Inqaku
I-methylene blue nesifo se-Alzheimer: ukutolika izilingo
Xa ukhangela i-methylene blue nesifo se-Alzheimer, ufumana amabali amabini ngaxeshanye. Elinye lithi idayi eluhlaza okwesibhakabhaka eneminyaka elikhulu ikhona yacothisa ukulahleka kwenkumbulo. Elinye lithi izilingo ezalandelayo aziphumelelanga. Omabini la mabali acaphula amaphepha ophando okwenene. Ukubhideka kuvela ekuthatheni iikhompawundi ezahlukeneyo njengechiza elinye.
Azilochiza elinye. Isilingo sokuqala savavanya i-methylthioninium chloride ekwimo ene-oxidation, ikhompawundi eqhelekileyo eluhlaza okwesibhakabhaka. Zonke izilingo ze-Alzheimer ezalandelayo zavavanya imo encitshisiweyo yazinziswa, i-leuco-methylthioninium, ngoku ebizwa ngokuba yi-hydromethylthionine mesylate (HMTM). Iidosi, ukufunxwa, kwanamaqela olawulo ayahluka phakathi kwezi nkqubo zimbini. Xa uzigcina zahlukene ezi khompawundi, imbali yezilingo iyacaca, kwaye ayikhokeleli ekusetyenzisweni kwezongezelelo.
Iikhompawundi ezimbini
I-methylene blue esebhotileni idla ngokuba yi-methylthioninium chloride, eshunqulelwa ngokuthi MTC. Inxalenye yayo esebenzayo yi-ion ye-methylthioninium ekwimo ene-oxidation, i-MT+, imolekyuli enentlawulo yombane neluhlaza okwesibhakabhaka ngokunzulu. Intlawulo yombane iyingxaki ebonakalayo emathunjini. Ukuze i-MT+ ikwazi ukuwela udonga lwamathumbu kakuhle, kufuneka kuqala incitshiswe ibe yimo ye-leuco engenantlawulo yombane nengenambala. Eli nyathelo lokuncitshiswa liyaguquguquka, kwaye kwiidosi eziphezulu ukunyibilika nokufunxwa kwe-MTC kuthintelwa bubungakanani bedosi, nto leyo eyenye yezizathu zokuba inkqubo yokuqala ye-Alzheimer ihlangabezane neengxaki zokwenziwa kwechiza.
Ichiza elalandelayo liyaliphepha elo nyathelo. I-LMTM, ekwanekhowudi ethi TRx0237 nengoku edla ngokubizwa ngokuba yi-HMTM, inikezela ngemolekyuli encitshisiweyo ngokuthe ngqo njengetyuwa ye-mesylate ezinzileyo eyikristale. I-methylthioninium encitshisiweyo ekhululekileyo ibuyela kwimo ene-oxidation neluhlaza okwesibhakabhaka kwimizuzu embalwa xa isemoyeni, ngoko imo yetyuwa yiyo eyenza ibe liyeza elinokugcinwa kunokuba ibe yinto enomdla kuphela elabhoratri. Ngamafutshane: i-MTC yikhompawundi eluhlaza okwesibhakabhaka ekwimo ene-oxidation, eguqulelwa emzimbeni ibe lichiza elisebenzayo, kodwa enokufunxwa okungalinganiyo; i-LMTM/HMTM yona yimo encitshisiweyo yazinziswa, eyenzelwe ukuba ubungakanani bechiza elifumaneka emzimbeni buqikeleleke. Amabango okusebenza yenye awasebenzi ngokuzenzekelayo kwenye, kwaye awasebenzi nakwizinyibiliko zedayi ezithengiswa ngaphandle komyalelo kagqirha. Kufanelekile ukuqonda ikhemistri yezi mo zine-oxidation nezincitshisiweyo ngaphambi kokufunda nasiphi na isihloko seendaba ngesilingo.
