Method for treating parkinsonism or parkinson's disease, and pharmaceutical composition

Abstract

The present invention relates to a method for treating Parkinsonism or Parkinson's disease, and a pharmaceutical composition, and specifically relates to a pharmaceutical composition, the use and a method of a peripheral μ-opioid receptor antagonist for treating Parkinsonism or Parkinson's disease. The pharmaceutical composition, use and method can significantly ameliorate symptoms of Parkinsonism or Parkinson's disease, including constipation, particularly constipation that is unresponsive or refractory to treatment with general-purpose constipation drugs.

Description

A method and pharmaceutical composition for treating parkinsonism or Parkinson's disease TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and relates to a new use or method of use of peripheral mu-opioid receptor antagonists (PAMORAs), in particular to pharmaceutical products, uses and methods of peripheral mu-opioid receptor antagonists for treating parkinsonism or Parkinson's disease, and in particular to pharmaceutical products, uses and methods of peripheral mu-opioid receptor antagonists for treating constipation in patients with parkinsonism or Parkinson's disease. BACKGROUND

[0002] Parkinsonism is a group of clinical syndromes related to motor function, including Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and corticobasal degeneration (CBD). Among them, Parkinson's disease, which has the largest number of patients, is the fastest growing neurological disease in the world. Due to the rapid development trend of aging in China, the number of people with Parkinsonism is also increasing rapidly. In 2016, the number of Parkinson's disease patients in China has exceeded 1.7 million. How to improve the quality of life of patients with Parkinsonism is also a major issue. Parkinsonism is mainly manifested in characteristic motor symptoms, and is also accompanied by pain, abnormal urination and defecation, and other non-motor symptoms, which will seriously affect the quality of life of patients with Parkinsonism.

[0003] Several drugs have been approved for the treatment of Parkinson's syndrome, and these drugs all exert their effects by entering the brain and acting on various receptors and enzymes in the brain (Sivanandy P, Leey TC, Xiang TC, Ling TC, Wey Han SA, Semilan SLA, Hong PK. Systematic Review on Parkinson's Disease Medications, Emphasizing on Three Recently Approved Drugs to Control Parkinson's Symptoms. Int J Environ Res Public Health. 2021 Dec 30; 19(1): 364. doi: 10.3390 / ijerph19010364. PMID: 35010624; PMCID: PMC8744877.). However, on the other hand, various known adverse reactions are considered to be caused by side effects after the drug enters the brain (Borovac JA. Side effects of a dopamine agonist therapy for Parkinson's disease: a mini-review of clinical pharmacology. Yale J Biol Med. 2016 Mar 24; 89(1): 37-47. PMID: 27505015; PMCID: PMC4797835.). Therefore, even if the existing drugs can improve Parkinson's syndrome, the side effects will greatly reduce the quality of life of patients. And since Parkinson's syndrome patients often take multiple drugs to treat various symptoms caused by Parkinson's syndrome (Bhagavathula AS, Tesfaye W, Vidyasagar K, Fialova D. Polypharmacy and Hyperpolypharmacy in Older Individuals with Parkinson's Disease: A Systematic Review and Meta-Analysis. Gerontology. 2022; 68(10): 1081-1090. doi: 10.1159 / 000521214. Epub 2022 Jan 13. PMID: 35026767; PMCID: PMC9677850.), the problem of reduced quality of life caused by drug side effects is even more serious.

[0004] As described above, Parkinson syndrome is also often accompanied by non-motor symptoms such as abnormal urination and defecation, among which the most common non-motor symptom is constipation. The same is true for Parkinson's disease, according to the study "Association between defecation frequency and Parkinson's disease in Chinese adults: a prospective cohort study" (Chinese Journal of Epidemiology, 2020, 41(1): 48-54), 20% to 89% of Parkinson's disease patients are accompanied by constipation, and the severity of constipation will increase as the disease progresses. In terms of treatment drugs, osmotic laxatives are commonly used drugs recommended for treating constipation in patients with Parkinson syndrome or Parkinson's disease, but are often accompanied by adverse reactions such as diarrhea, abdominal distension, drug tolerance may occur with long-term use, and some laxatives contain anthraquinone components, which are irritating and may cause decreased colon motility, colon melanosis, etc. In addition, 5-HT agonists such as mosapride and cinitapride are effective drugs for treating constipation, but their effects in patients with Parkinson syndrome or Parkinson's disease are still uncertain.

[0005] Currently, there is no treatment drug for constipation in patients with Parkinson syndrome or Parkinson's disease on the market, and there is no method of using peripheral μ-opioid receptor antagonists to treat constipation in patients with Parkinson syndrome or Parkinson's disease.

[0006] Therefore, there is an unmet medical need for new drugs and new methods for treating Parkinson syndrome or Parkinson's disease with fewer side effects, greater safety, and especially avoiding the side effects of drugs entering the brain and improving multiple symptoms at the same time. SUMMARY

[0007] An object of the present application is to provide a new pharmaceutical composition, use and method for treating Parkinson syndrome or Parkinson's disease in a patient.

[0008] Another object of the present application is to provide a new pharmaceutical composition, use and method for treating constipation in patients with Parkinson syndrome or Parkinson's disease.

[0009] The present inventors have unexpectedly found that peripheral μ-opioid receptor antagonists, naldemedine and avipropazin, can significantly improve the symptoms of Parkinson syndrome in a mouse Parkinson model after administration. Based on this finding, the present inventors have completed the present application, and thus the present application achieves the above objects.

[0010] The present application can be described from different aspects, and the application described in any of these aspects and any embodiment thereof is independent of each other and is associated with each other, and together constitutes the content of the present application.

[0011] A first aspect of the present application provides a method for treating Parkinson syndrome or Parkinson's disease in a patient, which comprises the step of administering to the patient a therapeutically effective amount of a peripheral μ-opioid receptor antagonist and optionally a dopaminergic drug.

[0012] In some embodiments of this aspect, there is provided a method of treating a patient for Parkinsonism or Parkinson's disease, wherein the patient is constipated, comprising the step of administering to the patient a therapeutically effective amount of a peripheral mu opioid receptor antagonist.

[0013] In some embodiments of this aspect, there is provided a method of treating a patient for Parkinsonism or Parkinson's disease, wherein the patient is constipated, comprising the step of administering to the patient a therapeutically effective amount of a peripheral mu opioid receptor antagonist.

[0014] In some embodiments of this aspect, there is provided a method of treating a patient for Parkinsonism or Parkinson's disease, wherein the patient is constipated, comprising the step of administering to the patient a therapeutically effective amount of a peripheral mu opioid receptor antagonist.

[0015] In particular embodiments of this aspect, the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, avipramine or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0016] In particular embodiments of this aspect, there is provided a method of treating a patient for Parkinsonism or Parkinson's disease, wherein the patient is constipated, comprising the step of administering to the patient a therapeutically effective amount of a peripheral mu opioid receptor antagonist.

[0017] In particular embodiments of this aspect, the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, avipramine or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0018] In particular embodiments of this aspect, the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, avipramine or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0019] In particular embodiments of this aspect, the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, avipramine or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments of this aspect, there is provided the use of a peripheral mu opioid receptor antagonist in the preparation of a medicament for treating dyskinesia in a patient with Parkinsonism or Parkinson's disease, wherein said patient is constipated.

[0021] In some embodiments of this aspect, there is provided the use of a peripheral mu opioid receptor antagonist in the preparation of a medicament for treating dyskinesia in a patient with Parkinsonism.

[0022] In other embodiments of this aspect, there is provided the use of a peripheral mu opioid receptor antagonist in the preparation of a medicament for treating constipation in a patient with Parkinsonism.

[0023] In particular embodiments of this aspect, the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0024] In particular embodiments of this aspect, there is provided the use of a peripheral mu opioid receptor antagonist in the preparation of a medicament for treating constipation in a patient with Parkinson's disease, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof. In a specific embodiment, the constipation is functional constipation caused or associated with Parkinson's disease. In another specific embodiment, the constipation is refractory, recurrent or intractable constipation caused or associated with Parkinson's disease that is difficult to treat with conventional constipation therapies.

