Ôàðìàêîäèíàìè÷åñêîå îáîñíîâàíèå ïðèìåíåíèÿ Ãëàòèîíà ïðè COVID-19
Ãëóòàòèîí ïðåäñòàâëÿåò ñîáîé ëèíåéíûé òðèïåïòèä ñ ñóëüôãèäðèëüíîé ãðóïïîé, â ñîñòàâ êîòîðîãî âõîäÿò L-ãëóòàìèí, L-öèñòåèí è ãëèöèí. Îí èãðàåò âàæíóþ ôóíêöèþ â çàùèòå êëåòîê îðãàíèçìà, ÿâëÿÿñü ñèëüíûì àíòèîêñèäàíòîì.  îðãàíèçìå ÷åëîâåêà íåõâàòêà ãëóòàòèîíà âåäåò ê âîçíèêíîâåíèþ ìíîãèõ áîëåçíåé, òàêèõ êàê áîëåçíü Ïàðêèíñîíà, òèðîçèíåìèÿ I òèïà, îòðàâëåíèå àëêîãîëåì è äðóãèå. Ýêñïåðèìåíòû in vivo è in vitro ïîêàçàëè, ÷òî íåõâàòêà ãëóòàòèîíà ìîæåò ïðèâåñòè ê ïîâðåæäåíèþ ìèòîõîíäðèé è ãèáåëè êëåòîê, âûçâàííûõ óâåëè÷åíèåì ÷èñëà òîêñè÷íûõ ôîðì êèñëîðîäà, ïðèâîäÿùèõ ê ïîâûøåíèþ êîëè÷åñòâà ñâîáîäíûõ ðàäèêàëîâ.(1)
Ãëóòàòèîí ñïîñîáåí ïðåäîòâðàùàòü ïîâðåæäåíèÿ êëåòîê ïîñðåäñòâîì ñîåäèíåíèÿ ñ òîêñè÷åñêèìè âåùåñòâàìè è/èëè èõ ìåòàáîëèòàìè. Îáåçâðåæèâàíèå êñåíîáèîòèêîâ ãëóòàòèîíîì ìîæåò îñóùåñòâëÿòüñÿ òðåìÿ ðàçëè÷íûìè ñïîñîáàìè: ïóòåì êîíúþãàöèè ñóáñòðàòà ñ ãëóòàòèîíîì, â ðåçóëüòàòå íóêëåîôèëüíîãî çàìåùåíèÿ è â ðåçóëüòàòå âîññòàíîâëåíèÿ îðãàíè÷åñêèõ ïåðîêñèäîâ äî ñïèðòîâ.(1)
Ñèñòåìà îáåçâðåæèâàíèÿ ñ ó÷àñòèåì ãëóòàòèîíà èãðàåò óíèêàëüíóþ ðîëü â ôîðìèðîâàíèè ðåçèñòåíòíîñòè îðãàíèçìà ê ñàìûì ðàçëè÷íûì âîçäåéñòâèÿì è ÿâëÿåòñÿ íàèáîëåå âàæíûì çàùèòíûì ìåõàíèçìîì êëåòêè.  õîäå áèîòðàíñôîðìàöèè íåêîòîðûõ êñåíîáèîòèêîâ ïðè ó÷àñòèè ãëóòàòèîíà îáðàçóþòñÿ òèîýôèðû, êîòîðûå çàòåì ïðåâðàùàþòñÿ â ìåðêàïòàíû, ñðåäè êîòîðûõ îáíàðóæåíû òîêñè÷íûå ïðîäóêòû. Íî êîíúþãàòû ãëóòàòèîíà ñ áîëüøèíñòâîì êñåíîáèîòèêîâ ìåíåå ðåàêöèîííîñïîñîáíû è áîëåå ãèäðîôèëüíû, ÷åì èñõîäíûå âåùåñòâà, à ïîýòîìó ìåíåå òîêñè÷íû è ëåã÷å âûâîäÿòñÿ èç îðãàíèçìà.(1)
