Note: Descriptions are shown in the official language in which they were submitted.
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METHODS OF PREVENTING OR TREATING DISEASES
AND CONDITIONS USING COMPLEX CARBOHYDRATES
FIELD OF THE INVENTION
The invention relates to novel uses for a composition
of matter comprising complex carbohydrates preferably as the
sole active ingredient,. applied topically, orally, mucosally
or parenterally to prevent or treat diseases and conditions
associated with allergies or the adhesion, metastatic or
coronary cascades. Also disclosed are methods of preventing
and treating the above-mentioned di,*eases and conditions by-
administering the complex carbohydrates of the present
invention. Additionally, this invention describes novel
uses for a composition of matter comprising at least one
:
complex carbohydrate and at least one transdermal or,
transmucosal carrier useful for effecting transdermal or-
transmucosal migration resulting in topical or mucosal
delivery of macromolecules, through the skin or mucous
membranes of mammals and into the bloodstream. Methods of
.preventing diseases and conditions of mammals associated
with allergies, autoimmune mechanisms, the adhesion cascade,
the metastatic cascade and the coronary cascade are also
described wherein the combination of complex carbohydrates
with essential oils is applied topically, orally, mucosally
or parenterally on a repeated basis until treatment is
complete.
BACKGROUND OF THE INVENTION
For purposes of this invention, complex carbohydrates
are defined as any polymer comprising more than two sugar
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moieties and include such classes of compounds as
polysaccharides and oligosaccharides. Polysaccharides
include mucopolysaccharides and mannans whereas
oligosaccharides are comprised of branched polysaccharides
such as sialylated sugars including milk sugars. The key
milk sugars (also called hexaoses) incorporated in the
general class of complex carbohydrates are difucosyllacto-N-
hexaose a and b, Disialyl-monofucosyllacto-N-hexaose and
monofucosyllacto-N-hexsaose I, II, and II (obtainable from
Oxford Glycosystems, Inc.).
One of the most active areas of research at present is
the study of the genetics and function of
mucopolysaccharides. These are glycosaminoglycans that can
be obtained from numerous sources {e.g. rooster combs,
trachea, umbilical cords, skin, articular fluids and certain
bacteria such as Streptococci spp). Most glycosaminoglycans
(hyaluronic acid, chondroitin sulfates A, B, and C, heparin
sulfate, heparin, keratan sulfate, dermatan sulfate, etc.)
are composed of repeating sugars such as
n-acetylglucosamine, glucuronic acid and n-acetyl
galactosamine (these are known as non-sulfated
glycosaminoglycans). If such glycosaminoglycans contain
sulfur groups they are known as sulfated glycosaminoglycans.
Heparin, hyaluronic acid and chondroitin sulfate are
the most studied mucopolysaccharides. Heparin has been used
for a number of years as an anticoagulant. Hyaluronic acid
has been used therapeutically since the 1970s as a
replacement for the vitreous humor of the eye post surgery
and, more recently, as replacement for joint fluid in
arthritic joints. The, mode of action for hyaluronic acid
injected directly into joints for treatment of arthritis has
been proposed to be lubrication and replacement of the
degraded joint fluid with highly viscous hyaluronic acid.
High molecular weight (>750,000 daltons) and high viscosity
have been reported to be critical for this use. (For
purposes of this patent, all molecular weights are expressed
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as daltons. The unit designation will not be added
hereinafter.)
In the 1980s, it was discovered that chondroitin
sulfate, or polysulfated glycosaminoglycan (known by its
commercial name as ADEQUAN ) could be injected
intramuscularly for reduction of pain and inflammation
associated with arthrosis of horses. The mechanism of
action of this glycosaminoglycan has been speculated to be
inhibition of certain degradative enzymes present in the
joint fluid that are up-regulated by trauma.
In the 1990s, chondroitin sulfate had developed into a
popular nutritional supplement being used extensively to
treat joint problems. Such treatment requires oral doses
between 1000 and 3000 mg/day for humans. Even with these
high doses (>15mg/Kg), relief from joint pain often takes 6-
9 months.
In 1989, it was discovered that intravenous,
intramuscular or subcutaneous delivery of hyaluronic acid
could reduce the pain of arthritis (U.S. Pat. No. 4,808,576
by Schultz et al) when the hyaluronic acid was delivered
remote to the site of the arthritis (not into the joint).
This Schultz et. al. patent specifically states that the
hyaluronic acid must be of high purity (>99% pure hyaluronic
acid). No mention is made of use of other complex
carbohydrates, mucopolysaccharides or glycosaminoglycans
administered by any method, or use of hyaluronate sodium
orally or mucosally, use of low purity glycosaminoglycans or
treatment of other diseases or conditions by parenteral
administration.
The importance of high molecular weight for
effectiveness of hyaluronic acid in the treatment of
arthritis is generally emphasized (see for example Balazs,
U.S. Pat. No. 4,14.1,973 and Howard and Mcllraith, The
Compendium, 15(3), March 1993) who summarize several
clinical studies conducted to determine the most efficacious
molecular weight range of hyaluronic acid injected intra-
articularly to treat traumatic arthritis in horses. The
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conclusion from these studies was that hyaluronic acid with
a molecular weight below 1 X 106 was not as effective as
hyaluronic acid with a molecular weight above this value.
The most recent studies on hyaluronic acid discuss
treatment of various types of cancer with very large doses
of this macromolecule (Falk, WO 97/40841). This Falk
application suggests that doses should exceed 750 mg per 70
Kg person, preferably, exceeding 1 g per 70 Kg person. This
dose level calculates to be approximately 10-20 mg/Kg. Such
doses are given intermittently post diagnosis and are not
suggested to be preventative or administered in continuous
low doses. Additionally, it is clear that the sodium
hyaluronate of the Falk invention needs to be pure enough
for injection even though oral administration is used in
addition to intravenous injection. In all cases, patients
were treated with hyaluronan in addition to chemotherapy.
Hyaluronan was not used as the sole active ingredient for
treatment of the cancer patients by Falk.
The adhesion cascade was first described in the early
1990s. In a summary by Adams and Shaw (The Lancet, 343,
Apr. 2, 1994) the adhesion cascade is supposed to describe
the mechanism by which pain and swelling are produced post
trauma. It is divided into four sequential steps of
tethering, triggering, strong adhesion and motility.
Tethering interactions are mediated by a family of three
lectin-like carbohydrate-binding molecules (selectins).
These interactions are strong enough to cause the leukocytes
to roll along the blood vessel walls to the site of trauma
instead of flowing freely through such vessels as they would
in a non-traumatized state. The triggering response is
stimulated by factors such as cytokines stimulated by a
traumatic event and mediated by adhesion molecules called
integrins. Integrins, by themselves, do not bind well to
epithelium. However, when activated, integrins promote
strong adhesion of the leukocyte to the epithelial surface.
Leukocytes bind to the epithelial cells via their receptor
sites such as CD44, CD31, etc. By a mechanism of attachment
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and detachment the leukocytes are guided to the site of
trauma. At the site of trauma the adhesion to the blood
vessel wall becomes stronger and the interaction of these
integrins with their ligands on the surface of the
leukocytes are responsible for cessation of movement and
flattening of the leukocyte. Finally, a process involving
VCAM-1 and LFA-1 and other such integrins allows leukocytes
to pass between endothelial cell junctions and into the
tissue that has been traumatized. Collection of leukocytes
at the site of trauma produces inflammation which is then
followed by pain or other sequelae.
The metastatic cascade is very similar to the adhesion
cascade. It has been proposed that tumor cells of all types
contain CD44 receptor sites on their surface. These CD44
receptor sites appear to be involved in metastasis
functioning similar to the receptor sites on leukocytes
tethering the tumor cells to the blood vessel wall and
providing the motility necessary for movement from one site
to another in the mammalian body. A significant portion of
the literature on CD44 and tumor cells/cancer teaches that
hyaluronic acid or hyaluronan actually stimulates metastasis
(Eur. J. Cancer, 1999, March; 35 (3), 473-480).
A coronary cascade has recently been described in the
Harvard Health Letter (December 1999, pg. 4-5) and SCIENCE
vol:285, 23 July, 1999, pg 595-599). This cascade describes
a new mechanism to explain the development of heart disease
and stroke. Rather than the traditional theory that plaques
are formed by a collection of cholesterol alone, the new
theory is based on the premise that there are stable and
unstable plaques produced on blood vessel walls. Unstable
plaques are the problem plaques because they are "swarming
with T cells and macrophages" that are responding to a site
of trauma and triggering the adhesion cascade resulting in
inflammation. It is the "swarming T cells and macrophages"
that make these plaques unstable. The T cells are described
as sending macrophages a signal to release a protein called
tissue factor which "spills out and encounters circulating
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blood, attracting platelets and triggering formation of a
clot that quickly blocks up the artery".
Accordingly, it is totally unexpected that complex
carbohydrates of the present invention could be administered
topically, orally, mucosally or parenterally, in low doses,
to prevent and treat diseases and conditions associated with
allergies, the adhesion cascade, the metastatic cascade and
the coronary cascade described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph demonstrating the effect of
treating an adult suffering with Attention Deficit Disorder
with various formulations of hyaluronic acid.
Figure 2 is a graph demonstrating the effect of
treating a 9 year old child suffering from Attention Deficit
Hyperactivity Disorder with hyaluronic acid.
SUMMARY OF THE INVENTION
The present invention relates to a method of preventing
and treating diseases and conditions associated with
allergies, autoimmunity, the adhesion cascade, the
metastatic cascade or the coronary cascade comprising
administering (i) at least one complex carbohydrate as the
sole active ingredient, or (ii) at least one pharmaceutical
composition which comprises as an active ingredient a
pharmacologically effective amount of at least one low
purity or cosmetic grade complex carbohydrate selected from
the group consisting of oligosaccharides, sialylated
oligosaccharides, polysaccharides and glycosaminoglycans,
and an effective amount of at least one transdermal or
transmucosal carrier (e.g. essential oil) in an amount
effective to deliver the complex carbohydrate into the blood
stream.
