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▎ Kūlana Tirzepatid
Puna: PubChem |
Kaʻina: 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 Hui Molekala: C 225H 348N 48O68 Kaumaha Molekala: 4813 g/mol Helu CAS: 2023788-19-2 PubChem CID: 163285897 Synonyms: Zepbound; Mounjaro |
▎ ʻImi ʻo Tirzepatid
He aha ke kumu noiʻi o Tirzepatid?
ʻO Tirzepatid kahi lāʻau polypeptide synthetic. Hoʻokumu ʻia kona hoʻomohala ʻana mai ka ʻike hohonu o nā palena o nā agonists loaʻa GLP-1 i ka mālama ʻana i ka maʻi diabetes mellitus type 2 (T2DM) a me ka momona. ʻOiai ua hōʻike ka GLP-1 receptor agonists i ka hana maikaʻi loa i ka mālama ʻana i ka glucose o ke koko a me ke kaumaha o ke kaumaha, ua ʻike nā ʻepekema ʻo kā lākou hoʻāla ʻana i ka mea loaʻa GIP he nāwaliwali, e kaupalena ana i ka hopena therapeutic o nā lāʻau lapaʻau. No laila, ua kūpaʻa ka hui noiʻi a me ka hoʻomohala ʻana i ka hoʻomohala ʻana i kahi ʻano lāʻau lapaʻau hou e hiki ai ke hoʻoikaika i ka GIPR a me GLP-1R i ka manawa like, me ka manaʻo e hoʻokō i ka ʻoi aku ka piha o ka glucose koko a me ka hoʻokele kaumaha [1].
I ka wā o ka noiʻi a me ka hoʻomohala ʻana, ua hana nā ʻepekema i kahi helu nui o nā noiʻi noiʻi kumu a me nā hoʻokolohua lapaʻau. I ka pae noiʻi preclinical, ua loiloi maikaʻi ʻia nā waiwai pharmacodynamic o Tirzepatid ma o nā hoʻokolohua holoholona, e hōʻoia ana i kona hiki ke hoʻomalu i ka glucose koko a me ka pohō kaumaha. Ua hōʻike nā hopena i hiki ke hoʻemi nui i ke kiʻekiʻe o ka glucose koko i nā ʻano holoholona a hōʻike i ka hana maikaʻi loa i ka mālama ʻana i ke kaumaha, e kau ana i ke kumu no nā hoʻokolohua lapaʻau ma hope.
Ma hope mai, ua hoʻokomo ʻia ka pae hoʻokolohua lapaʻau i nā hoʻāʻo Phase I, II, a me III. ʻO ka hoʻāʻo ʻana o ka Phase I i loiloi nui i ka palekana, ka hoʻomanawanui, a me nā waiwai pharmacokinetic o ka lāʻau. Ua hōʻike ʻia nā hopena he palekana maikaʻi ʻo Tirzepatid a me ka hoʻomanawanui. Ua ʻimi hou ka hoʻāʻo ʻana o ka Phase II i ka pono a me ka palekana o nā ʻokoʻa like ʻole o Tirzepatid i nā maʻi me T2DM, e hoʻoholo mua i kona pae hopena kūpono. ʻO nā hoʻokolohua lapaʻau koʻikoʻi o ka Phase III, e like me ka SURPASS series of study, i komo i ka nui o nā maʻi me T2DM. Ua hōʻike ʻia nā hopena i ʻoi aku ka maikaʻi o Tirzepatid ma mua o nā agonists receptor GLP-1, e like me semaglutide, i ka hōʻemi ʻana i ka glucose koko a me ke kaumaha, e hāʻawi ana i nā hōʻike ikaika no ka noi kūʻai ʻana o Tirzepatid [1].
He aha ke ʻano o ka hana a Tirzepatid?
Hoʻohaʻahaʻa ʻo Tirzepatid i ka glucose koko ma o nā hana like ʻole. I ka hoʻoulu ʻana i ka mea loaʻa GLP-1, hoʻopaʻa ʻo Tirzepatid i ka mea hoʻokipa GLP-1 ma nā pancreatic β-cells, e hoʻohālike ana i ka hana o ka GLP-1 maoli. ʻO GLP-1 kahi hormone i hana ʻia i loko o ka ʻōpū a he mea koʻikoʻi ia no ka mālama ʻana i ka homeostasis glucose. Hiki iā ia ke hoʻoikaika i ka insulin synthesis, huna, a me ka ʻike glucose, hoʻemi i ka huna ʻana o ka glucagon e hoʻoikaika i ka māʻona, a hoʻopau i ka ʻai.