Ãëóòàòèîí ñâÿçûâàåò îãðîìíîå êîëè÷åñòâî ëèïîôèëüíûõ ñîåäèíåíèé (ôèçè÷åñêîå îáåçâðåæèâàíèå), ïðåäîòâðàùàÿ èõ âíåäðåíèå â ëèïèäíûé ñëîé ìåìáðàí è íàðóøåíèå ôóíêöèé êëåòêè.Òàêèì îáðàçîì, ãëóòàòèîí óëó÷øàåò ñòàáèëüíîñòü êëåòî÷íîé ìåìáðàíû, çàùèùàåò ìåìáðàíó êëåòîê ïå÷åíè, óâåëè÷èâàåò àêòèâíîñòü ôåðìåíòîâ è ïå÷åíè è ñïîñîáñòâóåò äåòîêñèêàöèè è âîññòàíîâèòåëüíîé àêòèâíîñòè ïå÷åíè ïóòåì óíè÷òîæåíèÿ ñâîáîäíûõ ðàäèêàëîâ.(1)
Êàê ïîêàçûâàåò èìåþùèéñÿ îïûò - ââåäåíèå ïðåïàðàòà Ãëàòèîí â êîìïëåêñíóþ òåðàïèþ òÿæåëûõ ôîðì COVID-19 ïîçâîëÿåò ìèíèìèçèðîâàòü ðèñê ðàçâèòèÿ óãðîæàþùèõ æèçíè îñëîæíåíèé, âîññòàíàâëèâàÿ ýôôåêòèâíóþ ðàáîòó âíóòðåííèõ ñèñòåì çàùèòû îðãàíèçìà (èììóííîé, äåòîêñèöèðóþùåé, âûäåëèòåëüíîé è äðóãèõ ñèñòåì ñîõðàíåíèÿ è óñòðàíåíèÿ íàðóøåíèé ãîìåîñòàçà), ïîëíîöåííàÿ ðàáîòà êîòîðûõ ïðåäîïðåäåëÿåò áûñòðåéøåå âûçäîðîâëåíèå è îòíîñèòåëüíî ëåãêîå òå÷åíèå COVID-19. (19)
Áîëåå âûñîêèé óðîâåíü ñåðüåçíûõ çàáîëåâàíèé è ñìåðòåé îò êîðîíàâèðóñà SARS-CoV-2 (COVID-19) ñðåäè ïîæèëûõ ëþäåé è ëèö ñ ñîïóòñòâóþùèìè çàáîëåâàíèÿìè ñâèäåòåëüñòâóåò î òîì, ÷òî áèîëîãè÷åñêèå ïðîöåññû, ñâÿçàííûå ñ âîçðàñòîì è çàáîëåâàíèåì, äåëàþò òàêèõ ëþäåé áîëåå ÷óâñòâèòåëüíûìè ê ôàêòîðàì ñòðåññà îêðóæàþùåé ñðåäû, âêëþ÷àÿ èíôåêöèîííûå àãåíòû êàê êîðîíàâèðóñ SARS-CoV-2.(3)  ÷àñòíîñòè, íàðóøåíèå îêèñëèòåëüíî-âîññòàíîâèòåëüíîãî ãîìåîñòàçà è ñâÿçàííûé ñ íèì îêèñëèòåëüíûé ñòðåññ(4,6,8), ïî-âèäèìîìó, ÿâëÿþòñÿ âàæíûìè áèîëîãè÷åñêèìè ïðîöåññàìè, êîòîðûå ìîãóò îáúÿñíèòü ïîâûøåííóþ èíäèâèäóàëüíóþ âîñïðèèì÷èâîñòü ê ðàçëè÷íûì âîçäåéñòâèÿì îêðóæàþùåé ñðåäû. Íåñïîñîáíîñòü âíóòðåííèõ ñèñòåì çàùèòû ðåàëèçîâàòü ñâîé ïîòåíöèàë ïðèâîäèò ê ðàçâèòèþ òÿæåëîé ôîðìû COVID-19 è ÿâëÿåòñÿ ñëåäñòâèåì ñî÷åòàíèÿ öåëîãî ðÿäà íåãàòèâíûõ ñîñòàâëÿþùèõ, âçàèìíî óñèëèâàþùèõ äðóã äðóãà.