The 8 references with contexts in paper N. Baymeeva V., L. Krasnykh M., I. Miroshnichenko I., Н. Баймеева В., Л. Красных М., И. Мирошниченко И. (2018) “Мониторинг концентрации клозапина и норклозапина при терапии шизофрении // Monitoring of clozapine and norclozapine concentrations in schizophrenia treatment” / spz:neicon:vedomostincesmp:y:2016:i:4:p:53-57

1
Hazari N, Kate N, Grover S. Clozapine and tar dive movement disorders: a review. Asian J Psychiatr. 2013; (6): 439–51.
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    Âåäîìîñòè Íàó÷íîãî öåíòðà ýêñïåðòèçû ñðåäñòâ ìåäèöèíñêîãî ïðèìåíåíèÿ 2016; (4): 53–57. Êëîçàïèí ÿâëÿåòñÿ òðèöèêëè÷åñêèì ïðîèçâîäíûì äèáåíçîäèàçåïèíà: 8-õëîð-11-(4-ìåòèë-1-ïèïåðàçèíèë)-5Í-äèáåíçî-[b,å]
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    -äèàçåïèí. Ïî ôàðìàêîëîãè÷åñêîìó äåéñòâèþ êëîçàïèí îòíîñèòñÿ ê «àòèïè÷íûì »íåéðîëåïòèêàì (àíòèïñèõîòèêàì). Ïðèìåíÿåòñÿ äëÿ ëå÷åíèÿ ïðè îñòðûõ è õðîíè÷åñêèõ ôîðìàõ øèçîôðåíèè, ìàíèàêàëüíûõ ñîñòîÿíèÿõ, ìàíèàêàëüíî-äåïðåññèâíîì ïñèõîçå, ïñèõîìîòîðíîì âîçáóæäåíèè.

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    Ïðåïàðàò ýôôåêòèâåí ó ïàöèåíòîâ, ðåçèñòåíòíûõ ê äðóãèì àíòèïñèõîòè÷åñêèì ñðåäñòâàì. Îí âûçûâàåò ìèíèìàëüíûå ýêñòðàïèðàìèäàëüíûå ïîáî÷íûå ýôôåêòû, íå âûçûâàåò ïîçäíþþ äèñêèíåçèþ è â ìåíüøåé ñòåïåíè âëèÿåò íà ñåêðåöèþ ïðîëàêòèíà
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    . Èç-çà ñïîñîáíîñòè âûçûâàòü àãðàíóëîöèòîç (îïàñíîå äëÿ æèçíè ñîñòîÿíèå, êîòîðîå ÷àùå íàñòóïàåò â ïåðâûå 3 ìåñÿöà ëå÷åíèÿ, ñ óâåëè÷åíèåì ðèñêà âîçíèêíîâåíèÿ â 10 ðàç â âîçðàñòå îò 21 äî 50 ëåò è ñòàðøå) ïðèìåíåíèå êëîçàïèíà îãðàíè÷åííî [2].

2
O’Connor DW, Sierakowski C, Fei Chin L, Singh D. The safety and tolerability of clozapine in aged patients: A retrospective clinical file review. World J Biol Psychiatry 2010; (11): 788–91.
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    Èç-çà ñïîñîáíîñòè âûçûâàòü àãðàíóëîöèòîç (îïàñíîå äëÿ æèçíè ñîñòîÿíèå, êîòîðîå ÷àùå íàñòóïàåò â ïåðâûå 3 ìåñÿöà ëå÷åíèÿ, ñ óâåëè÷åíèåì ðèñêà âîçíèêíîâåíèÿ â 10 ðàç â âîçðàñòå îò 21 äî 50 ëåò è ñòàðøå) ïðèìåíåíèå êëîçàïèíà îãðàíè÷åííî
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    . Òåðàïåâòè÷åñêèé äèàïàçîí êîíöåíòðàöèé êëîçàïèíà â ïëàçìå êðîâè 350–600 íã/ìë [3]. Ôàðìàêîêèíåòè÷åñêèå ïàðàìåòðû êëîçàïèíà èìåþò áîëüøèå èíäèâèäóàëüíûå êîëåáàíèÿ, êîòîðûå çàâèñÿò îò âîçðàñòà, ïîëà è êóðåíèÿ òàáàêà (òàáë. 1).