[0025] A fourth aspect of the present application provides the use of a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent in the preparation of a medicament for treating constipation in a patient with Parkinsonism or Parkinson's disease while treating dyskinesia in said patient.

[0026] In particular embodiments of this aspect, the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0027] A fifth aspect of the present application provides a pharmaceutical composition comprising a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent and a pharmaceutically acceptable excipient for use in treating Parkinsonism or Parkinson's disease in a patient.

[0028] In some embodiments of this aspect, there is provided a pharmaceutical composition comprising a peripheral mu opioid receptor antagonist and a pharmaceutically acceptable excipient for use in treating Parkinsonism or Parkinson's disease in a patient, wherein said patient is constipated.

[0029] In some embodiments of this aspect, a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient is provided for treating motor disorders in patients with Parkinson's syndrome.

[0030] In other embodiments of this aspect, a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient is provided for treating constipation in patients with Parkinson's syndrome.

[0031] In a particular embodiment of this aspect, the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof, avimopan or a pharmaceutically acceptable salt thereof, naloxone or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0032] In a specific embodiment of this aspect, a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient is provided for treating constipation in patients with Parkinson's disease, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof, avimopan or a pharmaceutically acceptable salt thereof, naloxone or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof. In one specific embodiment, the constipation is functional constipation caused by or associated with Parkinson's disease. In another specific embodiment, the constipation is refractory, recurrent, or refractory constipation caused by or associated with Parkinson's disease, and is treated with commonly used constipation medications.

[0033] A sixth aspect of the invention provides a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and, optionally, a dopamine analogue and a pharmaceutically acceptable excipient, for treating constipation in a patient with Parkinson's syndrome or Parkinson's disease while treating motor dysfunction in that patient.

[0034] In a particular embodiment of this aspect, the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof, avimopan or a pharmaceutically acceptable salt thereof, naloxone or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0035] Based on the research results of this invention, it is anticipated that the pharmaceutical compositions, uses and methods of this invention can be used to treat Parkinson's syndrome, especially Parkinson's disease, effectively improve the symptoms of Parkinson's syndrome patients, including movement disorders and constipation, and delay the progression of Parkinson's syndrome.

[0036] The currently approved drugs for treating Parkinson's syndrome all act on various receptors and enzymes in the brain by entering the brain, and may have certain degree of brain-derived side effects, which can be avoided by peripheral μ-opioid receptor antagonists. Therefore, the pharmaceutical composition, use and method of the present application can improve the constipation and abdominal distension of Parkinson's syndrome patients while effectively improving the motor disorders of Parkinson's syndrome or Parkinson's disease, and can avoid the side effects caused by the drug entering the brain, have good tolerance and safety, and have no adverse events leading to decreased colon motility and colon melanosis. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 shows the effect of nadiliximab mesylate and aripiprazole on improving the motor disorders of mice in a MPTP-induced mouse Parkinson's model after injection administration.

[0038] Figure 2 shows the effect of nadiliximab mesylate and aripiprazole on increasing the stool frequency of mice in a MPTP-induced mouse Parkinson's model after injection administration.

[0039] Figure 3 shows the effect of nadiliximab mesylate and aripiprazole on increasing the wet stool weight of mice in a MPTP-induced mouse Parkinson's model after injection administration.

[0040] Figure 4 shows the effect of nadiliximab mesylate and aripiprazole on increasing the dry stool weight of mice in a MPTP-induced mouse Parkinson's model after injection administration.

[0041] Figures 5a, b, c show that a single administration of nadiliximab improves the constipation of a MPTP-induced Parkinson's mouse model.

[0042] Figures 6a, b, c, d show that continuous administration of nadiliximab improves the constipation of a MPTP-induced Parkinson's mouse model.

[0043] Figures 7a, b, c show that the combination of nadiliximab and levodopa improves the constipation of a MPTP-induced Parkinson's mouse model.

[0044] Figure 8 shows that the combination of nadiliximab does not inhibit the beneficial effect of levodopa on motor function.

[0045] Figures 9a, b, c, d show that the combination of nadiliximab and levodopa improves the constipation of a MPTP-induced Parkinson's mouse model.

[0046] Figure 10 shows that the continuous combination of nadiliximab does not inhibit the beneficial effect of levodopa on motor function.

[0047] Figure 11 shows that the defecation frequency of mice in the nadiliximab and naloxegol groups is significantly increased after food intake correction.

[0048] Figure 12 shows that the fecal wet weight ratio of mice in the naldemeton-, naloxoxol and methylnaltrexone groups was significantly increased after adjusting for food intake.

[0049] Figure 13 shows that the fecal dry weight ratio of mice in the naldemeton-, naloxoxol and methylnaltrexone groups was significantly increased after adjusting for food intake.

[0050] Figure 14 shows that nalidix has no effect on constipation caused by a low-fiber diet.

[0051] Figure 15 shows the changes in the expression of opioid-related molecular genes in an MPTP-induced Parkinson's mouse model. a: Changes in Oprm1 expression in the colon; b: Changes in Oprk1 expression in the colon; c: Changes in Oprd1 expression in the colon. Detailed Implementation

[0052] To facilitate understanding of this invention, certain terms used herein are defined. The definitions of these terms should be understood in conjunction with the understanding of those skilled in the art regarding the remainder of this specification. Unless otherwise specifically defined herein, all technical and scientific terms used in this invention have the same meaning as commonly understood by those skilled in the art. If the meaning of a term specifically defined herein differs from the commonly understood meaning by those skilled in the art, the meaning specifically defined herein shall prevail.

[0053] Unless the context otherwise requires, the term "constipation in patients with Parkinson's syndrome" as used herein refers to constipation occurring in patients with Parkinson's syndrome. Constipation in patients with Parkinson's disease refers to constipation caused by or associated with Parkinson's disease, also known as Parkinson's disease constipation. According to the Rome IV criteria, constipation in Parkinson's disease patients is classified as functional constipation (S. Pavan, M. Ballal, A. Prabhu, S. Gorthi, B. Das, A. Mutreja, T. Ramamurthy, A. Pai. Functional Constipation in Parkinson's Disease [abstract]. Mov Disord. 2021; 36(suppl1)). This type of constipation is characterized by its intractability, recurrence, or refractory nature, including resistance to or ineffectiveness of conventional laxatives. It differs from other types of constipation clinically, such as opioid-induced constipation (Aziz I, Whitehead WE, Palsson OS, ...). H, Simrén M. An approach to the diagnosis and management of Rome IV functional disorders of chronic constipation. Expert Rev Gastroenterol Hepatol. 2020 Jan; 14(1): 39-46.).

[0054] The term "treatment" as used herein means to eliminate one or more symptoms of the indicated condition, to reduce the severity of the indicated condition, or to prevent the occurrence of the indicated condition in the subject being treated. For example, the term "treatment of constipation in a patient with Parkinson's disease" includes one, two, or all of reducing the severity of constipation in a patient with Parkinson's disease, increasing the frequency of bowel movements in a patient with Parkinson's disease, and increasing the amount of bowel movements in a patient with Parkinson's disease. Similarly, the term "treatment of constipation in a patient with Parkinsonism" includes one, two, or all of reducing the severity of constipation in a patient with Parkinsonism, increasing the frequency of bowel movements in a patient with Parkinsonism, and increasing the amount of bowel movements in a patient with Parkinsonism.

[0055] The terms "patient", "subject", and "individual" as used herein have the same meaning and are used interchangeably in the present application.

[0056] The phrase "therapeutically effective amount" as used herein, unless otherwise expressly stated, means the amount of a peripheral mu opioid receptor antagonist used that, when administered to a patient, achieves the stated therapeutic effect. For example, the stated therapeutic effect can be the elimination of one or more symptoms of Parkinsonism (e.g., Parkinson's disease) or the reduction in the severity of the symptoms. The symptoms include motor impairment and constipation. Thus, the stated therapeutic effect includes one, two, or all of reducing the severity of constipation in a patient with Parkinson's disease, increasing the frequency of bowel movements in a patient with Parkinson's disease, and increasing the amount of bowel movements in a patient with Parkinson's disease.

