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BACKGROUND: The management of acute myocardial infarction (AMI) presents several challenges in patients with diabetes, among them the higher rate of recurrent thrombotic events, hyperglycemia and risk of subsequent heart failure (HF). The objective of our study was to evaluate effects of DPP-4 inhibitors (DPP-4i) on platelet reactivity (main objective) and cardiac risk markers. METHODS: We performed a single-center double-blind randomized trial. A total of 70 patients with type 2 diabetes (T2DM) with AMI Killip ≤2 on dual-antiplatelet therapy (aspirin plus clopidogrel) were randomized to receive sitagliptin 100 mg or saxagliptin 5 mg daily or matching placebo. Platelet reactivity was assessed at baseline, 4 days (primary endpoint) and 30 days (secondary endpoint) after randomization, using VerifyNow Aspirin™ assay, expressed as aspirin reaction units (ARUs); B-type natriuretic peptide (BNP) in pg/mL was assessed at baseline and 30 days after (secondary endpoint). RESULTS: Mean age was 62.6 ± 8.8 years, 45 (64.3%) male, and 52 (74.3%) of patients presented with ST-segment elevation MI. For primary endpoint, there were no differences in mean platelet reactivity (p = 0.51) between the DPP-4i (8.00 {-65.00; 63.00}) and placebo (-14.00 {-77.00; 52.00}) groups, as well in mean BNP levels (p = 0.14) between DPP-4i (-36.00 {-110.00; 15.00}) and placebo (-13.00 {-50.00; 27.00}). There was no difference between groups in cardiac adverse events. CONCLUSIONS: DPP4 inhibitor did not reduce platelet aggregation among patients with type 2 diabetes hospitalized with AMI. Moreover, the use of DPP-4i did not show an increase in BNP levels or in the incidence of cardiac adverse events. These findings suggests that DPP-4i could be an option for management of T2DM patients with acute MI.

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Purpose: Despite newer type 2 diabetes (T2D) medications, patients do not always achieve metabolic targets, remaining at risk for cardiorenal complications. Therapeutic decisions are generally made by the healthcare team without considering patients' preferences. We aimed to evaluate patients' T2D treatment preference in two Latin-American countries between two different oral medication profiles, one resembling dipeptidyl peptidase-4 inhibitors (DPP4i) and another resembling sodium-glucose cotransporter-2 inhibitors (SGLT2i). Patients and Methods: In this cross-sectional, multicenter study from June to September 2020, patients with T2D from Argentina and Mexico (n = 390) completed a discrete choice experiment questionnaire to identify preferences between DPP4i (medication profile A) and SGLT2i (medication profile B). The reason behind patients' choice, and the association between their baseline characteristics and their preference were evaluated using logistic regression methods. Results: Most participants (88.2%) preferred SGLT2i's profile. Participants with older age (p = 0.0346), overweight or obesity (p < 0.0001), high blood pressure (BP; p < 0.0001), high total cholesterol (p = 0.0360), and glycosylated hemoglobin (HbA1c) <7% (p = 0.0001) were more likely to choose SGLT2i compared with DPP4i's profile. The most and least important reasons to choose either drug profile were HbA1c reduction and genital infection risk, respectively. The likelihood of selecting the SGLT2i's profile significantly increased in participants with increased body mass index (BMI; odds ratio [OR] = 8.9, 95% confidence interval [CI]: 3.5-22.5, p < 0.05), high BP (OR = 4.9, 95% CI: 1.9-12.4, p < 0.05), and lower education level (OR = 3.6, 95% CI: 1.0-12.6, p < 0.05). Conclusion: Latin-American patients with T2D preferred medication with a profile resembling SGLT2i over one resembling DPP4i as a treatment option. A patient-centered approach may aid the healthcare team in decision-making for improved outcomes.

