Treatment of movement disorders

文档序号：53688 发布日期：2021-09-28 浏览：43次中文

阅读说明：本技术 运动障碍的治疗 (Treatment of movement disorders ) 是由 J·B·汉森 H-W·柳 R·瑞斯旺托于 2019-12-20 设计创作，主要内容包括：本公开涉及5-HT1A激动剂和左旋多巴在运动障碍,如帕金森氏病和左旋多巴引起的运动障碍(LID)的治疗管理中的优化给药方案。(The present disclosure relates to optimized dosing regimens of a 5-HT1A agonist and levodopa in the therapeutic management of dyskinesias, such as Parkinson's disease and levodopa-induced dyskinesia (LID).)

1. A pharmaceutical composition comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof;

wherein the composition further comprises dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, either separately or together;

with the proviso that the composition does not comprise an agonist of one or more serotonin receptors selected from the group of 5-HT1B, 5-HT1D and/or 5-HT1F receptors or a pharmaceutically acceptable derivative thereof;

for the treatment, prevention or alleviation of dyskinesia.

2. The composition for use according to claim 1, wherein said i)5-HT1A receptor agonist or pharmaceutically acceptable derivative thereof, and said ii) dopamine, dopamine agonist, dopamine precursor or dopamine prodrug are administered substantially simultaneously.

3. The composition for use according to any of the preceding claims, wherein said composition consists of i) a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof, and ii) dopamine, dopamine agonist, dopamine precursor or dopamine prodrug as the sole active pharmaceutical ingredient.

4. The composition for use according to any of the preceding claims, wherein the composition is administered 2 times per day, such as at least 2 times per day.

5. The composition for use according to any of the preceding claims, wherein the composition is administered 3 times per day, such as at least 3 times per day.

6. The composition for use according to any of the preceding claims, wherein the composition is administered 4 times per day, such as at least 4 times per day.

7. The composition for use according to any of the preceding claims, wherein the composition is administered 5 times per day, such as at least 5 times per day.

8. The composition for use according to any of the preceding claims, wherein the composition is administered 6 times per day, 7 times per day or 8 times per day; for example at least 6 times per day, at least 7 times per day or at least 8 times per day.

9. The composition for use according to any of the preceding claims, wherein said 5-HT1A receptor agonist is selected from the group consisting of buspirone, 6-hydroxybuspirone, tandospirone, gepirone, aleurone, buspirone, ixabepilone, perospirodol, befeladox, rapinotan, piczoltan, oximazoltan, fluoroxinkstan, flibanserin, salizotan, eltoprazine, F13714 and F15599, or a pharmaceutically acceptable derivative thereof.

10. The composition for use according to any of the preceding claims, wherein said 5-HT1A receptor agonist is buspirone or 6-hydroxybuspirone.

11. The composition for use according to any of the preceding claims, wherein the dopamine precursor or dopamine prodrug is selected from the group consisting of L-phenylalanine, L-tyrosine and L-DOPA or derivatives thereof.

12. The composition for use according to any of the preceding claims, wherein the dopamine precursor is L-DOPA (levodopa; L-DOPA ═ L-3, 4-dihydroxyphenylalanine) or a derivative thereof, such as a deuterated analogue or ester of L-DOPA.

13. The composition for use according to any of the preceding claims, wherein the dopamine precursor is a formulation comprising L-DOPA or derivatives thereof in solid, semi-solid or liquid form.

14. A composition for use according to any of the preceding claims, wherein the dopamine precursor is a preparation comprising only L-DOPA or derivatives thereof, including dopamine receptors and levodopa.

15. The composition for use according to any of the preceding claims, wherein the dopamine precursor is a formulation comprising L-DOPA or derivatives thereof in combination with one or more other active ingredients.

16. The composition for use according to any of the preceding claims, wherein the dopamine precursor is a preparation comprising L-DOPA or derivatives thereof in combination with a DOPA decarboxylase inhibitor.

17. The composition for use according to any of the preceding claims, wherein the dopamine precursor is a preparation comprising L-DOPA or a derivative thereof in combination with a DOPA decarboxylase inhibitor selected from the group consisting of carbidopa and benserazide.

18. The composition for use according to any of the preceding claims, wherein the dopamine precursor is a formulation comprising L-DOPA or a derivative thereof in combination with carbidopa, including rytary (nument) ryptoman (amet, Carbilev), medicinal DOPA, paropa and metodopa.

19. A composition for use according to any of the preceding claims, wherein the dopamine precursor is a formulation comprising L-DOPA or derivatives thereof in combination with benserazide, including metodopa or Prolopa.

20. A composition for use according to any of the preceding claims, wherein the dopamine precursor is a formulation comprising L-DOPA or derivatives thereof in combination with a COMT inhibitor.

21. The composition for use according to any of the preceding claims, wherein said dopamine precursor is a formulation comprising L-DOPA or a derivative thereof in combination with a COMT inhibitor selected from the group consisting of tolcapone, entacapone, nitecapone and apocapone.

22. Composition for use according to any of the preceding claims, wherein the dopamine precursor is a preparation comprising L-DOPA or derivatives thereof in combination with a DOPA decarboxylase inhibitor and a COMT inhibitor, such as staurow.

23. The composition for use according to any of the preceding claims, wherein the dopamine agonist is a dopamine receptor agonist.

24. The composition for use according to any of the preceding claims, wherein said dopamine receptor agonist is selected from the group consisting of bromocriptine (bromocriptine), pergolide mesylate (pergolide), palomist (pramipexole, senforo), ropinirole (ropinirole), piribedil (Pronora, Tesuda), cabergoline (Lacqueradine), apomorphine (Apomorphine), propylnorapomorphine, lisuride, ciladopa, dihydroscidine, dinaprine, polypurine, epilotine, quinagolide (norgonine), rotigotine (Neoprene), rocurone, sumanirole, fenoldopam, and derivatives thereof.

25. The composition for use according to any of the preceding claims, wherein the dopamine agonist is an indirect dopamine agonist, such as dopamine reuptake inhibitor/transporter blocker and dopamine releasing agent.

26. The composition for use according to any of the preceding claims, wherein the indirect dopamine agonist is selected from the group consisting of amphetamine and/or dextroamphetamine, bupropion (wibo meaning), amphetamine, nomifensine, lissedamide, methylphenidate (ritaline) or dextromethylphenidate, methylenedioxy-pyrrolidone (MDPV; "Sonic"), ketamine, phencyclidine (PCP), cathinone, cocaine, amphetamine, methamphetamine, methylenedioxy-methamphetamine (MDMA), phenethylamine, para-tyramine, lisdexamphetamine dimesylate (Vyvanse), phenmetrazine, pimoline, 4-methylaminourea (4-MAR), and benzylpiperazine, and vesicular monoamine transporter type ii (VMAT2) inhibitors, such as reserpine, tetrabenazine, and dessertpine.

27. Composition for use according to any of the preceding claims, wherein the composition comprises or consists of buspirone and levodopa.

28. The composition for use according to any of the preceding claims, wherein the composition does not comprise one or more agonists of serotonin receptors selected from the group of 5-HT1B, 5-HT1D and/or 5-HT1F receptors;

for example, agonists that do not contain two or more of the 5-HT1B, 5-HT1D, and 5-HT1F receptors;

such as triptan;

for example, the triptan is selected from the group consisting of zolmitriptan, rizatriptan, sumatriptan, naratriptan, almotriptan, frovatriptan, avitriptan, isomatriptan, aniracetam, and eletriptan.

29. The composition for use according to any of the preceding claims, wherein said composition comprises both i) a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof, and ii) dopamine, a dopamine agonist, a dopamine precursor or a dopamine prodrug.

30. The composition for use according to any of the preceding claims, wherein said composition comprises i) a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof, and ii) dopamine, a dopamine agonist, a dopamine precursor or a dopamine prodrug, respectively.

31. The composition for use according to any of the preceding claims, wherein said 5-HT1A receptor agonist or pharmaceutically acceptable derivative thereof is administered simultaneously, separately or sequentially with said dopamine, dopamine agonist, dopamine precursor or dopamine prodrug.

32. The composition for use according to any of the preceding claims, wherein said 5-HT1A receptor agonist or pharmaceutically acceptable derivative thereof and said dopamine, dopamine agonist, dopamine precursor or dopamine prodrug are administered simultaneously, separately or sequentially with each administration.

33. The composition for use according to any of the preceding claims, wherein said 5-HT1A receptor agonist, or a pharmaceutically acceptable derivative thereof, and said dopamine, dopamine agonist, dopamine precursor, or dopamine prodrug are administered simultaneously at each administration.

34. The composition for use according to any of the preceding claims, wherein said 5-HT1A receptor agonist, or pharmaceutically acceptable derivative thereof, and said dopamine, dopamine agonist, dopamine precursor or dopamine prodrug are administered separately or sequentially at substantially the same time for each administration.

35. The composition for use according to any of the preceding claims, wherein the 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof is administered in a daily dose of 0.01 to 10mg/kg body weight, such as 0.01 to 5mg/kg body weight, such as 0.1 to 1mg/kg body weight.

36. The composition for use according to any of the preceding claims, wherein the 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof is administered in a dose of 1-50mg per dose, such as 1-5mg per dose, such as 5-10mg per dose, such as 10-15mg per dose, such as 15-20mg per dose, such as 20-25mg per dose, such as 25-30mg per dose, such as 30-35mg per dose, such as 35-40mg per dose, such as 40-45mg per dose, such as 45-50mg per dose.

