JP2022064908A - L-4-クロロキヌレニンの治療的使用 - Google Patents
L-4-クロロキヌレニンの治療的使用 Download PDFInfo
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- JP2022064908A JP2022064908A JP2022004811A JP2022004811A JP2022064908A JP 2022064908 A JP2022064908 A JP 2022064908A JP 2022004811 A JP2022004811 A JP 2022004811A JP 2022004811 A JP2022004811 A JP 2022004811A JP 2022064908 A JP2022064908 A JP 2022064908A
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- chlorokynurenine
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Abstract
Description
本出願において示されるデータは、少なくとも部分的に米国国立衛生研究所(U.S.National Institutes of Health)による助成金交付番号2R44DA0 185 15-02の援助により得られた。米国政府は、本発明において一定の権利を有する。
薬学的に活性な薬剤のある特定の量から「本質的に成る」とは、その薬剤の追加の量がないことを意味する。例えば、添加剤及び/又は滑沢剤などの他の成分、又は組み合わせた異なる薬学的に活性な成分の存在は、除外されない。例えば、L-DOPAと4-クロロキヌレニンとの組合せが特に考えられ、同様に、これらを投与するための、4-クロロキヌレニンと、同時又は逐次的のいずれかで、ただしそれらが単一の組合せ医薬品として投与された場合と実質的に同じ治療効果が生じるような時間枠で投与される別の有効成分とを含む他の組成物及び方法も考えられる。
L-4-クロロキヌレニンは、米国特許第5,547,991号の方法によって合成されている。またより最近の合成方法も、Salituroら1994年などの医学文献で報告されている。好ましい合成方法は、公開された国際特許出願WO/2014/152752及びWO/2014/152835に記載されている。L-4-クロロキヌレニンはまた、BOC Sciences(Shirley、NY、USA)及びAdvanced Technology & Industrial Co.,Ltd.(Hong Kong、China)などの様々な供給元からも市販されている。Cambridge Major Laboratories(Germantown、WI、USA)は、本特許出願で論じられている臨床試験で用いられたL-4-クロロキヌレニンを製造した。
第1b相一施設ランダム化二重盲検プラセボ対照試験を、健常な男性及び女性対象においてL-4-クロロキヌレニンの多回経口投与に関して実施した。対象を、3コホート(360、1,080、及び1,440mg)のうちの1コホートにランダム化し、対象には連続14日間、経口1日用量を服用させた。各コホートには、最初に実薬に対して12名の対象が含まれ、プラセボに対して4名の対象が含まれるように計画された。しかしながら、合計50名の対象が本試験に登録された。コホート1において、12名の対象がL-4-クロロキヌレニンを服用し、5名の対象がプラセボを服用した。コホート2において、13名の対象がL-4-クロロキヌレニンを服用し、4名の対象がプラセボを服用した。コホート3において、12名の対象がL-4-クロロキヌレニンを服用し、4名の対象がプラセボを服用した。46名の対象がプロトコール毎に試験を完了した。安全性、薬物動態(PK)、治療の忍容性、及びカプサイシン誘発性痛覚過敏に対するL-4-クロロキヌレニンの痛覚過敏抑制効果を評価した。
臨床試験の1日目及び14日目に、カプサイシン250μgの皮内注射を2回、前腕の手掌側に交互に逐次的に注射して、灼熱痛、第2の痛覚過敏、及び発赤を生じさせた。カプサイシンUSP(米国薬局方)を、作業現場の標準的な手順に従って調製し、10mg/mLの濃度で20%のシクロデキストリンに溶解した。
疾患管理予防センター(Centers for Disease Control and Prevention)は、米国成人の約10%が「大うつ病」又は「他のうつ病」のいずれかであると定義される「現在のうつ病」の基準を満たすと推定する。大うつ病性障害(「MDD」)は、深刻な罹患率及び死亡率、自殺への寄与、精神疾患及びその有害転帰の存在、対人関係への干渉、物質乱用、並びに失職する時間と関連する。また、MDD及び双極性障害(BPD)などの再発性気分障害は慢性であり、しばしば生命を脅かすものである。例えば、自殺は、MDDを有する個体の最大約15%の死亡の原因と推定される。さらに、うつ病は他の病状に有害な作用を及ぼす。例えば、Musselmanら1988年を参照されたい。
本発明者らはまた、驚くべきことに、L-4-クロロキヌレニンの気分の高まり又は抗うつ活性を見出した。本出願に記載の臨床試験において、対象26名のうち5名は(プラセボ群において0名であったのと対照的に)、満足であるという気持ちを肯定的に報告した。これは、グルタミン酸作動性系がうつ病の病態生理に寄与し、ストレスがNMDA受容体の変化を誘導し得るという報告と一致する。例えば、Calabreseら、2012年を参照されたい。
男性及び女性の両方で、18~65歳のMDDと診断された25名の患者を、2週間、L-4-クロロキヌレニン(1,080又は1,440mg/日、経口で)で、同様の研究と同様のデザインで治療する[Ibrahimら2012年、Zarateら2013年、Zarateら2006年、Zarateら2005年]。うつ病の症状全体の改善は、ハミルトンうつ病評価尺度(HDRS)[Hamilton1959年]及びMontgomery Asbergうつ病評価尺度(MADRS)合計点[Montgomeryら1979年]のいずれか又は両方での著しい減少により示されている。所定の患者に対する治療の効果への追加の指標は、緩解(HDRS≦7)及び応答に達する対象の割合(HDRS合計点におけるベースラインから50%以上減少);ハミルトン不安評価尺度(HAM-A)[Hamilton1959年]、コロンビア自殺重症度評価尺度(C-SSRS)合計点[Posnerら2011年]、並びに、気分若しくは心理学的状態の他の尺度、例えば、ベックうつ病調査表(BDI)[Beckら1974年]、視覚アナログ尺度(VAS)[Aitken1969年]、簡易精神医学的評価尺度(BPRS)[Overallら1962年]、Clinician Administered Dissociative States Scale(CADSS)[Bremnerら1998年]、及びヤング躁病評価尺度(YMRS)[Youngら1978年]のベースラインからの変化でもあり得る。
