JP7021298B2 - L-4-クロロキヌレニンの剤形及び治療的使用 - Google Patents
L-4-クロロキヌレニンの剤形及び治療的使用 Download PDFInfo
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- JP7021298B2 JP7021298B2 JP2020115273A JP2020115273A JP7021298B2 JP 7021298 B2 JP7021298 B2 JP 7021298B2 JP 2020115273 A JP2020115273 A JP 2020115273A JP 2020115273 A JP2020115273 A JP 2020115273A JP 7021298 B2 JP7021298 B2 JP 7021298B2
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- chlorokynurenine
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- neuropathic pain
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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2R44DA018515-02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(cholorkynurenine)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Palfreymanら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らの「ストリキニン非感受性グリシンの酵素活性アンタゴニスト/NMDA受容体(Enzyme-Activated Antagonists of the Strychnine-Insensitive Glycine/NMDA Receptor)」、J.Med.Chem.1994年;37-334,336などの医学文献で報告されている。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AV-101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、対象に連続14日間、1日経口用量を服用させた。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AV-101の痛覚過敏抑制効果を評価した。
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。
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。
L-4-クロロキヌレニンの抗うつ活性
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、(プラセボ群において対象0名であったのと対照的に)対象26名のうち5名は、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、「ストレスにより誘発された海馬のNMDA受容体の変化:デュロキセチン治療によるモジュレーション(Stress-Induced Changes of Hippocampal NMDA Receptors:Modulation by Duloxetine Treatment)」、PLoS ONE 2012年、7巻(5号):e37916.doi:10.1371/journal.pone.0037916を参照されたい。
(参考文献)
本出願で言及された以下の学術誌の論文並びに他のすべての刊行物、特許及びテキストは、その全体を参照により組み込まれる。
(1)Carter AJ.「グリシンアンタゴニスト:ストリキニン非感受性グリシン部位によるNMDA受容体チャンネル複合体の調節(Glycine antagonist:Regulation of the NMDA receptor channel complex by the strychnine-insensitive glycine site)」,Drugs Future 1992;17:595-613。
(2)Catarziら「競合的Gly/NMDA受容体アンタゴニスト(Competitive Gly/NMDA receptor antagonists)」,Curr.Top.Med.Chem.2006;6(8):809-21。
(3)Hokari M、Wu H-Q、Schwarcz R、Smith QR.「4-クロロキヌレニンの脳の取り込みの促進及び7-クロロキヌレン酸への変換(Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid)」,Neuroreport 1996;8(1):15-18。
(4)Kemp JA、Foster AC、Leeson PD、Priestley T、Tridgett R、Iversen LLら「7-クロロキヌレン酸は、N-メチル-D-アスパラギン酸受容体複合体のグリシン修飾部位の選択的アンタゴニストである(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。
(5)Lee S-C、Schwarcz R.「興奮毒性の損傷は、in vivoのラットの線条体においてプロドラッグ誘発性7-クロロキヌレナート配合物を刺激する(Excitotoxic injury stimulates pro-drug-induced 7-chlorokynurenate formation in the rat striatum in vivo)」,Neuroscience Lett 2001;304(3):185-188。
(6)Leeson PD、Iversen LL.「NMDA受容体におけるグリシン部位:構造-活性の関係及び治療可能性(The glycine site on the NMDA receptor:Structure-activity relationships and therapeutic potential)」,J Med Chem 1994;37(24):4053-4067。
(7)Linderholmら「内因性キヌレン酸によるラット腹側被蓋領域ドーパミンニューロンの活性化:薬理学的分析(Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid:a pharmacological analysis)」,Neuropharmacology 2007;53(8):918-924。
