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1kits (Ebipipa 10) .
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▎ Enzimba ya Tirzepatid
Ensibuko: PubChem |
Omutendera: Tyr-{Aib}-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-{Aib}-Leu-Asp-Lys-Ile-Ala-Gln-{diaasidi-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 Ensengekera ya molekyu: C 225H 348N 48O68 Obuzito bwa molekyu: 4813 g/mol Ennamba ya CAS: 2023788-19-2 Ekitongole kya PubChem CID: 163285897 Ebigambo ebifaanagana: Zepbound; Mounjaro nga bwe |
▎ Okunoonyereza ku Tirzepatid
Kiki ekiva mu kunoonyereza ku Tirzepatid?
Tirzepatid ddagala lya polypeptide erikolebwa mu ngeri ey’ekikugu. Enkulaakulana yaayo eva mu kutegeera okw’amaanyi ku buzibu bw’ebirungo ebiziyiza GLP-1 receptor agonists ebiriwo mu kujjanjaba ssukaali ow’ekika eky’okubiri (T2DM) n’omugejjo. Wadde nga GLP-1 receptor agonists ziraga nti zikola bulungi nnyo mu kufuga glucose mu musaayi n’okugejja, bannassaayansi bakizudde nti okukola kwazo ku GIP receptor kunafu nnyo, ekikoma ku bujjanjabi bw’eddagala lino. N’olwekyo, ttiimu y’abanoonyereza n’okukulaakulanya ebadde yeewaddeyo okukola ekika ky’eddagala ekipya ekiyinza okukola GIPR ne GLP-1R omulundi gumu, nga kigenderera okutuuka ku kufuga kwa glucose mu musaayi n’okuddukanya obuzito mu ngeri enzijuvu era ennungi [1]..
Mu nkola y’okunoonyereza n’okukulaakulanya, bannassaayansi bakoze okunoonyereza okusookerwako okungi n’okugezesa mu malwaliro. Mu mutendera gw’okunoonyereza nga tekunnabaawo, eby’obugagga by’eddagala bya Tirzepatid byakeberebwa bulungi okuyita mu kugezesa ebisolo, okukakasa obusobozi bwayo mu kufuga glucose mu musaayi n’okugejja. Ebivuddemu biraga nti esobola okukendeeza ennyo ku mutindo gwa glucose mu musaayi mu bikolwa by’ebisolo era ne kiraga nti ekola bulungi nnyo mu kuddukanya obuzito, ne kiteekawo omusingi gw’okugezesebwa okw’obujjanjabi okuddirira.
Oluvannyuma, omutendera gw’okugezesebwa mu malwaliro gwalimu okugezesebwa kwa Phase I, II, ne III. Okugezesebwa kwa Phase I okusinga kwekenneenya obukuumi, okugumiikiriza, n’obulungi bw’eddagala lino. Ebivuddemu biraga nti Tirzepatid yalina obukuumi obulungi n’okugumira. Okugezesebwa kwa Phase II kwayongera okunoonyereza ku bulungibwansi n’obukuumi bwa ddoozi ez’enjawulo eza Tirzepatid mu balwadde abalina T2DM, ne kusooka okuzuula ddoozi zaayo ezikola. Okugezesebwa okusinga obukulu okwa Phase III clinical trials, nga SURPASS series of studies, kwalimu abalwadde bangi abalina T2DM. Ebivuddemu biraga nti Tirzepatid yali esinga nnyo eddagala eririwo erya GLP-1 receptor agonists, nga semaglutide, mu kukendeeza glucose mu musaayi n’obuzito, nga kiwa obujulizi obw’amaanyi ku kukozesa Tirzepatid mu kutunda [1]..
Enkola ya Tirzepatid ekola ki?
Tirzepatid ekendeeza ku glucose mu musaayi ng’ayita mu nkola eziwera ezikolagana. Nga ekola ku GLP-1 receptor, Tirzepatid yeekwata ku GLP-1 receptor ku pancreatic β-cells, nga ekoppa ekikolwa kya GLP-1 eky’obutonde. GLP-1 busimu obukolebwa mu byenda era nga bukulu nnyo mu kukuuma glucose homeostasis. Kiyinza okutumbula okukola insulini, okufulumya, n’okutegeera glucose, okukendeeza ku kufulumya glucagon okutumbula okukkuta, n’okuziyiza okwagala okulya.
