Aging is a complex process that frequently includes cognitive decline with memory loss. In the hippocampus, the number of somatostatin-positive (Sst) GABAergic interneurons in the hilar region of the dentate gyrus decreases with age. We previously showed that selective ablation of Sst dentate hilar interneurons is sufficient to induce cognitive dysfunction, resulting in a model of hippocampal aging (pseudo-aged mice). Brain insulin levels and insulin receptor expression also decline with age, and intranasal insulin (INS) has shown promise in improving learning and memory in Alzheimer's disease. Here, we investigated the effects of INS in pseudo-aged mice with genetically ablated dentate hilar Sst interneurons, which were generated by bilateral injection of AAV5-EF1α-mCherry-flex-dtA into the dentate hilus of Sst-IRES-Cre mice (3-5 months old). Following a 3-week recovery period post-injection, INS was administered daily for 9 days. INS treatment in pseudo-aged mice improved working memory in the Y-maze, recognition memory in the novel object recognition test, and non-declarative associative memory in trace fear conditioning. At the molecular level, INS reversed the increase in Iba-1 and pTBK1 expression, indicating attenuation of microglial activation and cGAS-STING pathway signaling, and restored hippocampal BDNF levels. No significant effects of INS were observed in control mice. These findings indicate that INS alleviates memory impairment and reduces neuroinflammation in this hippocampal aging model. Together, the results suggest that intranasal insulin may provide a non-invasive therapeutic approach for mitigating age-related cognitive decline by modulating neuroinflammatory and neurotrophic mechanisms.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder with inflammation-related flare-ups resulting in catastrophic heterotopic ossification (HO). Janus-associated kinase (JAK) inhibitors may have had a blocking effect on bone formation in controlling FOP flare-ups by blocking multiple inflammatory signaling pathways. Continuous JAK inhibitor tofacitinib treatment has shown preliminary safety and effect in preventing FOP flare-ups. There is concern that the use of long-term continuous JAK inhibitors might cause renal, hepatic, and hematological toxicity, as well as increased infections and cancers. We incorporated a six-week ruxolitinib (another JAK inhibitor) regimen given intermittently for empirical use at the flare-up onset in a teenager after she experienced three consecutive corticosteroid-refractory severe lower limb FOP flare-ups within 1 year. The regimen proved well-tolerated with efficacy in terms of blocking morbidity-generating heterotopic ossification and extending the flare-up-free intervals to 5, 12, and 36 months until subsequent flare-ups, respectively, accompanied by a stable cumulative analog joint involvement scale (CAJIS) score for the subsequent 5 years. The regimen appeared to inhibit new bone formation and may avoid long-term use-related toxicities in FOP patients.

Polymyxin B (PMB), a last-resort antibiotic for multidrug-resistant Gram-negative infections, carries significant neurotoxicity risks that remain underrecognized in clinical practice. Here, we present a case of life-threatening diaphragmatic paralysis induced by PMB in a patient with extensive neck and mediastinal infections caused by extensively drug-resistant Acinetobacter baumannii. The patient developed acute respiratory failure due to respiratory paralysis, which resolved completely upon PMB discontinuation. Concurrent use of nephrotoxic agents may have contributed to renal impairment during treatment. This case is helpful in detecting the serious neurotoxic reactions caused by PMB at an early stage; systematic therapeutic drug monitoring combined with real-time renal function assessment aided in the early detection of toxicity, thereby preventing a potentially fatal outcome.

Avacopan, an oral C5a receptor antagonist approved for treating anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis, has established efficacy and short-term safety from clinical trials, but its post-marketing adverse events (AEs) in real-world settings require further characterization. We conducted a retrospective analysis of the U.S. FDA Adverse Event Reporting System (FAERS) database from Q1 2022 to Q1 2025. After data cleaning, Avacopan-related AEs were extracted, coded using MedDRA terminology, and analyzed via four signal detection methods; subgroup analyses by age, sex, and reporter type were performed. Among 3529 reports, significant disproportionality signals emerged for known AEs (e.g., hepatobiliary disorders, serious infections) and unexpected signals including venous thromboembolism, cholestatic jaundice, and alopecia. Most AEs occurred within the first 30 days of treatment, with variations observed by age and sex. This study provides the first FAERS-based pharmacovigilance assessment of Avacopan, confirming known risks and identifying novel post-approval safety signals, underscoring the need for close early-treatment monitoring and personalized strategies. Further research is warranted to confirm emerging signals and explore their mechanisms.