Accordingly, the present invention relates to using
complex carbohydrates, including but not limited to
mucopolysaccharides and glycosaminoglycans, to bind to the
receptor sites on leukocytes (e.g. CD44 and CD31) blocking
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their ability to tether to the blood vessel walls,
inhibiting the motility to the site of trauma thus reducing
the pain, swelling and other sequelae associated therewith
(interrupting the adhesion cascade). Additionally, the
present invention teaches that complex carbohydrate
molecules, including but not limited to mucopolysaccharides
and glycosaminoglycans, bind to the. receptor sites on tumor
cells blocking their ability to tether to the blood vessel
walls and inhibit the tumor motility which, in turn,
inhibits the potential for metastasis.
The compositions of the present invention inhibit the
macrophages from swarming to a site of irritation or trauma
on a blood vessel wall wherein said macrophages would
normally accumulate producing the unstable plaques described
previously, thus preventing and treating heart disease and
stroke. Additionally, the compositions of the present
invention inhibit the T-cell and macrophage "swarming" thus
blocking the release of the tissue factor (referred to
previously) and preventing cardiac events caused by said
ruptured plaques.
In another embodiment of the present invention
allergies and allergy-related diseases, diseases associated
with the bodies' adverse reactions to stimuli such as foods,
inhalants and drugs wherein said adverse reactions include
but not limited to Attention Deficit Disease, Attention
Deficit Hyperactivity Disease, interstitial cystitis,
autism, migraines, asthma, Turret's Syndrome, fibromyalgia,
anaphylaxis, rhinitis, sinusitis and inflammation providing
the environment for yeast infections, bacterial infections
or virus infections and autoimmune diseases wherein the
bodies' macrophages attack its own body tissues and organs
producing diseases including but not limited to rheumatoid
and osteoarthritis, Lupus Erythematosis, multiple sclerosis,
polymyositis, muscular dystrophy, Diabetes, and potentially
Alzheimer's Disease, are associated by a mechanism similar
to the adhesion cascade. Therefore, CD44, CD31, RHAMM and
other similar receptors are involved in producing the
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allergic reaction and the autoimmune response. Again, the
binding of complex carbohydrates to these receptor sites
inhibit the reaction and/or response. Therefore,
allergies, allergy-related diseases and autoimmune diseases
respond to treatment by oral, mucosal, topical and
parenteral administration of complex carbohydrates as
described herein.
One of the most recent theories to explain the
significant neurological degeneration that occurs in
Alzheimer's Disease involves a substantial inflammatory
component (SCIENCE, vol: 286, 17 December, 1999, pgs 2352-
2355) which is concluded herein to be related to the
adhesion cascade. Therefore, the present inventors have
found that the complex carbohydrates of this invention can
be used to prevent and/or treat Alzheimer's Disease. Another
explanation for the development of dementia and Alzheimer's
Disease is that an amyloid protein is produced in the brain
resulting in the formation of amyloid plaques that lead to
neuronal degeneration. The neuronal degradation is
associated with diseases related to various types of
dementia including but not limited to Alzheimer's Disease.
Since it is known that CD44 is present in significant
amounts on neuronal cells in the brain, the complex
carbohydrates of the present invention bind to CD44 and/or
other receptor sites in the brain and inhibit the formation
of such amyloid plaques.
Accordingly, although not bound by any theory, the
invention relates to a composition of matter comprising
complex carbohydrates preferably as the sole active
ingredient, applied topically, orally, mucosally or
parenterally to prevent and treat diseases and conditions
associated with allergies, autoimmunity, and the adhesion,
metastatic or coronary cascades. However, the compositions
described in U.S. Patent 5,888,984 and in PCT/USOO/02328 may
also be utilized in the methods of the present invention.
Additionally, this invention describes a composition of
matter comprising at least one complex carbohydrate and at
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least one transdermal or transmucosal carrier useful for
effecting transdermal or transmucosal migration of said
complex carbohydrate, resulting in topical or mucosal
delivery of said molecules, through the skin or mucous
membranes of mammals and into the bloodstream in order to
prevent or treat the diseases and conditions associated with
allergic reactions, the adhesion cascade the metastatic
cascade or the coronary cascade. Transdermal carriers are
those compounds that allow molecules, including
macromolecules to pass through the skin and into the blood
stream of mammals. Transmucosal carriers are those
compounds that allow molecules including macromolecules to
pass through the mucous membranes and into the blood stream
of mammals. A patch or bandage can be embedded with the
complex carbohydrates of the present invention so as to
extend delivery of the molecules and/or provide slow release
over several days. In the use of the complex carbohydrates
of the present invention in bandages, they can be used
without the presence of transdermal or transmucosal carriers
with open wounds, or containing said carriers when used to
treat closed wounds or reduce scarring or scar tissue.
This invention further describes a method of preventing
and treating diseases and conditions of mammals associated
with allergies, autoimmunity, the adhesion cascade, the
metastatic cascade or the coronary cascade comprising
administering a composition of complex carbohydrates
topically, orally, mucosally or parenterally preferably on a
repeated basis (e.g. 2 times per day, preferably 4 times per
day, and most preferably 8 times per day, or simply "as
needed").
Applications of the present invention would be made on
a repeated basis for the term of the disease or condition or
as long as necessary to prevent the diseases or condition
from progressing, or to treat the diseases or conditions
until they are resolved.
Finally, this invention describes a mechanism by which
inflammation, including diseases and conditions associated
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therewith, tumor growth, tumor metastasis, allergies and
allergy-related diseases, autoimmune diseases, coronary
diseases and central nervous system diseases can be
prevented or treated by administering complex carbohydrates
topically, orally, mucosally, or parenterally.
It is understood that this invention describes the
prevention and treatment of numerous diseases and conditions
including but not limited to arthritis (osteoarthritis and
rheumatoid arthritis), gastritis, stomach or intestinal
ulcers, colitis, esophagitis, bronchitis, the common cold,
rhinitis, sore throat, tonsillitis, tendonitis,
fibromyalgia, chronic fatigue syndrome, interstitial
cystitis, polymyositis, autism, Lupus Erythematosis,
headaches including migraines, pancreatitis, anaphylaxis,
vaginitis, hemorrhoids, sunburn, heat burns,
temporomandibular joint (TMJ) condition, gingivitis, dental
caries, dental pain, post surgical pain, menstrual pain,
extremity cramps, pre and post partum pain, itching
associated with allergies and hypersensitivity (e.g. poison
ivy, oak and sumac and eczema), asthma, emphysema, Attention
Deficit Disorder, Attention Deficit Hyperactivity Disorder
(ADHD), fibromyalgia, Turret's Syndrome, Multiple Sclerosis,
Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's Disease,
Parkinson's Disease, high blood pressure, heart disease,
heart attack, vasculitis, stroke, increased degradation of
spinal nerves post spinal cord injury, head or brain trauma
post injury, adhesion formation post surgery or
chemotherapy, scar formation post surgery, non-healing
wounds, decubutis ulcers, irritation of nerve bundles (e.g.
trigger points) ganglion formation, dementia including but
not limited to Alzheimer's disease, Human Immunodeficiency
Virus infection (HIV), yeast infections, bacterial
infections, viral infections, encephalitis, epilepsy,
meningitis, peripheral neuropathy, Creuztfeldt-Jacob
Disease, Bell's Palsy, cognitive disorder, cancer, Diabetes,
skin problems such as acne, lick granulomas, hot spots,
psoriasis, rashes, wrinkles, and even hair loss.
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Such prevention and treatment are accomplished by
topically, orally, mucosally or parenterally applying
complex carbohydrates of the present invention to mammals in
an amount and number of applications so as to be effective
in preventing and treating.the target disease or condition.
It is understood that such prevention or treatment results
in blockage of receptor sites associated with allergies,
autoimmune mechanisms, the adhesion cascade, metastatic
cascade, or coronary cascade.
DETAILED DESCRIPTION OF THE INVENTION
This invention describes novel-uses for a composition
of matter comprising at least one complex carbohydrate that
is applied topically, orally, mucosally or parenterally to
prevent and/or treat diseases and conditions associated with
allergies, autoimmunity, the adhesion cascade, the,
metastatic cascade or the coronar[cascade. The invention
r
also encompasses novel uses for a composition comprising at
least one complex (carbohydrate and at least one transdermal
or transmucosal carrier. The invention also preferably
encompasses novel uses for a =composition of matter,
comprising complex carbohydrates as the sole active
ingredient. Further, the compositions disclosed in U.S.
Patent 5,888,984 and in PCT/tJS00/02328 may also be
utilized in the methods of the present invention.
More specifically, the present invention is directed to
a method of preventing and treating diseases and conditions
associated with allergies, autoimmunity, the adhesion
cascade, the metastatic cascade and the coronary cascade
comprising administering said complex carbohydrates to the
affected mammal topically, orally, mucosally or
parenterally. A significant feature of this invention is
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that the complex carbohydrates are preferably administered
in a low dose. By low dose is meant from 0.000001 mg/kg to
150 mg/kg, preferably from 0.001 mg/kg to 100 mg/kg and more
preferably from 0.01 mg/kg to 20 mg/kg.
The invention also describes a method for reducing the
sequelae of trauma in irritated or inflamed tissue of
mammals by the topical or mucosal application of a mixture
of a transdermal or transmucosal carrier and one or more
complex carbohydrates or mixtures thereof. The composition
described is applied directly on or over the traumatized
site or on a mucous membrane.
Finally, the invention describes a method for reducing
the sequelae of trauma in irritated or inflamed tissue of
mammals by topical, oral, mucosal or parenteral application
of a complex carbohydrate of the present invention or
mixture thereof as the only active ingredient. By trauma is
meant an event that produces an adverse effect on a mammal.
By sequelae of trauma is meant the pain, swelling,
inflammation, adhesion formation, nerve damage, nerve
sensitivity and any other physiological change that results
from trauma.
Many of the complex carbohydrates of the present
invention are macromolecules. Macromolecules as used herein
means any molecule with a molecular weight >1000 daltons
(Da). Mammals as used herein includes but is not limited to
humans, dogs, cats, horses, cattle, swine, rabbits, guinea
pigs, mice. Topical administration as used herein means
application to the dermis anywhere on the mammal, including
into the ear canal. Mucosal administration as used herein
means application to any mucous membrane of a mammal.
Mucous membranes include but are not limited to the mouth,
gums, nasal passage, throat, vagina and the rectum.
Transdermal as used herein means transfer of molecules,
including macromolecules through the skin of mammals so that
the complex carbohydrates may act systemically. Transmucosal
as used herein means transfer of molecules, including
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macromolecules through the mucous membranes of mammals so
that the complex carbohydrates may act systemically.