L-4-クロロキヌレニンは、うつ病及び本明細書に記載されている他の状態を治療するのに有用な他の薬剤と組み合わせて投与される場合があり、かかる組合せは、こうして投与される場合に、相乗的に効果的であり得る。2つの療法での相乗的な応答により、副作用、症状の管理、及び、例えば、MDDなどのうつ病に関連する思考過程における、程度、期間、又は低下に関して、所定の患者はより良好な成果に達する。
・リルゾール、ラモトリギン、トピラマート、プレガバリン、アカンプロサート、アニラセタム、EMQMCM、MTEP、LY341495、RO4491533、ACPT-1、AMN082、RS-PPGなどのグルタミン酸調節剤
・メマンチン、ラニセミン、GLYX-13、NRX-1074、トラキソプロジル、セルフォテル、セレスタット、デキストロメトルファン、ベソンプロジル、Ro25-6981などのNMDAを調整する他の化合物
・シタロプラム(Celexa)、エスシタロプラム(Lexapro、Cipralex)、パロキセチン(Paxil、Seroxat)、フルオキセチン(Prozac)、フルボキサミン(Luvox)、及びセルトラリン(Zoloft、Lustral)などの選択的セロトニン再取り込み阻害剤(SSRI)
・デスベンラファキシン(Pristiq)、デュロキセチン(Cymbalta)、レボミルナシプラン(Fetzima)、ミルナシプラン(Ixel、Savella)、トフェナシン(Elamol、Tofacine)、及びベンラファキシン(Effexor)などのセロトニン-ノルエピネフリン再取り込み阻害剤(SNRI)
・ビラゾドン(Viibryd)、ボルチオキセチン(Brintellix)などのセロトニン調節及び刺激薬(SMS)
・エトペリドン(Axiomin、Etonin)、及びトラゾドン(Desyrel)などのセロトニンアンタゴニスト及び再取り込み阻害剤(SARI)
・レボキセチン(Edronax)、ビロキサジン(Vivalan)、及びアトモキセチン(Strattera)などのノルエピネフリン再取り込み阻害剤(NRI)
・チアネプチン(Stablon)などのセロトニン再取り込み促進剤(SSRE)
・アミトリプチリン(Elavil、Endep)などの三環系抗うつ剤(TCA)
・ブトリプチリン(Evadene)、クロミプラミン(Anafranil)、デシプラミン(Norpramin、Pertofrane)、ドスレピン(Prothiaden)、ドキセピン(Adapin、Sinequan)、イミプラミン(Tofranil)、イプリンドール(Prondol)、ロフェプラミン(Feprapax、Gamanil、Lomont)
・メリトラセン(Melixeran)、ノルトリプチリン(Pamelor)、プロトリプチリン(Vivactil)、並びに
・トリミプラミン(Surmontil)
・オピプラモール(Insidon)などのシグマ受容体アゴニスト
・アモキサピン(Asendin)、マプロチリン(Ludiomil)、ミアンセリン(Bolvidon、Norval、Tolvon)、ミルタザピン(Remeron)、セチプチリン(Tecipul)などの四環系抗うつ剤(TeCA)
・ミアンセリン、ミルタザピン、及びセチプチリンなどのノルアドレナリン作動性・特異的セロトニン作動性抗うつ剤(NaSSA)(ミアンセリン、ミルタザピン、及びセチプチリンはまた、四環系抗うつ剤として記載される場合もある)
・イソカルボキサジド(Marplan)、フェネルジン(Nardil)、トラニルシプロミン(Parnate)、セレギリン(Eldepryl、Zelapar、Emsam)、メトラリンドール(Inkazan)、モクロベミド(Aurorix、Manerix)、ピルリンドール(Pirazidol)、トロキサトン(Humoryl)などのモノアミン酸化酵素阻害剤(MAOI)
・アゴメラチン(Valdoxan) - 5-HT2C受容体アンタゴニスト並びにMT1及びMT2受容体アゴニスト
・ブプレノルフィン(Subutex、Temgesic、Buprenex) - κ-オピオイド受容体アンタゴニスト及びμ-オピオイド受容体部分アゴニスト
・ブプロピオン(Wellbutrin) - いくつかの神経細胞のnACh受容体のNRI及び非競合的アンタゴニスト
・タンドスピロン(Sediel) - 5-HT1A受容体部分アゴニスト
・テニロキサジン(Lucelan、Metatone) - NRI及び5-HT2A受容体アンタゴニスト
・アリピプラゾール(Abilify)、ルラシドン(Latuda)、オランザピン(Zyprexa)、クエチアピン(Seroquel、Seroquel XR)、リスペリドン(Risperdal)、ジプラシドン(Geodon)などの非定型抗精神病薬
・ブスピロン(BuSpar) - 5-HT1A受容体部分アゴニスト;リチウム塩(Eskalith、Lithobid) - 気分安定剤;チロキシン(T4) - 甲状腺ホルモン;トリヨードチロニン(T3) - 甲状腺ホルモンなどの他のもの
・現在の組合せ製品
・オランザピン/フルオキセチン(Symbyax) - SSRI及び非定型抗精神病薬の組合せ
・セントジョーンズワートなどの生薬
大うつ病エピソードを経験し、彼らの臨床医より選択された抗うつ剤療法(ADT)を受ける患者は、時には、その薬剤に対する不適切な治療応答を有し、最初のものと組み合わせて別のADTを受ける[Horiら2012年、Kamijimaら2013年、Macfaddenら2011年、Quanteら2013年、Sepanjnia2012年]。別のADT(上記で論ずる)と共にL-4-クロロキヌレニンはかかる患者に投与される。ケタミン及びアルファ-アミノ-3-ヒドロキシ-5-メチル-4-イソキサゾールプロピオン酸(AMPA)の治療量以下の用量が投与される場合、当業者に公知の相乗的な応答と同様に、いずれかの薬物単体で見られる効果を超える、上記の尺度のうちの1つ又は複数によって決定されるような、症状の程度又は期間に対する改善が示される[Akinfiresoyeら2013年]。L-4-クロロキヌレニンの用量は、約20mg/日~最大約2,000mg/日、より好ましくは約300mg/日~約1,500mg/日、より好ましくは約700mg/日~約1,200mg/日から選択される。
