JP6395720B2 - How to restore histamine equilibrium - Google Patents

Description

Cross-reference of related applications

  This application claims the benefit of US Provisional Patent Application No. 61 / 733,630, dated December 5, 2012, the entire disclosure of which is incorporated herein by reference.

  Some embodiments of the invention generally relate to methods of restoring histamine equilibrium. In particular, some embodiments relate to restoring histamine levels to a normal range to treat various diseases or disorders.

  Histamine, chemically referred to as 2- (1H-imidazol-4-yl) ethanamine, is composed of an imidazole ring and an amino group linked by a chain of two carbon atoms (see FIG. 1). Histamine is the decarboxylation product of the amino acid histidine and is associated with a local immune response against foreign pathogens. For example, mast cell or leukocyte granules produce and / or accumulate histamine that is released upon injury or exposure to allergens. Histamine also functions as a neurotransmitter and plays a role in the gastric acid secretion pathway in the stomach.

  Dysregulation or imbalance of the histamine system can be a major cause of various pathologies and symptoms, many of which can be debilitating or life-threatening. For example, abnormally high histamine levels can cause excessive allergies (or excessive responses to allergens), hyperactivity, forced or compulsive behavior, dizziness, inner ear pressure, depression, anxiety, panic attacks, migraine, emotional sensitivity It can result in sensitization and / or a desire for suicide. Lowering histamine levels can lead to decreased metabolism and / or weight gain, paranoia, exaggeration, hallucinations (eg, classic schizophrenia symptoms), tinnitus, hirsutism, visual and auditory abnormalities, anxiety and food hypersensitivity. The potential costs (both emotional and financial) of histamine imbalance, related to lost social productivity and / or burden on the health care system, for individuals and for families Even so, it is immeasurable.

  Some embodiments of the invention relate to the use of agents that upregulate or downregulate the expression and / or activity of one or more histamine receptors. Naturally occurring or synthetic histamine agonists and antagonists are provided in some embodiments. For example, in one embodiment, histamine dose escalation is used to restore normal histamine function. In some embodiments, dosing regimens for restoring histamine function are useful in patients with insufficient or excessive histamine levels, and these dosing regimens play a role due to histamine imbalance. It can be used to treat or prevent any disorder that is present.

  While histamine is used as a therapeutic agent in many embodiments, the present invention is not limited to administration of histamine. For example, a therapeutic agent that mimics the effect of histamine is used in some embodiments. Histamine agonists, antagonists, and other agents that interact with or interfere with histamine receptors are used as therapeutic agents in some embodiments. The therapeutic agent can, for example, cause cessation of symptom progression or reduce or prevent the onset or severity of symptoms. A surprisingly versatile dosing regime has been developed for the administration of histamine or other therapeutic agents, which in some embodiments relies on sequential dosing segments. In some embodiments, each segment includes multiple incremental doses. For example, in one embodiment, a dosing regimen includes multiple dosing segments, each including multiple doses, each segment being defined by the same volume for any dose and the same time interval between any doses. The concentration of therapeutic agent (eg, histamine) is increased from dose to dose, with each successive segment being defined by a larger dosage volume and longer time interval between doses than the previous segment. As used herein, administration of histamine or other therapeutic agent includes administration of a pharmaceutically acceptable salt thereof, such as histamine phosphate, histamine dihydrochloride or any other histamine salt. Including. That is, histamine administration includes administration of pharmacologically acceptable salts and forms in some embodiments. Histamine receptor activators include, but are not limited to, histamine (and pharmacologically acceptable salts and other forms thereof).

  That is, in some embodiments, the invention includes (a) a first comprising two or more sequential doses of a therapeutic agent (eg, histamine) spaced one or more equal time intervals (“first time interval”). A first dosing segment in which the dose volume of each dose remains constant while the dose volume increases with each dose, and (b) one or more equal time intervals (“second time”) A second dosing segment that includes two or more sequential doses of a therapeutic agent (eg, histamine) spaced apart)), with doses increasing in concentration with each dose, while the dose volume of each dose remains constant An incremental dosing regimen that sequentially includes a second dosing segment, wherein the volume of each dose in the second dosing segment is greater than the volume of each dose in the first dosing segment, and the second time interval is the first time interval Contain a longer escalating dosing regimen or this Essentially constituted by a drug regimen. In some embodiments, the present invention includes a multivariate approach to increase or decrease histamine levels. The multivariate approach is beneficial in some embodiments because physiological parameters can be finely tuned. For example, regulating cell distribution and receptor contact so that selective activation of certain histamine receptors is achieved and other histamine receptors remain substantially unaffected. it can.

In some embodiments, the present invention provides (i) administering to a subject a first dose of a therapeutic agent (eg, histamine or histamine salt) in the range of 0.01 pg to 10 pg, thereby providing histamine H3 receptor and histamine H4. Activating a histamine receptor selected from the group consisting of at least one of the receptors, (ii) administering at least one of the histamine H3 receptor and the histamine H4 receptor by administering a second dose of the therapeutic agent. Activating a histamine receptor selected from the group consisting of: (iii) activating a histamine H1 receptor by administering a third dose of a therapeutic agent; and (iv) a fourth dose of a therapeutic agent. A first therapeutic zone comprising or consisting essentially of activating the histamine H2 receptor by administering Including the application of. A second treatment segment with an individual dose is further applied where the total amount of therapeutic agent is greater than the total amount given in the first treatment segment. A third treatment segment with an individual dose is further applied where the total amount of therapeutic agent is greater than the total amount given in the second treatment segment. Treatment categories such as fourth, fifth, sixth, etc. with escalation of the total dose may also be applied if desired. In one embodiment, the present invention ranges from about 200 ng to 600 ng for the first treatment segment, about twice that in the second treatment segment, and (as compared to the second treatment segment) in the third treatment segment. A kit or regime containing or consisting essentially of a therapeutic agent (eg, histamine or histamine salt) provided in a total volume of about 5 times (which can be provided in a single disposable vial, syringe or ampoule) ). As an example, if the total amount of treatment segment is 1000 ng, 4 vials of individual doses of 1 ng, 10 ng, 100 ng and 889 ng may be provided. The volume of these doses is also modified in some embodiments. Various volumes are particularly beneficial in some embodiments, as increasing volume results in different distributions and / or pharmacokinetic profiles. In some embodiments, the ratio of the total amount given in each treatment category is 1: 2: 3 (for 3 categories), 1: 2: 3: 4 (for 4 categories), 1: 2: 3 : 4: 5 (in the case of 5 categories). In some embodiments, the ratio of individual doses within a given treatment category is 1:10 ³ : 10 ⁶ : 3.5 × 10 ⁶ .

  In some embodiments, the method is used to treat histamine imbalance (this imbalance is a sub-optimal or sub-optimal histamine level in the bloodstream and / or urine, and / or histamine imbalance). As evidenced by other symptoms or characteristics). Thus, in some embodiments, a method of reducing histamine levels in a subject (eg, a human patient) having a histamine level higher than that required for optimal histamine function (as in histadelia), comprising: There is provided a method comprising administering histamine to said subject according to a dosing regime disclosed herein.

  As used herein, the terms “treat” and “treatment” shall be given their ordinary meanings, and these terms shall also cure, improve, stabilize the disease, pathological condition or disorder. Treatment of the patient with the intention of becoming or blocking. These terms refer to aggressive therapy (eg, treatment specifically directed to ameliorating the disease, pathological condition or disorder) and causal therapy (eg, treatment directed to eliminating the cause of the related disease, pathological condition or disorder). including. In addition, these terms also refer to palliative treatment (eg, treatment designed to alleviate symptoms), prophylactic treatment (eg, minimizing the occurrence of related diseases, pathological conditions or disorders, or Treatments directed to complete or complete inhibition) and supportive therapies (eg, treatments taken to supplement other specific therapies directed to ameliorating related diseases, morbidity or disorders).

  In some embodiments, the present invention includes selective activation and inactivation of histamine receptors, ie, H1, H2, H3 and H4. In some embodiments, histamine or other that binds to or blocks these receptors, or increases or decreases the ability of histamine (endogenous or exogenous histamine) to bind to the receptor. Use the therapeutic agent. In some embodiments, the invention includes down-regulation of the H1 receptor and up-regulation of one, two or all of the H2, H3 and H4 receptors. In some embodiments, the present invention includes therapeutic agents that modulate the endogenous histamine system. These therapeutic agents are provided in the dosing schedules described herein according to some embodiments. Accordingly, therapeutic agents are provided that increase or decrease histamine production, release, modification, uptake or degradation without (or in addition to) directly affecting histamine receptors. In one embodiment, a selective histamine reuptake inhibitor is used. In some embodiments, a therapeutic agent that up-regulates or down-regulates methyltransferase and / or diamine oxidase is used to reduce or increase endogenous histamine. In some embodiments, compositions comprising methyltransferase and / or diamine oxidase, or agents with similar functions are provided.

  In some embodiments, a therapeutic agent is provided that modulates endogenous GABA, which GABA affects the endogenous release of histamine. In one embodiment, histamine release is modulated by endogenous GABA through GABA-A and / or GABA-B receptors. In one embodiment, therapeutic agents are provided that modulate GABA-B receptors or other receptors located at histaminergic nerve terminals that modulate histamine release (eg, pre-synaptic or post-synaptic).

  In some embodiments, a method of increasing histamine levels in a subject (eg, a human patient) having a histamine level lower than that required for optimal histamine function (as in histapenia), comprising: Also provided are methods comprising administering to a subject a therapeutically effective amount of a therapeutic agent (eg, histamine) according to a dosing regime disclosed in the document. As used herein, the term “therapeutically effective amount” shall be given its ordinary meaning, which term also includes an amount of the therapeutic agent sufficient to elicit the desired biological response. Shall. Depending on the embodiment, the therapeutically effective amount may vary depending on the patient's age, gender and weight, and / or the patient's current medical condition.

  In some embodiments, a method of restoring histamine balance in a subject by normalizing histamine receptor activity through multiple doses administered in a continuous treatment segment, the first treatment segment, ie, a first dose. Activating one or more of histamine H3 receptor and histamine H4 receptor by administering to the subject one of the histamine receptor activators, and administering a second dose of histamine receptor activator to the subject Activating one or more of the histamine H3 receptor and the histamine H4 receptor, activating the histamine H1 receptor by administering a third dose of a histamine receptor activator to the subject, Activating histamine H2 receptor by administering to a subject a fourth dose of histamine receptor activator Applying a first treatment category, and applying a second treatment category comprising administering a greater amount of histamine receptor activator than the dose in the first treatment category, and in the second treatment category Also provided is a method comprising applying a third treatment category comprising administering a histamine receptor activator in an amount greater than the dose of. In some embodiments, the increased dose of histamine receptor activator in each successive treatment segment suppresses histamine H1 receptor activity and is selected from the group consisting of histamine H2, H3 and H4 receptors Histamine receptor activity is increased, thereby normalizing the activity of the histamine receptor, thereby restoring histamine equilibrium.

  In some embodiments, a method of restoring histamine balance in a subject by normalizing histamine receptor activity through multiple doses administered in a continuous treatment section, wherein the first treatment section is histamine H3 receptor. Administering to a subject a first dose of a therapeutic agent that binds to a histamine receptor selected from the group consisting of a body and a histamine H4 receptor (by administering a first dose of the therapeutic agent to the subject), histamine H3 receptor Administering to a subject a second dose of a therapeutic agent that binds to a histamine receptor selected from the group consisting of a body and a histamine H4 receptor (by administering a second dose of the therapeutic agent to the subject), histamine H1 receptor Administering to a subject a first dose of a therapeutic agent that binds to the body (by administering a third dose of the therapeutic agent to the subject), histamine Applying to a subject a first treatment category comprising administering to a subject a first dose of a therapeutic agent that binds to two receptors (by administering a fourth dose of the therapeutic agent to the subject), a second treatment category I.e., applying to the subject a second treatment category comprising administering a greater amount of therapeutic agent than the dose in the first treatment category, and more than the dose in the third treatment category, i.e. the second treatment category. Also provided is a method comprising applying to a subject a third treatment segment that includes administering a large amount of a therapeutic agent.

  Also, in some embodiments, a method of down-regulating histamine H1 receptor, the first dose of a therapeutic agent binding to a histamine receptor selected from the group consisting of histamine H3 receptor and histamine H4 receptor A second therapeutic agent that binds to a histamine receptor selected from the group consisting of a histamine H3 receptor and a histamine H4 receptor (by administering to the subject a first dose of the therapeutic agent). Administering a dose to a subject (by administering a second dose of the therapeutic agent to the subject), administering a first dose of a therapeutic agent that binds to the histamine H1 receptor to the subject (third dose of the treatment) Administering a first dose of a therapeutic agent that binds to the histamine H2 receptor to the subject (a fourth dose of the therapeutic agent is administered to the subject). Subject to the second treatment category, including applying the first treatment category, and administering the second (treatment) category, ie, administering a larger amount of therapeutic agent than the dose in the first treatment category. And applying to the third treatment category, ie, the third treatment category, ie, administering the third treatment category comprising administering a larger amount of the therapeutic agent than the dose in the second treatment category. The histamine H1 receptor activity is down-regulated by the increasing dose of therapeutic agent in each successive treatment category. If desired, additional treatment categories can be applied as well.

