ПРОТИВОВОЗРАСТНЫЕ И РАНОЗАЖИВЛЯЮЩИЕ СОСТАВЫ

Изобретение относится к биотехнологии. Предложены пептиды, которые происходят из проферментных форм матриксных металлопротеиназ и являются ингибиторами матриксных металлопротеиназ. Аминокислотная последовательность представлена в описании. Описана композиция для стимулирования развития здоровой кожи, содержащая терапевтически эффективное количество пептидов. Описаны перевязочный материала для ран, способ стимулирования развития здоровой кожи и лосьон для обработки кожи для уменьшения результатов воздействия старения и для стимулирования развития здоровой кожи и лечения ран на основе композиции. Раскрыто применение композиции для изготовления лекарственного средства, способствующего заживлению ран, предотвращению рубцевания, снижению образования морщин, уменьшению результатов воздействия старения или улучшения цвета кожи. Использование изобретения позволяет получить новые противовозрастные и ранозаживляющие агенты. 6 н. и 9 з.п. ф-лы, 24 ил., 6 табл.

МОДИФИЦИРОВАННЫЕ ИНГИБИТОРЫ ПРОТЕИНАЗЫ

Изобретение относится к биотехнологии и может быть использовано в селекции организмов, например растений. Цистатиновый ингибитор протеиназы (оризацистатин 1), имеющий делецию аспарагиновой кислоты в положении 86, и гибридный ингибитор протеиназы, включающий цистатин и ингибитор протеиназы, используют для борьбы с патогенами, паразитами или вредителями. Трансформация организма молекулой ДНК, кодирующей ингибиторы протеиназы, придает ему устойчивость к протеолитическому расщеплению. Ингибиторы протеиназ могут быть также получены с использованием праймеров. 7 с. и 11 з.п. ф-лы, 6 ил., 4 табл.

ПРИМЕНЕНИЕ СЛИТОГО КОНСТРУКТА ТИМП-ГФИ И СПОСОБ ЛЕЧЕНИЯ ПОВРЕЖДЕНИЙ КОЖИ ДЛЯ ПРЕДОТВРАЩЕНИЯ ИЛИ ИНГИБИРОВАНИЯ ОБРАЗОВАНИЯ РУБЦА

Изобретение относится к области биотехнологии, конкретно к получению слитых белков, и может быть использовано в медицине. Изобретение позволяет предотвратить образование рубца в процессе лечения повреждений кожи при использовании слитого конструкта, состоящего из аминокислотной последовательности тканевого ингибитора металлопротеиназ (ТИМП), связанного с якорем гликозилфосфатидилинозита (ГФИ). 2 н. и 8 з.п. ф-лы, 33 ил.

Белок, фармацевтическая композиция, лекарственное средство, устройство, набор

Изобретение относится к биотехнологии и представляет собой применение белка, который имеет последовательность по меньшей мере на 95% идентичную SEQ ID NO: 1, для ингибирования рекрутинга тромбоцитов, рекрутинга нейтрофилов, активации нейтрофилов и/или образования внеклеточных нейтрофильных ловушек (нетоза). Изобретение позволяет расширить ассортимент продуктов, используемых для ингибирования рекрутинга тромбоцитов, рекрутинга нейтрофилов, активации нейтрофилов и/или образования внеклеточных нейтрофильных ловушек. 10 з.п. ф-лы, 17 ил., 4 табл., 5 пр.

KLK5-ИНГИБИРУЮЩИЙ ПЕПТИД

Группа изобретений относится к биотехнологии. Представлены мутантный пептид SPINK2, который ингибирует протеазную активность активного человеческого KLK5, и где указанный пептид содержит определенные аминокислотные последовательности, полинуклеотид для получения мутантного пептида SPINK2, вектор для получения мутантного пептида SPINK2, клетка для получения мутантного пептида SPINK2, которая содержит полинуклеотид или вектор, способы получения мутантного пептида SPINK2, конъюгаты для ингибирования протеазной активности человеческого KLK5 и способы их получения, композиции и фармацевтические композиции для лечения и профилактики заболевания, ассоциированного с KLK5 и их применение, а также способы лечения или профилактики заболевания, ассоциированного с KLK5. Также описаны композиции для тестирования и для диагностики заболеваний, связанных с KLK5, экспрессией KLK5, экспрессией KLK7 и/или экспрессией KLK14, способ идентификации мутантного пептида SPINK2, ингибирующего KLK5, где указанный ...

МЕЧЕНЫЕ АНАЛОГИ ГЛУТАМИНА И ЛИЗИНА

Изобретение относится к соединениям формулы Y-(CR2 )n-X-NHJ, где Х представляет собой С=O или CR2; n является целым числом, имеющим значение от 1 до 6; Y представляет собой L(A)m- или R1R2 CR-, где L - металлокомплексообразующий агент, А представляет собой -CR2-, -NRCO-, -CONR- или полиалкиленгликоль; m является целым числом, имеющим значение от 0 до 10; где один из R1 и R2 является -NH(B)p Z1 и другой является -CO(B)qZ2, где р и q являются целыми числами, имеющими значение от 0 до 20, и каждый В независимо выбирают из Q или остатка аминокислоты, где Q является циклическим пептидом; Z1 и Z2 - защитные группы, которые являются биосовместимыми группами, которые ингибируют или подавляют метаболизм пептида in vivo; J и каждую R-группу независимо выбирают из Н, C1-4 алкила или С1-4 алкоксиалкила; при условии, что (i) общее число остатков аминокислот в R1 и R2 группах не превышает 20; (ii) если Х является CR2, то Y является -CRR1R2, и Z2 является металлокомплексообразующим агентом; (ii) если ...

ИНГИБИТОРЫ ТРОМБИНА, СПОСОБЫ ИХ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ИХ ОСНОВЕ

Изобретение относится к новым полипептидам, обладающим антитромбиновой активностью, которые получают из тканей или секреций пиявок отряда Rhynchobdellida преимущественно вида Theromyzon tessulatum. Полипептиды имеют молекулярный вес около 14 кДа, 9 кДа и могут использоваться в фармацевтических композициях для лечения расстройств и состояний, вызываемых тромбозом. Технический результат: расширение арсенала соединений - ингибиторов тромбина. 4 с. и 6 з.п. ф-лы, 10 ил., 2 табл.

СПОСОБ ПОЛУЧЕНИЯ ОВОМУКОИДА

Изобретение относится к области биохимии. Предложен способ получения овомукоида. К белку утиных яиц добавляют равный объем смеси 0,5 М водного раствора трихлоруксусной кислоты и органического растворителя в объемном отношении 1:1,8-2,3. Отделяют образующийся осадок фильтрованием при 0-5°С. Затем добавляют к фильтрату органический растворитель в объемном отношении органического растворителя и фильтрата 3-3,5:1. Удаляют надосадочную жидкость декантированием при 0-5°С. Удаляют низкомолекулярные примеси из овомукоида ультрафильтрацией. Лиофильно высушивают овомукоид. В качестве органического растворителя используют смесь этанола и ацетона в объемном отношении 40-65:60-35. Изобретение способствует повышению выхода овомукоида до 1,66 г/100 мл яичного белка и увеличению степени чистоты овомукоида до 99,5%. 1 табл., 5 пр.

ПРОИЗВОДНЫЕ 5-АМИНО-4-ОКСИГЕКСАНОВОЙ КИСЛОТЫ И СПОСОБ ИХ ПОЛУЧЕНИЯ

Использование: в медицине и биохимии. Сущность: производные 5-амино-4-оксигексановой кислоты ф-лы I: R1-B1-NH-CH(CH2R2 )-CH(OH)-CH2 -CH(CH2R3)-CO-A1-A2-N(R4,R5) с определенными буквенными значениями, способ их получения и производные 5-амино-4-оксигексановой кислоты, проявляющие активность при подавлении АSP-протеазы из ВИЧ-1. 3 табл.

ПРОИЗВОДНЫЕ БОРСОДЕРЖАЩИХ ПЕПТИДОВ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, ОБЛАДАЮЩАЯ ИНГИБИРУЮЩЕЙ АКТИВНОСТЬЮ К ТРИПСИНПОДОБНЫМ СЕРИНОВЫМ ПРОТЕАЗАМ

Использование: в биологии и медицине, в частности в химии борсодержащих пептидов для композиций, обладающих ингибирующей активностью к трипсиноподобным сериновым протеазам. Сущность изобретения: производные борсодержащих пептидов общей ф-лы 1: , где W - водород, N-защищающая группа: бензилоксикарбонил, C1 -C6-алканоил или C1-C6-алкоксикарбонил; Y - TMSal-Pro, (p-TBDPS-O-Me)Phal-Pro, n-OH-Me-Phal-Pro, TMSal-Adgly, или частичная пептидная последовательность ф-лы 2: -NH-CH(R3)-C(O)AA, где R3 - CH2-Si(CH3)3, -CH2C(CH3)3 или метилнафталиновая группа, или метилен-адамантил; AA - пептидный радикал: Pro, Gly, Ala, Leu, Val, Ile, Asp, Glu; Q1 и Q2 - вместе пинандиольная или группа -O-CH2CH2-O; R1 - водород, R2 - AX, где A - (CH2)Z: Z = 2-5; X - NH2, -NH-C(NH)-NH2, N3, C1-C4-алкокси, Si(CH3)3, или R1 и R2 - триметильная группа, и фармацевтическая композиция, содержащая фармацевтически приемлемый носитель и борсодержащий пептид ф-лы 1 в количестве 0,02-15 мг/кг тела. 2 с и 3 з.п. ф-лы, 2 табл.

КОНЪЮГАТЫ КОМПЛЕКСОВ ТС И ГРУППИРОВОК, ОБЕСПЕЧИВАЮЩИХ НАПРАВЛЕННУЮ ДОСТАВКУ, И ИХ ПРИМЕНЕНИЕ В ДИАГНОСТИКЕ МЕТОДОМ МАГНИТО-РЕЗОНАНСНОЙ ВИЗУАЛИЗАЦИИ

... 1. Композиция комплекса технеция, которая содержит металлический комплекс радиоизотопахТс с лигандом формулы (I) где каждый R1 и R2 независимо представляет собой R группу; х представляет собой 94m, 99 или 99m; Y представляет собой -(A)n-Z, где Z представляет собой биологическую группировку, обеспечивающую направленную доставку, с молекулярной массой менее 5000; -(А)n- представляет собой линкерную группу, где каждый А независимо представляет собой -СО-, -CR2-, -CR=CR-, -C≡C-, -CR2CO2-, -CO2CR2-, -NR-, -NRCO-, -CONR-, -NR(C=0)NR-, -NR(C=S)NR-, -SO2NR-, -NRSO2-, -CR2 OCR2-, -CR2SCR2-, -CR2NRCR2-, С4-8циклогетероалкиленовую группу, С4-8 циклоалкиленовую группу, С5-12ариленовую группу или С3-12гетероариленовую группу или полиалкиленгликольную группировку, группировку полимолочной кислоты или полигликолевой кислоты; n представляет собой целое число величины от 0 до 10; каждая R группа независимо представляет собой Н или C1-10алкил, С3-10алкиларил, С2-10алкоксиалкил, С1-10гидроксиалкил, С1-10фторалкил ...

Белок, фармацевтическая композиция, лекарственное средство, устройство, набор

ДОМЕН ИНГИБИТОРА ПРОТЕАЗЫ, ДНК, ВЕКТОР, КЛЕТКА, СПОСОБ ПОЛУЧЕНИЯ ИНГИБИТОРА ПРОТЕАЗЫ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, ПРИМЕНЕНИЕ ДОМЕНА ИНГИБИТОРА ПРОТЕАЗЫ

Вариант С-концевого протеазо-ингибиторного домена типа Кунитца цепи αколлагена VI человека, где указанный вариант содержит аминокислотную последовательность, приведенную в описании, где X- H или 1 - 5 натуральных аминокислотных остатков, за исключением Сys; каждый из X- X- независимо натуральный аминокислотный остаток, а X- ОН или 1 - 5 натуральных аминокислотных остатков, за исключением Суs; при условии, что по крайней мере один из аминокислотных остатков X- Xотличается от соответствующего аминокислотного остатка нативной последовательности.

МОДИФИЦИРОВАННЫЕ ВАРИАНТЫ ИНГИБИТОРОВ ПРОТЕАЗ Bowman Birk

... 1. Выделенный модифицированный вариант ингибитора протеаз Bowman Birk (BBPI), где вторая ингибирующая протеазная петля каркаса BBPI представляет собой связывающий пептид, и где указанный модифицированный вариант BBPI дополнительно содержит замененную аминокислоту по меньшей мере в одном аминокислотном положении, выбранном из положений, эквивалентных положениям 1, 4, 5, 11, 13, 18, 25, 27, 29, 31, 38, 40, 50, 52, 55 и 65 варианта BBPI с SEQ ID NO:187, и где указанный каркас BBPI представляет собой BBIt (SEQ ID NO:187).2. Выделенный модифицированный вариант BBPI по п.1, где указанный связывающий пептид выбран из связывающего VEGF пептида, связывающего FGF-5 пептида, связывающего TGFβ пептида и связывающего TNFα пептида.3. Выделенный модифицированный вариант BBPI по п.1, где указанная замещенная аминокислота в положении 1 выбрана из А и С, в положении 4 представляет собой V, в положении 5 выбрана из Р и А, в положении 11 представляет собой 11G, в положении 13 выбрана из 13Y, 13I, 13F, 13М, ...

НОВЫЙ ВАРИАНТ АЛЬФА-1-АНТИТРИПСИНА, СПОСОБ ЕГО ПОЛУЧЕНИЯ И ПРИМЕНЕНИЯ

... 1. Вариант альфа-1-антитрипсина, полученный путем замены аминокислоты в определенном сайте между 1-м и 25-м положениями N-конца альфа-1-антитрипсина с целью добавления сайта гликозилирования.2. Вариант альфа-1-антитрипсина по п. 1, отличающийся тем, что вариант альфа-1-антитрипсина имеет от 1 до 3 добавленных к нему сайтов гликозилирования.3. Вариант альфа-1-антитрипсина по п. 1, отличающийся тем, что определенный сайт присутствует между 3-м и 13-м положениями N-конца.4. Вариант альфа-1-антитрипсина по п. 1, отличающийся тем, что определенный сайт присутствует в 9или 12положении N-конца.5. Вариант альфа-1-антитрипсина по п. 1, отличающийся тем, что определенные сайты присутствуют в 4-м и 9-м положениях, 4-м и 12-м положениях или 9-м и 12-м положениях.6. Способ получения варианта альфа-1-антитрипсина, включающий:a) замену аминокислоты в определенном сайте между 1-м и 25-м положениями N-конца альфа-1-антитрипсина с целью добавления сайта гликозилирования;b) культивирование клеток, трансформированных ...

СПОСОБ ИНГИБИРОВАНИЯ РЕТРОВИРУСНОЙ ИНФЕКЦИИ, ИНГИБИТОР ПРОТЕАЗЫ, КОДИРУЮЩАЯ ЕГО НУКЛЕИНОВАЯ КИСЛОТА И СПОСОБ РЕКОМБИНАНТНОГО ПРОДУЦИРОВАНИЯ СЕРИНОВОГО ИНГИБИТОРА

Способы и фармацевтические композиции обеспечивают предотвращение ретровирусной инфекции клеток хозяина. Более конкретно, изобретение относится к предупреждению инфекции ВИЧ в клетках человека с помощью серинового ингибитора протеазы лейкоцитов (СЛПИ).

СПОСОБ ПОЛУЧЕНИЯ ЛАТЕНТНОГО АНТИТРОМБИНА III

... 1. Способ получения латентного антитромбина III, включающий инкубацию раствора нативного антитромбина III в присутствии ионов сульфата и буфера, выбранного из цвиттерионных буферов Good. 2. Способ по п.1, отличающийся тем, что указанные ионы сульфата предоставлены в виде соли, выбранной из сульфата аммония, сульфатов щелочных металлов и сульфатов щелочноземельных металлов. 3. Способ по п.2, отличающийся тем, что указанная соль сульфата представляет собой сульфат аммония. 4. Способ по любому из пп.1-3, отличающийся тем, что концентрация указанных ионов сульфата находится в диапазоне 0,5-2,0 М. 5. Способ по п.4, отличающийся тем, что концентрация ионов сульфата находится в диапазоне 0,7-1 М. 6. Способ по п.5, отличающийся тем, что концентрация ионов сульфата находится в диапазоне 0,8-0,9 М. 7. Способ по любому из пп.1-6, отличающийся тем, что указанный буфер включает буфер HEPES. 8. Способ по любому из пп.1-7, отличающийся тем, что концентрация указанного буфера находится в диапазоне 1-25 ...

ДОМЕН ИНГИБИТОРА ПРОТЕАЗЫ, ДНК, ВЕКТОР, КЛЕТКА, СПОСОБ ПОЛУЧЕНИЯ ИНГИБИТОРА ПРОТЕАЗЫ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, ПРИМЕНЕНИЕ ДОМЕНА

Вариант домена III ингибитора протеазы типа Кунитца, а именно, ингибитора метаболизма тканевого фактора, причем указанный вариант имеет аминокислотную последовательность (I), где Хпредставляет собой Н или 1 - 5 природных аминокислотных остатков за исключением Cys; каждый из Х- Х независимо представляет собой природный аминокислотный остаток; Х представляет собой ОН или 1 - 5 природных аминокислотных остатков за исключением Cys при условии, что по крайней мере один из аминокислотных остатков Х- Х отличается от соответствующего аминокислотного остатка нативной последовательности.

Нацеленное удаление гена

... 1. Способ удаления части трансгена после его интеграции в геном, заключающийся во фланкировании указанной части трансгена с каждой ее стороны областью присоединения Р (attP) бактериофага λ, причем область attP охватывает нуклеотидную последовательность, представленную SEQ ID NO:1, или ее фрагмент, который сохраняет ту же функцию, или нуклеиновые кислоты, которые гибридизуются в жестких условиях с ДНК SEQ ID NO:1 и функционируют как attP-область, или нуклеиновые кислоты, которые отличаются от ДНК SEQ ID NO:1 вследствие вырожденности генетического кода и которые функционируют как attP-область, и в индуцировании высокой частоты внутрихромосомной гомологичной рекомбинации между фланкирующими attP-областями, посредством чего удаляется указанная часть трансгена, помещенная между ними. 2. Способ по п.1, отличающийся тем, что указанный трансген включает маркерный ген, и/или векторную последовательность, и/или другую чужеродную вспомогательную нуклеиновую кислоту. 3. Способ по п.1 или 2, отличающийся ...

ВЫСОКОСЕЛЕКТИВНЫЙ ИНГИБИТОР КОНТАКТНОЙ АКТИВАЦИИ НА ОСНОВЕ ИНФЕСТИНА 4

... 1. Полипептид для ингибирования контактной активации в тестируемом образце крови или ее продукта, который характеризуется последовательностью мутанта инфестина 4 MutB (SEQ ID NO: 1) и по существу соответствует ей, где указанная последовательность может иметь модификации вне участка ингибирующей петли, существенно сохраняющие активность указанного полипептида, являющегося высокоселективным ингибитором фХIIа, селективность которого выше, чем у нативного инфестина 4 и Mut15, или активность которого выше, чем у нативного инфестина 4 и Mut15.2. Полипептид по п. 1, где модификации аминокислотной последовательности вне участка ингибирующей петли представляют собой изменения N- или С-концов последовательности SEQ ID NO: 1, делеции или вставки одного или нескольких аминокислотных остатков, а также консервативные аминокислотные замены.3. Применение полипептида по п. 1 для исследования свертывания в тестируемом образце крови или ее продукта, которое включаетa) получение образца для исследования свертывания ...

СПОСОБ ПРОИЗВОДСТВА ИЗВЛЕЧЕННОГО ИЗ НЕМАТОДЫ ПРОТИВОСВЕРТЫВАЮЩЕГО БЕЛКА (NAP)

... 1. Способ производства лекарственного вещества извлеченного из нематоды противосвертывающего белка (NAP), включающий (a) процесс ферментации, включающий продуцирование NAP в подходящем хозяине, где по меньшей мере одна последовательность, кодирующая NAP, интегрирована в геном хозяина, (b) процесс выделения, включающий отделение NAP от клеток и остатков клеток, и (c) процесс очистки, включающий очистку лекарственного вещества NAP от загрязнений. 2. Способ по п.1, где процесс очистки дополнительно включает введение вещества NAP в окончательную лекарственную композицию. 3. Способ по п.2, дополнительно включающий процесс заполнения для получения лекарственного продукта NAP. 4. Способ по п.1, где NAP выбран из группы, состоящей из rNAPc2, rNAPc2/пролин, AcaNAP5, AcaNAP6, AcaNAP23, AcaNAP31, AcaNAP42, AcaNAP48, AceNAP5, AceNAP7, AduNAP4, AcaNAP24, AcaNAP25, AcaNAP44 или AcaNAP46. 5. Способ по п.1, где NAP представляет собой rNAPc2/пролин. 6. Способ по п.2, где NAP выбран из группы, состоящей ...

