U.S. patent application number 12/643665 was filed with the patent office on 2010-04-22 for method for treating diabetic peripheral neuropathic pain.
This patent application is currently assigned to SCHWARZ PHARMA AG. Invention is credited to Norma Selve.
Application Number | 20100099770 12/643665 |
Document ID | / |
Family ID | 8176866 |
Filed Date | 2010-04-22 |
United States Patent
Application |
20100099770 |
Kind Code |
A1 |
Selve; Norma |
April 22, 2010 |
METHOD FOR TREATING DIABETIC PERIPHERAL NEUROPATHIC PAIN
Abstract
The present invention concerns the novel use of compounds of the
Formula I: for treating allodynia as major and unique pain symptom
independent of the nature of an underlying disease, but that is
often related to neuropathic pain or other different types of
chronic or phantom pain. ##STR00001##
Inventors: |
Selve; Norma; (Troisdorf,
DE) |
Correspondence
Address: |
HARNESS, DICKEY, & PIERCE, P.L.C
7700 Bonhomme, Suite 400
ST. LOUIS
MO
63105
US
|
Assignee: |
SCHWARZ PHARMA AG
Monheim
DE
|
Family ID: |
8176866 |
Appl. No.: |
12/643665 |
Filed: |
December 21, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/EP02/03032 |
Mar 19, 2002 |
|
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12643665 |
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Current U.S.
Class: |
514/616 |
Current CPC
Class: |
A61P 25/00 20180101;
A61K 31/165 20130101; A61P 25/04 20180101; A61P 27/16 20180101;
A61P 29/00 20180101; A61P 25/02 20180101; A61P 23/00 20180101 |
Class at
Publication: |
514/616 |
International
Class: |
A61K 31/16 20060101
A61K031/16; A61P 23/00 20060101 A61P023/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 21, 2001 |
EP |
01 107 026.5 |
Claims
1-9. (canceled)
10. A method for treating pain in a subject, comprising
administering to the subject a therapeutically effective amount of
a compound of formula (I): ##STR00003## wherein: Ar is phenyl which
is unsubstituted or substituted with at least one halo group; Q is
lower alkoxy containing 1-3 carbon atoms; and Q.sub.1 is methyl; or
a pharmaceutically acceptable salt thereof; wherein the pain
comprises diabetic peripheral neuropathic pain.
11. The method of claim 10, wherein the pain comprises
allodynia.
12. The method of claim 10, wherein the compound or salt thereof is
administered by an oral or parenteral route of administration.
13. The method of claim 10, wherein the compound is administered
orally in a pharmaceutical composition that further comprises a
pharmaceutically acceptable carrier.
14. The method of claim 13, wherein the pharmaceutical composition
is in a form of a tablet.
15. The method of claim 10, wherein the compound or salt thereof is
in the R configuration.
16. The method of claim 15, wherein the compound or salt thereof is
substantially enantiopure.
17. The method of claim 10, wherein the compound of formula (I) is
(R)-2-acetamido-N-benzyl-3-methoxypropionamide.
18. The method of claim 17, wherein the compound is orally
administered in a daily dose of about 1 mg to about 600 mg.
19. The method of claim 18, wherein the compound is orally
administered in a daily dose of about 1 mg to about 300 mg.
20. The method of claim 18, wherein the compound is orally
administered in a daily dose of about 300 mg to about 600 mg.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to the novel use of a group of
specific amino acid derivatives according to Formula I for the
preparation of pharmaceutical compositions useful for the treatment
of allodynia as a major and unique pain symptom independent of the
nature of an underlying disease, but that is often related to
neuropathic pain or other different types of chronic or phantom
pain. Particularly the present invention relates to the novel use
of harkoseride and its derivatives for the preparation of
pharmaceutical compositions useful for the treatment of allodynia
as a major and unique pain symptom independent of the nature of an
underlying disease, but that is often related to neuropathic pain,
or other different types of chronic or phantom pain.
[0002] The chemical name of SPM 927 which is also hereinafter
referred to as harkoseride is
(R)-2-Acetamido-N-benzyl-3-methoxypropionamide.
[0003] The compounds of the Invention are known agents useful in
antiseizure therapy for central nervous system disorders such as
epilepsy, stroke and cerebral ischemia.
[0004] The instant invention concerns the novel use of a compound
of Formula I below for the preparation of pharmaceutical
compositions useful for the treatment of pain, particularly for the
treatment of chronic pain disorders and especially for the
treatment of allodynia as a major and unique pain symptom
independent of the nature of an underlying disease, but that is
often related to neuropathic pain conditions, or other different
types of chronic or phantom pain and tinnitus aureum.
