U.S. patent application number 11/460012 was filed with the patent office on 2006-11-09 for systems and methods to treat pain locally.
This patent application is currently assigned to MEDTRONIC, INC.. Invention is credited to Eric N. Burright, Bill McKay, Lisa L. Shafer, John Zanella.
Application Number | 20060253100 11/460012 |
Document ID | / |
Family ID | 38590647 |
Filed Date | 2006-11-09 |
United States Patent
Application |
20060253100 |
Kind Code |
A1 |
Burright; Eric N. ; et
al. |
November 9, 2006 |
Systems and Methods to Treat Pain Locally
Abstract
Disclosed herein are systems and methods for contributing to the
local treatment of pain. More specifically, the disclosed systems
and methods contribute to the local treatment pain by inhibiting
the NF.kappa.B family of transcription factors.
Inventors: |
Burright; Eric N.; (Eagan,
MN) ; Shafer; Lisa L.; (Stillwater, MN) ;
McKay; Bill; (Memphis, TN) ; Zanella; John;
(Cordova, TN) |
Correspondence
Address: |
PRESTON GATES & ELLIS LLP
1900 MAIN STREET, SUITE 600
IRVINE
CA
92614-7319
US
|
Assignee: |
MEDTRONIC, INC.
710 Medtronic Parkway N.E.
Minneapolis
MN
|
Family ID: |
38590647 |
Appl. No.: |
11/460012 |
Filed: |
July 26, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10972157 |
Oct 22, 2004 |
|
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11460012 |
Jul 26, 2006 |
|
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Current U.S.
Class: |
604/512 ; 514/1;
604/93.01 |
Current CPC
Class: |
A61K 31/352 20130101;
A61K 9/0085 20130101; A61K 31/4168 20130101; A61P 29/00 20180101;
A61K 31/381 20130101; A61P 25/04 20180101; A61K 31/00 20130101;
A61K 31/192 20130101; G01N 2800/2842 20130101; A61M 37/0069
20130101; A61K 31/4402 20130101; A61K 31/498 20130101; A61M 5/14244
20130101; A61M 5/14276 20130101; A61P 25/02 20180101; A61K 9/0019
20130101; A61K 9/0024 20130101; A61K 31/185 20130101; A61K 9/1647
20130101; A61K 31/401 20130101; A61K 31/366 20130101 |
Class at
Publication: |
604/512 ;
604/093.01; 514/001 |
International
Class: |
A61M 31/00 20060101
A61M031/00; A61K 31/00 20060101 A61K031/00; A61M 37/00 20060101
A61M037/00; A01N 61/00 20060101 A01N061/00 |
Claims
1. A method of treating pain comprising: administering one or more
NF.kappa.B inhibiting compounds locally to a patient in need
thereof.
2. A method according to claim 1 wherein said one or more
NF.kappa.B inhibiting compounds are selected from the group
consisting of sulfasalazine, sulindac, clonidine, helenalin,
wedelolactone, pyrollidinedithiocarbamate (PDTC), Calbiochem IKK-2
inhibitor VI, Calbiochem IKK inhibitor III (BMS-345541), and
combinations thereof.
3. A method according to claim 1 wherein said administering of said
one or more NF.kappa.B inhibiting compounds inhibits the production
of one or more pro-inflammatory cytokines selected from the group
consisting of interleukin-1 beta (IL-1.beta.), tumor necrosis
factor alpha (TNF.alpha.) and interleukin-6 (IL-6).
4. A method according to claim 1 wherein said one or more
NF.kappa.B inhibiting compounds are administered locally to the
perispinal region of the lumbar region of a spinal cord or are
administered locally to the epidural space or the intrathecal space
of the lumbar region of a spinal cord.
5. A method according to claim 1 wherein said one or more
NF.kappa.B inhibiting compounds are administered locally from an
administration route selected from the group consisting of a
catheter and drug pump, one or more local injections, polymer
release, and combinations thereof.
6. A method according to claim 1 wherein said pain is acute or
neuropathic.
7. A method according to claim 1 wherein said pain is sciatica or
radicular pain.
8. A dosing regimen comprising one or more NF.kappa.B inhibiting
compounds and instructional information that directs the
administration of said one or more NF.kappa.B inhibiting compounds
for the local treatment of pain.
9. A dosing regimen according to claim 8 wherein said one or more
NF.kappa.B inhibiting compounds are selected from the group
consisting of sulfasalazine, sulindac, clonidine, helenalin,
wedelolactone, pyrollidinedithiocarbamate (PDTC), Calbiochem IKK-2
inhibitor VI, Calbiochem IKK inhibitor III (BMS-345541), and
combinations thereof.
10. A dosing regimen according to claim 8 wherein said
instructional information directs said one or more NF.kappa.B
inhibiting compounds to be administered locally to the perispinal
region of the lumbar region of a spinal cord or to be administered
locally to the epidural space or the intrathecal space of the
lumbar region of a spinal cord.
11. A dosing regimen according to claim 8 wherein said
instructional information directs said one or more NF.kappa.B
inhibiting compounds to be administered locally from an
administration route selected from the group consisting of a
catheter and drug pump, one or more local injections, polymer
release, and combinations thereof.
12. A dosing regimen according to claim 8 wherein said
instructional information directs said one or more NF.kappa.B
inhibiting compounds to be administered for the treatment of acute
or neuropathic pain.
13. A dosing regimen according to claim 8 wherein said
instructional information directs said one or more NF.kappa.B
inhibiting compounds to be administered for the treatment of
sciatica or radicular pain.
14. A dosing regimen according to claim 8 wherein said dosing
regimen is part of a kit used for the treatment of pain.
15. A kit according to claim 14 wherein said kit further comprises
an administration form.
16. A kit according to claim 15 wherein said administration form is
selected from the group consisting of a catheter and drug pump, one
or more syringes for local injections, compositions adapted for
polymer release, and combinations thereof.
17. A composition comprising one or more NF.kappa.B inhibiting
compounds wherein said compound is directed to be administered
locally for the treatment of pain.
18. A composition according to claim 17 wherein said one or more
NF.kappa.B inhibiting compounds are selected from the group
consisting of sulfasalazine, sulindac, clonidine, helenalin,
wedelolactone, pyrollidinedithiocarbamate (PDTC), Calbiochem IKK-2
inhibitor VI, Calbiochem IKK inhibitor III (BMS-345541), and
combinations thereof.
19. A composition according to claim 17 wherein said one or more
NF.kappa.B inhibiting compounds are directed to be administered
locally to the perispinal region of the lumbar region of a spinal
cord or are directed to be administered locally to the epidural
space or the intrathecal space of the lumbar region of a spinal
cord.
20. A composition according to claim 17 wherein said composition
comprising one or more NF.kappa.B inhibiting compounds is directed
to be administered locally from an administration route selected
from the group consisting of a catheter and drug pump, one or more
local injections, polymer release, and combinations thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 10/972,157 filed on Oct. 22, 2004 which is
incorporated by reference herein in its entirety for all
purposes.
FIELD OF THE INVENTION
[0002] The present invention relates to systems and methods for
contributing to the local treatment of pain. More specifically, the
systems and methods of the present invention contribute to the
local treatment of pain by inhibiting the NF.kappa.B family of
transcription factors.
BACKGROUND OF THE INVENTION
[0003] Pain can be divided into two types: acute pain and
neuropathic pain. Acute pain refers to pain experienced when tissue
is being damaged or is damaged. Acute pain serves at least two
physiologically advantageous purposes. First, it warns of dangerous
environmental stimuli (such as hot or sharp objects) by triggering
reflexive responses that end contact with the dangerous stimuli.
Second, if reflexive responses do not avoid dangerous environmental
stimuli effectively, or tissue injury or infection otherwise
results, acute pain facilitates recuperative behaviors. For
example, acute pain associated with an injury or infection
encourages an organism to protect the compromised area from further
insult or use while the injury or infection heals. Once the
dangerous environmental stimulus is removed, or the injury or
infection has resolved, acute pain, having served its physiological
purpose, ends.
