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Copyright of Chinese Journal of Clinical Healthcare is the property of Chinese Journal of Clinical Healthcare and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose : Peripheral neuropathy (PN) is common in multiple myeloma (MM) patients. More insight has been gained concerning the role of vitamin D in preventing PN. However, studies evaluating the effects of vitamin D3 supplementation on PN are lacking. The aims of this study are to (1) evaluate the effectiveness of a vitamin D3 regimen on achieving adequate vitamin D levels in deficient MM patients and to (2) exploratively evaluate the effect of vitamin D3 supplementation on PN. Methods: Thirty-nine MM patients with inadequate (< 75 nmol/L [= 30 ng/mL]) 25-hydroxyvitamin D (25(OH)D) levels were included in this multicenter, prospective, single-arm study, of whom 35 patients completed the study. They received oral vitamin D3 for 6 months according to a dose escalation regimen that consisted of one or two loading doses of 200,000 international units (IU), and maintenance doses of 800, 1600, or 3200 IU/day depending on the 25(OH)D level. A validated questionnaire was used to measure PN. Results: Median 25(OH)D increased from 38 (IQR 32–52) nmol/L at baseline to 77 (IQR 72–87) nmol/L after 6 months (P < 0.001). Adequate 25(OH)D levels were achieved by 66% of the subjects, and 34% were within the range of 50–75 nmol/L. Furthermore, in 37% of the participants, PN severity decreased (P = 0.007). Conclusion: The use of substantially higher vitamin D3 doses than recommended in current guidelines resulted in a significant increase in vitamin D levels in MM patients. Furthermore, evaluation of PN showed a significant decrease in PN grading. However, this exploratory evaluation needs further confirmatory research. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Clinical Healthcare is the property of Chinese Journal of Clinical Healthcare and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The ventral pallidum (VP) receives its primary inputs from the nucleus accumbens (NAC) and the basolateral amygdala (BLA). We demonstrated recently that in the VP, the D2 DA receptor (D 2 R) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, D 2 R can be found both on NAC and BLA terminals. According to our hypothesis, quinpirole microinjected into the VP can facilitate memory consolidation via modulation of synaptic plasticity on NAC and/or BLA terminals. The effect of intra-VP quinpirole on BLA-VP and NAC shell-VP synapses was investigated via a high frequency stimulation (HFS) protocol. Quinpirole was administered in three doses into the VP of male Sprague-Dawley rats after HFS; controls received vehicle. To examine whether an interaction between the NAC shell and the BLA at the level of the VP was involved, tetrodotoxin (TTX) was microinjected into one of the nuclei while stimulating the other nucleus. Our results showed that quinpirole dose-dependently modulates BLA-VP and NAC shell-VP synapses, similar to those observed in inhibitory avoidance and spatial learning, respectively. The lower dose inhibits BLA inputs, while the larger doses facilitates NAC shell inputs. The experiments with TTX demonstrates that the two nuclei do not influence each others' evoked responses in the VP. Power spectral density analysis demonstrated that independent from the synaptic facilitation, intra-VP quinpirole increases the amplitude of gamma frequency band after NAC HFS, and BLA tonically suppresses the NAC's HFS-induced gamma facilitation. In contrast, HFS of the BLA results in a delayed, transient increase in the amplitude of the gamma frequency band correlating with the LTP of the P1 component of the VP response to BLA stimulation. Furthermore, our results demonstrate that the BLA plays a prominent role in the generation of the delta oscillations: HFS of the BLA leads to a gradually increasing delta frequency band facilitation over time, while BLA inhibition blocks the NAC's HFS induced strong delta facilitation. These findings demonstrate that there is a complex interaction between the NAC shell region and the VP, as well as the BLA and the VP, and support the important role of VP D 2 Rs in the regulation of limbic information flow., Competing Interests: Declaration of competing interest Anthony A. Grace has received funds from Lundbeck, Pfizer, Lilly, Roche, Janssen, Alkermes, Newron, Takeda and Merck. The other author declares no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Adolescent stress (AS) has been associated with higher vulnerability to psychiatric disorders such as schizophrenia, depression, or drug dependence. Moreover, the alteration of brain catecholamine (CAT) transmission in the medial prefrontal cortex (mPFC) has been found to play a major role in the etiology of psychiatric disturbances. We investigated the effect of adolescent stress on CAT transmission in the mPFC of freely moving adult rats because of the importance of this area in the etiology of psychiatric disorders, and because CAT transmission is the target of a relevant group of drugs used in the therapy of depression and psychosis. We assessed basal dopamine (DA) and norepinephrine (NE) extracellular concentrations (output) by brain microdialysis in in the mPFC of adult rats that were exposed to chronic mild stress in adolescence. To ascertain the role of an altered release or reuptake, we stimulated DA and NE output by administering either different doses of amphetamine (0.5 and 1.0 mg / kg s.c.), which by a complex mechanism determines a dose dependent increase in the CAT output, or reboxetine (10 mg/kg i.p.), a selective NE reuptake inhibitor. The results showed the following: (i) basal DA output in AS rats was lower than in controls, while no difference in basal NE output was observed; (ii) amphetamine, dose dependently, stimulated DA and NE output to a greater extent in AS rats than in controls; (iii) reboxetine stimulated NE output to a greater extent in AS rats than in controls, while no difference in stimulated DA output was observed between the two groups. These results show that AS determines enduring effects on DA and NE transmission in the mPFC and might lead to the occurrence of psychiatric disorders or increase the vulnerability to drug addiction., Competing Interests: Declaration of competing interest On the behave of all authors I declare that all authors have no conflict of interest or any financial and personal relationships with other people or organizations that could inappropriately influence (bias) our work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The MDM2 oncogene is amplified and/or overexpressed in various human cancers and elevated expression of MDM2 protein acts as a survival factor promoting cancer progression through both p53-dependent and -independent pathways. Here, we report a novel small-molecule chemical compound (MX69-102) that we identified to induce MDM2 protein degradation, resulting in reactivation of p53, inhibition of XIAP, and potent cell growth inhibition and apoptosis in MDM2-overexpressing acute lymphoblastic leukemia (ALL) in vitro and in vivo. We have previously identified a compound (MX69) that binds to the MDM2 C-terminal RING domain and induces MDM2 protein degradation. In the present study, we performed structural modifications of MX69 and selected analog MX69-102, showing increased MDM2-targeting activity. MX69-102 exhibited significantly enhanced inhibitory and apoptotic effects on a group of MDM2-overexpressing ALL cell lines in vitro with IC 50 values of about 0.2 μM, representing an approximately 38-fold increase in activity compared to MX69. MX69-102 also showed effective inhibition on xenografted human MDM2-overexpressing ALL in SCID mice. Importantly, MX69-102 had minimal or no inhibitory effect on normal human hematopoiesis in vitro and was very well tolerated in vivo in animal models. Based on the strong inhibitory and apoptotic activity against MDM2-overexpressing ALL, along with minimal or no toxicity to normal cells/tissues, MX69-102 is a candidate for further development as a novel MDM2-targeted therapeutic drug for refractory/MDM2-overexpressing ALL., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Cyclophosphamide and ifosfamide are major alkylating agents but their therapeutics uses are limiting by the toxicity due to several toxicities. Indeed conventional chemotherapies are generally used with the maximum tolerated dose. In contrast, metronomic schedule aims to get a minimum dose for efficacy with a good safety. Depending on the dose, their mechanisms of action are different and offer a dual activity: at high dose, cyclophosphamide is mainly used in graft conditioning for its immunosuppressive properties, while at metronomic dose it is used as an immunoactive agent. Currently, at metronomic dose, cyclophosphamide is studied in clinic against various types of cancer, alone or in combination with others anticancer drugs (anti-angiogenic, immune-modulating agents, immune checkpoints blockers, vaccines, radiotherapy, others conventional anticancer agents), as a nth-line or first-line treatment. More than three quarters of clinical studies show promising results, mostly in breast, ovarian and prostate cancers. Taking advantage of the immune system, use dual antitumor action's chemotherapy is clearly a therapeutic strategy that deserves to be confirmed in order to improve the efficacy/toxicity balance of anticancer treatments, and to use CPM or analogues as a standard of care., 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.)

