AU2007259255A1 - Combination preparations comprising SLV308 and a L-DOPA - Google Patents
Combination preparations comprising SLV308 and a L-DOPA Download PDFInfo
- Publication number
- AU2007259255A1 AU2007259255A1 AU2007259255A AU2007259255A AU2007259255A1 AU 2007259255 A1 AU2007259255 A1 AU 2007259255A1 AU 2007259255 A AU2007259255 A AU 2007259255A AU 2007259255 A AU2007259255 A AU 2007259255A AU 2007259255 A1 AU2007259255 A1 AU 2007259255A1
- Authority
- AU
- Australia
- Prior art keywords
- slv308
- dopa
- treatment
- disease
- dopamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 title claims description 93
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Description
WO 2007/144421 PCT/EP2007/055955 COMBINATION PREPARATIONS COMPRISING SLV308 AND L-DOPA INDEX page 5 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 10 Definitions 7 Examples 10 Example 1: Pharmacological methods 10 Example 2: Pharmacological test results 12 Example 3: Pharmaceutical preparations 13 15 Legends to the Figures 1 - 7 15 References 16 Claims 19 Abstract 20 Figures 1 - 7 21 20 SUMMARY: TECHNICAL FIELD OF THE INVENTION 25 The invention concerns the use of a combination preparation of SLV308 or its N-oxide, or pharmacologically acceptable salts of those compounds: HN HN O HN [ OHNL' NH N CH 3 S N N-CH3 / N / SLV308 SLV308 N-oxide 30 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.
WO 2007/144421 PCT/EP2007/055955 BACKGROUND OF THE INVENTION Constant tremors in hands and legs, body movements that gradually become stiffer, slower and 5 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 10 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 15 (Blandini, 2000; Lledo, 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 20 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 25 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 30 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, 35 and other side-effects (Lozano, 1998; Bennett, 1999). It has been suggested that this could be overcome by using partial dopamine D 2
/
3 receptor agonists (i.e. compounds that do not maximally stimulate dopamine D 2
/
3 receptors) (Jenner 2002). Such compounds would 2 WO 2007/144421 PCT/EP2007/055955 hypothetically be capable of stimulating dopamine D 2
/
3 receptors when the dopaminergic tone is low, while being able to counteract excessive stimulation of the dopamine D 2 receptor when the dopaminergic tone is high, thereby resulting in "stabilisation" of dopaminergic transmission in the brain (Jenner, 2002). 5 5-HT1A receptor agonists may ameliorate the induction of dyskinesia since the 5-HT1A 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-HT1A receptor agonist and 10 dopamine receptor ligand, could ameliorate dyskinetic symptoms (Olanow, 2004; Bara-Jimenez, 2005; Bibbiani, 2001). The presence of 5-HT1A receptor agonist could be beneficial to the therapeutic effects of a partial D 2
/
3 receptor agonist (Johnston, 2003). Recently, different combination preparations containing L-DOPA and one or more other enzyme 15 inhibitors have been introduced. Well known are the combinations L-DOPAlcarbidopa (e.g. Sinemet®), L-DOPAlbenserazide (e.g. Madopar®) and L-DOPAlcarbidopa/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. 20 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 25 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 30 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 35 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 3 WO 2007/144421 PCT/EP2007/055955 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 5 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, 10 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 15 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, 20 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). 25 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 30 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, 35 1996). The other alternatives, benzodiazepines, opiates and anti-convulsants are not as uniformly effective as the dopaminergic agents (Chesson, 1999; Hening, 1999). Despite changes 4 WO 2007/144421 PCT/EP2007/055955 in their treatment regimes, 15-20% of patients find that all medications are inadequate because of adverse effects and limited treatment benefit 0 0 HN 0HN 0
NCH
3 N N-CH 3 SLV308 SLV308 N-oxide 5 SLV308, 7-[4-methyl-1 -piperazinyl]-2(3H)-benzoxazolone mono hydrochloride, binds to dopamine D 2 -like receptors and 5-HT1A receptors. It is a partial agonist at dopamine D 2 /3 receptors and a full agonist at serotonin 5-HT1A receptors. At cloned human dopamine D2,L receptors, SLV308 acted as a potent but partial D 2 receptor agonist (pECs 5 o=8.0 and pA 2 =8.4) 10 with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D 3 receptors, SLV308 acted as a partial agonist in the induction of [ 35 S]GTPyS binding (67% that of dopamine), had a higher degree of potency compared to quinpirole (pECs 5 o=9.2) and antagonized the dopamine induction of [ 3 5 S]GTPyS binding (pA 2 =9.0). SLV308 acted as a full 5-HT1A receptor agonist on forskolin induced cAMP accumulation at cloned 15 human 5-HT1A receptors (pEC50=6.3) similar to the 5-HT1A receptor agonist 8-OH-DPAT. In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D 2
/
3 receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K+-stimulated [ 3 H]dopamine release (pA 2 =8.5) from rat striatal slices. In the same paradigm the partial D 2 agonist terguride demonstrated a greater degree of 20 antagonism in the presence of quinpirole (pA 2 =10.3) similar to the D 2 antagonist haloperidol (pA 2 =9.3) but less than SLV308 (pA 2 =8.5). In conclusion, SLV308 combines high potency partial agonism at dopamine D 2
/
3 receptors (acting as a dopamine stabiliser) with full efficacy low potency serotonin 5-HT1A receptor agonism. (WO 00/29397; Feenstra, 2001; Johnston, 2 0 0 1 a,b. Hesselink, 2001, 2003, McCreary, 2001, 2006; Wolf,2003). In WO 2007/023141 it was disclosed 25 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 30 without its side effects: In particular without its characteristic "on-off effect", causing dyskinesias during "on"-periods, and bradykinetic episodes during "off"-periods. 5 WO 2007/144421 PCT/EP2007/055955 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 5 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, 10 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 15 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-D 2 and dopamine-D 3 receptors, as well as full agonism on serotonin 5-HT1A receptors, result in a blockade of the dyskinesias without reducing the therapeutic effect of L-DOPA. 20 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. 25 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 30 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 6 WO 2007/144421 PCT/EP2007/055955 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: 5 (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. 10 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: 15 (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. 20 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 25 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. 