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TirzepatidStructure 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 Tirzepatid
Ni ubuhe bushakashatsi bwakozwe na Tirzepatid?
Tirzepatid 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 glucose yamaraso no kugabanya ibiro, abahanga basanze mugihe bakora reseptor ya GLP-1, ingaruka zabo zo gukora kuri reseptor ya GIP ntizifite intege nke, kuburyo bugabanya 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 Tirzepatid, abahanga bakoze ubushakashatsi bwinshi bwibanze nubushakashatsi bwamavuriro. Mbere na mbere, mu cyiciro cy’ubushakashatsi bwibanze, imiterere ya farumodinamike ya Tirzepatid yasuzumwe cyane binyuze mu bushakashatsi bw’inyamaswa, kandi hasuzumwe ubushobozi bwayo mu kugenzura amaraso glucose no kugabanya ibiro. Ibisubizo byerekanye ko Tirzepatid ishobora kugabanya cyane glucose yamaraso mubyitegererezo byinyamaswa kandi ikanakora neza mugucunga ibiro. Ubu bushakashatsi bwiza bwashizeho urufatiro rukomeye rwibizamini byakurikiyeho.
Nyuma, Tirzepatid yinjiye mubyiciro byubuvuzi, harimo icyiciro cya I, II, na III. Mu cyiciro cya mbere cy'igeragezwa, hasuzumwe ahanini umutekano, ubworoherane, hamwe na farumasi ya farumasi, kandi ibisubizo byagaragaje ko Tirzepatid yari ifite umutekano mwiza no kwihanganira. Ikigeragezo cya kabiri cyakomeje gukora ubushakashatsi ku mikorere n’umutekano bya dosiye zitandukanye za Tirzepatid ku barwayi barwaye metabolism yo mu bwoko bwa 2, kandi bagena mbere na mbere urugero rwiza rwabyo. Ikigeragezo cyingenzi cyane icyiciro cya III cyamavuriro, nkurwego rwa SURPASS rwubushakashatsi, cyerekanye umubare munini wabarwayi bafite metabolism yo mu bwoko bwa 2. Ibisubizo byerekanye ko Tirzepatid yarutaga cyane GLP-1 yakira reseptor agoniste, nka semaglutide, mu kugabanya glucose yamaraso nuburemere. Igisubizo cyagezweho cyatanze ibimenyetso bifatika byo kwamamaza kwa Tirzepatid [1].
Tirzepatid ni polypeptide igizwe na acide 39 amine, aho aside amine ku giti cye yahinduwe muburyo bwo kunoza ituze no gukora neza. Igishushanyo mbonera kidasanzwe gifasha Tirzepatid guhuza ingaruka zimisemburo ibiri ya incretin, GIP na GLP-1, muri molekile imwe, kandi igakora imisemburo ya hormone igira uruhare mukugenzura glucose yamaraso hakoreshejwe uburyo bubiri bwibikorwa. By'umwihariko, Tirzepatid 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 gastrica no kongera guhaga, bigabanya ubushake bwo kurya no gufata ibiryo, bityo bikagera no gucunga ibiro. Ubu buryo bubiri bwibikorwa butanga Tirzepatid ibyiza byihariye mukuvura ubwoko bwa 2 metabolism mellitus n'umubyibuho ukabije, bigaha abarwayi uburyo bunoze bwo kuvura [1].
Nubuhe buryo bwo gukora bwa Tirzepatid?
Tirzepatid igabanya glucose yamaraso ikoresheje uburyo bwinshi bukorera hamwe, kuburyo bukurikira: Gukora reseptor ya GLP-1: Tirzepatid 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 imisemburo ya 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 rwamaraso glucose. Ku barwayi bafite metabolism yo mu bwoko bwa 2, gusohora insuline ntibihagije cyangwa se ingirabuzimafatizo za insuline zigabanuka, bigatuma glucose yiyongera. Tirzepatid yongerera insuline gusohora reseptor ya GLP-1, ifasha kunoza igenzura rya 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. Mu guhagarika ingaruka za glucagon, Tirzepatid irushaho kugabanya inkomoko ya glucose yamaraso, ifasha kugenzura glucose yamaraso [2] (Anonymous, 2023).
Gukora kwa reseptor ya GIP: Tirzepatid 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. Tirzepatid nicyiciro cya mbere cyo mu cyiciro cya kabiri cyitwa glucagon gisa na peptide-1 hamwe na glucose iterwa na insulineotropic polypeptide (GIP) igereranywa no kuvura abarwayi bakuze bafite 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 gastric 2.
Izi ngaruka ebyiri za reseptor agonist zituma Tirzepatid ikora neza mugutezimbere imisemburo ya insuline no kubuza glucagon gusohora kuruta GLP-1 yakira reseptor agonist [2].
