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TirzepatideStructure Imiterere ya
Inkomoko: PubChem |
Urukurikirane: Tyr- {Aib} -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile- {Aib} -Leu-Asp-Lys-Ile-Ala-Gln- {diacid-C20-gamm a-Glu- (AEEA) 2-Lys} -Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 Inzira ya molekulari: C 225H 348N 48O.68 Uburemere bwa molekuline: 4813 g / mol Numero ya CAS: 2023788-19-2 PubChem CID: 163285897 Synonyme: Zepbound; Mounjaro |
Research Ubushakashatsi bwa Tirzepatide
Ni ubuhe bushakashatsi bwakozwe na Tirzepatide?
Tirzepatide ni imiti ya polypeptide ikora, kandi iterambere ryayo rituruka ku gusobanukirwa byimazeyo aho ubushobozi bwa GLP-1 bwakira reseptor agoniste mu kuvura ubwoko bwa 2 metabolism mellitus n'umubyibuho ukabije. Nubwo GLP-1 yakira agoniste yamaze kwerekana imikorere myiza mugucunga amaraso glucose no kugabanya ibiro, abahanga basanze mugihe bakora reseptor ya GLP-1, ingaruka zabo zo gukora kuri reseptor ya GIP ni ntege nke, ibyo bikaba bigabanya urugero runaka rwo kuvura imiti. Niyo mpamvu, itsinda ry’ubushakashatsi n’iterambere ryiyemeje guteza imbere ubwoko bushya bw’ibiyobyabwenge bushobora gukora icyarimwe GIPR na GLP-1R icyarimwe, twizeye kuzagera ku buryo bunoze kandi bunoze bwo kugenzura amaraso ya glucose no gucunga ibiro [1] .
Mugihe cyubushakashatsi niterambere rya Tirzepatide, abahanga bakoze ubushakashatsi bwibanze nubushakashatsi bwamavuriro. Mbere na mbere, mu cyiciro cy’ubushakashatsi bwibanze, imiterere ya farumodinamike ya Tirzepatide yasuzumwe cyane binyuze mu bushakashatsi bw’inyamaswa, kandi hasuzumwe ubushobozi bwayo mu kugenzura amaraso glucose no kugabanya ibiro. Ibisubizo byerekanye ko Tirzepatide ishobora kugabanya cyane glucose yamaraso mubyitegererezo byinyamaswa kandi ikanakora neza mugucunga ibiro. Ubu bushakashatsi bwiza bwashizeho urufatiro rukomeye rwibizamini byakurikiyeho.
Nyuma, Tirzepatide yinjiye mu cyiciro cy’ibizamini byo kwa muganga, harimo icyiciro cya I, II, na III. Mu cyiciro cya I igeragezwa, hasuzumwe ahanini umutekano, ubworoherane, hamwe n’imiti ya farumasi, kandi ibisubizo byagaragaje ko Tirzepatide yari ifite umutekano n’ubworoherane. Ikigeragezo cya kabiri cyakomeje gukora ubushakashatsi ku mikorere n’umutekano bya dosiye zitandukanye za Tirzepatide ku barwayi barwaye metabolism yo mu bwoko bwa 2, kandi bagena mbere na mbere urugero rwiza rwabyo. Ikigeragezo cyingenzi cyane icyiciro cya gatatu cyamavuriro, nka SURPASS yubushakashatsi, cyerekanye umubare munini wabarwayi bafite metabolism yo mu bwoko bwa 2. Ibisubizo byerekanaga ko Tirzepatide yarutaga cyane GLP-1 yakira reseptor agoniste, nka semaglutide, mu kugabanya glucose yamaraso nuburemere. Igisubizo cyagezweho cyatanze ibimenyetso bifatika byo kwamamaza kwa Tirzepatide [1].