(7) Òàê, âûçâàííàÿ âèðóñîì âûñîêàÿ òîêñè÷åñêàÿ íàãðóçêà ñóììèðóåòñÿ è óñèëèâàåò íåãàòèâíûå èçìåíåíèÿ âíóòðåííèõ ñèñòåì çàùèòû, îáóñëîâëåííûõ çàáîëåâàíèåì (îæèðåíèå, ãèïåðòîíè÷åñêàÿ áîëåçíü, ñàõàðíûé äèàáåò, îíêîëîãèÿ è äð.) è ïîáî÷íûìè ýôôåêòàìè ñðåäñòâ ôàðìàêîòåðàïèè ïàöèåíòà. (10) Ñëåäñòâèåì òàêîãî ñî÷åòàíèÿ ñòàíîâÿòñÿ îðãàííûå è ñèñòåìíûå ôóíêöèîíàëüíûå íàðóøåíèÿ, èììóíîýíäîêðèííûå äèçðåãóëÿòîðíûå ðàññòðîéñòâà, êëåòî÷íûå äèñôóíêöèè, ïðèâîäÿùèå ê èçìåíåíèÿì ìåòàáîëèçìà, ñîïðÿæåííûìè ñ íåãàòèâíûì âëèÿíèåì íà ðåãóëèðóåìîñòü êëåòî÷íûõ, îðãàííûõ è ñèñòåìíûõ ïðîöåññîâ, ÷òî â èòîãå ïðåäîïðåäåëÿåò ôîðìèðîâàíèå ìíîæåñòâà ïîðî÷íûõ êðóãîâ, ñîçäàþùèõ ñðåäó, èçâðàùàþùóþ äåéñòâèå åñòåñòâåííûõ áèîðåãóëÿòîðîâ, ôàðìàêîëîãè÷åñêóþ àêòèâíîñòü ËÑ.(2)(22)
Íåñêîëüêî èññëåäîâàíèé ïîêàçûâàþò, ÷òî áîëåå âûñîêèå óðîâíè ãëóòàòèîíà ìîãóò óëó÷øèòü èíäèâèäóàëüíóþ ðåàêöèþ íà âèðóñíûå èíôåêöèè.(19) ÷àñòíîñòè, èçâåñòíî, ÷òî ãëóòàòèîí çàùèùàåò èììóííûå êëåòêè õîçÿèíà áëàãîäàðÿ ñâîåìó àíòèîêñèäàíòíîìó ìåõàíèçìó, à òàêæå îòâå÷àåò çà îïòèìàëüíîå ôóíêöèîíèðîâàíèå ìíîæåñòâà êëåòîê, êîòîðûå ÿâëÿþòñÿ ÷àñòüþ èììóííîé ñèñòåìû.(9) Âàæíî îòìåòèòü, ÷òî ñóùåñòâóþò äîêàçàòåëüñòâà òîãî, ÷òî ãëóòàòèîí ïîäàâëÿåò ðåïëèêàöèþ ðàçëè÷íûõ âèðóñîâ íà ðàçíûõ ýòàïàõ æèçíåííîãî öèêëà âèðóñà è ýòî ïðîòèâîâèðóñíîå ñâîéñòâî GSH, ïî-âèäèìîìó, ïðåäîòâðàùàåò óâåëè÷åíèå âèðóñíîé íàãðóçêè è ïîñëåäóþùåå ìàññîâîå âûñâîáîæäåíèå âîñïàëèòåëüíûõ êëåòîê. â ëåãêîå («öèòîêèíîâûé øòîðì»).(2)
