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Any polymorphic conversion of an active pharmaceutical ingredient (API), even if partial, is likely to lead to changes in its efficiency and safety. Posaconazole, an antifungal drug, is detected as Form-S in the commercially available oral suspensions. However, a mixture of Form-S and the initial Form I is likely to coexist depending either on the manufacturing process of the suspensions and/or to the storage conditions of the suspension. The simultaneous quantitation of these crystal forms in suspensions is challenging because of the dose inhomogeneity and the instability of Form-S at ambient conditions. Although X-ray Powder Diffraction (XRPD) was initially employed, preferred orientation issues in the suspension inhibited the successful quantitative determination of the polymorphs. In order to circumvent the problem Raman spectroscopy was selected for addressing this challenge, while the additional application of a home-made rotation system reduced the inhomogeneity problems. A separate calibration curve was generated for each polymorph using a conventional linear regression. The combination of these two relations led to the formation of a comprehensive equation relating the characteristic Raman peak intensities of posaconazole Form-S and Form I with the concentrations thereof. The method was validated and the results were confirmed through a partial least square regression (PLSR). The detection limits for Form-S and Form I were determined equal to 1.9 mg/mL and 2.2 mg/mL, respectively., 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 Elsevier B.V. All rights reserved.)

A novel micrometer-sized porous cyclodextrin polymer (PCDP) was synthesized through the cross-linking of carboxymethyl β-cyclodextrin with 1,6-diaminohexane. We hypothesized that PCDP could be utilized as a drug carrier to enhance the dissolution rate and oral bioavailability of poorly soluble drugs. Ibuprofen (IBU), selected as the model poorly soluble drug, was successfully loaded into PCDP, resulting in a significant improvement in IBU release within simulated gastric fluid. Compared to IBU alone, IBU-loaded PCDP markedly increased the oral bioavailability of IBU, with an approximately 4-fold increase in the area under the curve (AUC) and a 3-fold increase in C max , thereby enhancing the anti-inflammatory effects in rat models. Additionally, PCDP demonstrated good biocompatibility with Caco-2 cells. These findings suggest that the micrometer sized PCDP may be a promising drug carrier for improving the dissolution and oral bioavailability of poorly soluble drugs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xiangjun Zhang reports financial support was provided by Chongqing Medical University. Xiangjun Zhang, Sisi Yi and Tao Guo has patent pending to National Intellectual Property Administration, PRC. If there are other authors, they 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 Elsevier Ltd. All rights reserved.)

Background: Patients with non-valvular atrial fibrillation (nvAF) who experienced a cardioembolic (CE) event despite adequate oral anticoagulation (OAC) are at high risk of recurrence and the combination between percutaneous left atrial appendage closure (LAAC) and long-term OAC may be a valuable option. The aim of this study was to compare the safety and the efficacy of post-LAAC long-term assumption of direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs) in this population., Methods: Consecutive nvAF patients who experienced OAC failure despite adequate OAC therapy and underwent LAAC were retrospectively enrolled from three Italian centers. Patients were divided according to the anticoagulation strategy following LAAC: DOAC group and VKA group. The primary endpoint was a composite of all-cause death, CE event, and major bleeding, while secondary endpoint was a composite of CE event and major bleeding., Results: Overall, 132 patients (39 % females; mean age 69 ± 11 years), including 73 patients on DOAC and 59 patients on VKA, were enrolled. At a median follow up of 61 ± 23 months, the DOAC group reported lower rate of primary endpoint (HR 0.42, 95 %CI 0.18-0.99, p = 0.038) and lower rate of secondary endpoint (HR 0.28, 95 %CI 0.09-0.89, p = 0.02). No significant differences were detected regarding the type of DOAC assumed. Previous cerebrovascular events, CHA2DS2-VASc, CHADS2, HAS-BLED, and renal dysfunction were predictors of the primary endpoint., Conclusion: Long-term DOAC assumption was associated with higher free from primary and secondary endpoint with respect to VKA in nvAF patients undergoing LAAC for OAC failure., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal (IN) delivery to enhance the CNS delivery of riluzole (RLZ), a standard ALS treatment which is subject to blood-brain barrier efflux mechanisms. Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined. To quantify RLZ in vivo in mice, [ 14 C]-RLZ was synthesised using an optimised one-pot method. [ 14 C]-RLZ yield was 21.3 ± 3.4 %, measured by High Performance Liquid Chromatography (HPLC), with a specific activity of 40.4 ± 3.9 µCi/mg measured by HPLC and liquid scintillation counting. RLZ synthesis was verified using proton nuclear magnetic resonance ( 1 H NMR), and liquid chromatography-mass spectrometry. IN RLZ (5 mg/kg) produced double the maximum brain levels (1.11 ± 0.34 % Injected Dose (ID)/brain) at 30 min as oral RLZ (5 mg/kg). The uptake of RLZ in the liver was reduced by half for intranasal administration compared to oral administration. Intravenous ELC (5 mg/kg) substantially increased brain levels of IN RLZ to 3.52 ± 0.62 % ID/g brain at 60 min post-administration, compared to 1.87 ± 0.33 % ID/g brain in the absence of the efflux pump inhibitor. However, increased concentrations were also observed in the liver and blood. These results indicate that intranasal delivery of RLZ enhances brain targeting and reduces liver accumulation compared to the oral route. Brain uptake of IN RLZ was enhanced further by ELC, although not selectively as accumulation in the liver or blood was also observed. Further metabolic research using Chromatography-Mass spectrometry (LC-MS) or NMR along with excretion studies are warranted for a more comprehensive understanding of the pharmacokinetics of IN RLZ and IN RLZ/ELC. Additionally, employing suitable ALS animal models is crucial for understanding RLZ's effects on disease progression, mechanism of action, efficacy, and potential side effects to aid further development., 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.)

Decreased saliva production due to salivary gland damage can result in difficulty speaking and swallowing, significantly reducing quality of life for head and neck cancer patients receiving radiotherapy. It is therefore imperative that treatment options are available to mitigate the effects of these debilitating side effects. D-limonene, a naturally occurring terpene, has shown protective effects on saliva production during radiotherapy treatment of mice, however the lipophilic nature of the molecule has necessitated a high oral dose to facilitate sufficient absorption. In this study, lipid-based drug delivery systems have been utilised to formulate D-limonene in order to reduce undesirable gastrointestinal side effects and increase solubility for enhanced absorption. Lipid-based formulations produced up to 180-fold increased solubility over pure D-limonene, coupled with enhanced storage stability and protection against oxidation. Furthermore, pharmacokinetic evaluation of optimised lipid-based formulations in Sprague Dawley rats displayed up to a 51.25-fold increase in bioavailability relative to pure oral D-limonene. Finally, elevated levels of lipid-formulated D-limonene were localised within the submandibular salivary glands, indicating potential for local action on saliva production. Overall, the administration of D-limonene utilising lipid-based formulations shows significant promise for advancing prevention and treatment strategies for xerostomia., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Clive A Prestidge reports financial support was provided by LimRad Therapeutics. If there are other authors, they 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 use of in vitro markers able to reproduce the in vivo permeability and diffusivity of orally administered drugs, could represent an innovative starting point for the formulation of delivery systems, in particular for low soluble and low permeable drugs belonging to BCS class II and IV. Considering the great interest in the green pharmaceutical approaches and the increasing use of natural molecules as novel therapeutic drugs, in this study, rutin, hesperidin and curcumin have been selected as lipophilic model drugs to investigate their possible enhancement of their permeability and bioavailability after oral administration. As the low solubility of the three drugs hinders their application, β-cyclodextrins (CD), amphiphilic natural moieties able to form stable inclusion complexes, have been considered to promote their solubilization. Notably, hydroxypropyl-β-CD (HPBCD) and methyl-β-CD (MBCD), have been selected and the formation of the inclusion complexes with a stoichiometric ratio of 1:1 has been detected through phase-solubility studies and rationalized via docking calculations, revealing a strong complexation and an increased hydrophilicity of the systems. The diffusion experiments performed through the novel UV-Vis localized spectroscopy method confirmed a the extremely high stability of the CD-drugs complexes, especially in the cease of curcumin, which makes this as the predominant chemical specie to diffuse and permeates. The PermeaPad® plate, an in vitro cell-free assay, allowed to investigate the permeability behavior of the drugs, demonstrated that the type of β-cyclodextrins can influence the permeability through the biomimetic membrane, reflecting the effect of the unstirred water layer (UWL). Moreover, in the case of curcumin, the spectroscopic-mathematical approach suggested the formation of nano-supramolecular systems, detected by DLS, supporting the precision of the fitting model., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Interest in oral delivery of biological drug products, commonly prepared through lyophilization, is surging. Typically, low solid content solutions are employed for lyophilization to enhance mass transfer and minimize drying time. Yet, this approach often results in lyophilized powders with low bulk density and poor flowability, challenging downstream processing steps that are required for oral product development. Increasing solid content in a starting solution can, in theory, increase the density of lyophilized cakes and powders post-milling. However, the effectiveness of improving powder density and flowability using a higher solid content has not been experimentally verified. In addition, the impact of using a higher solid content on other physicochemical properties of lyophilized materials remains uncertain. To address the knowledge gaps, we lyophilized three common bulk cryoprotectants at two different solid contents (5% and 10%) and systematically evaluated their solid-state properties, bulk density, flowability, compaction characteristics, and physical stability. We found that powders prepared at a higher solid content (10%) exhibited higher bulk density, but they still failed to meet the requirements for easy oral product development. A change in solid content also leads todistinct solid-state properties, compaction behaviors, and stability, highlighting the importance of thorough characterization of lyophilized materials when solid content is changed in the course of oral solid dosage formulation development., 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 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Tianshu capsule (TSC) is a traditional Chinese medicine (TCM) preparation and has significant clinical effect on migraine. The composition characteristics of TSC formula are worth exploring for the treatment of migraine., Aim of the Study: Identify the compounds in vivo after oral administration of TSC, Gastrodin (GAS), ferulic acid, senkyunolide G and senkyunolide I in the blood of healthy and migraine rats were used as representative compounds for time-dependent processes investigation. And we focus on explaining the characteristics of TSC treatment on migraine from a pharmacokinetic perspective., Materials and Methods: In this study, Ultra-high performance liquid chromatography with Orbitrap tandem mass spectrometry (UPLC-Orbitrap-MS/MS) system were used to detect the compounds in rat plasma and brain after oral administration of TSC. A sensitive, selective and reliable ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQ-MS/MS) system method was established for the simultaneous quantitative analysis of multi-components and evaluate the pharmacokinetic behavior of four main compounds., Results: A total of 46 compounds were significantly identified in vivo of rat, including 35 compounds in plasma, 7 compounds only in brain and 4 compounds both in plasma and brain. The quantitative method has been confirmed to be feasible for multi-components content determination, pharmacokinetic parameters indicated that the four compounds absorbed into blood rapidly, and senkyunolide I also cross the blood-brain barrier (BBB) quickly into brain. GAS has relatively high concentrations in plasma, and the parameters AUC 0-t , CL z/F displayed significant differences between the normal and migraine rats. And the AUC 0-t and C max of GAS and ferulic acid exhibited dose-dependent way., Conclusions: we added compounds for the pharmacokinetic study of TSC, providing powerful help for clinical medication in the treatment of migraine., Competing Interests: Declaration of competing interest The authors confirm that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