[0057] The pharmaceutical active ingredient "Naldeimide" as used herein means a compound having the following chemical structure:

[0058] CN101228172B discloses the compound and its preparation method, the entire content of which is incorporated herein by reference. Reference to Naldeimide in the present application includes reference to stereoisomers, metabolites, and prodrugs thereof known in the art that have the same pharmacological activity as Naldeimide. Reference to Naldeimide in the present application also includes reference to solvates of Naldeimide or a pharmaceutically acceptable salt thereof, such as hydrates and the like. In addition, reference to Naldeimide in the present application also includes reference to isotopically labeled Naldeimide.

[0059] The pharmaceutical active ingredient "avipimoz" as used in the present application refers to a compound having the following chemical structure:

[0060] The chemical name of which is [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1- piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid. U.S. Patent No. 5,250,542 discloses avipimoz and its method of preparation, the entire contents of which are incorporated herein by reference. Reference to avipimoz in the present application includes reference to stereoisomers, metabolites or prodrugs thereof known in the art to have the same pharmacological activity as avipimoz. Reference to avipimoz in the present application also includes reference to solvates, such as hydrates, etc. of avipimoz or its pharmaceutically acceptable salts. In addition, reference to avipimoz in the present application also includes reference to isotopically-labeled avipimoz.

[0061] The pharmaceutical active ingredient "naloxegol" as used in the present application refers to a compound having the following chemical structure:

[0062] The chemical name of which is (5a,6a)-17-allyl-6-(2,5,8,11,14,17,20-hepta- oxabicyclo[22.2]octadecoxy)-4,5-epoxymorphinan-3,14-diol, having the molecular formula C 34 H 53 NO 11 The compound or its pharmaceutically acceptable derivatives can be prepared according to any of the methods disclosed in the prior art by a person skilled in the art. Reference to naloxegol in the present application includes reference to stereoisomers, metabolites or prodrugs thereof known in the art to have the same pharmacological activity as naloxegol. Reference to naloxegol in the present application also includes reference to solvates, such as hydrates, etc. of naloxegol or its pharmaceutically acceptable salts. In addition, reference to naloxegol in the present application also includes reference to isotopically-labeled naloxegol.

[0063] The pharmaceutical active ingredient "methylnaltrexone" as used in the present application refers to a compound having the following chemical structure:

[0064] The chemical name of which is (5a)-17-(cyclopropylmethyl)-3,14-dihydroxy-17- methyl-6-oxo-4,5-epoxymorphinan-17-ium, having the molecular formula C 21 H 26 NO4 +The compound or its pharmaceutically acceptable derivative thereof can be prepared according to any of the methods disclosed in the prior art by a person skilled in the art. Reference to methylnaltrexone in the present invention includes reference to its stereoisomers, metabolites or prodrugs thereof known in the art which have the same pharmacological activity as methylnaltrexone. Reference to methylnaltrexone in the present invention also includes reference to solvates of methylnaltrexone or its pharmaceutically acceptable salts, such as hydrates and the like. Furthermore, reference to methylnaltrexone in the present invention also includes reference to isotopically-labelled methylnaltrexone.

[0065] The isotopically-labelled nalmexone means that the isotopically-labelled nalmexone has the same chemical structure as nalmexone as shown above except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of suitable isotopes include isotopes of hydrogen, carbon, and nitrogen, such as, but not limited to 2 H, 3 H, 13 C, 14 C, and 15 N. The person skilled in the art knows that isotopically-labelled nalmexone can be prepared by replacing non-isotopically-labelled reagents by readily available isotopically-labelled reagents using methods known in the art.

[0066] The isotopically-labelled aviptadil means that the isotopically-labelled aviptadil has the same chemical structure as aviptadil as shown above except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of suitable isotopes include isotopes of hydrogen, carbon, and nitrogen, such as, but not limited to 2 H, 3 H, 13 C, 14 C, and 15 N. The person skilled in the art knows that isotopically-labelled aviptadil can be prepared by replacing non-isotopically-labelled reagents by readily available isotopically-labelled reagents using methods known in the art.

[0067] The isotopically-labelled naloxegol means that the isotopically-labelled naloxegol has the same chemical structure as naloxegol as shown above except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of suitable isotopes include isotopes of hydrogen, carbon, and nitrogen, such as, but not limited to 2 H, 3 H, 13 C, 14 C, and 15N.As will be appreciated by those of ordinary skill in the art, isotopically labeled naloxegol can be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents known in the art.

[0068] The isotopically labeled methylnaltrexone means that the isotopically labeled methylnaltrexone has the same chemical structure as methylnaltrexone as shown above except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of suitable isotopes include isotopes of hydrogen, carbon, and nitrogen, such as, but not limited to 2 H, 3 H, 13 C, 14 C and 15 N.As will be appreciated by those of ordinary skill in the art, isotopically labeled methylnaltrexone can be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents known in the art.

[0069] The phrase "pharmaceutically acceptable" is employed herein to refer to those substances or compositions that are chemically, physiologically, and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated.

[0070] The "pharmaceutically acceptable salts" of nalmexone, avipropazin, naloxegol or methylnaltrexone described herein include various pharmaceutically acceptable salts, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, formate, acetate, lactate, citrate, tartrate, ascorbate, succinate, maleate, fumarate, gluconate, glucaronate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and pamoate salts.

[0071] According to a first aspect of the present application, there is provided a method of treating Parkinsonism or Parkinson's disease in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent, wherein the peripheral mu opioid receptor antagonist is selected from nalmexone or a pharmaceutically acceptable salt thereof, avipropazin or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, there is provided a method of treating Parkinson's disease in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of nalmexone or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, a method of treating Parkinson's disease in a patient is provided, the method comprising the step of administering to the patient a therapeutically effective amount of aviprimorph or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, treating Parkinson's disease in a patient comprises treating constipation in the patient, e.g., intractable, recurrent, or refractory constipation with commonly used constipation therapies.

[0075] In other embodiments, treating Parkinson's disease in a patient comprises improving motor symptoms or improving motor function in the patient.

[0076] In still other embodiments, the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine, and pramipexole.

[0077] According to a second aspect of the present application, a method of treating constipation in a patient with Parkinsonism or Parkinson's disease while treating the patient's dyskinesia is provided, the method comprising the step of administering to the patient a therapeutically effective amount of a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, aviprimorph or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, a method of treating constipation in a patient with Parkinson's disease while treating the patient's dyskinesia is provided, the method comprising the step of administering to the patient a therapeutically effective amount of a peripheral mu opioid receptor antagonist, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, aviprimorph or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof, and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, a method of treating constipation in a patient with Parkinsonism or Parkinson's disease while treating the patient's dyskinesia is provided, the method comprising the step of administering to the patient a therapeutically effective amount of naldephine or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, a method of treating constipation in a patient with Parkinson's disease while treating the patient's dyskinesia is provided, the method comprising the step of administering to the patient a therapeutically effective amount of naldephine or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, there is provided a method of treating constipation in a patient with Parkinsonism or Parkinson's disease while treating motor impairment in the patient, the method comprising the step of administering to the patient a therapeutically effective amount of aviprimorph or a pharmaceutically acceptable salt thereof. In some embodiments, there is provided a method of treating constipation in a patient with Parkinson's disease while treating motor impairment in the patient, the method comprising the step of administering to the patient a therapeutically effective amount of aviprimorph or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the constipation is intractable, recurrent or refractory to treatment with a conventional constipation treatment.

[0083] In some embodiments, the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine and pramipexole.

[0084] According to a third aspect of the present application, there is provided the use of a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent in the manufacture of a medicament for treating Parkinsonism or Parkinson's disease in a patient, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldeptic or a pharmaceutically acceptable salt thereof, aviprimorph or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, there is provided the use of naldeptic or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Parkinson's disease in a patient.

[0086] In some embodiments, there is provided the use of aviprimorph or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Parkinson's disease in a patient.

[0087] In some embodiments, the treating Parkinson's disease in a patient comprises treating constipation, e.g. intractable, recurrent or refractory to treatment with a conventional constipation treatment, in the patient.

