Isihloko
I-methylene blue nesifo i-Alzheimer: ukuqonda imiphumela yezivivinyo
Uma usesha i-methylene blue nesifo i-Alzheimer, uthola izindaba ezimbili ngasikhathi sinye. Enye ithi udayi oluhlaza okwesibhakabhaka osuneminyaka eyikhulu wanciphisa ijubane lokulahleka kwenkumbulo. Enye ithi izivivinyo ezalandela aziphumelelanga. Zombili zicaphuna amaphepha ocwaningo angempela. Ukudideka kuvela ekuthatheni izinhlanganisela ezihlukene njengomuthi owodwa.
Akuzona umuthi owodwa. Isivivinyo sokuqala sahlola i-methylthioninium chloride esesimweni se-oxidation, inhlanganisela eluhlaza okwesibhakabhaka eyaziwayo. Zonke izivivinyo ze-Alzheimer ezalandela zahlola uhlobo oluzinzisiwe olusesimweni se-reduction, i-leuco-methylthioninium, manje olubizwa ngokuthi i-hydromethylthionine mesylate (HMTM). Imithamo, ukumuncwa emzimbeni, ngisho namaqembu okuqhathanisa kuyahluka phakathi kwalezi zinhlelo ezimbili. Uma ugcina izinhlanganisela zihlukene, umlando wezivivinyo uba sobala, futhi awukhombisi ukuthi kufanele kusetshenziswe izithasiselo.
Izinhlanganisela ezimbili
I-methylene blue esebhodleleni ngokuvamile iyi-methylthioninium chloride, efushaniswa ngokuthi MTC. Ingxenye yayo esebenzayo yi-ion ye-methylthioninium esesimweni se-oxidation, i-MT+, okuyi-molecule eneshaji kagesi neluhlaza okwesibhakabhaka ngokujulile. Le shaji idala inkinga emathunjini. Ukuze i-MT+ idlule kahle odongeni lwamathumbu, kufanele iqale iguqulwe nge-reduction ibe uhlobo lwe-leuco olungenashaji futhi olungenambala. Lesi sinyathelo se-reduction siyaguquguquka, futhi emithamweni ephakeme ukuncibilika nokumuncwa kwe-MTC kuba nomkhawulo ohlobene nomthamo, okungesinye sezizathu ezenza uhlelo lokuqala lwe-Alzheimer lwabhekana nezinkinga zokwakheka komuthi.
Umuthi owalandela uyasigwema leso sinyathelo. I-LMTM, nayo enekhodi ethi TRx0237 futhi manje ngokuvamile ebizwa ngokuthi HMTM, inikeza i-molecule esesimweni se-reduction ngokuqondile njengosawoti ozinzile we-mesylate owakheke njengamakristalu. I-methylthioninium yamahhala esesimweni se-reduction iphinde iguquke nge-oxidation ibe luhlaza okwesibhakabhaka phakathi nemizuzu lapho isemoyeni, ngakho uhlobo lukasawoti yilona oluyenza ibe umuthi ongagcinwa kunokuba ibe yinto emangalisayo yaselabhorethri nje. Ngamafuphi: i-MTC iyisandulela somuthi esiluhlaza okwesibhakabhaka, esisesimweni se-oxidation futhi esimuncwa ngokungalingani, kuyilapho i-LMTM/HMTM iwuhlobo oluzinzisiwe olusesimweni se-reduction, olwenzelwe ukutholakala komuthi emzimbeni ngendlela engabikezelwa. Izimangalo zokusebenza kahle kolunye uhlobo azisebenzi ngokuzenzakalelayo kolunye, futhi azisebenzi nasezixazululweni zikadayi ezithengwa ngaphandle kwencwadi kadokotela. Kubalulekile ukuqonda ikhemistri yezinhlobo ezisesimweni se-oxidation ne-reduction ngaphambi kokufunda noma yisiphi isihloko sezindaba zesivivinyo.
