U.S. patent application number 14/722990 was filed with the patent office on 2015-09-17 for botulinum toxin and the treatment of primary disorders of mood and affect.
The applicant listed for this patent is Botulinum Toxin Research Associates, Inc.. Invention is credited to Gary E. Borodic.
Application Number | 20150258183 14/722990 |
Document ID | / |
Family ID | 54067791 |
Filed Date | 2015-09-17 |
United States Patent
Application |
20150258183 |
Kind Code |
A1 |
Borodic; Gary E. |
September 17, 2015 |
Botulinum Toxin and the Treatment of Primary Disorders of Mood and
Affect
Abstract
A method of treating depression includes locally administering a
botulinum toxin subcutaneously to a face of a subject with
depression, thereby treating the depression by reducing the
occurrence of at least one symptom of depression. The botulinum
toxin may be immunotype A or B. The toxin may be administered by
injection to the forehead, scalp, face, and/or neck.
Inventors: |
Borodic; Gary E.; (Canton,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Botulinum Toxin Research Associates, Inc. |
Quincy |
MA |
US |
|
|
Family ID: |
54067791 |
Appl. No.: |
14/722990 |
Filed: |
May 27, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11447984 |
Jun 7, 2006 |
8926991 |
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14722990 |
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14552755 |
Nov 25, 2014 |
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11447984 |
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Current U.S.
Class: |
424/94.67 |
Current CPC
Class: |
A61K 9/1075 20130101;
A61K 47/44 20130101; A61K 38/4893 20130101; Y02A 50/469 20180101;
A61K 2121/00 20130101; A61K 9/08 20130101; A61K 9/0019 20130101;
A61K 9/0021 20130101; A61K 49/0004 20130101; Y02A 50/30 20180101;
C12Y 304/24069 20130101; A61K 47/10 20130101 |
International
Class: |
A61K 38/48 20060101
A61K038/48 |
Claims
1. A method of treating depression comprising the steps of: a)
identifying a subject with a depressive disorder or identifying a
subject with one or more symptoms of a depressive disorder; and b)
administering an effective amount of a composition comprising a
botulinum toxin and a pharmaceutically acceptable carrier to said
subject thereby reducing at least one symptom of depression.
2. The method of claim 1, wherein the botulinum toxin is immunotype
A, B, C, D, E, F, or G.
3. The method of claim 1, wherein the botulinum toxin is botulinum
toxin type A from Hall strain Clostridium botulinum.
4. The method of claim 1, wherein the composition is administered
by injection.
5. The method of claim 1, wherein there are at least two injection
sites.
6. The method of claim 4, wherein the injection is multifocal.
7. The method of claim 4, wherein the composition is administered
to the forehead.
8. The method of claim 4, wherein the composition is administered
to the scalp.
9. The method of claim 4, wherein the composition is administered
to the neck.
10-39. (canceled)
40. The method of claim 1, wherein said administration of said
botulinum toxin blocks at least one neurotransmitter.
41. The method of claim 40, wherein said at least one
neurotransmitter is at least one of acetylcholine, glutamate, and
norepinephrine.
42-115. (canceled)
116. A method of treating depression comprising administering a
therapeutically effective amount of a botulinum toxin subdermally,
non-intramuscularly to a face of a subject with depression, thereby
treating the depression by reducing the occurrence of a symptom of
the depression.
117. The method of claim 116, wherein the step of administering
further comprises administering the botulinum toxin to a periocular
region of the face.
118. The method of claim 116, wherein the step of administering
further comprises administering the botulinum toxin to areas of the
face that enhance venous drainage from the site of administration
to the central nervous system.
119. The method of claim 116, wherein the step of administering
further comprises administering the botulinum toxin to locations
that maximize uptake by a portal hypophyseal drainage.
120. The method of claim 116, wherein the botulinum toxin is a
botulinum toxin type A.
121. The method of claim 116, wherein the botulinum toxin is
administered subdermally.
122. The method of claim 116, wherein the botulinum toxin is
administered non-intramuscularly.
123. The method of claim 116, wherein the botulinum toxin is
administered directly.
124. The method of claim 116, wherein the botulinum toxin
administered further comprises a therapeutically effective amount
of the botulinum toxin.
125. The method of claim 116, wherein the step of administering
further comprises locally administering a therapeutically effective
amount of the botulinum toxin subdermally, non-intramuscularly to
the face of a patient with depression.
126. The method of claim 116, wherein the symptom of depression
further comprises at least one of the group consisting of:
depressed mood; markedly diminished interest or pleasure in
activities; significant weight loss or gain; insomnia or
hypersomnia; psychomotor agitation, anxiety, or retardation;
fatigue or energy loss; feelings of guilt and worthlessness;
impaired concentration and indecisiveness; and recurring thoughts
of death or suicide.
127. The method of claim 126, wherein the botulinum toxin is a
botulinum toxin type A.
128. The method of claim 126, wherein the botulinum toxin is
administered subdermally.
129. The method of claim 126, wherein the botulinum toxin is
administered non-intramuscularly.
130. The method of claim 126, wherein the botulinum toxin is
administered directly.
131. The method of claim 126, wherein the botulinum toxin
administered further comprises a therapeutically effective amount
of the botulinum toxin.
132. The method of claim 126, wherein the step of administering
further comprises locally administering a therapeutically effective
amount of the botulinum toxin subdermally, non-intramuscularly to
the face of a patient with depression.
133. The method of claim 116, wherein the depression further
comprises one of the group consisting of: major depression;
dysthymia; minor depression; seasonal affective disorder; and
atypical depression.
134. A method for treating a neurological disorder selected from
the group consisting of seizure disorders, chronic surgical wound
pain, pain syndrome, myofascial pain, muscle tension headache, or
trigeminal neuralgia, comprising the step of locally administering
a botulinum toxin to at least one of a scalp, face, or neck of a
patient with the neurological disorder, thereby treating the
neurological disorder by reducing the occurrence of a symptom of
the neurological disorder.
135. The method of claim 134, wherein the botulinum toxin is
selected from the group consisting of botulinum toxin types A, B,
C.sub.1, D, E, F and G.
136. The method of claim 134, wherein the botulinum toxin is a
botulinum toxin type A.
137. The method of claim 134, wherein the botulinum toxin is
administered subdermally.
138. The method of claim 134, wherein the botulinum toxin is
administered non-intramuscularly.
139. The method of claim 134, wherein the botulinum toxin is
administered directly.
140. The method of claim 134, wherein the botulinum toxin
administered further comprises a therapeutically effective amount
of the botulinum toxin.
141. The method of claim 134, wherein the step of administering
further comprises locally administering a therapeutically effective
amount of the botulinum toxin subdermally, non-intramuscularly to
the face of a patient with the neurological disorder.
142. The method of claim 134, wherein the neurological disorder is
selected from the group consisting of seizure disorders, chronic
surgical wound pain, and pain syndrome.
Description
[0001] This application claims benefit to U.S. Provisional
Application Ser. No. 60/690,162, filed on Jun. 14, 2005; U.S.