[0088] In other embodiments, the treating Parkinson's disease in a patient comprises reducing motor symptoms or improving motor function in the patient.

[0089] In some embodiments, the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine and pramipexole.

[0090] According to a fourth aspect of the application, there is provided the use of a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent in the manufacture of a medicament for treating constipation in a patient with dyskinesia or Parkinson's disease, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, anvilomipan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, there is provided the use of a peripheral mu opioid receptor antagonist in the manufacture of a medicament for treating constipation in a patient with dyskinesia or Parkinson's disease, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, anvilomipan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, there is provided the use of naldephine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating constipation in a patient with dyskinesia or Parkinson's disease.

[0093] In some embodiments, there is provided the use of naldephine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating constipation in a patient with dyskinesia or Parkinson's disease.

[0094] In some embodiments, there is provided the use of anvilomipan or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating constipation in a patient with dyskinesia or Parkinson's disease.

[0095] In some embodiments, there is provided the use of anvilomipan or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating constipation in a patient with dyskinesia or Parkinson's disease.

[0096] In some embodiments, the constipation is intractable, recurrent or refractory to common constipation treatment.

[0097] In yet some embodiments, the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine and pramipexole.

[0098] According to a fifth aspect of the present application, there is provided a pharmaceutical composition comprising a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent and a pharmaceutically acceptable excipient for use in treating Parkinsonism or Parkinson's disease in a patient, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, anvilmoφan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, there is provided a pharmaceutical composition comprising naldephine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in treating Parkinson's disease in a patient.

[0100] In some embodiments, there is provided a pharmaceutical composition comprising anvilmoφan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in treating Parkinson's disease in a patient.

[0101] In some embodiments, treating Parkinson's disease in a patient comprises treating constipation, e.g. intractable, recurrent or refractory constipation with conventional constipation therapies, in the patient.

[0102] In other embodiments, treating Parkinson's disease in a patient comprises reducing motor symptoms or improving motor function in the patient.

[0103] In still other embodiments, the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine and pramipexole.

[0104] According to a sixth aspect of the present application, there is provided a pharmaceutical composition comprising a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent and a pharmaceutically acceptable excipient for use in treating constipation in a Parkinsonism or Parkinson's disease patient concurrently with treating motor impairment in the patient, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, anvilmoφan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, there is provided a pharmaceutical composition comprising a peripheral mu opioid receptor antagonist and a pharmaceutically acceptable excipient for use in treating constipation in a Parkinson's disease patient concurrently with treating motor impairment in the patient, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, anvilmoφan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, there is provided a pharmaceutical composition comprising nadide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in treating constipation in a Parkinson's syndrome or Parkinson's disease patient concurrently with treating motor impairment in the patient.

[0107] In some embodiments, there is provided a pharmaceutical composition comprising nadide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in treating constipation in a Parkinson's disease patient concurrently with treating motor impairment in the patient.

[0108] In some embodiments, there is provided a pharmaceutical composition comprising avipracon or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in treating constipation in a Parkinson's syndrome or Parkinson's disease patient concurrently with treating motor impairment in the patient.

[0109] In some embodiments, there is provided a pharmaceutical composition comprising avipracon or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in treating constipation in a Parkinson's disease patient concurrently with treating motor impairment in the patient.

[0110] In some embodiments, the constipation is intractable, recurrent or refractory to common constipation treatment drugs.

[0111] In still some embodiments, the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine and pramipexole.

[0112] In particular, the present application can be expressed as one, more or all of the following embodiments:

[0113] Embodiment 1. A method of treating Parkinson's syndrome or Parkinson's disease in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent.

[0114] Embodiment 2. The method according to embodiment 1, wherein the patient suffers from constipation.

[0115] Embodiment 3. The method according to embodiment 1 or 2, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of nadide or a pharmaceutically acceptable salt thereof, avipracon or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0116] Embodiment 4. The method according to any one of embodiments 1-3, wherein the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine and pramipexole.

[0117] Embodiment 5. Use of a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent in the manufacture of a medicament for the treatment of Parkinsonism or Parkinson's disease in a patient.

[0118] Embodiment 6. Use according to embodiment 5, wherein the patient suffers from constipation.

[0119] Embodiment 7. Use according to embodiment 5 or 6, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of nalde- midine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0120] Embodiment 8. A method according to any one of embodiments 5 to 7, wherein the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine and pramipexole.

[0121] Embodiment 9. A pharmaceutical composition comprising a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent and a pharmaceutically acceptable excipient for use in the treatment of Parkinsonism or Parkinson's disease in a patient.

[0122] Embodiment 10. A pharmaceutical composition for use according to embodiment 9, wherein the patient suffers from constipation.

[0123] Embodiment 11. A pharmaceutical composition for use according to embodiment 9 or 10, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of nalde-midine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0124] Embodiment 12. A method according to any one of embodiments 9 to 11, wherein the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine and pramipexole.

[0125] Embodiment 13. A method of treating constipation in a patient suffering from Parkinsonism or Parkinson's disease, the method comprising the step of administering to the patient a therapeutically effective amount of a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent.

[0126] Embodiment 14. A method according to embodiment 13, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of nalde-midine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0127] Embodiment 15. The method according to embodiment 13 or 14, wherein the dopaminergic mimetic is selected from the group consisting of levodopa, carbidopa, comperidie, bromocriptine, piribedil, amantadine and pramipexole.

[0128] Embodiment 16. Use of a peripheral mu opioid receptor antagonist and optionally a dopaminergic mimetic for the preparation of a medicament for the treatment of constipation in a patient suffering from Parkinson's syndrome or Parkinson's disease.

[0129] Embodiment 17. The use according to embodiment 16, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldeimide or a pharmaceutically acceptable salt thereof, aviprimox or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0130] Embodiment 18. The method according to embodiment 16 or 17, wherein the dopaminergic mimetic is selected from the group consisting of levodopa, carbidopa, comperidie, bromocriptine, piribedil, amantadine and pramipexole.

[0131] Embodiment 19. A pharmaceutical composition comprising a peripheral mu opioid receptor antagonist and optionally a dopaminergic mimetic and a pharmaceutically acceptable excipient for use in the treatment of constipation in a patient suffering from Parkinson's syndrome or Parkinson's disease.

[0132] Embodiment 20. The pharmaceutical composition for use according to embodiment 19, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldeimide or a pharmaceutically acceptable salt thereof, aviprimox or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0133] Embodiment 21. The method according to embodiment 19 or 20, wherein the dopaminergic mimetic is selected from the group consisting of levodopa, carbidopa, comperidie, bromocriptine, piribedil, amantadine and pramipexole.

[0134] Embodiment 22. A peripheral mu opioid receptor antagonist for use in the treatment of Parkinson's syndrome or Parkinson's disease in a patient.

[0135] Embodiment 17. The peripheral mu opioid receptor antagonist for use according to embodiment 16, wherein the patient is suffering from constipation.

[0136] Embodiment 18. The peripheral mu opioid receptor antagonist for use according to embodiment 16 or 17, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldeimide or a pharmaceutically acceptable salt thereof, aviprimox or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0137] Embodiment 19. A peripheral mu opioid receptor antagonist for use in treating constipation in a patient with Parkinson's syndrome or Parkinson's disease.

[0138] Embodiment 20. The peripheral mu opioid receptor antagonist for use according to embodiment 19, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, avipropazin or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

[0139] The pharmaceutical composition of the present application can be prepared into dosage forms suitable for administration to a patient using methods known in the art using suitable pharmaceutical excipients. The choice of particular excipient will depend on the mode of administration or the type and state of the disease to be treated in a particular patient. For example, pharmaceutically acceptable excipients, carriers, fillers, binders, humectants, disintegrants, absorption accelerators, surface active agents, adsorptive carriers and lubricants, etc. which are conventional in the pharmaceutical field can be included as pharmaceutically acceptable excipients. If necessary, flavoring agents, preservatives, sweetening agents, etc. can also be added to the pharmaceutical composition. The method of preparing a suitable pharmaceutical composition for a particular mode of administration is well within the knowledge of those skilled in the pharmaceutical art.