Ïðîòèâîâèðóñíàÿ àêòèâíîñòü ãëóòàòèîíà áûëà ïðîäåìîíñòðèðîâàíà â èññëåäîâàíèè De Flora et al.(18), êîòîðûå ïîêàçàëè, ÷òî ïðîôèëàêòè÷åñêîå ââåäåíèå N-àöåòèëöèñòåèíà (NAC, ïðåäøåñòâåííèê ãëóòàòèîíà) â òå÷åíèå 6 ìåñÿöåâ çíà÷èòåëüíî ñíèæàåò ÷àñòîòó êëèíè÷åñêè î÷åâèäíûõ ãðèïïà è ãðèïïîïîäîáíûõ ýïèçîäîâ, îñîáåííî ó ïîæèëûõ ëþäåé èç ãðóïïû âûñîêîãî ðèñêà. Êðîìå òîãî, ïàòîôèçèîëîãè÷åñêèå ñîñòîÿíèÿ, òàêèå êàê ïîâðåæäåíèå êëåòîê ëåãêèõ è âîñïàëåíèå ó ïàöèåíòîâ ñ òÿæåëûì ÎÐÄÑ, áûëè îïðåäåëåíû êàê öåëè ëå÷åíèÿ N-àöåòèëöèñòåèíà.  ÷àñòíîñòè, áûëî îáíàðóæåíî, ÷òî äåôèöèò âîññòàíîâëåííîãî ãëóòàòèîíà â àëüâåîëÿðíîé æèäêîñòè ó ïàöèåíòîâ ñ ÎÐÄÑ óñèëèâàåò ïîâðåæäåíèå êëåòîê ëåãêèõ èç-çà ROS / îêèñëèòåëüíîãî ñòðåññà è âîñïàëåíèÿ, è ýòî ïîâðåæäåíèå ìîæíî ýôôåêòèâíî ïðåäîòâðàòèòü è ëå÷èòü ñ ïîìîùüþ ââåäåíèÿ N-àöåòèëöèñòåèíà.(19) Äåôèöèò ãëóòàòèîíà òàêæå ìîæåò ñïîñîáñòâîâàòü ïîâûøåííîé àêòèâàöèè ôàêòîðà ôîí Âèëëåáðàíäà, âûçûâàþùåãî êîàãóëîïàòèþ ó ïàöèåíòîâ ñ COVID-19.(3,9,13)
Ýíäîãåííûé äåôèöèò ãëóòàòèîíà, ïî-âèäèìîìó, ÿâëÿåòñÿ ðåøàþùèì ôàêòîðîì, óñèëèâàþùèì îêèñëèòåëüíîå ïîâðåæäåíèå ëåãêèõ, âûçâàííîå SARS-CoV-2, è, êàê ñëåäñòâèå, ïðèâîäèò ê ñåðüåçíûì ïðîÿâëåíèÿì, òàêèì êàê îñòðûé ðåñïèðàòîðíûé äèñòðåññ-ñèíäðîì, ïîëèîðãàííàÿ íåäîñòàòî÷íîñòü è ñìåðòü ïàöèåíòîâ ñ COVID-19. Êîãäà ïðèíèìàåòñÿ âî âíèìàíèå ïðîòèâîâèðóñíàÿ àêòèâíîñòü GSH, ëþäè ñ äåôèöèòîì ãëóòàòèîíà, èìåþò áîëåå âûñîêóþ âîñïðèèì÷èâîñòü ê íåêîíòðîëèðóåìîé ðåïëèêàöèè âèðóñà SARS-CoV-2 è, òàêèì îáðàçîì, ñòðàäàþò îò âîçðàñòàþùåé âèðóñíîé íàãðóçêè.(10) Âûðàæåííîñòü êëèíè÷åñêèõ ïðîÿâëåíèé ó ïàöèåíòîâ ñ COVID-19, ïî-âèäèìîìó, îïðåäåëÿåòñÿ ñòåïåíüþ íàðóøåíèÿ îêèñëèòåëüíî-âîññòàíîâèòåëüíîãî ãîìåîñòàçà, ñâÿçàííîãî ñ äåôèöèòîì âîññòàíîâëåííîãî ãëóòàòèîíà è ïîâûøåíèåì ïðîäóêöèè ÀÔÊ.  ÷àñòíîñòè, ïàöèåíòû ñ COVID-19 ñ óìåðåííûì è òÿæåëûì çàáîëåâàíèåì èìåëè áîëåå íèçêèé óðîâåíü ãëóòàòèîíà, áîëåå âûñîêèå óðîâíè ROS è áîëåå âûñîêèé îêèñëèòåëüíî-âîññòàíîâèòåëüíûé ñòàòóñ (ñîîòíîøåíèå ROS / GSH), ÷åì ïàöèåíòû ñ COVID-19 ñ ëåãêèì çàáîëåâàíèåì.