API-Drug Peptide Linaclotide: He pila no ka hoʻomaha a me ka hōʻoluʻolu

ʻO Linaclotide kahi peptide cyclic i loaʻa he 14 amino acids, ʻekolu o ia mau cysteine ​​e hana i nā paʻa disulfide.Pili ka Linaclotide i nā peptides endogenous guanylin a me uroguanylin, he mau ligands maoli o ka loaʻa ʻana o ka guanylate cyclase C (GC-C).Hōʻike ʻia ka GC-C receptor ma ka luminal surface o nā ʻōpū epithelial cell, kahi e hoʻoponopono ai i ka huna ʻana o ka wai a me ka motility ʻōpū.Hoʻopili ʻo Linaclotide i ka mea hoʻokipa GC-C me ka pilina kiʻekiʻe a me ka kikoʻī, a hoʻōla iā ia ma ka hoʻonui ʻana i nā pae intracellular o cyclic guanosine monophosphate (cGMP).ʻO cGMP kahi ʻelele ʻelua e hoʻopili ana i nā pane kelepona like ʻole, e like me ka chloride a me ka bicarbonate huna, hoʻomaha hoʻomaha ʻiʻo, a me ka hoʻololi ʻana i ka ʻeha.Hana ʻo Linaclotide ma ka ʻāina i loko o ka ʻōpū o ka ʻōpū, ʻaʻole ia e komo i ka pale koko-lolo a i ʻole e hoʻopilikia i ka ʻōnaehana o ke kikowaena.Hoʻopuka pū ʻo Linaclotide i kahi metabolite ikaika, MM-419447, nona nā waiwai pharmacological like me linaclotide.ʻO ka linaclotide a me kāna metabolite ke kū'ē i ka proteolytic degradation e nā enzymes intestinal, a ua hoʻopau nuiʻia me ka loliʻole i nā feces (MacDonald et al., Drugs, 2017).

Ma ka hoʻoulu ʻana i ka mea hoʻokipa GC-C, hoʻonui ka linaclotide i ka huna ʻana o ka wai i loko o ka lumen o ka ʻōpū, e hoʻomaʻamaʻa i ka ʻōpū a hoʻomaʻamaʻa i ka neʻe ʻana o ka ʻōpū.Hoʻemi pū ʻo Linaclotide i ka hypersensitivity visceral a me ka mumū e pili ana me ka irritable bowel syndrome (IBS) a me nā maʻi ʻeha ʻē aʻe.Hoʻololi ʻo Linaclotide i ka hana o ka ʻōnaehana nerve enteric a me nā colonic nociceptors, ʻo ia nā neurons sensory e hoʻouna i nā hōʻailona ʻeha mai ka ʻōpū i ka lolo.Hoʻemi ʻo Linaclotide i ka hōʻike ʻana o nā genes pili i ka ʻeha, e like me ka waiwai P a me ka calcitonin gene-related peptide (CGRP), a hoʻonui i ka hōʻike ʻana o nā mea loaʻa opioid, nāna e hoʻoponopono i ka analgesia.Hoʻemi pū ʻo Linaclotide i ka hoʻokuʻu ʻana o nā cytokine pro-inflammatory, e like me interleukin-1 beta (IL-1β) a me ka tumor necrosis factor alpha (TNF-α), a hoʻonui i ka hoʻokuʻu ʻana o nā cytokine anti-inflammatory, e like me interleukin-10 (IL). -10) a me ka hoʻololi ʻana i ka mea ulu beta (TGF-β).ʻO kēia mau hopena o ka linaclotide e hoʻomaikaʻi i nā hōʻailona o ka constipation a me ka ʻeha o ka ʻōpū i nā maʻi me IBS a i ʻole constipation mau (Lembo et al., The American Journal of Gastroenterology, 2018).

Ua hōʻike ʻia ʻo Linaclotide i ka maikaʻi a me ka ʻae ʻia i nā hoʻokolohua lapaʻau e pili ana i nā maʻi me CC a i ʻole IBS-C.I loko o kēia mau ho'āʻo, ua hoʻomaikaʻi ʻo linaclotide i nā maʻamau o ka ʻōpū, e like me ke alapine stool, kūlike, a me ka piha;hoemi i ka eha o ka opu a me ka pilikia ole;a hoʻonui i ka maikaʻi o ke ola a me ka ʻoluʻolu o ka maʻi.Ua hōʻike pū ʻo Linaclotide i kahi ʻōlelo palekana maikaʻi, me ka maʻi maʻi ka hopena maʻamau.ʻO ka loaʻa ʻana o ka maʻi maʻi maʻi i hilinaʻi ʻia i ka dosis a maʻamau ka maʻalahi a me ka haʻahaʻa i ka paʻakikī.Ua like nā hanana ʻino ʻē aʻe me ka placebo a i ʻole ka haʻahaʻa o ka pinepine.ʻAʻohe hanana koʻikoʻi koʻikoʻi a make paha i pili i ka mālama ʻana i ka linaclotide (Rao et al., Clinical Gastroenterology and Hepatology, 2015).