Note: Descriptions are shown in the official language in which they were submitted.
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COMBINATION PREPARATIONS COMPRISING SLV308 AND L-DOPA
INDEX page
Title of the invention 1
Index 1
Summary: technical field of the invention 1
Background of the invention 2
Detailed description of the invention 5
Definitions 7
Examples 10
Example 1: Pharmacological methods 10
Example 2: Pharmacological test results 12
Example 3: Pharmaceutical preparations 13
Legends to the Figures 1- 7 15
References 16
Claims 19
Abstract 20
Figures 1 - 7 21
SUMMARY: TECHNICAL FIELD OF THE INVENTION
The invention concerns the use of a combination preparation of SLV308 or its N-
oxide, or
pharmacologically acceptable salts of those compounds:
0 O
~
HN A O HN O
~\ /CH3
N~\N-CH3 / \ N ~N~
/ - ~ 0
~
SLV308 SLV308 N-oxide
and L-DOPA, for simultaneous, separate or sequential use in the treatment of
disorders
requiring recovery of dopaminergic function, in particular Parkinson's disease
and restless leg
syndrome.
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BACKGROUND OF THE INVENTION
Constant tremors in hands and legs, body movements that gradually become
stiffer, slower and
weaker, and mask-like facial expressions, are symptoms that have been observed
throughout
the history of mankind. In 1817 James Parkinson described this cluster of
symptoms as
`paralysis agitans', and shortly thereafter the disease was named after the
physician who first
described it in detail. The pathological cause of Parkinson's disease involves
destruction of
nerve cells in the substantia nigra, the part of the brain involved with
muscle movements. Loss
of around 80% of striatal dopamine in Parkinson's disease results in cardinal
symptoms of
akinesia, rigidity and bradykinesia (Hornykiewicz, 1966). Patients have
problems initiating
movement and exhibit postural instability and loss of coordination.
Current Parkinson's disease pharmacotherapy is based on recovery of
dopaminergic function
(Blandini, 2000; LIed6, 2000). Dopamine does not cross the blood brain barrier
and cannot
therefore be used to treat Parkinson's disease, its immediate precursor, L-
DOPA (the
levorotatory enantiomer of 3,4-dihydroxyphenylalanine, also referred to as
levodopa) is used
instead, because it penetrates the brain where it is decarboxylated to
dopamine. But levodopa is
decarboxylated in peripheral tissues too. Thus only a small portion of
administered levodopa is
transported to the brain. Carbidopa inhibits decarboxylation of peripheral
levodopa but cannot
itself cross the blood brain barrier, and has no effect on the metabolism of
levodopa in the brain.
The combination of carbidopa and levodopa is considered to be the most
effective treatment for
symptoms of Parkinson's disease. Nevertheless, certain limitations become
apparent within two
to five years of initiating therapy. As the disease progresses, the benefit
from each dose
becomes shorter ("the wearing off effect") and some patients fluctuate
unpredictably between
mobility and immobility ("the on-off effect"). "On" periods are usually
associated with high
plasma levodopa concentrations and often include abnormal involuntary
movements, i.e.,
dyskinesias. "Off" periods have been correlated with low plasma levodopa and
bradykinetic
episodes (Jankovic, 1993; Rascol, 2000). This has prompted clinicians to delay
the initiation of
L-DOPA treatment by prior treatment with dopaminergic agonists.
However, the use of full dopamine receptor agonists such as apomorphine,
bromocryptine,
lisuride, pergolide, pramipexol or ropinirole, also has its limitations: They
prime for dyskinesias,
induce psychotic-like symptoms including hallucinations, orthostatic
hypotension, somnolence,
and other side-effects (Lozano, 1998; Bennett, 1999). It has been suggested
that this could be
overcome by using partial dopamine D2/3 receptor agonists (i.e. compounds that
do not
maximally stimulate dopamine D2/3 receptors) (Jenner 2002). Such compounds
would
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hypothetically be capable of stimulating dopamine D2,3 receptors when the
dopaminergic tone is
low, while being able to counteract excessive stimulation of the dopamine D2
receptor when the
dopaminergic tone is high, thereby resulting in "stabilisation" of
dopaminergic transmission in
the brain (Jenner, 2002).
5-HT,A receptor agonists may ameliorate the induction of dyskinesia since the
5-HT,A receptor
agonist tandospirone reduced dyskinesia in L-DOPA treated Parkinson's disease
patients
(Kannari, 2002) and haloperidol-induced extrapyramidal side effects in
primates (Christoffersen,
1998). More recently it has been suggested that sarizotan, a 5-HT,A receptor
agonist and
dopamine receptor ligand, could ameliorate dyskinetic symptoms (Olanow, 2004;
Bara-Jimenez,
2005; Bibbiani, 2001). The presence of 5-HT,A receptor agonist could be
beneficial to the
therapeutic effects of a partial D2,3 receptor agonist (Johnston, 2003).
Recently, different combination preparations containing L-DOPA and one or more
other enzyme
inhibitors have been introduced. Well known are the combinations L-
DOPA/carbidopa (e.g.
Sinemet ), L-DOPA/benserazide (e.g. Madopar ) and L-DOPA/carbidopa/entacapone
(e.g.
Stalevo , (Jost, 2005)). More recently, catecholamine-O-methyltransferase
(COMT) inhibitors
such as tolcapone and entacapone have been proposed as adjunctive therapy to L-
DOPA.
These compounds extend the plasma half-life of L-DOPA, without significantly
increasing Cmax.
