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Objective: To investigate the protective effect of Zengye Decoction (增液汤, ZYD) on the submandibular glands (SMGs) in nonobese diabetic (NOD) mice.Methods: Twenty-seven female NOD mice were randomly equally divided into 3 groups: the model group, the hydroxychloroquine (HCQ) group, and the ZYD group. Nine C57/B6 mice served as the normal group. After 1-week acclimation, the HCQ and ZYD groups were intragastrically administered with HCQ and ZYD, respectively, and the normal and model groups were administered with normal saline. Changes in the salivary flow rate were observed. Mice from all 4 groups were sacrificed at the age of 20 weeks. The serum and SMGs were collected. Serum cytokines gamma-interferon (IFN-γ), interleukin-10 (IL-10) were detected by enzyme-linked immunosorbent assay. Histological changes in the submandibular glands were examined by hematoxylin and eosin staining. The mRNA expression of IFN-γ, IL-10 and vasoactive intestinal peptide (VIP) in the submandibular glands were measured by real-time polymerase chain reaction.Results: Compared with the model group, the salivary flow of the ZYD group significantly increased (P<0.05), the extent of the histological changes was ameliorated (P<0.05), and the Th1/Th2 cytokine imbalance was remedied (P<0.05). In the ZYD-treated mice, the VIP mRNA was up-regulated (P<0.05).Conclusions: ZYD is beneficial in protecting structure and function of SMGs in NOD mice. The mechanism may be associated with the correction of the Th1/Th2 cytokine imbalance, and with the prevention of a progressive decline of the VIP level. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate non-intravenously enhanced low-dose computed tomography with oral contrast (LDCT) for the assessment of pregnant women with right lower quadrant pain, when magnetic resonance imaging (MRI) is not immediately available.Methods: One hundred and thirty-eight consecutive pregnant women with acute abdominal pain were admitted in our emergency centre. Thirty-seven (27%) of them, with clinical suspicion of acute appendicitis, underwent abdominal ultrasonography (US). No further examination was recommended when US was positive for appendicitis, negative with low clinical suspicion or showed an alternative diagnosis which explained the clinical presentation. All other patients underwent LDCT (<2.5 mSv). Standard intravenously enhanced CT or MRI was performed when LDCT was indeterminate.Results: Eight (22%) of 37 US exams were reported normal, 25 (67%) indeterminate, 1 (3%) positive for appendicitis, 3 (8%) positive for an alternative diagnosis. LDCT was obtained in 29 (78%) patients. It was reported positive for appendicitis in 9 (31%), for alternative diagnosis in 2 (7%), normal in 13 (45%) and indeterminate in 5 (17%). Further imaging (standard CT or MRI) showed appendicitis in 2 of these 5 patients, was truly negative in 1, indeterminate in 1 and falsely positive in 1. An appendicitis was confirmed at surgery in 12 (32%) of the 37 patients. The sensitivity and the specificity of the algorithm for appendicitis were 100% (12/12) and 92% (23/25), respectively.Conclusions: The proposed algorithm is very sensitive and specific for detection of acute appendicitis in pregnant women; it reduces the need of standard CTs when MRI is not available as second-line imaging.Key Points: • In pregnant women, US is limited by an important number of indeterminate results • Low-dose CT can be used after an inconclusive US for the diagnosis of appendicitis in pregnant women • An algorithm integrating US and low-dose CT is highly sensitive and specific for appendicitis in pregnant women. [ABSTRACT FROM AUTHOR]

Physiologically based pharmacokinetic modeling and simulation is an important tool for predicting the pharmacokinetics, pharmacodynamics, and safety of drugs in pediatrics. Physiologically based pharmacokinetic modeling is applied in pediatric drug development for first-time-in-pediatric dose selection, simulation-based trial design, correlation with target organ toxicities, risk assessment by investigating possible drug-drug interactions, real-time assessment of pharmacokinetic-safety relationships, and assessment of non-systemic biodistribution targets. This review summarizes the details of a physiologically based pharmacokinetic modeling approach in pediatric drug research, emphasizing reports on pediatric physiologically based pharmacokinetic models of individual drugs. We also compare and contrast the strategies employed by various researchers in pediatric physiologically based pharmacokinetic modeling and provide a comprehensive overview of physiologically based pharmacokinetic modeling strategies and approaches in pediatrics. We discuss the impact of physiologically based pharmacokinetic models on regulatory reviews and product labels in the field of pediatric pharmacotherapy. Additionally, we examine in detail the current limitations and future directions of physiologically based pharmacokinetic modeling in pediatrics with regard to the ability to predict plasma concentrations and pharmacokinetic parameters. Despite the skepticism and concern in the pediatric community about the reliability of physiologically based pharmacokinetic models, there is substantial evidence that pediatric physiologically based pharmacokinetic models have been used successfully to predict differences in pharmacokinetics between adults and children for several drugs. It is obvious that the use of physiologically based pharmacokinetic modeling to support various stages of pediatric drug development is highly attractive and will rapidly increase, provided the robustness and reliability of these techniques are well established. [ABSTRACT FROM AUTHOR]

Introduction: This work describes the Medication and Adverse Drug Events from Electronic Health Records (MADE 1.0) corpus and provides an overview of the MADE 1.0 2018 challenge for extracting medication, indication, and adverse drug events (ADEs) from electronic health record (EHR) notes.Objective: The goal of MADE is to provide a set of common evaluation tasks to assess the state of the art for natural language processing (NLP) systems applied to EHRs supporting drug safety surveillance and pharmacovigilance. We also provide benchmarks on the MADE dataset using the system submissions received in the MADE 2018 challenge.Methods: The MADE 1.0 challenge has released an expert-annotated cohort of medication and ADE information comprising 1089 fully de-identified longitudinal EHR notes from 21 randomly selected patients with cancer at the University of Massachusetts Memorial Hospital. Using this cohort as a benchmark, the MADE 1.0 challenge designed three shared NLP tasks. The named entity recognition (NER) task identifies medications and their attributes (dosage, route, duration, and frequency), indications, ADEs, and severity. The relation identification (RI) task identifies relations between the named entities: medication-indication, medication-ADE, and attribute relations. The third shared task (NER-RI) evaluates NLP models that perform the NER and RI tasks jointly. In total, 11 teams from four countries participated in at least one of the three shared tasks, and 41 system submissions were received in total.Results: The best systems F1 scores for NER, RI, and NER-RI were 0.82, 0.86, and 0.61, respectively. Ensemble classifiers using the team submissions improved the performance further, with an F1 score of 0.85, 0.87, and 0.66 for the three tasks, respectively.Conclusion: MADE results show that recent progress in NLP has led to remarkable improvements in NER and RI tasks for the clinical domain. However, some room for improvement remains, particularly in the NER-RI task. [ABSTRACT FROM AUTHOR]

A side-by-side comparison of updated guidelines regarding contrast medium-induced acute kidney injury (CI-AKI) from the Swedish Society of Uroradiology (SSUR) and the European Society of Urogenital Radiology (ESUR) is presented. The major discrepancies include a higher glomerular filtration rate (GFR) threshold as a risk factor for CI-AKI and for discontinuation of metformin by SSUR, i.e., < 45 ml/min versus < 30 ml/min/1.73 m2 by ESUR, when intravenous or intra-arterial contrast media (CM) with second-pass renal exposure is administered. SSUR also continues to recommend consideration of traditional non-renal risk factors such as diabetes and congestive heart failure, while ESUR considers these factors as non-specific for CI-AKI and does not recommend any consideration. Contrary to ESUR, SSUR also recommends discontinuation of NSAID and nephrotoxic medication if possible. Insufficient evidence at the present time motivates the more cautionary attitude taken by SSUR. Furthermore, SSUR expresses GFR thresholds in absolute values in ml/min as recommended by the National Kidney Foundation for drugs excreted by glomerular filtration, while ESUR uses the relative GFR normalised to body surface area in ml/min/1.73 m2. CM dose/GFR ratio thresholds established for coronary angiography/interventions are also applied as recommendations for CM-enhanced CT by SSUR, since SSUR regards coronary procedures as a second-pass renal exposure of CM with no obvious difference in the incidence of AKI compared with IV CM administration. Finally, SSUR recommends reducing the gram-iodine dose/GFR ratio from < 1.0 in patients not at risk to < 0.5 in patients at risk of CI-AKI, while ESUR has no such recommendation. KEY POINTS: • The more cautionary attitude taken by SSUR compared with that of ESUR is motivated by insufficient evidence regarding risk for contrast medium-induced acute kidney injuries (CI-AKI). • SSUR recommends that absolute and not relative GFR should be used when dosing drugs eliminated by the kidneys such as contrast media. • According to SSUR the gram-iodine dose/GFR ratio should be < 0.5 in patients at risk of CI-AKI, while ESUR has no such recommendation. [ABSTRACT FROM AUTHOR]

