Shuɗin methylene da ALS: dalilin bambancin sakamako a samfuran gwaji

Idan ka bincika shuɗin methylene da ALS, za ka ga da'awoyi biyu da suke kamar suna saɓa wa juna. Ɗaya ta ce wannan rini mai shuɗi ya kare ƙwayoyin jijiyoyi a samfuran ALS. Ɗayar kuma ta ce bai yi komai ba a linzamin gwajin ALS. Dukansu suna ambaton takardun bincike na gaske, kuma duk takardun sun cancanci a ɗauke su da muhimmanci. Saɓanin ya gushe da zarar an bayyana manufar kowane gwaji: samfurin gwajin ne yake ƙayyade abin da za a iya da'awa.

Sakamakon da aka samu a tsutsa da'awa ce game da tsutsa. Sakamakon da aka samu a ɗan kifi da'awa ce game da ɗan kifi. Babu ɗaya da yake zama da'awa game da marar lafiya sai binciken tafiyar cuta a dabba mai shayarwa ya goyi bayan hakan. Wannan maƙala tana kwatanta takardun biyu da aka fi ambato domin ka ga dalilin bambancin amsoshinsu.

Gwaje-gwajen biyu a jadawali ɗaya

Ka riƙe wannan jadawalin a buɗe yayin karatu. Ya ƙunshi dukkan muhimman bambance-bambancen binciken biyu.

Halittar gado ta bambanta, nau'in halittar gwaji ya bambanta, hanyar ba da magani ta bambanta, lokacin farawa ya bambanta, ma'aunan sakamako kuma sun bambanta. Tsarin halittar gado ɗaya ne kawai cikin bambance-bambancen guda biyar, don haka waɗannan binciken biyu ba za su iya tabbatar da cewa shuɗin methylene yana aiki ne musamman a wata hanyar ALS guda ɗaya ba. Suna tabbatar da wani abu mafi takaita amma har yanzu mai amfani: babban ingantawa da aka samu ta hanyar bayyana kai tsaye ga sinadarin tun da wuri a samfura masu sauƙi bai bayyana ba a gwajin tafiyar cuta na dabba mai shayarwa da aka ba ta maganin ta baki na dogon lokaci.

Sakamakon ingantawa: abin da binciken tsutsotsi da kifaye ya nuna

Binciken tsutsotsi da kifaye na 2012 ya sa ƙwayoyin jijiyoyin motsi na tsutsotsi suka samar da TDP-43 ko FUS na ɗan Adam da ya sauya, sannan ya yi allurar mRNA na ɗan Adam da ya sauya cikin amfrayon kifaye. Waɗannan samfura ne na gubar furotin. Suna kwaikwayon illar furotin da ya sauya ga motsi da siffar ƙwayoyin jijiyoyi cikin kwanaki, ba cikakkiyar tafiyar ALS a manyan mutane cikin shekaru ba.

An fara amfani da maganin tun da wuri sosai. Tsutsotsin sun girma a kan agar mai ɗauke da shuɗin methylene tun daga ƙyanƙyashewa. An bar amfrayon kifaye cikin ruwan magani tsawon dare, daga sa'o'i 24 bayan haɗuwar ƙwayoyin haihuwa, sannan aka gwada halayensu bayan kusan kwana biyu. Babu shingen jini da ƙwaƙwalwa tsakanin maganin da ƙwayoyin jijiyoyi kamar yadda yake a dabba mai shayarwa, kuma ba a auna matakin maganin a plasma ko ƙwaƙwalwa ba.

