Moklobemid - Moclobemide

Moklobemid
Moclobemide.svg
Moclobemide3Dan.gif
Klinik ma'lumotlar
Savdo nomlariAmira, Aurorix, Clobemix, Depnil, Maneriks
AHFS /Drugs.comMicromedex iste'molchilar haqida batafsil ma'lumot
Homiladorlik
toifasi
  • AU: B3
Marshrutlari
ma'muriyat		og'zaki
ATC kodi
Huquqiy holat
Huquqiy holat
  • AU: S4 (Faqat retsept bo'yicha)
  • CA: ℞-faqat
  • Buyuk Britaniya: POM (Faqat retsept bo'yicha)
Farmakokinetik ma'lumotlar
Bioavailability55-95% (takroriy administratsiya bilan ortadi)[1][2]
Protein bilan bog'lanish50%[2][3]
MetabolizmJigar[6][4]
Yo'q qilish yarim hayot1-2 soat,[4] 4 soat (qariyalar)[2][5]
AjratishBuyrak, Najas (<5%)[3]
Identifikatorlar
CAS raqami
PubChem CID
IUPHAR / BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox boshqaruv paneli (EPA)
ECHA ma'lumot kartasi100.163.935 Buni Vikidatada tahrirlash
Kimyoviy va fizik ma'lumotlar
FormulaC13H17ClN2O2
Molyar massa268.74 g · mol−1
3D model (JSmol )
 ☒NtekshirishY (bu nima?)  (tasdiqlash)

Moklobemid (sifatida sotilgan Amira, Aurorix,[7] Clobemix , Depnil va Maneriks[8]) a Monoamin oksidaz-A ning qaytariladigan inhibitori (RIMA) preparati asosan davolash uchun ishlatiladi depressiya va ijtimoiy tashvish.[9][10][11] Qo'shma Shtatlarda foydalanish uchun tasdiqlanmagan,[12] ammo boshqa G'arb mamlakatlarida, masalan, Kanadada tasdiqlangan Buyuk Britaniya[11] va Avstraliya (TGA 2000 yil dekabrda tasdiqlangan).[13] Uni filiallari ishlab chiqaradi Hoffmann – La-Rosh farmatsevtika kompaniyasi. Dastlab, Aurorix, shuningdek, Roche tomonidan sotilgan Janubiy Afrika, lekin patent huquqlari tugaganidan keyin qaytarib olingan va Sipla Medpro-ning Depnil va Pharma Dynamic-ning Clorix-lari narxining yarmiga sotildi.

Moklobemid kabi aminlar bilan birlashganda qon bosimining sezilarli ko'tarilishi bo'lmaydi tiramin - tarkibida oziq-ovqat yoki pressoramin preparatlari, eskirganidan farqli o'laroq, qaytarib bo'lmaydigan va tanlanmagan monoamin oksidaz inhibitörleri (MAOI), bu qon bosimining keskin ko'tarilishiga olib keladi.[9] Yo'qligi sababli antikolinerjik, yurak-qon tomir, koknitik va psixomotor buzilishlar moklobemid keksa yoshdagi va yurak-qon tomir kasalliklariga chalingan kishilar uchun foydalidir.[9]

Tibbiy maqsadlarda foydalanish

Moklobemid kabi qaytariladigan selektiv MAOIlar yon ta'sir profillari qaytarilmas va selektiv bo'lmagan MAOI larnikiga o'xshash degan noto'g'ri tushunchalar tufayli juda kam tavsiflangan.[14] Moklobemid kabi MAOIlar boshqa antidepressant dorilar sinflariga nisbatan nisbatan tez ta'sirlanishiga ega,[15] va yon ta'sir jihatidan uzoq muddatli yaxshi tolerabiliteye ega.[16]

Bag'rikenglik paydo bo'lmaydiganga o'xshaydi; tadqiqotlar shuni ko'rsatdiki, moklobemid kamida bir yil davomida depressiyada foydali terapevtik xususiyatlarini saqlab qoladi.[17]

