Pioglitazone ha ho phekoloa lefu la tsoekere la mofuta oa 2

• LIHLOOHO: lefu la tsoekere, hyperglycemia, lihlekehleke tsa Langerhans, hepatotoxicity, troglitazone, rosiglitazone, pioglitazone, Baeta

Mochine o ka sehloohong oa pathogenesis ea lefu la tsoekere la mofuta oa 2 ke ho loants'oa ha "insulin", empa ho isang feela ho hyperglycemia, empa ho baka mabaka a kotsi bakeng sa nts'etsopele ea maloetse a pelo le methapo ea methapo ea methapo. Ntlheng ena, ho theha le ho sebelisoa ha kalafo ea bakuli ba nang le lithethefatsi tse amang ka ho toba IR ke tataiso e tšepisang kalafong ea lefu lena le tebileng.

Ho tloha ka 1996, ts'ebetsong ea bakuli ba nang le lefu la tsoekere la mofuta oa 2, sehlopha se secha sa lithethefatsi se sebelisitsoe, se kopantsoe ke mokhoa oa ts'ebetso ea bona ho sehlopha sa thiazolidinediones (TZD) kapa li-insulin sensitizer (ciglitazone, rosiglitazone, darglitazone, troglitazone, pioglitazone, anglitazone), ketso ea mantlha e lebisitsoeng ho matla a ho eketseha ha kutloisiso e lebisitsoeng ho matla a ho eketseha a kutloisiso. linama ho insulin. Leha ho bile le liphatlalatso tse ngata tsa 80-90s tsa lekholo la ho qetela tse sebelisitsoeng ho ithutoang esale pele ka polokeho le katleho ea lisebelisoa tsena, ke lithethefatsi tse tharo feela tse tsoang sehlopheng sena tse ileng tsa kenngoa ts'ebetsong ea bongaka - troglitazone, rosiglitazone le pioglitazone. Ka bomalimabe, hamorao troglitazone e ile ea thibeloa ho sebelisoa ka lebaka la hepatotoxicity e bonahatsoang nakong ea ts'ebeliso ea nako e telele.

Hajoale ho sebelisoa meriana e 'meli ho tsoa sehlopheng sa TZD: pioglitazone le rosiglitazone.

Seketso sa ts'ebetso ea thiazolidinediones

Phello e ka sehloohong ea kalafo ea TZD ho lefu la tsoekere la mofuta oa 2 ke ho fokotsa ho hanyetsa ha insulin ka ho eketsa kutloisiso ea mesifa ea pherekano ho insulin.

Ho hanyetsa insulin (IR) ho hlaha nako e telele pele ho pontšo ea lefu la tsoekere la mofuta oa 2. Boikutlo bo fokotsehileng ba lisele tsa mafura ho phello ea li-insulin li baka keketseho e sa foleng ea litaba tsa mahala tsa mafura acid (FFA) maling a mali. Li-FFAs le tsona li eketsa ho hanyetsa insulin maemong a sebete le mesifa ea mesifa, e lebisang ho gluconeogeneis e ngata le ho fokotsa ts'ebeliso ea glucose ke lisele tsena. Tlas'a maemo a joalo, lisele tsa mafura li hlahisa li-cytokine tse ngata haholo (tumor necrosis factor a - TNF-a), interleukin (IL-6 le resistin), e mpefatsang ho hanyetsa insulin le ho phahamisa atherogeneis. Ho hlahisoa ke lisele tsa mafura tsa cytokine e 'ngoe - adiponectin, e eketsang kutloisiso ea lisele tsa mmele ho insulin, e fokotsehile.

Li-Thiazolidinediones ke li-agonists tse phahameng tsa tumellano ea li-receptor tsa nyutlelie tse hlahisoang ke proliferator ea peroxisome - PPARg (peroxisome proliferators-activated receptor), tseo e leng tsa lelapa la lintlha tse ngotsoeng tse laolang polelo ea liphatsa tsa lefutso tse amanang le carbohydrate le metabolid metabolism ho adipose le mesifa ea mesifa. Li-isoforms tse 'maloa tsa PPAR li tsejoa: PPARa, PPARg (subtypes 1, 2) le PPARb / PPARd. PPARa, PPARg le PPARd, e phethang karolo ea bohlokoa ho tsamaiso ea adipogeneis le IR. Mofuta oa PPARγ liphoofolong tse 'maloa tsa liphoofolo tse anyesang, ho kenyelletsa le batho, o sebakeng sa 3 sa chromosome (locus 3p25). Li-receptor tsa PPARg li hlahisoa haholo liseleng tsa mafura le li-monocytes, tse fokolang mesifa ea masapo, sebete le liphio. Karolo ea bohlokoahali ea PPARg ke phapang ea lisele tsa adipose tsa lisele. Li-agonists tsa PPARg (TZD) li fana ka sebopeho sa li-adipocytes tse nyane tse amehang haholo ho insulin, e ts'oereng FFA ka mafolofolo le ho laola ho hlahisoa ha mafura ka mokhoa o ikhethileng mme eseng li-visceral fatty tis (3). Ntle le moo, ts'ebetso ea PPARg e lebisa ho ho eketseheng ha polelo le ho fetisoa ha ba tsamaisang tsoekere (GLUT-1 le GLUT-4) ho membrane ea sele, e lumellang glucose e tsamaisoe liseleng tsa sebete le tsa mesifa mme ka hona e fokotsa glycemia. Tlas'a tšusumetso ea li-agonists tsa PPARg, tlhahiso ea TNF-ea fokotseha le polelo ea adiponectin e eketseha, e leng se eketsang matla a ho utloahala ha litho tsa thipa ho insulin (4).

