A population pharmacokinetic model of remimazolam for general anesthesia and consideration of remimazolam dose in clinical practice.

BACKGROUND: Remimazolam besylate is a novel short-acting benzodiazepine. An appropriate pharmacokinetic model of remimazolam is desirable in anesthesia practice. The aim of the study was to develop a pharmacokinetic model using plasma samples from patients anesthetized with remimazolam. Influence of patient characteristics, context-sensitive decrement-times, and dose regimens were also examined. METHODS: Data were obtained from four trials on patients, and seven trials on healthy volunteers. The characteristics of 416 male and 246 female subjects were as follows: age, 18-93 years; body weight, 34-149 kg; and American Society of Anesthesiologists physical status (ASA-PS), I-IV. 2231 arterial and 3200 venous samples were used for the final model. The equilibration rate constant between arterial plasma and effect-site was estimated using the concept of time to peak effect. The final model was used to generate context-sensitive decrement times and dose regimens for general anesthesia. RESULTS: A three-compartment model plus virtual venous compartment with allometric scaling of adjusted body weight (ABW), age, sex, and ASA-PS as covariates were selected as the final model. Elimination clearance was lower in males, and in subjects with higher ABW and ASA-PS scores. Approximately 10% or 20% higher dose rate was necessary in females than in males or ASA-PS I/II than III/IV patient. The context-sensitive half-time for effect-site concentration in a 55-year-old, 70-kg, 170-cm male or female ASA-PS I/II patient after > 6-h infusion was 16.7 or 15.9 min. CONCLUSION: Remimazolam pharmacokinetic model for general anesthesia was successfully developed. ABW, ASA-PS, and sex has a considerable impact on the remimazolam concentration.

SPHERIOUSLY? The challenges of estimating sphere radius non-invasively in the human brain from diffusion MRI.

The Soma and Neurite Density Imaging (SANDI) three-compartment model was recently proposed to disentangle cylindrical and spherical geometries, attributed to neurite and soma compartments, respectively, in brain tissue. There are some recent advances in diffusion-weighted MRI signal encoding and analysis (including the use of multiple so-called 'b-tensor' encodings and analysing the signal in the frequency-domain) that have not yet been applied in the context of SANDI. In this work, using: (i) ultra-strong gradients; (ii) a combination of linear, planar, and spherical b-tensor encodings; and (iii) analysing the signal in the frequency domain, three main challenges to robust estimation of sphere size were identified: First, the Rician noise floor in magnitude-reconstructed data biases estimates of sphere properties in a non-uniform fashion. It may cause overestimation or underestimation of the spherical compartment size and density. This can be partly ameliorated by accounting for the noise floor in the estimation routine. Second, even when using the strongest diffusion-encoding gradient strengths available for human MRI, there is an empirical lower bound on the spherical signal fraction and radius that can be detected and estimated robustly. For the experimental setup used here, the lower bound on the sphere signal fraction was approximately 10%. We employed two different ways of establishing the lower bound for spherical radius estimates in white matter. The first, examining power-law relationships between the DW-signal and diffusion weighting in empirical data, yielded a lower bound of 7µm, while the second, pure Monte Carlo simulations, yielded a lower limit of 3µm and in this low radii domain, there is little differentiation in signal attenuation. Third, if there is sensitivity to the transverse intra-cellular diffusivity in cylindrical structures, e.g., axons and cellular projections, then trying to disentangle two diffusion-time-dependencies using one experimental parameter (i.e., change in frequency-content of the encoding waveform) makes spherical radii estimates particularly challenging. We conclude that due to the aforementioned challenges spherical radii estimates may be biased when the corresponding sphere signal fraction is low, which must be considered.

Body composition assessment in children with inflammatory bowel disease: A comparison of different methods.

AIM: To assess different techniques to measure body composition in paediatric patients with inflammatory bowel disease using dual energy X-ray absorptiometry as a reference method. We hypothesised that a three-compartment model may demonstrate superiority over other methods as skinfold thickness equations and bioelectrical impedance analysis. METHODS: Body composition was assessed using skinfold thickness equations, bioelectrical impedance analysis and the three-compartment model. Data obtained with these methods were compared to the results obtained by dual energy X-ray absorptiometry. Statistical analysis was performed using Spearman's correlation and Bland-Altman's limits of agreement method. RESULTS: Twenty-one paediatric patients with inflammatory bowel disease were included: 11 females and 10 males; mean age for the entire group: 14.3 years, range 12-16 years. In children with inflammatory bowel disease, skinfold thickness equations, bioelectrical impedance analysis and the three-compartment model showed reliable measurements with small differences in the percentage of total body fat and good limits of agreements. CONCLUSION: The assessment of body composition using bioelectrical impedance analysis provides a valid and accurate method in children with inflammatory bowel disease as compared to dual energy X-ray absorptiometry. In the future, superiority of 3-compartment model in research and clinical settings of nutritional intervention and disease status in children with inflammatory bowel disease remains to be demonstrated.

