Population Pharmacokinetic Modeling of Free Plasma and Free Brain Concentrations of Ceftaroline in Healthy and Methicillin-Resistant Staphylococcus aureus-Infected Wistar Rats.

A population pharmacokinetic model was developed to describe alterations in ceftaroline brain disposition caused by meningitis in healthy and methicillin-resistant Staphylococcus aureus (MRSA)-infected rats. Blood and brain microdialysate samples were obtained after a single bolus dose of ceftaroline fosamil (20 mg/kg) administered intravenously. Plasma data were modeled as one compartment, and brain data were added to the model as a second compartment, with bidirectional drug transport between plasma and brain (Qin and Qout). The cardiac output (CO) of the animals showed a significant correlation with the relative recovery (RR) of plasma microdialysis probes, with animals with greater CO presenting lower RR values. The Qin was approximately 60% higher in infected animals, leading to greater brain exposure to ceftaroline. Ceftaroline brain penetration was influenced by MRSA infection, increasing from 17% (Qin/Qout) in healthy animals to 27% in infected animals. Simulations of a 2-h intravenous infusion of 50 mg/kg every 8 h achieved >90% probability of target attainment (PTA) in plasma and brain for the modal MRSA MIC (0.25 mg/L), suggesting that the drug should be considered an option for treating central nervous system infections.

Usual dietary intake, physical activity, weight loss, and body composition after five years of Roux-en-Y gastric bypass.

OBJECTIVE: To estimate usual dietary intake (UDI), physical activity (PA), and their association with weight loss and body composition in patients who underwent Roux-en-Y gastric bypass (RYGB) after five years in the Federal District, Brazil. METHODS: We assessed anthropometry and body composition using bioimpedance, and dietary intake and PA with three nonconsecutive 24-h recalls. PC-Side was used to estimate UDI. Dietary patterns (DPs) were identified through principal component analysis, and association between UDI and PA with percentage of total weight loss (%TWL) and fat-free mass (FFM) through multinomial logistic regression. RESULTS: Sample (n = 124) presented mean (SD) age of 48.9 (9.4) years, median (IQR) of 9 years (7-10) post RYGB, current BMI = 32.3 kg/m² (28.8-35.7), %TWL = 24.7% (10.9), and FFM = 45.1 kg (41.1-51.9). Mean usual energy intake of 1556 kcal/d, with adequate protein intake, poor fiber intake, and excessive carbohydrate, total fat, and added sugar intake, compared to dietary guidelines. Calcium, vitamins C, D, and E presented the greatest inadequacy (15%, 24%, 32%, and 49% of individuals, respectively, reported usual intake below EAR); 83 participants were considered active/very active, according PA. DP with high energy, protein, total fat, saturated fat, and sodium intake, was negatively associated with %TWL (OR = 0.545, p = 0.037). Protein intake was positively associated with FFM (OR = 1.091, p = 0.004). PA was not associated with %TWL or FFM. CONCLUSION: Participants demonstrated intake of carbohydrate, fat, fiber, added sugar not in accordance with guidelines. A DP rich in energy, protein, total fat, saturated fat, and sodium appears to decrease TWL. However, protein intake appears to increase FFM.

Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia.

OBJECTIVES: Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. METHODS: The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). RESULTS: A two-compartment model was built using 483 data points from 45 patients (0.33-17.83 years of age) treated with MTX (0.25-5 g/m2) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as [Formula: see text]. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. CONCLUSION: The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size.

Impact of serum albumin concentration and neutrophil-lymphocyte ratio score on gastric cancer prognosis.

INTRODUCTION/AIM: Serum albumin concentration (COA) and neutrophil-lymphocyte ratio (NLR) could reflect immunological and nutritional status. We aim to evaluate the impact of COA-NLR score on the prognosis of gastric cancer (GC). MATERIAL AND METHODS: We perform a retrospective analysis on a database of 637 GC cases, between January 2010 and December 2017. In 396 patients, the inclusion criteria for this study were met (non-resectional or palliative surgery were excluded). Analytic data was only available in 203 patients. COA-NLR score was defined as follows: COA under 35 g/L and NLR value of 2.585 or higher, score 2; one of these conditions, score 1; and neither, score 0. RESULTS: In our population (n = 203), 87 patients were classified as score 0, 82 as score 1 and 34 as score 2. COA-NLR score was significantly associated with DFS (HR 1.674; CI 95% 1.115-2.513; p = 0.013) and with OS (HR 2.072; CI 95% 1.531-2.805; p < 0.001). Kaplan-Meier curve analysis (log rank test) revealed that a higher score of COA-NLR predicted a worse OS (p < 0.001) and DFS (p = 0.03). COA-NLR was an independent prognostic factor for OS when adjusted to pStage and age (adjusted HR 1.566; CI 95% 1.145-2.143; p = 0.005). CONCLUSIONS: Preoperative COA-NLR score was significantly associated with worse OS and DFS and, in this way, with worse prognosis on GC patients submitted to curative-intent resectional surgery.