Thus, they decrease the duration of wearing-off but tend to increase the
intensity of peak-dose
side effects including peak dose dyskinesias. Tolcapone appears to induce
significant liver
toxicity in a small percentage of patients. Another strategy aimed at slowing
down the
metabolism of dopamine is the use of monoamine oxidase-B (MAO-B) inhibitors in
combination
with L-DOPA. The administration of MAO inhibitors, however, is associated with
a number of
debilitating side effects that limit their use. These effects include, for
example, nausea,
dizziness, lightheadedness, fainting, abdominal pain, confusion,
hallucinations, dry mouth, vivid
dreams, dyskinesias, and headache. Characteristic for combination preparations
is that they
exist in many different dose combinations, because during the course of the
disease usually
higher doses of L-DOPA are necessary to keep the symptoms under control.
Combination
preparations in the form of tablets containing fixed amounts of drugs are easy
to use, but
simultaneously also offer limited flexibility. An illustration of the fact
that fixed combinations are
not universally useful is e.g. the use of the selective MAO-B inhibitor
selegiline in the treatment
of Parkinson's disease. In the early stage of the disease, selegiline may be
given as
monotherapy: the compound will slow down the metabolism of endogenous dopamine
enough
to keep the symptoms within tolerable limits. In later stages of the disease,
the use of L-DOPA
can become necessary. When the efficacy of L-DOPA starts to wear, usually the
first solution to
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that problem is the use of a decarboxylase inhibitor like carbidopa (see
above), and when also
that gets insufficient, co-therapy with selegiline will restore L-DOPA's
efficacy by reducing the
breakdown of the dopamine generated from the L-DOPA. Thus, in practice L-DOPA
and
selegiline are administered in separate preparations which may be given
simultaneously or
sequentially.
Victims seriously afflicted with Restless Leg Syndrome (RLS; also known as
Ekbom's
syndrome), are virtually unable to remain seated or even to stand still.
Activities that require
maintaining motor rest and limited cognitive stimulation, such as
transportation (car, plane, train,
etc.) or attending longer meetings, lectures, movies or other performances,
become difficult if
not impossible. Tortured by these sensations which become more severe at
night, RLS patients
find sleep to be virtually impossible, adding to the diminishing quality of
their lives. The urge to
move, which increases over periods of rest, can be completely dissipated by
movement, such
as walking. However, once movement ceases, symptoms return with increased
intensity. If an
RLS patient is forced to lie still, symptoms will continue to build like a
loaded spring and,
eventually, the legs will involuntary move, relieving symptoms immediately.
Rhythmic or semi-
rhythmic movements of the legs are observed if the patient attempts to remain
laying down
(Pollmacher, 1993). These movements are referred to as dyskinesias-while-awake
(DWA)
(Hening, 1986) or more commonly, periodic limb movements while awake (PLMW).
Clinically,
RLS is indicated when four diagnostic criteria are met: (1) a sensation of an
urge to move the
limbs (usually the legs); (2) motor restlessness to reduce sensations; (3)
when at rest,
symptoms return or worsen; and (4) marked circadian variation in occurrence or
severity of RLS
symptoms; that is, symptoms worsen in the evening and at night (Allen, 2001).
Current treatments for RLS are varied and plagued with undesirable side
effects. Therapies
have included the administration of dopamine agonists, other dopaminergic
agents,
benzodiazepines, opiates and anti-convulsants. In cases where RLS results from
a secondary
condition, such as pregnancy, end-stage renal disease, erythropoietin
treatment, or iron
deficiency, removing the condition, such as giving birth or treating with
traditional iron
supplementation, can reduce or eliminate symptoms in at least some cases
(Allen, 2001).
However, RLS resulting from non-secondary conditions ("idiopathic" RLS),
presents a greater
treatment challenge. Dopaminergic agents such as levodopa generally provide
effective initial
treatment, but with continued use, tolerance and symptom augmentation occur in
about 80% of
RLS patients (Allen, 1996); this complication is also common for dopamine
agonists (Earley,
1996). The other alternatives, benzodiazepines, opiates and anti-convulsants
are not as
uniformly effective as the dopaminergic agents (Chesson, 1999; Hening, 1999).
Despite changes
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in their treatment regimes, 15-20% of patients find that all medications are
inadequate because
of adverse effects and limited treatment benefit
0 O
~
HN A O HN O
~\ /CH3
N~\N-CH3 ~ ~ N ~N~
/ - ~ O
~
SLV308 SLV308 N-oxide
SLV308, 7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone mono hydrochloride,
binds to
dopamine D2-like receptors and 5-HT,A receptors. It is a partial agonist at
dopamine D2,3
receptors and a full agonist at serotonin 5-HT,A receptors. At cloned human
dopamine D2,L
receptors, SLV308 acted as a potent but partial D2 receptor agonist (pEC50=8.0
and pA2=8.4)
with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human
recombinant
dopamine D3 receptors, SLV308 acted as a partial agonist in the induction of
[35S]GTPyS
binding (67% that of dopamine), had a higher degree of potency compared to
quinpirole
(pEC50=9.2) and antagonized the dopamine induction of [35S]GTPyS binding
(pA2=9.0). SLV308
acted as a full 5-HT,A receptor agonist on forskolin induced cAMP accumulation
at cloned
human 5-HT,A receptors (pEC50=6.3) similar to the 5-HT,A receptor agonist 8-OH-
DPAT. In rat
striatal slices SLV308 concentration-dependently attenuated forskolin
stimulated accumulation
of cAMP, as expected for a dopamine D2,3 receptor agonist. SLV308 antagonized
the inhibitory
effect of quinpirole on K+-stimulated [3H]dopamine release (pA2=8.5) from rat
striatal slices. In
the same paradigm the partial D2 agonist terguride demonstrated a greater
degree of
antagonism in the presence of quinpirole (pA2=10.3) similar to the D2
antagonist haloperidol
(pA2=9.3) but less than SLV308 (pA2=8.5). In conclusion, SLV308 combines high
potency partial
agonism at dopamine D2,3 receptors (acting as a dopamine stabiliser) with full
efficacy low
potency serotonin 5-HT,A receptor agonism. (WO 00/29397; Feenstra, 2001;
Johnston, 2001a,b;
Hesselink, 2001, 2003, McCreary, 2001, 2006; Wo1f,2003). In WO 2007/023141 it
was disclosed
that in vivo the N-oxide of SLV308 is rapidly converted to SLV308, thus
functioning as `prodrug'.
