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Whether the magnitude of individual cytokine, cellular, and clinical responses to the intravenous lipopolysaccharide (LPS) challenge is constant in individuals over extended time periods is unknown. Nine healthy volunteers received an intravenous LPS injection of 2 ng/kg bodyweight twice at intervals of at least one year. Circulating cytokines and leukocyte subsets were quantified using a multiplex immunoassay and cytometry by time-of-flight, respectively. Self-reported symptoms and vital signs were also assessed. We observed moderate to strong intra-individual correlations in the responsiveness of most cytokines (IL-6 [AUC 0 - 10 ]: R = 0.93, p < 0.001; CRP [mg/dL]: R = 0.88, p = 0.004; IL-8 [AUC 0 - 10 ]: R = 0.71, p = 0.031; TNF-alpha [AUC 0 - 10 ]: R = 0.67, p = 0.047; IL-10 [AUC 0 - 10 ]: R = 0.42, p = 0.26) and cellular subsets (CD8 T lymphocytes: R = 0.9, p = 0.002; B lymphocytes [G/L]: R = 0.89, p = 0.003; CD4 T lymphocytes: R = 0.84, p = 0.001; neutrophils: R = 0.80, p = 0.017; monocytes: R = 0.16, p = 0.710) between the 1st and 2nd LPS challenges. Vital signs and symptoms were not reproducible. While the average cellular and clinical response was similar between the two LPS challenges, we found a significantly attenuated AUC 0 - 10 of IL-6 (percent difference, -41.9% [95% CI -73.0 - -10.7]) and TNF-alpha (percent difference, -35.7% [95% CI -70.0 - -1.6]) at the 2nd LPS challenge. Individual cytokine and cellular responses to intravenous LPS showed a significant degree of correlation when measured more than one year apart. These correlations did not translate to the reproducibility of clinical symptoms and vital signs, which showed greater variability and were not constant over time. The partly reduced cytokine release in the 2nd LPS challenge might be interpreted as an indicator of a long-lasting tolerance to endotoxin., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: The optimal systolic blood pressure (SBP) target in patients with increased cardiovascular risk remains uncertain. This study evaluated the efficacy and safety of intensive SBP control (<120 mm Hg) compared to standard SBP control (<140 mm Hg) in patients with increased cardiovascular risk., Methods: We conducted a systematic search of PubMed, Embase, Web of Science, and Cochrane Library for RCTs published from database inception through November 2024 that compared intensive SBP control (<120 mm Hg) with standard SBP control (<140 mm Hg) in adults with high cardiovascular risk. Efficacy outcomes included all-cause mortality, major adverse cardiovascular events (MACE), cardiovascular death, stroke, myocardial infarction (MI), and heart failure. Safety outcomes included hypotension, syncope, arrhythmia, acute kidney injury, and electrolyte abnormalities., Results: Five RCTs comprising 39,434 patients were included. The all-cause mortality was significantly lower in the intensive SBP control group (672 of 19,712 [3.4%]) compared to the standard SBP control group (778 of 19,722 [3.9%]) (risk ratio 0.87 [95% confidence interval, 0.76-0.99, p = 0.03]). The incidence of MACE, cardiovascular death, MI, stroke, and heart failure was significantly lower in the intensive SBP control group as compared to standard SBP control group. The treatment effect (MACE) was consistent across all subgroups. Conversely, intensive SBP control was associated with an increased risk of hypotension, syncope, arrhythmia, acute kidney injury, and electrolyte abnormalities., Conclusions: Targeting intensive SBP control to less than 120 mm Hg was associated with a lower incidence of all-cause mortality and MACE but a higher incidence of adverse events., (© 2025 The Association for the Publication of the Journal of Internal Medicine.)

In light of the introduction of new Janus kinase inhibitors (JAKi), new indications for JAKi and recent safety considerations that have arisen since the preceding consensus statement on JAKi therapy, a multidisciplinary taskforce was assembled, encompassing patients, health care professionals, and clinicians with expertise in JAKi therapy across specialties. This taskforce, informed by two comprehensive systematic literature reviews, undertook the objective to update the previous expert consensus for using JAKi developed in 2019. The taskforce deliberated on overarching principles, indications, dosage and comedication strategies, warnings and contraindications, screening protocols, monitoring recommendations, and adverse effect profiles. The methodology was based on the European Alliance of Associations for Rheumatology standard operating procedures, with voting on these important elements. Furthermore, an updated research agenda was proposed. The task force did not address when a JAKi should be prescribed but rather considerations once this decision has been made. This update aimed to equip clinicians with the necessary knowledge and guidance for the efficient and safe administration of this expanding and significant class of drugs., Competing Interests: Competing interests PN received grants for research, clinical trials, and for advice and lectures from Pfizer, Novartis, Janssen, UCB, Lilly, AbbVie, Samsung, BMS, Servatus, and Amgen. AK reports speakers bureau and consultancy for AbbVie, Amgen, Galapagos, Janssen, Eli Lilly, MSD, Novartis, Pfizer, and UCB. DA reports consultancy fees, speakers’ bureau fees, and grant/research support from AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz and Sanofi. TD reports consulting fees from Roche, Novartis, GSK, and Astra Zeneca and participation in advisory boards of GNE, Roche, and Novartis. RF is a consultant for AbbVie, Pfizer, and BMS. IM reports honoraria/consultation fees and grants/research supports from AbbVie, Amgen, BMS, Causeway Therapeutics, Cabaletta, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi, UCB, Evelo, Compugen, AstraZeneca, and Moonlake. JP reports honoraria from BMS and Pfizer. NS consulted for and/or received speaker honoraria from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi and received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. YT has received speaker fees and/or honoraria from Eli Lilly, AstraZeneca, AbbVie G.K., Gilead Sciences K.K., Chugai Pharmaceutical, Boehringer-Ingelheim, GlaxoSmithKline K.K, Eisai, Taisho Pharmaceutical, Bristol-Myers Squibb, and Pfizer and research grants from Mitsubishi Tanabe Pharma, Eisai, Chugai Pharmaceutical, and Taisho Pharmaceutical. MT is a speaker and/or consultant and/or advisory board member for Albireo, BiomX, Falk, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Intercept, Janssen, MSD, Madrigal, Novartis, Phenex, Pliant, Regulus, and Shire and reports grants/research support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. KW reports consultant honoraria or research grants from Pfizer, AbbVie, Lilly, BMS, and Galapagos. MdW has received honoraria for consultancies and speaking through Stichting Tools from AbbVie, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, and Roche. JA reports Karolinska Institutet has entered into agreements with the following entities, with JA as PI, regarding the ARTIS national safety monitoring of rheumatology immunomodulators: Abbvie, BMS, Eli Lilly, Galapagos, MSD, Pfizer, Roche, Samsung Bioepis, and Sanofi. XB reports grant/research support from AbbVie and Novartis; consulting fees from AbbVie, BMS, Chugai, MSD, Novartis, Pfizer, and UCB Pharma; speakers’ bureau fees from AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, and UCB Pharma. W-HB reports honoraria as a speaker and/or advisor from AbbVie, BMS, Pfizer, and Sanofi. PE reports advisory roles for AbbVie, Activa, Astra-Zeneca, BMS, Boehringer Ingelheim, Galapagos,Gilead, Immunovant, Janssen, Lilly, and Novartis and participation in clinical trials for AbbVie, BMS, Lilly, Novartis, Pfizer, and Samsung. LG reports grants from AbbVie, Biogen, Lilly, Novartis, and UCB; personal fees from AbbVie, BMS, Celltrion, Janssen, Novartis, Pfizer, and UCB; honoraria for lectures from AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, Stada, and UCB; and nonfinancial support from AbbVie, Amgen, Biogen, Janssen, MSD, Pfizer, and UCB, outside the submitted work. JDI reports consultant in AbbVie, Anaptys Bio, Annexon Biosciences, AstraZeneca, BMS, Cyxone AB, Dragonfly, Eli Lilly, Galapagos NV, Gilead Sciences Ltd, GSK, Istesso, Janssen, Kenko International, Kira Biotech, Ono Pharma, Pfizer, Revelo Biotherapeutics, Roche, Sail, Sanofi, Sonoma Biotherapeutics, Topas, and UCB. MK reports advisory boards/consultancy for Novartis, BMS, and GSK. WM has acted as a paid consultant/participated in advisory boards for AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB; received research and/or educational grants from AbbVie, Novartis, Pfizer, and UCB; and received speaker fees from AbbVie, Janssen, Novartis, Pfizer and UCB. JP reports grants/research from BMS, Janssen, Mallinckrodt, and Pfizer (Seattle Genetics); is a consultant for AbbVie, Amgen, Astra Zeneca, Boehringer Ingelheim, Boxer Capital, Bristol Myers Squibb, Celltrion Healthcare, Eli Lilly, Frensenius Kabi, GSK, Janssen, Merck, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Sandoz, Samsung, and Sanofi; is a speaker or in advisory board for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Certa, Eli Lilly, Frensenius Kabi, Janssen, Nordic Pharma, Novartis, Organon, Otsuka, Palleon, Pfizer, Sandoz, Sanofi, UCB, and Zura. MS-V received a grant for her PhD research from Roche and fees for lectures from Pfizer, outside the submitted work. KS reports speakers fees from UCB, Eli Lilly, and Rovi; research grants from Novo Nordic Foundation; and research support from the Danish Association for Rheumatism (Gigtforeningen). TS reports personal fees from AbbVie, Janssen, MSD, Novartis, and Roche, outside the submitted work. PCT reports research support from Galapagos (Alfasigma) and consultancy fees from Galapagos (Alfasigma), Gilead, Pfizer, AbbVie, and Lilly. TT reports speaking fee from AbbVie GK, Chugai, Eli Lilly Japan, Eisai, Gilead Sciences, Pfizer Japan, and Taisho Pharma and consultancy fees from AbbVie GK, Eli Lilly Japan, Gilead Sciences, Mitsubishi-Tanabe, and Taisho Pharma. FvdB reports speaker and/or consultancy fees from AbbVie, Amgen, Eli Lilly, Fresenius Kabi, Galapagos, Janssen, Novartis, and UCB. RW acted as a PI and advisor for Celltrion and Galapagos. JSS reports research grants to his institution from AbbVie, AstraZeneca, Galapagos, and Lilly and honoraria for consultancies and/or speaking engagements from AbbVie, Ananda, AstraZeneca, Astro, BMS, Celgene, Celltrion, Chugai-Roche, Galapagos-Gilead, Immunovant, Janssen, Lilly, Novartis- Sandoz, Pfizer, R-Pharma, and Samsung. VK, EBL, LS-T, and MZ: none., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile., Methods: A prospective, open-labelled, single-centre, pharmacokinetic (PK) drug-drug interaction study was performed in 15 healthy male subjects. Single-dose and steady-state PK were investigated using noncompartmental analysis after mono- and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80-125%., Results: The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination vs. monotherapy) was 112% (90% confidence interval: 104-120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112-168%). The study drugs were safe and well tolerated as mono- and combination therapy, with no major adverse events reported., Conclusion: A PK assessment of clomipramine and yohimbine indicated a clinically significant drug-drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI-related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25-<2-fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies., (© 2024 British Pharmacological Society.)