Development of a three-compartment toxicokinetic model for T-2 toxin in shrimp by blindfold particle swarm optimization algorithm.

Tricothecenes-2 toxin (T-2) is a major mycotoxin that is widely distributed in aquatic feeds and poses a huge challenge to the aquatic industry, but there is scant information on the toxicokinetics of T-2 in aquatic animals. Here, we describe the development of a three-compartment toxicokinetic model for the absorption, distribution, metabolism and elimination (ADME) of T-2 in shrimp. The three compartments were central (the hemolymph), slow metabolizing and fast metabolizing compartments to account for the varying ADME rates of T-2 in different shrimp organs. The toxicokinetic model was solved by the blindfold particle swarm optimization algorithm, and the values for the model equation parameters were obtained by applying the experimental data of T-2 concentrations in shrimp. The model had a good fit with the experimental data. It was revealed through the model that after i.m. administration, T-2 was rapidly absorbed into the hemolymph and distributed into shrimp organs. The hepatopancreas and intestine belonged to the fast and muscle to the slow metabolizing compartments, respectively, while the hemolymph had no capacity to metabolize T-2. The T-2 elimination rates in the hepatopancreas and intestine were similar and quite high while that in the muscle was very low. The methods used in developing and solving the model could be used for similar toxicokinetic and pharmacokinetic studies of other animals.

The non-linear relationship between sum of 7 skinfolds and fat and lean mass in elite swimmers.

Body composition can substantially impact elite swimming performance. In practice, changes in fat and lean mass of elite swimmers are estimated using body mass, sum of seven skinfolds (∑7) and lean mass index (LMI). However, LMI may be insufficiently accurate to detect small changes in body composition which could meaningfully impact swimming performance. This study developed equations which estimate dual-energy x-ray absorptiometry (DXA)-derived lean and fat mass using body mass and ∑7 data. Elite Australian swimmers (n = 44; 18 male, 26 female) completed a DXA scan and standardised body mass and ∑7 measurements. Equations to estimate DXA-derived lean and fat mass based on body mass, ∑7 and sex were developed. The relationships between ∑7, body mass and DXA-derived lean and fat mass were non-linear. Fat mass (Adjusted R2 = 0.91; standard error = 1.0 kg) and lean mass (Adjusted R2 = 0.99; standard error = 1.0 kg) equations were considered sufficiently accurate. Lean mass estimates outperformed the LMI in identifying the correct direction of change in lean mass (82% correct; LMI 71%). Using the accurate estimations produced by these equations will enhance the prescription and evaluation of programmes to optimise the body composition and subsequent performance in swimmers.

Impact of food and fluid intake on technical and biological measurement error in body composition assessment methods in athletes.

Two, three and four compartment (2C, 3C and 4C) models of body composition are popular methods to measure fat mass (FM) and fat-free mass (FFM) in athletes. However, the impact of food and fluid intake on measurement error has not been established. The purpose of this study was to evaluate standardised (overnight fasted, rested and hydrated) v. non-standardised (afternoon and non-fasted) presentation on technical and biological error on surface anthropometry (SA), 2C, 3C and 4C models. In thirty-two athletic males, measures of SA, dual-energy X-ray absorptiometry (DXA), bioelectrical impedance spectroscopy (BIS) and air displacement plethysmography (BOD POD) were taken to establish 2C, 3C and 4C models. Tests were conducted after an overnight fast (duplicate), about 7 h later after ad libitum food and fluid intake, and repeated 24 h later before and after ingestion of a specified meal. Magnitudes of changes in the mean and typical errors of measurement were determined. Mean change scores for non-standardised presentation and post meal tests for FM were substantially large in BIS, SA, 3C and 4C models. For FFM, mean change scores for non-standardised conditions produced large changes for BIS, 3C and 4C models, small for DXA, trivial for BOD POD and SA. Models that included a total body water (TBW) value from BIS (3C and 4C) were more sensitive to TBW changes in non-standardised conditions than 2C models. Biological error is minimised in all models with standardised presentation but DXA and BOD POD are acceptable if acute food and fluid intake remains below 500 g.

Penetration of piperacillin-tazobactam into human prostate tissue and dosing considerations for prostatitis based on site-specific pharmacokinetics and pharmacodynamics.

