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1.
Dermatol Ther ; 35(11): e15868, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36169160

RESUMO

Lichen planopilaris (LPP) is a scarring alopecia for which no treatment with remarkable effect has been identified. Pioglitazone has been reported as a possible therapeutic option. To compare the efficacy and safety of pioglitazone with clobetasol in LPP. This randomized, double-blind, parallel-group was conducted at Razi hospital. Patients were treated either with pioglitazone 15 mg/daily or clobetasol lotion 0.05% once at night for 6 months. Patients were visited every 2 months to assess the lichen planopilaris activity index (LPPAI) and record probable adverse events. Forty patients (mean age: 43.6 years; 62.5% female) were randomized 1:1. The mean of LPPAI at baseline and last session were 4.68 ± 1.97 and 2.59 ± 0.97 in the clobetasol group and 5.01 ± 1.71 and 3.04 ± 1.36 in the pioglitazone group, respectively. Both treatments significantly decreased the LPPAI over the two-month interval visits (p < 0.001). No significant difference in the LPPAI reduction was detected between groups. Regarding the safety profile, three clobetasol-treated patients developed folliculitis, and two in the pioglitazone group developed mild headaches. Pioglitazone effectively controlled the signs and symptoms of the LPP with no serious side effects. It can be considered a treatment option for LPP, although it was not superior to clobetasol.


Assuntos
Clobetasol , Líquen Plano , Humanos , Feminino , Adulto , Masculino , Clobetasol/uso terapêutico , Pioglitazona/efeitos adversos , Resultado do Tratamento , Líquen Plano/diagnóstico , Líquen Plano/tratamento farmacológico , Líquen Plano/induzido quimicamente , Alopecia/tratamento farmacológico
3.
Pharmacoepidemiol Drug Saf ; 31(10): 1039-1045, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35790047

RESUMO

PURPOSE: National regulators in Australia and the United Kingdom issued safety advisories on the association between pioglitazone use and bladder cancer in July 2011. The Australian advisory noted that males were at higher risk of bladder cancer than females, while the UK advisory highlighted a new recommendation, suggest careful consideration in the elderly due to increasing risk with age. This study examined whether these differences in the advisories had different age- and sex-based impacts in each country. METHODS: Interrupted time series analysis was used to compare pioglitazone use (prescriptions/100000 population) in Australia and the United Kingdom for the 24 months before and 11 months after the July 2011 safety advisories (study period July 2009-June 2012). Separate models were used to compare use by sex and age group (≥65 years vs. <65 years) in each country. RESULTS: Pioglitazone use fell in Australia (17%) and the United Kingdom (24%) following the safety advisories. Use of pioglitazone fell more for males (18%) than females (16%) in Australia, and more for females (25%) than males (23%) in the United Kingdom; however, neither difference was statistically significant (Australia p = 0.445, United Kingdom p = 0.462). Pioglitazone use fell to a similar extent among older people than younger people in the United Kingdom (23% vs. 26%, p = 0.354), and did not differ between age groups in Australia (both 18%, p = 0.772). CONCLUSIONS: The results indicate that differences in the Australian and UK safety advisories resulted in substantial reductions in pioglitazone use at the population level in both countries, however, differences by sub-groups were not observed.


Assuntos
Diabetes Mellitus Tipo 2 , Tiazolidinedionas , Neoplasias da Bexiga Urinária , Idoso , Austrália/epidemiologia , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Análise de Séries Temporais Interrompida , Masculino , Pioglitazona/efeitos adversos , Tiazolidinedionas/efeitos adversos , Reino Unido/epidemiologia , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/epidemiologia
4.
Int J Cancer ; 151(12): 2195-2205, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-35830207

