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1kits (Ebipipa 10) .
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▎ Enzimba ya Semaglutid
Ensibuko: Pub Chem |
Omutendera: 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-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH Ensengekera ya molekyu: C 187H 291N 45O59 Obuzito bwa molekyu: 4114 g/mol Ennamba ya CAS 910463-68-2 PubChem CID 56843331. Omuwandiisi w’ebitabo Ebigambo ebifaanagana: Rybelsus; Ozempic ow'ekika kya ; Wegovy |
▎ Okunoonyereza ku Semaglutid
Ensibuko y’okunoonyereza ku Semaglutid eri etya?
Semaglutid ye peptide-1 eringa glucagon y’omuntu (GLP-1) analog, esengekeddwa nga GLP-1 receptor agonist. GLP-1 busimu bwa butonde obufulumizibwa obutoffaali bw’ekyenda oluvannyuma lw’okulya. Kikola kinene mu kutumbula okufulumya insulini n’okuziyiza okufulumya glucagon, bwe kityo ne kitereeza emiwendo gya glucose mu musaayi. Enkula ya Semaglutid yasibuka mu kunoonyereza okw’obwegendereza ku mirimu gy’omubiri gya GLP-1. Wabula GLP-1 erina ekitundu ky’obulamu ekitono ennyo mu mubiri, ekimala eddakiika nga 1 ku 2 zokka, ekiva ku kusobola okuvunda olw’enziyiza za dipeptidyl peptidase-4 (DPP-4) mu mubiri. Okuvvuunuka ekkomo lino, bannassaayansi baakyusa ensengekera ya GLP-1 nga bayita mu kukyusa amino asidi ebitongole n’okugattako ebibinja ebikuuma, ne bayongera ku buziyiza bwayo eri enziyiza za DPP-4 era bwe batyo ne bawangaaza ebbanga lyayo ery’okukola [1] . Mu nsengekera ya Semaglutid, alanine mu kifo eky’omunaana ekyusiddwamu asidi wa α-aminoisobutyric (Aib). Enkyukakyuka eno tekoma ku kulongoosa butebenkevu bwa ddagala wabula era enyweza okusiba kwalyo ku GLP-1 receptor (Ma H, 2020). Okugatta ku ekyo, olujegere lw’amasavu olw’enjawulo oluyungiddwa ku C-terminus yaalwo, oluyungiddwa nga luyita mu γ-glutamine ku bisigalira bya lysine, lwongera okwongera ku kitundu ky’obulamu, ne kisobozesa okukuba empiso omulundi gumu buli wiiki oba omulundi gumu buli lunaku mu kamwa [1] . Mu kusooka nga yeesigamiziddwa ku kunoonyereza n’okukyusakyusa mu butonde bwa GLP-1, Semaglutid egenderera okuwa obujjanjabi obusingako obulungi eri abalwadde abalina enkyukakyuka y’omubiri ey’ekika kya 2 [1, 2] . Oluvannyuma lw’okulongoosa enzimba, ekuuma emirimu gy’omubiri gya GLP-1 ate nga erongoosa nnyo eby’obugagga byayo eby’eddagala, n’efuuka agonist enkulu ekola ebbanga eddene erikwata GLP-1. Okunoonyereza n’okukulaakulanya Semaglutid bikulu nnyo mu kujjanjaba enkyukakyuka y’omubiri ey’ekika eky’okubiri, nga kiwa abalwadde eby’okulonda ebipya. Nga elongoosa ensengekera, evvuunuka ekizibu ky’ekitundu ky’obulamu ekitono ekya GLP-1 ey’obutonde, okutumbula obutebenkevu bw’eddagala n’obudde bw’okukola.
Enkola ya Semaglutid ekola ki?
