Meta-analysis for bioequivalence studies : interchangeability of generic drugs and similar containing Hydrochlorothiazide is possible but not with Enalapril Maleate

INTRODUÇÃO: O programa de genéricos no Brasil propiciou maior acesso da população a medicamentos. Para garantir a intercambiabilidade entre medicamentos referência e genérico ou similar, é necessário que eles sejam bioequivalentes. Com o crescimento do número de medicamentos genéricos, é comum que pacientes o substituam por outro genérico ou similar. Contudo, essa troca pode não garantir a manutenção da bioequivalência. Para avaliar a segurança na intercambiabilidade entre diferentes genéricos e similares com Hidroclorotiazida e Maleato de Enalapril, foi realizada metanálise de vários estudos de bioequivalência que utilizaram esses medicamentos. MÉTODOS: Foram utilizados dados provenientes de estudos de bioequivalência de genéricos e similares registrados pela Agência Nacional de Vigilância Sanitária (Anvisa). A compatibilidade dos dados de cada um dos estudos foi analisada, e a determinação de um intervalo de confiança para as diferenças entre as médias dos parâmetros farmacocinéticos, área sob a curva (ASC) e concentração plasmática máxima (Cmáx ), foi feita para cada estudo por meio da metanálise. RESULTADOS: A intercambiabilidade entre as combinações dos três produtos com Hidroclorotiazida foi confirmada com base nos intervalos de confiança obtidos. Para os medicamentos com Maleato de Enalapril, a intercambiabilidade não foi confirmada em 50% das comparações estudadas dos produtos. CONCLUSÃO: A intercambiabilidade foi comprovada entre os três produtos com Hidroclorotiazida. No entanto, para o Maleato de Enalapril, metade dos produtos estudados não é intercambiável, uma vez que não contempla os intervalos preconizados pelos testes de bioequivalência; portanto, a resposta farmacocinética e, por conseguinte, a efetividade do medicamento podem ser alteradas.INTRODUCTION: The generic drugs program provided a better population's access to medicines. To ensure interchangeability between a brand-name and generic or similar drugs is necessary that they are bioequivalent. With the growing number of generic drugs, it is common for patients to replace a generic to another or one similar. However, this exchange can not guarantee the maintenance of bioequivalence. To evaluate the safety interchangeability between different generic and similar drugs with Hydrochlorothiazide and Enalapril Maleate, a meta-analysis was carried out with several bioequivalence studies with these drugs. METHODS: Data from bioequivalence of generic and similar drugs approved by the National Health Surveillance Agency (Anvisa) (drug regulatory agency in Brazil) were used. The compatibility of data from each study was analyzed and the determination of a confidence interval for the differences between the means of pharmacokinetic parameters, area under the curve (ASC0-t) and maximum plasma concentration (Cmax), was made for each study by meta-analysis. RESULTS: The interchangeability between the combinations of the three products with Hydrochlorothiazide was confirmed based on the obtained confidence intervals. For the drugs studied with Enalapril Maleate interchangeability has not been confirmed for 50% of the product comparisons. CONCLUSION: The exchange was established between the three products with hydrochlorothiazide. However, for the Enalapril Maleate half of the products studied are not interchangeable, considering they do not match the established intervals for bioequivalence tests, so the pharmacokinetics behavior and thus the effectiveness of the product may be changed

Idealized PPARγ-Based Therapies: Lessons from Bench and Bedside

The incidence of type 2 (T2D) diabetes and other chronic conditions associated with insulin resistance is increasing at an alarming rate, underscoring the need for effective and safe therapeutic strategies. Peroxisome-proliferator-activated receptor gamma (PPARγ) has emerged as a critical regulator of glucose homeostasis, lipid homeostasis, and vascular inflammation. Currently marketed drugs targeting this receptor, the thiazolidinediones (TZDs), have proven benefits on insulin resistance and hyperglycemia associated with T2D. Unfortunately, they have been associated with long-term unfavorable effects on health, such as weight gain, plasma volume expansion, bone loss, cardiovascular toxicity, and possibly cancer, and these safety concerns have led to reduced interest for many PPARγ ligands. However, over the last years, data from human genetic studies, animal models, and studies with ligands have increased our understanding of PPARγ's actions and provided important insights into how ligand development strategies could be optimized to increase effectiveness and safety of PPARγ-based therapies

Factors associated with mortality among patients with central venous catheter-related bloodstream infection in an intensive care unit