In this study, lyophilizates with the second-class antipsychotic agent lurasidone hydrochloride were developed as orodispersible platforms to improve patients' adherence. The primary aim was to evaluate the effect of the amino acid additive (L-arginine, L-lysine, L-histidine) and the freeze-drying stage on the pharmaceutical performance of the designed formulations. The composition was initially optimized using an experimental design approach. The amino acids (in particular L-histidine) acted as dispersing agents, prevented drug aggregation and assured high drug content uniformity within the lyophilizate matrix. The freeze-drying stage reduced the particles dimensions which significantly increased solubility of lurasidone hydrochloride, and consequently, it's dissolution rate. The presence of L-arginine in lyophilizate composition balanced out sufficient compression strength with a rapid drug release. Despite the fact that L-lysine enhanced the mechanical strength, it also caused delayed drug release. Notably, L-histidine and L-arginine accelerated transport of lurasidone hydrochloride through the porcine buccal epithelium with approximately 100% and 50% increase in absorption, respectively, when compared to commercial reference drug. Overall, the designed lyophilizates containing L-histidine and L-arginine, hold promise as orodispersible platforms for improved performance of lurasidone hydrochloride., 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.)

Ethnopharmacological Relevance: Multi-targeted drug therapy has received substantial attention for the treatment of diseases of multifactorial origin, such as neurodegenerative diseases. Manasamitra vatakam (MMV) is a traditional Ayurvedic formulation used to improve cognitive impairment and mental illness. Here we have used a unique method for leveraging the barrier properties of the intestinal and blood-brain barrier (BBB) to screen and identify the bioactive molecules against Alzheimer's disease (AD). The current method exemplifies a facile method to expedite drug discovery from traditional formulations., Aim of the Study: The present study aimed to identify the phytoconstituents of MMV that reach the brain tissue and to predict major bioactive constituents by computational docking studies., Materials and Methods: After oral administration of the formulation, brain samples from male Sprague Dawley rats were collected at different time intervals and analyzed by liquid chromatography-mass spectrometry (LC-MS) to identify the phytoconstituents. In silico molecular docking studies were carried out to analyze the binding affinity of the compounds to the target proteins of AD using Schrodinger Maestro. The molecular dynamic studies were carried out for all the docked complexes having higher docking scores., Results: 34 phytoconstituents were identified by LC-MS analysis of brain homogenates. In the in silico docking study, the phytoconstituents chrysin, convolvin, rutin, galangin, palmatoside G, isoliquiritigenin, quercetin, and naringenin showed higher docking score against the target proteins of AD. These compounds may serve as the primary bioactive compounds responsible for the neuroprotective activity of the herbal formulation. Furthermore, molecular dynamic studies indicated that the galangin-acetylcholinesterase enzyme complex has the highest stability among these eight compounds., Conclusion: The study, together with previous in vivo and in vitro efficacy results, suggests that BBB-permeable compounds with high binding affinities for the target proteins of AD might be responsible for the effectiveness of MMV against AD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Anju C NairSonu BennyAneesh TPMS SudheeshPK Lakshmi., (Copyright © 2024 Elsevier B.V. All rights reserved.)

As cannabis legalization expands, preclinical studies continue to investigate the impact of repeated exposure to delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in the plant. With the increasing popularity of cannabis infused foods, the rise of THC in medicinal applications have also expanded. The present study addresses a critical gap in existing literature by investigating the behavioral and neurobiological effects of low-dose edible THC in a preclinical rodent model. Adult male rats were administered synthetic-THC (Dronabinol) (0.0625 mg/kg, 0.125 mg/kg, and 0.25 mg/kg) or vehicle (sesame oil) through edible cookies, 90 min prior to eight locomotor sessions. Locomotor activity significantly increased in both 0.0625 mg/kg and 0.25 mg/kg THC groups, indicating a dose-dependent relationship. Repeated 0.25 mg/kg THC administration dose-dependently reduced cannabinoid receptor 1 expression in the hippocampus. The observed neurobiological change from low dose oral THC advances our understanding of repeated cannabis use. These findings also emphasize the importance of refining rodent models for translational relevance., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Busulfan at high doses has been associated with a risk of seizures. Phenytoin has been used traditionally as anti-seizure prophylaxis, and benzodiazepines and levetiracetam have been introduced more recently, providing data from retrospective series. The main purpose of this study was to evaluate the effectiveness of oral clonazepam as anti-seizure prophylaxis in adult patients receiving high doses of intravenous busulfan as part of the conditioning regimen for hematopoietic stem cell transplantation. The secondary objectives were to determine the feasibility of this regimen and to analyze the adverse events associated with the use of clonazepam., Methods: This prospective, single-center study included 64 adult patients who received conditioning regimens with high doses of intravenous busulfan and anti-seizure prophylaxis with oral clonazepam, at a dose of 1 mg/8 h, from 12 h before starting treatment with busulfan until 48 h after ending administration., Results: The effectiveness of the prophylaxis was 100%, with no episodes of seizures during busulfan treatment or in the 72 h afterwards. Treatment was feasible, and oral scheduled administration was completed in all patients. Adverse events that could be associated with clonazepam included the onset of somnolence, dizziness, and confusion, mostly mild., Conclusion: The oral clonazepam regimen described in this study has been prospectively shown to be an effective, feasible anti-seizure prophylaxis option with manageable toxicity., Competing Interests: Declarations. Ethics approval and consent to participate: Approval was granted by the Ethics Committee of University Hospital Virgen de la Arrixaca (17 February 2014/SDC-CLO-2013-01). Written informed consent from all included patients was obtained. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Abstract: Threatened miscarriage is a common complication of early pregnancy characterized by symptoms of vaginal bleeding with/without abdominal cramps/pain in the first trimester. Progestogens are often administered for the management of this condition. Presented herein is the protocol of an ongoing, multicentric clinical trial to investigate the efficacy and safety of micronized progesterone (natural progestogen) compared to dydrogesterone (synthetic isomer of progesterone). A total of 304 eligible pregnant women aged 20-39 years, diagnosed with threatened miscarriage, will be enrolled during 5-12 weeks of gestation and randomized equally to receive either oral dydrogesterone (40 mg stat, followed by 10 mg three times a day) or oral micronized progesterone (200 mg two times a day) up to one week after stoppage of bleeding or if bleeding does not stop, then treatment will be continued till a maximum of 14 weeks of gestation (unless miscarriage is confirmed earlier or the investigator decides to prolong treatment for better outcome or if bleeding relapses). Scheduled visits after enrollment will be conducted during 6-13, 8-14, 18-20 and 24-26 weeks of gestation, in addition to a visit at the end of treatment at 14 weeks and another after parturition. The primary endpoint of the study is the miscarriage rate before 20 weeks of gestation. Secondary endpoints include the ongoing pregnancy rate at 24 weeks, treatment-induced changes in serum levels of cytokines and time to symptom resolution. Apart from the incidence of treatment-emergent adverse events, safety endpoints include changes in complete blood count and the results of liver and kidney function tests from baseline to 14 and 24-26 weeks of gestation. Delivery outcomes are exploratory endpoints of the study., Lay Summary: Almost one out of four women face miscarriage during the first trimester of pregnancy; initial symptoms include vaginal bleeding with/without abdominal cramps/pain. This paper presents the plan of how an ongoing, multicentric study will be conducted to compare the efficacy and safety of oral medications known to reduce chances of miscarriage: micronized progesterone (which is a natural female sex hormone) versus synthetic progesterone. Women aged 20-39 years who are at risk of miscarriage during the first trimester of pregnancy will be randomly treated with either medication till one week after stoppage of bleeding during early pregnancy. If bleeding does not stop, treatment will be continued till a maximum of 14 weeks of pregnancy (unless miscarriage is confirmed earlier). The participants will be monitored until delivery. The study will evaluate the proportion of participants who experience miscarriage before 20 weeks of pregnancy and those who have an ongoing pregnancy at 24 weeks. It will also look at the time taken for relief from symptoms such as vaginal bleeding and abdominal pain, outcomes of delivery and incidence of any untoward event. In addition to routine tests and scans, additional tests will check for levels of biochemical parameters in the body, which are regulated by the natural or synthetic progesterone., Clinical Trial Registration Number: CTRI/2024/02/063174 [Registered on: 26/02/2024].

