CJC 1295 NO DAC 2 mg, Nws yog ib qho khoom tsim tawm kev loj hlob hormone tso tawm cov tshuaj hormone (GHRH) analog nrog cov mis molecular ntawm C152H252N44O42 thiab molecular hnyav ntawm 3367.89688 g / mol. Dawb rau cov hmoov dawb, me ntsis soluble nyob rau hauv dej, ethanol, thiab methanol, yuav tsum tau muab cia rau hauv ib tug inert gas ib puag ncig ntawm -20℃los tiv thaiv degradation. Nws cov qauv tseem ceeb khaws cia thaj chaw lom neeg lom zem ntawm natural GHRH (amino acids 1-29), tab sis tsis muaj kev hloov pauv ntawm cov tshuaj affinity complexes (DAC), ua rau lub neej luv luv (kwv yees li 30 feeb mus rau ob peb teev) thiab xav tau kev tswj xyuas ntau zaus kom tswj tau cov ntshav siab zoo.
Peb Cov Khoom Muag Khoom
CJC-1295 COA
Qhov tseem ceeb sib txawv ntawmCJC 1295 NO DAC 2 mgthiab CJC-1295 (feem ntau yog xa mus rau cov qauv uas muaj DAC) nyob rau hauv cov tshuaj pharmacokinetic tshwm sim los ntawm qhov sib txawv ntawm kev hloov kho cov qauv molecular. Cov yav tas los qhia tau hais tias muaj txiaj ntsig zoo hauv kev nyab xeeb, kev hloov pauv ntawm lub cev, thiab kev ua tau mus ntev los ntawm kev simulating pulsatile secretion hom ntawm natural growth hormone tso tawm hormone (GHRH).
Qhov sib txawv tseem ceeb ntawm CJC-1295 Tsis muaj DAC thiab cov qauv uas muaj DAC yog seb nws puas yog Drug Affinity Complex (DAC). DAC yog ib pab pawg hloov kho covalently khi los ntawm lysine thiab maleimide propionic acid (MPA), nrog rau qhov hnyav molecular ntawm 500-600 Da. Los ntawm cov tsis muaj covalent khi nrog ntshav albumin, nws ua rau lub sijhawm khaws cov tshuaj hauv cov hlab ntsha.
Xws li DAC version:
Pab pawg DAC tuaj yeem khi nrog albumin los ua ib qho nyuaj nrog lub cev hnyav ntawm kwv yees li 40 kDa, txuas ntxiv ib nrab - lub neej ntawm cov tshuaj mus rau 8 hnub. Txawm hais tias qhov kev hloov kho no txo qhov zaus ntawm kev tswj hwm (1-2 zaug hauv ib lub lis piam), nws ua rau cov tshuaj tso tawm hauv lub cev, cuam tshuam cov qauv pulsatile secretion ntawm GHRH (pulses txhua 3-4 teev nyob rau hauv circadian atherosclerosis).
Tsis muaj DAC version:
Yog tsis muaj qhov sib ntxiv ntawm DAC pawg, qhov hnyav molecular tsuas yog 3.4 kDa, nrog ib nrab ntawm - lub neej ntawm kwv yees li 30 feeb mus rau ob peb teev. Nws cov yam ntxwv metabolic yog ze dua rau ntuj GHRH, thiab los ntawm kev simulating physiological pulse secretion, nws zam kev pheej hmoo ntawm receptor desensitization. Piv txwv li, tom qab ib qho kev txhaj tshuaj ntawm 2 μ g / kg Tsis muaj DAC hauv cov ntsiab lus noj qab haus huv, plasma GH qib nce 2-10 zaug hauv 2 teev thiab rov qab mus rau hauv paus hauv 6 teev, ua raws li lub sijhawm ntawm lub cev nqaij daim tawv.