This study aimed to investigate the penetration of PIPC-TAZ into human prostate, and to assess effectiveness of PIPC-TAZ against prostatitis by evaluating site-specific PK-PD. Patients with prostatic hypertrophy (n = 47) prophylactically received a 0.5 h infusion of PIPC-TAZ (8:1.2-0.25 g or 4-0.5 g) before transurethral resection of the prostate. PIPC-TAZ concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were analyzed with a three-compartment PK model. The estimated model parameters were, then used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T > MIC, the PD indicator for antibacterial effects) in prostate tissue for six PIPC-TAZ regimens (2.25 or 4.5 g; once, twice, three times or four times daily; 0.5 h infusions). Prostate tissue/plasma ratio of PIPC was about 36% both for the maximum drug concentration (Cmax) and the area under the drug concentration-time curve (AUC). Against MIC distributions for isolates of Escherichia coli, Klebsiella species and Proteus species, regimens of 4.5 g twice daily and 2.25 g three times daily achieved a >90% probability of attaining the bacteriostatic target for PIPC (30% T > MIC) in prostate tissue; regimens of 4.5 g three times daily and 2.25 g four times daily achieved a >90% probability of attaining the bactericidal target for PIPC (50% T > MIC) in prostate tissue. However, against Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability. PIPC-TAZ is appropriate for the treatment of prostatitis from the site-specific PK-PD perspective.

Noninvasive ROS imaging and drug delivery monitoring in the tumor microenvironment.

Reactive oxygen species (ROS) that are overproduced in certain tumors can be considered an indicator of oxidative stress levels in the tissue. Here, we report a magnetic resonance imaging (MRI)-based probe capable of detecting ROS levels in the tumor microenvironment (TME) using ROS-responsive manganese ion (Mn2+)-chelated, biotinylated bilirubin nanoparticles (Mn@bt-BRNPs). These nanoparticles are disrupted in the presence of ROS, resulting in the release of free Mn2+, which induces T1-weighted MRI signal enhancement. Mn@BRNPs show more rapid and greater MRI signal enhancement in high ROS-producing A549 lung carcinoma cells compared with low ROS-producing DU145 prostate cancer cells. A pseudo three-compartment model devised for the ROS-reactive MRI probe enables mapping of the distribution and concentration of ROS within the tumor. Furthermore, doxorubicin-loaded, cancer-targeting ligand biotin-conjugated Dox/Mn@bt-BRNPs show considerable accumulation in A549 tumors and also effectively inhibit tumor growth without causing body weight loss, suggesting their usefulness as a new theranostic agent. Collectively, these findings suggest that Mn@bt-BRNPs could be used as an imaging probe capable of detecting ROS levels and monitoring drug delivery in the TME with potential applicability to other inflammatory diseases.

Longitudinal Magnetic Resonance Imaging with ROS-Responsive Bilirubin Nanoparticles Enables Monitoring of Nonalcoholic Steatohepatitis Progression to Cirrhosis.

Despite the vital importance of monitoring the progression of nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), an efficient imaging modality that is readily available at hospitals is currently lacking. Here, a new magnetic-resonance-imaging (MRI)-based imaging modality is presented that allows for efficient and longitudinal monitoring of NAFLD and NASH progression. The imaging modality uses manganese-ion (Mn2+)-chelated bilirubin nanoparticles (Mn@BRNPs) as a reactive-oxygen-species (ROS)-responsive MRI imaging probe. Longitudinal T1-weighted MR imaging of NASH model mice is performed after injecting Mn@BRNPs intravenously. The MR signal enhancement in the liver relative to muscle gradually increases up to 8 weeks of NASH progression, but decreases significantly as NASH progresses to the cirrhosis-like stage at weeks 10 and 12. A new dual input pseudo-three-compartment model is developed to provide information on NASH stage with a single MRI scan. It is also demonstrated that the ROS-responsive Mn@BRNPs can be used to monitor the efficacy of potential anti-NASH drugs with conventional MRI. The findings suggest that the ROS-responsive Mn@BRNPs have the potential to serve as an efficient MRI contrast for monitoring NASH progression and its transition to the cirrhosis-like stage.

[Dynamic magnetic resonance imaging of the pelvic floor: clinical application]. / Dynamische Magnetresonanztomographie des Beckenbodens: Klinische Anwendung.