Background: Catheter-associated urinary tract infections (CA-UTIs) are a common hospital-acquired infection. We examined ciprofloxacin activity in a novel CA-UTI in vitro model., Methods: Three ATCC strains [Escherichia coli (ECO)-25922, Klebsiella pneumoniae (KPN)-700721, Pseudomonas aeruginosa (PAE)-27853] and 45 clinical urinary isolates were assessed. Biofilm mass and planktonic bacterial density were quantified during drug-free incubation (72 h) and following ciprofloxacin exposure (equivalent 750 mg orally q12h, 3 days)., Results: ECO produced smaller biofilms (6.3 ± 1.1 log10 cfu/cm2) compared with KPN (7.1 ± 0.7 log10 cfu/cm2) and PAE (7.0 ± 1.2 log10 cfu/cm2), which extended along the entire catheter length. Following ciprofloxacin, all isolates with MIC > 4 mg/L had minimal biofilm disruption or planktonic kill. Ciprofloxacin resistance was most common in PAE isolates (10/16 isolates), compared with ECO (3/16 isolates) and KPN (6/16 isolates). Greater ciprofloxacin exposure (AUC0-24/MIC) was required for a 3 log10 biofilm kill for KPN (5858; R2 = 0.7774) compared with ECO (2117; R2 = 0.7907) and PAE (2485; R2 = 0.8260). Due to persistent growth in the bladder, ECO required greater ciprofloxacin exposure for a 3 log10 planktonic kill (5920; R2 = 0.8440) compared with KPN (2825; R2 = 0.9121) and PAE (1760; R2 = 0.8781). Monte Carlo simulation supported a 95% PTA for both a 3 log10 biofilm and planktonic kill for ECO and KPN isolates with MIC ≤ 0.5 mg/L and PAE isolates with MIC ≤ 1 mg/L., Conclusions: In a novel CA-UTI model, following simulated ciprofloxacin therapy, KPN biofilms were comparatively more difficult to disrupt, ECO planktonic growth frequently persisted in the bladder, and PAE had greater propensity for emergence of ciprofloxacin resistance., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Dersimelagon is a novel investigational orally administered selective agonist of the melanocortin-1 receptor. The drug-drug interaction (DDI) potential of dersimelagon was investigated in both nonclinical (in vitro) and clinical studies. The in vitro inhibition of CYP/UGT isoforms and efflux/uptake transporters by dersimelagon was assessed. The impact of 300-mg dersimelagon on the pharmacokinetics (PK) of substrate drugs and the effect of co-administering verapamil on 100-mg dersimelagon PK (as substrate drug) were investigated in healthy participants in a Phase 1 study. DDIs were assessed based on ratios of C max and AUC 0-∞ of substrate drug administered alone and with dersimelagon (or verapamil). Relatively potent in vitro inhibition of CYP2C9, CYP3A, UGT1A1, BCRP, P-gp, and OATPs by dersimelagon was observed. In the clinical study, exposures of atorvastatin (CYP3A, P-gp, BCRP, OATP substrate) rosuvastatin (BCRP and OATP substrate), and β-hydroxy simvastatin (metabolite of simvastatin) increased 2- to 3-fold (atorvastatin: C max LS mean ratio = 198.0%; AUC 0-∞ ratio = 196.6%; rosuvastatin: C max ratio = 316.5%, AUC 0-∞ ratio = 206.0%) when co-administered with dersimelagon. Midazolam (CYP3A substrate), digoxin (P-gp), pravastatin (OATP), and simvastatin (CYP3A) did not show any clinically relevant DDI effects when co-administered with dersimelagon. Dersimelagon exposure increased ~25% when co-administered with verapamil, an effect not considered clinically relevant. Dersimelagon 300 mg did not elicit major DDIs involving CYP/UGT enzymes and drug transporters; however, dersimelagon may have potential for clinically relevant DDIs with drugs that are substrates for BCRP, such as atorvastatin and rosuvastatin, and caution should be exercised when co-administering 300-mg dersimelagon with these statin drugs. Trial Registration: ClinicalTrials.gov: NCT04793295, NCT04402489, NCT04440592, NCT02834442, NCT03520036, NCT03503266., (© 2025 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background: Drug shortages are an increasing and worldwide problem. Oral antibiotics are one of the most used medicines worldwide and have recently been affected by drug shortages. Despite this, little is known about the impact of antibiotic shortages on prescribing practices., Aim: To explore the impact of oral antibiotic shortages on national antibiotic utilisation., Methods: A cross-sectional study of oral antibiotic shortages and antibiotic utilisation was conducted using Australian reimbursement and regulatory data from January 2022 to December 2023. All nationally reimbursed oral antibiotics were included in the study. The number and duration of reported antibiotic shortages per product were determined for each active ingredient. The clinical impact was assessed using national utilisation in Defined Daily Doses per 100 000 inhabitants. Changes in trends were analysed using Joinpoint regression., Results: Shortages were reported for eighteen of the twenty-one (86%) oral antibiotics reimbursed in Australia. For ten active ingredients, shortages did not coincide with changes in utilisation data. No clear relation between the number and duration of shortages and impact on utilisation was observed. Changes in utilisation coinciding with shortages were observed for eight active ingredients. For cefaclor (-20% decrease in utilisation) and roxithromycin (-26% decrease), the impact of shortages is most clearly reflected by decreases in utilisation. For the other six, minor changes in utilisation were observed coinciding with shortages., Conclusions: Antibiotic shortages were common in Australia during 2022 and 2023. The impact of shortages differs per antibiotic, for some antibiotics there are shortages coinciding with declines in utilisation. For others, shortages occur without apparent changes in utilisation., (© 2025 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Long-term evidence on maintenance doses of oral immunotherapy (OIT) for anaphylactic cow's milk allergy is insufficient., Methods: We retrospectively compared the three-year safety, efficacy, and adherence between OIT with a maintenance dose of 200 mL of cow's milk (HOIT, 2009-2013) and 3 mL of cow's milk (LOIT, 2013-2019). Patients aged 6-18 years with a history of anaphylaxis reacting to ≤3 mL of cow's milk during oral food challenge (OFC) were included. Adverse symptoms, OFC negative rate after 2 weeks of avoidance, dropout rate, and immunological changes were compared., Results: The median ages in the HOIT (n = 78) and LOIT (n = 99) groups were 8.1 and 7.8 years, with milk-specific IgE levels of 56.5 and 49.2 kUA/L, respectively. The percentages of doses triggering symptoms were 20.88%, 13.73%, and 7.31% in the HOIT group and 11.81%, 8.15%, and 6.30% in the LOIT group during years 1, 2, and 3, respectively. After 3 years, 29% of patients in the HOIT group passed the OFC with 200 mL, and 47%, 18%, and 5% of patients in the LOIT group passed the OFC with ≥25 mL, ≥50 mL, and 100 mL of cow's milk, respectively. After 3 years, the dropout rates were 24% and 11% in the HOIT and LOIT groups and milk-specific IgE levels decreased by 88% and 78% in the HOIT and LOIT groups, respectively., Conclusion: HOIT enables higher dose consumptions. LOIT might be safer and have higher adherence in patients with anaphylactic cow's milk allergy., (© 2025 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: New 6-month rifampicin-resistant tuberculosis treatment regimens containing bedaquiline, pretomanid, and linezolid (BPaL) with or without moxifloxacin or clofazimine, could improve treatment efficacy, safety, and tolerability, and free up resources within the health system. Following a change to WHO rifampicin-resistant tuberculosis treatment guidelines, countries are facing difficult decisions about when and how to incorporate new drug regimens into national guidelines. We aimed to assess the probability of BPaL-based regimens being cost-saving using data collected in the TB-PRACTECAL trial., Methods: This economic evaluation using a cost-utility analysis was embedded in five TB-PRACTECAL trial sites in Belarus, Uzbekistan, and South Africa. Between Nov 19, 2020, and Sept 27, 2022, we collected detailed primary unit cost data in six hospitals and four ambulatory health facilities and collected data on patient-incurred costs from 73 trial participants. The primary efficacy endpoint of the main trial, a composite of unfavourable outcomes (death, disease recurrence, treatment failure, early discontinuation of therapy, withdrawal, or loss to follow-up) and clinically important safety outcomes by 72 weeks of follow-up were incorporated into the analysis. Societal perspective cost data and effect outcome data were input into a Markov model to estimate the cost per disability-adjusted life-year (DALY) averted by BPaL-based regimens compared with the standard of care over a 20-year time horizon. We conducted a range of univariate and probabilistic sensitivity analyses to test our findings., Findings: BPaL-based regimens averted a mean of 1·28 DALYs and saved a mean of US$14 868 (SD 291) per person from the provider perspective compared with standard-of-care regimens over 20 years. Patient-incurred costs were reduced by a mean of $172 (SD 0·84) in BPaL-based regimen groups compared with standard of care. The main cost drivers for both providers and patients were inpatient bed-days; the duration of the inpatient period varied across countries. Varying a range of model parameters affected the degree of cost savings but did not change the finding that BPaL-based regimens are cost-saving compared with standard of care., Interpretation: This trial-based evidence adds to consistent indications from modelling studies that BPaL-based regimens are cost-saving for both the patient and health system. Urgent implementation of BPaL-based regimens in countries with a high burden of tuberculosis could improve treatment of rifampicin-resistant tuberculosis, reduce pill burden, and free up desperately needed resources within the health system., Funding: Médecins Sans Frontières., Competing Interests: Declaration of interests B-TN, CB, EK, PJ, SM, IM, TA, PSA, and NS were employees of Médecins Sans Frontières during the trial. SS, YVL, MPS, MD, and KF received salary funding paid to the London School of Hygiene & Tropical Medicine. MR was a member of the BPAL Community Access Program data monitoring committee and a member of the BEAT Tuberculosis data monitoring committee. All other authors declare no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The management of hormone receptor-positive (HR +) breast cancer (BC) relies on endocrine therapy (ET), with a primary focus on disrupting estrogen receptor (ER) signaling due to its critical role in BC tumorigenesis and progression. While effective for both early-stage and advanced breast cancers, ET frequently encounters resistance mechanisms, including both ligand-dependent and ligand-independent trajectories, ultimately leading to disease progression., Methods: We searched PubMed, EMBASE and Scopus databases to review the current evidence on the use of novel oral selective estrogen receptor degraders (SERDs) for the treatment of HR+ BC., Conclusions: Somatic activating mutations of the estrogen receptor 1 (ESR1) gene are known to sustain ER activity, boost ER-dependent gene transcription, and foster resistance to ET. The most significant gap remains after treatment failure with ET and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, where fulvestrant monotherapy typically results in a median progression-free survival of 2-3 months. Novel compounds, including oral SERDs, have been explored for their potential to overcome therapeutic resistance, both as monotherapy and in combination with other targeted therapies. Herein, we provide an overview on the latest findings on oral SERDs, examining their mechanism of action, safety data, and pharmacokinetics and pharmacodynamics profiles., Competing Interests: Declarations. Competing interests: C.C. consulting/advisory role/speaker bureau: Pfizer, Roche, MSD, Lilly, Novartis, Seagen, Gilead, AstraZeneca, Daiichi Sankyo. A.M. has received honoraria as a consultant, advisor or speaker from Roche and Menarini/Stemline; and has received travel and accommodation support from AstraZeneca. G.C. received honoraria for speaker’s engagements from Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, and MSD; honoraria for providing consultancy from Roche, Seattle Genetics, and NanoString; honoraria for participating in Advisory Board for Roche, Lilly, Pfizer, Foundation Medicine, Samsung, Celltrion, and Mylan; honoraria for writing engagement from Novartis and BMS; honoraria for participation in Ellipsis Scientific Affairs Group; Institutional research funding for conducting phase I and II clinical trials from Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, and Medimmune. The other authors have no relevant financial or non-financial interests to disclose. Ethical approval: Not Applicable. Consent to participate: Not Applicable. Consent to publish: Not Applicable., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: Oral antibiotic prophylaxis (OAP) lowers rates of surgical site infection (SSI) and may aid anastomotic healing in colorectal surgery. The aim of this study was to analyse the understudied impact of OAP on SSI microbiology after colorectal surgery., Method: A post hoc analysis was performed on a previous prospective, multicentre study of elective colorectal surgery. For 1000 patients with SSI, this study compared the microbiology of SSIs in procedures without OAP (SSI/OAP-) and with OAP (SSI/OAP+)., Results: There were 340 patients in the SSI/OAP- group and 660 in the SSI/OAP+ group. The use of OAP increased the presence of Gram-positive cocci (GPC) (OR 1.542, 95% CI 1.153-2.062) and fungi (OR 2.037, 95% CI 1.206-3.440), but reduced rates of Gram-negative bacteria (GNB) (OR 1.461, 95% CI 1.022-2.088) and anaerobe isolation (OR 0.331, 95% CI 0.158-0.696). Specifically, it led to increases in the isolation of Enterococcus faecium (OR 1.450, 95% CI 0.812-2.591), methicillin-resistant Staphylococcus aureus (OR 2.000, 95% CI 1.043-3.834) and Candida spp. (OR 2.037, 95% CI 1.206-3.440). In colon surgery with OAP, GPC infections were more likely (OR 1.461, 95% CI 1.022-2.088). In rectal surgery, organ/space SSIs had a higher risk of harbouring GPC (OR 1.860, 95% CI 1.153-2.999) and a lower risk of GNB (OR 0.321, 95% CI 0.200-0.515)., Conclusion: OAP reduced the presence of anaerobes and GNB in SSIs, but increased the isolation of GPCs and fungi, with E. faecium and Candida being of particular concern. This information should guide empirical antibiotic therapy for postoperative colorectal SSIs in patients who have received preoperative OAP., (© 2025 The Author(s). Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Background & Problems: Oral administration is the most common mode of medical treatment for pediatric patients. Although over 98% of the patients in the targeted pediatric unit require oral medication, the oral administration adherence rate in 2022 was 43.9%. The reasons for this low rate were identified as: (1) no relevant oral administration educational materials, (2) no relevant continued nursing education provided, and (3) lack of assistive tools and feeding aids to help administer oral medication to young children., Purpose: This project was developed to increase the adherence rate of oral administration of preschool pediatric inpatients in our hospital., Resolutions: The improvement strategies included the design of patient-centered oral medication care guidance leaflets and QR code (quick response code) video links, the development of therapeutic play aids, adding cartoon characters to medicine feeders, and the creation of a "Rescue the Forest" picture book and video and reward stickers., Results: The oral medication adherence rate increased from 43.9% pretest to 91.9% posttest., Conclusions: This project and its positive effect on the rate of oral medication adherence may be referenced by other pediatric units.