Okukola kuno kuyinza okutumbula okufulumya insulini. Insulin ye hormone enkulu ekendeeza sukaali mu mubiri, esobola okwongera okutwala n’okukozesa glucose obutoffaali, bwe kityo ne kikendeeza ku glucose mu musaayi. Mu balwadde abalina T2DM, okufulumya insulini tekumala oba obutoffaali okuwulira insulini kukendeera, ekivaako glucose mu musaayi okulinnya. Nga ekola ku GLP-1 receptor, Tirzepatid ayongera ku insulini, ekiyamba okulongoosa okufuga glucose mu musaayi.
Mu kiseera kye kimu, okukola kw’ekirungo kya GLP-1 nakyo kiziyiza okufulumya kwa glucagon. Glucagon etera okutumbula glycogenolysis ne gluconeogenesis mu kiseera ky’okusiiba, okwongera ku kukola glucose mu musaayi. Nga eziyiza ekikolwa kya glucagon, Tirzepatid eyongera okukendeeza ku nsibuko ya glucose mu musaayi, ekiyamba mu kufuga glucose mu musaayi [2]..
Nga ekola ku GIP receptor, Tirzepatid ekola ku GIP receptor omulundi gumu. Oluvannyuma lw’okukola, esobola okutumbula okuwulira kwa insulini n’okufulumya. GIP receptor esinga kubeera mu bitundu by’omubiri nga pancreatic β-cells. Oluvannyuma lw’okukola, okuyita mu kutambuza amakubo g’obubonero mu butoffaali, okufulumya insulini kweyongera, era okuddamu kw’obutoffaali eri insulini kulongooka, bwe kityo ne kikendeeza bulungi glucose mu musaayi.
Tirzepatid ye analog esooka mu mutindo gwa dual glucagon-like peptide-1 ne glucose-dependent insulinotropic polypeptide (GIP) analog, ekkirizibwa okujjanjaba abalwadde abakulu abalina T2DM ng’eky’okugatta ku mmere n’okukola dduyiro. Tirzepatid nsengekera ya kemiko ekoleddwa nga yeesigamiziddwa ku nsengekera ya GIP, ekoleddwa mu peptide ya amino acid 39. Kyongera ku kufulumya insulini, kikendeeza ku kufulumya glucagon mu ngeri eyeesigama ku glucose, kikendeeza ku glucose mu musaayi mu kisiibo n’oluvannyuma lw’okulya, kitumbula okukkuta, kikendeeza ku buzito bw’omubiri, n’okulwawo okufulumya amazzi mu lubuto. Kino dual receptor agonist effect kifuula Tirzepatid okukola obulungi okusinga single GLP-1 receptor agonists mu kutumbula okufulumya insulini n’okuziyiza okufulumya glucagon [2]..
Tirzepatid era asobola okulwawo okufulumya amazzi mu lubuto n’okwongera okukkuta. Kiyinza okulwawo okufulumya amazzi mu lubuto, ne kiwangaaza obudde emmere gy’emala mu lubuto n’okukendeeza ku sipiidi y’okunyiga ebiriisa, bwe kityo ne kyewala okulinnya ennyo kwa glucose mu musaayi oluvannyuma lw’okulya. Mu kunoonyereza okutali kwa bujjanjabi n’okujjanjaba, enkola ya Tirzepatid ku kuggyamu ebintu mu lubuto egeraageranyizibwa ku ya GLP-1 receptor agonists. Mu mbeba ezigejjulukuka ezireetebwa emmere, diguli y’okulwawo okufulumya amazzi mu lubuto nga Tirzepatid efaananako n’eya semaglutide, naye ebikolwa bino eby’okuziyiza eby’amangu bibula oluvannyuma lwa wiiki 2 nga bijjanjabiddwa.
