Method for treating amyotrophic lateral sclerosis and method for suppressing progress of amyotrophic lateral sclerosis

Abstract

To provide a method for treating amyotrophic lateral sclerosis.SOLUTION: A method for treating amyotrophic lateral sclerosis includes administering an effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof to a patient who is in need of treatment and meets two or more features selected from a group of identified features.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is based on and claims the benefit of priority to U.S. Application No. 62 / 567,873, filed October 4, 2017, which is based on and claims the benefit of priority to International Application No. PCT / US2018 / 020184, filed February 28, 2018, the disclosures of which are incorporated herein by reference in their entireties. Technical Field The present invention relates to a method for treating amyotrophic lateral sclerosis (hereinafter also referred to as ALS) or suppressing the progression of the disease, and a method for treating symptoms caused by ALS or suppressing the progression of the symptoms. [Background technology]

[0002] Riluzole, which inhibits glutamate transmission in glutamatergic neurons, has been approved as an effective drug for slowing the progression of ALS. However, it has also been reported that the efficacy of riluzole cannot be confirmed. Therefore, the evaluation of this drug is inconsistent. Summary of the Invention [Problem to be solved by the invention]

[0003] ALS, a type of motor neuron disease, is an incurable disease. ALS begins with early symptoms such as hand weakness, finger motor impairment and upper limb fasciculations. ALS then has muscle atrophy and / or weakness, bulbar paralysis and muscle fasciculations, eventually resulting in respiratory failure. Depending on the site of onset, ALS is classified into upper limb, bulbar, lower limb and mixed types. In all these types, as the condition progresses, muscle groups throughout the body are affected. [Means for solving the problem]

[0004] Summary of the invention A method for treating early stage amyotrophic lateral sclerosis according to one embodiment of the present invention comprises administering an effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof to a patient having at least two of identified characteristics 1 to 55. Identified characteristics 1 to 55 are selected from the following: 1. Gait abnormalities 2. Aldolase test 3. Antinuclear antibody (ANA) test 4. Cervical spondylosis without myelopathy 5. Creatine Kinase (CK): (CPK) Test 6. Cyanocobalamin (Vitamin B12) Test 7. Cervical disc degeneration 8. Cervical disc displacement without myelopathy 9. Swallowing problems 10. Folic acid; serum test 11. Serum immunofixation electrophoresis test 12. Magnetic resonance imaging examination 13.Manual therapy techniques 14. Muscle Weakness 15.Needle electromyography 16. Acquired deformities of the ankle and foot 17. Fatigue and fatigue 18.Physical Therapy Evaluation 19. Serum protein electrophoretic fractionation and quantitative testing 20. Erythrocyte Sedimentation Rate Test 21. Cervical spinal stenosis 22. Swallowing function test 23. Therapeutic procedures for neuromuscular reeducation 24. Therapeutic treatment for therapeutic exercises 25. Thyroid-stimulating hormone (TSH) test 26. Unspecified hereditary and idiopathic peripheral neuropathy 27. Nervous system disorders 28. Inherited and degenerative nervous system conditions 29. Connective tissue diseases 30. Non-traumatic joint diseases 31. Multiple sclerosis 32. Paraplegia 33. Paralysis 34. Other Neurological Diagnostic Procedures 35. Durable Medical Equipment (DME) and Consumables 36. Physical therapy 37. Laryngoscopy 38. Spinal tap 39. Speech therapy 40. Riluzole 41. Baclofen 42. Pyridostigmine 43. Anticonvulsants 44. Diazepam 45. Hydrocodone 46. ​​Propoxyphene 47. Sympathomimetic drugs 48. Glycopyrrolate 49. Prednisone 50. Pregabalin 51. Clonazepam 52. Tizanidine 53. Levodopa or Carbidopa 54. Quinine 55. Tolterodine

[0005] According to another embodiment of the present invention, a method for inhibiting the progression of amyotrophic lateral sclerosis in an early stage comprises administering an effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof to a patient having at least two of the identified characteristics 1 to 55. The identified characteristics 1 to 55 are selected from the following: 1. Gait abnormalities 2. Aldolase test 3. Antinuclear antibody (ANA) test 4. Cervical spondylosis without myelopathy 5. Creatine Kinase (CK): (CPK) Test 6. Cyanocobalamin (Vitamin B12) Test 7. Cervical disc degeneration 8. Cervical disc displacement without myelopathy 9. Swallowing problems 10. Folic acid; serum test 11. Serum immunofixation electrophoresis test 12. Magnetic resonance imaging examination 13.Manual therapy techniques 14. Muscle Weakness 15.Needle electromyography 16. Acquired deformities of the ankle and foot 17. Fatigue and fatigue 18.Physical Therapy Evaluation 19. Serum protein electrophoretic fractionation and quantitative testing 20. Erythrocyte Sedimentation Rate Test 21. Cervical spinal stenosis 22. Swallowing function test 23. Therapeutic procedures for neuromuscular reeducation 24. Therapeutic treatment for therapeutic exercises 25. Thyroid-stimulating hormone (TSH) test 26. Unspecified hereditary and idiopathic peripheral neuropathy 27. Nervous system disorders 28. Inherited and degenerative nervous system conditions 29. Connective tissue diseases 30. Non-traumatic joint diseases 31. Multiple sclerosis 32. Paraplegia 33. Paralysis 34. Other Neurological Diagnostic Procedures 35. Durable Medical Equipment (DME) and Consumables 36. Physical therapy 37. Laryngoscopy 38. Spinal tap 39. Speech therapy 40. Riluzole 41. Baclofen 42. Pyridostigmine 43. Anticonvulsants 44. Diazepam 45. Hydrocodone 46. ​​Propoxyphene 47. Sympathomimetic drugs 48. Glycopyrrolate 49. Prednisone 50. Pregabalin 51. Clonazepam 52. Tizanidine 53. Levodopa or Carbidopa 54. Quinine 55. Tolterodine

[0006] According to yet another embodiment of the present invention, a method for inhibiting the progression of amyotrophic lateral sclerosis in an early stage comprises administering an effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof to a patient having at least two of the identified characteristics 1 to 11. The identified characteristics 1 to 11 are selected from the following: 1. Fatigue and tiredness or muscle weakness 2. Non-traumatic joint diseases or acquired deformities of the ankle and foot 3. Connective tissue diseases 4.Skin diseases 5. Nervous System Disorders 6. Any change in speaking ability 7. Outpatient consultations with a physiotherapist, neurologist, orthopedic surgeon, gastroenterologist, or ENT specialist 8. Magnetic resonance imaging or needle electromyography 9. Riluzole, baclofen, pyridostigmine, anticonvulsants 10. Unusual increase in utilization of medical resources 11. Creatine Kinase (CK): (CPK) test, Cyanocobalamin (Vitamin B12) test, or Antinuclear Antibody (ANA) test.

[0007] A more complete appreciation of the present invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description when considered in conjunction with the accompanying drawings, in which: [Brief description of the drawings]

[0008] [Figure 1] 1 shows the top 20 2-feature combinations according to one embodiment of the present invention based on mutual information rank and value for a period of 3-6 months before a patient was diagnosed with ALS. [Diagram 2]1 shows the top 20 2-feature combinations according to one embodiment of the present invention based on mutual information rank and value for the period 6-9 months before a patient was diagnosed with ALS. [Diagram 3] 1 shows the top 20 2-feature combinations according to one embodiment of the present invention based on mutual information rank and value for a period of 9-12 months before a patient was diagnosed with ALS. [Figure 4] 1 shows the top 20 2-feature combinations according to one embodiment of the present invention based on mutual information rank and value for the period 12-18 months before the patient was diagnosed with ALS. [Diagram 5] 1 shows selected 3-feature combinations according to one embodiment of the present invention by mutual information rank. [Figure 6] 1 shows selected 4-feature combinations according to one embodiment of the present invention by mutual information rank. [Figure 7] 1 shows selected 5-feature combinations according to one embodiment of the present invention by mutual information rank. [Figure 8] The score distributions of the target (ALS patients) and control (control patients) of the model are shown. [Figure 9] ROC (Receiver Operating Characteristic) curves are shown; true positive rate, false positive rate, and PPV of the model vs. threshold. [Figure 10] The confusion matrix is ​​shown when the probability threshold is set to 0.1. [Figure 11] The confusion matrix is ​​shown when the probability threshold is set to 0.9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Detailed Description of the Preferred Embodiments DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Embodiments will now be described with reference to the accompanying drawings, in which like reference numerals indicate corresponding or identical elements throughout the various drawings.

