Dab tsi yog Mechanism of Action ntawm Pasireotide?

Pasireotide yog ib qho yooj yim qub ntawm somatostatin uas tau txais ib tuj ntawm kev txiav txim siab hauv thaj tsam ntawm endocrinology vim nws cov khoom siv tshuaj tshwj xeeb thiab xav tau kev siv tshuaj. Nws ua haujlwm raws li kev tsim kho cyclohexapeptide los ntawm kev khi rau thiab ua kom somatostatin receptors (SSTRs) hauv ntau lub cev nqaij. Hauv qhov kev nkag blog no, peb yuav tshawb fawb cov khoom lag luam ntawm kev ua haujlwm, sib piv nws nrog lwm cov somatostatin analogs thiab pom tias nws cov kev cuam tshuam rov qab zoo li cas los ntawm nws cov kev cai ntawm downstream flagging txoj kev thiab txwv rau SSTRs.

Kev txwv thiab ua kom cov somatostatin receptor (SSTR) yog pasireotide qhov tseem ceeb ntawm kev ua haujlwm. SSTRs yog G protein-coupled receptors (GPCRs) uas tau nthuav dav thoob plaws hauv ntau cov ntaub so ntswg, suav nrog cov txheej txheem tiv thaiv, pancreas, gastrointestinal ntau, thiab pituitary organ. Tsib subtypes ntawm SSTRs yog SSTR1, SSTR2, SSTR3, SSTR4, thiab SSTR5. Muaj qhov sib txawv ntawm lub cev muaj peev xwm thiab cov ntaub so ntswg conveyance rau txhua yam ntawm cov subtypes.

Pasireotide muaj thaj tsam ntawm lub zog rau SSTRs 1, 2, 3, thiab 5. Tsis tas li ntawd, nws muaj ntau yam khoom uas txwv. Optreotide thiab lanreotide, ib qho ntxiv ob qho tib si somatostatin analogs, ntawm qib yooj yim khi rau SSTR2. Tau lees paub nws yog qhov tsis txaus ntseeg hauv kev tswj hwm cov xwm txheej neuroendocrine xws li Cushing's kab mob thiab acromegaly vim nws qhov kev txwv ntau ntawm cov receptor limiting profile.

Thaum cov khoom sib txuas rau SSTRs, nws hloov ntau yam ntawm cov receptors, txhawb cov G proteins, tshwj xeeb tshaj yog tsev neeg Gi/o, uas tsis muaj zog rau pertussis tshuaj lom. Cov hluavtaws uas muaj kev pheej hmoo rau kev txhim kho cyclic AMP (cAMP), ib qho yooj yim thib ob xa mus nrog cov txheej txheem ntawm tes sib txawv, yog tswj thaum Gi/o proteins pib.

Pasireotide qhov txo qis hauv cAMP qib los ntawm thiab loj cuam tshuam rau neuroendocrine cell tshuaj thiab peptide outpouring. Adrenocorticotropic chemical (ACTH) emissions los ntawm pituitary corticotroph hlwb, uas yog lub hauv paus ua rau Cushing's kab mob cortisol overproduction, yog txo los ntawm cov khoom. Zoo ib yam li nws tswj kev tawm ntawm qhov kev loj hlob hormone (GH) thiab insulin zoo li kev loj hlob zoo (IGF-1) ntawm somatotroph hlwb, uas yog dysregulated hauv acromegaly, nws khi rau SSTR2, SSTR3, thiab SSTR5.

Qhov kev txwv ntawm cov khoom rau SSTRs tuaj yeem kho cov cell multiplication, apoptosis, thiab cov tshuaj tso tawm. Nws tau raug tso tawm kom tsis txhob muaj kev nce qib ntawm cov hlwb sib txawv, suav nrog cov qog nqaij hlav neuroendocrine, mob hauv siab thiab prostate, kev tsim mob neuroendocrine, thiab pituitary adenomas. Qhov kev tiv thaiv kev tiv thaiv no yog ntseeg tau los ntawm kev lees paub ntawm lub voj voog ntawm tes ntes thiab apoptosis nrog rau kev txwv tsis pub muaj kev nce qib hailing txoj hauv kev zoo li mitogen-ordered protein kinase (MAPK) thiab phosphatidylinositol 3-kinase (PI3K) txoj hauv kev .

