U.S. patent application number 09/780237 was filed with the patent office on 2001-08-16 for treatment of osteoarthritis by administering poly-n-acetyl-d-glucosamine.
This patent application is currently assigned to Lescarden, Inc.. Invention is credited to Gracy, Robert W., Sherman, William T..
Application Number | 20010014671 09/780237 |
Document ID | / |
Family ID | 21867188 |
Filed Date | 2001-08-16 |
United States Patent
Application |
20010014671 |
Kind Code |
A1 |
Sherman, William T. ; et
al. |
August 16, 2001 |
Treatment of osteoarthritis by administering
poly-N-acetyl-D-glucosamine
Abstract
The methods of the present invention relate to administering to
a mammal afflicted with osteoarthritis an effective amount of
poly-N-acetyl-D-glucosamine (poly-NAG), partially depolimerized
poly-NAG, pharmaceutically acceptable salts of poly-NAG, or
mixtures thereof, to treat osteoarthritis and/or alleviate the
symptoms of osteoarthritis such as pain, joint tenderness and
swelling and impaired joint mobility. The present invention also
comprises solid and liquid pharmaceutical dosage forms comprising
poly-NAG, its pharmaceutically acceptable salts and mixtures
thereof. These dosage forms may be administered orally and
by-injection to treat osteoarthritis and/or alleviate the symptoms
thereof.
Inventors: |
Sherman, William T.;
(Hendersonville, NC) ; Gracy, Robert W.; (Fort
Worth, TX) |
Correspondence
Address: |
DARBY & DARBY P.C.
805 Third Avenue
New York
NY
10022
US
|
Assignee: |
Lescarden, Inc.
|
Family ID: |
21867188 |
Appl. No.: |
09/780237 |
Filed: |
February 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09780237 |
Feb 9, 2001 |
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09467252 |
Dec 20, 1999 |
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09467252 |
Dec 20, 1999 |
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08990161 |
Dec 12, 1997 |
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6117851 |
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60032855 |
Dec 13, 1996 |
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Current U.S.
Class: |
514/62 ;
514/54 |
Current CPC
Class: |
A61P 19/02 20180101;
A61K 31/722 20130101; A61K 31/726 20130101 |
Class at
Publication: |
514/62 ;
514/54 |
International
Class: |
A61K 031/715 |
Claims
What is claimed is:
1. A method of treating osteoarthritis in mammals comprising
administering to a mammal in need of such treatment an effective
amount for treatment of osteoarthritis of a member selected from
the group consisting of a poly-N-acetyl-D-glucosamine (poly-NAG), a
pharmaceutically acceptable derivative of poly-NAG, and mixtures
thereof.
2. The method according to claim 1, wherein said material is said
poly-N-acetyl-D-glucosamine (poly-NAG).
3. The method according to claim 1, wherein said pharmaceutically
acceptable derivative of poly-NAG is selected from the group
consisting of hydroxy lower alkyl poly-NAG, carboxy lower alkyl
poly-NAG, a salt of carboxy lower alkyl poly-NAG, lower alkyl
poly-NAG, poly-NAG acetate, poly-NAG nitrate, poly-NAG citrate, and
poly-NAG phosphate.
4. The method according to claim 1, which comprises administering
said effective amount orally.
5. The method according to claim 1, which comprises administering
said effective amount by injection.
6. The method according to claim 4, wherein said effective amount
is between about 100 and about 10,000 mg/day.
7. The method according to claim 5, wherein said effective amount
is between about 100 and about 10,000 mg/day.
8. The method according to claim 1, wherein said mammal is a
human.
9. A method of alleviating the symptoms of osteoarthritis in
mammals comprising administering to a mammal suffering from such
symptoms a therapeutically effective amount of a material selected
from the group consisting of a poly-N-acetyl-D-glucosamine
(poly-NAG), a pharmaceutically acceptable derivative of poly-NAG,
and mixtures thereof, to alleviate at least one of the symptoms of
osteoarthritis.
10. The method according to claim 9, wherein said material is said
poly-N-acetyl-D-glucosamine (poly-NAG).
