Pioglitazone n'ịgwọ ụdị ọrịa shuga 2

• AMAOKWU: oria shuga, hyperglycemia, agwaetiti nke Langerhans, hepatotoxicity, troglitazone, rosiglitazone, pioglitazone, Baeta

Usoro dị mkpa nke pathogenesis nke ọrịa shuga 2 bụ insulin resistance (IR), nke na-eduga ọ bụghị naanị hyperglycemia, kamakwa na-akpalite ihe ndị dị ize ndụ maka mmepe nke ọrịa obi dị ka ọbara mgbali elu na dyslipidemia. N'akụkụ a, ịmepụta na iji ya na ọgwụgwọ nke ndị ọrịa nwere ọgwụ ọjọọ na-emetụta IR bụ ụzọ na-ekwe nkwa na ọgwụgwọ nke ọrịa a siri ike.

Kemgbe 1996, na usoro ọgwụgwọ nke ndị ọrịa nwere ụdị ọrịa shuga 2, ejirila ọgwụ ọhụrụ mee ihe, jikọtara ya na usoro nke usoro ha n'ime otu nke thiazolidinediones (TZD) ma ọ bụ insulin na-ahụ maka (ciglitazone, rosiglitazone, darglitazone, troglitazone, pioglitazone, anglitazone nke na-abawanye uru) anụ ahụ ka insulin. N’agbanyeghi otutu akwukwo nke ihe omumu nke 80-90 nke oge ikpeazu eweputara na omumu ihe banyere nchekwa na odi nma nke ihe ndi a, obu ogwu ato sitere n’otu a ka emeziri ka emesia na omume ulo ogwu - troglitazone, rosiglitazone na pioglitazone. Na nwute, esochikwara troglitazone maka ojiji ahụ kpatara ọrịa hepatotoxic gosipụtara n'oge eji ogologo oge.

Ugbu a, a na-eji ọgwụ abụọ sitere na otu TZD: pioglitazone na rosiglitazone.

Usoro nke thiazolidinediones

Mmetụta ọgwụgwọ bụ isi nke TZD na ụdị shuga nke abụọ bụ iji belata nguzogide insulin site na ịbawanyewanye ngwa ngwa anụ ahụ na insulin.

Nlegide insulin (IR) putara ogologo oge tupu oge ngosiputa ogwu nke udiri oria abuo. Mmetụta dị nro nke mkpụrụ ndụ abụba na mmetụta ọgwụ antilipolytic na insulin na-eduga na mmụba na-adịghị ala ala nke ọdịnaya abụba n'efu (FFA) na plasma ọbara. FFA, n'aka nke ya, na-abawanye nguzogide insulin na ọkwa nke imeju na akwara anụ ahụ, nke na-eduga n'ịba ụba gluconeogenesis na mbelata mgbatị ume site na anụ ahụ. N'okpuru ọnọdụ ndị dị otú ahụ, mkpụrụ ndụ abụba na-emepụta oke ibu nke cytokines (tumor necrosis factor a - TNF-a), interleukin (IL-6 na resistin), nke na-eme ka mmegide insulin dị adị ma na-akpali atherogenesis. Mmepụta ahụ site na mkpụrụ ndụ abụba nke cytokine ọzọ - adiponectin, nke na-eme ka ohere anụ ahụ dị na insulin belata.

Thiazolidinediones bụ ndị nwere mmetụta dị elu na ihe ndị na - anabata ihe ndị na - ewepụta ngwa ngwa nuklia site na peroxisome proliferator - PPARg (peroxisome proliferators-activation receptor), nke bụ nke ezinụlọ nke ihe ntụgharị na-achịkwa ịkọwapụta mkpụrụ ndụ ihe nketa nke na-achịkwa carbohydrate na akwara metabolism na adipose na akwara anụ ahụ. Ọtụtụ ihe ndị na-ekewapụ PPAR iche: PPARa, PPARg (ụdị 1, 2) na PPARb / PPARd. PPARa, PPARg na PPARd, ndị na-arụ ọrụ dị mkpa na usoro adipogenesis na IR. Ihe omumu PPAR in na otutu oke anumanu, tinyere mmadu, di na chromosome nke ato (locus 3p25). A na-egosipụtakarị ihe nnabata nke PPARg na sel abụba na monocytes, ọ dị obere n'ọkpụkpụ akwara, akwara na akụrụ. Ọrụ kachasị dị mkpa nke PPARg bụ ọdịiche dị n'etiti sel anụ adipose. PPARg agonists (TZD) na - ewepụta obere adipocytes nke nwere nlebara anya karị na insulin, nke na - etinye FFA n'ọrụ ma na - edozi oke abụba na subcutaneous na-abụghị visceral fatty tissue (3). Na mgbakwunye, ịgbalite PPARg na-eduga n'ịbawanye ụba ma na-ebugharị ndị na-ebugharị glucose (GLUT-1 na GLUT-4) gaa na mkpụrụ ndụ, nke na-enye ohere ibuga glucose na akwara na akwara mkpụrụ ndụ ma si otú ahụ belata glycemia. N'okpuru mmetụta nke ndị agonists PPARg, mmepụta nke TNF-mbelata yana ngosipụta nke adiponectin na-abawanye, nke na-emekwa ka nkwupụta nke anụ ahụ dị na insulin (4).

