Steady-state Plasma Research Articles

Quality by design optimization of formulation variables and process parameters for enhanced transdermal delivery of nanosuspension.

This investigation aims to fabricate, characterize, and optimize organogel containing andrographolide nanosuspension to enhance transdermal drug delivery into and across the skinin vitro. We identified the critical material attributes (CMAs) and critical process parameters (CPPs) that impact key characteristics of andrographolide nanosuspension using a systematic quality-by-design approach. We prepared andrographolide nanosuspension using the wet milling technique and evaluated various properties of the formulations. The CMAs were types and concentrations of polymers, types and concentrations of surfactants, drug concentration, and lipid concentration. The CPPs were volume of milling media and milling duration. Mean particle size, polydispersity index, encapsulation efficiency, and drug loading capacity as critical quality attributes were selected in the design for the evaluation and optimization of the formulations. Furthermore, we developed and evaluated organogel formulation to carry andrographolide nanosuspension 0.05% w/w. Drug release and permeation studies were conducted to assess the drug release kinetics and transdermal delivery of andrographolide. We presented the alteration in the average particle size, polydispersity index, encapsulation efficiency, drug-loading capacity, and drug release among various formulations to select the optimal parameters. The permeation study indicated that organogel delivered markedly more drug into the receptor fluid and skin tissue than DMSO gel (n = 3, p < 0.05). This enhancement in transdermal drug delivery was demonstrated by cumulative drug permeation after 24h, steady-state flux, permeability coefficient, and predicted steady-state plasma concentration. Drug quantity in skin layers, total delivery, delivery efficiency, and topical selectivity were also reported. Conclusively, andrographolide nanosuspension-loaded organogel significantly increased transdermal drug delivery in vitro.

Impact of Continuous Infusion Meropenem PK/PD Target Attainment on C-Reactive Protein Dynamics in Critically Ill Patients With Documented Gram-Negative Hospital-Acquired or Ventilator-Associated Pneumonia.

Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of antibiotics including C-reactive protein (C-RP) dynamics could be helpful in predicting the efficacy of antimicrobials. We developed a PK/PD model for assessing the impact of continuous infusion (CI) meropenem PK/PD target attainment on C-RP dynamics in critically ill patients with documented Gram-negative hospital- (HAP) or ventilator-acquired pneumonia (VAP). Patients were grouped according to the type of antibiotic treatment received [meropenem monotherapy; meropenem plus empirical anti-MRSA (methicillin-resistant Staphylococcus aureus) therapy; meropenem in combination with another anti-Gram-negative active agent; meropenem plus a targeted anti-MRSA therapy]. A one-compartment population PK model of CI meropenem was developed by including all patients. A full C-RP production inhibition model was developed for fitting the PD data by including only patients receiving meropenem monotherapy or meropenem plus empirical anti-MRSA therapy. Monte Carlo simulations explored the relationship between the type of PK/PD target attainment of CI meropenem, defined as optimal (steady-state plasma concentration [Css] to minimum inhibitory concentration [MIC] ratio = 4-8), quasi-optimal (Css/MIC = 1-4) and sub-optimal (Css/MIC < 1) and the magnitude of C-RP production inhibition over time. A total of 64 patients providing 211 meropenem concentrations were included in the PK analysis, whereas 47 patients providing 328 C-RP data were included in the PD model. Simulations showed that optimal PK/PD target attainment was associated with the highest and most rapid C-RP production inhibition (44% and 56% at days 2 and 4, respectively). Conversely, sub-optimal PK/PD target attainment was shown to be almost ineffective (< 5% at day 4 and < 10% at day 10). Our PK/PD model predicted that attaining optimal PK/PD target with CI meropenem may grant prompt and intense C-RP decrease among critically ill patients receiving targeted monotherapy for Gram-negative HAP/VAP, thus anticipating efficacy.

Impact of gut permeability on estimation of oral bioavailability for chemicals in commerce and the environment.