Patients' physiological reactions to competitive rehabilitation therapies assisted by robotic devices.

BACKGROUND: The aging of the population and the progressive increase in life expectancy in developed countries is leading to a high incidence of cerebrovascular diseases. Several studies have demonstrated that robot-assisted rehabilitation therapies combined with serious games can improve rehabilitation outcomes. Social interaction in the form of multiplayer games has been highlighted as a potential element to increase patient's motivation and exercise intensity, which professionals have described as one of the determining factors in maximizing rehabilitation outcomes. Despite this, it has not been widely studied. Physiological measures have been proven as an objective tool to evaluate patients' experience in robot-assisted rehabilitation environments. However, they have not been used to evaluate patients' experience in multiplayer robot-assisted rehabilitation therapies. The main objective of this study is to analyze whether the interpersonal interaction inherent in a competitive game mode affects the patients' physiological responses in robot-assisted rehabilitation environments. METHODS: A total of 14 patients participated in this study. The results of a competitive game mode were compared with a single-player game mode with different difficulty levels. Exercise intensity and performance were measured through parameters extracted from the game and the information provided by the robotic rehabilitation platforms. The physiological response of patients in each game mode was measured by the heart rate (HR) and the galvanic skin response (GSR). Patients were asked to fill out the IMI and the overall experience questionnaire. RESULTS: The exercise intensity results show that high-difficulty single-player game mode is similar in terms of intensity level to a competitive game mode, based on velocity values, reaction time and questionnaire results. However, the results of the physiological responses of the patients measured by GSR and HR are lower in the case of the competitive mode compared to the high-difficulty single-player game mode, obtaining results similar to those obtained in the low-difficulty single-player game mode. CONCLUSIONS: Patients find the competitive game mode the most fun, which is also the mode they report experiencing the most effort and stress level. However, this subjective evaluation is not in line with the results of physiological responses. This study concludes that interpersonal interaction inherent to a competitive game mode influences patients' physiological responses. This could mean that social interaction is an important factor to consider when interpreting the results obtained from physiological measurements.

Population Pharmacokinetic Modeling and Probability of Target Attainment of Ceftaroline in Brain and Soft Tissues.

Ceftaroline, approved to treat skin infections and pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA), has been considered for the treatment of central nervous system (CNS) infections. A population pharmacokinetic (popPK) model was developed to describe ceftaroline soft tissue and cerebrospinal fluid (CSF) distributions and investigate the probability of target attainment (PTA) of the percentage of the dosing interval that the unbound drug concentration exceeded the MIC (%fT>MIC) to treat MRSA infections. Healthy subjects' plasma and microdialysate concentrations from muscle and subcutaneous tissue following 600 mg every 12 h (q12h) and q8h and neurosurgical patients' plasma and CSF concentrations following single 600-mg dosing were used. Plasma concentrations were described by a two-compartment model, and tissue concentrations were incorporated as three independent compartments linked to the central compartment by bidirectional transport (clearance in [CLin] and CLout). Apparent volumes were fixed to physiological interstitial values. Healthy status and body weight were identified as covariates for the volume of the central compartment, and creatinine clearance was identified for clearance. The CSF glucose concentration (GLUC) was inversely correlated with CLin,CSF. Simulations showed a PTA of >90% in plasma and soft tissues for both regimens assuming an MIC of 1 mg/L and a %fT>MIC of 28.8%. Using the same target, patients with inflamed meninges (0.5 < GLUC ≤ 2 mmol/L) would reach PTAs of 99.8% and 97.2% for 600 mg q8h and q12h, respectively. For brain infection with mild inflammation (2 < GLUC ≤ 3.5 mmol/L), the PTAs would be reduced to 34.3% and 9.1%, respectively. Ceftaroline's penetration enhanced by meningeal inflammation suggests that the drug could be a candidate to treat MRSA CNS infections.

Preclinical Pharmacokinetic and Pharmacodynamic Investigation of 5'-Methoxynobiletin from Ageratum conyzoides: In vivo and In silico Approaches.

PURPOSE: 5'-methoxynobiletin (5'-MeONB), a polymethoxyflavone isolated from A. conyzoides, has shown anti-inflammatory property. Nevertheless, the antinociceptive activity and pre-clinical pharmacokinetics (PK) characteristics of 5'-MeONB remain unknown. Considering the anti-inflammatory potential of the 5'-MeONB, this study aimed to investigate the pre-clinical PK behavior of 5'-MeONB, as well as its time course antinociceptive activity. METHODS: 5'-MeONB plasma concentrations were determined in Wistar rats after intravenous (i.v.) (10 mg/kg) and oral (50 mg/kg) administration, and in Swiss mice after oral administration (100 mg/kg). Plasma samples were deproteinization and 5'-MeONB quantified by a validated UPLC-MS method. Additionally, the antinociceptive activity of 5'-MeONB was evaluated after 15, 30, 60, 180 and 360 min following oral administration on the acute nocifensive behavior of mice induced by formalin. RESULTS: 5'-MeONB rats and mice plasma concentration-time profiles were best one-compartment model. After i.v. administration to rats, a short half-life, a high clearance and moderate volume of distribution at steady state were observed. Similar results were obtained after oral administration. The oral bioavailability ranged from 8 to 11%. Additionally, 5'-MeONB exhibited antinociceptive activity in both formalin phases, especially in the inflammatory phase of the model, inhibiting 68% and 91% of neurogenic and inflammatory responses, respectively, after 30 min of oral administration. CONCLUSIONS: The results described here provide novel insights on 5'-MeONB pharmacokinetics and pharmacodynamic effect, serving as support for future studies to confirm this compound as anti-nociceptive and anti-inflammatory effective agent.