DETAILED DESCRIPTION OF THE INVENTION
The goal of the present invention was to develop a treatment as effective as L-
DOPA, but
without its side effects: In particular without its characteristic "on-off
effect", causing
dyskinesias during "on"-periods, and bradykinetic episodes during "off"-
periods.
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Surprisingly, in studies in MPTP-treated marmosets, an animal model with
predictive value for
Parkinson's disease, it was found that combined treatment with L-DOPA and
SLV308 reduced
peak locomotor activity as observed after L-DOPA alone, such that
hyperactivity was not
observed. The duration of activity ("on"-time) following L-DOPA was increased
by co-
administration of SLV308.
The subject matter of the invention are combination preparations of SLV308 or
its N-oxide, or
pharmacologically acceptable salts, hydrates and solvates thereof, and L-DOPA
and, optionally,
a decarboxylase inhibitor and/or, optionally, a COMT-inhibitor, and/or,
optionally, a MAO-B
inhibitor, for simultaneous, separate or sequential use in therapy of
disorders requiring recovery
of dopaminergic function, in particular Parkinson's disease and `Restless Leg
syndrome'.
The invention relates to the use of SLV308 or its N-oxide, a true `prodrug',
in cases in which a L-
DOPA induces dyskinesias, or can be anticipated to induce dyskinesias. In such
cases, the
specific pharmacological activities of the compound, viz., partial agonism on
dopamine-D2 and
dopamine-D3 receptors, as well as full agonism on serotonin 5-HT,A receptors,
result in a
blockade of the dyskinesias without reducing the therapeutic effect of L-DOPA.
The present invention relates to pharmaceutical formulations, comprising:
(i) SLV308, its N-oxide, or pharmacologically acceptable salts, hydrates and
solvates
thereof, and:
(ii) L-DOPA, in admixture with a pharmaceutically acceptable adjuvant, diluent
or carrier.
A further aspect of the present invention relates to kits of parts comprising:
(i) a vessel containing SLV308, its N-oxide, or pharmacologically acceptable
salts,
hydrates, and solvates thereof, optionally in admixture with a
pharmaceutically
acceptable adjuvant, diluent or carrier, and:
(ii) a vessel containing L-DOPA, optionally in admixture with a
pharmaceutically acceptable
adjuvant, diluent or carrier, and:
(iii) instructions for the sequential, separate or simultaneous administration
of SLV308 and
the L-DOPA, to a patient in need thereof.
According to a further aspect of the invention, there is provided a method of
making a kit of
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parts as defined herein, which method comprises bringing a component (i), as
defined above,
into association with a component (ii), as defined above, thus rendering the
two components
suitable for administration in conjunction with each other. Bringing the two
components into
association with each other, includes that components (i) and (ii) may be:
(i) provided as separate formulations (i.e. independently of one another),
which are
subsequently brought together for use in conjunction with each other in
combination
therapy; or
(ii) packaged and presented together as separate components of a "combination
pack" for
use in conjunction with each other in combination therapy.
Yet another aspect of the invention relates to methods for treatment of a
patient suffering from,
or susceptible to, a condition in which recovery of dopaminergic function is
required or desired,
which method comprises administering to the patient a therapeutically
effective total amount of:
(i) SLV308, its N-oxide, or pharmacologically acceptable salts, hydrates and
solvates
thereof, optionally in admixture with a pharmaceutically acceptable adjuvant,
diluent or
carrier; in conjunction with:
(ii) L-DOPA, optionally in admixture with a pharmaceutically acceptable
adjuvant, diluent or
carrier.
Still another aspect of the invention relates to the use of pharmaceutical
formulations,
comprising:
(i) SLV308, its N-oxide, or pharmacologically acceptable salts, hydrates and
solvates
thereof, and:
(ii) L-DOPA, in admixture with a pharmaceutically acceptable adjuvant, diluent
or carrier, in
the manufacture of a medicament for the treatment of a condition in which
recovery of
dopaminergic function is required or desired.
DEFINITIONS
Examples of decarboxylase inbitors are: carbidopa and benserazide. Examples of
catechol-
amine-O-methyl transferase (COMT) inhibitors are: entacapone, nitecapone and
tolcapone,
and monoamine oxidase-B (MAO-B) inhibitors include: deprenyl, (-)-deprenyl
(selegiline),
desmethyldeprenyl, N-propargyl-l-(R)-aminoindan (rasagaline), phenelzine
(nardil), tranyl-
cypromine (parnate), CGP3466, furazolidone, isocarboxazid, pargyline,
methyclothiazide and
procarbazine
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To provide a more concise description, some of the quantitative expressions
given
herein are not qualified with the term "about". It is understood that whether
the term "about" is
used explicitly or not, every quantity given herein is meant to refer to the
actual given value, and
it is also meant to refer to the approximation to such given value that would
reasonably be
inferred based on the ordinary skill in the art, including approximations due
to the experimental
and/or measurement conditions for such given value.
Throughout the description and the claims of this specification the word
"comprise" and
variations of the word, such as "comprising" and "comprises" is not intended
to exclude other
additives, components, integers or steps.