RESUMO

The N-nitroso-trischloroethylurea (NTCU)-induced mouse model of squamous lung carcinoma recapitulates human disease from premalignant dysplasia through invasive tumors, making it suitable for preclinical chemoprevention drug testing. Pioglitazone is a peroxisome proliferator-activated receptor γ (PPARγ) agonist shown to prevent lung tumors in preclinical models. We investigated pioglitazone's effect on lesion development and markers of potential preventive mechanisms in the NTCU model. Female FVB/N mice were exposed to vehicle, NTCU or NTCU + oral pioglitazone for 32 weeks. NTCU induces the appearance of basal cells in murine airways while decreasing/changing their epithelial cell makeup, resulting in development of bronchial dysplasia. H&E and keratin 5 (KRT5) staining were used to detect and grade squamous lesions in formalin fixed lungs. mRNA expression of epithelial to mesenchymal transition (EMT) markers and basal cell markers were measured by qPCR. Dysplasia persistence markers desmoglein 3 and polo like kinase 1 were measured by immunohistochemistry. Basal cell markers KRT14 and p63, club cell specific protein and ciliated cell marker acetylated tubulin were measured by immunofluorescence. Pioglitazone treatment significantly reduced squamous lesions and the presence of airway basal cells, along with increasing normal epithelial cells in the airways of NTCU-exposed mice. Pioglitazone also significantly influenced EMT gene expression to promote a more epithelial, and less mesenchymal, phenotype. Pioglitazone reduced the presence of squamous dysplasia and maintained normal airway cell composition. This work increases the knowledge of mechanistic pathways in PPARγ agonism for lung cancer interception and provides a basis for further investigation to advance this chemoprevention strategy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Camundongos , Feminino , Humanos , Animais , PPAR gama , Queratina-5 , Transição Epitelial-Mesenquimal , Pioglitazona/efeitos adversos , Tubulina (Proteína) , Desmogleína 3 , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/induzido quimicamente , Pulmão/patologia , Formaldeído/efeitos adversos , RNA Mensageiro
5.
Braz J Biol ; 84: e260091, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35584460

RESUMO

Epilepsy is one of the most common neurological disorders affecting most social, economic and biological aspects of human life. Most patients with epilepsy have uncontrolled seizures and drug side effects despite the medications. Patients with epilepsy often have problems with attention, memory, and information processing speed, which may be due to seizures, underlying causes, or anticonvulsants. Therefore, improving seizure control and reducing or changing the anti-epileptic drugs can solve these problems, but these problems will not be solved in most cases. In this work, we looked at the effects of pioglitazone, a Peroxisome Proliferator-Activated Receptor agonist used to treat type 2 diabetes, on pilocarpine-induced seizures in mice. The Racine scale was used to classify pilocarpine-induced convulsions. After that, all of the animals were beheaded, and the brain and hippocampus were dissected. Finally, biochemical techniques were used to determine the levels of Malondialdehyde and Catalase activity, as well as Superoxide Dismutase and Glutathione Reductase in the hippocampus. The results of this investigation suggest that pioglitazone's antioxidant action may play a key role in its neuroprotective properties against pilocarpine-induced seizure neuronal damage.


Assuntos
Diabetes Mellitus Tipo 2 , Epilepsia , Animais , Antioxidantes , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Humanos , Masculino , Camundongos , Pilocarpina/uso terapêutico , Pilocarpina/toxicidade , Pioglitazona/efeitos adversos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
6.
BMC Cancer ; 22(1): 559, 2022 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-35585577

RESUMO

BACKGROUND: Whether pioglitazone may affect breast cancer risk in female diabetes patients is not conclusive and has not been investigated in the Asian populations. METHODS: The reimbursement database of Taiwan's National Health Insurance was used to enroll an unmatched cohort and a propensity score-matched cohort of ever users and never users of pioglitazone in female patients with newly diagnosed type 2 diabetes during 1999-2008. The patients were alive on January 1, 2009 and were followed up for breast cancer incidence until December 31, 2011. Cox regression was used to estimate hazard ratios for ever users and tertiles of cumulative duration of pioglitazone therapy versus never users, and for cumulative duration of pioglitazone therapy treated as a continuous variable. Three models were created for the unmatched cohort and the matched cohort, respectively: 1) without adjustment for covariates; 2) after adjustment for covariates that differed with statistical significance (P-value < 0.05) between ever users and never users; and 3) after adjustment for all covariates. RESULTS: There were 174,233 never users and 6926 ever users in the unmatched cohort; and 6926 never users and 6926 ever users in the matched cohort. After a median follow-up of 2.8 years, the numbers of incident breast cancer were 1044 in never users and 35 in ever users in the unmatched cohort and were 41 and 35, respectively, in the matched cohort. Hazard ratios suggested a null association between pioglitazone and breast cancer in all three models in either the unmatched cohort or the matched cohort. The overall hazard ratio after adjustment for all covariates was 0.758 (95% confidence interval: 0.539-1.065) in the unmatched cohort and was 0.824 (95% confidence interval: 0.524-1.296) in the matched cohort. None of the hazard ratios for the tertiles of cumulative duration of pioglitazone therapy and for the cumulative duration being treated as a continuous variable were statistically significant. CONCLUSIONS: This study suggests a null association between pioglitazone and breast cancer risk in female patients with type 2 diabetes mellitus. However, because of the small breast cancer cases and the limited follow-up time, further studies are warranted to confirm our findings.