Physically inactive adults are the main users of sports dietary supplements in the capital of Brazil.

PURPOSE: This cross-sectional study aimed to provide estimates of dietary supplements (DS) use and to examine the relationship between sports dietary supplements (SDS) use and sociodemographic and lifestyle characteristic, body mass index and total daily physical activity (PA) in the adult population of Brasília, Brazil. METHODS: DS use was collected from 506 adults via a Food Frequency Questionnaire. DS were divided into multivitamin-minerals, electrolyte drinks, energy, protein, partial meal replacements, creatine, caffeine, and others. Electrolyte drinks, energy, and protein supplements were considered as SDS. PA was estimated from a 24-h PA recall, and total MET (metabolic equivalents)/day and MET-h/day were calculated. Participants were categorized as physically inactive or active according to MET-h/day. RESULTS: DS were used by 68% of adults; multivitamin-minerals (38%) and protein supplements (29%) were the most commonly used products. SDS use was associated with the highest socioeconomic level, younger age, and male gender, but not with PA. Also, most SDS users were physically inactive. CONCLUSION: These findings indicate that SDS may be used unnecessarily by adults in Brasília. Specific recommendations and control procedures for the use of SDS are warranted.

Dietary inflammatory index and its relationship with gut microbiota in individuals with intestinal constipation: a cross-sectional study.

OBJECTIVE: To determine whether there is an association between the inflammatory potential of the diet, measured by the dietary inflammatory index (DII®), and the composition of intestinal microbiota in adults with functional constipation (FC). METHODS: A cross-sectional study was carried out with 68 adults with FC. Energy-adjusted DII (E-DII) was calculated from data obtained from food surveys, serum inflammation markers were measured and the composition of the intestinal microbiota was evaluated using the 16S rRNA gene sequencing method. Participants were assigned into two groups: anti-inflammatory diet (AD: E-DII < 0) and pro-inflammatory diet (PD: E-DII ≥ 0). Associations of E-DII scores with microbial diversity and composition were examined using differences between the E-DII groups and linear and hierarchical regression. RESULTS: E- DII was inversely correlated with relative abundance of Hungatella spp. and Bacteroides fragilis and positively correlated with Bacteroides thetaiotaomicron and Bacteroides caccae (p < 0.05). B. fragilis was positively correlated with IL-10. The AD group had higher relative abundances for the genus Blautia and Hungatella, lower abundances of Bacteroides thetaiotamicron and Bacteroides spp. (p < 0.05), as well as higher frequency of evacuation (p = 0.02) and lower use of laxatives (p = 0.05). The AD group showed a reduction in the abundance of Desulfovibrio spp. and Butyrivibrio, Butyrivibrio crossotus, Bacteroides clarus, Bacteroides coprophilus and Bacteroides intestinalis (all p < 0.05). The greater abundance of Bacteroides clarus increased the individual's chance of performing a manual evacuation maneuver. CONCLUSION: Therefore, the results of this study demonstrated that the inflammatory potential of the diet is associated with the gut microbiota in individuals with FC.

Early consumption of ultra-processed foods among children under 2 years old in Brazil.

OBJECTIVE: To evaluate the complementary food consumption according to the extent and purpose of food processing based on NOVA classification among children aged 6-24 months of Federal District, Brazil. DESIGN: We performed a cross-sectional study using a 24-h recall to estimate the daily energy intake and nutrients according to NOVA classification. We conducted a linear regression to assess the association between the processed and ultra-processed foods (UPF) energy intake and the daily energy intake from saturated fat, daily energy intake from total sugars and daily intake of sodium. SETTING: Federal District, Brazil. PARTICIPANTS: Five hundred and thirty-eight children aged between 6 and 24 months attended at Primary Health Care Units from March 2017 to March 2018. RESULTS: On average, children aged from 6 to 12 and from 12 to 24 months consumed 2393 and 4054 kJ/d, respectively, and processed and UPF represented one-third of dietary energy intake. Group 2 (processed and UPF) was higher carbohydrate contributors, and lower protein, fibre and most micronutrient contributors, when compared with Group 1 (unprocessed, minimally processed foods and processed culinary ingredients). In addition, the higher the energy intake from processed and UPF, the higher was the daily energy intake from saturated fat, daily energy intake from total sugar and daily intake of sodium. CONCLUSION: Children are being exposed early to processed and UPF and their share affect the diet's nutritional quality.