МОДУЛЯЦИЯ УРОВНЯ ПРЕДШЕСТВЕННИКОВ АРОМАТА КОФЕ В СЫРЫХ (НЕОБЖАРЕННЫХ) КОФЕЙНЫХ ЗЕРНАХ

... 1. Изолированный полинуклеотид, содержащий нуклеотидную последовательность, кодирующую полипептид, обладающий цистеинпротеазной активностью, где аминокислотная последовательность полипептида и аминокислотная последовательность SEQ ID No. 2 идентичны, по меньшей мере, на 70%, предпочтительно, по меньшей мере, на 80%, при этом идентичность последовательностей основывается на методе выравнивания ClustalW, или комплемен нуклеотидной последовательности, где комплемент содержит такое же число нуклеотидов, что и нуклеотидная последовательность, и комплемент и нуклеотидная последовательность являются 100% комплементарными. 2. Полинуклеотид по п. 1, где аминокислотная последовательность полипептида и аминокислотная последовательность SEQ ID No. 2 идентичны, по меньшей мере, на 85%, предпочтительно, по меньшей мере, на 90%, необязательно, по меньшей мере, на 95%, при этом идентичность последовательностей основывается на методе выравнивания ClustalW. 3. Полинуклеотид по п. 1, где нуклеотидная последовательность ...

METHOD FOR OBTAINING DERIVATIVES OF DIPEPTIDES OR THEIR PHARMACOLOGICALLY ACCEPTABLE SALTS

METHOD FOR OBTAINING DERIVATIVES OF DIPEPTIDES OR THEIR PHARMACEUTICALLY ACCEPTABLE SALTS

Способ выделения калликреинтрипсин-ингибитора

Способ получения производных аминокислоты или их кислотно-аддитивных солей

Изобретение касается гетероциклических веществ, в частности получения производных аминокислот общей ф-лы C6H5-CH2-CH2-CHK-NHCHX-C(O)-Y, где K - C(O)OR1 X - (CH2)4-NH2 Y - N-A-C(O)OH, где R1-H или C2H5 A - группа: @ или их кислотно-аддитивных солей, обладающих гипотензивным и кардиозащитным действием, что может быть использовано в медицине. Цель - создание новых более активных веществ указанного класса. Синтез ведут реакцией соединения YH, с соответствующей аминокислотой, причем в группе Y карбоксил защищен C1-C4-алкилом, в присутствии конденсирующего агента с последующим снятием защитных групп омылением. Выделяют целевой продукт либо в свободном виде, либо в виде нужной соли. Для новых соединений достижение 50%-ного торможения активности энзима превращения ангиотензина достигается при меньшей концентрации вещества, чем в известном случае, т.е. (1,4.10-8-7,6.10-8)-(2,9.10-9-3,5.10-9) против 7.10-6для эналаприла. 1 табл.

Способ выделения антитромбина

Способ получения производных аминокислоты

Изобретение относится к амидам, в частности к получению производных аминокислоты фор-лы I R,-CH(SR )-СО- Ш-СН(СН5)-СО-А, где R, - водород, бензил, фенилэтил, R - водород, ацетил , бензоил, 4-хлор-З-сульфамоил- бензоил, пивалоил, пивалоилоксиметил, А - присоединенный пептидной связью через азот прелин, пивалоилоксиметил- пролин, фенилаланилпролин, валинпро- лин, пролинпролин, 4-карбокситиазоли- дин-З-ил, 7-карбокси-4,5,6,7-титрагидротиено 2 ,3-с пиридин-6-ил, 4-кар- бокси-4,5,6,7-тетрагидротиено 2,3-с1 пиридин-5-ил, N-циклопентилглицин, ...

Monoklonaler Antikörper und seine Verwendung in einem Immunoassay

VERWENDUNG DES SEKRETORISCHEN LEUKOZYTAREN PROTEASE INHIBITORS (SLPI) ALS TRYPTASE-INHIBITOR

ZUSAMMENSETZUNGEN UND METHODEN DER INHIBITION DER BETA-PROTEINFUNKTION

RENININHIBITORISCHE PEPTIDE, VERFAHREN ZU IHRER HERSTELLUNG UND IHRE VERWENDUNG IN ARZNEIMITTELN

Herstellung und Durchmusterung von hochgradig diversen Peptidbanken hinschtlich Bindungsaktivität

Inhibitoren retroviraler Proteasen

Aryloxy- und Arylacyloxymethyl-Ketone als Thiolprotease-Hemmungsstoffe.

Faktor X-LACI-Hybridprotein

PHOSPHINYLCYCLOALKYLCARBONYL- UND PHOSPHINYLCYCLOALKENYLCARBONYLDIPEPTIDE

HEMMSTOFFE FÜR KATHEPSIN-G UND ELASTASE ZUR VERHÜTUNG VON BINDEGEWEBSABBAU

Angiotensin-Converting-Enzyme-Hemmer

Hirudin-Analoge mit Antiblutplättchen-Aktivität

Schnellsynthese und Screening von Peptidmimetika

Methode zur Herstellung von Indan-Derivaten.

ENKASTINE: NEUE GLYCOPEPTIDE MIT ENKEPHALINASE-HEMMENDER WIRKUNG, VERFAHREN ZU IHRER HERSTELLUNG UND IHRE VERWENDUNG ALS PHARMAZEUTISCHE PRAEPARATE.

Glycopeptides of formula Sacch-A-B-R (I) and their physiologically acceptable salts are new. Sacch = monosaccharide residue, opt. having OH gps. partly or completely substd.; A = residue of a neutral L- or D-amino acid, but if B is omitted, it must be D-form; B is absent or is the residue of a neutral L- or D-amino acid, or of an opt. omega-substd. bifunctional acidic or basic L- or D-amino acid; R = OH, 1-8C alkoxy, amino (opt. substd. by 1 or 2 same or different 1-8C alkyl, 5-8C cycloalkyl, 5-8C heteroalkyl or 5-8C heteroaryl) or some other acid deriv. The cpds. N-(1-deoxy-beta-D-fructopyranos-1-yl)- Gly-(Gly or Ser)-OH are also claimed.

POLYPEPTID UND VERFAHREN ZU SEINER HERSTELLUNG.

HIV Protease hemmende Verbindungen

Verfahren zur Isolierung von alpha-Antitrypsin

REKOMBINANTE APROTININ-VARIANTEN-GENTECHNISCHES VERFAHREN ZUR MIKROBIELLEN HERSTELLUNG VON HOMOGEN PROZESSIERTEN APROTININ-VARIANTEN SOWIE DIE THERAPEUTISCHE ANWENDUNG DERSELBEN

PEPTIDYL-N HOCH G -CARBOXY-ARGININ- ALDEHYDE, VERFAHREN ZUR HERSTELLUNG DERSELBEN UND DIESE ENTHALTENDE ARZNEIMITTEL

Verfahren zur Herstellung von rekombinantem Aprotinin und rekombinanten Aprotinin Varianten mit der natürlichen N-terminlaen Sequenz

Heilungsverfahren unter Verwendung katalytischer Antikörper

MATRITZENMETALLOPROTEINASEPEPTIDE, IHRE WIRKUNG IN DIAGNOSE UND THERAPIE

PROTEASE-INHIBITOREN DES ALPHA-1-ANTITRYPSIN TYPS MIT MODIFIZIERTER AKTIEVER STELLE UND DEREN HERSTELLUNG.

Verfahren zur Verbesserung der Wirksamkeit von Insektentoxinen.

Verfahren zur Gewinnung eines Kallikrein-Inaktivators

Neue Thrombininhibitoren

Verfahren zur Gewinnung eines Trypsin-Inhibitors

Verfahren zur Gewinnung von hochreinem, virusinaktiviertem „ 1 -Antitrypsin mittels Anionenaustauscher-Chromatographie

A process is disclosed for extracting highly purified, virus-inactivated alpha 1-anti-trypsin from a cryoprecipitate by means of anion exchanger chromatography with so-called "tentacular" materials. Membrane chromatography with appropriately modified surfaces may also be used in addition to or instead of conventional column chromatography.

Expressions- und Ausscheidungsvektoren für Hirudin mittels transformierter Hefe.

Reagens und Verfahren.

CARBOXYALKYL DIPEPTIDES, PROCESSES FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Modifizierter C1-Esterase-Inhibitor zur Blockierung der Infektiosität von HIV

Es wird ein modifizierter C1-Esterase-Inhibitor beschrieben, der einerseits an die Oberfläche von HIV, andererseits aber nicht an humane Zellmembranen bindet. Dieser modifizierte C1-Esterase-Inhibitor ist zur Blockierung der Infektiosität von HIV in vivo und in vitro verwendbar.

DERIVATISIERUNG VON PROTEINEN IN WÄSSRIGEM LÖSUNGSMITTEL

Reinigungsverfahren auf Grundlage der Bindung von Enzymen and markierte Peptide

Inhibitor des Hepatozytwachstumsfaktoraktivators

New phosphinate-contg. peptide derivs. - as collagenase inhibitors e.g. for treating gangrene or dental infections

Peptide derivs. of formula R1-NH-CH(R2)-P(O)(OR3)-CH2-CH2-CO-R4-N(R5)-CH(R6)-CO-R7 (I) are new. R1 = H or an amino protecting gp. suitable for an alpha-amino acid or a gp. derived from an alpha-amino acid or a peptide bonded onto the NH via its CO end and having at its amino end, an H or an amino protecting gp. suitable for an alpha-amino acid; R2 = the side chain of an alpha-amino acid; R3 = H, a metal atom 1-5C alkyl or benzyl; R4 = a divalent gp. derived from an alpha-amino acid chosen from proline, hydroxyproline, thiazolidine and dehydroproline of the formulae (i)-(iv), bonded on the CO via their N atmos. R5 = H or 1-4C alkyl; R6 = 1-5C alkyl or the side chain of an alpha-amino acid; R7 = OR8; R8 = H, a metal atom, 1-5C alkyl or benzyl; or either R1 and R7 or R1 and R6 together form a divalent gp. derived from a alpha-amino acid or a peptide which contains 2-3 amino acid gps.. USE/ADVANTAGE - (I) are inhibitors of bacterial collagenases which belong to the class of Zn-contg. metal ...

STABILISIERTE WÄSSRIGE ZUSAMMENSETZUNGEN MIT GEWEBEFAKTORINHIBITOR (TFPI) ODER GEWEBEFAKTORINHIBITOR-VARIANTE

ELASTINPEPTID-FINGERABDRÜCKE UND ANALYSEVERFAHREN FÜR MIT COPD IN VERBINDUNG STEHENDES MMP12

Manufacture of seamless knitted non-run hosiery fabric

... 1,001,225. Knitting. VAN RAALTE CO. Inc. March 13, 1963 [May 7, 1962], No. 9912/63. Headings D1C and D1K. Circular stocking fabric knitted from two yarns S, M, consists entirely of tuck stitches each consisting of a held loop formed by both yarns and a tuck loop formed by one yarn the other yarn forming a float behind the stitch and modified tuck stitches where the tuck loop is knitted through one of the held loops. During knitting, yarn M is fed at a low position to all needles N and yarn S is fed at a higher position to alternate needles. Needles N have forwardly inclined hooks and, associated with each needle are pattern and auxiliary jacks P and J. A pattern drum operates levers 40 which select the jacks P to be elevated by cam 41, the selection being reversed with each rotation of the needle cylinder. Thus the needles are divided into two groups which after passing the yarn feed at two levels, the needles at the higher level are lowered by cam 30 and all the needles pass under stitch ...

Protein expression

RHEUMATOID ARTHRITUS TREATMENT

ANTITHROMBIN

PHOSPHINYLCYCLOALKYLCARBONYL AND PHOSPHINYLCYCLOALKENYLCARBONYL DIPEPTIDES

Thiol-active cysteinyl peptides for rheumatoid arthritis treatment

Mercaptoacyldipeptides

Compounds having the formula and alkyl esters and salts thereof. R1 is hydrogen, alkanoyl, benzoyl or R2 is hydrogen, alkyl, or phenylalkyl; n is 0 or 1; and A1 and A2 each is an ???-amino or ???-imino acid residue joined through a peptide bond, have hypotensive activity.

Protein variants and uses thereof

HUMAN ANTITHROMBIN III DNA SEQUENCES THEREFORE EXPRESSION VEHICLES AND CLONING VECTORS CONTAINING SUCH SEQUENCES AND CELL CULTURES TRANSFORMED THEREBY A PROCESS FOR EXPRESSING HUMAN ANTITHROMBIN III AND PHARMACEUTICAL COMPOSITIONS COMPRISING IT

RECOMBINANT DNA PRODUCT

HETEROCYCLIC AMIDES

FUSION PROTEINS CONTAINING N-TERMINAL FRAGMENTS OF HUMAN SERUM ALBUMIN

Immune response modulator alpha-2 macroglobulin

Carboxyalkyl dipeptides, proceeded for their pharmaceutical production and compositions the container.

Method of preparation of iminodiacides substituted.

Methods of producing effective recombinant serine protease inhibitors and uses of these inhibitors

Crystalline forms of et02c-ch2(r)cgl-aze-pab-oh

Crystalline forms of EtO2C-CH2-(R)Cgl-Aze-Pab-OH

There is provided EtO2C-CH2-(R)Cgl-Aze-Pab-OH, or pharmaceutically-acceptable salt thereof, in a form which is substantially crystalline. It has been found that crystalline forms of Et02C-CH2-(R)Cgl-Aze-Pab-OH have a high chemical and solid state stability when compared to amorphous forms of the compound.

Oligomeric peptides and their use for the treatment of HIV infections

Immune response modulator alpha-2 macroglobulin complex.

Activation of a2-macroglobulin (a2m)with a nucleophilic compounds followed by incubation of the activated a2m at elevated temperature with a biomolecule results, in covalent incorporation of the intact biomolecule into the a2m molecule, without the use of proteinases. The thus-formed structurally defined and stable complex may be used as an antigen for stimulating the immune response, for example, in the form of a vaccine. Enhanced antigen presentation of a particular biomolecule is provided, especially for thosed that are poorly immunogenic; reduction of the immunodominance of particular epitopes is also provided.

Crystalline forms of et02c-ch2(r)cgl-aze-pab-oh

Methods of producing effective recombinant serine protease inhibitors and uses of these inhibitors.

A method of producing a recombinant serine protease inhibitor capable of effectively modulating serine protease activity is provided. Compositions capable of modulating serine protease activity and use of such compositions to regulate inflammatory processes in cells are also provided.

Oligomeric peptides and their use for the treatment of hiv infections

Crystalline forms of eto2c-ch2-(r)cgl-aze-pab-oh.

Inhibitors of métalloendopeptidase neutral in the treatment of the hypertention.

Method of purifying protein

Methods of producing effective recombinant serine protease inhibitors and uses of these inhibitors

Inhibition of retrovirus infection

Immune response modulator alpha-2 macroglobulin complex.

Derived from acids isoindoledicarboxylic, their preparation and pharmaceutical compositions the container.

Composed having a nootrope effect, agents containing these compounds, and their use in the treatment and disease prevention of the disorders of the cognitive function.

Derived from cyclopeptides, usable like selective inhibitors, with respect to proteases with active serine.

Process of synthesis of acid alpha amino NR alkyls and their esters. Application to the synthesis of carboxyalkyl dipeptides.

Pharmaceutical Dosage Forms for the Release of Active Compounds

Pharmaceutical form containing at least an active compound and a polymeric matrix, wherein said polymeric matrix comprises at least one polymer of cationic nature and at least one biodegradable polymer, process for the preparation thereof, pharmaceutical formulations comprising said pharmaceutical form, and their uses. The pharmaceutical form provides enhanced absorption of active compounds across the mucosa.

Hydrophilic polymer compound having anticoagulation effect

A hydrophilic polymer compound includes a polymer compound which inhibits platelet adhesion, and a compound that inhibits blood coagulation reaction, bound to the polymer compound.

Treatment of a disease associated with retinal degenerative disorder

Treatment of a disease associated with retinal degenerative disorder. The present invention relates to human Transferrin or an active fragment thereof for use in the treatment of a disease associated with retinal degenerative disorder.

PROCESS FOR PRODUCTION OF BIVALIRUDIN

The invention relates to methods for the preparation of high purity Bivalirudin. The polypeptide is prepared in a high purity of at least 98.5% (by HPLC), wherein the total impurities amount to less than 1.5%, comprising not more than 0.5% [Asp-Bivalirudin] and each is impurity less than 1.0%, and preferably having a purity of at least about 99.0% by HPLC, wherein the total impurities amount to less than 1.0%, comprising not more than 0.5% [Asp-Bivalirudin] and each impurity is less than 0.5%. 149-. (canceled)50. A method of preparing Bivalirudin comprising: wherein the preparation of the Bivalirudin amino acid sequence comprises adding amino acids to the resin, and', 'wherein one or more of the amino acids being added to the resin has a protecting group on its α-amine residue that does not require a strong acid for removal;, '(a) preparing a Bivalirudin amino acid sequence coupled to a hyper acid labile resin that contains one or more protected amino acids,'}(b) treating the Bivalirudin amino acid sequence coupled to the resin with a cleavage solution comprising an acid to remove the Bivalirudin amino acid sequence from the resin and obtain crude Bivalirudin comprising an unprotected Bivalirudin amino acid sequence;(c) recovering crude Bivalirudin; and(d) purifying the crude Bivalirudin.51. The method of claim 50 , wherein the hyper acid labile resin is selected from the group consisting of a 2-Cl-Trt-Cl resin claim 50 , a HMPB-BHA resin claim 50 , a Rink acid resin claim 50 , and a TGT alcohol resin.52. The method of claim 50 , wherein the preparation of the Bivalirudin amino acid sequence further comprises removing the protecting group on the α-amine residue with a solution comprising a base.53. The method of claim 50 , wherein the protecting group on the α-amine residue of the one or more amino acids being added to the resin is Fmoc.54. The method of claim 50 , wherein the Bivalirudin amino acid sequence is coupled to the hyper acid labile resin via a highly ...

PROCESS FOR PRODUCTION OF BIVALIRUDIN

The invention relates to methods for the preparation of high purity Bivalirudin. The polypeptide is prepared in a high purity of at least 98.5% (by HPLC), wherein the total impurities amount to less than 1.5%, comprising not more than 0.5% [Asp-Bivalirudin] and each is impurity less than 1.0%, and preferably having a purity of at least about 99.0% by HPLC, wherein the total impurities amount to less than 1.0%, comprising not more than 0.5% [Asp-Bivalirudin] and each impurity is less than 0.5%. 149-. (canceled)50. A composition of solid phase synthetic Bivalirudin having a purity of at least about 98.5% as measured by high performance liquid chromatography (HPLC) after cleavage from a hyper acid labile resin and purification.51. The composition of claim 50 , wherein the solid phase synthetic Bivalirudin has Asp-Bivalirudin in an amount no greater than 0.5% as measured by HPLC.52. The composition of claim 50 , wherein the solid phase synthetic Bivalirudin comprises one or more impurities claim 50 , wherein each impurity is less than 1.0% as measured by HPLC.53. The composition of claim 50 , wherein the solid phase synthetic Bivalirudin has a purity of at least about 99.0% as measured by HPLC.54. The composition of claim 53 , wherein the solid synthetic Bivalirudin comprises one or more impurities claim 53 , wherein each impurity is less than 0.5% as measured by HPLC.55. A composition of solid phase synthetic Bivalirudin comprising one or more impurities claim 53 , wherein each impurity is less than 1.0% as measured by high performance liquid chromatography (HPLC) after cleavage from a hyper acid labile resin and purification.56. The composition of claim 55 , wherein the solid phase synthetic Bivalirudin has Asp-Bivalirudin in an amount no greater than 0.5% as measured by HPLC.57. The composition of claim 55 , wherein the solid phase synthetic Bivalirudin has a purity of at least about 99.0% as measured by HPLC.58. The composition of claim 57 , wherein each impurity is ...

PROCESS FOR PRODUCTION OF BIVALIRUDIN

The invention relates to methods for the preparation of high purity Bivalirudin. The polypeptide is prepared in a high purity of at least 98.5% (by HPLC), wherein the total impurities amount to less than 1.5%, comprising not more than 0.5% [Asp-Bivalirudin] and each is impurity less than 1.0%, and preferably having a purity of at least about 99.0% by HPLC, wherein the total impurities amount to less than 1.0%, comprising not more than 0.5% [Asp-Bivalirudin] and each impurity is less than 0.5%. 149-. (canceled)50. A composition of hybrid synthetic Bivalirudin having a purity of at least about 98.5% as measured by high performance liquid chromatography (HPLC) after purification.51. The composition of claim 50 , wherein the hybrid synthetic Bivalirudin has Asp-Bivalirudin in an amount no greater than 0.5% as measured by HPLC.52. The composition of claim 50 , wherein the hybrid synthetic Bivalirudin comprises one or more impurities claim 50 , wherein each impurity is less than 1.0% as measured by HPLC.53. The composition of claim 50 , wherein the hybrid synthetic Bivalirudin has a purity of at least about 99.0% as measured by HPLC.54. The composition of claim 53 , wherein the hybrid synthetic Bivalirudin comprises one or more impurities claim 53 , wherein each impurity is less than 0.5% as measured by HPLC.55. A composition of hybrid synthetic Bivalirudin comprising one or more impurities claim 53 , wherein each impurity is less than 1.0% as measured by high performance liquid chromatography (HPLC) after purification.56. The composition of claim 55 , wherein the hybrid synthetic Bivalirudin has Asp-Bivalirudin in an amount no greater than 0.5% as measured by HPLC.57. The composition of claim 55 , wherein the hybrid synthetic Bivalirudin has a purity of at least about 99.0% as measured by HPLC.58. The composition of claim 57 , wherein each impurity is less than 0.5% as measured by HPLC.59. A pharmaceutical composition comprising hybrid synthetic Bivalirudin and at least ...

