MX2008016225A - Combination preparations comprising slv308 and a l-dopa. - Google Patents

Abstract

The invention concerns the use of a combination preparation of SLV308 or its N-oxide, or pharmacologically acceptable salts of those compounds (I), (II) 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.

Description

COMBINATION PREPARATIONS COMPRISING SLV308 AND L- DOPA TECHNICAL FIELD OF THE INVENTION The invention relates to the use of a combination preparation of S LV308 or its N-oxide or pharmaceutically acceptable salts of these compounds: SLV308 SLV308 N-oxide and L-DOPA, for simultaneous, separate or sequential use in the treatment of disorders that require the recovery of dopaminergic function, in particular Parkinson's disease and restless legs syndrome.

BACKGROUND OF THE INVENTION Constant tremors in the hands and legs, body movements that gradually become stiffer, slower and weaker and facial expressions similar to a mask are symptoms that have been observed throughout the history of mankind. In 1817, James Parkinson described this set of symptoms as 'paralysis agitans', and shortly after the disease was named according to the doctor who first described it in detail. The pathological cause of Parkinson's disease involves the destruction of nerve cells in the substantia nigra, the part of the brain involved in muscle movements. The loss of approximately 80% of the striated dopamine in Parkinson's disease results in cardinal symptoms of akinesia, rigidity and bradykinesia (Hornykiewicz, 1966). Patients have problems starting a movement and exhibit postural instability and loss of coordination. The current pharmacotherapy of Parkinson's disease is based on the recovery of dopaminergic function (Blandini, 2000; Lledó, 2000). Dopamine does not cross the cerebral blood barrier and therefore can not be used for Parkinson's disease, instead L-DOPA (the levorotatory enantiomer of 3,4-dihydroxyphenylalanine, which is also referred to as levodopa), because it penetrates the brain where it is decarboxylated to dopamine. But levodopa is also decarboxylated in peripheral tissues. Therefore, only a small portion of the administered levodopa is transported to the brain. Carbidopa inhibits the decarboxylation of peripheral levodopa, but in turn it can not cross the cerebral blood barrier and has no effect on the metabolism of levodopa in the brain. The combination of carbidopa and levodopa is considered the most effective treatment for the symptoms of Parkinson's disease.

However, within two to five years after the start of therapy, certain limitations will appear. As the disease progresses, the benefit of each dose becomes shorter ("the end-of-dose deterioration effect" or "wearing off") and some patients fluctuate unpredictably between mobility and immobility (the effect of "onset"). off "or fluctuation." On "periods (activity) are usually associated with high concentrations of levodopa in the plasma and often include abnormal involuntary movements, ie, dyskinesias." Off "periods (inactivity) were often correlated with episodes of low concentrations of levodopa in plasma and bradykinesia (Jankovic, 1993, Rascol, 2000). This prompted clinicians to postpone the initiation of treatment with L-DOPA using a previous treatment with dopamine agonists. However, the use of complete dopamine receptor agonists such as apomorphine, bromocriptine, lisuride, pergolide, pramipexole or ropinirole also has its limitations: These agonists exalt dyskinesias, induce psychotic symptoms including hallucinations, orthostatic hypotension, somnolence and other side effects (Lozano, 1998, Bennett, 1999) .. It was suggested that this could be overcome by the use of partial dopamine D2 and D3 receptor agonists (ie compounds that do not maximally stimulate dopamine D2 and D3 receptors (Jenner 2002) Such compounds would hypothetically be able to stimulate dopamine D2 and D3 receptors when the dopaminergic tone is low, while they would be able to act against a stimulation.

