JP2022062174A - 心毒性を低減するための組成物及び方法 - Google Patents
心毒性を低減するための組成物及び方法 Download PDFInfo
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- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
- 229960002370 sotalol Drugs 0.000 description 1
- 229960004954 sparfloxacin Drugs 0.000 description 1
- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 229960005333 tetrabenazine Drugs 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- 229940068492 thiosalicylate Drugs 0.000 description 1
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 1
- 229960000488 tizanidine Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 150000007971 urates Chemical class 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 150000004669 very long chain fatty acids Chemical class 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
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Abstract
Description
与は、高い血中レベルをもたらし、より長い期間かけて投与された同量の薬物よりも、より心臓傷害を引き起こすことがある。より低用量の薬物をより高頻度に投与することによっても、より長い間隔での高用量の薬物と比較して、毒性を低下させることができる。
7Sc、64Cu、67Cu、89Sr、86Y、87Y、90Y、105Rh、111Ag、111In、117Sn、149Pm、153Sm、166Ho、177Lu、186Re、188Re、211At、212Bi及びそれらの組合せからなる群から選択される放射線治療剤である。別の態様において、心毒性のある治療処置は、アレムツズマブ、ベバシズマブ、セツキシマブ、ゲムツズマブ、パニツムマブ、リツキシマブ、トシツモマブ、トラスツズマブ及びそれらの組合せからなる群から選択される、モノクローナル抗体である。別の態様において、低減される又は緩和される心毒性は、左室駆出率の低下、駆出速度の低下、慢性心不全又はうっ血性心不全のうち少なくとも1つである。別の態様において、リン脂質は、心毒性のある治療剤を封入しない。別の態様において、化合物は、以下の構造式
塩、グルセプト酸塩、D-グルクロン酸塩、ヒベンズ酸塩、イセチオン酸塩、マロン酸塩、メチル硫酸塩、2-ナプシル酸塩、ニコチン酸塩、硝酸塩、オロト酸塩、ステアリン酸塩、トシル酸塩、チオシアン酸塩、アセフィリネート(acefyllinate)、アセチュレート(aceturate)、アミノサリチル酸塩、アスコルビン酸塩、ホウ酸塩、酪酸塩、ショウノ
ウ酸塩、カンホカーボネート(camphocarbonate)、デカン酸塩、ヘキサン酸塩、コール
酸塩、シピオン酸塩、ジクロロ酢酸塩、エデンテート(edentate)、エチル硫酸塩、フレート(furate)、フシジン酸塩、ガラクタル酸塩、ガラクツロン酸塩、没食子酸塩、ゲンチシン酸塩、グルタミン酸塩、グルタル酸塩、グリセロリン酸塩、ヘプタン酸塩、ヒドロキシ安息香酸塩、馬尿酸塩、フェニルプロピオン酸塩、ヨウ化物塩、キシナホ酸塩、ラクトビオン酸塩、ラウリン酸塩、マレイン酸塩、マンデル酸塩、メタンスルホン酸塩、ミリスチン酸塩、ナパジシル酸塩、オレイン酸塩、シュウ酸塩、パルミチン酸塩、ピクリン酸塩、ピバル酸塩、プロピオン酸塩、ピロリン酸塩、サリチル酸塩、サリチル硫酸塩、スルホサリチル酸塩、タンニン酸塩、テレフタル酸塩、チオサリチル酸塩、トリブロフェネート(tribrophenate)、吉草酸塩、バルプロ酸塩、アジピン酸塩、4-アセトアミド安息
