The 46 references with contexts in paper G. Gorodetskaya I., V. Kukes G., S. Belkov A., R. Kazakov E., S. Serebrova Yu., O. Muslimova V., T. Rodina A., A. Aleksandrov A., Г. Городецкая И., В. Кукес Г., С. Белков А., Р. Казаков Е., С. Сереброва Ю., О. Муслимова В., Т. Родина А., А. Александров А. (2018) “Фармакогенетическое тестирование в оптимизации терапии сахарного диабета 2 типа препаратами сульфонилмочевины // Pharmacogenetic testing in the treatment of type 2 diabetes with sulfonylurea drugs” / spz:neicon:vedomostincesmp:y:2017:i:4:p:233-241

1
Dedov II, Shestakova MV, Mayorov AYu, Vikulova OK, Galstyan GR, Kuraeva TL, et al. Standards of specialized diabetes care. Diabetes mellitus 2017; 20(1S): 1–112 (in Russian).
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    Öåëåâîé óðîâåíü HbA1c îïðåäåëÿåòñÿ âîçðàñòîì ïàöèåíòà, îæèäàåìîé ïðîäîëæèòåëüíîñòüþ åãî æèçíè è íàëè÷èåì îñëîæíåíèé — ðèñêîì òÿæåëûõ ãèïîãëèêåìèé è/èëè ðàçâèòèÿ ñåðäå÷íî-ñîñóäèñòûõ îñëîæíåíèé. Ãèïîãëèêåìèÿ äëÿ ïàöèåíòîâ ñ ÑÄ, ïîëó÷àþùèõ ñàõàðîñíèæàþùóþ òåðàïèþ, îïðåäåëÿåòñÿ ïðè óðîâíå ãëþêîçû ïëàçìû <3,9 ììîëü/ë
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    . Ñåêðåöèÿ èíñóëèíà, êàê áàçàëüíàÿ, òàê è ïîñòïðàíäèàëüíàÿ, îñóùåñòâëÿåòñÿ â äâóõ ñî÷åòàþùèõñÿ ïóëüñèðóþùèõ ðåæèìàõ ñ ïåðèîäè÷íîñòüþ 6–10 ìèí (âûñîêî÷àñòîòíûå êîëåáàíèÿ) è 90 ìèí (óëüòðàäèàííûå êîëåáàíèÿ).

2
Kukes VG, Sychev DA, Andreev DA, Arkhipov VV, Batischeva GA, Berdnikova NG, et al. Ñlinical pharmacology. 5th ed. Moscow: GEOTAR-Media; 2015 (in Russian).
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    Ýòî ïðîèñõîäèò êàê ñ óæå èìåþùèìèñÿ ãðàíóëàìè, òàêèñíîâûìè, îáðàçóþùèìèñÿ â ïðîöåññå ñèíòåçà èíñóëèíà. Âòîðàÿ ôàçà áîëåå äëèòåëüíàÿ, ñåêðåöèÿ èíñóëèíà íàðàñòàåò ïîñòåïåííî è ïðîäîëæàåòñÿ äî íîðìàëèçàöèè óðîâíÿ ãëþêîçû
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    . Ïðèíÿòî ñ÷èòàòü, ÷òî ïðè ÑÄ 2 òèïà àáñîëþòíûé äåôåêò ñåêðåöèè èíñóëèíà ïîÿâëÿåòñÿ ëèøü íà ïîçäíèõ ñòàäèÿõ çàáîëåâàíèÿ, à áîëüøóþ ÷àñòü ïåðèîäà áîëåçíè èìååòñÿ ñîõðàíåííàÿ è äàæå (íà ðàííèõ ñòàäèÿõ) óñèëåííàÿ ôóíêöèÿb-êëåòîê ïîäæåëóäî÷íîé æåëåçû, êîòîðàÿ ïîñòåïåííî ñíèæàåòñÿ [3].

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    Èññëåäîâàòåëè èçó÷àëè ñâÿçü ïîëèìîðôèçìà Å23Ê ãåíà KCNJ11ñ óðîâíåì ãëèêèðîâàííîãî ãåìîãëîáèíà íà ôîíå ïðèåìà ÏÑÌ (ãëèìåïèðèäà èëè ãëèáåíêëàìèÒàáëèöà 1 ÎÑÍÎÂÍÛÅ ÔÀÐÌÀÊÎÊÈÍÅÒÈ×ÅÑÊÈÅ ÏÎÊÀÇÀÒÅËÈ ÏÐÅÏÀÐÀÒΠÑÓËÜÔÎÍÈËÌÎ×ÅÂÈÍÛ
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    Ïðåïàðàòû (ÌÍÍ è ôîðìû ïðåïàðàòà)Tmax 1, ÷Áèîäîñ-òóïíîñòü, % Ñâÿçü ñ áåëêîì, % Ìåòàáîëèòû Ýëèìèíàöèÿ, (÷/ç ïî÷êè/ÆÊÒ)Ò1/2, ÷ Äëèòåëüíîñòü äåéñòâèÿ, ÷ Ãëèáåíêëàìèä îáû÷íàÿ ôîðìàîò 1–2 äî 4–6 £7095–99 íåàêòèâíûå ìåòàáîëèòû: 50 % ñ ìî÷îé; 50 % ÷åðåç ÆÊÒ îò 6–10 äî 16 £24 ìèêðîíèçèðîâàííàÿ ôîðìà îò <1 äî 1,5 100>324 Ãëèêëàçèä îáû÷íàÿ ôîðìà480–9085–97 íåàêòèâíûå 60–70 % ñ ìî÷îé; 30–40 % ÷åðåç ÆÊÒ

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    ; 10 % ÷åðåç ÆÊÒ 3–424 ãàñòðîèíòåñòèíàëüíàÿ òåðàïåâòè÷åñêàÿ ñèñòåìà (ÃÈÒÑ) 6–122–5>24 Ãëèêâèäîí2–3100>95íåàêòèâíûå 5 % ñ ìî÷îé; 95 % ÷åðåç ÆÊÒ 0,5–1,510–12 Ãëèìåïèðèä2,510099àêòèâíûé è íåàêòèâíûé 60 % ñ ìî÷îé; 40 % ÷åðåç ÆÊÒ îò 5–8 äî 9 >24 1Âðåìÿ äîñòèæåíèÿ ìàêñèìàëüíîé êîíöåíòðàöèè 2Óêàçàíî âðåìÿ âûõîäà íà ïëàòî Òàáëèöà 2 ÏÅÐÅ×ÅÍÜ ÍÅÆÅËÀÒÅËÜÍÛÕ ÐÅÀÊÖÈÉ, ÂÛÇÛÂÀÅÌÛÕ ÏÐÅÏÀÐÀÒÀÌÈ ÑÓËÜÔÎÍÈËÌÎ×ÅÂÈÍÛ
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    ×àñòûåÐåäêèå Ìåòàáîëè÷åñêèå: – ãèïîãëèêåìèÿ – ïîâûøåíèå ìàññû òåëà Æåëóäî÷íî-êèøå÷íûå íàðóøåíèÿ: – ïîòåðÿ àïïåòèòà – îòðûæêà – èçæîãà – òîøíîòà è èçðåäêà ðâîòà – îùóùåíèå òÿæåñòè â ýïèãàñòðèè – ìåòåîðèçì – àáäîìèíàëüíûå áîëè – äèàðåÿ èëè çàïîð Êîæíûå ðåàêöèè: – êîðåïîäîáíàÿ ñûïü – ïÿòíèñòî-ïàïóëåçíàÿ ñûïü – êðàïèâíèöà – äèñóëüôèðàìîïîäîáíàÿ ðåàêöèÿ Êîæíûå ðåàêöèè(ìîãóò ñîïðîâîæäàòüñÿ çóäîì): – ôî

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Reaven GM. Role of insulin resistance in human disease: Banting lecture 1988. Diabetes 1988; 3737(12): 1595–607.
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    Ïðèíÿòî ñ÷èòàòü, ÷òî ïðè ÑÄ 2 òèïà àáñîëþòíûé äåôåêò ñåêðåöèè èíñóëèíà ïîÿâëÿåòñÿ ëèøü íà ïîçäíèõ ñòàäèÿõ çàáîëåâàíèÿ, à áîëüøóþ ÷àñòü ïåðèîäà áîëåçíè èìååòñÿ ñîõðàíåííàÿ è äàæå (íà ðàííèõ ñòàäèÿõ) óñèëåííàÿ ôóíêöèÿb-êëåòîê ïîäæåëóäî÷íîé æåëåçû, êîòîðàÿ ïîñòåïåííî ñíèæàåòñÿ
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    . Ïðè ýòîì óñòîé÷èâîñòü ê ãèïåðèíñóëèíåìèè è ñêîðîñòü ðàçâèòèÿ èñòîùåíèÿ ñåêðåòîðíîãî àïïàðàòà ïîäæåëóäî÷íîé æåëåçû ãåíåòè÷åñêè äåòåðìèíèðîâàíû [4]. Ïî äàííûì ìíîãîöåíòðîâîãî èññëåäîâàíèÿ, ïðîâåäåííîãî â 2008 ãîäó â ÑØÀ, ñ ÑÄ 2 òèïà àññîöèèðîâàíî íå ìåíåå 17 ãåíåòè÷åñêèõ ëîêóñîâ [5].

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Matschinsky F, Liang Y, Kesavan P, Wang L, Froguel P, Velho G, et al. Glucokinase as pancreatic beta cell glucose sensor and diabetes gene. J Clin Invest. 1993; 3792(5): 2092–8.
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    ÑÄ 2 òèïà àáñîëþòíûé äåôåêò ñåêðåöèè èíñóëèíà ïîÿâëÿåòñÿ ëèøü íà ïîçäíèõ ñòàäèÿõ çàáîëåâàíèÿ, à áîëüøóþ ÷àñòü ïåðèîäà áîëåçíè èìååòñÿ ñîõðàíåííàÿ è äàæå (íà ðàííèõ ñòàäèÿõ) óñèëåííàÿ ôóíêöèÿb-êëåòîê ïîäæåëóäî÷íîé æåëåçû, êîòîðàÿ ïîñòåïåííî ñíèæàåòñÿ [3]. Ïðè ýòîì óñòîé÷èâîñòü ê ãèïåðèíñóëèíåìèè è ñêîðîñòü ðàçâèòèÿ èñòîùåíèÿ ñåêðåòîðíîãî àïïàðàòà ïîäæåëóäî÷íîé æåëåçû ãåíåòè÷åñêè äåòåðìèíèðîâàíû
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    . Ïî äàííûì ìíîãîöåíòðîâîãî èññëåäîâàíèÿ, ïðîâåäåííîãî â 2008 ãîäó â ÑØÀ, ñ ÑÄ 2 òèïà àññîöèèðîâàíî íå ìåíåå 17 ãåíåòè÷åñêèõ ëîêóñîâ [5]. Ïåðñîíàëèçàöèÿ äèàãíîñòèêè ìîæåò áûòü ñâÿçàíà ñ âûáîðîì ôàðìàêîòåðàïèè.

