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Neuroscience and Biobehavioral Reviews Sep 2023Mood disorders and type 2 diabetes mellitus (T2DM) are prevalent conditions that often co-occur. We reviewed the available evidence from longitudinal and Mendelian... (Review)
Review
Mood disorders and type 2 diabetes mellitus (T2DM) are prevalent conditions that often co-occur. We reviewed the available evidence from longitudinal and Mendelian randomisation (MR) studies on the relationship between major depressive disorder (MDD), bipolar disorder and T2DM. The clinical implications of this comorbidity on the course of either condition and the impact of antidepressants, mood stabilisers, and antidiabetic drugs were examined. Consistent evidence indicates a bidirectional association between mood disorders and T2DM. T2DM leads to more severe depression, whereas depression is associated with more complications and higher mortality in T2DM. MR studies demonstrated a causal effect of MDD on T2DM in Europeans, while a suggestive causal association in the opposite direction was found in East Asians. Antidepressants, but not lithium, were associated with a higher T2DM risk in the long-term, but confounders cannot be excluded. Some oral antidiabetics, such as pioglitazone and liraglutide, may be effective on depressive and cognitive symptoms. Studies in multi-ethnic populations, with a more careful assessment of confounders and appropriate power, would be important.
Topics: Humans; Diabetes Mellitus, Type 2; Mood Disorders; Depressive Disorder, Major; Hypoglycemic Agents; Pioglitazone
PubMed: 37391112
DOI: 10.1016/j.neubiorev.2023.105298 -
The Lancet. Neurology Jul 2021The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer's disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial.
BACKGROUND
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.
METHODS
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.
FINDINGS
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.
INTERPRETATION
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.
FUNDING
Takeda and Zinfandel.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers, Pharmacological; Cognitive Dysfunction; Double-Blind Method; Female; Humans; Male; Pioglitazone; Prognosis; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 34146512
DOI: 10.1016/S1474-4422(21)00043-0 -
Head & Neck Mar 2022Head and neck squamous cell carcinoma (HNSCC) requires new treatments and targeted approaches to improve survival. The peroxisome proliferator-activated receptor γ...
BACKGROUND
Head and neck squamous cell carcinoma (HNSCC) requires new treatments and targeted approaches to improve survival. The peroxisome proliferator-activated receptor γ (PPARγ) and retinoic X receptor alpha (RXRα) nuclear receptor pathways may be targetable with repurposed Food and Drug Administration (FDA)-approved agents for prevention and treatment.
METHODS
Oral cancer and leukoplakia cell lines were treated with the PPARγ agonist (pioglitazone) and RXRα activator (bexarotene). PPARγ activation, cellular proliferation, apoptosis activity and phenotype, including the pharmacodynamic marker, involucrin (IVL), were subsequently analyzed using a reporter gene assay, genomic data, MTT assay and western blot.
RESULTS
Microarray analysis of HNSCC tumor versus normal tissue shows IVL expression is significantly increased in normal tissue compared to HNSCC tumors (p < 0.0001). In MSK Leuk1 and CA 9-22 cell lines, pioglitazone increases PPARγ DNA binding activity and IVL promoter activity in a dose dependent manner (p < 0.01 and p < 0.0001). Combination treatment with pioglitazone and bexarotene increases PPARγ DNA binding activity and IVL promoter activity (p < 0.01 and p < 0.0001). MTT analysis shows decreases in cell proliferation when cells are treated with pioglitazone and bexarotene. Decreases in cell proliferation are significant to at least p < 0.05 for all combination versus single agent treatments. Western blot on whole-cell lysate from cells treated with pioglitazone and bexarotene alone or in combination for IVL showed increased protein levels with combination treatment.
CONCLUSIONS
Targeting the PPARγ/RXRα heterodimer with pioglitazone and bexarotene was effective in this preclinical project. This was functional in both preneoplastic and oral cancer cell lines. A better understanding of the molecular mechanism on downstream effects on cellular proliferation could potentially have implications clinically, both in oral preneoplasia and possibly head and neck cancer; however, more research needs to be done to explore the potential these medications have in chemoprevention.
Topics: Bexarotene; Chemoprevention; Head and Neck Neoplasms; Humans; Mouth Neoplasms; Pioglitazone; United States
PubMed: 34931381
DOI: 10.1002/hed.26959 -
Current Drug Safety 2022Thiazolidinediones are potent exogenous agonists of PPAR-γ that augment the effects of insulin to its cellular targets, mainly at the level of adipose tissue....