香酸塩、カンシル酸塩、オクタン酸塩、エストール酸塩、エシル酸塩、グリコール酸塩、チオシアン酸塩及びウンデシレン酸塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、亜鉛塩、アルミニウム塩、リチウム塩、コリン塩、リシニウム(lysinium)塩、アンモニウム塩、トロメタミン塩及びそれらの混合物からなる群から選択される。別の態様において、化合物は、単位用量あたり約1mg~単位用量あたり約200mgの間の量で存在する。別の態様において、化合物は、経口、舌下、経皮、坐薬、脊髄内、経腸、非経口、静脈内、腹腔内、皮膚、皮下、局所、肺、直腸、膣又は筋肉内投与のために調合される。別の態様において、経口投与のために調合された組成物は、錠剤、カプセル、カプレット、丸剤、粉末、トローチ、薬用キャンディー剤、スラリー、溶液、懸濁液、乳液、エリキシル又は経口フィルム(OTF)である。別の態様において、組成物は、固形状態、溶液、懸濁液又は軟質ゲル状態である。別の態様において、固形状態は、1又は2以上の賦形剤、結合剤、抗粘着剤、コーティング、崩壊剤、増量剤、香料、染料、着色料、流動促進剤、潤滑剤、保存料、吸着剤、甘味料、それらの誘導体又はそれらの組合せをさらに含む。別の態様において、結合剤は、ヒドロキシプロピルメチルセルロース、エチルセルロース、ポビドン、アクリル及びメタクリル酸コポリマー、薬学的グレーズ、ガム並びに乳誘導体からなる群から選択される。別の態様において、組成物は、副作用として心疾患を誘発する1又は2以上の薬剤をさらに含み、化合物は、心疾患を低減する又は除去する。別の態様において、副作用として心疾患を誘発する1又は2以上の薬剤は、アルブテロール、アルフゾシン、アマンタジン、アミオダロン、アミスルピリド、アミトリプチリン、アモキサピン、アンフェタミン、アナグレリド、アポモルヒネ、アルフォルモテロール、アリピプラゾール、三酸化ヒ素、アステミゾール、アタザナビル、アトモキセチン、アジスロマイシン、ベダキリン、ベプリジル、ボルテゾミブ、ボスチニブ、抱水クロラール、クロロキン、クロルプロマジン、シプロフロキサシン、シサプリド、シタロプラム、クラリスロマイシン、クロミプラミン、クロザピン、コカイン、クルクミン、クリゾチニブ、ダブラフェニブ、ダサチニブ、デシプラミン、デクスメデトミジン、デクスメチルフェニデート、デキストロアンフェタミン、アンフェタミン、ジヒドロアルテミシニン及びピペラキン、ジフェンヒドラミン、ジソピラミド、ドブタミン、ドフェチリド、ドラセトロン、ドンペリドン、ドーパミン、ドキセピン、ドロネダロン、ドロペリドール、エフェドリン、エピネフリン、アドレナリン、エリブリン、エリスロマイシン、エスシタロプラム、ファモチジン、フェルバメート、フェンフルラミン、フィンゴリモド、フレカイニド、フルコナゾール、フルオキセチン、ホルモテロール、ホスカルネット、ホスフェニトイン、フロセミド、フルセミド、ガランタミン、ガチフロキサシン、ゲミフロキサシン、グラニセトロン、ハロファントリン、ハロペリドール、ヒドロクロロチアジド、イブチリド、イロペリドン、イミプラミン、メリプラミン、インダパミド、イソプロテレノール、イスラジピン、イトラコナゾール、イバブラジン、ケトコナゾール、ラパチニブ、レバルブテロール、レボフロキサシン、レボメタジル、リスデキサンフェタミン、リチウム、
メソリダジン、メタプロテレノール、メサドン、メタンフェタミン、メチルフェニデート、ミドドリン、ミフェプリストン、ミラベグロン、ミルタザピン、モエキシプリル/HCTZ、モキシフロキサシン、ネルフィナビル、ニカルジピン、ニロチニブ、ノルエピネフリン、ノルフロキサシン、ノルトリプチリン、オフロキサシン、オランザピン、オンダンセトロン、オキシトシン、パリペリドン、パロキセチン、パシレオチド、パゾパニブ、ペンタミジン、ペルフルトレン脂肪ミクロスフェア、フェンテルミン、フェニレフリン、フェニルプロパノールアミン、ピモジド、ポサコナゾール、プロブコール、プロカインアミド、プロメタジン、プロトリプチリン、プソイドエフェドリン、クエチアピン、キニジン、キニーネ硫酸塩、ラノラジン、リルピビリン、リスペリドン、リトドリン、リトナビル、ロキシスロマイシン、サルブタモール、サルメテロール、サキナビル、セルチンドール、セルトラリン、セボフルラン、シブトラミン、ソリフェナシン、ソラフェニブ、ソタロール、スパルフロキサシン、スルピリド、スニチニブ、タクロリムス、タモキシフェン、テラプレビル、テラバンシン、テリスロマイシン、テルブタリン、テルフェナジン、テトラベナジン、チオリダジン、チザニジン、トルテロジン、トレミフェン、トラゾドン、トリメトプリム-スルファ、トリミプラミン、バンデタニブ、バルデナフィル、ベムラフェニブ、ベンラファキシン、ボリコナゾール、ボリノスタット又はジプラシドンの少なくとも1つから選択される。
