антагонистом гистамина.
Тучным клеткам придают большое значение в развитии ССД. Медиаторы тучных клеток (гистамин, гепарин и др.) дают профибротический эффект (H. M. Glaman, 1989). В ранней, воспалительной фазе ССД в коже обнаруживаются активированные фибробласты и увеличение содержания тучных клеток. Медиаторы тучных клеток способствуют пролиферации фибробластов и синтезу коллагена in vitro. Показано, что кетотифен подавляет развитие фиброза у линии мышей с плотной кожей, рассматривающихся как модель склеродермии (M. Walker и соавт., 1990). Имеются данные об эффективности кетотифена у больных прогрессирующей ССД, резистентной к D-пеницилламину (B. L. Gruber и соавт., 1990). Проведено двойное слепое контролируемое исследование кетотифена у 24 больных ССД в течение 6 мес. (B. L. Gruber и L. D. Kaufmann, 1991). Больные получали 3 мг кетотифена 2 раза в день. Не отмечено существенных различий с плацебо по клиническим параметрам, функции легких и общей оценке состояния больных, кроме кожного зуда.
15.22. Лефлуномид (Leflunomid)
Лефлуномид (Hoechst AG Werk Kalle-Albert) — производное изоксазола, является пролекарством, метаболизирует в кишечнике и печени с образованием активного вещества А77 1726, обладающего противовоспалительной и иммуномодулирующей активностью (R. R. Bartell и соавт., 1993). Препарат сильно связывается с белком и имеет продолжительность полужизни около 15 дней. Стабильная концентрация в сыворотке на фоне постоянного приема достигается через 16 недель.
Механизм действия
1.подавление высвобождения гистамина тучными клетками и реактивных кислородных радикалов лейкоцитами
2.подавление прилипания лейкоцитов к ЭК
3.подавление миграции лейкоцитов в ткани
4.подавление ранних этапов активации Т-лимфоцитов за счет ингибиции экспрессии ИЛ2Р и рецепторов для трансферина на Т-лимфоцитах
5.подавление синтеза ИЛ-2, ИЛ-3, ИЛ-4, ГМ-КСФ и ФНО-а Молекулярный механизм действия лефлуномида связывают с его способностью подавлять биосинтез пуринов и активность
тирозинкиназы.
Вэкспериментальных исследованиях было показано, что лефлуномид подавляет развитие адъювантного
ипротеогликанового артритов (R. R. Barlett и соавт., 1985), оказывает благоприятный эффект на течение болезни у MRL/lpr мышей и у крыс с экспериментальным аутоиммунным тубулоинтерстициальным нефритом (G. H. Thomas и соавт., 1991), предотвращает синтез антител к ацетилхолиновым рецепторам и развития паралича у животных при экспериментальных аутоиммунных заболеваниях нервной системы.
Клинические испытания
Эффективность лефлуномида была продемонстрирована Z. Dorniian и соавт. (1993) в 6-месячном двойном слепом контролируемом исследовании у 402 больных активным РА. Установлено, что лечение препаратов в дозе 10 мг в день и 25 мг в день вызывает достоверное улучшение следующих параметров по сравнению с плацебо: суставной счет, количество отекших и болезненных суставов, общая эффективность по оценке врача и больного. Побочные эффекты зависели от дозы и проявлялись болями в животе, расстройством стула, кожной сыпью, обратимой алопецией, похуданием. Безопасность и потенциальная эффективность лефлуномида (доза 5, 10 или 25 мг в день) по сравнению с плацебо была оценена у 350 больных РА в рамках фазы II клинических испытаний (B. Rozman и соавт., 1994). Длительность испытания составила 18 месяцев. Продемонстрирована определенная эффективность и низкая токсичность препарата в дозе 20 мг в день. По данным В. Rozman и соавт. (1994) однократный еженедельный прием лефлуномида в дозе 100 или 200 мг по эффективности не уступает ежедневному приему препарата в дозе 10 и 25 мг в день.
Проводится фаза II клинических испытаний препарата HR 325, который химически сходен с активным метаболитом лефлуномида А77 1726.
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