[0010] The causative factors of ALS have not yet been fully elucidated. The following hypotheses have been proposed as the main causative factors of ALS: (1) autoimmune theory (appearance of autoantibodies against Ca channels); (2) excess excitatory amino acids and / or intoxication theory (increase in extracellular glutamate and impaired transport of glutamate); (3) oxidative stress disorder theory (neuronal damage caused by genetic abnormalities of Cu / Zn superoxide dismutase (SOD) and free radicals); (4) cytoskeleton disorder theory (accumulation of neurofilaments and appearance of inclusions in motor neurons); and (5) deficiency of neurotrophic factors.

[0011] Examples of symptoms caused by ALS include clinical symptoms such as respiratory depression, speech disorder, swallowing disorder, and limb movement disorder. In the present invention, respiratory depression is an example to be selected. This term should be interpreted in the broadest sense as long as it fits the above definition, and should not be interpreted as being limited to the difference in disease name. A doctor can diagnose whether it is a disease corresponding to ALS.

[0012] Furthermore, a preferred example of the treatment and / or inhibition of progression of ALS or symptoms caused by ALS is the inhibition of decline in respiratory function in amyotrophic lateral sclerosis.

[0013] The active ingredient of the drug of the present invention is 3-methyl-1-phenyl-2-pyrazolin-5-one. 3-methyl-1-phenyl-2-pyrazolin-5-one can be represented by the following structural formula. 3-methyl-1-phenyl-2-pyrazolin-5-one has a tautomer represented by the following structural formula. However, any of these isomers can be used as the active ingredient of the drug of the present invention. chemical formula 1 [ka]

[0014] When a disease is found in the human body, a doctor may administer an appropriate treatment. Drug therapy is also one of the treatments. However, drug therapy may require the administration of a drug until the disease is cured. In contrast, for the drug and method of the embodiment of the present invention, two or more 14-day drug holidays are provided during the drug therapy period, i.e., a unit period including an administration period and a drug holiday is repeated two or more times. Here, when the administration period and the drug holiday are repeated two or more times, the end of this period is necessarily a drug holiday. However, it is not necessary to provide a final drug holiday. That is, for example, when the administration period and the drug holiday are repeated twice, this is the case of "administration period, drug holiday, administration period, drug holiday". However, the case of "administration period, drug holiday, and administration period" in which a final drug holiday is not provided is also included in the embodiment of the present invention. Furthermore, in the embodiment of the present invention, a drug holiday is a period during which no drug is administered for seven or more consecutive days.

[0015] In an embodiment of the present invention, the administration period is 14 days or includes 10 days out of 14 days. 10 days out of 14 days means any 10 days out of 14 consecutive days. The 10 days during which the drug is administered are 10 consecutive days or 10 non-consecutive days separated by 1-4 days during which the drug is not administered. The administration period can be selected based on the patient's condition.

[0016] Preferably, the drug holiday in this embodiment of the invention is 14 days.

[0017] When a 14-day administration period and a 14-day drug holiday period are repeated, the number of repetitions is not particularly limited as long as the number of repetitions is 2 or more. However, the number of repetitions is preferably 2 to 12 times, and more preferably 2 to 6 times.

[0018] When a 10-day administration period and a 14-day drug holiday period are repeated after the first 14-day administration period and the first 14-day drug holiday period, the number of times the 10-day administration period and the first 14-day drug holiday period are repeated is not particularly limited as long as the number of times is 1 or more. However, the number of times is preferably 1 to 11, and more preferably 1 to 5.

[0019] In another embodiment, administration of the drug can be repeated daily or nearly daily without providing a drug holiday.

[0020] In the administration of the active ingredient, the administration route is not particularly limited, and the active ingredient can be administered orally or parenterally. Furthermore, bolus administration and continuous administration are possible. In the case of continuous administration, intravenous administration by drip infusion, transdermal administration, oral administration using sublingual tablets, oral and rectal administration using sustained release preparations, etc. can be used. However, intravenous administration by drip infusion is preferred. When performing bolus administration by injection or intravenous administration by drip infusion, for example, the injections described in JP-A-63-132833 and JP-A-2011-62529 can be used. The entire disclosure of these documents is incorporated herein by reference.

[0021] The daily dose of the active ingredient can be appropriately selected depending on conditions such as the age and condition of the patient. In the case of intravenous administration by injection, which provides an administration period and a withdrawal period, the amount of 3-methyl-1-phenyl-2-pyrazolin-5-one (when the active ingredient is 3-methyl-1-phenyl-2-pyrazolin-5-one, the amount of 3-methyl-1-phenyl-2-pyrazolin-5-one; when the active ingredient is a physiologically acceptable salt of 3-methyl-1-phenyl-2-pyrazolin-5-one, the equivalent amount of 3-methyl-1-phenyl-2-pyrazolin-5-one) is preferably about 15 to 240 mg, more preferably about 30 to 180 mg, even more preferably about 60 to 120 mg, and particularly preferably about 60 mg, for adults. When 3-methyl-1-phenyl-2-pyrazolin-5-one is administered orally, the dose is preferably substantially equivalent to that of intravenous administration in terms of pharmacokinetics. A specific example is a dose at which the time-dependent change in the concentration of the administered 3-methyl-1-phenyl-2-pyrazoline or its physiologically acceptable salt in plasma of 3-methyl-1-phenyl-2-pyrazolin-5-one is found to be substantially equivalent. Examples of oral dosage forms include oral administration using suspensions, oral films, sublingual tablets, and sustained-release formulations. For adults, the daily dose of 3-methyl-1-phenyl-2-pyrazolin-5-one is preferably about 240 mg, about 800 mg, about 1,600 mg, about 2,400 mg, about 3,600 mg, and more preferably about 240 to 3,600 mg, such as about 800 to 2,400 mg.

[0022] When intravenous administration by injection is repeated daily or nearly daily without providing a drug holiday, the daily dose of 3-methyl-1-phenyl-2-pyrazolin-5-one is preferably about 60 mg, about 120 mg, or about 180 mg for an adult, and particularly preferably about 60 mg or about 120 mg.

[0023] When 3-methyl-1-phenyl-2-pyrazolin-5-one is administered orally, the daily dose of 3-methyl-1-phenyl-2-pyrazolin-5-one is preferably about 240 to 3,600 mg, such as about 240 mg, about 800 mg, about 1,600 mg, about 2,400 mg, about 3,600 mg, and more preferably about 800 to 2,400 mg, for an adult.

[0024] During the drug administration period, the number of times of administration per day is not limited, and the preferred number of times of administration per day can be selected while observing the condition of the patient.However, considering the burden on the patient, the number of times of administration per day is preferably 3, 2 and 1, and more preferably 1.

[0025] In the case of intravenous administration by injection, the administration rate is about 0.5 to 5 mg / min, about 0.5 to 1 mg / min, or about 1 to 5 mg / min in terms of the amount of 3-methyl-1-phenyl-2-pyrazolin-5-one, and in terms of time, about 15 to 480 minutes, and preferably about 30 to 120 minutes, more preferably about 30 to 60 minutes, and even more preferably about 60 minutes.

[0026] With respect to a drug, method of treatment, or method of inhibiting disease progression according to one embodiment of the present invention, a patient undergoing drug therapy has at least two of the following identified features 1 to 55: 1. Gait abnormalities 2. Aldolase test 3. Antinuclear antibody (ANA) test 4. Cervical spondylosis without myelopathy 5. Creatine Kinase (CK): (CPK) Test 6. Cyanocobalamin (Vitamin B12) Test 7. Cervical disc degeneration 8. Cervical disc displacement without myelopathy 9. Swallowing problems 10. Folic acid; serum test 11. Serum immunofixation electrophoresis test 12. Magnetic resonance imaging examination 13.Manual therapy techniques 14. Muscle Weakness 15.Needle electromyography 16. Acquired deformities of the ankle and foot 17. Fatigue and fatigue 18.Physical Therapy Evaluation 19. Serum protein electrophoretic fractionation and quantitative testing 20. Erythrocyte Sedimentation Rate Test 21. Cervical spinal stenosis 22. Swallowing function test 23. Therapeutic procedures for neuromuscular reeducation 24. Therapeutic treatment for therapeutic exercises 25. Thyroid-stimulating hormone (TSH) test 26. Unspecified hereditary and idiopathic peripheral neuropathy 27. Nervous system disorders 28. Inherited and degenerative nervous system conditions 29. Connective tissue diseases 30. Non-traumatic joint diseases 31. Multiple sclerosis 32. Paraplegia 33. Paralysis 34. Other Neurological Diagnostic Procedures 35. Durable Medical Equipment (DME) and Consumables 36. Physical therapy 37. Laryngoscopy 38. Spinal tap 39. Speech therapy 40. Riluzole 41. Baclofen 42. Pyridostigmine 43. Anticonvulsants 44. Diazepam 45. Hydrocodone 46. ​​Propoxyphene 47. Sympathomimetic drugs 48. Glycopyrrolate 49. Prednisone 50. Pregabalin 51. Clonazepam 52. Tizanidine 53. Levodopa or Carbidopa 54. Quinine 55. Tolterodine

[0027] "Gait abnormality" means that the patient has been diagnosed with or has symptoms corresponding to the disorder "gait abnormality" as designated by ICD-9 code 781.2.