[0005] According to the invention compounds are those of Formula
I
##STR00002##
or a pharmaceutically acceptable salt thereof wherein Ar is phenyl
which is unsubstituted or substituted with at least one halo group;
Q is lower alkoxy containing 1-3 carbon atoms and Q.sub.1 is
methyl; diastereomers and enantiomers of compounds of Formula I are
included in the invention.
[0006] Preferred compounds of the invention are those according to
Formula I in which the compounds are an (R), (S), or (R,S)
isomer.
[0007] The most preferred compound of the invention is
(R)-2-Acetamido-N-benzyl-3-methoxypropionamide or its
pharmaceutically acceptable salt thereof.
[0008] Pain is a subjective experience and the perception of pain
is performed in particular parts of the Central Nervous System
(CNS).
[0009] Usually noxious (peripheral) stimuli are transmitted to the
Central Nervous System beforehand, but pain is not always
associated with nociception.
[0010] A broad variety of different types of clinical pain exists,
that are derived from different underlying pathophysiological
mechanisms and that will need different treatment approaches.
[0011] The perception of pain may be characterized by three major
types of clinical pain: [0012] acute pain [0013] chronic pain
[0014] neuropathic pain
[0015] Acute clinical pain typically results from inflammation or
soft tissue injury. This type of pain is adaptive and has the
biologically relevant function of warning and enabling healing and
repair of an already damaged body part to occur undisturbed. A
protective function is achieved by making the injured/inflamed area
and surrounding tissue hypersensitive to all stimuli so that
contact with any external stimulus is avoided. The neuronal
mechanisms underlying this type of clinical pain are fairly well
understood and pharmacological control of acute clinical pain is
available and effective by means of e.g. Non-Steroidal
Anti-Inflammatory Drugs (NSAIDs) up to opioids depending on type
and extension of the sensation.
[0016] Chronic clinical pain appears as sustained sensory
abnormalities resulting from an ongoing peripheral pathology such
as cancer of chronic inflammation (e.g. arthritis) or it can be
independent of the initiating triggers. The latter being
maladaptive, offering no survival advantage and very often no
effective treatment is available.
[0017] Neuropathic pain is caused by injury or infection of
peripheral sensory nerves. It includes, but is not limited to pain
from peripheral nerve trauma, herpes virus infection, diabetes
mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and
vasculitis. Neuropathic pain is also caused by nerve damage from
chronic alcoholism, human immunodeficiency virus infection,
hypothyroidism, uremia, or vitamin deficiencies. Neuropathic pain
includes, but is not limited to pain caused by nerve injury such
as, for example, the pain diabetics suffer from.
[0018] Neuropathic pain shows two different pathophysiological
mechanisms which have to be considered:
[0019] First, enhanced activity of afferent nociceptive neurons
following sensitisation of (sleeping) neurons (e.g., inflammatory
pain, cancer pain, headache, lower back pain, visceral pain,
migraine) with the primary afferent nociceptive neuron remaining
intact, though the receptor activity is changed and reduced
thresholds, increase of firing rates and starting of or increase of
spontaneous activity are typically found.
[0020] Second, ectopic activity of afferent nociceptive neurons
following lesions of its axons (e.g., peripheral and central
neuropathic pain), with the primary afferent neuron being damaged.
This leads to irreversible peripheral and central biochemical,
morphological and functional changes. Therefore, (peripheral)
neuropathy is broadly defined as a disease of the (peripheral)
nervous system.
[0021] There are several causes of human neuropathy with
considerable variability in symptoms and neurological deficits.
Painful neuropathies are defined as neurological disorders
characterised by persistence of pain and hypersensitivity in a body
region, of which the sensory innervation has been damaged, but
damage to sensory nerves does not always produce neuropathic pain,
usually loss of sensation rather than hypersensitivity or pain are
observed.
[0022] Specific somatosensory disorders are referred to as
allodynia (innocuous somatosensory stimulation evokes abnormal
intense pain sensation with an explosive, radiating character often
outlasting stimulus duration like a trigger), hyperalgesia (noxious
stimulation evokes more intense and prolonged pain sensations),
paresthesia (spontaneous aversive but nonpainful sensations,
described as tingling or "pins and needles"), dysesthesia (evoked
as well as spontaneous abnormal sensations).
[0023] Several key events are agreed in as common
pathophysiological events of abnormal pain states particularly
following peripheral nerve injury. Thus, high frequency spontaneous
discharge from ectopic site is followed by an increased
responsiveness of dorsal horn neurons and expansion of the
receptive field, often defined as central sensitisation.