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INTRODUCTION: SGLT2 inhibitors or DPP-4 inhibitors are among the preferred options in patients with type 2 diabetes mellitus (T2DM) without established cardiovascular disease. OBJECTIVE: To evaluate the incremental cost-effectiveness of dapagliflozin versus DPP-4 inhibitors as a complement to metformin in the treatment ofT2D, from the perspective of the Colombian health system. METHODS: The Cardiff model was used to estimate the incremental cost-effectiveness ratio (ICER) of dapagliflozin plus metformin compared to DPP-4 inhibitors plus metformin in adults with T2DM who did not respond adequately to metformin monotherapy. We estimated the incidence of micro- and macrovascular complications from risk equations incorporating the effect of treatment. The time horizon for analysis was 5 years and a discount rate of 5% was applied, for both costs and outcomes. The costs were expressed in 2020 USD (1 USD = $3,693.36 COP). RESULTS: Dapagliflozin in association with metformin resulted in a higher number of quality-adjusted life years (QALYs) compared to the intervention. The ICER was US$1,964.80 per QALY gained. CONCLUSION: From the point of view of Colombian healthcare system, the combination of dapagliflozin with metformin is a cost-effective option compared to DPP-4 + metformin inhibitors in the treatment of T2D without established cardiovascular disease.

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Ante la aparición de un nuevo virus en la ciudad de Wuhan-China, llamado SARS-CoV-2, causante del conocido síndrome agudo respiratorio severo (COVID-19), muchos de científicos tratan de hallar una solución contra el virus que ha ocasionado una pandemia. En esta búsqueda, se encontró a una glicoproteína de transmembrana llamada dipeptidil peptidasa 4 o DPP-4 presente en la superficie de diferentes tipos de células y diana en la infección por el MERS-Co-V que abre una esperanza al sospechar que la DPP-4 puede ser un blanco en diferentes coronavirus al servir como estrategia terapéutica. A ello se suman resultados que encuentran la DPP-4 elevada en pacientes con complicaciones graves ante COVID-19, lo que puede ser un posible marcador de gravedad. Sin embargo, aún existe poco énfasis en la identificación y asociación de esta glicoproteína a la COVID-19. Para ello, se realizó una revisión bibliográfica sobre los aspectos más significativos de la Dipeptidil Peptidasa 4 y su función frente a la COVID-19(AU)

Given the appearance of a new virus in the of Wuhan city, China, called SARS-CoV-2, which causes the well-known severe acute respiratory syndrome (COVID-19), many scientists are trying to find a solution against the virus that has caused a pandemic. In this search, a transmembrane glycoprotein called dipeptidyl peptidase 4 or DPP-4 was found present on the surface of different types of cells and a target in MERS-Co-V infection, which opens hope by suspecting that DPP- 4 can be a target in different coronaviruses by serving as a therapeutic strategy. Added to this, there are results that find elevated DPP-4 in patients with severe complications from COVID-19, which may be a possible marker of severity. However, there is still little emphasis on the identification and association of this glycoprotein with COVID-19. To this effect, a bibliographic review was carried out on the most significant aspects of Dipeptidyl Peptidase 4 and its function against COVID-19(AU)

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Diabetic kidney disease is one of the most frequent complications in patients with diabetes mellitus and affects morbidity and mortality. The recent therapies include oral hypoglycemic drugs that, in addition to optimizing glycemic control and reducing the risk of hypoglycemia, may affect the development and progression of diabetic kidney disease; these novel therapies include inhibitors of the enzyme dipeptidyl peptidase 4 (DPP-4), a group of oral hypoglycemic therapeutic agents that act at the level of the incretin system. DPP-4 inhibitors show additional pleiotropic effects in in vitro models, reducing inflammation, fibrosis, and oxidative damage, further suggesting potential kidney protective effects. Although existing trials suggest a possible benefit in the progression of diabetic kidney disease, further studies are needed to demonstrate kidney-specific benefits of DPP-4 inhibitors.