The term "composition" as used herein encompasses a product comprising
specified
ingredients in predetermined amounts or proportions, as well as any product
that results,
directly or indirectly, from combining specified ingredients in specified
amounts. In relation to
pharmaceutical compositions, this term encompasses a product comprising one or
more active
ingredients, and an optional carrier comprising inert ingredients, as well as
any product that
results, directly or indirectly, from combination, complexation or aggregation
of any two or more
of the ingredients, or from dissociation of one or more of the ingredients, or
from other types of
reactions or interactions of one or more of the ingredients. In general,
pharmaceutical
compositions are prepared by uniformly and intimately bringing the active
ingredient into
association with a liquid carrier or a finely divided solid carrier or both,
and then, if necessary,
shaping the product into the desired formulation. The pharmaceutical
composition includes
enough of the active object compound to produce the desired effect upon the
progress or
condition of diseases. Accordingly, the pharmaceutical compositions of the
present invention
encompass any composition made by admixing a compound of the present invention
and a
pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is
meant the carrier,
diluent or excipient must be compatible with the other ingredients of the
formulation and not
deleterious to the recipient thereof.
Within the context of this application, the term `combination preparation'
comprises
both true combinations, meaning SLV308 and other medicaments physically
combined in one
preparation such as a tablet or injection fluid, as well as `kit-of-parts',
comprising SLV308 and
L-DOPA in separate dosage forms, together with instructions for use,
optionally with further
means for facilitating compliance with the administration of the component
compounds, e.g.
label or drawings. With true combinations, the pharmacotherapy by definition
is simultaneous.
The contents of `kit-of-parts', can be administered either simultaneously or
at different time
intervals. Therapy being either concomitant or sequential will be dependant on
the
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characteristics of the other medicaments used, characteristics like onset and
duration of action,
plasma levels, clearance, etc., as well as on the disease, its stage, and
characteristics of the
individual patient.
The dose of the composition to be administered will depend on the relevant
indication,
the age, weight and sex of the patient and may be determined by a physician.
The dosage will
preferably be in the range of from 0.01 mg/kg to 10 mg/kg. The typical daily
dose of the active
ingredients varies within a wide range and will depend on various factors such
as the relevant
indication, the route of administration, the age, weight and sex of the
patient and may be
determined by a physician. In general, oral and parenteral dosages will be in
the range of 0.1 to
1,000 mg per day of total active ingredients.
The term "therapeutically effective amount" as used herein refers to an amount
of a
therapeutic agent to treat a condition treatable by administrating a
composition of the invention.
That amount is the amount sufficient to exhibit a detectable therapeutic or
ameliorative
response in a tissue system, animal or human. The effect may include, for
example, treating the
conditions listed herein. The precise effective amount for a subject will
depend upon the
subject's size and health, the nature and extent of the condition being
treated,
recommendations of the treating physician (researcher, veterinarian, medical
doctor or other
clinician), and the therapeutics, or combination of therapeutics, selected for
administration.
Thus, it is not useful to specify an exact effective amount in advance.
The term "pharmaceutically acceptable salt" refers to those salts that are,
within the
scope of sound medical judgment, suitable for use in contact with the tissues
of humans and
lower animals without undue toxicity, irritation, allergic response, and the
like, and are
commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable
salts are well-
known in the art. They can be prepared in situ when finally isolating and
purifying the
compounds of the invention, or separately by reacting them with
pharmaceutically acceptable
non-toxic bases or acids, including inorganic or organic bases and inorganic
or organic acids.
Pharmaceutically acceptable salts may be obtained using standard procedures
well known in
the art, for example by mixing a compound of the present invention with a
suitable acid, for
instance an inorganic acid or an organic acid.
"Administration in conjunction with", includes that respective formulations
comprising
SLV308 and L-DOPA are administered, sequentially, separately and/or
simultaneously, over the
course of treatment of the relevant condition, which condition may be acute or
chronic.
Preferably, the term includes that the two formulations are administered
(optionally repeatedly)
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sufficiently closely in time for there to be a beneficial effect for the
patient, that is greater, over
the course of the treatment of the relevant condition, than if either of the
two formulations are
administered (optionally repeatedly) alone, in the absence of the other
formulation, over the
same course of treatment. Determination of whether a combination provides a
greater beneficial
effect in respect of, and over the course of treatment of, a particular
condition, will depend upon
the condition to be treated or prevented, but may be achieved routinely by the
person skilled in
the art. Thus, the term "in conjunction with" includes that one or other of
the two formulations
may be administered (optionally repeatedly) prior to, after, and/or at the
same time as,
administration with the other component. When used in this context, the terms
"administered
simultaneously" and "administered at the same time as" include that individual
doses of SLV308
and L-DOPA are administered within 48 hours, e.g. 24 hours, 18 hours, 12
hours, 6 hours, 3
hours, 2 hours, 1 hour or 30 minutes of each other.
The term "treatment" as used herein refers to any treatment of a mammalian,
preferably
human condition or disease, and includes: (1) inhibiting the disease or
condition, i.e., arresting
its development, (2) relieving the disease or condition, i.e., causing the
condition to regress, or
(3) stopping the symptoms of the disease.
As used herein, the term "medical therapy" intendeds to include prophylactic,
diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans
or other
mammals.
The term "subject" as used herein, refers to an animal, preferably a mammal,
most
preferably a human, who has been the object of treatment, observation or
experiment.
EXAMPLES
Treatment with the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine) leads to
depletion of dopamine in the caudate-putamen and `parkinsonian-like' behaviour
in non-human
and human primates (Lange, 1992; Langston, 1984; Langston, 1986).
EXAMPLE 1: Interaction between SLV308 and L-DOPA at therapeutically relevant
doses
Animals: adult common marmosets of either sex (Callithrix jacchus; n=6,
weighing 320-450g,
aged 2-3 years) were used in this study. Animals were housed singly or in
pairs under standard
conditions at a temperature of 24 2 C and relative humidity of 50%,
employing a 12 hour light-
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dark cycle, with free access to food and water. All experimental work was
carried out in
accordance with the Animals (Scientific Procedures Act) 1986, project license
nr PPL 70/4986.