Excessive dopamine D2 receptor when the dopaminergic tone is high, thus producing a stabilization of dopaminergic transmission in the brain (Jenner, 2002). 5-HTiA receptor agonists may improve the induction of dyskinesia, since the 5-HT-IA receptor agonist tandospirone reduced dyskinesia in patients with Parkinson's disease treated with L-DOPA (Kannari, 2002) and extrapyramidal side effects induced by haloperidol in primates (Christoffersen, 1998). More recently it was suggested that sarizotan, a 5-HTiA receptor agonist and dopamine receptor ligand, could improve dyskinetic symptoms (Olanow, 2004, Bara-Jimenez, 2005, Bibbiani, 2001). The presence of the 5-HT-IA receptor agonist could be beneficial for the therapeutic effects of a partial agonist of the D2 and D3 receptors (Johnston, 2003). Recently, different combination preparations containing L-DOPA and one or more other enzyme inhibitors have been introduced. The combinations L-DOPA / carbidopa (for example Sinemet®), L-DOPA / benserazide (for example Madopar®) and L-DOPA / carbidopa / entacapone (for example Stalevo®, (Jost, 2005)) are well known. More recently, catecholamine-O-methyltransferase (COMT) inhibitors such as tolcapone and entacapone were proposed as joint therapy with L-DOPA. These compounds extend the plasma half-life of L-DOPA, without significantly increasing Cmax. In this way the duration of the end-of-dose deterioration (wearing-off) decreases, but it has the effect of increasing the intensity of the side effects of the peak dose, including dyskinesias of the peak dose. It seems that tolcapone induces significant hepatic toxicity in a small percentage of patients. Another strategy with the purpose of slowing down the metabolism of dopamine is the use of inhibitors of monoamine oxidase B (MAO-B) 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, dizziness, fainting, abdominal pain, confusion, hallucinations, dry mouth, intense dreams, dyskinesias, and headache. A feature of combination preparations is that they exist in many different dose combinations, since higher doses of L-DOPA are usually needed during the course of the disease to keep the symptoms under control. Combination preparations in the form of tablets containing fixed amounts of drugs are easy to use, but simultaneously they also have limited flexibility. An illustration of the fact that fixed combinations are not always useful is, for example, the use of the selective MAO-B inhibitor selegiline in the treatment of Parkinson's disease. In the early stage of the disease, selegiline can be administered as monotherapy: the compound will slow the metabolism of endogenous dopamine sufficiently to keep the symptoms within tolerable limits. In later stages of the disease, the use of L-DOPA will be necessary. When the efficacy of L-DOPA begins to deteriorate, the first solution for this problem is usually the use of an inhibitor of decarboxylase such as carbidopa (see above), and when this is also insufficient, co-therapy with selegiline will restore the efficacy of L-DOPA by reducing the depletion of dopamine generated by L-DOPA. Therefore, in practice L-DOPA and selegiline are administered in separate preparations that can be administered simultaneously or sequentially. Victims severely affected by Restless Legs Syndrome (RLS, also known as Ekbom's syndrome) are virtually unable to sit still or even stand still. Activities that require maintaining motor rest and limited cognitive stimulation, such as transportation (automobile, airplane, train, etc.) or attend extended meetings, readings, movies or other activities, are difficult, if not impossible. Tortured by these sensations that are more severe during the night, patients with RLS find that falling asleep is virtually impossible, which further diminishes the diminished quality of their lives. The urge to move, which increases during periods of rest, can be completely dissipated by movements, such as walking. However, once the movement is interrupted, the symptoms return with increased intensity. If a patient with RLS is forced to lie still, the symptoms will continue to rise like a tensed spring and, eventually, the legs will move involuntarily, relieving the symptoms immediately. Rhythmic or semi-rhythmic movements of the legs are observed if the patient tries to remain lying down (Pollmacher, 1993). These movements are made reference as dyskinesias in awake state (dyskinesias-while-awake (DWA)) (Hening, 1986) or more commonly, periodic movements of limbs in awake state (periodic limb movements while awake (PLMW)). Clinically, RLS is indicated when four diagnostic criteria are met: (1) a feeling of impulse to move the limbs (usually the legs); (2) motor restlessness to reduce sensations; (3) return or worsening of symptoms during rest; and (4) a marked circadian variation in the occurrence or severity of RLS symptoms; that is, worsening of symptoms during the evening and night (Alien, 2001). Current RLS treatments are several and plagued with undesirable side effects. Therapies include the administration of dopamine agonists, other dopaminergic agents, benzodiazepines, opiates and anti-convulsants. When RLS results from a secondary condition, such as pregnancy, end-stage renal disease, treatment with erythroprogetin or iron deficiency, the symptoms can be reduced or eliminated in at least some cases by removing the condition, such as by delivery or treatment with supplements traditional iron (Alien, 2001). However, the treatment of RLS resulting from non-secondary conditions ("idiopathic" RLS) presents a greater challenge. Dopaminergic agents, such as levodopa, generally provide effective initial treatment, but with continued use there is drug tolerance and an increase in symptoms in approximately 80% of the patients. patients with RLS (Alien, 1996); This complication is also common with dopamine agonists (Earley, 1996). The other alternatives, benzodiazepines, opiates and anticonvulsants do not achieve as uniform an effect as dopaminergic agents (Chesson, 1999, Hening, 1999). Despite modifications in their treatment regimens, 15-20% of patients find that all medications are inadequate due to adverse effects and limited benefits of treatment.

