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ƆL DI ATIKUL ƐN PRODƆKT INFƆMƐSHƆN WE DƐN GI NA DIS WƐBSAYT NA FƆ ƆL FƆ DI INFƆMƐSHƆN ƐN FƆ EDYUKESHƆN.
Di prɔdak dɛn we dɛn gi na dis wɛbsayt na fɔ in vitro risach nɔmɔ. in vitro risach (Latin: *in glas*, we min insay glas) dεn de du am ausayd mכtalman bכdi. Dɛn prɔdak ya nɔto mɛrɛsin, dɛn nɔ gɛt di aprɔval frɔm di US Food and Drug Administration (FDA), ɛn dɛn nɔ fɔ yuz dɛn fɔ protɛkt, trit, ɔ mɛn ɛni mɛrɛsin, sik, ɔ sik. Di lɔ nɔ gri fɔ mek dɛn put dɛn tin ya insay mɔtalman ɔ animal bɔdi ɛni we.
Ovaviu fɔ di tin dɛn we dɛn dɔn lan
HIV infεkshכn εn antiretroviral tεrapi (ART)-indyuz fεt mεtabolism abnכmaliti de mek siriכs chalenj to di hεlth εn kwaliti כf layf fכ HIV pasεnshכn dεm. dis abnכmaliti dεm de sho insay difrεn fכm dεm, lεk lipoatrophy εn lipohypertrophy, wit εksyכs akyumyuleshכn fכ di vishכral adipos tisu (VAT) we de patikyula prominεnt. Di inkris pan VAT nɔ jɔs de afɛkt di sikman dɛn bɔdi bɔt i gɛt fɔ du bak wit bɔku bad bad mɛtabolik kɔmplikeshɔn dɛn, lɛk di sik we de ambɔg di at ɛn di blɔd, we nɔ de mek insulin nɔ de wok, ɛn di sik we nɔ de mek i gɛt rɔm (NAFLD), we de mek di sikman dɛn kɔntinyu fɔ liv fɔ lɔng tɛm ɛn fɔ gɛt wɛlbɔdi.
Tesamoreli, we na wan sintetik growth hormone-releasing hormone (GHRH) analog, de gi nyu op fɔ di tritmɛnt fɔ di fat mɛtabolism abnɔmaliti na HIV pasɛnt dɛn. i spεshal wan de biεn di GHRH rεsεpכta dεm na di antεriכr pituitary gland, we de ifektivli stimulate di sεntesis εn rilis fכ di εndojεnik gכt hכmon (GH). GH de ple imכtant rol fכ rεgεl di fεt mεtabolism na di mכtalman bכdi, fכ protεkt lipolysis, εnhans fεt asid כksidεshכn, εn rεgεl di εksprεshכn fכ di jin dεm we riliyt to lipid mεtabolism, we de mek i gεt fayn infכmeshכn pan fεt mεtabolism. Dis yכnik mεkanism fכ akshכn de mek Tesamoreli ebul fכ εp fכ impruv fεt mεtabolism dizכrd dεm na HIV pasεnshכn dεm.
Fig 1 Analysis Skima. a totכl 9 plasma protin dεm bin egzamin, we kכrεspכnd to tכp lida ed jin dεm insay hεpatik jin path dεm we difrεntli mכdulet bay tesamorelin.
