Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Model.

Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K-γ pathway. Five days after receiving a single bolus of 0.075 units of bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg of MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-ß1, oxidative loads, Masson's trichrome staining, extracellular collagen levels, positive staining of α-smooth muscle actin, PI3K-γ expression, and myonuclear apoptosis (p < 0.05). Decreased diaphragm contractility and peroxisome proliferator-activated receptor-γ coactivator-1α levels were also observed (p < 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K-γ activity (p < 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated by PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis.

Effects of pioglitazone and metformin on abdominal adhesion formation in an experimental model.

BACKGROUND: This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing histopathological, immunohistochemical, and biochemical analyses in an experimental adhesion model. METHODS: Fifty Wistar-Albino rats were divided into five groups: Group I (Control), Group II (Sham Treatment), Group III (Hy-aluronic Acid), Group IV (Metformin), and Group V (Pioglitazone). Adhesions were induced in the experimental groups, except for the sham group, using the scraping method. After 10 days, rats were euthanized for evaluation. Macroscopic adhesion degrees were assessed using Nair's scoring system. Immunohistochemical and enzyme-linked immunosorbent assay (ELISA) methods were utilized to assess serum, peritoneal lavage, and intestinal tissue samples. Fructosamine, interleukin-6 (IL-6), transforming growth factor-beta (TGF-ß), and fibronectin levels were measured in serum and peritoneal lavage samples. RESULTS: The groups exhibited similar Nair scores and Type I or Type III Collagen staining scores (all, p>0.05). Pioglitazone significantly reduced serum IL-6 and TGF-ß levels compared to controls (p=0.002 and p=0.008, respectively). Both metformin and pioglitazone groups showed elevated IL-6 in peritoneal lavage relative to controls, while fibronectin levels in the lavage were lower in pioglitazone-treated rats compared to the sham group (all, p<0.005). CONCLUSION: Pioglitazone, but not metformin, demonstrated a positive biochemical impact on preventing PIAA formation in an experimental rat model, although histological impacts were not observed. Further experimental studies employing different dose/duration regimens of pioglitazone are needed to enhance our understanding of its effect on PIAA formation.

Pioglitazone-induced alterations of purine metabolism in healthy male subjects.

Pioglitazone is class of thiazolidinediones that activates peroxisome proliferator-activated receptors (PPARs) in adipocytes to improve glucose metabolism and insulin sensitivity and has been used as a treatment for type 2 diabetes. However, the underlying mechanisms of associated pioglitazone-induced effects remain unclear. Our study aimed to investigate endogenous metabolite alterations associated with pioglitazone administration in healthy male subjects using an untargeted metabolomics approach. All subjects received 30 mg of pioglitazone once daily in the assigned sequence and period. Urine samples were collected before pioglitazone administration and for 24 h after 7 days of administration. A total of 1465 compounds were detected and filtered using a coefficient of variance below 30% and 108 metabolites were significantly altered upon pioglitazone administration via multivariate statistical analysis. Fourteen significant metabolites were identified using authentic standards and public libraries. Additionally, pathway analysis revealed that metabolites from purine and beta-alanine metabolisms were significantly altered after pioglitazone administration. Further analysis of quantification of metabolites from purine metabolism, revealed that the xanthine/hypoxanthine and uric acid/xanthine ratios were significantly decreased at post-dose. Pioglitazone-dependent endogenous metabolites and metabolic ratio indicated the potential effect of pioglitazone on the activation of PPAR and fatty acid synthesis. Additional studies involving patients are required to validate these findings.

Randomized, Double-blind, Phase III Trial of Lobeglitazone Add-on to Metformin in Type 2 Diabetes (SENSITIZE INDIA).