Performance of pharmacokinetic models developed using in vitro-to-in vivo extrapolation (IVIVE) methods may be improved by refining assumptions regarding fraction absorbed (Fabs) through the intestine, a component of oral bioavailability (Fbio). Although in vivo measures of Fabs are often unavailable for non-pharmaceuticals, in vitro measures of apparent permeability (Papp) using the Caco-2 cell line have been highly correlated with Fabs. We measured bidirectional Papp for over 400 non-pharmaceutical chemicals using the Caco-2 assay. A random forest quantitative structure-property relationship (QSPR) model was developed using these and peer-reviewed pharmaceutical data. Both Caco-2 data (R²=0.37) and the QSPR model (R²=0.29) were better at predicting human bioavailability compared to in vivo rat data (R²=0.23). After incorporation into a high throughput toxicokinetics (HTTK) framework for IVIVE, the Caco-2 data were used to estimate in vivo administered equivalent dose (AED) for bioactivity assessed in vitro, The HTTK-predicted plasma steady state concentrations (Css) for IVIVE were revised, with modest changes predicted for poorly absorbed chemicals. Experimental data were evaluated for sources of measurement uncertainty, which were then accounted for using the Monte Carlo method. Revised AEDs were subsequently compared with exposure estimates to evaluate effects on bioactivity:exposure ratios, a surrogate for risk. Only minor changes in the margin between chemical exposure and predicted bioactive doses were observed due to the preponderance of highly absorbed chemicals.

Impaired Suppression of Plasma Lipid Extraction and its Partitioning Away from Muscle by Insulin in Humans with Obesity.

Humans with obesity and insulin resistance exhibit lipid accumulation in skeletal muscle, but the underlying biological mechanisms responsible for the accumulation of lipid in the muscle of these individuals remain unknown. We investigated how plasma insulin modulates the extraction of circulating triglycerides (TGs) and non-esterified fatty acids (NEFAs) from ingested and endogenous origin in the muscle of lean, insulin-sensitive humans (Lean-IS) and contrasted these responses to those in humans with obesity and insulin resistance (Obese-IR). The studies were performed in a postprandial state associated with steady-state plasma TG concentrations. The arterio-venous blood sampling technique was employed to determine the extraction of circulating lipids across the forearm muscle before and after insulin infusion. We distinguished kinetics of TGs and NEFAs from ingested origin from those from endogenous origin across muscle by incorporating stable isotope-labeled triolein in the ingested fat. Insulin infusion rapidly suppressed the extraction of plasma TGs from endogenous, but not ingested, origin in the muscle of the Lean-IS, but this response was absent in the muscle of the Obese-IR. Furthermore, in the muscle of the Lean-IS, insulin infusion decreased the extraction of circulating NEFAs from both ingested and endogenous origin; however, this response was absent for NEFAs from ingested origin in the muscle of the Obese-IR subjects. Partitioning of circulating lipids away from the skeletal muscle when plasma insulin increases during the postprandial period is impaired in humans with obesity and insulin resistance.

A multicentric, randomized, controlled clinical trial to study the impact of bedside model-informed precision dosing of vancomycin in critically ill children—BENEFICIAL trial