  In some embodiments, the histamine receptor activator is altered concentration (eg, increased concentration compared to previous administration), altered volume (eg, increased concentration compared to previous administration). Or at one or more of the modified timings (eg, the frequency of administration is reduced in successive segments). In some embodiments, a trivariate approach is beneficial because cell distribution and receptor contact can be adjusted. In this way, selective activation of the receptor can be achieved. Furthermore, in some embodiments, the order of receptor activation can be altered depending on the condition being treated. For example, in some embodiments, the therapeutic agent preferentially activates or binds preferentially to the H1 receptor and increases histamine levels in the subject (eg, histapenia). It can be administered at a sufficient dose (to treat). Alternatively, the therapeutic agent may be administered at a dose sufficient to preferentially activate or bind to the H3 receptor (in some embodiments, eg, Histaderia). Inhibiting histamine H1 receptor activity and / or expression, such as when treating, causes a decrease in histamine levels).

  In some embodiments, the therapeutic agent and / or histamine receptor activator comprises histamine. In some embodiments, the histamine receptor activator comprises a histamine salt selected from the group consisting of histamine diphosphate, histamine phosphate and histamine dihydrochloride. In some embodiments, combinations of these salts or other various salts of histamine may be used.

  In some embodiments, the continuous treatment category (eg, second, third, etc. treatment category) comprises at least a first dose, a second dose, a third dose, and a fourth dose of a histamine receptor activator. Including. Optionally, some embodiments include application of at least a fourth treatment segment, which includes administering a greater amount of histamine receptor activator than the dose in the third treatment segment. .

  In some embodiments, the total dose of histamine receptor activator in the first treatment segment ranges from about 100 ng to 700 ng, from about 200 ng to about 600 ng, from about 300 ng to about 500 ng, about 400 ng, and Includes overlapping ranges. In some embodiments, the total dose of histamine receptor activator in the second treatment segment ranges from about 600 ng to about 1000 ng, from about 600 ng to about 800 ng, from about 650 ng to about 1000 ng, from about 800 ng to about 800 ng. 1000 ng, and their overlapping ranges are included. In some embodiments, the total dose of histamine receptor activator in the third treatment segment ranges from about 1050 ng to about 1600 ng, from about 1050 ng to about 1200 ng, from about 1200 ng to about 1300 ng, from about 1300 ng to about 1400 ng, about 1400 ng to about 1500 ng, about 1500 ng to about 1600 ng, about 1050 ng to about 1500 ng, and their overlapping ranges are included. In some embodiments, a multivariate approach is used to provide these doses in various volumes, so that in some embodiments, certain histamine receptors are larger than other histamine receptors. It is activated to the extent. For example, in some embodiments of the invention, utilizing the affinity in Table 1 induces a targeted and controlled pattern of histamine receptor activation.

  In some embodiments, the second treatment segment is longer in time than the first treatment segment, and the third treatment segment is longer in time than the second treatment segment. In embodiments that apply additional treatment segments, the continuous treatment segment is optionally longer in duration than the preceding segment (eg, each successive segment is longer in duration). In some embodiments, the frequency of administration of the therapeutic agent (eg, histamine receptor activator) is interval, such that increasing the duration of successive segments reduces the frequency of administration (compared to the previous segment). Remain constant throughout. By way of example, in some embodiments, the first treatment segment is performed over 10-16 days, the second treatment segment is performed over 20-35 days, and the third treatment segment is performed over 38-50 days. . In further embodiments, the first treatment segment may be applied in a compressed time frame as desired. For example, in some embodiments, the dose comprising the first treatment segment is administered within a shortened time frame (eg, about 30 seconds to about 5 minutes) in some embodiments. As a result, various receptor modulations occur in reduced time frames and, in some embodiments, occur simultaneously. In such embodiments, the first treatment segment advantageously “jump-starts” the regimen by co-receptor modulation. In some embodiments, the first treatment segment includes simultaneous delivery of each dose within that segment. In some embodiments, the first treatment segment is compressed to about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-10 minutes, about 10-20. Minutes, over a period of about 20-30 minutes and their overlapping ranges.

  In some embodiments, administration of the therapeutic agent (eg, histamine receptor activator) comprises subcutaneous injection of histamine or histamine salt, wherein the total dose for the first treatment segment is about 200 ng to about 600 ng. The total dose of the second treatment segment is about 650 ng to about 1000 ng, the total dose of the third treatment segment is about 1050 ng to about 1500 ng, the second treatment segment is longer than the first treatment system, and the third treatment The section is longer than the second treatment system.

  In additional embodiments, administration of the therapeutic agent (eg, histamine receptor activator) includes intravenous injection. In further embodiments, the therapeutic agent (eg, histamine receptor activator) is administered by the oral delivery route. In some embodiments, administration of the therapeutic agent (eg, histamine receptor activator) comprises a route selected from the group consisting of subcutaneous, intraarterial, intravenous, and combinations thereof. In some embodiments, a given segment may be delivered by a first route of administration (eg, subcutaneous) and another segment is delivered by a different route (eg, oral). In some embodiments, modification of the route of administration reduces the risk of side effects associated with a single route of administration. Furthermore, in some embodiments, by changing the route of administration, the percentage of histamine receptors can be reached in a certain organ bank. For example, oral administration can help restore the balance of histamine receptor activity in the gastrointestinal tract to a greater extent than intravenous administration. In some embodiments, the therapeutic agent is delivered by a non-invasive route of administration. In some embodiments, the therapeutic agent is self-administered. In some embodiments, the therapeutic agent is administered by, for example, a nurse, doctor, hospice care worker, and / or another health care provider, and in some embodiments, the therapeutic agent is not a medical professional. Administered by an individual (eg, a non-medical professional such as an acquaintance, family, spouse, etc.)

  In some embodiments, the subject being treated is prone to migraine, and restoration of histamine balance reduces the duration, frequency and / or intensity of migraine.

  In some embodiments, the subject being treated has histadelia, and histadelia is treated by restoring histamine balance. In some embodiments, the subject undergoing treatment has histapenia and histapenia is treated by restoration of histamine balance.

  In some embodiments, the therapeutic agent (eg, histamine receptor activator) is provided as a liquid formulation. In some embodiments, the first dose of histamine receptor activator in the first treatment segment is about 0.5 pg / mL, about 1 pg / mL, about 2 pg / mL, about 3 pg / mL, about 4 pg / mL. About 0.1 pg / mL to about 10 pg / mL, about 5 pg / mL, about 6 pg / mL, about 7 pg / mL, about 8 pg / mL, about 9 pg / mL, about 10 pg / mL, and concentrations therebetween Concentrations ranging up to mL.

  In some embodiments, the second dose of histamine receptor activator in the first treatment segment is about 0.5 ng / mL, about 1.0 ng / mL, about 2 ng / mL, about 3 ng / mL, about 4 ng. About 0.1 ng / mL to about 5 ng / mL, including about 5 ng / mL, about 6 ng / mL, about 7 ng / mL, about 8 ng / mL, about 9 ng / mL, about 10 ng / mL, and concentrations therebetween Concentrations ranging up to 10 ng / mL.

  In some embodiments, the third dose of histamine receptor activator in the first treatment segment is about 0.1 μg / mL, about 0.5 μg / mL, about 1 μg / mL, about 1.5 μg / mL, In the range from about 0.1 μg / mL to about 3.49 μg / mL, including about 2 μg / mL, about 2.5 μg / mL, about 3 μg / mL, about 3.49 μg / mL, and concentrations therebetween Has a concentration.

  In some embodiments, the fourth dose of histamine receptor activator in the first treatment segment is about 0.35 μg / mL, about. 75 μg / mL, about 1 μg / mL, about 1.5 μg / mL, about 2 μg / mL, about 2.5 μg / mL, about 3 μg / mL, about 3.5 μg / mL, about 4 μg / mL, about 4.5 μg / mL about 0.35 μg / mL to about 10 μg, including mL, about 5 μg / mL, about 6 μg / mL, about 7 μg / mL, about 8 μg / mL, about 9 μg / mL, about 10 μg / mL, and concentrations therebetween Concentrations ranging up to / mL.

  In some embodiments, the volume of each dose in the first treatment segment is about 0.01 mL to about 1 including about 0.1 mL, about 0.5 mL, about 0.75 mL, about 1 mL and a volume therebetween. The range is up to 0.0 mL. In some embodiments, the histamine receptor activator is administered once to three times a week during the first treatment segment, eg, twice a week during the first treatment segment.

  In some embodiments, the second treatment segment includes a first dose, a second dose, a third dose, and a fourth dose, and the first dose in the second treatment segment is from about 0.1 pg / mL to about 10 pg. Concentrations ranging up to / mL (eg, about 0.1 pg / mL, about 1 pg / mL, about 5 pg / mL, about 10 pg / mL and concentrations therebetween). In some embodiments, the second dose in the second treatment segment has a concentration ranging from about 0.1 ng / mL to about 10 ng / mL (eg, about 0.5 ng / mL, about 1.0 ng / mL). , About 5 ng / mL, about 10 ng / mL, and concentrations between them). In some embodiments, the third dose in the second treatment segment has a concentration ranging from about 0.1 μg / mL to about 3.49 μg / mL (eg, about 0.1 μg / mL, about about 1 μg / mL). , About 2 μg / mL, about 3 μg / mL, about 3.49 μg / mL, and concentrations between them). In some embodiments, the fourth dose in the second treatment segment has a concentration ranging from about 0.35 μg / mL to about 10 μg / mL (eg, about 0.35 μg / mL, about 1 μg / mL, about 1 0.5 μg / mL, approximately 3 μg / mL, approximately 3.5 μg / mL, approximately 4 μg / mL, approximately 4.5 μg / mL, approximately 6 μg / mL, approximately 8 μg / mL, approximately 10 μg / mL and the concentration therebetween) Have

  In some embodiments, the volume of each dose in the second treatment segment is, for example, about 0.2 mL, about 0.5 mL, about 0.75 mL, about 1 mL, about 1.5 mL, about 2 mL, and between The volume ranges from about 0.02 mL to about 2.0 mL.

  In some embodiments, the second treatment segment has a frequency between twice a week and once every 10 days during the second treatment segment, eg, once a week, twice a week, 1 in 8 days. Administration of histamine receptor activator once, every 10 days and at a frequency in between.

  In some embodiments, the third treatment segment includes a first dose, a second dose, a third dose, and a fourth dose, wherein the first dose in the third treatment segment is from about 0.1 pg / mL to about 10 pg. Concentrations ranging up to / mL (eg, about 0.1 pg / mL, about 1 pg / mL, about 5 pg / mL, about 10 pg / mL and concentrations therebetween). In some embodiments, the second dose in the third treatment segment has a concentration ranging from about 0.1 ng / mL to about 10 ng / mL (eg, about 0.5 ng / mL, about 1.0 ng / mL). , About 5 ng / mL, about 10 ng / mL, and concentrations between them). In some embodiments, the third dose in the third treatment segment has a concentration ranging from about 0.1 μg / mL to about 3.49 μg / mL (eg, about 0.1 μg / mL, about 1 μg / mL). , About 2 μg / mL, about 3 μg / mL, about 3.49 μg / mL, and concentrations between them). In some embodiments, the fourth dose in the third treatment segment has a concentration ranging from about 0.35 μg / mL to about 10 μg / mL (eg, about 0.35 μg / mL, about 1 μg / mL, about 1 0.5 μg / mL, approximately 3 μg / mL, approximately 3.5 μg / mL, approximately 4 μg / mL, approximately 4.5 μg / mL, approximately 6 μg / mL, approximately 8 μg / mL, approximately 10 μg / mL and the concentration therebetween) Have

  In some embodiments, the volume of each dose in the third treatment segment is, for example, about 0.3 mL, about 0.5 mL, about 0.75 mL, about 1 mL, about 2.0 mL, about 3.0 mL, and their The range is from about 0.03 mL to about 3.0 mL, including the volume between.

  In some embodiments, the third segment is a frequency between once a week and once every two weeks during the third treatment segment, eg, once a week, once every 8 days, once every 10 days. Administration of the histamine receptor activator once every 12 days, once every 14 days, and at a frequency in between.