BACKGROUND: The efficacy and safety of lobeglitazone sulfate has been reported only in the Korean population, and no study has been conducted in India. MATERIALS AND METHODS: In this 16-week randomized, double-blind, and multicenter study, the efficacy and safety of lobeglitazone sulfate 0.5 mg were evaluated with pioglitazone 15 mg. Type 2 diabetes mellitus (T2DM) patients with ≥7.5% glycated hemoglobin (HbA1c) ≤10.5% and on stable metformin dose were assigned to both treatment arms. The primary outcome was a mean change in HbA1c. Safety assessments included adverse events (AE), home-based glucose monitoring, vital parameters, electrocardiogram (ECG), and laboratory assessments. RESULTS: A total of 328 subjects were randomized equally in two groups. A statistically significant reduction in HbA1c at week 16 in the lobeglitazone group with the least square (LS) mean change: 1.01 [standard error (SE): 0.09] (p < 0.0001) was seen. The LS mean difference between the two groups was 0.05 (SE: 0.12) [95% confidence interval (CI): -0.18, 0.27], which was statistically significant (p = 0.0013). Statistically significant reductions were also observed in fasting and postprandial glucose. Treatment-emergent Aes (TEAE) were comparable between both groups. CONCLUSION: Lobeglitazone 0.5 mg once daily was found to be efficacious and safe in the treatment of T2DM in the Indian population. Lobeglitazone significantly improved glycemic parameters and was noninferior to pioglitazone; hence, it could be a promising insulin sensitizer in T2DM management in India.

FIB-4 as a screening and disease monitoring method in pre-fibrotic stages of metabolic dysfunction-associated fatty liver disease (MASLD).

AIMS: Guidelines emphasize screening high-risk patients for metabolic dysfunction-associated steatotic liver disease (MASLD) with a calculated FIB-4 score for therapy to reverse fibrosis. We aimed to determine whether FIB-4 can effectively screen and monitor changes in steatohepatitis (MASH). METHODS: Data were retrieved from the NIDDK-CR R4R central repository, of the CRN/PIVENS (pioglitazone vs vitamin E vs placebo) trial of adult patients without diabetes mellitus and with MASLD. RESULTS: 220 patients with MASLD had alanine transaminase (ALT), aspartate aminotransferase (AST) and platelet count, to calculate FIB-4, and repeat liver biopsies for histological MASLD activity scores (NAS). Compared to NAS score of 2, Fib-4 was higher at NAS 5) (p = 0.03), and NAS score of 6 (p = 0.02). FIB-4 correlated with cellular ballooning (r = 0.309, p < 0.001). Levels of ALT (ANOVA, p = 0.016) and AST (ANOVA p = 0.0008) were associated with NAS. NAS improved with pioglitazone by 39 %, p < 0.001 and with vitamin E by 36 %, p < 0.001. Pioglitazone and vitamin E both improved histological sub-scores for steatosis, and inflammation, without statistical changes in fibrosis grade. Changes in FIB-4 correlated with changes in NAS (r = 0.237, p < 0.001). CONCLUSIONS: In this post hoc analysis, changes in FIB-4 were associated with changes of steatohepatitis. Medication known to treat steatohepatitis, may be considered, before the onset of advanced fibrosis.

Identification of 1,3,4-Thiadiazolyl-Containing Thiazolidine-2,4-dione Derivatives as Novel PTP1B Inhibitors with Antidiabetic Activity.

Forty-one 1,3,4-thiadiazolyl-containing thiazolidine-2,4-dione derivatives (MY1-41) were designed and synthesized as protein tyrosine phosphatase 1B (PTP1B) inhibitors with activity against diabetes mellitus (DM). All synthesized compounds (MY1-41) presented potential PTP1B inhibitory activities, with half-maximal inhibitory concentration (IC50) values ranging from 0.41 ± 0.05 to 4.68 ± 0.61 µM, compared with that of the positive control lithocholic acid (IC50 = 9.62 ± 0.14 µM). The most potent compound, MY17 (IC50 = 0.41 ± 0.05 µM), was a reversible, noncompetitive inhibitor of PTP1B. Circular dichroism spectroscopy and molecular docking were employed to analyze the binding interaction between MY17 and PTP1B. In HepG2 cells, MY17 treatment could alleviate palmitic acid (PA)-induced insulin resistance by upregulating the expression of phosphorylated insulin receptor substrate and protein kinase B. In vivo, oral administration of MY17 could reduce the fasting blood glucose level and improve glucose tolerance and dyslipidemia in mice suffering from DM.

