U.S. patent application number 13/900067 was filed with the patent office on 2013-09-26 for therapeutic treatments using botulinum neurotoxin.
This patent application is currently assigned to Allergan, Inc.. The applicant listed for this patent is Allergan, Inc.. Invention is credited to Mitchell F. Brin, Aubrey N. Manack.
Application Number | 20130251830 13/900067 |
Document ID | / |
Family ID | 41063284 |
Filed Date | 2013-09-26 |
United States Patent
Application |
20130251830 |
Kind Code |
A1 |
Manack; Aubrey N. ; et
al. |
September 26, 2013 |
THERAPEUTIC TREATMENTS USING BOTULINUM NEUROTOXIN
Abstract
Methods for treating a coronary risk factor (such as
hypertension, diabetes, hyperlipidemia and obesity) and/or a
respiratory disorder (such as asthma, chronic obstructive pulmonary
disease and bronchitis) and/or arthritis by local administration of
a botulinum neurotoxin to at least one of a head, neck or shoulder
location (for example, by subdermal, subcutaneous or intramuscular
administration of the botulinum neurotoxin) of a patient with a
coronary risk factor, respiratory disorder or arthritis.
Inventors: |
Manack; Aubrey N.; (Costa
Mesa, CA) ; Brin; Mitchell F.; (Newport Beach,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
|
|
Assignee: |
Allergan, Inc.
Irvine
CA
|
Family ID: |
41063284 |
Appl. No.: |
13/900067 |
Filed: |
May 22, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12047482 |
Mar 13, 2008 |
8470337 |
|
|
13900067 |
|
|
|
|
Current U.S.
Class: |
424/780 |
Current CPC
Class: |
A61K 38/164 20130101;
A61P 19/02 20180101; A61P 9/00 20180101; A61P 25/00 20180101; A61P
11/00 20180101; A61K 38/4893 20130101 |
Class at
Publication: |
424/780 |
International
Class: |
A61K 38/16 20060101
A61K038/16 |
Claims
1. A method for treating a respiratory disorder in a patient in
need thereof, the method comprising the step of administering a
botulinum toxin to at least one of a head, neck or shoulder
location of the patient with a respiratory disorder, thereby
alleviating at least one symptom of the respiratory disorder and
treating the respiratory disorder of the patient.
2. The method of claim 1, wherein the botulinum toxin is selected
from the group consisting of botulinum toxins types A, B, C.sub.1,
D, E, F and G.
3. The method of claim 1, wherein the botulinum toxin is a
botulinum toxin type A.
4. The method of claim 1, wherein the respiratory disorder is
selected from the group consisting of asthma, bronchitis and
chronic obstructive pulmonary disease.
5. The method of claim 1, wherein the administration step is
carried out by intramuscular administration of the botulinum toxin
to a muscle at the at least one of the head, neck or shoulder
location of the patient.
6. The method of claim 1, wherein the patient also has a
headache.
7. The method of claim 1, wherein the patient also has a headache
selected from the group consisting of a tension headache, a
migraine headache, an episodic migraine, a chronic migraine, a
cluster headache, a sinus headache, a chronic progressive headache,
a hormone headache and a cervogenic headache.
8. A method for treating a coronary risk factor in a patient in
need thereof, the method comprising the step of administering a
botulinum toxin to at least one of a head, neck or shoulder
location of the patient with the coronary risk factor, thereby
treating the coronary risk factor.
9. The method of claim 8, wherein the coronary risk factor is
selected from the group consisting of hypertension, diabetes,
hyperlipidemia and obesity.
10. The method of claim 8, wherein the botulinum toxin is a
botulinum toxin type A or B and is administered to a muscle
selected from the group consisting of a frontalis muscle, a
glabellar muscle, an occipitalis muscle, a temporalis muscle, a
masseter muscle, a trapezius muscle, a semispinalis muscle and a
splenius capitis muscle.
11. The method of claim 10, wherein the administration is
intramuscular or subdermal and the patient suffers from
headaches.
12. The method of claim 11, wherein headaches suffered by the
patient are migraine headaches and are experienced by the patient
at least 15 days per month.
13. The method of claim 11, wherein headaches suffered by the
patient are migraine headaches and are experienced by the patient
at between 0 to eight days per month.
14. The method of claim 8, wherein the botulinum is a botulinum
toxin type A and is administered in an amount from about 10.sup.-3
U/kg to about 35 U/kg of patient weight.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a Divisional Application of U.S. patent
application Ser. No. 12/047,482, filed Mar. 13, 2008, which is
hereby incorporated herein by reference in its entirety.
BACKGROUND
[0002] The present invention relates to therapeutic methods
utilizing a botulinum neurotoxin such as for treating cardiac risk
factors (e.g. hypertension, diabetes, hyperlipidemia, and obesity)
and/or respiratory disorders (e.g. asthma, bronchitis and chronic
obstructive pulmonary disease (COPD)) and/or arthritis. More
particularly, the present invention relates to methods for treating
various cardiac risk factors and/or respiratory disorders and/or
arthritis utilizing local administration of at least one botulinum
neurotoxin.
[0003] Coronary Risk Factors
[0004] A coronary (or cardiac) risk factor is a condition and/or
behavior that increases a patient's chances of developing a
coronary heart disease. A coronary heart disease is also called
coronary artery disease (CAD), ischaemic heart disease or
atherosclerotic heart disease and is the end result of the
accumulation of atheromatous plaques in walls of the arteries that
supply heart muscle with oxygen and nutrients. The fewer total
number of risk factors that a patient has, the less risk the
patient has of developing a coronary heart disease. Additionally,
the greater the level of a particular risk factor (i.e. a
clinically measurable aspect of the risk factor, for example having
a total blood cholesterol level of 200 mg/dL or greater rather than
below 200 mg/dL), the greater is the risk that the patient will
develop a coronary heart disease.
[0005] Some coronary risk factors cannot be controlled. Examples of
uncontrollable coronary risk factors include, for example, age and
genetic disposition. The risk of developing some coronary heart
disease simply increases with every passing year. For example men
ages 45 and older and women ages 55 and older are at increased risk
of developing coronary heart disease as compared to younger
persons. Another factor to consider is family history. If a person
is the child of parents who developed coronary heart disease before
the age of 55, such offspring are more likely to develop coronary
heart disease themselves than their peers whose parents developed
coronary heart disease after the age 55 or not at all. Lastly,
studies have shown a person's racial or ethnic background can also
be considered a risk factor for developing coronary heart disease,
where African Americans, Mexican Americans, American Indians, and
other Native Americans are at greater risk than Caucasians.
[0006] Some coronary risk factors can be controlled. Examples of
controllable coronary risk factors include physical inactivity,
smoking, being overweight or obese, hypertension (high blood
pressure), high blood cholesterol and having diabetes. People with
inactive lifestyles simply have an increased risk of developing
heart disease at some point in their life. In order to reduce this
risk, it is generally advised that a person participate in 30-60
minutes of physical activity on most days. People who smoke
cigarettes have the greatest risk among the general population of
smokers (smoking being a risk factor in and of itself, as it
interferes with the ability of the body to prevent blood clotting),
with those who smoke cigars or pipes having a risk of developing
coronary heart disease that is less than those that smoke
cigarettes. Even if one does not smoke, exposure to other people's
second-hand smoke increases the risk of developing cardiovascular
disease. Naturally then, it follows that quitting smoking helps to
reduce the risk of developing and suffering coronary heart
disease.
[0007] Being overweight and/or obese is also a coronary risk factor
for developing coronary heart disease. Persons having too much body
fat are at an increased risk for developing coronary heart disease
and/or eventually experiencing a cardiac event, including instant
death or a nonfatal infarction. In particular, women with waist
measurements of more than 35 inches and men with waist measurements
of more than 40 inches (having too much fat around the waist),
increases that person's risk of developing heart disease. Another
method to measure if a person is at risk is to determine their Body
Mass Index (BMI). A BMI number is a number calculated and based
upon a person's weight and height. For most people, the BMI number
is a reliable indicator of the amount of fat the person carries,
and is typically used by health care professionals to screen for
weight categories that may lead to health problems, such as
diabetes and coronary heart disease. Persons having a BMI value of
25 or greater are considered to be at the highest risk of
developing coronary heart disease.
[0008] Hypertension, or high blood pressure, is blood pressure of
about 140/90 mmHg or higher. Nearly 1 in 3 American adults has high
blood pressure. Unfortunately, many people that suffer from high
blood pressure are unaware they have elevated pressures until they
experience trouble with their heart, brain, or kidneys. If not
treated, hypertension can lead to heart enlargement, aneurysms in
blood vessels such as at the aorta and arteries in the brain, legs,
and intestines. Furthermore, hypertension can lead to blood vessel
narrowing in the kidney, which may cause a kidney to fail.
Additionally and as stated above, hypertension is one of the many
coronary risk factors, and can lead to hardening of the arteries in
the body, especially those in the heart, brain and kidneys which
can lead to a heart attack, a stroke, or kidney failure.
[0009] Having high blood cholesterol and/or high triglyceride
levels are additional coronary risk factors. The term
hyperlipidemia means high lipid levels, and while hyperlipidemia
includes several conditions, it usually means that a patient has
high cholesterol and high triglyceride levels. Persons having total
blood cholesterol level of 200 mg/dL (milligrams/per deciliter) or
higher and/or triglyceride levels above 150 mm/dL have increased
risk for developing coronary heart disease. People that already
have other risk factors and have low-density lipoprotein (LDL)
cholesterol levels of 100 mg/dL or higher are at increased risk
also. Persons with no other risk factors but having low-density
lipoprotein (LDL) levels of 160 mg/dL or higher, and/or with
high-density lipoprotein (HDL) cholesterol levels of less than 40
mg/dL, are also considered to have an increased risk of developing
coronary heart disease. Commonly prescribed statins (or HMG-CoA
reductase inhibitors) are a class of drugs that are used to lower
cholesterol levels in people with or at risk of cardiovascular
disease. Cholesterol is lowered by inhibition of HMG-CoA reductase,
which is the rate-limiting enzyme of the pathway of cholesterol
synthesis, which stimulates LDL receptors, resulting in an
increased clearance of low-density lipoprotein (LDL) from the
bloodstream and a decrease in blood cholesterol levels.