Purpose: To explore the feasibility of using correlation-based time-delay (CTD) maps produced from time-resolved MR angiography (TRMRA) to diagnose perfusion abnormalities in patients suspected to have steno-occlusive lesions in the craniocervical arteries.Materials and Methods: Twenty-seven patients who were suspected to have steno-occlusive lesions in the craniocervical arteries underwent both TRMRA and brain single-photon emission computed tomography (SPECT). TRMRA was performed on the supra-aortic area after intravenous injection of a 0.03 mmol/kg gadolinium-based contrast agent. Time-to-peak (TTP) maps and CTD maps of the brain were automatically generated from TRMRA data, and their quality was assessed. Detection of perfusion abnormalities was compared between CTD maps and the time-series maximal intensity projection (MIP) images from TRMRA and TTP maps. Correlation coefficients between quantitative changes in SPECT and parametric maps for the abnormal perfusion areas were calculated.Results: The CTD maps were of significantly superior quality than TTP maps (p < 0.01). For perfusion abnormality detection, CTD maps (kappa 0.84, 95% confidence interval [CI] 0.67-1.00) showed better agreement with SPECT than TTP maps (0.66, 0.46-0.85). For perfusion deficit detection, CTD maps showed higher accuracy (85.2%, 95% CI 66.3-95.8) than MIP images (66.7%, 46-83.5), with marginal significance (p = 0.07). In abnormal perfusion areas, correlation coefficients between SPECT and CTD (r = 0.74, 95% CI 0.34-0.91) were higher than those between SPECT and TTP (r = 0.66, 0.20-0.88).Conclusion: CTD maps generated from TRMRA were of high quality and offered good diagnostic performance for detecting perfusion abnormalities associated with steno-occlusive arterial lesions in the craniocervical area.Key Points: • Generation of perfusion parametric maps from time-resolved MR angiography is clinically useful. • Correlation-based delay maps can be used to detect perfusion abnormalities associated with steno-occlusive craniocervical arteries. • Estimation of correlation-based delay is robust for low signal-to-noise 4D MR data. [ABSTRACT FROM AUTHOR]

Objective: To explore the use of two consecutive axial scans in triple-rule-out (TRO) examination on a 16 cm wide-detector CT for radiation dose reduction.Materials and Methods: Sixty TRO patients were assigned to either study group (Group A, n = 30) or control group (Group B, n = 30). Group A used a two-phasic contrast injection: 25mgI/kg/s for 12 s in 1st and at 3.0 ml/s injection rate for 7 s in 2nd phase. The pulmonary artery, coronary artery and aorta were scanned in succession with two axial scans using smart-coverage technique. Group B used the conventional protocol of scanning pulmonary arteries first in helical, followed by coronary arteries in axial and aorta in helical mode with contrast injection of 25mgI/kg/s for 14 s. All images were reconstructed with 80% ASIR-V. The qualitative and quantitative image assessment and effective dose of the two groups were statistically compared.Results: The demographic data and quantitative measurements and qualitative image scores between the two groups were statistically the same (p > 0.05). However, Group A reduced radiation dose by 52% (2.67 ± 0.98 mSv vs. 5.65 ± 1.37 mSv) (p < 0.001).Conclusion: Using two consecutive axial scans in triple-rule-out on a 16 cm wide-detector CT reduces radiation dose while maintaining image quality compared with the conventional TRO protocol.Key Points: • Triple-rule-out can be performed with two-axial scans on a wide-detector CT system. • TRO with two-axial scans maintain image quality compared with conventional protocol. • TRO with two-axial scans reduces 52% radiation dose over conventional protocol. [ABSTRACT FROM AUTHOR]

Background: Few studies, and with conflicting results, have evaluated the potential effects of iodinated contrast media on children's thyroid function.Objective: To investigate the effects of iodinated contrast medium on thyroid function in neonates, infants and young children with congenital heart disease undergoing cardiac computed tomography (CT).Materials and Methods: We retrospectively evaluated 10 neonates (group 1) and 23 infants and young children (group 2) without thyroid or renal disease for serum levels of thyroid-stimulating hormone, free triiodothyronine and free thyroxine before contrast-enhanced cardiac CT, 48 h after CT and at discharge from the hospital. Cardiac CT was performed with intravenous administration of 1.14±0.17 mL/kg of body weight of iopromide (containing 370 mg of iodine/mL).Results: Group 1 had a reduction of thyroid-stimulating hormone from baseline to 48 h post injection (P=0.002). Group 2 had a reduction of thyroid-stimulating hormone median levels from baseline to 48 h post injection and an increase from 48 h to discharge (P=0.0005 and P=0.0001, respectively).Conclusion: Intravenous iodinated contrast medium in children with congenital heart disease caused transient thyroid-stimulating hormone decrease 48 h after CT, with thyroid-stimulating hormone returning to normal range at discharge. [ABSTRACT FROM AUTHOR]

Background: Pediatric optic pathway gliomas are typically indolent but have a variable clinical course. Treatment is dictated by symptoms and changes on contrast-enhanced MRI examinations. Gadolinium retention in children has motivated parsimonious use of gadolinium-based contrast agents.Objectives: To determine surveillance MR factors that motivate changes in tumor-directed therapies and extrapolate cost-efficacy of a non-contrast follow-up protocol.Materials and Methods: Using an imaging database search we identified children with isolated optic pathway gliomas and ≥3 follow-up contrast-enhanced MRIs. We reviewed medical records and imaging for: (1) coincident changes on contrast-enhanced MRI and tumor-directed therapy, (2) demographics and duration of follow-up, (3) motivations for intervention, (4) assessment of gadolinium-based contrast agents' utility and (5) health care utilization data. We assessed cost impact in terms of relative value unit (RVU) burden.Results: We included 17 neurofibromatosis type 1 (NF1) and 21 non-NF1 patients who underwent a median 16.9 and 24.3 cumulative contrast-enhanced MR exams over 7.7 years and 8.1 years of follow-up, respectively. Eight children (one with NF1) had intervention based on contrast-enhanced MR findings alone. For these eight, increased tumor size was the only common feature, and it was apparent on non-contrast T2 sequences. For the median patient, a non-contrast follow-up protocol could result in 15.9 (NF1) and 23.3 (non-NF1) fewer gadolinium-based contrast agent administrations, and a 39% lower yearly RVU burden.Conclusion: Pediatric patients with isolated optic pathway gliomas undergo a large number of routine contrast-enhanced MR follow-up exams. Gadolinium might not be needed for these exams to inform management decisions. Secondary benefits of a non-contrast follow-up protocol include decreased cost and risk to the patient. [ABSTRACT FROM AUTHOR]

Purpose: To determine clinical predictors associated with corticosteroid administration and its association with ICU mortality in critically ill patients with severe influenza pneumonia.Methods: Secondary analysis of a prospective cohort study of critically ill patients with confirmed influenza pneumonia admitted to 148 ICUs in Spain between June 2009 and April 2014. Patients who received corticosteroid treatment for causes other than viral pneumonia (e.g., refractory septic shock and asthma or chronic obstructive pulmonary disease [COPD] exacerbation) were excluded. Patients with corticosteroid therapy were compared with those without corticosteroid therapy. We use a propensity score (PS) matching analysis to reduce confounding factors. The primary outcome was ICU mortality. Cox proportional hazards and competing risks analysis was performed to assess the impact of corticosteroids on ICU mortality.Results: A total of 1846 patients with primary influenza pneumonia were enrolled. Corticosteroids were administered in 604 (32.7%) patients, with methylprednisolone the most frequently used corticosteroid (578/604 [95.7%]). The median daily dose was equivalent to 80 mg of methylprednisolone (IQR 60-120) for a median duration of 7 days (IQR 5-10). Asthma, COPD, hematological disease, and the need for mechanical ventilation were independently associated with corticosteroid use. Crude ICU mortality was higher in patients who received corticosteroids (27.5%) than in patients who did not receive corticosteroids (18.8%, p < 0.001). After PS matching, corticosteroid use was associated with ICU mortality in the Cox (HR = 1.32 [95% CI 1.08-1.60], p < 0.006) and competing risks analysis (SHR = 1.37 [95% CI 1.12-1.68], p = 0.001).Conclusion: Administration of corticosteroids in patients with severe influenza pneumonia is associated with increased ICU mortality, and these agents should not be used as co-adjuvant therapy. [ABSTRACT FROM AUTHOR]