Diseases preventable and treatable by the present
invention include but are not limited to tonsillitis, the
common cold, pancreatitis, ulcerative colitis, stomach or
intestinal ulcers, cold sores, Lupus Erythematosis,
Parkinson's Disease, osteoarthritis, degenerative arthritis,
rheumatoid arthritis, polymyositis, Amyotrophic Lateral
Sclerosis (ALS) or Lou Gehrig's Disease, multiple sclerosis,
Creutzfeldt-Jakob Disease heart disease, heart attack,
vasculitis, stroke, Alzheimer's disease, asthma, emphysema,
allergy-related diseases, Human Immunodeficiency Virus
(HIV)disease, yeast infections, bacterial infections,
encephalitis, epilepsy, meningitis, peripheral neuropathy,
Bell's Palsey, Cerebral Palsey, cancer and Diabetes.
Conditions preventable and treatable by the above-described
complex carbohydrates include but are not limited to ulcers,
gastritis, esophagitis, bronchitis, sore throat, tendonitis,
fibromyalgia, headaches including migraines, vaginitis,
anaphylaxis, hemorrhoids, sunburn, heat burns,
temporomandibular joint (TMJ) condition, dental caries,
dental pain, gingivitis, post surgical pain, menstrual pain,
cramps, pre and post partum pain, interstitial cystitis,
itching associated with allergies and hypersensitivity
(poison ivy), pain associated with insect bites or stings,
Attention Deficit Disorder, Attention Deficit Hyperactivity
Disorder (ADHD), Turret's Syndrome, plaque formation in
arteries and veins, degradation of spinal nerves post spinal
cord injury, head and brain trauma post injury, adhesion
formation post surgery or post chemotherapy treatments, scar
formation post surgery, wound healing, decubutis ulcers,
irritation of nerve bundles (trigger points) ganglion
formation, cognitive disorder, skin problems such as acne,
eczema, lick granulomas, hot spots, psoriasis, rashes,
wrinkles, and even hair loss.
Particularly amenable conditions or diseases targeted
for such prevention or treatment include but are not limited
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to irritated or inflamed muscles, cramped muscles, inflamed
tendons, inflamed nerves or nerve bundles (e.g. inflamed
ganglion, lick granulomas, trigger points, fibromyalgia),
swollen and painful joints, inflamed bladder (interstitial
cystitis) bruised tissue, tired feet, allergic conditions of
the skin, other allergic conditions (e.g. hot spots,
psoriasis, asthma, ADD and ADHD), chronic fatigue syndrome,
open wounds, decubitis ulcers, burns, sunburns, inflamed
stomach or intestinal lining (gastritis, colitis, ulcers),
dental problems, inflamed bronchi or esophagial lining,
adhesions formed after surgery, trauma or chemotherapy, pain
post surgery, dental work or injury, plaques formed on veins
or arteries leading to heart disease and stroke,
inflammation associated with Alzheimer's Disease, Multiple
Sclerosis, amylotropic lateral sclerosis (ALS), head or
brain trauma, degration of the spinal cord post spinal cord
injury, tumor formation and tumor metastasis.
A significant advantage of this invention is that
pharmaceutical grade complex carbohydrates are not required
for topical, oral or mucosal application. The invention
preferably uses cosmetic or food grade (e.g. low purity)
complex carbohydrates for these applications. Such complex
carbohydrates can be obtained from any source as long as the
source is not contaminated with undesirable adventitious
agents (disease-producing viruses, bacteria, fungi,
parasites, etc.). Such low purity complex carbohydrates such
as mucopolysaccharides may be contaminated with up to 20%
wt/vol proteins, 15% wt/vol nucleic acids, 1% wt/vol
teichoic acids, 5% wt/vol lipids, fractions of hyaluronic
acid <30,000 (defined as reactive by both Balazs in U.S.
Pat. No. 4,141,973 and della Valle in U.S. Pat. No.
5,166,331), 5% wt/vol endotoxins and other small molecules.
They will cause reactions when injected into monkey eyes or
joints of horses but will not cause reactions when applied
to the skin of mammals or when delivered orally or mucosally
to such mammals. Because the low purity pharmaceutical
compositions of this invention are applied topically, orally
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or mucosally, these contaminants produce no adverse
reactions (e.g. irritation or blistering of skin).
Additionally, if one must select and use only certain
molecular weight ranges of hyaluronic acid or salts thereof,
the cost would be prohibitive. In fact, the presence of
multiple molecular weight fractions in compositions of the
immediate invention is preferable for efficacy.
In order to assure freedom from contaminating
microorganisms, the formulations of this invention can
include preservatives allowable in foods or topical
preparations. Allowable preservatives include but are not
limited to methyl and propyl parabens, propylene glycol,
ethylenediamine tetraacetic acid (EDTA), sorbitol, ascorbic
acid, sorbate and sorbic acid, benzoic acid, and any other
acceptable preservative, including mixtures thereof.
All molecular weight ranges of complex carbohydrates
are effective in formulations of this invention. For
instance, complex carbohydrates with a molecular weight of
<1,000, 1,000 to 30,000, 100,000-500,000, >1,000,000 or
>4,000,000 have proven to be effective. It has been found
that complex carbohydrates, especially glycosaminoglycans
with lower molecular weights (e.g. <30,000) act more quickly
than those with high molecular weights (e.g. >1,000,000).
Indeed, for treatment of allergy-related diseases and
autoimmune diseases or conditions, it is preferable to
administer glycosaminoglycans, especially sodium
hyaluronate, salts or derivatives thereof (also called
hyaluronic acid or hyaluronan) with a molecular weight
average below 300,000 Da. For inflammatory diseases,
diseases or conditions related to the adhesion cascade, the
metastatic cascade or the coronary cascade, the high
molecular weight glycosaminoglycans provide a longer-lasting
effect. The latter macromolecules are broken down by enzymes
in the body (hyaluronidase) to smaller molecules that are
active in binding or stimulate production of increased
amounts of lower molecular weight hyaluronic acid by the
mammals' own body. Therefore, there is a longer release of
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the more active smaller molecules producing a longer period
of efficacy. Thus, the preferred formulation for most
treatments includes a mixture of low and high molecular
weight complex carbohydrates.
It has been noted by the inventors that the optimum
molecular weight for treatment of allergies, allergy-related
diseases and conditions, asthma, ADD and ADHD is between
30,000 and 500,000 Da, preferably between 100,000 and
300,000. It has been determined that very high molecular
weight (>4 X 106) is essentially ineffective for treatment of
the above.
The complex carbohydrates useful in combination with
transdermal or transmucosal carriers for direct topical or
mucosal application on sites of trauma or to be absorbed
therein, may be of any type already recognized as useful for
parenteral treatment. Additionally, complex carbohydrates,
including polysaccharides, glycosaminoglycans or their
derivatives that bind to leukocyte receptor sites and/or
bind to selectins, integrins, or any other receptor sites
that are involved with the mechanisms by which leukocytes
move to sites of trauma or that enable metastasis of tumors
and that, when bound, serve to inhibit any of the steps of
the adhesion cascade, allergy or autoi_mmune mechanisms, the
metastatic cascade, or the coronary cascade would be useful
in such pharmaceutical compositions. Such compounds may be
obtained from any source. They can be extracted from
rooster combs (U.S. Pat. No. 4,141,973), produced by
fermentation of bacteria (U.S. Pat. No. 4,782,046), or
extracted from trachea, skin, umbilical cords, etc. and need
only be pure enough to be used as a cosmetic in that they do
not cause reactions when administered topically, orally or
mucosally. These molecules include but are not limited to
polysaccharides, glycosaminoglycans such as hyaluronic acids
and derivatives or salts thereof (Genzyme, Lifecore
Biomedicals, Meiji Seika Kaisha, Ltd.), chondroitin sulfates
A, B, or C or their derivatives (SIGMA Chemical Company),
keratan sulfate and derivatives thereof (SIGMA Chemical
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Company), heparin or heparin sulfate and derivatives thereof
(SIGMA Chemical Company, Rhone Poulenc Rorer
Pharmaceuticals), dermatan sulfate and derivatives thereof
(SIGMA Chemical Company) and certain sialylated sugars such
as trifucosyllacto-N-hexaose and sialyl Lewis" (Oxford
Glycosystems). The sources listed are exemplary only and
not limitations of the invention.
The preferred complex carbohydrates of this invention
are mucopolysaccharides (glycosaminoglycans) including
hyaluronic acid and salts, sulfates or derivatives thereof,
chondroitin sulfate and polysulfated forms, salts or
derivatives thereof, sialyl Lewisx and salts or derivatives
thereof, heparin and sulfates, salts or derivatives thereof,
dermatan, and sulfates, salts or derivatives thereof,
keratin and salts, sulfates and derivatives thereof, as well
as combinations of the above. The most preferred complex
carbohydrates are hyaluronic acid including salts, sulfates
or derivatives thereof, chondroitin sulfate including
polysulfated forms, low molecular weight heparin including
salts, sulfates and derivatives thereof and sialyl Lewisx
including salts and derivatives thereof and combinations
thereof.
It is a preferred embodiment of this invention that at
least two different molecular weight ranges of complex
carbohydrates be included in the composition. At least one
should be from a low molecular weight range (from 1000 to
<50,000 (e.g. 49,000)} and the other one or more should be
from a higher molecular weight range (from 100,000 to
500,000 or >1,000,000). Such complex carbohydrates may or
may not be a mixture of two or more different types of
complex carbohydrates. For instance, one complex
carbohydrate providing the high molecular weight moiety
could be selected from the group consisting of
glycosaminoglycans such as hyaluronic acid and another
complex carbohydrate in the same pharmaceutical composition
providing the low molecular weight moiety could be a second
polysaccharide or a sialylated sugar selected from the group
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consisting of chondroitin sulfate, keratan sulfate, heparin,
heparin sulfate, dermatan sulfate, acemannan, sialyl Lewis",
and hexaoses. When heparin is used, it is advantageous to
use low molecular weight heparin as it has been demonstrated
to be free of anti-coagulant activity. However, high
molecular weight heparin will be broken down to low
molecular weight heparin when administered orally or
mucosally.