Ya mere, thiazolidinediones na-emeziwanye oghere anụ ahụ na insulin, nke gosipụtara site na mbelata gluconeogenesis na imeju, mgbochi nke lipolysis na adipose anụ ahụ, mbelata nke mkpokọ FFA n'ọbara, yana nkwalite na ojiji nke glucose na uru ahụ (ọgụgụ 1).

Thiazoldinediones anaghị akpali insulin insulin ozugbo. Agbanyeghị, mbelata nke glucose ọbara na FFA n’ime ọbara mgbe ị na-ewere TZD na-ebelata glucose na mmetụta lipotoxic na mkpụrụ ndụ b na sel anụ ahụ, ka oge na-aga, ọ na-eduga n’inweta insulin na mma site na mkpụrụ ndụ b (sel 5). Ọmụmụ nke Miyazaki Y. (2002) na Wallace T.M. (2004), mmetụta dị mma nke TZD na arụ ọrụ ọrụ nke b-sel n'ụdị mbelata apoptosis na mmụba na ụba ha pụtara ihe (6, 7). N'ime ọmụmụ nke Diani A.R. (2004) egosiputara na ochichi nke pioglitazone nye umu anumanu ulo oria nke nwere oria nke abuo nyere aka na ichekwa ihe banyere agwaetiti nke Langerhans (8).

Ekwenyesiri ike na mbelata insulin na-emegide ihe nke pioglitazone na nyocha ụlọ ọgwụ site na ịtụle ihe NOMA homeostasis nlereanya (9). Kawamori R. (1998) gosipụtara mmezi ọrịre glucose anụ ahụ na -emegide ọgwụ kwa izu iri na abụọ n’ime podiglitazone na dose nke 30 mg / ụbọchị. atụnyere placebo (1.0 mg / kg × min. vs. 0.4 mg / kg × min, p = 0.003) (10). Ọmụmụ nke Benett S.M. et al. (2004), gosiputara na oge ejiri TZD (rosiglitazone) were izu iri na abụọ n'ime ndị nwere nnabata glucose, ihe ntụgharị insulin na-abawanye site na 24.3%, ebe ndị nọ n'ọnọdụ pọd ahụ, ọ belatara 18, 3% (11). N'ime ọmụmụ ihe a na-achịkwa nke TRIPOD, mmetụta nke troglitazone na ihe ize ndụ nke ụdị ọrịa shuga 2 na ụmụ nwanyị Latin America nwere akụkọ banyere ọrịa shuga na-amụ (12). Nsonaazụ nke ọrụ ahụ gosipụtara n'eziokwu ahụ na n'ọdịniihu ihe ọghọm nke ibute ọrịa shuga indị nke abụọ na ndị otu a belata 55%. Ọ kwesiri iburu n'uche na ihe kpatara ụdị ọrịa shuga 2 kwa afọ megide troglitazone bụ 5.4% ma e jiri ya tụnyere 12.1% megide placebo. Na nyocha PIPOD mepere emepe, nke bụ ihe na-aga n'ihu na nyocha nke TRIPOD, pioglitazone jikọtara ya na belata ihe egwu nke ịrịa ọrịa shuga 2 (ugboro ole ndị ọrịa chọpụtara ụdị shuga dị iche iche bụ 4.6% kwa afọ) (13).

Mmetụta shuga na-ebelata pioglitazone

Ọtụtụ nnyocha ọmụmụ pioglitazone gosipụtara n'ịgwọ arụmọrụ ya n'ọgwọ nke ndị ọrịa nwere ụdị shuga 2.