Daclatasvir is a first-in-class, highly selective, hepatitis C virus, non-structural protein 5a polymerase replication complex inhibitor with picomolar potency and broad genotypic coverage in vitro. Daclatasvir undergoes rapid absorption, with a time to reach maximum plasma concentration of 1-2 h and an elimination half-life of ~ 10 to 14 h observed in single-ascending dose studies. Steady state was achieved by day 4 in multiple-ascending dose studies. Daclatasvir can be administered without regard to food or pH modifiers. Daclatasvir exposure is similar between healthy subjects and subjects infected with hepatitis C virus. Intrinsic factors such as age, race, or sex do not impact daclatasvir exposure. No dose adjustment is necessary for patients with any degree of hepatic or renal impairment. Daclatasvir has low-to-moderate clearance with the predominant route of elimination via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion. Renal clearance is a minor route of elimination for daclatasvir. As a result, the dose of daclatasvir should be reduced from 60 to 30 mg once daily when co-administered with strong inhibitors of cytochrome P450 3A4. No dose adjustment is required when daclatasvir is co-administered with moderate inhibitors of cytochrome P450 3A4. The dose of daclatasvir should be increased from 60 to 90 mg once daily when co-administered with moderate inducers of cytochrome P450 3A4. Co-administration of daclatasvir with strong inducers of cytochrome P450 3A4 is contraindicated. Concurrent medications with inhibitory effects on P-glycoprotein without concurrent inhibition of cytochrome P450 3A4 are unlikely to cause marked changes in daclatasvir exposure, as the clearance of daclatasvir is through both cytochrome P450 3A4 and P-glycoprotein. The potential for daclatasvir to affect the pharmacokinetics of concomitantly administered drugs that are substrates of the cytochrome P450 enzyme system is low. In vitro, daclatasvir is a weak-to-moderate inhibitor of transporters including organic cation transporter 1, P-glycoprotein, organic transporting polypeptide 1B1, organic transporting polypeptide 1B3, and breast cancer resistance protein, although in clinical studies, daclatasvir has not altered the pharmacokinetics of concomitantly administered drugs that are substrates of these transporters to an appreciable degree, except for rosuvastatin. In summary, daclatasvir is a hepatitis C virus, non-structural protein 5a-selective inhibitor with a well-characterized pharmacokinetic profile that forms part of potent and well-tolerated all-oral treatment regimens for chronic hepatitis C virus infection. [ABSTRACT FROM AUTHOR]

Background and Aims: In this study, we evaluate the performance of allometric concepts to predict the implications of age and size on the pharmacokinetics of lamotrigine, and assess the dose rationale across different age groups from 0.2 to 91 years.Methods: An allometrically scaled pharmacokinetic model was developed using adolescent and adult data, taking into account the effect of comedications. Model parameters were then used to extrapolate lamotrigine pharmacokinetics to older adults (> 65 years), children (4-12 years) and infants and toddlers (0.2-2.0 years). In addition, simulations were performed to identify the implication of different doses and dosing regimens for each population, so as to ensure steady-state concentrations within a predefined reference range.Results: The pharmacokinetics of lamotrigine was best described using a one-compartment model with first-order absorption and elimination. Carbamazepine, phenytoin, and valproic acid changed systemic clearance (CL) by + 76.5, + 129, and - 47.4%, respectively. Allometric principles allowed accurate extrapolation of disposition parameters to older adults and children older than 4 years of age. A maturation function was required to describe changes in exposure in younger patients. Compared with adults, a child aged 1.7 years has a 31.5% higher CL, after correcting for body weight. Patients > 65 years of age showed a decrease in CL of approximately 15%.Conclusion: Population pharmacokinetic models are usually limited to a subgroup of patients, which may mask the identification of factors contributing to interindividual variability. The availability of an integrated model including the whole patient population provides insight into the role of age-related changes in the disposition of lamotrigine, and potential implications for maintenance dose optimisation in any future trials.Trial Registration: According to GlaxoSmithKline's Clinical Trial Register, data from the GlaxoSmithKline studies LAM100034 and LEP103944, corresponding to ClinicalTrials.gov identifiers NCT00113165 and NCT00264615, used in this work, have been used in previous publications (doi: https://doi.org/10.1212/01.wnl.0000277698.33743.8b , https://doi.org/10.1111/j.1528-1167.2007.01274.x ). [ABSTRACT FROM AUTHOR]

Background and Objectives: In-vitro data suggest that clearance of vilaprisan is mediated by cytochrome P450 3A4 (oxidation) and aldoketoreductases (reduction). To fully understand the elimination and biotransformation pathways of vilaprisan, a selective progesterone receptor modulator, and to quantify the impact of cytochrome P450 3A4 inhibition on the pharmacokinetics of vilaprisan, two clinical studies in healthy postmenopausal women were conducted.Methods: In study 1, pharmacokinetics, mass balance, and metabolite patterns were determined after single oral administration of 5 mg of [14C]-labeled vilaprisan in six subjects. In study 2, pharmacokinetics were determined after single oral administration of 4 mg of vilaprisan without and with concomitant administration of the strong cytochrome P450 3A4 inhibitor itraconazole (200 mg/day) in 14 subjects. In addition, a microtracer dose of vilaprisan was given intravenously to determine absolute bioavailability, clearance, and volume of distribution.Results: The dominant single compound in plasma was vilaprisan. No plasma metabolites exceeding 10% of total drug-related area under the concentration-time curve were detected. The absolute oral bioavailability of vilaprisan was ~ 60%. The mean clearance was ~ 7 L/h and the volume of distribution at steady state was ~ 360 L. Excretion occurred primarily via feces (73.5 ± 3.70% of dose; urine: 13.1 ± 1.71%; total recovery: 86.6 ± 2.81%), mostly in a metabolized form. Only small amounts of the parent drug were found in excreta. When vilaprisan was administered together with itraconazole, exposure to vilaprisan was increased 6.2-fold (90% confidence interval 5.4-7.2).Conclusions: Vilaprisan is predominantly metabolized in the liver to a complex variety of metabolites, which are mainly excreted with feces. The pivotal role of cytochrome P450 3A4 in the metabolism of vilaprisan was confirmed.Clinical Trial Registration: EudraCT numbers 2013-000707-16 (mass balance study) and 2014-004929-41 (drug-drug interaction/microtracer study); NCT02456129 (drug-drug interaction/microtracer study). [ABSTRACT FROM AUTHOR]

During the years, various techniques have been presented for optimal control of tumor growth for which its stochastic behavior has rarely been considered. This article uses the well-known Gompertz stochastic model, for describing tumor growth, and by receding horizon model predictive control (RH-MPC) scheme computes the drug dosage for minimizing the tumor-cell population. To do this, a predictive control problem is defined based on the difference between the probability density function of tumor-cell population and the desired probability density function. In the model, both the drug dosage limitation and the Fokker-Planck equation have been considered as constraints. By solving this problem, the drug dosage which is considered as an external input to tumor model, is computed. In this article, the Fokker-Planck equation is used (1) as a nonlinear observer of probability density function of tumor-cell population and (2) a mapping vehicle from stochastic to deterministic domain. The Fokker-Planck equation is written for the Gompertz stochastic model of tumor growth. The equation is then solved through the path integral method. In this way, the probability density function of tumor-cell population, which contains the entire stochastic characteristics of the tumor growth, is obtained for any instance of time. The simulation results have also been presented for the evaluation of the suggested approach. The results show that the tumor-cell population can be controlled within a number of time windows (15 time windows in our case study) if an appropriate desired PDF is selected. [ABSTRACT FROM AUTHOR]

Fat-free mass (FFM) represents the lean component of the body devoid of fat. It has been shown to be a useful predictor of drug dose requirements, particularly in obesity where the excess fat mass does not contribute to drug clearance. However, measuring FFM involves complex and/or expensive experimental methodologies that preclude their use in routine clinical practice. Thus, models to predict FFM from readily measurable variables, such as body weight and height, have been developed and are used in both population pharmacokinetic modelling and clinical practice. In this review, methods used to measure FFM are explained and compared in terms of their assumptions, precision, and limitations. These methods are broadly classified into six different principles: densitometry, hydrometry, bioimpedance, whole-body counting, dual energy X-ray absorptiometry, and medical imaging. They vary in their processes and key biological assumptions that are often not applicable in certain populations (e.g. children, elderly, and certain disease states). This review provides a summary of the various methods of FFM measurement and estimation, and links these methods to a scientific framework to help clinicians and researchers understand the usefulness and potential limitations of these methods. [ABSTRACT FROM AUTHOR]

We deal with the following scheduling problem: an infinite number of tasks must be scheduled for processing on a finite number of heterogeneous machines, such as all tasks are sent to execution with a minimum delay. The tasks have causal dependencies and are generated in the context of biomedical applications, and produce results relevant for the medical domain, such as diagnosis support or drug dose adjust measures. The proposed scheduling model had a starting point in two known bounded number of processors algorithms: Modified Critical Path and Highest Level First With Estimated Times. Several steps were added to the original implementation along with a merge stage in order to combine the results obtained for each of the previously scheduled tasks. Regarding the implementation, a simulator was used to analyze and design the scheduling algorithms. [ABSTRACT FROM AUTHOR]