Provisional Application Ser. No. 60/693,771, filed on Jun. 27,
2005; U.S. Provisional Application Ser. No. 60/721,060, filed on
Sep. 28, 2005; U.S. Provisional Application Ser. No. 60/738,981,
filed on Nov. 23, 2005, all of which are hereby incorporated herein
by reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to the treatment of primary
disorders of mood and affect with a neurotoxin, including
depressive, anxiety and sleep disorders as well as other CNS
disorders.
BACKGROUND OF THE INVENTION
[0003] Depression is one of the most prevalent and pervasive forms
of mental illness that affects individuals across age and gender
lines. (Gainotti et al. (2001) J. Neural Neurosurg. Psychiatr. 71:
258-261; Wong et al. (2001) Nature Rev. Neurosci. 2: 343-351;
Nestler et al. (2002) Neuron 34: 13-25). The lifetime risk of major
depression is about 12% in men and about 25% in women, generally,
(Kessler et al (1994) Arch. Gen. Psychiatry 51: 8). In addition,
about 5 to 10% of all patients in the primary care environment,
present with major depression, whereas about 3 to 5% of patients
are diagnosed with dysthymia. (Barrett et al. (1988) Arch. Gen.
Psychiatry 45: 1100). In an in-patient setting, however, between 10
and 14% of all patients are diagnosed with major depression.
(Blackburn et al. (1997) Br. J Psychiatry 171: 328). Major
depression is a particularly disabling and pernicious, in part,
because it is recurring. The rate of relapse for patients with
major depression is about 40% over a two-year period after a first
episode. The occurrence of relapse increases to about 75% within a
five year period after the diagnosis of a second episode of major
depression. (Solomon et al. (2000) Am. J Psychiatry 157: 229).
[0004] Depressive disorders are most commonly treated with three
main classes of compounds: 1) monamine oxidase inhibitors; 2)
heterocyclic antidepressants; and 3) selective serotonin reuptake
inhibitors (SSRIs). The known and currently prescribed
antidepressants are by numerous side effects. Monoamine oxidase
inhibitors were the first class of antidepressants used clinically.
Monoamine oxidase inhibitors, including isocarboxazid, phenelzine,
and tranylcypromine, inhibit the metabolism of phenylethylamine and
catabolism of dopamine, serotonin and norepinephrine. As a
consequence of numerous dietary restrictions associated with the
use of monoamine oxidase inhibitors, extensive side effects,
including hypertension, headache, myoclonic jerk, sleep disruption,
and gastrointestinal complications, monoamine oxidase inhibitors
are currently not used as a first-line antidepressant. The
tricyclic antidepressants, including, imipramine, desipramine,
nortrypline, amitrypline, doxepin and protrypline, produce a
variety of anticholinergic side effects, drowsiness, orthostatic
hypotension, cardiac arrhythmias and weight gain. Although
generally milder than the monoamine oxidase inhibitors and the
tricyclic antidepressants, SSRIs also produce numerous side
effects. For example, SSRIs, including fluoxetine, paroxetine,
fluvoxamine, sertraline, and citalopram, are associated with
gastrointestinal distress, jitteriness, agitation and sleep
disruption.
[0005] In addition to the numerous side effects associated with
traditional antidepressant medications, these therapeutics are also
characterized by marginal efficacy. Several studies on the efficacy
of antidepressant therapy for major depression have concluded that
the treatment of acute disease or maintenance therapy is associated
with a 50-60% response rate. (Schulberg et al. (1998) Arch. Gen.
Psychiatry 55: 1121). The average absolute response rate between
antidepressants and placebo is about 20-25%. (Williams et al.
(2000) Ann. Intern. Med. 132: 743). Consequently, there is a
current need for new antidepressant therapies.
[0006] In view of the sometimes severe adverse side effects and
marginal efficacy of. numerous antidepressant therapies, there is a
great need for improved pharmaceuticals that effectively treat
depressive disorders and sleep disorders without producing the side
effects associated with treatments of depression and/or sleep
disorders. The present invention provides compositions comprising
botulinum toxin neurotoxin for the treatment of depressive and/or
sleep disorders as well as other CNS disorders.
[0007] The effects of botulinum toxin-based pharmaceuticals for
medicinal applications has traditionally been though to act on the
peripheral motor and possibly sensory nerves. Such actions of these
agents have been used to explain most of the beneficial effects for
various indications including movement disorders, pain syndromes,
autonomic based syndromes and spastic disorders. To date, clinical
observations have been made by the inventor which are indicative of
the involvement of the central nervous system and cannot be
explained by peripheral effects. Effects on the central nervous
system are observed even when botulinum toxin is administered to
the scalp, facial or neck regions, including administration by any
form of injection except intracranial injection. Such observations
include: improvement in photophobia with peri-ocular injections;
improvement in sleep patterns and relief of insomnia; improvement
of anxiety out of proportion to problems corrected by
physical/muscular impairments; improvement in depression out of
proportion to problems created by physical/muscular impairment; and
effects on dysmenorrheal symptoms and potential effects on
gonadotropin hormones or other pituitary hormones.
[0008] Additionally, botulinum toxin has been shown to have effects
on neurotransmission within the central nervous system when the
agent is directly injected into brain parenchyma. Alterations have
included depression in electrode depolarization, depression in
glutamate release, GABA staining, and cleavage of SNAP-25 in
duration consistent with botulinum toxin effect. Intraparenchymal
brain injections have been associated with depression of seizure
activity within the cerebral hemispheres when seizure provoking
scarring is induced by caustic chemical injections. Direct
injection into the brain is not practical and in fact unlikely to
be conventionally practiced by a physician skilled in the treatment
of seizure disorders because of the possibility and risk associated
with induced hemorrhage, scarring, neuronal loss and placement
difficulty, infection (meningitis) and inconvenience associated
with necessary delivery mechanisms. Direct injection into the CNS
is highly impractical because of such complications associated with
invasive intracranial procedures. Described herein is a system for
delivery to the central nervous system (through methods of
administration and injection that expressly do not include
transcranial, intrathecal or intraspinal injection) of botulinum
toxin-based pharmaceuticals, allowing penetration into the central
nervous system with enhanced convenience and safety, with fewer or
mitigated adverse effects associated with direct delivery.
[0009] The present inventors have surprisingly and unexpectedly
discovered criteria for the selection of subjects for the treatment
of pain syndromes with botulinum toxin. The present invention
provides methods for identifying subjects with an increased
responsiveness to the treatment of pain with botulinum toxin.
Specifically, the inventors have discovered that atopic disease is
associated with various pain syndromes, and the presence of atopic
disease and relief of pain by tactile stimulation, geste
antagoniste phenomenon, seem to have predictive value in
forecasting pain response to botulinum toxin.
[0010] The application of botulinum toxin for the treatment of
myofacial pain initially included tension headaches, bruxism,
temporal mandibular joint syndrome, lower-back pain, and
post-surgical pain after cervical surgical incisions for the
treatment of acoustic neuroma (posterior fossa brain tumor).
Application of botulinum toxin for the treatment of migraine
headaches became popular after the coincident observation that
migraine headaches were relieved after the of botulinum toxin to
efface facial wrinkles on the forehead.