Nsonaazụ nke ọmụmụ ihe na - achịkwa ọtụtụ ebe egosila na pioglitazone belata glycemia ma na monotherapy yana yana ọgwụ hypoglycemic nke ọgwụ ọnụ, ọkachasị na metformin na sulfonylurea usoro eji n'ọtụtụ ebe n'ọgwụgwọ ndị ọrịa nwere ụdị shuga 2 (14, 15, 16, 16) 17).

Kemgbe ọnwa Febụwarị afọ 2008, akwadoghị TZD ọzọ, rosiglitazone maka iji ya na insulin n'ihi ihe ọghọm nke ọrịa obi afọ. N'akụkụ a, ọnọdụ ndị isi diabetologists nke USA na Europe, gosipụtara na "nkwupụta nkwenye nke ndị America Ọrịa shuga na European Association maka Ọrịa Ọrịa mamịrị" maka afọ a, bụtụtụghị anya, n'ihi na na-enye ohere ojiji insulin na pioglitazone jikọtara ọnụ. N'ụzọ doro anya, nkwupụta dị otú ahụ sitere na data sitere na ọmụmụ ihe gbasara ụlọ ọgwụ dị egwu. Ya mere, omumu ihe omimi nke gbara okpukpu abuo, ihe nlere anya nke puru iche, nke Matoo V nke emere na 2005 na ndi mmadu 289 nwere oria 2 gosiputara na ntinye nke pioglitazone na insulin na-eduga na mbelata ihe omimi glycated (HbA1c) na ibu onu glycemia (18) . Agbanyeghị, ọ bụ ihe dị egwu na, na-emegide nzụlite nke njikọta ọgwụ na ndị ọrịa, a na-ahụkarị ọrịa hypoglycemia nke ukwuu. Na mgbakwunye, mmụba nke ahụ mmadụ na ndabere nke insulin monotherapy dị ala karịa mgbe ejikọtara ya na pioglitazone (0.2 n'arọ vs. 4.05 n'arọ). N'otu oge ahụ, ngwakọta nke pioglitazone na insulin jikọtara ya na ezigbo mgbanwe n'ọdịdị ọbara na ọkwa nke akara nke ihe ize ndụ obi (PAI-1, CRP). Oge dị mkpirikpi nke ọmụmụ a (ọnwa 6) ekweghị ka nyocha nke nsonaazụ obi. N'ịtụle otu ihe ọghọm nke ọrịa obi ọrịa na ngwakọta nke rosiglitazone na insulin, na omume anyị anyị anaghị etinye ihe isi ike na njikọta nke pioglitazone ruo mgbe enwetara ihe ọmụma a pụrụ ịdabere na ya banyere nchekwa zuru oke nke ọgwụgwọ dị otú ahụ.

Mmetụta nke pioglitazone na ihe ndị dị ize ndụ maka ọrịa obi

Na mgbakwunye na mmetụta belata shuga, TZD nwekwara ike inwe mmetụta dị mma n'ọtụtụ ihe egwu maka mmepe nke ọrịa obi. Ihe kacha dị mkpa bụ mmetụta ọgwụ nwere ike ị nweta n'ọdịdị nke ọbara. N'ọtụtụ ọmụmụ emere n'ime afọ ndị na-adịbeghị anya, egosipụtara pioglitazone nwere mmetụta bara uru na ọkwa lipid. Yabụ, nyocha nke Goldberg R.B. (2005) na Dogrell S.A. (2008) gosiri na pioglitazone lowers triglycerides (19, 20). Na mgbakwunye, pioglitazone na-abawanye ọkwa nke mgbochi atherogenic nke nnukwu protein lipoprotein cholesterol (HDL). Ihe omuma ndi a kwekọrọ na nsonaazụ nke ihe omumu nke Proactive (PROspective pioglitAzone Clinical Trial In macroVascular Events), ebe ndi mmadu 5238 nwere oria 2 na akuko nke nsogbu akuko banyere akuko sonyere na afo ato. Nchikota pioglitazone ya na nri nri ya na onodu hypoglycemic onu ka oge nke afo ato mere ka mgbakwunye nke 9% na ọkwa HDL na mbelata 13% na triglycerides ma e jiri ya tụnyere nke mbu. N'ozuzu oke onwu, nsogbu nke ibute ọrịa myocardial infarction na nnukwu ọrịa ọrịa ụbụrụ iji pioglitazone belatara nke ukwuu. Ohere zuru oke nke ihe omume ndị a na ndị na-anata pioglitazone belatara site na 16%.

