Note: Descriptions are shown in the official language in which they were submitted.
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Combination of Flupirtine and Tolperisone or Eperisone for
the Treatment of Painful Conditions
A number of diverse painful disorders is associated
with elevated skeletal muscle tone. In some cases, the
development of pain is initiated by inflammations in a
joint, consequently a painful posture results and is
often accompanied by painful muscle spasms. The therapy
of such disorders includes, for
example,
benzodiazepines, but they entail a marked potential for
addiction and are thus of limited use. Treatment of the
underlying disorder, e.g. of the rheumatoid
inflammation, often does not result in appropriate
satisfactory therapeutic successes.
Additional
administration of analgesics and/or skeletal muscle
relaxants is therefore often indicated.
Centrally acting muscle relaxants are employed in
clinical practice in order to alleviate abnormally
elevated muscle tone in patients suffering from painful
muscle spasms and/or rigidity associated with
rheumatoid disorders or spasms connected with
neurological disorders. A number of corresponding
active substances is available commercially, but their
clinical efficacy is often doubtful or is limited by
unwanted side effects.
One class of such active substances are the Na+ channel
inhibiting substances. There are indications that they
are able to relax an elevated muscle tone. It has been
possible to show that propofol in clinically relevant
concentrations has a distinct inhibitory effect on the
sodium channels of the sarcolemma. This mechanism might
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contribute to reducing muscle tone (Haeseler et al.,
Anesth Analg 2001; 92:1192-8). It has likewise been
possible to show that inhibition of Na+ channels brings
about inhibition of neurotransmitter release from the
presynaptic ends (Obrenovitch, Int Rev Neurobiol 1997;
40:109-35). The neuroprotective active ingredient
riluzole is a sodium channel inhibitor and an anti-
excitotoxic substance employed for the treatment of
amyotrophic lateral sclerosis. Kennel et al. (J Neurol
Sci 2000; 180:55-61) have recently been able to show
that riluzole significantly delays the onset of
paralysis and the progression of functional parameters
in conjunction with muscle strength in the mouse model
of motor neurone disease. Metilexine, an antiarrhythmic
and antimyotonic substance, blocks the sodium channels
of skeletal muscles (Duranti et al., Eur J Med Chem
2000; 35:147-56) and solves skeletal muscle hyper-
excitability in the mouse model of hereditary myotonia
(De Luca et al., J Pharmacol Exp Ther 1997; 282:93-
100). The important function of skeletal muscle sodium
channels in maintaining normal tone is by the fact that
it has been possible to show an association between
mutations in the gene for the a subunit of the voltage-
induced Na + channel (SCN4A) with hereditary non-
dystrophic myotonia. It is of interest that the
myotonia dramatically resolved on administration of the
Na + channel-inhibiting substance flecainide (Rosenfeld
et al., Ann Neurol 1997; 42:811-4).
Tolperisone is a centrally acting muscle relaxant with
a relatively good clinical tolerability. Relatively few
publications to date have dealt with the mechanism of
action of tolperisone-like compounds. Tolperisone
depresses production of the spinal segment reflex and
effectively reduces the conduction, induced by C
fibers, of afferent nerves both in vivo and in vitro
(Farkas et al., Neurobiology 1997; 5:57-58). Compared
with lidocaine, a local anesthetic, the substance has a
smaller blocking effect on conduction of A fibers. Its
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most characteristic effect is strong inhibition of
mono- and polysynaptic spinal reflexes (Farkas et al.,
Neurobiology 1997; 5:57-58, Kocsis et al., Acta Pharm
Hung 2002; 72(1):49-61, Okada et al., Jpn J Pharmacol
2001; 86:134-136). Ono et al. (J Pharmacobio Dynam
1984; 7:171-178) were able to show that tolperisone
shows an effect similar to a local anesthetic
("membrane-stabilizing") both in motor neurones and in
primary afferents in vivo, and on the peripheral nerves
of rats in vitro. The effect of tolperisone appears to
be similar to that of lidocaine, which is known to act
as an inhibitor of voltage-gated sodium channels.