[0011] Multiple case reports suggest that botulinum toxin is
effective for the treatment of tension and migraine headaches, as
well as forms of myofacial pain syndrome. Despite this suggestion,
controlled trials using small numbers of patients in the study
groups, have failed to demonstrate the efficacy of botulinum toxin
for the treatment of myofascial and other forms of pain. (Wheeler
et al. (1998) A randomized, double-blind, prospective pilot study
of botulinum toxin injection for refractory, unilateral,
cervicothoracic, paraspinal, myofascial pain syndrome. Spine
23(15): 1662-6). The ineffectiveness of botulinum toxin to treat a
variety of pain syndromes, in controlled trial, has been attributed
to small sample size and relatively low statistical power. The need
for larger numbers of patients and further multi-center
investigations have been deemed necessary to provide stronger
evidence of effectiveness.
[0012] In view of case reports suggesting that botulinum toxin is
indeed effective for the treatment of migraine-headache-pain
syndromes, efforts were made to conduct larger-scale studies. In an
initial multi-center controlled study sponsored by the Allergan
Pharmaceutical Company, one of the largest suppliers of botulinum
toxin A (BOTOX-.TM.), efficacy of botulinum toxin to prevent the
repetitive occurrence of common migraine headaches (as defined by
the International Headache Classification--1988) was suggested. The
statistical significance of these results, however, was uncertain,
inconsistent between treatment groups, and exhibited unexplained
inverted dose response curves. (Silberstein et al. (2000) Botulinum
toxin type A as a migraine preventive treatment. Headache 40(6):
445-50).
[0013] Migraine, tension headaches, myofascial pain of the head,
and chronic atypical facial headaches are representative of
primary-headache disorders (headaches not associated with
structural pathology within the head or not secondary to another
disease process). Treatment of these conditions is associated with
very high placebo response rates (up to 35%), requiring large
numbers of patients to detect significant differences in clinical
trials between study and control groups. Utilization of selection
criteria (study-induction criteria) that identify a more responsive
patient population increases the response rate for subjects within
treatment groups of controlled studies, which, in turn, allows a
smaller test sample to establish therapeutic efficacy in controlled
trials. More importantly, selection criteria (diagnostic criteria)
are the basis for accurate and effective medical therapy for any
condition. Parameters which identify patients more likely to
respond to a given treatment allow: 1) prioritization among
therapies when multiple therapeutic options exist; 2) avoidance of
therapy unlikely to be successful; and 3) facilitation of informed
consent from patients considering risks and benefit ratios.
Effective selection criteria assist researchers to further
understand mechanisms of action based on clinical evidence.
[0014] The present invention provides methods of selecting patients
suffering from various pain syndromes, including, but not limited
to, myofascial pain, muscle tension headache, and chronic post
operative wound syndromes, based on retrospective and prospective
analysis in the application of botulinum toxin for the treatment of
pain syndromes involving the head and neck.
SUMMARY OF THE INVENTION
[0015] The present invention provides methods of treating
depressive, anxiety and sleep disorders comprising the
administration of pharmaceutical compositions comprising
neurotoxins.
[0016] The present invention provides methods for treating
depression comprising the steps of: a) identifying a subject with a
depressive disorder or identifying a subject with one or more
symptoms of a depressive disorder; and b) administering an
effective amount of a composition comprising a botulinum toxin and
a pharmaceutically acceptable carrier to said subject.
[0017] The present invention also provides methods of treating
anxiety comprising the steps of a) identifying a subject with an
anxiety disorder or identifying a subject with at least one symptom
of an anxiety disorder; and b) administering an effective amount of
a composition comprising a botulinum toxin and a pharmaceutically
acceptable carrier to said subject.
[0018] The present invention also provides methods of treating
sleep disorders comprising the steps of: a) identifying a subject
with a sleep disorder or identifying a subject exhibiting at least
one symptom of a sleep disorder; and b) administering an effective
amount of a composition comprising a botulinum toxin and a
pharmaceutically acceptable carrier to said subject.
[0019] The present invention also provides methods of treating
circadian rhythm disorders comprising the steps of: a) identifying
a subject with a circadian rhythm disorder; and b) administering an
effective amount of a composition comprising a botulinum toxin and
a pharmaceutically acceptable carrier to said subject.
[0020] The present invention also provides methods of delivering
botulinum toxin across a blood-brain barrier comprising the steps
of: a) identifying a subject with at least one neuropsychiatric
disorder; and b) administering a composition comprising a
neurotoxin and a pharmaceutically acceptable carrier to said
subject in an amount sufficient to deliver said neurotoxin across
the blood-brain harrier.
[0021] The present invention also provides methods of delivering
botulinum toxin across a blood-brain barrier comprising the steps
of: a) identifying a subject with at least one neuropsychiatric
disorder; and b) administering a composition comprising a
neurotoxin and a pharmaceutically acceptable carrier to said
subject in an amount sufficient to deliver said neurotoxin across
the blood-brain barrier, wherein said administration of said
injection of neurotoxin blocks at least one neurotransmitter. In a
preferred embodiment, the neurotransmitter is acetylcholine.
[0022] The present invention also provides methods of treating an
anxiety disorder comprising the steps of: a) identifying a subject
with at least one anxiety disorder or identifying a subject with
one or more symptoms of an anxiety disorder; and b) administering
to said subject a composition comprising a neurotoxin and a
pharmaceutically acceptable carrier said composition is delivered
across the blood-brain barrier in an amount sufficient to decrease
cholinergic neuron transmission.
[0023] The present invention also provides methods of treating a
sleep disorder comprising the steps of: a) identifying a subject
with at least one sleep disorder or identifying a subject with one
or more symptoms of a sleep disorder; and b) administering to said
subject a composition comprising a neurotoxin and a
pharmaceutically acceptable carrier said composition is delivered
across the blood-brain barrier in an amount sufficient to decrease
cholinergic neuron transmission. In a preferred embodiment, the
composition decreases choline acetyltransferase activity. In
another preferred embodiment, the composition decreases the
synthesis of acetylcholine. In another preferred embodiment, the
sleep disorder is insomnia. In another preferred embodiment, the
sleep disorder is narcolepsy, restless leg syndrome or sleep
apnea.
[0024] The present invention also provides methods of treating a
circadian rhythm disorder comprising the steps of: a) identifying a
subject with at least one circadian rhythm disorder or identifying
a subject with one or more symptoms of a circadian rhythm disorder;
and b) administering to said subject a composition comprising a
neurotoxin and a pharmaceutically acceptable carrier said
composition is delivered across the blood-brain barrier in an
amount sufficient to decrease cholinergic neuron transmission. In a
preferred embodiment, the composition decreases choline
acetyltransferase activity. In another preferred embodiment, the
composition decreases the synthesis of acetylcholine.
[0025] The present invention also provides methods of treating a
depressive disorder comprising the steps of: a) identifying a
subject with at least one depressive disorder or identifying a
subject with one or more symptoms of a depressive disorder; and b)
administering to said subject a composition comprising a neurotoxin
and a pharmaceutically acceptable carrier said composition is
delivered across the blood-brain barrier in an amount sufficient to
decrease cholinergic neuron transmission. In a preferred
embodiment, the composition decreases choline acetyltransferase
activity. In another preferred embodiment, the composition
decreases the synthesis of acetylcholine.