Mu beetabye mu kugezesebwa abalina n’abatalina T2DM, Tirzepatid omulundi gumu buli wiiki (≥5 mg ne ≥4.5 mg, mu kulondako) yalwawo okufulumya amazzi mu lubuto oluvannyuma lwa ddoozi emu. Mu beetabye abalamu, ekikolwa kyakendeera oluvannyuma lw’okukozesa dose eziwera eza Tirzepatid oba dulaglutide (Urva S, 2020). Mu kiseera kye kimu, era esobola okukola ku busimu obw’omu makkati, okwongera okukkuta, okukendeeza ku njagala y’okulya n’okulya emmere. Nga efuga emmere, eyamba mu ngeri etali butereevu okufuga emiwendo gya glucose mu musaayi, naddala esaanira ekizibu ky’omugejjo ekitera okuwerekerwako abalwadde abalina T2DM, era kiyamba okulongoosa obuziyiza insulini n’embeera y’enkyukakyuka mu mubiri okutwalira awamu [2]..
Tirzepatid kizuuliddwa nti ayongera ku muwendo gwa adiponectin, adipocytokine eyeekuusa ku kuwulira insulini. Okweyongera mu miwendo gya adiponectin kiyamba okulongoosa okuwuliziganya kwa insulini, okufuula obutoffaali okuddamu insulini, bwe kityo ne kitwala bulungi n’okukozesa glucose n’okukendeeza ku glucose mu musaayi [2] . Okugatta ku ekyo, Tirzepatid era esobola okulongoosa ensengeka y’amasavu era erina ekikolwa ekiyinza okukuuma obulamu bw’emisuwa n’emisuwa. Tirzepatid ekakasiddwa nti esobola okulongoosa puleesa, okukendeeza ku low-density lipoprotein (LDL) cholesterol ne triglycerides [3] , okwongera okuwagira emigaso gyayo egy’enjawulo mu kuddukanya glucose mu musaayi.
Ensibuko: PubMed [5] .
Okunoonyereza okukwatagana
Obulung’amu ku kuddukanya obuzito mu balwadde abagejjulukuka ne ssukaali ow’ekika eky’okubiri
Okunoonyereza kungi kukakasizza obulungi bwa Tirzepatid mu kuddukanya obuzito bw’omubiri mu balwadde abagejjulukuka ne T2DM. Mu kunoonyereza okwatuumibwa 'SURMOUNT-2', okwali kwa Phase 3, okugezesebwa okw'emirundi ebiri, okwa randomized, okwakolebwa mu mawanga musanvu. Abantu abakulu (emyaka ≥18) nga balina body mass index (BMI) ya 27 kg/m² oba okusingawo n’omutindo gwa glycated hemoglobin (HbA2c) ogwa 7 - 10% baaweebwa mu ngeri ey’ekifuulannenge okufuna empiso za Tirzepatid (10 mg oba 15 mg) oba placebo omulundi gumu buli wiiki wansi w’olususu okumala wiiki 72.
Ebivuddemu biraga nti mu wiiki 72, ebitundu by’okugejja mu bibinja bya Tirzepatid 10 mg ne 15 mg byali -12.8% ne -14.7%, okusinziira ku -3.2% mu kibinja kya placebo. Enjawulo mu bujjanjabi ebalirirwamu eza Tirzepatid 10 mg ne 15 mg bw’ogeraageranya n’ezo eza placebo zaali -9.6 ku buli 100 ne -11.6 ku buli 100, okusinziira ku, byombi byali bikulu mu bibalo (p < 0.0001). Okugatta ku ekyo, ekitundu ekinene eky’abalwadde abafuna obujjanjabi bwa Tirzepatid baatuuka ku kigero ky’okugejja ebitundu 5% oba okusingawo (79 - 83% vs 32%) [4]..
Mu kunoonyereza kwa 'SURMOUNT-2', obuzito obw'omusingi bwali 100.7 kg, BMI yali 36.1 kg/m², ate HbA1 yali 8.02%. Oluvannyuma lwa wiiki 72 ng’ajjanjabwa, Tirzepatid teyakoma ku kukendeeza nnyo ku buzito bw’omubiri naye era yalina akakwate akalungi ku kufuga glucose mu musaayi [4]..
