API-Drug Peptide Linaclotide: Ọgwụ maka enyemaka afọ na nkasi obi

Linaclotide bụ peptide cyclic nke nwere amino acid 14, atọ n'ime ha bụ cysteine ​​​​nke na-etolite njikọ disulfide.Linaclotide na-ejikọta ya na peptides endogenous guanylin na uroguanylin, nke bụ njikọ anụ ahụ nke guanylate cyclase C (GC-C).A na-egosipụta onye na-anabata GC-C n'elu luminal nke mkpụrụ ndụ epithelial intestinal, bụ ebe ọ na-achịkwa nzuzo nzuzo na motility eriri afọ.Linaclotide na-ejikọta ya na onye na-anabata GC-C nwere oke mmekọrịta na nkọwapụta, ma na-arụ ọrụ ya site na ịbawanye ọkwa intracellular nke cyclic guanosine monophosphate (cGMP).cGMP bụ onye ozi nke abụọ na-agbazi nzaghachi cellular dị iche iche, dị ka chloride na nzuzo bicarbonate, izu ike dị nro, na mgbanwe mgbu.Linaclotide na-arụ ọrụ n'ime mpaghara eriri afọ, ọ naghị abanyekwa n'ime mgbochi ụbụrụ ọbara ma ọ bụ na-emetụta usoro nhụjuanya nke etiti.Linaclotide na-emepụtakwa metabolite na-arụ ọrụ, MM-419447, nke nwere ọgwụ ọgwụ yiri ya na linaclotide.Ma linaclotide na metabolite ya na-eguzogide mmebi proteolytic site na enzymes eriri afọ, a na-ewepụkwa ya na-agbanweghi agbanwe na nsị (MacDonald et al., Drugs, 2017).

Site na ịgbalite onye na-anabata GC-C, linaclotide na-abawanye nzuzo nke mmiri n'ime lumen intestinal, nke na-eme ka stool dị nro ma na-eme ka eriri afọ dị nro.Linaclotide na-ebelatakwa visceral hypersensitivity na mbufụt nke jikọtara ya na mgbakasị obi (IBS) na ọrịa eriri afọ ndị ọzọ.Linaclotide na-emezigharị ọrụ nke sistemu ụjọ ahụ na-arụ ọrụ na nociceptors colonic, nke bụ neurons sensọ na-ebufe mgbaàmà mgbu site na eriri afọ gaa na ụbụrụ.Linaclotide na-ebelata okwu nke mkpụrụ ndụ ihe nketa metụtara mgbu, dị ka ihe P na peptide metụtara mkpụrụ ndụ calcitonin (CGRP), ma na-abawanye okwu nke ndị na-anabata opioid, nke na-emezi analgesia.Linaclotide na-ebelatakwa ntọhapụ nke cytokines pro-inflammatory, dị ka interleukin-1 beta (IL-1β) na tumor necrosis factor alpha (TNF-α), ma na-abawanye ntọhapụ nke cytokines mgbochi mkpali, dị ka interleukin-10 (IL). -10) na-agbanwe ihe na-eto eto beta (TGF-β).Mmetụta ndị a nke linaclotide na-eme ka mgbaàmà nke afọ ntachi na mgbu afọ na ndị ọrịa nwere IBS ma ọ bụ afọ ntachi na-adịghị ala ala (Lembo et al., The American Journal of Gastroenterology, 2018).

E gosipụtara Linaclotide ka ọ dị irè ma na-anabata ya nke ọma n'ọtụtụ ule ụlọ ọgwụ metụtara ndị ọrịa nwere CC ma ọ bụ IBS-C.N'ime ule ndị a, linaclotide kwalitere àgwà afọ, dị ka stool ugboro, nkwụsi ike, na izu oke;belata mgbu abdominal na ahụ erughị ala;na enwekwukwa ogo ndụ na afọ ojuju ndidi.Linaclotide gosikwara profaịlụ nchekwa dị mma, yana afọ ọsịsa bụ ihe ọjọọ kachasị emetụta.Mmetụta nke afọ ọsịsa na-adabere na dose ma na-adịkarị nwayọọ ma na-agafeghị oke n'ịdị njọ.Ihe omume ọjọọ ndị ọzọ na-adịkarị ka placebo ma ọ bụ obere ugboro.Ọ nweghị ihe ọjọọ dị njọ ma ọ bụ ọnwụ ekwuru na ọgwụgwọ linaclotide (Rao et al., Clinical Gastroenterology and Hepatology, 2015).