The Effect of Thiazolidinediones in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a complex endocrine condition affecting women of reproductive age. It is characterised by insulin resistance and is a risk for type 2 diabetes mellitus (T2DM). The aim of this study was to review the literature on the effect of pioglitazone and rosiglitazone in women with PCOS. METHODS: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane Library and the Web of Science in April 2020 and updated in March 2023. Studies were deemed eligible if they were randomised controlled trials (RCTs) reporting the effect of pioglitazone and rosiglitazone in PCOS. The study follows the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two reviewers independently extracted data and assessed the risk of bias using the Cochrane risk of bias tool. RESULTS: Out of 814 initially retrieved citations, 24 randomised clinical trials (RCTs) involving 976 participants were deemed eligible. Among women with PCOS, treatment with rosiglitazone compared to metformin resulted in a significant increase in the mean body weight (mean difference (MD) 1.95 kg; 95% CI 0.03-3.87, p = 0.05). Metformin treatment was associated with a reduction in mean body mass index (BMI) compared to pioglitazone (MD 0.85 kg/m2; 95% CI 0.13-1.57, p = 0.02). Both pioglitazone compared to placebo (MD 2.56 kg/m2; 95% CI 1.77-3.34, p < 0.00001) and rosiglitazone compared to metformin (MD 0.74 kg/m2; 95% CI 0.07-1.41, p = 0.03) were associated with a significant increase in BMI. Treatment with pioglitazone compared to placebo showed a significant reduction in triglycerides (MD - 0.20 mmol/L; 95% CI - 0.38 to - 0.03, p = 0.02) and fasting insulin levels (MD - 11.47 mmol/L; 95% CI - 20.20, - 2.27, p = 0.01). Rosiglitazone compared to metformin was marginally significantly associated with a reduction in the luteinising hormone (LH) (MD - 0.62; 95% CI - 1.25-0.00, p = 0.05). CONCLUSION: Both pioglitazone and rosiglitazone were associated with significant increases in body weight and BMI when compared with metformin or placebo. Pioglitazone significantly reduced triglycerides and fasting insulin when compared with placebo while rosiglitazone showed a modest reduction of LH when compared with metformin. PROSPERO REGISTRATION NO: CRD42020178783.

Management of Type 2 Diabetes Mellitus With Noninsulin Pharmacotherapy.

Type 2 diabetes mellitus is a chronic disease that is increasing in global prevalence. An individualized approach to pharmacotherapy should consider costs, benefits beyond glucose control, and adverse events. Metformin is the first-line therapy due to its low cost and effectiveness. Sulfonylureas and thiazolidinediones are additional low-cost oral hypoglycemic classes available in the United States; however, evidence shows variability in weight gain and hypoglycemia. Thiazolidinediones increase fluid retention and are not recommended in patients with New York Heart Association class III or IV heart failure. Newer medications, including glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors, have demonstrated weight loss, reduced cardiovascular events, decreased renal disease, and improved all-cause morbidity and mortality. Sodium-glucose cotransporter-2 inhibitors are recommended for people with known cardiovascular disease, heart failure, and chronic kidney disease but carry an increased risk of urinary tract and mycotic infections. Glucagon-like peptide-1 receptor agonists are contraindicated in patients with active multiple endocrine neoplasia type 2 or a personal or family history of medullary thyroid carcinoma; adverse effects include gastrointestinal upset and pancreatitis. Dipeptidyl-peptidase-4 inhibitors have a low risk of hypoglycemia but may increase the risk of pancreatitis and require a renal dose adjustment. Public and private programs to increase access to newer hypoglycemic medications are increasing; however, there are limitations to access, particularly for uninsured and underinsured people.

