JP2017519778A - How to treat or improve migraine - Google Patents
How to treat or improve migraine Download PDFInfo
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- JP2017519778A JP2017519778A JP2016575106A JP2016575106A JP2017519778A JP 2017519778 A JP2017519778 A JP 2017519778A JP 2016575106 A JP2016575106 A JP 2016575106A JP 2016575106 A JP2016575106 A JP 2016575106A JP 2017519778 A JP2017519778 A JP 2017519778A
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Abstract
ある種の実施形態では、本発明はペプチドNMDAR部分アゴニストを投与することにより、片頭痛(例えば、一過性片頭痛、慢性片頭痛、網膜片頭痛、眼筋麻痺性片頭痛、無痛性片頭痛、片頭痛障害、月経片頭痛、腹性片頭痛、小児周期性症候群及び/または群発性頭痛)を治療する方法に関する。ある種の実施形態では、本発明はまた、ペプチドNMDAR部分アゴニストを投与することにより、患者の片頭痛後の長期後遺症を治療または改善するための方法にも関する。ある種の他の実施形態では、本発明は、ペプチドNMDAR部分アゴニストを投与することを含む、必要とする患者の皮質拡延性抑制または皮質拡延性抑制を原因とする疾患若しくは病態を治療、抑制及び/または予防する方法に関する。例えば、本明細書では、てんかん、外傷性脳損傷及び/または脳卒中の治療方法を提供する。In certain embodiments, the present invention provides migraine (eg, transient migraine, chronic migraine, retinal migraine, ophthalmoplegic migraine, painless migraine by administering a peptide NMDAR partial agonist. , Migraine disorder, menstrual migraine, abdominal migraine, childhood periodic syndrome and / or cluster headache). In certain embodiments, the present invention also relates to a method for treating or ameliorating long-term sequelae after migraine in a patient by administering a peptide NMDAR partial agonist. In certain other embodiments, the present invention treats, inhibits and treats a disease or condition caused by cortical spreading depression or a cortical spreading depression in a patient in need comprising administering a peptide NMDAR partial agonist. It relates to a method for preventing. For example, provided herein are methods for treating epilepsy, traumatic brain injury and / or stroke.
Description
関連出願の相互参照
本出願は、2014年6月23日出願の米国仮出願第62/015,727号及び2015年1月29日出願の米国仮出願第62/109,386号の利益及び優先権を主張するものであり、同出願はそれぞれその全体が参照により本明細書に組み込まれる。
CROSS REFERENCE TO RELATED APPLICATIONS This application is a benefit and priority of US Provisional Application No. 62 / 015,727 filed June 23, 2014 and US Provisional Application No. 62 / 109,386 filed January 29, 2015. Each of which is incorporated herein by reference in its entirety.
片頭痛は、反復する消耗性発作を伴う一過性の一次性頭痛障害であり、血管誘因性に焦点を置いた既存の薬物療法では抑制が不十分である場合が多い。片頭痛発作の発症は閃輝暗点すなわち片頭痛前兆によって予見される場合が多く、皮質拡延性抑制(SD;Ayata,Headache,50:725−30,2010、Eikerman−Haerterら,Curr.Neurol.Neurosci.Rep.,10:167−73,2010、及びSanchez−del−Rioら,Curr.Opin.Neurol.,17(3):289−93,2004を参照)の現象により引き起こされる。SDは、細胞外カリウムの局所的増加及びグルタミン酸塩の放出によって誘導される、緩慢に伝播する皮質脳波活性の抑制であり、これは皮質部位の広範囲にわたって自己伝播する緩慢な脱分極波を生じさせる。片頭痛患者の約15〜30%が前兆のある片頭痛を経験している。 Migraine is a transient primary headache disorder with repetitive debilitating seizures and is often poorly controlled with existing medications that focus on vascular triggering. The onset of a migraine attack is often predicted by a flashing dark spot or a migraine aura, and cortical spreading inhibition (SD; Ayata, Headache, 50: 725-30, 2010, Eikeman-Haerter et al., Curr. Neurol. Neurosci. Rep., 10: 167-73, 2010, and Sanchez-del-Rio et al., Curr. Opin. Neurol., 17 (3): 289-93, 2004). SD is a suppression of slowly propagating cortical EEG activity induced by a local increase in extracellular potassium and glutamate release, which results in a slow depolarizing wave that self-propagates over a wide range of cortical sites . About 15-30% of migraine patients experience migraine with aura.
哺乳動物の中枢神経系(CNS)は、脳及び脊髄内で特異的シグナル伝達を生じさせるために、神経活性ペプチドであるソマトスタチン、コレシストキニン、VIP、サブスタンスP、エンケファリン、ニューロペプチドY(NPY)、ニューロテンシン、TRH、CCK及びダイノルフィンを含む多くの神経活性ペプチドを用いている(概要はThe Biochemical Basis of Neuropharmacology,Cooper,Bloom及びRoth,5th ed.,Oxford University Press,New York,1986を参照)。CNS内で作動する複雑なシグナル伝達経路の綿密な解明により、CNSと関連した各種障害の重要な治療標的を提示するこれらの神経活性ペプチドによって調節される特異的受容体が同定された。 The mammalian central nervous system (CNS) is responsible for producing specific signaling in the brain and spinal cord somatostatin, cholecystokinin, VIP, substance P, enkephalin, neuropeptide Y (NPY) , Neurotensin, TRH, CCK, and dynorphin, including many neuroactive peptides (for a review see The Biochemical Basis of Neuropharmacology, Cooper, Bloom and Roth, 5th ed., Oxford Presity, 1986). ). A thorough elucidation of the complex signaling pathways that operate within the CNS has identified specific receptors that are regulated by these neuroactive peptides that present important therapeutic targets for various disorders associated with the CNS.
N−メチル−D−アスパラギン酸(NMDA)受容体(NMDAR)は、脳卒中を伴う脳細胞死、痙攣性障害ならびに学習及び記憶を含む神経変性疾患に関与するとされているような受容体の一種である。NMDARは、中枢神経系の通常のシナプス伝達、シナプス可塑性及び興奮毒性を調節する際にも中心的役割を果たす。NMDARは更に、長期増強(LTP)にも関与している。LTPは、学習及び記憶の基盤をなすニューロン接続を持続的に強化するものである(Bliss and Collingridge,1993,Nature 361:31−39を参照)。 N-methyl-D-aspartate (NMDA) receptor (NMDAR) is a type of receptor that has been implicated in neurodegenerative diseases including brain cell death with stroke, convulsive disorders and learning and memory. is there. NMDAR also plays a central role in regulating normal synaptic transmission, synaptic plasticity and excitotoxicity in the central nervous system. NMDAR is also involved in long-term potentiation (LTP). LTP continually strengthens the neuronal connections that underlie learning and memory (see Bliss and Collingridge, 1993, Nature 361: 31-39).
中枢神経系(CNS)においては2つの一般的クラスのグルタミン酸受容体が特定されている。これはシグナル伝達タンパク質のGタンパク質共役受容体ファミリーに属する代謝型グルタミン酸受容体と、イオンチャネル型グルタミン酸受容体である(Muir and Lees,Stroke,1995,26,503−513)。イオンチャネル型クラスは、受容体を活性化する選択的リガンドに応じて、AMPA、カイニン酸塩及びNMDA受容体というサブタイプに更に細分化される。 Two general classes of glutamate receptors have been identified in the central nervous system (CNS). This is a metabotropic glutamate receptor belonging to the G protein-coupled receptor family of signal transduction proteins and an ion channel glutamate receptor (Muir and Lees, Stroke, 1995, 26, 503-513). The ion channel type class is further subdivided into subtypes AMPA, kainate and NMDA receptors, depending on the selective ligand that activates the receptor.
NMDAを調節する小分子アゴニストとアンタゴニストの化合物が潜在的治療用途向けに開発されてきた。しかしながら、これらの多くは非常に狭い治療指数、ならびに幻覚、運動失調、不合理な挙動及び有意な毒性を含む望ましくない副作用を伴い、そのいずれもが有効性及び/または安全性を制限する。 Small molecule agonist and antagonist compounds that modulate NMDA have been developed for potential therapeutic applications. However, many of these involve very narrow therapeutic indices and undesirable side effects, including hallucinations, ataxia, unreasonable behavior and significant toxicity, all of which limit efficacy and / or safety.
したがって、効能を増加させ、望ましくない副作用を低減させた化合物による、片頭痛及び他の関連疾患の改善された治療法が依然として必要とされている。 Accordingly, there remains a need for improved treatment of migraine and other related diseases with compounds that have increased efficacy and reduced undesirable side effects.
ある種の実施形態では、本開示は、それを必要とする患者に薬学的有効量のGLYXペプチドを投与することを含む、片頭痛の治療方法に関する。ある種の実施形態では、片頭痛は、一過性片頭痛、慢性片頭痛、網膜片頭痛、眼筋麻痺性片頭痛、無痛性片頭痛、片頭痛障害、月経片頭痛、腹性片頭痛、小児周期性症候群及び/または群発性頭痛であり得る。ある種の実施形態では、片頭痛は前兆のない片頭痛(一般的な片頭痛)である。ある種の実施形態では、片頭痛は前兆のある片頭痛(古典的片頭痛)である。ある種の実施形態では、片頭痛はアロディニアを伴う。 In certain embodiments, the present disclosure relates to a method for treating migraine comprising administering to a patient in need thereof a pharmaceutically effective amount of a GLYX peptide. In certain embodiments, migraine is transient migraine, chronic migraine, retinal migraine, ocular paralytic migraine, painless migraine, migraine disorder, menstrual migraine, abdominal migraine, It may be childhood periodic syndrome and / or cluster headache. In certain embodiments, the migraine is a migraine without aura (generic migraine). In certain embodiments, the migraine is a migraine with aura (classical migraine). In certain embodiments, the migraine is associated with allodynia.
例えば、本開示の化合物は、片頭痛(例えば、一過性片頭痛、慢性片頭痛、網膜片頭痛、眼筋麻痺性片頭痛、無痛性片頭痛、片頭痛障害、月経片頭痛、腹性片頭痛、小児周期性症候群及び/または群発性頭痛)の治療においてNMDARグリシン部位の作動と機能的に相互作用すること、または該グリシン部位の作動を調節することができる。 For example, compounds of the present disclosure can be used for migraine (eg, transient migraine, chronic migraine, retinal migraine, ocular paralytic migraine, analgesic migraine, migraine disorder, menstrual migraine, abdominal migraine Functionally interacts with or regulates the operation of the NMDAR glycine site in the treatment of headache, childhood periodic syndrome and / or cluster headache).
ある種の実施形態では、本開示は、それを必要とする患者に薬学的有効量のGLYXペプチドを投与することを含む、皮質拡延性抑制(SD)の治療、抑制及び/または予防方法に関する。ある種の実施形態では、本開示は、患者に薬学的有効量のGLYXペプチドを投与することを含む、それを必要とする患者での片頭痛後の長期後遺症の治療及び/または改善方法に関する。 In certain embodiments, the present disclosure relates to a method of treating, suppressing and / or preventing cortical spreading inhibition (SD) comprising administering to a patient in need thereof a pharmaceutically effective amount of a GLYX peptide. In certain embodiments, the present disclosure relates to a method of treating and / or ameliorating long-term sequelae after migraine in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a GLYX peptide.
ある種の実施形態では、GLYXペプチドは、以下の構造:
若しくはその薬学的に許容される塩、またはNMDAR部分アゴニスト活性を有するその誘導体を有する。
In certain embodiments, the GLYX peptide has the following structure:
Or a pharmaceutically acceptable salt thereof, or a derivative thereof having NMDAR partial agonist activity.
一態様では、本発明はそれを必要とする患者の片頭痛を治療する方法に関し、該方法は前記患者に以下に表す薬学的有効量の化合物またはその薬学的に許容される塩を投与することを含む。
In one aspect, the invention relates to a method of treating migraine in a patient in need thereof, said method comprising administering to said patient a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof as shown below: including.
別の態様では、本発明はそれを必要とする患者の皮質拡延性抑制を治療、抑制及び/または予防する方法に関し、該方法は前記患者に以下に表す薬学的有効量の化合物またはその薬学的に許容される塩を投与することを含む。
In another aspect, the present invention relates to a method of treating, suppressing and / or preventing cortical spreading depression in a patient in need thereof, said method comprising a pharmaceutically effective amount of a compound represented below or said pharmaceutical Administration of an acceptable salt.
別の態様では、本発明はそれを必要とする患者での片頭痛後の長期後遺症の治療及び/または改善方法に関し、該方法は前記患者に以下に表す薬学的有効量の化合物またはその薬学的に許容される塩を投与することを含む。
In another aspect, the present invention relates to a method for the treatment and / or amelioration of long-term sequelae after migraine in a patient in need thereof, said method comprising a pharmaceutically effective amount of a compound represented below or said pharmaceutical Administration of an acceptable salt.
以下により詳細に説明するように、前兆時点で投与されると有効である薬剤は、例えば片頭痛の初期段階での介入を可能にすることにより患者にとって有益となり得る。本明細書に記載する方法は、前兆時点でのGLYXペプチドの投与を含む、前兆のある片頭痛の治療に適用できると考えられる。 As will be described in more detail below, agents that are effective when administered at a precursor time may be beneficial to the patient, for example, by allowing intervention at an early stage of migraine. The methods described herein are believed to be applicable to the treatment of migraine with aura, including administration of GLYX peptide at the aura.
片頭痛の分類
片頭痛は1988年に初めて包括的に分類された。直近では2004年にInternational Headache Societyがその頭痛分類を更新した。この分類によれば、片頭痛は、その中でも緊張型頭痛及び群発頭痛とならび一次性頭痛に分類されている。
Migraine Classification Migraine was first comprehensively classified in 1988. Most recently, International Headache Society updated its headache classification in 2004. According to this classification, migraine is classified as tension headache, cluster headache, and primary headache.
片頭痛は次の7つのサブクラスに分類される(サブクラスの一部は更なる細分を含む)。 Migraine is divided into the following seven subclasses (some subclasses contain further subdivisions):
前兆のない片頭痛、すなわち「一般的な片頭痛」は、前兆を伴わない片頭痛を含む。 Migraine without aura, or “common migraine”, includes migraine without aura.
前兆のある片頭痛、すなわち「古典的片頭痛」は通常、前兆を伴う片頭痛を含む。あまり一般的ではないが、前兆は、無頭痛で、または非片頭痛性頭痛を伴って発症することがある。このほかに家族性片麻痺性片頭痛及び散発性片麻痺性片頭痛の2種があり、その患者は前兆及び付随する運動麻痺のある片頭痛を有する。近親者が同じ病態を有していた場合、それを「家族性」と呼び、それ以外の場合は「散発性」と呼ぶ。別の種類は脳底型片頭痛であり、この場合の頭痛及び前兆は、構音障害、回転性めまい、耳鳴りまたは多数の他の脳幹関連症状を伴うが、運動麻痺は伴わない。このタイプは当初、脳底動脈、すなわち脳幹に供給される動脈の痙攣によるものと考えられていた。前兆のある片頭痛の診断のためのガイドラインは、例えば、Eriksenら,European Journal of Neurology 11:583−591,2004及びInternational Classification of Headache Disorders,Second Edition(ICHD−II)に記載されている。前兆のある片頭痛のサブタイプとして、片頭痛性頭痛を伴う典型的前兆(IHS 1.2.1)、非片頭痛性頭痛を伴う典型的前兆(IHS 1.2.2)、頭痛のない典型的前兆(IHS 1.2.3)、家族性片麻痺性片頭痛(IHS 1.2.4)、散発性片麻痺性片頭痛(IHS 1.2.5)及び脳底型片頭痛(IHS 1.2.6)などのICHD−IIに定められたものが挙げられる。 A migraine with aura, or “classical migraine,” usually includes a migraine with aura. Less commonly, the aura may develop without headache or with a non-migraine headache. There are two other types of familial hemiplegic migraine and sporadic hemiplegic migraine, and the patient has migraine with aura and associated motor paralysis. When close relatives have the same pathology, it is called “familial”, otherwise it is called “sporadic”. Another type is basilar migraine, in which the headache and aura are accompanied by articulation disorders, rotational dizziness, tinnitus or many other brainstem-related symptoms but not motor paralysis. This type was initially thought to be due to spasm of the arteries supplied to the basilar artery, or brainstem. Guidelines for diagnosing migraine with aura are described, for example, in Eriksen et al., European Journal of Neurology 11: 583-591, 2004 and International Classification of Headache Disorders, Second Edition (HD). Subtypes of migraine with aura include typical aura with migraine headache (IHS 1.2.1), typical aura with non-migraine headache (IHS 1.2.2), no headache Typical aura (IHS 1.2.3), familial hemiplegic migraine (IHS 1.2.4), sporadic hemiplegic migraine (IHS 1.2.5) and basilar migraine ( And those defined in ICHD-II such as IHS 1.2.6).
片頭痛の一般的な先駆症状である小児周期性症候群は、周期性嘔吐(不定期な強度間隔の嘔吐)、腹性片頭痛(通常、悪心を伴う腹痛)及び小児期の良性発作性めまい(不定期なめまい発作)を含む。 Pediatric periodic syndrome, a common pioneer of migraine, is periodic vomiting (irregular intensity interval vomiting), abdominal migraine (usually nausea with nausea) and childhood benign seizure dizziness ( Including irregular vertigo attacks).
網膜片頭痛は、片目の視覚障害または一時的な失明をも伴う片頭痛を含む。 Retinal migraine includes migraine with visual impairment or temporary blindness in one eye.
片頭痛の合併症とは、異常に長いか、または異常に頻度が高い、あるいは発作または脳病変を伴う片頭痛性頭痛及び/または前兆を表す。 Migraine complications refer to migraine headaches and / or precursors that are abnormally long or abnormally frequent, or accompanied by seizures or brain lesions.
片頭痛の疑いとは、片頭痛の一部の特徴を有する病態であるが、確実にそれを片頭痛と診断する根拠が十分でない(薬物の過剰併用が存在する)場合を表す。 Suspected migraine is a condition that has some characteristics of migraine, but represents a case where there is not sufficient evidence to diagnose it as migraine (there is an overdose of drugs).
慢性片頭痛は、片頭痛の合併症であり、片頭痛の診断基準を満たし、より長い時間間隔で発生する頭痛である。具体的には、3か月を超えて15日/月以上である。 Chronic migraine is a complication of migraine that meets the diagnostic criteria for migraine and occurs at longer time intervals. Specifically, it is 15 days / month or more exceeding 3 months.
片頭痛には、(1)頭痛の数時間または数日前に発生する前駆症状、(2)頭痛の直前に起こる前兆、(3)頭痛段階として知られる痛みの段階、及び(4)後発症状、すなわち片頭痛発作に続いて経験される影響、の4つの段階が起こり得るが、この全段階が必ずしも生じるわけではない。 Migraine headaches include (1) prodrome that occurs hours or days before headache, (2) precursors that occur just before headache, (3) pain stage known as headache stage, and (4) late symptoms. That is, the four phases of effects experienced following a migraine attack can occur, but not all of these phases occur.