SLV308 SLV308 N-oxide SLV308, 7- [4-methyl-1-piperazinyl] -2 (3H) -benzoxazolone monohydrochloride, binds to receptors similar to those of dopamine D2 and to 5-HT1A receptors. It is a partial agonist of the dopamine D2 and D3 receptors and a complete agonist of serotonin 5-HT-IA receptors. With human dopamine D2, cloned L, SLV308 acts as a potent but partial agonist of the D2 receptor (pEC5o = 8.0 and pA2 = 8.4) with an efficiency of 50% on the accumulation of cAMP stimulated by forskolin. With recombinant human D3 dopamine receptors, SLV308 acted as a partial agonist in the induction of ligation of [35S] GTPyS (67% of the dopamine activity), had a higher degree of potency compared to quinpirole (pEC5o = 9.2) and antagonized the [35S] GTPyS ligation induced by dopamine (pA2 = 9.0). SLV 308 acted as a complete 5-HT1A receptor agonist on the accumulation of forscolin-induced cAMP with cloned human 5-HT1A receptors (pEC5o = 6.3), similar to the 5-HTiA receptor agonist 8-OH-DPAT . In striated rat sections, SLV308 attenuated the accumulation of cAMP stimulated by forskolin in dependence on concentration, as expected for a dopamine D2 / 3 receptor agonist. SLV308 antagonized the inhibitory effect of quinpirol on the release of [3 H] dopamine stimulated by K + (pA2 = 8.5) in rat striated sections. According to the same paradigm, the partial agonist D2 terguride showed a greater degree of antagonism in the presence of quinpirol (pA2 = 10.3), similar to the D2 antagonist haloperidol (pA2 = 9.3), but lower than SLV308 (pA2 = 8.5). In conclusion, SLV308 combines a high potential partial agonism with dopamine D2 / 3 receptors (acting as a dopamine stabilizer) with a fully effective low potency agonism of the serotonin 5-HTiA receptor. (WO 00/29397, Feenstra, 2001, Johnston, 2001a, Hesselink, 2001, 2003, McCreary, 2001, 2006, Wolf, 2003). In WO 2007/023141 it was revealed that in vivo the N-oxide of SLV308 is rapidly converted to SLV308, thus functioning as a "prodrug".

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: The effect of SLV308 (0.26 mg / kg, po) on locomotor activity after treatment with L-DOPA (7.5 mg / kg, po) in common marmosets injured with MPTP (n = 6). The points represent total counts of mean locomotor activity in 30-minute intervals for 7 hours. Arrow 1: Treatment with SLV308, Arrow 2: Treatment with L-DOPA. Symbols: open squares, vehicle; full squares, L-DOPA 7.5 mg / kg po; open triangles, SLV308 0.26 mg / kg po; full circles, SLV 308 followed by L-DOPA 7.5 mg / kg po. Figure 2: The effect of SLV308 (0.26 mg / kg, po) on locomotor activity after treatment with L-DOPA (12.5 mg / kg, po) in common marmosets injured with MPTP (n = 6). The points represent total counts of mean locomotor activity in 30-minute intervals for 7 hours. Arrow 1: Treatment with SLV308, Arrow 2: Treatment with L-DOPA. Symbols: empty squares, vehicle; full squares, L-DOPA 12.5 mg / kg po; empty triangles, SLV308 0.26 mg / kg po; full circles, SLV308 followed by L-DOPA 12.5 mg / kg po. Stroke lines: Line interrupted, threshold ON; continuous line, threshold of hyperactivity. Error bars are omitted for reasons of clarity. Figure 3: The effect of SLV308 (0.26 mg / kg, po) on the "ON" time of locomotor activity after treatment with L-DOPA (7.5 and 12.5 mg / kg, po). The bars represent the average of the total "ON" time in hours.