[0004] As contrasted to acute pain, neuropathic pain serves no
beneficial purpose. Neuropathic pain results when pain associated
with an injury or infection continues in an area once the injury or
infection has resolved. The biological basis for this type of pain
that exists absent physical injury or infection baffled scientists
for many years. Recently, however, evidence has mounted that
neuropathic pain is caused, at least in part, by on-going (and
unneeded) activation of the immune system after an injury or
infection has healed. See, for example, WATKINS & MAIER (2004),
PAIN, CLINICAL UPDATES, 1-4.
[0005] Local immune system activation begins when damaged cells
secrete signals that recruit immune system cells to the area. One
type of recruited immune system cell is the macrophage. Macrophages
release interleukin-1 beta ("IL-1.beta."), interleukin-6 ("IL-6")
and tumor necrosis factor alpha ("TNF.alpha."), pro-inflammatory
cytokines heavily involved in orchestrating the immediate and local
physiological effects of injury or infection. For instance, once
released, pro-inflammatory cytokines promote inflammation (swelling
and redness caused by increased blood flow to the area which
delivers recruited immune system cells more quickly) and also
increased sensitivity to pain (by increasing the excitability and
transmission of sensory nerves carrying pain information to the
brain). Thus, pro-inflammatory cytokines are involved in the
beneficial physiological and recuperative effects of acute
pain.
[0006] Normally after an injury or infection heals, the local
immune system response ceases, inflammation recedes and the
increased sensitivity to pain abates. In some individuals, however,
signals that terminate the immune system response are not effective
entirely and pro-inflammatory cytokine activity in the area remains
active. In these individuals, sensory nerves carrying pain
information to the brain remain sensitized in the absence of injury
or infection and the individuals can experience neuropathic
pain.
[0007] Sciatica provides an example of pain that can transition
from acute to neuropathic pain. Sciatica refers to pain associated
with the sciatic nerve which runs from the lower part of the spinal
cord (the lumbar region), down the back of the leg and to the foot.
Sciatica generally begins with a herniated disc. The herniated disc
itself leads to local immune system activation. The herniated disc
also may damage the nerve root by pinching or compressing it,
leading to additional immune system activation in the area. In most
individuals, the acute pain and immune system activation associated
with the injury cease once the damage has been repaired. In those
individuals where immune system activation does not abate
completely, however, neuropathic pain may result.
[0008] As the foregoing suggests, inhibiting the actions of
pro-inflammatory cytokines can provide an effective strategy for
treating acute and neuropathic pain. Inhibiting the immune system,
however, is problematic as a general treatment because it leaves an
individual vulnerable to infection and unable to repair tissue
injuries effectively. Thus, treatments that inhibit
pro-inflammatory cytokines throughout the body generally are not
appropriate except in the most extreme cases of neuropathic pain.
Other pain treatments likewise are not effective or appropriate for
treating acute or neuropathic pain caused by pro-inflammatory
cytokines. For example, narcotics do not treat pain mediated by the
pro-inflammatory cytokines because narcotics block opiate
receptors, a receptor type not directly involved in many effects of
the pro-inflammatory cytokines. A need exists, therefore, for a
locally-administered pain treatment that suppresses the actions of
the pro-inflammatory cytokines.
[0009] Generally, for a protein such as a pro-inflammatory cytokine
to exert an effect, the cell that will use or secrete the protein
must create it. To create a protein the cell first makes a copy of
the protein's gene sequence in the nucleus of the cell (this
process is called transcription). Transcription factors are
regulatory proteins that initiate the transcription process upon
binding with DNA. Following transcription, the newly made copy of
the gene sequence that encodes for the protein (called messenger
RNA ("mRNA")) leaves the nucleus and is trafficked to a region of
the cell containing ribosomes. Ribosomes read the sequence of the
mRNA and create the protein for which it encodes. This process of
new protein synthesis is known as translation. A variety of factors
affect the rate and efficiency of transcription and translation.
One of these factors includes the intracellular regulation of
transcription factors.
[0010] The NF.kappa.B family is one group of transcription factors
that plays an essential role in the inflammatory response through
transcriptional regulation of a variety of genes encoding
pro-inflammatory cytokines (TNF.alpha., IL-1.beta., IL-6),
chemokines (IL-8, MIP1.alpha.), inducible effector enzymes (iNOS
and COX-2), and other molecules. Pro-inflammatory cytokines that
are up-regulated by NF.kappa.B, such as TNF.alpha. and IL-1.beta.,
can also directly activate the NF.kappa.B pathway, thus
establishing an autoregulatory loop that can result in chronic
inflammation and pain. Activation of NF.kappa.B pathways has been
shown to be important in the pathogenesis of many chronic
inflammatory diseases including rheumatoid arthritis, inflammatory
bowel disease, and osteoarthritis.
[0011] Thus, NF.kappa.B pathway inhibition is an attractive
therapeutic strategy for the treatment of inflammatory and pain
disorders. Effective NF.kappa.B pathway blockade could result in
lower levels of an array of molecules including pro-inflammatory
cytokines that contribute to inflammation and pain. However,
because NF.kappa.B is also involved in normal cellular physiology,
such as mounting an effective immune response, systemic inhibition
of this pathway could result in serious side effects. For these
reasons, minimizing systemic exposure of animals to NF.kappa.B
inhibitory compounds is an important component of a safe
therapeutic strategy.
SUMMARY OF THE INVENTION
[0012] Embodiments according to the present invention can treat
pain through the local administration of one or more compounds that
inhibit the NF.kappa.B pathway. Local administration of these
compounds helps to prevent unwanted side effects, such as
immunosuppression, associated with systemic drug
administration.
[0013] Specifically, one embodiment according to the present
invention is a method of treating pain comprising administering one
or more NF.kappa.B inhibiting compounds locally to a patient in
need thereof. In specific embodiments, the one or more NF.kappa.B
inhibiting compounds are selected from the group consisting of
sulfasalazine, sulindac, clonidine, helenalin, wedelolactone,
pyrollidinedithiocarbamate (PDTC), Calbiochem.RTM. IKK-2 inhibitor
VI, Calbiochem.RTM. IKK inhibitor III (also known as BMS-345541),
and combinations thereof. The administering of the one or more
NF.kappa.B inhibiting compounds can inhibit the production of one
or more pro-inflammatory cytokines selected from the group
consisting of interleukin-1 beta (IL-1.beta.), tumor necrosis
factor alpha (TNF.alpha.) and interleukin-6 (IL-6).
[0014] In accordance with the present invention, the one or more
NF.kappa.B inhibiting compounds can be administered locally to the
perispinal region of the lumbar region of a spinal cord or can be
administered locally to the epidural space or the intrathecal space
of the lumbar region of a spinal cord. These compounds can also be
administered locally from an administration route selected from the
group consisting of a catheter and drug pump, one or more local
injections, polymer release, and combinations thereof.
[0015] Methods according to the present invention can be used to
treat, without limitation, acute pain, neuropathic pain, sciatica
and/or radicular pain.
[0016] The present invention also includes dosing regimens. In one
dosing regimen according to the present invention, the dosing
regimen comprises one or more NF.kappa.B inhibiting compounds and
instructional information that directs the administration of the
one or more NF.kappa.B inhibiting compounds for the local treatment
of pain. In certain embodiments of the dosing regimens, the one or
more NF.kappa.B inhibiting compounds directed to be administered
are selected from the group consisting of sulfasalazine, sulindac,
clonidine, helenalin, wedelolactone, pyrollidinedithiocarbamate
(PDTC), Calbiochem.RTM. IKK-2 inhibitor VI, Calbiochem.RTM. IKK
inhibitor III (BMS-345541), and combinations thereof.