Background: Benzodiazepine use is highly prevalent in elderly and late middle-aged populations and may be associated with an increased risk of dementia. Observational studies have suggested that benzodiazepine use may increase the risk of dementia, however there have been significant concerns regarding protopathic bias in these studies, precluding conclusive findings.Objective: The aim of our study was to investigate the risk of dementia associated with the use of benzodiazepines in elderly patients, after controlling for protopathic bias.Methods: We identified observational studies with more than 50 cases, adequate assessment of benzodiazepine exposure, and reliable dementia diagnosis ascertainment, from the MEDLINE, PubMed, EMBASE, CINAHL, LILACS and CENTRAL electronic databases through to 5 June 2018, with no language limits. The association of any current or former use of short- or long-acting benzodiazepines with incident dementia was analysed. A subgroup analysis was performed by the introduction of lag time to assess the effect of protopathic bias. We also performed analyses considering the effect of higher benzodiazepine cumulative doses and adjustment for psychiatric covariates. Study quality was investigated using the Newcastle-Ottawa Scale.Results: We identified 15 studies reported in 14 articles, involving 159,090 cases. Ever use of benzodiazepines was associated with a significantly increased risk of dementia [odds ratio (OR) 1.39, 95% confidence interval (CI) 1.21-1.59]. Those studies that implemented the longest lag times of ≥ 5 years, and hence most likely to overcome protopathic bias, found a risk estimate that was marginally attenuated, but still significant (OR 1.30, 95% CI 1.14-1.48). Long-acting benzodiazepines were associated with a marginally higher magnitude risk (OR 1.21, 95% CI 0.99-1.49) than short-acting benzodiazepines (OR 1.13, 95% CI 1.02-1.26), although the former failed to reach statistical significance (p = 0.059).Conclusions: Our findings indicate that the association between benzodiazepine use and dementia incidence is not purely an artefact due to protopathic bias. Reduction of inappropriate benzodiazepine prescription is likely to attenuate dementia risk. [ABSTRACT FROM AUTHOR]

Objectives: Time-resolved contrast-enhanced MR angiography (4D-MRA), which allows the simultaneous visualization of the vasculature and blood-flow dynamics, is widely used in clinical routine. In this study, the impact of two different contrast agent injection methods on 4D-MRA was examined in a controlled, standardized setting in an animal model.Methods: Six anesthetized Goettingen minipigs underwent two identical 4D-MRA examinations at 1.5 T in a single session. The contrast agent (0.1 mmol/kg body weight gadobutrol, followed by 20 ml saline) was injected using either manual injection or an automated injection system. A quantitative comparison of vascular signal enhancement and quantitative renal perfusion analyses were performed.Results: Analysis of signal enhancement revealed higher peak enhancements and shorter time to peak intervals for the automated injection. Significantly different bolus shapes were found: automated injection resulted in a compact first-pass bolus shape clearly separated from the recirculation while manual injection resulted in a disrupted first-pass bolus with two peaks. In the quantitative perfusion analyses, statistically significant differences in plasma flow values were found between the injection methods.Conclusions: The results of both qualitative and quantitative 4D-MRA depend on the contrast agent injection method, with automated injection providing more defined bolus shapes and more standardized examination protocols.Key Points: • Automated and manual contrast agent injection result in different bolus shapes in 4D-MRA. • Manual injection results in an undefined and interrupted bolus with two peaks. • Automated injection provides more defined bolus shapes. • Automated injection can lead to more standardized examination protocols. [ABSTRACT FROM AUTHOR]

Background: Secondary hyperparathyroidism (SHPT) is a serious major complication in hemodialysis patients with chronic kidney disease. Long-term maintenance of serum phosphate, calcium, and parathyroid hormone (PTH) levels in appropriate ranges in these patients is a major challenge. We investigated the efficacy and safety of long-term treatment with etelcalcetide, a novel intravenous calcimimetic, in Japanese SHPT patients on long-term hemodialysis.Methods: This study was a multicenter open-label study. A total of 191 hemodialysis patients with serum intact PTH (iPTH) > 240 pg/mL were enrolled. Etelcalcetide was administered thrice weekly for 52 weeks, with an initial dose of 5 mg and flexibility to adjust the dose between 2.5 and 15 mg and to adjust the dosing of concomitant medications for SHPT. The efficacy endpoint was the proportion of patients with serum iPTH decreased to the target range (60-240 pg/mL).Results: Serum iPTH levels decreased immediately after etelcalcetide was started. At the end of the study, 87.5% (95% confidence interval 81.4-92.2; 140/160 patients) of patients achieved target serum iPTH levels, with control of serum calcium and phosphate levels. Adverse events, mostly mild to moderate, were reported by 96.8% of patients and led to study discontinuation in 7.4% of patients. Nausea, vomiting, and symptomatic hypocalcemia were found in 4.7, 9.5, and 1.1%, with 0.5, 1.1, and 1.1% considered treatment-related.Conclusions: Etelcalcetide effectively maintained serum iPTH, calcium, and phosphate levels in appropriate ranges with concomitant medications for SHPT for 52 weeks in Japanese hemodialysis patients, and was safe and well tolerated.Registration Number: JapicCTI-142665. [ABSTRACT FROM AUTHOR]

Background Incorrect dosing is the most frequent prescribing error in neonatology, with antibiotics being the most frequently prescribed medicines. Computer physician order entry and clinical decision support systems can create consistency contributing to a reduction of medication errors. Although evidence-based dosing recommendations should be included in such systems, the evidence is not always available and subsequently, dosing recommendations mentioned in guidelines and textbooks are often based on expert opinion. Objective To compare dosage recommendations for antibiotics in neonates with sepsis provided by eight commonly used and well-established international reference sources. Setting An expert team from our Dutch tertiary care neonatal intensive care unit selected eight well-established international reference sources. Method Daily doses of the seven most frequently used antibiotics in the treatment of neonatal sepsis, classified by categories for birth weight and gestational age, were identified from eight well-respected reference sources in neonatology/pediatric infectious diseases. Main outcome measure Standardized average daily dosage. Results A substantial variation in dosage recommendations of antibiotics for neonatal sepsis between the reference sources was shown. Dosage recommendations of ampicillin, ceftazidime, meropenem and vancomycin varied more than recommendations for benzylpenicillin, cefotaxime and gentamicin. One reference source showed a larger variation in dosage recommendations in comparison to the average recommended daily dosage, compared to the other reference sources. Conclusion Antibiotic dosage recommendations for neonates with sepsis can be derived from important reference sources and guidelines. Further exploration to overcome variation in dosage recommendations is necessary to obtain standardized dosage regimens. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the significance of subcentimetre (≤1 cm) arterially enhancing and hepatobiliary hypointense lesions (SAELs) observed on gadoxetic acid-enhanced magnetic resonance imaging (MRI) of patients at risk of hepatocellular carcinoma (HCC).Methods: A SAEL was defined as a subcentimetre hypervascular nodule exhibiting a hepatobiliary phase defect on gadoxetic acid-enhanced MRI. We included 52 SAELs from 46 patients in a HCC surveillance population. The HCC reference standard was pathologic confirmation or a nodule >1 cm with typical imaging features of HCC at follow-up imaging. The malignancy rate and HCC-favourable imaging findings of SAELs were evaluated.Results: The malignancy rate among SAELs was 57.7% (30/52). At diagnosis, all SAELs that progressed to overt HCC were treatable with curative intention. Venous or late dynamic phase washout was more frequently observed with malignant SAELs than with benign SAELs (57.7% vs. 30.6%; P = 0.01). If SAELs exhibiting washout were considered as HCC, sensitivity, specificity, and positive predictive value was 83.3%, 50%, and 69.4%, respectively.Conclusion: Among patients at risk of HCC, SAELs on gadoxetic acid-enhanced MRI exhibited high malignant potential. However, close observation may be an appropriate strategy for isolated SAELs. A washout appearance may be helpful for predicting malignancy.Key Points: • Gadoxetic acid-enhanced MRI provides hepatobiliary phase (HBP) images. • Screening frequently detects subcentimetre arterially enhancing and hepatobiliary hypointense lesions (SAELs). • A majority of SAELs progressed to overt HCC within 2 years. • A venous-phase washout appearance correlated significantly with malignancy in SAELs. [ABSTRACT FROM AUTHOR]

Background: Near-infrared fluorescence imaging has been recently applied in the field of hepatobiliary surgery. Our objective was to apply blue light fluorescence imaging to cholangiography and liver mapping during laparoscopic surgery. Therefore, we designed a preclinical study to evaluate the feasibility of using blue light fluorescence for cholangiography and liver mapping in a rat model.Methods: Sodium fluorescein solution (1 mL to each individual) were administered intravenously to 20 male Sprague-Dawley rats (6 weeks old, 200-250 g), after laparotomy. Whole abdominal organs were observed under blue light (at a wavelength of 440-490 nm) emitted from a commercialized LED curing light.Results: Immediately after the tracer solution was administered into the circulatory system of the rat, it was possible to visualize the location of the kidneys and the bile duct under blue light emitted from the light source. The liver was vaguely stained green by the tracer, while the ureters were not. After establishing biliary retention via duct clamping in the left lateral segment of the liver, the green color of the segment became distinct by the tracer, which showed vague coloration following release of the clamp.Conclusion: We established the preclinical basis for using blue light fluorescence cholangiography and liver mapping in this study. The clinical feasibility of these techniques during laparoscopic cholecystectomy and hepatectomy remained to be demonstrated. [ABSTRACT FROM AUTHOR]

