Mphamvu ya pioglitazone pochiza odwala omwe ali ndi matenda a shuga a 2

MALANGIZO: shuga, hyperglycemia, zilumba za Langerhans, hepatotoxicity, troglitazone, rosiglitazone, pioglitazone, Baeta

Njira yofunika kwambiri ya pathogenesis ya matenda a 2 matenda a shuga ndi insulin kukana (IR), yomwe imangoyambitsa matenda a hyperglycemia, komanso, imayambitsa zinthu zomwe zingayambitse matenda a mtima monga matenda oopsa a mtima ndi matenda a dyslipidemia. Pachifukwa ichi, kupangidwa ndi kugwiritsa ntchito mankhwalawa kwa odwala omwe ali ndi mankhwala omwe akukhudzira IR ndi njira yolimbikitsira pakuchizira matenda oopsa.

Kuyambira mu 1996, pochiza odwala omwe ali ndi matenda a shuga a 2, gulu latsopano la mankhwala lakhala likugwiritsidwa ntchito, kuphatikiza njira ya zochita zawo pagulu la thiazolidinediones (TZD) kapena insulin sensitizer (ciglitazone, rosiglitazone, darglitazone, troglitazone, pioglitazone, anglitazone). zimakhala ndi insulin. Ngakhale kuti panali zofalitsa zambiri za 80-90s za zaka zapitazi zomwe zidaphunziridwa zachitetezo chazomwe zidachitika, mankhwala atatu okha kuchokera ku gululi adalowetsedwa muzochitika zamankhwala - troglitazone, rosiglitazone ndi pioglitazone. Tsoka ilo, pambuyo pake troglitazone adaletsedwa kugwiritsa ntchito chifukwa cha hepatotoxicity yowonetsedwa pakugwiritsa ntchito nthawi yayitali.

Pakadali pano, mankhwala awiri amagwiritsidwa ntchito kuchokera ku gulu la TZD: pioglitazone ndi rosiglitazone.

Limagwirira ntchito ya thiazolidinediones

Chithandizo chachikulu cha TZD mu mtundu 2 wa shuga ndikuchepetsa kukana kwa insulini ndikuwonjezera chidwi cha zotumphukira za insulin.

Kutsutsana ndi insulin (IR) kumawonekera patatsala nthawi yayitali kuti chiwonetsero cha matenda ashuga chidziwike. Kuzindikira kwamachepera kwama cell kwama cell kupita ku antilipolytic zotsatira za insulin kumabweretsa kuwonjezeka kosatha kwa zomwe zili ndi mafuta acids aulere (FFA) m'magazi am'magazi. FFAs, imakulitsa kukana kwa insulini pamlingo wa chiwindi ndi minofu minofu, zomwe zimabweretsa kuchuluka kwa gluconeogeneis ndikuchepetsa kukhudzana ndi glucose chifukwa cha izi. M'mikhalidwe yotero, maselo amafuta amapanga kuchuluka kwama cytokines (tumor necrosis factor a - TNF-a), interleukin (IL-6 ndi resistin), yomwe imakulitsa kukana kwa insulini ndikuwonjezera atherogenesis. Kupanga kwa maselo amafuta a cytokine ina - adiponectin, komwe kumawonjezera chidwi cha minyewa mpaka insulin, kumachepetsedwa.

Thiazolidinediones ndi othandizira okonda kugwirizira mphamvu zama nyukiliya zolandilira zomwe zimapangidwa ndi peroxisome proliferator - PPARg (peroxisome proliferators-activated receptor), omwe ndi am'banja la zolembedwa zomwe zimawongolera kuyankhula kwa majini omwe amalamula kupangika kwa metabolic ndi lipid metabolism mu adipose ndi minofu minofu. Ma isoform angapo a PPAR amadziwika: PPARa, PPARg (subtypes 1, 2) ndi PPARb / PPARd. PPARa, PPARg ndi PPARd, omwe amagwira ntchito yofunika kwambiri pakuwongolera adipogeneis ndi IR. Mtundu wa PPARγ mwa zinyama zingapo, kuphatikizapo anthu, uli pa 3 chromosome (locus 3p25). PPARg receptor imafotokozedwa makamaka m'maselo am'mafuta ndi ma monocytes, ochepera minofu ya mafupa, chiwindi ndi impso. Udindo wofunikira kwambiri wa PPARg ndi kusiyanitsa kwa maselo amtundu wa adipose. PPARg agonists (TZD) imapereka kupangika kwa ma adipocytes ang'ono omwe amakhudzidwa kwambiri ndi insulin, yomwe imayamwa mwachangu FFA ndikuwongolera kuyika kwa mafuta mu subcutaneous osati visceral mafuta minofu (3). Kuphatikiza apo, kutsegula kwa PPARg kumabweretsa kuwonjezereka kwa kufotokozera ndi kusamutsidwa kwa omwe amayendetsa glucose (GLUT-1 ndi GLUT-4) kupita ku membrane wam'maselo, omwe amalola kuti glucose iperekedwe ku chiwindi ndi minofu ya minofu ndikuchepetsa glycemia. Mothandizidwa ndi agonists a PPARg, kupanga TNF-kumatsika ndipo mawu a adiponectin amawonjezeka, omwe amathandizanso chidwi cha zotumphukira kuti insulin (4).

