Explore the vast range of titles available.

Evogliptin is a newly developed oral glucose-lowering medication of the dipeptidyl peptidase 4 (DPP-4) inhibitor class for type 2 diabetes mellitus. The combination of a DPP-4 inhibitor with pioglitazone is a promising therapeutic option. The aim of the present study was to evaluate the pharmacokinetic and pharmacodynamic interaction between evogliptin and pioglitazone. A randomized, open-label, multiple-dose, three-treatment, three-period, six-sequence crossover study was conducted in healthy Korean male subjects. All subjects received evogliptin 5 mg once daily for 7 days (EVO), pioglitazone 30 mg once daily for 7 days (PIO) and co-administration of evogliptin 5 mg and pioglitazone 30 mg once daily for 7 days (EVO+PIO) according to the assigned sequence and period. Serial blood samples were collected for 24 hours for pharmacokinetic analysis and 3 hours after the oral glucose tolerance test for the pharmacodynamic analysis. Thirty-four subjects completed the study. EVO+PIO and EVO showed a similar maximum plasma concentration at steady state (C ) and area under the concentration-time curve during the dosing interval at the steady state (AUC ) of evogliptin, with geometric mean ratios (GMRs) (90% confidence interval (CI)) of 1.01 (0.97-1.05) and 1.01 (0.98-1.04), respectively. EVO+PIO and PIO showed a similar C and AUC of pioglitazone, with GMRs (90% CI) of 1.07 (0.99-1.17) and 1.08 (0.99-1.17), respectively. Reduction of the glucose level after EVO+PIO was larger compared to PIO and similar with EVO. Concomitant administration of evogliptin and pioglitazone showed similar glucose-lowering effects with those of evogliptin alone without pharmacokinetic interactions when compared to the intake of each drug alone.

The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Takeda and Zinfandel.

Peroxisome proliferator-activator receptor (PPAR) γ is a nuclear hormone receptor that regulates glucose homeostasis, lipid metabolism, and adipocyte function. PPARγ is a target for thiazolidinedione (TZD) class of drugs which are widely used for the treatment of type 2 diabetes. Recently, lobeglitazone was developed as a highly effective TZD with reduced side effects by Chong Kun Dang Pharmaceuticals. To identify the structural determinants for the high potency of lobeglitazone as a PPARγ agonist, we determined the crystal structures of the PPARγ ligand binding domain (LBD) in complex with lobeglitazone and pioglitazone at 1.7 and 1.8 Å resolutions, respectively. Comparison of ligand-bound PPARγ structures revealed that the binding modes of TZDs are well conserved. The TZD head group forms hydrogen bonds with the polar residues in the AF-2 pocket and helix 12, stabilizing the active conformation of the LBD. The unique p -methoxyphenoxy group of lobeglitazone makes additional hydrophobic contacts with the Ω-pocket. Docking analysis using the structures of TZD-bound PPARγ suggested that lobeglitazone displays 12 times higher affinity to PPARγ compared to rosiglitazone and pioglitazone. This structural difference correlates with the enhanced affinity and the low effective dose of lobeglitazone compared to the other TZDs.

Rheumatoid arthritis (RA) is characterized by synovial inflammation, synoviocyte expansion and damage to cartilage and bone. We recently reported that peroxisome proliferator-activated receptor (PPAR)-γ inhibited the proliferation and activation of fibroblast-like synoviocytes (FLS), and was downregulated in RA synovial. In this study we investigated the role of PPAR-γ in RA and the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced in rats; from D15, AIA rats were orally administered pioglitazone (30 mg·kg −1 ·d −1 ) or rosiglitazone (4 mg·kg −1 ·d −1 ) for 14 days. Collagen-induced arthritis (CIA) was induced in wild-type and Ppar-γ +/− mice. We showed that the expression of PPAR-γ was significantly reduced, whereas that of TNF-α was markedly increased in human RA FLS. In CIA mice, knockdown of PPAR-γ expression ( Ppar-γ +/− ) aggravated the ankle inflammation. Similarly, T0070907 (a PPAR-γ antagonist) or si-PPAR-γ promoted the activation and inflammation of TNF-α-induced FLS in vitro. On the contrary, administration of PPAR-γ agonist pioglitazone or rosiglitazone, or injection of ad-Ppar-γ into the ankle of AIA rat in vivo induced overexpression of PPAR-γ, reduced the paw swelling and inflammation, and downregulated activation and inflammation of FLS in RA. Interesting, injection of ad-Ppar-γ into the ankle also reversed the ankle inflammation in Ppar-γ +/− CIA mice. We conducted RNA-sequencing and KEGG pathway analysis, and revealed that PPAR-γ overexpression was closely related to p53 signaling pathway in TNF-α-induced FLS. Co-IP study confirmed that p53 protein was bound to PPAR-γ in RA FLS. Taken together, PPAR-γ alleviates the inflammatory response of TNF-α-induced FLS by binding p53 in RA.