Cov yam ntxwv metabolic ntawmCJC 1295 NO DAC 2 mgua kom nws zoo dua rau DAC uas muaj cov qauv hauv qab no:
Receptor activation hom:
Ntuj GHRH activates GHRH receptor (GHRH-R) ntawm lub anterior pituitary cell membrane los ntawm pulsed tso, ua rau lub cAMP/PKA signaling txoj kev thiab txhawb GH noob transcription. Lub DAC uas muaj cov qauv yuav ua rau muaj kev ua kom muaj zog ntawm GHRH-R vim qhov kev tso tawm tsis tu ncua, uas tuaj yeem ua rau receptor phosphorylation thiab endocytosis, txo qis receptor rhiab heev. Cov kev sim tsiaj tau pom tias ntev - siv cov nas uas muaj DAC version txo cov pituitary GH cia los ntawm 30%, thaum qhov tshwm sim no tsis tau pom hauv No DAC version.
GH / IGF-1 axis kev tswj:
Tsis muaj DAC qhib lub siab GH receptor (GHR) thiab txhawb nqa IGF-1 synthesis los ntawm kev tso tawm ntawm GH. Ib nrab-lub neej ntawm IGF-1 yog kwv yees li 20 teev, thiab nws theem hloov pauv nrog GH pulses. Cov qauv uas muaj DAC tuaj yeem ua rau nce siab ntau ntawm IGF-1 qib vim tias GH tso tawm, ua rau muaj kev pheej hmoo ntawm cov teeb meem metabolic xws li insulin tsis kam thiab mob pob qij txha. Cov ntaub ntawv kho mob qhia tau hais tias IGF-1 theem ntawm cov neeg siv uas tsis muaj DAC version nce 1.5-3 zaug hauv 9-11 hnub, thaum cov neeg siv nrog DAC version tuaj yeem ntsib qhov nce ntawm 3-5 zaug hauv IGF-1 qib, nrog kev hloov pauv ntau dua.
Drug clearance pathway:
Tsis muaj DAC feem ntau yog tshem tawm los ntawm lub raum pom (qhov hnyav molecular<50 kDa) and protease degradation, with no risk of liver toxicity accumulation. The version containing DAC may be metabolized through the endocytic pathway of liver cells due to its binding with albumin, increasing the burden on the liver. When using the No DAC version in patients with renal insufficiency (creatinine clearance rate<30 mL/min), the dose should be halved; The DAC containing version, due to its metabolic dependence on albumin, requires dose adjustment based on liver function.
Physiological nyhuv optimization: ntau cov ntaub so ntswg kho thiab kev cai metabolic
CJC-1295 Tsis muaj DAC ua tiav cov txiaj ntsig ntawm lub cev kom zoo los ntawm kev tswj cov GH / IGF-1 axis ntawm qib hauv qab no:
Kev loj hlob thiab kho cov leeg nqaij:
GH txhawb nqa cov leeg nqaij fiber ntau los ntawm kev ua kom lub xovtooj ntawm tes nthuav dav thiab IGF-1 mediated mTOR txoj hauv kev. Tsis muaj DAC version ntawm pulsed GH tso tawm tuaj yeem tiv thaiv cov leeg hlwb apoptosis los ntawm kev txhawb nqa siab ntawm GH (los ntawm kev ua kom JNK txoj hauv kev). Cov kev sim tsiaj tau pom tias cov neeg siv tsis muaj DAC version muaj 40% nce hauv cov leeg nqaij kho qhov chaw piv rau pawg tswj hauv 48 teev, thaum cov neeg siv ntawm DAC version tsuas muaj 25% nce hauv thaj chaw kho.
