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Edemede na ozi ngwaahịa niile enyere na webụsaịtị a bụ naanị maka mgbasa ozi na ebumnuche mmụta.
Ngwaahịa ndị enyere na webụsaịtị a bụ naanị maka nyocha in vitro. A na-eme nyocha in vitro (Latin: * na iko *, nke pụtara na ihe eji enyo) na mpụga ahụ mmadụ. Ngwaahịa ndị a abụghị ọgwụ, ndị US Food and Drug Administration (FDA) akwadoghị ya, ha agaghịkwa eji ya gbochie, gwọọ, ma ọ bụ gwọọ ọnọdụ ahụike ọ bụla, ọrịa, ma ọ bụ ọrịa. Iwu amachibidoro nke ọma iwebata ngwaahịa ndị a n'ime ahụ mmadụ ma ọ bụ anụmanụ n'ụdị ọ bụla.
Ibu ibu na-aghọ ihe na-esiwanye njọ n'ụwa niile, na-emetụta ọ bụghị naanị ahụike anụ ahụ kamakwa ọ na-ejikọta ya na ọrịa na-adịghị ala ala dịka ọrịa obi na akwara ozi na ụdị ọrịa shuga 2. Ịchọta ụzọ dị mma ma dị irè iji belata ibu ibu bụ isi ihe nyocha ahụike na-elekwasị anya. Tizepatide bụ ọgwụ na-arụ ọrụ na ndị na-anabata ya abụọ, na-enye ụzọ ọhụrụ maka ọgwụgwọ oke ibu.
Ọnụọgụ 1: Nhazi na nzọụkwụ mbụ nke akara ngosi mkpụrụ ndụ site na GIPR na GLP1R na GIPR-GLP1R dual agonists RG7697-NNCOO90-2746 na LY3298176.
Usoro nke abụọ nke Tizepatide Agonist Agonist
(1) GIP Nnabata Agonist Mechanism
Ndabere gbasara anụ ahụ nke onye nnabata GIP
Onye na-anabata GIP bụ onye na-anabata mkpụrụ ndụ pụrụ iche nke achọtara n'ọtụtụ akụkụ, gụnyere pancreas, anụ ahụ adipose, imeju, na mọzụlụ. N'elu mkpụrụ ndụ beta nke islet pancreatic, mgbe hormone GIP na-ejikọta na onye na-anabata ya, ọ na-eme ka ụzọ mgbaàmà intracellular rụọ ọrụ, na-eduga na mmụba na ọkwa cAMP intracellular. cAMP na-arụ ọrụ protein kinase A, nke, site na usoro mmeghachi omume, na-akwalite mmepụta insulin.
N'ime anụ ahụ adipose, ịgbalite onye na-anabata GIP na-achịkwa metabolism adipocyte. Ọ na-akwalite nnabata glucose site na adipocytes, na-abawanye njikọ nke fatty acid na nchekwa, na-egbochi lipolysis. Nnyocha na-egosi na usoro a nwere ike jikọta ya na mmụba nke ọnụ ọgụgụ ndị na-ebu glucose (GLUT4), nke na-eme ka glucose banye adipocytes, na-enye akụrụngwa maka njikọ abụba.
Mmetụta Tizepatide na GIP Nnabata
Tizepatide nwere usoro yiri nke homonụ GIP ma nwee ike ijikọ ma mee ka ndị na-anabata GIP rụọ ọrụ. E jiri ya tụnyere GIP endogenous, Tizepatide nwere njikọ njikọ siri ike maka ndị na-anabata ya, na-eme ka ọ rụọ ọrụ nke ọma nke ụzọ mgbaàmà. Nnyocha egosila na mgbe ejikọtara ya na ndị na-anabata ya, ọ nwere ike ịbawanye ọkwa CAMP na-adịgide adịgide, si otú ahụ na-akwalite mmepụta insulin nke ọma. N'ime anụ ahụ adipose, nhazi ya ziri ezi nke metabolism lipid mgbe ịgbalite nnabata na-enyere ma nnabata glucose site na adipocytes na njikọ ziri ezi na nchekwa nke fatty acids, na-egbochi mkpokọta abụba gabigara ókè-ihe dị mkpa na-ejigide metabolism lipid nkịtị.