Background: Olpasiran, a small interfering RNA (siRNA), blocks lipoprotein(a) (Lp(a)) production by preventing translation of apolipoprotein(a) mRNA. In phase 2, higher doses of olpasiran every 12 weeks (Q12W) reduced circulating Lp(a) by >95%., Objectives: This study sought to assess the timing of return of Lp(a) to baseline after discontinuation of olpasiran, as well as longer-term safety., Methods: OCEAN(a)-DOSE (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study) was a phase 2, dose-finding trial that enrolled 281 participants with atherosclerotic cardiovascular disease and Lp(a) >150 nmol/L to 1 of 4 active doses of olpasiran vs placebo (10 mg, 75 mg, 225 mg Q12W, or an exploratory dose of 225 mg Q24W given subcutaneously). The last dose of olpasiran was administered at week 36; after week 48, there was an extended off-treatment follow-up period for a minimum of 24 weeks., Results: A total of 276 (98.2%) participants entered the off-treatment follow-up period. The median study exposure (treatment combined with off-treatment phases) was 86 weeks (Q1-Q3: 79-99 weeks). For the 75 mg Q12W dose, the off-treatment placebo-adjusted mean percent change from baseline in Lp(a) was -76.2%, -53.0%, -44.0%, and -27.9% at 60, 72, 84, and 96 weeks, respectively (all P < 0.001). The respective off-treatment changes in Lp(a) for the 225 mg Q12W dose were -84.4%, -61.6%, -52.2%, and -36.4% (all P < 0.001). During the extension follow-up phase, no new safety concerns were identified., Conclusions: Olpasiran is a potent siRNA with prolonged effects on Lp(a) lowering. Participants receiving doses ≥75 mg Q12W sustained a ∼40% to 50% reduction in Lp(a) levels close to 1 year after the last dose. (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study [OCEAN(a)-DOSE]; NCT04270760)., Competing Interests: Funding Support and Author Disclosures The OCEAN(a)-DOSE study was funded by Amgen. Dr O’Donoghue has received grant funding through Brigham and Women’s Hospital from Novartis, Amgen, AstraZeneca, and Janssen; and has received honoraria from Novartis, Amgen, AstraZeneca, and Janssen. Dr Rosenson has received institutional grant funding from Amgen, Arrowhead, Lilly, Novartis, and Regeneron; has received consulting fees from Amgen, Arrowhead, CRISPER Therapeutics, Lilly, Novartis, Precision Biosciences, Regeneron, and Ultragenyx; has received nonpromotional speaker fees from Amgen and Kowa; and has held stock in MediMergent. Dr López is an employee of Amgen; and/or has owned Amgen stock or stock options. Dr Lepor has received grant support from Amgen, Novartis, Regeneron, New Amsterdam, Merck, Arrowhead, and AstraZeneca; and has received speaker and/or consulting fees from Amgen, Novartis, Regeneron, Merck, AstraZeneca, and Boehringer Ingelheim. Dr Baum has received consulting fees from Altimmune, Amgen, Axcella, Boehringer Ingelheim, Lilly, Esperion, Ionis, Madrigal, Merck, Novartis, and Regeneron; and has received speaker fees from Amgen, Lilly, and Regeneron. Dr Gaudet has received grants and personal fees from Amgen during the conduct of the study; has received grants from Acasti, Kowa, Uniqure, Sanofi, Aegerion, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Ceapro, Dalcor, Esperion, Arrowhead, Regeneron, Akcea, Allergan, Amryt, Ionis, Novartis, Novo Nordisk, Pfizer, Lilly, and The Medicine Company, outside the submitted work; and has received personal fees from Arrowhead, Regeneron, Akcea, Allergan, Amryt, Ionis, Novartis, Novo Nordisk, Pfizer, Lilly, CRISPR Therapeutics, Saliogen, and Ceapro, outside the submitted work. Dr Knusel is an employee of Amgen; and/or has owned Amgen stock or stock options. Ms Kuder has served as a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences. Ms Murphy has served as a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences. Dr H. Wang is an employee of Amgen; and/or has owned Amgen stock or stock options. Dr Wu is an employee of Amgen; and/or has owned Amgen stock or stock options. Dr Shah is an employee of Amgen; and has owned Amgen stock. Dr J. Wang is an employee of Amgen; and has owned Amgen stock. Dr Wilmanski is an employee of Amgen; and has owned Amgen stock. Dr Sohn is an employee of Amgen; and/or has owned Amgen stock or stock options; and has existing or pending patents related to olpasiran. Dr Kassahun is an employee of Amgen; and/or has owned Amgen stock or stock options; and has existing or pending patents related to olpasiran. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, Inc, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis, Merck, Novartis, Pfizer, Saghmos Therapeutics, and Verve Therapeutics; has served as a consultant for Amgen, AMPEL BioSolutions, Anthos Therapeutics, Inc, AstraZeneca, Beren Therapeutics, Boehringer Ingelheim, Dr Reddy’s Laboratories, Fibrogen, Merck, Moderna, Novo Nordisk, Precision BioSciences, and Silence Therapeutics; and has served as a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from ARCA Biopharma, Janssen Research and Development, Siemens Healthcare Diagnostics, Softcell Medical Limited, Regeneron, Roche, and Zora Biosciences. Dr Stout has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Animal studies modeling recreational opioid use show more severe withdrawal symptoms in male compared to female rats, whereas our study modeling opioid use for pain showed a greater withdrawal-induced decrease in wheel running in female rats. The objective of this experiment was to determine whether sex differences in spontaneous morphine withdrawal are caused by differences in assessment method (i.e., wheel running vs. somatic symptoms). Twice daily injections of morphine (5 - 20 mg/kg, s.c.) for 5 days produced a dose and time dependent decrease in wheel running that was greater in male compared to female rats. Termination of morphine administration resulted in an overall decrease in running and a decrease in the amount of running during the dark phase of the light cycle from 95 % to approximately 75 %. In male rats, this decrease in the percent of dark running was caused by a large decrease in dark phase running, whereas female rats had a slightly higher increase in light phase running. Withdrawal also reduced maximal running speed and caused a decrease in body weight that was larger in male than female rats. Withdrawal symptoms were greatest on the day following the last morphine injection, but persisted for all 3 days of assessment. Morphine withdrawal produced a greater decrease in dark phase wheel running and body weight in male rats and a greater increase in light phase running in female rats. Voluntary home cage wheel running provides a continuous measure of opioid withdrawal that is consistent with other measures of opioid withdrawal., Competing Interests: Conflict of Interest Neither author has a conflict of interest, financial or personal, related to this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Caffeine exerts a biphasic effect on zebrafish behavior. High doses of caffeine have been associated with increased stress and anxiety, whereas low doses have been found to enhance performance on tasks requiring focus and attention. However, the sex-specific nature of these biphasic effects on behavior and physiology remains unclear. This study assessed the behavioral responses and hormone levels in male and female zebrafish after acute exposure to caffeine ranging from 0.3 to 600 mg/L. The results showed no significant difference in caffeine intake between males and females after acute exposure at each concentration. Caffeine-induced behavioral and physiological responses indicated a threshold dosage existed between 30 and 300 mg/L. Female fish displayed increased anxiety-like behavioral phenotypes, i.e., latency to upper and freezing, whereas males exhibited more erratic movement following acute exposure to a high-dose treatment. In addition, females exhibited a significant increase in whole-body cortisol levels, while males experienced a testosterone elevation at 300 mg/L of caffeine acute exposure. There was a significant decrease in the duration of erratic movements in males treated with the androgen receptor antagonist flutamide compared to the control group. The transcriptome analysis uncovered 511 and 592 up-regulated and 761 and 922 down-regulated differential expression genes in males and females, respectively, compared to the control. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway analysis revealed that caffeine has the potential to impact various pathways in zebrafish, including phototransduction and steroid hormone biosynthesis. Our findings demonstrate that testosterone and cortisol play a combined role in regulating stress responses in both behavior and physiology. Furthermore, our study highlights the significance of encompassing both male and female zebrafish as a model system., Competing Interests: Declaration of Competing interest The authors declare no competing or financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The complicated relevance between stress and pain has been identified. Neurotransmitters and neuropeptides of various brain areas play a role in this communication. Pain inhibitory response is known as stress-induced analgesia (SIA). The studies demonstrated that the nucleus accumbens (NAc) is critical in modulating pain. As a neuropeptide, orexin is crucially involved in initiating behavioral and physiological responses to threatening and unfeeling stimuli. However, the role of the orexin receptors of the NAc area after exposure to restraint stress (RS) as acute physical stress in the modulation of acute pain is unclear. One hundered twenty adult male albino Wistar rats (230-250 g) were used. Animals were unilaterally implanted with cannulae above the NAc. The SB334867 and TCS OX2 29 were used as antagonists for OX1r and OX2r, respectively. Different doses of the antagonists (1, 3, 10, and 30 nmol/0.5 µl DMSO) were microinjected intra-NAc five minutes before exposure to RS (3 hours). Then, the tail-flick test as a model of acute pain was performed, and the nociceptive threshold (Tail-flick latency; TFL) was measured in 60-minute time set intervals. According to this study's findings, the antinociceptive effects of RS in the tail-flick test were blocked during intra-NAc administration of SB334867 or TCS OX2 29. The RS as acute stress increased TFL and deceased pain-like behavior responses. The 50 % effective dose values of the OX1r and OX2r antagonists were 12.82 and 21.64 nmol, respectively. The result demonstrated contribution of the OX1r into the NAc was more remarkable than that of the OX2r on antinociceptive responses induced by the RS. Besides, in the absence of RS, the TFL was attenuated. The current study's data indicated that OX1r and OX2r into the NAc induced pain modulation responses during RS in acute pain. In conclusion, the findings revealed the involvement of intra-NAc orexin receptors in improving SIA., Competing Interests: Declaration of Competing Interest The authors have no financial or non-financial interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Demodex species are associated with many dermatological diseases, so an acaricidal agent that is effective against them and safe for skin applications may benefit many diseases. This study aims to investigate the anti-demodex potential of spilanthol, a product obtained from the Spilanthes Acmella plant, by determining the minimal effective dose for the first time in the literature. Demodex mites were obtained from 70 patients with standard superficial skin biopsy. Spilanthol extract was used at 1%, 2%, 3%, 4%, and 5%. Standard immersion oil was used for the negative control, and permethrin 5% was used for the positive control group. The dependent variable is the survival time of the mite. Comparisons with the negative control group, the anti-demodex effect demonstrated itself in all groups, creating a statistically significant difference (p < 0.001). The positive control group, had 3%, 4%, and 5% spilanthol rates which were very similar to the results with 5% permethrin (p > 0.05). Higher concentrations than 3% did not make any additional contribution to survival times. This is the first attempt to show the dose-dependent acaricidal effect of spilanthol on demodex mites. Even the 3% dose shows similar results to 5% permethrin, and no additional effect increase was observed at higher doses. Therefore, in vivo, studies may be planned with a 3% spilanthol dose for further studies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Vancomycin therapeutic drug monitoring is challenging, especially in the paediatric population where evidence is scarce. The main objective of this study was to analyse the achievement of therapeutic concentrations of vancomycin in paediatric patients and to evaluate the current monitoring method (trough levels), doses used, and the time required to achieve target concentrations., Methods: Paediatric patients on treatment and monitored with vancomycin from November 2019 to December 2021 were included. Those with only one determination of serum vancomycin concentration were excluded. Demographic variables, analytical and microbiological parameters and toxicity data were collected. Pharmacokinetic parameters were assessed at baseline and during treatment., Results: 225 patients (40.9% female; 108 neonates, 49 infants and 68 children or adolescents) were included in the study. The main indications for vancomycin treatment were sepsis (33.9%) and fever of unknown origin (29.3%). Microbiological cultures were positive in 71.1%, mostly with Gram-positive bacteria (60.4%). Therapeutic levels of vancomycin were reached in only 20.1% of the participants in the first determination. After pharmacokinetic monitoring, 81.7% of patients reached therapeutic concentrations, requiring a 23% increase in the initial dose, a 2-day lag time and 1-2 dosage adjustments until the therapeutic concentration was reached. Of the total patients, 13 developed nephrotoxicity, nine neutropenia and one patient developed red man syndrome., Conclusions: In our sample of paediatric patients, the recommended doses of vancomycin were insufficient to achieve therapeutic concentrations. Revision of the recommendations and/or a change in the method of pharmacokinetic monitoring is crucial to optimise treatment in this population., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The objective of this study was to explore factors that affect the clearance of imipenem in critically ill patients and to provide a dosing regimen for such patients., Methods: A prospective open-label study enrolled 51 critically ill patients with sepsis. Patients were between the ages of 18 and 96. Blood samples were collected in duplicate before (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours after imipenem administration. The plasma imipenem concentration was determined by the high-performance liquid chromatography-ultraviolet detection (HPLC-UV) method. A population pharmacokinetic (PPK) model was developed using nonlinear mixed-effects modelling methods to identify covariates. Monte Carlo simulations were performed using the final PPK model to explore the effect of different dosing regimens on the probability of target attainment (PTA)., Results: The imipenem concentration data were best described by a two-compartment model. Creatinine clearance (CrCl, mL/min) was a covariate that affected central clearance (CLc). Patients were divided into four subgroups based on different CrCl rates. Monte Carlo simulations were performed to assess the PTA differences between empirical dosing regimens (0.5 g every 6 hours (q6h), 0.5 g every 8 hours (q8h), 0.5 g every 12 hours (q12h), 1 g every 6 hours (q6h), 1 g every 8 hours (q8h), and 1 g every 12 hours (q12h)) and to determine the target achievement rate covariate., Conclusion: This study identified covariates for CLc, and the proposed final model can be used to guide clinicians administering imipenem in this particular patient population., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Statin is crucial for acute myocardial infarction (AMI) patients. However, the risk of new-onset diabetes mellitus (NODM) associated with statin is a concern. This study aimed to determine the incremental diabetogenic effects of statins according to their intensity and dose in AMI patients undergoing percutaneous coronary intervention (PCI). Among 13,104 patients enrolled in the Korea AMI Registry between 2011 and 2015, 6152 patients without diabetes mellitus (DM) who underwent PCI and received moderate-to-high-intensity atorvastatin and rosuvastatin were selected for the study. The endpoints were NODM and major adverse cardiovascular events (MACE), composite of all-cause mortality, recurrent MI, and revascularization up to 3 years. Among the participants, 3747 and 2405 received moderate- and high-intensity statins, respectively. The Kaplan-Meier curves demonstrated a higher incidence of NODM in patients with high-intensity statins than those with moderate-intensity. High-intensity statin was a significant predictor of NODM after adjusting for other co-variables (HR = 1.316, 95% CI 1.024-1.692; P < 0.032). Higher dose of rosuvastatin was associated with a higher cumulative incidence of NODM, but this dose-dependency was not apparent with atorvastatin. Cumulative incidence of MACE decreased dose-dependently only with atorvastatin. High-intensity statin was associated with a higher cumulative incidence of NODM in AMI patients, and this association was more evident in rosuvastatin. The different diabetogenic effects of the two statins provide supporting evidence for understanding the nuanced nature of statin treatment in relation to NODM., (© 2024. The Author(s).)