Assuntos
Neoplasias da Mama , Diabetes Mellitus Tipo 2 , Metformina , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/epidemiologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Incidência , Pioglitazona/efeitos adversos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia
7.
Sci Rep ; 12(1): 4026, 2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35256739

RESUMO

Inflammation is a biological response of the immune system, which can be triggered by many factors, including pathogens. These factors may induce acute or chronic inflammation in various organs, including the reproductive system, leading to tissue damage or disease. In this study, the RNA-Seq technique was used to determine the in vitro effects of peroxisome proliferator-activated receptor gamma (PPARγ) ligands on the expression of genes and long non-coding RNA, and alternative splicing events (ASEs) in LPS-induced inflammation of the porcine endometrium during the follicular phase of the estrous cycle. Endometrial slices were incubated in the presence of LPS and PPARγ agonists (PGJ2 or pioglitazone) and a PPARγ antagonist (T0070907). We identified 169, 200, 599 and 557 differentially expressed genes after LPS, PGJ2, pioglitazone or T0070907 treatment, respectively. Moreover, changes in differentially expressed long non-coding RNA and differential alternative splicing events were described after the treatments. The study revealed that PPARγ ligands influence the LPS-triggered expression of genes controlling the DNA damage response (GADD45ß, CDK1, CCNA1, CCNG1, ATM). Pioglitazone treatment exerted a considerable effect on the expression of genes regulating the DNA damage response.


Assuntos
RNA Longo não Codificante , Tiazolidinedionas , Animais , Dano ao DNA , Endométrio/metabolismo , Feminino , Inflamação/metabolismo , Ligantes , Lipopolissacarídeos/metabolismo , PPAR gama/metabolismo , Pioglitazona/efeitos adversos , Prostaglandina D2/metabolismo , RNA Longo não Codificante/metabolismo , Suínos , Tiazolidinedionas/efeitos adversos
8.
Nutr Metab Cardiovasc Dis ; 32(3): 529-536, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35144855

RESUMO

AIM: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. After identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, the experts decided to perform a systematic review and meta-analysis on the effect of pioglitazone with this respect. DATA SYNTHESIS: A MEDLINE database search was performed to identify RCTs, up to June 1st, 2021, with duration≥52 weeks, in which pioglitazone was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Eight RCTs were included in the analysis for MACEs and HF (5048 and 5117 patients in the pioglitazone and control group, respectively), and 24 in that for all-cause mortality (10,682 and 9674 patients). Pioglitazone neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 0.90, 95% CI 0.78-1.03, 0.91, 95% CI 0.77, 1.09, and 1.16, 95% CI 0.73, 1.83, respectively). Pioglitazone was associated with a significant reduction of MACE in patients with prior cardiovascular events (MH-OR 0.84, 95% CI 0.72-0.99). CONCLUSIONS: This meta-analysis showed no significant effects of pioglitazone on incident MACE, all-cause mortality, and HHF.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/efeitos adversos , Pioglitazona/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Artigo em Inglês | MEDLINE | ID: mdl-35177899

RESUMO

BACKGROUND: Pioglitazone's effect on chronic obstructive pulmonary disease (COPD) has rarely been studied. PURPOSE: This retrospective observational study investigated whether the use of pioglitazone would affect the risk of COPD in patients with type 2 diabetes mellitus. PATIENTS AND METHODS: The Taiwan's National Health Insurance database was used to enroll 9487 matched pairs of ever users and never users of pioglitazone based on propensity score from a cohort of 350,536 patients. The enrolled patients had a new diagnosis of type 2 diabetes mellitus between 1999 and 2008 and were not having a diagnosis of COPD before January 1, 2009. They were then followed up for COPD, starting from January 1, 2009 until December 31, 2011. Diagnosis of COPD was based on the codes of 491 for chronic bronchitis and 492 for emphysema based on the International Classification of Diseases, Ninth Revision, Clinical Modification. Cox regression was used to estimate hazard ratios. The interactions between pioglitazone and COPD risk factors including pneumonia, pulmonary tuberculosis and tobacco abuse were also investigated. RESULTS: In 9487 never users and 9487 ever users of pioglitazone, the case numbers of incident COPD were 359 and 295, respectively. The respective incidence rates of COPD were 1484.73 and 1167.61 per 100,000 person-years. The overall hazard ratio (95% confidence interval) for COPD that compared ever to never users was 0.778 (0.667-0.908). The hazard ratios for the tertiles of cumulative duration of pioglitazone therapy (cutoffs: <11.0, 11.0-19.6 and >19.6 months) to never users were 0.904 (0.729-1.121), 0.727 (0.578-0.914) and 0.715 (0.570-0.896), respectively. No interactions between pioglitazone and COPD risk factors including pneumonia, pulmonary tuberculosis and tobacco abuse were noted. CONCLUSION: Pioglitazone use is associated with a significantly lower risk of COPD.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Doença Pulmonar Obstrutiva Crônica , Estudos de Coortes , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Hipoglicemiantes/efeitos adversos , Incidência , Metformina/uso terapêutico , Pioglitazona/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia
10.
Eur J Gastroenterol Hepatol ; 34(1): 104-111, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33852508