A more preferred embodiment of this invention comprises
a mixture of at least two glycosaminoglycans. One of the
glycosaminoglycans would be of a low molecular weight range
(<30,000). The second glycosaminoglycan would be of a high
molecular weight (>500,000 Da).
The most preferred embodiment of this invention
comprises a mixture of two or more molecular weight ranges
of hyaluronic acid or salts or derivatives thereof, such as
sulfates, acetates, phosphates, methylates and nitrates.
Said composition comprises for instance, a hyaluronic acid
or salt or derivative thereof with a molecular weight of
<100,000 Da combined with a hyaluronic acid or salt or
derivative thereof which has a molecular weight >1,000,000
Da.
Routes of administration of the complex carbohydrates
of the present invention include parenteral (discussed
below), topical whereby the compounds may or may not be
combined with transdermal carriers including but not limited
to essential oils; oral whereby the compounds may or may not
be mixed with transmucosal carriers including but not
limited to essential oils or other transmucosal carriers,
coated with protective oral delivery materials such as
hydrogels, carbopols, etc., or delivered orally without a
coating wherein the complex carbohydrates are the sole
active ingredient, mucosally wherein the complex
carbohydrates are the sole active ingredients or
parenterally. For purposes of this invention, mucosal
delivery includes but is not limited to application of the
compounds to the mucous membranes of the nose, eyes, mouth,
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throat, gums, tonsils, eyes, esophagus, stomach, colon,
rectum, vagina, or any other mucous membrane.
It should be understood that complex carbohydrates used
for parenteral administration to mammals must be pure enough
to be injected safely without causing adverse local or
systemic effects and of a viscosity allowing ease of
injection. The preferred viscosity is that which is safe to
administer without stimulating an adverse effect in a
mammal. The intravenous route would require a lower
viscosity than other parenteral routes of administration.
For instance, a viscosity of 500 centipois should not cause
problems. A preferred viscosity is less than 200 centipois.
In the case of parenteral injections, especially those
administered IV, pharmaceutical grade complex carbohydrates
may be necessary. Parenteral injections may be administered
intramuscularly (IM), intravenously IV), subcutaneously
(SC), intradermally (ID), intraparitoneally (IP) and/or
injected into tumors.
The parenteral formulation of the present invention may
be in an aqueous form as a liquid or gel that is safe when
injected IM, SC, IV, ID, IP, or by any other route of
administration. This formulation must be purer and be of a
pharmaceutical grade. By a pharmaceutical grade is meant
that it should be sterile, contain <3% protein (w/w),
<5~1g/mL nucleic acids as measured by UV absorbance at 260nm,
<0.5 EU/mL endotoxin as measured by LAL, <80 ppm (w/w) iron
and <1.0 ppm heavy metals. The most effective injectable
formulation would contain mucopolysaccharides or
glycosaminoglycans, more specifically, low molecular weight
heparin, hyaluronic acid of all molecular weights,
chondroitin sulfate, dermatan sulfate and/or keratin
sulfate. If hyaluronic acid is used, the viscosity must be
at a level acceptable to be injected by the route chosen
without causing adverse reactions. For instance, high
viscosity hyaluronic acid >1000 centipoise would not be
injected intravenously whereas it could be injected
subcutaneously or intramuscularly. Low viscosity hyaluronic
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acid <500 centipoise could be injected intravenously,
subcutaneously or intramuscularly.
Administration of complex carbohydrates by the
parenteral routes of administration has been found to be
particularly effective in the treatment of any type of
inflammation, pain, nerve damage, nerve sensitivity,
autoimmunity and/or itching which is associated with the
adhesion cascade, tumors associated with the metastatic
cascade and development of heart diseases and stroke
associated with the coronary cascade described earlier.
This route of administration is preferable for treatment of
pain post surgery or dental procedures, treatment for
various types of cancer wherein patients cannot ingest food
or liquids, treatment of degenerative muscle and joint
diseases including the treatment of Multiple Sclerosis, ALS,
osteoarthritis, rheumatoid arthritis, or post partum pain.
It is also useful for treatment of spinal cord injuries,
treatment of heart attacks and stroke (e.g. heart disease
due to high blood pressure and stroke), treatment of pain
and swelling and/or fractures resulting from athletic
injuries, treatment of inflammation and pain associated with
bursitis, reduction of inflammation (edema) in extremities
resulting from diabetes, reduction of inflammation and pain
in association with interstitial cystitis, treatment of
decubitus ulcers resulting from poor circulation by diabetic
patients or bedridden patients, treatment of inflammation
and itching of skin resulting from severe allergic reactions
such as poison ivy and insect bites/stings, treatment of
sever ADD, ADHD or autism, treatment of anaphylaxis,
treatment of polymyositis, treatment of inflammation and
pain associated with tendonitis, treatment of inflammatory
skin conditions such as severe acne or psoriasis and
treatment of burns or sunburn. In severe situations,
treatment may include both parenteral injection and oral,
mucosal or topical application of one or more complex
carbohydrates.
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As indicated earlier, the most recent theories to
explain heart attacks and stroke involves the eruption of
unstable plaques which have been found to be infiltrated
with T-cells and macrophages thus linking these disease
syndromes to the adhesion cascade. Thus, the present
inventors have determined that heart disease (high blood
pressure, heart attacks and stroke) can be treated with the
complex carbohydrates of this invention. Further,
hyaluronic acid, chondroitin sulfate, heparin sulfate, low
molecular weight heparin, keratin sulfate or dermatan
sulfate, including salts or derivatives thereof can be taken
daily as a preventative for heart disease and stroke.
Preferably, amounts from lmg/day to 20 mg/day are used to
prevent heart disease and stroke. This could be
administered orally or mucosally. Acute disease, including
heart attacks could be treated by parenteral injection of
the complex carbohydrates of the present invention.
Alternately, a mixture of hyaluronic acid and chondroitin
sulfate could be administered daily for prevention of heart
disease and stroke. Again, the daily dose would preferably
be less than a total of 100 mg. Repeated low doses have
been demonstrated to be between 0.0001 mg and 100 mg.
For topical, oral and mucosal deliver, transdermal or
transmucosal carriers can be added to enhance the
penetration of the complex carbohydrates through the skin or
mucous membranes. Transdermal and transmucosal carriers
include but are not limited to essential oils, polymer
blends containing low density polyethylene copolymer or
ethylene and 1-butene, 1-hexene, or 1-octene and a linear
low density polyethylene copolymer, chemical esters,
salicylates, dimethyl sulfoxide (DMSO) and glycocholates.
It is preferred that very low concentrations of essential
oils be used to orally or mucosally deliver the complex
carbohydrates of the present invention, including the
macromolecules, through mucous membranes and, consequently,
into the blood stream. By very low concentration of
essential oils for use in mucosal or parenteral
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administration is meant that the essential oil is added to a
concentration in an amount from 0.00001% to no more than 1%,
preferably, no more than 0.01%, more preferably no more than
0.005%. Therefore, concentrations of essential oils around
0.00001% and 0.005% are preferred for transmucosal delivery.
Transdermal formulations of the present invention
utilize slightly higher concentrations of essential oils.
These range from 0.05% to 5.0%, preferably from 0.5% to
3.0%.
The essential oils of the present invention may be
either natural or synthetic and may be obtained from any
source. For instance, natural Eucalyptus Oil, Rosemary Oil,
Pine Needle Oil, Tea Tree Oil, Sage Oil, Jojoba Oil,
Cinnamon Oil, Anise Oil, Lemon Oil, Lime Oil, Orange Oil,
Peppermint Oil, Spearmint Oil, Wintergreen Oil, Clove Leaf
Oil, Almond Oil, White Pine Oil, Camphor Oil, Cardamon Oil,
Cedar Leaf Oil, Sweet Birch Oil and many others can be
purchased from Lorrann Oils. Synthetic Wintergreen Oil,
Anise Oil, Fir Tree Oil, Rose Oil and Camphor Oil can be
obtained from the same source. Menthol and derivatives
thereof can be obtained from SIGMA Chemical Company. The
purity of these essential oils is of little concern as long
as they meet the requirements for a food or cosmetic and do
not produce adverse reactions when applied to the skin of
mammals. An example of an animal-derived essential oil is
EMU oil, extracted from the skin of the EMU.
The formulation of a complex carbohydrate with a
natural or synthetic essential oil should be adequate to
form an emulsion, suspension, solution, cream or ointment at
the time of application. A liquid formulation will not be
effective if the oil is separated from the aqueous phase.
However, a suspension or solution that may be resuspended by
shaking prior to application is acceptable for use. Any
cream or ointment base that does not interfere with the
effectiveness of the active ingredients may be included in
the formulation. Therefore, one embodiment of this
invention is a cream base containing at least one complex
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carbohydrate and at least one essential oil. Another
embodiment is an ointment base containing at least one
complex carbohydrate and at least one essential oil. One
preferred embodiment is a liquid or gel formulation in an
aqueous base that contains at least one complex carbohydrate
and at least one essential oil. A significant advantage of
this liquid formulation is that the preparation is not
greasy or oily, does not leave a greasy or oily film on the
skin and does not leave a lingering odor on the skin. The
most preferred embodiment is a liquid or gel formulation in
an aqueous base that contains at least one complex
carbohydrate as the sole active ingredient.
The complex carbohydrates of the present invention can
also be prepared as a solid and incorporated into bandages.
Preferably a 1% solution is used. It can be embedded into
the bandage material remaining moist, or dried. It can also
be formulated into a solid polymer by addition of cross-
linking agents. The latter may be applied to open wounds or
to scars to assist with the healing process and/or reduce
scar formation.
The treatment of irritated or inflamed mammalian tissue
by direct topical application requires a dose or total dose
regimen effective to reduce or alleviate the results of the
trauma. It is preferred to administer at least about
0.000001 mg/Kg of body weight of each ingredient over the
site of trauma at least once per day or as often as
necessary. The components of this formulation are
naturally-occurring substances and are safe when applied
topically. There is no inherent upper limit to the tolerable
dose. However, as in all medicinal treatments it is prudent
to use no more than is necessary to achieve the desired
effect. It has been noted that more intense inflammation
and pain require more dose applications for relief. A dose
of 100 mg/Kg of body weight has been used safely and could
serve as an upper limit for use. Similar dose regimens are
recommended for wound healing whereas the pharmaceutical
composition is applied on the wound until adequate promotion
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of granulation of the wound has occurred and healing is
complete.