PROCESS FOR PRODUCTION OF BIVALIRUDIN

The invention relates to methods for the preparation of high purity Bivalirudin. The polypeptide is prepared in a high purity of at least 98.5% (by HPLC), wherein the total impurities amount to less than 1.5%, comprising not more than 0.5% [Asp-Bivalirudin] and each is impurity less than 1.0%, and preferably having a purity of at least about 99.0% by HPLC, wherein the total impurities amount to less than 1.0%, comprising not more than 0.5% [Asp-Bivalirudin] and each impurity is less than 0.5%. 149-. (canceled)50. A method of preparing Bivalirudin comprising: (i) adding amino acids to a hyper acid labile resin to form a portion of a Bivalirudin amino acid sequence coupled to the resin, wherein one or more of the amino acids being added to the resin has a protecting group on its α-amine residue that does not require a strong acid for removal; and', '(ii) treating the portion of the Bivalirudin amino acid sequence coupled to the resin with a cleavage solution comprising an acid to remove the portion of the Bivalirudin amino acid sequence from the resin and obtain the fragment of Bivalirudin;, '(a) preparing two or more fragments of Bivalirudin that contain one or more protected amino acids, wherein one or more of the fragments is formed by(b) coupling the two or more fragments together to form a final amino acid sequence of Bivalirudin, wherein one or more of the amino acids in the final amino acid sequence has at least one protecting group;(c) treating the final amino acid sequence with a solution comprising a strong acidic composition to remove protecting groups from the amino acids in the final amino acid sequence and obtain crude Bivalirudin;(d) recovering crude Bivalirudin; and(e) purifying the crude Bivalirudin.51. The method of claim 50 , wherein the hyper acid labile resin is selected from the group consisting of a 2-Cl-Trt-Cl resin claim 50 , a HMPB-BHA resin claim 50 , a Rink acid resin claim 50 , and a TGT alcohol resin.52. The method of claim 50 , wherein ...

NOVEL THROMBIN INHIBITORS

The present invention provides isolated peptides, variants and fragments thereof that are capable of binding with a high level of specificity to thrombin and inhibiting its activity. There is also provided uses of such peptides in methods of diagnosis and treatment, coating of medical devices and nucleic acids encoding the same. 1. An isolated thrombin inhibitor comprising an amino acid sequence selected from the group comprising SEQ ID NO: 1 , a variant or fragment thereof , and SEQ ID NO: 2 , a variant or fragment thereof , SEQ ID NO: 22 , a variant or fragment thereof , SEQ ID NO: 23 , a variant or fragment thereof , SEQ ID NO: 24 , a variant or fragment thereof and SEQ ID NO: 25 , a variant or fragment thereof.2. The isolated thrombin inhibitor of claim 1 , wherein the amino acid sequence is selected from the group comprising SEQ ID NO: 3 claim 1 , SEQ ID NO: 4 claim 1 , SEQ ID NO: 5 claim 1 , SEQ ID NO: 6 claim 1 , SEQ ID NO: 7 claim 1 , SEQ ID NO: 8 claim 1 , SEQ ID NO: 9 claim 1 , SEQ ID NO: 10 claim 1 , SEQ ID NO: 11 claim 1 , SEQ ID NO: 12 claim 1 , SEQ ID NO: 13 claim 1 , SEQ ID NO: 14 claim 1 , SEQ ID NO: 15 claim 1 , SEQ ID NO: 16 claim 1 , SEQ ID NO: 17 claim 1 , SEQ ID NO: 18 claim 1 , SEQ ID NO: 19 claim 1 , SEQ ID NO: 20 claim 1 , SEQ ID NO: 21 claim 1 , SEQ ID NO: 22 claim 1 , SEQ ID NO: 23 claim 1 , SEQ ID NO: 24 and SEQ ID NO: 25.3. The isolated thrombin inhibitor of claim 1 , wherein said inhibitor has an amino acid sequence selected from the group consisting of SEQ ID NO: 2 claim 1 , SEQ ID NO: 9 claim 1 , SEQ ID NO: 10 claim 1 , SEQ ID NO: 11 claim 1 , SEQ ID NO: 12 claim 1 , SEQ ID NO: 13 claim 1 , SEQ ID NO: 14 claim 1 , SEQ ID NO: 15 claim 1 , SEQ ID NO: 16 claim 1 , SEQ ID NO: 17 claim 1 , SEQ ID NO: 18 claim 1 , SEQ ID NO: 19 claim 1 , SEQ ID NO: 20 and SEQ ID NO: 21.4. The isolated thrombin inhibitor of claim 1 , wherein said inhibitor inhibits thrombin fibrinogenolytic activity and/or inhibits thrombin amidolytic activity.5. The thrombin ...

SYNTHETIC PLATELETS

Provided herein are particles comprising a polymer substrate comprising one or more hyaluronic acid chains; and two or more peptide moieties bound directly to each hyaluronic acid chain. In some embodiments, the two or more peptide moieties comprising collagen-binding peptide (CBP) and von Willebrand binding peptide (VBP). The particles can be utilized in, e.g., methods of hemostatic treatment. 1. A particle comprisinga polymer substrate comprising one or more hyaluronic acid chains; andtwo or more peptide moieties bound directly to each hyaluronic acid chain, the two or more peptide moieties comprising collagen-binding peptide (CBP) and von Willebrand binding peptide (VBP).2. The particle of claim 1 , wherein the two or more peptide moieties comprise:a peptide comprising SEQ ID NO: 1 and a peptide comprising at least one of SEQ ID NOs: 2, 6, and 7.3. The particle of claim 1 , wherein the two or more peptide moieties comprise:a peptide comprising SEQ ID NO: 1 and a peptide comprising SEQ ID NO: 7.4. The particle of claim 1 , wherein the two or more peptide moieties further comprise at least one of a platelet binding peptide; a wound healing peptide; a tPA-binding peptide; a clot binding peptide; an anti-thrombotic peptide; and a thrombolytic peptide.5. The particle of claim 4 , wherein the two or more peptide moieties comprise two or more of:a peptide comprising SEQ ID NO: 1; a peptide comprising SEQ ID NO: 2;a peptide comprising SEQ ID NO: 3; a peptide comprising SEQ ID NO: 4; a peptide comprising SEQ ID NO: 5; a peptide comprising SEQ ID NO: 8; a peptide comprising SEQ ID NO: 7; heparin; and tPA.6. The particle of claim 1 , wherein the two or more peptide moieties further comprise fibrinogen mimetic peptide (FMP).7. The particle of claim 6 , wherein the two or more peptide moieties comprise:a peptide comprising SEQ ID NO: 1; a peptide comprising at least one of SEQ ID NOs: 2, 6, and 7; and a peptide comprising at least one of SEQ ID NOs: 3, 4, 8, and 9.8. The ...

Crystalline forms of plasma kallikrein inhibitors

Pure crystalline forms of 1-benzyl-N-(4-carbamimidoylbenzyl)-1H-pyrazole-4-carboxamide acetate, and an amorphous form, pharmaceutical compositions thereof, and methods for making the same, are disclosed.

FACTOR XIA MACROCYCLE INHIBITORS BEARING A NON-AROMATIC P2' GROUP

The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same. 9. (canceled)10. A pharmaceutical composition comprising one or more compounds according to and a pharmaceutically acceptable carrier or diluent.11. A method for the treatment and/or prophylaxis of a thromboembolic disorder claim 1 , comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a stereoisomer claim 1 , a tautomer claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein the thromboembolic disorder is selected from arterial cardiovascular thromboembolic disorders claim 1 , venous cardiovascular thromboembolic disorders claim 1 , and thromboembolic disorders in the chambers of the heart or in the peripheral circulation.12. A method according to claim 11 , wherein the thromboembolic disorder is selected from unstable angina claim 11 , an acute coronary syndrome claim 11 , atrial fibrillation claim 11 , myocardial infarction claim 11 , transient ischemic attack claim 11 , stroke claim 11 , atherosclerosis claim 11 , peripheral occlusive arterial disease claim 11 , venous thrombosis claim 11 , deep vein thrombosis claim 11 , thrombophlebitis claim 11 , arterial embolism claim 11 , coronary arterial thrombosis claim 11 , cerebral arterial thrombosis claim 11 , cerebral embolism claim 11 , kidney embolism claim 11 , pulmonary embolism claim 11 , and thrombosis resulting from medical implants claim 11 , devices claim 11 , or procedures in which blood is exposed to an artificial surface that promotes thrombosis.13. (canceled)14. A compound ...

Method of producing bivalirudin

The present disclosure provides a method of producing bivalirudin using a peptide fragment or peptide fragments on solid phase peptide synthesis that minimizes, or eliminates, the production of bivalirudin molecules having too few or too many glycine residues.

COMPOSITION AND METHOD FOR REDUCING THROMBOCYTOPENIA

Disclosed herein are methods of reducing or preventing thrombocytopenia, in a clinically relevant manner, that is caused by chemotherapy or radiation therapy by administering plinabulin to a subject. 1. A method of reducing thrombocytopenia , comprising administering plinabulin or a pharmaceutically acceptable salt thereof to a subject in need thereof.2. The method of claim 1 , wherein the thrombocytopenia is induced by administration of one or more chemotherapeutic agents or by administration of radiation therapy.3. The method of or claim 1 , wherein the thrombocytopenia is induced by administration of one or more chemotherapeutic agents.4. The method of any one of to claim 1 , wherein the thrombocytopenia is induced by administration of gemcitabine or a chemotherapeutic composition comprising gemcitabine.5. The method of any one of to claim 1 , wherein the thrombocytopenia is induced by administration of docetaxel or a chemotherapeutic composition comprising Docetaxel.6. A method of increasing platelet production in a patient claim 1 , comprising administering plinabulin or a pharmaceutically acceptable salt thereof to the subject in need thereof.7. A method of stimulating platelet formation in a patient claim 1 , comprising administering plinabulin or a pharmaceutically acceptable salt thereof to the subject in need thereof.8. A method of increasing platelet count in a patient receiving a chemotherapeutic treatment claim 1 , comprising administering plinabulin or a pharmaceutically acceptable salt thereof to the subject in need thereof.9. A method of preventing thrombocytopenia in a subject receiving a chemotherapeutic treatment claim 1 , comprising administering plinabulin or a pharmaceutically acceptable salt thereof to the subject in need thereof.10. A method of increasing platelet count in a subject administered gemcitabine claim 1 , comprising administering plinabulin or a pharmaceutically acceptable salt thereof to a subject in need thereof.11. A method of ...

Method for preparing heterodimer snake venom protein

Provided are recombinant plasmids containing the heterodimeric snake venom protein Agkisacutacin A chain gene and Agkisacutacin B chain gene, respectively, cell strains containing the recombinant plasmids, and a method for expressing the heterodimeric snake venom protein Agkisacutacin. The expression level of Agkisacutacin in the present method exceeds 10 mg/L, and the purity level can reach more than 95% by means of two steps of purification. 1. Plasmid pPIC9K-A shown in , wherein the sequence of Agkisacutacin A chain gene is shown in SEQ ID NO. 1.2. Plasmid pUCZ-B shown in , wherein the sequence of Agkisacutacin B chain gene is shown in SEQ ID NO.2.3. A transformant comprising one or a combination of the plasmid of .4. The transformant according to claim 3 , which expresses recombinant heterodimer snake venom protein claim 3 , wherein the heterodimer snake venom protein consists of two peptide chains of A chain and B chain claim 3 , the A chain amino acid sequence is shown in SEQ ID NO.3 claim 3 , and the B chain amino acid sequence is shown in SEQ ID NO.4.5Pichia. The transformant according to claim 4 , wherein the transformant is a strain.6Pichia pastoris. The transformant according to claim 5 , which has the accession number CCTCC No. M2016358 and is classified as GS115.7. (canceled)8. A method of mass expression of a recombinant heterodimer snake venom protein claim 5 , comprising the steps of:{'claim-ref': {'@idref': 'CLM-00004', 'claim 4'}, 'Batch phase: introducing a secondary seed of the transformant according to into a basic salt medium with pH 4.0 to 6.0, adding glycerin to 4% to amplify bacteria and when the dissolved oxygen (DO) content rises sharply, the batch phase ends;'}Conversion phase: continuously supplying 50% glycerol solution containing 10-15 ml/L PTM1, with a flow rate of 10-15 ml/h/L, which process lasting until to a wet weight of 190-200 g/L;Methanol induction phase: stopping adding glycerin when the wet weight reaching 190-200 g/L, adding ...

METHOD OF PREVENTING OF SYSTEMIC-TO-PULMONARY-ARTERY SHUNT THROMBOSIS

The present invention is directed to the use of cangrelor for the treatment and/or prevention of shunt thrombosis in patients suffering congenital heart diseases undergoing shunt surgery. The invention is also directed to the use of cangrelor for the treatment and/or prevention of stent thrombosis in pediatric patients undergoing stent implantation. 1. A method of treating or preventing shunt thrombosis in a patient comprising administering a pharmaceutical composition comprising cangrelor to the patient wherein the patient is suffering from congenital heart disease.2. The method of wherein the patient is undergoing shunt surgery.3. The method of wherein the shunt surgery is selected from the group consisting of systemic-to-pulmonary artery shunt claim 2 , Blalock-Taussing shunt claim 2 , central shunt claim 2 , and right ventricle to pulmonary artery palliative shunt.4. The method of wherein the shunt surgery is systemic-to-pulmonary artery shunt surgery.5. A method of treating or preventing shunt thrombosis in a patient comprising administering a pharmaceutical composition comprising cangrelor to the patient claim 3 , wherein the patient is a pediatric patient suffering from congenital heart disease.6. The method of wherein the patient is undergoing shunt surgery or stent implantation.7. The method of wherein the shunt surgery or stent implantation is selected from the group consisting of systemic-to-pulmonary artery shunt claim 6 , Blalock-Taussing shunt claim 6 , central shunt claim 6 , right ventricle to pulmonary artery palliative shunt claim 6 , and ductus arterious stent.8. The method of wherein the patients suffer single ventricle physiology palliated with systemic-to-pulmonary artery shunt.9. The method of wherein the administration is intravenous.10. The method of wherein the intravenous administration is a continuous infusion.11. The method of wherein the amount of cangrelor administered is between about 0.1 and about 4 μg/kg/min.12. The method of ...

PENTOSAN POLYSULFATE, PHARMACEUTICAL COMPOSITION, AND ANTICOAGULANT

The present invention provides pentosan polysulfate having a weight average molecular weight of 5000 or less and a content of acetyl groups of 0% to 2.0% by mass, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The pentosan polysulfate of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof exhibits an anti-Xa activity and an anti-Xa/anti-IIa activity ratio, which are suitable for practical use, and is useful as a pharmaceutical composition such as an anticoagulant. 18-. (canceled)9. A hardwood-derived pentosan polysulfate having a weight average molecular weight of 5000 or less and a content of acetyl groups of 0% to 0.3% by mass , or a pharmaceutically acceptable salt thereof , or a pharmaceutically acceptable solvate thereof.10. The pentosan polysulfate according to claim 9 , which has a content of acetyl groups of 0% by mass claim 9 , or a pharmaceutically acceptable salt thereof claim 9 , or a pharmaceutically acceptable solvate thereof.11. The pentosan polysulfate according to claim 9 , which has a weight average molecular weight of 4000 or less claim 9 , or a pharmaceutically acceptable salt thereof claim 9 , or a pharmaceutically acceptable solvate thereof.13. The pentosan polysulfate according to claim 12 , wherein claim 12 , in Formula 1 claim 12 , X represents sodium claim 12 , or a pharmaceutically acceptable salt thereof claim 12 , or a pharmaceutically acceptable solvate thereof.14. The pentosan polysulfate according to claim 9 , which has a dispersion degree of 1.00 or more and 1.20 or less claim 9 , or a pharmaceutically acceptable salt thereof claim 9 , or a pharmaceutically acceptable solvate thereof.15. A pharmaceutical composition comprising claim 9 , as an active ingredient claim 9 , the pentosan polysulfate according to claim 9 , or a pharmaceutically acceptable salt thereof claim 9 , or a pharmaceutically acceptable solvate ...

Process for the Production of Bivalirudin

The present invention relates to a process for the production of bivalirudin, a 20-mer peptide of formula H- D -Phe 1 -Pro-Arg-Pro-Gly 5 -Gly-Gly-Gly-Asn-Gly 10 -Asp-Phe-Glu-Glu-Ile 15 -Pro-Glu-Glu-Tyr-Leu 20 -OH   (I) via a convergent five-fragment synthesis, and to several peptide intermediates thereof.

GUANIDYL-CONTAINING P2Y12 RECEPTOR ANTAGONIST AND PREPARATION METHOD AND APPLICATION THEREOF

A P2Y12 receptor antagonist containing a guanidyl, and a preparation method and the use thereof. In particular, the present disclosure provides a pyridazinone-guanidine compound that is a compound of structural formula (I), or a stereoisomer of the above-mentioned compound, a pro-drug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof. Such a compound has multiple pharmacological activities, especially has an inhibitory effect on platelet aggregation, and can be used for preparing an anti-platelet aggregation pharmaceutical composition. 4. A pharmaceutical composition claim 1 , comprising a compound according to claim 1 , or stereoisomer claim 1 , pro-drug claim 1 , pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof claim 1 , and optionally a pharmaceutical acceptable excipient.5. A use for preparing medicines for anti-platelet aggregation of the compound according to claim 1 , or stereoisomer claim 1 , pro-drug claim 1 , pharmaceutically acceptable salt claim 1 , pharmaceutically acceptable solvate thereof or of the pharmaceutical composition of .6. A use for preparing a medicine for treating cardiovascular and cerebrovascular claim 1 , especially thromboembolic diseases of the compound according to claim 1 , or stereoisomer claim 1 , pro-drug claim 1 , pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof or the pharmaceutical composition of .7. A use for preparing a medicine for treating or preventing unstable angina pectoris (coronary heart disease) claim 1 , percutaneous transluminal coronary angioplasty (PCTA) claim 1 , myocardial infarction claim 1 , peripheral thrombolysis claim 1 , and atherosclerotic thrombotic arterial complications of the compound according to claim 1 , or stereoisomer claim 1 , pro-drug claim 1 , pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof or the pharmaceutical composition of .8. A use for ...

ANTIPLATELET ACTIVITY OF THE ACANTHUS MOLLIS SEEDS' TOTAL EXTRACT AND ITS CONSTITUENTS

seeds' methanol extract exhibits an advantageous antiplatelet activity towards AA- and TRAP-6-induced platelet aggregation, i.e., inhibits two important pathways leading to platelet aggregation (pathway mediated by TxAformed from AA by the action of COX-1 as well as thrombin receptor PAR-1-mediated platelet aggregation, respectively). The antiplatelet activity towards AA is due to the DIBOA-Glc content. The DIBOA-Glc activity is enhanced in the presence of Verbascoside and/or Isoverbascoside. The antiplatelet activity towards TRAP-6 is exclusively attributed to Isoverbascoside. The constituents of seeds is a new therapeutic agent for CVD patients which can replace aspirin in aspirin resistant patients (DIBOA-Glc alone or in combination with Verbascoside or/and Isoverbascoside) and also may be used as a specific antagonist of the platelet thrombin receptor PAR-1 (Isoverbascoside). Moreover, the total extract may be used as a supplement with aspirin and a P2Y12 antagonist in some patients. 16-. (canceled)7Acanthus mollis. Use of a total methanolic extract of seeds for preparation of a medicament or a supplement for human use having a dual antiplatelet and , therefore , antithrombotic activity by specifically inhibiting an AA-pathway and a PAR-1 receptor pathway.8. Use of DIBOA-Glc for preparing a medicament for human use having an antiplatelet effect and , therefore , antithrombotic activity by specifically inhibiting an arachidonic acid-induced platelet aggregation.9. Use of Isoverbascoside for preparing a medicament for human use having a specific inhibitory action towards platelet aggregation mediated through a PAR-1 receptor.10. Use of a combination of DIBOA-Glc with Isoverbascoside or Verbascoside , or both , for preparing a medicament for human use exhibiting a synergistic effect towards arachidonic acid-induced platelet aggregation. The present invention relates to the antiplatelet activity expressed by the total extract of seeds as well by each one of its ...