  Further, in some embodiments, the frequency, duration and / or intensity of migraine in a subject is reduced, ameliorated, prevented and / or inhibited through normalization of the activity and / or expression of one or more histamine receptors. A first histamine dosing category comprising identifying a subject susceptible to migraine and having histamine imbalance, comprising a first dose, a second dose, a third dose and a fourth dose of histamine, One dose is administered subcutaneously at a concentration between about 0.1 pg / mL and about 10 pg / mL to activate a histamine receptor selected from the group consisting of histamine H3 receptor and histamine H4 receptor; Two doses are administered subcutaneously at a concentration between about 0.1 ng / mL and about 10 ng / mL and consist of histamine H3 receptor and histamine H4 receptor And a third dose of histamine is administered subcutaneously at a concentration between about 0.1 μg / mL and about 3.49 μg / mL to activate the histamine H1 receptor, A fourth dose is administered subcutaneously at a concentration between about 0.35 μg / mL and about 10 μg / mL to activate the histamine H2 receptor, except that each dose in the first dosage segment has the same volume, Applying a first histamine dosing segment to the subject, wherein each successive dose contains a greater amount of histamine compared to the previous dose, ranging from about 0.01 mL to about 1.0 mL, A second histamine dosing segment comprising a first dose, a second dose, a third dose and a fourth dose, wherein the concentration of histamine administered at each dose is a corresponding histamine for each dose of the first dosing segment. Equal to the stamin concentration, each dose in the second dosing segment has the same volume, the volume ranges between about 0.02 mL to about 2.0 mL, and the histamine delivered in the second dosing segment Applying a second histamine dosing segment to the subject, the total amount being greater than the delivered amount in the first dosing segment, the first, second, third and fourth doses of histamine A third histamine dosing section, wherein the concentration of histamine administered at each dose is equivalent to the corresponding histamine concentration of each dose of the first dosing section, and each dose in the third dosing section has the same volume The volume ranges between about 0.03 mL and about 3.0 mL, and the total amount of histamine delivered in the third dosage segment is greater than the delivered amount in the second dosage segment. 3 histamine throw The indicator which method comprises applying to said subject. In some embodiments, an increase in the amount of histamine administered in each successive dosage segment suppresses H1 receptor activity and increases H2, H3 and / or H4 receptor activity, thereby causing histamine reception. Body activity and / or expression is normalized and the duration, frequency and / or intensity of migraine in the subject is reduced.

In some embodiments, the ratio of individual doses in any of the first, second, or third treatment segments is 1:10 ³ : 10 ⁶ : 3.5 × 10 ⁶ . As discussed above, if a subject requires an increase or decrease in histamine activity (or receptor expression), these proportions can be adjusted (by adjusting either volume or concentration). The method also optionally includes administration of additional agonists or antagonists of any of the histamine H1, H2, H3 or H4 receptors. In addition, the method may include, in some embodiments, identifying a subject having histamine imbalance (eg, measuring serum and / or urine histamine levels) and directing administration of a therapeutic agent. Including one or more.

  It is also used herein to equilibrate the histamine system by up-regulating certain histamine receptors and down-regulating other histamine receptors and thus migraine, Parkinson's disease, Alzheimer's disease It provides histamine receptor activators that may be useful in the treatment of amyotrophic lateral sclerosis, epilepsy and other disorders. In some embodiments, further, migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or by administering a dosage of histamine receptor activator divided into at least three treatment categories Providing histamine receptor activator (s) for use in the treatment of epilepsy, wherein the total dose of histamine receptor activator in the first treatment segment is from about 200 ng to about 600 ng; The total dose of histamine receptor activator in the segment is from about 650 ng to about 1000 ng, and the total dose of histamine receptor activator in the third treatment segment is from about 1050 ng to about 1500 ng.

  Also provided is the histamine receptor activator used in the treatment of migraine by subcutaneous administration of the histamine receptor activator. In some embodiments, the histamine receptor activator comprises histamine and / or a histamine salt selected from the group consisting of one or more of histamine diphosphate, histamine phosphate and histamine dihydrochloride. .

  Also, migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, epilepsy (or other chronic minor illness) in patients who show an increased amount of circulating histamine and patients are circulating Provided is histamine receptor activator (s) for use in the treatment of chronic mild illnesses that show a reduced amount of histamine. Accordingly, in some embodiments, the present invention includes, but is not limited to, histamine receptor activators for modulating endogenous histamine levels, including but not limited to migraine, Parkinson's disease, Alzheimer's disease, muscle Restores histamine balance in a subject by use in the treatment of amyotrophic lateral sclerosis and / or epilepsy.

  In some embodiments, the invention inhibits the activity and / or expression of a histamine receptor selected from the group consisting of a histamine H1 receptor, a histamine H2 receptor, a histamine H3 receptor and a histamine H4 receptor. Histamine receptor activator (s) for use in the treatment of migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or epilepsy. In some embodiments, the histamine receptor activator inhibits histamine H1 receptor activity and / or expression.

  In some embodiments, the present invention relates to diseases associated with overexpression and / or overactivity of histamine H1 receptor, such as migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and epilepsy. Contains a histamine receptor activator for use in one or more treatments. Similarly, in some embodiments, diseases associated with underexpression and / or underactivity of one or more of the histamine H2, H3 and / or H4 receptors, such as migraine, Parkinson's disease, Alzheimer's disease, muscle, Provided is a histamine receptor activator for use in the treatment of amyotrophic lateral sclerosis and epilepsy.

  In some embodiments, the present invention provides for migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and / or epilepsy in combination with sequential or individual administration in combination with full or partial antagonists of histamine H1 receptors Contains histamine receptor activator (s) for use in treatment.

  In some embodiments, the invention inhibits histamine H1 receptor activity and / or expression for use in the treatment of migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or epilepsy. Contains agents.

  Further provided herein is a first dosing segment comprising two or more sequential doses of histamine at a first time interval, wherein at these doses the dose volume of each dose remains constant and the histamine concentration for each dose. A second dosing segment comprising two or more sequential doses of histamine separated by a second time interval, wherein the dosing volume of each dose remains constant for each dose Includes a second dosing segment in which the histamine concentration increases, wherein the volume of each histamine dose in the second dosing segment is greater than the volume of each histamine dose in the first dosing segment, and the second time interval is longer than the first time interval Provide an incremental histamine dosing regimen.

  In some embodiments of the histamine dosing regimen, the concentration of histamine administered during the first dosing segment is the same as the concentration of histamine administered during the second dosing segment and is administered during the first dosing segment. The number of doses is equal to the number of doses administered during the second dosing segment, and the first and second dosing segments are separated by a first time interval.

  If desired, the histamine dosing regimen may further comprise a third dosing segment comprising two or more sequential doses of histamine separated by a third time interval, wherein at these doses the dosing volume of each dose is constant. The histamine concentration increases with each dose, the volume of each dose in the third dosing segment is larger than the volume of each dose administered in the second dosing segment, and the third time interval is longer than the second time interval. In these embodiments, the concentration of histamine administered during the third dosing segment is the same as the concentration of histamine administered during the second dosing segment, and the number of doses administered during the third dosing segment is Equal to the number of doses administered during the two dosing segment, the second and third dosing segments are separated by a second time interval.

  Depending on the embodiment, each dosing segment can include three or more doses, for example, in some embodiments, each dosing segment includes four doses, five doses, six doses, eight doses, or ten doses.

  As discussed herein, some embodiments also provide an extended duration regimen, such as a regimen comprising 10 (or more) consecutive dosing segments, In these regimens, each dosing segment includes two or more sequential doses of histamine separated by one or more equal time intervals, where the dose volume of each dose remains constant and the histamine concentration is The volume of each histamine dose in the subsequent dosing segment is greater than the volume of each histamine dose in the preceding dosing segment, and the time interval in each subsequent dosing segment is longer than the time interval in the preceding dosing segment The concentration of histamine administered is the same in each dosage category, the number of doses administered in each segment is equal, and / or each subsequent dosage category is It is divided and just before dosing classified by time interval observed for minute.

  For example, in some extended dosing regimen embodiments comprising 10 dosing segments, the volume per dose in the first segment is about 0.1 mL and the volume of each dose in each subsequent segment is About 0.1 mL more than the volume administered.

  In some embodiments, the histamine concentration of each dose in each segment ranges from about 1 attogram / ml to 20 μg / ml, for example a concentration range of about 1 pg / ml to about 3.5 μg / ml (each dose About). In some embodiments, the first dosing interval has a duration in the range of about 1 day to 1 week, and the second dosing interval has a duration in the range of about 3 days to 2 weeks. Subsequent dosing intervals, in some embodiments, increase in duration continuously, for example, the third dosing interval can range from about 1 week to about 3 weeks.

  Depending on the embodiment, the histamine used in the histamine dosing regimen may be present as the free base, a pharmaceutically acceptable salt thereof, or a combination thereof. Depending on the embodiment, the route of administration is by subcutaneous, intravenous, intramuscular, infusion and / or sublingual administration.

  Also described herein is a method of reducing histamine levels in a human patient having a histamine level that exceeds levels required for optimal histamine function, wherein the histamine or pharmaceutically acceptable thereof is in accordance with a dosing regimen described herein. A method comprising administering to the patient a possible salt. A method of increasing histamine levels in a human patient having a histamine level below that required for optimal histamine function, wherein the histamine or a pharmaceutically acceptable salt thereof is added according to a dosing regimen described herein. Administering to a patient. In some embodiments, the assessment of histamine levels required for optimal histamine function is based on plasma or urinary histamine levels and diagnostic tests to measure them. In some embodiments, the histamine level required for optimal histamine function is between about 45 ng and about 50 ng per ml of plasma. However, in some embodiments, restoration of histamine levels to a concentration that is normal for a particular individual, although at levels below or below that range, is achieved.

FIG. 1 shows the chemical structure of histamine. FIG. 2 shows a schematic representation of the various signaling pathways in which histamine plays a role and examples of symptoms that can result from the activity of histamine receptors in certain tissues. FIG. 3 shows a general schematic of histamine signaling through G-protein coupled receptors. FIG. 4 shows a summary of previous clinical data related to serum histamine levels in various populations during asymptomatic conditions. FIG. 5 shows a summary of previous clinical data related to serum histamine levels in various populations during migraine events.

Detailed Description of the Invention

Some embodiments of the invention employ a multivariate approach to treat histamine imbalances. The multivariate approach includes, in some embodiments, alterations in concentration, volume and timing, and advantageously affects in vivo distribution, thereby selectively (or enhanced) activation of certain histamine receptors. Can be achieved. Using targeted and regulated patterns of receptor activation, up-regulating and / or down-regulating receptors restores histamine balance and is greater in patients suffering from histamine dysregulation Can result in relief of symptoms.
(Outline)

  Histamine, first identified as an otacoid with vasoactive properties and sometimes referred to as “Substance H” in context, is a member of the biosynthetic amine family and is an amino acid due to the activity of L-histidine decarboxylase (HDC). Synthesized from histidine. Histazine decarboxylase (HDC) is found in the central nervous system (neurons), gastric mucosa (mural cells), mast cells (which may contain about 3 pg histamine per cell) and basophil cells (about 1 pg per cell). An enzyme that is expressed in various cells throughout the body, including histamine. Histamine includes but is not limited to immune and allergic responses, endocrine function and homeostasis and cell proliferation, differentiation, hematopoiesis, embryonic development, regeneration, wound healing, aminergic neurotransmission, various other brain functions Involved in a variety of different physiological functions, including (sleep, nociception, food intake and aggressive behavior), secretion of pituitary hormones, regulation of the digestive and cardiovascular systems, and various other signaling pathways Yes. Histamine also correlates with allergies (eg, drug allergies, hay fever, allergic asthma, etc.). Also, high histamine has been detected in skin and plasma samples from patients with skin with atopic dermatitis (AD), chronic urticaria (CU), multiple sclerosis (MS) and / or psoriasis. In Parkinson's disease patients, histamine levels have been shown to be enhanced in certain brain regions such as the putamen, substantia nigra, and outer pallidum. In Alzheimer's disease, certain histaminergic neurons exhibit degeneration and tangle formation. Also, reduced histamine levels and / or HDC activity are associated with Alzheimer's disease and Down syndrome.