A convenient topical application formulation is a
combination of one or more complex carbohydrates such as
polysaccharides, oligosaccharides, or glycosaminoglycans at
a total concentration of between 0.1% and 5% wt/vol. These
can be used without a transdermal carrier or with a
transdermal carrier including one or more essential oils.
If essential oils are used, they are preferably combined
with the complex carbohydrates at a total concentration of
between 0.5% and 20% vol/vol with the remainder of the
formulation being made up of a liquid, cream or ointment
base. The liquid base may be aqueous.
A preferred embodiment of the topical formulation is a
combination of one or more glycosaminoglycans at a total
concentration of between 0.1% and 5% wt/vol with one or more
essential oils at a total concentration of between 0.5% and
5% vol/vol with the remainder of the formulation being a
cream, ointment or aqueous base.
A more preferred embodiment of the invention is a
combination of equal amounts of two or more molecular weight
ranges of glycosaminoglycans(one below 30,000 and one above
500,000) at a combined concentration of between 0.5% and
3.0% wt/vol with two or more essential oils having a total
concentration of between 0.5% and 5.0% vol/vol with the
remainder of the formulation being an aqueous, cream or
ointment base.
The most preferred embodiment of the topical
formulation is a combination of hyaluronic acid (sodium
hyaluronate or hyaluronan) with a molecular weight <30,000
with hyaluronic acid with a molecular weight between 100,000
and 500,000 or >750,000 at a total hyaluronic acid
concentration of between 0.5% and 3.0% wt/vol and an
essential oil selected from the group comprising Rosemary
Oil, Tea Tree Oil, Wintergreen Oil, Eucalyptus Oil, Menthol
and Camphor at a concentration of between 1.0% and 3.0%
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vol/vol with the remainder of the formulation being DI
water.
Preferred complex carbohydrates include heparin,
preferably low molecular weight, hyaluronic acid,
chondroitin sulfate, dermatan sulfate, keratan sulfate, and
acemannan (active ingredient of Aloe Vera).
Preferred essential oils include Tea Tree Oil, Rosemary
Oil, Eucalyptus Oil, Wintergreen Oil, Sage Oil, Jojoba Oil,
White Pine Oil, Camphor Oil, Cinnamon oil, Oil of Clove,
Spearmint Oil, Peppermint Oil, EMU Oil and Menthol.
The oral and mucosal formulations of the present
invention include any of the complex carbohydrates listed
above, alone or in combinations, whereby the formulation is
administered as a form selected from the group consisting of
a liquid, an emulsion, a suspension, a cream, an ointment, a
gel, a foam, a spray, a solid, a powder and a gum. It is
contemplated that the liquid or solid could be added to a
drink or drink mix, to food, be a part of a soft drink or
any other type of carbonated drink, a supplement drink, used
as a mouthwash, or added to a mouthwash, as a toothpaste, as
a gargle, as a spray, added to a vaporizer, as a liquid
center of a gum or throat lozenge, added to a food, cookie
or treat, or used in any other way so as to retain the
effectiveness of the complex carbohydrate. A gel form can
include a gel applied by mouth, to the gums, to the tongue,
under the tongue, to the eyes, to the nose, to the vaginal
area or vagina, or to the rectum. A foam could be added to
wounds, to the mouth, to the gums, to the vagina or any
other mucous membrane. A solid can be incorporated into
food, treats such as candy or treats for animals, a chewing
gum, a dissolvable gum, a lozenge, capsules, tablets,
dissolvable tablets, suppositories, a bandage and any other
form that would not damage the effectiveness of the complex
carbohydrates or the essential oils, if used in the
formulation. Other additives may be added to said oral
formulations to improve taste and palatability or enhance
the flavor. For instance, treats for horses may include
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sugar, flavorings such as apple or peppermint or a liquid or
gel may be applied to a sugar cube, food or other treat.
Treats for dogs may include liver, apple, peppermint, yeast
or any other palatable flavoring.
The same formulations as mentioned for oral use can be
used for mucosal delivery of the complex carbohydrates. The
only limitation is that the formulation remain in contact
with a mucosal surface for a period of at least 2 to 10
seconds.
Although the complex carbohydrates may be added to
foods that are then baked, it is preferred to add the
complex carbohydrates to the surface of the food after
baking is complete. This retains the greatest activity.
It is contemplated that the complex carbohydrates of
the present invention may be added to nutritional
supplements to enhance their effectiveness. For instance, a
mixture of complex carbohydrates and zinc, zinc gluconate,
zinc gluconate glycine could be used for more effective
treatment of sore throat and colds. A mixture of the
complex carbohydrates of this invention and capsicum may
produce an even more effective treatment for joint pain and
swelling. Addition of vitamins, minerals and other
nutritional additives may produce enhancement of the
nutritional activity by the complex carbohydrates.
The most recent theory to explain the significant
neurological degeneration that occurs in Alzheimer's Disease
involves a substantial inflammatory component (SCIENCE, vol:
286, 17 December, 1999, pgs 2352-2355) which appears to be
related to the Adhesion cascade. Therefore, the present
inventors have determined that the complex carbohydrates of
this invention can be used to prevent and/or treat
Alzheimer's Disease. For example, it is contemplated that
hyaluronic acid, salts or derivatives thereof could be
administered daily as a preventative for Alzheimer's
Disease. Amounts from lmg/day to 20 mg/day should prevent
the degradation apparent in Alzheimer's Disease. This could
be taken orally. Preferably, it would be taken mucosally.
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Acute Alzheimer's Disease could be treated by parenteral
injection. Alternately, a mixture of hyaluronic acid and
chondroitin sulfate could be administered daily for
prevention or treatment of Alzheimer's Disease. Again, the
daily dose would preferably be less than a total of 100 mg.
The significant neurological degeneration that occurs
after spinal cord injuries leading to irreparable paralysis,
is attack by the leukocytes rushing to the site of trauma
(via the mechanism of the adhesion cascade) to help repair
the traumatized area, but instead, degrading the ends of the
nerves in the spinal cord, fraying them which effectively
inhibits their potential realignment and partial or complete
repair. Paralysis resulting from spinal cord injuries may be
prevented or treated effectively using the complex
carbohydrates of this invention. In this case, since the
patient may not be able to take an oral medication, the
medication may be administered mucosally using suppositories
(rectal or vaginal) or parenterally, injecting IN, SC, or
delivering IV. The dose may need to be higher, in the range
of 20 to 1, 000 mg per day. Drugs to assist repair of nerves
would preferably be administered concurrently.
The invention is further illustrated but is not
intended to be limited by the following examples.
EXAMPLE 1
An 18 year old female suffered from chronic
fibromyalgia localized in the face and neck. This condition
had existed for approximately 5 years. There was nothing
that provided relief for her condition. Prior to use of the
compositions of the present invention, she had taken pain
relievers, acupuncture, and numerous other procedures to
treat, her condition. Nothing had provided substantial
relief without severe side effects. She was given a
formulation containing a mixture of high and low molecular
weight 1% sodium hyaluronate. This formulation was prepared
from hyaluronic acid powder obtained from Collaborative
Laboratories, Inc. which was made up to a 1% s,olution in
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deionized, distilled water. One half of the final 1%
solution was removed and its molecular weight was broken
down by alkaline hydrolysis. The pH was adjusted to between
11 and 14 using 1ON NaOH. Then the solution was heated
while mixing at a temperature between 37 and 50 C. When a
molecular weight of between 10,000 and 50,000 was obtained
as measured by viscosity (Brookfield Viscometer), the pH was
adjusted back to neutral (between 6.0 and 7.0). The final
mixture was then prepared by combining 1 liter of this low
molecular weight preparation with 1 liter of the original 1%
solution (high molecular weight of > 1 X 106) of sodium
hyaluronate. The patient was instructed to take this
formulation orally, holding the liquid in the mouth for
several seconds to allow mucosal adsorption before
swallowing it. She took 10 mg two times per day (AM and
PM). This represented a dose of approximately 0.2 mg/Kg.
She reported that after only 1 day, her symptoms were
greatly improved. After one week of daily use, she reported
essentially no pain. She has continued to take the same
dose for 6 months and has reported no return of her
fibromyalgia as long as she takes the formulation.
Therefore, a condition that has historically remained
untreatable, and which appears to be related to the adhesion
cascade and, perhaps, to allergies has been shown to be
treatable with the compositions of the present invention.
EXAMPLE 2
A 9 year old male suffering from severe Attention
Deficit Hyperactivity Disorder (ADHD) complicated by
Turret's Syndrome, who was being treated by diet control
with little success, was given a sample of the mixture used
in EXAMPLE 1. This treatment was not complicated by
concurrent treatment with drugs such as Ritalin as his
parents were adverse to using this medication. Therefore,
any response observed was related to the use of the complex
carbohydrates of the present invention. He took 10 mg in the
morning and 10 mg in the evening, using the solution as a
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mouthwash (holding it in his mouth for about 10 to 20
seconds and then swallowing). His parents kept very strict
records of his activity and noted that his Turret's Syndrome
was fully controlled and he suffered no tics while taking
the sodium hyaluronate. The one day that he forgot to take
his morning dose he had a recurrence of his tics and became
almost uncontrollable. However, within 15 minutes of his
receiving the missing dose, he became calm and returned to
normal. This boy has remained totally under control for 6
months. This had never been observed before, even when he
was taking Ritalin. He had discontinued taking Ritalin 1.5
year before because of problems with side effects. The
sodium hyaluronate provided no adverse reactions or side
effects. It has been concluded that a disease typically
thought to be related to a nervous disorder or to allergies
was treatable by the complex carbohydrates of the present
invention.
EXAMPLE 3
A 60 year old male and 55 year old female (brother and
sister) who routinely suffered severe sunburns the first few
times that they were in the sun each summer, had been taking
oral sodium hyaluronate gel for treatment of pain associated
with a cervical disc stenosis (male) and chronic
osteoarthritis of both knees (female). Pain from the
conditions being treated was totally controlled by taking 5-
10 mg twice per day. This dose represented 0.14 and 0.18
mg/Kg respectively. The sodium hyaluronate gel was prepared
by adding sodium hyaluronate (Collaborative Laboratories,
Inc) to deionized, distilled water to a 1% concentration.
