JP2014514352A - ネコレトロウイルス感染症の治療に使用するための化合物 - Google Patents
ネコレトロウイルス感染症の治療に使用するための化合物 Download PDFInfo
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- JP2014514352A JP2014514352A JP2014509609A JP2014509609A JP2014514352A JP 2014514352 A JP2014514352 A JP 2014514352A JP 2014509609 A JP2014509609 A JP 2014509609A JP 2014509609 A JP2014509609 A JP 2014509609A JP 2014514352 A JP2014514352 A JP 2014514352A
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- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
・ AZT(3’−アジド−2’,3’−ジデオキシチミジンまたはジドブジン):ネコにおける一般的な副作用は、非再生性貧血である。骨髄抑制を有するネコを治療するべきではない。FIVのAZT耐性変異体は、早ければ治療開始6カ月後に生じ得る。FIV治療についてのAZTの有効性は、非常に限定的なものである。
・ ヒトインターフェロン−アルファに対する中和抗体が生じるので、ヒトインターフェロン−アルファは、3〜7週間後にはFIVに対して効果がなくなる。
・ ネコインターフェロン−オメガ(Virbagen Omega(登録商標),VIRBAC)は、ネコで耐容性が良好であり、イン・ビトロではFIVに対して活性を有するが、今のところノネコで実施された唯一の研究では、プラセボ群と比較した場合に生存率の有意な変化は示されなかった〔デ マリ(de Mari)ら、2004〕。
・ FeLV−Aは、重度の免疫抑制を引き起こす。
・ FeLV−Bは、FeLV−A単独感染ネコよりも新生物疾患(すなわち、腫瘍およびその他の異常な組織成長)を引き起こす。
・ FeLV−Cは、重度の貧血を引き起こす。
の化合物、その溶媒和化合物、獣医学的に許容され得る塩、代謝産物またはプロドラッグである。
の化合物、その溶媒和化合物、獣医学的に許容され得る塩、代謝産物またはプロドラッグである。好ましい実施形態において、前記のモノハロメチル、ジハロメチルおよびトリハロメチルは、モノフルオロメチル、ジフルオロメチルおよびトリフルオロメチルである。
材料および方法
化合物を、10mg/mlの濃度で0.05N水酸化ナトリウム溶液に溶解させた。クランデル・リースネコ腎(CrFK)細胞を、1%重炭酸ナトリウム(Life Technologies)と5%ウシ胎仔血清(FCS、Biochrom)をと含むダルベッコ最小必須培地(DMEM、Life Technologies)中で成長させた。5000個のCrFK細胞を96ウェルプレートに播種し、5%CO2を含む加湿環境において37℃で24時間インキュベーションした。続いて、50μg/mlのDEAE−デキストランを含む100μlのリン酸緩衝食塩水(PBS)で細胞を洗浄し、漸増用量の化合物(0.4;2;10および50μg/ml)の存在下で100CCID50のFeLVを接種した。2時間インキュベーションしてウイルスを細胞に侵入させた後、上清を除去し、細胞をPBSで洗浄した。5%FCSおよび漸増用量の化合物を含むDMEMを感染細胞に添加した。化合物が添加されていない感染細胞を陽性対照(ウイルス対照)として含め、非感染細胞を陰性対照(細胞対照)として含めた。これらの細胞を6日間インキュベーションしてウイルス上清を回収し、FeLVp27抗原の産生については酵素結合免疫吸着測定法(ELISA)によって分析し、FeLV RNAの産生についてはリアルタイムRT−qPCRによって分析した。