Hydrochlorothiazide (Hctz) is an antihypertensive drug acting as diuretic. In order to prolong the drug activity, various formulations of Hctz were developed. This work was aimed at developing a sustained-release formulation using glyceryl behenate (Compritol 888 ATO, C888) as a waxy retardant matrix and Hctz as the model of slightly water-soluble drug. Two different ratios of Hctz/C888 (1:1 and 1:2) were tried to determine if increasing the C888 fraction will retard the release of Hctz. Melt granulation and direct compression have been tested on the two ratios in order to identify which one is most effective to modify the release of Hctz. The results showed that the 1:2 ratio (Hctz 25 mg versus C888 50 mg) successfully retarded the dissolution of Hctz. On the other hand, hot fusion method was found to be more effective than compression of physical mixtures in retarding the drug dissolution from the matrix. Thus, formulations based on the appropriate matrix of Compritol 888 ATO can be used to produce prolonged-release tablets for slightly water-soluble drugs like Hctz. [ABSTRACT FROM AUTHOR]

A mathematical model for combination therapy of glioma with oncolytic therapy and TNF-α inhibitors is analyzed as an optimal control problem. In the objective, a weighted average between the tumor volume and the total amount of viruses given is minimized. It is shown that optimal controls representing the virus administration are generically of the bang-bang type, i.e., the virus should be applied at maximal allowed dose with possible rest periods. On the other hand, optimal controls representing the dosage of TNF-α inhibitors follow a continuous regimen of concatenations between pieces that lie on the boundary and in the interior of the control set. [ABSTRACT FROM AUTHOR]

The article discusses a research paper on the comparison between two doses of teriflunomide with placebo in patients with clinically isolated syndrome (CIS). It references the study "Oral Teriflunomide for Patients With a First Clinical Episode Suggestive of Multiple Sclerosis (TOPIC): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial," by A. E. Miller et al., published in a 2014 issue of "The Lancet Neurology." It mentions multiple sclerosis therapies that are effective for CIS.

Background: Clinical role of low-dose aspirin (LDA) in pathogenesis of gastroesophageal reflux disease is by far controversial. This can be attributed to the paucity of basic research detailing the mechanism of LDA-induced esophageal mucosal injury (EI) on underlying chronic acid reflux esophagitis (RE).Aim: The aim of this study was to clarify the effect of LDA on chronic RE in rats.Methods: Esophagitis was induced in 8-week-old male Wistar rats by ligating the border between forestomach and glandular portion with a 2-0 silk tie and covering the duodenum with a small piece of 18-Fr Nélaton catheter. Seventy-eight chronic RE rat models were divided into five treatment groups, consisting of orally administered vehicle (controls), and aspirin doses of 2, 5, 50 or 100 mg/kg once daily for 28 days. EI was assessed by gross area of macroscopic mucosal injury, severity grade of esophagitis and microscopic depth of infiltration by inflammatory cells.Results: Area of esophagitis in animals with aspirin dose of 100 mg/kg/day showed a 36.5% increase compared with controls, although it failed to achieve statistical significance (p = 0.812). Additionally, the rate of severe EI was increased in animals with aspirin dose of 100 mg/kg/day as compared with controls (p < 0.05). The grade of severity correlated with the depth of inflammation (r s = 0.492, p < 0.001).Conclusions: Maximal dose aspirin (100 mg/kg/day) contributed in exacerbating preexisting EI. LDA (2 and 5 mg/kg/day), on the other hand, did not affect chronic RE in this model. LDA seems to be safe for use in patients with chronic RE. [ABSTRACT FROM AUTHOR]

Introduction: In hypo-albuminemia, the extent of albumin binding of a drug decreases. The resulting change in plasma protein binding only rarely leads to clinically relevant changes in unbound drug exposure. Nevertheless, in the critically ill, a tendency to increase dosing of anti-infective therapy is seen in patients experiencing hypo-albuminemia. To reconcile basic pharmacological principles with current clinical practice, this work presents a pharmacologically-based pharmacokinetic simulation study to emphasize the (lack of) effect of altered plasma protein binding on a drug's concentration-time profile and associated pharmacokinetic parameters.Methods: Four virtual compounds, representing a broad chemical space (low/high clearance/volume of distribution), were created and administered to a virtual population of normal patients and three types of hypo-albuminemic patients in Simcyp®. The influence of decreased plasma protein binding in hypoalbuminemia on the pharmacokinetic parameters and profiles of these four compounds was investigated.Results: Simulation results showed that while high-clearance compounds suffer from increased unbound exposure with decreased plasma protein binding, the unbound exposure of low-clearance compounds was unaffected. However, for the subset of low-clearance compounds with a small volume of distribution, it appeared that there were still alterations in their plasma concentration-time profiles. Since this may lead to different times above a minimum inhibitory concentration value, this might affect the bacterial killing for some anti-infective drugs. Overall, for any compound involved in the simulations, the unbound exposure did not decrease in plasma protein binding subjects relative to normal plasma protein binding subjects.Discussion: This finding is in line with the few case-controlled studies in the literature. Hence, increasing the dose/dosing frequency seems futile and might reduce the benefit-risk ratio for narrow therapeutic index drugs. Moreover, these simulations indicate that when only total plasma concentrations and derived pharmacokinetic parameters are considered, incorrect conclusions will be drawn. [ABSTRACT FROM AUTHOR]

Paclitaxel is an anticancer agent efficacious in the treatment of ovarian, breast, and lung cancer. Due to a strong link between the pharmacokinetics and therapeutic efficacy of paclitaxel, we reviewed the literature on paclitaxel pharmacokinetics. Systematic data mining was performed to extract the maximum concentration (C max), clearance (CL), and time of paclitaxel plasma concentration above 0.05 µmol/L (T > 0.05 µmol/L) following monotherapy of both the widely used cremophor-diluted paclitaxel and nanoparticle albumin-bound (nab-)paclitaxel. We identified a total of 53 studies yielding 121 aggregated pharmacokinetic profiles for paclitaxel monotherapy and extracted reported mean and median estimates of pharmacokinetic parameters. Paclitaxel has been studied formally at doses of 15-825 mg/m2 and infused over 0.5-96 h; included studies examined both weekly and every 3-weeks dosing cycles. The most widely used dose of cremophor-diluted paclitaxel, 175 mg/m2 given as a 3-h infusion, leads to an interstudy median C max of 5.1 µmol/L [interquartile range (IQR) 4.5-5.7], CL of 12.0 L/h/m2 (IQR 10.9-12.9), and T > 0.05 µmol/L of 23.8 h (IQR 21.5-26.8). Importantly, the significant interindividual variation widely reported in the literature is not reflected in these interstudy estimates of pharmacokinetic parameters. Cremophor-diluted paclitaxel pharmacokinetics are non-linear following short (<6 h) but not long (>24 h) infusions. A similar pattern of non-linearity was observed for nab-paclitaxel, although the number of studies was limited. The pharmacokinetics of paclitaxel monotherapy have been widely studied at numerous dose levels of the Cremophor EL® formulation, but are less well-characterized for the newer nab-paclitaxel formulation. In conclusion, paclitaxel pharmacokinetics are non-linear for short infusion times but not for longer infusions. Whether a similar conclusion can be drawn for nab-paclitaxel formulations requires further study. [ABSTRACT FROM AUTHOR]

Purpose: Bilastine is an H antagonist whose pharmacokinetics (PK) and pharmacodynamics (PD) have been resolved in adults with a therapeutic oral dose of 20 mg/day. Bilastine has favorable characteristics for use in pediatrics but the PK/PD and the optimal dose in children had yet to be clinically explored. The purpose is to: (1) Develop an ontogenic predictive model of bilastine PK linked to the PD in adults by integrating current knowledge; (2) Use the model to design a PK study in children; (3) Confirm the selected dose and the study design through the evaluation of model predictability in the first recruited children; (4) Consider for inclusion the group of younger children (< 6 years). Methods: A semi-mechanistic approach was applied to predict bilastine PK in children assuming the same PD as described in adults. The model was used to simulate the time evolution of plasma levels and wheal and flare effects after several doses and design an adaptive PK trial in children that was then confirmed using data from the first recruits by comparing observations with model predictions. Results: PK/PD simulations supported the selection of 10 mg/day in 2 to <12 year olds. Results from the first interim analysis confirmed the model predictions and design hence trial continuation. Conclusion: The model successfully predicted bilastine PK in pediatrics and optimally assisted the selection of the dose and sampling scheme for the trial in children. The selected dose was considered suitable for younger children and the forthcoming safety study in children aged 2 to <12 years. [ABSTRACT FROM AUTHOR]

Purpose: Many future drug products will be based on innovative manufacturing solutions, which will increase the need for a thorough understanding of the interplay between drug material properties and processability. In this study, hot melt extrusion of a drug-drug mixture with minimal amount of polymeric excipient was investigated. Methods: Using indomethacin-cimetidine as a model drug-drug system, processability of physical mixtures with and without 5% ( w/w) of polyethylene oxide (PEO) were studied using Differential Scanning Calorimetry (DSC) and Small Amplitude Oscillatory Shear (SAOS) rheometry. Extrudates containing a co-amorphous glass solution were produced and the solid-state composition of these was studied with DSC. Results: Rheological analysis indicated that the studied systems display viscosities higher than expected for small molecule melts and addition of PEO decreased the viscosity of the melt. Extrudates of indomethacin-cimetidine alone displayed amorphous-amorphous phase separation after 4 weeks of storage, whereas no phase separation was observed during the 16 week storage of the indomethacin-cimetidine extrudates containing 5% ( w/w) PEO. Conclusions: Melt extrusion of co-amorphous extrudates with low amounts of polymer was found to be a feasible manufacturing technique. Addition of 5% ( w/w) polymer reduced melt viscosity and prevented phase separation. [ABSTRACT FROM AUTHOR]