RESUMO

OBJECTIVE: Diabetes is the fifth leading cause of death in the People's Republic of China. The aim of the article is to compare the effects of nursing care on the laboratory findings and ultrasound results of diabetic patients with chronic liver diseases (CLD) who were treated with antiglycemic drugs. METHODS: Diabetic were patients treated with metformin hydrochloride in combination with gliclazide, pioglitazone hydrochloride, sitagliptin, exenatide or liraglutide. Non-alcoholic fatty liver disease (NAFLD) was evaluated by abdominal ultrasound, and fibrosis stages were evaluated at baseline and 8 months. All the patients were equally divided into two groups depending on the therapeutic approach. RESULTS: The first group of patients additionally received nursing care, and the second group adhered to the prescribed therapy on their own. In total 90 patients, or 55.6%, had NAFLD at baseline, and its course was dependent upon changes in the weight (P = 0.009) and waist circumference (P = 0.012). The proportions of patients who demonstrated an ultrasonographic improvement in the control group were: 24 (56.8%) with gliclazide, 15 (41.3%) with pioglitazone hydrochloride, 28 (66.1%) with sitagliptin, 16 (79%) with exenatide and 15 (66.7%) with liraglutide (P = 0.2). For the group that received nursing care an ultrasonographic improvement was in: 29 (68.16%) with gliclazide, 18 (49.56%) with pioglitazone hydrochloride, 33 (79.32%) with sitagliptin, 19 (94.8%) with exenatide and 21 80.04% with liraglutide (P = 0.2). CONCLUSIONS: Outcomes from the type 2 diabetes treatment paralleling of CLD were presented. Treatment of type 2 diabetes with pioglitazone hydrochloride, gliclazide, sitagliptin, liraglutide and exenatide was proven effective.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Hepatopatia Gordurosa não Alcoólica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enfermagem , Exenatida/efeitos adversos , Gliclazida/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Liraglutida/efeitos adversos , Metformina/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/enfermagem , Pioglitazona/efeitos adversos , Fosfato de Sitagliptina/efeitos adversos
11.
Cardiovasc Diabetol ; 20(1): 109, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006325

RESUMO

Since 1985, the thiazolidinedione pioglitazone has been widely used as an insulin sensitizer drug for type 2 diabetes mellitus (T2DM). Although fluid retention was early recognized as a safety concern, data from clinical trials have not provided conclusive evidence for a benefit or a harm on cardiac function, leaving the question unanswered. We reviewed the available evidence encompassing both in vitro and in vivo studies in tissues, isolated organs, animals and humans, including the evidence generated by major clinical trials. Despite the increased risk of hospitalization for heart failure due to fluid retention, pioglitazone is consistently associated with reduced risk of myocardial infarction and ischemic stroke both in primary and secondary prevention, without any proven direct harm on the myocardium. Moreover, it reduces atherosclerosis progression, in-stent restenosis after coronary stent implantation, progression rate from persistent to permanent atrial fibrillation, and reablation rate in diabetic patients with paroxysmal atrial fibrillation after catheter ablation. In fact, human and animal studies consistently report direct beneficial effects on cardiomyocytes electrophysiology, energetic metabolism, ischemia-reperfusion injury, cardiac remodeling, neurohormonal activation, pulmonary circulation and biventricular systo-diastolic functions. The mechanisms involved may rely either on anti-remodeling properties (endothelium protective, inflammation-modulating, anti-proliferative and anti-fibrotic properties) and/or on metabolic (adipose tissue metabolism, increased HDL cholesterol) and neurohormonal (renin-angiotensin-aldosterone system, sympathetic nervous system, and adiponectin) modulation of the cardiovascular system. With appropriate prescription and titration, pioglitazone remains a useful tool in the arsenal of the clinical diabetologist.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Sistema Cardiovascular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , PPAR gama/agonistas , Pioglitazona/uso terapêutico , Animais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Hipoglicemiantes/efeitos adversos , PPAR gama/metabolismo , Pioglitazona/efeitos adversos , Medição de Risco , Fatores de Risco , Transdução de Sinais , Resultado do Tratamento
12.
Environ Mol Mutagen ; 62(2): 143-154, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33496997

