Pioglitazone a lura da ciwon sukari na 2

• KEYWORDS: ciwon sukari, hauhawar jini, tsibirin na Langerhans, hepatotoxicity, troglitazone, rosiglitazone, pioglitazone, Baeta

Babban mahimmancin kwayar cutar pathogenesis na nau'in ciwon sukari na 2 shine juriya na insulin (IR), wanda ke haifar da ba kawai zuwa hyperglycemia ba, har ma yana tsokani abubuwan haɗari don haɓaka cututtukan zuciya kamar hawan jini da jijiyoyin jini da dyslipidemia. Dangane da wannan, ƙirƙirar da amfani a cikin lura da marasa lafiya da kwayoyi kai tsaye suna shafar IR ƙaƙƙarfan jagora ne mai kyau a cikin lura da wannan mummunan cuta.

Tun 1996, a cikin lura da marasa lafiya da nau'in ciwon sukari na 2, an yi amfani da sabon aji na kwayoyi, haɗe da tsarin aikin su cikin rukuni na thiazolidinediones (TZD) ko insulin masu saka idanu (ciglitazone, rosiglitazone, darglitazone, troglitazone, pioglitazone, anglitazone gwargwadon ƙarfin hali), wadatar karɓar abin da ake so, an karɓi aikin ne na farko, an ƙara himma ne kawai, kyallen takarda zuwa insulin. Duk da yawan ɗakunan littattafai na 80-90s na karni na ƙarshe waɗanda aka keɓe don ingantaccen nazarin aminci da ingancin waɗannan mahadi, magunguna uku ne kawai daga wannan rukuni daga baya aka gabatar da su a cikin aikin asibiti - troglitazone, rosiglitazone da pioglitazone. Abin takaici, daga baya an dakatar da troglitazone don amfani saboda hepatotoxicity da aka bayyana yayin amfani da shi na tsawan lokaci.

A halin yanzu, ana amfani da magunguna biyu daga ƙungiyar TZD: pioglitazone da rosiglitazone.

Hanyar aikin thiazolidinediones

Babban tasirin warkewa na TZD a cikin nau'in ciwon sukari na 2 shine rage juriya na insulin ta hanyar ƙara ƙarfin jijiyar kyallen takarda zuwa insulin.

Insulin jurewar insulin (IR) ya bayyana tun kafin bayyanuwar asibiti game da ciwon sukari na 2. Rage hankalin mai kitse zuwa tasirin maganin kwayar cutar insulin yana haifar da hauhawar karuwa a cikin abubuwanda ke haifar da kitse na kitse (FFA) a cikin jini na jini. FFAs, bi da bi, suna ƙaruwa da juriya na insulin a matakin hanta da ƙwayar tsoka, wanda ke haifar da ƙara yawan gluconeogenesis da rage tasirin glucose ta waɗannan kyallen. A karkashin irin wannan yanayin, ƙwayoyin mai suna samar da adadin ƙwayar cytokines mai yawa (tumor necrosis factor a - TNF-a), interleukin (IL-6 da resistin), waɗanda ke haɓaka juriya na insulin kuma suna haɓaka atherogenesis. Haɓakar ƙwayoyin kitse na wani cytokine - adiponectin, wanda ke ƙara ƙarfin jijiyoyin sel zuwa insulin, yana raguwa.

Thiazolidinediones suna daɗaɗɗar ƙarfin ra'ayi na masu karɓar makamin nukiliya wanda ke gudana ta hanyar peroxisome mai haɓakawa - PPARg (peroxisome proliferators-receptor receptor), wanda ke cikin gidan abubuwan da ke rikodin abubuwan da ke sarrafa faɗar kwayoyin halittar da ke daidaita carbohydrate da ƙwayar lipid a cikin adipose da ƙwayar tsoka. Yawancin PPAR isoforms an san su: PPARa, PPARg (subtypes 1, 2) da PPARb / PPARd. PPARa, PPARg da PPARd, waɗanda ke taka muhimmiyar rawa a cikin dokar adipogenesis da IR. Tsarin halittar PPARγ a cikin dabbobi masu shayarwa masu yawa, haɗu da ɗan adam, yana kan chromosome na 3 (wuri 3p25). Ana karɓar mai karɓar PPARg a cikin ƙwayoyin mai da monocytes, ƙasa da ƙwaƙwalwar kasusuwa, hanta da kodan. Mafi mahimmancin rawar PPARg shine bambance bambancen ƙwayoyin tsopose nama. PPARg agonists (TZD) suna samar da ƙananan adipocytes waɗanda suka fi dacewa da insulin, waɗanda suke ɗaukar FFA sosai kuma suna tsara adadin mai da yawa a cikin ƙirar subcutaneous kuma ba ƙarancin mai gani mai gani ba (3). Bugu da ƙari, kunnawa na PPARg yana haifar da karɓar magana da canzawa da masu jigilar glucose (GLUT-1 da GLUT-4) zuwa membrane na sel, wanda ke ba da izinin jigilar glucose zuwa hanta da ƙwayoyin tsoka kuma don haka rage glycemia. A karkashin tasirin Pong agonists, samar da TNF-mai raguwa kuma bayyanar adiponectin yana ƙaruwa, wanda kuma yana ƙara haɓakar jijiyoyin ƙwayar cuta zuwa insulin (4).

