U.S. patent application number 15/803564 was filed with the patent office on 2018-10-04 for methods for restoration of histamine balance.
The applicant listed for this patent is BioHealthonomics Inc.. Invention is credited to Cristian Arnou.
Application Number | 20180280353 15/803564 |
Document ID | / |
Family ID | 51687197 |
Filed Date | 2018-10-04 |
United States Patent
Application |
20180280353 |
Kind Code |
A1 |
Arnou; Cristian |
October 4, 2018 |
METHODS FOR RESTORATION OF HISTAMINE BALANCE
Abstract
Several embodiments provided herein relate to histamine dosing
regimens are and uses of such regimens in the restoration of
histamine balance in subjects suffering from, for example,
histapenia and/or histadelia. Several embodiments also relate to
the use of histamine dosing regimens for the treatment and/or
prevention of migraine headaches.
Inventors: |
Arnou; Cristian; (Santa
Monica, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BioHealthonomics Inc. |
Santa Monica |
CA |
US |
|
|
Family ID: |
51687197 |
Appl. No.: |
15/803564 |
Filed: |
November 3, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15341839 |
Nov 2, 2016 |
9808444 |
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15803564 |
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14684174 |
Apr 10, 2015 |
9511054 |
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15341839 |
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14315206 |
Jun 25, 2014 |
9023881 |
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14684174 |
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PCT/US2013/046420 |
Jun 18, 2013 |
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14315206 |
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61733630 |
Dec 5, 2012 |
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61867966 |
Aug 20, 2013 |
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62002613 |
May 23, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/417 20130101 |
International
Class: |
A61K 31/417 20060101
A61K031/417; A61K 45/06 20060101 A61K045/06 |
Claims
1. (canceled)
2. A decreasing histamine dosing regimen comprising in sequential
order: a) a first dosing segment comprising two or more sequential
doses of histamine separated by one or more equal time intervals
(the "first time interval"), wherein the doses decrease in
histamine concentration from dose to dose while the administered
volume of each dose stays constant; and b) a second dosing segment
comprising two or more sequential doses of histamine separated by
one or more equal time intervals (the "second time interval"),
wherein the doses decrease in histamine concentration from dose to
dose while the administered volume of each dose stays constant;
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.
3. A histamine dosing regimen comprising in sequential order: a) a
first dosing segment comprising two or more sequential doses of
histamine separated by one or more equal time intervals (the "first
time interval"), wherein the histamine concentration varies from
dose to dose while the administered volume of each dose decreases;
and b) a second dosing segment comprising two or more sequential
doses of histamine separated by one or more equal time intervals
(the "second time interval"), wherein the histamine concentration
varies from dose to dose while the administered volume of each dose
decreases; wherein the volume of each histamine dose in the second
dosing segment is less than the volume of each histamine dose in
the first dosing segment, and the second time interval is longer
than the first time interval.
4. A histamine dosing regimen comprising in sequential order: a) a
first dosing segment comprising two or more sequential doses of
histamine separated by one or more equal time intervals (the "first
time interval"), wherein the histamine concentration varies from
dose to dose while the administered volume of each dose remains
constant; and b) a second dosing segment comprising two or more
sequential doses of histamine separated by one or more equal time
intervals (the "second time interval"), wherein the histamine
concentration varies from dose to dose while the administered
volume of each dose remains constant; wherein the second time
interval is longer than the first time interval.
Description
RELATED CASES
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/341,839, filed Nov. 2, 2016, which is a
continuation of U.S. patent application Ser. No. 14/684,174, now
U.S. Pat. No. 9,511,054, filed Apr. 10, 2015, which is a
continuation of U.S. patent application Ser. No. 14/315,206, now
U.S. Pat. No. 9,023,881, filed Jun. 25, 2014, which is a
continuation in part of International Application No.
PCT/US2013/046420, filed Jun. 18, 2013, which claims the benefit of
U.S. Provisional Application No. 61/733,630, filed Dec. 5, 2012.
U.S. patent application Ser. No. 14/315,206 also claims the benefit
of U.S. Provisional Application No. 61/867,966, filed on Aug. 20,
2013 and U.S. Provisional Application No. 62/002,613, filed on May
23, 2014. The entire disclosure of each of the applications listed
above is incorporated by reference herein.
BACKGROUND
Field
[0002] Several embodiments of the present invention relate
generally to methods for the restoration of histamine balance. In
particular, several embodiments related restoring histamine levels
to normal ranges in order to treat various illnesses or
disorders.
Description of the Related Art
[0003] Histamine, also referred to chemically as
2-(1H-imidazol-4-yl)ethanamine is composed of an imidazole ring and
an amino group connected by a chain of two carbon atoms (see FIG.
1). Histamine is the decarboxylation product of the amino acid
histidine and is associated with local immune responses to foreign
pathogens. For example, the granules of mast cells or white blood
cells generate and/or store histamine which is released upon injury
or exposure to allergens. Histamine also functions as a
neurotransmitter and plays a role in the pathways of gastric acid
secretion in the stomach.
SUMMARY
[0004] Dysregulation or imbalances of the histamine system can be a
leading contributor to a variety of disease states and symptoms,
many of which can be debilitating or life-disruptive. For example,
abnormally high histamine levels can lead to excessive allergies
(or hyperactive responses to allergens), hyperactivity, compulsive
or obsessive behavior, vertigo, inner ear pressure, depression,
anxiety, panic attacks, migraine headaches, heightened emotional
sensitivity and/or suicidal tendencies. Reduced histamine levels
can lead to depressed metabolism and/or weight gain, paranoia,
grandiosity, hallucinations (e.g., classic schizophrenic symptoms),
tinnitus, hirsutism, visual and auditory abnormalities, anxiety and
food sensitivities. The potential costs (both emotional and
financial) of histamine imbalance, be they to an individual person
or family, related to societal lost productivity and/or burdens on
the medical system, are immense. In 2012 America will have spent
$200 billion in direct costs for those with Alzheimer's Disease.
Caring for people with Alzheimer's Disease is estimated to cost at
least $20 trillion over the next 40 years. Furthermore, the
economic burden of Parkinson's disease is at least $14.4 billion a
year with an estimate that the prevalence of Parkinson's disease
will more than double by year 2040.
[0005] Several embodiments of the present invention relate to the
use of agents that up-regulate or down-regulate expression and/or
activity of one or more histamine receptors. Histamine agonists and
antagonists, naturally-occurring or synthetic, are provided in
several embodiments. For example, in one embodiment, titrated
histamine dosing regimens are used to restore normal histamine
function. The dosing regimens are useful, in several embodiments,
for restoring histamine function in patients having deficient or
excessive levels of histamine, and can be used to treat or prevent
any disorders in which histamine imbalance plays a causative
role.
[0006] Although histamine is used as the therapeutic agent in many
embodiments, the invention is not limited to the administration of
histamine. For example, therapeutic agents that mimic the effects
of histamine are used in some embodiments. Histamine agonists,
antagonists, and other agents that interact or interfere with
histamine receptors are used as therapeutic agents in several
embodiments. Therapeutic agents may, for example, provide stop the
progression of symptoms, or may reduce or prevent the onset or
severity of symptoms. A surprising versatile dosing regimen has
been developed for the administration of histamine, or other
therapeutic agent, that relies, in several embodiments, on
sequential dosing segments. In several embodiments, each segment
includes a plurality of escalating doses. For example, in one
embodiment, the regimen comprises a plurality of dosing segments,
each comprising a plurality of doses, wherein each segment is
defined by the same volume for every dose and the same time
interval between every dose, but concentrations of the therapeutic
agent (e.g., histamine) are increased from dose to dose, and each
successive segment is defined by a greater dosing volume than the
previous segment and a longer time interval between doses. The
administration of histamine or other therapeutic agent, as used
herein, includes the administration of its pharmaceutically
acceptable salt (such as, for example, histamine phosphate,
histamine dihydrochloride or any other histamine salt). Thus,
references to the administration of histamine encompass the
administration of pharmacologically acceptable salts and forms in
several embodiments. A histamine receptor activator includes but is
not limited to histamine (and its pharmacologically acceptable
salts and other forms). Moreover, in several embodiments, adjunct
therapeutic interventions are used, either in place of, or in
conjunction with administration of histamine and/or an additional
therapeutic agent. For example, in several embodiments, an
electromagnetic device is used to generate a magnetic field that
can be focused (or applied diffusely) to a subject having
imbalanced histamine levels. In several embodiments,
electromagnetic energy is delivered to a subject to return
histamine levels to within normal ranges. In some embodiments, the
electromagnetic energy is tailored (e.g., by frequency, wavelength,
field strength, etc.) to target one or more specific histamine
receptors. In several embodiments, the use of electromagnetic
devices acts synergistically with administration of histamine to
return histamine levels to normal ranges. However, as discussed
above, in several embodiments, such devices are used independent of
histamine administration (or administration of other therapeutic
agents).
[0007] Thus, in several embodiments, the invention comprises or
consists essentially of an escalating dosing regimen comprising in
sequential order (a) a first dosing segment comprising two or more
sequential doses of a therapeutic agent (e.g., histamine) separated
by one or more equal time intervals (the "first time interval"),
wherein the doses increase in histamine concentration from dose to
dose while the administered volume of each dose stays constant; and
(b) a second dosing segment comprising two or more sequential doses
of a therapeutic agent (e.g., histamine) separated by one or more
equal time intervals (the "second time interval"), wherein the
doses increase in concentration from dose to dose while the
administered volume of each dose stays 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, and the second
time interval is longer than the first time interval. In several
embodiments, the invention comprises a multi-variable approach for
increasing or decreasing histamine levels. The multi-variable
approach is beneficial in several embodiments because physiological
parameters can be more finely-tuned. For example, cellular
distribution and receptor contact can be modulated to achieve
selective activation of certain histamine receptors, while leaving
other histamine receptors substantially unaffected.
[0008] In several embodiments, the invention includes administering
(or instructing the administration of) several doses of a
therapeutic agent (such as histamine or a histamine salt), as
described herein in various embodiments. For example, in some
embodiments, the invention includes administering a first therapy
segment that comprises or consists essentially of (i) activating a
histamine H3 receptor by administering to a subject a first dose of
a therapeutic agent (such as histamine or a histamine salt); (ii)
activating a histamine H4 receptor by administering a second dose
of the therapeutic agent; (iii) activating a histamine H1 receptor
by administering a third dose of the therapeutic agent; and (iv)
activating a histamine H2 receptor by administering a fourth dose
of the therapeutic agent. In additional embodiments, the invention
includes administering a first therapy segment that comprises or
consists essentially of (i) activating a histamine receptor
selected from the group consisting of at least one of a histamine
H3 receptor and a histamine H4 receptor by administering to a
subject a first dose of a therapeutic agent (such as histamine or a
histamine salt) in the range of 0.01 pg to 10 pg; (ii) activating a
histamine receptor selected from the group consisting of at least
one of a histamine H3 receptor and a histamine H4 receptor by
administering a second dose of the therapeutic agent; (iii)
activating a histamine H1 receptor by administering a third dose of
the therapeutic agent; and (iv) activating a histamine H2 receptor
by administering a fourth dose of the therapeutic agent. A second
therapy segment having individual doses is further administered in
which the total amount of therapeutic agent is greater than the
total amount given in the first therapy segment. A third therapy
segment having individual doses is further administered in which
the total amount of the therapeutic agent is greater than the
amount given in the second therapy segment. A fourth, fifth, sixth,
etc. therapy segment with escalating total dose amounts may be
optionally administered. In one embodiment, the invention includes
of a kit or regimen that comprises or consists essentially of a
therapeutic agent (such as histamine or a histamine salt) provided
in total amount (which can be provided in single one-time
disposable vials, syringes, or ampules) ranging from about 200 ng
to 600 ng for the first therapy segment, 2 times as much in the
second therapy segment, and 1.5 times as much (as compared to the
second therapy segment) in the third therapy segment. As an
example, if the total amount of a therapy segment is 1000 ng, four
vials of individual doses of 1 ng, 10 ng, 100 ng, and 889 ng can be
provided. The volumes of the doses are also altered in several
embodiments. The varying volumes are particularly beneficial, in
some embodiments, because increased volumes provide for a different
distribution and/or pharmacokinetic profile. In some embodiments,
the ratio of total amounts given in each therapy segment is 1:2:3
(for three segments), 1:2:3:4 (for four segments), 1:2:3:4:5 (for
five segments). In some embodiments, the ratio of individual doses
within in a given therapy segment is
1:10.sup.3:10.sup.6:3.5.times.10.sup.6.
[0009] In some embodiments, the method is used to treat imbalances
of histamine (the imbalance being evidenced by sub-optimal or
supra-optimal histamine levels in the bloodstream and/or urine,
and/or other symptoms or characteristics of histamine imbalance).
Thus, in several embodiments, there is provided a method of
lowering histamine levels in a subject (e.g., a human patient)
having a histamine level above a level required for optimum
histamine function (as in histadelia), comprising administering
histamine thereof to the subject according to the dosing regimens
disclosed herein.
[0010] As used herein, the terms "treating" and "treatment", shall
be given their ordinary meanings and shall also include providing a
therapy to a patient with the intent to cure, ameliorate,
stabilize, or prevent a disease, pathological condition, or
disorder. The terms include active treatment (e.g., treatment
directed specifically toward the improvement of a disease,
pathological condition, or disorder) and causal treatment (e.g.,
treatment directed toward removal of the cause of the associated
disease, pathological condition, or disorder). In addition, these
terms shall also include palliative treatment (e.g., treatment
designed for the relief of symptoms), preventative treatment (e.g.,
treatment directed to minimizing or partially or completely
inhibiting the development of an associated disease, pathological
condition, or disorder) and supportive treatment (e.g., treatment
employed to supplement another specific therapy directed toward the
improvement of the associated disease, pathological condition, or
disorder).
[0011] In several embodiments, the invention comprises selective
activation and deactivation of the histamine receptors, namely H1,
H2, H3 and H4. Histamine or other therapeutic agents that bind or
block these receptors, or increase or decrease the ability of
histamine (endogenous or exogenous histamine) to bind to the
receptors are used in several embodiments. In some embodiments, the
invention comprises the downregulation of the H1 receptor and the
upregulation of one, two or all of the H2, H3 and H4 receptor. In
several embodiments, the invention includes therapeutic agents that
regulate the endogenous histamine system. These therapeutic agents
are provided in dosing schedules as described herein according to
several embodiments. Thus, instead of (or in addition to) affecting
histamine receptors directly, a therapeutic agent that increases or
decreases the manufacture, release, modification, uptake or
degradation of histamine is provided. In one embodiment, selective
histamine reuptake inhibitors are used. In some embodiments,
therapeutic agents that up-regulate or down-regulate
methyltransferase and/or diamine oxidase are used to decrease or
increase endogenous histamine. Compositions that include
methyltransferase and/or diamine oxidase, or agents with similar
function, are provided in some embodiments.
[0012] In several embodiments, therapeutic agents that regulate
endogenous GABA are provided, which in turn affects 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 that regulate
GABA-B receptors or other receptors located on the histaminergic
nerve terminals that modulate histamine release (e.g.,
pre-synaptically or post-synaptically) are provided.
[0013] In several embodiments, there is also provided a method of
increasing histamine levels in a subject (e.g., a human patient)
having a histamine level below a level required for optimum
histamine function (as in histapenia), comprising administering a
therapeutically effective amount of a therapeutic agent (e.g.,
histamine) to a subject according to the dosing regimens disclosed
herein. As used herein, the term "therapeutically effective amount"
shall be given its ordinary meaning and shall also include an
amount of a therapeutic agent sufficient to elicit a desired
biological response. Depending on the embodiment, the
therapeutically effective amount may depend on the age, sex and
weight of the patient, and/or the current medical condition of the
patient.
[0014] In several embodiments, there is also provided a method for
restoring histamine balance in a subject by normalizing activity of
histamine receptors through multiple doses administered in
successive therapy segments, comprising administering a first
therapy segment, that first therapy segment comprising activating a
histamine H3 receptor by administering to a subject a first dose of
a histamine receptor activator, activating a histamine H4 receptor
by administering to a subject a second dose of the histamine
receptor activator, activating a histamine H1 receptor by
administering to a subject a third dose of the histamine receptor
activator, activating a histamine H2 receptor by administering to a
subject a fourth dose of the histamine receptor activator, and
administering a second therapy segment, comprising administering
the histamine receptor activator in an amount greater than the
amount administered in the first therapy segment, and administering
a third therapy segment, comprising administering the histamine
receptor activator in an amount greater than the amount
administered in the second therapy segment. In additional
embodiments, there is also provided a method for restoring
histamine balance in a subject by normalizing activity of histamine
receptors through multiple doses administered in successive therapy
segments, comprising administering a first therapy segment, that
first therapy segment comprising activating one or more of a
histamine H3 receptor and a histamine H4 receptor by administering
to a subject a first dose of a histamine receptor activator,
activating a one or more of a histamine H3 receptor and a histamine
H4 receptor by administering to a subject a second dose of the
histamine receptor activator, activating a histamine H1 receptor by
administering to a subject a third dose of the histamine receptor
activator, activating a histamine H2 receptor by administering to a
subject a fourth dose of the histamine receptor activator, and
administering a second therapy segment, comprising administering
the histamine receptor activator in an amount greater than the
amount administered in the first therapy segment, and administering
a third therapy segment, comprising administering the histamine
receptor activator in an amount greater than the amount
administered in the second therapy segment. In several embodiments,
the increasing amount of the histamine receptor activator
administered in each successive therapy segment suppresses activity
of the histamine H1 receptor and enhances activity of a histamine
receptor selected from the group consisting of the histamine H2,
H3, and H4 receptors, thereby normalizing the activity of the
histamine receptors and restoring histamine balance.
[0015] In several embodiments, there is also provided a method for
restoring histamine balance in a subject by normalizing activity of
histamine receptors through multiple doses administered in
successive therapy segments, comprising administering a first
therapy segment to the subject, the first segment comprising
administering to a subject a first dose of a therapeutic agent that
binds a histamine H3 receptor by administering to the subject a
first dose of a therapeutic agent, administering to the subject a
second dose of a therapeutic agent that binds a histamine H4
receptor by administering to the subject a second dose of the
therapeutic agent, administering to the subject a first dose of a
therapeutic agent that binds a histamine H1 receptor by
administering to the subject a third dose of the therapeutic agent,
administering to the subject a first dose of a therapeutic agent
that binds a histamine H2 receptor by administering to the subject
a fourth dose of the therapeutic agent, administering a second
therapy segment to the subject, the second segment comprising
administering the therapeutic agent in an amount greater than the
amount administered in the first therapy segment, and administering
a third therapy segment to the subject, the third segment
comprising administering the therapeutic agent in an amount greater
than the amount administered in the second therapy segment.
