Miracle-dz/UniFAR-FTUs huggingface dataset:
Correlation Between Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid in Liver Transplant Patients

This study investigated the relationship between pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA) in liver transplant patients receiving mycophenolate mofetil (MMF). Total and free plasma MPA concentrations were determined by high‐performance liquid chromatography before MMF dose and at 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after dosing in 27 patients. The inhibitory capacity of serum MPA on proliferation of CEM cells was monitored at 0, 1, and 2 hours. The concentration of free MPA at 0, 1, and 2 hours (C0h, C1h, C2h) and the area under the concentration‐time curve at 0 to 12 hours (AUC0‐12h) of free MPA were significantly related to those of total MPA (P < .05). C1h and C2h of total and free MPA were conversely related with the rate of proliferation of CEM cells (P < .05). At 1 and 2 hours after an MMF dose, the percentage of CEM cell proliferation was below 40% in the majority of patients compared with the percentage before dosing. Thus, there was a significant relationship between total and free plasma MPA concentrations in liver transplant patients. After MMF dose, the inhibitory capacity of serum MPA on proliferation of CEM cells was enhanced significantly. This effect was related greatly to MPA concentrations.
Metabolism and Excretion of [14C] Febuxostat, a Novel Nonpurine Selective Inhibitor of Xanthine Oxidase, in Healthy Male Subjects

Absorption, metabolism, and excretion of one 80 mg oral dose of [14C] febuxostat ([thiazole‐4‐14C] 2‐[3‐cyano‐4‐isobutoxyphenyl]‐4‐methyl‐5‐thiazolecarboxylic acid) were studied in 6 healthy subjects. Mean cumulative recovery in excreta was 94% (49% urine and 45% feces) of the dose over 9 days; 87% of the dose was profiled. Seventeen radioactive peaks were observed in urine and fecal chromatograms. Unchanged febuxostat contributed to a combined total in excreta of 10% to 18% of the dose, indicating that it was extensively metabolized and well absorbed. Metabolites were 67M‐1 (10%) and 67M‐2 (11%) hydroxylated febuxostat, febuxostat acyl‐glucuronide (30%), 67M‐4 di‐carboxylic acid (14%), 67M‐1 sulfate conjugate (3%), and dehydrated 67M‐1/67M‐2 acyl‐glucuronide (0.5%). Febuxostat and these metabolites accounted for 82% of profiled dose; unidentified peaks individually contributed <1.3% of the dose. Febuxostat and total radioactivity plasma Cmax values were observed at 0.5 hour postdose, suggesting that febuxostat was quickly absorbed. At 4 hours postdose, plasma chromatographic profiles contained 6 peaks: febuxostat (85%), 67M‐1 (4%), 67M‐2 (5%), febuxostat acyl‐glucuronide (4%), 67M‐4 (1%), and 67M‐1 sulfate (0.5%). Compared to total radioactivity, febuxostat accounted for 94% at Cmax and 83% of the area under the concentration‐time curve (AUC) values. Based on the whole blood to plasma total radioactivity, little radioactivity was associated with red blood cells.
Clinical Pharmacology Tyramine Challenge Study to Determine the Selectivity of the Monoamine Oxidase Type B (MAO‐B) Inhibitor Rasagiline

Rasagiline is a selective, monoamine oxidase (MAO)‐B inhibitor indicated for treatment of Parkinson's disease. This double‐blind, placebo‐controlled study determined the tyramine sensitivity factor (TSF) and degree of MAO‐A inhibition (ie, reduction in plasma dihydroxyphenylglycol) in healthy volunteers who received phenelzine (15 mg, 3 times daily; positive control), selegiline (5 mg, twice daily), or rasagiline (1–6 mg, once daily) for 14 days or rasagiline 2 mg/d for 30 days. The selegiline/rasagiline groups were randomized to placebo or active drug. TSF was highest with phenelzine (17.3) and lowest with placebo (1.5). TSF with selegiline was 2.5. TSFs for rasagiline were as follows: 2.0 for 1 mg/d; 3.3 and 2.4 for 2 mg/d administered for 14 and 30 days, respectively; 4.5 for 4 mg/d; and 5.1 for 6 mg/d. Plasma dihydroxyphenylglycol concentrations suggested that rasagiline 1 mg/d had no effect, whereas rasagiline 2 mg/d had only minimal effect. In contrast, rasagiline 4 and 6 mg/d reduced dihydroxyphenylglycol to a degree approaching that achieved by the positive control phenelzine. Results demonstrate that rasagiline selectively inhibits MAO‐B and is not associated with increased tyramine sensitivity at the indicated dose (1 mg/d). These data allowed removal of dietary tyramine restriction from rasagiline US labeling.
Drug Burden Index and Beers Criteria: Impact on Functional Outcomes in Older People Living in Self‐Care Retirement Villages

