ÎÃËßÄ Í.Â. Êàëèíêèíà Äîíåöêèé ãîñóäàðñòâåííûé ìåäèöèíñêèé óíèâåðñèòåò Êëþ÷åâûå ñëîâà: àíòðàöèêëèíû, êàðäèîòîêñè÷íîñòü, ÷àñòîòà, ôàêòîðû ðèñêà. ÏÎÂÐÅÆÄÅÍÈß ÑÅÐÄÖÀ ÀÍÒÐÀÖÈÊËÈÍÀÌÈ: ×ÀÑÒÎÒÀ È ÔÀÊÒÎÐÛ ÐÈÑÊÀ Ðåçþìå. Àíòðàöèêëèíîâûå àíòèáèîòèêè øèðîêî èñïîëüçóþò â êëèíè÷åñêîé ïðàêòèêå ïðè ãåìîáëàñòîçå, ëèìôîïðîëèôåðàòèâíûõ çàáîëåâàíèÿõ è çëîêà÷åñòâåííûõ îïóõîëÿõ ðàçëè÷íîé ëîêàëèçàöèè. Îäíàêî ïðèìåíåíèå ýòèõ ïðåïàðàòîâ îãðàíè÷åíî, ÷òî îáóñëîâëåíî ðàçâèòèåì â ïåðèîä ëå÷åíèÿ îñëîæíåíèé, íàèáîëåå îïàñíûì èç êîòîðûõ ÿâëÿåòñÿ ïîâðåæäåíèå ñåðäöà. ×àñòîòà âîçíèêíîâåíèÿ òàêèõ îñëîæíåíèé ïðè èñïîëüçîâàíèè àíòðàöèêëèíîâ ñîñòàâëÿåò îò 1,5 äî 67%. Íàèáîëåå âûðàæåííîé êàðäèîòîêñè÷íîñòüþ îáëàäàåò äîêñîðóáèöèí, îñîáåííî ïðè âûñîêîé ñêîðîñòè ââåäåíèÿ è êóìóëÿòèâíîé äîçå 550 ìã/ì2. Çíà÷èòåëüíî ïîâûøåí ðèñê âîçíèêíîâåíèÿ ïîâðåæäåíèÿ ñåðäöà ó äåòåé, ó áîëüíûõ â âîçðàñòå ñòàðøå 65 ëåò è ó æåíùèí. Âåðîÿòíîñòü îñëîæíåíèé âîçðàñòàåò ïðè ïðåäøåñòâîâàâøåé èëè ïàðàëëåëüíî ïðîâîäèìîé ëó÷åâîé òåðàïèè íà îáëàñòü ñðåäîñòåíèÿ, ñî÷åòàííîì ïðèåìå äðóãèõ öèòîñòàòè÷åñêèõ ñðåäñòâ è íàëè÷èè ñîïóòñòâóþùåé ïàòîëîãèè ñåðäå÷íî-ñîñóäèñòîé ñèñòåìû. Àíòðàöèêëèíîâûå àíòèáèîòèêè äîêñîðóáèöèí, äàóíîðóáèöèí, ýïèðóáèöèí è äð. øèðîêî èñïîëüçóþò äëÿ ëå÷åíèÿ ïàöèåíòîâ ñ ãåìîáëàñòîçîì, ëèìôîïðîëèôåðàòèâíûìè çàáîëåâàíèÿìè è çëîêà÷åñòâåííûìè îïóõîëÿìè ðàçëè÷íîé ëîêàëèçàöèè (Anderlini P. et al., 1995; Bulock F.A. et al., 1995; Lipshultz S.E. et al., 1995; Sorensen K. et al., 1995). Îäíàêî ïðèìåíåíèå ýòèõ ïðåïàðàòîâ îãðàíè÷åíî âñëåäñòâèå ðàçâèâàþùèõñÿ â ïåðèîä ëå÷åíèÿ îñëîæíåíèé, èç êîòîðûõ íàèáîëåå îïàñíîå ïîâðåæäåíèå ñåðäöà (Pihkala J. et al., 1996; Postma A. et al., 1996). Íåðåäêî êàðäèîòîêñè÷åñêîå äåéñòâèå àíòðàöèêëèíîâ íàñòîëüêî ñåðüåçíî, ÷òî ëå÷åíèå èìè ïðåêðàùàþò äî äîñòèæåíèÿ îò÷åòëèâîãî ïðîòèâîîïóõîëåâîãî ýôôåêòà (Ëè÷èíèöåð Ì.Ð. è ñîàâò., 1994). Ýòî îáúÿñíÿåò íåîáõîäèìîñòü èçó÷åíèÿ ðàñïðîñòðàíåííîñòè è ôàêòîðîâ ðèñêà ðàçâèòèÿ àíòðàöèêëèíîâîé êàðäèîìèîïàòèè (ÀÊ), îáóñëîâëåííîé äåéñòâèåì àíòðàöèêëèíîâûõ ïðåïàðàòîâ. ×àñòîòà âîçíèêíîâåíèÿ êàðäèàëüíûõ îñëîæíåíèé ïðè ëå÷åíèè àíòðàöèêëèíàìè, ïî äàííûì ðàçíûõ àâòîðîâ, ñîñòàâëÿåò îò 1,5 äî 67% (òàáë. 1). Ðàñõîæäåíèå ýòîãî ïîêàçàòåëÿ, âåðîÿòíî, ñâÿçàíî ñ âîçäåéñòâèåì íåñêîëüêèõ ôàêòîðîâ. Ïî äàííûì ëèòåðàòóðû, ðàñïðîñòðàíåííîñòü àíòðàöèêëèíîâûõ ïîðàæåíèé ñåðäöà, ïðåæäå âñåãî, çàâèñèò îò âèäà Òàáëèöà 1 ×àñòîòà ðàçâèòèÿ êàðäèàëüíûõ îñëîæíåíèé ïðè ëå÷åíèè àíòðàöèêëèíàìè Àâòîðû, ãîä Êîëè÷åñòâî áîëüíûõ ×àñòîòà, % K. Sorensen è ñîàâòîðû, 1995 6493 1,5 F.A. Bulock è ñîàâòîðû, 1996 125 24 D. De Wolf è ñîàâòîðû, 1996 97 25 A. Postma è ñîàâòîðû, 1996 120 33 L.H. Wexler è ñîàâòîðû, 1996 23 45 L.Y. Godoy è ñîàâòîðû, 1997 31 58 J.P. Krischer è ñîàâòîðû, 1997 15 67 ïðåïàðàòà (Ãåðøàíîâè÷ Ì.