Meta-analysis of the global distribution of clinically relevant CYP2C8 alleles and their inferred functional consequences.

BACKGROUND: CYP2C8 is responsible for the metabolism of 5% of clinically prescribed drugs, including antimalarials, anti-cancer and anti-inflammatory drugs. Genetic variability is an important factor that influences CYP2C8 activity and modulates the pharmacokinetics, efficacy and safety of its substrates. RESULTS: We profiled the genetic landscape of CYP2C8 variability using data from 96 original studies and data repositories that included a total of 33,185 unrelated participants across 44 countries and 43 ethnic groups. The reduced function allele CYP2C8*2 was most common in West and Central Africa with frequencies of 16-36.9%, whereas it was rare in Europe and Asia (< 2%). In contrast, CYP2C8*3 and CYP2C8*4 were common throughout Europe and the Americas (6.9-19.8% for *3 and 2.3-7.5% for *4), but rare in African and East Asian populations. Importantly, we observe pronounced differences (> 2.3-fold) between neighboring countries and even between geographically overlapping populations. Overall, we found that 20-60% of individuals in Africa and Europe carry at least one CYP2C8 allele associated with reduced metabolism and increased adverse event risk of the anti-malarial amodiaquine. Furthermore, up to 60% of individuals of West African ancestry harbored variants that reduced the clearance of pioglitazone, repaglinide, paclitaxel and ibuprofen. In contrast, reduced function alleles are only found in < 2% of East Asian and 8.3-12.8% of South and West Asian individuals. CONCLUSIONS: Combined, the presented analyses mapped the genetic and inferred functional variability of CYP2C8 with high ethnogeographic resolution. These results can serve as a valuable resource for CYP2C8 allele frequencies and distribution estimates of CYP2C8 phenotypes that could help identify populations at risk upon treatment with CYP2C8 substrates. The high variability between ethnic groups incentivizes high-resolution pharmacogenetic profiling to guide precision medicine and maximize its socioeconomic benefits, particularly for understudied populations with distinct genetic profiles.

Insulin interacts with PPARγ agonists to promote bovine adipocyte differentiation.

Insulin is a potent adipogenic hormone that triggers a series of transcription factors that regulate the differentiation of preadipocytes into mature adipocytes. Ciglitazone specifically binds to peroxisome proliferator-activated receptor-γ (PPARγ), thereby promoting adipocyte differentiation. As a natural ligand of PPARγ, oleic acid (OA) can promote the translocation of PPARγ into the nucleus, regulate the expression of downstream genes, and promote adipocyte differentiation. We hypothesized that ciglitazone and oleic acid interact with insulin to enhance bovine preadipocyte differentiation. Preadipocytes were cultured 96 h in differentiation medium containing 10 mg/L insulin (I), 10 mg/L insulin + 10 µM cycloglitazone (IC), 10 mg/L insulin + 100 µM oleic acid (IO), or 10 mg/L insulin + 10 µM cycloglitazone+100 µM oleic acid (ICO). Control preadipocytes (CON) were cultured in differentiation medium (containing 5% fetal calf serum). The effects on the differentiation of Yanbian cattle preadipocytes were examined using molecular and transcriptomic techniques, including differentially expressed genes (DEGs) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis. I, IC, IO, and ICO treatments produced higher concentrations of triglycerides (TAG) and lipid droplet accumulation in preadipocytes compared with CON treatment (P < 0.05). Co-treatment of insulin and PPARγ agonists significantly increased the expression of genes involved in regulating adipogenesis and fatty acid synthesis. (P < 0.05). Differential expression analysis identified 1488, 1764, 1974 and 1368 DEGs in the I, IC, IO and ICO groups, respectively. KEGG pathway analysis revealed DEGs mainly enriched in PPAR signalling, FOXO signaling pathway and fatty acid metabolism. These results indicate that OA, as PPARγ agonist, can more effectively promote the expression of bovine lipogenesis genes and the content of TAG and adiponectin when working together with insulin, and stimulate the differentiation of bovine preadipocytes. These findings provide a basis for further screening of relevant genes and transcription factors in intramuscular fat deposition and meat quality to enhance breeding programs.