During the treatment the "ON" time increased (p's <0.001, Friedman's test). # p < 0.02, Significant difference compared to only L-DOPA (Wilcoxon assay). Figure 4: The effect of SLV308 (0.26 mg / kg, po) on the cumulative counts of locomotor activity after treatment with L-DOPA (7.5 and 12.5 mg / kg, po). The bars represent the mean total counts for 6 hours after oral administration of SLV308 (0.26 mg / kg po; n = 6). The increase in counts was significant during the treatment (p's <0.001, Kruskall Wallis). * p < 0.002, significant difference compared to the vehicle (Mann Wthitney test). Figure 5: The effect of SLV308 (0.26 mg / kg, po) on the reversal of motor disability by L-DOPA (7.5 mg / kg, po) in common marmosets injured with MPTP (n = 6). The individual points represent the average score of the total disability at 30-minute intervals for 7 hours after treatment with L-DOPA. Symbols: open squares, vehicle; filled squares, L-DOPA (7.5 mg / kg po), open triangles, SLV308 (0.26 mg / kg po), and full circles, SLV 308 followed by L-DOPA (7.5 mg / kg po). Error bars are omitted for reasons of clarity. Figure 6: The effect of SLV308 (0.26 mg / kg, po) on the reversal of motor disability by L-DOPA (12.5 mg / kg, po) in common marmosets injured with MPTP (n = 6). The individual points represent the average score of the total disability at 30-minute intervals for 7 hours after treatment with L-DOPA. Symbols: open squares, vehicle; full squares, L-DOPA (12.5 mg / kg po); open triangles, SLV308 (0.26 mg / kg, po), and full circles, SLV 308 followed by L-DOPA (12.5mg / kg po). Error bars are omitted for reasons of clarity. Figure 7: The effect of SLV308 (0.26 mg / kg, po) on cumulative motor disability after treatment with L-DOPA (7.5 and 12.5 mg / kg, po). The bars represent the mean total counts for 6 hours after oral administration of SLV308 (0.26 mg / kg po; n = 6). The increase in disability was significant during treatment (p < 0.0005, Kruskall Wallis). * p < 0.001, significant difference compared to the vehicle (Mann Wthitney test). # p < 0.002 in comparison with L-DOPA (7.5 mg / kg, per) (Mann Whitney test).

DETAILED DESCRIPTION OF THE INVENTION It was the object of the present invention to develop a treatment as effective as L-DOPA, but without its side effects: particularly without its "on-off effect" (activity-inactivity) characteristics, which cause dyskinesias during "on" periods and episodes. bradykinetics during "off" periods Surprisingly, in studies with marmosets treated with MPTP, an animal model with a positive prognosis for Parkinson's disease, it was found that a combined treatment with L-DOPA and SLV308 reduced the peak locomotor activity observed after treatment alone with L- DOPA, so hyperactivity was not observed. The duration of activity ("on" time) after administration of L-DOPA was increased by co-administration of SLV308. The subject of the invention are combination preparations of SLV308 or its N-oxide or the pharmacologically acceptable salts, hydrates and solvates thereof, together with L-DOPA and, optionally, a decarboxylase inhibitor and / or, optionally, an inhibitor of COMT and / or, optionally, an inhibitor of MAO-B, for the simultaneous, separate or sequential use in a therapy of disorders requiring the recovery of dopaminergic function, in particular Parkinson's disease and "leg syndrome" restless. " The invention relates to the use of SLV308 or its N-oxide, a true "prodrug", in cases in which L-DOPA induces dyskinesias, or it can be anticipated that it induces dyskinesias. In such cases, the specific pharmacological activities of the compound, ie, a partial agonism on dopamine D2 and dopamine D3 receptors, as well as a complete agonism on serotonin 5-HT- | A receptors, result in a blockade of dyskinesias , without reducing the therapeutic effect of L-DOPA. The present invention relates to pharmaceutical formulations, comprising: (i) SLV 308, its N-oxide or pharmacologically acceptable salts, hydrates and solvates thereof, and: (ü) L-DOPA, mixed with a pharmaceutically acceptable adjuvant, diluent or carrier. A further aspect of the present invention relates to equipment of parts comprising: (i) a container containing SLV308, its N-oxide, or pharmacologically acceptable salts, hydrates and solvates thereof, optionally mixed with an adjuvant, diluent or pharmaceutically acceptable support, and: (ii) a container containing L-DOPA, optionally mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, and: (iii) instructions for the sequential, separate or simultaneous administration of SLV308 and L-DOPA to a patient who needs it. According to a further aspect of the invention, there is provided a method for manufacturing an equipment of parts as defined herein, a method comprising assembling a component (i), as defined above, with a component (ii), as defined above, thus making the two components suitable for co-administration. Bringing together the two components includes that components (i) and (ii) can: (i) be provided as separate formulations (ie, independently from each other), by pooling the components subsequently for their joint use in a combination therapy; or (I) package and present the components together in the form of separate components of a "combination package" for use together in a combination therapy. Yet another aspect of the invention relates to methods for the treatment of a patient suffering from, or susceptible to, a condition in which the recovery of dopaminergic function is required or desired, which method comprises administering to the patient an amount Therapeutically effective total of: (i) SLV 308, its N-oxide or pharmacologically acceptable salts, hydrates and solvates thereof, optionally mixed with a pharmaceutically acceptable adjuvant, diluent or carrier; together with: (ii) L-DOPA, mixed with a pharmaceutically acceptable adjuvant, diluent or carrier. Yet another aspect of the invention relates to the use of pharmaceutical formulations comprising: (i) SLV 308, its N-oxide or pharmacologically acceptable salts, hydrates and solvates thereof, and: (ii) L-DOPA, mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, in the manufacture of a medicament for the treatment of a condition in which the recovery of the dopaminergic function is required or desired.

