Linaclotide ke peptide ea cyclic e nang le li-amino acid tse 14, tse tharo tsa tsona ke li-cysteine tse etsang li-bond tsa disulfide.Linaclotide e amana ka mokhoa o hlophisitsoeng le li-peptide tsa endogenous guanylin le uroguanylin, tseo e leng li-ligand tsa tlhaho tsa guanylate cyclase C (GC-C) receptor.Mokelikeli oa GC-C o hlahisoa ka holim'a leseli la lisele tsa mala a epithelial, moo e laolang ho ntša metsi le ho tsamaea ha mala.Linaclotide e tlama ho receptor ea GC-C ka kamano e phahameng le e ikhethang, 'me e e kenya tšebetsong ka ho eketsa maemo a intracellular a cyclic guanosine monophosphate (cGMP).cGMP ke len messengerosa la bobeli le kopanyang likarabo tse fapaneng tsa cellular, joalo ka secretion ea chloride le bicarbonate, ho phomola ha mesifa e boreleli, le ho feto-fetoha ha bohloko.Linaclotide e sebetsa sebakeng sa heno ka har'a pampitšana ea mala, 'me ha e kenelle mokoallong oa mali le boko kapa ho ama tsamaiso ea methapo e bohareng.Linaclotide e boetse e hlahisa metabolite e sebetsang, MM-419447, e nang le thepa e tšoanang ea pharmacological ho linaclotide.Ka bobeli linaclotide le metabolite ea eona li hanana le ho senyeha ha proteolytic ke li-enzyme tsa mala, 'me li ntšoa ka mokhoa o sa fetoheng mantleng (MacDonald et al., Lithethefatsi, 2017).
Ka ho kenya tšebetsong receptor ea GC-C, linaclotide e eketsa tlhahiso ea mokelikeli ka har'a lumen ea mala, e nolofatsang mantle le ho tsamaisa mala.Linaclotide e boetse e fokotsa ho ruruha ha visceral le ho ruruha ho amanang le lefu la mala le halefisang (IBS) le mafu a mang a mala.Linaclotide e fetola mosebetsi oa tsamaiso ea methapo ea enteric le li-nociceptors tsa colonic, e leng li-neuron tsa kutlo tse fetisang matšoao a bohloko ho tloha ka mpeng ho ea bokong.Linaclotide e fokotsa polelo ea liphatsa tsa lefutso tse amanang le bohloko, joalo ka ntho P le calcitonin peptide e amanang le liphatsa tsa lefutso (CGRP), 'me e eketsa polelo ea li-receptor tsa opioid, tse sebetsanang le analgesia.Linaclotide e boetse e fokotsa ho lokolloa ha li-cytokine tse thibelang ho ruruha, tse kang interleukin-1 beta (IL-1β) le tumor necrosis factor alpha (TNF-α), 'me e eketsa ho lokolloa ha li-cytokine tse thibelang ho ruruha, tse kang interleukin-10 (IL). -10) le ho fetola sekhahla sa kholo ea beta (TGF-β).Litlamorao tsena tsa linaclotide li ntlafatsa matšoao a ho patoa le bohloko ba mpeng ho bakuli ba nang le IBS kapa ba sa foleng (Lembo et al., The American Journal of Gastroenterology, 2018).
Linaclotide e bontšitsoe e sebetsa hantle ebile e mamelloa hantle litekong tse 'maloa tsa bongaka tse amang bakuli ba nang le CC kapa IBS-C.Litekong tsena, linaclotide e ntlafalitse mekhoa ea mala, joalo ka makhetlo a mantle, ho tsitsa, le botlalo;fokotsa bohloko ba mpeng le ho se phutholohe;le boleng bo ntlafetseng ba bophelo le khotsofalo ea mokuli.Linaclotide e boetse e bonts'a boemo bo botle ba polokeho, 'me letšollo e le ketsahalo e mpe e atileng haholo.Ketsahalo ea letšollo e ne e itšetlehile ka tekanyo ea litekanyetso 'me hangata e ne e le bobebe ho isa ho e itekanetseng ka matla.Liketsahalo tse ling tse mpe ka kakaretso li ne li tšoana le placebo kapa khafetsa khafetsa.Ha ho liketsahalo tse mpe tse mpe kapa lefu le bakoang ke kalafo ea linaclotide (Rao et al., Clinical Gastroenterology le Hepatology, 2015).
Linaclotide ke moriana o mocha le o sebetsang bakeng sa bakuli ba nang le CC le IBS-C ba sa kang ba arabela hantle kalafong e tloaelehileng.E sebetsa ka ho etsisa ketso ea li-peptide tsa endogenous tse laolang tšebetso ea mala le maikutlo.Linaclotide e ka ntlafatsa mekhoa ea mala, ea fokotsa bohloko ba ka mpeng le ho ntlafatsa boleng ba bophelo ba bakuli bana.
Setšoantšo sa 1. Bohloko ba ka mpeng / bohloko ba mpa le tekanyo ea IBS ea liphallelo tsa beke le beke ba arabelang libeke tsa 12., placebo;, linaclotide 290 μg.
(Yang, Y., Fang, J., Guo, X., Dai, N., Shen, X., Yang, Y., Sun, J., Bhandari, BR, Reasner, DS, Cronin, JA, Currie, MG, Johnston, JM, Zeng, P., Montreewasuwat, N., Chen, GZ, and Lim, S. (2018) Linaclotide in irritable bowel syndrome le constipation: Teko ea Phase 3 e sa tloaelehang Chaena le libaka tse ling. Journal of Gastroenterology. le Hepatology, 33: 980–989. doi: 10.1111/jgh.14086.)
Re baetsi ba polypeptide Chaena, ba nang le phihlelo ea lilemo tse 'maloa tlhahiso ea polypeptide.Hangzhou Taijia Biotech Co., Ltd. ke moetsi oa thepa e tala ea polypeptide, e ka fanang ka mashome a likete a lisebelisoa tse tala tsa polypeptide hape e ka etsoa ho latela litlhoko.Boleng ba lihlahisoa tsa polypeptide bo botle haholo, 'me bohloeki bo ka fihla ho 98%, e' nileng ea hlokomeloa ke basebelisi lefatšeng lohle.