Factors associated with treatment responses to pioglitazone in patients with steatotic liver disease: A 3-year prospective cohort study.

AIM: The response rate to pioglitazone and the predictive factors for its effects on improving liver biochemistry in patients with steatotic liver disease (SLD) remain elusive, so we aimed to investigate these issues. METHODS: A 3-year prospective cohort study of 126 Taiwanese patients with SLD treated with pioglitazone (15-30 mg/day) was conducted. Phospholipase domain-containing protein 3 I148M rs738409, methylenetetrahydrofolate reductase rs1801133, aldehyde dehydrogenase 2 (ALDH2) rs671 and lipoprotein lipase rs10099160 single nucleotide polymorphisms were assessed in the patients. RESULTS: Of 126 patients, 78 (61.9%) were men, and the mean and median ages were 54.3 and 56.5 years, respectively. Pioglitazone responders were defined as those with decreased alanine aminotransferase (ALT) levels at 6 months post-treatment, and 105 (83.3%) patients were responders. Compared with non-responders, responders were more frequently women and had higher baseline ALT levels. The proportion of patients with the ALDH2 rs671 GG genotype was lower among responders (38.6% vs. 66.6%, p = .028). Female sex [odds ratio (OR): 4.514, p = .023] and baseline ALT level (OR: 1.015, p = .046; cut-off level: ≥82 U/L) were associated with pioglitazone response. Among responders, the liver biochemistry and homeostasis model assessment of insulin resistance improved from 6 to 24 months post-treatment. The total cholesterol levels decreased within 6 months, while increases in high-density lipoprotein cholesterol levels and decreases in triglyceride levels and fibrosis-4 scores were noted only at 24 months post-treatment. The 2-year cumulative incidences of cardiovascular events, cancers and hepatic events were similar between responders and non-responders. CONCLUSIONS: Regarding liver biochemistry, over 80% of Taiwanese patients with SLD had a pioglitazone response, which was positively associated with female sex and baseline ALT levels. Insulin resistance improved as early as 6 months post-treatment, while liver fibrosis improvement was not observed until 24 months post-treatment. The link between the pioglitazone response and the ALDH2 genotype warrants further investigation.

Synthesis, biological evaluation and molecular docking study of pyrimidine linked thiazolidinedione derivatives as potential antimicrobial and antitubercular agents.

The design and development of novel antimicrobial agents are highly desired to combat the emergence of medication resistance against microorganisms that cause infections. A series of new pyrimidine-linked thiazolidinedione derivatives (5a-j) were synthesized, characterized, and their antimicrobial properties assessed in the current investigation. Here, novel pyrimidine-linked thiazolidinedione compounds were designed using the molecular hybridization approach. Elemental and spectral techniques were used to determine the structures of the synthesized hybrids. The majority of compounds showed encouraging antibacterial properties. Among the active compounds, 5g, 5i, and 5j showed 1.85, 1.15, and 1.38 times the activity of streptomycin against S. aureus, respectively, with MIC values of 6.4, 10.3, and 8.6 µM. With MIC values of 10.8, 21.9, and 15.4 µM, respectively, the compounds 5g, 5i, and 5j showed 2.14, 1.05, and 1.50 times the activity of linezolid against the methicillin-resistant S. aureus (MRSA) strain. Furthermore, when compared to the reference medications, compounds 5g, 5i, and 5j demonstrated broad-range antimicrobial efficacy against all tested strains of bacteria and fungus. Out of all the compounds that were investigated, compounds 5g, 5i, and 5j showed noteworthy anti-tubercular activity. 5g is the most effective, 1.59 times more effective than reference drug isoniazid. To anticipate the binding manner, the synthesized potent compounds were subjected to molecular docking into the active binding site of MRSA and the mycobacterial membrane protein large 3 (MmpL3) protein. The compounds 5g, 5i, and 5j may eventually serve as lead compounds in the search for antimicrobial and anti-TB therapeutic agents.

