Pharmacokinetic profiles of the active metamizole metabolites in healthy horses

Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, swine and dogs. MT is rapidly hydrolysed to the active primary metabolite 4-methylaminoantipyrine (MAA). MAA is formed in much larger amounts compared with other minor metabolites. Among other secondary metabolites, 4-aminoantipyrine (AA) is also relatively active. The aim of this research was to evaluate the pharmacokinetic profiles of MAA and AA after dose of 25 mg/kg MT by intravenous (i.v.) and intramuscular (i.m.) routes in healthy horses. Six horses were randomly allocated to two equally sized treatment groups according to a 2 9 2 crossover study design. Blood was collected at predetermined times within 24 h, and plasma was analysed by a validated HPLC-UV method. No behavioural changes or alterations in health parameters were observed in the i.v. or i.m. groups of animals during or after (up to 7 days) drug administration. Plasma concentrations of MAA after i.v. and i.m. administrations of MT were detectable from 5 min to 10 h in all the horses. Plasma concentrations of AA were detectable in the same range of time, but in smaller amounts. Maximum concentration (Cmax), time to maximum concentration (Tmax) and AUMC0-last of MAA were statistically different between the i.v. and i.m. groups. The AUCIM/AUCIV ratio of MAA was 1.06. In contrast, AUC0-last of AA was statistically different between the groups (P < 0.05) with an AUCIM/AUCIV ratio of 0.54. This study suggested that the differences in the MAA and AA plasma concentrations found after i.m. and i.v. administrations of MT might have minor consequences on the pharmacodynamics of the drug

Reactive oxygen species inhibit the succinate oxidation-supported generation of membrane potential in wheat mitochondria

In order to gain a first insight into the effects of reactive oxygen species (ROS) on plant mitochondria, we studied the effect of the ROS producing system consisting of xanthine plus xanthine oxidase on the rate of membrane potential (ΔΨ) generation due to either succinate or NADH addition to durum wheat mitochondria as monitored by safranin fluorescence. We show that the early ROS production inhibits the succinate-dependent, but not the NADH-dependent, ΔΨ generation and oxygen uptake. This inhibition appears to depend on the impairment of mitochondrial permeability to succinate. It does not involve mitochondrial thiol groups sensitive to either mersalyl or N-ethylmaleimide and might involve both protein residues and/or membrane lipids, as suggested by the mixed nature. We propose that, during oxidative stress, early generation of ROS can affect plant mitochondria by impairing metabolite transport, thus preventing further substrate oxidation, ΔΨ generation and consequent large-scale ROS production. © 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved

Interpenetrating Hydrogel Networks Enhance Mechanical Stability, Rheological Properties, Release Behavior and Adhesiveness of Platelet-Rich Plasma

Platelet‐rich plasma (PRP) has attracted much attention for the treatment of articular cartilage defects or wounds due to its intrinsic content of growth factors relevant for tissue repair. However, the short residence time of PRP in vivo, due to the action of lytic enzymes, its weak mechanical properties and the consequent short‐term release of bioactive factors has restricted its application and efficacy. The present work aimed at designing new formulation strategies for PRP, based on the use of platelet concentrate (PC)‐loaded hydrogels or interpenetrating polymer networks, directed at improving mechanical stability and sustaining the release of bioactive growth factors over a prolonged time‐span. The interpenetrating hydrogels comprised two polymer networks interlaced on a molecular scale: (a) a first covalent network of thermosensitive and biodegradable vinyl sulfone bearing p(hydroxypropyl methacrylamide‐lacate)‐polyethylene glycol triblock copolymers, tandem cross‐linked by thermal gelation and Michael addition when combined with thiolated hyaluronic acid, and (b) a second network composed of cross‐linked fibrin. The PC‐loaded hydrogels, instead, was formed only by network (a). All the designed and successfully synthesized formulations greatly increased the stability of PRP in vitro, leading to significant increase in degradation time and storage modulus of PRP gel. The resulting viscoelastic networks showed the ability to controllably release platelet derived growth factor and transforming growth factr β1, and to improve the tissue adhesiveness of PRP. The newly developed hydrogels show great potential for application in the field of wound healing, cartilage repair and beyond