[0028] "Aldolase test" means that the patient is receiving "aldolase" treatment as indicated by CPT code 82085 or an equivalent treatment.

[0029] "Antinuclear antibody (ANA) test" means that the patient is receiving treatment for "Antinuclear antibody (ANA)" as indicated by CPT code 86038 or an equivalent treatment.

[0030] "Cervical spondylosis" means that the patient has been diagnosed with or has symptoms corresponding to the disease "cervical spondylosis without myelopathy," as designated by ICD-9 code 721.0.

[0031] "Cyanocobalamin (vitamin B12) test" means that the patient is receiving treatment with "Cyanocobalamin (vitamin B12)" as indicated by CPT code 82607 or an equivalent treatment.

[0032] "Cervical disc degeneration" means that the patient has been diagnosed with or has symptoms corresponding to the disease "cervical disc degeneration," as designated by ICD-9 code 722.4.

[0033] "Cervical disc displacement without myelopathy" means that the patient has been diagnosed with or has symptoms corresponding to the disease "cervical disc displacement without myelopathy," as designated by ICD-9 code 722.0.

[0034] "Dysphagia" means that the patient has been diagnosed with or has symptoms corresponding to the disorder "Dysphagia; unspecified," as designated by ICD-9 code 787.20.

[0035] "Folate; serum" means that the patient is receiving a "Folate; serum" treatment as indicated by CPT code 82746 or an equivalent treatment.

[0036] "Serum immunofixation electrophoresis test" means that the patient has undergone a procedure designated by CPT code 86334, "Immunofixation electrophoresis; serum," or an equivalent procedure.

[0037] A "magnetic resonance imaging examination" is when a patient undergoes a procedure indicated by CPT code A9579, which is "injection; gadolinium-based magnetic resonance imaging agent; not specified (nos); per ml," a procedure indicated by CPT code 70551, which is "magnetic resonance (e.g., proton) imaging; brain (including brain stem); no contrast; followed by contrast and subsequent sequences," a procedure indicated by CPT code 70553, which is "magnetic resonance (e.g., proton) imaging; brain (including brain stem); no contrast; followed by contrast and subsequent sequences," and a procedure indicated by CPT code 70554, which is "magnetic resonance (e.g., proton) imaging; brain (including brain stem); no contrast; followed by contrast and subsequent sequences." " means the patient has undergone a procedure designated by CPT code 72141, "magnetic resonance (e.g., proton) imaging; spinal canal and contents; cervical; no contrast," or a procedure designated by CPT code 72148, "magnetic resonance (e.g., proton) imaging; spinal canal and contents; lumbar; no contrast," or a procedure designated by CPT code 72156, "magnetic resonance (e.g., proton) imaging; spinal canal and contents; no contrast; followed by contrast and subsequent sequences; cervical," or an equivalent procedure.

[0038] "Manual therapy techniques" means the patient is receiving a procedure designated by CPT code 97140, "Manual therapy techniques (e.g., mobilization / manipulation; manual lymphatic drainage; manual traction); one or more areas; 15 minutes each" or its equivalent.

[0039] "Muscle weakness" means that the patient has been diagnosed with or has symptoms corresponding to the disease "Muscle weakness (generalized)" as designated by ICD-9 code 728.87.

[0040] "Needle EMG test" means the patient has undergone a "Needle EMG; one limb with or without involved paraspinal regions" procedure, as indicated by CPT code 95860, or a "Needle EMG; two limbs with or without involved paraspinal regions" procedure, as indicated by CPT code 95861, or an equivalent procedure.

[0041] "Other acquired deformities of the ankle and foot" means that the patient has been diagnosed with or has symptoms corresponding to the disorder "Other acquired deformities of the ankle and foot," as designated by ICD-9 code 736.79.

[0042] "Fatigue and fatigue" means that the patient has been diagnosed with or has symptoms corresponding to the illness "other fatigue and fatigue" as indicated by ICD-9 code 780.79.

[0043] "Physical therapy evaluation" means that the patient is undergoing a "physical therapy evaluation" procedure as indicated by CPT code 97001 or an equivalent procedure.

[0044] "Serum protein electrophoretic fractionation and quantification test" means that the patient has undergone a procedure designated by CPT code 84165, "Protein; Electrophoretic fractionation and quantification; Serum," or an equivalent procedure.

[0045] "Erythrocyte sedimentation rate test" means that the patient is undergoing a "sedimentation rate; red blood cells; automated" procedure indicated by CPT code 85652 or a "sedimentation rate; red blood cells; non-automated" procedure indicated by CPT code 85651, or an equivalent procedure.

[0046] "Cervical spinal stenosis" means that the patient has been diagnosed with or has symptoms corresponding to the disease "cervical spinal stenosis," as designated by ICD-9 code 723.0.

[0047] "Swallowing function; cineradiography / videoradiography" means that the patient has undergone a procedure designated by CPT code 74230, "Swallowing function; cineradiography / videoradiography," or an equivalent procedure.

[0048] "Therapeutic treatment for neuromuscular reeducation of movement; balance; coordination; kinesthetics; posture; and / or proprioception for sitting and / or standing activities" means the patient is receiving a treatment or equivalent indicated by CPT code 97112, "Therapeutic treatment; one or more areas; 15 minutes each; neuromuscular reeducation of movement; balance; coordination; kinesthetics; posture; and / or proprioception for sitting and / or standing activities."

[0049] "Therapeutic treatment for therapeutic exercises to develop strength and endurance; range of motion and flexibility" means the patient is receiving treatment designated by CPT code 97110, "Therapeutic treatment; one or more areas; 15 minutes each; Therapeutic exercises to develop strength and endurance; range of motion and flexibility," or an equivalent treatment.

[0050] "Thyroid-stimulating hormone (TSH) test" means that the patient is receiving a "Thyroid-stimulating hormone (TSH)" treatment, as indicated by CPT code 84443, or an equivalent treatment.

[0051] "Unspecified hereditary and idiopathic peripheral neuropathy" means that the patient has been diagnosed with or has symptoms corresponding to the disease "Unspecified hereditary and idiopathic peripheral neuropathy," as designated by ICD-9 code 356.9.

[0052] By "nervous system disorder" it is meant that the patient has been diagnosed with or has symptoms corresponding to the illness "other nervous system disorder."

[0053] "Inherited and degenerative nervous system conditions" means that the patient has been diagnosed with or has symptoms corresponding to an "Other inherited and degenerative nervous system conditions" disease.

[0054] By "connective tissue disorder" it is meant that the patient has been diagnosed with or has symptoms corresponding to the disorder "connective tissue disorder."

[0055] "Non-traumatic joint disease" means that the patient has been diagnosed with or has symptoms corresponding to the disease "Other non-traumatic joint disease."

[0056] "Multiple sclerosis" means that a patient has been diagnosed with or has symptoms corresponding to the disease "multiple sclerosis."

[0057] "Paraplegic" means that the patient has been diagnosed with or has symptoms corresponding to the disease "paraplegia."

[0058] "Paralysis" means that the patient has been diagnosed with or has symptoms corresponding to the disease "Paralysis."

[0059] "Other nervous system diagnostic procedures" means that the patient is undergoing a procedure or an equivalent of "Other nervous system diagnostic procedures."

[0060] "Durable medical equipment (DME) and consumables" means that the patient is receiving a "DME and consumables" procedure or an equivalent procedure.

[0061] "Physical therapy" means that the patient is undergoing "physical therapy" treatment or an equivalent treatment.

[0062] "Laryngoscopy" means that a patient is undergoing a "laryngoscopy" procedure or an equivalent procedure.

[0063] "Spinal tap" means that a patient has undergone a "spinal tap" procedure or an equivalent procedure.

[0064] "Speech ability treatment" means that the patient is receiving a "speech ability treatment" procedure or an equivalent procedure.

[0065] "Riluzole" means that the patient is prescribed a medication that contains "riluzole" as the active ingredient.

[0066] "Baclofen" means that the patient has been prescribed "baclofen."

[0067] "Pyridostigmine" means that the patient is prescribed a medication that contains "pyridostigmine" as an active ingredient.

[0068] "Anticonvulsant" means that the patient is prescribed a medication that includes an active ingredient that is classified as an "anticonvulsant."

[0069] "Diazepam" means that the patient has been prescribed a medication that contains "diazepam" as an active ingredient.