Accumulating evidence suggests that specific probiotic strains exert effects on hemolytic jaundice (HJ), and probiotic strains of Lactobacillus rhamnosus exhibit potential beneficial effects against HJ. This study aimed to determine the effects of L. rhamnosus MP108 (MP108) on rats with acetylphenylhydrazine (APH)-induced HJ. One week of oral MP108 administration (16 × 10 9 CFU/kg·day) significantly reversed the HJ-induced body-weight reduction and normalized serum levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-PX), hydrogen peroxide (H 2 O 2 ), and superoxide anion (O 2- ) in HJ rats. Furthermore, significant improvements were observed in the pathological changes of liver and intestinal tissues. 16S rRNA high-throughput sequencing of fecal samples demonstrated that MP108 altered gut microbiota composition by increasing Lacticaseibacillus spp. abundance, which correlated with the serum levels of ALT, AST, TBIL, T-SOD, GSH-PX, H 2 O 2 , and O 2- . In summary, these results provide evidence that MP108 has the potential to improve HJ symptoms by alleviating hepatic impairment, which is associated with changes in gut microbiota composition. PRACTICAL APPLICATION: The study indicates that MP108 can modulate the gut microbiota, improve liver function, and thereby alleviate the symptoms of hemolytic jaundice (HJ). These findings suggest a promising therapeutic approach for HJ, offering potential benefits to patients with related conditions., (© 2025 Institute of Food Technologists.)

Background: Ulcerative colitis (UC), an inflammatory disease characterized by intestinal barrier dysfunction, poses significant challenges because of the toxicity and adverse effects commonly associated with conventional therapies. Safer and more efficacious treatment strategies are needed., Purpose: The purpose of this study was to treat UC with Folium Artemisiae Argyi exosome-like nanovesicles (FAELNs) and to explore its related mechanism to provide a safer and more effective means for the treatment of ulcerative colitis., Methods: We established an in vivo model of acute UC in mice and an in vitro inflammatory model using HT-29 human colorectal cancer cells. To evaluate the therapeutic effect of FAELNs on UC, we adopted various proxies, including changes in body weight and disease activity index (DAI) of mice, and measurement of colon length. The concentrations of myeloperoxide, interleukin (IL-1β), IL-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interferon-gamma in sera of mice were detected by ELISA. Immunohistochemistry, hematoxylin and eosin staining, and Alyssin blue staining were performed. The effect of HT-29 cells on oxidative stress was detected using an active oxygen probe, diacetyldichlorofluorescein, and flow cytometry. Western blotting was performed to detect the expression levels of Bax and Bcl-2 in HT-29 cells treated with FAELNs. The effects of FAELNs on IL-6 and IL-1β were detected by fluorescence quantitative PCR. Fecal 16S bacteria were detected, and the role of FAELNs was verified by α diversity and β diversity analyses, principal component analysis, species distribution, and function prediction. For microRNA sequencing of FAELNs, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed. To detect the metabolic and lipid groups of FAELNs, the components were identified and a pharmacological network was constructed to explore the related mechanisms and diseases., Results: FAELNs effectively alleviated the pathogenesis of UC induced by dextran sodium sulfate in animal models, restoring the integrity of the intestinal barrier and reversing an imbalance of the intestinal microbiota., Conclusion: Our findings demonstrate the therapeutic potential of FAELNs in UC management, highlighting their scalability for mass production and encouraging prospects for clinical transformation., 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. Published by Elsevier GmbH.)

Oral probiotics have significant potential for preventing and treating many diseases. Yet, their efficacy is often hindered by challenges related to survival and colonization within the gastrointestinal tract. Nanoparticles emerge as a transformative solution, offering robust protection and enhancing the stability and bioavailability of these probiotics. This review explores the innovative application of nanoparticle-armored engineered probiotics for precise disease treatment, specifically addressing the physiological barriers associated with oral administration. A comprehensive evaluation of various nano-armor probiotics and encapsulation methods is provided, carefully analyzing their respective merits and limitations, alongside strategies to enhance probiotic survival and achieve targeted delivery and colonization within the gastrointestinal tract. Furthermore, the review explores the potential clinical applications of nano-armored probiotics in precision therapeutics, critically addressing safety and regulatory considerations, and proposing the innovative concept of 'probiotic intestinal colonization with nano armor' for brain-targeted therapies. Ultimately, this review aspires to guide the advancement of nano-armored probiotic therapies, driving progress in precision medicine and paving the way for groundbreaking treatment modalities., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors gave their consent for publication. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Introduction: Daily oral antipsychotics (OAPs) are the mainstay of schizophrenia treatment; however, long-acting injectable antipsychotics (LAIs) are associated with better treatment adherence and improved outcomes., Methods: This study assessed the real-world comparative effectiveness of LAIs and daily OAPs using claims data from a nationally representative sample of fee-for-service Medicare beneficiaries with schizophrenia. Antipsychotic discontinuation, psychiatric hospitalization, and treatment failure were compared relative to different reference groups using within-individual Cox regression models., Results: The study included 152,835 patients (mean age, 53.5 years; 54.0% male and 61.5% white). LAIs when grouped by dosing intervals were associated with significantly lower risk of antipsychotic discontinuation (hazard ratios [HRs] 0.27-0.69), psychiatric hospitalization (HRs 0.76-0.88), and treatment failure (HRs 0.55-0.74) compared with OAPs. When LAIs of different dosing intervals and OAPs were broken out by type of agent and compared with oral risperidone, second-generation LAIs, specifically LAI paliperidone (every 3 months [Q3M] and monthly [Q1M]), LAI aripiprazole (Q1M), and LAI risperidone (primarily every 2 weeks), had a significantly lower risk of antipsychotic discontinuation (HRs 0.19-0.67), psychiatric hospitalization (HRs 0.76-0.91), and treatment failure (HRs 0.53-0.85). Second-generation LAI paliperidone (Q3M) had the lowest risk for negative outcomes relative to OAPs; this effect was maintained when the reference group was changed to oral risperidone, LAI risperidone, LAI aripiprazole (Q1M), and LAI haloperidol (Q1M) (33-47% lower risk)., Conclusion: Efforts are needed to enhance identification of appropriate candidates for LAIs and increase their uptake, especially longer dosing interval LAIs, in the Medicare population., Competing Interests: Declarations. Conflict of Interest: Pengxiang Li reported receiving personal fees from Cobbs Creek Healthcare and SKB Consulting Inc, all unrelated to the submitted work. Zhi Geng has nothing to disclose. Carmela Benson and Charmi Patel reported being employees of Janssen Scientific Affairs, LLC and stockholders of Johnson and Johnson. Jalpa Doshi reported receiving grants from Janssen Scientific Affairs, LLC during the conduct of the study; personal fees from AbbVie, Acadia, Janssen, Merck, Otsuka, and Takeda; and grants from Merck and Spark Therapeutics unrelated to the submitted work. No other authors had disclosures to report. Ethical Approval: This study was conducted in accordance with the Helsinki Declaration of 1964 and its later amendments. The University of Pennsylvania Institutional Review Board deemed this study exempt from review., (© 2025. The Author(s).)

Withanone (WN), a bioactive phytochemical isolated from the medicinal herb Withania somnifera, has shown multiple pharmacological and therapeutic successes, including neuroprotective and anti-cancer activities. However, detailed pharmacokinetic (PK) properties of pure WN were not well defined. Pharmacokinetic (PK) characteristics, dose proportionality, and absolute bioavailability of pure WN were explored in rats using an efficient, reliable, and sensitive LC-MS/MS assay to address this gap. The method shows excellent linearity over 0.5-500 ng/mL (r 2  ≥ 0.99), is accurate, and requires less analysis time. A dose proportionality and absolute bioavailability of pure WN were determined in Sprague-Dawley (SD) rats through three ascending oral (10, 20, and 40 mg/kg) and single intravenous (5 mg/kg) PK studies. The peak concentration (Cmax) of WN was 60.53 ± 20.33, 116.30 ± 16.89, and 91.62 ± 6.20 ng/mL, corresponding to oral dosage of 10, 20, and 40 mg/kg, respectively. WN shows poor systemic exposure upon oral administration, leading to low oral bioavailability (<15 %). Additionally, the dose proportionality studies of WN revealed its saturable bioavailability and non-proportional systemic exposure over the dosage range of 10-40 mg/kg in rats. The obtained PK findings of this study would be valuable for better understanding the pharmacological effects of WN, dose regimen optimization for future studies, and relevance for clinical reference to support its future development as a potential therapeutic molecule., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Muhammad Wahajuddin reports financial support was provided by The Council of Scientific and Industrial Research. If there are other authors, they 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 Inc. All rights reserved.)

Chronic nerve compression disorders, such as carpal tunnel syndrome, are common and can significantly impair daily activities due to motor and sensory dysfunctions. Currently, no systemic pharmacotherapy exists for preventing or treating disease progression. This study aims to investigate whether Neurotropin®, an established analgesic, has therapeutic effects. A chronic nerve compression model was created by wrapping a silicone tube around the sciatic nerve in C57BL/6 mice. Nerves were evaluated electrophysiologically and histologically 2 weeks post-surgery. To confirm the preventive effect on disease onset, we administered Neurotropin® subcutaneously. Additionally, continuous subcutaneous administration of Neurotropin® was started 2 weeks post-surgery, and the therapeutic effects were evaluated at 4 and 8 weeks. Furthermore, the therapeutic effects of daily oral administration of Neurotropin®, starting 2 weeks post-surgery, were evaluated at 8 weeks. Significant decreases in nerve conduction velocity and axonal myelination were observed at 2 weeks post-injury. Neurotropin® administration initiated concurrently with model creation did not prevent disease onset at 2 weeks post-surgery. However, starting administration of Neurotropin® 2 weeks post-injury significantly improved outcomes at 8 weeks post-surgery compared to the control group, with continuous subcutaneous and daily oral administration. Neurotropin® may exhibit therapeutic effects for chronic nerve compression disorders., Competing Interests: Declaration of competing interest The funding sponsor, Nippon Zoki Pharmaceutical Co., Ltd., had no role in the design of the study; collection, analyses, or interpretation of data; writing of the manuscript; or decision to publish the results. The authors have declared that no further conflict of interest exists., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Binimetinib is a MEK1/2 inhibitor particularly active in cells harboring activating mutations in the MAP kinase pathway, especially in BRAF and NRAS. Binimetinib, in combination with encorafenib, has received marketing approval in several jurisdictions for the treatment of patients with BRAF V600E or V600K mutant melanoma. The absorption, distribution, metabolism, and excretion of binimetinib were evaluated by administering a carbon 14-labeled binimetinib 45 mg dose (containing 40 μCi of radiolabeled material) to 6 healthy male participants. A total of 62.3% of the radioactivity was eliminated in the feces, while 31.4% was eliminated in the urine. The overall recovery of radioactivity in the excreta for all 6 participants was 93.6% (3.27%), indicating that good mass balance was achieved. The total percentage of the dose in the excreta of all metabolites containing the N-demethylation clearance of binimetinib by CYP1A2 and CYP2C19 was approximately 17.8%. The contribution of direct glucuronidation to the clearance of binimetinib was estimated to be 61.2% and represented the majority of the clearance. Additionally, excretion of unchanged binimetinib into the urine was estimated to have contributed 6.9% to the overall clearance. Based on study results, binimetinib is at least ≈ 50% absorbed, but based on its PK properties and because its glucuronide conjugates are unstable in the GI tract, absorption is thought to be significantly higher., (© 2025 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Relugolix is an oral gonadotropin-releasing hormone receptor antagonist that suppresses sex steroid hormones and is approved as monotherapy for prostate cancer and as a fixed-dose combination with estradiol/norethindrone for the treatment of endometriosis and uterine fibroids. The aim of this postmarketing study was to determine the pharmacokinetics and quantify the amount of relugolix excreted into breast milk of healthy lactating women. Following a single, oral dose of 40 mg relugolix, breast milk was sampled over 120 h. Pharmacokinetic parameters were determined, including the cumulative amount of relugolix excreted into breast milk to derive the total infant dose. The safety and tolerability of relugolix were also assessed. Eight healthy lactating women were enrolled and completed the study per protocol. Relugolix was safe and well tolerated based on adverse events and other safety data. It was excreted into breast milk with a median time to peak concentration (t max ) of 5.81 h and a geometric mean peak concentration (C max ) of 15.7 ng/mL, similar to corresponding plasma data from previous clinical studies. The mean cumulative amount of relugolix excreted was 0.0051 mg over 24 h and 0.0067 mg over 120 h, corresponding to 0.0128% and 0.0167% of the maternal dose, respectively. The body weight-adjusted relative daily infant dose of approximately 0.25% suggests a 400-fold lower newborn than maternal relugolix exposure. Relevant effects of relugolix on the breastfed child appear unlikely given its limited excretion into breast milk of lactating women but cannot be fully excluded in the absence of infant safety data., (© 2025 The Author(s). Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Aims: The aim of the current analyses was to develop a population pharmacokinetic model for nepadutant in infants with colic, and a pharmacokinetic-pharmacodynamic model based on observations of duration of crying and fussing following oral nepadutant administration in infants (3-25 weeks) with colic., Methods: The models were developed based on data obtained at baseline and following treatment with placebo, nepadutant 0.1 mg/kg or nepadutant 0.5 mg/kg administered for 7 days. A continuous response variable, duration of crying and fussing in minutes within 2 h interval, was assembled based on records from "baby's day" diary., Results: The pharmacokinetics of nepadutant was described by a one-compartment model with first-order absorption and elimination with body weight as a structural covariate incorporated allometrically. For an infant weighing 5.3 kg, the estimated apparent clearance was 68.6 L/h (12% relative standard error) and exhibited large variability (78% coefficient of variation). The pharmacokinetic-pharmacodynamic model described (i) a circadian rhythm in the response with lowest and highest observations at 4 a.m. and 9 p.m., respectively, (ii) a placebo effect increasing and flattening out with time in an exponential manner, and (iii) a statistically significant (P < .01) linearly increasing response with dose. The observed and model predicted relative change in response from baseline was -35% and -28% (95% prediction interval -36%; -19%) following placebo, and -44% and -36% (-46%; -27%) after 0.5 mg/kg., Conclusions: Population pharmacokinetic and dose-response models were successfully developed characterizing the available nepadutant pharmacokinetics and duration of crying and fussing data in infants., (© 2024 British Pharmacological Society.)

Background: Patients with advanced solid tumors have a suboptimal prognosis. This study investigated the safety and feasibility of linperlisib, a selective phosphatidylinositol 3-kinase delta isoform (PI3Kδ) inhibitor, for treating patients with advanced solid tumors., Methods: In this phase Ib, single-arm, open-label, multi-center clinical trial, patients with histologically confirmed advanced solid tumors from eight centers in China were enrolled to receive oral linperlisib (80 mg/day). The primary endpoint was safety., Results: Between August 2019 and June 2022, 94 patients were enrolled in the trial and received the study treatment. The most common (≥ 20%) treatment emergent adverse events (TEAEs) of all grades irrespective of causality were increased aspartate aminotransferase (AST) (26.6%), proteinuria (26.6%), decreased appetite (25.5%), increased alanine aminotransferase (ALT) (22.3%), weight loss (21.3%), and anemia (21.3%). The most common grade ≥ 3 TEAEs were diarrhea (4.3%), increased AST (3.2%), increased ALT (3.2%), neutropenia (3.2%), anemia (3.2%), increased blood alkaline phosphatase (3.2%). The objective response rate (ORR) was 1.1% (95% confidence interval [CI] 0.0-5.8), and the disease control rate (DCR) was 37.2% (95% CI 27.5-47.8). As of the data cutoff, the median follow-up time was 4.2 months (95% CI 2.8-6.9). The median progression-free survival (PFS) was 1.85 months (95% CI 1.79-1.88). The median overall survival (OS) was not reached., Conclusion: Linperlisib showed an acceptable safety profile and preliminary clinical benefit in patients with a range of advanced solid tumors. Further studies of linperlisib safety and efficacy are warranted., Competing Interests: Declarations. Conflict of interest: Hanying Bao, Zusheng Xu and Zuhong Xu are employees of the Shanghai Yingli Pharmaceutical Co., Ltd., and the other authors declare that no conflict interests exist. Ethical approval and consent to participate: The study was conducted with the approval of independent ethics committees or institutional review boards of all the study centers and in accordance with the principles of the Declaration of Helsinki, International Conference on Harmonization-Good Clinical Practice, and other applicable regulatory requirements. Institutional review board approval was obtained from the ethical committee of the East Hospital Affiliated to Tongji University. All patients involved in the study provided written informed consent. The study was registered at clinicaltrials.gov with the identifier NCT04049929 (A Phase I Study of YY-20394 in Patients With Advanced Solid Tumors)., (© 2024. The Author(s).)