前駆症状または予兆症状は、片頭痛患者の約60%に生じ、痛みの開始または前兆の2時間〜2日前に発症する。この症状には、気分の変調、過敏性、抑うつまたは多幸感、疲労感、特定の食物への過剰な欲求、筋肉のこり(特に頸部)、便秘または下痢、及び臭いまたは騒音に対する過敏性を含め、多種多様な現象が含まれ得る。これは前兆のある片頭痛の患者にも前兆のない片頭痛の患者にも発生し得る。 Prodrome or prodrome occurs in about 60% of migraine patients and develops 2 hours to 2 days before the onset or aura. Symptoms include mood swings, irritability, depression or euphoria, fatigue, excessive desire for certain foods, muscle stiffness (especially the cervix), constipation or diarrhea, and odor or noise sensitivity. A wide variety of phenomena can be included. This can occur in migraine patients with or without aura.
前兆とは、頭痛の前またはその期間中に発生する一過性の限局性神経現象である。これは数分間にわたって段階的に出現し、通常は60分も持続しない。症状は性質として視覚性、感覚性または運動性であり得、多くの人が複数を経験する。視覚性影響が最も発生頻度が高く、症例の最大99%に発生し、症例の50%超では感覚性または運動性の影響を伴わない。視覚障害は多くの場合、閃輝暗点(点滅する視界の部分的な変化領域であり、読み取りまたは運転の妨げとなる場合がある)。これらは通常、視野の中心付近で始まり、その後、城の要塞または壁のように見えると形容されるジグザグ線を伴って、視野の端へと拡大していく。通常、線は白黒であるが、色のついた線を見る人もいる。視野の一部が欠ける(同名半盲として知られる)人もあれば、視野のぼけを経験する人もある。 Aura is a transient focal neurological phenomenon that occurs before or during a headache. This appears in stages over several minutes and usually does not last as long as 60 minutes. Symptoms can be visual, sensory, or motor in nature, and many people experience more than one. Visual effects occur most frequently and occur in up to 99% of cases, with more than 50% of cases without sensory or motor effects. Visual impairment is often a flashing dark spot (a part of the blinking field of view that can interfere with reading or driving). These usually begin near the center of the field of view and then expand to the edge of the field of view with a zigzag line that is described as looking like a castle fortress or wall. Lines are usually black and white, but some people see colored lines. Some people lack part of their vision (known as the same name half-blind), and others experience blurry vision.
感覚前兆は、2番目に一般的なタイプであり、前兆のある患者の30〜40%に発生する。多くの場合、最初に手及び腕の片側にしびれ感が発生し、同側の鼻から口の領域まで広がる。刺痛が止んだ後、位置感覚の消失と共に、通常は麻痺が発生する。前兆段階のその他の症状としては、発話または言語障害、回転性めまい及びあまり一般的ではないが運動性の問題を挙げることができる。運動症状では、片頭痛が片麻痺性片頭痛であり、他の前兆とは異なり、衰弱が1時間より長く持続する場合が多い。 Sensory aura is the second most common type and occurs in 30-40% of patients with aura. In many cases, numbness initially develops on one side of the hand and arm and extends from the ipsilateral nose to the mouth area. After stabbing stops, paralysis usually occurs with loss of position sensation. Other symptoms at the precursor stage include speech or language disturbances, dizziness, and less common motility problems. In motor symptoms, the migraine is a hemiplegic migraine, and unlike other precursors, the weakness often lasts longer than 1 hour.
前兆が後続の頭痛を伴わずに発生する場合もある。サイレント片頭痛とも呼ばれる無痛性片頭痛は、比較的まれであり、前兆及び他の症状を含むが、後続の頭痛を伴わない(すなわち、痛み段階がない)。 In some cases, precursors may occur without a subsequent headache. Painless migraine, also called silent migraine, is relatively rare and includes aura and other symptoms but is not accompanied by a subsequent headache (ie, no pain stage).
痛み段階の間、頭痛は通常、片側、拍動性であり、強度は中程度から重度である。通常は徐々に出現し、身体活動によって悪化する。しかしながら症例の40%超では、痛みが両側にある場合があり、一般に頸痛を伴う。両側の痛みは特に、前兆のない片頭痛を有する患者によく見られる。あまり一般的ではないが、主として後頭部または頭頂部に痛みが生じる場合もある。痛みは通常、成人では4〜72時間持続するが、幼児では1時間も持続しない場合が多い。発作の頻度は持続期間中に数回から週に数回までさまざまであり、平均して約月1回である。 During the pain phase, headaches are usually unilateral, pulsatile and moderate to severe in intensity. It usually appears gradually and is aggravated by physical activity. However, in more than 40% of cases, the pain may be bilateral and is generally associated with neck pain. Bilateral pain is particularly common in patients with migraine without aura. Although less common, pain may occur primarily at the back of the head or the top of the head. Pain usually lasts from 4 to 72 hours for adults, but often does not last for an hour for infants. The frequency of seizures varies from several times during the duration to several times a week, on average about once a month.
痛みは、悪心、嘔吐、光に対する感受性、音に対する感受性、臭いに対する感受性、疲労感及び過敏性を伴う場合が多い。脳底型片頭痛、すなわち脳幹に関連した神経学的な症状を有する、または身体の両側に神経学的な症状を有する片頭痛では、一般的な影響として、回転性めまい感、ふらつき及び錯乱が挙げられる。悪心は患者のほぼ90%に発生し、嘔吐は約1/3に発生する。その他の症状として、霧視、鼻詰まり、下痢、頻尿、蒼白または発汗を含み得る。頸部のこりが発生し得るのと同様に、頭皮の腫脹または圧痛が発生する場合がある。 Pain is often accompanied by nausea, vomiting, sensitivity to light, sensitivity to sound, sensitivity to odor, fatigue and irritability. In migraine with basilar migraine, i.e. neurological symptoms related to the brainstem, or neurological symptoms on both sides of the body, common effects include rotational dizziness, lightheadedness and confusion. Can be mentioned. Nausea occurs in nearly 90% of patients and vomiting occurs in about 1/3. Other symptoms may include foggy, nasal congestion, diarrhea, frequent urination, pallor or sweating. Just as neck stiffness can occur, scalp swelling or tenderness may occur.
主たる頭痛が終息した後、片頭痛の影響が数日間持続する場合がある。これを片頭痛の後発症状と呼ぶ。多くが片頭痛のあった領域に痛みを感じると訴えており、頭痛が止んだ後の数日間、思考障害を訴える患者もいる。患者は疲労を感じる場合や、頭部の痛み、認知障害、胃腸症状、気分の変化及び虚弱を有する場合がある。 The migraine effect may persist for several days after the main headache ends. This is called a late symptom of migraine. Many complain that they feel pain in the migraine area, and some patients complain of thinking problems for a few days after the headache stops. Patients may feel tired or have head pain, cognitive impairment, gastrointestinal symptoms, mood changes and weakness.
GLYXペプチド
GLYX−13は、N−メチル−D−アスパラギン酸型グルタミン酸受容体(NMDAR)の活性化に対して、先例のない調節作用を有する新開発の即効性、長期持続性の抗うつ剤である。この抗うつ剤は、NMDA受容体の活性化に必要なNMDA受容体上の必須コアゴニストグリシン部位に作用し、この重要な受容体の活性を正常化し、低すぎる場合は増加させ、高すぎる場合は抑制する。この作用によってGLYX−13は、LTDを抑制しつつシナプス強度の長期増強(LTP)の誘発を増強できると共に、加齢動物からの海馬スライスにおいて正常なLTPを回復させることができる。
GLYX Peptide GLYX-13 is a newly developed fast-acting, long-lasting antidepressant with unprecedented regulatory action on the activation of N-methyl-D-aspartate glutamate receptor (NMDAR) is there. This antidepressant acts on the essential co-agonist glycine site on the NMDA receptor required for NMDA receptor activation, normalizes the activity of this important receptor, increases if it is too low, and increases if it is too high Suppresses. This action allows GLYX-13 to enhance the induction of long-term potentiation of synaptic strength (LTP) while suppressing LTD and to restore normal LTP in hippocampal slices from aging animals.
本明細書中で使用する場合、用語「GLYXペプチド」は、NMDARグリシン部位の部分アゴニスト/アンタゴニスト活性を有するペプチドを指す。GLYXペプチドは、参照により本明細書に組み込まれる、米国特許第5,763,393号及び同第4,086,196号に記載されているような、周知の組換えまたは合成方法によって得ても良い。いくつかの実施形態では、GLYXは、アミノ酸配列Thr−Pro−Pro−ThrまたはL−スレオニル−L−プロリル−L−プロリル−L−スレオニンアミドを有するテトラペプチドを指す。 As used herein, the term “GLYX peptide” refers to a peptide having partial agonist / antagonist activity at the NMDAR glycine site. GLYX peptides may be obtained by well known recombinant or synthetic methods, such as those described in US Pat. Nos. 5,763,393 and 4,086,196, incorporated herein by reference. good. In some embodiments, GLYX refers to a tetrapeptide having the amino acid sequence Thr-Pro-Pro-Thr or L-threonyl-L-prolyl-L-prolyl-L-threonine amide.
例えば、GLYX−13は、以下に表す化合物を指す。
式I
For example, GLYX-13 refers to the compound represented below.
Formula I
また、限定されないが酢酸塩のようなGLYX−13の多形体、ホモログ、水和物、溶媒和物、遊離塩基及び/または好適な塩の形態も企図される。このペプチドは、US5,763,393に更に記載されているように、環式形態であっても非環式形態であっても良い。いくつかの実施形態では、GLYX−13アナログが、1以上のThr群またはPro群に挿入または欠失部分、例えば、CH2、OHまたはNH2部分の欠失を含んでいて良い。他の実施形態では、GLYX−13は、1つ以上のハロゲン、C1〜C3アルキル(場合によりハロゲンまたはアミノと置換される)、ヒドロキシ及び/またはアミノと場合により置換されていても良い。NMDARのグリシン部位の部分的アゴニストは、その内容全体が参照により本明細書に組み込まれる、US5,763,393、US6,107,271及びWoodら,NeuroReport,19,1059−1061,2008に記載されている。 Also contemplated are polymorphs, homologs, hydrates, solvates, free bases and / or suitable salt forms of GLYX-13, such as but not limited to acetate. This peptide may be in cyclic or acyclic form, as further described in US 5,763,393. In some embodiments, GLYX-13 analog, insertion or deletion portion to one or more Thr groups or Pro groups, for example, may include a deletion of CH 2, OH or NH 2 moieties. In other embodiments, GLYX-13 is one or more halogens, (optionally substituted with halogen or amino optionally) C 1 -C 3 alkyl, it may be optionally substituted with hydroxy and / or amino. Partial agonists of the glycine site of NMDAR are described in US 5,763,393, US 6,107,271 and Wood et al., NeuroReport, 19, 1059-1061, 2008, the entire contents of which are incorporated herein by reference. ing.
本明細書で開示されるペプチドは、天然アミノ酸及び非天然アミノ酸の両方、例えば、全体が天然アミノ酸(若しくはその誘導体)、全体が非天然アミノ酸(若しくはその誘導体)、または天然アミノ酸と非天然アミノ酸の混合物を含み得ると理解して良い。例えば、GLYX‐13中の、1、2、3またはそれ以上のアミノ酸がそれぞれ独立してD配置またはL配置を有していて良い。 The peptides disclosed herein are both natural and non-natural amino acids, eg, whole natural amino acids (or derivatives thereof), whole unnatural amino acids (or derivatives thereof), or natural and non-natural amino acids. It can be understood that a mixture can be included. For example, 1, 2, 3 or more amino acids in GLYX-13 may each independently have a D configuration or an L configuration.
GLYX−13は、主にNR2B含有NMDARに作用することができ、既知のNMDARモジュレーター、例えばCPC−101,606及びケタミンなどの古典的な副作用を示すことがない。ある種の実施形態では、GLYX−13を治療有効量で対象に投与したとき、GLYX−13によって本質的に鎮静作用を伴わずに抗片頭痛または他の治療効果を得ることができる。更に他の実施形態では、GLYX−13は濫用可能性(例えば、習慣性でなくても良い)を有することがない。 GLYX-13 can act primarily on NR2B-containing NMDARs and does not show classical side effects such as known NMDAR modulators such as CPC-101,606 and ketamine. In certain embodiments, when GLYX-13 is administered to a subject in a therapeutically effective amount, GLYX-13 can provide an anti-migraine or other therapeutic effect with essentially no sedation. In yet other embodiments, GLYX-13 does not have abuse potential (eg, it may not be addictive).
いくつかの実施形態では、GLYX−13はAMPA GluR1セリン845のリン酸化を増加させることができる。ある種の実施形態では、GLYX−13はグリコーゲンシンターゼキナーゼ3β(GSK−3β)を活性化することができる。場合によっては、GLYX−13の投与後、β−カテニンのレベルが変化し得る。 In some embodiments, GLYX-13 can increase AMPA GluR1 serine 845 phosphorylation. In certain embodiments, GLYX-13 can activate glycogen synthase kinase 3β (GSK-3β). In some cases, the level of β-catenin may change after administration of GLYX-13.
いくつかの実施形態では、GLYX−13またはGLYX−13を含む組成物は、血漿レベルに対して、インビボ力価及び/または脳内濃度が高い静脈投与を可能にし得る。 In some embodiments, a composition comprising GLYX-13 or GLYX-13 may allow intravenous administration with high in vivo titers and / or brain concentrations relative to plasma levels.
加えて、GLYX−13はグリシン部位アンタゴニスト、例えばL−701,324、または治療指数が狭く、その結果、治療効果と運動失調との間の用量範囲が非常に狭くなる他のグリシン部位アンタゴニストと比較して、大きい治療指数を有することができる。例えば、L−701,324は抗けいれん効果を有する用量で運動失調が生じた(Bristowら、JPET279:492−501,1996)。同様に、一連のMerz社の化合物は抗けいれん効果を有する用量で運動失調が生じた(Parsonsら,JPET283:1264−1275,1997)。 In addition, GLYX-13 is compared to glycine site antagonists such as L-701,324 or other glycine site antagonists that have a narrow therapeutic index, resulting in a very narrow dose range between therapeutic effects and ataxia And can have a large therapeutic index. For example, L-701,324 produced ataxia at doses with an anticonvulsant effect (Bristow et al., JPET 279: 492-501, 1996). Similarly, a series of Merz compounds produced ataxia at doses with anticonvulsant effects (Parsons et al., JPET283: 1264-1275, 1997).
方法
一態様では、本発明はそれを必要とする患者の片頭痛を治療する方法に関し、該方法は前記患者に以下に表す薬学的有効量の化合物またはその薬学的に許容される塩を投与することを含む。
In one aspect, the invention relates to a method of treating migraine in a patient in need thereof, said method administering to said patient a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described below: Including that.
ある種の実施形態では、本化合物は、約0.01mg/kg〜約1000mg/kgまたは約1mg/kg〜約500mg/kgの化合物の用量で患者に投与される。 In certain embodiments, the compound is administered to the patient at a dose of about 0.01 mg / kg to about 1000 mg / kg or about 1 mg / kg to about 500 mg / kg of the compound.
ある種の実施形態では、片頭痛は、一過性片頭痛、慢性片頭痛、網膜片頭痛、眼筋麻痺性片頭痛、無痛性片頭痛、片頭痛障害、月経片頭痛、腹性片頭痛、小児周期性症候群または群発性頭痛である。 In certain embodiments, migraine is transient migraine, chronic migraine, retinal migraine, ocular paralytic migraine, painless migraine, migraine disorder, menstrual migraine, abdominal migraine, Pediatric periodic syndrome or cluster headache.
ある種の実施形態では、片頭痛は、一過性片頭痛、慢性片頭痛、網膜片頭痛、眼筋麻痺性片頭痛、無痛性片頭痛または群発性頭痛である。 In certain embodiments, the migraine is a transient migraine, chronic migraine, retinal migraine, ophthalmoplegic migraine, analgesic migraine or cluster headache.
ある種の実施形態では、片頭痛は前兆のある片頭痛(古典的片頭痛)である。 In certain embodiments, the migraine is a migraine with aura (classical migraine).
ある種の実施形態では、片頭痛は前兆のない片頭痛(一般的な片頭痛)である。 In certain embodiments, the migraine is a migraine without aura (generic migraine).
ある種の実施形態では、片頭痛はアロディニアを伴う。 In certain embodiments, the migraine is associated with allodynia.
ある種の実施形態では、方法は、約1〜10mg/kg、約10mg/kg〜約250mg/kg、約20mg/kg〜約150mg/kg、約30mg/kg〜約125mg/kg、約40mg/kg〜約110mg/kg、約50mg/kg〜約100mg/kg、約60mg/kg〜約90mg/kgまたは約70mg/kg〜約90mg/kgの化合物を投与することを含む。 In certain embodiments, the method comprises about 1-10 mg / kg, about 10 mg / kg to about 250 mg / kg, about 20 mg / kg to about 150 mg / kg, about 30 mg / kg to about 125 mg / kg, about 40 mg / kg. administering from about kg to about 110 mg / kg, from about 50 mg / kg to about 100 mg / kg, from about 60 mg / kg to about 90 mg / kg, or from about 70 mg / kg to about 90 mg / kg.
ある種の実施形態では、方法は、約1mg/kg、約2.5mg/kg、約5mg/kg、約10mg/kg、約15mg/kg、約20mg/kg、約25mg/kg、約30mg/kg、約50mg/kg、約70mg/kgまたは約100mg/kgの化合物を投与することを含む。 In certain embodiments, the method comprises about 1 mg / kg, about 2.5 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg. administering about 50 kg / kg, about 70 mg / kg or about 100 mg / kg of the compound.
ある種の実施形態では、方法は、約1日2回、ほぼ毎日、2日毎、3日毎、4日毎、5日毎、約週1回、約2週毎または約4週毎に化合物を投与することを含む。 In certain embodiments, the method administers the compound about twice a day, about every day, every 2 days, every 3 days, every 4 days, every 5 days, about once a week, about every 2 weeks, or about every 4 weeks. Including that.
別の態様では、本発明はそれを必要とする患者の皮質拡延性抑制または皮質拡延性抑制を原因とする疾患若しくは病態を治療、抑制及び/または予防する方法に関し、該方法は前記患者に以下に表す薬学的有効量の化合物またはその薬学的に許容される塩を投与することを含む。
In another aspect, the invention relates to a method for treating, suppressing and / or preventing a cortical spreading depression or a disease or condition caused by cortical spreading depression in a patient in need thereof, said method comprising: Administering a pharmaceutically effective amount of a compound represented by or a pharmaceutically acceptable salt thereof.
別の態様では、本発明はそれを必要とする患者での片頭痛後の長期後遺症の治療及び/または改善方法に関し、該方法は前記患者に以下に表す薬学的有効量の化合物またはその薬学的に許容される塩を投与することを含む。
In another aspect, the present invention relates to a method for the treatment and / or amelioration of long-term sequelae after migraine in a patient in need thereof, said method comprising a pharmaceutically effective amount of a compound represented below or said pharmaceutical Administration of an acceptable salt.
ある種の実施形態では、化合物は、約0.01mg/kg〜約1000mg/kgの化合物の用量で患者に投与される。ある種の実施形態では、化合物は、約1mg/kg〜約500mg/kgの化合物の用量で患者に投与される。 In certain embodiments, the compound is administered to the patient at a dose of about 0.01 mg / kg to about 1000 mg / kg of the compound. In certain embodiments, the compound is administered to the patient at a dose of about 1 mg / kg to about 500 mg / kg of the compound.
