Steady-state Plasma Research Articles

Therapeutic drug monitoring versus Bayesian AUC-based dosing for vancomycin in routine practice: a cost-benefit analysis.

AUC-based dosing with validated Bayesian software is recommended as a good approach to guide bedside vancomycin dosing. To compare treatment and vancomycin-associated acute kidney injury (AKI) costs between Bayesian AUC-based dosing and conventional therapeutic drug monitoring (TDM) using steady-state plasma concentrations of vancomycin administered as continuous infusion in hospitalized non-critically ill patients with severe Gram-positive infection. A cost-benefit analysis presented as a return on investment (ROI) analysis from a hospital perspective was conducted using a decision tree model (TDM versus AUC-based dosing) to simulate treatment cost (personnel, serum sampling and drug cost), vancomycin-associated AKI risk and cost up to 14 days. ROI was calculated against AUC-based software cost. One-way and probabilistic sensitivity analyses (respectively OWSA and PSA) were performed to check for robustness. In base case, an overall cost per patient of €621.0 with TDM and €543.6 with AUC-based dosing resulted in a treatment saving of €77.4 per patient when applying AUC-based dosing. This saving against the software cost (€26.9/patient) generated an ROI per patient of €1.9 per invested € in software [€1.9 (95% CI 1.6-2.2) in PSA]. Enrolling 900 AUC-based dosed patients annually translated to a net saving of €45 469. Software break-even was reached after 313 patients. In OWSA, a higher AKI risk with TDM strongly contributed to a positive ROI. AUC-based dosing appeared a cost-saving strategy compared with conventional TDM when applying base-case settings of vancomycin-associated AKI risk, treatment and AKI costs.

Predictions of gyrokinetic turbulent transport in hydrogen-boron plasmas on EHL-2 spherical torus

Abstract The EHL-2 spherical torus at ENN is the next-generation experimental platform under conceptual design, aiming at realizing hydrogen-boron (H-B11) thermonuclear fusion which is an attractive pathway towards neutron-free fusion. In order to achieve high performance steady-state plasma, it is extremely necessary to study the turbulence transport characteristics with high boron content in the plasma core. This work investigates the transport properties in the core internal transport barrier (ITB) region of hydrogen-boron plasma utilizing the gyrokinetic code GENE in view of the high ion temperature scenario of EHL-2, specifically focusing on the impact of boron fractions and plasma β on the microinstabilities and corresponding transport features. Numerical findings indicate that the inclusion of boron species effectively suppresses the trapped electron modes (TEMs) as well as promoting a transition from electromagnetic to electrostatic turbulence with increased boron fraction, which is a result of the suppression of microinstabilities by effective charge and mass. Moreover, it has been identified that the external E×B rotational shear has a notable inhibitory influence on transport which can reduce the transport level by 2-3 orders of magnitude especially at medium boron contents. The suppressive effects of E×B on turbulence is weakened once the kinetic ballooning mode (KBM) is excited and the transport shows a rapid increase with β together with a reduction in zonal flow amplitude which is consistent with previous findings. Therefore, it is strongly suggested that exploring advanced strategies for mitigating turbulent transport at high β regimes are necessary for the active control of plasma behavior regarding H-B11 plasma based fusion devices such as EHL-2.

Absorption, single-dose and steady-state metabolism, excretion, and pharmacokinetics of adagrasib, a KRASG12C inhibitor.

This study investigated absorption, metabolism, and excretion of adagrasib after a single oral 600mg dose (1µCi [14C]-adagrasib) in 7 healthy subjects and compared the metabolite profile to the profile at steady-state in 4 patients dosed at 600mg twice daily. Plasma, urine, and feces were collected post [14C]-adagrasib administration and total radioactivity and pooled sample metabolite profiles were determined. Adagrasib pharmacokinetics were determined in plasma and urine. The steady-state plasma metabolite profile was examined in patients and in vitro studies were performed to understand adagrasib's potential to inhibit CYP enzymes and identify CYPs involved in its metabolism. The total mean recovery of the administered radioactivity was 79.2%, with 74.7% and 4.49% of total radioactivity recovered from feces and urine, respectively. Only 1.8% of the dose was excreted in urine as unchanged adagrasib, indicating negligible renal clearance. Adagrasib, M55a, M11, and M68 were major plasma components accounting for 38.3%, 13.6%, 13.4%, and 11.0% of the total plasma radioactivity exposure, respectively. Metabolite M55a was not detected in plasma at steady state where only M68 (24%) and M11 (17.1%) were abundant. In vitro data showed that CYP3A4 (72%) and CYP2C8 (28%) are main contributors to metabolism and adagrasib is a time-dependent inhibitor of CYP3A4. Elimination of adagrasib is mainly by fecal excretion. Adagrasibs altered metabolite profile at steady state is likely due to CYP3A4 autoinhibition. The abundant steady-state plasma metabolites, M68 and M11, are not human specific and do not contribute significantly to the pharmacological activity of adagrasib.