Chifukwa chake, thiazolidinediones imathandizira chidwi chamtundu wa insulin, chomwe chimawonetsedwa ndi kuchepa kwa gluconeogenesis m'chiwindi, kuletsa kwa lipolysis mu minofu ya adipose, kuchepa kwa ndende ya FFA m'magazi, komanso kusintha magwiritsidwe a shuga m'mitsempha (Chithunzi 1).

Thiazoldinediones samalimbikitsa mwachindunji insulin. Komabe, kutsika kwa glucose wamagazi ndi FFA m'magazi pomwe mukumwa TZD kumachepetsa mphamvu ya glucose ndi lipotoxic pazomera za b-cell ndi zotumphukira ndipo, pakapita nthawi, zimabweretsa kubisalira kwa insulini ndi b-cell (5). Kafukufuku wolemba ndi Miyazaki Y. (2002) ndi Wallace T.M. (2004), zotsatira zabwino za TZD pakuwoneka kwa ntchito ya b-cell m'njira yochepetsera apoptosis ndikuwonjezereka kwa kuchuluka kwawo kwatsimikiziridwa (6, 7). Mu kafukufuku wolemba Diani A.R. (2004) zidawonetsedwa kuti kukhazikitsidwa kwa pioglitazone ku nyama yamulembera yokhala ndi matenda amtundu wa 2 kunathandizira kuti asungidwe a zisumbu za Langerhans (8) atetezedwe.

Kutsika kwa kukana kwa insulin motsogozedwa ndi pioglitazone kunatsimikiziridwa motsimikiza mu kafukufuku wazachipatala powunika chitsanzo cha NOMA homeostasis (9). Kawamori R. (1998) adawonetsa kusintha kwa zotumphukira za m'magazi polimbana ndi pixlitazone ya milungu iwiri pa mlingo wa 30 mg / tsiku. poyerekeza ndi placebo (1.0 mg / kg × min. vs 0.4 mg / kg × min, p = 0.003) (10). Kafukufuku wopangidwa ndi Benett S.M. et al. (2004), adawonetsa kuti TZD (rosiglitazone) itagwiritsidwa ntchito kwa masabata 12 mwa anthu omwe ali ndi vuto lolepheretsa glucose, index insitivity index idakwera ndi 24.3%, pomwe kutsutsana ndi maziko a placebo, kunatsika ndi 18, 3% (11). Pakafukufuku wopangidwa ndi placebo wowongoleredwa ndi TRIPOD, zotsatira za troglitazone pachiwopsezo cha matenda a shuga 2 azimayi aku Latin America omwe adaphunzira mbiri yakale ya matenda a edzi (12). Zotsatira za ntchitoyi zidatsimikizira kuti mtsogolomo chiopsezo chokhala ndi matenda amtundu wa 2 m'gulu ili la odwala amachepetsa ndi 55%. Tiyenera kudziwa kuti kuchuluka kwa matenda ashuga a mtundu 2 pachaka motsutsana ndi troglitazone anali 5.4% poyerekeza ndi 12.1% motsutsana ndi placebo. Pakafukufuku wotseguka wa PIPOD, komwe kunali kupitiliza kwa kafukufuku wa TRIPOD, pioglitazone imagwirizananso ndi chiopsezo chochepetsa matenda a shuga 2 (pafupipafupi omwe amapezeka ndi matenda a shuga 2 anali 4,6% pachaka) (13).

Kuchepetsa shuga kwa pioglitazone

Kafukufuku wambiri wa kugwiritsa ntchito pioglitazone kuchipatala kwatsimikizira kugwira ntchito kwake pothandizira odwala omwe ali ndi matenda a shuga a 2.