Kahoo, thiazolidinediones e ntlafatsa haholo methapo ea kutlo ea insulin ho "insulin", e bonts'ang ho fokotseha ha gluconeogeneis ka har'a sebete, thibelo ea lipolysis ho lithane tsa adipose, ho fokotseha ha khatello ea FFA maling, le ntlafatso ea ts'ebeliso ea glucose mesifa (Setšoantšo sa 1).

Li-Thiazoldinediones ha li khothale ka ho toba secretion ea insulin. Leha ho le joalo, ho fokotseha ha tsoekere ea mali le FFA maling ha o ntse o nka TZD ho theola tsoekere le lipotoxic ho li-b-cell le li-peripheral tishu mme, ha nako e ntse e tsamaea, ho lebisa ho secretion e ntlafalitsoeng ke insulin ka li-b-cell (5). Boithuto bo entsoeng ke Miyazaki Y. (2002) le Wallace T.M. (2004), phello e tobileng ea TZD ts'ebetsong e sebetsang ea li-b-cell ka mokhoa oa ho fokotseha ha apoptosis le keketseho ea kholo ea bona e netefalitsoe (6, 7). Thutong e entsoeng ke Diani A.R. (2004) ho ile ha bontšoa hore tsamaiso ea pioglitazone ho liphoofolo tse sebetsang ka lefu la tsoekere la mofuta oa 2 e kentse letsoho ho bolokoeng ha sebopeho sa lihlekehleke tsa Langerhans (8).

Ho fokotseha ha khanyetso ea insulin tlasa ts'usumetso ea pioglitazone ho netefalitsoe ka mokhoa o kholisang thutong ea bongaka ka ho hlahloba mohlala oa NOMA homeostasis (9). Kawamori R. (1998) o bonts'itse ntlafatso ea phetoho ea tsoekere ea "glucose" khahlanong le tekanyetso ea libeke tse leshome le metso e 'meli ea pioglitazone ka tekanyo ea 30 mg / ka letsatsi. bapisoa le placebo (1.0 mg / kg × min. vs.4 mg / kg × min, p = 0.003) (10). Phuputso e entsoeng ke Benett S.M. et al. (2004), e bonts'itse ha TZD (rosiglitazone) e sebelisoa libeke tse 12 ho batho ba nang le mamello ea glucose e sa tsitsang, index ea sensulin ea insulin e eketsehile ka 24.3%, ha e le khahlano le semelo sa placebo, e fokotsehile ka 18, 3% (11). Phuputsong e laoloang ke placebo ea TRIPOD, phello ea troglitazone kotsing ea lefu la tsoekere la 2 ho basali ba Latin America ba nang le nalane ea lefu la tsoekere la gestational le ithutile (12). Liphetho tsa mosebetsi li netefalitse 'nete ea hore nakong e tlang kotsi ea ho ba le lefu la tsoekere la mofuta ona mecheng ena ea bakuli e fokotsehile ka 55%. Re lokela ho tseba hore liketsahalo tsa lefu la tsoekere la mofuta oa 2 ka selemo khahlanong le troglitazone e ne e le 5.4% ha li bapisoa le 12.1% khahlano le placebo. Phuputsong e bulehileng ea PIPOD, eo e neng e le tsoelo-pele ea thuto ea TRIPOD, pioglitazone e ne e boetse e amahanngoa le kotsi e fokolisitsoeng ea ho ba le lefu la tsoekere la mofuta oa 2 (khafetsa la linyeoe tse sa tsoa fumanoa tsa lefu la tsoekere la 2 e ne e le 4,6% ka selemo) (13).

Tsoekere e theolang phello ea pioglitazone

Liphuputso tse ngata tsa tšebeliso ea bongaka ba pioglitazone li netefalitse katleho ea tsona kalafong ea bakuli ba nang le lefu la tsoekere la mofuta oa 2.