[0026] The present invention provides methods of selecting a
subject for the treatment of pain with botulinum toxin, comprising
the step of identifying a subject suffering from a pain syndrome
and a condition selected from the group consisting of a depressive
disorder, an anxiety disorder and a sleep disorder, wherein the
identification of a subject with a pain syndrome and a condition
selected from the group consisting of a depressive disorder, an
anxiety disorder and a sleep disorder is predictive of increased
responsiveness to the treatment of pain with botulinum toxin. In a
preferred embodiment, the pain syndrome is any one or a combination
of the pain syndromes selected from the group consisting of;
myofacial pain; migraine headache; post operative would pain;
sinusitis-related headaches; muscle tension headaches;
post-traumatic headaches; cluster headaches; temporal mandibular
joint syndrome; fibromyalgia; atypical facial pain; post incisional
wound pain; cervical radiculopathy; and whiplash.
[0027] In another embodiment of the present invention, subjects
suffering from a condition selected from the group consisting of a
depressive disorder, an anxiety disorder and a sleep disorder were
identified by determining that a subject has a medical history of a
depressive disorder, an anxiety disorder, or a sleep disorder,
respectively.
[0028] The present invention also provides methods of identifying a
subject with increased responsiveness to treating a pain disorder
with botulinum toxin, comprising the step of screening a population
of subjects to identify those subjects that suffer from a pain
disorder and a condition selected from the group consisting of a
depressive disorder, an anxiety disorder and a sleep disorder,
wherein the identification of a subject with a pain syndrome and a
condition selected from the group consisting of a depressive
disorder, an anxiety disorder and a sleep disorder is predictive of
increased responsiveness to the treatment of pain with botulinum
toxin. In a preferred embodiment, the pain syndrome is any one or a
combination of the pain syndromes selected from the group
consisting of: myofacial pain; migraine headache; post operative
would pain; sinusitis-related headaches; muscle tension headaches;
post-traumatic headaches; cluster headaches; temporal mandibular
joint syndrome; fibromyalgia; atypical facial pain; post incisional
wound pain; cervical radiculopathy; and whiplash.
[0029] The present invention provides a method that comprises the
steps of identifying or diagnosing a pain syndrome; diagnosing or
eliciting a history of a condition selected from the group
consisting of a depressive disorder, an anxiety disorder and a
sleep disorder; and classifying the identified pain syndrome as one
with increased responsiveness to treatment with botulinum toxin. In
one embodiment, a pain syndrome is identified according to the
International Headache Classification System (The International
Headache Society (I.H.S.)).
[0030] The present invention provides a method of selecting
patients for the treatment of human headache disorders with a
botulinum toxin based pharmaceutical, comprising diagnosing
headache type occurring in a patient suffering from a depressive
disorder, an anxiety disorder, obsessive compulsive behavioral
traits, or a sleep disorder and administering a therapeutically
effective amount of botulinum toxin. In one embodiment the headache
disorder is migraine, tension headache, combined tension and
migraine headache, myofascial headache, sinus headache, headache
associated with temporal mandibular joint syndrome, headache
associated with fibromyalgia, or headache associated with
neuralgia.
[0031] The present invention also provides a method of selecting
patients for the treatment of human facial pain disorders with a
botulinum toxin based pharmaceutical, comprising diagnosing a
facial pain disorder occurring in a patient suffering from a
depressive disorder, an anxiety disorder, obsessive compulsive
behavioral traits, or a sleep disorder and administering a
therapeutically effective amount of botulinum toxin. In one
embodiment, the facial pain disorder is trigeminal neuralgia, the
facial pain disorder is associated with bruxism, or the facial pain
disorder is post operative chronic surgical wound pain.
[0032] The compositions of the present invention comprise botulinum
toxin and a pharmaceutically acceptable carrier. In a preferred
embodiment, the botulinum toxin is immunotype A, B, C, D, E, F, or
G. In a more preferred embodiment, the botulinum toxin is botulinum
toxin type A from Hall strain Clostridium botulinum.
[0033] The methods of the present invention may preferably be
practiced by administering the botulinum toxin compositions by
injection, including transcutaneous, percutaneous, subcutaneous,
intraperitoneal, transdermal, intramuscular and intraosseous, but
expressly not intracranial, transcranial, intrathecal or
intraspinal injection or administration. In one embodiment, there
are at least two injection sites. In another embodiment, the
injections are multifocal. The botulinum toxin may be preferably
administered to the forehead, scalp or neck or other locations such
as the periocular region and other areas of the face that enhance
maximize venous drainage from the site of administration to the
central nervous system (CNS). In another embodiment, the botulinum
toxin may be administered to the soft tissues outside the
neurocranium. In another embodiment, the botulinum toxin may be
administered in locations that maximize uptake by the portal
hypophyseal drainage.
[0034] Examples of compounds and formulations which can be used in
the present invention include botulinum toxin stabilized with a
protein such as serum albumin or hyaluronidase. In a preferred
embodiment the serum albumin or hyaluronidase is recombinant. In
another embodiment, the serum albumin is present at a concentration
of greater than 500 .mu.g/100 LD.sub.50 units botulinum toxin. The
botulinum toxin pharmaceutical may be further stabilized with a
simple stabilizing sugar or polysaccharide (e.g. sucrose, lactose
or trehalose). The botulinum toxin is preferably a monocomponent
neurotoxin of a molecular weight of 150,000 daltons that is free of
complex botulinum toxin proteins. The compositions disclosed herein
may also comprise a polyethylene glycol polymer; a vegetable
fat-based nanoemulsion; and any nanoemulsion using one or more
monounsaturated or polyunsaturated oils. In a preferred embodiment,
the botulinum toxin compositions used in the methods of the present
invention are formulated to enhance penetration of the botulinum
toxin into and through the skin.
[0035] Recent advances in pharmaceutical technology have focused on
enhanced delivery systems such as transdermal or transcutaneous
delivery systems. Such systems are thought to be more convenient
and associated with less pain. The problems associated with such
systems include poor penetration of materials through the epidermis
and dermis. Hyaluronidase offers improved penetration.
[0036] A pharmaceutical composition comprising botulinum
neurotoxin, hyaluronidase, and sugars (both simple and
oligosaccharides) is suitable for the methods of the present
invention. The botulinum toxin pharmaceutical formulations suitable
for use in for the methods of the present invention are preferably
devoid of any human blood or recombinant blood products and will be
either stabilized in flash or freeze dried form. The pH is
preferably between pH 3.0 to 7.4 and the preparation may be used as
an injection, transdermal or topical agent. The botulinum toxin
pharmaceutical formulations suitable for use in for the methods of
the present invention may be administered by injection, needleless
delivery systems and methods requiring disruption techniques such
as electroporation, sonication, and high pressure air gas flow
injection or in the form of a micro-needle. Micro-needles are
generally from 150 to 600 microns. Furthermore, the botulinum toxin
pharmaceutical formulations suitable for use in for the methods of
the present invention may further comprise polycationic
proteins.
[0037] Currently, hyaluronidase is available at a number of
specific activities. For example, sheep based materials can have a
specific activity of 1,500 U per mg or 1.5 U per meg. Typically,
75-300 U are used for injection, such as conducted with peri-bulbar
anesthesia for intra-ocular surgery. This would correspond to about
100-450 mg in mass of enzymatic protein, enough to act as a
stabilizing excipient.