A ƙarƙashin waɗannan yanayi, tasirin ya kasance babba kuma mai daidaito. Duk 6 da 60 μM sun rage shanyewar jiki mai ƙaruwa da shekaru a tsutsotsin TDP-43 da FUS. A ranar 12 bayan balaga, kusan kashi 80 na tsutsotsin TDP-43 da ba a ba su magani ba sun shanye, idan aka kwatanta da kusan kashi 10 na waɗanda aka fara ba su magani tun daga ƙyanƙyashewa. Gwajin haɗin ƙwayoyin jijiyoyi ya nuna irin wannan sakamako: tsutsotsin TDP-43 suna da matuƙar saurin amsawa ga aldicarb, wani magani da ake amfani da shi wajen bincika isar da saƙo tsakanin jijiyoyi da tsokoki, kuma shuɗin methylene ya mayar da amsar kusa da yadda take a al'ada. Yawan rassan ƙwayoyin jijiyoyin motsi da suke lalacewa ya ragu, kuma tasirin ya fi bayyana a 60 μM. A kifaye, ninkayar da taɓawa take tayarwa ta inganta sosai, kuma axon na motsi da suka gajarta sun sake girma zuwa kusa da tsawon al'ada a 30 ko 60 μM, duk da cewa ingantawar ba ta cika ba.

Bayanan damuwar oksidatif sun dace da fassarar cewa akwai tasirin kariya daga oksideshin. Tsutsotsi da kifaye masu sauyin halittar gado sun nuna ƙaruwar ma'aunan nau'ikan oxygen masu saurin shiga mu'amalar sinadarai, waɗanda suka ragu bayan amfani da maganin. Haka kuma, tsutsotsi na al'ada da aka ba shuɗin methylene sun rayu na tsawon lokaci sosai bayan gwajin fallasa su ga abin da ke ƙara oksideshin, fiye da tsutsotsin da ba a ba magani ba. Amma akwai iyakoki biyu masu muhimmanci. Jimillar matakan furotin TDP-43 da FUS da suka sauya ba ta ragu ba, kuma binciken bai auna tarin furotin kai tsaye ba. Don haka ya nuna ingantawar aiki ba tare da tabbatar da kawar da tarin furotin ba. Duk mai bibiyar yadda ake bayyana hasashen redox da mitochondria ya kamata ya ɗauki wannan hanyar aiki a matsayin wadda ke da goyon bayan shaida, amma ba wadda aka tabbatar gaba ɗaya ba.

Lokacin farawa shi ne mafi bayyana darasin binciken. Lokacin da marubutan suka jira har ranar 5 bayan balaga kafin fara magani, adadin shanyewar jiki a ranar 12 ya kasance kusan kashi 55, maimakon kusan kashi 10 da aka samu lokacin da aka fara maganin daga ƙyanƙyashewa. Magani ɗaya, tsutsa ɗaya, sauyin halittar gado ɗaya, amma tasiri mafi ƙanƙanta sosai. Bayyana ga sinadarin tun da wuri da nufin rigakafi ne ya samar da mafi yawan amfanin da aka gani.

Sakamakon rashin ingantawa: abin da binciken linzayen SOD1 ya nuna

Binciken linzaye na 2011 ya yi tambaya mafi wahala a tsarin gwaji mafi tsauri. Linzayen SOD1 G93A masu tushen halittar gado iri ɗaya suna ci gaba daga rawar ƙafafun baya zuwa matsalar tafiya da rasa martanin juyawa su koma daidai, har zuwa wani matakin ƙarshe da aka ƙayyade tun farko. An fara maganin kafin bayyanar alamomi a ranar 45, aka ci gaba kullum, yayin da masu lura suke tantance yanayin jijiyoyi a ma'aunin 0 zuwa 6. Wannan gwaji ne na cikakkiyar tafiyar cuta, wanda ya fi kusanci da abin da marar lafiya zai damu da shi fiye da kowane jadawalin shanyewar jiki a tsutsa.