Zotsatira za kafukufuku wam'magawo ambiri olamulidwa ndi placebo zawonetsa kuti pioglitazone imachepetsa glycemia onse mu monotherapy komanso kuphatikiza mankhwala ena apakamwa a hypoglycemic, makamaka ndi metformin ndi zotumphukira za sulfonylurea zomwe zimagwiritsidwa ntchito kwambiri pothandizira odwala omwe ali ndi matenda a shuga a 2 (14, 15, 16, 16). 17).

Kuyambira mu February 2008, TZD ina, rosiglitazone, siinalimbikitsidwe kuti igwiritsidwe ntchito limodzi ndi insulin chifukwa choopsa cha kulephera kwa mtima kwaponseponse. Pankhaniyi, momwe omwe akutsogolera odwala matenda ashuga ku USA ndi ku Europe, akuwonetsera mu "Chigwirizano cha American Diabetes Association ndi European Association for the Study of Diabetes" chaka chino, ndizosayembekezeka, chifukwa amalola kuphatikiza kwa insulin ndi pioglitazone. Mwachidziwikire, mawu oterewa adakhazikitsidwa ndi data kuchokera ku maphunziro akulu azachipatala. Chifukwa chake, kafukufuku wakhungu lachiwiri, losasinthika komanso lodalirika loyesedwa ndi Matoo V. mu 2005 ndi odwala 289 omwe ali ndi matenda amtundu wa 2 adawonetsa kuti kuwonjezeredwa kwa pioglitazone ku insulin therapy kumabweretsa kuchepa kwakukulu kwa glycated hemoglobin (HbA1c) ndi glycemia wofulumira (18) . Komabe, ndizowopsa kuti, mosiyana ndi maziko a mankhwala ophatikiza odwala, zochitika za hypoglycemia zimawonedwa kwambiri nthawi zambiri. Kuphatikiza apo, kuwonjezeka kwa kulemera kwa thupi kumbuyo kwa insulin monotherapy kunali kocheperako poyerekeza ndi pioglitazone (0,2 kg vs. 4.05 kg). Nthawi yomweyo, kuphatikiza kwa pioglitazone ndi insulin kumayendera limodzi ndi kusintha kwamphamvu m'magazi a lipid sipekitiramu komanso milingo yokhala ndi vuto la mtima (PAI-1, CRP). Kutalika kochepa kwa phunziroli (miyezi 6) sikunalole kuwunika kwa zotsatira za mtima. Popeza tili ndi chiopsezo chotukuka mtima wosakhazikika ndi kuphatikiza kwa rosiglitazone ndi insulin, machitidwe athu sitiika pachiwopsezo chophatikiza chomaliza ndi pioglitazone mpaka chidziwitso chodalirika cha chitetezo chokwanira chotere.

Mphamvu ya pioglitazone pachiwopsezo cha matenda amtima

Kuphatikiza pa zotsatira za hypoglycemic, TZD imathanso kukhala ndi zotsatira zabwino pazinthu zingapo zowopsa pakukula kwa matenda a mtima. Chofunika kwambiri ndi zotsatira za mankhwala omwe amapezeka pakhungu la lipid. M'maphunziro angapo omwe adachitika zaka zaposachedwa, pioglitazone awonetsedwa kuti ali ndi phindu pamlingo wa lipid. Chifukwa chake, kafukufuku wochitidwa ndi Goldberg R.B. (2005) ndi Dogrell S.A. (2008) adawonetsa kuti pioglitazone lowers triglycerides (19, 20). Kuphatikiza apo, pioglitazone imawonjezera gawo la anti-atherogenic kachigawo kakakulu kachulukidwe lipoprotein cholesterol (HDL). Izi ndizogwirizana ndi zotsatira za kafukufuku wa Proactive (PROspective pioglitAzone Clinical Tental In MacroVascular Events), pomwe odwala 5238 omwe ali ndi matenda a shuga a 2 komanso mbiri ya zovuta zazikulu zomwe adachita nawo zaka zitatu. Kuphatikizidwa kwa pioglitazone ndi othandizira pakamwa komanso othandizira pakamwa kwa hypoglycemic pazaka 3 zowunikira kunawonjezera kuchuluka kwa 9% m'magulu a HDL komanso kuchepa kwa 13% mu triglycerides poyerekeza ndi koyambirira. Kwambiri kufa, chiopsezo chotenga matenda osapsa a myocardial infarction ndi ngozi yapathengo yamatsenga pogwiritsa ntchito pioglitazone inachepa kwambiri. Mwayi wonse wa zochitika izi mwa anthu omwe amalandila pioglitazone unatsika ndi 16%.