Ọnụọgụ 2: Mmetụta ntụnyere nke RG7697/NNCOO90-2746 na LY3298176 site na ule ụlọ ọgwụ, ma e wezụga ebe asterisks na-egosi (gosiri naanị na òké).
(2) Usoro nnabata nnabata GLP-1
Ndabere gbasara anụ ahụ nke ndị nnabata GLP-1
Onye nnabata GLP-1 bụkwa onye na-anabata mkpụrụ ndụ nke ekesara na sel beta pancreatic, akụkụ eriri afọ, na ụbụrụ. N'ime mkpụrụ ndụ beta pancreatic, GLP-1 na-ejikọta ya na onye na-anabata ya ma na-arụ ọrụ ụzọ mgbaàmà iji kwalite nzuzo insulin. N'adịghị ka GIP, a na-achịkwa mmetụta GLP-1 site na ọkwa glucose ọbara: ọ na-akwalite mmepụta insulin mgbe glucose ọbara dị elu na mmetụta ya na-ada mbà mgbe glucose ọbara dị nkịtị, na-eme ka ọ dị nchebe.
N'ime eriri afọ, ịgbalite onye na-anabata GLP-1 na-agbatị nri n'ime afọ, na-egbochi ngwa ngwa glucose ọbara postprandial, ma na-egbochi secretion acid gastric, na-echebe mucosa eriri afọ. N'ụbụrụ, ọ na-arụ ọrụ na mpaghara na-achịkwa agụụ, na-ebelata agụụ na ụbara satiety, si otú ahụ na-eduga ná mbelata nri oriri.
Mmetụta Tizepatide na GLP-1 nnabata
Tizepatide nwere njikọ njikọ siri ike maka ndị na-anabata GLP-1, na mgbe ịgbalite ya, ọ na-emepụta mmetụta yiri nke GLP-1 endogenous. N'ihe gbasara usoro glucose ọbara, ọ na-akwalite mmepụta insulin dabere na ọkwa glucose ọbara, si otú a na-achịkwa glucose ọbara ka mma. N'ime eriri afọ nke eriri afọ, mmetụta ya nke igbu oge igbu oge na-apụta ìhè karịa nke ọgwụ ọdịnala ụfọdụ. N'ụbụrụ, mmetụta na-egbochi agụụ ya na-adịgide adịgide, na-enyere aka n'ibelata ibu.
(3) Mmetụta mmekọrịta nke abụọ nnabata Agonism
Mmetụta mmekọrịta chiri anya na Iwu Glucose Ọbara
Tizepatide na-arụ ọrụ na GIP na GLP-1 ndị na-anabata ya, na-eme ka usoro glucose ọbara dịkwuo mma. GIP na-akwalite mmepụta insulin ngwa ngwa n'oge mmalite postprandial, na-ebelata ọnụ ọgụgụ glucose ọbara; GLP-1 na-aga n'ihu na-arụ ọrụ n'ime usoro postprandial niile, ọ bụghị naanị na-akwalite mmepụta insulin kamakwa ọ na-egbu oge ịgbasa afọ, na-ebelata oriri, na ịnọgide na-enwe ọkwa glucose ọbara kwụsiri ike. Ịgbalite ma ndị na-anabata ya n'otu oge na-ebute njikwa glucose ọbara kacha mma mgbe nri gasịrị. Dịka ọmụmaatụ, na nnwale anụmanụ na-arịa ọrịa shuga, Tizepatide belatara mmụba nke glucose ọbara postprandial karịa ọgwụ GIP ma ọ bụ GLP-1 naanị, glucose ọbara laghachiri na nkịtị ngwa ngwa.