ANTIBODIES TO COAGULATION FACTOR XIa AND USES THEREOF

In one aspect, antibodies, or antigen-binding fragments thereof, that specifically bind to activated Factor XI (FXIa) are provided. Also provided are methods of obtaining such antibodies and nucleic acids encoding the same. In another aspect, compositions and therapeutic prevention of thrombotic diseases, disorders or conditions are provided. In another aspect, anti-idiotype antibodies that bind anti-FXIa antibodies of the disclosure, as well as compositions comprising the anti-idiotype antibodies, methods of obtaining the antibodies and nucleic acids encoding the same, are also provided.

Monoclonal antibodies against the active site of factor XI and uses thereof

The present invention provides novel anti-factor XI (FXI) antibodies and compositions comprising such antibodies. The anti-FXI antibodies of the invention specifically bind to the active center of FXI and inhibit the functional activity of FXI. The invention further provides humanized versions of the anti-FXI antibodies that are useful in the prevention and treatment of conditions in which pathological thrombus formation or thrombo-embolism are involved. The invention further provides nucleic acid molecules encoding the anti-FXI antibodies, cells expressing the anti-FXI antibodies and methods for producing the anti-FXI antibodies.

ANTICOAGULANT COMPOSITIONS AND USES THEREOF

The invention relates to novel compositions managing or inhibiting blood clotting and related uses. 1. A liquid parenteral pharmaceutical composition comprising (i) about 2 μg/ml to about 20 mg/ml dabigatran or a pharmaceutically acceptable salt thereof.2. The composition of claim 1 , further comprising (ii) about 0 to about 0.2 M of an acidulant; and (iii) about 0 to about 75% (weight/volume) of a polar aprotic agent claim 1 , based on the total volume of the composition.3. A method for managing or inhibiting blood coagulation during a procedure in a subject claim 1 , comprising administering parenterally to the subject or the blood thereof an effective amount of dabigatran so that the blood dabigatran concentration is about 200 ng/ml to about 30 claim 1 ,000 ng/ml.4. The method of claim 3 , wherein the blood dabigatran concentration is about 2 claim 3 ,400 ng/ml to about 20 claim 3 ,000 ng/ml.5. The method of claim 4 , wherein the blood dabigatran concentration is about 9 claim 4 ,600 ng/ml to about 20 claim 4 ,000 ng/ml.6. The method of claim 3 , wherein the administering step comprises administering to the subject or the blood thereof a liquid pharmaceutical composition comprising about 2 μg/ml to about 20 mg/ml dabigatran or a pharmaceutically acceptable salt thereof.7. The method of claim 3 , wherein the procedure is a cardiopulmonary bypass procedure or an extracorporeal circulation procedure.8. The method of claim 3 , further comprising conducting the cardiopulmonary bypass or extracorporeal circulation procedure claim 3 , wherein the dabigatran is administered to the subject before or during the procedure.9. The method of claim 3 , wherein the dabigatran is administered to a prime volume of the subject in vitro in a heart-lung machine for the procedure.10. The method of claim 3 , further comprising administering to the subject an effective amount of a second anticoagulant.11. The method of claim 10 , wherein the second anticoagulant is a direct-acting ...

Application of earthworm protein peptide in preparation of medicine for preventing and/or treating thrombotic disease

The present invention relates to application of an earthworm protein peptide in the preparation of a medicine for preventing and/or treating a thrombotic disease, which belongs to the technical field of prevention and treatment of cardiovascular and cerebrovascular diseases. The earthworm protein peptide is one or more members selected from a group consisting of Leu-Val-Thr-Leu-Gly-Asn-Glu, Leu-Leu-Ala-Pro-Pro, Leu-Leu-Pro-Ala-Pro and Thr-Val-Ala-Pro-Phe. The earthworm protein peptide provided by the present invention can significantly inhibit the thrombin activity, thus achieving the anticoagulant effect. In vivo, the earthworm protein peptide provided by the present invention has a significant inhibitory effect on carrageenan-induced rat tail thrombosis; and in vitro and in vivo studies of rats with thrombus, the earthworm protein peptide provided by the present invention shows good anticoagulant effects. The earthworm protein peptide provided by the present invention has effects of thrombosis inhibition, thrombolysis, anticoagulation and fibrinolysis promotion, and can effectively prevent and treat thrombotic disease.

PHARMACEUTICAL COMPOSITIONS AND METHODS FOR THE TREATMENT OF THROMBOSIS AND DELIVERY BY MEDICAL DEVICES

A pharmaceutical composition and a method of using the pharmaceutical composition for the treatment of thrombosis are provided. The pharmaceutical composition can include a mixture of proteolytic enzymes, and optionally, additional compounds. The pharmaceutical composition can include an antiaggregatory or anti-thrombotic compound, such as Lisini racemici acetylsalicylase. The method can include administering the pharmaceutical composition to a patient in need thereof, including administration of the pharmaceutical composition to a thrombus until the thrombus is dissolved. The method can also include administering one or more balloon catheters to the patient. 1. A method for treating thrombosis in a patient in need thereof , comprising:administering a pharmaceutical composition comprising a proteolytic enzyme or mixture of proteolytic enzymes to the patient, andadministering a first balloon catheter to the patient.2. The method according to claim 1 , wherein the first balloon catheter comprises a balloon claim 1 , a first tube claim 1 , and a second tube claim 1 , the first and second tubes each having an inlet located at the same side of the balloon claim 1 ,wherein the first tube has an outlet inside of the balloon to inflate the balloon, and the second tube has an outlet located on another end of the balloon distant from the inlet to be located between the balloon and the thrombus.3. The method according to claim 1 , further comprising administering a second balloon catheter to the patient.4. The method according to claim 1 , wherein the pharmaceutical composition further comprises Lisini racemici acetylsalicylase.5. The method according to claim 4 , wherein the mixture of proteolytic enzymes comprises Krill enzymes.6. A method of treating thrombosis in a patient claim 4 , comprising:a) blocking a vessel containing a thrombus downstream of said thrombus with a first balloon catheter to form a small volume between the first balloon catheter and the thrombus,b) ...

RECOMBINANT PROTHROMBIN ANALOGUES AND USES THEREOF

During the process of coagulation, prothrombin is activated to α-thrombin by prothrombinase. Key residues in the structure of prothrombin allow for modulation of the activation of prothrombin. In certain embodiments, a recombinant prothrombin with at least one point mutation or deletion is provided. 1. A method of modulating coagulation in a subject who has or is at risk of having unwanted coagulation , the method comprising:identifying an individual susceptible to unwanted coagulation; andadministering an impotent recombinant prothrombin molecule with an amino acid modification from residue 472 to 487, to the individual.2. The method of claim 1 , wherein the modification occurs in at least one of amino acid residues Ser claim 1 , Leu claim 1 , and Gln.3. The method of claim 1 , wherein the modification is a modification of amino acid residue Ser.4. The method of claim 1 , wherein the modification is a modification of amino acid residue Leu.5. The method claim 1 , wherein the modification is a modification of amino acid residue Gln.6. The method claim 1 , wherein the modification is a modification of amino acid residues Ser claim 1 , Leu claim 1 , and Gln.7. The method of claim 1 , wherein the modification is a deletion of at least one of amino acid residues Ser claim 1 , Leu claim 1 , and Gln.8. The method of claim 1 , wherein the prothrombin molecule comprises a deletion of amino acid residues Ser claim 1 , Leu claim 1 , and Glnor a substitution of Ser claim 1 , Leu claim 1 , and Glnwith alanine.9. The method of claim 1 , wherein the prothrombin molecule comprises a substitution of amino acid residues Ser claim 1 , Leu claim 1 , and Glnwith alanine.10. A method for producing an impotent prothrombin molecule having an amino acid. sequence of prothrombin with an amino acid modification from residue 472 to 487 claim 1 , the method comprising:(a) introducing into a host cell an expression vector which contains a nucleotide sequence which encodes a prothrombin molecule ...

SUBCUTANEOUS ADMINISTRATION OF A P2Y12 RECEPTOR ANTAGONIST

The present invention relates to a P2Y12 receptor antagonist selected from the group consisting of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4 carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester, (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol, and (1S,2R,3S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol, or a pharmaceutically acceptable salt thereof, for use as a medicament by subcutaneous or intradermal administration. 1. A method for the prevention or treatment of a disease selected from acute arterial thromboses and acute venous thromboses , the method comprising administering a pharmaceutically effective amount of a P2Y12 receptor antagonist , or a pharmaceutically acceptable salt thereof , to a patient in need thereof; wherein the P2Yreceptor antagonist is 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester; and wherein the P2Yreceptor antagonist is administered and/or is to be administered to the patient by intradermal or subcutaneous administration.2. The method according to claim 1 , wherein the disease is selected from acute coronary syndromes claim 1 , myocardial infarction claim 1 , peripheral ischaemia claim 1 , amaurosis claim 1 , sudden cardiac death claim 1 , ischaemic stroke and transient ischaemic attack.3. The method according to claim 1 , wherein the P2Yreceptor antagonist is administered prior to hospitalization.4. The method according to claim 3 , wherein the P2Yreceptor antagonist is administered by patient self-administration.5. A method for the emergency treatment of suspected acute coronary syndromes claim 3 , the method comprising administering a pharmaceutically effective amount of a P2Y12 ...

MACROCYCLIC DERIVATIVES AS FACTOR XIA INHIBITORS

Macrocyclic derivatives, preparation methods therefor and pharmaceutical compositions comprising said derivatives, and uses thereof as therapeutic agents, especially as factor XIa inhibitors and in drugs for treating and preventing thromboembolisms and other diseases. Specifically disclosed is a compound represented by formula (I), and an isomer and pharmaceutically acceptable salt thereof. 8. (canceled)9. (canceled)10. (canceled)16. (canceled)17. (canceled)19. (canceled)20. (canceled)21. (canceled)22. The compound as defined in claim 1 , the isomer thereof or the pharmaceutically acceptable salt thereof claim 1 , wherein claim 1 , the Tis N claim 1 , CH or CF.26. A pharmaceutical composition comprising a therapeutically effective amount of the compound in claim 1 , the isomer thereof or the pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.27. A method for inhibiting factor XIa in a subject in need thereof claim 1 , comprising: administering an effective amount of the compound as defined in claim 1 , the isomer thereof or the pharmaceutically acceptable salt thereof to the subject.28. A method for inhibiting factor XIa in a subject in need thereof claim 26 , comprising: administering an effective amount of the pharmaceutical composition as defined in to the subject. This application claims the following priorityApplication number: CN201910668575.3, application date: Jul. 23, 2019.The present disclosure relates to a novel class of macrocyclic derivatives, preparation method thereof and pharmaceutical composition comprising the derivatives, and uses thereof as therapeutic agents, especially as inhibitors of factor XIa and drugs for the treatment and prevention of diseases such as thromboembolism.Antithrombotic drugs are mainly divided into antiplatelet drugs (such as clopidogrel, aspirin, ticagrelor, etc.), anticoagulant drugs (such as heparin, low molecular weight heparin, hirudin, warfarin, etc.) and thrombolytic drugs ( ...

Derivatized dendrimer with low citotoxicity for in vivo, ex vivo, in vitro or in situ chelation of heavy metals or actinides

The present invention considers derivatized nanomolecules with proven effectiveness to bind to actinides, more specifically uranium, during in vivo, ex vivo, in vitro or in situ assays. When assayed in vivo, the invention showed a reduction in at least kidney damage due to exposition to uranium.

APTAMER-BASED ANALYTE ASSAYS

The present invention relates to aptamer-based assays to capture and/or detect analytes comprising primary and secondary aptamers, as well as compositions comprising such primary and secondary aptamers, wherein analytes comprise small molecules that offer limited mutually non-competitive epitopes to antibodies, that is, with limited ability to measure in non-competitive sandwich assays using primary and secondary antibodies or primary and secondary aptamers. 1. An assay for testing a sample for the presence and/or amount of an analyte of interest comprising contacting at least a portion of the sample with effective amounts of (1) a primary aptamer comprising a core sequence that binds to the analyte and (2) an anti-aptamer which is complementary to at least a portion of the primary aptamer , wherein the primary aptamer and/or anti-aptamer comprise a detectable moiety(ies) which detect whether the primary aptamer and anti-aptamer are bound to each other or unbound; and wherein a primary aptamer bound to the analyte does not bind to its anti-aptamer.2. The assay of wherein the primary aptamer comprises a fluorescent label.3. The assay of claim 1 , where the anti-aptamer comprises a quencher moiety.4. The assay of claim 1 , where the anti-aptamer is complementary to at least 85 percent of the primary aptamer5. The assay of claim 4 , where the anti-aptamer is complementary to at least 95 percent of the primary aptamer.6. The assay of claim 1 , where the analyte is selected from the group consisting of glucose claim 1 , hydrocortisone claim 1 , phenylalanine claim 1 , dehydroisoandrosterone claim 1 , deoxycortisone claim 1 , testosterone claim 1 , aldosterone claim 1 , dopamine claim 1 , sphingosine-1-phosphate claim 1 , serotonin claim 1 , melatonin claim 1 , tyrosine claim 1 , tobramycin claim 1 , amikacin claim 1 , methylene blue claim 1 , ammonium claim 1 , boronic acid claim 1 , and epinephrine.7. A method of detecting or measuring the presence or amount of an ...

METHOD FOR THE TREATMENT OF IMMUNE THROMBOCYTOPENIA

The disclosure relates to a method of treating or preventing immune (idiopathic) thrombocytopenic purpura (ITP) in a human in need thereof, the method comprising administering to the human in the range of 1 to 5 doses of an anti-FcRn antibody or antigen binding fragment thereof over a treatment period of 1 to 12 weeks, wherein the aggregate dose in the treatment period is in the range of 1 to 30 mg per kg. 1. A method of treating or preventing immune (idiopathic) thrombocytopenic purpura (ITP) in a human in need thereof , the method comprising administering to the human in the range of 1 to 5 doses of an anti-FcRn antibody or antigen binding fragment thereof over a treatment period of 1 to 12 weeks , wherein the aggregrate dose in the treatment period is in the range of 1 to 30 mg per kg.2. An anti-FcRn antibody or binding fragment thereof for use in the treatment or prevention of immune (idiopathic) thrombocytopenic purpura (ITP) in a human in need thereof , comprising administering to the human in the range of 1 to 5 doses of the antibody or antigen binding fragment thereof over a treatment period of 1 to 12 weeks , wherein the aggregrate dose in the treatment period is in the range of 1 to 30 mg per kg.3. Use of an anti-FcRn antibody or antigen binding fragment thereof for the manufacture of a medicament for the treatment or prevention of immune (idiopathic) thrombocytopenic purpura (ITP) , comprising administering in the range of 1 to 5 doses of the antibody or binding fragment thereof over a treatment period of 1 to 12 weeks , wherein the aggregrate dose in the treatment period is in the range of 1 to 30 mg per kg4. A method , an anti-FcRn antibody or antigen binding fragment thereof or a use according to any one of to , wherein the antibody or binding fragment thereof comprises:a. a heavy chain or heavy chain fragment having a variable region, wherein said variable region comprises three CDRs having the sequences given in SEQ ID NO: 1 for CDR H1, SEQ ID NO: 2 ...

BINDING PROTEINS TO THE HUMAN THROMBIN RECEPTOR, PAR4

The present disclosure is directed to human protease activated receptor 4 (PAR4) binding proteins (e.g. antibodies). In particular, anti-PAR4 binding proteins which are antagonists of human PAR4, as well as methods and uses thereof. 1. A protease activated receptor 4 (PAR4) binding protein which is an anti-PAR4 recombinant or synthetic or monoclonal antibody or antigen-binding fragment thereof , wherein the binding protein inhibits cleavage of cell surface expressed human PAR4 by equal to or greater than 50% in the presence of thrombin.2. The PAR4-binding protein according to claim 1 , wherein the protein inhibits (i) 60% or greater or (ii) 70% or greater or (iii) 80% or greater cleavage of cell surface expressed PAR4 in the presence of thrombin.3. The PAR4-binding protein according to or claim 1 , wherein the protein inhibits 90% or greater cleavage of cell surface expressed PAR4 in the presence of thrombin.4. The PAR4-binding protein according to any one of to claim 1 , which specifically binds to an epitope which spans the thrombin cleavage site of PAR4.5. The PAR4-binding protein according to claim 4 , wherein the epitope comprises the sequence APRGY and wherein the thrombin cleavage site corresponds to RG.6. The PAR4-binding protein according to or claim 4 , wherein the epitope comprises or consists of a sequence selected from ILPAPRGY or APRGYPGQV.7. The PAR4-binding protein according to any one of to wherein the antibody binds to the Ala120 and/or the Thr120 variant of human PAR4.8. The PAR4-binding protein according to any one of to claim 4 , wherein the protein does not bind claim 4 , or does not substantially bind to claim 4 , human PAR1 claim 4 , PAR2 claim 4 , or PAR3.15. The PAR4-binding protein according to or claim 4 , wherein the VL comprises the CDR2 sequence GAS (SEQ ID NO:28).23. The PAR4-binding protein according to any one of to claim 4 , wherein the VL comprises the CDR2 sequence AAS (SEQ ID NO:51).25. The PAR4-binding protein according any ...

SOLID PHASE PEPTIDE SYNTHESIS VIA SIDE CHAIN ATTACHMENT

The present application discloses peptides and peptaibols of high purity may be obtained by solid phase peptide synthesis using as the starting resin hydroxy amino acids, hydroxy amino acid amides, hydroxy amino alcohols or small peptides containing hydroxy amino acids attached to polymers through their side chain. 2. (canceled)3. A method for the preparation of the resin conjugates of the formulae I-VI of comprising the following steps:preparing a hydroxyl containing amino acid or amino alcohol or peptide derivative that is unprotected on at least one of the side chains of the contained hydroxyl amino acids or of the contained amino alcohol or selectively deprotecting the hydroxyl amino acid or the hydroxyl amino alcohol or a peptide derivative at the side chain of the hydroxyl amino acid or the hydroxyl amino alcohol and then attaching it to a suitable resin by its reaction with a resin halide, wherein the resin is selected from the group of the trityl type resins and linkers or the benzhydryl type resins or the benzyl-type resins; andan alcohol or thioalcohol is added to mask any unreacted resin halide.4. A process for the preparation of monoalkylated Fmoc-amino di-alcohols claim 1 , the process comprising the reaction of the Fmoc-di-amino alcohol with alkylhalide in the presence of a base such as a tertiary amine base in an organic solvent claim 1 , such as dichloromethane; and wherein alkyl is a triarylmethyl selected from trityl claim 1 , 4-methyltrityl claim 1 , 4-methoxytrityl and 2-chlorotrityl.5. A process for the solid phase synthesis of biologically active free or partially protected peptides claim 1 , cyclic peptides and peptaibols claim 1 , wherein the process comprises the use of the resin conjugates of as functionalized resins in the solid phase peptide synthesis.6. A peptide of the formula E-D-2-Nal-Cys(A)-Tyr(C)-D-Trp(F)-Lys(E)-Val-Cys(A)-Thr(Resin)-NHwherein:D—designates the chirality of the amino acid that follows as a D-amino acid;each A is ...

ANTI-COAGULANT AGENT, ANTICOAGULATION DEVICE, BLOOD COAGULATION CURING METHOD, VASCULAR ENDOTHELIAL CELL FUNCTION IMPROVING METHOD, AND METABOLISM IMPROVING METHOD

An object of the present invention is to provide a method other than the scavenger function against reactive oxygen species for molecular hydrogen to improve life functions, in the fields of medical science, medical care, health industry, agriculture, animal husbandry, and fisheries, and an effect of improving mitochondrial function utilizing the same, and an anticoagulation agent, a blood coagulation curing device, a blood coagulation curing method, and a vascular endothelial cell function improving method. Provided is an anticoagulation agent composed of hydrogen gas or an anticoagulation agent composed of water containing molecular hydrogen. Preferably the anticoagulation agent is such that molecular hydrogen improves mitochondrial function by increasing mitochondrial hydrogenase activity, thereby improving blood clotting. 1. (canceled)2. (canceled)3. (canceled)4. An anticoagulation device characterized in that the device delivers hydrogen gas or a mixed gas containing hydrogen to a subject.5. The anticoagulation device according to claim 4 , wherein molecular hydrogen cures blood coagulation by increasing mitochondrial hydrogenase activity.6. A blood coagulation curing method claim 4 , including a step of administering water containing molecular hydrogen or hydrogen gas to a subject.7. A vascular endothelial cell function improving method claim 4 , comprising a step of administering water containing molecular hydrogen or hydrogen gas to a subject.8. The vascular endothelial cell function improving method according to claim 7 , wherein molecular hydrogen improves a vascular endothelial cell function by inhibiting generation of reactive oxygen species through a mitochondrial electron rectification.9. A method of protecting mitochondria claim 7 , wherein molecular hydrogen improves a mitochondrial function or protects mitochondria by inhibiting generation of reactive oxygen species through mitochondrial electron rectification.10. A metabolism improving method claim ...