Administration of MPTP: (1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine
hydrochloride;
Research Biochemical International, UK) was dissolved in 0.9% sterile saline
solution and
administered by subcutaneous (sc) injection (Pearce, 1998). To induce the full
lesion, MPTP
(2.0 mg/kg, sc) was administered once daily for 5 consecutive days. During
MPTP-treatment
and for the following six to eight weeks, animals were hand fed on a marmoset
jelly diet until
they had recovered sufficiently to feed themselves and their body weights had
stabilised. All
animals were determined responsive to L-DOPA administration prior to use.
Testing
commenced only when animals had recovered from the acute effects of MPTP
treatment. In this
study this was 70 days after commencement for MPTP treatment.
Drugs: SLV308 was dissolved in 10% sucrose and given in a volume of 2 ml/kg
and
administered by oral gavage. Doses are expressed as mg/kg free base. L-DOPA
methyl ester
(Sigma, UK) was dissolved in 10% sucrose in given in a volume of 2 ml/kg and
administered by
oral gavage. Carbidopa (Merck Sharp and Dohme, UK) was suspended in 10%
sucrose in given
in a volume of 2 ml/kg and administered directly into the mouth of the animal.
Domperidone
(Sigma, UK) was suspended in 10% sucrose in given in a volume of 2 ml/kg and
administered
directly into the mouth of the animal. Doses were based on a previous study
with SLV308 in
which it was shown that the optimal effect of SLV308 on locomotor activity and
disability scores
was achieved at 0.26 mg/kg, po. Doses of L-DOPA were chosen to reflect a
moderate and high
dose of L-DOPA (7.5 and 12.5 mg/kg, po respectively).
Procedure: On the day of experimentation, animals were weighed, treated with
domperidone (2
mg/kg, po) directly into the mouth and after 60 minutes were treated with
either SLV308 (0.26
mg/kg, po) or vehicle by oral gavage. After 30-minutes, carbidopa (12.5 mg/kg,
po) was
administered, and 30-minutes later L-DOPA (7.5 or 12.5 mg/kg, po) or its
vehicle was
administered. A modified latin square design was employed with one week wash-
out periods
between treatments. Animals were assessed for locomotor activity and
disability as described
below.
Assessment of locomotor activity: The animals were placed individually into
activity cages
(50 x 60 x 70 cm) fitted with a clear perspex door to allow clear visibility
for observation. Each
cage was equipped with 8 horizontally orientated infrared photocell emitters
and their
corresponding detectors arranged so as to permit maximum assessment of
movement.
Locomotor activity was assessed as the number of light beam interruptions
caused by
movement of the animals accumulated in 10-minute intervals for up to 7 hours.
The animals
were allowed a 60-minute acclimatisation period in the activity cages during
which baseline
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activity was assessed, before drug administration. 'On' Threshold was defined
as 3 times
baseline activity in MPTP-treated marmosets. Hyperactivity was defined as 3
times normal
activity in naive marmosets. `On' time was the period of time in minutes that
activity was above
the `On' Threshold.
Rating of disability: The animals were monitored through a one-way mirror by
experienced
observers, blinded to treatment, and rated for the degree of motor
dysfunction. Motor
dysfunction was scored on a disability rating scale; alertness (normal = 0,
reduced = 1, sleepy =
2); checking (present = 0, reduced = 1, absent = 2); posture (normal = 0,
abnormal trunk +1,
abnormal tail + 1, abnormal limbs + 1, flexed = 4); balance (normal = 0,
impaired = 1, unstable =
2, spontaneous falls = 3); reaction to stimuli (normal = 0, reduced = 1, slow
= 2, absent = 3);
vocalisation (normal = 0, reduced = 1, absent = 2); motility (normal = 0,
bradykinesia or
hyperkinesia = 1, akinesia or severe hyperkinesia = 2). These values were
summed to give a
maximum score of 18.
Analysis and Statistics: Total locomotor activity counts and total disability
scores were
analysed for the effect of treatment using the Friedman Test (SPSS, Version
10) followed by
Wicoxon or Mann-Whitney post-hoc tests to determine individual differences.
The significance
level was set at 5%.
EXAMPLE 2: Effects of SLV308 on L-DOPA induced reversal of motor disabilities
Spontaneous Locomotor Activity: SLV308 (0.26 mg/kg, po) increased locomotor
activity
within 30 minutes of administration (Figure 1). Peak activity was seen 180
minutes after
treatment and locomotor activity, and lasted for the 7 hour observation
period. L-DOPA (7.5 and
12.5 mg/kg, po) produced an immediate increase in locomotor activity which
peaked 60-90 min
after administration (Figure 1 and 2). The duration of activity was 150-240
min. Peak activity
following L-DOPA (7.5 and 12.5 mg/kg, po) was greater than that seen following
SLV308 (0.26
mg/kg, po) alone. Following pretreatment with SLV308 (0.26 mg/kg, po), peak
and duration of
activity after L-DOPA (7.5mg/kg, po) were similar to that seen following
SLV308 (0.26 mg/kg,
po) alone (Figure 1). Combined treatment with L-DOPA (7.5 mg/kg, po) plus
SLV308 (0.26
mg/kg, po) reduced peak locomotor activity following L-DOPA (7.5 mg/kg, po)
alone to a level
similar to that seen after SLV308 (0.26 mg/kg, po) alone such that
hyperactivity was not
observed (Figure 1). SLV308 (0.26 mg/kg, po) failed to reduce, but did not
increase, the peak
activity seen after L-DOPA (12.5 mg/kg, po). However, the duration of activity
('ON' time)
following L-DOPA (7.5 and 12.5 mg/kg, po) was increased by co-administration
of SLV308 (0.26
mg/kg, po), reflecting the duration of activity of SLV308 (Figure 3). Total
locomotor activity was
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WO 2007/144421 PCT/EP2007/055955
increased following all treatments compared to a vehicle treated group (Figure
4) although no
other differences were observed.