Mmetụta mmekọrịta dị na Metabolism ike
N'ihe gbasara metabolism ike, ndị na-anabata GIP agonists na-akwalite nnabata glucose site na mkpụrụ ndụ abụba, mana n'okpuru mmetụta nke Tizepatide, njikọ abụba anaghị agbakọta nke ukwuu. Ka ọ dị ugbu a, GLP-1 agonists ndị na-anabata ya na-ebelata agụụ, na-abawanye afọ ojuju, belata oriri calorie, na-akwalite ọkụ abụba na mmefu ike. Omume abụọ a na-edozi oriri ike na mmefu. Dịka ọmụmaatụ, n'ime nnwale anụmanụ na oke ibu, mgbe ejiri Tizepatide mee ihe ruo oge ụfọdụ, ịdị arọ anụ ahụ na-ebelata, abụba anụ ahụ na-ebelata, na metabolism basal na-abawanye ngwa ngwa.
Ọnụọgụ 3: Ọdịiche dị n'etiti agonists synergistic (chimeras) na nhazi peptide fusion
Ngwa Tizepatide na ọgwụgwọ oke ibu
(1) Mmetụta Mbelata ibu
Ihe akaebe nyocha nke preclinical
N'ime nnwale anụmanụ, ụmụ oke buru ibu a na-elekọta Tizepatide gosipụtara mbelata ịdị arọ nke nta nke nta ka oge na-aga, yana mbelata nke ukwuu ma e jiri ya tụnyere otu njikwa. Nyocha nke abụba anụ ahụ gosiri na ọ bụghị naanị na ọ na-ebelata oke abụba kamakwa ọ na-eme ka nkesa abụba dịkwuo mma, na-ebelata mkpokọta abụba visceral. Usoro ndị bụ isi bụ ụzọ abụọ: nke mbụ, ịgbalite onye na-anabata GLP-1 na-egbochi agụụ site na igbochi etiti agụụ ụbụrụ; nke abụọ, ọ na-akwalite abụba ọkụ ma na-abawanye mmefu ike.
Ihe akaebe nnwale ụlọ ọgwụ
N'ime ule ụlọ ọgwụ ezubere iche maka ndị ọrịa buru oke ibu, Tizepatide gosikwara mmetụta dị oke ibu dị arọ. Nnwale ndị a na-achịkwa n'ọtụtụ n'usoro gosiri na ka oge ọgwụgwọ gasịrị, ịdị arọ ahụ ndị ọrịa belatara nke ukwuu. Dịka ọmụmaatụ, n'ime nyocha nke izu 24, otu ọgwụgwọ ahụ nwetara nkezi ibu arọ nke ihe dịka 10%, ebe ndị otu placebo gosipụtara obere mgbanwe. Na mgbakwunye, okirikiri úkwù ndị ọrịa na úkwù ebelatakwara, na-egosi na ọ bụghị nanị na-akwalite ibu ibu kamakwa ọ na-akwalite nkesa abụba ma na-ebelata ohere nke ọrịa ndị metụtara oke ibu.
(2) Mmelite ihe ngosi metụtara Metabolic Syndrome
Nhazi ọkwa glucose ọbara emelitere
Ndị ọrịa buru ibu na-enwekarị nsogbu glucose ọbara, na Tizepatide na-eme ka njikwa glucose ọbara dịkwuo mma ma na-akwalite mbelata ibu. N'ime ule ụlọ ọgwụ, ndị ọrịa nwetara mbelata dị ukwuu na glucose ọbara na-ebu ọnụ, glucose ọbara postprandial, na haemoglobin A1c (ihe na-egosi njikwa glucose ọbara ogologo oge) mgbe ọgwụgwọ gasịrị. Nke a bụ n'ihi na ọ na-arụ ọrụ site na usoro nnabata abụọ, na-akwalite mmepụta insulin ma na-eme ka mmetụta insulin dịkwuo elu, ebe ọ na-egbukwa oge ịgbasa gastric ma na-ebelata nnabata nri ngwa ngwa. E jiri ya tụnyere ọgwụ mgbochi ọrịa shuga ọdịnala, ọ bụghị naanị na ọ na-ebelata glucose ọbara kamakwa na-akwalite mbelata ibu, na-enye nnukwu uru maka ndị ọrịa buru ibu nwere ọrịa shuga.