Understanding the mechanisms underpinning vascular smooth muscle contraction, which are critical targets for cardiovascular disease treatment, is essential for developing novel therapeutic agents. Recently, the role of mitochondrial fission as a key modulatory event in the vascular contractile process has been questioned. Therefore, the present study, conducted on ex vivo rat aorta rings, aimed to elucidate its role. As mitochondrial dynamics is a Ca-dependent process, experiments were performed using preparations incubated in a Ca-free medium, depleted of sarcoplasmic reticulum Ca content, and stimulated by Ba. Contractile responses evoked by Ba, either alone or in the presence of phenylephrine or (S)-(-)-Bay K 8644, occurred without mitochondrial fission. Furthermore, hallmarks of mitochondrial fusion were observed in rings stimulated by Ba alone. The Drp1 inhibitors mdivi-1 and dynasore antagonized Ba-induced contraction, whereas the dynasore analogue dyngo-4a and the dynamin stimulator ryngo 1-23 synergized with Ba-induced contraction. All tested compounds, except mdivi-1, induced mitochondrial fission, with particularly pronounced effects observed with dynasore. Similar results were obtained in rings stimulated by Ba in the presence of either phenylephrine or (S)-(-)-Bay K 8644. In conclusion, these findings indicate that rat aorta contraction can occur independently of mitochondrial fission. Moreover, Ba, used in place of Ca as a vasoconstricting agent, provides a valuable experimental framework for identifying off-target effects of dynamin modulators.

Immunomodulatory drugs (IMIDs) and proteasome inhibitors (PIs) are part of the frontline treatment landscape for multiple myeloma (MM). Despite their effectiveness, these drugs are associated with adverse effects, particularly clinically significant drug-induced peripheral neuropathy. The aim of this study was to evaluate the association between peripheral neuropathy and IMIDs and PIs used in MM, stratified by type of nerve dysfunction. VigiBase, the World Health Organization's global database of individual case safety reports (ICSRs), was analyzed. All ICSRs reported from 1 December 2001 to 31 May 2023 were extracted. Peripheral neuropathy cases were identified using MedDRA-preferred terms (neuropathy peripheral, autonomic neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy) and standardized MedDRA queries (SMQ: peripheral neuropathy). Disproportionality signals were assessed using the reporting odds ratio (ROR) and information component (IC). Associations with peripheral neuropathy were found for all IMIDs and PIs. Both IMIDs and PIs were associated with peripheral sensory neuropathy. Associations with autonomic neuropathy were observed for bortezomib (ROR 12.90; 95% CI: 9.01-18.47), ixazomib (ROR 19.01; 95% CI: 7.89-45.80), carfilzomib (ROR 9.35; 95% CI: 3.01-29.10) thalidomide (ROR 8.86; 95% CI: 4.21-18.70). Associations with peripheral motor neuropathy were detected for bortezomib (ROR 63.87; 95% CI: 51.78-78.80), thalidomide (ROR 30.62; 95% CI: 22.67-41.40), lenalidomide (ROR 2.95; 95% CI: 2.11-4.14), pomalidomide (ROR 5.03; 95% CI: 2.91-8.69). Signals of autonomic neuropathy were identified for bortezomib, carfilzomib, ixazomib, and thalidomide, while signals of peripheral motor neuropathy were observed for bortezomib, thalidomide, lenalidomide, and pomalidomide. Associations with peripheral sensory neuropathy were detected for all IMIDs and PIs analyzed.