Ë., 1982; Lipshultz S.E. et al., 1995) è ðåæèìà åãî ââåäåíèÿ (Sorensen K. et al., 1995). Ïîâûøàåòñÿ âåðîÿòíîñòü ðàçâèòèÿ êàðäèàëüíûõ îñëîæíåíèé òàêæå ïðè ïðåäøåñòâîâàâøåé èëè ïàðàëëåëüíî ïðîâîäèìîé ëó÷åâîé òåðàïèè íà îáëàñòü ñðåäîñòåíèÿ (Kakadecar A.P. et al., 1997), ñî÷åòàííîì ïðèåìå äðóãèõ öèòîñòàòè÷åñêèõ ñðåäñòâ (Bellamy W.T. et al., 1995; Gehl J. et al., 1996), íàëè÷èè ñîïóòñòâóþùåé ïàòîëîãèè ñåðäå÷íî-ñîñóäèñòîé ñèñòåìû (Âàëâåðå Â.Þ. è ñîàâò., 1989).  îïðåäåëåííîé ìåðå ÷àñòîòà âîçíèêíîâåíèÿ ÀÊ çàâèñèò îò âîçðàñòà (Godoy L.Y. et al., 1997; Niitsu N. et al., 1997) è ïîëà (Lipshultz S.E. et al., 1995) ïàöèåíòà. Ïðåïàðàòû. Ðåçóëüòàòû àíàëèçà ëèòåðàòóðû ïîçâîëÿþò âûäåëèòü äîêñîðóáèöèí êàê ïðåïàðàò, îáëàäàþùèé íàèáîëåå âûðàæåííîé êàðäèîòîêñè÷íîñòüþ. Ïðè÷åì â íà÷àëå åãî ïðèìåíåíèÿ èññëåäîâàòåëè îòìå÷àëè íåçíà÷èòåëüíóþ ðàñïðîñòðàíåííîñòü ïîâðåæäåíèé ñåðäöà. Òàê, ïî äàííûì êëèíè÷åñêîãî èññëåäîâàíèÿ (Praga C. et al., 1979), ïðîâîäèìîãî 12 åâðîïåéñêèìè îíêîëîãè÷åñêèìè öåíòðàìè ñ ó÷àñòèåì 1273 ïàöèåíòîâ, ïîëó÷àâøèõ äîêñîðóáèöèí, óñòàíîâëåíî, ÷òî íåïîñðåäñòâåííî îáóñëîâëåííîå ïðèìåíåíèåì àíòðàöèêëèíà âîçíèêíîâåíèå êàðäèîìèîïàòèè îòìå÷åíî òîëüêî ó 1,7% èç íèõ, ïðåäïîëîæèòåëüíî îáóñëîâëåííîå ó 3%, ïîëó÷èâøèõ êóðñîâóþ äîçó 268 ìã/ì 2 ïîâåðõíîñòè òåëà (15 1251 ìã/ì 2). Ëåòàëüíîñòü ñîñòàâèëà ñîîòâåòñòâåííî 0,6 è 1%.  ïîñëåäíèå ãîäû èñïîëüçîâàíèå ñîâðåìåííîé äèàãíîñòè÷åñêîé òåõíèêè (ýõîêàðäèîãðàôèè ÝõîÊÃ, ñòðåññ-ÝõîÊÃ, õîëòåðîâñêîãî ìîíèòîðèðîâàíèÿ, áèîïñèè ìèîêàðäà) ñïîñîáñòâîâàëî òîìó, ÷òî ïîâðåæäåíèÿ ìèîêàðäà ïîä äåéñòâèåì àíòðàöèêëèíîâûõ ïðåïàðàòîâ ñòàëè âûÿâëÿòü ÷àùå, íà áîëåå ðàííèõ, äîêëèíè÷åñêèõ, ñòàäèÿõ è, ïî äàííûì íåêîòî- Ó Ê Ð À ¯ Í Ñ Ü Ê È É Ì Å Ä È × Í È É × À Ñ Î Ï È Ñ ¹ 2 (16) III/IV 2000 25 ÎÃËßÄ ðûõ àâòîðîâ, ïðè ïðèåìå â âûñîêèõ äîçàõ äîêñîðóáèöèíà äîñòèãàëè 67% (Wexler L.H. et al., 1996). ×àñòî äîêñîðóáèöèí èñïîëüçóþò êàê ñâîåîáðàçíûé ýòàëîí äëÿ ñðàâíåíèÿ êàðäèîòîêñè÷íîñòè äðóãèõ ïðåïàðàòîâ ãðóïïû àíòðàöèêëèíà. Òàê, ñòåïåíü ïîâðåæäåíèÿ ñåðäöà âñëåäñòâèå ïðèìåíåíèÿ ïðåïàðàòîâ íîâîãî ïîêîëåíèÿ îöåíèâàëè â ñðàâíåíèè ñ òàêîâîé äîêñîðóáèöèíà (=1): ïèðàðóáèöèí=0,8, ìèòîêñàíòðîí=3,4, äàóíîðóáèöèí=0,5, àêëàðóáèöèí=0, ýïèðóáèöèí=0,6 (Okada