Objectives: The real-world effectiveness of the oral antivirals nirmatrelvir-ritonavir and molnupiravir against the SARS-CoV-2 Omicron variant remains uncertain. We aimed to estimate their effectiveness in non-hospitalized adults with COVID-19., Methods: This retrospective cohort study used data from the Municipal Department for Public Health Services of Vienna, Austria, to identify non-hospitalized adults with confirmed SARS-CoV-2 infection between January 2022 and May 2023. Nirmatrelvir-ritonavir users were compared with untreated controls and molnupiravir users with untreated controls by calculating adjusted risk differences (aRDs) using a covariate-adjusted logistic regression model with inverse probability weighting. Outcomes were hospitalization and all-cause death within 28 days., Results: We identified 113 399 eligible cases (90 481 untreated controls, 12 166 nirmatrelvir-ritonavir users, and 10 752 molnupiravir users). Over 96% of the patients were immunized by previous infection or vaccination. In the nirmatrelvir-ritonavir analysis, the estimated risk of hospitalization was 0.57% (95% CI, 0.35-0.78) in nirmatrelvir-ritonavir users and 1.09% (95% CI, 0.86-1.32) in untreated controls (aRD, -0.53%; 95% CI, -0.77 to -0.28). The estimated risk of death was 0.0% (95% CI, 0.0-0.0) in nirmatrelvir-ritonavir users and 0.13% (95% CI, 0.08-0.18) in untreated controls (aRD, -0.13%, 95% CI, -0.18 to -0.08). The number needed to treat to prevent hospitalization and death was 190 (95% CI, 130-356) and 792 (95% CI, 571-1289), respectively. These statistically significant aRDs were restricted to the subgroup of patients ≥60 years. In the molnupiravir analysis, the estimated risk of hospitalization was 1.36% (95% CI, 0.95-1.77) in molnupiravir users and 1.16% (95% CI, 0.93-1.39) in untreated controls (aRD, 0.2%; 95% CI, -0.08 to 0.49). The estimated risk of death was 0.12% (95% CI, 0.01-0.23) in molnupiravir users and 0.14% (95% CI, 0.06-0.21) in untreated controls (aRD, -0.01%; 95% CI, -0.08 to -0.06)., Discussion: Among outpatients aged ≥60 years with COVID-19 in an Omicron-dominated era, treatment with nirmatrelvir-ritonavir was associated with a lower risk of hospitalization and all-cause death within 28 days, albeit with wide CIs and high numbers needed to treat. This finding was not observed in molnupiravir users and younger nirmatrelvir-ritonavir users., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Plasma protein binding (PPB) is a critical factor in drug therapy and understanding free compound exposure across preclinical and clinical species is vital for developing new antibiotics. Optimizing beta-lactam dosing based on unbound drug concentrations has garnered significant interest, yet comprehensive data on how inter-species differences in protein binding affect the attainment of targeted unbound concentrations remain sparse., Methods: This study aimed to examine the protein binding of three beta-lactams: cefiderocol, ceftriaxone, and temocillin using human, bovine, and rat plasma. Total and unbound beta-lactam concentrations were measured through ultrafiltration. An interspecies comparison of PPB was conducted to evaluate variability in protein binding across the different species., Results: The findings revealed that PPB was highest in human plasma for all three beta-lactam antibiotics tested. In rat plasma, PPB was higher for cefiderocol and ceftriaxone compared to bovine plasma, while bovine plasma exhibited higher PPB for temocillin compared to rat plasma., Conclusion: Significant variability in protein binding was observed among and between different species for the tested drugs. The study highlights substantial interspecies differences in the plasma protein binding of cefiderocol, ceftriaxone, and temocillin. Our findings indicate the need for careful consideration of species-specific PPB in the optimization of beta-lactam dosing and the development of new pharmaceuticals., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To assess whether initial fluid resuscitation with lactated Ringer's solution compared with 0.9% saline is associated with improved clinical outcomes in patients with sepsis-induced hypotension., Design: Secondary analysis of the randomized controlled Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial., Setting: ICUs and emergency departments in 60 U.S. centers from March 2018 to January 2022., Patients: Participants from the CLOVERS trial. Adult patients with a suspected or confirmed infection and hypotension caused by sepsis., Interventions: Participants received 1-3 L of crystalloid fluid for initial fluid resuscitation before randomization. In this analysis, participants were categorized into a lactated Ringer's group and a 0.9% saline group based on the fluid type predominantly used for the initial fluid resuscitation (i.e., ≥ 95% of pre-randomization fluid)., Measurements and Main Results: Of 1563 participants with sepsis-induced hypotension included in the CLOVERS trial, 622 (39.8%) received lactated Ringer's solution and 690 (44.1%) received 0.9% saline as solution for the initial fluid bolus. Death before discharge home by day 90 occurred in 76 of 622 participants (12.2%) in the lactated Ringer's group and in 110 of 690 participants (15.9%) in the 0.9% saline group, resulting in an adjusted hazard ratio of 0.71 (95% CI, 0.51-0.99; p = 0.043). Patients receiving lactated Ringer's solution had more hospital-free days at 28 days than those receiving 0.9% saline (16.6 ± 10.8 vs. 15.4 ± 11.4, respectively; adjusted mean difference, 1.6 d [95% CI, 0.4-2.8 d; p = 0.009]). Treatment with 0.9% saline was associated with higher levels of serum chloride and decreased levels of serum bicarbonate., Conclusions: Initial fluid resuscitation with lactated Ringer's solution, compared with 0.9% saline, might be associated with improved survival in patients with sepsis-induced hypotension., Competing Interests: Dr. Gelbenegger disclosed this article was prepared with data from the National Heart, Lung, and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center. Drs. Shapiro and Douglas received support for article research from the National Institutes of Health. Dr. Jilma received funding from Sanofi and Looplab. Dr. Douglas’ institution received funding from the NHLBI. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Background: Amiodarone is used in shockable out-of-hospital cardiac arrest (OHCA), but the ideal dose is unknown., Methods: This was an analysis from the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry (2011-2015). Patients with shockable OHCA who received 5 or more defibrillation attempts and treatment with 300 or 450 mg of amiodarone were included. Outcomes were ROSC at ED arrival, survival at hospital discharge, and favorable neurologic function at discharge. Group-differences were adjusted for using inverse probability weighting and a multiple logistic regression model., Results: The present study included 910 patients; 426 received amiodarone 300 mg and 484 received amiodarone 450 mg. The amiodarone 300 mg group had a higher estimated probability of ROSC at ED arrival as compared with the amiodarone 450 mg group (30.8% [95% CI, 26.6-35.1] vs 24.2% [95% CI, 20.5-27.9], respectively; adjusted probability difference, 6.6% (0.9-12.3), p=0.0234). The group differences in survival at hospital discharge (21.3% [95% CI, 17.2-25.4] vs 18.0% [95% CI, 14.6-21.5]; adjusted probability difference, 3.3% [-2.3-8.8]) and favorable neurologic outcome at discharge (16.5% [95% CI, 12.9-20.2] vs 12.7% [95% CI, 9.5-16.0]; adjusted probability difference, 3.8% [95% CI, -1.2-8.7]) did not reach statistical significance., Conclusion: In patients with shockable OHCA who received 5 or more defibrillation attempts, a dose of amiodarone 300 mg was associated with a similar survival compared with a total dose of amiodarone 450 mg. Further study is needed to evaluate the need for a second administration of amiodarone in patients with shockable OHCA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