Purpose: Non-adherence to the antiretroviral (ARV) regimen is a critical factor in determining efficacy of ARV drugs for pre-exposure prophylaxis (PrEP). A long-acting parenteral formulation may be an effective alternative to daily oral dosing. A pharmacokinetic and tissue distribution study of drug-loaded nanoparticle (NP) was performed in female humanized CD34-NSG mice. Methods: Mice received 200 mg/kg each of tenofovir alafenamide (TAF) and elvitegravir (EVG) as free drugs (TAF + EVG solution) or as drug loaded NP (TAF + EVG NP) formulation by subcutaneous (SubQ) administration. Plasma and tissue were collected to determine tenofovir (TFV) and EVG concentrations using LC-MS/MS. Non-compartmental analysis was performed using WinNonlin. Results: SubQ administration of TAF + EVG NP formulation resulted in long residence time and exposure for both drugs. The AUC of TFV and EVG was 14.1 ± 2.0, 7.2 ± 1.8 μg × hr./mL from drugs in solution (free) and the AUC for the same drugs was 23.1 ± 4.4, 39.7 ± 6.7 μg × hr./mL from NPs. The observed elimination half-life (t) for TFV of free and NPs were 14.2 h, 5.1 days and for EVG 10.8 h, 3.3 days, respectively. Conclusion: This study documents that a TAF + EVG NP provides sustained release, which can overcome patient non-adherence to dosing and may facilitate prediction of appropriate protective drug concentration for HIV prophylaxis. [ABSTRACT FROM AUTHOR]

Purpose: A series of novel polycyclic aromatic compounds that augment the rate of glucose uptake in L6 myotubes and increase glucose-stimulated insulin secretion from beta-cells were synthesized. Designing these molecules, we have aimed at the two main pathogenic mechanisms of T2D, deficient insulin secretion and diminished glucose clearance. The ultimate purpose of this work was to create a novel antidiabetic drug candidate with bi-functional mode of action. Methods: All presented compounds were synthesized, and characterized in house. INS-1E cells and L6 myoblasts were used for the experiments. The rate of glucose uptake, mechanism of action, level of insulin secretion and the druggability of the lead compound were studied. Results: The lead compound (6-(1,3-dithiepan-2-yl)-2-phenylchromane), dose- and time-dependently at the low μM range increased the rate of glucose uptake in L6 myotubes and insulin secretion in INS-1E cells. The compound exerted its effects through the activation of the LKB1 (Liver Kinase B1)-AMPK pathway. In vitro metabolic parameters of this lead compound exhibited good druggability. Conclusions: We anticipate that bi-functionality (increased rate of glucose uptake and augmented insulin secretion) will allow the lead compound to be a starting point for the development of a novel class of antidiabetic drugs. [ABSTRACT FROM AUTHOR]

Background: Since pregnant women are considerably underrepresented in clinical trials, information on optimal dosing in pregnancy is widely lacking. Physiologically based pharmacokinetic (PBPK) modeling may provide a method for predicting pharmacokinetic changes in pregnancy to guide subsequent in vivo pharmacokinetic trials in pregnant women, minimizing associated risks.Objectives: The goal of this study was to build and verify a population PBPK model that predicts the maternal pharmacokinetics of three predominantly renally cleared drugs (namely cefazolin, cefuroxime, and cefradine) at different stages of pregnancy. It was further evaluated whether the fraction unbound (f u) could be estimated in pregnant women using a proposed scaling approach.Methods: Based on a recent literature review on anatomical and physiological changes during pregnancy, a pregnancy population PBPK model was built using the software PK-Sim®/MoBi®. This model comprised 27 compartments, including nine pregnancy-specific compartments. The PBPK model was verified by comparing the predicted maternal pharmacokinetics of cefazolin, cefuroxime, and cefradine with observed in vivo data taken from the literature. The proposed scaling approach for estimating the f u in pregnancy was evaluated by comparing the predicted f u with experimentally observed f u values of 32 drugs taken from the literature.Results: The pregnancy population PBPK model successfully predicted the pharmacokinetics of cefazolin, cefuroxime, and cefradine at all tested stages of pregnancy. All predicted plasma concentrations fell within a 2-fold error range and 85% of the predicted concentrations within a 1.25-fold error range. The f u in pregnancy could be adequately predicted using the proposed scaling approach, although a slight underestimation was evident in case of drugs bound to α1-acidic glycoprotein.Conclusion: Pregnancy population PBPK models can provide a valuable tool to predict a priori the pharmacokinetics of predominantly renally cleared drugs in pregnant women. These models can ultimately support informed decision making regarding optimal dosing regimens in this vulnerable special population. [ABSTRACT FROM AUTHOR]

Purpose: Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects.Methods: Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted.Results: No clinically relevant safety observations were noted in Part 1. During Part 2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680 mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10 ms at all timepoints and at supratherapeutic C max. Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful.Conclusions: Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval. CLINICALTRIALS.GOV: NCT02271438. [ABSTRACT FROM AUTHOR]

Objectives: To compare dynamic-contrast-enhanced MRI (DCE) and diffusion-weighted imaging (DWI) in quantifying synovial inflammation in juvenile idiopathic arthritis (JIA).Methods: Regions of interest (ROI) were drawn in the synovium of JIA patients on T1 DCE and T2 DWI, followed by extraction of the maximum enhancement (ME), maximum initial slope (MIS), time to peak (TTP), % of different time intensity curve shapes (TIC) and apparent diffusion coefficient (ADC) of the ROIs. Mann-Whitney-U test was used for comparing parameters between MRI-active and -inactive patients (defined by the juvenile arthritis MRI scoring system). Spearman's rank was used to analyse the correlation between DCE and DWI.Results: Thirty-five JIA patients (18 MRI active and 17 MRI inactive) were included. Median age was 13.1 years and 71% were female. ME, MIS, TTP, % TIC 5 and ADC were significantly different in MRI-active versus MRI-inactive JIA with median ADC 1.49 × 10-3mm2/s in MRI-active and 1.25 × 10-3mm2/s in MRI-inactive JIA, p = 0.001, 95% confidence interval of difference in medians =0.11-0.53 × 10-3mm2/s. ADC correlated to ME, MIS and TIC 5 shapes (r = 0.62, r = 0.45, r = -0.51, respectively, all p < 0.05).Conclusions: Similar to DCE parameters, DWI-derived ADC is significantly different in MRI-active JIA as compared to MRI-inactive JIA. The non-invasiveness of DWI combined with its possibility to detect synovial inflammation shows the potential of DWI.Key Points: • MRI can quantify: dynamic contrast-enhanced and diffusion-weighted MRI can quantify synovitis • Both DWI and DCE can differentiate active from inactive JIA • The DWI-derived apparent diffusion coefficient (ADC) is higher in active JIA • DWI is non-invasive and thus safer and more patient-friendly • DWI is a potentially powerful and non-invasive imaging biomarker for JIA. [ABSTRACT FROM AUTHOR]

Lymphatic filariasis (LF) affects 73 countries, causes morbidity and impedes socioeconomic development. We had found no difference in safety and micro (Mf) and macro filarial action of single-dose diethylcarbamazine (DEC) and DEC + albendazole (ABZ) in an F01 study done in India (year 2000). There was a programmatic need to evaluate safety and efficacy of multiple annual treatments (F02). Subjects (155) from the F01 study, meeting inclusion-exclusion criteria, were enrolled in F02 and treated with further two annual doses of DEC or DEC + ABZ. Efficacy was evaluated for Mf positivity by peripheral smear (PS) and nucleopore (NP) filter, circulating filarial antigen (CFA) and filarial dance sign (FDS) positivity and Mf count at yearly follow-up. Safety was assessed for 5 days after drug administration. Total of 139 subjects evaluated for efficacy (69 DEC and 70 DEC + ABZ group). Mf positivity prevalence declined progressively by 95% (PS), 66% (NP), and 95% (PS) and 86% (NP); CFA positivity prevalence declined by 15% and 9%; FDS by 100% each; Mf count declined by 75.5 and 76.9% with three annual treatment of DEC and DEC + ABZ, respectively. Addition of ABZ did not show any advantage over DEC given as three annual rounds for LF. DEC and DEC + ABZ were well tolerated. There was no correlation between result of CFA and FDS, (both claimed to be indicative of adult worm). Analysis of published studies and our data indicate that macrofilaricidal effect of DEC/DEC + ABZ may be seen in children and not adults, with three or more annual dosing. [ABSTRACT FROM AUTHOR]

