кавинтон в терапии хрони×еской недостато×ности мозгового

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
 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. Â 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
 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. Â
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.
Ðåçóëüòàòû êëèíè÷åñêèõ èññëåäîâàíèé ñâèäåòåëüñòâóþò, ÷òî ïåðîðàëüíîå ïðèìåíåíèå Êàâèíòîíà ÿâëÿåòñÿ ýôôåêòèâíûì â òåðàïèè áîëüíûõ ñ õðîíè÷åñêîé öåðåáðàëüíîé äèñôóíêöèåé ñîñóäèñòîãî
ãåíåçà, à ïëàöåáî-êîíòðîëèðóåìûõ èññëåäîâàíèé —
êîãíèòèâíûå ôóíêöèè, ðå÷ü è ïîâåäåíèå äîñòîâåðíî óëó÷øàþòñÿ, àïàòèÿ è äâèãàòåëüíûå ðàññòðîéñòâà — óìåíüøàþòñÿ. Äîêàçàíî, ÷òî êóðñîâàÿ òåðàïèÿ Êàâèíòîíîì ñïîñîáñòâóåò óëó÷øåíèþ îáùåãî
ñîñòîÿíèÿ áîëüíûõ, èõ óìñòâåííîé è ôèçè÷åñêîé
ðàáîòîñïîñîáíîñòè. Óëó÷øåíèå êîãíèòèâíûõ ôóíêöèé ïðè ëå÷åíèè Êàâèíòîíîì îáóñëîâëåíî åãî êîððèãèðóþùèì äåéñòâèåì íà ðàçëè÷íûå çâåíüÿ õðîíè÷åñêîé ãèïîïåðôóçèè ãîëîâíîãî ìîçãà.
ËÈÒÅÐÀÒÓÐÀ
Backhauss C., Karkoutly C., Welsch M., Krieglstein J. (1992)
A mouse model of focal cerebral ischemia for screening neuroprotective drug effects. J. Pharmacol. Toxicol. Methods, 27: 27–32.
Balestreri R., Fontana L., Astengo F. (1987) A double-blind
placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction. J. Am. Geriatr. Soc., 35: 425–430.
Bhardwaj A., Northington F.J., Koehler R.C., Stiefel T., Hanley D.F., Traystman R.J. (1995) Adenosine modulates N-methylD-aspartate-stimulated hippocampal nitric oxide production in
vivo. Stroke, 26: 1627–1633.
Blaha L., Erzigkeit H., Adamczyk A. et al. (1989) Clinical evidence of the effectiveness of vinpocetine in the treatment of organic psychosyndrome. Hum. Psychopharmacol., 4: 103–111.
ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 6 (44) – XI/XII 2004
ÎÃËßÄ
Blaustein M.P., Goldman W.F., Fontana G., Krueger B.K.,
Santiago E.M., Steele T.D., Weiss D.N., Yarowsky P.J. (1991)
Physiological roles of the sodium-calcium exchanger in nerve and
muscle. Ann. N.Y. Acad. Sci., 639: 254–274.
Bliss T.V., Collingridge G.L. (1993) A synaptic model of memory:
long-term potentiation in the hippocampus. Nature, 361: 31–39.
Brodie C., Blumberg P.M., Jacobson K.A. (1998) Activation
of the A2A adenosine receptor inhibits nitric oxide production in
glial cells. FEBS Lett., 429: 139–142.
Choi D.W. (1988) Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends
Neurosci., 11: 465–469.
Coleston D.M., Hindmarch I. (1988) Possible memory-enhancing properties of vinpocetine. Drug Dev. Res., 14: 191–193.
Csanda E., Harcos P., Bacsy Zs. et al. (1988) Ten years of
experience with Cavinton. Drug Dev. Res., 14: 185–187.
De Jong G.I., De Vos R.A., Steur E.N., Luiten P.G. (1997)
Cerebrovascular hypoperfusion: a risk factor for Alzheimer’s disease? Animal model and postmortem human studies. Ann. N.Y.
Acad. Sci., 826: 56–74.
