WO2017111052A1 - Therapeutic agent for autoimmune disease - Google Patents

Therapeutic agent for autoimmune disease Download PDF

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WO2017111052A1
WO2017111052A1 PCT/JP2016/088434 JP2016088434W WO2017111052A1 WO 2017111052 A1 WO2017111052 A1 WO 2017111052A1 JP 2016088434 W JP2016088434 W JP 2016088434W WO 2017111052 A1 WO2017111052 A1 WO 2017111052A1
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therapeutic agent
arginine
autoimmune disease
ham
treatment
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PCT/JP2016/088434
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French (fr)
Japanese (ja)
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博 ▲高▼嶋
仁 荒田
松浦　英治
田代　雄一
匡宏 安藤
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国立大学法人鹿児島大学
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Priority to JP2017558275A priority Critical patent/JP6749022B2/en
Publication of WO2017111052A1 publication Critical patent/WO2017111052A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]

Definitions

  • the present invention relates to an autoimmune disease therapeutic agent containing, for example, L-arginine hydrochloride as an active ingredient.
  • HTLV-1 Human T lymphocyte-directed virus type 1
  • HTLV-1 Human T lymphocyte-directed virus type 1
  • HTLV-1 is a retrovirus that is incorporated into the genomic DNA of CD4-positive T lymphocytes and spreads within and between individuals.
  • HTLV-1 is an adult T-cell leukemia caused by tumor formation of infected cells.
  • HTLV-1 associated myelopathy HTLV-1 associated myelopathy
  • HU uveitis
  • infected cells infiltrated into the eyeball.
  • Root therapy for HAM has not been established, and oral administration of an anti-inflammatory drug, corticosteroid (prednisolone), which has been used empirically, is insufficient, although it reduces HTLV-1 provirus level to some extent and improves symptoms .
  • corticosteroids has many side effects (steroid diabetes, osteoporosis, immunosuppression, etc.), and long-term treatment is difficult.
  • interferon ⁇ is the only drug that has been approved for medical insurance against HAM.
  • interferon ⁇ is expensive, has little improvement in symptoms, and needs attention to side effects. Long-term decline in activity due to fever and depression leads to a decline in motor function.
  • L-arginine is used as a therapeutic agent for hyperammonemia and congenital urea cycle abnormalities as arginine hydrochloride, 20 g of Argy U intravenous infusion from Awai Pharma, and Ajinomoto as an internal medicine.
  • arginine hydrochloride 20 g of Argy U intravenous infusion from Awai Pharma, and Ajinomoto as an internal medicine.
  • doctor-led trials are also being conducted on treatment with L-arginine hydrochloride for MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes) in mitochondrial diseases.
  • MELAS Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes
  • L-arginine hydrochloride has never been used as a therapeutic agent for HAM.
  • the present invention aims to provide a therapeutic agent for autoimmune diseases such as HAM in view of the above situation.
  • the present invention includes the following.
  • autoimmune diseases such as HAM can be treated more safely and inexpensively.
  • the autoimmune disease therapeutic agent according to the present invention contains L-arginine hydrochloride as an active ingredient.
  • examples of the autoimmune disease include HAM, autoimmune encephalopathy, multiple sclerosis, atopic dermatitis, myositis, bronchial asthma, allergic rhinitis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, Behcet's disease Rheumatoid arthritis, Hashimoto's disease, glomerulonephritis, interstitial pneumonia, sarcoidosis and the like.
  • the administration of the therapeutic agent according to the present invention can significantly improve gait disturbance and urination disorder in HAM patients.
  • the L-arginine hydrochloride which is an active ingredient in the therapeutic agent according to the present invention, is commercially available from, for example, Argy U Intravenous Infusion 20 g commercially available from AY Pharma Co., Ltd. and Ajinomoto Pharmaceutical Co., Ltd., EA Pharma Co., Ltd. Algi U-containing granules (Argi U granules) can be used.
  • the therapeutic agent according to the present invention can be administered by various methods known per se according to the dosage form, and the dosage, administration site, administration interval, period, etc. are determined depending on the age and weight of the patient. It can be appropriately determined in consideration of a medical condition or a combination with other drugs and treatment methods.
  • the administration method is not particularly limited, and examples thereof include oral administration, injection, and intravenous infusion.
  • the dosage of the therapeutic agent according to the present invention varies depending on the dosage form, administration method, or symptoms to be treated.
  • the dosage per kg body weight is 0.125 g in terms of active ingredient (L-arginine hydrochloride).
  • the administration period is preferably a lifetime.
  • the form of the therapeutic agent according to the present invention examples include, for example, infusion, tablets, capsules, powders, granules, suppositories, and injections, but are not particularly limited.
  • the therapeutic agent according to the present invention may contain components such as a pharmaceutical carrier, an excipient, and a stabilizer.
  • the present invention also relates to a method for treating an autoimmune disease, comprising administering L-arginine hydrochloride to a subject (patient) such as a human or an animal.
  • a subject such as a human or an animal.
  • the dosage form, administration mode, dosage and the like of L-arginine hydrochloride can be determined according to the above-described therapeutic agent according to the present invention.
  • Case 1 Treatment of HAM with L-arginine hydrochloride 1.
