ÎÃËßÄ Ø. Õîðâàò Ïåøòñêàÿ îáëàñòíàÿ ìóíèöèïàëüíàÿ áîëüíèöà, ã. Êèøòàð÷à, Âåíãðèÿ Êëþ÷åâûå ñëîâà: Êàâèíòîí, ýòèëàïîâèíêàìèíàò, õðîíè÷åñêàÿ ãèïîïåðôóçèÿ ìîçãà, êîãíèòèâíûå íàðóøåíèÿ, èçìåíåíèÿ áåëîãî âåùåñòâà, òåðàïèÿ. ÊÀÂÈÍÒÎÍ Â ÒÅÐÀÏÈÈ ÕÐÎÍÈ×ÅÑÊÎÉ ÍÅÄÎÑÒÀÒÎ×ÍÎÑÒÈ ÌÎÇÃÎÂÎÃÎ ÊÐÎÂÎÎÁÐÀÙÅÍÈß Ðåçþìå. Ïàòîëîãè÷åñêèå ñîñòîÿíèÿ, íàçûâàåìûå õðîíè÷åñêîé íåäîñòàòî÷íîñòüþ ìîçãîâîãî êðîâîîáðàùåíèÿ (ÕÍÌÊ), à òàêæå ñîñóäèñòîé ìîçãîâîé íåäîñòàòî÷íîñòüþ èëè öåðåáðîâàñêóëÿðíîé äèñôóíêöèåé, âûçâàíû õðîíè÷åñêîé ãèïîïåðôóçèåé ãîëîâíîãî ìîçãà.  êëèíè÷åñêîé êàðòèíå ÕÍÌÊ ÷àñòî ïðåîáëàäàþò êîãíèòèâíûå íàðóøåíèÿ (ïñèõîîðãàíè÷åñêèé ñèíäðîì), âûðàæåííîñòü êîòîðûõ ìîæåò äîñòèãàòü ñòåïåíè äåìåíöèè (ïîäêîðêîâàÿ àòåðîñêëåðîòè÷åñêàÿ ëåéêîýíöåôàëîïàòèÿ, ñîñóäèñòàÿ äåìåíöèÿ, äåìåíöèÿ àëüöãåéìåðîâñêîãî òèïà è ò.ä.). Ïàòîëîãè÷åñêèå èçìåíåíèÿ ïðè ÕÍÌÊ êàñàþòñÿ ãëàâíûì îáðàçîì áåëîãî âåùåñòâà (äåìèåëèíèçàöèÿ, àêòèâàöèÿ ãëèè, ïîðàæåíèÿ êëåòîê îëèãîäåíäðîãëèè), à òàêæå õàðàêòåðèçóþòñÿ ðàññåÿííîé ãèáåëüþ êëåòîê. Ïðè òàêèõ çàáîëåâàíèÿõ íàèáîëüøóþ ïîëüçó ìîæíî îæèäàòü îò ëå÷åíèÿ, ñïîñîáíîãî êîððèãèðîâàòü ïàòîáèîõèìè÷åñêèå è ïàòîôèçèîëîãè÷åñêèå èçìåíåíèÿ, âûçâàííûå õðîíè÷åñêîé ãèïîïåðôóçèåé ãîëîâíîãî ìîçãà. Êàâèíòîí (ðàöèîíàëüíîå õèìè÷åñêîå íàçâàíèå «ýòèëàïîâèíêàìèíàò») îêàçûâàåò ïîëîæèòåëüíîå äåéñòâèå íà ðàçëè÷íûå çâåíüÿ ïàòîëîãè÷åñêîãî ïðîöåññà ïðè õðîíè÷åñêîé ãèïîïåðôóçèè ãîëîâíîãî ìîçãà ðàçíîé ýòèîëîãèè. ÂÂÅÄÅÍÈÅ Õðîíè÷åñêàÿ ãèïîïåðôóçèÿ ãîëîâíîãî ìîçãà ïî ñèìïòîìàòèêå, ïàòîëîãè÷åñêèì, ïàòîôèçèîëîãè÷åñêèì è êëèíè÷åñêèì ïîñëåäñòâèÿì — ÿâëåíèå, åùå íå äî êîíöà èññëåäîâàííîå.  ïîñëåäíèå ãîäû çíà÷èòåëüíî ðàñøèðèëîñü èçó÷åíèå ïàòîìîðôîëîãè÷åñêèõ è áèîõèìè÷åñêèõ èçìåíåíèé, ïðîèñõîäÿùèõ â ðåçóëüòàòå õðîíè÷åñêîé íåäîñòàòî÷íîñòè ìîçãîâîãî êðîâîîáðàùåíèÿ (ÕÍÌÊ) (Waxman S.G. et al., 1992; Sekhon L.H. et al., 1994; 1997a, b). Óñòàíîâëåíî, ÷òî õðîíè÷åñêàÿ ãèïîïåðôóçèÿ ìîçãà âûçûâàåò ãëàâíûì îáðàçîì èçìåíåíèÿ áåëîãî âåùåñòâà (äåìèåëèíèçàöèÿ, ïîðàæåíèå êëåòîê îëèãîäåíäðîãëèè, àêòèâàöèÿ è ðàçðàñòàíèå ìèêðîãëèè è àñòðîöèòîâ), à òàêæå ïðèâîäèò ê àïîïòîçó. Ñëåäñòâèåì õðîíè÷åñêîé ãèïîïåðôóçèè ñ÷èòàþò äèôôóçíîå èçìåíåíèå áåëîãî âåùåñòâà — ëåéêîàðåîç (Hachinski V.C. et al., 1987), âûÿâëÿåìûé ñ ïîìîùüþ ðåíòãåíîâñêîé êîìïüþòåðíîé è ìàãíèòíî-ðåçîíàíñíîé òîìîãðàôèè. Ëåéêîàðåîç ÷àñòî ñî÷åòàåòñÿ ñ êîãíèòèâíûìè ðàññòðîéñòâàìè, åãî ÷àñòî îòìå÷àþò ïðè áîëåçíÿõ, ñîïðîâîæäàþùèõñÿ äåìåíöèåé (áîëåçíü Áèíñâàíãåðà, áîëåçíü Àëüöãåéìåðà), íî òàêæå è ó ïðàêòè÷åñêè çäîðîâûõ ëþäåé (George A.E. et al., 1986; Lechner H., Schmidt R., 1989). Íà âîçíèêíîâåíèå õðîíè÷åñêîé ãèïîïåðôóçèè ìîçãà âëèÿþò ïîðàæåíèÿ ýêñòðà- è èíòðàêðàíèàëüíûõ ñîñóäîâ, õðîíè÷åñêàÿ ñåðäå÷íàÿ íåäîñòàòî÷íîñòü ðàçëè÷íîé ýòèîëîãèè, íàðóøåíèå ìèêðîöèðêóëÿöèè âñëåäñòâèå õðîíè÷åñêîãî èçìåíåíèÿ ñîäåðæàíèÿ ôîðìåííûõ ýëåìåíòîâ è(èëè) êîìïîíåíòîâ ïëàçìû è ò.ä. Íàèáîëåå õàðàêòåðíûìè êëèíè÷åñêèìè ñèìïòîìàìè, êîòîðûå íåçàâèñèìî îò îñíîâíîãî çàáîëåâàíèÿ ìîæíî ñâÿçàòü ñ õðîíè÷åñêîé ãèïîïåðôóçèåé ìîçãà, ÿâëÿþòñÿ: ñíèæåíèå óìñòâåííîé è ôèçè÷åñêîé ðàáîòîñïîñîáíîñòè îò óìåðåííîãî äî ðåçêî âûðàæåííîãî (èñòîùàåìîñòü è ïîâûøåííàÿ óòîìëÿåìîñòü, ìíåñòè÷åñêèå è èíòåëëåêòóàëüíûå ðàññòðîéñòâà), íå÷åòêîñòü çðåíèÿ (Russell R.W., Page N.G., 1983), ýìîöèîíàëüíàÿ ëàáèëüíîñòü è äðóãèå èçìåíåíèÿ â äàííîé ñôåðå, íàðóøåíèå ñíà, ãîëîâîêðóæåíèå, çâîí â óøàõ, ãîëîâíàÿ áîëü (Lechner H., Schmidt R., 1989), ïñèõîîðãàíè÷åñêèé ñèíäðîì (ëè÷íîñòíûå ðàññòðîéñòâà, ïðîáëåìû ñîöèàëüíîé àäàïòàöèè, äåìåíöèÿ è äð.). Óêàçàííûé ñèìïòîìîêîìïëåêñ áåç óòî÷íåíèÿ åãî ýòèîëîãèè ÷àñòî îáîçíà÷àþò òåðìèíàìè «öåðåáðîâàñêóëÿðíàÿ íåäîñòàòî÷íîñòü», «õðîíè÷åñêàÿ ìîçãîâàÿ äèñôóíêöèÿ ñîñóäèñòîé ýòèîëîãèè», «äèñöèðêóëÿòîðíàÿ ýíöåôàëîïàòèÿ», «àòåðîñêëåðîç», «àðòåðèîñêëåðîç», «ïîñòèíñóëüòíîå ñîñòîÿíèå», «õðîíè÷åñêàÿ öåðåáðàëüíàÿ äèñôóíêöèÿ», «ñîñòîÿíèå ïîñëå òðàíçèòîðíûõ èøåìè÷åñêèõ àòàê». Íàêîïëåíû ìíîãî÷èñëåííûå äàííûå îòíîñèòåëüíî ëå÷åíèÿ áîëüíûõ ñ óêàçàííûì ñèìïòîìîêîìïëåêñîì. Ó áîëüíûõ, êîòîðûì íàçíà÷àëè ëå÷åíèå, ïðè÷èíà çàáîëåâàíèÿ áûëà ðàçíîé, ó ìíîãèõ èç íèõ — íåÿñíîé. Íåñìîòðÿ íà ýòî, íà ïðîòÿæåíèè äåñÿòèëåòèé íàêîïëåí îáíàäåæèâàþùèé îïûò ëå÷åíèÿ òàêèõ ïàöèåíòîâ. Îäíèì èç íàèáîëåå èçâåñòíûõ, äåòàëüíî èçó÷åííûõ ëåêàðñòâåííûõ ïðåïàðàòîâ ÿâëÿåòñÿ ýòèëàïîâèíêàìèíàò, èëè âèíïîöåòèí (Êàâèíòîí ïðîèçâîäñòâà êîìïàíèè «Ðèõòåð Ãåäåîí Ðò.»). ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 6 (44) – XI/XII 2004 5 ÎÃËßÄ Öåëü äàííîé ðàáîòû — êðàòêî îáîáùèòü ïàòîáèîõèìè÷åñêèå è ïàòîôèçèîëîãè÷åñêèå èçìåíåíèÿ, âîçíèêàþùèå â ïðîöåññå õðîíè÷åñêîé ãèïîïåðôóçèè ìîçãà, ðàññìîòðåòü òåðàïåâòè÷åñêèå ýôôåêòû Êàâèíòîíà è îáîñíîâàòü ýôôåêòèâíîñòü Êàâèíòîíà ïðè ëå÷åíèè ïàöèåíòîâ ñ õðîíè÷åñêîé öåðåáðàëüíîé äèñôóíêöèåé, âûçâàííîé õðîíè÷åñêîé ãèïîïåðôóçèåé ãîëîâíîãî ìîçãà è ïðîÿâëÿþùåéñÿ íàðóøåíèÿìè êîãíèòèâíûõ ôóíêöèé. Ïîäðîáíûé àíàëèç ôàðìàêîëîãè÷åñêèõ ýôôåêòîâ Êàâèíòîíà ïðèâåäåí â äðóãèõ îáîáùàþùèõ ðàáîòàõ (Kovacs L., 1988; Kiss B., Karpati E., 1996; Nagy Z. et al., 1996). ÕÐÎÍÈ×ÅÑÊÀß ÃÈÏÎÏÅÐÔÓÇÈß ÃÎËÎÂÍÎÃÎ ÌÎÇÃÀ È ÝÔÔÅÊÒÛ ÊÀÂÈÍÒÎÍÀ Äëÿ õðîíè÷åñêîé ãèïîïåðôóçèè ìîçãà õàðàêòåðíû íèçêîå ïåðôóçèîííîå äàâëåíèå, çàìåäëåíèå öåðåáðàëüíîãî êðîâîòîêà, ñíèæåíèå ñîäåðæàíèÿ êèñëîðîäà è ãëþêîçû â êðîâè, èçìåíåíèå ìåòàáîëèçìà ãëþêîçû â ñòîðîíó àíàýðîáíîãî ãëèêîëèçà, ëàêòàòàöèäîç è ãèïåðîñìîëÿðíîñòü. Ðàçâèâàþùèéñÿ íåäîñòàòîê êèñëîðîäà ìîçãîâàÿ òêàíü ïûòàåòñÿ âîñïîëíèòü çà ñ÷åò óñèëåíèÿ ïîãëîùåíèÿ êèñëîðîäà èç êðîâè. Äåôîðìèðóåìîñòü êðàñíûõ êðîâÿíûõ òåëåö óìåíüøàåòñÿ, óñèëèâàåòñÿ ñêëîííîñòü ê òðîìáîçó. Ãèïåðîñìîëÿðíîñòü è ëàêòàò-àöèäîç ïðèâîäÿò ê äàëüíåéøåìó óìåíüøåíèþ ïåðôóçèè, ðàçâèâàåòñÿ êàïèëëÿðíûé ñòàç. Ïðè çíà÷åíèÿõ êðîâîòîêà íèæå îïðåäåëåííîãî óðîâíÿ ìåõàíèçìû êîìïåíñàöèè èñòîùàþòñÿ, ýíåðãåòè÷åñêîå îáåñïå÷åíèå ãîëîâíîãî ìîçãà ñòàíîâèòñÿ íåäîñòàòî÷íûì, â ðåçóëüòàòå ÷åãî ñíà÷àëà ðàçâèâàþòñÿ ôóíêöèîíàëüíûå ðàññòðîéñòâà ìîçãîâîé òêàíè, à çàòåì ïðîèñõîäèò åå íåîáðàòèìîå ìîðôîëîãè÷åñêîå ïîðàæåíèå. Óëó÷øåíèå ìîçãîâîãî êðîâîîáðàùåíèÿ, óâåëè÷åíèå ïðèòîêà êèñëîðîäà ïóòåì óìåíüøåíèÿ ãèïîêñèè è îïòèìèçàöèè ìåòàáîëèçìà ñíèæàþò ñòåïåíü íàðóøåíèÿ ôóíêöèé è ñîäåéñòâóþò ñîõðàíåíèþ ìîçãîâîé òêàíè. Òåðàïåâòè÷åñêîå äåéñòâèå Êàâèíòîíà âî ìíîãîì ñâÿçàíî ñ åãî ñïîñîáíîñòüþ óâåëè÷èâàòü öåðåáðàëüíûé êðîâîòîê è ñíàáæåíèå ìîçãîâîé òêàíè êèñëîðîäîì. Êàâèíòîí ñíèæàåò ñîïðîòèâëåíèå ñîñóäîâ ìîçãà, íå âûçûâàÿ îáùåé âàçîäèëàòàöèè, è òåì ñàìûì èçáèðàòåëüíî óñèëèâàåò ìîçãîâîå êðîâîîáðàùåíèå, íå îêàçûâàÿ ïðè ýòîì ñóùåñòâåííîãî âîçäåéñòâèÿ íà àðòåðèàëüíîå äàâëåíèå (Szobor A., Klein M., 1976). Ýòî ïîäòâåðæäåíî ðåçóëüòàòàìè èññëåäîâàíèÿ ïåðîðàëüíîãî êóðñîâîãî ïðèåìà Êàâèíòîíà ó áîëüíûõ ñ öåðåáðîâàñêóëÿðíîé íåäîñòàòî÷íîñòüþ, â òîì ÷èñëå ñ ïðèìåíåíèåì ðàäèîèçîòîïíûõ ìåòîäîâ (Tamaki N. et al., 1985) è òðàíñêðàíèàëüíîé äîïïëåðîãðàôèè (Miyazaki M., 1995). Ðàñøèðåíèå ñîñóäîâ ãîëîâíîãî ìîçãà âîçíèêàåò âñëåäñòâèå âîçäåéñòâèÿ íà ìåòàáîëèçì öèêëè÷åñêèõ íóêëåîòèäîâ â êëåòêàõ ãëàäêèõ ìûøö ñîñóäèñòîé ñòåíêè — òîðìîæåíèÿ ôåðìåíòà ôîñôîäèýñòåðàçû, ðàñùåïëÿþùåãî öÃÌÔ è çàâèñÿùåãî îò Ñà2+-êàëüìîäóëèíà (Hagiwara M. et al., 1984; Choi D.W., 1988). 6 Ïåðîðàëüíûé ïðèåì Êàâèíòîíà ïðè ñîñóäèñòîé äåìåíöèè áèíñâàíãåðîâñêîãî òèïà ïàðàëëåëüíî ñ ïîâûøåíèåì êîíöåíòðàöèè ÀÒÔ â ýðèòðîöèòàõ âûçûâàåò óñèëåíèå ñðîäñòâà ãåìîãëîáèíà ê êèñëîðîäó è åãî ñïîñîáíîñòè îòäàâàòü êèñëîðîä, à òàêæå óëó÷øàåò èñïîëüçîâàíèå èìåþùåãîñÿ îáúåìà êèñëîðîäà (Tohgi H. et al. 1990). Ýôôåêòèâíîñòü Êàâèíòîíà êàê ñðåäñòâà, óëó÷øàþùåãî ìîçãîâîå êðîâîîáðàùåíèå, ïîâûøàåòñÿ áëàãîäàðÿ åãî ïîëîæèòåëüíîìó âëèÿíèþ íà ãåìîðåîëîãè÷åñêèå ñâîéñòâà êðîâè. Âûÿâëåíî ñíèæåíèå âÿçêîñòè êðîâè è ïëàçìû (Osawa M., Maruyama S., 1985) ó áîëüíûõ ñ ÕÍÌÊ ïðè òåðàïèè Êàâèíòîíîì â òå÷åíèå 2 íåä. Ïðè ýêñïåðèìåíòàëüíîì ëàêòàò-àöèäîçå è ãèïåðîñìîëÿðíîñòè, òî åñòü ïðè ñîñòîÿíèè, êîòîðîå îòìå÷àþò ó áîëüíûõ ñ öåðåáðàëüíîé ãèïîïåðôóçèåé, Êàâèíòîí â òåðàïåâòè÷åñêèõ äîçàõ ïîâûøàåò äåôîðìèðóåìîñòü ýðèòðîöèòîâ, çíà÷èòåëüíî óëó÷øàÿ ìèêðîöèðêóëÿöèþ (Schmid-Schonbein H. et al., 1988). Ýôôåêò áûë ïîäòâåðæäåí â êëèíè÷åñêèõ èññëåäîâàíèÿõ êàê ó çäîðîâûõ äîáðîâîëüöåâ (Hayakawa M., 1992a), òàê è ó áîëüíûõ, ïåðåíåñøèõ èíñóëüò (Hayakawa M., 1992b). Èìåþòñÿ äàííûå, ñâèäåòåëüñòâóþùèå î òîì, ÷òî Êàâèíòîí òàêæå ñíèæàåò àãðåãàöèîííóþ ñïîñîáíîñòü ýðèòðîöèòîâ (Lebedeva N.V. et al., 1990) è òðîìáîöèòîâ (Kuzuya F., 1982; Lebedeva N.V. et al., 1990; Lindgren S.H. et al., 1990). Ïî äàííûì ïîçèòðîííîé ýìèññèîííîé òîìîãðàôèè îäíîêðàòíîå âíóòðèâåííîå ââåäåíèå