Indlela yokusebenza evavanywayo nayo icuthene ngakumbi kunokuba iingxelo zamajelo eendaba zibonisa. Le nkqubo ijolise ekudibaneni kwe-tau, oko kukuthi ukuhlanganisana kweprotheyini ye-tau ibe yimisonto namaqhina ngaphakathi kwiiseli zemithambo-luvo, kunokuba ijolise kumacwecwe e-amyloid. Loo nto iyenza ibe yindlela eyahlukileyo kweyezilwa-buhlungu ezijolise kwi-amyloid, kwaye ihamba kunye nomsebenzi owahlukileyo waphambi kwezilingo ebantwini ophonononga iindlela zokususwa kwe-amyloid kunye nophononongo olubanzi lweengcamango nge-mitochondria nokukhuselwa kweeseli zemithambo-luvo, ekungafanele kuthathwe njengobungqina bezilingo ebantwini.
Ikhompawundi kwisilingo ngasinye
Le yitheyibhile ekufuneka uyigcine ukuze ubuyele kuyo. Umqolo ngamnye uchaza ikhompawundi kanye, iidosi, imilinganiselo yeziphumo, nesazisi sesilingo, kuba ezo nkcukacha zezona zidla ngokugqwethwa zizishwankathelo.
| Isilingo (ikhompawundi) | Iidosi ezavavanywayo | Isazisi sesilingo | Imilinganiselo ephambili yeziphumo | Isiphumo sokwabiwa ngokungakhethiyo |
|---|---|---|---|---|
| Rember, isigaba 2 (MTC, i-methylene blue ekwimo ene-oxidation) | 69, 138, 228 mg/day ezilingana ne-MT xa zithelekiswa ne-placebo, iiveki ezingama-24 | NCT00515333 | ADAS-cog kwiiveki ezingama-24; ADCS-CGIC, MMSE, ukuhamba kwegazi nge-SPECT njengemilinganiselo yesibini | Akukho mpendulo ngokwedosi xa kujongwa zonke iziphumo. Iqela elincinane elinesifo esiphakathi elifumana i-138 mg/day laphucuka ngamanqaku ayi-5.4 e-ADAS-cog xa lithelekiswa ne-placebo (p elungisiweyo = 0.047); izigulana ezinesifo esingekaqini azizange zehle kangako kwi-placebo, ngoko ukuthelekisa kwakungenakwenzeka; eyona dosi iphezulu yayineengxaki zokufunxwa |
| TRx237-015, isigaba 3 (LMTM) | 150, 250 mg/day xa zithelekiswa nolawulo olunechiza elisebenzayo le-8 mg/day, iiveki ezingama-65 | NCT01689246 | Utshintsho kwimilinganiselo ephambili emibini, i-ADAS-Cog ne-ADCS-ADL, ukuya kwiveki yama-65 | Ayiphumelelanga. Iidosi eziphezulu phantse azizange zilugqithe ulawulo lwe-8 mg/day nakowuphi na umlinganiselo |
| TRx237-005, isigaba 3 (LMTM) | 200 mg/day xa ithelekiswa nolawulo olunechiza elisebenzayo le-8 mg/day, iiveki ezingama-78 | NCT01689233 | Imilinganiselo ephambili emibini, i-ADAS-cog11 ne-ADCS-ADL23, kwiiveki ezingama-78 | Ayiphumelelanga ngokwamaqela abelwe ngokungakhethiyo (ukwehla ngamanqaku e-ADAS-cog ayi-+6.41 xa kuthelekiswa ne-+6.27; amandla okwenza imisebenzi ayefana). Inzuzo yavela kuphela kuhlalutyo lwamaqela amancinane afumana eli chiza lodwa nangazange abelwe ngokungakhethiyo |
| Lucidity, isigaba 3 (inkqubo ye-HMTM 16 mg/day) | 16 mg/day, 8 mg/day, nolawulo olune-MTC encinane kakhulu, iiveki ezingama-52 kunye nokuqalisa okulibazisiweyo ukuya kwiiveki ezili-104 | NCT03446001 | Imilinganiselo ephambili emibini, i-ADAS-cog11 ne-ADCS-ADL23, kwiiveki ezingama-52 | Iqela lolawulo lafikelela kumanqanaba echiza asebenzayo ngokungalindelekanga, ngoko ukuthelekisa ichiza ne-placebo ngaphandle kokudideka kwakungenakwenzeka; uhlalutyo oluxeliweyo luxhomekeke kutshintsho ukusuka kwinqanaba lokuqala, ekuqaliseni okulibazisiweyo, nasekuthelekisweni kweziphawuli zebhayoloji |
Upapasho olupheleleyo: ingxelo yesigaba 2 se-Rember, isilingo sokuqala se-LMTM sesigaba 3, uhlalutyo lweqela lesilingo sesibini sesigaba 3, uhlalutyo oluphindwayo lobudlelwane phakathi kobungakanani bechiza emzimbeni nempendulo, kunye nephepha elichaza uyilo lwe-Lucidity.