[0017] Instructional information used in accordance with the
present invention can direct the one or more NF.kappa.B inhibiting
compounds to be administered locally to the perispinal region of
the lumbar region of a spinal cord or to be administered locally to
the epidural space or the intrathecal space of the lumbar region of
a spinal cord. The instructional information can also direct the
one or more NF.kappa.B inhibiting compounds to be administered
locally from an administration route selected from the group
consisting of a catheter and drug pump, one or more local
injections, polymer release, and combinations thereof.
[0018] In another embodiment of the dosing regimens according to
the present invention, the instructional information directs the
one or more NF.kappa.B inhibiting compounds to be administered for
the treatment of acute pain, neuropathic pain, sciatica and/or
radicular pain.
[0019] In another embodiment of the dosing regimens, the dosing
regimen is part of a kit used for the treatment of pain. Kits
according to the present invention can include one or more of: (i)
an administration form generally; (ii) an administration form
comprising a catheter and drug pump, (iii) an administration form
comprising one or more syringes for local injections, (iv) an
administration form comprising compositions adapted for polymer
release and (v) combinations thereof.
[0020] The present invention also includes compositions. In one
embodiment of the compositions according to the present invention,
the composition comprises one or more NF.kappa.B inhibiting
compounds wherein the one or more NF.kappa.B inhibiting compounds
are directed to be administered locally for the treatment of pain.
In another embodiment of the compositions, the one or more
NF.kappa.B inhibiting compounds are selected from the group
consisting of sulfasalazine, sulindac, clonidine, helenalin,
wedelolactone, pyrollidinedithiocarbamate (PDTC), Calbiochem IKK-2
inhibitor VI, Calbiochem IKK inhibitor III (BMS-345541) and
combinations thereof.
[0021] Compositions according to the present invention can be
directed to be administered locally to the perispinal region of the
lumbar region of a spinal cord or can be directed to be
administered locally to the epidural space or the intrathecal space
of the lumbar region of a spinal cord. The compositions can also be
directed to be administered locally from an administration route
selected from the group consisting of a catheter and drug pump, one
or more local injections, polymer release and combinations
thereof.
BRIEF DESCRIPTION OF THE FIGURES
[0022] FIG. 1 depicts a schematic representation of the NF.kappa.B
activation pathway.
[0023] FIGS. 2 and 3 show the effect of the NF.kappa.B inhibitor
sulfasalazine on pain sensitivity as measured by paw withdrawal
latencies.
[0024] FIG. 4 shows the effect of the NF.kappa.B inhibitor
sulfasalazine on pain sensitivity as measured in a mechanical
allodynia paradigm.
[0025] FIGS. 5A-5B show the effect of additional NF.kappa.B
inhibitors on pain sensitivity measured by paw withdrawal latencies
and in a mechanical allodynia paradigm.
[0026] FIG. 6 shows the effect of the NF.kappa.B inhibitor
clonidine on pain sensitivity as measured by paw withdrawal
latencies.
DETAILED DESCRIPTION
[0027] While the sensation of pain can serve beneficial purposes,
in many instances, such as neuropathic pain (which occurs in the
absence of injury or infection) it does not and is highly
undesirable. Problematic pain requiring treatment is believed to be
caused at least in part due to local immune activation. The local
immune activation is mediated largely by pro-inflammatory cytokines
including interleukin-1 beta ("IL-1.beta."), tumor necrosis factor
alpha ("TNF.alpha.") and interleukin-6 ("IL-6"). Sciatica provides
one non-limiting example of pain that can be caused by local
pro-inflammatory cytokine activity.
[0028] As the foregoing suggests, inhibiting the actions of
pro-inflammatory cytokines can provide an effective strategy for
treating pain. Inhibiting the immune system, however, is
problematic as a general treatment because it leaves an individual
vulnerable to infection and unable to repair tissue injuries
effectively. Thus, treatments that systemically inhibit
pro-inflammatory cytokines throughout the body are not appropriate
except in the most extreme cases.
[0029] For a protein such as a pro-inflammatory cytokine to exert
an effect, the cell that will use or secrete the protein must
create it. Thus, one avenue to inhibit the local actions of
pro-inflammatory cytokines is to inhibit intracellular mechanisms
that lead to their production and release. The NF.kappa.B family is
the primary group of transcription factors that plays an essential
role in regulating the transcription of genes encoding
pro-inflammatory cytokines (TNF.alpha., IL-1.beta., IL-6),
chemokines (IL-8, MIP1.alpha.), inducible effector enzymes (iNOS
and COX-2), and other molecules. Thus, NF.kappa.B pathway
inhibition is one attractive therapeutic strategy for the treatment
of inflammatory and pain disorders. Effective NF.kappa.B pathway
blockade can result in lower levels of an array of molecules
including pro-inflammatory cytokines that contribute to
inflammation and pain. However, because NF.kappa.B is also involved
in normal cellular physiology such as mounting an effective immune
response, systemic inhibition of the pathway may result in serious
side effects. For example global inhibition of the NF.kappa.B
pathway in adult animals can render them susceptible to
opportunistic infections. Further, gene targeting studies in mice
have shown that complete inactivation of nearly any member of the
NF.kappa.B pathway (at least during development) results in
significant immune system defects and/or embryonic lethality. For
these reasons, minimizing systemic exposure of animals to
NF.kappa.B inhibitory compounds is an important component to a safe
therapeutic strategy for the treatment of pain.
[0030] The NF.kappa.B transcription factor family represents a
group of structurally related and evolutionarily conserved proteins
that includes five members in mammals: Rel (c-Rel), RelA (p65),
RelB, NF.kappa.B1 (p50), and NF.kappa.B2 (p52). These molecules
form functional transcription factors by complexing into hetero- or
homodimers of the NF.kappa.B/Rel protein subunits. The most
prevalent form of NF.kappa.B is a heterodimer of the p65 and p50
subunits.
[0031] NF.kappa.B pathway activation (see FIG. 1) is regulated
through a series of events. In unstimulated cells, NF.kappa.B is
sequestered in the cytoplasm in an inactive form, bound to
regulatory proteins called inhibitors of .kappa.B (I.kappa.B). A
variety of stimuli including pro-inflammatory cytokines such as
TNF.alpha. and IL-1.beta. induce the phosphorylation of the
I.kappa.B proteins (I.kappa.B.alpha. and I.kappa.B.beta.) at
specific NH.sub.2-terminal serine residues. The phosphorylated
I.kappa.B proteins quickly become ubiquinated and degraded by the
proteasome. The released NF.kappa.B proteins are then able to
translocate to the cell nucleus and induce the transcription of a
variety of genes containing their cognate DNA binding recognition
sequences.
[0032] A key step in NF.kappa.B activation described in the
preceding paragraph is the phosphorylation of the I.kappa.B
proteins. This phosphorylation event is mediated by a specific
protein complex known as I.kappa.B kinase (IKK). IKK is composed of
two catalytic subunits IKK.alpha. and IKK.beta., and a regulatory
subunit named NF.kappa.B essential modulator (NEMO) or IKK.gamma..
Cells deficient in either IKK.alpha. or IKK.beta. retain some
inducible NF.kappa.B activity suggesting their distinct roles in
NF.kappa.B pathway activation. Conversely, in cells lacking
IKK.gamma., NF.kappa.B activation is completely blocked upon the
induction of a variety of stimuli (including TNF.alpha., IL-1, and
lipopolysaccharide (LPS) exposure).
[0033] Regarding the use of NF.kappa.B inhibitors to treat pain,
endoneural injections of an NF.kappa.B transcription factor decoy
(at the site of peripheral injury) have been shown to significantly
reduce thermal hyperalgesia in a rat model of neuropathic pain. In
this model NF.kappa.B inhibition also results in lower levels of a
variety of pro-inflammatory mediators (including TNF.alpha.,
IL-1.beta., IL-6, IFN-.gamma., and iNOS). Sakaue et al.,
(Neuroreport. 2001, 12(10):2079). Spinal administration of
NF.kappa.B inhibitors (ODN decoys and pyrrolidine dithiocarbamate
(PDTC)) have also been shown to significantly reduce mechanical
allodynia and thermal hyperalgesia in the Complete Freund's
Adjuvant (CFA) inflammatory pain model. Lee et al., (Euro J.