Distorção da imagem corporal em adolescentes: um estudo de comparação entre dois instrumentos

 Objective: to compare two instruments classically utilized by the literature and indicated to evaluate possible distortions of body image in adolescents and adults of both sexes.Method: the Body Shape Questionnaire (BSQ) and the Silhouette Figure Scale (SFS) was applied in 118 students, aged 16.5 ± 1.2 years, 62 boys and 56 girls of 4 public schools. The BSQ measures body shape concerns and the feeling of being “fat”; while the SFS evaluates the actual shape perception and the desirable shape, based on 15 silhouettes of each sex, presented in individual cards, with progressive variations, from the thinner (BMI = 12.5 Kg/m 2) to the larger (BMI = 47.5 Kg/m2).Besides that, weight and height were measured for the Body Mass Index (BMI) calculation and posterior comparison with the SFS. The data were submitted to the statistical treatment consisted in a descriptive analysis, a Pearson’s correlation test between the instruments and the Student’s T-Test  for comparison between the sexes. Results: The BSQ showed that 14.5% of the boys and 60.7% of the girls presented some level of body image distortion. The SFS on girls showed a “actual” BMI of 26.9 Kg/m.The EFS on boys showed a “actual” BMI of 23.7 Kg/m 2, while the real BMI were 21.0 Kg/m2 , indicating a prevalence of body image distortion in both sexes. The statistical analysis showed a significant positive correlation (r=0.8) between the two instruments, however, the SFS did not presented differences between the sexes (p=0.93), while the BSQ detected a higher level of distortion by the girls [F(1,110)=13.80; p&lt;0.001)]. Conclusion: the body image distortion was detected by both instruments, however, the BSQ detected differences due to sex, while SFS appears not sufficiently sensible to detect sex differences in adolescents.  Objetivo : comparar dois instrumentos classicamente utilizados pela literatura especializada, indicados para avaliar possíveis distorções da imagem corporal em adolescentes e adultos de ambos os sexos. Metodologia: aplicou-se o Questionário de Imagem Corporal (BSQ) e a Escala de Figuras de Silhuetas (EFS) em 118 estudantes, com idade média de 16,5 anos (± 1,2), sendo 62 meninos e 56 meninas, de 4 escolas públicas estaduais. O primeiro instrumento mede as preocupações com a forma do corpo, a auto-depreciação devido à aparência física e a sensação de estar “gordo”; enquanto o segundo avalia a percepção do estado atual e do estado desejado, através de 15 silhuetas de cada gênero, apresentadas em cartões individuais, com variações progressivas na escala de medidas, da figura mais magra (IMC = 12,5 Kg/m 2) para a mais larga (IMC = 47,5 Kg/m2). Além disso, aferiu-se peso e altura para cálculo do Índice de Massa Corporal (IMC) e posterior comparação com a EFS. A análise dos resultados foi realizada através da escala de avaliação do BSQ e o tratamento estatístico consistiu na análise descritiva dos resultados, além da aplicação de um teste de correlação de Pearson entre os instrumentos e do Teste t de Student  para comparação entre os sexos. Resultados: através do BSQ observou-se que 14,5% dos meninos e 60,7% das meninas apresentaram algum grau de distorção da imagem corporal. Já a EFS demonstrou que no grupo feminino, o IMC médio escolhido como “atual” foi de 26,9 Kg/m 2 enquanto o IMC médio real foi de 21,5 Kg/m2 e no grupo masculino, o IMC médio “atual” escolhido foi 23,7 Kg/m 2, enquanto a média do IMC real foi de 21,0 Kg/m2 , indicando uma prevalência de distorção da imagem corporal em ambos os sexos. A análise estatística mostrou uma correlação positiva significativa (r=0,38) entre os dois instrumentos, entretanto, a EFS não apresentou diferença devido ao sexo (p=0,93), enquanto o BSQ detectou um maior grau de distorção no sexo feminino [F(1,110)=13,80; p&lt;0,001)]. Conclusão: ambos os instrumentos detectaram distorções da imagem corporal, porém, o BSQ conseguiu detectar diferenças devido ao sexo enquanto a EFS parece não ser suficientemente sensível para diferenciar os dois sexos