The objectives of this study were to determine whether Drug Burden Index (DBI), a measure of individuals' exposure to anticholinergic and sedative drugs, and Beers criteria, an explicit measure of potentially inappropriate drug use, are associated with function in older adults living in low‐level care facilities; and to compare DBI with Beers criteria as a predictor of function in older people. The study population consisted of 115 residents living in low‐level care facilities in Sydney, Australia. Data on demographics, drugs, and comorbidities were collected. Outcomes included objective measures of physical function Short Performance Physical Battery (SPPB) and grip strength. In total, 50 (44%) participants were exposed to DBI drugs, 51 (44%) participants received at least 1 Beers criteria drug, and 30 (26%) were exposed to both. After adjusting for confounders, for every unit increase in DBI, the SPPB score decreased by 1.3 (P = .04). DBI was not associated with weaker grip strength. Beers criteria were not associated with any of the outcomes. In older adults living in self‐care retirement villages, DBI was associated with impairments in physical functioning. Exposure to Beers criteria drugs was common; however, Beers criteria did not predict functional outcomes in this population of older adults.
Solute Clearance and Tissue Clearance Times

In recent years there has been concern for the undertreatment of hemodialysis patients. In clinical practice, there are a number of limitations to increasing the “dose” of dialysis. Three of the parameters that affect prescribed clearance are the dialyzer characteristics (KoA), the blood flow rate (BFR), and the dialysate flow rate (DFR) (1). Current dialysis practice may involve “high-efficiency’ ’ dialyzers with KoAs of 800-1,100 mL/min, BRFs of 400-500 mL/min, and DFRs of 800 mL/min, which are approaching physical limits. The fourth parameter that can be manipulated to increase dialysis dose is treatment time. Unfortunately, extending dialysis time is often unacceptable to patients, complicates patient transportation, and increases the cost of each dialysis treatment. Although urea kinetic modeling (UKM) is now firmly established as an approach to the problem of estimating hemodialysis adequacy, the significance of UKM also lies in providing insights into underlying solute transport mechanisms. These insights may lead to novel dialysis strategies and help to optimize clinical prescription procedures and practices. Urea kinetic models were first developed by Dedrick and Bischoff (2). However, it was Gotch and coworkers who applied a single pool urea kinetic model to a clinical population when analyzing the results of the National Cooperative Dialysis Study (3) . This analysis used a variable-volume single-pool model of urea distribution and expressed the hemodialysis dose as KtN where K, t denote dialyzer clearance and treatment time, respectively, and V denotes the single-pool urea distribution volume. More recently, urea kinetic models were developed to explain the postdialysis urea rebound (4) which was noted clinically to increase with the normalized rate of dialysis clearance, WV. In the two-pool UKM, urea is assumed to be distributed in two well-mixed pools (initially identified as intraand extracellular compartments) between which solute transport occurs by diffusion. If urea transfers vary rapidly between the pools, the twopool simplifies to the one-pool model. Subsequently, Schneditz and coworkers (5-7) have shown that variations in regional blood flow could result in a multicompartmental distribution of urea. On this basis they could account for the postdialysis urea re-
In Vitro and In Vivo Assessment of Renal Drug Transporters in the Disposition of Mesna and Dimesna