ある種の実施形態では、方法は、約1mg/kg〜10mg/kg、約1mg/kg〜20mg/kg、約10mg/kg〜約250mg/kg、約20mg/kg〜約150mg/kg、約30mg/kg〜約125mg/kg、約40mg/kg〜約110mg/kg、約50mg/kg〜約100mg/kg、約60mg/kg〜約90mg/kgまたは約70mg/kg〜約90mg/kgの化合物を投与することを含む。 In certain embodiments, the method comprises about 1 mg / kg to 10 mg / kg, about 1 mg / kg to 20 mg / kg, about 10 mg / kg to about 250 mg / kg, about 20 mg / kg to about 150 mg / kg, about 30 mg. / Kg to about 125 mg / kg, about 40 mg / kg to about 110 mg / kg, about 50 mg / kg to about 100 mg / kg, about 60 mg / kg to about 90 mg / kg or about 70 mg / kg to about 90 mg / kg of the compound. Administration.
ある種の実施形態では、方法は、約20mg/kg、約25mg/kg、約30mg/kg、約50mg/kg、約70mg/kg、1mg/kg、5mg/kg、10mg/kg、15mg/kg、20mg/kgまたは約100mg/kgの化合物を投与することを含む。 In certain embodiments, the method comprises about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 50 mg / kg, about 70 mg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg. 20 mg / kg or about 100 mg / kg of the compound.
ある種の実施形態では、方法は、約1日2回、ほぼ毎日、2日毎、3日毎、4日毎、5日毎、約週1回または約2週毎、または例えば毎月化合物を投与することを含む。 In certain embodiments, the method comprises administering the compound about twice a day, about every day, every 2 days, every 3 days, every 4 days, every 5 days, about once a week or about every 2 weeks, or for example monthly. Including.
ある種の実施形態では、方法は、オピオイド、抗うつ剤、抗てんかん薬、非ステロイド性抗炎症薬(NSAID)、セロトニン5HT1B/1Dアゴニスト、N−メチル−D−アスパラギン酸アンタゴニストまたは抗炎症化合物との共投与を更に含む。 In certain embodiments, the method comprises an opioid, an antidepressant, an antiepileptic drug, a nonsteroidal anti-inflammatory drug (NSAID), a serotonin 5HT1B / 1D agonist, an N-methyl-D-aspartate antagonist or an anti-inflammatory compound. Further co-administration.
NMDAR活性は、多くの実験的状況においてSDの現象を促進することができ、または更にはそれに必須でもあり得る。したがって、NMDARの過剰活性化を防止する化合物は、片頭痛発作の発症を減少させ、更には予防するための重要な新規治療法であり得る。例えば、GLYX−13は、後述するようにインビトロの海馬スライスにおいてSDの発生及び伝播を抑制する。特定の実験において、GLYX−13は、細胞外カリウム濃度の局所的増加によってSDの誘発を完全に防止することができ、及び/または完全にブロックしない場合でも、SDの伝播速度を低下させることができる。更に、GLYX−13は、SD後、樹状突起スパインの元のサイズへの復帰を改善することができる。例えば、本明細書では、予防的に及び/または急性時に患者の片頭痛を治療する方法を提供するこのような投与により、患者の重症な片頭痛発作を改善する(または、いくつかの実施形態では早期に抑える)ことができる。 NMDAR activity can promote the phenomenon of SD in many experimental situations, or even be essential to it. Thus, compounds that prevent overactivation of NMDAR may be an important novel therapy for reducing and even preventing the development of migraine attacks. For example, GLYX-13 suppresses the occurrence and propagation of SD in in vitro hippocampal slices as described below. In certain experiments, GLYX-13 can completely prevent the induction of SD by local increase in extracellular potassium concentration and / or can reduce the propagation speed of SD even if not completely blocked. it can. Furthermore, GLYX-13 can improve the return of dendritic spines to their original size after SD. For example, herein, such administration, which provides a method for treating a patient's migraine prophylactically and / or during an acute period, improves a patient's severe migraine attack (or some embodiments) Can be suppressed early).
ある種の実施形態では、患者はヒトである。企図される患者には、女性患者及び/または青年期の患者を含む。 In certain embodiments, the patient is a human. Contemplated patients include female patients and / or adolescent patients.
また本明細書では、治療耐性患者での片頭痛(例えば、一過性片頭痛、慢性片頭痛、網膜片頭痛、眼筋麻痺性片頭痛、無痛性片頭痛、片頭痛障害、月経片頭痛、腹性片頭痛、小児周期性症候群または群発性頭痛)の治療方法、または難治性片頭痛、例えば少なくとも1つのまたは少なくとも2つの他の化合物または治療法の適切なクールに反応しない、及び/または反応しなかった片頭痛に罹患している患者の治療方法も提供する。例えば、a)場合により患者を治療耐性と同定すること、及びb)GLYX−13の有効量を前記患者に投与することを含む、治療耐性患者での片頭痛(例えば、一過性片頭痛、慢性片頭痛、網膜片頭痛、眼筋麻痺性片頭痛、無痛性片頭痛、片頭痛障害、月経片頭痛、腹性片頭痛、小児周期性症候群または群発性頭痛)の治療方法を提供する。ある種の実施形態では、片頭痛は前兆のある片頭痛である。 Also herein, migraine (eg, transient migraine, chronic migraine, retinal migraine, ocular paralytic migraine, painless migraine, migraine disorder, menstrual migraine, Abdominal migraine, childhood periodic syndrome or cluster headache) or refractory migraine, eg not responding to and / or responding to an appropriate course of at least one or at least two other compounds or therapies Also provided is a method of treating a patient suffering from a migraine that has not. For example, migraine (e.g., transient migraine) in a treatment resistant patient comprising a) optionally identifying the patient as treatment resistant, and b) administering an effective amount of GLYX-13 to said patient. A method for treating chronic migraine, retinal migraine, ocular paralytic migraine, painless migraine, migraine disorder, menstrual migraine, abdominal migraine, childhood periodic syndrome or cluster headache) is provided. In certain embodiments, the migraine is a migraine with aura.
本明細書の一実施形態では、有効量のGLYXペプチド、例えば単一単位用量を投与することを含む、それを必要とする患者での片頭痛(例えば、一過性片頭痛、慢性片頭痛、網膜片頭痛、眼筋麻痺性片頭痛、無痛性片頭痛、片頭痛障害、月経片頭痛、腹性片頭痛、小児周期性症候群または群発性頭痛)の急性治療方法を提供する。例えば、本明細書の一実施形態では、有効量(例えば単一単位用量)のGLYX−13ペプチドを急性投与することを含む、片頭痛発作を発症しているそれを必要とする患者での片頭痛の治療方法を企図する。このような方法は、前記投与後の約2週間以下、1週間以下、1日以下または1時間以下(例えば15分以下、30分以下)で少なくとも1種の片頭痛症状の患者を回復させることができる。いくつかの実施形態では、このような方法は、前記投与後の約1日以上、1週間以上または2週間以上で少なくとも1種の片頭痛症状の患者を回復させることができる。例えば、本明細書では片頭痛を罹患している患者に有効量のGLYXペプチドを投与することを含む方法を提供し、ここでの前記患者はGLYXペプチドの最初の投与後、片頭痛治療用の別の薬剤を投与した同じ患者と比較して、実質的に早期に少なくとも1種の片頭痛症状が軽減される。当業者であれば、このような急性投与方法は入院または外来環境において有利であり得ることが理解されよう。本明細書に記載する方法は、前兆のある片頭痛期間中に発生するアロディニアの治療にも有益であり得る。 In one embodiment herein, a migraine in a patient in need thereof (eg, transient migraine, chronic migraine, including administration of an effective amount of a GLYX peptide, eg, a single unit dose, A method of acute treatment of retinal migraine, ocular paralytic migraine, painless migraine, migraine disorder, menstrual migraine, abdominal migraine, childhood periodic syndrome or cluster headache). For example, in one embodiment herein, a fragment in a patient in need of developing a migraine attack comprising acutely administering an effective amount (eg, a single unit dose) of a GLYX-13 peptide. Contemplate a method for treating headaches. The method recovers at least one migraine symptomatic patient in about 2 weeks or less, 1 week or less, 1 day or less or 1 hour or less (eg, 15 minutes or less, 30 minutes or less) after the administration. Can do. In some embodiments, such methods can recover at least one migraine symptomatic patient about 1 day or more, 1 week or 2 weeks or more after the administration. For example, provided herein is a method comprising administering an effective amount of a GLYX peptide to a patient suffering from migraine, wherein the patient is used for treating migraine after the initial administration of the GLYX peptide. At least one migraine symptom is relieved substantially early compared to the same patient who has been administered another drug. One skilled in the art will appreciate that such acute administration methods may be advantageous in hospitalized or outpatient settings. The methods described herein may also be beneficial for the treatment of allodynia that occurs during a predictive migraine period.
本発明の方法は、抑うつ症を有する患者、外傷性脳損傷、てんかんに罹患した患者、または脳卒中の危険性がある患者の治療に使用しても良い。例えば、本明細書の一実施形態では、有効量のGLYXペプチド、例えばGLYX−13を投与することを含む、外傷性脳損傷を治療するための方法を提供する。他の実施形態では、有効量のGLYXペプチド、例えばGLYX−13を投与することを含む、てんかんを治療するための方法を提供する。 The methods of the invention may be used to treat patients with depression, traumatic brain injury, patients with epilepsy, or patients at risk for stroke. For example, in one embodiment herein, there is provided a method for treating traumatic brain injury comprising administering an effective amount of a GLYX peptide, such as GLYX-13. In other embodiments, a method for treating epilepsy comprising administering an effective amount of a GLYX peptide, eg, GLYX-13, is provided.
前兆のある片頭痛の患者は、心臓血管症状に加えて、他の神経性及び/または心理性病態及び障害の危険が増加する場合がある。例えば、前兆のある片頭痛と大うつ病または自殺企図との併発は、非誘発発作を生じる危険性を増加させたことが示されている(Hesdorfferら、Epilepsy Res.75(2−3):220−223,2007)。前兆のある片頭痛と関連した他の病態として、NO活性マーカーが有意に高いこと、抑うつ症の発生率が増加すること、及び一般的な集団の場合よりも遺伝バイオマーカーと脳卒中との相関性が実質的に高いことが挙げられる(Etminanら、#MJ330(7482):63,2005)。これらの病態のいずれかを有する、またはその危険性のある片頭痛患者は、この疾患を治療するまたはそれに対処するための投薬を受けている場合があり、このような薬剤が前兆のある片頭痛の治療に現在使用されている薬剤と悪い相互作用を起こす場合がある。本明細書に示すように、これらの病態の一部はトリプタン治療(例えば、脳卒中及びスマトリプタン治療)にとって禁忌である。加えて、セロトニン症候群に関して、FDAが2006年に公衆衛生勧告を出した。これはトリプタンをセロトニン再摂取阻害剤(SSRI)または選択的なセロトニン/ノルエピネフリン再摂取阻害剤(SNRI)である特定の抗抑うつ剤と併用するときに発生する場合がある致命的病態である。したがって、本明細書に記載する方法は、抑うつ症を有する患者または脳卒中患者またはその危険性のある患者の治療に有益であり得る。 Migraine patients with aura may have increased risk of other neurological and / or psychological conditions and disorders in addition to cardiovascular symptoms. For example, concomitant witnessed migraine and major depression or suicide attempts have been shown to increase the risk of uninduced seizures (Hesdorfer et al., Epilepsy Res. 75 (2-3): 220-223, 2007). Other conditions associated with predictive migraine include significantly higher NO activity markers, increased incidence of depression, and correlation between genetic biomarkers and stroke than in the general population Is substantially higher (Etminan et al., # MJ330 (7482): 63, 2005). Migraine patients with or at risk for any of these conditions may be taking medications to treat or deal with the disease, and such drugs may have migraine with signs May cause adverse interactions with drugs currently used in the treatment of As shown herein, some of these conditions are contraindicated for triptan treatment (eg, stroke and sumatriptan treatment). In addition, the FDA issued public health recommendations in 2006 regarding serotonin syndrome. This is a fatal condition that can occur when triptan is used in combination with certain antidepressants that are serotonin reuptake inhibitors (SSRI) or selective serotonin / norepinephrine reuptake inhibitors (SNRI). Thus, the methods described herein may be beneficial for the treatment of patients with depression or stroke patients or patients at risk thereof.
用量
本発明のどの組成物も、患者の症状、年齢及び体重、治療及び予防される障害の性質及び重度、投与経路、ならびに対象組成物の形態に応じて用量が異なる。どの対象製剤も単一用量または分割用量で患者に投与して良い。本開示の組成物の用量は、当業者に既知の手法によって、または本明細書で教示する手法によって容易に決定することができる。一般に、本化合物は、例えば0.05mg〜3000mg(固体形態として測定)、例えば約10mg〜約500mg、または例えば約1〜約200mg/kgの1日用量でヒトに投与されるとき満足な結果を得ることができる。用量範囲には、例えば10〜1000mg(例えば50〜800mg)を含む。いくつかの実施形態では、50、100、150、200、225、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950または1000mgの化合物が投与される。あるいは、患者の体重を用いて用量を算出することができる。例えば、患者に投与される化合物、またはその医薬組成物の用量は、1〜500mg/kg(例えば5〜250mg/kg)の範囲内であって良い。例示的非限定的実施形態では、用量は5〜200mg/kg(例えば、1、2、2.5、5、10、15、20、25、30、35、40、45または50mg/kg)、または15〜100mg/kg(例えば、55、60、65、70、75、80、85、90、95、100、110、120、130、140、150、160、170、180、190または200mg/kg)の範囲内であって良い。例示的非限定的実施形態では、用量は、1〜15mg/kg、50〜100mg/kg、60〜90mg/kgまたは70〜80mg/kgの範囲内であって良い。
Dosage Any composition of the invention will vary in dosage depending on the patient's condition, age and weight, the nature and severity of the disorder to be treated and prevented, the route of administration, and the form of the subject composition. Any subject formulation may be administered to the patient in a single dose or in divided doses. The dosage of the compositions of the present disclosure can be readily determined by techniques known to those skilled in the art or by the techniques taught herein. In general, the compounds provide satisfactory results when administered to humans at daily doses of, for example, 0.05 mg to 3000 mg (measured as a solid form), such as about 10 mg to about 500 mg, or such as about 1 to about 200 mg / kg. Can be obtained. Dosage ranges include, for example, 10 to 1000 mg (eg 50 to 800 mg). In some embodiments, 50, 100, 150, 200, 225, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of compound Is administered. Alternatively, the dose can be calculated using the patient's weight. For example, the dose of a compound or pharmaceutical composition administered to a patient can be in the range of 1-500 mg / kg (eg, 5-250 mg / kg). In exemplary non-limiting embodiments, the dose is 5 to 200 mg / kg (eg, 1, 2, 2.5, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 mg / kg), Or 15-100 mg / kg (e.g. 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 mg / kg ). In exemplary non-limiting embodiments, the dose may be in the range of 1-15 mg / kg, 50-100 mg / kg, 60-90 mg / kg or 70-80 mg / kg.
GLYX−13は、高い治療指数を提供することができる。例えば、GLYX−13は、約1〜約10mg/kg、約10〜約200mg/kg、例えば約30mg/kg、約75mg/kgまたは約100mg/kgの静脈内投与または皮下投与の用量範囲で、治療的に有効であり得る。いくつかの実施形態では、例えば500mg/kgの静脈内投与用量で運動失調が発生しない。 GLYX-13 can provide a high therapeutic index. For example, GLYX-13 is administered at a dosage range of about 1 to about 10 mg / kg, about 10 to about 200 mg / kg, such as about 30 mg / kg, about 75 mg / kg or about 100 mg / kg administered intravenously or subcutaneously. It can be therapeutically effective. In some embodiments, ataxia does not occur at an intravenous dose of, for example, 500 mg / kg.
治療用途で必要とされるGLYXペプチドの治療有効量は、治療される病態の形態、要求される治療時間の長さ、患者の年齢及び病態によって異なり、最終的には主治医によって決定される。利便上、2週、1週、6日、5日、4日、3日、2日または1日にわたって有効である単一用量で、あるいは適切な間隔、例えば1日当たり2回、3回、4回またはそれ以上の分割用量で投与される複数回用量として望ましい用量を投与して良い。 The therapeutically effective amount of GLYX peptide required for therapeutic use will depend on the form of the condition being treated, the length of treatment time required, the age and condition of the patient and will ultimately be determined by the attending physician. For convenience, a single dose effective over 2 weeks, 1 week, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day, or at appropriate intervals, eg 2 times, 3 times, 4 times a day The desired dose may be administered as multiple doses administered in one or more divided doses.
本開示の任意の特定の組成物に対して、有効用量または有効量、及び製剤を投与するタイミングに及ぼされ得る何らかの影響を特定することが必要な場合がある。これは、1つ以上の動物群(好ましくは群当たり少なくとも5匹の動物)を使用した、本明細書に記載する定期的な実験によって、または必要に応じてヒトの試験にて得ることができる。任意の対象組成物の有効性及び治療または予防の方法は、組成物を投与した後、1つ以上の該当する指数を測定して、この指数の治療後値と同一指数の治療前値とを比較して投与効果評価することにより、評価することができる。 For any particular composition of the present disclosure it may be necessary to identify an effective dose or amount and any effect that may be exerted upon the timing of administering the formulation. This can be obtained by routine experiments as described herein using one or more groups of animals (preferably at least 5 animals per group) or in human studies as needed. . The effectiveness of any subject composition and the method of treatment or prevention can be determined by measuring one or more relevant indices after administering the composition and determining a post-treatment value of this index and a pre-treatment value of the same index. It can evaluate by comparing and evaluating a dosing effect.
所与の患者において最も有効な治療をもたらす正確な投与時間及び任意の特定の対象組成物の量は、対象組成物の活性、薬動動態及び生物学的利用能、患者の生理学的条件(年齢、性別、疾患の種別及びステージ、全身状態、所与の用量に対する応答性、ならびに薬剤の種類を含む)、投与経路などに依存する。本明細書に提示されるガイドラインを利用すると、治療を最適化する、例えば、最適な時間及び/または投与量を決定することができ、対象のモニタリングならびに用量及びタイミングの調整からなる典型的な実験しか必要としない。 The exact time of administration and the amount of any particular subject composition that provides the most effective treatment in a given patient depends on the activity, pharmacokinetics and bioavailability of the subject composition, the patient's physiological conditions (age , Sex, disease type and stage, general condition, responsiveness to a given dose, and drug type), route of administration, etc. The guidelines presented herein can be used to optimize treatment, for example, to determine the optimal time and / or dose, and to perform typical experiments consisting of subject monitoring and dose and timing adjustments I only need it.