Motor Disability: L-DOPA (7.5 and 12.5mg/kg po) produced an immediate reversal
of disability
that peaked at 90 minutes after administration, with a score of 2.5 (Figure 5
and 6). The
duration of this effect was 150 and 180 minutes for L-DOPA at 7.5 and
12.5mg/kg po,
respectively. SLV308 (0.26 mg/kg po) reduced disability scores immediately
after administration
(Figure 5). A maximum improvement in disability (score 3) was maintained from
1 to 7 hours
after administration. Following pretreatment with SLV308 (0.26 mg/kg) followed
by L-DOPA (7.5
and 12.5 mg/kg po), the duration of the reversal of disability were similar to
that seen following
SLV308 (0.26 mg/kg po) alone (median duration of activity: 420min, 420 min and
390 min
respectively). Total disability scores were reduced over the 7 hours after
administration of
SLV308 (0.26 mg/kg po) administered alone or in combination with L-DOPA
(7.5mg/kg or 12.5
po) (Figure 7). Addition of SLV308 (0.26 mg/kg po) to L-DOPA (7.5mg/kg po),
caused an
increase in total disability score compared to L-DOPA (7.5mg/kg po) alone
(Figure 7).
Conclusion: These data confirm that both L-DOPA (7.5 and 12.5 mg/kg, po) and
SLV308 (0.26
mg/kg, po) reverse the MPTP-induced akinesia and disability. Both the high and
low doses of
L-DOPA had short durations of action and produced periods of hyperactivity.
The duration of
activity of SLV308 was considerably longer than that for L-DOPA, but
hyperactivity was not
observed. When given in combination, pretreatment with SLV308 prevented the
hyperactivity
following L-DOPA. No such interaction between SLV308 and L-DOPA was observed
in the
disability scores, since the effect of the combination of SLV308 and L-DOPA
resembled the
effect of SLV308 alone.
EXAMPLE 3: PHARMACEUTICAL PREPARATIONS
Types of pharmaceutical compositions that may be used include, but are not
limited to, tablets,
chewable tablets, capsules (including microcapsules), solutions, parenteral
solutions, ointments
(creams and gels), suppositories, suspensions, and other types disclosed
herein or apparent to
a person skilled in the art from the specification and general knowledge in
the art. The
compositions are used for oral, intravenous, subcutaneous, tracheal,
bronchial, intranasal,
pulmonary, transdermal, buccal, rectal, parenteral or other ways to
administer. The
pharmaceutical formulation contains at least one preparation of the invention
in admixture with a
pharmaceutically acceptable adjuvant, diluent and/or carrier. The total amount
of active
ingredients suitably is in the range of from about 0.1 %(w/w) to about 95%
(w/w) of the
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WO 2007/144421 PCT/EP2007/055955
formulation, suitably from 0.5% to 50% (w/w) and preferably from 1% to 25%
(w/w). The molar
ratio between SLV308 (or its N-oxide) and L-DOPA may be in the range of from
about 1000:1 to
about 1:1000, suitably lies in the range of from 300:1 to 1:300, and
preferably from 50:1 to 1:50.
The preparations of the invention can be brought into forms suitable for
administration by
means of usual processes using auxillary substances such as liquid or solid,
powdered
ingredients, such as the pharmaceutically customary liquid or solid fillers
and extenders,
solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer
substances. Frequently used
auxillary substances include magnesium carbonate, titanium dioxide, lactose,
saccharose,
sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein,
gelatin, starch,
amylopectin, cellulose and its derivatives, animal and vegetable oils such as
fish liver oil,
sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as,
for example,
sterile water and mono- or polyhydric alcohols such as glycerol, as well as
with disintegrating
agents and lubricating agents such as magnesium stearate, calcium stearate,
sodium stearyl
fumarate and polyethylene glycol waxes. The mixture may then be processed into
granules or
pressed into tablets.
The active ingredients may be separately premixed with the other non-active
ingredients,
before being mixed to form a formulation. The active ingredients may also be
mixed with each
other, before being mixed with the non-active ingredients to form a
formulation.
Soft gelatine capsules may be prepared with capsules containing a mixture of
the active
ingredients of the invention, vegetable oil, fat, or other suitable vehicle
for soft gelatine capsules.
Hard gelatine capsules may contain granules of the active ingredients. Hard
gelatine capsules
may also contain the active ingredients together with solid powdered
ingredients such as
lactose, saccharose, sorbitol, mannitol, potato starch, corn starch,
amylopectin, cellulose
derivatives or gelatine. Dosage units for rectal administration may be
prepared (i) in the form of
suppositories that contain the active substance mixed with a neutral fat base;
(ii) in the form of a
gelatine rectal capsule that contains the active substance in a mixture with a
vegetable oil,
paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in
the form of a ready-made
micro enema; or (iv) in the form of a dry micro enema formulation to be
reconstituted in a
suitable solvent just prior to administration.
Liquid preparations may be prepared in the form of syrups, elixirs,
concentrated drops or
suspensions, e.g. solutions or suspensions containing the active ingredients
and the remainder
consisting, for example, of sugar or sugar alcohols and a mixture of ethanol,
water, glycerol,
propylene glycol and polyethylene glycol. If desired, such liquid preparations
may contain
coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl
cellulose or
other thickening agents. Liquid preparations may also be prepared in the form
of a dry powder,
reconstituted with a suitable solvent prior to use. Solutions for parenteral
administration may be
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WO 2007/144421 PCT/EP2007/055955
prepared as a solution of a formulation of the invention in a pharmaceutically
acceptable
solvent. These solutions may also contain stabilizing ingredients,
preservatives and/or buffering
ingredients. Solutions for parenteral administration may also be prepared as a
dry preparation,
reconstituted with a suitable solvent before use.