(22) Äëèòåëüíûå è òÿæåëûå ïðîÿâëåíèÿ èíôåêöèè COVID-19 ó îäíîãî èç íàøèõ ïàöèåíòîâ ñ âûðàæåííûì äåôèöèòîì ãëóòàòèîíà ïðåäïîëàãàþò, ÷òî ñòåïåíü ñíèæåíèÿ ãëóòàòèîíà îòðèöàòåëüíî êîððåëèðóåò ñî ñêîðîñòüþ ðåïëèêàöèè âèðóñà è ÷òî óâåëè÷åíèå âèðóñíîé íàãðóçêè óñóãóáëÿåò îêèñëèòåëüíîå ïîâðåæäåíèå ëåãêèõ. Ýòî îòêðûòèå ïðåäïîëàãàåò, ÷òî âèðóñ íå ìîæåò àêòèâíî ðåïëèöèðîâàòüñÿ ïðè áîëåå âûñîêèõ óðîâíÿõ êëåòî÷íîãî ãëóòàòèîíà, è, ñëåäîâàòåëüíî, áîëåå ëåãêèå êëèíè÷åñêèå ñèìïòîìû íàáëþäàþòñÿ ïðè áîëåå íèçêèõ âèðóñíûõ íàãðóçêàõ.(2)
Äåôèöèò ãëóòàòèîíà - ýòî ïðèîáðåòåííîå ñîñòîÿíèå, ñâÿçàííîå ñî ñíèæåíèåì áèîñèíòåçà è / èëè ïîâûøåííûì èñòîùåíèåì ýíäîãåííîãî ïóëà GSH ïîä âëèÿíèåì òàêèõ ôàêòîðîâ ðèñêà, êàê ñòàðåíèå, ìóæñêîé ïîë, êîìîðáèäíîñòü è êóðåíèå îòäåëüíî èëè â ñî÷åòàíèè.(10,12,15) Äåôèöèò ãëóòàòèîíà ó ïàöèåíòîâ ñ COVID-19 ñ ñåðüåçíûìè çàáîëåâàíèÿìè òàêæå ìîæåò áûòü ðåçóëüòàòîì ñíèæåíèÿ ïîòðåáëåíèÿ ñâåæèõ îâîùåé è ôðóêòîâ (îñîáåííî â çèìíèé è âåñåííèé ñåçîíû), ÷òî ñîñòàâëÿåò áîëåå 50% ïîòðåáëåíèÿ ãëóòàòèîíà ñ ïèùåé. Ãèïîòåçà ïðåäïîëàãàåò, ÷òî SARS-CoV -2 ïðåäñòàâëÿåò îïàñíîñòü òîëüêî äëÿ ëþäåé ñ ýíäîãåííûì äåôèöèòîì ãëóòàòèîíà, íåçàâèñèìî îò òîãî, êàêèå èç ôàêòîðîâ ñòàðåíèÿ, ñîïóòñòâóþùèå õðîíè÷åñêèå çàáîëåâàíèÿ, êóðåíèå èëè íåêîòîðûå äðóãèå áûëè ïðè÷èíîé ýòîãî äåôèöèòà.(10) Ãèïîòåçà äàåò íîâîå ïîíèìàíèå ýòèîëîãèè è ìåõàíèçìîâ, îòâåòñòâåííûõ çà ñåðüåçíûå ïðîÿâëåíèÿ èíôåêöèè COVID-19, è îïðàâäûâàåò ìíîãîîáåùàþùèå âîçìîæíîñòè äëÿ ýôôåêòèâíîãî ëå÷åíèÿ è ïðîôèëàêòèêè áîëåçíè çà ñ÷åò âîññòàíîâëåíèÿ ãëóòàòèîíà ñ ïîìîùüþ N-àöåòèëöèñòåèíà è âîññòàíîâëåííîãî ãëóòàòèîíà.