37. The composition for use according to any of the preceding claims, wherein the L-DOPA or the pharmaceutically acceptable derivative thereof is administered at a dose of 100-10000 mg/day, such as 100-250 mg/day, such as 250-500 mg/day, such as 500-750 mg/day, such as 750-1000 mg/day, such as 1000-2000 mg/day, such as 2000-2500 mg/day, such as 2500-3000 mg/day, such as 3000-4000 mg/day, such as 4000-5000 mg/day, such as 5000-6000-7000-mg/day, such as 6000-7000-8000-mg/day, such as 8000-900 mg/day, such as 9000-10000 mg/day.

38. The composition for use according to any of the preceding claims, wherein the composition further comprises one or more pharmaceutically acceptable carriers and/or excipients.

39. The composition for use according to any of the preceding claims, wherein the composition further comprises one or more additional active ingredients selected from the group consisting of compounds that ameliorate the symptoms of or are useful for treating parkinson's disease, including but not limited to peripheral inhibitors that convert L-DOPA (or other dopamine prodrugs) to dopamine, such as carboxylase inhibitors, e.g. carbidopa (lobdosin) or benserazide; or NMDA antagonists, such as amantadine (amantadine, gcrovi, osmolex); catechol-o-methyltransferase (COMT) inhibitors such as tolcapone, entacapone, nitecapone and apicapone; MAO-B inhibitors such as selegiline and rasagiline; a serotonin receptor modulator; a kappa opioid receptor agonist; a GABA modulator; neuronal potassium channel modulators, such as flupirtine and retigabine; A2A receptor antagonists, such as istradefylline; and glutamate receptor modulators, such as amantadine, dextromethorphan, and deuterated dextromethorphan.

40. The composition for use according to any of the preceding claims, wherein the movement disorder is selected from the group consisting of: dyskinesias associated with altered or impaired synaptic dopamine levels; parkinson's disease; dyskinesias associated with parkinson's disease, such as bradykinesia, bradykinesia and dyskinesia; tardive dyskinesia and aphasia.

41. The composition for use according to any of the preceding claims, wherein the movement disorder is selected from the group consisting of ataxia, dystonia, essential tremor, huntington's disease, myoclonus, rett syndrome, gilles de tourette's syndrome, wilson's disease, chorea, machado-joseph disease, restless leg syndrome, spastic torticollis and genital spasm, or a movement disorder associated therewith.

42. The composition for use according to any of the preceding claims, wherein the dyskinesia is associated with or caused by the treatment of parkinson's disease, such as anti-parkinson's disease therapy, including but not limited to dopamine, dopamine agonists, dopamine precursors, dopamine prodrugs, dopamine mimetics and dopaminergic drugs, such as L-DOPA.

43. Composition for use according to any of the preceding claims, wherein the dyskinesia is L-DOPA-induced dyskinesia (LID).

44. The composition for use according to any of the preceding claims, wherein the dyskinesia is caused by or associated with drug therapy, including neuroleptics, antipsychotics, antidepressants and anti-emetics.

45. The composition for use according to any of the preceding claims, wherein the dyskinesia is caused by or associated with drug withdrawal, including opioids, barbiturates, cocaine, benzodiazepines, alcohol and amphetamines.

46. The composition for use according to any of the preceding claims, wherein the movement disorder is caused by an idiopathic disease, a genetic dysfunction, an infection or other condition resulting in dysfunction of the basal ganglia and/or resulting in altered levels of synaptic dopamine.

47. The composition for use according to any of the preceding claims, wherein the dyskinesia is not Tardive Dyskinesia (TD).

48. A composition for use according to any of the preceding claims comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof and separately or together comprising dopamine, a dopamine agonist, a dopamine precursor or a dopamine prodrug;

for the treatment, prevention or alleviation of L-DOPA-induced dyskinesia (LID).

49. A composition for use according to claim 48, wherein the composition comprises buspirone and L-DOPA, with the proviso that the composition does not comprise a triptan, for example the triptan is selected from the group consisting of zolmitriptan, rizatriptan, sumatriptan, naratriptan, almotriptan, frovatriptan, avitriptan, isomatriptan and eletriptan.

50. A composition for use according to any of the preceding claims, comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof,

wherein the composition optionally further comprises dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, respectively or simultaneously;

for the treatment, prevention or alleviation of Tardive Dyskinesia (TD);

wherein the composition is administered at least 5 times per day.

51. A pharmaceutical composition comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof;

wherein the composition optionally further comprises dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, respectively or simultaneously;

for the treatment, prevention or alleviation of dyskinesia;

wherein the composition is administered in the following manner:

i) as a continuous administration;

ii) as a long acting injection; or

iii) as a sustained release formulation.

Technical Field

The present disclosure relates to optimized dosing regimens of a 5-HT1A agonist and levodopa in the treatment management of dyskinesias, such as Parkinson's disease and levodopa-induced dyskinesia (LID).

Background

Dyskinesias are a group of diseases that affect the production and control of body movements, and are often associated with neurological disorders or conditions associated with neurological dysfunction. Dyskinesias may manifest as abnormal fluency or speed of movement, excessive or involuntary movements, or a slowing or lack of voluntary movement.

Dyskinesias are often caused by impaired regulation of dopamine neurotransmission. Parkinson's Disease (PD) is an example of a movement disorder associated with dysfunction of dopamine neurotransmission caused by progressive degeneration of dopamine neurons, and tardive dyskinesia is another example of a movement disorder associated with dysfunction of dopamine neurotransmission regulation.

To replace lost dopamine, PD is currently treated with e.g. levodopa (L-DOPA, a precursor of dopamine). Unfortunately, treatment of PD with L-DOPA often causes some particular type of dyskinesia, known as L-DOPA-induced dyskinesia (LID), which is caused in part by an excessive level of dopamine in the synapse.

Dopamine release and reuptake is regulated by a variety of neurotransmitters, including serotonin (5-HT). Serotonin acts by binding to a number of different serotonin receptors, some of which have been investigated for the treatment of movement disorders.

LID may be improved or prevented using serotonin (5-HT) neurotransmission modulators alone. An example of this is thalidomide, which is both a 5-HT1A agonist and a dopamine receptor antagonist (Gregoire et al: Parkinsonism Relat Disord.2009; 15(6): 445-52). Solizotan mitigated LID in preclinical and clinical studies. However, in phase 2b and 3 studies, it was found that sarizontan did not show significant effects compared to placebo. Serzoptan has been shown to have an effect on preclinical models of tardive dyskinesia (Rosegarten et al: Progress in Neuro-Psychopharmacology & Biological psychotherapy 30(2006) 273-279). Selective antagonists of the dopamine D4 receptor also attenuate LID in non-human primate models (p.huot et al: JPET 342: 576-585,2012).

Buspirone and 5-HT1A agonists have generally been shown to reduce abnormal involuntary movements associated with L-DOPA treatment of Parkinson's disease (L-DOPA induced dyskinesia, LID) (see reviews such as P.Huot at al: Pharmacol Rev65: 171-Bucky 222,2013) and to reduce Tardive Dyskinesia (TD) associated with neuroleptic treatment of schizophrenia. (e.g., Naidu et al: Eur J Pharmacol.2001, 28; 428(1): 81-6; Creed et al: The Journal of Neuroscience,2012,32(28): 9574-9581).

The effect of the partial agonist buspirone of 5-HT1A on Parkinson's disease was studied in a small open study (Ludwig et al: Clin neuropharmacol.1986; 9(4):373-8) and the doses commonly used to treat patients with anxiety (10-60 mg/day) were found to have no effect on Parkinson's disease or dyskinesias. At higher doses (100 mg/day), buspirone was observed to reduce dyskinesia, but with a marked worsening of disability grade. This suggests that high doses of buspirone may exacerbate parkinsonian disability. Other studies have shown that buspirone can alleviate L-DOPA-induced dyskinesia in exploratory clinical studies (bonifatti et al, 1994, Kleedorfer et al, 1991). In addition, buspirone also showed efficacy in clinical studies of tardive dyskinesia (Moss et al, 1993).

High doses of 5-HT1A agonist may lead to the development of serotonin syndrome or serotonin toxicity, a form of intoxication. Due to the severity of serotonin syndrome, it is important to maintain low exposure to 5-HT1A agonist.

Serotonin syndrome is caused by increased activation of the 5-HT1A and 5-HT2A receptors. By definition, serotonin syndrome is a group of symptoms that manifest as mental changes, autonomic nervous system dysfunction, and neuromuscular abnormalities. Patients may develop conditions of confusion, agitation, diarrhea, sweating, chills, hypertension, fever, increased white cell count, ataxia, significantly increased reflexes, muscle twitching, tremors, extreme stiffness, and seizures or even coma that vary in severity from mild to fatal.

To increase the efficacy of a 5-HT1A agonist in alleviating LID in animal models, a combination of 5-HT1A and 5-HT1B agonists (e.g., a combination of two or more of the foregoing) is testedet al:Brain.2008；131:3380-94；et al, Experimental Neurology219(2009) 298-. Eltoprazine, a combined agonist of 5-HT1A and 5-HT1B, has also been proposed for the treatment of LID (WO2009/156380), and two or more agonists of 5-HT1B, 5-HT1D and 5-HT1F receptors were assayed in LID animal models with 5-HT1A agonists, effectively raising their therapeutic index (WO 2012/048710).