(8)Parsons CG、Danysz W、Quack G、Hartmann S、Lorenz B、Wollenburg Cら「N-メチル-D-アスパラギン酸受容体のグリシン部位の新規な全身的に活性のアンタゴニスト:電気生理学的、生化学的及び行動の特性付け(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。
(9)Rao TS、Gray NM、Dappen MS、Cler JA、Mick SJ、Emmett MRら「インドール-2-カルボキシレート、N-メチル-D-アスパラギン酸(NMDA)関連グリシン認識部位の新規なアンタゴニスト:in vivoにおける特性付け(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。
(10)Rundfeldt C、Wlaz P、Loscher W.「てんかんのキンドリングモデルにおけるNMDA受容体関連グリシン部位についてのアンタゴニスト及び部分アゴニストの抗けいれん活性(Anticonvulsant activity of antagonists and partial agonists for the NMDA receptor-associated glycine site in the kindling model of epilepsy)」,Brain Res 1994;653(1-2):125-130。
(11)Wu HQ、Lee SC、Scharfman HE、Schwarcz R.「L-4-クロロキヌレニンは、ラットにおいてカイニン酸誘発性発作及び病変を減弱する(L-4-chlorokynurenine attenuates kainate-induced seizures and lesions in the rat)」,Exp Neurol 2002;177(1):222-232。
(12)Wu H-Q、Lee S-C、Schwarcz R.「4-クロロキヌレニンの全身投与は、ラットの海馬においてキノリン酸の神経毒性を予防する(Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus)」,Eur J Pharm 2000;390:267-274。
Claims (10)
- 治療有効量のL-4-クロロキヌレニンを含む、神経障害性疼痛を治療するための医薬組成物。
- 単位用量当たり約50mgから約1,800mgの量のL-4-クロロキヌレニンと薬学的に許容される成分とを含む、請求項1に記載の医薬組成物。
- 単位用量当たり約360mgから約1,440mgの量のL-4-クロロキヌレニンと薬学的に許容される成分とを含む、請求項1に記載の医薬組成物。
- 神経障害性疼痛が、痛覚過敏である、請求項1又は3に記載の医薬組成物。
- 神経障害性疼痛が、糖尿病に関連する、請求項1~3のいずれか一項に記載の医薬組成物。
- 神経障害性疼痛が、化学療法に関連する、請求項1~3のいずれか一項に記載の医薬組成物。
- 神経障害性疼痛が、切断に関連する、請求項1~3のいずれか一項に記載の医薬組成物。
- 神経障害性疼痛が、末梢性神経障害性疼痛である、請求項1~3のいずれか一項に記載の医薬組成物。
- 神経障害性疼痛が、中枢性神経障害性疼痛である、請求項1~3のいずれか一項に記載の医薬組成物。
- 単位用量剤型が、L-4-クロロキヌレニン及び薬学的に許容される成分から本質的になる錠剤又はカプセルである、請求項1~9のいずれか一項に記載の医薬組成物。
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CA2898619C (en) | 2013-01-22 | 2021-10-19 | Vistagen Therapeutics, Inc. | Dosage forms and therapeutic uses of l-4-chlorokynurenine |
DK3297619T3 (da) * | 2015-05-22 | 2022-08-15 | Vistagen Therapeutics Inc | Terapeutiske anvendelser af L-4-chlorkynurenin |
CA2996308A1 (en) * | 2015-09-08 | 2017-03-16 | Cephalon, Inc. | Prodrugs of chlorokynurenines |
US11427530B2 (en) | 2018-02-09 | 2022-08-30 | Vistagen Therapeutics, Inc. | Synthesis of 4-chlorokynurenines and intermediates |
CN109223785A (zh) * | 2018-10-29 | 2019-01-18 | 中国药科大学 | 犬尿喹啉酸或其衍生物在制备改善慢性精神应激相关病理损伤药物中的应用 |
WO2022082100A1 (en) * | 2020-10-16 | 2022-04-21 | Vistagen Therapeutics, Inc. | Cocrystals of l-4-chlorokynurenine, compositions and therapeutic uses thereof |
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WO2003015713A2 (en) | 2001-08-20 | 2003-02-27 | Maiken Nedergaard | Treatment of glial tumors with glutamate antagonists |
EP1545551A4 (en) | 2002-09-06 | 2008-10-22 | Durect Corp | DISTRIBUTION OF MODULATORS OF THE GLUTAMAT-MEDIATED NEUROTRANSMISSION TO THE INNER EAR |
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EA200802054A1 (ru) | 2006-04-12 | 2009-04-28 | Пробиодруг Аг | Ингибиторы фермента |
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