TRICYCLIC HETEROARYL-SUBSTITUTED QUINOLINE AND AZAQUINOLINE COMPOUNDS AS PAR4 INHIBITORS

Disclosed are compounds of Formula (I) to (VIII): 5. The compound according to or a salt thereof claim 4 , wherein Ris:(i) pyridazinyl, benzo[d]oxazolyl, benzo[d]thiazolyl, pyrrolopyridinyl, tetrahydroisoquinolinyl, methyl imidazopyridinyl, or oxo-dihydrobenzo[d]oxazolyl;(ii) phenyl substituted with zero to 1 substituent selected from ≥CN and —C(O)(morpholinyl);{'sub': 3', '3', '1-2', '2', '3', '2', '2', '3', '3', '3', '2', '2', '3', '2', '2', '3', '2, '(iii) pyridinyl substituted with zero to two substituents independently selected from F, Cl, Br, —CN, —OH, —CH, —CF, Calkoxy, phenoxy, —NH, —N(CH), —C(O)NH, —C(O)OC(CH), —C(O)OCH, —CH(OH)CHOH, —CH═CH, —NHC(O)CH, —OCHCHN(CH), phenyl, pyrrolidinyl, thiophenyl, and methyl triazolyl; or'}{'sub': '3', '(iv) pyrimidinyl substituted with Cl or —CH.'}6. The compound according to or a salt thereof claim 1 , wherein said compound is selected from:(R)-(4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7,8-dihydro-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]thiazol-7-yl)methyl(6-methoxypyridin-3-yl)carbamate (1);(S)-(4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7,8-dihydro-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]thiazol-7-yl)methyl(6-methoxypyridin-3-yl)carbamate (2);(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methyl-7,8-dihydro-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]thiazol-7-yl)methyl(2-hydroxypyridin-4-yl)carbamate (3);(R)-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methyl-7,8-dihydro-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]thiazol-7-yl)methyl(6-methoxypyridin-3-yl)carbamate (4);(R)-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methyl-7,8-dihydro-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]thiazol-7-yl)methyl pyridin-3-ylcarbamate (5);(R)-(6-chloro-8-(2-methoxy-7-methylquinoxalin-5-yl)-2,3-dihydro-[1,4]dioxino[2,3-e]benzofuran-3-yl)methyl(6-methylpyridin-3-yl)carbamate (7);(R)-(6-chloro-8-(2-methoxy-7-methylquinoxalin-5-yl)-2,3-dihydro-[1,4]dioxino[2,3-e]benzofuran-3-yl)methyl(2-methylpyridin-4-yl)carbamate (8);(R)-(6-chloro-8-(2-methoxy-7-methylquinoxalin-5-yl)-2,3- ...

ACETOGENIN MOLECULES HAVING ANTIPLATELET AND/OR ANTITHROMBIC ACTIVITIES, AND METHODS AND COMPOSITIONS THEREOF

The present disclosure relates, according to some embodiments, to acetogenin molecules that may have antiplatelet and/or antithronibic activities. In some embodiments, the present disclosure relates to an acetogenin molecule selected from the group comprising: Acetogenin 1, Acetogenin 2, Acetogenin 3, Acetogenin 4, Acetogenin 5, Acetogenin 6, Acetogenin 7, Acetogenin 8, Acetogenin 9, Acetogenin 10, Acetogenin 11, Acetogenin 12, Acetogenin 13, and Acetogenin 14. The present disclosure relates in some embodiments to a pharmaceutical composition comprising a first acetogenin molecule and a delivery vehicle, wherein the first acetogenin molecule is selected from the group comprising: Acetogenin 1, Acetogenin 2, Acetogenin 3, Acetogenin 4, Acetogenin 5, Acetogenin 6, Acetogenin 7, Acetogenin 8, Acetogenin 9, Acetogenin 10, Acetogenin 11, Acetogenin 12, Acetogenin 13, and Acetogenin 14. 1. An acetogenin molecule selected from the group comprising: Acetogenin 1 , Acetogenin 2 , Acetogenin 3 , Acetogenin 4 , Acetogenin 5 , Acetogenin 6 , Acetogenin 7 , Acetogenin 8 , Acetogenin 9 , Acetogenin 10 , Acetogenin 11 , Acetogenin 12 , Acetogenin 13 , and Acetogenin 14 , and hydrates , dehydrates , acetoxylates , deacetoxylates , acid salts , base salts , stereoisomers , or derivatives thereof , wherein the acetogenin molecule has at least one of an antiplatelet activity and an antithrombic activity.2. A pharmaceutical composition comprising a pharmaceutically-effective amount of one or more acetogenin molecules , each selected from the group consisting of: Acetogenin 1 , Acetogenin 2 , Acetogenin 3 , Acetogenin 4 , Acetogenin 5 , Acetogenin 6 , Acetogenin 7 , Acetogenin 8 , Acetogenin 9 , Acetogenin 10 , Acetogenin 11 , Acetogenin 12 , Acetogenin 13 , and Acetogenin 14; anda pharmaceutically-acceptable agent.3. A pharmaceutical composition according to claim 2 , wherein the one or more acetogenin molecules comprises a first acetogenin molecule and a second acetogenin molecule ...

USE OF ALGINATE OLIGOMERS IN THE ANTICOAGULATION THERAPY OF SUBJECTS AT RISK OF BLOOD CLOTS WHICH HAVE AN ABNORMALLY DENSE MICROSTRUCTURE

An alginate oligomer for use in the anticoagulation therapy of a human or non-human vertebrate subject at risk of blood clots which have an abnormally dense microstructure. In certain embodiments, the incidence of blood clots which have an abnormally dense microstructure in the subject is reduced and/or the occurrence of blood clots which have an abnormally dense microstructure in the subject is inhibited and/or the abnormal microstructure of the subject's clots is normalized. Corresponding methods of anticoagulation therapy and products of use therein are further provided. 1. (canceled)2. A method for the anticoagulation therapy of a human or non-human vertebrate subject at risk of blood clots which have an abnormally dense microstructure , said method comprising administering an alginate oligomer to said subject when in need thereof.3. The method of claim 2 , wherein said anticoagulation therapy comprises treating or preventing a disease or condition associated with blood clots which have an abnormally dense microstructure4. The method of claim 2 , wherein the incidence of blood clots which have an abnormally dense microstructure in the subject is reduced and/or the occurrence and/or formation of blood clots which have an abnormally dense microstructure in the subject is inhibited.5. The method of claim 2 , wherein the microstructure density of blood clots in the subject is reduced and/or a normal microstructure density in blood clots during the formation thereof in the subject is promoted.6. A method to reduce the incidence of claim 2 , or to inhibit the occurrence of claim 2 , or inhibit the formation of claim 2 , blood clots which have an abnormally dense microstructure in a human or non-human vertebrate subject at risk of blood clots which have an abnormally dense microstructure claim 2 , said method comprising administering an alginate oligomer to said subject.7. A method to reduce the density of blood clot microstructure or to promote a normal microstructure ...

Soluble Complement Receptor Type 1 Variant Conjugates and Uses Thereof

A soluble complement receptor type 1 (sCR1) conjugate comprising a sCR1 variant and a) a protein comprising an antigen binding domain that binds to a target and inhibits signaling by or via the target; orb) a protein comprising an antigen binding domain that binds to a blood coagulation factor. 1. A soluble complement receptor type 1 (sCR1) conjugate comprising: a) an amino acid sequence corresponding to amino acids 42 to 939 of SEQ ID NO: 1;', 'b) an amino acid sequence corresponding to amino acids 490 to 1392 of SEQ ID NO: 1; and, '(i) a sCR1 variant comprising an amino acid sequence selected from the group consisting of(ii) a protein comprising an antigen binding domain that binds to a target and inhibits signaling by or via the target.2. The sCR1 conjugate of claim 1 , wherein the sCR1 variant comprises:(i) an amino acid sequence corresponding to amino acids 42 to 1392 of SEQ ID NO: 1;(ii) an amino acid sequence corresponding to amino acids 42 to 939 of SEQ ID NO: 1;(iii) an amino acid sequence corresponding to amino acids 490 to 1392 of SEQ ID NO: 1; or(iv) an amino acid sequence corresponding to amino acids 490 to 1971 of SEQ ID NO: 1.3. The sCR1 conjugate of or claim 1 , wherein the sCR1 variant comprises an amino acid sequence corresponding to amino acids 42 to 1392 of SEQ ID NO: 1.4. The sCR1 conjugate according to any one of to claim 1 , wherein the sCR1 variant has increased complement inhibitory activity compared to a sCR1 comprising a sequence set forth in SEQ ID NO: 2.5. The sCR1 conjugate according to any one of to claim 1 , wherein the sCR1 variant has increased complement inhibitory activity in the classical pathway claim 1 , the lectin pathway and/or alternative complement pathway compared to a sCR1 comprising a sequence set forth in SEQ ID NO: 2.6. The sCR1 conjugate according to any one of to claim 1 , wherein the sCR1 variant comprises long homologous repeat (LHR) regions selected from the group consisting of:(i) LHR-A and LHR-B;(ii) LHR-A, LHR- ...

COMPOSITIONS AND METHODS OF DETECTING AND TREATING THROMBOSIS AND VASCULAR PLAQUES

The invention provides nanodroplets labeled with targeting ligands that are useful in the detection and treatment of vascular thromboses (e.g., fibrin clots) and vascular plaques, or related diseases and conditions, as well as methods of preparation and use thereof. 1. An aqueous emulsion or suspension of microbubbles and/or nanodroplets having one or more fibrin-binding ligands attached thereto.2. The aqueous emulsion or suspension of claim 1 , wherein each of microbubbles and/or nanodroplets is conjugated to a plurality of the fibrin-binding ligands.3. The aqueous emulsion or suspension of claim 1 , wherein substantially all of microbubbles and/or nanodroplets is conjugated to a plurality of the fibrin-binding ligands.4. The aqueous emulsion or suspension of claim 1 , wherein the one or more fibrin-binding ligands are fibrin-binding peptides having from about 11 to about 16 amino acids.5. The aqueous emulsion or suspension of claim 4 , wherein the fibrin-binding peptides are selected from Table 1.6. The aqueous emulsion or suspension of claim 1 , wherein the fibrin-binding ligands are conjugated to the microbubbles and/or nanodroplets via a polyethylene glycol (PEG) linker.7. The aqueous emulsion or suspension of claim 6 , wherein the PEG linker has a number average molecular weight (MW) in the rage from about 1 claim 6 ,000 to about 10 claim 6 ,000 Daltons.8. The aqueous emulsion or suspension of claim 1 , wherein the microbubbles and/or nanodroplets are filled with a gaseous material.9. The aqueous emulsion or suspension of claim 1 , wherein the gaseous material comprises a fluorinated gas.10. The aqueous emulsion or suspension of claim 9 , wherein the fluorinated gas is selected from perfluoromethane claim 9 , perfluoroethane claim 9 , perfluoropropane claim 9 , perfluorocyclopropane claim 9 , perfluorobutane claim 9 , perfluorocyclobutane claim 9 , perfluoropentane claim 9 , perfluorocylcopentane claim 9 , perfluorohexane claim 9 , perfluorocyclohexane claim 9 ...

METHODS FOR INCREASING PLATELET COUNT BY INHIBITING BILIVERDIN IXBETA REDUCTASE

The present disclosure provides methods of treating a human having a disease or disorder that would benefit from increasing platelet counts. The method involves inhibiting the enzyme activity of biliverdin IXβ reductase (BLVRB) activity or inhibiting the expression of BLVRB gene. 120.-. (canceled)21. A method of treating a subject having a disease or disorder that would benefit from increasing platelet counts , the method comprising:administering to the subject therapeutically effective amount of an agent that inhibits biliverdin IXβ reductase (BLVRB) enzymatic activity and increases the platelet count of the subject.22. The method of claim 21 , wherein the disease or disorder is selected from the group consisting of a decreased production of platelets claim 21 , an increased breakdown of platelets claim 21 , an increased use of platelets claim 21 , and trapping of platelets in the spleen.23. The method of claim 22 , wherein the decreased production of platelets is due to a condition selected from the group consisting of cancer claim 22 , anemia claim 22 , viral infection claim 22 , chemotherapy and heavy alcohol consumption.24. The method of claim 23 , wherein the cancer is leukemia.25. The method of claim 22 , wherein the increased breakdown of platelets is due to a condition selected from the group consisting of pregnancy claim 22 , autoimmune disease claim 22 , bacterial infection and medication.26. The method of claim 25 , wherein the autoimmune disease is selected from the group consisting of lupus and rheumatoid arthritis.27. The method of claim 25 , wherein the medication is selected from the group consisting of heparin claim 25 , quinine claim 25 , sulfa-containing antibiotics and anticonvulsants.28. The method of claim 22 , wherein the increased use of platelets is due to a thrombotic thrombocytopenic purpura condition.29. The method of claim 22 , wherein the increased use of platelets is thrombocytopenia.30. The method of claim 21 , wherein decreased ...

USE OF 3,4,7-TRIHYDROXYISOFLAVONE OR 3-METHOXYDAIDZEIN IN PREPARATION OF DRUG FOR INHIBITING PLATELET AGGREGATION AND THROMBOSIS

A use of 3,4,7-trihydroxyisoflavone or 3-methoxydaidzein is provided for implementation in preparation of a drug for inhibiting platelet aggregation. The 3,4,7-trihydroxyisoflavone or 3-methoxydaidzein has a significant inhibition effect on platelet aggregation, and bleeding test conducted with these embodiments show that all of the mice administrated with 3,4,7-trihydroxyisoflavone and 3-methoxydaidzein did not show any significant hemorrhagic activity, while the control group, i.e., the group administrated with the same concentration of clopidogrel showed very significant hemorrhagic activity. Thus, the use of such a drug of the present invention is useful in inhibiting platelet aggregation, and the use of such a drug can reduce the risk of bleeding, is safe for use, and expands the clinical and medical applications thereof. 110.-. (canceled)12. The use of claim 11 , wherein a dosage form of the drug is an oral preparation.13. The use of claim 12 , wherein an administration dosage of 3 claim 12 ,4 claim 12 ,7-trihydroxyisoflavone depending on patients of different body weights is ≥10 μmol/kg.14. The use of claim 12 , wherein an administration dosage of 3-methoxydaidzein depending on patients of different body weights is ≥100 μmol/kg.15. The use of claim 11 , wherein the platelet aggregation is generated as induced by collagen and adenosine diphosphate.16. The use of claim 15 , wherein a dosage form of the drug is an oral preparation.17. The use of claim 16 , wherein an administration dosage of 3 claim 16 ,4 claim 16 ,7-trihydroxyisoflavone depending on patients of different body weights is ≥10 μmol/kg.18. The use of claim 16 , wherein an administration dosage of 3-methoxydaidzein depending on patients of different body weights is ≥100 μmol/kg.20. The use of claim 19 , wherein a dosage form of the drug is an oral preparation.21. The use of claim 20 , wherein an administration dosage of 3 claim 20 ,4 claim 20 ,7-trihydroxyisoflavone depending on patients of ...

AGENT FOR ELIMINATING SENESCENT CELLS

The present invention provides an agent or pharmaceutical composition for eliminating senescent cells, comprising an SGLT2 inhibitor. 111-. (canceled)12. A method for eliminating senescent cells , comprising administrating an effective amount of an SGLT2 inhibitor to a subject in need thereof.13. A method for preventing or treating a disease in which the disease state is expected to be improved by eliminating senescent cells , comprising administrating an effective amount of an SGLT2 inhibitor to a subject in need thereof.14. The method according to claim 12 , wherein the SGLT 2 inhibitor is at least one selected from the group consisting of low molecular weight compounds claim 12 , SGLT2 expression inhibitors claim 12 , and SGLT2-specific binding substances.15. The method according to claim 12 , wherein the SGLT 2 inhibitor is at least one selected from the group consisting of canagliflozin claim 12 , empagliflozin claim 12 , ipragliflozin claim 12 , dapagliflozin claim 12 , luseogliflozin claim 12 , tofogliflozin claim 12 , sergliflozin etabonate claim 12 , remogliflozin etabonate claim 12 , ertugliflozin claim 12 , sotagliflozin claim 12 , and pharmaceutically acceptable salts thereof.16. The method according to claim 13 , wherein the disease in which the disease state is expected to be improved by eliminating the senescent cells is a senescence-related disease.17. The method according to claim 16 , wherein the senescence-related disease is at least one selected from the group consisting of heart failure claim 16 , arteriosclerosis claim 16 , arteriosclerotic cerebrovascular or cardiovascular disease claim 16 , hypertension claim 16 , cerebral infarction claim 16 , cerebral hemorrhage claim 16 , dyslipidemia claim 16 , pulmonary fibrosis claim 16 , emphysema claim 16 , skeletal muscle atrophy (sarcopenia) claim 16 , osteoarthritis claim 16 , dementia claim 16 , frailty claim 16 , cancer claim 16 , chronic kidney disease claim 16 , cataract claim 16 , glaucoma ...

SOLID PHASE PEPTIDE SYNTHESIS

An improved method of deprotection in solid phase peptide synthesis is disclosed. In particular the deprotecting composition is added in high concentration and small volume to the mixture of the coupling solution, the growing peptide chain, and any excess activated acid from the preceding coupling cycle, and without any draining step between the coupling step of the previous cycle and the addition of the deprotection composition for the successive cycle. Thereafter, the ambient pressure in the vessel is reduced with a vacuum pull to remove the deprotecting composition without any draining step and without otherwise adversely affecting the remaining materials in the vessel or causing problems in subsequent steps in the SPPS cycle. 1. A system for microwave assisted solid phase peptide synthesis comprising:a microwave source positioned to direct microwave radiation into a microwave cavity;a microwave transparent reaction vessel in said cavity; anda vacuum source connected to said reaction vessel.2. A method according to further comprising a trap between said reaction vessel and said vacuum Source.3. A method according to wherein said cavity can support a single mode of microwave radiation at the microwave frequencies produced by said microwave source.4. A method according to where wherein said reaction vessel comprises:a (glass) frit for draining liquids from said reaction vessel; anda spray head for delivery of reagents to said reaction vessel.5. A system according to further comprising a fiber optic temperature probe positioned to read the temperature of said reaction vessel in said cavity (for controlling the microwave power delivered to said reaction vessel).6. A system according to that incorporates nitrogen pressure to transfer all reagents and to provide an inert environment during peptide synthesis.7. A system according to further comprising a nitrogen source in communication with said reaction vessel to bubble the contents of said reaction vessel for mixing ...

METHOD FOR THE TREATMENT OF THROMBOEMBOLISM

A method for the treatment of thromboembolism comprising administering a thrombolytic agent directly to the thromboembolism in the presence of ultrasound. The total dose of thrombolytic agent administered is between 1 and 12 mg and the time over which the total dose is delivered is less than 15 hours. 1. A method for a treatment of a thromboembolism comprising administering a thrombolytic agent directly to the thromboembolism in a presence of ultrasound , wherein a total dose of the thrombolytic agent administered is between 1 and 12 mg and a time over which the total dose is delivered is less than 15 hours.2. The method according to wherein the total dose of the thrombolytic agent administered is between 1 and 10 mg.3. The method according to wherein the total dose of the thrombolytic agent administered is between 2 and 6 mg.4. The method according to wherein the total dose of the thrombolytic agent administered is between 2 and 4 mg.5. The method according to wherein the total dose of the thrombolytic agent administered is 2 mg.6. The method according to wherein the thrombolytic agent is delivered as a bolus dose.7. The method according to wherein the thrombolytic agent is infused at a rate of 2 mg/hour.8. The method according to wherein the thrombolytic agent is infused at rate of 1 mg/hour.9. The method according to wherein the thrombolytic agent is recombinant tissue plasminogen activator (r-tPA) or urokinase.10. The method according to wherein the ultrasound is provided at a frequency of between 2-3 MHz.11. The method according to wherein a maximum pulse power of the ultrasound is 50 W.12. A method for a treatment of a pulmonary embolism comprising:providing a catheter with a fluid delivery lumen having at least one outlet and a plurality of ultrasound radiating members, said ultrasound radiating members arranged in a region of the fluid outlet and being connected to an electrical power source which is located externally to the catheter and arranged to drive ...