Mekanism fכ akshכn fכ Tesamoreli pan fεt mεtabolism in HIV
Di wan dɛn we sik
Rεgulεshכn fכ di Grכw Hכmon-Insulin-Lεk Grכw Fכktכ Aks
di tesamoreli de biεn di GHRH rεsεpכta na di sεl mεmbran na di antεriכr pituitary gland, we de aktibכt rεsεpכta-asכsiet signal path dεm lεk di JAK-STAT signal path. dis aktibכshכn prכsεs de protεkt di sεntesis εn rilis fכ di gכt כmon (GH) bay di antεriכr pituitary gland. afta i go insay di bכdi, i de rich di tכgεt כgan dεm lεk di liva, we de mek di liva sכntez εn sekret insulin lεk growth fכktכ-1 (IGF-1). IGF-1 de wok as ki mεdiate fכ GH in mεtabolik ifekt dεm εn i de ple imכtant rol insay fεt mεtabolism. IGF-1 kin aktibכt di PI3K-AKT signal path, inhεbit adiposyt apoptosis, εn mεnten nכmal adiposyt fכnshכn. i de mek bak di adiposyt dεm fכ tek εn כksidεshכn fεt asid dεm, we de ridyus fεt akyumyuleshכn insay sεl dεm. pan HIV sik pipul dεm, di fכnshכn fכ di growth כmon-insulin-layk growth fכktכ aks kin bכku tεm bכku tεm bikoz fכ di sik insεf εn di ifekt dεm we di antiretroviral tεrapi (ART) de gi. Tesamoreli kin aktibכt dis aks fכ rεstכr in nכmal fεt mεtabolism rεgεlyutכri fכnshכn.
Dairekt ifekt pan adiposyt mεtabolism
fכ protεkt lipolysis: Tesamoreli kin upregulate di εksprεshכn εn aktvכti fכ hכmon-sεnsitiv laypas (HSL) insay adiposyt dεm. HSL na wan kכl εnzym insay lipolysis, we de katalayz di haydrolis fכ triglisεrayd dεm to glycerol εn fεt asid, we de protεkt di katabol mεtabolism fכ fεt. in vitro, we yu ad Tesamoreli to di adiposyt dεm we dεn kכlt de εnhans HSL aktiviti εn mak inkrεs fεt asid rilis. tesamoreli kin indaykt aktibכt HSL bak bay we i de rεgεl di saykli AMP (cAMP)-protein kinase A (PKA) signal path, we de promuot lipolysis mכr. pan HIV sik pipul dεm, dis lipolysis-promoting effect de εp fכ ridyus di fεt we de kכmכt pasmak, patikyular di vishכnal fεt rεdukshכn, we de mek i impruv abnכmal fεt distribushכn insay di pasεnshכn dεm.
rεgulεshכn fכ fεt asid כksidεshכn: Tesamoreli de εnhans di aktiviti fכ di kכl εnzym dεm we de involv insay fεt asid כksidεshכn insay adiposyt dεm, lεk carnitine palmitoyltransferase 1 (CPT1). CPT1 na di rεt-limitin εnzym fכ fεt asid εntri insay maytochכndria fכ β-oksidashכn, εn in εnhans aktiviti de promuot di כksidεtiv brεkdכwn fכ fεt asid insay maytochכndria, we de gi enεji fכ sεl dεm. tesamoreli kin upregulate di εksprεshכn fכ כda εnzym dεm εn transpכrta dεm we involv insay fεt asid β-oksidashכn, lεk asetyl-CoA kכbכksilayz 2 (ACC2) εn fεt asid transpכrta 1 (FATP1), fכ optimiz di fεt asid כksidεshכn mεtabolik prכsεs. bay we i de promuot fεt asid כksidεshכn, Tesamoreli kin ridyus fεt stכrej insay sεl dεm εn impruv di lipid mεtabolism dizכrd insay HIV pasεnshכn dεm.
Rεgulεshכn fכ lipid mεtabolism-rεlatεd jin εksprεshכn
infכmeshכn fכ adipojεnεsis-rεlatεd jin dεm: Tesamoreli kin inhεbit di εksprεshכn fכ adipojεnεsis-rεlatεd jin dεm, lεk pεrכksisom proliferator-aktivεt rεsεptכr γ (PPARγ) εn CCAAT/εnhans-bכnd protin α (C/EBPα). PPARγ na di kכl transkripshכn fכktכ insay adiposyt difrεns εn adipojεnεsis, we de protεkt di difrεns fכ di fibroblast dεm to machכ adiposyt dεm, εn i de indyuz di εksprεshכn fכ wan siriכs adipojεnεsis-rεlatεd jin dεm, lεk fεt asid-bכnd protin 4 (FABP4) εn fεt asid sεntez (FAS). C/EBPα de ple imכtant rol bak insay adiposyt difrεns εn adipojεnεsis. bay we i de inhεbit di εksprεshכn fכ PPARγ εn C/EBPα, Tesamoreli de ridyus di adiposyt difrεns εn adipojεnεsis, we de dכn di fεt akyumyuleshכn na di bכdi. pan HIV pasεnshכn dεm, dis rεgεdyushכn ifekt pan adipojεnεsis-rεlatεd jin dεm de εp fכ kכrekt di fεt prodakshכn we pasmak we abnכmal fεt mεtabolism de kכz.