p27の検出については、供給業者(European Veterinary Laboratory)の説明書にしたがって、50μlの上清を1%トリトンX100中で10分間インキュベーションし、プレコーティングしたELISAプレート上にアプライした。FeLV RNAの検出については、QIAamp viral RNA kit(Qiagen)を使用して、140μlの上清を抽出した。抽出したRNAは、ランダムヘキサマーおよび供給業者のプロトコール(Applied Biosystems)を使用してTaqman逆転写試薬キットによってcDNAに変換した。リアルタイムPCRは、TaqMan Fast Universal PCR Mastermix(Applied Biosystems)、およびStepOne cycler(Applied Biosystems)を使用する標準的なFastサイクリングプロトコールを使用して実施した。PCR混合液では、CattoriおよびHofmann−Lehmann(2008)によって発表されたように、最適化された300nMの各フォワードプライマーおよびリバースプライマー、ならびに100nMのFAM−BHQ1標識プローブを使用した。EC50値は、ウイルス対照と比較してウイルスRNAまたはp27の産生の50%を阻害した化合物濃度として決定した。
p27のELISAおよび定量RT−PCR(RT−qPCR)によって測定した場合に、FeLV複製の50%を有効に阻害する濃度(EC50)を表3に示す。表3に示される値は、3回の独立したアッセイの平均値(±標準偏差)を表す。
材料および方法
中性付近のpH条件(pH6〜9)の適切な水酸化ナトリウム緩衝水溶液に化合物を溶解させて、50〜250mg/mLの濃度範囲とした。
特異的症状を有するネコの治療結果を以下で考察する。
口内の徴候は、限定されないが、口内炎、歯肉炎、口峡炎、舌炎、歯周炎、歯肉口内炎、扁桃腺および舌の潰瘍、流涎などそれ自体として現れ得る。口内炎および歯肉炎の治療についての化合物の有効性の例を以下に示す。
○ 重度の口内炎を有するネコ。
FIV陽性ネコは、中咽頭後部の口内炎(caudal stomatitis)および頬の口内炎(buccostomatitis)の重症例を有していた。治療により、口内炎は有意に減少した(腫れおよび発赤の消失)。その他の治療は併用しなかった。
○ 重度の歯肉炎を有するネコ
FIV陽性ネコは、特発出血を伴う歯肉炎の重症例を有していた。治療により、歯肉炎は有意に減少した。特発出血はもはや観察されず、血のような赤色の炎症はわずかにピンク色の所見にまで軽減した。その他の治療は併用しなかった。
FIVは、レトロウイルスとして、そのウイルスRNAゲノムをプロウイルスDNAに逆転写し、続いてこれがその宿主のゲノムに挿入される。血漿中のウイルスRNA(ウイルス量)の検出は、活性FIVの複製が進行中であることを示すので、ウイルス圧の尺度である。ウイルス量の減少は、ネコのFIV感染症を制御するのに重要である。製剤化された化合物は、FIV陽性ネコのウイルス量(血漿1mLあたりのFIVビリオンとして表わされる)を有意に減少させる。図1A、図1Bおよび図1Cのグラフは、3匹の異なるネコにおける化合物による治療前後のウイルス量を表す。その他の治療は併用しなかった。
以下の臨床徴候を有するFIV陽性ネコが獣医に提示された:嗜眠、衰弱、歩行困難、椅子に跳び上がる/椅子から跳び降りることができない、戸外に出る欲求がない、睡眠パターンの延長。予後はネコを安楽死させる予定であった。
化合物による治療を開始して数週間以内に、ネコは正常に戻り、体重が増加し(0.6kg)、歩いて遊び回り、数日間連続で戸外に出ていた。ネコの全身状態は正常に戻った。その他の治療は併用しなかった。