Don haka, thiazolidinediones da farko haɓaka jijiyar nama zuwa insulin, wanda aka bayyana ta hanyar rage gluconeogenesis a cikin hanta, hanawar lipolysis a cikin adipose nama, raguwa a cikin FFA a cikin jini, da haɓakawa game da amfani da glucose a cikin tsokoki (Figure 1).

Thiazoldinediones basa motsa insulin kai tsaye. Koyaya, raguwar glucose jini da FFA a cikin jini yayin ɗaukar TZD yana rage tasirin glucose da tasirin lipotoxic akan ƙwayoyin b-sel da keɓaɓɓiyar ƙwayoyin cuta kuma, a tsawon lokaci, yana haifar da ingantaccen ɓoye insulin ta hanyar ƙwayoyin b-sel (5). Nazarin da Miyazaki Y. (2002) da Wallace T.M. (2004), sakamako mai kyau na TZD kai tsaye a kan aikin aikin sel Kwayoyin a cikin nau'i na raguwa a cikin apoptosis kuma an tabbatar da karuwa a cikin haɓaka (6, 7). A cikin binciken da Diani A.R. (2004) an nuna cewa gudanar da pioglitazone ga dabbobi masu dakin gwaje-gwaje tare da nau'in ciwon sukari na 2 sun ba da gudummawa ga kiyaye tsarin tsibirin na Langerhans (8).

Rage ƙarfin insulin juriya a ƙarƙashin tasirin pioglitazone an tabbatar da tabbaci a cikin binciken asibiti ta ƙididdige samfurin homeostasis na NOMA (9). Kawamori R. (1998) ya nuna haɓakawa a cikin ɗakunan ƙwayar ƙwayar ƙwayar nama a cikin kashi goma sha biyu na pioglitazone a kashi 30 MG / rana. idan aka kwatanta da placebo (1.0 mg / kg × min. vs 0.4 mg / kg × min, p = 0.003) (10). Nazarin da Benett S.M. et al. (2004), ya nuna cewa lokacin da aka yi amfani da TZD (rosiglitazone) na tsawon makonni 12 a cikin mutane masu fama da raunin glucose, ƙimar kulawar insulin ya karu da kashi 24.3%, yayin da tushen yanayin ƙwallon ƙafa, ya ragu da 18, 3% (11). A cikin binciken da ake sarrafawa na TRIPOD, sakamakon troglitazone akan hadarin kamuwa da cuta mai nau'in 2 a cikin matan Latin Amurka wadanda ke da tarihin cutar sankara ta mahaifa (12). Sakamakon aikin ya tabbatar da gaskiyar cewa a nan gaba haɗarin haɗarin kamuwa da cutar sukari nau'in 2 a cikin wannan rukuni na marasa lafiya an rage shi da 55%. Ya kamata a sani cewa faruwar nau'in ciwon sukari na 2 a shekara a kan troglitazone ya kasance 5.4% idan aka kwatanta da 12.1% da placebo. A cikin binciken PIPOD bude, wanda ya kasance ci gaba ne na binciken TRIPOD, pioglitazone ya kasance yana da alaƙa da rage haɗarin kamuwa da cutar sukari nau'in 2 (yawan sabbin cututtukan da aka gano a cikin nau'in ciwon sukari na 2 shine 4,6% a kowace shekara) (13).