Background Tamoxifen (TAM) is a chemotherapeutic drug widely utilized to treat breast cancer. On the other hand, it exerts deleterious cellular effects in clinical applications as an antineoplastic agent, such as liver damage and cirrhosis. TAM-induced hepatic toxicity is mainly attributed to oxidative stress and inflammation. Pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, is utilized to treat diabetes mellitus type-2. PIO has been reported to exert anti-inflammatory and antioxidant effects in different tissues. This research assessed the impact of PIO against TAM-induced hepatic intoxication. Methods Rats received PIO (10 mg/kg) and TAM (45 mg/kg) orally for 10 days. Results TAM increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT), triggered several histopathological alterations, NF-κB p65, increased hepatic oxidative stress, and pro-inflammatory cytokines. PIO protects against TAM-induced liver dysfunction, reduced malondialdehyde (MDA), and pro-inflammatory markers along with improved hepatic antioxidants. Moreover, PIO, increased hepatic Bcl-2 expression while reducing Bax expression and caspase-3 levels. In addition, PIO decreased Keap-1, Notch1, and Hes-1 while upregulated HO-1, Nrf2, and SIRT1. Molecular docking showed the binding affinity of PIO for Keap-1, NF-κB, and SIRT1. Conclusion PIO mitigated TAM hepatotoxicity by decreasing apoptosis, inflammation, and oxidative stress. The protecting ability of PIO was accompanied by reducing Keap-1 and NF-κB and regulating Keap1/Nrf2/HO-1 and Sirt1/Notch1 signaling. Graphical abstract A schematic diagram illustrating the protective effect of PIO against TAM hepatotoxicity. PIO prevented TAM-induced liver injury by regulating Nrf2/HO-1 and SIRT1/Notch1 signaling and mitigating oxidative stress, inflammation, and apoptosis.

Because the breakdown of the blood–brain spinal cord barrier (BBSCB) worsens many central nervous system (CNS) diseases, prevention of BBSCB breakdown has been a major therapeutic target, especially for spinal cord injury (SCI). However, effective drugs that protect BBSCB function have yet to be developed. The purpose of the current study was 1) to develop a high-throughput screening assay (HTSA) to identify candidate drugs to protect BBSCB function, 2) to identify candidate drugs from existing drugs with newly developed HTSA, and 3) to examine the therapeutic effects of candidate drugs on SCI. Our HTSA included a culture of immortalized human brain endothelial cells primed with candidate drugs, stress with H2O2, and evaluation of their viability. A combination of the resazurin-based assay with 0.45 mM H2O2 qualified as a reliable HTSA. Screening of 1,570 existing drugs identified 90 drugs as hit drugs. Through a combination of reproducibility tests, exclusion of drugs inappropriate for clinical translation, and dose dependency tests, berberine, mubritinib, and pioglitazone were identified as a candidate. An in vitro BBSCB functional test revealed that berberine and mubritinib, but not pioglitazone, protected BBSCB from oxygen–glucose deprivation and reoxygenation stress. Additionally, these two drugs minimized BBSCB breakdown 1 day after cervical SCI in mice. Furthermore, berberine and mubritinib reduced neuronal loss and improved gait performance 8 weeks after SCI. Collectively, the current study established a useful HTSA to identify potential neuroprotective drugs by maintaining BBSCB function and demonstrated the neuroprotective effect of berberine and mubritinib after SCI.

Arsenic (As) is a common contaminant in drinking water in northeastern Mexico, which reduces the expression of cytochrome P450 (CYP 450). This enzyme group metabolizes numerous drugs, such as oral antidiabetic drugs such as pioglitazone (61% CYP 3A4, 49% CYP 2C8). When CYP 450’s function is inadequate, it has decreased therapeutic activity in type 2 diabetes mellitus (T2DM). This study aimed to establish the effect of As on pioglitazone metabolism in patients with T2DM. Methodology: Urine, water, and plasma samples from a healthy population (n = 11) and a population with T2DM (n = 20) were obtained. Samples were analyzed by fluorescence spectroscopy/hydride generation (As) and HPLC (pioglitazone). Additionally, CYP 3A4 and CYP 2C8 were studied by density functional theory (DFT). Results: The healthy and T2DM groups were exposed via drinking water to >0.010 ppm, Ka values with a factor of 4.7 higher, Cl 1.42 lower, and ABCt 1.26 times higher concerning the healthy group. In silico analysis (DFT) of CYP 3A4 and CYP 2C8 isoforms showed the substitution of the iron atom by As in the active sites of the enzymes. Conclusions: The results indicate that the substitution of Fe for As modifies the enzymatic function of CYP 3A4 and CYP 2C8 isoforms, altering the metabolic process of CYP 2D6 and CYP 3A4 in patients with T2DM. Consequently, the variation in metabolism alters the bioavailability of pioglitazone and the expected final effect.