  • Yagona qutbli depressiya. Moklobemid davolash va davolashda samaradorlik va samaradorlikni namoyish etdi katta depressiv buzilish,[18] ham endogen, ham endogen bo'lmagan tushkunlikka javob berish bilan; bundan tashqari moklobemid boshqa antidepressantlarga nisbatan tez ta'sirga ega va trisiklik antidepressantlarga qaraganda ancha toqatlidir.[19] Xavfsizlik darajasi juda yaxshi va nojo'ya ta'sirlarning past darajasi tufayli moklobemid depressiyadan aziyat chekayotgan shaxslar tomonidan yuqori darajada qabul qilinishi mumkin.[20] Yuqori dozalar (> kuniga 450 mg) og'ir ruhiy tushkunlikda samaraliroq bo'lishi mumkin, past dozada davolangan bemorlar davolanganlarga qaraganda kamroq ta'sir ko'rsatadi trisiklik antidepressantlar.[21]
Psixotik depressiya, bir qutbli endogen depressiya, melankolik depressiya, sustkashlik, qo'zg'atilgan depressiya va nevrotik depressiya barchasi moklobemidga javob beradi.[22] Xuddi shunday atipik tushkunlik.[23] Unipolar endogen depressiya moklobemid terapiyasiga eng yaxshi ta'sir ko'rsatishi haqida xabar berilgan.[24][25] Moklobemid berilgan depressiyadan aziyat chekadigan odamlar moklobemidni yaxshilaganidan ikki baravar yuqori platsebo.[26] Antidepressantning salbiy ta'siridan tashvishlanish jinsiy funktsiya buzilishidir; ammo, moklobemid aslida libidoni kuchaytirishi va shuningdek, buzilgan erektsiya, bo'shashish va orgazmni yaxshilashi aniqlandi.[27] Yurak-qon tomir toksikligi trisiklik antidepressantlar kabi antidepressantlar, shuningdek qaytarib bo'lmaydigan MAOIlar bilan xavotirda; yurak-qon tomir toksikligi xavotirga soladigan bo'lsa, SSRIlar yoki moklobemid kabi qaytariladigan MAOIlar mavjud, chunki ular nojo'ya ta'sir jihatidan va shuningdek, haddan tashqari dozada yurak-qon tomir toksikligining etishmasligi yoki sezilarli darajada pasayishi bilan ajralib turadi.[28]
Achchiq depressiyada moklobemidning samaradorligi shunga teng imipramin kabi sedativ antidepressantlar amitriptilin, mianserin va maprotilin. Ajitilgan depressiv odamlarda terapevtik reaktsiya qo'zg'almagan depressiyada kuzatilganiga o'xshaydi; ammo antidepressantlardan foydalanishning o'tmish tarixi muvaffaqiyatli terapevtik javob berish imkoniyatini kamaytiradi. A qo'shilishi benzodiazepin moklobemid terapiyasi ushbu aholi guruhida foydali ekanligi aniqlanmagan.[29] Moklobemid kamroq yon ta'sirga sabab bo'ladi imipramin.[30][31] va u bilan solishtirganda toqat qilish qobiliyati yaxshiroqdir TCAlar.[32][33]
  • Bipolyar depressiya. Odatda bitta klinik tekshiruvda bipolyar depressiya uchun monoterapiya sifatida tavsiya etilmasa ham (barcha antidepressantlarda bo'lgani kabi) u paydo bo'ldi (p = 0,05 da statistik ahamiyatga ega bo'lmasa ham) moklobemid bir xil darajada samarali bo'lgan imipramin depressiv simptomlarni kamaytirishda, ammo maniksga o'tishni keltirib chiqarish xavfi ancha past edi.[34] Bu so'nggi topilmalar bilan mos keladi MAOIlar bipolyar depressiyani davolashda sinf boshqa antidepressantlardan (ularning manikk kommutatsiyasining nisbatan past darajasi va samaradorligi jihatidan) ustundir.[35]
  • Distimiya; moklobemid ushbu depressiv kasallikni davolash va davolashda samarali ekanligi aniqlandi.[36]
  • Ijtimoiy fobiya. Moklobemid qisqa muddatli va uzoq muddatli platsebo nazorati ostida o'tkaziladigan klinik sinovlarda ijtimoiy tashvishlanishni davolash uchun samarali ekanligi aniqlandi.[37] Moklobemid ijtimoiy fobiyani davolashda samarali, ammo qaytarib bo'lmaydigan MAOIlar singari samarasiz.[38] Maksimal foyda olish uchun 8 - 12 hafta vaqt ketishi mumkin.[39] Agar birgalikda kasallik bo'lsa, davolanishni to'xtatish xavfi katta spirtli ichimliklarni suiiste'mol qilish ammo.[40] The Avstraliya dori-darmonlari bo'yicha qo'llanma ijtimoiy fobiyani qabul qilingan, ammo litsenziyalanmagan ko'rsatkich sifatida ro'yxatlaydi.[10] Ijtimoiy anksiyete kasalliklarini davolashda moklobemiddan foydalanish platsebo bilan taqqoslaganda yuqori dozalarda (> 300 mg / d) javob berish tendentsiyasi bilan aralash natijalar berdi.[41]
  • Chekishni tashlash. Moklobemid tamaki chekishni o'z-o'zini davolashning bir shakli bo'lishi mumkin degan nazariya asosida og'ir qaram chekuvchilarda platseboga qarshi sinovdan o'tkazildi. katta depressiya,[42] va moklobemid MAO-A inhibitiv ta'sirini taqlid qilganligi sababli moklobemid tufayli abstentsiya stavkalarini oshirishga yordam berishi mumkin. tamaki tutuni. Moklobemid 3 oy davomida kiritildi va keyin to'xtatildi; 6 oylik kuzatuvda moklobemidni 3 oy davomida iste'mol qilganlarning platsebo guruhiga qaraganda ancha yuqori muvaffaqiyatli tark etishlari aniqlandi. Biroq, 12 oylik kuzatuvda platsebo guruhi va moklobemid guruhi o'rtasidagi farq endi ahamiyatli emas edi.[43]
  • Vahima buzilishi. Moklobemid vahima buzilishini davolash va davolashda foydalidir.[44] Vahima buzilishi Avstraliya dori-darmonlari bo'yicha qo'llanmada qabul qilingan, ammo litsenziyasiz ko'rsatma sifatida qayd etilgan.[10]
  • DEHB. Diqqat etishmovchiligi bo'lgan odamlarda moklobemidning foydasini baholaydigan ikkita kichik tadqiqotlar moklobemidning yaxshi natijalar berganligini aniqladi.[22]
  • Fibromiyalgiya, moklobemid ushbu guruhdagi odamlarda og'riqni va ishlashni yaxshilashi aniqlandi.[45]
  • O'chokli. Moklobemid migrenni davolashda samarali ekanligi xabar qilingan surunkali kuchlanish bosh og'rig'i.[46][47]

Boshqa MAOIlarga o'xshab, moklobemid kabi qaytariladigan MAOIlar boshqa psixiatrik kasalliklarda ham samarali bo'lishi mumkin.[22][48] Menopoz yuvish moklobemidga ham ta'sir qilishi mumkin.[49] Moklobemid shuningdek, Parkinson kasalligi bilan og'rigan ayrim bemorlarga ta'sirini kengaytirish va kuchaytirish orqali foydali bo'lishi mumkin l-dopa.[50]