Also provided according to the present invention are formulations and `kits of
parts'
comprising one or more containers filled with one or more of the ingredients
of a pharmaceutical
composition of the invention, for use in medical therapy. Associated with such
container(s) can
be various written materials such as instructions for use, or a notice in the
form prescribed by a
governmental agency regulating the manufacture, use or sale of pharmaceuticals
products,
which notice reflects approval by the agency of manufacture, use, or sale for
human or
veterinary administration. The use of formulations of the present invention in
the manufacture of
medicaments for use in treating a condition in which recovery of dopaminergic
function is
required or desired, and methods of medical treatment or comprising the
administration of a
therapeutically effective total amount of at least one preparation of the
invention to a patient
suffering from, or susceptible to, a condition in which recovery of
dopaminergic function is
required or desired.
LEGENDS TO THE FIGURES 1-7
Figure 1: The effect of SLV308 (0.26 mg/kg, po) on locomotor activity
following treatment with
L-DOPA (7.5 mg/kg po) in MPTP-lesioned common marmosets (n=6). Points
represent median
total locomotor activity counts in 30 minute intervals over 7 hours. Arrow 1:
SLV308 treatment,
Arrow 2 L-DOPA treatment. Symbols: open squares vehicle group, filled squares
L-DOPA 7.5
mg/kg po, open triangle SLV308 0.26 mg/kg po, and filled circles SLV308
followed by L-DOPA
7.5 mg/kg po.
Figure 2: The effect of SLV308 (0.26 mg/kg, po) on locomotor activity
following treatment with
L-DOPA (12.5 mg/kg, po) in MPTP-lesioned common marmosets (n=6). Points
represent
median total locomotor activity counts in 30-minute intervals over 7 hours.
Arrow 1: SLV308
treatment, Arrow 2 L-DOPA treatment Symbols: empty squares vehicle group,
filled (black)
squares: L-DOPA 12.5 mg/kg po, empty triangles SLV308 0.26 mg/kg po, and
filled circles
SLV308 followed by L-DOPA 12.5 mg/kg po. Dashed lines : Broken line- 'ON'
threshold,
Unbroken line-hyperactivity threshold. Error bars are omitted for clarity.
CA 02654719 2008-12-08
WO 2007/144421 PCT/EP2007/055955
Figure 3: The effect of SLV308 (0.26 mg/kg, po) on locomotor 'ON' time
following treatment
with L-DOPA (7.5 and 12.5mg/kg, po). Bars represent median total counts over 6
hours after
oral administration of SLV308 (0.26 mg/kg po; n=6). Bars represent median
total 'ON' time in
hours. There was an increase in 'ON' time across treatment (p's <0.001,
Friedman Test). #
p<0.02, Significant difference compared to L-DOPA alone (Wilcoxon Test).
Figure 4: The effect of SLV308 (0.26 mg/kg, po) on cumulative locomotor
activity counts
following treatment with L-DOPA (7.5 and 12.5 mg/kg, po). Bars represent
median total counts
over 6 hours after oral administration of SLV308 (0.26 mg/kg po; n=6). The
increase in counts
was significant across treatment (p's <0.001, Kruskall Wallis). * p<0.002,
Significant difference
compared to vehicle (Mann Whitney Test).
Figure 5: The effect of SLV308 (0.26 mg/kg, po) on motor disability reversal
by L-DOPA (7.5
mg/kg, po) in MPTP-common marmosets (n=6). Individual points represent the
median total
disability score in 30-minute intervals over the 7 hours after treatment with
L-DOPA. Arrow 1:
SLV308 treatment, Arrow 2 L-DOPA treatment: Symbols: empty squares vehicle
group, filled
squares L-DOPA (7.5 mg/kg, po), empty triangle SLV308 (0.26 mg/kg, po), and
filled circles
SLV308 followed by L-DOPA (7.5 mg/kg, po). Error bars are omitted for clarity.
Figure 6: The effect of SLV308 (0.26 mg/kg, po) on motor disability reversal
by L-DOPA (12.5
mg/kg, po) in MPTP-common marmosets (n=6). Individual points represent the
median total
disability score in 30-minute intervals over the 7 hours after treatment with
L-DOPA. Arrow 1:
SLV308 treatment, arrow 2 L-DOPA treatment. Symbols: empty squares vehicle
group, filled
squares L-DOPA (12.5 mg/kg, po), empty triangles SLV308 (0.2 6mg/kg, po), and
filled circles
SLV308 followed by L-DOPA 12.5mg/kg po. Error bars are omitted for clarity.
Figure 7: The effect of SLV308 (0.26 mg/kg, po) on cumulative motor disability
following
treatment with L-DOPA (7.5 and 12.5mg/kg po). Bars represent median total
counts over 6
hours after oral administration of SLV308 (0.26 mg/kg, po; n=6). The decrease
in disability was
significant across treatment (p <0.0005, Kruskall Wallis). * p<0.001,
Significant difference
compared to vehicle (Mann Whitney Test). # p<0.002 compared to L-DOPA (7.5
mg/kg, po)
(Mann Whitney Test).
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REFERENCES
Allen and Earley `Augmentation of the restless leg syndrome with
carbidopa/levodopa. Sleep
19: 205-213, 1996.
Allen and Earley, Restless leg syndrome: a review of clinical and
pathophysiologic features. J
Clin Neurophysiol 18: 128-147, 2001
Bara-Jimenez W et al,. 2005. Effects of serotonin 5-HTIA agonist in advanced
Parkinson's
disease. Movement Disorders 20: 932-936;
Bennett and Piercey, Pramipexole - a new dopamine agonist for the treatment of
Parkinson's
disease. J Neurol Sci 163: 25-31, 1999.
