JP2014530844A - 粘膜炎の治療および/または予防のためのメラトニンの使用 - Google Patents
粘膜炎の治療および/または予防のためのメラトニンの使用 Download PDFInfo
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Abstract
Description
放射線療法もしくは化学療法、または両者の結合による悪性腫瘍の治療はますます効果的になっては来ているが、短期および長期副作用を伴っている。これらの副作用には、口腔粘膜の機能および健全に関する傷害がある。結果としては、重篤な潰瘍形成(粘膜炎)および口の真菌による重複感染(カンジダ症、鵞口瘡)が挙げられる。この疾患によって誘発されるこれらの合併症とその治療は、嚥下の際の苦痛、嚥下困難、栄養失調、化学療法による投薬での遅延、放射線療法計画における中断、腫瘍学的治療の有効性の喪失、長期間にわたる入院日数、費用の嵩み、および幾人かの患者では、潜在的に致命的な感染症(敗血症)を伴う。
本発明は、粘膜炎の治療および/または予防のための医薬組成物を調製するための2.5〜5%(w/v)の濃度でメラトニンまたはその誘導体を含んでなる組成物の使用を記載する。
「n」は、1〜4の整数であり、
R1およびR3は、同一または異なる直鎖状または分岐状の(C1−C4)アルキル基であり、および
R2は、水素、直鎖状または分岐状のC1−C4アルキル、−C(=O)O−Ra基または−C(=O)−N(H)−Ra基であって、Raが直鎖状または分岐状のC1−C4アルキル基であるものである)
を表す。
この特許資料で提供される下記の具体例は、本発明の性質を例示するのに役立つ。これらの例は、説明の目的のためにのみ含まれるのであり、本明細書で主張される発明に対する制限と解釈してはならない。従って、下記の例は、その出願の分野を制限することなく発明を説明する。
本発明の組成物を、実験で用いる動物に様々な投与経路によって投与し、ヒト患者による実験も行った。
B.1.酸化的損傷のマーカー
−細胞膜および細胞内膜(LPO)の酸化の評価
遊離酸素ラジカルが細胞損傷を生じることができる極めて重要な機構は、細胞およびミトコンドリア膜両方の脂質過酸化による。脂質過酸化は、ポリ不飽和脂肪酸に対するフリーラジカルの作用によって起こる。細胞膜構造におけるこれらの変化は、その物理化学特性を変化させ、透過性を増加させかつ機能を漸進的に喪失することにより、結果として細胞死へと至る可能性がある。膜の脂質過酸化度の測定は、常に酸化的ストレスインジケーターとして極めて重要なパラメーターであると考えられてきた。脂質過酸化(LPO)インデックスは、試料に含まれるマロニルジアルデヒドと4−ヒドロキシアルケナール(MDA+4−HDA)を定量することによって提供され、これらはポリ不飽和脂肪酸と関連エステルから誘導される過酸化物の分解による重要な生成物である。マロニルジアルデヒドと4−ヒドロキシアルケナールの濃度並びにヒドロペルオキシドの濃度は、脂質過酸化に対する好適なインデックスを提供する。
細胞の酸化防止剤系には、生理学的条件で細胞中のフリーラジカルの解毒に関与する酵素の群があり、これらの酵素は本質的に
−グルタチオンペルオキシダーゼ(GPx):この酵素は、補助因子として還元グルタチオンを用い、過酸化水素(H2O2)を除去する。
−グルタチオンレダクターゼ(GRd):この酵素は、グルタチオンペルオキシダーゼ活性によって生成した酸化型グルタチオンを還元型グルタチオンに再変換する。
フリーラジカルの産生増加に伴うミトコンドリア機能不全は、細胞死の原因である。従って、呼吸鎖輸送複合体(I、II、IIIおよびIV)の活性および複合体の発現の測定は、ミトコンドリア損傷の程度を知る上で基本的なことである。
活性酸素種(ROS)の生成は、放射線照射によって損傷したミトコンドリアで増加し、ミトコンドリア成分の酸化的変化とミトコンドリア膜透過性遷移孔(MTP)の開口を引き起こす。ミトコンドリア膜透過性は、アポトーシスまたは壊死で終了するプログラム細胞死経路の活性化における不可逆点を表す(Schroder K, et al. Cell. 2010; 140:821-832; LatzE, Curr. Opin. Immunol, 2010; 22: 28-33. Epub 2010)。
核因子κB(NF−κB)経路は、炎症応答にも関与している。インフラマソームとの差は、NF−κB経路が、膜上でトール様受容体(TLR)を介して活性化され、一方インフラマソームはサイトゾル性NOD様受容体(ヌクレオチドオリゴマー化ドメイン様受容体)(NLR)を介して活性化されることである。
アポトーシスを調節するタンパク質は、Bcl2(B細胞リンパ腫2)のような抗アポトーシス性タンパク質およびBaxのようなアポトーシス促進性タンパク質に分類される。従って、Bax/Bcl2比は、アポトーシスのレベルを直接反映するので、極めて重要な比である。タンパク質p53は、DNA修復酵素を活性化して、検出される損傷を治療する。DNAの損傷が修復不能である場合には、異常DNAを含む細胞の増殖を防止するために、アポトーシスに入ることは防御の最終機構である。p53は、BAXのようなアポトーシス促進性遺伝子の発現を活性化する。