A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for post-traumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin's potential effect on fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin's effect on fear extinction are not understood. In this study, we used a delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin also exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, although these changes were sensitive to dose. Analysis of sex differences showed that females may respond to a narrower range of doses than males. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug's effects. Cotreatment with a 5-HT 2A receptor antagonist blocked psilocybin's effects for extinction, extinction retention, and fear renewal, whereas 5-HT 1A receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin's ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.

Background: Among therapeutic options for severe and critical COVID- 19 infection, dexamethasone six milligrams once daily for ten days has demonstrated mortality benefit and is guideline recommended at this dose. In practice, variable doses of steroids have been used, especially in critical care settings. Our study aimed to determine the pattern of steroid dosing and outcomes in terms of critical care mortality, occurrence of dysglycaemias, and occurrence of superadded infections in patients with critical COVID-19., Methods: A retrospective cohort study was carried out on all eligible patients admitted to the Aga Khan University Hospital, Nairobi, with critical COVID-19 between 1st March 2020 and 31st December 2021. The intervention of interest was corticosteroids quantified as the average daily dose in milligrams of dexamethasone. A steroid dose of six milligrams once a day was compared to high dose steroid dosing, which was defined as any dose greater than this. The primary outcome measure was ICU mortality and secondary outcomes included occurrence of dysglycaemias, superadded infections and duration of critical care admission., Results: The study included 288 patients. The median age was 61.2 years (IQR: 49.7, 72.5), with 71.2% of patients being male. The most common comorbidities were diabetes mellitus (60.7%), hypertension (58%), and heart disease (12.2%). The average oxygen saturation and C-reactive protein at admission were 82% [IQR: 70.0-89.0]and 113.0 [IQR: 54.0-186.0], respectively. Fifty-eight percent of patients received a standard dose (6mg) of steroids. The mortality rate was higher in the high-dose group compared to the standard-dose group; however, the difference was not statistically significant (47.9% vs 43.7% p = 0.549). The two most common steroid associated adverse effects were uncomplicated hyperglycemia (62.2%) and superimposed bacterial pneumonia (20.1%). The high-dose group had a higher incidence of uncomplicated hyperglycemia compared to the standard-dose group (63.6% vs 61.1%). However, the incidence of diabetic ketoacidosis was lower in the high dose group (0.6% vs 6.6%). Oxygen saturation at admission was associated with survival where it was lower among non-survivor patients with critical COVID-19., Conclusion: The study found that high-dose steroids in the treatment of critically ill patients with COVID-19 pneumonia did not confer any mortality benefit and were associated with an increased risk of dysglycemia and superimposed infections., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Odhiambo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cutaneous leishmaniasis (CL) is considered a public health problem. Current treatments have disadvantages because they are invasive and have serious side effects, and thus there is a need for research into new, more effective pharmacological alternatives. Plants are promising sources of bioactive substances, and new analogues can be obtained through chemical reactions. The present study aimed to evaluate the antileishmanial effects of the analog dillapiole n-butyl ether (DBE) extracted from Piper aduncum leaves. The cytotoxic potential of DBE was evaluated at concentrations of 15.62 to 500 µM in peritoneal macrophages for 48 h, and in RAW 264.7 macrophages for 72 h using a dose-response method. The antileishmanial activity in L. amazonensis promastigotes used concentrations of 0.2 to 4.5 µM for 24, 48 and 72 h and the quantification of the cellular infection rate used a concentration of 4.5 µM of DBE against the amastigote forms internalized in macrophages for 24 h and 48 h. Nitric oxide was quantified from macrophages previously treated with DBE for 24 h and 48 h. The dosage of reactive oxygen species used a concentration of 4.5 µM of DBE incubated together with dichlorofluorescein acetate for 1, 3, 6, and 24 h. For the molecular modeling of DBE, the Leishmania protein, available in the "Protein Data Bank" database, was used. The studied molecule was not toxic to cells and presented a CC50 of 413 µM in peritoneal macrophages and 373.5 µM in RAW 264.7. The analogue inhibited promastigote forms of L. amazonensis with an IC50 of 1.6 µM for 72 h. DBE presented an infection rate of 17% and 12%, dillapiole of 24% and 14% and Pentacarinat® of 10% and 9% over 48 h. DBE demonstrated a binding energy of -7.8 for the U53 enzyme. It is concluded that the analogue showed promising antileishmanial activity for future in vivo tests.