BACKGROUND
Thiazolidinediones are potent exogenous agonists of PPAR-γ that augment the effects of insulin to its cellular targets, mainly at the level of adipose tissue. Pioglitazone, the main thiazolidinedione in clinical practice, has shown cardiovascular and renal benefits in patients with type 2 diabetes, durable reduction of glycated hemoglobulin levels, important improvements of several components of the metabolic syndrome, and beneficial effects of non-alcoholic fatty liver disease.
OBJECTIVE
Despite all of its established advantages, the controversy for an increased risk of developing bladder cancer, combined with the advent of newer drug classes that achieved major cardiorenal effects, have significantly limited its use spreading a persistent shadow of doubt for its future role.
METHODS
Pubmed, Google, and Scope databases have been thoroughly searched, and relevant studies were selected.
RESULTS
This paper thoroughly explores both in vitro and in vivo (animal models and humans) studies that investigated the possible association of pioglitazone with bladder cancer.
CONCLUSION
Currently, the association of pioglitazone with bladder cancer cannot be based on solid evidence. This evidence cannot justify its low clinical administration, especially in the present era of individualised treatment strategies. Definite clarification of this issue is imperative and urgently anticipated from future high quality and rigorous pharmacoepidemiologic research, keeping in mind its unique mechanism of action and its significant pleiotropic effects.
Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Pioglitazone; Thiazolidinediones; Urinary Bladder Neoplasms
PubMed: 35249505
DOI: 10.2174/1574886317666220304124756 -
Mediators of Inflammation 2021The effects of () and pioglitazone (a PPAR- agonist) alone and in combination, on systemic inflammation and oxidative stress induced by inhaled paraquat (PQ) as a...
The effects of () and pioglitazone (a PPAR- agonist) alone and in combination, on systemic inflammation and oxidative stress induced by inhaled paraquat (PQ) as a herbicide, which induced inflammation in rats, were examined. Rats were exposed to (1) saline (control) and (2) 54 mg/m PQ aerosols (8 times, every other day, each time for 30 min) without treatment or treated with (3 and 4) two doses of (200 and 800 mg/kg/day), (5 and 6) two doses of pioglitazone (5 and 10 mg/kg/day), (7) low doses of . + pioglitazone, (Pio-5+Z-200 mg/kg/day) or (8) dexamethasone (0.03 mg/kg/day) for 16 days, after the last PQ exposure. Different variables were measured at the end of the treatment period. Exposure to PQ significantly increased total and differential white blood cells (WBC) counts, serum levels of nitrite (NO), malondialdehyde (MDA), interleukin- (IL) 17, and tumor necrosis factor alpha (TNF-), but reduced thiol, superoxide dismutase (SOD), catalase (CAT), IL-10, and interferon-gamma (INF-) ( < 0.05 to < 0.001). Most measured parameters were significantly improved in groups treated with either doses of the extract, pioglitazone, Pio-5+Z-200 mg/kg/day, or dexamethasone compared to the PQ group ( < 0.05 to < 0.001). The combination of low doses of Pio-5+Z-200 mg/kg/day showed significantly higher effects compared to each one alone ( < 0.05 to < 0.001). Systemic oxidative stress and inflammation due to inhaled PQ were improved by and pioglitazone. Higher effects of Pio-5+Z-200 mg/kg/day compared to each one alone suggest modulation of PPAR- receptors by the plant extract, but further studies using PPAR- antagonists need to be done in this regard.
Topics: Animals; Inflammation; Lamiaceae; Oxidative Stress; Paraquat; Pioglitazone; Rats
PubMed: 34054344
DOI: 10.1155/2021/5575059 -
Trials Sep 2023Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide....
SPIOMET4HEALTH-efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind,...
BACKGROUND
Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs.
METHODS
In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO.
DISCUSSION
The present study will be the first to evaluate-in a randomised, double-blind, placebo-controlled way-the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention.
TRIAL REGISTRATION
EudraCT 2021-003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 .
Topics: Adolescent; Female; Humans; Carotid Intima-Media Thickness; Clinical Trials, Phase II as Topic; Insulin; Life Style; Metformin; Multicenter Studies as Topic; Pioglitazone; Polycystic Ovary Syndrome; Quality of Life; Randomized Controlled Trials as Topic; Spironolactone; Young Adult
PubMed: 37715279
DOI: 10.1186/s13063-023-07593-6 -
International Journal of Molecular... Jun 2022The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently...