  • Case 1 (i) Patient, material and method The case is a 70-year-old woman. There was a known HTLV-1-related myelopathy (HAM), and the patient was admitted to the hospital with a chief complaint of lower leg muscle weakness. At this time, it was diagnosed as a combination of myopathy and HTLV-1 myelopathy. Muscle biopsy revealed mitochondrial dysfunction. L-arginine infusion was used as a treatment for mitochondrial dysfunction. L-arginine was used at Argy U 10 g / 42.0 kg / day for 7 days.
  • HAM HTLV-1-related myelopathy
  • the neopterin level which is a biomarker for HTLV-1-related myelopathy, had decreased from 14 pmol / ml to 9 pmol / ml before treatment.
  • the quantitative value of HTLV-1 DNA decreased from 81.3 to 31.7.
  • the HTLV-1 DNA quantitative value decreased to 7.7. Probably more effective in HTLV-1-related myelopathy against HAM than muscle disease.
  • Case 2 (i) Patient, material and method The case is a 63 year old female. A history of rheumatoid arthritis. He had limb reflexes, spastic gait, positive pathological reflexes, and dysuria since 1 year ago. He was diagnosed with HAM because he was positive for HTLV-1 antibody in the Department of Neurology. She was referred to our hospital and hospitalized because of symptom progression.
  • Case 3 (i) Patient, material and method The case is a 54 year old female. Diagnosed as HTLV-1 carrier 25 years ago. Lower sweating of the lower body from 4 years ago, and abnormal sensation of the lower limbs from 3 years ago. He had difficulty running and stumbles for two years and was diagnosed with HAM a year ago. He was admitted to the hospital for close examination and treatment. The patient was Osame grade 4 at the time of admission (handrail needed to climb the stairs).
  • Cerebrospinal fluid protein which is thought to reflect spinal cord inflammation, was improved from 48.8 to 36.4 (mg / dL).
  • Case 4 (i) Patient, material and method The patient is a 74 year old female. He has been aware of lower limb motor dysfunction and dysuria for about 20 years. It progressed gradually over the course of 20 years and improved with steroid treatment 6 and 5 years ago, but no improvement was observed with steroid treatment 3 years ago. Since muscular weakness was gradually observed, treatment with intravenous infusion of L-arginine was attempted.
  • Arginine was used for 7 days at Argy U 15g / day.
  • Case 5 (i) Patient, material and method The patient is a 82 year old male. He has frequent urination around the age of 60, and his gait disturbance gradually progresses. He was diagnosed with HAM at the age of 64. The spastic gait of both lower limbs is remarkable, and it is a double cane walking. Because of dysuria, it was necessary to change the urine collection pad 5 times at night. He was admitted to the hospital for close examination and treatment. OABSS, the scale of Osame grade 6 on admission and dysuria, was 14 points.
  • Knee joint spasticity was reduced on the third day of internal use, and the muscle tone evaluation scale (Modified Ashworth scale) showed improvement from 1+ before internal use to 1 after internal use.
  • the pain of sticking the needles in the lower limbs was markedly improved from 8.5cm to 0cm on Visual Analogue scale at the time of hospitalization.
  • OABSS overactive bladder Syndrome score
  • the arginine level increased from 60.2 nmol / ml to 275.8 nmol / ml in the internal use, and it was confirmed that the internal use was sufficiently transferred into the blood.
  • Hematological immunoassay shows that adiponectin, a cytokine involved in the inflammatory response, decreases from 9.0 to below the measurement limit ( ⁇ 8.0), suggesting improved inflammation and inducing IL-6 production It also decreased from 8.1 before internal use to 7.1 two weeks after the start of treatment.
  • NK cell activity one of the NK cell function indicators involved in the control of immune response, decreases the antitumor effect when the activity decreases, but this function is E / T 10: 1 increased from 5.8 to 6.5%, and E / T 20: 1 increased from 10.9 to 12.4%, suggesting an increase in antitumor effects.
  • Case 6 Patient, material and method The case is a 52 year old female. ATL family history (mother) and 3 younger sisters are HTLV-1 carriers. Constipation has occurred since his teenage years, and he became aware of spasticity of the lower limbs around the age of 38, making it difficult to move up and down the stairs. At 48 years of age, he developed overactive bladder, was positive for HTLV-1, and was diagnosed with HAM. He was admitted to the hospital for close examination and treatment. The OABSS, which is the scale of Osame grade 4 at the time of admission and overactive bladder, was 5 points.
  • the abdominal muscles improved from 4 to 4+ in the manual strength test, making it easier to get up from the bed.
  • the anterior tibial muscle was improved from 4 to 5 in the manual strength test.
  • OABSS Overactive bladder syndrome score
  • the arginine level increased from 86.0 nmol / ml to 350.6 nmol / ml in the internal use, and the internal arginine was transferred into the blood.

Abstract

The purpose of the present invention is to provide a medicament for treating an autoimmune disease. The present invention pertains specifically to a therapeutic agent for an autoimmune disease such as HTLV-associated myelopathy, which contains L-arginine hydrochloride as an active ingredient.

Description

自己免疫疾患治療剤Autoimmune disease treatment
　本発明は、例えばL-アルギニン塩酸塩を有効成分として含有する自己免疫疾患治療剤に関する。 The present invention relates to an autoimmune disease therapeutic agent containing, for example, L-arginine hydrochloride as an active ingredient.