Background High‐yielding dairy cows develop insulin resistance during late gestation associated with disruption of the growth hormone (GH)–insulin‐like growth factor (IGF)‐I axis and cause metabolic and reproductive disorders. Objective This study aimed to determine the effects of dietary pioglitazone (PIO) supplementation as an insulin sensitizer agent on milk yield, plasma metabolite status and GH–IGF‐I axis in transition Holstein dairy cows. Methods Twenty multiparous cows were randomly assigned into two experimental groups (n = 10 animals per group) and either fed with a basal diet (control) or the basal diet supplemented with 6 mg PIO/kg body weight (BW) from day 14 before parturition to day 21 postpartum. The BW and body condition score (BCS), non‐esterified fatty acids, beta‐hydroxybutyrate (BHBA), insulin, glucose, GH and IGF‐I concentrations, milk production and composition were measured weekly. Results BW and BCS losses were lower in PIO than in control cows (p < 0.05). The percentage and amount of milk fat were decreased, and the amount of protein increased only in the first post‐calving week in the PIO‐treated cows compared to the control (p < 0.05). Dietary PIO supplementation increased glucose concentration at calving, but insulin concentration was increased at calving and in the first post‐calving week (p < 0.05). Plasma concentrations of IGF‐I and the ratio of IGF to GH were increased in the PIO group (p < 0.05). The mean revised quantitative insulin sensitivity check index with BHBA, as an insulin sensitivity index, was greater in PIO‐supplemented cows (p < 0.05). Conclusions Our results showed beneficial effects of PIO supplementation on improving insulin sensitivity and the GH–IGF‐I axis that may cause lower negative energy balance and better metabolic and health status in transition dairy cows. The high‐yielding dairy cows suffer from insulin resistance during the periparturient period. Dietary supplementation of pioglitazone hydrochloride, an insulin‐resistance drug and synthetic agonist for PPRAγ, improved the insulin sensitivity index (RQICKI‐BHBA) in Holstein dairy cows during the transition period.

Using cell-free binding assays, they demonstrated that only the S form bound and activated PPARγ, while both S and R enantiomers could inhibit the MPC. [...]to negate PPARγ-agonism, they further developed and tested the deuterated R-pioglitazone, or PXL065, which was found to improve liver fat, inflammation, and fibrosis in mouse NASH models without significant weight gain or fluid retention. [...]it is only partial stabilization and much more needs to be understood about its mechanisms of action. [...]it is still unclear if inhibition of the mitochondrial pyruvate carrier is a viable target in NASH. Since patients likely develop NASH by a variety of different mechanisms, targeting the MPC might be valuable in a subset of patients in whom the generation of precursors for de novo lipogenesis is driven by glucose excess and glycolysis.

The purpose of this study was to determine the efficacy and safety profile of pioglitazone compared with placebo (PBO) in patients with type 2 diabetes (T2D) inadequately controlled with metformin and dapagliflozin. In this prospective, multicenter, randomized, double-blind, PBO-controlled trial, 366 patients with T2D who did not meet glycemic targets (7.0% ≤ glycosylated hemoglobin [HbA1c] ≤ 10.5%), despite treatment with metformin ≥1000 mg and dapagliflozin 10 mg, received either a PBO, 15 mg of pioglitazone daily (PIO15), or 30 mg of pioglitazone daily (PIO30). The primary end point was the mean change in HbA1c from baseline at 24 weeks across the groups. For the 366 participants (PBO, n = 124; PIO15, n = 118; PIO30, n = 124), the mean age was 55.6 years and mean duration of diabetes was 8.7 years, with a baseline HbA1c of 7.9%. After 24 weeks, HbA1c reduced significantly in the PIO15 and PIO30 groups from baseline, with intergroup differences of −0.38% and −0.83%, respectively, compared with the PBO group. The proportion of patients with HbA1c levels <7% was significantly higher in the PIO15 and PIO30 groups than in the PBO group. The adverse event rates did not significantly differ across the groups, indicating favorable safety profiles for triple combination therapy using metformin, dapagliflozin, and pioglitazone. The addition of pioglitazone as a third oral antidiabetic medication is an appropriate option for patients with T2D inadequately controlled with metformin and dapagliflozin based on the resulting significant efficacy in glycemic control and favorable safety profile. ClinicalTrials.gov identifier: NCT04885712.