Asosiy depressiv buzuqlikni davolash bo'yicha samaradorlik tadqiqotlarida moklobemid trisiklik antidepressantlar (TCA) va selektiv serotoninni qaytarib olish inhibitörleri (SSRI) kabi samaraliroq bo'lgan va platsebodan sezilarli darajada samaraliroq bo'lib, yoshi kattaroq, qaytarilmas MAOIlar fenelzin va tranilsipromin. Biroq, bardoshlik nuqtai nazaridan moklobemid SSRI bilan taqqoslanadigan va TCA va eski MAOIlarga qaraganda yaxshiroq muhosaba qilinganligi aniqlandi.[12] O'z-o'zidan yoki SSRI kabi boshqa antidepressantlar bilan birgalikda moklobemidning samarali ekanligi haqida ba'zi dalillar mavjud. davolashga chidamli depressiya va kombinatsiyani serotonin sindromini rivojlanishisiz boshqarish mumkin; ammo, bunday kombinatsiyani tavsiya etishdan oldin qo'shimcha tadqiqotlar o'tkazish kerak.[9][51] Keyingi tadqiqotlar shuni ko'rsatadiki, antidepressantlardan doimiy foydalanish depressiyani vaqt o'tishi bilan yaxshilanishga olib keladi; va shuningdek, moklobemid antidepressant sifatida terapevtik samaradorligini kamida bir yil davomida saqlab qolishini namoyish etdi. Ushbu uzoq muddatli samaradorlik boshqa antidepressant sinflarida ko'rilgan natijalarga tengdir.[14]

Qaytarib bo'lmaydigan MAOI kasalligi bo'lgan odamlar ushbu antidepressantlarni umumiy behushlikdan ikki hafta oldin to'xtatishlari kerak, ammo moklobemidni teskari tabiati tufayli foydalanish bunday bemorlarga antidepressant terapiyasini davom ettirishga imkon beradi.[52][53]

A deksametazonni bostirish testi (DST) va plazma va siydik metoksigidroksifenilglikol (MHPG) testidan moklobemid antidepressant terapiyasiga kim javob berishi mumkinligini taxmin qilish uchun foydalanish mumkin.[54]

Homiladorlik va laktatsiya davri

Ona sutidagi moklobemidning dozalari juda past (moklobemidning 0,06% ona sutida tiklanadi) va shuning uchun moklobemid emizikli bolaga salbiy ta'sir ko'rsatishi mumkin emas degan xulosaga kelishdi.[8]

Bolalar

Bolalarda ulardan foydalanish tavsiya etilmaydi, chunki ushbu bemorlarda ularning xavfsizligi va samaradorligini baholash uchun ma'lumotlar etarli emas.[10][11]

Qariyalar

Moklobemid kabi qaytariladigan MAOIlar depressiyani davolashda afzalliklarga ega bo'lishi mumkin Altsgeymer kasalligi noradrenalinga ta'siri tufayli.[55] Depressiyani moklobemid bilan davolashda aql-idrok kasalligi bo'lgan odamlarda kognitiv buzilishlarning yaxshilanishi aniqlandi.[22] Xavfsizligi yuqori bo'lganligi sababli moklobemid keksa yoshdagi depressiyani davolash uchun birinchi qator agenti sifatida tavsiya etilgan.[56] Moklobemidning yon ta'siri profilidan kelib chiqqan holda, bu boshqa antidepressantlarga qaraganda ushbu kichik guruh uchun yaxshi variant bo'lishi mumkin.[57] Tadqiqotlar moklobemidning anti-xolinergik (Scopolamine) keltirib chiqaradigan kognitiv buzilishlarga qarshi tura oladiganligini isbotladi, shuning uchun moklobemidni keksa yoshdagi va demansi bo'lgan odamlarda depressiyada yaxshi tanlov qiladi.[58]

Yomon ta'sir

Noqulay hodisalarning paydo bo'lishi yoshga bog'liq emas; ammo, noxush hodisalar erkaklarga qaraganda ko'proq ayollarda uchraydi.[59] Moklobemid odatda xavfsiz antidepressant sifatida qaraladi va uning yon ta'sirining qulayligi tufayli uni birinchi darajali terapevtik antidepressant deb hisoblash mumkin.[60] Moklobemidning nojo'ya ta'siri juda past,[20] bilan uyqusizlik, bosh og'rig'i va bosh aylanishi moklobemid bilan davolashning dastlabki bosqichlarida eng ko'p uchraydigan nojo'ya ta'sirlardir.[61] Ko'p antidepressantlar jinsiy funktsiyaga salbiy ta'sir ko'rsatadi; ammo, moklobemid bilan davolash aslida jinsiy funktsiyani yaxshilashi aniqlandi.[62] Moklobemid kognitiv qobiliyatlarga hech qanday salbiy ta'sir ko'rsatmaydi, shuning uchun moklobemid terapiyasining xotirada, diqqat funktsiyalarida buzilishlar mavjud emas yoki transport vositasini boshqarish qobiliyatiga salbiy ta'sir ko'rsatmaydi.[63] Moklobemid, hatto 600 mg yuqori dozalarda ham, transport vositasini boshqarish qobiliyatini buzmaydi.[8][64] Moklobemidning chidamliligi ayollar va erkaklarnikiga o'xshashdir va qariyalarda ham yaxshi muhosaba qilinadi.[65] Moklobemiddan yuqori ekanligi aniqlandi trisiklik va nojo'ya ta'sirlari jihatidan qaytarilmas MAOI antidepressantlari, chunki bu sabab bo'lmaydi antikolinerjik, sedativ yoki yurak-qon tomir salbiy ta'sirlari[9] shuningdek, kilogramm o'sishiga olib kelmaydi.[64]

Qaytarib bo'lmaydigan MAOIlardan farqli o'laroq, moklobemid bilan jigar toksikligining isboti yo'q.[66] Moklobemid boshqa antidepressantlar bilan taqqoslaganda xuddi shunday samaradorlik profiliga ega, ammo klassik MAOI va trisikliklardan bardoshlik va xavfsizlik profilidan ustundir.[67] Moklobemid ozgina ta'sir qiladi psixomotor funktsiyalari.[68] Boshqa nojo'ya ta'sirlarga ko'ngil aynish, uyqusizlik, titroq va bosh aylanishi kiradi; ortostatik gipotenziya (tik turgan holda bosh aylanishi) hatto qariyalar orasida ham kam uchraydi.[12] Xulq-atvor toksikligi yoki boshqa kundalik hayot bilan bog'liq buzilishlar moklobemid bilan yuzaga kelmaydi, faqat 400 mg yoki undan yuqori dozalarda periferik reaktsiya vaqti buzilishi mumkin.[69] Periferik shish moklobemid bilan bog'langan.[70]