Preservatives selected from methyl paraben (0.17%),
propylparaben (0.025%) and propylene glycol (10%) were added
to maintain sterility of the liquid preparation. The pH of
this preparation was between 6 and 8 and the preparation had
a molecular weight of >1,000,000. The gel was being applied
directly on the tongue by dropper bottle. Both went on
vacation together and spent most of 5 days in the bright sun
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in a boat. They did not use a sun blocker. Each previous
year both had suffered severe discomfort from sunburn after
the first day's exposure. This time, at the end of the 5
days, both noted that they were not sunburned, had suffered
no discomfort and were developing a nice tan. It is
concluded that the preparation of this invention prevented
sunburn, allowing tanning to occur. Additionally, it was
noted that the formulation of this invention was able to
control the pain associated with cervical disc degeneration
and osteoarthritis. All such conditions are associated with
the adhesion cascade, confirming that diseases and
conditions associated therewith are preventable or treatable
by the complex carbohydrates of the present invention.
EXAMPLE 4
A 60 year old male suffering from colon cancer had been
unable to tolerate his colostomy and demanded that his
surgeon remove the colostomy and reconnect his colon. He
refused chemotherapy. He was given a formulation of 1%
sodium hyaluronate (Collaborative Laboratories, Inc) which
was prepared with a mixture of molecular weights of
hyaluronate (as described in EXAMPLE 1). When he began
taking the hyaluronate preparation, his CEA was 70.1. He
has taken the hyaluronate at a dose of 10 mg three times per
day mucosally and after 6 months of treatment his CEA has
dropped to 4.1. He has taken no other treatments. This
patient had also suffered from polymyositis for
approximately 15 years. For this condition he was taking 50
mg of Prednisone daily with little relief. He reported that
after 1 week of taking the hyaluronate preparation of the
present invention, he felt significant relief from the pain
caused by his polymyositis. After 6 months of treatment
with hyaluronate, he has been able to reduce his Prednisone
to 5 mg every other day. His physician has reported that
his polymyositis has gone into remission. This treatment of
cancer demonstrates the successful use of the complex
carbohydrates of the present invention to treat a disease
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associated with the metatastic cascade. The polymyositis
that was successfully treated in this example was thought to
represent treatment of a disease associated with the
adhesion cascade or autoimmune disease.
EXAMPLE 5
The subject adult was a 48 year old female who had
suffered all her life with attention deficit disorder (ADD).
She never knew what her problem was until recently when
she was diagnosed. She described her childhood as unfocused
and explained that she felt as though she was in a constant
mental fog -- unable to think clearly, or for that matter,
unable to focus on a thought at all. She found that she had
allergies to almost everything including most foods (dairy
products, wheat and corn, sugar, corn syrup, etc.) and most
environmental inhalants, the worst being mold. Exposure to
only a few minutes in a moldy room caused this individual to
become dazed, unable to think, focus or even stay awake. She
had only been able to do menial jobs. She spent most of her
time staring out the window with no thoughts in her mind
and, even if she tried, could not focus on a thought or
task. She described herself as believing all her life that
she was just stupid and unable to learn. She had been to
multiple physicians and psychiatrists seeking treatment with
no success. She had taken Ritalin with little relief. It
allowed her to function partially but she was always tired
and unable to focus on anything but the simplest of tasks.
She agreed to take the oral sodium hyaluronate product and
her family would report how she reacted. She did not believe
that she could record her own responses because she was
unable to concentrate long enough for such a task. She was
initially provided low molecular weight sodium hyaluronate
(<30,000), prepared as described in EXAMPLE 1. She began by
taking 20 mg 3 to 4 times per day. Within five days of the
start of treatment, she reported that she could focus enough
to write a note about how she felt each day. As she was on
the instant composition longer, her notes became more
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coherent and within about 10 days she was able to determine
exactly which foods caused her the most problems and which
environmental exposures caused the major difficulty. She
discovered that various types of foods were actually
producing her "mental fog" reaction, an anger reaction,
welts on her face and neck and even anaphylaxis. After 30
days of taking the sodium hyaluronate oral formulation, she
described her response as follows: "Before starting the
oral formulation, I was in a continual state of feeling
tired, foggy, feeling cold, having rashes and welts all
over, and having a 'tight head'. I couldn't function well
enough to drive or hold any type of job. I now believe that
I know what a normal person must feel like. I'm having
longer periods of well being, energy and clear thinking.
Each week I have seen a progression of positive responses.
This is the first time I have been able to define periods of
allergic reaction. I can observe when reactions start and
end. I'm not using nasal spray (Flonase) in the morning when
I wake up or, especially before I go to bed. Before starting
the oral formulation, I had to use this spray before bedtime
or I would wake up in the middle of the night, coughing and
choking with a lot of phlegm. I am able to start and finish
projects. I have even been able to work crossword puzzles -
- something that I could never even look at prior to
treatment. My quality of life is far superior than ever
before. I have been offered a real job at an advertising
agency. I feel like I can handle the job and do not get
frustrated and spacey. I am also able to drive a car --
something that I haven't done for at least 15 years."
Figure 1 plots the response of this patient while
taking the compositions of the present invention. It is
based on the patient's own description of her average daily
activities and reactions. The scale runs from a -30 (a
reaction in which the patient responded in a manner wherein
she was unable to function or focus on any activity) to +30
(energy, clear-thinking, able to focus, feel great). If
there were no significant negative or positive responses
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during a day, the reaction rate was recorded as 0. The
graph clearly demonstrates that the oral glycosaminoglycan
(sodium hyaluronate) improved this patient's quality of life
and reduced the reactions (after eating or exposure to
environmental reactants). Toward the latter part of
treatment, this patient was provided with a high molecular
weight (>1,000.000) oral hyaluronate formulation. Her
family reported an immediate lack of response that continued
during the time when she continued to take this formulation.
She was unable to work or drive a car during this period of
time. After 9 days on the high molecular weight formulation
she was switched to a formulation that contained a mixture
of molecular weights of hyaluronate (as described in EXAMPLE
1). This formulation was prepared by mixing 3 parts of low
molecular weight (<30,000) with 1 part of high molecular
weight (>1,000,000). She demonstrated an immediate positive
response that has continued. She has reported that whereas
while taking the low molecular weight hyaluronate she felt.
extremely energetic and capable of doing anything and
everything, when she ate or was exposed to something that
caused her significant problems, she suffered from extreme
"crashes". These "crashes" were observed by the inventor
and would be described as a catatonic state in which this
patient did not respond. She sat and stared into space or
fell asleep. While. taking the mixed molecular weight
hyaluronate, she was not experiencing "highs" or "crashes".
Instead, she maintained a feeling of focus, felt good and
was capable of completing her work and family tasks as she
thought a normal person would do. As can be observed in the
graph in Figure 1, when the low molecular weight sodium
hyaluronate was replaced with high molecular weight sodium
hyaluronate (without the patient's knowledge) the patient
reported a total lack of efficacy. When she was placed back
on the mixed molecular weight preparation, she returned to a
state where she was functioning well, had excess energy and
was able to focus. This individual has now periodically
replaced the sodium hyaluronate with liquid 5% chondroitin
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sulfate. The positive response continued while taking this
low dose chondroitin sulfate.
EXAMPLE 6
The patient from EXAMPLE 5 did experience 2
anaphylactic reactions after eating certain foods containing
corn syrup or being exposed to mold. During such reactions
she would become catatonic and collapse. After the first
such reaction, a pharmaceutical grade low molecular weight
sodium hyaluronate (approximately 350,000 MW) was
administered intramuscularly. She was observed for her
response. Within 10 minutes she became conscious and was
able to speak haltingly. She was unable to focus well on
the conversation. Within 30 minutes she appeared normal and
was able to carry on a coherent, intelligent conversation.
She had no idea what had happened.
When a similar anaphylactic reaction occurred at a
later date, it was decided to treat with oral hyaluronate.
She again was catatonic and unconscious. Approximately 1 mL
of low molecular weight (<30,000) sodium hyaluronate was
applied under her tongue and around her gums. This
treatment brought an initial response of consciousness
within 30 minutes. Halting speech without the ability to
focus occurred by 45 minutes post treatment. By 60 minutes
post treatment she was able to carry on a focused
conversation and appeared normal. This demonstrates that a
glycosaminoglycan such as hyaluronate can be used to treat
anaphylaxis when administered either parenterally or
orally/mucosally.
EXAMPLE 7
The subject child was a 9 year old male who has
suffered with ADHD all his life. He had demonstrated
learning disabilities compounded with behavioral problems.
He was described as unable to focus, did not read, write or
draw. Additionally, his-behavior was such that he could not
socialize with other children or with adults. When in
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contact with other children he was unable to play, often
became angered and caused physical harm to others. He had
been under treatment by several physicians, psychologists
and allergists all his life but none were able to help his
condition. The allergists determined that he had allergies
to most all foods, dust, molds, soaps and just about
everything in his environment. At one time he was
prescribed Ritalin daily. However, while taking this drug
he suffered hallucinations and became even more
uncontrollable. At the time that he began treatment
according to the present invention, the physician who was
treating him was convinced that his ADHD was related to his
severe allergies. Eating a certain food, such as corn,
immediately produced anger and rage in this child. Similar
responses were noted after eating or being exposed to other
foods or mold.
This boy attended a special school in which his
Teachers reported his daily activity to his parents so that
they could try to monitor his eating habits. They provided a
daily numerical score. A score of 100 was excellent. This
child averaged daily scores of 0 to 10, at best. This child
was placed on the low molecular weight oral
glycosaminoglycan, sodium hyaluronate. A dose of 20-30 mg
BID was applied orally in food or drinks. It was added to
rice milk for breakfast and made into icing for cookies for
snacks as he was not cooperative enough to take it on his
own. His response was monitored by using the numerical
score provided by his teachers and averaging it with a
numerical score of his behavior at home provided by his
parents. The child responded positively within a few days.
The average scores plotted in Figure 2, ranged from -40 to
+40. Normal non-aggressive behavior was given a score of 0.
The teachers at school were not informed of this treatment.
Within 5 days of beginning treatment the comments from his
teachers were: "He appears happy, having a good time but
needs direction. Awesome day. Plays well with classmates.
Helps other children who are having problems". His parents
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have commented that he has awakened in the morning and is
happy, cheerful and cooperative in getting ready for school.