対象が治療されている間、治療期間中の所定時間で1つ以上の関連指数を測定することにより、患者の健康をモニタリングしても良い。このようなモニタリングの結果に応じて、組成物、量、投与時間及び製剤を含めた、治療法を最適化しても良い。同一パラメータを測定することによって、改善の程度を特定し、患者を周期的に再評価することができる。これらの再評価に基づいて、投与される対象組成物量及び場合により投与時間の調整を行っても良い。 While the subject is being treated, the health of the patient may be monitored by measuring one or more relevant indices at a predetermined time during the treatment period. Depending on the results of such monitoring, the treatment regimen, including composition, amount, time of administration and formulation, may be optimized. By measuring the same parameters, the degree of improvement can be identified and the patient can be re-evaluated periodically. Based on these reevaluations, the amount of the target composition to be administered and, optionally, the administration time may be adjusted.
化合物の最適容量未満である少ない用量から、治療を開始しても良い。その後、最適な治療効果が得られるまで、少量ずつ用量量を増加させても良い。 Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is achieved.
対象組成物の使用により、別の薬剤の効果の開始及び期間を補完(complimentary)できるため、組成物に含有される何らかの個々の薬剤の必要用量を減らすことができる。 The use of a subject composition can compliment the onset and duration of the effect of another drug, thereby reducing the required dose of any individual drug contained in the composition.
対象組成物の毒性及び治療効能は、細胞培養または実験動物についての標準的な薬学的手順、例えばLD50及びED50を決定するための手順によって測定することができる。 Toxicity and therapeutic efficacy of a subject composition can be measured by standard pharmaceutical procedures for cell cultures or experimental animals, such as procedures for determining LD50 and ED50.
これらの細胞培養アッセイ及び動物試験から得たデータを、ヒトに使用される用量の範囲を処方する際に使用することができる。いずれの対象組成物の用量も、ほとんどまたは全く毒性を有しないED50に収まる循環濃度の範囲内であることが好ましい。用いる剤形及び利用される投与経路に応じて、この範囲内で用量を変えることができる。最初に本開示の組成物に合わせて、細胞培養アッセイから治療有効量を推定しても良い。 Data obtained from these cell culture assays and animal studies can be used in formulating a range of doses for use in humans. The dose of any subject composition is preferably within a range of circulating concentrations that will fit in the ED50 with little or no toxicity. Depending on the dosage form used and the route of administration utilized, dosages can vary within this range. A therapeutically effective dose may be estimated initially from cell culture assays, consistent with the compositions of the present disclosure.
ある種の実施形態では、GLYXペプチドは予防手段として(すなわち、前駆症状段階の前に)投与される。ある種の実施形態では、GLYXペプチドは前駆症状の期間に投与される。ある種の実施形態では、GLYXペプチドは前兆時に投与される。「前兆時」とは、前兆の発症後かつ片頭痛の痛みの発症前の任意の時間を意味する。ある種の実施形態では、GLYXペプチドは片頭痛の痛みを発症した後に投与される。ある種の実施形態では、GLYXペプチドは、例えばその症状を軽減するために、後発症状期間に投与される。 In certain embodiments, the GLYX peptide is administered as a prophylactic measure (ie, prior to the prodrome stage). In certain embodiments, the GLYX peptide is administered during the prodromal period. In certain embodiments, the GLYX peptide is administered at the precursor. By “precursor time” is meant any time after the onset of symptoms and before the onset of migraine pain. In certain embodiments, the GLYX peptide is administered after onset of migraine pain. In certain embodiments, the GLYX peptide is administered during a late symptom period, for example, to alleviate the symptoms.
本明細書で使用する場合、用語「予防する」は、本明細書に記載する疾患、障害または病態の1種以上の症状または病態(例えば、前兆のある痛みまたは片頭痛、及びアロディニアの有無にかかわらない痛みまたは片頭痛)を予防する予防療法または治療法を指す。予防療法は、例えば、疾患、障害または病態の発症に先立つ事象(例えば片頭痛前兆)の前(「曝露前予防」)、または後(「曝露後予防」)に開始することができる。本明細書に記載するGLYXペプチド、またはその薬学的に許容される塩若しくはその溶媒和物、またはその医薬組成物の投与を含む予防療法は、急性、短期、または慢性であり得る。予防療法のクール中に投与用量を変更しても良い。Kanieckiら、「Treatment of Primary Headache:Preventive Treatment of Migraine」、Standards of Care for Headache Diagnosis and Treatment.Chicago(IL):National Headache Foundation;2004,p.40−52所収も参照されたい。 As used herein, the term “prevent” refers to one or more symptoms or conditions of a disease, disorder, or condition described herein (eg, with or without symptomatic pain or migraine, and allodynia). It refers to prophylactic treatment or treatment that prevents pain or migraines that are not involved. Prophylactic therapy can be initiated, for example, before (“pre-exposure prophylaxis”) (“pre-exposure prophylaxis”) or after (“post-exposure prophylaxis”) prior to the onset of a disease, disorder or condition (eg, a migraine aura). Prophylactic therapy including administration of the GLYX peptide described herein, or a pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition thereof can be acute, short term, or chronic. The dose may be changed during the course of preventive therapy. Kaniecki et al., “Treatment of Primary Headache: Preferential Treatment of Migration”, Standards of Care for Diagnosis and Treatment. Chicago (IL): National Headache Foundation; 2004, p. See also 40-52 inventory.
製剤
本開示のGLYXペプチドは、使用目的に応じて、当該技術分野において周知である各種手段によって投与することができる。例えば、本開示の組成物を経口投与しようとする場合、組成物を錠剤、カプセル、顆粒、粉末またはシロップとして製剤化することができる。あるいは、本開示の製剤を注射(静脈内、筋肉内または皮下)、滴下注入製剤または坐剤として非経口的に投与しても良い。眼の粘膜経路による適用の場合、本開示の組成物を点眼薬または眼軟膏として処方しても良い。これらの製剤は従来の手段によって調製でき、必要に応じて、任意の従来的添加剤、例えば賦形剤、バインダー、崩壊剤、潤滑剤、矯味剤、可溶化剤、懸濁助剤、乳化剤またはコーティング剤と混合しても良い。
Formulation The GLYX peptide of the present disclosure can be administered by various means well known in the art depending on the purpose of use. For example, if the composition of the present disclosure is to be administered orally, the composition can be formulated as a tablet, capsule, granule, powder or syrup. Alternatively, the formulations of the present disclosure may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), drop infusion formulations or suppositories. For application by the ocular mucosal route, the compositions of the present disclosure may be formulated as eye drops or eye ointments. These formulations can be prepared by conventional means, optionally with any conventional additive such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension aids, emulsifiers or You may mix with a coating agent.
発現ベクターに組み込まれる、GLYXペプチドをコードするDNAを既知の投与方法のいずれかを用いて投与し、インビボでGLYXペプチドを発現させることができる。 DNA encoding the GLYX peptide, which is incorporated into the expression vector, can be administered using any of the known methods of administration to express the GLYX peptide in vivo.
本発明の製剤では、湿潤剤、乳化剤及び滑沢剤、例えばラウリル硫酸ナトリウム及びステアリン酸マグネシウム、ならびに着色剤、放出剤、コーティング剤、甘味剤、香料及び芳香剤、防腐剤及び抗酸化剤が製剤内に存在しても良い。 In the formulations of the present invention, wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, fragrances and fragrances, preservatives and antioxidants are formulated. It may exist in the inside.
対象組成物は、経口、局所(口腔及び舌下を含む)、経直腸、経膣、エアゾール状及び/または非経口投与に好適なものであっても良い。製剤は利便上、単位用量形態で存在する場合もあり、薬学分野で周知であるいずれかの方法によって調製されても良い。単一用量を製造するために担体材料と組み合わせることができる組成物の量は、治療される対象及び特定の投与様式に応じて異なる。 The subject compositions may be suitable for oral, topical (including buccal and sublingual), rectal, vaginal, aerosol and / or parenteral administration. The formulation may conveniently be present in unit dosage form and may be prepared by any method well known in the pharmaceutical arts. The amount of composition that can be combined with the carrier materials to produce a single dose will vary depending upon the subject being treated and the particular mode of administration.
このような製剤の調製方法は、本開示の関連組成物と担体及び場合により1種以上の補助的成分と混合する工程を含む。一般に製剤は、関連剤と液体担体若しくは微粒子状固体担体、またはその両方とを均一かつ緊密に混合した後、必要に応じて生成物を成形することにより調製される。 Methods for preparing such formulations include mixing the related compositions of the present disclosure with a carrier and optionally one or more auxiliary ingredients. In general, formulations are prepared by uniformly and intimately mixing the relevant agents with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
経口投与に好適な製剤は、カプセル、カシェ剤、ピル、錠剤、トローチ剤(風味をつけた基剤、通常はスクロース及びアカシアまたはトラガカントを使用)、粉末、顆粒の形態、または水性若しくは非水性液体の溶液若しくは懸濁液の形態、または水中油型若しくは油中水型液体エマルジョンの形態、またはエリキシル若しくはシロップの形態、またはパステル剤の形態(ゼラチン及びグリセリンまたはスクロース及びアカシアなどの不活性塩基を使用)であって良く、それぞれ所定量のその対象組成物を活性成分として含有し得る。本開示の組成物は、ボーラス、舐剤またはペーストとして投与しても良い。 Formulations suitable for oral administration include capsules, cachets, pills, tablets, troches (with flavored bases, usually sucrose and acacia or tragacanth), powders, granular forms, or aqueous or non-aqueous liquids Or in the form of an oil-in-water or water-in-oil liquid emulsion, or in the form of an elixir or syrup, or in the form of a pastel (using an inert base such as gelatin and glycerin or sucrose and acacia) And each may contain a predetermined amount of the target composition as an active ingredient. The compositions of the present disclosure may be administered as a bolus, electuary or paste.
経口投与用の固体投与形態(カプセル、錠剤、ピル、糖衣錠、粉末、顆粒など)の場合、対象組成物は1種以上の薬学的に許容される担体、例えばクエン酸ナトリウムまたはリン酸二カルシウム及び/または以下、(1)充填剤または増量剤、例えばデンプン、ラクトース、スクロース、グルコース、マンニトール及び/またはケイ酸、(2)バインダー、例えばカルボキシメチルセルロース、アルギネート、ゼラチン、ポリビニルピロリドン、スクロース及び/またはアカシアなど、(3)湿潤剤、例えばグリセロール、(4)崩壊剤、例えば寒天、炭酸カルシウム、ジャガイモまたはタピオカデンプン、アルギン酸、特定のケイ酸塩及び炭酸ナトリウム)、(5)溶液緩染剤、例えばパラフィン、(6)吸収促進剤、例えば第四級アンモニウム化合物、(7)湿潤剤、例えば、アセチルアルコール及びグリセロールモノステアレート、(8)吸収剤、例えばカオリン及びベントナイト粘土、(9)潤滑剤、例えばタルク、ステアリン酸カルシウム、ステアリン酸マグネシウム、固体ポリエチレングリコール、ラウリル硫酸ナトリウム及びこれらの混合物;ならびに(10)着色剤、のいずれかと混合される。カプセル、錠剤及びピルの場合、組成物は緩衝剤を含む場合もある。同類の固体組成物を、ラクトースすなわち乳糖のような賦形剤、ならびに高分子量ポリエチレングリコールなどを使用した軟質及び硬質のゼラチンカプセルの充填剤として用いても良い。 In the case of solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject composition comprises one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and And / or (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid, (2) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia (3) wetting agents such as glycerol, (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate), (5) solution dyeing agents such as paraffin (6) Absorption enhancers such as quaternary ammo (7) wetting agents such as acetyl alcohol and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol , Sodium lauryl sulfate and mixtures thereof; and (10) colorants. In the case of capsules, tablets and pills, the composition may also comprise a buffer. Similar solid compositions may be used as fillers for soft and hard gelatin capsules using excipients such as lactose or lactose, and high molecular weight polyethylene glycols.
場合により1種以上の補助成分と共に、圧縮または成形によって錠剤を作成しても良い。圧縮錠剤はバインダー(例えば、ゼラチンまたはヒドロキシプロピルメチルセルロース)、潤滑剤、不活性希釈剤、防腐剤、崩壊剤(例えば、ナトリウムデンプングリコレートまたは架橋カルボキシメチルセルロースナトリウム)、表面活性剤または分散剤を使用して調製することができる。不活性希釈液で湿らせた対象組成物の混合物を好適な機械で成形することにより、成形錠剤を作製することができる。糖衣剤、カプセル、ピル及び顆粒などの錠剤及びその他の固体剤形は、場合により薬学的製剤分野で周知の腸溶性コーティングまたはその他のコーティングなどのコーティング剤及びシェルを用いて打錠または調製して良い。 Tablets may be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets use binders (eg gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg sodium starch glycolate or crosslinked sodium carboxymethylcellulose), surfactants or dispersants. Can be prepared. Molded tablets can be made by molding with a suitable machine a mixture of the subject composition moistened with an inert diluent. Tablets and other solid dosage forms such as dragees, capsules, pills and granules may optionally be compressed or prepared using coatings and shells such as enteric coatings or other coatings well known in the pharmaceutical formulating art. good.
経口投与用の液体剤形には、薬学的に許容されるエマルジョン、ミクロエマルジョン、溶液、懸濁液、シロップ、及びエリキシルが含まれる。液体剤形には、対象組成物に加えて、当該技術分野において一般に使用される不活性希釈剤、例えば、水またはその他の溶媒、可溶化剤及び乳化剤、例えばエチルアルコール、イソプロピルアルコール、炭酸エチル、酢酸エチル、ベンジルアルコール、安息香酸ベンジル、プロピレングリコール、1,3−ブチレングリコール、油(具体的には綿実油、落花生油、コーン油、胚芽油、オリーブ油、ひまし油及びゴマ油)、グリセロール、テトラヒドロフリルアルコール、ソルビタンのポリエチレングリコール及び脂肪酸エステル、シクロデキストリンならびにこれらの混合物を含有し得る。 Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms include, in addition to the subject composition, inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, Ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, It may contain sorbitan polyethylene glycols and fatty acid esters, cyclodextrins and mixtures thereof.
懸濁液には、対象組成物に加えて、懸濁剤、例えば、エトキシル化イソステアリルアルコール、ポリオキシエチレンソルビトール及びソルビタンエステル、微晶質セルロース、アルミニウムメタヒドロキシド、ベントナイト、寒天及びトラガカント、ならびにこれらの混合物を含有し得る。 Suspensions include, in addition to the subject composition, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and Mixtures of these may be included.
経直腸または経膣投与用の製剤は、坐剤として与えられても良く、対象組成物と、例えば、カカオ脂、ポリエチレングリコール、座薬ワックスまたはサリチレートを含む、1種以上の好適な非刺激性賦形剤または担体と混合することにより調製できる。更に坐剤は、室温では固形だが、体温では液体であり、それによって体腔内で溶け、活性剤を放出する。経膣投与に好適な製剤には、当業者に適切であることが知られているような担体を含むペッサリー、タンポン、クリーム、ジェル、ペースト、フォームまたはスプレー製剤がある。 Formulations for rectal or vaginal administration may be given as a suppository and include one or more suitable nonirritating formulations comprising the subject composition and, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate. It can be prepared by mixing with a form or carrier. In addition, suppositories are solid at room temperature but liquid at body temperature, thereby dissolving in the body cavity and releasing the active agent. Formulations suitable for vaginal administration include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing carriers as are known to be appropriate to those skilled in the art.
対象組成物の経皮投与用剤形としては、粉末、スプレー、軟膏、ペースト、クリーム、ローション、ジェル、溶液及びパッチが挙げられる。 Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches.
局所眼投与の場合、本発明の組成物は溶液、ジェル、軟膏、懸濁液または固体挿入物の形態をとることができ、単位用量が治療有効量の活性成分を含むように、または併用療法の場合にはその何倍かを含むように製剤化され得る。 For topical ocular administration, the compositions of the invention can take the form of solutions, gels, ointments, suspensions or solid inserts, such that the unit dose contains a therapeutically effective amount of the active ingredient, or combination therapy In this case, it can be formulated to contain several times that amount.
非経口投与に好適な本発明の医薬組成物は、1種以上の薬学的に許容される無菌等張水溶液または非水溶液、分散液、懸濁液若しくはエマルジョン、または使用直前に無菌注射剤または分散液にて復元できる無菌粉末と組み合わせられた対象組成物を含む。これは抗酸化剤、緩衝剤、静菌薬、製剤が意図されたレシピエントの血液と等張性を示す溶質、または懸濁剤若しくは増粘剤を含有し得る。 A pharmaceutical composition of the present invention suitable for parenteral administration is one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions or emulsions, or a sterile injection or dispersion immediately before use. The subject composition is combined with a sterile powder that can be reconstituted with a liquid. It may contain antioxidants, buffers, bacteriostats, solutes that are isotonic with the blood of the recipient for whom the formulation is intended, or suspending or thickening agents.
本発明の医薬組成物に用いることができる好適な水溶性及び非水溶性担体の例として、水、エタノール、ポリオール(例えばグリセロール、プロピレングリコール、ポリエチレングリコールなど)、及びこれらの好適な混合物、オリーブ油のような植物油、ならびに注入可能な有機エステル、例えばオレイン酸エチル及びシクロデキストリンが挙げられる。例えば、レシチンのようなコーティング材料を使用することにより、また分散性の場合には必要な粒子サイズを維持することにより、更に界面活性物質を使用することにより、適切な流動性を維持することができる。 Examples of suitable water-soluble and water-insoluble carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, olive oil And vegetable oils such as injectable organic esters such as ethyl oleate and cyclodextrins. The proper fluidity can be maintained, for example, by using a coating material such as lecithin, by maintaining the required particle size in the case of dispersibility, and by further using a surfactant. it can.
併用療法
本明細書に記載するGLYXペプチド(例えば、GLYX−13)はいずれも、単独でまたは他の薬剤と組み合わせて使用することで、本明細書で述べる疾患または病態のいずれをも治療または予防することができる。例えば一部の併用療法において、1種以上の治療化合物の用量を、単独で投与されたときの標準用量よりも低減することができる。
Combination Therapy Any of the GLYX peptides described herein (eg, GLYX-13) can be used alone or in combination with other drugs to treat or prevent any of the diseases or conditions described herein. can do. For example, in some combination therapies, the dose of one or more therapeutic compounds can be reduced from a standard dose when administered alone.
本発明の方法は、オピオイド、抗抑うつ剤、抗てんかん薬、非ステロイド性抗炎症薬(NSAID)、セロトニン5HT1B/1Dアゴニスト、N−メチル−D−アスパラギン酸アンタゴニストまたは抗炎症化合物と、GLYXペプチドとの共投与も含む。 The methods of the present invention comprise an opioid, an antidepressant, an antiepileptic drug, a nonsteroidal anti-inflammatory drug (NSAID), a serotonin 5HT1B / 1D agonist, an N-methyl-D-aspartate antagonist or an anti-inflammatory compound, a GLYX peptide, Including co-administration.