  Histamine is synthesized by a variety of cells including, but not limited to, mast cells, basophils, platelets, histaminergic neurons and enterochromophilic cells. The activity of HDC is regulated by various cytokines, including inflammatory cytokines such as interleukin (IL) -1, IL-3, IL-12, IL-18 and tumor necrosis factor (TNF). Histamine accumulates intracellularly in vesicles and is released by certain stimulating factors such as stress, circadian rhythms, drugs and allergens. Mast cells are relatively widely distributed throughout the body, and mast cell population density is determined by anatomical sites that interact with the external environment (eg, skin, airways and gastrointestinal tract) and blood vessels, nerves, smooth muscle Very high in areas very close to cells, epithelial cells, mucosa-producing cells and hair follicles. Given that histamine is accumulated in granules in a “release ready” fashion, a significant amount of pre-formed histamine can be released in response to a single stimulator, and many different triggers are large and sudden Mast cells are the primary cellular source of histamine because it can induce histamine release (eg, via mast cell degranulation). For example, in an allergic reaction, for example, histamine is released from basophils and / or mast cells in response to specific allergens. Histamine transmits many biological responses such as immune responses (eg, inflammatory responses, modulation of immune responses) and degranulation of mast cells after specific allergen recognition. Histamine-induced signaling can also be achieved, for example, by neuropeptides, complement factors, cytokines, hypertonicity, lipoproteins, adenosine, superoxidase, hypoxia, certain drugs, peptides, venoms and / or other “release facilitators” Reaction, physical injury (due to heat, vibration, radiation or physical movement), stress factors (eg chemical, thermal, traumatic or osmotic stress factors), alcohols that can activate mast cells and It plays a role in response to many other non-immunological stimulators such as seed foods and drugs, and / or spontaneous basophil release (which occurs more frequently in atopic individuals). Histamine can also potentially increase allergen influx by dilating blood vessels and increasing vascular wall permeability, so that allergic reactions such as excessive sneezing are caused by activation of histamine-based pathways. Be enhanced. FIG. 2 (reproduced with permission from Maintz et al., Histamine and Histamine Information, The American Journal of clinical Nutrition, 85: 1185-1196 (2007)) plays a role with histamine signaling. Examples of the variability of different pathways and the symptoms that can result from histamine dysregulation are shown. As a result of the large number of tissues in which histamine signaling occurs, dysregulation of histamine function is a confounding symptom (eg, one that is not necessarily directly associated with a particular organ system, eg, histamine regulation in the cardiovascular system) Can appear with dizziness as a result of failure. Accordingly, some embodiments of the methods and compositions (and uses thereof) disclosed herein for restoration of histamine balance may improve (or improve symptoms of histamine dysregulation in one or more tissues or tissue types). Is particularly useful.

  Certain individuals are sensitive to histamine or intolerant. As discussed above, histamine is produced from L-histidine. Imbalance in accumulation (eg, production) and reduction (eg, degradation and / or metabolism) can cause susceptibility and / or intolerance to histamine. The main enzyme for the metabolism of ingested histamine is diamine oxidase (DAO). Reduced histamine degradation based on insufficient DAO activity can result in excess histamine and induce symptoms that mimic allergic reactions. DAO is located in the plasma membrane associated vesicle structure and is secreted into the bloodstream after stimulation. The second major enzyme for histamine metabolism is histamine-N-methyltransferase (HNMT), which is a cytosolic protein and can only metabolize intracellular histamine. Despite their different, non-competitive, non-competitive positional relationships, reduced function of one or both of these enzymes can cause histamine imbalance and / or sensitivity or intolerance to histamine. As discussed above, those imbalances can cause a variety of adverse physiological consequences, and some embodiments of the methods disclosed herein can be used for therapeutic agents (eg, histamine). Restores histamine balance through administration.

  Endogenous histamine acts on a wide variety of different cell types including smooth muscle, neurons, endocrine and exocrine cells, blood cells and cells of the immune system. Histamine is expressed through one of several receptors including the H1 receptor (H1R), the H2 receptor (H2R), the H3 receptor (H3R) and more recently the H4 receptor (H4R). It exerts various biological effects. The receptors operate through various G protein subunits and are differentially expressed in various cell types, each of which is a G protein coupled receptor. The receptors have been detected on various tissues and several types of leukocytes and hematopoietic cells, including but not limited to the mammalian brain, respiratory, urogenital and vascular systems. H1 receptors are primarily involved in the regulation of vascular permeability and smooth muscle contraction. H2 receptor stimulation induces increased gastric acid secretion, increased mucus secretion in the bronchi, and relaxation of small vessel smooth muscle. H3 receptors are classified as presynaptic receptors that control neurotransmission in the central nervous system. H4 receptor signaling appears to regulate immune system processes and inflammatory responses. The main receptors throughout the body are the H1 and H2 receptors, and the H3 and H4 receptors are thought to have a somewhat more localized expression profile. In some cases, histamine signaling through H1R and / or H2R may transmit excitation and long-term enhancement of excitability. In contrast, H3R autoreceptors provide feedback control of histamine synthesis, release and electroactivity. As heteroreceptors, histamine receptors also function to control exocytosis of several other neurotransmitter systems (eg, GABA, dopamine, serotonin, etc.). Histamine also plays a role in several homeostasis and / or higher integrated brain functions (such as novelty-induced attention (as opposed to spontaneous attention) and adaptation to changing environments). It is known to play. Although there is some overlap between functions, receptor activity can generally be summarized as in Table 1.

In some embodiments, histamine is provided in a multivariate approach, where the concentration, volume and timing can be altered. Other variables (eg, injection time, histamine form, pH, etc.) can also be altered. In some embodiments, a multivariate pharmacokinetic approach results in selective or enhanced activation of certain receptors. In some embodiments, the affinity shown below is used to induce specific and controlled histamine receptor activation, thereby reducing many of the side effects associated with programs that do not employ the approaches described herein. It can be reduced or prevented. These side effects that may result in non-compliance when employing this treatment can be avoided or reduced in many embodiments.
Histamine H1 receptor

The distribution and occupancy of histamine H1 receptors (H1R) in humans has been mapped using functional imaging techniques to test the sedative properties and blood brain barrier (BBB) permeability of various H1R antihistamines. Similar trials have been conducted in the context of age-related and neuropsychiatric disorders such as Alzheimer's disease, schizophrenia and depression. In most of these studies, H1R binding has been found to be lower than that of age-matched healthy controls, indicating that histamine imbalance is at least partially high in some embodiments. It shows that it can be induced by receptor expression. It should be noted that H1R stimulation has a feed-forward effect on H1R expression (eg, stimulation of the receptor induces upregulation in receptor expression). It is believed that histamine-induced upregulation of H1 receptor expression is conveyed by protein kinase C-δ signaling. Mapping tests also show a correlation between the appearance of various symptoms and increased detection of histamine H1 receptor mRNA, as well as H1R and allergic responses (or responses to antihistamines used to treat allergies). A strong correlation between them was revealed. For example, drugs for treating allergic symptoms (eg, antihistamines) reduce not only IL-4 and / or Il-5 expression, but also H1 receptor gene expression. H1R histamine activation releases several neurotransmitters (eg, serotonin, dopamine and norepinephrine), including but not limited to brainstem, hypothalamus, thalamus, amygdala, septum, hippocampus and cerebral cortex. Excites neurons in most brain regions, including H1R has increased calcium signaling, signaling by cyclic guanosine monophosphate (cGMP), nuclear factor κB (NF-κB), increased phospholipase C (PLC) activity, increased phospholipase A2 and / or D activity, cyclic Signals through one or more of adenosine monophosphate activity (cAMP) and / or nitric oxide synthase activity, and thus, for example, cell proliferation, cell differentiation, apoptosis, cytoskeletal remodeling, vesicular transport, ion channels A great variety of signaling cascades associated with these pathways can be driven, such as conductivity, endocrine function and neurotransmission. See Figure 3 for an overview of histamine receptor signaling.
Histamine H2 receptor

Activation of H2R regulates various functions of histamine, including cardiac contraction, gastric acid secretion, cell proliferation, differentiation and immune response. In the brain, the highest density of H2R is found in the basal ganglia, hippocampus, amygdala and cerebral cortex, and expression is reduced in the cerebellum and hypothalamus. H2R stimulates cAMP accumulation in various tissues including gastric cells, heart tissue and brain. In contrast to H1R, H2R activation is primarily responsible for the inhibitory activity of histamine. For example, it has been demonstrated that H2R activity can inhibit various functions within the immune system and that H2R activity negatively regulates histamine release in basophils and mast cells. H2R-based inhibition of antibody synthesis, T cell proliferation, cellular cell lysis, and cytokine production is further evidence of the presence of H2R on lymphocytes and its negative (eg, suppressive) effect on histamine .
Histamine H3 receptor

  As indicated above, H3 receptors are predominantly expressed in the central nervous system, particularly on histaminergic neurons. The H3 receptor inhibits adenylate cyclase function by coupling to the Gi / o subunit, thus inhibiting cAMP formation in addition to calcium accumulation and stimulation of the mitogen-activated protein kinase (MAPK) pathway Is done. H3R also transmits histamine synthesis, and their activation causes inhibition of histamine release from histaminergic neurons. Thus, in some embodiments, preferential stimulation of H3R can counteract the activity of H1R (thus reducing the feed-forward increase in H1R expression), thereby facilitating restoration of histamine balance. Conversely, H3 receptor blockers can enhance neurotransmitter release. In addition, activation of H3 receptors includes, but is not limited to, many neurons that are nonhistaminergic, including those that signal through glutamate, acetylcholine, dopamine, noradrenaline, serotonin, GABA and various peptides. Causes an inhibitory effect on synapses.

Histaminergic dysregulation has been found in a variety of different CNS disorders, and thus various H3 ligands have been investigated for clinical use in CNS disorders such as obesity, memory impairment, learning deficits and epilepsy. . Furthermore, loss of H3R function is associated with behavioral abnormalities, mobility loss, bulimia, late-onset obesity, metabolic syndrome with increased insulin and leptin levels and high severity neuroinflammatory diseases. In some embodiments, the methods disclosed herein restore histamine balance / function by taking advantage of the pharmacological properties of H3R.
Histamine H4 receptor

H4 receptors are involved in cellular mechanisms associated with the immune system, inflammatory processes and allergic reactions. As discussed above, H4 receptors are found in bone marrow, spleen, peripheral blood, small intestine, heart, colon, lung and hematopoietic cells, neutrophils, mast cells, eosinophils, basophils, monocytes, It is expressed on T cells and dendritic cells. H4R mediates eosinophil shape change and mast cell chemotaxis, a result of the βγ subunit acting on phospholipase C, calcium release, subsequent actin polymerization and ultimately inflammation Causes mast cell chemotaxis to the site.
Histamine imbalance and histamine receptor modulation method

Normal serum histamine levels (eg, levels in otherwise healthy subjects without allergic events) range from about 40 to about 55 ng / mL. Thus, in some embodiments, restoring histamine equilibrium normalizes serum histamine levels from 40 to about 55 ng / mL. In other embodiments, serum histamine levels are normalized by reducing or increasing about 30% -70% histamine levels relative to baseline when restoring histamine equilibrium. As an example, and according to further considerations below, histamine normalization for migraine patients can be reducing histamine from 120 ng / mL to 70 ng / mL. As discussed above, the low histamine state is referred to as histapenia, and those with low histamine levels are referred to as “histapenic”. The high histamine condition is known as histadelia, and those with high histamine levels are referred to as histadelic.
Indications for histamine therapy

Various chronic mild illnesses and / or illnesses can be induced, exacerbated, or associated with imbalances in histamine levels and / or various histamine receptor functionality. As discussed above, normal serum histamine levels range from about 40 to about 55 ng / mL. Histamine levels include but are not limited to migraine, vascular headache, Alzheimer's disease, Parkinson's disease, epilepsy, obesity, schizophrenia, attention deficit / hyperactivity disorder, Huntington's disease, allergy, asthma, autism Disease, Rouguerig disease, atherosclerosis, dementia, addiction and obsessive compulsive disorder, metabolic syndrome, rheumatoid arthritis, sleep disorder, alcoholism, drug abuse, cancer, malaria, HIV / AIDS, central nervous system (CNS) ) Chronic mild illness or disease including dysfunction (eg, stress, anxiety, depression, movement disorders, anxiety / fear related disorders, bulimia and cerebral ischemia), prediabetes, diabetes, lupus erythematosus, cardiac arrhythmia Have lost balance (eg, higher or lower than normal). For example, serum histamine levels in migraine patients during painless periods (not suffering from allergies) can range from about 60 to about 74 ng / mL. That is, “normal” histamine levels for migraine patients are higher than for non-migraine patients. Thus, migraine patients may tend to develop migraine symptoms due to this histamine imbalance. In migraine patients also suffering from allergies, resting (eg, painless) serum concentrations can range from about 70 to about 95 ng / mL, indicating further histamine imbalance (see FIG. 4). ). These histamine levels are further increased during actual migraine events (see FIG. 5). According to many physiological parameters, histamine concentrations can vary from individual to individual, but imbalances compared to a particular individual's “normal histamine” concentration (eg, measured by serum and / or urine concentrations) Can cause and / or exacerbate various chronic mild illnesses and / or illnesses. Thus, in some embodiments, used in the treatment of diseases (and / or symptoms) including, but not limited to, migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or epilepsy. To provide histamine receptor activator (s). Also described herein are migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, epilepsy (or other chronic minor illness) in patients with increased circulating histamine, and patients with reduced circulating histamine levels. Provide histamine receptor activator (s) for use in the treatment of chronic mild illness. Accordingly, in some embodiments, the present invention comprises a histamine receptor activator for use in the treatment of migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or epilepsy. , Associated with restoration of histamine balance in the subject. In some embodiments, the invention provides a histamine receptor activator or histamine H2, H3 and / or H4 for use in the treatment of a disease associated with overexpression and / or overactivity of histamine H1 receptor. A histamine receptor activator for use in the treatment of diseases associated with underexpression and / or underactivity of one or more of the receptors.
Histamine therapy for migraine

  While the embodiments disclosed herein are non-limiting and are applicable to several neurological and other conditions, many embodiments are particularly useful for migraine. As discussed above, histamine imbalance is common in migraine patients. In the United States alone, over 30 million people suffer from migraine. Approximately 25% of women and 9% of men experience migraine, resulting in an average of 4-6 working days lost each year. This adds up to approximately 64 million to 150,000,000 working days lost annually (over the whole country), which is comparable to the direct and indirect costs of nearly $ 50 billion in the United States alone. (According to The National Headache Foundation; see also JD Bartleson, Treatment of Migrate Headaches, Mayo Clin. Proc. 1999; 74; 702-708). Headaches and related symptoms are responsible for nearly 2% of all visits to the emergency department. Migraine is generally described as recurring unilateral headache, lasting from 4 to 72 hours for untreated symptoms. The International Headache Society of Headaches has the following symptoms for headaches that should be considered migraine: unilateral, pulsatile, pain associated with daily activity With the presence of at least two of exacerbations and moderate to severe intensity, it lists at least one of the following characteristics: nausea and / or vomiting and photophobia and sound phobia.