Neurosci. 2004, 19:3375). Further, Tegeder et al., (J Neurosci.
2004, 24(7):1637) have reported that a specific IKK-.beta.
inhibitor (S1627) reduces hyperalgesia in inflammatory and
neuropathic pain models (zymosan-induced paw inflammation) in rats.
In addition, this inhibitor also reduces tactile allodynia in the
chronic constriction injury model (CCI) of neuropathic pain. These
studies demonstrate the efficacy of NF.kappa.B pathway blockade in
the treatment of inflammatory and neuropathic pain.
[0034] Co-pending application publication number US2005/0095246Apb
1 ("the '246 application") to which this application claims
priority and which is incorporated by reference fully herein
describes techniques to treat neurological disorders by attenuating
the production of pro-inflammatory mediators. The '246 application
describes the use of devices such as pumps/catheters and
polymer-based drug depots for the local (peripheral, intrathecal,
intraparenchymal) delivery of inhibitors of pro-inflammatory
mediators (including members of the NF.kappa.B pathway;
IKK-.alpha., .beta., and .gamma.) to treat inflammatory disorders.
Embodiments described in the present application stem from these
initial disclosures and also provide novel compounds to locally
inhibit NF.kappa.B in the local treatment of pain through the local
administration of these compounds.
EXAMPLES
[0035] The behavioral animal model of chronic constriction injury
("CCI") was chosen to evaluate the efficacy of NF.kappa.B
inhibitors as a pain treatment. This model may mimic pain
associated with sciatica in humans. To induce CCI, each animal was
anesthetized by intraperitoneal ("i.p.") injection of sodium
pentobarbital at a dose of 60 mg/kg body weight. The animal's right
common sciatic nerve was exposed and freed from adherent tissue at
mid-thigh by separating the muscle (biceps femoris) by blunt
dissection. Four loose ligatures were placed 1 mm apart, using
chromic gut (4-0 absorbable suture, Jorgensen Laboratories Inc.,
Loveland, Colo.).
Example 1
[0036] Animals were randomly assigned to treatment groups and
administered control or test compounds as follows: animals received
either vehicle (Phosphate Buffered Saline; PBS), the protein-based
TNF.alpha. inhibitor, Enbrel.RTM. as a positive control (3 mg/kg
Immunex Corp., Seattle, Wash.) or sulfasalazine, a small molecule
inhibitor of NF.kappa.B at a dose of 5 mg/kg or 50 mg/kg.
[0037] Animal behavioral testing was conducted on Days 7, 14 and 21
after CCI. In the thermal hyperalgesia test, animals were placed in
the clear plastic chamber of a plantar analgesia instrument and
allowed to acclimate to the environment for 15 minutes. After the
acclimation period, a radiant (heat) beam source stimulus was
applied to the CCI hind paw of each animal. The heat source device
was set at an intensity of 50, and a maximum latency period of 15
seconds was set to prevent tissue damage according to the
recommendations of the instrument manufacturer. If a paw withdrawal
occurred within the 15 second period, an automated control
interrupted both the stimulus and timer, turning off the radiant
beam and recording the latency of time to paw withdrawal. Data was
analyzed using a one-way analysis of variance at each test day.
[0038] FIG. 2 demonstrates that the protein-based pro-inflammatory
cytokine inhibitor Enbrel.RTM. is effective to inhibit pain
associated with CCI on all test days. NF.kappa.B inhibitors,
however, were more effective at inhibiting pain associated with CCI
on all test days. Specifically, animals that received vehicle
showed mean paw withdrawal latencies of about 45%, 50% and 53% over
baseline on test days 7, 14 and 21 respectively. Animals that
received Enbrel.RTM. showed mean paw withdrawal latencies of about
60%, 63% and 75% over baseline on test days 7, 14 and 21
respectively. Animals receiving 5 mg/kg sulfasalazine showed mean
paw withdrawal latencies of about 80%, 83% and 87% over baseline
while those receiving 50 mg/kg showed mean paw withdrawal latencies
of about 74%, 79% and 83% over baseline on test days 7, 14 and 21
respectively. This data demonstrates that NF.kappa.B inhibition can
provide an effective mechanism to decrease pain sensitivity.
Example 2
[0039] In a subsequent study, additional lower doses of
sulfasalazine were evaluated for their effectiveness as a pain
treatment using the CCI model. Specifically, the same methods as
described above were used except that sulfasalazine was
administered at doses of 5 mg/kg; 1 mg/kg or 0.2 mg/kg. As can be
seen in FIG. 3, control animals receiving vehicle showed paw
withdrawal latencies averaging an increase of about 45%, 41% and
39% over baseline on test days 7, 14 and 21 respectively. Positive
control animals receiving the protein-based TNF.alpha. inhibitor,
Enbrel.RTM. increased paw withdrawal latencies to about 51%, 63%
and 62% over baseline on test days 7, 14 and 21 respectively.
Again, however, all doses of sulfasalazine increased paw withdrawal
latencies on all test days even further (to an average of between
about 65% to about 85% over baseline measures on all test days),
again suggesting that sulfasalazine and NF.kappa.B inhibition can
provide an effective pain treatment. Indeed, this data suggests
that sulfasalazine can provide a more effective pain treatment than
protein-based inhibitors such as Enbrel.RTM..
Example 3
[0040] The ability of sulfasalazine to inhibit pain was also
evaluated using a different sensitivity measure following CCI,
namely mechanical (or tactile) allodynia. In this study, mechanical
allodynia was determined in reaction to probing with von Frey
filaments (Stoelting, Wood Dale, Ill.). Mechanical sensitivity was
measured on Days 8, 15 and 22 following CCI by determining the
median 50% foot withdrawal threshold for von Frey filaments using
the up-down method described in Chaplan et al. (J Neurosci Methods
1994; 54:55) which is incorporated by reference herein for its
teachings regarding the up-down method. Rats were placed under a
plastic cover (9.times.9.times.20 cm) on a metal mesh floor. The
area tested was the middle glabrous area between the footpads of
the plantar surface of the injured hind paw within the L4
innervation area. The plantar area was touched with a series of 9
von Frey hairs with approximately exponentially incremental bending
forces (von Frey values: 3.61, 3.8, 4.0, 4.2, 4.41, 4.6, 4.8, 5.0,
and 5.2; equivalent to: 0.41, 0.63, 1.0, 1.58, 2.51, 4.07, 6.31,
10, and 15.8 g). The von Frey hair was presented perpendicular to
the plantar surface with sufficient force to cause slight bending
and held for approximately 3 to 4 seconds. Abrupt withdrawal of the
foot (paw flinching) was recorded as a response. Any rat showing a
mechanical threshold of more than 3.24 g was eliminated from the
study. As can be seen in FIG. 4, Enbrel.RTM. and sulfasalazine both
decreased sensitivity in this paradigm when compared to controls,
further suggesting that sulfasalazine and NF.kappa.B inhibition can
provide an effective pain treatment when administered at
appropriate dosages.
Example 4
[0041] Next, the ability of other NF.kappa.B inhibitors to decrease
pain sensitivity in the paw withdrawal and mechanical allodynia
paradigms following CCI were evaluated. In this study, the
previously described methods for CCI, paw withdrawal and mechanical
allodynia testing were followed except that animals received
vehicle control; 3 mg/kg Enbrel.RTM. as a positive control; 20
mg/kg or 100 mg/kg pyrollidinedithiocarbamate (PDTC); 2 mg/kg or 10
mg/kg sulindac; or 0.02 mg/kg or 0.1 mg/kg clonidine. As can be
seen in FIG. 5A, vehicle controls showed average paw withdrawal
latencies of about 41% over baseline on all three test days.