Hiki i kēia hana ke hoʻoikaika i ka huna ʻana o ka insulin. ʻO ka insulin ka hormone hypoglycemic nui i loko o ke kino, hiki ke hoʻonui i ka lawe ʻana a me ka hoʻohana ʻana i ka glucose e nā cell, a laila e hōʻemi ana i nā pae glucose koko. I nā poʻe maʻi me T2DM, ʻaʻole lawa ka huna ʻana o ka insulin a i ʻole ka emi ʻana o ka naʻau o nā cell i ka insulin, e alakaʻi ana i ke kiʻekiʻe o ka glucose koko. Ma ka hoʻoulu ʻana i ka mea hoʻokipa GLP-1, hoʻonui ʻo Tirzepatid i ka huna ʻana o ka insulin, e kōkua ana i ka hoʻomaikaʻi ʻana i ka mana glucose koko.
I ka manawa like, ʻo ka hoʻoulu ʻana o ka mea hoʻokipa GLP-1 e kāohi i ka hoʻokuʻu ʻana o ka glucagon. Hoʻoikaika pinepine ʻo Glucagon i ka glycogenolysis a me ka gluconeogenesis i ka wā hoʻokē ʻai, e hoʻonui ana i ka hana glucose koko. Ma ka pale ʻana i ka hana o ka glucagon, hoʻemi hou ʻo Tirzepatid i ke kumu o ka glucose koko, e hāʻawi ana i ka mana glucose koko [2].
I ka hoʻoulu ʻana i ka mea loaʻa GIP, hana ʻo Tirzepatid i ka mea loaʻa GIP i ka manawa like. Ma hope o ka hoʻoulu ʻana, hiki ke hoʻonui i ka naʻau a me ka huna ʻana o ka insulin. Loaʻa ka loaʻa ʻana o ka GIP i nā ʻiʻo e like me nā pancreatic β-cells. Ma hope o ka ho'ā ʻana, ma o ka hoʻouna ʻana i nā ala hōʻailona intracellular, hoʻonui ʻia ka huna ʻana o ka insulin, a hoʻomaikaʻi ʻia ka pane ʻana o ka cell i ka insulin, no laila e hoʻemi maikaʻi ai i ka glucose koko.
ʻO Tirzepatid kahi mea like ʻelua glucagon-like peptide-1 a me ka glucose-dependent insulinotropic polypeptide (GIP) analog, i ʻae ʻia no ka mālama ʻana i nā maʻi makua me T2DM ma ke ʻano he mea hoʻohui i ka meaʻai a me ka hoʻoikaika kino. ʻO Tirzepatid kahi hana kemika synthetic e pili ana i ke kaʻina GIP, i haku ʻia me kahi peptide 39-amino acid. Hoʻonui ia i ka huna ʻana o ka insulin, hoʻemi i ka hoʻokuʻu ʻana o ka glucagon ma ke ʻano pili i ka glucose, hoʻohaʻahaʻa i ka pae glucose koko ma hope o ka ʻai ʻana, hoʻoikaika i ka māʻona, hoʻemi i ke kaumaha o ke kino, a hoʻopaneʻe i ka hoʻokuʻu ʻana o ka ʻōpū. ʻO kēia hopena agonist ʻelua ʻelua e ʻoi aku ka maikaʻi o Tirzepatid ma mua o ka GLP-1 receptor agonists i ka hāpai ʻana i ka huna ʻana o ka insulin a me ka pale ʻana i ka hoʻokuʻu glucagon [2].
Hiki nō hoʻi iā Tirzepatid ke hoʻopaneʻe i ka hoʻokuʻu ʻana o ka ʻōpū a hoʻonui i ka satiety. Hiki iā ia ke hoʻopaneʻe i ka hoʻokuʻu ʻana o ka ʻōpū, hoʻolōʻihi i ka manawa noho o ka meaʻai i loko o ka ʻōpū a hoʻolohi i ka helu absorption o nā meaʻai, no laila e pale ai i ka piʻi nui o ka glucose koko postprandial. I nā haʻawina non-clinical a me nā hoʻokolohua lapaʻau, ʻo ka hopena o Tirzepatid i ka hoʻohemo ʻana o ka ʻōpū e like me ka GLP-1 receptor agonists. I nā ʻiole momona i hoʻokomo ʻia i ka meaʻai, ua like ke kiʻekiʻe o ka hoʻokaʻawale ʻana o ka ʻōpū e Tirzepatid me ka semaglutide, akā nalo kēia mau hopena inhibitory ma hope o 2 mau pule o ka mālama ʻana.