Y. et al., 1997). Òàêèì îáðàçîì, àíòðàöèêëèíû íîâîãî ïîêîëåíèÿ (âåðîÿòíî, çà èñêëþ÷åíèåì ìèòîêñàíòðîíà) îáëàäàþò íåçíà÷èòåëüíûì êàðäèîòîêñè÷åñêèì äåéñòâèåì. Îäíàêî äàííûå îòíîñèòåëüíî äåéñòâèÿ ìèòîêñàíòðîíà òðåáóþò äàëüíåéøåãî óòî÷íåíèÿ, òàê êàê ðåçóëüòàòû äðóãèõ èññëåäîâàíèé (Coleman R.E. et al., 1984) íå ïîäòâåðæäàþò åãî âûñîêîé òîêñè÷íîñòè. Äàóíîðóáèöèí îêàçûâàë êàðäèîòîêñè÷åñêèé ýôôåêò ó 1,512% ïàöèåíòîâ (Berchem G.J. et al., 1996). Ó 1718% áîëüíûõ, ïðèíèìàâøèõ êàðìèíîìèöèí, âîçíèêëà áîëü â îáëàñòè ñåðäöà, îòìå÷åíû èçìåíåíèÿ íà ÝÊÃ, íî ñåðäå÷íàÿ íåäîñòàòî÷íîñòü íå ðàçâèâàëàñü, âñå ïàöèåíòû æèâû (Ãåðøàíîâè÷ Ì.Ë., 1982). Ïîâðåæäåíèÿ ìèîêàðäà ïðè ëå÷åíèè ýïèðóáèöèíîì çàðåãèñòðèðîâàíû ó 13,323,1% áîëüíûõ (Âàëâåðå Â.Þ. è ñîàâò., 1989; Venturini R. et al., 1996). Äîçà. ×àñòîòà ðàçâèòèÿ êàðäèàëüíûõ îñëîæíåíèé ïðè ïðèåìå àíòðàöèêëèíîâ îò÷åòëèâî êîððåëèðóåò ñ èõ êóìóëÿòèâíîé äîçîé. Ïðè îáùåé êóðñîâîé äîçå äîêñîðóáèöèíà 250400 ìã/ì2 ïðîÿâëåíèÿ êàðäèîòîêñè÷íîñòè îáíàðóæåíû ó 15% ïàöèåíòîâ, 400500 ìã/ì 2 ó 510%, ñâûøå 550 ìã/ì2 ðèñê âîçíèêíîâåíèÿ êàðäèàëüíûõ îñëîæíåíèé ðåçêî âîçðàñòàåò, äîñòèãàÿ 40% ïðè 600 ìã/ì2 (Praga C. et al., 1979) (ðèñóíîê). ×àñòîòà ðàçâèòèÿ êàðäèàëüíûõ îñëîæíåíèé, % 40 35 30 25 20 15 10 5 0 200 250 300 350 400 450 500 550 600 Êóìóëÿòèâíàÿ äîçà, ìã/ì 2 Ðèñóíîê. ×àñòîòà ðàçâèòèÿ êàðäèàëüíûõ îñëîæíåíèé ïðè ïðèåìå äîêñîðóáèöèíà â çàâèñèìîñòè îò êóìóëÿòèâíîé äîçû 26 Íåêîòîðûå èññëåäîâàòåëè îòìå÷àëè ñóáêëèíè÷åñêèå èçìåíåíèÿ êàðäèàëüíîé ôóíêöèè ïðè ïðèåìå äîêñîðóáèöèíà â äîçå 350500 ìã/ì2 ó 5867% áîëüíûõ (Ëè÷èíèöåð Ì.Ð. è ñîàâò., 1994; Postma A. et al., 1996; Wexler L.H. et al., 1996). ×àñòîòà âûðàæåííîé êàðäèîìèîïàòèè ñ ðàçâèòèåì çàñòîéíîé ñåðäå÷íîé íåäîñòàòî÷íîñòè (ÇÑÍ) ïðè ñóììàðíûõ äîçàõ ìåíåå 550 ìã/ì2 ñîñòàâëÿåò 0,27%, âûøå 550 ìã/ì2 30% (Balcerzak S.P. et al., 1978). ×àñòîòà ïîâðåæäåíèÿ ñåðäöà ïðè èñïîëüçîâàíèè äðóãèõ àíòðàöèêëèíîâûõ àíòèáèîòèêîâ â çàâèñèìîñòè îò ñóììàðíîé äîçû íåäîñòàòî÷íî èçó÷åíà. Èìåþùèåñÿ äàííûå ïîçâîëÿþò ñäåëàòü âûâîä î ìåíåå âûðàæåííîé, ïî ñðàâíåíèþ ñ äîêñîðóáèöèíîì, êàðäèîòîêñè÷íîñòè ýòèõ ïðåïàðàòîâ (Coleman R.E. et al., 1984; Ðàéíîâ Þ. è ñîàâò., 1993) (òàáë. 2). Ýïèðóáèöèí è äàóíîðóáèöèí ïðè êóìóÒàáëèöà 2 ×àñòîòà ðàçâèòèÿ êàðäèàëüíûõ îñëîæíåíèé ó âçðîñëûõ ïðè ïðèåìå àíòðàöèêëèíîâûõ àíòèáèîòèêîâ Ïðåïàðàò Êóìóëÿòèâíàÿ ×àñòîòà, % äîçà, ìã/ì2 Ñóáêëèíè÷åñêèå ÇÑÍ èçìåíåíèÿ Ìèòîêñàíòðîí 140 13 2,6 200 29,4 5,9 Äàóíîðóáèöèí 1,5 <600 1000 12 Ýïèðóáèöèí 13,3 < 