Kraemerら2002年で詳述された「バイオマーカー」又は「モデレーター」は、「治療を施す対象に、及び条件下に特異的な」因子である。これら因子は、患者が治療に対して最も反応し、患者に対してのより適切な他の治療を探求し得ることも、臨床医に示唆している。予測し、うつ病並びに他の精神医学的疾患及び状態に対しての治療に続くのに用いられる、数種類のバイオマーカーの先例がある[Hunterら2011年、Isingら2007年、Jiら2011年、Siegleら2012年、Wolkowitzら2012年]。
強迫性障害(OCD)の患者は、OCDの症状を軽減するためにL-4-クロロキヌレニンで治療される。患者は、OCD視覚アナログ尺度(OCD-VAS)及びYale-Brown強迫観念・脅迫行為尺度(Y-BOCS)などの評価試験での評価に基づいて改善を示す。L-4-クロロキヌレニンの用量は、約20mg/日~最大約2,000mg/日、より好ましくは約300mg/日~約1,500mg/日、より好ましくは約700mg/日~約1,200mg/日から選択される。
耳鳴は、一般に耳鳴りとして記載されているが、聴覚刺激の非存在下での音の認識である。米国のおよそ10人に1人の成人が、過去1年で少なくとも5分間続く耳鳴を経験しており、少なくとも100人に1人は、耳鳴が生活の質に著しい影響を与えている。これは西欧及び米国で1億3,000万人超が深刻な耳鳴を有することになる[Vioら2005年、Axelssonら1989年]。しばしば、重症の耳鳴は、うつ病、不安、及び不眠症に関連する[Langguthら2007年、Cronleinら2007年]。「米国復員軍人援護局2013年給付報告書(US Veterans Administration 2013 Benefits Report)」では、耳鳴を、新規の復員軍人で最も多い軍務関係の身体障害の1つと位置付けており、すべての支払額の9.5%を占めていた(http://www.benefits.va.gov/REPORTS/abr/ABR-Combined-FY13-09262014.pdf)。
耳鳴の治療に対するL-4-クロロキヌレニンの効果を実証する臨床試験は、プロスペクティブランダム化二重盲検プラセボ対照並行群間用量漸増デザインである。片耳又は両耳の慢性耳鳴が少なくとも3か月間続く、20~65歳の100名の男性又は女性の患者を試験に登録した。患者は薬物群又はプラセボ群にランダム化され、ベースラインの心理測定及び健康測定を行い、続いて14日間、L-4-クロロキヌレニン(初期用量180mg)又はプラセボのいずれかを1日1回経口投与で盲検投与される。続く心理測定及び健康測定を投薬後3、7、及び14日目(次の薬物投与の前)に行う。14日目及び28日目に、AV-101の用量を、それぞれ720及び1440mg/日に増加する。42日目及び70日目に、すべての患者に心理測定及び健康測定のパネルを渡す。
2014年現在、世界中で推定3億8,700万人が糖尿病を有し[WHO2013年]、2型糖尿病(T2DM)が症例の約90%に上る[Shiら2014年]。これは、成人人口の8.3%に当たり[Shiら2014年]、男女共に同じ割合である[Vosら2012年]。2012~2014年で、糖尿病は毎年150~490万人の死亡につながると推定される[WHO2013年、Vosら2012年]。糖尿病により、個人の死亡リスクが少なくとも2倍になる[WHO2015年]。糖尿病の人数は、2035年までに5億9,200万人に増加すると予想される[WHO2013年]。
本明細書で言及された又は下に挙げられた以下の学術誌の論文並びに他のすべての刊行物、特許及び文献は、その全体を参照により組み込まれる。
Aitken, R.C., (1969) Measurement of feelings using visual analogue scales. Proc R Soc Med 62(10):989-93
Akinfiresoye, L. and Y. Tizabi, (2013) Antidepressant effects of AMPA and ketamine combination: role of hippocampal BDNF, synapsin, and mTOR. Psychopharmacology (Berl) 230(2):291-8
Amiel, S.A., et al., (2008) Hypoglycaemia in Type 2 diabetes. Diabet Med 25(3):245-54
Axelsson, A. and A. Ringdahl, (1989) Tinnitus--a study of its prevalence and characteristics. Br J Audiol 23(1):53-62
Beck, A.T. and A. Beamesderfer, (1974) Assessment of depression: the depression inventory. Mod Probl Pharmacopsychiatry 7(0):151-69
Bay-Richter, C., et al. (2015) "A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality." Brain Behav Immun 43:110-117
Bremner, J.D., et al., (1998) Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress 11(1):125-36
Burris, R.E. and M. Hebrok, (2007) Pancreatic innervation in mouse development and beta-cell regeneration. Neuroscience 150(3):592-602