Yon ta'sirlarning aksariyati vaqtinchalik bo'lib, davolanishdan keyin 2 hafta ichida yo'qoladi.[71] Jiddiy charchoq, bosh og'rig'i, bezovtalik, asabiylashish va uyquning buzilishi moklobemid terapiyasining nojo'ya ta'siri sifatida tavsiflangan.[72] A paradoksal depressiyaning yomonlashuvi ba'zi bir odamlarda bir nechta tadqiqotlarda qayd etilgan,[73] va o'z joniga qasd qilish yoki o'z joniga qasd qilish fikri haqida xabarlar moklobemidning kamdan-kam uchraydigan salbiy ta'siri sifatida qayd etilgan.[74] Umuman olganda, antidepressantlar o'z joniga qasd qilish xavfini kamaytiradi.[75] Moklobemid faqat kichik prokonvulsant ta'sirga ega;[76] ammo kamdan-kam hollarda soqchilik paydo bo'lishi mumkin.[77] Gipertenziya moklobemid terapiyasi bilan juda kamdan-kam hollarda yuz berishi haqida xabar berilgan.[12]

Moklobemid nisbatan yaxshi muhosaba qilinadi. Quyida yuzaga kelishi mumkin bo'lgan salbiy ta'sirlar va ularning tegishli hodisalari keltirilgan:[13][78]

Oddiy (> 1% insidans) salbiy ta'sir
  • Bulantı
  • Quruq og'iz
  • Kabızlık
  • Diareya
  • Uyqusizlik
  • Bosh aylanishi
  • Tashvish
  • Bezovta
Noyob / kamdan-kam (<1%) salbiy ta'sir
  • Uyquga ketish qiyinligi
  • Kabuslar / tushlar
  • Gallyutsinatsiyalar
  • Xotira buzilishi
  • Chalkashlik
  • Yo'nalishni buzish
  • Xayollar
  • Depressiyaning kuchayishi
  • Hayajonlanish / asabiylashish
  • Gipomaniya
  • Mania
  • Agressiv xatti-harakatlar
  • Apatiya
  • Kuchlanish
  • O'z joniga qasd qilish g'oyasi
  • O'z joniga qasd qilish harakati
  • O'chokli
  • Ekstrapiramidal ta'sir
  • Tinnitus
  • Paresteziya
  • Dizartriya
  • Oshqozon yonishi
  • Gastrit
  • Meteorizm
  • Oshqozon buzilishi
  • Gipertenziya
  • Bradikardiya
  • Ekstrasistollar
  • Angina / ko'krak og'rig'i
  • Flebetik alomatlar
  • Yuvish
  • Ekzantema / toshma
  • Terining allergik reaktsiyasi
  • Qichishish
  • Gingivit
  • Stomatit
  • Quruq teri
  • Konyunktivit
  • Qichima
  • Urticaria
  • Noto'g'ri buzilishlar (dizuriya, poliuriya, tenesmus)
  • Metrorragiya
  • Uzoq muddatli hayz ko'rish
  • Umumiy buzuqlik
  • Skelet / mushak og'rig'i
  • O'zgartirilgan ta'm sezgi
  • Issiq oqishlar / sovuq hislar
  • Fotopsiya
  • Dispniya
  • Vizual buzilishlar
  • Bilan bog'liq klinik oqibatlarsiz jigar fermentlarining ko'payishi.

Qo'llash mumkin bo'lmagan holatlar

Quyidagi joylardan foydalanishdan saqlaning:[10]

  • Konfuzion holatlar
  • Bipolyar buzilish (garchi u imipraminga qaraganda kamroq bo'lsa ham, manik kalitga olib kelishi mumkin)[34])
  • Feoxromotsitoma

va ehtiyotkorlik quyidagilarda tavsiya etiladi:[11]

O'zaro aloqalar

Giyohvand moddalar

Moklobemid qaytarilmas MAOIlarga qaraganda kamroq ta'sir o'tkazadi. Simetidin ammo, moklobemid darajasining sezilarli darajada ko'tarilishiga olib keladi va shu sababli kombinatsiyadan foydalansangiz, moklobemidning past dozalari tavsiya etiladi.[79] Moklobemid bilan birlashganda spirtli ichimliklar ta'sirida ozgina o'sish kuzatiladi[79] va aslida moklobemid spirtli ichimliklar bilan bog'liq buzilishlarning pasayishiga olib keladi.[68] Moklobemid ham o'zaro ta'sir qiladi petsidin / meperidin,[80] va dekstropropoksifen.[67] Efedrin moklobemid bilan birgalikda yurak-qon tomir tizimiga salbiy ta'sir qilish xavfini oshiradi.[81] Moklobemid ham o'zaro ta'sir qilishi mumkin varfarin.[82]Moklobemidning retsept bo'yicha yoki retseptsiz birikmasi sempatomimetik dorilar dori vositalarining muhim ta'sir o'tkazish ehtimoli tufayli tavsiya etilmaydi.[83]