600 23,1 10,6 > 1000 Èäàðóáèöèí 150 18 5 >290 Àêëàðóáèöèí 175 6 300 12 ëÿòèâíîé äîçå íèæå 600 ìã/ì2 ïðàêòè÷åñêè íå îêàçûâàåò òîêñè÷åñêîãî äåéñòâèÿ íà ñåðäöå, ïðè ïîâûøåíèè èõ äîçû âåðîÿòíîñòü êàðäèàëüíûõ îñëîæíåíèé âîçðàñòàåò (Ðàéíîâ Þ. è ñîàâò., 1993). Òàê, èç 85 ïàöèåíòîâ, ïîëó÷àâøèõ ýïèðóáèöèí â ñðåäíåé äîçå 1000 ìã/ì2, ó 9 (10,6%) ðàçâèëàñü ÇÑÍ, 1 áîëüíîé (1,2%) óìåð îò êàðäèàëüíûõ îñëîæíåíèé (Jensen B.V. et al., 1996). Ïðè ïðèåìå êàðìèíîìèöèíà â ñóììàðíîé äîçå 350400 ìã/ì2 îòìå÷àëè íåçíà÷èòåëüíî âûðàæåííûå ïðîÿâëåíèÿ êàðäèîòîêñè÷íîñòè (Ãåðøàíîâè÷ Ì.Ë., 1982); èäàðóáèöèíà â äîçå 150 ìã/ì2 ñóáêëèíè÷åñêèå èçìåíåíèÿ ôðàêöèè âûáðîñà ëåâîãî æåëóäî÷êà (ïî äàííûì ýõîêàðäèîãðàôèè ó 18%), âûøå 290 ìã/ì2 ðàçâèòèå êàðäèîìèîïàòèè ó 5% áîëüíûõ (Anderlini P. et al., 1995). Ïðèìåíåíèå ìèòîêñàíòðîíà (êóìóëÿòèâíàÿ äîçà 140 ìã/ì2) îáóñëîâèëî ðàçâèòèå ÇÑÍ ó 2,6% ïàöèåíòîâ, ñóáêëèíè÷åñêèå íàðóøåíèÿ êàðäèàëüíîé ôóíêöèè ó 13% (Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication ¹ 832621). Ìèòîêñàíòðîí â äîçå 200 ìã/ì2 îáóñëîâëèâàë íàðóøåíèÿ ôðàêöèè âûáðîñà ëåâîãî æåëóäî÷êà ó 29,4%, ñåðäå÷íóþ íåäîñòàòî÷íîñòü ó 5,9% áîëüíûõ (Coleman R.E. et al., 1984). Ïðè ïðèåìå àêëàðóáèöèíà (êóðñîâàÿ äîçà 175 ìã/ì2) èçìåíåíèÿ íà ÝÊà íàáëþäàëè â 12%, à ïðè 175 ìã/ì2 â 6% ñëó÷àåâ (Åãîðîâ Ë.Å., Ðåùèêîâ Â.Ï., 1989). Ó Ê Ð À ¯ Í Ñ Ü Ê È É Ì Å Ä È × Í È É × À Ñ Î Ï È Ñ ¹ 2 (16) III/ IV 2000 ÎÃËßÄ Êóìóëÿòèâíàÿ äîçà öèòîñòàòèêà îäèí èç îñíîâíûõ ôàêòîðîâ ðèñêà ðàçâèòèÿ ÀÊ (Lipshultz S.E. et al., 1995; Sorensen K. et al., 1995; Pihkala J. et al., 1996; Okada Y. et al., 1997). Òåì íå ìåíåå ðîëü ýòîãî ôàêòîðà íå ñëåäóåò àáñîëþòèçèðîâàòü, òàê êàê íåáëàãîïðèÿòíîå âëèÿíèå äðóãèõ ôàêòîðîâ ìîæåò îáóñëîâèòü ïîâðåæäåíèå ñåðäöà è ïðè íåâûñîêèõ ñóììàðíûõ äîçàõ. Ðåæèì ââåäåíèÿ. Âåðîÿòíîñòü ðàçâèòèÿ êàðäèîìèîïàòèè âîçðàñòàåò ïðè âûñîêîé ñêîðîñòè ââåäåíèÿ àíòðàöèêëèíîâ (Lipshultz S.E. et al., 1995; Sorensen K. et al., 1995).  ïðåäåëàõ îäíîé è òîé æå ñóììàðíîé äîçû ââåäåíèå âûñîêèõ ðàçîâûõ äîç öèòîñòàòèêà (50 ìã/ì2 è âûøå) ïðèâîäèò ê âûñîêîé êîíöåíòðàöèè ïðåïàðàòà â êðîâè è ïîâûøåíèþ ðèñêà ðàçâèòèÿ è óñóãóáëåíèþ òÿæåñòè êàðäèàëüíûõ îñëîæíåíèé (Lipshultz S.E. et al., 1995; Sorensen K. et al., 1995; Krisher J.P. et al., 1997). Âåðîÿòíî, èñêëþ÷åíèåì èç îáùåãî ïðàâèëà ÿâëÿåòñÿ ýïèðóáèöèí. Òàê, G.J. Berchem è ñîàâòîðû (1996) îáíàðóæèëè, ÷òî íåäåëüíàÿ äîçà ýòîãî ïðåïàðàòà ñâûøå 40 ìã/ì 2 íå áîëåå òîêñè÷íà, ÷åì åãî íèçøèå äîçû. Âîçðàñò. Ó äåòåé è áîëüíûõ â âîçðàñòå ñòàðøå 65 ëåò çíà÷èòåëüíî ïîâûøåí ðèñê âîçíèêíîâåíèÿ ïîâðåæäåíèÿ ñåðäöà ïðè ïðèåìå àíòðàöèêëèíîâ äàæå â íåâûñîêèõ äîçàõ. ×àñòîòà ðàçâèòèÿ êàðäèàëüíûõ îñëîæíåíèé ó äåòåé, ïðèíèìàâøèõ àíòðàöèêëèíîâûå àíòèáèîòèêè, ïî äàííûì ðàçíûõ àâòîðîâ, ñîñòàâëÿåò îò 1,6 äî 45% (Hale J.P., Lewis I.J., 1994; Sorensen K. et al., 1995; De Wolf D. et al., 1996; Godoy L.Y. et al., 1997; Schiavetti A. et al., 1997).  èññëåäîâàíèè J.P. Krisher è ñîàâòîðîâ (1997), ïðîâîäèâøåìñÿ ñ 1974 ïî 1990 ã. â ÑØÀ è îáúåäèíèâøåì 6493 ðåáåíêà, ïîëó÷àâøèõ àíòðàöèêëèíû ïî ïîâîäó ðàçëè÷íûõ çëîêà÷åñòâåííûõ îïóõîëåé, êàðäèîòîêñè÷íîñòü ïîäòâåðæäåíà ó 106 (1,6%) ïàöèåíòîâ: ó 43 âûÿâëåíû ñóáêëèíè÷åñêèå èçìåíåíèÿ êàðäèàëüíîé ôóíêöèè, ó 58 ÇÑÍ, 5 âíåçàïíî óìåðëè, ïðåäïîëîæèòåëüíî, îò êàðäèàëüíûõ îñëîæíåíèé. Ïðè÷åì â 89,5% ñëó÷àåâ ðàííÿÿ êàðäèîòîêñè÷íîñòü îòìå÷åíà â òå÷åíèå 1 ãîäà ïîñëå ëå÷åíèÿ. Ïî ðåçóëüòàòàì, ïîëó÷åííûì äðóãèìè èññëåäîâàòåëÿìè (Bulock F.A. et al., 1995; Sorensen K. et al., 1995; De Wolf D. et al., 1996; Krisher J.P. et al., 1997), ïðåäïîëàãàåòñÿ áîëåå âûñîêàÿ ðàñïðîñòðàíåííîñòü àíòðàöèêëèíîâûõ ïîâðåæäåíèé ñåðäöà ó äåòåé (òàáë. 3). Ïðè÷åì ÷àùå (1345%) îòìå÷àþò ñóáêëèÒàáëèöà 3 ×àñòîòà ðàçâèòèÿ ïîâðåæäåíèé ñåðäöà ïîä âëèÿíèåì àíòðàöèêëèíîâûõ ïðåïàðàòîâ ó äåòåé (ïî äàííûì ðàçíûõ àâòîðîâ) Àâòîðû, ãîä Êîëè÷åñòâî ×àñòîòà, % áîëüíûõ Ñóáêëèíè÷åñêèå ÇÑÍ èçìåíåíèÿ F.A. Bulock è ñîàâòîðû, 1995 226 28 K. Sorensen è ñîàâòîðû, 1995 125 19 5 F.A. Bulock è ñîàâòîðû, 1996 120 28 5 J. Pihkala è ñîàâòîðû, 1996 97 25 D. De Wolf è ñîàâòîðû, 1996 91 32 L.Y. Godoy è ñîàâòîðû, 1997 23 45 A. Schiavetti è ñîàâòîðû, 1997 15 13 6,6 íè÷åñêèå èçìåíåíèÿ êàðäèàëüíîé ôóíêöèè, ðåæå (56%) ðàçâèòèå ÇÑÍ. L.Y. Godoy è ñîàâòîðû (1997) ïðè èññëåäîâàíèè, ïðîâåäåííîì ó 120 äåòåé (ñ 1985 ïî 1994 ãã.), ïðèíèìàâøèõ àíòðàöèêëèíîâûå àíòèáèîòèêè, îáíàðóæèëè ñóáêëèíè÷åñêóþ êàðäèàëüíóþ äèñôóíêöèþ ó 33 (28%) èç íèõ, ÇÑÍ ó 6 (5%). Ðàííèå ïðîÿâëåíèÿ êàðäèîòîêñè÷íîñòè îòìå÷àëè óæå ïðè äîçå 180 ìã/ì2. À âñå çàðåãèñòðèðîâàííûå êàðäèàëüíûå îñëîæíåíèÿ ðàçâèâàëèñü ïðè êóìóëÿòèâíîé äîçå 180380 ìã/ì2, ïðè÷åì ó äåòåé â âîçðàñòå ìëàäøå 4 ëåò ðèñê ïîáî÷íîãî äåéñòâèÿ âîçðàñòàë. F.A. Bulock è ñîàâòîðû (1995) ïðè ïðîâåäåíèè èññëåäîâàíèÿ ñ ó÷àñòèåì 226 äåòåé, êîòîðûõ ëå÷èëè àíòðàöèêëèíàìè, ó 28% èç íèõ âûÿâèëè ñóáêëèíè÷åñêèå íàðóøåíèÿ ôóíêöèè ñåðäöà, ïðè ýòîì ó 40% áîëüíûõ ñóììàðíàÿ äîçà ïðåïàðàòîâ ñîñòàâèëà íèæå 400 ìã/ì2. Ó áîëüíûõ â âîçðàñòå ñòàðøå 65 ëåò êàðäèàëüíûå îñëîæíåíèÿ òàêæå ìîãóò âîçíèêàòü ïðè íåâûñîêèõ (250300 ìã/ì2) êóìóëÿòèâíûõ äîçàõ àíòðàöèêëèíîâ (Praga C. et al., 1979; Anderlini P et al., 1995; Niitsu N. et al., 1997). Ïîë. Èìåþòñÿ äàííûå î òîì, ÷òî æåíñêèé ïîë ÿâëÿåòñÿ îäíèì èç ôàêòîðîâ ðèñêà ðàçâèòèÿ ÀÊ (Krisher J.P. et al., 1997). Òàê, ïðè èññëåäîâàíèè 120 ïàöèåíòîâ, ïðèíèìàâøèõ ýòè ïðåïàðàòû ïî ïîâîäó ðàçëè÷íûõ îíêîëîãè÷åñêèõ çàáîëåâàíèé, îòìå÷åíî, ÷òî ó æåíùèí ïðè áîëåå íèçêîé êóìóëÿòèâíîé äîçå ðàçâèâàþòñÿ áîëåå ÷àñòûå è òÿæåëûå ïîâðåæäåíèÿ ñåðäöà (Lipshultz S.E. et al., 1995). Ëó÷åâàÿ òåðàïèÿ. Ðåàëèçàöèè êàðäèîòîêñè÷åñêèõ ýôôåêòîâ àíòðàöèêëèíîâûõ àíòèáèîòèêîâ ñïîñîáñòâóåò ïðåäøåñòâóþùåå èëè ïðîâîäèìîå îäíîâðåìåííî ñ õèìèîòåðàïèåé îáëó÷åíèå ñðåäîñòåíèÿ, ÷òî äàåò îñíîâàíèå ìíîãèì àâòîðàì ðåêîìåíäîâàòü â òàêèõ ñëó÷àÿõ îãðàíè÷åíèå äîçû öèòîñòàòèêîâ äî 400 ìã/ì2 (Praga C. et al., 1979; Kakadekar A.P. et al., 1997). Òàê, íàðóøåíèÿ ñîêðàòèìîñòè ëåâîãî æåëóäî÷êà îòìå÷åíû ó 32% áîëüíûõ, ïðèíèìàâøèõ àíòðàöèêëèíû â äîçå 410 ìã/ì2, òîãäà êàê â ñî÷åòàíèè ñ ëó÷åâîé òåðàïèåé êàðäèàëüíûå îñëîæíåíèÿ âîçíèêëè ó 50% ïðè äîçå 360 ìã/ì2 (Pihkala J. et al., 1996). Îäíàêî èìåþòñÿ ðàáîòû, â êîòîðûõ íå îòìå÷åíî ïîòåíöèðóþùåå äåéñòâèå ëó÷åâîé òåðàïèè íà ðàçâèòèå ïîâðåæäåíèé ñåðäöà (Kakaderkar A.P. et al., 1997). Êîìáèíèðîâàííàÿ õèìèîòåðàïèÿ. Âåðîÿòíîñòü àíòðàöèêëèíîâûõ ïîâðåæäåíèé ñåðäöà âîçðàñòàåò ïðè îäíîâðåìåííîì ïðèåìå öèêëîñïîðèíà À (Bellamy W.T. et al., 1995) è âèíêðèñòèíà (Praga C. et al., 1979). Ñâåäåíèÿ îá àíàëîãè÷íîì äåéñòâèè öèêëîôîñôàíà íåîäíîçíà÷íû (Praga C. et al., 1979). Íåò åäèíîãî ìíåíèÿ è ïî ïîâîäó êîìáèíèðîâàííîãî ïðèåìà ïàêëèòàêñåëà è àíòðàöèêëèíîâ (Gianni L. et al., 1995; Gehl J. et al., 1996; Conte P.F. et al., 1997). Òàê, èç 30 æåíùèí, ïðèíèìàâøèõ äîêñîðóáèöèí (ñóììàðíàÿ äîçà 369 ìã/ì 2) è ïàêëèòàêñåë ïî ïîâîäó ðàêà ìîëî÷íîé æåëåçû, ó 15 (50%) áûëè îòìå÷åíû ñóáêëèíè÷åñêèå íàðóøåíèÿ äåÿòåëüíîñòè ñåðä- Ó Ê Ð À ¯ Í Ñ Ü Ê È É Ì Å Ä È × Í È É × À Ñ Î Ï È Ñ ¹ 2 (16) III/IV 2000 27 ÎÃËßÄ öà, ó 6 (20%) ÇÑÍ (Gehl J. et al., 1996). Ïðîòèâîïîëîæíûå ðåçóëüòàòû ïîëó÷åíû â äðóãîì èññëåäîâàíèè, â êîòîðîì êîìáèíàöèÿ ïàêëèòàêñåëà è ýïèðóáèöèíà íå òîëüêî íå ïîâûøàëà ðèñê ðàçâèòèÿ êàðäèàëüíûõ îñëîæíåíèé, íî, íàïðîòèâ, ñíèæàëà åãî (Conte P.E. et al., 1997). Ñîïóòñòâóþùàÿ ïàòîëîãèÿ.  