RESUMO

Pioglitazone (PIO), an oral hypoglycemic agent, is used in the treatment of type 2 diabetes. Some studies have suggested that an increased risk of bladder cancer with PIO exposure, while the others reported there is no such relationship. Therefore, it is doubtful whether PIO can increase the risk of bladder cancer. The effects of PIO on DNA damage and/or transformation of human bladder cells are not fully known. We investigated the effects of PIO on cytotoxicity, DNA single and double strand breaks and repair and neoplastic transformation in human bladder cells (hTU1) treated with 10, 20, and 40 µM PIO for 24, 48 and 72 hr. PIO decreased cell viability in a concentration-dependent manner. Increased levels of comet parameters showed that PIO and its metabolites can significantly induce DNA double strand breaks at all concentrations tested. PIO also significantly induced the formation of phosphorylated H2AX and p53 binding protein 1 foci. DNA damage was not repaired in a 24 hr recovery period. PIO can also induce malignant transformation of human bladder cells exhibiting loss of contact inhibition and anchorage independent growth. This is the first study to indicate that PIO can induce DNA damage and malignant transformation, reduce or alter the DNA repair capacity in human bladder cells. From these results, we suggest that patients with diabetes treated with PIO may have an increased risk of bladder cancer.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , DNA/efeitos dos fármacos , Pioglitazona/efeitos adversos , Neoplasias da Bexiga Urinária/induzido quimicamente , Bexiga Urinária/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Células Epiteliais/efeitos dos fármacos , Humanos , Pioglitazona/farmacologia , Neoplasias da Bexiga Urinária/genética
13.
Mol Med ; 26(1): 128, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33308138

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited chronic kidney disorder (CKD) that is characterized by the development of numerous fluid-filled cysts in kidneys. It is caused either due to the mutations in the PKD1 or PKD2 gene that encodes polycystin-1 and polycystin-2, respectively. This condition progresses into end-stage renal disorder if the renal or extra-renal clinical manifestations remain untreated. Several clinical trials with a variety of drugs have failed, and the only Food and Drugs Administration (FDA) approved drug to treat ADPKD to date is tolvaptan that works by antagonizing the vasopressin-2 receptor (V2R). The pathology of ADPKD is complex and involves the malfunction of different signaling pathways like cAMP, Hedgehog, and MAPK/ERK pathway owing to the mutated product that is polycystin-1 or 2. A measured yet substantial number of preclinical studies have found pioglitazone to decrease the cystic burden and improve the renal function in ADPKD. The peroxisome proliferator-activated receptor-gamma is found on the epithelial cells of renal collecting tubule and when it gets agonized by pioglitazone, confers efficacy in ADPKD treatment through multiple mechanisms. There is only one clinical trial (ongoing) wherein it is being assessed for its benefits and risk in patients with ADPKD, and is expected to get approval from the regulatory body owing to its promising therapeutic effects. This article would encompass the updated information on the epidemiology, pathophysiology of ADPKD, different mechanisms of action of pioglitazone in the treatment of ADPKD with preclinical and clinical shreds of evidence, and related safety updates.