Indlela yokusebenza ehlolwayo nayo igxile kokuncane kunalokho okushiwo yizindaba. Uhlelo luqondise ekuqoqaneni kwe-tau, okuwukunqwabelana kwephrotheni ye-tau ibe yimicu neziphithiphithi ngaphakathi kwamaseli ezinzwa, kunokuba luqondise kuma-plaque e-amyloid. Lokho kwenza kube isu elihlukile kunama-antibody alwa ne-amyloid, futhi kuhambisana nocwaningo oluhlukile lwangaphambi kwezivivinyo kubantu ngezindlela zokususa i-amyloid kanye nokubuyekezwa okubanzi kwemibono ephathelene nama-mitochondria nokuvikelwa kwamaseli ezinzwa, okungafanele kuthathwe njengobufakazi obutholwe ezivivinyweni kubantu.
Inhlanganisela ngesivivinyo ngasinye
Leli yithebula okufanele ulibeke kubhukhimakhi. Umugqa ngamunye usho inhlanganisela eqondile, imithamo, imiphumela eyayilinganiswa nesihlonzi sesivivinyo, ngoba kuleyo mininingwane yilapho izifinyezo eziningi ziphambuka khona.
| Isivivinyo (inhlanganisela) | Imithamo eyahlolwa | Isihlonzi sesivivinyo | Imiphumela eyinhloko eyayilinganiswa | Umphumela wokwabiwa ngokungahleliwe |
|---|---|---|---|---|
| Rember, isigaba 2 (MTC, i-methylene blue esesimweni se-oxidation) | 69, 138, 228 mg/day okulingana ne-MT kuqhathaniswa ne-placebo, amasonto angu-24 | NCT00515333 | ADAS-cog emasontweni angu-24; ADCS-CGIC, MMSE, ukugeleza kwegazi okulinganiswa nge-SPECT njengemiphumela yesibili | Kwakungekho ukusabela okuphelele okuhambisana nomthamo. Iqembu elincane elinesifo esisezingeni eliphakathi elathola 138 mg/day lathuthuka ngamaphuzu angu-5.4 e-ADAS-cog uma liqhathaniswa ne-placebo (p elungisiwe = 0.047); iziguli ezinesifo esisezingeni elincane azizange ziwohloke kangako lapho zithola i-placebo, ngakho ukuqhathanisa kwakungenakwenzeka; umthamo ophakeme kakhulu wawunezinkinga zokumuncwa |
| TRx237-015, isigaba 3 (LMTM) | 150, 250 mg/day kuqhathaniswa neqembu lokuqhathanisa elathola umuthi osebenzayo ongu-8 mg/day, amasonto angu-65 | NCT01689246 | Ukushintsha kwe-ADAS-Cog ne-ADCS-ADL kuze kube isonto 65, kokubili njengemiphumela eyinhloko | Akuphumelelanga. Imithamo ephakeme ayizange idlule iqembu lokuqhathanisa le-8 mg/day cishe ngalutho kuzo zombili izikali |
| TRx237-005, isigaba 3 (LMTM) | 200 mg/day kuqhathaniswa neqembu lokuqhathanisa elathola umuthi osebenzayo ongu-8 mg/day, amasonto angu-78 | NCT01689233 | ADAS-cog11 ne-ADCS-ADL23 emasontweni angu-78, kokubili njengemiphumela eyinhloko | Akuphumelelanga lapho kuhlaziywa ngokwamaqembu abiwa ngokungahleliwe (ukuwohloka ngamaphuzu e-ADAS-cog angu-+6.41 kuqhathaniswa nangu-+6.27; amandla okwenza imisebenzi ayefana). Inzuzo yabonakala kuphela ekuhlaziyweni kwamaqembu amancane ayethola lo muthi wodwa, ayengabiwanga ngokungahleliwe |
| Lucidity, isigaba 3 (uhlelo lwe-HMTM engu-16 mg/day) | 16 mg/day, 8 mg/day, neqembu lokuqhathanisa elathola i-MTC encane kakhulu, amasonto angu-52 bese kuba ukuqala okubambezelekile kuze kufike emasontweni angu-104 | NCT03446001 | ADAS-cog11 ne-ADCS-ADL23 emasontweni angu-52, kokubili njengemiphumela eyinhloko | Iqembu lokuqhathanisa lafinyelela emazingeni omuthi asebenzayo obekungalindelekile, ngakho ukuqhathanisa okucacile komuthi ne-placebo kwakungenakwenzeka; ukuhlaziya okubikiwe kuncike ekushintsheni kusukela ezingeni lokuqala, ekuqaleni okubambezelekile nasekuqhathaniseni izinkomba zebhayoloji |
Imibhalo eshicilelwe ephelele: umbiko we-Rember wesigaba 2, isivivinyo sokuqala se-LMTM sesigaba 3, ukuhlaziywa kweqoqo lababambiqhaza lesibili lesigaba 3, ukuhlaziywa kabusha kobudlelwano phakathi kwezinga lomuthi emzimbeni nokusabela, kanye nephepha elichaza ukwakhiwa kwe-Lucidity.