[0070] "Hydrocodone" means that the patient is prescribed a medication that contains "hydrocodone" as an active ingredient.

[0071] "Propoxyphene" means that the patient is prescribed a medication that contains "propoxyphene" as an active ingredient.

[0072] "Propoxyphene" means that the patient is prescribed a medication that contains a "sympathomimetic drug" as the active ingredient.

[0073] "Glycopyrrolate" means that the patient is prescribed a medication that contains "glycopyrrolate" as an active ingredient.

[0074] "Prednisone" means that the patient is prescribed a medication that contains "prednisone" as an active ingredient.

[0075] "Pregabalin" means that the patient is prescribed a medication that contains "pregabalin" as an active ingredient.

[0076] "Clonazepam" means that the patient has been prescribed a medication that contains "Clonazepam" as the active ingredient.

[0077] "Tizanidine" means that the patient has been prescribed a medication that contains "tizanidine" as an active ingredient.

[0078] "Levodopa or carbidopa" means that the patient is prescribed a medication that includes "levodopa" as an active ingredient, or a medication that includes "carbidopa" as an active ingredient.

[0079] "Quinine" means that the patient is prescribed a medication that contains "quinine" as an active ingredient.

[0080] "Tolterodine" means that the patient has been prescribed a medication that contains "tolterodine" as the active ingredient.

[0081] Patients having the characteristics identified by the present invention are more likely to be ALS patients than other patients, and administration of a pharmaceutical agent comprising 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof to the patient is expected to be particularly effective.

[0082] Furthermore, with respect to a drug, method of treatment or method of inhibiting disease progression according to one embodiment of the present invention, the patient undergoing drug therapy has one or more of the following characteristics: - skin diseases - Any change in ability to speak - Outpatient consultations with a physiotherapist, neurologist, orthopedic surgeon, gastroenterologist, or ENT specialist - Unusually increased utilization of medical resources (i.e., increased hospital visits, procedures (MRI, EMG), new diagnoses, prescriptions) -Excessively high utilization of health care

[0083] A change in speech that is noticeable, noticeable, discernible, and / or recognized by health care professionals such as doctors, nurses, therapists, and health care providers.

[0084] A noticeable, significant, discernible, and / or perceived abnormal increase in utilization of health care resources by health care professionals such as doctors, nurses, therapists, and health care providers.

[0085] Noticeable, significant, discernible, and / or perceived abnormally high utilization of health care by health care professionals such as doctors, nurses, therapists, and health care providers.

[0086] With respect to the drug, the method of treatment, or the method of inhibiting progression of a disease according to one embodiment of the present invention, it is preferred that a patient undergoing drug therapy has at least two of Features 1 to 55 during a period of time prior to receiving a first dose of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof. The period of time may be a period of time within 120 months prior to receiving the first dose. More preferably, the period of time is a period of time within 96 months, 72 months, 60 months, 48 ​​months, 36 months, 24 months, or 12 months prior to receiving the first dose.

[0087] The start and end of the period are not particularly limited as long as it is within 120 months before the first administration. The period may include one period or two or more periods, and the length of the periods may be the same or different. The number of periods is not particularly limited, but is preferably 1 to 20, more preferably 1 to 15, and even more preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. The length of the period is not particularly limited, but may be 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 30 months, 36 months, 48 ​​months, 60 months, 72 months, 96 months, and 120 months. In some embodiments, at least one of the following periods: 0-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 24-36 months, and 36-48 months prior to receiving the first dose, the patient receiving the drug therapy has at least two of Features 1-55.

[0088] In another embodiment of the present invention, with respect to a drug, a method of treatment, or a method of inhibiting progression of a disease, a patient undergoing drug therapy has at least one pair of characteristics identified in Pair 1 to Pair 46 below: 1. Features (1) and (14) 2. Features (1) and (18) 3. Features (1) and (30) 4. Features (2) and (5) 5. Features (3) and (5) 6. Features (3) and (6) 7. Features (3) and (18) 8. Features (3) and (31) 9. Features (4) and (14) 10. Features (5) and (6) 11. Features (5) and (18) 12. Features (5) and (20) 13. Features (5) and Features (25) 14. Features (5) and (26) 15. Features (5) and Features (31) 16. Features (6) and (10) 17. Features (6) and (13) 18. Features (6) and (14) 19. Features (6) and (16) 20. Features (6) and (18) 21. Features (6) and (20) 22. Features (6) and (24) 23. Features (6) and (26) 24. Features (6) and (31) 25. Features (7) and (14) 26. Features (8) and (14) 27. Features (9) and (28) 28. Features (11) and (13) 29. Features (12) and (14) 30. Features (13) and (16) 31. Features (14) and (15) 32. Features (14) and (18) 33. Features (14) and (20) 34. Features (14) and Features (22) 35. Features (14) and Features (27) 36. Features (15) and (21) 37. Features (17) and Features (30) 38. Features (18) and (19) 39. Features (18) and (21) 40. Features (18) and Features (22) 41. Features (18) and Features (30) 42. Features (18) and Features (31) 43. Features (18) and Features (32) 44. Features (21) and Features (30) 45. Features (23) and Features (30) 46. ​​Features (29) and Features (30)

[0089] Characteristic (1) is "abnormal gait"; Characteristic (2) is "aldolase"; Characteristic feature (3) is "antinuclear antibodies (ANA)"; Characteristic (4) is "cervical spondylosis without myelopathy"; Feature (5) is "creatine kinase (CK); (CPK); total"; Characteristic (6) is "cyanocobalamin (vitamin B12)"; Feature (7) is "cervical disc degeneration"; Feature (8) is "displacement of cervical disc without myelopathy"; Feature (9) is "Dysphagia; unspecified"; Characteristic (10) is "Folic acid; serum"; The characteristic (11) is "injection; gadolinium-based magnetic resonance imaging agent; not otherwise specified (nos); per 1 ml"; Feature (12) is "magnetic resonance (e.g., proton) imaging; brain (including brain stem); no contrast agent"; Feature (13) is "magnetic resonance (e.g., proton) imaging; brain (including brain stem); no contrast agent; followed by contrast agent and subsequent sequence"; Characteristics (14) are "magnetic resonance (e.g., proton) imaging; spinal canal and contents; cervical; no contrast"; Characteristics (15) are "magnetic resonance (e.g., proton) imaging; spinal canal and contents; lumbar region; no contrast"; Feature (16) is "magnetic resonance (e.g., proton) imaging; spinal canal and contents; no contrast; followed by contrast and subsequent sequences; cervical"; Characteristics (17) were "manual therapy techniques (e.g., mobilization / manipulation; manual lymphatic drainage; manual traction); one or more areas; 15 minutes each"; Characteristic (18) is "muscle weakness (generalized)"; Characteristics (19) are "Needle electromyography; one limb with or without involved paravertebral regions"; Characteristics (20) are "needle electromyography; two limbs with or without involved paravertebral regions"; Characteristic feature (21) is "other acquired deformities of the ankle and foot"; Characteristic (22) is "other malaise and fatigue"; Feature (23) is “Physical Therapy Assessment”; Characteristics (24) are "Protein; electrophoretic fractionation and quantification; serum"; Characteristics (25) are "sedimentation rate; red blood cells; automatic"; Characteristics (26) are "sedimentation rate; red blood cells; non-autonomous"; Feature (27) is "cervical spinal stenosis"; Feature (28) is "Swallowing function; by cineradiography / videoradiography"; The characteristics (29) are "therapeutic procedures; one or more areas; 15 minutes each; neuromuscular re-education of movement; balance; coordination; kinesthetics; posture; and / or proprioception for sitting and / or standing activities"; Characteristics (30) are "therapeutic treatment; one or more areas; 15 minutes each; therapeutic exercises to develop strength and endurance; range of motion and flexibility"; Characteristic (31) is "Thyroid-stimulating hormone (TSH)"; Characteristic feature (32) is "unspecified hereditary and idiopathic peripheral neuropathy."