Positive control animals receiving Enbrel.RTM. increased paw
withdrawal latencies to an average of about 51% over baseline on
all three test days. Animals receiving 2 mg/kg sulindac increased
latencies to about 65% over baseline on all three test days while
those receiving 10 mg/kg increased latencies to about 65%, 81% and
75% over baseline on test days 7, 41 and 21 respectively. Animals
receiving 0.02 mg/kg clonidine showed an increase in paw withdrawal
latencies over baseline of about 75%-79% on all three test days and
those receiving 0.1 mg/kg clonidine showed an increase of about
78%, 60% and 61% over baseline on test days 7, 41 and 21
respectively. This data suggests that NF.kappa.B inhibitors reduce
pain sensitivity further suggesting that NF.kappa.B inhibition can
provide an effective pain treatment. Interestingly, in this study,
while PDTC did increase paw withdrawal latencies over control
levels, this compound was not as effective at reducing pain
sensitivity as other NF.kappa.B inhibiting compounds. This result
could be a function of dose or administration route. Indeed,
animals receiving 100 mg/kg PDTC were removed from the study
following the second day of testing due to drug toxicity.
[0042] In the mechanical allodynia test, as can be seen in FIG. 5B,
all NF.kappa.B inhibitors, (with the potential exception of PDTC),
decreased pain sensitivity when compared to control animals
receiving vehicle or Enbrel.RTM.. Both doses of sulindac and the
higher dose (0.1 mg/kg) of clonidine most significantly decreased
pain sensitivity. These compounds decreased pain sensitivity on
days 8, 15 and 22 respectively as follows: sulindac (2 mg/kg):
about 66%, 50% and 35%; sulindac (10 mg/kg): about 68%, 58% and
60%; clonidine (0.1 mg/kg): about 58%, 20% and 48%. Animals
receiving vehicle or Enbrel.RTM. showed increases between about 19%
and 25%. Again, while PDTC showed some effect in decreasing pain
sensitivity, the effect was not as strong as that seen with
sulindac or clonidine. Further, while the low dose of clonidine
decreased sensitivity, it did not show as strong as an effect in
the mechanical allodynia test. This result may indicate that the
higher dose of clonidine is a more appropriate dose for its use in
the treatment of pain.
Example 5
[0043] Following the previous experiment, the effect of local doses
of clonidine on pain sensitivity was explored. Animals were
administered vehicle or test substances through a subcutaneously
implanted Alzet pump. Again, the previously described methods for
CCI and paw withdrawal latency measurements were followed except
that in the presently described experiment animals received either
vehicle control; 1 .mu.g/hour Enbrel.RTM. as a positive control;
0.01 .mu.g/hour clonidine; 0.05 .mu.g/hour clonidine; or 0.25
.mu.g/hour clonidine. As can be seen in FIG. 6, vehicle controls
showed average paw withdrawal latencies of about 39%, 43% and 47%
over baseline on test days 7, 14 and 21 respectively. Animals
receiving Enbrel.RTM. showed paw withdrawal latencies of about 45%,
60% and 71% over baseline on test days 7, 14 and 21 respectively.
Animals receiving 0.01 .mu.g/hour clonidine showed paw withdrawal
latencies of about 60%, 64% and 79% over baseline on test days 7,
14 and 21 respectively. Animals receiving 0.05 .mu.g/hour clonidine
showed paw withdrawal latencies of about 68%, 64% and 83% over
baseline on test days 7, 14 and 21 respectively. Animals receiving
0.25 .mu.g/hour clonidine showed paw withdrawal latencies of about
63%, 70% and 82% over baseline on test days 7, 14 and 21
respectively. In this study, all doses of clonidine caused
significant increases in paw withdrawal latencies on all three test
days. Therefore, these results further suggest that clonidine can
provide an effective pain treatment when administered locally.
Dosing of compounds such as clonidine can substantially reduce the
systemic exposure of the drug without compromising the efficacy of
treatment. In the example given, there was a 25 fold dose reduction
without loss of efficacy.
[0044] The disclosed invention describes the use of a therapeutic
agent to block activation of the NF.kappa.B signaling pathway to
alleviate pain. Pain is likely reduced by these inhibitors through
their effect in reducing levels of pro-inflammatory cytokines and
other molecules involved in the inflammation response. The
therapeutic agent may be a small molecule inhibitor of NF.kappa.B
pathway activation or other effective NF.kappa.B inhibitors.
Non-limiting examples of potential therapeutic agents for use in
accordance with the present invention can include anti-oxidants
that have been shown to inhibit NF.kappa.B, proteasome and protease
inhibitors that inhibit NF.kappa.B, and I.kappa.B.alpha.
phosphorylation and/or degradation inhibitors. Examples of such
compounds include, without limitation, .alpha.-lipoic acid,
.alpha.-tocopherol, allicin,
2-amino-1-methyl-6-phenylimidazo[4,5-]pyridine,
anetholdithiolthione, apocynin, 5,6,3',5'-tetramethoxy
7,4'-hydroxyflavone, astaxanthin, benidipine, bis-eugenol,
bruguiera gymnorrhiza compounds, butylated hydroxyanisole,
cepharanthine, caffeic acid phenethyl ester, carnosol,
.beta.-carotene, carvedilol, catechol derivatives, chlorogenic
acid, cocoa polyphenols, curcumin, dehydroepiandrosterone and
dehydroepiandrosterone sulfate, dibenzylbutyrolactone lignans,
diethyldithiocarbamate, diferoxamine, dihydroisoeugenol,
dihydrolipoic acid, dilazep+fenofibric acid,
dimethyldithiocarbamates, dimethylsulfoxide, disulfiram, ebselen,
edaravone, epc-k1, epigallocatechin-3-gallate, ergothioneine,
ethylene glycol tetraacetic acid, flavonoids (crataegus; boerhaavia
diffusa root; xanthohumol), .gamma.-glutamylcysteine synthetase,
ganoderma lucidum polysaccharides, garcinol, ginkgo biloba extract,
hematein, 23-hydroxyursolic acid, iron tetrakis, isovitexin,
kangen-karyu extract, I-cysteine, lacidipine, lazaroids, lupeol,
magnolol, maltol, manganese superoxide dismutase, extract of the
stem bark of mangifera indica I, melatonin, mulberry anthocyanins,
n-acetyl-I-cysteine, nacyselyn, nordihydroguaiaritic acid,
ochnaflavone, orthophenanthroline, hydroquinone, tert-butyl
hydroquinone, phenylarsine oxide, phyllanthus urinaria,
pyrrolinedithiocarbamate, quercetin (low concentrations), redox
factor 1, rotenone, roxithromycin, s-allyl-cysteine, sauchinone,
spironolactone, strawberry extracts, taxifolin, tempol, tepoxaline,
vitamin C, vitamin B6, vitamin E derivatives, .alpha.-torphryl
succinate, .alpha.-torphryl acetate,
2,2,5,7,8-pentamethyl-6-hydroxychromane, yakuchinone .alpha. and
.beta., n-acetyl-leucinyl-leucynil-norleucynal,
n-acetyl-leucinyl-leucynil-methional,
carbobenzoxyl-leucinyl-leucynil-norvalinal,
carbobenzoxyl-leucinyl-leucynil-leucynal, lactacystine,
.beta.-lactone, boronic acid peptide, ubiquitin ligase inhibitors,
bortezomib, salinosporamide .alpha., cyclosporin .alpha.,
tacrolimus, deoxyspergualin, 15 deoxyspergualin, analogs of
15-deoxyspergualin, n-acetyl-dl-phenylalanine-.beta.-naphthylester,
n-benzoyl I-tyrosine-ethylester, 3,4-dichloroisocoumarin,
diisopropyl fluorophosphate, n-.alpha.-tosyl-I-phenylalanine
chloromethyl ketone, n-.alpha.-tosyl-I-lysine chloromethyl ketone,
desloratadine, salmeterol, fluticasone propionate, protein-bound
polysaccharide from basidiomycetes, calagualine, golli bg21,
npm-alk oncoprotein, Iy29, Iy30, Iy294002, evodiamine, rituximab,
kinase suppressor of ras, pefabloc, rocaglamides, betaine, tnap,
geldanamycin, grape seed proanthocyanidins, pomegranate fruit
extract, tetrandine,
4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-.alpha.) quinoxaline,
2-amino-3-cyano-4-aryl-6-(2-hydroxy-phenyl)pyridine derivatives,
acrolein, anandamide, as602868, cobrotoxin, dihydroxyphenylethanol,
herbimycin .alpha., inhibitor 22, isorhapontigenin, manumycin
.alpha., mlb120, nitric oxide, nitric oxide donating aspirin,
thienopyridine, acetyl-boswellic acids, .beta.-carboline, cyl-19s,
cyl-26z, synthetic .alpha.-methylene-.gamma.-butyrolactone
derivatives,
2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl
nicotinonitrile, plant compound .alpha., flavopiridol,
cyclopentones, jesterone dimmer, ps-1145,
2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides, 1'
acetoxychavicol acetate, apigenin, cardamomin, synthetic
triterpenoid, chs 828 (anticancer drug), diosgenin,
furonaphthoquinone, guggulsterone, heparin-binding epidermal growth
factor-like growth factor, falcarindol, hepatocyte growth factor,
honokiol, hypoestoxide, .gamma.-mangostin, garcinone .beta.,
kahweol, kava derivatives, ml120b, mx781 (retinoid antagonist),
n-acetylcysteine, nitrosylcobalamin (vitamin B12 analog),
non-steroidal anti-inflammatory drugs (NSAIDs), hepatits c virus
ns5b, pan1 (aka nalp2 or pypaf2), n-(4-hydroxyphenyl) retinamide,
sulforaphane, phenylisothiocyanate, survanta, piceatannol,
5-hydroxy-2-methyl-1,4-naphthoquinone, pten (tumor suppressor),
theaflavin, tilianin, zerumbone, silibinin, sulfasalazine,
sulfasalazine analogs, rosmarinic acid, staurosporine, .gamma.