It has been possible to show that tolperisone, similar
to lidocaine, blocks tetrodotoxin (TTX)-sensitive and
TTX-resistant currents and thus suggests an inhibitory
effect on both types of voltage-gated sodium channels
(Bastigkeit, MMW-Forschr Med 2000; 142:50-51; Kocsis et al., Acta
Pharm Hung 2002; 72(1):49-61). It is probable in this
connection that the mechanism of action of tolperisone
is somewhat different from that of lidocaine. There are
moreover indications that tolperisone reduces sodium
permeability. This effect might be responsible for the
excitability-reducing effect of tolperisone and thus
for the antispastic effect which it has been possible
to document in clinical observations (Hinck and
Koppenhofer, Gen Physiol Biophys 2001; 20:413-29). In
addition, it has been possible to show in voltage clamp
experiments on snail neurones that tolperisone and its
analogs inhibit voltage-gated calcium currents
(Novalies-Li et al., Eur J Pharmacol 1989; 168:299-
305). Tolperisone analogs such as eperisone and
silperisone showed a similar behavior in electro-
physiological experiments. Thus, it was possible to
show for example that silperisone reduces sodium
permeability (During and Koppenhofer, Gen Physiol
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Biophys 2001; 20:157-73). It can be concluded from this
that these substances might reduce spastic skeletal
muscle tone.
It was further possible to show in clinical studies
that these substances can alleviate painful spasms
associated with neurological or rheumatoid disorders.
It has been reported that tolperisone is employed
effectively in the treatment of muscle spasms (Pratzel
et al., Pain 1996; 67:417-25). Some derivatives of
tolperisone, e.g. eperisone, likewise showed efficacy
in the treatment of painful muscle spasms (Bose,
Methods Find Exp Clin Pharmacol 1999; 21:209-13). Under
certain pathological conditions, neurones are in a
state of continuous depolarization so that their sodium
channels respond more sensitively to the inhibitory
effect of certain substances. This makes it possible to
alleviate muscle spasms and pain with a favorable
profile of side effects. Recent data indicate that
tolperisone and its analogs have selective inhibitory
effects on voltage-gated sodium channels. This
mechanism might be responsible for their spinal reflex-
suppressing and muscle-relaxant effect. In addition,
this property might bring about the analgesic effect
which, on the basis of the small differences observed,
might be free of side effects in contrast to lidocaine.
A further class of muscle-relaxant substances are the
potassium channel openers. These include for example
flupirtine from a class of triaminopyridines, which is
employed as non-opioid analgesic with muscle-relaxant
properties. It has been possible to show that
flupirtine reduces skeletal muscle tone when employed
in doses comparable to those for the antinociceptive
effect (Nickel et al., Arzn Forsch/Drug Res 1990a;
40:909-11).
Since diazepam and other benzodiazepines are frequently
employed as muscle relaxants, it was obvious to compare
the pharmacodynamic properties of flupirtine with those
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of the benzodiazepines. In receptor-binding studies, no
affinity was detected for specifics CH] flunitrazepam
up to a concentration of 10 pmo1/1 (Nickel et al., Arzn
Forsch/Drug Res 1990b; 40:905-908). In relation to the
changes in the EEG, distinct differences were
detectable in the profiles induced by flupirtine and
benzodiazepines (Nickel, Postgrad Med J 1987; 63:19-
28). Electrophysiological investigations showed that
flupirtine influences GABAergic conduction by
potentiating the effect of GABA (Weiser et al., Arch
Pharmacol 1992; 346(Suppl.):R22). Data from in vitro
and in vivo analyses suggests that flupirtine behaves
like a functional N-methyl-D-aspartate (NMDA)
antagonist. It might be concluded from this that this
mechanism might be involved in the muscle-relaxant
effect of flupirtine (Schwarz et al., Neuroreport 1994;
5:1981-4). Recent investigations indicate that
flupirtine activates voltage-independent potassium
channels (Kornhuber et al., J Neural Transm 1999;
106:857-67). This potassium channel-opening effect of
flupirtine might be responsible for its analgesic and
skeletal muscle-relaxant effect.
The described prior art clearly shows that although
there is a number of substances employed for treating
painful conditions with elevated muscle tone, there are
frequently limitations to this due to unwanted side
effects. Thus, for example, flupirtine in higher dosage
shows neurotoxic effects such as drowsiness,
coordination impairment. Tolperisone shows no serious
unwanted side effects, but its efficacy and duration of
action in muscle relaxation are unsatisfactory,
possibly owing to the relatively low bioavailability
and the short half-life in humans (Ito et al., Arch Int
Pharmacodyn Ther 1985; 275:105-22, Matsunaga et al.,
Jpn J Pharmacol 1997; 73:215-20).