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A dysregulated immune response characterized by the hyperproduction of several pro-inflammatory cytokines (a.k.a. 'cytokine storm') plays a central role in the pathophysiology of severe coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this Perspective article we discuss the evidence for synergistic anti-inflammatory and immunomodulatory properties exerted by vitamin D and dipeptidyl peptidase-4 (DPP-4) inhibitors, the latter being a class of antihyperglycemic agents used for the treatment of Type 2 diabetes, which have also been reported as immunomodulators. Then, we provide the rationale for investigation of vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i) as an immunomodulation strategy to ratchet down the virulence of SARS-CoV-2, prevent disease progression and modulate the cytokine storm in COVID-19.

Lay abstract The so-called 'cytokine storm' that drives the hyperproduction of pro-inflammatory mediators, plays a central role in the pathophysiology of severe coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vitamin D has increasingly been shown to play anti-inflammatory and immunomodulatory properties beyond its role in the regulation of bone homeostasis. Similarly, dipeptidyl peptidase-4 inhibitors (DPP-4i) ­ a class of antihyperglycemic agents used for the treatment of Type 2 diabetes ­ have been reported as immunomodulators regardless of their glucose-lowering properties. We, therefore, discuss the role of vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i) as a potential immunomodulation strategy to prevent the development and/or halt the progression of the COVID-19-induced cytokine storm, particularly in patients with diabetes and cardiovascular disease.

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ABSTRACT Background: Recently, studies had shown that incretin-based therapies could reduce the levels of pro-inflammatory markers. The data on the effects of incretin-based therapies on serum high-sensitivity C-reactive protein (hs-CRP) in type 2 diabetes (T2DM) were inconsistent. Objective: The objective of the study was to assess the effects of incretin-based therapies on hs-CRP in patients with T2DM by meta-analysis. Methods: We searched PubMed, EMBASE, the Cochrane Collaboration Library, and Web of Science to identify the eligible randomized clinical trials until August 2019. The pooled standard mean differences (SMD) were calculated by random-effects model using STATA 11.0. Results: Twenty-five studies with 28 randomized controlled trials were finally included into the meta-analysis. Meta-analysis revealed a significant reduction in hs-CRP following treatment with incretin-based regimens compared to controls (SMD = −0.452, p < 0.001). Subgroup analysis of different class of incretin-based drugs showed that therapy with both dipeptidyl peptidase 4 inhibitors (DPP-4Is, SMD = −0.338, p = 0.026) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs, SMD = −0.544, p = 0.003) caused significant reductions in hs-CRP. Besides, there was a significant reduction in hs-CRP with an intervention duration more than 24 weeks (SMD = −0.465, p = 0.001), while no significant difference with <24 weeks. Meta-regression analyses showed that better glycemic control and more body mass index (BMI) decline were associated with hs-CRP reduction after incretin-based therapies. Conclusions: This meta-analysis suggests that incretin-based therapies, both GLP-1 RAs and DPP-4Is, can cause a significant reduction in hs-CRP in patients with T2DM, which is related to long intervention duration, better glycemic control, and more BMI decline.

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Resumen La enfermedad metabólica diabetes mellitus tipo 2 ocasiona alteraciones en la estructura y en la funcionalidad miocárdica por diferentes mecanismos bioquímicos los cuales pueden ocasionar disfunción diastólica y sistólica, por lo cual el uso de los antihiperglicemiantes aparte de su efecto en la reducción de la hiperglicemia y la hemoglobina glicosilada, algunos han demostrado reducción en la mortalidad cardiovascular y de las hospitalizaciones por insuficiencia cardiaca, basado en estudios clínicos sobre este impacto en el miocardio. También se ha evaluado el efecto de estos fármacos por medio del ecocardiograma transtorácico. El objetivo de este articulo es analizar los valores de los parámetros ecocardiográficos sistólicos y diastólicos en pacientes diabéticos tipo 2 o alguna cardiopatía de base como antecedente de infarto al miocardio e insuficiencia cardiaca con el uso de metformina, sulfonilureas, los inhibidores de la dipeptidilpeptidasa 4 (sitagliptina, alogliptina y linagliptina, vildagliptina), los análogos de GLP1 (liraglutide, albiglutide y exenatide).