[0024] Common analgesics like opioids and non-steroidal
anti-inflammatory drugs (NSAIDs) improve only insufficiently
chronic abnormal pain syndromes. In the search for alternative
treatment regimes to produce satisfactory and sustained pain
relief, corticosteroids, conduction blockade, glycerol,
antidepressants, local anesthetics, gangliosids and
electrostimulation have been tried, but mainly anti-convulsants
have been found useful against various types of neuropathic pain
conditions, but appear to be most effective in cases of paroxysmal,
lancinating events, e.g. trigeminal neuralgia.
[0025] If general overactivity and unleaded low threshold
activation of sensory neurons is considered as one of the main
syndromes of neuropathy and neuropathic pain sensation with a
marked mechanoallodynia as the most disabling clinical symptom,
selective inhibition of this pathophysiological event instead of
general inhibition of high threshold noxious stimuli (by e.g. local
anesthetics) of the normal sensory nociception provides clear
advantages.
[0026] The conditions listed above are known to be poorly treated
by currently marketed analgesics such as opioids or nonsteroidal
anti-inflammatory drugs (NSAID's) due to insufficient efficacy or
limiting side effects.
[0027] It is an object of this invention to provide a novel use of
compounds according to the aforementioned Formula I and its
derivatives for the preparation of pharmaceutical compositions
useful for the treatment of allodynia as a major and unique pain
symptom independent of the nature of an underlying disease, but
that is often related to neuropathic pain, or other different types
of chronic or phantom pain.
[0028] Particularly it is an object of this invention to provide a
novel use of harkoseride for the preparation of
pharmaceutical-compositions useful for the treatment of allodynia
as a major and unique pain symptom independent of the nature of an
underlying disease, but that is often related to neuropathic pain,
or other different types of chronic or phantom pain.
[0029] Harkoseride, which chemical name is
(R)-2-Acetamido-N-benzyl-3-methoxypropion-amide is one derivative
selected of the group of specific amino acid derivatives.
[0030] This group of substances is disclosed in U.S. Pat. No.
5,378,729; U.S. Pat. Nos. 5,654,301 and 5,773,475. They show
activity for the treatment of epilepsy and stroke. But there is no
disclosure in the above references to make obvious the present
invention.
[0031] The compounds of the present invention may form
pharmaceutically acceptable salts with both organic and inorganic
acids or bases.
[0032] For example, the acid addition salts of the basic compounds
are prepared either by dissolving the free base in aqueous or
aqueous alcohol solution or other suitable solvents containing the
appropriate acid and isolating the salt by evaporating the
solution.
[0033] Examples of pharmaceutically acceptable salts are
hydrochlorides, hydrobromides, hydrosulfates, etc. as well as
sodium, potassium, and magnesium, etc. salts.
[0034] The compounds of the present invention can contain one or
several asymmetric carbon atoms. The invention includes the
individual diastereomers or enantiomers, and the mixtures thereof.
The individual diastereomers or enantiomers may be prepared or
isolated by methods already well-known in the art.
[0035] According to the invention it is preferred that the
compounds are in the (R)-configuration. It is preferred that the
compounds are substantially enantiopure. Most preferred is the
compound (R)-2-Acetamido-N-benzyl-3-methoxypropionamide.
[0036] The compounds of this invention may be synthesized as
disclosed in the documents U.S. Pat. No. 5,378,729; U.S. Pat. No.
5,654,301 and U.S. Pat. No. 5,773,475.
[0037] The compounds made by the synthetic methods can be used as
pharmaceutical compositions as agent in the treatment of pain when
an effective-amount of a compound of the Formula I, together with a
pharmaceutically acceptable carrier is used. The pharmaceutical can
be used in a method for treating such disorders in mammals,
including human, suffering therefrom by administering to such
mammals an effective amount of the compounds described above in
unit dosage form.
[0038] The pharmaceutical compound, made in accordance with the
present invention, can be prepared and administered in a wide
variety of dosage forms by either oral or parenteral routes of
administration. For example, these pharmaceutical compositions can
be made in inert, pharmaceutically acceptable carriers which are
either solid or liquid. Solid form preparations include powders,
tablets, dispersible granules, capsules, cachets, and
suppositories. Other solid and liquid form preparations could be
made in accordance with known methods of the art and administered
by the oral route in an appropriate formulation, or by a parenteral
route such as intravenous, intramuscular, or subcutaneous injection
as a liquid formulation.