Tsis tas li ntawd, nws tau pom tias Pasireotide inhibition ntawm SSTRs muaj cov nyhuv immunomodulatory, qhia tias nws yuav ua tau zoo dua li kev kho mob rau qee yam mob. Ntau hom kev ruaj ntseg, suav nrog monocytes, lymphocytes, thiab macrophages, qhia SSTRs. Nws tuaj yeem pib SSTRs, uas tuaj yeem hloov kho lub peev xwm ntawm cov hlwb tiv thaiv thiab npog tsim cov cytokines raug mob.

Hauv kev xaus,PasireotideCov txiaj ntsig tau txais txiaj ntsig feem ntau yog vim nws lub peev xwm los khi rau somatostatin receptors, tshwj xeeb tshaj yog SSTR1, SSTR2, SSTR3, thiab SSTR5, los ntawm ntau yam txheej txheem, suav nrog kev tiv thaiv kab mob, tshuaj emission inhibition, apoptosis, thiab kev loj hlob hloov. Raws li qhov tshwm sim ntawm nws qhov dav receptor txwv qhov profile, nws muaj txiaj ntsig zoo hauv kev kho qee qhov teeb meem neuroendocrine. Hauv qhov no, nws yuav muaj txiaj ntsig zoo hauv ntau yam xwm txheej uas SSTRs raug kaw nrog cov kab mob pathogenesis.

Thaum pasireotide sib txuas rau somatostatin receptors (SSTRs), qhov kev nce qib ntawm qhov tshwm sim ntawm qhov tshwm sim tshwm sim, uas thaum kawg cuam tshuam cov kev cuam tshuam ntawm cov tshuaj. Muaj ntau yam intracellular couriers, kinases, thiab cov ntaub ntawv tseem ceeb koom nrog cov kev sib txawv thiab txoj kev sib txawv. Peb yuav tshuaj xyuas Pasireotide qhov tseem ceeb ntawm cov kev taw qhia hauv qab thiab lawv cov kev cuam tshuam ntawm cov tshuaj cov txheej txheem ntawm kev ua hauv ntu no.

Ib qho ntawm cov kev taw qhia tseem ceeb uas cov khoom siv yog lub voj voog AMP (cAMP) txoj hauv kev. Raws li tau hais yav dhau los, nws khi rau SSTRs thiab ua rau Gi / o proteins, txo qis hauv cov qib cAMP thiab inhibiting adenylyl cyclase. Qhov kev txo qis hauv cAMP tseem ceeb cuam tshuam cov txheej txheem ntawm tes sib txawv, suav nrog cov tshuaj tso tawm, xov tooj ntawm tes, thiab kev ua kom zoo.

Nws stifles lub emission ntawm ACTH thiab GH nyob rau hauv neuroendocrine hlwb, piv txwv li, pituitary corticotrophs thiab somatotrophs, los ntawm kev cuam tshuam cAMP chij. Qhov no yog ua tiav los ntawm kev hloov pauv ntau yam downstream effectors ntawm cAMP, xws li protein kinase A (PKA) thiab kev lag luam proteins pib los ntawm cAMP ncaj qha (Epacs). Vim tias nws inhibits PKA thiab Epacs, nws muaj kev cuam tshuam rau cov qauv ntawm cov noob qhia hauv cov hlwb nrog rau kev tawm tsam ntawm cov tshuaj hormone synthesis thiab tso tawm.

Lwm txoj hauv kev loj heev uas tau hloov pauv los ntawm nws yog txoj hauv kev mitogen-impelled protein kinase (MAPK). Txoj kev MAPK, tus tswj hwm tseem ceeb ntawm kev loj hlob ntawm tes, kev sib txawv, thiab kev ciaj sia, tau txuas nrog ntau yam kab mob neoplastic thiab inflammatory kab mob. Nws tau raug pom tias khi rau SSTRs, inhibiting kev ua haujlwm ntawm Raf, MEK, thiab ERK kinases thiab lwm yam MAPK txoj hauv kev.

Hauv ntau hom mob qog noj ntshav, Pasireotide's antiproliferative thiab apoptotic teebmeem tau txhim kho los ntawm nws qhov inhibition ntawm txoj kev MAPK. Piv txwv li, cov khoom lag luam zais ntawm MAPK chij tau pom tias txhawm rau txhawm rau lub voj voog ntawm tes thiab ua kom apoptosis hauv pituitary adenomas, uas ua rau muaj kev loj hlob inhibition thiab cov txiaj ntsig kho mob. Ib yam li ntawd, Pasireotide lub peev xwm ua kom mob qog noj ntshav qeeb thiab txhim kho kev ua tau zoo ntawm lwm cov kev kho mob pom zoo tau cuam tshuam los ntawm nws lub peev xwm los sib npaug ntawm MAPK txoj hauv kev hauv cov qog nqaij hlav neuroendocrine.