Carter AJ. Glycine antagonist: Regulation of the NMDA receptor channel complex by the strychnine-insensitive glycine site. Drugs Future 1992;17:595-613
Calabrese et al., 2012 "Stress-Induced Changes of Hippocampal NMDA Receptors: Modulation by Duloxetine Treatment," PLoS ONE 2012, 7(5): e37916. doi:10.1371/journal.pone.0037916
Catarzi et al., Competitive Gly/NMDA receptor antagonists, Curr. Top. Med. Chem. 2006;6(8):809-21
Cronlein, T., et al., (2007) Tinnitus and insomnia. Prog Brain Res 166:227-33
Erhardt, S., et al. (2013) "Connecting inflammation with glutamate agonism in suicidality." Neuropsychopharmacology 38:743-752
Guitton, M.J., et al., (2003) Salicylate induces tinnitus through activation of cochlear NMDA receptors. J Neurosci 23(9):3944-52
Guitton, M.J. and Y. Dudai, (2007) Blockade of cochlear NMDA receptors prevents long-term tinnitus during a brief consolidation window after acoustic trauma. Neural Plast 2007:80904
Group, T.S., (2013) Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and beta-cell function in TODAY. Diabetes Care 36(6):1749-57
Hainer, V., (2014) Overview of new antiobesity drugs. Expert Opin Pharmacother 15(14):1975-8
Hallam, R.S., S.C. Jakes, and R. Hinchcliffe, (1988) Cognitive variables in tinnitus annoyance. Br J Clin Psychol 27 ( Pt 3):213-22
Hamilton, M., (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62
Hamilton, M., (1959) The assessment of anxiety states by rating. Br J Med Psychol 32(1):50-5
Hokari M, Wu H-Q, Schwarcz R, Smith QR. Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid. Neuroreport 1996;8(1): 15-18
Hori, H. and H. Kunugi, (2012) The efficacy of pramipexole, a dopamine receptor agonist, as an adjunctive treatment in treatment-resistant depression: an open-label trial. ScientificWorldJournal 2012:372474
Hunter, A.M., et al., (2011) The antidepressant treatment response index and treatment outcomes in a placebo-controlled trial of fluoxetine. J Clin Neurophysiol 28(5):478-82
Ibrahim, L., et al., (2012) A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. J Clin Psychopharmacol 32(4):551-7
IDF. Diabetes Atlas, Sixth edition 2013
IDF. Diabetes Atlas, 6th edition. 2014; Available from:
http://www.idf.org/diabetesatlas/update-2014
Inagaki, N., et al., (1995) Expression and role of ionotropic glutamate receptors in pancreatic islet cells. FASEB J 9(8):686-91
Ising, M., et al., (2007) Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression - a potential biomarker? Biol Psychiatry 62(1):47-54
Ji, Y., et al., (2011) Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics-informed pharmacogenomics. Clin Pharmacol Ther 89(1):97-104
Kamijima, K., et al., (2013) Aripiprazole augmentation to antidepressant therapy in Japanese patients with major depressive disorder: a randomized, double-blind, placebo-controlled study (ADMIRE study). J Affect Disord 151(3):899-905