Mesna and its dimer, dimesna, are coadministered for mitigation of ifosfamide‐ and cisplatin‐induced toxicities, respectively. Dimesna is selectively reduced to mesna in the kidney, producing its protective effects. In vitro screens of uptake and efflux transporters revealed saturable uptake by renal organic anion transporters OAT1, OAT3, and OAT4. Efflux transporters breast cancer resistance protein; multidrug and toxin extrusion 1 (MATE1); multidrug resistance proteins MRP1, MRP2, MRP4, and MRP5; and P‐glycoprotein (Pgp) significantly reduced dimesna accumulation. Further investigation demonstrated that renal apical efflux transporters MATE1, MRP2, and Pgp were also capable of mesna efflux. Administration of OAT inhibitor probenecid to healthy subjects significantly increased combined mesna and dimesna plasma exposure (91% ± 34%) while decreasing the renal clearance due to net secretion (67.0% ± 12.7%) and steady‐state volume of distribution (45.2% ± 13.4%). Thus, the kidney represents a significant sink of total mesna, whereas function of renal drug transporters facilitates clearance in excess of glomerular filtration rate and likely the presence of active mesna in the urine. Loss of renal transporter function due to genetic variability or drug—drug interactions may decrease the efficacy of chemoprotectants, increasing the risk of ifosfamide‐ and cisplatin‐induced toxicities.
Consideration of dynamic photothermal effect for evaluation of scanning light sources in optical devices using pulsed source criteria

Abstract. Quantitative evaluation of the potential radiation hazards of scanning light sources in medical optical devices is critical. Currently, point scanning light sources of continuous radiation are treated as pulsed sources, where the dwell time at each point is equal to the pulse duration. This study compares the photothermal effects from scanning light and pulsed sources using numerical calculation for scanning without restricting aperture and with various spot sizes. The calculation results show that the thermal damage threshold of scanning source not restricted by measurement aperture does not significantly differ from that of pulsed source. Temporal temperature response and size-dependent photothermal effect also confirm the similarity between scanning and pulsed sources.
Classification of Unarmed/Armed Personnel Using the NetRAD Multistatic Radar for Micro-Doppler and Singular Value Decomposition Features

In this letter, we present the use of experimental human micro-Doppler signature data gathered by a multistatic radar system to discriminate between unarmed and potentially armed personnel walking along different trajectories. Different ways of extracting suitable features from the spectrograms of the micro-Doppler signatures are discussed, particularly empirical features such as Doppler bandwidth, periodicity, and others, and features extracted from singular value decomposition (SVD) vectors. High classification accuracy of armed versus unarmed personnel (between 90% and 97% depending on the walking trajectory of the people) can be achieved with a single SVD-based feature, in comparison with using four empirical features. The impact on classification performance of different aspect angles and the benefit of combining multistatic information is also evaluated in this letter.
Identification of suitable fundus images using automated quality assessment methods

Abstract. Retinal image quality assessment (IQA) is a crucial process for automated retinal image analysis systems to obtain an accurate and successful diagnosis of retinal diseases. Consequently, the first step in a good retinal image analysis system is measuring the quality of the input image. We present an approach for finding medically suitable retinal images for retinal diagnosis. We used a three-class grading system that consists of good, bad, and outlier classes. We created a retinal image quality dataset with a total of 216 consecutive images called the Diabetic Retinopathy Image Database. We identified the suitable images within the good images for automatic retinal image analysis systems using a novel method. Subsequently, we evaluated our retinal image suitability approach using the Digital Retinal Images for Vessel Extraction and Standard Diabetic Retinopathy Database Calibration level 1 public datasets. The results were measured through the F1 metric, which is a harmonic mean of precision and recall metrics. The highest F1 scores of the IQA tests were 99.60%, 96.50%, and 85.00% for good, bad, and outlier classes, respectively. Additionally, the accuracy of our suitable image detection approach was 98.08%. Our approach can be integrated into any automatic retinal analysis system with sufficient performance scores.
Should Clinical Pharmacokinetic Bridging Studies Between Caucasian and Asian Populations Be Required for Approval of Monoclonal Antibodies?