[0140] The pharmaceutical composition of the present application can be prepared into a unit dosage form for administration. The administration dosage form can be a liquid dosage form or a solid dosage form. The liquid dosage form can be a solution type, a gel type, an emulsion dosage form or a suspension dosage form, etc. The solid dosage form can be, for example, a tablet, a powder, a suppository, a granule or a capsule, etc. Other dosage forms include an aerosol, an implant, a patch or a rub, etc. The term "unit dosage form" used in the present application means a physically discrete unit suitable for use as a unit dosage for a human subject, especially a patient with Parkinson's disease, each unit containing a predetermined quantity of the peripheral mu opioid receptor antagonist of the present application calculated to produce the desired therapeutic effect.

[0141] The pharmaceutical composition of the present application can be administered by any means and in any form known in the art. For example, the pharmaceutical composition of the present application can be administered by a mode selected from the group consisting of oral, spray inhalation, rectal, nasal, vaginal, topical, parenteral such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection, of which oral, intramuscular, intraperitoneal or intravenous injection is preferred. Preferably, the pharmaceutical composition of the present application is administered to a patient in need thereof by oral administration.

[0142] For oral administration, the pharmaceutical compositions of the present application can be formulated by combining the pharmaceutical composition with any suitable pharmaceutical excipients, using formulation techniques known in the art, into solid formulations such as tablets, capsules, and powders, or into liquid formulations such as solutions, syrups, suspensions, and emulsions.

[0143] For parenteral administration, the pharmaceutical compositions of the present application can be formulated by combining the pharmaceutical composition with any suitable pharmaceutical excipients, using formulation techniques known in the art, into formulations suitable for parenteral administration such as sterile injection solutions, lyophilized powders, transdermal patches, aerosols, oral and nasal inhalers, and suppositories, etc. The parenteral routes of administration include intravenous, intraperitoneal, subcutaneous, intramuscular, transdermal, nasal, intrapulmonary, intrathecal, rectal, and topical routes, etc.

[0144] In the methods, uses, or pharmaceutical compositions of the present application, the peripheral mu opioid receptor antagonist, especially, naldephine or a pharmaceutically acceptable salt thereof and aviprimophan or a pharmaceutically acceptable salt thereof, is administered in a single dose of about 0.01 mg to about 13 mg, preferably, about 0.1 mg to about 0.5 mg. The administration is once a day for 1 to 2 times a day, preferably, once a day. Therefore, advantageously, the pharmaceutical composition or medicament comprising the peripheral mu opioid receptor antagonist in unit dosage form in the present application contains 0.01 mg to about 13 mg (e.g., 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, or 12 mg), preferably, about 0.1 mg to about 0.5 mg of the peripheral mu opioid receptor antagonist, especially, naldephine or a pharmaceutically acceptable salt thereof and aviprimophan or a pharmaceutically acceptable salt thereof.

[0145] Based on the results of the present application, it is expected that the methods, uses, and pharmaceutical compositions of the present application can be effective in treating constipation in patients with Parkinson's syndrome or Parkinson's disease, have good tolerability and safety, do not cause adverse events such as decreased colonic motility and colonic melanosis, and can improve abdominal distension in patients, thereby improving the quality of life of patients with Parkinson's syndrome or Parkinson's disease.

[0146] Examples

[0147] The exemplary compositions, uses, and methods of the present application described above, the following examples of the present application are provided, which are only for illustration and do not limit the present application. Unless otherwise specifically stated, the materials used in the present application are obtained from the market.

[0148] Example 1: Construction of a mouse model of Parkinson's disease induced by MPTP and evaluation of the effects of drugs (motor disorders)

[0149] A mouse model of Parkinson's disease was constructed by intraperitoneal injection of MPTP, and the efficacy of the experimental drugs in treating motor disorders caused by MPTP was investigated.

[0150] • Experimental animals: C57BL / 6J mice, 8 weeks old, male.

[0151] • Drugs:

[0152] MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), physiological saline, methylcellulose, sodium nortriptyline mesylate, and aripiprazole.

[0153] • Preparation of the MTPT solution:

[0154] MPTP was weighed and added to physiological saline to prepare a 3 mg / ml solution, which was mixed well and stored frozen. The dose administered was 10 ml / kg.

[0155] • Preparation of the sodium nortriptyline mesylate solution:

[0156] Sodium nortriptyline mesylate was weighed into a transparent test tube, then physiological saline containing 0.5% methylcellulose was added, and after vortexing well, a 0.01 mg / ml solution of sodium nortriptyline mesylate was obtained. The dose administered was 10 ml / kg.

[0157] • Preparation of the aripiprazole solution:

[0158] Aripiprazole was weighed into a transparent test tube, then physiological saline containing 0.5% methylcellulose was added, and after vortexing well, a 0.1 mg / ml solution of aripiprazole was obtained. The dose administered was 10 ml / kg.

[0159] • Construction of the mouse model and administration of drugs:

[0160] A total of 32 mice were randomly divided into 4 groups, with 8 mice in each group.

[0161] The model group was intraperitoneally injected with 30 mg / kg of MPTP every day from day 1 to day 8.

[0162] The sham model group was intraperitoneally injected with physiological saline every day from day 1 to day 8.

[0163] Before the experiment, the mice were acclimated to the environment for 1 week, and each mouse was given a health check, including an assessment of the fur, limbs, and mouth, and each mouse was checked for any signs of abnormal posture or movement.

[0164] • Table 1: Composition of the administration

[0165] • Grip strength analysis

[0166] On day 9, the mice were orally administered with the drugs. One hour after the administration, the grip strength test was performed.

[0167] In the grip strength test, the mice were allowed to hold the metal grid of the grip strength meter with their forelimbs, and then the tail of the mouse was gently pulled backward until the mouse could no longer hold the grid. The average grip strength observed in 10 trials was recorded and calculated.

[0168] • Statistical analysis

[0169] When the difference was significant, the effects of sodium neldipine tosylate and aviprimopan in the model were tested by Kruskal-Wallis test, and then compared with the vehicle by Conover's multiple comparison test.

[0170] The comparison between the model medium group and the sham model group was performed by two-tailed Mann-Whitney test (###P<0.001). When the difference was significant, the effects of sodium neldipine tosylate and aviprimopan in the model were tested by Kruskal-Wallis analysis, and then compared with the model medium group by Conover multiple test (*P<0.05, **P<0.01).

[0171] • Experimental results

[0172] According to the administration dose and route shown in Table 1, the mice were administered according to the above method, and the results are shown in Figure 1. As shown in Figure 1, from a statistical point of view, the grip strength of the model medium group was significantly lower than that of the sham model medium group, and in the model group, the grip strength of the sodium neldipine tosylate administration group and the aviprimopan administration group was also significantly increased compared with the medium group.

[0173] The results show that the peripheral μ opioid receptor antagonists neldipine and aviprimopan can improve the motor impairment of Parkinson's disease patients.

[0174] Example 2: Construction of MPTP-induced mouse Parkinson's model and evaluation of drug effects (constipation)

[0175] A mouse model of Parkinson's disease was constructed by intraperitoneal injection of MPTP in mice, and the therapeutic effects of the experimental drugs on the intestinal peristalsis inhibition caused by MPTP were studied.

[0176] • Experimental animals: C57BL / 6J mice, 8 weeks old, male.

[0177] • Drugs: MPTP, physiological saline, methyl cellulose, sodium neldipine tosylate, and aviprimopan.

[0178] • Preparation of MTPT solution:

[0179] MPTP was weighed and dissolved in normal saline to make a 3 mg / ml solution, mixed well and stored in ice. The administration dose was 10 ml / kg.

[0180] · Preparation of sodium neldtamycin tosylate solution:

[0181] Sodium neldtamycin tosylate was weighed into a transparent test tube, then normal saline containing 0.5% methyl cellulose was added, and a 0.01 mg / ml solution of sodium neldtamycin tosylate was obtained after vortexing. The administration dose was 10 ml / kg.