It is therefore an object of this invention to provide
a medicament for the treatment of painful conditions
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associated with elevated muscle tone, which shows fewer
side effects with a comparable effect or which has an
increased efficacy at the same dose.
It has been possible to bring this about according to
the invention by the novel combination of a potassium
channel opener and of a sodium channel inhibitor.
It has been possible to show that the muscle-relaxant
effect is increased by the combination of sodium
channel inhibiting or influencing active substances and
potassium channel openers.
Examples of Na + channel inhibiting or influencing
substances which can be employed are: tolperisone and
its analogs eperisone and silperisone, riluzole,
propafenone, lidocaine, flecainide, metixene, and their
pharmaceutically usable salts.
Flupirtine is to be mentioned as example of potassium
channel opener.
According to one aspect of the invention there is
provided use of flupirtine or a pharmaceutically
acceptable salt thereof, in a synergistic combination
with tolperisone or it eperisone, or a pharmaceutically
acceptable salt thereof, for production of a medicament
for the treatment of a painful condition associated with
elevated muscle tone.
According to a further aspect of the invention there is
provided a pharmaceutical composition comprising
flupirtine or a pharmaceutically acceptable salt
thereof, together in a synergistic combination with
tolperisone or eperisone, or a pharmaceutically
acceptable salt thereof, for the treatment of a painful
condition associated with elevated muscle tone.
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The combination of the invention makes the treatment of
painful conditions associated with elevated muscle tone
more effective and safe. The combination of sodium
channel inhibiting or influencing substances and
potassium channel openers such as flupirtine leads to
an increased therapeutic effect or improved
tolerability. It has been possible to show for example
that the muscle-relaxant effect of flupirtine can be
enhanced by Na channel inhibiting or influencing active
substances such as tolperisone, and vice versa.
However, particularly surprising and unexpected for the
skilled worker is the effect that the skeletal muscle-
relaxant effect of flupirtine is enhanced super-
additively by tolperisone, and vice versa. In contrast
thereto, the neurotoxicity of flupirtine is not
enhanced by tolperisone.
The combination of the two substances can be employed
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for the treatment of painful conditions associated with
disorders of skeletal muscles which are associated with
hypermyotonia and restricted mobility, especially those
caused by injuries to the spinal cord, osteoporosis,
arthritis and stiffening/spastic conditions. It is
additionally effective for painful conditions caused by
the following: lumbar neurolathyrism, arthritis,
disorders of the peripheral circulatory system,
menopausal muscular and vascular symptoms, trismus,
myogenic headache, rheumatic disorders associated with
muscle hypertonia, spasms, pain, inflammatory symptoms
and restricted mobility, multiple sclerosis, and in the
postoperative treatment of trauma patients, and for the
treatment of lower spastic paraparesis syndrome: lower
paraspasm, transverse myelitis, multiple sclerosis,
hereditary inferior spastic paraplegia (Stuempel's
paraplegia), impairments of the spinal blood
circulation, cerebral paralysis with lower spastic
paresis, tetraparesis associated with cervical
myelopathy, vertebral dysplasia, tension headache and
cervical brachialgia.
According to one embodiment of the invention there is
provided a use of potassium channel openers in
combination with sodium channel inhibiting or
influencing substances and their therapeutically
employable salts as described herein for the treatment
of neuralgias.
According to another embodiment of the invention there
is provided a use of potassium channel openers in
combination with sodium channel inhibiting or
influencing substances and their therapeutically
employable salts as described herein for the treatment
of arthritis and arthroses.
According to a further embodiment of the invention there
is provided a use of potassium channel openers in
combination with sodium channel inhibiting or
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influencing substances and their therapeutically
employable salts as described herein for the treatment
of chronic or episodic tension headache.
According to yet another embodiment of the invention
there is provided a use of potassium channel openers in
combination with sodium channel inhibiting or
influencing substances and their therapeutically
employable salts as described herein for the treatment
of Parkinson's disease.
Pharmacological examples
1: Muscle-relaxant effect on reserpine-induced muscle
rigidity in rats
Results
Both flupirtine and tolperisone reduce dose-dependently
the reserpine-induced skeletal muscle rigidity in
conscious rats. The intraperitoneal (i.p.) ED50 for
flupirtine was 6.45 mg/kg. The ED50 for tolperisone was
32.4 mg/kg i.p.
