U.S. patent application number 10/907149 was filed with the patent office on 2005-09-22 for method and compositions for treatment of chronic neuropathic pain.
Invention is credited to Apkarian, A. Vania.
Application Number | 20050209317 10/907149 |
Document ID | / |
Family ID | 34964544 |
Filed Date | 2005-09-22 |
United States Patent
Application |
20050209317 |
Kind Code |
A1 |
Apkarian, A. Vania |
September 22, 2005 |
Method and compositions for treatment of chronic neuropathic
pain
Abstract
Chronic pain is treated in an individual suffering from chronic
pain by administering to the individual an amount of a therapeutic
containing a glycine receptor agonist such as D-cycloserine or a
GlyT-1 glycine transporter antagonist such as sarcosine in an
amount effective to treat the chronic pain. The therapeutic may
also contain a secondary analgesic such as opiates, NSAIDs or cox-2
inhibitors. The analgesic can be formulated in a pharmaceutical
composition in the form of an injectable solution that contains at
least two different analgesics, at least one of the analgesics of
which is a glycine receptor agonist or a GlyT-1 glycine transporter
antagonist. Suitable pharmaceutical compositions contain
D-cycloserine and/or sarcosine, optionally in combination with
opiates, NSAIDs or cox-2 inhibitors.
Inventors: |
Apkarian, A. Vania;
(Chicago, IL) |
Correspondence
Address: |
OPPEDAHL AND LARSON LLP
P O BOX 5068
DILLON
CO
80435-5068
US
|
Family ID: |
34964544 |
Appl. No.: |
10/907149 |
Filed: |
March 22, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60555264 |
Mar 22, 2004 |
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Current U.S.
Class: |
514/471 ;
514/561 |
Current CPC
Class: |
A61K 31/42 20130101;
A61K 31/198 20130101; A61K 31/365 20130101; A61P 25/04 20180101;
A61K 2300/00 20130101; A61K 31/198 20130101; A61K 2300/00 20130101;
A61K 45/06 20130101; A61K 31/42 20130101 |
Class at
Publication: |
514/471 ;
514/561 |
International
Class: |
A61K 031/365; A61K
031/198 |
Goverment Interests
[0002] This invention was made in part with funds from NIH Grants
Nos. NS 35115 and NS 42660. The United States Government may have
certain rights in the invention.
Claims
What is claimed is:
1. A method for treating chronic pain in an individual suffering
from chronic pain, comprising administering to the individual an
amount of a therapeutic comprising a glycine receptor agonist or a
GlyT-1 glycine transporter antagonist in an amount and for a period
of time effective to treat the chronic pain.
2. The method of claim 1, wherein a glycine receptor agonist is
administered.
3. The method of claim 2, wherein the glycine receptor agonist is
D-cycloserine.
4. The method of claim 3, further comprising the step of
co-administering a secondary analgesic different from the glycine
receptor agonist.
5. The method of claim 4, wherein the secondary analgesic is an
opiate, NSAID or cox-2 inhibitor.
6. The method of claim 1, wherein a GlyT-1 glycine receptor
antagonist is administered.
7. The method of claim 6, wherein the GlyT-1 glycine receptor
antagonist is sarcosine.
8. The method of claim 7, further comprising the step of
co-administering a secondary analgesic different from the glycine
receptor agonist.
9. The method of claim 8, wherein the secondary analgesic is
opiate, NSAID or cox-2 inhibitor.
10. The method of claim 1, wherein the glycine receptor agonist or
a GlyT-1 glycine transporter antagonist is administered orally.
11. The method of claim 10, wherein a glycine receptor agonist is
administered.
12. The method of claim 11, wherein the glycine receptor agonist is
D-cycloserine.
13. The method of claim 12, wherein D-cycloserine is administered
to a human individual in an amount of from 10 to 1000 mg per
day.
14. The method of claim 11, further comprising the step of
co-administering a secondary analgesic different from the glycine
receptor agonist.
15. The method of claim 14, wherein the secondary analgesic is an
opiate, NSAID or cox-2 inhibitor.
