U.S. patent application number 11/241248 was filed with the patent office on 2006-04-27 for nutritional supplement compositions.
Invention is credited to Patrick Cadet, Kirk J. Mantione, George B. Stefano, Wei Zhu.
Application Number | 20060088607 11/241248 |
Document ID | / |
Family ID | 36143157 |
Filed Date | 2006-04-27 |
United States Patent
Application |
20060088607 |
Kind Code |
A1 |
Stefano; George B. ; et
al. |
April 27, 2006 |
Nutritional supplement compositions
Abstract
Dietary supplement compositions containing one or more compounds
such as arginine, selenium, calcium, calcium sources, morphine
precursors (e.g., reticuline), morphine, and
morphine-6.beta.-glucuronide are provided.
Inventors: |
Stefano; George B.;
(Melville, NY) ; Cadet; Patrick; (Elmont, NY)
; Mantione; Kirk J.; (Patchogue, NY) ; Zhu;
Wei; (West Babylon, NY) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
PO BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Family ID: |
36143157 |
Appl. No.: |
11/241248 |
Filed: |
September 30, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60714769 |
Sep 6, 2005 |
|
|
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60615048 |
Oct 1, 2004 |
|
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Current U.S.
Class: |
424/702 ; 514/23;
514/282; 514/565 |
Current CPC
Class: |
A61P 19/02 20180101;
A61P 29/00 20180101; A61K 31/198 20130101; A61P 9/10 20180101; A23L
33/10 20160801; A61K 33/06 20130101; A61K 31/198 20130101; A61P
25/22 20180101; A23V 2250/1626 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A23V 2250/30 20130101; A61K 2300/00
20130101; A23V 2200/322 20130101; A23V 2250/0606 20130101; A23V
2002/00 20130101; A61K 31/194 20130101; A61K 31/485 20130101; A61K
2300/00 20130101; A23V 2002/00 20130101; A61K 2300/00 20130101;
A61K 31/7052 20130101; A61P 17/00 20180101; A61K 31/485 20130101;
A61K 31/7052 20130101; A61K 33/04 20130101; A61K 33/04 20130101;
A61P 25/00 20180101; A61P 25/16 20180101; A61K 45/06 20130101; A61K
31/472 20130101; A61P 25/28 20180101; A61P 25/30 20180101; A61K
33/06 20130101; A61P 25/24 20180101; A61P 25/18 20180101; A61P
43/00 20180101 |
Class at
Publication: |
424/702 ;
514/023; 514/282; 514/565 |
International
Class: |
A61K 31/7052 20060101
A61K031/7052; A61K 31/485 20060101 A61K031/485; A61K 31/198
20060101 A61K031/198; A61K 33/04 20060101 A61K033/04 |
Goverment Interests
STATEMENT AS TO FEDERALLY SPONSORED RESEARCH
[0002] Funding for the work described herein was provided by the
federal government, which may have certain rights in the invention.
Claims
1. A dietary supplement composition comprising morphine or
morphine-6.beta.-glucuronide in an amount that results in less than
0.05 mg of said morphine or morphine-6.beta.-glucuronide being
administered to a human per kg of body weight of said human.
2. The composition of claim 1, wherein said composition comprises
less than 4.0 mg of said morphine or
morphine-6.beta.-glucuronide.
3. The composition of claim 1, wherein said composition comprises
less than 1.0 mg of said morphine or
morphine-6.beta.-glucuronide.
4. The composition of claim 1, wherein said composition comprises a
morphine precursor.
5. The composition of claim 1, wherein said composition is in the
form of a tablet.
6. The composition of claim 1, wherein said composition comprises
selenium.
7. The composition of claim 1, wherein said composition comprises
L-arginine.
8. The composition of claim 1, wherein said composition comprises a
calcium source.
9. The composition of claim 1, wherein said morphine or
morphine-6.beta.-glucuronide is in an amount that results in less
than 0.025 mg of said morphine or morphine-6.beta.-glucuronide
being administered to said human per kg of body weight of said
human.
10. The composition of claim 1, wherein said morphine or
morphine-6.beta.-glucuronide is in an amount that results in less
than 0.01 mg of said morphine or morphine-6.beta.-glucuronide being
administered to said human per kg of body weight of said human.
11. The composition of claim 1, wherein said composition comprises
morphine.
12. The composition of claim 1, wherein said composition comprises
morphine and morphine-6.beta.-glucuronide.