Oral administration of buspirone undergoes extensive first pass metabolism which limits the bioavailability of the parent compound (4% in humans). This may shorten the duration of action of the compound and require higher or multiple doses of buspirone. Buspirone is metabolized by cytochrome P450 enzymes, which in turn may increase the risk of drug interactions, which is particularly important for dyskinetic patients who often receive more than one drug.

Disclosure of Invention

The inventors aimed to achieve a better relationship between the therapeutic effect of a 5-HT1A agonist on the one hand and the observed side effects associated with an effective dose of a 5-HT1A agonist on the other hand. This may be achieved by multiple doses or administration forms similar to multiple doses (e.g., sequential administration of 5-HT1A agonist) and/or more simultaneous administration of 5-HT1A agonist and L-DOPA formulation to achieve higher simultaneous exposure of both compounds.

Accordingly, the present disclosure relates to compositions for treating, preventing or ameliorating movement disorders. The compositions of the present disclosure comprise a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof, and further comprise dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, respectively or simultaneously. The compositions of the present disclosure do not comprise one or more agonists of serotonin receptors selected from the group of 5-HT1B, 5-HT1D and/or 5-HT1F receptors, or pharmaceutically acceptable derivatives thereof.

Definition of

The term "agonist" herein refers to a substance capable of binding to and activating the receptor(s). Thus, a 5-HT1A receptor agonist (5-HT1A agonist) is capable of binding to and activating the 5-HT1A receptor. Agonists of two or more of the 5-HT1B, 5-HT1D and 5-HT1F receptors (5-HT1B/D/F agonists) are capable of binding to and activating two or three of the 5-HT1B, 5-HT1D and 5-HT1F receptors. The terms "5-HT 1 agonist", "5-HT 1 receptor agonist" and "agonist of 5-HT1 receptor" are used interchangeably herein.

The term "partial agonist" herein refers to a compound that is capable of binding to and activating a given receptor, but has only partial efficacy at the receptor relative to a "full agonist". Partial agonists may be used as antagonists when they compete with full agonists for receptor occupancy and when their rate of receptor activation is net decreased compared to the effect or activation observed with full agonists alone.

The term "antagonist" as used herein refers to a substance capable of inhibiting the action of a receptor agonist.

The terms "dopamine", "DA" and "4- (2-aminoethyl) benzene-1, 2-diol" refer to catecholamine neurotransmitters and hormones. Dopamine is a precursor to adrenal (adrenaline) and noradrenaline (noradrenaline) and activates five types of dopamine receptors, including D1, D2, D3, D4, and D5-and variants thereof.

The term "L-DOPA" or "3, 4-dihydroxyphenylalanine" refers to precursors of the neurotransmitters dopamine, norepinephrine (noradrenaline) and epinephrine (adrenaline). L-DOPA is able to cross the blood-brain barrier and is converted to dopamine by an aromatic L-Amino Acid Decarboxylase (AADC), also known as DOPA Decarboxylase (DDC). L-DOPA is used for the treatment of Parkinson's disease.

The terms "parkinson's disease," "parkinsonism," and "PD" refer to a neurological syndrome characterized by dopamine deficiency, which is caused by degenerative, vascular, or inflammatory changes in the substantia nigra basal ganglia. The term also refers to syndromes similar to Parkinson's disease, but which may or may not be caused by Parkinson's disease, such as the Parkinson's-like side effects caused by certain antipsychotic drugs. Parkinson's disease is also known as parkinsonism and numbing tremors.

The terms "serotonin", "5-hydroxytryptamine" and "5-HT" refer to the phenolamine neurotransmitter produced by hydroxylation and decarboxylation of tryptophan in serotonergic neurons of the central nervous system and in enterochromaffin cells of the gastrointestinal tract. Serotonin is a precursor of melatonin.

The term "pharmaceutically acceptable derivative" as used herein includes pharmaceutically acceptable salts, which refer to salts that are not harmful to the patient. Such salts include pharmaceutically acceptable basic or acidic addition salts as well as pharmaceutically acceptable metal, ammonium and alkylated ammonium salts. Pharmaceutically acceptable derivatives further include esters and prodrugs, or other precursors of the compounds, which can be metabolized to the active compound or crystalline form of the compound.

As used herein, the term "therapeutically effective amount" of a compound refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially inhibit the clinical manifestations of a particular disease or disorder and its complications.

The terms "treatment" and "treating" as used herein refer to the management and care of a patient for the purpose of combating a condition, disease or disorder. The term is intended to include all-round treatments directed to the particular condition from which the patient is suffering, for example administration of the active compound for the purposes of: alleviating or alleviating the symptoms or complications; delay of progression of the condition, disease or disorder; cure or eliminate the condition, disease or disorder; and/or preventing a condition, disease or disorder. Wherein "preventing" or "prevention" is understood to mean managing and caring for a patient in order to hinder the progression of a condition, disease or disorder, including administering an active compound to prevent or reduce the risk of onset of symptoms or complications. The patient to be treated is preferably a mammal, particularly preferably a human.

The term "triptan" herein is a compound moiety of the tryptamine-based drug family, useful as ineffective drugs for the treatment of migraine and cluster headache. Triptans are agonists of several (e.g., two or more) serotonin receptors, and have varying potency at different 5-HT1 receptor subtypes, including primarily the 5-HT1B, 5-HT1D, 5-HT1E, and/or 5-HT1F receptors.

Detailed Description

In one embodiment, the composition according to the present disclosure is a pharmaceutical composition, a pharmaceutically acceptable composition and/or a pharmaceutically safe composition. The compositions according to the present disclosure comprise at least a 5-HT1A receptor agonist as an active ingredient.

One aspect of the present disclosure provides a pharmaceutical composition comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof;

wherein the composition optionally further comprises dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, respectively or simultaneously;

for the treatment, prevention or alleviation of dyskinesia.

Also disclosed herein is the use of a pharmaceutical composition comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment, prevention or alleviation of movement disorders;

wherein the composition optionally further comprises dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, respectively or simultaneously;

with the proviso that the composition does not comprise one or more agonists of serotonin receptors selected from the group of 5-HT1B, 5-HT1D and/or 5-HT1F receptors or pharmaceutically acceptable derivatives thereof.

In another embodiment, there is provided a method of treating, preventing or ameliorating movement disorders in a subject in need thereof, the method comprising one or more steps of administering a pharmaceutical composition comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof;

wherein the composition optionally further comprises dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, respectively or simultaneously;

with the proviso that the composition does not comprise an agonism of one or more serotonin receptors selected from the group of 5-HT1B, 5-HT1D and/or 5-HT1F receptors or a pharmaceutically acceptable derivative thereof.

Also disclosed herein are combination therapies comprising, separately or together, i) a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof and ii) dopamine, dopamine agonist, dopamine precursor or dopamine prodrug for the treatment, prevention or alleviation of dyskinesia.

Accordingly, one aspect of the present disclosure provides such compositions disclosed herein, wherein the composition further comprises, either separately or simultaneously, dopamine agonist, dopamine precursor or dopamine prodrug.

In certain embodiments, the compositions disclosed herein consist of a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof, and dopamine, dopamine agonist, dopamine precursor or dopamine prodrug as the sole active pharmaceutical ingredient.

Accordingly, one aspect of the present disclosure provides a pharmaceutical composition comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof;

wherein the composition further comprises dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, either separately or together;

for the treatment, prevention or alleviation of dyskinesia.

In one embodiment, the compositions used as disclosed herein comprise or consist of both: i) a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof, and ii) dopamine, dopamine agonist, dopamine precursor or dopamine prodrug.

A composition comprising more than one compound at the same time is meant to cover embodiments wherein two or more compounds are contained in the same single pharmaceutical composition, wherein said pharmaceutical composition may have any form known to the person skilled in the art.

In one embodiment, the compositions used as disclosed herein comprise or consist of, respectively: i) a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof, and ii) dopamine, dopamine agonist, dopamine precursor or dopamine prodrug.

Compositions comprising more than one compound each are meant to encompass embodiments in which two or more compounds are contained in separate or distinct pharmaceutical compositions, or distinct compartments (compartments) of a co-pharmaceutical composition, wherein the pharmaceutical compositions may have any form known to those skilled in the art.

Combined administration

One aspect of the present disclosure provides a pharmaceutical composition comprising, separately or together, i) a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof, and ii) dopamine, a dopamine agonist, a dopamine precursor or a dopamine prodrug.

It will be understood that for compositions comprising a plurality of compounds, each of the compounds may be administered simultaneously, separately or sequentially.

In one embodiment, a pharmaceutical composition is provided comprising, separately or together, i) a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof, and ii) dopamine, dopamine agonist, dopamine precursor or dopamine prodrug;

for the treatment, prevention or alleviation of dyskinesia;

wherein the 5-HT1A receptor agonist or pharmaceutically acceptable derivative thereof and the dopamine, dopamine agonist, dopamine precursor or dopamine prodrug are administered simultaneously, separately or sequentially.

In one embodiment, the composition is administered more than once daily, e.g., at least 2 times daily, at least 3 times daily, at least 4 times daily, at least 5 times daily, at least 6 times daily, at least 7 times daily, or at least 8 times daily.