Serotonin sindromi moklobemidni boshqa serotonin kuchaytiruvchi dorilar bilan birgalikda qabul qilinganda xabar berilgan; ammo, moklobemidning qayta tiklanadigan MAO inhibisyonu tufayli, serotonin sindromi moklobemid bilan yuzaga kelish ehtimoli ancha katta, bu eski qaytarilmas MAOIlarga qaraganda.[10][84][85] Serotonin sindromi qachon bo'lganligi haqida xabar berilgan trazodon to'satdan moklobemid bilan almashtirildi.[86] Bir vaqtning o'zida qabul qilish yoki moklobemidni boshlash to'xtatilgandan keyin tezda boshlanadi klomipramin, yoki SSRI kabi boshqa serotoninni qaytarib olish inhibitörleri serotonin sindromining rivojlanishiga olib kelishi mumkin.[67][87] SNRIlar, masalan, venlafaksin moklobemid bilan birgalikda serotonin sindromi bilan ham bog'liq.[88] Simetidin, qon plazmasidagi moklobemid miqdorining ikki baravar ko'payishiga olib keladi.[8] Qon plazmasidagi darajalar trimipramin va maprotilin va ehtimol boshqa trisiklik antidepressantlar moklobemid bilan birgalikda ishlatilganda ko'payadi va agar kombinatsiya davolashga chidamli depressiya uchun ishlatilsa dozani o'zgartirishni talab qilishi mumkin.[89] Yo'q qilish zolmitriptan moklobemid bilan kamayadi va agar kombinatsiyadan foydalanilsa, zolmitriptanning dozasini kamaytirish tavsiya etiladi.[90] Moklobemid metabolizmini pasaytiradi dekstrometorfan.[91] Moklobemid CYP2C19 inhibisyonu tufayli diazepam, omeprazol, proguanil, propranolol va boshqalarning metabolizmini kamaytirishi mumkin.[92]

Diyetik

Qaytarib bo'lmaydigan MAOI noxush va vaqti-vaqti bilan xavfli bo'lgan a gipertonik inqirozlar kabi bilvosita ta'sir qiluvchi sempatomimetik aminlarni o'z ichiga olgan oziq-ovqat yoki ichimliklar qabul qilingandan keyin tiramin. Buni ba'zan "pishloq effekti" deb atashadi. Ushbu yon ta'sirlar ichak va vazomotor neyronlarda MAO ning qaytarilmas inhibisyoniga bog'liq. Biroq, moklobemid kabi qaytariladigan MAOI antidepressantlari bu borada juda boshqacha yon ta'sir profiliga ega.[8] Moklobemid bilan MAO-A bilan qaytariladigan bog'lanish tiramin kabi ominlarga moklobemidni MAO-A dan siqib chiqarishga imkon beradi va bu metabolizmga imkon beradi va qaytarib bo'lmaydigan MAO inhibatsiyasi bilan yuzaga keladigan gipertonik inqiroz xavfini yo'qotadi.[93] 600 mg gacha bo'lgan dozalarda moklobemid bilan davolangan ko'plab klinik tadkikotlarda 2300 kishidan parhez cheklovlari bo'lmagan, ularning hech biri tiramin vositachiligiga duch kelmagan. gipertonik reaktsiya.[65] Moklobemidning pressor ta'siri juda past bo'lganligi sababli, qaytarib bo'lmaydigan MAOIlardan farqli o'laroq, oddiy dietani iste'mol qiladigan odamlarda parhez cheklovlari shart emas.[9] Ammo yuqori tiramin darajasiga ega bo'lgan ba'zi noyob pishloqlar, ehtimol pressor ta'sirini keltirib chiqarishi va ehtiyotkorlikni talab qilishi mumkin.[94] Tiraminning pressor ta'sirini moklobemid bilan kuchaytirish qaytarilmas MAOIlarning atigi ettidan o'ndan biriga teng.[95] Ushbu quvvatni minimallashtirish uchun moklobemidni ovqatdan so'ng (ovqatdan so'ng qabul qilish) tavsiya etiladi.[8] Moklobemid va birgalikda foydalanish selegilin dietada cheklovlarni talab qiladi, chunki kombinatsiya tarkibida tiramin bo'lgan oziq-ovqat mahsulotlarining pressor ta'siriga nisbatan sezgirlikni oshirishi mumkin.[96]

Faqatgina qabul qilingan moklobemid yoki qaytarib bo'lmaydigan MAO-B selektiv inhibitori selegilin pressor ta'siriga juda kam ta'sir qiladi va dietada cheklov talab etilmaydi, seligilin moklobemid bilan pressor ta'sirining sezilarli darajada yaxshilanishiga olib keladi va bunday birikma tarkibida ko'p miqdordagi tiramin.[97] Moklobemid va qaytariladigan MAO-B inhibitori kombinatsiyasi dietada tiraminni cheklashlarini talab qiladi.[98]

Dozani oshirib yuborish

Moklobemid keksa antidepressantlarga qaraganda, masalan, trisiklik antidepressantlar va qaytarib bo'lmaydigan va tanlanmagan MAOIlar bilan taqqoslaganda, dozani oshirib yuborishda kamroq toksik hisoblanadi,[9] keksa odamlarda yoki jismoniy kasalliklari bo'lgan odamlarda uni xavfsizroq antidepressantga aylantirish.[64] Klinik tadkikotlar paytida moklobemidni dozasini oshirib yuborgan 18 kishidan barchasi to'liq tiklandi va moklobemid statsionar va ambulatoriya sharoitida xavfsiz deb topildi.[99] Bitta agent sifatida moklobemid bilan zaharlanish odatda yumshoq bo'ladi; ammo trisiklik yoki SSRI antidepressantlari bilan birlashganda, dozani oshirib yuborish juda toksik va o'limga olib kelishi mumkin.[100][101] Dozani oshirib yuborishda moklobemidning past toksikligi tufayli o'z joniga qasd qilish xavfi bo'lgan bemorlar uchun shifokorlar moklobemidni afzal ko'rishadi.[102] Aralash intoksikatsiya bilan og'rigan bemorlarda (masalan, boshqa CNS faol dorilar bilan) og'ir yoki hayot uchun xavfli alomatlar namoyon bo'lishi mumkin va kasalxonaga yotqizilishi kerak. Davolash asosan simptomatik bo'lib, hayotiy funktsiyalarni ta'minlashga qaratilgan bo'lishi kerak.