BackgroundVancomycin is a commonly prescribed antibiotic to treat serious Gram-positive infections in children. The efficacy of vancomycin is known to be directly related to the pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration–time curve (AUC) divided by the minimal inhibitory concentration (MIC) of the pathogen. In most countries, steady-state plasma concentrations are used as a surrogate parameter for this target AUC/MIC, but this practice has some drawbacks. Hence, AUC-based dosing using model-informed precision dosing (MIPD) tools has been proposed for increasing the target attainment rate and reducing vancomycin-related nephrotoxicity. Solid scientific evidence for these claimed benefits is lacking in children. This randomized controlled trial aims to investigate the large-scale utility of MIPD dosing of vancomycin in critically ill children.MethodsParticipants from 14 neonatal intensive care, pediatric intensive care, and pediatric hemo-oncology ward units from 7 hospitals are randomly allocated to the intervention or standard-of-care comparator group. In the intervention group, a MIPD dosing calculator is used for AUC-based dosing, in combination with extra sampling for therapeutic drug monitoring in the first hours of treatment, as compared to standard-of-care. An AUC24h between 400 and 600 is targeted, assuming an MIC of 1 mg/L. Patients in the comparator group receive standard-of-care dosing and monitoring according to institutional guidelines. The primary endpoint is the proportion of patients reaching the target AUC24h/MIC of 400–600 between 24 and 48 h after the start of vancomycin treatment. Secondary endpoints are the proportion of patients with (worsening) acute kidney injury during vancomycin treatment, the proportion of patients reaching target AUC24h/MIC of 400–600 between 48 and 72 h after the start of vancomycin treatment, time to clinical cure, ward unit length-of-stay, hospital length-of-stay, and 30-day all-cause mortality.DiscussionThis trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment in critically ill children.Trial registrationEudract number: 2019–004538-40. Registered on 2020–09-08ClinicalTrials.gov NCT046666948. Registered on 2020–11-28

A loading dose of clofazimine to rapidly achieve steady-state-like concentrations in patients with nontuberculous mycobacterial disease.

Clofazimine is a promising drug for the treatment of nontuberculous mycobacterial (NTM) diseases. Accumulation of clofazimine to reach steady-state plasma concentrations takes months. A loading dose may reduce the time to steady-state-like concentrations. We evaluated the pharmacokinetics (PK), safety and tolerability of a loading dose regimen in patients with NTM disease. Adult participants received a 4-week loading dose regimen of 300 mg clofazimine once daily, followed by a maintenance dose of 100 mg once daily (combined with other antimycobacterial drugs). Blood samples for PK analysis were collected on three occasions. A population PK model for clofazimine was developed and simulations were performed to assess the time to reach steady-state-like (target) concentrations for different dosing regimens. Twelve participants were included. The geometric mean peak and trough clofazimine concentrations after the 4-week loading phase were 0.87 and 0.50 mg/L, respectively. Adverse events were common, but mostly mild and none led to discontinuation of clofazimine. Our loading dose regimen reduced the predicted median time to target concentrations by 1.5 months compared to no loading dose (3.8 versus 5.3 months). Further time benefit was predicted with a 6-week loading dose regimen (1.4 versus 5.3 months). A 4-week loading dose regimen of 300 mg once daily reduced the time to target clofazimine concentrations and was safe and well-tolerated. Extending the loading phase to 6 weeks could further decrease the time to target concentrations. Using a loading dose of clofazimine is a feasible strategy to optimize treatment of NTM disease. NCT05294146.

Impact of UGT1A4 and UGT2B7 polymorphisms on lamotrigine plasma concentration in patients with bipolar disorder.

The purpose of this study was to evaluate the effect of UGT1A4 and UGT2B7 polymorphisms on the plasma concentration of lamotrigine in Chinese patients with bipolar disorder. A total of 104 patients were included in this study. Steady-state plasma lamotrigine concentrations were determined in each patient after at least 21 days of continuous treatment with a set dose of the drug. Lamotrigine plasma concentrations were ascertained using ultra-performance liquid chromatography. Simultaneously, plasma samples were used for patient genotyping. The age, sex, BMI, daily lamotrigine dose, plasma lamotrigine concentration, and lamotrigine concentration/dose ratio of patients exhibited significant differences, and these were associated with differences in the genotype [ UGT1A4 -142T>G and UGT2B7 -161C>T ( P < 0.05)]. Patients with the GG and GT genotypes in UGT1A4 -142T>G had significantly higher lamotrigine concentration/dose values (1.6 ± 1.1 and 1.7 ± 0.5 μg/ml per mg/kg) than those with the TT genotype (1.4 ± 1.1 μg/ml per mg/kg). Likewise, patients with the UGT2B7 -161C>T TT genotype had significantly higher lamotrigine concentration/dose values (1.6 ± 1.1 μg/ml per mg/kg) than those with the CC genotype (1.3 ± 1.3 μg/ml per mg/kg). Multiple linear regression analysis showed that sex, lamotrigine dose, UGT1A4 -142T>G, and UGT2B7 -161C>T were the most important factors influencing lamotrigine pharmacokinetics ( P < 0.001). The study results suggest that the UGT1A4 -142T>G and UGT2B7 -161C>T polymorphisms affect lamotrigine plasma concentrations in patients with bipolar disorder.