Additionally, maintaining a "heart-healthy" diet and increased
exercise is also advised to patients having high blood cholesterol
and/or high triglyceride levels.
[0010] Diabetes is another coronary risk factor. Diabetes mellitus
is a chronic disease in which blood glucose (sugar) levels are too
high. Normal regulation of the hormone, insulin, is responsible for
maintaining proper glucose levels in the blood. Abnormally high
levels of glucose can damage the small and large blood vessels,
leading to diabetic blindness, kidney disease, amputations of
limbs, stroke, and heart disease. Generally, there are two types of
diabetes, Type 1 diabetes is usually (but not always) diagnosed in
children and young adults. The islets of Langerhans, in the
pancreas of people who have type 1 diabetes, do not produce
insulin, and thus such people rely on external insulin, typically
injected subcutaneously or as recently developed inhaled. People
with type 2 diabetes mellitus have insulin resistance, not enough
insulin (low insulin production), or both; they may or may not
eventually require externally supplied insulin to control their
glucose levels and can take oral, systemic medication such as,
metformin (FORTAMET, GLUCOPHAGE, and RIOMET). About 17 million
people in America have Diabetes mellitus, and about 1 million new
cases are diagnosed each year.
[0011] Respiratory Disorders
[0012] It has been estimated that about 350,000 people in the
United States die from lung disease and that lung disease is the
number three killer in America, responsible for one in seven
deaths. About 25 million Americans live with chronic lung disease,
which affect people of all ages and genders.
[0013] Bronchitis, asthma and chronic obstructive pulmonary disease
(COPD) are example of some respiratory disorders.
[0014] Chronic obstructive pulmonary disease (COPD) is a chronic
lung disease, marked by damage to the lungs and includes two main
illnesses: chronic bronchitis and emphysema, both of which make
breathing difficult. In COPD, the respiratory airways and air sacs
(alveoli) lose their shape, become slack and in some cases, the
walls between sacs are even destroyed. Additionally, excessive
mucus is produced in the airways, as well as the walls of the
airways become inflamed and thickened. As a result, less air gets
in and less air goes out of the lungs. Unfortunately, there is no
cure for COPD.
[0015] Cigarette smoking is the most common cause of COPD, and
breathing other kinds of lung irritants such as pollution, dust, or
chemical fumes over a long period of time may also cause or
contribute to COPD.
[0016] Bronchitis is an inflammation of the bronchi (medium-size
airways) in the lungs which can be acute (e.g. caused by a virus,
bacteria, dust and fumes) or chronic. In persons with chronic
bronchitis, the bronchial tubes become permanently thickened and/or
inflamed. The patient with chronic bronchitis typically exhibits a
persistent, continuous cough with mucus. A person is diagnosed as
having chronic bronchitis if they cough most days for at least
three months a year in two consecutive years. Smoking, air
pollution and dust or toxic gases can contribute to the chronic
bronchitis. In some instances, chronic inflammation of the airways
may lead to asthma. Typical treatment includes antibiotics (if
bacterial), rest, ingestion of copious amounts of fluids, and
over-the-counter cough medication.
[0017] Asthma is typically an allergic disorder of respiration,
characterized by bronchospasm, wheezing, and difficulty in
expiration. It can also be accompanied by coughing and feelings of
chest constriction. Asthma occurs when the main bronchial tubes are
inflamed, resulting in a tightening of the muscles of the bronchial
walls, and can be accompanied by excessive mucus production. As a
result, wheezing up to and including severe difficulty in breathing
can be brought on. In some instances the severity of the
constriction is such that the person experiences an asthma attack,
which can be life-threatening.
[0018] The signs of asthma and symptoms can vary from person to
person and from episode to episode and can range from mild to
severe. Occasional asthma episodes with mild, short-lived symptoms
such as wheezing can be experienced wherein between episodes no
difficulty in breathing is experienced. Other asthma sufferers may
experience chronic coughing and wheezing punctuated by severe
asthma attacks, which are typically preceded by warming signs, such
as increased shortness of breath or wheezing, coughing, chest
tightness or pain. In children, an audible whistling or wheezing
sound when exhaling can sometimes be heard, even without a
stethoscope (especially after vigorous activities e.g. running,
playing, climbing etc. . . . ) and frequent coughing spasms.
[0019] Medications to treat asthma vary from person to person. In
general, a combination of long-term control medications and quick
relief medications is typically utilized. Medications generally
fall into one of three categories: long-term-control medications,
quick-relief medications and medications for allergy-induced
asthma. Long-term control medications are usually taken every day
on a long-term basis, to control persistent asthma, while quick
relief medications are utilized to relieve symptoms of short-term,
asthma attacks. For allergy-induced asthma, medications are taken
to decrease a person's sensitivity to a particular allergen and
prevent or decrease an immune system reaction to a particular
allergen or allergens.
[0020] Exemplary long term medications to treat asthma include
inhaled corticosteroids which are anti-inflammatory drugs that
reduce inflammation in the airways and prevent blood vessels from
leaking fluid into the airway tissues. Exemplary inhaled
corticosteroids include fluticasone (FLOVENT), budesonide
(PULMICORT), triamcinolone (AZMACORT), flunisolide (AEROBID) and
beclomethasone (QVAR). Another long-term medication are the
long-acting beta-2 agonists (LABAs), bronchodilators that dialate
constricted airways. Examples include salmeterol (SEREVENT DISKUS)
and formoterol (FORADIL). Still additional long term medications
include leukotriene modifiers, which reduce the production or block
the action of leukotrienes, which are release by cells in the lungs
during an asthma attack. Leukotrienes release results in inflamed
airways, leading to wheezing, mucus overproduction and coughing.
Exemplary leukotriene modifiers include montelukast (SINGLULAIR)
and zafirlukast (ACCOLATE).
[0021] Additional long term medications to treat asthma include
cromolyn (INTAL) and nedocromil (TILADE), which require daily
inhaled use, to help prevent attacks of mild to moderate asthma.
Theophylline (dimethylxanthine) requires daily administration,
which is a bronchodilator in pill form.
[0022] Quick-relief medications are typically short active
bronchodilators which are designed to address the symptoms of an
oncoming or in progress asthma attack. Examples of quick-relief
medications include short-acting beta-2 agonists, such as
albuterol, prednisone, methylprednisolone and hydrocortisone.
[0023] Allergy-desensitization shots (immunotherapy) can also be
utilized, where a series of therapeutic injections containing small
doses of those allergens. These injections are administered once a
week for a few months, then once a month for a period of three to
five years, the theory being that over time, the patient will lose
their sensitivity to the allergens. Additionally, blocking the
action of human immunoglobulin E (IgE), which is commonly involved
with allergies when present in high amounts in the body, is still
another route for treating asthma. Omalizumab (marketed under the
name XOLAIR) is a monoclonal antibody made by Genentech/Novartis
and used mainly in allergy-related asthma therapy, with the purpose
of reducing allergic hypersensitivity. XOLAIR (omalizumab) is a
recombinant DNA-derived humanized IgG1k monoclonal antibody that
selectively binds to human immunoglobulin E (IgE), and limits the
degree of release of mediators of the allergic response, and thus
attenuates the asthmatic response.
[0024] Arthritis
[0025] Arthritis is a joint disorder that results in inflammation
at an area of a patient where two different bones meet. As such,
arthritis is typically accompanied by joint pain, that can be the
result of wear and tear of cartilage (e.g. osteoarthritis) to pain
associated with inflammation resulting from an overactive immune
system (e.g. rheumatoid arthritis). Arthritis is classified as a
rheumatic disease and as such affects joints, muscles, ligaments,
cartilage, tendons, and may have the potential to affect internal
body organs.
[0026] Rheumatoid arthritis (RA) is a long-term disease that causes
inflammation of the joints and surrounding tissues and may affect
other organs/tissues depending on the patient. RA is considered an
autoimmune disease, and it appears to affected women more often
than men. Joints of the extremities (i.e. arms and legs) are most
commonly affected and including but limited to the wrists, fingers,
knees, feet, and ankles.
[0027] Symptoms of arthritis include inflammation; pain and limited
joint function e.g., joint stiffness, swelling, redness, and
warmth. In persons suffering RA, symptoms in some patients can
include fever, joint swelling, fatigue, and pain in various organs
such as the lungs, heart, or kidneys.
[0028] Various treatment options are typically utilized to treat
arthritis and include NSAIDs (nonsteroidal anti-inflammatory
drugs), COX-2 inhibitors, various analgesics and corticosteroids.
In some instances, a physician may choose to directly inject a
medicament into the affected joint. This is known as
viscosupplementation, and involves injection of gel-like substances
(hyaluronates) into the subject a joint to supplement the viscous
properties of synovial fluid in the joint. For example,
SYNVISC.RTM. is an FDA-approved elastic and viscous substance made
from hyaluronan that is injected into the knee to provide pain
relief from osteoarthritis.
[0029] Clostridial Toxins
[0030] The genus Clostridium has more than one hundred and twenty
seven species, grouped according to their morphology and functions.
The anaerobic, gram positive bacterium Clostridium botulinum
produces a potent polypeptide neurotoxin, botulinum toxin, which
causes a neuroparalytic illness in humans and animals referred to
as botulism. The spores of Clostridium botulinum are found in soil
and can grow in improperly sterilized and sealed food containers of
home based canneries, which are the cause of many of the cases of
botulism. The effects of botulism typically appear 18 to 36 hours
after eating the foodstuffs infected with a Clostridium botulinum
culture or spores. The botulinum toxin can apparently pass
unattenuated through the lining of the gut and attack peripheral
motor neurons. Symptoms of botulinum toxin intoxication can
progress from difficulty walking, swallowing, and speaking to
paralysis of the respiratory muscles and death.
[0031] About 50 picograms of a commercially available botulinum
toxin type A (a purified neurotoxin complex available from
Allergan, Inc., of Irvine, Calif. under the tradename BOTOX.RTM. in
100 unit vials) is a LD.sub.50 in mice (i.e. 1 unit). One unit of
BOTOX.RTM. contains about 50 picograms (about 56 attomoles) of
botulinum toxin type A complex. Interestingly, on a molar basis,
botulinum toxin type A is about 1.8 billion times more lethal than
diphtheria, about 600 million times more lethal than sodium
cyanide, about 30 million times more lethal than cobra toxin and
about 1 2 million times more lethal than cholera. Singh, Critical
Aspects of Bacteria/Protein Toxins, pages 63-84 (chapter 4) of
Natural Toxins II, edited by B. R. Singh et al., Plenum Press, New
York (1976) (where the stated LD.sub.50 of botulinum toxin type A
of 0.3 ng equals 1 unit is corrected for the fact that about 0.05
ng of BOTOX.RTM. equals 1 unit). One unit (U) of botulinum toxin is
defined as the LD.sub.50 upon intraperitoneal injection into female
Swiss Webster mice weighing 18 to 20 grams each.