The current standard method for the analysis of potential drug-drug interactions (pDDIs) is time-consuming and includes the use of multiple clinical decision support systems (CDSSs) and the interpretation by healthcare professionals. With the emergence of large language models developed with artificial intelligence, an interesting alternative arose. This retrospective study included 30 patients with polypharmacy, who underwent a pDDI analysis between October 2022 and August 2023, and compared the performance of Chat GPT and established CDSSs (MediQ®, Lexicomp®, Micromedex®) in the analysis of pDDIs. A multidisciplinary team interpreted the obtained results and decided upon clinical relevance and assigned severity grades using three categories: (i) contraindicated, (ii) severe, (iii) moderate. The expert review identified a total of 280 clinically relevant pDDIs (3 contraindications, 13 severe, 264 moderate) using established CDSSs, compared with 80 pDDIs (2 contraindications, 5 severe, 73 moderate) using Chat GPT. Chat GPT almost entirely neglected pDDIs with the risk to QTc prolongation (85 vs. 8), which could also not be sufficiently improved by using a specific prompt. To assess the consistency of the results provided by Chat GPT, we repeated each query and found inconsistent results in 90% of the cases. In contrast, Chat GPT provided acceptable and comprehensible recommendations for specific questions on side effects. The use of Chat GPT for the identification of pDDIs cannot be recommended currently, because clinically relevant pDDIs were not detected, there were obvious errors and results were inconsistent. However, if these limitations are addressed accordingly, it is a promising platform for the future., (© 2025 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Multidrug resistance-associated proteins (MRPs) have a widespread tissue distribution. They play an important role in drug disposition and drug-drug interactions (DDIs) and have been associated with various diseases. PET with 6-bromo-7-[ 11 C]methylpurine ([ 11 C]BMP) has been used to assess MRP1 function in the brain and lungs of mice. [ 11 C]BMP crosses cellular membranes by passive diffusion followed by intracellular conjugation with glutathione and MRP1-mediated efflux of the radiolabelled glutathione-conjugate. In this study, we assessed the effect of the prototypical organic anion transporter inhibitor probenecid on the whole-body disposition of [ 11 C]BMP to examine its suitability for measuring the function of MRP1 and possibly other MRP subtypes across multiple tissues., Methods: Seven healthy volunteers (3 women, 4 men) underwent two dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [ 11 C]BMP, without and with pre-treatment with a single oral dose of probenecid. Volumes of interest were outlined for several MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, skeletal muscle, kidneys, and liver). Tissue time-activity curves were corrected for the contribution of vascular radioactivity and the elimination rate constant (k E , h - 1 ) was calculated as a parameter for tissue MRP function., Results: Radioactivity was primarily excreted into the urinary bladder and urinary clearance was significantly decreased after probenecid administration (- 50 ± 16%). Following probenecid administration, k E was significantly decreased in the kidneys (- 43 ± 20%), liver (- 18 ± 15%), myocardium (- 16 ± 12%), skeletal muscle (- 51 ± 34%), and retina (- 57 ± 29%, non-blood-corrected)., Conclusion: Our study highlights the great potential of LAFOV PET/CT to assess drug disposition and transporter-mediated DDIs in humans at a whole-body, multi-tissue level. Due to the slow elimination of [ 11 C]BMP-derived radioactivity from the human brain, [ 11 C]BMP appears unsuitable to measure cerebral MRP1 function in humans, but it may be used to assess the function of MRP1 and possibly other MRP subtypes in various peripheral tissues., Trial Registration: EudraCT 2021-006348-29. Registered 15 December 2021., Competing Interests: Declarations. Ethical approval: This study was conducted in accordance with the ICH-GCP guidelines and the Declaration of Helsinki. The trial was registered in the EudraCT database (2021-006348-29) and was approved by the Ethics Committee of the Medical University of Vienna and the Austrian Agency for Health and Food Safety. Conflicts of interest/competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Purpose: Appropriate antifungal therapy is a major determinant of survival in critically ill patients with invasive fungal disease. We sought to describe whether contemporary dosing of antifungals achieves therapeutic exposures in critically ill patients., Methods: In a prospective, open-label, multicenter pharmacokinetic study, intensive care unit (ICU) patients prescribed azoles, echinocandins, or polyene antifungals for treatment or prophylaxis of invasive fungal disease were enrolled. Blood samples were collected on two occasions, with three samples taken during a single dosing interval on each occasion. Total concentrations were centrally measured using validated chromatographic methods. Pharmacokinetic parameters were estimated using noncompartmental methods. Antifungal dosing adequacy was assessed using predefined PK/PD targets., Results: We included 339 patients from 30 ICUs across 12 countries. Median age 62 (interquartile range [IQR], 51-70) years, median APACHE II score 22 (IQR, 17-28), and 61% males. Antifungal therapy was primarily prescribed for treatment (80.8%). Fluconazole was the most frequently prescribed antifungal (40.7%). The most common indication for treatment was intra-abdominal infection (30.7%). Fungi were identified in 45% of patients, of which only 26% had a minimum inhibitory concentration available. Target attainment was higher for patients receiving prophylaxis (> 80% for most drugs). For patients receiving treatment, low target attainment was noted for voriconazole (57.1%), posaconazole (63.2%), micafungin (64.1%) and amphotericin B (41.7%)., Conclusion: This study highlights the varying degrees of target attainment across antifungal agents in critically ill patients. While a significant proportion of patients achieved the predefined PK/PD targets, wide variability and subtherapeutic exposures persist., Trial Registration: ClinicalTrials.gov Identifier: NCT03136926, 2017-04-21., Competing Interests: Declarations. Conflicts of interest: JA Roberts has consulted or provided lectures for Qpex, Gilead, Advanz Pharma, Sandoz, Pfizer, MSD, Gilead and Cipla. JJ De Waele has consulted for Biomerieux, Menarini, Monlycke, MSD, Pfizer, Roche Diagnostics, ThermoFisher and Viatris (fees and honoraria paid to institution)., (© 2025. The Author(s).)

Background: In the preclinical development of new drugs, animal models are often employed to predict their efficacy in humans, relying on translational pharmacokinetic/pharmacodynamic (PK/PD) studies. We performed in vitro experiments focusing on the comparison of plasma protein binding (PPB) and bacterial growth dynamics of clindamycin, a commonly used antimicrobial agent, across a range of drug concentrations and plasma environments., Methods: Human, bovine and rat plasma were used for determining PPB of clindamycin at various antibiotic concentrations in buffer and media containing 20% to 70% plasma or pure plasma using ultrafiltration (UF) and equilibrium dialysis (ED). Also bacterial growth and time-kill assays were performed in Mueller-Hinton broth (MHB) containing various percentages of plasma., Results: Protein binding of clindamycin correlated well between UF and ED. Notably, clindamycin exhibited substantially lower protein binding to rat plasma compared with human and bovine plasma. Staphylococcus aureus growth was significantly reduced in 70% human, bovine, and rat plasma after 4, 8 and 24 h compared with standard MHB. Time-kill data demonstrated that bacterial counts at both 20% and 70% plasmas were less when compared with MHB at drug concentrations lower than MIC after 4 and 8 h of incubation. For rat plasma, the difference was maintained over 24 h of incubation. Furthermore, a complete bacterial killing at 16 mg/L was observed after 24 h in 20% and 70% human and bovine plasma, but not for rat plasma., Conclusions: Recognizing interspecies differences in PB might be essential for optimizing the translational relevance of preclinical studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