本開示のある種の実施形態では、片頭痛(例えば、一過性片頭痛、慢性片頭痛、網膜片頭痛、眼筋麻痺性片頭痛、無痛性片頭痛、片頭痛障害、月経片頭痛、腹性片頭痛、小児周期性症候群または群発性頭痛)を治療する薬剤を製造するために、GLYXペプチド(複数可)を単独でまたは1種以上の他の抗うつ治療薬、例えば三環系抗うつ薬、MAO−I、SSRI及び二重若しくは三重の摂取阻害剤ならびに/または抗不安薬と組み合わせて使用することに関する。GLYXペプチドと組み合わせて使用できる例示的な薬物として、Anafranil、Adapin、Aventyl、Elavil、Norpramin、Pamelor、Pertofrane、Sinequan、Surmontil、Tofranil、Vivactil、Parnate、Nardil、Marplan、Celexa、Lexapro、Luvox、Paxil、Prozac、Zoloft、Wellbutrin、Effexor、Remeron、Cymbalta、Desyrel(トラゾドン)及びLudiomillが挙げられる。 In certain embodiments of the present disclosure, migraine (eg, transient migraine, chronic migraine, retinal migraine, ocular paralytic migraine, analgesic migraine, migraine disorder, menstrual migraine, abdomen GLYX peptide (s) alone or in combination with one or more other antidepressant drugs, eg tricyclic antidepressants, for the manufacture of a medicament for the treatment of sexual migraine, childhood periodic syndrome or cluster headache It relates to use in combination with drugs, MAO-I, SSRI and double or triple ingestion inhibitors and / or anxiolytics. Exemplary drugs that can be used in combination with GLYX peptides include Anafranil, Adapin, Aventyl, Elavil, Norpramin, Pamelor, Pertoflane, Sinequan, Surmontil, Tofranil, Vivactil, Parnate, Nardil, Pirate, Nardil , Zoloft, Wellbutrin, Effexor, Remeron, Cymbalta, Desylel (Trazodon) and Ludiomill.
ある種の実施形態では、オピオイドは、アルフェンタニル、ブトルファノール、ブプレノルフィン、デキストロモラミド、デゾシン、デキストロプロポキシフェン、コデイン、ジヒドロコデイン、ジフェノキシレート、エトルフィン、フェンタニル、ヒドロコドン、ヒドロモルホン、ケトベミドン、ロペラミド、レボルファノール、レボメサドン、メプタジノール、メサドン、モルヒネ、モルヒネ−6−グルクロニド、ナルブフィン、ナロキソン、オキシコドン、オキシモルホン、ペンタゾシン、ペチジン、ピリトラミド、プロポキシフェン、レミフェンタニル、スルフェンタニル、チリジン及びトラマドールからなる群から選択される。 In certain embodiments, the opioid is alfentanil, butorphanol, buprenorphine, dextromoramide, dezocine, dextropropoxyphene, codeine, dihydrocodeine, diphenoxylate, etorphine, fentanyl, hydrocodone, hydromorphone, ketobemidone, loperamide, levorphan Nord, levomethadone, meptazinol, methadone, morphine, morphine-6-glucuronide, nalbuphine, naloxone, oxycodone, oxymorphone, pentazocine, pethidine, pyritramide, propoxyphene, remifentanil, sulfentanyl, tyridine and tramadol.
ある種の実施形態では、抗抑うつ剤は、アジナゾラム、アラプロクラート、アミネプチン、アミトリプチリン/クロルジアゼポキシド併用、アチパメゾール、アザミアンセリン、バジナプリン、ベフラリン、ビフェメラン、ビノダリン、ビペナモール、ブロファロミン、カロキサゾン、セリクラミン、シアノプラミン、シモキサトン、シタロプラム、クレメプロール、クロボキサミン、ダゼピニル、デアノール、デメキシプチリン、ジベンゼピン、ドチエピン、ドロキシドパ、エネフェキシン、エスタゾラム、エトペリドン、フェモキセチン、フェンガビン、フェゾラミン、フルオトラセン、イダゾキサン、インダルピン、インデロキサジン、イプリンドール、レボプロチリン、リチウム、リトキセチン、ロフェプラミン、メジホキサミン、メタプラミン、メトラリンドール、ミアンセリン、ミルナシプラン、ミナプリン、ミルタザピン、モンチレリン、ネブラセタム、ネホパム、ニアラミド、ノミフェンシン、ノルフルオキセチン、オロチレリン、オキサフロザン、ピナゼパム、ピルリンドール、ピゾチリン、リタンセリン、ロリプラム、セルクロレミン(sercloremine)、セチプチリン、シブトラミン、スルブチアミン、スルピリド、テニロキサジン、トザリノン、チロリベリン、チアネプチン、チフルカルビン、トラゾドン、トフェナシン、トフィソパム、トロキサトン、トモキセチン、ベラリプリド、ビロキサジン、ビクァリン、ジメリジン及びゾメタピンからなる群から選択される。 In certain embodiments, the antidepressant is azinazolam, alaprochlorate, amineptin, amitriptyline / chlordiazepoxide combination, atipamezole, azamianserin, baginapurine, befuraline, bifemalan, vinodaline, bipenamol, brophalomine, caloxazone, celifamamine, cyanopramine, , Cremeprole, Cloboxamine, Dazepinyl, Deanol, Demexeptiline, Dibenzepin, Dothiepine, Droxidopa, Enefexin, Estazolam, Etoperidone, Femoxetine, Fengabine, Fezolamine, Fluotracene, Idazoxan, Indalpine, Indeloxazine, Proprinthine, Tipurine Respirin Medioxamine, Tapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, montilerin, nebracetam, nefopam, niaramide, nomifensine, norfluoxetine, olothyrelin, oxafurozan, pinazepam, pirulindole, pizotirin, ritanserin, rolipram, cerlochlemin It is selected from the group consisting of sibutramine, sulbutiamine, sulpiride, teniloxazine, tozalinone, tiroliberin, tianeptine, tiflucarbine, trazodone, tofenacin, tofisopam, troxaton, tomoxetine, veraliprid, viloxazine, biquarine, dimeridine and zometapine.
ある種の実施形態では、抗てんかん薬は、カルバマゼピン、フルピルチン、ガバペンチン、ラモトリジン、オキスカルバゼピン、フェニトイン、レチガビン、トピラマート及びバルプロエートからなる群から選択される。 In certain embodiments, the antiepileptic drug is selected from the group consisting of carbamazepine, flupirtine, gabapentin, lamotrigine, oxcarbazepine, phenytoin, retigabine, topiramate and valproate.
ある種の実施形態では、NSAIDは、アセメタシン、アスピリン、セレコキシブ、デラコキシブ、ジクロフェナク、ジフルニサル、エテンザミド、エトフェナマート、エトリコキシブ、フェノプロフェン、フルフェナム酸、フルルビプロフェン、ロナゾラク、ロルノキシカム、イブプロフェン、インドメタシン、イソキシカム、ケブゾン、ケトプロフェン、ケトロラク、ナプロキセン、ナブメトン、ニフルム酸、スリンダク、トルメチン、ピロキシカム、メクロフェナム酸、メフェナム酸、メロキシカム、メタミゾール、モフェブタゾン、オキシフェンブタゾン、パレコキシブ、フェニドン、フェニルブタゾン、ピロキシカム、プロパセタモール、プロピフェナゾン、ロフェコキシブ、サリチルアミド、スプロフェン、チアプロフェン酸、テノキシカム、バルデコキシブ、4−(4−シクロヘキシル−2−メチルオキサゾール−5−イル)−2−フルオロベンゼンスルホンアミド、N−[2−(シクロヘキシルオキシ)−4−ニトロフェニル]メタンスルホンアミド、2−(3,4−ジフルオロフェニル)−4−(3−ヒドロキシ−3−メチルブトキシ)−5−[4−(メチルスルホニル)フェニル]−3(2H)−ピリダジノン及び2−(3,5−ジフルオロフェニル)−3−[4−(メチルスルホニル)フェニル]−2−シクロペンテン−1−オンからなる群から選択される。 In certain embodiments, the NSAID is acemetacin, aspirin, celecoxib, deracoxib, diclofenac, diflunisal, etenzamide, etofenamate, etoroxixib, phenoprofen, flufenamic acid, flurbiprofen, ronazolac, lornoxicam, ibuprofen, indomethacin, Isoxicam, kebzone, ketoprofen, ketorolac, naproxen, nabumetone, niflumic acid, sulindac, tolmethine, piroxicam, meclofenamic acid, mefenamic acid, meloxicam, metamizole, mofebutazone, oxyfenbutazone, parecoxib, phenidone, phenylbutazone, piroxicam, protaxicam Mol, propifenazone, rofecoxib, salicylamide, suprofen, thiaprofenic acid, Noxicam, valdecoxib, 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide, N- [2- (cyclohexyloxy) -4-nitrophenyl] methanesulfonamide, 2- ( 3,4-difluorophenyl) -4- (3-hydroxy-3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and 2- (3,5-difluorophenyl) Selected from the group consisting of -3- [4- (methylsulfonyl) phenyl] -2-cyclopenten-1-one.
ある種の実施形態では、セロトニン5HT1B/1Dアゴニストは、エレトリプタン、フロバトリプタン、ナラトリプタン、リザトリプタン、スマトリプタン及びゾルミトリプタンからなる群から選択される。 In certain embodiments, the serotonin 5HT1B / 1D agonist is selected from the group consisting of eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan.
ある種の実施形態では、N−メチル−D−アスパラギン酸アンタゴニストは、アマンタジン、アプチガネル、ベソンプロジル、ブジピン、コナントキンG、デルセミン、デキサナビノール、デキストロメトルファン、デキストロプロポキシフェン、フェルバマート、フルオロフェルバマート、ガシクリジン、グリシン、イペノキサゾン、カイトセファリン、ケタミン、ケトベミドン、ラニセミン、リコスチネル、ミダホテル、メマンチン、D−メサドン、D−モルヒネ、ミルナシプラン、ネラメキサン、オルフェナドリン、レマセミド、スルファゾシン、FPL−12,495(ラセミド(racemide)代謝産物)、トピラマート、(αR)−α−アミノ−5−クロロ−1−(ホスホノメチル)−1H−ベンズイミダゾール−2−プロパン酸、1−アミノシクロペンタンカルボン酸、[5−(アミノメチル)−2−[[[(5S)−9−クロロ−2,3,6,7−テトラヒドロ−2,3−ジオキソ−1H−,5H−ピリド[1,2,3−de]キノキサリン−5−イル]アセチル]アミノ]フェノキシ]−酢酸、α−アミノ−2−(2−ホスホノエチル)−シクロヘキサンプロピオン酸、α−アミノ−4−(ホスホノメチル)−ベンゼン酢酸、(3E)−2−アミノ−4−(ホスホノメチル)−3−ヘプテン酸、3−[(1E)−2−カルボキシ−2−フェニルエテニル]−4,6−ジクロロ−1H−インドール−2−カルボン酸、2−ヒドロキシ−N,N,N−トリメチル−エタンアミニウムとの8−クロロ−2,3−ジヒドロピリダジノ[4,5−b]キノリン−1,4−ジオン5−酸化物塩、N’−[2−クロロ−5−(メチルチオ)フェニル]−N−メチル−N−[3−(メチルチオ)フェニル]−グアニジン、N’−[2−クロロ−5−(メチルチオ)フェニル]−N−メチル−N−[3−[(R)−メチルスルフィニル]フェニル]−グアニジン、6−クロロ−2,3,4,9−テトラヒドロ−9−メチル−2,3−ジオキソ−1H−インデノ[1,2−b]ピラジン−9−酢酸、7−クロロチオキヌレン酸、(3S,4aR,6S,8aR)−デカヒドロ−6−(ホスホノメチル)−3−イソキノリンカルボン酸、(−)6,7−ジクロロ−1,4−ジヒドロ−5−[3−(メトキシメチル)−5−(3−ピリジニル)−4−H−1,2,4−トリアゾル−4−イル]−2,3−キノキサリンジオン、4,6−ジクロロ−3−[(E)−(2−オキソ−1−フェニル−3−ピロリジニリデン)メチル]−1H−インドール−2−カルボン酸、(2R,4S)−rel−5,7−ジクロロ−1,2,3,4−テトラヒドロ−4−[[(フェニルアミノ)カルボニル]アミノ]−2−キノリンカルボン酸、(3R,4S)−rel−3,4−ジヒドロ−3−[4−ヒドロキシ−4−(フェニルメチル)−1−ピペリジニル]−2H−1−ベンゾピラン−4,7−ジオール、2−[(2,3−ジヒドロ−1H−インデン−2−イル)アミノ]−アセトアミド、1,4−ジヒドロ−6−メチル−5−[(メチルアミノ)メチル]−7−ニトロ−2,3−キノキサリンジオン、[2−(8,9−ジオキソ−2,6−ジアザビシクロ[5.2.0]ノン−1(7)−エン−2−イル)エチル]−ホスホン酸、(2R,6S)−1,2,3,4,5,6−ヘキサヒドロ−3−[(2S)−2−メトキシプロピル]−6,11,11−トリメチル−2,6−メタノ−3−ベンゾアゾシン−9−オル、2−ヒドロキシ−5−[[(ペンタフルオロフェニル)メチル]アミノ]−安息香酸、1−[2−(4−ヒドロキシフェノキシ)エチル]−4−[(4−メチルフェニル)メチル]−4−ピペリジノール、1−[4−(1H−イミダゾール−4−イル)−3−ブチニル]−4−(フェニルメチル)−ピペリジン、2−メチル−6−フェニルエチニル)−ピリジン、3−(ホスホノメチル)−L−フェニルアラニン及び3,6,7−テトラヒドロ−2,3−ジオキソ−N−フェニル−1H,5H−ピリド[1,2,3−de]キノキサリン−5−アセトアミドからなる群から選択される。 In certain embodiments, the N-methyl-D-aspartic acid antagonist is amantadine, aptiganel, besonprodil, budipine, conanthkin G, delcemin, dexanabinol, dextromethorphan, dextropropoxyphene, felbamate, fluorofelbamate , Gacyclidine, glycine, ipenoxazone, kitecephalin, ketamine, ketobemidone, ranisemin, lycostine, midahotel, memantine, D-methadone, D-morphine, milnacipran, neramexane, orphenadrine, remasemid, sulfazosin, FPL-12,495 (Racemide metabolites), topiramate, (αR) -α-amino-5-chloro-1- (phosphonomethyl) -1H-benzimidazole-2-propaprop Acid, 1-aminocyclopentanecarboxylic acid, [5- (aminomethyl) -2-[[[(5S) -9-chloro-2,3,6,7-tetrahydro-2,3-dioxo-1H- , 5H-pyrido [1,2,3-de] quinoxalin-5-yl] acetyl] amino] phenoxy] -acetic acid, α-amino-2- (2-phosphonoethyl) -cyclohexanepropionic acid, α-amino-4- (Phosphonomethyl) -benzeneacetic acid, (3E) -2-amino-4- (phosphonomethyl) -3-heptenoic acid, 3-[(1E) -2-carboxy-2-phenylethenyl] -4,6-dichloro- 1-H-indole-2-carboxylic acid, 8-hydroxy-2,3-dihydropyridazino [4,5-b] quinoline-1,4 with 2-hydroxy-N, N, N-trimethyl-ethanaminium - ON 5-oxide salt, N ′-[2-chloro-5- (methylthio) phenyl] -N-methyl-N- [3- (methylthio) phenyl] -guanidine, N ′-[2-chloro-5- (Methylthio) phenyl] -N-methyl-N- [3-[(R) -methylsulfinyl] phenyl] -guanidine, 6-chloro-2,3,4,9-tetrahydro-9-methyl-2,3- Dioxo-1H-indeno [1,2-b] pyrazine-9-acetic acid, 7-chlorothioquinurenic acid, (3S, 4aR, 6S, 8aR) -decahydro-6- (phosphonomethyl) -3-isoquinolinecarboxylic acid, (−) 6,7-Dichloro-1,4-dihydro-5- [3- (methoxymethyl) -5- (3-pyridinyl) -4-H-1,2,4-triazol-4-yl]- 2,3-quinoxalinedione, 4 6-dichloro-3-[(E)-(2-oxo-1-phenyl-3-pyrrolidinylidene) methyl] -1H-indole-2-carboxylic acid, (2R, 4S) -rel-5,7-dichloro- 1,2,3,4-tetrahydro-4-[[(phenylamino) carbonyl] amino] -2-quinolinecarboxylic acid, (3R, 4S) -rel-3,4-dihydro-3- [4-hydroxy- 4- (phenylmethyl) -1-piperidinyl] -2H-1-benzopyran-4,7-diol, 2-[(2,3-dihydro-1H-inden-2-yl) amino] -acetamide, 1,4 -Dihydro-6-methyl-5-[(methylamino) methyl] -7-nitro-2,3-quinoxalinedione, [2- (8,9-dioxo-2,6-diazabicyclo [5.2.0] Non-1 7) -En-2-yl) ethyl] -phosphonic acid, (2R, 6S) -1,2,3,4,5,6-hexahydro-3-[(2S) -2-methoxypropyl] -6 11,11-trimethyl-2,6-methano-3-benzoazocin-9-ol, 2-hydroxy-5-[[(pentafluorophenyl) methyl] amino] -benzoic acid, 1- [2- (4-hydroxy Phenoxy) ethyl] -4-[(4-methylphenyl) methyl] -4-piperidinol, 1- [4- (1H-imidazol-4-yl) -3-butynyl] -4- (phenylmethyl) -piperidine, 2-methyl-6-phenylethynyl) -pyridine, 3- (phosphonomethyl) -L-phenylalanine and 3,6,7-tetrahydro-2,3-dioxo-N-phenyl-1H, 5H-pyrido [1 , 2,3-de] quinoxaline-5-acetamide.
ある種の実施形態では、抗炎症化合物は、アスピリン、セレコキシブ、コーチゾン、デラコキシブ、ジフルニサル、エトリコキシブ、フェノプロフェン、イブプロフェン、ケトプロフェン、ナプロキセン、プレドニソロン、スリンダク、トルメチン、ピロキシカム、メフェナム酸、メロキシカム、フェニルブタゾン、ロフェコキシブ、スプロフェン、バルデコキシブ、4−(4−シクロヘキシル−2−メチルオキサゾール−5−イル)−2−フルオロベンゼンスルホンアミド、N−[2−(シクロヘキシルオキシ)−4−ニトロフェニル]メタンスルホンアミド、2−(3,4−ジフルオロフェニル)−4−(3−ヒドロキシ−3−メチルブトキシ)−5−[4−(メチルスルホニル)フェニル]−3(2H)−ピリダジノン及び2−(3,5−ジフルオロフェニル)−3−[4−(メチルスルホニル)フェニル]−2−シクロペンテン−1−オンからなる群から選択される。 In certain embodiments, the anti-inflammatory compound is aspirin, celecoxib, cortisone, delacoxib, diflunisal, etlicoxib, fenoprofen, ibuprofen, ketoprofen, naproxen, prednisolone, sulindac, tolmetine, piroxicam, mefenamic acid, meloxicam, phenylbutazone , Rofecoxib, suprofen, valdecoxib, 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide, N- [2- (cyclohexyloxy) -4-nitrophenyl] methanesulfonamide, 2- (3,4-Difluorophenyl) -4- (3-hydroxy-3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and 2- (3 - is selected from difluorophenyl) -3- [4- (methylsulfonyl) phenyl] -2-cyclopenten-1 consists on the group.
本開示は、以下の非限定的な実施例によって示される複数の態様を有する。 The present disclosure has multiple aspects as illustrated by the following non-limiting examples.