11. The method according to claim 9, wherein said pharmaceutically
acceptable derivative of poly-NAG is selected from the group
consisting of hydroxy lower alkyl poly-NAG, carboxy lower alkyl
poly-NAG, a salt of carboxy lower alkyl poly-NAG, lower alkyl
poly-NAG, poly-NAG acetate, poly-NAG nitrate, poly-NAG citrate, and
poly-NAG phosphate.
12. The method according to claim 9, which comprises administering
said effective amount via the oral route.
13. The method according to claim 12, wherein said effective amount
is between about 100 and about 10,000 mg/day.
14. The method according to claim 9, which comprises administering
said effective amount in a solid dosage form.
15. The method according to claim 9, which comprises administering
said effective amount by injection.
16. The method according to claim 9, wherein said mammal is a
human.
17. A pharmaceutical dosage form comprising a material selected
from the group consisting of a poly-N-acetyl-D-glucosamine
(poly-NAG), a pharmaceutically acceptable derivative of poly-NAG,
and mixtures thereof.
18. The pharmaceutical dosage form according to claim 17, wherein
said material is said poly-N-acetyl-D-glucosamine (poly-NAG).
19. The pharmaceutical dosage form according to claim 17, wherein
said pharmaceutically acceptable derivative of poly-NAG is selected
from the group consisting of hydroxy lower alkyl poly-NAG, carboxy
lower alkyl poly-NAG, a salt of carboxy lower alkyl poly-NAG, lower
alkyl poly-NAG, poly-NAG acetate, poly-NAG nitrate, poly-NAG
citrate, and poly-NAG phosphate.
20. The pharmaceutical dosage form of claim 17, wherein said dosage
form is a solid oral dosage form selected from the group consisting
of a tablet, a capsule, a pellet and a powder.
21. The pharmaceutical dosage form of claim 17, wherein said dosage
form is a suspension for oral administration.
22. The pharmaceutical dosage form of claim 17, wherein said dosage
form is an injection.
Description
[0001] This application claims priority pursuant to 35 U.S.C.
.sctn.119 from U.S. Provisional Application Ser. No. 60/032,855
filed Dec. 13, 1996, the entire disclosure of which is hereby
incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention relates to methods for treating
osteoarthritis in mammals using pharmaceutical formulations
comprising poly-N-acetyl-D-glucosamine (poly-NAG), a
pharmaceutically acceptable derivative of poly-NAG, or mixtures
thereof. The invention also relates to solid and liquid
pharmaceutical dosage forms for oral and by-injection
administration of poly-NAG and its derivatives.
BACKGROUND OF THE INVENTION
[0003] Osteoarthritis is a degenerative joint disease affecting
articular cartilage developing in the fourth and fifth decades of
life that was initially believed to be a disease of wear and tear
due to mechanical stress on the joints. It is now known that the
pathology of osteoarthrosis is not entirely mechanical and involves
changes in the joint metabolism. Specifically, altered glucosamine
metabolism appears to play a key role in the development of
osteoarthritis.
[0004] An effective treatment of osteoarthritis must address two
types of problems: (i) pain, and joint tenderness, swelling and
stiffness must be alleviated as an immediate patient's problem; and
(ii) the degenerative process must be stopped preferably at its
earlier stages. Treatment with anti-rheumatics and nonsteroidal
anti-inflammatory drugs has not proven successful. Anti-rheumatics,
although quickly effective, were recently shown to impair the very
function that physicians were trying to improve, and
anti-inflammatory drugs alleviate the pain but do not address the
underlying degenerative disorder.
[0005] Recent biochemical and pharmacological studies have
suggested a novel and more effective treatment of osteoarthritis.
These studies have shown that administration of glucosamine tends
to normalize cartilage metabolism, inhibiting degradation, and
stimulating the synthesis of proteoglycans resulting in partial
restoration of the articular function. The therapeutic
effectiveness of a treatment with glucosamine has been demonstrated
in a number of animal and human studies.
[0006] Glucosamine is a building block of the ground substance of
the articular cartilage, the proteoglycans. Glucosamine is also the
preferential substrate and a stimulant of proteoglycan
biosynthesis. Furthermore, glucosamine inhibits the degradation of
proteoglycans and rebuilds the experimentally damaged cartilage.