Definitions Examples of decarboxylase inhibitors are: carbidopa and benserazide. Examples of catecholamine-O-methyltransferase (COMT) inhibitors are: entacapone, nitecapone and tolcapone, and inhibitors of monoaminoxidase B (MAO-B) include: deprenyl, (-) - deprenyl (selegiline), desmethyldeprenyl, N-propargyl-1- (R) -aminoindane (rasagalin), phenelzine (nardyl), tranil-cipromine (parnate), CGP3466, furazolidone, isocarboxazid, pargyline, methylclothiazide and procarbazine. To provide a more concise descriptive memory, some of the quantitative expressions given in it are not qualified by the term "approximately". It is understood that the term "approximately", whether used explicitly or not, means that any amount indicated therein refers to the actual value given and also to an approximation of such value that could reasonably be inferred by the person skilled in the art, including approximations. due to experimental conditions or measurement of such given value. Throughout the description and claims of this specification, the word "understand" and variations thereof, such as "comprising" and "comprising", are not intended to exclude other additives, components, numbers or additional steps. The term "composition", as used herein, comprises a product that contains specific ingredients in predetermined amounts or proportions, as well as any resulting product, direct or indirectly, from the combination of specific ingredients in specified quantities. In relation to pharmaceutical compositions, this term comprises a product that contains one or more active ingredients and an optional support comprising inert ingredients, as well as any product that results, directly or indirectly, from the combination, formation of a complex or aggregate of any of two or more ingredients, or of the dissociation of one or more ingredients, or of other types of reaction or interaction of one or more ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately contacting the active ingredient with a liquid excipient or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition includes a sufficient amount of the active compound object of this invention to produce the desired effect on the progress or condition of diseases. Therefore, the pharmaceutical compositions of the present invention comprise any composition prepared by mixing a compound of the present invention with a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and must not be harmful to the recipient thereof. Within the context of this application, the term "combined preparation" includes both true combinations, which means SLV308 and other drugs physically combined into one preparation, such as a tablet or an injectable fluid, as well as a "kit of parts", comprising SLV308 and L-DOPA in separate dosage forms, together with instructions for use, optionally with additional means to facilitate the acceptance of the component compounds by the regulator, for example labels or drawings. With true combinations, pharmacotherapy is simultaneous by definition. The contents of a "team of parts" can be administered simultaneously or at different time intervals. Whether the therapy is concomitant or sequential will depend on the characteristics of the other medications used, characteristics such as onset and duration of action, plasma levels, elimination, etc., as well as the disease, its stage and the characteristics of the individual patient. . The dose of the composition to be administered will depend on the relevant indication, age, weight and sex of the patient and can be determined by a physician. The dose will preferably be in the range of 0.01 mg / kg to 10 mg / kg. The typical daily dose of active ingredients varies within a wide range and will depend on various factors such as the relevant indication, route of administration, age, weight and sex of the patient and can be determined by a physician. Generally, oral and parenteral dosages of the total active ingredients will be in the range of 0.1 to 1,000 mg per day. The term "therapeutically effective amount", as used herein, refers to an amount of a therapeutic agent to treat a treatable condition by administering a composition of the invention. This amount is sufficient to exhibit a therapeutic response or detectable improvement in an animal or human tissue system. The effect may include, for example, treating the conditions listed therein. The exact effective amount for a subject will depend on the size and health of the subject, the nature and severity of the condition to be treated, the recommendations of the attending physician (researcher, veterinarian, medical doctor or other clinician), and therapeutic products. or the combination of therapeutic products selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. The term "pharmaceutically acceptable salt" refers to those salts which, within the limits of a sound medical evaluation, they are suitable to be used in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and which are commensurable with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. They can be prepared in situ during the isolation and final purification of the compounds of the invention, or they can be prepared separately, by reacting the compounds of the invention with non-toxic pharmaceutically acceptable bases or acids, including inorganic or organic bases and inorganic acids or organic Pharmaceutically acceptable salts can be obtained by standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for example 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, during 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 in repeated form) in sufficiently close times so that a beneficial effect for the patient is produced, effect during the course of the treatment of the relevant condition is greater than that produced by the administration (optionally repeatedly) of the two formulations alone, in the absence of the other formulation, during the same course of treatment. The determination whether during the course of the treatment a combination provides a greater beneficial effect with respect to a particular condition will depend on the condition to be treated or prevented, but can be performed by the person skilled in the art in a routine manner. Thus, the term "in conjunction with" includes that either of the two formulations may be administered (optionally repeatedly) before, after and / or simultaneously with the other component. As used in this context, the terms "administered simultaneously" and "administered at the same time" include the administration of individual doses of SLV308 and L-DOPA within 48 hours. hours, for example, with a separation interval of 24 hours, 18 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour or 30 minutes. The term "treatment", as used herein, refers to any treatment of a condition or disease of a mammal, preferably a human, and includes: (1) inhibiting the disease or condition, i.e., stopping its development, (2) ) relieve the disease or condition, that is, cause the condition to regress, or (3) stop the symptoms of the disease. As used herein, the term "medical therapy" is intended to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo with humans or other mammals. The term "subject", as used herein, refers to an animal, preferably a mammal, more preferably a human, which has been the object of treatment, observation or experiment.