Background: This study aimed to determine the 50% effective dose of remimazolam co-administered with remifentanil for loss of consciousness in men and women as well as to investigate whether there are between-sex differences., Methods: Using a modified Dixon's up-and-down allocation approach, we sequentially enrolled male and female patients aged 19-60 years with American Society of Anesthesiologists class I or II who were scheduled for robotic surgery. For both sexes, the starting remimazolam dose was 0.15 mg/kg, with a step size of 0.05 mg/kg. After achievement of a target effect-site concentration 2.0 ng/ml of remifentanil, and administration of a bolus dose of remimazolam, we assessed whether adequate loss of consciousness (defined as a Modified Observer's Assessment of Alertness/Sedation scale score < 2 within 2 min) was achieved., Results: We included 22 male and 22 female patients. Based on Dixon's up-and-down method, the 50% effective dose of remimazolam (mean ± standard error) was 0.13 ± 0.01 mg/kg and 0.17 ± 0.01 mg/kg in the male and female groups, respectively (P = 0.34). Isotonic regression analysis revealed that the 95% effective dose (95% confidence interval) was 0.19 (0.18-0.20) mg/kg in the male group and 0.29 (0.29-0.30) mg/kg in the female group., Conclusions: There was no between-sex difference in the 50% effective dose of remimazolam for loss of consciousness; however, the 95% effective dose was significantly higher in female patients than in male patients., Trial Registration: This study protocol was registered at Clinical Research Information Service (CRIS No. KCT0007951, 02/12/2022)., (© 2024. The Author(s).)

Our study focuses on synthesizing and exploring the potential of three N-(4) substituted thiosemicarbazones derived from cinnamic aldehyde, alongside their Ru(II)-(η 6 -p-cymene)/(η 6 -benzene) complexes. The synthesized compounds were comprehensively characterized using a range of analytical techniques, including FT-IR, UV-visible spectroscopy, NMR ( 1 H, 13 C), and HRMS. We investigated their electronic and physicochemical properties via density functional theory (DFT). X-ray crystal structures validated structural differences identified by DFT. Molecular docking predicted promising bioactivities, supported by experimental observations. Notably, docking with EGFR suggested an inhibitory potential against this cancer-related protein. Spectroscopic titrations revealed significant DNA/BSA binding affinities, particularly with DNA intercalation and BSA hydrophobic interactions. RuPCAM displayed the strongest binding affinity with DNA (K b = 6.23 × 10 7 M -1 ) and BSA (K b = 9.75 × 10 5 M -1 ). Assessed the cytotoxicity of the complexes on cervical cancer cells (HeLa), and breast cancer cells (MCF-7 and MDA-MB 231), revealing remarkable potency. Additionally, selectivity was assessed by examining MCF-10a normal cell lines. The active complexes were found to trigger apoptosis, a vital cellular process crucial for evaluating their potential as anticancer agents utilizing staining assays and flow cytometry analysis. Intriguingly, complexation with Ru(II)-arene precursors significantly amplified the bioactivity of thiosemicarbazones, unveiling promising avenues toward the creation of powerful anticancer agents.

Environmental chemicals may contribute to the global burden of cardiovascular disease, but experimental data are lacking to determine which substances pose the greatest risk. Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes are a high-throughput cardiotoxicity model that is widely used to test drugs and chemicals; however, most studies focus on exploring electro-physiological readouts. Gene expression data may provide additional molecular insights to be used for both mechanistic interpretation and dose-response analyses. Therefore, we hypothesized that both transcriptomic and functional data in human iPSC-derived cardiomyocytes may be used as a comprehensive screening tool to identify potential cardiotoxicity hazards and risks of the chemicals. To test this hypothesis, we performed concentration-response analysis of 464 chemicals from 12 classes, including both pharmaceuticals and nonpharmaceutical substances. Functional effects (beat frequency, QT prolongation, and asystole), cytotoxicity, and whole transcriptome response were evaluated. Points of departure were derived from phenotypic and transcriptomic data, and risk characterization was performed. Overall, 244 (53%) substances were active in at least one phenotype; as expected, pharmaceuticals with known cardiac liabilities were the most active. Positive chronotropy was the functional phenotype activated by the largest number of tested chemicals. No chemical class was particularly prone to pose a potential hazard to cardiomyocytes; a varying proportion (10-44%) of substances in each class had effects on cardiomyocytes. Transcriptomic data showed that 69 (15%) substances elicited significant gene expression changes; most perturbed pathways were highly relevant to known key characteristics of human cardiotoxicants. The bioactivity-to-exposure ratios showed that phenotypic- and transcriptomic-based POD led to similar results for risk characterization. Overall, our findings demonstrate how the integrative use of in vitro transcriptomic and phenotypic data from iPSC-derived cardiomyocytes not only offers a complementary approach for hazard and risk prioritization, but also enables mechanistic interpretation of the in vitro test results to increase confidence in decision-making.

XELOX therapy, which comprises capecitabine and oxaliplatin, is the standard first-line chemotherapeutic regimen for colorectal cancer. However, its myelosuppressive effects pose challenges for its clinical management. Mathematical modeling combining pharmacokinetics (PK) and toxicodynamics (TD) is a promising approach for optimizing dosing strategies and reducing toxicity. This study aimed to develop a translational PK-TD model using rat data to inform dosing strategies and TD implications in humans. The rats were administered capecitabine, oxaliplatin, or XELOX combination regimen, and PK and TD data were collected. PK parameters were analyzed using sequential compartment analysis, whereas TD responses were assessed using Friberg's semiphysiological model. A toxicity intensity-based nomogram recommends optimal dosing strategies. Translational modeling techniques using the hybrid PK-TD model were employed to predict clinical responses. The PK-TD model successfully predicted the time-course profiles of hematological responses in rats following monotherapy and XELOX combination treatment. Interactive effects on lymphocytopenia were identified with the coadministration of capecitabine and oxaliplatin. A model-based recommended combination of the dose reduction rate for escaping severe lymphocytopenia was proposed as 40% and 60% doses of capecitabine and oxaliplatin, respectively. The current translational model techniques successfully simulated the time-course profiles of blood cell counts with confidence intervals in patients using rat data. Our study provides valuable insights into dose optimization strategies for each individual drug within the XELOX regimen and underscores the potential of translational modeling to improve patient outcomes. In addition to dose determination, these data will lay the groundwork for advancing drug development processes in oncology. SIGNIFICANCE STATEMENT: This study introduced a novel translational modeling approach rooted in a rat PK-TD model to optimize dosing strategies for the XELOX regimen for colorectal cancer treatment. Our findings highlight the interactive effects on lymphocytopenia and suggest a toxicity intensity-based nomogram for dose reduction, thus advancing precision medicine. This translational modeling paradigm enhances our understanding of drug interactions, offering a tool to tailor dosing, minimize hematological toxicity, and improve therapeutic outcomes in patients undergoing XELOX therapy., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Nicotinamide riboside (NR), a NAD + precursor, has received attention due to several health benefits it has induced in experimental models. Studies in cultured cells, animals, and humans consistently show increased NAD + availability after NR supplementation, which is considered the only mode of NR action that leads to health benefits. In the present study, we show that a persistently low NR concentration (1 μM) in the growth medium of BEAS-2B human cells, grown in a monolayer, induces energy stress, which precedes a cellular NAD + increase after 192 h. NR concentrations greater than 1 μM under the specified conditions were cytotoxic in the 2D cell culture model, while all concentrations tested in the 3D cell culture model (BEAS-2B cell spheroids exposed to 1, 5, 10, and 50 μM NR) induced apoptosis. Shotgun proteomics revealed that NR modulated the abundance of proteins, agreeing with the observed effects on cellular energy metabolism and cell growth or survival. Energy stress may activate pathways that lead to health benefits such as cancer prevention. Accordingly, the premalignant 1198 cell line was more sensitive to NR cytotoxicity than the phenotypically normal parent BEAS-2B cell line. The role of a mild energy stress induced by low concentrations of NR in its beneficial effects deserves further investigation. On the other hand, strategies to increase the bioavailability of NR require attention to toxic effects that may arise.