Ebi O. (1985) Open-labeled phase III clinical trials with vinpocetine in Japan. Ther. Hung., 33: 41–49.
Erdo S.A., Molnar P., Lakics V., Bence J.Z., Tomoskozi Z.
(1996) Vincamine and vincanol are potent blockers of voltage-gated Na+ channels. Eur. J. Pharmacol., 314: 69–73.
Erdo S.L., Cai N.S., Wolff J.R., Kiss B. (1990) Vinpocetin
protects against excitotoxic cell death in primary cultures of rat cerebral cortex. Eur. J. Pharmacol., 187: 551–553.
Fenzl E., Apecechea M., Schaltenbrand R. et al. (1986) Longterm study concerning tolerance and efficacy of vinpocetine in elderly patients suffering from a mild to moderate organic psychosyndrome. In: A. Bes et al. (Eds.) Senile Dementias: Early Detection.
J. Libbey, London — Paris, p. 580–585.
Fern R., Ransom B.R., Stys P.K., Waxman S.G. (1993) Pharmacological protection of CNS white matter during anoxia: actions of phenytoin, carbamazepine and diazepam. J. Pharmacol.
Exp. Ther., 266: 1549–1555.
Fredholm Â.Â., Lindgren E., Lindstrom K., Vernet L. (1983)
The effect of some drugs with purported antianoxic effects on veratridine-induced purine release from isolated rat hypothalamic synaptosomes. Acta Pharmacol. Toxicol. (Copenh)., 53: 236–244.
George A.E., de Leon M.J., Kalnin A., Rosner L., Goodgold A.,
Chase N. (1986) Leukoencephalopathy in normal and pathologic
aging: 2. MRI of brain lucencies. AJNR Am. J. Neuroradiol.,
7: 567–570.
Groo D., Palosi E., Szporny L. (1989) Effect of vinpocetine in
memory disturbances induced by different damaging agents. In:
J. Krieglstein (Ed.) Pharmacology of Cerebral Ischemia, Wissenschaftliche Verlagsgesellschaft mbH., Stuttgart.
Hachinski V.C., Potter P., Merskey H. (1987) Leuko-araiosis.
Arch. Neurol., 44: 21–23.
Hagiwara M., Endo T., Hidaka H. (1984) Effects of vinpocetine on cyclic nucleotide metabolism in vascular smooth muscle.
Biochem. Pharmacol., 33: 453–457.
Hayakawa M. (1992a) Comparative efficacy of vinpocetine,
pentoxifylline and nicergoline on red blood cell deformability. Arzneimittelforschung, 42: 108–110.
Hayakawa M. (1992b) Effect of vinpocetine on red blood cell deformability in stroke patients. Arzneimittelforschung, 42: 425–427.
Hindmarch I., Fuchs H.H., Erzigkeit H. (1991) Efficacy and tolerance of vinpocetine in ambulant patients suffering from mild to moderate organic psychosyndromes. Int. Clin. Psychopharmacol., 6: 31–43.
Ishihara K., Katsuki H., Sugimura M., Satoh M. (1989) Idebenone and vinpocetine augment long-term potentiation in hippocampal slices in the guinea pig. Neuropharmacology, 28: 569–573.
Kakihana M., Suno M., Shibota M. et al. (1982) Protective
effects of vinpocetine on experimental brain ischemia. Folia Pharmacol. Jpn., 80: 225–229.
Kaneko S., Sugimura M., Inoue T., Satoh M. (1991) Effects
of several cerebroprotective drugs on NMDA channel function: eval-
uation using Xenopus oocytes and [3H]MK-801 binding. Eur. J.
Pharmacol., 207: 119–128.
King G.A. (1987) Protective effects of vinpocetine and structurally related drugs on the lethal consequences of hypoxia in mice.
Arch. Int. Pharmacodyn. Ther., 286: 299–307.
Kiss B., Karpati E. (1996) Mechanism of action of vinpocetine. Acta Pharm. Hung., 66: 213–224.
Kovacs L. (1988) A Cavinton hatasmechanizmusarol. RGD:
37444/4.