EXAMPLES Treatment with the MPTP neurotoxin (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine) leads to depletion of dopamine in the caudate-putamen and to a "Parkinsonian-like" behavior in non-human and human primates ( Lange, 1992; Langston, 1984; Langston, 1986).

EXAMPLE 1 Interaction between SLV308 and L-DOPA in therapeutically relevant doses Animals: Adult common marmosets of either sex (Callithrix jacchus, n = 6, weight 320-450g, age 2-3 years) were used in this study. Animals moved away alone or in pairs under standard conditions at a temperature of 24 ± 2 ° C and a relative humidity of 50%, using a 12-hour light-dark cycle, with free access to food and water. All experimental work was carried out in accordance with the Animáis (Scientific Procedures Act) 1986, project license No. PPL 70/4986.

Administration of MPTP: 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine hydrochloride (Research Biochemical International, UK) was dissolved in sterile physiological solution and administered by subcutaneous injection (se) (Pearce, 1998). To induce complete injury, MPTP (2.0 mg / kg, se) was administered once per day for 5 consecutive days. During MPTP treatment and the following six to eight weeks, the animals were hand-fed with a diet of marihuana jelly until sufficient recovery to feed themselves and stabilize their body weights. In all the animals, the response to the administration of L-DOPA before use was determined. The fresh trial began when the animals had recovered from the acute effects of MPTP treatment. In this study, the necessary recovery time was 70 days after the start of treatment with MPTP.

Drugs SLV308 was dissolved in 10% sucrose and administered in a volume of 2 ml / kg by oral gavage. The doses are expressed as mg / kg of free base. Methyl ester of L-DOPA (Sigma UK) was dissolved in 10% sucrose and administered in a volume of 2ml / kg by oral gavage. Carbidopa (Merck Sharp and Dohme, UK) was suspended in 10% sucrose and administered in a volume of 2 ml / kg directly into the animal's mouth. Domperidone (Sigma, UK) was suspended in 10% sucrose and administered in a volume of 2 ml / kg directly into the animal's mouth. The 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 with 0.26 mg / kg, po. The 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, the animals were weighed, treated with domperidone (2mg / kg, po) directly in the mouth, and after 60 minutes treated with SLV308 (0.26 mg / kg, po) or with vehicle using oral probe 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 their vehicle was administered. A modified Latin square design was used with periods of one week of washing between the treatments. Locomotor activity and disability were evaluated as described below.

Evaluation of locomotor activity The animals were placed individually in activity cages (50 x 60 x 70 cm) equipped with a transparent perspex door to allow a clear visibility for observation. Each cage was equipped with 8 horizontally oriented infrared emitting photocells and their corresponding detectors, arranged to allow a maximum evaluation of the movement. The locomotor activity was evaluated as the number of interruptions of the light beam caused by the movement of the animals, accumulated in intervals of 10 minutes for up to 7 hours. Before the administration of the drug, the animals were allowed to acclimate for a period of 60 minutes in the activity cages, during which period the baseline activity was evaluated. The "on" threshold was defined as 3 times the activity of the baseline in marmosets treated with MPTP. Hyperactivity was defined as 3 times the normal activity of untreated marmosets. The "on" time was the period of time in minutes during which the activity was above the "on" threshold.