[0039] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 1 mg to about
2.times.300 mg per day per patient. A daily dose range of about 1
mg to about 300 mg is preferred. The dosages, however, may be
varied depending upon the requirement with a patient, the severity
of the condition being treated, and the compound being employed.
Determination of the proper dosage for particular situations is
within the skill of the art.
[0040] The following working examples selected from specific animal
models show the anti-neuropathic pain activity of harkoseride and
its derivatives in general and the antiallodynia efficacy of
harkoseride and its derivatives in particular.
1. EXAMPLE 1
Formalin Test, Rat
[0041] Significant and dose dependent efficacy of harkoseride could
be demonstrated in the late phase of the rat formalin test.
[0042] The formalin test is a chemically-induced tonic pain model
in which biphasic changes of nociceptive behaviour are assessed and
spinal/supraspinal plasticity of nociception is considered as a
molecular basis for neuropathic pain particularly during the second
(=late) phase of the test, during which most clinically used drugs
against neuropathic pain are active. These features have resulted
in the formalin test being accepted as a valid model of persistent
clinical pain.
[0043] The compound was tested for anti-nociceptive properties by
use of the weighted behavioural scoring method: Freely moving
animals underwent observational assessment of the position of the
left hind paw according to a rating score scaled 0-3 before and 10,
20, 30 and 40 min after injection of 0.05 ml of sterile 2.5%
formalin under the skin on the dorsal surface of the paw.
Harkoseride, administered i.p. just prior to formalin injection
produced dose dependant reduction of the formalin-induced tonic
inflammatory nociceptive behaviour as shown in table 1 (weighted
pain scores.+-.SEM, n=11-12/group).
TABLE-US-00001 TABLE 1 Weight d pain scor, formalin t st, rat Dose
No. of Time After Injection of formalin and SPM 927 [mg/kg] Animals
BASELINE 10 MIN 20 MIN 30 MIN 40 MIN 0 11 0.00 .+-. 0.00 0.30 .+-.
0.16 0.93 .+-. 0.21 1.84 .+-. 0.19 2.10 .+-. 0.24 5 12 0.01 .+-.
0.01 0.31 .+-. 0.11 0.78 .+-. 0.23 1.47 .+-. 0.20 1.46 .+-. 0.19*
10 11 0.00 .+-. 0.00 0.42 .+-. 0.17 0.33 .+-. 0.16* 1.02 .+-. 0.27*
1.05 .+-. 0.19* 20 12 0.00 .+-. 0.00 0.48 .+-. 0.18 0.57 .+-. 0.14
0.78 .+-. 0.18* 1.02 .+-. 0.24* 40 12 0.00 .+-. 0.00 0.12 .+-. 0.05
0.10 .+-. 0.04* 0.09 .+-. 0.06* 0.12 .+-. 0.06* *= Significant
difference from vehicle (ANOVA corrected for multiple comparisons p
.ltoreq. 0.05. The term ANOVA stands for Analysis of Variance.
[0044] These results support and confirm the hypothesized
anti-neuropathic pain activity of the compound.
[0045] Data reported here support and give the necessary scientific
basis for the activity observed earlier in the writhing test and
the mouse formalin test. The former data being limited due to the
fact that the writhing test is considered a very unspecific test
with some tonic chemically-induced nociceptive aspects that usually
gives positive results for all psychoactive drug muscle relaxants
etc. therefore not being specific enough to claim specific
activity. In addition, the former results obtained in the mouse
formalin test, lacks clear evidence of dose relationship and
therefore specificity of the observed effects for harkoseride.
Furthermore, the only and highest dose giving significant effects
in the first investigation already was found to cause clear
behavioral side effects. Therefore, these drugs include changes in
behavior, these drug-related changes cannot be claimed as
antinociceptive any longer.
[0046] Therefore, only the newly reported data provided here can be
considered an in vivo proven antinociceptive effect of harkoseride,
with dose dependency serving as measure of specificity and
improvement of antinociceptive behavior as being unrelated to toxic
effects.
EXAMPLE 2
Chronic Constriction Injury
CCI, Bennett-Model
[0047] The effectiveness of harkoseride in reducing spontaneous
chronic pain, mechanical allodynia, and thermal hyperalgesia was
tested using the chronic constriction injury (CCI) model of
peripheral neuropathy, one of the best characterised in vivo animal
models used to study chronic pain due to peripheral nerve injury.