I nā poʻe i komo me ka T2DM a me ka ʻole o ka T2DM, ʻo Tirzepatid i hoʻokahi pule i hoʻokahi pule (≥5 mg a me ≥4.5 mg, kēlā me kēia) lohi i ka hoʻokuʻu ʻana o ka ʻōpū ma hope o hoʻokahi maʻa. I nā poʻe komo olakino, ua hoʻemi ʻia ka hopena ma hope o nā nui o Tirzepatid a i ʻole dulaglutide (Urva S, 2020). I ka manawa like, hiki iā ia ke hana i ke kikowaena o ke kikowaena, hoʻonui i ka satiety, hoʻemi i ka makemake, a me ka ʻai ʻana i ka meaʻai. Ma ke kāohi ʻana i ka ʻai meaʻai, kōkua ʻole ia i ka mālama ʻana i nā pae glucose koko, kūpono loa no ka pilikia obesity i hele pinepine ʻia e nā mea maʻi me T2DM, a kōkua i ka hoʻomaikaʻi ʻana i ka insulin resistance a me ke kūlana metabolic holoʻokoʻa [2].
Ua ʻike ʻia ʻo Tirzepatid e hoʻonui i ke kiʻekiʻe o ka adiponectin, kahi adipocytokine e pili ana i ka ʻike insulin. ʻO ka hoʻonui ʻana i nā pae adiponectin e kōkua i ka hoʻomaikaʻi ʻana i ka naʻau o ka insulin, e hoʻonui ai i nā cell i ka insulin, no laila ʻoi aku ka maikaʻi o ka lawe ʻana a me ka hoʻohana ʻana i ka glucose a hoʻemi i ke koko koko [2] . Eia kekahi, hiki i ka Tirzepatid ke hoʻomaikaʻi i ka lipid profile a loaʻa i kahi hopena pale i ke olakino cardiovascular. Ua hōʻike ʻia ʻo Tirzepatid e hiki ke hoʻomaikaʻi i ke kahe koko, e hoʻemi i ka lipoprotein haʻahaʻa haʻahaʻa (LDL) cholesterol a me nā triglycerides [3] , e kākoʻo hou ana i kāna mau pono piha i ka hoʻokele glucose koko.
Puna: PubMed [5]
Ka noiʻi pili
ʻO ka maikaʻi o ka hoʻokele kaumaha i nā maʻi me ka momona a me ke ʻano diabetes mellitus type 2
Ua hōʻoia ka nui o nā haʻawina hauʻoli i ka pono nui o Tirzepatid i ka mālama ʻana i ke kaumaha o ke kino i nā mea maʻi me ka momona a me ka T2DM. I loko o kahi noiʻi i kapa ʻia ʻo 'SURMOUNT-2', ʻo ia ka Phase 3, pālua-makapō, randomized, placebo-controlled hoʻokolokolo i mālama ʻia ma ʻehiku mau ʻāina. ʻO nā mākua (nā makahiki ≥18 makahiki) me ka helu kino kino (BMI) o 27 kg/m² a i ʻole ke kiʻekiʻe aʻe a me ka pae glycated hemoglobin (HbA₁c) o 7 - 10% i hāʻawi wale ʻia no ka loaʻa ʻana o hoʻokahi pule i hoʻokahi pule ma lalo o ka ʻili o Tirzepatid (10 mg a i ʻole 15 mg) a i ʻole placebo no 72 pule.
Ua hōʻike nā hopena i ka pule 72, ʻo ka pakeneka o ka pohō kaumaha ma ka hui Tirzepatid 10 mg a me 15 mg he -12.8% a me -14.7%, i hoʻohālikelike ʻia me -3.2% i ka hui placebo. ʻO nā ʻokoʻa hoʻomaʻamaʻa i manaʻo ʻia o Tirzepatid 10 mg a me 15 mg i hoʻohālikelike ʻia me ka placebo he -9.6 pakeneka pākēneka a me -11.6 pakeneka pākēneka, ʻo ia mau mea ʻelua i helu nui (p <0.0001). Eia kekahi, ʻoi aku ka nui o nā mea maʻi e loaʻa ana i ka mālama ʻana iā Tirzepatid i ka paepae o ka pohō kaumaha o 5% a ʻoi aku paha (79 - 83% vs 32%) [4].
Ma ke aʻo ʻana ʻo 'SURMOUNT-2', ʻo 100.7 kg ka awelika kaumaha kumu, ʻo ka BMI he 36.1 kg/m², a ʻo ka HbA₁c he 8.02%. Ma hope o 72 mau pule o ka mālama ʻana, ʻaʻole wale ʻo Tirzepatid i hoʻemi nui i ke kaumaha o ke kino akā ua loaʻa ka hopena maikaʻi i ka mana glucose koko [4].
