Shuɗin Methylene da Cutar Bipolar: Nazarin Binciken Asibiti

Taƙaitaccen bayani

An daɗe ana nazarin shuɗin methylene kan cutar bipolar fiye da yadda yawancin mutane suka sani, tun daga shekarun 1970s lokacin da masu bincike suka nemi madadin lithium da magungunan da za a haɗa da shi. Jimillar shaidun binciken kaɗan ce: jerin bayanan marasa lafiya guda ɗaya da ba a ɓoye maganin da aka bayar ba, tsofaffin gwaje-gwaje guda biyu masu rukunin kwatance, da binciken zamani guda ɗaya na musayar jiyya da aka rarraba mahalarta ba-zata. Abin da ya bayyana iri ɗaya a dukansu shi ne sauƙin alamomin baƙin ciki da waɗanda suka rage bayan jiyya lokacin da aka ƙara shuɗin methylene ga jiyyar da ake yi. Babu binciken da ya nuna tasirin rage mania, kuma babu wanda ya nuna wata bayyananniyar alamar sauyawa zuwa mania, duk da cewa adadin mahalartan ya yi ƙanƙanta ƙwarai don warware wannan tambaya. Duk wanda ke tantance wannan sinadari ya kamata ya karanta waɗannan a matsayin binciken ƙarin jiyya, ba shaidar amfani da shi shi kaɗai ba, kuma ya auna gargaɗin hulɗarsa da wasu magunguna kafin yanke wani hukuncin amfani da shi a aikace.

Dalilin da ya sa cutar bipolar ta jawo hankali tun da wuri

Dalilin binciken ba wai shuɗin methylene ya yi kama da maganin daidaita yanayi na al'ada ba ne. Tsarinsa yana kama da na phenothiazines, kuma masu binciken farko sun yi hasashen cewa zai iya mayar da vanadate da ke cikin ruwan jini zuwa wani nau'i mai ƙarancin aiki, ta haka ya canza aikin sodium-potassium ATPase da aka danganta da sauyin yanayi mai maimaituwa. Don gwada wannan ra'ayi, Naylor da abokan aikinsa sun yi wa marasa lafiya biyu masu ci gaba da sauyawar yanayi jiyya, suka ga tsawon lokutan da yanayinsu ya kasance daidai; wannan ya ƙarfafa duk binciken da ya biyo baya. Bayanin tarihi na Howland game da shuɗin methylene a fannin tabin hankali ya bayyana mahallin wannan aikin, yana bin diddigin sinadarin daga abin da ake ƙera phenothiazine da shi zuwa sinadarin gwaji mai tasiri ga tunani da yanayi.

Binciken hanyoyin aikinsa da aka yi daga baya ya sake kafa dalilin nazarinsa bisa aikin mitochondria da daidaiton redox. An danganta matsalar aikin mitochondria da cutar bipolar ta hanyar binciken iyalai, sakamakon binciken yadda kwayoyin gado ke aiki bayan mutuwa, da samfurorin dabbobi kamar bera mai sauyin kwayar gado ta POLG1, wanda halayensa masu kama da bipolar suke amsawa wani ɓangare ga lithium. Bitar Alda ta 2019 kan shuɗin methylene a cututtukan jijiyoyi da tabin hankali ta bayyana cewa ikon sinadarin na jigilar electrons su wuce wuraren da suka toshe a sarkar jigilar electrons, tare da rage zubar nau'ikan oxygen masu saurin yin hulɗar sinadarai, ya sa yake da amfani wajen gwada ra'ayoyi a matsayin mai sauya aikin mitochondria. Wata bita kan shuɗin methylene a matsayin sinadarin da zai iya zama maganin baƙin ciki ta ƙara hana aikin MAO-A, toshe aikin nitric oxide synthase da guanylate cyclase, da tasirin rage kumburi ga bayanin hanyoyin aikinsa. Sai dai hanyoyin aiki hasashe ne. Tambayar asibiti ita ce abin da gwaje-gwajen suka auna, da kuma yanayin da aka yi hakan.

