API-Drug Peptide Linaclotide: Piritsi lothandizira matumbo komanso chitonthozo

Linaclotide ndi cyclic peptide yomwe ili ndi 14 amino acid, atatu mwa iwo ndi ma cysteines omwe amapanga zomangira za disulfide.Linaclotide imagwirizana mwadongosolo ndi ma peptides amkati guanylin ndi uroguanylin, omwe ndi mitsempha yachilengedwe ya guanylate cyclase C (GC-C) receptor.Cholandira cha GC-C chimawonetsedwa pamwamba pa kuwala kwa maselo am'mimba a epithelial, komwe kumayang'anira katulutsidwe kamadzimadzi komanso kuyenda kwamatumbo.Linaclotide imamangiriza ku cholandilira cha GC-C chokhala ndi kuyanjana kwakukulu komanso kutsimikizika, ndikuyambitsanso powonjezera milingo ya intracellular ya cyclic guanosine monophosphate (cGMP).cGMP ndi mthenga wachiwiri yemwe amayankhira mayankho osiyanasiyana a ma cell, monga chloride ndi bicarbonate secretion, kupumula kwa minofu yosalala, komanso kusinthasintha kwa ululu.Linaclotide imagwira ntchito m'dera la m'mimba, ndipo sichidutsa chotchinga chamagazi-muubongo kapena kukhudza dongosolo lapakati lamanjenje.Linaclotide imapanganso metabolite yogwira, MM-419447, yomwe ili ndi zofanana zapharmacological za linaclotide.Onse a linaclotide ndi metabolite yake amalimbana ndi kuwonongeka kwa proteolytic ndi ma enzymes am'mimba, ndipo amachotsedwa makamaka osasinthika mu ndowe (MacDonald et al., Mankhwala osokoneza bongo, 2017).

Pogwiritsa ntchito cholandilira cha GC-C, linaclotide imawonjezera katulutsidwe kamadzimadzi m'matumbo am'mimba, omwe amafewetsa chopondapo ndikuthandizira kutuluka kwamatumbo.Linaclotide imachepetsanso visceral hypersensitivity ndi kutupa komwe kumagwirizanitsidwa ndi matenda opweteka a m'mimba (IBS) ndi matenda ena am'mimba.Linaclotide imayendetsa ntchito ya enteric nervous system ndi colonic nociceptors, zomwe zimakhala zomverera zomwe zimatumiza zizindikiro zowawa kuchokera m'matumbo kupita ku ubongo.Linaclotide imachepetsa kufotokoza kwa majini okhudzana ndi ululu, monga mankhwala P ndi calcitonin peptide yokhudzana ndi jini (CGRP), ndipo imawonjezera kufotokozera kwa opioid receptors, omwe amathandizira kuthetsa ululu.Linaclotide imachepetsanso kutulutsa kwa ma cytokines oyambitsa kutupa, monga interleukin-1 beta (IL-1β) ndi tumor necrosis factor alpha (TNF-α), ndipo imawonjezera kutulutsa kwa anti-inflammatory cytokines, monga interleukin-10 (IL). -10) ndikusintha kukula kwa beta (TGF-β).Zotsatira za linaclotide zimakulitsa zizindikiro za kudzimbidwa komanso kupweteka kwa m'mimba mwa odwala omwe ali ndi IBS kapena kudzimbidwa kosatha (Lembo et al., The American Journal of Gastroenterology, 2018).

Linaclotide yasonyezedwa kuti ndi yothandiza komanso yolekerera m'mayesero angapo azachipatala okhudza odwala omwe ali ndi CC kapena IBS-C.M'mayesero awa, linaclotide imapangitsa kuti matumbo aziyenda bwino, monga kuchuluka kwa chimbudzi, kusasinthika, komanso kukwanira;kuchepetsa kupweteka kwa m'mimba ndi kusapeza bwino;ndi kupititsa patsogolo moyo wabwino komanso kukhutira kwa odwala.Linaclotide adawonetsanso mbiri yabwino yachitetezo, kutsekula m'mimba kukhala vuto lodziwika bwino kwambiri.Kutsekula m'mimba kunali kotengera mlingo ndipo nthawi zambiri kumakhala kochepa kwambiri mpaka kocheperako.Zochitika zina zoyipa nthawi zambiri zinali zofanana ndi placebo kapena zochepa pafupipafupi.Palibe zovuta zoyipa kapena imfa zomwe zidachitika chifukwa cha chithandizo cha linaclotide (Rao et al., Clinical Gastroenterology and Hepatology, 2015).