30 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), 35 desmethyldeprenyl, N-propargyl-1l-(R)-aminoindan (rasagaline), phenelzine (nardil), tranyl cypromine (parnate), CGP3466, furazolidone, isocarboxazid, pargyline, methyclothiazide and procarbazine 7 WO 2007/144421 PCT/EP2007/055955 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 5 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 10 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 15 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 20 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 25 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. 30 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. 35 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 8 WO 2007/144421 PCT/EP2007/055955 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. 5 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 10 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. 15 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 20 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 25 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. 30 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 35 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) 9 WO 2007/144421 PCT/EP2007/055955 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 5 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 10 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 15 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, 20 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. 25 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 30 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 35 conditions at a temperature of 24 ± 20C and relative humidity of 50%, employing a 12 hour light 10 WO 2007/144421 PCT/EP2007/055955 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 5 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 10 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 15 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 20 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 25 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 30 (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 35 were allowed a 60-minute acclimatisation period in the activity cages during which baseline 11 WO 2007/144421 PCT/EP2007/055955 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. 5 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 = 10 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 15 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 20 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 25 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 30 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 35 mg/kg, po), reflecting the duration of activity of SLV308 (Figure 3). Total locomotor activity was 12 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 5 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 10 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 15 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 20 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. 25 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 30 (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 35 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 13 WO 2007/144421 PCT/EP2007/055955 formulation, suitably from 0.5% to 50% (wlw) and preferably from 1% to 25% (wlw). 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 5 means of usual processes using auxiliary 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 auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, 10 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 15 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 20 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 25 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. 30 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 35 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 14 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. 5 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, 10 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 15 suffering from, or susceptible to, a condition in which recovery of dopaminergic function is required or desired. LEGENDS TO THE FIGURES 1-7 20 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 25 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 30 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. 15 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). # 5 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 10 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 15 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. 20 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 25 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 30 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). 16 WO 2007/144421 PCT/EP2007/055955 REFERENCES Allen and Earley 'Augmentation of the restless leg syndrome with carbidopa/levodopa. Sleep 19: 205-213, 1996. 5 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 10 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. 15 Bibbiani et al., 2001. Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models. Neurology 57: 1829-1834; 20 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. 25 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. 30 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. 35 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 40 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-D 2 receptor agonism 45 with serotonin 5-HTIA receptor agonism: In vitro and in vivo neurochemistry Soc. Neurosci. Abstr., 27(1), page 531, 2001 17 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: S1,2151,2003. 5 Hornykiewicz O (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. 10 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 15 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 (Callithrixjacchus)', Soc. Neurosci. Abstr., 27(1), page 531, 2001b 20 Johnston, L.C., et al., Association between Intrinsic Activity and the Antiparkinsonian Effects of a Novel Dopamine D 2 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. 25 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. 30 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, 35 485-507. Langston et al,. (1984). MPTP-induced parkinsonism in humans and non-human primates Clinical and experimental aspects. Acta Neurol Scand 70, 49-54). 40 Lled6, 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. 45 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 D 2 / D 3 partial 50 agonist and 5-HTA full agonist for the treatment of Parkinson's disease. Mov Dis. 21:S13, P93), 2006. 18 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; 5 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 10 Rascol et al., A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole orlevodopa. N Engl J Med 342: 1484-1491, 2000 Wolf, W.A., 'SLV308 SOLVAY, Current Opinion in Investigational Drugs, 4(7), 878-882, 2003 15 WO 00/29397 WO 2007/023141 19
Claims (10)
1. Combination preparation comprising (i) SLV308 or its N-oxide: IO HN O HN O N N CH 3 N\ N-CH 3 O 5 SLV308 SLV308 N-oxide or pharmacologically acceptable salts of these compounds, and (ii) L-DOPA, or pharmacologically acceptable salts thereof, for simultaneous, separate or sequential use in therapy of disorders requiring recovery of dopaminergic function. 10