Ïîñêîëüêó ïðîòèâîâèðóñíûé ýôôåêò ãëóòàòèîíà íåñïåöèôè÷åñêèé, åñòü îñíîâàíèÿ ïîëàãàòü, ÷òî ãëóòàòèîí òàêæå àêòèâåí ïðîòèâ SARS-CoV-2.(3,11,18) Òàêèì îáðàçîì, âîññòàíîâëåíèå óðîâíÿ ãëóòàòèîíà ó ïàöèåíòîâ ñ COVID-19 áûëî áû ìíîãîîáåùàþùèì ïîäõîäîì ê ëå÷åíèþ íîâîãî êîðîíàâèðóñà SARS-CoV-2. Ïðèìå÷àòåëüíî, ÷òî äëèòåëüíîå ïåðîðàëüíîå ââåäåíèå N-àöåòèëöèñòåèíà óæå áûëî ïðîòåñòèðîâàíî êàê ýôôåêòèâíàÿ ïðîôèëàêòè÷åñêàÿ ìåðà ïðîòèâ ðåñïèðàòîðíûõ âèðóñíûõ èíôåêöèé.(18) N-àöåòèëöèñòåèí øèðîêî äîñòóïåí, áåçîïàñåí è äåøåâ è ìîæåò èñïîëüçîâàòüñÿ «íå ïî íàçíà÷åíèþ». Áîëåå òîãî, ïàðåíòåðàëüíàÿ èíúåêöèÿ âîññòàíîâëåííîãî ãëóòàòèîíà (GSH áîëåå áèîäîñòóïåí, ÷åì NAC) ìîæåò áûòü ýôôåêòèâíîé òåðàïèåé äëÿ ïàöèåíòîâ ñ COVID-19 ñ ñåðüåçíûì çàáîëåâàíèåì. (19)
Âîò ñïèñîê êëèíè÷åñêèõ èññëåäîâàíèé, êîòîðûå áûëè îðãàíèçîâàíû â ðàçëè÷íûõ ñòðàíàõ ìèðà äëÿ ëå÷åíèÿ COVID-19 ïóòåì óâåëè÷åíèÿ ñèíòåçà ãëóòàòèîíà:
Study title |
Country |
Link |
|
|
Antioxidant therapy for COVID-19 |
Nigeria |
|
||
Efficacy of NAC in Preventing COVID-19 From Progressing to Severe Disease |
US |
|
||
COVID-19 Algae Treatment Trial (CATT) Spirulina and N-acetylcysteine in COVID-19 Infection |
Iran |
|
||
NAC in treatment and recovery of patients with COVID-19 admitted in Hospital |
Iran |
|||
High dose IV NAC in Covid-19 Patients |
US |
|||
Effect of N-acetylcysteine on COVID-19 treatment |
Saudi Arabia |
|||
IV NAC/Methylene Blue for Treatment of Covid-19 Patients |
Iran |
|||
Comparison of the administration of Vit D3 and NAC tablets in COVID-19 patients and their effect on recovery |
Iran |
|||
IV NAC for Treatment of Severe COVID |
Brazil |
|||
nebulized Heparin-N-acetylcysteine in COVID-19 Patients by Evaluation of pulmonary function (HOPE)) |
US |
|||
Treatment of Pulmonary Fibrosis Due to 2019-nCoV Pneumonia |
China |
|||
Study to demonstrate evaluation of dendrimer NAC in COVID-19 patients |
US |
|||
Trial of Famotidine & N-Acetyl Cysteine for Outpatients With COVID-19 |
US |
|||
Efficacy of Inhaled NAC in COVID-19 |
Iran |
|||
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