HUMAN ANTIBODIES AND PROTEINS

The present invention provides composite proteins, including antibodies, which show reduced immunogenicity. In particular, composite antibodies for use in humans are provided, in particular antibodies which have been modified to remove one or more T-cell epitopes. Methods for generating such proteins are also provided. 1. A modified antibody or antigen-binding fragment thereof wherein the heavy and light chain variable regions of the modified antibody or antigen-binding fragment are each composed of two or more segments of amino acid sequence from one or more other antibodies or antigen-binding fragments , whereby the segments are neither whole CDRs nor framework regions.236-. (canceled)37. A method for screening composite antibody variable regions comprising:generating a library of genes encoding composite antibody variable regions derived from multiple segments of amino acid sequence of 2 to 31 amino acids long from other antibodies or antigen-binding fragments, wherein the multiple segments are neither whole CDRs nor whole framework regions;screening the composite antibody variable regions to avoid T cell epitopes; andexpressing at least a portion of the library and screening the expressed antibody variable regions for binding to one or more antigens of interest.38. The method of claim 37 , wherein the multiple segments of amino acid sequence are derived from human antibodies.39. The method of claim 37 , wherein the expressed antibody variable regions form part of expressed antibodies.40. The method of claim 37 , wherein the expressed antibody variable regions form part of expressed antigen-binding fragments.41. The method of claim 40 , wherein the expressed antigen-binding fragments are selected from Fv's claim 40 , Fab's claim 40 , Fab2's claim 40 , SCA's claim 40 , single domain antibodies claim 40 , and multimeric derivatives of each of these.42. A method for producing copies of a composite antibody variable region of interest comprising:generating a library ...

METHOD FOR PRODUCING PROTEIN BY PRECIPITATION

The present invention provides a method for producing a target protein in the form of a fusion protein at a high recovery ratio. The present invention relates to a method for producing a fusion protein made of a protein having a self-assembly capability and a target protein comprising the following steps (1) to (4): 1. A method for producing a fusion protein made of a protein having a self-assembly capability and a target protein , comprising the following steps (1) to (4):(1) preparing a solution containing the fusion protein; {'br': None, 'the recovery ratio (%)=[an amount of the fusion protein in a solution obtained in step (4) /{the amount of the fusion protein in the solution obtained in step (4)+an amount of the fusion protein in a solution after solid separation in step (3)}]×100;'}, '(2) adjusting a pH of the solution obtained in step (1) to such a pH that a recovery ratio calculated according to the following equation is 10% or more, wherein'}(3) separating a solid from the solution obtained in step (2); and(4) dissolving the solid separated in step (3) into a solution having a pH of 12 or below but higher than the pH of the solution obtained in step (2) by 0.1 or more.2. The method according to claim 1 , wherein the protein having a self-assembly capability is a cell surface protein.3. The method according to claim 2 , wherein the cell surface protein is a CspB mature protein or a portion thereof.4. The method according to claim 3 , wherein the CspB mature protein or the portion thereof is any one of the following (a) and (b):(a) a protein consisting of an amino acid sequence of SEQ ID NO: 3; and(b) a protein having a homology of 95% or more with the amino acid sequence of SEQ ID NO: 3.5. The method according to claim 3 , wherein the portion of the CspB mature protein is a sequence consisting of 6 to 250 amino acid residues from the N-terminus of the CspB mature protein.6. The method according to claim 5 , wherein the portion of the CspB mature protein is ...

SOLID PHASE PEPTIDE SYNTHESIS

An improved method of deprotection in solid phase peptide synthesis is disclosed. In particular the deprotecting composition is added in high concentration and small volume to the mixture of the coupling solution, the growing peptide chain, and any excess activated acid from the preceding coupling cycle, and without any draining step between the coupling step of the previous cycle and the addition of the deprotection composition for the successive cycle. Thereafter, the ambient pressure in the vessel is reduced with a vacuum pull to remove the deprotecting composition without any draining step and without otherwise adversely affecting the remaining materials in the vessel or causing problems in subsequent steps in the SPPS cycle. 1. A method of deprotection in solid phase peptide synthesis in which the improvement comprises:adding the deprotecting composition in high concentration and small volume to the mixture of the coupling solution, the growing peptide chain, and any excess activated acid from the preceding coupling cycle; andwithout any draining step between the coupling step of the previous cycle and the addition of the deprotection composition for the successive cycle.2. A method according to further comprising adding the next successive acid to the mixture of the coupling solution claim 1 , the growing peptide chain following the step of adding the deprotection composition.3. A method according to comprising adding an organic base as the deprotecting composition.4. A method according to comprising adding an organic base selected from the group consisting of piperidine claim 3 , pyrrolidone claim 3 , and 4-methyl piperidine.5. A method according to comprising adding the organic base neat.6. A method according to comprising adding an organic base is a liquid added neat to the coupling solution mixture in a ratio of between about 1:20 and 1:3 based upon the volume of the coupling solution.7. A method according to comprising adding an organic base selected from ...

THERAPEUTIC COMPOUNDS AND COMPOSITIONS

Provided herein are compounds and compositions that inhibit Factor XIa or kallikrein and methods of using these compounds and compositions. 2. The crystalline pharmaceutically acceptable salt of claim 1 , having an XRPD pattern with characteristic peaks between and including the following values of 2θ in degrees: 7.4 to 7.8 claim 1 , 13.3 to 13.7 claim 1 , 14.3 to 14.7 claim 1 , 15.2 to 15.6 claim 1 , 16.3 to 16.7 claim 1 , 17.2 to 17.6 claim 1 , 18.8 to 19.2 claim 1 , 20.2 to 20.6 claim 1 , 23.5 to 23.9 claim 1 , and 26.7 to 27.1.3. The crystalline pharmaceutically acceptable salt of claim 1 , having an XRPD pattern with characteristic peaks at the following values of 2θ in degrees: 7.6 claim 1 , 13.5 claim 1 , 14.5 claim 1 , 15.4 claim 1 , 16.5 claim 1 ,17. 4 claim 1 , 19.0 claim 1 , 20.4 claim 1 , 23.7 claim 1 , and 26.9.4. The crystalline pharmaceutically acceptable salt of claim 1 , having an XRPD pattern with characteristic peaks between and including the following values of 2θ in degrees: 7.4 to 7.8 claim 1 , 14.3 to 14.7 claim 1 , 16.3 to 16.7 claim 1 , 18.8 to 19.2 claim 1 , and 20.2 to 20.6.5. The crystalline pharmaceutically acceptable salt of claim 1 , having an XRPD pattern with characteristic peaks at the following values of 2θ in degrees: 7.6 claim 1 , 14.5 claim 1 , 16.5 claim 1 , 19.0 claim 1 , and 20.4.6. The crystalline pharmaceutically acceptable salt of claim 1 , having an XRPD pattern substantially as depicted in .7. The crystalline pharmaceutically acceptable salt of claim 1 , having an XRPD pattern substantially as depicted in .8. The crystalline pharmaceutically acceptable salt of claim 1 , wherein the crystalline pharmaceutically acceptable salt melts at a Tfrom about 178° C. to about 192° C. as determined by DSC at a ramp rate of 10° C./min.9. The crystalline pharmaceutically acceptable salt of claim 1 , having a DSC thermogram substantially as depicted in .11. The amorphous pharmaceutically acceptable salt of claim 10 , having an ...

METHODS FOR SAFELY REDUCING THROMBOPOIETIN

Provided herein are methods, compounds, and compositions for safely reducing thrombopoietin in a cell or an individual. Such methods, compounds, and compositions maintain platelet count within a safe hemostatic range. Such methods, compounds, and compositions are useful to safely treat, prevent, or ameliorate a disease that can benefit from platelet count reduction in an individual. Such methods, compounds, and compositions are useful for treating or preventing diseases in which thrombopoietin contributes to the presence or activation of platelets contributes to and promotes disease initiation or progression, and/or adversely affects disease outcome. 1. A method of safely treating , preventing , or ameliorating a disease or condition in an individual , wherein TPO contributes to initiation of the disease or condition , the method comprising administering a compound comprising a safe TPO-specific inhibitor to the individual , thereby treating , preventing , or ameliorating the disease in the individual.2. A method of safely treating , preventing , or ameliorating a disease or condition in an individual , wherein TPO contributes to progression of the disease or condition , the method comprising administering a compound comprising a safe TPO-specific inhibitor to the individual , thereby treating , preventing , or ameliorating the disease in the individual.3. A method of safely treating , preventing , or ameliorating a disease or condition in an individual , wherein platelet activity contributes to initiation of the disease or condition , the method comprising administering a compound comprising a safe TPO-specific inhibitor to the individual , thereby treating , preventing , or ameliorating the disease in the individual.4. A method of safely treating , preventing , or ameliorating a disease or condition in an individual , wherein platelet activity contributes to progression of the disease or condition , the method comprising administering a compound comprising a safe ...

FACTOR VIII (FVIII) GENE THERAPY METHODS

Methods of using vvectors comprising nucleic acid and nucleic acid variants encoding FVIII protein are disclosed. In particular embodiments, a method of treating a human having hemophilia A includes administering a recombinant adeno-associated virus (rAAV) vector comprising a nucleic acid encoding Factor VIII (FVIII) or nucleic acid variant encoding Factor VIII (FVIII) having a B domain deletion (hFVIII-BDD). In some aspects, a nucleic acid variant has 95% or greater identity to SEQ ID NO:7 and/or a nucleic acid variant has no more than 2 cytosine-guanine dinucleotides (CpGs). In other aspects, a rAAV vector is administered to the human at a dose of less than about 6×10vector genomes per kilogram (vg/kg). 1. A method of treating a human having hemophilia A , comprising administering a recombinant adeno-associated virus (rAAV) vector wherein the vector genome comprises a nucleic acid variant encoding Factor VIII (FVIII) having a B domain deletion (hFVIII-BDD) , wherein the nucleic acid variant has 95% or greater identity to SEQ ID NO:7.2. A method of treating a human having hemophilia A , comprising administering a recombinant adeno-associated virus (rAAV) vector wherein the vector genome comprises a nucleic acid variant encoding Factor VIII (FVIII) having a B domain deletion (hFVIII-BDD) , wherein the nucleic acid variant has no more than 2 cytosine-guanine dinucleotides (CpGs).3. A method of treating a human having hemophilia A , comprising administering a recombinant adeno-associated virus (rAAV) vector wherein the vector genome comprises a nucleic acid encoding Factor VIII (FVIII) or encoding Factor VIII (FVIII) having a B domain deletion (hFVIII-BDD) , wherein the dose of rAAV vector administered to the human is less than 6×10vector genomes per kilogram (vg/kg).4. The method of or , wherein the dose of rAAV vector administered to the human is between about 1×10to about 1×10vg/kg , inclusive.5. The method of or , wherein the dose of rAAV vector administered to ...

Polymers and microspheres

New cationic polymers are provided that are suitable for the preparation of microspheres. The microspheres are capable of loading and eluting anionic species such as drugs and find use in i.a. embolotherapy

COAGULATION FACTOR BINDING PROTEINS AND USES THEREOF

A membrane targeted binding protein that binds to at least one blood coagulation factor, wherein the binding protein has pro-coagulant activity. 1) A membrane targeted binding protein that binds to at least one blood coagulation factor , wherein the binding protein has pro-coagulant activity.2) The protein of claim 1 , wherein the protein comprises a first binding region that specifically binds to the blood coagulation factor and a second binding region that specifically binds to a component of a plasma membrane of a mammalian cell claim 1 , wherein the first binding region has pro-coagulant activity.3. (canceled)4. The protein of or claim 1 , wherein the first and/or second binding region comprises:(i) a single chain Fv fragment (scFv);(ii) a dimeric scFv (di-scFv);(iii) a diabody;(iv) a triabody;(v) a tetrabody;(vi) a Fab;(vii) a F(ab′)2;(viii) a Fv;(ix) one of (i) to (viii) linked to a constant region of an antibody, Fc or a heavy chain constant domain (CH) 2 and/or CH3; or(x) an antibody or antigen binding fragment thereof, an antibody mimetic, a domain antibody, a chimeric antibody or a fusion protein.5. (canceled)6. The protein of claim 2 , wherein the first binding region is monospecific claim 2 , bispecific claim 2 , or multispecific.7. The protein of claim 1 , wherein the blood coagulation factor is selected from the group consisting of Factor I claim 1 , Factor II (prothrombin)/thrombin claim 1 , Factor III claim 1 , Factor V claim 1 , Factor VII claim 1 , Factor VIII claim 1 , Factor IX claim 1 , Factor X claim 1 , Factor XI claim 1 , Factor XII Factor XIII and an activated form of any of the foregoing.8. The protein of claim 2 , wherein the first binding region is an anti-Factor IX antibody or Factor IX binding fragment thereof claim 2 , wherein the anti-Factor IX antibody or Factor IX binding fragment thereof binds to non-activated Factor IX (FIX) and/or activated Factor IX (FIXa).9. (canceled)10. The protein of claim 2 , wherein the first binding ...

COMPOSITIONS AND METHODS FOR THROMBOEMBOLISM DISSOLUTION

Disclosed herein are novel thrombolytic formula for safe and effective treatment of blood clots. In clinical trials, cats of various breeds and ages presented partial or full paralysis of one or more limbs, due to arterial thromboembolism (ATE). Average treatment ranged from 3 days to 2 weeks, depending on the clot size and time elapsed since clot was dislodged from the subject's heart. These are significant findings considering the lack of treatment options available in veterinary medicine for cats with HCM and ATE. Veterinarians often euthanize cats presenting ATE, as no safe and effective thrombolytic agent is currently available for veterinary use. Previous thrombolytics were shown to have an average mortality rate of 60% due to reperfusion injury and hemorrhaging. The disclosed formula, on the other hand, overcomes these shortcomings. 1. A thrombolytic composition comprising nattokinase and an enteric coating.2. The thrombolytic composition of claim 1 , further comprising rutin bioflavonoid.3. The thrombolytic composition of claim 2 , wherein the supplement is in a tablet form.4. The thrombolytic composition of claim 3 , wherein the concentration of nattokinase is approximately 37.5 mg/750 fibrinolytic units.5. The thrombolytic composition of claim 3 , wherein the supplement is in the form of a tablet having nattokinase at approximately 37.5 mg/750 fibrinolytic units claim 3 , and rutin bioflavonoid at approximately 50 mg.6. A method of dissolving a thrombus comprising:administering an enzymatic formula containing nattokinase and an enteric coating.7. The method of claim 6 , wherein the enzymatic formula further comprises rutin bioflavonoid.8. The method of claim 6 , wherein the enzymatic formula contains nattokinase at approximately 37.5 mg/750 fibrinolytic units.9. The method of claim 6 , wherein the thrombus comprises a feline arterial thromboembolism.10. The method of claim 6 , wherein the enzymatic formula contains rutin bioflavonoid at approximately 50 mg ...

Pharmaceutical composition containing ginkgolide b and blood platelet prostaglandin cyclooxygenase inhibitor and method for preparation thereof and use thereof

Provided is a pharmaceutical composition containing ginkgolide B and the blood platelet prostaglandin cyclooxygenase inhibitor aspirin, a method for preparation of the pharmaceutical composition and a use thereof. When used together, ginkgolide B and aspirin have a synergistic effect in resisting platelet aggregation.

ACTIVATION OF (NA++K+)-ATPASE INHIBITS PLATELET AGGREGATION AND PREVENTS THROMBOSIS

Methods of inhibiting platelet activation and aggregation using antibodies or peptide vaccines having binding specificity for the a subunit of the (Na+K)-ATPase are provided, along with methods for inhibiting or preventing or treating thrombosis in a subject using such antibodies. 1. A method for inhibiting platelet activation , aggregation , and thrombosis without causing bleeding in a subject comprising administering to the subject an pharmaceutical effective amount of an antibody comprising a heavy chain variable domain and a light chain variable domain that specifically binds to an epitope of the α subunit of any isoform of (Na+K)-ATPase to a subject in need thereof , said epitope is represented by SEQ ID NOs: 3 and 4.2. The method of claim 1 , wherein the antibody is antibody SSA78 having a binding specificity of SEQ ID NO: 3 claim 1 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 8 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 9 claim 1 , wherein the antibody comprises humanized or human versions thereof claim 1 , or a fragment thereof wherein the fragment is a single-chain antibody claim 1 , and optionally claim 1 , wherein the fragment comprises one or more conservative amino acid substitutions.3. The method of claim 1 , wherein the antibody is antibody SSA401 having a binding specificity of SEQ ID NO: 4 claim 1 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 10 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 11 claim 1 , wherein the antibody comprises humanized or human versions thereof claim 1 , or a fragment thereof wherein the fragment is a single-chain antibody claim 1 , and optionally claim 1 , wherein the fragment comprises one or more conservative amino acid substitutions.4. The method of claim 1 , wherein the antibody is a polyclonal antibody or a monoclonal antibody.5. The method of claim 1 , ...

METHODS FOR INCREASING PLATELET COUNT BY INHIBITING BILIVERDIN IXBETA REDUCTASE

The present disclosure provides methods of treating a human having a disease or disorder that would benefit from increasing platelet counts. The method involves inhibiting the enzyme activity of biliverdin IXβ reductase (BLVRB) activity or inhibiting the expression of BLVRB gene. 16.-. (canceled)7. A pharmaceutical composition comprising a chemical compound that inhibits the enzymatic activity of BLVRB.8. The pharmaceutical composition of claim 7 , wherein the BLVRB enzymatic activity is inhibited by at least about 30% to about 100%.9. A pharmaceutical composition that inhibits the expression of BLVRB gene claim 7 , the composition comprising a small interfering RNA (siRNA) molecule or an antisense oligonucleotide specific to a region in the mRNA of the BLVRB gene.10. The pharmaceutical composition of claim 9 , wherein the BLVRB gene expression is inhibited by at least about 30% to about 100%.1120.-. (canceled) The present application is a divisional of co-pending application having U.S. Ser. No. 15/765,317, filed on Apr. 2, 2018, which is a 371 of International application having Serial No. PCT/US2016/055446, filed on Oct. 5, 2016, which claims the benefit of priority from U.S. Provisional Application No. 62/238,236, filed on Oct. 7, 2015, the content of which is incorporated herein by reference in its entirety.The present invention was made with government support under grant number HL119096 awarded by the National Institute of Health (NIH). The government has certain rights in the invention.The Sequence Listing in the ASCII text file, named as R8740_US_SequenceListing.txt of 5 KB, created on May 12, 2020, and submitted to the United States Patent and Trademark Office via EFS-Web, is incorporated herein by reference.Platelets mediate the critical first-step in hemostasis (Bahou, W F, (2003) 54, 343-369; Bahou, W F (2002) 8, 1082-1083), and qualitative platelet disorders cause bleeding syndromes (Bahou, W F (2006) (ed D. Kumar) 221-248 (Oxford University Press). ...

NOVEL DIPEPTIDE COMPOUNDS AND USES THEREOF

Provided herein are novel compounds of Formula I, or a pharmaceutically acceptable salt thereof or pharmaceutical compositions comprising the same. Also provided are methods of preparing the compounds of Formula I, or pharmaceutically acceptable salt thereof. Further provided are methods of using the novel compounds of Formula I, or a pharmaceutically acceptable salt thereof, for example, for inhibiting thrombin and/or for the use in the prevention and/or treatment of thrombin-mediated and thrombin-related diseases. 2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein{'sup': '1', 'sub': '1-6', 'Ris an optionally substituted Calkyl.'}3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris an unsubstituted Calkyl.4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris methyl claim 1 , ethyl claim 1 , n-propyl claim 1 , isopropyl claim 1 , n-butyl claim 1 , sec-butyl claim 1 , or tert-butyl.7. The compound of claim 5 , or a pharmaceutically acceptable salt thereof claim 5 , wherein Ris an unsubstituted linear or branched Calkyl (e.g. claim 5 , n-hexyl).8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof claim 7 , wherein Ris an unsubstituted linear or branched Calkyl claim 7 , e.g. claim 7 , ethyl claim 7 , n-propyl claim 7 , isopropyl claim 7 , n-butyl claim 7 , n-pentyl claim 7 , or n-hexyl.10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof claim 9 , wherein n is 1 claim 9 , 2 claim 9 , or 3.11. The compound of claim 9 , or a pharmaceutically acceptable salt thereof claim 9 , wherein Ris hydrogen claim 9 , a Calkyl (e.g. claim 9 , a Calkyl e.g. claim 9 , ethyl claim 9 , n-propyl claim 9 , isopropyl claim 9 , n-butyl claim 9 , n-pentyl claim 9 , or n-hexyl) claim 9 , phenyl claim 9 , or benzyl.13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof claim 12 , wherein Ris hydrogen ...