Pulni tortib olish va bag'rikenglik

Boshqa antidepressantlar bilan taqqoslaganda moklobemid bilan olib tashlash alomatlari juda kam uchraydi[iqtibos kerak ]; bitta bemorda yuqori dozali moklobemid terapiyasining tez pasayishidan keyin 7 kun davomida saqlanib turadigan nisbatan engil grippga o'xshash alomatlar haqida bitta xabar.[103] Moklobemidni olib tashlash REM uyqusida tiklanishni keltirib chiqaradi.[8]

Moklobemid olib tashlash alomatlarini oldini olmaydi serotoninni qaytarib olish inhibitörleri.[104]

Moklobemidni to'xtatish yon ta'sirlarni minimallashtirish uchun bosqichma-bosqich amalga oshirilishi tavsiya etiladi (masalan, davolanayotgan holatning tez qaytarilishi va / yoki chekish belgilari paydo bo'lishi). Terapevtik ta'sirlarga nisbatan bag'rikenglik MAOI foydalanuvchilari sonining kam qismida, shu jumladan moklobemid haqida xabar berilgan.[14]

Farmakologiya

Qayta tiklanadigan 150 mg tabletkalarning surati MAOI moklobemid preparati, Aurorix markasi.

Moklobemid - bu benzamid,[12] hosilasi morfolin,[105] farmakologik jihatdan selektiv vazifasini bajaradigan, monoamin oksidaza-A ning qaytariladigan inhibitori (RIMA),[9] monoamin oksidaz inhibitori (MAOI) ning bir turi va uning darajasini oshiradi noradrenalin (noradrenalin), dopamin va ayniqsa serotonin[106][107] neyron hujayralarida ham sinaptik pufakchalar; hujayradan tashqari darajalar ham oshib boradi, natijada ular ko'payadi monoamin retseptorlarini stimulyatsiya qilish va bostirish REM uyqu, pastga tartibga solish Beta-3 adrenergik retseptorlari. Bir martalik 300 mg dozali moklobemid monoamin oksidaza-A (MAO-A) ning 80% va monoamin oksidaz-B (MAO-B) ning 30% inkor qiladi, norepinefrin, serotonin va ozroq darajada dopaminning parchalanishini bloklaydi. Bundan tashqari, moklobemidning ba'zi dalillari mavjud neyroprotektiv kemiruvchilar modellaridagi xususiyatlar.[8] Uzoq muddatli qabul qilinganda moklobemidning markazlashgan ta'siri yo'q.[8] Moklobemidni uzoq muddatli qo'llash bilan ahamiyatli narsa mavjud pastga tartibga solish ning B-adrenoreseptorlar.[8] 100-300 mg moklobemid bilan bir martalik yoki takroriy dozalash, deaminatsiyalangan metabolitlarining kamayishiga olib keladi ominlar kabi 3,4-dihidroksifenilasetik kislota, 3,4-dihidroksifeniletilglikol shu qatorda; shu bilan birga 5-HIAA. Chiqarish homovanil kislotasi va vanililmandel kislotasi siydik orqali ham kamayadi. Shuningdek, vaqtincha o'sish mavjud prolaktin 100-300 mg moklobemidni dastlabki qabul qilish paytida.[8] L-dihidroksifenilalanin ham kamayadi.[108] Serotonin metabolitining inhibatsiyasi norepinefrin metabolitiga qaraganda unchalik sezilmaydi, bu MAO-A dan tashqari serotonin uchun boshqa asosiy metabolik yo'llar mavjudligini anglatadi.[109]

U "sekin bog'lovchi inhibitor" deb ta'riflangan, shu bilan konkformatsion o'zgarishlar yoki moklobemid yoki MAO-A fermenti asta-sekin bir-biriga chambarchas bog'langan kompleks hosil qiladi va natijada moklobemid tomonidan raqobatbardosh bo'lmagan MAO inhibatsiyasi paydo bo'ladi.[8] Kundalik uch marta dozalash bilan MAO-A inhibatsiyasi moklobemid bilan nisbatan doimiy edi.[110] Moklobemidning MAO inhibatsiyasi taxminan 8-10 soat davom etadi va dozadan keyin 24 soat o'tgach butunlay tugaydi.[8][107] MAO-A ning moklobemid bilan inhibisyoni qaytarilmas MAOIlarga qaraganda 10 baravar kuchliroqdir. fenelzin va taxminan teng tranilsipromin va izokarboksazid.[8]

Moklobemid hujayradan tashqaridagi darajani oshiradi monoaminlar va kalamush miyasida ularning metabolitlari miqdorini pasaytiradi; moklobemidni surunkali qo'llash bilan ushbu ta'sirlarga nisbatan bag'rikenglik ko'rinmaydi. Moklobemid etishmaydi antikolinerjik effektlar va kognitiv buzilishlar moklobemid yordamida yaxshilanishi mumkin.[111] Moklobemid ba'zi birlarning stimulyatsiz chiqarilishini bostiradi proinflamatuar sitokinlar katta depressiya patofizyologiyasida ishtirok etadi va yallig'lanishga qarshi sitokinlarning chiqarilishini rag'batlantiradi.[112] Moklobemid bilan uzoq muddatli davolanish ko'payishiga olib keladi tsiklik adenozin monofosfat (cAMP) ga ulanish cAMP ga bog'liq protein kinaz (PKA).[113]

Moklobemid qaytarilmas MAOI antidepressantlari bilan kimyoviy aloqasi yo'q va faqat og'iz orqali yuboriladigan juda zaif bosim ta'siriga ega. tiramin.[114] Odamlarda moklobemid va moklobemidning n-oksidi metabolitlari MAO-A inhibisyonining katta qismini ishlab chiqaradigan birikmalardir; boshqa metabolitlar ota-ona birikmasidan sezilarli darajada kam kuchga ega.[8]

Sog'lom odamlarda moklobemid nisbatan kichikroq bostiruvchi ta'sirga ega REM uyqu; farqli o'laroq, moklobemid bilan davolangan ruhiy tushkunlikka tushgan odamlar, 4-hafta davomida asta-sekin yaxshilangan uyquni namoyon etishadi, bu esa 2-bosqichda tez bo'lmagan ko'z harakati (NREM) uyqusi va tezkor ko'z harakati (REM) uyqusida.[8] Moklobemidni o'zgartirish bo'yicha qarama-qarshi xulosalar mavjud kortizol darajasi va moklobemidning ko'payishi o'sish gormoni darajalar.[8] Testosteron depressiyalangan erkaklarda moklobemidni uzoq muddatli qo'llash bilan darajalar sezilarli darajada oshadi.[115]