Semaglutid ye glucagon-like peptide-1 (GLP-1) receptor agonist ekola ebbanga eddene, era enkola yaayo ey’okukola eri bweti:
Okulungamya Glucose mu musaayi: Nga ekirungo ekipya ekiringa glucagon-like peptide-1 receptor agonist (GLP-1RA), Semaglutid okusinga ekendeeza ku kwegomba kw’abalwadde emmere n’okukendeeza ku kwegomba kwabwe emmere erimu amasavu amangi nga enyigiriza okwagala okulya. Kitereeza ekifo eky’okuliisa mu hypothalamus, okukendeeza ku mmere gye balya, okwongera okukkuta, okuziyiza okufulumya amazzi mu lubuto, n’okukendeeza ku kutambula kw’olubuto, bwe kityo ne kituuka ku kiruubirirwa ky’okugejja. Okugejja kiyamba okulongoosa obuziyiza bwa insulini n’okwongera okutereeza emiwendo gya glucose mu musaayi [3] (Kim HS, 2021). Semaglutid ereeta okugejja mu biwuka okuyita mu makubo g’obusimu agasaasaanyiziddwa. Okunoonyereza kulaga nti Semaglutid ekola butereevu ku bitundu nga ekikolo ky’obwongo, septal nucleus, ne hypothalamus. Wadde nga tesomoka kiziyiza omusaayi n’obwongo, ekwatagana n’obwongo okuyita mu bitundu by’omubiri ebyetooloola n’ebitundu ebitongole okumpi n’ennywanto. Kireetera central c-Fos activation mu bitundu by’obwongo 10, omuli ebitundu by’obwongo obw’emabega ebigendereddwa butereevu Semaglutid n’ebitundu eby’okubiri ebitaliiko nkolagana ya GLP-1R butereevu, gamba nga lateral parabrachial nucleus. Okwekenenya okw’obwengula kulaga nti okukola kuyinza okuba nga kwekuusa ku kukomya emmere efugibwa obusimu obuyitibwa neurons mu lateral parabrachial nucleus, bwe kityo ne kitereeza emiwendo gya glucose mu musaayi [4]..
Okulungamya olubuto: Semaglutid ekola ku bikwata GLP-1 mu nkola y’olubuto. Okuyita mu kkubo erikwata ku busimu bwa vagus, kikola ku bitundu mu bwongo nga nucleus y’omukutu ogw’omuntu omu ne dorsal motor nucleus y’obusimu bwa vagus okulung’amya entambula y’olubuto n’ekyenda. Kiyinza okuziyiza okukonziba kw’omusuwa gw’olubuto, okwongera okusika omuguwa gw’omu lubuto, okwongera ku budde emmere gy’emala mu lubuto, n’okulwawo okuyingira mu lubuto, ne kiziyiza okulinnya amangu kwa glucose mu musaayi oluvannyuma lw’okulya n’okufuula enkyukakyuka za glucose mu musaayi okubeera ennywevu [5] (Katsurada K, 2016). Okugatta ku ekyo, Semaglutid ekola ku bikwata GLP-1 mu nkola y’obusimu obw’omu makkati, okusinga mu bitundu nga arcuate nucleus ne paraventricular nucleus of the hypothalamus. Kiziyiza okufulumya ebintu ebisitula okwagala okulya nga neuropeptide Y (NPY) ne agouti-related protein (AgRP), ate mu kiseera kye kimu kikola obusimu obuyitibwa pro-opiomelanocortin (POMC) neurons, okutumbula okufulumya obusimu obusitula α-melanocyte (α-MSH) [5] . Ebikolwa bino bireeta okuwulira ng’okkuta, bikendeeza enjala, n’okukendeeza ku mmere gy’olya, mu ngeri etali ya butereevu ne bikola bulungi ku kufuga glucose mu musaayi.