Abstract Metabolic disease type 2 diabetes mellitus causes alterations in both structure and myocardial functionality by different biochemical mechanisms which can cause diastolic and systolic dysfunction, which is why the use of antihyperglycemic agents apart from its effect in the reduction of hyperglycemia and glycosylated hemoglobin, some groups have shown reduction in cardiovascular mortality and hospitalizations for heart failure this based on clinical studies, by hypothesis, theories and pleiotropic mechanisms on this impact on the myocardium. On the other hand, the effect of these drugs on the myocardium has also been evaluated by transthoracic echocardiography. Therefore, the aim of this article is to analyze the values of systolic and diastolic echocardiographic parameters in type 2 diabetic patients or some underlying heart disease as a history of myocardial infarction and heart failure with the use of metformin, sulfonylureas, inhibitors of the dipeptidylpeptidase 4 (sitagliptin, alogliptin and linagliptin, vildagliptin), GLP1 analogues (liraglutide, albiglutide and exenatide).

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Background Bullous pemphigoid has been associated to dipeptidase-4 inhibitors. Objectives Addressing the potential Bullous pemphigoid-dipeptidase-4 inhibitors association based on pharmacovigilance data currently available in Spain in order to obtain a composite disproportionality estimator from all the data generated by the case-non case studies conducted to this date. Setting The Spanish Pharmacovigilance System for Human Use Drugs database. Method Case-non case study based on the Spanish Pharmacovigilance System for Human Use Drugs notifications submitted between 2007 and 2018 (n = 169,280), using the Medical Dictionary for Regulatory Activities term (Preferred Term) 'pemphigoid' for sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin (n = 1952). As negative control, we used acetaminophen, while furosemide was the positive control. A pooled reported odds ratio analysis in the French, Japanese, and Spanish national pharmacovigilance databases was performed. On The Spanish Pharmacovigilance System for Human Use Drugs, we conducted a bullous pemphigoid-metformin association analysis within the period 1982-2018. Main outcome measure Adverse reaction cases in pharmacovigilance databases and the disproportionality through the reporting odds ratio. Results Within The Spanish Pharmacovigilance System for Human Use Drugs, we found 45 cases of bullous pemphigoid in dipeptidase-4 inhibitors patients. Median age was 77 years (range 72-82). The median latency period was 7 months (range 0.23-86). The Bullous pemphigoid-dipeptidase-4 inhibitors association was established with a reporting odd ratio = 70.0 (95% confidence intervals 49.1-10.1). In the combined analysis of the three aforementioned pharmacovigilance databases, the pooled reporting odd ratio was 81.0 (95% confidence intervals 69.5-94.4). Conclusion The composite estimator for the three national pharmacovigilance databases yields clear evidence of a Bullous pemphigoid-dipeptidase-4 inhibitors association, which was statistically significant for both the pharmacological class as a whole and each of the dipeptidase-4 inhibitors agents under investigation. Metformin's role in the incidence of bullous pemphigoid appeared casual rather than causal. No differences between Caucasian and Asian populations were noted.

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Up to date, the management of hepatotoxicity induced by a suicidal or unintentional overdose of acetaminophen (APAP) remains a therapeutic challenge. The present study aimed to elucidate the potential effect of sitagliptin, a DPP-4 inhibitor, to ameliorate the acute injurious effects of acetaminophen on the liver. APAP toxicity was induced in mice by an intraperitoneal injection of APAP (400 mg/kg). The effect of treatment with sitagliptin, initiated 5 days prior to APAP injection, was evaluated. Serum indices of hepatotoxicity, oxidative stress markers in liver tissues, serum IL-1ß, and TNF-α in addition to hepatic- NF-E2-related factor-2 (Nrf2) were determined. Our results showed that APAP induced marked hepatic injury as evidenced by an increase in serum levels of ALT and AST, in addition to the deterioration of histological grading. Oxidative stress markers, serum TNF-α, and IL-1ß were also elevated. Sitagliptin successfully ameliorated the histological changes induced by APAP, improving liver function tests and liver oxidant status accompanied with a marked increase in Nrf2 level in hepatic tissues. Thus, the hepatoprotective effects of sitagliptin in this animal model seem to involve Nrf2 modulation, coincidental with its anti-inflammatory and antioxidant effects