BACKGROUND: Dynamic magnetic resonance imaging (MRI) of the pelvic floor plays a key role in imaging complex pelvic floor dysfunction. The simultaneous detection of multiple findings in a complex anatomic setting renders correct analysis and clinical interpretation challenging. OBJECTIVES: The most important aspects (anatomy of the pelvic floor, three compartment model, morphological and functional analysis, reporting) for a successful clinical use of dynamic MRI of the pelvic floor are summarized. MATERIALS AND METHODS: Review of the scientific literature on dynamic pelvic MR imaging with special consideration of the joint recommendations provided by the expert panel of ESUR/ESGAR in 2016. RESULTS: The pelvic floor is a complex anatomic structure, mainly formed by the levator ani muscle, the urethral support system and the endopelvic fascia. Firstly, morphological changes of these structures are analysed on the static sequences. Secondly, the functional analysis using the three compartment model is performed on the dynamic sequences during squeezing, straining and defecation. Pelvic organ mobility, pelvic organ prolapse, the anorectal angle and pelvic floor relaxation are measured and graded. The diagnosis of cystoceles, enteroceles, rectoceles, the uterovaginal as well as anorectal decent, intussusceptions and dyssynergic defecation should be reported using a structured report form. CONCLUSIONS: A comprehensive analysis of all morphological and functional findings during dynamic MRI of the pelvic floor can provide information missed by other imaging modalities and hence alter therapeutic strategies.

Monitoring of explosive residues in lake-bottom water using Polar Organic Chemical Integrative Sampler (POCIS) and chemcatcher: determination of transfer kinetics through Polyethersulfone (PES) membrane is crucial.

Between 1920 and 1967, approximatively 8200 tons of ammunition waste were dumped into some Swiss lakes. This study is part of the extensive historical and technical investigations performed since 1995 by Swiss authorities to provide a risk assessment. It aims to assess whether explosive monitoring by passive sampling is feasible in lake-bottom waters. Polar organic chemical integrative sampler (POCIS) and Chemcatcher were first calibrated in a channel system supplied with continuously refreshed lake water spiked with two nitroamines (HMX and RDX), one nitrate ester (PETN), and six nitroaromatics (including TNT). Exposure parameters were kept as close as possible to the ones expected at the bottom of two affected lakes. Sixteen POCIS and Chemcatcher were simultaneously deployed in the channel system and removed in duplicates at 8 different intervals over 21 days. Sorbents and polyethersulfone (PES) membranes were separately extracted and analyzed by UPLC-MS/MS. When possible, a three-compartment model was used to describe the uptake of compounds from water, over the PES membrane into the sorbent. Uptake of target compounds by sorbents was shown not to approach equilibrium during 21 days. However, nitroaromatics strongly accumulated in PES, thus delaying the transfer of these compounds to sorbents (lag-phase up to 9 days). Whereas sampling rate (RS) of nitroamines were in the range of 0.06-0.14 L day-1, RS of nitroaromatics were up to 10 times lower. As nitroaromatic accumulation in PES was integrative over 21 days, PES was used as receiving phase for these compounds. The samplers were then deployed at lake bottoms. To ensure that exposure conditions were similar between calibration and field experiments, low-density polyethylene strips spiked with performance reference compounds were co-deployed in both experiments and dissipation data were compared. Integrative concentrations of explosives measured in the lakes confirmed results obtained by previous studies based on grab sampling.

A Three-Compartment Pharmacokinetic Model to Predict the Interstitial Concentration of Talaporfin Sodium in the Myocardium for Photodynamic Therapy: A Method Combining Measured Fluorescence and Analysis of the Compartmental Origin of the Fluorescence.

To evaluate the effectiveness of photodynamic therapy occurring in the interstitial space of the myocardium, we estimated the interstitial concentration of talaporfin sodium in the canine myocardium by constructing a three-compartment pharmacokinetic model based on measured changes in talaporfin sodium plasma concentration and myocardial fluorescence. Differential rate equations of talaporfin sodium concentration in the plasma, interstitial space, and cell compartment were developed with individual compartment volume, concentration, and rate constants. Using measured volume ratios based on histological examinations, we defined that the myocardial fluorescence consisted of the linear addition of fluorescence generated from these three compartments. The rate constants were obtained by fitting to minimize the sum of the squared errors between the measured talaporfin sodium concentrations and the calculated concentrations divided by the number of data points using the conjugate gradient method in MATLAB. We confirmed that this fitting operation may be appropriate, because a coefficient of determination between the measured talaporfin sodium changes and the calculated concentrations using our equations was 0.99. Consequently, to estimate the interstitial concentration in the canine myocardium, we propose a three-compartment pharmacokinetic model construction methodology using measured changes in talaporfin sodium plasma concentration and changes in myocardial fluorescence.