実施例1
本明細書に記載する試験には、インビトロ海馬スライスにおける、細胞外複数部位でのSD伝播速度の電気生理学的モニタリング、及びSDが誘発する樹状突起スパインのサイズ変化をリアルタイムにイメージングするための2光子レーザー走査顕微鏡を利用した。NMDAR受容体グリシン部位に機能する新規部分アゴニストであるGLYX−13の効果を、SD伝播の閾値及び速度、ならびに樹状突起スパインのモルホロジーに与えるSDのリアルタイム効果に基づいて検討した。GLYX−13は、場合により細胞外カリウム濃度の局所的増加によるSDの誘発を完全に防止し、かつSDの伝搬速度を持続的に低下させた。海馬CA1領域をSDが通過すると、樹状突起スパインは急速な収縮を生じ、ニューロン脱分極の復帰後に逆進した。GLYX−13は、樹状突起スパインがSD後に元のサイズ及び位置に戻る速度及び程度を改善した。これは、NMDA受容体活性を調節する薬物及びその他が、反復性片頭痛発作で起こり得る損傷から脳のシナプス接続を保護できることを示す。
Example 1
The studies described herein include electrophysiological monitoring of the rate of SD propagation at multiple extracellular sites in in vitro hippocampal slices, and 2 for real-time imaging of SD-induced dendritic spine size changes. A photon laser scanning microscope was used. The effect of GLYX-13, a novel partial agonist that functions at the NMDAR receptor glycine site, was examined based on the threshold and rate of SD propagation and the real-time effect of SD on the morphology of dendritic spines. GLYX-13 completely prevented the induction of SD, possibly by a local increase in extracellular potassium concentration, and sustainedly reduced the propagation speed of SD. When SD passed through the hippocampal CA1 region, the dendritic spine caused rapid contraction and regressed after reversion of neuronal depolarization. GLYX-13 improved the speed and extent to which dendritic spines return to their original size and position after SD. This indicates that drugs that modulate NMDA receptor activity and others can protect brain synaptic connections from damage that can occur with recurrent migraine attacks.
一般的な試験法
薬物
外部溶液及びパッチピペット溶液は全て、脱イオン蒸留水(抵抗率>18MΩcm-2;Milli−Qシステム)を用いて作製した。細胞外及び細胞内溶液を作製するための化学物質は、Sigma−Aldrich(St.Louis,MO,USA)から購入した。AlexaFluor 594はMolecular Probesから購入した。
General Test Methods Drugs All external solutions and patch pipette solutions were made using deionized distilled water (resistivity> 18 MΩcm −2 ; Milli-Q system). Chemicals for making extracellular and intracellular solutions were purchased from Sigma-Aldrich (St. Louis, MO, USA). AlexaFluor 594 was purchased from Molecular Probes.
スライスの調製及び細胞外記録法
14〜21日齢のSprague−Dawley(登録商標)ラット(Taconic Farms、Hudson,NY)からの海馬スライスで実験を実施した。ラットをイソフルオレンで深麻酔して犠牲死させ、素早く脳を切除し、酸素化した(95%O2―5%CO2)氷冷人工脳脊髄液(ACSF)中に配置した。ACSFはNaCl 126、KCl 2.5、CaCl2 2.6、MgCl2 1.3、NaH2PO4 1.25、NaHCO3 26及びグルコース 11(単位mM)を含有する。脳を二等分して前頭葉を切除し、個々の脳半球をシアノアクリレート接着剤を使用してステージに固定し、スライスする間、連続して酸素添加された氷冷ACSF中に浸漬した。ビブラトーム(Leica 1200s)を使用して、海馬を含む400μm厚の冠状スライスを切り出して、インターフェイス式保持チャンバーに移し、室温にて最低1時間培養した後、Haas型インターフェイス式チャンバーに移して32℃で記録した。実験開始前に95%O2/5%CO2で飽和させたACSF(4mL/min、ACSF(mM):NaCl 126;KCl 3;NaH2PO4 1.25;MgCl 1.3;CaCl2 2.5;NaHCO3 26;グルコース 10)をスライスに灌流させ、全ての薬物を浴適用した。
Slice preparation and extracellular recording. Experiments were performed on hippocampal slices from 14-21 day old Sprague-Dawley® rats (Taconic Farms, Hudson, NY). Rats were sacrificed by deep anesthesia with isofluorene and the brains were quickly excised and placed in oxygenated (95% O 2 -5% CO 2 ) ice-cold artificial cerebrospinal fluid (ACSF). ACSF contains NaCl 126, KCl 2.5, CaCl 2 2.6, MgCl 2 1.3, NaH 2 PO 4 1.25, NaHCO 3 26 and glucose 11 (unit: mM). The frontal lobe was excised by bisecting the brain, and individual brain hemispheres were fixed to the stage using cyanoacrylate glue and immersed in ice-cold ACSF with continuous oxygenation during slicing. Using a vibratome (Leica 1200s), a 400 μm thick coronal slice containing the hippocampus was cut out, transferred to an interface holding chamber, incubated at room temperature for at least 1 hour, then transferred to a Haas type interface chamber at 32 ° C. Recorded. ACSF (4 mL / min, ACSF (mM): NaCl 126; KCl 3; NaH 2 PO 4 1.25; MgCl 1.3; CaCl 2 2 saturated with 95% O 2 /5% CO 2 before the start of the experiment .5; NaHCO 3 26; glucose 10) was perfused into the slices and all drugs were bath applied.
細胞外記録は、Clampex(v.9)付属MultiClamp 700B(Axon Instruments)を使用して実施し、1kHzでフィルタリングし、3kHzでデジタル化した。低抵抗(ACSF充填後1〜2MΩ)の記録用電極を薄壁ボロシリケートガラスで作製して、CA1領域の放線状層にあるシャファー側枝の終端野の先端樹状領域に、SDを開始するピペットから約150mmの距離間隔で挿入し、SDの広がりをモニターした。浸漬された記録チャンバーを赤外線微分干渉コントラスト(DIC)光学素子を備えるZeiss Axioskop 2FS直立顕微鏡に載置した。SDによって生じるスライスの輝度変化を、10倍の対物レンズを使用して撮像した。PTIマスターシステムによって制御された冷却CCDカメラ(CoolSNAP HQ)を用いて100ms毎に輝度変化を撮像した。電気生理学的データはClampfit 9を用いて分析した。イメージングデータはImageJ(NIH)を用いてデジタル化及び再構築した。 Extracellular recording was performed using MultiClamp 700B (Axon Instruments) with Clampex (v.9), filtered at 1 kHz and digitized at 3 kHz. A pipe for starting SD at the tip dendritic region of the terminal field of the shuffler side branch in the CA1 region of the radial layer of the low-resistance (1-2 MΩ after ACSF filling) recording electrode is made of thin-walled borosilicate glass Inserted at a distance of about 150 mm, and the spread of SD was monitored. The immersed recording chamber was placed on a Zeiss Axioskop 2FS upright microscope equipped with an infrared differential interference contrast (DIC) optical element. The slice brightness change caused by SD was imaged using a 10x objective lens. Luminance changes were imaged every 100 ms using a cooled CCD camera (CoolSNAP HQ) controlled by the PTI master system. Electrophysiological data was analyzed using Clampfit 9. Imaging data was digitized and reconstructed using ImageJ (NIH).
双極性ステンレス刺激電極(FHC、Bowdoin,ME)をCA3領域のシャファー側枝−交連繊維に置き、30秒毎に1回、最大fEPSPの約50%を誘起するように調節された刺激強度で電流パルスを印加した(50〜100pA;継続時間100μs)。ISO−Flex製アイソレータからの電気刺激は、Master 8−パルス発生器(AMPI、Jerusalem,Israel)によって制御し、Multiclamp 700B(Molecular Devices、Sunnyvale,CA)によって作動させた。Digidata 1322を用いて信号をデジタル化し、Multiclamp 700B増幅器を使用して記録した。負の最大偏向の20〜80%を基にした線形補間によってfEPSPの傾きを測定し、実験開始前の少なくとも15分間、傾きが10%以内で安定していることを確認した。IBM互換パーソナルコンピューター上でClampfit(Version 9;Axon Instrument)を使用してデータを分析した。少なくとも30分の安定なベースライン期間について、放線状層の先端樹状野で、誘起されたfEPSP(最大振幅の50%、2〜4mV)を記録した。 A bipolar stainless stimulating electrode (FHC, Bowdoin, ME) is placed on the shuffler side branch-commissural fiber in the CA3 region and current pulse with a stimulation intensity adjusted to induce about 50% of the maximum fEPSP once every 30 seconds. Was applied (50-100 pA; duration 100 μs). Electrical stimulation from an ISO-Flex isolator was controlled by a Master 8-pulse generator (AMPI, Jerusalem, Israel) and actuated by a Multilamp 700B (Molecular Devices, Sunnyvale, Calif.). The signal was digitized using Digidata 1322 and recorded using a Multilamp 700B amplifier. The slope of fEPSP was measured by linear interpolation based on 20-80% of the negative maximum deflection, and it was confirmed that the slope was stable within 10% for at least 15 minutes before the start of the experiment. Data were analyzed using Clampfit (Version 9; Axon Instrument) on an IBM compatible personal computer. Induced fEPSPs (50% of maximum amplitude, 2-4 mV) were recorded at the apical dendritic field of the stratified layer for a stable baseline period of at least 30 minutes.
海馬拡延性抑制の誘発
海馬の尖端冠状スライスを顕微鏡ステージ上の浸漬した記録チャンバーに移し、温めたACSF(32℃)を灌流させ、3mL/minの灌流速度で細胞外[K+]を8mMまで上昇させた。ガラスピペットによって3MのKClを加圧注入パフ(pressure−injecting puff)して拡延性抑制を開始した。50〜100ms持続する8〜10psiの圧力パルスを、Picospritzer II(Parker Hannifin、Hollis,NH)によって作動させた。3MのKClを充填したときのピペット抵抗は、2±0.2MΩであった。
Induction of hippocampal spreading inhibition Transfer the apical coronal slices of the hippocampus to an immersion recording chamber on a microscope stage, perfuse with warm ACSF (32 ° C.), and increase extracellular [K + ] to 8 mM at a perfusion rate of 3 mL / min. Raised. 3M KCl was pressure-injecting puffed with a glass pipette to initiate spreading suppression. A pressure pulse of 8-10 psi lasting 50-100 ms was actuated by Picospritzer II (Parker Hannifin, Hallis, NH). The pipette resistance when filled with 3M KCl was 2 ± 0.2 MΩ.
樹状突起スパインの収縮/回復の動的イメージング分析
海馬スライスのCA1錘体神経にAlexa Fluor 594(100μM)を15分間充填した後、以前に記載されているように(Zhangら,2008)、60x/1.1nAの水浸赤外線対物レンズ及び4倍デジタルズームを備えるカスタマイズされた2光子レーザー走査顕微鏡Olympus BX61WIを使用して3次樹状突起を撮像した。移動誤差を回避するために、0.5μmのzステップ間隔で、焦点層から+/−3μm範囲のXYZ走査モードを使用した。各画像の完了まで0.45秒を要し、単一の深さプロファイル時間は7秒であった。蛍光の飽和と、過剰な励起光からの小さい樹状突起スパインに対する何らかの光毒性の徴候の両方を回避するように十分に注意した。起こり得る色素の光退色及び光毒性を低減するため、深さプロファイルを5分間隔で反復した。810nmに調整したMai/Taiレーザー(Solid−State Laser、Mountain View,CA)を励起に使用し、Olympus FluoviewFV300ソフトウェア(Olympus America,Melville,NY)によって画像取得を制御した。ピンホールを最大開口し、発光スペクトル窓を背景上の信号に最適化した共焦点レーザー走査ヘッドの光電子増倍管によって落射蛍光を検出した。トランス蛍光経路において、565nmのダイクロイックミラーを使用して、緑と赤の蛍光を分離し、それぞれHQ525/50及びHQ605/50発光フィルター(Chroma Technology、Rockingham,VT)を通過させて、透過または反射された励起光を除去して、2つの光電子増倍管によって同時に検出した。図は6μmの全体的なZプロファイルからの圧縮画像を示し、及び各投影を使用して、スパインの体積指数としての強度を算出した。
Dynamic imaging analysis of dendritic spine contraction / recovery CA1 pyramidal nerves of hippocampal slices were filled with Alexa Fluor 594 (100 μM) for 15 min, followed by 60 × as previously described (Zhang et al., 2008). Tertiary dendrites were imaged using a customized two-photon laser scanning microscope Olympus BX61WI equipped with a /1.1 nA immersion infrared objective lens and 4 × digital zoom. In order to avoid movement errors, an XYZ scanning mode in the range of +/− 3 μm from the focal layer was used with a z-step interval of 0.5 μm. Each image took 0.45 seconds to complete and a single depth profile time was 7 seconds. Care was taken to avoid both fluorescence saturation and any signs of phototoxicity to small dendritic spines from excessive excitation light. To reduce possible dye photobleaching and phototoxicity, the depth profile was repeated at 5 minute intervals. A Mai / Tai laser (Solid-State Laser, Mountain View, CA) tuned to 810 nm was used for excitation and image acquisition was controlled by Olympus Fluoview FV300 software (Olympus America, Melville, NY). Epifluorescence was detected by a photomultiplier tube of a confocal laser scanning head with a maximum pinhole and an emission spectral window optimized for background signals. In the trans-fluorescence path, a 565 nm dichroic mirror is used to separate green and red fluorescence and pass or reflect through HQ525 / 50 and HQ605 / 50 emission filters (Chroma Technology, Rockingham, VT), respectively. The excitation light was removed and detected simultaneously by two photomultiplier tubes. The figure shows a compressed image from the overall Z profile of 6 μm, and each projection was used to calculate the intensity as a volume index of the spine.
データ分析
1kHzの遮断周波数を有する8極ベッセル低域フィルターを通して記録信号をフィルタリングし、100μs間隔でClampex(V.9)によってサンプリングした。Clampfit(V.9)によってfEPSP傾きを算出した後、そのデータをOrigin 6.1(Microcal Software、MA)によって更に処理し、CorelDraw 10(Corel、Ottawa,Ontario,Canada)を用いて表示した。全データをSPSSソフトウェア(SPSS Inc.,Chicago,IL)を使用して、一元配置分散分析(ANOVA)またはスチューデントのt検定によって分析した。統計的有意差は、p<0.05に指定した。データは、実験全体の平均±SEMを表す。
Data analysis The recorded signal was filtered through an 8-pole Bessel low-pass filter with a cut-off frequency of 1 kHz and sampled by Clampex (V.9) at 100 μs intervals. After calculating the fEPSP slope by Clampfit (V.9), the data was further processed by Origin 6.1 (Microcal Software, MA) and displayed using CoreDraw 10 (Corel, Ottawa, Ontario, Canada). All data were analyzed by one-way analysis of variance (ANOVA) or Student's t-test using SPSS software (SPSS Inc., Chicago, IL). Statistical significance was designated as p <0.05. Data represent the mean ± SEM of the entire experiment.
結果
限局性の高[K+]によって海馬スライスのCA1野に誘発される拡延性抑制
[K+]oを32℃で8mMまで上昇させた人工脳脊髄液(ACSF)中で、CA1放線状層(図1、左上)の領域上に3M[K+]oを1回、局所的にパフ(100ms)すると、海馬のCA1全領域にわたって9±5.4mm/min(n=16)の伝搬速度で広がるSDが確実に誘発された。負電位シフト(図1、右上)を特徴とするSDは、海馬CA1領域の放線状層シナプス層で−8±1.5mV(n=30)の最大シフトを示し、通常これは45秒以上持続した。
Results Spatial inhibition induced in the CA1 area of hippocampal slices by localized high [K +] In artificial cerebrospinal fluid (ACSF) in which [K + ] o was increased to 8 mM at 32 ° C. When 3M [K + ] o is locally puffed (100 ms) on the area shown in FIG. 1, upper left), the propagation speed is 9 ± 5.4 mm / min (n = 16) over the entire CA1 area of the hippocampus. Spreading SD was reliably induced. SD characterized by a negative potential shift (Fig. 1, upper right) shows a maximum shift of -8 ± 1.5 mV (n = 30) in the radial synaptic layer of the hippocampal CA1 region, which usually lasts over 45 seconds did.
SDを10分毎に誘発して、負電位シフト(図1、右上、斜線領域)、有効な振幅の測定値、及びK+の細胞外空間伝導の持続時間が反復したSDで安定的であるかを試験した。開始電極から記録された負電位シフトの領域が、600μm離れた遠位の記録用電極よりも大きくなった一方(図1、下)、いずれの部位でも、10分間隔で誘発された反復性の経時的なSDの個々の現象出現に関して振幅または伝播速度に有意差は見られなかった(Bonferroniの多重比較検定、P>0.20)。これらの結果は、再現可能なSDの負電位シフトを、少なくとも最初の10分間、海馬のCA1野に安定的に反復して誘起できることを示す。 SD is triggered every 10 minutes and is stable with negative potential shift (FIG. 1, upper right, shaded area), effective amplitude measurement, and repeated K + extracellular space conduction duration. Was tested. While the region of negative potential shift recorded from the starting electrode was larger than the distal recording electrode 600 μm away (FIG. 1, bottom), repetitive effects induced at 10 min intervals at either site There was no significant difference in amplitude or propagation velocity with respect to the appearance of individual events in SD over time (Bonferroni's multiple comparison test, P> 0.20). These results indicate that a reproducible negative SD shift can be stably and repeatedly induced in the CA1 field of the hippocampus for at least the first 10 minutes.
GLYX−13は、海馬の拡延性抑制の伝播を抑制し、不応期を延長する
NMDA受容体グリシンコアゴニスト部位の新規部分アゴニストGLYX−13が、NMDA受容体の活性化を生理学的範囲内に調節し、過剰な活性化を防止することにより、SDの閾値を上げること、またはSDを阻止することができるという仮説を検証するために、GLYX−13を1、10または50μmで海馬スライスに30分間、浴適用した後、CA1領域の放線状層に高[K+]を短時間放出(パッチピペットで1mM)し、SDの誘発を試みた。ナイーブスライスに高[K+]が最初に放出されたときと、それから30分間、それぞれ3つの試験濃度(1、10または50μM)のGLYX−13で浴適用した後に基づいて用量反応関係を確定し、一方でSDを検出するためにDC電位を記録した。
GLYX-13 suppresses spread of hippocampal spreading inhibition and prolongs the refractory period A novel partial agonist GLYX-13 at the NMDA receptor glycine co-agonist site modulates NMDA receptor activation within the physiological range In order to test the hypothesis that the threshold of SD can be raised by preventing excessive activation or that SD can be blocked, GLYX-13 can be applied to hippocampal slices at 1, 10 or 50 μm for 30 minutes. After applying the bath, high [K +] was released in a short time (1 mM with a patch pipette) in the CA1 region of the striatal layer to try to induce SD. Establish a dose-response relationship based on when the high [K +] was first released in the naive slice and then after 30 minutes bath application with 3 test concentrations (1, 10 or 50 μM) of GLYX-13 respectively. On the other hand, DC potential was recorded to detect SD.