[0038] Prior studies have show that a protein excipient, such as
human serum albumin, can stabilize the botulinum toxin. Test
studies conducted demonstrate that hyaluronidase also stabilizes
the botulinum toxin at the same levels observed for the human serum
albumin.
[0039] The compositions disclosed herein may be such that the doses
are formulated into a concentration suitable for administration as
an eye drop to facilitate transconjunctival penetration for the
treatment of ocular surface diseases. The compositions disclosed
herein may be such that the LD.sub.50 units range from 1.25 U-3,000
units of botulinum toxin type A. The compositions disclosed herein
may be such that the LD.sub.50 units range from 1.25-20,000 U of
botulinum type B. The compositions disclosed herein may be such
that the formulation is delivered into the nose or oral cavity as
an aerosol to facilitate intracranial delivery of a botulinum toxin
based pharmaceutical. The compositions disclosed herein may be such
that the formulation is delivered into the ear canal as an aerosol
to facilitate intracranial delivery of a botulinum based
pharmaceutical
[0040] The present invention provides methods for delivering a
botulinum toxin based pharmaceutical to the central nervous system
of a subject by any injection or topical application method, except
intracranial, transcranial, intrathecal or intraspinal injection,
in a therapeutically effective amount sufficient to decrease at
least one central nervous system neurotransmitter when compared to
an untreated subject. In a preferred embodiment, the at least one
central nervous system neurotransmitter is glutamate,
norepinephrine, or acetyl-choline. In a more preferred embodiment,
the at least one central nervous system neurotransmitter is
glutamate. In another embodiment, the methods of the present
invention decrease at least one central nervous system
neurotransmitter when compared to an untreated subject sufficiently
to reduce at least one symptom of insomnia, a sleep disorder, an
anxiety disorder, a depressive disorder, dysmenorrhea, an appetite
or eating disorder, or a seizure disorder. In a preferred
embodiment the seizure disorder is generalized, focal motor, or
partial complex.
[0041] Glutamate is a neurotransmitter that exhibits endogenous
neurotoxic activity that is observed in a number of
neurodegenerative diseases and disorders, vascular accidents such
as stroke and in seizure disorders. For example, subjects with mild
to moderate dementia and probable Alzheimer's Disease have been
shown to exhibit elevated levels of glutamate in the central
nervous system. Elevated glutamate in the central nervous system is
reflective of increased glutamatergic activity in the early stages
of Alzheimer's Disease. The progressive neuronal loss observed in
Alzheimer's Disease and other neurodegenerative disorders and
diseases correlate with elevated glutamate and the increased
excitotoxicity associated with elevated levels of this
neurotransmitter.
[0042] The present invention provides methods for reducing
glutamate levels in the central nervous system, the brain or
portions of the brain comprising the step of administering a
botulinum toxin pharmaceutical to a subject, by any injection or
topical application method, except intracranial, transcranial,
intrathecal or intraspinal injection, in an amount sufficient to
reduce glutamate levels in the central nervous system, the brain or
portions of the brain compared to an untreated subject.
[0043] The present invention provides methods for neuroprotection
comprising the step of administering a botulinum toxin
pharmaceutical to a subject, by any injection or topical
application method, except intracranial, transcranial, intrathecal
or intraspinal injection, in an amount sufficient to reduce
neuronal loss in the central nervous system, the brain or portions
of the brain compared to an untreated subject.
[0044] The present invention also provides methods for delivering a
botulinum toxin based pharmaceutical to the central nervous system
of a subject by injection into the nasal sinuses in a
therapeutically effective amount sufficient to decrease at least
one central nervous system neurotransmitter when compared to an
untreated subject. In a preferred embodiment, the at least one
central nervous system neurotransmitter is glutamate,
norepinephrine, or acetyl-choline. In a more preferred embodiment,
the at least one central nervous system neurotransmitter is
glutamate. In another embodiment, the methods of the present
invention decrease at least one central nervous system
neurotransmitter when compared to an untreated subject sufficiently
to reduce at least one symptom of insomnia, a sleep disorder, an
anxiety disorder, a depressive disorder, dysmenorrhea, or a seizure
disorder. In a preferred embodiment the seizure disorder is
generalized, focal motor, or partial complex.
[0045] The present invention also provides methods for delivering a
botulinum toxin based pharmaceutical to the central nervous system
of a subject by any injection or topical application method, except
intracranial, transcranial, intrathecal or intraspinal injection,
in a therapeutically effective amount sufficient to decrease at
least one central nervous system neurotransmitter when compared to
an untreated subject. In a preferred embodiment, the at least one
central nervous system neurotransmitter is glutamate,
nor-epinephrine, or acetyl-choline. In a more preferred embodiment,
the at least one central nervous system neurotransmitter is
glutamate. In another embodiment, the methods of the present
invention decrease at least one central nervous system
neurotransmitter when compared to an untreated subject sufficiently
to reduce an agitated behavior associated with mental retardation,
schizophrenia, Huntington's Chorea or Alzheimer's Disease.
[0046] The present invention also provides methods for delivering a
botulinum toxin based pharmaceutical to the central nervous system
of a subject by any injection or topical application method, except
intracranial, transcranial, intrathecal or intraspinal injection,
in a therapeutically effective amount sufficient to decrease at
least one central nervous system neurotransmitter when compared to
an untreated subject. In a preferred embodiment, the at least one
central nervous system neurotransmitter is glutamate,
nor-epinephrine, or acetyl-choline. In a more preferred embodiment,
the at least one central nervous system neurotransmitter is
glutamate. In another embodiment, the methods of the present
invention decrease at least one central nervous system
neurotransmitter when compared to an untreated subject sufficiently
to reduce at least one symptom of a neurodegenerative disease
associated with inflammation.
[0047] The present invention also provides for the use of botulinum
toxin or a botulinum toxin composition of the present invention in
the production of a medicament for the treatment of any one of the
disorders, diseases or conditions disclosed herein, including
depressive disorders, anxiety disorders, sleep disorders, circadian
rhythm disorders, neuropsychiatric disorders, Alzheimer's Disease
and the like, and for the treatment of pain, such as various
headache pain, associated with a pain syndrome.
BRIEF DESCRIPTION OF THE DRAWINGS
[0048] FIG. 1 depicts the decreased glutamate receptor activity in
the neostriatum of a botulinum-toxin-treated mouse as compared to
an untreated mouse.
DETAILED DESCRIPTION OF THE INVENTION
A. Definitions
[0049] As used herein, "administration" of a composition means any
route of administration, including but not limited to oral, nasal,
transcutaneous, percutaneous, subcutaneous, intraperitoneal,
transdermal, intramuscular and intraosseous, but expressly excludes
administered by any method, except intracranial, transcranial,
intrathecal or intraspinal injection.
[0050] As used herein, "Botulinum toxin" means a protein toxin and
its complexes isolated from strains of Clostridium botulinum,
including various immunotypes such as A, B, C1, C2, C3, D, E, F and
G.
[0051] As used herein, "depressive disorder" means major
depression, dysthymia, and atypical depression or depression not
otherwise specified.
