|
1kits （10Ibikoresho）
| Umubare: | |
|---|---|
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 nibiyobyabwenge bya polypeptide. Iterambere ryayo rituruka ku gusobanukirwa byimazeyo aho ubushobozi bwa GLP-1 bwakira reseptor agonist mu kuvura indwara ya diyabete yo mu bwoko bwa 2 (T2DM) n'umubyibuho ukabije. Nubwo agoniste ya GLP-1 yerekanye imikorere myiza mugucunga glucose yamaraso no kugabanya ibiro, abahanga basanze imikorere yabo ya reseptor ya GIP idakomeye, ibyo bikaba bigabanya ingaruka zo kuvura imiti. Niyo mpamvu, itsinda ry’ubushakashatsi n’iterambere ryiyemeje guteza imbere ubwoko bushya bw’ibiyobyabwenge bishobora gukora icyarimwe GIPR na GLP-1R, bigamije kugera ku buryo bunoze kandi bunoze bwo kurwanya glucose y’amaraso no gucunga ibiro [1].
Mugihe cyubushakashatsi niterambere, abahanga bakoze umubare munini wubushakashatsi bwibanze nubushakashatsi bwamavuriro. Mu cyiciro cy’ubushakashatsi bwibanze, imiti ya Tirzepatide ya farumasi yasesenguwe neza binyuze mu bushakashatsi bw’inyamaswa, igenzura ubushobozi bwayo mu kugenzura amaraso glucose no kugabanya ibiro. Ibisubizo byerekanye ko bishobora kugabanya cyane urugero rwa glucose yamaraso mubyitegererezo byinyamanswa kandi bikerekana imikorere myiza mugucunga ibiro, bigashyiraho urufatiro rwibizamini byakurikiyeho.
Icyakurikiyeho, icyiciro cyo kugerageza kwa clinique cyarimo icyiciro cya mbere, II, na III. Ikigeragezo cyo mu cyiciro cya mbere cyasuzumye cyane cyane umutekano, kwihanganira, hamwe n’imiti ya farumasi. Ibisubizo byagaragaje ko Tirzepatid yari ifite umutekano mwiza no kwihanganira. Ikigeragezo cyo mu cyiciro cya II cyongeye gukora ubushakashatsi ku mikorere n’umutekano bya dosiye zitandukanye za Tirzepatid ku barwayi barwaye T2DM, byerekana mbere na mbere urugero rwiza rwabyo. Ikigeragezo gikomeye cyicyiciro cya gatatu cyamavuriro, nka SURPASS yubushakashatsi, cyarimo umubare munini wabarwayi bafite T2DM. Ibisubizo byerekanye ko Tirzepatid yarutaga cyane GLP-1 yakira reseptor agoniste, nka semaglutide, mu kugabanya glucose yamaraso nuburemere, bitanga ibimenyetso bifatika byerekana ko Tirzepatide ikoreshwa mu kwamamaza [1].
Nubuhe buryo bwo gukora bwa Tirzepatid?
Tirzepatid igabanya glucose yamaraso binyuze muburyo bwinshi bukorera hamwe. Iyo ukora reseptor ya GLP-1, Tirzepatid ihuza reseptor ya GLP-1 kuri pancreatic β-selile, yigana ibikorwa bya GLP-1 karemano. GLP-1 ni imisemburo ikorwa mu mara kandi ni ingenzi mu kubungabunga glucose homeostasis. Irashobora guteza imbere insuline ya insuline, gusohora, hamwe no kumva glucose, kugabanya imisemburo ya glucagon kugirango iteze guhaga, kandi igabanye ubushake bwo kurya.
Uku gukora kurashobora guteza imbere gusohora insuline. Insuline ni imisemburo nyamukuru ya hypoglycemic mu mubiri, ishobora kongera gufata no gukoresha glucose na selile, bityo bikagabanya urugero rwa glucose. Ku barwayi barwaye T2DM, gusohora kwa insuline ntibihagije cyangwa ingirabuzimafatizo zo kumva insuline zigabanuka, bigatuma glucose yamaraso yiyongera. Mugukoresha reseptor ya GLP-1, Tirzepatid yongera imisemburo ya insuline, ifasha kunoza igenzura ryamaraso glucose.
Muri icyo gihe, ibikorwa bya GLP-1 byakira nabyo bibuza kurekura glucagon. Ubusanzwe Glucagon itera glycogenolysis na gluconeogenezi mugihe cyo kwiyiriza ubusa, byongera umusaruro wamaraso glucose. Mu guhagarika ibikorwa bya glucagon, Tirzepatid irushaho kugabanya inkomoko ya glucose yamaraso, igira uruhare mu kurwanya glucose yamaraso [2].