Gutinda gusiba gastrica no kongera guhaga: Tirzepatide irashobora gutinza gusiba gastrica, kongera igihe cyo gutura ibiryo mu gifu, kugabanya umuvuduko wintungamubiri zintungamubiri, bityo ukirinda kwiyongera gukabije kwa glucose yamaraso nyuma yo kubyara. Mu bushakashatsi bwibanze n’ubuvuzi, ingaruka za Tirzepatid ku gusiba gastrica ziragereranywa n’iza GLP-1 reseptor agonist. Imbeba zifite umubyibuho ukabije ziterwa nimirire, urugero rwo gutinda gukuramo gastrica na Tirzepatid rusa na semaglutide, ariko izo ngaruka zikomeye zo kubuza zirashira nyuma yibyumweru 2 bivuwe. Abitabiriye amahugurwa hamwe nubwoko bwa 2 metabolism mellitus, rimwe mu cyumweru Tirzepatid (≥5 na .54.5mg,) yatinze gusiba gastric nyuma yumuti umwe. Mu bitabiriye ubuzima bwiza, iyi ngaruka yagaragaye nyuma ya dosiye nyinshi ya Tirzepatid 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 urugero rwa glucose yamaraso, cyane cyane bikwiranye n’ikibazo cy’umubyibuho ukabije gikunze guherekezwa 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: Tirzepatid yasanze yongera urugero rwa adiponectine, ari 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, Tirzepatid irashobora kandi kunoza imiterere ya lipide kandi ikagira ingaruka zo kurinda ubuzima bwumutima. Tirzepatid byagaragaye ko ishobora kuzamura umuvuduko wamaraso, kugabanya cholesterol ya lipoproteine (LDL) nkeya 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’amavuriro bwemeje ingaruka zikomeye zo kugabanya ibiro: Mu bushakashatsi bwiswe 'SURMOUNT-2 ', uru rubanza rwabaye icyiciro cya 3, impumyi ebyiri, zidahwitse, zagenzuwe 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 Tirzepatid (10mg cyangwa 15mg) cyangwa umwanya wa byumweru 72. Ibisubizo byagaragaje ko ku cyumweru cya 72, ijanisha ryo kugabanuka ibiro mu matsinda ya Tirzepatid 10mg na 15mg ryari -12.8% na -14.7%, mu gihe mu itsinda rya placebo ryari -3.2%. Ikigereranyo cyo kuvura cya Tirzepatid 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 Tirzepatid 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, Tirzepatid ntiyagabanije cyane ibiro 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 agoniste (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-iterwa na insuline polypeptide reseptor agonist (GIP-RA) / GLP-1RA, Tirzepatid 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), na GLBS, GLUT4 umurongo wa selile ya neuroblastoma (SHSY5Y). Ibisubizo ku nshuro ya mbere byibanze ku ruhare rwa Tirzepatid mu gukora inzira ya pAkt / CREB / BDNF no kumanuka werekana kasake, ndetse ningaruka zayo muri neuroprotection. Yerekanye kandi ko Tirzepatid ishobora kurwanya ingaruka zijyanye na hyperglycemia hamwe no kurwanya insuline kurwego rwa neuronal. Kubwibyo, Tirzepatid irashobora guteza imbere neurodegeneration iterwa na hyperglycemia kandi igatsinda insuline irwanya insuline, igatanga ubumenyi bushya bwo kunoza imitekerereze ya metabolism iterwa na metabolism [6] .
Iterambere ryubushakashatsi mukuvura ubwoko bwa 2 metabolism mellitus:
Ubushakashatsi bumwe bwerekanye ko Tirzepatid, nk'ubwoko bushya bw'imiti ya hypoglycemic, ibaye agoniste ya mbere ya GIP / GLP-1R yemewe yo kuvura metabolisme 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 n'ubushobozi bukomeye mu kurinda umutima. Mubyongeyeho, igitekerezo cya peptide ya syntetique yafunguye ibintu byinshi bitazwi kuri Tirzepatid. 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 bwumutima nimiyoboro:
Tirzepatid irashobora kugabanya ibyago byindwara zifata umutima nimiyoboro itera kugabanya ibiro. Ubushakashatsi bwasuzumye ingaruka za Tirzepatid 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 Tirzepatid, nyuma yo kuvurwa na 15mg ya Tirzepatid, 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 z'umutima-damura, 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’ibyago ryagabanutseho 2,4% naho kugabanuka kwa 23,6%, bivuze ko miliyoni 2 z’indwara zifata umutima n’umutima zishobora gukumirwa mu myaka 10.
Mu gusoza, Tirzepatid nigitabo gishya cya agonist ya GIP na GLP-1 yakira 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 itari inzoga, syndrome de apnea, hamwe 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 cyane, ubushobozi bwibikorwa byabo bya buri munsi nubuzima bwiza burashobora kwiyongera, icyizere cyabo cyo kurwanya indwara kirashobora kwiyongera, umutwaro wabo wo mumitekerereze 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 cy’ubuvuzi 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 cyane kuri sisitemu yumutima nimiyoboro yumutima. Ibikorwa bye byamenyekanye cyane kandi byubahwa, cyane cyane byiswe Umushakashatsi wavuzwe cyane mu cyiciro cya Cross-Field mu myaka ya 2023 na 2024, byerekana ingaruka n’ingaruka zikomeye 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 bunini, Dr. Garvey yagize uruhare mu gusobanukirwa byimbitse n’uburyo bw’imiterere y’imihindagurikire y’imihindagurikire y’ikirere kandi yafashije mu gushyiraho umurongo ngenderwaho w’amavuriro na protocole y’ubuvuzi mu bijyanye na endocrinology na metabolism. Dr. William T. Garvey yanditse ku rutonde rw'ibisobanuro byatanzwe [5].
