JP5955767B2 - 損傷性前庭障害の処置における使用のためのセロトニン5−ht3受容体拮抗薬 - Google Patents
損傷性前庭障害の処置における使用のためのセロトニン5−ht3受容体拮抗薬 Download PDFInfo
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- JP5955767B2 JP5955767B2 JP2012511287A JP2012511287A JP5955767B2 JP 5955767 B2 JP5955767 B2 JP 5955767B2 JP 2012511287 A JP2012511287 A JP 2012511287A JP 2012511287 A JP2012511287 A JP 2012511287A JP 5955767 B2 JP5955767 B2 JP 5955767B2
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- vestibular
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- ondansetron
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Description
前庭(内耳)疾患は、潜在的に、ヒトの日々の機能、仕事の能力、家族および友人との関係、ならびに生活の質に影響を起こすことを伴う、眩暈、空間識失調、平衡失調、聴覚変化、嘔吐、倦怠感、不安神経症、注目困難、および他の症状を生じ得る。
前庭障害の病因学は大部分が未知であるが、前庭障害(前庭欠損とも称する)が前庭器官に付随する症状の莫大な系統群を構成することは広く受け入れられている。それらの疾患は、推定される起源により区別され得、それ故、1つは、(1)損傷性前庭障害、および(2)非損傷性前庭障害に識別される。
1)損傷性前庭障害は、内耳細胞および/または前庭神経の損傷が存在する、または疾患経過時間の間に現れるであろう前庭障害に関する。この場合、前庭の機能は臨床機能検査(VOR、VNG)を用いて観察することができるほどに損なわれる。損傷性前庭障害は、
−感染症が、可逆的および/または不可逆的ダメージを誘発し、内耳および/または前庭神経に炎症を起こす前庭障害。この群の症状の1例として、前庭神経炎がある。
−内耳液の度合が影響を受けるような(内リンパにおける量、組成、および/または圧力の異常)前庭障害、それらの疾患は大抵、疾患経過時間の間に損傷が発生する。この群の症状の1例として、メニエール病および2次内リンパ水腫がある。それらは、現在耳鳴および難聴と関連づけられる。
−前庭末端器官の傷害または損傷により誘発される前庭障害。上記症状の例として、局所性虚血、興奮毒性、側頭骨に影響する外傷により生じる空間識失調がある。
を含む。
2)非損傷性前庭障害は、内耳細胞および/または前庭神経の損傷が観察されない、一過性およびしばしば反復性空間識失調の急性発症により支持される前庭障害に関する。この場合、機能検査(VOR、VNG)を用いて空間識失調の急性発症の間に評価される前庭の機能性は健常な前庭と異なることがない。非損傷性前庭障害は、
−内耳部分の中で壊死組織片が集まった前庭障害。この壊死組織片は、耳石と呼ばれ、炭酸カルシウムの小さな結晶で生成され、転じて、偽の信号を脳に送る。上記症状の例としては、頭位眩暈症がある。
−耳鳴または難聴のない未知の起源の反復性前庭障害。
を含む。
ヒトにおける前庭末端器官の形態機能的変化は、直接評価することができない(IRMにより検出される大きな損傷を除いて)。むしろ間接的な影響評価方法は現在、前庭の機能性の損失を評価するために使用される。一般的に行動性検査の方法がENTクリニック/病院で行われる。それらの内、我々は、熱または回転性の検査を用いて、vestibulonystagmography(VNG)、前庭眼反射影響検査(VOR)を挙げることができる。
最近の前庭欠損の処置は、主に、抗催吐薬を使用することにより自律神経反応を制限する一方、vestibulopegic薬により空間識失調の急性発症を減少させることに注目する。副腎皮質ステロイドおよび抗ウイルス薬は前庭神経炎の場合の前庭ダメージの伝播を制限しようとする薬物療法でのみある(細菌性またはウイルス感染症に因り想定される)。それらの効果は、多くの前庭欠損における病因論の欠如に関する討論下で維持される。例えば、前庭神経炎後の修復は大抵不完全である。60人の患者の研究において、三半規管の不全麻痺が症候の発病後1ヶ月で約90%に発見され、そして6ヶ月後には80%に発見された(熱反応はたった42%に基準化される)。その症状の発生率に基づいて、前庭眼反射の実質的で永続する1側性の機能的欠損(他の機構により補償することのできない)が米国において1年で約4000人に発生する。この欠損は歩行中、特には影響される耳に対する頭部運動中に欠陥的視覚、姿勢の不均等を導く。