1273 2012 52 1273-1276 P bridging studies are routinely requested by regulatory agencies of Asian countries to extrapolate clinical data obtained in Caucasian populations for the development of new therapeutic agents. Obviously, the purpose of these studies is to ensure that proper dose regimens are recommended for the appropriate patient populations of different ethnicities. For this purpose, the International Conference on Harmonization (ICH) E5 Guideline has been developed to provide a recommended framework for evaluating the impact of ethnic factors on the efficacy and safety of a therapeutic agent at a particular dose or dose regimen. ICH E5 acknowledges that although ethnic differences among populations may cause differences in the safety and/or efficacy of a medicine, many medicines have comparable characteristics and effects across ethnic populations. The latter concept is important to discuss with respect to the differences that exist in the characteristics of small molecules and therapeutic monoclonal antibodies (mAbs). As described in ICH E5, ethnic factors can be classified as either intrinsic or extrinsic. Whereas extrinsic ethnic factors include environmental and cultural factors, intrinsic ethnic factors define and identify a subpopulation and influence the ability to extrapolate clinical data between ethnic groups (eg, genetic polymorphism). Because of many of these intrinsic ethnic factors, the development of many small molecules as therapeutic agents often includes pharmacokinetic studies as a bridging strategy across populations. However, therapeutic proteins, such as mAbs, are less likely to be sensitive to extrinsic or intrinsic ethnic factors and therefore may not require pharmacokinetic bridging studies. A major distinguishing factor between small molecules and mAbs is their specific elimination pathways. Small molecules are usually eliminated by noncatabolic pathways such as hepatic metabolism, renal excretion, and biliary excretion. The clearance of small molecules can be altered by hepatic cytochrome P450 (CYP450) enzymes that are predominantly involved in drug metabolism. The polymorphisms that exist for certain CYP450 isoenzymes (eg, CYP2C19, CYP2C9, CYP2D6) in Asians and Caucasians make these important intrinsic factors that can contribute to interethnic or interracial differences in the pharmacokinetics of small molecules. Systemic exposure of small molecules may also be affected by extrinsic factors such as food and dietary components and concomitant medications. In contrast, mAbs undergo both nonspecific and specific catabolic elimination pathways via intracellular catabolism followed by fluid-phase or receptor-mediated endocytosis. Additionally, because mAbs are administered intravenously or parenterally,
The Quadriceps Snip Facilitates Exposure in Revision Total Knee Arthroplasty

Good exposure of the knee is required in revision total knee arthroplasty to allow for component removal, management of bone defects, and implantation of the new prosthesis. Failure to gain adequate exposure can lead to complications including component malpositioning and extensor mechanism disruption that may compromise the long-term success of the operation. In the revision setting, where factors such as limited motion, intra-articular fibrosis, and patellar baja may make exposure of the knee difficult, the surgeon must be familiar with advanced techniques for optimizing exposure. The quadriceps snip is one of the previously described methods for facilitating exposure in these more challenging cases. In this article, the indications and technique for and results of quadriceps snip in total knee arthroplasty are reviewed.
Population Pharmacokinetics of Valproic Acid in Pediatric Patients With Epilepsy: Considerations for Dosing Spinal Muscular Atrophy Patients

Valproic acid (VPA) dosing strategies used in recent clinical trials in patients with spinal muscular atrophy (SMA) have utilized a paradigm of monitoring trough levels to estimate drug exposure with subsequent dose titration. The validity of this approach remains uncertain and could be improved by understanding sources of pharmacokinetic variability. A population pharmacokinetic analysis of VPA in pediatric patients with epilepsy was recently performed. The pooled data set included 52 subjects with epilepsy, ages 1 to 17 years, who received intravenous and/or various oral formulations. The data was best fit by a 2‐compartment model; inclusion of age and weight reduced intersubject variability for clearance (41%), central volume (70%), and peripheral volume (42%) over the base model. The final model for clearance and volume parameters was clearance = 0.854 · (weight/70)0,75; central volume of distribution = 10.3 · (weight/70)1,0 · (age/8.5)−0.267; peripheral volume of distribution = 4.08 · (weight/70)1,0; and intercompartmental clearance = 5.34 · (weight/70)0,75. Application of the model to data from a clinical trial in SMA patients suggests altered kinetics, perhaps based on underlying physiologic differences such as alterations in lean body mass. Future studies in SMA should incorporate modeling and simulation techniques to support individualized dosing and further assess if additional patient‐specific factors necessitate alternative dosing strategies.
Brivaracetam Disposition in Renal Impairment