In embodiments, wherein the composition is administered more than once daily, the 5-HT1A receptor agonist or pharmaceutically acceptable derivative thereof and the dopamine, dopamine agonist, dopamine precursor or dopamine prodrug are administered simultaneously, separately or sequentially at each administration.

In one embodiment, the 5-HT1A receptor agonist or pharmaceutically acceptable derivative thereof and the dopamine, dopamine agonist, dopamine precursor or dopamine prodrug are administered simultaneously on each administration.

"substantially simultaneously" shall encompass any mode of simultaneous, separate or sequential administration of i) a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof, and ii) dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, which occurs without delay or intentional delay, but which allows sufficient time for simultaneous, separate or sequential administration of the two compounds.

Multiple doses

In certain embodiments, the compositions disclosed herein are administered in multiple doses, or in any other form of administration similar to a multiple dose regimen.

Accordingly, in one aspect herein is provided a pharmaceutical composition comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof;

wherein the composition optionally further comprises dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, respectively or simultaneously;

for the treatment, prevention or alleviation of dyskinesia;

wherein the composition is administered at least 2 times per day.

In one embodiment, the composition is administered at least 3 times per day.

In one embodiment, the composition is administered at least 4 times per day.

In one embodiment, the composition is administered at least 5 times per day.

In one embodiment, the composition is administered at least 6 times daily, at least 7 times daily, or at least 8 times daily.

In one embodiment, the composition is administered 2 times per day, such as 3 times per day, such as 4 times per day, such as 5 times per day, such as 6 times per day, such as 7 times per day, such as 8 times per day, or more times per day.

In one embodiment, the composition is administered 2-3 times per day, such as 3-4 times per day, such as 4-5 times per day, such as 5-6 times per day, such as 6-7 times per day, such as 7-8 times per day, or more times per day.

In certain embodiments, the compositions disclosed herein are administered in a form of administration similar to a multiple dose regimen.

A multiple dose regimen may allow a lower dose to be administered at each administration, which in turn results in a lower and constant concentration being maintained in the blood.

Accordingly, in one aspect herein is provided a pharmaceutical composition comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof;

wherein the composition optionally further comprises dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, respectively or simultaneously;

for the treatment, prevention or alleviation of dyskinesia;

wherein the composition is administered in the following manner:

i) as a continuous administration;

ii) as a long acting (depot) injection; or

iii) as a sustained release formulation.

Compositions comprising compounds

The present disclosure provides a pharmaceutical composition or (simply) the use of a composition comprising:

i) a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof; and

ii) optionally dopamine, dopamine agonist, dopamine precursor or dopamine prodrug;

with the proviso that the composition does not comprise an agonist of one or more serotonin receptors selected from the group of 5-HT1B, 5-HT1D and/or 5-HT1F receptors, or a pharmaceutically acceptable derivative thereof, as defined herein.

In one embodiment, the composition does not comprise one or more agonists of serotonin receptors selected from the group of 5-HT1B, 5-HT1D and/or 5-HT1F receptors.

In one embodiment, the composition does not comprise an agonist of two or more of the 5-HT1B, 5-HT1D, and 5-HT1F receptors.

In one embodiment, the composition does not comprise triptan.

In one embodiment, the composition does not comprise a triptan selected from the group consisting of zolmitriptan, rizatriptan, sumatriptan, naratriptan, almotriptan, frovatriptan, avitriptan (avitriptan), isomatriptan (imotriptan), and eletriptan.

Compound i)5-HT1A receptor agonists

In one embodiment, the compound i)5-HT1A agonist is a full agonist or a partial agonist.

In one embodiment, the 5-HT1A agonist used herein is selected from the group consisting of buspirone (8- [4- (4-pyrimidin-2-ylpiperazin-1-yl) butyl ] -8-azaspiro [4.5] decane-7, 9-dione), tandospirone ((1R,2R,6S,7S) -4- {4- [4- (pyrimidin-2-yl) piperazin-1-yl ] butyl } -4-azatricyclo [5.2.1.02,6] decane-3, 5-dione), gepirone (4, 4-dimethyl-1- [4- (4-pyrimidin-2-ylpiperazin-1-yl) butyl ] piperidine-2, 6-dione), Alpha-spirone ((+) -4-dihydro-2H-benzopyran-3-yl ] -propylamino ] butyl ] -8-azaspiro [4.5] decane-7, 9-dione), buspirone (8- [2- (2, 3-dihydro-1, 4-benzodioxan-2-ylmethylamino) ethyl ] -8-azaspiro [4.5] decane-7, 9-dione), ixabepilone (9, 9-dioxo-8- [4- (4-pyrimidin-2-ylpiperazin-1-yl) butyl ] -9 lambda 6-thio-8-azabicyclo [4.3.0] nonane-1, 3, 5-triethyltetramin-7-one), Piperapirone (3aR,7aS) -2- {4- [4- (1, 2-benzisothiazol-3-yl) piperazin-1-yl ] butyl } hexahydro-1H-isoindole-1, 3(2H) -dione, befradadol (befiadol) (F-13,640) (3-chloro-4-fluorophenyl- [ 4-fluoro-4- ([ (5-methylpyridin-2-yl) methylamino ] methyl) piperidin-1-yl ] methanone, repinotan (repinotan) ((R) - (-) -2- [4- [ (chroman-2-ylmethyl) -amino ] -butyl ] -1, 1-dioxo-benzo [ d ] isothiazolone), Picrozoltan (3-chloro-4- [4- [4- (2-pyridyl) -1,2,3, 6-tetrahydropyridin-1-yl ] butyl ] -1, 4-benzoxazin-5 (4H) -one), oximometazone (5- (3- [ ((2S) -1, 4-benzodioxan-2-ylmethyl) amino ] propoxy) -1, 3-hydrocinnamocarb-ol), fluoroxingchen (4-fluoro-N- [2- [4- [ (3S) -3- (hydroxymethyl) -2, 3-dihydro-1, 4-benzodioxan-8-yl ] piperazin-1-yl ] ethyl ] benzamide), Flibanserin (1- (2- {4- [3- (trifluoromethyl) phenyl ] piperazin-1-yl } ethyl) -1, 3-dihydro-2H-benzimidazol-2-one) and thalidomide (EMD-128,130) (1- [ (2R) -3, 4-dihydro-2H-chroman-2-yl ] -N- ([5- (4-fluorophenyl) pyridin-3-yl ] methyl) methylamine), or a pharmaceutically acceptable derivative thereof.

Thus, in a preferred embodiment, the 5-HT1A agonist is selected from the group consisting of buspirone, tandospirone, gepirone, alepirone, buspirone, ixabepilone, perospirodol, rapanotan, pivalotan, oxtemozotan, fosinophen, flibanserin, salizotan, eltoprazine, F13714 and F15599, and pharmaceutically acceptable derivatives thereof.

In a particular embodiment, the 5-HT1A agonist is buspirone, tandospirone, or gepirone. In another specific embodiment, said 5-HT1A agonist is buspirone or tandospirone. In yet another specific embodiment, the 5-HT1A agonist is buspirone.

Buspirone (8- [4- (4-pyrimidin-2-ylpiperazin-1-yl) butyl ] -8-azaspiro [4.5] decane-7, 9-dione) is an azapirone chemical approved for the treatment of anxiety disorders. Buspirone is a partial agonist of the serotonin 5-HT1A receptor and is believed to have modulatory anxiolytic and antidepressant effects. In addition, it is a presynaptic dopamine antagonist and partial α 1 receptor agonist for the D2, D3 and D4 receptors.

Compound ii) dopamine, dopamine agonist, dopamine precursor or dopamine prodrug

The present disclosure provides the use of a pharmaceutical composition or (simply) a composition comprising

i) A 5-HT1A receptor agonist, or a pharmaceutically acceptable derivative thereof; and

ii) dopamine, dopamine agonist, dopamine precursor or dopamine prodrug.

In one embodiment, compound ii) is an agent that increases the concentration of dopamine in the synaptic cleft.

In one embodiment, compound ii) is selected from the group consisting of dopamine, dopamine agonists, dopamine precursors and dopamine prodrugs.

In one embodiment, compound ii) is selected from the group consisting of dopamine, dopamine precursors and dopamine prodrugs. Dopamine precursors are substances that can be converted to dopamine in vivo.

In one embodiment, compound ii) is dopamine.

In one embodiment, compound ii) is a dopamine prodrug, dopamine precursor or dopaminergic precursor. Known dopamine precursors include L-phenylalanine, L-tyrosine and L-DOPA.

In a preferred embodiment, compound ii) is L-DOPA (levodopa; l-3, 4-dihydroxyphenylalanine). Trade names include dopamine receptor (Dopar) and levodopa (Larodopa).

Alternatively, compound ii) may be a L-DOPA derivative, such as a deuterated analogue of L-DOPA or an ester of L-DOPA.

L-DOPA can cross the protective blood brain barrier, whereas dopamine itself cannot. Thus, L-DOPA is used to increase dopamine concentrations in the treatment of Parkinson's disease and dopamine-responsive dystonia.

It is understood that any formulation or composition comprising L-DOPA, for example any commercially available formulation or composition comprising L-DOPA, is encompassed by the present disclosure. These include both immediate release and sustained release solid formulations as well as liquid formulations.