Classification of disability The animals were monitored through a one-way mirror by experienced observers, who did not know the applied treatment (blind monitoring) and classified by the degree of motor dysfunction. The motor dysfunction was assigned a score according to a disability classification scale: wakefulness (normal = 0, reduced = 1, sleepy = 2); control (present = 0, reduced = 1, absent = 2); posture (normal = 0, abnormal trunk +1, abnormal tail +1, abnormal limbs +1, flexion = 4); balance (normal = 0, defective = 1, unstable = 2, spontaneous failures = 3); reaction to stimuli (normal = 0, reduced = 1, slow = 2, absent = 3); vocalization (normal = 0, reduced = 1, absent = 2); mobility (normal = 0, bradykinesia or hyperkinesia = 1, akinesia or severe hyperkinesia = 2). These values were added together to provide a maximum score of 18.

Analysis and Statistics The total locomotor activity counts and the total disability scores were analyzed to determine the effect of the treatment, using the Friedman test (SPSS, Version 10) followed by the post hoc Wicoxon or Mann-Whitney tests to determine differences individual The level of significance was adjusted to 5%.

EXAMPLE 2 Effects of SLV308 on the reversal of motor disabilities induced by L-DOPA Spontaneous locomotor activity SLV308 (0.26 mg / kg, po) increased locomotor activity within 30 minutes after administration (Figure 1). An activity peak was observed 180 minutes after the treatment and the locomotor activity remained during the 7 hours of the observation period. L-DOPA (7.5 and 12.5 mg / kg, po) produced an immediate increase in locomotor activity that peaked at 60-90 min after administration (Figures 1 and 2). The duration of the activity was 150-240 min. Peak activity after administration of L-DOPA (7.5 and 12.5 mg / kg, po) was greater than that observed after administration of only SLV308 (0.26 mg / kg, po). After a pretreatment with SLV308 (0.26 mg / kg, po), the peak and duration of activity after administration of L-DOPA (7.5 mg / kg, po) were equal to those observed after administration of only SLV308 (0.26 mg / kg, po) (Figure 1). Combined treatment with L-DOPA (7.5 mg / kg, po) plus SLV308 (0.26 mg / kg, po) reduced peak locomotor activity after administration of only L-DOPA (7.5 mg / kg, po) at a similar to that observed after the administration of only SLV308 (0.26 mg / kg, per), so hyperactivity was not observed (Figure 1). SLV308 (0.26 mg / kg, po) did not reduce, but neither did the observed peak activity increase after administration of L-DOPA (12.5 mg / kg, po). However, the activity duration ("on" time) after administration of L-DOPA (7.5 and 125 mg / kg, po) was increased by co-administration of SLV308 (0.26 mg / kg, po) reflecting the duration of the activity of SLV308 (Figure 3). Total locomotor activity increased after all treatments compared to a vehicle-treated group (Figure 4), although no other differences were observed.

Motor impairment: L-DOPA (7.5 and 12.5 mg / kg, po) produced an immediate reversal of disability, a reversal that reached its peak 90 minutes after administration with a score of 2.5 (Figures 5 and 6). The duration of this effect was 150 and 180 minutes for L-DOPA at 7.5 and 12.5 mg / kg po, respectively. SLV308 (0.26 mg / kg, po) reduced disability scores immediately after administration (Figure 5). A maximum disability improvement was maintained (score 3) from 1 to 7 hours after administration. With a pretreatment with SLV308 (0.26 mg / kg) followed by the administration of L-DOPA (7.5 and 12.5 mg / kg, po), the duration of the reversal of disability was similar to that observed after administering only SLV308 (0.26 mg / kg, po) (median activity duration: 420 min, 420 min and 390 min respectively). The total disability scores were reduced during the 7 hours after the administration of SLV308 (0.26 mg / kg, po), either administered alone or in combination with L-DOPA (7.5 mg / kg or 12.5 mg / kg, po) (Figure 7). The addition of SLV308 (0.26 mg / kg, po) to L-DOPA (7.5 mg / kg, po), caused an increase in the total disability score compared to L-DOPA (7.5 mg / kg po) only (Figure 7).

Conclusion These data confirm that both L-DOPA (7.5 and 12.5 mg / kg, po) as well as SLV308 (0.26 mg / kg, po) reverse the akinesia and disability induced by MPTP. Both the high dose as well as the low dose of L-DOPA had short duration of action and produced periods of hyperactivity. The duration of SLV308 activity was considerably longer than that of L-DOPA, but hyperactivity was not observed. When the two drugs are administered in combination, pretreatment with SLV308 prevented the hyperactivity produced by L-DOPA. No interaction between SLV308 and L-DOPA was observed with respect to disability scores, since the effect of the combination of SLV308 and L-DOPA was similar to the effect of SLV308 only.