tocotrienol, wedelolactone, betulinic acid, ursolic acid,
thalidomide, interleukin-10, mollusum contagiosum virus mc159
protein, monochloramine, glycine chloramine, anethole,
anti-thrombin III, artemisia vestita, aspirin, sodium salicylate,
azidothymidine, baoganning,
e3((4-methylphenyl)-sulfonyl)-2-propenenitrile,
e3((4-t-butylphenyl)-sulfonyl)-2-propenenitrile, benzyl
isothiocyanate, cyanidin 3-o-glucoside, cyanidin
3-o-(2(g)-xylosylrutinoside, cyanidin 3-o-rutinoside,
buddlejasaponin IV, cacospongionolide .beta., carbon monoxide,
carboplatin, cardamonin, chorionic gonadotropin, cycloepoxydon,
1-hydroxy-2-hydroxymethyl-3-pent-1-enylbenzene, decursin,
dexanabinol, digitoxin, diterpenes (synthetic), docosahexaenoic
acid, extensively oxidized low density lipoprotein,
4-hydroxynonenal, fragile histidine triad protein, gabexate
mesilate, [6]-gingerol, casparol, imatanib, glossogyne tenuifolia,
ibuprofen, indirubin-3'-oxime, interferon-.alpha., licorice
extracts, methotrexate, nafamostat mesilate, oleandrin, omega 3
fatty acids, panduratin .alpha., petrosaspongiolide m, pinosylvin,
plagius flosculosus extract polyacetylene spiroketal, phytic acid,
prostaglandin .alpha.1, 20(s)-protopanaxatriol, rengyolone,
rottlerin, saikosaponin-d, saline (low Na.sup.+ istonic), salvia
miltiorrhizae water-soluble extract, pseudochelerythrine,
13-methyl-[1,3]-benzodioxolo-[5,6-c]-1,3-dioxolo-4,5
phenanthridinium), scoparone, silymarin, socs1, statins, sulindac,
thi 52
(1-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline),
1,2,4-thiadiazolidine derivatives, vesnarinone, xanthoangelol d,
yc-1, yopj, acetaminophen, activated protein c, alachlor,
.alpha.-melanocyte-stimulating hormone, amentoflavone, artemisia
capillaris thunb extract, artemisia iwayomogi extract, I-ascorbic
acid, antrodia camphorate, aucubin, baicalein, .beta.-lapachone,
blackberry extract, buchang-tang, capsaicin, catalposide, core
protein of hepatitis c virus, cyclolinteinone, diamide,
dihydroarteanniun, dobutamine, e-73 (cycloheximide analog), ecabet
sodium, emodin, ephedrae herba, equol, erbstatin, estrogen,
ethacrynic acid, fosfomycin, fungal gliotoxin,
gamisanghyulyunbueum, genistein, genipin, glabridin, glimepiride,
glucosamine sulfate, glutamine, gumiganghwaltang, heat shock
protein-70, hypochlorite, interleukin-13, isomallotochromanol,
isomallotochromene, vaccinia virus protein, kochia scoparia fruit,
leflunomide metabolite, losartin, 5'-methylthioadenosine, momordin
I, morinda officinalis extract, murr1 gene product,
neurofibromatosis-2 protein, u0126, penetratin, pervanadate,
.beta.-phenylethyl and 8-methylsulphinyloctyl isothiocyanates,
phenytoin, platycodin saponins, polymyxin .beta., poncirus
trifoliata fruit extract, probiotics, pituitary adenylate
cyclase-activating polypeptide, prostaglandin
15-deoxy-delta(12,14)-pgj(2), resiniferatoxin, sabaeksan,
saccharomyces boulardii anti-inflammatory factor, sesquiterpene
lactones (parthenolide; ergolide; guaianolides), st2
(interleukin-1-like receptor secreted form), thiopental,
tipifarnib, titanium, tnp-470, stinging nettle (urtica dioica)
plant extracts, trichomomas vaginalis infection, triglyceride-rich
lipoproteins, ursodeoxycholic acid, xanthium strumarium I,
vasoactive intestinal peptide, HIV-1 vpu protein, epoxyquinone a
monomer, ro106-9920, conophylline, mol 294, perrilyl alcohol,
mast205, rhein, 15-deoxy-prostaglandin j(2), antrodia camphorata
extract, .beta.-amyloid protein, surfactant protein .alpha., dq
65-79 (aa 65-79 of the .alpha. helix of the -chain of the class II
HLA molecule dqa03011), c5a, glucocorticoids (dexamethasone,
prednisone, methylprednisolone), interleukin-10, interleukin-11,
.alpha.-pinene, vitamin D, fox1j, dioxin, agastache rugosa leaf
extract, alginic acid, astragaloside iv, atorvastatin, blue
honeysuckle extract, n(1)-benzyl-4-methylbenzene-1,2-diamine,
buthus martensi karsch extract, canine distemper virus protein,
carbaryl, celastrol, chiisanoside, dehydroxymethylepoxyquinomicin,
dipyridamole, diltiazem, eriocalyxin .beta., estrogen enhanced
transcript, gangliosides, glucorticoid-induced leucine zipper
protein, harpagophytum procumbens extracts, heat shock protein 72,
hirsutenone, indole-3-carbinol, jm34 (benzamide derivative),
6-hydroxy-7-methoxychroman-2-carboxylic acid phenylamide,
leptomycin .beta., levamisole, 2-(4-morpholynl) ethyl butyrate
hydrochloride, nls cell permeable peptides, 2',8''-biapigenin,
nucling, o,o'-bismyristoyl thiamine disulfide, oregonin,
1,2,3,4,6-penta-o-galloyl-.beta.-d-glucose, platycodi radix
extract, phallacidin, piperine, pitavastatin, pn-50, rela peptides
(p1 and p6), retinoic acid receptor-related orphan
receptor-.alpha., rhubarb aqueous extract, rolipram, salvia
miltiorrhoza bunge extract, sc236 (a selective cox-2 inhibitor),
selenomethionine, sophorae radix extract, sopoongsan, sphondin,
younggaechulgam-tang, zud protein, zas3 protein, clarithromycin,
fluvastatin, leflunomide, oxidized
1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine,
serratamolide, moxifloxacin, sorbus commixta cortex, cantharidin,
cornus officinalis extract, neomycin, omapatrilat, enalapril, cgs
25462, onconase, paeoniflorin, rapamycin, sargassum hemiphyllum
methanol extract, shenfu, tripterygium polyglycosides, triflusal,
hepatoma protein, andrographolide, melittin, 1'-acetoxychavicol
acetate, 2-acetylaminofluorene, actinodaphine, adiponectin,
nicotinamide, 3-aminobenzamide, 7-amino-4-methylcoumarin, amrinone,
angiopoietin-1, anthocyanins, sequiterpene lactones, artemisinin,
atrial natriuretic peptide, atrovastat, avra protein, baicalein,