[0090] Further, with respect to the drug, method of treatment or method of inhibiting disease progression according to yet another embodiment, a patient undergoing drug therapy has at least three, preferably at least four, and more preferably at least five of the following identified characteristics: 1. Fatigue and tiredness or muscle weakness 2. Non-traumatic joint diseases or acquired deformities of the ankle and foot 3. Connective tissue diseases 4.Skin diseases 5. Nervous System Disorders 6. Any change in speaking ability 7. Outpatient consultation with a physiotherapist, neurologist, orthopedic surgeon, gastroenterologist, or ENT specialist 8. Magnetic resonance imaging or needle electromyography 9. Riluzole, baclofen, pyridostigmine, anticonvulsants 10. Unusual increase in utilization of medical resources 11. Creatine Kinase (CK): (CPK) test, Cyanocobalamin (Vitamin B12) test, or Antinuclear Antibody (ANA) test

[0091] With respect to the drug, method of treatment or method of inhibiting disease progression of another embodiment, at least one of 0-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 24-36 months, and 36-48 months prior to receiving the first dose of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof, the patient receiving the drug therapy has at least three, preferably at least four, and more preferably at least five of the following identified characteristics: 1. Fatigue and tiredness or muscle weakness 2. Non-traumatic joint diseases or acquired deformities of the ankle and foot 3. Connective tissue diseases 4.Skin diseases 5. Nervous System Disorders 6. Any change in speaking ability 7. Outpatient consultations with a physiotherapist, neurologist, orthopedic surgeon, gastroenterologist, or ENT specialist 8. Magnetic resonance imaging or needle electromyography 9. Riluzole, baclofen, pyridostigmine, anticonvulsants 10. Unusual increase in utilization of medical resources 11. Creatine Kinase (CK): (CPK) test, Cyanocobalamin (Vitamin B12) test, or Antinuclear Antibody (ANA) test

[0092] In this embodiment, a weighting may be performed for each identified feature by appropriately selecting a value between 0 and 1 for each identified feature, such that the sum of the values ​​of the identified features is 3 or more, preferably 4 or more, and more preferably 5 or more, for at least one of the periods 0-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 24-36 months, and 36-48 months for patients undergoing drug therapy prior to receiving the first dose of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof.

[0093] Further, with respect to a drug, method of treatment or method of inhibiting progression of a disease according to another embodiment, the total number of the following identified characteristics possessed by a patient undergoing drug therapy in a period of 0-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 24-36 months, and 36-48 months prior to receiving the first dose of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof is at least 15, preferably at least 20, and more preferably at least 25:

[0094] 1. Fatigue and tiredness or muscle weakness 2. Non-traumatic joint diseases or acquired deformities of the ankle and foot 3. Connective tissue diseases 4.Skin diseases 5. Nervous System Disorders 6. Any change in speaking ability 7. Outpatient consultations with a physiotherapist, neurologist, orthopedic surgeon, gastroenterologist, or ENT specialist 8. Magnetic resonance imaging or needle electromyography 9. Riluzole, baclofen, pyridostigmine, anticonvulsants 10. Unusual increase in utilization of medical resources 11. Creatine Kinase (CK): (CPK) test, Cyanocobalamin (Vitamin B12) test, or Antinuclear Antibody (ANA) test

[0095] For the drug, method of treatment or method of inhibiting progression of a disease according to this embodiment, a value between 0 and 1 may be appropriately selected for each identified feature and weighting may be performed for each feature, where the sum of the values ​​of the identified features is 15 or more, preferably 20 or more, and more preferably 25 or more for the patient undergoing drug therapy prior to receiving the first dose of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof during the periods 0-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 24-36 months, and 36-48 months.

[0096] With respect to a drug, method of treatment or method of inhibiting progression of a disease according to another embodiment, a step may be provided in which the identified characteristic is selected prior to receiving a first dose of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof.

[0097] Figure 1 shows the top 20 2-feature combinations based on mutual information rank and value for the 3-6 month period before a patient was diagnosed with ALS. The top 20 2-feature combinations for the 3-6 month period before diagnosis plotted on a feature-feature heatmap. Each axis lists all the single features included in the combination. A block representation of the mutual information values ​​of the feature combinations is plotted at the intersections of the features on the grid, with larger, darker blocks representing higher mutual information values.

[0098] Figure 2 shows the top 20 2-feature combinations based on mutual information rank and value for the 3-6 month period before a patient was diagnosed with ALS. The top 20 2-feature combinations for the 6-9 month period before diagnosis plotted on a feature-feature heatmap. Each axis lists all the single features included in the combination. A block representation of the mutual information values ​​of the feature combinations is plotted at the intersections of the features on the grid, with larger, darker blocks representing higher mutual information values.

[0099] Figure 3 shows the top 20 2-feature combinations based on mutual information rank and value for the 3-6 month period before the patient was diagnosed with ALS. The top 20 2-feature combinations for the 9-12 month period before diagnosis plotted on a feature-feature heatmap. Each axis lists all the single features included in the combination. A block representation of the mutual information values ​​of the feature combinations is plotted at the intersections of the features on the grid, with larger, darker blocks representing higher mutual information values.

[0100] Figure 4 shows the top 20 2-feature combinations based on mutual information rank and value for the period 3-6 months before the patient was diagnosed with ALS. The top 20 2-feature combinations for the period 12-18 months before diagnosis plotted on a feature-feature heatmap. Each axis lists all the single features included in the combination. A block representation of the mutual information values ​​of the feature combinations is plotted at the intersections of the features on the grid, with larger, darker blocks representing higher mutual information values.

[0101] Figure 5 shows the selected 3-feature combinations by mutual information rank for the periods 36-48 months, 24-36 months, 18-24 months, 12-18 months, 9-12 months, 6-9 months, and 3-6 months before the patient was diagnosed with ALS.

[0102] Figure 6 shows the selected 4-feature combinations by mutual information rank for the periods 18-24 months, 12-18 months, 9-12 months, 6-9 months, and 3-6 months before the patient was diagnosed with ALS.

[0103] Figure 7 shows the selected 5-feature combinations by mutual information rank for the periods 118–24 months, 12–18 months, 9–12 months, 6–9 months, and 3–6 months before the patient was diagnosed with ALS.

[0104] In FIG. 7, features (1) to (32) are the same as above. Feature (33) is "Immunofixation electrophoresis; serum."

[0105] International Publication No. WO 2002 / 034264 describes that 3-methyl-1-phenyl-2-pyrazolin-5-one is useful for treating ALS. However, the dosage form, dose, number of administrations, etc. of this compound to ALS patients are not specifically disclosed. International Publication No. WO 2005 / 075434 describes a drug for treating and / or inhibiting the progression of symptoms caused by amyotrophic lateral sclerosis or amyotrophic lateral sclerosis, comprising 3-methyl-1-phenyl-2-pyrazolin-5-one as an active ingredient, in which a drug-free period of one or more days is set during the period of treating and / or inhibiting the progression of the disease. Furthermore, a method has been reported in which 30 mg of 3-methyl-1-phenyl-2-pyrazolin-5-one is administered to an ALS patient by infusion for 14 days, followed by administration for 10 days per month (Neurotherapy, 2003, Vol. 20, No. 5, pages 557-564). A method of treating ALS has been reported in which 3-methyl-1-phenyl-2-pyrazolin-5-one is administered to ALS patients who require treatment and who have a particularly high therapeutic effect.

[0106] Diagnostic criteria for ALS include the EL Escorial diagnostic criteria, the EL Escorial revised Airlie House diagnostic criteria, and the Awaji diagnostic criteria.

[0107] The average time from the appearance of the initial symptoms of ALS to receiving a diagnosis of ALS is reported to be one year. There are multiple factors that contribute to the delay in the diagnosis of ALS. The first is the long period from the appearance of the initial symptoms to the first consultation. The second is that the early symptoms of ALS are similar to those of other diseases. From the first consultation to receiving a final diagnosis, ALS patients visit their first three doctors on average (Paganoni S, et al. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15(5~6), 453). Therefore, new treatment and suppression methods are needed to shorten the period from the appearance of the initial symptoms of ALS to receiving a final diagnosis and to treat ALS patients at an early stage or suppress the progression of ALS in ALS patients at an early stage.

[0108] The ALSFRS-R (ALS Functional Rating Scale) is a severity index for ALS patients, and includes the sum of 12 evaluation items related to limb motor dysfunction, bulbar dysfunction, and respiratory dysfunction. For example, in a clinical trial, the effect of an active ingredient can be confirmed by comparing the ALSFRS-R score before the start of administration of the active ingredient to a patient, the ALSFRS-R score for a certain period after the start of administration, and / or the ALSFRS-R score after administration.

[0109] An example of a method for synthesizing 3-methyl-1-phenyl-2-pyrazolin-5-one, which is an active ingredient of the present invention, is the preparation method described in European Patent No. 208874 (or Japanese Patent Publication No. 5-31523). The entire disclosures of these publications are incorporated herein by reference.

[0110] Examples of the active ingredient of the drug of the present invention include 3-methyl-1-phenyl-2-pyrazolin-5-one, its physiologically acceptable salts, its hydrates, and its solvates. Physiologically acceptable salts include salts with mineral acids such as hydrochloric acid, hydrobromide, and phosphoric acid; salts with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, oxalic acid, citric acid, and malic acid; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as magnesium; and salts with amines such as ammonia, ethanolamine, and 2-amino-2-methyl-1-propanol. Furthermore, the type of salt is not particularly limited as long as the salt is physiologically acceptable.