Gwaje-gwajen, ɗaya bayan ɗaya

Jerin marasa lafiya na Narsapur da Naylor: marasa lafiya da ba su amsa jiyya ba, jiyya ba tare da ɓoye maganin ba

Rahoton farko jerin marasa lafiya 24 ne ba tare da rukunin kwatance ba, waɗanda suka daɗe suna rashin lafiya ko kuma rashin lafiyarsu ta yi tsanani. An ba su shuɗin methylene a matsayin ƙarin magani a 200 ko 300 mg kowace rana, na lokutan da suka kama daga kwanaki zuwa fiye da shekara ɗaya. Goma sha tara suna da cutar bipolar (mania da baƙin ciki), kuma an yanke cewa 14 daga cikin waɗannan 19 sun sami sauƙi tabbatacce, wato kashi 74 cikin ɗari sun amsa jiyya. Marasa lafiya uku waɗanda ba a tabbatar da ganowar bipolar a kansu ba ba su amsa jiyyar ba.

A ɗauki wannan a matsayin abin samar da hasashe, ba bayanan tabbatar da ingancin magani ba. Ba a rarraba mahalarta ba-zata ba, ba a ɓoye maganin da aka bayar ba, ba a yi amfani da daidaitaccen ma'auni ba, kuma ba a bayar da cikakken rahoton sauran magungunan da suke sha ba. Adadin kashi 74 cikin ɗari daga jerin marasa lafiya da ba su amsa jiyya ba, inda ba a ɓoye maganin ba, yana nuna hukuncin mai lura da yadda aka zaɓi mahalarta kamar yadda yake nuna aikin maganin.

Naylor da abokan aikinsa, 1986: rigakafin dawowar alamomi na shekara biyu ta musayar jiyya tare da lithium

Wannan shi ne binciken farko mafi faɗin buri: gwajin shekara biyu na musayar jiyya, wanda aka rarraba mahalarta ba-zata kuma aka ɓoye bayanin maganin ga mahalarta da masu tantancewa, a marasa lafiya 31 masu cutar bipolar. An tsara kowane mahalarci ya karɓi 300 mg kowace rana na shekara ɗaya, da 15 mg kowace rana a ɗayar shekarar, bisa tsarin da aka zaɓa ba-zata. An yi amfani da 15 mg a matsayin abin kwatance, musamman saboda sauyin launin fitsari ya sa ba zai yiwu a ɓoye amfani da maganin bogi wanda ba shi da wani aikin magani kwata-kwata ba. Abu mai muhimmanci shi ne kowane mahalarci ya ci gaba da shan lithium a duk lokacin, don haka tun daga farko wannan rigakafin ƙari ne ga jiyyar da ake yi.

Goma sha bakwai daga cikin 31 sun kammala shekarun biyu. A cikin waɗanda suka kammala, alamomin baƙin ciki sun kasance masu ƙarancin tsanani bisa ma'aunin kididdiga a shekarar 300 mg fiye da shekarar 15 mg, yayin da tsananin alamomin mania bai bambanta tsakanin adadin maganin biyu ba. An ruwaito cewa yawan kwantar da marasa lafiya a asibiti ya ragu a lokacin gwajin idan aka kwatanta da kafin sa, duk da cewa bitar Alda ta baya ta nuna cewa hakan ya faru har a lokutan 15 mg, wanda ya sa fassarar sakamakon ta fi rikitarwa. Masu binciken da kansu sun bayyana raunin binciken: ƙarancin mahalarta, ficewar kashi 45 cikin ɗari, ma'aunan tantancewa masu sauƙi, shakku kan ingancin ɓoye magani, da rashin tabbas ko 15 mg ba shi da aikin magani. Wannan damuwar ta ƙarshe ta zama mai hangen nesa, kamar yadda aka bayyana a ƙasa.

Binciken Naylor kan ƙaramin adadin magani ga baƙin ciki: dalilin da ya sa “maganin bogi” mai yiwuwa yana da aiki

Wani kwatance da aka yi daga baya na makonni uku, tare da ɓoye maganin ga mahalarta da masu tantancewa, ya gwada 15 mg kowace rana da maganin bogi marar aiki a marasa lafiya 35 masu tsananin baƙin ciki, ya kuma gano shuɗin methylene ya fi maganin bogi bisa ma'aunin kididdiga. Wannan rukuni ne da yawancinsa ke da cutar baƙin ciki marar bipolar, ba gwajin bipolar ba, don haka ya dace da shaidun baƙin ciki na gaba ɗaya maimakon rukunin bipolar. Muhimmancinsa ga masu karatu kan bipolar yana cikin tsarin bincike: adadin 15 mg da aka yi amfani da shi wajen kwatance a gwaje-gwajen musayar jiyya biyu, shi kansa ya riga ya fi maganin bogi marar aiki. Don haka duk wani bambancin jiyya da aka auna da 15 mg a matsayin abin kwatance mai yiwuwa yana nuna bambanci ƙasa da cikakken bambancin da za a samu idan ba a bayar da magani mai aiki ba. Haka kuma yana nufin babu ɗaya daga cikin tsofaffin gwaje-gwajen da ya kasance da rukuni na maganin bogi na gaskiya.