Central venous catheterization is a common practice in the management of critically ill patients and is associated with various complications, such as Bloodstream Infections (BSI), which are major determinants of increased morbidity, mortality and healthcare expenses. Few studies have addressed factors that predict mortality in patients with this complication. The aim of this study was to investigate factors associated with mortality in patients with Central Venous Catheter (CVC)-related BSI in an intensive care unit of a tertiary care hospital in the Federal District, Brazil. This was a retrospective and observational study, in which all CVC-related BSI that occurred between January 2008 and December 2010 were reviewed. We obtained demographic, clinical, biochemical and microbiological data from medical records and investigated its association with mortality during ICU stay. There were 4,504 ICU admissions during the study period and 68 were complicated by CVC-related BSI (4.09 per 1000 catheter-days), most due to gram-negative organisms (45.6%). Overall mortality was 59.7%. Death risk was significantly associated with mechanical ventilation (OR 27.8, 95% CI 3.28-250, p<0.001), the mean number of invasive devices other than the CVC (1.44 Vs 2.37 in controls Vs cases, p<0.001) and increased serum levels of urea (mean value of 44.2 mg dL-1 in survivors vs. 73.9 mg dL-1 in non-survivors, p = 0.001). Mortality was not associated with other clinical or biochemical features, neither with microbiological variables, although lethality was high among patients with gram-positive infections (77% Vs 58.33% for fungi and 54.83% for gram-negative). CVC-related BSI was associated with high absolute mortality, which was predicted by mechanical ventilation and a higher number of invasive devices other than the CVC. Knowledge of local factors predictive of mortality is critical for planning strategies to reduce death risk associated with this complication

Effects of dual blockade in heart failure and renal dysfunction: Systematic review and meta-analysis

OBJECTIVE: The effect of dual renin-angiotensin system (RAS) inhibition in heart failure (HF) is still controversial. Systematic reviews have shown that dual RAS blockade may reduce mortality and hospitalizations, yet it has been associated with the increased risk of renal dysfunction (RD). Surprisingly, although RD in patients with HF is frequent, the effect of combining RAS inhibitors in HF patients with RD has never been studied in a meta-analysis. METHODS: A systematic review and meta-analysis of randomized clinical trials involving HF patients with RD who received dual blockade analyzing death, cardiovascular (CV) death or HF hospitalization, and adverse events. RESULTS: Out of 2258 screened articles, 12 studies were included (34,131 patients). Compared with monotherapy, dual RAS inhibition reduced hazard ratio of death to 0.94 (p=0.07) and significantly reduced CV death or HF hospitalization to 0.89 (p=0.0006) in all individuals, and to 0.86 (p=0.005) in patients with RD and to 0.91 (p=0.04) without RD. Nevertheless, dual RAS blockade significantly increased the risk of renal impairment (40%), hyperkalemia (44%), and hypotension (42%), although discontinuation of treatment occurs only in 3.68% versus 2.19% (p=0.00001). CONCLUSIONS: Dual RAS inhibition therapy reduces the risk of CV death or HF hospitalization. However, cautions monitoring for specific adverse events may be warranted

Hipotireoidismo neonatal transitório em um menino com translocação não balanceada t(8;16)

Defeitos genéticos resultando em deficiência hormonal tireoidiana podem ser encontrados em cerca de 10% dos pacientes com hipotireoidismo congênito permanente, porém a identificação de anormalidades genéticas associadas à forma transitória da doença é extremamente rara. Relatamos o caso de um menino com hipotireoidismo neonatal transitório não diagnosticado no teste de triagem neonatal, associado a malformações extratireoidianas e retardo mental. O paciente é portador de translocação não balanceada t(8;16), e seu tio materno tinha fenótipo similar. A análise cromossômica definiu o cariótipo do paciente como 46,XY,der(8)t(8;16)(q24.3;q22)mat,16qh+. A análise cromossômica array-CGH com o DNA do paciente revelou deleção terminal de ~80 kb no cromossomo 8q24.3qter, e duplicação de ~21 Mb no cromossomo 16q22qter. O gene ZNF252, mapeado na região da deleção no cromossomo 8 do paciente, é altamente expresso na tireoide e pode ser um gene candidato no hipotireoidismo neonatal transitório do paciente. Esse é o primeiro relato de associação de uma translocação cromossômica com a forma transitória do hipotireoidismo congênito. Essa descrição descortina novas hipóteses para a fisiopatologia do hipotireoidismo congênito transitório e também pode contribuir para a definição do fenótipo da translocação não balanceada t(8;16)(q24.3;q22), nunca descrito anteriormente.Genetic defects resulting in deficiency of thyroid hormone synthesis can be found in about 10% of the patients with permanent congenital hypothyroidism, but the identification of genetic abnormalities in association with the transient form of the disease is extremely rare. We report the case of a boy with transient neonatal hypothyroidism that was undiagnosed in the neonatal screening, associated with extrathyroid malformations and mental retardation. The boy carries an unbalanced translocation t(8;16), and his maternal uncle had a similar phenotype. Chromosomal analysis defined the patient's karyotype as 46,XY,der(8)t(8;16)(q24.3;q22)mat,16qh+. Array-CGH with patient's DNA revealed a ~80 kb terminal deletion on chromosome 8q24.3qter, and a ~21 Mb duplication on chromosome 16q22qter. ZNF252 gene, mapped to the deleted region on patient's chromosome 8, is highly expressed in the thyroid, and may be a candidate gene for our patient's transient neonatal thyroid dysfunction. This is the first report on the association of a chromosomal translocation with the transient form of congenital hypothyroidism. This description creates new hypothesis for the physiopathology of transient congenital hypothyroidism, and may also contribute to the definition of the unbalanced translocation t(8;16)(q24.3;q22) phenotype, which has never been described before