13. The composition of claim 1, wherein said composition comprises
thebaine, codeine, reticuline, norlaudanosoline, salutaridine,
dopamine, L-DOPA, tyrosine, tyramine, phenylalanine, 3,4
dihydroxyphenyl pyruvate, or dihydroxyphenyl acetaldehyde.
14. A dietary supplement composition comprising morphine and a
compound selected from the group consisting of selenium and
arginine.
15 15. The composition of claim 14, wherein said composition
comprises between 35 .mu.g and 700 .mu.g of morphine.
16. The composition of claim 14, wherein said composition comprises
between 55 .mu.g and 300 .mu.g of selenium.
17. The composition of claim 14, wherein said composition comprises
between 1 mg and 500 mg of arginine.
18. The composition of claim 14, wherein said composition comprises
a calcium source.
19. The composition of claim 18, wherein said composition comprises
between 1 g and 1.3 g of said calcium source.
20. The composition of claim 18, wherein said calcium source is
calcium citrate.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/714,769, filed Sep. 6, 2005 and U.S.
Provisional Application Ser. No. 60/615,048, filed Oct. 1, 2004,
each of which is incorporated by reference in its entirety into
this specification.
BACKGROUND
[0003] 1. Technical Field
[0004] The document relates to nutritional supplement compositions.
For example, this document relates to nutritional supplement
compositions containing one or more compounds such as arginine,
selenium, calcium, calcium sources, morphine precursors (e.g.,
reticuline), morphine, and morphine-6.beta.-glucuronide.
[0005] 2. Background Information
[0006] Many people suffer from conditions such as depression,
neurodegenerative diseases, pro-inflammatory diseases, autoimmune
disorders, and atherosclerosis. In many cases, few, if any,
successful treatments are available for these people.
[0007] Analgesic compounds such as morphine are routinely used to
reduce pain in humans. For example, surgery patients are typically
instructed to take 5 to 10 mg of morphine per person to alleviate
pain caused by the surgical procedure. In some cases, patients
suffering from extreme pain (e.g., bum victims or cancer patients)
are instructed to take higher doses of morphine.
SUMMARY
[0008] This document provides compositions containing one or more
compounds such as arginine, selenium, calcium, calcium sources,
morphine precursors (e.g., reticuline), morphine, and
morphine-6.beta.-glucuronide. For example, this document provides
compositions containing a low dose of morphine (e.g., a dose that
is below that which is given to relieve a mammal of pain). The
compositions provided herein can be used as nutritional supplement
compositions. For example, the compositions provided herein can be
used to provide a mammal with a long-term, low level of morphine
that can allow the mammal to experience behavioral changes (e.g., a
general overall calm feeling). In addition, the compositions
provided herein can be used to provide a mammal with a long-term,
low level of morphine that can allow the mammal to experience
reduced *inflammatory responses and can allow the mammal to
maintain an increased, basal level of constitutive nitric oxide
release. In some cases, the compositions provided herein can be
used to down regulate immune, vascular, neural, and
gastrointestinal tissues via nitric oxide produced within a mammal.
For example, the compositions provided herein can be used to reduce
the excited state of inflamed gastrointestinal tissues in mammals
having Crohn's disease. In some cases, the compositions provided
herein can be used to treat (e.g., reduce the severity of symptoms)
neural conditions (e.g., schizophrenia, chronic pain, mania,
depression, psychosis, paranoia, autism, stress, Alzheimer's
disease, or Parkinson's disease), immune conditions (e.g.,
pro-inflammatory diseases, autoimmune disorders, histolytic
medullary reticulosis, lupus, or arthritis), vascular conditions
(e.g., atherosclerosis or neuronal vasculopathy), gastrointestinal
conditions (e.g., colitis, Crohn's disease, or irritable bowel
syndrome), or addiction (e.g., opiate addiction). For example, a
nutritional supplement composition containing morphine or a
morphine precursor such as reticuline, norlaudanosoline, L-DOPA, or
codeine can be used to treat neural conditions such as
neurovascular alterations involving hypothalamic hormone secretion
(e.g., reproductive and growth hormones).
