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SemaglutidStructure Imiterere ya
Inkomoko: Pub Chem |
Urukurikirane: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys (Aeea-Aeea-γ-glu-octadecanedioic) -Glu-Phe-Ile-Ala-Tr-Arp-Leu Inzira ya molekulari: C 187H 291N 45O.59 Uburemere bwa molekuline: 4114 g / mol CAS Umubare 910463-68-2 PubChem CID 56843331 Synonyme: Rybelsus; Ozempic; Wegovy |
Research Ubushakashatsi bwa Semaglutid
Ni ubuhe bushakashatsi bwakozwe na Semaglutid?
Semaglutid ni glucagon yumuntu isa na peptide-1 (GLP-1), yashyizwe mubikorwa nka GLP-1 reseptor agonist. GLP-1 ni imisemburo karemano isohoka mu ngirangingo zo munda nyuma yo kurya. Ifite uruhare mu guteza imbere imisemburo ya insuline no guhagarika imisemburo ya glucagon, bityo igenga urugero rwa glucose mu maraso. Iterambere rya Semaglutid ryaturutse kubushakashatsi bwimbitse bwimikorere ya physiologique ya GLP-1. Nyamara, GLP-1 ifite igice gito cyane cyubuzima bwumubiri, kimara iminota 1 kugeza kuri 2 gusa, ibyo bikaba biterwa no kwandura kwangirika na enzyme ya dipeptidyl peptidase-4 (DPP-4) mumubiri. Kugira ngo iyi mbogamizi igerweho, abahanga bahinduye imiterere ya GLP-1 binyuze mu gusimbuza aside amine yihariye no kongeramo amatsinda akingira, byongera imbaraga zo kurwanya imisemburo ya DPP-4 bityo bikongerera igihe ibikorwa byayo [1] . Mu miterere ya Semaglutid, alanine kumwanya wa 8 isimburwa na α-aminoisobutyric aside (Aib). Iri hinduka ntiritezimbere gusa ibiyobyabwenge ahubwo binashimangira guhuza kwa reseptor ya GLP-1 (Ma H, 2020). Byongeye kandi, urunigi rudasanzwe rwa aside irike ihuza C-terminus, ihuza binyuze kuri γ-glutamine n'ibisigazwa bya lysine, bikomeza ubuzima bwa kimwe cya kabiri, bigatuma inshinge imwe mu cyumweru cyangwa rimwe na rimwe imiyoborere yo mu kanwa [1] . Mu ikubitiro hashingiwe ku bushakashatsi no guhindura GLP-1 karemano, Semaglutid igamije gutanga uburyo bunoze bwo kuvura abarwayi bafite metabolism yo mu bwoko bwa 2 [1, 2] . Nyuma yuburyo bwiza, bugumana ibikorwa bya physiologique ya GLP-1 mugihe itezimbere cyane imiti ya farumasi, ihinduka ingirakamaro ya GLP-1 yakira reseptor agonist. Ubushakashatsi niterambere rya Semaglutid bifite akamaro kanini mukuvura metabolism yo mu bwoko bwa 2, bitanga amahitamo mashya kubarwayi. Mugutezimbere imiterere, itsinze ikibazo cyigihe gito cyubuzima bwa GLP-1 karemano, byongera imiti ihamye nigihe cyo gukora.
Nubuhe buryo bwo gukora bwa Semaglutid?