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INTRODUCTION: Linagliptin is a high-cost oral antidiabetic that has been widely used, and studies on its effectiveness and safety for the treatment of type 2 diabetes mellitus (DM2) in the real world is rare and necessary. OBJECTIVE: To analyze the values of glycated hemoglobin (HbA1c) and adverse events before and after the use of linagliptin in the post-marketing context of a pilot study. METHODS: This is a descriptive observational and exploratory study with a retrospective longitudinal approach, conducted between January 2014 and December 2016. All patients who participated in the study were over 18 years of age, with DM2, assisted by the Brazilian Public Health System (Sistema Único de Saúde - SUS) and had been indicated for use of linagliptin. The users were followed up and the variables of interest were collected from a computerized health information system (sistema informatizado de saúde - SIS) and patient records. For effectiveness analysis, HbA1c before (T0) and after (T1) the use of linagliptin was considered in patients registered as having collected linagliptin at the pharmacy for at least three consecutive months. For safety analysis, registered adverse events (AE) were verified in patients' records. The sample was stratified according to the pharmacotherapeutic scheme of the users. To compare the means before (T0) and after (T1), a paired t-test (data with normal distribution) and Wilcoxon Signed Rank Sum test (non-normal distribution data) were performed. RESULTS: Considering the total population of the study, in a different pharmacotherapeutic regimen, a median reduction in HbA1c of -0.86% (p < 0.05) was observed. After stratification by pharmacotherapeutic regimen, the most significant reduction of HbA1c was -1.07% (p = 0.014) for the linagliptin group associated with insulins and oral antidiabetic agents (n = 13). On the other hand, patients taking linagliptin in monotherapy had the lowest HbA1c reduction, -0.48% (p > 0.05). AE occurred in 12 (36.4%) patients, and 16.7% were in monotherapy. CONCLUSION: Linagliptin did not presented, in real world, the desired performance as showed in randomized premarketing clinical trials and it should be carefully evaluated in public health services.

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A drug repurposing strategy could be a potential approach to overcoming the economic costs for diabetes mellitus (DM) treatment incurred by most countries. DM has emerged as a global epidemic, and an increase in the outbreak has led developing countries like Mexico, India, and China to recommend a prevention method as an alternative proposed by their respective healthcare sectors. Incretin-based therapy has been successful in treating diabetes mellitus, and inhibitors like sitagliptin, vildagliptin, saxagliptin, and alogliptin belong to this category. As of now, drug repurposing strategies have not been used to identify existing therapeutics that can become dipeptidyl peptidase-4 (DPP-4) inhibitors. Hence, this work presents the use of bioinformatics tools like the Activity Atlas model, flexible molecular docking simulations, and three-dimensional reference interaction site model (3D-RISM) calculations to assist in repurposing Food and Drug Administration (FDA)-approved drugs into specific nonsteroidal anti-inflammatory medications such as DPP-4 inhibitors. Initially, the Activity Atlas model was constructed based on the top scoring DPP-4 inhibitors, and then the model was used to understand features of nonsteroidal anti-inflammatory drugs (NSAIDs) as a function of electrostatic, hydrophobic, and active shape features of DPP-4 inhibition. The FlexX algorithm was used to infer protein-ligand interacting residues, and binding energy, to predict potential draggability towards the DPP-4 mechanism of action. 3D-RISM calculations on piroxicam-bound DPP-4 were used to understand the stability of water molecules at the active site. Finally, piroxicam was chosen as the repurposing drug to become a new DPP-4 inhibitor and validated experimentally using fluorescence spectroscopy assay. These findings are novel and provide new insights into the role of piroxicam as a new lead to inhibit DPP-4 and, taking into consideration the biological half-life of piroxicam, it can be proposed as a possible therapeutic strategy for treating diabetes mellitus.