Tirzepatide ni polypeptide igizwe na aside amine 39, aho aside amine ku giti cye yahinduwe mu buryo kugira ngo iteze imbere kandi ikore neza. Igishushanyo mbonera kidasanzwe gifasha Tirzepatide guhuza ingaruka zimisemburo ibiri ya incretin, GIP na GLP-1, muri molekile imwe, kandi igakora imisemburo ya hormone igira uruhare mukurwanya glucose yamaraso hakoreshejwe uburyo bubiri bwibikorwa. By'umwihariko, Tirzepatide irashobora gukora kuri pancreas na sisitemu yo hagati yo hagati. Ku ruhande rumwe, itera gusohora insuline kandi ikabuza gusohora glucagon, bityo bikagabanya neza glucose yamaraso; kurundi ruhande, mugutinda gusiba gastric no kongera guhaga, bigabanya ubushake bwo kurya no gufata ibiryo, bityo bikagera no gucunga ibiro. Ubu buryo bubiri bwibikorwa butanga Tirzepatide inyungu zidasanzwe mukuvura ubwoko bwa 2 metabolism mellitus n'umubyibuho ukabije, bigaha abarwayi uburyo bunoze bwo kuvura [1].
Ni ubuhe buryo bwo gukora bwa Tirzepatide?
Tirzepatide igabanya glucose yamaraso binyuze muburyo bwinshi bukorera hamwe, kuburyo bukurikira: Gukora reseptor ya GLP-1: Tirzepatide ihuza reseptor ya GLP-1 kuri selile pancreatic β selile, yigana ingaruka za GLP-1. GLP-1 ni imisemburo ikorwa mu mara kandi ni ingenzi cyane mu kubungabunga glucose homeostasis 2. Irashobora guteza imbere insimburangingo ya insuline, gusohora insuline, no kumva glucose, kandi ikagabanya ururenda rwa glucagon kugira ngo ihaze kandi ibuze ubushake bwo kurya 2.
Uku gukora kurashobora guteza imbere gusohora insuline. Insuline ni umusemburo nyamukuru wamaraso ugabanya glucose mumubiri, ushobora kongera gufata no gukoresha glucose ukoresheje selile, bityo bikagabanya urugero rwa glucose yamaraso. Ku barwayi bafite metabolism yo mu bwoko bwa 2, gusohora kwa insuline ntibihagije cyangwa se ingirabuzimafatizo za insuline zigabanuka, bigatuma glucose yiyongera. Tirzepatide yongera imisemburo ya insuline ikora reseptor ya GLP-1, ifasha kunoza igenzura ryamaraso glucose. Muri icyo gihe, ibikorwa bya reseptor ya GLP-1 birashobora kandi kubuza irekurwa rya glucagon. Ubusanzwe Glucagon iteza glycogenolysis na gluconeogenez mu gihe cyo kwiyiriza ubusa, bikongera umusaruro w'amaraso glucose. Muguhagarika ingaruka za glucagon, Tirzepatide irushaho kugabanya inkomoko ya glucose yamaraso, ifasha kugenzura glucose yamaraso [2] (Anonymous, 2023).
Gukora kwa reseptor ya GIP: Tirzepatide ikora kuri reseptor ya GIP icyarimwe. Nyuma yo gukora, irashobora kongera insuline no gusohora. GIP reseptor igaragara cyane mubice nka pancreatic β selile. Nyuma yo gukora, binyuze mumiyoboro yinzira yerekana ibimenyetso, insuline yiyongera, kandi ingirabuzimafatizo zakira insuline ziratera imbere, bityo bikagabanya cyane glucose yamaraso 2. Tirzepatide nicyiciro cya mbere cyicyiciro cya glucagon kimeze nka peptide-1 hamwe na glucose iterwa na insulineotropique polypeptide (GIP) igereranya imiti ya metabolisme ya mitiweli. hashingiwe ku ruhererekane rwa GIP, rugizwe na peptide ya aside amine 39. Yongera imisemburo ya insuline, igabanya irekurwa rya glucagon muburyo buterwa na glucose, igabanya kwiyiriza ubusa hamwe na glucose yamaraso nyuma yinyuma, itera guhaga, kugabanya ibiro, no gutinda gusiba gastrica 2.
Izi ngaruka ebyiri za reseptor agonist zituma Tirzepatide ikora neza mugutezimbere insuline no kubuza glucagon gusohora kuruta GLP-1 reseptor agonist [2].