Vascular endothelial growth factor receptor 2 (VEGFR-2) stands as a prominent therapeutic target in oncology, playing a critical role in angiogenesis, tumor growth, and metastasis. FDA-approved VEGFR-2 inhibitors are associated with diverse side effects. Thus, finding novel and more effective inhibitors is of utmost importance. In this study, a deep learning (DL) classification model was first developed and then employed to select putative active VEGFR-2 inhibitors from an in-house chemical library including 187 druglike compounds. A pool of 18 promising candidates was shortlisted and screened against VEGFR-2 by using molecular docking. Finally, two compounds, RHE-334 and EA-11, were prioritized as promising VEGFR-2 inhibitors by employing PLATO, our target fishing and bioactivity prediction platform. Based on this rationale, we prepared RHE-334 and EA-11 and successfully tested their anti-proliferative potential against MCF-7 human breast cancer cells with IC 50 values of 26.78±4.02 and 38.73±3.84 μM, respectively. Their toxicities were instead challenged against the WI-38. Interestingly, expression studies indicated that, in the presence of RHE-334, VEGFR-2 was equal to 0.52±0.03, thus comparable to imatinib equal to 0.63±0.03. In conclusion, this workflow based on theoretical and experimental approaches demonstrates effective in identifying VEGFR-2 inhibitors and can be easily adapted to other medicinal chemistry goals., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

A series of naphtho[1,8-ef]isoindole-7,8,10(9H)-trione derivatives as novel theranostic agents for photodynamic therapy and multi-subcellular organelles localization were designed and synthesized. Most of them possess moderate fluorescence quantum yield and long wavelength absorption simultaneously, which made them possible for dual effects of imaging and therapy. Notably, compounds 7 b and 7 d exhibited significant light-toxicity but slight dark-toxicity. Confocal fluorescence microscopy experiments demonstrated that compound 7 b can locate and image in special multi-subcellular organelles. All the research results implied that naphtho[1,8-ef] isoindole-7,8,10(9H)-trione derivatives can be applied as a new series of theranostic agents with the characteristics of photodynamic therapy and multi-subcellular organelles imaging., (© 2024 Wiley-VCH GmbH.)

Metastasis is responsible for about 90 % of cancer deaths. Anti-metastatic drugs, termed as migrastatics, offer a distinctive therapeutic approach to address cancer migration and invasion. However, therapeutic exploitation of metastasis-specific targets remains limited, and the effective prevention and suppression of metastatic cancer continue to be elusive. Lysophosphatidic acid receptor 1 (LPA 1 ) is activated by an endogenous lipid molecule LPA, leading to a diverse array of cellular activities. Previous studies have shown that the LPA/LPA 1 axis supports the progression of metastasis for many types of cancer. In this study, we report the synthesis and biological evaluation of fluorine-containing triazole derivatives as potent LPA 1 antagonists, offering potential as migrastatic drugs for triple negative breast cancer (TNBC). In particular, compound 12 f, the most potent and highly selective in this series with an IC 50 value of 16.0 nM in the cAMP assay and 18.4 nM in the calcium mobilization assay, inhibited cell survival, migration, and invasion in the TNBC cell line. Interestingly, the compound did not induce apoptosis in TNBC cells and demonstrated no cytotoxic effects. These results highlight the potential of LPA 1 as a migrastatic target. Consequently, the LPA 1 antagonists developed in this study hold promise as potential migrastatic candidates for TNBC., (© 2024 Wiley-VCH GmbH.)

Quaternary ammonium compound (QAC) disinfectants represent one of our first lines of defense against pathogens. Their inhibitory and bactericidal activities are usually tested through minimum inhibitory concentration (MIC) and time-kill assays, but these assays can become cumbersome when screening many compounds. We investigated how the dynamic surface tension (DST) measurements of QACs correlate with these antimicrobial activities by testing a panel of potent and structurally varied QACs against the gram-positive Staphylococcus aureus and the gram-negative Pseudomonas aeruginosa. We found that DST values correlated well with bactericidal activity in real-world disinfection conditions but not with MIC values. Moreover, no correlation between these two antimicrobial activities of QACs (bactericidal and inhibition) was observed. In addition, we observed that the bactericidal activity of our QAC panel against the gram-negative P. aeruginosa was severely affected in the presence of hard water. Interestingly, we found that the counterion of the QAC affects the killing of bacteria in these conditions, a phenomenon not observed in most MIC assessments. Moreover, some of our best-in-class QACs show enhanced bactericidal activity when combined with a commercially available QAC. In conclusion, we determined that an intrinsic physical property of QACs (DST) can be used as a technique to screen for bactericidal activity of QACs in conditions that mimic real-world disinfection conditions., (© 2024 Wiley-VCH GmbH.)

Tumour-derived sialoglycans, bearing the charged nonulosonic sugar sialic acid at their termini, play a critical role in tumour cell adhesion and invasion, as well as evading cell death and immune surveillance. Sialyltransferases (ST), the enzymes responsible for the biosynthesis of sialylated glycans, are highly upregulated in cancer, with tumour hypersialylation strongly correlated with tumour growth, metastasis and drug resistance. As a result, desialylation of the tumour cell surface using either targeted delivery of a pan-ST inhibitor (or sialidase) or systemic delivery of a non-toxic selective ST inhibitors are being pursued as potential new anti-metastatic strategies against multiple cancers including pancreatic, ovarian, breast, melanoma and lung cancer. Herein, we have employed molecular modelling to give insights into the selectivity observed in a series of selective ST inhibitors that incorporate a uridyl ring in place of the cytidine of the natural donor (CMP-Neu5Ac) and replace the charged phosphodiester linker of classical ST inhibitors with a neutral α-hydroxy-1,2,3-triazole linker. The inhibitory activities of the nascent compounds were determined against recombinant human ST enzymes (ST3GAL1, ST6GAL1, ST8SIA2) showing promising activity and selectivity towards specific ST sub-types. Our ST inhibitors are non-toxic and show improved synthetic accessibility and drug-likeness compared to earlier nucleoside-based ST inhibitors., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Targeting the protein arginine methyltransferase 1 (PRMT1) has emerged as a promising therapeutic strategy in cancer treatment. The phase 1 clinical trial for GSK3368715, the first PRMT1 inhibitor to enter the clinic, was terminated early due to a lack of clinical efficacy, extensive treatment-emergent effects, and dose-limiting toxicities. The incidence of the latter two events may be associated with inhibition-driven pharmacology as a high and sustained concentration of inhibitor is required for therapeutic effect. The degradation of PRMT1 using a proteolysis targeting chimera (PROTAC) may be superior to inhibition as proceeds via event-driven pharmacology where a PROTAC acts catalytically at a low dose. PROTACs containing the same pharmacophore as GSK3368715, combined with a motif that recruits the VHL or CRBN E3-ligase, were synthesised. Suitable cell permeability and target engagement were shown for selected candidates by the detection of downstream effects of PRMT1 inhibition and by a NanoBRET assay for E3-ligase binding, however the candidates did not induce PRMT1 degradation. This paper is the first reported investigation of PRMT1 for targeted protein degradation and provides hypotheses and insights to assist the design of PROTACs for PRMT1 and other novel target proteins., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

In case of an adverse analytical finding, a low (estimate) urine concentration can be the consequence of 2 very different situations: it can be the tail end of a drug voluntarily consumed to enhance athletic performance, even by microdosing (which is not effective for all drugs), or it can be the result of a contamination, irrespective of its source. For numerous doping agents, a hair test can allow discriminating doping from contamination based on the measured concentration or even the absence of the target drug. Given hair produces incremental concentrations, its analysis offers the possibility of establishing a pattern of drug use and thus, verifying self-reported histories of exposure. In order to provide a retrospective calendar of drug use, segmental analysis of the hair strand can be performed. In doping, the usual practice is to test the substance in short segments, such as 1 cm to avoid drug dilution when using larger segments. During the last months, seven athletes have returned an adverse analytical finding for the diuretic chlortalidone, with reported urine concentrations in the range 20 to 50 ng/mL. All these athletes submitted, via their legal team, their hair for establishing a pattern of exposure. Results were always consistent with incidental contamination (hair concentration lower than 5 pg/mg), although the source of contamination was never identified. The interpretation of the findings was established in the light of the limited literature, including hair tests after microdosing and therapeutic use., 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.)

In a groundbreaking study, Eckert and colleagues introduce DecryptE, an innovative approach to dose-resolved proteomics that significantly advances our understanding of drug effects at the proteomic level. This method integrates cutting edge sample preparation and mass spectrometry technologies, establishing a robust platform for high-throughput proteome analysis. DecryptE enables the quantification of more than 7,000 proteins per hour and was employed to study 144 clinical drugs and research compounds, generating more than 1 million dose-response curves using Jurkat acute T-cell leukemia cells as a model system. The platform demonstrates outstanding reproducibility, ensuring reliable and consistent results across multiple experiments. By providing detailed information on drug potency and efficacy, DecryptE allows the identification of subtle changes in protein expression and facilitates the clustering of drugs based on their proteomic profiles. This study not only reveals novel drug mechanisms but also creates a comprehensive resource that can be utilized by the broader research community. Furthermore, it highlights the potential of integrating proteomics-and potentially other omics modalities in the future-with dose-response analysis to advance pharmacological research and improve therapeutic strategies., (©2024 American Association for Cancer Research.)

The US FDA's Project Optimus initiative that emphasizes dose optimization prior to marketing approval represents a pivotal shift in oncology drug development. It has a ripple effect for rethinking what changes may be made to conventional pivotal trial designs to incorporate a dose optimization component. Aligned with this initiative, we propose a novel seamless phase II/III design with dose optimization (SDDO framework). The proposed design starts with dose optimization in a randomized setting, leading to an interim analysis focused on optimal dose selection, trial continuation decisions, and sample size re-estimation (SSR). Based on the decision at interim analysis, patient enrollment continues for both the selected dose arm and control arm, and the significance of treatment effects will be determined at final analysis. The SDDO framework offers increased flexibility and cost-efficiency through sample size adjustment, while stringently controlling the Type I error. This proposed design also facilitates both accelerated approval (AA) and regular approval in a "one-trial" approach. Extensive simulation studies confirm that our design reliably identifies the optimal dosage and makes preferable decisions with a reduced sample size while retaining statistical power., (© 2024 John Wiley & Sons Ltd.)