Efavirenz (EFV) is the first-line treatment for acquired immunodeficiency syndrome. However, capsaicin may affect its properties, although the underlying mechanisms remain unknown. This study aimed to investigate the effects of dihydrocapsaicin (DHC) on the pharmacokinetics of EFV both in vivo and in vitro. Twelve Sprague-Dawley rats were divided into two groups including experimental and control. The experimental group was pretreated with DHC (10 mg/kg/day) for two weeks with 5% sodium carboxymethyl cellulose prior to receiving EFV. After a single-dose oral administration of 56 mg/kg EFV, blood samples (50 μL) were collected from the caudal vein and analyzed. The effects of DHC on EFV in vitro were further studied in rat liver microsomes (RLMs). The area under the plasma concentration-time curve for EFV increased from 8821.45 ± 2877.31 to 22347.15 ± 7579.96 μg/mL/h (p < 0.05); the maximum plasma time increased from 2.50 ± 0.84 to 3.50 ± 0.55 h (p < 0.05) and elimination half-life increased from 3.13 ± 0.87 to 3.51 ± 0.79 h (p < 0.05). In contrast, the plasma clearance rate decreased from 6.71 ± 2.48 to 2.65 ± 0.98 L/h/kg (p < 0.05) in the experimental group compared to that in the control group. Additionally, the results showed that DHC significantly inhibited the metabolism of EFV in RLMs. Drug-drug interactions were observed between DHC and EFV, altering the pharmacokinetics of EFV both in vivo and in vitro. The dosage of capsaicin should be monitored and adjusted in patients receiving EFV maintenance therapy.

Drug interactions commonly occur through the activities of cytochrome P450 (CYP). In this study, we evaluated the effects of the Chinese herbal medicine Botrychium Ternatum (Thunb) Sw. (BT) on six CYP enzymes. Twelve healthy male Sprague-Dawley rats were randomly divided into two groups (n = 6 each), which were administered the same doses of the probe drugs via gavage. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was performed to detect the plasma concentrations of the probe drugs and their metabolites. Serum biochemical indicators in rats were analyzed to determine the effect of BT on hepatocytes and their anabolism. Real-time fluorescence quantitative PCR was performed to assess the expression level of enzymes. The BT group showed lower AUC values and higher clearance rates for the probe drugs compared with the control group. Additionally, BT significantly increased the expression of six enzymes and decreased the levels of aspartate aminotransferase in rats. Therefore, dosage adjustment should be considered when patients are administered adjuvant BT-extract-containing drugs in combination with other drugs that are metabolized by the cytochrome P450 (CYP) enzymes.

We developed a computational model, called "Unbiased microRNA-disease association predictor (UBMDA)," to predict microRNA-disease associations. UBMDA has two major differences from those reported previously. First, we did not apply a similarity-based feature extraction method, which is the main basis of previous studies. Instead, we used International Classification of Diseases 11th Revision disease codes and microRNA nucleotide sequences as input features. Thus, UBMDA can be applied to newly discovered or poorly studied microRNAs and diseases. Second, we constructed an appropriate negative sample dataset. A positive sample dataset consisting of microRNAs and diseases pairs with proven associations between microRNAs and diseases is publicly available. However, datasets reporting no associations between microRNAs and diseases are rare. Therefore, a negative sample dataset was created by combining microRNAs and diseases. Because more commonly studied microRNAs and diseases are more likely to be included in the positive sample dataset, creating a negative sample dataset without taking this bias into consideration could cause an imbalance in disease and microRNA frequencies between positive and negative sample datasets, leading to biased prediction. To prevent such an imbalance, we created a negative sample dataset considering the frequency of each microRNA and disease in the positive sample dataset, such that these frequencies were similar between the negative and positive sample datasets. We successfully developed a computational model with a simple and intuitive structure. UBMDA will contribute to accelerating the development of microRNA-related biomarkers and therapeutics.