[0182] · Preparation of aviprimocin solution:

[0183] Aviprimocin was weighed into a transparent test tube, then normal saline containing 0.5% methyl cellulose was added, and a 0.1 mg / ml solution of aviprimocin was obtained after vortexing. The administration dose was 10 ml / kg.

[0184] · Mouse model construction and administration:

[0185] A total of 32 mice were randomly divided into 4 groups, 8 mice in each group.

[0186] The model group was intraperitoneally injected with 30 mg / kg of MPTP every day from the 1st day to the 7th day.

[0187] The sham group was intraperitoneally injected with normal saline every day from the 1st day to the 7th day.

[0188] Before the experiment, the mice were acclimated for 1 week, and each mouse was given a health check, including an assessment of fur, limbs, and mouth, and each mouse was checked for any abnormal signs of posture and movement.

[0189] · Table 2: Administration composition

[0190] · Fecal analysis:

[0191] On the 7th day, the mice were fasted and deprived of water for 12 hours. On the 8th day, the mice were given food and water for 2 hours. 1.5 hours later, the mice were given oral administration. 30 minutes later, each mouse was placed in a clean separate box for 1 hour, then returned to the original cage. The feces were collected, counted and weighed, then dried at 65°C overnight to evaluate the dry weight of feces.

[0192] · Statistical analysis

[0193] The comparison between the model medium group and the sham group was performed using a two-tailed Mann-Whitney test (#P<0.05). When the difference was significant, the effect of the test compound was tested by Kruskal-Wallis analysis, and then compared with the model medium group by Dunn's multiple comparison test (*P<0.05, **P<0.01, ***P<0.001).

[0194] • Experimental results

[0195] The mice were administered according to the above method according to the administration dose and route shown in Table 2, and the results are shown in FIGS. 2-4. After injection of MPTP, the number of stools and the weight of wet and dry stools of the mice were reduced, showing signs of constipation.

[0196] As shown in FIG. 2, the number of stools was increased compared to the model medium group after administration of nadilox 0.1 mg / kg body weight and aviprimox 1 mg / kg body weight.

[0197] As shown in FIG. 3, the weight of wet stools was increased compared to the model medium group after administration of nadilox 0.1 mg / kg body weight and aviprimox 1 mg / kg body weight.

[0198] As shown in FIG. 4, the weight of dry stools was increased compared to the model medium group after administration of nadilox 0.1 mg / kg body weight and aviprimox 1 mg / kg body weight.

[0199] The above results show that the number of stools and the weight of stools were increased compared to the model medium group after administration of nadilox 0.1 mg / kg body weight and aviprimox 1 mg / kg body weight, and the constipation of the Parkinson's disease mice was significantly improved. Therefore, it can be expected that nadilox or aviprimox can be used to treat constipation in patients with Parkinson's syndrome or Parkinson's disease.

[0200] Example 3: Dose-dependent evaluation of drug effects in a MPTP-induced Parkinson's mouse model (single / continuous administration, in combination with levodopa)

[0201] A Parkinson's disease mouse model was constructed by intraperitoneal injection of MPTP into mice, and the therapeutic effect of the test compound on constipation caused by MPTP was investigated under conditions of continuous administration and in combination with levodopa.

[0202] • Test animals: C57BL / 6J mice, 8 weeks, male

[0203] • Medicines: Nadilox, MPTP, methylcellulose, levodopa, benserazide, and physiological saline.

[0204] • Preparation of an MTPT solution:

[0205] MPTP was weighed into normal saline to prepare a 3 mg / ml solution, mixed well, and stored in the freezer. The dosage was 10 ml / kg.

[0206] · Preparation of medium solution:

[0207] The placebo was weighed into a transparent test tube, then 0.5% MC normal saline was added, and after vortexing well, a 0.001 mg / ml medium solution was obtained.

[0208] · Preparation of sodium tolmesilate solution:

[0209] Sodium tolmesilate was weighed into a transparent test tube, then 0.5% MC normal saline was added, and after vortexing well, a 0.001 mg / ml sodium tolmesilate solution was obtained. 3 ml of medium solution was mixed with 7 mg of 0.001 mg / ml sodium tolmesilate solution to obtain 10 ml of 0.003 mg / ml sodium tolmesilate solution. The dosage was 10 ml / kg.

[0210] · Preparation of levodopa solution:

[0211] Levodopa was weighed into normal saline to prepare a 2 mg / ml solution. The dosage was 5 ml / kg.

[0212] · Preparation of benserazide solution:

[0213] Benserazide was weighed into normal saline to prepare a 3 mg / ml solution. The dosage was 5 mg / kg.

[0214] · Mouse model construction, administration, and evaluation:

[0215] A total of 56 mice were randomly divided into 7 groups, 8 mice per group.

[0216] The model group was intraperitoneally injected with 30 mg / kg MPTP every day from the 1st day to the 13th day.

[0217] The sham model group was intraperitoneally injected with normal saline every day from the 1st day to the 13th day.

[0218] From the 8th day to the 14th day, the mice were administered with medium or test drug every day, respectively.

[0219] Before the test, the mice were acclimated for 1 week, and each mouse was given a health check, including evaluation of fur, limbs, and mouth, and checking each mouse for abnormal signs of posture and movement.

[0220] From the 7th day to the 12th day at 8 pm, all mice were fasted and deprived of water for 12 hours.

[0221] On day 8 and day 13, the mice were allowed to eat and drink for 2 hours before the fecal analysis.

[0222] Grip strength test was performed on day 9 and day 14.

[0223] Table 3: Dosing Composition

[0224] Fecal analysis:

[0225] On day 8 and day 13, the mice were allowed to eat and drink for 2 hours before the fecal analysis.

[0226] Grip strength analysis:

[0227] On day 9 and day 14, the mice were allowed to grip the metal grid of the grip strength meter with their forelimbs and the mice were gently pulled backwards with their tails until they could no longer hold onto the grid. The average grip strength observed in 10 trials was recorded and calculated.

[0228] Statistical analysis

[0229] Results are expressed as mean ± standard error of the mean (SEM). Comparison between groups was performed by Kruskal-Wallis test and Conover's multiple comparison test. (*P < 0.05, **P < 0.01, ***P < 0.001).

[0230] Test results - fecal analysis results after single dosing

[0231] As shown in Figure 5a, the number of defecation and fecal wet weight of the model mice were significantly decreased compared to the sham mice, indicating the constipation performance of the MPTP-induced Parkinson mouse model. The effect of nadiliximab was evaluated for the constipation performance of the model. As shown in Figures 5b, 5c, the number of defecation and fecal wet weight of the model mice after single oral dosing of nadiliximab were increased in a dose-dependent manner compared to the vehicle model mice, while the fecal water content did not change; the increase in the number of defecation and fecal wet weight caused by 0.01 mg / kg body weight of nadiliximab was statistically significant, indicating that single dosing of nadiliximab improved the constipation of the MPTP-induced Parkinson mouse model.

[0232] Test results - fecal analysis results after continuous dosing

[0233] First, the body weight change from the first day of dosing (day 8) to the day before fasting (day 12) was evaluated in the model groups to assist the fecal analysis. As shown in Figure 6a, oral administration of nadidegib at 0.003 mg / kg body weight and 0.01 mg / kg body weight for five consecutive days did not affect the body weight of the mice compared to the model vehicle group. As shown in Figures 6b, 6c, 6d, on day 13, the intestinal function of the sham model or model group mice was evaluated; the model mice administered with nadidegib at 0.003 mg / kg body weight or 0.01 mg / kg body weight for five consecutive days showed a significant increase in the number of defecation and fecal wet weight, but not in the fecal water content, indicating that the administration of nadidegib for five consecutive days improved the constipation in the MPTP-induced Parkinson’s mouse model.