In humans, the conversion of L-DOPA to dopamine occurs not only within the central nervous system, but cells in the peripheral nervous system perform the same task. Thus, L-DOPA alone also results in increased peripheral dopamine signaling. Excessive peripheral dopamine signalling is undesirable, however, because it can lead to many undesirable side effects when L-DOPA is administered alone.

To avoid peripheral conversion of L-DOPA to dopamine, standard clinical practice is to co-administer L-DOPA with a peripheral DOPA decarboxylase inhibitor (DDCI).

In one embodiment, compound ii) is a L-DOPA-containing formulation or composition, including any commercially available L-DOPA-containing formulation or composition, optionally in combination with one or more other active ingredients.

In one embodiment, the compound ii) L-DOPA or a formulation or composition comprising L-DOPA is selected from the group consisting of:

i) L-DOPA in combination with a DOPA decarboxylase inhibitor, comprising

a.L-DOPA and carbidopa (levodopa (levocarb) or co-careldopa):

i. such as, for example, believed to be wheat (Atamet, cardlev), the drugs dopa (pharmacope), paropa and medopa;

e.g. L-DOPA with lodoxine (Lodosyn) (carbidopa);

l-DOPA and benserazide:

i. such as MEDOPA or Prolopa

ii) L-DOPA in combination with a COMT inhibitor (catecholamine-o-methyltransferase);

a. including L-DOPA and tolcapone, L-DOPA and entacapone, L-DOPA and apicapone (opiopone), and L-DOPA and nitecapone (nitecapone);

iii) combination of L-DOPA with decarboxylase inhibitors, COMT inhibitors

a. E.g. Stalevo (carbidopa/levodopa/entacapone), including Stalevo 50, 75, 100, 125, 150 and 200.

In another embodiment, compound ii) is a dopamine agonist.

In one embodiment, compound ii) is a dopamine receptor agonist.

Dopamine receptor agonists are compounds that activate dopamine receptors. Dopamine receptor agonists activate the signaling pathway by trimerizing G-proteins and β -arrestins, ultimately leading to alterations in gene transcription. Agonists are available for several dopamine receptor subtypes (D1, D2, D3), which treat these signaling pathways differently, called preferential agonists.

In one embodiment, compound ii) is a partial dopamine agonist, a selective dopamine agonist or a full dopamine agonist.

In one embodiment, compound ii) is a dopamine receptor agonist selected from the group consisting of bromocriptine (bromocriptine), pergolide mesylate (pergolide), palomist (pramipexole, semforol), ropinirole (ropinirole), piribedil (probora, tashida), cabergoline (Lacqueradine), apomorphine (Apomorphine), propylnorapomorphine, lisuride, ciladopa, dihydroxidine (dihydrexidine), dinalprenol, polypurin, epidopisine, quinagolide (norostine), rotigotine (nup), roconile, sumanidol, fenoldopam, and derivatives thereof.

In one embodiment, compound ii) is an indirect dopamine agonist. In one embodiment, the indirect dopamine agonist is selected from the group consisting of a dopamine reuptake inhibitor/transporter blocker and a dopamine releasing agent.

In one embodiment, the indirect dopamine agonist is selected from the group consisting of amphetamine and/or dextroamphetamine, bupropion (wibo meaning), amphetamine, nomifensine, lissedamine, methylphenidate (litrine) or dextromethylphenidate, methylenedioxy-pyrrolidone (MDPV; "Sonic"), ketamine, phencyclidine (PCP), cathinone, cocaine, amphetamine, methamphetamine, methylenedioxymethamphetamine (MDMA), phenethylamine, p-tyramine, lisdexamphetamine dimesylate (Vyvanse), phenmetrazine, pimoline, 4-methylaminourea (4-MAR), and benzylpiperazine, and type ii vesicle transporter (VMAT2) inhibitors (e.g., reserpine, tetrabenazine, and disoprene).

In one embodiment, the present disclosure provides the use of a pharmaceutical composition comprising buspirone and L-DOPA (levodopa).

The compositions of the present disclosure do not comprise one or more agonists of serotonin receptors selected from the group of 5-HT1B, 5-HT1D and/or 5-HT1F receptors, or pharmaceutically acceptable derivatives thereof.

The agonist of one or more of the 5-HT1B, 5-HT1D and 5-HT1F receptors may be an agonist of one, two or three serotonin receptors selected from the group consisting of 5-HT1B, 5-HT1D and 5-HT1F receptors. Thus, it may be an agonist of one of the 5-HT1B, 5-HT1D and 5-HT1F receptors, while in other embodiments it is a combined agonist of the 5-HT1B receptor and the 5-HT1D receptor, or a combined agonist of the 5-HT1B receptor and the 5-HT1F receptor, or a combined agonist of the 5-HT1D receptor and the 5-HT1F receptor, or a combined agonist of the 5-HT1B receptor, the 5-HT1D receptor and the 5-HT1F receptor. It may also have some agonist activity at the 5-HT1A receptor (in whole or in part).

In one embodiment, the agonist of one or more of the 5-HT1B, 5-HT1D, and 5-HT1F receptors is an agonist of two or more of the 5-HT1B, 5-HT1D, and 5-HT1F receptors.

In one embodiment, the agonist of two or more of the 5-HT1B, 5-HT1D, and 5-HT1F receptors is triptan. As used herein, "triptan" is a compound moiety of the tryptamine-based drug family, and is an ineffective drug for the treatment of migraine and cluster headache. Triptans are agonists of several serotonin receptors, having different potency at different subtypes of the 5-HT1 receptor, mainly the 5-HT1B, 5-HT1D, 5-HT1E and/or 5-HT1F receptors.

In one embodiment, the agonist of one or more (e.g., two or more) 5-HT1B, 5-HT1D, and 5-HT1F receptors is selected from the group consisting of zolmitriptan ((S) -4- ({3- [2- (dimethylamino) ethyl ] -1H-indol-5-yl } methyl) -1, 3-oxazolidin-2-one), rizatriptan (N, N-dimethyl-2- [5- (1H-1,2, 4-triazol-1-ylmethyl) -1H-indol-3-yl ] ethylamine), sumatriptan (1- [3- (2-dimethylaminoethyl) -1H-indol-5-yl ] -N-methyl-methanesulfonamide), Naratriptan (N-methyl-2- [3- (1-methylpiperidin-4-yl) -1H-indol-5-yl ] ethanesulfonamide), almotriptan (N, N-dimethyl-2- [5- (pyrrolidin-1-ylsulfonylmethyl) -1H-indol-3-yl ] -ethylamine), frovatriptan ((+) - (R) -3-methylamino-6-carboxamido) -1,2,3, 4-tetrahydrocarbazole) and eletriptan ((R) -3- [ (-1-methylpyrrolidin-2-yl) methyl ] -5- (2-benzenesulfonylethyl) -1H-indole), or a pharmaceutically acceptable derivative thereof.

The triptan may be selected from the group consisting of zolmitriptan, rizatriptan, sumatriptan, naratriptan, almotriptan, frovatriptan, avitriptan (avitriptan), imotriptan (imotriptan), aniracetam and eletriptan, and pharmaceutically acceptable derivatives thereof.

The triptan may also be selected from the group consisting of zolmitriptan, rizatriptan, sumatriptan, naratriptan, almotriptan, frovatriptan, avitriptan, isomatriptan, eletriptan, and pharmaceutically acceptable derivatives thereof.

Triptan can also be zolmitriptan, rizatriptan, frovatriptan, eletriptan, or naratriptan. Zolmitriptan, rizatriptan, naratriptan and eletriptan are full agonists of 5-HT1D, 5-HT1B and 5-HT1A, as well as partial agonists of 5-HT 1B.

Movement disorder

The present disclosure relates to compositions for treating dyskinesias comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof, as defined herein, and optionally dopamine, dopamine agonist, dopamine precursor or dopamine prodrug. The term "treatment" includes treatment, prevention/prophylaxis (reducing risk) and amelioration.

In one embodiment, the movement disorder is a disorder associated with altered or impaired synaptic dopamine levels.

In one embodiment, the dyskinesia according to the present disclosure is selected from the group consisting of parkinson's disease, a parkinsonian-related dyskinesia, bradykinesia, attention deficit hyperactivity disorder, dyskinesia, L-DOPA-induced dyskinesia, tardive dyskinesia, ataxia, akathisia, dystonia, essential tremor, huntington's disease, myoclonus, rett syndrome, gilles de tourette syndrome, wilson's disease, chorea, machado-joseph disease, restless leg syndrome, spastic torticollis, genital spasm, or a dyskinesia associated therewith.

Parkinson's disease is associated with muscle stiffness, tremors, postural abnormalities, gait abnormalities, slowing of body movement (bradykinesia) and, in extreme cases, loss of body movement (akinesia). PD is caused by degeneration and death of dopaminergic neurons in the substantia nigra pars compacta, which leads to dysfunction in dopamine neurotransmission.

In a particular embodiment of the present disclosure, the movement disorder is parkinson's disease. In a particular embodiment of the present disclosure, dyskinesias refer to parkinson's disease or related dyskinesias, dyskinesias and bradykinesias, or dyskinesias associated with parkinson's disease or parkinson's disease treatment, such as L-DOPA-induced dyskinesia (LID).

In a particular embodiment of the present disclosure, the dyskinesia is L-DOPA-induced dyskinesia (LID).