Safety evaluation of targeted osmotic lysis therapy in Beagles.

The objective of this study was to satisfy the US FDA's Center for Devices and Radiological Health regarding the safety of targeted osmotic lysis (TOL), a novel treatment for advanced carcinomas, in Beagle dogs. 12 intact Beagle dogs, 6 males and 6 females, were divided into 2 treatment groups of 6, each receiving 3 TOL cycles. For each 6-day cycle, digoxin was administered orally at 0.007 mg/kg q 12 h X 6 days to achieve steady-state plasma concentrations. On days 5 and 6 of each cycle, the animals were exposed to pulsed electric field (PEF) stimulation at a field strength of either 18 or 40 V/min for 2 hours. Following the completion of cycles 1 and 2, animals were observed for 7 days. On the day following the end of cycle 3, the animals were euthanized. A complete macroscopic examination was performed, and tissues were collected for microscopic examination. As there were no concurrent untreated control animals, only qualitative comparisons were performed to assess potential differences between group 1, which received the digoxin plus 18 V/min PEF, and group 2, which received digoxin plus 40 V/min PEF. No adverse events related to TOL exposure were observed in either group. Neither group demonstrated gross or microscopic lesions following 3 rounds of exposure to TOL. Due to the lack of toxicity noted in the treated animals, TOL warrants consideration as either a standalone treatment option or as an adjunct to surgery or chemotherapy for managing malignant cancer.

Pharmacokinetic Prediction of Immediate- and Extended-Release Tablets for Patients with Liver Disease Using Whole Body Physiologically-Based Pharmacokinetic Modeling for the Antipsychotic Drug Quetiapine.

Although quetiapine metabolism occurs extensively in the liver and careful dosing is recommended in patients with liver disease, there has been a paucity of pharmacometric studies to adjust the clinical dose of quetiapine according to liver-disease severity. This study aimed to establish a whole-body, physiologically-based pharmacokinetic (WB-PBPK) model to explain interindividual variability in quetiapine PK and quantitatively predict PK in patients with liver disease. The developed WB-PBPK model well described the PK characteristics of different quetiapine regimens in healthy populations. The PK predictions could also be applied to patients with schizophrenia (without significant differences from healthy subjects). For the same total dose of quetiapine, both immediate-release (IR) and extended-release (ER) tablets showed significantly increased exposure and decreased clearance in patients with liver disease compared to healthy subjects. The model showed that steady-state plasma quetiapine concentrations exceeded the usual therapeutic range after multiple doses of IR tablets 250mg three times daily or ER tablets 800mg once daily in patients with liver disease. Therefore, the doses of quetiapine IR or ER tablets could be reduced by 0.10-0.50 times depending on liver-disease severity, so that mean steady-state plasma concentrations could be positioned near the therapeutic range. WB-PBPK modeling for quetiapine enabled quantitative prediction of PK according to IR or ER formulation and liver-disease severity. The results of this study provide useful data for improving the therapeutic use of quetiapine by enabling dose selection based on formulation and liver-disease severity.

Effects of the Japanese Kampo Medicines Rikkunshito, Shakuyakukanzoto and Goreisan on Lenvatinib Plasma Concentrations in Japanese Patients with Thyroid Cancer.

Kampo medicines are often used in Japan as therapy for the side effects induced by oral kinase inhibitors. However, the pharmacokinetic interactions between Kampo medicines and oral kinase inhibitors such as lenvatinib have not been studied. We investigated the effects of Kampo medicines (rikkunshito, shakuyakukanzoto and goreisan) on the steady-state plasma trough concentration (C0) of lenvatinib in patients with thyroid cancer. Thirty-nine patients receiving lenvatinib therapy at Ito Hospital between May 2015 and December 2019 were enrolled. The mean C0 of lenvatinib with Kampo medicine, at the same dose as before initiating Kampo medicines, was used. After the repeated administration of rikkunshito (n = 21), shakuyakukanzoto (n = 10) or goreisan (n = 8), the mean C0 of lenvatinib and the laboratory test values of patients did not change significantly. In contrast to rikkunshito, which alleviates emesis by enhancing gastric emptying, the C0 values of lenvatinib with a proton pump inhibitor (PPI) (n = 16) or histamine H2 receptor antagonist (H2RA) (n = 4) were significantly lower than the C0 values without a PPI or H2RA (P = 0.007). The mean (range) change rate of the C0 of lenvatinib with a PPI or H2RA versus without a PPI or H2RA was 88.6% (69.9-115%), and was significantly greater than the change rate for rikkunshito (P = 0.029). There was no significant difference between the C0 of lenvatinib with a prokineticagent (n = 7) versus without a prokinetic agent (P = 0.365). Although these Kampo medicines are reported to inhibit drug-metabolizing enzymes and drug transporters, the risk of drug interactions for patients receiving lenvatinib therapy is low. Patients should feel confident that they can receive Kampo medicines as supportive care for lenvatinib therapy without a risk of drug interactions that could affect treatment efficacy.

Characterization of the Proinflammatory Cytokine Profile during Acute SARS-CoV-2 Infection in People with Human Immunodeficiency Virus.

Persistent inflammation during chronic human immunodeficiency virus (HIV) infection may affect the immune response against severe acute respiratory syndrome-coronavirus 2 (SARS- CoV-2) infection. Plasma levels of multiple proinflammatory cytokines during acute SARS-CoV-2 infection were measured in people with HIV (PWH) with effective combination antiretroviral therapy. There were no significant differences in any of the measured cytokines between severity levels of coronavirus disease 2019 (COVID-19) in PWH, while most were significantly higher in HIV-uninfected individuals with severe COVID-19, suggesting that excess cytokines release by hyperinflammatory responses do not occur in individuals with severe COVID-19 with HIV infection. The strong associations between the cytokines observed in HIV-uninfected individuals, particularly between IFN-α/TNF-α and other cytokines, were lost in PWH. The steady-state plasma levels of IP-10, ICAM-1, and CD62E were significantly higher in PWH, indicating that they were in an enhanced inflammatory state. The absence of several inter-cytokine correlations was observed in in vitro lipopolysaccharide stimulus-driven cytokine production in PWH. These data suggest that inflammatory responses during SARS-CoV-2 infection in PWH are distinct from those in HIV-uninfected individuals, partially because of the underlying inflammatory state and/or impairment of innate immune cells.

Studies of beam ion confinement to enhance plasma performance on EAST

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-I p NBI injections are upgraded to co-I p 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-I p tangential and counter-I p perpendicular injections is reversed to co-I p tangential and co-I p perpendicular injections, respectively. Due to the 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 is mainly contributed by improvement of beam-ion confinement. This study can provide potential support for beam operation and high-T i experiment on EAST tokamak.

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.

Preparation and Evaluation of Transdermal Formulations of Ciprofloxacin hydrochloride

Ciprofloxacin hydrochloride is a fluoroquinolone antibiotic which exhibits its potent antibacterial activity through its inhibitory action on DNA gyrase and topoisomerase IV enzymes, essential for bacterial DNA replication. It has a short elimination half-life of approximately 4 hours and requires frequent dosing. It is similar to other antibiotics that upon oral administration the most frequently reported adverse reactions is gastrointestinal discomfort. The objective of the present work aimed to formulate and evaluate transdermal gel formulation of Ciprofloxacin HCl and to study the extent of its percutaneous absorption. Thus, maintaining a steady-state plasma level of the drug without passing through the liver. Transdermal gel formulations of Ciprofloxacin HCl were prepared, including gel bases of different concentrations, namely (Carboxymethylcellulose (CMC), Hydroxypropylmethylcellulose (HPMC) and Carbopol 940). Ciprofloxacin HCl was incorporated into the previous bases at 1% concentration, and the formulated gel bases were assessed for appearance, pH, rheological properties and in-vitro release. HPMC 3% hydrogel formula with peppermint oil as enhancer was chosen as it showed better release (98.9%) characteristics at pH 7.4 after three hours than other formulations, good homogeneity with pH of 6.12, and the gel exhibited first-order kinetics and pseudoplastic flow. The permeation study of this formula showed a sustained release profile within 24 hours, through rabbit membrane.

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.

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.