Kemp JA, Foster AC, Leeson PD, Priestley T, Tridgett R, Iversen LL, et al. 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl- D-aspartate receptor complex. Proc Natl Acads Sci U.S.A. 1988;85(17):6547-6550
Kraemer, H.C., et al., (2002) Mediators and moderators of treatment effects in randomized clinical trials. Arch Gen Psychiatry 59(10):877-83
Kuwabara, T., et al., (2011) Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb. EMBO Mol Med 3(12):742-54
Langguth, B., et al., (2007) Tinnitus severity, depression, and the big five personality traits. Prog Brain Res 166:221-5
Lee S-C, Schwarcz R. Excitotoxic injury stimulates pro-drug-induced 7-chlorokynurenate formation in the rat striatum in vivo. Neuroscience Lett 2001;304(3):185-188
Leeson PD, Iversen LL. The glycine site on the NMDA receptor: Structure-activity relationships and therapeutic potential. J Med Chem 1994;37(24):4053-4067
Linderholm, et al., Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis, Neuropharmacology 2007;53(8):918-924
Marquard, J., et al. (2015) "Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment." Nat Med 21:363-372
Macfadden, W., et al., (2011) Adjunctive long-acting risperidone in patients with bipolar disorder who relapse frequently and have active mood symptoms. BMC Psychiatry 11:171
Montgomery, S.A. and M. Asberg, (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382-9
Musselman, D. et al. (1988). “The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment." Arch. Gen. Psychiatry 55(7): 580-592 (1988)
Myint, A. M., et al. (2007) "Kynurenine pathway in major depression: evidence of impaired neuroprotection." J Affect Disord 98:143-151
Nondahl, D.M., et al., (2007) The impact of tinnitus on quality of life in older adults. J Am Acad Audiol 18(3):257-66
Oestreicher, E., et al., (1998) Memantine suppresses the glutamatergic neurotransmission of mammalian inner hair cells. ORL J Otorhinolaryngol Relat Spec 60(1):18-21
Overall, J.E. and D.R. Gorham, (1962) The Brief Psychiatric Rating Scale. Psychological Reports 10(3):799-812
Parsons CG, Danysz W, Quack G, Hartmann S, Lorenz B, Wollenburg C, et al. Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization. J Pharmacol Exp Ther 1997;283(3): 1264-1275
Peng, B.G., S. Chen, and X. Lin, (2003) Aspirin selectively augmented N-methyl-D-aspartate types of glutamate responses in cultured spiral ganglion neurons of mice. Neurosci Lett 343(1):21-4
Posner K., et al., (2011) The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 168(12):1266-77
Quante, A., et al., (2013) Quetiapine as combination treatment with citalopram in unipolar depression with prominent somatic symptoms: a randomised, double-blind, placebo-controlled pilot study. Psychiatr Danub 25(3):214-20