Obukuumi bw’emisuwa: Semaglutid esobola okutumbula obutoffaali bw’emisuwa okufulumya ensonga ezigaziya emisuwa nga nitric oxide (NO), okutumbula obusobozi bw’okugaziya emisuwa n’okulongoosa okufuuwa omusaayi. Mu kiseera kye kimu, kiziyiza okuddamu kw’okuzimba n’okunyigirizibwa okw’okwokya, kikendeeza ku kwonooneka kw’obutoffaali bw’emisuwa, era kikendeeza ku bulabe bw’okuzimba emisuwa. Ekirala, mu kukendeeza ku njagala n’okulya emmere, Semaglutid eyamba mu kugejja, etereeza obuzibu mu nkyukakyuka y’amasavu, ekendeeza ku miwendo gya triglycerides ne low-density lipoprotein cholesterol (LDL-C), era eyongera ku muwendo gwa high-density lipoprotein cholesterol (HDL-C). Era kiyinza okuba n’omugaso ku puleesa nga kitereeza enkola y’omusaayi mu kibumba n’emirimu gy’obusimu, okukendeeza ku bulabe bwa puleesa n’ensonga ezireeta endwadde z’emisuwa [6]..
Semaglutid n’okulungamya okuwandiika kw’okukyusa WAT okudda mu BAT n’okukola kwa BAT.
Ensibuko: PubMed [12] .
Biki ebikulu ebigezeseddwa n’okunoonyereza?
Design and Optimization of Chemical Structure: Bwe baali bakola dizayini ya Semaglutid, enkola y’okusiba okuddamu ku albumin yakwatibwa okwongera ku bbanga eddagala lye limala nga likola. Nga tusalawo omugatte ogusinga obulungi ogwa asidi z’amasavu n’ebiyunga, ate nga tukuuma obulungi bw’ekirungo ekikwata GLP-1 (GLP-1R), obusobozi bw’okusiba albumin bwasukkiridde [7]..
Okukozesa eddagala: Semaglutid ye glucagon-like peptide-1 receptor agonist (GLP-1 RA) nga erina ekitundu ky’obulamu ekiwanvu ennyo eky’okuggyawo, ekisobozesa okukuba empiso omulundi gumu buli wiiki wansi w’olususu. Mu balwadde abalina ekika kya 2 metabolism (T2DM), ekikolwa ky’okugejja eky’okukuba empiso ya Semaglutid omulundi gumu buli wiiki wansi w’olususu kisinga ku GLP-1RA endala eziweebwa omulundi gumu buli wiiki. Mu kugezesebwa okwa phase II dose-exploration ku balwadde abagejjulukuka abatalina T2DM, empiso ya Semaglutid omulundi gumu buli lunaku wansi w’olususu yalaga nti ekendeeza ku buzito okusinga placebo ne liraglutide 3.0 mg omulundi gumu buli lunaku. Diguli y’okugejja okuva ku Semaglutid mu kunoonyereza kuno yasukka omutindo gw’eddagala erigejja ogwateekebwawo ekitongole ky’eddagala ekya Bulaaya (EMA) n’ekitongole kya Amerika ekivunaanyizibwa ku by’emmere n’eddagala (FDA), era tekirina bulabe, ekiraga nti empiso ya Semaglutid omulundi gumu buli lunaku wansi w’olususu erina obusobozi okufuuka eddagala erikendeeza ku mugejjo mu biseera eby’omu maaso [8]..
Obujjanjabi bw’endwadde z’emisuwa n’emitima nga tulongoosa enkola y’omutima: Ebyavudde mu kugezesebwa kwa STEP-HFpEF biraga nti eddagala eritta ssukaali eriringa glucagon 1 agonist Semaglutid erya dose ennene lyalongoosa nnyo obubonero obukwatagana n’okulemererwa kw’omutima n’ekitundu ekikuumibwa ejection fraction (HFpEF) era ne kikendeeza ku mutindo gwa N-terminal pro-B-type natriuretic peptide (NT-proBNP) (NT-proBNP) nga bwe kiri. Okugezesebwa mu kunoonyereza kuzudde nti obujjanjabi obw’amangu ne Semaglutid busobola okwongera okusika omuguwa kw’emisuwa gy’omuntu emirundi egisukka mu esatu mu ngeri eyesigamiziddwa ku ddoozi, awatali kwongera ku mpisa ya arrhythmia. Ekikolwa kino kiyinza okuba nga kiva ku kweyongera mu kutwalibwa kwa Ca2+ okukolebwa sarcoplasmic reticulum. Obujjanjabi n’eddagala lya Semaglutid erya ddoozi ennene mu balwadde abalina omutima okulemererwa kiyinza okulongoosa enkola y’emisuwa, bwe kityo ne kiwummuza obubonero [9]..