TISSUE PLASMINOGEN ACTIVATOR ANTIBODIES AND METHOD OF USE THEREOF

The present invention provides tissue plasminogen activator antibody molecules and their uses. More particularly, the presently-disclosed invention provides humanised antibody molecules which specifically bind tissue plasminogen activator (TPA) and their use in treating TPA induced haemorrhage, in particular treating systemic haemorrhage such as brain haemorrhage after treatment of ischemic stroke or myocardial infarction, or systemic bleeding after TPA treatment of pulmonary embolism, ischemic stroke or myocardial infarction. 1. An antibody molecule that binds specifically to a human tissue plasminogen activator (TPA) or a TPA mutant to inhibit degradation of human fibrin clots , wherein the antibody has sub-nanomolar affinity to inhibit fibrin-dependent plasminogen activation with an IC50<5 nM , and wherein the amino acid sequence of said TPA mutant has at least 65% identity to SEQ ID NO: 1 or SEQ ID NO: 2; wherein the antibody comprises a heavy chain variable domain with a CDR1 of SEQ ID NO: 3 or 4 , a CDR2 of SEQ ID NO: 5 or 6 , and a CDR3 of SEQ ID NO: 7 or 8 , and a light chain variable domain with a CDR1 of SEQ ID NO: 9 or 10 , a CDR2 of SEQ ID NO: 11 or 12 , and a CDR3 of SEQ ID NO: 13.2. The antibody molecule of which comprises a heavy chain variable domain with a CDR1 of SEQ ID NO: 3 claim 1 , a CDR2 of SEQ ID NO: 5 claim 1 , and a CDR3 of SEQ ID NO: 7 claim 1 , and a light chain variable domain with a CDR1 of SEQ ID NO: 9 claim 1 , and a CDR2 of SEQ ID NO: 11.3. The antibody molecule of which comprises a heavy chain variable domain selected from SEQ ID NOs: 14 to 28 and a light chain variable domain of SEQ ID NO: 29 or 30.4. The antibody molecule of which comprises a heavy chain variable domain selected from SEQ ID NOs: 14 to 28 claim 3 , and a light chain variable domain of SEQ ID NO: 29.5. The antibody molecule of which comprises a heavy chain variable domain of SEQ ID NO: 14 claim 3 , and a light chain variable domain of SEQ ID No: 29 claim 3 , or a ...

HAEMADIPSA SYLVESTRIS ANTITHROMBOTIC PEPTIDE SYLVESTIN AND USE THEREOF

Provided are a antithrombotic peptide Sylvestin and the use thereof, falling within the technical field of biomedicine. The antithrombotic peptide sylvestin can inhibit FXIIa and kallikrein, has anti-thrombus/infarction effects and alleviates injuries caused by cerebral ischemia, and can also be used in the preparation of inhibitors of FXIIa and kallikrein and drugs for anti-thrombus/infarction and anti-cerebral ischemic injuries. 1Haemadipsa sylvestris. A polypeptide having anti-thrombus activity , which is derived from antithrombotic peptide Sylvestin , comprising(1) a sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 1, or(2) a sequence obtained by adding, deleting, or replacing one or more amino acids in the amino acid sequence set forth in SEQ ID NO: 1.2. The polypeptide according to claim 1 , comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1.3Haemadipsa sylvestris. The polypeptide according to claim 1 , comprising the amino acid sequence set forth in SEQ ID NO: 1 claim 1 , wherein the amino acid other than the amino acid set forth in SEQ ID NO: 1 is identical to the amino acid at the corresponding position of the amino acid sequence encoded by antithrombotic peptide cDNA in nature.4. The polypeptide according to claim 1 , which is produced by genetic engineering or chemical synthesis.57.-. (canceled)8. A method for inhibiting FXIIa and/or kallikrein claim 1 , comprising exposing the polypeptide according to to FXIIa and/or kallikrein.9. A method of preventing and/or treating a disease caused by blood coagulation claim 1 , comprising administering the polypeptide according to to a subject in need thereof.10. The method according to claim 9 , wherein the disease caused by blood coagulation is a disease caused by intravascular infarction and/or thrombus claim 9 , for example claim 9 , a disease ...

Use of nadph for preparation of a drug for antiplatelet aggregation

Use of NADPH for preparation of a drug for antiplatelet aggregation, according to the research, it is found that in-vitro administration of exogenous NADPH inhibits ADP-induced platelet aggregation of rats in a dose-dependent mode; in-vitro administration of exogenous NADPH inhibits Thrombin-induced platelet aggregation of rats in a dose-dependent mode; preventive administration of NADPH in the rats can remarkably inhibit ADP-induced platelet aggregation; preventive administration of NADPH in the rats can remarkably inhibit Thrombin-induced platelet aggregation. Therefore, NADPH has a platelet aggregation inhibition function and can be used as a potential drug for antiplatelet aggregation.

USE OF VITAMIN K IN COMBINATION WITH ANTICOAGULANTS

A method of treating or preventing a condition characterized by unacceptable blood clotting and/or an increased risk thereof, the method including administering to a subject in need thereof a combination of vitamin K2 and at least one anticoagulant, the at least one anticoagulant having a first anticoagulant configured to inhibit free Factor Xa and/or Factor Xa bound in a prothrombinase complex of the subject.

METHODS FOR INCREASING PLATELET COUNT BY INHIBITING BILIVERDIN IXBETA REDUCTASE

The present disclosure provides methods of treating a human having a disease or disorder that would benefit from increasing platelet counts. The method involves inhibiting the enzyme activity of biliverdin IXβ reductase (BLVRB) activity or inhibiting the expression of BLVRB gene. 1. A method of treating a subject having a disease or disorder that would benefit from increasing platelet counts , the method comprising administering to the subject therapeutically effective amount of an agent that inhibits biliverdin reductase (BLVRB) enzymatic activity , thereby treating the subject.2. The method of claim 1 , wherein the agent is a chemical compound.3. The method of claim 1 , wherein the BLVRB enzymatic activity is inhibited by at least about 30% to about 100%.4. A method of treating a subject having a disease or disorder that would benefit from increasing platelet counts claim 1 , the method comprising administering to the subject therapeutically effective amount of an agent that inhibits the expression of biliverdin IXβ reductase (BLVRB) gene claim 1 , thereby treating the subject.5. The method of claim 4 , wherein the agent is a small interfering RNA (siRNA) molecule or an antisense oligonucleotide specific to a region in the mRNA of BLVRB gene.6. The method of claim 4 , wherein the BLVRB gene expression is inhibited by at east about 30% to about 100%.7. A pharmaceutical composition comprising a chemical compound that inhibits the enzymatic activity of BLVRB.8. The pharmaceutical composition of claim 7 , wherein the BLVRB enzymatic activity is inhibited by at least about 30% to about 100%.9. A pharmaceutical composition that inhibits the expression of BLVRB gene claim 7 , the composition comprising a small interfering RNA (siRNA) molecule or an antisense oligonucleotide specific to a region in the mRNA of the BLVRB gene.10. The pharmaceutical composition of claim 9 , wherein the BLVRB gene expression is inhibited by at least about 30% to about 100%.11. The method of ...

MULTI-TARGET COMPOUND WITH ANTICOAGULATION AND ANTIPLATELET ACTIVITY, PREPARATION METHOD THEREFOR, AND USE THEREOF

Provided is a multi-target compound with anticoagulation and platelet GPIIb/IIIa receptor antagonism. The formula of the multi-target compound is as follows: A-L-B-L′-C. A and B are binding sites with a thrombin, C is a binding site with a platelet GPIIb/IIIa receptor, L is a first linking group, and U is a second linking group. Also provided are a preparation method for the compound and use of the compound. The compound has the effects on inhibiting human thrombin activity and a platelet GPIIb/IIIa receptor in vitro, and has the effects on antiplatelet aggregation in vitro/in vivo, and anticoagulation and antithrombosis in vivo. 1. A multi-target compound with anticoagulation and platelet GPIIb/IIIa receptor antagonism , said compound having a structure as shown in Formula (1):{'br': None, 'A-L-B-L′-C\u2003\u2003Formula (1)'}wherein A and B are thrombin binding sites, C is a platelet GPIIb/IIIa receptor binding site, L is a first linker, and L′ is a second linker.2. The compound according to claim 1 , wherein L′ has a structure as shown in Formula (2):{'br': None, 'sub': n1', 'n2', 'n3, '((Gly)-(Ser))\u2003\u2003Formula (2)'}wherein n1 is 1, 2, 3 or 4; n2 is 0 or 1; and n3 is 0, 1, 2 or 3; or {'br': None, 'sub': 'n1', '(Glu-Ala-Ala-Ala-Lys)\u2003\u2003Formula (3)'}, 'L′ has a structure as shown in Formula (3)wherein n1 is 0, 1, 2 or 3; or {'br': None, 'sub': 'n1', '(Arg-Val-Leu-Ala-Glu-Ala)\u2003\u2003Formula (4)'}, 'L′ has a structure as shown in Formula (4)wherein n1 is 0, 1, 2 or 3.3. (canceled)4. (canceled)5. The compound according to claim 1 , wherein A has a structure as shown in Formula (5):{'br': None, 'A1-A2-A3-A4\u2003\u2003Formula (5)'}wherein A1 is D-Phe; A2 is Pro or Pip; A3 is Arg, Lys, Orn or Har; and A4 is Pro, D-Pro or Ser.6. The compound according to claim 5 , wherein B has a structure as shown in Formula (6):{'br': None, 'B1-B2-B3-B4-B5\u2003\u2003Formula (6)'}wherein B1 is a dipeptide consisting of any two acidic amino acids;B2 is Val, Leu, Ile, ...

RECOMBINANT PROTHROMBIN ANALOGUES AND USES THEREOF

During the process of coagulation, prothrombin is activated to α-thrombin by prothrombinase. Key residues in the structure of prothrombin allow for modulation of the activation of prothrombin. In certain embodiments, a recombinant prothrombin with at least one point mutation or deletion is provided. 1. A recombinant prothrombin polypeptide with an amino acid modification from residue 472 to 487.2. The recombinant prothrombin polypeptide of claim 1 , wherein the modification occurs in at least one of amino acid residues Ser claim 1 , Leu claim 1 , and Gln.3. The recombinant prothrombin polypeptide of claim 1 , wherein the modification is a modification of amino acid residue Ser.4. The recombinant prothrombin polypeptide of claim 1 , wherein the modification is a modification of amino acid residue Leu.5. The recombinant prothrombin of polypeptide claim 1 , wherein the modification is a modification of amino acid residue Gln.6. The recombinant prothrombin of polypeptide claim 1 , wherein the modification is a modification of amino acid residues Ser claim 1 , Leu claim 1 , and Gln.7. The recombinant prothrombin of polypeptide claim 1 , wherein the modification is a deletion of at least one of amino acid residues Ser claim 1 , Leu claim 1 , and Gln.8. A method of modulating coagulation in a subject who has or is at risk of having thrombosis claim 1 , the method comprising administering a polypeptide according to any one of -.9. An isolated polynucleotide which encodes a polypeptide characterized by:(a) having anti-coagulant activity; and(b) having the amino acid sequence of prothrombin with an amino acid modification at a residue from 472 to 487.10. A host cell which contains the polynucleotide of .11. A recombinant expression vector which contains the polynucleotide of .12. The vector of claim 11 , wherein the vector is a plasmid.13. The vector of claim 11 , wherein the vector is a virus.14. A method for producing a polypeptide having an amino acid sequence of ...

POLYMORPHS OF BETRlXABAN & ITS MALEATE SALT

The present application relates to solid state forms of Betrixaban and its Maleate salt, and processes for preparation thereof.

SYNTHETIC PLATELETS

Provided herein are various functionalized particles comprising a shell, dendritic linkers, and functional moieties. The dendrimer linkers allow very large numbers of functional moieties to be bound to the shell. The functional moieties may comprise peptides which synergistically promote platelet aggregation and hemostasis in wounded tissues. The functionalized particles may further be effectors of wound healing, thrombolysis and other functions, depending on the selection of functional moiety. Functionalized polymers having these functions are provided as well. 1. A functionalized particle , comprisinga substrate for the attachment of dendrimer linkers;dendrimer linkers, coupled to the surface of the substrate; andone or more functional moieties at the terminal ends of the dendrimer linkers;whereina) the substrate is a polymer or protein-polymer bilayer; and/orb) the substrate is hyaluronic acid and the functional moiety is a peptide.2. The functionalized particle of claim 1 , wherein the peptide is a hemostatic peptide.3. The functionalized particle of claim 1 , wherein the polymer is hyaluronic acid claim 1 , polyvinyl alcohol claim 1 , DOX-GEM-gly-HA claim 1 , or polylactic-co-glycolic acid.4. The functionalized particle of claim 1 , further comprising a thrombolytic agent in the interior of the particle.7. The functionalized particle of claim 4 , wherein the thrombolytic agent is tPA.8. The functionalized particle of claim 1 , whereinthe dendrimer linkers comprise PAMAM dendrimers.9. The functionalized particle of claim 1 , whereinthe dendrimer linkers are omitted and the functional moieties are bound directly to the substrate.10. The functionalized particle of claim 1 , whereinthe one or more functional moieties comprise two or more of: a wound targeting ligand; a platelet binding agent; a wound binding peptide; a wound healing peptide; a tPA-binding moiety; a wound or clot binding moiety; a hemostatic peptide; an anti-thrombotic agent; and a thrombolytic ...

TRICYCLIC HETEROARYL-SUBSTITUTED QUINOLINE AND AZAQUINOLINE COMPOUNDS AS PAR4 INHIBITORS

Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein Ris a tricyclic heteroaryl group substituted with Rand zero to 2 R; and R, R, R, R, R, and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder. 7. A pharmaceutical composition claim 1 , which comprises a pharmaceutically acceptable carrier and a compound according to or a pharmaceutically acceptable salt thereof claim 1 , alone or in combination with another therapeutic agent.8. A method for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder claim 1 , which comprises the steps of administering to a patient in need thereof a therapeutically effective amount of a compound according to or a pharmaceutically acceptable salt thereof claim 1 , wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders claim 1 , venous cardiovascular thromboembolic disorders claim 1 , and thromboembolic disorders in the chambers of the heart or in the peripheral circulation.9. The method according to wherein the thromboembolic disorder is selected from the group consisting of unstable angina claim 8 , an acute coronary syndrome claim 8 , atrial fibrillation claim 8 , myocardial infarction claim 8 , transient ischemic attack claim 8 , stroke claim 8 , atherosclerosis claim 8 , peripheral occlusive arterial disease claim 8 , venous thrombosis claim 8 , deep vein thrombosis claim 8 , thrombophlebitis claim 8 , arterial embolism claim 8 , coronary arterial thrombosis claim 8 , cerebral arterial ...

Coagulation factor ix compositions and methods of making and using same

The present invention relates to compositions comprising factor IX coagulation factors linked to extended recombinant polypeptide (XTEN), isolated nucleic acids encoding the compositions and vectors and host cells containing the same, and methods of making and using such compositions in treatment of coagulation factor-related diseases, disorders, and conditions.

Platelet biomarkers and diagnostic methods for vascular diseases

The present invention relates to biomarkers and diagnostic and prognostic methods for vascular diseases. In particular, proteins of platelet-derived exosomes have been identified as biomarkers that can be used to detect platelet activation associated with pathogenesis of vascular diseases, including cardiovascular and cerebrovascular diseases. The invention also provides compositions for detecting biomarkers as well as compositions and methods useful for treating vascular diseases.

Antagonists of il-6 to prevent or treat thrombosis

The present invention is directed to therapeutic methods using IL-6 antagonists such as antibodies and fragments thereof having binding specificity for IL-6 to prevent or treat thrombosis in diseases associated with abnormal blood coagulation or fibrinolysis. In preferred embodiments these patients will comprise those exhibiting elevated D-dimer or other coagulation cascade related proteins and optionally will further exhibit elevated C reactive protein prior to treatment. The subject therapies also may include the administration of other actives such as chemotherapeutics, anti-coagulants, statins, et al.

MEDIUM MOLECULAR WEIGTH HEPARIN

The present invention concerns medium molecular weight heparin (MMWH 10.5 kD) for prevention and treatment of venous thromboembolism in malignant disease. 1. A medium molecular weight heparin for use in the treatment of venous thromboembolism in malignant disease.2. A medium molecular weight heparin according to claim 1 , further comprising an average molecular weight of more than 9 kD and less than 12 kD.3. A medium molecular weight heparin according to for use in the treatment of venous thromboembolism in cancer.4. A medium molecular weight heparin according to claim 3 , for use in the treatment of venous thromboembolism in cancer complicated by renal disease.5. A method of using a medium molecular weight heparin for the treatment of venous thromboembolism in malignant disease. The present invention concerns medium molecular weight heparin (MMWH 10.5 kD) for prevention and treatment of venous thromboembolism in malignant disease.Malignancies and major surgery related are associated with extraordinary high risks of venous thromboembolism (VTE) and bleeding complications that defy the established therapeutic measures.VTE is a frequent complication of the primary illness in hospital-patients and those having undergone for example total hip replacement, abdominal or pelvic operation for cancer. The majority of pulmonary emboli originating in deep vein thrombosis” (DVT) occur without premonitory signs.From the prior art it is known to prevent such type of complications by applying an effective method of prophylaxis with unfractionated heparin (UFH) or low molecular weight heparins (LMWHs). The latter are dealt with as a class in the international guidelines—the leading one being the “Antithrombotic Therapy and Prevention of Thrombosis” (9Ed. ACCP Guidelines 2012)—because LMWHs do not differ in terms of effectiveness and bleeding complications associated, i.e., in their benefit-risk ratio.With respect to the aforementioned heparin agents known from the prior art, there ...

A GENETICALLY MODIFIED YEAST CELL AND IMPROVED PROCESS FOR PRODUCTION OF CLOT-SPECIFIC STREPTOKINASE

Disclosed herein is an expression system for the production and secretion of biologically active clot-specific streptokinase (CSSK) protein in methylotrophic yeast. Yeast-expressed CSSK protein displays improved plasminogen activation and fibrin selectivity. Further disclosed are methylotrophic yeast transformed with at least one copy of functional cDNA sequence encoding CSSK adjunct with modified signal sequence which results in secretion of mature and correctly processed CSSK. 1. An expression cassette comprising a polynucleotide , said polynucleotide comprising a yeast methanol inducible promotor sequence , a modified alpha signal gene sequence , a nucleic acid sequence encoding clot specific streptokinase and a transcription terminator sequence , wherein the nucleic acid sequence encoding clot specific streptokinase has an 85% identity to the nucleotide sequence selected from the group consisting of SEQ ID NO: 2 , SEQ ID NO: 4 , SEQ ID NO: 6 and SEQ ID NO: 8.2. The expression cassette according to claim 1 , wherein the nucleic acid sequence encoding clot specific streptokinase is selected from the group consisting of SEQ ID NO: 2 claim 1 , SEQ ID NO: 4 claim 1 , SEQ ID NO: 6 and SEQ ID NO: 8.3. The expression cassette as claimed in claim 1 , wherein the modified alpha signal gene sequence is as set forth in SEQ ID NO: 10.4. An expression vector comprised of the expression cassette according to .5. The expression vector as claimed in claim 4 , wherein the expression vector comprises a polynucleotide having at least 85% identity to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 2 claim 4 , SEQ ID NO: 4 claim 4 , SEQ ID NO: 6 claim 4 , SEQ ID NO: 8 claim 4 , SEQ ID NO: 23 claim 4 , SEQ ID NO: 26 and SEQ ID NO: 28.6Streptococcus equisimilis. A transformed yeast cell expressing the expression cassette as claimed in claim 1 , wherein the nucleic acid sequence encoding a clot specific streptokinase (CSSK) comprises: (a) streptokinase (SK) ...

READY-TO-USE BIVALIRUDIN COMPOSITIONS

Ready-to-use liquid bivalirudin compositions, methods of using the ready-to-use bivalirudin compositions, and methods of preparing the ready-to-use liquid bivalirudin compositions are provided herein. The liquid ready-to-use bivalirudin compositions comprise a pharmaceutically acceptable amount of bivalirudin. 1. An injectable ready-to-use bivalirudin composition comprising:a. bivalirudin (SEQ ID NO: 1), or salts thereof,b. a buffering agent,c. one or more pharmaceutically acceptable agent(s) selected from the group consisting of tonicity-adjusting agents, stabilizing agents, antioxidants, and pH adjusting agents, andd. a pH ranging from 5.0 to about 5.7,wherein the percentage of total impurities increases by no more than about 9% from the time of manufacture up to 12 months of storage at 5° C. or up to 1 month of storage at 25° C. as determined by high performance liquid chromatography at a wavelength of 215 nm.2. The composition of claim 1 , wherein the one or more pharmaceutically acceptable agent(s) comprises a tonicity-adjusting agent and/or a stabilizing agent.3. The composition of claim 2 , wherein the tonicity-adjusting agent and/or the stabilizing agent comprises(i) an inorganic chloride,(ii) a saccharide, a sugar alcohol, or an amino sugar(iii) an amino acid,(iv) an organic solvent, or(vi) any combination of (i)-(iv).4. The composition of claim 2 , wherein the tonicity-adjusting and/or the stabilizing agent comprises polyethylene glycol (PEG) claim 2 , mannitol claim 2 , sucrose claim 2 , glycerol claim 2 , ethanol claim 2 , sorbitol claim 2 , glycine claim 2 , proline claim 2 , or any combination thereof.5. (canceled)6. The composition of claim 1 , wherein the buffering agent has at least one pKa from about 4.0 to about 6.7.7. The composition of claim 1 , wherein the concentration of the buffering agent is at least about 1 mM.8. The composition of claim 1 ,wherein from the time of manufacture up to 12 months of storage at 5° C. or up to 1 month of storage ...