Novel treatment for PXE: Recombinant ENPP1 enzyme therapy

Pseudoxanthoma elasticum (PXE) is a genetic multisystem ectopic calcification disorder caused by inactivating mutations in the ABCC6 gene encoding ABCC6, a hepatic efflux transporter. ABCC6-mediated ATP secretion by the liver is the main source of plasma inorganic pyrophosphate (PPi), a potent endogenous calcification inhibitor. The deficiency of plasma PPi underpins PXE. Recent studies demonstrated that INZ-701, a recombinant human ENPP1, the principal PPi-generating enzyme, restored plasma PPi levels and prevented ectopic calcification in the muzzle skin of an Abcc6-/- mouse model of PXE. This study examined the pharmacokinetics, pharmacodynamics, and potency of a new ENPP1-Fc isoform, BL-1118, in Abcc6-/- mice. When Abcc6-/- mice received a single subcutaneous injection of BL-1118 at 0.25, 0.5, or 1 mg/kg, they had dose-dependent elevations in plasma ENPP1 enzyme activity and PPi levels, with an enzyme half-life of approximately 100 hours. When Abcc6-/- mice were injected weekly from 5 to 15 weeks of age, BL-1118 dose-dependently increased steady-state plasma ENPP1 activity and PPi levels and significantly reduced ectopic calcification in the muzzle skin and kidneys. These results suggest that BL-1118 is a promising enzyme therapy for PXE, a disease currently lacking preventive or therapeutic options.

Deuterium plasma induced preferential erosion in ultra-high temperature ceramics TiB2 and ZrB2*

Abstract Steady-state deuterium plasma exposures were performed on ultra-high temperature ceramics titanium diboride (TiB2) and zirconium diboride (ZrB2) using the PISCES-RF linear plasma device (LPD) as early screening for first wall, plasma-facing applications. Deuterium plasma exposures were performed using 40 eV ion energies at 240, 525, and 800 °C sample temperatures and 90 eV ion energies at 240 °C sample temperatures to analyze TiB2 and ZrB2 surface morphology and chemistry evolution behavior. Post-plasma exposure chemistry characterization of the near surface ( &lt; 50 nm) region of the samples all show transition metal enrichment, indicating boron preferential erosion. Transition metal to boron fractions vary with plasma exposure temperature under the 40 eV ion energy; metal enrichment is maximized at 800 °C and then minimized at 525 °C. SEM micrographs of all plasma exposed sample surfaces show no significant or noticeable plasma induced damage from cracking or blistering.

Effect of nicotine mouth spray on urges to vape: A randomized, placebo-controlled, pharmacodynamic clinical trial in exclusive e-cigarette users.