Semaglutid ni glucagon ikora nka peptide-1 (GLP-1) reseptor agonist, kandi uburyo bwibikorwa ni ubu bukurikira:
Amaraso ya Glucose Amabwiriza: Nka glucagon isa na peptide-1 yakira reseptor agonist (GLP-1RA), Semaglutid igabanya cyane cyane abarwayi bifuza ibiryo kandi bikagabanya guhitamo ibiryo birimo amavuta menshi mugukumira ubushake bwo kurya. Igenga ikigo cyo kugaburira muri hypothalamus, kugabanya gufata ibiryo, kongera guhaga, kubuza igifu, no kugabanya umuvuduko wa gastrointestinal, bityo ukagera ku ntego yo kugabanya ibiro. Kugabanya ibiro bifasha kunoza insuline no kurushaho kugabanya glucose yamaraso [3] (Kim HS, 2021). Semaglutid itera kugabanuka mubibabi binyuze mumihanda yagabanijwe. Ubushakashatsi bwerekanye ko Semaglutid ikora mu buryo butaziguye nk'ubwonko, septal nucleus, na hypothalamus. Nubwo itarenga inzitizi yubwonko bwamaraso, ikorana nubwonko ikoresheje ingingo zuzenguruka hamwe nuturere tumwe na tumwe hafi ya ventricles. Itera ibikorwa bya c-Fos hagati yibice 10 byubwonko, harimo uturere twinyuma twibasiwe na Semaglutid hamwe nakarere ka kabiri nta mikoranire ya GLP-1R, nka nucleus ya parabrachial. Isesengura ryikora ryerekana ko gukora bishobora kuba bifitanye isano no guhagarika amafunguro agenzurwa na neurone muri nucleus ya parabrachial, bityo bikagenga urugero rwa glucose yamaraso [4].
Amabwiriza ya Gastrointestinal: Semaglutid ikora kuri reseptor ya GLP-1 mu nzira ya gastrointestinal. Binyuze mu nzira ya afferent ya nervice ya vagus, ikora mubice byubwonko nka nucleus yumuhanda wonyine hamwe na moteri ya dorsal nucleus ya nervice ya vagus kugirango igabanye umuvuduko wa gastrointestinal. Irashobora kubuza kugabanuka kwa antrum gastrica, kongera umuvuduko wa pyloric sphincter, kongera igihe cyo gutura ibiryo mu gifu, no gutinda kwinjira muri duodenum, bikarinda izamuka ryihuse rya glucose yamaraso nyuma yindwara kandi bigatuma glucose yamaraso ihinduka neza [5] (Katsurada K, 2016). Byongeye kandi, Semaglutid ikora kuri reseptor ya GLP-1 muri sisitemu yo hagati yo hagati, cyane cyane mubice nka arcuate nucleus na paraventricular nucleus ya hypothalamus. Irabuza kurekura ibintu bitera ubushake bwo kurya nka neuropeptide Y (NPY) hamwe na poroteyine ifitanye isano na agouti (AgRP), kandi icyarimwe ikora neuron ya pro-opiomelanocortin (POMC), igatera imisemburo ya hormone itera α-melanocyte (α-MSH) [5] . Izi ngaruka zitanga ibyiyumvo byo guhaga, kugabanya inzara, no kugabanya ibiryo, ku buryo butaziguye bigira ingaruka nziza ku kugenzura amaraso glucose.
Kurinda umutima-mitsi: Semaglutide irashobora guteza imbere ingirabuzimafatizo ya endoteliyale kugirango irekure ibintu bya vasodilatory nka nitide ya nitric (OYA), byongera ubushobozi bwo kwaguka kwamaraso no kunoza amaraso. Muri icyo gihe, irabuza ibisubizo bitera umuriro hamwe na stress ya okiside, igabanya kwangirika kwingirabuzimafatizo ya endoteliyale, kandi ikagabanya ibyago byo kurwara aterosklerose. Byongeye kandi, mu kugabanya ubushake bwo kurya no gufata ibiryo, Semaglutid ifasha mu kugabanya ibiro, itezimbere indwara ya lipide metabolism, igabanya urugero rwa triglyceride na cholesterol ya lipoprotein nkeya (LDL-C), kandi ikongera urugero rwa cholesterol ya lipoproteine (HDL-C). Irashobora kandi kugira ingaruka nziza kumuvuduko wamaraso muguhindura impyiko zimpyiko nimirimo ya neuroendocrine, bikagabanya ibyago byo kurwara hypertension nindwara zifata umutima-mitsi [6].
Semaglutid na transcriptional amabwiriza ya WAT guhinduranya BAT no gukora BAT.
Inkomoko: Byatangajwe [12]
Ni ubuhe bushakashatsi bw'ingenzi n'ubushakashatsi?
Gutegura no Kuringaniza Imiterere ya Shimi: Mugihe hateguwe Semaglutid, hafashwe uburyo bwo guhinduranya alubumu kugirango hongerwe igihe ibiyobyabwenge. Mu kumenya uburyo bwiza bwo guhuza aside irike hamwe nu muhuza, mugihe ukomeza gukora neza ya reseptor ya GLP-1 (GLP-1R), ubushobozi bwo guhuza albumin bwarushijeho kuba bwiza [7].