Rage tasirin sukari-pioglitazone

Yawancin bincike game da amfani da asibiti na pioglitazone sun tabbatar da ingancinsa a cikin lura da marasa lafiya da ke dauke da ciwon sukari na 2.

Sakamakon binciken da aka sarrafa na multicenter placebo ya nuna cewa pioglitazone yadda yakamata yana rage glycemia duka a cikin monotherapy kuma a hade tare da sauran magunguna na maganin hypoglycemic, musamman tare da hanyoyin maganin metformin da sulfonylurea waɗanda aka yi amfani dasu sosai wurin maganin marasa lafiya da nau'in ciwon sukari na 2 (14, 15, 16, 17).

Tun daga watan Fabrairu na 2008, wani TZD, rosiglitazone, ba a ba da shawarar amfani dashi hade da insulin ba saboda haɗarin haɗarin ciwon zuciya. Dangane da wannan, matsayin yanzu na manyan masu binciken likitanci na Amurka da Turai, wanda aka nuna a cikin “Bayanin ra’ayi na kungiyar masu cutar sukari ta Amurka da kungiyar Turai don Nazarin ciwon sukari” na wannan shekarar, ba karamin abu bane, saboda yana ba da izinin amfani da insulin da pioglitazone a hade. Babu shakka, irin wannan bayanin yana dogara ne akan bayanai daga mummunan nazarin asibiti. Don haka, makaho mai sau biyu, bazuwar, binciken sarrafawa wanda Matoo V ya jagoranta a cikin 2005 tare da marasa lafiya 289 da ke da nau'in ciwon sukari na 2 sun nuna cewa ƙari na pioglitazone zuwa maganin insulin yana haifar da raguwa mai yawa a cikin gemocated haemoglobin (HbA1c) da azumin glycemia (18) . Koyaya, yana da matukar damuwa cewa, a bango na maganin haɗin gwiwa a cikin marasa lafiya, an lura da yawan lokuta mafi yawan cututtukan cututtukan jini. Bugu da ƙari, karuwar nauyin jikin mutum a kan asalin insulin monotherapy ya kasance ƙasa da lokacin da aka haɗu da pioglitazone (0.2 kg vs. 4.05 kg). A lokaci guda, haɗin pioglitazone tare da insulin yana tare da haɓaka masu tasiri a cikin rawar jini na jini da matakan alamun alamun haɗarin cututtukan zuciya (PAI-1, CRP). Shortan taƙaitaccen lokacin wannan binciken (watanni 6) bai ba da izinin nazarin sakamakon cututtukan zuciya ba. Idan akai la'akari da wani haɗarin haɗarin bugun zuciya tare da haɗarin rosiglitazone tare da insulin, a cikin al'adarmu ba mu haɗarin haɗuwa da ƙarshen tare da pioglitazone har sai an sami ingantaccen bayani game da cikakken amincin irin wannan magani.

Tasirin pioglitazone akan abubuwan haɗari don cutar zuciya

Baya ga tasirin hypoglycemic, TZD kuma yana iya samun tasiri mai kyau a cikin wasu abubuwan haɗari don haɓaka cututtukan zuciya. Muhimmiyar mahimmanci shine tasirin kwayoyi a cikin ganyayyaki na jini. A cikin binciken da yawa da aka gudanar a cikin 'yan shekarun nan, an nuna pioglitazone yana da amfani mai amfani ga matakan lipid. Don haka, binciken da Goldberg R.B. ya gudanar (2005) da Dogrell S.A. (2008) ya nuna cewa pioglitazone lowers triglycerides (19, 20). Bugu da ƙari, pioglitazone yana ƙaruwa matakin ƙwayar rigakafin atherogenic na babban sinadarin lipoprotein cholesterol (HDL). Waɗannan bayanan sun yi daidai da sakamakon binciken Proactive (PROspective pioglitAzone Clinical Trial In macroVascular Events), a cikin abin da 5238 marasa lafiya da ke da nau'in ciwon sukari na 2 da kuma tarihin rikice-rikice na macrovascular suka halarci shekaru 3. Haɗin pioglitazone tare da abincin abinci da wakilai na hypoglycemic na baki a cikin tsawon shekaru 3 na kallo ya haifar da karuwar 9% a cikin matakan HDL da raguwar 13% a cikin triglycerides idan aka kwatanta da na farkon. Gaba ɗaya mace-mace, haɗarin haɓaka rashin ƙarfi na rauni mai rauni da haɗarin cerebrovascular tare da yin amfani da pioglitazone ya ragu sosai. Yiwuwar yanayin waɗannan abubuwan a cikin mutane masu karɓar pioglitazone ya ragu da 16%.