　ヒトTリンパ球指向性ウイルス1型(以下、「HTLV-1」と称する)はCD4陽性Tリンパ球のゲノムDNAに組み込まれて体内及び個体間で感染伝播するレトロウイルスである。HTLV-1は、感染細胞の腫瘍化による成人T細胞白血病、感染細胞が脊髄内に浸潤し、痙性脊髄麻痺、排尿障害等をきたすHTLV-1関連脊髄症(HTLV-1 associated myelopathy：以下、「HAM」と称する)や感染細胞が眼球内に浸潤したブドウ膜炎(HU)等の炎症性疾患を引き起こす。 Human T lymphocyte-directed virus type 1 (hereinafter referred to as “HTLV-1”) is a retrovirus that is incorporated into the genomic DNA of CD4-positive T lymphocytes and spreads within and between individuals. HTLV-1 is an adult T-cell leukemia caused by tumor formation of infected cells. HTLV-1 associated myelopathy (HTLV-1 associated myelopathy), which causes infected cells to infiltrate the spinal cord and cause spastic spinal cord paralysis and dysuria. Causes inflammatory diseases such as uveitis (HU) and infected cells infiltrated into the eyeball.
　HAMに対する根治療法は未樹立であり、経験的に用いられる抗炎症薬の副腎皮質ステロイド(プレドニゾロン)経口投与は、ある程度のHTLV-1プロウイルス量減少、症状改善効果があるものの、不十分である。また、当該副腎皮質ステロイド投与は、副作用(ステロイド糖尿病、骨粗鬆症、免疫抑制等)も多く、長期的な治療が困難となっている。 Root therapy for HAM has not been established, and oral administration of an anti-inflammatory drug, corticosteroid (prednisolone), which has been used empirically, is insufficient, although it reduces HTLV-1 provirus level to some extent and improves symptoms . In addition, administration of such corticosteroids has many side effects (steroid diabetes, osteoporosis, immunosuppression, etc.), and long-term treatment is difficult.
　また、インターフェロンαは、HAMに対して唯一医療保険適応となっている薬剤である。しかしながら、インターフェロンαは、高価で、且つ症状の改善もわずかで、副作用にも注意する必要がある。発熱やうつ状態による長期間の活動性低下は運動機能の低下につながる。 In addition, interferon α is the only drug that has been approved for medical insurance against HAM. However, interferon α is expensive, has little improvement in symptoms, and needs attention to side effects. Long-term decline in activity due to fever and depression leads to a decline in motor function.
　このように、従来において、HAMに対して特に有効な治療法が存在しているとは言えず、より安全で、安価で、且つ有効なHAMに対する治療法が求められている。 Thus, it cannot be said that there is a particularly effective treatment for HAM in the past, and there is a need for a safer, less expensive and effective treatment for HAM.
　一方、L-アルギニンは、アルギニン塩酸塩として、アルギU点滴静注20gがエイワイファーマより、また内服薬として味の素製薬から、高アンモニア血症や先天性尿素サイクル異常症の治療薬として用いられている。また、ミトコンドリア病のMELAS(Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes)に対するL-アルギニン塩酸塩を用いた治療についても医師主導試験が行われている。 On the other hand, L-arginine is used as a therapeutic agent for hyperammonemia and congenital urea cycle abnormalities as arginine hydrochloride, 20 g of Argy U intravenous infusion from Awai Pharma, and Ajinomoto as an internal medicine. . In addition, doctor-led trials are also being conducted on treatment with L-arginine hydrochloride for MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes) in mitochondrial diseases.
　しかしながら、従来において、HAMの治療薬としてL-アルギニン塩酸塩が用いられたことはない。 However, L-arginine hydrochloride has never been used as a therapeutic agent for HAM.
　本発明は、上述した実情に鑑み、HAM等の自己免疫疾患治療剤を提供することを目的とする。 The present invention aims to provide a therapeutic agent for autoimmune diseases such as HAM in view of the above situation.
　上記課題を解決するため鋭意研究を行った結果、歩行障害を有するHAM患者に対してアルギニン塩酸塩を投与したところ、当該患者における歩行障害の有意な改善が認められ、また、HAMの活動性のマーカーである髄液ネオプテリン値の改善が見られ、アルギニン塩酸塩がHAM等の自己免疫疾患の治療に有効であることを見出し、本発明を完成するに至った。 As a result of diligent research to solve the above problems, when arginine hydrochloride was administered to HAM patients with gait disturbance, significant improvement in gait disturbance in the patients was observed, and the activity of HAM The marker cerebrospinal fluid neopterin level was improved, and arginine hydrochloride was found to be effective in the treatment of autoimmune diseases such as HAM, thereby completing the present invention.
　すなわち、本発明は、以下を包含する。 That is, the present invention includes the following.
　（１）L-アルギニン塩酸塩を有効成分として含有する自己免疫疾患治療剤。 (1) An autoimmune disease therapeutic agent containing L-arginine hydrochloride as an active ingredient.
　（２）自己免疫疾患がHAMである、（１）記載の自己免疫疾患治療剤。 (2) The autoimmune disease therapeutic agent according to (1), wherein the autoimmune disease is HAM.
　（３）0.125g～0.5g/kg体重/日のL-アルギニン塩酸塩を投与するためのものである、（２）記載の自己免疫疾患治療剤。 (3) The therapeutic agent for autoimmune diseases according to (2), for administering L-arginine hydrochloride of 0.125 g to 0.5 g / kg body weight / day.