16. The method of claim 10, wherein a GlyT-1 glycine receptor
antagonist is administered.
17. The method of claim 16, wherein the GlyT-1 glycine receptor
antagonist is sarcosine.
18. The method of claim 17, further comprising the step of
co-administering a secondary analgesic different from the glycine
receptor agonist.
19. The method of claim 18, wherein the secondary analgesic is
opiate, NSAID or cox-2 inhibitor.
20. A pharmaceutical composition comprising at least two different
analgesics, wherein at least one of the analgesics is a glycine
receptor agonist or a GlyT-1 glycine transporter antagonist.
21. The composition of claim 20, wherein the solution comprises
D-cycloserine.
22. The composition of claim 21, wherein the solution further
comprises an opiate, NSAID or cox-2 inhibitor.
23. The composition of claim 20, wherein the solution comprises
sarcosine.
24. The composition of claim 21, wherein the solution further
comprises an opiate, NSAID or cox-2 inhibitor.
25. The composition of claim 20, wherein the composition is
formulated for oral administration.
26. The composition of claim 20, wherein the composition is
formulated for injection.
Description
STATEMENT OF RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/555,264, filed Mar. 22, 2004, which
application is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0003] This application relates to the use of glycine receptor
agonists and glycine transporter antagonists for the treatment of
chronic pain.
[0004] Treatment of chronic pain is a challenge for physicians and
patients since there are no medications that specifically target
the condition, and since the medications presently used result in
very little relief and are based on their efficacy in acute pain
conditions or on their efficacy on relieving secondary effects like
anxiety and depression. Incidence of chronic pain is increasing in
society and its burden on society is huge in both health care and
lost productivity. Currently there are no scientifically validated
therapies for relieving chronic pain. As a result, the health
community targets `pain management` where multi-modal therapies are
used concurrently with the hope of providing some improvement in
quality of life. Thus, there is an urgent need for drugs that can
relieve chronic pain.
SUMMARY OF THE INVENTION
[0005] The present invention answers this need by providing a
method for treating chronic pain in an individual suffering from
chronic pain, comprising administering to the individual an amount
of a therapeutic comprising glycine receptor agonist or glycine
transporter antagonist in an amount effective to treat the chronic
pain. In specific embodiments, the therapeutic comprises
D-cycloserine and/or sarcosine. The therapeutic may also contain a
secondary analgesic such as opiates, NSAIDs, and cox-2
inhibitors.
[0006] The invention also provides a pharmaceutical composition in
the form of an injectable solution comprising at least two
different analgesics, wherein at least one of the analgesics is a
glycine receptor agonist or a GlyT-1 glycine transporter
antagonist. Suitable pharmaceutical compositions comprise
D-cycloserine and/or sarcosine, optionally in combination with
opiates, NSAIDs, and cox-2 inhibitors.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] The invention will be described with respect to a drawing in
several figures.
[0008] FIG. 1 shows structures of glycine receptor agonists.
[0009] FIGS. 2A-C show results from tests of D-cycloserine in a rat
model for neuropathic pain due to injury.
[0010] FIG. 3A-C show results from tests of D-cycloserine in a rat
model for neuropathic pain due to injury.
[0011] FIG. 4 shows effects of D-cycloserine in a rat model of
drug-indused neuropathy.
[0012] FIG. 5 shows analgesia following infusion of D-cycloserine
into different parts of a rat brain.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Definitions:
[0014] As used in the specification and claims of this application,
the following terms should be understood to have the following
meaning:
[0015] (1) "chronic pain" refers to pain that persists even after
healing or a cure of an underlying condition has been achieved. In
this case, the brain continues to perceive pain, even though there
is no apparent injury or cause. Thus, chronic pain is pain which
persists following normal healing time, for example beyond 3 months
after an injury. Chronic pain may include pain associated with
cancer or cancer treatments, persistent and degenerative
conditions, and neuropathy, or nerve damage.
[0016] (2) "administering" refers to the process of introducing a
therapeutic agent into an individual to be treated. The route of
administration may be tailored to the need of the individual.