There is accumulating evidence that cerebrospinal fluid (CSF) concentrations of nimodipine correlate with long-term outcome of patients after subarachnoidal hemorrhage (aSAH) by impeding cerebral ischemia. However, pharmacological data on simultaneous serum vs. CSF and intraparenchymal nimodipine values are rarely reported in larger patient groups. Nimodipine concentrations were determined in plasma, CSF, and cerebral interstitial fluid (ISF), at steady state after oral (6 × 60 mg/day) and intravenous (0.5, 1, 1.5 and 2 mg/h) administrations in 10 patients after aSAH. Area under the concentration time curve (AUC 0-24 ) for intravenous nimodipine was highest at an infusion rate of 2 mg/h in plasma (1335.87 ± 591.09 mg*h/L), followed by CSF (39.53 ± 23.07 mg*h/L), resulting in an overall CSF penetration ratio of 3.8% (±1.5) (AUC CSF /AUC plasma ). In contrast, nimodipine levels were significantly lower in both plasma (AUC 0-24 298.32 ± 206.52 mg*h/L) and CSF (AUC 0-24 34.8 ± 16.56 mg*h/L) after oral administration. In cerebral ISF, low amounts of nimodipine were detectable in only 4 patients at an infusion rate of 1.5 and 2 mg/h as well as following oral administration. We found significantly higher CSF nimodipine levels in patients during intravenous compared to oral administration. In contrast, only low amounts of nimodipine were detected in the ISF after both oral and intravenous administration. Our findings strongly suggest that the main clinical nimodipine effect of impeding life threatening cerebral ischemia is mediated through significant higher CSF levels after intravenous administration, more likely effective than oral administration., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Cefazolin is used as a prophylactic antibiotic to reduce surgical site infections (SSIs). Obesity has been identified as a risk factor for SSIs. Cefazolin dosing recommendations and guidelines are currently inconsistent for obese patients. As plasma and target-site exposure might differ, pharmacokinetic data from the sites of SSIs are essential to evaluate treatment efficacy: these data can be obtained via tissue microdialysis. This analysis was designed to evaluate the need for dosing adaptations in obese patients for surgical prophylaxis., Methods: Data from 15 obese (BMI median  = 52.6 kg m -2 ) and 15 age- and sex-matched nonobese patients (BMI median  = 26.0 kg m -2 ) who received 2 g cefazolin i.v. infusion for infection prophylaxis were included in the analysis. Pharmacokinetic data from plasma and interstitial space fluid (ISF) of adipose tissue were obtained and analysed simultaneously using nonlinear mixed-effects modelling. Dosing regimens were evaluated by calculating the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for plasma and ISF using unbound cefazolin concentration above minimum inhibitory concentration 100% of the time as target (fT >MIC  = 100%). Dosing regimens were considered adequate when PTA and CFR were ≥90%., Results: Evaluation of cefazolin doses of 1 and 2 g with redosing at either 3 or 4 h by PTA and CFR in plasma and ISF found 2 g cefazolin with redosing at 4 h to be the most suitable dosing regimen for both obese and nonobese patients (PTA >90% and CFR >90% for both)., Conclusions: This model-based analysis, using fT >MIC  = 100% as a target, showed that cefazolin dosing adaptations are not required for surgical prophylaxis in obese patients., Competing Interests: Declarations of interest DBi, DBu, RM, and LA have no conflict of interest. CK and WH report grants from an industry consortium (AbbVie Deutschland GmbH & Co. K.G., Astra Zeneca, Boehringer Ingelheim Pharma GmbH & Co. K.G., F. Hoffmann-La Roche Ltd., Merck KGaA, Novo Nordisk, and Sanofi) for the PharMetrX PhD programme (Berlin/Potsdam, Germany). CK reports an additional grant from the Innovative Medicines Initiative-Joint Undertaking (‘DDMoRe’) and grants from the Federal Ministry of Education and Research within the Joint Programming Initiative on Antimicrobial Resistance Initiative (JPIAMR) and from the European Commission within in the Horizon 2020 framework programme (‘FAIR’), all outside the submitted work. HW and PS received grants from Pfizer (Investigator Initiated Trial Program, Berlin, Germany) and InfectoPharm (Heppenheim, Germany), both for the clinical microdialysis trials. PS reports lecture fees from InfectoPharm (Heppenheim, Germany). HW received lecture fees from Arjo (Mainz-Kastel, Germany)., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: There is conflicting evidence as to whether the combined administration of two vaccines can lead to poorer immunogenicity and reactogenicity. The co-administration of the Omicron-adapted COVID-19 vaccine from Novavax (NVX-CoV2601) and a 20-valent pneumococcal conjugate vaccine (PCV20) has not been previously investigated., Methods: In this randomised, double-blind, placebo-controlled, non-inferiority trial, immunocompetent participants aged ≥60 years were randomised in a 1:1:1:1 ratio to four groups: NVX-CoV2601 plus PCV20 (combination group); NVX-CoV2601 plus placebo (NVX-only group); PCV20 plus placebo (PCV20-only group); or placebo plus placebo (placebo group). The primary outcome was Omicron-specific anti-spike protein IgG ELISA units at day 28 in the combination group compared with the NVX-only group. Non-inferiority was established if the lower limit of the two-sided 95% CI of the geometric mean titre ratio was above the non-inferiority margin of 0.67. Secondary outcomes included anti-pneumococcal capsular polysaccharide (PCP) IgG ELISA units. Solicited local and systemic adverse events were collected for 7 days after vaccination. This study was registered with ClinicalTrials.gov, number NCT05767606, and the EU Clinical Trials Register, EudraCT number 2022-004118-12., Results: All 256 randomised participants completed the study. The baseline characteristics were similar in the four groups. Overall, the median age was 64 (IQR 61 to 69) and 105 (41%) of 256 were male. At day 28, the geometric mean anti-spike protein IgG ELISA units were 534 U/mL (95% CI 432-660) in the combination group and 556 U/mL (95% CI 460-672) in the NVX-only group, resulting in a geometric mean titre ratio of 0.96 (95% CI 0.73-1.27), thereby meeting the criteria for non-inferiority. Anti-PCP IgG ELISA units at day 28 were 507 U/mL (95% CI 416-619) in the combination group and 592 U/mL (95% CI 485-723) in the PCV20-only group. Local and systemic reactogenicity was similar in the three active treatment groups. No safety concerns or serious adverse events were observed., Conclusions: Immunogenicity following co-administration of NVX-CoV2601 with PCV20 was non-inferior to administration of NVX-CoV2601 alone. Given the similar safety and reactogenicity profile, our findings may help to overcome concerns about concomitant vaccination and pave the way for combination vaccines., Funding: Novavax., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The rise in global obesity prevalence has increased the need to understand the pharmacokinetics of drugs in overweight and obese individuals. Tuberculosis remains a significant health challenge, and its treatment outcomes can be influenced by the pharmacokinetic profiles of antitubercular agents. This literature review aims to point out the clinical pharmacokinetics of antitubercular drugs in the overweight and obese patient population, highlighting considerations for potential dosage adjustments. We conducted a comprehensive search of the PubMed US National Library of Medicine from inception to January 2024. Articles focusing on the pharmacokinetics of antitubercular agents used for both drug-susceptible and multidrug-resistant tuberculosis in overweight and obese adults were included. In total, 349 scientific articles were identified and examined for human pharmacokinetic parameters. Of these, 19 were included in this article. To highlight potential differences, pharmacokinetic data for normal-weight tuberculosis patients are also presented, albeit selectively. In general, pharmacokinetic studies of antitubercular agents in overweight and obese individuals are lacking. Fixed-dose combinations often used in the treatment of drug-susceptible tuberculosis are not recommended when treating these population groups. Rather, individual dosing based on therapeutic drug monitoring and the known solubility of the substance should be considered. To improve the management of tuberculosis in overweight and obese patients, there is an urgent need for pharmacokinetic studies and, ultimately, adequate dosing in this patient population, especially given the increasing prevalence of obesity., Competing Interests: Declarations. Funding: Open access funding provided by Medical University of Vienna. No sources of funding were used to assist with the preparation of this review. Conflict of interest: The authors do not have any conflict of interest directly relevant to the content of this review. Markus Zeitlinger is an Editorial Board member of Clinical Pharmacokinetics. Markus Zeitlinger was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Author's Contributions: Marlene Prager, Valentin al Jalali, and Markus Zeitlinger contributed to the concept and writing of the paper. Ethics Approval: Not applicable. This review article does not involve any primary data collection from human participants. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Availability of Data and Material: Not applicable. The data used in this review is sourced from publicly available literature. Code Availability: Not applicable. This review does not involve the use of any software code that requires sharing., (© 2025. The Author(s).)

In vitro time-kill curve (TKC) experiments are an important part of the pharmacokinetic- pharmacodynamic (PKPD) characterisation of antibiotics. Traditional TKCs use Mueller-Hinton broth (MHB), which lacks specific plasma components that could potentially influence the bacterial growth and killing dynamics, and affect translation to in vivo. This study aimed to evaluate the impact of plasma on the PKPD characterisation of two antibiotics; cefazolin and clindamycin. TKC experiments were conducted in pure MHB, and MHB spiked with 20% and 70% human plasma. Plasma protein binding (PPB) data were available, and a linear model described cefazolin's PPB, while clindamycin's PPB was best described by a second-order polynomial model. PKPD models were developed based on pure MHB and described drug effects using an E max model, with consideration of adaptive resistance for cefazolin. The observed bacterial growth and killing in the plasma-spiked MHB TKC data was insufficiently described when applying the developed PPB and PKPD models. In plasma spiked MHB, a growth delay was observed, estimated to 0.25 h (20% plasma), or 2.90 h (70% plasma) for cefazolin, and 0.64 h (20% plasma), or 1.40 h (70% plasma) for clindamycin. Furthermore, the drug effect was higher than expected in plasma-spiked MHB, with bacterial stasis and/or killing at unbound concentrations below MIC, necessitating drug effect parameter scaling (C 50 for cefazolin, Hill coefficient for clindamycin). The findings highlight significant differences in bacterial growth and killing dynamics between pure MHB and plasma-spiked MHB and exemplify how PKPD modelling may be used to improve the translation of in vitro results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Colchicine is an anti-inflammatory herbal medicine with a history stretching back thousands of years. It is a cornerstone in the acute and prophylactic treatment of gout and has secured a permanent place in the standard pharmacological repertoire for familial Mediterranean fever, pericarditis, neutrophilic dermatoses, Behçet's disease and severe aphthous ulcers refractory to oral treatment. The US Food and Drug Administration (FDA) has recently approved colchicine to reduce the risk of myocardial infarction, stroke, coronary revascularization and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular diseases. The recommendation level for cardiovascular prophylaxis was raised from IIb to IIa in the current European Society of Cardiology (ESC) guidelines from 2024. Clinical studies in recent years also demonstrated an effect for acute coronary syndrome and atrial fibrillation. This review article highlights the efficacy and safety profile of colchicine and provides insights into recent and potential future evidence-based fields of application., Competing Interests: Interessenkonflikt: R. Lunzer, G. Delle-Karth, M. Zeitlinger, M. Prager und L.M. Pracher geben an, dass kein Interessenkonflikt besteht., (© 2025. The Author(s).)

Aims: The beta-lactam antibiotic temocillin is increasingly used to treat extended-spectrum beta-lactamase (ESBL-producing) strains; however, its protein binding is complex. This study aims to predict unbound temocillin concentrations in various participant groups to determine its impact on the probability of target attainment (PTA) and to improve dosing recommendations., Methods: The plasma pharmacokinetics were analysed using non-linear mixed-effects modelling. Data from individuals in four groups: healthy volunteers (HV), urinary tract infection patients (UTI), ventriculitis patients and sepsis-ICU patients were included. Simulations were performed to compare the PTA for different dosing regimens and participant-groups., Results: A two-compartment protein-binding model best fitted the 1085 concentrations (543 unbound, 542 total). Temocillin clearance was influenced by creatinine clearance, serum albumin (ALB) and C-reactive protein (CRP). For 2 g q8h intermittent infusion, the PTAs at an MIC of 16 mg/L were 2.3%, 39.5%, 10.0% and 72.5%, for HV, UTI, ventriculitis and sepsis-ICU patients, respectively. The effects of the covariates on the PTA were simulated for two example patients with intermittent infusion: the PTAs at an MIC of 8 mg/L for a sepsis-ICU patient (CRP 300 mg/L, albumin 15 g/L) and a mild-UTI patient (CRP 30 mg/L, albumin 35 g/L) were 94.3% and 62.4%, respectively. Continuous infusion consistently outperformed intermittent infusion in achieving the desired pharmacodynamic target (time above MIC)., Conclusions: Our study underscores the significant variation in temocillin clearance and unbound fractions among different participant groups, challenging the efficacy of traditional 2 g q12h dosing. For patients with enhanced renal function and lower inflammation, continuous infusion emerges as a more effective strategy to achieve optimal target attainment., (© 2025 British Pharmacological Society.)