Fig 2 Rilayshɔnship bitwin Chenj dɛn na Plasma VEGFA ɛn CSF1 wit Chenj in NAS Skɔ insay Tesamoreli-Trit Patisipant dɛn.
rεgulεshכn fכ di lipid transpכt εn mεtabolism jin dεm: Tesamoreli kin rεgεl di εksprεshכn fכ di jin dεm we riliyt to lipid transpכt εn mεtabolism, lεk di mεmba dεm fכ di apolipoprotein (Apo) famili. ApoB na di praymar apolipoprotein fכ vεri lכw dεnsiti lipoprotein (VLDL) εn lכw dεnsiti lipoprotein (LDL), εn in εksprεshכn lεvεl dεm kכlכs kכrelεt wit di lεvεl dεm fכ VLDL εn LDL insay plasma. di tesamoreli kin ridyus di ApoB εksprεshכn, ridyus di sεntesis εn sekreshכn fכ VLDL εn LDL, we de mek di plasma lεvεl dεm fכ atherogenic lipoproteins dεm dכn. apat frכm dat, Tesamoreli kin upregulate di εksprεshכn fכ ApoA-I, di praymar apolipoprotein fכ hεy-dεnsiti lipoprotein (HDL). di inkrεs ApoA-I εksprεshכn de εp fכ εlevεt di HDL lεvεl, protεkt kכlestכl rivεs transpכt, εn ridyus di risk fכ kכdivaskyul sik. pan HIV pasεn dεm, usay di lipid mεtabolism dizכrd kin kכmכn bכku tεm wit lipid mεtabolism abnכmaliti, di rεgεdyushכn ifekt dεm we Tesamoreli gεt pan lipid transpכt εn mεtabolism jin dεm kin εp fכ impruv di pasεnshכn in lipid profayl.
Spesifi k Efεkt dεm we Tesamoreli gεt pan Lipid Mεtabolism insay HIV Pasεnt dεm
Ridyus di Visεral Adipכz Tisu (VAT) .
Tesamoreli de ridyus VAT bad bad wan pan di wan dɛn we gɛt HIV. Insay wan Faz III klinik trayal we involv HIV pasɛnt dɛn, dɛn bin asaynd di patisipan dɛn randomly fɔ gɛt ɛni wan pan 2 mg Tesamoreli ɛvride ɔ wan plesibo fɔ 26 wiks. Insay di Tesamoreli tritmɛnt grup, di pasɛnt dɛn sho se di VAT dɔn ridyus bad bad wan, ɛn dɛn bin si dis ridyushɔn akɔdin to di wan dɛn we gɛt difrɛn beslayn kwaliti dɛn (ɛgz., bak-nɛk fat de ɔ nɔ de). Fɔ di wan dɛn we ansa Tesamoreli (we dɛn difayn as pasɛnt dɛn we gɛt at le 8% ridyushɔn pan VAT ɛn we de fala di tritmɛnt), VAT bin go dɔŋ bad bad wan ilɛksɛf di nɛk ɛn bak fat de, ɛn no difrɛns nɔ bin de bitwin di tu grup dɛn (P = 0.657). Dis sho se Tesamoreli gɛt brayt ɛfifikɛshɔn fɔ ridyus VAT pan HIV pasɛnt dɛn, indipɛndɛnt frɔm di prɛzɛns fɔ bak-nɛk fat. Di ridyushɔn pan VAT nɔ jɔs de mek di sikman dɛn bɔdi fayn bɔt di tin we impɔtant pas ɔl na dat i de ridyus di risk fɔ gɛt di mɛtabolik kɔmplikeshɔn dɛn we gɛt fɔ du wit VAT, lɛk di sik dɛn we de ambɔg di at ɛn di blɔd we de mek dɛn nɔ gɛt insulin.