Exposure to pesticide could contribute to neurodevelopmental and neurodegenerative disorders. Notably, research suggests that prenatal or early postnatal exposure to paraquat (PQ), an herbicide, might trigger neurodevelopmental toxicity in neural stem cells (NSCs) via oxidative stress. However, the molecular mechanisms of PQ-induced perturbations in NSCs, particularly at the metabolite level, are not fully understood. Using a dose-response metabolomics approach, we examined metabolic changes in murine NSCs exposed to different PQ doses (0, 10, 20, 40 μM) for 24h. At 20 μM, PQ treatment led to significant metabolic alterations, highlighting unique toxic mechanisms. Metabolic perturbations, mainly affecting amino acid metabolism pathways (e.g., phenylalanine, tyrosine, arginine, tryptophan, and pyrimidine metabolism), were associated with oxidative stress, mitochondrial dysfunction, and cell cycle dysregulation. Dose-response models were used to identify potential biomarkers (e.g., Putrescine, L-arginine, ornithine, L-histidine, N-acetyl-L-phenylalanine, thymidine) reflecting early damage from low-dose PQ exposure. These biomarkers could be used as points of departure (PoD) for characterizing PQ exposure hazard in risk assessment. Our study offers insights into mechanisms and risk assessment related to PQ-induced neurotoxicity in NSCs., 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.)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives: Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods: This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results: Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with www.clinicaltrials.gov (NCT04396756).

The rise of cutting-edge precision cancer treatments has led to a growing significance of the optimal biological dose (OBD) in modern oncology trials. These trials now prioritize the consideration of both toxicity and efficacy simultaneously when determining the most desirable dosage for treatment. Traditional approaches in early-phase oncology trials have conventionally relied on the assumption of a monotone relationship between treatment efficacy and dosage. However, this assumption may not hold valid for novel oncology therapies. In reality, the dose-efficacy curve of such treatments may reach a plateau at a specific dose, posing challenges for conventional methods in accurately identifying the OBD. Furthermore, achieving reliable identification of the OBD is typically not possible based on a single small-sample trial. With data from multiple phase I and phase I/II trials, we propose a novel Bayesian random-effects dose-optimization meta-analysis (REDOMA) approach to identify the OBD by synthesizing toxicity and efficacy data from each trial. The REDOMA method can address trials with heterogeneous characteristics. We adopt a curve-free approach based on a Gamma process prior to model the average dose-toxicity relationship. In addition, we utilize a Bayesian model selection framework that uses the spike-and-slab prior as an automatic variable selection technique to eliminate monotonic constraints on the dose-efficacy curve. The good performance of the REDOMA method is confirmed by extensive simulation studies., (© 2024 John Wiley & Sons Ltd.)

Purpose: This study aimed to establish the 95% effective dose (ED95) of esketamine in combination with propofol for hysteroscopy and then to evaluate its efficacy and safety profile., Patients and Methods: This prospective, double-blind, randomized controlled trial consisted of two cohorts. In cohort 1, 45 women aged 18-65 years undergoing hysteroscopy were randomly assigned to either group E (esketamine + propofol) or group A (alfentanil + propofol). Dixon's up-and-down method was used to determine the ED95 of esketamine and alfentanil. In cohort 2, 86 patients were randomized to group E and group A, with the calculated ED95 dose of the study drugs used for induction. The success rate of anesthesia using the ED95% dose, along with parameters related to anesthesia induction, recovery, and adverse events were also recorded., Results: The ED95 of esketamine was 0.254 mg/kg (95% CI: 0.214-1.004), while that of alfentanil was 9.121 μg/kg (95% CI: 8.479-13.364). The anesthesia success rate was 93.0% in group E and 95.2% in group A (p = 0.664). After resuscitation, both groups achieved a 100% success rate. The induction time was significantly shorter in group E (60.0 [55.0-70.0] s) compared to group A (67.0 [61.0-79.3] s) (p = 0.006). Group E had lower rates of respiratory depression (p < 0.001), hypoxia (p = 0.006), minimum perioperative SpO 2 (p = 0.010), and hypotension (p = 0.001). Esketamine had less effect on respiratory rate, heart rate, mean blood pressure, and end-tidal carbon dioxide compared to alfentanil (all p < 0.001). There were no significant differences in postoperative pain between the two groups., Conclusion: This study determined the ED 95 dose of esketamine for intravenous general anesthesia during hysteroscopy. Esketamine showed less respiratory and hemodynamic depression, as well as fewer adverse effects compared to alfentanil. Esketamine is an ideal anesthetic agent compared to alfentanil for hysteroscopic anesthesia., Trial Registration: www.chictr.org.cn, (ChiCTR2300077283); registered November 3, 2023., Competing Interests: The authors report no conflicts of interest with respect to this work., (© 2024 Weng et al.)

Background: Vitamin D supplementation may prevent acute respiratory infections (ARIs). This study aimed to identify the optimal methods of vitamin D supplementation., Methods: PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry were searched from database inception through July 13, 2023. Randomized-controlled trials (RCTs) were included. Data were pooled using random-effects model. The primary outcome was the proportion of participants with one or more ARIs., Results: The analysis included 43 RCTs with 49320 participants. Forty RCTs were considered to be at low risk for bias. The main pairwise meta-analysis indicated there were no significant preventive effects of vitamin D supplementation against ARIs (risk ratio [RR]: 0.99, 95% confidence interval [CI]: 0.97 to 1.01, I 2  = 49.6%). The subgroup dose-response meta-analysis indicated that the optimal vitamin D supplementation doses ranged between 400-1200 IU/day for both summer-sparing and winter-dominant subgroups. The subgroup pairwise meta-analysis also revealed significant preventive effects of vitamin D supplementation in subgroups of daily dosing (RR: 0.92, 95% CI: 0.85 to 0.99, I 2  = 55.7%, number needed to treat [NNT]: 36), trials duration < 4 months (RR: 0.81, 95% CI: 0.67 to 0.97, I 2  = 48.8%, NNT: 16), summer-sparing seasons (RR: 0.85, 95% CI: 0.74 to 0.98, I 2  = 55.8%, NNT: 26), and winter-dominant seasons (RR: 0.79, 95% CI: 0.71 to 0.89, I 2  = 9.7%, NNT: 10)., Conclusion: Vitamin D supplementation may slightly prevent ARIs when taken daily at doses between 400 and 1200 IU/d during spring, autumn, or winter, which should be further examined in future clinical trials., (© 2024. The Author(s).)

Background: Rapid sequence intubation (RSI) have been shown to be effective in preventing reflux aspiration in patients with a full stomach during anaesthesia induction and endotracheal intubation. However, there is currently no standardized operation protocol or anaesthesia induction drug standard for RSI. Furthermore, there is a lack of evidence regarding the use of RSI in patients older than 65. In this study, we aimed to investigate the cardiovascular effects of different doses of alfentanil combined with propofol and etomidate during RSI in elderly patients aged 65-80 years., Methods: A total of 96 patients aged 65-80 years who underwent general anaesthesia with tracheal intubation were selected for this study. The patients were randomly assigned to one of four groups using a random number table. Group A patients received an induction dose of 10 µg/kg alfentanil, group B patients received 15 µg/kg alfentanil, group C patients received 20 µg/kg alfentanil, and group D patients received 25 µg/kg alfentanil. Heart rate (HR), mean arterial pressure (MAP), cardiac index (CI), and ejection fraction (EF) were measured at three time points: 5 min before anaesthesia induction (T0), 1 min after endotracheal intubation (T1), and 5 min after endotracheal intubation (T2). Concurrently, 4 ml of arterial blood was collected from patients at three time points, and the concentrations of norepinephrine (NE) and cortisol (Cor) in plasma were detected. Occurrences of hypertension, hypotension, bradycardia and tachycardia during anesthesia induction to 5 min after tracheal intubation were noted., Results: Compared with T0, the HR, MAP, NE and Cor concentrations in group A and group B were increased at the T1 and T2 time points, CI and EF values were decreased (P < 0.05). HR and MAP in groups C and D were increased at the T1 time point, while they were decreased at the T2 time point in group D (P < 0.05). The changes in CI and EF values, concentrations of NE and Cor, were not significant at T1 and T2 time points in group C (P > 0.05). Additionally, they were not significant in group D at the T1 time point (P > 0.05), but decreased at the T2 time point (P < 0.05). Compared with group A, the HR, MAP, NE and Cor concentrations in groups C and D were decreased at T1 and T2 time points (P < 0.05). The CI and EF values of groups C and D were increased at T1 time point but decreased at T2 time point in group D (P < 0.05). The incidence of hypertension and tachycardia in group A was significantly higher than that in group C and group D (P < 0.05), and the incidence of hypotension and bradycardia in group D was significantly higher than that in group A and group B (P < 0.05)., Conclusion: Alfentanil 20 µg/kg for RSI in elderly patients, can effectively inhibit the violent cardiovascular reaction caused by intubation, and avoid the inhibition of cardiovascular system caused by large dose, hemodynamics more stable., Trial Registration: ChiCTR2200062034 ( www.chictr.org.cn )., (© 2024. The Author(s).)