In another embodiment of the present disclosure, the movement disorder is caused by an idiopathic disease, a genetic dysfunction, an infection, or other condition that results in dysfunction of the basal ganglia and/or results in altered levels of synaptic dopamine.

In one embodiment, the movement disorder according to the present disclosure is associated with the use of a drug, or drug/drug therapy.

In one embodiment of the disclosure, dyskinesias are associated with or caused by the treatment of parkinson's disease, such as anti-parkinson therapy, including but not limited to dopamine, dopamine agonists, dopamine precursors, dopamine prodrugs, dopamine mimetics and dopaminergic agents, such as L-DOPA.

In one embodiment of the disclosure, the movement disorder is associated with or caused by neuroleptic, antipsychotic, antidepressant and antiemetic drugs.

In one embodiment, the movement disorder is caused by or associated with the use of antipsychotics, antidepressants, and antiemetics or drug therapy. Antipsychotics are, for example, haloperidol, droperidol, pimozide, trifluoperazine, amisulpride, risperidone, aripiprazole, asenapine, and dachiazolol; antidepressants such as fluoxetine, paroxetine, venlafaxine, and trazodone; antiemetic agents are, for example, dopamine blockers, such as metoclopramide (metoclopramide) and prochlorperazine (prochlorperazine).

In yet another embodiment of the present disclosure, the movement disorder is caused by or associated with withdrawal of opioids, barbiturates, cocaine, benzodiazepines, alcohol, or amphetamines.

One aspect of the present disclosure provides a composition as defined herein for use in a method of treating a movement disorder.

One aspect of the present disclosure provides a composition as defined herein for use in the preparation of a medicament for the treatment of movement disorders.

In one embodiment, the composition for use in a method of treating a movement disorder as defined herein is administered to a subject in need thereof.

As referred to herein, an individual in need thereof is an individual who may benefit from administration of a compound or pharmaceutical composition according to the present disclosure. Such individuals may suffer from, or be at risk of developing, dyskinesias. The individual may be any person, male or female, infant, middle aged or elderly. The movement disorder to be treated or prevented in an individual may be related to the age of the individual, the general health of the individual, the drugs used to treat the individual, and the past history of the disease or disorder that the individual is likely to have or has induced the movement disorder in the individual.

The present disclosure relates to the treatment of individuals at risk (e.g., increased risk) of having a movement disorder. In one embodiment, the individual at risk of having a movement disorder is a human being or about to be treated with a dopamine prodrug, such as L-DOPA (e.g. levodopa).

Embodiments of the present disclosure provide pharmaceutical compositions comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof, and separately or together with dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, for use in the treatment, prevention or alleviation of L-DOPA-induced dyskinesia (LID);

In one embodiment, the composition comprises a 5-HT1A agonist selected from the group consisting of buspirone, 6-hydroxybuspirone, tandospirone, gepirone, alepirone, buspirone, ixabepilone, peropiropirone, befeladox, rapitant, piczolpidem, oximidotan, fosinopril, flibanserin, sapraztan, eltoprazine, F13714 and F15599, and L-DOPA for the treatment, prevention or alleviation of L-DOPA-induced dyskinesia (LID).

In one embodiment, the composition comprises buspirone and L-DOPA for the treatment, prevention or alleviation of L-DOPA-induced dyskinesia (LID).

In one embodiment, the composition comprises 6-hydroxybuspirone and L-DOPA for use in the treatment, prevention or alleviation of L-DOPA induced dyskinesia (LID).

In one embodiment, the composition comprises a 5-HT1A agonist selected from the group consisting of buspirone, tandospirone, gepirone, alepirone, buspirone, ixabepilone, peroxolone, befelado, rapinotan, piczolpidem, oximazolpidem, ficinkreb, flibanserin, thalidomide, eltoprazine, F13714 and F15599, and L-DOPA for the treatment, prevention or alleviation of L-DOPA-induced dyskinesia (LID);

wherein the composition is to be administered multiple times per day, e.g., at least 2 times per day, at least 3 times per day, at least 4 times per day, at least 5 times per day, at least 6 times per day, at least 7 times per day, or at least 8 times per day.

Further embodiments of the present disclosure provide pharmaceutical compositions comprising a 5-HT1A receptor agonist or a pharmaceutically acceptable derivative thereof;

wherein the composition optionally further comprises dopamine, dopamine agonist, dopamine precursor or dopamine prodrug, respectively or simultaneously;

for the treatment, prevention or alleviation of Tardive Dyskinesia (TD);

wherein the composition is administered at least 5 times per day.

Administration and dosage

Notably, the preferred route of administration will depend upon the general condition and age of the subject to be treated, the nature of the condition to be treated, the location of the tissue to be treated in the body and the active ingredient.

In one embodiment, the route of administration allows the compound or composition to cross the blood-brain barrier.

Systemic treatments according to the present disclosure can introduce a compound or composition into the bloodstream, ultimately targeting the site of desired action.

Systemic treatment includes administration by enteral and parenteral routes, including oral, rectal, nasal, vaginal, rectal, pulmonary, bronchial, buccal, sublingual, transdermal, topical, intracisternal, intraperitoneal, subcutaneous, intramuscular, intrathecal, intravenous and intradermal administration. Suitable dosage forms for such administration can be prepared by conventional techniques.

The compounds or compositions according to the present disclosure may be used as a topical treatment, i.e., introduced directly into the site of action. Thus, the composition may be applied directly to the skin or mucosa, or the composition may be injected into the site of action, for example into the diseased tissue or directly into the peripheral artery (intracavernosal, intravitreal, intraarticular, intracerebral, intrathecal, epidural) of the diseased tissue.

The pharmaceutical compositions of the present disclosure may be administered once or several times a day, for example 1 to 2 times a day, for example 2 to 3 times a day, for example 3 to 4 times a day, for example 4 to 5 times a day, for example 5 to 6 times a day, for example 6 to 7 times a day, for example 7 to 8 times a day. In one embodiment, the composition is administered once daily, such as 2 times daily, such as 3 times daily, such as 4 times daily, such as 5 times daily, such as 6 times daily.

In a particular embodiment, the composition is administered at least twice daily, such as at least 3 times daily, such as at least 4 times daily, such as at least 5 times daily, such as at least 6 times daily, or more times daily.

Administration may be carried out within a defined time period, for example from 1 or 2 days to 7 days, for example 7 days to 14 days, for example 14 days to a month, for example a month to several months (2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months); or the administration may be chronic, the treatment may be chronic from the start of diagnosis, e.g. throughout the lifetime of the individual, or as long as the individual benefits from it, i.e. when dyskinesia is present or the risk of dyskinesia is increased, e.g. during treatment with L-DOPA or other drugs (e.g. antipsychotics, antidepressants, antiemetics) or during the discontinuation of certain drugs causing dyskinesia.

In one embodiment, the pharmaceutical formulation is taken whenever dyskinesia is present or the risk of dyskinesia is increased.

Dosage form

The concentration of each active ingredient (i.e., 5-HT1A agonist and optionally dopamine, dopamine agonist, dopamine precursor or dopamine prodrug) in the pharmaceutical compositions of the invention is optimized to obtain the appropriate dosage for each drug.

In one embodiment, the 5-HT1A receptor agonist or pharmaceutically acceptable derivative thereof is administered in a dose of 0.1-100mg per dose, such as 0.1-1mg per dose, such as 1-5mg per dose, such as 5-10mg per dose, such as 10-15mg per dose, such as 15-20mg per dose, such as 20-25mg per dose, such as 25-30mg per dose, such as 30-35mg per dose, such as 35-40mg per dose, such as 40-45mg per dose, such as 45-50mg per dose, such as 50-75mg per dose, such as 75-100mg per dose.

In one embodiment, the 5-HT1A receptor agonist or pharmaceutically acceptable derivative thereof is administered in a daily dose of 0.01-10mg/kg body weight, such as 0.01-5mg/kg body weight, for example 0.1-1mg/kg body weight.

In one embodiment, the 5-HT1A receptor agonist or pharmaceutically acceptable derivative thereof is administered in a daily dose of 0.001-100mg/kg body weight, such as 0.001-0.005mg/kg body weight, such as 0.005-0.01mg/kg body weight, such as 0.01-0.05mg/kg body weight, such as 0.05-0.1mg/kg body weight, such as 0.1-0.5mg/kg body weight, such as 0.5-1.0mg/kg body weight, such as 1-2mg/kg body weight, such as 2-5mg/kg body weight, such as 5-10mg/kg body weight, such as 10-15mg/kg body weight, such as 15-20mg/kg body weight, such as 20-30mg/kg body weight, such as 30-40mg/kg body weight, such as 50-75mg/kg body weight, for example 75-100mg/kg body weight.

L-DOPA is typically administered in an initial dose, followed by a maintenance dose.

In one embodiment, the L-DOPA or the pharmaceutically acceptable derivative thereof is administered at a dose of 100-10000 mg/day, such as 100-250 mg/day, such as 250-500 mg/day, such as 500-750 mg/day, such as 750-1000 mg/day, such as 1000-2000 mg/day, such as 2000-2500 mg/day, such as 2500-3000 mg/day, such as 3000-4000 mg/day, such as 4000-5000 mg/day, such as 5000-6000 mg/day, such as 6000-7000 mg/day, such as 7000-8000 mg/day, such as 8000-900 mg/day or 9000-10000 mg/day.