[0009] In general, the compositions provided herein can include one
or more of the following: arginine, selenium, calcium, calcium
sources, morphine precursors (e.g., reticuline), morphine, and
morphine-6.beta.-glucuronide. As described herein, a long-term, low
level of morphine can be achieved in a mammal by administering a
low dose of morphine, by administering a morphine precursor, or by
administering a combination of morphine and morphine precursors. In
some cases, inhibitors such as dopamine .beta.-hydroxylase
inhibitors can be used to inhibit the dopamine to norepinephrine
step in adrenaline synthesis, which can result in an endogenous
dopamine level increase as well as an endogenous morphine level
increase.
[0010] As disclosed herein, prolonged treatment with a low dose of
morphine can result the continued positive effects of morphine such
as nitric oxide release, without the need to escalate morphine
dosages with time to achieve the same beneficial effects. In
addition, the use of low doses of morphine can allow mammals to
experience the beneficial effects of morphine, while not
experiencing possible negative effects of morphine (e.g., addiction
or powerful analgesia). Likewise, providing mammals with a morphine
precursor such as reticuline can allow mammals to experience the
beneficial effects of morphine, while not experiencing possible
negative effects of morphine (e.g., addiction or powerful
analgesia). For example, using a morphine precursor such as
reticuline can allow patients to receive a low dose of morphine
indirectly with a reduced risk of overdosing.
[0011] In general, one aspect of this document features a dietary
supplement composition comprising, or consisting essentially of,
morphine or morphine-6.beta.-glucuronide in an amount that results
in less than 0.05 mg of the morphine or
morphine-6.beta.-glucuronide being administered to a human per kg
of body weight of the human. The composition can comprise less than
4.0 mg (e.g., 3.0, 2.0, 1.0, 0.5, 0.1, 0.05 mg) of the morphine or
morphine-6.beta.-glucuronide. The composition can comprise less
than 1.0 mg of the morphine or morphine-6.beta.-glucuronide. The
composition can comprise a morphine precursor. The composition can
be in the form of a tablet. The composition can comprise selenium.
The composition can comprise L-arginine. The composition can
comprise a calcium source. The morphine or
morphine-6.beta.-glucuronide can be in an amount that results in
less than 0.025 mg of the morphine or morphine-6.beta.-glucuronide
being administered to the human per kg of body weight of the human.
The morphine or morphine-6.beta.-glucuronide can be in an amount
that results in less than 0.01 mg of the morphine or
morphine-6.beta.-glucuronide being administered to the human per kg
of body weight of the human. The composition can comprise morphine.
The composition can comprise morphine and
morphine-6.beta.-glucuronide. The composition can comprise
thebaine, codeine, reticuline, norlaudanosoline, salutaridine,
dopamine, L-DOPA, tyrosine, tyramine, phenylalanine, 3,4
dihydroxyphenyl pyruvate, dihydroxyphenyl acetaldehyde, or
combinations thereof.
[0012] Another aspect of this document features a dietary
supplement composition comprising, or consisting essentially of,
morphine and a compound selected from the group consisting of
selenium and arginine. The composition can comprise between 35
.mu.g and 700 .mu.g of morphine. The composition can comprise
between 55 .mu.g and 300 .mu.g of selenium. The composition can
comprise between 1 mg and 500 mg of arginine. The composition can
comprise a calcium source. The composition can comprise between 1 g
and 1.3 g of the calcium source. The calcium source can be calcium
citrate.
[0013] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention pertains.
Although methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the
present invention, suitable methods and materials are described
below. All publications, patent applications, patents, and other
references mentioned herein are incorporated by reference in their
entirety. In case of conflict, the present specification, including
definitions, will control. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting.
[0014] Other features and advantages of the invention will be
apparent from the following detailed description, and from the
claims.
DETAILED DESCRIPTION
[0015] This document provides methods and materials related to
nutritional supplement compositions containing one or more of the
following compounds: arginine, selenium, morphine, morphine
precursors (e.g., tyrosine, tyramine, phenyl alanine, 3,4
dihydroxyphenyl pyruvate, dihydroxyphenyl acetaldehyde, dopamine,
L-DOPA, reticuline, norlaudanosoline, salutaridine, thebaine, or
codeine), morphine-6.beta.-glucuronide, inhibitors of morphine
synthesis or activity, or inhibitors of dopamine synthesis. Such
nutritional supplement compositions can be used to treat diseases,
to reduce inflammation, or to restore normal function.