However, in general administration via topical, nasal or oral
administration, or by systemic routes such as parenteral,
intramuscular or intravenous injection is suitable. Administration
may be done spatially proximate to the location of the perceived
chronic pain, although since the mechanism of action is believed to
be centered in the cerebral cortex, such administration would
either be relying on a placebo affect, or include a supplemental
analgesic.
[0017] (3) "an amount effective to treat" is an amount that results
in a reduction in the chronic pain as experienced by the individual
for a period of time. Complete elimination of the pain is not
required, nor is permanence of the reduction.
[0018] (4) the "individual" being treated is a mammal suffering
from chronic pain. Frequently, the individual will be a human.
However, the invention is also applicable to other mammals, notably
animals such as dogs, cats, and horses.
[0019] (5) the term "glycine receptor agonist" refers to a compound
that is at least a partial agonist of the glycine binding site of
the N-methyl-D-aspartate ("NMDA") receptor. An agonist produces the
same affect as glycine on the receptor.
[0020] (6)"GlyT-1 glycine transporter antagonist" or "glycine
transporter antagonist" refers to a molecule that interacts with
the GlyT-1 glycine transporter to inhibit transport of glycine.
GlyT-1 is also known as the sodium and chloride dependent
transporter 1.
[0021] Mechanistic Basis for the Invention
[0022] Current pharmacology of pain pursues peripheral afferent
conduction of nociceptive information and spinal cord manipulations
for pain control. Such an approach, however, fails to effectively
address chronic pain. For example, research conducted in humans and
rodents indicates that a large proportion of neuropathic pain, a
form of chronic pain, is supraspinal.
[0023] Specifically, Applicant's studies in humans with chronic
pain, chronic back pain, post herpetic neuropathy, complex regional
pain syndrome, indicate that medial prefrontal cortex is activated
with the chronic pain, reflecting the intensity of this pain.
Moreover, this activity is mediated through
thalamic-prefrontal-amygdala circuitry. Therefore, chronic pain can
be viewed as a pain conditioned state with inability to extinguish.
Apkarian et al. Am. Pain Soc. Abstracts 2003. Apkarian et al. Soc.
Neurosci. Abstracts 2003. Apkarian et al. Neurosci. Lett., 311, 193
(2001).
[0024] Treatment of pain as a conditioned state has not been
reported. However, extinguishing of other conditioned states,
notably fear, using therapeutic agents has been studied. Recent
studies in other labs have shown that the medial frontal cortex is
involved in extinction of fear conditioning, and that enhancing or
blocking the glycine receptor in the medial frontal cortex can
respectively increase or eliminate extinction. Walker D L et al. J.
Neurosci 22, 2343 (2002); Santini E et al. J. Neurosci. 21, 9009
(2001); Morrow B A et al. J. Neurosci. 19, 5666 (1999), Herry C et
al. J. Neurophys. 85, 2827 (1999); Morgan A M and LeDoux J E, Beh
Neurosci. 109, 681 (1995); Quirk G J et al. J. Neurosci 20, 6225
(2000); Milad M R and Quirk G J, Nature 420, 70 (2002).
[0025] The present invention applies the mechanisms for extinction
of fear conditioning to extinction of pain conditioning. Thus, in
accordance with the present invention, compounds that act as
glycine receptor agonists or glycine transporter antagonists are
used as therapeutics for treatment of chronic pain.
[0026] Examples of Glycine Receptor Agonists
[0027] A primary example of a glycine receptor agonist is
D-cycloserine. D-cycloserine is an analog to D-alanine. It has
antibiotic activity against Gram-negative bacteria. See: Stammer C
H, et al. J. Am. Chem Soc. 77, 2346 (1995). El-Obeid H A and
Al-Badr A A, In: Analytical profiles of drug substances, vol: 18,
p. 567 (Academic Press, NY, 1989). Kuehl F A, Jr, et al. J. Am.