A randomized, open-label, 2-period, 2-sequence crossover study was conducted to evaluate the pharmacokinetics and bioequivalence of 2 oral formulations of vildagliptin tablets under both fasting and fed conditions in healthy Chinese subjects. A total of 56 healthy subjects were randomized to receive a single 50-mg dose of either a generic vildagliptin tablet (T) or the reference formulation (R). The washout period was 3 days. Blood samples were collected up to 24 hours postdosing during each period and analyzed for vildagliptin using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The 90% confidence intervals for the geometric mean ratios (T:R) of maximum serum concentration, area under the serum concentration-time curve from time 0 to the last measurable concentration, and area under the serum concentration-time curve from time 0 to infinity were all within the predefined bioequivalence range of 80%-125%. This indicates that the generic and reference formulations are bioequivalent under both fasting and fed states. All adverse events reported were mild and transient. High-fat meals delayed absorption and reduced the maximum peak concentration of both formulations; however, they did not affect the overall exposure. Therefore, vildagliptin can be taken without regard to meals., (© 2024, The American College of Clinical Pharmacology.)

The treatment of cardiac thrombus after ST-segment elevation myocardial infarction (STEMI) is anticoagulation. There are conflicting data on the effectiveness and safety of novel oral anticoagulants (NOACs) versus warfarin. Using the national Medicare data, we identified patients with an admission diagnosis of STEMI and cardiac thrombus within 6 months after STEMI. Patients were divided into 2 groups based on initial type of anticoagulation medication (NOACs vs warfarin). The 2 main outcomes were ischemic stroke/transient ischemic attack and bleeding. Follow-up was performed through the end of 2023. Kaplan-Meier curves and Cox proportional hazard models were used. Of 881 patients prescribed anticoagulation after STEMI with subsequent cardiac thrombus, 496 patients were prescribed NOACs (56.3%) and 385 patients (43.7%) were prescribed warfarin. For ischemic stroke, the median follow-up time was 177 days (95% confidence interval [CI] 148 to 193) for warfarin and 266 days (95% CI 204 to 326) for NOACs. There was a significantly lower risk of ischemic stroke or transient ischemic attack in patients with cardiac thrombus treated with NOACs than those treated with warfarin [hazard ratio 0.73 (0.57 to 0.93)]. For bleeding, the median follow-up time was 192 days (95% CI 175 to 232) for warfarin and 277 days (95% CI 212 to 332) for NOACs. There was also a lower risk of bleeding in patients treated with NOACs than those treated with warfarin (hazard ratio 0.78, CI 0.66 to 0.92). In conclusion, patients with STEMI with cardiac thrombus had a lower risk of ischemic stroke and bleeding when treated with NOACs than when treated with warfarin. Prospective randomized studies are needed to confirm these findings and further examine the comparative effectiveness of different anticoagulant strategies., Competing Interests: Declaration of competing interest The authors have no competing interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Anal sac impaction is common in dogs. Manual expression may be effective, yet recurrence can be problematic. To facilitate physiological emptying of the sacs, it is important to maintain bulky stool consistency., Objectives: The study evaluated if supplementation with a complementary feed product formulated as a chew containing Bacillus velezensis C-3102 and fibre sources, reduced anal sac impaction recurrence., Animals: Thirty-five client-owned dogs with anal sac impaction were enrolled., Materials and Methods: Prospective, randomised, negative controlled field clinical trial with 22 dogs receiving the chew orally for 90 consecutive days and 13 dogs with no treatment. Dogs were evaluated on Day (D) 30, 60, 90 and 120 for the presence of clinical signs of anal sac impaction and the need to empty the sacs. Any animal that required manual expression of the sacs was classified as a failure and was withdrawn from the study., Results: The cumulative percentage of failures in the untreated group increased steadily from the first follow-up visit on D30 (15%) to the last visit on D120 (61.5%). However, in the group receiving the chew the cumulative percentage of failures increased at a much slower rate and stabilised at 19% from the D90 visit (last administration day) until the end of the study on D120, with statistically significant differences (p = 0.025). Animals receiving the chew also showed reduction in clinical signs., Conclusion and Clinical Relevance: The probiotic and fibre chew was a safe and effective management option for recurrent anal sac impaction in dogs., (© 2024 The Author(s). Veterinary Dermatology published by John Wiley & Sons Ltd on behalf of ESVD and ACVD.)

Despite the continued clinical application of traditional herbal medicines, scientific evidence such as toxicological safety profile of Yongdamsagan-tang water extract (YSTW) has not yet been established. The purpose of this study was to investigate the potential toxicity profile of YSTW following a 13-week repeated oral administration at various concentrations to Sprague Dawley rats. YSTW was administered orally to rats once daily at doses of 0, 1000, 2000, and 5000 mg/kg bw/day for 13 weeks. During the experimental period, there were no significant toxicological changes related to YSTW treatment. These results indicate that the administration of YSTW for 13 weeks in the rat resulted in no signs of toxicity at up to 5000 mg/kg bw/day, which was considered the no-observed-adverse-effect level., (© 2024 The Author(s). Journal of Applied Toxicology published by John Wiley & Sons Ltd.)

Background: Iron deficiency anemia in the perioperative setting is treated predominantly with intravenous iron formulation, of which ferric carboxymaltose may induce hypophosphatemia by modulating fibroblast growth factor 23., Methods: In this single-center, prospective, randomized, double-blind trial, we consented 92 adult patients scheduled for elective major abdominal or thoracic surgery. These patients either had isolated iron deficiency (plasma ferritin <100 ng/mL or transferrin saturation < 20 %) or iron deficiency anemia (hemoglobin (Hb) 100-130 g/L with plasma ferritin <100 ng/mL or transferrin saturation < 20 %). Preoperatively, participants received a single preoperative intravenous dose of ferric carboxymaltose and were then randomly assigned to receive either phosphate or placebo, administered orally three times a day for 30 days corresponding to an 18 mmol dose of daily phosphate supplementation in the intervention group. The primary endpoint was the minimum serum phosphate concentration during follow-up visits. The key secondary efficacy endpoint was mean perioperative hemoglobin concentration of postoperative days 0, 2 and 4, assessing the non-inferiority of additional phosphate supplementation., Results: We randomly consented 46 patients in each group (mean ± SD age 56 ± 17 years, 57 % female). Minimal phosphate concentration was 0.49 ± 0.21 mmol/L in the treatment group and 0.42 ± 0.17 mmol/L in the placebo group (p = 0.12, two-sided p-value). Average mean hemoglobin was 110 ± 16 g/L in the treatment and 113 ± 13 g/L in the placebo group (p = 0.023, one-sided p-value for non-inferiority). Hypophosphatemia occurred in 32 patients (70 %) of the treatment group and in 39 patients (85 %) of the placebo group (odds ratio 0.15, 95 % CI from 0.02 to 0.77, p = 0.014). Secondary outcomes, such as rescue medication use, core muscle strength and MOCA test scores, did not differ between groups., Conclusion: Co-administration of oral phosphate supplementation to ferric carboxymaltose cannot prevent hypophosphatemia. However, hypophosphatemia occurs in fewer patients. Phosphate co-administration did not impede the treatment of iron deficiency anemia with ferric carboxymaltose., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Donat R. Spahn reports financial support was provided by CSL Vifor. Donat R. Spahn reports financial support was provided by Swiss Foundation for Anesthesia Research. Alexander Kaserer received lecture honoraria from Bayer AG (Switzerland), CSL Behring GmbH (Switzerland) and advisory honoraria from AstraZeneca AG (Switzerland) and Pharmacosmos (Switzerland). Julia Braun, Alexander Mair, Andreas Hülsmeier, Gergely Karsai, Julian Rössler, Samira Akbas, Greta Gasciauskaite, Heike A. Bischoff-Ferrari, Pierre-Alain Clavien and Matthias Turina have no conflicts of interest to declare. Dr. Gabriela H. Spahn received honoraria for lectures from CSL Vifor (Switzerland) Villars-sur-Glâne, Switzerland. Martin Schläpfer has no conflicts of interest related to this study but has obtained unrestricted research grants from Roche Diagnostics International (Rotkreuz, Switzerland) and Sedana Medical (Danderyd, Sweden) and has submitted one patent for mitigating the negative effects of surgery and anesthesia with O2/ CO2 mixtures and one for an injectable formula to attenuate the harmful effects of sepsis. Isabelle Opitz has no real conflicts of interest. The following could be perceived as such: Roche (Institutional Grant and Speakers Bureau), AstraZeneca (Advisory Board and Speakers Bureau), MSD (Advisory Board), BMS (Advisory Board), Medtronic (Institutional Grant and Advisory Board), Intuitive (Proctorship). Donat R. Spahn: Dr. Spahn's former academic department is receiving grant support from the Swiss National Science Foundation, Berne, Switzerland, the Swiss Society of Anesthesiology and Perioperative Medicine (SSAPM), Berne, Switzerland, the Swiss Foundation for Anesthesia Research, Zurich, Switzerland, and CSL Vifor (International) AG, St. Gallen, Switzerland. Donat R. Spahn is co-chair of the ABC-Trauma Faculty, sponsored by unrestricted educational grants from Alexion Pharma Germany GmbH, Munich, Germany, CSL Behring GmbH, Marburg, Germany, and LFB Biomédicaments, Courtaboeuf Cedex, France. Donat R. Spahn received honoraria / travel support for consulting or lecturing from: Alliance Rouge, Bern, Switzerland, Danube University of Krems, Austria, European Society of Anesthesiology and Intensive Care, Brussels, BE, International Foundation for Patient Blood Management, Basel, Switzerland, Korean Society of Anesthesiologists, Seoul, Korea, Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis, Paris, France, Society for the Advancement of Blood Management, Mount Royal NJ, Alexion Pharmaceuticals Inc., Boston, MA, AstraZeneca AG, Baar, Switzerland, Bayer AG, Zürich, Switzerland, B. Braun Melsungen AG, Melsungen, Germany, Baxter AG, Glattpark, Switzerland, CSL Behring GmbH, Hattersheim am Main, Germany and Berne, Switzerland, CSL Vifor (Switzerland) Villars-sur-Glâne, Switzerland, CSL Vifor (International), St. Gallen, Switzerland, Celgene International II Sàrl, Couvet, Switzerland, Daiichi Sankyo AG, Thalwil, Switzerland, Haemonetics, Braintree, MA, USA, iSEP, Nantes, France, LFB Biomédicaments, Courtaboeuf Cedex, France, Merck Sharp & Dohme, Kenilworth, New Jersey, USA, Novo Nordisk Health Care AG, Zurich, Switzerland, Octapharma AG, Lachen, Switzerland, Pharmacosmos A/S, Holbaek, Denmark, Pierre Fabre Pharma, Alschwil, Switzerland, Portola Schweiz GmbH, Aarau, Switzerland, Roche Diagnostics International Ltd., Reinach, Switzerland, Sarstedt AG & Co., Sevelen, Switzerland and Nümbrecht, Germany, Shire Switzerland GmbH, Zug, Switzerland, Takeda, Glattpark, Switzerland, Werfen, Bedford, MA, Zuellig Pharma Holdings, Singapore, Singapore. If there are other authors, they 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 The Authors. Published by Elsevier Inc. All rights reserved.)