To determine whether nicotine mouth spray provides rapid and prolonged relief of urges to vape and measure the steady-state plasma nicotine levels during vaping and ad libitum mouth spray usage in e-cigarette users. Randomized, parallel group, double-blind trial. Single site at Hammersmith Medicines Research Ltd (HMR), London, UK. 216 (25.9% females, average age 27.6±7.63 [standard deviation, SD]) exclusive vapers who used their e-cigarette within 30 minutes of waking up and had vaped about 2years on average. Two sprays of 1mg nicotine mouth spray (Nicorette QuickMist Freshmint, n = 109), or placebo (identical in appearance and presentation, n = 107). Urge to vape was rated on a 100 mm visual analogue scale before and repeatedly for 2hours after administration. The primary outcome measured average change from baseline in urges to vape ratings during the first hour. Nicotine mouth spray achieved statistically significantly greater reductions in urges to vape than placebo from the first assessment point at 30 seconds to 1hour, when the estimated mean treatment difference was 11.90 mm (95% confidence interval [CI] = 6.86-16.95, P < 0.001). The integrated urge to vape over 11 hours ad libitum usage showed a statistically significant benefit compared with placebo (2.00 [0.88 SD] vs 2.51 [0.84 SD], P< 0.001). Mean steady-state plasma nicotine concentrations were lower after nicotine mouth spray usage compared with vaping (6.22 [4.70 SD] ng/ml vs 9.91 [7.59 SD] ng/ml, respectively). Adverse events were more commonly reported in the nicotine mouth spray group and were mostly mild. Among regular e-cigarette users, nicotine mouth spray provided statistically significant and fast relief of urges to vape one hour after dosing. Nicotine mouth spray showed statistically significant reductions in urges to vape as soon as 30 seconds and up to 2hours after dosing compared with placebo, and nicotine mouth spray was well-tolerated and safe.

A multi-centre, tolerability study of a cannabidiol-enriched Cannabis Herbal Extract for chronic headaches in adolescents: The CAN-CHA protocol

Introduction Cannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents. Methods and analysis Youth, parents, and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2–0.4 mg/kg of CBD per day and escalating monthly up to 0.8–1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE. Discussion This protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials. Trial registration CAN-CHA trial is registered with ClinicalTrials.gov with a number of register NCT05337033.

Dosing Evaluation of Ceftazidime-Avibactam in Intensive Care Unit Patients Based on Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling and Simulation.

P. aeruginosa is the most common microorganism involved in many ICU-acquired infections. A correct dosage regimen is pivotal to avoiding resistance development, worse outcomes and higher mortality rates. The aim of this study was to perform a pharmacokinetic-pharmacodynamic (PK/PD) evaluation of recommended dosing regimens of ceftazidime-avibactam (CAZ-AVI) in ICU patients with different degrees of renal function for a specific strain of Pseudomonas aeruginosa. A semi-mechanistic PK/PD model has been developed. It allows for the simulation of CAZ-AVI steady-state plasma level curves and the evolution of bacterial growth curves. The percentage of bacterial load reduction and the value of the recommended PK/PD indices have been taken into account to define the success or failure of the regimens. Probabilistic analysis was performed using Monte Carlo simulations of two populations: control and ICU. In both populations, dosing regimens endorsed for patients with CLcr higher than 10 mL/min reach the PK/PD indices recommended, T > MIC > 90% and Cmin/MIC > 1.3. While dosage regimens endorsed for patients with CLcr of 10 mL/min or lower fail (T > MIC < 60% and Cmin/MIC < 0.35). However, proposed dosing regimens based on shortening dosing intervals for these patients would be successful, increasing bacterial load reduction by almost 50% and reaching the proposed PK/PD indices. Therefore, CAZ-AVI dosing strategies based on model-informed precision dosing (MIPD) could directly influence the efficacy of results in ICU patients with renal insufficiency.

Associations between accurate measures of adiposity and fitness, blood proteins, and insulin sensitivity among South Asians and Europeans.

South Asians (SAs) may possess a unique predisposition to insulin resistance (IR). We explored this possibility by investigating the relationship between 'gold standard' measures of adiposity, fitness, selected proteomic biomarkers, and insulin sensitivity among a cohort of SAs and Europeans (EURs). A total of 46 SAs and 41 EURs completed 'conventional' (lifestyle questionnaires, standard physical exam) as well as 'gold standard' (dual energy X-ray absorptiometry scan, cardiopulmonary exercise test, and insulin suppression test) assessments of adiposity, fitness, and insulin sensitivity. In a subset of 28 SAs and 36 EURs, we also measured the blood-levels of eleven IR-related proteins. We conducted Spearman correlation to identify correlates of steady-state plasma glucose (SSPG) derived from the insulin suppression test, followed by multivariable linear regression analyses of SSPG, adjusting for age, sex and ancestral group. Sixteen of 30 measures significantly associated with SSPG, including one conventional and eight gold standard measures of adiposity, one conventional and one gold standard measure of fitness, and five proteins. Multivariable regressions revealed that gold standard measures and plasma proteins attenuated ancestral group differences in IR, suggesting their potential utility in assessing IR, especially among SAs. Ancestral group differences in IR may be explained by accurate measures of adiposity and fitness, with specific proteins possibly serving as useful surrogates for these measures, particularly for SAs.