[0032] Seven immunologically distinct botulinum neurotoxins have
been characterized, these being respectively botulinum neurotoxin
serotypes A, B, C.sub.1, D, E, F and G, each of which is
distinguished by neutralization with type-specific antibodies. The
different serotypes of botulinum toxin vary in the animal species
that they affect and in the severity and duration of the paralysis
they evoke. For example, it has been determined that botulinum
toxin type A is 500 times more potent, as measured by the rate of
paralysis produced in the rat, than is botulinum toxin type B.
Additionally, botulinum toxin type B has been determined to be
non-toxic in primates at a dose of 480 U/kg which is about 12 times
the primate LD.sub.50 for botulinum toxin type A. Moyer E et al.,
Botulinum Toxin Type 8: Experimental and Clinical Experience, being
chapter 6, pages 71-85 of "Therapy With Botulinum Toxin," edited by
Jankovic, J. et al. (1994), Marcel Dekker, Inc. Botulinum toxin
apparently binds with high affinity to cholinergic motor neurons,
is translocated into the neuron, and blocks the release of
acetylcholine. Additional uptake can take place through low
affinity receptors, as well as by phagocytosis and pinocytosis.
[0033] Regardless of stereotype, the molecular mechanism of toxin
intoxication appears to be similar and to involve at least three
steps or stages. In the first step of the process, the toxin binds
to the presynaptic membrane of the target neuron through a specific
interaction between the heavy chain, H chain, and a cell surface
receptor; the receptor is thought to be different for each type of
botulinum toxin and for tetanus toxin. The carboxyl end segment of
the H chain, H.sub.C, appears to be important for targeting of the
toxin to the cell surface. In the second step, the toxin crosses
the plasma membrane of the poisoned cell. The toxin is first
engulfed by the cell through receptor-mediated endocytosis, and an
endosome containing the toxin is formed. The toxin then escapes the
endosome into the cytoplasm of the cell. This step is thought to be
mediated by the amino end segment of the H chain, H.sub.N, which
triggers a conformational change of the toxin in response to a pH
of about 5.5 or lower. Endosomes are known to possess a proton pump
which decreases intra-endosomal pH. The conformational shift
exposes hydrophobic residues in the toxin, which permits the toxin
to embed itself in the endosomal membrane. The toxin (or at a
minimum the light chain) then translocates through the endosomal
membrane into the cytoplasm.
[0034] The last step of the mechanism of botulinum toxin activity
appears to involve reduction of the disulfide bond joining the
heavy chain, H chain, and the light chain, L chain. The entire
toxic activity of botulinum and tetanus toxins is contained in the
L chain of the holotoxin; the L chain is a zinc (Zn.sup.2+)
endopeptidase which selectively cleaves proteins essential for
recognition and docking of neurotransmitter-containing vesicles
with the cytoplasmic surface of the plasma membrane, and fusion of
the vesicles with the plasma membrane. Tetanus neurotoxin,
botulinum toxin types B, D, F, and G, cause degradation of
synaptobrevin (also called vesicle-associated membrane protein
(VAMP)), a synaptosomal membrane protein. Most of the VAMP present
at the cytoplasmic surface of the synaptic vesicle is removed as a
result of any one of these cleavage events. Botulinum toxin
serotype A and E cleave SNAP-25. Botulinum toxin serotype C.sub.1
was originally thought to cleave syntaxin, but was found to cleave
syntaxin and SNAP-25. Each of the botulinum toxins specifically
cleaves a different bond, except botulinum toxin type B (and
tetanus toxin) which cleave the same bond. Each of these cleavages
block the process of vesicle-membrane docking, thereby preventing
exocytosis of vesicle content.
[0035] Botulinum toxins have been used in clinical settings for the
treatment of neuromuscular disorders characterized by hyperactive
skeletal muscles (i.e. motor disorders). Almost twenty years ago,
in 1989, a botulinum toxin type A complex was approved by the U.S.
Food and Drug Administration for the treatment of blepharospasm,
strabismus and hemifacial spasm. Subsequently, a botulinum toxin
type A was also approved by the FDA for the treatment of cervical
dystonia and for the treatment of glabellar lines, and a botulinum
toxin type B was approved for the treatment of cervical dystonia.
Non-type A botulinum toxin serotypes apparently have a lower
potency and/or a shorter duration of activity as compared to
botulinum toxin type A. Clinical effects of peripheral
intramuscular botulinum toxin type A are usually seen within one
week of injection. The typical duration of symptomatic relief from
a single intramuscular injection of botulinum toxin type A averages
about three months, although significantly longer periods of
therapeutic activity have been reported.
[0036] Although all the botulinum toxin serotypes apparently
inhibit release of the neurotransmitter acetylcholine at the
neuromuscular junction, they do so by affecting different
neurosecretory proteins and/or cleaving these proteins at different
sites. For example, botulinum types A and E both cleave the 25
kiloDalton (kD) synaptosomal associated protein (SNAP-25), but they
target different amino acid sequences within this protein.
Botulinum toxin types B, D, F and G act on vesicle-associated
protein (VAMP, also called synaptobrevin), with each serotype
cleaving the protein at a different site. Finally, botulinum toxin
type C.sub.1 has been shown to cleave both syntaxin and SNAP-25.
These differences in mechanism of action may affect the relative
potency and/or duration of action of the various botulinum toxin
serotypes. Apparently, a substrate for a botulinum toxin can be
found in a variety of different cell types. See e.g. Biochem J 1;
339 (pt 1):159-65.1999, and MovDisord, 10(3):376:1995 (pancreatic
islet B cells contains at least SNAP-25 and synaptobrevin).
[0037] The molecular weight of the botulinum toxin protein
molecule, for all seven of the known botulinum toxin serotypes, is
about 150 kD. Interestingly, the botulinum toxins are released by
Clostridial bacterium as complexes comprising the 150 kD botulinum
toxin protein molecule along with associated non-toxin proteins.
Thus, the botulinum toxin type A complex can be produced by
Clostridial bacterium as 900 kD, 500 kD and 300 kD forms. Botulinum
toxin types B and C.sub.1 are apparently produced as only a 700 kD
or 500 kD complex.
[0038] Botulinum toxin type D is produced as both 300 kD and 500 kD
complexes. Finally, botulinum toxin types E and F are produced as
only approximately 300 kD complexes. The complexes (i.e. molecular
weight greater than about 150 kD) are believed to contain a
non-toxin hemaglutinin protein and a non-toxin and non-toxic
nonhemaglutinin protein. These two non-toxin proteins (which along
with the botulinum toxin molecule comprise the relevant neurotoxin
complex) may act to provide stability against denaturation to the
botulinum toxin molecule, and protection against digestive acids
when toxin is ingested. Additionally, it is possible that the
larger (greater than about 150 kD molecular weight) botulinum toxin
complexes may result in a slower rate of diffusion of the botulinum
toxin away from a site of intramuscular injection of a botulinum
toxin complex.
[0039] In vitro studies have indicated that botulinum toxin
inhibits potassium cation induced release of both acetylcholine and
norepinephrine from primary cell cultures of brainstem tissue.
Additionally, it has been reported that botulinum toxin inhibits
the evoked release of both glycine and glutamate in primary
cultures of spinal cord neurons and that in brain synaptosome
preparations botulinum toxin inhibits the release of each of the
neurotransmitters acetylcholine, dopamine, norepinephrine
(Habermann E., et al., Tetanus Toxin and Botulinum A and C
Neurotoxins Inhibit Noradrenaline Release From Cultured Mouse Brain
J Neurochem 51(2); 522-527:1988)), CGRP, substance P, and glutamate
(Sanchez-Prieto, J., et al., Botulinum Toxin A Blocks Glutamate
Exocytosis From Guinea Pig Cerebral Cortical Synaptosomes, Eur J.
Biochem 165; 675-681:1897). Thus, when adequate concentrations are
used, stimulus-evoked release of most neurotransmitters is blocked
by botulinum toxin. See e.g. Pearce, L. B., Pharmacologic
Characterization of Botulinum Toxin For Basic Science and Medicine,
Toxicon 35(9); 1 373-1 412 at 1393; Bigalke H., et al., Botulinum A
Neurotoxin Inhibits Non-Cholinergic Synaptic Transmission in Mouse
Spinal Cord Neurons in Culture, Brain Research 360; 318-324:1985;
Habermann E., Inhibition by Tetanus and Botulinum A Toxin of the
release of [3H] Noradrenaline and [3H]GABA From Rat Brain
Homogenate, Experientia 44; 224-226: 1988, Bigalke H., et al.,
Tetanus Toxin and Botulinum A Toxin Inhibit Release and Uptake of
Various Transmitters, as Studied with Particulate Preparations From
Rat Brain and Spinal Cord, Naunyn-Schmiedeberg's Arch Pharmacol 31
6; 244-251:1 981, and; Jankovic J. et al., Therapy With Botulinum
Toxin, Marcel Dekker, Inc., (1994), page 5.