Additionally, in several embodiments, there is also provided a
method for restoring histamine balance in a subject by normalizing
activity of histamine receptors through multiple doses administered
in successive therapy segments, comprising administering a first
therapy segment to the subject, the first segment comprising
administering to a subject a first dose of a therapeutic agent that
binds 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 a therapeutic agent, administering
to the subject a second dose of a therapeutic agent that binds a
histamine receptor selected from the group consisting of a
histamine H3 receptor and a histamine H4 receptor by administering
to the subject a second dose of the therapeutic agent,
administering to the subject a first dose of a therapeutic agent
that binds a histamine H1 receptor by administering to the subject
a third dose of the therapeutic agent, administering to the subject
a first dose of a therapeutic agent that binds a histamine H2
receptor by administering to the subject a fourth dose of the
therapeutic agent, administering a second therapy segment to the
subject, the second segment comprising administering the
therapeutic agent in an amount greater than the amount administered
in the first therapy segment, and administering a third therapy
segment to the subject, the third segment comprising administering
the therapeutic agent in an amount greater than the amount
administered in the second therapy segment.
[0016] There is also provided, in several embodiments, methods for
down-regulating a histamine H1 receptor comprising administering a
first therapy segment, comprising administering to a subject a
first dose of a therapeutic agent that binds a histamine H3
receptor administering to the subject a first dose of the
therapeutic agent, administering to the subject a second dose of a
therapeutic agent that binds a histamine H4 receptor by
administering to the subject a second dose of the therapeutic
agent, administering to the subject a first dose of a therapeutic
agent that binds a histamine H1 receptor by administering to the
subject a third dose of the therapeutic agent, administering to the
subject a first dose of a therapeutic agent that binds a histamine
H2 receptor by administering to the subject a fourth dose of the
therapeutic agent, administering to the subject a second therapy
segment, the second segment comprising administering the
therapeutic agent in an amount greater than the amount administered
in the first therapy segment, administering a third therapy segment
to the subject, the third segment comprising: administering the
therapeutic agent in an amount greater than the amount administered
in the second therapy segment, wherein the increasing amount of the
therapeutic agent administered in each successive therapy segment
down-regulates activity of the histamine H1 receptor There is also
provided, in several embodiments, methods for down-regulating a
histamine H1 receptor comprising administering a first therapy
segment, comprising administering to a subject a first dose of a
therapeutic agent that binds 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 to the subject a second dose of a
therapeutic agent that binds a histamine receptor selected from the
group consisting of a histamine H3 receptor and a histamine H4
receptor by administering to the subject a second dose of the
therapeutic agent, administering to the subject a first dose of a
therapeutic agent that binds a histamine H1 receptor by
administering to the subject a third dose of the therapeutic agent,
administering to the subject a first dose of a therapeutic agent
that binds a histamine H2 receptor by administering to the subject
a fourth dose of the therapeutic agent, administering to the
subject a second therapy segment, the second segment comprising
administering the therapeutic agent in an amount greater than the
amount administered in the first therapy segment, administering a
third therapy segment to the subject, the third segment comprising:
administering the therapeutic agent in an amount greater than the
amount administered in the second therapy segment, wherein the
increasing amount of the therapeutic agent administered in each
successive therapy segment down-regulates activity of the histamine
H1 receptor. Optionally, additional therapy segments can be
administered as well.
[0017] In several embodiments, the histamine receptor activator is
administered in one or more of varied concentration (e.g.,
increased concentration as compared to a preceding administration),
varied volume (e.g., increased concentration as compared to a
preceding administration), or with a varied timing (e.g., the
frequency of administration is reduced with successive segments).
The tri-variable approach is beneficial in several embodiments,
because cellular distribution and receptor contact can be adjusted.
In this manner, selective activation of receptors can be achieved.
Moreover, in several embodiments, the sequence of receptor
activation can be altered depending on the condition being treated.
For example, in several embodiments, a therapeutic agent can be
administered at a dose sufficient to preferentially activate or
bind an H1 receptor, and increase histamine levels in a subject
(e.g., to treat histapenia). Alternatively, a therapeutic agent can
be administered at a dose sufficient to preferentially activate or
bind H2 and/or H3 receptor (which in several embodiments suppresses
the activity and/or expression of the histamine H1 receptor and
leads to reduction in histamine levels, such as when treating
histadelia).
[0018] In several embodiments, the therapeutic agent and/or
histamine receptor activator comprises histamine. In several
embodiments, the histamine receptor activator comprises a histamine
salt selected from the group consisting of histamine diphosphate,
histamine phosphate, and histamine dihydrochloride. Combinations of
these salts or other various salts of histamine may also be used,
depending on the embodiment.
[0019] In several embodiments the successive therapy segments
(e.g., the second, third, etc. therapy segment) comprises at least
a first dose, a second dose, a third dose and a fourth dose of the
histamine receptor activator. Optionally several embodiments
comprise administering at least a fourth therapy segment, wherein
the fourth therapy segment comprises administering the histamine
receptor activator in an amount greater than the amount
administered in the third therapy segment.
[0020] In several embodiments, the total dose of the histamine
receptor activator in the first therapy segment ranges from about
100 ng to 700 ng, including about 200 ng to about 600 ng, about 300
ng to about 500 ng, about 400 ng, and overlapping ranges thereof.
In several embodiments, the total dose of the histamine receptor
activator in the second therapy segment ranges from about 600 ng to
about 1000 ng, including about 600 ng to about 800 ng, about 650 ng
to about 1000 ng, about 800 ng to about 1000 ng, and overlapping
ranges therein. In several embodiments, the total dose of the
histamine receptor activator in the third therapy segment ranges
from about 1050 ng to about 1600 ng, including about 1050 ng to
about 1200 ng, about 1200 ng to about 1300 ng, 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 overlapping
ranges thereof. In several embodiments, these doses are provided in
varying volumes using a multi-variable approach, which in some
embodiments, results in certain histamine receptors being activated
to a greater degree than other histamine receptors. For example,
the affinities in Table 1 are exploited in several embodiments of
the invention to induce a targeted, sequenced and controlled
histamine receptor activation pattern.
[0021] In several embodiments, the second therapy segment is longer
in time than the first therapy segment and wherein the third
therapy segment is longer in time than the second therapy segment.
In embodiments wherein additional therapy segments are
administered, successive therapy segments are optionally longer in
duration than those preceding it (e.g., each successive segment is
longer in duration). In several embodiments, the frequency of
administration of the therapeutic agent (e.g., a histamine receptor
activator) remains constant from segment to segment, such that the
increased duration of successive segments reduces the
administration frequency (as compared to the previous segment). By
way of example, in several embodiments, the first therapy segment
occurs over 10-16 days, the second therapy segment occurs over
20-35 days, and the third therapy segment occurs over 38-50 days.
In additional embodiments, the first therapy segment is optionally
administered on a compressed time-frame. For example, in several
embodiments the doses comprising the first therapy segment are, in
several embodiments, administered within a shortened time frame
(e.g., about 30 seconds to about 5 minutes). As a result, the
modulation of the various receptors occurs on a reduced time-frame,
and in some embodiments, simultaneously. In such embodiments, the
first therapy segment advantageously "jump-starts" the regimen by
concurrent receptor modulation. In several embodiments, the first
therapy segment comprises simultaneously delivery of each of the
doses within the segment. In several embodiments, the first therapy
segment is compressed to occur over about 1-2 minutes, about 2-3
minutes, about 3-4 minutes, about 4-5 minutes, about 5-10 minutes,
about 10-20 minutes, about 20-30 minutes, and overlapping ranges
thereof.
[0022] In several embodiments, the administration of the
therapeutic agent (e.g., a histamine receptor activator) comprises
subcutaneous injection of histamine or a histamine salt, wherein
the total dose of the first therapy segment is about 200 ng to
about 600 ng, wherein the total dose of the second therapy segment
is about 650 ng to about 1000 ng, wherein the total dose of the
third therapy segment is about 1050 ng to about 1500 ng, wherein
the second therapy segment is longer than the first therapy system,
and wherein the third therapy segment is longer than the second
therapy system.
[0023] In additional embodiments, administration of the therapeutic
agent (e.g., a histamine receptor activator) comprises intravenous
injection. In still further embodiments, the therapeutic agent
(e.g., a histamine receptor activator) is administered by an oral
delivery route. In still further embodiments, the therapeutic agent
(e.g., a histamine receptor activator) is administered by
inhalation. In still further embodiments, the therapeutic agent
(e.g., a histamine receptor activator) is administered through a
transdermal patch. In several embodiments, the administration of
the therapeutic agent (e.g., a histamine receptor activator)
comprises a route selected from the group consisting of
subcutaneous, intraarterial, intravenous, and combinations thereof.
Depending on the embodiment, a given segment may be delivered by a
first route of administration (e.g., subcutaneous), while another
segment is delivered by a different route (e.g., oral). In several
embodiments, modification of the administration route reduces risk
of side effects associated with a single administration route.
Moreover, in several embodiments, the change in administration
route enables a greater proportion of the histamine receptors in
certain organ banks to be reached. For example, oral administration
may facilitate restoration of balance of histamine receptor
activity in the gastrointestinal tract to a greater degree than
intravenous administration. In several embodiments, the therapeutic
agent is delivered by a non-invasive administration route. In
several embodiments, the therapeutic agent is self-administered. In
several embodiments, the therapeutic agent is administered by, for
example, a nurse, a physician, a hospice care worker, and/or
another medical provider, while in some embodiments, the
therapeutic agent is administered by a an individual who is not a
medical professional (e.g., a non-medical professional, such as,
for example, an acquaintance, family member, spouse, etc.).
[0024] In several embodiments, the subject receiving therapy is
susceptible to migraine headaches and the restored histamine
balance leads to a reduction in duration, frequency and/or
intensity of migraine headaches.
[0025] In several embodiments, the subject receiving therapy has
histadelia and the restored histamine balance treats the
histadelia. In several embodiments, the subject receiving therapy
has histapenia and the restored histamine balance treats the
histapenia.
[0026] In several embodiments, therapeutic agent (e.g., a histamine
receptor activator) is provided as a liquid formulation. In several
embodiments, the first dose of the histamine receptor activator in
the first therapy segment has a concentration ranging from between
about 0.1 pg/mL to about 10 pg/mL, including about 0.5 pg/mL, about
1 pg/mL, about 2 pg/mL, about 3 pg/mL, about 4 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.
[0027] In several embodiments, the second dose of the histamine
receptor activator in the first therapy segment has a concentration
ranging from between about 0.1 ng/mL to about 10 ng/mL, including
about 0.5 ng/mL, about 1.0 ng/mL, about 2 ng/mL, about 3 ng/mL,
about 4 ng/mL, 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.
[0028] In several embodiments, the third dose of the histamine
receptor activator in the first therapy segment has a concentration
ranging from between about 0.1 .mu.g/mL to about 2.999 .mu.g/mL
(e.g., about 0.1 .mu.g/mL to about 2.999 .mu.g/mL), including about
0.1 .mu.g/mL, about 0.5 .mu.g/mL, about 1 .mu.g/mL, about 1.5
.mu.g/mL, about 2 .mu.g/mL, about 2.5 .mu.g/mL, about 2.999
.mu.g/mL, and concentrations therebetween. In several embodiments,
the third dose of the histamine receptor activator in the first
therapy segment has a concentration ranging from between about 0.1
.mu.g/mL to about 3.49 .mu.g/mL, including about 0.1 .mu.g/mL,
about 0.5 .mu.g/mL, about 1 .mu.g/mL, about 1.5 .mu.g/mL, about 2
.mu.g/mL, about 2.5 .mu.g/mL, about 3 .mu.g/mL, about 3.49
.mu.g/mL, and concentrations therebetween.
[0029] In several embodiments, the fourth dose of the histamine
receptor activator in the first therapy segment has a concentration
ranging from between about 3.0 .mu.g/mL to about 10 .mu.g/mL,
including about 3 .mu.g/mL, about 3.5 .mu.g/mL, about 4 .mu.g/mL,
about 4.5 .mu.g/mL, about 5 .mu.g/mL, about 6 .mu.g/mL, about 7
.mu.g/mL, about 8 .mu.g/mL, about 9 .mu.g/mL, about 10 .mu.g/mL,
and concentrations therebetween. In several embodiments, the fourth
dose of the histamine receptor activator in the first therapy
segment has a concentration ranging from between about 0.35
.mu.g/mL to about 10 .mu.g/mL, including about 0.35 .mu.g/mL, about
0.75 .mu.g/mL, about 1 .mu.g/mL, about 1.5 .mu.g/mL, about 2
.mu.g/mL, about 2.5 .mu.g/mL, about 3 .mu.g/mL, about 3.5 .mu.g/mL,
about 4 .mu.g/mL, about 4.5 .mu.g/mL, about 5 .mu.g/mL, about 6
.mu.g/mL, about 7 .mu.g/mL, about 8 .mu.g/mL, about 9 .mu.g/mL,
about 10 .mu.g/mL, and concentrations therebetween.
[0030] In several embodiments, the volume of each dose in the first
therapy segment ranges from between about 0.01 mL to about 1.0 mL,
including about 0.1 mL, about 0.5 mL, about 0.75 mL, about 1 mL,
and volumes therebetween. In several embodiments, the histamine
receptor activator is administered with a frequency of between one
and three times per week during the first therapy segment, such as,
for example, two times per week during the first therapy
segment.
[0031] In several embodiments, the second therapy segment comprises
a first dose, a second dose, a third dose, and a fourth dose, and
the first dose in the second therapy segment has a concentration
ranging from between about 0.1 pg/mL to about 10 pg/mL (e.g., about
0.1 pg/mL, about 1 pg/mL, about 5 pg/mL, about 10 pg/mL and
concentrations therebetween). In several embodiments, the second
dose in the second therapy segment has a concentration ranging from
between about 0.1 ng/mL to about 10 ng/mL (e.g., about 0.5 ng/mL,
about 1.0 ng/mL, about 5 ng/mL, about 10 ng/mL, and concentrations
therebetween). In several embodiments, the third dose in the second
therapy segment has a concentration ranging from between about 0.1
.mu.g/mL to about 2.999 .mu.g/mL (e.g., about 0.1 .mu.g/mL, about
about 1 .mu.g/mL, about 2 .mu.g/mL, about 2.5 .mu.g/mL, about 2.999
.mu.g/mL, and concentrations therebetween). In several embodiments,
the fourth dose in the second therapy segment has a concentration
ranging from between about 3.0 .mu.g/mL to about 10 .mu.g/mL (e.g.,
about 3.0 .mu.g/mL, about 3.5 .mu.g/mL, about 4 .mu.g/mL, about 4.5
.mu.g/mL, about 6 .mu.g/mL, about 8 .mu.g/mL, about 10 .mu.g/mL,
and concentrations therebetween). In additional embodiments, the
third dose in the second therapy segment has a concentration
ranging from between about 0.1 .mu.g/mL to about 3.49 .mu.g/mL
(e.g., about 0.1 .mu.g/mL, about about 1 .mu.g/mL, about 2
.mu.g/mL, about 3 .mu.g/mL, about 3.49 .mu.g/mL, and concentrations
therebetween). In several embodiments, the fourth dose in the
second therapy segment has a concentration ranging from between
about 0.35 .mu.g/mL to about 10 .mu.g/mL (e.g., about 0.35
.mu.g/mL, about 1 .mu.g/mL, about 1.5 .mu.g/mL, about 3 .mu.g/mL,
about 3.5 .mu.g/mL, about 4 .mu.g/mL, about 4.5 .mu.g/mL, about 6
.mu.g/mL; about 8 .mu.g/mL, about 10 .mu.g/mL, and concentrations
therebetween).
[0032] In several embodiments, the volume of each dose in the
second therapy segment ranges from between about 0.02 mL to about
2.0 mL, such as, 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 volumes
therebetween.
[0033] In several embodiments, the second segment comprises
administration of the histamine receptor activator with a frequency
of between 2 times per week and once every 10 days during the
second therapy segment, such as, for example, once per week, twice,
per week, once every eight days, once every ten days, and
frequencies therebetween.
[0034] In several embodiments, the third therapy segment comprises
a first dose, a second dose, a third dose, and a fourth dose, and
the first dose in the third therapy segment has a concentration
ranging from between about 0.1 pg/mL to about 10 pg/mL (e.g., about
0.1 pg/mL, about 1 pg/mL, about 5 pg/mL, about 10 pg/mL and
concentrations therebetween). In several embodiments, the second
dose in the third therapy segment has a concentration ranging from
between about 0.1 ng/mL to about 10 ng/mL (e.g., about 0.5 ng/mL,
about 1.0 ng/mL, about 5 ng/mL, about 10 ng/mL, and concentrations
therebetween). In several embodiments, the third dose in the third
therapy segment has a concentration ranging from between about 0.1
.mu.g/mL to about 2.999 .mu.g/mL (e.g., about 0.1 .mu.g/mL, about
about 1 .mu.g/mL, about 2 .mu.g/mL, about 2.999 .mu.g/mL, and
concentrations therebetween). In several embodiments, the fourth
dose in the third therapy segment has a concentration ranging from
between about 3.0 .mu.g/mL to about 10 .mu.g/mL (e.g., about 3
.mu.g/mL, about 3.5 .mu.g/mL, about 4 .mu.g/mL, about 4.5 .mu.g/mL,
about 6 .mu.g/mL, about 8 .mu.g/mL, about 10 .mu.g/mL, and
concentrations therebetween). In several embodiments, the third
dose in the third therapy segment has a concentration ranging from
between about 0.1 .mu.g/mL to about 3.49 .mu.g/mL (e.g., about 0.1
.mu.g/mL, about about 1 .mu.g/mL, about 2 .mu.g/mL, about 3
.mu.g/mL, about 3.49 .mu.g/mL, and concentrations therebetween). In
several embodiments, the fourth dose in the third therapy segment
has a concentration ranging from between about 0.35 .mu.g/mL to
about 10 .mu.g/mL (e.g., about 0.35 .mu.g/mL, about 1 .mu.g/mL,
about 1.5 .mu.g/mL, about 3 .mu.g/mL, about 3.5 .mu.g/mL, about 4
.mu.g/mL, about 4.5 .mu.g/mL, about 6 .mu.g/mL, about 8 .mu.g/mL,
about 10 .mu.g/mL, and concentrations therebetween).
[0035] In several embodiments, the volume of each dose in the third
therapy segment ranges from between about 0.03 mL to about 3.0 mL,
such as, 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 volumes
therebetween.