　（４）0.2g～0.5g/kg体重/日のL-アルギニン塩酸塩を投与するためのものである、（３）記載の自己免疫疾患治療剤。 (4) The therapeutic agent for autoimmune diseases according to (3), for administering L-arginine hydrochloride of 0.2 g to 0.5 g / kg body weight / day.
　（５）経口投与するためのものである、（２）～（４）のいずれか１記載の自己免疫疾患治療剤。 (5) The autoimmune disease therapeutic agent according to any one of (2) to (4), which is for oral administration.
　（６）毎日投与するためのものである、（２）～（５）のいずれか１記載の自己免疫疾患治療剤。 (6) The autoimmune disease therapeutic agent according to any one of (2) to (5), which is for daily administration.
　（７）投与期間は、一生涯である、（２）～（６）のいずれか１記載の自己免疫疾患治療剤。 (7) The autoimmune disease therapeutic agent according to any one of (2) to (6), wherein the administration period is a lifetime.
　本明細書は本願の優先権の基礎となる日本国特許出願番号2015-249621号の開示内容を包含する。 This specification includes the disclosure of Japanese Patent Application No. 2015-249621, which is the basis of the priority of the present application.
　本発明によれば、HAM等の自己免疫疾患をより安全で、且つ安価に治療することができる。 According to the present invention, autoimmune diseases such as HAM can be treated more safely and inexpensively.
　本発明に係る自己免疫疾患治療剤(以下、「本発明に係る治療剤」と称する)は、L-アルギニン塩酸塩を有効成分として含有するものである。 The autoimmune disease therapeutic agent according to the present invention (hereinafter referred to as “therapeutic agent according to the present invention”) contains L-arginine hydrochloride as an active ingredient.
　ここで、自己免疫疾患としては、例えばHAM、自己免疫性脳症、多発性硬化症、アトピー性皮膚炎、筋炎、気管支喘息、アレルギー性鼻炎、全身性エリテマトーデス、潰瘍性大腸炎、クローン病、ベーチェット病、関節リウマチ、橋本病、糸球体腎炎、間質性肺炎、サルコイドーシス等が挙げられる。特に、本発明に係る治療剤の投与により、HAM患者において歩行障害や排尿障害を有意に改善することができる。 Here, examples of the autoimmune disease include HAM, autoimmune encephalopathy, multiple sclerosis, atopic dermatitis, myositis, bronchial asthma, allergic rhinitis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, Behcet's disease Rheumatoid arthritis, Hashimoto's disease, glomerulonephritis, interstitial pneumonia, sarcoidosis and the like. In particular, the administration of the therapeutic agent according to the present invention can significantly improve gait disturbance and urination disorder in HAM patients.
　本発明に係る治療剤における有効成分であるL-アルギニン塩酸塩としては、例えばエイワイファーマ株式会社や味の素製薬株式会社から市販されているアルギU点滴静注20g、EAファーマ株式会社等から市販されているアルギU配合顆粒(アルギU顆粒)等を使用することができる。 The L-arginine hydrochloride, which is an active ingredient in the therapeutic agent according to the present invention, is commercially available from, for example, Argy U Intravenous Infusion 20 g commercially available from AY Pharma Co., Ltd. and Ajinomoto Pharmaceutical Co., Ltd., EA Pharma Co., Ltd. Algi U-containing granules (Argi U granules) can be used.
　本発明に係る治療剤は、その剤形に応じてそれ自体公知の種々の方法で投与することが可能であり、その投与量、投与部位、投与する間隔、期間等は、患者の年齢や体重、病状あるいは他の薬剤や治療法と併用した場合等を考慮して適宜決定することができる。投与方法としては、特に制限されないが、例えば、経口投与、注射や点滴静注等が挙げられる。 The therapeutic agent according to the present invention can be administered by various methods known per se according to the dosage form, and the dosage, administration site, administration interval, period, etc. are determined depending on the age and weight of the patient. It can be appropriately determined in consideration of a medical condition or a combination with other drugs and treatment methods. The administration method is not particularly limited, and examples thereof include oral administration, injection, and intravenous infusion.
　本発明に係る治療剤の投与量は、その剤形、投与方法、又は治療しようとする症状により異なるが、例えば、体重1kg当たりの投与量として有効成分(L-アルギニン塩酸塩)換算で0.125g～0.5g、好ましくは0.2g～0.5gとすることができ、1日1回又は数回、あるいは持続点滴等、さらには数日毎に1回、毎日1回というような、適当な投与頻度によって投与することが可能である。また、投与期間は一生涯であることが好ましい。 The dosage of the therapeutic agent according to the present invention varies depending on the dosage form, administration method, or symptoms to be treated.For example, the dosage per kg body weight is 0.125 g in terms of active ingredient (L-arginine hydrochloride). 0.5 g, preferably 0.2 g to 0.5 g, depending on an appropriate administration frequency such as once or several times a day, continuous infusion, etc., once every several days, once a day, etc. It is possible to administer. In addition, the administration period is preferably a lifetime.