Rao TS, Gray NM, Dappen MS, Cler JA, Mick SJ, Emmett MR, et al. Indole-2- carboxylates, novel antagonists of the N-methyl-D-aspartate (NMDA)-associated glycine recognition sites: in vivo characterization. Neuropharmacol 1993;32(2): 139-147
Rodriguez-Diaz, R., et al., (2012) Real-time detection of acetylcholine release from the human endocrine pancreas. Nat Protoc 7(6):1015-23
Rosenstock, J., et al., (2014) Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-S). J Diabetes Complications 28(3):386-92
Rundfeldt C , Wlaz P , Loscher W . Anticonvulsant activity of antagonists and partial agonists for the NMDA receptor-associated glycine site in the kindling model of epilepsy. Brain Res 1994;653(l-2): 125-130
Salituro et al., (1994) Enzyme-Activated Antagonists of the Strychnine-Insensitive Glycine/NMDA Receptor, J. Med. Chem. 1994:37-334,336
Schwartz, M.W., et al., (2013) Cooperation between brain and islet in glucose homeostasis and diabetes. Nature 503(7474):59-66
Shi, Y. and F.B. Hu, (2014) The global implications of diabetes and cancer. Lancet 383(9933):1947-8
Sepanjnia, K., et al., (2012) Pioglitazone adjunctive therapy for moderate-to-severe major depressive disorder: randomized double-blind placebo-controlled trial. Neuropsychopharmacology 37(9):2093-100
Siegle, G.J., et al., (2012) Toward clinically useful neuroimaging in depression treatment: prognostic utility of subgenual cingulate activity for determining depression outcome in cognitive therapy across studies, scanners, and patient characteristics. Arch Gen Psychiatry 69(9):913-24
Skrivanek, Z., et al., (2014) Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5). Diabetes Obes Metab 16(8):748-56
Soltani, N., et al., (2011) GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc Natl Acad Sci U S A 108(28):11692-7
Tambasco et al. (2012) N. et al "Clinical Aspects and Management of Levodopa-Induces Dyskinesia," Parkinson's Disease, Article ID 745947, doi:10.1 155/2012/745947
Tasyurek, H.M., et al., (2014) Incretins: their physiology and application in the treatment of diabetes mellitus. Diabetes Metab Res Rev 30(5):354-71
Tyler, R.S. and D. Conrad-Armes, (1983) The determination of tinnitus loudness considering the effects of recruitment. J Speech Hear Res 26(1):59-72
Van Hook, M.P., B. Berkman, and R. Dunkle, (1996) Assessment tools for general health care settings: PRIME-MD, OARS, and SF-36. Primary Care Evaluation of Mental Health Disorders. Older Americans Resources and Services Questionnaire; Short Form-36. Health Soc Work 21(3):230-4
Vetterli, L., et al., (2012) Delineation of glutamate pathways and secretory responses in pancreatic islets with beta-cell-specific abrogation of the glutamate dehydrogenase. Mol Biol Cell 23(19):3851-62
Vio, M.M. and R.H. Holme, (2005) Hearing loss and tinnitus: 250 million people and a US$10 billion potential market. Drug Discov Today 10(19):1263-5