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    ñòàòèñòè÷åñêîãî àíàëèçà áûëà âûÿâëåíà äîñòàòî÷íî çíà÷èìàÿ êîððåëÿöèîííàÿ çàâèñèìîñòü ìåæäó êîíöåíòðàöèåé (ÑCloz,ÑNor) è äîçîé êëîçàïèíà: ÑCloz= –63,9 + 3,27D;Kcorr= 0,57;P= 0,0017 (1) ÑNor= 5,4 + 0,71D;Kcorr= 0,58;P= 0,0016 (2)  äàëüíåéøåì äëÿ àíàëèçà ìåæèíäèâèäóàëüíûõ ðàçëè÷èé íàìè èñïîëüçîâàëñÿ òàêîé âçâåøåííûé ïîÒàáëèöà 1 ÇÍÀ×ÅÍÈß ÏÀÐÀÌÅÒÐΠÔÀÐÌÀÊÎÊÈÍÅÒÈÊÈ È ÄÎÇÈÐÎÂÀÍÈß ÊËÎÇÀÏÈÍÀ
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    Ëåêàðñòâåííàÿ ôîðìàÒàáëåòêè 25 ìã è 100 ìã Äîçèðîâàíèå12,5 ìã ñ ïîñòåïåííûì óâåëè÷åíèåì äî 25–100 ìã â íåäåëþ, çàòåì 300–400 ìã â äåíü Òåðàïåâòè÷åñêàÿ êîíöåíòðàöèÿ350–600 íã/ìë Ìàêñèìàëüíàÿ êîíöåíòðàöèÿ â ïëàçìå,Ñmax0,14 ìã/ìë; îò 0,07 äî 0,34 ìã/ìë ÷åðåç 1,5 ÷ (ïîñëå ïåðîðàëüíîãî ïðèåìà 100 ìã) Ìàêñèìàëüíàÿ ñóòî÷íàÿ äîçà900 ìã/ñóòêè Áèîäîñòóïíîñòü55±12 % (ïåðîðàëüíûé ïðèåì) ÁèîòðàíñôîðìàöèÿÂûðàæ

3
Miroshnichenko II. Rational dosing and monitoring of medicines. Moscow: Meditsinskoe informatsionnoe agentstvo; 2011 (in Russian).
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    Èç-çà ñïîñîáíîñòè âûçûâàòü àãðàíóëîöèòîç (îïàñíîå äëÿ æèçíè ñîñòîÿíèå, êîòîðîå ÷àùå íàñòóïàåò â ïåðâûå 3 ìåñÿöà ëå÷åíèÿ, ñ óâåëè÷åíèåì ðèñêà âîçíèêíîâåíèÿ â 10 ðàç â âîçðàñòå îò 21 äî 50 ëåò è ñòàðøå) ïðèìåíåíèå êëîçàïèíà îãðàíè÷åííî [2]. Òåðàïåâòè÷åñêèé äèàïàçîí êîíöåíòðàöèé êëîçàïèíà â ïëàçìå êðîâè 350–600 íã/ìë
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    . Ôàðìàêîêèíåòè÷åñêèå ïàðàìåòðû êëîçàïèíà èìåþò áîëüøèå èíäèâèäóàëüíûå êîëåáàíèÿ, êîòîðûå çàâèñÿò îò âîçðàñòà, ïîëà è êóðåíèÿ òàáàêà (òàáë. 1). Êëîçàïèí â çíà÷èòåëüíîé ñòåïåíè ìåòàáîëèçèðóåòñÿ â ïå÷åíè, òîëüêî 2–4 % îò ïðèíÿòîé äîçû ïðåïàðàòà âûâîäèòñÿ ñ ìî÷îé â íåèçìåíåííîì âèäå.

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Dragovic S, Gunness P, Ingelman-Sundberg M, Vermeulen NPE, Jan NM. Commandeur characterization of human cytochrome P450s involved in the bioactivation of clozapine. Drug Metab Dispos. 2013; 41: 651–8.
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    Âåäîìîñòè Íàó÷íîãî öåíòðà ýêñïåðòèçû ñðåäñòâ ìåäèöèíñêîãî ïðèìåíåíèÿ 2016; (4): 53–57. Êëîçàïèí ÿâëÿåòñÿ òðèöèêëè÷åñêèì ïðîèçâîäíûì äèáåíçîäèàçåïèíà: 8-õëîð-11-(4-ìåòèë-1-ïèïåðàçèíèë)-5Í-äèáåíçî-[b,å]
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    -äèàçåïèí. Ïî ôàðìàêîëîãè÷åñêîìó äåéñòâèþ êëîçàïèí îòíîñèòñÿ ê «àòèïè÷íûì »íåéðîëåïòèêàì (àíòèïñèõîòèêàì). Ïðèìåíÿåòñÿ äëÿ ëå÷åíèÿ ïðè îñòðûõ è õðîíè÷åñêèõ ôîðìàõ øèçîôðåíèè, ìàíèàêàëüíûõ ñîñòîÿíèÿõ, ìàíèàêàëüíî-äåïðåññèâíîì ïñèõîçå, ïñèõîìîòîðíîì âîçáóæäåíèè.

