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Ксарелто Монография Химическая структура и модели на животных

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РАЗДЕЛ 6
ХИМИЧЕСКАЯ СТРУКТУРА И МОДЕЛИ НА ЖИВОТНЫХ

Химическая структура

Ривароксабан — это высокоспецифичный прямой конкурентный и обратимый ингибитор фактора Ха48, являющийся производным окса-золидинона. Это негигроскопичный порошок без примесей и запаха, бело-желтой окраски. Ривароксабан — это (Б)-энантиомер 5-хлоро-^ ({(5Б)-2-оксо-3-[4-(3-оксоморфолин-4-ил)-фенил]-1,3-оксазолидин-5-ил} метил)тиофен-2-карбоксамид48. Химическая структура ривароксабана представлена на рис. 9.

Модели тромбоза на животных

Антитромботический эффект ривароксабана продемонстрированы in у^она моделяхвенозного иартериальноготромбоза укрысикроликов59. На модели венозного стаза у крыс под влиянием ривароксаба-на (введенного с профилактической целью) отмечено дозозависимое уменьшение формирования тромба, продолжительность кровотечения на фоне применения антикоагулянта не увеличивалась. Следовательно, ривароксабану свойственен благоприятный баланс между активностью антикоагулянта и риском возникновения кровотечения55.

Рис.9. Химическая формула ривароксабана (Ксарелто®).

  • При предварительном внутривенном введении ривароксабана (0,03, 0,10 и 0,30 мг/кг) отмечено дозозависимое уменьшение объем тромба, ED50 (доза, обеспечивающая 50% максимального эффекта) составила 0,1 мг/кг55
  • Ривароксабан дозозависимо ингибировал активность фактора Ха и увеличивал протромбиновое время, что способствовало уменьшению объема тромба69.

Антитромботическая эффективность введенного внутрь риварокса-бана также изучена на двух моделях экспериментального тромбоза у кроликов, установлена потенциальная эффективность его как при профилактике, так и при лечении венозного тромбоза54.

  • В профилактической модели ривароксабан способствовал существенному дозозависимому уменьшению формирования тромба.
  • На модели лечения с применением ривароксабана отмечено замедление увеличения тромба, аналогичное таковому при использовании фондапаринукса.
  • При назначении ривароксабана внутрь не увеличивалась длительность кровотечения

При применении ривароксабана внутрь установлен дозозависимый антитромботический эффект на моделях артериального тромбоза после его введния внутрь и внутривенно крысам и кроликами59.

  • Ривароксабан дозозависимо ингибировал частоту артериального тромбоза на модели артерио-венозного шунта у кроликов
  • Ривароксабан в дозе 3,0 мг/кг почти полностью ингибировал формирование тромба, в то время как под влиянием фондапаринукса скорость формирования тромба уменьшалась максимум на 59%. Поэтому прямое ингибирование фактора Ха ривароксабаном может быть предпочтительнее непрямого антитромбин-зависимого ингибирования в предотвращении артериального тромбоза

На модели у мышей установлено, что внутривенное введение рива-роксабана предотвращало тромбоэмболическую смерть, индуцированную инъекцией тканевого фактора.

  • При применении ривароксабана дозозависимо снижалась вероятность тромбоэмболической смерти: ED50 состовляла (0,32 ± 0,05) мг/кг; выжили 97% животных, которым ввели 1 мг/кг, в то время как из мышей, которым вводили фондапаринукс в дозе 3 и 10 мг/кг, выжили соответственно 17 и 20%78.

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