Semaglutid enoonyezebwa okujjanjaba obulwadde bw’ekibumba obutali bwa mwenge (NASH): Enteekateeka entuufu eya Semaglutid ekoze kinene mu kulongoosa okufuga glucose mu musaayi, obuzito bw’omubiri, puleesa, amasavu mu musaayi, enkola y’obutoffaali bwa β, n’enkola y’emisuwa gy’omutima mu balwadde abalina enkyukakyuka y’omubiri ey’ekika eky’okubiri. Okugatta ku ekyo, okukola eddagala lya Semaglutid eriweebwa mu kamwa kiyinza okuwa enkizo endala mu nsonga z’okugoberera obujjanjabi bw’abalwadde [7]..
Njawulo ki eri mu bikolwa bya Semaglutid mu kugejja mu bika eby’enjawulo?
Abantu abakulu abalina endwadde z’emisuwa n’emisuwa ezaaliwo edda, abagejjulukuka oba omugejjo naye nga tebalina nkyukakyuka mu mubiri: Mu kugezesebwa kwa SELECT cardiovascular outcomes, Semaglutid yakendeeza ku bikulu ebizibu ebiva mu misuwa n’emisuwa ebitundu 20% mu bantu abakulu 17,604 abalina endwadde z’emisuwa n’emisuwa ezaaliwo edda, abagejjulukuka oba omugejjo, era nga tebalina nkyukakyuka mu mubiri [10] (Ryan DH, 2024). Mu kwekenneenya kuno okwalagirwa nga tekunnabaawo, abanoonyereza beekenneenya ebikolwa bya Semaglutid ku buzito bw’omubiri, ebiva mu anthropometric, obukuumi, n’okugumiikiriza okusinziira ku baseline body mass index (BMI). Abalwadde abaali bafuna Semaglutid baafuna okukendeera kw’obuzito bw’omubiri obutasalako mu wiiki 65, okumala emyaka 4. Ku wiiki 208, bw’ogeraageranya n’ekibinja kya placebo, Semaglutid yaleetawo okukendeera kwa wakati mu buzito bw’omubiri (-10.2%), okwetooloola ekiwato (-7.7 cm), n’omugerageranyo gw’ekiwato n’obuwanvu (-6.9%), ate ekibinja kya placebo kyalina okukendeera kwa (-1.5%, -1.3 cm, ne -1.0%), era okugeraageranya kwonna ne placebo kwali kwa bibalo amakulu. Okugejja okw’amakulu mu bujjanjabi kwaliwo mu basajja n’abakazi, amawanga gonna, ebika by’omubiri, n’ebitundu. Semaglutid yali ekwatagana n’ebizibu eby’amaanyi ebitono. Ku buli kibinja kya BMI (<30, 30 okutuuka ku <35, 35 okutuuka ku <40, ne ≥40 kg/m²), ebiseera by’ebizibu eby’amaanyi ebya Semaglutid (omuwendo gw’ebintu ebyetegereza buli muntu-emyaka 100) byali wansi (43.23, 43.54, 51.07, ne 47.06 ku Semaglutid, ne 50.48, 49.66, 52.73, ne 60.85 ku ddagala lya placebo). Semaglutid yali ekwatagana n’omutindo ogweyongera ogw’okuyimiriza ekintu ekigezeseddwa. Omutendera gwa BMI bwe gwakendeera, omuwendo gw’abayimirizaawo gweyongera. Mu kugezesebwa kwa SELECT, ku wiiki 208, Semaglutid yavaamu okugejja okw’amaanyi mu bujjanjabi n’okulongoosa mu miwendo gya anthropometric bw’ogeraageranya n’ekirungo kya placebo, era okugejja kwasigala okumala emyaka 4.