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Florez JC. The genetics of type 2 diabetes: a realistic appraisal. J Clin Endocrinol Metab. 2008; 3793(12): 4633–42.
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    Ïðè ýòîì óñòîé÷èâîñòü ê ãèïåðèíñóëèíåìèè è ñêîðîñòü ðàçâèòèÿ èñòîùåíèÿ ñåêðåòîðíîãî àïïàðàòà ïîäæåëóäî÷íîé æåëåçû ãåíåòè÷åñêè äåòåðìèíèðîâàíû [4]. Ïî äàííûì ìíîãîöåíòðîâîãî èññëåäîâàíèÿ, ïðîâåäåííîãî â 2008 ãîäó â ÑØÀ, ñ ÑÄ 2 òèïà àññîöèèðîâàíî íå ìåíåå 17 ãåíåòè÷åñêèõ ëîêóñîâ
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    . Ïåðñîíàëèçàöèÿ äèàãíîñòèêè ìîæåò áûòü ñâÿçàíà ñ âûáîðîì ôàðìàêîòåðàïèè. Íàïðèìåð, ãåíTCF7L2 êîäèðóåò òðàíñêðèïöèîííûé ôàêòîð (TCF-4), êîòîðûé ó÷àñòâóåò â ðåãóëÿöèè êëåòî÷íîé ïðîëèôåðàöèè è äèôôåðåíöèðîâêè.

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Pearson ER, Donnelly LA, Kimber C, Whitley A, Doney AS, McCarthy MI, et al. Variation in TCF7L2 influences therapeutic response to sulfonylureas: a GoDARTs study. Diabetes 2007; 3756(8): 2178–82.
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    R. è äð. äîêàçàëè, ÷òî ïàöèåíòû, ãåíåòè÷åñêè ïðåäðàñïîëîæåííûå ê ðàçâèòèþ ÑÄ 2 òèïà (ñîãëàñíî ïîëèìîðôíûì ìàðêåðàì rs12255372 è rs7903146), â ìåíüøåé ñòåïåíè ðåàãèðóþò íà ïðåïàðàòû ñóëüôîíèëìî÷åâèíû (ÏÑÌ) èç-çà ñíèæåíèÿ ôóíêöèèb-êëåòîê
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    . Äëèòåëüíîå îòñóòñòâèå àáñîëþòíîãî äåôåêòà ñåêðåöèè èíñóëèíà ïðè ÑÄ 2 òèïà ïîçâîëÿåò äîëãîå âðåìÿ âîçäåðæèâàòüñÿ îò ïðîâåäåíèÿ çàìåñòèòåëüíîé òåðàïèè, èñïîëüçóÿ ïåðîðàëüíûå ñàõàðîñíèæàþùèå ïðåïàðàòû è/èëè èíêðåòèíîàêòèâíûå ñðåäñòâà.

7
Shvedova AM. Pharmacoepidemiological and pharmacoeconomic evaluation of oral hypoglycemic therapy of diabetes mellitus of the 2nd type in the ambulatory practice. International journal of endocrinology 2007; 4(10). Available from: http://www.mif-ua.com/archive/article/2875 (in Russian).
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    â îïòèìèçàöèè ëå÷åíèÿ ïàöèåíòîâ ñ ñàõàðíûì äèàáåòîì 2 òèïà ïðåïàðàòàìè ñóëüôîíèëìî÷åâèíû è îáîñíîâàíèå èñïîëüçîâàíèÿ ìåòîäèêè ôåíîòèïèðîâàíèÿ (ëîçàðòàíîâîãî òåñòà) â òåðàïèè äàííîãî çàáîëåâàíèÿ. Ñóùåñòâóåò òðè ïîêîëåíèÿ ÏÑÌ.  íàñòîÿùåå âðåìÿ ÏÑÌ ïåðâîãî ïîêîëåíèÿ â Ðîññèè íå ïðèìåíÿþòñÿ. Íàèáîëåå ÷àñòî (áîëåå ÷åì â 70 % ñëó÷àåâ) áîëüíûå ïîëó÷àþò ãëèêëàçèä, ãëèáåíêëàìèä èëè ãëèìåïèðèä
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    , ïðè ýòîì ÏÑÌ â ïîëîâèíå ñëó÷àåâ èñïîëüçóþòñÿ êàê ìîíîïðåïàðàòû äëÿ ìîíîòåðàïèè, à â ïîëîâèíå — êîìáèíèðóþòñÿ ñ äðóãèìè ËÑ, â òîì ÷èñëå â âèäå êîìáèíèðîâàííûõ ïðåïàðàòîâ ñ ìåòôîðìèíîì [8]. Äåéñòâèå ÏÑÌ îïîñðåäóåòñÿ ÷åðåç ðåöåïòîðû ñóëüôîíèëìî÷åâèíû (SUR), êîòîðûå ïðåäñòàâëÿþò ñîáîé ðåãóëÿòîðíóþ ñóáúåäèíèöó ÀÒÔ-çàâèñèìîãî K+-êàíàëà.

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Shestakova MV. Actual clinical practice of treatment of diabetes type 2 in the Russian Federation according to the prospective open observational program «DIA-CONTROL». Diabetes mellitus 2011; (4): 75–80 (in Russian).
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    Íàèáîëåå ÷àñòî (áîëåå ÷åì â 70 % ñëó÷àåâ) áîëüíûå ïîëó÷àþò ãëèêëàçèä, ãëèáåíêëàìèä èëè ãëèìåïèðèä [7], ïðè ýòîì ÏÑÌ â ïîëîâèíå ñëó÷àåâ èñïîëüçóþòñÿ êàê ìîíîïðåïàðàòû äëÿ ìîíîòåðàïèè, à â ïîëîâèíå — êîìáèíèðóþòñÿ ñ äðóãèìè ËÑ, â òîì ÷èñëå â âèäå êîìáèíèðîâàííûõ ïðåïàðàòîâ ñ ìåòôîðìèíîì
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    . Äåéñòâèå ÏÑÌ îïîñðåäóåòñÿ ÷åðåç ðåöåïòîðû ñóëüôîíèëìî÷åâèíû (SUR), êîòîðûå ïðåäñòàâëÿþò ñîáîé ðåãóëÿòîðíóþ ñóáúåäèíèöó ÀÒÔ-çàâèñèìîãî K+-êàíàëà. Ðàçëè÷àþò äâà òèïà ýòèõ ðåöåïòîðîâ: SUR1, ëîêàëèçóþùèåñÿ íà ïîâåðõíîñòè ìåìáðàí b-êëåòîê ïîäæåëóäî÷íîé æåëåçû, êîòîðûå ó÷àñòâóþò â ðåãóëÿöèè ñåêðåöèè èíñóëèíà è ñòèìóëèðóþòñÿ âñåìè ÏÑÌ, è SUR2, ðàñïîëàãàþùèåñÿ â ìèîêàðäå (SUR2à) è ñòåíêàõ àðòåðèàëüí

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Ashcroft FM, Gribble FM. ATP-sensitive K+ channels and insulin secretion: their role in helht and disease. Diabetologia 1999; 3742(8): 903–19.
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    Ïàðàëëåëüíî îòêðûâàþòñÿ ïîòåíöèàëçàâèñèìûå Ñà2+-êàíàëû, ÷òî îáåñïå÷èâàåò áûñòðîå ïîñòóïëåíèå â öèòîïëàçìó èîíîâ êàëüöèÿ, íàêîïëåíèå êîòîðûõ âb-êëåòêàõ ïîäæåëóäî÷íîé æåëåçû âûçûâàåò ýêçîöèòîç ãðàíóë è âûñâîáîæäåíèå èíñóëèíà èç êëåòêè
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    . Ãëèáåíêëàìèä è ãëèìåïèðèä, ïîìèìî ñóëüôîíèëìî÷åâèííîé ãðóïïèðîâêè, ñîäåðæàò åùå áåíçàìèäíóþ ãðóïïó, êîòîðàÿ òàêæå ñâÿçûâàåòñÿ ñ SUR. Ñ÷èòàåòñÿ, ÷òî òàêàÿ ñòðóêòóðà îáóñëîâëèâàåò íàèáîëüøåå ñðîäñòâî ýòèõ ËÑ ê ðåöåïòîðó [10].

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Nedosugova LV, Balabolkin MI. Algorithm treatment diabetes type 2 diabetes. Moscow: MedExpertPress; 2008 (in Russian).
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    Ãëèáåíêëàìèä è ãëèìåïèðèä, ïîìèìî ñóëüôîíèëìî÷åâèííîé ãðóïïèðîâêè, ñîäåðæàò åùå áåíçàìèäíóþ ãðóïïó, êîòîðàÿ òàêæå ñâÿçûâàåòñÿ ñ SUR. Ñ÷èòàåòñÿ, ÷òî òàêàÿ ñòðóêòóðà îáóñëîâëèâàåò íàèáîëüøåå ñðîäñòâî ýòèõ ËÑ ê ðåöåïòîðó
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    . Ãëèáåíêëàìèä îáëàäàåò ñàìûì ñèëüíûì ñðîäñòâîì ê SUR1, îïðåäåëÿþùèì ïîñòîÿííûé äëèòåëüíûé ñàõàðîñíèæàþùèé ýôôåêò ïðåïàðàòà.  îòëè÷èå îò íåãî ãëèìåïèðèä, ñâÿçûâàþùèéñÿ ñ íèçêîìîëåêóëÿðíûì ó÷àñòêîì SUR1, îáëàäàåò â 2–3 ðàçà ìåíüøèì ñðîäñòâîì ê SUR1,íî â 2,5–3 ðàçà áîëåå âûñîêîé ÷àñòîòîé àññîöèàöèè ñ ðåöåïòîðîì è â 8–9 ðàç áîëåå âûñîêîé ÷àñòîòîé äèññîöèàöèè [11].

11
Muller G, Hartz D, Punter J, Okonomopulos R, Kramer W. Differential interaction of glimepiride and glibenclamide with the beta–cell sulfonylurea receptor. I. Binding characteristics. Biochim Biophys Acta 1994; 371191(2): 267–77.
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     îòëè÷èå îò íåãî ãëèìåïèðèä, ñâÿçûâàþùèéñÿ ñ íèçêîìîëåêóëÿðíûì ó÷àñòêîì SUR1, îáëàäàåò â 2–3 ðàçà ìåíüøèì ñðîäñòâîì ê SUR1,íî â 2,5–3 ðàçà áîëåå âûñîêîé ÷àñòîòîé àññîöèàöèè ñ ðåöåïòîðîì è â 8–9 ðàç áîëåå âûñîêîé ÷àñòîòîé äèññîöèàöèè
    Exact
    [11]
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    . Ãëèêëàçèä ÿâëÿåòñÿ ñåëåêòèâíûì SUR1-àãîíèñòîì ñî ñâîáîäíûì îáðàòèìûì ñâÿçûâàíèåì ñ ðåöåïòîðîì [12]. Âîçäåéñòâóÿ íà SUR1, âñå ÏÑÌ ñòèìóëèðóþò åñòåñòâåííóþ ñåêðåöèþ èíñóëèíà, íî ïî-ðàçíîìó âëèÿþò íà êàæäóþ èç äâóõ ôàç ñåêðåöèè.

