EA023913B1 - Способы лечения метаболических нарушений, использующие эпиметаболические переключатели, многоаспектные внутриклеточные молекулы или факторы влияния - Google Patents

Способы лечения метаболических нарушений, использующие эпиметаболические переключатели, многоаспектные внутриклеточные молекулы или факторы влияния Download PDF

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EA023913B1
EA023913B1 EA201101523A EA201101523A EA023913B1 EA 023913 B1 EA023913 B1 EA 023913B1 EA 201101523 A EA201101523 A EA 201101523A EA 201101523 A EA201101523 A EA 201101523A EA 023913 B1 EA023913 B1 EA 023913B1
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coenzyme
structural element
obesity
agents
oxidative phosphorylation
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EA201101523A
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EA201101523A1 (ru
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Найвен Раджин Нэрейн
Джон Патрик Маккук
Рангапрасад Сарангараджан
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БЕРГ ФАРМА ЭлЭлСи
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Publication of EA201101523A1 publication Critical patent/EA201101523A1/ru
Publication of EA023913B1 publication Critical patent/EA023913B1/ru

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Abstract

Описаны способы и композиции для лечения метаболических нарушений у людей с использованием эпиметаболических переключателей, многоаспектных внутриклеточных молекул или факторов влияния.

Description

(57) Описаны способы и композиции для лечения метаболических нарушений у людей с использованием эпиметаболических переключателей, многоаспектных внутриклеточных молекул или факторов влияния.
023913 Β1

Claims (24)

