• Korean Journal of Clinical Pharmacy
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• v.18 no.1
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• pp.6-10
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• 2008

This study investigated the effect of long-term administration of pioglitazone on the pharmacokinetics of verapamil in rats. Pharmacokinetic parameters of verapamil were determined after oral administration of verapamil (9 mg/kg) in rats coadministered pioglitazone (0.5 mg/kg) or pretreated with pioglitazone (0.5 mg/kg) for 3 and 9 days. Compared to oral control group, the presence of pioglitazone significantly (p<0.05) increased the area under the plasma concentration-time curve (AUC) of verapamil by 48.6% (coad), 61.1% (3 days) and 56.5% (9 days), and the peak concentration($C_{max}$) by 65.1% (coad), 76.8% (3 days) and 66.4% (9 days). The absolute bioavailability (AB%) of verapamil was significantly (p<0.05) higher by 6.2% (coad), 6.7% (3 days), 6.5% (9 days) compared to control (4.2%), and presence of pioglitazone was no significant change in the terminal half-life ($t_{1/2}$) and the time to reach the peak concentration($T_{max}$) of verapamil. Our results indicate that pioglitazone significantly enhanced oral bioavailability of verapamil in rats, implying that presence of pioglitazone could be effective to inhibit the CYP3A4-mediated metabolism of verapamil in the intestine. Drug interactions should be considered in the clinical setting when verapamil is coadministrated with pioglitazone.

• Polymer(Korea)
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• v.34 no.6
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• pp.527-533
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• 2010

The pioglitazone loaded poly(lactide-co-glycolide)(PLGA) nanospheres were prepared by emulsion-evaporation method and optimized for particle size and entrapment efficiency. The optimized particles were 125~170 nm in size with narrow size distribution and showed above 85% entrapment efficiency at 30% of pioglitazone loading when prepared with 3% w/v of poly(vinyl alcohol) (PVA) as a surfactant. These particulate carriers exhibited a controlled in vitro release of pioglitazone for 40 days at a nearly constant rate. The pioglitazone loaded PLGA nanospheres were not only effective to reduce the blood sugar level of diabetic rats but also non-toxic for the animal body, in particular for sensitive organs like kidney, liver, heart, lung and spleen. These results indicate that PLGA nanospheres have a great potential for oral delivery of pioglitazone.

• Journal of Korean Neurosurgical Society
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• v.63 no.6
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• pp.689-697
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• 2020

Objective : Cerebral edema is the predominant mechanism of secondary inflammation after intracerebral hemorrhage (ICH). Pioglitazone, peroxisome proliferator-activated receptor gamma agonist has been shown to play a role in regulation of central nervous system inflammation. Here, we examined the pharmacological effects of pioglitazone in an ICH mouse model and investigated its regulation on NLRP3 inflammasome and glucose metabolism. Methods : The ICH model was established in C57 BL/6 mice by the stereotactical inoculation of blood (30 µL) into the right frontal lobe. The treatment group was administered i.p. pioglitazone (20 mg/kg) for 1, 3, and 6 days. The control group was administered i.p. phosphate-buffered saline for 1, 3, and 6 days. We investigated brain water contents, NLRP3 expression, and changes in the metabolites in the ICH model using liquid chromatography-tandem mass spectrometry. Results : On day 3, brain edema in the mice treated with pioglitazone was decreased more than that in the control group. Expression levels of NLRP3 in the ICH model treated with pioglitazone were decreased more than those of the control mice on days 3 and 7. The pioglitazone group showed higher levels of glycolytic metabolites than those in the ICH mice. Lactate production was increased in the ICH mice treated with pioglitazone. Conclusion : Our results demonstrated less brain swelling following ICH in mice treated with pioglitazone. Pioglitazone decreased NLRP3-related brain edema and increased anaerobic glycolysis, resulting in the production of lactate in the ICH mice model. NLRP3 might be a therapeutic target for ICH recovery.

