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Abstract: Ischemic heart disease gravely threatens human health and even results in death. Kirenol is predominantly derived from the Herba Siegesbeckiae plant species and possesses a wide range of biological effects (such as antibacterial, anti-inflammatory, anticancer, and cardioprotective). However, the regulatory effects and associated mechanisms of kirenol in myocardial ischemia/reperfusion injury (MI/RI) remain unclear. In this study, first, the MI/RI rat model was established. It was demonstrated that kirenol protected against the aggravation of cardiac function in MI/RI rats. In addition, the inflammation was induced by ischemia reperfusion (IR), which was likewise affected by kirenol (5 or 10 mg/kg). Moreover, IR enhanced oxidative stress, a process that was counteracted by kirenol. Next, cell apoptosis was discovered to be heightened after IR, but this effect was neutralized by kirenol. Finally, it was revealed that kirenol has the ability to block the activation of the NF-κB pathway. In conclusion, it was disclosed that kirenol alleviated inflammation and oxidative stress through modulating the NF-κB pathway to improve MI/RI in rats. This work may offer novel insights for searching useful drugs for treating MI/RI., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This study describes the effects of introducing a protocol omitting preoperative α-blockade dose-escalation (de-escalation) in a prospective patient group., Background: The decline of mortality and morbidity associated with pheochromocytoma resection is frequently attributed to the introduction of preoperative α-blockade. Current protocols require preoperative α-blockade dose-escalation and multiple-day hospital admissions. However, correlating evidence is lacking. Moreover, recent data suggest equal perioperative safety regardless of preoperative α-blockade escalation., Methods: Single-institution evaluation of protocol implementation, including patients who underwent adrenalectomy for pheochromocytoma between 2015 and 2023. Intraoperative hemodynamic control was regulated by active adjustment of blood pressure using vasoactive agents. The primary outcome was intraoperative hypertension, defined as the time-weighted average of systolic blood pressure (TWA-SBP) above 200 mm Hg. Secondary outcomes included perioperative hypotension, postoperative blood pressure support requirement, hospital stay duration, and complications., Results: Of 102 pheochromocytoma patients, 82 were included; 44 in the de-escalated preoperative α-adrenergic protocol and 38 following the previous dose-escalation protocol. Median [IQR] TWA-SBP above 200 mm Hg was 0.01 [0.0-0.4] mm Hg in the de-escalated group versus 0.0 [0.0-0.1] mm Hg in the dose-escalated group ( P =0.073). The median duration of postoperative continuous norepinephrine administration was 0.3 hours [0.0-5.5] versus 5.1 hours [0.0-14.3], respectively ( P =0.003). Postoperative symptomatic hypotension occurred in 34.2% versus 9.1% of patients ( P =0.005). Median hospital stay was 2.5 days [1.9-3.6] versus 7.1 days [6.0-11.9] ( P <0.001). No significant differences in complication rates were observed., Conclusion: Our data suggest that adrenalectomy for pheochromocytoma employing a de-escalated preoperative α-blockade protocol is safe and results in a shorter hospital stay., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This study reports the outcomes of the 0.18-mg intravitreal fluocinolone acetonide implant in the treatment of pediatric noninfectious uveitis., Methods: A retrospective cohort study was performed on patients under 18 years old who received fluocinolone acetonide implant between June 1, 2020 and March 1, 2023. Data collected included demographics, uveitis diagnosis, use of anti-inflammatory therapy, visual acuity, intraocular pressure, and grading of uveitis activity. Uveitis recurrence was defined as increased inflammation that required additional anti-inflammatory therapy., Results: Eleven eyes from seven patients were included in this study. One patient (one eye) had a diagnosis of immune recovery uveitis and the remaining six patients (10 eyes) had pars planitis. The rate of remaining recurrence-free was 82% at 6 months, 60% at 12 months, and 60% at 24 months. Two of the six phakic eyes at baseline required cataract extraction during follow-up. Two of the four eyes that did not have intraocular pressure-lowering surgery before implantation required surgery in follow-up., Conclusion: The 0.18-mg fluocinolone acetonide implant has a similar efficacy for the treatment of pediatric uveitis, particularly pars planitis, as in the adult population, although with higher rates of ocular hypertension requiring intervention.

Background: Unusually high variability in blood Δ9-tetrahydrocannabinol (THC) concentrations have been observed in subjects inhaling similar cannabis products over similar time periods when consumption is ad libitum. This makes simple gravimetric dose estimation a poor predictor of THC exposure. Population pharmacokinetic analyses of blood THC concentration versus time data are routinely used to estimate pharmacokinetic parameters. The aim of this study was to estimate the inhaled dose of THC in occasional and daily users of high potency market cannabis., Methods: Blood THC concentrations were measured for 135 minutes from 29 participants who either smoked high concentration flower or inhaled concentrates ad libitum during a 15-minute session. Frequent blood samples were obtained over the following 135 minutes., Results: The estimated central and rapidly equilibrating volumes of distribution of a 3-compartment model were 19.9 ± 1.2 and 51.6 ± 4.7 L whereas the intercompartmental clearances were 1.65 ± 0.14 and 1.75 ± 0.10 L/min, respectively. Covariate-adjusted analysis revealed that the estimated inhaled THC dose was considerably less among occasional users compared with daily users., Conclusions: Three-compartment pharmacokinetics of THC did not differ among the 3 user groups, and the early phase (first 135 minutes postinception of inhalation) kinetics were similar to those previously described after smoking low potency cannabis products. Therefore, inhaled THC dose can be estimated from pharmacokinetic data and covariate-driven adjustments can be used to estimate THC doses, based on the participant cannabis usage pattern (occasional versus daily), improving the accuracy of THC exposure estimates compared with those derived from weighed THC content alone., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: This study comprehensively examined the demographic and clinical characteristics of patients undergoing valproic acid therapy and explored their potential impact on plasma valproic acid concentrations. All enrolled patients were administered the extended-release formulation. An in-depth investigation of factors, including dose, age, sex, body mass index, co-administered medications, and laboratory test findings, was conducted to evaluate their potential influence on study outcomes., Methods: In total, 164 patients met the inclusion criteria and were included in the analysis. The patient age ranged from 13 to 60 years, with a median age of 25.71 years. Most patients (89%) received a daily dose of 1 g valproic acid. Co-administered psychiatric medications included aripiprazole, quetiapine, and lorazepam. Laboratory test results, such as hemoglobin and transaminase levels, were also collected as part of the study., Results: The average plasma valproic acid plasma concentration was 79.8 mg/L. The dose significantly affected valproic acid concentrations, as a higher percentage of measurements exceeded the therapeutic range at a daily dose of 1 g. Furthermore, females exhibited significantly higher valproic acid concentrations compared with males at the same dose ( P < 0.05). However, different age groups showed no statistically significant differences in valproic acid concentrations ( P > 0.05). The co-administered antipsychotic and antidepressant medications significantly affected valproate concentrations, as reflected in the multiple regression model ( P < 0.01)., Conclusions: This study offers valuable insights into the demographic and clinical characteristics of patients undergoing valproic acid therapy. It highlights the influence of dose, sex, and concomitant medications on plasma valproic acid concentrations. Overall, these findings can help guide dose adjustments and implement personalized treatment strategies in valproic acid therapy., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: There is limited evidence to support the currently suggested lamotrigine (LTG) therapeutic reference range of 2.5-15 mg/L for the treatment of seizures. The objective of this study was to evaluate the association of LTG plasma concentrations with the efficacy and toxicity of the treatment in patients with epilepsy., Methods: Patients whose LTG plasma concentration was measured between January 2013 and February 2022 were included. Efficacy was defined as seizure freedom for at least 6 months around the time of measured LTG concentration. Toxicity was defined as any LTG-related adverse drug effect documented in each patient's health record or when the reason for measuring the LTG concentration was toxicity. In addition, the dose-concentration relationship of LTG was assessed., Results: In total, 549 concentrations from 259 patients with epilepsy were included. The most common reasons for therapeutic drug monitoring were suspected inefficacy (39%) and pregnancy (21%). The LTG plasma concentration was not associated with efficacy (adjusted odds ratio = 0.94; 95% confidence interval, 0.85-1.04). The LTG plasma concentration was positively associated with the incidence of toxicity after adjusting for age, sex, and number of antiepileptic drugs (odds ratio = 1.11; 95% confidence interval, 1.04-1.19). The daily dose had a significant linear correlation with the LTG plasma concentration ( P < 0.001)., Conclusions: The LTG plasma concentration was associated with toxicity, whereas no association with efficacy was found. A reference range of 2.5-10 mg/L may be considered to decrease the risk of toxicity while maintaining similar efficacy. Therapeutic drug monitoring may be useful when LTG-related toxicity is suspected and in cases of pharmacokinetic changes (eg, pregnancy and concomitant use of interacting drugs) that can influence the LTG plasma concentration., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Emergence agitation (EA) is an adverse complication during early recovery from sevoflurane anesthesia. Continuous intravenous infusion of dexmedetomidine (DEX) is commonly used for EA prevention. However, a wide dose range is used for preventing EA, and the optimal dose remains unknown. This study was aimed at determining the optimal dose (the 90% effective dose [ED90]) of DEX for continuous intraoperative infusion for EA prevention in children., Methods: We enrolled children aged 3 to 7 years who underwent dental treatment under sevoflurane anesthesia. DEX was continuously infused from the time of the establishment of the intravenous access until 5 minutes before the end of surgery. The initial DEX dose was 0.5 µg/kg/h, and subsequent dose adjustments were determined based on the response of the previous patient by using an up-down sequential allocation with a biased-coin design. The primary outcome was the ED90 for continuous DEX infusion based on the success or failure of the EA-preventing dose., Results: Forty-five patients were enrolled in the study. The DEX dose ranged from 0.50 to 0.90 µg/kg/h. The estimated ED90 (95% confidence interval [CI]) for preventing EA was 0.74 µg/kg/h (0.67-1.05 µg/kg/h). The duration of surgery (mean ± standard deviation [SD]) was 113 ± 30 minutes. The times (mean ± SD) for extubation, time to emergence, and recovery time were 5 ± 2 minutes, 27 ± 9 minutes, and 39 ± 7 minutes, respectively., Conclusions: The ED90 for continuous intraoperative DEX infusion for EA prevention in pediatric patients receiving dental treatment under sevoflurane anesthesia was 0.74 µg/kg/h (95% CI, 0.67-1.05 µg/kg/h)., (Copyright © 2023 International Anesthesia Research Society.)