Bibbiani et al., 2001. Serotonin 5-HTlA agonist improves motor complications
in rodent and
primate parkinsonian models. Neurology 57: 1829-1834;
Blandini et al., `Functional changes of the basal ganglia circuitry in
Parkinson's disease',. Prog
Neurobiol 62, 63-88, 2000.
Chesson et al (1999) Practice parameters for the treatment of restless leg
syndrome and
periodic limb movement disorder. An American Academy of Sleep Medicine Report.
Standards of Practice Committee of the American Academy of Sleep Medicine.
Sleep 22:
961-968;
Christoffersen and Meltzer, 1998. Reversal of haloperidol-induced
extrapyramidal side effects in
cebus monkeys by 8-hydroxy-2-(di-n-propylamino)tetralin and its enantiomers.
Neuropsychopharmacology 18: 399-402).
Earley and Allen (1996) Pergolide and carbidopa/levodopa treatment of the
restless leg
syndrome and periodic leg movements in sleep in a consecutive series of
patients. Sleep
19: 801-810.
Feenstra, et al., SLV308, Drugs of the Future, 26(2), 128-132, 2001
Hening et al., (1986) Dyskinesias while awake and periodic movements in sleep
in restless leg
syndrome: treatment with opioids. Neurology 36: 1363-6
Hening et al., (1999) The treatment of restless leg syndrome and periodic limb
movement
disorder. An American Academy of Sleep Medicine Review. Sleep 22: 970-999
Hesselink et al., SLV308, a molecule combining potent partial dopamine-D2
receptor agonism
with serotonin 5-HTIA receptor agonism: In vitro and in vivo neurochemistry
Soc.
Neurosci. Abstr., 27(1), page 531, 2001
17
CA 02654719 2008-12-08
WO 2007/144421 PCT/EP2007/055955
Hesselink et al., DU 127090, SLV308 and SLV318: characterization of a
chemically related
class of partial dopamine agonists with varying degrees of 5-HTIA agonism,
Eur. J. Neurol.
10: S 1, 2151, 2003.
Hornykiewicz 0 (1966). Dopamine (3-hydroxytyramine) and brain function.
Pharmacol Reviews,
18, 925-964).
Jankovic, J.,'Natural course and limitations of levodopa therapy'. Neurology
43: S14-S17, 1993.
Jenner P. Pharmacology of dopamine agonists in the treatment of Parkinson's
disease.
Neurology 26: S1-8, 2002.
Johnston, L.C., et al., `The novel dopamine-d2 receptor partial agonist, SLV-
308, reverses
motor disability in MPTP-lesioned common marmosets (Callithrix jacchus)', Br.
J.
Pharmacol., 133, U-70, 2001 a.
Johnston, L.C., et al., `SLV-308: Antiparkinsonian effects in the MPTP-treated
common
marmosets (Callithrix jacchus)', Soc. Neurosci. Abstr., 27(1), page 531, 2001
b.
Johnston, L.C., et al., Association between Intrinsic Activity and the
Antiparkinsonian Effects of
a Novel Dopamine D2 Agonist series in the 1-methyl-4-phenyl-1,2,3,6-
terahydropyridine
Treated Primate Model of Parkinson's Disease. Eur. J. Neurol. 10: S1, 2158,
2003.
Jost, W.H. et al., `Efficacy and tolerability of Stalevo in patients with
Parkinson's disease
experiencing wearing-off, Aktuelle Neurologie, 32, Suppl. 6, S318-S325, 2005.
Kannari et al., Tandospirone citrate, a selective 5-HTIA agonist, alleviates L-
DOPA induced
dyskinesia in patients with Parkinson's disease. No To Shinkei 54: 133-137,
2002.
Lange K.W., et al. (1992). Terguride stimulates locomotor activity at 2 months
but not 10 months
after MPTP-treatment of common marmosets. Eur J of Pharmacology, 212, 247-52;
Langston and Irwin (1986). MPTP: Current concepts and controversies. Clin
Neuropharmacol 9,
485-507.
Langston et al,. (1984). MPTP-induced parkinsonism in humans and non-human
primates-
Clinical and experimental aspects. Acta Neurol Scand 70, 49-54).
Lledo, A., `Dopamine agonists: the treatment for Parkinson's disease in the
XXI century?
Parkinsonism Relat Disord 7, 51-58, 2000.
Lozano et al., New developments in understanding the etiology of Parkinson's
disease and in its
treatment. Curr Opin Neurobiol 8: 783-90, 1998.
McCreary et al., `SLV308: a Novel Antiparkinsonian Agent with Antidepressant
and Anxiolytic
Efficacy'. Soc Neurosci Abstr 27: 220.2, 2001
McCreary et al., The in vitro characterization of SLV308: a novel dopamine D2
/ D3 partial
agonist and 5-HTIA full agonist for the treatment of Parkinson's disease. Mov
Dis. 21:S13,
P93), 2006.
18
CA 02654719 2008-12-08
WO 2007/144421 PCT/EP2007/055955
Olanow et al, 2004, Multicenter, open label, trial of sarizotan in Parkinson
disease patients with
levodopa-indiced dyskinesias (the SPLENDID Study). Clin Neuropharmacol 27: 58-
62;
Pearce, et al., De Novo Administration of Ropinirole and Bromocriptine Induces
Less Dyskinesia
than L-DOPA in the MPTP-treated Common Marmoset. Mov Dis, Mar, 13(2), 234-41,
1998
Pollmacher and Schulz, `Periodic leg movements (PLM): their relationship to
sleep stages.
Sleep 16: 572-577, 1993
Rascol et al., A five-year study of the incidence of dyskinesia in patients
with early Parkinson's
disease who were treated with ropinirole or levodopa. N Engl J Med 342: 1484-
1491, 2000
Wolf, W.A., 'SLV308 SOLVAY, Current Opinion in Investigational Drugs, 4(7),
878-882, 2003
WO 00/29397
WO 2007/023141
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