COMPOSITIONS FOR INTERFERON BLOCKADE AND METHODS OF USING SAME

Disclosed are compositions that may include one or more inhibitors of interferon activity for the treatment of a disease state, for example, a disorder associated with increased interferon levels such as thrombotic microangiopathy (“TMA”). Also disclosed are methods of treating an individual having a disease state such as thrombotic microangiopathy. Further disclosed are methods of diagnosing an individual with TMA. 17-. (canceled)8. A method of treating an individual having TMA , comprising the step of administering emapalumab to said individual.9. (canceled)10. The method of claim 8 , wherein said TMA is post-transplant TMA claim 8 , pregnancy associated TMA claim 8 , TMA secondary to severe inflammation claim 8 , TMA secondary to cytokine storm syndrome (CRS) due to chimeric antigen receptor T cell (CART) therapy claim 8 , or combinations thereof.11. The method of claim 8 , wherein said TMA is characterized by having one or both ofa. a histological TMA diagnosis in tissue biopsy; and i. LDH above normal value for age,', 'ii. schistocytes on peripheral blood smear,', 'iii. de novo thrombocytopenia or required platelet transfusions,', 'iv. de novo anemia or required RBC transfusions,', 'v. hypertension >99% for age (<18 y of age) or 14/90 (>18 y of age) or receiving antihypertensive therapy;', 'vi. proteinuria ≥30 mg/dL on random urinalysis ×2 or random urine protein creatinine ratio >1 mg/mg; and', 'vii. terminal complement activation, characterized by elevated plasma sC5b-9 above normal limit of (≥24 4ng/m1)., 'b. four or markers selected from'}12. The method of claim 8 , wherein said TMA is high risk TMA and is characterized by having proteinuria ≥30 mg/dL on random urinalysis ×2 or random urine protein creatinine ratio >1 mg/mg; and terminal complement activation claim 8 , characterized by elevated plasma sC5b-9 above normal limit of (≥244 ng/ml).13. The method of wherein said TMA is associated with or secondary to a disease or condition selected from post- ...

Method of preventing and treating thrombosis

A method of preventing or treating thrombosis in a patent is disclose, wherein the method comprises administering to the patient an amount of fostamatinib or a form or metabolite thereof effective to prevent or treat the thrombosis, respectively.

NON-ANTICOAGULANT SULFATED OR SULFONATED POLYSACCHARIDES

The present invention provides non-anticoagulant sulfated or sulfonated polysaccharides (NASPs), which accelerate the blood clotting process. Also provided are pharmaceutical formulations comprising a NASP of the invention in conjunction with a pharmaceutically acceptable excipient and, in various embodiments, these formulations are unit dosage formulations. The invention provides a NASP formulation, which is orally bioavailable. Also provided are methods for utilizing the compounds and formulations of the invention to promote blood clotting in vivo as therapeutic and prophylactic agents and in vitro as an aid to studies of the blood clotting process. 1. A unit dosage formulation for use in a method for treating a subject in need of enhanced blood coagulation comprising administering a therapeutically effective amount of a composition comprising a non-anticoagulant sulfated or sulfonated polysaccharide (NASP) to the subject wherein the sulfated or sulfonated polysaccharide is a member selected from α-cyclodextrin , β-cyclodextrin , melezitose , stachyose , raffinose , maltotriose , maltotetraose , maltopentaose , cellotriose , cellotetraose , cellopentaose , xylan , icodextrin , 6-carboxyicodextrin , characterized in that the unit dosage formulation is administered to the subject at a dosage of from about 0.01 mg/kg to about 20 mg/kg of said NASP.2. The unit dosage formulation of claim 1 , wherein the NASP is in an amount sufficient to enhance blood coagulation in a subject to whom the unit dosage formulation is administered.3. The unit dosage formulation of claim 1 , wherein the unit dosage formulation is an oral unit dosage formulation.4. A method for treating a subject in need of enhanced blood coagulation comprising administering a therapeutically effective amount of a composition comprising a non-anticoagulant sulfated or sulfonated polysaccharide (NASP) to the subject claim 1 , wherein the sulfated or sulfonated polysaccharide is a member selected from α- ...

METHODS OF PREVENTION AND TREATMENT OF THROMBOSIS

Provided herein are methods for preventing and treating thrombosis in critically ill patients or in a patient being admitted to an intensive care unit by administering to the patient a therapeutically effective amount of betrixaban, or a pharmaceutically acceptable salt thereof, or a crystalline polymorph of betrixaban, or a crystalline polymorph of a pharmaceutically acceptable salt of betrixaban. 1. A method for the prevention or treatment of thrombosis in a critically ill patient , comprising administering to the patient a therapeutically effective amount of betrixaban , or a pharmaceutically acceptable salt thereof , or a crystalline polymorph of betrixaban , or a crystalline polymorph of a pharmaceutically acceptable salt of betrixaban.2. A method for prophylaxis of venous thromboembolism (VTE) in a patient who is admitted to an intensive care unit for an acute medical illness , wherein the method comprises administering to the patient a therapeutically effective amount of betrixaban , or a pharmaceutically acceptable salt thereof , or a crystalline polymorph of betrixaban , or a crystalline polymorph of a pharmaceutically acceptable salt of betrixaban.3. A method for prophylaxis of venous thromboembolism (VTE) in a patient being cared for in an intensive care unit comprising administering betrixaban , or a pharmaceutically acceptable salt thereof , or a crystalline polymorph of betrixaban , or a crystalline polymorph of a pharmaceutically acceptable salt of betrixaban to the patient.4. The method of claim 1 , wherein the patient is at risk of developing a venous thromboembolic disease.5. The method of claim 1 , wherein the patient suffers from one or more of (a) acutely decompensated heart failure claim 1 , (b) acute respiratory failure claim 1 , (c) acute infection without septic shock claim 1 , (d) an acute rheumatic disorder or (e) cancer.6. The method of claim 1 , wherein the patient suffers from decreased mobility.7. The method of claim 1 , wherein ...

PROPHYLACTIC TREATMENT OF VENOUS THROMBOEMBOLISM

Method of prophylactic treatment of acutely ill medical patients with rivaroxaban to reduce venous thromboembolism (VTE) and VTE-related death during hospitalization and post-hospital discharge. 1. A method of prophylactic treatment against venous thromboembolism (VTE) and VTE-related death during hospitalization and post-hospital discharge in an adult human patient admitted for an acute medical illness and at risk for thromboembolic complications due to moderate or severe restricted mobility and other risks factors for VTE , the method comprising administering rivaroxaban to the adult human patient in an effective amount to prophylactically treat against VTE and VTE-related death during hospitalization and post-hospital discharge in an adult human patient admitted for an acute medical illness and at risk for thromboembolic complications due to moderate or severe restricted mobility and other risks factors for VTE , wherein the rivaroxaban is administered orally in the effective amount of 10 mg once daily , and wherein the adult human patient is not at high risk of bleeding.2. The method of claim 1 , wherein the acute medical illness comprises heart failure claim 1 , active cancer claim 1 , acute ischemic stroke claim 1 , acute infectious and inflammatory disease and acute respiratory insufficiency.3. The method of claim 1 , wherein the acute medical illness comprises COVID-19.4. The method of claim 1 , wherein other risks factors for VTE comprise prolonged immobilization claim 1 , age 75 or older claim 1 , history of cancer claim 1 , history of VTE claim 1 , history of heart failure claim 1 , thrombophilia claim 1 , acute infections disease contributing to hospitalization claim 1 , and body mass index (BMI) equal to or greater than 35 kg/m.5. The method of claim 1 , wherein risk factors for high risk of bleeding are selected from the list consisting of: active cancer claim 1 , medical history of bronchiectasis/pulmonary cavitation claim 1 , dual antiplatelet ...

PHARMACEUTICAL COMPOSITIONS AND METHODS FOR THE TREATMENT OF THROMBOSIS AND DELIVERY BY MEDICAL DEVICES

A pharmaceutical composition and a method of using the pharmaceutical composition for the treatment of thrombosis are provided. The pharmaceutical composition can include a mixture of proteolytic enzymes, and optionally, additional compounds. The pharmaceutical composition can include an antiaggregatory or anti-thrombotic compound, such as Lisini racemici acetylsalicylase. The method can include administering the pharmaceutical composition to a patient in need thereof, including administration of the pharmaceutical composition to a thrombus until the thrombus is dissolved. The method can also include administering one or more balloon catheters to the patient. 1. A method for treating thrombosis in a patient in need thereof , comprising:administering a pharmaceutical composition comprising a proteolytic enzyme or mixture of proteolytic enzymes to the patient, andadministering a first balloon catheter to the patient.2. The method according to claim 1 , wherein the first balloon catheter comprises a balloon claim 1 , a first tube claim 1 , and a second tube claim 1 , the first and second tubes each having an inlet located at the same side of the balloon claim 1 ,wherein the first tube has an outlet inside of the balloon to inflate the balloon, and the second tube has an outlet located on another end of the balloon distant from the inlet to be located between the balloon and the thrombus.3. The method according to claim 1 , further comprising administering a second balloon catheter to the patient.4. The method according to claim 1 , wherein the pharmaceutical composition further comprises Lisini racemici acetylsalicylase.5. The method according to claim 4 , wherein the mixture of proteolytic enzymes comprises Krill enzymes.6. A method of treating thrombosis in a patient claim 4 , comprising:a) blocking a vessel containing a thrombus downstream of said thrombus with a first balloon catheter to form a small volume between the first balloon catheter and the thrombus,b) ...

Fusion proteins, method for their production and their use

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A fusion protein of the general formula Met - Xn - D' - Y - Z in which n is zero or 1, X is a sequence of 1 to 12 genetically codable amino acids, D' is a sequence of about 70 amino acids in the region of the sequence of amino acids 23 - 93 of the D-peptide in the trp operon of E. coli, Y denotes a sequence of one or more genetically codable amino acids which permits the following amino acid sequence Z to be cleaved off, and Z is a sequence of genetically codable amino acids. 1. Claims for the Contracting State : AT A process for the preparation of a fusion protein of the general formula (1) Met - Xn - D' - Y - Z in which n is zero or 1, X is a sequence of 1 to 12 genetically codable amino acids, D' is a sequence of about 70 amino acids in the region of the sequence of amino acids 23 - 93 of the D-peptide in the trp operon of E. coli, Y denotes a sequence of one or more genetically codable amino acids which permits the following amino acid sequence Z to be cleaved off, and Z is a sequence of genetically codable amino acids, characterized by expressing a gene structure which codes for these fusion proteins in a host cell, and separating the fusion protein.

Inhibitors of thrombin induced platelet aggregation

The present invention describes a therapeutic method useful for treating or preventing a condition of platelet aggregation in a subject including administering a pharmaceutically effective amount of a compound or composition that inhibits JAK-3 and/or tyrosine phosphorylation of STAT-3 and inhibits thrombin induced platelet aggregation. The condition of platelet aggregation includes hematopoietic and cerbrovascular diseases.

Improved process for the preparation of the salts of 4-(benzimidazolylmethylamino)-benzamides

The invention relates to a process for preparing a salt of an optionally substituted 4-benzimidazol-2-ylmethylamino)-benzamidine, characterised in that (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, b) i) the product thus obtained is hydrogenated, ii) optionally the amidino group is carbonylated, without isolating the intermediate product of the hydrogenation beforehand and iii) without prior isolation of the intermediate product of the carbonylation the desired salt is isolated.

Low frequency vibration assisted blood perfusion system and apparatus

An emergency system for the treatment of a patient (20) experiencing an acute thrombotic vascular occlusion, comprising a non-invasive, vibration device (10), in conjunction with pharmacological agents, for disrupting and lysing thrombosis, relieving spasm (if associated), and thereby restoring blood perfusion. The vibration device (10) is operable to deliver vibration within the 1-1000 Hz range, at a selectable displacement amplitude of 0.1-10 mm. For acute myocardial infarction cases, an operator places an attachment interface comprising a pair of contacts (12), to bridge the sternum of the patient at the fourth intercostal space. Vibration is initiated at 50 Hz (or any frequency, preferably within the 40 - 120 Hz range), and adjusts vibration to a maximal displacement amplitude deemed tolerable and safe to the patient (20), concurrently with the administration of thrombolytic agents, or any other form of medical therapy. A synergistic effect is achieved between vibration and medical agents to facilitate the disruption of thrombosis, and restore blood perfusion.

Chimeric clotting factors

The invention provides chimeric clotting factors comprising an activatable clotting factor and an enhancer moiety. The activatable clotting factor allows the chimeric clotting factor to be activated at the site of coagulation. The enhancer moiety can additionally improve procoagulation activities of the chimeric clotting factors. The chimeric clotting factors can further be improved by fusion to a half-life extender, which improves a pharmacokinetics property of the chimeric clotting factor. The invention also includes methods of making and methods of using these chimeric clotting factors.

Procoagulant compounds

The present disclosure provides protease-activatable procoagulant compounds comprising a procoagulant polypeptide, e.g., a procoagulant peptide and/or clotting factor, and a linker comprising a protease-cleavable substrate (e.g., a synthetic thrombin substrate) and a self-immolative spacer (e.g., p-amino benzyl carbamate). Upon cleavage of the protease-cleavable substrate by a protease (e.g., thrombin), the self-immolative spacer cleaves itself from the procoagulant polypeptide such that the polypeptide is in an underivatized and active form. Also provided are pharmaceutical compositions, methods for treating bleeding disorders using the disclosed compounds, methods of enhancing in vivo efficacy of procoagulant polypeptides, methods of increasing the efficacy of proteolytic cleavage of compounds comprising procoagulant polypeptides, methods of activating procoagulant polypeptides, and methods of releasing a procoagulant polypeptide from a heterologous moiety such as PEG.

Chimeric clotting factors

The invention provides chimeric clotting factors comprising an activatable clotting factor and an enhancer moiety. The activatable clotting factor allows the chimeric clotting factor to be activated at the site of coagulation. The enhancer moiety can additionally improve procoagulation activities of the chimeric clotting factors. The chimeric clotting factors can further be improved by fusion to a half-life extender, which improves a pharmacokinetics property of the chimeric clotting factor. The invention also includes methods of making and methods of using these chimeric clotting factors.

Procoagulant compounds

The present disclosure provides protease-activatable procoagulant compounds comprising a procoagulant polypeptide, e.g., a procoagulant peptide and/or clotting factor, and a linker comprising a protease-cleavable substrate (e.g., a synthetic thrombin substrate) and a self-immolative spacer (e.g., p-amino benzyl carbamate). Upon cleavage of the protease-cleavable substrate by a protease (e.g., thrombin), the self-immolative spacer cleaves itself from the procoagulant polypeptide such that the polypeptide is in an underivatized and active form. Also provided are pharmaceutical compositions, methods for treating bleeding disorders using the disclosed compounds, methods of enhancing in vivo efficacy of procoagulant polypeptides, methods of increasing the efficacy of proteolytic cleavage of compounds comprising procoagulant polypeptides, methods of activating procoagulant polypeptides, and methods of releasing a procoagulant polypeptide from a heterologous moiety such as PEG.

Chimeric clotting factors

The invention provides chimeric clotting factors comprising an activatable clotting factor and an enhancer moiety. The activatable clotting factor allows the chimeric clotting factor to be activated at the site of coagulation. The enhancer moiety can additionally improve procoagulation activities of the chimeric clotting factors. The chimeric clotting factors can further be improved by fusion to a half-life extender, which improves a pharmacokinetics property of the chimeric clotting factor. The invention also includes methods of making and methods of using these chimeric clotting factors.

Procoagulant compounds

The present disclosure provides protease-activatable procoagulant compounds comprising a procoagulant polypeptide, e.g., a procoagulant peptide and/or clotting factor, and a linker comprising a protease-cleavable substrate (e.g., a synthetic thrombin substrate) and a self-immolative spacer (e.g., p-amino benzyl carbamate). Upon cleavage of the protease-cleavable substrate by a protease (e.g., thrombin), the self-immolative spacer cleaves itself from the procoagulant polypeptide such that the polypeptide is in an underivatized and active form. Also provided are pharmaceutical compositions, methods for treating bleeding disorders using the disclosed compounds, methods of enhancing in vivo efficacy of procoagulant polypeptides, methods of increasing the efficacy of proteolytic cleavage of compounds comprising procoagulant polypeptides, methods of activating procoagulant polypeptides, and methods of releasing a procoagulant polypeptide from a heterologous moiety such as PEG.

Procoagulant compounds

The present disclosure provides protease-activatable procoagulant compounds comprising a procoagulant polypeptide, e.g., a procoagulant peptide and/or clotting factor, and a linker comprising a protease-cleavable substrate ( e.g ., a synthetic thrombin substrate) and a self-immolative spacer ( e.g ., p-amino benzyl carbamate). Upon cleavage of the protease-cleavable substrate by a protease ( e.g ., thrombin), the self-immolative spacer cleaves itself from the procoagulant polypeptide such that the polypeptide is in an underivatized and active form. Also provided are pharmaceutical compositions, methods for treating bleeding disorders using the disclosed compounds, methods of enhancing in vivo efficacy of procoagulant polypeptides, methods of increasing the efficacy of proteolytic cleavage of compounds comprising procoagulant polypeptides, methods of activating procoagulant polypeptides, and methods of releasing a procoagulant polypeptide from a heterologous moiety such as PEG.

Procoagulant compounds

Anti-coagulation factor XI antibodies

Antibodies that bind the apple 3 domain of human coagulation Factor XI and inhibit activation of FXI by coagulation factor XIIa as well as activation of FIX by FXIa are described.

Anti-coagulation factor XI antibodies

Antibodies that bind the apple 3 domain of human coagulation Factor XI and inhibit activation of FXI by coagulation factor XIIa as well as activation of FIX by FXIa are described.

Anti-coagulation factor XI antibodies

Antibodies that bind the apple 3 domain of human coagulation Factor XI and inhibit activation of FXI by coagulation factor XIIa as well as activation of FIX by FXIa are described.

抗-凝血因子xi抗体

描述了结合人凝血因子XI的苹果3结构域并抑制凝血因子XIIa激活FXI以及FXIa激活FIX的抗体。

METHODS OF MANUFACTURING A HIGH MOLECULAR WEIGHT HEPARIN COMPOUND

A method of manufacturing a high molecular weight heparin (HMWH) compound is disclosed. The method comprises dissolving heparin to form a heparin solution and fractionating the heparin solution via tangential flow filtration (TFF) using a membrane with a molecular weight cut off (MWCO) between about 8 kDa and about 12 kDa. The TFF yields a retentate comprising fractionated heparin with a weight average molecular weight of about 20 kDa or greater, i.e., a high molecular weight heparin compound. A substantial proportion of heparin chains in the fractionated heparin may have a high molecular weight, e.g., 50% of the heparin chains or greater may have a molecular weight of 20 kDa or greater.

ヒト組織因子抑制因子

(57)【要約】 （修正有） 【課題】 組織因子抑制因子（ＴＦＩ）あるいはリボタ ンパク質関連凝固抑制因子（ＬＡＣＩ）として知られる 凝固抑制因子に関する。更に詳細には、本発明は全長Ｔ ＦＩを本質的に表現しているｃＤＮＡクローンに関す る。 【解決手段】 本質的に組織因子抑制因子の全長を示す ｃＤＮＡクローンの完全コード配列およびアミノ酸配列 の決定。

Patent JPS613330B2

Anticoagulant factor XI antibody

인간 응고 인자 XI의 애플 3 도메인에 결합하고 응고 인자 XIIa에 의한 FXI의 활성화뿐만 아니라 FXIa에 의한 FIX의 활성화를 억제하는 항체가 기재된다. An antibody that binds to the Apple 3 domain of human coagulation factor XI and inhibits the activation of FXI by coagulation factor XIIa as well as FIX by FXIa is described.

包含高分子量聚环氧乙烷的多价平台分子

本发明提供了包含高分子量聚环氧乙烷基团的化合价平台分子及其与生物学活性分子的缀合物以及它们的制备方法。高分子量聚环氧乙烷基团的分子量为例如大于22,000道尔顿，例如至少40,000道尔顿。在一种实施方式中，提供了包含化合价平台分子的组合物，其中该分子的多分散性小于约1.2。还提供了化合价平台分子与生物学活性分子的缀合物，所述生物学活性分子是例如糖、多(糖)、氨基酸、多(氨基酸)、核酸或脂质。还提供了包含如本文所公开的缀合物和药学上可接受的载体的药学上可接受的组合物以及制备和使用这些缀合物和组合物的方法。

N-alkyl-2-substituted atp analogues

There are disclosed compounds of formula (I) wherein R?1 and R2¿ independently represent hydrogen or halogen, R?3 and R4¿ independently represent phenyl, or alkyl C¿1-6? optionally substituted by one or more substituents selected from OR?5¿, alkylthio C¿1-6?, NR?6R7¿, phenyl, COOR8 and halogen, R?5, R6, R7 and R8¿ independently represent hydrogen or alkyl C¿1-6?, and X represents an acidic moiety, and pharmaceutically acceptable salts thereof. Processes for their production and pharmaceutical compositions and methods of treatment involving their use are also described.