[0036] In several embodiments, the third segment comprises
administration of the histamine receptor activator with a frequency
of between once per week and once every two weeks during the third
therapy segment, such as, for example, once per week, once every
eight days, once every ten days, once every twelve days, once every
fourteen days, and frequencies therebetween.
[0037] Additionally, there are provided, in several embodiments,
methods for reducing, ameliorating, preventing, and/or inhibiting
the frequency, duration and/or intensity of migraine headaches in a
subject through normalization of the activity and/or expression of
one or more histamine receptors, comprising identifying a subject
susceptible to migraine headaches and having a histamine imbalance,
administering to the subject a first histamine dosing segment
comprising a first, a second, a third, and a fourth dose of
histamine, wherein the first dose is administered subcutaneously at
a concentration between about 0.1 pg/mL to about 10 pg/mL and
activates a histamine receptor selected from the group consisting
of a histamine H3 receptor and a histamine H4 receptor, wherein the
second dose of histamine is administered subcutaneously at a
concentration between about 0.1 ng/mL to about 10 ng/mL and
activates a histamine receptor selected from the group consisting
of a histamine H3 receptor and a histamine H4 receptor, wherein the
third dose of histamine is administered subcutaneously at a
concentration between about 0.1 .mu.g/mL to about 3.49 .mu.g/mL
(for example, between about 0.1 .mu.g/mL to about 2.999 .mu.g/mL)
and activates a histamine H1 receptor, wherein the fourth dose of
histamine is administered subcutaneously at a concentration between
about 0.35 .mu.g/mL to about 10 .mu.g/mL (for example, about 3.0
.mu.g/mL to about 10 .mu.g/mL) and activates a histamine H2
receptor, wherein each dose in the first dosing segment has the
same volume and wherein the volume ranges from between about 0.01
mL to about 1.0 mL, wherein each successive dose comprises a larger
amount of histamine as compared to the preceding dose;
administering to the subject a second histamine dosing segment
comprising a first, a second, a third, and a fourth dose of
histamine, wherein the concentration of the histamine administered
in each dose is equivalent to the corresponding concentration of
histamine each dose of the first dosing segment, wherein each dose
in the second dosing segment has the same volume, and wherein the
volume ranges from between about 0.02 mL to about 2.0 mL, wherein
the total amount of histamine delivered in the second dosing
segment is greater than the amount delivered in the first dosing
segment; and administering to the subject a third histamine dosing
segment comprising a first, a second, a third, and a fourth dose of
histamine, wherein the concentration of the histamine administered
in each dose is equivalent to the corresponding concentration of
histamine each dose of the first dosing segment, wherein each dose
in the third dosing segment has the same volume, and wherein the
volume ranges from between about 0.03 mL to about 3.0 mL, wherein
the total amount of histamine delivered in the third dosing segment
is greater than the amount delivered in the second dosing segment.
In several embodiments, the increase in the amount of histamine
administered with each successive dosing segment suppresses
activity of the H1 receptor and enhances activity of the H2, H3
and/or H4 receptors, thereby normalizing the activity and/or
expression of the histamine receptors and reducing the duration,
frequency and/or intensity of migraine headaches in the
subject.
[0038] In several embodiments, the ratio of individual doses within
any of the first, second, or third therapy segment is
1:10.sup.3:10.sup.6:3.5.times.10.sup.6. As discussed above, these
ratios (either by adjustment of volume or concentration) can be
adjusted if a subject requires an increase or a decrease in
histamine activity (or receptor expression). The methods also
optionally include administration of an additional agonist or an
antagonist of any of the histamine H1, H2, H3, or H4 receptors.
Moreover, the methods, in several embodiments, include one or more
of identifying a subject having histamine imbalance (such as for
example, but measuring the serum and/or urine histamine
concentrations) and instructing administration of the therapeutic
agent.
[0039] There are also provided herein histamine receptor activators
for use in up-regulating certain histamine receptors and
down-regulating other histamine receptors to balance the histamine
system, which in turn may be useful for the treatment of migraine
headaches, Parkinson's Disease, Alzheimer's Disease, coronary
disease, leukemia, amyotrophic lateral sclerosis, epilepsy
histadelia and/or histapenia and other disorders. In several
embodiments, there is additionally provided a histamine receptor
activator(s) for use in the treatment of migraine headaches,
Parkinson's Disease, Alzheimer's Disease, coronary disease,
leukemia, amyotrophic lateral sclerosis and/or epilepsy, histadelia
and/or histapenia by administration of a dosage of the activator
divided into at least three therapy segments, wherein the total
dose of the histamine receptor activator in the first therapy
segment is about 200 ng to about 600 ng, wherein the total dose of
the histamine receptor activator in the second therapy segment is
about 650 ng to about 1000 ng, and wherein the total dose of the
histamine receptor activator in the third therapy segment is about
1050 ng to about 1500 ng.
[0040] There is also provided a histamine receptor activator for
use in the treatment of migraine headaches by subcutaneous
administration of said histamine receptor activator. In several
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.
[0041] Also provided herein is a histamine receptor activator (or
activators) for use in the treatment of migraine headaches,
Parkinson's Disease, Alzheimer's Disease, coronary disease,
leukemia, amyotrophic lateral sclerosis epilepsy, histadelia and/or
histapenia (or other ailments) in patients showing an elevated
amount of circulating histamine as well as ailments in which
patients show a reduced amount of circulating histamine. Thus, in
several embodiments, the invention comprises a histamine receptor
activator for regulating endogenous histamine levels, including but
not limited to use in the treatment of migraine headaches,
Parkinson's Disease, Alzheimer's Disease, coronary disease,
leukemia, amyotrophic lateral sclerosis, epilepsy, histadelia
and/or histapenia to restore histamine balance in the subject.
[0042] In several embodiments, the invention comprises a histamine
receptor activator (or activators) for use in the treatment of
migraine headaches, Parkinson's Disease, Alzheimer's Disease,
coronary disease, leukemia, amyotrophic lateral sclerosis,
epilepsy, histadelia and/or histapenia by inhibiting the activity
and/or expression of a histamine receptor selected from the group
consisting of the histamine H1 receptor, the histamine H2 receptor,
the histamine H3 receptor, and the histamine H4 receptor. In
several embodiments, the histamine receptor activator inhibits the
activity and/or expression of the histamine H1 receptor.
[0043] In several embodiments, the invention comprises a histamine
receptor activator for use in the treatment of diseases associated
with the over-expression and/or over-activity of the histamine H1
receptor, such as, for example, one or more of migraine headaches,
Parkinson's Disease, Alzheimer's Disease, coronary disease,
leukemia, amyotrophic lateral sclerosis epilepsy, histadelia and/or
histapenia. Similarly, there is provided, in several embodiments, a
histamine receptor activator for use in the treatment of diseases
associated with the under-expression and/or under-activity one or
more of the histamine H2, H3, and/or H4 receptors, such as, for
example, migraine headaches, Parkinson's Disease, Alzheimer's
Disease, coronary disease, leukemia, amyotrophic lateral sclerosis,
epilepsy, histadelia and/or histapenia.
[0044] In several embodiments, the invention comprises, a histamine
receptor activator(s) for use in the treatment of migraine
headaches, Parkinson's Disease, Alzheimer's Disease, coronary
disease, leukemia, amyotrophic lateral sclerosis, epilepsy,
histadelia and/or histapenia by combined, sequential, or separate
administration with a complete or partial antagonist of a histamine
H1 receptor.
[0045] In several embodiments, the invention comprises an inhibitor
of the activity and/or expression of a histamine H1 receptor for
use in the treatment of migraine headaches, Parkinson's Disease,
Alzheimer's Disease, coronary disease, leukemia, amyotrophic
lateral sclerosis, epilepsy, histadelia and/or histapenia.
[0046] Additionally provided herein is an escalating histamine
dosing regimen comprising a first dosing segment comprising two or
more sequential doses of histamine separated by a first time
interval, wherein the doses increase in histamine concentration
from dose to dose while the administered volume of each dose stays
constant and a second dosing segment comprising two or more
sequential doses of histamine separated by a second time interval,
wherein the doses increase in histamine concentration from dose to
dose while the administered volume of each dose stays constant
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. In several embodiments, the first dosing
segment comprises a first, a second, a third, and a fourth dose. In
some such embodiments, the first dose is administered
subcutaneously at a concentration of 1.1 ng/mL +/-20-30% and
activates a histamine H3 receptor, the second dose of histamine is
administered subcutaneously at a concentration of 3 ng/mL +/-40-50%
and activates a histamine H4 receptor, the third dose of histamine
is administered subcutaneously at a concentration of 1.1 .mu.g/mL
+/-20-30% and activates a histamine H1 receptor, and the fourth
dose of histamine is administered subcutaneously at a concentration
of 3.33 .mu.g/mL +/-20-30% and activates a histamine H2
receptor.
[0047] In several embodiments of the histamine dosing regimen, the
concentrations of histamine administered during the first dosing
segment are the same as the concentrations of histamine
administered during the second dosing segment, the number of doses
administered during the first dosing segment is equal to the number
of doses administered during the second dosing segment, the first
dosing segment and the second dosing segment are separated by the
first time interval.
[0048] Optionally, 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 the
doses increase in histamine concentration from dose to dose while
the administered volume of each dose stays constant, the volume of
each dose in the third dosing segment is greater 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 such,
embodiments, the concentrations of histamine administered during
the third dosing segment are the same as the concentrations of
histamine administered during the second dosing segment, the number
of doses administered during the third dosing segment is equal to
the number of doses administered during the second dosing segment,
and the second dosing segment and the third dosing segment are
separated by the second time interval.
[0049] Depending on the embodiment, each dosing segment may
comprise three or more doses, for example, in some embodiments,
each dosing segment comprises four doses, five doses, six doses,
eight doses, or ten doses.
[0050] As discussed herein, there are also provided, in several
embodiments, extended duration regimens, such as those comprising
up to ten (or more) sequential dosing segments, wherein each dosing
segment comprises two or more sequential doses of histamine
separated by one or more equal time intervals, the doses in each
segment increase in histamine concentration from dose to dose while
the administered volume of each dose stays constant, the volume of
each histamine dose in a succeeding dosing segment is greater than
the volume of each histamine dose in the preceding dosing segment,
the time interval in each succeeding dosing segment is longer than
the time interval in the preceding dosing segment, the
concentrations of histamine administered are the same in each
dosing segment, the number of doses administered during each
segment is equal, and/or each succeeding dosing segment is separate
from the immediately preceding dosing segment by the time interval
observed for the immediately preceding dosing segment.
[0051] For example, in some extended dosing regimen embodiments
comprising ten dosing segments, the volume per dose in the first
segment is about 0.1 mL and the volume of each dose in each
succeeding segment is about 0.1 mL greater than the volume
administered in the immediately preceding segment.
[0052] In several embodiments, the histamine concentration of each
dose in each segment ranges from about 1 attogram/ml to 20
.mu.g/ml, such as for example concentrations ranging (for each
dose) from about 1 pg/ml to about 3.5 .mu.g/ml. (or, as in one
embodiment, 1 pg/ml to about 2.999 .mu.g/ml). In several
embodiments, the first dosing interval ranges from about one day to
one week in duration, and the second dosing interval ranges from
about three days to two weeks in duration. Subsequent dosing
intervals, in several embodiments, successively increase in
duration, such as for example, a third dosing interval may range
from about one week to about three weeks.
[0053] Depending on the embodiment, histamine used in the histamine
dosing regimen can be present as a free base, a pharmaceutically
acceptable salt thereof, or combinations thereof. Depending on the
embodiments, the route of administration is via subcutaneous,
intravenous, intra-muscular, infusion, transdermal, inhalation
and/or sub-lingual administration.
[0054] There are also provided herein methods for lowering
histamine levels in a human patient having a histamine level above
a level required for optimum histamine function, comprising
administering histamine or a pharmaceutically acceptable salt
thereof to the patient according to the dosing regimens described
herein. A method of increasing histamine levels in a human patient
having a histamine level below a level required for optimum
histamine function, comprising administered histamine or a
pharmaceutically acceptable salt thereof to the patient according
to the dosing regimens described herein. In several embodiments,
the assessment of the level of histamine required for optimum
histamine function is based on plasma histamine levels or urine
histamine levels, and diagnostic tests for measuring same. In
several embodiments, the level required for optimum histamine
function is between about 45 and about 50 ng/ml of plasma. However,
in several embodiments, restoration of histamine levels to a level
above or below that range, but to a concentration that is normal
for a particular individual, is achieved.
[0055] In several embodiments, a method for restoring histamine
balance is provided. In some embodiments, normalizing activity of
histamine receptors is achieved through administration of (or
instructing the administration of) multiple doses of a histamine
receptor activator administered in successive therapy segments. In
several embodiments, the methods comprise administering at least a
first, a second, and a third initial therapy segments, each of the
initial segments comprising activating a histamine H3 or H4
receptor by administering to a subject a first dose of a histamine
receptor activator, activating a histamine H1 receptor by
administering to a subject a second dose of the histamine receptor
activator, activating a histamine H2 receptor by administering to a
subject a third dose of the histamine receptor activator, and
administering a plurality of escalating therapy segments, each of
the escalating therapy segments comprising activating a histamine
H3 or H4 receptor by administering to a subject a first dose of the
histamine receptor activator, activating a histamine H1 receptor by
administering to a subject a second dose of the histamine receptor
activator, activating a histamine H2 receptor by administering to a
subject a third dose of the histamine receptor activator thereby
normalizing the activity of the histamine receptors and restoring
histamine balance.
[0056] In several additional embodiments, a method for restoring
histamine balance is provided, the method comprising normalizing
activity of histamine receptors through multiple doses administered
in successive therapy segments. In several embodiments
normalization of receptor activity is accomplished by
administering, or instructing the administration of, at least a
first, a second, and a third initial therapy segments, each of the
initial segments comprising activation of a histamine H3 receptor
by administering to a subject a first dose of a histamine receptor
activator, activation of a histamine H4 receptor by administering
to a subject a second dose of a histamine receptor activator,
activation of a histamine H1 receptor by administering to a subject
a third dose of the histamine receptor activator, activation of a
histamine H2 receptor by administering to a subject a fourth dose
of the histamine receptor activator, administering, or instructing
the administration of, a plurality of escalating therapy segments,
each of the escalating therapy segments comprising activation of a
histamine H3 receptor by administering to a subject a first dose of
the histamine receptor activator, activation of a histamine H4
receptor by administering to a subject a second dose of the
histamine receptor activator, activation of a histamine H1 receptor
by administering to a subject a third dose of the histamine
receptor activator, activation of a histamine H2 receptor by
administering to a subject a fourth dose of the histamine receptor
activator. In several embodiments, the amount of the histamine
receptor activator in the second initial therapy segment is greater
than the amount of the histamine receptor activator in the first
initial therapy segment, the amount of the histamine receptor
activator in the third initial therapy segment is greater than the
amount of the histamine receptor activator in the second initial
therapy segment, the amount of the histamine receptor activator
administered in each successive escalating therapy segment is
greater than the preceding escalating therapy segment, and the
increasing of amount histamine receptor activator administered
enhances activity of a histamine receptor selected from the group
consisting of the histamine H1, H2, H3, and H4 receptors, thereby
normalizing the activity of the histamine receptors and restoring
histamine balance.
[0057] In several embodiments, the amount of the histamine receptor
activator in the second initial therapy segment is greater than the
amount of the histamine receptor activator in the first initial
therapy segment and the amount of the histamine receptor activator
in the third initial therapy segment is greater than the amount of
the histamine receptor activator in the second initial therapy
segment. In those embodiments where additional initial therapy
segments are administered, the amount of the histamine receptor
activator administered in each successive initial therapy segment
is greater than the preceding segment. In several embodiments, the
amount of the histamine receptor activator administered in each
successive escalating therapy segment is greater than the preceding
escalating therapy segment. In several embodiments, the wherein the
increasing of amount histamine receptor activator administered
leads to suppression of the activity of the histamine H1 receptor,
but enhances activity of a histamine receptor selected from the
group consisting of the histamine H2, H3, and H4 receptors, thereby
normalizing the activity of the histamine receptors and restoring
histamine balance.
[0058] There is provided a method for restoring histamine balance
in a subject by normalizing activity of histamine receptors through
an escalating dosing regimen, comprising administering a plurality
of therapy segments, each of the segments comprising activating a
histamine H3 receptor or H4 receptor by administering to a subject
a first dose of a histamine receptor activator, activating a
histamine H1 receptor by administering to a subject a second dose
of the histamine receptor activator, activating a histamine H2
receptor by administering to a subject a third dose of the
histamine receptor activator, wherein the amount of the histamine
receptor activator administered in each successive escalating
therapy segment is greater than the preceding escalating therapy
segment, and wherein the increasing of amount histamine receptor
activator administered leads to suppression of the activity of the
histamine H1 receptor while the activity of a histamine receptor
selected from the group consisting of the histamine H2, H3, and H4
receptors is enhanced, resulting in a normalization of the activity
of the histamine receptors and restoring histamine balance.
[0059] In several embodiments, the first dose, the second dose, and
the third dose in each escalating therapy segment is administered
within a total time frame of less than about 5 minutes, (e.g., less
than 4 minutes, less than 3 minutes, less than 2 minutes, less than
1 minute).
[0060] In several embodiments, the histamine receptor activator
comprises histamine. In additional embodiments, the histamine
receptor activator comprises a histamine salt selected from the
group consisting of histamine diphosphate, histamine phosphate, and
histamine dihydrochloride.
[0061] In several embodiments, the administration of the histamine
receptor activator comprises subcutaneous injection.
[0062] Also provided herein is a kit comprising formulations
suitable for achieving the histamine normalization methods
disclosed herein. In several embodiments, the invention comprises a
kit (or dosing regimen) comprising formulations in concentrations
set forth on any one of Tables 2-7.
[0063] In several embodiments, there is a provided a method of
restoring histamine balance, comprising providing at least one
histamine receptor activator and instructing the administration of
the composition at concentrations suitable for activating one or
more of the histamine H1, H2, H3, and/or H4 receptors. In several
embodiments, the method further comprises providing an additional
therapeutic composition that can either agonize or antagonize on or
more of the histamine H1, H2, H3, and/or H4 receptors. In several
embodiments, the at least one histamine receptor activator is
histamine or a histamine salt. In several embodiments the at least
one histamine receptor activator is provided as a concentrated
composition (e.g., a liquid or a solid, such as a lyophilized
powder) and is suitable for dilution into various concentrations
that are used to specifically target one or more of the histamine
receptors.
[0064] The methods summarized above and set forth in further detail
below describe certain actions taken by a practitioner; however, it
should be understood that they can also include the instruction of
those actions by another party. Thus, actions such as
"administering a histamine agonist" include "instructing the
administration of a histamine agonist."