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    Êëîçàïèí â çíà÷èòåëüíîé ñòåïåíè ìåòàáîëèçèðóåòñÿ â ïå÷åíè, òîëüêî 2–4 % îò ïðèíÿòîé äîçû ïðåïàðàòà âûâîäèòñÿ ñ ìî÷îé â íåèçìåíåííîì âèäå. Îñíîâíûì ïðîäóêòîì îêèñëèòåëüíîãî äåçàëêèëèðîâàíèÿ ÿâëÿåòñÿ N-äåñìåòèëüíîå ïðîèçâîäíîå, îáëàäàþùåå ñëàáîé ôàðìàêîëîãè÷åñêîé àêòèâíîñòüþ
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    . Ðåàêöèÿ êàòàëèçèðóåòñÿ ôåðìåíòàìè ñèñòåìû öèòîõðîìà Ð450: CYP1A2 è CYP3A4.  äàëüíåéøåì ãèäðîêñèëèðîâàííûå ìåòàáîëèòû âûâîäÿòñÿ ñ ìî÷îé â âèäå êîíúþãàòîâ. Èçìåðåíèå êîíöåíòðàöèè ìåòàáîëèòà ÿâëÿåòñÿ íåîáõîäèìûì óñëîâèåì ïðè íàçíà÷åíèè ïðîëåêàðñòâ [5] èëè ïðåïàðàòîâ, ïðè ìåòàáîëèçìå êîòîðûõ, îáðàçóåòñÿ ïðîäóêò, îáëàäàþùèé çíà÷èòåëüíîé òåðàïåâòè÷åñêîé àêòèâíîñòüþ [6].

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Rodina TA, Melnikov ES, Sokolov AV, Belkov SV, Ramenskaya GV. Definition of enalapril and enalaprilat, the active metabolite in the blood plasma by HPLC-MS/MS in the personalization of pharmacotherapy of patients with hypertension. Eksperimentalnaya i klinicheskaya farmakologiya 2015; 78(10): 15–20 (in Russian).
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    Ðåàêöèÿ êàòàëèçèðóåòñÿ ôåðìåíòàìè ñèñòåìû öèòîõðîìà Ð450: CYP1A2 è CYP3A4.  äàëüíåéøåì ãèäðîêñèëèðîâàííûå ìåòàáîëèòû âûâîäÿòñÿ ñ ìî÷îé â âèäå êîíúþãàòîâ. Èçìåðåíèå êîíöåíòðàöèè ìåòàáîëèòà ÿâëÿåòñÿ íåîáõîäèìûì óñëîâèåì ïðè íàçíà÷åíèè ïðîëåêàðñòâ
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    èëè ïðåïàðàòîâ, ïðè ìåòàáîëèçìå êîòîðûõ, îáðàçóåòñÿ ïðîäóêò, îáëàäàþùèé çíà÷èòåëüíîé òåðàïåâòè÷åñêîé àêòèâíîñòüþ [6]. Îïðåäåëåíèå ñîäåðæàíèÿ N-äåìåòèëêëîçàïèíà (íîðêëîçàïèíà) ìîæåò äàòü ïîëåçíóþ èíôîðìàöèþ îòíîñèòåëüíî ïîáî÷íûõ ðåàêöèé êëîçàïèíà.