Gutinda gusiba gastrica no kongera guhaga: Tirzepatide irashobora gutinza ubusa gastrica, ikongerera igihe cyo gutura ibiryo mu gifu, igabanya umuvuduko wintungamubiri zintungamubiri, bityo ukirinda kwiyongera gukabije kwa glucose yamaraso nyuma yo gutangira. Mu bushakashatsi bwibanze n’ubuvuzi, ingaruka za Tirzepatide ku gusiba gastrica ziragereranywa n’iza GLP-1 reseptor agonist. Imbeba zifite umubyibuho ukabije ziterwa nimirire, urugero rwo gutinda gukuramo gastrica na Tirzepatide rusa nubwa semaglutide, ariko izi ngaruka zikomeye zo kubuza zirashira nyuma yibyumweru 2 bivuwe. Abitabiriye amahugurwa hamwe nubwoko bwa 2 metabolism mellitus, rimwe mu cyumweru Tirzepatide (≥5 na .5 4.5mg,) yatinze gusohora gastric nyuma yumuti umwe. Abitabiriye ubuzima bwiza, iyi ngaruka yagaragaye nyuma ya dosiye nyinshi ya Tirzepatide cyangwa dulaglutide [3] .
Muri icyo gihe, irashobora kandi gukora kuri sisitemu yo hagati yo hagati, kongera guhaga, no kugabanya ubushake bwo kurya no gufata ibiryo. Mu kugenzura ibiryo, bifasha mu buryo butaziguye kugenzura amaraso ya glucose, cyane cyane bikwiranye n’ikibazo cy’umubyibuho ukabije uherekejwe n’abarwayi bafite metabolism yo mu bwoko bwa 2, kandi bigafasha kunoza insuline ndetse n’imiterere rusange ya metabolike [2].
Kunoza ibyiyumvo bya insuline hamwe na metabolisme ya lipide: Tirzepatide yasanze yongera urugero rwa adiponectine, ikaba adipocytokine ijyanye no kumva insuline. Kwiyongera kurwego rwa adiponectine bifasha kunoza insuline, bigatuma selile zumva insuline, bityo gufata neza no gukoresha glucose, kugabanya glucose yamaraso [2].
Byongeye kandi, Tirzepatide irashobora kandi kunoza imiterere ya lipide kandi ikagira ingaruka zo kurinda ubuzima bwumutima. Tirzepatide byagaragaye ko ishobora kuzamura umuvuduko wamaraso, kugabanya cholesterol ya lipoproteine (LDL) nkeya na cholesterol na triglyceride [4] .Ibi kandi bishyigikira inyungu zayo zose mugucunga glucose yamaraso.
Ubushakashatsi bujyanye
Ingaruka zo gucunga ibiro ku barwayi bafite umubyibuho ukabije n'ubwoko bwa 2 metabolism mellitus:
Ubushakashatsi bwinshi bw’ubuvuzi bwemeje ingaruka zikomeye zo kugabanya ibiro: Mu bushakashatsi bwiswe 'SURMOUNT-2 ', uru rubanza rwabaye icyiciro cya 3, impumyi ebyiri, impumyi, itabigenewe, igenzurwa n’ibibanza byakorewe mu bihugu birindwi. Abakuze (bafite imyaka 18) bafite icyerekezo rusange cy'umubiri (BMI) cya 27 kg / m² cyangwa hejuru hamwe na glycated hemoglobine (HbA₁c) ya 7 - 10% bahawe amahirwe yo guhabwa inshuro imwe mucyumweru inshinge ya Tirzepatide (10mg cyangwa 15mg) cyangwa umwanya wa byumweru 72. Ibisubizo byerekanye ko ku cyumweru cya 72, ijanisha ryo kugabanya ibiro mu matsinda ya Tirzepatide 10mg na 15mg ryari -12.8% na -14.7%, mu gihe mu itsinda rya placebo ryari -3.2%. Ikigereranyo cyo kuvura cya Tirzepatide 10mg na 15mg ugereranije na placebo cyari -9,6 ku ijana na -11,6 ku ijana, byombi byari bifite imibare (p ＜ 0.0001). Byongeye kandi, abarwayi benshi bavuwe na Tirzepatide bageze ku ntera yo kugabanuka ibiro 5% cyangwa birenga (79 - 83% vs 32%) [5] (Garvey WT, 2023). Njye n 'SURMOUNT-2 ' ubushakashatsi, uburemere bwibanze buringaniye bwari 100.7 kg, BMI yari 36.1 kg / m², naho HbA₁c yari 8.02%. Nyuma y'ibyumweru 72 bivurwa, Tirzepatide ntabwo yagabanije ibiro gusa ahubwo yanagize uruhare runini mu kurwanya glucose yamaraso [5].