Cov roj metabolism:
GH txhawb nqa cov roj oxidation los ntawm kev tswj cov lipase kev ua haujlwm thiab inhibiting adipocytes sib txawv. Tsis muaj DAC version ntawm pulsed GH tso tawm tuaj yeem zam cov tshuaj insulin tsis kam nyob rau hauv adipocytes los ntawm kev txhawb nqa siab ntawm GH (los ntawm inhibiting GLUT4 thauj). Tom qab siv tsis muaj DAC version hauv cov neeg mob rog rog, thaj chaw muaj roj visceral txo qis los ntawm 12% thiab ceev cov ntshav qabzib poob los ntawm 0.8 mmol / L; Thiab cov neeg siv nrog DAC version tau ntsib qhov txo qis ntawm 8% ntawm cov roj visceral thiab 0.5 mmol / L txo cov ntshav qab zib.
Pob txha metabolism:
GH txhawb nqa osteoblast proliferation, thaum IGF-1 txhawb cov pob txha matrix synthesis. Tsis muaj DAC version ntawm pulsed GH tso tawm tuaj yeem zam qhov nce pob txha resorption los ntawm kev txhawb nqa siab ntawm GH (los ntawm inhibiting RANKL / OPG piv). Tom qab siv tsis muaj DAC version nyob rau hauv tus qauv osteoporosis nas, lub thickness ntawm cov pob txha trabeculae nce 25% thiab lub sij hawm kho pob txha raug luv los ntawm 30%; Cov neeg siv nrog DAC version tau paub txog 18% nce hauv trabecular thickness thiab 20% txo lub sijhawm kho.
CJC-1295 Tsis muaj DAC ua tau zoo tshaj qhov DAC uas muaj cov qauv hauv cov ntsiab lus ntawm metabolic kinetics, physiological teebmeem, thiab kev nyab xeeb los ntawm kev simulating pulsatile secretion hom ntawm natural GHRH. Nws lub siab GH tso tawm tuaj yeem zam tsis tau receptor desensitization thiab metabolic ntshawv siab, ua tiav cov kev cai ntawm cov leeg nqaij loj hlob, rog metabolism, thiab kho pob txha.
CJC 1295 NO DAC 2 mgyog ib qho khoom tsim tawm kev loj hlob hormone tso tawm cov tshuaj hormone (GHRH) analog uas simulates lub physiological muaj nuj nqi ntawm tej yam ntuj tso GHRH, activates anterior pituitary hlwb tso tawm kev loj hlob hormone (GH), thiab tswj cov metabolism, txhawb cov ntaub so ntswg kho thiab loj hlob los ntawm GH / IGF-1 axis.
Kev tsim qauv molecular yog nyob ntawm thaj tsam tseem ceeb (1-29 amino acids) ntawm ntuj GHRH (1-44 peptide), thiab kev ua haujlwm zoo yog ua tiav los ntawm kev txhim kho cov qauv hauv qab no:
Amino acid sequence optimization: Khaws cov seem tseem ceeb hauv GHRH (1-29) uas khi rau receptors (xws li Tyr ¹, Asp ³, Phe ⁶, Arg ¹⁹, Lys ² ⁰), thaum hloov qee cov amino acids (xws li Ala ² hloov pauv Ala ² thiab Leu A) ruaj khov.
C- hloov kho lub davhlau ya nyob twg: Ntxiv ib daim ntawv cog lus amide (- CONH ₂) ntawm C- davhlau ya nyob twg los tiv thaiv cov saw peptide los ntawm kev degradation los ntawm carboxypeptidase, txuas ntxiv ib nrab ntawm - lub neej mus rau 30 feeb mus rau ob peb teev (natural GHRH ib nrab- lub neej tsuas yog 2-5 feeb).
Tsis muaj kev hloov kho DAC: Tsis zoo li cov uas muaj DAC, Tsis muaj DAC version tsis ntxiv cov tshuaj affinity complexes (DAC) kom tsis txhob muaj ib nrab - lub neej txuas ntxiv los ntawm kev khi rau cov ntshav albumin (DAC version muaj ib nrab - lub neej txog li 8 hnub), yog li khaws ntau lub cev pulsatile GH tso tawm hom.