Background: Spinal anesthesia (SA) is a conventional method for proper nerve block in abdominopelvic and lower extremity surgeries. Compared to general anesthesia, SA has reduced perioperative complications significantly. The hyperbaric type of bupivacaine hydrochloride (HB) induces spinal anesthesia more efficiently with a lower incidence of life-threatening adverse reactions like Perioperative hemodynamic changes and respiratory depression. More investigations are needed to define the best dosage that provides adequate anesthesia while reducing adverse effects for each surgical procedure., Methods: This double-blinded randomized clinical trial compared the consequences of the (12.5mg,15mg,20mg) dosages of HB-bupivacaine in elective lower limb orthopedic surgery. Using block randomization, we allocated 60 participants to three (n = 20) study groups. Utilizing the same protocol of anesthesia induction, outcome variables assumed and measured as the incidence of the adverse effects (Hypotension, Anxiety, Bradycardia, Nausea and Vomiting(N/V), Hypoventilation, and Decreased o2 saturation), and the requirement for intervention to control the unwanted reaction. Addressing that, outcome variables were measured 10 times perioperatively. One-way ANOVA test, the chi 2 test, or repeated measures ANOVA test with the Bonferroni adjustment were utilized as appropriate., Results: We found that the incidence of hypotension (P-value:0.02) and the N/V (P-value < 0.001) are associated with the HB-bupivacaine dosage. Contrary, our findings indicate that the incidence of apnea, bradycardia, and hypoventilation did not exhibit a significant dose-dependent pattern between the groups. Repeated measures analysis revealed significant intergroup differences for Herat rate, systolic, diastolic, and mean arterial pressure (group*time Pvalue < 0.001). The observed differences were more prominent 10-30 min after injection of HB-bupivacaine. The regression model claimed that gender (P-value:0.002) and drug dosage (P-value:0.03) significantly predict the incidence of adverse effects., Conclusion: Our results, suggest that the administration of the 12.5mg HB-bupivacaine provides adequate anesthesia while minimizing the risk of adverse events for lower limb orthopedic surgeries lasting up to 180 min., Trial Registration: The study was registered at the Clinical Trial Registry Center (IRCT20160202026328N7), Registered on 2022.01.10., (© 2024. The Author(s).)

Ovarian cancer has the worst case-to-fatality ratio of all gynecologic malignancies. The main reasons for the high mortality rate are relapse and the development of chemoresistance. In this paper, the cytotoxic activity of two new multiaction platinum(IV) derivatives of cisplatin and oxaliplatin in a panel of ovarian cancer cells is reported. Cis,cis,trans -[Pt(NH 3 ) 2 Cl 2 (IPA)(DCA)] ( 1 ) and trans -[Pt(DACH)(OX)(IPA)(DCA)] ( 2 ) (IPA = indole-3-propionic acid, DCA = dichloroacetate, DACH = 1R,2R -1,2-diaminocyclohexane, OX = oxalate) were synthesized and characterized by elemental analysis, ESI-MS, FT-IR, and 1 H, 13 C, and 195 Pt NMR spectroscopy. The biological activity was evaluated in A2780, PEA1, PEA2, SKOV3, SW626, and OVCAR3 cells. Both complexes are potent cytotoxins. Remarkably, complex 2 is 14 times more active in OVCAR3 cells than cisplatin and is able to overcome cisplatin resistance in PEA2 and A2780cis cells, which are models of post-treatment patient-developed and laboratory-induced resistance. This complex also shows activity in 3D cancer models of the A2780 cells. Mechanistic studies revealed that the complexes induce apoptosis via DNA damage and ROS generation.

Background: New evidence suggested that propolis might reduce serum levels of inflammatory mediators; therefore, in this study we aimed to prove the potential effect of propolis on serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) through conducting a systematic review and meta-analysis., Methods: Databases including PubMed, ClinicalTrials.gov, Scopus, Cochrane Library, and ISI Web of Science were searched until October 2023. In the present meta-analysis, we detected the overall effect sizes using extracted standard mean differences (SMD) and the standard deviations (SDs) from both study groups through DerSimonian and Laird method. Exploring the statistical heterogeneity was done through Cochran's Q test and I-squared statistic., Results: In total, seventeen and sixteen studies were included in the systematic review and meta-analysis, respectively. The overall estimate indicated that the propolis significantly reduced serum levels of IL-6 (SMD = -3.47, 95% confidence interval (95%CI): -5.1, -1.84; p < 0.001), CRP (SMD= -1.73, 95%CI: -2.82, -0.65; p = 0.002), and TNF-α (SMD= -1.42, 95%CI= -2.15, -0.68; p < 0.001). These results also revealed geographical region and propolis dose were the critical points to get the beneficial effects., Conclusion: According to our result, propolis supplementation can decrease serum levels of IL-6, CRP, and TNF-α; therefore, it might be considered as complementary therapy for the treatment of certain chronic diseases., (© 2024. The Author(s).)

Background: Sjögren's disease is a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease., Methods: This randomised, double-blind, placebo-controlled, phase 2b study, conducted at 71 sites in 23 countries, enrolled patients aged 18 years or older fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) 2016 criteria. In the dose-ranging cohort 1, patients with a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or higher were randomly assigned (1:1:1:1) to subcutaneous iscalimab 150 mg, 300 mg, 600 mg, or placebo. In the proof-of-concept cohort 2, patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher were randomly assigned (1:1) to iscalimab 600 mg or placebo. The sponsor, investigator, site personnel, and patients were masked to the treatment assignment. The primary objectives were to demonstrate a dose-response relationship of iscalimab based on the change in ESSDAI from baseline to week 24 in cohort 1 by Multiple Comparison Procedure-Modelling (MCP-Mod), and to assess the effect of iscalimab 600 mg on ESSPRI at week 24 in cohort 2. All the efficacy analyses included all patients who were randomly assigned, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03905525), and is complete., Findings: Between Oct 1, 2019, and Feb 28, 2022, 460 patients were screened; 173 patients were assigned to cohort 1 (44 to iscalimab 150 mg, 43 to 300 mg, 43 to 600 mg, and 43 to placebo) and 100 to cohort 2 (50 to each group). In cohort 1, the MCP step showed a significant dose-response relationship for placebo-adjusted ESSDAI change from baseline in one of four models (Linlog model, one-sided p=0·0041). ESSDAI decreased from baseline to week 24 with all three doses of iscalimab; 150 mg and 600 mg doses showed statistically significant improvement (placebo-adjusted least squares [LS] mean difference -3·0 [95% CI -4·9 to -1·1]; p=0·0025 for 150 mg and -2·9 [-4·9 to -1·0]; p=0·0037 for 600 mg). In cohort 2, ESSPRI showed a trend towards improvement with iscalimab 600 mg (placebo-adjusted LS mean change from baseline -0·57 points [95% CI -1·30 to 0·15]; p=0·12). Serious adverse events were reported in nine patients in cohort 1 (one [2%] of 43 in the placebo group, one [2%] of 44 in the iscalimab 150 mg group, three [7%] of 42 in the 300 mg group, four [9%] of 44 in the 600 mg group) and four patients in cohort 2 (two [4%] of 50 in each group). No deaths occurred over the 24-week period., Interpretation: The study met the primary objective of demonstrating a significant dose-response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials., Funding: Novartis Pharma., Competing Interests: Declaration of interests BAF received consulting fees from Novartis, Roche, BMS, Galapagos, Janssen, Servier, UCB, and Sanofi; and funding to his institution for collaborative research from Janssen, Celgene, Galapagos, and Servier. XM received consulting fees from BMS, Galapagos, GSK, Novartis, Pfizer, and Servier. AP received grants or research support from Novartis, Viela Bio, and Exosome Dx. TG-B received travel assistance from Novartis and has participated in the scientific advisory board of Novartis. W-FN provided consultation services for Novartis, AbbVie, BMS, Sanofi, Argenx, Janssen, Resolve Therapeutics, Bain Capitals, and UCB. SF reports consulting fees from AstraZeneca and Novartis; payment for sponsored talks or courses from AbbVie, Chugai, Galapagos, Novartis, and UCB; participation in the scientific advisory boards of AstraZeneca and Novartis; and a research grant from Novartis for their institution. GN received consulting fees from Novartis and Janssen; and participated in the scientific advisory boards of Novartis and Janssen. JH reported that his institution received research grants and study fees from Novartis, and he received honoraria for lectures from Lilly, MSD, AbbVie, Novartis, and Astro Pharma; travel support from Novartis; and participated in the scientific advisory boards of Lilly and Pfizer. SSM received consulting fees from Novartis, BMS, Otsuka, Visterra, Target RDW, Horizon, Kinksa, and iCell; and payment for educational content development. EA received grants from National Eye Institute, Novartis, Ocular Therapeutics, W.L. Gore & Associates, IRIS Registry Research Fund, and US Department of Defense; received speaker and consultation fees from Adelphi Values, Dompe, FirstString Medical Research, HanAll, Novalique, Regeneron Healthcare Solutions, Sinqi, Xequel, Kyria, and Hawkeye. MS, W-LL, CS, and WH are employees of Novartis and own stocks in Novartis. MM-P was an employee of Novartis at the time of the study and until the initial stages of the development of this manuscript and currently is an employee of Alcon. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Improving patient selection and development of biological therapies such as vedolizumab in IBD requires a thorough understanding of the mechanism of action and target binding, thereby providing individualised treatment strategies. We aimed to visualise the macroscopic and microscopic distribution of intravenous injected fluorescently labelled vedolizumab, vedo-800CW, and identify its target cells using fluorescence molecular imaging (FMI)., Design: Forty three FMI procedures were performed, which consisted of macroscopic in vivo assessment during endoscopy, followed by macroscopic and microscopic ex vivo imaging. In phase A, patients received an intravenous dose of 4.5 mg, 15 mg vedo-800CW or no tracer prior to endoscopy. In phase B, patients received 15 mg vedo-800CW preceded by an unlabelled (sub)therapeutic dose of vedolizumab., Results: FMI quantification showed a dose-dependent increase in vedo-800CW fluorescence intensity in inflamed tissues, with 15 mg (153.7 au (132.3-163.7)) as the most suitable tracer dose compared with 4.5 mg (55.3 au (33.6-78.2)) (p=0.0002). Moreover, the fluorescence signal decreased by 61% when vedo-800CW was administered after a therapeutic dose of unlabelled vedolizumab, suggesting target saturation in the inflamed tissue. Fluorescence microscopy and immunostaining showed that vedolizumab penetrated the inflamed mucosa and was associated with several immune cell types, most prominently with plasma cells., Conclusion: These results indicate the potential of FMI to determine the local distribution of drugs in the inflamed target tissue and identify drug target cells, providing new insights into targeted agents for their use in IBD., Trial Registration Number: NCT04112212., Competing Interests: Competing interests: GD received research grants from Royal DSM, Takeda and Janssen Pharmaceuticals and speaker fees from AbbVie, Pfizer, Takeda and Janssen Pharmaceuticals. EAMF is supported by a ZonMW Clinical Fellowship grant (project number 90719075) and has received an unrestricted research grant from Takeda. MD and SJ are employees and shareholders of Regeneron Pharmaceuticals., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH., Methods: In this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control., Results: All 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was -27.3% in the crinecerfont group and -10.3% in the placebo group (least-squares mean difference, -17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (-299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, -345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups., Conclusions: Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.)., (Copyright © 2024 Massachusetts Medical Society.)