　本発明に係る治療剤の形態としては、例えば、点滴、錠剤、カプセル剤、散剤、顆粒剤、坐剤、注射剤等が挙げられるが、特に制限されない。また、本発明に係る治療剤は、例えば製剤担体、賦形剤、安定剤等の成分を含有することもできる。 Examples of the form of the therapeutic agent according to the present invention include, for example, infusion, tablets, capsules, powders, granules, suppositories, and injections, but are not particularly limited. In addition, the therapeutic agent according to the present invention may contain components such as a pharmaceutical carrier, an excipient, and a stabilizer.
　また、本発明は、L-アルギニン塩酸塩をヒトや動物等の被験体(患者)に投与することを含む、自己免疫疾患の治療方法に関する。L-アルギニン塩酸塩の剤形、投与様式、投与量等は、上述の本発明に係る治療剤に準じて決定することができる。 The present invention also relates to a method for treating an autoimmune disease, comprising administering L-arginine hydrochloride to a subject (patient) such as a human or an animal. The dosage form, administration mode, dosage and the like of L-arginine hydrochloride can be determined according to the above-described therapeutic agent according to the present invention.
　以下、実施例を用いて本発明をより詳細に説明するが、本発明の技術的範囲はこれら実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail using examples, but the technical scope of the present invention is not limited to these examples.
〔実施例１〕L-アルギニン塩酸塩によるHAMの治療
1．症例１
(i)患者、材料及び方法
　症例は70歳女性。既知のHTLV-1関連脊髄症(以下HAM)があり、下肢筋力低下の進行を主訴に入院精査した。この時、筋疾患とHTLV-1脊髄症の合併と診断した。筋生検にてミトコンドリア機能異常を認められた。ミトコンドリア機能障害に対する治療としてL-アルギニン点滴を使用した。L-アルギニンは、アルギU 10g/42.0kg/日で7日間使用した。 [Example 1] Treatment of HAM with L-arginine hydrochloride
1． Case 1
(i) Patient, material and method The case is a 70-year-old woman. There was a known HTLV-1-related myelopathy (HAM), and the patient was admitted to the hospital with a chief complaint of lower leg muscle weakness. At this time, it was diagnosed as a combination of myopathy and HTLV-1 myelopathy. Muscle biopsy revealed mitochondrial dysfunction. L-arginine infusion was used as a treatment for mitochondrial dysfunction. L-arginine was used at Argy U 10 g / 42.0 kg / day for 7 days.
(ii)結果及び考察
　頸部、脊柱起立筋、下肢筋力の改善と歩様の改善を認めた。 (ii) Results and discussion Improvements in cervical, spine standing muscle, lower limb strength and gait were observed.
　また、HTLV-1関連脊髄症のバイオマーカーとされるネオプテリン値が、治療前14 pmol/mlから9 pmol/mlに低下していた。HTLV-1DNA定量値は81.3から31.7に低下していた。2回目のLアルギニン点滴にて、HTLV-1DNA定量値は7.7まで低下している。筋疾患よりもHAMに対してHTLV-1関連脊髄症に有効であったと考えられる。 Also, the neopterin level, which is a biomarker for HTLV-1-related myelopathy, had decreased from 14 pmol / ml to 9 pmol / ml before treatment. The quantitative value of HTLV-1 DNA decreased from 81.3 to 31.7. In the second L-arginine infusion, the HTLV-1 DNA quantitative value decreased to 7.7. Probably more effective in HTLV-1-related myelopathy against HAM than muscle disease.
2．症例２
(i)患者、材料及び方法
　症例は63歳女性。関節リウマチの既往がある。1年前からの四肢反射、痙性歩行、病的反射陽性、排尿障害があり、前医神経内科にてHTLV-1抗体陽性を指摘されHAMと診断された。症状進行のため当科紹介・入院となった。 2． Case 2
(i) Patient, material and method The case is a 63 year old female. A history of rheumatoid arthritis. He had limb reflexes, spastic gait, positive pathological reflexes, and dysuria since 1 year ago. He was diagnosed with HAM because he was positive for HTLV-1 antibody in the Department of Neurology. She was referred to our hospital and hospitalized because of symptom progression.
　症例１の経験から、L-アルギニン点滴を行った。アルギニンはアルギU 15g/52.5kg/日で7日間使用した。 From the experience of case 1, L-arginine infusion was performed. Arginine was used at Argy U 15g / 52.5kg / day for 7 days.
(ii)結果及び考察
　HAM臨床症状評価尺度として使用される10m歩行では18秒25歩から15秒23歩に改善を認めた。 (ii) Results and discussion 10m walking used as the HAM clinical symptom evaluation scale showed improvement from 18 seconds 25 steps to 15 seconds 23 steps.
3．症例３
(i)患者、材料及び方法
　症例は54歳女性。25年前にHTLV-1キャリアと診断されている。4年前からの下半身発汗低下、3年前から下肢異常感覚を認めている。2年前から走行困難、つまづきやすさがあり、1年前にHAMと診断された。精査加療目的で入院となった。入院時Osame grade 4(階段昇降に手すり必要)であった。 3． Case 3
(i) Patient, material and method The case is a 54 year old female. Diagnosed as HTLV-1 carrier 25 years ago. Lower sweating of the lower body from 4 years ago, and abnormal sensation of the lower limbs from 3 years ago. He had difficulty running and stumbles for two years and was diagnosed with HAM a year ago. He was admitted to the hospital for close examination and treatment. The patient was Osame grade 4 at the time of admission (handrail needed to climb the stairs).