12
Haffner SM, Miettinen H, Stern MP. The homeostasis model in the San Antonio Heart Study. Diabetes Care 1997; 20(7): 1087–92.
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     îòëè÷èå îò íåãî ãëèìåïèðèä, ñâÿçûâàþùèéñÿ ñ íèçêîìîëåêóëÿðíûì ó÷àñòêîì SUR1, îáëàäàåò â 2–3 ðàçà ìåíüøèì ñðîäñòâîì ê SUR1,íî â 2,5–3 ðàçà áîëåå âûñîêîé ÷àñòîòîé àññîöèàöèè ñ ðåöåïòîðîì è â 8–9 ðàç áîëåå âûñîêîé ÷àñòîòîé äèññîöèàöèè [11]. Ãëèêëàçèä ÿâëÿåòñÿ ñåëåêòèâíûì SUR1-àãîíèñòîì ñî ñâîáîäíûì îáðàòèìûì ñâÿçûâàíèåì ñ ðåöåïòîðîì
    Exact
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    . Âîçäåéñòâóÿ íà SUR1, âñå ÏÑÌ ñòèìóëèðóþò åñòåñòâåííóþ ñåêðåöèþ èíñóëèíà, íî ïî-ðàçíîìó âëèÿþò íà êàæäóþ èç äâóõ ôàç ñåêðåöèè.  îòëè÷èå îò ãëèáåíêëàìèäà, êîòîðûé â çíà÷èòåëüíîé ìåðå ñòèìóëèðóåò âòîðóþ ôàçó, ãëèìåïèðèä óñèëèâàåò îáå ôàçû ñåêðåöèè èíñóëèíà (ïðè íîðìî- è ãèïåðãëèêåìèè) [13], à ãëèêëàçèä â îñíîâíîì âëèÿåò íà ïåðâóþ ôàçó [14], õîòÿ èìåþòñÿ äàííûå î åãî ñïîñîáíîñòè âîññòàíàâëèâ

13
Attorrese G, Massi-Benedetti M. Quality and behaviour generic versus amaryl under stress conditions. Diabetes Technology and Therapeutics 2007; 379(3): 287–96.
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    Âîçäåéñòâóÿ íà SUR1, âñå ÏÑÌ ñòèìóëèðóþò åñòåñòâåííóþ ñåêðåöèþ èíñóëèíà, íî ïî-ðàçíîìó âëèÿþò íà êàæäóþ èç äâóõ ôàç ñåêðåöèè.  îòëè÷èå îò ãëèáåíêëàìèäà, êîòîðûé â çíà÷èòåëüíîé ìåðå ñòèìóëèðóåò âòîðóþ ôàçó, ãëèìåïèðèä óñèëèâàåò îáå ôàçû ñåêðåöèè èíñóëèíà (ïðè íîðìî- è ãèïåðãëèêåìèè)
    Exact
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    , à ãëèêëàçèä â îñíîâíîì âëèÿåò íà ïåðâóþ ôàçó [14], õîòÿ èìåþòñÿ äàííûå î åãî ñïîñîáíîñòè âîññòàíàâëèâàòü ðàííþþ ôàçó è íîðìàëèçîâàòü âòîðóþ [15].  çàâèñèìîñòè îò ôàðìàêîêèíåòè÷åñêèõ õàðàêòåðèñòèê, ÏÑÌ âòîðîãî ïîêîëåíèÿ ìîæíî ðàçäåëèòü íà äâå ïîäãðóïïû (òàáë. 1): – ËÑ ñ îáû÷íîé ôàðìàêîêèíåòèêîé; – ËÑ ñ óëó÷øåííîé ôàðìàêîêèíåòèêîé.

14
Cozma LS, Luzio SD, Dunseath GJ, Langendorg KW, Pieber T, Owens DR. Comparison of the effects of three insulinotropic drugs on plasma insulin levels after a standard meal. Diabetes Care 2002; 3725(8): 1271–6.
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     îòëè÷èå îò ãëèáåíêëàìèäà, êîòîðûé â çíà÷èòåëüíîé ìåðå ñòèìóëèðóåò âòîðóþ ôàçó, ãëèìåïèðèä óñèëèâàåò îáå ôàçû ñåêðåöèè èíñóëèíà (ïðè íîðìî- è ãèïåðãëèêåìèè) [13], à ãëèêëàçèä â îñíîâíîì âëèÿåò íà ïåðâóþ ôàçó
    Exact
    [14]
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    , õîòÿ èìåþòñÿ äàííûå î åãî ñïîñîáíîñòè âîññòàíàâëèâàòü ðàííþþ ôàçó è íîðìàëèçîâàòü âòîðóþ [15].  çàâèñèìîñòè îò ôàðìàêîêèíåòè÷åñêèõ õàðàêòåðèñòèê, ÏÑÌ âòîðîãî ïîêîëåíèÿ ìîæíî ðàçäåëèòü íà äâå ïîäãðóïïû (òàáë. 1): – ËÑ ñ îáû÷íîé ôàðìàêîêèíåòèêîé; – ËÑ ñ óëó÷øåííîé ôàðìàêîêèíåòèêîé.

15
Hosker JP, Rudenski AS, Burnett MA, Matthews DR, Turner RC. Similar reduction of first- and second-phase â-cell responses at three different glucose levels in type II diabetes and the effect of gliclazide therapy. Metabolism 1989; 3738(8): 767–72.
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     îòëè÷èå îò ãëèáåíêëàìèäà, êîòîðûé â çíà÷èòåëüíîé ìåðå ñòèìóëèðóåò âòîðóþ ôàçó, ãëèìåïèðèä óñèëèâàåò îáå ôàçû ñåêðåöèè èíñóëèíà (ïðè íîðìî- è ãèïåðãëèêåìèè) [13], à ãëèêëàçèä â îñíîâíîì âëèÿåò íà ïåðâóþ ôàçó [14], õîòÿ èìåþòñÿ äàííûå î åãî ñïîñîáíîñòè âîññòàíàâëèâàòü ðàííþþ ôàçó è íîðìàëèçîâàòü âòîðóþ
    Exact
    [15]
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    .  çàâèñèìîñòè îò ôàðìàêîêèíåòè÷åñêèõ õàðàêòåðèñòèê, ÏÑÌ âòîðîãî ïîêîëåíèÿ ìîæíî ðàçäåëèòü íà äâå ïîäãðóïïû (òàáë. 1): – ËÑ ñ îáû÷íîé ôàðìàêîêèíåòèêîé; – ËÑ ñ óëó÷øåííîé ôàðìàêîêèíåòèêîé. Ãëèáåíêëàìèä (ãëèáóðèä â ÑØÀ) âõîäèò â «Îðàíæåâóþ êíèãó».

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Davis SN. The role of glimepiride in the effective management of type 2 diabetes. J Diabetes Complications 2004; 3718(6): 367–76.
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    Òàê, åñëè ãëèáåíêëàìèä âëèÿåò è íà ïîñòïðàíäèàëüíóþ, è íà áàçàëüíóþ ñåêðåöèþ èíñóëèíà, ñîçäàâàÿ ïîñëåäíèì óãðîçó ãèïîãëèêåìèè, òî ãëèìåïèðèä ñòèìóëèðóåò ñåêðåöèþ èíñóëèíà ïî÷òè èñêëþ÷èòåëüíî âî âðåìÿ ïðèåìîâ ïèùè, ÷òî îáåñïå÷èâàåò îòíîñèòåëüíî íèçêèé ðèñê ðàçâèòèÿ ãèïîãëèêåìèé
    Exact
    [16]
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    . Ñàõàðîñíèæàþùåå äåéñòâèå âñåõ ÏÑÌ, êàê è ðàçâèòèå íåæåëàòåëüíûõ ðåàêöèé, íîñèò äîçîçàâèñèìûé õàðàêòåð. Ïðè ïðèìåíåíèè ëþáîãî ÏÑÌ ñóùåñòâóåò áîëüøèé èëè ìåíüøèé ðèñê âîçíèêíîâåíèÿ ãèïîãëèêåìèè, ñâÿçàííîé ñ íàðóøåíèåì äèåòû è ðåæèìà ôèçè÷åñêèõ íàãðóçîê (òàáë. 2).

17
Holstein A, Plaschke A, Egberts EH. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev. 2001; 3717(6): 467–73.
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     ñðàâíèòåëüíîì èññëåäîâàíèè ÷àñòîòû òÿæåëûõ ãèïîãëèêåìèé, òðåáîâàâøèõ äëÿ êóïèðîâàíèÿ âíóòðèâåííîãî ââåäåíèÿ ãëþêîçû èëè ãëþêàãîíà, áûëî ïîêàçàíî, ÷òî ó áîëüíûõ, ïîëó÷àâøèõ ãëèìåïèðèä, îíà áûëà â 6,5 ðàç ìåíåå âûðàæåíà, ÷åì ïðè èñïîëüçîâàíèè ãëèáåíêëàìèäà. Òàêèì îáðàçîì, ãëèìåïèðèä áîëåå áåçîïàñåí, ÷åì ãëèáåíêëàìèä
    Exact
    [17]
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    . Åùå áåçîïàñíåå îêàçûâàåòñÿ ãëèêëàçèä: ïðè îäèíàêîâîì óðîâíå ãëèêåìè÷åñêîãî êîíòðîëÿ ãèïîãëèêåìèè â ãðóïïå ïàöèåíòîâ, ïîëó÷àâøèõ ãëèìåïèðèä, âîçíèêàëè â 12,2 % ñëó÷àåâ ïðîòèâ 4,2 % íà ôîíå ãëèêëàçèäà [18].

18
Schernthaner G, Grimaldi A, Di-Mario U, Drzewoski J, Kempler P, Kvapil M, et al. GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest. 2004; 3734(8): 535–42.
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    Åùå áåçîïàñíåå îêàçûâàåòñÿ ãëèêëàçèä: ïðè îäèíàêîâîì óðîâíå ãëèêåìè÷åñêîãî êîíòðîëÿ ãèïîãëèêåìèè â ãðóïïå ïàöèåíòîâ, ïîëó÷àâøèõ ãëèìåïèðèä, âîçíèêàëè â 12,2 % ñëó÷àåâ ïðîòèâ 4,2 % íà ôîíå ãëèêëàçèäà
    Exact
    [18]
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    . ÃåíûKCNJ11èABCC8(SUR1) êîäèðóþò Kir6.2 ñóáúåäèíèöó è SUR1-ñóáúåäèíèöó Ê+ÀÒÔ-êàíàëà, ñîîòâåòñòâåííî. Áûëà îáíàðóæåíà ñâÿçü ïîëèìîðôèçìà E23K ãåíàKCNJ11ñ ðèñêîì ðàçâèòèÿ âòîðè÷íîé äåêîìïåíñàöèè ïðè ïðèåìå ÏÑÌ.