Abantu ssekinnoomu abagejjulukuka oba abagejjulukuka naye nga tebalina nkyukakyuka mu mubiri: Okwekenenya okutegekeddwa kwekenneenya obulungi n’obukuumi bwa Semaglutid mu bantu ssekinnoomu abagejjulukuka oba abagejjulukuka naye nga tebalina nkyukakyuka mu mubiri [11] . Okuddamu okwetegereza kuno kwagatta ebivudde mu kugezesebwa okw’obujjanjabi okungi, nga kussa essira ku bikolwa bya Semaglutid ku kugejja, ebipimo by’enkyukakyuka y’emmere, n’ebiva mu bulamu okutwalira awamu. Ebivuddemu biraga nti Semaglutid yakwatagana n’okugejja ennyo n’okulongoosa mu bipimo by’obulamu ebikwatagana n’omugejjo, era eyinza okuba enkola ey’omuwendo ey’obujjanjabi eri abalwadde abagejjulukuka.
Abalwadde abatali ba ssukaali (obujulizi okuva mu RCTs eziwera): Mu kugezesebwa 4 okwafugibwa mu ngeri ey’ekifuulannenge, abalwadde abaali n’obuzito bw’omubiri obusookerwako obwa kkiro 96 okutuuka ku 105 baafuna empiso ya Semaglutid 2.4 mg wansi w’olususu buli wiiki n’okuyingira mu bulamu (okubuulirira, emmere, n’okukola emirimu gy’omubiri) olw’obujjanjabi bw’okugejja. Okugezesebwa okumu okwafugibwa mu ngeri ey’ekifuulannenge ku balwadde abatali ba ssukaali (N = 1961) kwalaga nti oluvannyuma lwa wiiki 68, okugejja okwa wakati kwali 15% (kkiro 15), nga kino kyali kya njawulo nnyo mu bibalo ku 2% (kkiro 3) mu kibinja kya placebo. Ekitundu ky’abalwadde abagejja ≥5% kyali 86% bw’ogeraageranya ne 32% mu kibinja kya placebo, era omuwendo ogwetaagisa okujjanjaba (NNT) = 2; ekitundu ky’abalwadde abagejja ≥10% kyali 69% bw’ogeraageranya ne 12% mu kibinja kya placebo, ne NNT = 2. Okugejja kwatuuka ku ddaala ku wiiki nga 60. Ebiseera by’ebizibu ebiva mu lubuto (AEs) byali 74% bw’ogeraageranya ne 48% mu kibinja kya placebo, n’omuwendo ogwetaagisa okukola obulabe (NNH) = 3. Ekitundu ky’abalwadde abayimiriza obujjanjabi olw’ebizibu ebizibu kyali 7% bw’ogeraageranya ne 3% mu kibinja kya placebo, ne NNH = 25. Mu kugezesebwa okulala okwafugibwa mu ngeri ey’ekifuulannenge n’okuyingira mu bulamu obw’amaanyi (N = 611), okugejja mu kibinja kya Semaglutid kwali 16% (kkiro 17), nga kino kyali kya njawulo nnyo mu bibalo ku 6% (kkiro 6) mu kibinja kya placebo. Mu dose-exploration randomized controlled trial eri abalwadde ba ssukaali (N = 1210), abalwadde baweebwa buli wiiki 2.4 mg za Semaglutid, buli wiiki 1.0 mg za Semaglutid, oba placebo. Oluvannyuma lwa wiiki 68, okugejja okwa wakati kwali 10% (2.4 mg), 7% (1.0 mg), ne 3% (placebo). Ekitundu ky’abalwadde abagejja ≥5% kyali 69% (2.4 mg), 57% (1.0 mg) bw’ogeraageranya ne 29% mu kibinja kya placebo. Ku ddoozi za 2.4 mg ne 1.0 mg, NNT = 9. Ebizibu ebyavaamu byali bifaanagana mu ddoozi ez’enjawulo. Mu kugezesebwa okufugibwa okukuuma obuzito (N = 803), abeetabye mu kugezesebwa abatali balwadde ba ssukaali baafuna obujjanjabi buli wiiki nga bakozesa 2.4 mg za Semaglutid okumala wiiki 20, n’oluvannyuma ne baawulwamu mu ngeri ey’ekifuulannenge mu kibinja ekigenda mu maaso n’obujjanjabi bwa Semaglutid oba ekibinja kya placebo. Oluvannyuma lwa wiiki 48, ekibinja ekyagenda mu maaso n’obujjanjabi bwa Semaglutid kyakendeeza ku buzito bw’omubiri gwabwe ebitundu 8%, ate ekibinja ekya placebo kyakendeeza ku buzito bw’omubiri gwabwe ebitundu 7%.