される、モノクローナル抗体である。別の態様において、低減される又は緩和される心毒性は、左室駆出率の低下、駆出速度の低下、慢性心不全又はうっ血性心不全のうち少なくとも1つである。別の態様において、ホスファチジルグリセロールは、心毒性のある化学療法剤を封入しない。
誘発性の心毒性を抑制する脂質であって、例えば、経口、非経口(静脈内若しくは皮下)投与により、心毒性のある薬物の前に提供することができ、又は、心毒性のリスクを示すことが既知である治療剤の前に、同時に若しくは順次に、空のリポソームとして提供することができる、脂質を提供することを含む。
ルス剤(stealthing agents)等のような1又は2以上の表面修飾をさらに包含すること
ができる。本発明とともに使用するための空のリポソームの非限定的例は、限定されないが、例えば、1,2-ジミリストイル-sn-グリセロ-3-ホスホリルコリン(DMPC)、1,2-ジミリストイル-sn-グリセロ-3-ホスホリルグリセロール(DMPG)、DMPC/DMPG、1-ミリストイル-2-ヒドロキシ-sn-グリセロ-3-ホスホ-(1’-rac-グリセロール)(LysoPG)、及び1-ミリストイル-2-ヒドロキシ-sn-グリセロ-3-ホスホ-(1’-rac-グリセロール)(LysoPG)を包含する。一実施形態において、リポソームは、例えば、LysoPG、ミリ
ストイルモノグリセリド及びミリスチン酸を含む、リポソーム又はリポソーム前駆体である。特定の非限定的な一例において、組成物は、リポソーム中又はその近くに活性薬剤も含み、組成物は、リン脂質の活性薬剤に対する、3:1、1:1、0.3:1及び0.1:1の比を有する。
を有する。
関連遺伝子チャネル遮断の機序は、外部から適用された第四級アンモニウム誘導体の作用と同様であり、このことは間接的に、DMPC/DMPGリポソーム又はその代謝体の抗遮断効果の作用機序を示唆し得る。阻害定数及びチャネル阻害のための相対結合エネルギーは、より疎水性の第四級アンモニウムが、より高い親和性遮断を有し、一方、陽イオン-π相互作用又はサイズ作用が、第四級アンモニウムによるチャネル阻害における決定性因子ではないことを示す。また、テトラエチルアンモニウムよりも長い尾部基又はより大きい頭部基のいずれかを有する疎水性の第四級アンモニウムは、細胞膜に浸透し、遺伝子チャネル内の高親和性の内部結合部位に容易に接近し、より強い遮断を発揮する。
1. 28日目の時点での15~25msのQTc延長は、86日目(屠殺)まで着実に増加する(図1)。
2. 有意により高い平均動脈血圧(図2)
3. 慢性高血圧が、
a. 肥大の発生を伴う左室の拡張(図3、4)
b. より低い駆出速度(図5)
c. より低い左室収縮終末期圧(図6)
d. より低い左室内径短縮率(図7)
により特徴づけられる、うっ血性心不全をもたらす。
4. 治療期間にわたる有意な体重低減(図8)
5. 心筋傷害を示す、有意により高いトロポニンIレベル(図9)
1. 0日目のデータに対するQTc間隔における変化なし
2. うっ血性心機能不全をもたらす可能性が低い、より低い平均動脈圧
3. 肥大、左室動態の変化及び体重低減を包含するうっ血性心不全の、有意により低い症状
を示した。
ular fractional shortening)の低下を予防することを示すグラフである。図7において、LV内径短縮率(LV fractional shortening)の低下は、初期の心筋リモデリングに起因する。スニチニブ単独で治療された動物は、LV駆出率の低下をもたらす、LV内径短縮率の時間依存性低下を示し、これはスニチニブ及び本発明を用いて治療された動物において観察されなかった。2群の動物間の差異は、86日間の治療後に統計学的に有意であった。
本明細書において「を含む」という用語と合わせて使用される場合、「1つ」を意味し得るが、「1又は2以上」「少なくとも1つ」及び「1又は1を超える」の意味とも一致する。特許請求の範囲における「又は」という用語の使用は、選択肢のみを指す又は選択肢が互いに排他的であることを明白に示さない限り、「及び/又は」を意味するために使用されるが、本開示は、選択肢のみ及び「及び/又は」を指すという定義を支持する。本出願中、「約」という用語は、値が、デバイス、値を決定するのに利用される方法の固有の誤差変動、又は試験対象中に存在する変動を包含することを示すのに使用される。