19
Sesti G, Laratta E, Cardellini M, Andreozzi F, Del Guerra S, Irace C, et al. The E23K variant of KCNJ11 encoding the pancreatic beta-cell adenosine 5’-triphosphate-sensitive potassium channel subunit Kir6.2 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes. J Clin Endocrinol Metab.
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    Ïîä âòîðè÷íîé äåêîìïåíñàöèåé ïîíèìàëîñü óâåëè÷åíèå óðîâíÿ ãëþêîçû ïëàçìû >16,6 ììîëü/ë íåñìîòðÿ íà ïðîâîäèìóþ òåðàïèþ ÏÑÌ è ìåòôîðìèíîì ïðè ñîáëþäåíèè äèåòû è îòñóòñòâèè äðóãèõ ïðè÷èí, ñïîñîáíûõ âûçâàòü ãèïåðãëèêåìèþ
    Exact
    [19]
    Suffix
    . Èññëåäîâàòåëè èçó÷àëè ñâÿçü ïîëèìîðôèçìà Å23Ê ãåíà KCNJ11ñ óðîâíåì ãëèêèðîâàííîãî ãåìîãëîáèíà íà ôîíå ïðèåìà ÏÑÌ (ãëèìåïèðèäà èëè ãëèáåíêëàìèÒàáëèöà 1 ÎÑÍÎÂÍÛÅ ÔÀÐÌÀÊÎÊÈÍÅÒÈ×ÅÑÊÈÅ ÏÎÊÀÇÀÒÅËÈ ÏÐÅÏÀÐÀÒΠÑÓËÜÔÎÍÈËÌÎ×ÅÂÈÍÛ [2] Ïðåïàðàòû (ÌÍÍ è ôîðìû ïðåïàðàòà)Tmax 1, ÷Áèîäîñ-òóïíîñòü, % Ñâÿçü ñ áåëêîì, % Ìåòàáîëèòû Ýëèìèíàöèÿ, (÷/ç ïî÷êè/ÆÊÒ)Ò1/2, ÷ Äëèòåëüíîñòü äåéñòâèÿ, ÷ Ãëèáåíêëàìèä îáû÷íàÿ ôîð

20
6; 3791(6): 2334–9. 20. Holstein A, Hahn M, Stumvoll M, Kovacs P. The E23K variant of KCNJ11 and the risk for severe sulfonylurea-induced hypoglycemia in patients with type 2 diabetes. Horm Metab Res. 2009; 3741(5): 387–90.
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    îñòðàÿ ïå÷åíî÷íàÿ, òàê è ïîçäíÿÿ êîæíàÿ) Ãåïàòîòîêñè÷åñêèå ýôôåêòû: – òðàíçèòîðíîå ïîâûøåíèå – àêòèâíîñòè ïå÷åíî÷íûõ ôåðìåíòî⠖ ãåïàòèò – âíóòðèïå÷åíî÷íûé õîëåñòàç (õîëåñòàòè÷åñêàÿ æåëòóõà) – ïå÷åíî÷íàÿ íåäîñòàòî÷íîñòü äà) ó 98 ïàöèåíòîâ.  õîäå èññëåäîâàíèé áûëà îáíàðóæåíà àññîöèàöèÿ ïîëèìîðôèçìà Å23Ê ñ îòâåòîì íà òåðàïèþ ÏÑÌ, óðîâíåì ãëèêèðîâàííîãî ãåìîãëîáèíà è ðèñêîì ðàçâèòèÿ ãèïîãëèêåìèè
    Exact
    [20]
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    . Áûëî ïðîäåìîíñòðèðîâàíî âëèÿíèå ãåíåòè÷åñêîãî ïîëèìîðôèçìà SUR1íà ýôôåêò ãèïîãëèêåìè÷åñêîé òåðàïèè ÏÑÌ.  ÷àñòíîñòè, áûëî ïîêàçàíî, ÷òî ïàöèåíòû «äèêîãî òèïà »(ãåíîòèï C/C SUR116 ýêçîíà) èìåëè ñóùåñòâåííî áîëåå íèçêèå óðîâíè ãëèêèðîâàííîãî ãåìîãëîáèíà, ÷åì ïàöèåíòû ñ ãåíîòèïîì T/T [21].

21
Nikolac N, Simundic AM, Katalinic D, Topic E, Cipak A, Zjacic Rotkvic V. Metabolic control in type 2 diabetes is associated with sulfonylurea receptor-1 (SUR-1) but not with KCNJ11 polymorphisms. Arch Med Res. 2009; 40(5): 387–92.
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    Áûëî ïðîäåìîíñòðèðîâàíî âëèÿíèå ãåíåòè÷åñêîãî ïîëèìîðôèçìà SUR1íà ýôôåêò ãèïîãëèêåìè÷åñêîé òåðàïèè ÏÑÌ.  ÷àñòíîñòè, áûëî ïîêàçàíî, ÷òî ïàöèåíòû «äèêîãî òèïà »(ãåíîòèï C/C SUR116 ýêçîíà) èìåëè ñóùåñòâåííî áîëåå íèçêèå óðîâíè ãëèêèðîâàííîãî ãåìîãëîáèíà, ÷åì ïàöèåíòû ñ ãåíîòèïîì T/T
    Exact
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    . ÏÑÌ òàêæå îáëàäàþò ýôôåêòàìè, íå ñâÿçàííûìè ñ ïàíêðåàòè÷åñêèìèb-êëåòêàìè, êîòîðûå îáóñëîâëèâàþò ïîâûøåíèå ÷óâñòâèòåëüíîñòè ê èíñóëèíó ïåðèôåðè÷åñêèõ òêàíåé, â ïåðâóþ î÷åðåäü æèðîâîé è ìûøå÷íîé, è óëó÷øåíèþ óñâîåíèÿ ãëþêîçû êëåòêàìè [22].

22
Balabolkin MI, Kreminskaya VM, Klebanova EM. Modern tactics of treatment of diabetes mellitus type 2. Consilium medicum 2001; 373(11): 535–40 (in Russian).
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    ÏÑÌ òàêæå îáëàäàþò ýôôåêòàìè, íå ñâÿçàííûìè ñ ïàíêðåàòè÷åñêèìèb-êëåòêàìè, êîòîðûå îáóñëîâëèâàþò ïîâûøåíèå ÷óâñòâèòåëüíîñòè ê èíñóëèíó ïåðèôåðè÷åñêèõ òêàíåé, â ïåðâóþ î÷åðåäü æèðîâîé è ìûøå÷íîé, è óëó÷øåíèþ óñâîåíèÿ ãëþêîçû êëåòêàìè
    Exact
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    . Âíåïàíêðåàòè÷åñêèé ìåõàíèçì äåéñòâèÿ ãëèáåíêëàìèäà ñïîñîáñòâóåò óòèëèçàöèè äîïîëíèòåëüíîãî êîëè÷åñòâà ãëþêîçû è ñíèæåíèþ óðîâíÿ ãëèêåìèè çà ñ÷åò íåðåãóëèðóåìîé àêòèâíîñòè [23].  îòëè÷èå îò ãëèêëàçèäà, ÿâëÿþùåãîñÿ SUR1-ñåëåêòèâíûì ÏÑÌ, ãëèáåíêëàìèä è ãëèìåïèðèä îáà âëèÿþò íà SUR2àìèîêàðäà è SUR2bàðòåðèàëüíûõ ñîñóäîâ, îäíàêî íåðàâíîçíà÷íî âîçäåéñòâóþò íà «èøåìè÷åñêîå ïðåêîíäèöèîíèðîâàíèå »ìèîêà

23
Fronzo RA, Simonson DC. Oral sulfonylurea agents suppress hepatic glucose production in non-insulin-dependent diabetic individuals. Diabetes Care 1984; 377(1): 72–80.
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    îáëàäàþò ýôôåêòàìè, íå ñâÿçàííûìè ñ ïàíêðåàòè÷åñêèìèb-êëåòêàìè, êîòîðûå îáóñëîâëèâàþò ïîâûøåíèå ÷óâñòâèòåëüíîñòè ê èíñóëèíó ïåðèôåðè÷åñêèõ òêàíåé, â ïåðâóþ î÷åðåäü æèðîâîé è ìûøå÷íîé, è óëó÷øåíèþ óñâîåíèÿ ãëþêîçû êëåòêàìè [22]. Âíåïàíêðåàòè÷åñêèé ìåõàíèçì äåéñòâèÿ ãëèáåíêëàìèäà ñïîñîáñòâóåò óòèëèçàöèè äîïîëíèòåëüíîãî êîëè÷åñòâà ãëþêîçû è ñíèæåíèþ óðîâíÿ ãëèêåìèè çà ñ÷åò íåðåãóëèðóåìîé àêòèâíîñòè
    Exact
    [23]
    Suffix
    .  îòëè÷èå îò ãëèêëàçèäà, ÿâëÿþùåãîñÿ SUR1-ñåëåêòèâíûì ÏÑÌ, ãëèáåíêëàìèä è ãëèìåïèðèä îáà âëèÿþò íà SUR2àìèîêàðäà è SUR2bàðòåðèàëüíûõ ñîñóäîâ, îäíàêî íåðàâíîçíà÷íî âîçäåéñòâóþò íà «èøåìè÷åñêîå ïðåêîíäèöèîíèðîâàíèå »ìèîêàðäà [24].

24
Klepzig H, Kober G, Matter C, Luus H, Schneider H, Boedeker KH, et al. Sulfonylureas and ischemic preconditioning. A double-blind, placebo-controlled evolution of glimepiride and glibenclamide. Eur Heart J. 1999; 20(6): 439–46.
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     îòëè÷èå îò ãëèêëàçèäà, ÿâëÿþùåãîñÿ SUR1-ñåëåêòèâíûì ÏÑÌ, ãëèáåíêëàìèä è ãëèìåïèðèä îáà âëèÿþò íà SUR2àìèîêàðäà è SUR2bàðòåðèàëüíûõ ñîñóäîâ, îäíàêî íåðàâíîçíà÷íî âîçäåéñòâóþò íà «èøåìè÷åñêîå ïðåêîíäèöèîíèðîâàíèå »ìèîêàðäà
    Exact
    [24]
    Suffix
    . Ãëèìåïèðèä, ñâÿçûâàÿñü ñ íèçêîìîëåêóëÿðíûì ó÷àñòêîì SUR, îñòàâëÿåò îòêðûòûìè ÀÒÔ-çàâèñèìûå Ê+-êàíàëû ìèòîõîíäðèàëüíûõ ìåìáðàí êàðäèîìèîöèòîâ [25]. ÖÈÒÎÕÐÎÌÛ P450  ÁÈÎÒÐÀÍÑÔÎÐÌÀÖÈÈ ËÅÊÀÐÑÒÂÅÍÍÛÕ ÑÐÅÄÑÒ Ó÷àñòèå â ìåòàáîëèçìå ÏÑÌ èçîôåðìåíòà öèòîõðîìà Ð450 2C9 ïîäòâåðæäåíî â ðÿäå èññëåäîâàíèé [26].

25
Nagashima K, Takahashi A, Ikeda H, Hamasaki A, Kuwamura N, Yamada Y, et al. Sulfonylurea and non-sulfonylurea hypoglycemic agents: pharmacological properties and tissue selectivity. Diabetes Res Clin Pract. 2004; 66 (Suppl. 1): S75–8.
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     îòëè÷èå îò ãëèêëàçèäà, ÿâëÿþùåãîñÿ SUR1-ñåëåêòèâíûì ÏÑÌ, ãëèáåíêëàìèä è ãëèìåïèðèä îáà âëèÿþò íà SUR2àìèîêàðäà è SUR2bàðòåðèàëüíûõ ñîñóäîâ, îäíàêî íåðàâíîçíà÷íî âîçäåéñòâóþò íà «èøåìè÷åñêîå ïðåêîíäèöèîíèðîâàíèå »ìèîêàðäà [24]. Ãëèìåïèðèä, ñâÿçûâàÿñü ñ íèçêîìîëåêóëÿðíûì ó÷àñòêîì SUR, îñòàâëÿåò îòêðûòûìè ÀÒÔ-çàâèñèìûå Ê+-êàíàëû ìèòîõîíäðèàëüíûõ ìåìáðàí êàðäèîìèîöèòîâ
    Exact
    [25]
    Suffix
    . ÖÈÒÎÕÐÎÌÛ P450  ÁÈÎÒÐÀÍÑÔÎÐÌÀÖÈÈ ËÅÊÀÐÑÒÂÅÍÍÛÕ ÑÐÅÄÑÒ Ó÷àñòèå â ìåòàáîëèçìå ÏÑÌ èçîôåðìåíòà öèòîõðîìà Ð450 2C9 ïîäòâåðæäåíî â ðÿäå èññëåäîâàíèé [26]. Ãëèáåíêëàìèä ïî÷òè ïîëíîñòüþ ìåòàáîëèçèðóåòñÿ â ïå÷åíè ýòèì èçîôåðìåíòîì(CYP3A4 ñòåíêè êèøêè èãðàåò âñïîìîãàòåëüíóþ ðîëü) ñ îáðàçîâàíèåì äâóõ àêòèâíûõ ìåòàáîëèòîâ: 4-òðàíñ-ãèäðîêñè-ãëèáåíêëàìèäà è 3-öèñ-ãèäðîêñè-ãëèáåíêëàìèäà, êîòîðûå ýêñêðåòèðóþ

26
Indiana University. Department of Medicine. P450 Drug Interaction Table. Available from: http://medicine.iupui.edu/clinpharm/ddis/ main-table.
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    Ãëèìåïèðèä, ñâÿçûâàÿñü ñ íèçêîìîëåêóëÿðíûì ó÷àñòêîì SUR, îñòàâëÿåò îòêðûòûìè ÀÒÔ-çàâèñèìûå Ê+-êàíàëû ìèòîõîíäðèàëüíûõ ìåìáðàí êàðäèîìèîöèòîâ [25]. ÖÈÒÎÕÐÎÌÛ P450  ÁÈÎÒÐÀÍÑÔÎÐÌÀÖÈÈ ËÅÊÀÐÑÒÂÅÍÍÛÕ ÑÐÅÄÑÒ Ó÷àñòèå â ìåòàáîëèçìå ÏÑÌ èçîôåðìåíòà öèòîõðîìà Ð450 2C9 ïîäòâåðæäåíî â ðÿäå èññëåäîâàíèé
    Exact
    [26]
    Suffix
    . Ãëèáåíêëàìèä ïî÷òè ïîëíîñòüþ ìåòàáîëèçèðóåòñÿ â ïå÷åíè ýòèì èçîôåðìåíòîì(CYP3A4 ñòåíêè êèøêè èãðàåò âñïîìîãàòåëüíóþ ðîëü) ñ îáðàçîâàíèåì äâóõ àêòèâíûõ ìåòàáîëèòîâ: 4-òðàíñ-ãèäðîêñè-ãëèáåíêëàìèäà è 3-öèñ-ãèäðîêñè-ãëèáåíêëàìèäà, êîòîðûå ýêñêðåòèðóþòñÿ ïî÷êàìè è ïå÷åíüþ ïðèìåðíî ïîðîâíó [27].

27
Christ OE, Heptner W, Rupp W. Investigations on absorption, excretion and metabolism in man after administration of 14C-labelled HB 419. Horm Metab Res. 1969; 1 (Suppl. l): 51–4.
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    Ãëèáåíêëàìèä ïî÷òè ïîëíîñòüþ ìåòàáîëèçèðóåòñÿ â ïå÷åíè ýòèì èçîôåðìåíòîì(CYP3A4 ñòåíêè êèøêè èãðàåò âñïîìîãàòåëüíóþ ðîëü) ñ îáðàçîâàíèåì äâóõ àêòèâíûõ ìåòàáîëèòîâ: 4-òðàíñ-ãèäðîêñè-ãëèáåíêëàìèäà è 3-öèñ-ãèäðîêñè-ãëèáåíêëàìèäà, êîòîðûå ýêñêðåòèðóþòñÿ ïî÷êàìè è ïå÷åíüþ ïðèìåðíî ïîðîâíó
    Exact
    [27]
    Suffix
    . Ãëèêëàçèä ìåòàáîëèçèðóåòñÿ äî íåñêîëüêèõ íåàêòèâíûõ ìåòàáîëèòîâ, â îñíîâíîì ìåòèëãèäðîêñèëèðîâàííîãî è êàðáîêñèëèðîâàííîãî ïðîèçâîäíûõ ãëèêëàçèäà, CYP2C9 ó÷àñòâóåò â îáðàçîâàíèè ãèäðîêñèãëèêëàçèäà [28].

28
Peart GF, Boutagy J, Shenfield GM. The metabolism of glyburide in subjects of known debrisoquine phenotype. Clin Pharmacol Ther. 1989; 3745(3): 277–84.
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    Ãëèêëàçèä ìåòàáîëèçèðóåòñÿ äî íåñêîëüêèõ íåàêòèâíûõ ìåòàáîëèòîâ, â îñíîâíîì ìåòèëãèäðîêñèëèðîâàííîãî è êàðáîêñèëèðîâàííîãî ïðîèçâîäíûõ ãëèêëàçèäà, CYP2C9 ó÷àñòâóåò â îáðàçîâàíèè ãèäðîêñèãëèêëàçèäà
    Exact
    [28]
    Suffix
    . Ìåòàáîëèçì ãëèêëàçèäà îñóùåñòâëÿåòñÿ èçîôåðìåíòîì CYP2C19 ñ äîïîëíèòåëüíûì ó÷àñòèåì CYP2C9 [29, 30]. Ãëèìåïèðèä â ïåðâîé ôàçå áèîòðàíñôîðìàöèè ìåòàáîëèçèðóåòñÿ â ïå÷åíè èçîôåðìåíòîì CYP2C9 ñ îáðàçîâàíèåì ãèäðîêñèëüíîãî ìåòàáîëèòà, ïðèìåðíî â òðè ðàçà ìåíåå àêòèâíîãî èñõîäíîãî âåùåñòâà, â äàëüíåéøåì ïîä âëèÿíèåì öèòîçîëüíûõ ôåðìåíòîâ ÷àñòè÷íî ïðåîáðàçóþùåãîñÿ â ëèøåííîå àêòèâíîñòè êàðáîêñèëüíîå ï

29
Xu H, Williams KM, Liauw WS, Murray M, Day RO, McLachlan AJ. Effects of St John’s wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide. Br J Pharmacol. 2009; 37153(7): 1579–86.
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    Ãëèêëàçèä ìåòàáîëèçèðóåòñÿ äî íåñêîëüêèõ íåàêòèâíûõ ìåòàáîëèòîâ, â îñíîâíîì ìåòèëãèäðîêñèëèðîâàííîãî è êàðáîêñèëèðîâàííîãî ïðîèçâîäíûõ ãëèêëàçèäà, CYP2C9 ó÷àñòâóåò â îáðàçîâàíèè ãèäðîêñèãëèêëàçèäà [28]. Ìåòàáîëèçì ãëèêëàçèäà îñóùåñòâëÿåòñÿ èçîôåðìåíòîì CYP2C19 ñ äîïîëíèòåëüíûì ó÷àñòèåì CYP2C9
    Exact
    [29, 30]
    Suffix
    . Ãëèìåïèðèä â ïåðâîé ôàçå áèîòðàíñôîðìàöèè ìåòàáîëèçèðóåòñÿ â ïå÷åíè èçîôåðìåíòîì CYP2C9 ñ îáðàçîâàíèåì ãèäðîêñèëüíîãî ìåòàáîëèòà, ïðèìåðíî â òðè ðàçà ìåíåå àêòèâíîãî èñõîäíîãî âåùåñòâà, â äàëüíåéøåì ïîä âëèÿíèåì öèòîçîëüíûõ ôåðìåíòîâ ÷àñòè÷íî ïðåîáðàçóþùåãîñÿ â ëèøåííîå àêòèâíîñòè êàðáîêñèëüíîå ïðîèçâîäíîå [31].

30
Abulula M, Baranov V, Vorokhobina N, Zagorodnikova K. CYP2Ñ9 genotype and clinical effects of gliclazide. Clinical Therapeutics 2015; 378(37): e144–e145.
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  1. In-text reference with the coordinate start=16565
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    Ãëèêëàçèä ìåòàáîëèçèðóåòñÿ äî íåñêîëüêèõ íåàêòèâíûõ ìåòàáîëèòîâ, â îñíîâíîì ìåòèëãèäðîêñèëèðîâàííîãî è êàðáîêñèëèðîâàííîãî ïðîèçâîäíûõ ãëèêëàçèäà, CYP2C9 ó÷àñòâóåò â îáðàçîâàíèè ãèäðîêñèãëèêëàçèäà [28]. Ìåòàáîëèçì ãëèêëàçèäà îñóùåñòâëÿåòñÿ èçîôåðìåíòîì CYP2C19 ñ äîïîëíèòåëüíûì ó÷àñòèåì CYP2C9
    Exact
    [29, 30]
    Suffix
    . Ãëèìåïèðèä â ïåðâîé ôàçå áèîòðàíñôîðìàöèè ìåòàáîëèçèðóåòñÿ â ïå÷åíè èçîôåðìåíòîì CYP2C9 ñ îáðàçîâàíèåì ãèäðîêñèëüíîãî ìåòàáîëèòà, ïðèìåðíî â òðè ðàçà ìåíåå àêòèâíîãî èñõîäíîãî âåùåñòâà, â äàëüíåéøåì ïîä âëèÿíèåì öèòîçîëüíûõ ôåðìåíòîâ ÷àñòè÷íî ïðåîáðàçóþùåãîñÿ â ëèøåííîå àêòèâíîñòè êàðáîêñèëüíîå ïðîèçâîäíîå [31].

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    Ìå÷íèêîâà, â ãðóïïå áîëüíûõ ÑÄ 2 òèïà, ïîëó÷àþùèõ ãëèêëàçèä, áûëî ïîêàçàíî äîñòîâåðíî áîëåå ÷àñòîå ðàçâèòèå ãèïîãëèêåìèè ó íîñèòåëåé àëëåëåé CYP2C9*2 è CYP2C9*3, ÷åì ó áîëüíûõ «äèêîãî òèïà »(p< 0,05).  äàííîì èññëåäîâàíèè èñïîëüçîâàëè îïðåäåëåíèå HbA1c è äàííûõ CGMS
    Exact
    [30]
    Suffix
    . Ðàçëè÷èÿ ôåðìåíòàòèâíîé àêòèâíîñòè ìîãóò íàáëþäàòüñÿ â ðàìêàõ îäíîãî è òîãî æå ãåíîòèïà. Íàïðèìåð, ïîêàçàíà íå çàâèñÿùàÿ îò ãåíåòè÷åñêîãî ïîëèìîðôèçìà ñóùåñòâåííàÿ âàðèàáåëüíîñòü òðàíñêðèïöèè ãåíà CYP2C19 [39].

31
Kukes VG, Grachev SV, Sychev DA, Ramenskaya GV. Metabolism of drugs: scientific basis of personalized medicine. Moscow: GEOTAR-Media; 2008 (in Russian).
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    Ãëèìåïèðèä â ïåðâîé ôàçå áèîòðàíñôîðìàöèè ìåòàáîëèçèðóåòñÿ â ïå÷åíè èçîôåðìåíòîì CYP2C9 ñ îáðàçîâàíèåì ãèäðîêñèëüíîãî ìåòàáîëèòà, ïðèìåðíî â òðè ðàçà ìåíåå àêòèâíîãî èñõîäíîãî âåùåñòâà, â äàëüíåéøåì ïîä âëèÿíèåì öèòîçîëüíûõ ôåðìåíòîâ ÷àñòè÷íî ïðåîáðàçóþùåãîñÿ â ëèøåííîå àêòèâíîñòè êàðáîêñèëüíîå ïðîèçâîäíîå
    Exact
    [31]
    Suffix
    . Êëþ÷åâîé äëÿ ìåòàáîëèçìà ÏÑÌ ôåðìåíò CYP2C9 ïðîäóöèðóåòñÿ â îñíîâíîì â êëåòêàõ ïå÷åíè, íà÷èíàåò ñèíòåçèðîâàòüñÿ ÷åðåç 1 ìåñÿö ïîñëå ðîæäåíèÿ; åãî àêòèâíîñòü íå ìåíÿåòñÿ ñ âîçðàñòîì [32]. ÐÎËÜ ÃÅÍÅÒÈ×ÅÑÊÎÃÎ ÏÎËÈÌÎÐÔÈÇÌÀ  ÁÈÎÒÐÀÍÑÔÎÐÌÀÖÈÈ ÏÐÅÏÀÐÀÒΠÑÓËÜÔÎÍÈËÌÎ×ÅÂÈÍÛ Àêòèâíîñòü öèòîõðîìà Ð450 2C9 çàâèñèò îò ðÿäà ýíäîãåííûõ è ýêçîãåííûõ ôàêòîðîâ.

  2. In-text reference with the coordinate start=22451
    Prefix
    Èíäóêòîðû ñîîòâåòñòâóþùèõ èçîôåðìåíòîâ CYP450 (ðèôàìïèöèí, áàðáèòóðàòû) ñïîñîáñòâóþò ñíèæåíèþ êîíöåíòðàöèè ñîîòâåòñòâóþùèõ ÏÑÌ â ïëàçìå è èõ ãèïîãëèêåìèçèðóþùåé àêòèâíîñòè. Êîíêóðèðóÿ çà áåëêè êðîâè, ñóëüôàíèëàìèäû äëèòåëüíîãî äåéñòâèÿ, ïðîèçâîäíûå ñàëèöèëîâîé êèñëîòû, ôèáðàòû ïîâûøàþò êîíöåíòðàöèþ ÏÑÌ â ïëàçìå
    Exact
    [31]
    Suffix
    . Èññëåäîâàíèÿ, ïîñâÿùåííûå ïîèñêó àññîöèàöèé ãåíåòè÷åñêîãî ïîëèìîðôèçìà ñ ãèïîãëèêåìèÿìè, áûëè ðåçóëüòàòèâíû â ñëó÷àÿõ, êîãäà îïðåäåëÿëàñü êîíöåíòðàöèÿ ÏÑÌ.  íàñòîÿùåå âðåìÿ àêòèâíî èñïîëüçóþòñÿ ìåòîäû îöåíêè àêòèâíîñòè ôåðìåíòàòèâíûõ ñèñòåì, ó÷àñòâóþùèõ â ôàðìàêîêèíåòè÷åñêèõ ïðîöåññàõ ËÑ, ïðåæäå âñåãî ôåíîòèïèðîâàíèå ôåðìåíòîâ ñèñòåìû öèòîõðîìà Ð450.

32
Woolf TF, ed. Handbook of drug metabolism. New York: Dekker; 1999.
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    ãèäðîêñèëüíîãî ìåòàáîëèòà, ïðèìåðíî â òðè ðàçà ìåíåå àêòèâíîãî èñõîäíîãî âåùåñòâà, â äàëüíåéøåì ïîä âëèÿíèåì öèòîçîëüíûõ ôåðìåíòîâ ÷àñòè÷íî ïðåîáðàçóþùåãîñÿ â ëèøåííîå àêòèâíîñòè êàðáîêñèëüíîå ïðîèçâîäíîå [31]. Êëþ÷åâîé äëÿ ìåòàáîëèçìà ÏÑÌ ôåðìåíò CYP2C9 ïðîäóöèðóåòñÿ â îñíîâíîì â êëåòêàõ ïå÷åíè, íà÷èíàåò ñèíòåçèðîâàòüñÿ ÷åðåç 1 ìåñÿö ïîñëå ðîæäåíèÿ; åãî àêòèâíîñòü íå ìåíÿåòñÿ ñ âîçðàñòîì
    Exact
    [32]
    Suffix
    . ÐÎËÜ ÃÅÍÅÒÈ×ÅÑÊÎÃÎ ÏÎËÈÌÎÐÔÈÇÌÀ  ÁÈÎÒÐÀÍÑÔÎÐÌÀÖÈÈ ÏÐÅÏÀÐÀÒΠÑÓËÜÔÎÍÈËÌÎ×ÅÂÈÍÛ Àêòèâíîñòü öèòîõðîìà Ð450 2C9 çàâèñèò îò ðÿäà ýíäîãåííûõ è ýêçîãåííûõ ôàêòîðîâ. Ãåí, êîäèðóþùèé ýòîò èçîôåðìåíò, îáëàäàåò ãåíåòè÷åñêèì ïîëèìîðôèçìîì.

33
Becker ML, Visser LE, Trienekens PH, Hofman A, van Schaik RH, Stricker BH. Cytochrome P450 2C9 *2 and *3 polymorphisms and the dose and effect of sulfonylurea in type II diabetes mellitus. Clin Pharmacol Ther. 2008; 3783(2): 288–92.
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    , ïðîâåäåííîì â 2007 ãîäó ñ ó÷àñòèåì 7983 ïàöèåíòîâ ïîæèëîãî âîçðàñòà ñ ÑÄ 2 òèïà, áûëî äîêàçàíî, ÷òî àêòèâíîñòü ôåðìåíòà CYP2C9 ó íîñèòåëåé àëëåëÿ CYP2C9*3 íèæå, ÷åì ó íîñèòåëåé «äèêîãî òèïà »(CYP2C9*1/*1), ÷òî îáóñëîâëèâàåò áîëåå âûñîêèé óðîâåíü ÏÑÌ â ïëàçìå. Áûë ñäåëàí âûâîä, ÷òî íîñèòåëÿì àëëåëÿ CYP2C9*3 òðåáóåòñÿ ìåíüøàÿ äîçà ÏÑÌ äëÿ ïîääåðæàíèÿ óðîâíÿ ãëèêåìèè, ÷åì ïàöèåíòàì «äèêîãî òèïà »
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    [33]
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    . Àíàëîãè÷íûå äàííûå ïîëó÷åíû íà ïàöèåíòàõ ñ ÑÄ 2 òèïà, ïðèíèìàâøèõ ÏÑÌ. Îêàçàëîñü, ÷òî ñíèæåíèå óðîâíÿ HbA1c áûëî áîëåå âûðàæåíî ó ïàöèåíòîâ ñ ãåíîòèïîì CYP2C9*1/*3 ïî ñðàâíåíèþ ñ ãåíîòèïîì CYP2C9*1/*1.

34
Suzuki K, Yanagawa T, Shibasaki T, Kaniwa N, Hasegawa R, Tohkin M. Effect of CYP2C9 genetic polymorphisms on the efficacy and pharmacokinetics of glimepiride in subjects with type 2 diabetes. Diabetes Res Clin Pract. 2006; 3772(2): 48–54.
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    Ïëîùàäü ïîä ôàðìàêîêèíåòè÷åñêîé êðèâîé ïðè ïðèåìå ãëèáåíêëàìèäà ó íîñèòåëåé ãåíîòèïà CYP2C9*1/*3 áûëà â 2,5 ðàçà áîëüøå, ÷åì ó íîñèòåëåé ãåíîòèïà CYP2C9*1/*1. Êëèðåíñ ãëèáåíêëàìèäà ó íîñèòåëåé àëëåëüíîãî âàðèàíòà CYP2C9*3 áûë íèæå, ÷åì ó íîñèòåëåé «äèêîãî òèïà »
    Exact
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    . Àíàëîãè÷íûå ðåçóëüòàòû èññëåäîâàíèé íà 80 ïàöèåíòàõ áûëè ïîëó÷åíû Surendiran A. è äð., êîòîðûå ïîêàçàëè, ÷òî ýôôåêòèâíîñòü òåðàïèè ãëèáåíêëàìèäîì áûëà âûøå ó áîëüíûõ ÑÄ 2 òèïà ñ ãåíåòè÷åñêè îáóñëîâëåííûì äåôèöèòîì àêòèâíîñòè CYP2C9 [35].

35
Surendiran A, Pradhan SC, Agraval A, Subrahmanyam DK, Rajan S, Anichavezhi D, et al. Influence of CYP2C9 gene polymorphism on response to glibenclamide in type 2 diabetes mellitus patients. Eur J Clin Pharmacol. 2011; 3767(8): 797–801.
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    Àíàëîãè÷íûå ðåçóëüòàòû èññëåäîâàíèé íà 80 ïàöèåíòàõ áûëè ïîëó÷åíû Surendiran A. è äð., êîòîðûå ïîêàçàëè, ÷òî ýôôåêòèâíîñòü òåðàïèè ãëèáåíêëàìèäîì áûëà âûøå ó áîëüíûõ ÑÄ 2 òèïà ñ ãåíåòè÷åñêè îáóñëîâëåííûì äåôèöèòîì àêòèâíîñòè CYP2C9
    Exact
    [35]
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    . Ïî äàííûì Holstein A. è äð., ñóùåñòâóåò ñâÿçü ïîëèìîðôèçìà ãåíà CYP2C9 ñ ðàçâèòèåì îñòðîé ãèïîãëèêåìèè íà ôîíå ïðèåìà ÏÑÌ.  èññëåäîâàíèè ïðîâîäèëîñü ñðàâíåíèå óðîâíÿ ìåòàáîëèçìà â ãðóïïå èç 20 ïàöèåíòîâ ñ ýïèçîäîì îñòðîé ãèïîãëèêåìèè â àíàìíåçå íà ôîíå ïðèåìà ÏÑÌ ñ êîíòðîëüíîé ãðóïïîé èç 337 ïàöèåíòîâ ñ ÑÄ 2 òèïà áåç ðàçâèòèÿ ãèïîãëèêåìèè âî âðåìÿ ëå÷åíèÿ ÏÑÌ.

36
Holstein A, Plaschke A, Ptak M, Egberts EH, El-Din J, Brockmoller J, et al. Association between CYP2C9 slow metabolizer genotypes and severe hypoglycaemia on medication with sulphonylurea hypoglyacemic agents. Br J Clin Pharmacol 2005; 60(1): 103–6.
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    ïðîâîäèëîñü ñðàâíåíèå óðîâíÿ ìåòàáîëèçìà â ãðóïïå èç 20 ïàöèåíòîâ ñ ýïèçîäîì îñòðîé ãèïîãëèêåìèè â àíàìíåçå íà ôîíå ïðèåìà ÏÑÌ ñ êîíòðîëüíîé ãðóïïîé èç 337 ïàöèåíòîâ ñ ÑÄ 2 òèïà áåç ðàçâèòèÿ ãèïîãëèêåìèè âî âðåìÿ ëå÷åíèÿ ÏÑÌ. Áûëî ïîêàçàíî, ÷òî â ãðóïïå ïàöèåíòîâ ñ ãèïîãëèêåìèåé ãåíîòèïû CYP2C9*3/*3, CYP2C9*2/*3, àññîöèèðóþùèåñÿ ñî ñíèæåííûì ìåòàáîëèçìîì ÏÑÌ, âñòðå÷àþòñÿ ÷àùå (10 ïðîòèâ 2 %)
    Exact
    [36]
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    .  ðàáîòå Ragia G. è äð. òàêæå áûëî ïðîäåìîíñòðèðîâàíî íàëè÷èå àññîöèàöèè ãèïîãëèêåìèè ñ ïîëèìîðôèçìîì ãåíà CYP2C9. Ïðè ó÷åòå ïîïðàâîê íà âîçðàñò, èíäåêñ ìàññû òåëà (ÈÌÒ), ñðåäíåñóòî÷íûå äîçû ÏÑÌ, äëèòåëüíîñòü ÑÄ 2 òèïà è ôóíêöèþ ïî÷åê óñòàíîâëåíî, ÷òî ó íîñèòåëåé ãåíîòèïà CYP2C9*1/*3 ðèñê ãèïîãëèêåìèè â îòâåò íà ïðèåì ÏÑÌ óâåëè÷åí (îòíîøåíèå øàíñî⠗ 1,687;ð= 0,011) [37].

37
Ragia G, Petridis I, Tavridou A, Christakidis D, Manolopoulos VG. Presence of CYP2C9*3 allele increases risk for hypoglycemia in Type 2 diabetic patients treated with sulfonylureas. Pharmacogenomics 2009; 10(11): 1781–7.
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    Ïðè ó÷åòå ïîïðàâîê íà âîçðàñò, èíäåêñ ìàññû òåëà (ÈÌÒ), ñðåäíåñóòî÷íûå äîçû ÏÑÌ, äëèòåëüíîñòü ÑÄ 2 òèïà è ôóíêöèþ ïî÷åê óñòàíîâëåíî, ÷òî ó íîñèòåëåé ãåíîòèïà CYP2C9*1/*3 ðèñê ãèïîãëèêåìèè â îòâåò íà ïðèåì ÏÑÌ óâåëè÷åí (îòíîøåíèå øàíñî⠗ 1,687;ð= 0,011)
    Exact
    [37]
    Suffix
    .  Íîâîñèáèðñêîé îáëàñòè áûëî ïðîâåäåíî îäíîìîìåíòíîå ïîïåðå÷íîå îáñëåäîâàíèå 750 áîëüíûõ (194 ìóæ÷èí è 556 æåíùèí), ïîëó÷àâøèõ òåðàïèþ ÏÑÌ. Ñðåäíèé âîçðàñò îáñëåäîâàííûõ ñîñòàâèë 60,4±8,8 ëåò, äëèòåëüíîñòü ÑÄ 2 òèïà — 7,4±6,1 ëåò, óðîâåíü HbA1c 8,8±2,0 %.

38
Shabelnikova OYu, Bondar IA, Filipenko ML, Sokolova EA. The Association of CYP2C9 gene polymorphism with response to therapy with sulfonylureas in the Novosibirsk region [Internet]. Available from: http://rusendo.com/index.php/REC/VIIREC/paper/view/878 (in Russian).
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    Â çàâèñèìîñòè îò óðîâíÿ HbA1c ïàöèåíòû áûëè ðàñïðåäåëåíû íà ãðóïïû: äîñòèãøèõ öåëåâîãî óðîâíÿ HbA1c íà ôîíå òåðàïèè ÏÑÌ (n= 286) è íå äîñòèãøèõ ïðè ïðèåìå ìàêñèìàëüíîé äîçû ÏÑÌ (n= 464). Èññëåäîâàíèå íå âûÿâèëî àññîöèàöèè ïîëèìîðôèçìà ãåíà CYP2C9 ñ îòâåòîì íà òåðàïèþ ÏÑÌ, ÷òî ìîæåò áûòü ñâÿçàíî ñ äèçàéíîì èññëåäîâàíèÿ
    Exact
    [38]
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    .  èññëåäîâàíèè, ïðîâåäåííîì íà áàçå Ñåâåðî-Çàïàäíîãî ãîñóäàðñòâåííîãî ìåäèöèíñêîãî óíèâåðñèòåòà èìåíè È. È. Ìå÷íèêîâà, â ãðóïïå áîëüíûõ ÑÄ 2 òèïà, ïîëó÷àþùèõ ãëèêëàçèä, áûëî ïîêàçàíî äîñòîâåðíî áîëåå ÷àñòîå ðàçâèòèå ãèïîãëèêåìèè ó íîñèòåëåé àëëåëåé CYP2C9*2 è CYP2C9*3, ÷åì ó áîëüíûõ «äèêîãî òèïà »(p< 0,05).

39
Tingle M, Burns K, Helsby N. Control of variable CYP2C19 expression within metaboliser categories. UPCP 2012: Up Close and Personalized International Congress on Personalized Medicine 2012, February 25; Florence, Italy. Program and Abstracts. P. 105.
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    Ðàçëè÷èÿ ôåðìåíòàòèâíîé àêòèâíîñòè ìîãóò íàáëþäàòüñÿ â ðàìêàõ îäíîãî è òîãî æå ãåíîòèïà. Íàïðèìåð, ïîêàçàíà íå çàâèñÿùàÿ îò ãåíåòè÷åñêîãî ïîëèìîðôèçìà ñóùåñòâåííàÿ âàðèàáåëüíîñòü òðàíñêðèïöèè ãåíà CYP2C19
    Exact
    [39]
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    . Ïî äàííûì ëèòåðàòóðû àêòèâíîñòü èçîôåðìåíòîâ ñèñòåìû öèòîõðîìà Ð450 ñíèæàåòñÿ ó ïàöèåíòîâ ñ ÑÄ 2 òèïà, àññîöèèðóþùèìñÿ ñ íåàëêîãîëüíîé æèðîâîé áîëåçíüþ ïå÷åíè [40]. Ó áîëüíûõ ñ äåêîìïåíñàöèåé õðîíè÷åñêîé ñåðäå÷íîé íåäîñòàòî÷íîñòè îòìå÷åíà èñõîäíî íèçêàÿ àêòèâíîñòü ÑYP2C9 ñ ïîâûøåíèåì íà ôîíå ëå÷åíèÿ [41].

40
Ledyaev YM. The value of pharmacokinetic analysis of isoenzyme CYP2C9 and optimization of pharmacotherapy of diabetes mellitus type 2. Cand. Med. Sci [thesis]. Volgograd; 2011 (in Russian).
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    Íàïðèìåð, ïîêàçàíà íå çàâèñÿùàÿ îò ãåíåòè÷åñêîãî ïîëèìîðôèçìà ñóùåñòâåííàÿ âàðèàáåëüíîñòü òðàíñêðèïöèè ãåíà CYP2C19 [39]. Ïî äàííûì ëèòåðàòóðû àêòèâíîñòü èçîôåðìåíòîâ ñèñòåìû öèòîõðîìà Ð450 ñíèæàåòñÿ ó ïàöèåíòîâ ñ ÑÄ 2 òèïà, àññîöèèðóþùèìñÿ ñ íåàëêîãîëüíîé æèðîâîé áîëåçíüþ ïå÷åíè
    Exact
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    . Ó áîëüíûõ ñ äåêîìïåíñàöèåé õðîíè÷åñêîé ñåðäå÷íîé íåäîñòàòî÷íîñòè îòìå÷åíà èñõîäíî íèçêàÿ àêòèâíîñòü ÑYP2C9 ñ ïîâûøåíèåì íà ôîíå ëå÷åíèÿ [41]. Áûëî îïèñàíî ñíèæåíèå ôåðìåíòàòèâíîé àêòèâíîñòè ó ïàöèåíòà ñ ãåíîòèïîì CYP2C9*1/*3 ïðè òèðåîòîêñèêîçå [42].

41
Anikin GS. The value of estimating the activity of the isoenzyme of cytochrome P450 2C9 on the pharmacokinetics of losartan and its metabolite E-3174 to optimize pharmacotherapy. Cand. Med. Sci [thesis]. Moscow; 2010 (in Russian).
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    Ïî äàííûì ëèòåðàòóðû àêòèâíîñòü èçîôåðìåíòîâ ñèñòåìû öèòîõðîìà Ð450 ñíèæàåòñÿ ó ïàöèåíòîâ ñ ÑÄ 2 òèïà, àññîöèèðóþùèìñÿ ñ íåàëêîãîëüíîé æèðîâîé áîëåçíüþ ïå÷åíè [40]. Ó áîëüíûõ ñ äåêîìïåíñàöèåé õðîíè÷åñêîé ñåðäå÷íîé íåäîñòàòî÷íîñòè îòìå÷åíà èñõîäíî íèçêàÿ àêòèâíîñòü ÑYP2C9 ñ ïîâûøåíèåì íà ôîíå ëå÷åíèÿ
    Exact
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    . Áûëî îïèñàíî ñíèæåíèå ôåðìåíòàòèâíîé àêòèâíîñòè ó ïàöèåíòà ñ ãåíîòèïîì CYP2C9*1/*3 ïðè òèðåîòîêñèêîçå [42]. CYP2C9 ÿâëÿåòñÿ ôåðìåíòîì ïåðâîé ôàçû áèîòðàíñôîðìàöèè ìíîãèõ ËÑ, âêëþ÷àÿ íåñòåðîèäíûå ïðîòèâîâîñïàëèòåëüíûå ïðåïàðàòû (ÍÏÂÏ), ôåíèòîèí, íåïðÿìûå àíòèêîàãóëÿíòû (âàðôàðèí, àöåíîêóìàðîë).