benfotiamine, .beta.-catenin, biliverdin, bisphenol .alpha., bovine
serum albumin, brazilian, bromelain, calcium/calmodulin-dependent
kinase kinase, calcitriol, campthothecin, sutherlandia frutescens,
caprofin, capsiate, carbocisteine, cat's claw bark, maca,
celecoxib, germcitabine, cheongyeolsaseuptang, chitosan,
ciclosporin, cinnamaldehyde, 2-methoxycinnamaldehyde, 2-
hydroxycinnamaldehyde, guaianolide 8-deoxylactucin, chlorophyllin,
chondrotin sulfate proteoglycan degradation product,
clarithromycin, cloricromene, commerical peritoneal dialysis
solution, compound K, 6-hydroxy-7-methoxychroman-2-carboxylic acid
phenylamide, cryptotanshinone, cyanoguanidine, cytochalasin d,
da-9201 (from black rice), danshenshu, decoy oligonucleotides,
diarylheptanoid
7-(4'-hydroxy-3'-methoxyphenyl)-1-phenylhept-4-en-3-one,
.alpha.-difluoromethylornithine, dim/13c, diterpenoids from isodon
rubescens or liverwort jungermannia,
4,10-dichloropyrido[5,6:4,5]thieno[3,2-d':3,2- d]-1, 2,
3-ditriazine, e3330, ent-kaurane diterpenoids, epinastine
hydrochloride, epoxyquinol .alpha., erythromycin, evans blue,
fenoldopam, fexofenadine hydrochloride, fibrates, fk778, flunixin
meglumine, flurbiprofen, fomes fomentarius methanol extracts,
fucoidan, glycoprotein-120, gallic acid, ganoderma lucidum,
homeobox protein, geranylgeraniol, ghrelin, ginkgolide .beta.,
glycyrrhizin, halofuginone, helenalin, herbal compound 861, HIV-1
resistance factor, hydroxyethyl starch, hydroxyethylpuerarin,
hypercapnic acidosis, hypericin, interleukin 4, IKB-like proteins,
imd-0354, insulin-like growth factor binding protein-3,jsh-21
(n1-benzyl-4-methylbenzene-1,2-diamine), kamebakaurin, kaposi's
sarcoma-associated herpesvirus k1 protein, ketamine, kt-90
(morphine synthetic derivative), linoleic acid, lithospermi radix,
lovastatin, macrolide antibiotics, mercaptopyrazine,
2-methoxyestradiol, 6 (methylsulfinyl)hexyl isothiocyanate, metals
(chromium, cadmium, gold, lead, mercury, zinc, arsenic), mevinolin,
monomethylfumarate, moxifloxacin, myricetin, myxoma virus mnf,
ndpp1, n-ethyl-maleimide, naringen, nicorandil, nicotine,
nilvadipine, nitrosoglutathione, extracts of ochna macrocalyx bark,
leucine-rich effector proteins of salmonella & shigella,
omega-3 fatty acids oridonin
1,2,3,4,6-penta-o-galloyl-beta-d-glucose, interferon inducible
protein, p21 (recombinant), peptide nucleic acid-DNA decoys,
pentoxifylline (1-(5'-oxohexyl) 3,7-dimetylxanthine, peptide yy,
pepluanone, perindopril, 6(5h)-phenanthridinone and benzamide,
phenyl-n-tert-butylnitrone, phyllanthus amarus extracts, protein
inhibitor of activatated stat1, pioglitazone, pirfenidone,
polyozellin, prenylbisabolane 3, pro-opiomelanocortin,
prostaglandin e2, protein-bound polysaccharide, pypaf1 protein,
pyridine n-oxide derivatives, pyrithione, quinadril, quinic acid,
raf kinase inhibitor protein, rapamycin, raloxifene, raxofelast,
rebamipide, rhus verniciflua stokes fruits 36 kda glycoprotein,
ribavirin, rifamides, ritonavir, rosiglitazone, sanggenon c,
santonin diacetoxy acetal derivative, secretory leucoprotease
inhibitor, n-(p-coumaroyl) serotonin, sesamin, simvastatin,
sinomenine, sirt1 deacetylase overexpression, siva-1, sm-7368,
solana nigrum I, 150 kda glycoprotein, sun c8079, tanacetum
larvatum extract, tansinones, taurine+niacine, thiazolidinedione
mcc-555, trichostatin .alpha., triclosan plus cetylpyridinium
chloride, triptolide, tyrphostin ag-126, uteroglobin, vascular
endothelial growth factor, verapamil, withaferin .alpha.,
5,7-dihydroxy-8-methoxyflavone, xylitol, yan-gan-wan, yin-chen-hao,
yucca schidigera extract, amp-activated protein kinase, apc0576,
artemisia sylvatica, bsasm, bifodobacteria, bupleurum fruticosum
phenylpropanoids, ebv protein, chromene derivatives,
dehydroevodiamine, 4'-demethyl-6-methoxypodophyllotoxin, ethyl
2-[(3-methyl-2,5-dioxo(3-pyrrol inyl))amino]-4-(trifluoromethyl)
pyrimidine-5-carboxylate, cycloprodigiosin hycrochloride,
dimethylfumarate, fructus benincasae recens extract,
glucocorticoids (dexametasone, prednisone, methylprednisolone),
gypenoside xlix, histidine, HIV-1 protease inhibitors (nelfinavir,
ritonavir, or saquinavir), 4-methyl-
-(3-phenyl-propyl)-benzene-1,2-diamine, kwei ling ko, ligusticum
chuanxiong hort root, nobiletin, NF.quadrature.B repression
factors, phenethylisothiocyanate, 4-phenylcoumarins, phomol, pias3,
pranlukast, psychosine, quinazolines, resveratrol, ro31-8220,
saucerneol d and saucerneol e, sb203580, tranilast,
3,4,5-trimethoxy-4'-fluorochalcone, uncaria tomentosum plant
extract, mesalamine, mesuol, pertussis toxin binding protein,
9-aminoacridine derivatives (including the antimalaria drug
quinacrine), adenosine and cyclic amp,
17-allylamino-17-demethoxygeldanamycin, 6-aminoquinazoline
derivatives, luteolin, manassantins .alpha. and .beta.,
paromyxovirus sh gene products, qingkailing, shuanghuanglian,
smilax bockii warb extract, tetracyclic a, tetrathiomolybdate,
trilinolein, troglitazone, witheringia solanacea leaf extracts,
wortmannin, .alpha.-zearalenol, antithrombin, rifampicin, and
mangiferin (see
http://people.bu.edu/gilmore/nf-kb/inhibitors/index.html which is
incorporated by reference herein for a list of potential
inhibitors). The presently disclosed invention can be especially
beneficial because pain patients treated with protein-based
cytokine inhibitors (for example and without limitation, etanercept
or infliximab) often have immune responses directed against the
recombinant (therapeutic) proteins. In the present invention, it is
unlikely that there will be a significant immune response against a
small molecule therapeutic compound.