Background and Objectives: To compare effectiveness and safety of dinoprostone, misoprostol and Cook's balloon as labour-inducing agents in women with intrauterine growth restriction (IUGR) at term.Methods: Retrospective cohort chart review of women diagnosed with foetal growth restriction at term in Reina Sofia Hospital, Cordoba, Spain from January 2014 to December 2015. Registration of baseline characteristics and method of induction was made. The main outcome was time from induction to delivery. Obstetric and perinatal outcomes were also collected.Results: A total of 99 women were diagnosed with IUGR in the mentioned period. Of them, 21 women were induced with dinoprostone [dinoprostone group (DG)], 20 with misoprostol (MG) and in 58 with Cook's balloon (CG). Groups were homogeneous regarding pre-induction Bishop score and parity. The CG required more time (24.36 vs. 19.23 h; p = 0.02) and more oxytocin dose for conduction of labour from induction to delivery (6.75 vs. 1.24 mUI; p < 0.01) than DG. Moreover, the CG also needed more oxytocin than MG, 6.75 vs. 2.37 mUI (p < 0.001). Caesarean rate was 5, 14.9 and 17.3% in MG, DG and CG, respectively. No differences were observed in rates of uterine tachysystole, non-reassuring foetal status and neonatal adverse events.Interpretation and Conclusions: Prostaglandins were more effective than Cook's balloon to induce labour and achieve vaginal birth in this sample of women with IUGR at term, with a similar safety profile. [ABSTRACT FROM AUTHOR]

Objectives: A national retrospective survey on patient doses was performed by the French Society of Medical physicists to assess reference levels (RLs) in interventional radiology as required by the European Directive 2013/59/Euratom.Methods: Fifteen interventional procedures in neuroradiology, vascular radiology and osteoarticular procedures were analysed. Kerma area product (KAP), fluoroscopy time (FT), reference air kerma and number of images were recorded for 10 to 30 patients per procedure. RLs were calculated as the 3rd quartiles of the distributions.Results: Results on 4600 procedures from 36 departments confirmed the large variability in patient dose for the same procedure. RLs were proposed for the four dosimetric estimators and the 15 procedures. RLs in terms of KAP and FT were 90 Gm.cm2 and 11 mins for cerebral angiography, 35 Gy.cm2 and 16 mins for biliary drainage, 75 Gy.cm2 and 6 mins for lower limbs arteriography and 70 Gy.cm2 and 11 mins for vertebroplasty. For these four procedures, RLs were defined according to the complexity of the procedure. For all the procedures, the results were lower than most of those already published.Conclusions: This study reports RLs in interventional radiology based on a national survey. Continual evolution of practices and technologies requires regular updates of RLs.Key Points: • Delivered dose in interventional radiology depends on procedure, practice and patient. • National RLs are proposed for 15 interventional procedures. • Reference levels (RLs) are useful to benchmark practices and optimize protocols. • RLs are proposed for kerma area product, air kerma, fluoroscopy time and number of images. • RLs should be adapted to the procedure complexity and updated regularly. [ABSTRACT FROM AUTHOR]

Background: Both air and radiopaque liquid contrast are used to reduce ileocolic intussusception under fluoroscopy. Some suggest air lowers radiation dose due to shorter procedure times. However, air enema likely lowers radiation dose regardless of fluoroscopy time due to less density over the automatic exposure control cells.Objectives: We test the hypothesis that air enema reduction of ileocolic intussusception results in lower radiation dose than liquid contrast enema independent of fluoroscopy time. We describe a role for automatic exposure control in this dose difference.Materials and Methods: We retrospectively evaluated air and liquid intussusception reductions performed on a single digital fluoroscopic unit during a 26-month period. We compared patient age, weight, gender, exam time of day and year, performing radiologist(s), radiographic image acquisitions, grid and magnification use, fluoroscopy time and dose area product. We compared categorical and continuous variables statistically using chi-square and Mann-Whitney U tests, respectively.Results: The mean dose area product was 2.7-fold lower for air enema, 1.3 ± 0.9 dGy·cm2, than for liquid, 3.5 ± 2.5 dGy·cm2 (P<0.005). The mean fluoroscopy time was similar between techniques. The mean dose area product/min was 2.3-fold lower for air, 0.6 ± 0.2 dGy·cm2/min, than for liquid, 1.4 ± 0.5 dGy·cm2/min (P<0.001). No group differences were identified in other measured dose parameters.Conclusion: Fluoroscopic intussusception reduction using air enema uses less than half the radiation dose of liquid contrast enema. Dose savings are independent of fluoroscopy time and are likely due to automatic exposure control interaction. [ABSTRACT FROM AUTHOR]

Epidemic increases in opioid use in the USA and globally highlight the need for effective adjunctive therapies to opioid-based analgesia. Given the shortcomings of behavioral adjuncts to opioid-based pain treatment, an urgent need exists for pain-related behavioral interventions that resonate with broad patient populations, can be delivered confidentially in any environment, and can incorporate new content automatically. Understanding the potential for automated behavioral therapies like music therapy in modulating the experience of pain may unlock methods to transition patients to lower doses of pharmacologic therapy or provide alternatives to opioids during acute exacerbations of pain. This manuscript describes the neurologic mechanism of action, theoretical basis, and potential applications of personalized music as a smartphone-based mHealth intervention for acute and chronic pain management. [ABSTRACT FROM AUTHOR]

The integration of phase-contrast magnetic resonance images (PC-MRI) and computational fluid dynamics (CFD) is a way to obtain detailed information of patient-specific hemodynamics. This study proposes a novel strategy for imposing a pressure condition on the outlet boundary (called the outlet pressure) in CFD to minimize velocity differences between the PC-MRI measurement and the CFD simulation, and to investigate the effects of outlet pressure on the numerical solution. The investigation involved ten patient-specific aneurysms reconstructed from a digital subtraction angiography image, specifically on aneurysms located at the bifurcation region. To evaluate the effects of imposing the outlet pressure, three different approaches were used, namely: a pressure-fixed (P-fixed) approach; a flow rate control (Q-control) approach; and a velocity-field-optimized (V-optimized) approach. Numerical investigations show that the highest reduction in velocity difference always occurs in the V-optimized approach, where the mean of velocity difference (normalized by inlet velocity) is 19.3%. Additionally, the highest velocity differences appear near to the wall and vessel bifurcation for 60% of the patients, resulting in differences in wall shear stress. These findings provide a new methodology for PC-MRI integrated CFD simulation and are useful for understanding the evaluation of velocity difference between the PC-MRI and CFD. [ABSTRACT FROM AUTHOR]

Purpose: To demonstrate the relative importance of organic anion-transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) in the hepatic elimination of substrate drugs. Methods: A cocktail of subtherapeutic doses of bosentan, repaglinide, clarithromycin, darunavir, simeprevir, and midazolam (CYP3A probe) was administered orally to eight healthy volunteers. Rifampicin (OATP inhibitor; 600 mg, p.o.) and itraconazole (CYP3A inhibitor; 200 mg, i.v.) were coadministered with the cocktail in the second and third phases, respectively. Based on the extended clearance concept, in vivo β values (fraction of metabolism plus biliary excretion among all the intracellular fates of drugs including basolateral efflux) and R values (ratio of diffusional uptake to active uptake) were estimated. Results: Rifampicin increased plasma AUCs of bosentan (×3.2), repaglinide (×1.9), clarithromycin (×1.9) and simeprevir (×7.2). Itraconazole increased those of clarithromycin (×2.3), simeprevir (×2.2) and midazolam (×3.7), which had relatively small β values. The plasma AUC of bosentan (with relatively large β and small R) was dominated by OATP-mediated uptake. The AUC of simeprevir was also dominated by OATP-mediated uptake because of its small R value. Conclusions: The DDI study clarified the rate-determining processes of OATP/CYP3A substrates. Our analyses provide valuable information for predicting complex drug-drug interactions involving multiple processes. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study is to improve the accuracy of dynamic contrast-enhanced ultrasound (DCE-US) for prostate cancer (PCa) localization by means of a multiparametric approach.Materials and Methods: Thirteen different parameters related to either perfusion or dispersion were extracted pixel-by-pixel from 45 DCE-US recordings in 19 patients referred for radical prostatectomy. Multiparametric maps were retrospectively produced using a Gaussian mixture model algorithm. These were subsequently evaluated on their pixel-wise performance in classifying 43 benign and 42 malignant histopathologically confirmed regions of interest, using a prostate-based leave-one-out procedure.Results: The combination of the spatiotemporal correlation (r), mean transit time (μ), curve skewness (κ), and peak time (PT) yielded an accuracy of 81% ± 11%, which was higher than the best performing single parameters: r (73%), μ (72%), and wash-in time (72%). The negative predictive value increased to 83% ± 16% from 70%, 69% and 67%, respectively. Pixel inclusion based on the confidence level boosted these measures to 90% with half of the pixels excluded, but without disregarding any prostate or region.Conclusions: Our results suggest multiparametric DCE-US analysis might be a useful diagnostic tool for PCa, possibly supporting future targeting of biopsies or therapy. Application in other types of cancer can also be foreseen.Key Points: • DCE-US can be used to extract both perfusion and dispersion-related parameters. • Multiparametric DCE-US performs better in detecting PCa than single-parametric DCE-US. • Multiparametric DCE-US might become a useful tool for PCa localization. [ABSTRACT FROM AUTHOR]