Liphetho tsa liphuputso tse laoloang ke maloetse a mangata li bontšitse hore pioglitazone e fokotsa glycemia ka bobeli monotherapy le hammoho le lithethefatsi tse ling tsa molomo tse amanang le kalafo, haholoholo le litekanyetso tsa metformin le sulfonylurea tse sebelisoang haholo kalafong ea bakuli ba nang le lefu la tsoekere la mofuta oa 2 (14, 15, 16, 16). 17).

Ho tloha ka Pherekhong 2008, TZD e 'ngoe, rosiglitazone, ha e khothalletsoe hore e sebelisoe hammoho le insulin ka lebaka la kotsi e ka bang teng ea ho nyekeloa ke pelo. Mabapi le sena, boemo ba hajoale ba litsebi tse etellang pele tsa lefu la tsoekere ho la USA le Europe, bo bonahetse ho "Polelo ea tumellano ea Mokhatlo oa Amerika oa Lefu la Tsoekere le Mokhatlo oa Europe bakeng sa Thupelo ea Lefu la Tsoekere" selemong se haufinyane, ka tsela e itseng e sa lebelloang, hobane e lumella ts'ebeliso e kopaneng ea insulin le pioglitazone. Ho hlakile hore polelo e joalo e thehiloe ho data ho tsoa lithutong tse tebileng tsa kliniki. Kahoo, lipatlisiso tse sa sebetseng hantle tse sa sebetseng hantle, tse sa hlophiseheng, tse laoloang ke placebo tse entsoeng ke Matoo V. ka 2005 ka bakuli ba 289 ba nang le lefu la tsoekere la 2 li bonts'itse hore ho eketsoa ha pioglitazone ho kalafo ea insulin ho lebisa ho fokotseha ho hoholo ha hemoglobin (HbA1c) le glycemia e potlakileng (18). . Leha ho le joalo, hoa tšosa hore, khahlano le semelo sa phekolo e kopaneng ho bakuli, liketsahalo tsa hypoglycemia li ile tsa bonoa hangata haholo. Ntle le moo, keketseho ea boima ba 'mele mokokotlong oa insulin monotherapy e ne e le tlase ho feta ha e kopantsoe le pioglitazone (0,2 kg vs. 4.05 kg). Ka nako e ts'oanang, motsoako oa pioglitazone o nang le insulin o ne o tsamaisana le liphetoho tse ntle sebopeng sa lipid ea mali le maemo a matšoao a kotsi ea lefu la pelo (PAI-1, CRP). Nako e khuts'oanyane ea thuto ena (likhoeli tse 6) ha ea ka ea lumella tlhahlobo ea sephetho sa pelo. Ha re fuoa kotsi e itseng ea ho ba le ho nyekeloa ke pelo ho kopaneng le rosiglitazone le insulin, ts'ebetsong ea rona ha re kotsing ea ho kopanya ntho ea morao le pioglitazone ho fihlela tlhahisoleseling e tšepahalang mabapi le polokeho e phethahetseng ea kalafo e joalo e fumanoa.

Matla a pioglitazone maemong a kotsi a lefu la pelo

Ntle le phello ea hypoglycemic, TZD e kanna ea ba le phello e ntle linthong tse 'maloa tsa kotsi bakeng sa nts'etsopele ea maloetse a pelo le pelo. Ntho ea bohlokoa ka ho fetisisa ke phello ea lithethefatsi maling a lipid. Boithuto bo 'maloa bo entsoeng lilemong tsa morao tjena, pioglitazone e bontšitsoe e na le phello e molemo maemong a lipid. Kahoo, lipatlisiso tse entsoeng ke Goldberg R.B. (2005) le Dogrell S.A. (2008) e bonts'itse hore pioglitazone lowers triglycerides (19, 20). Ntle le moo, pioglitazone e eketsa sekhahla sa anti-atherogenic sekhechana sa high density lipoprotein cholesterol (HDL). Lintlha tsena li tsamaellana le liphetho tsa Phuputso ea Proactive (Teko ea Procpective pioglitAzone Clinical Tental In liketsahalo tsa macroVascular), moo bakuli ba 5238 ba nang le lefu la tsoekere la 2 le nalane ea mathata a macrovascular ba nkileng lilemo tse 3. Motsoako oa pioglitazone le lijo le li-activator tsa hypoglycemic nakong ea lilemo tse 3 tsa ho shebella li lebisitse keketseho ea 9% maemong a HDL le ho theoha ha 13% ho li-triglycerides ha li bapisoa le ea pele. Ho shoa ha batho ka kakaretso, kotsi ea ho ba le lefu le sa bonahaleng la myocardial infrection le ho senyeha ha kotsi ea ts'ebetso ea methapo ka ts'ebeliso ea pioglitazone e fokotsehile haholo. Monyetla o akaretsang oa liketsahalo tsena ho batho ba amohelang pioglitazone o fokotsehile ka 16%.