BRIEF DESCRIPTION OF THE DRAWINGS
[0065] FIG. 1 depicts the chemical structure of histamine.
[0066] FIG. 2 depicts a schematic of 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.
[0067] FIG. 3 depicts general schematic of histamine signaling
through a G-protein coupled receptor.
[0068] FIG. 4 depicts a summary of previous clinical data related
to serum histamine concentrations in various populations during
symptom free states.
[0069] FIG. 5 depicts a summary of previous clinical data related
to serum histamine concentrations in various populations during
migraine events.
[0070] FIG. 6 depicts a summary of previous clinical data related
to brain histamine levels in patients with Parkinson's disease
versus healthy subjects
[0071] FIG. 7 depicts a summary of previous clinical data related
to brain histamine concentration in patients with Alzheimer's
disease versus healthy subjects
[0072] FIG. 8 depicts a summary of previous clinical data related
to histamine blood concentration in patients with coronary disease
versus healthy subjects
[0073] FIG. 9 depicts a summary of previous clinical data related
to plasma histamine levels in patients with Myelogenous Leukemia
versus healthy subjects
DETAILED DESCRIPTION
[0074] Several embodiments of the invention employ a multi-variable
approach to treat imbalances of the histamine system. The
multi-variable approach, which includes altering concentration,
volume, and timing in some embodiments, may advantageously affect
in vivo distribution to achieve selective (or enhanced) activation
of certain histamine receptors. By employing a targeted and
controlled pattern of receptor activation, receptors can be up
and/or down regulated to rebalance the histamine system and offer
profound relief for those who suffer from dysregulation of the
histamine system.
General
[0075] Histamine, first identified as an autacoid having vasoactive
properties, and also referred to in some contexts as "substance H",
is a member of the biogenic amines family and is synthesized from
the amino acid histidine by the activity of L-histidine
decarboxylase (HDC). Histadine decarboxylase (HDC) is an enzyme
that is expressed in various cells throughout the body, including
central nervous systems (neurons), gastric-mucosa (parietal cells),
mast cells (which can contain .about.3 pg of histamine per cell),
and basophils (which can contain .about.1 pg of histamine per
cell). Histamine is involved in a variety of different
physiological functions, including but not limited to, immune and
allegoric responses, endocrine system function and homeostasis as
well as cell proliferation, differentiation hematopoiesis,
embryonic development, regeneration, wound healing, aminergic
neurotransmission, various other brain functions (sleep,
nociception, food intake and aggressive behavior), secretion of
pituitary hormones, regulation of gastrointestinal and
cardiovascular systems, and other various signaling pathways.
Histamine has also been correlated with allergies (e.g., drug
allergies, hay fever, allergic asthma, etc.). Elevated histamine
has also been detected in skin and plasma samples from patients
with atopic dermatitis (AD), chronic urticaria (CU), multiple
sclerosis (MS) and/or psoriatic skin. In Parkinson's Disease
patients, histamine levels have been shown to be increased in
specific brain regions, such as the putamen, substantia nigra and
external globus pallidus. In Alzheimer's disease, certain
histaminergic neurons display degeneration and tangle formation.
Also, a decline in histamine levels and/or HDC activity has been
associated with Alzheimer's disease and Down's syndrome.
[0076] Histamine is synthesized by a variety of cells, including,
but not limited to mast cells, basophils, platelets, histaminergic
neurons, and enterochromaffin cells. The activity of HDC is
modulated by various cytokines, including inflammatory cytokines
such as interleukin (IL)-1, IL-3, IL-12, IL-18 and tumor necrosis
factor (TNF). Histamine is stored intracellularly in vesicles and
released by particular stimuli, such as stress, circadian rhythms,
drugs and allergens. Mast cells are relatively widely distributed
throughout the body and the population density of mast cells is
very high in anatomical sites which interface with the external
environment (e.g., skin, airways, and gastrointestinal tract) as
well as regions in close proximity to blood vessels, nerves, smooth
muscle cells, epithelial cells, mucus producing cells and hair
follicles. Given that histamine is stored in granules in a "ready
to release" fashion, substantial amounts of preformed histamine can
be released in response to a single stimulus, and a multitude of
various triggers can elicit large-scale and rapid-onset histamine
release (e.g., via mast cell degranulation), mast cells are a major
cellular source of histamine. For example, in allergic reactions,
for example, histamine is released from basophils and/or mast cells
in response to particular allergens. Histamine mediates numerous
biologic reactions, such as, for example, immune responses (e.g.,
inflammatory reactions, modulation of the immune response) and the
degranulation of mast cells after their recognition of specific
allergens. Histamine-induced signaling also plays a role in
responses to many other nonimmunologic stimuli, such as, for
example, neuropeptides, complement factors, cytokines,
hyperosmolarity, lipoproteins, adenosine, superoxidases, hypoxia,
reactions with certain drugs, peptides, venom, and/or other
"liberators", physical insults (such as, for example, thermal,
vibratory, radiant, or exertion), stressors (such as, for example,
chemical, thermal, traumatic, or osmotic stressors), alcohol and
certain food and drugs that may activate mast cells, and/or
spontaneous basophil release (which occurs with higher frequency in
atopic individuals). Allergic reactions such as, for example,
excessive sneezing, are potentiated by the activation of
histamine-based pathways because histamine also dilates blood
vessels and increases permeability of vessel walls, thereby
allowing potentially greater influx of allergens. FIG. 2
(reproduced with permission from Maintz, et al., Histamine and
Histamine Intolerance, The American Journal of clinical Nutrition,
Vol. 85: 1185-1196 (2007)) depicts the variety of different
pathways in which histamine signaling plays a role, and examples of
symptoms that may arise from dysregulation of histamine. As a
result of the multitude of tissues in which histamine signaling
occurs, dysregulation of histamine function can present with
confounding symptoms (e.g., those not necessarily directly
associated with a particular organ system, for example vertigo as a
result of histamine dysregulation in the cardiovascular system). As
such, several embodiments of the methods and compositions (and uses
thereof) disclosed herein for restoration of histamine balance are
particularly useful for amelioration (or elimination) of symptoms
of histamine dysregulation in one or more tissues or tissue
types.
[0077] Certain individuals are either sensitized to, or intolerant
of, histamine. As discussed above, histamine is produced from
L-histidine. Imbalance in the accumulation (e.g., production) and
reduction (e.g., degradation and/or metabolism) can lead to the
sensitization and or intolerance to histamine. The primary enzyme
for metabolism of ingested histamine is diamine oxidase (DAO).
Reduced histamine degradation based on insufficient DAO activity
and can result in excess histamine and may cause symptoms mimicking
allergic reactions. DAO is located in plasma membrane-associated
vesicular structures and is secreted into the bloodstream after
stimulation. The second major enzyme for metabolism of histamine is
histamine-N-methyltransferase (HNMT), which is a cytosolic protein,
and is therefore only capable of metabolizing intracellular
histamine. Notwithstanding their differing, and seemingly
non-competitive locations, reduced function of one or both of the
enzymes can lead to histamine imbalance and/or sensitization to or
intolerance of histamine. As discussed above, such imbalances can
lead to a variety of adverse physiological consequences, and
several embodiments of the methods disclosed herein restore
histamine balance through the administration of a therapeutic agent
(e.g., histamine).
[0078] Endogenous histamine acts on a large variety of different
cell types including smooth muscle, neurons, endocrine and exocrine
cells, blood cells and cells of the immune system. Histamine exerts
its multiple biological actions via one of several receptors
including the H1 receptor (H1R), H2 receptor (H2R), H3 receptor
(H3R) and more recently, H4 receptors (H4R). Each of the receptors
is a G protein coupled receptor, though they operate through
various G-protein subunits and are differentially expressed in
various cell types. The receptors have been detected in various
tissues, including but not limited to, mammalian brain, respiratory
tract, genito-urinary system and vascular system, as well as on
several types of leukocytes and hematopoietic cells. The H1
receptors are mainly involved in the regulation of vascular
permeability and smooth muscle contraction. The H2 receptor
stimulation evokes an increase of gastric acid secretion, an
increase in mucus secretion in the bronchi and the relaxation of
smooth muscles of small blood vessels. The H3 receptors are
classified as presynaptic receptors controlling neurotransmission
in the central nervous system. H4 receptor signaling appears to
modulate immune system processes and inflammatory reactions. It is
believed that the principal receptors throughout the body are the
H1 and H2 receptors, while H3 and H4 receptors have somewhat more
localized expression profiles. In some instances, histamine
signaling through H1R and/or H2R mediates excitation and long-term
potentiation of excitation. In contrast, the H3R autoreceptors
provide feedback control of histamine synthesis, release, and
electrical activity. As heteroreceptors histamine receptors also
function to control exocytosis of several other neurotransmitter
systems (e.g., GABA, dopamine, serotonin, etc.). Histamine is also
known to play a role in several homoeostatic and/or higher
integrative brain functions (such as novelty-induced attention (as
opposed to voluntary attention) and adaptation to changing
environments). While some overlap between function exists, the
activity of the receptors can generally be summarized as in Table
1.
[0079] In several embodiments, histamine is provided in a
multi-variable approach, in which concentration, volume, and timing
can be varied. Other variables can also be changed (such as
infusion time, form of histamine, pH, etc.). In several
embodiments, a multi-variable pharmacokinetic approach results in
selective or enhanced activation of certain receptors. The
affinities provided below are used in several embodiments to induce
specific and controlled histamine receptor activation, which may in
turn reduce or prevent many of the side-effects associated with
programs that do not employ the approaches described herein. These
side-effects, which may result in non-compliance in taking the
therapy, can be avoided or reduced in many embodiments.
TABLE-US-00001 TABLE 1 Characteristics of Histamine Receptors
G-protein Affinity for Receptor Function Expression Subunits
Histamine H1 Smooth muscle Neurons, smooth G.alpha.q/11 ~1.1
.mu.g/mL contraction (most muscle muscle (e.g., airways, other than
vascular vascular), epithelial, smooth muscle); endothelial cells,
vasodilation; increases in neutrophils, vascular permeability
eosinophils, monocytes, dendritic cells, T-cells, B cells,
hepatocytes, and chondrocytes H2 Leukocyte function, Gastric mucosa
parietal G.alpha.s ~3.33 .mu.g/mL gastric parietal cell cells,
smooth-muscle, function (e.g., acid heart, epithelial, secretion),
cardiac endothelial cells, stimulation neutrophils, eosinophils,
monocytes, dendritic cells, T-cells, B cells, hepatocytes, and
chondrocytes H3 Central Nervous System Histaminergic neurons, Gi/o
~1.1 ng/mL neurotransmission; with relatively low neurotransmission
at expression elsewhere histaminergic peripheral nerve terminals H4
Hematopoietic and Bone marrow and Gi/o ~2.2-4.4 ng/mL
immunocompetent cell peripheral function hematopoietic cells,
relatively low expression elsewhere
Histamine H1 Receptor
[0080] The distribution and occupancy of the histamine H1 receptor
(H1R) in humans has been mapped using functional imaging techniques
to study the sedative properties and blood-brain barrier (BBB)
permeability of various H1R antihistamines. Similar studies have
been performed in the context of aging and neuropsychiatric
disorders, such as Alzheimer's disease, schizophrenia and
depression. In most of these studies, H1R binding was found to be
lower than in the age matched healthy controls, indicating that
histamine imbalance, in several embodiments may be caused, at least
in part by elevated H1 receptor expression. Of note is that H1R
stimulation has a feed-forward effect on H1R expression (e.g.,
stimulation of the receptor induces up-regulation in receptor
expression). Histamine-induced up-regulation of H1 receptor
expression is thought to be mediated by protein kinase C-.delta.
signaling. Mapping studies have also identified a correlation
between appearance of various disease symptoms and detection of
increased histamine H1 receptor mRNA, as well as a strong
correlation between H1R and allergic responses (or responses to
antihistamines used to treat allergy). For example, drugs for
treatment of allergic symptoms (e.g., antihistamines) not only
reduce IL-4 and/or Il-5 expression but also H1 receptor gene
expression. Histamine activation of the H1R leads to the release of
the several neurotransmitters (e.g., serotonin, dopamine and
norepinephrine) and excitation of neurons in most brain regions,
including, but not limited to, brain stem, hypothalamus, thalamus,
amygdala, septum, hippocampus and cortex. The H1R signals through
one or more of, increased calcium signaling, cyclic guanosine
monophosphate (cGMP) mediated signaling, nuclear factor .kappa.B
(NF-.kappa.B), increased phospholipase C (PLC) activity, increased
phospholipase A2 and/or D activity, cyclic adenosine monophosphate
activity (cAMP) and/or nitric oxide synthase activity, and thus can
set in motion an enormous variety of signaling cascades associated
with these pathways, such as, for example, as cell proliferation,
cell differentiation, apoptosis, cytoskeleton remodeling, vesicular
trafficking, ion channel conductance, endocrine function and
neurotransmission. See FIG. 3 for a schematic representation of
histamine receptor signaling.
Histamine H2 Receptor
[0081] The activation of H2R regulates various functions of
histamine including heart contraction, gastric acid secretion, cell
proliferation, differentiation and immune response. In the brain,
the highest densities of H2R are found in the basal ganglia,
hippocampus, amygdale and cerebral cortex, with lower expression in
cerebellum and hypothalamus. H2R stimulates accumulation of cAMP in
a variety of tissue including gastric cells, cardiac tissue and
brain. In contrast to H1R, activation of H2R is mostly involved in
suppressive activities of histamine. For example, it has been
demonstrated that H2R activity can inhibit a variety of functions
within the immune system and that H2R activity negatively regulates
release of histamine in basophils and mast cell. H2R-based
inhibition of antibody synthesis, T-cell proliferation, cell
mediated cytolysis, and cytokine production is further evidence of
H2R presence on lymphocytes, and its negative (e.g., suppressive)
effects on histamine.
Histamine H3 Receptor
[0082] As indicated above, H3 receptors are primarily expressed in
the central nervous system, particularly on histaminergic neurons.
H3 receptors couple to Gi/o subunits to inhibit the function of
adenylate cyclase and therefore inhibition of cAMP formation, along
with accumulation of calcium and stimulation of mitogen-activated
protein kinase (MAPK) pathways. H3Rs also mediate synthesis of
histamine and their activation leads to inhibition of histamine
release from histaminergic neurons. Thus, in several embodiments,
preferential stimulation of H3R can counteract activity of the H1R
(and thus reducing the feed-forward increase in H1R expression),
thereby facilitating restoration of histamine balance. Conversely,
H3 receptor blockers may enhance the release of neurotransmitters.
Also, activation of H3 receptors leads to inhibitory effects on
many neuronal synapses that are non-histaminergic, including, but
not limited to those signaling through glutamate, acetylcholine,
dopamine, noradrenaline, serotonin, GABA and various peptides.
[0083] Histaminergic dysregulation has been found in a variety of
different CNS disorders and, as such, various H3 ligands have been
investigated for clinical utility in CNS disorders, such as
obesity, memory disorders, learning deficit and epilepsy.
Additionally, loss of H3R function has been associated with
behavioral abnormalities, reduced locomotion, a metabolic syndrome
with hyperphagia, late-onset obesity, increased insulin and leptin
levels and an increased severity of neuroinflammatory diseases. In
several embodiments, the pharmacological properties of the H3R are
advantageously exploited in the methods disclosed herein to restore
histamine balance/function.
Histamine H4 Receptor
[0084] The H4 receptor is involved in cellular mechanisms related
to immune systems, inflammatory processes, and allergic reactions.
As discussed above, H4 receptors are expressed in bone marrow,
spleen, peripheral blood, small intestine, heart, colon, lung, as
well as hematopoietic cells, neutrophils, mast cells, eosinophils,
basophils, monocytes, T cells and dendritic cells. The H4R mediates
eosinophil shape change and mast cell chemotaxis as a result of the
.beta..gamma. subunits acting on phospholipase C, which leads to
calcium release, subsequent actin polymerisation and eventually
chemotaxis of the mast cells to a site of inflammation.
Histamine Imbalance and Methods of Histamine Receptor
Modulation
[0085] Normal serum histamine levels (e.g., levels in otherwise
healthy subjects without an allergic event) range from about 40 to
about 55 ng/mL. Thus, in several embodiments, the rebalancing of
the histamine system normalizes the serum histamine level to 40 to
about 55 ng/mL. In other embodiments, the rebalancing of the
histamine system normalizes the serum histamine level by decreasing
or increasing histamine levels by about 30%-70% with respect to
baseline. As an example, and as further discussed below,
normalizing histamine for a migraine sufferer may be reducing
histamine from 120 ng/mL to 70 ng/mL. As discussed above, a
condition of low histamine is referred to as histapenia, and a
person having low histamine levels is referred to as "histapenic."
A condition of high histamine is known as histadelia, and a person
having high histamine levels is referred to as histadelic.
Indications for Histamine Therapy
[0086] Various ailments and/or illnesses may be caused by,
exacerbated by, or linked with an imbalance in the levels of
histamine and/or the functionality of the various histamine
receptors. As discussed above, normal serum histamine levels range
from about 40 to about 55 ng/mL. Histamine levels are imbalanced
(e.g., higher or lower than normal) in subjects with ailments or
diseases including, but not limited to migraine headaches, vascular
headaches, Alzheimer's disease, Parkinson's disease, coronary
disease, leukemia, epilepsy, obesity, schizophrenia,
Attention-Deficit Hyperactivity Disorders, Huntington's disease,
allergies, asthma, autism, Lou Gehrig's disease, atherosclerosis,
dementia, addiction and compulsion, metabolic syndrome, rheumatoid
arthritis, sleep disorders, alcoholism, substance abuse, cancer,
malaria, HIV/AIDS, Central Nervous System (CNS) dysfunctions (e.g.,
stress, anxiety, depression, movement disorders,
anxiety/fear-related disorders, hyperalgesia and brain ischemia),
pre-diabetes, diabetes, lupus, cardiac arrhythmias. For example,
serum histamine levels in migraine sufferers (who do not also
suffer from allergies) during a pain free period can range from
about 60 to about 74 ng/mL. Thus, the "normal" histamine levels for
a migraine sufferer are elevated as compared to non-migraine
sufferers. Thus, migraine sufferers may be inclined to have a
migraine episode because of this histamine imbalance. In migraine
sufferers who do also suffer from allergies, the resting (e.g.,
pain free) serum concentrations can range from about 70 to about 95
ng/mL, indicative of a further histamine imbalance (see FIG. 4).