2. Preparation as claimed in claim 1, further comprising a decarboxylase inhibitor.
3. Preparation as claimed in claim 1 or claim 2, further comprising a COMT inhibitor. 15
4. Preparation as claimed in any of the claims 1, 2 or 3, further comprising a MAO-B inhibitor.
5. Use of a preparation as claimed in any of the claims 1-4, for the manufacture of a medication for the treatment of disorders requiring recovery of dopaminergic function. 20
6. Use as claimed in claim 5, wherein said disorder is Parkinson's disease.
7. Use as claimed in claim 5, wherein said disorder is restless leg syndrome.
8. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable 25 carrier and/or at least one pharmaceutically acceptable auxiliary substance, a pharmacologically active amount of a preparation as claimed in any of the claims 1-4, as active ingredients.
9. A method of treating Parkinson's disease, or restless leg syndrome, in a human or animal 30 patient in need of such treating, comprising administering to the patient simultaneously, separately or sequentially, an amount of SLV308 or its N-oxide, or a pharmacologically acceptable salt thereof, and an amount of L-DOPA, wherein the amounts are efficacious for the treating. 35
10. The method of claim 9 wherein additionally an amount of a decarboxylase inhibitor and/or a COMT inhibitor and/or a MAO-B inhibitor is administered. 20
Applications Claiming Priority (5)
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US81405106P | 2006-06-16 | 2006-06-16 | |
EP06115583.4 | 2006-06-16 | ||
EP06115583 | 2006-06-16 | ||
US60/814,051 | 2006-06-16 | ||
PCT/EP2007/055955 WO2007144421A1 (en) | 2006-06-16 | 2007-06-15 | Combination preparations comprising slv308 and a l-dopa |
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AU2007259255A1 true AU2007259255A1 (en) | 2007-12-21 |
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AU2007259255A Abandoned AU2007259255A1 (en) | 2006-06-16 | 2007-06-15 | Combination preparations comprising SLV308 and a L-DOPA |
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EP (1) | EP2035002A1 (en) |
JP (1) | JP2009539941A (en) |
KR (1) | KR20090031908A (en) |
AU (1) | AU2007259255A1 (en) |
CA (1) | CA2654719A1 (en) |
EA (1) | EA015073B1 (en) |
IL (1) | IL195532A0 (en) |
MY (1) | MY148457A (en) |
NO (1) | NO20090164L (en) |
WO (1) | WO2007144421A1 (en) |
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GB0027020D0 (en) | 2000-11-03 | 2000-12-20 | Univ Manchester | Treatment of movement disorders |
US20090247537A1 (en) * | 2008-03-25 | 2009-10-01 | William Dale Overfield | Methods for preventing or treating bruxism using dopaminergic agents |
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US7596407B2 (en) * | 2004-03-26 | 2009-09-29 | Solvay Pharmaceuticals, B.V. | Transdermal iontophoretic delivery of piperazinyl-2(3H)-benzoxazolone compounds |
JP5081622B2 (en) * | 2004-09-21 | 2012-11-28 | 山▲東緑▼叶制▲薬▼有限公司 | Long-acting sustained-release preparation containing dopamine receptor agonist and method for producing the same |
KR20080046205A (en) * | 2005-08-22 | 2008-05-26 | 솔베이 파마슈티칼스 비. 브이 | N-oxides as prodrugs of piperazine & piperidine derivatives |
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2007
- 2007-06-15 AU AU2007259255A patent/AU2007259255A1/en not_active Abandoned
- 2007-06-15 KR KR1020097001024A patent/KR20090031908A/en not_active Application Discontinuation
- 2007-06-15 CA CA002654719A patent/CA2654719A1/en not_active Abandoned
- 2007-06-15 EA EA200970021A patent/EA015073B1/en not_active IP Right Cessation
- 2007-06-15 WO PCT/EP2007/055955 patent/WO2007144421A1/en active Search and Examination
- 2007-06-15 JP JP2009514809A patent/JP2009539941A/en active Pending
- 2007-06-15 EP EP07730193A patent/EP2035002A1/en not_active Withdrawn
- 2007-06-15 MY MYPI20085078A patent/MY148457A/en unknown
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2008
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2009
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EP2035002A1 (en) | 2009-03-18 |
NO20090164L (en) | 2009-01-14 |
CA2654719A1 (en) | 2007-12-21 |
KR20090031908A (en) | 2009-03-30 |
IL195532A0 (en) | 2009-09-01 |
EA200970021A1 (en) | 2009-06-30 |
WO2007144421A1 (en) | 2007-12-21 |
JP2009539941A (en) | 2009-11-19 |
EA015073B1 (en) | 2011-04-29 |
MY148457A (en) | 2013-04-30 |
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