1. Способ лечения, облегчения симптомов, предотвращения прогрессирования или профилактики ожирения у млекопитающих, включающий введение нуждающемуся в этом млекопитающему терапевтически эффективного количества фармацевтической композиции, содержащей коэнзим 010 или по меньшей мере один структурный элемент коэнзима 010.
2. Способ по п.1, отличающийся тем, что коэнзим 010 или по меньшей мере один структурный элемент коэнзима 010 селективно вызывает в больных клетках млекопитающего переключение клеточного энергетического метаболизма в направлении нормализованного митохондриального окислительного фосфорилирования.
3. Способ по п.2, отличающийся тем, что коэнзим 010 или по меньшей мере один структурный элемент коэнзима 010, по существу, не вызывает в нормальных клетках млекопитающих переключения клеточного энергетического метаболизма в направлении митохондриального окислительного фосфорилирования.
4. Способ по п.1, отличающийся тем, что млекопитающим является человек (или не являющееся человеком млекопитающее).
5. Способ по п.1, отличающийся тем, что ожирение поддается или чувствительно к воздействию коэнзима 010, или его метаболитов, или аналогов.
6. Способ по п.1, отличающийся тем, что ожирение характеризуется дисрегуляцией функции митохондриального окислительного фосфорилирования, что приводит к изменению регуляции генов и/или взаимодействию белок-белок, что способствует или непосредственно приводит к ожирению.
7. Способ по п.1, отличающийся тем, что по меньшей мере один структурный элемент коэнзима 010 включает:
(a) бензохинон или по меньшей мере одну молекулу, которая способствует биосинтезу бензохинонового кольца, и (b) по меньшей мере одну молекулу, которая способствует синтезу и/или присоединению изопреноидных единиц к бензохиноновому кольцу.
8. Способ по п.7, отличающийся тем, что вышеупомянутая по меньшей мере одна молекула, которая способствует биосинтезу бензохинонового кольца, включает в себя Ь-фенилаланин, ОЬ-фенилаланин, Ό-фенилаланин, Ь-тирозин, ПЬ-тирозин, Ό-тирозин, 4-гидроксифенилпируват, 3-метокси-4гидроксиманделат (ванилилмандалата или УМА), ванилиновую кислоту, пиридоксин или пантенол.
9. Способ по п.7, отличающийся тем, что вышеупомянутая по меньшей мере одна молекула, которая способствует синтезу и/или присоединению изопреноидных единиц к бензохиноновому кольцу, включает в себя фенилацетат, 4-гидроксибензоат, мевалоновую кислоту, ацетилглицин, ацетил-СоА или фарнезил.
10. Способ по п.1, отличающийся тем, что по меньшей мере один структурный элемент коэнзима 010 включает:
(a) один или несколько из Ь-фенилаланина, Ь-тирозина и 4-гидроксифенилпирувата;
(b) один или несколько из 4-гидроксибензоата, фенилацетата и бензохинона.
11. Способ по п.1, отличающийся тем, что коэнзим 010 или по меньшей мере один структурный элемент коэнзима 010:
(a) ингибирует экспрессию Вс1-2 и/или стимулирует экспрессию каспазы-3 и/или (b) ингибирует клеточную пролиферацию.
12. Способ по п.1, отличающийся тем, что концентрация коэнзима 010 или по меньшей мере одного структурного элемента коэнзима 010 в тканях человека, подвергающегося лечению, отличается от концентрации в контрольном стандарте ткани человека, находящегося в здоровом или нормальном состоянии.
13. Способ по п.1, отличающийся тем, что форма коэнзима 010 или по меньшей мере одного структурного элемента коэнзима 010, вводимого человеку, отличается от преобладающей формы, находимой в системе кровотока у человека.
14. Способ по п.1, отличающийся тем, что количество фармацевтической композиции, достаточное для лечения ожирения у человека:
a) повышающе регулирует или понижающе регулирует митохондриальное окислительное фосфорилирование или
b) модулирует анаэробное использование глюкозы и/или биосинтез лактата.
15. Способ по п.1, отличающийся тем, что лечение происходит благодаря взаимодействию коэнзима 010 или по меньшей мере одного структурного элемента коэнзима 010 с НОТЧ-альфа или трансальдолазой.
16. Способ по п.1, где метаболическим нарушением является коэнзим 010 или по меньшей мере один структурный элемент коэнзима 010, действующий на окисление в митохондриях бета-клеток, уменьшающий размер адипоцитов и/или контролирующий уровни кортизола.
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17. Способ избирательного усиления митохондриального окислительного фосфорилирования в больных клетках млекопитающих, нуждающихся в лечении ожирения, включающий введение вышеупомянутому млекопитающему терапевтически эффективного количества фармацевтической композиции, содержащей коэнзим ф10 или по меньшей мере один структурный элемент коэнзима φ10, тем самым избирательно усиливая митохондриальное окислительное фосфорилирование в вышеупомянутых больных клетках млекопитающего.
18. Способ по п.17, отличающийся тем, что дополнительно включает:
a) повышающее регулирование экспрессии одного или более генов, выбранных из группы, состоящей из молекул, перечисленных в табл. 2-4, 6-28 и 63-68, имеющих позитивное кратное изменение; и/или понижающее регулирование экспрессии одного или более генов, выбранных из группы, состоящей из молекул, перечисленных в табл. 2-4, 6-28 и 63-68, имеющих негативное кратное изменение; или
b) модулирование экспрессии одного или более генов, выбранных из группы, состоящей из ΗΝΡ4альфа, Вс1-х1, Вс1-х8, ВМР-2, Вс1-2, В1гс6, Вс1-2-Ь11, ХАР, 20 ВКАР, Вах, с-1ип, ВтР, РИМА, сМус, трансальдолазы 1, СОф1, СОф3, СОф6, пренилтрансферазы, 4-гидробензоата, цитозольного фактора нейтрофилов 2, синтазы оксида азота 2А, супероксиддисмутазы 2, УЭЛС, Вах канала, ΆΝΤ, Цитохрома с, комплекса I, комплекса II, комплекса III, комплекса ТО, Рохо 3а, ΏΙ-1, ГОН-1, Ср!1С и Сат киназы II.
19. Способ по п.1, отличающийся тем, что вышеупомянутое лечение, облегчение симптомов, предотвращение прогрессирования или профилактика ожирения приводят к снижению объема талии, снижению содержания внутреннего жира, снижению уровня триглицеридов в плазме натощак или повышению уровня липопротеина высокой плотности натощак.
20. Способ по любому из пп.1, 17-19, отличающийся тем, что дополнительно включает введение дополнительного терапевтического агента.
21. Способ по п.20, отличающийся тем, что дополнительный терапевтически агент выбирается из группы, состоящей из агентов для лечения сахарного диабета, агентов для лечения осложнений диабета, антигиперлипемических агентов, гипотензивных или антигипертензивных агентов, агентов от ожирения, диуретиков, химиотерапевтических агентов, иммунотерапевтических агентов и иммуносупрессоров.
22. Способ уменьшения уровней липидов у пациента, включающий введение пациенту эффективного количества фармацевтической композиции, содержащей коэнзим ф10 или по меньшей мере один структурный элемент коэнзима ф10.
23. Способ лечения, облегчения симптомов, профилактики прогрессирования или предупреждения поддающегося воздействию коэнзима ф10 нарушения у млекопитающих, включающий введение нуждающемуся в этом млекопитающему терапевтически эффективного количества фармацевтической композиции, содержащей коэнзим ф10 или по меньшей мере один структурный элемент коэнзима ф10, где коэнзим ф10 или по меньшей мере один структурный элемент коэнзима ф10 избирательно вызывает в больных клетках млекопитающего переключение клеточного энергетического метаболизма в направлении уровней гликолиза и митохондриального окислительного фосфорилирования, наблюдаемых в нормальных клетках млекопитающих при нормальных физиологических условиях, где нарушением, поддающимся воздействию коэнзима ф10, является ожирение.
24. Способ по п.1, 17, 22 или 23, в котором фармацевтическая композиция содержит от 1 до 25 мас.% коэнзима ф10 или по меньшей мере одного структурного элемента коэнзима ф10.
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