  At present, there is no known cure for migraine. Migraine treatment is broadly classified as non-pharmacological or pharmacological treatment. Some embodiments disclosed herein are associated with pharmacological methods (eg, administration of therapeutic agents such as histamine) for restoring histamine balance and treating migraine. In some embodiments, non-pharmacological methods and / or combinations of pharmacological and non-pharmacological methods are used.

  Non-pharmacological treatment typically involves targeting and / or avoiding actions and behaviors known to induce migraine. For example, non-pharmacological treatments can include, in some embodiments, regular sleep patterns, routine exercise, and avoidance of known triggers. Depending on the individual migraine patient, the trigger may vary. Depending on the embodiment, food incentives include, but are not limited to, ripened cheese (eg, cheddar, emmental, stilton, brie and camembert), chocolate, marinades, pickles or fermented foods, foods containing nitrates or nitrites (Eg, bacon, hot dog, prepared meat) or MSG (eg, soy sauce, meat softener, seasoning salt), sour cream, nuts, peanut butter, natural yeast bread, various legumes (eg, broad beans, rye beans) Caffeine-containing beverages and / or alcoholic beverages such as figs, dried grapes, papaya, avocado, red plums, citrus fruits, tea, coffee or cola. In women, the menstrual cycle can be an incentive and is probably related to changes in estrogen levels. Light intensity, light patterns (eg, flickering light) can also act as triggers. Stress (eg, anxiety, anxiety, shock, sadness, etc.) can also be an incentive because it can drive a signaling cascade that induces histamine imbalance. Strong odors (eg, perfumes, chemical odors, certain cooked food odors, etc.) can also be incentives. In some embodiments, incentives may change over time (eg, strong odors may be incentives in one case but not in other cases). In some embodiments, non-pharmacological treatment also includes, for example, relaxation training, biofeedback training, cognitive and / or behavioral therapy, hypnosis, percutaneous peripheral nerve electrical stimulation, spine reduction, and / or High pressure oxygen treatment is mentioned. In some embodiments, the therapeutic dosing regimen (eg, histamine) is supplemented with one or more non-pharmacological treatments.

  Pharmacological treatment for migraine can generally be divided into two main classes: abortive therapy and prophylactic therapy. As used herein, the term “abortion therapy” is given its ordinary meaning, which is also an act to reduce and / or ameliorate already existing migraine symptoms Refers to therapy. In some embodiments, abortive therapy can be further divided into subcategories of non-specific therapy and migraine specific therapy. In some embodiments, the therapeutic dosing regimen (eg, histamine) is supplemented with one or more pharmacological treatments. Non-specific therapies optionally used in some embodiments include, but are not limited to, analgesics / NSAIDS (eg, acetaminophenone, aspirin, ibuprofen, naproxen sodium, ketorolac), and anesthesia There are sex analgesics (eg, meperidine and butorphanol), and adjuvant therapies (eg, metoclopramide, prochlorperazine). Migraine specific abortion therapy optionally used in some embodiments includes, but is not limited to, ergotamine and / or ergotamine derivatives (eg, ergotamine, caffeine + ergotamine, dihydroergotamine) and tryptamine based triptans There are family members (eg, sumatriptan, naratriptan, rizatriptan and zolmitriptan). Antihistamines are also used in some embodiments to preferentially and / or specifically target the activity of certain histamine receptors.

  As used herein, the term “prophylactic treatment” is intended to have its ordinary meaning, and the term prevents, avoids, limits and / or otherwise points to the frequency and / or intensity of migraine. Including reduction therapy. Prophylactic therapy is generally divided into first-line drugs and second-line drugs. In some embodiments, the first line treatment for migraine prevention in adults includes propranolol, timolol, amitriptyline, divalloproex, sodium valproate, and / or topiramate. In some embodiments, the second-line drug includes gabapentin, naproxen or naproxen sodium, sustained release dihydroergotamine mesylate, candesartan, lisinopril, atenolol, metoprolol, nadolol, fluoxetine, verapamil, magnesium, vitamin B2 (riboflavin), One or more of coenzyme Q10, hormone therapy (eg, estradiol topical gel) and botulinum toxin type A (Botox) are included.

  Despite optimal therapy with current available therapeutics, many patients continue to experience migraine. However, in some embodiments, in migraine patients, restoration of histamine balance, as disclosed herein, alone or in some embodiments in combination with non-pharmacological and / or pharmacological treatments. By doing so, the frequency and / or intensity of migraine can be reduced, limited, prevented and / or reduced.

  In some embodiments, the therapeutic agent (eg, histamine agonist or antagonist, naturally occurring or synthetic) is administered to a subject that is a migraine patient, in some embodiments, the histamine front piece. Establish a circulating concentration of the therapeutic agent that results in suppression of headache action. In some embodiments, administration of a therapeutic agent (eg, histamine, or synthetic histamine, or agonist and / or antagonist) results in a concentration of a selective interaction between the H3R and the therapeutic agent. As discussed above, activation of H3R can reduce histamine synthesis and / or release, thus reducing H1R expression (because its activity induced an increase in expression), resulting in: Potential dominance of H1R can be reduced and equilibrium between histamine receptors can be restored. Thus, the various histamine receptors depend on histamine receptor activator (s) for use in the treatment of migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, epilepsy and other disorders. Specifically targeted.

  Previous trials were directed toward histamine dosing regimens. For example, during a controlled double-blind clinical trial for migraine prevention, histamine was administered twice a week for 12 weeks in a continuously increasing subcutaneous dose (0.1-1 ng) to prevent histamine for migraine prevention. Efficacy was compared with placebo. Guerrero RO et al., Histamine as a therapeutic alternative in migraine prophylaxis: a randomized, placebo-controlled, Vol. 6- (19), Vol.

  In another study, administration of Na-methylhistamine at a dose of 1-3 ng twice a week significantly reduced the frequency, intensity and duration of migraine attacks, and the need for rescue analgesics (P <.0001). However, at doses above 3 ng, the patient experienced adverse side effects that manifested as severe headaches. Millan-Guerrero RO et al., Nα-Methylhistamine Safety and Efficacy in Migraine Prophylaxis: Phase I and Phase II Studies, Headache Vol. 43: 389-394 (2003) and Millan-Guerrero RO et al., Nα-Methyl Histamine Safety and Efficacy in Migraine Prophylaxis: Phase III Study Can. J. et al. Neurol. Sci. 33: 195-199 (2006).

  In another comparative study, subcutaneous histamine (10 μg / mL in Evans solution) was administered twice weekly, the first dose was 1 μg (0.1 mL), and the dose was gradually increased to 10 μg (0.1 mL) over 12 weeks. . Histamine was compared to placebo, sodium valproate, and topiramate administration. The histamine group reported reduced headache frequency (50%), reduced pain intensity (51%), reduced migraine length (45%), and reduced analgesic use (52%). Millan-Guerreroa RO et al., Nueva alternata terapeutica en profilaxis de migana con histana coma agonista de receptores H4 G4, Med.

  Histamine was also compared to sodium valproate in a 12-week double-blind controlled clinical trial. Subcutaneous administration of histamine (1-10 ng twice a week) was compared to oral administration of sodium valproate (500 mg daily dose). Data collected during the fourth, eighth and twelfth weeks of treatment show that histamine causes a significantly greater reduction (P <0.001) in the intensity and duration of migraine attacks and analgesic intake Was revealed. No difference in seizure frequency or MIDAS was detected. Milian-Guerreroa RO, et al., Subcutaneous histos versatile sodium valproate randomized, controlled, double-blind study European 108, 107. In a similar study, histamine subcutaneous administration (twice 1-10 ng weekly) was compared to topiramate oral administration (100 mg daily dose). See Millan-Guerreroa RO, et al., Subcutaneous Histamine versus Topiramate in Migrate Prophylaxis: A Double-Blind Study, Eur Neurol; Vol. 59: 237-242. In additional studies, histamine (subcutaneous, 1-10 ng, twice weekly) was compared to Botox injection (50 units, 1 injection cycle). Millan-Guerrero RO et al., Subcutaneous histosine versus botulinum toxin type A in migraine prophylaxis: a randomized, double-blinded.

  Additional studies show that in migraine subjects, relatively high doses of histamine intravenously (eg, 0.5 mg / kg per minute for 20 minutes) induce immediate headache during infusion, followed by Showed to have a migraine attack. These side effects can be stopped by pretreatment with the H1R antagonist mepyramine. See Krabbe and Olesen (Krabe AA, 1980) and Lassen et al. (Lassen LH, 1995).

  Other studies report how to determine a histamine dosing regimen. One such approach is empirical optimal dosing, and another approach is objective endpoint escalation. Empirical optimal dosing regimens include histamine injections at a specified frequency of once or twice a week (for example) and begin treatment with daily sublingual droplet supplementation. The histamine dose is increased to the optimal clinical response point without further deterioration. In the objective endpoint escalation approach, the dose of histamine that induces an allergic response is determined (eg, a continuous, more concentrated intradermal dose is administered until allergic wheal occurs). The dose is defined as the treatment dose, and subcutaneous injections of that dose are administered infrequently.

  Despite advanced histamine research and the use of histamine in various therapeutic situations, the body's natural histamine function can be restored, e.g. induced by imbalances in the body's release and metabolism of histamine, such as migraine There remains a need for histamine dosing regimens that can treat certain conditions. Further, a therapeutic effect may not be realized by a subject treated with therapy according to the studies discussed above, and / or such therapeutic effect may be associated with side effects. Furthermore, in contrast to the methods disclosed herein, many currently attempted therapeutic uses of histamine do not explain the selective activation of specific histamine receptors (as disclosed Some embodiments of the method are based on the utilization of different pharmacological properties of the histamine receptor), and this selective activation unexpectedly leads to histapenia, histadelia, and / or histamine imbalance. Exceptional therapeutic results and treatments for related or concomitant disorders are provided.

  Accordingly, some embodiments of the present invention provide (a) a therapeutic agent (eg, histamine, or a salt thereof, such as histamine phosphate, or one or more equal time intervals (“first time interval”)). A first dosing segment comprising two or more sequential doses of histamine dihydrochloride, etc.), wherein the dosing volume of each dose remains constant while increasing the therapeutic agent concentration for each dose, and (B) a second dosing segment comprising two or more sequential doses of the therapeutic agent separated by one or more equal time intervals (“second time interval”), each increasing the therapeutic agent concentration for each dose, An incremental dosing regimen that sequentially includes a second dosing segment in which the dose volume remains constant, wherein the volume of each dose in the second dosing segment is greater than the volume of each dose in the first dosing segment, Incremental throws with 2 hour intervals longer than the first time interval To provide a regimen.

  As used herein, the terms “first” and “second” are used in conjunction with each other and are not used for an overall dosing regimen. Thus, the dosing regimen may include more than two dosing segments, where the first dosing segment may refer to any dosing segment within the dosing regime other than the final dosing segment, and the second dosing segment May refer to any dosing segment performed after the first dosing segment. Depending on the embodiment, the regimen may include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more total dosage segments. Thus, the first medication segment can be any of segments 1 through 9, and the second medication segment can be any successive medication segment from 2 to 10.