Gushyira mu bikorwa ibiyobyabwenge: Semaglutid ni glucagon isa na peptide-1 yakira reseptor agonist (GLP-1 RA) ifite igihe kirekire cyo kurandura igice cyubuzima, ikemerera gutera inshinge rimwe mu cyumweru. Ku barwayi bafite metabolism yo mu bwoko bwa 2 (T2DM), ingaruka zo kugabanya ibiro byo gutera inshuro imwe mu cyumweru inshinge zo mu bwoko bwa Semaglutid ziruta iz'izindi GLP-1RAs rimwe mu cyumweru. Mu cyiciro cya II igeragezwa rya dose-ubushakashatsi ku barwayi bafite umubyibuho ukabije udafite T2DM, inshuro imwe ku munsi yo gutera inshinge munsi ya Semaglutid yerekanaga ingaruka nziza zo kugabanya ibiro kuruta umwanya wa platbo na rimwe buri munsi 3.0 mg liraglutide. Urwego rwo kugabanya ibiro rwatewe na Semaglutid muri ubu bushakashatsi rwarenze ibipimo by’imiti igabanya ibiro byashyizweho n’ikigo cy’ubuvuzi cy’ibihugu by’Uburayi (EMA) n’ikigo cy’Amerika gishinzwe ibiryo n’ibiyobyabwenge (FDA), kandi gifite umutekano, byerekana ko inshuro imwe buri munsi yo gutera inshinge munsi ya Semaglutid ifite amahirwe yo kuzaba imiti igabanya ibiro [8].
Kuvura indwara z'umutima n'imitsi mu kunoza imikorere y'umutima: Ibyavuye mu igeragezwa rya STEP-HFpEF byagaragaje ko urugero rwinshi rwa antidiabete glucagon imeze nka peptide 1 agonist Semaglutid yazamuye cyane ibimenyetso bifitanye isano no kunanirwa k'umutima hamwe n'igice cya N-terminal pro-B-natriuretic peptide. Ubushakashatsi bwakozwe bwerekanye ko kuvura cyane hamwe na Semaglutid bishobora kongera ubukana bwa trabeculae yo mu bwoko bwa trabeculae inshuro zirenga eshatu mu buryo buterwa na dose, nta kwiyongera kwa aritite. Izi ngaruka zishobora guterwa no kwiyongera kwa Ca2 + na reticulum ya sarcoplasme. Kuvura hamwe na Semaglutide ikabije ku barwayi bafite ikibazo cy'umutima birashobora kunoza imikorere ya atiri, bityo bikagabanya ibimenyetso [9].
Semaglutid iri gukurikiranwa kugirango ivurwe na steatohepatitis idafite inzoga (NASH): Igishushanyo mbonera cya Semaglutid cyagize uruhare runini mu kunoza igenzura rya glucose yamaraso, uburemere bwumubiri, umuvuduko wamaraso, lipide yamaraso, imikorere ya selile, hamwe na sisitemu yumutima nimiyoboro y'amaraso ku barwayi bafite metabolism yo mu bwoko bwa 2. Byongeye kandi, guteza imbere umunwa wa Semaglutid birashobora gutanga inyungu zinyongera mubijyanye no kuvura abarwayi [7].
Ni irihe tandukaniro mu ngaruka zo kugabanya ibiro bya Semaglutid mubantu batandukanye?