Ukufunda isiphumo ngasinye ngendlela abaza kuyifunda ngayo abayili bezilingo
Qala nge-Rember. Yayine-placebo yokwenene, nto leyo ilungileyo, kodwa idayi eluhlaza okwesibhakabhaka yenza kube nzima ukufihla ukuba ngubani ofumana oluphi unyango. Ukutshintsha kombala womchamo nelindle kunokubonisa ukuba ngubani othatha ichiza elisebenzayo, kwaye abaphandi bavuma ukuba iqela le-placebo lalingenalo olo phawu. Babahlula abavavanyi bokhuseleko nabavavanyi bokusebenza kwechiza baza babhekisa kwidatha yemifanekiso yezonyango ukuxhasa iziphumo, kodwa kusekho umngcipheko wokutyhileka konyango olufunyanwayo. Xa udibanisa oku nomqondiso owabonakala kuphela kwiqela elincinane kunye neyona dosi iphezulu engaphumelelanga, isigwebo esinyanisekileyo sesokuba iziphumo zinomdla kodwa azomelelanga. Yiyo loo nto inkqubo yatshintshela kwikhompawundi entsha endaweni yesilingo esikhulu ngakumbi se-MTC.
Izilingo ezimbini ze-LMTM zesigaba 3 zalungisa ingxaki yokufihla unyango ngenye indlela zaza zadala ingxaki entsha. Ukuze umchamo uqhubeke utshintsha umbala kwiqela lolawulo, zombini izilingo zanika elo qela i-8 mg/day ye-LMTM yokwenene. Ukuba i-8 mg/day nayo iyasebenza, ukuthelekisa idosi ephezulu nolawulo kuthelekisa unyango ezimbini, kwaye isiphumo esingabonisi mahluko asinakwahlula phakathi kokuthi "zombini ziyasebenza" nokuthi "akukho nanye esebenzayo." Uhlalutyo olwenziwa kamva lokusetyenziswa kwechiza lodwa nolwamanqanaba echiza egazini luthi idosi ephantsi yayisebenza ngokwenene, kwaye uncwadi lophononongo lokwaluphala luxoxa ngale ngxaki yokuguqulela iziphumo zophando ekusetyenzisweni, kodwa olo hlalutyo alusagcini ukwabiwa ngokungakhethiyo. Ukuba isigulana sasithatha i-LMTM yodwa okanye kunye namachiza aqhelekileyo e-Alzheimer kwakuxhomekeke kumayeza esasisele siwamiselweyo, kungekhona ekwabiweni ngokungakhethiyo, ngoko umahluko ekumiseleni amayeza nakwimpilo ekuqaleni unokuchaza inxalenye yomahluko weziphumo. Umsebenzi ophonononga ubudlelwane phakathi kobungakanani bechiza emzimbeni nempendulo womeleza ingcaciso yebhayoloji ngaphandle kokubonelela ngothelekiso olungekhoyo ne-placebo engasebenziyo.
I-Lucidity yaphinda le ndlela kwiidosi eziphantsi. Ulawulo lwaluneedosi ezincinane ze-MTC ezinikwa kabini ngeveki, ezazenzelwe kuphela ukufaka umbala kumchamo, kodwa abathathi-nxaxheba abaninzi kwiqela lolawulo baqokelela amanqanaba echiza anokusebenza emzimbeni. Umxhasi wachaza ngokucacileyo ukuba uthelekiso olucetyiweyo ne-placebo engasebenziyo lwalungenakwenziwa. Iingxelo ezalandelayo zigxininisa umahluko kwizi phawuli zebhayoloji nasekuqaliseni okulibazisiweyo, nto leyo enika ulwazi ngebhayoloji yesifo kodwa ayifani nokuphumelela ngokuchasene ne-placebo kwisilingo esicwangciswe kwangaphambili. Ukususela ngo-2024 ukuya ku-2025 le khompawundi yayisaphandwa, isicelo semvume e-UK sasingenisiwe, kwaye iphepha lokuqinisekisa iziphawuli zebhayoloji lalisaphantsi kovavanyo lwezinye iingcali.