膝窩リンパ節腫脹(スコア4;重症度を0〜10の尺度でスコア化し、0は正常な臨床像を表し、10は最も重度の徴候である)を有する雄のFIV陽性ネコを化合物で治療した。腫脹は、2週間以内にスコア2に下がった。化合物による6週間の治療期間の終了時には、スコア1が見られた;0は、正常な臨床像を表す。
雌のFIV陽性ネコについても同じことが見られた。膝窩リンパ節は、治療前には腫脹していた(スコア2)。リンパ節は治療後2週間で正常に戻り(スコア0)、化合物による6週間の治療期間を通してこれが維持された。
2匹のFIV陽性ネコについて、同様の観察結果が得られた。下顎リンパ節は、治療開始時には腫脹していた(それぞれスコア2および3)。これは、化合物による6週間の治療終了までに正常に戻った(スコア0)。
雌のFIV陽性ネコは、抗菌治療の併用にもかかわらず、化合物による治療を開始する前には慢性眼炎を患っていた。治療後、眼は全快に向かった。
慢性的に毎日下痢をしている雄のFIV陽性ネコを化合物で治療した。糞便は、2週間以内に正常に戻った。
左前肢および左後肢の急性不全麻痺を患っている雄のFIV陽性ネコを、神経症状(CNS障害および末梢神経障害の疑い)を示した1日後から製剤化された化合物で治療した。その他の治療は併用しなかった。ネコは、治療1週間後には真っすぐに座って、自力で食事をすることができた。治療をさらに4週間継続した後には、ネコは、自力で歩行、階段の上り下りおよび食事をすることができた。その後直ぐに全快が認められた。
ネコ用に改良したカルノフスキースコア(Hartmann and Kuffer,Eur J Med Res 1998)は、ネコの生活の質および幸福についての客観的尺度(0〜100%の段階)である。0%のスコアは死を表すのに対して、100%は、ネコが通常の活動を行うことができ、正常な行動を示し、不満および臨床徴候の証拠がないことを示す。カルノフスキースコアは、抗ウイルス化合物の有効性を評価および比較するのに妥当であることがネコで証明されている(Hartmann et al.,J Acquir Immune Defic Syndr Hum Retrovirol 1998)。表4は、化合物による治療前、治療中および治療後における2匹のFIV陽性ネコのカルノフスキースコアを要約したものである。その他の治療は併用しなかった。化合物治療後の両方の症例において、ネコの生活の質および幸福について有意な増加が見られた。
材料および方法
化合物は、50〜250mg/mlの濃度範囲および中性付近のpH条件(pH6〜9)で、適切な水酸化ナトリウム緩衝水溶液に溶解させた。製剤化された化合物は、1週間あたり10〜175mg/kgの範囲の総用量で、皮下経路により少なくとも週1回投与した。治療期間は、1週間〜3カ月間とした。
・ 高ウイルス量を有するネコ(ウイルス血症のネコ)
RT−qPCR(Cattori and Hofmann−Lehmann,2008)を使用してFeLVウイルス量を定量化した雌のFeLV陽性ネコを化合物で治療した。ウイルス量は、血漿1mLあたりFeLVビリオン15500個から3200個に有意に減少した。
58.5%の低いカルノフスキースコアにつながるFeLV関連の臨床徴候、例えば、口内炎、リンパ節症(lymphadenopthy)、下痢などを有する雄のFeLV陽性ネコを化合物で治療した。治療後、臨床徴候は改善した。その結果として、カルノフスキースコアは、3週間の治療期間の終了時において80%に増加した。
材料および方法
化合物を、10mg/mlの濃度で0.05N水酸化ナトリウム溶液に溶解させた。基準化合物PMEDAPおよびPMEAを、10mg/mlの濃度で重炭酸ナトリウム緩衝液に溶解させた。
ELISAおよび定量RT−PCRによって測定した場合に、FeLVおよびFIV複製の50%を有効に阻害する濃度(EC50)を以下の表に示す。
材料および方法