[0052] As used herein, "an effective amount" is an amount
sufficient to reduce one or more symptoms associated with a
depressive, anxiety or sleep disorder or any of the disorders
described herein.
[0053] As used herein, the term "pharmaceutically acceptable
carrier" means a chemical composition with which the active
ingredient may be combined and which, following the combination,
can be used to administer the active ingredient to a subject.
"Pharmaceutically acceptable carrier" also includes, but is not
limited to, one or more of the following: excipients; surface
active agents; dispersing agents; inert diluents; granulating and
disintegrating agents; binding agents; lubricating agents;
sweetening agents; flavoring agents; coloring agents;
preservatives; physiologically degradable compositions such as
gelatin; aqueous vehicles and solvents; oily vehicles and solvents;
suspending agents; dispersing or wetting agents; emulsifying
agents, demulcents; buffers; salts; thickening agents; fillers;
emulsifying agents; antioxidants; antibiotics; antifungal agents;
stabilizing agents; and pharmaceutically acceptable polymeric or
hydrophobic materials. Other "additional ingredients" which may be
included in the pharmaceutical compositions of the invention are
known in the art and described, for example in Genaro, ed., 1985,
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pa., which is incorporated herein by reference.
[0054] As used herein, "increased responsiveness" refers to an
increase in the ratio of subjects responsive to pain treatment with
botulinum toxin to total subjects (responsive and unresponsive to
botulinum toxin).
[0055] As used herein, "response ratio" refers to the ratio of
subjects responsive to pain treatment with botulinum toxin to total
subjects (responsive and unresponsive to botulinum toxin).
[0056] As used herein, the term "screening a population" means a
retrospective review and analysis of the medical history of a
subject or an identification of a specific contemporaneous
diagnosis.
[0057] The formulations of the pharmaceutical compositions
described herein may be prepared by any method known or hereafter
developed in the art of pharmacology. In general, such preparatory
methods include the step of bringing the active ingredient into
association with a carrier or one or more other accessory
ingredients, and then, if necessary or desirable, shaping or
packaging the product into a desired single- or multi-dose
unit.
[0058] Although the descriptions of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for ethical administration to
humans, it will be understood by the skilled artisan that such
compositions are generally suitable for administration to animals
of all sorts. Modification of pharmaceutical compositions suitable
for administration to humans in order to render the compositions
suitable for administration to various animals is well understood,
and the ordinarily skilled veterinary pharmacologist can design and
perform such modification with merely ordinary, if any,
experimentation. Subjects to which administration of the
pharmaceutical compositions of the invention is contemplated
include, but are not limited to, humans and other primates, and
other mammals.
[0059] The relative amounts of the active ingredient, the
pharmaceutically acceptable carrier, and any additional ingredients
in a pharmaceutical composition of the invention will vary,
depending upon the identity, size, and condition of the subject
treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between 0.1% and 100% (w/w) active
ingredient. In addition to the active ingredient, a pharmaceutical
composition of the invention may further comprise one or more
additional pharmaceutically active agents. Particularly
contemplated additional agents include anti-emetics and scavengers
such as cyanide and cyanate scavengers. Controlled- or
sustained-release formulations of a pharmaceutical composition of
the invention may be made using conventional technology.
[0060] As used herein, the term "physiologically acceptable" ester
or salt means an ester or salt form of the active ingredient which
is compatible with any other ingredients of the pharmaceutical
composition, which is not deleterious to the subject to which the
composition is to be administered.
B. Depressive Disorders
[0061] Depressive disorders encompass the diagnoses of major
depression, dysthymia, and atypical depression or depression not
otherwise specified ("minor depression"). The different subgroups
of depressive disorders are categorized and defined by the
Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition (DSM-IV). (American Psychiatric Association. Diagnostic and
Statistical Manual of Mental Disorders, 4.sup.th Ed., Primary Care
Version (DSM-IV-PC). American Psychiatric Association Press,
Washington, DC 1995), According to the DSM-IV, a diagnosis of
"major depression" requires that a patient present with at least
five of the following nine symptoms during the diagnostic period:
1) depressed mood most of the day (most acute in the morning); 2)
markedly diminished interest or pleasure in nearly all activities
(anhedonia); 3) significant weight loss or gain; 4) insomnia or
hypersomnia; 5) psychomotor agitation or retardation; 6) fatigue or
energy loss; 7) feelings of guilt and worthlessness; 8) impaired
concentration and indecisiveness; and 9) recurring thoughts of
death or suicide. To support a diagnosis of major depression, a
depressed mood or loss of interest (anhedonia) must be one of the
five observed symptoms. In contrast, a diagnosis of "atypical
depression" or "depression not otherwise specified" (also referred
to as "minor depression"), the most common form of depression,
requires between 2 and 4 depressive symptoms that are present daily
or for most of the day for at least a two week period. Dysthymia is
a chronic, low intensity mood disorder characterized by anhedonia,
low self esteem and low energy that persists for more than two
years, consecutively. Seasonal affective disorder is considered to
be a form of major depression characterized by seasonal
variation.
[0062] Depressive disorders do not include normal emotional
reactions, a normal grief reaction or reactions secondary to an
organic cause such as a physical illness or drug exposure. As used
herein, depressive disorders refer to primary disorders of mood and
sleep patterns and not secondary or reaction disorders. Such
reactionary disorders occur secondarily to other medical disorders
such as hyperhydrosis, cervical dystonia, migraine headache,
tension headaches, various pain syndromes, jaw spasms,
blepharospasm, strabismus, inflammatory local and systemic
diseases, post operative pain syndromes, hemifacial spasms, cancer,
myocardial infarction, stroke, degenerative neurological diseases,
or any other physical ailment causing an emotional reaction.
C. Anxiety
[0063] Anxiety is a group of disorders characterized by a number of
both mental and physical symptoms, with no apparent explanation.
Apprehension, fear of losing control, fear of going "crazy", fear
of pending death, impending danger, or uneasiness are among the
most common mental symptoms. Common physical symptoms include
dizziness, lightheadedness, chest pain, abdominal pain, nausea,
increased hear rates or diarrhea. Chronic anxiety, also referred to
as Generalized Anxiety Disorder, manifests as persistent worries,
fears, and negative thoughts lasting a minimum of six months.
Chronic anxiety often results in excessive worry over daily
activities, headaches and nausea. Sleep disorders or early
awakening, depression, tension, muscle aches and fatigue can all
accompany chronic anxiety.
[0064] Acute anxiety, or Panic Disorder, comes on as a sudden
attack or fear accompanied by symptoms that may resemble a heart
attack, such as palpitations, chest pain and dizziness. Shortness
of breath, stomach upset, chills, cold sweats, hot flashes, or
irrational fears of death can combine with these symptoms to create
a terrifying experience for the individual experiencing them.
Excessive levels of nor epinephrine are seen to increase the rates
of breathing and pulse in panic attack sufferers. Post-traumatic
Stress Disorder is also classed as an anxiety disorder, and can be
triggered by anyone experiencing or witnessing a deeply traumatic
event. Some symptoms of Post-Traumatic Stress Disorder can be
anger, depression, emotional numbness, flashbacks, nightmares and a
tendency to startle easily.