Iyo ukora 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 mu kwanduza inzira zerekana ibimenyetso, insuline ziyongera, kandi selile yitabira insuline iratera imbere, bityo bikagabanya neza glucose yamaraso.
Tirzepatid ni icyiciro cya mbere mu byiciro bibiri bya glucagon isa na peptide-1 hamwe na glucose iterwa na insulineotropique polypeptide (GIP), yemejwe kuvura abarwayi bakuze bafite T2DM nk'umugereka w'imirire no gukora siporo. Tirzepatid ni imiterere yimiti yubukorikori ishingiye kumurongo wa GIP, igizwe 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 byumubiri, no gutinda gusohora gastric. Izi ngaruka zibiri za reseptor agonist zituma Tirzepatid ikora neza kuruta GLP-1 yakira reseptor agoniste mugutezimbere insuline no kubuza glucagon gusohora [2].
Tirzepatid irashobora kandi gutinza ubusa gastrica no kongera guhaga. Irashobora gutinza gusiba gastrica, ikongerera igihe cyo gutura ibiryo mu gifu no kugabanya umuvuduko wintungamubiri zintungamubiri, bityo ikirinda kuzamuka gukabije kwa glucose yamaraso nyuma yinyuma. Mu bushakashatsi butari amavuriro n’ubuvuzi, ingaruka za Tirzepatid ku gusiba gastrica ziragereranywa n’iza GLP-1 reseptor agonist. Imbeba zifite umubyibuho ukabije ziterwa nimirire, urugero rwo gutinda kwa gastrica na Tirzepatid rusa na semaglutide, ariko izi ngaruka zikomeye zo kubuza zirashira nyuma yibyumweru 2 bivuwe.
Abitabiriye amahugurwa hamwe na T2DM kandi idafite, Tirzepatide rimwe mu cyumweru (mg5 mg na .5 4.5 mg) yatinze gusohora gastric nyuma yo kunywa inshuro imwe. Mu bitabiriye ubuzima bwiza, ingaruka zagaragaye nyuma yingero nyinshi za Tirzepatid cyangwa dulaglutide (Urva S, 2020). Muri icyo gihe, irashobora kandi gukora kuri sisitemu yo hagati yo hagati, kongera guhaga, 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 T2DM, kandi kigafasha kunoza insuline ndetse n’imiterere rusange ya metabolike [2].
Tirzepatid yasanze yongera urugero rwa adiponectine, adipocytokine ijyanye no kumva insuline. Kwiyongera kwa adiponectine bifasha kunoza insuline, bigatuma selile zitabira insuline, bityo gufata neza no gukoresha glucose no 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 lipoprotein (LDL) nkeya na triglyceride [3] , bikarushaho gushyigikira inyungu zayo zose mu micungire y’amaraso glucose.
Inkomoko: PubMed [5]
Ubushakashatsi bujyanye
Ingaruka zo gucunga ibiro ku barwayi bafite umubyibuho ukabije na diyabete yo mu bwoko bwa 2
Ubushakashatsi bwinshi bw’amavuriro bwemeje imikorere ya Tirzepatid mu micungire y’ibiro by’umubiri ku barwayi bafite umubyibuho ukabije na T2DM. Mu bushakashatsi bwiswe 'SURMOUNT-2 ', bwari Icyiciro cya 3, impumyi ebyiri, impumyi, igenzurwa na platbo ikorerwa mu bihugu birindwi. Abakuze (bafite imyaka 18) bafite indangagaciro z'umubiri (BMI) za kg 27 / m² cyangwa hejuru hamwe na glycated hemoglobine (HbA₁c) ya 7 - 10% bahawe amahirwe yo kwakira inshuro imwe mu cyumweru inshinge za Tirzepatid (mg 10 cyangwa mg 15) cyangwa umwanya wa byumweru 72.
Ibisubizo byagaragaje ko mu cyumweru cya 72, ijanisha ryo kugabanuka ibiro muri Tirzepatid 10 mg na 15 mg byari -12.8% na -14.7%, ugereranije na -3.2% mu itsinda rya placebo. Ikigereranyo cyo kuvura cya Tirzepatid 10 mg na mg 15 ugereranije na placebo cyari -9,6 ku ijana na -11,6 ku ijana, byombi byari bifite imibare (p <0.0001). Byongeye kandi, umubare munini w’abarwayi bahabwa imiti ya Tirzepatid wageze ku ntera yo kugabanuka ibiro 5% cyangwa birenga (79 - 83% vs 32%) [4].