Based on these findings, different types of glucosamine were
introduced in the therapy of osteoarthritis. The clinical
experience with preparations containing glucosamine derivatives
confirmed the efficacy and the safety of the glucosamine treatment.
The following is a brief summary of recent developments concerning
the use of glucosamine sulfate to treat osteoarthritis.
[0007] Glucosamine sulfate is an artificially synthesized salt of
glucosamine. Based on animal models, glucosamine sulfate has the
potential to slow the degeneration of cartilage by stimulating
cartilage cells to synthesize glucosamine, glycans and
proteoglycans, the building components of cartilage. See Setnikar
et al., Anti-Arthritic Effects of Glucosamine Sulfate Studied in
Animal Models, Drug Research, 41:542-549 (1991). This study has
also reported that glucosamine sulfate has anti-inflammatory
properties by acting through a mechanism that inhibits the activity
of proteolytic enzymes.
[0008] In the early 1980s, a number of small controlled human
trials were conducted to study the clinical use of glucosamine
sulfate in the treatment of osteoarthritis. Scientists evaluated
glucosamine sulfate both as a symptomatic treatment and as a basic
therapy to slow the underlying degenerative process. See Vaz, A.
L., Double Blind Clinical Evaluation of the Relative Efficacy of
Ibuprofen and Glucosamine Sulfate in the Management of
Osteoarthritis of the Knee in Out-patients, Curr. Med. Res. Opin.,
8:145-149 (1982); Vajaradul, Y., Double Blind Clinical Evaluation
of Intra-Articular Glucosamine in Outpatients with Gonarthrosis,
Clin. Therapeutics, 3:336-343 (1981); Pujalte, A. M., et al.,
Double Blind Clinical Evaluation of Oral Glucosamine Sulfate in the
Basic Treatment of Osteoarthrosis, Curr. Med. Res. Opin.,
7:1010-1014 (1980); Crolle, G. and D'Este, E., Glucosamine Sulfate
for the Management of Arthrosis: A Controlled Clinical
Investigation, Curr. Med. Res. Opin., 7:104-109 (1980).
[0009] These studies have shown that administration of glucosamine
sulfate produces significant improvement in the symptoms of pain,
joint tenderness, swelling and mobility. In addition, the treatment
helped restore the patients' cartilage. Furthermore, the treatment
was shown not to have any adverse side effects or undesirable
interactions with other drugs normally used by elderly arthritic
patients.
[0010] Glucosamine sulfate can be administered by interarticular,
intramuscular and intravenous injection as well as orally. See
D'Ambrosio et al., In Glucosamine Sulfate: a Controlled Clinical
Investigation in Arthrosis, Pharmatherapeutica, 2:504-508 (1981).
Vagaradul, Y., Clin. Therapeutics, 3:336-343 (1981), has reported a
combination treatment using both intramuscular and oral
administration. In all reported clinical trials oral glucosamine
sulfate was administered at 1.5 g/day. For example, Pujalte teaches
administration of 500 mg of glucosamine sulfate three times a day
for a period of 6 to 8 weeks. Crolle teaches administration of one
intramuscular injection of glucosamine sulfate (400 mg/day) for 7
days followed by oral administration of 500 mg of glucosamine
sulfate three times a day for a period of 14 days. Vaz discloses an
8 week treatment by oral administration of 500 mg of glucosamine
sulfate three times a day. The dose of 1.5 g glucosamine sulfate is
equivalent to about one gram of D-glucosamine base.
[0011] The bioavailability of glucosamine was studied extensively.
A number of studies reported the pharmacokinetics, organ
distribution, metabolism and excretion of glucosamine. The studies
were done in dog, rat and man. See Setnikar, I., et al.,
Phannacokinetics of Glucosamine in the Dog and Man,
Arzneim-Forsch/Drug Res. 36:729-35 (1986); Setnikar, I. et al.,
Absorption, Distribution and Excretion of Radioactivity After a
Single Intravenous or Oral Administration of [14]C Glucosamine to
the Rat, Pharmatherapeutica, 3:538-50 (1984); Levin, R. et al.,
Glucosamine and Acetyl-Glucosamine Tolerance in Man; J. Lab. Clin.
