects Brain. Histamine Concentration Alzheimer's Disease vs. Healthy Population & siggittsy is: ... Alzheirner's. Nié) Figure 7: Brain Histamine Concentration in Patients with Alzheimer's Disease vs. Healthy Population Patent Application Publication Jul. 30, 2015 Sheet 7 of 7 US 2015/0209331 A1 Histamine Blood Concentration Coronary Disease Patients vs. Healthy 79.5 it is State of it. ." at Calify yet is tie is firgi's rid Ir, s: St. ii. 8. Nrisis. ... , is . S.S., 2. 3.35 Figure 8: Histamine Blood Concentration in Patients with Coronary Disease vs. Healthy Population Plasma. Histamine Leve Myelogenous Leukemia Patients vs. Healthy 19.6 7.6 Healthy Acute Myelogerous leukemia Chronic Myelogenous leukemia (Ns 10) (Nas13) Figure 9: Plasma Histamine Levels in Patients with Myelogenous Leukemia vs. Healthy Population US 2015/0209331 A1 Jul. 30, 2015 HISTAMINE BALANCE RESTORATION one embodiment, titrated histamine dosing regimens are used METHODS to restore normal histamine function. The dosing regimens are useful, in several embodiments, for restoring histamine RELATED CASES function in patients having deficient or excessive levels of 0001. This application is a continuation of U.S. patent histamine, and can be used to treat or prevent any disorders in application Ser. No. 14/315,206, filed Jun. 25, 2014, which is which histamine imbalance plays a causative role. a continuation in part of International Application No. PCT/ 0008 Although histamine is used as the therapeutic agent US2013/046420, filed Jun. 18, 2013, which claims the benefit in many embodiments, the invention is not limited to the of U.S. Provisional Application No. 61/733,630, filed Dec. 5, administration of histamine. For example, therapeutic agents 2012. This application also claims the benefit of U.S. Provi that mimic the effects of histamine are used in some embodi sional Application No. 61/867,966, filed on Aug. 20, 2013 ments. Histamine agonists, antagonists, and other agents that and U.S. Provisional Application No. 62/002,613, filed on interact or interfere with histamine receptors are used as May 23, 2014. The entire disclosure of each of the applica therapeutic agents in several embodiments. Therapeutic tions listed above is incorporated by reference herein. agents may, for example, provide stop the progression of symptoms, or may reduce or prevent the onset or severity of BACKGROUND symptoms. A Surprising versatile dosing regimen has been developed for the administration of histamine, or other thera 0002 1. Field peutic agent, that relies, in several embodiments, on sequen 0003. Several embodiments of the present invention relate tial dosing segments. In several embodiments, each segment generally to methods for the restoration of histamine balance. includes a plurality of escalating doses. For example, in one In particular, several embodiments related restoring hista embodiment, the regimen comprises a plurality of dosing mine levels to normal ranges in order to treat various illnesses segments, each comprising a plurality of doses, wherein each or disorders. segment is defined by the same volume for every dose and the 0004 2. Description of the Related Art same time interval between every dose, but concentrations of 0005. Histamine, also referred to chemically as 2-(1H the therapeutic agent (e.g., histamine) are increased from imidazol-4-yl)ethanamine is composed of an imidazole ring dose to dose, and each Successive segment is defined by a and an amino group connected by a chain of two carbonatoms greater dosing Volume than the previous segment and alonger (see FIG. 1). Histamine is the decarboxylation product of the time interval between doses. The administration of histamine amino acid histidine and is associated with local immune or other therapeutic agent, as used herein, includes the admin responses to foreign pathogens. For example, the granules of istration of its pharmaceutically acceptable salt (such as, for mast cells or white blood cells generate and/or store hista example, histamine phosphate, histamine dihydrochloride or mine which is released upon injury or exposure to allergens. any other histamine salt). Thus, references to the administra Histamine also functions as a neurotransmitter and plays a tion of histamine encompass the administration of pharma role in the pathways of gastric acid secretion in the stomach. cologically acceptable salts and forms in several embodi ments. A histamine receptor activator includes but is not SUMMARY limited to histamine (and its pharmacologically acceptable 0006 Dysregulation or imbalances of the histamine sys salts and other forms). Moreover, in several embodiments, tem can be a leading contributor to a variety of disease states adjunct therapeutic interventions are used, either in place of and symptoms, many of which can be debilitating or life or in conjunction with administration of histamine and/or an disruptive. For example, abnormally high histamine levels additional therapeutic agent. For example, in several embodi can lead to excessive allergies (or hyperactive responses to ments, an electromagnetic device is used to generate a mag allergens), hyperactivity, compulsive or obsessive behavior, netic field that can be focused (or applied diffusely) to a Vertigo, inner ear pressure, depression, anxiety, panic attacks, Subject having imbalanced histamine levels. In several migraine headaches, heightened emotional sensitivity and/or embodiments, electromagnetic energy is delivered to a Sub Suicidal tendencies. Reduced histamine levels can lead to ject to return histamine levels to within normal ranges. In depressed metabolism and/or weight gain, paranoia, grandi Some embodiments, the electromagnetic energy is tailored osity, hallucinations (e.g., classic Schizophrenic symptoms), (e.g., by frequency, wavelength, field strength, etc.) to target tinnitus, hirsutism, visual and auditory abnormalities, anxiety one or more specific histamine receptors. In several embodi and food sensitivities. The potential costs (both emotional ments, the use of electromagnetic devices acts synergistically and financial) of histamine imbalance, be they to an indi with administration of histamine to return histamine levels to vidual person or family, related to societal lost productivity normal ranges. However, as discussed above, in several and/or burdens on the medical system, are immense. In 2012 embodiments, such devices are used independent of hista America will have spent $200 billion in direct costs for those mine administration (or administration of other therapeutic with Alzheimer's Disease. Caring for people with Alzhe agents). imer's Disease is estimated to cost at least S20 trillion over the 0009. Thus, in several embodiments, the invention com next 40 years. Furthermore, the economic burden of Parkin prises or consists essentially of an escalating dosing regimen sons disease is at least S14.4 billion a year with an estimate comprising in sequential order (a) a first dosing segment that the prevalence of Parkinson's disease will more than comprising two or more sequential doses of a therapeutic double by year 2040. agent (e.g., histamine) separated by one or more equal time 0007. Several embodiments of the present invention relate intervals (the “first time interval”), wherein the doses increase to the use of agents that up-regulate or down-regulate expres in histamine concentration from dose to dose while the sion and/or activity of one or more histamine receptors. His administered Volume of each dose stays constant; and (b) a tamine agonists and antagonists, naturally-occurring or syn second dosing segment comprising two or more sequential thetic, are provided in several embodiments. For example, in doses ofatherapeutic agent (e.g., histamine) separated by one US 2015/0209331 A1 Jul. 30, 2015 or more equal time intervals (the “second time interval’).
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