Oko kuthethwa koku kumfundi ocinga ngokusebenzisa i-methylene blue
Oku kukhokelela kumanqaku amathathu asebenzisekayo.
Okokuqala, amachiza ezilingo akasiso isongezelelo. I-HMTM yityuwa yamayeza ecocekileyo ekwimo enye, enikwa ngeedosi ze-8 ukuya kwi-16 mg/day kwinkqubo yangoku. I-methylene blue esebhotileni idla ngokuba yi-chloride ekwimo ene-oxidation, enobunyulu obahlukeneyo, inikwe ngesixhobo samathontsi, yaye yahluke ekufunxweni nakwiintlobo zobumdaka obukuyo. Ukunyamezeleka kwechiza kwizilingo ze-HMTM ezineedosi eziphantsi akuthethi nto ngokuzinika izinyibiliko zedayi ixesha elide.
Okwesibini, iimpawu zomngcipheko wokhuseleko zexesha leedosisi eziphezulu kufuneka zithathelwe ingqalelo nangona iidosi zangoku ziphantsi. Kwinkqubo enkulu yesigaba 3, urhudo lwachaphazela malunga nesigulana esinye kwezine ezazifumana idosi ephezulu, kwaye isicaphucaphu, ukugabha, nemfuneko engxamisekileyo yokuchama nazo zanda ngokucacileyo. Abantu abaswele i-G6PD babengafakwanga kuba amachiza e-methylthioninium anokubangela ukophuka kweeseli ezibomvu zegazi kweli qela. Ukusebenzisana kwawo namachiza okudakumba achaphazela i-serotonin kuyinyani ngokwendlela amayeza asebenza ngayo emzimbeni, kuba i-methylene blue sisithinteli esinamandla se-MAO-A esisebenza ngendlela enokubuyiselwa umva, nangona izilingo ze-Alzheimer zabhala kuphela iimpawu zexeshana kubasebenzisi abambalwa be-SSRI kunokuba ziqinisekise isindromu ye-serotonin. Nabani na odibanisa la machiza kufuneka abekwe esweni yingcali yezonyango, nto leyo echazwe ngakumbi kwisikhokelo sokhuseleko nokusebenzisana kwamachiza.
Okwesithathu, lindela iziphumo ngokomgangatho wobungqina obukhoyo. Umqondiso kwiqela elincinane, kunye nothelekiso olubini olwabelwe ngokungakhethiyo nolungaphumelelanga, kunye neqela lolawulo elinezinto ezidida iziphumo, yingcamango yophando, hayi isincomo sonyango. Iintsapho ezivavanya iindlela ezinokukhethwa ziya kufumana ulwazi olunokusetyenziswa ngakumbi kwindlela ezenziwa ngayo ngenene izigqibo zokhathalelo lwe-Alzheimer kunakuyo nayiphi na inkqubo yokusebenzisa idayi esasazwa kwi-intanethi.
Isishwankathelo silula ngokwaneleyo ukuba singachazwa ngesivakalisi esinye. I-methylene blue ekwimo ene-oxidation yavelisa umqondiso omnye ongomelelanga kwisigaba 2, onezilumkiso malunga nokufihla unyango nokufunxwa kwechiza; ikhompawundi encitshisiweyo eyayilandela ayiphumelelanga kuthelekiso olubini lweedosi olwabelwe ngokungakhethiyo; kwaye inkqubo yeedosi eziphantsi ayikavelisi ukuphumelela okucacileyo kwisilingo esinolawulo lwe-placebo. Oko kungatshintsha ngopapasho lwexesha elizayo okanye ngophononongo lwabasemagunyeni abalawula amayeza. De kube njalo, i-methylene blue yesifo se-Alzheimer ikudidi lwenzululwazi enzulu engekabi liyeza.