Med, 59:927-931 (1961); Gaulden, E. C. and Keating, W. C., The
Effect of Intravenous N-acetyl-D-Glucosamine on the Blood and Urine
Sugar Concentration of Normal Subjects, Metabolism, 13:466-472
(1964); Kohn P. et al., Metabolism of D-Glucosamine and
N-acetyl-D-Glucosamine in the Intact Rat, J. Bio. Chem.,
237:304-307 (1962); Weiden, S. and Wood, I. J., The Fate of
Glucosamine Hydrochloride Injected Intravenously in Man, J. Clin.
Path. 11:343-349 (1958).
[0012] These studies have shown that glucosamine is found in the
plasma immediately after intravenous administration, from where it
readily diffuses into organs and tissues. See Setnikar et al.
(1986). In both dog and man, glucosamine disappears quickly from
plasma, usually after 30 to 60 minutes, and gets incorporated into
.alpha. and .beta., globulins. The protein incorporation of
glucosamine reaches a peak after 8 hours and slowly disappears,
having a half-life of 2.9 days. The glucosamine is excreted 34% in
urine mainly as glucosamine and 1.7% in the feces. It is also
degraded and excreted as CO.sub.2. The liver and kidney show
significant incorporation of glucosamine. In addition, the
articular cartilage shows an active uptake. Setnikar also teaches
that the distribution of glucosamine after oral administration is
similar to the distribution after the intravenous administration.
In addition, these studies have shown that N-acetyl-D-glucosamine
(NAG) metabolizes in the body to glucosamine.
[0013] Other studies have also shown that the half-life of
glucosamine in the blood is relatively short due to its degradation
and/or incorporation into other bodily compounds. See Gaulden and
Keating; Weiden et al.; and Levin et al. Accordingly, it is
difficult to maintain adequate therapeutic levels in vivo which
requires prolonged treatments and multiple daily
administrations.
[0014] It has now been surprisingly discovered that
poly-N-acetyl-D-glucosamine (poly-NAG), can be used as a source of
glucosamine to treat osteoarthritis and/or alleviate symptoms
thereof. This is surprising since it is generally known that
poly-NAG is highly resistant to chemical attack except that of a
most drastic nature. Furthermore, it was surprisingly discovered
that individuals who ingest poly-NAG have higher serum levels of
NAG and glucosamine. Poly-NAG maintains these serum levels for a
longer period of time than when NAG is ingested alone and therefore
provides a longer lasting source of glucosamine for the treatment
of osteoarthritis. Thus, treatment with poly-NAG offers unexpected
advantages over the prior art treatments with glucosamine and
NAG.
[0015] In addition, poly-NAG, which need not be highly refined and
purified, is considerably cheaper than glucosamine and NAG.
According to the 1995 Sigma Chemical Company catalogue, the price
of poly-NAG (chitin) is $55/kg, while glucosamine and NAG cost
$86/kg and $391/kg, respectively. Commercial quantities of poly-NAG
suitable for ingestion may be obtained at an even lower price
($25/kg). Accordingly, treatment with poly-NAG also offers the cost
advantages over the prior art treatments with glucosamine and
NAG.
BRIEF DESCRIPTION OF THE INVENTION
[0016] It has now been surprisingly discovered that
poly-N-acetyl-D-glucosamine (poly-NAG) can be used to treat
osteoarthritis. Furthermore, it has also been surprisingly
discovered that individuals who ingest poly-NAG have higher serum
levels of NAG and glucosamine for a longer period of time than the
individuals who ingest a comparable amount of NAG alone. Poly-NAG
thus increases the observed time that NAG and glucosamine remain in
the serum and accordingly provides clinically proven beneficial
therapeutic properties of glucosamine for a longer period of time.
Thus, treatment of osteoarthritis with poly-NAG is superior to the
treatment with glucosamine or NAG taught by the prior art.
[0017] One object of the present invention is to provide a method
for treating osteoarthritis in mammals by administering to a mammal
in need of such treatment an effective amount of poly-NAG for
treatment of osteoarthritis.
[0018] Another object of the present invention relates to a method
of alleviating the symptoms of osteoarthritis in mammals, such as
pain, joint tenderness and swelling, and impaired joint mobility,
by administering poly-NAG to a mammals having such symptoms in an
amount effective to alleviate at least one of the symptoms of
osteoarthritis.