Purpose of Review: To highlight the recent evidence for antibiotic pharmacokinetics and pharmacodynamics (PK/PD) in enhancing patient outcomes in sepsis and septic shock. We also summarise the limitations of available data and describe future directions for research to support translation of antibiotic dose optimisation to the clinical setting., Recent Findings: Sepsis and septic shock are associated with poor outcomes and require antibiotic dose optimisation, mostly due to significantly altered pharmacokinetics. Many studies, including some randomised controlled trials have been conducted to measure the clinical outcome effects of antibiotic dose optimisation interventions including use of therapeutic drug monitoring. Current data support antibiotic dose optimisation for the critically ill. Further investigation is required to evolve more timely and robust precision antibiotic dose optimisation approaches, and to clearly quantify whether any clinical and health-economic benefits support expanded use of this treatment intervention., Summary: Antibiotic dose optimisation appears to improve outcomes in critically ill patients with sepsis and septic shock, however further research is required to quantify the level of benefit and develop a stronger knowledge of the role of new technologies to facilitate optimised dosing., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Studies have shown that the ideal dose of epidural dexmedetomidine is 0.4 μg mL-1 for epidural labor analgesia. However, the appropriate dose of ropivacaine when combined with 0.4 μg mL-1 of dexmedetomidine for epidural labor analgesia is still unknown. Therefore, we aimed to determine the dose-response of ropivacaine when using 0.4 μg mL-1 of dexmedetomidine as epidural adjuvant for labor analgesia., Methods: One hundred of nulliparous singleton pregnant patients were randomized allocated into 1 of 5 groups with epidural ropivacaine concentration of 0.05%, 0.0625%, 0.075%, 0.0875%, and 0.1%. Labor analgesia was initialed with 12 mL of the mixed study solution. Effective analgesia was defined as a visual analogue scale <10 mm 30 minutes after the initial epidural bolus. The EC50 and EC95 for epidural ropivacaine was calculated by probit regression., Results: Ninety-three of parturients were involved into the final analysis. Totals of 63.2% (12/19), 73.7% (14/19), 88.9% (16/18), 94.7% (18/19), and 100% (18/18) of parturients in group 0.05, 0.0625, 0.075, 0.0875, and 0.1 received effective epidural labor analgesia. The calculated EC50 and EC95 of epidural ropivacaine were 0.046% (95% CI 0.028-0.054%) and 0.086% (95% CI 0.074-0.137%), respectively., Conclusions: Under the condition of the study, a bolus of 12 mL ropivacaine 0.086% and dexmedetomidine 0.4 μg mL-1 could afford 95% of nulliparous singleton pregnant patients without suffering labor pain after a test dose of lidocaine 45 mg., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The relationship between folate intake and risk of endometrial cancer (EC) is debatable. The goal of this study was to examine the relationship between folate consumption and EC and then conduct a dose-response analysis in accordance with this., Methods: Up until February 1, 2024, we conducted a thorough search using PubMed, EMBASE, the Cochrane Library, and Web of Science. Stata 14 software was used to analyze the findings of the article. The study protocol was registered in PROSPERO (CRD42024505943), and the meta-analysis was conducted in accordance with PRISMA guidelines., Results: Nine case-control studies and 6 cohort studies were included, comprising 379,570 participants and 8660 EC cases. The highest level of folate consumption was associated with a 10% reduction in the occurrence of EC (relative risk [RR] = 0.90, 95% confidence intervals [CIs]: 0.78-1.05, I2 = 63.2%) compared to the lowest level of intake. The association exhibited a statistically significant linear trend (P = .231), with a combined RR of 0.974 (95% CI: 0.968-0.981) for each daily intake of 50 µg folate., Conclusion: Folate intake may reduce the risk of EC., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: This study aimed to explore the efficacy of the clonidine adhesive patch for participants with Tourette syndrome (TS)., Methods: This randomized, double-blind, placebo-controlled, multicenter phase IV clinical trial included participants with TS at 20 centers between May 2012 and March 2015. Treatment efficacy at week 8 was the primary outcome. The Clinical Global Impression-Severity scale and Improvement scale were the secondary endpoints., Results: This trial included 488 participants, with 121 participants in the 2.0-mg/wk group, 119 participants in the 1.5-mg/wk group, 126 participants in the 1.0-mg/wk group, and 122 participants in the placebo group. For Yale Global Tic Severity Scale score reduction rate, compared with the placebo group (39.60 ± 25.56), those of the 2.0-mg/wk group (63.21 ± 32.60) and the 1.5-mg/wk group (68.16 ± 25.88) were statistically significantly different (all P < 0.001). For total Yale Global Tic Severity Scale score, compared with the placebo group (17.0 ± 8.03), the score for the 2.0-mg/wk group was 9.9 ± 8.36 ( P < 0.001); 1.5-mg/wk group, 9.6 ± 8.03 ( P < 0.001); and 1.0-mg/wk group, 10.5 ± 9.28 ( P < 0.001). The Clinical Global Impression-Severity scale and Improvement scale scores were statistically significantly different in the 3 clonidine (or experimental) groups compared with the placebo group (all P < 0.001)., Conclusions: Larger doses of the clonidine adhesive patch such as 1.5 and 2.0 mg/wk are effective in improving the symptoms and overall function of participants with TS., Competing Interests: Conflicts of Interest and Source of Funding: J.H. was employed by China National Pharmaceutical Group Shanxi Rfl Pharmaceutical Co Ltd, China. The other authors have no conflicts of interest to declare. This research was supported at the Shanghai Jiaotong University and contracts between China National Pharmaceutical Group Shanxi Rfl Pharmaceutical Co Ltd and Shanghai Mental Health Center. The study drug was provided by the China National Pharmaceutical Group Shanxi Rfl Pharmaceutical Co. Ltd. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for the treatment of children 6-17 years of age with functional constipation (FC). This study evaluated the dose-response, safety, and efficacy of 4 weeks of linaclotide compared with placebo in children 2-5 years of age with FC., Methods: In this phase 2, randomized, double-blind, placebo-controlled, multidose study, 35 children with FC (based on Rome III criteria) were randomized 3:1 to receive linaclotide (18, 36, or 72 μg, for groups 1, 2, and 3, respectively) and 5:1 to receive linaclotide 9, 18, 36, or 72 μg (group 4), or matching placebo. Key endpoints were the changes from baseline in overall spontaneous bowel movement (SBM) frequency (SBMs/week), stool consistency, and straining, as well as the proportion of days with fecal incontinence during the study intervention period. Adverse events (AEs) were recorded., Results: Of the randomized patients, 34 (97.1%) completed the treatment period and 33 (94.3%) completed the posttreatment period. Mean change from baseline over the treatment period for three of the four key efficacy endpoints showed greater improvement in the linaclotide 72 μg group versus placebo. A dose-response trend was seen for stool consistency in patients receiving linaclotide. Four patients randomized to linaclotide experienced treatment-emergent AEs, one of which was treatment-related (mild diarrhea). All AEs were mild or moderate and none were severe., Conclusions: Linaclotide was well tolerated in this pediatric population and an efficacy trend was seen with linaclotide 72 μg versus placebo., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: Multiple studies in patients with Crohn's disease (CD) treated with anti-tumor necrosis factor alpha agents have shown that proactive therapeutic drug monitoring (TDM) during the maintenance phase leads to improved outcomes. We aimed to assess whether accelerated (IFX) administration during induction resulted in improved outcomes., Methods: This retrospective study included CD patients aged 5-17.9 years that were treated with IFX. We compared outcomes of patients treated during induction with 5-8 mg/kg dosing at Weeks 0, 2, 6, and 14 (Group 1), versus accelerated dosing (≥8 mg/kg and/or >4 infusions until Week 14, Group 2) of IFX. Primary outcome was steroid-free clinical remission by Week 52., Results: Sixty-eight patients were included, of whom seven discontinued IFX before Week 14, due to infusion reactions, immunogenic failure, or primary nonresponse. Comparison of Group 1 (n = 25) and Group 2 (n = 36) showed similar clinical characteristics, as well as inflammatory markers, at IFX initiation. Despite receiving significantly more IFX, and reaching a higher trough level by Week 14 (10.3 ± 1.2 vs. 3.3 ± 0.7, p < 0.001), the median Pediatric Crohn's disease Activity Index (PCDAI) was slightly higher in Group 2 versus Group 1 (14 [5-20] vs. 5 [0-15], p = 0.02). However, at Weeks 26 and 52 the PCDAI and inflammatory markers were comparable between the groups. Moreover, about 70% in both groups achieved the desirable trough IFX levels by Week 52., Conclusion: Accelerated IFX dosing during induction did not result in improved outcomes up to 12 months follow-up. Prospective studies are required to determine the exact timing in which proactive TDM should be