Ingaruka nziza kuri metabolism ijyanye na neuropathie:
Ubushakashatsi bumwe bwerekanye ko glucagon imeze nka peptide 1 ya reseptor agonist (GLP1-RAs) ishobora kugabanya ibyago byo guta umutwe ku barwayi bafite metabolism yo mu bwoko bwa 2 mu kunoza kwibuka, kwiga, no gutsinda ubumuga bwo kutamenya. Nka glucose ebyiri iterwa na insuline polypeptide reseptor agonist (GIP-RA) / GLP-1RA, Tirzepatide yakozweho ubushakashatsi ku ngaruka zayo ku bimenyetso byo gukura kw'imitsi (CREB na BDNF), apoptose (igipimo cya BAX / Bcl2), gutandukanya (pAkt, MAP2, GAP43, na AGBL4, GLUT4, GLUT GLUT) umurongo wa selile ya neuroblastoma (SHSY5Y). Ibisubizo ku nshuro ya mbere byibanze ku ruhare rwa Tirzepatide mu gukora inzira ya pAkt / CREB / BDNF no kumanuka werekana kasake, ndetse ningaruka zayo muri neuroprotection. Yerekanye kandi ko Tirzepatide ishobora kurwanya ingaruka zijyanye na hyperglycemia hamwe no kurwanya insuline kurwego rwa neuronal. Kubwibyo, Tirzepatide irashobora guteza imbere neurodegeneration iterwa na hyperglycemia kandi igatsinda insuline ya insuline, itanga ubumenyi bushya bwo kunoza imitekerereze ya neuropathie iterwa na metabolism [6] .
Iterambere ryubushakashatsi mukuvura ubwoko bwa 2 metabolism mellitus:
Ubushakashatsi bumwe bwerekanye ko Tirzepatide, nk'ubwoko bushya bw'imiti ya hypoglycemic, ibaye iyambere ya GIP / GLP-1R agonist yemewe yo kuvura metabolism muri Amerika. Byemejwe ko bifite ingaruka zikomeye zo kugabanya glucose no kugabanya ibiro mu bigeragezo byinshi binini by’amavuriro, kandi hari ibimenyetso byerekana ko bifite imbaraga nyinshi mu kurinda umutima. Mubyongeyeho, igitekerezo cya peptide yubukorikori cyafunguye ibintu byinshi bitazwi kuri Tirzepatide. Ibigeragezo bikomeje (NCT04166773) n'ibimenyetso byerekana ko bigaragara ko ari imiti itanga icyizere mu bijyanye n'indwara y'umwijima idafite inzoga (NAFLD), impyiko na neuroprotection, n'ibindi [7].
Ingaruka ndende za T irzepatide kubuzima bwimitsi yumutima:
Tirzepatide irashobora kugabanya ibyago byindwara zifata umutima nimiyoboro itera kugabanya ibiro. Ubushakashatsi bwasuzumye ingaruka za Tirzepatide ku mubyibuho ukabije ndetse n’indwara zifata umutima n’umutima ku bantu bakuze b'Abanyamerika [8] . Ubushakashatsi bwerekanye ko mu Banyamerika bakuze bemerewe kuvurwa na Tirzepatide, nyuma yo kuvurwa na 15mg ya Tirzepatide, byagereranijwe ko 70,6% na 56.7% by’abantu bakuru bafite ibiro byibura ≥15% na ≥20%, bivuze ko umubare w’abantu bafite umubyibuho ukabije wa ≥15% na ≥20%. Ku bantu badafite indwara zifata umutima, bivugwa ko imyaka 10 y’indwara zifata umutima n’umutima zagabanutse ziva kuri 10.1% mbere yo kuvurwa zigera kuri 7.7% nyuma yo kuvurwa, ibyo bikaba byerekana ko igabanuka ry’impanuka ryagabanutseho 2,4% ndetse n’ikigereranyo cyo kugabanuka kwa 23,6%, bivuze ko miliyoni 2 z’indwara zifata umutima n’umutima zishobora gukumirwa mu myaka 10.