Objective: We aimed to investigate the association of electrocardiogram (ECG) findings with outcomes in patients with chronic coronary syndrome., Methods: This secondary analysis of the ISCHEMIA and ISCHEMIA-CKD trials divided patients with chronic coronary syndrome into two groups, those with a normal ECG tracing and abnormal ECG tracing. Repolarization abnormalities included ST-segment depression ≥ 0.5 mm and T-wave inversion ≥ 1 mm; conduction abnormalities included left and right bundle branch block (LBBB and RBBB). The primary endpoint was cardiovascular death. Outcomes were assessed using a covariate-adjusted Cox-regression model., Results: Of 5876 patients, 2901 (49.4%) had a normal and 2975 (50.6%) an abnormal ECG tracing. An abnormal ECG tracing at baseline, compared with a normal ECG tracing, was associated with an increased risk of cardiovascular death (257 of 2975 [8.6%] vs. 97 of 2901 [3.3%], adjusted hazard ratio [aHR] 2.01, 95% CI 1.58-2.55) over a median follow-up period of 3.1 years (IQR 2.1-4.2). This finding was consistent across subgroups except for patients with black skin color and current smokers, in whom an abnormal ECG was not significantly associated with increased risk of cardiovascular death. Individual ECG abnormalities (ST-segment depression [aHR 2.0, 95% CI 1.52-2.63], T-wave inversion [aHR 1.89, 95% CI 1.40-2.54], LBBB [aHR 1.74, 95% CI 1.05-2.90], and RBBB [aHR 1.52, 95% CI 1.04-2.22]) were independently associated with an increased risk of cardiovascular death., Conclusion: In patients with chronic coronary syndrome, an abnormal ECG tracing was associated with an increased risk of cardiovascular death. Our findings underscore the importance of the ECG in cardiovascular risk stratification and prognostication., Trial Registration: NCT01471522, BioLINCC ID 14539., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cefiderocol may potentially be used to treat skin and soft tissue infections (SSTIs). However, the pharmacokinetics of cefiderocol in human soft tissues have not yet been determined. The objective of the present PK study was to investigate whether target-site concentrations of cefiderocol are sufficiently high for the treatment of SSTIs., Methods: In this pharmacokinetic study, a single intravenous dose of 2 g cefiderocol was administered to eight healthy male volunteers. Drug concentrations were determined in plasma, muscle and subcutis over 8 h. Free plasma concentrations were calculated using the plasma protein binding determined with ultrafiltration. Free tissue concentrations were obtained using microdialysis. Penetration ratios were calculated as AUC0-8h&#95;free&#95;tissue/AUC0-8h&#95;free&#95;plasma. A population pharmacokinetic model was developed, and the probability of target attainment (PTA) was determined using Monte Carlo simulations., Results: Cefiderocol showed good tissue penetration, with mean penetration ratios ± standard deviation of 0.99 ± 0.33 and 0.92 ± 0.30 for subcutis and muscle, respectively. Cefiderocol pharmacokinetics in plasma were best described with a two-compartment model, and tissue concentrations were described by scaling the tissue concentrations to concentrations in the peripheral compartment of the plasma model. For a thrice-daily regimen with 2 g doses intravenously infused over 3 h, PTA was ≥90% for MIC values up to 4 mg/L, both based on free plasma and soft tissue pharmacokinetics., Conclusions: This study indicates that a dose of 2 g cefiderocol achieves concentrations in plasma considered sufficient for treating relevant bacterial species. Assuming a comparable PK/PD target for soft tissues, sufficiently high concentrations would also be achieved in soft tissues., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: The rise in carbapenem-resistant bacteria and the limited number of effective antibiotics pose a major health-care threat. The combination of ceftazidime (CAZ) and avibactam (AVI) represents an approved treatment option for carbapenem-resistant intra-abdominal infections. However, data on the pharmacokinetic profile of AVI in the hepatobiliary compartment is lacking., Objectives: To provide clinical in vivo data on the concentration of AVI in bile fluid as a surrogate for hepatobiliary excretion., Methods: A single dose of 2000/500 mg CAZ/AVI was administered prolonged over 2 h to 10 patients prior to abdominal surgery, with bile samples available in nine patients in this phase IIb study (DRKS-ID: DRKS00023533). Antibiotic concentrations in plasma (0-8 h), bile (after resection) and pharmacodynamic parameters were determined., Results: The mean concentration across individuals in bile was 33.5 mg/L (±20.5 mg/L) for CAZ and 7.1 mg/L (±3.5 mg/L) for AVI, resulting in bile/plasma ratios of 0.58 (±0.26) and 0.61 (±0.18). The Cmax in plasma was 87.2 mg/L (±25.0 mg/L) for CAZ and 18.6 mg/L (±6.29 mg/L) for AVI, with AUC0-∞ values of 351 h·mg/L (±104 h·mg/L) and 72.1 h·mg/L (±32.1 h·mg/L), respectively. Plasma concentrations of both CAZ and AVI remained more than 50% of the dosing interval above the minimum inhibitory concentrations (T>MIC > 50%; MICCAZ = 8 mg/L, MICAVI = 1 mg/L) in all patients. No antibiotic-associated side effects were reported during the 30-day follow-up., Conclusions: The concentrations of CAZ and AVI in bile suggest their potential as a valuable therapeutic option for multi-resistant biliary infections., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Multidrug resistance-associated protein 1 (MRP1) is a transport protein with a widespread tissue distribution, which has been implicated in the pathophysiology of Alzheimer's and chronic respiratory disease. PET with 6-bromo-7-[ 11 C]methylpurine ([ 11 C]BMP) has been used to measure MRP1 function in rodents. In this study, [ 11 C]BMP was for the first time characterised in humans to assess the function of MRP1 and other MRP subtypes in different tissues., Methods: Thirteen healthy volunteers (7 men, 6 women) underwent dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [ 11 C]BMP. Three subjects of each sex were scanned a second time to assess reproducibility. Volumes of interest were outlined for MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, kidneys, and liver). From the time-activity curves, the elimination rate constant (k E , h - 1 ) was derived as a parameter for tissue MRP function and its test-retest variability (TRTV, %) was calculated. Radiation dosimetry was calculated using the Medical Internal Radiation Dose (MIRD) methodology., Results: Mean k E and corresponding TRTV values were: cerebral cortex: 0.055 ± 0.010 h - 1 (- 4 ± 24%), cerebellum: 0.033 ± 0.009 h - 1 (1 ± 39%), choroid plexus: 0.292 ± 0.059 h - 1 (0.1 ± 16%), retina: 0.234 ± 0.045 h - 1 (30 ± 38%), lungs: 0.875 ± 0.095 h - 1 (- 3 ± 11%), myocardium: 0.641 ± 0.105 h - 1 (11 ± 25%), kidneys: 1.378 ± 0.266 h - 1 (14 ± 16%), and liver: 0.685 ± 0.072 h - 1 (7 ± 9%). Significant sex differences were found for k E in the cerebellum, lungs and kidneys. Effective dose was 4.67 ± 0.18 µSv/MBq for men and 4.55 ± 0.18 µSv/MBq for women., Conclusion: LAFOV PET/CT with [ 11 C]BMP potentially allows for simultaneous assessment of MRP function in multiple human tissues. Mean TRTV of k E in different tissues was in an acceptable range, except for the retina. The radiation dosimetry of [ 11 C]BMP was in the typical range of 11 C-tracers. LAFOV PET/CT holds great potential to assess at a whole-body, multi-tissue level molecular targets relevant for drug disposition in humans., Trial Registration: EudraCT 2021-006348-29. Registered 15 December 2021., (© 2024. The Author(s).)

Cefiderocol, a novel siderophore cephalosporin, demonstrates promising in vitro activity against multidrug-resistant Gram-negative bacteria, including carbapenemase-producing strains. Nonetheless, only a few reports are available regarding the acquisition of resistance in clinical settings, primarily due to its recent usage. This study aimed to investigate cefiderocol resistance using an in vitro resistance development model to gain insights into the underlying molecular resistance mechanisms. Cefiderocol susceptible reference strains (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa) and a clinical Acinetobacter baumannii complex isolate were exposed to increasing cefiderocol concentrations using a high-throughput resistance development model. Cefiderocol susceptibility testing was performed using broth microdilution. Whole-genome sequencing was employed to identify newly acquired resistance mutations. Our in vitro resistance development model led to several clones of strains exhibiting cefiderocol resistance, with MIC values 8-fold to 512-fold higher than initial levels. In total, we found 42 different mutations in 26 genes, of which 35 could be described for the first time. Putative loss-of-function mutations were detected in the envZ, tonB, and cirA genes in 13 out of 17 isolates, leading to a decrease in cefiderocol influx. Other potential resistance mechanisms included multidrug efflux pumps (baeS, czcS, nalC), antibiotic-inactivating enzymes (ampR, dacB), and target mutations in penicillin-binding-protein genes (mrcB). This study reveals new insights into underlying molecular resistance mechanisms against cefiderocol. While mutations leading to reduced influx via iron transporters was the most frequent resistance mechanism, we also detected several other novel resistance mutations causing cefiderocol resistance., (© 2024. The Author(s).)