çíà÷èòåëüíîé ñòåïåíè êàðäèîòîêñè÷åñêîìó äåéñòâèþ àíòðàöèêëèíîâ ñïîñîáñòâóåò íàëè÷èå ñîïóòñòâóþùèõ çàáîëåâàíèé ñåðäå÷íî-ñîñóäèñòîé ñèñòåìû: èøåìè÷åñêàÿ áîëåçíü ñåðäöà, ïîðîê ñåðäöà, ìèîêàðäèò, àðòåðèàëüíàÿ ãèïåðòåíçèÿ (Praga C. et al., 1979; Anderlini P. et al., 1995; Sorensen K. et al., 1995). Òàê, ó áîëüíûõ, ïîëó÷àâøèõ àäðèàìèöèí èëè ôàðìîðóáèöèí, ïðèçíàêè êàðäèîòîêñè÷íîñòè âîçíèêëè òîëüêî ó ïàöèåíòîâ ñ ñîïóòñòâóþùèìè ñåðäå÷íî-ñîñóäèñòûìè çàáîëåâàíèÿìè (Âàëüâåðå Â.Þ. è ñîàâò., 1989). Òàêèì îáðàçîì, ìîæíî îòìåòèòü, ÷òî ðèñê ðàçâèòèÿ ÀÊ íàèâûñøèé ó äåòåé è ëèö â âîçðàñòå ñòàðøå 65 ëåò, îñîáåííî ó æåíùèí, ïîëó÷àþùèõ äîêñîðóáèöèí â ñóììàðíîé äîçå âûøå 550 ìã/ì2, ïðè ðàçîâîé äîçå ïðåïàðàòà âûøå 50 ìã/ì2, ïðåäøåñòâóþùåé èëè ïðîâîäèìîé îäíîâðåìåííî ëó÷åâîé òåðàïèè, êîìáèíèðîâàííîé õèìèîòåðàïèè, íàëè÷èè ñîïóòñòâóþùåé ïàòîëîãèè ñåðäå÷íî-ñîñóäèñòîé ñèñòåìû. ËÈÒÅÐÀÒÓÐÀ Âàëâåðå Â.Þ., Øõâàöàáàÿ Ë.Â., Íþ-Òÿíü-äå Ã.Á (1989) Ñðàâíèòåëüíàÿ îöåíêà êàðäèîòîêñè÷åñêîãî äåéñòâèÿ ïðîòèâîîïóõîëåâûõ àíòèáèîòèêîâ àäðèàìèöèíà è ôàðìîðóáèöèíà. Êàðäèîëîãèÿ, 29(9): 6466. Ãåðøàíîâè÷ Ì.Ë. (1982) Îñëîæíåíèÿ ïðè õèìèî- è ãîðìîíîòåðàïèè çëîêà÷åñòâåííûõ îïóõîëåé. Ìåäèöèíà, Ìîñêâà, ñ. 8997. Åãîðîâ Ë.Å., Ðåùèêîâ Â.Ï. (1989) Íîâûé ïðîòèâîëåéêîçíûé àíòèáèîòèê àíòðàöèêëèíîâîãî ðÿäà àêëàðóáèöèí. Ãåìàòîëîãèÿ è òðàíñôóçèîëîãèÿ, 8: 3439. Ëè÷èíèöåð Ì.Ð., Âûøèíñêàÿ Ã.Â., Ìèíüêîâ Å.Ä., Íàõàëîâà Ò.À., Îäæàðîâà À.À., Ãàðèí À.Ì. 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ÏÎØÊÎÄÆÅÍÍß ÑÅÐÖß ÀÍÒÐÀÖÈÊ˲ÍÀÌÈ: ×ÀÑÒÎÒÀ ² ×ÈÍÍÈÊÈ ÐÈÇÈÊÓ Í.Â. Êàëèíêèíà Ðåçþìå. Àíòðàöèêë³íîâ³ àíòèá³îòèêè øèðîêî âèêîðèñòîâóþòü ó êë³íè÷í³é ïðàêòèö³ ïðè ãåìîáëàñòîç³, ë³ìôîïðîë³ôåðàòèâíèõ çàõâîðþâàííÿõ ³ çëîÿê³ñíèõ ïóõëèíàõ ð³çíî¿ ëîêàë³çàö³¿. Îäíàê çàñòîñóâàííÿ öèõ ïðåïàðàò³â îáìåæåíå, ùî çóìîâëåíî ðîçâèòêîì â ïåð³îä ë³êóâàííÿ óñêëàäíåíü, íàéá³ëüø íåáåçïå÷íèì ç ÿêèõ º ïîøêîäæåííÿ ñåðöÿ. ×àñòîòà âèíèêíåííÿ òàêèõ óñêëàäíåíü ïðè âèêîðèñòàíí³ àíòðàöèêë³í³â ñêëàäຠâ³ä 1,5 äî 67%. Íàéá³ëüø âèðàæåíó êàðä³îòîêñè÷í³ñòü ìຠäîêñîðóá³öèí, îñîáëèâî ïðè âèñîê³é øâèäêîñò³ ââåäåííÿ ³ êóìóëÿòèâí³é äîç³ 550 ìã/ì2. Çíà÷íî ï³äâèùåíèé ðèçèê âèíèêíåííÿ ïîøêîäæåííÿ ÐÅÔÅÐÀÒÈÂÍÀ Ðàííÿÿ äèàãíîñòèêà èøåìè÷åñêîé áîëåçíè ñåðäöà ó áîëüíûõ õðîíè÷åñêèìè îáñòðóêòèâíûìè çàáîëåâàíèÿìè ëåãêèõ Ïàëååâ Í.Ð., ×åðåéñêàÿ Í.Ê., Àôîíàñüåâà È.À., Ôåäîðîâà Ñ.