[0019] A further object of the invention is to provide a method of
treating osteoarthritis and/or alleviating the symptoms thereof in
mammals by administering orally poly-NAG, its pharmaceutically
acceptable salts, or mixtures thereof, to a mammal in need of such
treatment in an amount effective to treat osteoarthritis and/or
alleviate the symptoms thereof.
[0020] A still further object of the invention is to provide a
method of treating osteoarthritis and/or alleviating the symptoms
thereof in mammals by injecting a mammal in need of such treatment
with poly-NAG, its pharmaceutically acceptable salts, or mixtures
thereof, in an amount effective to treat osteoarthritis and/or
alleviate the symptoms thereof. The injection may be intravenous,
intramuscular, intra-articular or subcutaneous.
[0021] Yet another object of the invention relates to a method of
treating osteoarthritis and/or alleviating the symptoms thereof by
combining the oral and by-injection administrations of
poly-NAG.
[0022] An additional object of the invention relates to solid and
liquid dosage forms containing poly-NAG, its pharmaceutically
acceptable salts, or mixtures thereof, and adapted for oral or
by-injection administration.
[0023] These and other objects of the present invention will be
apparent from the detailed description of the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0024] FIG. 1 is a chart illustrating the effect of the oral
ingestion of NAG or poly-NAG on serum NAG levels. Blood sample
values for subjects that ingested NAG are represented by closed
circles. Blood sample values for the subjects that ingested
poly-NAG are represented by open squares.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The methods of the present invention relate to administering
to a mammal afflicted with osteoarthritis an effective amount of
poly-N-acetyl-D-glucosamine (poly-NAG), partially depolimerized
poly-NAG, pharmaceutically acceptable salts of poly-NAG, or
mixtures thereof, to treat osteoarthritis and/or alleviate the
symptoms of osteoarthritis such as pain, joint tenderness and
swelling and impaired joint mobility.
[0026] The products of the present invention comprise solid and
liquid pharmaceutical dosage forms for oral and by-injection
administration comprising poly-NAG, its pharmaceutically acceptable
salts and mixtures thereof. These dosage forms may be administered
orally and by-injection to treat osteoarthritis and/or alleviate
the symptoms thereof.
[0027] As used herein, poly-NAG refers to
poly-N-acetyl-D-glucosamine, pharmaceutically acceptable salts of
poly-N-acetyl-D-glucosamine, and mixtures thereof.
[0028] Poly-NAG is a polysaccharide, also known as chitin, which
forms the cell walls of fungi and the hard cells of insects and
crustaceans. Poly-NAG, is nontoxic and very inexpensive. It has now
been surprisingly found that poly-NAG provides a longer lasting
source of blood NAG (N-acetyl-D-glucosamine) in humans as compared
to administration of comparable amounts of NAG. The NAG is known to
degrade in the body of a mammal to glucosamine. This is a result of
a slow degradation of poly-NAG which thus becomes a continuous
source of NAG monomers, NAG dimers, other oligomers and glucosamine
monomers. The fact that poly-NAG would be degraded in the blood to
NAG and glucosamine was not readily apparent given that poly-NAG is
highly resistant to chemical degradation.
[0029] Poly-NAG has been previously used in the form of ground
chitin to promote wound healing as taught by Balassa in U.S. Pat.
Nos. 3,632,754; 3,903,268; 3,911,116; and 3,914,413.
[0030] Poly-NAG used in the present invention may be naturally
occurring (extracted from fungi or shells) or synthetic. Suitable
natural sources of poly-NAG are from lobsters, shrimp and other
crustacea as well as from fungal origin. The non-limiting examples
of useful fungi that can be used as a useful source of chitin are
Mucor spinosus, Aspergillus niger, Penicillium and
Cryptococcus.
[0031] Methods of preparing natural chitin, i.e., poly-NAG, are
taught by Balassa in U.S. Pat. Nos. 3,903,268; 3,911,116 and
3,914,413 and J. Ornum, Infofish International, 6:48-52 (1992).