New thiazolidine-2,4-diones as potential anticancer agents and apoptotic inducers targeting VEGFR-2 kinase: Design, synthesis, in silico and in vitro studies.

BACKGROUND: VEGFR-2 has emerged as a prominent positive regulator of cancer progression. AIM: Discovery of new anticancer agents and apoptotic inducers targeting VEGFR-2. METHODS: Design and synthesis of new thiazolidine-2,4-diones followed by extensive in vitro studies, including VEGFR-2 inhibition assay, MTT assay, apoptosis analysis, and cell migration assay. In silico investigations including docking, MD simulations, ADMET, toxicity, and DFT studies were performed. RESULTS: Compound 15 showed the strongest VEGFR-2 inhibitory activity with an IC50 value of 0.066 µM. Additionally, most of the synthesized compounds showed anti-proliferative activity against HepG2 and MCF-7 cancer cell lines at the micromolar range with IC50 values ranging from 0.04 to 4.71 µM, relative to sorafenib (IC50 = 2.24 ± 0.06 and 3.17 ± 0.01 µM against HepG2 and MCF-7, respectively). Also, compound 15 showed selectivity indices of 1.36 and 2.08 against HepG2 and MCF-7, respectively. Furthermore, compound 15 showed a significant apoptotic effect and arrested the cell cycle of MCF-7 cells at the S phase. Moreover, compound 15 had a significant inhibitory effect on the ability of MCF-7 cells to heal from. Docking studies revealed that the synthesized thiazolidine-2,4-diones have a binding pattern approaching sorafenib. MD simulations indicated the stability of compound 15 in the active pocket of VEGFR-2 for 200 ns. ADMET and toxicity studies indicated an acceptable pharmacokinetic profile. DFT studies confirmed the ability of compound 15 to interact with VEGFR-2. CONCLUSION: Compound 15 has promising anticancer activity targeting VEGFR-2 with significant activity as an apoptosis inducer.

Thiazolidinediones are Partially Effective Bitter Blockers.

PURPOSE: The bad bitter taste of some medicines is a barrier to overcoming noncompliance with medication use, especially life-saving drugs given to children and the elderly. Here, we evaluated a new class of bitter blockers (thiazolidinediones, TZDs). METHODS: In this study, 2 TZDs were tested, rosiglitazone (ROSI) and a simpler form of TZD, using a high-potency sweetener as a positive control (neohesperidin dihydrochalcone, NHDC). We tested bitter-blocking effects using the bitter drugs tenofovir alafenamide fumarate (TAF), a treatment for HIV and hepatitis B infection, and praziquantel (PRAZ), a treatment for schistosomiasis, by conducting taste testing with 2 separate taste panels: a general panel (N = 97, 20-23 years, 82.5% female, all Eastern European) and a genetically informative panel (N = 158, including 68 twin pairs, 18-82 years, 76% female, 87% European ancestry). Participants rated the bitterness intensity of the solutions on a 100-point generalized visual analog scale. FINDINGS: Person-to-person differences in drug bitterness were striking; TAF and PRAZ were weakly or not bitter for some people but moderately to highly bitter for others. Participants in both taste panels rated the bitter drugs TAF and PRAZ as less bitter on average when mixed with NHDC than when sampled alone. ROSI partially suppressed the bitterness of TAF and PRAZ, but effectiveness differed between the 2 panels: bitterness was significantly reduced for PRAZ but not TAF in the general panel and for TAF but not PRAZ in the genetically informative panel. ROSI was a more effective blocker than the other TZD. IMPLICATIONS: These results suggest that TZDs are partially effective bitter blockers and the suppression efficacy differs from drug to drug, from person to person, and from panel to panel, suggesting other TZDs should be designed and tested with more drugs and on diverse populations to define which ones work best with which drugs and for whom. The discovery of bitter receptor blockers can improve compliance with medication use.