Okulongoosa ekikolwa ku bulwadde bw’obusimu obukwatagana ne ssukaali
ome okunoonyereza kulaga nti GLP1-RAs zisobola okukendeeza ku bulabe bw’okusannyalala mu balwadde abalina T2DM nga zilongoosa okujjukira, okuyiga, n’okuvvuunuka obuzibu mu kutegeera. Nga GIP-RA/GLP-1RA ey’emirundi ebiri, Tirzepatid yasomesebwa mu layini y’obutoffaali bwa neuroblastoma (SHSY5Y) olw’ebikolwa byayo ku bubonero bw’okukula kw’obusimu (CREB ne BDNF), apoptosis (BAX/Bcl2 ratio), okwawukana (pAkt, MAP2, GAP43, ne AGBL4), n’okuziyiza insulini (GLUT1, GLUT4, GLUT3, ne SORBS1).
Ebivuddemu omulundi ogusoose byaggumiza omulimu gwa Tirzepatid mu kukola ekkubo lya pAkt/CREB/BDNF n’obusimu obulaga obubonero wansi, awamu n’obulungi bwayo obw’okukuuma obusimu. Era kyalaga nti Tirzepatid yasobola okuziyiza ebikosa ebikwatagana ne hyperglycemia n’okuziyiza insulini ku mutendera gw’obusimu. Nolwekyo, Tirzepatid esobola okulongoosa okuvunda kw’obusimu obuva ku sukaali omungi n’okuvvuunuka okuziyiza insulini y’obusimu, okuwa amagezi amapya ku kulongoosa obulwadde bw’obusimu obukwatagana ne sukaali [5]..
Okunoonyereza kugenda mu maaso mu kujjanjaba obulwadde bwa sukaali obw’ekika eky’okubiri
Okunoonyereza okumu kulaga nti ng’ekika ekipya eky’eddagala erikendeeza sukaali, Tirzepatid efuuse eddagala erisooka erya dual GIP/GLP-1R agonist eryakkirizibwa okujjanjaba ssukaali mu Amerika. Kikakasiddwa nti kirina kinene kye kikola ku kukendeeza glucose mu musaayi n’okukendeeza ku buzito bw’omubiri mu kugezesebwa okunene okuwerako, era waliwo obujulizi obulaga nti era kirina obusobozi bungi mu kukuuma emisuwa gy’omutima.
Okugatta ku ekyo, endowooza ya peptides ezikoleddwa egguddewo ebintu bingi ebitamanyiddwa eri Tirzepatid. Okugezesebwa okugenda mu maaso (NCT04166773) n’obujulizi biraga nti lirabika nga ddagala erisuubiza mu bintu nga obulwadde bw’ekibumba obutali bwa masavu (NAFLD), okukuuma ekibumba, n’okukuuma obusimu [6]..
Ebikolwa bya tirzepatide eby’ekiseera ekiwanvu ku bulamu bw’emisuwa
Tirzepatid eyinza okukendeeza ku bulabe bw’endwadde z’emisuwa ng’etumbula okugejja. Okunoonyereza kwekenneenya enkola ya Tirzepatid ku mugejjo n’endwadde z’emisuwa mu bantu abakulu mu Amerika (Wong ND, 2024). Okunoonyereza kuno kwazuula nti mu bantu abakulu mu Amerika abalina ebisaanyizo okuweebwa obujjanjabi bwa Tirzepatid, oluvannyuma lw’okujjanjabwa n’eddagala lya Tirzepatid 15 mg, kyabalirirwa nti abantu abakulu 70.6% ne 56.7% baali bakendedde ku buzito bwa ≥15% ne ≥20%, ekitegeeza nti omuwendo gw’abantu abagejjulukuka gwakendeera ebitundu 58.8%.
Mu abo abatalina ndwadde za misuwa, obulabe obubalirirwamu obw'emyaka 10 obw'endwadde z'emisuwa bwakendeera okuva ku 10.1% 'nga tebannaba kujjanjabwa' okutuuka ku 7.7% 'oluvannyuma lw'okujjanjabwa', ekiraga okukendeeza ku bulabe obw'enkomeredde ebitundu 2.4% n'okukendeeza ku bulabe obw'enjawulo okwa 23.6%, ekitegeeza nti ebiseera by'endwadde z'emisuwa obukadde 2 bisobola okuziyizibwa mu myaka 10.