These histamine levels are further increased during actual migraine
events (see FIG. 5). As with many physiologic parameters, there may
be individual-to-individual variability in the concentrations of
histamine, however, an imbalance as compared a specific
individual's "normal histamine" concentrations (as measured, for
example, by serum and/or urine concentrations) can lead to and/or
exacerbate various ailments and/or illnesses. Thus, in several
embodiments, a histamine receptor activator(s) is provided for use
in the treatment of diseases (and/or symptoms) that include but are
not limited to migraine headaches, Parkinson's Disease (FIG. 6),
Alzheimer's Disease (FIG. 7), coronary disease (FIG. 8), leukemia
(FIG. 9), amyotrophic lateral sclerosis and/or epilepsy. Also
provided herein are histamine receptor activator (or activators)
for use in the treatment of migraine headaches, Parkinson's Disease
(FIG. 6), Alzheimer's Disease (FIG. 7), coronary disease (FIG. 8),
leukemia (FIG. 9), amyotrophic lateral sclerosis, epilepsy,
histadelia and/or histapenia (or other ailments) in patients
showing an elevated amount of circulating histamine as well as
ailments in which patients show a reduced amount of circulating
histamine. Thus, in several embodiments, the invention comprises a
histamine receptor activator for use in the treatment of migraine
headaches, Parkinson's Disease, Alzheimer's Disease, coronary
disease, leukemia, amyotrophic lateral sclerosis, epilepsy,
histadelia and/or histapenia and is associated with restoration of
histamine balance in the subject. In several embodiments, the
invention comprises histamine receptor activator for use in the
treatment of diseases associated with the over-expression and/or
over-activity of the histamine H1 receptor, or a histamine receptor
activator for use in the treatment of diseases associated with the
under-expression and/or under-activity one or more of the histamine
H2, H3, and/or H4 receptors.
Histamine Therapy for Migraine Headache
[0087] Although embodiments disclosed herein are non-limiting and
are applicable to several neurological and other conditions, many
embodiments are especially useful for migraines. As discussed
above, histamine imbalance is common in migraine headache
sufferers. Migraine headaches affect more than 30 million people in
the United States alone. Roughly 25% of women and 9% of men
experience migraine headaches which results in an average of 4 to 6
working days lost each year. In total, this results in an annual
loss (nationwide) of between about 64 to 150 million workdays, in
turn, equating to direct and indirect costs of nearly $50 billion
in the United States alone (according to The National Headache
Foundation; see also, J D Bartleson, Treatment of Migraine
Headaches, Mayo Clin. Proc. 1999; 74; 702-708). Headache and
associated symptoms are responsible for approximately 2% of all
visits to emergency departments. Migraine headaches are generally
described as recurring, unilateral headache with untreated symptoms
lasting from 4 to 72 hours. The international headache Society
Classification of headaches lists the presence of at least two of
the following symptoms for a headache to be considered a migraine
headache: unilateral location, throbbing character, worsening pain
with routine activity, and moderate to severe intensity coupled
with at least one of the following features: nausea and/or vomiting
and photophobia and phonophobia.
[0088] At present, there is no known cure for migraine headaches.
Migraine treatments are broadly classified as non-pharmacologic or
pharmacologic treatments. While several embodiments disclosed
herein are related to pharmacologic methods (e.g., administration
of a therapeutic agent, such as histamine) to restore histamine
balance and treat migraine headaches, in some embodiments,
non-pharmacologic and/or combinations of pharmacologic and
non-pharmacologic methods are used.
[0089] Non-pharmacologic treatments typically involve targeting
and/or avoidance of actions and behaviors known to trigger migraine
headaches. For example, the non-pharmacologic treatments may
include, in several embodiments, regular sleep patterns, routine
exercise, avoidance of known triggers. Depending on the individual
migraine sufferer, triggers can vary. Food triggers, depending on
the embodiment include, but are not limited to ripened cheeses
(e.g., cheddar, Emmentaler, Stilton, Brie, and Camembert),
chocolate, marinated, pickled, or fermented food, foods that
contain nitrites or nitrates (e.g., bacon, hot dogs, deli meats) or
MSG (e.g., soy sauce, meat tenderizers, seasoned salt), sour cream,
nuts, peanut butter, sourdough bread, various legumes (e.g., broad
beans, lima beans, fava beans, snow peas), figs, raisins, papayas,
avocados, red plums, citrus fruits, caffeinated beverages such as
tea, coffee, or cola, and/or alcoholic beverages. For women, the
menstrual cycle may be a trigger, perhaps related to changes in
estrogen levels. Light intensity, light patterns (e.g., flickering
lights) can also serve as triggers. Stress (e.g., anxiety, worry,
shock, sadness, etc.) can also be triggers, as it may set into
motion signaling cascades that induce histamine imbalance. Strong
odors (e.g., perfumes, chemical odors, odors of certain cooked
foods etc.) can also be triggers. In several embodiments, triggers
may change over time (e.g., a strong odor may be a trigger in once
instance, but not in another). In several embodiments,
non-pharmacologic therapies also include, for example, relaxation
training, biofeedback training, cognitive and/or behavioral
therapy, hypnosis, transcutaneous electrical nerve stimulation,
cervical manipulation, and/or hyperbaric oxygen treatments. In
several embodiments, the therapeutic agent dosing regimens (e.g.,
histamine) are supplemented with one or more non-pharmacologic
treatments.
[0090] Pharmacologic treatments for migraine headaches can
generally be divided into two main classes, namely abortive
therapies and prophylactic therapies. As used herein, the term
"abortive therapies" shall be given its ordinary meaning and shall
also refer to therapies that are act to reduce and/or ameliorate
symptoms of a migraine that already exists. In several embodiments,
the abortive therapies can be further subcategorized into
non-specific therapies and migraine specific therapies. In several
embodiments, the therapeutic agent dosing regimens (e.g.,
histamine) are supplemented with one or more pharmacologic
treatments. Non-specific therapies that are optionally used in
several embodiments include, but are not limited to, for example,
analgesics/NSAIDS (e.g., acetaminophen, aspirin, ibuprofen,
naproxen sodium, ketorolac), and narcotic analgesics (e.g.,
meperidine and butorphanol), and adjunctive therapy (e.g.,
metoclopramide, prochlorperazine). Migraine specific abortive
therapies that are optionally used in several embodiments include,
but are not limited to ergotamine and/or ergotamine derivatives
(e.g., ergotamine, caffeine plus ergotamine, dihydroergotamine) and
the members of the tryptamine-based Triptans family (e.g.,
sumatriptan, naratriptan, rizatriptan, and zolmitriptan).
Antihistamines are also used, in several embodiments to
preferentially and/or specifically target the activity of certain
histamine receptors.
[0091] The term "prophylactic therapy" as used herein, shall be
given its ordinary meaning and shall include therapies that
prevent, avoid, limit and/or otherwise reduce the frequency and/or
intensity of migraine headaches. Prophylactic therapies are
generally divided into the first-line agents and second-line
agents. In several embodiments, first-line therapies for migraine
prophylaxis in adults include propranolol, timolol, amitriptyline,
divalproex, sodium valproate, and/or topiramate. In several
embodiments, second-line agents include one or more of gabapentin,
naproxen or naproxen sodium, timed-release dihydroergotamine
mesylate, candesartan, lisinopril, atenolol, metoprolol, nadolol,
fluoxetine, verapamil, magnesium, vitamin B2 (riboflavin), coenzyme
Q10, hormone therapy (e.g., estradiol topical gel), and botulinum
toxin type A (Botox).
[0092] Many patients continue to experience migraine headaches
despite optimal therapy with the currently available therapies.
However, in several embodiments, restoration of histamine balance,
as disclosed herein, and either alone or in some embodiments, in
combination with non-pharmacologic and/or pharmacologic treatments,
migraine sufferers can reduce, limit, prevent and/or lessen the
frequency and/or intensity of migraine headaches.
[0093] In several embodiments, a therapeutic agent (e.g., histamine
agonists or antagonists, naturally-occurring or synthetic) is
administered to a subject who is a migraine sufferer, in order to
establish circulating concentrations of the agent that result, in
several embodiments, in suppression of the pro-migraine effects of
histamine. In several embodiments, the administration of the
therapeutic agents (e.g., histamine, or a synthetic histamine, or
an agonist and/or antagonist) result in the concentration of
selective interaction of the agents with H3R and/or H2R. As
discussed above, activation of the H3R and/or H2R can reduce the
synthesis and/or release of histamine, which in turn can reduce the
expression of the H1R (due its activity induced increase in
expression), and thereby reduce the potential dominance of the H1R
and restore balance among the histamine receptors. The various
histamine receptors are thus specifically targeted by a histamine
receptor activator(s) for use in the treatment of migraine
headaches, Parkinson's Disease, Alzheimer's Disease, coronary
disease, leukemia, amyotrophic lateral sclerosis, epilepsy,
histadelia and/or histapenia, and other disorders.
[0094] Previous studies have been directed towards histamine
administration regimens. For example, during a controlled,
double-blinded, clinical trial for migraine prevention, histamine
was administered, twice a week and for 12 weeks, in consecutively
increasing subcutaneous doses (0.1 to 1 ng) to compare efficacy of
histamine versus to placebo for prophylaxis of migraine. See
Guerrero R O, et al., Histamine as a therapeutic alternative in
migraine prophylaxis: a randomized, placebo-controlled,
double-blind study, Headache, Vol. 39(8): 576-80 (1999).
[0095] In another study, N.sup..alpha.-methylhistamine was
administered at doses of 1 to 3 ng twice a week, which
significantly reduced (P<0.0001) the frequency, intensity, and
duration of migraine attacks, as well as the need for rescue
analgesics. However, at doses greater than 3 ng, patients
experienced adverse side effects manifest as intense headache. See
Millan-Guerrero R O, et al., N.sup..alpha.-Methylhistamine Safety
and Efficacy in Migraine Prophylaxis: Phase I and Phase II Studies,
Headache Vol. 43:389-394 (2003) and Millan-Guerrero R O, et al.,
N.alpha.-Methyl Histamine Safety and Efficacy in Migraine
Prophylaxis: Phase III Study Can. J. Neurol. Sci., Vol. 33: 195-199
(2006).
[0096] In another comparative study, subcutaneous histamine (10
.mu.g/mL in Evan's solution) was administered twice weekly, with an
initial administration of 1 .mu.g (0.1 mL) and gradually increasing
dose to 10 .mu.g (1.0 mL) over a 12-week period. Histamine was
compared to placebo, sodium valproate, and topiramate
administration. The histamine group reported a reduction of
headache frequency (50%), decrease in pain intensity (51%), length
of migraine attacks (45%) and painkiller use (52%). See
Millan-Guerreroa R O, et al., Nueva alternativa terapeutica en
profilaxis de migrana con histamina como agonista de receptores H3
Gac Med Mex Vol. 144 No. 4: 291-295 (2008).
[0097] 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 with oral
administration of sodium valproate (500 mg daily dose). Data
collected during the 4th, 8th and 12th weeks of treatment revealed
that histamine caused a significantly greater reduction
(P<0.001) in intensity and duration of migraine attacks as well
as in analgesic intake. No difference was detected in the frequency
of attacks or in MIDAS. See Milian-Guerreroa R O, et al.,
Subcutaneous histamine versus sodium valproate randomized,
controlled, double-blind study European Journal of Neurology, Vol.
14: 1079-1084 (2007). A similar trial compared subcutaneous
administration of histamine (1-10 ng twice a week) with oral
administration of topiramate (100 mg daily dose). See
Millan-Guerreroa R O, et al., Subcutaneous Histamine versus
Topiramate in Migraine Prophylaxis: A Double-Blind Study, Eur
Neurol; Vol. 59:237- 242 (2008). An additional trial compared
histamine (subcutaneous, 1-10 ng, twice per week) with Botox
injection (50 Units, one injection cycle). See Millan-Guerrero R O,
et al., Subcutaneous histamine versus botulinum toxin type A in
migraine prophylaxis: a randomized, double-blind study, European
Journal of Neurology, Vol. 16: 88-94 (2009).
[0098] Additional studies have shown that in migraine subjects,
intravenous administration of relatively high doses of histamine
(e.g., 0.5 mg/kg per minute for 20 min) caused an immediate
headache during the infusion, followed by a delayed migraine
attack. Those side effects could abolished by pre-treatment with
the H1R antagonist mepyramine. See Krabbe and Olesen (Krabbe A A,
1980) and Lassen et al. (Lassen L H, 1995).
[0099] Other studies report methods of determining histamine dosing
regimens. One such approach is empiric optimum dosing while another
is objective endpoint titration. Empiric optimum dosing involves
injection of histamine with a particular frequency (e.g.,) once or
twice a week to initiate treatment in conjunction with
supplementation by daily sublingual drops. The dose of histamine is
increased to the point of optimum clinical response, but short of
aggravation. An objective endpoint titration approach involves
determining the dose of histamine that induces an allergic response
(e.g., successively more concentrated intracutaneous doses are
administered until an allergic wheal results). That dose is defined
as the treatment dose, and subcutaneous injections of that dose are
administered at a declining frequency.
[0100] In spite of ongoing histamine research and uses of histamine
in various therapeutic contexts, there remains a need for histamine
dosing regimens that are capable of restoring the body's natural
histamine function, and that can treat disease states caused by
imbalances in the body's release and metabolism of histamine, such
as, for example, migraine headache. Additionally, therapeutic
benefit may not be realized by subjects who are treated with
therapies in accordance to the studies discussed above, and/or such
therapeutic benefit may be associated with side effects. Moreover,
in contrast to the methods disclosed herein, many current attempted
therapeutic uses of histamine do not account for the selective
activation of specific histamine receptors (several embodiments of
the disclosed methods are based on the exploitation of the
differing pharmacological characteristics of the histamine
receptors), which unexpectedly provides exceptional therapeutic
results and treatments for histapenia, histadelia, and/or disorders
that are related to or associated with histamine imbalance.
[0101] Thus, several embodiments of the invention provide an
escalating dosing regimen comprising in sequential order (a) a
first dosing segment comprising two or more sequential doses of a
therapeutic agent (e.g., histamine, or a salt thereof, such as, for
example, histamine phosphate or histamine dihydrochloride)
separated by one or more equal time intervals (the "first time
interval"), wherein the concentration of the agent is increased
from dose to dose while the administered volume of each dose stays
constant; and (b) a second dosing segment comprising two or more
sequential doses of the therapeutic agent separated by one or more
equal time intervals (the "second time interval"), wherein the
concentration of the agent increases from dose to dose while the
administered volume of each dose stays 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, and the second
time interval is longer than the first time interval.
[0102] As used herein, the terms "first" and "second" are used in
relation to one another, and not to the overall dosing regimen.
Thus, the dosing regimen can comprise more than two dosing
segments, in which case the first dosing segment can refer to any
dosing segment within the dosing regimen other than the last dosing
segment, and the second dosing segment can refer to any dosing
segment performed after the first dosing segment. Depending on the
embodiment, the regimen may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or
more total dosing segments. Thus, the first dosing segments can be
any of segments 1 through 9, while the second dosing segment can be
any succeeding dosing segment 2 through 10.
[0103] In several embodiments, the dosing regimen is a fixed
regimen, in that the complete regimen is administered to the
patient in order to achieve optimal therapeutic benefits (e.g., if
the regimen is 10 segments, then all 10 segments are completed).
However, in several embodiments, the regimen is optionally
truncated for one or more of a variety of reasons. In several
embodiments, the regimen is truncated because the patient received
the regimen has experienced a sufficient therapeutic benefit. For
example, in several embodiments directed to migraine treatment, the
subject may have experienced a significant reduction in pain,
frequency, duration, and/or intensity of migraine episodes. In
several embodiments, the subject can restart a regimen after a
given period of time, for example several days to several months,
including 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, about 8 weeks to about 12 weeks, and overlapping
ranges thereof. A subject may restart a regimen at the point that
the regimen was optionally truncated (e.g., picking up where the
subject left off). The regimen may also be restarted from the point
of inception (e.g., dose #1 of segment #1). Restarting the regimen
may be due to a reduction in the benefits from the prior
administration of the regimen (e.g., return of symptoms and/or
increase in, for example, migraine frequency). While several
embodiments of the methods disclosed herein are surprisingly
without side effects (e.g., in some segments, the doses of
histamine exceed those that have caused side effects in other
studies, but do not induce side effects such as migraines), in
several embodiments, the regimen is optionally truncated due to
side effects. Depending on the clinical conditions, the regimen can
be cut short either by stopping at a particular dosing volume
within a dosing segment, or by stopping before performing a
succeeding segment. In several embodiments, rather than a
truncation, a subject can maintain a particular segment of the
regimen for one or more time periods (e.g., repeat segment #4 for a
plurality of time intervals), or repeat a previously administered
segment one or more times (e.g., rather than administer segment #4,
re-administer segment #3 for one or more time periods).
[0104] In several 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 several
embodiments, one or all of the segments can comprise 2, 3, 4, 5, 6,
7, 8 or more doses. In several embodiments, four individual doses
are given in the first dosing segment. In several embodiments,
subsequent dosing segments have four individual doses. In some
embodiments, the number of doses is greater or lesser, depending on
the needs and clinical symptoms of a given patient. For example, in
several embodiments 2-3, 3-4, 4-8, 8-12, or 12-24 (and overlapping
ranges thereof) doses are administered within a given dosing
segment. Each dosing segment can comprise a different number of
doses although, as noted above, in several embodiments, each
segment preferably includes the same number of doses.
[0105] Additionally, in several embodiments, the first dosing
segment and the second dosing segment are separated by a first time
interval. In several embodiments, the time interval ranges from
about 3 to about 30 days, including 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 to about 30 days, and
overlapping ranges thereof. As discussed herein, in certain
embodiments, the time interval varies between, for example the
first and second segments, as compared to, for example, the fourth
and fifth segments. In several embodiments, the time interval is
determined by a subject's responsiveness (or refractoriness) to a
dosing segment. In additional embodiments, the dosing segment
interval is determined by other variables, such as for example,
convenience or personal preference of the subject. In several
embodiments, the first dosing segment is optionally administered on
a compressed time-frame. For example, in several embodiments the
doses comprising the first therapy segment are, in several
embodiments, administered within a shortened time frame 1-2
minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes,
about 5-10 minutes, about 10-20 minutes, about 20-30 minutes, and
overlapping ranges thereof. In several embodiments, the first
therapy segment comprises simultaneously delivery of each of the
doses within the segment. As a result, the modulation of the
various receptors occurs on a reduced time-frame, and in some
embodiments, simultaneously.
[0106] In several embodiments, the dosing regimen further comprises
at least a third dosing segment comprising two or more sequential
doses of the therapeutic agent (e.g., histamine) separated by one
or more equal time intervals (the "third time interval"). In
several embodiments, the concentration of the agent increases from
dose to dose while the administered volume of each dose within the
segment stays constant, and the volume of each dose in the third
dosing segment is greater than the volume of each dose administered
in the second dosing segment. Further, in several embodiments the
third time interval is longer than the second time interval
(though, in some embodiments, the time interval can optionally be
altered to be equivalent to, or shorter than, the time interval of
a preceding dosing segment). This third dosing segment can be any
segment that follows the second segment in a multiple segment
regimen.