Zotsatira za kafukufuku wa CHICAGO (2006) ndi ntchito yochitidwa ndi Langenfeld M.R. et al. (2005) (21), adawonetsa kuti ndi makonzedwe a pioglitazone, makulidwe a khoma lamitsempha amachepa ndipo, motero, chitukuko cha atherosulinosis chimachepetsa. Kafukufuku woyeserera wolemba Nesto R. (2004) akuwonetsa kusintha pakukonzanso kwamkono wamanzere ndikuchira pambuyo pa ischemia ndikubwezeretsanso kugwiritsa ntchito TZD (22). Tsoka ilo, zovuta zakusintha kwa morimoli pazotsatira za mtima wazaka sizinaphunzire, zomwe mosakayikira zimachepetsa kufunikira kwawo kwamankhwala.

Zotsatira zoyipa za pioglitazone

M'maphunziro onse azachipatala, pioglitazone, komanso TZD ina, idatsatana ndi kuwonjezeka kwa kulemera kwa thupi ndi 0.5-3.7 kg, makamaka m'miyezi 6 yoyambirira yamankhwala. Pambuyo pake, kulemera kwa odwala kumakhazikika.

Inde, kulemera kumabweretsa vuto losafunikira lililonse la mankhwala pochiza odwala omwe ali ndi matenda a shuga a 2, chifukwa odwala ambiri ndi onenepa kapena onenepa kwambiri. Komabe, ndikofunikira kutsindika kuti kudya pioglitazone kumayendetsedwa, makamaka, ndi kuchuluka kwa mafuta ochulukirapo, pomwe kuchuluka kwa mafuta a visceral mwa odwala omwe amalandira TZD kumachepa. Mwanjira ina, ngakhale mutapeza phindu lozama mutatenga pioglitazone, chiopsezo chokhala ndi / kapena kupita patsogolo kwa mtima sikukula (23). Ndikofunikira kudziwa kuti kuchuluka kwa kuwonjezeka kwa thupi kumagwirizanitsa mwachindunji ndi chithandizo chochepetsera shuga, i.e. kunenepa kwambiri ndikokwera kwambiri kwa odwala omwe amalandira kuphatikiza kwa TZD ndi insulin kapena sulfonylureas, komanso otsika ndi metformin.

Poyerekeza ndi momwe mankhwalawo amathandizira ndi pioglitazone, 3-15% ya odwala amakhala ndi madzi osungidwa, zomwe zimayambitsa zomwe sizimamveka bwino. Chifukwa chake, pali malingaliro akuti chifukwa cha kuchepa kwa sodium excretion ndi kuwonjezeka kwa madzi osungunuka, kuwonjezeka kwa kuchuluka kwa magazi ozungulira kumachitika. Kuphatikiza apo, TZD imathandizira pakuwonjezera vasodilation ndi kuwonjezereka kwamphamvu kwa voliyumu ya extracellular fluid (22). Ndi zotsatira zoyipa za TZD zomwe kusokonekera kwamtima kumalumikizidwa. Chifukwa chake, pofufuza kopambana kwakukulu, kusinthasintha kwa matenda opezeka ndi mtima wambiri ndi pioglitazone mankhwala kunali kwakukulu kwambiri kuposa kwa placebo (11% vs 8%, p 7% patatha miyezi itatu chiyambi cha matenda a hypoglycemic ndi chifukwa chofotokozera osakanikirana a hypoglycemic mankhwala.

Mphamvu ya pioglitazone, monga TZD ina, imayesedwa ndi mulingo wa HbA1c. Kukwanira kwa mlingo komanso kugwira ntchito kwa mankhwala ena ochepetsa shuga omwe amachepetsa shuga (gluconeogeneis) kapena kupangitsa kuti insulin itulutsidwe ndi maselo athu a b. TZD, pang'onopang'ono kuchepetsa kukana kwa insulini, musakhale ndi mphamvu yofulumira kwambiri, yomwe ndiyosavuta kuyesa kudziletsa. Pankhaniyi, odwala omwe amalandila pioglitazone makamaka ayenera kuwongolera HbA1c kamodzi kamodzi miyezi itatu. Pokhapokha kukwaniritsa zomwe mukufuna glycated values (HbA1c