Mu kumaliriza ,Tirzepatid ye novel dual agonist of GIP ne GLP-1 receptors, nga kino kya makulu nnyo mu kujjanjaba T2DM n’omugejjo. Kiyinza okutumbula obulungi okufulumya insulini, okuziyiza okufulumya kwa glucagon, okutereeza obulungi glucose mu musaayi, okukendeeza ku bulabe bw’ebizibu, okulongoosa enkola y’obutoffaali bwa β obw’omu lubuto, n’okulwawo okukula kwa ssukaali. Era erina ekikolwa eky’obukuumi ku nkola y’emisuwa gy’omutima.
Mu kujjanjaba omugejjo, kisobola bulungi okukendeeza ku mmere gye balya, okukendeeza ku njagala y’okulya, okwongera okukkuta, okuyamba abalwadde abagejjulukuka okugejja, n’okukendeeza ku bulabe bw’ebizibu ebiva ku mugejjo. Era esobola okulongoosa obuziyiza bwa insulini n’okukyusakyusa amasavu. Okugatta ku ekyo, eraga nti erina obusobozi mu kujjanjaba endwadde ezeekuusa ku buzibu bw’okukyusakyusa emmere nga non-alcoholic steatohepatitis, sleep apnea syndrome, n’okulemererwa kw’omutima. Kiyinza okulongoosa ebipimo by’enkyukakyuka y’emmere ebingi omulundi gumu, ne kiwa enteekateeka y’obujjanjabi enzijuvu.
Enkola yaayo ey’okukuba empiso omulundi gumu buli wiiki nnyangu okukozesa era esobola okulongoosa mu kugoberera obujjanjabi bw’abalwadde.
Ebikwata ku Muwandiisi
Ebintu ebyogeddwako waggulu byonna binoonyerezeddwako, birongooseddwa era ne bikung’aanyizibwa kkampuni ya Cocer Peptides.
Omuwandiisi wa Scientific Journal
Dr. William T. Garvey mukenkufu era munoonyereza ow’ekitiibwa alina akakwate n’amatendekero ag’ekitiibwa agawerako, omuli Yunivasite y’e Alabama e Birmingham, Yunivasite ya Aston, ne Birmingham Veterans Affairs Medical Center. Obuyigirize bwe n’obumanyirivu bwe mu by’emikono bikwata ku bintu bingi mu by’obusawo ne ssaayansi. Dr. Garvey akoze kinene mu bintu by’endwadde z’omu lubuto n’enkyukakyuka mu mubiri, endya n’endya, eby’obutonde n’eby’obulamu ebya molekyu, wamu n’obusawo obw’enjawulo n’obw’omunda, ng’essira aliteeka nnyo ku nkola y’emisuwa n’omutima. Omulimu gwe gubadde gumanyiddwa nnyo era ne guweebwa ekitiibwa, naddala okulondebwa ng’Omunoonyereza Amanyiddwa ennyo mu mutendera gwa Cross-Field mu mwaka gwombi 2023 ne 2024, ekiraga enkosa ennene n’enkola y’okunoonyereza kwe ku kibiina kya ssaayansi ekigazi.
Dr. Garvey by’ayagala mu kunoonyereza n’obukugu bituuka ku bintu eby’enjawulo ebikwata ku ndwadde z’enkyukakyuka mu mubiri n’enzirukanya yazo. Abadde yeenyigira nnyo mu kunoonyereza ku ssukaali, omugejjo, n’ebizibu ebikwatagana nabyo, ng’agenderera okuzuula enkola empya ez’obujjanjabi n’okulongoosa ebiva mu balwadde. Omulimu gwe guzingiramu okunoonyereza kwa ssaayansi okusookerwako, okugezesa mu bujjanjabi, n’okunoonyereza ku kuvvuunula, okuziba ekituli wakati w’ebizuuliddwa mu laboratory n’okukozesebwa mu by’obujjanjabi mu nsi entuufu. Okuyita mu kunoonyereza kwe okunene, Dr. Garvey ayambye okutegeera ennyo enkola ezisibukamu obuzibu mu nkyukakyuka y’emmere era ayambye okukola ebiragiro by’obujjanjabi n’enkola z’obujjanjabi mu by’endocrinology n’enkyukakyuka y’emmere. Dr. William T. Garvey awandiikiddwa mu kiwandiiko ekijuliziddwa [4]..