In this model, loose ligatures are placed around the sciatic nerve,
which produces axonal swelling and a partial deafferentation
manifested as a significant but incomplete loss of axons in the
distal portion of the peripheral nerve. One of the prominent
behaviours seen following sciatic nerve ligation is the appearance
of hind paw guarding, thought to be an indication of an ongoing
spontaneous chronic pain. Support for this idea is derived from
reports of increased spinal cord neural activity, and increased
spontaneous neuronal discharge in spinothalamic tract neurons and
in the ventrobasal thalamus in the absence of overt peripheral
stimulation. In addition to the appearance of spontaneous pain
behaviours, several abnormalities in stimulus evoked pain occur as
a result of CCI, including thermal hyperalgesia and mechanical
allodynia. The development of these abnormal stimulus-evoked pains
has also been reported as occurring in areas outside the territory
of the damaged nerve, areas innervated by uninjured nerves.
[0048] Behavioural tests for spontaneous pain, thermal
hyperalgesia, and mechanical allodynia were conducted to evaluate
different components of neuropathic pain. Baseline data for each
test was collected prior to any experimental procedure; in
addition, all animals were tested for the development of chronic
pain behaviours 13-25 days after CCI surgery 1 day prior to the day
of vehicle (0.04 ml sterile water/10 g body weight) or drug
administration and after vehicle/drug administration. The sequence
of the tests was (1) spontaneous pain-related behaviour (2)
mechanical allodynia, (3) thermal hyperalgesia in order to minimise
the influence of one test on the result of the next. The testing
procedures and results are presented separately for each aspect of
chronic pain. Either 0 (vehicle, 0.04 ml/10 g body weight), 5, 10,
20 or 40 mg/kg of SPM 927 (n=7-23/group) was administered i.p. 15
minutes before the first behavioural test.
[0049] Spontaneous pain (ongoing pain without an apparent external
stimulus) of the ligated paw was assessed for 5 min following a 10
min acclimation period by use of a rating score (weighted behaviour
score scaled 0-5).
[0050] Harkoseride did not change the level of spontaneous pain
induced by unilateral chronic constriction injury as shown in table
2 (weighted pain scores.+-.SEM).
TABLE-US-00002 TABLE 2 Spontaneous nociception, CCI model, rat Dose
No. of [mg/kg] Animals Baseline Post-op Post-op + Drug 0 23 0 .+-.
0 1.4 .+-. 0.15 1.2 .+-. 0.14 5 9 0 .+-. 0 2.0 .+-. 0.10 1.8 .+-.
0.18 10 20 0.0019 .+-. 0.0019 1.5 .+-. 0.10 1.5 .+-. 0.11 20 8 0
.+-. 0 1.1 .+-. 0.17 0.9 .+-. 0.14 40 10 0.0004 .+-. 0.0004 1.3
.+-. 0.12 0.8 .+-. 0.28
[0051] Thermal hyperalgesia was assessed by means of withdrawal
latency in response to radiant heat applied to the subplantar
surface of the ligated rat hind paw. As compared to the baseline
latency (s), a significant decrease in the (postoperative) latency
of foot withdrawal in response to the thermal stimulus was
interpreted as indicating the presence of thermal hyperalgesia
following chronic constriction injury.
[0052] Harkoseride dose dependently reduced chronic constriction
injury-induced thermal hyperalgesia as shown in table 3 [latencies
(s).+-.SEM]. Significant effects were observed only at the highest
doses tested (20 and 40 mg/kg i.p.) with the maximum effect seen
already at 20 mg/kg i.p.
TABLE-US-00003 TABLE 3 Thermal hyperalgesia, CCI model, rat Dose
No. of [mg/kg] Animals Baseline Post-op Post-op + Drug 0 13 9.8
.+-. 0.74 7.0 .+-. 0.29 7.3 .+-. 0.43 5 7 10.5 .+-. 0.68 8.1 .+-.
0.59 9.2 .+-. 0.98 10 7 9.2 .+-. 0.68 7.1 .+-. 0.60 8.1 .+-. 0.59
20 8 10.0 .+-. 0.70 7.0 .+-. 0.56 9.7 .+-. 0.96* 40 8 8.3 .+-. 0.57
7.4 .+-. 0.48 10.2 .+-. 0.75* *= Significant difference from
vehicle (ANOVA corrected for multiple comparisons p .ltoreq.
0.05.
[0053] Mechanical sensitivity and allodynia of the ligated rat hind
paw was quantified by brisk foot withdrawal in response to normally
innocuous mechanical stimuli as described previously.
Responsiveness to mechanical stimuli was tested with a calibrated
electronic Von Frey pressure algometer connected to an online
computerised data collection system. A significant decrease in the
post operative compared to baseline pressure (g/mm.sup.2) necessary
to elicit a brisk foot withdrawal in response to this mechanical
stimulus is interpreted as mechanical allodynia.