Metformin and sitAgliptin in patients with impAired glucose tolerance and a recent TIA or minor ischemic Stroke (MAAS): study protocol for a randomized controlled trial

Background: Impaired glucose tolerance is present in one third of patients with a TIA or ischemic stroke and is associated with a two-fold risk of recurrent stroke. Metformin improves glucose tolerance, but often leads to side effects. The aim of this study is to explore the feasibility, safety, and effects on glucose metabolism of metformin and sitagliptin in patients with TIA or minor ischemic stroke and impaired glucose tolerance. We will also assess whether a slow increase in metformin dose and better support and information on this treatment will reduce the incidence of side effects in these patients. Methods/Design: The Metformin and sitAgliptin in patients with impAired glucose tolerance and a recent TIA or minor ischemic Stroke trial (MAAS trial) is a phase II, multicenter, randomized, controlled, open-label trial with blinded outcome assessment. Non-diabetic patients (n = 100) with a recent (<6 months) TIA, amaurosis fugax or minor ischemic stroke (modified Rankin scale ≤ 3) and impaired glucose tolerance, defined as 2-hour post-load glucose levels between 7.8 and 11.0 mmol/L after repeated standard oral glucose tolerance test, will be included. Patients with renal or liver impairment, heart failure, chronic hypoxic lung disease stage III-IV, history of lactate acidosis or diabetic ketoacidosis, pregnancy or breastfeeding, pancreatitis and use of digoxin will be excluded. The patients will be randomly assigned in a 1:1:2 ratio to metformin, sitagliptin or "no treatment." Patients allocated to metformin will start with 500 mg twice daily, which will be slowly increased during a 6-week period to a twice daily dose of 1000 mg. Patients allocated to sitagliptin will be treated with a daily fixed dose of 100 mg. The study has been registered as NTR 3196 in The Netherlands Trial Register. Primary outcomes include percentage still on treatment, percentage of (serious) adverse events, and the baseline adjusted difference in 2-hour post-load glucose levels at 6 months. Discussion: This study will give more information about the feasibility and safety of metformin and sitagliptin as well as the effect on 2-hour post-load glucose levels at 6 months in patients with TIA or ischemic stroke and impaired glucose tolerance

Three-Dimensional Automated, Machine-Learning-Based Left Heart Chamber Metrics: Associations with Prevalent Vascular Risk Factors and Cardiovascular Diseases

Background. Three-dimensional transthoracic echocardiography (3DE) powered by artificial intelligence provides accurate left chamber quantification in good accordance with cardiac magnetic resonance and has the potential to revolutionize our clinical practice. Aims. To evaluate the association and the independent value of dynamic heart model (DHM)-derived left atrial (LA) and left ventricular (LV) metrics with prevalent vascular risk factors (VRFs) and cardiovascular diseases (CVDs) in a large, unselected population. Materials and Methods. We estimated the association of DHM metrics with VRFs (hypertension, diabetes) and CVDs (atrial fibrillation, stroke, ischemic heart disease, cardiomyopathies, &gt;moderate valvular heart disease/prosthesis), stratified by prevalent disease status: participants without VRFs or CVDs (healthy), with at least one VRFs but without CVDs, and with at least one CVDs. Results. We retrospectively included 1069 subjects (median age 62 [IQR 49–74]; 50.6% women). When comparing VRFs with the healthy, significant difference in maximum and minimum indexed atrial volume (LAVi max and LAVi min), left atrial ejection fraction (LAEF), left ventricular mass/left ventricular end-diastolic volume ratio, and left ventricular global function index (LVGFI) were recorded (p &lt; 0.05). In the adjusted logistic regression, LAVi min, LAEF, LV ejection fraction, and LVGFI showed the most robust association (OR 3.03 [95% CI 2.48–3.70], 0.45 [95% CI 0.39–0.51], 0.28 [95% CI 0.22–0.35], and 0.22 [95% CI 0.16–0.28], respectively, with CVDs. Conclusions. The present data suggested that novel 3DE left heart chamber metrics by DHM such as LAEF, LAVi min, and LVGFI can refine our echocardiographic disease discrimination capacity