[0040] Botulinum toxin type A can be obtained by establishing and
growing cultures of Clostridium botulinum in a fermenter and then
harvesting and purifying the fermented mixture in accordance with
known procedures. All the botulinum toxin serotypes are initially
synthesized as inactive single chain proteins which must be cleaved
or nicked by proteases to become neuroactive. The bacterial strains
that make botulinum toxin serotypes A and G possess endogenous
proteases and serotypes A and G can therefore be recovered from
bacterial cultures in predominantly their active form. In contrast,
botulinum toxin serotypes C.sub.1, D and E are synthesized by
nonproteolytic strains and are therefore typically unactivated when
recovered from culture. Serotypes B and F are produced by both
proteolytic and nonproteolytic strains and therefore can be
recovered in either the active or inactive form. However, even the
proteolytic strains that produce, for example, the botulinum toxin
type B serotype, only cleave a portion of the toxin produced. The
exact proportion of nicked to unnicked molecules depends on the
length of incubation and the temperature of the culture. Therefore,
a certain percentage of any preparation of, for example, the
botulinum toxin type B toxin, is likely to be inactive, possibly
accounting for the known significantly lower potency of botulinum
toxin type B, as compared to botulinum toxin type A (and thus the
routine use of many thousands of units of botulinum toxin type B,
as known in the art, see e.g. "Long-term safety, efficacy, and
dosing of botulinum toxin type B (MYOBLOC.RTM.) in cervical
dystonia (CD) and other movement disorders" Kumar R and Seeberger L
C. Mov Disord 2002; 17(Suppl 5):S292-S293). The presence of
inactive botulinum toxin molecules in a clinical preparation will
contribute to the overall protein load of the preparation, which
has been linked to increased antigenicity, without contributing to
its clinical efficacy. Additionally, it is known that botulinum
toxin type B has, upon intramuscular injection, a shorter duration
of activity and is also less potent than botulinum toxin type A at
the same dose level.
[0041] High quality crystalline botulinum toxin type A can be
produced from the Hall A strain of Clostridium botulinum with
characteristics of .gtoreq.3.times.10.sup.7 U/mg, an
A.sub.260/A.sub.278 of less than 0.60 and a distinct pattern of
banding on gel electrophoresis. The known Schantz process can be
used to obtain crystalline botulinum toxin type A, as set forth in
Schantz, E. J., et al, Properties and use of Botuilnum toxin and
Other Microbial Neurotoxins in Medicine, Microbiol Rev. 56;
80-99:1992. Generally, the botulinum toxin type A complex can be
isolated and purified from an anaerobic fermentation by cultivating
Clostridium botulinum type A in a suitable medium. The known
process can also be used, upon separation out of the non-toxin
proteins, to obtain pure botulinum toxins, such as for example:
purified botulinum toxin type A with an approximately 150 kD
molecular weight with a specific potency of 1-2.times.10.sup.8
LD.sub.50 U/mg or greater; purified botulinum toxin type B with an
approximately 156 kD molecular weight with a specific potency of
1-2.times.10.sup.8 LD.sub.50 U/mg or greater; and purified
botulinum toxin type F with an approximately 155 kD molecular
weight with a specific potency of 1-2.times.10.sup.7 LD.sub.50 U/mg
or greater.
[0042] Botulinum toxins and/or botulinum toxin complexes can be
obtained from List Biological Laboratories, Inc., Campbell, Calif.;
the Centre for Applied Microbiology and Research, Porton Down,
U.K.; Wako (Osaka, Japan), Metabiologics (Madison, Wis.) as well as
from Sigma Chemicals of St Louis, Mo. Pure botulinum toxin can also
be used to prepare a pharmaceutical composition for use in
accordance with the present disclosure.
[0043] As with enzymes generally, the biological activities of
botulinum toxins (which are intracellular peptidases) is dependant,
at least in part, upon their 3-dimensional conformation. Thus,
botulinum toxin type A is detoxified by heat, various chemicals,
surface stretching, and surface drying. Additionally, it is known
that dilution of the toxin complex obtained by the known culturing,
fermentation and purification to the much lower toxin
concentrations used for pharmaceutical composition formulation
results in rapid detoxification of the toxin unless a suitable
stabilizing agent is present. Dilution of the toxin from milligram
quantities to a solution containing nanograms per milliliter
presents significant difficulties because of the rapid loss of
specific toxicity upon such great dilution. Since the toxin may be
used months or years after the toxin containing pharmaceutical
composition is formulated, the toxin can be stabilized with a
stabilizing agent such as albumin and gelatin.
[0044] A commercially available botulinum toxin containing
pharmaceutical composition is sold under the trademark BOTOX.RTM.
(available from Allergan, Inc., of Irvine, Calif.). BOTOX.RTM.
consists of a purified botulinum toxin type A complex, albumin and
sodium chloride packaged in sterile, vacuum-dried form. Botulinum
toxin type A is made from a culture of the Hall strain of
Clostridium botulinum grown in a medium containing N-Z amine and
yeast extract. The botulinum toxin type A complex is purified from
the culture solution by a series of acid precipitations to a
crystalline complex consisting of the active high molecular weight
toxin protein and an associated hemagglutinin protein. The
crystalline complex is re-dissolved in a solution containing saline
and albumin and sterile filtered (0.2 microns) prior to
vacuum-drying. The vacuum-dried product is stored in a freezer at
or below -5.degree. C. BOTOX.RTM. can be reconstituted with
sterile, non-preserved saline prior to intramuscular injection.
Each vial of BOTOX.RTM. contains about 100 U of Clostridium
botulinum toxin type A purified neurotoxin complex, 0.5 milligrams
of human serum albumin and 0.9 milligrams of sodium chloride in a
sterile, vacuum-dried form without a preservative.
[0045] To reconstitute vacuum-dried BOTOX.RTM., sterile normal
saline without a preservative (0.9% Sodium Chloride Injection) is
used by drawing up the proper amount of diluent in the appropriate
size syringe. Since BOTOX.RTM. may be denatured by bubbling or
similar violent agitation, the diluent is gently injected into the
vial. For sterility reasons BOTOX.RTM. is preferably administered
within four hours after the vial is removed from the freezer and
reconstituted. During these four hours, reconstituted BOTOX.RTM.
can be stored in a refrigerator at about 2.degree. C. to about
8.degree. C. Reconstituted, refrigerated BOTOX.RTM. has been
reported to retain its potency for at least about two weeks
(Neurology, 48:249-53, 1997). It has been reported that botulinum
toxin type A has been used in clinical settings as follows:
(1) about 75-125 U of BOTOX.RTM. per intramuscular injection
(multiple muscles) to treat cervical dystonia; (2) 5-10 U of
BOTOX.RTM. per intramuscular injection to treat glabellar lines
(brow furrows) (5 units injected intramuscularly into the procerus
muscle and 10 units injected intramuscularly into each corrugator
supercilii muscle); (3) about 30-80 U of BOTOX.RTM. to treat
constipation by intrasphincter injection of the puborectalis
muscle; (4) about 1-5 Upper muscle of intramuscularly injected
BOTOX.RTM. to treat blepharospasm by injecting the lateral
pre-tarsal orbicularis oculi muscle of the upper lid and the
lateral pre-tarsal orbicularis oculi of the lower lid; (5) to treat
strabismus, extraocular muscles have been injected intramuscularly
with between about 1-5 U of BOTOX.RTM., the amount injected varying
based upon both the size of the muscle to be injected and the
extent of muscle paralysis desired (i.e. amount of diopter
correction desired); (6) to treat upper limb spasticity following
stroke by intramuscular injections of BOTOX.RTM. into five
different upper limb flexor muscles, as follows: (a) flexor
digitorum profundus: 7.5 U to 30 U (b) flexor digitorum sublimus:
7.5 U to 30 U (c) flexor carpi ulnaris: 10 U to 40 U (d) flexor
carpi radialis: 15 U to 60 U (e) biceps brachii: 50 U to 200 U.
Each of the five indicated muscles has been injected at the same
treatment session, so that the patient receives from 90 U to 360 U
of upper limb flexor muscle BOTOX.RTM. by intramuscular injection
at each treatment session; (7) to treat migraine, pericranial
(injected symmetrically into glabellar, frontalis and temporalis
muscles) injection of 25 U of BOTOX.RTM. has showed significant
benefit as a prophylactic treatment of migraine compared to vehicle
as measured by decreased measures of migraine frequency, maximal
severity, associated vomiting and acute medication use over the
three month period following the 25 U injection.
[0046] It is known that botulinum toxin type A can have an efficacy
for up to 12 months (European J. Neurology 6 (Supp 4): S111-S1150:
1999), and in some circumstances for as long as 27 months, when
used to treat glands, such as in the treatment of hype rhydrosis.
See e.g. Bushara K., Botulinum toxin and rhinorrhea, Otolaryngol
Head Neck Surg 1996; 114(3):507, and The Laryngoscope
109:1344-1346:1999. However, the usual duration of effect of an
intramuscular injection of BOTOX.RTM. is typically about 3 to 4
months.
[0047] The success of botulinum toxin type A to treat a variety of
clinical conditions has led to interest in other botulinum toxin
serotypes. Two commercially available botulinum type A preparations
for use in humans are BOTOX.RTM. available from Allergan, Inc., of
Irvine, Calif., and DYSPORT.RTM. available from Beaufour Ipsen,
Porton Down, England. A botulinum toxin type B preparation
(MYOBLOC.RTM.) is available from Solstice Pharmaceuticals of San
Francisco, Calif.
[0048] A botulinum toxin has also been proposed for or has been
used to treat otitis media of the ear (U.S. Pat. No. 5,766,605),
inner ear disorders (U.S. Pat. Nos. 6,265,379; 6,358,926), tension
headache, (U.S. Pat. No. 6,458,365), migraine headache pain (U.S.
Pat. No. 5,714,468), post-operative pain and visceral pain (U.S.
Pat. No. 6,464,986), hair growth and hair retention (U.S. Pat. No.
6,299,893), psoriasis and dermatitis (U.S. Pat. No. 5,670,484),
injured muscles (U.S. Pat. No. 6,423,319) various cancers (U.S.
Pat. No. 6,139,845), smooth muscle disorders (U.S. Pat. No.
5,437,291), and neurogenic inflammation (U.S. Pat. No. 6,063,768).
Controlled release toxin implants are known (see e.g. U.S. Pat.
Nos. 6,306,423 and 6,312,708) as is transdermal botulinum toxin
administration (U.S. patent application Ser. No. 10/194,805). U.S.
Patent Application Publication 2007/0048334 A1, Ser. No. 11/211,311
and filed Aug. 24, 2005, discloses the use of a botulinum toxin to
improve gastric emptying and/or treating gastroesophageal reflux
disease (GERD) by administration to a patient's head, neck and
shoulder muscles. It is known that a botulinum toxin can be used to
weaken the chewing or biting muscle of the mouth so that self
inflicted wounds and resulting ulcers can heal (Payne M., et al,
Botulinum toxin as a novel treatment for self mutilation in
Lesch-Nyhan syndrome, Ann Neurol 2002 September; 52(3 Supp
1):S157).). U.S. Patent Application Publication 20050191321 A1,
Ser. No. 11/039,506 and filed Jan. 18, 2004, discloses treating
medication overuse disorders (MOD), by local administration of a
Clostridial toxin. U.S. Patent Application Publication 20050147626
A1, Ser. No. 10/964,898 and filed Oct. 12, 2004 discloses treating
or preventing, by peripheral administration of a botulinum toxin to
or to the vicinity of a trigeminal sensory nerve, a neurological
disorder and/or a neuropsychiatric disorder.