る(has)」のような、を有する(having)の任意の型)、「を包含する(including)」(並びに「を包含する(includes)」及び「を包含する(include)」のような、を包含
する(including)の任意の型)、又は「を含有する(containing)」(並びに「を含有
する(contains)」及び「を含有する(contain)」のような、を含有する(containing
)の任意の型)という語は、包括的又は制限のないものであり、さらなる、列挙されていない要素又は方法ステップを除外しない。本明細書において提供されている、組成物及び方法のいずれかの実施形態において、「を含む」は、「本質的に~からなる」又は「からなる」と代替することができる。本明細書において使用される場合、「本質的に~からなる」という語法は、特定の完全体又はステップ、並びに特許請求される本発明の特徴又は機能に物質的な影響を及ぼさないものを必要とする。本明細書において使用される場合、「からなる」という用語は、列挙された完全体(例えば、特色、要素、特徴、特質、方法(method/process)ステップ若しくは制限)又は完全体の群(例えば、特色、要素、特徴、特質、方法(method/process)ステップ若しくは制限)の存在のみを示すために使用される。
動することがある。
1. U.S. Patent No. 8,372,830
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168851/
3.https://academic.oup.com/toxsci/article/120/1/14/1665205/Cardiotoxicity-Associated-with-Targeting-Kinase
4. The importance of drug metabolites synthesis: the case-study of cardiotoxicanticancer drugs. Hrynchak I, Sousa E, Pinto M, Costa VM. Drug Metab Rev. 2017;25:1-39
5. Cardiac Complications of Cancer Therapy: Pathophysiology, Identification,Prevention, Treatment, and Future Directions. Jain D, Russell RR, Schwartz RG,Panjrath GS, Aronow W. Curr Cardiol Rep. 2017; 19(5):36
6. Beyond Anthracyclines: Preemptive Management of Cardiovascular Toxicity inthe Era of Targeted Agents for Hematologic Malignancies. Sethi TK, Basdag B,Bhatia N, Moslehi J, Reddy NM. Curr Hematol Malig Rep. 2017; 12(3):257-267
7. The Myocyte-Damaging Effects of the BCR-ABL1-Targeted Tyrosine KinaseInhibitors Increase with Potency and Decrease with Specificity. Hasinoff BB,Patel D, Wu X. Cardiovasc Toxicol. 2016
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11. Left ventricular dysfunction predicted by early troponin I release afterhigh-dose chemotherapy. Cardinale D, Sandri MT, Martinoni A, Tricca A, CivelliM, Lamantia G, Cinieri S, Martinelli G, Cipolla CM, Fiorentini C. J Am CollCardiol. 2000; 36(2):517-22
12. Orphanos GS, I. G. (2009). Cardiotoxicity induced by tyrosine kinaseinhibitors. Acta Oncol. , 48 (7), pp. 964-970