Ukufunda umphumela ngamunye ngendlela ababeyiklama ngayo
Qala ngokubheka i-Rember. Yayine-placebo yangempela, okuyinto enhle, kodwa udayi oluhlaza okwesibhakabhaka wenza kube nzima ukufihla ukuthi ubani othola muphi umuthi. Ukushintsha kombala womchamo nendle kungadalula ukuthi ubani othola umuthi osebenzayo, futhi abacwaningi bavuma ukuthi iqembu le-placebo lalingenalo lolo phawu. Bahlukanisa abahloli bokuphepha nabahloli bokusebenza kahle komuthi, base bebhekisela emininingwaneni yezithombe zezokwelapha ukuze basekele imiphumela, kodwa isekhona ingozi ethile yokudaluleka kokwelashwa okwatholwa. Uma ungeza uphawu lwenzuzo olwabonakala eqenjini elincane kuphela kanye nokungaphumeleli komthamo ophakeme kakhulu, isinqumo esithembekile sithi imiphumela iyathakazelisa kodwa ubufakazi bayo abuqinile. Yingakho uhlelo lwadlulela enhlanganiselweni entsha kunokuba lwenze isivivinyo esikhulu se-MTC.
Izivivinyo ezimbili ze-LMTM zesigaba 3 zalungisa inkinga yokufihla ukwelashwa ngenye indlela, zadala inkinga entsha. Ukuze umchamo uhlale ushintshe umbala eqenjini lokuqhathanisa, zombili izivivinyo zanikeza lelo qembu i-LMTM yangempela engu-8 mg/day. Uma i-8 mg/day nayo isebenza, khona-ke ukuqhathanisa umthamo ophakeme neqembu lokuqhathanisa kuwukuqhathanisa izindlela ezimbili zokwelapha, futhi umphumela ongakhombisi mehluko awukwazi ukuhlukanisa ukuthi "zombili ziyasebenza" noma "akukho okusebenzayo." Ukuhlaziya kwakamuva kokusebenzisa lo muthi wodwa nokwamazinga awo egazini kuphakamisa ukuthi umthamo ophansi wawusebenza ngempela, futhi imibhalo yokubuyekeza ephathelene nokuguga ixoxa ngale nkinga yokudlulisela ucwaningo ekusetshenzisweni, kodwa lokho kuhlaziya akusagcini ukwabiwa ngokungahleliwe. Ukuthi isiguli sasithatha i-LMTM yodwa noma kanye nemithi evamile ye-Alzheimer kwakuncike emithini esasivele siyinikezwe, hhayi ekukhethweni ngenhlanhla, ngakho umehluko wokunikezwa kwemithi nowesimo sempilo ekuqaleni ungachaza ingxenye yomehluko wemiphumela. Ucwaningo lobudlelwano phakathi kwezinga lomuthi emzimbeni nokusabela luqinisa incazelo yebhayoloji ngaphandle kokunikeza ukuqhathanisa okushodayo ne-placebo engasebenzi.
I-Lucidity yabe isiphinda le ndlela ngemithamo ephansi. Iqembu lokuqhathanisa lathola imithamo emincane ye-MTC kabili ngesonto, eyayihloselwe ukushintsha umbala womchamo kuphela, kodwa ababambiqhaza abaningi kuleli qembu baqongelela amazinga omuthi ayengaba nomthelela ngokwesayensi yemithi. Umxhasi wakusho ngokusobala ukuthi ukuqhathanisa okwakuhlosiwe ne-placebo engasebenzi kwakungenakwenzeka. Imibiko eyalandela igcizelela umehluko wezinkomba zebhayoloji nowokuqalisa okubambezelekile, okuwusizo ekuqondeni ibhayoloji yesifo kodwa okungafani nokuphumelela uma kuqhathaniswa ne-placebo ngokohlelo olwamiswa kusengaphambili. Ngo-2024 kuya ku-2025 le nhlanganisela yayisacwaningwa, isicelo sokugunyazwa e-UK sesifakiwe, kanti iphepha lezinkomba zebhayoloji eliqinisekisayo lalisadlula ekubuyekezweni ngochwepheshe.