Objectives: To evaluate whether the effectiveness and safety of low (81 mg daily) versus high-dose (325 mg daily) aspirin is consistent across races among patients with established atherosclerotic cardiovascular disease (ASCVD)., Design: A secondary analysis of the randomised controlled trial ADAPTABLE was performed., Setting: The study was conducted in 40 centres and one health plan participating in the National Patient-Centred Clinical Research Network (PCORnet) in the USA., Participants: Among 15 076 participants with established ASCVD, 14 096 had self-reported race available and were included in the analysis. Participants were divided according to self-reported race as Black (n=1311, 9.3%), White (n=11 990, 85.1%) or other race (n=795, 5.6%)., Interventions: Participants were randomised to open-label daily aspirin doses of 81 mg versus 325 mg in a 1:1 ratio for a median of 26.2 months., Primary and Secondary Outcomes Measures: The primary effectiveness endpoint was a composite of death from any cause, hospitalisation for myocardial infarction or hospitalisation for stroke. The primary safety endpoint was hospitalisation for bleeding requiring blood product transfusion., Results: Estimated cumulative incidence of the primary effectiveness endpoint at median follow-up with the 81 mg and the 325 mg daily doses were 6.70% and 7.12% in White participants (adjusted HR: 1.00 [95% CI: 0.88 to 1.15]); 12.27% and 10.69% in Black participants (adjusted HR: 1.40 [95% CI: 1.02 to 1.93]); and 6.88% and 7.69% in other participants (adjusted HR: 0.86 [95% CI: 0.54 to 1.39]) (p-interaction=0.12), respectively. There was no significant interaction between self-reported race and assigned aspirin dose regarding the secondary effectiveness and the primary safety endpoints., Conclusion: Race is not an effect modifier on the impact of aspirin dosing on effectiveness and safety in patients with established ASCVD. In clinical practice, treatment decisions regarding aspirin dose in secondary prevention of ASCVD should not be influenced by race., Trial Registration Number: NCT02697916., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

According to the World Health Organization, the number of tuberculosis (TB) infections and the drug-resistant burden worldwide increased by 4.5% and 3.0%, respectively, between 2020 and 2021. Disease severity and complexity drive the interest for undertaking new clinical trials to provide efficient treatment to limit spread and drug resistance. TB Alliance conducted a phase 2 study in 106 patients to guide linezolid (LZD) dose selection using early bactericidal activity over 14 days of treatment. LZD is highly efficient for drug-resistant TB treatment, but treatment monitoring is required since serious adverse events can occur. The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model to analyze the dose-response relationship between linezolid exposure and efficacy biomarkers. Using time to positivity (TTP) and colony-forming unit (CFU) count data, we developed a PKPD model in six dosing regimens, differing on LZD dosing intensity. A one-compartment model with five transit absorption compartments and non-linear auto-inhibition elimination described best LZD pharmacokinetic characteristics. TTP and CFU logarithmic scaled [log(CFU)] showed a bactericidal activity of LZD against Mycobacterium tuberculosis . TTP was defined by a model with two significant covariates: the presence of uni- and bilateral cavities decreased baseline TTP value by 24%, and an increase on every 500 mg/L/h of cumulative area under the curve increased the rate at which TTP and CFU change from baseline by 20% and 11%, respectively., Clinical Trials: This study is registered with ClinicalTrials.gov as NCT02279875., Competing Interests: The authors declare no conflict of interest.

Background: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM)., Methods and Results: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation., Conclusions: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

Background: Heart failure mortality remains high despite recent progress in pharmacological treatment. AZD3427 is a selective long-acting analog of relaxin, a vasodilatory hormone with antifibrotic effects. We assessed the safety, pharmacokinetics, and pharmacodynamics of AZD3427 in healthy volunteers and patients with heart failure on standard-of-care therapy., Methods and Results: In this first-in-human, phase 1a/b, randomized, single-blind, placebo-controlled study, healthy volunteers were randomized 6:2 to receive a single dose of AZD3427 or placebo by subcutaneous injection in 5 mixed-ethnicity cohorts (5, 10, 30, 90, or 270 mg) and 1 Japanese-descent cohort (270 mg), or by intravenous injection in 1 cohort (15 mg). After confirming safety and tolerability in healthy volunteers, 3 cohorts of patients with heart failure and left ventricular ejection fraction ≤40% and 3 cohorts with ejection fraction ≥41% were randomized 6:2 to receive 5 weekly doses of AZD3427 (5, 15, or 45 mg) or placebo by subcutaneous injection. In total, 56 healthy volunteers and 48 patients with heart failure were randomized. AZD3427 was well tolerated at all doses. After subcutaneous administration, AZD3427 was absorbed slowly, and exposure was approximately linear across the dose range. In patients with heart failure, AZD3427 terminal half-life was 13 to 14 days and there were numerical increases in stroke volume and estimated glomerular filtration rate. No treatment-emergent antidrug antibodies were detected., Conclusions: AZD3427 had favorable safety and pharmacokinetic profiles. Hemodynamic changes in patients with heart failure were consistent with the anticipated effects of a relaxin analog. These findings support further development of AZD3427 as a novel long-term treatment for patients with heart failure., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04630067.

Amyloid-peptide (Aβ) monomeric forms (ABM) occurring in presymptomatic Alzheimer's disease (AD) brain are thought to be devoid of neurotoxicity while the transition/aggregation of ABM into oligomers is determinant for Aβ-induced toxicity since Aβ is predominantly monomeric up to 3 µM and aggregates over this concentration. However, recent imaging and/or histopathological investigations revealed alterations of myelin in prodromal AD brain in absence of aggregated Aβ oligomers, suggesting that ABM may induce toxicity in myelin-producing cells in early AD-stages. To check this hypothesis, here we studied ABM effects on the viability of the Human oligodendrocyte cell line (HOG), a reliable oligodendrocyte model producing myelin proteins. Furthermore, to mimic closely interactions between oligodendrocytes and other glial cells regulating myelination, we investigated also ABM effects on mouse brain primary mixed-glial cell cultures. Various methods were combined to show that ABM concentrations (600 nM-1 µM), extremely lower than 3 µM, significantly decreased HOG cell and mouse brain primary mixed-glial cell survival. Interestingly, flow-cytometry studies using specific cell-type markers demonstrated that oligodendrocytes represent the most vulnerable glial cell population affected by ABM toxicity. Our work also shows that the neurosteroid 3α-O-allyl-allopregnanolone BR351 (250 and 500 nM) efficiently prevented ABM-induced HOG and brain primary glial cell toxicity. Bicuculline (50-100 nM), the GABA-A-receptor antagonist, was unable to block/reduce BR351 effect against ABM-induced HOG and primary glial cell toxicity, suggesting that BR351-evoked neuroprotection of these cells may not depend on GABA-A-receptor allosterically modulated by neurosteroids. Altogether, our results suggest that further exploration of BR351 therapeutic potential may offer interesting perspectives to develop effective neuroprotective strategies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)