applied., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objective: Warfarin has a narrow therapeutic window and large variability in dosing that are affected by clinical and genetic factors. To help guide the dosing of warfarin, the Clinical Pharmacogenetics Implementation Consortium has recommended the use of pharmacogenetic algorithms, such as the ones developed by the International Warfarin Pharmacogenetics Consortium (IWPC) and by Gage et al. when genotype information is available., Methods: In this study, simulations were performed in Chinese cohorts to explore how dosing differences between Western (by IWPC and Gage et al.) and Chinese algorithms (by Miao et al.) would mean in terms of anticoagulation effect in clinical trials. We first tried to replicate a published clinical trial comparing genotype-guided dosing to routine clinical dosing in Chinese patients. We then made simulations where Chinese cohorts received daily doses recommended by Gage, IWPC, and Miao algorithms., Results: We found that in simulation conditions where dosing specifications were strictly followed, genotype-guided dosing by IWPC and Lenzini formulae was more likely to overshoot the upper limit of the therapeutic window by day 15, and thus may have a lower % time in therapeutic range (%TTR) than that of clinical dosing group. Also, in comparing Gage, IWPC, and Miao algorithms, we found that the Miao dosing cohort has the highest %TTR and the lowest risk of over-anticoagulation by day 28., Conclusion: In summary, our results confirmed that algorithms developed based on data from local patients may be more suitable for achieving therapeutic international normalized ratio window in Chinese population., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The Trial Remifentanil DEXmedetomidine (TREX) trial aimed to determine whether, in children less than 2 yr old, low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia is superior to standard-dose sevoflurane anesthesia in terms of global cognitive function at 3 yr of age. The aim of the current secondary analyses was to compare incidence of intraoperative hypotension and bradycardia, postoperative pain, time to recovery, need for treatment of intraoperative hypotension and bradycardia, incidence of light anesthesia and need for treatment, need for postoperative pain medications, and morbidity and mortality outcomes at 5 days between the two arms., Methods: This phase III randomized active controlled, parallel group, assessor blinded, multicenter, superiority trial was performed in 20 centers in Australia, Italy, and the United States. A total of 455 infants less than 2 yr of age expected to undergo general anesthesia for at least 2 h were enrolled. They were randomized between low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia and standard-dose sevoflurane. The short-term perioperative outcomes noted above were compared between these two groups., Results: There was less hypotension (risk difference, -11.6%; 95% CI, -18.9 to -4.3%) and more bradycardia (risk difference, 18.2%; 95% CI, 8.8 to 27.7%) in the low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia compared to the standard-dose sevoflurane arm. There were more patients with episodes of light anesthesia (89 vs. 4), and protocol abandonments (1 vs. 0) in the low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia arm. Time from eye opening to postanesthesia care unit discharge was similar in both arms, as were morbidity and mortality. One patient in each arm suffered a life-threatening event, but neither suffered long-term sequelae., Conclusions: These early postoperative results suggest that in children less than 2 yr of age receiving greater than 2 h of general anesthesia, the low-dose sevoflurane/dexmedetomidine/remifentanil anesthesia technique and the standard sevoflurane anesthesia technique are broadly clinically similar, with no clear evidence to support choosing one technique over the other., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists.)

Objectives: To investigate the signal-enhancement properties of the tetrameric gadolinium-based contrast agent (GBCA) gadoquatrane in relation to the administered dose and compare its properties to those of a standard dose of gadobutrol, as a representative of the currently established macrocyclic GBCAs for magnetic resonance imaging., Materials and Methods: In this randomized, single-blind, 4 × 4 crossover study, 43 healthy adults (19-50 years of age) received 3 single IV injections of gadoquatrane (0.01, 0.03, and 0.06 mmol gadolinium/kg body weight) and 1 injection of gadobutrol (0.1 mmol gadolinium/kg body weight) in randomized sequence with 1-week washout periods between administrations. The relative signal enhancement (RSE) was determined in predefined areas of interest in magnetic resonance image sets of the head-neck region. RSE-vs-dose curves (dose-response curves) were established by linear regression, and comparator-equivalent doses were determined by Bayesian inverse regression analysis. Further, 3 blood samples were taken after each injection for pharmacokinetic analyses, and safety data were assessed., Results: The RSE increased with gadoquatrane dose. A linear function adequately fitted this relationship. In line with the more than 2-fold higher r1 relaxivity of gadoquatrane per gadolinium ion, gadobutrol-equivalent RSE was achieved with gadoquatrane at less than half the gadolinium dose and less than one eighth of the molecule dose.Administration of gadoquatrane and gadobutrol resulted in very similar dose-normalized gadolinium concentrations in plasma, indicating that the pharmacokinetic profiles are essentially the same. Both contrast agents were well tolerated. Adverse events were rare and not dependent on the dose administered., Conclusions: Gadoquatrane has the potential to be an effective GBCA that can be used at substantially lower doses in clinical routine than the currently established macrocyclic GBCAs., Competing Interests: Conflicts of interest and sources of funding: The study was sponsored by Bayer AG. All authors are or were working at Bayer AG or on behalf of Bayer AG., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: The drug titration paradox describes that, from a population standpoint, drug doses appear to have a negative correlation with its clinical effect. This paradox is a relatively modern discovery in anesthetic pharmacology derived from large clinical data sets. This review will interpret the paradox using a control engineering perspective., Recent Findings: Drug titration is a challenging endeavor, and the medication delivery systems used in everyday clinical practice, including infusion pumps and vaporizers, typically do not allow for rapid or robust titration of medication being delivered. In addition, clinicians may be reluctant to deviate from a predetermined plan or may be content to manage patients within fixed goal boundaries., Summary: This drug titration paradox describes the constraints of how the average clinician will dose a patient with an unknown clinical response. While our understanding of the paradox is still in its infancy, it remains unclear how alternative dosing schemes, such as through automation, may exceed the boundaries of the paradox and potentially affect its conclusions., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Activated partial thromboplastin time (aPTT) is the standard for monitoring bivalirudin but demonstrates a nonlinear response at higher drug concentrations. The objective of this study was to assess the relationship between bivalirudin dose and aPTT in patients receiving extracorporeal membrane oxygenation (ECMO) to determine a threshold where aPTT unresponsiveness occurs. Two hundred fourteen adults receiving bivalirudin during ECMO between 2018 and 2022 were included. Piecewise regression in a linear mixed effects model was used to determine a bivalirudin dose threshold of 0.21 mg/kg/hr for aPTT unresponsiveness. For doses of less than 0.21 mg/kg/hr (n = 135), every 0.1 mg/kg/hr dose increase led to an aPTT increase of 11.53 (95% confidence interval [CI] = 9.85-13.20) seconds compared to only a 3.81 (95% CI = 1.55-6.06) seconds increase when dose was greater than or equal to 0.21 mg/kg/hr (n = 79) ( pinteraction < 0.001). In multivariable logistic regression, venovenous configuration (odds ratio [OR] = 2.83, 95% CI = 1.38-5.77) and higher fibrinogen concentration (OR = 1.22, 95% CI = 1.05-1.42) were associated with greater odds of unresponsiveness, whereas older age (OR = 0.79, 95% CI = 0.63-0.98), kidney dysfunction (OR = 0.48, 95% CI = 0.25-0.92), and a higher baseline aPTT (OR = 0.89, 95% CI = 0.82-0.97) were associated with lower odds. Alternative methods are necessary to ascertain bivalirudin's hemostatic impact when doses exceed 0.21 mg/kg/hr during ECMO., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