Manyan sakamakon ba su nuna bambanci mai muhimmanci ba. Fara cuta gaba ɗaya ya zo a kwanaki 121 ga rukunin kwatanci, idan aka kwatanta da kwanaki 124 ga waɗanda aka ba shuɗin methylene; wannan bambancin bai da muhimmancin ƙididdiga. Rayuwa har zuwa matakin ƙarshe ta kasance kwanaki 167 idan aka kwatanta da kwanaki 170, wanda shi ma bai da muhimmancin ƙididdiga. Wasu ƙananan sakamako na biyu sun fi karkata ga maganin: linzaye mata sun nuna jinkirin fara cuta na kusan kwana 7, kuma dabbobin da aka ba magani sun ɗan fi daɗewa a matakai marasa tsanani, suka kuma yi ƙasa da lokaci a matakai masu tsanani. Saboda ƙananan rukunonin da aka raba bisa jinsi da kuma yawan kwatanta matakai, waɗannan sakamakon sun fi zama tushen sabon hasashe maimakon hujjar tabbatarwa. Ba a ƙidaya ƙwayoyin jijiyoyi ba, ba a yi gwajin taruwar SOD1 ba, kuma ba a auna alamomin oksideshin ko kumburin martanin jiki ba. Saboda haka, binciken ba zai iya cewa maganin ya kai inda aka nufa amma ya kasa aiki, ko kuwa bai taɓa yin tasiri a wuraren da aka nufa ba a wannan adadi. Adadin magani guda ɗaya kawai aka gwada.

Marubutan da kansu sun nuna mafi girman iyakar binciken, wadda ta shafi fassarar sakamako a duk ɓangarorin biyu. Samfurin SOD1 G93A mai kwafe masu yawa yana kwaikwayon cutar gubar SOD1 da kyau, amma cutar SOD1 ƙaramin ɓangare ce na ALS na gado a iyali, kuma yanayin halittarta ya bambanta da mafi yawan ALS da ke faruwa ba tare da tarihin gado a iyali ba. Sun ba da shawarar sake gwada sinadaran da ake bincika a samfuran dabbobi masu shayarwa da suka dogara da TDP-43. Tun daga lokacin, wannan shawarar ta ƙara rikitarwa, saboda marubutan binciken tsutsotsi da kifaye sun lura cewa wani bincike daban na shuɗin methylene a linzayen TDP-43 shi ma bai inganta sakamakon motsi ba. Saboda haka, sinadari zai iya nuna tasiri mai ƙarfi a wani tsarin TDP-43 amma ya kasa nuna tasiri a wani tsarin TDP-43. Tsarin gwajin yana da muhimmanci kamar ƙwayar gado.

Dalilin da ya sa ingantawa a tsutsa ko kifi ba zai tabbatar da amfani ga marasa lafiya ba

Ka ɗauki kowane samfurin gwaji a matsayin mai amsa wata tambaya dabam.

Na farko, yanayin halitta ya bambanta. TDP-43 da FUS furotin ne masu ɗaurewa da nucleic acid, kuma suna da mu'amalolin halittar gado da suke tarayya a waɗannan tsare-tsare masu sauƙi. Gubar SOD1 kuwa tana aiki ta hanyoyin farko da suka bambanta a wani ɓangare. Maganin da yake rage wata damuwa ta gubar furotin ba lallai ya rage ɗayar ba. Nasara kan samar da furotin fiye da kima a amfrayo kuma ba lallai ta hasashen nasara kan lalacewar jijiyoyi sannu a hankali a babba ba, inda akwai kumburin martanin jiki, shigar ƙwayoyin glia, da tabarbarewar jiki gaba ɗaya.

Na biyu, yadda ake bayyana ga sinadarin ya bambanta. Ci gaba da jiƙawa a matakan micromolar ba daidai yake da ba da magani ta baki ba. Shigar magani daga hanji, sarrafa shi a wucewarsa ta farko, ɗaurewarsa da furotin na plasma, shigarsa ƙwaƙwalwa, da cire shi daga jiki duk suna tsakanin maganin da aka haɗiye da ƙwayar jijiyar motsi ta lakar ƙashin baya. Babu ɗaya daga cikin binciken da ya auna matakan magani a tsarin jijiyoyi, don haka babu wanda zai iya danganta matakin sinadarinsa da na ɗayan.

Na uku, lokacin farawa ya bambanta. Amfanin da aka gani a tsutsotsi da kifaye ya dogara sosai da fara magani kafin sauye-sauyen cuta su taru. An kuma fara maganin linzaye kafin bayyanar alamomi, wanda ƙarfi ne na binciken. Amma ga mutane, kusan ko da yaushe za a fara magani bayan bayyanar alamomi, wato a wani lokaci mafi jinkiri. Alamar tasirin rigakafi a gwajin amfrayo na kwana biyu mafarin bincike ce, ba samfurin amfani da magani a asibiti ba.