Txawm hais tias txoj hauv kev cAMP thiab MAPK, Pasireotide txwv tsis pub SSTRs tuaj yeem sib npaug ntawm phosphatidylinositol 3-kinase (PI3K) txoj hauv kev. Kev ua kom lub PI3K txoj hauv kev-ib qho tseem ceeb ntawm kev tswj hwm ntawm tes kev loj hlob, kev zom zaub mov, thiab kev ua siab ntev- tau txuas rau ntau yam kab mob thiab cov teeb meem metabolic. Nws tau raug nthuav tawm tias nws ua rau PI3K txoj hauv kev hauv ntau hom cell, suav nrog cov hlwb neuroendocrine thiab pituitary qog nqaij hlav.

Cov khoom lag luam tswj hwm txoj hauv kev PI3K muaj qhov cuam tshuam loj rau nws cov teebmeem metabolic thiab antitumor. Hauv pituitary adenomas, piv txwv li, qhov npog ntawm PI3K tshaj tawm nws tau pom tias rov tsim kho qhov txaus ntawm mTOR inhibitors, ua rau muaj kev txhim kho tseem ceeb dua thiab cuam tshuam ntawm cov txiaj ntsig kho mob. Cov khoom lag luam inhibition ntawm PI3K txoj hauv kev hauv pancreas tuaj yeem muaj kev cuam tshuam ntxiv ntawm kev zom cov piam thaj thiab tso tawm insulin, tab sis cov ntsiab lus tseeb tseem yog qhov tsis paub.

PasireotideKev khi rau SSTRs tuaj yeem cuam tshuam rau lwm cov txheej txheem ntawm tes thiab kev taw qhia txoj hauv kev zoo li calcium signaling, ion channel ua haujlwm, thiab cytoskeletal reorganization. Cov kev cuam tshuam ntau yam no pab txhawb rau cov khoom lag luam pleiotropic hauv ntau cov ntaub so ntswg thiab kab mob.

Qhov sib npaug ntawm ntau txoj hauv kev hauv qab ntug dej hiav txwv, suav nrog cAMP, MAPK, thiab PI3K txoj hauv kev, tsim cov khoom lag luam ntawm cov haujlwm. Raws li qhov tshwm sim ntawm Pasireotide inhibition ntawm txoj hauv kev no, ntau cov teebmeem ntawm tes raug ntxias, suav nrog kev hloov pauv hauv cov metabolism, txo qis hauv cell proliferation, nce apoptosis, thiab txo qis hauv cov tshuaj hormones. Pasireotide qhov muaj txiaj ntsig thiab kev txhim kho cov kev kho tshiab rau cov mob neuroendocrine thiab lwm yam xwm txheej uas SSTRs ua lub luag haujlwm tseem ceeb yuav tsum muaj kev nkag siab zoo txog kev sib raug zoo ntawm cov kab lus no thiab lawv cov ntaub so ntswg ua haujlwm.

Pasireotide yog ib qho ntawm ntau cov tshuaj uas suav tias yog somatostatin analogues. Octreotide thiab lanreotide yog ob tus tswv cuab ntawm pawg no. Thaum cov kev kho mob no qhia ob peb qhov zoo sib xws hauv lawv txoj kev npaj ua, muaj qhov sib txawv tseem ceeb uas tau teeb tsa rau sab thiab qhia txog nws qhov kev txhawb nqa zoo kawg nkaus. Hauv ntu no, peb yuav sib piv cov khoom lag luam ntawm kev ua haujlwm nrog lwm cov tshuaj somatostatin thiab sib tham txog qhov kev sib txawv no txhais tau li cas rau lawv daim ntawv thov kho mob.

Lub receptor txwv cov profiles ntawm cov khoom thiab lwm yam somatostatin analogs yog qhov tseem ceeb sib txawv. Octreotide thiab lanreotide, thawj tiam somatostatin analogs, feem ntau khi rau SSTR2, nrog qis dua rau SSTR3 thiab SSTR5. Ntawm qhov tod tes, nws muaj ntau qhov sib txawv ntawm qhov chaw sib txuas thiab muaj kev sib raug zoo rau SSTR1, SSTR2, SSTR3, thiab SSTR5.