化合物は、(50〜250mg/mlの濃度範囲および中性付近のpH条件(pH6〜9)で)適切な水酸化ナトリウム緩衝水溶液に溶解させた。製剤化された化合物は、1週間あたり10〜175mg/kgの範囲の総用量で、皮下経路により少なくとも週1回投与した。治療期間は、1週間〜3カ月間とした。
FIVおよびFeLVは、レトロウイルスとして、それらのウイルスRNAゲノムをプロウイルスDNAに逆転写させ、続いてこれがその宿主のゲノムに挿入される。血漿中のウイルスRNA(ウイルス量)の検出は、活性FIV/FeLVの複製が進行中であることを示すので、ウイルス圧(およびウイルス血症)の尺度である。ウイルス量の減少は、ネコのFIV/FeLV感染症を制御するのに重要である。製剤化された化合物は、FIV/FeLV陽性ネコのウイルス量(血漿1mLあたりのFIV/FeLVビリオンとして表わされる)を有意に減少させる。図2のグラフは、FIVおよびFeLV同時感染ネコにおける化合物による治療前後のウイルス量を表す。その他の治療は併用しなかった。
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Claims (25)
- ネコ白血病ウイルスに感染したネコ科動物の予防および治療に使用するための式(I):
(式中、「*」は立体中心を示し;
R1は、アデニン、シトシンまたは2,6−ジアミノプリンであり;
R2は、メチルまたはモノフルオロメチルであり、ただし、R1がアデニンである場合、R2はメチルではなく;
R3およびR4は、水素である)
の化合物、その溶媒和化合物、獣医学的に許容され得る塩、代謝産物またはプロドラッグ。 - 式(I):
の立体異性的に純粋な化合物である、請求項1に記載の化合物。 - 前記ネコ科動物が、例えば、ネコ免疫不全ウイルスなどの他のレトロウイルスにも感染している、請求項1または2に記載の化合物、またはその溶媒和化合物、獣医学的に許容され得る塩、代謝産物もしくはプロドラッグ。
- R1が2,6−ジアミノプリンであり、R2がメチルである、請求項1〜3のいずれか1項に記載の化合物、その溶媒和化合物、獣医学的に許容され得る塩、代謝産物またはプロドラッグ。
- R1がアデニンであり、R2がモノフルオロメチルである、請求項1〜4のいずれか1項に記載の化合物、その溶媒和化合物、獣医学的に許容され得る塩、代謝産物またはプロドラッグ。
- 少なくとも週1回、10〜175mg/kgの合計投与量で、1〜6週間にわたりネコ科動物に投与される、請求項1〜5のいずれか1項に記載の化合物。
- 皮下注射によって投与される、請求項1〜6のいずれか1項に記載の化合物。
- ネコ科動物がFeLVの臨床症状にり患したものである、請求項1〜7のいずれか1項に記載の化合物。
- 前記治療がFeLVの1つ以上の臨床症状を緩和することを含む、請求項8に記載の化合物。
- 臨床症状が、口内炎、歯肉炎、口腔の炎症、腫瘍、下痢、神経学的症状、嗜眠、体重減少およびリンパ節炎からなる群から選択される、請求項8または9に記載の化合物。
- ネコ免疫不全ウイルスに感染したネコ科動物における1つ以上の臨床症状の治療に使用するための式(I)(式中、R1は2,6−ジアミノプリンであり、R2はメチルまたはモノフルオロメチルであり、R3およびR4は水素である)の化合物、その溶媒和化合物、獣医学的に許容され得る塩、代謝産物またはプロドラッグ。
- 式(I):
の立体異性的に純粋な化合物である、請求項11に記載の化合物。 - 前記1つ以上の症状が、体重減少、不安、嗜眠、貧弱被毛状態、発熱、貧血、同時感染、胃腸炎、歯肉炎、好中球減少、熱症状、白血球減少、無食欲、新組織形成、口内炎、歯肉口内炎、鼻炎、下痢;皮膚、眼、尿路、気道の慢性または頻回感染;リンパ節炎、糸球体腎炎、出血性腸炎、挙動変化または発作を生じ得る神経系の疾患、同腹仔の流産、および癌からなる群から選択される、請求項10または11に記載の化合物、その溶媒和化合物、獣医学的に許容され得る塩、代謝産物またはプロドラッグ。