Purpose: Manganese porphyrins are redox-active drugs and superoxide dismutase mimics, which have been shown to chemosensitize lymphoma, a cancer which frequently occurs in dogs. This study aimed to identify critical information regarding the pharmacokinetics and toxicity of Mn(III) meso-tetrakis (N-n-butoxyetylpyridium-2-yl) porphyrin, (MnTnBuOE-2-PyP5+, MnBuOE) in dogs as a prelude to a clinical trial in canine lymphoma patients.Methods: A single-dose pharmacokinetic (PK) study in normal dogs was performed to determine the plasma half-life (t 1/2) of MnBuOE. A dose reduction study was performed to establish the maximum tolerated dose (MTD) of MnBuOE. The safety and PK of a multi-dosing protocol was assessed.Results: Peak plasma drug concentration occurred 30 min post-injection. The t 1/2 was defined as 7 h. MnBuOE induced an anaphylactic reaction and prolonged tachycardia. The MTD was defined as 0.25 mg/kg. The dogs were given MTD 3×/week for 2-3 weeks. The highest recorded tissue drug levels were in the lymph nodes (4-6 μM), followed by kidney and liver (2.5, 2.0 uM, respectively).Conclusions: We obtained critical information regarding the PK and toxicity of MnBuOE in dogs. The acute drug reaction and tachycardia post-injection have not been described in other species and may be specific to canines. The high tissue drug levels in lymph nodes have not been previously reported. MnBuOE accumulation in lymph nodes has important implications for the utility of adjuvant MnBuOE to treat lymphoma. With MnBuOE lymph node accumulation, reduction in the dose and/or administration frequency could be possible, leading to reduced toxicity. [ABSTRACT FROM AUTHOR]

The present study outlines the clinical impact and risk factors of oral mucositis in 79 patients with multiple myeloma following high-dose melphalan for autologous transplant. All patients underwent daily prophylactic low-level indium gallium aluminum phosphate diode laser therapy (660 nm, 15 mW, 3.75 J/cm2, 10 s per point) from the beginning of the conditioning regimen up to day +2. Oral mucositis assessments were made daily until hospital discharge. For analysis, oral mucositis was divided into two groups according to severity: group 1, patients with oral mucositis grade

Purpose: To develop the first photoactive biomaterial coating capable of controlled drug dosing via inclusion of synthesised drug-3,5-dimethoxybenzoin (DMB) conjugates in a poly(2-methyoxyethyl acrylate) (pMEA) scaffold. Methods: Flurbiprofen- and naproxen-DMB conjugates were prepared via esterification and characterised via NMR spectroscopy and mass spectrometry following chromatographic purification. Conjugate photolysis was investigated in acetonitrile solution and within the pMEA matrix following exposure to low-power 365 nm irradiation. Photo-liberation of drug from pMEA into phosphate buffered saline was monitored using UV-vis spectroscopy. Results: The synthetic procedures yielded the desired drug conjugates with full supporting characterisation. Drug regeneration through photolysis of the synthesised conjugates was successful in both acetonitrile solution and within the pMEA scaffold upon UV irradiation. Conjugates were retained within the pMEA scaffold with exclusive drug liberation following irradiation and increased drug dose with increasing exposure. Multi-dosing capacity was demonstrated though the ability of successive irradiation periods to generate further bursts of drug. Conclusion: This study demonstrates the first application of photochemically controlled drug release from a biomaterial coating and the feasibility of using pMEA as a scaffold for housing the photoactive drug-DMB conjugates. [ABSTRACT FROM AUTHOR]

Purpose: As a tocolytic agent, ritodrine has been used in European and Asian countries but has lost popularity due to safety concerns. This study aimed to investigate the relationship between adverse drug events caused by ritodrine and the CACNA1C polymorphisms in preterm labor patients. Methods: Data were collected from medical records including maternal age, gestational age, body mass index, dilation score, effacement score, modified Bishop score, maximum infusion rate, and adverse drug events. Five single-nucleotide polymorphisms of the CACNA1C gene (rs10774053, rs215994, rs215976, rs2239128, and rs2041135) were analyzed. Results: One hundred eighty-six patients were included, 33 of whom had adverse drug events. A allele carriers of rs10774053 showed about 0.293-fold lower adverse drug events than GG genotype carriers ( p = 0.012, absolute risk reduction = 16.5%) after adjusting for other confounding variables; the number needed to genotype for preventing one patient with GG genotype from suffering higher incidence of adverse drug events was calculated to be 14.6. Increase in maximum infusion rate of 1 mL/h was associated with a 1.03-fold (95% CI 1.01~1.06, p = 0.005) increased risk of adverse drug events. None of the patients with a CC genotype of rs215994 had adverse drug events, whereas 22.1% of the T allele carriers had adverse drug events. Conclusion: This study showed that CACNA1C gene polymorphisms could alter the probability of adverse drug event risk when ritodrine is used in preterm labor. [ABSTRACT FROM AUTHOR]

Quantitative myocardial and blood T1 have recently achieved clinical utility in numerous pathologies, as they provide non-invasive tissue characterization with the potential to replace invasive biopsy. Native T1 time (no contrast agent), changes with myocardial extracellular water (edema, focal or diffuse fibrosis), fat, iron, and amyloid protein content. After contrast, the extracellular volume fraction (ECV) estimates the size of the extracellular space and identifies interstitial disease. Spatially resolved quantification of these biomarkers (so-called T1 mapping and ECV mapping) are steadily becoming diagnostic and prognostically useful tests for several heart muscle diseases, influencing clinical decision-making with a pending second consensus statement due mid-2017. This review outlines the physics involved in estimating T1 times and summarizes the disease-specific clinical and research impacts of T1 and ECV to date. We conclude by highlighting some of the remaining challenges such as their community-wide delivery, quality control, and standardization for clinical practice. [ABSTRACT FROM AUTHOR]

Albiglutide is a long-acting, glucagon-like peptide-1 receptor agonist for subcutaneous administration with a recommended dose of 30-50 mg once weekly. The aim of this article is to outline the pharmacokinetic and pharmacodynamic properties of albiglutide including the clinical efficacy and safety data underlying the approval of albiglutide for the treatment of type 2 diabetes mellitus in both Europe and USA. Albiglutide is cleared from the circulation (by a mechanism partially dependent on renal function) with an elimination half-life of 5 days, allowing once-weekly administration. In the clinical trial program called HARMONY, albiglutide demonstrated placebo-corrected reductions in glycosylated hemoglobin of 0.8-1.0%. In addition, reductions in fasting plasma glucose in the range of 1.3-2.4 mmol/L compared with placebo were reported. Albiglutide caused weight reductions at a level comparable to placebo in the HARMONY trials, possibly related to limited central nervous system penetration of the large albiglutide molecule. Albiglutide demonstrated a generally favorable safety profile, although with a signal of an increased risk of pancreatitis. The well-known adverse events related to glucagon-like peptide-1 receptor activation such as nausea, diarrhea, and vomiting were less frequent with albiglutide compared with another glucagon-like peptide-1 receptor agonist, liraglutide, but slightly more frequent following treatment with albiglutide than with placebo or active comparators from other classes of anti-hyperglycemic drugs. The full risk-benefit profile for albiglutide used in treating type 2 diabetes will not be clear until reporting of the long-term cardiovascular outcome trial (HARMONY Outcome) with planned completion in 2019. [ABSTRACT FROM AUTHOR]

Purpose: This study was designed to test the short-term toxicity of DHA-dFdC in a mouse model and its efficacy in a mouse model of leukemia at or below its repeat-dose maximum tolerated dose (RD-MTD). Method: A repeat-dose dose-ranging toxicity study was designed to determine the tolerability of DHA-dFdC when administered to DBA/2 mice by intravenous (i.v.) injection on a repeat-dose schedule (i.e. injections on days 0, 3, 7, 10, and 13). In order to determine the effect of a lethal dose of DHA-dFdC, mice were injected i.v. with three doses of DHA-dFdC at 100 mg/kg on days 0, 3, and 5 (i.e. a lethal-RD). The body weight of mice was recorded two or three times a week. At the end of the study, major organs (i.e. heart, liver, spleen, kidneys, lung, and pancreas) of mice that received the lethal-RD or RD-MTD were weighed, and blood samples were collected for analyses. Finally, DHA-dFdC was i.v. injected into DBA/2 mice with syngeneic L1210 mouse leukemia cells to evaluate its efficacy at or below RD-MTD. Results: The RD-MTD of DHA-dFdC is 50 mg/kg. At 100 mg/kg, a lethal-RD, DHA-dFdC decreases the weights of mouse spleen and liver and significantly affected certain blood parameters (i.e. white blood cells, lymphocytes, eosinophils, and neutrophil segmented). At or below its RD-MTD, DHA-dFdC significantly prolonged the survival of L1210 leukemia-bearing mice. Conclusion: DHA-dFdC has dose-dependent toxicity, affecting mainly spleen at a lethal-RD. At or below its RD-MTD, DHA-dFdC is effective against leukemia in a mouse model. [ABSTRACT FROM AUTHOR]