　症例１及び２の経験からHAMに対するL-アルギニン加療を行った。アルギニンはアルギU 15g/59.0kg/日で7日間使用した。 From the experience of cases 1 and 2, L-arginine treatment for HAM was performed. Arginine was used at Argy U 15g / 59.0kg / day for 7 days.
(ii)結果及び考察
　腸腰筋と大腿二頭筋の筋力の改善、Osame grade 1(手すりなしで階段昇降可、小走り可)まで改善している。 (ii) Results and discussion Improvement of muscular strength of iliopsoas and biceps femoris, Osame grade 1 (steps can be moved up and down without handrails, small runs allowed).
　脊髄の炎症を反映していると考えられる髄液蛋白は48.8→36.4(mg/dL)に改善していた。 Cerebrospinal fluid protein, which is thought to reflect spinal cord inflammation, was improved from 48.8 to 36.4 (mg / dL).
4．症例４
(i)患者、材料及び方法
　患者は74歳女性。20年ほど前より下肢の運動機能障害および排尿障害を自覚していた。20年の経過中徐々に進行し続け、6年前、5年前に各々ステロイドによる治療を受け改善をしていたが、3年前のステロイド治療では改善を認めなかった。徐々に筋力低下が認められたため、L-アルギニンの点滴静注による治療を試みた。 Four. Case 4
(i) Patient, material and method The patient is a 74 year old female. He has been aware of lower limb motor dysfunction and dysuria for about 20 years. It progressed gradually over the course of 20 years and improved with steroid treatment 6 and 5 years ago, but no improvement was observed with steroid treatment 3 years ago. Since muscular weakness was gradually observed, treatment with intravenous infusion of L-arginine was attempted.
　アルギニンはアルギU 15g/日で7日間使用した。 Arginine was used for 7 days at Argy U 15g / day.
(ii)結果及び考察
　静脈内投与により、30m歩行では、歩数は72歩が60歩に、所要時間は62秒が44秒と著しく改善を認めた。OABSSは10点が6点に改善した。 (ii) Results and discussion With intravenous administration, the number of steps for 30m walking was 72 steps to 60 steps, and the required time was 62 seconds to 44 seconds. OABSS improved from 10 to 6 points.
5．症例５
(i)患者、材料及び方法
　患者は82歳男性。60歳ごろからの頻尿があり、歩行障害も徐々に進行し、64歳時にHAMと診断されている。両下肢の痙性歩行が著しく、二本杖歩行となっている。排尿障害のため夜間に5回の尿とりパッドの交換が必要であった。精査加療目的で入院となった。入院時Osame grade 6、排尿障害のスケールであるところのOABSSは14点であった。 Five. Case 5
(i) Patient, material and method The patient is a 82 year old male. He has frequent urination around the age of 60, and his gait disturbance gradually progresses. He was diagnosed with HAM at the age of 64. The spastic gait of both lower limbs is remarkable, and it is a double cane walking. Because of dysuria, it was necessary to change the urine collection pad 5 times at night. He was admitted to the hospital for close examination and treatment. OABSS, the scale of Osame grade 6 on admission and dysuria, was 14 points.
　症例１～４の経験から、L-アルギニンの内服加療を試みた。アルギニンは、アルギU顆粒 20g/54.0kg体重/日内服とし7日間使用した。なお自宅で3ヶ月前以降はアルギニン以外の内服やリハビリ内容の変更は行なっていないことを確認している。 From the experiences of cases 1 to 4, I tried internal treatment with L-arginine. Arginine was used for 7 days as Argi U granule 20g / 54.0kg body weight / day. It has been confirmed that no changes have been made to internal use or rehabilitation other than arginine after 3 months at home.
(ii)結果及び考察
　10m歩行は入院時103秒であったものが、内服1週間後に87.8秒に短縮していた。3m up and go testでは93秒から87.3秒に短縮していた。 (ii) Results and discussion Although walking 10m was 103 seconds at the time of admission, it was shortened to 87.8 seconds one week after oral administration. In 3m up and go test, it was reduced from 93 seconds to 87.3 seconds.
　膝関節の痙縮が内服3日目に軽減しており、筋緊張評価スケール(Modified Ashworth scale)では内服前1+から内服後1へと改善を認めた。 Knee joint spasticity was reduced on the third day of internal use, and the muscle tone evaluation scale (Modified Ashworth scale) showed improvement from 1+ before internal use to 1 after internal use.
　下肢の針を刺す痛みが入院時のVisual Analogue scaleで8.5cmから0cmへと著しい改善を認めた。 The pain of sticking the needles in the lower limbs was markedly improved from 8.5cm to 0cm on Visual Analogue scale at the time of hospitalization.
　排尿障害については夜間の尿おむつパッドの交換が入院時5回必要であったものが、内服後3回に軽減しており、失禁回数も減少し、過活動性膀胱の重症度を示すOveractive bladder syndrome score(;OABSS)は14点から12点へと改善した。 For dysuria, replacement of urine diaper pad at night was required 5 times at the time of hospitalization, but it was reduced to 3 times after internal use, the number of incontinence decreased, and Overactive bladder indicating the severity of overactive bladder Syndrome score (; OABSS) improved from 14 points to 12 points.