Êàâèíòîíà áîëüíûì ñ ÕÍÌÊ óñèëèâàåò â ìîçãîâîé òêàíè ðåãèîíàðíûé (â ïåðâóþ î÷åðåäü â òàëàìóñå, áàçàëüíûõ ãàíãëèÿõ, ïåðâè÷íîé çîíå çðèòåëüíîé êîðû) òðàíñïîðò è â îïðåäåëåííîé ñòåïåíè — ìåòàáîëèçì ãëþêîçû (Szakall Sz. et al., 1998). ÍÅÉÐÎÏÐÎÒÅÊÒÎÐÍÛÅ ÝÔÔÅÊÒÛ ÊÀÂÈÍÒÎÍÀ  ýêñïåðèìåíòàëüíûõ èññëåäîâàíèÿõ ïðîäåìîíñòðèðîâàí çíà÷èòåëüíûé íåéðîïðîòåêòîðíûé ýôôåêò Êàâèíòîíà: ïðè ìîäåëèðîâàíèè îñòðîé èøåìèè â ñëó÷àÿõ ïðîôèëàêòè÷åñêîãî ïðèìåíåíèÿ Êàâèíòîíà çîíà èíôàðêòà óìåíüøàëàñü íà 25–50% (Sauer D. et al., 1988; Backhauss C. et al., 1992). Êàêîâ æå ìåõàíèçì ñòîëü çíà÷èìîãî íåéðîïðîòåêòîðíîãî ýôôåêòà Êàâèíòîíà? Ðîëü Na+- è Ñà2+-êàíàëîâ â õðîíè÷åñêîé ãèïîïåðôóçèè  óñëîâèÿõ ãèïîêñèè è àíîêñèè ñíèæàåòñÿ ñîäåðæàíèå ÀÒÔ â êëåòêàõ, âñëåäñòâèå ÷åãî íàðóøàåòñÿ Na+/Ê+-íàñîñíàÿ ôóíêöèÿ êëåòî÷íûõ ìåìáðàí, ïîâûøàåòñÿ ñîäåðæàíèå âíåêëåòî÷íîãî Ê+ è âíóòðèêëåòî÷íîãî Na+.  äåïîëÿðèçàöèè êëåòîê áîëüøîå çíà÷åíèå èìåþò ïðèòîê Na+ ÷åðåç ïîòåíöèàëçàâèñèìûå Na+-êàíàëû, à òàêæå âûñâîáîæäåíèå âîçáóæäàþùèõ àìèíîêèñëîò, íàðóøåíèå Na+-çàâèñèìîãî îáðàòíîãî ïðèòîêà ãëóòàìàòà â êëåòêè (Leigh P.N., Meldrum B.S., 1996). Àêòèâàöèÿ ïîòåíöèàëçàâèñèìûõ Na+- è Ñà2+-êàíàëîâ èãðàåò ðåøàþùóþ ðîëü â îñòðîì è õðîíè÷åñêîì ïîâðåæäåíèè êëåòîê (Choi D.W., 1988). ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 6 (44) – XI/XII 2004 ÎÃËßÄ Â îòëè÷èå îò ïîðàæåíèÿ êëåòîê ñåðîãî âåùåñòâà ïðè èõ ÷ðåçìåðíîì âîçáóæäåíèè (ýêñàéòîòîêñè÷åñêèé ìåõàíèçì) â àíîêñè÷åñêè-èøåìè÷åñêîì ïîðàæåíèè áåëîãî âåùåñòâà îñíîâíóþ ðîëü èãðàåò äðóãîé ìåõàíèçì ïàòîëîãè÷åñêèõ èçìåíåíèé. Áåëîå âåùåñòâî ñîñòîèò â îñíîâíîì èç ìèåëèíèçèðîâàííûõ àêñîíîâ, àñòðî-, îëèãî- è ìèêðîãëèè, à òàêæå èç ñîñóäèñòûõ ýëåìåíòîâ. Ñòåïåíü àíîêñè÷åñêîãî ïîðàæåíèÿ áåëîãî âåùåñòâà çàâèñèò â ïåðâóþ î÷åðåäü îò êîëè÷åñòâà âíå- è âíóòðèêëåòî÷íîãî Ñà 2+ (Stys P.K. et al., 1990a). Óñèëåííûé ïðèòîê Ñà2+ â àêñîíû â ðåçóëüòàòå óâåëè÷åíèÿ êîëè÷åñòâà âíóòðèàêñîíàëüíîãî Ñà2+ ïðèâîäèò ê òÿæåëîìó ïîðàæåíèþ àêñîíàëüíîãî öèòîñêåëåòà (Waxman S.G. et al., 1992). Íè ïîòåíöèàëçàâèñèìûå Ñà2+-êàíàëû, íè Ñà2+-êàíàëû, ðåãóëèðóåìûå âîçáóæäàþùèìè àìèíîêèñëîòàìè, íå èãðàþò îñîáîé ðîëè â íàðàñòàíèè ïðèòîêà Ñà2+ â ìèåëèíèçèðîâàííûå àêñîíû (Stys P.K. et al., 1990b). Äëÿ ïîääåðæàíèÿ Ñà2+-ãîìåîñòàçà â áåëîì âåùåñòâå îòòîê Ñà2+ îáåñïå÷èâàåòñÿ Na+–Ñà2+-îáìåííûì òðàíñìåìáðàííûì ïðîòåèíîì, êîòîðûé â íîðìàëüíûõ óñëîâèÿõ îñóùåñòâëÿåò çàìåíó âíóòðèàêñîíàëüíîãî — âíóòðèêëåòî÷íîãî Ñà2+ íà Na+, ñîõðàíÿÿ íèçêèé óðîâåíü âíóòðèêëåòî÷íîãî Ñà 2+ (Blaustein M.P. et al., 1991). Ñíèæåíèå óðîâíÿ ÀÒÔ ïðè èøåìèè ïðèâîäèò ê óìåíüøåíèþ òðàíñìåìáðàííîãî ïîòåíöèàëà. Ïî ïîòåíöèàëçàâèñèìûì Nà +-êàíàëàì, êîòîðûå ïî ýòîé ïðè÷èíå îñòàþòñÿ îòêðûòûìè, ïðèòîê Na + ïðîèñõîäèò ïîñòîÿííî, âíóòðèêëåòî÷íàÿ êîíöåíòðàöèÿ Na+ ïîâûøàåòñÿ, ÷òî â åùå áîëüøåé ñòåïåíè óñèëèâàåò äåïîëÿðèçàöèþ ìåìáðàíû. Ïðè äåïîëÿðèçàöèè ìåìáðàíû îáìåííûé ìåõàíèçì Na+/Ca2+ íà÷èíàåò ôóíêöèîíèðîâàòü â îáðàòíîì ïîðÿäêå, âîçðîñøåå ñîäåðæàíèå âíóòðèêëåòî÷íîãî Na+ ìåíÿåòñÿ íà Ñà2+, ÷òî ñîäåéñòâóåò ïðèòîêó Ñà2+ è òåì ñàìûì ïðèâîäèò ê ïîâûøåíèþ åãî êîíöåíòðàöèè (Stys P.K. et al., 1992). Ñ÷èòàåòñÿ, ÷òî â àíîêñè÷åñêîì ïîðàæåíèè áåëîãî âåùåñòâà ýòîò ìåõàíèçì èãðàåò ðåøàþùóþ ðîëü. Âîçäåéñòâèå Êàâèíòîíà íà Na+-êàíàëû Òîðìîæåíèå ïðèòîêà Na+, ïîñòóïàþùåãî ïî ïîòåíöèàëçàâèñèìûì Nà+-êàíàëàì, ñ ïîìîùüþ òåòðîäîòîêñèíà, áëîêèðóþùåãî Nà+-êàíàëû (Stys P.K. et al., 1991), èëè ñ ïîìîùüþ äðóãèõ ïðåïàðàòîâ (ôåíèòîèí, êàðáàìàçåïèí) (Fern R. et al., 1993), ïðèâîäèò ê ñóùåñòâåííîìó óìåíüøåíèþ àíîêñè÷åñêîãî ïîðàæåíèÿ áåëîãî âåùåñòâà. Êàâèíòîí, êàê è áëîêèðóþùèé Nà+-êàíàëû ôåíèòîèí, â àíàëîãè÷íîé ñòåïåíè äîçîçàâèñèìî òîðìîçèò ôóíêöèîíèðîâàíèå ïîòåíöèàëçàâèñèìûõ Nà+-êàíàëîâ (Molnar P., Erdo S.L., 1995; Erdo S.A. et al., 1996), ïðåïÿòñòâóÿ ïðèòîêó Na +, ïðîèñõîäÿùåìó ïîä âîçäåéñòâèåì äåïîëÿðèçàöèè.  