Krieglstein J., Rischke R. (1991) Vinpocetine increases the
neuroprotective effect of adenosine in vitro. Eur. J. Pharmacol.,
205: 7–10.
Kuzuya F. (1982) Effects of vinpocetine on platelet aggregability and erythrocyte deformability. Geriatr. Med., 20: 151–156.
Lakics V., Sebestyen M.G., Erdo S.L. (1995) Vinpocetine is a highly
potent neuroprotectant against veratridine-induced cell death in primary cultures of rat cerebral cortex. Neurosci Lett., 185: 127–130.
Lebedeva N.V., Lobkova T.N., Ionova V.G. et al. (1990) Status
of microcirculation and rheological properties of blood in patients
with cerebral circulatory disorders. Klin. Med. (Mosk.), 68: 31–33.
Lechner H., Schmidt R. (1989) The management of chronic
cerebral ischemia. In: J.S. Chopra, K. Jagannathan, I.M.S. Sawhney (Eds.) Advances in Neurology. International Congress Series
883, Proceedings of the XIVth World Congress of Neurology, New
Delhi, India, October 22–27, 1989. Excerpta Medica, Elsevier
Science Publishers B.V., p. 145–172.
Leigh P.N., Meldrum B.S. (1996) Excitotoxicity in ALS. Neurology, 47(Suppl. 4): S221–S227.
Lindgren S.H., Andersson T.L., Vinge E., Andersson K.E.
(1990) Effects of isozyme-selective phosphodiesterase inhibitors on
rat aorta and human platelets: smooth muscle tone, platelet aggregation and cAMP levels. Acta Physiol. Scand., 140: 209–219.
Madison D.V., Malenka R.C., Nicoll R.A. (1991) Mechanisms
underlying long-term potentiation of synaptic transmission. Ann.
Rev. Neurosci., 14: 379–397.
Manconi E., Binaghi F., Pitzus F. (1986) A double-blind clinical trial of vinpocetine in the treatment of cerebral insufficiency of
vascular and degenerative origin. Curr. Ther. Res., 40: 702–709.
Miyazaki M. (1995) The effect of a cerebral vasodilator, vinpocetine, on cerebral vascular resistance evaluated by Doppler ultrasonic technique in patients with cerebrovascular disease. Angiology, 46: 53–58.
Molnar P., Erdo S.L. (1995) Vinpocetine is as potent as phenytoin to block voltage-gated Na+ channels in rat cortical neurons.
Eur. J. Pharmacol., 273: 303–306.
Molnar P., Gaal L., Horvath C. (1994) The impairment of
long-term potentiation in rats with medial septal lesion and its restoration by cognition enhancers. Neurobiology (Bp.), 2: 255–266.
Nagy Z., Bonoczk P., Panczel Gy. et al. (1996) Cavinton review. Praxis, 5: 1–6.
Nagy Z., Varga P., Kovacs L. et al. (1998) Cavinton metaanalizis. Praxis, 7: 63–68.
Ohta H., Nishikawa H., Kimura H., Anayama H., Miyamoto M. (1997) Chronic cerebral hypoperfusion by permanent internal carotidligation produces learning impairment without brain
damage in rats. Neuroscience, 79: 1039–1050.
Olah A.V., Balla G., Balla J. et al. (1990) An in vitro study of
the hydroxyl scavenger effect of Cavinton. Acta Pediatr. Hung.,
30: 309–316.
Osawa M., Maruyama S. (1985) Effects of TCV-3B (Vinpocetine) on blood viscosity in ischemic cerebrovascular diseases. Ther.
Hung., 33: 7–12.
Otomo E., Atarashi J., Araki G. et al. (1985) Comparison of
vinpocetine with ifenprodil tartarate and dihydroergotoxine mesylate treatment and results of long-term treatment with vinpocetine. Curr. Ther. Res., 37: 811–821.
Peruzza M., De Jacobis M. (1986) A double-blind placebo
controlled evaluation of the efficacy and safety of vinpocetine in
the treatment of patients with chronic vascular or degenerative senile cerebral dysfunction. Adv. Ther., 3: 201–209.