Budesonide is a first-line inhaled glucocorticoid (ICS) for asthma treatment in adults and children. The purpose of this study was to compare the pharmacokinetics and assess the bioequivalence between two budesonide pressurized metered-dose inhalers (pMDIs, 200 μg/actuation × 1 actuation) in healthy Chinese subjects. The study was conducted in 32 healthy Chinese subjects using a single-center, randomized, open-label, four-period and crossover design with a 3-day washout between periods. Blood samples were collected up to 16 h post-dose. Plasma concentrations of budesonide were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Reference-scaled average bioequivalence (RSABE) or average bioequivalence (ABE) method was applied to evaluate the bioequivalence, on the basis of the within-subject standard deviation (S) of the reference product (Budiair), and the safety was also assessed. Eventually, 31 subjects completed this study. For the maximum concentration (C) (within-subject standard deviation, S ≥ 0.294), the RSABE method showed a geometric mean ratio (GMR) of 97.13% with a 95% upper confidence bound of < 0. For the area under plasma concentration-time curve from time zero to the last measurable concentration (AUC) and the area under plasma concentration-time curve extrapolated to infinity (AUC) (S < 0.294), ABE yielded GMRs of 104.81% and 104.61%, with 90% confidence intervals (CIs) of 99.98%-109.86% and 99.81%-109.63%, respectively. All adverse events (AEs) were mild to moderate and transient, with no serious adverse events (SAEs) reported. The two budesonide pMDIs (200 μg) were bioequivalent and well tolerated in healthy Chinese subjects. Trial Registration: Chinese Clinical Trial Registry, Registration No. CTR20244600; ClinicalTrials.gov identifier: NCT06924190.

Medication errors, often linked to inadequate numeracy skills, pose significant risks to patient safety. To address this, Kent and Medway Medical School (KMMS) became the first UK medical school to integrate safeMedicate, a validated e-learning platform, into its Year 1 undergraduate medical curriculum. This study aimed to evaluate its impact on student engagement, numeracy competence, and confidence. The entire cohort of 111 first-year medical students (2024 intake) was introduced to the safeMedicate Essential Skills module within the Year 1 module titled Professional Development and Person-Centred Practice. Engagement was assessed via platform analytics (logins, time, completion), numeracy competence through a formative online test, and perceptions via an anonymous survey. Engagement was high, with students averaging 9.1 logins and 124.2 min on the platform. Completion rates were near universal (95%). The average test score was 85.4%, with 75% of students achieving ≥ 85%. Competency analysis showed strong performance in conceptual, calculation, and technical measurement skills. Survey responses indicated that 89% found safeMedicate helpful for test preparation and 83% reported increased confidence in numeracy. Students valued the clarity, usability, and practice-based learning approach. Early integration of safeMedicate demonstrated improved engagement, numeracy performance, and student confidence. Although limited to one institution and formative assessment, findings support continued use of structured digital tools to strengthen medication safety education. Embedding safeMedicate into undergraduate curricula may reduce prescribing errors and better prepare future doctors for safe clinical practice.

Environmental stressors, such as ionizing radiation, accelerate aging by causing DNA damage and triggering pathways that lead to cell cycle arrest, apoptosis, and subsequent inflammation. The thrombopoietin receptor agonist romiplostim (RP), which is used as a clinical treatment for chronic idiopathic thrombocytopenic purpura and aplastic anemia, is known to be promising in reducing radiation-induced tissue damage. In this study, we established a mouse model of radiation-induced premature aging to evaluate the potential of RP in ameliorating this process. Female C57BL/6JJcl mice were subjected to total body irradiation with various irradiation schedules. Mice irradiated with 5 Gy every 4 weeks (total dose of 10 Gy over 2 months) showed a significant aging phenotype, including graying hair and elevated serum aging markers (CDKN2A/p16, tumor necrosis factor-α (TNF-α), and C-reactive protein), compared with sham-irradiated controls. RP was intraperitoneally administered to the mouse model (10 μg/kg weekly or 50 μg/kg every 4 weeks). Treatment significantly reduced TNF-α levels by 15% and the area of graying body hair by 70%. Although bone marrow cell recovery was incomplete, spleen cell counts were significantly restored (2-fold) by 50 μg/kg RP, and SA-β-gal activity, a marker of cellular senescence, was also significantly suppressed by approximately 15%. These findings suggest that RP may partially ameliorate radiation-induced premature aging, providing a basis for future research addressing health issues associated with aging and radiation exposure.