[0049] Additionally, a botulinum toxin may have an effect to reduce
induced inflammatory pain in a rat formalin model. Aoki K., et al,
Mechanisms of the antinociceptive effect of subcutaneous
BOTOX.RTM.: Inhibition of peripheral and central nociceptive
processing, Cephalalgia 2003 September; 23(7):649. Furthermore, it
has been reported that botulinum toxin nerve blockage can cause a
reduction of epidermal thickness. Li Y, et al., Sensory and motor
denervation influences epidermal thickness in rat foot glabrous
skin, Exp Neurol 1997; 147:452-462 (see page 459). U.S. Patent
Application Publication 20050266029 A1, Ser. No. 11/159,569 and
filed on Jun. 22, 2005 relates to methods for treating pain
associated with arthritis. Finally, it is known to administer a
botulinum toxin to the foot to treat excessive foot sweating
(Katsambas A., et al., Cutaneous diseases of the foot: Unapproved
treatments, Clin Dermatol 2002 November-December; 20(6):689-699;
Sevim, S., et al., Botulinum toxin-A therapy for palmar and plantar
hyperhidrosis, Acta Neurol Belg 2002 December; 102(4):167-70),
spastic toes (Suputtitada, A., Local botulinum toxin type A
injections in the treatment of spastic toes, Am J Phys Med Rehabil
2002 October; 81(10):770-5), idiopathic toe walking (Tacks, L., et
al., Idiopathic toe walking: Treatment with botulinum toxin A
injection, Dev Med Child Neurol 2002; 44(Suppl 91):6), and foot
dystonia (Rogers J., et al., Injections of botulinum toxin A in
foot dystonia, Neurology 1993 April; 43(4 Suppl 2)). Tetanus toxin,
as wells as derivatives (i.e. with a non-native targeting moiety),
fragments, hybrids and chimeras thereof can also have therapeutic
utility. The tetanus toxin bears many similarities to the botulinum
toxins. Thus, both the tetanus toxin and the botulinum toxins are
polypeptides made by closely related species of Clostridium
(Clostridium tetani and Clostridium botulinum, respectively).
[0050] Additionally, both the tetanus toxin and the botulinum
toxins are dichain proteins composed of a light chain (molecular
weight about 50 kD) covalently bound by a single disulfide bond to
a heavy chain (molecular weight about 100 kD). Hence, the molecular
weight of tetanus toxin and of each of the seven botulinum toxins
(non-complexed) is about 150 kD. Furthermore, for both the tetanus
toxin and the botulinum toxins, the light chain bears the domain
which exhibits intracellular biological (protease) activity, while
the heavy chain comprises the receptor binding (immunogenic) and
cell membrane translocational domains.
[0051] Additionally, both the tetanus toxin and the botulinum
toxins exhibit a high, specific affinity for gangliocide receptors
on the surface of presynaptic cholinergic neurons. Receptor
mediated endocytosis of tetanus toxin by peripheral cholinergic
neurons results in retrograde axonal transport, blocking of the
release of inhibitory neurotransmitters from central synapses and a
spastic paralysis. Contrarily, receptor mediated endocytosis of
botulinum toxin by peripheral cholinergic neurons results in little
if any retrograde transport, inhibition of acetylcholine exocytosis
from the intoxicated peripheral motor neurons and a flaccid
paralysis.
[0052] Finally, the tetanus toxin and the botulinum toxins resemble
each other in both biosynthesis and molecular architecture. Thus,
there is an overall 34% identity between the protein sequences of
tetanus toxin and botulinum toxin type A, and a sequence identity
as high as 62% for some functional domains. Binz T. et al., The
Complete Sequence of Botulinum Neurotoxin Type A and Comparison
with Other Clostridial Neurotoxins, J Biological Chemistry 265(16);
9153-9158:1990.
Acetylcholine
[0053] Typically only a single type of small molecule
neurotransmitter is released by each type of neuron in the
mammalian nervous system. The neurotransmitter acetylcholine is
secreted by neurons in many areas of the brain, but specifically by
the large pyramidal cells of the motor cortex, by several different
neurons in the basal ganglia, by the motor neurons that innervate
the skeletal muscles, by the preganglionic neurons of the autonomic
nervous system (both sympathetic and parasympathetic), by the
postganglionic neurons of the parasympathetic nervous system, and
by some of the postganglionic neurons of the sympathetic nervous
system. Essentially, only the postganglionic sympathetic nerve
fibers to the sweat glands, the piloerector muscles and a few blood
vessels are cholinergic as most of the postganglionic neurons of
the sympathetic nervous system secret the neurotransmitter
norepinephine. In most instances acetylcholine has an excitatory
effect. However, acetylcholine is known to have inhibitory effects
at some of the peripheral parasympathetic nerve endings, such as
inhibition of heart rate by the vagal nerve.
[0054] The efferent signals of the autonomic nervous system are
transmitted to the body through either the sympathetic nervous
system or the parasympathetic nervous system. The preganglionic
neurons of the sympathetic nervous system extend from preganglionic
sympathetic neuron cell bodies located in the intermediolateral
horn of the spinal cord. The preganglionic sympathetic nerve
fibers, extending from the cell body, synapse with postganglionic
neurons located in either a paravertebral sympathetic ganglion or
in a prevertebral ganglion. Since, the preganglionic neurons of
both the sympathetic and parasympathetic nervous system are
cholinergic, application of acetylcholine to the ganglia will
excite both sympathetic and parasympathetic postganglionic
neurons.
[0055] Acetylcholine activates two types of receptors, muscarinic
and nicotinic receptors. The muscarinic receptors are found in all
effector cells stimulated by the postganglionic neurons of the
parasympathetic nervous system, as well as in those stimulated by
the postganglionic cholinergic neurons of the sympathetic nervous
system. The nicotinic receptors are found in the synapses between
the preganglionic and postganglionic neurons of both the
sympathetic and parasympathetic. The nicotinic receptors are also
present in many membranes of skeletal muscle fibers at the
neuromuscular junction.
[0056] Acetylcholine is released from cholinergic neurons when
small, clear, intracellular vesicles fuse with the presynaptic
neuronal cell membrane. A wide variety of non-neuronal secretory
cells, such as, adrenal medulla (as well as the PC12 cell line) and
pancreatic islet cells release catecholamines and parathyroid
hormone, respectively, from large dense-core vesicles. The PC12
cell line is a clone of rat pheochromocytoma cells extensively used
as a tissue culture model for studies of sympathoadrenal
development. Botulinum toxin inhibits the release of both types of
compounds from both types of cells in vitro, permeabilized (as by
electroporation) or by direct injection of the toxin into the
denervated cell. Botulinum toxin is also known to block release of
the neurotransmitter glutamate from cortical synaptosomes cell
cultures.
[0057] What is needed therefore are effective and efficient methods
for treating arthritis, respiratory disorders, such as COPD,
asthma, bronchitis and for treating/alleviating (e.g. lowering)
coronary risk factors, such as hypertension, high cholesterol, high
triglyceride levels, diabetes, hyperlipidemia, and obesity that do
not require daily administration and/or strict patient
compliance.
SUMMARY
[0058] The present invention meets this need and provides methods
for treating a respiratory disorder and/or arthritis or and/or
coronary risk factor by intramuscular, subcutaneous or intradermal
administration of a botulinum toxin to at least one of a head or
neck and shoulder location of a patient in need thereof, that is, a
patient with a respiratory disorder and/or arthritis and/or a
coronary risk factor. Intracranial administration of a botulinum
neurotoxin, that is, administration within the cranium and into
brain tissue, is specifically excluded from the scope of the
present invention.
[0059] According to one aspect of the present invention, the
botulinum toxin is one of the botulinum toxin types A, B, C.sub.1,
D, E, F and G and is preferably botulinum toxin type A. The
botulinum toxin (as a complex or as a pure, about 150 kDa protein)
can be formulated with the excipient (such as an albumin) in an
amount of between about 1 unit and about 25,000 units of the
botulinum toxin. Preferably, the quantity of the botulinum toxin
administered is between about 5 units and about 1500 units of a
botulinum toxin type A. Where the botulinum toxin is botulinum
toxin type B, preferably, the quantity of the botulinum toxin
associated with the carrier can be between about 250 units and
about 25,000 units of a botulinum toxin type B.
[0060] The amount of a botulinum toxin administered within the
scope of the present invention during a given period can be between
about 10.sup.-3 U/kg and about 35 U/kg per patient weight for a
botulinum toxin type A and up to about 1500 U/kg per patient weight
for other botulinum toxins, such as a botulinum toxin type B.
[0061] Preferably, the amount of a type A botulinum toxin
administered is between about 10.sup.-2 U/kg and about 25 U/kg.
Preferably, the amount of a type B botulinum toxin administered
during a given period is between about 10.sup.-2 U/kg and about
1000 U/kg. More preferably, the type A botulinum toxin is
administered in an amount of between about 10.sup.-1 U/kg and about
15 U/kg. Most preferably, the type A botulinum toxin is
administered in an amount of between about 1 U/kg and about 10
U/kg. In many instances, administration of from about 1 unit to
about 500 units of a botulinum toxin type A can provide effective
and long lasting therapeutic relief. More preferably, from about 5
units to about 300 units of a botulinum toxin, such as a botulinum
toxin type A, can be used and most preferably, from about 10 units
to about 200 units of a neurotoxin, such as a botulinum toxin type
A, can be locally administered into a target tissue with
efficacious results. In a particularly preferred embodiment of the
present invention, from about 20 units to about 300 units of a
botulinum toxin, such as botulinum toxin type A, can be
administered with therapeutically effective results.
[0062] The botulinum toxin can be made by Clostridium botulinum.
Additionally, the botulinum toxin can be a modified botulinum
toxin, that is, a botulinum toxin that has at least one of its
amino acids deleted, modified or replaced, as compared to the
native or wild type botulinum toxin. Furthermore, the botulinum
toxin can be a recombinant produced botulinum toxin or a derivative
or fragment thereof.