Mu bushakashatsi bwa 'SURMOUNT-2 ', uburemere bw'ibanze bwari ibiro 100.7, BMI yari 36.1 kg / m², naho HbA₁c yari 8.02%. Nyuma y'ibyumweru 72 bivurwa, Tirzepatid ntabwo yagabanije cyane ibiro byumubiri gusa ahubwo yanagize ingaruka nziza mugucunga glucose yamaraso [4].
Ingaruka nziza kuri diabete ifitanye isano na neuropathie
ubushakashatsi bwa ome bwerekanye ko GLP1-RAs ishobora kugabanya ibyago byo guta umutwe ku barwayi barwaye T2DM mu kunoza kwibuka, kwiga, no gutsinda ubumuga bwo kutamenya. Nka GIP-RA / GLP-1RA ebyiri, Tirzepatid yakorewe ubushakashatsi kumurongo wa selile ya neuroblastoma (SHSY5Y) kubera ingaruka zayo ku bimenyetso byerekana imikurire ya neuronal (CREB na BDNF), apoptose (igipimo cya BAX / Bcl2), itandukaniro (pAkt, MAP2, GAP43, na AGBL4, GLUT, GLUT1).
Ibisubizo ku nshuro ya mbere byibanze ku ruhare rwa Tirzepatid mu gukora inzira ya pAkt / CREB / BDNF no kumanuka werekana kasake, ndetse no gukora neza kwa neuroprotective. Yagaragaje kandi ko Tirzepatid yashoboye kurwanya ingaruka ziterwa na hyperglycemia na insuline irwanya urwego rwa neuronal. Kubwibyo rero, Tirzepatid irashobora guteza imbere neurodegeneration iterwa na hyperglycemia kandi igatsinda insuline irwanya insuline, igatanga ubumenyi bushya bwo kunoza indwara ya diabete iterwa na diyabete [5].
Iterambere ryubushakashatsi mukuvura diyabete yo mu bwoko bwa 2
Ubushakashatsi bumwe bwerekanye ko nk'ubwoko bushya bw'imiti ya hypoglycemic, Tirzepatid ibaye agoniste ya mbere ya GIP / GLP-1R yemewe yo kuvura diyabete muri Amerika. Byemejwe ko bifite ingaruka zikomeye mu kugabanya glucose yamaraso no kugabanya ibiro byumubiri mugupima kwinshi kwamavuriro, kandi hari ibimenyetso byerekana ko nayo ifite imbaraga nyinshi mukurinda 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 bice nk'indwara y'umwijima idafite inzoga (NAFLD), kurinda impyiko, na neuroprotection [6].
Ingaruka ndende za tirzepatide kubuzima bwumutima
Tirzepatid irashobora kugabanya ibyago byindwara zifata umutima nimiyoboro itera kugabanya ibiro. Ubushakashatsi bwasuzumye ingaruka za Tirzepatid ku mubyibuho ukabije n'indwara z'umutima n'imitsi ku bantu bakuze b'Abanyamerika (Wong ND, 2024). Ubushakashatsi bwerekanye ko mu Banyamerika bakuze bemerewe kuvurwa na Tirzepatid, nyuma yo kuvurwa hamwe na mg 15 za Tirzepatid, byagereranijwe ko 70,6% na 56.7% by’abantu bakuru bakuze ibiro ≥15% na 20%, bivuze ko umubare w’abantu bafite umubyibuho ukabije wagabanutseho 58.8%.
Mu badafite indwara z'umutima n'imitsi, 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% 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 ir Tirzepatid nigitabo gishya cya agonist ya GIP na GLP-1 yakira, ifite akamaro kanini mukuvura T2DM n'umubyibuho ukabije. Irashobora guteza imbere neza gusohora kwa insuline, ikabuza gusohora glucagon, kugenzura neza glucose yamaraso, kugabanya ibyago byo guhura nibibazo, kunoza imikorere ya pancreatic β-selile, no gutinza iterambere rya diyabete. 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 metabolisme ya lipide. Byongeye kandi, yerekanye ubushobozi mu kuvura indwara ziterwa na metabolike ziterwa na metabolike nka steatohepatite idafite inzoga, syndrome de apnea, no kunanirwa k'umutima. Irashobora kunoza ibipimo byinshi bya metabolike icyarimwe, itanga gahunda yuzuye yo kuvura.
Uburyo bwa buri cyumweru bwo gutera inshinge biroroshye gukoresha kandi birashobora kunoza uburyo bwo kuvura abarwayi.
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 diyabete mellitus, umubyibuho ukabije, hamwe n’ingaruka ziterwa 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'ibitekerezo [4].