[0054] Harkoseride dose dependently reduced the intensity of
mechanical allodynia induced by unilateral nerve ligation as shown
in table 4 [pressure (g/mm.sup.2).+-.SEM]. Regression analysis
showed a positive linear correlation between the dose of
Harkoseride and the increase in the amount of force required to
produce foot withdrawal
TABLE-US-00004 TABLE 4 Mechanical allodynia, CCI model, rat Dose
No. of [mg/kg] Animals Baseline Post-op Post-op + Drug 0 20 41.6
.+-. 2.20 18.8 .+-. 2.09 20.2 .+-. 1.90 5 11 53.6 .+-. 3.35 16.4
.+-. 2.56 21.8 .+-. 2.34 10 17 42.9 .+-. 2.55 21.2 .+-. 2.13 29.2
.+-. 2.85* 20 8 46.1 .+-. 2.62 24.7 .+-. 2.78 39.6 .+-. 3.62* 40 9
48.4 .+-. 3.84 23.9 .+-. 2.23 43.0 .+-. 5.48* *= Significant
difference from vehicle (ANOVA corrected for multiple comparisons,
p .ltoreq. 0.05).
[0055] These results support and confirm the hypothesised
anti-allodynia efficacy of Harkoseride. Furthermore this effect is
additionally related to neuropathic pain and therefore supports the
potential clinical use of the compound by mimicking the clinical
situation of symptom related treatment as close as possible.
[0056] Further proof of specificity of the anti-allodynia effect of
harkoseride was given by negative results in the tail flick test
excluding typical opioid-like analgesia of the compound. The former
data obtained in mice could be repeated and confirmed in a second
species, the rat, by additional means of more appropriate choice of
the doses tested:
EXAMPLE 3
Tail Flick Test, Rat
[0057] Harkoseride was additionally tested for potential activity
in acute spinal thermal nociception using the tail flick test. In
this model of acute thermal spinal/reflex hyperalgesia radiant heat
is applied to the animal's tail approximately 2 cm from the tip and
time latency for withdrawal reaction is automatically assessed by
an algometer, a defined maximal stimulus time prevents tissue
damage. This test is widely used as an assay for the
anti-nociceptive efficacy of pharmacological agents and is highly
predictive of acute analgesic efficacy in humans. Usually pure
analgesics of the opioid type are most active; neither adjuvants
like amitryptiline nor anti-epileptics nor NSAIDs (non-steroidal
anti-inflammatory drugs) are active.
[0058] Results for 20 and 40 mg/kg harkoseride i.p are shown in
table 5 [percent anti-nociception, calculated as [{(post-drug
latency)-(pre-drug-latency)}/{(max. latency)-(pre-drug
latency)}.times.100].+-.SEM, n=12/group]. A baseline or pre-drug
tail-flick latency was determined by averaging 5 consecutive
measurements taken 2 minutes apart. Vehicle (sterile water 0.04
ml/10 g body weight) or harkoseride were then administered and tail
flick latencies recorded at 10-minute intervals for the next 60
minutes. Even at doses giving maximum effect in the rat formalin
test (see above), harkoseride had little or no effect on the
latency of the tail flick reflex.
TABLE-US-00005 TABLE 5 Acute thermal hyperalgesia, tail flick, rat
Anti-nociceptive effect [%] of different Time after doses [mg/kg]
of i.p. Harkoseride SPM 927 [min] 0 20 40 10 -2.1 .+-. 3.08 5.0
.+-. 3.94 -1.6 .+-. 12.82 20 -0.5 .+-. 3.19 9.7 .+-. 7.51 -4.3 .+-.
14.04 30 4.4 .+-. 4.71 9.7 .+-. 2.37 -2.3 .+-. 9.14 40 10.4 .+-.
5.91 1.7 .+-. 7.42 -4.4 .+-. 11.44 50 7.6 .+-. 4.58 5.4 .+-. 4.12
0.3 .+-. 15.50 60 7.4 .+-. 6.07 8.1 .+-. 5.20 -5.5 .+-. 14.11
[0059] Therefore no anti-nociceptive effect of harkoseride was
detectable in the tail-flick test, this supports the hypothesised
profile of harkoseride with highly specific anti-allodynia
properties and not being active in conditions of acute pain.
EXAMPLE 4
The Anti-Nociceptive Activity of Harkoseride in Comparison with
Gabapentin
[0060] In the following explained study the used harkoseride is
hereinafter abbreviated as SPM 927 and gabapentin is hereinafter
abbreviated as GBP.