[0016] In one embodiment, this document provides compositions
containing morphine, morphine precursors,
morphine-6.beta.-glucuronide, or combinations thereof. Morphine or
morphine-6.beta.-glucuronide can be formulated into compositions
designed to deliver a low dose of morphine or
morphine-6.beta.-glucuronide to a mammal. Typically, a low dose of
morphine is a dose that is below that which is given to relieve a
mammal of pain. For example, a low dose of morphine can be between
0.5 and 10 .mu.g (e.g., between 1 and 9 .mu.g, between 1 and 8
.mu.g, between 1 and 7 .mu.g, between 1 and 6 .mu.g, between 1 and
5 .mu.g, between 2 and 10 .mu.g, between 3 and 10 .mu.g, between 4
and 10 .mu.g, or between 5 and 10 .mu.g) per kg of body weight per
day. A low level of morphine-6.beta.-glucuronide can be similar to
those of morphine. For example, a low dose of
morphine-6.beta.-glucuronide can be between 1 and 10 .mu.g (e.g.,
between 1 and 9 .mu.g, between 1 and 8 .mu.g, between 1 and 7
.mu.g, between 1 and 6 .mu.g, between 1 and 5 .mu.g, between 2 and
10 .mu.g, between 3 and 10 .mu.g, between 4 and 10 .mu.g, or
between 5 and 10 .mu.g) per kg of body weight per day. In some
cases, morphine or morphine-6.beta.-glucuronide can be formulated
to deliver between 35 and 700 .mu.g of morphine or
morphine-6.beta.-glucuronide for a 70 kg individual. In some cases,
a low dose can be any amount that is high enough to cause cells
within the mammal to release nitric oxide yet low enough to not
cause the mammal to experience analgesia. Such a dose can be,
without limitation, about 5 .mu.g per kg of body weight per
day.
[0017] When given orally, morphine or morphine-6.beta.-glucuronide
can be formulated into a pill or tablet that contains between 10
and 1000 .mu.g (e.g., between 10 and 900 .mu.g, between 10 and 800
.mu.g, between 10 and 700 .mu.g, between 10 and 600 .mu.g, between
10 and 500 .mu.g, between 30 and 1000 .mu.g, between 35 and 1000
.mu.g, between 40 and 1000 .mu.g, between 50 and 1000 .mu.g,
between 35 to 700 .mu.g, or between 35 and 500 .mu.g) of morphine
or morphine-6.beta.-glucuronide. For example, a tablet can be
designed to contain 100 .mu.g of morphine. In these cases, a mammal
weighing about 70 kg can be instructed to take between one and
three pills or tablets per day. Mammals weighing more or less than
70 kg can be instructed to take the appropriate number of pills or
tablets to achieve a similar final concentration. The term
"morphine" as used herein includes dihydromorphine, morphine
sulfate, morphine hydrochloride, and morphine acetate.
[0018] The compositions provided herein can contain one or more
than one (e.g., two, three, four, five, or more) morphine
precursors without containing morphine or
morphine-6.beta.-glucuronide. Examples of morphine precursors
include, without limitation, tyrosine, tyramine, dopamine, L-DOPA,
3,4 dihydroxyphenyl pyruvate, dihydroxyphenyl acetaldehyde,
phenylalanine, reticuline, norlaudanosoline, salutaridine,
thebaine, and codeine. As described herein, a composition can be
designed to contain tyrosine, tyramine, dopamine, L-DOPA, 3,4
dihydroxyphenyl pyruvate, dihydroxyphenyl acetaldehyde,
phenylalanine, reticuline, norlaudanosoline, salutaridine,
thebaine, codeine, or combinations thereof. Such compositions can
contain any amount of the morphine precursors such as an amount
between 1 and 10 mg per person weighing about 70 kg. For example, a
composition can contain between 1 and 10 mg of reticuline.
[0019] The compositions provided herein can contain one or more
(e.g., two, three, four, five, or more) morphine precursors in
addition to morphine or morphine-6.beta.-glucuronide or in addition
to a combination of morphine and morphine-6.beta.-glucuronide. In
some cases, a composition can contain morphine and reticuline.