Background: P-glycoprotein (P-gp) is an efflux transporter which is abundantly expressed at the blood-brain barrier (BBB) and which has been implicated in the pathophysiology of various brain diseases. The radiolabelled antiemetic drug [ 11 C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [ 11 C]metoclopramide can detect increased P-gp function in the human brain, we employed drug-resistant temporal lobe epilepsy (TLE) as a model disease with a well characterised, regional P-gp up-regulation at the BBB., Methods: Eight patients with drug-resistant (DRE) TLE, 5 seizure-free patients with drug-sensitive (DSE) focal epilepsy, and 15 healthy subjects underwent brain PET imaging with [ 11 C]metoclopramide on a fully-integrated PET/MRI system. Concurrent with PET, arterial blood sampling was performed to generate a metabolite-corrected arterial plasma input function for kinetic modelling. The choroid plexus was outmasked on the PET images to remove signal contamination from the neighbouring hippocampus. Using a brain atlas, 10 temporal lobe sub-regions were defined and analysed with a 1-tissue-2-rate constant compartmental model to estimate the rate constants for radiotracer transfer from plasma to brain (K 1 ) and from brain to plasma (k 2 ), and the total volume of distribution (V T = K 1 /k 2 )., Results: DRE patients but not DSE patients showed significantly higher k 2 values and a trend towards lower V T values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (k 2 : hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%)., Conclusions: [ 11 C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant k 2 seems to be the most sensitive parameter to measure increased P-gp function with [ 11 C]metoclopramide. Our study provides evidence that disease-induced alterations in P-gp expression at the BBB can lead to changes in the distribution of a central nervous system-active drug to the human brain, which could affect the efficacy and/or safety of drugs. [ 11 C]Metoclopramide PET may be used to assess or predict the contribution of increased P-gp function to drug resistance and disease pathophysiology in various brain diseases., Trial Registration: EudraCT 2019-003137-42. Registered 28 February 2020., (© 2024. The Author(s).)

Introduction: Polypharmacy is a growing concern in healthcare systems. While available data on potential drug-drug interactions (pDDI) from emergency department (ED) patients is derived from heterogenous populations, this study specifically focused on patients with atrial fibrillation (AF). We hypothesized that patients with AF have similar comorbidities, receive similar drugs, and have similar pDDIs. The overarching aim was to highlight frequent pDDIs, providing practical guidance for treating healthcare professionals and consequently reduce the risk of adverse drug reactions., Methods: Two hundred patients ≥18 years with AF, who received rate- or rhythm-controlling medication at the ED of the University Hospital Vienna, and who were on long-term medication before admission, were eligible. Long-term medication alone, as well as in combination with medication administered at the ED were analyzed for pDDIs using the Lexicomp ® Drug interactions database., Results: Within the long-term medication of patients', we identified 664 pDDIs. Drugs administered at the ED increased pDDIs more than 3-fold to 2085. Approximately, every fifth patient received a contraindicated drug combination (on average 0.24 per patient), while 70% received drug combinations for which therapy modifications are recommended (on average 1.59 per patient). The most frequently involved drugs included amiodarone, propofol, bisoprolol, enoxaparin, and acetylsalicylic acid. Increased risk of bleeding, QTc prolongation, and myopathy were among the most relevant potential consequences of these interactions., Discussion: In conclusion, an optimization of medication would be advisable in almost every AF patient. Treating healthcare professionals should be cautious of drugs that increase bleeding risk, prolong QTc, or bear a risk for myopathy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Bischof, Nagele, Kalkofen, Blechschmidt, Domanovits, Zeitlinger, Schoergenhofer and Cacioppo.)

Background: Viral diseases represent a substantial global health challenge, necessitating the urgent development of effective antiviral medications., Objectives: This review aims to present a thorough examination of systemic antiviral drugs approved by the European Medicines Agency (EMA) since its founding, excluding those targeting HIV, with a focus on preclinical and clinical studies in the drug development process., Sources: Data was extracted from the European Public Assessment Reports and Summary of Product Characteristics issued by the EMA., Content: In total, 21 currently approved agents were analysed with a focus on preclinical and clinical studies. The majority of substances have been approved for hepatitis C (38%) and B (19%) followed by influenza and SARS-CoV-2 (14% and 10%, respectively). A smaller subset obtained approval for the indications of hepatitis D, cytomegalovirus, and pox viruses. As for preclinical studies, heterogeneity in the methods used for efficacy studies was observed, which is at least partly explained by the diverse nature of viruses and their hosts and the lack of general guidelines for antiviral pharmacokinetics and pharmacodynamics studies by the EMA. Clinical studies varied in sample sizes, ranging from a few hundred to several thousand patients. Many antiviral agents have a high potential for cytochrome P450 (CYP) and other enzyme interactions, resulting in the need for a high number of drug-drug interaction studies. Special market authorizations are available, including conditional approval for urgently required drugs such as nirmatrelvir/ritonavir for the treatment of COVID-19, and authorization under exceptional circumstances when comprehensive data cannot be provided, as seen with tecovirimat for pox viruses., Implications: Streamlining the drug development process of antiviral substances and providing more guidelines would be crucial given the ongoing demand for effective treatment options for existing and new viral diseases., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Temocillin is increasingly considered as an alternative to carbapenems. However, there is no consensus on optimal dosing strategies and limited data on temocillin efficacy in systemic infections., Objectives: We compared temocillin dosing strategies using pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation based on plasma exposure and in vitro time-kill data., Methods: Temocillin effects on four Escherichia coli strains were evaluated using static time-kill experiments and the hollow-fibre infection model, in which unbound plasma concentrations following intermittent and continuous infusion regimens of 4 and 6 g daily were replicated over 72 h. A PK/PD model was developed to describe the time-kill data. The PK/PD model was coupled to a population PK model of temocillin in critically ill patients to predict bacterial killing and resistance development following various dosing regimens., Results: Amplification of resistant subpopulations was observed within 24 h for all strains. The PK/PD model described the observed bacterial kill kinetics and resistance development from both experimental systems well. Simulations indicated dose-dependent bacterial killing within and beyond the currently used daily dose range, and a superiority of continuous compared with intermittent infusions. However, regrowth of resistant subpopulations was frequently observed. For two strains, bacteriostasis over 72 h was predicted only with doses that are higher than those currently licensed., Conclusions: Continuous infusions and 6 g daily doses of temocillin kill E. coli more effectively than 4 g daily doses and intermittent infusions, and may increase efficacy in the treatment of systemic infections. However, higher daily doses may be required to suppress resistance development., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Patient-derived tumour organoids (PDOs) are highly advanced in vitro models for disease modelling, yet they lack vascularisation. To overcome this shortcoming, organoids can be inoculated onto the chorioallantoic membrane (CAM); the highly vascularised, not innervated extraembryonic membrane of fertilised chicken eggs. Therefore, we aimed to (1) establish a CAM patient-derived xenograft (PDX) model based on PDOs generated from the liver metastasis of a colorectal cancer (CRC) patient and (2) to evaluate the translational pipeline (patient - in vitro PDOs - in vivo CAM-PDX) regarding morphology, histopathology, expression of C-X-C chemokine receptor type 4 (CXCR4), and radiotracer uptake patterns., Results: The main liver metastasis of the CRC patient exhibited high 2-[ 18 F]FDG uptake and moderate and focal [ 68 Ga]Ga-Pentixafor accumulation in the peripheral part of the metastasis. Inoculation of PDOs derived from this region onto the CAM resulted in large, highly viable, and extensively vascularised xenografts, as demonstrated immunohistochemically and confirmed by high 2-[ 18 F]FDG uptake. The xenografts showed striking histomorphological similarity to the patient's liver metastasis. The moderate expression of CXCR4 was maintained in ovo and was concordant with the expression levels of the patient's sample and in vitro PDOs. Following in vitro re-culturing of CAM-PDXs, growth, and [ 68 Ga]Ga-Pentixafor uptake were unaltered compared to PDOs before transplantation onto the CAM. Although [ 68 Ga]Ga-Pentixafor was taken up into CAM-PDXs, the uptake in the baseline and blocking group were comparable and there was only a trend towards blocking., Conclusions: We successfully established an in vivo CAM-PDX model based on CRC PDOs. The histomorphological features and target protein expression of the original patient's tissue were mirrored in the in vitro PDOs, and particularly in the in vivo CAM-PDXs. The [ 68 Ga]Ga-Pentixafor uptake patterns were comparable between in vitro, in ovo and clinical data and 2-[ 18 F]FDG was avidly taken up in the patient's liver metastasis and CAM-PDXs. We thus propose the CAM-PDX model as an alternative in vivo model with promising translational value for CRC patients., (© 2024. The Author(s).)

Purpose: Severe burn injuries are often accompanied by infections and associated with high morbidity and mortality. This study aimed to compare the prevalence and clinical impact of bacteremia between patients receiving intensive care with and without burns., Methods: This single-center retrospective cohort study at the University Hospital Vienna, Austria, analyzed blood cultures from intensive care unit (ICU) patients with and without burns (2012-2022) to assess the prevalence of bacteremia, the associated pathogen distribution and the 60-day all-cause mortality., Results: In 1170 ICU patients, 303 with burns and 867 without, the prevalence of bacteremia was similar among patients with at least one blood culture (31/157 [19.7%] versus 44/213 [20.7%], OR [95%CI] = 0.95 [0.57-1.57]). Burn patients exhibited a significantly higher frequency of microbiological sampling (51.5% versus 24.5%, p < 0.001), resulting in a higher overall prevalence of bacteremia (10.2% versus 5.1%, p = 0.002). 16.2% of all identified pathogens were multidrug-resistant (MDR). The 60-day all-cause mortality was higher in patients with MDR pathogens than in patients without bacteremia (41.7% versus 10.6%, p = 0.026)., Conclusion: Bacteremia prevalence was similar in burn and non-burn patients, with high rates of multidrug-resistant Gram-negative pathogens. The 60-day all-cause mortality was significantly higher in patients with MDR pathogens than in patients without bacteremia., (© 2024. The Author(s).)