Monitoring renal function : measured and estimated glomerular filtration rates : a review

Chronic kidney disease (CKD) is a world-wide public health problem, with adverse outcomes of kidney failure, cardiovascular disease, and premature death. This finding has led to the hypothesis that earlier recognition of kidney disease and successful intervention may improve outcome. The National Kidney Foundation, through its Kidney Disease Outcomes Quality Initiative (K/DOQI), and other National institutions recommend glomerular filtration rate (GFR) for the definition, classification, screening, and monitoring of CKD. Blood creatinine clearance, the most widely used clinical marker of kidney function, is now recognized as an unreliable measure of GFR because serum creatinine is affected by age, weight, muscle mass, race, various medications, and extra-glomerular elimination. Cystatin C concentration is a new and promising marker for kidney dysfunction in both native and transplanted kidneys. Because of its low molecular weight, cystatin C is freely filtered at the glomerulus and is almost completely reabsorbed and catabolized, but not secreted, by tubular cells. Given these characteristics, cystatin C concentration may be superior to creatinine concentration in detecting chronic kidney disease. This review aims to evaluate from recent literature the clinical efficiency and relevance of these GFR markers in terms of screening CKD

The inflammatory status of soluble microenvironment influences the capacity of melanoma cells to control t-cell responses

The development of immunotherapeutic approaches for the treatment of melanoma requires a better understanding of immunoescape mechanisms of tumor cells and how they interact with other tumor-resident cell types. Here, we evaluated how the conditioned media of resting (rCM) and immune-activated PBMCs (iCM) influence the ability of a metastatic melanoma cell line (MeWo) to control T-cells function. MeWo cells were expanded in RPMI, rCM, or iCM and the secretome generated after cell expansion was identified as MeSec (RPMI), niSec (non-inflammatory), or iSec (inflammatory secretome), respectively. Then, the immunomodulatory potential of such secretomes was tested in PHA-activated PBMCs. iCM induced higher levels of IFN-γ and IL-10 in treated melanoma cells compared to rCM, as well as higher IDO and PD-L1 expression. The iSec was able to inhibit T-cell activation and proliferation. Interestingly, PBMCs treated with iSec presented a reduced expression of the regulators of Th1 and Th2 responses T-BET and GATA-3, as well as low expression of IFN-γ, and co-stimulatory molecules TIM-3 and LAG-3. Importantly, our findings show that melanoma may benefit from an inflammatory microenvironment to enhance its ability to control the T-cell response. Interestingly, such an immunomodulatory effect involves the inhibition of the checkpoint molecules LAG-3 and TIM-3, which are currently investigated as important therapeutic targets for melanoma treatment. Further studies are needed to better understand how checkpoint molecules are modulated by paracrine and cell contact-dependent interaction between melanoma and immune cells. Such advances are fundamental for the development of new therapeutic approaches focused on melanoma immunotherapy

GQ-16, a TZD-derived partial PPARγ agonist, induces the expression of thermogenesis- related genes in brown fat and visceral white fat and decreases visceral adiposity in obese and hyperglycemic mice