The results in tables 1 and 2 show clearly that there
is a surprising superadditive enhancement of the
skeletal muscle-relaxant effect of flupirtine by
tolperisone and vice versa.
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Table 1. Effect of flupirtine administered intra-
peritonealy in combination with tolperisone on
reserpine-induced skeletal muscle rigidity in conscious
rats
Treatment Muscle relaxation (%)
calculated measured
Flupirtine + tolperisone 52.2 71.1*
5 mg/kg 12.5 mg/kg
Flupirtine + tolperisone 75.4 90.7*
5 mg/kg 25 mg/kg
Flupirtine + tolperisone 121.0 163.2*
5 mg/kg 50 mg/kg
Table 2. Effect of tolperisone administered intra-
peritonealy in combination with flupirtine on
reserpine-induced skeletal muscle rigidity in conscious
rats
Treatment Muscle relaxation (%)
calculated measured
Tolperisone + flupirtine 44.7 60.2*
25 mg/kg 1 mg/kg
Tolperisone + flupirtine 60.0 81.4*
25 mg/kg 3 mg/kg
Tolperisone + flupirtine 75.4 92.1*
25 mg/kg 5 mg/kg
Description of the experiment
Male Sprague-Dawley rats weighing 200-220 g were kept
in two groups under standard conditions (temperature
22 C, humidity 40-60%) without food and water
restriction. Illumination took place from 6.00-18.00 h.
The experiments were approved by the local animal
health committee responsible for the protection and
proper use of experimental animals.
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The experimental design has already been described in
detail (Nickel et al., Arzn Forsch/Drug Res 1997;
47:1081-6). Described briefly, the muscle rigidity was
measured on skeletal muscles by successive measurement
of the resistance of the flexor and extensor muscles
which have contrary effects in the joint during
stretching and flexion of the foot. The differences in
pressure generated by the foot movement were
continuously recorded. The signals were analyzed by
means of a PC program which calculated the values for
the resistance of flexor and extensor in the foot over
10 min periods.
The active substances were made up fresh each day and
administered i.p. in various doses simultaneously 16 h
after the reserpine injection (2 mg/kg,
intraperitoneal).
Statistical analysis of the differences between the
calculated and measured values was carried out by one-
way ANOVA. (*) identifies the significant level p<0.01.
2: Investigations on the skeletal muscle tone of mice
in the so-called inclined screen test
Results
It was possible convincingly to verify the surprising
results of example 1 in an experiment on mice.
Both flupirtine and tolperisone reduce the skeletal
muscle tone dose-dependently in conscious mice and thus
provide information on their muscle-relaxant effect.
The intraperitoneal (i.p.) ED50 for flupirtine is
10.8 mg/kg. The ED50 for tolperisone is 51.0 mg/kg i.p.
The results in tables 3 and 4 show clearly that on
simultaneous i.p. administration of various doses of
flupirtine and tolperisone the skeletal muscle-relaxant
effect of flupirtine is enhanced superadditively by
tolperisone and vice versa.
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Table 3. Effect of flupirtine administered intra-
peritonealy in combination with tolperisone on the
skeletal muscle tone of conscious mice.
Treatment Number of animals falling
from incline in %
calculated measured
Flupirtine + tolperisone 14 54*
1 mg/kg 12.5 mg/kg
Flupirtine + tolperisone 28 62*
1 mg/kg 25 mg/kg
Flupirtine + tolperisone 54 75*
1 mg/kg 50 mg/kg
Table 4. Effect of tolperisone administered intra-
peritonealy in combination with flupirtine on the
skeletal muscle tone of conscious mice.
Treatment Number of animals falling
from incline in %
calculated measured
Tolperisone + flupirtine 28 50*
_25 mg/kg 1 mg/kg
Tolperisone + flupirtine 37 60*
25 mg/kg 3 mg/kg
Tolperisone + flupirtine 46 70*
25 mg/kg 5 mg/kg
Description of the experiment
NMRI mice weighing 22-24 g were kept in four groups
under standard conditions (temperature 22 C, humidity
40-60%) without food and water restriction.
Illumination took place from 6.00-18.00 h. All the
experiments were approved by the local animal health
committee responsible for the protection and proper use
of experimental animals.