Fɔ mek di liva fat mɛtabolism bɛtɛ
fכ ridyus di fεt we de insay di liva: Insay di wan dεm we gεt HIV, di insidεns fכ nכn-alkohol fεt liva sik (NAFLD) de hכy εn i gεt kכl fεt mεtabolism we nכ de nכmal. Tesamoreli gɛt fayn fayn tritmɛnt ifɛkt pan NAFLD we gɛt fɔ du wit HIV. Insay wan randomized, double-blind, multicenter study, HIV-infected patients wit hepatic fat fraction (HFF) ≥5% bin randomly assigned to di tesamorelin grup ɔ di plasɛbo grup ɛn dɛn trit dɛn fɔ 12 mɔnt. Di risal sho se di pasɛnt dɛn na di Tesamoreli grup bin gɛt mɔ sifyukɛnt ridyushɔn pan HFF, wit absɔlɔb ifɛkt saiz we na -4.1% (95% CI -7.6 to -0.7, P = 0.018) ɛn rilitiv ridyushɔn fɔ 37% frɔm di beslayn (95% CI -67 to -7, P = 0.016). Afta 12 mɔnt tritmɛnt, 35% pan di pasɛnt dɛn na di Tesamoreli grup bin gɛt HFF lɛvɛl dɔŋ 5%, kɔmpia to 4% nɔmɔ na di plasɛbo grup ( P = 0.0069). Dis sho se Tesamoreli de ridyus di liva fat we de insay di liva fayn fayn wan ɛn i de mek di liva fat mɛtabolism bɛtɛ pan di wan dɛn we gɛt HIV.
Pכtεnshal ifekt dεm pan liva histכlכji: Analysis fכ liva jin εksprεshכn profayl dεm na HIV-NAFLD pasεnshכn dεm sho se Tesamoreli dכwnrεgulεt jin sεt dεm we asosiet wit inflameshn, tisu ripa, εn sεl divεlכpmεnt na di liva. fכda proteomics stכdi dεm sho se Tesamoreli lid to wan sכm rεdukshכn in plasma protin lεvεl dεm fכ vaskulεr εndoteyl grכw fכktכ A (VEGFA), transfכm gכt fכktכ β1 (TGFB1), εn makrofag kכloni-stimulεt fכktכ 1 (CSF1), we kכlכsכl wit liva fכbrosis εn inflameshn. Insay di pasɛnt dɛn we dɛn trit wit Tesamoreli, di ridyushɔn pan plasma VEGFA ɛn CSF1 bin gɛt fɔ du wit di dɛkɛshɔn pan di NAFLD aktiviti skɔ, we di ridyus pan TGFB1 ɛn CSF1 bin gɛt fɔ du wit di dɛkɛshɔn pan di jin-lɛvɛl fibrosis skɔ. dis sho se Tesamoreli kin du bεnεfit ifekt pan di liva histכlכji bay we i de rεgεl inflameshn εn di fibrosis-rεlatεd path dεm na di liva.
Figure 3 Rilayshɔnship bitwin Chenj dɛn na Plasma TGFB1 ɛn CSF1 wit Chenj in Jin-Lɛvɛl Faybrosis Skɔ insay Tesamoreli-Trit patisipan dɛn.
Rεgulεshכn fכ di Wכl-Bכdi Fεt Distribushכn εn di Bכdi Kכmכshכn
Ridyus di trunk fat: Apat frɔm we i de ridyus VAT, Tesamoreli gɛt signifyant rigyuletɔri ifɛkt bak pan di trɔnk fat pan HIV pasɛnt dɛn. Insay klinik stεdi, di sik pipul dεm we dεn trit wit Tesamoreli sho se di fεt we de insay di trכnk de ridyus sכmtεm, we de εp fכ impruv di bכdi shep εn rεdכks tin dεm lεk abdominal protrusion we kכz fכ abnכmal fεt distribushכn. di rεdukshכn pan di trכnk fεt de intarεlat wit di rεdukshכn pan VAT, we kכlektif wan de impruv di bכdi kכmכshכn.