Chem. Soc. 77, 2344 (1955). D-cycloserine is an excitatory amino
acid and partial agonist at the glycine binding site of the NMDA
receptor. At low doses, it enhances learning and memory. At
high-doses, it is utilized as an anti-convulsant. See: Schneider J
S et al, Brain Res. 860,190 (2000). Wlaz P et al. Epilepsia 37, 610
(1996). Nakazato E, et al. Life Sci. 67,1139 (2000). Pitkanen M et
al., J. Neual Transm Park Dis Dement 9,133 (1995). Disterhoft J F
et al, Soc Neurosci Abstracts 2003. D-cycloserine is reported to
relieve symptoms of opioid withdrawal. See: Oliveto A. et al., Exp
Clin Psychopharmacol 11, 237 (2003). D-cycloserine has also been
tested in schizophrenia, autism, anxiety disorders, and Alzheimer's
disease. D-cycloserine has also been shown to be an effective agent
for extinguishing fear conditioning in rodents when administered
systemically or in the amygdala.
[0028] Because D-cycloserine is a known therapeutic with existing
toxicology data, it is an attractive molecule for use in the method
of the present invention. There are, however, other glycine
receptor agonsists. For example, the compositions shown in FIG. 1
are reported to act as glycine receptor agonists.
http://www.bris.ac.uk/Depts/Synaptic/in-
fo/pharmacology/MDA.html.
[0029] D-serine and D-alanine may also be used in the method of the
present invention.
[0030] U.S. Pat. No. 6,667,297, which is incorporated herein by
reference, discloses methods for treating neuropsychiatric
disorders using therapeutic agents that interact with the glycine
receptor. The therapeutic agents of this disclosure are suitably
used in the method of the present invention.
[0031] In addition to the specific compounds, pharmaceutically
acceptable salts or esters may be employed. In addition, precursor
compounds that are converted (e.g. metabolized) into the active
agent in vivo can be employed. For example, D-alanine, D-serine,
and/or D-cycloserine and/or N-methylglycine can be substituted with
a modified version of the amino acid, such as a salt, ester,
alkylated form, or a precursor of the amino acid. For example, the
amino acid can be in the form of a sodium salt, potassium salt,
calcium salt, magnesium salt, zinc salt, or ammonium salt. Such
salt forms of D-serine, D-alanine, N-methylglycine and
D-cycloserine can be made in accordance with conventional methods
(see, e.g., Organic Chemistry, pgs. 822-823, Morrison and Boyd,
ed., Fifth Edition, Allyn and Bacon, Inc., Newton, Mass.). Other
modified forms of D-serine, D-alanine, N-methylglycine and
D-cycloserine also can be used in the methods of the invention. For
example, the carboxy group of the amino acid can be converted to an
ester group by reaction with an alcohol in accordance with standard
esterification methods (Id. at 841-843). For example, alcohols
having 1-20 carbon atoms can be used to produce an ester of
D-serine, D-alanine, N-methylglycine or D-cycloserine for use in
the invention (e.g., methyl-, ethyl-, propyl-, isopropyl-, butyl-,
isobutyl-, sec-butyl-, tert-butyl-, pentyl-, isopentyl-,
tert-pentyl-, hexyl-, heptyl-, octyl-, decyl-, dodecyl-,
tetradecyl-, hexadecyl-, octadecyl-, and phenyl-alcohols can be
used). In another variation, the amino group of the amino acid can
be alkylated, using conventional methods, to produce a secondary or
tertiary amino group by ammonolysis of halides or reductive
amination (Id. at 939-948). For example, an alkyl group having 1-20
carbon atoms can be added to the amino acid to produce an alkylated
amino acid (e.g., methyl-, ethyl-, propyl-, isopropyl-, butyl-,
isobutyl-, sec-butyl-, tert-butyl-, pentyl-, isopentyl-,
tert-pentyl-, hexyl-, heptyl-, octyl-, decyl-, dodecyl-,
tetradecyl-, hexadecyl-, octadecyl- and phenyl-groups can be added
to the amino acid). D-phosphoserine and L-phosphoserine are
examples of precursors of D-serine, and are commercially available
(e.g., from Sigma Chemical, St. Louis, Mo.). N,N,N-trimethylglycine
(betaine) and N,N-dimethylglycine are examples of precursors of
N-methylglycine.