CJC-1295 Tsis muaj DAC activates GHRH receptor (GHRH-R) ntawm lub anterior pituitary cell membrane los ntawm cov kauj ruam hauv qab no:
Receptor recognition: N-terminus (Tyr ¹ - Asp ³) ntawm Tsis muaj DAC khi rau lub extracellular domain (ECD) ntawm GHRH-R, tsim hydrogen bonds thiab hydrophobic interactions; Lub C-terminal (Arg ¹⁹ - Lys ² ⁰) khi rau thaj tsam hnab tshos ntawm receptor transmembrane domain (TMD), stabilizing lub receptor conformation.
Kev hloov pauv: Tom qab receptor khi, TMD rotates, ua kom cov kab mob hauv lub cev G (Gs) thiab ua rau kev ua kom adenylate cyclase (AC).
Kev xa xov thib ob: AC catalyzes hloov dua siab tshiab ntawm ATP rau hauv cyclic adenosine monophosphate (cAMP), uas ua raws li tus tub txib thib ob los ua kom cov protein kinase A (PKA) thiab tom qab phosphorylate downstream cov hom phiaj protein (xws li CREB).
Cov pov thawj tseem ceeb:
Cov kev sim hauv vitro tau pom tias Tsis muaj DAC tuaj yeem txhawb nqa thawj cov nas pituitary hlwb kom tso GH ntawm qhov concentration ntawm 10 ⁻⁹ M, nrog rau cov nyhuv piv rau ntuj GHRH.
Molecular docking simulations tau lees paub tias lub zog ruaj khov ntawm Tsis muaj DAC rau GHRH-R (-52.3 kcal / mol) yog qis dua li ntawm natural GHRH (-48.7 kcal / mol), qhia tias muaj kev sib raug zoo dua qub.
CJC 1295 NO DAC 2 mgactivates GHRH-R, ua rau cov kev taw qhia hauv qab no kom ua tiav GH synthesis thiab secretion:
GH gene transcriptional activation: PKA phosphorylates CREB, txhawb kev khi ntawm cAMP cov ntsiab lus teb (CRE) hauv thaj av GH gene txhawb nqa thiab txhim kho GH mRNA transcription.
GH secretion txoj cai:
Cov nyhuv hnyav: cAMP txhawb kev sib xyaw ntawm GH secretory granules nrog cov cell membrane los ntawm Epac (piv cov protein ncaj qha activates cAMP) txoj hauv kev, ua tiav kev tso tawm sai (hauv feeb).
Cov teebmeem ntev: PKA phosphorylates lipid phosphatase PTEN, inhibits PI3K / Akt txoj hauv kev, thiab txo qis cov lus pom tsis zoo inhibition ntawm GH secretion.
IGF-1 synthesis: GH qhib txoj hauv kev JAK2/STAT5 los ntawm GH receptor (GHR) ntawm daim siab cell membrane, txhawb kev sib txuas thiab tso tawm ntawm insulin zoo li kev loj hlob factor-1 (IGF-1). IGF-1 ntxiv dag zog rau kev loj hlob ntawm cov leeg, pob txha, thiab lwm yam ntaub so ntswg los ntawm nws cov teebmeem autocrine / paracrine.
Clinical data support:
Tom qab ib qho kev txhaj tshuaj tsis muaj DAC (2 μ g / kg) hauv cov khoom noj qab haus huv, cov ntshav plasma GH nce 2-10 zaug hauv 2 teev thiab kav ntev li 6 hnub; IGF-1 qib nce los ntawm 1.5-3 zaug hauv 3 hnub thiab nyob twj ywm rau 9-11 hnub.
Kev siv lub sijhawm ntev (12 lub lis piam) tuaj yeem ua rau lub cev hnyav (+2.3 kg), txo cov rog (-1.8 kg), thiab nce pob txha ceev (+1.5%).
Cim npe nrov: cjc 1295 no dac 2mg, Tuam Tshoj cjc 1295 no dac 2mg manufacturers, lwm tus neeg