[0107] In several embodiments comprising at least three
administration segments, (i) the concentrations of the therapeutic
agent (e.g., histamine, such as histamine phosphate or histamine
dihydrochloride) administered during the third dosing segment are
the same as the concentrations of the therapeutic agent (e.g.,
histamine, such as histamine phosphate or histamine
dihydrochloride) administered during the second dosing segment;
(ii) the number of doses administered during the third dosing
segment is equal to the number of doses administered during the
second dosing segment; and (iii) the second dosing segment and the
third dosing segment are separated by the second time interval.
[0108] In some embodiments, the dosing regimen comprises up to 10
sequential dosing segments, wherein (a) each dosing segment
comprises two or more sequential doses of the therapeutic agent
(e.g., histamine) separated by one or more equal time intervals,
(b) concentration of the agent increases from dose to dose while
the administered volume of each dose stays constant; (c) the volume
of each dose in a succeeding dosing segment is greater than the
volume of each dose in the preceding dosing segment; (d) the time
interval in each succeeding dosing segment is longer than the time
interval in the preceding dosing segment; (e) the concentrations of
the agent administered are the same in each dosing segment; (f) the
number of doses administered during each segment is equal; and (g)
each succeeding dosing segment is separate from the immediately
preceding dosing segment by the time interval observed for the
immediately preceding dosing segment.
[0109] As discussed above, in several embodiments, the individual
doses within a segment are given in a constant volume. For example,
in several embodiments, the first dosing segment comprises a
plurality of individual doses, each administered in a volume of
between about 0.01 to about 1.0 mL, including about 0.01 mL to
about 0.05 mL, about 0.05 mL to about 0.10 mL, about 0.10 mL to
about 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 overlapping volumes therebetween. In several
embodiments, the volume of therapeutic agent (e.g., histamine)
administered in each subsequent segment is greater than the volume
of the therapeutic agent administered in the immediately preceding
segment. For example, if the volume of the therapeutic agent
administered in a first segment is 0.1 mL, the volume of the
therapeutic agent administered in the next segment is greater than
0.1 mL. In several embodiments, the volume of the therapeutic agent
administered in a given dosing segment is 0.1 ml greater than the
previous segment. In several embodiments, the volume of the
therapeutic agent administered in the last segment ranges from
about 0.1 to about 10 mL, including about 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
5.0 mL to about 7.5 mL, about 7.5 mL to about 10.0 mL, and
overlapping volumes therebetween. In several embodiments, the
volume of the therapeutic agent administered in the last segment is
about 1.0 mL.
[0110] In several embodiments, the concentration of the therapeutic
agent (e.g., histamine) administered within each segment increases
with each individual dose. For example, in the first (e.g., the
starting) segment, the concentration of the therapeutic agent can
range from about 0.1 attogram/mL to about 10 .mu.g/mL, including
about 0.1 attogram/mL to about 1 attogram/mL, about 1 attogram/mL
to about 1 femtogram/mL, about 1 femtogram/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 .mu.g/mL, about 0.1 .mu.g/mL to about 3 .mu.g/mL, and overlapping
ranges thereof. In several embodiments, the next dose is greater
than the immediately preceding dose. In several embodiments, the
final dose in a segment ranges from about 0.1 .mu.g/mL to about 20
.mu.g/mL, including from about 1 .mu.g/mL to about 2 .mu.g/mL,
about 2 .mu.g/mL to about 3 .mu.g/mL, about 3 .mu.g/mL to about 3.5
.mu.g/mL, about 3.5 .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.
Thus, the concentrations from the initial dose within a segment to
the final dose within a segment range from about 0.1 attogram/mL to
about 20 .mu.g/mL, from about 1 pg/mL to about 1 ng/mL, from about
1 ng/mL to about 1 .mu.g/mL, from about 1 .mu.g/mL to about 3.5
.mu.g/mL, from about 3.5 .mu.g/mL to about 15 .mu.g/mL, from about
15 .mu.g/mL to about 20 .mu.g/mL, and overlapping ranges thereof.
In some embodiments, the ratio of total amounts given in each
therapy segment is 1:2:3 (for three segments), 1:2:3:4 (for four
segments), 1:2:3:4:5 (for five segments). In some embodiments, the
ratio of individual doses within in a given therapy segment is
1:10.sup.3:10.sup.6:3.5.times.10.sup.6. The concentrations of the
therapeutic agents (e.g., histamine) provided herein can be the
dose administered to the subject, or in certain embodiments, the
plasma concentration achieved.
[0111] In several embodiments, the overall dose for a segment
(e.g., the total quantity of a therapeutic agent, such as
histamine, administered in each dose within a segment) preferably
falls with the following ranges: [0112] Segment 1 [0113] Initial
Dose: about 0.1 attogram to about 1 ng, or about 100 attograms to
about 10 pg [0114] Concluding Dose: about 1 ng to about 1 .mu.g, or
about 100 ng to about 500 ng [0115] Segment 2 [0116] Initial Dose:
about 1000 attograms to about 1 ng, or about 0.1 pg to about 100 pg
[0117] Concluding Dose: about 10 ng to about 10 .mu.g, or about 1
.mu.g to about 5 .mu.g
[0118] More specifically, in several embodiments, each individual
dose within a segment is designed to target a specific histamine
receptor (or receptors), based on the affinity of the various
receptors for histamine (see e.g. Table 1). For example, an initial
dosing segment that comprises four doses, D1, D2, D3, and D4, with
D1 being the lowest concentration and D4 being the highest
concentration would target, respectively H3/H4, H3/H4, H1, and H2.
Further, as a non-limiting example, in embodiments in which
histamine is administered, the total amount of histamine
administered in D1 ranges from about from about 0.0001 pg to about
999 pg, the total amount of histamine administered in D2 ranges
from about from about 1 ng to about 999 ng, the total amount of
histamine administered in D3 ranges from about from about 1 .mu.g
to about 3.499 .mu.g (for example about 1 .mu.g to about 2.999
.mu.g), and the total amount of histamine administered in D4 ranges
from about from about 3.0 .mu.g to about 10 .mu.g (for example
about 3.5 .mu.g to about 10 .mu.g). As discussed above, and
continuing the non-limiting example, a second dosing segment
comprising 4 doses, D5, D6, D7, and D8, which, in several
embodiments, are of a greater volume than the doses in the first
dosing segment, results in administration of greater amounts of
histamine (not only with respect to the corresponding dose in the
previous segment, but also with respect to the immediately
preceding dose within the current segment, if any). Thus, for
example, the total amount of histamine administered in D5 ranges
from about from about 0.0002 pg to about 1998 pg, the total amount
of histamine administered in D6 ranges from about from about 2 ng
to about 1998 ng, the total amount of histamine administered in D7
ranges from about from about 2 .mu.g to about 5.998 .mu.g (for
example about 2 .mu.g to about 5.998 .mu.g), and the total amount
of histamine administered in D8 ranges from about from about 7.0
.mu.g to about 20 .mu.g. In some embodiments, the ratio of total
amounts given in each therapy segment is 1:2:3 (for three
segments), 1:2:3:4 (for four segments), 1:2:3:4:5 (for five
segments). In some embodiments, the ratio of individual doses
within in a given therapy segment is
1:10.sup.3:10.sup.6:3.5.times.10.sup.6.
[0119] As a further example of the targeting of a specific
histamine receptor (or receptors) based on dose, timing of
administration, concentration, etc. the concept of natural/resonant
frequencies may be informative. A given object possesses a natural
frequency at which it will vibrate upon excitation. For example, a
guitar string tuned to a specific pitch and plucked with a given
force will vibrate at a natural frequency. A different string tuned
to a different pitch will vibrate at its own natural frequency. The
measure of natural frequency depends on the composition of a
particular object, its size, structure, weight and shape. If a
vibrating force is applied to an object with the frequency of the
vibrating force equal to the natural frequency, a resonance
condition results. The histamine receptors can conceptually be
analogized to objects with differing resonant frequencies. For
example, if the H1 receptor has a resonant frequency of X, the H2
receptor has a resonant frequency of Y, the H3 receptor has a
resonant frequency of Z, and the H4 receptor has a resonant
frequency of A, application of a vibration force (e.g., a histamine
concentration) at X, Y, Z, or A will result in specific stimulation
of one of the histamine receptor types. As a further example,
consider three blocks (one for H1 receptors, one for H2 receptors,
and one for H3 receptors), each with a different natural frequency.
Application of a vibration force (e.g., a histamine concentration)
at or near the natural frequency of the block (e.g., the
concentration at which histamine activates the specific receptor
type) will cause resonant frequency movement of that block (e.g.,
receptor activation) while the other blocks, although perhaps
moving, are not at their resonant frequencies (e.g., the receptors
may have some activation, but less than that of the peak activation
resulting from certain concentrations of histamine). Further, when
a vibration force greater than the natural frequency of a block is
applied, the block may no longer respond or may respond to a lesser
degree. However, an additional block, that didn't respond to the
first force, may respond to the second force, if it approaches the
natural frequency of the block. See also, for example the video at
http://www.youtube.com/watch?v=LV_UuzEznHs (by Professor O. Kwan,
Department of Civil Engineering, University of Toronto; video
incorporated by reference herein). Further in several embodiments,
the blocks (e.g., various histamine receptors) may respond at
different harmonics, multiples of the resonant frequency (e.g.,
multiples or fractions of a histamine concentration that causes
receptor activation). As discussed in more detail herein, not all
histamine concentrations produce the same effect on the histamine
receptors (H1R-H4R) and exciting a specific histamine receptor at a
given histamine concentration approximating its specific affinity
for histamine, forces that specific receptor to "resonate",
resulting in increased specific receptor activation.
[0120] Depending on the embodiment, the duration of each dosing
segment can vary. In several embodiments, the duration of the
segment ranges from about one day to about one week, including
about 1 to about 2 days, about 2 to about 4 days, about 4 days to
about 6 days, about 5 days to about 7 days, and overlapping ranges
thereof. In several embodiments, the dosing segments range from
about 1 week to about 16 weeks, including 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 12 weeks,
about 12 to about 16 weeks, and overlapping ranges thereof. In
several embodiments, a subsequent dosing segment is longer in
duration that it's immediately preceding dosing segment.
[0121] For example, in several embodiments, wherein a first dosing
segment is about 2 weeks, a second dosing segment is, for example,
about 2 to about 4 weeks in duration. In several embodiments,
comprising additional segments, the duration of each segment
continues to increase. In several embodiments, a subsequent dosing
segment is longer in duration than its immediately preceding dosing
segment. Depending on the embodiment (e.g., the duration of the
dosing segment and the number of individual doses within a
segment), the dosing frequency within a segment can range from
daily dosing to dosing once every several weeks. In several
embodiments, dosing within a segment occurs daily, every two days,
every third day, every fifth day, once per week, twice per week,
once every 10 days, once every two weeks, once every three weeks,
once every month, once every six weeks, and frequencies within
those listed. In several embodiments, as the number of dosing
segments increases, a subsequent dosing segment has a reduced
dosing frequency as compared to its immediately preceding dosing
segment. In several embodiments, a subsequent dosing segment not
only longer in duration than its immediately preceding dosing
segment, the subsequent dosing segment has a reduced dosing
frequency as compared to its immediately preceding dosing segment.
Table 2 depicts a non-limiting example of a dosing regimen in
accordance with several embodiments disclosed herein. In some
embodiments, one or more segment durations are compressed by 50% to
99% (e.g., 60%, 75%, 85%, 90%, 95%). As a non-limiting example, the
4 steps of Segment 1 can be done in a single day.
[0122] In several embodiments, the invention comprises a dosing
regimen in which the volume, concentration, and/or timing of
administration of a therapeutic agent (e.g., histamine or salt of
histamine) is administered variably. Other approaches employ
singular variability (e.g., changing only one of concentration,
volume, or timing). Advantageously, however, several embodiments of
the methods employ such three-dimensional variability and result an
unexpectedly more robust therapeutic effect. In several
embodiments, the improved therapeutic effect is achieved without
significant side effects. In several embodiments, the improved
efficacy is derived from the more specific histamine receptor
targeting that the varied concentrations for each dose achieve
(e.g., the concentrations of the various doses exploit the varied
affinity of the H1R-H4R for histamine, or other therapeutic agent).
In several embodiments, the increase in volume from segment to
segment allows a greater proportion of the histamine receptors in a
given area to be activated (or suppressed depending on the
particular receptor and/or the amount of histamine given). The
varied timing, in several embodiments, helps prevent receptor
desensitization that could result if frequency of administration
were constant over time. In such a case, an increased dose would be
administered at constant intervals, which could result in one or
more of the histamine receptors becoming refractory to the
histamine, particularly in view of the increased dose from segment
to segment. Thus, as a subject proceeds through the segments in a
given regimen, the variability in concentration, volume, and timing
result in effects on the various histamine receptors (e.g.,
upregulation or downregulation in activity and/or expression) that
result in restoration of histamine balance.
[0123] In several embodiments, dosing regimens in accordance with
the methods disclosed herein (a non-limiting example of which is
shown in Table 2) can be used to return patients histamine
concentrations to optimum histamine ranges, whether their histamine
levels are above or below the optimum (healthy population)
histamine level (plasma or urine). Advantageously, depending on the
embodiment, the concentration range presented in each step (for
example Segment 1, Step Number 2) allows for multiple
"sub-concentrations" to be implemented as part of the dosing
regimen. For example, as discussed in more detail below, Table 3
shows a non-limiting embodiment where C1=1.1 ng/mL and C2 is 3
ng/mL.
[0124] In several embodiments, the methods enable the lowering of
histamine levels in a patient having a histamine level above a
level required for optimum histamine function (e.g., histadelia),
comprising administering histamine (synthetic to natural), a
histamine agonist or antagonist, or a pharmaceutically acceptable
salt thereof to the patient according to the dosing regimens
disclosed herein. In several embodiments, the methods disclosed
herein enable the increase of histamine levels in a patient having
a histamine level below a level required for optimum histamine
function (e.g., histapenia), comprising administered histamine
(synthetic to natural), a histamine agonist or antagonist, or a
pharmaceutically acceptable salt thereof to the patient according
to the dosing regimens disclosed herein.
[0125] In several embodiments, there are also provided
"combination" dosing regimens that are used to facilitate returning
a patient's histamine concentrations to within optimum ranges for
that individual (e.g., whether that particular patient's histamine
levels are above or below the average of a healthy population. As
with several other embodiments disclosed herein, the combination
regimen enables the lowering of histamine levels in a patient
having a histamine level above a level required for optimum
histamine function (e.g., histadelia). The method comprises, in
several embodiments, administering histamine (synthetic or
natural), a histamine agonist or antagonist, or a pharmaceutically
acceptable salt thereof to the patient according to the
non-limiting dosing regimen shown in Table 3. In several
embodiments, the combination dosing regimen enables the increase of
histamine levels in a patient having a histamine level below a
level required for optimum histamine function (e.g., histapenia),
the method comprising administering histamine (synthetic or
natural), a histamine agonist or antagonist, or a pharmaceutically
acceptable salt thereof to the patient according to the
non-limiting dosing regimen shown in Table 3.
[0126] In several embodiments, the combination regimen comprises a
plurality (e.g., 2, 3, 4, 5, 6, or more) of initial segments, each
comprising, for example, four individual doses (although a greater
number of doses may optionally be administered). As discussed in
relation to other embodiments disclosed herein, the concentration
of each dose is increased with respect to one another, but the
volume administered is held constant across a given dosing segment.
In additional embodiments, one or more of the concentration or
volume may also be varied, based on the individual subject's needs
and/or symptoms. In some embodiments, the initial segments serve as
a "loading period", in that histamine is initially administered in
a reciprocating pattern. For example, segment 1 of Table 3
comprises four doses, each increasing in concentration relative to
one another. The first dose of segment 2, however, is lower than
the final dose of segment 1. Thus the doses increase over a given
segment, then drop back to concentrations that are less than the
concentration of the last dose administered. This "two step
forward, one step back" approach enables the gradual manipulation
of the various histamine receptors and a more gradual
re-establishment of histamine levels, which advantageously reduces
risk of side effects. After the initial segments have been
administered, a "loading dose" of histamine (or agonist/antagonist,
etc.) has been established and, advantageously, one or more of the
individual doses can be eliminated in subsequent dosing segments.
Therefore, in several embodiments, dosing regimens, such as the
non-limiting embodiment of the dosing regimen shown in Table 3, can
be directed to only a portion of the histamine receptors. For
example, the non-limiting embodiment of the dosing regimen shown in
Table 3 is directed to the H1, H2, H3 and H4 receptors. In
additional embodiments, however, doses and/or volumes are adjusted
to enable targeting of, as an example, H1 and/or H2, and/or H3
receptors. Additionally, in some embodiments, dosing regimens
target only two histamine receptors. In such embodiments, the
volumes and concentrations are adjusted accordingly. For example,
the non-limiting example dosing regimen in Table 3 could be
adjusted to target H2 and H3 receptors or H2 and H4 receptors.
[0127] Additionally, as shown in an additional non-limiting
embodiment in Table 3A, after dosing segment 3, each subsequent
dosing segment comprises 3 doses, with concentration 1 (C1) having
been eliminated from the doses. In several embodiments,
concentration 1 is eliminated because both C1 and C2 are directed
at the H3 and/or H4 receptors. Thus, multiple doses directed to
these two receptors may, in several embodiments, induce a
refractoriness to histamine (e.g., the H3 and/or H4 receptor may
become less sensitive if over stimulated) or may induce a change in
expression (e.g., a reduction or increase in gene, or protein, that
would reduce the efficacy of doses targeting H3 and/or H4).
Moreover, in several embodiments, the use of a single dose
targeting the H3 and/or H4 receptors reduces risks of adverse side
effects or sensitivity to histamine (or an agonist or antagonist
thereof, depending on the embodiment). Therefore, in several
embodiments, dosing regimens, such as the non-limiting embodiment
of the dosing regimen shown in Table 3A, are directed to only a
portion of the histamine receptors. For example, the non-limiting
embodiment of the dosing regimen shown in Table 3A is directed to
the H1, H2 and H3 receptors. In additional embodiments, however,
doses and/or volumes are adjusted to enable targeting of the H4
receptor in addition to the H1, H2, and/or H3 receptors.
Additionally, in some embodiments, dosing regimens target only two
histamine receptors. In such embodiments, the volumes and
concentrations are adjusted accordingly. For example, the
non-limiting example dosing regimen in Table 3A could be adjusted
to target H2 and H3 receptors.