[0063] A method herein disclosed can be carried out by
administration of a botulinum toxin to a patient in need thereof,
i.e., having a coronary risk factor and/or arthritis and/or a
respiratory disorder to be treated. Notably, the botulinum toxin is
administered to a head, neck or shoulder location of a patient to
provide a therapeutic effect upon the arthritis, coronary risk
factor or respiratory disorder. Thus, the botulinum toxin is not
administered so as to provide a therapeutic effect at the local
site of administration of the botulinum toxin. Quiet the contrary
i.e. administration of a botulinum toxin (as by intramuscular
administration) to a head, neck or shoulder location (e.g. to an
intramuscular site to one or more of the well known frontalis
muscle, glabellar muscle, occipitalis muscle, temporalis muscle,
masseter muscle, trapezius muscle, semispinalis muscle and splenius
capitis muscles, and/or subcutaneously or intradermally at or in
the vicinity of these muscles) has a therapeutic effect, as
determined by alleviation of at least one symptom associated with
arthritis, coronary risk factor or a respiratory disorder.
[0064] The botulinum toxin (as either a complex or as a pure [i.e.
about 150 kDa molecule] can be a botulinum toxin A, B, C, D, E, F
or G. Administration of the botulinum toxin in accordance with the
instant disclosure can be by a transdermal route (i.e. by
application of a botulinum toxin in a cream, patch or lotion
vehicle), subdermal route (i.e. subcutaneous or intramuscular), or
intradermal route of administration to at least one of a patient's
head, neck or shoulder.
[0065] A hypothesized physiological reason for the efficacy of my
invention is that the head, neck and/or administration of a
botulinum toxin according to my invention reduces, inhibits and/or
eliminates sensory input (afferent) from peripheral location(s) of
the head and/or neck and/or shoulder into the central nervous
system (including to the brain) which input kindles, generates,
exacerbates and/or facilitates development, worsening or
maintenance of a coronary risk factor, arthritis, or a respiratory
disorder in a patient.
[0066] A particular dose of a botulinum used in a particular
patient according to the present invention is typically less than
the amount of a botulinum toxin that would be used to paralyze
(i.e. result in complete loss of function or tone of a muscle) a
muscle, since an intent of a method according to the present
invention is not to paralyze a muscle but to reduce a sensory
output from sensory neurons located in or on a muscle, or in or
under the skin. As medicaments are typically utilized in the art,
botulinum neurotoxin is administered to a particular patient at a
starting amount, after which the patient is follow up with and any
beneficial effect is noted. If no change and no adverse effect to
the administered toxin is observed, the attending medical
profession may choose to increase the dose of toxin administered
and/or alter the location(s) of administration of the toxin.
[0067] The present invention encompasses a method for treating
arthritis, a coronary risk factor or a respiratory disorder by
administering a botulinum toxin to a head and/or neck and/or
shoulder location of a patient with arthritis and/or coronary risk
factor and/or a respiratory disorder, thereby treating the
arthritis, coronary risk factor or a respiratory disorder. The
botulinum toxin can be a botulinum toxins types A, B, C.sub.1, D,
E, F or G. Most preferably, the botulinum toxin is a botulinum
toxin type A. The botulinum toxin administered can be a botulinum
toxin complex (i.e. from about 300 kDa to about 900 kDa in
molecular weight) or a pure botulinum toxin, that is, the about 150
kDa neurotoxic component of a botulinum toxin complex.
[0068] The coronary risk factor to be treated can be hypertension,
diabetes, hyperlipidemia, and obesity, for example. The respiratory
disorder treated can be, for example, asthma, bronchitis and
chronic obstructive pulmonary disease.
[0069] Administration of a botulinum toxin according to the method
disclosed herein can be by intramuscular or subdermal
administration of the botulinum toxin to a head and/or neck and/or
shoulder muscle of the patient. In some embodiments the patient can
have a coronary risk factor and/or a respiratory disorder and/or
arthritis as well as a headache, such as a tension headache,
migraine (episodic or chronic), hormonal headache, cluster
headache, sinus headache and cervogenic headache. A patient is said
to suffer from chronic migraine headache when experiencing a
migraine headache for fifteen days or greater per month, while a
patient that suffers between 0 to eight days of migraine headaches
per month is considered to suffer from episodic migraines.
[0070] In one aspect, a method for treating a respiratory disorder
in a patient in need thereof comprises the step of administering a
botulinum toxin to at least one of a head, neck or shoulder
location of the patient with a respiratory disorder to thereby
alleviate at least one symptom of the respiratory disorder and
treat the respiratory disorder. In a particular embodiment, the
administration step is carried out by intramuscular administration
of the botulinum toxin to a muscle at the at least one of the head,
neck or shoulder location of the patient.
[0071] Exemplary coronary risk factors that can be alleviated and
treated in accordance with the instant disclosure include
hypertension, diabetes, hyperlipidemia and obesity, for
example.
[0072] In some embodiments the botulinum toxin is a botulinum toxin
type A or B and is administered to a muscle selected from the group
consisting of a frontalis muscle, a glabellar muscle, an
occipitalis muscle, a temporalis muscle, a masseter muscle, a
trapezius muscle, a semispinalis muscle and a splenius capitis
muscle. The locations of all of these muscles are well known to
those of ordinary skill in the art, and can easily be found in any
of several medical anatomy texts, for example.
[0073] In still other embodiments, a method for treating arthritis
in a patient in need thereof comprises the step of intramuscular
administration of a therapeutically effective amount of a botulinum
neurotoxin, such as toxin type A or a botulinum toxin type B, to at
least one muscle selected from the group consisting of a frontalis
muscle, glabellar muscle, occipitalis muscle, temporalis muscle,
masseter muscle, trapezius muscle, semispinalis muscle and splenius
capitis muscle of a patient with arthritis. The patient can also
suffer from headaches, such as chronic or episodic migraines. In
some examples, the botulinum toxin administered is from about 5 to
about 2500 units of a botulinum toxin type A or from about 100 to
about 25,000 units of a botulinum toxin type B. An exemplary
administered amount of botulinum neurotoxin can be from about 5
units to about 2500 units, depending upon factors such as the
botulinum neurotoxin serotype used, the mass of the patient treated
and the severity of the patient's condition, of course.
[0074] In one detailed embodiment of a method for treating a
respiratory disorder and/or coronary risk factor and/or arthritis
in a patient, according to the present invention, intramuscular
administration of a therapeutically effective amount of a botulinum
toxin type A to each of the frontalis, glabellar, occipitalis,
temporalis, masseter, trapezium, semispinalis and splenius capitis
muscles of a patient in need thereof, that is, with arthritis, a
respiratory disorder and/or coronary risk factor, thereby treating
the arthritis and/or respiratory disorder and/or coronary risk
factor of the patient.
[0075] In still other aspects, the present invention provides for
treatment of an arthritis pain in a patient in need thereof
comprising the step of intramuscular administration of a
therapeutically effective amount of a botulinum toxin type A or a
botulinum toxin type B to at least two muscles selected from the
group consisting of a frontalis muscle, glabellar muscle,
occipitalis muscle, temporalis muscle, masseter muscle, trapezius
muscle, semispinalis muscle and splenius capitis muscle of the
patient. In particular embodiments, the patient experiences
arthritis pain located at joint of an extremity (i.e. an arm of
leg), for example, such as a wrist joint, finger joint, elbow
joint, toe joint, ankle joint, hip joints and knee joint, shoulder
joint. In some embodiments, the botulinum toxin administered is
from about 5 to about 2500 units of a botulinum toxin type A or
from about 100 to about 25,000 units of a botulinum toxin type B.
Additionally, the patient may also suffer a headache, such as a
tension headache, a migraine headache, an episodic migraine, a
chronic migraine, a cluster headache, a sinus headache, a chronic
progressive headache, a hormone headache and a cervogenic headache.
In particular instances, the migraine headache can be a chronic
migraine or episodic migraine.
DEFINITIONS
[0076] The following definitions apply herein.
[0077] "About" means plus or minus ten percent of the value so
qualified.
[0078] "Biocompatible" means that there is an insignificant
inflammatory or immunogenic response from use of a botulinum toxin
according to the present invention.
[0079] "Biologically active compound" means a compound which can
effect a beneficial change in the subject to which it is
administered. For example, "biologically active compounds" include
neurotoxins.
[0080] "Therapeutically effective amount" as applied to the
biologically active compound (such as a botulinum toxin) means that
amount of the compound which is generally sufficient to effect a
desired change in a patient. For example, where the desired effect
is treatment of a coronary risk factor and/or a respiratory
disorder, an effective amount of the compound is that amount which
causes an alleviation of the a coronary risk factor and/or a
respiratory disorder, as observed clinically, without a significant
systemic toxicity resulting.
[0081] "Neurotoxin" means an agent which can interrupt nerve
impulse transmission across a neuromuscular or neuroglandular
junction, block or reduce neuronal exocytosis of a neurotransmitter
or alter the action potential at a sodium channel voltage gate of a
neuron.
[0082] "Treatment" or "treating" means any treatment of a disease
in a mammal, and includes: (i) preventing the disease from
occurring or; (ii) inhibiting the disease, i.e., arresting its
development; (iii) relieving the disease, i.e., reducing the
incidence or severity (i.e. alleviation) of symptoms of or causing
regression of the disease, such as, for example, by a reduction in
blood pressure, reduction in number and/or severity of asthma
attacks, a reduction in a need for, or elimination of, a medication
associated with a respiratory disorder or coronary risk factor,
reduced blood cholesterol or triglyceride levels, for example.
Treating or alleviation of at least one symptom associated with
arthritis, a coronary risk factor or respiratory disorder is
considered to be treating the particular arthritis, coronary risk
factor and/or respiratory disorder suffered by the patient in need
of the treatment.
[0083] Each and every feature described herein, and each and every
combination of two or more of such features, is included within the
scope of the present invention provided that the features included
in such a combination are not mutually inconsistent. In addition,
any feature or combination of features may be specifically excluded
from any embodiment of the present invention
DESCRIPTION
[0084] The present invention is based upon a method for treating
arthritis and/or a coronary risk factor and/or a respiratory
disorder by local administration of a botulinum neurotoxin to a
head, neck or shoulder location of a patient with a coronary risk
factor and/or a respiratory disorder. Thus and in particular,
treatment is preferably by intramuscular injection of a botulinum
neurotoxin to a head, neck or shoulder location of the patient.