Moklobemid shuningdek, anti-anti-neuroprotektiv xususiyatlarga egagipoksiya yoki qarshiishemiya effektlar; moklobemidning o'xshash neyro-qutqaruvchi xususiyatlarga ega bo'lishi ehtimoli mavjud selegilin ammo, buni aniqlash uchun izlanish talab etiladi.[8] Moklobemid shuningdek, bitta dozani o'rganish bo'yicha o'tkazilgan tadqiqotda namoyish etildi antinotsitseptiv xususiyatlari.[116]

MAO trombotsitlari MAO-B ga tegishli va bu odamlarda faqat ozgina darajada inhibe qilinadi; inhibisyon MAO-B inhibitiv xususiyatlariga ega bo'lgan moklobemid metabolitlarining past darajalariga bog'liq.[117] Moklobemid kalamushlarda aralash MAO-A / MAO-B inhibitori ekanligi xabar qilingan, ammo odamda u sof MAO-A inhibitori bo'lgan,[118] norepinefrin, serotonin va ozgina miqdorda dopaminning parchalanishini blokirovka qilish. Yo'q qaytarib olish har qanday narsaning inhibatsiyasi neyrotransmitterlar sodir bo'ladi. Farmakodinamik harakatlar faollashishni, kayfiyatni ko'tarishni va shunga o'xshash simptomlarni yaxshilashni o'z ichiga oladi disforiya, charchoq va kontsentratsiyadagi qiyinchiliklar. Uyquning davomiyligi va sifati yaxshilanishi mumkin. Depressiyani davolashda antidepressant ta'sir terapiyaning birinchi haftasida tez-tez namoyon bo'ladi (odatda TCA / SSRI bilan qayd etilganidan oldin).

MAO inhibatsiyasi 24 soatdan keyin butunlay normal holatiga qaytadi, bu esa moklobemidning oxirgi dozasidan 24 soat o'tgach boshqa antidepressantga o'tishga imkon beradi.[8]

Farmakokinetikasi

Odamlarda moklobemid tezda va deyarli to'liq so'riladi va jigar orqali butunlay metabolizmga uchraydi.[119] Plazmadagi eng yuqori darajalar og'iz orqali qabul qilinganidan keyin 0,3 dan 2 soat o'tgach sodir bo'ladi. Bioavailability terapiyaning birinchi haftasida 60% dan 80% gacha va undan ko'prog'iga ko'payadi. Yarim parchalanish davri taxminan 2 soat.[8][120] Bu, ayniqsa, plazma oqsillari bilan o'rtacha darajada bog'langan albumin.[8] Biroq, qisqa moyillik takroriy dozadan keyin yarim umr biroz oshadi; moklobemidning yarim umr ko'rish uchun oraliq eliminatsiyasi mavjud tizimli tozalash va oraliq tarqatish hajmi.[119] Qisqa yarim umr bo'lishiga qaramay, bitta dozaning farmakodinamik ta'siri taxminan 16 soat davom etadi. Preparat deyarli jigarda metabollanadi; bu substrat CYP2C19 va ning inhibitori CYP2C19, CYP2D6 va CYP1A2.[121] Preparatning 1 foizdan kamrog'i o'zgarmagan holda chiqariladi; Metabolizm qilingan preparatning 92 foizi dastlabki 12 soat ichida ajralib chiqadi.[6] Asosiy metabolitlar morfolin N-oksidlanish orqali hosil bo'lgan N-oksidi Ro 12-5637 va morfolin C-oksidlanish orqali hosil bo'lgan laktam hosilasi Ro 12-8095;[122][123] faol metabolitlar faqat izlar miqdorida bo'ladi. O'zgarmas dori (1% dan kam), shuningdek metabolitlar buyrak orqali (siydik bilan) ajralib chiqadi. Moklobemidning asosiy parchalanish yo'li oksidlanishdir.[124] Preparatning taxminan 44 foizi tufayli yo'qoladi birinchi o'tish effekti jigar orqali.[125] Yoshi va buyrak funktsiyasi moklobemidning farmakokinetikasiga ta'sir qilmaydi. Shu bilan birga, jigar funktsiyasi sezilarli darajada kamaygan bemorlar moklobemid metabolizmining sezilarli darajada sekinlashishi tufayli dozani kamaytirishni talab qiladi.[126] Ovqat so'rilishini sekinlashtiradi, ammo moklobemidning biologik mavjudligiga ta'sir qilmaydi.[8]

Barqaror konsentratsiyalar bir haftadan so'ng o'rnatiladi.[119] Dozani o'zgartirish bir haftadan kam vaqt oralig'ida amalga oshirilmasligi tavsiya qilingan.[4] Moklobemid yaxshi tarqaladi qon miya to'sig'i markaziy asab tizimidagi plazmadagi eng yuqori darajalar administratsiyadan 2 soat o'tgach sodir bo'ladi.[127]

Hayvonlarning toksikologiyasi

  • O'tkir toksiklik: Og'iz orqali LD50 sichqoncha va kalamushdagi qiymatlar juda yuqori, bu kenglikni bildiradi terapevtik indeks. LD50 sichqonlar uchun 730 mg / kg, kalamushlar uchun 1300 mg / kg. Itlarda 300 mg / kg dan ortiq dozalar paydo bo'ldi qusish, tupurik, ataksiya va uyquchanlik.
  • Surunkali toksiklik: 18 oy davomida o'tkazilgan tadqiqotda 10 mg / kg bo'lgan kalamushlarda surunkali toksiklik belgilari aniqlanmadi, 50 mg / kg va 250 mg / kg vaznning ozgina pasayishi va 250 mg / kg engil ko'tarildi. Ishqoriy fosfataza va Gamma-GT. Itlarda olib borilgan tadqiqotlar natijasida odamlar uchun hech qanday zaharlanish aniqlanmagan. Buning iloji yo'q jigar yoki yurak-qon tomir zaharliligi aniqlandi.