Rosdy B., Balazs M., Szporny L. (1976) Biochemical effects of
ethyl apovincaminate. Arzneimittelforschung, 1976, 26: 1923–1926.
ÓÊÐÀ¯ÍÑÜÊÈÉ ÌÅÄÈ×ÍÈÉ ×ÀÑÎÏÈÑ – ¹ 6 (44) – XI/XII 2004
11
ÎÃËßÄ
Rudolphi K.A., Schubert P. (1997) Modulation of neuronal
and glial cell function by adenosine and neuroprotection in vascular dementia. Behav. Brain. Res., 83: 123–128.
Russell R.W., Page N.G. (1983) Critical perfusion of brain and
retina. Brain, 106: 419–434.
Sauer D., Rischke R., Beck T., Rossberg C., Mennel H.D.,
Bielenberg G.W., Krieglstein J. (1988) Vinpocetine prevents ischemic cell damage in rat hippocampus. Life Sci., 43: 1733–1739.
Schmid-Schonbein H., Grebe R., Teitel P. et al. (1988)
Restoration of microsieve filterability of human red cells after exposure to hyperosmolarity and lactacidosis: effect of vinpocetine.
Drug Dev. Res., 14: 205–211.
Schubert P., Ogata T., Marchini C., Ferroni S., Rudolphi K.
(1997) Protective mechanisms of adenosine in neurons and glial
cells. Ann. N.Y. Acad. Sci., 825: 1–10.
Sekhon L.H., Morgan M.Ê., Spence I., Weber N.C. (1994)
Chronic cerebral hypoperfusion and impaired neuronal function
in rats. Stroke, 25: 1022–1027.
Sekhon L.H., Morgan M.K., Spence I., Weber N.C. (1997a)
Chronic cerebral hypoperfusion: pathological and behavioral consequences. Neurosurgery, 40: 548–556.
Sekhon L.H., Spence I., Morgan M.K., Weber N.C. (1997b)
Chronic cerebral hypoperfusion inhibits calcium-induced long-term
potentiation in rats. Stroke, 28: 1043–1048.
Stys P.K., Ransom B.R., Waxman S.G., Davis P.K. (1990a)
Role of extracellular calcium in anoxic injury of mammalian central white matter. Proc. Natl. Acad. Sci. USA, 87: 4212–4216.
Stys P.K., Ransom B.R., Waxman S.G. (1990b) Effects of polyvalent cations and dihydropyridine calcium channel blockers on recovery
of CNS white matter from anoxia. Neurosci. Lett., 115: 293–299.
Stys P.K., Waxman S.G., Ransom B.R. (1991) Na(+)-Ca2+
exchanger mediates Ca2+ influx during anoxia in mammalian central nervous system white matter. Ann. Neurol., 30: 375–380.
Stys P.K., Waxman S.G., Ransom B.R. (1992) Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+
channels and Na(+)-Ca2+ exchanger. J. Neurosci., 12, 430–439.
Subhan Z., Hindmarch I. (1985) Psychopharmacological effects of vinpocetine in normal healthy volunteers. Eur. J. Clin. Pharmacol., 28: 567–571.
Szakall Sz., Boros I., Balkay L., Emri M., Fekete I., Kerenyi L., Lehel S., Marian T., Molnar T., Varga J., Galuska L.,
Tron L., Bereczki D., Csiba L., Gulyas B. (1998) Cerebral effects
of a single dose of intravenous vinpocetine in chronic stroke patients: a PET study. J. Neuroimaging, 8: 197–204.
Szobor A., Klein M. (1976) Ethyl apovincaminate therapy in
neurovascular diseases. Arzneimittelforschung, 26: 1984–1989.
Tamaki N., Kusunoki T, Matsumoto S. (1985) Effect of vinpocetine on cerebral blood flow in patients with cerebrovascular disorders. Adv. Ther., 2: 53–59.
Tohgi H., Sasaki K., Chiba K., Nozaki Y. (1990) Effect of vinpocetine on oxygen release of hemoglobin and erythrocyte organic
polyphosphate concentrations in patients with vascular dementia
of the Binswanger type. Arzneimittelforschung, 40: 640–643.
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