Most preferably, botulinum neurotoxin type A is utilized,
permitting delivery of long-lasting therapeutic amounts of a
bioactive botulinum toxin to treat the arthritis and/or coronary
risk factor and/or respiratory disorder. After administration of
the botulinum neurotoxin in accordance with the teachings of the
present invention, at least one symptom of at least one of a
coronary risk factor or symptom of a respiratory disorder and/or
arthritis are alleviated.
[0085] Administration of a botulinum neurotoxin can be used to
treat a coronary risk factor, arthritis pain and respiratory
disorders is surprising because of the apparent lack of systemic
connection or control/biofeedback mechanisms between the head, neck
and/or shoulder location to which the botulinum toxin is
administered and the at least one coronary risk factor and/or
respiratory disorder and/or arthritis pain to be treated.
Additionally, in some instances, patients in need of treatment of
their coronary risk factor and/or arthritis pain and/or respiratory
disorder(s) can also have a headache, such as a tension headache, a
migraine headache, an episodic migraine, a chronic migraine, a
cluster headache, a sinus headache, a chronic progressive headache,
a hormone headache and a cervogenic headache.
[0086] Additionally, whereas the botulinum neurotoxin is to be
administered at a head, neck or shoulder location, at least one
arthritis symptoms is alleviated at distal joint location(s), such
as a finger joint, a toe joint, an ankle joint, an elbow joint, a
knee joint, a wrist joint and a hip joint for example.
[0087] The therapeutic dose of administered botulinum toxin is such
that there are nominal or insignificant systemic effects due to any
botulinum neurotoxin which passes into the circulatory system.
[0088] Preferably, the botulinum to neurotoxin used to practice a
method within the scope of the present invention is one of the
serotype A, B, C.sub.1, D, E, F or G botulinum neurotoxins.
Preferably, the botulinum neurotoxin used is botulinum toxin type
A, because of its high potency in humans, ready availability, and
known safe and efficacious use for treatment of various disorders
for over two decades.
[0089] The present invention includes within its scope the use of
any botulinum neurotoxin which has a therapeutic effect to treat
arthritis or coronary risk factor or respiratory disorder according
to the present invention (i.e. administered to a head neck or
shoulder location). For example, neurotoxins made by any of the
species of the toxin producing Clostridium bacteria, such as
Clostridium botulinum, Clostridium butyricum, and Clostridium
beratti can be used or adapted for use in the methods of the
present invention. Additionally, all of the botulinum serotypes A,
B, C.sub.1, D, E, F and G can be advantageously used in the
practice of the present invention, although type A is the most
preferred serotype, as explained above.
[0090] The present invention includes within its scope: (a) a
botulinum neurotoxin complex as well as a pure botulinum neurotoxin
obtained or processed by bacterial culturing, toxin extraction,
concentration, preservation, freeze drying and/or reconstitution
and; (b) modified or recombinant botulinum neurotoxin, that is
botulinum neurotoxin that has had one or more amino acids or amino
acid sequences deliberately deleted, modified or replaced by known
chemical/biochemical amino acid modification procedures or by use
of known host cell/recombinant vector recombinant technologies, as
well as derivatives or fragments of botulinum neurotoxins so made,
and includes botulinum neurotoxins with one or more attached
targeting moieties for a cell surface receptor present on a
cell.
[0091] Botulinum toxins for use according to the present invention
can be stored in lyophilized or vacuum dried form in containers
under vacuum pressure. Prior to lyophilization, the botulinum toxin
can be combined with pharmaceutically acceptable excipients,
stabilizers and/or carriers, such as albumin. The lyophilized or
vacuum dried material can be reconstituted with saline or water in
accordance with known methods of reconstitution. Additionally, the
botulinum toxin for use in accordance with the method herein
disclosed can be provided as ready-to-use injectable solutions from
their manufacturer. For example, Myobloc.RTM. (Botulinum Toxin Type
B) is provided as an injectable solution in vials containing 5000
units of botulinum toxin type B per mL in 0.05% human serum
albumin, 0.01 M sodium succinate, 0.1 M sodium chloride at
approximately pH 5.6.
[0092] Methods for determining the appropriate dosage is generally
determined on a case by case basis by the attending physician. Such
determinations are routine to one of ordinary skill in the art (see
for example, Harrison's Principles of Internal Medicine (1998),
edited by Anthony Fauci et al., 14.sup.th edition, and published by
McGraw Hill). Appropriate dosage administration of botulinum toxin,
and modification thereof, is a feature of administration that one
of ordinary skill in the art is familiar. Exemplary dosages are
provided below to guide the practitioner. However and in accordance
with common medical practice, dosages may be increased or
decreased, according to the particular outcome/results observed
after a particular botulinum neurotoxin is administered to a
particular patient at a particular location.
[0093] For example, Table 1 provides a medical practitioner with a
guide to exemplary amounts of administration (location and units)
of a botulinum toxin type A (BOTOX.RTM.) to a patient:
TABLE-US-00001 TABLE 1 Bilateral Muscle Area Number of Units
Injection Total Dose (U) Frontalis/Glabellar About 25 to No About
25 to about about 40 40 Occipitalis About 10 Yes 20 Temporalis
About 10 to Yes About 20 to about about 25 50 Masseter About 0 to
about Yes About 0 to about (optional) 25 50 Trapezius About 10 to
Yes About 20 to about about 30 60 Semispinalis About 5 to about Yes
About 10 to about 10 20 Splenius capitis About 5 to about Yes About
10 to 10 about 20 Total Dose Range About 105 to about 260
[0094] BOTOX.RTM. is available from Allergan, Irvine, Calif., and
each vial contains 100 U of Clostridium botulinum toxin type A, 0.5
mg albumin (human), and 0.9 mg sodium chloride in a sterile,
vacuum-dried form without a preservative. One U corresponds to the
calculated median lethal intraperitoneal dose (LD.sub.50) in mice.
The vials are stored in a freezer between -20 degrees Centigrade
and -5.degree Centigrade before use. Toxin can be administered to
only one of the muscles of Table 1 or at least two or more, as best
seen fit by the medical practitioner. Note, as set forth in the
table above, as little as 5 units of BOTOX.RTM. can be administered
if only one muscle is injected with the botulinum toxin. The units
listed above are of BOTOX.RTM., but different serotypes or strains
of a botulinum toxin can be used, and different amounts may be
administered. For example, about 3-4 times of DYSPORT.RTM. (a
botulinum toxin type A) may be utilized (i.e. up to about 1040
units), and about 40-50 times of NEUROBLOC.RTM./MYOBLOC.RTM. may be
utilized (i.e. up to about 13,000 units) relative to BOTOX.RTM.
units, to achieve a desired therapeutic effect, respectively.
EXAMPLES
[0095] The following examples set forth specific compositions and
methods encompassed by the present invention and are not intended
to limit the scope of the present invention.
Example 1
Method for Treating Asthma
[0096] A 20 year old male presents with wheezing, shortness of
breath and coughing. He states that he coughs and wheezes
practically every day for about 6 hours per day, the coughing and
wheezing being exacerbated when he exerts himself playing tennis or
basketball. On occasion he reports that he sometimes experiences
tightness of the chest, which ends his games early. After a review
of the patient's symptoms, medical history, and physical
examination, his physician conducts a pulmonary (lung) function
test, utilizing a spirometer. The physician determines that the
patient suffers from asthma, and he is provided with an inhalable
short-acting medication, inhaled/metered albuterol
(.beta.2-adrenergic receptor agonist), to inhale when his chest
tightening and coughing is exacerbated. After 1-month, the patient
returns to his physician to report the inhaler is not effective,
and that he continually misplaces it, which does not allow him to
inhale the albuterol when he needs it most.
[0097] The patient is therefore treated by administration of a
botulinum neurotoxin into one or more head, neck and shoulder
muscles, for example, by intramuscular administration. In
particular, a botulinum toxin type A (BOTOX.RTM.) is administered
in the following pattern and amounts. Intramuscularly and utilizing
a 26-gauge needle, about 5 units of botulinum toxin type A is
symmetrically and bilaterally injected at two sites, separated by 1
cm, into each of the occipitalis muscles (4 total injections into
the occipitalis muscles, for about 20 units), 5 units is
symmetrically and bilaterally injected at four sites in the
frontalis muscle (2 injection sites at about 0.5 inch above the
eyebrows and vertical to the medial canthus, and 2 injection sites,
each 1 inch laterally and upward to the hairline in a "V"
configuration from the first two injections, for a total of 20
units into the frontalis muscle), and 1 injection of 5 units into
approximately the center of each of the temporalis muscles (total
of 10 units into the temporalis muscles) for a total of about 50
units of botulinum toxin.
[0098] At a follow up one month later, the patient reports that
within 7 days of botulinum toxin administration he wheezes less
than 1.5 hours/day and that he can participate in and complete a
whole game of tennis. An in-office measurement of lung function
shows improvement of forced vital capacity (amount of air exhaled
with force after inhalation as deeply as possible) as well as
forced expiratory volume (amount of air you can exhale with force
in one breath, measured at 1 second (FEV1), 2 seconds (FEV2), or 3
seconds (FEV3).
Example 2
Method for Treating Bronchitis
[0099] A 39 year old female presents with a rough cough that
produces copious amounts of mucus. Additionally, the patient
complains of shortness of breath, fatigue, swelling of her feet and
ankles and has blue-tinged lips as a result of low levels of
oxygen, and is running a low grade fever of about 38.5 degrees
Celsius. The patient has had these symptoms for over two months,
and after conducting a pulmonary function test (PFT) and high
resolution computed tomography (HRCT) to observe her lungs, and her
physician notes she has a heavy mucus buildup in her bronchi. The
patient is treated with bronchodilator medications and instructed
to get at least nine hours of sleep per day. The patent returns
after two months, reporting no alleviation of her symptoms. The
doctor determines that she is suffering from bronchitis and decides
to administer a botulinum toxin to her temporalis, trapezius and
frontalis muscles.