[0032] Poly-NAG derivatives are also within the scope of the
invention. The poly-NAG derivatives contemplated are materials such
as ethers formed with pharmaceutically acceptable radicals and
esters or salts with pharmaceutically acceptable acids. Examples of
suitable derivatives include hydroxy lower alkyl poly-NAG such as
hydroxyethyl poly-NAG, carboxy alkyl poly-NAG such as carboxymethyl
poly-NAG, salts of carboxy lower alkyl poly-NAG such as the zinc
salt, lower alkyl poly-NAG such as methyl poly-NAG and ethyl
poly-NAG, poly-NAG acetate, poly-NAG nitrate, poly-NAG citrate,
poly-NAG phosphate, N-acyl derivatives derived from monocarboxylic
aliphatic acids such as N-formyl, N-acetyl, N-propionyl, N-caproyl,
etc.
[0033] Combinations of the therapeutically effective agents
described above with poly-NAG and/or poly-NAG derivatives may be
administered to treat osteoarthritis according to the present
invention. Pharmaceutical dosage forms containing these materials
in combination with poly-NAG and its derivatives are within the
scope of this invention.
[0034] To treat osteoarthritis and/or alleviate its symptoms,
poly-NAG may be administered orally or by injection. Oral poly-NAG
may be in the form of a liquid as a suspension, or alternatively in
solid form as a tablet, pellet, powder or capsule. Poly-NAG may be
also administered by injection, i.e., intravenously,
intramuscularly, intraarticularly or subcutaneously in the form of
a sterile suspension.
[0035] Liquid pharmaceutical dosage forms for oral administration
of poly-NAG such as suspensions of poly-NAG in pharmaceutically
acceptable liquids are within the scope of the invention and may be
prepared according to conventional techniques well known in the
art. Satisfactory pharmaceutically acceptable liquids include
water, sugar suspensions, and aqueous glycols which may be
compounded with coloring agents and synthetic or natural
flavors.
[0036] Solid dosage forms for oral administration of poly-NAG, such
as pellets, capsules, tablets or powder can also be used in
practicing the present invention. The tablets and capsules may be
prepared in accordance with conventional procedures in which
poly-NAG is combined with the well known pharmaceutical excipients
such as starch, sugar, bentonite clays, and other commonly used
carriers.
[0037] To prepare dosage forms to be administered by injection it
is necessary to prepare a dispersion of poly-NAG in a
pharmaceutically acceptable liquid. Colloidal suspensions of
poly-NAG may be prepared using the method described by Lingappa and
Lockwood in Nature, 189:158 (1961). Aqueous dosage forms for
subcutaneous, intravenous and intraarticular administration are
prepared by admixing poly-NAG in a suitable sterile mixture of
pharmaceutical materials commonly used for compounding injectable
suspensions (preferably 1 to 10%). The sterile extract may contain
preservatives such as methyl and/or propyl paraben.
[0038] Modifications of the above-described dosage forms for oral
and by-injection administration of poly-NAG will be apparent to
those skilled in the art and are considered to be within the scope
of this invention.
[0039] The quantity of effective dose supplied by each capsule,
tablet or injection is relatively unimportant since the total
dosage can be reached by administration of either one or a
plurality of liquid doses, capsules or tablets, or both, or by one
or more injections.
[0040] The methods of the present invention relate to treatment
and/or alleviation of the symptoms of osteoarthritis by
administering orally or by injection a pharmaceutically effective
amount of poly-NAG to a mammal in need of such treatment and/or
suffering from such symptoms. The effective amount of administered
poly-NAG depends upon the severity of condition, the stage of the
disease and the individual inflammatory characteristics of a mammal
being treated. Generally, an effective amount of poly-NAG
administered orally is in the range from about 100 milligrams to
about 10,000 milligrams of poly-NAG per day and preferably from
about 100 to about 2,500 milligrams per day. It is especially
preferred to administer about 1,500 mg per day. A preferred mode of
oral administration of poly-NAG is in a solid oral dosage form (as
a tablet, capsule or pellet) although aqueous suspensions or syrup
formulations are employed with success.
[0041] An effective amount of poly-NAG administered by intravenous
or subcutaneous injection is from about 100 to about 10,000 mg of
poly-NAG a day and preferably from about 100 to about 1,000 mg per
day. The effective amount for intraarticular injection is generally
one tenth of the amount used for intravenous injection because
poly-NAG is delivered directly to the affected joint.