[0065] Phobias, or irrational fears, and Obsessive Compulsive
Disorder, a tendency towards repetitive or uncontrollable behavior,
are also classed with anxiety disorders. These may co-exist
together, as many individuals with obsessive compulsive disorder
have phobias of germs or lack of cleanliness and may was their
hands or bathe excessively.
[0066] Anxiety disorders do not include normal emotional reactions,
a normal reaction to stress or reactions secondary to an organic
cause such as a physical illness or drug exposure.
D. Sleep Disorders
[0067] Circadian rhythm describes the approximately 24-hour cycles
that are generated by an organism. Most physiological systems
demonstrate circadian variations. The systems with the most
prominent variations are the sleep-wake cycle, thermoregulation,
and the endocrine system. Circadian rhythm disturbances can be
categorized into two main groups: transient disorders (e.g., jet
lag, altered sleep schedule due to work, social responsibilities,
illness) and chronic disorders. The most common chronic disorders
are delayed sleep-phase syndrome (DSPS), advanced sleep-phase
syndrome (ASPS), and irregular sleep-wake cycle. Katzenberg et al.
have suggested a genetic correlation (i.e., clock polymorphisms) to
circadian rhythm patterns. DSPS is characterized by a persistent
inability (more than 6 mo) to fall asleep and awaken at socially
accepted times. Once asleep, these patients are able to maintain
their sleep and have normal total sleep times. (In contrast,
patients with insomnia have a lower than normal total sleep time,
due to difficulties in initiating or maintaining sleep.) ASPS is
characterized by persistent early evening sleep onset (between 6:00
and 9:00 pm) with an early morning wake-up time, generally between
3:00 and 5:00 am. ASPS occurs much less frequently than DSPS and is
seen most commonly in the elderly and in individuals who are
depressed.
[0068] The neural basis of the circadian rhythm, the
suprachiasmatic nuclei (SCN), is located in the anterior ventral
hypothalamus and has been identified as the substrate that
generates circadian activity. Lesions of the SCN produce loss of
circadian rhythmicity of the sleep-wake cycle, the activity-rest
cycle, skin temperature, and corticosteroid secretion. Other
pacemakers exist that are not located in the SCN. For instance,
core body temperature rhythm persists in spite of bilateral
ablation of SCN. Furthermore, free-running studies have provided
evidence for multiple circadian oscillators. Under free-running
conditions, circadian rhythm may split into independent
components.
[0069] The SCN are the site of the master circadian clock in
mammals. The SCN clock is mainly entrained by the light-dark cycle.
Light information is conveyed from the retina to the SCN through
direct, retinohypothalamic fibers. The SCN also receive other
projections, like cholinergic fibers from basal forebrain.
Cholinergic afferents and transmission have been shown to be
involved in regulation of light-induced circadian rhythms. (Erhardt
et al. 2004 The Neuroanantomy of the Circadian Rhythm.).
[0070] In the United States, DSPS is common. Approximately 7-10% of
patients who complain of insomnia are diagnosed with a circadian
rhythm disorder, most often DSPS. The prevalence of DSPS is
probably higher than that because the total sleep time is typically
normal in patients with DSPS and because patients with DSPS adjust
their lifestyle to accommodate their sleep schedule and do not seek
medical treatment. In adolescence, the prevalence is approximately
7%. In contrast, true ASPS probably is quite rare. An age-related
phase advance, however, is common in the elderly, who tend to go to
sleep early and get up early.
[0071] The diagnosis of circadian rhythm disorders is based
primarily on a thorough social, physical and neurological history.
Differentiation of transient disorders from chronic disorders and
primary disorders from secondary disorders influences the direction
of evaluation and treatment plans. As with all medical and
psychiatric histories, the nature of the complaint is the first
order of business. In cases of sleeplessness, distinguishing
individuals with difficulty initiating sleep from those with
difficulty maintaining sleep, those with significant daytime
impairment, and those complaining of nonrestorative sleep is
important.
[0072] Disorders associated with various sleep disorders include
narcolepsy, cataplexy, restless-leg syndrome, and sleep apnea.
Anxiety disorders do not include normal emotional reactions, a
normal reaction to stress or reactions secondary to an organic
cause such as a physical illness or drug exposure.
E. CNS Disorders
[0073] The present invention is also directed to methods of using
botulinum toxin based pharmaceuticals injected transcutaneously or
by any of the routes of administration disclosed herein, to induce
a central nervous system depressive effect for the treatment of
various CNS disorders. The inventor has found that botulinum toxin
exerts a CNS depressive effect in rats injected transcutaneously in
the scalp. The injections are not intracranial or directly into the
brain, but may include or specifically exclude intrathecal and
intraspinal injection or administration. It is hypothesized that
transcutaneous administration of botulinum toxin penetrates the
blood/brain barrier. The present invention provides methods for
using the botulinum toxin based pharmaceuticals disclosed herein
for the treatment of seizures, anxiety, agitation, mania, bipolar
disorders, generalized seizures, mental retardation, delirium,
hyperactivity syndrome, attention deficit disorder (ADD), dementia,
Huntington's disease, Alzheimer's disease, Parkinson's disease,
psychosis, schizophrenia, insomnia and other CNS disorders.
[0074] In certain embodiments, the botulinum toxin based
pharmaceuticals disclosed herein are used at various dosage levels
to induce a generalized atrophic effect in the CNS. This effect is
useful in the treatment of various CNS disorders. The inventor has
found that rats injected with high doses of botulinum toxin (i.e.
doses at or near the LD.sub.50) exhibit expanded or enlarged
lateral ventricles in their brains. Controls show no such effects
while treated animals show a marked effect. Generalized brain
atrophy is indicative of biological activity at the level of
neurotransmitters that is induced by transcutaneous administration
of botulinum toxin. The evidence is consistent with a suppressive
effect in the hypothalamus in the treated animals. This could cause
direct effects on the release of hormones such as thyroid releasing
factors, gonadotropin releasing factor, etc.
[0075] All books, articles, patents or other publications and
references are hereby incorporated by reference in their
entireties. Reference to any compound herein includes the racemate
as well as the single enantiomers.
EXAMPLES
[0076] The following Examples serve to further illustrate the
present invention and are not to be construed as limiting its scope
in any way.
Example 1
[0077] A 78-year-old male who noted sleep disturbances and anxiety
was initially diagnosed with blepharospasm. Botulinum toxin was
administered by injection, and the subject noted improved sleep and
reduced anxiety.
Example 2
[0078] A 44-year-old bus driver was diagnosed with hemifacial spasm
and reported symptoms of anxiety. Botulinum toxin was administered
by injection. The subject noted a better ability to cope with
work-related stresses and cope with difficult situations with less
stress.
Example 3
[0079] A 72-year-old consultant diagnosed with hemifacial spasm who
reported sleep disturbances and anxiety was treated with botulinum
toxin that was administered by injection. The subject reported
improved sleep and reduced anxiety and less agitation.
Example 4
[0080] A 45-year-old woman was treated for cosmetic indications
with botulinum toxin. The initial diagnosis was cosmetic rhytides.
The subject noted fewer symptoms of depression and less anxiety for
a period of two months.