[0128] In several embodiments, the volumes are adjusted
proportionately, such that, for example, segment 1 would comprise
two concentrations (one targeting each receptor) and volumes for
each of 0.05 mL, thereby retaining the 0.1 mL total volume
delivered. Likewise, the total volume for Segment 2 would still add
up to be 0.2 mL, but would be delivered in 2 administration volumes
of 0.1 mL (one for each concentration), and 0.3 mL for Segment 3
(delivered in 2 administration volumes of 0.15 mL, one for each
concentration), and the like.
[0129] In several embodiments, as discussed above, doses can be
administered on a compressed time scale, e.g., two, three, four (or
more) doses administered within a few seconds, a few minutes,
within an hour, within several hours, etc. In several embodiments,
this approach advantageously reduces risk of side effects, which is
particularly beneficial for individuals who are sensitive to
histamine (or its agonists/antagonists). Also, in several
embodiments, such a dosing regimen increases compliance because, as
shown in Table 3, after the first 3 segments, each subsequent
segment not only comprises a smaller number of doses, but each
segment is also is administered on a compressed time frame. Thus,
as an example, segment 4 is administered all within a single day
(e.g., May 13) and no additional doses need be administered until 2
weeks later. The compressed dosing schedule is such that the
entirety of a segment can be considered a single "dose" even though
the various concentrations of histamine (or its
agonists/antagonists) are administered separately (within a time
frame of several seconds, e.g., within about 5 seconds, within
about 10 seconds, within about 15 seconds, etc.). Additionally, as
the segment number increases, the duration between segments
increases, and with the compressed doses within each segment, the
actual administration of histamine (or its agonist or antagonist)
occurs within a very short relative period of time. As such, the
treatment of histamine imbalance need not be an intrusion into the
day to day lives of patients, but can be addressed in a matter of
moments, once every few weeks (or longer). Lastly, the segment
sequence can be rearranged, depending on the condition, in order to
achieve optimum results.
TABLE-US-00002 TABLE 3 "Combination" Dosing Regimen for Histadelia
and/or Histapenia Segment Dose Concen- Administration Dosing Number
Number tration Volume Date Frequency 1 1 C1 0.1 mL February 4
2x/week 2 C2 0.1 mL February 7 3 C3 0.1 mL February 11 4 C4 0.1 mL
February 14 2 5 C1 0.2 mL February 18 1 x/week 6 C2 0.2 mL February
25 7 C3 0.2 mL March 4 8 C4 0.2 mL March 11 3 9 C1 0.3 mL March 18
1 x/2 10 C2 0.3 mL April 1 weeks 11 C3 0.3 mL April 15 12 C4 0.3 mL
April 29 4 13 C1 0.1 mL May 13 2 weeks C2 0.1 mL (+/-1 C3 0.1 mL
week) C4 0.1 mL 5 14 C1 0.15 mL June 3 3 weeks C2 0.15 mL (+/-2 C3
0.15 mL weeks) C4 0.15 mL 6 15 C1 0.2 mL July 1 4 weeks C2 0.2 mL
(+/-2 C3 0.2 mL weeks) C4 0.2 mL 7 16 C1 0.25 mL August 5 5 weeks
C2 0.25 mL (+/-3 C3 0.25 mL weeks) C4 0.25 mL 8 17 C1 0.3 mL
September 9 6 weeks C2 0.3 mL (+/-4 C3 0.3 mL weeks) C4 0.3 mL C1 =
1.1 ng/mL +/- 30% histamine base C2 = 3 ng/mL +/- 50% histamine
base C3 = 1.1 .mu.g/mL +/- 30% histamine base C4 = 3.33 .mu.g/mL
+/- 30% histamine base
TABLE-US-00003 TABLE 3A "Combination" Dosing Regimen for Histadelia
and/or Histapenia Segment Dose Concentration/ Administration Dosing
Number Number Volume Date Frequency 1 1 C1/0.1 mL February 4
2x/week 2 C2/0.1 mL February 7 3 C3/0.1 mL February 11 4 C4/0.1 mL
February 14 2 5 C1/0.2 mL February 18 1x/week 6 C2/0.2 mL February
25 7 C3/0.2 mL March 4 8 C4/0.2 mL March 11 3 9 C1/0.3 mL March 18
1x/2 10 C2/0.3 mL April 1 weeks 11 C3/0.3 mL April 15 12 C4/0.3 mL
April 29 4 13 C2/0.1 mL May 13 2 weeks C3/0.1 mL C4/0.1 mL 5 14
C2/0.13 mL June 3 3 weeks C3/0.13 mL C4/0.13 mL 6 15 C2/0.17 mL
July 1 4 weeks C3/0.17 mL C4/0.17 mL 7 16 C2/0.2 mL August 5 5
weeks C3/0.2 mL C4/0.2 mL 8 17 C2/0.23 mL September 9 6 weeks
C3/0.23 mL C4/0.23 mL 9 18 C2/0.27 mL October 28 7 weeks C3/0.27 mL
C4/0.27 mL 10 19 C2/0.3 mL December 23 8 weeks C3/0.3 mL C4/0.3 mL
11 20 C2/0.33 mL February 24 9 weeks C3/0.33 mL C4/0.33 mL C1 = 1.0
pg/mL histamine base C2 = 1.0 ng/mL histamine base C3 = 1.0
.mu.g/mL histamine base C4 = 3.5 .mu.g/mL histamine base
[0130] The concentrations identified in Tables 3 and 3A represent
"histamine base" concentrations (e.g., the amount of histamine
itself). For example, in the case of histamine phosphate, two
molecules of phosphoric acid are attached to each molecule of
histamine. Since the molecular weight of histamine phosphate is
307.15 and that of histamine itself is 111.15, 2.75 mg of the salt
are required to obtain 1 mg of active principle. The administration
dates are identified as an example only. Additionally, within a
segment, the administration sequence can be varied (e.g., rather
than administration of C1, C2, C3 and C4, administration could be,
for example C3, C3, C2 and C1) to any desired order depending on
the embodiment. Further, in some embodiments, any one (or more) of
segments 4, 5, 6, 7 or 8 in Table 3 or Table 3A can be inserted
within any or all of segments 1, 2 and 3 (e.g., segment 4 is
"nested" into segment 1)
[0131] In several embodiments, there are also provided "escalating"
dosing regimens that are used to facilitate returning a patient's
histamine concentrations to within optimum ranges. The method
comprises, in several embodiments, administering histamine
(synthetic or natural), a histamine agonist or antagonist, or a
pharmaceutically acceptable salt thereof to the patient according
to the non-limiting escalating dosing regimen shown in Table 4. In
several embodiments, the escalating dosing regimen enables the
increase of histamine levels in a patient having a histamine level
below a level required for optimum histamine function (e.g.,
treatment of histapenia). In several embodiments, the escalating
dosing regimen enables the decrease of histamine levels in a
patient having histamine levels above those required for optimum
histamine function (e.g., histadelia). As discussed herein, in
several embodiments, the method comprises administration of
histamine (synthetic or natural), a histamine agonist or
antagonist, or a pharmaceutically acceptable salt thereof to the
subject.
[0132] In several embodiments, the escalating dosing regimen
comprises a plurality (e.g., 2, 3, 4, 5, 6, or more) of segments,
each comprising, for example, a plurality of individual doses. In
several embodiments, the concentration of each dose within a
segment is increased with respect to the prior dose, but the volume
administered is held constant across a given dosing segment while
all doses are administered with a short amount of time (e.g. 5
minutes). Advantageously, should individuals have sensitivity to
histamine, in several embodiments, dosing regimens, such as the
non-limiting embodiment of the dosing regimen shown in Table 4, are
directed to only a portion of the histamine receptors. For example,
the non-limiting embodiment of the dosing regimen can be directed
to the H1, H2 and H3 receptors (though additional embodiments,
however, comprise adjusted concentrations and/or volumes to enable
targeting of the H4 receptor in addition to the H1, H2, and/or H3
receptors). Additionally, in some embodiments, dosing regimens
target only two histamine receptors. In such embodiments, the
volumes and concentrations are adjusted accordingly. For example,
the non-limiting example dosing regimen in Table 4 could be
adjusted to target H1 and H2 receptors or H2 and H4 receptors. In
several embodiments, the volumes are adjusted proportionately, such
that, for example, even with fewer doses (since only targeting 2
receptors), the total volume administered would remain as shown in
Table 4.
[0133] In several embodiments, the escalating dosing regimen
comprises segments having 3 individual doses per segment (see e.g.,
the non-limiting embodiment in Table 4A). In several embodiments,
concentration 1 (C2) has been eliminated from the segments. As
discussed above, in some embodiments both C1 and C2 target the H3
and/or H4 receptors. Thus, the elimination of the C1 dose, in
several embodiments, prevents or otherwise reduces risk of the
subject developing refractoriness to histamine and helps maintain
the expression of the receptors at levels that promote proper
histamine balance. Moreover, as the use of a single dose targeting
the H3 and/or H4 receptors reduces risk of adverse side effects or
sensitivity to histamine (or an agonist or antagonist thereof,
depending on the embodiment), the escalating regimen does not
employ a "loading period". Thus, the escalating dose regimen may be
particularly suited to individuals with a known elevated histamine
tolerance (e.g., the elimination of the loading period and
elimination of the C1 dose is unlikely to induce adverse
responses). Advantageously, should individuals have sensitivity to
histamine, in several embodiments, dosing regimens, such as the
non-limiting embodiment of the dosing regimen shown in Table 4A,
are directed to only a portion of the histamine receptors. For
example, the non-limiting embodiment of the dosing regimen shown in
Table 4A is directed to the H1, H2 and H3 receptors (though
additional embodiments, however, comprise adjusted concentrations
and/or volumes to enable targeting of the H4 receptor in addition
to the H1, H2, and/or H3 receptors). Additionally, in some
embodiments, dosing regimens target only two histamine receptors.
In such embodiments, the volumes and concentrations are adjusted
accordingly. For example, the non-limiting example dosing regimen
in Table 4A could be adjusted to target H1 and H2 receptors. In
several embodiments, the volumes are adjusted proportionately, such
that, for example, even with fewer doses (since only targeting 2
receptors), the total volume administered would remain as shown in
Table 4A.
[0134] As discussed above, while the doses are administered
separately, they can be considered a single "dose" because the
entirety of a segment is administered on a reduced time frame
(e.g., within about 5 seconds, within about 10 seconds, within
about 15 seconds, etc.). Additionally, as the segment number
increases, the duration between segments increases, and as such the
actual administration of histamine (or its agonist or antagonist)
occurs within a very short relative period of time, thereby
facilitating compliance of the subject and continued maintenance of
the dosing regimens.
TABLE-US-00004 TABLE 4 "Escalating" Dosing Regimen for Histadelia
and/or Histapenia Segment Dose Concen- Administration Dosing Number
Number tration Volume Date Frequency 1 1 C1 0.05 mL January 6 2
weeks C2 0.05 mL (+/-1 C3 0.05 mL week) C4 0.05 mL 2 2 C1 0.1 mL
January 20 3 week.sup. C2 0.1 mL (+/-1.5 C3 0.1 mL weeks) C4 0.1 mL
3 3 C1 0.15 mL February 10 4 weeks C2 0.15 mL (+/-2 C3 0.15 mL
weeks) C4 0.15 mL 4 4 C1 0.2 mL March 10 6 weeks C2 0.2 mL (+/-3 C3
0.2 mL weeks) C4 0.2 mL 5 5 C1 0.25 mL April 21 8 weeks C2 0.25 mL
(+/-4 C3 0.25 mL weeks) C4 0.25 mL 6 6 C1 0.3 mL June 16 10 weeks
C2 0.3 mL (+/-5 C3 0.3 mL weeks) C4 0.3 mL C1 = 1.1 ng/mL +/- 30%
histamine base C2 = 3 ng/mL +/- 50% histamine base C3 = 1.1
.mu.g/mL +/- 30% histamine base C4 = 3.33 .mu.g/mL +/- 30%
histamine base
TABLE-US-00005 TABLE 4A "Escalating" Dosing Regimen for Histadelia
and/or Histapenia Segment Dose Concentration/ Administration Dosing
Number Number Volume Date Frequency 1 1 C2/0.03 mL January 6
C3/0.03 mL C4/0.03 mL 2 2 C2/0.07 mL January 13 1 week.sup. C3/0.07
mL C4/0.07 mL 3 3 C2/0.1 mL January 27 2 weeks C3/0.1 mL C4/0.1 mL
4 4 C2/0.13 mL February 17 3 weeks C3/0.13 mL C4/0.13 mL 5 5
C2/0.17 mL March 17 4 weeks C3/0.17 mL C4/0.17 mL 6 6 C2/0.2 mL
April 21 5 weeks C3/0.2 mL C4/0.2 mL 7 7 C2/0.23 mL June 2 6 weeks
C3/0.23 mL C4/0.23 mL 8 8 C2/0.27 mL July 21 7 weeks C3/0.27 mL
C4/0.27 mL 9 9 C2/0.33 mL September 15 8 weeks C3/0.3 mL C4/0.3 mL
10 10 C2/0.33 mL November 17 9 weeks C3/0.33 mL C4/0.33 mL C1 = 1.0
pg/mL histamine base C2 = 1.0 ng/mL histamine base C3 = 1.0
.mu.g/mL histamine base C4 = 3.5 .mu.g/mL histamine base
[0135] The concentrations identified in Table 4 and Table 4A
represent "histamine base" concentrations (e.g., the amount of
histamine itself). For example, in the case of histamine phosphate,
two molecules of phosphoric acid are attached to each molecule of
histamine. Since the molecular weight of histamine phosphate is
307.15 and that of histamine itself is 111.15, 2.75 mg of the salt
are required to obtain 1 mg of active principle. As with other
tables, the dates provides on the table are for guidance only
(e.g., to represent time intervals as opposed to actual dates).
Additionally, within a segment, the administration sequence can be
varied (e.g., rather than administration of C1, C2, C3 and C4,
administration could be, for example C3, C3, C2 and C1) to any
desired order depending on the embodiment.
[0136] There is provided, in several embodiments of the invention,
a histamine receptor activator (e.g., histamine) for use in the
treatment of patients showing an elevated amount of circulating
histamine or in patients showing a reduced amount of circulating
histamine, such patients being afflicted with migraine headaches,
Parkinson's Disease, Alzheimer's Disease, coronary disease,
leukemia, amyotrophic lateral sclerosis, epilepsy, histadelia
and/or histapenia. Also provided is a histamine receptor activator
for use in the treatment of migraine headaches, Parkinson's
Disease, Alzheimer's Disease, coronary disease, leukemia,
amyotrophic lateral sclerosis, epilepsy, histadelia and/or
histapenia with associated restoration of histamine balance. Some
embodiments of the invention comprise a histamine receptor
activator for use in the treatment of diseases associated with the
over-expression and/or over-activity of the histamine H1 receptor
and/or for use in the treatment of diseases associated with the
under-expression and/or under-activity one or more of the histamine
H2, H3, and/or H4 receptors.
[0137] As discussed above, the treatment according to the methods
disclosed herein may be based on clinical assessment that a patient
is suffering from histapenia or histadelia, such as by a diagnostic
assay indicating the presence of histamine levels above or below
standard plasma histamine levels or standard urine histamine
levels. For example, histamine levels in the range of 45 to about
50 ng/ml of plasma are used as an indicator for optimum histamine
function in some embodiments, and plasma levels above or below this
range indicate that the patient may benefit from the methods
disclosed herein.
[0138] Dietary supplements are also optionally used, in several
embodiments to facilitate rebalance of histamine. For example, in
several embodiments, supplements that help promote methylation of
histamine (e.g., to facilitate metabolism of histamine) are
optionally used to supplement certain of the methods disclosed
herein for treating histadelia). Methylation-promoting supplements
include, but are not limited to, S-adenosylmethionine (SAM-e),
methyl-B12, and trimethylglycine (TMG), dimethylglycine (DMG), or
combinations thereof. Additionally, calcium (which helps mobilize
histamine into the bloodstream) and/or vitamin C (which facilitates
excretion of histamine) supplements can be used to help reduce
histamine, in conjunction with the dosing regimens disclosed
herein. Magnesium supplementation is used, in several embodiments,
to facilitate stabilization of mast cells (thereby reducing
degranulation and histamine release). Low-histamine diets are also
used in certain embodiments wherein a reduction in histamine is
desired. Also, copper is associated with the enzymes that degrade
histamine, thus, in several embodiments, reduction in dietary
copper intake is beneficial in treating histapenia.
Histamine Compositions and Administration
[0139] In several embodiments, histamine is administered as a
pharmaceutically acceptable salt. In several embodiments, the
diphosphate (H.sub.3PO.sub.4) salt of histamine is employed. In
several embodiments, histamine phosphate is used. Other salts may
also be used, including but not limited to, acid addition salts
formed with inorganic acids such as hydrochloric acid (e.g.,
histamine dihydrochloride), hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like, or with organic acids such as
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-naphthalenesulfonic 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, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid,
and the like, as well as combinations thereof.
[0140] In addition, in several embodiments, pharmaceutically
acceptable salts of histamine can be formed when an acidic proton
present is capable of reacting with inorganic or organic bases.
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.
[0141] As used, herein the term "pharmaceutically acceptable" shall
be given its ordinary meaning and shall also include components,
compounds, chemicals, etc. useful in the preparation of a
pharmaceutical composition that is generally safe, non-toxic and
neither biologically nor otherwise undesirable and includes that
which is acceptable for veterinary use as well as human
pharmaceutical use. As used, herein, the term "pharmaceutically
acceptable salts" shall be given its ordinary meaning and shall
include salts of compounds that are pharmaceutically acceptable, as
defined above, and/or that possess the desired pharmacological
activity.
[0142] In several embodiments, the methods employ a comprise
administration of one or more agonist and/or antagonist compounds.
Depending on the embodiments the agonist or antagonist may be
administered in order to increase or decrease the function of a
particular histamine receptor. For example, in several embodiments
an H3R agonist may be administered, while in some embodiments, an
H1R antagonist is administered. The agonists may be superagonists,
full agonists, partial agonists, or inverse agonists. Antagonists,
depending on the embodiment, can be competitive, non-competitive,
uncompetitive, or silent antagonists. The agonists and antagonists
can also be either selective or non-selective, depending on the
embodiment. In several embodiments, the use of one or more agonist
or antagonist compounds is in addition to use of anther therapeutic
agent (e.g., histamine).