Background Beige adipocytes comprise a unique thermogenic cell type in the white adipose tissue (WAT) of rodents and humans, and play a critical role in energy homeostasis. In this scenario, recruitment of beige cells has been an important focus of interest for the development of novel therapeutic strategies to treat obesity. PPARγ activation by full agonists (thiazolidinediones, TZDs) drives the appearance of beige cells, a process so-called browning of WAT. However, this does not translate into increased energy expenditure, and TZDs are associated with weight gain. Partial PPARγ agonists, on the other hand, do not induce weight gain, but have not been shown to drive WAT browning. The present study was designed to investigate the effects of GQ-16 on BAT and on browning of WAT in obese mice. Methods Male Swiss mice with obesity and hyperglycemia induced by high fat diet were treated with vehicle, rosiglitazone (4 mg/kg/d) or the TZD-derived partial PPARγ agonist GQ-16 (40 mg/ kg/d) for 14 days. Fasting blood glucose, aspartate aminotransferase, alanine aminotransferase and lipid profile were measured. WAT and brown adipose tissue (BAT) depots were excised for determination of adiposity, relative expression of Ucp-1, Cidea, Prdm16, Cd40 and Tmem26 by RT-qPCR, histological analysis, and UCP-1 protein expression analysis by immunohistochemistry. Liver samples were also removed for histological analysis and determination of hepatic triglyceride content. Results GQ-16 treatment reduced high fat diet-induced weight gain in mice despite increasing energy intake. This was accompanied by reduced epididymal fat mass, reduced liver triglyceride content, morphological signs of increased BAT activity, increased expression of thermogenesis- related genes in interscapular BAT and epididymal WAT, and increased UCP-1 protein expression in interscapular BAT and in epididymal and inguinal WAT. Conclusion This study suggests for the first time that a partial PPARγ agonist may increase BAT activity and induce the expression of thermogenesis-related genes in visceral WAT. General Significance These findings suggest that PPARγ activity might be modulated by partial agonists to induce WAT browning and treat obesity

LL-37 boosts immunosuppressive function of placenta-derived mesenchymal stromal cells

Background: Although promising for graft-versus-host disease (GvHD) treatment, MSC therapy still faces important challenges. For instance, increasing MSC migratory capacity as well as potentializing immune response suppression are of interest. For GvHD management, preventing opportunistic infections is also a valuable strategy, since immunocompromised patients are easy targets for infections. LL-37 is a host defense peptide (HDP) that has been deeply investigated due to its immunomodulatory function. In this scenario, the combination of MSC and LL-37 may result in a robust combination to be clinically used. Methods: In the present study, the effects of LL-37 upon the proliferation and migratory capacity of human placenta-derived MSCs (pMSCs) were assessed by MTT and wound scratch assays. The influence of LL-37 over the immunosuppressive function of pMSCs was then investigated using CFSE cell division kit. Flow cytometry and real-time PCR were used to investigate the molecular mechanisms involved in the effects observed. Results: LL-37 had no detrimental effects over MSC proliferation and viability, as assessed by MTT assay. Moreover, the peptide promoted increased migratory behavior of pMSCs and enhanced their immunomodulatory function over activated human PBMCs. Strikingly, our data shows that LL-37 treatment leads to increased TLR3 levels, as shown by flow cytometry, and to an increased expression of factors classically related to immunosuppression, namely IDO, IL-10, TGF-β, IL-6, and IL-1β. Conclusions: Taken together, our observations may serve as groundwork for the development of new therapeutic strategies based on the combined use of LL-37 and MSCs, which may provide patients not only with an enhanced immunosuppression regime, but also with an agent to prevent opportunistic infections

Exposure to endocrine-disrupting chemicals and anthropometric measures of obesity : a systematic review and meta-analysis

Objective Endocrine-disrupting chemicals (EDCs) are viewed as a major potential link between the environment and obesity development. We did a systematic review and meta-analysis to examine the association between exposure to EDCs and obesity. Data sources, design and eligibility criteria PubMed, Scopus and Web of Science were searched from inception to 6 June 2018 for studies primarily addressing the association between exposure to EDCs after the age of 2 years and anthropometric measures of obesity or body fat. The Newcastle-Ottawa scale was used to assess the risk of bias. Data extraction and synthesis Two independent reviewers screened and conducted data extraction and synthesis. A third reviewer resolved disagreements. Results A total of 73 studies investigating bisphenol A (32 286 individuals), organochlorine compounds (34 567 individuals), phthalates (21 401 individuals), polybrominated biphenyls (2937 individuals), polycyclic aromatic hydrocarbons (5174 individuals), parabens (4097 individuals), benzoic acid (3671 individuals) and polyfluoroalkyl substances (349 individuals) met our inclusion criteria. Most had a cross-sectional design and low or medium risk of bias. In qualitative analysis, bisphenol A and phthalates were consistently associated with general and abdominal obesity, in children and adults, and some studies suggested this association was age-dependent and gender-dependent. Meta-analysis indicated a significant association between exposure to bisphenol A and overweight (OR 1.254, 95%CI 1.005 to 1.564), obesity (OR 1.503, 95%CI 1.273 to 1.774) and increased waist circumference (OR 1.503, 95%CI 1.267 to 1.783) in adults, and between exposure to 2,5-dichlorophenol and obesity in children (OR 1.8, 95%CI 1.1018 to 3.184). Conclusion Most observational studies supported a positive association between obesity and exposure to EDCs. Although causality cannot be determined from these data, they underscore the need to limit human exposure to EDCs in light of the evidence from animal and cellbased studies indicating the effects of these chemicals on adiposity