Vos, T., et al., (2012) Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859):2163-96
WHO. The top 10 causes of death Fact sheet. 2013; Fact sheet N°310:[Available from:
http://www.who.int/mediacentre/factsheets/fs310/en/
WHO. Diabetes Fact Sheet, N 312. 2015; Available from:
http://www.who.int/mediacentre/factsheets/fs312/en/
Wolkowitz, O.M., et al., (2012) Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response. Mol Psychiatry 17(2):164-72
Wu HQ, Lee SC, Scharfman HE, Schwarcz R. L-4-chlorokynurenine attenuates kainate-induced seizures and lesions in the rat. Exp Neurol 2002;177(l):222-232
Wu H-Q, Lee S-C, Schwarcz R. Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus. Eur J Pharm 2000;390:267-274
Young, R.C., et al., (1978) A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133:429-35
Yang, W., et al., (2013) Economic costs of diabetes in the U.S. in 2012. Diabetes Care 36(4):1033-46
Zarate, C.A., Jr., et al., (2013) A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biol Psychiatry 74(4):257-64
Zarate, C.A.J., et al., (2005) An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry 57:430-432
Zarate, C.A., Jr., et al., (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856-64
Palfreyman et al.らの米国特許第5,547,991号
公開された国際特許出願WO/2014/152752
公開された国際特許出願WO/2014/152835
他の記載と重複するが、本発明を以下に示す。
[発明1]
L-4-クロロキヌレニンの有効量を投与することによる、耳鳴を治療する方法。
[発明2]
L-4-クロロキヌレニンの有効量を投与することによる、強迫性障害を治療する方法。
[発明3]
医薬組成物が、1~約30日、連日投与又は間欠投与で投与される、発明1~2のいずれか1項に記載の方法。
[発明4]
L-4-クロロキヌレニンの前記有効量が、1日約50mg~約1,800mgの範囲で投与される、発明1~2のいずれか1項に記載の方法。
[発明5]
医薬組成物が、担体及び添加剤などの薬学的に許容される成分と共に、約360、1,080又は1,440mgを含む群からの量のL-4-クロロキヌレニンから本質的に成る、発明5に記載の方法。
[発明6]
耳鳴及び強迫性障害を含む群から選択される状態の治療のためのこの組成物の使用を表示するラベルと共に包装されたL-4-クロロキヌレニンを含む、医薬組成物。
Claims (6)
- L-4-クロロキヌレニンの有効量を投与することによる、耳鳴を治療する方法。
- L-4-クロロキヌレニンの有効量を投与することによる、強迫性障害を治療する方法。
- 医薬組成物が、1~約30日、連日投与又は間欠投与で投与される、請求項1~2のいずれか1項に記載の方法。
- L-4-クロロキヌレニンの前記有効量が、1日約50mg~約1,800mgの範囲で投与される、請求項1~2のいずれか1項に記載の方法。
- 医薬組成物が、担体及び添加剤などの薬学的に許容される成分と共に、約360、1,080又は1,440mgを含む群からの量のL-4-クロロキヌレニンから本質的に成る、請求項5に記載の方法。
- 耳鳴及び強迫性障害を含む群から選択される状態の治療のためのこの組成物の使用を表示するラベルと共に包装されたL-4-クロロキヌレニンを含む、医薬組成物。
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JP2017560663A JP2018521007A (ja) | 2015-05-22 | 2016-05-23 | L−4−クロロキヌレニンの治療的使用 |
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JP2022004811A Pending JP2022064908A (ja) | 2015-05-22 | 2022-01-17 | L-4-クロロキヌレニンの治療的使用 |
JP2024000227A Pending JP2024050575A (ja) | 2015-05-22 | 2024-01-04 | L-4-クロロキヌレニンの治療的使用 |
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US20220202756A1 (en) * | 2019-04-09 | 2022-06-30 | Vistagen Therapeutics, Inc. | Genetic variants associated with response to treatment of neurological disorders |