A multicentre, double-blind, placebo-controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add-on therapy in type 2 diabetic patients treated with metformin and dapagliflozin.

AIM: To investigate the efficacy and safety of pioglitazone compared to placebo when added to metformin plus dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, for patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In a multicentre study, with a randomized, double-blind, placebo-controlled design, 249 Korean patients with T2DM suboptimally managed on metformin and dapagliflozin were assigned to receive either pioglitazone (15 mg daily) or placebo for 24 weeks, followed by a 24-week pioglitazone extension. Primary outcomes included changes in glycated haemoglobin (HbA1c), with secondary outcomes assessing insulin resistance, adiponectin levels, lipid profiles, liver enzymes, body weight and waist circumference. RESULTS: Pioglitazone administration resulted in a significant reduction in HbA1c levels (from 7.80% ± 0.72% to 7.27% ± 0.82%) compared with placebo (from 7.79% ± 0.76% to 7.69% ± 0.86%, corrected mean difference: -0.42% ± 0.08%; p < 0.01) at 24 weeks. Additional benefits from pioglitazone treatment included enhanced insulin sensitivity, increased adiponectin levels, raised high-density lipoprotein cholesterol levels and reduced liver enzyme levels, resulting in improvement in nonalcoholic fatty liver disease liver fat score. Despite no serious adverse events in either group, pioglitazone therapy was modestly but significantly associated with weight gain and increased waist circumference. CONCLUSIONS: Adjunctive pioglitazone treatment in T2DM inadequately controlled with metformin and dapagliflozin demonstrates considerable glycaemic improvement, metabolic benefits, and a low risk of hypoglycaemia. These advantages must be weighed against the potential for weight gain and increased waist circumference.

Clinical pharmacokinetics of leriglitazone and a translational approach using PBPK modeling to guide the selection of the starting dose in children.

Leriglitazone is a unique peroxisome proliferator-activated receptor-gamma (PPARγ) agonist that crosses the blood-brain barrier in humans and clinical trials have shown evidence of efficacy in neurodegenerative diseases. At clinical doses which are well-tolerated, leriglitazone reaches the target central nervous system (CNS) concentrations that are needed for PPARγ engagement and efficacy; PPARγ engagement is also supported by clinical and anti-inflammatory biomarker changes in the Cerebrospinal fluid in the CNS. Plasma pharmacokinetics (PK) of leriglitazone were determined in a phase 1 study in male healthy volunteers comprising a single ascending dose (SAD) and a multiple ascending dose (MAD) at oral doses of 30, 90, and 270 mg and 135 and 270 mg, respectively. Leriglitazone was rapidly absorbed with no food effect on overall exposure and showed a linear PK profile with dose-exposure correlation. A physiologically based pharmacokinetic (PBPK) model was developed for leriglitazone based on phase 1 data (SAD part) and incorporated CYP3A4 (fmCYP3A4 = 24%) and CYP2C8-mediated (fmCYP2C8 = 45%) metabolism, as well as biliary clearance (feBIL = 19.5%) derived from in vitro data, and was verified by comparing the observed versus predicted concentration-time profiles from the MAD part. The PBPK model was prospectively applied to predict the starting pediatric doses and was preliminarily verified with data from five pediatric patients.

Assessing the potential for precision medicine in body weight reduction with regard to type 2 diabetes mellitus therapies: A meta-regression analysis of 120 randomized controlled trials.