Mmelite Iwu Lipid
Dyslipidemia na-esokarị oke ibu, dị ka triglycerides dị elu na ọkwa lipoprotein dị obere (HDL). Tizepatide nwere ike ịhazi lipids: mgbe nchịkwa gasịrị, ndị ọrịa nwetara mbelata triglyceride na ọkwa HDL dị elu. Nke a nwere ike jikọta ya na nhazi nke metabolism lipid, dị ka ịkwalite nnabata glucose site na mkpụrụ ndụ abụba, ibelata ntọhapụ nke fatty acid, na ịkwalite oxidation abụba, si otú ahụ na-eme ka profaịlụ lipid dịkwuo elu ma na-ebelata ihe ize ndụ nke ọrịa obi.
(3) Uru enwere ike maka sistemu obi
Usoro ọbara mgbali elu
Oke ibu bụ otu n'ime ihe ndị nwere ike ibute ọbara mgbali elu. Nnyocha ụlọ ọgwụ achọpụtala na mgbe ọgwụgwọ Tizepatide gasịrị, systolic na ọbara mgbali diastolic nke ndị ọrịa na-ebelata. Nke a nwere ike jikọta na mbelata ibu na metabolism ka mma: oke ibu na-ebelata ibu dị n'obi, yana mmụba nke glucose ọbara na ọkwa lipid na-enyere aka iweghachi ahụike vaskụla ma belata nguzogide vaskụla. Ọzọkwa, mmetụta ya na tract gastrointestinal nwere ike imetụta usoro neuroendocrine n'ụzọ na-edoghị anya, si otú ahụ na-achịkwa ọbara mgbali.
Mmetụta nchebe akwara
Ọrịa na-adịghị ala ala na nrụgide oxidative na-adịkarị na ndị ọrịa buru ibu, nke nwere ike imebi endothelium vaskụla ma kwalite atherosclerosis. Tizepatide na-echebe endothelium vaskụla site na imeziwanye metabolism, ibelata ntọhapụ nke ihe na-akpasu iwe, na ibelata nrụgide oxidative. Nnyocha na-egosi na mgbe ọgwụgwọ gasịrị, ihe nrịbama nke ndị ọrịa dị ka C-reactive protein (CRP) na-ebelata, na vaskụla endothelial ọrụ egosi dị ka nitric oxide ntọhapụ mụbara, na-egosi mma vaskụla ahụ ike na inye aka na mgbochi nke ọrịa obi.
Mmechi
Tizepatide na-egosiputa ikike dị ukwuu na ọgwụgwọ oke ibu site na ime ihe n'otu oge na ndị na-anabata GIP na GLP-1. Ọ bụghị naanị na ọ na-akwalite oke ibu, kamakwa ọ na-eme ka ihe ngosi metabolic dị ka glucose ọbara na ọkwa lipid, ebe ọ na-enye nchebe obi. Site na usoro omume ya nwere ọtụtụ akụkụ, ọ na-enye nhọrọ ọgwụgwọ ọhụrụ maka oke ibu na ọnọdụ ndị metụtara ya.
Isi mmalite
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[2] Jensen TL, Nden ABO, Karstoft K, et al. Tirzepatid. Dual GLP-1/GIP agonist receptor, Ọgwụgwọ ụdị ọrịa shuga 2 na oke ibu [J]. Ọgwụ nke Ọdịnihu, 2023. DOI:10.3389/fendo.2022.1004044
[3] Willard FS, Douros JD, Gabe MB, et al. Tirzepatid bụ GIP abụọ na-anabataghị nke ọma na GLP-1 agonist [J]. Jci Insight, 2020,5 (17).DOI:10.1172/jci.insight.140532.
[4] Bastin M, Andreelli F. Dual GIP-GLP1-Receptor Agonists na ọgwụgwọ nke ụdị ọrịa shuga 2: Ntụle dị mkpirikpi na data na-apụta na ike ọgwụgwọ [J]. Ọrịa shuga Metabolic ọrịa shuga na oke ibu-Ezubere na ọgwụgwọ, 2019,12:1973-1985.DOI:10.2147/DMSO.S191438.
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