ñâÿçè ñ èçëîæåííûì áëîêèðîâàíèå Na+-êàíàëîâ ìîæåò áûòü ÷ðåçâû÷àéíî âàæíûì êîìïîíåíòîì íåéðîïðîòåêòîðíîãî ýôôåêòà Êàâèíòîíà (King G.A., 1987; Sauer D. et al., 1988; Lakics V. et al., 1995). Âîçäåéñòâèå Êàâèíòîíà íà Ñà2+-êàíàëû  êóëüòóðå íåðâíûõ êëåòîê, ïîäâåðãíóòûõ äåéñòâèþ âîçáóæäàþùèõ àìèíîêèñëîò, Êàâèíòîí ïðåäîòâðàùàåò ãèáåëü îò 1/3 äî 2/3 îáùåãî ÷èñëà êëåòîê (Erdo S.L. et al., 1990). Çíà÷èìûì êîìïîíåíòîì íåéðîïðîòåêòîðíîãî äåéñòâèÿ Êàâèíòîíà ÿâëÿåòñÿ íåêîíêóðåíòíîå òîðìîæåíèå ðåöåïòîðîâ âîçáóæäàþùèõ àìèíîêèñëîò (ïðåäïîëîæèòåëüíî — ïóòåì âîçäåéñòâèÿ íà ôóíêöèè èîííûõ êàíàëîâ). S. Kaneko è ñîàâòîðû (1991) êîíñòàòèðîâàëè, ÷òî Êàâèíòîí ïðåïÿòñòâóåò ïðèòîêó Ñà2+ â êëåòêè ÷åðåç ïîòåíöèàëçàâèñèìûå è êîíòðîëèðóåìûå NMDA-ðåöåïòîðîì Ñà2+-êàíàëû. Âûÿâëåííîå ýêñïåðèìåíòàëüíî äåéñòâèå Êàâèíòîíà íà òðàíñìåìáðàííîå äâèæåíèå Ñà2+ ðàçëè÷íîãî òèïà èçó÷àåòñÿ â ñîîòâåòñòâóþùèõ êëèíè÷åñêèõ èññëåäîâàíèÿõ. Àóòîïðîòåêòîðíàÿ ðîëü äèñôóíêöèè ãëèàëüíûõ êëåòîê è àäåíîçèíà ïðè èøåìèè Ïðè èøåìèè ìîçãà àêòèâèðóþòñÿ àóòîïðîòåêòîðíûå ìåõàíèçìû, êîòîðûå â îòëè÷èå îò äåéñòâèÿ âîçáóæäàþùèõ àìèíîêèñëîò îáëàäàþò îãðàíè÷åííûì ýôôåêòîì, íî ÷ðåçâû÷àéíî âàæíû. Ïðè ýòîì ñóùåñòâåííóþ ðîëü èãðàåò àäåíîçèí. Åñëè ñòåïåíü ìîçãîâîé èøåìèè äîñòèãàåò îïðåäåëåííîãî óðîâíÿ, êîëè÷åñòâî àäåíîçèíà â çîíå èøåìèè âî âíåêëåòî÷íîì ïðîñòðàíñòâå çíà÷èòåëüíî âîçðàñòàåò. Àäåíîçèí â ñåðîì âåùåñòâå, ñâÿçûâàÿñü ñ ïðåñèíàïòè÷åñêèìè àäåíîçèíîâûìè ðåöåïòîðàìè íåéðîíîâ, ïðåïÿòñòâóåò âûñâîáîæäåíèþ âîçáóæäàþùèõ àìèíîêèñëîò è, êàê ñëåäñòâèå, — îáðàçîâàíèþ NO-ìîíîîêñèäà àçîòà (Bhardwaj A. et al., 1995), à ñòèìóëèðóÿ ïîñòñèíàïòè÷åñêèé ðåöåïòîð àäåíîçèíà, óìåíüøàåò ïðèòîê Ñà2+, îïîñðåäîâàííûé ãëóòàìàòíûì ðåöåïòîðîì. Äèñôóíêöèè ãëèàëüíûõ êëåòîê îòâîäèòñÿ âñå áîëüøàÿ ðîëü â èñõîäå öåðåáðàëüíîé èøåìèè, â ïàòîôèçèîëîãèè è ïàòîìîðôîëîãèè äåìåíöèè êàê ñîñóäèñòîé, òàê è äåãåíåðàòèâíîé ýòèîëîãèè (Rudolphi K.A., Schubert P., 1997). Ó æèâîòíûõ, ïî íàáëþäåíèÿì Í. Wakita è ñîàâòîðîâ (1994), èíäóöèðîâàííàÿ õðîíè÷åñêàÿ ãèïîïåðôóçèÿ âûçûâàëà â áåëîì âåùåñòâå ñíà÷àëà àêòèâàöèþ ìèêðîãëèè, çàòåì àñòðîãëèîç, ïîñëå ÷åãî ïðîèñõîäèëî ïîðàæåíèå áåëîãî âåùåñòâà. Àêòèâèðîâàííàÿ ìèêðîãëèÿ âûðàáàòûâàåò íåéðîòîêñèíû: ïðîòåàçû, NO, öèòîêèíû (ôàêòîð íåêðîçà îïóõîëè — ÔÍÎ-α, èíòåðëåéêèí-1β). Öèòîêèíû, îáðàçóþùèåñÿ â ðåçóëüòàòå èøåìèè, íåéðîäåãåíåðàòèâíîãî ïðîöåññà è àêòèâàöèè ìèêðîãëèè, èíäóöèðóþò ïðîëèôåðàöèþ àñòðîöèòîâ. Äèôôåðåíöèðîâàííûå çðåëûå àñòðîöèòû â íîðìå ñóùåñòâåííî ïîääåðæèâàþò âíåêëåòî÷íûé èîííûé è íåéðîòðàíñìèòòåðíûé ãîìåîñòàç. Ïðè èøåìèè àñòðîöèòû óòðà÷èâàþò ðàçëè÷èÿ è àêòèâèðóþòñÿ. Ðåàêòèâíûå àñòðîöèòû ñîçäàþò ìåíüøå ôàêòîðîâ äëÿ ðîñòà íåðâíûõ êëåòîê (nerve growth factor/NGF) è â ìåíüøåé ñòåïåíè ñïîñîáíû ïîääåðæèâàòü âíåêëåòî÷íûé ãîìåîñòàç (êàê èîííûé, òàê è íåéðîòðàíñìèòòåðíûé). Äèñôóíêöèÿ àñòðîãëèè ñïîñîáñòâóåò òîìó, ÷òî ñèíàïòè÷åñêàÿ ñòèìóëÿöèÿ ãëóòàìàòà ïðè- ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 6 (44) – XI/XII 2004 7 ÎÃËßÄ âîäèò ê ïîâûøåíèþ åãî óðîâíÿ äî òîêñè÷åñêîãî, âûçûâàþùåãî ðîñò êîíöåíòðàöèè âíóòðèêëåòî÷íîãî Ñà2+ è àïîïòîç íåéðîíîâ. Âûðàáîòàííûå ãëèàëüíûìè êëåòêàìè ñâîáîäíûå ðàäèêàëû, îáðàçîâàííûå ìèêðîãëèåé ïðîòåàçû è ÔÍÎ-α, à òàêæå ñíèæåíèå êîíöåíòðàöèè NGF ïðèâîäÿò ê ãèáåëè êëåòêè. Àäåíîçèí ðåãóëèðóåò ñòåïåíü äèôôåðåíöèðîâàííîñòè àñòðîãëèè, à òàêæå ñòåïåíü àêòèâàöèè è ïðîëèôåðàöèè ãëèè ïóòåì êîíòðîëÿ ñîîòíîøåíèÿ ìîëåêóëÿðíûõ ñèãíàëîâ, çàâèñÿùèõ îò Ñà2+ è öÀÌÔ (Schubert P. et al., 1997). Åñëè êîíöåíòðàöèÿ àäåíîçèíà íèçêàÿ — ïðåîáëàäàåò ñåðèÿ ñèãíàëîâ, çàâèñÿùèõ îò Ñà2+, åñëè óâåëè÷èâàåòñÿ êîëè÷åñòâî âíåêëåòî÷íîãî àäåíîçèíà — óñèëèâàþòñÿ ñèãíàëû, çàâèñÿùèå îò öÀÌÔ, â óùåðá ñèãíàëàì, çàâèñÿùèì îò Ñà2+. Ïðè èøåìèè àäåíîçèí âûðàáàòûâàåòñÿ â áîëüøîì êîëè÷åñòâå â ðåçóëüòàòå áûñòðîãî ðàñïàäà ÀÒÔ, è åãî ñîäåðæàíèå ìîæåò âîçðàñòè äàæå â 100 ðàç. Ïîä âîçäåéñòâèåì àäåíîçèíà ïîâûøàåòñÿ óðîâåíü âíóòðèêëåòî÷íîãî öÀÌÔ, ÷òî ñòèìóëèðóåò àêòèâèðîâàííûå ãëèàëüíûå êëåòêè ê äèôôåðåíöèðîâêå è, ñëåäîâàòåëüíî, ê óìåíüøåíèþ âûðàáîòêè ñâîáîäíûõ ðàäèêàëîâ (Brodie C. et al., 1998), à ýòî ñïîñîáñòâóåò âîññòàíîâëåíèþ íîðìàëüíîé èîííîé ñðåäû. Òàêèì îáðàçîì, ïðÿìîå èëè îïîñðåäîâàííîå ïîâûøåíèå óðîâíÿ àäåíîçèíà îáóñëîâëèâàåò íåéðîïðîòåêòîðíûé ýôôåêò. Ââåäåíèå àãîíèñòîâ àäåíîçèíà â òêàíåâóþ êóëüòóðó âûçûâàëî çíà÷èòåëüíîå ñíèæåíèå ñòåïåíè ïðîëèôåðàöèè ìèêðîãëèè è îáðàçîâàíèÿ ìàêðîôàãîâ, à òàêæå ñóùåñòâåííîå óìåíüøåíèå âûðàáîòêè àêòèâèðîâàííîé ìèêðîãëèåé ñâîáîäíûõ ðàäèêàëîâ è öèòîêèíîâ (Schubert P. et al., 1997). Âëèÿíèå Êàâèíòîíà íà êîíöåíòðàöèþ àäåíîçèíà Êàâèíòîí ïðåïÿòñòâóåò ïîñòóïëåíèþ àäåíîçèíà â ýðèòðîöèòû è ñèíàïòîñîìû, òåì ñàìûì ïðîÿâëÿÿ ñâîéñòâà íåïðÿìîãî àãîíèñòà àäåíîçèíà (Rosdy B. et al., 1976; Fredholm Â.