[0234] • Test results - fecal analysis after single administration of nadidegib in combination with levodopa

[0235] To evaluate the efficacy of nadidegib when administered in combination with levodopa (standard therapy for motor symptoms of Parkinson’s disease), model mice in Groups 5, 6, and 7 were intraperitoneally administered with levodopa at 10 mg / kg body weight and benserazide at 15 mg / kg body weight to achieve a clinically relevant range of levodopa plasma concentration. As shown in Figures 7a, 7b, the administration of nadidegib at 0.003 mg / kg body weight or 0.01 mg / kg body weight in combination with levodopa to the model mice significantly increased the number of defecation and fecal wet weight, while the combination of vehicle and levodopa did not show a significant difference. As shown in Figure 7c, there was no significant difference in the fecal water content among all groups. These results indicate that the combination of nadidegib and levodopa improved the constipation in the MPTP-induced Parkinson’s mouse model.

[0236] • Test results - grip strength analysis after two administrations of nadidegib in combination with levodopa

[0237] On day 9, the grip strength of the mice in each group after two administrations was evaluated. As shown in Figure 8, the mice in the model vehicle group showed a significantly decreased grip strength compared to the mice in the sham vehicle group, indicating that the motor function of the MPTP-induced Parkinson’s mouse model was impaired on day 9. The mice in the combination of nadidegib and levodopa showed a significantly higher grip strength compared to the mice in either the model vehicle group or the levodopa vehicle group, indicating that the combination of nadidegib did not inhibit the beneficial effect of levodopa on motor function.

[0238] • Test results - fecal analysis after five administrations of nadidegib in combination with levodopa

[0239] As shown in FIG. 9a, the body weight of each group of mice in the model group showed no difference from day 8 to day 12. As shown in FIG. 9b, on day 13, the mice in the model group that had been administered 0.003 mg / kg body weight or 0.01 mg / kg body weight of nadiliximab combined with levodopa for 6 consecutive days had a significantly higher defecation frequency compared to the mice in the model medium group. As shown in FIG. 9c, the administration of 0.01 mg / kg body weight of nadiliximab combined with levodopa for consecutive days significantly increased the fecal wet weight compared to the model medium group. As shown in FIG. 9d, there was no significant difference in the water content of the feces among all groups. These results indicate that the administration of nadiliximab in combination with levodopa improves constipation in the MPTP-induced Parkinson's mouse model.

[0240] • Test results - grip strength analysis after consecutive administration of levodopa in combination

[0241] On day 14, the grip strength of the mice in each group after 7 days of treatment was evaluated. As shown in FIG. 10, the mice in the model medium group had significantly lower grip strength compared to the mice in the sham model medium group, indicating impaired motor function in the MPTP-induced Parkinson's mouse model. The mice in the nadiliximab combined with levodopa administration group exhibited significantly higher grip strength compared to the mice in both the model medium group and the levodopa medium group, indicating that the consecutive administration of nadiliximab did not inhibit the beneficial effects of levodopa on motor function.

[0242] Example 4: Dose-dependent evaluation of the effects of opioid receptor antagonists in a MPTP-induced mouse Parkinson's model

[0243] A mouse model of Parkinson's disease was constructed by intraperitoneal injection of MPTP, and the efficacy of opioid receptor antagonists in treating constipation caused by MPTP was investigated.

[0244] • Test animals: C57BL / 6J mice, 7-8 weeks old, male

[0245] • Drugs: Nadiliximab mesylate, naloxegol, methylnaltrexone, MPTP, methyl cellulose, physiological saline.

[0246] • Preparation of nadiliximab mesylate solution:

[0247] Weigh the nadiliximab mesylate into a transparent test tube, then add physiological saline containing 0.5% MC, and after vortexing thoroughly, we obtain a 0.001 mg / ml solution of nadiliximab mesylate. The administration dose is 10 ml / kg.

[0248] • Preparation of naloxegol solution:

[0249] Naloxegol was weighed into the medium solution to make a 10 mg / ml solution. 1.5 ml of 10 mg / ml naloxegol solution was mixed with 3.5 mg of medium solution to obtain 5 ml of 3 mg / ml naloxegol solution. 1.5 ml of 3 mg / ml naloxegol solution was mixed with 3.5 mg of medium solution to obtain 5 ml of 1 mg / ml naloxegol solution. The dosage was 10 ml / kg.

[0250] • Preparation of methylnaltrexone solution:

[0251] Methylnaltrexone was weighed into the medium solution to make a 0.5 mg / ml solution. 1 ml of 0.5 mg / ml methylnaltrexone solution was mixed with 4 mg of double distilled water to obtain 5 ml of 0.1 mg / ml methylnaltrexone solution. 1 ml of 0.1 mg / ml methylnaltrexone solution was mixed with 4 mg of double distilled water to obtain 5 ml of 0.02 mg / ml methylnaltrexone solution. The dosage was 5 mg / kg.

[0252] • Mouse model construction, administration and evaluation:

[0253] A total of 72 mice were randomly divided into 9 groups, 8 mice in each group.

[0254] The model group was intraperitoneally injected with 30 mg / kg MPTP to the mice from the 1st day to the 7th day.

[0255] The sham group was intraperitoneally injected with normal saline to the mice from the 1st day to the 7th day.

[0256] On the 8th day, the mice were administered with the medium or the test drug, respectively.

[0257] Before the test, the mice were acclimated for 1 week, and each mouse was given a health check, including evaluation of fur, limbs and mouth, and checking whether each mouse had any abnormal signs in posture and movement.

[0258] • Table 4: Administration composition

[0259] • Fecal analysis:

[0260] On the 8th day, the mice were allowed to eat and drink freely for 2 hours after being fasted and deprived of water for 12 hours. After 2 hours, each mouse was placed in a clean individual box for 1 hour and then returned to the original cage. The feces were collected, counted and weighed, and then dried overnight at 65°C to evaluate the dry weight of the feces.

[0261] • Statistical analysis

[0262] In vivo animal test data are expressed as mean ± standard error of the mean (SEM). Statistical analysis was performed using the following methods: One Way ANOVA followed by Multiple comparison test, or Kruskal Wallis test followed by Conover test, or Two Way ANOVA followed by Dunnett's multiple comparison test. When sample size is too small or data does not conform to Gaussian distribution, non-parametric tests such as Mann-Whitney are used. (*P < 0.05, **P < 0.01, ***P < 0.001).

[0263] • Test results

[0264] As shown in Figure 11, compared with the sham model medium group, the stool frequency ratio corrected by food intake of the mice in the model medium group was significantly reduced. Compared with the model medium group, the stool frequency ratio corrected by food intake of the mice in the nadiliximab 0.01 mg / kg body weight group and the naloxegol 100 mg / kg body weight group was significantly increased.

[0265] As shown in Figure 12, compared with the sham model medium group, the feces wet weight ratio corrected by food intake of the mice in the model medium group was significantly reduced. Compared with the model medium group, the feces wet weight ratio corrected by food intake of the mice in the nadiliximab 0.01 mg / kg body weight group and the naloxegol 100 mg / kg body weight group, the methylnaltrexone 0.5 mg / kg body weight group and the methylnaltrexone 2.5 mg / kg body weight group was significantly increased.

[0266] As shown in Figure 13, compared with the sham model medium group, the feces dry weight ratio corrected by food intake of the mice in the model medium group was significantly reduced. Compared with the model medium group, the feces dry weight ratio corrected by food intake of the mice in the nadiliximab 0.01 mg / kg body weight group and the naloxegol 100 mg / kg body weight group and the methylnaltrexone 2.5 mg / kg body weight group was significantly increased.

[0267] Example 5: Efficacy evaluation in low-fiber diet-induced constipation mouse model

[0268] A constipation mouse model was constructed by inducing constipation symptoms in mice with a low-fiber diet, and the efficacy of nadiliximab in treating constipation induced by a low-fiber diet was studied.

[0269] • Test animals: C57BL / 6J mice, 7-8 weeks old, male

[0270] • Drugs: Nadiliximab tosylate, methylcellulose, physiological saline.

[0271] • Preparation of nadiliximab tosylate solution:

[0272] The natediline tosylate was weighed into a transparent test tube, then 0.5% MC physiological saline was added, and after vortexing, a 0.016 mg / ml natediline tosylate solution was obtained. 6 ml of the medium solution was mixed with 2 mg of the 0.016 mg / ml natediline tosylate solution to obtain 8 ml of a 0.004 mg / ml natediline tosylate solution. 6 ml of the medium solution was mixed with 2 mg of the 0.004 mg / ml natediline tosylate solution to obtain 8 ml of a 0.001 mg / ml natediline tosylate solution. The dose was 10 ml / kg.

[0273] • Mouse model construction, administration and evaluation:

[0274] A total of 40 mice were randomly divided into 5 groups, 8 mice in each group.

[0275] The mice in the model group were fed with low-fiber feed every day.

[0276] The mice in the sham group were fed with ordinary feed every day.

[0277] From the 2nd day to the 8th day, the mice were administered with the medium or the test drug, respectively.

[0278] Before the test, the mice were acclimated for 1 week, and each mouse was given a health check, including an assessment of the fur, limbs and mouth, and each mouse was checked for any abnormal signs of posture and movement.

[0279] • Table 5: Administration composition

[0280] • Fecal analysis:

[0281] On the 5th day, the mice were fasted for 12 hours and then administered with natediline or the medium, respectively, and then allowed to eat and drink freely for 2 hours. After 2 hours, each mouse was placed in a clean separate box for 1 hour and then returned to the original cage. The feces were collected, counted and weighed, and then dried overnight at 65°C to evaluate the dry weight of the feces.

[0282] • Statistical analysis

[0283] The results are expressed as mean ± SEM. Statistical analysis was performed using t-test, two-way ANOVA, and if significant, post-hoc Dunnett's test. When the sample size was too small or the data did not follow a Gaussian distribution, non-parametric tests such as Mann-Whitney and Kruskal-Wallis were used. (*P < 0.05, **P < 0.01, ***P < 0.001).

[0284] • Test results

[0285] As shown in Fig. 14, the number of defecation and the wet weight of feces of the model medium group mice were significantly decreased compared with the sham medium group. No difference in the number of defecation and the wet weight of feces was observed between the normethanidine group and the model medium group. This indicates that normethanidine has no effect on constipation caused by low-fiber diet.

[0286] Example 6: Clinical evaluation of the effect of normethanidine use in Parkinson's disease patients.

[0287] To evaluate the effectiveness of normethanidine use in Parkinson's disease patients in terms of constipation and motor symptoms, the following clinical study was conducted.

[0288] Parkinson's disease patients classified as 1 to 4 in Hoehn & Yahr severity, and patients with ROME IV criteria for constipation symptoms, such as an average of less than 3 spontaneous bowel movements per week, were selected as subjects. The effectiveness and safety of normethanidine were verified through clinical and biological monitoring.

[0289] The subject patients orally took 0.2 mg to 2.5 mg of normethanidine or placebo once a day. The administration period was about 1 to 4 weeks. The effectiveness of constipation symptoms was evaluated objectively using, for example, the number of spontaneous bowel movements after the first administration, the amount of change and progression in the number of spontaneous bowel movements per week after the start of administration, the number of completely spontaneous bowel movements (spontaneous bowel movements without a feeling of residual stool), the amount of change and progression in the number of completely spontaneous bowel movements per week after the start of administration, the progression of the Bristol Stool Form Scale score per week after the start of administration, the use of rescue medication, and the like. The effectiveness of motor symptoms was evaluated using, for example, the MDS Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

[0290] Example 7: Evaluation of mRNA levels of opioid-related molecules in the intestines of MPTP-induced mouse Parkinson's model

[0291] A Parkinson's disease mouse model was constructed by intraperitoneal injection of MPTP into mice, and the mRNA levels of opioid-related molecules in the intestines of MPTP model mice and control mice were evaluated.

[0292] • Test animals: C57BL / 6J mice, 7 to 8 weeks

[0293] • Drugs: MPTP, physiological saline

[0294] • Preparation of MPTP solution:

[0295] MPTP was weighed and added to physiological saline to prepare a 3 mg / mL solution, which was mixed well and stored frozen. The administration dose was 10 mL / kg of animal body weight.

[0296] • Mouse model construction, administration, and evaluation:

[0297] A total of 16 mice were randomly divided into 2 groups, 8 mice in each group.

[0298] The model group was intraperitoneally injected with 30 mg / kg of MPTP per animal weight per day from day 1 to day 7.

[0299] The sham group was intraperitoneally injected with saline per day from day 1 to day 7.

[0300] The entire study lasted for 8 days.

[0301] Table 6: Composition of administration

[0302] mRNA analysis:

[0303] On day 8, RNA was extracted from ileum and colon tissues, and the expression of each gene was determined by qPCR.

[0304] Statistical analysis

[0305] Results are expressed as mean ± standard error of the mean (SEM). Statistical analysis was performed using Mann-Whitney. Differences were considered significant when p < 0.05.

[0306] Results of the test

[0307] In the MPTP-induced Parkinsonian mouse model, it was investigated whether the expression of genes encoding opioid-related molecules (Oprm1, Oprk1, Oprd1, Penk, Pomc, and PDyn) changed.

[0308] The results showed that only Oprm1 in the colon was significantly upregulated in the model mice, and no significant changes were found in the other 5 genes in the model mice. In the ileum, no significant changes were found in all 6 genes. According to this result, the constipation in the MPTP-induced Parkinsonian mouse model may be related to the upregulation of Oprm1 expression in the colon.

Claims

1. Use of a peripheral mu opioid receptor antagonist in the manufacture of a medicament for the treatment of parkinsonism or Parkinson's disease in a patient.

2. Use according to claim 1, wherein the patient also suffers from constipation.

3. Use according to claim 1 or 2, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

4. Use of a peripheral mu opioid receptor antagonist and a dopaminergic agent in the manufacture of a medicament for the treatment of parkinsonism or Parkinson's disease in a patient.

5. Use according to claim 4, wherein the patient suffers from constipation.

6. Use according to claim 4 or 5, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

7. Use according to any one of claims 4 to 6, wherein the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine and pramipexole.

8. Use of a peripheral mu opioid receptor antagonist in the manufacture of a medicament for the treatment of constipation in a patient suffering from parkinsonism or Parkinson's disease.

9. Use according to claim 8, wherein the constipation is intractable, recurrent or refractory to conventional constipation therapies.

10. Use according to claim 8 or 9, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

11. Use of a peripheral mu opioid receptor antagonist in the manufacture of a medicament for the treatment of constipation caused by Parkinson's disease.

12. Use according to claim 11, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

13. A method of treating parkinsonism or Parkinson's disease in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent.

14. A method according to claim 13, wherein the patient suffers from constipation.

15. A method according to claim 13 or 14, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of naldephine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methylnaltrexone or a pharmaceutically acceptable salt thereof.

16. A method according to any one of claims 13 to 15, wherein the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine and pramipexole.

17. A pharmaceutical composition for use in the treatment of Parkinsonism or Parkinson's disease in a patient, the pharmaceutical composition comprising a peripheral mu opioid receptor antagonist and optionally a dopaminergic agent and one or more pharmaceutically acceptable excipients.

18. The pharmaceutical composition for use according to claim 17, wherein the patient suffers from constipation.

19. The pharmaceutical composition for use according to claim 17 or 18, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of nalde- midine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methadone or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition for use according to any one of claims 17 to 19, wherein the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine and pramipexole.

21. A peripheral mu opioid receptor antagonist for use in the treatment of Parkinsonism or Parkinson's disease in a patient.

22. The peripheral mu opioid receptor antagonist for use according to claim 21, wherein the patient suffers from constipation.

23. The peripheral mu opioid receptor antagonist for use according to claim 21 or 22, wherein the peripheral mu opioid receptor antagonist is selected from the group consisting of nalde- midine or a pharmaceutically acceptable salt thereof, alvimopan or a pharmaceutically acceptable salt thereof, naloxegol or a pharmaceutically acceptable salt thereof and methadone or a pharmaceutically acceptable salt thereof.

24. The peripheral mu opioid receptor antagonist for use according to any one of claims 21 to 23, wherein the peripheral mu opioid receptor antagonist is administered in combination with a dopaminergic agent.

25. The peripheral mu opioid receptor antagonist for use according to claim 24, wherein the dopaminergic agent is selected from the group consisting of levodopa, carbidopa, selegiline, bromocriptine, piribedil, amantadine and pramipexole.

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