- R1が2,6−ジアミノプリンであり、R2がメチルである、請求項10〜12のいずれか1項に記載の化合物、その溶媒和化合物、獣医学的に許容され得る塩、代謝産物またはプロドラッグ。
- 少なくとも週1回、10〜175mg/kgの合計投与量で、1〜6週間にわたりネコ科動物に投与される、請求項10〜14のいずれか1項に記載の化合物。
- 皮下注射によって投与される、請求項10〜15のいずれか1項に記載の化合物。
- R3およびR4が、同じであるかまたは互いに異なり、CH2C(O)N(R5)2、CH2C(O)OR5、CH2OC(O)R5、CH(R5)OC(O)R5(R、SまたはRS立体化学)、CH2C(R5)2CH2OH、またはCH2OR5であり;R5が、非置換であるかまたはヒドロキシ、酸素、窒素もしくはハロゲンで置換されたC1−C20アルキル、アリールまたはアリール−アルキルである、請求項1〜16のいずれか1項に記載の化合物のプロドラッグ。
- ネコ免疫不全ウイルスまたはネコ白血病ウイルスに感染したネコ科動物における、食欲不振、体重減少、好中球減少、熱症状、白血球減少、無食欲、新組織形成、不安、無関心、貧弱被毛状態、発熱、貧血、同時感染、胃腸炎、歯肉炎、口内炎、歯肉口内炎、鼻炎、下痢;皮膚、眼、尿路、気道の慢性または頻回感染;リンパ肉腫、呼吸困難、口腔の一般的炎症、下痢、リンパ節炎、粘膜蒼白、胃腸障害、糸球体腎炎、出血性腸炎、挙動変化または発作を生じ得る神経系の疾患、同腹仔の流産、腫瘍および癌からなる群から選択される1つ以上の症状の治療に使用するための式(I)(式中、R1は、ピリミジン、プリン、2,6−ジアミノプリン、2−アミノプリン、シトシン、グアニンまたはそれらのアザもしくはデアザ類似体であり;
R2は、水素、メチルまたはモノフルオロメチルであり;
R3およびR4は水素である)
の化合物、その溶媒和化合物、獣医学的に許容され得る塩、代謝産物またはプロドラッグ。 - R1が2,6−ジアミノプリン、2−アミノプリン、シトシン、グアニンまたはそれらのアザもしくはデアザ類似体である、請求項18に記載の化合物、その溶媒和化合物、獣医学的に許容され得る塩、代謝産物またはプロドラッグ。
- R1がジアミノプリンである、請求項18に記載の化合物、その溶媒和化合物、獣医学的に許容され得る塩、代謝産物またはプロドラッグ。
- R2がメチルである、請求項18〜20のいずれか1項に記載の化合物、その溶媒和化合物、獣医学的に許容され得る塩、代謝産物またはプロドラッグ。
- 少なくとも週1回、10〜175mg/kgの合計投与量で、1〜6週間にわたりネコ科動物に投与される、請求項18〜21のいずれか1項に記載の化合物。
- 皮下注射によって投与される、請求項18〜22のいずれか1項に記載の化合物。
- 前記ネコ科動物が、ネコ免疫不全ウイルスおよびネコ白血病ウイルスに感染している、請求項18〜23のいずれか1項に記載の化合物。
- 式中、R3およびR4が、同じであるかまたは互いに異なり、CH2C(O)N(R5)2、CH2C(O)OR5、CH2OC(O)R5、CH(R5)OC(O)R5(R、SまたはRS立体化学)、CH2C(R5)2CH2OH、またはCH2OR5であり、R5が、非置換であるかまたはヒドロキシ、酸素、窒素もしくはハロゲンで置換されたC1−C20アルキル、アリールまたはアリール−アルキルである、請求項18〜24のいずれか1項に記載の化合物のプロドラッグ。
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JPN6015014206; Antimicrobial Agents and Chemotherapy Vol.39, No.3, 1995, p.746-749 * |
JPN6015014209; Electrophoresis Vol.30, 2009, p.2245-2254 * |
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