Na huɗu, ma'aunan sakamako sun bambanta. Shanyewar jiki a kwanaki 12, saurin amsawa ga aldicarb, tsawon axon a micrometers, da nisan ninkaya duk halaye ne na kusa da tasirin farko. Fara cuta da tsawon rayuwa a dabba mai shayarwa suna haɗa dukkan hanyoyin daidaitawa da abubuwan da ke rikitar da yanayi a jiki. Sau da yawa magunguna suna sauya ma'aunan tasirin farko ba tare da sauya tsawon rayuwa ba. Wannan ne ya sa ake amfani da ma'aunan lokacin zuwa aukuwar wani lamari a dabbobi masu shayarwa.

Masu karatu da suke son jerin abubuwan dubawa don labarin bincike na gaba za su iya aro daga yadda ake karanta binciken da ake yi kafin gwajin asibiti: tambayi nau'in halittar gwaji, ƙwayar gadon da aka shigar, adadin magani da hanyar ba da shi, ko an auna matakan maganin, lokacin fara amfani da shi idan aka kwatanta da faruwar sauye-sauyen cuta, ko ma'aunin sakamakon hali ne na ɗan gajeren lokaci ko tafiyar cuta, da kuma ko wani dakin gwaje-gwaje na biyu ya maimaita tasirin. Tarin shaidun shuɗin methylene a mutane shi ne wurin da ya kamata a duba ko ɗaya daga cikin waɗannan alamomin farko ya bunƙasa zuwa bayanan gwajin asibiti.

Abin da wannan yake nufi ga marasa lafiya da iyalai

Waɗannan takardun ba su samar da wata tabbatacciyar ƙa'idar amfani da shuɗin methylene ga ALS ba. Binciken da ya nuna ingantawa yana goyon bayan ƙarin bincike kan hanyoyin oksideshin da haɗin ƙwayoyin jijiyoyi a yanayin halittar TDP-43 da FUS. Binciken da bai nuna ingantawa ba yana rage goyon bayan tsammanin sauya tafiyar cuta ta amfani da magani ta baki na dogon lokaci, a wannan matakin bayyana ga sinadarin, a cuta irin ta SOD1. A tare, suna bayyana rashin daidaiton sakamako tsakanin samfuran gwaji, ba shawarar jiyya ba.

Ya kamata a tattauna aminci da irin natsuwa da taka-tsantsan da ake tattauna tasirin magani. Binciken ALS a linzaye bai nuna adadin magani mai aminci ga mutane ba. Haka kuma, shuɗin methylene yana da haɗurra na gaske ta hanyar lalacewar jajayen ƙwayoyin jini ga masu ƙarancin G6PD da kuma gubar serotonin idan aka haɗa shi da magungunan da suke shafar serotonin. Zargin ƙarancin G6PD, amfani da magungunan rage baƙin ciki a halin yanzu, da duk wani canjin magani da ake shirin yi abubuwa ne da ya kamata a tattauna da ƙwararren ma'aikacin lafiya. Haka kuma, ya kamata a duba bayanan aminci na shuɗin methylene gaba ɗaya kafin wani ya ɗauki mataki bisa kanun labaran gwaje-gwaje.

A takaice, za a iya bayyana ma'anar a jimla ɗaya. Shuɗin methylene ya samar da ingantawa mai ƙarfi bayan bayyana ga sinadarin tun da wuri a halayen samfuran tsutsotsi da ƙananan kifaye na TDP-43 da FUS, amma kusan babu amfani wajen jinkirta fara cuta ko tsawaita rayuwa a binciken linzayen SOD1 da aka ba maganin ta baki na dogon lokaci; don haka fassarar gaskiya ita ce shaida mai dogaro da samfurin gwaji, wadda ba ta goyon bayan amfani da shi ga marasa lafiya.