Lokhu kusho ukuthini kumfundi ocabangela i-methylene blue
Kulandela amaphuzu amathathu asebenzisekayo.
Okokuqala, imithi yezivivinyo ayisona isithasiselo. I-HMTM ingusawoti womuthi ohlanziwe, wohlobo olulodwa, onikezwa ngo-8 kuya ku-16 mg/day ohlelweni lwamanje. I-methylene blue esebhodleleni ngokuvamile iyi-chloride esesimweni se-oxidation, enobumsulwa obuhlukahlukene, enikezwa ngomshini wokukhipha amaconsi, futhi enezindlela zokumuncwa nezilinganiso zokungcola ezihlukile. Ukubekezeleleka kwemithamo ephansi ye-HMTM ezivivinyweni akusho lutho ngokuphathelene nokuzinikeza izixazululo zikadayi isikhathi eside.
Okwesibili, izimpawu eziphathelene nokuphepha ezavela ngesikhathi semithamo ephakeme kufanele zithathwe ngokungathí sina nakuba imithamo yamanje iphansi. Ohlelweni olukhulu lwesigaba 3, uhudo lwathinta cishe isiguli esisodwa kwezine ezazithola imithamo ephakeme, kanti isicanucanu, ukuhlanza nesidingo esiphuthumayo sokuchama nakho kwanda ngokusobala. Abantu abanesimo sokuntuleka kwe-G6PD abazange bafakwe ezivivinyweni ngoba imithi ye-methylthioninium ingabangela ukubhidlika kwamangqamuzana egazi abomvu kuleli qembu. Ukusebenzisana kwayo nemithi yokudangala ethinta i-serotonin kuyinto yangempela ngokwesayensi yemithi, njengoba i-methylene blue iyisivimbeli esinamandla se-MAO-A esisebenza ngendlela ehlehlisekayo, nakuba izivivinyo ze-Alzheimer zaqopha izimpawu zesikhashana kuphela kubasebenzisi abambalwa be-SSRI, hhayi i-serotonin syndrome eqinisekisiwe. Noma ubani ohlanganisa le mithi udinga ukuqashwa uchwepheshe wezokwelapha, okuyiphuzu elichazwa kabanzi kumhlahlandlela wokuphepha nokusebenzisana kwemithi.
Okwesithathu, gcina okulindele kuhambisana nesigaba ubufakazi obukuso. Uphawu lwenzuzo eqenjini elincane, kanye nokuqhathanisa okubili okwabiwe ngokungahleliwe okungaphumelelanga, kanye neqembu lokuqhathanisa elinezici ezidida imiphumela, kwakha umbono ocwaningwayo, hhayi isincomo sokwelashwa. Imindeni ecabangela izindlela ezikhona izothola ulwazi olungasetshenziswa kakhulu endleleni izinqumo zokunakekelwa kwe-Alzheimer ezenziwa ngayo empeleni kunakunoma yiluphi uhlelo lokusebenzisa udayi olusabalala ku-inthanethi.
Isiphetho silula ngokwanele ukuba sishiwo ngomusho owodwa. I-methylene blue esesimweni se-oxidation yaveza uphawu olulodwa lwenzuzo esigabeni 2 olwalungenabo ubufakazi obuqinile futhi lwalunezixwayiso mayelana nokufihla ukwelashwa nokumuncwa, uhlobo olwayilandela olusesimweni se-reduction aluphumelelanga ekuqhathanisweni kwemithamo okubili okwabiwe ngokungahleliwe, futhi uhlelo lwemithamo ephansi alukakavezi ukuphumelela okucacile esivivinyweni esineqembu le-placebo. Lokho kungase kushintshe ngemibhalo ezoshicilelwa esikhathini esizayo noma ngokubuyekezwa yiziphathimandla ezilawula imithi. Kuze kwenzeke lokho, i-methylene blue yesifo i-Alzheimer isesigabeni sesayensi ebalulekile engakabi umuthi wokwelapha.