Osimertinib has become the standard of care for epidermal growth factor receptor ( EGFR )-mutated non-small cell lung cancer (NSCLC). In order to prevent or treat toxicity, the osimertinib dose may be reduced. However, data regarding the impact of dose reduction during treatment are limited. We aimed to compare the efficacy of osimertinib early dose reduction during the first 3 months of treatment with late dose reduction in EGFR -mutated advanced NSCLC. This retrospective study included patients with EGFR -mutated advanced NSCLC who received osimertinib. We constituted two groups: 'early dose reduction' (early) with patients receiving a reduced dose of osimertinib from 80 to 40 mg within the 3 months of osimertinib initiation and 'late dose reduction' (late) with patients receiving a reduced dose after 3 months of full-dose treatment. Thirty-five patients were included, with 17 and 18 patients in the early and late groups, respectively, and a higher median age in the early group (76 vs. 67 years). The real-world progression-free survival (rwPFS) at 1 year was 70.5% in the early group and 88.9% in the late group ( P  = 0.31). Median rwPFS was 32.7 and 24.6 months ( P  = 0.98), and the median overall survival was 46.9 versus not reached in early and late groups, respectively ( P  = 0.17). Central nervous system rwPFS was not different between the early and late groups: 29.8 and 35.8 months, respectively ( P  = 0.39). We showed that a reduced dose of osimertinib within the first 3 months of treatment, compared to a later reduced dose, could influence treatment response or patient survival., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The number of trials investigating the effects of deep neuromuscular blockade (NMB) on surgical conditions and patient outcomes is steadily increasing. Consensus on which surgical procedures benefit from deep NMB (a posttetanic count [PTC] of 1 to 2) and how to implement it has not been reached. The European Society of Anaesthesiology and Intensive Care does not advise routine application but recommends use of deep NMB to improve surgical conditions on indication. This study investigates the optimal dosing strategy to reach and maintain adequate deep NMB during total intravenous anesthesia., Methods: Data from three trials investigating deep NMB during laparoscopic surgery with total intravenous anesthesia (n = 424) were pooled to analyze the required rocuronium dose, when to start continuous infusion, and how to adjust. The resulting algorithm was validated (n = 32) and compared to the success rate in ongoing studies in which the algorithm was not used (n = 180)., Results: The mean rocuronium dose based on actual bodyweight for PTC 1 to 2 was (mean ± SD) 1.0 ± 0.27 mg · kg-1 ·h-1 in the trials, in which mean duration of surgery was 116 min. An induction dose of 0.6 mg ·kg-1 led to a PTC of 1 to 5 in a quarter of patients after a mean of 11 min. The remaining patients were equally divided over too shallow (additional bolus and direct start of continuous infusion) or too deep; a 15-min wait after PTC of 0 for return of PTC to 1 or higher. Using the proposed algorithm, a mean 76% of all 5-min measurements throughout surgery were on target PTC 1 to 2 in the validation cohort. The algorithm performed significantly better than anesthesiology residents without the algorithm, even after a learning curve from 0 to 20 patients (42% on target, P ≤ 0.001, Cohen's d = 1.4 [95% CI, 0.9 to 1.8]) to 81 to 100 patients (61% on target, P ≤ 0.05, Cohen's d = 0.7 [95% CI, 0.1 to 1.2])., Conclusions: This study proposes a dosing algorithm for deep NMB with rocuronium in patients receiving total intravenous anesthesia., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Background: Propofol is a widely used intravenous hypnotic. Dosing is based mostly on weight, with great interindividual variation in consumption. Suggested factors affecting propofol requirements include age, sex, ethnicity, anxiety, alcohol consumption, smoking, and concomitant valproate use. Genetic factors have not been widely explored., Methods: This study considered 1,000 women undergoing breast cancer surgery under propofol and remifentanil anesthesia. Depth of anesthesia was monitored with State Entropy (GE Healthcare, Finland). Propofol requirements during surgery were recorded. DNA from blood was genotyped with a genome-wide array. A multivariable linear regression model was used to assess the relevance of clinical variables and select those to be used as covariates in a genome-wide association study. Imputed genotype data were used to explore selected loci further. In silico functional annotation was used to explore possible consequences of the discovered genetic variants. Additionally, previously reported genetic associations from candidate gene studies were tested., Results: Body mass index, smoking status, alcohol use, remifentanil dose (ln[mg · kg-1 · min-1]), and average State Entropy during surgery remained statistically significant in the multivariable model. Two loci reached genome-wide significance (P < 5 × 10-8). The most significant associations were for single-nucleotide polymorphisms rs997989 (30 kb from ROBO3), likely affecting expression of another nearby gene, FEZ1, and rs9518419, close to NALCN (sodium leak channel); rs10512538 near KCNJ2 encoding the Kir2.1 potassium channel showed suggestive association (P = 4.7 × 10-7). None of these single-nucleotide polymorphisms are coding variants but possibly affect the regulation of nearby genes. None of the single-nucleotide polymorphisms previously reported as affecting propofol pharmacokinetics or pharmacodynamics showed association in the data., Conclusions: In this first genome-wide association study exploring propofol requirements, This study discovered novel genetic associations suggesting new biologically relevant pathways for propofol and general anesthesia. The roles of the gene products of ROBO3/FEZ1, NALCN, and KCNJ2 in propofol anesthesia warrant further studies., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Background: Unlike expired sevoflurane concentration, propofol lacks a biomarker for its brain effect site concentration, leading to dosing imprecision particularly in infants. Electroencephalography monitoring can serve as a biomarker for propofol effect site concentration, yet proprietary electroencephalography indices are not validated in infants. The authors evaluated spectral edge frequency (SEF95) as a propofol anesthesia biomarker in infants. It was hypothesized that the SEF95 targets will vary for different clinical stimuli and an inverse relationship existed between SEF95 and propofol plasma concentration., Methods: This prospective study enrolled infants (3 to 12 months) to determine the SEF95 ranges for three clinical endpoints of anesthesia (consciousness-pacifier placement, pain-electrical nerve stimulation, and intubation-laryngoscopy) and correlation between SEF95 and propofol plasma concentration at steady state. Dixon's up-down method was used to determine target SEF95 for each clinical endpoint. Centered isotonic regression determined the dose-response function of SEF95 where 50% and 90% of infants (ED50 and ED90) did not respond to the clinical endpoint. Linear mixed-effect model determined the association of propofol plasma concentration and SEF95., Results: Of 49 enrolled infants, 44 evaluable (90%) showed distinct SEF95 for endpoints: pacifier (ED50, 21.4 Hz; ED90, 19.3 Hz), electrical stimulation (ED50, 12.6 Hz; ED90, 10.4 Hz), and laryngoscopy (ED50, 8.5 Hz; ED90, 5.2 Hz). From propofol 0.5 to 6 μg/ml, a 1-Hz SEF95 increase was linearly correlated to a 0.24 (95% CI, 0.19 to 0.29; P < 0.001) μg/ml decrease in plasma propofol concentration (marginal R2 = 0.55)., Conclusions: SEF95 can be a biomarker for propofol anesthesia depth in infants, potentially improving dosing accuracy and utilization of propofol anesthesia in this population., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Background: Nonopioid management of postsurgical pain remains a major unmet need. Few studies have evaluated transient receptor potential vanilloid subfamily member 1 agonists for analgesia after surgery. This study examines intraoperative vocacapsaicin, a novel prodrug of the transient receptor potential vanilloid subfamily member 1 agonist capsaicin, in a validated model of postsurgical pain., Methods: This was a triple-blinded, randomized, placebo-controlled, dose-ranging trial in patients undergoing bunionectomy. Patients were randomized 1:1:1:1 to surgical site administration of 14 ml of placebo or one of three vocacapsaicin concentrations: 0.30, 0.15, or 0.05 mg/ml. The prespecified primary endpoint was the area-under-the-curve of the numerical rating scale pain score at rest through 96 h for the 0.30 mg/ml group. Prespecified ordered, secondary endpoints for the 0.30 mg/ml group included the percentage of patients who did not require opioids from 0 to 96 h, total opioid consumption through 96 h, and the area-under-the-curve of the numerical rating scale pain score for the first week., Results: The 147 patients were randomized. During the first 96 h, vocacapsaicin (0.30 mg/ml) reduced pain at rest by 33% versus placebo (primary endpoint, 95% CI [10%, 52%], effect size [Cohen's d] = 0.61, P = 0.005). Of patients receiving vocacapsaicin (0.30 mg/ml), 26% did not require postoperative opioids for analgesia (P = 0.025) versus 5% of patients receiving placebo. Vocacapsaicin (0.30 mg/ml) reduced opioid consumption over the first 96 h by 50% versus placebo (95% CI [26%, 67%], effect size = 0.76, P = 0.002). Vocacapsaicin (0.30 mg/ml) reduced pain over the first week by 37% versus placebo (95% CI [12%, 57%], effect size = 0.62, P = 0.004). The treatment effect persisted for at least 2 weeks. All study endpoints showed an administered concentration-versus-response relationship. Vocacapsaicin was well tolerated with no differences between groups in any safety parameter., Conclusions: A single, local administration of vocacapsaicin during surgery reduced pain and opioid consumption for at least 96 h after surgery compared to control., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists.)