Success in assessments requires that both the knowledge and processing demands of questions are addressed. The focus of students, however, tends to be on knowledge demands oftentimes failing to address adequately or misinterpreting assessment processing demands. While there is a universal list of assessment action verbs used for conveying processing demands, these often take on nuanced meanings within disciplines. To-date there is a paucity of studies investigating pharmacology assessment processing demands. Our study purpose was threefold: (i) identify the most frequent action verbs and collocated words in pharmacology summative written assessments, (ii) determine the meaning(s) lecturers attribute to them, and (iii) reach consensus on their meanings. Using NVivo software, a frequency analysis of action verbs and collocated words embedded in pharmacology summative written assessments was performed on over 200 exam papers (2010-2020), totaling 1,200 questions. An online survey gathered educators' meanings of common assessment action verbs and their collocated words. Seven common assessment action verbs identified were "discuss", "describe", "outline", "include", "explain", "give", and "write", their weighted frequencies differing across programmes and academic years. High frequency collocated words included "the pharmacology of" and "mechanism of action". Survey analysis identified diverse educators' meanings for all except the action verb, "discuss" highlighting the importance of our study. A follow-on focus group defined both action verb and collocated word meanings commonly used in pharmacology assessments. Ultimately, assessment effectiveness must encompass transparency of language, so students are assessed on their knowledge rather than their ability to align with educators' interpretation(s).

The rational use of medications is essential for optimal healthcare delivery, especially in developing countries. This research delves into prescribing patterns within the healthcare system of Pakistan and Yemen against World Health Organization (WHO) prescribing indicators to uncover variances from recommended practices. A cross-sectional study was conducted in the outpatient department of different hospitals in Pakistan and Yemen, including 400 prescriptions. Demographic details and prescription data were collected, focusing on WHO prescribing indicators including the average number of drugs per encounter, the percentage of drugs prescribed by generic name, the percentage of drugs prescribed from the essential drug list, and the prevalence of antibiotic and injectable prescriptions. The mean age of patients was 43.54 ± 16.92 and 38.81 ± 18.67 years in Pakistan and Yemen, respectively. Polypharmacy was observed in both populations, with an average of 5.44 ± 1.16 drugs per encounter in Pakistan and 6.18 ± 1.09 in Yemen. Irrational antibiotic use was observed, with rates of 65% and 72.5% encounters in Pakistan and Yemen, respectively. The mean injectable medications per hospital were 28.5 (57%) and 34 (68%) in Pakistan and Yemen, respectively. In Pakistan, the mean percentage of generic prescribing was 74.18%, while in Yemen, it was 78.24%. The total percentage of drugs prescribed from the essential drug list was 98.24% in Pakistan, whereas 97.87% in Yemen. The findings reveal significant deviations from WHO prescribing indicators marked by polypharmacy and excessive antimicrobial and injectable utilization, which pose risks to patient safety and contribute to antimicrobial resistance.