Liphetho tsa thuto ea CHICAGO (2006) le mosebetsi o etsoang ke Langenfeld M.R. et al. (2005) (21), e bonts'itse hore ka tsamaiso ea pioglitazone, botenya ba lebota la vascular bo fokotseha, ka hona, nts'etsopele ea atherosclerosis e ea fokotseha. Phuputso e entsoeng ke Nesto R. (2004) e bonts'a ntlafatso lits'ebetsong tsa ho nchafatsa mochini o tsoang ka letsohong le letšehali le ho hlaphoheloa kamora ts'ebeliso ea ischemia le ho pheta-pheta ts'ebeliso ea TZD (22). Ka bomalimabe, litlamorao tsa liphetoho tsena tse ntle tsa morphological liphellong tsa pelo le nako e telele ha li e-so ithutoe, tseo ntle ho pelaelo li fokotsang bohlokoa ba tsona ba kliniki.

Litlamorao tse ka bang teng tsa pioglitazone

Lithutong tsohle tsa kliniki, pioglitazone, hammoho le TZD tse ling, li ne li tsamaea le keketseho ea boima ba 'mele ka kilo ea 0.5-3.7, haholoholo likhoeling tse 6 tsa pele tsa kalafo. Kamora nako, boima ba bakuli boa tsitsa.

Ho joalo, ho nona haholo ke litlamorao tse sa rateheng tsa lithethefatsi leha e le life kalafong ea bakuli ba nang le lefu la tsoekere la mofuta oa 2, hobane boholo ba bakuli bo batenya kapa ba batenya haholo. Leha ho le joalo, ho bohlokoa ho totobatsa hore tekanyo ea pioglitazone e tsamaea le, haholoholo, ka keketseho ea bophahamo ba mafura a subcutaneous, ha palo ea mafura a visceral ho bakuli ba fumanang TZD e fokotseha. Ka mantsoe a mang, ho sa natsoe phaello ea boima ba 'mele ha u nka pioglitazone, menyetla ea ho ba le lefu la "pelo le tsoelang pele" ha e eketsehe (23). Ho bohlokoa ho hlokomela hore tekanyo ea ho eketseha ha boima ba 'mele e lumellana ka ho toba le kalafo e fokotsang tsoekere, i.e. boima ba 'mele bo phahame ho bakuli ba fumanang motsoako oa TZD ka litokisetso tsa insulin kapa sulfonylurea, hape e tlase le metformin.

Boteng ba kalafo ea pioglitazone, 3-15% ea bakuli ba na le ho bolokoa ha mokelikeli, lisosa tsa eona li sa utloisisoe ka botlalo. Kahoo, ho na le ntlha ea maikutlo ea hore ka lebaka la ho fokotseha ha sodium excretion le keketseho ea ho bolokoa ha mokelikeli, keketseho ea palo ea mali a potoloha e etsahala. Ntle le moo, TZD e ka kenya letsoho ho arodial vasodilation ka keketseho e latelang ea molumo oa metsi a tsoang kantle ho motho (22). Ke ka litlamorao tsena tsa TZD moo ho hloleha ha pelo ho anngoeng. Kahoo, thutong e kholo ea projeke, khafetsa ea linyeoe tse sa tsoa fumanoa tsa ho nyekeloa ke pelo ka mokhoa oa phekolo ea pioglitazone li ne li phahame haholo ho feta ka placebo (11% vs 8%, p 7% likhoeli tse tharo kamora ho qala kalafo ea hypoglycemic ke lebaka la ho hlahisa bonyane motsoako oa hypoglycemic. kalafo.

Ho sebetsa hantle ha pioglitazone, hammoho le TZD tse ling, ho hlahlojoa ke boemo ba HbA1c. Ho lekana ha tekanyetso le katleho ea lithethefatsi tse ling tse fokotsang tsoekere tse nkang khatello ea gluconeogenesis kapa ho tsosa secretion ka li-cell tsa rona tsa b e ka khethoa ka mokhoa o hlakileng ke matla a matla a tsoang ho basal kapa postprandial glycemia. TZD, butle-butle e fokotsa ho hanyetsa insulin, ha e na phello e potlakileng ea hypoglycemic, eo ho leng bonolo ho e lekola ka boitaolo ba lapeng. Mabapi le sena, bakuli ba fumanang pioglitazone ka ho khetheha ba hloka taolo ea HbA1c bonyane hanngoe ka likhoeli tse tharo. Ntle le ho fihlela katleho ea sepheo sa boleng bo glycated (HbA1c