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    Ïîñëå ïðèåìà ëîçàðòàíà åãî ãèïîòåíçèâíîå äåéñòâèå äîñòèãàåò ìàêñèìóìà ÷åðåç 6 ÷ è ïîñòåïåííî (â òå÷åíèå 24 ÷) óìåíüøàåòñÿ. Ïðè ïðîâåäåíèè ëîçàðòàíîâîé ïðîáû èñïîëüçóåòñÿ îäíîêðàòíûé ïðèåì 50 ìã âåùåñòâà, ïðè ýòîì â öåëÿõ áåçîïàñíîñòè ïàöèåíòà êîíòðîëèðóþò ÀÄ
    Exact
    [41]
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    . Âûÿâëåíèå íèçêîé àêòèâíîñòè CYP2Ñ9 ïî ðåçóëüòàòàì ëîçàðòàíîâîãî òåñòà àññîöèèðóåòñÿ ñ îòíîñèòåëüíî íåáîëüøèìè ýôôåêòèâíûìè äîçàìè âàðôàðèíà [44]. Îïðåäåëåíèå àêòèâíîñòè CYP2Ñ9 ïî êîíöåíòðàöèè ëîçàðòàíà è åãî ìåòàáîëèòà Å-3174 ïðè ïðîâåäåíèè ëîçàðòàíîâîãî òåñòà ìîæåò ïðîãíîçèðîâàòü ïîääåðæèâàþùóþ äîçó âàðôàðèíà ó áîëüíûõ ïîñëå ïðîòåçèðîâàíèÿ êëàïàíîâ ñåðäöà, ÷òî ñïîñîáñòâóåò ïîâûøåíèþ ýôôåêòèâíîñ

42
Lee JE, Ryu DH, Jeong HJ, Kim JH, Jun JE, Kim JS, et al. Extremely elevated international normalized ratio of warfarin in a patient with CYP2C9*1/*3 and thyrotoxicosis. J Korean Med Sci 2014; 3729(9): 1317–9.
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    Ó áîëüíûõ ñ äåêîìïåíñàöèåé õðîíè÷åñêîé ñåðäå÷íîé íåäîñòàòî÷íîñòè îòìå÷åíà èñõîäíî íèçêàÿ àêòèâíîñòü ÑYP2C9 ñ ïîâûøåíèåì íà ôîíå ëå÷åíèÿ [41]. Áûëî îïèñàíî ñíèæåíèå ôåðìåíòàòèâíîé àêòèâíîñòè ó ïàöèåíòà ñ ãåíîòèïîì CYP2C9*1/*3 ïðè òèðåîòîêñèêîçå
    Exact
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    . CYP2C9 ÿâëÿåòñÿ ôåðìåíòîì ïåðâîé ôàçû áèîòðàíñôîðìàöèè ìíîãèõ ËÑ, âêëþ÷àÿ íåñòåðîèäíûå ïðîòèâîâîñïàëèòåëüíûå ïðåïàðàòû (ÍÏÂÏ), ôåíèòîèí, íåïðÿìûå àíòèêîàãóëÿíòû (âàðôàðèí, àöåíîêóìàðîë). Íîñèòåëüñòâî àëëåëåé CYP2C9*2 è CYP2C9*3, ïîâûøàþùåå ðèñê ðàçâèòèÿ ÍÏÂÏ-èíäóöèðîâàííûõ æåëóäî÷íî-êèøå÷íûõ êðîâîòå÷åíèé ó ïàöèåíòîâ ñ ïîëèîñòåîàðòðîçîì, ÿâëÿåòñÿ íåçàâèñèìûì ôàêòîðîì ðèñêà [43].

43
Ignatov YuD, Kukes VG, Mazurov VI. Clinical pharmacology of nonsteroidal anti-inflammatory drugs. Moscow: GEOTAR-Media; 2010 (in Russian).
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    CYP2C9 ÿâëÿåòñÿ ôåðìåíòîì ïåðâîé ôàçû áèîòðàíñôîðìàöèè ìíîãèõ ËÑ, âêëþ÷àÿ íåñòåðîèäíûå ïðîòèâîâîñïàëèòåëüíûå ïðåïàðàòû (ÍÏÂÏ), ôåíèòîèí, íåïðÿìûå àíòèêîàãóëÿíòû (âàðôàðèí, àöåíîêóìàðîë). Íîñèòåëüñòâî àëëåëåé CYP2C9*2 è CYP2C9*3, ïîâûøàþùåå ðèñê ðàçâèòèÿ ÍÏÂÏ-èíäóöèðîâàííûõ æåëóäî÷íî-êèøå÷íûõ êðîâîòå÷åíèé ó ïàöèåíòîâ ñ ïîëèîñòåîàðòðîçîì, ÿâëÿåòñÿ íåçàâèñèìûì ôàêòîðîì ðèñêà
    Exact
    [43]
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    . Ïîäáîð äîçû âàðôàðèíà ïîä êîíòðîëåì ìåæäóíàðîäíîãî íîðìàëèçîâàííîãî îòíîøåíèÿ (ÌÍÎ) áûâàåò çàòðóäíåí ó ïàöèåíòîâ ñ CYP2C9*3. Èíäóêòîðû ñîîòâåòñòâóþùèõ èçîôåðìåíòîâ CYP450 (ðèôàìïèöèí, áàðáèòóðàòû) ñïîñîáñòâóþò ñíèæåíèþ êîíöåíòðàöèè ñîîòâåòñòâóþùèõ ÏÑÌ â ïëàçìå è èõ ãèïîãëèêåìèçèðóþùåé àêòèâíîñòè.

44
Sychev D, Antonov I, Ignatev I, Kasakov R. Advantages of pharmacogenetic approach (polymorphisms of genes CYP2C9 and VKORC1 study) to warfarin dosing, against the standard method for Russian patients with contestant form atrial fibrillation. J Basic and Clinical Pharmacology 2009; 105: 73–74.
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    Ïðè ïðîâåäåíèè ëîçàðòàíîâîé ïðîáû èñïîëüçóåòñÿ îäíîêðàòíûé ïðèåì 50 ìã âåùåñòâà, ïðè ýòîì â öåëÿõ áåçîïàñíîñòè ïàöèåíòà êîíòðîëèðóþò ÀÄ [41]. Âûÿâëåíèå íèçêîé àêòèâíîñòè CYP2Ñ9 ïî ðåçóëüòàòàì ëîçàðòàíîâîãî òåñòà àññîöèèðóåòñÿ ñ îòíîñèòåëüíî íåáîëüøèìè ýôôåêòèâíûìè äîçàìè âàðôàðèíà
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    [44]
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    . Îïðåäåëåíèå àêòèâíîñòè CYP2Ñ9 ïî êîíöåíòðàöèè ëîçàðòàíà è åãî ìåòàáîëèòà Å-3174 ïðè ïðîâåäåíèè ëîçàðòàíîâîãî òåñòà ìîæåò ïðîãíîçèðîâàòü ïîääåðæèâàþùóþ äîçó âàðôàðèíà ó áîëüíûõ ïîñëå ïðîòåçèðîâàíèÿ êëàïàíîâ ñåðäöà, ÷òî ñïîñîáñòâóåò ïîâûøåíèþ ýôôåêòèâíîñòè è áåçîïàñíîñòè ôàðìàêîòåðàïèè ó ïàöèåíòîâ [45].

45
Smirnov VV, Aslanbekov SM, Sychev DA, Mirzaev KB, Kazakov RE. Cytochrome P450 (CYP2C9) activeness, evaluated via losartan test, as prediction marker for the warfarin treatment dosage choice in patients with delayed outcomes after heart valves replacement. Russian Journal of Cardiology 2015; 126(10): 70–4 (in Russian).
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  1. In-text reference with the coordinate start=24017
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    Îïðåäåëåíèå àêòèâíîñòè CYP2Ñ9 ïî êîíöåíòðàöèè ëîçàðòàíà è åãî ìåòàáîëèòà Å-3174 ïðè ïðîâåäåíèè ëîçàðòàíîâîãî òåñòà ìîæåò ïðîãíîçèðîâàòü ïîääåðæèâàþùóþ äîçó âàðôàðèíà ó áîëüíûõ ïîñëå ïðîòåçèðîâàíèÿ êëàïàíîâ ñåðäöà, ÷òî ñïîñîáñòâóåò ïîâûøåíèþ ýôôåêòèâíîñòè è áåçîïàñíîñòè ôàðìàêîòåðàïèè ó ïàöèåíòîâ
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    [45]
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    . Ôàðìàêîãåíåòè÷åñêîå òåñòèðîâàíèå ïî CYP2C9 ìîæåò áûòü èñïîëüçîâàíî â ôîðìèðîâàíèè ãðóïï â èññëåäîâàíèÿõ áèîýêâèâàëåíòíîñòè ÏÑÌ [46–49]. ÇÀÊËÞ×ÅÍÈÅ Ñïîñîáíîñòü ÏÑÌ óñèëèâàòü ñåêðåöèþ èíñóëèíà çàâèñèò îò öåëîãî ðÿäà ôàêòîðîâ: êîìïëàåíòíîñòè ïàöèåíòà, ïàòîãåíåòè÷åñêîé îáîñíîâàííîñòè âûáîðà ïðåïàðàòà, îñîáåííîñòè ðåöåïòîðíîãî âçàèìîäåéñòâèÿ, ïðî÷íîñòè ñâÿçè ñ SUR1, âëèÿíèÿ ïðåèìóùåñòâåííî íà ïåðâóþ,

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Sychev DA. Recommendations for pharmaceutical companies to study the biotransformation and transporters of new drugs: study design, data analysis and entry of information in the instructions for use. Moscow; 2009. Available from: https://goo.gl/1xCWuu (in Russian).
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  1. In-text reference with the coordinate start=24151
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    êîíöåíòðàöèè ëîçàðòàíà è åãî ìåòàáîëèòà Å-3174 ïðè ïðîâåäåíèè ëîçàðòàíîâîãî òåñòà ìîæåò ïðîãíîçèðîâàòü ïîääåðæèâàþùóþ äîçó âàðôàðèíà ó áîëüíûõ ïîñëå ïðîòåçèðîâàíèÿ êëàïàíîâ ñåðäöà, ÷òî ñïîñîáñòâóåò ïîâûøåíèþ ýôôåêòèâíîñòè è áåçîïàñíîñòè ôàðìàêîòåðàïèè ó ïàöèåíòîâ [45]. Ôàðìàêîãåíåòè÷åñêîå òåñòèðîâàíèå ïî CYP2C9 ìîæåò áûòü èñïîëüçîâàíî â ôîðìèðîâàíèè ãðóïï â èññëåäîâàíèÿõ áèîýêâèâàëåíòíîñòè ÏÑÌ
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    [46–49]
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    . ÇÀÊËÞ×ÅÍÈÅ Ñïîñîáíîñòü ÏÑÌ óñèëèâàòü ñåêðåöèþ èíñóëèíà çàâèñèò îò öåëîãî ðÿäà ôàêòîðîâ: êîìïëàåíòíîñòè ïàöèåíòà, ïàòîãåíåòè÷åñêîé îáîñíîâàííîñòè âûáîðà ïðåïàðàòà, îñîáåííîñòè ðåöåïòîðíîãî âçàèìîäåéñòâèÿ, ïðî÷íîñòè ñâÿçè ñ SUR1, âëèÿíèÿ ïðåèìóùåñòâåííî íà ïåðâóþ, âòîðóþ èëè îáå ôàçû ñåêðåöèè èíñóëèíà.