Ka hopena hoʻomaikaʻi i ka neuropathy pili i ka maʻi diabetes
Ua hōʻike ʻia kekahi mau haʻawina e hiki i nā GLP1-RA ke hōʻemi i ka hopena o ka dementia i nā maʻi me T2DM ma o ka hoʻomaikaʻi ʻana i ka hoʻomanaʻo, ke aʻo ʻana, a me ka lanakila ʻana i ka hemahema o ka naʻau. Ma keʻano he GIP-RA / GLP-1RAʻelua, ua aʻoʻiaʻo Tirzepatid i ka laina pūnaewele neuroblastoma (SHSY5Y) no kona mau hopena ma nā hōʻailona o ka uluʻana o neuronal (CREB a me BDNF), apoptosis (BAX / Bcl2 ratio), kaʻokoʻa (pAkt, MAP2, GAP43, a me AGBL4), a me ka insulin resistance (GLUT4, 1, GLUT1, GLUT1, GLUT1).
ʻO nā hualoaʻa no ka manawa mua i hoʻokūpaʻa i ka hana a Tirzepatid i ka hoʻouluʻana i ke ala pAkt / CREB / BDNF a me nā hōʻailona hōʻailona lalo, a me kona pono neuroprotective. Ua hōʻike pū ʻia ua hiki iā Tirzepatid ke kūʻē i nā hopena e pili ana i ka hyperglycemia a me ka pale ʻana o ka insulin ma ka pae neuronal. No laila, hiki iā Tirzepatid ke hoʻomaikaʻi i ka neurodegeneration i hoʻokumu ʻia e ka hyperglycemia a lanakila i ka pale ʻana o ka insulin neuronal, e hāʻawi ana i nā ʻike hou no ka hoʻomaikaʻi ʻana i ka neuropathy pili i ka maʻi diabetes [5].
ʻO ka holomua o ka noiʻi ʻana i ka mālama ʻana i ka maʻi diabetes type 2
Ua kuhikuhi kekahi mau haʻawina ma ke ʻano he ʻano hou o ka lāʻau hypoglycemic, ua lilo ʻo Tirzepatid i ka agonist GIP/GLP-1R ʻelua i ʻae ʻia no ka mālama ʻana i ka maʻi diabetes ma ʻAmelika Hui Pū ʻIa. Ua hōʻoia ʻia he hopena koʻikoʻi i ka hoʻohaʻahaʻa ʻana i ka glucose koko a me ka hoʻohaʻahaʻa ʻana i ke kaumaha o ke kino i nā hoʻokolohua lapaʻau nui nui, a aia kekahi mau hōʻike e hōʻike ana he hiki nō hoʻi ia i ka pale cardiovascular.
Eia kekahi, ua wehe ka manaʻo o nā peptides synthetic i nā mea i ʻike ʻole ʻia no Tirzepatid. Ke hoʻomau nei nā ho'āʻo (NCT04166773) a me nā hōʻike hōʻike e ʻike ʻia he lāʻau lapaʻau maikaʻi loa ia i nā kula e like me ka maʻi ʻaʻai momona ʻole (NAFLD), ka pale ʻana i ka renal, a me ka neuroprotection [6].
Nā hopena lōʻihi o ka tirzepatide i ke olakino cardiovascular
Hiki i ka Tirzepatid ke hoʻemi i ka pilikia o nā maʻi cardiovascular ma o ka hoʻoikaika ʻana i ka pohō kaumaha. Ua nānā ʻia kahi noiʻi i ka hopena o Tirzepatid i ka momona a me nā hanana maʻi cardiovascular i nā pākeke ʻAmelika (Wong ND, 2024). Ua ʻike ʻia ka noiʻi ʻana i waena o nā poʻe ʻAmelika e pono ai no ka mālama ʻana iā Tirzepatid, ma hope o ka mālama ʻana me 15 mg o Tirzepatid, ua manaʻo ʻia ʻo 70.6% a me 56.7% o nā pākeke i loaʻa i ke kaumaha o ≥15% a me ≥20%, ʻo ia hoʻi, he 58.8% ka emi ʻana o ka poʻe obese.
Ma waena o ka poʻe me ka maʻi ʻole o ka maʻi cardiovascular, ua hoʻemi ʻia ka maʻi cardiovascular he 10 mau makahiki mai ka 10.1% 'ma mua o ka mālama ʻana' a i ka 7.7% 'ma hope o ka mālama ʻana', e hōʻike ana i ka emi ʻana o ka pilikia o 2.4% a me ka hōʻemi ʻana o 23.6%, ʻo ia hoʻi he 2 miliona mau hanana maʻi cardiovascular hiki ke pale ʻia i loko o 10 mau makahiki.