Jatropha gossypifolia L., a member of the Euphorbiaceae family, has been traditionally used in the treatment of various ailments. However, its neuropharmacological, cytotoxic, and anthelmintic potentials have not been thoroughly investigated. The methanolic fruit extract of J. gossypifolia (JGF-ME) was evaluated for anxiolytic activity using the Elevated Plus Maze (EPM), Hole Board Test (HBT), and Light-Dark Box Test (LDT); antidepressant activity using the Forced Swimming Test (FST) and Tail Suspension Test (TST); and sedative effects through the Open Field and Hole Cross tests. Cytotoxicity was assessed via the Brine Shrimp Lethality Assay (BSLA), and anthelmintic activity was evaluated against Pheretima posthuma. GC-MS was used for phytochemical screening, followed by molecular docking and ADME/T analyses of the identified compounds. JGF-ME exhibited a significant, dose-dependent anxiolytic effect in EPM, HBT, and LDT. At 400 mg/kg, it significantly reduced immobility in FST and TST (p < 0.001), indicating significant antidepressant activity. The extract also exhibited notable sedative effects, as evidenced by reduced locomotor activity in the Open Field and Hole Cross tests at doses of 200 and 400 mg/kg. In BSLA, JGF-ME displayed moderate cytotoxicity (LC = 327.87 μg/mL) compared to colchicine (LC = 38.81 μg/mL). It also produced a dose-dependent anthelmintic effect by paralyzing and killing P. posthuma. Molecular docking revealed high binding affinities of the identified compounds to selected human receptors, and in silico analysis suggested acceptable drug-likeness; experimental validation is needed. The study confirms the neuropharmacological, cytotoxic, and anthelmintic potential of J. gossypifolia extract, supporting its traditional use and therapeutic promise.

Inhibition of vasocontraction accounts for side effects in treating voiding symptoms in benign prostatic hyperplasia (BPH). We examined the vasoactivity of compounds previously showing inhibition of prostate smooth muscle contraction. Contractions of porcine renal interlobar and coronary arteries were induced by agonists or electric field stimulation (EFS). Examined compounds included inhibitors for Rac GTPases (EHT1864, NSC23766), cytohesin GEFs (SecinH3), LIMK (SR7826, LIMKi3), βARKs (CMPD101), PAK (FRAX486), and ILK (Cpd22). Agonist- and EFS-induced contractions in renal and coronary arteries were completely inhibited by 100 μM EHT1864, and nearly completely at 10 μM. In renal arteries, 100 μM NSC23766 right-shifted concentration response curves (increased EC) for α-adrenergic agonists, halved U46619-induced and fully inhibited EFS-induced contractions. Right shifts (increased EC) for phenylephrine still occurred at 10 and 1 μM. In coronary arteries, 100 μM NSC23766 produced right shifts (increased EC) for cholinergic agonists. SecinH3 (30 μM) reduced cholinergic contractions in coronary but not renal arteries. In renal arteries, SR7826, but not LIMKi3 (both 1 μM), partly inhibited (< 50%) agonist- and EFS-induced contractions. CMPD101 (50 μM) inhibited (≥ 50%) α-adrenergic and U46619-induced contractions, but no endothelin-1- or EFS-induced contractions. Neither FRAX486 (30 μM), nor Cpd22 (3 μM) affected contractions. Vasorelaxation by EHT1864 and NSC23766 may exclude application in BPH but may allow simultaneous treatment of cardiovascular disease and BPH. NSC23766 shows previously unrecognized α-adrenoceptor antagonism. Findings with SecinH3 suggest an organ-selective involvement of cytohesin-2/Arf6 signaling in smooth muscle contractions. SR7826 may cause cardiovascular effects, while side-effect risks limit kinase inhibitors in non-malignant disease.

Nalfurafine is the only clinically approved kappa opioid receptor (KOPr) agonist that can cross the blood-brain barrier and exert CNS effects. Because its clinical use is not associated with dysphoria, it is widely believed to have an atypical pharmacological profile. Nalfurafine's atypical properties are proposed to result from its G-protein-biased KOPr agonist property, leading to the widespread use of nalfurafine as a nonaversive KOPr agonist in preclinical research. The validity of nonaversive claims for nalfurafine was investigated in mice by comparing its antinociceptive and aversive effects with those of the typical, nonbiased KOPr agonist U50,488 in tail withdrawal and conditioned place aversion (CPA) tests. Dose responses for tail withdrawal with nalfurafine and U50,488 were determined in warm (52°C) water in adult male and female C57BL/6J mice. Doses of U50,488 produced antinociception from 5 mg/kg, and doses of nalfurafine from 0.06 mg/kg. Four-fold lower doses of either KOPr agonist (U50,488: 1.25 mg/kg; nalfurafine: 0.015 mg/kg) were subthreshold for antinociception. No sex differences were seen. Antinociceptive effects were fully blocked by the KOPr antagonist norBNI (10 mg/kg). Antinociceptive doses of nalfurafine (0.06 mg/kg) and U50,488 (5.0 mg/kg) both induced CPA. Subantinociceptive doses of nalfurafine (0.015 mg/kg) and U50,488 (1.25 mg/kg) were nonaversive in CPA. Thus, in mice, at doses that are antinociceptive, CPA was evident for both KOPr agonists. Neither nalfurafine nor U50,488 showed a separation between their antinociceptive and aversive effects, contradicting the hypothesis that nalfurafine is a nonaversive analgesic in mice. The findings caution against assuming nalfurafine is a nonaversive KOPr agonist for use in preclinical research.