[0143] In several embodiments, the methods optionally comprise
administration of an antihistamine compound. For example, in
several embodiments an antagonist of the H1 receptor is
administered in conjunction with the histamine dosing regimen, and
the reduction of H1 receptor activity by the antagonist further
potentiates the suppressive effects of the H2/H3 receptors. For
example, H1 antagonists that may be used include, but are not
limited to aceprometazine, acrivastine, alcaftadine, alimemazine,
antazoline, aptazapine, astemizole, azatadine, azelastine,
bamipine, bepotastine, bilastine, bisulepine, bromazine,
brompheniramine, carbinoxamine, carbinoxamine/pseudoephedrine,
cetirizine, chlorcyclizine, chloropyramine, chlorothen,
chlorphenamine, chlorphenoxamine, cinnarizine, clemastine,
clemizole, clobenzepam, clobenztropine, clocinizine,
cyanodothiepin, cyclizine, cyproheptadine, dacemazine, deptropine,
desloratadine, dexbrompheniramine, dexchlorpheniramine,
dimenhydrinate, dimetindene, diphenhydramine, diphenylpyraline,
doxylamine, drixoral, ebastine, embramine, emedastine, epinastine,
esmirtazapine, etymemazine, fexofenadine, histapyrrodine,
homochlorcyclizine, hydroxyethylpromethazine, hydroxyzine,
hydroxyzine, isopromethazine, isothipendyl, ketotifen,
latrepirdine, levocabastine, levocetirizine, loratadine,
mebhydrolin, mepyramine, methafurylene, methapyrilene,
methdilazine, 4-methyldiphenhydramine, mianserin, mirtazapine,
mizolastine, moxastine, olopatadine, orphenadrine, oxatomide,
pemirolast, phenindamine, pheniramine, phenyltoloxamine, pirolate,
promethazine, propiomazine, pseudoephedrine/loratadine,
pyrrobutamine, repirinast, resporal, rupatadine, setastine,
setiptiline, talastine, terfenadine, thenalidine, thenyldiamine,
thiazinamium metilsulfate, thonzylamine, tolpropamine, toplexil,
tripelennamine, triprolidine, and combinations thereof. In other
embodiments, agonist compounds may be used (e.g., depending on
whether a subject is affected with histapenia or histadelia). In
some embodiments, H1 agonists may be used, such as for example,
when treating a subject with histapenia. Suitable H1 agonists
include, but are not limited to 2-Pyridylethylamine
dihydrochloride, Histamine trifluoromethyl toluidide, as well as
the various salts of histamine (either synthetic or naturally
occurring) disclosed herein, or combinations thereof.
[0144] In several embodiments, agonists of the H2R are used,
including, but not limited to, for example, arpromidine, amthamine,
impromidine, dimaprit, sopromidine, 4-methylhistamine, and
combinations thereof. Also, in several embodiments, H2R antagonists
are used, including, but not limited to, for example, cimetidine,
mifentidine, nizatidine, ranitidine, titotidine, famotidine,
zolantidine, iodoaminopotentidine, compound SKF 92857, mepyramine,
loxtidine, and combinations thereof
[0145] H3 receptor agonists are used in several embodiments.
Suitable H3R agonists include, but are not limited to
(R)-.alpha.-methylhistamine, cipralisant, immepip, imetit,
immethridine, methimepip, proxyfan, and combinations thereof.
Conversely, H3R antagonists may be used, depending on the
embodiment. Suitable H3R antagonists include, but are not limited
to A-349,821, ABT-239, betahistine, burimamide, ciproxifan,
conessine, clobenpropit, impentamine, iodophenpropit, thioperamide,
VUF-5681 (4-[3-(1H-Imidazol-4-yl)propyl]piperidine), and
combinations thereof.
[0146] H4 receptor agonists are used in several embodiments.
Suitable H4R agonists include, but are not limited to VUF-8430
(2-[(aminoiminomethyl)amino]ethyl carbamimidothioic acid ester),
OUP-16, 4-methylhistamine, and the various salts of histamine
(either synthetic or naturally occurring) disclosed herein, or
combinations thereof. H4R antagonists may be used, depending on the
embodiment. 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.
[0147] In several embodiments, the invention comprises a histamine
receptor activator for use in the treatment of migraine headaches,
Parkinson's Disease, Alzheimer's Disease, coronary disease,
leukemia, amyotrophic lateral sclerosis, epilepsy, histadelia
and/or histapenia by inhibiting the activity and/or expression of a
histamine receptor selected from the group consisting of the
histamine H1 receptor, the histamine H2 receptor, the histamine H3
receptor, and the histamine H4 receptor. In several embodiments,
the histamine receptor activator inhibits the activity and/or
expression of the histamine H1 receptor and thus is beneficial for
use in the treatment of diseases associated with the
over-expression and/or over-activity of the histamine H1 receptor.
Moreover, in several embodiments, the histamine receptor activator
(or activators) are for use in the treatment of diseases associated
with the under-expression and/or under-activity one or more of the
histamine H2, H3, and/or H4 receptors.
[0148] In several embodiments, the invention comprises a histamine
receptor activator for use in the treatment of migraine headaches,
Parkinson's Disease, Alzheimer's Disease, coronary disease,
leukemia, amyotrophic lateral sclerosis, epilepsy, histadelia
and/or histapenia by combined, sequential, or separate
administration with a complete or partial antagonist of a histamine
H1 receptor. Moreover, in several embodiments, the invention
comprises an inhibitor of the activity and/or expression of a
histamine H1 receptor for use in the treatment of migraine
headaches, Parkinson's Disease, Alzheimer's Disease, coronary
disease, leukemia, amyotrophic lateral sclerosis and/or
epilepsy.
[0149] Depending on the embodiment, the histamine compositions used
in the methods disclosed herein can be used in one or more of a
variety of forms, depending on the route of administration.
Administration can be, for example oral, ophthalmic, otologic,
and/or nasal, urogenital, rectal, transdermal, via implantation,
transdermal, inhalation and/or via infusion. Patches may be used in
one embodiment. Oral delivery can be, for example, enteral (e.g.,
to the digestive tract), buccal (e.g., sublingual), and/or inhaled
(e.g., to the respiratory tract). Depending on the embodiment, oral
forms include, but are not limited to liquid, solid, and/or
semi-solid forms. In several embodiments, enteral administration is
by way of administration of one or more of pills, tablets,
capsules, gel-caps, (including timed release forms) osmotic
delivery systems, elixirs, suspension, syrup, emulsions, hydrogels,
wafer, molecular encapsulation forms, softgels, solution,
suspensions, syrups, tinctures, and/or tisanes. Buccal
administration, in several embodiments, is by way of administration
of one or more of orally disintegrating tablets or pills, films,
lozenges, chewing gums, popsicles, lollipops, mouthwashes, mouth
rinses, toothpaste, ointment, and/or oral sprays.
[0150] In several embodiments, oral forms may include one or more
inert diluent and/or an edible carrier. For example, the
compositions may be enclosed in gelatin capsules (for oral use) or
compressed into tablets (for oral or buccal use) or formulated into
troches or sublingual liquids (for buccal use). In several
embodiments, the active histamine compound can be incorporated with
excipients and and/or various pharmaceutically compatible carriers,
binding agents, and/or adjuvant materials. Oral forms, may,
depending on the embodiment, contain any of the following
ingredients, or compounds of a similar nature: a binder such as
microcrystalline cellulose, gum tragacanth or gelatin; an excipient
such as starch or lactose, a disintegrating agent such as alginic
acid, or corn starch; a lubricant such as magnesium stearate; a
gliding such as colloidal silicon dioxide; a sweetening agent such
as sucrose or saccharin; or a flavoring agent or agents such as
mint, methyl salicylate, or fruit flavors, candy flavors,
combinations of flavors, etc. When the dosage unit form is a
capsule, it can optionally contain, in addition to material of the
above type, a liquid carrier such as a fatty oil. In addition,
dosage unit forms can contain various other materials which modify
the physical form of the dosage unit, for example, coatings of
sugar, shellac, or other enteric agents. Administration to the
respiratory tract, in several embodiments, is by way of
administration of one or more of a dry powder inhaler, nebulize,
vaporizer, metered dose-inhaler, respiratory mask, oxygen
concentrator, nasal cannula, and the like.
[0151] Ophthalmic, otologic, and/or nasal administration are used
in several embodiments, and in some such embodiments are
advantageous because of the rapid absorption of the histamine
compositions through, for example, the mucous membranes. Forms for
delivery via the eye, nose, or ear include, but are not limited to,
for example, nasal spray, ear drops, eye drops, ointments,
hydrogels, nanosphere suspensions or emulsions, mucoadhesive
microdisc (e.g., microsphere tablets) and the like.
[0152] Urogenital and/or rectal administration forms include, but
are not limited to ointments, pessary (e.g., vaginal suppository),
vaginal rings, vaginal douches, intrauterine devices (IUD),
extra-amniotic infusions, intravesical infusions, suppositories,
enema, and/or Murphy drip, etc.
[0153] Dermal administration forms, depending on the embodiment,
include, but are not limited to ointments, liniments, pastes,
films, hydrogels, liposomes, transfersome vesicles, creams, lotion,
balms, salves, shampoos, dermal patches (e.g., transdermal patch),
transdermal spray, direct or jet injector, etc.
[0154] Injection or infusion may also be used, depending on the
embodiment. For example, delivery of histamine can be intradermal,
subcutaneous, via a transdermal implant, intravenous,
intramuscular, intraperitoneal, intraarterial, intracavernous,
intracerebral, intrathecal, epidural, and the like.
[0155] In several 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 (an individual who is not a medical professional, such
as for example, an acquaintance, family member, spouse, etc.).
[0156] Combinations of the various administration routes are also
used, in several embodiments. For example, an oral medication can
be used in conjunction with a subcutaneous administration.
Likewise, both intramuscular and subcutaneous administration routes
are optionally employed, for example. Solutions or suspensions used
for injection or infusion can optionally include one or more of the
following components: a sterile diluent such as water for
injection, saline solution, fixed oils, polyethylene glycols,
glycerin, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens;
antioxidants such as ascorbic acid or sodium bisulfite; chelating
agents such as ethylenediaminetetraacetic acid (EDTA); buffers such
as acetates, citrates or phosphates and agents for the adjustment
of tonicity such as sodium chloride, mannitol and dextrose.
Depending on the embodiments, an injectable preparation can
optionally be enclosed in ampoules, disposable syringes or multiple
dose vials made of glass or plastic, or other suitable material.
When used in conjunction with histamine compositions as disclosed
herein, anti-histamines may also be in any of the above forms.
[0157] Concentrations and dosages provided in the examples below
and the tables above are for a subject weight of 75-85 kg and can
be adjusted proportionally for different weights according to
several embodiments. In several embodiments, kits comprising
pre-filled syringes, vials or other containers are provided with
the doses of therapeutic agent described herein. Instructions for
use, including for example a paper or electronic calendar system or
other alert for scheduling self-treatment, are provided in one
embodiment.
EXAMPLES
[0158] The examples provided herein are non-limiting examples of
some embodiments of the invention.
Example 1--Histamine Dosing Regimen for Treatment of Neurological
Disorders
[0159] In several embodiments, a histamine dosing regimen according
to the methods disclosed above is used for the reduction and/or
prevention of neurological disorders, including migraine headaches,
Parkinson's and Alzheimer's and ALS and epilepsy. A long-term
migraine sufferer was treated with the regimen shown in Table 5
(administration dates identified as an example only). Histamine was
administered subcutaneously according to the indicated times and
concentrations.
[0160] Another possible regimen in accordance with several
embodiments is shown in Table 5A (administration dates identified
as an example only).
[0161] The concentrations identified in Table 5 and Table 5A
represent "histamine base" concentrations (e.g., the amount of
histamine itself). For example, in the case of histamine phosphate,
two molecules of phosphoric acid are attached to each molecule of
histamine. Since the molecular weight of histamine phosphate is
307.15 and that of histamine itself is 111.15, 2.75 mg of the salt
are required to obtain 1 mg of active principle. Additionally,
within a segment, the administration sequence can be varied (e.g.,
rather than administration of C1, C2, C3 and C4, administration
could be, for example C3, C3, C2 and C1) to any desired order
depending on the embodiment.
[0162] As a result of the histamine dosing regimen above, the
subject (a migraine suffer for over 35 years) experienced a
significant reduction in frequency of migraine episodes, as well as
a reduction in intensity of migraines when they did occur. Prior to
the dosing regimen, the subject experienced about 3-5 migraines per
week, on average. This frequency was despite the use of various
prescription drugs, over the counter drugs, dietary changes, and/or
alternative medicine approaches. Migraine events resulted in
numerous missed work days, and reduced work efficiency. Migraines
also caused loss of certain occupational promotional opportunities
and, outside of work, loss of the ability to exercise (as physical
exertion triggered migraine attacks). Overall the migraine events
led to a consistent decline in quality of life.
[0163] As a result of implementing the above mentioned histamine
dosing regimen, the intensity and frequency of migraines has been
drastically reduced in this subject, who currently experiences
approximately only 1 migraine every 2 months. Drastically improved
quality of life has resulted, as has the subject's ability to spend
interactive time with the subject's family, being able to
participate in family and social events, being able to exercise and
becoming a productive member of society. This regimen also resulted
in limited side effects associated with the regimen (e.g., no
histamine-induced headaches). After segment 5 was completed, the
subject restarted the dosing regimen at segment 1 after a period of
time had elapsed. As discussed above, the prevalence of histamine
in various physiological functions, and histamine imbalance in a
variety of diseases and/or disorders make several embodiments of
the invention useful for treatment of other diseases and/or
disorders including, but not limited to 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 e.g., 50% to 99% (e.g., 60%, 75%, 85%,
90%, 95%).
Example 2--Extended Histamine Dosing Regimen for Treatment
[0164] In several embodiments, an extended histamine dosing regimen
is used for the reduction and/or prevention of neurological
disorders, including migraine headaches, Parkinson's and
Alzheimer's, coronary disease, leukemia, ALS, epilepsy, histadelia
and/or histapenia (among others).
[0165] The concentrations identified in Table 6 represent
"histamine base" concentrations (e.g., the amount of histamine
itself). For example, in the case of histamine phosphate, two
molecules of phosphoric acid are attached to each molecule of
histamine. Since the molecular weight of histamine phosphate is
307.15 and that of histamine itself is 111.15, 2.75 mg of the salt
are required to obtain 1 mg of active principle. In some
embodiments, one or more segment durations may be compressed or
expanded by e.g., 50% to 99% (e.g., 60%, 75%, 85%, 90%, 95%). Other
histamine compounds may be used instead of or in addition to
histamine phosphate. Additionally, within a segment, the
administration sequence can be varied (e.g., rather than
administration of C1, C2, C3 and C4, administration could be, for
example C3, C3, C2 and C1) to any desired order depending on the
embodiment.
Example 3--Extended Histamine Dosing Regimen
[0166] In several embodiments, an extended histamine dosing regimen
is used for the reduction and/or prevention of neurological
disorders, including migraine headaches, Parkinson's and
Alzheimer's, ALS epilepsy, histadelia and/or histapenia, among
others.
[0167] The concentrations identified in Table 7 represent
"histamine base" concentrations (e.g., the amount of histamine
itself). For example, in the case of histamine phosphate, two
molecules of phosphoric acid are attached to each molecule of
histamine. Since the molecular weight of histamine phosphate is
307.15 and that of histamine itself is 111.15, 2.75 mg of the salt
are required to obtain 1 mg of active principle. In some
embodiments, one or more segment durations may be compressed or
expanded by e.g., 50% to 99% (e.g., 60%, 75%, 85%, 90%, 95%). Other
histamine compounds may be used instead of or in addition to
histamine phosphate. Additionally, within a segment, the
administration sequence can be varied (e.g., rather than
administration of C1, C2, C3 and C4, administration could be, for
example C3, C3, C2 and C1) to any desired order depending on the
embodiment.
Example 4--Representative Formulation
[0168] A representative formulation for use in several embodiments
of the histamine dosing regimens disclosed herein is a formulation
suitable for subcutaneous injection comprising, histamine base 1
mg/mL (histamine phosphate 2.75 mg/mL) in glycerin 50% (v/v). As
disclosed herein, other histamine receptor activators can be used
instead of or in addition to histamine phosphate. Moreover, other
diluents/carriers can be used instead of, or in addition to
glycerin (e.g., saline, sterile water, etc.).
[0169] Although the examples above and several embodiments discuss
the histamine system, the approaches described herein may be used
to rebalance other systems. For example, in some embodiments,
therapeutic agents include agents that affect neurotransmission,
such as agents that affect one or more of the dopamine,
noradrenaline, serotonin, GABA and acetylcholine systems. The
targeted and controlled pattern of receptor modulation may be
particularly effective for neurological disorders. Thus, agonists
and antagonists of these neurotransmission pathways, according to
the approaches described herein, are encompassed within this
disclosure.
[0170] When the singular forms "a," "an" and "the" or like terms
are used herein, they will be understood to include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "an agent" includes two or more agents, and
the like. The word "or" or like terms as used herein means any one
member of a particular list and also includes any combination of
members of that list.
[0171] Throughout the description and claims of this specification,
the word "comprise" and variations of the word, such as
"comprising" and "comprises," means "including but not limited to,"
and is not intended to exclude, for example, other additives,
components, integers or steps.
[0172] It is contemplated that various combinations or
subcombinations of the specific features and aspects of the
embodiments disclosed above may be made and still fall within one
or more of the inventions. Further, the disclosure herein of any
particular feature, aspect, method, property, characteristic,
quality, attribute, element, or the like in connection with an
embodiment can be used in all other embodiments set forth herein.
Accordingly, it should be understood that various features and
aspects of the disclosed embodiments can be combined with or
substituted for one another in order to form varying modes of the
disclosed inventions. Thus, it is intended that the scope of the
present inventions herein disclosed should not be limited by the
particular disclosed embodiments described above. Moreover, while
the invention is susceptible to various modifications, and
alternative forms, specific examples thereof have been shown in the
drawings and are herein described in detail. It should be
understood, however, that the invention is not to be limited to the
particular forms or methods disclosed, but to the contrary, the
invention is to cover all modifications, equivalents, and
alternatives falling within the spirit and scope of the various
embodiments described and the appended claims. Any methods
disclosed herein need not be performed in the order recited. The
methods disclosed herein include certain actions taken by a
practitioner; however, they can also include any third-party
instruction of those actions, either expressly or by implication.
For example, actions such as "administering histamine" include
"instructing the administration of histamine." The ranges disclosed
herein also encompass any and all overlap, sub-ranges, and
combinations thereof. Language such as "up to," "at least,"
"greater than," "less than," "between," and the like includes the
number recited. Numbers preceded by a term such as "about" or
"approximately" include the recited numbers. For example, "about 3
mm" includes "3 mm."
* * * * *
References