[0100] Taking an imaginary vertical line down the midline and front
of the patient's forehead, the forehead is imagined to be divided
into two halves. Three injections of 10 units each of botulinum
toxin type A (DYSPORT.RTM.) are made laterally and midway between
the hairline and eyebrows, to the left from this imaginary midline
and towards the patients temple, evenly spaced apart about 1.5 cm.
The same is done to the right, for a total of six injections into
the frontalis muscle (60 units of DYSPORT.RTM. into the forehead).
Additionally, one injection of 20 units is administered into each
of the two temporalis muscles (40 units total of DYSPORT.RTM. to
temporalis muscles), and 50 units is administered into each of the
trapezius muscles (100 units total of DYSPORT.RTM. into the
trapezius muscles). Within 3 days, the patient reports that the
swelling of her feet and ankles has decreased and she no longer
coughs when breathing and no longer has blue-tinged lips.
Additionally, the symptoms of her bronchitis remain alleviated for
approximately 3 months.
Example 3
Method for Treating COPD
[0101] A 57 year old chain-smoking man presets with a hacking,
chronic cough. He informs his doctor that he has smoked since he
was 10 years old and has several very bad colds each winter for the
last few years. He further informs the doctor that he has the most
difficulty breathing in the morning and evening. The patient finds
that short walks result in breathlessness and walking up the stairs
in front of his house is difficult. After a thorough physical exam,
the doctor determines that patient has both chronic bronchitis and
emphysema (COPD), which are obstructing his airflow (in and out of
his lungs), thus interfering with normal breathing.
[0102] The patient is treated by administering from about 100 to
200 units of a botulinum toxin type A (BOTOX.RTM.) (or from 4000 to
about 8000 units of a botulinum toxin type B (MYOBLOC.RTM.). Into
each of his trapezius muscles, 20 units of botulinum toxin type A
is administered (total of 40 units bilaterally) and 10 units is
administered to each of the semispinalis dorsi, semispinalis
cervicis semispinalis capitis (total of 60 units bilaterally).
Within 10 days after this administration protocol, the patient's
breathlessness and walking up stairs is alleviated, and coughs only
in the early morning.
Example 4
Method for Treating Hypertension and Obesity
[0103] A 43 year old partner at a successful advertising agency
complains to his doctor that he hears ringing in his ears and is
suffering dizzy spells at least once a day. The doctor notes that
his 5 foot 6 inch, 302 pound patient appears to sweat continuously
and appears to be under a great amount of stress. Taking his blood
pressure, it is noted that it reads 202/120 mmHg. Despite previous
prescriptions of
2-[4-[2-hydroxy-3-(1-methylethylamino)propoxy]phenyl]ethanamide, a
.beta.1 receptor specific antagonist (trade name Tenormin), his
patient's hypertension is unaffected. The doctor administers about
10 units of a botulinum toxin type A (BOTOX.RTM.) to each of the
muscles listed in Table 1 (for a total of about 140 units). During
a follow up visit two weeks later, the patient's blood pressure is
taken again, this time reading at 155/90 mmHg, a positive
alleviation of the hypertension. It is also noted that the patient
has lost approximately 6 pounds since his last weigh in. The
patient also reports that since administration of the botulinum
toxin, he no longer experiences ringing in his ears and has only
been dizzy only once since his last visit.
[0104] The doctor follows up with the patient a month later, and
notes that his blood pressure now reads at 142/87 mmHg and the
patient weights 6 pounds less. It is determined that the patient be
administered a regime of botulinum toxin, as administered to him in
the first instance, every 4.5 months. As a result and within one
year, the patient loses 53 pounds and has an average blood pressure
of 136/78 mmHg.
Example 5
Method for Treating Diabetes
[0105] A 64 year old woman, 5 feet, 2 inches tall and weighing 187
pounds, presents to her doctor, complaining of headaches, blurred
vision and an insatiable thirst. Her physician determines her
fasting blood glucose level after an overnight fast (not eating
anything after midnight). The patient registers a value of 152
mg/dl the first time her blood glucose level is measured, and 163
mg/dl a week later. It is determined, after conducting an oral
glucose tolerance test performed in the doctor's office, that the
patient is diabetic (oral glucose tolerance tests shows that her
blood glucose level at 2 hours is equal to or more than 223
mg/dl).
[0106] She is administered 200 units of a botulinum toxin type B
(e.g. MYOBLOC.RTM.) intramuscularly into each of her temporalis
muscles on each side of her head, at points approximately 1 inch
from the top of her earlobe and towards the head's apex (two
injections for a total of 400 units of a botulinum toxin type B
into the temporalis muscles), and 200 units bilaterally and about
one inch above the top of her eyebrow arches, into the frontalis
(two injections for a total of 400 units of a botulinum toxin type
B in the frontalis) and 100 units into each of two injections into
glabellar muscle, utilizing her glabellar lines as guides (two
injections for a total of 200 units of botulinum toxin type B), for
a grand total of 1000 units of botulinum toxin type B. Within eight
days, the patient reports that her thirst has lessened and no
longer experiences headaches. At the doctor's office 2 months
later, an oral glucose tolerance test reveals that the patient has
impaired glucose tolerance (i.e., a 2-hour glucose result from an
oral glucose tolerance test registering 145 mg/dl) instead of
diabetes, which is lower that when first measured (223 mg/dl).
Example 5
Method for Treating Hyperlipidemia
[0107] A 26 year old male presents with a total blood cholesterol
level of 370 mg/dL, an LDL cholesterol level of 210 mg/dL and an
HDL level of 32 mg/dL. Although the patient exercises regularly
(3.times./week for 1 hour each time) and takes a statin prescribed
by his doctor to lower his LDL levels, his lipid profile does not
improve. His physician decides that the patient will be
administered a botulinum toxin type A (BOTOX.RTM.), where about 20
units evenly divide among 4 injection points are intramuscularly
administered into his glabellar lines, and about 50 units into each
of his temporalis muscles (for a total of 100 units into the
temporalis muscles), and about 50 units into each of his trapezius
muscles (about 100 units into the trapezius muscles), for a total
administration of about 220 units of botulinum toxin type A.
[0108] After 1 month, the patient returns and his cholesterol
levels are lower, now having a total blood cholesterol level of 260
mg/dL and his LDL cholesterol level is 162 mg/dL and HDL level is
40 mg/dL. After one year, the doctor notes that the patient's total
blood cholesterol level is now 210 mg/dL and his LDL cholesterol
level is 110 mg/dL and has an HDL level of 42 mg/dL.
Example 6
Method for Treating Arthritis
[0109] A 57 year old mechanic reports to his doctor that pain due
to the arthritis in his hands and fingers is becoming unbearable,
and rates his pain at a 9 on the visual analogue scale for pain
(VAS) at the doctor's office. Application of various topical creams
that contain ingredients such as methyl salicylate, menthol and
capsaicin are simply ineffective. The physician decides to
administer a botulinum toxin type A in order to treat the arthritis
to the patient's trapezius, frontalis and occipitalis muscles.
[0110] The doctor administers a total of 100 units of a botulinum
toxin type A (BOTOX.RTM.) as follows: about 50 units into the
frontalis muscle (five injections of about 10 units each across the
forehead of the patient (along an approximately horizontal midline
between the eyebrows and hairline of the patient) and 40 units into
the trapezius muscles (two injections/10 units each into the left
and two injections/10 units each into the right trapezius, for a
total of 40 units into the trapezius muscles) and 10 units into the
occipitalis muscles (two injections/5 units each). After about 8
days, the patient reports that his arthritic pain is alleviated and
ranks his pain at only a 2 on the same VAS. The arthritic pain
remains alleviated for about at least about 3 months.
Example 7
Method for Treating Arthritis
[0111] A 39 year old female long distance runner (and known
osteoarthritis sufferer) complains to her family doctor that her
knee joints ache most of the time, and that her running regimen is
being hampered by the pain, rating as an 8 on the doctor's visual
analogue scale for pain (VAS). After prescribing NSAIDs for 2
months, the patient reports that no improvement or alleviation of
the pain. Accordingly, the doctor decides to treat the arthritis
pain by administration of a botulinum toxin into the splenius
capitis and temporalis muscles. About 50 units of a botulinum toxin
type A (DYSPORT.RTM.) is bilaterally injected, i.e. about 25 units
into the left and right splenius capitis muscles, and 100 units is
bilaterally injected, i.e. 50 units into each of her temporalis
muscles.
[0112] After 10 days, the patient reports returns to the doctor's
office for a follow up and reports that the pain in her knees is
alleviated, and now when asked to rate her pain on the visual
analogue scale for pain (VAS), she rates it as a 3, a good and
desirable improvement. The patient is similarly administered the
botulinum toxin every 6 months thereafter.
[0113] Compositions and methods according to the invention
disclosed herein have many advantages, including that a botulinum
toxin can be used to provide therapeutically effective treatment of
coronary risk factors, a respiratory disorder and arthritis.
[0114] All references, articles, publications and patents and
patent applications cited herein are incorporated by reference in
their entireties.
[0115] Although the present invention has been described in detail
with regard to certain preferred methods, other embodiments,
versions, and modifications within the scope of the present
invention are possible. For example, a wide variety of neurotoxins
can be effectively used in the methods of the present invention.
Additionally, the present invention includes formulations wherein
two or more neurotoxins, such as two or more botulinum toxins, are
administered concurrently or consecutively. For example, botulinum
toxin type A can be administered until a loss of clinical response
or neutralizing antibodies develop, followed by administration of a
botulinum toxin type B or E. Alternately, a combination of any two
or more of the botulinum serotypes A-G can be locally administered
to control the onset and duration of the desired therapeutic
result.
[0116] Furthermore, non-neurotoxin compounds can be administered
prior to, concurrently with or subsequent to administration of the
neurotoxin formulation so as to provide an adjunct effect such as
enhanced or a more rapid onset of denervation before the
neurotoxin, such as a botulinum toxin, begins to exert its
therapeutic effect.
[0117] The present invention also includes within its scope the use
of a neurotoxin, such as a botulinum toxin, in the preparation of a
medicament for use to treat a treating coronary risk factor and/or
respiratory disorders and/or arthritis by administration of the
botulinum toxin to a head, neck and/or shoulder location of a
patient with a coronary risk factor and/or respiratory disorder
and/or arthritis.
[0118] Accordingly, the spirit and scope of the following claims
should not be limited to the descriptions of the preferred
embodiments set forth above.
* * * * *