Mu gusoza, Tirzepatide nigitabo gishya cya agonist ya reseptor ya GIP na GLP-1 kandi gifite akamaro kanini mukuvura ubwoko bwa 2 metabolism mellitus n'umubyibuho ukabije. Irashobora guteza imbere neza gusohora kwa insuline, ikabuza gusohora glucagon, kugenzura neza glucose yamaraso, kugabanya ibyago byingaruka, kunoza imikorere ya selile pancreatic β selile, no gutinza iterambere rya metabolism. Ifite kandi ingaruka zo gukingira sisitemu yumutima. Mu kuvura umubyibuho ukabije, irashobora kugabanya neza gufata ibiryo, kugabanya ubushake bwo kurya, kongera guhaga, gufasha abarwayi bafite umubyibuho ukabije guta ibiro, no kugabanya ibyago by’ingaruka ziterwa n'umubyibuho ukabije. Irashobora kandi kunoza insuline irwanya na metabolism ya lipide. Byongeye kandi, irerekana ubushobozi mukuvura indwara ziterwa na metabolike idasanzwe nka statohepatite idafite inzoga, syndrome de apnea, no kunanirwa k'umutima, kandi irashobora icyarimwe kunoza ibipimo byinshi bya metabolike, itanga gahunda yuzuye yo kuvura. Uburyo bwayo bwo gutera inshinge rimwe mucyumweru biroroshye gukoresha kandi birashobora kunoza uburyo bwo kuvura abarwayi. Mugucunga neza glucose yamaraso nuburemere no kugabanya ibyago byingaruka, ubuzima bwumurwayi burashobora kunozwa kuburyo bugaragara, ubushobozi bwibikorwa byabo bya buri munsi nubuzima bwiza burashobora kwiyongera, icyizere cyo kurwanya indwara kirashobora kwiyongera, umutwaro wimitekerereze yabo urashobora kugabanuka, kandi imibereho yabo irashobora guhinduka.
Ibyerekeye Umwanditsi
Ibikoresho byavuzwe haruguru byose byakorewe ubushakashatsi, byahinduwe kandi byakozwe na Cocer Peptides.
Umwanditsi w'ikinyamakuru
Dr. William T. Garvey ni intiti n’umushakashatsi uzwi cyane bifitanye isano n’ibigo byinshi bizwi, birimo kaminuza ya Alabama i Birmingham, kaminuza ya Aston, n’ikigo nderabuzima cya Birmingham. Amashuri ye n'uburambe bw'umwuga bikubiyemo amasomo atandukanye mu buvuzi na siyansi. Dr. Garvey yagize uruhare runini mu bijyanye na endocrinology na metabolism, imirire n’imirire, ibinyabuzima na biyolojiya y’ibinyabuzima, ndetse n’ubuvuzi rusange ndetse n’imbere, yibanda cyane kuri sisitemu yumutima nimiyoboro y’umutima. Ibikorwa bye byamenyekanye cyane kandi byubahwa, cyane cyane byiswe Umushakashatsi wavuzwe cyane mu cyiciro cyambukiranya imipaka mu myaka ya 2023 na 2024, byerekana ingaruka n’ingaruka z’ubushakashatsi bwe ku muryango mugari wa siyansi.
Ubushakashatsi bwa Dr. Garvey n'ubuhanga bugera no mu bice bitandukanye by'indwara ziterwa na metabolike. Yagize uruhare runini mu kwiga metabolism mellitus, umubyibuho ukabije, hamwe n’ibibazo bifitanye isano nayo, agamije kuvumbura ingamba zo kuvura udushya no kunoza umusaruro w’abarwayi. Ibikorwa bye bikubiyemo ubushakashatsi bwibanze bwa siyansi, ibizamini by’amavuriro, n’ubushakashatsi bw’ubuhinduzi, bikuraho itandukaniro riri hagati y’ibyavuye muri laboratoire hamwe n’ubuvuzi busanzwe ku isi. Binyuze mu bushakashatsi bwe bwimbitse, Dr. Garvey yagize uruhare mu gusobanukirwa byimbitse n’uburyo bw’imiterere y’imihindagurikire y’imihindagurikire y’ikirere kandi yafashije gushyiraho umurongo ngenderwaho w’amavuriro na protocole y’ubuvuzi mu bijyanye na endocrinology na metabolism. Dr. William T. Garvey yashyizwe ku rutonde rw'ibisobanuro byatanzwe [5].