−感染症が、可逆的および/または不可逆的ダメージを誘発し、内耳および/または前庭神経に炎症を起こす前庭障害。この群の症状の1例として、前庭神経炎がある。
−内耳液の度合が影響を受けるような(内リンパにおける量、組成、および/または圧力の異常)前庭障害、それらの疾患は大抵、疾患経過時間の間に損傷が発生する。この群の症状の例として、メニエール病および2次内リンパ水腫がある。それらは、現在耳鳴および難聴に付随される。
−前庭末端器官の侵襲または病変により誘発される前庭障害。上記症状の例として、局所性虚血、興奮毒性、側頭骨に影響する外傷により生じる空間識失調がある。
を含む。
の化合物およびその薬理学上許容される塩、遊離酸の形、遊離塩基の形および溶媒和化合物(例えば水和物)であり得る。
−急速に粘膜に吸収され、生物学的利用能が高いとされる活性化合物の投与量を減らすことができること
−治療作用の発現が速いこと
−肝臓初回通過代謝が回避されること
−消化管の代謝を回避することができること
−患者のコンプライアンスが改善されること
以下で実施例は、本発明を実施する好ましい様式の一部について説明する。しかしながら、実施例は単に例示の目的であり、本発明の範囲を限定するものではないことを理解すべきである。さらに、実施例における説明が過去形で示されていない限り、テキストは明細書の残りの部分のように、実験は実際に行われたか、または、データが実際に得られたことを示唆するものではない。
前庭の薬理学的標的の免疫組織化学的局在。
我々は、雌成体ラット(Wistar系、200〜220グラム、n=2)へペントバルビタール(0.4%)で麻酔をかけた。動物は、固定液(4%パラホルムアルデヒド、1%ピクリン酸、5%スクロース)とサンプル固定後に、ヘパリンPBS(0.01M)で経心的に灌流した。我々は、4%アガロースへ前庭神経節と上皮を埋め込み、40μmの厚さの断片に切断した。ブロッキング溶液中でプレインキュベーション(0.5%魚ゼラチン、PBS中の0.5%トリトンX−100および1%BSA)は、非特異的結合を防止した。次に、試料を一次抗体とともにインキュベートした:ウサギポリクローナル抗体抗5HT−3A受容体(1:200、AB5657、Millipore,Billerica,MA)。制御のために、我々は調査した一次抗体を省略した。二次抗体は、特定のAlexa594で標識した結合ロバ抗ウサギ血清であることを明らかにした(1:200,Molecular Probes,Eugene,OR)。走査型レーザー共焦点顕微鏡(RIOイメージング、モンペリエ、フランス)のZeiss社5ライブデュオは、スライドに取り付けられたサンプルの観察を可能にした。
図2に示されているように、5HT−3受容体は、スカルパのガングリオン(図2A)において表される。すべての一次前庭神経細胞(矢印)、5HT−3A受容体のために染色し、大規模だけでなく、小さなサイズのソーマは、免疫蛍光した。シュワン細胞および内皮細胞が標識されなかった。前庭感覚上皮(図2B−D)において、5HT−3A受容体は、特に感覚上皮を取り巻く移行細胞(大矢印)によって、いくつかの神経線維(矢印)へ発現させた。ニューロフィラメントおよびカルシウム結合タンパク質(データは示していない)との共染色が強く明確な修飾線維に非常に制限された発現を示唆している。
本実施例では、オンダンセトロン、グラニセトロン、トロピセトロン、またはヒトで観察されたパロノセトロンから成る群から選択可能なセロトニン5−HT3受容体拮抗薬を、前庭末端器官で回復させる効果を前庭欠損の動物モデルで検証していく。また、そのプロセスに関与する生物学的プロセス(保護/修復)を決定するつもりである。これは、片側性および両側性前庭欠損の両方のモデルにおいて、該セロトニン5−HT3受容体拮抗薬の適用下での組織学的損傷および前庭欠損の経時変化を比較することによって評価する。前庭欠損の2つの別個の動物モデルの組み合わせは、該セロトニン5−HT3受容体拮抗薬の使用の恩恵を決定することを可能にする。我々の知識によると、それらは、哺乳類前庭システムに焦点を当てた第一のパラダイムである。前庭における該セロトニン5−HT3受容体拮抗薬の回復効果において、生物学的プロセスの決定は、今後の臨床試験で使用される治療のウィンドウを定義することを可能にする。
該セロトニン5−HT3受容体拮抗薬の回復効果の検証は、両方の興奮毒性病変の出現ならびに除去の経時変化の分析、および、続いて起こる、グルタミン酸アゴニストの内耳での適用の間に前庭末端器官内で発生する前庭欠損の分析によって評価する。前庭末端器官において、カイニン酸の大規模な適用は、感覚器官の神経回路網の興奮毒性障害を誘発する(swelling of terminals that contact hair cells−Brugeaud et al.,2007)。興奮毒性病変の拡大および縮小の組織学的研究は、光や電子顕微鏡を用いて実施ししている。前庭欠損の行動評価は、前庭機能の特定の行動テストを用いて行われている。ラットで開発されたパラダイムのもとで、カイニン酸の鼓膜を介した適用は、内耳におけるその拡散を可能にする。ほとんどの場合、興奮毒性病変の12時間後に絶頂に達し、2〜3日以内に消失する。カイニン酸侵襲の1時間後の該セロトニン5−HT3拮抗薬の腹腔内注射による該セロトニン5−HT3拮抗薬の投与後に、保護が検討される。