Â. et al., 1983). Èññëåäîâàíèÿ, ïðîâåäåííûå íà êëåòî÷íîé êóëüòóðå, ïîäòâåðäèëè, ÷òî â óñëîâèÿõ ãèïîêñèè Êàâèíòîí â çíà÷èòåëüíîé ñòåïåíè óñèëèâàåò íåéðîïðîòåêòîðíûé ýôôåêò àäåíîçèíà (Krieglstein J., Rischke R., 1991). Èñõîäÿ èç ýòîãî, ìîæíî ïðåäïîëîæèòü, ÷òî êëèíè÷åñêè çíà÷èìûé íåéðîïðîòåêòîðíûé ýôôåêò Êàâèíòîíà ñâÿçàí ñ åãî âëèÿíèåì íà ìåòàáîëèçì àäåíîçèíà. Àíòèîêñèäàíòíûå ýôôåêòû Êàâèíòîíà Ýêñïåðèìåíòàëüíûìè èññëåäîâàíèÿìè óñòàíîâëåíî, ÷òî â íåéòðàëèçàöèè ãèäðîêñèëüíûõ ðàäèêàëîâ Êàâèíòîí òàê æå ýôôåêòèâåí, êàê è òîêîôåðîë (âèòàìèí Å). Ýòè èññëåäîâàíèÿ ïîêàçûâàþò ðîëü Êàâèíòîíà êàê àíòèîêñèäàíòà, óìåíüøàþùåãî êîëè÷åñòâî ñâîáîäíûõ ðàäèêàëîâ, âûðàáàòûâàåìûõ ïðè èøåìèè (Olah A.V. et al., 1990), à òàêæå âûçûâàþùåãî òîðìîæåíèå ïåðåêèñíîãî îêèñëåíèÿ ëèïèäîâ (Kakihana M. et al., 1982). Óëó÷øåíèå ïàìÿòè  íåêîòîðûõ îòäåëàõ íåðâíîé ñèñòåìû ïåðåìåùåíèå ñèíàïòè÷åñêîãî âîçáóæäåíèÿ ïîä âëèÿíèåì 8 ïîâòîðíûõ ïîòåíöèàëîâ äåéñòâèÿ, âîçíèêàþùèõ â ïðåñèíàïòè÷åñêèõ íåéðîíàõ, óñèëèâàåòñÿ ïîñòîÿííî (êàæäûé ÷àñ è äåíü). Èññëåäîâàíèÿ äàííîãî ÿâëåíèÿ â ÖÍÑ êàñàþòñÿ â ïåðâóþ î÷åðåäü íåéðîíîâ ãèïïîêàìïà; ýêñïåðèìåíòàëüíàÿ ìîäåëü ñîçäàåòñÿ ñ ïîìîùüþ ðàçäðàæåíèÿ ïðåñèíàïòè÷åñêèõ íåéðîíîâ âûñîêî÷àñòîòíûì ðàçäðàæèòåëåì (äîëãîâðåìåííàÿ àêòèâàöèÿ — Long Term Potentiation/LTP). LTP îñîáåííî âàæíà â íà÷àëüíîé ñòàäèè îáó÷åíèÿ è çàïîìèíàíèÿ, ïîñêîëüêó íàðàñòàíèå ïåðåäà÷è âîçáóæäåíèÿ ïðèâîäèò ê óâåëè÷åíèþ îáúåìà îáðàáàòûâàåìîé èíôîðìàöèè (Madison D.V. et al., 1991). LTP ÿâëÿåòñÿ îäíîé èç íàèáîëåå ÷àñòî ïðèìåíÿåìûõ ìîäåëåé êëåòî÷íîãî ìåõàíèçìà îáó÷åíèÿ è ïàìÿòè, çàâèñÿùèõ îò àêòèâíîñòè è ïëàñòè÷íîñòè ñèíàïòè÷åñêîé ïåðåäà÷è (Bliss T.V., Collingridge G.L., 1993). Ýêñïåðèìåíòàëüíîå óìåíüøåíèå ìîçãîâîãî êðîâîòîêà íà 25–50% âûçûâàåò ðàññòðîéñòâà ïîâåäåíèÿ ïðèìåðíî ÷åðåç 6 ìåñ. Îòìå÷àþò íàðóøåíèÿ ìîòîðèêè è ýìîöèîíàëüíîé ñôåðû, óõóäøàþòñÿ ïàìÿòü è ñïîñîáíîñòü ê îáó÷åíèþ (De Jong G.I. et al., 1997; Ohta H. et al., 1997; Sekhon L.H. et al., 1997a). Ýòî ìîæåò îáúÿñíÿòüñÿ òåì, ÷òî ïðè õðîíè÷åñêîé ãèïîïåðôóçèè ìîçãà íàðóøàåòñÿ ìåõàíèçì LTP (Sekhon L.H. et al., 1997b). Âëèÿíèå Êàâèíòîíà íà ðàññòðîéñòâà ïàìÿòè Ëþáîé ýôôåêò, ñïîñîáñòâóþùèé LTP, óëó÷øàåò ñïîñîáíîñòü ê îáó÷åíèþ è ñîõðàíåíèþ èíôîðìàöèè. Êàâèíòîí êàê â ýêñïåðèìåíòå, òàê è â êëèíè÷åñêèõ èññëåäîâàíèÿõ óñèëèâàåò LTP. Ïî ðåçóëüòàòàì ýêñïåðèìåíòàëüíûõ èññëåäîâàíèé Ê. Ishihara è ñîàâòîðîâ (1989) Êàâèíòîí â íèçêîé êîíöåíòðàöèè (10-7 è 10-6 Ì) ïî÷òè â 3 ðàçà ïîâûøàåò LTP â ãèïïîêàìïå. Ïîòåíöèðóþùåå äåéñòâèå Êàâèíòîíà íà LTP ïîäòâåðæäåíî òàêæå in vivo: ñíèçèâøàÿñÿ ïðè ïàòîëîãèè ñðåäíåãî óõà LTP âîññòàíîâèëàñü â ðåçóëüòàòå 6-äíåâíîãî ïåðîðàëüíîãî ïðèåìà Êàâèíòîíà (Molnar P. et al., 1994). Z. Subhan è I. Hindmarch (1985), à òàêæå D.M. Coleston è I. Hindmarch (1988) îòìåòèëè äîñòîâåðíîå óëó÷øåíèå êðàòêîâðåìåííîé ïàìÿòè ó çäîðîâûõ äîáðîâîëüöåâ ïîñëå ïåðîðàëüíîãî ïðèåìà 40 ìã Êàâèíòîíà â ñóòêè. D. Groo è ñîàâòîðû (1989) â ýêñïåðèìåíòå îáíàðóæèëè, ÷òî Êàâèíòîí óìåíüøàåò âûðàæåííîñòü ðàññòðîéñòâ îáó÷åíèÿ ðàçëè÷íîãî ãåíåçà, à òàêæå óëó÷øàåò ïàìÿòü, âñëåäñòâèå ÷åãî åãî îòíîñÿò ê ãðóïïå òàê íàçûâàåìûõ «êîãíèòèâíûõ óñèëèòåëåé» (íîîòðîïîâ). Àâòîðû ðåêîìåíäóþò íàçíà÷àòü ïðåïàðàò äëÿ óëó÷øåíèÿ êîãíèòèâíûõ ôóíêöèé, â ïåðâóþ î÷åðåäü ïðè íàðóøåíèÿõ ïàìÿòè ó ëþäåé ïîæèëîãî âîçðàñòà. ÊËÈÍÈ×ÅÑÊÈÅ ÈÑÑËÅÄÎÂÀÍÈß ÊÀÂÈÍÒÎÍÀ Êàâèíòîí ïðèìåíÿþò â ïðàêòè÷åñêîé ìåäèöèíå ñ 1978 ã. â ïåðâóþ î÷åðåäü äëÿ ëå÷åíèÿ ïàöèåíòîâ ñ îñòðîé è õðîíè÷åñêîé ñîñóäèñòîé ìîçãîâîé íåäîñòàòî÷íîñòüþ. Ðåçóëüòàòû ìíîãî÷èñëåííûõ èññëåäîâàíèé êàê â Âåíãðèè (Csanda E. et al., 1988), òàê è â äðóãèõ ñòðàíàõ ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 6 (44) – XI/XII 2004 ÎÃËßÄ äîêàçàëè ýôôåêòèâíîñòü ïðåïàðàòà ïðè ýòèõ ïàòîëîãè÷åñêèõ ïðîöåññàõ. Ê íàñòîÿùåìó âðåìåíè Êàâèíòîí ïðèìåíÿþò â 40 ñòðàíàõ, íà 4 êîíòèíåíòàõ (Nagy Z. et al., 1996). Ñðåäè êëèíè÷åñêèõ èññëåäîâàíèé çíà÷èòåëüíóþ ÷àñòü ñîñòàâëÿþò ðàíäîìèçèðîâàííûå ïëàöåáî-êîíòðîëèðóåìûå ñòàíäàðòèçèðîâàííûå èññëåäîâàíèÿ â ßïîíèè, Çàïàäíîé Ãåðìàíèè è Èòàëèè. Ìåòîäèêè ïðîâåäåíèÿ è àíàëèçà ðåçóëüòàòîâ ðàáîò, âûïîëíåííûõ â 80-õ ãîäàõ ïðîøëîãî âåêà, ïîëíîñòüþ ñîîòâåòñòâîâàëè ñîâðåìåííîìó óðîâíþ íàó÷íûõ èññëåäîâàíèé. Äèàãíîçû è ñèìïòîìàòèêà ó áîëüíûõ, èññëåäîâàííûõ â 3 ñòðàíàõ, áûëè ðàçíîîáðàçíûìè, ÷òî îïðåäåëÿëî ñïåöèôèêó âîçìîæíîãî ìåòààíàëèçà, êîòîðûé ïðåäñòàâëåí â îäíîé èç ïðåäûäóùèõ ïóáëèêàöèé (Nagy Z. et al., 1998). Ðåçóëüòàòû èññëåäîâàíèé ñîïîñòàâèìû. Äàëåå ïðèâåäåì èõ àíàëèç.  