[0111] The active ingredient of the drug of the present invention, 3-methyl-1-phenyl-2-pyrazolin-5-one or its salt, can be directly administered to the patient. However, it is preferable to provide a formulation obtained by adding the active ingredient and pharmacologically and pharma- ceutical acceptable additives.

[0112] Examples of pharmacologically and pharma- ceutically acceptable additives that can be used include excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, pigments, diluents, bases, solubilizers or dissolution aids, isotonicity agents, pH adjusters, stabilizers, propellants, adhesives, etc. Examples of preparations suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, syrups, etc. Examples of preparations suitable for parenteral administration include injections, eye drops, patches, suppositories, etc.

[0113] As additives for formulations suitable for oral administration, for example, the following additives can be used: excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; disintegrants or disintegration aids such as carboxymethylcellulose, starch, or carboxymethylcellulose calcium; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; coating agents such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, or titanium oxide; and bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat.

[0114] For preparations suitable for injection or infusion, the following formulation additives can be used: solubilizers or dissolution aids capable of forming aqueous injectable drugs or injectable drugs that can be dissolved upon use, such as distilled water for injection, physiological saline, propylene glycol, etc.; isotonicity agents such as glucose, sodium chloride, D-mannitol, glycerin, etc.; pH adjusters such as inorganic acids, organic acids, inorganic bases, or organic bases; etc.

[0115] A brain protector (injection) containing 3-methyl-1-phenyl-2-pyrazolin-5-one as an active ingredient has already been used clinically (generic name: "Edaravone"; trade names: "Radicut (registered trademark)" and "Radicava (registered trademark)": manufactured and sold by Mitsubishi Tanabe Pharma). Therefore, the above preparation may be directly used as 3-methyl-1-phenyl-2-pyrazolin-5-one used in the drug and method of the present invention. EXAMPLES

[0116] Hereinafter, the embodiments of the present invention will be further described based on examples. However, the scope of the present invention is not limited to the following examples.

[0117] method This analysis used the TruvenMarketScan® database, which contains patient-level claims for over 170 million patients, without any code preselection.

[0118] Patients with ALS were identified using ICD-9 code 335.20 and ICD-10 code G12.21. Patient demographics were reported for the national set of patients with ALS ICD-9 or ICD-10 codes between January 2010 and June 2016. Patients from the complete national adjudicated claims database spanning 2006 to 2014 with an ALS ICD-9 code and at least 1 year of adjudicated claims history prior to ALS diagnosis were included in the frequency analysis. Patients from the complete national adjudicated claims database spanning 2006 to 2014 with an ALS ICD-9 code and at least 5 years of adjudicated claims history prior to ALS diagnosis were included in the progression analysis.

[0119] The analysis utilized two data ranking methods: frequency and mutual information (MI); the MI measure was used to quantify the statistical relevance of features in MarketScan® to future ALS diagnoses in the United States; the relative frequency of relevant events was computed to rank the differentiating features.

[0120] In these analyses, we included patients from the complete national dataset (n=13,882).

[0121] Characteristics considered included diagnosis codes, procedure codes, medications, standard provider type, and standard nursing facility type.

[0122] To optimize the selection and ranking of ALS diagnostic predictors, a suite of ensemble classifiers developed through machine learning techniques was applied to the MarketScan® claims database.

[0123] Diagnostic predictors were derived from discriminatory features selected by mutual information and ranked using machine learning techniques.

[0124] Features were analyzed in combinations, in addition to individual features; combinations of up to five drugs, procedures, and diagnoses; combinations of the same feature type (drug 1 + drug 2, treatment 1 + treatment 2) as well as multiple feature types (treatment + diagnosis).

[0125] Diagnostic predictors were specifically searched within the following time ranges: 3, 6, 9, 12, 18, 24, 36, 48, and 60 months before initial ALS diagnosis.

[0126] The mutual information (MI) values ​​for Feature 1-Feature 2 combinations for the periods 3-6 months, 6-9 months, 9-12 months, and 12-18 months prior to initial ALS diagnosis are shown in the following table, along with the top 20 MI values ​​for each of these periods.

[0127] [Table 1] [Table 2] [Table 3] [Table 4]

[0128] The numbers in each cell indicate the mutual information (MI) value of the combination of feature 1 and feature 2. The shaded cells indicate combinations that do not fall within the top 20 MI values.

[0129] In the table above, patients with the combination of feature 1 and feature 2 are likely to have ALS, and administering drugs containing 3-methyl-1-phenyl-2-pyrazolin-5-one to ALS patients in the early stages of the disease is particularly effective.

[0130] Correspondence between features (1)-(33) and features, codes, and code types in ICD-9 codes, CPT codes, or HCPCS codes

[0131] [Table 5] [Table 6]

[0132] The top 20 2-feature combinations for 3–6, 6–9, 9–12, and 12–18 months prior to diagnosis plotted in feature-feature heatmaps (Figures 1–4). Block representations of mutual information values ​​for feature combinations are plotted at the intersections of features on the grid, with larger, darker blocks representing higher mutual information values.

[0133] Diagnostic labs such as antinuclear antibodies, creatine kinase, thyroid-stimulating hormone, and cyanocobalamin (vitamin B12) tend to cluster together.

[0134] There appears to be significant overall muscle weakness that over time is combined with various lab tests and imaging.

[0135] Muscle weakness and fatigue / fatigue are a robust pair of features over the 18 months prior to diagnosis.

[0136] Physical therapy is an important part of the 2-feature combination.

[0137] Tool #1 :Patient or physician checklist [Table 7]

[0138] How to use Tool #1: If any symptoms or events listed in the "Symptoms or Events" column have been experienced within the past three years, check the cells to the right corresponding to all items that apply.

[0139] Interpretation: If a patient experiences 4 or more of the 9 "symptoms / events," the patient is likely to have ALS and administering a drug containing 3-methyl-1-phenyl-2-pyrazolin-5-one to the patient would be particularly effective.

[0140] Tool #2 :To be completed by patient or physician. [Table 8]

[0141] How to use Tool #2: If the patient has experienced a symptom or event listed in the "I have experienced" column, check the cells in the "Check all that apply" column corresponding to all that apply. Optionally, provide additional information in the "How many months ago did you first experience this symptom or event?" and "Is this symptom or event persistent (yes or no)?" columns.

[0142] Interpretation: Patients who meet the following criteria are likely to have ALS, and administering drugs containing 3-methyl-1-phenyl-2-pyrazolin-5-one to these patients would be particularly effective: · The patient is experiencing three or more of the five “symptoms / events” listed in Category A; or The patient is experiencing 2 or more of the symptoms / events listed in Category A + 3 of the symptoms / events listed in Category B.

[0143] Tool #3 :To be completed by the patient as part of their medical history. [Table 9]

[0144] Tool #3: Example [Table 10]

[0145] How to use Tool #3: If the patient has experienced an event listed in the leftmost column in the periods 0-3 months, 3-6 months, 6-9 months, 9-12 months, 12-18 months, 18-24 months, 24-36 months, and 36-48 months prior to using Tool #3, check all cells for the appropriate periods.

[0146] Interpretation: If the patient scores a 5 in any time frame or if the patient's total score is greater than 25, the patient is likely to have ALS and would benefit from treatment with a drug that contains 3-methyl-1-phenyl-2-pyrazolin-5-one, among other things:

[0147] Tool #4 : Algorithms derived from Tool #3 that can be uploaded to an Electronic Health Record database A risk potential for a future ALS diagnosis is calculated. If the risk potential is >X, the patient is likely to have ALS and administering a drug containing 3-methyl-1-phenyl-2-pyrazolin-5-one to the patient would be particularly effective.

[0148] Risk Potential = (Event: Fatigue or Weakness * # of Time Frames the Event Occurred) + (Event: Ankle or Foot Deformity * # of Time Frames the Event Occurred) + (Event: Connective Tissue Disorder * # of Time Frames the Event Occurred) + (Event: Nervous System Disorder * # of Time Frames the Event Occurred) + (Event: Labs Checked or Monitored for CK, Vitamin B12, or ANA * # of Time Frames the Event Occurred) + (Event: Imaging: MRI or EMG * # of Time Frames the Event Occurred) + (Event: Unusually High Healthcare Utilization * # of Time Frames the Event Occurred)

[0149] If the event / symptom occurred, assign a value of "1". If the event / symptom did not occur, assign a value of "0". ·Add a value to the equation to take combinatorial considerations into account. Possibility to weight values ​​up to the time frame they occurred

[0150] [Table 11]

[0151] Interpretation: If the risk potential is >X, the patient is likely to have ALS and administering a drug containing 3-methyl-1-phenyl-2-pyrazolin-5-one to the patient would be particularly effective.