• Molecular & Cellular Toxicology
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• v.4 no.1
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• pp.72-77
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• 2008

The present study was undertaken to determine whether pioglitazone treatment influences on the agonist-induced vascular smooth muscle contraction and, if so, to investigate the related mechanism. The measurement of isometric contractions using a computerized data acquisition system was combined with molecular experiments. Pioglitazone decreased Rho-kinase activating agonist-induced contraction but not phorbol ester-induced contraction suggesting the least involvement of $Ca^{2+}$-independent thin filament regulation of contractility. Furthermore, pioglitazone decreased thromboxane $A_2$ mimeticinduced phosphorylation of MYPT1 at Thr855, the newly-highlighted site, instead of Thr696. In conclusion, this study provides the evidence and possible related mechanism concerning the vasorelaxing effect of pioglitazone as an antihypertensive on the agonist-induced contraction in rat aortic rings regardless of endothelial function.

• YAKHAK HOEJI
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• v.53 no.6
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• pp.357-367
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• 2009

A meta-analysis of 63 randomized controlled trials of Pioglitazone and Rosiglitazone in patients with type 2 diabetes was conducted. Pioglitazone significantly lowered fasting plasma glucose and triglyceride (TG) level and increased high-density lipoprotein cholesterol (HDL) level. Rosiglitazone significantly lowered hemoglobin A1C level and fasting plasma glucose, whereas it increased all kinds of lipids (HDL, LDL (low-density lipoprotein cholesterol), TG, total cholesterol). In comparison, glucose lowering effect was higher in Rosiglitazone, and Pioglitazone produced a more favorable lipid profile.

• Clinical and Experimental Reproductive Medicine
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• v.38 no.2
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• pp.98-102
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• 2011

Objective: To investigate the effects of pioglitazone on controlled ovarian stimulation (COS), IVF outcomes, and follicular fluid (FF) cytokine concentrations in patients with polycystic ovary syndrome (PCOS). Methods: Eighty-six infertile patients with PCOS resistant to clomiphene citrate were randomized to receive pioglitazone (30 mg/day) or placebo on the starting day of oral contraceptive (OC) pretreatment, followed by an IVF protocol using a GnRH antagonist. Pioglitazone or placebo was administered once daily from the starting day of OC to the day of hCG injection. Results: Total dose and days of recombinant follicle-stimulating hormone administered, and the numbers of retrieved and mature oocytes, were significantly lower in the pioglitazone group than in the control group. FF tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and interleukin-6 (IL-6) concentrations at oocyte retrieval were also significantly lower in the pioglitazone group. The clinical pregnancy rate was higher and the incidence of severe ovarian hyperstimulation syndrome was lower in the pioglitazone group, but the differences were not statistically significant. Conclusion: Pioglitazone reduces FF TNF-${\alpha}$ and IL-6 levels, and may improve ovarian response to COS in patients with PCOS.

• Clinical and Experimental Reproductive Medicine
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• v.32 no.2
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• pp.155-164
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• 2005

Objective: This study was performed to investigate the effects of pioglitazone, an insulin sensitizing agent, on insulin resistance, ovarian function and intraovarian stromal blood flow in patients with polycystic ovarian syndrome (PCOS). Material and Methods: Thirty patients with PCOS, aged 18~34 years, were recruited. Criteria for diagnosis of PCOS were as defined in 2003 Rotterdam consensus. They were treated for 6 months with pioglitazone at a dose of 30 mg/day orally. The hormonal blood profile, fasting serum glucose levels, a glycemic response to 75 g oral glucose tolerance test (OGTT), and an ovarian stromal artery (OSA) blood flow were assessed at baseline and after 6 months of treatment. Results: Eighteen (60.0%) of 30 patients treated with pioglitazone demonstrated a spontaneous ovulation After pioglitazone treatment, fasting insulin concentrations, serum glucose levels after 75 g OGTT significantly decreased (p=0.001, p=0.04, respectively), and fasting glucose to insulin (G/I) ratio significantly increased (p<0.001). The pioglitazone treatment induced a significant reduction in serum LH, testosterone (T) and free T levels (p<0.001, p=0.02, p=0.002, respectively). The resistance index (RI) values of OSA significantly increased after treatment (p<0.001). In analyzing pioglitazone-treated patients according to their body mass index (BMI), nonobese group as well as obese group showed a significant improvement in fasting G/I ratio (p<0.01). The pioglitazone treatment induced a significant reduction in serum LH and free T levels in nonobese group (p<0.001, p<0.05, respectively) as well as obese group (p=0.001, p<0.05, respectively). The RI values of OSA significantly increased in both nonobese and obese groups after pioglitazone treatment (p<0.001, p=0.003, respectively). Conclusions: Pioglitazone could ameliorate the glycoinsulinemic metabolism, and this beneficial effects of this drug could improve the endocrine-reproductive condition associated with the decrease of ovarian stromal artery blood flow, in both nonobese and obese patients with PCOS.