Prediction of Persistent Impaired Glucose Tolerance in Patients with Minor Ischemic Stroke or Transient Ischemic Attack

Background: Impaired glucose tolerance (IGT) in patients with ischemic stroke can return to normal, reflecting an acute stress response, or persist. Persistent IGT is associated with an increased risk of recurrent stroke, other cardiovascular diseases and unfavorable outcome after stroke. We aim to validate our previously developed model to identify patients at risk of persistent IGT in an independent data set, and, if necessary, update the model. Methods: The validation data set consisted of 239 nondiabetic patients with a minor ischemic stroke or TIA and IGT in the acute phase (2-hour post-load glucose levels between 7.8 and 11.0 mmol/l). The outcome was persistent versus normalized IGT, based on repeated oral glucose tolerance test after a median of 46 days. The discriminative ability of the original model was assessed with the area under the ROC curve (AUC). The updated model was internally validated with bootstrap resampling and cross-validated in the development population of the original model. Results: One-hundred eighteen of 239 (49%) patients had persistent IGT. The original model, with the predictors age, current smoking, statin use, triglyceride, hypertension, history of cardiovascular diseases, body mass index (BMI), fasting plasma glucose performed poorly (AUC .60). The newly developed model included only BMI, hypertension, statin use, atrial fibrillation, 2-hour post-load glucose levels, HbA1c, large artery atherosclerosis, and predicted persistent IGT more accurately (internally validated AUC 0.66, externally validated AUC .71). Conclusions: This prediction model with simple clinical variables can be used to predict persistent IGT in patients with IGT directly after minor stroke or TIA, and may be useful to optimize secondary prevention by early identification of patients with disturbed glucose metabolism

Quantification of Myocardial Contraction Fraction with Three-Dimensional Automated, Machine-Learning-Based Left-Heart-Chamber Metrics: Diagnostic Utility in Hypertrophic Phenotypes and Normal Ejection Fraction

Aims: The differentiation of left ventricular (LV) hypertrophic phenotypes is challenging in patients with normal ejection fraction (EF). The myocardial contraction fraction (MCF) is a simple dimensionless index useful for specifically identifying cardiac amyloidosis (CA) and hypertrophic cardiomyopathy (HCM) when calculated by cardiac magnetic resonance. The purpose of this study was to evaluate the value of MCF measured by three-dimensional automated, machine-learning-based LV chamber metrics (dynamic heart model [DHM]) for the discrimination of different forms of hypertrophic phenotypes. Methods and Results: We analyzed the DHM LV metrics of patients with CA (n = 10), hypertrophic cardiomyopathy (HCM, n = 36), isolated hypertension (IH, n = 87), and 54 healthy controls. MCF was calculated by dividing LV stroke volume by LV myocardial volume. Compared with controls (median 61.95%, interquartile range 55.43–67.79%), mean values for MCF were significantly reduced in HCM—48.55% (43.46–54.86% p &lt; 0.001)—and CA—40.92% (36.68–46.84% p &lt; 0.002)—but not in IH—59.35% (53.22–64.93% p &lt; 0.7). MCF showed a weak correlation with EF in the overall cohort (R2 = 0.136) and the four study subgroups (healthy adults, R2 = 0.039 IH, R2 = 0.089; HCM, R2 = 0.225; CA, R2 = 0.102). ROC analyses showed that MCF could differentiate between healthy adults and HCM (sensitivity 75.9%, specificity 77.8%, AUC 0.814) and between healthy adults and CA (sensitivity 87.0%, specificity 100%, AUC 0.959). The best cut-off values were 55.3% and 52.8%. Conclusions: The easily derived quantification of MCF by DHM can refine our echocardiographic discrimination capacity in patients with hypertrophic phenotype and normal EF. It should be added to the diagnostic workup of these patients

Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.

In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis.Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points.A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3,1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm.In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib.ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981