EP4171554A1 (en) * | 2020-06-24 | 2023-05-03 | Biohaven Therapeutics Ltd. | Compositions and methods for treating obsessive-compulsive disorder |
WO2022221423A1 (en) * | 2021-04-13 | 2022-10-20 | Vistagen Therapeutics, Inc. | Treatment of autoimmune anti-nmda-receptor encephalitis |
CN115677519A (zh) * | 2021-07-22 | 2023-02-03 | 立科时代(武汉)生物科技有限公司 | L-4-溴-犬尿氨酸及其在制备治疗抑郁症药物中的应用 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009510047A (ja) * | 2005-09-28 | 2009-03-12 | アウリス メディカル アクチエンゲゼルシャフト | 蝸牛興奮毒性によって誘導される耳鳴りを処置する方法 |
WO2014031975A1 (en) * | 2012-08-23 | 2014-02-27 | Weg Stuart L | Anxiolytic composition, formulation and method of use |
WO2014116739A1 (en) * | 2013-01-22 | 2014-07-31 | Vistagen Therapeutics, Inc. | Dosage forms and therapeutic uses l-4-chlorokynurenine |
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Publication number | Priority date | Publication date | Assignee | Title |
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US5484814A (en) | 1991-02-28 | 1996-01-16 | Merrell Dow Pharmaceuticals Inc. | NMDA antagonists |
WO1999045906A1 (en) * | 1998-03-09 | 1999-09-16 | Trustees Of Tufts College | Treatment of compulsive behaviours in man and animals |
TW518218B (en) * | 1999-05-27 | 2003-01-21 | Merck Patent Gmbh | Pharmaceutical compositions comprising 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazine or its physiologically acceptable salts for use in the treatment of sub-type anxiety disorders |
CN1486180A (zh) * | 2000-12-07 | 2004-03-31 | 纽热莫勒丘乐有限公司 | 用nmda受体拮抗物治疗神经精神病紊乱的方法 |
JP2009533393A (ja) * | 2006-04-12 | 2009-09-17 | プロビオドルグ エージー | 酵素阻害薬 |
US8058243B2 (en) * | 2006-10-13 | 2011-11-15 | Hsc Research And Development Limited Partnership | Method for treating a brain cancer with ifenprodil |
BRPI0820406A2 (pt) * | 2007-11-06 | 2015-05-19 | Univ Emory | Métodos para identificar aumento de antagonistas do receptor nmda |
TW201026667A (en) * | 2008-09-30 | 2010-07-16 | Merz Pharma Gmbh & Co Kgaa | Glycine b antagonists |
CN105164096A (zh) | 2013-03-14 | 2015-12-16 | 维斯塔津治疗公司 | 手性犬尿氨酸化合物和中间体的合成 |
US9834801B2 (en) | 2013-03-14 | 2017-12-05 | Vistagen Therapeutics, Inc. | Methods for the synthesis of chiral kynurenine compounds |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009510047A (ja) * | 2005-09-28 | 2009-03-12 | アウリス メディカル アクチエンゲゼルシャフト | 蝸牛興奮毒性によって誘導される耳鳴りを処置する方法 |
WO2014031975A1 (en) * | 2012-08-23 | 2014-02-27 | Weg Stuart L | Anxiolytic composition, formulation and method of use |
WO2014116739A1 (en) * | 2013-01-22 | 2014-07-31 | Vistagen Therapeutics, Inc. | Dosage forms and therapeutic uses l-4-chlorokynurenine |
Non-Patent Citations (1)
Title |
---|
GUITTON, MATTHIEU J. ET AL., EUROPEAN JOURNAL OF NEUROSCIENCE, vol. 22, no. 10, JPN6022055650, 2005, pages 2675 - 2678, ISSN: 0005145145 * |
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