An integral approach to plasma-wall interaction modelling for EU-DEMO

Abstract The integral approach to plasma-wall interaction (PWI) modelling for DEMO is presented, which is a part of EUROfusion Theory and Advanced Simulation Coordination (E-TASC) activities that were established to advance the understanding and predictive capabilities for modelling of existing and future fusion devices using a modern advanced computing approach. In view of DEMO design, the aim of PWI modelling activities is to assess safety-relevant information regarding erosion of plasma-facing components (PFC), including its impact on plasma contamination, dust production, fuel inventory, and material response to transient events. This is achieved using a set of powerful and validated computer codes that deal with particular PWI aspects and interact with each other by means of relevant data exchange. Steady state erosion of tungsten PFC and subsequent transport and re-deposition of eroded material are simulated with the ERO2.0 code using a DEMO plasma background produced by dedicated SOLPS-ITER simulations. Dust transport simulations in steady state plasma also rely on the respective SOLPS-ITER solution and are performed with the MIGRAINe code. On the way to improved simulations of tungsten erosion in the divertor of DEMO, relevant high density sheath models are being developed based on Particle-in-Cell (PIC) simulations with the state-of-the-art BIT code family. PIC codes of the SPICE code family, in turn, provide relevant information on multi-emissive sheath physics, such as semi-empirical scaling laws for field-assisted thermionic emission. These scalings laws are essential for simulations of material melting under transient heat loads that are performed with the recently developed MEMENTO code, the successor of MEMOS-U. Fuel retention simulations assess tritium retention in tungsten and structural materials and permeation to coolant accounting for neutron damage, in particular for divertor monoblocks of different sizes, using the FESTIM code, and for the first wall, in particular in view of tritium self-sufficiency, using the TESSIM code. Respective code-code dependencies and interactions, as well as modelling results achieved to date are discussed in the contribution.

Pharmacokinetics, Safety and Tolerability of Single-dose or Multiple-dose Cefiderocol in Hospitalized Pediatric Patients Three Months to Less Than Eighteen Years Old With Infections Treated With Standard-of-care Antibiotics in the PEDI-CEFI Phase 2 Study.

Multidrug-resistant Gram-negative bacterial infections are increasing globally in neonates, infants and children; antibiotic options are limited. This international, multicenter, open-label phase 2 study, investigated the pharmacokinetics, safety and tolerability of single-dose and multiple-dose cefiderocol [as a 3-hour infusion (every 8 hours) dosed at 2000 mg for body weight ≥34 kg and at 60 mg/kg for body weight <34 kg], over a range of renal function, in hospitalized pediatric patients with aerobic Gram-negative bacterial infection; multiple-dose patients required standard-of-care systemic antibiotics for 5-14 days. Four cohorts of pediatric patients were enrolled (cohort 1: 12 to <18 years, cohort 2: 6 to <12 years, cohort 3: 2 to <6 years and cohort 4: 3 months to <2 years). A total of 53 patients (median age: 73.5 months) were enrolled. Plasma concentration profiles were similar with single-dose (n = 24) and multiple-dose (n = 29) cefiderocol, irrespective of age and body weight in those with normal renal function or mild renal impairment. Geometric mean concentrations at the end of infusion ranged between 72.7 and 97.1 μg/mL for single-dose cefiderocol and between 88.8 and 106.0 μg/mL after multiple doses. At 8 hours, corresponding trough concentrations ranged from 7.86 to 10.8 μg/mL with single-dose cefiderocol and from 9.64 to 18.1 μg/mL with multiple doses. There were no deaths, no cefiderocol-related serious adverse events, significant related laboratory abnormalities or discontinuations. Multiple-dose cefiderocol, administered for 5-14 days and according to body weight, achieved steady-state plasma concentrations that remained above the susceptibility breakpoints of Gram-negative bacteria throughout the dosing period. Cefiderocol was well tolerated.