  In some embodiments, the dosing regimen applies the complete regimen to the patient for optimal therapeutic effect (eg, if the regimen is 10 categories, complete all 10 categories). It is a fixed regimen. However, in some embodiments, the regimen may be aborted as desired for one or more of a variety of reasons. In some embodiments, the regimen is discontinued because the patient receiving the regimen has already experienced a sufficient therapeutic effect. For example, in some embodiments directed to migraine treatment, the subject may have experienced a significant reduction in the pain, frequency, duration and / or intensity of migraine onset. In some embodiments, the subject has a predetermined period of time, such as about 2 to about 7 days, about 7 to about 14 days, about 14 to about 21 days, about 21 days to about 4 weeks, about 4 weeks to about 8 weeks. After a period of days to months, including about 8 weeks to about 12 weeks, and their overlapping ranges, the regimen can be resumed. The subject may resume the regimen from the point at which the regimen is terminated as desired (eg, restarting where the subject stopped). The regimen can also be restarted from the starting point (eg, dose # 1 of segment # 1). Resumption of the regimen may be due to a reduced effect from application of the previous regimen (eg, symptom relapse and / or increased migraine frequency, for example). Some embodiments of the methods disclosed herein are surprisingly free of side effects (eg, in some categories, the dose of histamine that could induce side effects in other studies). But does not induce side effects such as migraine), in some embodiments, the regimen is optionally truncated due to side effects. Depending on the clinical condition, the regimen may be shortened by stopping at a specific dose volume within the dosing segment or by stopping prior to performing subsequent segments. In some embodiments, rather than censoring, the subject maintains a particular segment of the regimen for one or more periods (eg, repeats segment # 4 at multiple time intervals) or earlier The performed partition can be repeated one or more times (e.g., partition # 3 is performed again for one or more periods rather than partition # 4).

  In some embodiments, the number of doses administered during the first dosing segment is equal to the number of doses administered during the second dosing segment. In some embodiments, one or all of the segments can include 2, 3, 4, 5, 6, 7, 8 or more doses. In some embodiments, four individual doses are given in the first dosing segment. In some embodiments, the subsequent dosing segment has four individual doses. In some embodiments, the number of doses is increased or decreased depending on the needs and clinical symptoms of a given patient. For example, in some embodiments, 2-3, 3-4, 4-8, 8-12, or 12-24 (and overlapping ranges thereof) doses are administered within a given dosing segment. As indicated above, in some embodiments, each segment preferably includes the same number of doses, but each dosing segment can include a different number of doses.

  Further, in some embodiments, the first dosing segment and the second dosing segment are separated by a first time interval. In some embodiments, the time interval is about 3 to about 5, about 5 to about 7, about 7 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25. Range from about 3 to about 30 days, including about 30 days and overlapping ranges thereof. As discussed herein, in certain embodiments, the time interval varies, for example, between the first and second segments, for example, as compared to the fourth and fifth segments. In some embodiments, the time interval is determined by the subject's responsiveness (or refractory) to the dosing segment. In further embodiments, the dosing interval is determined by other variables such as subject convenience or personal preference. In some embodiments, the first dosing segment is performed in an optionally compressed time frame. For example, in some embodiments, the dose comprising the first treatment segment is, in some embodiments, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about It is administered within a shortened time frame such as 5-10 minutes, about 10-20 minutes, about 20-30 minutes and their overlapping ranges. In some embodiments, the first treatment segment includes the delivery of each dose simultaneously within that segment. As a result, various receptor modulations occur in a reduced time frame, and in some embodiments, simultaneously.

  In some embodiments, the dosing regimen comprises at least a third dosing segment comprising two or more sequential doses of a therapeutic agent (eg, histamine) separated by one or more equal time intervals (“third time interval”). Further included. In some embodiments, the therapeutic agent concentration increases with each dose while keeping the dose volume of each dose within the segment constant, and each dose volume in the third dose segment is administered in the second dose segment. Greater than the volume of the dose. Further, in some embodiments, the third time interval is longer than the second time interval (although in some embodiments, the time interval is optionally equal to the time interval of the preceding medication segment, or Can be modified to be shorter). The third dosing segment can be any segment that follows the second segment in a multi-segment regimen.

  In some embodiments comprising at least three dosage segments, (i) the concentration of the therapeutic agent (eg, histamine, eg, histamine phosphate or histamine dihydrochloride) administered during the third dosage segment is the second The same as the concentration of therapeutic agent (eg, histamine, eg, histamine phosphate or histamine dihydrochloride) administered during the dosing segment, (ii) the number of doses administered during the third dosing segment is Equal to the number of doses administered in the two dosing segments, and (iii) the second and third dosing segments are separated by a second time interval.

  In some embodiments, the dosing regimen comprises 10 or fewer consecutive dosing segments, wherein (a) each dosing segment is of a therapeutic agent (eg, histamine) separated by one or more equal time intervals. Comprising two or more sequential doses, (b) the dose volume of each dose remains constant, the concentration of the therapeutic agent increases from dose to dose, and (c) the volume of each dose in the subsequent dosing segment Greater than the volume of each dose in the segment, (d) the time interval in each subsequent dosing segment is longer than the time interval in the preceding dosing segment, and (e) the concentration of therapeutic agent administered is the same in each dosing segment (F) the number of doses administered in each segment is equal, and (g) each subsequent dosing segment is separated from the immediately preceding dosing segment by the time interval allowed for the immediately preceding dosing segment.

  As discussed above, in some embodiments, individual doses within a segment are given in a constant volume. For example, in some embodiments, the first dosage segment comprises a plurality of individual doses, each dose being from 0.01 mL to about 0.05 mL, from about 0.05 mL to about 0.10 mL, from about 0.10 mL to about 0.10 mL. 0.15 mL, about 0.15 mL to about 0.20 mL, about 0.20 mL to about 0.50 mL, about 0.50 mL to about 0.75 mL, about 0.75 mL to about 1.0 mL, and overlap between them From about 0.01 to about 1.0 mL. In some embodiments, the volume of therapeutic agent (eg, histamine) administered in each successive segment is greater than the volume of therapeutic agent administered in the immediately preceding dosing segment. For example, if the volume of therapeutic agent administered in the first segment is 0.1 mL, the volume of therapeutic agent administered in the next segment is greater than 0.1 mL. In some embodiments, the volume of therapeutic agent administered in a given dosage segment is 0.1 ml greater than the previous segment. In some embodiments, the volume of therapeutic agent administered in the final segment is 0.1 mL to about 1.0 mL, about 1.0 mL to about 2.0 mL, about 2.0 mL to about 5.0 mL, about 5 Ranges from about 0.1 to about 10 mL, including 0.0 mL to about 7.5 mL, about 7.5 mL to about 10.0 mL, and overlapping volumes therebetween. In some embodiments, the volume of therapeutic agent administered in the final segment is about 1.0 mL.

In some embodiments, the concentration of therapeutic agent (eg, histamine) administered within each segment is increased at each individual dose. For example, in the first (eg, starting) segment, the therapeutic agent concentration is about 0.1 attogram / mL to about 1 attogram / mL, about 1 attogram / mL to about 1 femtogram / mL, about 1 femtogram / mL. mL to about 1 picogram / mL (pg / mL), about 1 pg / mL to about 100 pg / mL, about 100 pg / mL to about 200 pg / mL, about 200 pg / mL to about 300 pg / mL, about 300 pg / mL to about 400 pg / ML, about 400 pg / mL to about 500 pg / mL, about 500 pg / mL to about 600 pg / mL, about 600 pg / mL to about 700 pg / mL, about 700 pg / mL to about 800 pg / mL, about 800 pg / mL to about 900 pg / ML, about 900 pg / mL to about 1 ng / mL, about 1 ng / mL to about 5 μg / mL, about 0.1 μg / mL to about 3 μg / mL, And includes a range of their overlap, it can range from about 0.1 Atoguramu / mL to about 10 [mu] g / mL. In some embodiments, the next dose is greater than the immediately preceding dose. In some embodiments, the final dose in a segment is about 1 μg / mL to about 2 μg / mL, about 2 μg / mL to about 3 μg / mL, about 3 μg / mL to about 3.5 μg / mL, about 3.5 μg. About 0 .mu.g / mL to about 4 .mu.g / mL, about 4 .mu.g / mL to about 6 .mu.g / mL, about 6 .mu.g / mL to about 8 .mu.g / mL, about 8 .mu.g / mL to about 10 .mu.g / mL, and overlapping ranges thereof. It ranges from 1 μg / mL to about 20 μg / mL. Thus, the concentration from the initial dose within a segment to the final dose within a segment is from about 0.1 attogram · mL to about 20 μg / mL, from about 1 pg / mL to about 1 ng / mL, about 1 ng / mL. mL to about 1 μg / mL, about 1 μg / mL to about 3.5 μg / mL, about 3.5 μg / mL to about 15 μg / mL, about 15 μg / mL to about 20 μg / mL, and their It is an overlapping range. In some embodiments, the ratio of the total amount given in each treatment category is 1: 2: 3 (for 3 categories), 1: 2: 3: 4 (for 4 categories), 1: 2: 3: 4: 5 (in the case of 5 categories). In some embodiments, the ratio of individual doses within a given treatment category is 1:10 ³ : 10 ⁶ : 3.5 × 10 ⁶ . The concentration of the therapeutic agent (eg, histamine) provided herein can be the dose administered to the subject, or in certain embodiments, the plasma concentration reached.

In some embodiments, the overall dose for a segment (eg, the total amount of therapeutic agent such as histamine administered at each dose within a segment) is preferably included within the following ranges:
Category 1
Initial dose: about 0.1 attogram to about 1 ng, or about 100 attogram to about 10 pg
Final dose: about 1 ng to about 1 μg, or about 100 ng to about 500 ng
Category 2
Initial dose: about 1000 attogram to about 1 ng, or about 0.1 pg to about 100 pg
Final dose: about 10 ng to about 10 μg, or about 1 μg to about 5 μg

More specifically, in some embodiments, each individual dose within a segment is targeted to a specific histamine receptor (s) based on the affinity of the various receptors for histamine. Designed (see, for example, Table 1). For example, the first dosing segment containing 4 doses, ie D1, D2, D3 and D4, with D1 being the lowest concentration and D4 being the highest concentration targets H3 / H4, H3 / H4, H1 and H2, respectively. . Further, as a non-limiting example, in embodiments where histamine is administered, the total amount of histamine administered at D1 ranges from about 0.0001 pg to about 999 pg, and the total amount of histamine administered at D2 is about The total amount of histamine administered at D3 ranges from about 1 μg to about 3.499 μg and the total amount of histamine administered at D4 ranges from about 3.5 μg to about 10 μg. It is a range. As discussed above, and following non-limiting examples, some embodiments include four doses having a volume greater than the dose in the first dosing segment, ie, D5, D6, D7 and D8. The second dosing segment results in the administration of a larger amount of histamine (not only with respect to the corresponding dose in the previous segment, but also with respect to the previous dose within the current segment, if any). Thus, for example, the total amount of histamine administered at D5 ranges from about 0.0002 pg to about 1998 pg, and the total amount of histamine administered at D6 ranges from about 2 ng to about 1998 ng, administered at D7. The total amount of histamine to be administered ranges from about 2 μg to about 6.998 μg, and the total amount of histamine administered at D8 ranges from about 7.0 μg to about 20 μg. In some embodiments, the ratio of the total amount given in each treatment category is 1: 2: 3 (for 3 categories), 1: 2: 3: 4 (for 4 categories), 1: 2: 3: 4: 5 (in the case of 5 categories). In some embodiments, the ratio of individual doses within a given treatment category is 1:10 ³ : 10 ⁶ : 3.5 × 10 ⁶ .

  Depending on the embodiment, the duration of each dosing segment may vary. In some embodiments, the duration of the segment ranges from about 1 to about 2 days, from about 2 to about 4 days, from about 4 days to about 6 days, from about 5 days to about 7 days, and overlapping ranges thereof. Including about 1 day to about 1 week. In some embodiments, the dosage section is about 1 to about 2 weeks, about 2 to about 3 weeks, about 3 to about 4 weeks, about 4 to about 6 weeks, about 6 to about 9 weeks, about 9 to about The range is from about 1 week to about 16 weeks, including 12 weeks, about 12 to about 16 weeks, and their overlapping ranges. In some embodiments, the subsequent dosing segment has a longer duration than the immediately preceding dosing segment.