The side effects and safety of cannabidiol (CBD) products are currently discussed in different contexts. Of all adverse effects, hepatotoxic effects have been reported most frequently in previous studies. However, the threshold for liver toxicity of CBD in humans is uncertain due to the lack of adequately designed studies in humans below the lowest observed adverse effect level (LOAEL) of 300 mg/day. In a randomised, three-arm, double-blind, crossover study, the effects of two CBD products (oil and solubilisate (solu) containing 60 mg CBD) were investigated during a high-intensity exercise protocol. Seventeen well-trained subjects (26±4 years, 181±5 cm, 85.6±9.4 kg) participated in the intervention. All subjects were healthy and had no physiological or psychological injuries. Participants were divided into advanced (Ad) and highly advanced (Hi) athletes … They consumed 60 mg of the compound in each microcycle over 7 days. To evaluate possible effects of short-term repeated use of 60 mg CBD on oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), gamma-glutamyl transferase (GGT) and creatinine (CREA) were analysed before and after each microcycle. GOT increased significantly in both performance levels of the placebo groups (Ad: p≤0.001; Hi: p=0.003). This increase was significantly reduced in the Ad group by both CBD oil (p=0.050, ES=0.66) and CBD solu (p=0.027; ES=0.75). GPT also increased significantly in both placebo groups (Ad: p≤0.001; Hi: p=0.032). This increase was significantly reduced in the Ad group by both CBD oil (p=0.027; ES=0.75) and CBD solu (p=0.023; ES=0.77). These effects were not observed in the Hi group for either parameter. Our results show that short-term repeated use of 60 mg CBD can inhibit exercise-induced liver activity. Furthermore, under the conditions of the present study, there was no evidence for hepatotoxic effects of oral intake of CBD at 60 mg for seven days. Nevertheless, despite the inhibitory effect on exercise-induced liver activity, the study provides evidence for the pharmacological effects of CBD on the liver even at low CBD dose and does not exclude adverse effects in sensitive individuals., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of heart failure cases globally, and this incidence is increasing due to extended lifespans and accumulating comorbidities. Emerging evidence suggests that Wnt signaling plays a role in cardiomyocyte hypertrophy and cardiac fibrosis, which are key features of HFpEF. Furthermore, Porcupine (PORCN) inhibitors, which negatively regulate Wnt signaling, have shown promising results in improving cardiac function and reducing cardiac hypertrophy and/or fibrosis. This study investigated whether acute oral administration of the PORCN inhibitor, Wnt-c59, alters the maladaptive structural and/or functional features in a mouse model of HFpEF. Male mice were given a high-fat diet and L-NAME (0.5 g L -1 ) in drinking water for 5 weeks, followed by a 2-week intervention of orally administered Wnt-c59 (5 mg kg -1  day -1 ). HFpEF mice were characterized by hypertension, cardiac hypertrophy and fibrosis, and diastolic dysfunction, although there was no evidence of activation of Wnt signaling in the heart. Despite this, short-term treatment of HFpEF mice with Wnt-c59 ameliorated adverse cardiac remodeling by increasing the ratio of the more compliant collagen type 3 to that of the more tensile collagen type 1 in the heart. Furthermore, Wnt-c59 also improved diastolic dysfunction, which was associated with the increased cardiac expression of brain natriuretic peptide, a known promoter of ventricular compliance. Our findings demonstrate that even short-term administration of a PORCN inhibitor improves both the structural and functional features of experimental HFpEF., (© 2025 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background: The impact of post-stroke antithrombotic regimen in atrial fibrillation is uncertain., Objective: This study aimed to describe antithrombotic therapy prescribing patterns after ischemic stroke and the impact on outcomes., Methods: A total of 23,165 patients with atrial fibrillation experiencing ischemic stroke were identified. Subsequent post-stroke events included recurrent ischemic stroke, intracranial hemorrhage, major bleeding, mortality, and composite outcomes., Results: Of those who were nonanticoagulated before a stroke, 33.5% remained nonanticoagulated and 39.2% were prescribed only antiplatelet agents (APs) after a stroke. Compared with non-vitamin K antagonist oral anticoagulants (NOACs) after stroke, there was a significant increase in ischemic stroke and mortality in nonanticoagulated patients (adjusted hazard ratio [aHR], 2.09 and 3.92) and AP users (aHR, 1.32 and 1.28). Post-stroke warfarin was associated with a significantly increased risk of major bleeding compared with NOACs (aHR, 1.23). Of 769 patients receiving NOACs before stroke and continuing NOACs after stroke, those switching to a different NOAC were associated with significantly higher risk of ischemic stroke (aHR, 2.07) and composite outcomes (aHR, 1.36-1.85) with no difference in intracranial hemorrhage, major bleeding, or mortality compared with those receiving the same NOAC after stroke. Of patients receiving NOACs before stroke, the risks of clinical events were similar between patients taking NOACs alone and those taking NOAC plus AP after stroke., Conclusion: NOAC alone after stroke was associated with a better clinical outcome compared with nonanticoagulation, AP, or warfarin. Of patients already taking NOACs before stroke, the addition of AP did not confer additional benefits compared with NOACs alone. A change of NOAC types after stroke was associated with a 2-fold higher risk of ischemic stroke and composite outcomes., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

This study aims to investigate the effects of oral and non-oral migraine prophylaxis on subjective sleep quality in migraine patients with sleep problems. A bidirectional relationship between migraine and sleep is presumed, although this relationship is not fully clarified. Possibly, prophylactic treatment of migraine aiming at a reduction of migraine attack frequency can also positively affect the quality of sleep for patients with migraine with sleep problems. PubMed, Cochrane, Embase and CINAHL databases were searched in March 2022 for studies evaluating prophylactic treatment of migraine and the impact on perceived sleep quality (Pittsburgh Sleep Quality Index or Insomnia Severity Index). A systematic review using the McMaster Tool and a random-effects meta-analysis (effect size Cohen's d) were conducted. Seven studies were identified, including 989 participants, of which 844/989 (85.3%) female, with a mean (SD) age of 41.3 (12.1) years. In 6/7 (85.7%) studies, monthly migraine days improved (p < 0.002). Five out of six (83.3%) studies presented a relevant improvement in quality of sleep (p < 0.05), and one study reported a clinically meaningful improvement in the treatment group (Insomnia Severity Index change >7, in >50% of participants). The meta-analysis showed a large effect size of 1.09 (95% confidence interval 0.57-1.62; overall p < 0.001; Cochran's Q < 0.0001) for migraine prophylaxis on improving sleep quality. In conclusion, prophylactic migraine treatment improves sleep quality in patients with migraine and sleep problems, as measured with self-reported questionnaires Pittsburgh Sleep Quality Index and Insomnia Severity Index. Unfortunately, some included studies used prophylactic treatment that is not in current (international) guidelines. The evidence for this improvement in quality of sleep is strong, and seems a generic effect of migraine prophylaxis., (© 2024 European Sleep Research Society.)