カイニン酸(KA)、グルタミン酸作動性アゴニストは、中耳に鼓膜を通じて注射し、そのあとでそれは内耳に丸窓を通して拡散し(前庭と渦巻管)、それは求心性神経線維に作用する場所である。これは前庭欠損に至る病理学的に発生する興奮毒性損傷のメカニズムを模倣する。我々は、前庭欠損の行動試験および誘導病変の組織学的定量を用いてKA注入の効果を評価する。
KA注入1時間後、動物の前庭動作は、治療群におけるオンダンセトロン注射に続いてテストされた。対照動物は、オンダンセトロン注射を受けなかった。その後、動物はKAの注射の後2時間、6時間、24時間および48時間で試験した。組織学的および形態学的分析は、オンダンセトロンの治療の存在下および非存在下におけるKAの注射後2時間と24時間で行った。
前庭評価スコアは、前述のように推定された(Brugeaud et al.,2007;Boadas−Vaello et al.2005)。動物は、最大前庭欠損に対する通常の動作にそれぞれ対応して、0〜4の範囲でスコア化した。評価1は、動作が正常ではないが特定の前庭欠損を効果的に決定されていないことを意味し、評価2は、特定されているが僅かな前庭欠損に対応しており、評価3は、同定された明らかな障害を示している。前庭欠損を評価するために、6種の試験を順番にスコア化し、積算した。1−首の異常な断続的な後方の拡張が観察された場合の頭部の揺れ;2−旋回運動無しから動物の腰周りの強制的な旋回運動の円までの、旋回常同運動;3−後方突進、前庭欠損を反映した典型的な後方徒歩;4−尾吊り下げ反射、それは通常、地面に到達するために、正常な前肢の拡張を誘発し、その結果、前庭欠損が最大となる時、体および尾の柄が腹部で曲がる;5−接触障害の反射は、通常は仰臥位で金属グリッドへ動物を保持して背中が地面に触れると戻るように導くが、参照の体の向きの欠如を伴う前庭欠損の場合には、この反射は無くなり、動物は仰臥位で金属グリッドへ保持されたままになる;6―空気立ち直り反射は、仰臥位から落ちる時に自分の足で着地するために動物にとって必要であり、前庭機能障害は、この通常の反転を阻害し、最大の障害は、発泡体のクッションの上に40cmの高さから落下した場合に、動物がその背面で着陸することにつながる。前庭評価スコアは、t=0の時のスコアのパーセンテージとして、各時点に対して表した。
感覚上皮の半薄切片の調製。我々はペントバルビタール(0.4%)で雌の成体ラット(Wistar;200−220g;各治療についてn=3)へ麻酔をかけた。動物は、固定液(2%のパラホルムアルデヒド、2.5%グルタルアルデヒド、1%ピクリン酸、5%スクロース)に続いて、ヘパリンPBS(0.01M)で経心的に灌流し、サンプルを後固定した。我々は全体の前庭器官の前庭上皮を2%OsO4へ埋め込み、脱水し、アラルダイトに埋め込み、1μmの厚さの切片を切断した。Nanozoomerスライドスキャナ(RIO imaging,Montpellier,France)は、観察やスライドに取り付けられたサンプルのスキャンを可能にした。
鼓膜を通したカイニン酸の注射後、ラットは、48時間で徐々に減少する強い興奮毒性誘発される前庭欠損を示す(図3B)。前庭欠損の減少のこの時間経過は、動物がオンダンセトロンを用いて治療する場合に、24時間で有意に前庭欠損が減少する(*p=0.022、Mann Whitney試験;n≧8)というように、変化する。その後、両方の処理および未処理の動物は、内因性の代償機構のために同様の前庭欠損のレベルに回復する。
セロトニン5−HT3拮抗薬の回復効果の検証は、興奮毒性病変および続いて生じる前庭欠損の後のニトリル類の中毒の出現および除去の両方の経時変化を分析することによって、両側前庭欠損の動物モデルで評価する(IP injection−Seoane et al.,J.Comp.Neurol.2001,439:385−399)。ニトリル類の代謝に続いて、それらの急性適用の3日以内に、耳毒性/興奮毒性障害および前庭欠損識別を誘発する。保護機能は、以下の異なるスケジュールに従って(慢性中毒の開始から、24時間および48時間後)、該セロトニン5−HT3拮抗薬の投与によって評価する。
IDPN(1g/kg、ip)は、前庭感覚上皮の破壊を通じて、両側および永久的な前庭欠損を引き起こす。この進行性傷害は、72時間後にその最大程度に達する。我々は、前庭欠損の行動試験を用いてIDPN注射の効果を評価した。我々は、IDPN注射後の障害の進行の時間経過を通して、オンダンセトロンの前庭保護可能性を決定するためにオンダンセトロンの単回または二回注射の保護効果を評価する。オンダンセトロンの各用量は4mg/kgで腹腔内(ip)に注射した。