• Analytical Science and Technology
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• v.22 no.1
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• pp.101-108
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• 2009

The bioequivalence of two pioglitazone tablets, Actos$^{(R)}$ tablet (Takeda Chemical Industries, reference drug) and Pioglitazone tablet (Boryung Company, test drug) was evaluated according to the guidelines of Korea Food and Drug Administration. Twenty-eight healthy male Korean volunteers received each medicine (pioglitazone dose of 30 mg) in a $2{\times}2$ crossover study with one week washout interval. After drug administration, blood samples were collected at specific time intervals from 0-36 hours. The plasma concentrations of pioglitazone were determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The total chromatographic run time was 5 min and calibration curves were linear over the concentration range of 5-2000 ng/mL for pioglitazone. The method was validated for selectivity, sensitivity, linearity, accuracy and precision. The pharmacokinetic parameters were determined from the plasma concentration-time profiles of both formulations. The primary calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the two preparations. The 90% confidence intervals of the $AUC_t$ ratio and the $C_{max}$ ratio for Pioglitazone tablet and Actos$^{(R)}$ tablet were log0.9422~log1.1040 and log0.9200~log1.1556, respectively. Based on the statistical considerations, we can conclude that the test drug, Pioglitazone tablet was bioequivalent to the reference drug, Actos$^{(R)}$ tablet.

• Polymer(Korea)
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• v.32 no.2
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• pp.143-149
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• 2008

We synthesized PEG-PLA (or PLGA) amphiphilic di-block copolymers, which consist of PEG as biocompatible and hydrophilic block and PLA (or PLGA) as biodegradable and hydrophobic block, by ring opening polymerization of LA in the presence of methoxy PEG as a macroinitiator. The compositions and the molecular weights of the copolymers were controlled by changing the feed ratio of LA (and GA) to PEG initiator. The di-block copolymers could self-assemble in aqueous media to form micellar structure. A hydrophobic model drug, pioglitazone, was loaded into the polymer micelle using solid dispersion and dialysis methods, and the drug-loaded micelles were characterized by AFM, DLS and HPLC measurements. The drug loading capacity and in vitro release studies were performed and evaluated under various conditions. These results indicated that the amphiphilic di-block copolymers of PEG-PLA (or PLGA) could solubilize pioglitazone by solid dispersion method and the drug release was modulated according to micellar chemical compositions.

• Biomolecules & Therapeutics
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• v.21 no.1
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• pp.84-88
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• 2013

High risk of cardiovascular diseases caused by existing PPAR-${\gamma}$ agonists such as rosiglitazone and pioglitazone has been recently reported. CKD-501 is a novel selective PPAR-${\gamma}$ agonist as a potential target to reduce cardiovascular risk in non-insulin dependent diabetes mellitus (NIDDM). In this study, We investigated potential cardiotoxicity of CKD-501 and compared its toxicity with that of rosiglitazone or pioglitazone using db/db mice. After 12-week repeated administration of CKD-501 at doses of 3, 10 and 30 mg/kg/day or rosiglitazone at doses of 10 and 30 mg/kg/day or pioglitazone at doses of 200 and 540 mg/kg/day, animals were sacrificed for investigation of potential toxicities. Diameters of left ventricles and areas of cardiomyocytes were measured. And lipid accumulation and apoptosis in heart muscle were examined by oil red O staining and TUNEL staining, respectively. Diameters of left ventricles were significantly increased in high dose treatment group of pioglitazone compared to control (p<0.05), while other groups showed a tendency for an increase. All test articles induced significantly the increase of area of cardiomyocytes in heart compared to control (p<0.01), in regular order as pioglitazone > CKD-501 ${\geq}$ rosiglitazone. However, lipid accumulation and apoptotic changes in heart were not observed in all dosing groups. Taken together, the myocardial cell hypertrophy of CKD-501 are relatively lower than that of pioglitazone and similar to rosiglitazone. And it is suggested that the myocardial cell hypertrophy of CKD-501 are less adverse in clinical use for the management of the NIDDM.