Baxdrostat is a novel, highly potent, selective, competitive inhibitor of human aldosterone synthase currently under development for the treatment of uncontrolled and resistant hypertension and chronic kidney disease. We assessed the risk of QTc-interval prolongation with baxdrostat using concentration-QTc (C-QTc) modeling in healthy adult participants using data from two placebo-controlled Phase 1 studies: a multiple-ascending dose (MAD) study of baxdrostat 0.5-5 mg (N = 56; NCT05500820) and a Phase 1 four-way crossover thorough QT/QTc (TQT) study assessing the pharmacokinetics, pharmacodynamics, safety and tolerability of baxdrostat at supratherapeutic doses of 16 and 32 mg (N = 28; NCT06194032). In the TQT study, 28 participants were randomized to one of four treatment sequences (each n = 7) of baxdrostat 16 mg, baxdrostat 32 mg, placebo and open-label moxifloxacin 400 mg. Digital electrocardiogram and pharmacokinetic data were collected at baseline and up to 48 h post dose. Dependent and independent variables of the pre-specified linear mixed-effect model were placebo-corrected baseline-adjusted ΔΔQTcF and baxdrostat plasma concentrations, respectively. Results were consistent between the two C-QTc modeling analyses. Baxdrostat treatment did not produce QT-interval prolongation, both at concentrations of interest and geometric mean of the maximum observed plasma concentration. Upper bounds of the two-sided 90% confidence interval for the ΔΔQTcF mean estimates were < 10 ms. Pharmacokinetic data for the 16 and 32 mg doses in the TQT study were as expected, and both doses were well tolerated. These data illustrate that baxdrostat is not associated with the risk of QT-interval prolongation at therapeutic and supra-therapeutic concentrations.

Postoperative central nervous system (CNS) infections are associated with high mortality and present a therapeutic challenge due to limited antibiotic penetration into the brain extracellular fluid (ECF). Vancomycin, frequently used in this setting, requires therapeutic drug monitoring; however, its quantification in brain ECF via microdialysis is limited by the need for accurate calibration of relative recovery (RR). This study aimed to determine the in vitro RR of vancomycin under conditions simulating clinical neuromonitoring to support application in clinical practice. Vancomycin RR was assessed using forward dialysis and retrodialysis techniques at a fixed perfusion rate of 0.3 μL/min, consistent with standard neuromonitoring protocols. Vancomycin concentrations were measured using a homogeneous enzyme immunoassay across subtherapeutic, therapeutic, and supratherapeutic levels. RR was calculated as the ratio of microdialysate to reference solution concentrations. Mean RR was 86.5% (SD 3.6%) for forward dialysis and 86.4% (SD 2.1%) for retrodialysis, with no significant difference between techniques (p = 0.957). RR remained consistent across all tested concentration levels (p = 0.051). A strong correlation was observed between vancomycin concentrations in the microdialysate and the study solution (r = 0.997, p < 0.001). The high and stable RR achieved under clinically relevant conditions supports the use of this in vitro microdialysis model as a reliable calibration tool. This model may aid in estimating vancomycin concentrations in brain fluid, facilitating dose optimization in patients undergoing microdialysis-based monitoring for postoperative CNS infections.