Assuntos
Predisposição Genética para Doença , Pioglitazona/uso terapêutico , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/genética , Animais , Biomarcadores , Gerenciamento Clínico , Regulação da Expressão Gênica , Estudos de Associação Genética , Humanos , Mutação , Fenótipo , Pioglitazona/administração & dosagem , Pioglitazona/efeitos adversos , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/epidemiologia , Transdução de Sinais , Resultado do Tratamento
14.
J Stroke Cerebrovasc Dis ; 29(10): 105048, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912514

RESUMO

OBJECTIVE: Standards for reporting and analyzing adherence to medical therapy have recently improved due to international consensus efforts. If applied to clinical trial research in patients with stroke, these improvements have the potential to identify when in the sequence of trial operations participants are at risk for non-adherence and opportunities to safeguard adherence. METHODS: We analyzed three phases of adherence according to the European Society for Patient Adherence, COMpliance, and Persistence (ESPACOMP) Medication Adherence Reporting Guideline (EMERGE) taxonomy in the Insulin Resistance Intervention after Stroke (IRIS) trial: initiation (did patient start drug), implementation (did patient take a drug holiday, defined as temporary cessation lasting ≥14 days), and persistence (did patient prematurely and permanently discontinue drug). IRIS was a randomized, placebo controlled, double-blind trial testing pioglitazone to prevent stroke or myocardial infarction in patients with a recent ischemic stroke or transient ischemic attack. Adherence was classified by self-report. Researchers used coaching algorithms to seek adherence recovery if participants went off drug. RESULTS: During 2005-2013, 3876 participants were enrolled from 179 sites in seven countries and followed for a mean of 4.8 years. Less than 1% of participants in each group did not initiate study drug. 20% of patients assigned to pioglitazone and 17% assigned to placebo took at least one drug holiday. 36% and 30%, respectively, discontinued the study drug prematurely with or without a prior holiday. The risk for stopping the study drug (temporarily or permanently) in the first year after randomization was twice the risk in each of the subsequent four years. This was true both for patients assigned to active therapy and placebo. More participants assigned to pioglitazone, compared to placebo, took a drug holiday or permanently stopped study drug, but the difference in rates of discontinuation was only evident in year one. In years two through five, rates of discontinuation were similar in the two treatment groups. The difference in rates during year one was the result of adverse effects related to the active study drug, pioglitazone. During the remainder of the trial, the attribution of discontinuations to adverse effects potentially related to pioglitazone was reduced but still higher in those assigned to active drug. Other reasons for discontinuation were similar between treatment groups and were largely unrelated to pharmacodynamic effects of the study drug. Rates of discontinuation varied widely among research sites. CONCLUSION: Patients in a drug trial for stroke prevention are at greatest risk for premature drug discontinuation early after randomization. Reasons for discontinuation change over time. Variable discontinuation rates among sites suggests that adherence can be improved by using best practices from high-performing sites.


Assuntos
Hipoglicemiantes/administração & dosagem , Resistência à Insulina , Ataque Isquêmico Transitório/prevenção & controle , Adesão à Medicação , Infarto do Miocárdio/prevenção & controle , Pioglitazona/administração & dosagem , Prevenção Secundária , Acidente Vascular Cerebral/prevenção & controle , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Ataque Isquêmico Transitório/etiologia , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/fisiopatologia , Pioglitazona/efeitos adversos , Recidiva , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
15.
Sci Rep ; 10(1): 15781, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978507

RESUMO

The safety and usefulness of pioglitazone (Pio) is repeatedly called into question due to the contradictory information available about it. A meta-analysis and risk benefit assessment was conducted to address the various points of debate regarding Pio. Electronic database search (Cochrane library, Embase & PubMed) resulted in 10 citations eligible for this meta-analysis (prospective, randomised studies), which was conducted using CMA software version 3 (Biostat Inc., Englewood, NJ, USA). The meta-analysis was registered with PROSPERO (ID: CRD42019122403) and compared pioglitazone with a control (anti-hyperglycemic agents without pioglitazone) in patients with either established cardiovascular disease or having high cardiovascular risk. Sensitivity and subgroup analysis were conducted to differentiate the effect of Pio against active controls and placebo. The use of Pio compared to the control group that did not use Pio resulted in a 14% and 23% significant reduction in odds of major adverse cardiac events (MACE: MH-OR, 0.86; 95% CI 0.75-0.98), and stroke (MH-OR, 0.77; 95% CI 0.60-0.99), respectively. This reduction in stroke was not significant in comparison to placebo on subgroup analysis. However, Pio significantly increased odds of heart failure (HF) (MH-OR, 1.47; 95% CI 1.26-1.71) as well as hospitalization for heart failure (hHF) (MH-OR, 1.48; 95% CI 1.21-1.81). In addition, the use of Pio was associated with a significant increase in odds of fractures in women (MH-OR, 2.05; 95% CI 1.28-3.27) and anaemia (MH-OR, 2.56; 95% CI 1.55-4.21). Pio has no significant effect on bladder cancer nor macular oedema. Pio has salutary effects on MACE. The positive effects are completely offset by the harm they seem to cause by way of heart failure, fractures, and anaemia. Pio should therefore be reserved for treatment of T2D with high CV risk or established cardiovascular (CV) disease only in selected patients where other antidiabetics are precluded and not routinely.