Compositions containing morphine and a morphine precursor as well
as compositions containing morphine-6.beta.-glucuronide and a
morphine precursor can contain any amount of the morphine precursor
such as between 0.1 and 100 mg (e.g., between 0.1 and 90 mg,
between 0.1 and 75 mg, between 0.1 and 50 mg, between 0.1 and 25
mg, between 0.1 and 10 mg, between 0.5 and 100 mg, between 1 and
100 mg, between 1 and 50 mg, or between 1 and 10 mg) of the
morphine precursor. For example, a composition can contain between
10 and 100 .mu.g of morphine, between 10 and 100 .mu.g of
morphine-6.beta.-glucuronide, and between 1 and 10 mg of
reticuline.
[0020] A composition (e.g., pill or tablet) designed to deliver a
low dose of morphine, designed to deliver a low dose of
morphine-6.beta.-glucuronide, designed to contain one or more
morphine precursors, or designed to contain any combination thereof
(e.g., both morphine and one or more morphine precursors) can be
formulated to contain additional components such as L-arginine,
selenium, and Ca.sup.++. L-arginine can be included to promote a
cell's ability to release nitric oxide in response to morphine via
nitric oxide synthesis from L-arginine metabolism. Selenium can be
added to enhance mu3 opiate receptor gene expression. Calcium
sources such as calcium citrate or CaCO.sub.3 can be added to help
facilitate the metabolism of L-arginine into nitric oxide via a
calcium-dependent constitutive nitric oxide synthase. To reduce
acid reflux problems in oral applications, CaCO.sub.3 can be used
as a calcium source. In some cases, a pill or tablet designed to
deliver a low dose of morphine can be formulated to contain 35 to
700 .mu.g morphine (e.g., 0.1 mg morphine), 1 mg to 500 mg
L-arginine (e.g., 300 mg L-arginine), 55 .mu.g to 200 .mu.g
selenium (e.g., 100 .mu.g selenium), and 1000 to 1300 mg Ca.sup.++
(e.g., 1000 mg Ca.sup.++). In some cases, a pill or tablet can be
formulated to contain 1 to 10 mg reticuline (e.g., 5 mg
reticuline), 1 mg to 500 mg L-arginine (e.g., 300 mg L-arginine),
55 .mu.g to 200 .mu.g selenium (e.g., 100 .mu.g selenium), and 1000
to 1300 mg Ca.sup.++ (e.g., 1000 mg Ca.sup.++). Other components
that can be included in a composition provided herein include,
without limitation, pharmaceutically acceptable aqueous vehicles,
pharmaceutically acceptable solid vehicles, steroids, antibacterial
agents, anti-inflammatory agents, immunosuppressants, dilators,
vaso-constrictors, anti-cholinergics, anti-histamines, antioxidant,
and combinations thereof.
[0021] In some cases, a composition (e.g., pill or tablet) designed
to deliver a low dose of morphine, designed to deliver a low dose
of morphine-6.beta.-glucuronide, designed to contain one or more
morphine precursors, or designed to contain any combination thereof
(e.g., both morphine and one or more morphine precursors) can be
formulated to contain one or more inhibitors of morphine synthesis
(e.g., a CYP2D6 or CYP2D7 inhibitor) or activity (e.g., naloxone),
one or more inhibitors of dopamine synthesis or activity, or
combinations thereof. Examples of CYP2D6 inhibitors include,
without limitation, amiodarone, chloroquine, cimetidine,
clomipramine, diphenhydramine, duloxetine, fluoxetine,
hydroxychloroquin, paroxetine, propafenone, propoxyphene, and
quinidine, terbinafine.
[0022] A pharmaceutically acceptable aqueous vehicle can be, for
example, any liquid solution that is capable of dissolving morphine
or a morphine precursor (e.g., reticuline) and is not toxic to the
particular individual receiving the composition. Examples of
pharmaceutically acceptable aqueous vehicles include, without
limitation, saline, water, and acetic acid. Typically,
pharmaceutically acceptable aqueous vehicles are sterile. A
pharmaceutically acceptable solid vehicle can be formulated such
that morphine or a morphine precursor is suitable for oral
administration. For example, capsules or tablets can contain
reticuline in enteric form. The dose supplied by each capsule or
tablet can vary since an effective amount can be reached by
administrating either one or multiple capsules or tablets. Any well
known pharmaceutically acceptable material such as gelatin and
cellulose derivatives can be used as a pharmaceutically acceptable
solid vehicle. In addition, a pharmaceutically acceptable solid
vehicle can be a solid carrier including, without limitation,
starch, sugar, or bentonite. Further, a tablet or pill formulation
of morphine or a morphine precursor can follow conventional
procedures that employ solid carriers, lubricants, and the
like.