Abakuze bafite indwara z'umutima-damari zabayeho mbere, umubyibuho ukabije cyangwa umubyibuho ukabije ariko nta metabolisme: Mu igeragezwa ry’ibisubizo by’umutima n’umutima, Semaglutid yagabanije 20% by’indwara zikomeye zifata umutima n’amaraso ku bantu 17,604 bakuze bafite indwara zifata umutima n’umutima, umubyibuho ukabije cyangwa umubyibuho ukabije, kandi nta metabolisme [10] (Ryan DH, 2024). Muri iri sesengura ryabanje gusobanurwa, abashakashatsi basuzumye ingaruka za Semaglutid ku buremere bw'umubiri, ibisubizo bya antropometrike, umutekano, no kwihanganira ukurikije ibipimo fatizo by’umubiri (BMI). Abarwayi bakira Semaglutid bahuye nigabanuka ryuburemere bwumubiri mugihe cyibyumweru 65, bikageza kumyaka 4. Mugihe cibyumweru 208, ugereranije nitsinda rya placebo, Semaglutid yatumye igabanuka ryikigereranyo cyibiro byumubiri (-10.2%), umuzenguruko wikibuno (-7,7 cm), hamwe nu rukenyerero -kuburebure (-6.9%), mugihe itsinda rya placebo ryagabanutseho (-1.5%, -1,3 cm, na -1.0%), kandi byose byagereranijwe na placebo. Kugabanya ibiro bifite akamaro byagaragaye kubagabo nabagore, amoko yose, ubwoko bwumubiri, nakarere. Semaglutid yahujwe nibintu bike bikomeye byabaye bibi. Kuri buri cyiciro cya BMI (<30, 30 kugeza <35, 35 kugeza <40, na ≥40 kg / m²), umubare w’ibintu bibi byakorewe Semaglutid (umubare w’ibyabaye byagaragaye ku myaka 100-muntu) wari muke (43.23, 43.54, 51.07, na 47.06 kuri Semaglutid, na 50.48, 49.66, 52.73, Semaglutid yajyanye no kwiyongera kwihagarikwa ryibicuruzwa byageragejwe. Mugihe icyiciro cya BMI cyagabanutse, igipimo cyo guhagarika cyariyongereye. Mu igeragezwa RYITONDERWA, mu byumweru 208, Semaglutid yabyaye ibiro byinshi by’amavuriro no kunoza indangagaciro za antropometrike ugereranije na placebo, kandi gutakaza ibiro byakomeje imyaka 4.
Abantu bafite umubyibuho ukabije cyangwa umubyibuho ukabije ariko badafite metabolisme: Isuzuma rifatika ryasuzumye imikorere n'umutekano bya Semaglutid ku bantu bafite umubyibuho ukabije cyangwa ufite ibiro byinshi ariko badafite metabolism [11] . Iri suzuma ryagaragaje ibisubizo by’ibigeragezo byinshi by’amavuriro, bishimangira ingaruka za Semaglutid ku kugabanya ibiro, ibipimo bya metabolike, hamwe n’ubuzima muri rusange. Ibisubizo byerekanye ko Semaglutid yari ifitanye isano no kugabanya ibiro cyane no kunoza ibipimo by’ubuzima bijyanye n’umubyibuho ukabije, kandi birashobora kuba uburyo bwiza bwo kuvura abarwayi bafite umubyibuho ukabije.
Abarwayi badafite diyabete (ibimenyetso biva muri RCT nyinshi): Mu bigeragezo 4 byateganijwe, abarwayi bafite ibiro fatizo by’ibiro 96 kugeza kuri 105 bahawe inshinge zo munsi ya mg 2.4 za Semaglutid hamwe n’ubuzima bwabo (ubujyanama, indyo, n’ibikorwa by’umubiri) kugira ngo bavure ibiro. Ikigeragezo kimwe cyagenzuwe ku barwayi badafite diyabete (N = 1961) cyerekanye ko nyuma y'ibyumweru 68, impuzandengo y'ibiro byari 15% (15 kg), ibyo bikaba byari bitandukanye cyane na 2% (3 kg) mu itsinda rya placebo. Umubare w'abarwayi bafite ibiro ≥5% wari 86% ugereranije na 32% mu itsinda rya placebo, n'umubare ukenewe kuvura (NNT) = 2; igipimo cy’abarwayi bafite ibiro ≥10% cyari 69% ugereranije na 12% mu itsinda rya placebo, na NNT = 2. Kugabanya ibiro