A.オンダンセトロン(単回投与)およびIDPNの同時注射
B.IDPN注射の24時間後に、オンダンセトロンの注射(単回投与)
C.IDPN注射の48時間後に、オンダンセトロンの注射(単回投与)
D.IDPN注射の24時間後および48時間後に、オンダンセトロンの2注射(2回投与)
増加する前庭欠損の時間経過は、動物がオンダンセトロンをIDPNと同時に注射された場合、有意に変化しない(p≦0.05、Mann Whitney試験、n≧5)(図6B)。
オンダンセトロンベースを約8mg/ml含む溶液を25℃で1ヶ月、および4℃で1ヶ月保存した後、物理的に安定であることが判明した。
Brugeaud A,Travo C,Dememes D,Lenoir M,Llorens J,Puel JL,Chabbert C.Control of hair cell excitability by vestibular primary sensory neurons.J Neurosci. 2007;27(13):3503−11.
Gil−Loyzaga P,Bartolome MV,Vicente−Torres MA.Serotonergic innervation of the organ of Corti of the cat cochlea.Neuroreport.1997;8(16):3519−22.
Johnson DS,Heinemann SF.Embryonic expression of the 5−HT3 receptor subunit,5−HT3R−A,in the rat:an in situ hybridization study.Mol Cell Neurosci.1995;6(2):122−38.
Seoane A,Dememes D,Llorens J.Relationship between insult intensity and mode of hair cell loss in the vestibular system of rats exposed to 3,3’−iminodipropionitrile.J Comp Neurol.2001;439(4):385−99.
Turconi M,Nicola M,Quintero MG,Maiocchi L,Micheletti R,Giraldo E,Donetti A.Synthesis of a new class of 2,3−dihydro−2−oxo−1H−benzimidazole−1−carboxylic acid derivatives as highly potent 5−HT3 receptor antagonists.J Med Chem.1990 Aug;33(8):2101−8.
Claims (4)
- 対象において損傷性前庭障害の治癒的治療に使用するためのセロトニン5−HT3受容体拮抗薬であって、前記セロトニン5−HT3受容体拮抗薬は、
― 化学式(I)の化合物であり、
― オンダンセトロン、パロノセトロン、トロピセトロン、レリセトロン、アロセトロン、グラニセトロン、ドラセトロン、ベルネセトロン、ラモセトロン、アザセトロン、イタセトロン、ザコプリド、およびシランセトロンからなる群から選択される化合物である、セロトニン5−HT3受容体拮抗薬。 - 前記前庭障害は、前庭神経炎、ウイルス性神経炎、内耳炎、ウイルス性内リンパ性内耳炎、薬物誘発性難聴、メニエール病、内リンパ水腫、損傷性前庭障害を備えた頭部外傷、内耳出血、慢性または急性の内耳の感染症、漿液性内耳、気圧性外傷、自己免疫性内耳疾患、慢性メニエール病、および毒性前庭障害からなる群から選択される、請求項1に記載のセロトニン5−HT3受容体拮抗薬。
- 鼻経路によって投与される、請求項1または2に記載の、損傷性前庭障害の治癒的治療に使用するためのセロトニン5−HT3受容体拮抗薬。
- 請求項1〜3のいずれか一項に記載の、損傷性前庭障害の治癒的治療に使用するためのセロトニン5−HT3受容体拮抗薬の経鼻投与用デバイス。
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EP09305464.1A EP2253316B1 (en) | 2009-05-20 | 2009-05-20 | Serotonin 5-HT3 receptor antagonists for use in the treatment or prevention of an inner ear pathology with vestibular deficits |
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