[0152] Another exemplary model for features such as diagnosis, drugs and treatments is shown below: Features having the same terms and phrases above share the same definitions.

[0153] [Table 12] [Table 13]

[0154] "Abnormal involuntary movements" means that the patient has been diagnosed with or has symptoms corresponding to a disorder, as designated by CD-9 code 781.0, of "abnormal involuntary movements."

[0155] "Brachial neuritis or radiculitis NOS" means that the patient has been diagnosed with or has symptoms corresponding to the disease "brachial neuritis or radiculitis NOS," as designated by ICD-9 code 723.4. "Anterior neck pain" means that the patient has been diagnosed with or has symptoms corresponding to the disorder "anterior neck pain" as designated by ICD-9 code 723.1. "Cutaneous sensory disorder" means that the patient has been diagnosed with or has symptoms corresponding to the disorder "Cutaneous sensory disorder," as designated by ICD-9 code 782.0. "Dysarthria" means that the patient has been diagnosed with or has symptoms corresponding to the disorder "dysarthria", as designated by ICD-9 code 355.9.

[0156] "Mononeuritis of unspecified site" means that the patient has been diagnosed with or has symptoms corresponding to the disease "mononeuritis of unspecified site," as designated by ICD-9 code 784.51. "Myopathy; unspecified" means that the patient has been diagnosed with or has symptoms corresponding to the disease "myopathy; unspecified," as indicated by ICD-9 code 359.9. "Other musculoskeletal conditions associated with the hands and feet" means that the patient has been diagnosed with or has symptoms corresponding to the condition "Other musculoskeletal conditions associated with the hands and feet," as indicated by ICD-9 code 729.89. "Other language disorder" means that the patient has been diagnosed with or has symptoms corresponding to the disorder "other language disorder," as designated by ICD-9 code 784.59.

[0157] "Pain in the extremities" means that the patient has been diagnosed with or has symptoms corresponding to the disorder "pain in the extremities" as designated by ICD-9 code 729.5. "Thoracic or lumbosacral neuritis or radiculitis; unspecified" means that the patient has been diagnosed with or has symptoms corresponding to the disease "Thoracic or lumbosacral neuritis or radiculitis; unspecified," as indicated by ICD-9 code 724.4. "Gabapentin" means that the patient has been prescribed a medication that contains "gabapentin" as the active ingredient.

[0158] "Hydrocodone & Combination" means that the patient is prescribed a medication that contains, as the active ingredient, "hydrocodone or a combination of hydrocodone with another drug." "Metformin & Combination" means that the patient is prescribed a medication that includes "metformin or a combination of metformin and another drug" as the active ingredient.

[0159] "Nerve conduction, amplitude and latency / velocity study, each nerve; motor, no F-wave study" means the patient has undergone a procedure designated by CPT code 95900, "Nerve conduction, amplitude and latency / velocity study, each nerve; motor, no F-wave study," or its equivalent. "Nerve conduction, amplitude and latency / velocity study, each nerve; motor, with F-wave study" means the patient has undergone a procedure designated by CPT code 95903, "Nerve conduction, amplitude and latency / velocity study, each nerve; motor, with F-wave study," or an equivalent procedure. "Nerve conduction, amplitude and latency / velocity study, each nerve; sensory" means the patient is receiving a procedure designated by CPT code 95904, "Nerve conduction, amplitude and latency / velocity study, each nerve; sensory," or an equivalent procedure.

[0160] "Outpatient or other outpatient visit for evaluation and management of an established patient" means that the patient is receiving an "outpatient or other outpatient visit for evaluation and management of an established patient" procedure, as indicated by CPT code 99212, or its equivalent.

[0161] The model is applied to the pre-diagnosis history of known ALS patients and requests the history of demographically matched control patients (non-ALS controls). Based on the selected features, each patient in the group of known ALS patients and the group of control patients received a score representing the probability of being an ALS patient. Varying the sensitivity and specificity of the model can be achieved by adjusting the probability threshold for considering a patient an ALS patient, as described below.

[0162] Figure 8 shows the distribution of scores for the target (ALS patient) and control (control patient) of the model. In Figure 8, the horizontal axis shows the score, and the vertical axis shows the percentage of each score for the target and control. The higher the score, the more likely the patient is to be the target (ALS patient).

[0163] FIG. 9 shows the ROC (Receiver Operating Characteristic) curves; true positive rate, false positive rate, and PPV of the model vs. threshold.

[0164] Figure 10 shows the confusion matrix when the probability threshold is set to 0.1. When the probability threshold is set to 0.1, patients with a probability of 10% or more being ALS patients are considered to have ALS. This probability threshold gives good performance based on accuracy and true positive rate. The high number of false positives is due to the low threshold. This is an appropriate threshold to use when the true positive rate is more important than the false positive rate. A lower threshold is advantageous for situations where false positives are acceptable in order to achieve more true positives.

[0165] Figure 11 shows the confusion matrix when the probability threshold is set to 0.9. When the probability threshold is set to 0.9, patients with a probability of 90% or more being ALS patients are considered to have ALS. This probability threshold results in good performance and true positive rate. This probability threshold results in good performance based on accuracy and true positive rate. The low number of false positives is due to the high threshold. This is an appropriate threshold to use when the false positive rate is more important than the true positive rate. A higher threshold is advantageous for situations where true positives can be sacrificed to minimize false positives.

[0166] The table below shows a heat map of the 2-feature combinations that were most highly correlated with future ALS diagnosis compared to control patients. In the table, darker hues indicate greater relative importance of the feature combination within a particular time period. Each row represents different time periods before ALS diagnosis that were assessed in the MI analysis. Each vertical column contains the 2-feature combinations that were included in the top 3 common differentiators (as determined by the MI analysis) in the individual time periods before ALS diagnosis. If a combination was included in the top 3 in multiple time periods, it will be listed in the earliest time period in which it appeared in the top 3 and replaced by the next highest combination in subsequent time periods to maintain 3 combinations per time period.

[0167] A combination of physical therapy and gait abnormalities can begin to differentiate patients as early as 48-60 months before diagnosis.

[0168] A combination including magnetic resonance imaging (MRI) of the brain or spine, muscle weakness, and electromyography (EMG) differentiates patients with ALS as early as 36-48 months before diagnosis.

[0169] A combination including assessment of muscle weakness, other malaise and fatigue, and serum levels of antinuclear antibodies (ANA), creatine kinase, or vitamin B-12, begins to differentiate ALS patients as early as 24-36 months before diagnosis and steadily increases as the initial diagnosis approaches.

[0170] The combination of dysphagia and swallowing function is an important differentiator in the year prior to diagnosis.

[0171] Serum evaluation for thyroid stimulating hormone and the combination of muscle wasting or vitamin B12 begin to differentiate patients 6 months before diagnosis.

[0172] Echocardiography-related combinations were in the top 3 differentiators 48-60 months prior to diagnosis, continued to be differentiators until 24 months prior to diagnosis, and then were no longer in the top 100 differentiators after 24 months.

[0173] The influenza vaccine and immunization combination was the top differentiator only 18-24 months prior to diagnosis.

[0174] Several concomitant diagnoses that could differentiate ALS patients were identified prior to their initial ALS diagnosis. Again, looking at a combination of features in the patient's claims history, ALS patients were differentiated many years prior to their initial ALS diagnosis. Methods according to embodiments of the present invention may be applied to identify ALS patients earlier to facilitate appropriate intervention. [Table 14]

[0175] Patients with certain characteristics are more likely to have ALS, and administering drugs containing 3-methyl-1-phenyl-2-pyrazolin-5-one to early-stage patients is particularly effective.