Background: Remimazolam, a recently developed anesthetic characterized by its rapid and ultra-short-acting properties, exhibits pharmacological attributes that make it potentially suitable for painless surgical abortion procedures. The objective of this study was to determine the effective dose of remimazolam when administered in combination with sufentanil, with the intention of inhibiting body movement during surgical abortion. Additionally, a secondary objective was to assess the recovery profile from general anesthesia., Methods: The study enrolled a total of 25 healthy women aged 20 to 40, with a body mass index between 18 and 28 kg/m2, in their first trimester of pregnancy (up to 12 weeks), and American Society of Anesthesiologists status I and II. Anesthesia induction was initiated by administering sufentanil at a dose of 0.1 μg/kg. The modified Dixon up-and-down method was employed to determine the induction dose of remimazolam for each patient., Results: The 50% and 95% effective dose of remimazolam for inhibitory effects of body movement was estimated using centered isotonic regression to be 0.145 mg/kg (95% CI: 0.115, 0.207), and 0.242 mg/kg (95% CI: 0.232, 0.620), respectively. Five out of 25 (20%) experienced hiccups, with 1 patient having persistent hiccups until the end of the surgery. The mean time to first eye-opening was 51.4 ± 20.5 seconds, and the time to obey verbal command was 54.5 ± 20.6 seconds. Upon arrival at the postanesthesia care unit, 95.7% of the patients achieved a Modified Aldrete score ≥ 9., Conclusions: The 50% and 95% effective dose of remimazolam for inhibiting body movement during surgical abortion when used in combination with 0.1 μg/kg of sufentanil were 0.145 mg/kg and 0.242 mg/kg, respectively., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: Dr. Karamchandani received funding from Philips Healthcare and Eagle Pharmaceuticals. Dr. Jabaley has disclosed that he does not have any potential conflicts of interest.

Background: Polyphosphate (polyP), a procoagulant released from platelets, activates coagulation via the contact system and modulates cardiomyocyte viability. High-dose intravenous polyP is lethal in mice, presumably because of thrombosis. Previously, we showed that HRG (histidine-rich glycoprotein) binds polyP and attenuates its procoagulant effects. In this study, we investigated the mechanisms responsible for the lethality of intravenous polyP in mice and the impact of HRG on this process., Methods: The survival of wild-type or HRG-deficient mice given intravenous synthetic or platelet-derived polyP in doses up to 50 mg/kg or saline was compared. To determine the contribution of thrombosis, the effect of FXII (factor XII) knockdown or enoxaparin on polyP-induced fibrin deposition in the lungs was examined. To assess cardiotoxicity, the ECG was continuously monitored, the levels of troponin I and the myocardial band of creatine kinase were quantified, and the viability of a cultured murine cardiomyocyte cell line exposed to polyP in the absence or presence of HRG was determined., Results: In HRG-deficient mice, polyP was lethal at 30 mg/kg, whereas it was lethal in wild-type mice at 50 mg/kg. Although FXII knockdown or enoxaparin administration attenuated polyP-induced fibrin deposition in the lungs, neither affected mortality. PolyP induced dose-dependent ECG abnormalities, including heart block and ST-segment changes, and increased the levels of troponin and myocardial band of creatine kinase, effects that were more pronounced in HRG-deficient mice than in wild-type mice and were attenuated when HRG-deficient mice were given supplemental HRG. Consistent with its cardiotoxicity, polyP reduced the viability of cultured cardiomyocytes in a dose-dependent manner, an effect attenuated with supplemental HRG., Conclusions: High-dose intravenous polyP is cardiotoxic in mice, and HRG modulates this effect., Competing Interests: Disclosures J. Crosby and A.S. Revenko are employees of Ionis Pharmaceuticals. J.I. Weitz has served as a consultant and has received honoraria from Alnylam, Anthos, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Pfizer, Regeneron, and Servier. The other authors report no conflicts.

Abstract: Objective: To explore the effect of a stratified dose of norepinephrine (NE) on cellular immune response in patients with septic shock, and to construct a prognostic model of septic shock. Methods: A total of 160 patients with septic shock (B group) and 58 patients with sepsis (A group) were given standard cluster therapy. Patients with septic shock were divided into four groups (B1-B4 groups: 0.01-0.2, 0.2-0.5, 0.5-1.0, and >1 μg/kg/min) according to the quartile method of the early (72 h) time-weighted average dose of NE and clinical application. The cellular immune indexes at 24 h (T0) and 4-7 days (T1) after admission were collected. The difference method was used to explore the effect of NE stratified dose on cellular immune effect in patients with septic shock. A multivariate COX proportional risk regression model was used to analyze the independent prognostic risk factors, and a prognostic risk model was constructed. Results: The differences of ΔIL-1β, ΔIL-6, ΔIL-10, absolute value difference of T lymphocyte (ΔCD3+/CD45+#) and Th helper T cell (ΔCD3+ CD4+/CD45+#), CD64 infection index difference, ΔmHLA-DR, regulatory T lymphocyte ratio difference (ΔTregs%) between group A, B1, B2, B3, and B4 were statistically significant ( P < 0.05). There was a nonlinear relation between the stratified dose of NE and ΔIL-6, ΔIL-10, ΔCD3+/CD45+#, ΔmHLA-DR%. The threshold periods of NE-induced proinflammatory and anti-inflammatory immune changes were 0.3-0.5 μg/kg/min. Multivariate COX model regression analysis showed that age, nutritional patterns, weighted average dose of norepinephrine, IL-6, absolute value of T lymphocytes, and mHLA-DR were independent risk factors affecting the prognosis of patients with septic shock ( P < 0.05). The prognostic risk model was constructed (AUC value = 0.813, 95% CI: 0.752-0.901). Conclusion: NE has a certain inhibitory effect on cellular immune function in patients with septic shock. A prognostic risk model was constructed with stronger prediction efficiency for the prognosis of patients with septic shock., Competing Interests: Conflicts of Interest: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2024 by the Shock Society.)

Objective: The aim of the study is to evaluate the safety of onabotulinumtoxinA treatment for spasticity across dose ranges in real-world practice., Design: Adult Spasticity International Registry was a multicenter, prospective, observational study (NCT01930786) of onabotulinumtoxinA treatment for adult spasticity over 2 yrs. Adverse events, serious adverse events, treatment-related adverse events, and serious treatment-related adverse events were sorted into five categories (≤200, 201-400, 401-600, 601-800, ≥801 U) based on cumulative dose per session., Results: In 3103 treatment sessions ( T ), 730 patients received ≥1 dose of onabotulinumtoxinA. Dose categories included the following: ≤200 U ( n = 312, T = 811), 201-400 U ( n = 446, T = 1366), 401-600 U ( n = 244, T = 716), 601-800 U ( n = 69, T = 149), and ≥801 U ( n = 29, T = 61). Of these patients, 261 reported 827 adverse events, 94 reported 195 serious adverse events, 20 reported 23 treatment-related adverse events, and 2 patients treated with 201-400 U onabotulinumtoxinA reported 3 serious treatment-related adverse events. Treatment-related adverse events reported included ≤200 U (8/811, 0.9%), 201-400 U (7/1366, 0.5%), 401-600 U (6/716, 0.8%), 601-800 U (1/149, 0.7%), and ≥801 U (1/61, 1.6%)., Conclusions: In this post hoc analysis, most treatment sessions were performed with 201-400 U onabotulinumtoxinA. Patients treated with 201-400 U onabotulinumtoxinA had an adverse event profile consistent with onabotulinumtoxinA package inserts globally (e.g., United States, European Union, United Kingdom, Canada). No new safety signals were identified., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Botulinum toxin A to the glabella is a popular cosmetic intervention. Functional musculature differences may arise from chronic behavioral adjustment to high sun exposure levels, requiring greater doses. This could affect clinical practice globally. This study investigated the effect of climate on real-world doses., Methods: The authors conducted a comparative cohort study using data from a registry from a single provider practicing across two centers: the United Kingdom and Malta. They classified one center as low sun exposure (United Kingdom winter month treatment) and the other as high sun exposure (Malta summer months). Patients were followed up once every 3 weeks and received top-up doses until full clinical paralysis was achieved. To standardize the comparison, the study included only women aged 35 to 60 years undergoing glabellar botulinum toxin treatment by experienced clinicians following standard procedures from 2012 to 2019. Smokers, those not seeking maximal paralysis, those documented as not compliant with posttreatment advice, those with colds or fevers, and those with broken cold supply chains were excluded. Univariable and multivariable analyses were undertaken., Results: A total of 523 patients were included: 292 "high-sun" patients and 231 "low-sun" patients. Mean total doses were significantly higher in the high-sun group (29.2 units versus 27.3 units; P = 0.0031). When correcting for age in multivariable analysis, the low-sun group still had lower total dose requirements ( P = 0.00574)., Conclusion: Patients injected with glabellar botulinum toxin in high-sun climates may have significantly increased dose requirements to achieve maximal paralysis., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: Sildenafil, approved for pulmonary arterial hypertension (PAH), has a recommended adult dose of 20 mg TID, with a previously approved 5-mg TID dose by the US Food and Drug Administration. Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality. To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH., Methods: This randomized, double-blind study compared sildenafil at doses of 5, 20, or 80 mg TID in adults with PAH. The primary objective was noninferiority of 80 mg of sildenafil versus 5 mg for all-cause mortality. Secondary end points included time to clinical worsening and change in 6-minute walk distance at 6 months. Interim analyses were planned at 50% and 75% of the anticipated mortality events. Safety and tolerability were assessed in the intention-to-treat population., Results: The study was halted after the first interim analysis, demonstrating noninferiority for 80 mg of sildenafil versus 5 mg. Of 385 patients enrolled across all dose groups, 78 died. The primary analysis showed a hazard ratio of 0.51 (99.7% CI, 0.22-1.21; P <0.001 for noninferiority) for overall survival comparing 80 mg of sildenafil with 5 mg. Time to clinical worsening favored 80 mg of sildenafil compared with 5 mg (hazard ratio, 0.44 [99.7% CI, 0.22-0.89]; P <0.001). Sildenafil at 80 mg improved 6-minute walk distance from baseline at 6 months compared with 5 mg (least square mean change, 18.9 m [95% CI, 2.99-34.86]; P =0.0201). No significant differences were found between 80 mg of sildenafil and 20 mg in mortality, clinical worsening, and 6-minute walk distance. Adverse event-related drug discontinuations were numerically higher with 80 mg of sildenafil., Conclusions: Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of sildenafil over 5 mg. On the basis of these findings, the Food and Drug Administration recently revoked the approval of 5 mg of sildenafil for adults with PAH, reinforced 20 mg TID as the recommended dose, and now allows dose titration up to 80 mg TID, if needed., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487., Competing Interests: Disclosures M.M.H. is a paid consultant and speaker of pharmaceutical companies including Actelion, Acceleron, AOP Health, Bayer, Ferrer, Gossamer, Janssen, Keros, and MSD. R.E. is a paid consultant for advisory boards and scientific lectures from Janssen, Boehringer Ingelheim, AOP, United Therapeutic, Novartis, AstraZeneca, and OMT. P.J. is a paid consultant and speaker for numerous pharmaceutical companies and has received financial grant for Janssen Pharmaceutical Companies of Johnson & Johnson, AOP Orphan, Bayer Healthcare, MSD, and Arena Pharmaceuticals Inc. Y.S. is an employee of NSC MD Strazhesko Institute of Cardiology, Clinical and Regenerative Medicine of the National AMS of Ukraine. A.S. is a paid consultant of pharmaceutical companies including Gossamer Bio, AOP Orphan, and Medison Pharma, and is paid as a speaker for KRKA, Altavant Sciences. C.B. is currently employee of Pfizer and hold stocks in Pfizer and Viatris. S. Hackley is a former employee of Pfizer and current employee of Viatris and hold stocks in Viatris. S.V. is an employee of MEDA Pharma GmbH & Co KG (A Viatris Company). P.A. hold shares of Pfizer. S. Haughie hold stocks in Viatris. T.H. is currently employee of Viatris and hold stocks of Viatris. R.J.O. is a principal investigator in studies and attends ad hoc advisory boards sponsored by Aerovate, Gossamer Bio, Janssen, Keros, Merck, and United Therapeutics. He is a paid speaker for Janssen and United Therapeutics.