Other active ingredients

Another aspect of the present disclosure is to provide a pharmaceutical composition as defined herein, wherein the composition combines or comprises one or more further active ingredients, which are understood to be further therapeutic compounds (active pharmaceutical ingredients) or pharmaceutically acceptable derivatives thereof.

In one embodiment, the composition further comprises one or more additional active ingredients that are compounds that ameliorate the symptoms of PD or are useful for treating PD.

These include, but are not limited to, peripheral inhibitors that convert L-DOPA (or other dopamine prodrugs) to dopamine, for example carboxylase inhibitors such as carbidopa (lotoxin) or benserazide; NMDA antagonists, such as amantadine (amantadine, gcrovi, osmolex); catechol-o-methyltransferase (COMT) inhibitors such as tolcapone, entacapone, nitecapone and apicapone; MAO-B inhibitors such as selegiline and rasagiline; a serotonin receptor modulator; a kappa opioid receptor agonist; a GABA modulator; neuronal potassium channel modulators, such as flupirtine and retigabine; A2A receptor antagonists, such as, for example, istradefylline; and glutamate receptor modulators, such as amantadine, dextromethorphan, and deuterated dextromethorphan.

Examples

A procedure for evaluating the benefit of multiple daily doses of 5-HT1A agonist in the treatment of levodopa-induced dyskinesia.

General principles

Studies in a rat model of levodopa-induced dyskinesia (LID) can be used to determine the effect of a 5-HT1A agonist on Abnormal Involuntary Movements (AIMS).

Simultaneous administration of drugs

Dose-dependent reduction in AIMS can be achieved when a 5-HT1A agonist is administered prior to (or substantially simultaneously with) administration of levodopa.

For example, when 5-HT1A agonist is administered 2 hours prior to levodopa administration, the D/R curve will shift to the right, indicating that a higher dose of 5-HT1A agonist is required to reduce AIMS.

As shown in the literature, a study to assess side effects has shown that higher doses of buspirone can lead to side effects (e.g. sedation).

Thus, it is expected that a beneficial efficacy/side effect ratio will be obtained when the 5-HT1A agonist is administered substantially simultaneously with levodopa.

Multiple dose administration

When 3 low doses of 5-HT1A agonist (e.g., 1mg/kg) are administered daily prior to (or substantially simultaneously with) levodopa administration and an AIMS test is performed at each levodopa administration (i.e., 3), AIMS reduction can be achieved in each and all three AIMS tests of the AIMS test.

When the high dose of 5-HT1A agonist, which is related to the first dose of levodopa, is administered only once prior to (or substantially simultaneously with) levodopa administration, which is the sum of the three low doses of 5-HT1A as described above (i.e., 3mg/kg in this case), and the remaining two levodopa administrations alone, are followed by an AIMS test after each of the three levodopa administrations, a significant reduction in AIMS is found in the first AIMS test, but a lesser or no reduction in AIMS is found in the second and third AIMS tests.

Furthermore, the sum of all three AIMS tests showed a more significant reduction in the group administered with a low dose of 5-HT1A agonist at each levodopa administration compared to the group administered with only one high dose of 5-HT1A agonist (and levodopa alone in the remaining two times) in relation to the first dose of levodopa. This may indicate that frequent dosing, rather than dose differences of the 5-HT1A agonist, produces 5-HT1A agonist benefits.

Thus, it is expected that beneficial efficacy will be obtained when 5-HT1A agonist is administered multiple times with levodopa.

Evaluation of the 5-HT1A agonist buspirone for use in the treatment of dyskinesia associated with Parkinson's disease and LID.

This study describes the evaluation of the 5-HT1A agonist buspirone in a 6-OHDA rat model.

The 6-OHDA rat model described below can be used to evaluate compounds for the treatment of dyskinesias associated with parkinson's disease and LID. 6-OHDA (6-hydroxydopamine) is a neurotoxin that selectively kills dopaminergic and noradrenergic neurons and induces a reduction in dopamine levels in the brain. Administration of L-DOPA to unilateral 6-OHDA injured rats induced Abnormal Involuntary Movements (AIM). These are axial, limb and mouth movements, occurring only on the body side ipsilateral to the injury. AIM rat models have proven useful because they respond to a number of drugs that have been shown to inhibit human dyskinesias, including PD.

Test program

Animals: male Sprague-duller (Sprague-Dawley) rats (domestic, from SLAC laboratory animals ltd) from shanghai SLAC ltd, 9 weeks old, 200-g body weight, reached the laboratory at least 1 week prior to the behavioral test. Rats were housed in groups of n-2/cage, and standard rodent chow and water were available ad libitum. The animal holding room and the laboratory are maintained under controlled environmental conditions and at a very close distance from each other. The animal feeding room was in a 12 hour light-dark cycle, lit at 6:00 in the morning and maintained at 70F/21 deg.C (in the range of 68-72F/20-22 deg.C) and a humidity in the range of 20-40%. The test chamber was maintained at 68-72F with a humidity range of 20-40%.

6-OHDA lesion surgery:

dopamine (DA) denervation was achieved by unilateral injection of 6-OHDA in the nigrostriatal ascending pathway. Rats were anesthetized with 40mg/kg of sodium pentobarbital (i.p.) and placed in a stereotactic frame. 6-OHDA was injected into the right ascending DA beam at the following coordinates (in millimeters) relative to bregma and dural surface: (1) -2.3, a-4.4, L-1.2, V-7.8, (7.5ug 6-OHDA), (2) 0.4, a-4.0, L-0.8, V-8.0 mm (6ug 6-OHDA). Alternatively, only one injection is performed using the following coordinates: rack: -3.3mm, AP: 1.8mm, ML: 2.0mm, DV: 8.6mm (18. mu.g/6. mu.l 6-OHDA). Neurotoxin injection was performed at a rate of 1 μ l/min, and then the injection cannula was placed for an additional 2-3 min.

After surgical recovery, rats with almost complete (> 90%) injury were selected by apomorphine-induced spin test, i.e. they were administered an intraperitoneal injection of 0.5mg/kg apomorphine hydrochloride (Sigma) in physiological saline to induce contralateral diversion, which is considered to be the result of a DA receptor denervation hypersensitivity reaction on the injured side. Rotational behavior in response to DA agonists is closely related to the severity of injury. For rats, quantification of the rotational response was done by counting the revolutions in 30 minutes. Selecting rats with the rotation score more than or equal to 6 r/min for the next test. The animals were then divided into two well-matched subgroups (rotated according to amphetamine) and received daily treatment as described below.

Medicaments and treatment regimens

L-DOPA methyl ester (Sigma, Cat. No. D9628, Lot. No. 030M1604V) was administered at a dose of 6mg/kg/day in combination with 15mg/kg/day benserazide hydrochloride. All well-injured rats were chronically treated with L-DOPA and benserazide at this dose for 3 weeks or more to induce the gradual onset of dyskinetic-like movement. Thereafter, rats that did not develop dyskinesia were excluded from the study, and rats with a cumulative AIM score of > 28 points (grading of severity of dyskinesia in each axis, limb and orolingual score of > 2) over five test periods continued to receive a regimen of drug treatment with L-DOPA/benserazide injections at least twice a week to maintain a stable AIM score. Selected rats were assigned to 9-12 animals per group, and the severity of their AIM was balanced. The animals were then treated with the drugs and drug combinations described below.

AIM induced by L-DOPA and drug screening assays

AIM scoring was performed by a investigator who was unaware of the drug treatment received for each rat (experimental blinding). To quantify the severity of AIM, rats were individually observed in standard cages 20-180 minutes after L-DOPA injection, every 20 minutes. AIM was divided into four subtypes:

(A) axial AIM, i.e. dystonia or choreoid torsion contralateral to the injury in the trunk and neck. Mild cases: lateral bending of the neck or twisting of the upper torso to the opposite side of the lesion. With repeated injections of L-DOPA, this movement may progress to a marked and sustained dystonia-like axial torsion.

(B) Extremity AIM, i.e. the jerky and/or dystonic movement of the contralateral forelimb. Mild cases: injury to contralateral forelimb hyperkinesia, jerky stepping movements, or small circular movements of the forelimb to and from the oronasal part. As the severity of dyskinesia increases (typically with repeated dosing of L-DOPA), the magnitude of abnormal movement increases and a mixed profile of dystonia and hyperkinesia is exhibited. Dystonic movements are caused by persistent co-contraction of agonist/antagonist muscles; they are slow moving and force body parts into unnatural positions. The multi-motion type motion refers to a motion that is fast and irregular in speed and direction. Sometimes the forelimbs do not exhibit jerky movements but are in a continuous dystonic posture, which is also scored according to the time of their performance.

(C) Orolingual AIM, i.e. oral facial muscle twitching, a hollow burst of masticatory motion is accompanied by a tongue projection contralaterally to the injury. This form of movement disorder affects the face, tongue and masticatory muscles. It can be identified as a burst of hollow chewing motion with varying degrees of mandibular opening, lateral mandibular displacement, facial muscle twitching and tongue protrusion contralaterally to the injury. In extremely severe cases, this dyskinetic subtype acts with significant strength on all the above mentioned muscle groups and may also be complicated by self-injuring bites on the skin of the forelimb contralateral to the injury (easily identified by the fact that the circular spot of skin becomes free of hair).