Claims (8)
- 1又は2以上のホスファチジルグリセロール含有化合物を含む、心毒性のある治療剤又は治療処置を受けることに伴う左室駆出率の低下、駆出速度の低下、慢性心不全又はうっ血性心不全のうち少なくとも1つの抑制剤又は低下剤であって、
対象が、前記心毒性のある治療剤又は治療処置からの心臓保護の必要がある者として特定され、
前記対象の心臓に対して心臓保護的である有効量の前記1又は2以上のホスファチジルグリセロール含有化合物が送達され、それにより前記対象への前記心毒性のある治療処置の適用に伴う左室駆出率の低下、駆出速度の低下、慢性心不全又はうっ血性心不全のうち少なくとも1つを抑制する又は低下させる、
前記抑制剤又は低下剤。 - 心毒性のある治療処置が、化学療法であり、
1若しくは2以上のホスファチジルグリセロール含有化合物が、
心毒性のある治療処置の前、間、若しくは後のうち少なくとも1つに提供される、又は、
心血管疾患も治療する活性薬剤と組み合わせて送達されるホスファチジルグリセロールである、
請求項1に記載の抑制剤又は低下剤。 - 心毒性のある治療処置が、アントラサイクリン、ドキソルビシン、ダサチニブ、イマチニブメシル酸塩、ラパチニブ、ニロチニブ、ソラフェニブ、スニチニブ、スニチニブ及びドキソルビシン若しくはトラスツズマブのうち少なくとも1つを用いた処置から選択される、又はカネルチニブ(CI 1033)、エルロチニブ、ゲフィチニブ、イマチニブメシル酸塩、レフルノミド(SU101)、ラパチニブ、セマキシニブ(SU5416)、ソラフェニブ(BAY 43-9006)、スニチニブ、バタラニブ(PTK787/ZK222584)、バンデタニブ(ZD6474)及びそれらの組合せからなる群から選択されるチロシンキナーゼ阻害剤である、又はアレムツズマブ、ベバシズマブ、セツキシマブ、ゲムツズマブ、パニツムマブ、リツキシマブ、トシツモマブ、トラスツズマブ及びそれらの組合せからなる群から選択されるモノクローナル抗体である、請求項1又は2に記載の抑制剤又は低下剤。
- 心毒性のある治療処置が、47Sc、64Cu、67Cu、89Sr、86Y、87Y、90Y、105Rh、111Ag、111In、117Sn、149Pm、153Sm、、166Ho、177Lu、186Re、188Re、211At、212Bi及びそれらの組合せからなる群から選択される放射線治療剤である、請求項1に記載の抑制剤又は低下剤。
- 1又は2以上のホスファチジルグリセロール含有化合物が、1,2-ジミリストイル-sn-グリセロ-3-ホスホリルグリセロール(DMPG)を含むホスファチジルグリセロール含有化合物である、請求項1~4のいずれか1項に記載の抑制剤又は低下剤。
- ホスファチジルグリセロール含有化合物が、心毒性治療剤を封入しない、請求項1~5のいずれか1項に記載の抑制剤又は低下剤。
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AU2022200076A1 (en) | 2022-02-03 |
AU2018298150A1 (en) | 2020-01-30 |
AU2022200076B2 (en) | 2023-11-23 |
KR102432210B1 (ko) | 2022-08-12 |
US20190008878A1 (en) | 2019-01-10 |
AU2018298150B2 (en) | 2021-11-11 |
CA3068047A1 (en) | 2019-01-10 |
JP2024037882A (ja) | 2024-03-19 |
KR20220119168A (ko) | 2022-08-26 |
EP3648772A4 (en) | 2020-07-22 |
MX2023008324A (es) | 2023-07-24 |
KR102561758B1 (ko) | 2023-07-31 |
CN110869026A (zh) | 2020-03-06 |
WO2019010352A1 (en) | 2019-01-10 |
KR20200008670A (ko) | 2020-01-28 |
EP3648772A1 (en) | 2020-05-13 |
JP2020526488A (ja) | 2020-08-31 |
MX2019015503A (es) | 2020-07-28 |
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