Objective
[0061] The major aim of this study was to assess the
anti-nociceptive activity of SPM 927 and gabapentin (GBP) in rodent
models for inflammatory pain and to compare the in vivo effects of
each drug with each other.
Methods:
[0062] Carrageenan-induced mechanical hyperalgesia in rats was
induced by subplantar injection of a 0.1 ml of a 2% carrageenan
suspension and measured 3 h afterwards by the paw pressure
(Randall-Sellito) test.
[0063] Subchronic inflammatory nocicpetion in mice was induced by
the subplantar injection of formalin (0.02 ml of a 5% solution).
Nociceptive behaviour (paw licking) was measured and quantified
between 0 and 5 min (acute pain) and between 20 and 30 min
(subchronic inflammatory pain) after formalin.
[0064] Drugs and experimental design: SPM 927 and GBP were
suspended in 1% methylcellulose and administered i.p. at doses of
10 mg/kg, 20 mg/kg and 40 mg/kg. Pre-treatment time was 30 min
before pain measurement. One group of animals served as controls
and consequently received an injection of solvent (10 ml/kg) and
another group of animals received a reference compound (Carrageenan
test: 10 mg/kg indomethacin; Formalin test: 10 mg/kg morphine).
Each compound was tested in a separate experiment and each
experiment included a control and a reference group. 10 rats per
group were used in the Carrageenan test and 6 mice per group in the
formalin test.
Results:
[0065] Carrageenan-induced mechanical hvperalgesia in rats: Results
are summarized in the following table 6.
TABLE-US-00006 TABLE 6 VEHICLE VEHICLE non-inflamed inflamed SPM
927 SPM 927 SPM 927 Indomethacin paw paw [10] [20] [40] [10]
nociceptive 330 .+-. 16 164 .+-. 15.sup.a 324 .+-. 15.sup.b 426
.+-. 24.sup.b 444 .+-. 13.sup.b 384 .+-. 11.sup.b threshold VEHICLE
VEHICLE non-inflamed inflamed Indomethacin paw paw GBP [10] GBP
[20] GBP [40] [10] nociceptive 396 .+-. 15 204 .+-. 10.sup.a 254
.+-. 39 296 .+-. 31 282 .+-. 33 370 .+-. 15.sup.b threshold
.sup.aindicates a significant difference in comparison with the
non-inflamed paw (p < 0.05; Student's t-test) .sup.bindicates a
significant difference in comparison with the vehicle treated group
(p < 0.05; Dunnett's test)
[0066] In all three experiments significant mechanical hyperalgesia
developed as shown by significant differences in the nociceptive
threshold in the inflamed as compared to the non-inflamed paw.
[0067] All doses of SPM 927 resulted in a full reversal of
Carrageenan-induced mechanical hyperalgesia.
[0068] The antinociceptive of SPM 927 was comparable to that of the
reference compound Indomethacin.
[0069] GBP had no significant effect on Carrageenan induced
mechanical hyperalgesia at the doses tested.
[0070] Subchronic inflammatory nociception in mice (formalin test):
Results are summarized in the following table 7.
TABLE-US-00007 TABLE 7 SPM SPM Phase VEHICLE 927 [10] 927 [20] SPM
927 [40] Morphine [10] nociceptive early 84 .+-. 16 67 .+-. 15 69
.+-. 8 8 .+-. 8.sup.a 6 .+-. 3.sup.a threshold [s] late 119 .+-. 18
58 .+-. 16.sup.a 128 .+-. 16 17 .+-. 17.sup.a 10 .+-. 8.sup.a
VEHICLE GBP [10] GBP [20] GBP [40] Morphine [10] nociceptive early
106 .+-. 15 98 .+-. 20 102 .+-. 17 72 .+-. 10 8 .+-. 6.sup.a
threshold [s] late 111 .+-. 24 133 .+-. 30 118 .+-. 13 73 .+-. 13 0
.+-. 0.sup.a .sup.aindicates a significant difference in comparison
with the vehicle treated group (p < 0.05; Dunnett's test)
[0071] A clear nociceptive response was induced by formalin.
SPM-927 dose dependently suppressed the nociceptive response. The
efficacy of SPM 927 was similar to that of morphine i.e. a near
complete reversal of the formalin-induced nociception. GBP slightly
but not significantly inhibited the nociceptive response induced by
formalin
EXAMPLE 5
[0072] The following Tables 8 and 9 show the effects of harkoseride
(hereinafter referred tows SPM 927), carbamazepine, levetiracetam,
gabapentin and morphine in the neuropathic pain (CHUNG) test in the
rat. Eight (8) rats per group were used.