[0032] Examples of Glycine Transporter Antagonists
[0033] As an alternative to the use of a glycine receptor agonist,
compounds that oppose glycine transport via the GlyT-1 transporter
can also be employed in the method of the invention. Non-limiting
examples of glycine transporter antagonists include N-methyl
glycine, sarcosine, and sarcosine derivatives such as
N[3-(4"-fluorophenyl)-3-(4"-phenylphenoxy)p- ropyl] sarcosine,
described in Herdon et al., Neuropharmacology. 2001
July;41(1):88-96. See also WO 97/45115, which is incorporated
herein by reference. Spiro(2h-1-benzopyran-2,4-piperidine)
derivatives may also be used as GlyT-1 inhibitors as described in
U.S. Pat. No. 6,645,973 which is incorporated herein by reference.
Glycyidodecylamide (GDA) is identified as a glycine transport
inhibitor on U.S. Pat. No. 5,837,730. which is incorporated herein
by reference.
[0034] U.S. Pat. No. 6,361,957, which is incorporated herein by
reference discloses an assay system for identifying glycine
transport antagonists.
[0035] Preparation of cells expressing GlyT-1 transporter sequences
that can be used in assaying for inhibitors is disclosed in U.S.
Pat. No. 6,251,617, which is incorporated herein by reference.
[0036] In addition to the specific compounds, pharmaceutically
acceptable salts or esters may be employed. In addition, precursor
compounds that are converted (e.g. metabolized) into the active
agent in vivo can be employed. For example, in the in case of
N-methyl glycine, suitable precursors are N,N,N-trimethylglycine
(betaine), or N,N-dimethylglycine).
[0037] Method of the Invention
[0038] In accordance with the method of the invention, a glycine
receptor agonist or a GlyT-1 glycine transporter antagonist is
administered to an individual, including a human individual,
suffering from chronic pain. The therapeutic agent is administered
in an amount sufficient to be effective, without inducing toxicity
or saturating the system such that the agent loses efficacy. The
specific amounts will depend on various factors including the
therapeutic agent employed (higher specific activity=lower dose),
mode of administration (more immediate administration to the
brain/greater ability to pass the blood brain barrier=lower dose),
and frequency of administration (continuous or more frequent
administration=lower dose), and the determination of appropriate
dosages is within the skill in the art.
[0039] As observed in U.S. Pat. No. 6,667,297, typically, a dosage
of 100 .mu.g to 100 g (e.g., 1 mg to 100 g; 1 mg to 100 mg; 10 mg
to 100 g; 10 mg to 10 g; or 10 to 500 mg) is suitable for
D-alanine, D-serine, and N-methylglycine. D-cycloserine is
administered at a dosage of 10 to 1000 mg, for example 100 to 500
mg, to human patients. When the patient is treated with both
D-serine and D-alanine, D-serine and D-alanine can be administered
to the patient simultaneously or sequentially, e.g., by formulating
the D-serine and D-alanine as a single pharmaceutical composition
or as two or more pharmaceutical compositions. Likewise, the
patient can be treated with both D-serine and D-cycloserine, or
D-serine and N-methylglycine, or D-alanine and N-methylglycine, or
D-cycloserine and N-methylglycine simultaneously or sequentially.
In one, but not the only, suitable method of treatment, the
pharmaceutical composition is administered to the patient at least
once daily for at least one week. If desired, the pharmaceutical
composition can be administered to the patient in more than one
dose per day (e.g., 2, 3, or 4 doses). Generally, the patient is
treated for at least one week; typically, the patient is treated
for at least several weeks (e.g., at least 4, 6, or 8 weeks) or
months (e.g., at least 4, 8, or 12 months). If necessary, the
treatment can continue indefinitely to keep the patient's symptoms
under control throughout his or her life. These same amounts and
protocols can be used in the method of the present invention.
[0040] By way of particular example, in the case where the
therapeutic agent being administered is D-cycloserine, the
following protocols are appropriate and are being implemented as
Phase 11 clinical trials.