Background: Various SARS-CoV-2 variants of concerns (VOCs) characterized by higher transmissibility and immune evasion have emerged. Despite reduced vaccine efficacy against VOCs, currently available vaccines provide protection. Population-based evidence on the humoral immune response after booster vaccination is crucial to guide future vaccination strategies and in preparation for imminent COVID-19 waves., Methods: This multicenter, population-based cohort study included 4697 individuals ≥18 years of age who received a booster vaccination. Antibody levels against SARS-CoV-2 receptor binding domain (RBD) and neutralizing antibodies against wild-type (WT) virus and Omicron variants were assessed at baseline (day of booster vaccination) and after four weeks. Safety was evaluated daily within the first week using a participant-completed electronic diary. Antibody levels were compared across different vaccination strategies, taking into account individual host factors., Results: Our main model including 3838 participants revealed that individuals who received a booster with mRNA-1273 compared to BNT162b2 vaccine had a significantly higher increase (95 %CI) in anti-RBD-antibody levels (37,707 BAU/mL [34,575-40,839] vs. 27,176 BAU/mL [26,265-28,087]), and of neutralization levels against WT (1,681 [1490-1872] vs. 1141 [1004-1278] and Omicron variant (422 [369-474] vs. 329 [284-374]). Neutralizing antibody titres highly correlated with anti-RBD antibodies, with neutralizing capacity 4.4 fold higher against WT compared to Omicron. No differences in safety were found between the two booster vaccines., Conclusion: Our study underlines the superiority of a booster vaccination with mRNA-1273, independent of the primary vaccination and therefore provides guidance on the vaccination strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Considering the re-emergence of poliomyelitis (PM) in non-endemic regions, it becomes apparent that vaccine preventable diseases can rapidly develop epi- or even pandemic potential. Evaluation of the current vaccination status is required to inform patients, health care providers and policy makers about vaccination gaps., Methods: Between October 28 2022 and November 23 2022, 5,989 adults from the VACCELEREATE Volunteer Registry completed an electronic case report form on their previous PM vaccine doses including number, types/-valencies and the time of administration based on their vaccination records. A uni-/multivariable regression analysis was performed to assess associations in participant characteristics and immunization status., Results: Among German volunteers (n = 5,449), complete PM immunization schedule was found in 1,981 (36%) participants. Uncertain immunization, due to unknown previous PM vaccination (n = 313, 6%), number of doses (n = 497, 9%), types/-valencies (n = 1,233, 23%) or incoherent immunization schedule (n = 149, 3%) was found in 40% (n = 2,192). Out of 1,276 (23%) participants who reported an incomplete immunization schedule, 62 (1%) never received any PM vaccine. A total of 5,074 (93%) volunteers reported having been vaccinated at least once and 2,087 (38%) indicated that they received vaccination within the last ten years. Female sex, younger age, as well as availability of first vaccination record were characteristics significantly associated with complete immunization (p < 0.001)., Conclusion: Full PM immunization schedule was low and status frequently classified as uncertain due to lack of details on administered doses. There is an obviousneed for improved recording to enable long-term access to detailed vaccination history in the absence of a centralized immunization register., (© 2024. The Author(s).)

Introduction: Lipopolysaccharide (LPS) stimulation of human whole blood ex vivo has been widely used to investigate human innate immune responses. However, there are uncertainties regarding the reproducibility and reliability of this assay., Methods: In this prospective, single-center study, cytokine responses (interleukin 8, interferon-α, interferon-γ, interleukin 10, interleukin 1-β, interleukin 6, and tumor necrosis factor-α) to ex vivo whole blood LPS stimulation were assessed in 12 healthy volunteers. Cytokine levels were measured at 0, 2, and 4 h using a multiplex immunoassay (Luminex ® ). Stimulation was repeated after six weeks. We examined reproducibility across technical and biological replicates at baseline and between repeated experiments after 6 weeks based on the area under the curve (AUC) of the individual cytokines using Pearson's correlation coefficient and the mean coefficient of variation., Results: The lowest mean coefficients of variation were observed for the technical replicates (5.4 to 9.2%), followed by the biological replicates (8.1 to 24.8%), and the repeated experiments after 6 weeks (17 to 31.2%). Between the baseline and 6-week AUCs, the following Pearson correlation coefficients R were observed: interleukin 10, 0.97; interferon-α, 0.84; interleukin 1-β, 0.83; interleukin 8, 0.79; interleukin 6, 0.73; interferon-γ, 0.73; and tumor necrosis factor-α, 0.63., Discussion: The level of agreement between the baseline and week-6 cytokine response to ex vivo LPS stimulation was high across the seven cytokines analyzed. While interleukin 10 exhibited the lowest level of variability over time, tumor necrosis factor-α showed the highest variability in repeated experiments, which should be considered in the design and interpretation of future studies., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Jorda et al.)

Background: Early fluid management in patients with advanced chronic kidney disease (CKD) and sepsis-induced hypotension is challenging with limited evidence to support treatment recommendations. We aimed to compare an early restrictive versus liberal fluid management for sepsis-induced hypotension in patients with advanced CKD., Methods: This post-hoc analysis included patients with advanced CKD (eGFR of less than 30 mL/min/1.73 m 2 or history of end-stage renal disease on chronic dialysis) from the crystalloid liberal or vasopressor early resuscitation in sepsis (CLOVERS) trial. The primary endpoint was death from any cause before discharge home by day 90., Results: Of 1563 participants enrolled in the CLOVERS trial, 196 participants had advanced CKD (45% on chronic dialysis), with 92 participants randomly assigned to the restrictive treatment group and 104 assigned to the liberal fluid group. Death from any cause before discharge home by day 90 occurred significantly less often in the restrictive fluid group compared with the liberal fluid group (20 [21.7%] vs. 41 [39.4%], HR 0.5, 95% CI 0.29-0.85). Participants in the restrictive fluid group had more vasopressor-free days (19.7 ± 10.4 days vs. 15.4 ± 12.6 days; mean difference 4.3 days, 95% CI, 1.0-7.5) and ventilator-free days by day 28 (21.0 ± 11.8 vs. 16.5 ± 13.6 days; mean difference 4.5 days, 95% CI, 0.9-8.1)., Conclusions: In patients with advanced CKD and sepsis-induced hypotension, an early restrictive fluid strategy, prioritizing vasopressor use, was associated with a lower risk of death from any cause before discharge home by day 90 as compared with an early liberal fluid strategy., Trial Registration: NCT03434028 (2018-02-09), BioLINCC 14149., (© 2024. The Author(s).)

Background: Little is known about the pharmacodynamic characteristics of liposomal bupivacaine. Hypothesizing that they would not identify pharmacodynamic differences from plain bupivacaine during the initial period after administration, but would find better long-term pharmacodynamic characteristics, the authors designed a randomized, controlled, triple-blinded, single-center study in volunteers., Methods: Volunteers aged 18 to 55 yr (body mass index, 18 to 35 kg/m2) received two ulnar nerve blocks under ultrasound guidance. Using a crossover design with a washout phase of 36 days or more, one block was performed with liposomal and one with plain bupivacaine. Which came first was determined by randomization. Sensory data were collected by pinprick testing and motor data by thumb adduction, either way in comparison with the contralateral arm. Endpoints included success, time to onset, and duration of blockade. Residual efficacy was assessed by the volunteers keeping a diary. Statistical analysis included Wilcoxon signed-rank and exact McNemar's tests, as well as a generalized estimation equation model., Results: Successful sensory blockade was noted in 8 of 25 volunteers (32%) after liposomal and in 25 of 25 (100%) after plain bupivacaine (P < 0.0001). Significant differences emerged for time to onset, defined as 0% response to pinpricking in four of five hypothenar supply areas (P < 0.0001), and for time from onset to 80% or 20% in one of five areas (P < 0.001; P < 0.001). Carryover effects due to the randomized sequencing were unlikely (estimate, -0.6286; sequence effect, 0.8772; P = 0.474). Self-assessment greater than 3.5 days did reveal, for liposomal bupivacaine only, intermittent but unpredictable episodes of residual sensory blockade., Conclusions: The results show that liposomal bupivacaine is not a suitable "sole" drug for intraoperative regional anesthesia. Findings of its limited long-term efficacy add to existing evidence that a moderate effect, at best, should be expected on postoperative pain therapy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists.)