The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlovid and the polymerase inhibitor molnupiravir, both targeting mutant-prone viral components, were approved for high-risk COVID-19 patients. Nevertheless, effective therapeutics to treat COVID-19 are urgently needed, especially small molecules acting independently of VoCs and targeting genetically stable cellular pathways which are crucial for viral replication. Pamapimod is a selective inhibitor of p38 Mitogen-Activated Protein Kinase alpha (p38 MAPKα) that has been extensively clinically evaluated for the treatment of rheumatoid arthritis. Signaling via p38 has recently been described as a key pathway for the replication of SARS-CoV-2. Here, we reveal that the combination of pamapimod with pioglitazone, an anti-inflammatory and approved drug for the treatment of type 2 diabetes, possesses potent and synergistic activity to inhibit SARS-CoV-2 replication in vitro. Both drugs showed similar antiviral potency across several cultured cell types and similar antiviral activity against SARS-CoV-2 Wuhan type, and the VoCs Alpha, Beta, Gamma, Delta, and Omicron. These data support the combination of pamapimod and pioglitazone as a potential therapy to reduce duration and severity of disease in COVID-19 patients, an assumption currently evaluated in an ongoing phase II clinical study.
Topics: Antiviral Agents; Diabetes Mellitus, Type 2; Humans; Pioglitazone; Pyridones; Pyrimidines; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35743273
DOI: 10.3390/ijms23126830 -
Ulusal Travma Ve Acil Cerrahi Dergisi =... Jun 2024This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing...
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-β), 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-β 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.
Topics: Animals; Pioglitazone; Metformin; Tissue Adhesions; Rats, Wistar; Rats; Disease Models, Animal; Hypoglycemic Agents; Male; Thiazolidinediones; Postoperative Complications
PubMed: 38863295
DOI: 10.14744/tjtes.2024.61732 -
Head & Neck Apr 2020This study aimed to evaluate the association between pioglitazone use and the occurrence of head and neck cancer.
BACKGROUND
This study aimed to evaluate the association between pioglitazone use and the occurrence of head and neck cancer.
METHODS
Data for this case-control study were retrieved from the Taiwan National Health Insurance Research Database. A total of 21 464 diabetic patients newly diagnosed with head and neck cancers were identified. We used propensity score matching to select 64 392 comparison patients (3:1 ratio). Multiple logistic regression modeling was used to examine the association of head and neck cancer with pioglitazone use in the 5 years preceding the cancer diagnosis.
RESULTS
Bivariate analysis showed a significant difference in the prevalence of prior using pioglitazone between cases and controls (19.3% vs 18.5%, P < .001) was observed. Multiple regression analysis showed adjusted odds of pioglitazone use of 1.06 (95% CI: 1.02-1.10) among cases relative to controls.
CONCLUSIONS
Prior pioglitazone use was associated with oral cavity cancer.
Topics: Case-Control Studies; Head and Neck Neoplasms; Humans; Hypoglycemic Agents; Pioglitazone; Taiwan
PubMed: 31833151
DOI: 10.1002/hed.26046 -
Journal of Cellular Biochemistry Aug 2023As a master transcription factor, c-Myc plays an important role in promoting tumor immune escape. In addition, PPARγ (peroxisome proliferator-activated receptor γ)...
As a master transcription factor, c-Myc plays an important role in promoting tumor immune escape. In addition, PPARγ (peroxisome proliferator-activated receptor γ) regulates cell metabolism, inflammation, and tumor progression, while the effect of PPARγ on c-Myc-mediated tumor immune escape is still unclear. Here we found that cells treated with PPARγ agonist pioglitazone (PIOG) reduced c-Myc protein expression in a PPARγ-dependent manner. qPCR analysis showed that PIOG had no significant effect on c-Myc gene levels. Further analysis showed that PIOG decreased c-Myc protein half-life. Moreover, PIOG increased the binding of c-Myc to PPARγ, and induced c-Myc ubiquitination and degradation. Importantly, c-Myc increased PD-L1 and CD47 immune checkpoint protein expression and promoted tumor immune escape, while PIOG inhibited this event. These findings suggest that PPARγ agonist inhibited c-Myc-mediated tumor immune escape by inducing its ubiquitination and degradation.
Topics: Humans; Colorectal Neoplasms; Gene Expression Regulation; Pioglitazone; PPAR gamma; Thiazolidinediones; Tumor Escape; Proto-Oncogene Proteins c-myc
PubMed: 37393598
DOI: 10.1002/jcb.30437