Описание
Препарат Тиогуанин — противоопухолевый цитостатический препарат, антиметаболит пуринового основания (сульфгидрильное производное гуанина). Является S-фазоспецифичным препаратом. Метаболизируясь в активную форму — тиогуаниловую кислоту, способен нарушать синтез пуринов и взаимопревращение пуриновых нуклеотидов. Обладает избирательностью в отношении клеток костного мозга. Основное действующее вещество — тиогуанин.
Применяют преимущественно в комбинированной терапии острых и хронических лейкозов. Эффективность применения зависит от возраста и предшествующей химиотерапии. Особенно результативен в комбинации с цитарабином и преднизолоном при острых и хронических миелолейкозах ( при бластном кризе и в предбластной стадии). Может применяться также в комбинации с противоопухолевыми антибиотиками.
Показания к применению:
- Острый лейкоз (миелобластный, монобластный, лимфобластный, недифференцированный);
- хронический миелолейкоз;
- может применяться также в комбинации с противоопухолевыми антибиотиками.
Состав препарата Тиогуанин
Одна таблетка содержит
- активное вещество — тиогуанин 40 мг,
- дополнительные вещества: лактозы моногидрат, крахмал картофельный, кислота стеариновая, акация, магния стеарат.
Фармакодинамика
Противоопухолевое средство, антиметаболит пуринового основания (сульфгидрильное производное гуанина). Является S-фазоспецифичным препаратом. Метаболизируясь в активную форму — тиогуаниловую кислоту-, тем самым нарушает синтез пуринов и взаимопревращение пуриновых нуклеотидов. Обладает избирательностью в отношении клеток костного мозга.
Механизм действия взаимосвязан с нарушением синтеза ДНК и с ингибированием митотического процесса в опухолевой клетке. Тиогуанин обладает избирательностью к клеткам костного мозга.
Являясь антиметаболитом группы аналогов пурина, обладает S-фазовой специфичностью, в человеческом организме тиогуанин быстро метаболизируется в активные внутриклеточные производные, ведущим из которых является 6-тиогуаниловая кислота. Данная кислота способна ингибировать ферменты, принимающие участие в синтезе и утилизации пуриновых нуклеотидов. После превращения в ди- и трифосфатные производные кислота встраивается в oбразующиеся цепи РНК и ДНК в виде «фиктивных» фoсфодиэфирных мостиков, тем самым, нарушая их синтез. Данные о корреляции резистентности экспериментальных опухолей у животных к действию тиогуанина с потерей активности фермента свидетельствуют в пользу этого механизма, который превращает тиогуанин в тиогуаниловую кислоту. Другим механизмом устойчивости к воздействию тиогуанина может быть повышение катаболизма тиогуаниловой кислоты неспецифическими фосфатазами. Угнетает гемопоэз.
В опытах на крысах показано тератогенное действие тиогуанина в дозировке, в пять раз превышающей дозировку для человека.
Применяют преимущественно в комбинированной терапии острых и хронических лейкозов. Эффективность применения зависит от возраста и предшествующей химиотерапии. Особенно результативен в комбинации с цитарабином и преднизолоном при острых и хронических миелолейкозах ( при бластном кризе и в предбластной стадии). Может применяться также в комбинации с противоопухолевыми антибиотиками.
Исследования, проведенные в ходе клинического эксперимента с радиомеченным тиогуанином, предоставили данные о том, что после перорального использования тиогуанин абсорбируется не полностью и вариабельно. В среднем из ЖКТ всасывается приблизительно 30 процентов принятой дозы (колебания от 14 до 46 процентов). Максимум радиоактивности в плазме достигался через 8 часов, и впоследствии уровень радиоактивности медленно понижался. При этом сам тиогуанин в течение всего периода измерений практически не определялся в плазме.
Фармакокинетика
Абсорбция
После приема внутрь всасывается из ЖКТ около 30 процентов принятой дозы тиогуанина. Проникает через гематоэнцефалический барьер.
Метаболизм/биотрансформация
Биотрансформируется главным образом в печени, превращаясь сначала в активные производные, а затем подвергаясь катаболизму, преимущественно путем метилирования.
Элиминация/ выведение
Элиминируется почками практически полностью в виде метаболитов. Исходное вещество обнаруживается в моче в следовых количествах. Метилированный метаболит тиогуанина — 2-амино−6-метилтиопурин — появляется в моче достаточно быстро, и его количество достигает в ней максимума через 6–8 часов, а экскреция продолжается и через 12–22 часов после приема. Продукты дальнейшего катаболизма метилированного производного — неорганические сульфаты, несколько позднее появляются в моче, но через 8 часов после приема становятся главными метаболитами. Также в небольших количествах в моче обнаруживаются также тиомочевая кислота и некоторые неидентифицированные соединения. Период полувыведения (T1/2 ) составляет в среднем 80 минут. Выводится почками в виде метаболитов.