EXAMPLE 3 Pharmaceutical preparations Types of pharmaceutical compositions that can 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 therein or apparent to a person skilled in the art from of descriptive memory and a general knowledge of art. The compositions are used orally, intravenously, subcutaneously, tracheally, bronchially, intranasally, pulmonarily, transdermally, buccally, rectally, parenterally or by other routes of administration. The pharmaceutical formulation contains at least one preparation of the invention mixed with a pharmaceutically acceptable adjuvant, diluent and / or carrier. The total amount of active ingredients is suitably in the range of from about 0.1% (w / w) of the 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 can be in the range of from about 1000: 1 to about 1: 1000, conveniently 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 usual processes using auxiliary substances such as liquid or powdered solid ingredients, such as pharmaceutically customary liquid or solid fillers and solvents, solvents, emulsifiers, lubricants, flavorings, colorants and pH regulating substances. Frequently used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, sucrose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as oil of fish liver, sunflower oil, peanut or sesame, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol, as well as disintegrating agents and lubricating agents such as magnesium stearate, calcium, sodium stearyl fumarate and polyethylene glycol waxes. The mixture can then be processed into pellets or compressed into tablets. The active ingredients can be premixed separately with the other non-active ingredients, before preparing the final mixture to form a formulation. The active ingredients can also be mixed together, before being mixed with the non-active ingredients to form a formulation. Soft gelatin capsules can 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 gelatin capsules may contain granules of the active ingredients. Hard gelatin capsules can also contain the active ingredients together with powdered solid ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, amylopectin corn starch, cellulose derivatives or gelatin. Dosage units for rectal administration can be prepared (i) in the form of suppositories containing the active substance mixed with a neutral fat base; (ii) in the form of a rectal gelatin capsule containing the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for rectal gelatin capsules; (iii) in the form of a microenema prepared for use; or (iv) in the form of a dry microenema formulation that must be reconstituted in a suitable solvent immediately prior to administration. The liquid preparations can be prepared in the form of syrups, elixirs, drops or concentrated suspensions, for example solutions or suspensions containing the active ingredients, the remainder consisting of, for example, 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, saccharin and carboxymethyl cellulose or other thickening agents. Liquid preparations can also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration can be prepared in the form of a solution containing a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and / or pH regulating ingredients.

Solutions for parenteral administration can also be prepared in the form of a dry preparation, reconstituted with a suitable solvent before use. . The present invention also provides formulations and "parts kits" 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. With such a container (such containers) may be associated various written materials, such as instructions for use or a note in the form required by a government agency that regulates the manufacture, use or sale of pharmaceutical products, note that reflects approval by the manufacturing agency, the use or sale for human or veterinary administration. The use of formulations of the present invention in the manufacture of medicaments to be used to treat a condition in which the recovery of dopaminergic function is required or desired, and methods of medical treatment 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 the recovery of the dopaminergic function is required or desired.

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Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS combination preparation comprising (i) SLV308 N-oxide: SLV 308 N-oxide or pharmacologically acceptable salts thereof, and (ii) L-DOPA or pharmacologically acceptable salts thereof, for simultaneous, separate or sequential use in therapy of disorders requiring the recovery of dopaminergic function. 2 - A combination preparation comprising (i) SLV308 or its N-oxide: SLV308 or pharmacologically acceptable salts of these compounds, and (ii) L-DOPA or pharmacologically acceptable salts thereof, further comprising a decarboxylase inhibitor, for simultaneous, separate or sequential use in therapy of disorders that require the recovery of dopaminergic function. 3. The preparation according to claim 1 or 2, further characterized in that it also comprises a COMT inhibitor. 4. The preparation according to any of claims 1, 2 or 3, further characterized in that it also comprises an inhibitor of MAO-B. 5. The use of a preparation according to any of claims 1-4, for the manufacture of a medicament useful for the treatment of disorders that require the recovery of dopaminergic function. 6. - The use as claimed in claim 5, wherein said disorder is Parkinson's disease. 7. The use as claimed in claim 5, wherein said disorder is the syndrome of restless legs. 8. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable excipient and / or at least one pharmaceutically acceptable auxiliary substance, as active ingredient a pharmacologically active amount of a preparation of any of claims 1-4.