[0023] Steroids can be any compound containing a
hydrocyclopentanophenanthrene ring structure. Examples of steroids
include, without limitation, prednisone, dexamethasone, and
hydrocortisone. An antibacterial agent can be any compound that is
active against bacteria, such as penicillin, erythromycin,
neomycin, gentamicin, and clindamycin. An anti-inflammatory agent
can be any compound that counteracts inflammation, such as
ibuprofen and salicylic acid. An immunosuppressant can be any
compound that suppresses or interferes with normal immune function,
such as cyclosporine. A dilator can be any compound that causes the
expansion of an orifice, such as albuterol. A vaso-constrictor can
be any compound that constricts or narrows blood vessels, such as
phenylephrine hydrochloride, cocaine, and epinephrine. An
anti-cholinergic can be any compound that blocks parasympathetic
nerve impulses, such as ipratropium bromide. An anti-histamine can
be any compound that opposes the action of histamine or its release
from cells (e.g.,.mast cells), such as terfenadine and
astemizole.
[0024] Any method can be used to obtain morphine,
morphine-6.beta.-glucuronide, morphine precursors, or any
additional component of a composition provided herein. In some
cases, the components of the compositions provided herein can be
obtained using common chemical extraction, isolation, or synthesis
techniques. For example, reticuline can be obtained as described
elsewhere (Brochmann-Hanssen and Nielsen, Tetrahedron Lett.,
18:1271-4 (1965) and U.S. Pat. No. 3,894,027). In some cases, the
components of the compositions provided herein can be obtained from
commercial vendors. For example, morphine,
morphine-6.beta.-glucuronide, codeine, norlaudanosoline, and
salutaridine can be ordered from Sigma, Inc.
[0025] Any method can be used to formulate a composition provided
herein. For example, common formulation mixing and preparation
techniques can be used to make a composition having the components
described herein. In addition, the compositions provided herein can
be in any form. For example, a composition provided herein can be
in the form of a solid, liquid, and/or aerosol including, without
limitation, powders, crystalline substances, gels, pastes,
ointments, salves, creams, solutions, suspensions, partial liquids,
sprays, nebulae, mists, atomized vapors, tinctures, pills,
capsules, tablets, and gelcaps. In some cases, the composition can
be a dietary supplement. In some embodiments, a composition
containing morphine, one or more morphine precursors, or a
combination thereof can be prepared for oral administration by
mixing the components with one or more of the following: a filler,
a binder, a disintegrator, a lubricant, and a coloring agent.
Lactose, corn starch, sucrose, glucose, sorbitol, crystalline
cellulose, silicon dioxide, or the like can be used as the filler.
Polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl
cellulose, acacia, tragacanth, gelatin, shellac, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, calcium citrate, dextrin,
or pectin can be used as the binder. Magnesium stearate, talc,
polyethylene glycol, silica, or hardened plant oil can be used as
the lubricant. A pharmaceutically acceptable coloring agent can be
used as the coloring agent. Cocoa powder, mentha water, aromatic
acid, mentha oil, borneol, or powdered cinnamon bark also can be
added. In some cases, a composition containing morphine, one or
more morphine precursors, or a combination thereof can be prepared
for injection by mixing the components with one or more of the
following: a pH adjusting agent, a buffer, a stabilizer, and a
solubilizing agent.
[0026] The compositions provided herein can be administered to any
mammal (e.g., rat, mouse, dog, cat, horse, cow, goat, pig, monkey,
or human). In addition, any route of administration (e.g., oral or
parenteral administration) can be used to administer a composition
provided herein to a mammal. For example, a composition containing
morphine or reticuline can be administered orally or parenterally
(e.g., a subcutaneous, intramuscular, intraorbital, intracapsular,
intraspinal, intrastemal, or intravenous injection).