3 ñòðàíàõ ïðåïàðàò ïðèìåíÿëè â îáùåé ñëîæíîñòè ïðèìåðíî ó 1100 áîëüíûõ, â òîì ÷èñëå ó 846 — â ðàìêàõ ïëàöåáî-êîíòðîëèðóåìûõ èññëåäîâàíèé.  öåëÿõ ïðîñòîòû èçëîæåíèÿ íàó÷íûå ðàáîòû ñãðóïïèðîâàíû ïî ãåîãðàôè÷åñêîìó ïðèíöèïó. Îáîáùàÿ ïîëó÷åííûå äàííûå, íóæíî îòìåòèòü, ÷òî ïðèåì Êàâèíòîíà òàê æå óëó÷øàë ñîñòîÿíèå áîëüíûõ êàê ñ íåäîñòàòî÷íîñòüþ ìîçãîâîãî êðîâîîáðàùåíèÿ, òàê è ñ íåéðîäåãåíåðàòèâíûì ïðîöåññîì, ïðèâîäÿùèì ê äåìåíöèè. Çàáîëåâàíèÿ ïðîÿâëÿëèñü óõóäøåíèåì ïàìÿòè è ñîîáðàçèòåëüíîñòè, íàðóøåíèåì êîãíèòèâíûõ ôóíêöèé è ñíèæåíèåì îáùåé ðàáîòîñïîñîáíîñòè, ó ÷àñòè ïàöèåíòîâ — íàëè÷èåì óìåðåííûõ èëè âûðàæåííûõ î÷àãîâûõ íåâðîëîãè÷åñêèõ ðàññòðîéñòâ. Èññëåäîâàíèÿ, ïðîâåäåííûå â ßïîíèè Ýôôåêòèâíîñòü äëèòåëüíîé òåðàïèè Êàâèíòîíîì èçó÷àëè 12 ðàáî÷èõ ãðóïï ó 288 ïàöèåíòîâ ñ öåðåáðîâàñêóëÿðíûì çàáîëåâàíèåì. Áîëüøèíñòâî ïàöèåíòîâ (80%) áûëè â âîçðàñòå îò 50 äî 70 ëåò. Áîëüíûå ïîëó÷àëè ïåðîðàëüíî Êàâèíòîí â ñóòî÷íîé äîçå 15 ìã (ïî 1 òàáëåòêå 3 ðàçà â äåíü); äëèòåëüíîñòü òåðàïèè íå ïðåâûøàëà 9 ìåñ. Ýôôåêòèâíîñòü è áåçîïàñíîñòü ïðåïàðàòà îöåíèâàëè â áàëëàõ ïî øêàëàì îáùåãî âïå÷àòëåíèÿ î êëèíè÷åñêîì óëó÷øåíèè (Global Improvement Rating/GIR), áåçîïàñíîñòè (Overall Safety Rating/OSR) è ïîëåçíîñòè (Global Usefulness Rating/GUR). Óëó÷øåíèå ñîñòîÿíèÿ áûëî îòìå÷åíî ó 77% áîëüíûõ, ïðè÷åì ñóùåñòâåííûõ ðàçëè÷èé â ñòåïåíè óëó÷øåíèÿ ìåæäó ãðóïïàìè áîëüíûõ ñ ðàçíûìè çàáîëåâàíèÿìè íå âûÿâëåíî. Íàèáîëåå çíà÷èòåëüíî èçìåíèëàñü îöåíêà áîëüíûìè ñâîåãî ñîñòîÿíèÿ. Ó 78% ïàöèåíòîâ óìåíüøèëèñü æàëîáû, ó 61% — óëó÷øèëîñü ïñèõè÷åñêîå ñîñòîÿíèå è ðàáîòîñïîñîáíîñòü, ó 49% — óìåíüøèëàñü âûðàæåííîñòü íåâðîëîãè÷åñêèõ ðàññòðîéñòâ. Òîëüêî 1% áîëüíûõ ïðåêðàòèëè ïðèåì ïðåïàðàòà èç-çà ïîÿâëåíèÿ íåçíà÷èòåëüíûõ êîæíûõ ðåàêöèé èëè ãîëîâîêðóæåíèÿ. Íà îñíîâàíèè ðåçóëüòàòîâ ïðîâåäåííûõ èññëåäîâàíèé Êàâèíòîí ðåêîìåíäîâàí äëÿ ëå÷åíèÿ ïàöèåíòîâ ñ öåðåáðîâàñêóëÿðíûìè çàáîëåâàíèÿìè (Ebi O., 1985). Èññëåäîâàíèÿ, ïðîâåäåííûå â Èòàëèè  1986–1987 ãã. 3 ðàáî÷èå ãðóïïû èññëåäîâàëè äåéñòâèå Êàâèíòîíà ó áîëüíûõ ïîæèëîãî âîçðàñòà (ñðåäíèé âîçðàñò 77 ëåò) ñ õðîíè÷åñêèì íàðóøåíèåì ìîçãîâûõ ôóíêöèé, êîòîðîå â áîëüøèíñòâå ñëó÷àåâ èìåëî ñîñóäèñòîå ïðîèñõîæäåíèå è ïðîÿâëÿëîñü êîãíèòèâíûìè ðàññòðîéñòâàìè (Manconi E. et al., 1986; Peruzza M., De Jacobis M., 1986; Balestreri R. et al., 1987). Äâîéíîå ñëåïîå ïëàöåáî-êîíòðîëèðóåìîå èññëåäîâàíèå áûëî çàâåðøåíî ñ ó÷àñòèåì 160 (96,4%) áîëüíûõ. Èç íèõ 83 áîëüíûõ íà ïðîòÿæåíèè 1 ìåñ ïîëó÷àëè Êàâèíòîí ïåðîðàëüíî â äîçå 10 ìã 3 ðàçà â äåíü, çàòåì â òå÷åíèå 2 ìåñ — 5 ìã 3 ðàçà â äåíü; 77 áîëüíûõ ïîëó÷àëè ïëàöåáî. Ýôôåêòèâíîñòü ïðåïàðàòà îöåíèâàëè ïî äèíàìèêå íåâðîëîãè÷åñêîãî ñòàòóñà, øêàëå îáùåãî êëèíè÷åñêîãî âïå÷àòëåíèÿ (Clinical Global Impression/CGI), èçìåíåíèþ ïîâåäåíèÿ, ýìîöèé, ïàìÿòè, ïîâñåäíåâíîé àêòèâíîñòè è ñïîñîáíîñòè ê ñàìîîáñëóæèâàíèþ (øêàëà Sandoz Clinical Assessment-Geriatric/SCAG), à òàêæå ïî îðèåíòàöèè âî âðåìåíè è ïðîñòðàíñòâå, ñ÷åòó, ïàìÿòè, ïñèõè÷åñêèì ôóíêöèÿì áîëåå âûñîêîãî ïîðÿäêà, ðåøåíèþ çàäà÷, êðàòêîé îöåíêå ïñèõè÷åñêîãî ñòàòóñà (Mini Mental Status Questionnaire/MMSQ). Àíàëèç ðåçóëüòàòîâ 3 èññëåäîâàíèé ñâèäåòåëüñòâóåò, ÷òî â ãðóïïå ïàöèåíòîâ, ëå÷åííûõ Êàâèíòîíîì, ïî øêàëå CGI ñîñòîÿíèå óëó÷øèëîñü ó 84% áîëüíûõ, îñòàëîñü áåç èçìåíåíèé — ó 13%, óõóäøèëîñü — ó 3%, â òî âðåìÿ êàê â ãðóïïå ïàöèåíòîâ, ïîëó÷àâøèõ ïëàöåáî, ñîñòîÿíèå óëó÷øèëîñü òîëüêî ó 30% áîëüíûõ, íå èçìåíèëîñü — ó 58%, óõóäøèëîñü — ó 12%. Ñðåäè ïàöèåíòîâ, ëå÷åííûõ Êàâèíòîíîì, òÿæåñòü çàáîëåâàíèÿ óìåíüøèëàñü ó 62%, íå èçìåíèëàñü — ó 37%, óâåëè÷èëàñü — ó 1%; â òî æå âðåìÿ â ãðóïïå ïàöèåíòîâ, ïîëó÷àâøèõ ïëàöåáî, òÿæåñòü çàáîëåâàíèÿ óìåíüøèëàñü òîëüêî ó 8% èç íèõ, íå èçìåíèëàñü — ó 87% è âîçðîñëà — ó 5%. Ñðåäè ïîëó÷àâøèõ Êàâèíòîí ïàöèåíòîâ ïîëîæèòåëüíûå èçìåíåíèÿ ïîâåäåíèÿ, êîãíèòèâíûõ ôóíêöèé, ýìîöèîíàëüíîé ñôåðû è óìåíüøåíèå ñîìàòè÷åñêèõ æàëîá (øêàëà SCAG) îòìå÷åíû ó 61% áîëüíûõ, ñîñòîÿíèå íå èçìåíèëîñü ó 38%, óõóäøèëîñü — ó 1%.  ãðóïïå ïàöèåíòîâ, ïîëó÷àâøèõ ïëàöåáî, ïîëîæèòåëüíûå èçìåíåíèÿ íàáëþäàëè òîëüêî ó 7% áîëüíûõ, îòñóòñòâèå äèíàìèêè — ó 88%, óõóäøåíèå ñîñòîÿíèÿ — ó 5%. Íàèáîëåå çàìåòíîå óëó÷øåíèå ïî 19-áàëëüíîé øêàëå ïðîÿâëÿëîñü óìåíüøåíèåì ðàññåÿííîñòè, óëó÷øåíèåì êðàòêîâðåìåííîé ïàìÿòè, ñíèæåíèåì ýìîöèîíàëüíîé ëàáèëüíîñòè, óìåíüøåíèåì ãîëîâîêðóæåíèé è óñòàëîñòè. Êëèíè÷åñêàÿ ýôôåêòèâíîñòü êîíñòàòèðîâàíà ó 60% áîëüíûõ, ïðèíèìàâøèõ Êàâèíòîí, è òîëüêî ó 13% áîëüíûõ â ãðóïïå ïëàöåáî. Ðàçëè÷èå áûëî äîñòîâåðíûì. Ñóùåñòâåííûõ ïîáî÷íûõ ÿâëåíèé, êîòîðûå ìîæíî áûëî áû îòíåñòè íà ñ÷åò äåéñòâèÿ ïðåïàðàòà, íå íàáëþäàëîñü. Èññëåäîâàíèÿ, ïðîâåäåííûå â Ãåðìàíèè Å. Fenzl è ñîàâòîðû (1986), I. Hindmarch è ñîàâòîðû (1991), L. Blaha è ñîàâòîðû (1989) ïðîâåëè ðàíäîìèçè- ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 6 (44) – XI/XII 2004 9 ÎÃËßÄ ðîâàííûå äâîéíûå ñëåïûå ïëàöåáî-êîíòðîëèðóåìûå èññëåäîâàíèÿ ýôôåêòèâíîñòè Êàâèíòîíà â ðàçëè÷íûõ äîçàõ (ïî 5, 10 è 20 ìã 3 ðàçà â ñóòêè ïåðîðàëüíî) â îáùåé ñëîæíîñòè ó 685 áîëüíûõ â âîçðàñòå ñòàðøå 60 ëåò ñ ïñèõîîðãàíè÷åñêèì ñèíäðîìîì ëåãêîé èëè ñðåäíåé ñòåïåíè òÿæåñòè. Íà îñíîâàíèè êëèíè÷åñêèõ äàííûõ íåëüçÿ áûëî óñòàíîâèòü, ÿâëÿåòñÿ ëè ýòîò ñèíäðîì ïåðâè÷íûì äåãåíåðàòèâíûì ïðîöåññîì èëè æå ñôîðìèðîâàëñÿ âñëåäñòâèå ìóëüòèèíôàðêòíîé äåìåíöèè. Ïðè âêëþ÷åíèè áîëüíûõ â èññëåäîâàíèå èñïîëüçîâàëè êðèòåðèè îïðåäåëåíèÿ ïñèõîîðãàíè÷åñêèõ ñèíäðîìîâ ïî Í. Lauter (1980). Èç èññëåäîâàíèé áûëè èñêëþ÷åíû áîëüíûå ñ î÷àãîâûìè ñèìïòîìàìè âñëåäñòâèå îðãàíè÷åñêîãî çàáîëåâàíèÿ ãîëîâíîãî ìîçãà, äèñìåòàáîëè÷åñêîé ýíöåôàëîïàòèè, ïñèõè÷åñêîãî çàáîëåâàíèÿ, à òàêæå áîëüíûå ñ àëêîãîëüíîé è íàðêîòè÷åñêîé çàâèñèìîñòüþ. Èññëåäîâàëè êîíöåíòðàöèþ âíèìàíèÿ è ïàìÿòü, íàñòðîåíèå è ïîâåäåíèå, à òàêæå îáùåå ñîñòîÿíèå áîëüíûõ. Äëÿ îöåíêè ðåçóëüòàòîâ ëå÷åíèÿ ïðèìåíÿëè øêàëó CGI, êðàòêèé òåñò êîãíèòèâíîé ñïîñîáíîñòè, à òàêæå ðàçëè÷íûå øêàëû îïðåäåëåíèÿ ýôôåêòèâíîãî ôîíà è êà÷åñòâà æèçíè áîëüíûõ. Ìåòààíàëèç èññëåäîâàíèé: âûâîäû Ìåòààíàëèç ðåçóëüòàòîâ èññëåäîâàíèé ñâèäåòåëüñòâóåò îá óëó÷øåíèè ñîñòîÿíèÿ ó 85% áîëüíûõ, ïðèíèìàâøèõ Êàâèíòîí (â òîì ÷èñëå çíà÷èòåëüíîå — ó 51%).  òî æå âðåìÿ â ãðóïïå ïëàöåáî óëó÷øåíèå îòìå÷åíî ó 62% áîëüíûõ (çíà÷èòåëüíîå — ó 20%). Ðàçëè÷èå ðåçóëüòàòîâ ëå÷åíèÿ ìåæäó äâóìÿ ãðóïïàìè áûëî ñòàòèñòè÷åñêè äîñòîâåðíûì.  ãðóïïå ïàöèåíòîâ, ëå÷åííûõ Êàâèíòîíîì, îòìå÷åíî äîñòîâåðíîå óìåíüøåíèå âûðàæåííîñòè ðàññòðîéñòâ âíèìàíèÿ, ïàìÿòè, íàñòðîåíèÿ è ïîâåäåíèÿ. Ó áîëüíûõ óëó÷øèëîñü ýìîöèîíàëüíîå ñîñòîÿíèå, óäîâëåòâîðåííîñòü æèçíüþ è ïîâñåäíåâíàÿ àêòèâíîñòü. Ñîãëàñíî âûâîäàì èññëåäîâàòåëåé, ëå÷åíèå Êàâèíòîíîì äîñòîâåðíî óìåíüøàåò âûðàæåííîñòü ðàññòðîéñòâ âíèìàíèÿ è ïàìÿòè, à òàêæå óëó÷øàåò îáùåå ñîñòîÿíèå áîëüíûõ. Äðóãèå èññëåäîâàíèÿ Ïîìèìî óïîìÿíóòûõ, ïðîâåäåíû ìíîãî÷èñëåííûå èññëåäîâàíèÿ ýôôåêòèâíîñòè Êàâèíòîíà íà ðàçíûõ ïî ÷èñëåííîñòè ïîïóëÿöèÿõ áîëüíûõ, â õîäå êîòîðûõ Êàâèíòîí ïðèìåíÿëè êàê ïåðîðàëüíî, òàê è âíóòðèâåííî â îñòðûé ïåðèîä èíñóëüòà è ïðè ïîñòèíñóëüòíûõ ñîñòîÿíèÿõ (âíóòðèìûøå÷íîå ââåäåíèå ïðåïàðàòà ïðîòèâîïîêàçàíî). Îäíàêî ðåçóëüòàòû ýòèõ èññëåäîâàíèé íåëüçÿ îöåíèòü ñ ïîìîùüþ ìåòààíàëèçà èç-çà ìåòîäîëîãè÷åñêèõ ðàçëè÷èé.  öåëîì ðåçóëüòàòû êàæäîãî èç ýòèõ èññëåäîâàíèé ñâèäåòåëüñòâóþò, ÷òî ëå÷åíèå Êàâèíòîíîì ñíèæàëî òÿæåñòü ñîñòîÿíèÿ áîëüíûõ, óëó÷øàëî èõ ñàìî÷óâñòâèå è êîãíèòèâíûå ôóíêöèè. Ïîáî÷íûå ýôôåêòû âîçíèêàëè ðåäêî è áûëè íåçíà÷èòåëüíûìè (Otomo E. et al., 1985; Csanda E. et al., 1988). ÇÀÊËÞ×ÅÍÈÅ Ñîñòîÿíèÿ, èçâåñòíûå ïîä íàçâàíèÿìè «õðîíè÷åñêàÿ íåäîñòàòî÷íîñòü ìîçãîâîãî êðîâîîáðàùåíèÿ», à òàêæå «ñîñóäèñòàÿ ìîçãîâàÿ íåäîñòàòî÷10 íîñòü» èëè «öåðåáðîâàñêóëÿðíàÿ äèñôóíêöèÿ», îáóñëîâëåíû õðîíè÷åñêîé ãèïîïåðôóçèåé ìîçãà. Ýêñïåðèìåíòàëüíûå èññëåäîâàíèÿ ïàòîëîãè÷åñêèõ èçìåíåíèé, âûçâàííûõ õðîíè÷åñêîé ãèïîïåðôóçèåé ãîëîâíîãî ìîçãà, à òàêæå âëèÿíèÿ ïîñëåäíåé íà ïðîöåññû îáó÷åíèÿ è ïàìÿòü âûäâèíóëè íà ïåðåäíèé ïëàí ñòðàòåãèþ ëå÷åíèÿ áîëüíûõ ñ êîãíèòèâíûìè ðàññòðîéñòâàìè áåç î÷àãîâîãî íåâðîëîãè÷åñêîãî äåôèöèòà. Õðîíè÷åñêàÿ ãèïîïåðôóçèÿ ãîëîâíîãî ìîçãà èãðàåò êëþ÷åâóþ ðîëü â âîçíèêíîâåíèè è ðàçâèòèè âñåõ ðàññòðîéñòâ êîãíèòèâíûõ ôóíêöèé — îò ñëàáîé äî ñàìîé òÿæåëîé ñòåïåíè âûðàæåííîñòè, à òàêæå ïñèõîîðãàíè÷åñêèõ èçìåíåíèé, îòðèöàòåëüíî âëèÿþùèõ íà êà÷åñòâî æèçíè è ôîðìèðóþùèõñÿ ãëàâíûì îáðàçîì (íî íå èñêëþ÷èòåëüíî) ó ïàöèåíòîâ ïîæèëîãî âîçðàñòà. Èçâåñòíûå ýôôåêòû Êàâèíòîíà èìåþò ìíîãî «òî÷åê ïåðåñå÷åíèÿ» ñ ãåìîäèíàìè÷åñêèìè è áèîõèìè÷åñêèìè ïàòîôèçèîëîãè÷åñêèìè èçìåíåíèÿìè ïðè õðîíè÷åñêîé ãèïîïåðôóçèè ãîëîâíîãî ìîçãà è ÕÍÌÊ. Åãî íåéðîïðîòåêòîðíûé ýôôåêò ìîæåò áûòü ñâÿçàí ñî ñïîñîáíîñòüþ îïîñðåäîâàííî ïîâûøàòü êîëè÷åñòâî «àóòîïðîòåêòîðíîãî» àäåíîçèíà, à òàêæå áëîêèðîâàòü Na+-êàíàëû è âëèÿòü íà Ñà2+-òðàíñïîðò. Ïðè ïðèìåíåíèè Êàâèíòîíà ñèñòåìíîå êðîâîîáðàùåíèå íå èçìåíÿåòñÿ, â òî æå âðåìÿ ïåðôóçèÿ ãîëîâíîãî ìîçãà âîçðàñòàåò, ñíàáæåíèå åãî êèñëîðîäîì è ãëþêîçîé óëó÷øàåòñÿ, àãðåãàöèÿ ôîðìåííûõ ýëåìåíòîâ óìåíüøàåòñÿ, ÷òî ïðèâîäèò ê óëó÷øåíèþ äèíàìè÷åñêèõ õàðàêòåðèñòèê êðîâîòîêà è îáóñëîâëèâàåò àíòèòðîìáîòè÷åñêèé ýôôåêò. 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Wakita H., Tomimoto H., Akiguchi I., Kimura J. (1994) Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study. Acta Neuropathol. (Berl.), 87: 484–492. Waxman S.G., Black J.A., Stys P.K., Ransom B.R. (1992) Ultrastructural concomitants of anoxic injury and early post-anoxic recovery in rat optic nerve. Brain Res., 574: 105–119. ÊÀ²ÍÒÎÍ Ó ÒÅÐÀϲ¯ ÕÐÎͲ×Íί ÍÅÄÎÑÒÀÒÍÎÑÒ² ÌÎÇÊÎÂÎÃÎ ÊÐÎÂÎÎÁ²ÃÓ Ø. Õîðâàò Ðåçþìå. Ïàòîëîã³÷í³ ñòàíè, ùî íàçèâàþòü õðîí³÷íîþ íåäîñòàòí³ñòþ ìîçêîâîãî êðîâîîá³ãó (ÕÍÌÊ), à òàêîæ ñóäèííîþ ìîçêîâîþ íåäîñòàòí³ñòþ àáî öåðåáðî12 âàñêóëÿðíîþ äèñôóíêö³ºþ, âèêëèêàí³ õðîí³÷íîþ ã³ïîïåðôó糺þ ãîëîâíîãî ìîçêó. Ó êë³í³÷í³é êàðòèí³ ÕÍÌÊ ÷àñòî ïåðåâàæàþòü êîãí³òèâí³ ïîðóøåííÿ (ïñèõîîðãàí³÷íèé ñèíäðîì), âèðàæåí³ñòü ÿêèõ ìîæå äîñÿãàòè ñòóïåíÿ äåìåíö³¿ (ï³äê³ðêîâà àòåðîñêëåðîòè÷íà ëåéêîåíöåôàëîïàò³ÿ, ñóäèííà äåìåíö³ÿ, äåìåíö³ÿ àëüöãåéìåð³âñüêîãî òèïó òîùî). Ïàòîëîã³÷í³ çì³íè ïðè ÕÍÌÊ ñòîñóþòüñÿ ãîëîâíèì ÷èíîì á³ëî¿ ðå÷îâèíè (äå쳺ë³í³çàö³ÿ, àêòèâàö³ÿ ã볿, óðàæåííÿ êë³òèí îë³ãîäåíäðîã볿), à òàêîæ õàðàêòåðèçóþòüñÿ ðîçñ³ÿíîþ çàãèáåëëþ êë³òèí. Ïðè òàêèõ çàõâîðþâàííÿõ íàéá³ëüøó êîðèñòü ìîæíà ÷åêàòè â³ä ë³êóâàííÿ, çäàòíîãî êîðèãóâàòè ïàòîá³îõ³ì³÷í³ ³ ïàòîô³ç³îëîã³÷í³ çì³íè, âèêëèêàí³ õðîí³÷íîþ ã³ïîïåðôó糺þ ãîëîâíîãî ìîçêó. Êàâ³íòîí (ðàö³îíàëüíà õ³ì³÷íà íàçâà «åòèëàïîâ³íêàì³íàò») ÷èíèòü ïîçèòèâíó ä³þ íà ð³çí³ ëàíêè ïàòîëîã³÷íîãî ïðîöåñó ïðè õðîí³÷í³é ã³ïîïåðôó糿 ãîëîâíîãî ìîçêó ð³çíî¿ åò³îëî㳿. Êëþ÷îâ³ ñëîâà: Êàâ³íòîí, åòèëàïîâ³íêàì³íàò, õðîí³÷íà ã³ïîïåðôóç³ÿ ìîçêó, êîãí³òèâí³ ïîðóøåííÿ, çì³íè á³ëî¿ ðå÷îâèíè, òåðàï³ÿ. CAVINTON IN THE TREATMENT OF CHRONIC CEREBROVASCULAR INSUFFICIENCY S. Horvath Summary. The pathological states that are called «chronic cerebral insufficiency» (CCI) and «cerebrovascular insufficiency» or «cerebrovascular dysfunction» are caused by chronic cerebral hypoperfusion. Among its clinical manifestations there prevails cognitive impairment (psychoorganic syndrome) of different rates which sometimes develops into dementia (subcortical arteriolosclerotic leucoencephalopathy, vascular dementia, dementia of Alzheimer type and so on). Among neuropathomorphological findings in cases of CCI there are primarily white matter abnormalities (demyelination, glial activation, loss of oligodendrocytes) and disseminated neuronal loss. Among therapeutic methods those which are capable to correct the pathological, biochemical and pathophysiological abnormalities induced by chronic cerebral hypoperfusion are supposed to be most effective. Cavinton (ethyl-apovincaminate) produces a positive impact on different levels of the pathological process in patients with chronic cerebral hypoperfusion of various etiologies. Key words: Cavinton, ethyl-apovincaminate, chronic cerebral hypoperfusion, cognitive impairment, white matter abnormalities, therapy. ‘ Ïîäãîòîâëåíî ïî ìàòåðèàëàì ïóáëèêàöèè â «Íåâðîëîãè÷åñêîì æóðíàëå» (2004, 9: 39–46), ïðåäîñòàâëåííîé ïðåäñòàâèòåëüñòâîì êîìïàíèè «Ðèõòåð Ãåäåîí Ðò.» â Óêðàèíå. Çà äîïîëíèòåëüíîé èíôîðìàöèåé îáðàùàéòåñü â ïðåäñòàâèòåëüñòâî êîìïàíèè «Ðèõòåð Ãåäåîí Ðò.» â Óêðàèíå ïî àäðåñó: 01054, Êèåâ, óë. Òóðãåíåâñêàÿ, 17Á Òåë.: (044) 492-99-11, 492-99-19, ôàêñ: (044) 492-99-10 E-mail: ukraine@richter.kiev.ua ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 6 (44) – XI/XII 2004