[0073] Table 8 shows the examined effects by tactile stimulation on
lesioned paw.
[0074] Table 9 shows the examined effects by thermal stimulation on
lesioned paw.
[0075] In general, all compounds showed more pronounced effects on
tactile nociceptive stimulation than on thermal nociceptive
stimulation, and SPM 927 was minimum comparable, but usually more
potent than the reference compounds.
TABLE-US-00008 TABLE 8 EFFECTS OF SPM 927, CARBAMAZEPINE,
LEVETIRACETAM GABAPENTIN AND MORPHINE IN THE NEUROPATHIC PAIN
(CHUNG) TEST IN THE RAT (8 RATS PER GROUP) TACTILE STIMULATION
(lesioned paw) FORCE INDUCING PAW-WITHDRAWAL TREATMENT (g) (mg/kg)
p i.p. -30 min mean .+-. s.e.m. value % change Sham control 63.3
.+-. 4.5 -- -- Lesioned control 17.4 .+-. 2.2*** (a) 0.000 -73% (a)
SPM 927 (8) 27.2 .+-. 4.9 NS (b) 0.094 +56% (b) SPM 927 (16) 24.4
.+-. 3.0 NS (b) 0.086 +40% (b) SPM 927 (32) 37.6 .+-. 6.1** (b)
0.008 +116% (b) Carbamazepine 21.0 .+-. 2.3 NS (b) 0.275 +21% (b)
(16) Carbamazepine 38.4 .+-. 8.1* (b) 0.026 +121% (b) (32)
Carbamazepine 39.2 .+-. 9.1* (b) 0.036 +125% (b) (64) Levetiracetam
23.0 .+-. 4.0 NS (b) 0.243 +32% (b) (16) Levetiracetam 25.0 .+-.
5.2 NS (b) 0.199 +44% (b) (32) Levetiracetam 19.8 .+-. 4.1 NS (b)
0.612 +14% (b) (64) Gabapentin (32) 17.2 .+-. 3.0 NS (b) 0.959 -1%
(b) Gabapentin (64) 23.5 .+-. 4.2 NS (b) 0.219 +35% (b) Gabapentin
(128) 33.6 .+-. 6.7* (b) 0.038 +93% (b) Morphine (16) 45.9 .+-.
8.8** (b) 0.007 +164% (b) Student's t t st (non-paired): NS = Not
Significant; *= p < 0.05; **= p < 0.01; ***= p < 0.001 (a)
compared with sham control (b) compared with lesioned control
TABLE-US-00009 TABLE 9 EFFECTS OF SPM 927, CARBAMAZEPINE,
LEVETIRACETAM GABAPENTIN AND MORPHINE IN THE NEUROPATHIC PAIN
(CHUNG) TEST IN THE RAT (8 RATS PER GROUP) THERMAL STIMULATION
(lesioned paw) PAW-WITHDRAWAL LATENCY TREATMENT (sec) (mg/kg) p
i.p. -30 min mean .+-. s.e.m. value % change Sham control 40.6 .+-.
2.2 -- -- Lesioned control 16.3 .+-. 4.4*** (a) 0.000 -60% (a) SPM
927 (8) 26.1 .+-. 5.4 NS (b) 0.180 +60% (b) SPM 927 (16) 16.8 .+-.
4.5 NS (b) 0.933 +3% b) SPM 927 (32) 21.1 .+-. 5.6 NS (b) 0.512
+29% (b) Carbamazepine 35.6 .+-. 4.1** (b) 0.006 +118% (b) (16)
Carbamazepine 22.7 .+-. 4.3 NS (b) 0.315 +39% (b) (32)
Carbamazepine 28.8 .+-. 6.9 NS (b) 0.147 +77% (b) (64)
Levetiracetam 19.0 .+-. 3.6 NS (b) 0.641 +17% (b) (16)
Levetiracetam 17.1 .+-. 2.9 NS (b) 0.882 +5% (b) (32) Levetiracetam
26.6 .+-. 6.0 NS (b) 0.187 +63% (b) (64) Gabapentin (32) 19.3 .+-.
3.6 NS (b) 0.611 +18% (b) Gabapentin (64) 28.5 .+-. 5.4 NS (b)
0.101 +75% (b) Gabapentin (128) 27.1 .+-. 5.2 NS (b) 0.135 +66% (b)
Morphine (16) 42.4 .+-. 1.9*** (b) 0.000 +160% (b) Stud nt's t t st
(non-paired): NS = Not Significant; **= p < 0.01; ***= p <
0.001 (a) compared with sham control (b) compared with lesioned
control
* * * * *