This is something that they had not experienced in the past.
He has suffered no adverse reactions from taking the complex
carbohydrates of the present invention. Figure 2 shows the
response of this child to oral low molecular weight
hyaluronic acid. The y axis is a numerical analysis of this
child's ability to cooperate with other children and adults.
If his behavior was belligerent, bossy, angry or non-
cooperative he was scored as a -40 for the day. If his
reactions to foods or environmental stimuli produced such a
response it was recorded as a -40. If he responded as a
normal 9 year old, the score was recorded as 0. If he
responded extraordinarily well, helping other children,
reading quietly, drawing or writing, he was given a score of
+40. It was quite surprising that this child responded
almost immediately becoming "a different child". His parents
had thought that he did not know how to read, write or draw.
Almost automatically, he requested books from the library
and began reading quietly, he began drawing very intricate
drawings and writing poems and stories. He also began
preparing very elaborate meals for his parents (without any
assistance). Figure 2 demonstrates this superior behavior
quite well. It also demonstrates that when treatment was
stopped for approximately 2 weeks, there was a reversion to
his original non-cooperative behavior. Upon restarting the
treatment his behavior improved dramatically. It is thus
clear that the glycosaminoglycans of the present invention
can treat ADHD very effectively. Any route of, administration
may produce similar effects. In the most severe cases, the
treatment would begin with a parenteral injection followed
by oral or mucosal daily doses.
EXAMPLE 8
The patient was a 37 year old female who had suffered
from interstitial cystitis for eight years. She had seen
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many doctors and been to Mayo Clinic to seek treatment that
could provide her with relief. This condition presents as a
constant pain in the bladder that produces "excruciating
pain" and a sensation of an intense need to urinate
(urgency). It appears to be caused by inflammation of the
lining of the bladder. Cysts or sores develop that are
irritated by the urine in the bladder. Since the bladder
cannot empty, there is constant irritation and constant
pain. A recent theory is that the irritation is produced by
allergic reactions to certain foods or drinks and by sexual
intercourse. This patient had been to all types of
physicians and even to the Mayo Clinic to obtain relief from
her pain. She had been taking 100 mg per day of macrodantin
and 20 mg per day of feldene that caused severe side
effects. Additionally, she had taken 200 mg TID of Elmiron
to reduce the inflammation in the bladder lining. This did
not help. In order to sleep she took Prosed/DS, Ultram,
Hydroxyzine HC1, Cardura, Amitriptyline. Sometimes all were
taken at some time during the day or night. Even this
regimen was unable to treat the pain. This patient was
supplied with the mixed molecular weight preparation of
sodium hyaluronate as described in EXAMPLE 1. She was also
supplied with a topical preparation containing 1% wt/vol.
Sodium hyaluronate at a molecular weight of <30,000 combined
with 1% Oil of Wintergreen, 0.5% Spearmint Oil and 0.2%
Peppermint Oil. She took 10mg of the oral preparation 4
times per day. The last dose was taken before going to bed.
Additionally, at bedtime, she rubbed her lower abdomen (over
the bladder) with the topical preparation. She reported
that she was able to sleep at least 6-7 hours without pain
and without the need to get up to urinate. Within a week
after. starting this treatment she was able to discontinue
all other medications. Now, all she requires is 1-2 Tylenol
plus the 'sodium hyaluronate preparation of the present
invention and she has continued to remain pain free. This
demonstrates that inflammation, even in the bladder where
the sodium hyaluronate does not penetrate, can be
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successfully treated with the compositions of the present
invention. The additional fact that the topical preparation
provided "an extra bonus of immediate relief" indicates that
the topical use of the compositions of the present invention
are extremely effective in treating extreme pain. It is
proposed that the allergic reactions that stimulate this
condition were successfully treated to relieve the constant
irritation of the bladder.
EXAMPLE 9
A 49 year old female who was diagnosed with Lupus
Erythematosis 24 years ago, presented with an acute outbreak
of the disease. Her face was covered with eruptions as was
the skin on her forearms. She was also feeling very tired
and complained of general joint pain. She was provided with
a sodium hyaluronate preparation with a molecular weight of
<30,000. She was instructed to initially take 10 to 20 mg
of the liquid TID. She reported that after taking the first
dose, the eruptions on her face began "drying up". By the
third dose the eruptions were significantly reduced and
beginning to heal. Within 3 days, the eruptions had
essentially disappeared. This patient has been treated with
the composition of the present invention for a period of 8
months without a recrudescence of the disease. She also
reported that the constant aching and pain in her joints had
disappeared and she felt 100% improvement.
Lupus Erythematosis is known to be an autoimmune
disease. Therefore, the complex carbohydrate compositions
of the present are able to successfully treat said
autoimmune disease.
EXAMPLE 10
An 80 years old female had been diagnosed with ovarian
cancer that had spread to the lungs, liver and spleen. She
refused chemotherapy. She was told that she had 3 weeks at
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most to live. She was provided treatment with the complex
carbohydrate compositions of the present invention. When
first provided with oral/mucosal sodium hyaluronate of mixed
molecular weights (prepared according to the methods
described in EXAMPLE 1), she had not eaten in 6 months and
was unable to keep anything down, she was in extreme
discomfort from extensive build up of fluids in the abdomen
and chest and pain in the legs and feet which were extremely
swollen. She was on an IV solution to restore fluids since
she could not drink liquids. She was instructed to place as
much as possible of the oral preparation in her mouth and
let it absorb under her tongue. This was to be repeated as
often as possible. Within 2 weeks she was able to eat small
amounts of food. At this time, she received injections of
10 mg doses of sodium hyaluronate three times per week. Her
condition continued to improve. As of this writing, she
continues to improve, eats better each day and has survived
for 4 months. She has received no chemotherapy and no other
treatments. She indicates that she feels stronger each day
and has been able to begin sitting in a chair and standing
up. She has indicated that she has no pain since beginning
to take the oral complex carbohydrates of the present
invention. This demonstrates that even a terminal cancer
patient who was near death can respond to treatment with the
complex carbohydrate compositions of the present invention.
EXAMPLE 11
A 38 year old male had suffered from high blood
pressure most of his adult life. He had tried taking
numerous drugs to treat his condition with little to no
success. He agreed to try a complex carbohydrate of this
invention to determine whether it might have a positive
effect. He was supplied with a 1% solution of sodium
hyaluronate formulation with a molecular weight range
between 10,000 and 50,000. He took 10mg in the morning and
10mg in the evening. Sometimes he supplemented with a 10mg
dose after lunch if he was having a particularly stressful
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day. The patient's weight was 163 lbs. Therefore, each
dose was 0.06 mg/Kg. Table 1 shows the results. The
patient's blood pressure ranged around 160/115 prior to
treatment. Within three days of starting treatment his
blood pressure was dropping. By one week post initiation of
treatment, his blood pressure was within the normal range.
It has remained well within the normal range for six months
during treatment with the complex carbohydrates of this
invention. It is evident that high blood pressure can be
effectively treated with the complex carbohydrate
formulations of the present invention.
Table 1 Treatment of High Blood Pressure with Sodium
Hyaluronate
Day BP, Prior to BP 5 min BP 1 hours post BP 2 hours
medication Post medication post
medication medication
-3 168/121 N/A N/A N/A
-2 166/119 N/A N/A N/A
-1 169/121 N/A N/A N/A
0 167/119 N/A N/A N/A
1 166/114 160/100 142/98 140/88
2 160/100 154/110 150/104 141/89
3 158/90 154/100 143/89 144/89
4 148/98 144/99 140/89 139/85
5 149/99 143/87 140/80 139/78
6 150/87 145/89 139/85 138/77
7 146/86 144/89 135/78 136/79
8 139/78 136/87 135/78 139/81
9 135/85 136/76 133/79 139/78
10 138/87 133/77 134/77 133/78
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11 137/76 139/88 138/79 141/87
12 137/88 137/89 134/80 135/77
13 136/77 136/78 133/76 134/75
14 137/79 134/81 133/75 133/75
15 138/77 133/76 132/78 135/74
16 133/74 133/77 134/77 132/68
17 140/78 139/76 133/76 133/77
18 133/76 8/78 32/75 133/78
19 135/75 131/73 131/75 133/74
20 133/76 131/74 133/73 132/76
30 134/74 135/76 134/71 135/74
180 133/78 135/78 136/73 133/72
BP = Blood Pressure
EXAMPLE 12
An eleven year old Labrador retriever had suffered from
lick granulomas for at least 3 years. This condition of
dogs are reportedly caused by nervousness wherein the dog
continues to lick a certain site until an open wound is
produced. Licking is continued and the open wound becomes
significantly irritated and swollen. This dog's granuloma
was located on the left hind leg above the pasturn. The
swelling around the leg measured 8 inches in diameter and
the open wound measured 4 X 3 inches. The dog had been
treated with cortisone injections and hydrocortisone 'creams
with little success. This dog was injected with 10 mg of
sodium hyaluronate having a molecular weight ranging from
30,000 to 400,000 (1.0 mL intramuscularly - equivalent to 10
mg). The open wound began to heal. This injection was
followed up with topical application of a low molecular
weight hyaluronic acid prepared by making a 1% (wt/vol)
solution of hyaluronic acid (Medea Ltd) containing 1%
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Wintergreen Oil (Loranne Oil), 1% Spearmint Oil (Loranne
Oil) and 0.5o Peppermint Oil (Loranne Oil) . The topical
formulation was applied at least two times per day. Over a
period of 2 months the lick granuloma healed completely and
the swelling reduced to a diameter of 3 inches. The dog has
not' licked this area since treatment began. Therefore, the
complex carbohydrates of the present invention are able to
successfully treat lick granulomas (a previously untreatable
condition of dogs) and eliminate the cause of the licking.
EXAMPLE 13
Dogs often develop areas on their skin that become
irritated and that they lick until the area is raw and
oozing. Often these areas become infected with normal flora
(bacteria) on the skin. Additionally, the hair around the
area is usually either licked off or sloughs off. These
areas are termed "hot spots". They are extremely difficult
to treat and are thought to be caused by allergies to foods
or environmental stimuli. Treatment generally includes
cortisone by injection or by mouth followed by antibiotics
(oral or topical) to treat the complication of bacterial
infection. Three dogs with severe hot spots were treated
with the complex carbohydrates of the present invention. Dog
#1 had a large hot spot on the top of the head (diameter 3 X
2 inches) and smaller ones around the muzzle area. Dog #2
had a large hot spot on its back just in front of the tail.