Background: Concerns have been raised regarding the updated Beers Criteria that recommended avoiding rivaroxaban use for long-term treatment of older adults with nonvalvular atrial fibrillation (AF)., Objectives: We sought to compare the effectiveness and safety of rivaroxaban with oral anticoagulants in older adults with nonvalvular AF., Methods: We used an administrative healthcare database and included adults with AF aged ≥65 years who were new users of rivaroxaban or the comparators. We created 3 pairwise comparisons: rivaroxaban vs warfarin; rivaroxaban vs dabigatran; and rivaroxaban vs apixaban. Study outcomes included stroke or systemic embolism (effectiveness) and gastrointestinal or intracranial bleeding (safety). In the propensity score-matched sample, we used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs., Results: In the matched cohorts, use of rivaroxaban (vs warfarin) increased risk of bleeding (HR, 1.13; 95% CI, 1.03-1.23) with no difference in ischemic stroke or systemic embolism (HR, 0.90; 95% CI, 0.79-1.02); use of rivaroxaban (vs dabigatran) increased risk of bleeding (HR, 1.18; 95% CI, 1.03-1.35) with no difference in ischemic stroke and systemic embolism (HR, 1.00; 95% CI, 0.83-1.22); and use of rivaroxaban (vs apixaban) increased risk of stroke and systemic embolism (HR, 1.23; 95% CI, 1.08-1.40) and bleeding (HR, 1.60; 95% CI, 1.45-1.76)., Conclusion: In this comparative effectiveness and safety study of older adults with nonvalvular AF, use of rivaroxaban was associated with a significantly increased risk of ischemic stroke and systemic embolism compared with apixaban and bleeding compared with warfarin, dabigatran, and apixaban. Our findings may inform anticoagulant selection in older adults with nonvalvular AF., Competing Interests: Declaration of competing interests G.K.D. receives funding from the National Institutes of Health and American Society of Hematology. G.K.D. received Honoria from Valley Health Winchester Medical Center and BMS for educational talks that are not related to this work. A.C. has served as a consultant for MingSight, Pfizer, Sanofi, and Synergy and has received authorship royalties from UpToDate., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Acetaminophen (APAP) overdose-induced acute liver injury (ALI) is characterized by extensive oxidative stress, and the clinical interventions for this adverse effect remain limited. Astilbin is an active compound found in the rhizome of Smilax glabra Roxb. with anti-inflammatory and antioxidant activities. Due to its low oral bioavailability, astilbin can accumulate in the intestine, which provides a basis for the interaction between astilbin and gut microbiota (GM). In the present study we investigated the protective effects of astilbin against APAP-induced ALI by focusing on the interaction between astilbin and GM. Mice were treated with astilbin (50 mg·kg -1 ·d -1 , i.g.) for 7 days. After the last administration of astilbin for 2 h, the mice received APAP (300 mg/kg, i.g.) to induce ALI. We showed that oral administration of astilbin significantly alleviated APAP-induced ALI by altering the composition of GM and enriching beneficial metabolites including hydroxytyrosol (HT). GM depletion using an "antibiotics cocktail" or paraoral administration of astilbin abolished the hepatoprotective effects of astilbin. On the other hand, administration of HT (10 mg/kg, i.g.) caused similar protective effects in APAP-induced ALI mice. Transcriptomic analysis of the liver tissue revealed that HT inhibited reactive oxygen species and inflammation-related signaling in APAP-induced ALI; HT promoted activation of the Nrf2 signaling pathway to combat oxidative stress following APAP challenge in a sirtuin-6-dependent manner. These results highlight that oral astilbin ameliorates APAP-induced ALI by manipulating the GM and metabolites towards a more favorable profile, and provide an alternative therapeutic strategy for alleviating APAP-induced ALI., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Introduction: Needle-free procedural sedation (PS) is an attractive option for children presenting to the emergency department (ED) who require a painful procedure, as it avoids inflicting additional pain either with intravenous line placement or intramuscular injection. While use of oral (PO) ketamine has been reported in the literature, limited information is available to guide ED-based use in children., Methods: This is a descriptive study of the patient experience receiving PS with the following regimen: PO ketamine 6 mg/kg (max of 200 mg) with or without PO midazolam 0.5 mg/kg (max 15 mg) approximately 30 minutes before a procedure. We performed a retrospective chart review of children younger than 18 years receiving this PS regimen at a tertiary care children's hospital ED and an affiliated community hospital ED from January 1 through September 30, 2023., Results: Fifty-eight children were sedated with PO ketamine during the study period. The most common procedure performed was laceration repair (46.5%), followed by incision and drainage (17.3%). All but 2 children received PO midazolam along with PO ketamine. Eight patients received additional medications due to inadequate sedation. Sedation depth was clinician-reported as moderate in 74.1% (43), mild in 15.5% (9), and deep in 10.3% (6). Procedures were completed in 98.3% (57) cases. 93.1% (54) of patients had no adverse event (AE) of any kind and no patient had a significant adverse event (SAE)., Discussion: PO ketamine with or without midazolam resulted in procedure completion of a variety of procedures in the pediatric ED with minimal AE, no SAE, and without need for additional sedative medications in 86.2% (50). This regimen is an option for needle-free moderate PS in this setting. Further study is needed to clarify the benefit of the addition of midazolam to PO ketamine, rates of AE and SAE, sedation duration, and recovery times., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

6,7-dihydroxy-2,4-dimethoxyphenanthrene (PC4), isolated and identified from Chinese yam, was one of the important characteristic active ingredients. The present study established simulated gastrointestinal digestion and caco-2 intestinal epithelial models to investigate the digestive and metabolic characteristics of PC4. The results indicated that PC4 was mainly digested and metabolized in the intestine, with a digestion rate of 94 %, producing active characteristic metabolites including 2,6-dimethoxy-4-phenanthrenol (MC1) and 1-methoxyphenanthrene (MC2). Molecular docking indicated that the COX-2 enzyme inhibitory activity of MC1 might be superior to that of the prototype PC4. During 24 h co-incubation of PC4 with caco-2 monolayer epithelial, the signal pathway related to lipid decomposition was up-regulated within 0-12 h, while the diabetes complications AGE-RAGE was inhibited just in 0-6 h period significantly. The research database provided scientific basis for the digestion and metabolism of PC4, and laid theoretical foundation for the scientific development of Chinese yam functional foods., Competing Interests: Declaration of competing interest The authors declare that they have no financial interest or personal relationships which influenced the work reported in this paper. The authors have no conflict of interest in this manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Describe direct oral anticoagulant (DOAC) level ordering and interpretation practices in association with clinical outcomes at a vascular medicine clinic. Methods: This study was a retrospective, observational study including patients who had a DOAC level ordered and assessed while on DOAC therapy. The primary outcome was the proportion of DOAC levels within previously reported ranges. Secondary outcomes included thrombotic events, major and clinically relevant non-major bleeding events, and the proportion of DOAC level results which prompted a change in the therapeutic plan. Results: A total of 43 patients who had a DOAC level ordered while on DOAC therapy were included in the study. More patients were on apixaban than other DOACs, and the most common indication for anticoagulation was deep vein thrombosis (DVT) or pulmonary embolism (PE). The most common reasons for ordering DOAC levels included history of gastric bypass (n = 20) and drug-drug interactions (n = 8). Most patients on apixaban had in-range levels (n = 24) compared to out of-range levels (5 patients). More patients on rivaroxaban had a level out-of-range (n = 10) than in-range (n = 4). One patient had a DVT, resulting in hospitalization and change in DOAC therapy. Two patients had bleeding events, with 1 hospitalization and change in DOAC therapy. DOAC level results also prompted changes in therapeutic plans for 9 of the patients. Conclusion: DOAC level results did not always correlate with expected outcomes, and further research is warranted to clarify which clinical situations may benefit from ordering DOAC levels., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Simnotrelvir (SIM0417), an inhibitor of the 3CL protease of SARS-CoV-2, has been identified as a CYP3A sensitive substrate. This study investigated the pharmacokinetics, metabolism, and mass balance of simnotrelvir following a single oral dose of 750 mg in six healthy Chinese male subjects, co-administered with four doses of 100 mg ritonavir. Analysis using 19 F qNMR combined with LC-MS/MS showed that the parent drug M0 constituted over 90% of the drug-related components in plasma. Of the administered dose, 55.4% (54.3% of M0) was recovered in urine, while 36.7% (4.57% of M0) was excreted in feces. UPLC/Q-TOF MS was used to identify metabolites in human plasma, urine and feces. Notably, oxidative metabolites catalyzed by CYP3A were scarcely detected in these matrixes. The amide hydrolyzed metabolite M9 and the cyano hydrolyzed metabolite M10 were recognized as the predominant metabolites, with the main excretion being through feces (19.0% and 12.7% of the administered dose, respectively). In vitro experiments indicated that M10 is primarily formed in the duodenum and jejunum, with further metabolism to M9 by microbiota in the large intestine. Overall, the co-administration of simnotrelvir with ritonavir led to predominant metabolism by intestinal enzymes or microbiota, resulting in hydrolyzed metabolites. These findings highlight the critical role of intestinal metabolism in the pharmacokinetics of simnotrelvir and emphasize the need to consider interactions with antibiotics and individual differences of intestinal microbiota., Competing Interests: Competing interests: YY and JC are employees of Simcere Zaiming Pharmaceutical Co. Ltd. ZJG, SSX, and AHG are employees of Jiangsu Simcere Pharmaceutical Co., Ltd. The other authors declare that they have no competing interests., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

NLRP3 inflammasome inhibitor is a highly attractive drug target for the treatment of various inflammatory diseases. Here, we report the discovery of pyridazine derivatives as a new class of scaffold for NLRP3 inflammasome inhibitors. We optimized HTS hit 2a to improve both in vitro IL-1β inhibitory activity and the mean photo effect (MPE) value in the in vitro 3T3 neutral red uptake (NRU) phototoxicity test. As a result, we identified compound 5e (ASP0965) with brain penetrability and showing efficacy in the brain on oral administration in the rat pharmacodynamics (PD) model and the mouse α-synuclein injection model. These findings suggest that compound 5e is a promising clinical candidate for α-synucleinopathy therapeutics., 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 Elsevier Ltd. All rights reserved.)

Purpose: The objective of this meta-analysis was to evaluate the efficacy of administering preoperative oral carbohydrates (CHO) compared to a control treatment in improving postoperative recovery outcomes for patients undergoing laparoscopic cholecystectomy (LC)., Design: A meta-analysis of randomized controlled trials., Methods: Through systematic searches in PubMed, Embase, and the Cochrane Library, randomized controlled trials focusing on preoperative oral carbohydrates for patients undergoing LC were collected. Data analysis was conducted using the Revman 5.3 software., Findings: The meta-analysis incorporated 19 randomized studies, with a total of 1,568 participants. Meta-analysis results indicated that patients receiving CHO reported notably lower postoperative pain compared to those fasting (P = .006) or on placebo (P = .003). Furthermore, a significant reduction in preoperative hunger was observed in the CHO group compared to the controls (P = .002). A notable difference was also identified in the postoperative Homeostasis Model Assessment-IR changes between the CHO and control groups (P = .02). No significant variations were observed in thirst, postoperative nausea and vomiting, insulin level alterations, glucose level changes, duration of hospital stay, or recovery quality., Conclusions: Preoperative oral carbohydrates may alleviate hunger and pain, and attenuate postoperative insulin resistance more effectively than either overnight fasting or placebo in patients undergoing LC., Competing Interests: Declaration of Competing Interest None to report., (Copyright © 2025 The American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)