[0041] Protocol for Post-Herpetic Neuraligia
[0042] To treat post-herpetic neuralgia in human patients, 100 mg
D-cycloserine in tablet form is taken once daily (generally at
night) for a period of 1 week, to confirm patient tolerance to the
treatment. If side effects/tolerance are acceptable, the dosage may
be increased to 100 mg, twice daily, (generally morning and night)
as needed for pain. Additional gradual dosage increases subject to
tolerance may be made as needed to control pain to a daily maximum
dosage of 1 g.
[0043] Chemotherapy-Induced Peripheral Neuropathic Pain
[0044] To treat chemotherapy-induced pain in human subjects, for
example pain following chemotherapy treatment with 2 mg/kg twice
weekly cisplatin, 250 mg D-cycloserine in tablet form is taken once
daily. Increased dosage to a maximum of 1 g per day may be used,
preferably in temporally-separate doses spread over the day.
Concurrent usage of opiates or other pain killers may be made,
although the goal is the reduction in the usage of opiate and
similar pain killers. This same type of therapy could be used for
treatment of pain following administration of pain following
administration of taxanes.
[0045] Chronic Low Back Pain
[0046] To treat chronic low back pain in human subjects, 250 mg
D-cycloserine in tablet form is taken once daily. Increased dosage
to a maximum of 1 g per day may be used, preferably in
temporally-separate 250 mg doses, i.e., 3 to 4 times per day.
[0047] In the method of the invention, combinations of two or more
glycine receptor agonists and/or GlyT-1 glycine transport
antagonists can be employed. Furthermore, the additional analgesics
may be suitably used in combination with a glycine receptor
agonists and/or a GlyT-1 glycine transport antagonists, or a
combination thereof. Suitable analgesics include, without
limitation, opiates, NSAIDs, and cox-2 inhibitors. These analgesics
may be used at the same or lower dosages as in conventional pain
management, since the combination should potentiate the effects of
either treatment used alone.
[0048] Pharmaceutical Compositions
[0049] The invention also provides a pharmaceutical composition in
the form of an injectable solution comprising at least two
different analgesics, wherein at least one of the analgesics is a
glycine receptor agonist or a GlyT-1 glycine transporter
antagonist. Suitable pharmaceutical compositions comprise
D-cycloserine and/or sarcosine, optionally in combination with
opiates, NSAIDs, and cox-2 inhibitors. Examples of opiates include
without limitation Opium, Codeine, Morphine, Heroin, Hydromorphone
(Dilaudid), Oxycodone (Percodan), Oxymorphone (Numorphan),
Hydrocodone (Vicodin), Meperidine (Demerol), Fentanyl, Methadone
(Dolophine), Darvon, Talwin. Examples of NSAIDs include without
limitation aspirin, ibuprofen, naproxen and nabumetone. Examples of
cox-2 inhibitors include without limitation celecoxib, etoricoxib,
rofecoxib, lumiracoxib and valdecoxib.
[0050] Liquid compositions for oral administration prepared in
water or other aqueous vehicles can include solutions, emulsions,
syrups, and elixirs containing, together with the active
compound(s), wetting agents, sweeteners, coloring agents, and
flavoring agents. Various liquid and powder compositions can be
prepared by conventional methods for inhalation into the lungs of
the patient to be treated. Tablet compositions can also be
formulated using techniques known in the art. By way of
non-limiting example, oral formulations providing 25 to 250 mg of
D-cycloserine for administration one or more times per day are
suitable.
[0051] Injectable compositions may contain various carriers such as
vegetable oils, dimethylacetamide, dimethylformamide, ethyl
lactate, ethyl carbonate, isopropyl myristate, ethanol, polyols
(glycerol, propylene glycol, liquid polyethylene glycol, and the
like). For intravenous injections, the compounds may be
administered by the drip method, whereby a pharmaceutical
composition containing the active compound(s) and a physiologically
acceptable excipient is infused. Physiologically acceptable
excipients may include, for example, 5% dextrose, 0.9% saline,
Ringer's solution or other suitable excipients. For intramuscular
preparations, a sterile composition of a suitable soluble salt form
of the compound can be dissolved and administered in a
pharmaceutical excipient such as Water-for-Injection, 0.9% saline,
or 5% glucose solution, or depot forms of the compounds (e.g.,
decanoate, palmitate, undecylenic, enanthate) can be dissolved in
sesame oil. Alternatively, the pharmaceutical composition can be
formulated as a chewing gum, lollipop, or the like.