[0027] While not being limited to any particular mode of action,
the compositions provided herein can be used to increase or
maintain a basal level of nitric oxide release by cells (e.g.,
cells expressing mu3 opiate receptors). The administration of
morphine precursors such as reticuline to a mammal can lead to the
conversion of the morphine precursor into morphine. The morphine
produced from the morphine precursor or the morphine provided
directly by a composition containing morphine or the
morphine-6.beta.-glucuronide provided directly by a composition
containing morphine-6.beta.-glucuronide can activate mu3 opiate
receptors, which are coupled to nitric oxide release, and can down
regulate the activated state of tissues within the mammal making
them less excitable. For example, administering morphine or
reticuline can limit undesired excitation and restore basal
activity levels within a mammal. In addition, certain mammals may
not produce enough endogenous morphine to fulfill the needs of
processes normally using this material to down regulate their
excitatory state (e.g., a run-away pro-inflammatory state, mental
disorders, vascular disorders). Administering a morphine precursor
such as reticuline can provide mammals with the morphine needed to
down regulate excitatory states without administering a controlled
substance. Administering morphine or morphine-6.beta.-glucuronide
directly at a low dose can provide mammals with the morphine needed
to down regulate excitatory states without triggering tolerance to
the administered morphine or morphine-6.beta.-glucuronide. For
example, as described herein, morphine can be administered
chronically (e.g., a long duration) at a low dose without observing
a reduction of morphine's effects (e.g., nitric oxide release) over
time. In addition, administering morphine-6.beta.-glucuronide can
provide mammals with nitric oxide release in the periphery as
opposed to the brain since morphine-6.beta.-glucuronide exhibits a
limited ability to cross the blood brain barrier.
[0028] The compositions provided herein can be administered to a
mammal in any amount, at any frequency, and for any duration.
Typically, a composition provided herein can be administered to a
mammal in an amount, at a frequency, and for a duration effective
to induce nitric oxide release in the mammal. In some cases, a
composition provided herein can be administered to a mammal in an
amount, at a frequency, and for a duration effective to reduce the
severity of a symptom of a disease or condition (e.g.,
schizophrenia, mania, depression, psychosis, chronic pain,
paranoia, autism, stress, Alzheimer's disease, Parkinson's disease,
pro-inflammatory diseases, autoimmune disorders, histolytic
medullary reticulosis, lupus, arthritis, atherosclerosis, neuronal
vasculopathy, or addiction).
[0029] An effective amount of a composition provided herein or of
morphine or of a morphine precursor (e.g., reticuline) can be any
amount that induces cells to release nitric oxide without producing
significant toxicity to the mammal. In some cases, an effective
amount of a composition provided herein or of morphine or of a
morphine precursor (e.g., reticuline) can be any amount that
reduces, prevents, or eliminates a symptom of a disease or
condition upon administration to a mammal without producing
significant toxicity to the mammal. In some cases involving
morphine precursors, an effective amount can be any amount that
results in the production of detectable amounts of morphine within
a tissue sample.
[0030] Again, a composition provided herein can be administered to
a mammal in any amount. In some embodiments, the amount of a
composition provided herein or of morphine or of a morphine
precursor (e.g., reticuline) can be greater than 0.01 mg/kg of body
weight. In some cases, the amount of a composition provided herein
or of morphine or of a morphine precursor (e.g., reticuline) can be
between about 0.01 and about 50 mg/kg (e.g., between about 0.01 and
about 45 mg/kg; between about 0.1 and about 25 mg/kg; or between
about 1 and about 5 mg/kg) of body weight. The effective amount can
vary depending upon the disease to be treated (if any), the site of
administration, and the mammal to be treated. Such effective
amounts can be determined using the methods and materials provided
herein. For example, the level of morphine production can be
assessed using routine experimentation in vitro or in vivo. For
example, a patient having a particular condition can receive 5
mg/kg body weight of reticuline. If the patient fails to respond or
produce morphine, then the amount can be increased by, for example,
ten fold. After receiving this higher concentration, the patient
can be monitored for both responsiveness to the treatment and
toxicity symptoms, and adjustments made accordingly.
[0031] Various factors can influence the actual amount used for a
particular application. For example, the frequency of
administration, duration of treatment, combination of other agents,
site of administration, stage of disease (if present), and the
anatomical configuration of the treated area may require an
increase or decrease in the actual amount administered.
[0032] The frequency of administration of a composition provided
herein can be any frequency. For example, the frequency of
administration can be from about four times a day to about once a
month, or more specifically, from about twice a day to about once a
week. In addition, the frequency of administration can remain
constant or can be variable during the duration of treatment. As
with the amount administered, various factors can influence the
actual frequency of administration used for a particular
application. For example, the amount, duration of treatment,
combination of agents, site of administration, stage of disease (if
present), and the anatomical configuration of the treated area may
require an increase or decrease in administration frequency. In one
embodiment, a composition containing reticuline can be administered
daily at a dose of about 1 to about 5 mg of reticuline per kg of
body weight.