[0176] According to an embodiment of the present invention, treating amyotrophic lateral sclerosis at an early stage or inhibiting the progression of amyotrophic lateral sclerosis at an early stage comprises administering an effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof to a patient having at least two of identified characteristics 1 to 55. Identified characteristics 1 to 55 are selected from the following:

[0177] 1. Gait abnormalities 2. Aldolase test 3. Antinuclear antibody (ANA) test 4. Cervical spondylosis without myelopathy 5. Creatine Kinase (CK): (CPK) Test 6. Cyanocobalamin (Vitamin B12) Test 7. Cervical disc degeneration 8. Cervical disc displacement without myelopathy 9. Swallowing problems 10. Folic acid; serum test 11. Serum immunofixation electrophoresis test 12. Magnetic resonance imaging examination 13.Manual therapy techniques 14. Muscle Weakness 15.Needle electromyography 16. Acquired deformities of the ankle and foot 17. Fatigue and fatigue 18.Physical Therapy Evaluation 19. Serum protein electrophoretic fractionation and quantitative testing 20. Erythrocyte Sedimentation Rate Test 21. Cervical spinal stenosis 22. Swallowing function test 23. Therapeutic procedures for neuromuscular reeducation 24. Therapeutic treatment for therapeutic exercises 25. Thyroid-stimulating hormone (TSH) test 26. Unspecified hereditary and idiopathic peripheral neuropathy 27. Nervous system disorders 28. Inherited and degenerative nervous system conditions 29. Connective tissue diseases 30. Non-traumatic joint diseases 31. Multiple sclerosis 32. Paraplegia 33. Paralysis 34. Other Neurological Diagnostic Procedures 35. Durable Medical Equipment (DME) and Consumables 36. Physical therapy 37. Laryngoscopy 38. Spinal tap 39. Speech therapy 40. Riluzole 41. Baclofen 42. Pyridostigmine 43. Anticonvulsants 44. Diazepam 45. Hydrocodone 46. ​​Propoxyphene 47. Sympathomimetic drugs 48. Glycopyrrolate 49. Prednisone 50. Pregabalin 51. Clonazepam 52. Tizanidine 53. Levodopa or Carbidopa 54. Quinine 55. Tolterodine

[0178] In some embodiments, a 14 day dosing period and a 14 day rest period can be repeated, or an initial 14 day dosing period followed by an initial 14 day rest period followed by a 10 day dosing period and a 14 day rest period can be repeated. Preferably, an initial 14 day dosing period followed by an initial 14 day rest period followed by a 10 day dosing period and a 14 day rest period can be repeated.

[0179] In another embodiment, administration of the drug can be repeated daily without providing a drug holiday.

[0180] Symptoms caused by amyotrophic lateral sclerosis are preferably clinical symptoms such as decreased respiratory function, speech disorder, swallowing disorder, and movement disorder of the limbs.

[0181] During the period from 60 months before the first administration of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof to the patient, the patient preferably satisfies at least two of the above characteristics 1 to 55. A more preferable period is from 18 months before the first administration to the first administration.

[0182] Furthermore, one embodiment of the present invention includes a drug containing 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof as an active ingredient for treating or inhibiting the progression of amyotrophic lateral sclerosis. A patient receiving drug therapy has at least two of the identified characteristics 1 to 55.

[0183] Identified features 1 to 55 are selected from the following:

[0184] 1. Gait abnormalities 2. Aldolase test 3. Antinuclear antibody (ANA) test 4. Cervical spondylosis without myelopathy 5. Creatine Kinase (CK): (CPK) Test 6. Cyanocobalamin (Vitamin B12) Test 7. Cervical disc degeneration 8. Cervical disc displacement without myelopathy 9. Swallowing problems 10. Folic acid; serum test 11. Serum immunofixation electrophoresis test 12. Magnetic resonance imaging examination 13.Manual therapy techniques 14. Muscle Weakness 15.Needle electromyography 16. Acquired deformities of the ankle and foot 17. Fatigue and fatigue 18.Physical Therapy Evaluation 19. Serum protein electrophoretic fractionation and quantitative testing 20. Erythrocyte Sedimentation Rate Test 21. Cervical spinal stenosis 22. Swallowing function test 23. Therapeutic procedures for neuromuscular reeducation 24. Therapeutic treatment for therapeutic exercises 25. Thyroid-stimulating hormone (TSH) test 26. Unspecified hereditary and idiopathic peripheral neuropathy 27. Nervous system disorders 28. Inherited and degenerative nervous system conditions 29. Connective tissue diseases 30. Non-traumatic joint diseases 31. Multiple sclerosis 32. Paraplegia 33. Paralysis 34. Other Neurological Diagnostic Procedures 35. Durable Medical Equipment (DME) and Consumables 36. Physical therapy 37. Laryngoscopy 38. Spinal tap 39. Speech therapy 40. Riluzole 41. Baclofen 42. Pyridostigmine 43. Anticonvulsants 44. Diazepam 45. Hydrocodone 46. ​​Propoxyphene 47. Sympathomimetic drugs 48. Glycopyrrolate 49. Prednisone 50. Pregabalin 51. Clonazepam 52. Tizanidine 53. Levodopa or Carbidopa 54. Quinine 55. Tolterodine

[0185] Further, embodiments of the present invention include 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof for treating or inhibiting the progression of amyotrophic lateral sclerosis. A patient receiving drug therapy has at least two of the identified characteristics 1 to 55.

[0186] Identified features 1 to 55 are selected from the following:

[0187] 1. Gait abnormalities 2. Aldolase test 3. Antinuclear antibody (ANA) test 4. Cervical spondylosis without myelopathy 5. Creatine Kinase (CK): (CPK) Test 6. Cyanocobalamin (Vitamin B12) Test 7. Cervical disc degeneration 8. Cervical disc displacement without myelopathy 9. Swallowing problems 10. Folic acid; serum test 11. Serum immunofixation electrophoresis test 12. Magnetic resonance imaging examination 13.Manual therapy techniques 14. Muscle Weakness 15.Needle electromyography 16. Acquired deformities of the ankle and foot 17. Fatigue and fatigue 18.Physical Therapy Evaluation 19. Serum protein electrophoretic fractionation and quantitative testing 20. Erythrocyte Sedimentation Rate Test 21. Cervical spinal stenosis 22. Swallowing function test 23. Therapeutic procedures for neuromuscular reeducation 24. Therapeutic treatment for therapeutic exercises 25. Thyroid-stimulating hormone (TSH) test 26. Unspecified hereditary and idiopathic peripheral neuropathy 27. Nervous system disorders 28. Inherited and degenerative nervous system conditions 29. Connective tissue diseases 30. Non-traumatic joint diseases 31. Multiple sclerosis 32. Paraplegia 33. Paralysis 34. Other Neurological Diagnostic Procedures 35. Durable Medical Equipment (DME) and Consumables 36. Physical therapy 37. Laryngoscopy 38. Spinal tap 39. Speech therapy 40. Riluzole 41. Baclofen 42. Pyridostigmine 43. Anticonvulsants 44. Diazepam 45. Hydrocodone 46. ​​Propoxyphene 47. Sympathomimetic drugs 48. Glycopyrrolate 49. Prednisone 50. Pregabalin 51. Clonazepam 52. Tizanidine 53. Levodopa or Carbidopa 54. Quinine 55. Tolterodine

[0188] The embodiments of the present invention include drug administration methods and drugs useful for treating or inhibiting the progression of ALS or symptoms caused by ALS. Furthermore, the drug administration methods and drugs according to the embodiments of the present invention allow for administration of drugs to patients at an early stage of ALS onset. Furthermore, the drug administration methods and drugs according to the embodiments of the present invention allow for selection of patients at an early stage of ALS onset, and can provide a high therapeutic effect or a high disease suppression effect.

[0189] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

1. 1. A method for treating amyotrophic lateral sclerosis, comprising administering to a patient in need thereof an effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof, the method comprising administering to said patient at least two of the following characteristics selected from Characteristics 1 to 55: Features 1 to 55 are as follows:

1. Gait abnormalities 2. Aldolase test 3. Antinuclear antibody (ANA) test 4. Cervical spondylosis without myelopathy 5. Creatine Kinase (CK): (CPK) Test 6. Cyanocobalamin (Vitamin B12) test 7. Cervical disc degeneration 8. Cervical disc displacement without myelopathy 9. Swallowing problems 10. Folic acid: Serum test 11. Serum immunofixation electrophoresis test 12. Magnetic resonance imaging 13. manual therapy techniques 14. Muscle weakness 15. Needle electromyography 16. Acquired deformities of the ankle and foot 17. Malaise and fatigue 18. Physical Therapy Evaluation 19. Serum Protein Electrophoretic Fractionation and Quantitative Tests 20. Erythrocyte Sedimentation Rate Test 21. Cervical spinal stenosis 22. Swallowing function test 23. Therapeutic procedures for neuromuscular reeducation 24. Therapeutic treatment for therapeutic exercises 25. Thyroid-stimulating hormone (TSH) test 26 Unspecified Hereditary and Idiopathic Peripheral Neuropathies 27. Nervous system disorders 28. Inherited and Degenerative Neurological Conditions 29. connective tissue disease 30. Non-traumatic joint diseases 31 Multiple sclerosis 32 Paraplegia 33. paralysis 34. Other Neurological Diagnostic Procedures 35. Durable Medical Equipment (DME) and Consumables 36. physical therapy 37 Laryngoscopy 38. spinal tap 39. Speech treatment 40. Riluzole 41. Baclofen 42. Pyridostigmine 43 Anticonvulsants 44. Diazepam 45. Hydrocodone 46. ​​Propoxyphene 47 Sympathomimetic drugs 48. Glycopyrrolate 49. Prednisone 50. Pregabalin 51. Clonazepam 52 Tizanidine 53. Levodopa or Carbidopa 54 Quinine 55. Tolterodine That is, the method.

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