Alda da abokan aikinsa, 2017: gwajin zamani na ƙarin jiyya ta musayar magani

Binciken da ya fi tsauri a tsarin gwaji zuwa yanzu ya rarraba manya 37 masu cutar bipolar I ko II da alamomin da suka rage bayan jiyya ba-zata, don karɓar shuɗin methylene 195 mg kowace rana da 15 mg kowace rana, kowanne na makonni 13 ta tsarin musayar jiyya. An bayyana wannan a sarari a matsayin ƙarin jiyya: kowane mahalarci ya kasance yana shan lamotrigine cikin kwanciyar hankali na aƙalla watanni uku kuma ya ci gaba da shi. An kuma ba da damar lithium, divalproex, magungunan rage alamomin tabin hankali, da magungunan baƙin ciki a adadin da bai canza ba. An jera gwajin a PubMed 27284082. Alamomin farko sun kasance daga marasa tsanani zuwa matsakaici, da matsakaicin maki na baƙin ciki na Hamilton kusan 7.6 da na Montgomery-Asberg kusa da 12.7.

Sakamakon ya fi nuna amfani ga 195 mg a ma'aunan baƙin ciki da fargaba. A cikin waɗanda suka kammala, girman tasirin ya kasance kusan 0.71 a ma'aunin baƙin ciki na Hamilton, 0.80 a ma'aunin Montgomery-Asberg, da 0.79 a ma'aunin fargaba na Hamilton, kowanne yana da muhimmanci bisa kididdiga. Binciken duk marasa lafiya 37 ta hanyar amfani da sakamakon lura na ƙarshe a madadin bayanan da suka ɓace ya bayar da sakamako mai kama da haka kuma mai muhimmanci bisa kididdiga. Makin mania sun ci gaba da kasancewa ƙanana ba tare da sauyi ba, kuma babu tasirin jiyya a kansu. Tarin gwaje-gwajen fahimi bai nuna wani muhimmin amfani ga ƙwaƙwalwar kalmomi, aikin tsara da sarrafa tunani, ko ma'aunan mai da hankali ba. Mahalarta goma sun fice saboda dalilai da suka haɗa da ƙara tsanantar alamomin bipolar, fargaba, taruwar ruwa a jiki, da janye yardar shiga binciken. Illolin da aka fi gani sun kasance zafi yayin fitsari na ɗan lokaci, rashin jin daɗin ciki da hanji, da ciwon kai.

Teburin gwaje-gwajen asibiti: abin da aka gwada a zahiri

Fahimtar abin da sakamakon ke nunawa cikin gaskiya

Abubuwa uku sun tsaya duk da iyakokin binciken. Na farko, tasirin da aka gani ya nufi abu iri ɗaya: alamomin baƙin ciki da waɗanda suka rage bayan jiyya sun sami sauƙi da adadin magani mafi girma a binciken bipolar guda biyu masu rukunin kwatance, tare da matsakaicin girman tasiri a gwajin zamani. Na biyu, babu abin da ke cikin waɗannan wallafe-wallafen da ke goyon bayan da'awar rage mania. Gwajin da aka keɓe wa mania bai nuna amfani ba, kuma binciken musayar jiyya bai sami bambanci a mania ba. Wannan rashin nuna ingancin rage mania ne, ba shaidar daidaita yanayi a ɓangarorin biyu na cutar ba. Na uku, ba a ga alamar mania da ta bayyana bayan fara jiyya ba, amma wannan magana ba ta da nauyi sosai. Makin mania a farko sun kasance kusa da sifili, kuma adadin waɗanda aka ba maganin ya kasance 'yan dozin kawai, don haka waɗannan binciken ba za su iya gano haɗarin sauyawa mai girman da yake da muhimmanci a asibiti ba. Sahihiyar magana ita ce ba a ga alamar sauyawa ba, ba wai an tabbatar da babu haɗarin sauyawa ba.