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BACKGROUND: Worldwide, the progress in reducing neonatal mortality has been very slow. The rate of preterm birth has increased over the last 20 years in low-income and middle-income countries. Its association with increased mortality and morbidity is based on experimental studies and neonatal outcomes from countries with socioeconomic differences, which have considered implementing alternative healthcare strategies to prevent and reduce preterm births. METHODS: Currently, there is no widely effective strategy to prevent preterm birth. Pharmacological therapies are directed at inhibiting myometrial contractions to prolong parturition. Some drugs, medicinal plants and microorganisms possess myorelaxant, anti-inflammatory and immunomodulatory properties that have proved useful in preventing preterm birth associated with inflammation and infection. RESULTS: This review focuses on the existing literature regarding the use of different drugs, medicinal plants, and microorganisms that show promising benefits for the prevention of preterm birth associated with inflammation and infection. New alternative strategies involving the use of PDE-4 inhibitors, medicinal plants and probiotics could have a great impact on improving prenatal and neonatal outcomes and give babies the best start in life, ensuring lifelong health benefits. CONCLUSION: Despite promising results from well-documented cases, only a small number of these alternative strategies have been studied in clinical trials. The development of new drugs and the use of medicinal plants and probiotics for the treatment and/or prevention of preterm birth is an area of growing interest due to their potential therapeutic benefits in the field of gynecology and obstetrics.

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La diabetes mellitus tipo 1 (DM1), es una enfermedad crónica caracterizada por la deficiencia de insulina debido a la pérdida de células ß pancreáticas, las alteraciones hormonales en la DM 1 no se limitan a la deficiencia de insulina; existiendo también secreción inadecuadada de glucagón en el período postprandial. Aunque el control glucémico con terapias intensivas con insulina ha reducido la incidencia de complicaciones microvascular y macrovasculares. La mayoría de las personas con DM1 tienen un control glucémico subóptimo; Por lo tanto, el uso de farmacoterapia adyuvante para mejorar el control ha sido de interés clínico. El uso de estos nuevos medicamentos brindaría la oportunidad de imitar más de cerca la fisiología pancreática normal, y contrarrestar otros mecanismos fisiopatológicos diferentes a Insulinopenia; contribuyendo a lograr un mejor control metabólico y expectativa de vida.

Type 1 diabetes mellitus (T1DM), is a chronic disease characterized by insulin deficiency due to the loss of pancreatic ß cells, the hormonal alterations in T1DM are not limited to insulin deficiency; there is also a deregulated glucagon secretion in the postprandial period. Although glycemic control with intensive therapies with insulin has reduced the incidence of microvascular and macrovascular complications, most people with T1DM1 glycemic control; therefore, the use of adjuvant pharmacotherapy to improve control has been of clinical interest. The use of these new drugs would offer the opportunity to imitate more closely the normal pancreatic physiology, and to counteract other physiopathological mechanisms different from insulinopenia; contributing to achieve better metabolic control and life expectancy.