È. (1999). Òåð. àðõ., 71(9): 5256. Öåëü èññëåäîâàíèÿ èçó÷åíèå ÷àñòîòû, îñîáåííîñòåé òå÷åíèÿ, ïðèíöèïîâ äèàãíîñòèêè è òåðàïèè ÈÁÑ ó áîëüíûõ õðîíè÷åñêèìè îáñòðóêòèâíûìè çàáîëåâàíèÿìè ëåãêèõ (ÕÎÇË). Îáñëåäîâàëè 60 áîëüíûõ áðîíõèàëüíîé àñòìîé (ÁÀ) è õðîíè÷åñêèì îáñòðóêòèâíûì áðîíõèòîì (ÕÎÁ) ñòàðøå 40 ëåò. Ïðîâîäèëè îáùåêëèíè÷åñêèå èññëåäîâàíèÿ: çàïèñü ÝÊÃ, ðåíòãåíîãðàôèþ îðãàíîâ ãðóäíîé êëåòêè, ÝõîÊÃ, õîëòåðîâñêîå ìîíèòîðèðîâàíèå ÝÊÃ, ïî ïîêàçàíèÿì êîðîíàðîãðàôèþ. Èçó÷åíû ìàòåðèàëû àóòîïñèé 20 óìåðøèõ îò ÕÎÇË. Ïî äàííûì àíàìíåçà, ÝÊÃ, ÝõîÊÃ, õîëòåðîâñêîãî ìîíèòîðèðî- ñåðöÿ ó ä³òåé, ó õâîðèõ â³êîì ñòàðøå 65 ðîê³â ³ ó æ³íîê. ³ðîã³äí³ñòü óñêëàäíåíü çðîñòຠï³ñëÿ ðàí³øå ïðîâåäåíî¿ àáî ïðè îäíî÷àñíîìó çä³éñíåíí³ ïðîìåíåâî¿ òåðàﳿ íà ä³ëÿíêó ñåðåäîñò³ííÿ, ïîºäíàíîìó ïðè çàñòîñóâàíí³ ³íøèõ öèòîñòàòè÷íèõ çàñîá³â ³ íàÿâíîñò³ ñóïóòíüî¿ ïàòîëî㳿 ñåðöåâî-ñóäèííî¿ ñèñòåìè. Êëþ÷îâ³ ñëîâà: àíòðàöèêë³íè, êàðä³îòîêñè÷í³ñòü, ÷àñòîòà, ÷èííèêè ðèçèêó. ANTHRACYCLINE-INDUCED HEART DAMAGE: FREQUENCY AND RISK FACTORS N.V. Kalinkina Summary. The anthracycline antibiotics are widely used in modern clinic against various malignancies. But their therapeutic value is limited by different complications, one of the most dangerous of them is myocardial damage. The frequency of the anthracycline-induced cardial complications is from 1.5 to 67%. Doxorubicin exerts the most intensive toxic influence on the heart. There is an increased incidence of drug-induced cardiotoxicity at doxorubicin cumulative doses exceeding 550 mg/m2 and maximal doses 50 mg/m2. The risk of developing of the cardial complications can increase in children, elderly patients (>65 years) and women. Cardiotoxicity may occur at lower doses in patients with prior and parallel mediastinal irradiation, combined therapy with other cytostatics and pre-existing heart disease. Key words: anthracycline, cardiotoxicity, frequency, risk factors. Àäðåñ äëÿ ïåðåïèñêè: Êàëèíêèíà Íàòàëüÿ Âàëåðüåâíà 86010, Ìàêååâêà, áóëüâ. 8-ãî Ñåíòÿáðÿ 4, êâ. 21 ²ÍÔÎÐÌÀÖ²ß âàíèÿ ÝÊÃ, âåëîýðãîìåòðè÷åñêîé ïðîáû, êîðîíàðîãðàôèè äèàãíîç ÈÁÑ âïåðâûå áûë óñòàíîâëåí ó 53,3% áîëüíûõ ÁÀ è ÕÎÁ. Áåçáîëåâûå ôîðìû èøåìèè ìèîêàðäà âñòðåòèëèñü â 84,4% ñëó÷àåâ ÷àùå, ÷åì â îáùåé ïîïóëÿöèè áîëüíûõ ÈÁÑ. Ó 70% áîëüíûõ ïðè ëå÷åíèè ïðåäóêòàëîì (òðèìåòàçèäèíîì) îòìå÷àëîñü óìåíüøåíèå ÷àñòîòû ýïèçîäîâ áåçáîëåâîé èøåìèè ìèîêàðäà. Ìàòåðèàëû àóòîïñèé ñâèäåòåëüñòâîâàëè î âûñîêîé ðàñïðîñòðàíåííîñòè ïîðàæåíèÿ àòåðîñêëåðîçîì àîðòû è êîðîíàðíûõ àðòåðèé ó áîëüíûõ ÕÎÇË. Ñóùåñòâóþò çíà÷èòåëüíûå òðóäíîñòè äèàãíîñòèêè ÈÁÑ ïðè ÕÎÇË, îòñóòñòâóþò ÷åòêèå êîððåëÿöèè ìåæäó êëèíè÷åñêîé êàðòèíîé ÈÁÑ è äàííûìè èíñòðóìåíòàëüíûõ èññëåäîâàíèé. Îäíèì èç ïðåïàðàòîâ âûáîðà ëå÷åíèÿ ÈÁÑ ó áîëüíûõ ÕÎÇË ìîæåò áûòü ïðåäóêòàë. Ó Ê Ð À ¯ Í Ñ Ü Ê È É Ì Å Ä È × Í È É × À Ñ Î Ï È Ñ ¹ 2 (16) III/IV 2000 29