Purpose: The goal of this study was to evaluate the dose-response relationship between dexmedetomidine and propofol in sedating patients and to determine the optimal dosage of dexmedetomidine during gastrointestinal endoscopy., Methods: One hundred fifty patients were divided into 5 groups, each receiving a loading dose of dexmedetomidine (0.4, 0.6, 0.8, 1.0 µg/kg) or saline, with propofol for sedation. The median effective concentration (EC50) of propofol was calculated using the modified Dixon up-and-down approach. Adverse effects, vital signs, procedure, and recovery times were recorded., Results: The EC50 of propofol in groups NS, D0.4, D0.6, D0.8, and D1.0 were 3.02, 2.44, 1.97, 1.85, and 1.83 µg/mL, respectively. Heart rate in the dexmedetomidine groups decreased more than the NS group (P < .001). The mean arterial pressure (MAP) in the NS group experienced a decline compared to groups D0.8 and D1.0 when the plasma concentration and effect-site concentration reached equilibrium. Additionally, the respiratory rate was found to be lower in groups NS, D0.4, D0.6, and D0.8 (P < .05). Recovery time in groups D0.8 and D1.0 was longer than the NS group (P < .05). Bruggemann comfort scales score was higher in group D1.0 (P < .05). No significant difference was found in the incidences of hypotension and bradycardia, and the dose of ephedrine and atropine. Respiratory depression was significantly reduced in groups D0.8 and D1.0 compared to the NS group., Conclusion: A single dose of 0.6 to 0.8 µg/kg of dexmedetomidine should be recommended in combination with propofol for gastrointestinal endoscopy. And the EC50 of propofol is 1.97 to 1.85 µg/mL., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations., Methods: A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia., Results: A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses., Conclusions: The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Tocilizumab in the treatment of rheumatoid arthritis (RA) is a potential candidate for concentration-guided tapering because the standard dose of tocilizumab results in a wide range of serum concentrations, usually above the presumed therapeutic window, and an exposure-response relationship has been described. However, no clinical trials have been published to date on this subject. Therefore, the objective of this study was to assess the feasibility of the tapering of intravenous (iv) tocilizumab with the use of a pharmacokinetic model-based algorithm in RA patients., Methods: A randomized controlled trial with a double-blind design and follow-up of 24 weeks was conducted. RA patients who received the standard of tocilizumab for at least the past 24 weeks, which is 8 mg/kg every 4 weeks, were included. Patients with a tocilizumab serum concentration above 5 mg/L at trough were randomized between concentration-guided dose tapering, referred to as therapeutic drug monitoring (TDM), or the standard 8 mg/kg dose. In the TDM group, the tocilizumab dose was tapered with a recently published model-based algorithm to achieve a target concentration of 4-6 mg/L after 20 weeks of dose tapering., Results: Twelve RA patients were included and 10 were randomized between the TDM and standard dose group. The study was feasible regarding the predefined feasibility criteria and patients had a positive attitude toward therapeutic drug monitoring. In the TDM group, the tocilizumab trough concentration within patients decreased on average by 24.5 ± 18.3 mg/L compared with a decrease of 2.8 ± 12 mg/L in the standard dose group. None of the patients in the TDM group reached the drug range of 4-6 mg/L. Instead, tocilizumab concentrations of 1.6 and 1.5 mg/L were found for the 2 patients who completed follow-up on the tapered dose. No differences in RA disease activity were observed between the 2 study groups., Conclusions: This study was the first to show that it is feasible to apply a dose-reduction algorithm based on a pharmacokinetic model in clinical practice. However, the current algorithm needs to be optimized before it can be applied on a larger scale., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Obesity is associated with an increased risk of cancers, such as breast cancer. Roux-en-Y gastric bypass (RYGB) is a common surgical intervention used to induce weight loss, reduce comorbidities, and improve overall survival. Due to alterations in the gastrointestinal tract, RYGB is associated with changes in oral drug disposition, which can affect treatment outcomes. Oral antihormonal agents were monitored in 9 patients who previously underwent RYGB. The results of therapeutic drug monitoring and estradiol concentrations were analyzed, and a review of the relevant literature was performed. As only 1 of the 6 patients prescribed tamoxifen achieved a therapeutic endoxifen concentration with the standard dose of 20 mg/d, a higher starting dose of 40 mg/d was recommended to increase the probability of attaining a therapeutic plasma concentration. All patients with decreased CYP2D6 metabolic activity could not achieve therapeutic plasma concentrations; therefore, CYP2D6 genotyping was recommended before the initiation of tamoxifen therapy to identify patients who should be switched to aromatase inhibitors. Anastrozole and letrozole exposure in patients who underwent RYGB patients appeared sufficient, with no dose adjustment required. However, until more data become available, monitoring aromatase inhibitor efficacy is recommended. Monitoring the drug concentrations is a viable option; however, only indicative data on therapeutic drug monitoring are available. Therefore, estradiol concentrations should be measured., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response., Methods: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. The authors conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics., Results: Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/ml at low and high dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/ml at low and high dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47 ± 0.20 µg/ml. The steady state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51 ± 0.04 µg/ml. A concentration of 1 µg/ml ENA-001 was required for full reversal of the propofol effect at the propofol concentration that reduced the hypoxic ventilatory response by 50%., Conclusions: In this pilot study, the authors demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Objective: We aim to develop a personalized dosing tool for tricyclic antidepressants (TCAs) that integrates CYP2D6 and CYP2C19 gene variants and their effects while also considering the polypharmacy effect., Methods: The study first adopted a scoring system that assigns weights to each genetic variant. A formula was then developed to compute the effect of both genes' variants on drug dosing. The output of the formula was assessed by a comparison with the clinical pharmacogenetics implementation consortium recommendation. The study also accounts for the effect of the co-administration of inhibitors and inducers on drug metabolism. Accordingly, a user-friendly tool, Clinical Dosing Tool ver.2, was created to assist clinicians in dosing patients on TCAs., Results: The study provides a comprehensive list of all alleles with corresponding activity values and phenotypes for both enzymes. The tool calculated an updated area under the curve ratio that utilizes the effects of both enzymes' variants for dose adjustment. The tool provided a more accurate individualized dosing that also integrates the polypharmacy effect., Conclusion: To the best of our knowledge, the literature misses such a tool that provides a numerical adjusted dose based on continuous numerical activity scores for the considered patients' alleles and phenoconversion., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This study aimed to investigate the prognostic relationship between relative dose intensity (RDI) of adjuvant S-1 chemotherapy and psoas muscle mass volume (PMV) in patients with resected pancreatic ductal adenocarcinoma. We enrolled 105 patients with histologically confirmed pancreatic ductal adenocarcinoma who had undergone pancreatectomy. Adjuvant S-1 chemotherapy was administered to 72 (68.6%) of the 105 patients and not to the remaining 33 patients. Patients who received adjuvant S-1 chemotherapy were stratified into high- and low-RDI groups by the cutoff value for RDI. Five-year overall survival (OS) and relapse-free survival (RFS) rates were significantly higher in the high- than in the low-RDI group. Similarly, both the 5-year OS and RFS rates were significantly greater among patients in the high-PMV group than among patients in the low-PMV group. The RDI was an independent prognostic factor in our study patients. Furthermore, patients who received adjuvant S-1 chemotherapy were stratified into 3 groups: those with both high RDI and high-PMV, Group A; those with either high RDI or high PMV (but not both), Group B; and those with both low RDI and low-PMV, group C. There were statistically significant differences in 5-year OS and RFS between 3 patient groups (5-year overall survival: P = .023, 5-year relapse-free survival: P = .001). The area under the curve for the combination of RDI and PMV (0.674) was greater than that for RDI alone (0.645). A sufficient dosage of adjuvant S-1 chemotherapy is important in improving survival of patients with resected pancreatic ductal adenocarcinoma. A combination of RDI and PMV may predict the prognosis of patients with resected pancreatic ductal adenocarcinoma more effective than RDI alone., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Infants undergoing magnetic