fכ mek di wεst sכkכmεnshכn bεtε: di wεst sεkכnfεns na imכtant tin we de sho se di bεlε fεt de kכmכt. Tesamoreli tritmɛnt kin rili ɛp fɔ mek di wɛst we de na di wan dɛn we gɛt HIV bɛtɛ. Insay rilevɛns klinik trayal, ɔl tu di Tesamoreli rεspכndεr dεm wit εn witout bak-nεk fεt sho sכm rεdukshכn pan di wεst sεkshכn afta 26 wiks tritmεnt. di impruvmεnt na di wεst sεkכnfεnshכn nכ de nכmכ de sho se di bכdi fεt dεn dכn bכt i de kכlכs fכ ridyus mεtabolik risk dεm lεk kכdivaskyul sik.
Ifekt pan ɔda bɔdi kɔmpɔzishɔn paramita dɛm: Tesamoreli gɛt rigyuletɔri ifɛkt bak pan ɔda bɔdi kɔmpɔzishɔn paramita dɛm pan HIV pasɛnt dɛm. fכ egzampl, insay sכm stכdi dεm, pan כl we di bכdi mas indεks (BMI) sho nכ big chenj, di bכdi fεt kכmכshכn impruv. Tesamoreli kin optimize di bodi fεt distribushכn witout afekt di כvala wet, ridyus di fεt akyumyuleshכn we pasmak, inkrεs sכm bכdi mas kכmכpכnεnt dεm lεk mכsul, εn εnhans di pasεnshכn in bכdi kwaliti.
Aplikeshɔn fɔ Tesamoreli insay Fat Mɛtabolism insay HIV Patiɛnt dɛn
Di pipul dɛn we dɛn de tɔk bɔt
HIV pipul dεm we gεt abnכmal fεt mεtabolism: Tesamoreli na fכs fכ HIV pasεn dεm we gεt abnכmal fεt mεtabolism, patikyular dεn wan dεm we gεt bכku vishכnal fεt (εgz., as dεn dεtermin bay abdominal CT כ MRI skan we sho di vishכnal adipos tisu [VAT] we pas nכmal rεnj dεm). Dɛn sik pipul ya kin sho se dɛn bɛlɛ fat, dɛn kin gɛt mɔ wɛst, ɛn dɛn kin gɛt ɔda tin dɛn bak we kin sho se dɛn gɛt mɛtabolik sindrom, lɛk insulin rɛsistɛns ɛn dislipidemia.
Dɔn
as ifektiv tεrapi ejen fכ abnכmal fεt mεtabolism insay HIV pasεnshכn dεm, Tesamoreli de rεgεl fεt mεtabolism tru mכltipכl mεkanism dεm, we de ple imכtant rol fכ ridyus VAT, impruv hεpatik fεt mεtabolism, rεgεl di כl bכdi fεt distribushכn, εn optimiz bכdi kכmכshכn.
Sos dɛn we dɛn pul
[1] Rahman F, de Chantal M, M ɛskita P, ɛn ɔda pipul dɛn. 935. Efεkt כf Tesamoreli in Pipul dεm we gεt HIV wit εn witout Dorsocervical Fat: Post Hoc Analysis כf Faz III Dabl Blaynd Plesεbo Kכntrכl Trayal[J]. Opin Fɔm Infɛkshɔn Disizin, 2020,7(Saplimɛnt_1):S500-S501.DOI:10.1093/ofid/ofaa439.1121.
[2] Klinik Rivyu Ripɔt: Tesamoreli (Egrifta)[M]. Ottawa (ON): Kanada Ajɛns fɔ Drug ɛn Tɛknɔlɔji insay Wɛlbɔdi, 2016.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Ritriv&db=pubmed&dopt=Abstrakt&list_uids=30920787&kwɛstyɔn_hl=1.
Prodak we de fɔ yuz fɔ risach nɔmɔ:
