Search

The advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, especially the triple therapy combining the drugs elexacaftor, tezacaftor, ivacaftor (ETI), has significantly changed the course of the disease in people with cystic fibrosis (pwCF). ETI, which is approved for the majority (80-90%) of pwCF, partially restores CFTR channel function, resulting in improved mucociliary clearance and, consequently, improved lung function, respiratory symptoms and pulmonary exacerbations. The bacterial burden of classical CF pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus is reduced without reaching eradication in the majority of infected patients. Limited data is available on less common or emerging bacterial pathogens. ETI has a positive effect on the lung microbiome but does not fully restore it to a healthy state. Due to the significant reduction in sputum production under ETI, respiratory samples such as deep-throat swabs are commonly taken, despite their inadequate representation of lower respiratory tract pathogens. Currently, there are still unanswered questions related to this new therapy, such as the clinical impact of infection with cystic fibrosis (CF) pathogens, the value of molecular diagnostic tests, the durability of the effects on respiratory infection and the role of fungal and viral infections. This article reviews the changes in bacterial lung infections and the microbiome in CF to provide evidence for the use of antibiotics in the era of ETI., Competing Interests: Conflict of interest: J. Milczewska reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceuticals (Poland) Sp. z o.o. Z. Syunyaeva reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceuticals, and support for attending meetings from Vertex Pharmaceuticals. A. Żabińska-Jaroń has nothing to disclose. D. Sands reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceuticals and Pfizer, support for attending meetings from Vertex Pharmaceuticals, participation on a data safety monitoring board or advisory board with Vertex Pharmaceuticals, and leadership roles with ECFS (Board member) and Polish CF Society (President). S. Thee reports payment or honoraria for lectures, presentations, manuscript writing or educational events from PARI Medical Holding, Vertex Pharmaceuticals and Viatris, support for attending meetings from Vertex Pharmaceuticals and Viatris, and leadership roles with ECFS (THCF working group and pulmonary exacerbation group) and ERS (CRC AMR-lung)., (Copyright ©The authors 2024.)

Introduction: Mutation-specific disease modifying drugs such as the triple combination Elexacaftor/Tezacaftor/Ivacaftor (ETI), are associated with significant improvements in physical health. Reproductive health and a pursuit of parenthood are of increased relevance; a dramatic increase in childbirth rates for females with CF has already been observed., Areas Covered: Fertility in males and females with CF, and any subsequent impact of CFTR modulator therapy, is reviewed. The potential impacts of maternal use of CFTR modulator drugs on offspring health are considered, as constituent components have been found in fetal circulation in animals and humans, and the implications for maternal continuation or cessation of treatment. Clinical data are reassuring, although cases of lens opacities, and missed CF diagnoses due to false negative newborn screening results have been reported., Expert Opinion: More research and high-quality evidence are needed to characterize maternal, fetal and long-term offspring outcomes following CFTR modulator therapy use during pregnancy and breastfeeding. There is a potential therapeutic impact of targeting CFTR-related organ dysfunction in CF-fetuses via maternal-administration of CFTR modulators. Additionally, any consequences of CFTR-modulation in heterozygote carrier infant warrants urgent and collective consensus regarding ethical and clinical research programs to evaluate this discrete population.

Background and Objective: Inadequate response to antidepressant monotherapy is common among patients with major depressive disorder (MDD). The efficacy and safety of adjunctive brexpiprazole 2 mg/day has recently been confirmed during the 6-week, randomized, placebo-controlled phase 2/3 (BLESS) study, which evaluated brexpiprazole at 1 mg/day and 2 mg/day versus placebo as adjunctive therapy to antidepressant therapies in 740 Japanese patients with MDD and an inadequate response to antidepressant monotherapy. This study evaluated the long-term safety and efficacy of adjunctive fixed-dose brexpiprazole 2 mg/day in Japanese patients with MDD., Methods: An open-label, 52-week study enrolled rollover patients who completed the 6-week, double-blind, randomized, placebo-controlled phase 2/3 BLESS study (NCT03697603), and de novo patients aged ≥ 65 years. Patients were titrated to fixed-dose brexpiprazole 2 mg/day from Week 1. Safety assessments included treatment-emergent adverse events (TEAEs; primary outcome) and clinical and laboratory variables. Efficacy was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression-Improvement (CGI-I) scale, Hamilton Depression Rating Scale (HAM-D) 17-item total score, and Sheehan Disability Scale (SDS) score., Results: In total, 247 patients [rollover, n = 216; de novo (previously unexposed), n = 31] were included in the safety/efficacy populations, and 138 (rollover, n = 132; de novo, n = 6; 55.9%) completed the study. Common TEAEs (incidence ≥ 10%) were weight gain [33.2% (n = 82)], akathisia [23.5% (n = 58)], nasopharyngitis [21.1% (n = 52)], and somnolence [10.5% (n = 26)]. TEAEs leading to treatment discontinuation occurred in 26.7% of patients receiving brexpiprazole and 58.1% of de novo patients. The mean (SD) increase in body weight from baseline to Week 52 [observed cases (OC)] was 4.2 (6.5) kg (n = 138); 44.5% (n = 110) had weight gain ≥ 7% at any postbaseline visit. There were no cases of tardive dyskinesia and no AEs related to suicide/suicide attempts. One death occurred (unknown cause), which was unrelated to study treatment. Improvements in the MADRS total score were observed from baseline over the course of the 52-week study [mean (SD) change at Week 52 (OC): - 7.3 (8.7)] for all patients receiving brexpiprazole. The overall MADRS response rate and remission rate in patients receiving brexpiprazole was 41.3% (n = 57) and 34.8% (n = 48), respectively, at Week 52 (OC). Improvements in CGI-S, HAM-D 17 item total score, and SDS mean scores were also observed from baseline over the 52-week study, with a mean (SD) change from baseline at Week 52 (OC) of - 0.8 (1.0), - 5.9 (6.3), and - 1.0 (2.2), respectively, indicating a sustained improvement in symptoms with long-term brexpiprazole treatment., Conclusions: This is the first study to evaluate the safety profile of brexpiprazole 2 mg/day in Japanese patients with MDD, including older adults, which is similar to previous reports, with no new safety risks, and continued efficacy over 52 weeks., Study Registration: ClinicalTrials.gov (NCT03737474; registered on 29 July 2018)., (© 2024. The Author(s).)

Purpose of Review: In 2019, the United States Food and Drug Administration approved a breakthrough therapeutic for cystic fibrosis, elexacaftor-tezacaftor-ivacaftor (ETI), because of its profound effect on lung function in large phase III clinical trials. ETI acts directly on the dysfunctional protein that causes the systemic manifestations of cystic fibrosis and also leads to improvement in nonpulmonary symptoms of cystic fibrosis. Transplant recipients were excluded from the pivotal clinical trials of ETI but may stand to benefit from correction of the underlying protein defect. Drug interactions between the three drugs in ETI and immunosuppression medications are one of the primary concerns about using ETI after transplant. No rigorous studies exist to assess the safety of ETI in transplant recipients., Recent Findings: Multiple recent publications describe the use of ETI after solid organ transplantation, including lung and nonlung transplants, and the real-world evidence for drug interactions between ETI and immunosuppression medications. In nonlung transplant recipients, the pulmonary benefits of ETI have been confirmed, but adverse events occur and may have implications for their transplanted organ (e.g. liver biopsy in the setting of elevated transaminases). Lung transplant recipients may have higher rates of ETI discontinuation than nontransplant recipients given a lack of direct pulmonary benefit and frequency of side effects. Drug interactions have not been difficult to manage, with most studies reporting variable rates of mild to moderate increased tacrolimus levels after initiation of ETI., Summary: Limited data exist to support the use of ETI after solid organ transplantation and further research is warranted. Given the unknown risks and benefits, case by case consideration of ETI use is indicated when extra-pulmonary manifestations are present in lung transplant recipients with cystic fibrosis. Given the proven benefit in cystic fibrosis lung disease, benefits likely outweigh the risks of ETI for nonlung solid organ transplant recipients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The objective of this study was to describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers., Study Design: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period., Results: Among 608 patients on ETI, 109 (17.9%) reported at least 1 AE. The majority (n = 85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA P value .026)., Conclusions: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Elexacaftor-tezacaftor-ivacaftor (ETI) is a highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulating therapy for people with CF and at least one F508del variant. However, there is limited data about the safety and efficacy of this therapy in pediatric populations and in real-world settings. This study aimed at evaluating the effectiveness, tolerability, and safety of ETI in children with CF., Methods: This was a prospective observational study including all children aged 6-11 years who initiated ETI therapy between October 2022 and March 2023 at the Pediatric CF Center of Milan (Italy). Study outcomes included changes in sweat chloride concentration, FEV 1 , LCI 2.5 , body mass index (BMI), tolerance, and safety. Mean changes in study outcomes from baseline through 24 weeks were estimated using mixed-effects regression models., Results: The study included 34 children with CF (median age: 8.3 years). At Week 12, we observed an average decrease in LCI 2.5 of 2.3 units (95% confidence interval [CI]: -3.1; -1.5). At Week 24, sweat chloride concentration decreased by 63 mEq/L (95% CI: -69; -58), FEV 1 increased by 8.8 percentage point (95% CI: 3.7; 13.9) and BMI increased by 0.15 standard deviation scores (95% CI: 0.04; 0.25). Skin rashes appeared in 6 patients which spontaneously resolved within a few days. One month after treatment initiation, one patient experienced an elevation in liver function test results, which subsequently decreased during follow-up visits without necessitating discontinuation of therapy., Conclusions: Our data indicate that ETI therapy is well tolerated by children with CF and is effective in improving signs of lung function abnormalities from early childhood., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by progressive cognitive and functional decline. Nearly all patients with AD develop neuropsychiatric symptoms (NPSs). Agitation is one of the most distressing and challenging NPS. Brexpiprazole is an oral antipsychotic and is the first approved pharmacologic agent in the United States for the treatment of agitation associated with dementia due to AD. Its effect is thought to be from its partial serotonin 5-HT 1A and dopamine D 2 receptor agonist activity and serotonin 5-HT 2A receptor antagonism. Brexpiprazole is a maintenance medication, and it should not be used "as needed" or as a "PRN" treatment for breakthrough agitation. Brexpiprazole is a major substrate of CYP2D6 and CYP3A4. Dose adjustments may be required for drug interactions or impaired renal or hepatic function. Clinical trials found brexpiprazole 2 to 3 mg/d demonstrated significant improvements in agitation, with brexpiprazole showing an approximate 5-point greater reduction on change in the Cohen-Mansfield Agitation Inventory total score at week 12 from baseline compared with placebo. Brexpiprazole is generally well tolerated and safe, and common adverse reactions when used for this indication include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections. Like other antipsychotics used for agitation in AD, brexpiprazole is associated with higher mortality rates compared with placebo. In a long-term care setting, there are several considerations for its use. Benefits include an oral agent that is well tolerated and clinical data showing statistically significant effects on agitation. However, brexpiprazole has not been studied in head-to-head clinical trials against other antipsychotics, and there are differing opinions if the agitation score reductions translate to a clinically meaningful difference. The approval of brexpiprazole signals favorably for upcoming agents for this indication, including escitalopram and dextromethorphan-bupropion. Both escitalopram and dextromethorphan-bupropion are currently undergoing clinical trials., Competing Interests: Disclosures E.D.C. reports personal fees from Genomadix Inc and a grant to her institution from Alzheon. A.P.P. reports personal fees from Acadia Pharmaceuticals, Athira, BMS, Cognitive Research Corp, Eisai, IQVIA, Lundbeck, Novartis, ONO Pharmaceuticals, WCG, WebMD, and Xenon; and grants to his institution from Alector, Athira, Biogen, Cassava, Eisai, Eli Lilly, Genentech/Roche, Vaccinex, NIA, NIMH, and DOD. He is a member of the Scientific Advisory Board of Alzheon. D.L. and I.M.A. declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Recent randomized controlled trials (RCTs) have shown a benefit of brexpiprazole in managing agitation in patients with Alzheimer's disease (AD). However, its efficacy and safety remain unclear. We systematically searched PubMed, Embase, and Cochrane Library for RCTs comparing brexpiprazole with placebo in patients with agitation and AD. Three studies comprising 1,048 patients were included. In patients with agitation and AD, brexpiprazole significantly improved the Cohen-Mansfield Agitation Inventory total score (CMAI) at any dose (MD -3.05; 95% CI -5.12, -0.98; p < 0.01; I 2  = 19%) and at 2 mg (MD -4.36; 95% CI -7.02, -1.70; p < 0.01; I 2  = 0%) over 12 weeks. Brexpiprazole at any dose and 2 mg also showed benefit in the Clinical Global Impression - Severity of illness (CGI-S) score as related to agitation over 12 weeks (MD -0.20; 95% CI -0.36, -0.05; p < 0.01; I 2  = 35%). There is no significant difference between the groups in the incidence of at least one treatment-emergent adverse events (TEAEs; RR 1.14; 95% CI 0.95, 1.37; p = 0.16; I 2  = 45%) and all-cause mortality (RR 1.99; 95% CI 0.37, 10.84; p = 0.42; I 2  = 0%). Brexpiprazole at any dose significantly increased the Simpson-Angus Scale (SAS; MD 0.47; 95% CI 0.28, 0.66; p < 0.01). Our results suggest that brexpiprazole is more efficacious than placebo in the treatment of agitation in AD patients. Further studies are still necessary to confirm long-term effects of brexpiprazole.Prospero registry: CRD42023486694., (© 2024. Fondazione Società Italiana di Neurologia.)

Background: On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally., Methods: MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant., Results: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively)., Discussion: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration . NCT04047420., Competing Interests: Potential conflicts of interest. S. A. R. received research grants from Gilead Sciences and Merck. P. L. A. received research contracts from Gilead Sciences paid to his institution. S. L. H. received research grants and consulting fees from Merck. G. F. D. received research grants from Gilead Sciences. C. W. H. has received clinical research funding from Gilead Sciences and Merck; he is a coinventor of 2 issued US patents related to microbicides; and is founder of Prionde BioPharma, LLC, a microbicide company. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract: A phase 2, international, open-label, nonrandomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary end point was objective response rate (ORR); secondary end points included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n = 38 angioimmunoblastic T-cell lymphoma (AITL), n = 25 PTCL not otherwise specified, and n = 2 other T-cell lymphomas. The ORR was 39.7% (95% confidence interval [CI], 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in patients with AITL (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the nonresponder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pretreated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. This trial was registered at www.ClinicalTrials.gov as #NCT02464228., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Obsessive-compulsive disorder (OCD) is a common and debilitating psychiatric disorder with an approximate incidence of 2.5% in the general population. Serotonin reuptake inhibitors (SRIs) are considered the first line of pharmacological treatment but up to 50% of patients fail to achieve clinical remission or response. Atypical antipsychotics are one of the most common augmentation strategies in OCD treatment resistant patients. Brexpiprazole, a novel atypical antipsychotic with dopamine partial agonism action, has never been studied in addition to SRIs treatment in OCD resistant patients. This study retrospectively investigated the safety and efficacy of a 12 week brexpiprazole augmentation trial in 34 OCD resistant patients. SRI treatment resistance was defined as failing to improve the YBOCS total score by more than 25% from the beginning of the SRI trial. Brexpiprazole augmentation response was defined as at least a 25% improvement in the YBOCS total score. At the end of the study, 17 patients (50.0%) met the response criteria of ≥25% improvement in YBOCS total score vs. baseline. No safety issues were raised throughout the observation period. A total of 19 patients (55.9%) reported adverse experiences, generally mild and not requiring medical intervention. This is the first study to examine the safety and efficacy of brexpiprazole augmentation in resistant OCD patients. Our findings show that brexpiprazole may be a promising and well-tolerated augmentation strategy for SRI-resistant OCD patients. However, further research in larger populations is needed to confirm these results and investigate the long-term safety and tolerability of brexpiprazole in OCD patients.

Objective: Elexacaftor/tezacaftor/ivacaftor (E/T/I) has provided life-changing pharmacotherapy for many people with cystic fibrosis (CF), but conflicting literature exists regarding the effect on mental health. While some reports suggest E/T/I may induce adverse psychiatric symptoms, others report improvements in mental health symptoms. To add to this growing body of knowledge, we retrospectively analyzed depression and anxiety symptoms before and after E/T/I initiation in adults with CF at a single large US CF center., Method: Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) scores recorded in a database were studied. Patients with scores collected before and after E/T/I initiation were included. Regression analyses described associations between score changes and age, race, ethnicity, sex, CFTR variant, and prior depression and/or anxiety diagnoses. Secondary analyses examined possible confounding effects of the COVID-19 pandemic., Results: There was no change in mean GAD-7 (0.5 ± 5.3, p = 0.41) or PHQ-9 (-0.02 ± 6.0, p = 0.97) scores following initiation of E/T/I (N = 86). A trend between a prior diagnosis of depression and worsening in PHQ-9 post-E/T/I was observed (OR 3.58; p = 0.054)., Conclusions: Treatment with E/T/I does not lead to changes in depression or anxiety symptoms at the population level in this single center cohort study. A prior diagnosis of depression trended towards an increased odds of worsening PHQ-9 scores after E/T/I initiation., (© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Competing Interests: Conflict of interest or source of funding: The authors declared no conflicts of interest.

Introduction: Inflammatory bowel disease [IBD] patients have a relapsing-remitting disease course, and amongst environmental factors that aggravate the disease course, common drugs aside from non-steroidal anti-inflammatory drugs have not been studied in detail. While the microbiome is considered to play a significant role on the disease course, the impact of antibiotics is poorly understood. This study investigated the potential impact of different classes of antibiotics on the course of disease in IBD using the Danish National Patient Registry., Methods: Danish IBD patients were studied using two nested case-control cohorts exploring associations between antibiotic types and IBD flare-ups, defined as IBD-related hospitalizations and/or high-dose systemic steroid exposure. Multivariate logistic regression and eXtreme Gradient Boosted decision tree [GBDT] machine learning methods evaluated antibiotic risks., Results: Two cohorts with 15 636 and 5178 patients were analysed for risk of hospitalization and course of steroids, respectively. The risk of a flare-up was significantly increased with antecedent exposure to quinolones (ATC:J01M; odds ratio [OR]: 3.04-3.82), antimycotics [ATC:J02A; OR: 1.50-2.30], agents against amoebiasis and protozoal infections [ATC:P01A; OR: 1.95-3.18], intestinal anti-infectives [ATC:A07A; OR: 2.09-2.32], and beta-lactam antibiotics [ATC:J01C; OR: 1.36]. The GBDT models achieved an area under the curve of 0.71-0.85 for predicting flare-ups, with the same above-mentioned antibiotics being in the ten most important variables., Conclusion: We found distinctive antibiotics to be significantly associated with an increased risk of IBD flare-ups. Our findings are corroborated by our GBDT machine learning models. Healthcare providers should be aware of the deleterious potential of specific antibiotic groups in patients with IBD only using these agents in a restrictive manner or preferentially consider alternative antibiotic groups., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: The onset of psychotic symptoms occurs prior to age 19 in 39% of the patients with schizophrenia. There are limited approved treatment options for adolescents with schizophrenia. Brexpiprazole was approved by the United States Food and Drug Administration (FDA) for treatment of schizophrenia in adolescents in 2022., Areas Covered: Extrapolation of adult data to youth and use of pharmacologic modeling coupled with open long-term safety data were used by the FDA to approve brexpiprazole for adolescent schizophrenia. They were all reviewed herein., Expert Opinion: D2 receptor partial agonist antipsychotic agents are preferred in the early phase of treatment of psychotic disorders. Approval of brexpiprazole in adolescent schizophrenia provides an additional option. Brexpiprazole was approved by the FDA on the basis of extrapolation of adult data without controlled trials in adolescents. This reduces placebo exposure in young people. Two previous agents (asenapine and ziprasidone) approved for adult schizophrenia failed to separate from placebo in adolescent schizophrenia studies; this partially undermines the process of extrapolation. For brexpiprazole, the paucity of data in adolescents relegates it to a second-line agent. More research on brexpiprazole is needed to delineate its relative role in the management of adolescent schizophrenia.

Background: Nemonoxacin malate is a novel non-fluorinated quinolone for oral and intravenous (IV) administration. This phase 3, multicentre, randomised, double-blind, double-dummy, parallel-controlled clinical trial (NCT02205112) evaluated the efficacy and safety of IV nemonoxacin vs. levofloxacin for the treatment of community-acquired pneumonia (CAP) in adult patients., Methods: Eligible patients were randomised to receive 500 mg nemonoxacin or levofloxacin via IV infusion, once daily for 7-14 days. The primary endpoint was the clinical cure rate at the test-of-cure (TOC) visit in the modified intent-to-treat (mITT) population. Secondary efficacy and safety were also compared between nemonoxacin and levofloxacin., Results: Overall, 525 patients were randomised and treated with nemonoxacin (n = 349) or levofloxacin (n = 176). The clinical cure rate was 91.8% (279/304) for nemonoxacin and 85.7% (138/161) for levofloxacin in the mITT population (P > 0.05). The clinical efficacy of nemonoxacin was non-inferior to levofloxacin for treatment of CAP. Microbiological success rate with nemonoxacin was 88.8% (95/107) and with levofloxacin was 87.8% (43/49) (P > 0.05) at the TOC visit in the bacteriological mITT population. The incidence of drug-related adverse events (AEs) was 37.1% in the nemonoxacin group and 22.2% in the levofloxacin group. These AEs were mostly local reactions at the infusion site, nausea, elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST), and QT interval prolongation. The nemonoxacin-related AEs were mostly mild and resolved after discontinuation of nemonoxacin., Conclusions: Nemonoxacin 500 mg IV once daily for 7-14 days is effective and safe and non-inferior to levofloxacin for treating CAP in adult patients., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Modulators of cystic fibrosis transmembrane conductance regulator (CFTR) improved cystic fibrosis (CF) patients' outcome. The elexacaftor/tezacaftor/ivacaftor (ETI) combination was safe and effective improving lung function in patients with different CFTR genotypes, including at least one F508del mutation. However, cases with liver damage were reported. We describe 105 CF patients heterozygous for F508del in trans with another CFTR mutation, treated for 1 year with ETI. We analyzed liver biochemical parameters and cholesterol metabolism, including lathosterol and phytosterols, surrogate markers of cholesterol de-novo synthesis and absorption, respectively. The treatment significantly improved sweat chloride, body mass index and forced expiratory volume in 1 s, whereas it caused a significant increase of total and conjugated bilirubin, ALT and GGT, even if no patients developed CF liver disease. Such alterations were less relevant than those previously observed in ETI-treated F508del homozygous patients. Furthermore, ETI treatment significantly increased serum cholesterol by enhancing its absorption (correlation between serum cholesterol and phytosterols). Whereas, we observed a normalization of de-novo biosynthesis (lathosterol reduction) that was not observed in homozygous patients. These data suggest that the second mutation in trans with the F508del contributes to reduce the liver cholesterol accumulation and thus, the triggering of liver inflammation. However, no differences in the alteration of biochemical indexes were observed between CF patients with and without liver steatosis, and between patients with different mutations in trans with the F508del. Such data suggest to further investigate the effects of ETI therapy on liver function indexes and new predictive biomarkers., (© 2024. The Author(s).)

Background: Statins are widely used in cardiovascular disease (CVD) as a common lipid-lowering drug, while quinolones are widely used for the treatment of infectious diseases. It is common to see CVD in combination with infectious diseases, therefore it is often the case that statins and quinolones are used in combination. Data suggest combinations of statin and quinolone may be associated with potentially life-threatening myopathy, rhabdomyolysis and acute hepatitis. This systematic review aims to characterize data regarding patients affected by the statin-quinolone interaction., Methods: The purpose of this systematic review was to collect and evaluate the evidence surrounding statin-quinolone drug interactions and to discuss related risk mitigation strategies. The following databases were searched: PubMed (Medline), Embase, Scopus, and Cochrane Library. The systematic electronic literature search was conducted with the following search terms. In this study, three types of search terms were used: statins-related terms, quinolones-related terms, and drug interactions-related terms., Results: There were 16 case reports that met the criteria for qualitative analysis. Patients were involved in the following adverse reactions: rhabdomyolysis (n = 12), acute hepatitis (n = 1), muscle weakness (n = 1), hip tendinopathy (n = 1), or myopathy (n = 1). In the included literature, patients vary in the dose and type of statins they take, including simvastatin (n = 10) at a dose range of 20-80 mg/d and atorvastatin (n = 4) at a dose of 80 mg/d. There were 2 patients with unspecified statin doses, separately using simvastatin and atorvastatin. The quinolones in combination were ciprofloxacin (n = 9) at a dose range of 800-1500 mg/d, levofloxacin (n = 6) at a dose range of 250-1000 mg/d, and norfloxacin (n = 1) in an unspecified dose range. 81% of the case patients were over 60 years of age, and about 1/3 had kidney-related diseases such as diabetic nephropathy, post-transplantation, and severe glomerulonephritis. Nearly two-third of the patients were on concomitant cytochrome P450 3A4 (CYP3A4) inhibitors, P-glycoprotein (P-gp) inhibitors, or organic anion transporting polypeptide 1B1 (OATP1B1) inhibitors., Conclusion: Patients treated with statin-quinolone combination should be monitored more closely for changes in aspartate aminotransferase or creatine kinase (CK) levels, and muscle symptoms, especially in patients with ciprofloxacin or levofloxacin, with simvastatin and high-dose atorvastatin, over 60 years of age, with kidney-related diseases, and on concomitant CYP3A4 inhibitors., (© 2024. The Author(s).)

DA-9601 extracted from Artemisia asiatica contains a bioactive compound - eupatilin - that can protect against gastric mucosal damage through anti-inflammatory and anti-oxidative properties and is approved for treating acute and chronic gastritis in Korea, but their ability to protect gastrointestinal (GI) bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is unclear. We aimed to compare the protective effects of DA-9601 to those of proton pump inhibitors (PPI) and rebamipide against upper and lower GI bleeding in patients with rheumatoid arthritis (RA) undergoing long-term NSAIDs therapy using the Korean Health Insurance Review and Assessment database. In this nationwide retrospective cohort study, we evaluated patients with RA who concurrently received NSAIDs for >3 months with DA-9601, PPI, or rebamipide between January 2015 and December 2017. The index date was the date of NSAIDs initiation, and all patients were followed up until December 2020 to detect upper and lower GI bleeding. In total, 24,258 patients with RA were eligible, and 5468 (22.5%), 4417 (18.2%), and 14,373 (59.3%) received DA-9601, PPI, or rebamipide, respectively, on the index date. During follow-up, upper and lower GI bleeding occurred in 508 (2.1%) and 402 (1.6%) patients with RA, respectively. The incidence rate of upper and lower GI bleeding was 615/100,000 and 485/100,000 person-years, respectively. Among patients with RA receiving DA-9601, PPI, or rebamipide, the frequencies of NSAIDs-induced upper GI bleeding were 0.5%, 0.4%, and 1.2%, respectively. The frequencies of NSAIDs-induced lower GI bleeding were 0.4%, 0.4%, and 0.9%, respectively. The incidence of NSAIDs-induced upper GI bleeding in patients with RA receiving DA-9601, PPI, and rebamipide was 601/100,000, 705/100,000, and 596/100,000 person-years, respectively, while the incidence of NSAIDs-induced lower GI bleeding in the same groups was 449/100,000, 608/100,000, and 465/100,000 person-years, respectively. In the multivariate Cox regression analysis, no significant difference was observed in lower and upper GI bleeding hazards between patients with RA using DA-9601, PPI, and rebamipide. Our results suggest that DA-9601 may exhibit protection against NSAIDs-induced GI bleeding that is comparable to those of PPI and rebamipide in patients with RA., Competing Interests: All authors declare no conflicts of interest., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Liver-related side effects are a known complication of treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for cystic fibrosis (CF). Gilbert's syndrome is caused by a genetic mutation that reduces activity of the enzyme UDP glucuronosyltransferase 1 polypeptide A1 (UGT1A1), causing elevated levels of unconjugated bilirubin in the blood and duodenal bile. The presence of Gilbert's syndrome and CF might represent additive risk factors for liver-related adverse events during ETI treatment. This case series describes six people with CF (pwCF) in whom previously unknown Gilbert's syndrome was unmasked after initiation of treatment with ETI. Although all patients had some level of hepatic dysfunction and/or elevated levels of bilirubin after initiation of ETI, the clinical course varied. Only one patient had to stop ETI therapy altogether, while the others were able to continue treatment (some at a reduced dosage and others at the full recommended daily dosage). All patients, even those using a lower dosage, experienced clinical benefit during ETI therapy. Gilbert's syndrome is not a contraindication for ETI therapy but may be mistaken for a risk factor for liver-related adverse events in pwCF. This is something that physicians need to be aware of in pwCF who show liver adverse events during ETI therapy., (© 2024. The Author(s).)