resonance imaging (MRI) often require pharmacological sedation. Dexmedetomidine serves as a novel sedative agent that induces a unique unconsciousness similar to natural sleep, and therefore has currently been used as the first choice for sedation in infants and young children., Objective: To determine the 50% effective dose (ED50) and 95% confidence interval (95%CI) of intranasal dexmedetomidine for MRI in preterm and term infants, and to observe the incidence of adverse events. To explore whether there were differences in ED50 and 95%CI, heart rate (HR) and blood oxygen saturation (SpO2), the induction time and wake-up time and the incidence of adverse events between the 2 groups, so as to provide guidance for clinical safe medication for the meanwhile., Methods: A total of 68 infants were prospectively recruited for MRI examination under drug sedation (1 week ≤ age ≤ 23 weeks or weight ≤ 5kg). The children were divided into 2 groups according to whether they had preterm birth experience (Preterm group, Atterm group). The Dixon up-and-down method was used to explore ED50. The basic vital signs of the 2 groups were recorded, and the heart rate and SpO2 were recorded every 5 minutes until the infants were discharged from the hospital. The induction time, wake-up time and adverse events were recorded., Results: The ED50 (95%CI) of intranasal dexmedetomidine in the Preterm group and the Atterm group were 2.23 (2.03-2.66) μg/kg and 2.64 (2.49-2.83) μg/kg, respectively (P < .05). the wake-up time was longer in Preterm group (98.00min) than in Atterm group (81.00 min) (P < .05), the incidence of bradycardia in Preterm group was 3/33, which was higher than that in Atterm group (1/35). There was no difference in the induction time between the 2 groups (P > .05), and there was no significant difference in other adverse events., Conclusions: Intranasal dexmedetomidine can be safely used for sedation in preterm infants undergoing MRI. Compared with term infants, preterm infants have a lower dose of dexmedetomidine, a higher incidence of bradycardia, and a longer weak-up time., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for treatment of children 6-17 years old with functional constipation (FC). This study evaluated the safety and efficacy of several linaclotide doses in children 6-17 years old with FC., Methods: In this multicenter, randomized, double-blind, placebo-controlled phase 2 study, 173 children with FC (based on Rome III criteria) were randomized to once-daily linaclotide (A: 9 or 18 μg, B: 18 or 36 μg, or C: 36 or 72 μg) or placebo in a 1:1:1:1 ratio for 6- to 11-year-olds (dosage determined by weight: 18 to <35 or ≥35 kg) and linaclotide (18, 36, 72, or 145 μg) or placebo in a 1:1:1:1:1 ratio for 12- to 17-year-olds. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency throughout the 4-week treatment period. Adverse events (AE), clinical laboratory values, and electrocardiograms were monitored., Results: Efficacy and safety were assessed in 173 patients (52.0% aged 6-11 years; 48.0% aged 12-17 years); 162 (93.6%) completed the treatment period. A numerical improvement in mean SBM frequency was observed with increasing linaclotide doses (1.90 in 6- to 11-year-olds [36 or 72 μg] and 2.86 in 12- to 17-year-olds [72 μg]). The most reported treatment-emergent AE was diarrhea, with most cases being mild; none were severe., Conclusions: Linaclotide was well tolerated in this pediatric population, with a trend toward efficacy in the higher doses, warranting further evaluation., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Benign masseteric hypertrophy (BMH) is a condition in which the thickness of the masseter muscle is increased, resulting in jawline prominence with an undesirable cosmetic appearance. Botulinum toxin type A (BTA) injection is a promising treatment option, but its effective dose remains debated., Methods: Adults older than 19 diagnosed with BMH through visual examination and palpation related to a masseter muscle prominence were selected, and 80 patients were randomly assigned into five groups (placebo group and four groups with different doses of BTA: 24 U, 48 U, 72 U, or 96 U, on both sides of the jaw) and treated with placebo or BTA once at their baseline visit. During each follow-up, the treatment efficacy was evaluated with ultrasound examination of the masseter muscle, three-dimensional facial contour analysis, visual evaluation by the investigator, and patient satisfaction evaluation., Results: The mean age of the 80 patients was 42.7 ± 9.98 years; 68.75% were women. The mean change in masseter muscle thickness during the maximum clenching state after 12 weeks of drug administration compared with baseline in the 24-U, 48-U, 72-U, and 96-U groups were -2.33 ± 0.41 mm, -3.35 ± 0.42 mm, -2.86 ± 0.42 mm, and -3.79 ± 0.42 mm, respectively. All treatment groups showed a statistically significant decrease compared with placebo. Regarding subjective satisfaction, all treatment groups, except the 24-U group at 4 weeks, showed higher satisfaction than the placebo group during all visits. No significant adverse events were noted., Conclusion: BTA administration of at least 48 U for BMH is more cost-effective than high-dose units and has a low risk of side effects., Clinical Question/level of Evidence: Therapeutic, II., (Copyright © 2023 by the American Society of Plastic Surgeons.)

To explore the anticoagulant effect and safety of utilizing different doses of rivaroxaban for the treatment of patients with atrial fibrillation (AF) in the real world. A retrospective case-control analysis was performed by applying the hospital database, and 3595 patients with non-valvular atrial fibrillation (NVAF) who were hospitalized and taking rivaroxaban at Wuhan Asia Heart Hospital and Wuhan Asia General Hospital from March 2018 to December 2021 were included in the study, and were divided into the rivaroxaban 10 mg and 15 mg groups according to the daily prescribed dose, of which 443 cases were in the 10 mg group and 3152 cases were in the 15 mg group. The patients were followed up regularly, and the incidence of thrombotic events, bleeding events and all-cause deaths were recorded and compared between the 2 groups, and logistic regression was applied to analyze the influencing factors for the occurrence of adverse events. Comparison of the incidence of thrombosis, bleeding and all-cause death between the 2 groups of patients showed that the 10 mg group was higher than the 15 mg group, but the difference was not statistically significant (χ2 = 0.36, 3.26, 1.99, all P > .05); the incidence of total adverse events between the 2 groups of patients was higher in the 10 mg group than in the 15 mg group, with a statistically significant difference (χ2 = 4.53, P = .033); multifactorial logistic regression results showed that age [OR (95% CI) = 1.02 (1.00-1.04)], diabetes mellitus [OR (95% CI) = 1.69 (1.09-2.62)], D-dimer level [OR (95% CI) = 1.06 (1.00-1.11)] and persistent AF [OR (95% CI) = 1.54 (1.03-2.31)] were risk factors for adverse events (P < .05). In the real world, Asian clinicians recommend rivaroxaban 10 mg once daily for NVAF patients for a variety of reasons; however, this dose is not superior or even inferior to the 15 mg group in terms of effectiveness and safety. Advanced age, elevated D-dimer levels, history of diabetes mellitus, and persistent AF are risk factors for adverse events, and the optimal dosage of rivaroxaban or optimal anticoagulation strategy for Asian patients with nonvalvular AF requires further study., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Therapeutic drug monitoring of clozapine in children and adolescents has received insufficient attention. Calculation of concentration-to-dose (C/D) ratios from trough steady-state concentrations estimate drug clearance., Methods: A systematic electronic literature search was conducted in 3 article databases from inception until January 10, 2023, and articles reporting clozapine concentrations in children and adolescents were retrieved. The pharmacokinetic quality of the studies was assessed, and clozapine C/D ratios were calculated using the sample mean clozapine dose and concentration., Results: Of the 37 articles of potential interest, only 7 reported clozapine trough and steady-state concentrations. After excluding case reports and a study confounded by fluvoxamine, 4 studies on psychosis from Europe and the United States were included. The clozapine C/D ratios were similar to published adult values and ranged from 0.82 to 1.24 with a weighted mean of 1.08 ng/mL per mg/d. The weighted means were 334 mg/d for the dose and 380 ng/mL for the concentration. The stratified analysis of the weighted mean clozapine C/D ratios from 2 studies showed lower values in 52 male (1.05 ng/mL per mg/d) than in 46 female (1.46 ng/mL per mg/d) children and adolescents, with values similar to those reported for European adult nonsmokers. Two female adolescents had high clozapine C/D ratios (2.54 ng/mL per mg/d), an Asian American patient with borderline obesity and a patient with intellectual disability with low dosage (mean = 102 mg/d) and concentration (mean = 55 ng/mL)., Conclusions: Reports on clozapine therapeutic drug monitoring in children and adolescents are limited in number and quality. Future studies should focus on basic pharmacokinetic issues, such as stratification by sex, smoking, and relevant comedications with inductive or inhibitory properties., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Objectives: Lasmiditan holds important potential in treating migraine, but its ideal dose remains elusive. This meta-analysis is conducted based on aggregate data and aims to