(D) Maneuvering AIM, i.e., movement that increases contralateral deflection. The latter AIM subtype was documented in agreement with the original description of the rat AIM scale, although it was later demonstrated that motorized AIMs provide no specific measure of dyskinesia, but rather a correlation of contralateral steering behavior with unilateral 6-OHDA injury in rodents.

Each of the four subtypes mentioned above can be scored for severity from 0 to 4, where 0 is absent, 1 is present for less than half of the observation time, 2 is present for more than half of the observation time, 3 is present but can be inhibited by an external stimulus, and 4 is present and can not be inhibited by an external stimulus.

The AIM test was performed on rats as described above, except that the sum of the motor (LO) or Axial (AX), Limb (LI) and Orolingual (OL) AIM scores for each test phase was used for statistical analysis.

Simultaneous administration of drugs

To determine the effect of substantially simultaneous administration of buspirone and levodopa, as well as the effect of buspirone administration prior to levodopa administration, the following set of settings were used:

carrier: (physiological saline, 30 minutes before L-DOPA administration, n ═ 6)

Buspirone (0.1-10mg/kg, i.p., n ═ 6) was administered 180, 120, 90, 60, 30 minutes prior to L-DOPA administration.

Buspirone (0.1-10mg/kg i.p., n ═ 6) was administered 5 minutes prior to L-DOPA administration, substantially simultaneously with L-DOPA administration.

We have previously demonstrated that dose-dependent reduction of L-DOPA-induced involuntary movements by buspirone.

Low/high dose and multiple doses

To determine the effect of low dose buspirone given multiple times (3 times per day) simultaneously with levodopa, and the effect of high dose buspirone given only once simultaneously with levodopa, the following set of settings were used:

group 1 (n ═ 8):

the vehicle (saline, intraperitoneal injection, L-DOPA, n ═ 8) was injected 5-10 minutes before L-DOPA administration, and administered substantially simultaneously with L-DOPA, 3 times per day.

Group 2 (n ═ 8):

buspirone (1mg/kg i.p., n-8) was administered 5-10 minutes prior to L-DOPA administration, substantially simultaneously with L-DOPA, 3 times daily.

Group 3 (n ═ 8):

buspirone (3mg/kg i.p., n-8) was administered 5-10 minutes prior to L-DOPA administration and was administered substantially simultaneously with L-DOPA, only once, at the first dose of levodopa.

The vehicle (saline, intraperitoneal injection, L-DOPA, n ═ 8) was injected 5-10 minutes prior to L-DOPA administration, and was administered substantially simultaneously with the second and third L-DOPA.

Efficacy of multiple doses of buspirone in L-DOPA-induced dyskinesia was assessed by comparing the AIMS score at each time point, or the sum of all three AIMS tests over the entire day between the three groups. In groups 2 and 3, the total daily dose of buspirone was the same, so the difference in the sum of AIMS would result from the frequency of buspirone administration.

Evaluation of side effects

This study describes the evaluation of 5-HT1A agonists (e.g., buspirone) in an in vivo model for determining sedative side effects. By using the method, the sedative effect and/or its effect on motility can be evaluated for treatment with the compounds of the present disclosure compared to sedated rats and rats injected with saline only.

Rotation test

The purpose of the spin test was to detect the potentially harmful effects of the compound studied on the motor performance and coordination of the rats. Briefly, 30 SD male rats (180-220g, housed from SLAC laboratory animals Co., Ltd.) aged 9 weeks were trained twice daily for a period of 3 days. Rats were placed on an accelerating bar apparatus with an initial speed of 4 revolutions per minute (rpm), increasing gradually and automatically to 40rpm over 300 s. Each training trial was completed if the animal dropped or grasped the apparatus and rotated two consecutive turns. The time the rat stayed on the rotating rod was recorded. The residence time recorded from the last training trajectory was used as a baseline and rats were grouped according to a randomly distributed baseline.

For the test period on day four, rats were evaluated on a rotarod with the same set-up parameters as above, at 5 and 30 minutes post-dose. The drug as described below was administered to rats, and administration and rotation measurement were performed by two researchers, respectively. Pentobarbital (15mg/kg, i.p.) was used as a positive control.

Compound experimental set-up:

carrier: normal saline, intraperitoneal injection is carried out 5 or 30 minutes before test, and n is 10

Positive control: pentobarbital 15mg/kg, i.e. intraperitoneal injection 5 or 30 minutes before test, and n is 10

Buspirone (0.1-30mg/kg, i.p.: intraperitoneal injection is carried out 5 or 30 minutes before test, and n is 10

Statistical analysis: the spin bar performance is expressed as the total number of seconds spent on the acceleration bar. Data were analyzed using One-Way analysis of variance (One-Way ANOVA) and graph-based post-hoc test (Tukey post-hoc test).

As a result:

buspirone can affect the performance of the rotarod model in a dose-dependent manner compared to vehicle-only rats, indicating that the motor capacity and coordination of rats can be significantly reduced following buspirone administration. In addition, pentobarbital also significantly reduces the time spent on spinning the rod.

Open field test

The open field test is used to determine the effect of a drug on locomotor activity. At 30 minutes after administration, the rats were placed in an open air room (size 40 cm. times.40 cm). After 15 minutes of acclimation, the movement data was recorded and analyzed by Enthovision video tracking software (Noldus information technology, Netherlands) for 60 minutes. All athletic activities were performed during the dark phase and the arena was thoroughly cleaned with 70% v/v ethanol between each test in order to eliminate olfactory signals.

Compound experimental set-up:

carrier: normal saline, intraperitoneal injection is carried out 5 or 30 minutes before test, and n is 10

Positive control: pentobarbital 15mg/kg, i.e. intraperitoneal injection 5 or 30 minutes before test, and n is 10

Buspirone (0.1-30mg/kg, i.p.) was injected i.p. 5 or 30 minutes before testing, n-10

Statistical analysis: the total amount of locomotor activity was expressed as the total distance traveled (cm) and the average speed (cm/s) over 60 minutes. Data were analyzed using one-way anova and graph-based post-hoc analysis. The amount of locomotor activity at the six time points was expressed as distance traveled per 10 minutes (cm) and average speed (cm/s). Data were analyzed at each time point using one-way anova and graph-based post-hoc analysis.

As a result:

measurements over an observation period of 60 minutes showed that dose-dependence of buspirone can affect the performance of the open field test compared to vehicle-only rats. Pentobarbital significantly reduced its motor performance throughout the observation period.

When buspirone is administered concurrently with L-DOPA, a therapeutic index can be determined by comparing the dose of buspirone that reduces abnormal involuntary movements caused by L-DOPA with the dose of buspirone that causes sedation. This would indicate a beneficial therapeutic index in the case of buspirone administered with L-DOPA multiple times per day.

Comparison of the dose of buspirone capable of alleviating abnormal involuntary movements caused by L-DOPA when buspirone is administered 120, 90 or 60 minutes prior to L-DOPA administration will indicate the therapeutic index of buspirone at a time (1-2 times per day) different from that of L-DOPA administration.

Revised test procedure for assessing the effect of multiple doses of buspirone on levodopa-induced dyskinesia

6-OHDA lesion surgery:

dopamine (DA) denervation was performed by unilateral injection of 6-OHDA in the ascending nigrostriatal pathway.

Apomorphine-induced spin test:

screening models by subcutaneous injection of apomorphine.

The medicine and the treatment scheme are as follows:

L-DOPA methyl ester (Sigma) was administered at a dose of 6mg/kg/day in combination with 15mg/kg/day benserazide hydrochloride. All well-injured rats were chronically treated with L-DOPA and benserazide at this dose for 3 weeks or more to induce a gradual progression of dyskinetic-like movements. Thereafter, rats that did not develop dyskinesia were excluded from the study and rats with cumulative AIM score > 28 points (dyskinesia severity score > 2 on each axis, limb and orolingual) were maintained on a medication regimen with L-DOPA/benserazide injections at least twice a week during five tests to maintain a stable AIM score. Selected rats were divided into 6 groups, each group being balanced in the severity of AIM.

AIM and drug screening assays by L-DOPA:

buspirone will be administered at various time points prior to the administration of L-DOPA as described above. Rats were observed individually in standard cages 20-180 minutes after injection of L-DOPA, every 20 minutes.

Setting a group: n-6, SC:

1. carrier: physiological saline, administered 5-10 minutes before administration of L-DOPA;

2. buspirone (0.3mg/kg) was administered 120 minutes prior to L-DOPA administration;

3. buspirone (1mg/kg) was administered 120 minutes prior to L-DOPA administration;

4. buspirone (3mg/kg) was administered 120 minutes prior to L-DOPA administration;

5. buspirone (10mg/kg) was administered 120 minutes prior to L-DOPA administration;

6. buspirone (0.1mg/kg) is administered 5-10 minutes prior to L-DOPA, substantially simultaneously with L-DOPA;

7. buspirone (0.3mg/kg) is administered 5-10 minutes prior to L-DOPA, substantially simultaneously with L-DOPA;

8. buspirone (1mg/kg) is administered 5-10 minutes prior to L-DOPA, substantially simultaneously with L-DOPA;

9. buspirone (3mg/kg) was administered 5-10 minutes prior to L-DOPA, substantially simultaneously with L-DOPA.

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