Objective: The timing and dosing of antimicrobial therapy are key in the treatment of pneumonia in critically ill patients. It is uncertain whether the presence of lung inflammation and injury affects tissue penetration of intravenously administered antimicrobial drugs. The effects of lung inflammation and injury on tissue penetration of two antimicrobial drugs commonly used for pneumonia were determined in an established model of unilateral lung injury., Methods: Unilateral lung injury was induced in the left lung of 13 healthy pigs through cyclic rinsing; the right healthy lung served as control. Infusions of meropenem and vancomycin were administered and concentrations of these drugs in lung tissue, blood, and epithelial lining fluid (ELF) were compared over a period of 6 h., Results: Median vancomycin lung tissue concentrations and penetration ratio were higher in inflamed and injured lungs compared with uninflamed and uninjured lungs (AUC 0-6h : P = 0.003 and AUC dialysate /AUC plasma ratio: P = 0.003), resulting in higher AUC 0-24 /MIC. Median meropenem lung tissue concentrations and penetration ratio in inflamed and injured lungs did not differ from that in uninflamed and uninjured lungs (AUC 0-6 : P = 0.094 and AUC dialysate /AUC plasma ratio: P = 0.173). The penetration ratio for both vancomycin and meropenem into ELF was similar in injured and uninjured lungs., Conclusion: Vancomycin penetration into lung tissue is enhanced by acute inflammation and injury, a phenomenon barely evident with meropenem. Therefore, inflammation in lung tissue influences the penetration into interstitial lung tissue, depending on the chosen antimicrobial drug. Measurement of ELF levels alone might not identify the impact of inflammation and injury., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: To date, evidence has been lacking regarding bevacizumab pharmacokinetics in the cerebrospinal fluid (CSF)., Objective: This study assessed the penetration of bevacizumab, as part of a metronomic antiangiogenic treatment regimen, into the CSF of children, adolescents, and young adults with recurrent brain tumors., Patients and Methods: Serum and CSF concentrations, malignant cells, and vascular endothelial growth factor A (VEGF-A) were analyzed in 12 patients (5-27 years) following 10 mg/kg bevacizumab intravenous biweekly administration (EudraCT number 2009-013024-23). A population pharmacokinetic model including body weight, albumin, and tumor type as influential factors was extended to quantify the CSF penetration of bevacizumab., Results: Apart from in serum (minimum concentration/maximum concentration [C min /C max ] 77.0-305/267-612 mg/L, median 144/417 mg/L), bevacizumab could be quantified in the CSF (0.01-2.26 mg/L, median 0.35 mg/L). The CSF/serum ratio was 0.16 and highly variable between patients. Malignant cells could be detected in CSF before initiation of treatment in five of 12 patients; after treatment, the CSF was cleared in all patients. VEGF-A was detected in three patients before treatment (mean ± SD: 20 ± 11 pg/mL), and was still measurable in one of these patients despite treatment (16 pg/mL)., Conclusions: This pharmacokinetic pilot study indicated penetration of bevacizumab into the CSF in a population of children, adolescents, and young adults with recurrent brain tumors., (© 2024. The Author(s).)

Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Background: The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo., Objectives: A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143)., Methods: Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40 mg) were tested under fasted and fed (10 mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30 mg) were administered once daily for 7 days in three sequential cohorts., Results: No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean Tmax range of 0.88 to 1.53 h). Food affected the PK of alpibectir, characterized by a slower absorption (mean Tmax 3.87 h), a lower Cmax (-17.7%) and increased AUC0-t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both Cmax and AUC0-tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0-tau) compared with Cmax (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing., Conclusions: Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: There is conflicting evidence whether prediabetes is associated with adverse clinical outcomes in patients with chronic coronary syndrome. We aimed to assess the effect of prediabetes in patients with chronic coronary syndrome on clinical outcomes., Methods: This is a secondary analysis of data from the ISCHEMIA and ISCHEMIA-CKD trials, including patients with chronic coronary syndrome determined by coronary computed tomography angiography or exercise-stress testing. Participants were assigned to the normoglycemia group (HbA1c < 5.7% [< 39 mmol/mol]), prediabetes group (HbA1c 5.7-6.4% [40-47 mmol/mol]), or diabetes group (HbA1c ≥ 6.5% [≥ 48 mmol/mol]). The primary end point of this study was all-cause mortality. Secondary endpoints included major adverse cardiovascular events and composites thereof., Results: Overall, the primary endpoint all-cause mortality occurred in 330 (8.4%) of 3910 patients over a median follow-up time of 3.1 years (IQR 2.1-4.1). The primary endpoint all-cause mortality occurred in 37 (5.2%) of 716 patients in the normoglycemia group, in 63 (6.9%) of 911 in the prediabetes group, and in 230 (10.1%) of 2283 in the diabetes group. In the covariate-adjusted Cox model analysis, the estimated adjusted HR (aHR) in the prediabetes group as compared with the normoglycemia group was 1.45 (95%CI, 0.95-2.20). The aHR in the diabetes group as compared with the normoglycemia group was 1.84 (95%CI, 1.29-2.65). Prediabetes, compared with normoglycemia, was associated with an increased risk of stroke (aHR, 3.44, 95%CI, 1.15-10.25). Subgroup analyses suggested an increased risk of all-cause death associated with prediabetes in males and patients under 65 years., Conclusions: In patients with chronic coronary syndrome, diabetes but not prediabetes was associated with significantly increased risk of all-cause death within a median follow-up period of 3.1 years. Trial Registration NCT01471522, BioLINCC ID 13936., (© 2024. The Author(s).)

Background: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited., Materials and Methods: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus., Results: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ± 1.68 mg/L (mean ± SD) and 106 ± 32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ± 0.03, 0.94 ± 0.46 and 27.1 ± 17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ± 32.1, 1.68 ± 0.72, 22.6 ± 11.0 and 650 ± 426 mg·h/L, respectively., Conclusion: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [ 11 C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [ 11 C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: This study investigates how surfactants affect the in-vitro anti-infective efficacy of micafungin, caspofungin, anidulafungin, and amphotericin B in treating pulmonary mycoses., Methods: MIC values for antifungal agents were determined against Candida krusei (now Pichia kudriavzevii) ATCC 6258, Candida albicans ATCC 90028, and 18 clinical isolates using the broth microdilution method in RPMI medium, following EUCAST recommendations. MIC assays included testing with and without Curosurf® surfactant at 1 mg/mL for C. krusei ATCC 6258 and all C. krusei isolates. Subsequent Time-kill studies in Sabouraud broth involved testing both C. albicans ATCC 90028 and C. krusei ATCC 6258 strains at concentrations equal their respective MIC values, with and without surfactant, using all four antifungals. CFU/mL were assessed at multiple time points up to 24 h. TKCs with different surfactant concentrations for C. krusei ATCC 6258 and mini-TKCs at various concentrations relative to the MIC of C. krusei isolates and the reference strain were conducted with micafungin, anidulafungin, and caspofungin., Results: MIC results showed that 1 µg/mL surfactant reduced killing of micafungin and anidulafungin against C. krusei, while caspofungin was unaffected. Amphotericin B's MIC decreased by half. TKCs demonstrated significant effects of surfactant on micafungin and anidulafungin against C. krusei, with complete abolition of anidulafungin's activity against C. albicans., Conclusion: This in-vitro study highlights the concentration-dependent inhibitory effect of surfactant on antifungal activity against C. krusei and, to some extent, C. albicans, necessitating further clinical validation for invasive lung mycoses treatment., (© 2024. The Author(s).)

Objective: Predictions of antimicrobial effects typically rely on plasma-based pharmacokinetic-pharmacodynamic (PK-PD) targets, ignoring target-site concentrations and potential differences in tissue penetration between antibiotics. In this study, we applied PK-PD modelling to compare target site-specific effects of antibiotics by integrating clinical microdialysis data, in vitro time-kill curves, and antimicrobial susceptibility distributions. As a case study, we compared the effect of lefamulin and ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA) at soft-tissue concentrations., Methods: A population PK model describing lefamulin concentrations in plasma, subcutaneous adipose and muscle tissue was developed. For ceftaroline, a similar previously reported PK model was adopted. In vitro time-kill experiments were performed with six MRSA isolates and a PD model was developed to describe bacterial growth and antimicrobial effects. The clinical PK and in vitro PD models were linked to compare antimicrobial effects of ceftaroline and lefamulin at the different target sites., Results: Considering minimum inhibitory concentration (MIC) distributions and standard dosages, ceftaroline showed superior anti-MRSA effects compared to lefamulin both at plasma and soft-tissue concentrations. Looking at the individual antibiotics, lefamulin effects were highest at soft-tissue concentrations, while ceftaroline effects were highest at plasma concentrations, emphasising the importance of considering target-site PK-PD in antibiotic treatment optimisation., Conclusion: Given standard dosing regimens, ceftaroline appeared more effective than lefamulin against MRSA at soft-tissue concentrations. The PK-PD model-based approach applied in this study could be used to compare or explore the potential of antibiotics for specific indications or in populations with unique target-site PK., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: 6-Bromo-7-[ 11 C]methylpurine ([ 11 C]BMP) is a radiotracer for positron emission tomography (PET) to measure multidrug resistance-associated protein 1 (MRP1) transport activity in different tissues. Previously reported radiosyntheses of [ 11 C]BMP afforded a mixture of 7- and 9-[ 11 C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [ 11 C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data., Results: [ 11 C]BMP was synthesised by regioselective N 7 -methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [ 11 C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [ 11 C]BMP was obtained within a total synthesis time of approximately 43 min in a decay-corrected radiochemical yield of 20.5 ± 5.2%, based on starting [ 11 C]methyl iodide, with a radiochemical purity > 99% and a molar activity at end of synthesis of 197 ± 130 GBq/μmol (n = 28). An extended single-dose toxicity study conducted in male and female Wistar rats under good laboratory practice after single intravenous (i.v.) administration of unlabelled BMP (2 mg/kg body weight) revealed no test item related adverse effects. Human dosimetry estimates, based on dynamic whole-body PET data in female C57BL/6J mice, suggested that an i.v. injected activity amount of 400 MBq of [ 11 C]BMP will deliver an effective dose in the typical range of 11 C-labelled radiotracers., Conclusions: [ 11 C]BMP can be produced in sufficient amounts and acceptable quality for clinical use. Data from the non-clinical safety evaluation showed no adverse effects and suggested that the administration of [ 11 C]BMP will be safe and well tolerated in humans., (© 2024. The Author(s).)