Tarix

Qaytarib bo'lmaydigan MAOI antidepressantlari 1950-yillarda tasodifan topilgan, ammo ularning toksikligi, ayniqsa ularning oziq-ovqat bilan xavfli o'zaro ta'siri aniqlanib, raqib trisiklik antidepressantlar topilganligi sababli ularning mashhurligi pasaygan. Qayta tiklanadigan MAOIlar depressiv kasalliklarda samaradorlikni beradi, ammo eski qaytarib bo'lmaydigan birikmalarning toksikligi kamroq bo'lgan degan umidda ishlab chiqilgan; moclobemide kashfiyoti va marketingi xavfli bo'lmaganligi sababli MAOIlarga bo'lgan qiziqishni qayta tikladi tiramin oziq-ovqatning o'zaro ta'siri va kuchli antidepressant ta'siri.[16][128] 1992 yilda moklobemid jahon bozorlariga chiqarildi.[129] Moklobemid keng tarqaladigan birinchi qaytariladigan MAO-A inhibitori edi[130] Moklobemid, shuningdek SSRI kabi boshqa yangi antidepressantlar retseptlarning o'zgarishiga olib keladi va depressiv kasalliklarni davolash usullarini kengaytirdi.[131]

Moklobemid 1972 yilda Shveytsariyada topilganida,[12] u birinchi bo'lib an deb faraz qilingan edi antipaemik yoki antibiotik, ammo skrininglar salbiy edi. Antikolinerjik testlarga asoslangan antidepressant sifatlarini izlash ham salbiy natijani ko'rsatdi va keyinchalik o'ziga xos va qaytariladigan MAO-A inhibisyon fazilatlari aniqlanmasdan oldin moklobemid antipsikotik deb gumon qilindi. Tiramin bosimiga javoban tegishli aralashuv yo'qligi aniqlangandan so'ng, 1977 yilda klinik tadkikotlar boshlandi va keyingi sinovlar RIMAlarning antidepressant faolligini tasdiqladi.[132] U birinchi marta Buyuk Britaniyada va Evropada MAO-A ning birinchi qaytariladigan va tanlab olingan inhibitori sifatida tasdiqlangan va hozirda dunyoning 50 dan ortiq mamlakatlarida tasdiqlangan.[12] Keyingi tadqiqotlar shuni ko'rsatdiki, keksa bemorlarda moklobemid yaxshi muhosaba qilinadi[133] va nojo'ya ta'sirlari, bardoshliligi va haddan tashqari dozasi jihatidan trisiklik antidepressantlardan ancha ustundir. Depressiyani davolash samaradorligiga kelsak, moklobemid barcha asosiy antidepressant dorilar sinflari kabi samarali ekanligi aniqlandi. Qayta tiklanmaydigan MAO'larga chalingan odamlardan farqli o'laroq parhez cheklovlariga hojat yo'q va SSRI va petidin kabi boshqa serotonergik kuchaytiruvchi vositalar bilan muhim o'zaro ta'sirdan tashqari, dori-darmonlarning jiddiy o'zaro ta'siri kam va shu afzalliklari tufayli moklobemid foydali qo'shimchalar sifatida qabul qilindi. tibbiy "retseptsiya arsenaliga".[85][134] Bundan tashqari, moklobemid, bozordagi boshqa antidepressantlardan farqli o'laroq, jinsiy funktsiyalarning barcha jihatlarini yaxshilashi aniqlandi.[135] Bu klinik amaliyotda qo'llaniladigan yagona qayta tiklanadigan MAOI.[8] Moklobemidning farmakokinetik xususiyatlarining yoshga qarab o'zgarmasligi, keksa yoshdagi odamlarda bilimning yaxshilanishi va moklobemidning oziq-ovqat va dori vositalarining o'zaro ta'sirida past salohiyatga ega ekanligi haqiqatni davolash uchun yangi yo'l ochdi. katta depressiv buzilish.[8] Moliyaviy rag'batning etishmasligi, masalan, ma'qullash uchun zarur bo'lgan sinovlarni o'tkazish xarajatlari, moklobemid AQSh farmatsevtika bozorida mavjud emas.[12] 2016 yilda moklobemid Braziliyada tijorat sabablari bilan to'xtatildi.[136]

Jamiyat va madaniyat

Brendlar

U butun dunyo bo'ylab ko'plab savdo nomlari ostida sotiladi.[137]

Brend nomi ro'yxatlari

Apo-Moclob, Apo-Moclobemide, Auromid, Aurorix, Bei Su, Biorix, Depnil, Eutac, Hai Bei Lin, Langtian, Manerix, Mobemid, Moclamine, Moclo A, Moclobemid - 1 A Pharma kabi ko'plab savdo nomlari ostida sotiladi. , Moclobemid AL, Moclobemid HEXAL, Moclobemid ratiopharm, Moclobemida, Moclobemida Genedec, Moclobemida Teva, Moclobemide Actavis, Moclobemide Aurobindo, Moclobemide CF, Moclobemide Mylan, Moclobemide Sandoc, Moclobemide, Moclobemide, Moclobemide, Moclobemid , moclodura, Moclostad, Mocrim, Modafinil Arrow, Moklar, Teva-Moclobemide, Tian Tai, Ya Zheng va Zorix.[137]

Adabiyotlar

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  3. ^ a b Shoerlin, MP; Mayersohn, M; Korn, A; Eggers, H (oktyabr 1987). "Monoamin oksidaz-A ferment inhibitori moklobemidning dispozitsiya kinetikasi: oddiy odamlarda bir martalik va ko'p martalik dozalash". Klinik farmakologiya va terapiya. 42 (4): 395–404. doi:10.1038 / clpt.1987.169. PMID  3665338. S2CID  46130982.
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