For example, in some embodiments where the first dosing segment is about 2 weeks, the second dosing segment is, for example, about 2 to about 4 weeks in duration. In some embodiments including additional segments, the duration of each segment continues to increase. In some embodiments, the subsequent dosing segment has a longer duration than the immediately preceding dosing segment. Depending on the embodiment (eg, duration of dosing segment and number of individual doses within the segment), the dosing frequency within the segment can range from daily dosing to dosing once every few weeks. In some embodiments, dosing within a segment is daily, every 2 days, every 3 days, every 5 days, once a week, twice a week, once every 10 days, once every two weeks. Once every three weeks, once every month, once every six weeks, and at a frequency within the listed range. In some embodiments, as the number of dosing segments increases, the dosing frequency is reduced in subsequent dosing segments compared to the immediately preceding dosing segment. In some embodiments, the subsequent dosing segment is not only longer in duration than the immediately preceding dosing segment, but the subsequent dosing segment has a reduced dosing frequency compared to the immediately preceding dosing segment. Table 2 lists non-limiting examples of dosing regimens according to some embodiments disclosed herein. In some embodiments, the one or more segment durations are compressed by 50% to 99% (eg, 60%, 75%, 85%, 90%, 95%). As a non-limiting example, the four stages of Category 1 can be performed in one day.

^* Table 2: All concentrations represent the concentration of the active ingredient of the therapeutic agent. For example, in the case of an agent salt, the concentration corresponds to the molecular weight of the salt relative to the molecular weight of the agent alone.

  In some embodiments, the invention includes a dosing regimen in which the dosage volume, concentration and timing of a therapeutic agent (eg, histamine or a salt of histamine) is controlled. Other approaches employ single variability (eg, change only one of concentration, volume or timing). However, advantageously, some embodiments of the method employ the above three-dimensional variability to provide an unexpectedly more robust therapeutic effect. In some embodiments, an improved therapeutic effect is achieved without significant side effects. In some embodiments, the improved efficacy is derived from more specific histamine receptor targeting achieved by varying concentrations for each dose (eg, by varying dose concentrations, The altered affinity of H1R-H4R or other therapeutic agents is exploited). In some embodiments, the increase in volume per segment increases the proportion of histamine receptors in a given area to be activated (or suppresses depending on the specific receptor and / or histamine dose). ). In some embodiments, changing the timing helps to prevent receptor desensitization that can occur when the frequency of administration is constant over time. In such cases, administration of increased doses at regular intervals can result in one or more of the histamine receptors becoming refractory to histamine, particularly because of increased doses for each category. Thus, when a subject continues through a segment in a given regimen, the variability in concentration, volume, and timing causes the effect of restoring histamine balance for various histamine receptors (eg, activity and / or expression of Up regulation or down regulation).

  In some embodiments, the patient's histamine levels are optimal (healthy population) histamine levels by using a dosing regimen according to the methods disclosed herein (non-limiting examples of which are shown in Table 2). Whether higher or lower (in plasma or urine), patient histamine concentrations can be returned to the optimal histamine range. In some embodiments, the methods allow for reducing histamine levels in patients having histamine levels that exceed those required for optimal histamine function (eg, histadelia), Administering to the patient according to a disclosed dosing regimen histamine (synthetic to natural), a histamine agonist or antagonist, or a pharmaceutically acceptable salt thereof. In some embodiments, the methods disclosed herein allow for increasing histamine levels in patients with histamine levels that are less than those required for optimal histamine function (eg, histapenea). Thus, the method includes administering histamine (synthetic to natural), a histamine agonist or antagonist, or a pharmaceutically acceptable salt thereof to the patient according to the dosing regimen disclosed herein.

  In some embodiments of the invention, a histamine receptor activator (e.g., for use in the treatment of a patient exhibiting an increased amount of circulating histamine or a patient exhibiting a decreased amount of circulating histamine). The patient suffers from migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or epilepsy. Also provided are histamine receptor activators for use in the treatment of migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or epilepsy associated with restoration of histamine balance. Some embodiments of the invention are for use in the treatment of diseases associated with overexpression and / or overactivity of histamine H1 receptors and / or of histamine H2, H3 and / or H4 receptors Histamine receptor activators for use in the treatment of diseases associated with one or more underexpression and / or underactivity.

  As discussed above, treatment with the methods disclosed herein can be achieved by patients, such as by diagnostic assays that indicate the presence of standard plasma histamine levels or histamine levels that are higher or lower than standard urinary histamine levels. Can be based on a clinical assessment that they are affected by hisapenia or histaderia. For example, histamine levels in the range of 45 to about 50 ng / ml in plasma are used as an indicator for optimal histamine function in some embodiments, and plasma levels above or below this range are It shows that it can benefit from the method disclosed in the specification.

Also, in some embodiments, nutritional supplements may be used as desired to help restore histamine equilibrium. For example, in some embodiments, to supplement certain of the methods disclosed herein for the treatment of histadelia, optionally assists in promoting histamine methylation (e.g., reduces histamine metabolism). Nutritional supplements may be used (to encourage). Methylation-promoting nutritional supplements include, but are not limited to, S-adenosylmethionine (SAM-e), methyl-B12, and trimethylglycine (TMG), dimethylglycine (DMG), or combinations thereof There is. In addition, in conjunction with the dosage regimen disclosed herein, calcium (helping histamine transition into the bloodstream) and / or vitamin C (promoting histamine excretion) nutritional support to help reduce histamine Agents can be used. In some embodiments, magnesium supplementation is used to promote mast cell stabilization (which reduces degranulation and histamine release). Also, in certain embodiments where histamine reduction is desired, a low histamine diet is used. Also, because copper is associated with enzymes that degrade histamine, in some embodiments, reducing dietary copper intake is beneficial for the treatment of histapene.
Histamine composition and administration

In some embodiments, histamine is administered as a pharmaceutically acceptable salt. In some embodiments, the diphosphate (H ₃ PO ₄ ) salt of histamine is used. In some embodiments, histamine phosphate is used. Other salts may also be used, such as, but not limited to, inorganic acids such as hydrochloric acid (eg, histamine dihydrochloride), hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or Acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- ( 4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalene Sulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene -1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, There are acid addition salts formed with organic acids such as glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and combinations thereof.

  Further, in some embodiments, a pharmaceutically acceptable salt of histamine can be formed when an acidic proton present can react with an inorganic or organic base. Acceptable inorganic bases include, but are not limited to sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include, but are not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

  As used herein, the term “pharmaceutically acceptable” shall be given its ordinary meaning, and the term is also generally safe, non-toxic, biologically Or other components, compounds, chemicals, etc. useful for the preparation of pharmaceutical compositions, including those acceptable for use in veterinary medicine and in human medicine. It shall be. As used herein, the term “pharmaceutically acceptable salt” shall be given its ordinary meaning, and the term shall be pharmaceutically acceptable as defined above, and And / or salts of compounds having the desired pharmacological activity.

  In some embodiments, the method employs administration of one or more agonist and / or antagonist compounds. In some embodiments, agonists or antagonists can be administered to enhance or decrease the function of certain histamine receptors. For example, in some embodiments, an H3R agonist can be administered, and in some embodiments, an H1R antagonist is administered. The agonist may be a super agonist, full agonist, partial agonist, or inverse agonist. In some embodiments, the antagonist can be a competitive, non-competitive, uncompetitive or silent antagonist. Agonists and antagonists can also be either selective or non-selective, depending on the embodiment. In some embodiments, the use of one or more agonist or antagonist compounds takes the form of addition to the use of another therapeutic agent (eg, histamine).

  In some embodiments, the method optionally includes administration of an antihistamine compound. For example, in some embodiments, the inhibitory effect of the H2 / H3 receptor is further enhanced by administering an antagonist of the H1 receptor in conjunction with a histamine dosing regimen and reducing the H1 receptor activity by the antagonist. The For example, H1 antagonists that can be used include, but are not limited to, acepromethazine, acribastine, alcaftadine, alimemazine, antazoline, apazapine, astemizole, azatadine, azelastine, bamipine, bepotastine, vilastin, bislepine, bromazine, brompheniramine , Carbinoxamine, carbinoxamine / pseudoephedrine, cetirizine, chlorcyclidine, chloropyramine, chloroten, chlorphenamine, chlorphenoxamine, cinnarizine, clemastine, clemizole, clobenzepam, clobenztropine, crocinidine, cyanodothiepin, cyclidine, tropemazine Loratadine, dexbrompheniramine, dexchlorphenilla , Dimenhydrinate, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, drixolal, ebastine, embramin, emedastine, epinastine, esmirtazapine, etimemazine, fexofenadine, histapyrozine, homochlorcyclidine, hydroxyzine, hydroxyzine , Isopromethazine, isothipentil, ketotifen, latepiridine, levocabastine, levocetirizine, loratadine, mebhydroline, mepyramine, metafurylene, metapyrylene, methodirazine, 4-methyldiphenhydramine, mianserin, mirtazapine, mizolastine, moxasthine, olopatodarine, olopatamazine , Phenylami , Phenyltoloxamine, pyrolate, promethazine, propiomazine, pseudoephedrine / loratadine, pyrobutamine, repirinast, resporal, lupatadine, cetastine, cetiptyline, tarastin, terfenadine, tenaridine, tenenyldiamine, thiadinium methylsulfate, tondiamine, tolpromine, tolpromine , Tripelenamine, triprolidine, and combinations thereof. In other embodiments, agonist compounds may be used (eg, depending on whether the subject is afflicted with histapenia or histadelia). In some embodiments, an H1 agonist can be used, such as when treating a subject with hisapenia. Suitable H1 agonists include, but are not limited to, 2-pyridylethylamine dihydrochloride, histamine trifluoromethyl toluide, and the histamine disclosed herein (either synthetic or naturally occurring). There are various salts, or combinations thereof.

  In some embodiments, agonists of H2R are used, including but not limited to, for example, alpromidine, amtamamine, impromidine, dimaprit, sopromidine, 4-methylhistamine, and combinations thereof. Also, some embodiments include, but are not limited to, for example, cimetidine, mifentidine, nizatidine, ranitidine, cytotidine, famotidine, zolanthidine, iodoaminopotentidine, compound SKF92857, mepyramine, roxitidine, and combinations thereof. H2R antagonists are used.

  H3 receptor agonists are used in some embodiments. Suitable H3R agonists include, but are not limited to, (R) -α-methylhistamine, cypralysant, inmepip, imetit, imetridine, metimepip, proxyphane, and combinations thereof. Conversely, in some embodiments, H3R antagonists can be used. Suitable H3R antagonists include, but are not limited to, A-349,821, ABT-239, betahistine, brimamide, siproxyphan, connessin, clobenpropit, inpentamine, iodofenpropit, thioperamide, VUF -5681 (4- [3- (1H-imidazol-4-yl) propyl] piperidine), and combinations thereof.

  H4 receptor agonists are used in some embodiments. Suitable H4R agonists include, but are not limited to, VUF-8430 (2-[(aminoiminomethyl) amino] ethylcarbamimidothioate), OUP-16, 4-methylhistamine, and the present specification. There are various salts of histamine (either synthetic or naturally occurring) disclosed in the literature, or combinations thereof. H4R antagonists may be used in some embodiments. Suitable H4R antagonists include, but are not limited to, thioperamide, JNJ 7777120, VUF-6002 (1-[(5-chloro-1H-benzimidazol-2-yl) carbonyl] -4-methylpiperazine), A987306, A943931, and combinations thereof.

  In some embodiments, the present invention inhibits the activity and / or expression of a histamine receptor selected from the group consisting of a histamine H1 receptor, a histamine H2 receptor, a histamine H3 receptor, and a histamine H4 receptor. Histamine receptor activator for use in the treatment of occasional migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or epilepsy. In some embodiments, the histamine receptor activator inhibits histamine H1 receptor activity and / or expression, such that in the treatment of diseases associated with overexpression and / or overactivity of histamine H1 receptor. Useful for use. Further, in some embodiments, the histamine receptor activator (s) is associated with an underexpression and / or underactivity of one or more of the histamine H2, H3 and / or H4 receptors. For use in treatment.

  In some embodiments, the invention relates to migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or epilepsy in combination with a full or partial antagonist of histamine H1 receptor, sequential or individual administration. A histamine receptor activator for use in the treatment of Further, in some embodiments, the present invention provides histamine H1 receptor activity and / or expression for use in the treatment of migraine, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or epilepsy. Inhibitors of

  In some embodiments, the histamine composition used in the methods disclosed herein can be used in one or more of various forms, depending on the route of administration. Administration can be, for example, by mouth, eye, ear and / or nose, genitourinary, rectal, transdermal, by implantation, and / or by injection. In one embodiment, a patch may be used. Oral delivery can be, for example, enteral (eg, to the digestive tract), buccal (eg, sublingual), and / or by inhalation (eg, to the respiratory tract). Depending on the embodiment, oral forms include, but are not limited to, liquid, solid and / or semi-solid forms. In some embodiments, enteral administration comprises pills, tablets, capsules, gel caps, osmotic delivery systems (including sustained release forms), elixirs, suspensions, syrups, emulsions, hydrogels, By administration of one or more of wafers, molecular encapsulated forms, soft gels, solutions, suspensions, syrups, tinctures and / or medicated baths. Oral administration is, in some embodiments, one of orally disintegrating tablets or pills, films, lozenges, chewing gum, popsicles, lollipops, mouthwashes, mouthwashes, toothpastes, ointments and / or mouth sprays. By more than one dose.