Cov khoom lag luam rov tsim kho kom txaus thiab cov khoom ntawm kev ua haujlwm tau cuam tshuam loj heev los ntawm nws qhov dav receptor txwv profile. Pasireotide, nyob rau hauv sib piv rau ntau qhov tshwj xeeb somatostatin analogs, tuaj yeem ua kom muaj zog thiab muaj kev cuam tshuam ntau dua ntawm cov tshuaj lom neeg tawm thiab kev txhim kho qog noj ntshav los ntawm kev tsom mus rau ntau yam SSTR subtypes. Hauv cov xwm txheej zoo li Cushing's mob thiab acromegaly, qhov twg ntau yam SSTR subtypes cuam tshuam nrog kev mob pathogenesis, qhov no yog qhov tseem ceeb.

Piv txwv li, corticotroph adenomas hauv Cushing tus kab mob muaj cov qib siab ntawm SSTR5, uas tsis tau raug xaiv los ntawm octreotide lossis lanreotide. Nws muaj txiaj ntsig zoo inhibits ACTH secretion thiab normalizes qib cortisol hauv ntau tus neeg mob Cushing tus kab mob uas tau ua tsis tiav lossis tsis tuaj yeem raug phais vim tias nws muaj kev sib raug zoo rau SSTR5. Qhov kev ua tau zoo dua qub no tau pom nyob rau hauv cov kev tshawb fawb soj ntsuam ua ntej, qhov twg cov khoom tau tshaj tawm kev kho mob cuav thiab lwm yam kev kho mob hauv cov ntsiab lus ntawm cov txiaj ntsig.

Somatotroph adenomas kuj qhia ntau yam SSTR subtypes, suav nrog SSTR2, SSTR3, thiab SSTR5, hauv acromegaly. Txawm hais tias octreotide thiab lanreotide tuaj yeem txo GH thiab IGF-1 qib hauv ntau tus neeg uas muaj acromegaly, muaj lub caij nyoog uas qee tus yuav tiv taus cov kev kho mob lossis tso tseg tag nrho. Txoj kev tshawb fawb PAOLA qhia tias nws qhov dav receptor binding profile tuaj yeem pab cov neeg mob kov yeej kev tiv thaiv thiab txhim kho kev tswj hwm biochemical.

Pasireotide's ntau dua receptor txwv profile kuj tseem yuav muab cov txiaj ntsig hais txog nws cov tshuaj tiv thaiv kab mob thiab tshuaj tiv thaiv kab mob, txawm hais tias nws muaj peev xwm zoo dua hauv kev tswj cov tshuaj emission. Los ntawm zeroing nyob rau hauv ntau yam SSTR subtypes, nws tuaj yeem kho qhov ntau dua ntawm txoj hauv kev qis qis qis qis nrog kev txhim kho ntawm tes thiab kev ua siab ntev, zoo ib yam li MAPK thiab PI3K txoj hauv kev. Qhov no yuav muaj kev cuam tshuam zoo npaum li cas nws tuaj yeem txhawb apoptosis thiab nres cov qog loj hlob hauv ob qho tib si neuroendocrine thiab cov qog tsis-neuroendocrine.

Nyob rau hauv txhua rooj plaub, nws yog ib qho tsim nyog yuav tsum tau soj ntsuam tias cov khoom lag luam ntau dua receptor limiting profile yuav zoo sib xws nrog rau lwm qhov kev cuam tshuam qhov profile sawv tawm ntawm lwm cov tshuaj somatostatin. Qhov sib txawv tshaj plaws yog Pasireotide qhov kev pheej hmoo ntawm hyperglycemia thiab ntshav qab zib mellitus. Qhov no tau lees paub tias yog qhov tshwm sim ncaj qha ntawm cov khoom lag luam siab tshaj plaws rau SSTR5, uas tau xa mus rau hauv pancreatic beta hlwb thiab cia siab tias yuav muaj ib ntu hauv kev tso tawm insulin. Los ntawm inhibiting insulin secretion, nws tuaj yeem ua rau lossis ua rau hyperglycemia hnyav dua, yuav tsum tau ua tib zoo saib xyuas thiab tswj cov ntshav qabzib thaum kho.