　生化学検査では内服にてアルギニン値が60.2 nmol/mlから275.8 nmol/mlへと上昇し、内服したものが十分に血中へ移行していることを確認した。 In the biochemical examination, the arginine level increased from 60.2 nmol / ml to 275.8 nmol / ml in the internal use, and it was confirmed that the internal use was sufficiently transferred into the blood.
　血液免疫学的検査では、炎症反応に関与するサイトカインである血清IL-6が9.0から測定限界以下(<8.0)へ減少し、炎症の改善が示唆され、IL-6産生を誘導するとされるアディポネクチンも内服前8.1から治療開始後2週間後で7.1まで低下した。 Hematological immunoassay shows that adiponectin, a cytokine involved in the inflammatory response, decreases from 9.0 to below the measurement limit (<8.0), suggesting improved inflammation and inducing IL-6 production It also decreased from 8.1 before internal use to 7.1 two weeks after the start of treatment.
　免疫反応の制御に関わるとされるNK細胞の機能指標の一つであるNK細胞活性は、活性が低下すると抗腫瘍効果が低下することが知られているが、この機能がE/T 10:1が5.8→6.5%へ上昇、E/T 20:1が10.9→12.4%へと上昇し、抗腫瘍効果の上昇が示唆された。 It is known that NK cell activity, one of the NK cell function indicators involved in the control of immune response, decreases the antitumor effect when the activity decreases, but this function is E / T 10: 1 increased from 5.8 to 6.5%, and E / T 20: 1 increased from 10.9 to 12.4%, suggesting an increase in antitumor effects.
　L-アルギニンを内服したことで、炎症・免疫反応の指標であるIL-6、アディポネクチンが減少しており、免疫調節に関わるNK細胞活性が上昇しており、HAMの臨床症状が改善していたことから、L-Arginineが疾病の自己免疫的機序に抑制的に作用したことが示唆された。 By taking L-arginine, IL-6 and adiponectin, which are indicators of inflammation and immune response, decreased, NK cell activity related to immune regulation increased, and clinical symptoms of HAM were improved These results suggest that L-Arginine has an inhibitory effect on the autoimmune mechanism of the disease.
6．症例６
(i)患者、材料及び方法
　症例は52歳女性。ATL家族歴(母親)、妹3人がHTLV-1キャリアである。10代から便秘があり、38歳ごろから下肢の痙縮を自覚し階段昇降が困難となった。48歳には過活動性膀胱を発症し、HTLV-1陽性を指摘され、HAMと診断された。精査加療目的で入院となった。入院時Osame grade 4、過活動性膀胱のスケールであるところのOABSSは5点だった。 6． Case 6
(i) Patient, material and method The case is a 52 year old female. ATL family history (mother) and 3 younger sisters are HTLV-1 carriers. Constipation has occurred since his teenage years, and he became aware of spasticity of the lower limbs around the age of 38, making it difficult to move up and down the stairs. At 48 years of age, he developed overactive bladder, was positive for HTLV-1, and was diagnosed with HAM. He was admitted to the hospital for close examination and treatment. The OABSS, which is the scale of Osame grade 4 at the time of admission and overactive bladder, was 5 points.
　症例１～４の経験から、L-アルギニンの内服加療を試みた。アルギニンは、アルギU顆粒 20g/56.0kg体重/日内服とし7日間使用した。なお外来加療で3ヶ月前以降はアルギニン以外の内服の変更を行なっていないことを確認している。 From the experiences of cases 1 to 4, I tried internal treatment with L-arginine. Arginine was used for 7 days as Argi U granule 20g / 56.0kg body weight / day. In addition, it has been confirmed that no change in internal use other than arginine has been made since 3 months before outpatient treatment.
(ii)結果及び考察
　10m歩行は入院時11.9秒、22歩であったものが、内服1週間後に10.3秒19歩に短縮していた。歩数の減少は痙縮の軽減が示唆される。3m up and go testでは12.0秒から10.2秒に短縮していた。 (ii) Results and discussion The 10m walk was 11.9 seconds and 22 steps on admission, but it was shortened to 10.3 seconds and 19 steps one week after internal use. A decrease in the number of steps suggests a reduction in spasticity. In 3m up and go test, it was shortened from 12.0 seconds to 10.2 seconds.
　膝関節の痙縮が内服3日目に軽減しており、特に左下肢の間代が偽性間代に軽減していた。 痙 Spasticity of the knee joint was reduced on the third day of oral administration, especially the left lower limb clones were reduced to pseudoclones.
　腹筋が徒手筋力テストにて4から4+へと改善し、ベッドからの起床が容易となった。前脛骨筋が徒手筋力テストで4から5レベルへと改善した。 The abdominal muscles improved from 4 to 4+ in the manual strength test, making it easier to get up from the bed. The anterior tibial muscle was improved from 4 to 5 in the manual strength test.
　排尿障害については夜間尿が5-8回であったものが、内服1週間後に2-3回まで減少しており、過活動性膀胱の重症度を示すOveractive bladder syndrome score(;OABSS)は5点から3点へと軽減した。 As for dysuria, the number of nocturnal urine was 5-8 times, but decreased to 2-3 times one week after internal use, and Overactive bladder syndrome score (; OABSS) indicating the severity of overactive bladder was 5 Reduced from 3 to 3.