Matsalolin tsarin bincike guda biyu sun cancanci a jaddada su saboda sun shafi dukkan shaidun. Tsarin ɓoye magani ya samu rauni a kowane binciken musayar jiyya, domin shuɗin methylene yana canza launin fitsari, kuma an zaɓi ƙaramin adadin magani a matsayin abin kwatance ne musamman don kwaikwayon wannan tasiri tare da zato cewa ba shi da aikin magani. Amma wannan zato bai tabbata ba: ƙaramin adadin maganin ya fi maganin bogi marar aiki wajen baƙin ciki. Wannan yana nufin muhimman kwatancen sun kasance tsakanin adadin magani biyu masu yiwuwar aiki, maimakon gwajin magani da maganin bogi. Girman tasirin da aka auna ta wannan hanyar yana da wahalar fassara, kuma ba za a iya haɗa shi da gwaje-gwajen magungunan baƙin ciki na al'ada masu amfani da maganin bogi a matsayin abin kwatance ba.

Tsayawa cikin iyakar abin da binciken ya shafa yana da muhimmanci a nan. Waɗannan gwaje-gwajen bipolar ne masu ma'aunan sakamakon bipolar, kuma bai kamata a gauraya su da shaida daga wasu rukunin mutane ba. Masu karatu masu sha'awar binciken da ke da alaƙa ya kamata su duba sakamakon bincike kan fargaba, binciken fahimi, da bayanin aminci da hulɗar magunguna dabam-dabam, domin kowanne yana da tsarin bincike da abubuwan la'akari da haɗari daban.

Bayanin aminci ga amfani da magunguna da yawa a bipolar

Gargaɗi biyu suna da alaƙa kai tsaye da marasa lafiya masu bipolar, waɗanda galibi ake rubuta wa magungunan da ke shafar serotonin. Shuɗin methylene da sinadarin da yake samarwa bayan sarrafawa a jiki, Azure B, masu hana aikin MAO-A ne masu ƙarfi waɗanda tasirinsu zai iya juyawa. Haɗa su da SSRIs, SNRIs, da sauran magungunan da ke shafar serotonin na iya jawo ciwon yawaitar serotonin. Kusan duk rahotannin guba da aka wallafa sun shafi shuɗin methylene da aka bayar ta jijiya. Kuma gwajin bipolar na zamani ya ba da damar magungunan baƙin ciki ga mahalarta 20 cikin 37 ba tare da wata matsala mai alaƙa da serotonin ba. Amma wannan ƙaramin gogewa ba ya soke gargaɗin hulɗar magunguna, kuma bayanan lakabin samfurin da ake bayarwa ta jijiya a yanzu suna ɗauke da gargaɗi a cikin akwati kan wannan batu. A gefe guda, ƙarancin glucose-6-phosphate dehydrogenase dalili ne na rashin amfani da maganin domin shuɗin methylene na iya jawo tarwatsewar jajayen ƙwayoyin jini, kuma gwajin zamani ya ware irin waɗannan marasa lafiya. Duk wanda yake haɗa waɗannan magunguna yana buƙatar kulawar ƙwararren mai jiyya; wannan hulɗar magunguna ce mai hanyoyin haifar da illa na gaske, ba wata hulɗa marar haɗari da ƙarin abinci ba.

Inda wannan ya bar tambayar

Binciken shuɗin methylene a cutar bipolar ya ƙunshi kaɗan daga tsofaffin wallafe-wallafe masu nuna yiwuwar amfani, tare da binciken gwaji na farko na zamani guda ɗaya mai inganci. Taƙaitaccen bayani na gaskiya shi ne: shuɗin methylene a matsayin ƙarin magani, a kusan 195 zuwa 300 mg kowace rana, ya sauƙaƙa alamomin baƙin ciki da waɗanda suka rage bayan jiyya akai-akai a ƙananan rukunin mahalarta; ya nuna alamar tasiri ga fargaba sau ɗaya; bai nuna amfanin fahimi ba; bai nuna tasirin rage mania ba; kuma bai nuna wata alamar sauyawa zuwa mania da irin waɗannan ƙananan rukunin za su iya ganowa ba. Ba a yi manyan gwaje-gwaje masu maganin bogi na gaskiya a matsayin abin kwatance, a rukunin masu tsananin baƙin ciki na bipolar na yanzu, tare da sa ido kan sauyawa zuwa mania da aka tsara tun farko da isassun hanyoyin ɓoye magani ba. Har sai an yi su, shuɗin methylene zai kasance ƙarin jiyya da ake bincike a wannan yanayi, mai jan hankali da zai sa a ƙara nazarinsa, amma shaidunsa sun yi kaɗan ƙwarai don su goyi bayan yanke hukunci.