薬物を含まないACSF中で少なくとも3回のSDが最初に誘起された後、スライスにGLYX−13を灌流させ、10分毎にSDの誘発を継続した。図2上部に例示するように、10μMのGLYX−13の場合、開始部位でのSDの個々の経時的な現象出現に関してベースライン領域との間に有意差は見られなかった(Bonferroniの多重比較検定、P>0.20)。このことは、GLYX−13がSDの開始を変化させなかったことを示す。 After at least 3 SDs were first induced in ACSF without drug, the slices were perfused with GLYX-13 and induction of SD was continued every 10 minutes. As illustrated in the upper part of FIG. 2, in the case of 10 μM GLYX-13, there was no significant difference from the baseline region regarding the appearance of individual time courses of SD at the start site (Bonferroni's multiple comparisons). Test, P> 0.20). This indicates that GLYX-13 did not change the onset of SD.
次にGLYX−13が、SDの反復による、近い(近位)記録部位と遠い(遠位)記録部位でのSDの振幅の関係に影響を及ぼしたかどうかを確認する試験を行った。スライスに10μMのGLYX−13を灌流させ、10分毎にSDの誘発を継続した(図2、下)。Bonferroniの多重比較検定(P>0.20)は再度、対照スライスでのSDの個々の経時的な現象出現に関して領域間で有意差を示さなかった。近位の記録部位で、GLYX−13はSDの負電位シフトの開始に影響を及ぼさなかった。 A test was then performed to see if GLYX-13 affected the SD amplitude relationship at the near (proximal) and far (distal) recording sites due to SD repetition. Slices were perfused with 10 μM GLYX-13 and SD induction continued every 10 minutes (FIG. 2, bottom). Bonferroni's multiple comparison test (P> 0.20) again showed no significant differences between regions with respect to the appearance of individual time courses of SD in control slices. At the proximal recording site, GLYX-13 did not affect the onset of SD negative potential shift.
開始部位でのSDの振幅は、遠位記録では、SDの負電位シフトの領域と相関していた(図2、下)。その結果、GLYX−13の有無による近位/遠位領域比を比較した。図2下部に示したように、遠位部位と開始部位との間の領域比は、10μMのGLYX−13の存在下では、6回目のSD(第6のSD)の適用により激減した。二元ANOVAは次の、1)観察全体にわたる同じスライスでのSDの反復による時間的効果(F(1、12)=5.17、p<0.05);2)薬物治療による効果(F(1,12)=5.07、p<0.05);及び3)時間と治療との相互作用(F(1,12)=30.91、p<0.01)の3つの有意な効果を示した。これらの結果は、SDの周期的な負電位シフトが遠位部位と開始部位との間の振幅比を変化させること、及びこの抑制がGLYX−13によって著しく増強されたことを示す。これらの知見は、特に複数のSD事象後、GLYX−13が脳経由のSD伝播を有意に抑制できることを示している。 The amplitude of SD at the start site correlated with the area of negative SD shift in the distal recording (FIG. 2, bottom). As a result, the proximal / distal region ratio with and without GLYX-13 was compared. As shown in the lower part of FIG. 2, the area ratio between the distal site and the start site was drastically reduced by the sixth SD (6th SD) application in the presence of 10 μM GLYX-13. Two-way ANOVA follows: 1) Temporal effect by repeated SD on the same slice across observations (F (1,12) = 5.17, p <0.05); 2) Effect by drug treatment (F (1,12) = 5.07, p <0.05); and 3) three significant interactions of time and treatment (F (1,12) = 30.91, p <0.01) Showed the effect. These results indicate that the periodic negative potential shift of SD changes the amplitude ratio between the distal site and the start site, and that this suppression was significantly enhanced by GLYX-13. These findings indicate that GLYX-13 can significantly suppress SD propagation through the brain, especially after multiple SD events.
前述の試験において、GLYX−13が負電位シフトの振幅を減少させること、及び伝導速度を低下させることにより、SDの伝播を制限でき、効果は複数のSD後に最大であることが実証された。各SDの開始間隔を短縮することにより、対照スライスでの各SDが次の正常なSD(n=7)では3〜4分間の絶対不応期を有したことを見出した。10μMのGLYX−13は、この不応期を5〜6分(n=6)まで延長させた。図3に示すように、対照スライス(対照)では前回のSDの5分後にSDが正常に誘起されたが、GLYX−13(GLYX−13 30’)で処置したスライスでは誘発できなかった。 In the foregoing test, it was demonstrated that GLYX-13 can limit the propagation of SD by reducing the amplitude of the negative potential shift and reducing the conduction velocity, and the effect is greatest after multiple SDs. By shortening the start interval of each SD, it was found that each SD in the control slice had an absolute refractory period of 3-4 minutes in the next normal SD (n = 7). 10 μM GLYX-13 extended this refractory period to 5-6 minutes (n = 6). As shown in FIG. 3, SD was successfully induced 5 minutes after the previous SD in the control slice (control), but not in slices treated with GLYX-13 (GLYX-13 30 ').
SDが誘発する細胞外空間の体積シフトにより生じる光学濃度の内在的変化を利用した、SD伝播の測定
SDにより、脱分極された細胞に流体が流出し、細胞が膨張するにつれ、細胞外空間体積の大きな収縮を誘発する。これはインビボの内在的光学濃度の変化として表れ得る。このような輝度強度の変化は、透過光DIC顕微鏡を使用して脳スライス中に容易に検出することもできる。図4Aは、SD「前兆」である輝度の増加が開始ピペットから広がり、スライス全体に伝播していることを示し、更にこれはSD伝導速度の算出に使用できる(図4B)。電気生理学的記録を使用した、SDの負の最大電位シフトと、輝度増加の時間経過とは良好に相関した。このように、距離を用いて輝度変化の時間経過を算出することは、SD伝導速度を測定する正確かつ利便な方法を提供する。
Measurement of SD propagation using intrinsic changes in optical density caused by volume shift of extracellular space induced by SD. Extracellular space volume as SD swells and fluid flows to depolarized cells. Induces a large contraction of This can appear as a change in the intrinsic optical density in vivo. Such a change in luminance intensity can also be easily detected in a brain slice using a transmitted light DIC microscope. FIG. 4A shows that the SD “precursor” luminance increase spreads from the starting pipette and propagates throughout the slice, which can also be used to calculate the SD conduction velocity (FIG. 4B). SD negative maximum potential shift using electrophysiological recording correlated well with the time course of luminance increase. Thus, calculating the time course of luminance change using the distance provides an accurate and convenient way to measure the SD conduction velocity.
SDの反復が同一伝導速度を示すかどうかを判定するために、図4A上部に図示たように、150μm離れた5箇所で輝度変化をモニターした。反復測定一元ANOVAは、SDが個々のスライスの範囲内で、P1からP5まで安定した伝達速度を維持することを示した(F(5,35)=2.42、p>0.05)。その結果、伝達速度を使用して、P1からP5まで、連続した現象出現にわたり、SDの安定性を試験することができた。SDの平均伝播速度は9.07±0.55mm/minであり、範囲は7.54〜11.14mm/min(n=16)であった。 In order to determine whether the repetition of SD shows the same conduction velocity, the luminance change was monitored at five locations separated by 150 μm as shown in the upper part of FIG. 4A. Repeated measurement one-way ANOVA showed that SD maintained a stable transmission rate from P1 to P5 within individual slices (F (5,35) = 2.42, p> 0.05). As a result, it was possible to test the stability of SD over successive phenomena from P1 to P5 using transmission speed. The average propagation speed of SD was 9.07 ± 0.55 mm / min, and the range was 7.54 to 11.14 mm / min (n = 16).
SDの反復した現象出現が安定な速度を維持したかどうか、及びGLYX−13がSD伝導速度に影響を及ぼしたかどうかを検証するために、図5に示したように、反復測定値によるANOVA試験を使用し、連続する6回のSDを分析した。分析により、対照とGLYX−13処置したスライスとの間に有意差が見られた(F(1,50)=3.66、p<0.01)。SDの数列は、全分散の38.5%を占めた。このことは、SD伝播速度がSD回数の増加と共に有意に低下したことを示す(F(5,50)=14.01、p<0.01)。二元ANOVAでは、反復する全SDにわたるSD伝播速度に対するGLYX−13効果は有意に達しなかったが、SDの回数とGLYX−13処置との間には有意な相互作用があった(F(5,50)=2.53、P<0.05)。このことは、GLYX−13(黒丸)が7回目のSDによってのみSD伝播速度を有意に低下させたことを反映している。 In order to verify whether the recurrent appearance of SD maintained a stable rate and whether GLYX-13 affected the SD conduction velocity, the ANOVA test with repeated measurements as shown in FIG. Were used to analyze 6 consecutive SDs. The analysis showed a significant difference between the control and GLYX-13 treated slices (F (1,50) = 3.66, p <0.01). The sequence of SDs accounted for 38.5% of the total variance. This indicates that the SD propagation speed decreased significantly with increasing number of SDs (F (5,50) = 14.01, p <0.01). Dual ANOVA did not significantly reach the GLYX-13 effect on SD propagation velocity across all repetitive SDs, but there was a significant interaction between the number of SDs and GLYX-13 treatment (F (5 50) = 2.53, P <0.05). This reflects that GLYX-13 (black circle) significantly reduced the SD propagation speed only by the seventh SD.
拡延性抑制は、CA1錘体神経樹状突起スパインの可逆的な体積縮小を引き起こす
脳内の錘体神経樹状突起の解剖学的微細構造は、意外にも多様な刺激に応答して不安定化する。脱分極、酸素/グルコース欠乏及びN−メチル−D−アスパラギン酸は全て、インビボの海馬CA1錘体神経の樹状突起スパインの収縮をもたらすことが示されている。SDに対するスパインの応答を検討するために、単一のCA1錘体神経に蛍光色素AlexaFluor−594を充填して、2光子レーザー走査顕微鏡から収集された連続したzスタック断面(5μmにわたり0.2μmステップずつ)を利用して樹状突起スパインの形状を撮像した。AlexaFluror−594をCA1錘体神経に充填して30分後、ニューロン内で平衡分布に到達したら、海馬スライスのCA1領域の放線状層に、高[K+]を短時間放出(パッチピペットで1M)することによりSDを開始させた。このときシャファー側枝アクソンがCA1錘体神経の先端樹状突起にシナプスを形成する。図6A及び6Bに示すように、SDによって生じる脱分極は、圧縮されたzスタック層の蛍光振幅によって測定される、実質的なスパイン収縮を誘発した。スパイン体積は最初のSD後20〜30分で完全に回復する。これにより、SDが誘発する脱分極の後遺症の1つが、樹状突起スパインのモルホロジーの変化であることが確認された。
Extensive inhibition causes reversible volume reduction of the CA1 pyramidal spine dendritic spine The anatomical microstructure of the pyramidal dendritic spine in the brain is unexpectedly unstable in response to various stimuli Turn into. Depolarization, oxygen / glucose deprivation and N-methyl-D-aspartate have all been shown to result in dendritic spine contraction of hippocampal CA1 pyramidal nerves in vivo. To examine the response of spine to SD, a single CA1 pyramidal nerve was loaded with the fluorescent dye AlexaFluor-594 and a continuous z-stack cross-section collected from a two-photon laser scanning microscope (0.2 μm step over 5 μm). The shape of the dendritic spine was imaged using each). 30 minutes after filling AlexaFluor-594 in the CA1 pyramidal nerve, when the equilibrium distribution is reached in the neuron, high [K +] is released in a short time (1M with a patch pipette) into the radial layer of the CA1 region of the hippocampal slice. To start SD. At this time, the Schaffer side branch Axon forms a synapse at the tip dendrite of the CA1 pyramidal nerve. As shown in FIGS. 6A and 6B, the depolarization caused by SD induced substantial spine contraction as measured by the fluorescence amplitude of the compressed z-stack layer. Spine volume fully recovers 20-30 minutes after the first SD. This confirmed that one of the sequelae of depolarization induced by SD is a change in the morphology of dendritic spines.
GLYX−13は、拡延性抑制に続く樹状突起スパインの回復を改善する
最後に、GLYX−13の効果を、SDに対する樹状突起スパインの動的なモルホロジー応答について検討した。GLYX−13がSDに応答してスパインの収縮を低減できるか、またはスパインの回復を改善できるかを調べた。図6Aは、対照の錘体神経内での2回のSD現象出現に応答したスパイン収縮を示し、一方の図6Bは10μMのGLYX−13存在下での同様の過程を示す。図6C上部に示されたように、反復測定ANOVAによると、樹状突起スパインから測定した蛍光強度は有意に達した(F(8,64)=17.53、p<0.001)。更にこの有意性は、主にSD後の時間経過に起因したものであった(F(8,64)=6.18、p<0.01)。このことは、GLYX−13(黒丸)がSDによって引き起こされた収縮を変化させなかったが、SD後のスパインのサイズの回復を助けることを明らかにしている(F(8,64)=2.81、p<0.05)。
GLYX-13 improves dendritic spine recovery following spreading suppression Finally, the effect of GLYX-13 was examined on the dynamic morphological response of dendritic spines to SD. It was investigated whether GLYX-13 could reduce spine contraction in response to SD or improve spine recovery. FIG. 6A shows spine contraction in response to the appearance of two SD events in the control pyramidal nerve, while FIG. 6B shows a similar process in the presence of 10 μM GLYX-13. As shown in the upper part of FIG. 6C, according to repeated measurements ANOVA, the fluorescence intensity measured from dendritic spines reached significant (F (8,64) = 17.53, p <0.001). Furthermore, this significance was mainly attributed to the time course after SD (F (8,64) = 6.18, p <0.01). This reveals that GLYX-13 (black circles) did not change the contraction caused by SD but helps to restore spine size after SD (F (8,64) = 2. 81, p <0.05).
実施例2
海馬スライスの調製:14〜21日齢のSprague−Dawley(登録商標)ラット(Taconic Farms)を使用して実験を実施した。ラットをイソフルオレンで深麻酔して犠牲死させ、素早く脳を切除し、酸素化した(95%O2―5%CO2)氷冷人工脳脊髄液(ACSF)中に配置した。ACSFはNaCl 126、KCl 2.5、CaCl2 2.6、MgCl2 1.3、NaH2PO4 1.25、NaHCO3 26及びグルコース 11(単位mM)を含有する。脳を二等分して前頭葉を切除し、個々の脳半球をシアノアクリレート接着剤を使用してステージに固定し、スライスする間、連続して酸素添加された氷冷ACSF中に浸漬した。ビブラトーム(Leica 1200s)を使用して海馬を含む400μm厚の冠状スライスを切り出して、インターフェイス式保持チャンバーに移し、実験開始前に最低1時間室温にて培養した。
Example 2
Preparation of hippocampal slices: Experiments were performed using 14-21 day old Sprague-Dawley® rats (Taconic Farms). Rats were sacrificed by deep anesthesia with isofluorene and the brains were quickly excised and placed in oxygenated (95% O 2 -5% CO 2 ) ice-cold artificial cerebrospinal fluid (ACSF). ACSF contains NaCl 126, KCl 2.5, CaCl 2 2.6, MgCl 2 1.3, NaH 2 PO 4 1.25, NaHCO 3 26 and glucose 11 (unit: mM). The frontal lobe was excised by bisecting the brain, and individual brain hemispheres were fixed to the stage using cyanoacrylate glue and immersed in ice-cold ACSF with continuous oxygenation during slicing. A 400 μm thick coronal slice containing the hippocampus was cut out using a vibratome (Leica 1200s), transferred to an interface-type holding chamber, and incubated at room temperature for a minimum of 1 hour before starting the experiment.
海馬拡延性抑制の誘発:海馬の尖端冠状スライスを顕微鏡ステージ上の浸漬した記録チャンバーに移し、温めたACSF(32℃)を灌流させ、3mL/minの灌流速度で細胞外[K+]を8mMまで上昇させた。ガラスピペットによって3MのKClを加圧注入パフして拡延性抑制を開始した。通常は50ms持続する8〜10psiの圧力パルスを、Picospritzerによって作動させた。3MのKClを充填したときのピペット抵抗は、2±0.2MΩであった。 Induction of hippocampal distensibility suppression: apical coronal slices of hippocampus were transferred to an immersion recording chamber on a microscope stage, perfused with warm ACSF (32 ° C.), and extracellular [K +] up to 8 mM at a perfusion rate of 3 mL / min Raised. 3M KCl was pressure-injected with a glass pipette and puffing suppression was started. A pressure pulse of 8-10 psi, usually lasting 50 ms, was actuated by a Picosprizer. The pipette resistance when filled with 3M KCl was 2 ± 0.2 MΩ.
電気生理学的記録方法:細胞外記録は、Clampex(v.9)付属MultiClamp 700B(Axon Instruments)を使用して実施し、1kHzでフィルタリングし、3kHzでデジタル化した。低抵抗(ACSF充填後1〜2MΩ)の記録用電極を薄壁ボロシリケートガラスで作製し、CA1領域の放線状層にあるシャファー側枝の終端野の先端樹状領域に、SDを開始しているピペットから約150mmの距離間隔で挿入し、SDの広がりをモニターした。浸漬された記録チャンバーを赤外線微分干渉コントラスト(DIC)光学素子を備えるZeiss Axioskop 2FS直立顕微鏡に載置した。SDによって生じるスライスの輝度変化を、10倍の対物レンズを使用して撮像した。PTIマスターシステムによって制御された冷却CCDカメラ(CoolSNAP HQ)を用いて100ms毎に輝度変化を撮像した。電気生理的データはClampfit 9を用いて分析した。イメージングデータはImageJ(NIH)を用いてデジタル化及び再構築した。すべての実験は、National Institutes of Healthガイドラインに準拠した承認プロトコルに従って実施した。 Electrophysiological recording method: Extracellular recording was performed using MultiClamp 700B (Axon Instruments) with Clampex (v.9), filtered at 1 kHz and digitized at 3 kHz. A low-resistance (1-2 MΩ after ACSF filling) recording electrode is made of thin-walled borosilicate glass, and SD is started at the tip dendritic region of the terminal area of the shuffler side branch in the radial layer of the CA1 region Insertion was performed at a distance of about 150 mm from the pipette, and the spread of SD was monitored. The immersed recording chamber was placed on a Zeiss Axioskop 2FS upright microscope equipped with an infrared differential interference contrast (DIC) optical element. The slice brightness change caused by SD was imaged using a 10x objective lens. Luminance changes were imaged every 100 ms using a cooled CCD camera (CoolSNAP HQ) controlled by the PTI master system. Electrophysiological data was analyzed using Clampfit 9. Imaging data was digitized and reconstructed using ImageJ (NIH). All experiments were performed according to an approved protocol that complies with the National Institutes of Health guidelines.
実施例1の結果は、女性及び青年期の患者に関する調査である。この実験的プロトコルを、インビトロで海馬脳内スライスのCA1領域における拡延性脱分極(SD)を開始するために使用した。拡延性抑制の開始部位からの距離及びSD伝播速度を、視覚的に広範囲にわたって良好に観察するため、実施例1の10倍対物レンズを4倍対物レンズに置き換えて視野範囲を1.6mmまで拡大した。両側からスライスを灌流して、脳スライスへの十分な酸素供給だけでなく、安定した細胞外環境の維持の補助にも効果的な灌流にするために記録チャンバーを変更した。これは拡延性抑制の各現象出現により、細胞外及び細胞内の両方で大幅なイオン組成変化が生じるためである。 The result of Example 1 is a survey on women and adolescent patients. This experimental protocol was used to initiate diffuse depolarization (SD) in the CA1 region of hippocampal brain slices in vitro. In order to observe the distance and the SD propagation speed from the start site for suppressing the spreadability over a wide range visually, the 10 × objective lens of Example 1 is replaced with a 4 × objective lens to expand the field of view to 1.6 mm. did. The recording chamber was modified to perfuse the slices from both sides to provide an effective perfusion not only for providing sufficient oxygen to the brain slices but also for maintaining a stable extracellular environment. This is because a significant change in ionic composition occurs both extracellularly and intracellularly due to the appearance of each phenomenon of spreading suppression.