Vim lawv qhov tshwj xeeb khi rau SSTR2, octreotide thiab lanreotide, ntawm qhov tod tes, muaj cov kab mob metabolic zoo dua thiab tsis tshua muaj peev xwm ua rau hyperglycemia. Muab rau hauv tus account tus neeg mob qhov ntsuas glycemic xwm txheej thiab lwm yam kev pheej hmoo, qhov sib txawv ntawm cov nyhuv profile yuav ua rau nws yooj yim dua rau xaiv somatostatin.

Muab txhua yam rau hauv tus account,PasireotideCov txheej txheem ntawm kev ua ub no txawv ntawm lwm cov tshuaj somatostatin hauv paus vim tias nws muaj feem cuam tshuam rau SSTR1, SSTR2, SSTR3, thiab SSTR5 receptor txwv cov profiles. Vim tias nws tsom mus rau ntau yam ntawm SSTR subtypes, nws muaj txiaj ntsig zoo ntawm kev tswj hwm cov tshuaj hormones thiab inhibiting qog loj hlob, tshwj xeeb tshaj yog thaum muaj ntau yam SSTR subtypes koom nrog. Txawm li cas los xij, cov tshuaj tsis muaj kev cuam tshuam rau theem nrab, tshwj xeeb tshaj yog kev twv txiaj ntxiv ntawm hyperglycemia, tseem cuam tshuam los ntawm nws qhov kev txwv ntau dua receptor txwv profile. Kev nkag siab txog cov kev tsim nyog no yog qhov txaus ntshai rau kev xaiv qhov tsim nyog tshaj plaws somatostatin hauv paus rau cov neeg mob thiab hloov kho cov txiaj ntsig kev kho mob thaum txwv tsis pub muaj kev cuam tshuam.

1. Colao, A., Petersenn, S., Newell-Price, J., Findling, JW, Gu, F., Maldonado, M., ... & Boscaro, M. (2012). Ib 12-hli theem 3 kev tshawb fawb ntawm pasireotide hauv Cushing tus kab mob. New England Journal of Medicine, 366(10), 914-924.

2. Gadelha, MR, Bronstein, MD, Brue, T., Coculescu, M., Fleseriu, M., Guitelman, M., ... & Pasireotide C2305 Study Group. (2014). Pasireotide tiv thaiv txuas ntxiv kev kho mob nrog octreotide lossis lanreotide hauv cov neeg mob uas tswj tsis tau acromegaly (PAOLA): ib qho randomised, theem 3 sim. Lancet Diabetes & Endocrinology, 2(11), 875-884.

3. Cuevas-Ramos, D., & Fleseriu, M. (2014). Somatostatin receptor ligands thiab tiv thaiv kev kho mob hauv pituitary adenomas. Phau ntawv Journal of Molecular Endocrinology, 52(3), R223-R240.

4. Bruns, C., Lewis, I., Briner, U., Meno-Tetang, G., & Weckbecker, G. (2002). SOM230: ib qho tshiab somatostatin peptidomimetic nrog dav somatotropin tso tawm inhibiting factor (SRIF) receptor binding thiab ib qho tshwj xeeb antisecretory profile. European Journal of Endocrinology, 146(5), 707-716.

5. Schmid, HA, & Schoeffter, P. (2004). Kev ua haujlwm ntawm cov multiligand analog SOM230 ntawm tib neeg recombinant somatostatin receptor subtypes txhawb nws cov txiaj ntsig hauv cov qog nqaij hlav neuroendocrine. Neuroendocrinology, 80(Suppl. 1), 47-50.

6. Lacroix, A., Gu, F., Gallardo, W., Pivonello, R., Yu, Y., Witek, P., ... & Boscaro, M. (2018). Kev ua tau zoo thiab kev nyab xeeb ntawm pasireotide ib hlis ib zaug hauv Cushing tus kab mob: kev sim tshuaj 12 lub hlis. Lancet Diabetes & Endocrinology, 6(1), 17-26.

7. Silverstein, JM (2016). Hyperglycemia tshwm sim los ntawm pasireotide hauv cov neeg mob Cushing's kab mob lossis acromegaly. Pituitary, 19(5), 536-543.

8. Henry, RR, Ciaraldi, TP, Armstrong, D., Burke, P., Ligueros-Saylan, M., & Mudaliar, S. (2013). Hyperglycemia cuam tshuam nrog pasireotide: tshwm sim los ntawm kev tshawb fawb txog kev siv tshuab hauv cov neeg ua haujlwm noj qab haus huv. Phau ntawv Journal of Clinical Endocrinology & Metabolism, 98(8), 3446-3453.