Mu kumaliriza, Semaglutid ddagala lya GLP-1 receptor agonist nga lirina omugaso gw’okukozesa mu nnimiro eziwera. Mu by’obujjanjabi bw’enkyukakyuka mu mubiri, efuga bulungi emiwendo gya glucose mu musaayi nga yesiba ku bikwata GLP-1, okutumbula okufulumya insulini, n’okuziyiza okufulumya glucagon, ne kiwa enkola enkulu ey’obujjanjabi eri abalwadde abalina enkyukakyuka y’omubiri ey’ekika eky’okubiri. Mu nsonga y’okujjanjaba omugejjo, Semaglutid ekendeeza nnyo ku maanyi agayingira ng’ayita mu nkola nga okuziyiza okulya emmere mu makkati n’okulwawo okufulumya amazzi mu lubuto, okuyamba abalwadde abagejjulukuka okugejja n’okulongoosa embeera yaabwe ey’okukyusakyusa emmere. Okugatta ku ekyo, Semaglutid era eraga essuubi eriyinza okukozesebwa mu kuziyiza n’okujjanjaba endwadde z’emisuwa. Okulongoosa kwayo ensonga z’obulabe eri emisuwa n’emisuwa kiwa enkola empya ey’okukendeeza ku bikolwa by’emisuwa n’emitima.
Ebikwata ku Muwandiisi
Ebintu ebyogeddwako waggulu byonna binoonyerezeddwako, birongooseddwa era ne bikung’aanyizibwa kkampuni ya Cocer Peptides.
Omuwandiisi wa Scientific Journal
Hegner P munoonyereza mu yunivasite y’e Regensburg. Omulimu gwe gukwata ku Chemistry, Cardiovascular System, ne Cardiology. Mu Chemistry, anoonyereza ku reactions ezisibiddwa ku bulamu bw’emisuwa n’emisuwa. Mu kunoonyereza ku nkola y’emisuwa gy’omutima, anoonyereza ku nkola y’omutima n’emisuwa, ng’anoonya amagezi agakwata ku bujjanjabi. Okunoonyereza kwe ku Cardiology kusinga kukwata ku kuziyiza endwadde z’omutima, okuzuula n’okuzijjanjaba.
Ebintu Hegner by’akola bikulu nnyo. Okutegeera kwe okw’eddagala kuleetedde okukola eddagala eppya ery’emisuwa. Omulimu gwe ku nkola y’omutima n’emisuwa gwongedde okutegeera endwadde z’emisuwa. Mu bujjanjabi, okunoonyereza kwe kulongoosezza enkola y’okuddukanya endwadde z’omutima, ne kusitula omutindo gw’okulabirira abalwadde. Okutwaliza awamu, enkola ya Hegner ey’eby’emikono mingi egaggawaza eddagala ly’emisuwa n’emisuwa, n’ewa essuubi okukendeeza ku buzito bw’endwadde n’ebiva mu balwadde ebirungi. Hegner P awandiikiddwa mu kiwandiiko ekijuliziddwa mu kiwandiiko ekijuliziddwa [9]..