Brivaracetam is a novel high‐affinity SV2A ligand currently in clinical development for epilepsy. The objective was to characterize its disposition in patients with renal impairment. A single oral dose of 200 mg brivaracetam was administered to 9 patients with severe renal impairment not requiring dialysis (creatinine clearance <15 mL/ min, n = 6; 15–29 mL/min, n = 3) and 9 matched healthy controls. Plasma and urinary concentrations of brivaracetam and 3 pharmacologically inactive metabolites (acid, hydroxy, and hydroxyacid) were determined up to 72 hours postdose, and noncompartmental pharmacokinetic parameters were derived. The Cmax of brivaracetam was unchanged relative to healthy controls, whereas AUC was slightly increased (mean ratio, 1.21; 90% confidence interval, 1.01–1.45). Nonrenal and renal clearances of brivaracetam decreased from 47 and 4.5 to 41 and 1.7 mL/min/1.73 m2. Exposure to the acid, hydroxy, and hydroxyacid metabolites was markedly increased: Cmax by 2.4‐, 2.0‐, and 11.7‐fold and AUC by 3.2‐, 4.1‐, and 21.5‐fold. Renal clearance of these rapidly cleared metabolites was decreased 10‐fold in patients with severe renal impairment. Nonclinical toxicology studies concluded to the absence of safety issues related to the increased levels of metabolites. These observations suggest that dose adjustment of brivaracetam should not be required at any stage of renal dysfunction.
SUSCEPTIBILITY OF ALLERGIC AND NONALLERGIC PERSONS TO RHUS TOXICODENDRON

In reviewing the literature of poison ivy dermatitis one observes contradictory trends of opinion on various phases of the subject. The nature of the process is in question. Is it merely a contact dermatitis or a manifestation of allergy ? Vaughan 1 expressed the thought that poison ivy dermatitis is probably not allergic. Coca and Grove, 2 using the Prausnitz-Kustner test, failed to demonstrate sensitizing bodies in the blood of persons sensitive to poison ivy. Rostenberg and Sulzberger 3 stated that the result of a patch test is much more liable to be positive in contact dermatitis than in the atopic variety. Spain and Cooke 4 concluded that sensitization is transmitted from the original focus to other parts of the skin and mucous membranes by the blood and lymph. Recently Straus and Coca, 5 after experimentation on rhesus monkeys decided that sensitization develops only in connected skin by continuity, and hence,
Investigation of influences of the paraformaldehyde fixation and paraffin embedding removal process on refractive indices and scattering properties of epithelial cells

Abstract. The scattering properties and refractive indices (RI) of tissue are important parameters in tissue optics. These parameters can be determined from quantitative phase images of thin slices of tissue blocks. However, the changes in RI and structure of cells due to fixation and paraffin embedding might result in inaccuracies in the estimation of the scattering properties of tissue. In this study, three-dimensional RI distributions of cells were measured using digital holographic microtomography to obtain total scattering cross sections (TSCS) of the cells based on the first-order Born approximation. We investigated the slight loss of dry mass and drastic shrinkage of cells due to paraformaldehyde fixation and paraffin embedding removal processes. We propose a method to compensate for the correlated changes in volume and RI of cells. The results demonstrate that the TSCS of live cells can be estimated using restored cells. The percentage deviation of the TSCS between restored cells and live cells was only −8%. Spatially resolved RI and scattering coefficients of unprocessed oral epithelium ranged from 1.35 to 1.39 and from 100 to 450 cm−1, respectively, estimated from paraffin-embedded oral epithelial tissue after restoration of RI and volume.
Input filter interactions in peak-current-mode-controlled buck converter operating in CICM

Peak-current-mode (PCM) control is a widely used method to control switched-mode converters. Most often an input filter is necessary to meet electromagnetic interference requirements. The input filter can cause instability and degradation of input and output dynamics if not properly designed. The input filter design from the output dynamics viewpoint has been addressed in numerous papers, resulting in well-agreed results in the case of direct duty-ratio control. The same methods and criteria have also been applied to PCM control, but the results have turned out to be conflicting. This paper shows that the adverse effect of the input filter on the output performance of a peak-current-controlled buck converter in continuous inductor-current mode is insignificant. The input performance is, however, significantly affected, necessitating the use of proper damping. It is also shown that the instability is caused solely by the instability of the input filter under negative incremental resistance. The methods used are unified in nature, but the results obtained in this study cannot be generalized to be valid for types of converters other than a buck converter.