Nsonaazụ nke ihe omumu nke CHICAGO (2006) na oru nke Langenfeld M.R. et al. (2005) (21), gosipụtara na site na nchịkwa nke pioglitazone, ọkpụrụkpụ nke mgbidi vaskụla na-ebelata ma, yabụ, mmepe nke atherosclerosis na-adalata. Nnyocha nyocha nke Nesto R. (2004) na-egosi mmụba na usoro nke idozi ventricle aka ekpe na mgbake mgbe ischemia na ị nweta ike iji TZD (22). O di nwute, na uto mgbanwe mgbanwe omumu ndia di nma na obi uto akaghi anya, nke n’enweghi ntukwasi obi idilata ogwu ha.

Mmetụta ndị nwere ike ịmetụta pioglitazone

Na nyocha niile nke ụlọ ọgwụ, pioglitazone, yana TZD ndị ọzọ, mmụba na-abawanye aru site na 0,5-3.7 n'arọ, ọkachasị na ọnwa 6 mbụ nke ọgwụgwọ. Mgbe nke a gasịrị, ịdị arọ nke ndị ọrịa kwụsịrị.

N’ezie, ịba ụba bụ ihe mmetụta adịghị njọ n’akụkụ ọ bụla nke ọgwụ ọ bụla na ọgwụgwọ ndị ọrịa nwere ụdị shuga 2, n’ihi imirikiti ndị ọrịa buru oke ibu ma ọ bụ bu oke ibu. Agbanyeghị, ọ dị mkpa imesi ike na a na-ejikọ pioglitazone, ọkachasị, site na mmụba nke abụba subcutaneous, ebe ọnụọgụ visceral na ndị ọrịa na-anata TZD na-ebelata. N'ikwu ya, n'agbanyeghị oke ibu mgbe ị na-ewere pioglitazone, ihe ize ndụ nke ịmalite na / ma ọ bụ inwe ọrịa obi anaghị arị elu (23). Ọ dị mkpa ịmara na ogo nke mmụba anụ ahụ na-adabaghị na usoro ọgwụgwọ na-ebelata shuga, i.e. Iba ibu karie na ndị ọrịa na-anata mkpokọta nke TZD yana insulin ma ọ bụ ọgwụ sulfonylurea, na obere metformin.

Na agbanyeghị usoro ọgwụgwọ na pioglitazone, 3-15% nke ndị ọrịa na-enweta njigide mmiri, ihe ndị a na-aghọtaghị nke ọma. Yabụ, enwere echiche na n'ihi mbelata nke mmiri sodium na mmụba na njigide mmiri, mmụba nke olu na-emegharị ọbara na-eme. Na mgbakwunye, TZD nwere ike itinye aka na vasodilation akwara na mmụba na-esote olu mmiri extracellular (22). Ọ bụ na nsonaazụ n'akụkụ a nke TZD ka enwere nkụchi obi mgbada. Yabụ, n'ọtụtụ ọmụmụ ihe PROactive, ugboro ole ndị ọrịa chọpụtara ọhụụ nke ọrịa obi ọrịa na pioglitazone ọgwụgwọ dị elu karịa na placebo (11% vs 8%, p 7% ọnwa atọ mgbe mmalite hypoglycemic ọgwụgwọ bụ ihe kpatara ịdepụta opekempe hypoglycemic hypoglycemic. ọgwụ.

A na-enyocha arụmọrụ nke pioglitazone, yana TZD ndị ọzọ site na ọkwa HbA1c. Ekwesiri ịpụta oke nke ogo ahụ na arụmọrụ nke ọgwụ shuga ndị ọzọ na - eme ka gluconeogenesis ma ọ bụ iji mee ka insulin na - arụ ọrụ nke mkpụrụ ndụ nke anyị nwere ike ikpebi nke ọma site na mgbanwe dị mma site na basal ma ọ bụ postprandial glycemia. TZD, jiri nwayọ belata nguzogide insulin, enweghi mmetụta hypoglycemic dị ngwa, nke dị mfe iji nyochaa njikwa onwe onye n'ụlọ. N'akụkụ a, ndị ọrịa na-anakwere pioglitazone kwesịrị nchịkwa nke HbA1c ọbụlagodi otu ọnwa atọ. Na enweghị nke rụzuru nke lekwasịrị glycated ụkpụrụ (HbA1c