Example 5
[0081] A 44-year-old woman diagnosed with severe tension headaches
and sleep disturbances was treated with botulinum toxin by
injection. The subject noted improved sleep patterns and fewer
headaches up to two months after treatment.
Example 6
[0082] A 73-year-old male with essential blepharospasm reported
sleep disturbances and anxiety characterized as "nervous tension."
Botulinum toxin was administered by injection. The subject noted
less anxiety and improved sleep after the injections. The reduced
symptoms lasted two to three months and ultimately recurred.
Example 7
[0083] A 43-year-old person with myofacial pain and sleep problems
was treated with botulinum toxin by injection. The subject noted
better sleep patterns after injections that lasted three
months.
Example 8
[0084] A 42-year-old person was diagnosed with myofacial pain,
tension headaches and depression and treated with botulinum toxin
administered by injection. The subject noted some improvement in
sleep pattern after the toxin injections.
Example 9
[0085] The subject is a 54-year-old person diagnosed with essential
blepharospasm and depression. Botulinum toxin was introduced by
injection. The subject noted fewer symptoms of depression after the
botulinum toxin injections.
Example 10
[0086] The subject is a 57-year-old physician diagnosed with
essential blepharospasm. Botulinum toxin was introduced by
injection. The subject noted a feeling of euphoria, well being and
improved mood after the botulinum toxin injections.
Example 11
[0087] A 47 year old woman with a history of cervicogenic headache
and frequent problems of insomnia. The insomnia was characterized
by difficulty initiating sleep, intermittent awakening,
early-morning awakening, and inability to maintain sleep.
Injections were given in the regions generally used to treat
spasmodic torticollis as well as in multiple locations along the
hairline, both anterior and posterior. Doses ranged between 5-20
units per subcutaneous injection site with a total dose of 100 U.
Within 3-5 days, improvement in the insomnia occurred and lasted
between 10-14 weeks. Improvement in each component of her sleep
disorder occurred. Recurrence of the sleep disorder occurred after
the 10-14 week period.
Example 12
[0088] A 52 year old woman received botulinum injections for the
effacement of glabellar rhytides (facial wrinkles). Further
injections were given in multiple locations along the hairlines,
she also suffered from insomnia with difficulty initiating sleep
and sustaining sleep. After injection with botulinum toxin, sleep
pattern improved and lasted the duration of about 10-12 weeks.
Total dose administered in multiple locations was 30 Units.
Example 13
[0089] A 71 year old man with essential blepharospasm was injected
with 60 U divided along the peri-ocular region and the forehead.
Improvement in sleep pattern characterized by more continuous sleep
was noted after each injection. The benefit lasted about 3 months
and has been noted over 3 injection cycles. When brought to the
patient's attention, he associated the improvement to the botulinum
toxin injections. Insomnia recurred when he felt the time for
repeat injection with botulinum toxin.
Example 14
[0090] A botulinum toxin composition is prepared from any
immunotype (A-G) consisting of monocomponent neurotoxin molecules
free of accessory or complex proteins, containing human serum
albumin, and a nanoemulsion, with various charges. The nanoemulsion
may contain polymers consisting of any of the following:
polyethylene glycol, vegetable oil, a vegetable oil derivative or a
monounsaturated or polyunsaturated oil. The pH may be altered in
the preparation to enhance permeability. Alternatively, botulinum
toxin is prepared from immunotypes A-G consisting of a
monocomponent neurotoxin, without a nanoemulsion carrier; albumin
and an acidic pH between 1-6 units. The effect on the central
nervous system from transcutaneous injection was demonstrated using
a rodent animal model typically used for research in
neurodegenerative disease (20-30 gram mice). Injections were given
over the scalp region with botulinum type A toxin at a dose close
and approximating the LD.sub.50 for this animal. Surviving animals
were subjected to autopsy and serial brain cutting and
histologically stained using a standard Nissle formula. Substantial
atrophy of basal ganglion and periventriclular cells was noted.
Such changes are not usually seen with systemic illness without
direct brain pathology. The neuropathologic assessment is that
direct suppressant effects do occur within the central nervous
system at high dose (close to the LD.sub.50 for the animal model).
More subtle changes are anticipated and seen at lower therapeutic
doses based on clinical observations of efficacy for insomnia,
dysmenorrhea, depression and anxiety. The experimentation described
herein indicates blockage of neurotransmission usually of
excitatory neurotransmitters to the extent that pathologic change
occurs in brain structures. The major central nervous system
neuroransmitters blocked include glutamate, norepinephrine,
acetylcholine. GABA effects are augmented. SNAP-25 is noted to be
cleaved throughout the targeted areas.
Example 15
[0091] The effect on the central nervous system from transcutaneous
injection was demonstrated using a rodent animal model typically
used for research in neurodegenerative disease (20-30 gram mice).
Four injections of botulinum toxin (totaling 0.8 LD.sub.50 units)
were given over the scalp region. Surviving animals were subjected
to autopsy and serial brain cutting and histologically stained
using a standard Nissle formula. Substantial atrophy of basal
ganglion and periventriclular cells was noted. Substantial decrease
of cholinergic neurons was noted. Substantial decrease in the
amount of choline acetyltransferase was noted. More subtle changes
are anticipated at lower therapeutic doses based on clinical
observations of efficacy for insomnia, dysmenorrhea, depression and
anxiety. The experimentation described herein demonstrates blockage
of neurotransmission usually of excitatory neurotransmitters to the
extent that pathologic change occurs in brain structures. The major
central nervous system neuroransmitters blocked include glutamate,
norepinephrine, and acetylcholine. GABA effects are augmented.
SNAP-25 is noted to be cleaved throughout the targeted areas.
Example 16
[0092] The effect on the central nervous system from transcutaneous
injection was demonstrated using a rodent animal model typically
used for research in neurodegenerative disease (20-30 gram mice).
Four injections of botulinum toxin (totaling 0.8 LD.sub.50 units)
were given over the scalp region. Surviving animals were subjected
to autopsy and serial brain cutting and histologically stained
using a standard Nissle formula. Serial cut mouse tissue sections
were stained for Nissle substance using cresyl violet and
immunostained for glutamate receptor activity. Sections were rinsed
in TRIS-buffered saline with Tween 20 (TBS-T) containing 10% normal
goat serum for one hour. Sections were then incubated overnight in
TBS-T with 0.1% sodium azide and anti-GluR4. Sections were rinsed
three times in TBS-T, followed by a 2-3 hour incubation in TBS-T
containing a goat anti-mouse peroxidase-conjugated secondary
antibody to detect glutamate. Sections were then rinsed three times
in TBS-T. Antibody complexes were visualized using
diaminobenzidine. Preabsorbtion with excess target protein, or
omission of either primary or secondary antibody, were used to
demonstrate antibody specificity and background generated from the
detection assay. Tissue sections were examined using a Nikon
Eclipse E800 microscope with a Spot RT digital camera. Photographs
of tissue sections of neostriatum in an untreated mouse (sham
injection) and a botulinum toxin treated mouse (four injections
totaling 0.8 LD.sub.50 BOTOX.RTM. injected transdermally over the
scalp reason) shown in FIG. 1.
* * * * *