[0045] The present invention can be used to treat a variety of
conditions related to NF.kappa.B activation and pro-inflammatory
cytokine responses. For example, embodiments according to the
present invention could be used to contribute to the treatment of
without limitation, osteoarthritis, alkylosing spondylitis,
psoriasis, rheumatoid arthritis (RA), sepsis and degenerative disc
disease. Further, it may be beneficial to coat implantable medical
devices such as, without limitation, stents and stent graft with
small molecule NF.quadrature.B pathway inhibitors.
[0046] In one embodiment according to the present invention, the
therapeutic agents described herein are delivered locally in order
to minimize undesirable side effects associated with systemic
delivery of the immunosuppressive agents. When delivered to local
sites containing cells that have a responsive NF.kappa.B pathway,
the therapeutic agents can be delivered through a device consisting
of an infusion pump and a catheter. Local sites of delivery can
include, but are not limited to the nerve root, the dorsal root
ganglion (DRG), and focal sites of inflammation (containing
infiltrating inflammatory cells). The distal, delivery end of the
catheter can be surgically positioned in the tissue in close
proximity to the targeted site (nerve root, DRG, etc).
Alternatively, the distal end of the catheter may be positioned to
deliver the therapeutic compound into the intrathecal space of the
spinal cord. For acute therapeutic compound delivery, the proximal
end of the catheter could remain outside of the patient's body and
be attached to an external, refillable pump. For chronic
administration of the compound, the proximal end of the catheter
could be attached to a pump implanted subcutaneously within a
patient. In this case, the pump would be able to be periodically
refilled using transcutaneous syringe injection.
[0047] The NF.kappa.B inhibitors can be locally delivered by
catheter and drug pump systems, delivered by direct local injection
or through the use of polymers and/or drug-eluting stents as
described in co-pending U.S. patent application Ser. No. 10/972,157
which is incorporated by reference herein. In one embodiment, a
"controlled administration system" including a direct and local
administration system can be used. A controlled administration
system can be a depot or a pump system, such as, without
limitation, an osmotic pump or an infusion pump. An infusion pump
can be implantable and can be, without limitation, a programmable
pump, a fixed rate pump, and the like. A catheter can be operably
connected to the pump and configured to deliver agents of the
present invention to a target tissue region of a subject. A
controlled administration system can be a pharmaceutical depot (a
pharmaceutical delivery composition) such as, without limitation, a
capsule, a microsphere, a particle, a gel, a coating, a matrix, a
wafer, a pill, and the like. A depot can comprise a biopolymer. The
biopolymer can be a sustained-release biopolymer. The depot can be
deposited at or near, generally in close proximity, to a target
site. Embodiments of the present invention also can be delivered
through the use of liposomes, polyethyleneimine, by iontophoresis,
or by incorporation into other vehicles, such as biodegradable or
non-biodegradable nanocapsules. The delivery technology (drug pump
or polymer formulations) can also be useful for the delivery of
small molecules directed against other gene targets for other
clinical indications.
[0048] The present invention also includes kits. In one embodiment,
the kits of the present invention comprise NF.kappa.B inhibitors of
the present invention. In another embodiment, a kit of the present
invention can contain one or more of the following in a package or
container: (1) one or more NF.kappa.B inhibitors of the present
invention; (2) one or more pharmaceutically acceptable adjuvants or
excipients; (3) one or more vehicles for administration, such as
one or more syringes; (4) one or more additional bioactive agents
for concurrent or sequential administration; (5) instructions for
administration; and/or (6) a catheter and drug pump. Embodiments in
which two or more of components (1)-(6) are found in the same
container can also be used.
[0049] When a kit is supplied, the different components of the
compositions included can be packaged in separate containers and
admixed immediately before use. Such packaging of the components
separately can permit long-term storage without losing the active
components' functions. When more than one bioactive agent is
included in a particular kit, the bioactive agents may be (1)
packaged separately and admixed separately with appropriate
(similar or different) vehicles immediately before use, (2)
packaged together and admixed together immediately before use or
(3) packaged separately and admixed together immediately before
use. If the chosen compounds will remain stable after admixture,
however, the admixture need not occur immediately before use but
can occur at a time before use, including in one example, minutes,
hours, days, months or years before use or in another embodiment at
the time of manufacture.
[0050] The compositions included in particular kits of the present
invention can be supplied in containers of any sort such that the
life of the different components are preserved and are not adsorbed
or altered by the materials of the container. For example, sealed
glass ampules can contain lyophilized agents or variants or
derivatives thereof or other bioactive agents, or buffers that have
been packaged under a neutral, non-reacting gas, such as, without
limitation, nitrogen. Ampules can consist of any suitable material,
such as, without limitation, glass, organic polymers, such as,
polycarbonate, polystyrene, etc., ceramic, metal or any other
material typically employed to hold similar reagents. Other
examples of suitable containers include, without limitation, simple
bottles that may be fabricated from similar substances as ampules,
and envelopes, that can comprise foil-lined interiors, such as
aluminum or an alloy. Other containers include, without limitation,
test tubes, vials, flasks, bottles, syringes, or the like.
Containers can have one or more sterile access ports, such as a
bottle having a stopper that can be pierced by a hypodermic
injection needle. Other containers may have two compartments that
are separated by a readily removable membrane that upon removal
permits the components to be mixed. Removable membranes may be,
without limitation, glass, plastic, rubber, etc.
[0051] As stated earlier, kits can also be supplied with
instructional materials. Instructions may be printed on paper or
other substrate, and/or may be supplied as an electronic-readable
medium, such as a floppy disc, CD-ROM, DVD-ROM, Zip disc,
videotape, audiotape, flash memory device, etc. Detailed
instructions may not be physically associated with the kit;
instead, a user may be directed to an internet web site specified
by the manufacturer or distributor of the kit, or supplied as
electronic mail.
[0052] The terms "a" and "an" and "the" and similar referents used
in the context of describing the invention (especially in the
context of the following claims) are to be construed to cover both
the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. Recitation of ranges of values
herein is merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range. Unless otherwise indicated herein, each individual value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g. "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed. No
language in the specification should be construed as indicating any
non-claimed element essential to the practice of the invention.
[0053] Groupings of alternative elements or embodiments of the
invention disclosed herein are not to be construed as limitations.
Each group member may be referred to and claimed individually or in
any combination with other members of the group or other elements
found herein. It is anticipated that one or more members of a group
may be included in, or deleted from, a group for reasons of
convenience and/or patentability. When any such inclusion or
deletion occurs, the specification is herein deemed to contain the
group as modified thus fulfilling the written description of all
Markush groups used in the appended claims.
[0054] Certain embodiments of this invention are described herein,
including the best mode known to the inventors for carrying out the
invention. Of course, variations on these certain embodiments will
become apparent to those of ordinary skill in the art upon reading
the foregoing description. The inventor expects skilled artisans to
employ such variations as appropriate, and the inventors intend for
the invention to be practiced otherwise than specifically described
herein. Accordingly, this invention includes all modifications and
equivalents of the subject matter recited in the claims appended
hereto as permitted by applicable law. Moreover, any combination of
the above-described elements in all possible variations thereof is
encompassed by the invention unless otherwise indicated herein or
otherwise clearly contradicted by context.
[0055] Furthermore, numerous references have been made to patents
and printed publications throughout this specification. Each of the
above cited references and printed publications are herein
individually incorporated by reference in their entirety.
[0056] In closing, it is to be understood that the embodiments of
the invention disclosed herein are illustrative of the principles
of the present invention. Other modifications that may be employed
are within the scope of the invention. Thus, by way of example, but
not of limitation, alternative configurations of the present
invention may be utilized in accordance with the teachings herein.
Accordingly, the present invention is not limited to that precisely
as shown and described.
* * * * *
References