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Baymeeva NV, Bondarenko EV, Potanin SS, Miroshnichenko II. Quantitative determination of aripiprazole, risperidone and its active metabolites in human plasma by liquid chromatography tandem-mass spectrometry (HPLC/MS/MS). Razrabotka i registratsiya lekarstvennyh sredstv 2014; 3(8): 32–7 (in Russian).
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    Èçìåðåíèå êîíöåíòðàöèè ìåòàáîëèòà ÿâëÿåòñÿ íåîáõîäèìûì óñëîâèåì ïðè íàçíà÷åíèè ïðîëåêàðñòâ [5] èëè ïðåïàðàòîâ, ïðè ìåòàáîëèçìå êîòîðûõ, îáðàçóåòñÿ ïðîäóêò, îáëàäàþùèé çíà÷èòåëüíîé òåðàïåâòè÷åñêîé àêòèâíîñòüþ
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    . Îïðåäåëåíèå ñîäåðæàíèÿ N-äåìåòèëêëîçàïèíà (íîðêëîçàïèíà) ìîæåò äàòü ïîëåçíóþ èíôîðìàöèþ îòíîñèòåëüíî ïîáî÷íûõ ðåàêöèé êëîçàïèíà. Îòíîøåíèå êîíöåíòðàöèè êëîçàïèí/íîðêëîçàïèí â ïëàçìå êðîâè ìîæåò âîçðàñòàòü ïðè îäíîâðåìåííîì ïðèåìå ïàöèåíòîì ïðåïàðàòîâ, èíãèáèðóþùèõ ñèñòåìó öèòîõðîìà P450, òàêèõ êàê öèìåòèäèí è ôëóâîêñàìèí.

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Krasnykh LM, Platova AI, Baymeeva NV, Vasilenko GF. Measurement of clozapine and norclozapine in blood plasma by tandem mass spectrometry. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya 2014; (1): 37–41 (in Russian).
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    Êðîâü öåíòðèôóãèðîâàëè â âàêóóìíûõ ïðîáèðêàõ, ñûâîðîòêó îòáèðàëè â ïîëèïðîïèëåíîâûå ïðîáèðêè è äî àíàëèçà õðàíèëè ïðè òåìïåðàòóðå ìèíóñ 20 °Ñ. Äëÿ êîëè÷åñòâåííîãî îïðåäåëåíèÿ êëîçàïèíà â ñûâîðîòêå êðîâè ïðèìåíÿëè âàëèäèðîâàííûé ìåòîä ÂÝÆÕ â ñî÷åòàíèè ñ òàíäåìíûì ìàññ-ñïåêòðîìåòðè÷åñêèì äåòåêòîðîì
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    .  îáðàçöû ñûâîðîòêè êðîâè îáúåìîì 500 ìêë äîáàâëÿëè 50 ìêë ðàñòâîðà àíàñòðàçîëà, êàê âíóòðåííåãî ñòàíäàðòàC= 2500 íã/ìë, â îáðàçöàõ êîíöåíòðàöèÿ ñîñòàâëÿëà 250 íã/ìë. Ê êàëèáðîâî÷íûì îáðàçöàì è îáðàçöàì êîíòðîëÿ êà÷åñòâà äîáàâëÿëè 50 ìêë ñòàíäàðòíîãî ðàñòâîðà ñîîòâåòñòâóþùåé êîíöåíòðàöèè.

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Couchman L, Morgan PE, Spencer EP, Flanagan RJ. Plasma clozapine, norclozapine, and the clozapine:norclozapine ratio in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service 1993–2007. Ther Drug Monit. 2010; 32(4): 438–47.
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    Óñòàíîâëåíî, ÷òî íîðêëîçàïèí ïðîÿâëÿåò ïñèõîôàðìàêîëîãè÷åñêóþ àêòèâíîñòü â ýêñïåðèìåíòàõ in vitro.  òî æå âðåìÿ àêòèâíîñòüin vivoíå äîêàçàíà. Òåì íå ìåíåå îòíîøåíèå êîíöåíòðàöèè ïðåïàðàòà ê óðîâíþ ìåòàáîëèòà Cloz/Nor ÿâëÿåòñÿ ïîëåçíûì ïîêàçàòåëåì ýôôåêòèâíîñòè ïðîâîäèìîé òåðàïèè
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    . Îöåíêà ýòîãî ïàðàìåòðà ïîçâîëÿåò èçáåãàòü ïåðåäîçèðîâêè, îòñëåæèâàòü ðåãóëÿðíîñòü ïðèåìà è ïåðåíîñèìîñòü ïðåïàðàòà è óñòàíàâëèâàòü õàðàêòåð ìåòàáîëè÷åñêîé àêòèâíîñòè CYP1A2.  èññëåäîâàííîé íàìè âûáîðêå êîíöåíòðàöèÿ êëîçàïèíà â îñíîâíîì ïðåâîñõîäèò êîíöåíòðàöèþ ìåòàáîëèòà â 3 ðàçà (çíà÷åíèå ìåäèàíû 3,05 (ðèñ. 4).