[0042] The oral and by-injection administration may be combined in
the same treatment. The treatment with poly-NAG can also be
combined with other therapies for treating osteoarthritis or other
degenerative skeletal diseases such as analgesics (narcotics and
non-narcotics), commercial and experimental therapeutic agents as
well as medical devices used for such treatments. Modifications of
these regimens will be apparent to those skilled in the art.
[0043] Daily doses for both the oral and by-injection treatments
can be administered once a day or a number of times per day.
[0044] The duration of the treatment by the compositions of the
invention depends on the patients condition and will be apparent to
those skilled in the art. For example, administration within the
dosage levels described above may go on for between about 2 to
about 8 weeks, and preferably from between about 4 to about 6
weeks. The treatment at these dosage levels is continued until
there is a noticeable amelioration of the patient's condition at
which time daily doses may be reduced by one half. Thus, a patient
receiving the preferred oral dose of 500 milligrams per day would
be treated at this dosage level until there was a noticeable (at
least 25% improvement) amelioration of symptoms (as measured by
increased range of motion, i.e., joint mobility, decreased level of
pain, decreased swelling in affected joints, decreased joint
tenderness) at which time the patient's daily doses would be
reduced to 250 mg of poly-NAG. The 250 mg/day dose would be
continued until the patient's symptoms (i.e., joint tenderness,
swelling etc.) went into remission. Treatments may be repeated as
required by the patient's condition.
[0045] Given the detailed disclosure and guidance in the present
specification, those skilled in the art can optimize, using routine
testing, effective amounts of poly-NAG, administration regimens and
the duration of treatment to suit the needs of individual patients.
The mammals that may be treated with the present invention include
humans as well as animals including cats, horses and dogs.
[0046] The dosage forms, effective amounts and administration
schedules are generally the same for treating and alleviating the
symptoms of osteoarthritis. Generally, the following symptoms are
monitored: pain, joint tenderness and swelling, and joint mobility.
The treatment is generally continued until at least one of the
symptoms is alleviated, and then continued at a reduced dose until
all symptoms are in remission. Given the detailed guidance in this
specification, one skilled in the art would know how to optimize
the invention to suit the individual patient's symptoms. Any such
modifications are considered to be within the scope of this
invention.
[0047] The following are non-limiting examples that show the manner
of using poly-NAG to treat and/or alleviate symptoms of
osteoarthritis.
EXAMPLE 1
[0048] Poly-NAG Increases Serum NAG Levels and Hydrolyses to
Glucosamine in vivo
[0049] Ten normal, healthy subjects (five men and five women ages
36-50) were randomly divided into two groups (designated as A and
B). On Day-1 a fasting blood sample was collected from each
patient. Following this, group A orally ingested 1.0 gram of NAG
and group B ingested 1.0 gram of poly-NAG. On Day-2 the subjects
again ingested one gram of the appropriate test substance before
breakfast. On the third day a fasting blood sample was taken at
time T=0. Subsequently, they consumed the final 1.0 gram of the
appropriate test substance, and nonfasting blood samples were taken
at 1, 2, 4, and 8 hours. Fasting blood samples were taken at 24 and
48 hours thereafter. On Days 4-7 the subjects did not consume any
of the test material, but continued their normal diets. On Day-8,
after a fasting blood sampling, the groups were switched (i.e.,
group A took poly-NAG while group B consumed NAG) and the same
procedure as shown above was repeated.
[0050] The data were analyzed using analytical HPLC procedure based
on published methods for amino sugar analysis. The chromatographic
system consisted of a Hewlett-Packard 1090M Liquid
Chromatograph/Work Station equipped with a Diode Array Detector.
Separation was by isocratic elution at 40.degree. C. from a
300.times.7.8 mm Rezex Organic Acid Column (Phenomenex; N>75000
P/m) with 0.005N H.sub.2SO.sub.4 at a flow rate of 0.6 ml/min. The
analytical conditions had been developed for resolution of the
aminosugar/acetylated aminosugar components of physiological
fluids, and the diode array detector was optimized at 193 nm for
maximum sensitivity and minimum interference. The system was
calibrated with standards before, during and after the study to
assure there were no significant changes due to wear and tear or
aging of the system. The chromatographic data were transferred to a
spreadsheet and statistically tested with ANOVA (Single Factor,
Two-Factor without Replication, Two-Factor with Replication) and
paired T-tests.