compare the efficacy of lasmiditan 200 mg versus 100 mg for acute treatment of migraine attack., Methods: PubMed, Embase, Web of Science, EBSCO, and Cochrane Library databases were systematically searched, and we included the randomized controlled trials comparing the efficacy of lasmiditan 200 mg versus 100 mg for migraine patients. This meta-analysis was conducted using the random-effect model or fixed-effect model based on the heterogeneity. The primary outcome was pain free at 2 hours. Secondary outcomes included pain relief at 2 hours, pain free at 24 hours, most bothersome symptom free at 2 hours, and adverse events., Results: Seven randomized controlled trials and 6515 patients were included in this meta-analysis. Compared with lasmiditan 100 mg for migraine patients, lasmiditan 200 mg was able to significantly improve pain free at 2 hours (odd ratio [OR], 1.28; 95% confidence interval [CI], 1.14-1.44; P < 0.0001) and pain free at 24 hours (OR, 1.35; 95% CI, 1.14-1.60; P = 0.0005), but showed no effect on pain relief at 2 hours (OR, 1.00; 95% CI, 0.90-1.12; P = 0.98) or most bothersome symptom free at 2 hours (OR, 0.93; 95% CI, 0.83-1.03; P = 0.17). Lasmiditan 200 mg was associated with the increase in adverse events compared with lasmiditan 100 mg (OR, 1.28; 95% CI, 1.15-1.43; P < 0.0001)., Conclusions: Lasmiditan 200 mg is more effective to improve pain free at 2 hours and 24 hours than lasmiditan 100 mg for the acute treatment of migraine patients., Competing Interests: Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Gadolinium-based contrast agents (GBCAs) are indispensable in contrast-enhanced magnetic resonance imaging. A higher risk of gadolinium deposition in linear GBCAs required the introduction of macrocyclic GBCAs with a stable molecular structure. We conducted the first-in-human study to evaluate the safety, tolerability, and pharmacokinetics (PKs) of HNP-2006, a novel macrocyclic GBCA, in healthy male subjects., Materials and Methods: A randomized, placebo-controlled, double-blind, single-ascending dose study was conducted. Subjects received either a single intravenous bolus injection of HNP-2006 or its matching placebo with a treatment-to-placebo ratio of 6:2 at the dose level of 0.02, 0.05, 0.1, 0.2, and 0.3 mmol/kg. Safety was assessed through routine clinical assessments. Blood sampling and urine collection were performed up to 72 hours postdose for PK assessments. Noncompartmental methods were used to calculate PK parameters, and a population PK model was constructed., Results: Overall, 40 subjects completed the study. Fourteen subjects reported 22 treatment-emergent adverse events (TEAEs). The severity of all TEAEs was mild, and the HNP-2006 dose was associated with the incidence of TEAEs. The most common TEAEs included nausea and dizziness, which occurred within an hour of administration. HNP-2006 was rapidly eliminated by urinary excretion with a half-life of 1.8-2.0 hours and showed a dose-proportional PK. A 2-compartment model had the best fit with the population PK analysis., Conclusions: A single intravenous dose of HNP-2006 was well-tolerated and safe up to 0.30 mmol/kg. HNP-2006 was rapidly excreted in urine and exhibited dose-independent PK profiles., Competing Interests: Conflicts of interest and sources of funding: The study was supported by Hana Pharm Co, Ltd, Seoul, South Korea. H.L. is the employee of Hana Pharm Co, Ltd. The other authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim of this study was to evaluate the pharmacokinetics and safety profile of MT218, a peptide-targeted gadolinium-based contrast agent, in healthy males., Materials and Methods: This was a double-blind, randomized, placebo-controlled, single-ascending-dose study including 30 healthy male subjects. In each dose group (0.01, 0.02, 0.04, and 0.08 mmol/kg), 4 subjects received MT218 and 2 subjects received placebo (saline) in bolus injections. The highest dose group (0.08 mmol/kg) was assessed in 2 cohorts, 1 fasted and 1 nonfasted. Clinical laboratory tests, vital signs, and electrocardiograms were investigated. Gadolinium concentrations were measured in plasma samples collected before administration and over a 24-hour period postinjection, and in urine specimens collected until 22 days. A noncompartmental model was used for pharmacokinetic analysis. A clinical and biological safety follow-up was carried out for up to 6 months., Results: No clinically significant modifications in biochemistry, hematology, urinalysis, electrocardiogram parameters, or vital signs were reported at any time point for any treatment group. No serious adverse events were observed in any dose group. Transient dizziness, hyperhidrosis, and injection site coldness were the main adverse events reported in both the MT218 and placebo groups. The mean total apparent clearance decreased slightly with increasing dose, and the median plasma t 1/2 ranged from 1.7 hours in the 0.01 mmol/kg group to 2.7 hours in the 0.08 mmol/kg nonfasted group. MT218 was rapidly excreted via renal filtration with 42.9% to 52.8% of the injected dose measured in urine within the first hour after administration, and 92.5% to 117.3% in urine within 24 hours. No Gd was detected by inductively coupled plasma mass spectrometry in urine after 21 days., Conclusion: Single intravenous administration of MT218 was safely tolerated in the healthy males. Its pharmacokinetic parameters and safety profile are well aligned with those of other gadolinium-based contrast agents., Competing Interests: Conflicts of interest none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The hypothesis "General anesthesia consists of producing both loss of consciousness and the inhibition of noxious stimuli reaching the brain and causing arousal" was used as a basis for the review of published data on general anesthetic interactions with antinociceptive agents: opioids, α 2 adrenergic agonists, and systemic sodium channel blockers. This review is focused on a specific type of anesthetic interaction-the transformation of antinociceptive agents into general anesthetic adjuncts. The primary aim is to answer 2 questions. First, how does an antinociceptive agent transform the effect of an anesthetic in providing a certain component of anesthesia-hypnosis, immobility, or hemodynamic response to noxious stimulation? Second, does a combination of an anesthetic with an adjunct result in a simple summation of their respective effects or in a supra-additive or infra-additive interaction? The Medline database was searched for data describing the interactions of antinociceptive agents and general anesthetics. The following classes of antinociceptive agents were considered: opioids, α 2 adrenergic agonists, and systemic sodium channel blockers. Drugs used in combination with antinociceptive agents were general anesthetics and benzodiazepines. The following terms related to drug interactions were used: anesthetic interactions, synergy, antagonism, isobolographic analysis, response surface analysis, and fractional analysis. The interactions of antinociceptive agents with general anesthetics result in a decrease of general anesthetic requirements, which differ for each of the components of general anesthesia: hypnosis, immobility, and hemodynamic response to noxious stimulation. Most studies of the nature of anesthetic interactions are related to opioid-general anesthetic combinations, and their conclusions usually confirm supra-additivity., Competing Interests: The author declares no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Background: This study aimed to assess the effect of perampanel dose, age, sex, and antiseizure medication cotherapy on steady-state free-perampanel concentration in children with refractory epilepsy, as well as the relationship between inflammation and the pharmacokinetics of perampanel., Methods: This prospective study in China included 87 children with refractory epilepsy treated with adjunctive perampanel therapy. Free and total perampanel concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Free-perampanel concentration was compared among patients with various potential influencing factors., Results: A total of 87 pediatric patients (44 female children) aged 2-14 years were enrolled. The mean free-perampanel concentration and free concentration-to-dose (CD) ratio in plasma were 5.7 ± 2.7 ng/mL (16.3 ± 7.7 nmol/L) and 45.3 ± 21.0 (ng/mL)/(mg/kg) [129.6 ± 60.1 (nmol/L)/(mg/kg)], respectively. The protein binding of perampanel in plasma was 97.98%. A linear relationship was observed between perampanel dose and free concentration in plasma, and a positive relationship was found between the total and free-perampanel concentrations. Concomitant use of oxcarbazepine reduced the free CD ratio by 37%. Concomitant use of valproic acid increased the free CD ratio by 52%. Five patients had a plasma high-sensitivity C-reactive protein (Hs-CRP) level of >5.0 mg/L (Hs-CRP positive). The total and free CD ratios of perampanel were increased in patients with inflammation. Two patients with inflammation developed adverse events, which disappeared as the Hs-CRP level returned to normal, and neither required perampanel dose reduction. Age and sex did not influence the free-perampanel concentration., Conclusions: This study found complex drug interactions between perampanel and other concomitant antiseizure medications, providing valuable information to enable clinicians to apply perampanel in the future reasonably. In addition, it may be important to quantify both the total and free concentrations of perampanel to assess complex pharmacokinetic interactions., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)