The 26 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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    (ÌÍÍ è ôîðìû ïðåïàðàòà)Tmax 1, ÷Áèîäîñ-òóïíîñòü, % Ñâÿçü ñ áåëêîì, % Ìåòàáîëèòû Ýëèìèíàöèÿ, (÷/ç ïî÷êè/ÆÊÒ)Ò1/2, ÷ Äëèòåëüíîñòü äåéñòâèÿ, ÷ Ïðåïàðàòû 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]
    Suffix
    . 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».

16
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. 2006; 3791(6): 2334–9.
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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]
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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 [2] (ÌÍÍ è ôîðìû ïðåïàðàòà)Tmax 1, ÷Áèîäîñ-òóïíîñòü, % Ñâÿçü ñ áåëêîì, % Ìåòàáîëèòû Ýëèìèíàöèÿ, (÷/ç ïî÷êè/ÆÊÒ)Ò1/2, ÷ Äëèòåëüíîñòü äåéñòâèÿ, ÷ Ïðåïàðàòû Ãëèáåíêëàìèä îáû÷íàÿ ôîð

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
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    [23]
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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].

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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  1. In-text reference with the coordinate start=15669
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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
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    [24]
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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 [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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  1. In-text reference with the coordinate start=15816
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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
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    . 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

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Indiana University. Department of Medicine. P450 Drug Interaction
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  1. In-text reference with the coordinate start=15967
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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
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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 [27].