[0051] Table 1 summarizes the concentrations of NAG in serum
following ingestion of 1.0 g per day of either NAG or poly-NAG.
1TABLE 1 (nanomoles per ml of serum) NAG-Ingestors
POLY-Nag-Ingestors Time Avg +SD Avg +SD Pre 10.3 4.4 13.4 7.0 T0
15.4 8.7 23.0 18.3 T1 18.2 10.0 15.6 6.0 T2 21.0 18.4 24.3 19.9 T4
22.9 16.7 23.7 20.8 T8 14.6 9.3 13.8 10.4 T24 13.6 12.0 18.6 14.1
T48 12.7 8.3 23.0 13.2
[0052] However, due to individual differences and because subjects
were not fasting in the T=1 through T=8 hour periods, it is more
informative to view the quantitative responses of each individual.
For example, comparison of serum NAG levels at T=0 with the pretest
values showed that 65% of the subjects (13/20) increased serum NAG
concentrations. The NAG-ingestors and poly-NAG-ingestors were
essentially equal (6/20 and 7/20, respectively). Since the T=0
sample was taken in the morning before taking the "final dose" of
the drug, another important comparison was between the pretest
value and the T=1 hour value. In this case, 70% of subjects (14/20)
showed an increase in serum NAG (6/20 for poly-NAG ingestors and
8/20 for NAG ingestors). These data establish that ingestion of
either NAG or poly-NAG results in absorption and elevation of serum
NAG.
[0053] Upon cessation of ingestion of NAG or poly-NAG, the levels
of serum NAG did not immediately return to the prior baseline
levels (FIG. 1). At 24 hours following cessation of ingestion of
either NAG or poly-NAG, only 20% of the subjects (4/20) showed
decreased serum NAG levels. At 48 hours after ceasing the dietary
supplement, 55% of the subjects still showed higher levels of serum
NAG than at the pretest. These data show that clearance of the NAG
is not complete by 48 hours. More importantly, when patients
ingested poly-NAG as compared to NAG, the serum levels of NAG were
at a higher level and remained elevated for a longer period of time
in the patients that took poly-NAG. (FIG. 1).
[0054] Since glucosamine can arise from the hydrolysis
(deacetylation) of NAG and is a normal breakdown product of NAG,
serum glucosamine levels were also measured. The serum glucosamine
levels during the washout period were elevated at 24 and 48 hours
over the pretest values. For example, at 48 hours the serum
glucosamine levels were elevated 10.2% and 12.8% over the pretest
levels for the NAG-ingestors and poly-NAG ingestors, respectively.
These data show that the orally administered NAG and poly-NAG are
hydrolyzed to glucosamine prior to further metabolism or
excretion.
[0055] The patients reported no side effects, the compliance with
the protocol was maintained without problems and there were no
differences in responses between males and females.
EXAMPLE 2
[0056] Treatment/Alleviation of Symptoms of Osteoarthritis by Oral
Administration of poly-NAG
[0057] Twenty patients with osteoarthritis are randomly divided in
two groups designated as group A and group B. Group A is orally
administered before breakfast three tablets comprising poly-NAG
each containing 500 mg of poly-NAG. Poly-NAG is administered each
day for a period of 6 weeks. No other analgesic, antirheumatic or
anti-inflammatory drugs are administered at the same time. Group B
is administered lactose placebo. Pain and joint swelling,
tenderness and mobility are monitored in both groups and compared.
The treatment is repeated as needed depending on the individual
condition of each patient.
EXAMPLE 3
[0058] Treatment/Alleviation of Symptoms of Osteoarthritis by
Intravenous Administration of poly-NAG
[0059] Twenty patients with osteoarthritis are randomly divided in
two groups designated as group A and group B. Group A is
administered one injection a day containing 500 mg of poly-NAG. The
treatment is repeated every day for a period of 6 weeks. No other
analgesic, antirheumatic or anti-inflammatory drugs are
administered at the same time. Group B is administered a saline
solution. Pain and joint swelling, tenderness, and mobility are
monitored in both groups and compared. The treatment is repeated as
needed depending on the individual condition of each patient.
* * * * *