I ka hopena ， ʻO Tirzepatid kahi moʻolelo ʻelua agonist o GIP a me GLP-1 receptors, he mea nui ia i ka mālama ʻana i ka T2DM a me ka momona. Hiki iā ia ke hoʻoikaika maikaʻi i ka huna ʻana o ka insulin, kaohi i ka huna ʻana o ka glucagon, hoʻoponopono pololei i ka glucose koko, hoʻemi i ka hopena o nā pilikia, hoʻomaikaʻi i ka hana o nā pancreatic β-cells, a hoʻopaneʻe i ka holomua o ka maʻi diabetes. Loaʻa iā ia kahi hopena pale i ka ʻōnaehana cardiovascular.
I ka mālama ʻana i ka momona, hiki iā ia ke hōʻemi pono i ka ʻai ʻana i ka meaʻai, hoʻemi i ka ʻai, hoʻonui i ka māʻona, kōkua i nā poʻe maʻi obese e hoʻemi i ke kaumaha, a hoʻemi i ka pilikia o nā pilikia pili i ka momona. Hiki iā ia ke hoʻomaikaʻi i ka insulin resistance a me ka lipid metabolism. Eia kekahi, ua hōʻike ia i ka hiki ke mālama i nā maʻi e pili ana i ka metabolic disorder e like me ka steatohepatitis non-alcoholic, sleep apnea syndrome, a me ka pau ʻole o ka naʻau. Hiki iā ia ke hoʻomaikaʻi i nā hōʻailona metabolic he nui i ka manawa like, e hāʻawi ana i kahi hoʻolālā lapaʻau piha.
He mea maʻalahi kona hoʻohana ʻana i hoʻokahi pule i kēlā me kēia pule a hiki ke hoʻomaikaʻi i ka mālama ʻana o nā maʻi.
No ka mea kakau
ʻO nā mea i ʻōlelo ʻia ma luna nei ua noiʻi ʻia, hoʻoponopono ʻia a hōʻuluʻulu ʻia e Cocer Peptides.
Mea kākau moʻolelo ʻepekema
ʻO Kauka William T. Garvey he kanaka naʻauao kaulana a me ka mea noiʻi i hui pū ʻia me nā ʻoihana hanohano he nui, ʻo ia hoʻi ke Kulanui o Alabama ma Birmingham, Aston University, a me ka Birmingham Veterans Affairs Medical Center. ʻO kona ʻano hoʻonaʻauao a me kāna ʻike ʻoihana e pili ana i nā ʻano aʻoaʻo i loko o ka lāʻau lapaʻau a me ka ʻepekema. Ua hāʻawi nui ʻo Kauka Garvey i nā ʻano o ka endocrinology a me ka metabolism, ka meaʻai a me ka meaʻai, biochemistry a me ka molecular biology, a me ka lāʻau lapaʻau maʻamau a i loko, me ka nānā pono ʻana i ka ʻōnaehana cardiovascular a me ka cardiology. Ua ʻike nui ʻia a hoʻohanohano ʻia kāna hana, ʻoiai ua kapa ʻia ʻo ia he Highly Cited Researcher ma ka Cross-Field category no 2023 a me 2024, e hōʻike ana i ka hopena nui a me ka mana o kāna noiʻi ʻana i ke kaiāulu ʻepekema ākea.
Hoʻonui ʻia ko Kauka Garvey makemake noiʻi a me ke akamai i nā ʻano like ʻole o nā maʻi metabolic a me kā lākou hoʻokele. Ua komo ikaika ʻo ia i ke aʻo ʻana i ka maʻi diabetes mellitus, ka momona, a me kā lākou mau pilikia pili, me ka manaʻo e wehe i nā hoʻolālā therapeutic hou a hoʻomaikaʻi i nā hopena maʻi. Hoʻopili ʻia kāna hana i ka noiʻi ʻepekema kumu, nā hoʻokolohua lapaʻau, a me nā noiʻi unuhi, e hoʻopaʻa ana i ka ʻokoʻa ma waena o nā ʻike noiʻi a me nā noi lapaʻau honua maoli. Ma o kāna noiʻi nui, ua hāʻawi ʻo Kauka Garvey i ka ʻike hohonu ʻana i nā ʻano kumu o nā maʻi metabolic a ua kōkua i ke ʻano o nā alakaʻi alakaʻi a me nā protocol lapaʻau ma ke kahua o ka endocrinology a me ka metabolism. Ua helu ʻia ʻo Kauka William T. Garvey ma ka ʻōlelo kuhikuhi [4].