  In some embodiments, the oral form can include one or more inert diluents and / or edible carriers. For example, the composition can be enclosed in a gelatin capsule (oral) or compressed into a tablet (oral or buccal) or formulated into a troche or sublingual solution (oral) Can be done. In some embodiments, the active histamine compound can be incorporated by excipients and / or various pharmaceutically compatible carriers, binders, and / or auxiliary materials. The oral form may contain, in some embodiments, any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, gum tragacanth or gelatin, excipients such as starch or lactose Disintegrants such as alginic acid or corn starch, lubricants such as magnesium stearate, gliding agents such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin, or flavoring agent (s), eg mint, Methyl salicylate or fruit flavors, candy flavors, flavor combinations, etc. When the dosage unit form is a capsule, it can optionally contain a liquid carrier such as a fatty oil in addition to the types of materials described above. In addition, the dosage unit form may include various other materials that modify the physical form of the dosage unit, such as sugar coating, shellac, or other enteric solvents. Administration to the respiratory tract is in some embodiments by administration of one or more of a dry powder inhaler, nebulizer, nebulizer, metered dose inhaler, respiratory mask, oxygen concentrator, nasal cannula, and the like.

  In some embodiments, administration from the eyes, ears and nose is used, and in some such embodiments, the histamine composition is advantageously absorbed rapidly, eg, through the mucosa. Delivery forms by eye, nose or ear include, but are not limited to, for example, nasal sprays, ear drops, eye drops, ointments, hydrogels, nanosphere suspensions or emulsions, mucoadhesive microdiscs ( Examples are microsphere tablets).

  Urogenital and / or rectal dosage forms include, but are not limited to, ointments, pessaries (eg, vaginal suppositories), vaginal rings, vaginal irrigators, intrauterine devices (IUD), extraamniotic infusions, bladder For example, internal injections, suppositories, enemas, and / or Murphy drip.

  Skin dosage forms include, but are not limited to, ointments, coatings, pastes, films, hydrogels, liposomes, transfersome vesicles, creams, lotions, balms, salves, shampoos, skin patches ( Examples include transdermal patches), transdermal sprays, direct or jet injectors.

  In some embodiments, injection or infusion can also be used. For example, histamine delivery can be intravenous, intramuscular, intraperitoneal, intraarterial, intracavernosal, intracerebral, intrathecal, dura mater, intradermal, subcutaneous, percutaneous transplantation. It can be external.

  In some embodiments, the therapeutic agent is self-administered. In some embodiments, the therapeutic agent is administered to a subject in need thereof by a non-medical professional (eg, an acquaintance, family member, spouse, non-health professional individual).

  In some embodiments, combinations of various administration routes are also used. For example, oral dosing can be used in conjunction with subcutaneous administration. Similarly, for example, both intramuscular and subcutaneous routes are used as desired. Solutions or suspensions used for injection or infusion can optionally contain one or more of the following components: sterile diluents such as water for injection, saline solutions, fixed oils, polyethylene glycols, glycerin, propylene glycol Or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl paraben, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid (EDTA), buffers such as acetic acid, citric acid or phosphate buffer Solutions and tonicity adjusting agents, such as sodium chloride, mannitol and dextrose. In some embodiments, the injectable preparation can be contained in ampoules, disposable syringes or multi-dose vials made of glass or plastic or other suitable material as desired. When used in conjunction with the histamine compositions disclosed herein, antihistamines can also take any of the above forms.

  The concentrations and dosages provided in the examples below and in the table above are for subjects weighing 75-85 kg, and according to some embodiments, different weights can be adjusted proportionally. In some embodiments, a kit comprising a pre-filled syringe, vial or other container is provided with a dose of the therapeutic agent described herein. Instructions are provided in one embodiment including, for example, a paper or electronic calendar system or other self-treatment schedule alert.

The examples provided herein are non-limiting examples of some embodiments of the invention.
Example 1-Histamine dosing regimen for treatment of neurological disorders

In some embodiments, a histamine dosing regimen according to the methods disclosed above is used for the reduction and / or prevention of neurological disorders, including migraine, Parkinson's disease and Alzheimer's disease and ALS and epilepsy. Long-term migraine patients were treated with the regimen shown in Table 3 (the day of dosing is only an example). Histamine was administered subcutaneously according to the indicated times and concentrations.
^* C1 = 1.0 pg / mL histamine base C2 = 1.0 ng / mL histamine base C3 = 1.0 μg / mL histamine base C4 = 3.5 μg / mL histamine base

  The concentrations shown in Table 3 represent “histamine base” concentrations (eg, the amount of histamine itself). For example, in the case of histamine phosphate, two molecules of phosphate are bound to each molecule of histamine. Since the molecular weight of histamine phosphate is 307.15 and the molecular weight of histamine itself is 111.15, 2.75 mg of the above salt is required to obtain 1 mg of active ingredient.

  As a result of the histamine dosing regimen, subjects (those with a migraine history of more than 35 years) experienced a significant reduction in the incidence of migraine and a reduction in the intensity of migraine when migraine occurred. Prior to this dosing regimen, the subject experienced an average of about 3-5 migraines per week. This frequency was in spite of various prescription and non-prescription drug use, dietary changes, and / or alternative medical approaches. The migraine event took away a lot of working days and reduced work efficiency. Migraine also resulted in the loss of certain occupational opportunities for promotion and loss of motor skills outside work (because physical exercise induced migraine attacks). General migraine events consistently reduced quality of life.

As a result of implementing the histamine dosing regimen described above, the intensity and frequency of migraine is greatly reduced in this subject, who now experiences only about one migraine every two months. . The subject can spend time interacting with the subject's family, participate in home and social events, exercise, become a productive member of society, etc. , Resulted in a significant improvement in the quality of life. The regimen also had limited side effects associated with the regimen (eg, no histamine-induced headache). After completing Category 5, the subject resumed the dosing regimen in Category 1 after a period of time. As discussed above, due to the predominance of histamine in various physiological functions and histamine imbalance in various diseases and / or disorders, some embodiments of the present invention are not limited. Although not, it has been useful in the treatment of other diseases and / or disorders, including Parkinson's disease, Alzheimer's disease, epilepsy, ALS, and other disorders disclosed herein. In some embodiments, one or more segment durations may be compressed or expanded by, for example, 50% to 99% (eg, 60%, 75%, 85%, 90%, 95%).
Example 2 Extended Histamine Dosing Regimens for Treatment of Neuropathy

In some embodiments, an extended histamine dosing regimen is used for the reduction and / or prevention of neuropathy, including in particular migraine, Parkinson's disease, Alzheimer's disease, ALS and epilepsy.
^* C1 = 1.0 pg / mL histamine base C2 = 1.0 ng / mL histamine base C3 = 1.0 μg / mL histamine base C4 = 3.5 μg / mL histamine base

The concentrations shown in Table 4 represent “histamine base” concentrations (eg, the amount of histamine itself). For example, in the case of histamine phosphate, two molecules of phosphate are bound to each molecule of histamine. Since the molecular weight of histamine phosphate is 307.15 and the molecular weight of histamine itself is 111.15, 2.75 mg of the above salt is required to obtain 1 mg of active ingredient. In some embodiments, one or more segment durations may be compressed or expanded by, for example, 50% to 99% (eg, 60%, 75%, 85%, 90%, 95%). Other histamine compounds may be used instead of or in addition to histamine phosphate.
Example 3-Representative formulations

  An exemplary formulation for use in some embodiments of the histamine dosing regime disclosed herein is 1 mg / mL histamine base (2.75 mg histamine phosphate in 50% (v / v) glycerin. / ML) and is suitable for subcutaneous injection. Other histamine receptor activators can be used in place of or in addition to histamine phosphate, as disclosed herein.

  While the above examples and some embodiments discuss the histamine system, the approaches described herein can also be used to restore the equilibrium of other systems. For example, in some embodiments, the therapeutic agent includes an agent that affects neurotransmission, such as an agent that affects one or more of the dopamine, noradrenaline, serotonin, GABA and acetylcholine systems. Targeted and regulated receptor modulation patterns can be particularly effective for neurological disorders. Accordingly, agonists and antagonists of these neurotransmission pathways according to the approaches described herein are encompassed by this disclosure.

  While embodiments of the invention have been disclosed in the context of certain preferred embodiments and examples, the invention is not confined to the specifically disclosed embodiments and other alternative embodiments of the invention and It will be apparent to those skilled in the art that the use and / or expansion to obvious modifications and equivalents thereof. Moreover, while many variations of the invention have been shown and described in detail, other modifications falling within the scope of the invention should be readily apparent to those skilled in the art based on this disclosure. In addition, various combinations or subcombinations of specific features and aspects of the embodiments may be formed and still be included within one or more of the present invention. Further, the disclosure herein of specific features, aspects, methods, characteristics, attributes, qualities, attributes, elements, etc. associated with the embodiments may be used in all other embodiments presented herein. . Thus, it will be appreciated that various features and aspects of the disclosed embodiments may be combined with or replaced with each other to form various modes of the disclosed invention. For all of the embodiments described herein, the steps of the method need not be performed sequentially. Accordingly, the scope of the invention disclosed herein should not be limited by the particular disclosed embodiments described above.

  The ranges disclosed herein also encompass all overlap, subranges and combinations thereof. For example, terms such as “below”, “at least”, “greater than”, “less than”, “between”, and the like include the recited numbers. Numbers preceded by a word such as “about” or “approximately” include the recited numbers. For example, “about 10 nanometers” includes “10 nanometers”.

  As used herein, the singular forms “a”, “an”, and “the” or like terms are understood to encompass a plurality of referents unless the context clearly indicates otherwise. The Thus, for example, “an agent” includes the case of two or more agents. As used herein, the term “or” or similar word means any member of a particular list and also encompasses any combination of members of that list.

  Throughout this description and claims, “comprise” and variations of this term, such as “including” and “comprises”, are not intended to be limiting, Including, for example, is not intended to exclude other additives, components, integers or steps.

Claims (8)

A histamine receptor activator composition for use in the treatment of migraine in a subject comprising:
Administration of the histamine receptor activator composition comprises:
Subjecting the subject to a first administration of a first dose of a histamine receptor activator composition;
Performing a first administration of a second dose of the histamine receptor activator composition to the subject;
The first administration of the first dose and the second dose are separated by a first time interval;
The concentration of the histamine receptor activator composition and the administration volume of the first dose, wherein the second dose of the first administration is higher than the concentration of the first dose of the histamine receptor activator composition; Have the same dose volume;
Performing a second administration of the first dose of the histamine receptor activator composition to the subject;
And subjecting the subject to a second administration of the second dose of the histamine receptor activator composition,
The second administration of the first dose and the second dose is separated by a second time interval;
The second dose of the second administration is higher than the concentration of the first dose of the histamine receptor activator composition, the concentration of the histamine receptor activator composition and the administration volume of the first dose; Have a dose volume that is the same and greater than the dose volume of the second dose of the first dose ;
The histamine receptor activator composition comprises histamine;
Histamine receptor activator composition wherein repeated administration of the first and second doses of the histamine receptor activator composition comprises normalizing the activity of one or more histamine receptors in the subject object.   The histamine receptor activator composition for use according to claim 1, wherein the histamine receptor activator composition comprises a pharmaceutically acceptable histamine salt.   The histamine receptor activator for use according to claim 2, wherein the pharmaceutically acceptable histamine salt is selected from the group consisting of histamine diphosphate, histamine phosphate and histamine dihydrochloride. Composition.   The use according to claim 1, further comprising at least a third administration of the first dose of the histamine receptor activator composition and at least a third administration of the second dose of the histamine receptor activator composition. For histamine receptor activator composition. Normalizing the activity of the one or more histamine receptors;
Regulates histamine H3 receptor and inhibits histamine release from one or more histaminergic neurons, and regulates histamine H1 receptor and upregulates expression of histamine H1 receptor to feed in histamine production The histamine receptor activator composition according to claim 1, comprising at least one of inducing a forward effect. Wherein to normalize one or more activities of the histamine receptor, modulate histamine H3 receptor, comprising inhibiting histamine release from one or more histaminergic neurons, histamine according to claim 1 Receptor activator composition. Wherein the subject is susceptible to the migraine as excess result of the circulation amount of histamine, to reduce the frequency and / or intensity of the migraine by decreasing circulating amount of histamine, histamine receptor as described in claim 1 Activator composition. Further comprising administering to the subject a third administration of at least a first dose and a second dose of a histamine composition, wherein the second dose has a histamine concentration greater than the first dose, the first dose The histamine receptor activator composition of claim 1 , wherein the second dose is separated by a third time interval.