byagabanutse mu byumweru 60. Indwara ziterwa na gastrointestinal (AEs) zari 74% ugereranije na 48% mu itsinda rya placebo, kandi umubare ukenewe kugira ngo ugirire nabi (NNH) = 3. Umubare w’abarwayi bahagarika kwivuza bitewe n’ibihe bibi wari 7% ugereranije na 3% mu itsinda rya placebo, na NNH = 25. Mu kindi kigeragezo cyagenzuwe hamwe n’ubuzima bukomeye (N = 611), ibiro 16% bitandukanye cyane na 6% (6 kg) mumatsinda ya placebo. Mu bushakashatsi bwakozwe ku bushakashatsi bwakozwe ku barwayi ba diyabete (N = 1210), abarwayi bahabwaga buri cyumweru mg 2,4 ya Semaglutid, buri cyumweru 1.0 mg ya Semaglutid, cyangwa umwanya wabo. Nyuma yibyumweru 68, impuzandengo yo gutakaza ibiro yari 10% (2,4 mg), 7% (1.0 mg), na 3% (placebo). Umubare w'abarwayi bafite ibiro bya ≥5% wari 69% (2,4 mg), 57% (1.0 mg) ugereranije na 29% mu itsinda rya placebo. Kuri dosiye ya 2,4 mg na 1.0 mg, NNT = 9. Ibyabaye bibi byari bisa na dosiye zitandukanye. Mu kubungabunga ibiro byateganijwe kugenzurwa (N = 803), abitabiriye badafite diyabete bavuwe buri cyumweru hamwe na mg 2,4 za Semaglutid mu byumweru 20, hanyuma bagabanywa mu itsinda ryakomeje kuvura Semaglutid cyangwa itsinda rya placebo. Nyuma yibyumweru 48, itsinda rikomeje kuvura Semaglutid ryatakaje 8% byuburemere bwumubiri, mugihe itsinda rya placebo ryiyongereyeho 7% byuburemere bwumubiri.
Mugusoza, Semaglutid numuti wa GLP-1 reseptor agonist ufite agaciro gakoreshwa mubice byinshi. Mu rwego rwo kuvura metabolisme, igenzura neza urugero rwa glucose yamaraso ihuza reseptor ya GLP-1, igatera imisemburo ya insuline, kandi ikabuza gusohora glucagon, itanga uburyo bwingenzi bwo kuvura abarwayi bafite metabolism yo mu bwoko bwa 2. Mu rwego rwo kuvura umubyibuho ukabije, Semaglutid igabanya cyane gufata ingufu binyuze mu buryo bwo guhagarika ubushake bwo kurya no gutinda gusohora gastrica, gufasha abarwayi bafite umubyibuho ukabije guta ibiro no kuzamura imiterere yabo. Byongeye kandi, Semaglutid yerekana kandi amahirwe yo gukoreshwa mugukumira no kuvura indwara zifata umutima. Gutezimbere kwingaruka zumutima nimiyoboro yimitsi itanga uburyo bushya bwo kugabanya indwara zifata umutima.
Ibyerekeye Umwanditsi
Ibikoresho byavuzwe haruguru byose byakorewe ubushakashatsi, byahinduwe kandi byakozwe na Cocer Peptides.
Umwanditsi w'ikinyamakuru
Hegner P ni umushakashatsi muri kaminuza ya Regensburg. Ibikorwa bye bikubiyemo Chimie, Sisitemu Yumutima, na Cardiology. Muri Chimie, akora ubushakashatsi bujyanye nubuzima bwumutima. Mu bushakashatsi bwimikorere yumutima, asuzuma imikorere yumutima nimiyoboro, ashakisha ubushishozi bwo kuvura. Ubushakashatsi bwe bw'umutima bwibanze ku kwirinda indwara z'umutima, gusuzuma, no kuvura.
Umusanzu wa Hegner urakomeye. Ubushishozi bwe bwimiti bwatumye imiti mishya yumutima itera. Ibikorwa bye kumikorere yumutima nubwato byongereye gusobanukirwa indwara zifata umutima. Mubuvuzi, ubushakashatsi bwe bwateje imbere imicungire yindwara z'umutima, bizamura ibipimo byita ku barwayi. Muri rusange, uburyo bwa Hegner butandukanye butandukanye butungisha imiti yumutima nimiyoboro y'amaraso, bitanga ibyiringiro byo kugabanya imitwaro yindwara nibisubizo byiza byabarwayi. Hegner P yanditse kurutonde rwerekana [9].