Assuntos
Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/tratamento farmacológico , Pioglitazona/efeitos adversos , Pioglitazona/uso terapêutico , Medição de Risco , Humanos , Estudos Prospectivos
16.
Cardiovasc Diabetol ; 19(1): 94, 2020 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-32563247

RESUMO

BACKGROUND: Studies assessing the efficacy of pioglitazone solely for primary stroke prevention in Asian patients with type 2 diabetes mellitus (DM) and present multiple cardiovascular (CV) risk factors are rare. Thus, we aimed to assess the effect of pioglitazone on primary stroke prevention in Asian patients with type 2 DM without established CV diseases but with risk factors for CV diseases. METHODS: Between 2000 and 2012, we enrolled patients aged ≥ 18 years, who were newly diagnosed with type 2 diabetes and had at least one of the following CV risk factors: hypertension and hyperlipidemia. Patients with a history of stroke and those using insulin or glucagon-like peptide-1 agonist for more than 3 months were excluded. Patients were divided into the pioglitazone and non-pioglitazone groups based on their receipt of pioglitazone during the follow-up period. Propensity-score matching (1:1) was used to balance the distribution of the baseline characteristics and medications. Follow-up was terminated upon ischemic stroke development, withdrawal from the insurance system, or on December 31, 2013, whichever occurred first. The overall incidence of new-onset ischemic stroke in the two groups was subsequently compared. The subgroup analyses of ischemic stroke were conducted using different baseline features. Additionally, the effect of pioglitazone exposure dose on the occurrence of ischemic stroke was evaluated. Chi square test, Student's t-test, competing risk regression models, Kaplan-Meier method, and log-rank test were some of the statistical tests conducted. RESULTS: A total of 13 078 patients were included in the pioglitazone and non-pioglitazone groups. Compared with patients who did not receive pioglitazone, those administered pioglitazone had a lower risk of developing ischemic stroke (adjusted hazard ratio: 0.78; 95% confidence interval: 0.62-0.95). The subgroup analyses defined by different baseline features did not reveal significant alterations in the observed effect of pioglitazone. Moreover, a significant decreasing trend in ischemic stroke risk with an increase in pioglitazone dose (p-value for trend = 0.04) was observed. CONCLUSION: Pioglitazone use decreased the risk of new-onset ischemic stroke in Asian patients with type 2 DM and CV risk factors. Trial registration number CMUH104-REC2-115-CR4.


Assuntos
Isquemia Encefálica/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Pioglitazona/uso terapêutico , Prevenção Primária , Acidente Vascular Cerebral/prevenção & controle , Idoso , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etnologia , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etnologia , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pioglitazona/efeitos adversos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etnologia , Taiwan/epidemiologia , Fatores de Tempo , Resultado do Tratamento
17.
Cardiovasc Diabetol ; 19(1): 93, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32560724

RESUMO

BACKGROUND: The potential for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes (T2DM) is of persistent attention. The PRESS XII study primarily aimed to evaluate the efficacy and safety of saroglitazar (2 mg and 4 mg) as compared to pioglitazone 30 mg on glycemic control in patients with type 2 diabetes mellitus. METHODS: In this randomized double-blind study, patients with T2DM [glycosylated hemoglobin (HbA1c) ≥ 7.5%] were enrolled from 39 sites in India. Patients received once-daily doses of either saroglitazar or pioglitazone (1:1:1 allocation ratio) for a total of 24 weeks. Patients were continued in a double blind extension period for an additional 32 weeks. Efficacy evaluations of glycemic parameters [HbA1c (Primary endpoint at week 24), FPG and PPG] and other lipid parameters (TG, LDL-C, VLDL-C, HDL-C, TC, Non HDL-C, Apo A1 and Apo B) were conducted at week 12, 24 and 56 and compared to the baseline levels. The efficacy analyses were performed by using paired t-test and ANCOVA model. RESULTS: A total of 1155 patients were enrolled in this study. The baseline characteristics were similar between the three treatment groups. The within group mean (± SD) change in HbA1c (%) from baseline of the saroglitazar (2 mg and 4 mg) and pioglitazone treatment groups at week 24 were: - 1.38 ± 1.99 for saroglitazar 2 mg; - 1.47 ± 1.92 for saroglitazar 4 mg and - 1.41 ± 1.86 for pioglitazone, respectively. Statistically significant reduction from baseline in HbA1c was observed in each treatment group at week 24 with p-value < 0.016. There was a significant reduction in TG, LDL-C, VLDL-C, TC and Non HDL-C with a significant increase in HDL-C from baseline levels (< 0.016). Most of the AE's were 'mild' to 'moderate' in severity and were resolved by the completion of the study. CONCLUSIONS: Saroglitazar effectively improved glycemic control and lipid parameters over 56 weeks in patients of T2DM receiving background metformin therapy and has a promising potential to reduce the cardiovascular risk in T2DM patients. Trial registration CTRI/2015/09/006203, dated 22/09/2015.