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BACKGROUND: The first treatment approach for type 2 diabetes mellitus is lifestyle change and metformin, but it is usually not sufficient. For some time, the anti-hyperglycemic classes of sulfonylureas and dipeptidyl peptidase-4 (DPP-4) inhibitors were considered second-line of treatment, since they show similar efficacy effect. However, the recent ADA-EASD consensus gives the preference to DPP-4 inhibitors compared to sulfonylureas, except if cost is a major problem. We performed a meta-analysis for safety and tolerability profile to comprehend which treatment has less adverse events. METHODS: PUBMED and EMBASE databases were searched from inception until July 2017 to retrieve RCT studies comparing DPP-4 inhibitors and sulfonylureas treatments in adult type 2 diabetes patients. There was no language restriction. We extracted and combined data from studies comparison that reported safety profile and weight change. A random effect, meta-analytic model was applied to all calculations. Cochrane collaboration tool was used to assess quality and bias of the included studies. Trial registered with PROSPERO (CRD42017075823). FINDINGS: Out of 1472 articles identified in our search and screened for eligibility, 36 studies comparing DPP-4 inhibitors and sulfonylureas were identified. DPP-4 inhibitors in combination with metformin had less overall adverse events (RR: 0·90; 95% CI, 0·86-0·94; p < 0·0001; I2 = 83%; 17 studies), cardiovascular events (RR: 0·54; 95% CI, 0·37-0·79; p = 0·002; I2 = 0%; 6 studies), hypoglycemia (RR: 0·17; 95% CI, 0·13-0·22; p < 0·00001; I2 = 76%; 17 studies) and severe hypoglycemic events (RR: 0·10; 95% CI, 0·05-0·19; p < 0·00001; I2 = 0%; 12 studies). The mean difference of the weight change was 1·92 kg in favor of DPP-4 inhibitors in combination with metformin in relation to sulfonylureas in combination with metformin. Monotherapy with DPP-4 inhibitors also had less rates of hypoglycemia (RR: 0·31; 95% CI, 0·24-0·41; p < 0·00001; I2 = 0%; 8 studies) and severe hypoglycemic events (RR: 0·26; 95% CI, 0·10-0·66; p = 0·004; I2 = 0%; 8 studies) and patients did not gain 1·19 kg. INTERPRETATION: These results suggest better safety profile for DPP-4 inhibitors than sulfonylureas for both comparisons, and it is more notable when the treatment regimen includes metformin. FUNDING: This study was funded by Takeda Pharmaceuticals, Brazil.

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OBJECTIVES: To determine whether the drug saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor which is utilized for the treatment of Diabetes Mellitus, has neuroprotective effects in the animal model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA) in rats. METHODS: Male Wistar rats (weighing 280-300 g) received a bilateral infusion of 6-OHDA in the substantia nigra. Twenty-four hours later, they were treated with saxagliptin (1 mg/kg, p.o) once daily, for 21 days. The motor function was evaluated using the open field and rotarod (RT) tests. In addition, cognition was assessed with the novel object recognition test (ORT). After the evaluation of the behavioural tests, the animals were transcardially perfused to perform immunohistochemistry staining for tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc). KEY FINDINGS: Saxagliptin impaired the memory of animals in the sham group. CONCLUSIONS: Saxagliptin treatment did not exhibit neuroprotection and it did not improve the cognitive and motor deficits in the 6-OHDA model of PD. Interestingly, when saxagliptin was administered to the sham animals, a cognitive decline was observed. Therefore, this drug should be investigated as a possible treatment for PTSD.

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The aim of this study was to evaluate the relaxant and anti-inflammatory effects of two thalidomide analogs as phosphodiesterase-4 (PDE-4) inhibitors in pregnant rat uterus. Uteri from Wistar female rats were isolated at 19 day of pregnancy. Uterine samples were used in functional studies to evaluate the inhibitory effects of the thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe), on prostaglandin-F2α (PGF2α)-induced phasic, K+-induced tonic, and Ca2+-induced contractions. Accumulation of cAMP was quantified in uterine homogenates by ELISA. Anti-inflammatory effect was assessed by using ELISA for determination of the pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin (IL)-1ß, and anti-inflammatory IL-10, from uterine explants stimulated with lipopolysaccharide (LPS). Nifedipine, forskolin and rolipram were used as positive controls where required. Both thalidomide analogs induced a significant inhibition of the uterine contractions induced by the pharmaco- and electro-mechanic stimuli. Nifedipine and forskolin were more potent than the analogs to inhibit the uterine contractility, but these were more potent than rolipram, and 4APDPMe was equieffective to nifedipine. Thalidomide analogs increased uterine cAMP-levels in a concentration-dependent manner. The LPS-induced TNFα and IL-1ß uterine secretion was diminished in a concentration-dependent fashion by both analogs, whereas IL-10 secretion was increased significantly. The thalidomide analogs induced utero-relaxant and anti-inflammatory effects, which were associated with the increased cAMP levels as PDE-4 inhibitors in the pregnant rat uterus. Such properties place these thalidomide analogs as potentially safe and effective tocolytic agents in a field that urgently needs improved pharmacological treatments, as in cases of preterm labor.