　生化学検査では、内服にてアルギニン値が86.0 nmol/mlから350.6 nmol/mlへと上昇し、内服したアルギニンが血中へ移行していることを確認した。 In the biochemical examination, it was confirmed that the arginine level increased from 86.0 nmol / ml to 350.6 nmol / ml in the internal use, and the internal arginine was transferred into the blood.
　血液免疫学的検査では、炎症性サイトカインであるIL-6産生を誘導するとされる血清アディポネクチンが9.8から内服1週間後に8.6、2週間後に7へと漸減し、抗炎症効果が示唆された。 炎症促進作用を持つレプチンも31.3から26.7へと低下していた。免疫反応の制御に関わるとされるNK細胞の機能を反映するNK細胞活性は、E/T 10:1が8.90→10.5%へ増加、E/T 20:1が15.9→19.0%へと増加し、抗腫瘍効果が示唆された。 In the blood immunological test, serum adiponectin, which is supposed to induce the production of IL-6, an inflammatory cytokine, gradually decreased from 9.8 to 8.6 one week after oral administration and 7 after two weeks, suggesting an anti-inflammatory effect.レ Leptin, which has a pro-inflammatory effect, also decreased from 31.3 to 26.7. NK cell activity, which reflects the function of NK cells that are said to be involved in the control of immune responses, increased from 8.90 to 10.5% for E / T 10: 1, and from 15.9 to 19.0% for E / T 20: 1. Antitumor effect was suggested.
　L-アルギニンを内服したことで、炎症・免疫反応の指標であるレプチン、アディポネクチンが減少しており、免疫調節に関わるNK細胞活性が上昇しており、HAMの臨床症状が改善していたことから、L-アルギニンがHAM疾病の自己免疫的機序に抑制的に作用したことが示唆された。 Taking L-arginine reduced leptin and adiponectin, which are indicators of inflammation and immune response, increased NK cell activity related to immune regulation, and improved clinical symptoms of HAM These results suggest that L-arginine has an inhibitory effect on the autoimmune mechanism of HAM disease.
　本明細書で引用した全ての刊行物、特許及び特許出願はそのまま引用により本明細書に組み入れられるものとする。 All publications, patents and patent applications cited in this specification are incorporated herein by reference in their entirety.

Claims (7)

  1. 　L-アルギニン塩酸塩を有効成分として含有する自己免疫疾患治療剤。 An autoimmune disease therapeutic agent containing L-arginine hydrochloride as an active ingredient.
  2. 　自己免疫疾患がHTLV-1関連脊髄症である、請求項１記載の自己免疫疾患治療剤。 The autoimmune disease therapeutic agent according to claim 1, wherein the autoimmune disease is HTLV-1-related myelopathy.
  3. 　0.125g～0.5g/kg体重/日のL-アルギニン塩酸塩を投与するためのものである、請求項２記載の自己免疫疾患治療剤。 The therapeutic agent for autoimmune diseases according to claim 2, which is for administering 0.125 g to 0.5 g / kg body weight / day of L-arginine hydrochloride.
  4. 　0.2g～0.5g/kg体重/日のL-アルギニン塩酸塩を投与するためのものである、請求項３記載の自己免疫疾患治療剤。 The therapeutic agent for autoimmune diseases according to claim 3, which is for administering 0.2 g to 0.5 g / kg body weight / day of L-arginine hydrochloride.
  5. 　経口投与するためのものである、請求項２～４のいずれか１項記載の自己免疫疾患治療剤。 The therapeutic agent for autoimmune diseases according to any one of claims 2 to 4, which is for oral administration.
  6. 　毎日投与するためのものである、請求項２～５のいずれか１項記載の自己免疫疾患治療剤。 The therapeutic agent for autoimmune diseases according to any one of claims 2 to 5, which is for daily administration.
  7. 　投与期間は、一生涯である、請求項２～６のいずれか１項記載の自己免疫疾患治療剤。 The autoimmune disease therapeutic agent according to any one of claims 2 to 6, wherein the administration period is a lifetime.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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JP2000184865A (en) * 1998-12-21 2000-07-04 Nobuko Koga Food

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0789862A (en) * 1990-05-29 1995-04-04 Toyobo Co Ltd Anti-inflammatory, immunosuppressive and analgesic composition and method for treating autoimmune disease using the same
JP2000184865A (en) * 1998-12-21 2000-07-04 Nobuko Koga Food

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Title
"Recombinant Human Interferon Beta-1a (Avonex) for the Treatment of Patients with HTLV-1 Associated Myelopathy (HAM", CLINICALTRIALS, NCT ID: NCT00001785, 3 March 2008 (2008-03-03), pages 1 - 5, XP055397467, Retrieved from the Internet <URL:http://clinicaltrials.gov/archive/NCT00001785> *
KOHEI OTA: "Tahatsusei Kokasho Management Handbook", December 2013 (2013-12-01), pages 82 - 90, Retrieved from the Internet <URL:http://ms-supportnavi.jp/med/avx/self_injection/pdf/manage.pdf> [retrieved on 20170201] *
YOSHIHISA YAMANO ET AL.: "Pathophysiology, treatment and biomarkers for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP", JAPANESE JOURNAL OF CLINICAL MEDICINE, vol. 71, no. 5, May 2013 (2013-05-01), pages 870 - 875, ISSN: 0047-1852 *

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