Characteristics of fluctuations in the equatorial and polar directions of a compact dipole plasma driven at steady state

The fluctuations in the plasma potential (Vs̃) and electron density (Nẽ) are measured in the steady-state dipole plasma confined in a spherical vacuum chamber using a single permanent dipole magnet. Measurements are made from a radial distance r = 0.5–17 cm, from the surface of the magnet in the equatorial (θ=90°) and polar (θ=180°) directions, using a 4-pin probe setup, and have been characterized by power spectra, cross-phase, cross-coherence, induced transport, and energy spectra. The fluctuations are stronger near the surface of the dipole magnet for θ=90°, thereafter their magnitude decreases gradually with the radial distance. However, a peaked profile of potential fluctuations with the peak around r = 9 cm is observed for θ=180°. The locations of strong fluctuations are around the locations of smaller values of the electron neutral collision frequency. Frequency-resolved power spectra show that the fluctuations in the dipole plasma, predominantly, belong to the very low-frequency range. The values of cross-phase (≤45°) and |Vs̃/Te|/|Nẽ/Ne|≤1 indicate the presence of drift wave instability in both planes, where Te and Ne are equilibrium values of the electron temperature and density. The radial variation of fluctuation-induced electron flux (Γr) verifies the “inward diffusion” of electrons in the equatorial plane.

Semi-analytical modeling of prompt redeposition in a steady-state plasma

Abstract A steady-state, 1D semi-analytical model for prompt redeposition based on the separation between redeposition caused by the electric field in the sheath and redeposition related to gyromotion is here described. The model allows for the estimation of not only the fraction of promptly redeposited flux but also the energy and angular distribution of the non-promptly redeposited population, along with their average charge state. Thus, the temperature and mean parallel-to-B velocity of the non-promptly redeposited flux are also available. The semi-analytical model was validated against equivalent Monte Carlo simulations across a broad range of input parameters. In this paper the eroded material under exam was tungsten (W) for which the code demonstrated consistent agreement with respect to numerical results, within its defined validity limits. The model can theoretically provide a solution for any material, temperature and electron density profile in the sheath, monotonic potential drop profile, and sputtered particles energy and angular distribution at the wall. As such, this code emerges as a potential tool for addressing the boundary redeposition phenomenon in fluid impurity transport simulations.

Studies of beam ion confinement to enhance plasma performance on EAST

Abstract A key physics issue for achieving steady-state high-performance plasmas on EAST tokamak is to decrease beam-ion losses to improve plasma confinement during neutral beam injections (NBIs). To decrease the beam losses, previous counter-Ip NBI injections are upgraded to co-Ip injections. Analysis shows that due to the reversed direction of drift across the flux surfaces caused by the pitch angle, the beam prompt loss fraction decreases from about 49% to 3% after the upgrade. Moreover, because of the change of entire beam path, beam shine-through (ST) loss fraction for counter-Ip tangential and counter-Ip perpendicular injections is reversed to co-Ip tangential and co-Ip perpendicular injections, respectively. Due to change in the initial trapped-confined beam ion fraction caused by the peaked pitch profiles, the losses induced by toroidal ripple field are also reversed after the upgrade. To further improve the beam-ion confinement under the present NBI layout, the amplitudes of toroidal field are increased from 1.75 to 2.20 T. Result shows that, due to the smaller orbit width and peaked pitch angle profile, the beam prompt loss power is lower with higher toroidal field. Due to the synergy of higher initial trapped-confined beam ion fraction and narrower Goldston-White-Boozer (GWB) boundary, the loss induced by ripple diffusion is higher with higher toroidal field. The combined effect of beam ST loss, prompt loss, and ripple loss, contributes to the increase in beam ion density. The decrease in beam loss power enhances beam heating efficiency, especially the fraction of beam heating ions. Finally, comparison between simulation and measurement by 235U fission chamber (FC) indicates that the increase in neutron rate are mainly contributed by improvement of beam-ion confinement. This study can provide potential support for beam operation and high-Ti experiment on EAST tokamak.