現在のコホート研究に、2か月齢の卵巣切除したSprague−Dawley(登録商標)雌ラットの2群を加えた。卵巣切除されたラットのうち1群は、施術後7日目から7日間、毎日エストロゲンを注入したが、もう1群は対照として、実験実施前の7日間、オイルビヒクルのみを注入した。 Two groups of 2 month old ovariectomized Sprague-Dawley® female rats were added to the current cohort study. One group of ovariectomized rats was injected with estrogen daily for 7 days from the 7th day after the treatment, while the other group was injected with oil vehicle only for 7 days before the experiment as a control.
3Mのカリウムのパフ後、輝度変化を視覚的に、失敗(<100mm)、局所的に拡延(>100mm;<800mm)、または完全な広がり(>800mm)に分類した。8匹のオイル処置したラットからの39枚のスライス及び7匹のエストロゲン処置したラットからの35枚のスライスにて、SDの誘発を試みた。表1は、2群について同様の方法によって誘起されたSDの発生頻度をまとめたものである。オイル処置群では、エストロゲン処置群よりも失敗率が有意に高かった(カイ二乗検定、P=0.014)。このことは、エストロゲン自体が限局性の脱分極時にSDを呈する脳組織の傾向を強化することを示している。
表1
After 3M potassium puffing, luminance changes were classified visually, failure (<100 mm), locally expanded (> 100 mm; <800 mm), or fully expanded (> 800 mm). We attempted to induce SD in 39 slices from 8 oil-treated rats and 35 slices from 7 estrogen-treated rats. Table 1 summarizes the frequency of occurrence of SD induced by the same method for the two groups. The oil treatment group had a significantly higher failure rate than the estrogen treatment group (chi-square test, P = 0.014). This indicates that estrogen itself enhances the tendency of brain tissue to exhibit SD upon focal depolarization.
Table 1
以下の図7に示すように、輝度変化を使用して、拡延性抑制の伝達速度を評価した。3Mのカリウムの局所的パフによって誘発される局所的なSDと完全なSDの両方から、観察部位間のSDの距離を、SDがこの各観察部位間の移動に要した時間で割ることにより、伝播速度を算出した。図7に示したように、エストロゲン処置したラットからのスライスでの平均拡延速度は、0.121±0.013mm/sであり、オイル処置した対照ラットからのスライスでの伝播速度よりも有意に速かった(0.083±0.005mm/s、P<0.05、スチューデントのt検定)。このデータは、エストロゲンが海馬及び場合により新皮質においてもSDの傾向及び速度の両方を増強する重要な役割を担っていることを示す。 As shown in FIG. 7 below, the change in brightness was used to evaluate the transmission rate of the spread suppression. By dividing the distance of the SD between observation sites from the local SD and complete SD induced by a 3M potassium local puff, divided by the time SD took to move between each observation site, The propagation speed was calculated. As shown in FIG. 7, the average distraction rate in slices from estrogen-treated rats was 0.121 ± 0.013 mm / s, significantly higher than the propagation rate in slices from oil-treated control rats. Fast (0.083 ± 0.005 mm / s, P <0.05, Student's t test). This data shows that estrogens play an important role in enhancing both the tendency and speed of SD in the hippocampus and possibly also in the neocortex.
エストロゲンがSDの重度にどのように影響を及ぼすかについて、開始部位から離れて伝播するSDの最大距離を測定することにより試験を実施した。図8に示すように、シャファー側枝経路に沿った拡延性の終点を、検出可能な最小輝度変化(ベースラインからの変化>5%)を示した観察部位の開始部位からの距離と、検出できない輝度変化を示した近接観察部位の距離を平均し、更に開始部位からのこの距離を測定することによって評価した。図8に示すように、エストロゲン処置したラットからのスライスでのSD(0.594±0.071mm;n=18)は、オイル処置したラットからのスライスでのSD(0.394±0.051mm;n=16、P<0.05、スチューデントのt検定)よりも有意に長距離を移動した。したがって、エストロゲン処置したラットのSDは、容易に誘発されただけでなく、より長距離を伝播した。 A test was performed to determine how estrogen affects the severity of SD by measuring the maximum distance of SD that propagates away from the start site. As shown in FIG. 8, the end point of the extensibility along the Schaffer side branch path cannot be detected as the distance from the start part of the observation part showing the minimum detectable change in luminance (change from baseline> 5%). Evaluation was performed by averaging the distances of the close observation sites that showed a change in luminance and measuring this distance from the start site. As shown in FIG. 8, SD (0.594 ± 0.071 mm; n = 18) in slices from estrogen treated rats is SD (0.394 ± 0.051 mm) in slices from oil treated rats. N = 16, P <0.05, Student's t-test). Thus, SD in estrogen-treated rats was not only easily induced, but also propagated longer distances.
次に10分間隔で2回のSDが誘発された後、10μMのGLYX−13を灌流液に添加し、引き続き10分毎にSDを誘発させ、SDの速度及び規模が影響を受けたかどうかを判定した。図9は、GLYX−13の適用前と、10μMの浴適用したGLYX−13に50分間曝露した後での、エストロゲン処置したラットからのスライスで誘発されたSDの代表的な差を示す。10の観察部位の輝度変化を測定して、SDに対するGLYX−13の効果を評価した。図9Bに示すように、SDは依然として直ちに誘起されたが、図9AはSDと関連した輝度変化がGLYX−13の存在下で遅延したことを明らかに示している。対応のあるt検定は、GLYX−13が平均SD伝播速度を6.56±0.57mm/minから4.96±0.28mm/minへと有意に低下させたことを示した(n=5、P<0.01、対応のあるt検定)。オイル処置したラットからの海馬スライスについて、同様の実験を実施した。GLYX−13が平均SD伝播速度を5.09±0.61mm/minから4.50±0.39mm/min(n=5)へと低下させたが、この低下は統計的有意差に達しなかった。 Next, after 2 SDs were induced at 10 minute intervals, 10 μM GLYX-13 was added to the perfusate and subsequently induced every 10 minutes to see if the speed and magnitude of the SD were affected. Judged. FIG. 9 shows representative differences in SD induced in slices from estrogen-treated rats before application of GLYX-13 and after 50 minutes exposure to 10 μM bath-applied GLYX-13. The change in luminance at 10 observation sites was measured to evaluate the effect of GLYX-13 on SD. As shown in FIG. 9B, SD was still induced immediately, but FIG. 9A clearly shows that the brightness change associated with SD was delayed in the presence of GLYX-13. A paired t-test showed that GLYX-13 significantly reduced the mean SD propagation velocity from 6.56 ± 0.57 mm / min to 4.96 ± 0.28 mm / min (n = 5 , P <0.01, paired t test). Similar experiments were performed on hippocampal slices from oil-treated rats. GLYX-13 decreased the average SD propagation velocity from 5.09 ± 0.61 mm / min to 4.50 ± 0.39 mm / min (n = 5), but this decrease did not reach statistical significance. It was.
2群全体のSD伝播速度に対するGLYX−13の効果を調べるために、二元反復ANOVAも実施した。図10が示すように、GLYX−13の適用前後でのエストロゲン処置したラットに第1の有意性が見られ(F(1,8)=3.1;p<0.05)、GLYX−13曝露前の2群間で第2の有意性が生じている(F(1,8)=4.2;p<0.05)。この結果は、GLYX−13がエストロゲン処置したラットにおいて強い効果を有し、SDの伝播速度をオイル処置したラットのレベルにまで有意に低下させることを示す。 To examine the effect of GLYX-13 on the SD propagation rate across the two groups, a two-way repeated ANOVA was also performed. As FIG. 10 shows, first significance was seen in estrogen-treated rats before and after application of GLYX-13 (F (1,8) = 3.1; p <0.05), and GLYX-13 A second significance has occurred between the two groups before exposure (F (1,8) = 4.2; p <0.05). This result shows that GLYX-13 has a strong effect in estrogen-treated rats and significantly reduces the propagation speed of SD to the level of oil-treated rats.
実施例3
方法
動物
成体雄(2〜3か月齢)Sprague−Dawley(登録商標)(SD)ラットをHarlan(USA)から購入した。ポプラ材チップの寝床を有するLucite製ケージにラットを収容し、12時間:12時間の明暗サイクル(午前5時に点灯)を維持し、研究期間を通じて、随時Purina(登録商標)ラット用餌(USA)及び水道水を摂取できるようにした。
Example 3
Methods Animals Adult male (2-3 months old) Sprague-Dawley® (SD) rats were purchased from Harlan (USA). Rats are housed in Lucite cages with a bed of poplar chips, maintained on a 12 hour: 12 hour light / dark cycle (lights on at 5 am), and at any time throughout the study, Purina® Rat Diet (USA) And tap water.
外傷性脳損傷の誘発
Goldsteinら(Goldstein,L.E.ら.(2012)「Chronic traumatic encephalopathy in blast−exposed military veterans and a blast neurotrauma mouse model」,Science Translational Medicine 4:134ra160)のプロトコルに従って、ラットで使用するために改変し、一次爆風誘発性の外傷性脳損傷を誘発させた。成体雄Sprague−Dawley(登録商標)ラットをイソフルランで麻酔して、ラットの両耳に耳栓を挿入し、0.014インチのポリエステルフィルムを穿孔して生じるヘリウムの一次爆風(約42PSI)をラットに与える。シャム対照を爆風半径外に配置した。以降、爆風を受けた1時間後、動物にrapastinel(3mg/kgをIV)または0.9%の無菌生理食塩水ビヒクル(1mL/kgをIV)を投与し、ラットを最初に3.5〜4%のイソフルランを使用して麻酔した後、両耳を1.5×1.5mmの発泡プラグ(Pura−Fit耳栓、Moldex−Metric INC、Culver City,California)で保護した。頭部入口付き齧歯類用胸部拘束装置(Stoelting、USA)にラットを入れて胴体を保護すると同時に、アルミニウム衝撃波管(183×61cm;L−3 Applied Technologies、USA)の端から10cmに頭部を置き、頭部は自由に動くようにした。ラットに0.014インチのポリエステルフィルムを穿孔して生じるヘリウムの一次爆風(約42PSI)を与えた。シャム対照を爆風半径外に配置した。爆風を受けた1時間後、動物にrapastinel(3mg/kgをIV)または0.9%の無菌生理食塩水ビヒクル(1mL/kgをIV)を投与した。麻酔から回復するまでの潜在時間を記録した(図11A)。回復は、瞬目反射及び正向反射の表れ、ならびに通常の歩行(標準的な周期ゲート、非環状ゲート、完全な体重支持、何らかの嗅ぐ動作及び探索行動の徴候)と定義した。爆風を受けた1時間後、動物にGLYX−13(3mg/kgをIV)または0.9%の無菌生理食塩水ビヒクル(1mL/kgをIV)を投与した。群当たりN=4−6、*P<0.05(図11A)ANOVA。
Induction of traumatic brain injury. Modified for use in and induced primary blast-induced traumatic brain injury. Adult male Sprague-Dawley® rats were anesthetized with isoflurane, earplugs were inserted into both ears of rats, and a primary blast of helium (about 42 PSI) generated by perforating 0.014 inch polyester film was given to the rats. To give. Sham controls were placed outside the blast radius. Thereafter, 1 hour after receiving the blast, the animals were administered rapastine (3 mg / kg IV) or 0.9% sterile saline vehicle (1 mL / kg IV), and the rats were initially treated with 3.5- After anesthesia using 4% isoflurane, both ears were protected with a 1.5 × 1.5 mm foam plug (Pura-Fit earplugs, Moldex-Metric INC, Culver City, Calif.). A rod is placed in a rodent chest restraint device (Stoelting, USA) with a head entrance to protect the torso, and at the same time, the head is 10 cm from the end of an aluminum shock tube (183 x 61 cm; L-3 Applied Technologies, USA). The head was allowed to move freely. Rats were given a primary helium blast (approximately 42 PSI) produced by perforating a 0.014 inch polyester film. Sham controls were placed outside the blast radius. One hour after receiving the blast, animals were administered rapastine (3 mg / kg IV) or 0.9% sterile saline vehicle (1 mL / kg IV). The latency to recover from anesthesia was recorded (FIG. 11A). Recovery was defined as the appearance of blink and forward reflexes, as well as normal gait (standard periodic gates, non-annular gates, full body weight support, some sniffing and signs of exploratory behavior). One hour after receiving the blast, animals received GLYX-13 (3 mg / kg IV) or 0.9% sterile saline vehicle (1 mL / kg IV). N = 4-6 per group, * P <0.05 (FIG. 11A) ANOVA.
積極的感情学習(PEL)図11Bは、対象間計画を使用して、単一の3分間の積極的感情学習(PEL)試験セッションを、爆風を受けた24時間後に実施した結果を示す。群当たりN=4−6であった。FisherのPLSD事後検定を使用して、結果を評価した(rapastinel+TBI対ビヒクル+TBI)。 Positive Emotional Learning (PEL) FIG. 11B shows the results of conducting a single 3-minute positive emotional learning (PEL) test session 24 hours after receiving the blast using inter-subject planning. N = 4-6 per group. Fisher's PLSD post-test was used to evaluate the results (rapastine + TBI vs. vehicle + TBI).
以前に記述されたように(Burgdorf,J.ら、(2011)「Positive emotional learning is regulated in the medial prefrontal cortex by GluN2B−containing NMDA receptors」,Neuroscience 192:515−523)、異種特異的な闘争遊びを実施した。試験は投薬後2週間に3時間、実施した。異種特異的な闘争遊びの刺激は、実験者の右手で施した。15秒の異種特異的遊びブロックと15秒の非刺激とを交互に構成した3分の異種特異的遊びを動物に経験させた。前述のように(同著)、高周波の超音波発声(USV)を記録して、Avasoft SASlab Pro(Germany)を用いてソノグラムによって分析した。非刺激期間の各々で発生した周波数変調された50kHzのUSVを定量化して、PELを測定した。試験前、動物に遊び刺激の習慣はなかった。 As previously described (Burdorf, J. et al., (2011) “Positive emotional learning is regulated in the media pre-prepared cortex by GluN2B-containing NMDA rec51 Carried out. The study was conducted for 3 hours 2 weeks after dosing. The experimenter's right hand was used to stimulate different types of struggle play. The animals were allowed to experience a 3 minute heterospecific play consisting of alternating 15 second heterospecific play blocks and 15 seconds unstimulated. As described above (ibid), high frequency ultrasound vocalizations (USV) were recorded and analyzed by sonogram using Avasoft SASlab Pro (Germany). PEL was measured by quantifying the frequency-modulated 50 kHz USV generated during each non-stimulation period. Prior to the test, the animals had no habit of play stimulation.
結果
図11Aに示すように、TBIを受けた動物は、シャム対照動物と比較して、麻酔からの回復時間が長かった[F(1,13)=41.7、P<0.05]。図11Bに示すように、rapastinel(3mg/kgをIV)は、積極的感情学習のTBI誘発性抑制を改善した[F(2,12)=10.0、P<.05、FisherのPLSD事後検定、rapastinel+TBI対ビヒクル+TBI、シャム対ビヒクル+TBI対、P<0.05]。加えて、麻酔回復時間は、PELの率と有意に相関しなかった[r(15)=−0.14、P>.05]。積極的感情学習試験において、単一用量のrapastinel(3mg/kgをIV)は、TBIによって誘発される学習及び感情の欠如を完全に改善した。このように、この臨床前モデルでは、rapastinelがTBIの中枢認知及び情緒的症状の治療に効果的であり、rapastinelはPTSD治療に対する治療的可能性を有すると思われる。
Results As shown in FIG. 11A, animals receiving TBI had a longer recovery time from anesthesia compared to sham control animals [F (1,13) = 41.7, P <0.05]. As shown in FIG. 11B, rapastine (3 mg / kg IV) improved TBI-induced suppression of active emotion learning [F (2,12) = 10.0, P <. 05, Fisher's PLSD post-test, rapastine + TBI vs. vehicle + TBI, Sham vs. vehicle + TBI pair, P <0.05]. In addition, anesthesia recovery time did not significantly correlate with the rate of PEL [r (15) = − 0.14, P>. 05]. In an active emotion learning study, a single dose of rapastine (3 mg / kg IV) completely improved the learning and emotional deficits induced by TBI. Thus, in this preclinical model, rapasine is effective in treating central cognition and emotional symptoms of TBI, and rapasine appears to have therapeutic potential for PTSD treatment.
等価物
本開示の具体的実施形態を示したが、上記の具定例は例示的なものであり、限定的はでない。本開示の多くの変形は、本明細書を確認すれば当業者に明らかであろう。本開示の完全な範囲は、等価物の完全な範囲を併記した特許請求の範囲、及びこのような変形を併記した本明細書を参照することにより特定されるものである。
Equivalents While specific embodiments of the present disclosure have been shown, the above specific examples are illustrative and not limiting. Many variations of the disclosure will be apparent to those skilled in the art upon review of this specification. The full scope of the disclosure is to be determined by reference to the claims, along with the full scope of equivalents, and the specification, along with such variations.
特段の指定がない限り、本明細書及び特許請求の範囲で使用される、成分量、反応条件、パラメータ、記述的特徴などを表す全ての数値は、いずれの場合においても「約」という語で修飾されるものとして理解されるべきである。したがって、それと反対の指示がない限り、本明細書及び添付の特許請求の範囲内に示される数値パラメータは、本開示を用いて当業者が得ようとする所望の特性に応じて変動し得る近似値である。 Unless otherwise specified, all numerical values used in the specification and claims to indicate amounts of ingredients, reaction conditions, parameters, descriptive features, etc. are in each case the word “about”. It should be understood as being modified. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that can vary depending on the desired characteristics sought by those skilled in the art using this disclosure. Value.
本明細書で引用される全ての刊行物及び特許出願は、以下に示す項目を含め、個別の刊行物または特許出願がそれぞれ具体的かつ個別に参照により本明細書に組み込まれた場合と同様に、その全体が参照により本明細書に組み込まれる。矛盾が生じる場合には、本明細書に記載の定義を含めて本明細書が優先される。 All publications and patent applications cited herein are the same as if each individual publication or patent application were specifically and individually incorporated herein by reference, including the items set forth below. , Which is incorporated herein by reference in its entirety. In case of conflict, the present specification, including definitions herein, will control.
Claims (26)
A method for treating migraine in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof as shown below:
A method for the treatment, suppression and / or prevention of cortical spreading inhibition in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof as shown below: Including said method.
A method for the treatment and / or amelioration of long-term sequelae after migraine in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound shown below or a pharmaceutically acceptable salt thereof Said method.
A method for the treatment and / or amelioration of traumatic brain injury in a patient in need thereof comprising administering to said patient a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described below: , Said method.
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