Беременность и грудное вскармливание
Применение при беременности
Категория действия на плод по FDA — D. В экспериментальных исследованиях установлено тератогенное и эмбриотоксическое действие тиогуанина.
Женщины детородного возраста при использовании тиогуанина и в течение последующих 6 месяцев должны пользоваться надёжными методами контрацепции.
В случае отсутствия менструации, наступления беременности или при подозрении на вероятную беременность пациентка должна сообщить об этом своему лечащему врачу. В случае, если тиогуанин используется в период беременности или беременность наступила во время лечения тиогуанином, пациентка должна быть извещена о потенциальной опасности для плода. Противопоказано при беременности (особенно I триместр).
Применение в период грудного вскармливания
Не проведилось специальных исследований по безопасности использования тиогуанина в период грудного вскармливания. Не рекомендуется грудное вскармливание из-за вероятного риска для грудных детей (неблагоприятные эффекты, канцерогенное и мутагенное действие).
Ограничения к применению
- Пожилой возраст (более вероятны возрастные нарушения функции почек, что может потребовать снижения дозировки);
- предшествующая лучевая терапия.
Меры предосторожности вещества Тиогуанин
Необходимо регулярно (не реже 2 раз в неделю) контролировать показатели функции печени, гематологические показатели и при первых признаках выраженной тромбоцитопении, лейкопении, нарушениях функции печени (желтуха), почек, кровотечений прекратить лечение с вероятным его возобновлением после восстановления лабораторных показателей и в более низкой дозировке. Следует предупреждать развитие инфекции при развитии лейкопении (лечение возможно только после ее купирования). Рекомендуется ограничить число венопункций, увеличить потребление жидкости, контролировать выделения на скрытую кровь, последующее усиление диуреза, назначение аллопуринола с целью выведения мочевой кислоты. Во время лечения исключается употребление алкоголя, ацетилсалициловой кислоты.
По возможности следует завершить стоматологические вмешательства до начала лечения или отложить до нормализации картины крови (возможно повышение риска проявлений микробных инфекций,кровоточивость десен, замедление процессов заживления). В процессе лечения соблюдать осторожность при использовании зубных щеток, зубочисток или нитей.
Больным, ранее получавшим цитотоксические препараты или лучевую терапию в течение 4–6 недель назначают с осторожностью.
Необходимо принимать каждый препарат в назначенное время и соблюдать осторожность при комбинированной терапии.
В период применения лечения не рекомендуется проведение вакцинации вирусными вакцинами, рекомендуется избегать контакта с людьми, получившими вакцину против полиомиелита, с людьми с бактериальными инфекциями. У больных лейкозом в стадии ремиссии не следует применять живые вирусные вакцины по крайней мере в течение 3 месяцев после последнего курса химиотерапии. Следует отсрочить иммунизацию пероральной вакциной против полиомиелита людей, находящихся в близком контакте с таким больным, особенно членов семьи.
Проявление признаков угнетения функции костного мозга, необычных кровоизлияний или кровотечений, крови в моче или кале, черного дегтеобразного стула или точечных красных пятен на коже требует немедленной консультации врача.
Следует соблюдать осторожность в избежание случайных порезов острыми предметами (безопасные ножницы, бритва), избегать занятий контактными видами спорта и других ситуаций, при которых вероятны травмы или кровоизлияния.
В период лечения и в последующие 6 месяцев обязательно использование надежных контрацептивов.
Фармацевтические характеристики
Аналог гуанина, по структуре и свойствам близок к меркаптопурину.
Бледно-желтый или зеленовато-желтый кристаллический порошок без запаха или со слабым запахом. Практически нерастворим в воде, спирте и хлороформе; растворим в разбавленных растворах щелочей. Молекулярная масса 167,19 (безводный).
Таблетки палевого цвета с зеленовато-желтым оттенком, двояковыпуклые.
Упаковка, срок годности, условия хранения
Таблетки по 0,04 г (40 мг) в банках темного стекла по 50 штук или в пленке поливинилхлоридной.
Хранить тиогуанин в защищенном от света месте.
Наша компания работает как на территории Казахстана, так и осуществляет доставку в страны ближнего зарубежья. Обращайтесь к нам за консультациями по контактным телефонам.
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