AIMS: To assess the potential for precision medicine in type 2 diabetes by quantifying the variability of body weight as response to pharmacological treatment and to identify predictors which could explain this variability. METHODS: We used randomized clinical trials (RCTs) comparing glucose-lowering drugs (including but not limited to sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and thiazolidinediones) to placebo from four recent systematic reviews. RCTs reporting on body weight after treatment to allow for calculation of its logarithmic standard deviation (log[SD], i.e., treatment response heterogeneity) in verum (i.e., treatment) and placebo groups were included. Meta-regression analyses were performed with respect to variability of body weight after treatment and potential predictors. RESULTS: A total of 120 RCTs with a total of 43 663 participants were analysed. A slightly larger treatment response heterogeneity was shown in the verum groups, with a median log(SD) of 2.83 compared to 2.79 from placebo. After full adjustment in the meta-regression model, the difference in body weight log(SD) was -0.026 (95% confidence interval -0.044; 0.008), with greater variability in the placebo groups. Scatterplots did not show any slope divergence (i.e., interaction) between clinical predictors and the respective treatment (verum or placebo). CONCLUSIONS: We found no major treatment response heterogeneity in RCTs of glucose-lowering drugs for body weight reduction in type 2 diabetes. The precision medicine approach may thus be of limited value in this setting.

Synthetic Strategies of Thiazolidine-2,4-dione Derivatives for the Development of New Anti-diabetic Agents: Compressive Review.

BACKGROUND: Thiazolidine-2,4-dione (2,4-TZD) is a flexible pharmacophore and a privileged platform and contains a five-membered ring with a 2-oxygen atom with double bond 2,4- position and one nitrogen atom as well as sulphur containing in the heterocyclic compound. A famous electron-rich nitrogen transporter combines invigorating electronic properties with the prospective for elemental applications. Thiazolidine-2,4-dione analogues have been synthesized using a variety of methods, all of which have shown to have a strong biological effect. OBJECTIVES: The study of the biological activity of Thiazolidine-2,4-dione derivatives has been a fascinating field of pharmaceutical chemistry and has many purposes. This derivative described in the literature between 1995 to 2023 was the focus of this study. Thiazolidine-2,4-diones have been discussed in terms of their introduction, general method, synthetic scheme and antidiabetic significance in the current review. CONCLUSION: Thiazolidine-2,4-diones are well-known heterocyclic compounds. The synthesis of Thiazolidine-2,4-diones has been described using a variety of methods. Antidiabetic activity has been discovered in several Thiazolidine-2,4-dione derivatives, which enhance further research. The use of Thiazolidine-2,4-diones to treat antidiabetics has piqued researchers' interest in learning more about thiazolidine-2,4-diones.

Effect of Drugs Used in Pharmacotherapy of Type 2 Diabetes on Bone Density and Risk of Bone Fractures.

This review summarizes the complex relationship between medications used to treat type 2 diabetes and bone health. T2DM patients face an increased fracture risk despite higher bone mineral density; thus, we analyzed the impact of key drug classes, including Metformin, Sulphonylureas, SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 agonists, and Thiazolidinediones. Metformin, despite promising preclinical results, lacks a clear consensus on its role in reducing fracture risk. Sulphonylureas present conflicting data, with potential neutral effects on bone. SGLT-2 inhibitors seem to have a transient impact on serum calcium and phosphorus, but evidence on their fracture association is inconclusive. DPP-4 inhibitors emerge as promising contributors to bone health, and GLP-1 agonists exhibit positive effects on bone metabolism, reducing fracture risk. Thiazolidinediones, however, demonstrate adverse impacts on bone, inducing loss through mesenchymal stem cell effects. Insulin presents a complex relationship with bone health. While it has an anabolic effect on bone mineral density, its role in fracture risk remains inconsistent. In conclusion, a comprehensive understanding of diabetes medications' impact on bone health is crucial. Further research is needed to formulate clear guidelines for managing bone health in diabetic patients, considering individual profiles, glycemic control, and potential medication-related effects on bone.