[0052] In formulating injectable solutions, it will be recognized
that the greater the concentration, the lower the volume that needs
to be injected to attain the same dosage. Accordingly, it is
desirable to have the solution as concentrated as possible, bearing
in mind solubility of the therapeutic agent and the need to avoid a
shock effect at the point of administration if the solution is too
concentrated.
[0053] The invention will now be further described with reference
to the following non-limiting examples.
Example 1
[0054] Rats with mechanically injured paws were used as models of
neuropathic pain. In the test, a weight is applied to the injured
paw, and the pain response is assessed. More effective pain control
allows the rat to tolerate a greater weight. Rats (groups or 8-10
rats per treatment) were treated with oral saline (control) or 3,
10 or 30 mg/kg of D-cycloserine for a period of two weeks. Pain was
monitored from two days before the treatment commenced for a period
of 35 days total.
[0055] FIG. 2A shows a graphical representation of the results of
this study, with the period of oral treatment with D-cycloserine
shown in the shaded region. The open squares represent the control.
The black squares represent 30 mg/kg dosage. The two intermediate
lines are 3 (lighter) and 10 mg/kg (darker). As can be seen, during
the time of treatment, there is a generally dose-dependent
response. Post-treatment, the animals show long-lasting analgesia,
with a return to initial neuropathy levels at day 35.
[0056] FIG. 2B shows a graphical representation of results when the
rats originally treated with 30 mg/kg were retreated with 30 mg/kg
of D-cycloserine commencing 1 day after the end of the original 35
day test. The black squares are the retreated animals, the white
squares are the controls and the intermediate colored squares are
animals treated for the first time with 30 mg/kg. As shown, the
analgesic effectiveness is about twice as great on
re-treatment.
[0057] FIG. 2C shows results from a longer treatment period at a
dosage of 30 mg/kg. As shown, the analgesic effect increases with
treatment for a period of three weeks, after which a plateau is
reached. Further, the animals that are treated for a longer period
show a longer post treatment duration of analgesia, with
significant analgesic affect being observed 30 days after cessation
of treatment.
[0058] FIGS. 3A-C show results for the same test animals as FIGS.
2A-C, except using a test based on paw position as opposed to
tolerance to applied weight. In this case, lower numbers reflect
lesser pain. As can be seen, this measure of pain also indicates
the effectiveness of the D-cycloserine.
[0059] Acute oral or intrathecal administration of D-cycloserine
had only minimal analgesic effects on the neuropathic behavior
observed in this rat model. Thus, treatment of chronic pain
requires a treatment regimen that extends over a period of time,
for example at least one week, sufficient to provide a benefit to
the individual being treated.
Example 2
[0060] To model drug-induced pain, rats were treated with cisplatin
(2 mg/kg), a common chemotherapy drug. As shown graphically in FIG.
4, after 14 days of treatment, the rats had developed mechanical
sensitivity. In the next 14 days of treatment with cisplatin, oral
treatment with 30 mg/kg of D-cycloserine, two treatments per day,
result in a partial reversal of the mechanical sensitivity (gray
bars). In contrast, sensitivity was maintained in rats treated with
a saline control (white bars). Thus, in rat models of
cisplatin-induced neuropathy, pain behavior decreases 50% in two
weeks in animals treated with cycloserine compared with animals
treated with placebo.
Example 3
[0061] FIG. 5 shows the effects of infusing D-cycloserine (50
.mu.g) into the medial prefrontal cortex (black squares), bilateral
amygdala (black triangles), and visual cortex (white triangles) as
compared to a saline infusion in the medial prefrontal cortex
(white squares) in a rat exhibiting mechanical sensitivity Only
medial prefrontal cortex and amygdala infusions result in
analgesia.
* * * * *
References