Overview of recent experimental results on the EAST Tokamak

Since the last IAEA-FEC in 2021, significant progress on the development of long pulse steady state scenario and its related key physics and technologies have been achieved, including the reproducible 403 s long-pulse steady-state H-mode plasma with pure radio frequency (RF) power heating. A thousand-second time scale (∼1056 s) fully non-inductive plasma with high injected energy up to 1.73 GJ has also been achieved. The EAST operational regime of high β P has been significantly extended (H 98y2 > 1.3, β P ∼ 4.0, β N ∼ 2.4 and n e/n GW ∼ 1.0) using RF and neutral beam injection (NBI). The full edge localized mode suppression using the n = 4 resonant magnetic perturbations has been achieved in ITER-like standard type-I ELMy H-mode plasmas with q 95 ≈ 3.1 on EAST, extrapolating favorably to the ITER baseline scenario. The sustained large ELM control and stable partial detachment have been achieved with Ne seeding. The underlying physics of plasma-beta effect for error field penetration, where toroidal effect dominates, is disclosed by comparing the results in cylindrical theory and MARS-Q simulation in EAST. Breakdown and plasma initiation at low toroidal electric fields (<0.3 V m−1) with EC pre-ionization is developed. A beneficial role on the lower hybrid wave injection to control the tungsten concentration in the NBI discharge is observed for the first time in EAST suggesting a potential way toward steady-state H-mode NBI operation.

Effect of Genetic Polymorphisms of ABCB1, ABCG2, and SLC22A1 on the Steady-State Plasma Concentrations of Lamotrigine in Treatment-Resistant Depressed Patients Treated With Lamotrigine Augmentation Therapy.

The authors have demonstrated that a plasma lamotrigine concentration of 12.7 μmol/L may be a threshold for a good therapeutic response to lamotrigine augmentation therapy in treatment-resistant depressed patients. Lamotrigine is a substrate of P-glycoprotein, breast cancer resistant protein and organic cation transporter 1, which are encoded by ABCB1 , ABCG2 , and SLC22A1 , respectively. There have been several polymorphisms that affect its function. The present study investigated the relationship between these polymorphisms and the steady-state plasma concentrations (Css) of lamotrigine in treatment-resistant depressed patients receiving lamotrigine as augmentation therapy. One hundred twenty-nine treatment-resistant depressed patients were included in this study. Treatment resistance is defined as lack of therapeutic response to at least 3 psychotropics despite adequate doses and duration. Their diagnoses were as follows: major depressive disorder (n = 58), bipolar II disorder (n = 52), and bipolar I disorder (n = 19). Lamotrigine augmentation therapy for 8 weeks was conducted. The final lamotrigine doses were 75 mg/d for 39 patients with valproate and 100 mg/d for 90 without it. Blood was sampled at 8:00 am after the 8th week of treatment. Plasma lamotrigine levels were quantified by using LC/MS/MS. The polymorphisms of ABCB1 1236C>T, 2677G>T/A, 3435C>T, ABCG2 421C>A, and SLC22A1 1222G>A were detected by polymerase chain reaction analyses. No significant relationships were observed between these polymorphisms and the Css of lamotrigine in the patients with or without valproate. The present study suggests that these genetic polymorphisms do not play a role in controlling the Css of lamotrigine in treatment-resistant depressed patients treated with lamotrigine augmentation therapy.