C.1− 口腔で局所経路による1%、3%および5%(w/v)ゲル中のメラトニンの使用
放射線によって引き起こされる酸化的ストレスは、細胞膜の損傷を引き起こし、これは、膜脂質の酸化の増加が対照に対して50%を上回ることによって表される(図1、p<0.001)。この損傷は、放射線がこれらの組織を傷つけて粘膜炎を引き起こすことを示している。3%メラトニンは放射線療法の影響を完全に逆転させるが、1%メラトニンはLPOレベルを部分的に逆転させるだけである。3%を上回るメラトニン濃度、例えば5%のようなメラトニン濃度を用いるときには、酸化的ストレスの中和において3%濃度と同じ効果を有する(図1)。
粘膜炎を逆転させるための最も好適な投与経路を決定するために、口腔で局所経路による3%メラトニンゲルの投与と腹腔内経路(i.p.)によるメラトニンの投与を、同一用量(1日45mg)で比較した。
PGC1α(ペルオキシソーム増殖因子活性化受容体γコアクチベーター1−α)、NRF1(核呼吸因子1)およびTFAM(転写因子A、ミトコンドリア)を測定することによってミトコンドリアバイオジェネシスを測定すると、放射線照射がPGC1αを阻害したが、ミトコンドリア損傷を埋め合わせるためのNRF1およびTFAMの増加はないことが観察された(図13)。
3%メラトニンゲルを投与された患者は、放射線療法に一層よく耐え、オピオイドの投与を必要としなかった。これらの患者は経鼻胃管を必要とせず、入院はせず、治療を中断する必要はなかった。メラトニンを投与されない患者は総て強オピオイドを必要とし、彼らは総て最高等級の放射線皮膚炎を引き起こした。幾人かは、入院し、治療を中断しなければならなかった。
1%メラトニンを含んでなる医薬組成物は、放射線療法によって引き起こされる粘膜炎を逆転させない。しかしながら、3%メラトニンを含んでなる医薬組成物は、5%メラトニンを含んでなる組成物によって起こるのと同様に、放射線療法によって引き起こされる粘膜炎を完全に逆転させる。これらの結果は、放射線療法によって引き起こされる粘膜炎の副作用の治療における3%〜5%メラトニンを含んでなる組成物の有用性を明らかにしている。
Claims (22)
- 一般式(I):
「n」は1〜4の整数であり、
R1およびR3は、同一または異なる、直鎖状または分岐状の(C1−C4)アルキル基であり、かつ
R2は、水素、直鎖状または分岐状の(C1−C4)アルキル基、−C(=O)O−Ra基または−C(=O)−N(H)−Ra基であり、式中、Raは、直鎖状または分岐状の(C1−C4)アルキル基である)
の化合物またはその塩、プロドラッグもしくは溶媒和物を含んでなる組成物の使用であって、
前記化合物が、粘膜炎の治療および/または予防のための医薬組成物を調製するため、2.5〜5%(w/v)の濃度である、使用。 - R1およびR3は、同一または異なる、(C1−C2)アルキル基である、請求項1に記載の使用。
- R1およびR3がメチル基である、請求項2に記載の使用。
- nが1である、請求項1〜3のいずれか一項に記載の使用。
- R2が水素である、請求項1〜4のいずれか一項に記載の使用。
- 化合物がメラトニンである、請求項1〜5のいずれか一項に記載の使用。
- 化合物の濃度が3%(w/v)である、請求項1〜6のいずれか一項に記載の使用。
- 粘膜炎が放射線療法および/または化学療法によって引き起こされる、請求項1〜7のいずれか一項に記載の使用。
- 粘膜炎が口腔、咽頭、食道、胃または腸粘膜炎である、請求項1〜8のいずれか一項に記載の使用。
- 粘膜炎が口腔粘膜炎である、請求項1〜9のいずれか一項に記載の使用。
- 粘膜炎がヒト粘膜炎である、請求項1〜10のいずれか一項に記載の使用。
- 組成物が、少なくとも1種類の薬学上許容可能な賦形剤またはアジュバントをさらに含んでなる、請求項1〜11のいずれか一項に記載の使用。
- 組成物が、ゲル化剤をさらに含んでなる、請求項1〜12のいずれか一項に記載の使用。
- ゲル化剤が、ポリエチレンとポリプロピレンとのコポリマー、セルロースおよびグアーガムを含んでなるリストから選択される、請求項13に記載の使用。
- 組成物が、少なくとも1種類の防腐剤をさらに含んでなる、請求項1〜14のいずれか一項に記載の使用。
- 組成物が、酸化防止剤をさらに含んでなる、請求項1〜15のいずれか一項に記載の使用。
- 組成物が、薬学上許容可能なキャリアをさらに含んでなる、請求項1〜16のいずれか一項に記載の使用。
- 組成物が、局所、口腔、腹腔内、皮内または皮下投与に好適な投薬形態である、請求項1〜17のいずれか一項に記載の使用。
- 組成物が、局所投与に好適な投薬形態である、請求項18に記載の使用。
- 投与される1日用量が37.5mg〜75mgである、請求項19に記載の使用。
- 投与される1日用量が45mgである、請求項20に記載の使用。
- 15mgを1日3回の投薬計画の用量で投与する、請求項21に記載の使用。
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