Sakamakon binciken CHICAGO (2006) da kuma aikin Langenfeld M.R. et al. (2005) (21), ya nuna cewa tare da gudanar da pioglitazone, kauri daga bangon bugun jini yana raguwa kuma, saboda haka, ci gaban atherosclerosis yana raguwa. Nazarin gwaji na Nesto R. (2004) yana nuna ci gaba a cikin ayyukan gyaran ventricle na hagu da murmurewa bayan ischemia da sake farfadowa tare da amfani da TZD (22). Abin takaici, tasirin waɗannan canje-canje masu ƙwaƙwalwa mai kyau akan sakamakon jijiyoyin jini na dogon lokaci ba a yi nazari ba, wanda babu shakka yana rage mahimmancin asibiti.

Matsanancin sakamako na pioglitazone

A duk nazarin karatun asibiti, pioglitazone, har ma da sauran TZD, yana tare da haɓaka nauyin jikin mutum ta hanyar kilogiram 0.5-3.7, musamman a farkon watanni 6 na jiyya. Bayan haka, nauyin marasa lafiya ya dage.

Tabbas, ƙimar nauyi shine mummunan sakamako wanda ba a ke so ba na kowane magani a cikin lura da marasa lafiya da ke da nau'in ciwon sukari na 2, saboda Mafi yawan marasa lafiya suna da kiba ko kiba. Koyaya, yana da mahimmanci a jaddada cewa yawan ƙwayar pioglitazone yana haɗuwa, akasari, ta hanyar ƙaruwa da kitsen subcutaneous, yayin da yawan kitsen visceral a cikin marasa lafiya da ke karɓar TZD yana raguwa. A takaice dai, duk da girman nauyin lokacin shan pioglitazone, haɗarin haɓaka da / ko ci gaba da cututtukan zuciya baya ƙaruwa (23). Yana da mahimmanci a lura cewa matakin ƙaruwar nauyin jiki kai tsaye yana daidaita tare da haɗin gwiwa na rage sukari, i.e. karin nauyi yana da girma a cikin marasa lafiya da ke karɓar haɗin TZD tare da insulin ko sulfonylureas, da ƙananan tare da metformin.

A kan asalin jiyya tare da pioglitazone, 3-15% na marasa lafiya suna fuskantar riƙewar ruwa, abubuwan da ba a fahimta sosai ba. Don haka, akwai wani ra'ayi wanda sakamakon raguwa a cikin fitar sodium excretion da haɓaka riƙewar ruwa, haɓaka ƙarar jini yana gudana. Bugu da kari, TZD na iya ba da gudummawa ga jijiyoyin jijiyoyin jiki tare da karuwa mai zuwa a cikin karin kwayoyin halittar ruwa (22). Yana tare da wannan gefen sakamako na TZD cewa lalacewar zuciya yana haɗuwa. Don haka, a cikin babban binciken PROactive, yawan sabbin lokuta da aka gano na cututtukan zuciya na nakasa tare da pioglitazone therapy ya kasance mafi girma sama da placebo (11% vs 8%, p 7% watanni uku bayan farawa na rage sukari shine dalilin don ƙirƙirar aƙalla haɗuwa na rage yawan sukari. far.

An tantance tasirin pioglitazone, kamar sauran TZD, gwargwadon matakin HbA1c. Cancantar kashi da kuma tasirin sauran kwayoyi masu rage sukari da ke aiki don hana gluconeogenesis ko kuma tayar da insulin ta hanyar kwayoyin namu na iya tabbatuwa ta hanyar ingantacciyar hanyar daga tasoshin glint ko postprandial glycemia. TZD, sannu a hankali yana rage juriya na insulin, ba su da irin wannan tasirin hypoglycemic mai sauri, wanda yake mai sauƙin kimantawa tare da kula da gida. A wannan batun, marasa lafiya da ke karɓar ƙwayar pioglitazone musamman suna buƙatar sarrafa HbA1c aƙalla sau ɗaya a kowane watanni uku. Idan babu nasarar cimma manufar glycated darajar (HbA1c