The pharmacological model employed to make it possible
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to predict the muscle-relaxant properties was the so-
called 30 degrees inclined screen test (Simiand et al.,
Arch Int Pharmacodyn Ther 1989; 297:272-85). The
inclined screen consists of a wooden frame with a wire
mesh screen which can be inclined at any angle (in this
case: 80 ). The lower part of the screen is 15 cm above
the table. The animals are placed on the inclined
screen, and their ability to stay on the inclined
screen is observed over a period of 30 s. The number of
animals falling off the screen is counted and the
proportion of them in the total number in each group is
calculated.
The active substances were made up fresh each day and
administered simultaneously i.p. in various doses 1 h
before starting the experiments to analyze the skeletal
muscle tone.
Statistical analysis of the differences between the
calculated and measured values were carried out by one-
way ANOVA. (*) indicates the significant level p<0.01.
3: Possible neurotoxic effects of the substances,
measured in the rotating rod test on rats
Results
Centrally acting substances may have neurotoxic side
effects which might restrict their therapeutic use. The
results in tables 5 and 6 show clearly that the
combination of flupirtine and tolperisone has an
additive effect on motor coordination. No superadditive
effect can be observed, i.e. the flupirtine +
tolperisone combination does not lead to an increase in
unwanted central nervous effects.
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Table 5. Effect of flupirtine administered intra-
' peritonealy in combination with tolperisone on motor
coordination of rats by means of the rotating rod.
Treatment Number of animals falling
from incline in %
calculated measured
Flupirtine + tolperisone 38 42
1 mg/kg 12.5 mg/kg
Flupirtine + tolperisone 50 49
1 mg/kg 25 mg/kg
Flupirtine + tolperisone 70 67
1 mg/kg 50 mg/kg
Table 6. Effect of tolperisone administered intra-
peritonealy in combination with flupirtine on motor
coordination of rats by means of the rotating rod.
Treatment Number of animals falling
from incline in %
calculated measured
Tolperisone + flupirtine 49 50
25 mg/kg 1 mg/kg
Tolperisone + flupirtine 57 50
25 mg/kg 3 mg/kg
Tolperisone + flupirtine 66 67
25 mg/kg 5 mg/kg
Description of the experiment
Male Sprague-Dawley rats weighing 200-220 g were kept
in two groups under standard conditions (temperature
22 C, humidity 40-60%) without food and water
restriction. Illumination took place from 6.00-18.00 h.
The experiments were approved by the local animal
health committee responsible for the protection and
proper use of experimental animals.
The motor coordination and balance of the animals was
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analyzed in the so-called rotating rod test (Jones and
Roberts, J Pharm Pharmacol 1968; 20:302-304). The
animals are placed on a rotating rod (diameter 10 cm;
length 60 cm; 5 rpm) and the number of animals
remaining on the rod after a period of 2 minutes is
counted. The active substances were made up fresh each
day and administered simultaneously in various doses
intraperitonealy 30 min before starting the
experiments.
The described experiments clearly show the effects of
the flupirtine/tolperisone combination. It is possible
to infer from the comparable mechanisms of actions of
the potassium channel openers and sodium channel
inhibiting or influencing substances that other
combinations of substances of these classes of
substances will have the same positive effect.
The combinations of Na+ channel inhibiting or
influencing active substances and potassium channel
openers and their pharmaceutically usable salts can be
administered in all oral, enteral, rectal, lingual,
intravenous, intramuscular,
intraperitoneal,
transdermal, subcutaneous or intracutaneous dosage
forms. Preferred oral dosage forms are, for example,
tablets, film-coated tablets, sugar-coated tablets,
hard capsules, soft capsules, chewable tablets,
suckable tablets, syrup, preparations with controlled
release (e.g. dual formulation, sustained release
formulation), pellets, chewable tablets or soluble
granules. Examples of further suitable dosage forms
are: solutions for injection,
suspensions,
suppositories, creams, ointments, gels, transdermal
administration forms, sub- or intracutaneous implants.
The substances can be administered simultaneously,
successively or in a fixed combination. They can be
administered together in one dosage form or in two
dosage forms which may be identical or different. They
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can be administered simultaneously or successively,
either in quick succession or with larger time
intervals, e.g. flupirtine in the evening and
tolperisone in the morning.
The active substances can be administered between 1 and
8 times a day in sufficient quantity to achieve the
desired effect. The active substances are preferably
administered one to four times a day.
The daily dose should comply with the authorized amount
of the respective substances employed in the
combination. This is for the preferred combination for
example between 150 and 450 mg/day tolperisone for
adults, flupirtine 100-800 mg/day, preferably between
200 and 400 mg/day.