[0033] The duration of administration of a composition provided
herein can be any duration. For example, a duration of
administration of a composition provided herein can be longer than
a week, month, three months, six months, nine months, a year, two
years, or three years. In some cases, an effective duration can be
any duration that reduces, prevents, or eliminates a symptom of a
disease upon administration to a mammal without producing
significant toxicity to the mammal. Such an effective duration can
vary from several days to several weeks, months, or years. In
general, an effective duration for the treatment of an acute
disease can range in duration from several days to several months.
Once administration of the composition is stopped, however, disease
symptoms may return. In such cases, an effective duration for the
prevention of certain conditions can last for as long as the
individual is alive.
[0034] Multiple factors can influence the actual duration used for
a particular treatment or prevention regimen. For example, an
effective duration can vary with the frequency of administration,
the amount administered, combination of multiple agents, site of
administration, state of disease (if present), and anatomical
configuration of the treated area.
[0035] If the administration of a composition provided herein
(e.g., a composition containing reticuline) is toxic, the mammal
can be treated with a combination of L-DOPA and dopamine to inhibit
the production of morphine that results from the administered
composition. For example, a combination of L-DOPA and dopamine can
be used to reduce that amount of morphine produced from a
composition containing a morphine precursor such that only 95, 90,
80, 70, 60, 50, 40, 30, 20, 10, or less percent of the morphine
normally produced following administration of the composition is
actually produced.
[0036] This document also provides methods for inducing nitric
oxide release from cells. Such cells can be in vitro or in vivo. In
addition, the cells can be any type of cell including, without
limitation, neuronal, vascular, respiratory, immune, or digestive
cells. To induce nitric oxide release from cells, the compositions
provided herein can be administered as described herein. For
example, a composition containing morphine can be administered to a
mammal in an amount and at a frequency such that the mammal
receives between 0.5 .mu.g and 10 .mu.g of morphine per kg of body
weight per day for a duration of more than one month (e.g., more
than two, three, four, five, six, seven, eight, nine, or more
months).
[0037] In addition, this document provides methods for treating a
mammal having a disease or condition using a composition provided
herein. Examples of diseases or conditions that can be treated
using the compositions provided herein include, without limitation,
rheumatoid arthritis, systemic lupus erythematosus, systemic
scleroderma, Behcet disease, periarteritis, ulcerative colitis,
Crohn's disease, active chronic hepatitis, glomerular nephritis,
autoimmune diseases, osteoarthritis, gout, atherosclerosis,
psoriasis, atopic dermatitis, pulmonary diseases with granuloma,
encephalitis, endotoxin shock, sepsis, inflammatory colitis,
diabetes, acute myelocytic leukemia, pneumonia, heart
transplantation, encephalomylitis, anorexia, acute hepatitis,
chronic hepatitis, drug-induced hepatic injury, alcoholic
hepatitis, viral hepatitis, jaundice, hepatic cirrhosis, hepatic
insufficiency, atrial myxoma, Castleman syndrome, multiple myeloma,
Rennert T lymphomatosis, mesangial nephritis, renal cell carcinoma,
cytomegaloviral hepatitis, cytomegaloviral retinopathy, adenoviral
cold syndrome, adenoviral pharyngoconjunctival fever, adenoviral
ophthalmia, AIDS, atherosclerosis, arteriosclerosis, vasculopathy
associated with diabetes, mania, depression, chronic pain,
schizophrenia, psychosis, and paranoia. To treat a mammal having
such a disease or condition, the compositions provided herein can
be administered as described herein. For example, a composition
containing morphine can be administered to a mammal in an amount
and at a frequency such that the mammal receives between 0.5 .mu.g
and 10 .mu.g of morphine per kg of body weight per day for a
duration of more than one month (e.g., more than two, three, four,
five, six, seven, eight, nine, or more months). In some cases, the
compositions provided herein can be used to reduce the severity of
a symptom of the disease or condition, or to prevent the
development or onset of the disease or condition.
Other Embodiments
[0038] It is to be understood that while the invention has been
described in conjunction with the detailed description thereof, the
foregoing description is intended to illustrate and not limit the
scope of the invention, which is defined by the scope of the
appended claims. Other aspects, advantages, and modifications are
within the scope of the following claims.
* * * * *