This area measured approximately 6 inches in diameter. Dog
#3 had hot spots down the back of both hind legs and on the
groin area of both hind legs. Parenteral sodium hyaluronate
was administered to Dog #1. This dog received 3 X 10 mg
doses at one week intervals. The hot spot on dog #2 was
treated with topical sodium hyaluronate. The formulation
was the same as that described in EXAMPLE 15. The topical
formulation was applied BID directly on the hot spot. Dog
#3 received sodium hyaluronate administered orally. This
dog received 5 mg BID on its food.
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Hot Spots: Reports on the treatment progress were made by
the owners and are shown in Table 2. Table 2 indicates that
all of the treatments were effective. It appears that the
parenterally administered sodium hyaluronate was slightly
more effective than the orally or topically administered
product. However, all were more effective than the previous
treatments used. Additionally, none of the dogs have had
recurrent hot spots, even one year after the initial
treatment.
Table 2 Response of Dogs with Hot Spots to Treatment with
Sodium Hyaluronate
Days Post
Treatment Dog #1 Dog #2 Dog #3
Initiation
1 NC NC NC
2 Dog Quit Licking NC Dog Quit Licking
3 Drying Dog Quit Licking Drying
4 Same Same Same
5 Healing Well Drying Healing Well
6 Same Same Same
7 Same Same Same
8 Significantly Healing Well Significantly
improved Improved
9 Same Same Same
10 Same Significantly Same
Improved
11 Size now 1 inch Same Same
in diameter
12 Same Size now 2 Size now 1 inch
inches in in diameter
diameter
13 Essentially Same Same
healed
14 Same Size now 1 inch Essentially
in diameter healed
Hair growing Essentially Hair growing
back healed back
16 Hair growing Hair growing Hair growing
back back back
17 Same Same Same
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18 Same Same Same
19 Same Same Same
20 Completely Can still see a Hair almost
healed slight lesion grown back
21 No new lesions Same Same
22 Same Completely Completely
healed healed
23 Same Same Same
24 Same Same Same
25 Same Same Same
26 Same Same Same
27 Same Same Same
28 Same Same Same
29 Same Same Same
NC = No Change
EXAMPLE 14
An 83 year old female suffered from chronic eczema --
scaly and red areas on her neck and arms. She had also been
diagnosed with a yeast infection associated with the eczema.
She had tried all types of treatments, including cortisone
with no significant effect. She initially used a topical
preparation prepared according to this invention. This
contained a mixture of low and high molecular weight sodium
hyaluronate (prepared as in EXAMPLE 1) mixed with 1%
Wintergreen Oil, 1% Spearmint Oil, and 0.5% Peppermint Oil.
She applied it topically for four weeks. She noted that the
bright redness of the eczema subsided. However, there was
still itching and redness. She then began to orally take
the 1% mixture of low and high molecular weight sodium
hyaluronate described in example 1. She reported that
within 2 weeks all signs of the eczema had disappeared, the
itching was gone and she felt better than she had felt for
years. The oral dose required was 5 mg TID for this 91
pound female. Therefore, the dose was 0.05 mg/Kg. This
demonstrates that the complex carbohydrates of the present
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invention is effective in treating severe cases of eczema
even when they are complicated with a yeast infection.
EXAMPLE 15
In order to determine whether low doses of other
complex carbohydrates taken orally or mucosally could show
effects similar to hyaluronic acid, 3 patients presenting
with Lupus Erythematosis, interstitial cystitis and high
blood pressure were treated with oral liquid chondroitin
sulfate. None of these patients had taken chondroitin
sulfate previously. A 5% (wt/vol) solution of chondroitin
sulfate (Infinity Laboratories, Inc) without essential oils
was prepared. This was dispensed into 30 ml bottles and
provided to the three patients with instructions to take 1.0
mL orally BID, holding it in the mouth for approximately 10
seconds prior to swallowing it. This represented a dose of 5
mg BID. The weight of the two patients were 155 lbs and 128
lbs, respectively. Therefore, the doses administered were
0.07 mg/Kg and 0.09 mg/Kg. This provided relief (within 15
minutes). However, the relief lasted only 1-3 hours. The
patients reported that they had to take the chondroitin
Sulfate solution three to five times per day to obtain
successful treatment. After two months of this regimen, the
patients were given a mixture of the 5% chondroitin sulfate
and 1% high molecular weight hyaluronic acid. They were
instructed to take this as often as necessary. Each
reported that this product was effective when taken only 2
times per day and the effect lasted from 8 to 10 hours for
the Lupus patient and for the interstitial cystitis patient.
This demonstrates that a mixture of low and high molecular
weight complex carbohydrates is more effective and that
significantly lower doses (100 to 1000 fold less than
currently suggested for OTC use) of chondroitin sulfate are
required for more effective treatment of Lupus
Erythematosis, interstitial cystitis and high blood
pressure. Chondroitin sulfate is widely known and used in
tablets for arthritis. However, it is used for such
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treatment at very high doses (greater than 1000 mg per day).
We have found that very low concentrations when administered
in liquid form orally, mucosally or topically, is more
effective than the higher doses in a powder form.
Additionally, the inventors are not aware of any use of
chondroitin sulfate for any of our other indications of the
treatments and diseases listed.
EXAMPLE 16
A 55 year old female and a 56 year old male felt that
they were coming down with a cold. Both had oral sodium
hyaluronate prepared as described in EXAMPLE 1 available to
them and began taking a 3 to 5 mg dose orally every 3 to 4
hours. They commented that the pain of the sore throat was
gone within 15 minutes of taking the oral preparation.
Additionally, the cold seemed to be very mild and quickly
progressed through the normal stages, each stage being much
milder than normal for these individuals. The female
reported that her cold lasted only 4 days as compared with
her historical colds that lasted 21 to 24 days. The male
reported that he seldom noticed the symptoms of his cold and
felt fine in 3 to 4 days. Historically, his colds lasted
approximately 14 days. These results indicate that the
complex carbohydrates of the present invention reduce the
symptoms of colds and that they have anti-viral activity.
EXAMPLE 17
In order to determine whether scar tissue could be
reduced by application of the complex carbohydrates of the
present invention. Sodium hyaluronate having a molecular
weight range of between 10,000 and 2 million was formulated
so that it could be used as a scar reduction patch. The
formulation was prepared as follows: To 50 mL of 1% sodium
hyaluronate (Medex Ltd) was added 7 grams of alphy-hydroxy
acid. The solution was mixed until a clear solution was
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produced. Then 20 mL of USP Glycerol was added and this was
mixed to homogeniety. Finally, 1% sodium hyaluronate was
added to QS the volume to a total of 100 mL. After the
final HA addition, the solution thickened and was spread
evenly on the bottom of a petri dish. It was allowed to dry
for 48 hours at room temperature after which it was used to
treat a fresh scar produced as a result of reconstructive
surgery on the left hand of a 50 year old female patient.
The solidified HA was cut into a shape slightly larger than
the scar. It was applied over the scar and held in place by
applying an ace bandage. Approximately 1/2 of the scar was
left untreated so as to serve as a control. The Bandage was
allowed to remain over the scar for a period of 2 weeks.
Intermittently, the HA patch was removed and the scar was
cleaned. If the solidified HA patch dried out, it was
moistened slightly with water and reapplied. After only two
weeks of application the raised scar tissue (adhesion) had
essentially disappeared. This demonstrates that scar
reduction can be accomplished by use of the complex
carbohydrates of the present invention.
EXAMPLE 18
In order to determine whether open wounds could be
stimulated to heal faster, gauze was soaked in 1% sodium
hyaluronate having a molecular weight range from 30,000 to
500,000 and allowed to dry. This HA-containing gauze was
applied to open wounds of the following types: 1) a rug
burn produced by sliding on artificial turf on a football
field; 2) a surgical wound resulting from a hip
replacement; and 3) a cut finger resulting from a piece of
broken glass. The bandages were kept on the wounds until
they were healed well enough to remain uncovered. It was
reported that the rug burn was healed within 3 days. This
compared with a 2 week healing period normally experienced
by this patient. The surgical wound healed within 5 days,
again almost 10 days sooner than expected. The cut finger
was healed within 3 days. The conclusion was that a
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glycosaminoglycan is very effective in stimulating wound
healing when incorporated into gauze and used as a bandage.
EXAMPLE 19
Ten patients taking oral preparations of 1% sodium
hyaluronate (1 taking low molecular weight ranging (from
10,000 to 300,000), 4 taking medium molecular weight
(ranging from 100,000 to 600,000), and 5 taking high
molecular weight (ranging from 500,000 to 2 million),)
reported separately that they had noticed the following
positive effects in addition to the treatment effects for
which they were taking the complex carbohydrate. They were
impressed in the increased cognitive effects that they
noticed. They reported that their memory had significantly
improved as had their ability to focus on information and
tasks (cognitive function). Additionally, each reported
that they experienced thickening of their hair and
fingernails as well as improvement in their skin condition
(their skin was more supple and the wrinkles in their face
were reduced). These effects resulted directly from the use
of the complex carbohydrates of the present invention.
EXAMPLE 20
Four of the patients taking oral or mucosal complex
carbohydrates (1 taking 5% chondroitin sulfate and three
taking 1% sodium hyaluronate with a molecular weight range
from 30,000 to 500,000) have reported that, prior to taking
the complex carbohydrates of the present invention, they had
been plagued with repeated vaginal yeast infections. All
had been suffering from yeast infections at the initiation
of the present treatment. They were not taking other
medications to treat these yeast infections. All four
patients reported that their yeast infections disappeared
within 3 to 7 days of beginning treatment with the complex
carbohydrates of the present invention. They have remained
on the present treatments for approximately 14 months and
have remained yeast infection free. It is concluded that
CA 02417867 2006-10-25
WO 02/09723 PCT/USO1/41473
49 -
the complex carbohydrates of the present invention are able
to treat and/or prevent yeast infections.
Although the invention has been described in detail in
the foregoing, for the. purpose of illustration it is to be
understood that such detail is solely for that purpose and
that variations can be made therein by those skilled in the
art without departing from the spirit and scope of the
invention except as.it may be limited by the claims.
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