Assuntos
Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Lipídeos/sangue , Fenilpropionatos/administração & dosagem , Pioglitazona/administração & dosagem , Pirróis/administração & dosagem , Biomarcadores/sangue , Glicemia/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Método Duplo-Cego , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Índia/epidemiologia , Fenilpropionatos/efeitos adversos , Pioglitazona/efeitos adversos , Estudos Prospectivos , Pirróis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
18.
Psychopharmacology (Berl) ; 237(8): 2367-2380, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32445052

RESUMO

RATIONALE: Proinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPARγ) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPARγ activity may have therapeutic potential in alcohol dependence. OBJECTIVES: We conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving. METHODS: Participants were treated for withdrawal, if needed, and then randomized to pioglitazone (target dose 45 mg/day) or placebo. Once at target dose, they completed two experimental manipulations: guided imagery, which used personalized auditory scripts to induce alcohol cravings, and a low-dose challenge with i.v. lipopolysaccharide (LPS; 0.8 ng/kg) or placebo, on two separate sessions, in counterbalanced order. Behavioral and endocrine responses as well as CSF levels of proinflammatory cytokines were evaluated. RESULTS: The study was prematurely terminated after randomization of 16 subjects, following an independent review that established a high risk of myopathy in the active treatment group. Analysis of those who completed the study indicated that pioglitazone was associated with elevated, rather than suppressed alcohol cravings in response to alcohol-associated stimuli. LPS did not induce cravings for alcohol and thus did not lend itself to evaluating pioglitazone effects; however, pioglitazone increased the neuroendocrine stress response to LPS. CSF levels of IL-6, TNF-α, or MCP-1 were unaffected by pioglitazone treatment. CONCLUSIONS: Both safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence. CLINICAL TRIAL REGISTRATION: NCT01631630.


Assuntos
Alcoolismo/metabolismo , Fissura/efeitos dos fármacos , Doenças Musculares/induzido quimicamente , Doenças Musculares/metabolismo , PPAR gama/metabolismo , Pioglitazona/uso terapêutico , Adulto , Alcoolismo/tratamento farmacológico , Animais , Fissura/fisiologia , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Imaginação/efeitos dos fármacos , Imaginação/fisiologia , Lipopolissacarídeos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/diagnóstico , Pioglitazona/efeitos adversos , Estudo de Prova de Conceito , Recidiva , Adulto Jovem
19.
J Pak Med Assoc ; 70(4): 757-761, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32296231
20.
Metab Syndr Relat Disord ; 18(3): 168-171, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32250209

RESUMO

Background: Pioglitazone is an effective treatment option in clinical practice for managing type 2 diabetes mellitus. It is challenged by a lot of adverse effects, primarily body weight gain, peripheral edema, as well as congestive heart failure. Case Report: This is a case of a 76-year-old woman with no evidence of cardiac disease, who developed edema as well as bilateral pleural effusion after using pioglitazone. She got a weight decrease and complete resolution of the pleural effusion after stopping use of pioglitazone and rational use of diuretics. Conclusion: Common side effects of pioglitazone have been widely reported. However, little attention was drawn on pleural effusion in diabetic patients with no pre-existing heart dysfunction. In this case, we show the use of pioglitazone results in pleural effusion, with emphasis on the clinical recognition and management.


Assuntos
Hipoglicemiantes/efeitos adversos , Pioglitazona/efeitos adversos , Derrame Pleural/induzido quimicamente , Idoso , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diuréticos/uso terapêutico , Edema/induzido quimicamente , Edema/diagnóstico , Edema/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Pioglitazona/uso terapêutico , Derrame Pleural/diagnóstico , Derrame Pleural/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
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