A pharmacokinetic (PK) bridging approach was successfully employed to support the dosing regimen and approval of brexpiprazole in pediatric patients aged 13-17 years with schizophrenia. Brexpiprazole was approved in 2015 for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder in adults based on efficacy and safety data from clinical trials. On January 13, 2020, the US Food and Drug Administration issued a general advice letter to sponsors highlighting the acceptance of efficacy extrapolation of certain atypical antipsychotics from adult patients to pediatric patients considering the similarity in disease and exposure-response relationships. Brexpiprazole is the first atypical antipsychotic approved in pediatrics using this approach. The PK data available from pediatric patients aged 13-17 years have shown high variability due to the limited number of PK evaluable subjects, which limits a robust estimation of differences between adult and pediatric patients. The PK model-based approach was thus utilized to evaluate the appropriateness of the dosing regimen by comparing PK exposures in pediatric patients aged 13-17 years with exposures achieved in adults at the approved doses. In addition to exposure matching, safety data from a long-term open-label clinical study in pediatric patients informed the safety profile in pediatric patients. This report illustrates the potential of leveraging previously collected efficacy, safety, and PK data in adult patients to make a regulatory decision in pediatric patients for the indication of schizophrenia., (© 2024, The American College of Clinical Pharmacology.)

Objectives: To characterize the effects of adjunctive brexpiprazole on patient life engagement and depressive symptoms in patients with major depressive disorder (MDD) using patient-reported outcomes., Methods: An 8-week, Phase 4, open-label, interventional study was conducted at 15 Canadian trial sites between April 2021 and May 2022. Adult outpatients with MDD (at least moderately severe) and inadequate response to 1-2 antidepressants continued their current antidepressant and received oral adjunctive brexpiprazole 0.5-2 mg/day. Co-primary endpoints were change from baseline to Week 8 in Inventory of Depressive Symptomatology Self-Report (IDS-SR) 10-item Life Engagement subscale score, and IDS-SR 30-item total score. Safety was assessed by standard variables., Results: Of 122 enrolled patients, 120 (98.4%) were treated (mean [ SD ] dose: 1.2 [0.4] mg/day) and analyzed, and 111 (91.0%) completed the study. Statistically significant least squares mean improvements to Week 8 were observed on IDS-SR 10 Life Engagement subscale score (baseline mean [ SD ]: 16.1 [4.7]; change [95% confidence interval]: -8.11 [-9.34, -6.88]; p  < 0.001) and IDS-SR total score (baseline mean [ SD ]: 41.3 [9.8]; change [95% confidence interval]: -17.38 [-20.08, -14.68]; p  < 0.001). Improvements were observed from Week 2, onwards. Treatment-emergent adverse events with incidence ≥5% were fatigue ( n  = 13, 10.8%), headache ( n  = 13, 10.8%), insomnia ( n  = 12, 10.0%), nausea ( n  = 9, 7.5%), tremor ( n  = 8, 6.7%), and weight increase ( n  = 7, 5.8%). Six patients (5.0%) discontinued due to adverse events. Mean ( SD ) change in body weight from baseline to last visit was +1.9 (3.4) kg., Conclusions: Using an exploratory patient-reported outcome measure, patients with MDD and inadequate response to antidepressants who received open-label adjunctive brexpiprazole showed early and clinically meaningful improvement in patient life engagement, which should be further assessed in a prospective randomized controlled trial. Patient-rated depressive symptoms (on the validated 30-item IDS-SR) also improved. Adjunctive brexpiprazole was well tolerated, and no new safety signals were observed., Clinical Trial Registration: ClinicalTrials.gov identifier: NCT04830215., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FT is a full-time employee of Otsuka Canada Pharmaceutical Inc.; CW is a full-time employee of Otsuka Pharmaceutical Development & Commercialization Inc.; PC has served as speaker/received consultant fees from AbbVie, Lundbeck, Janssen, Otsuka, Purdue, and Takeda, and has received research/grant support from AbbVie, Lundbeck, Otsuka, Takeda, Janssen, Telus, and Mitacs; JH has served as a speaker/ad board participant or performed scientific planning committee work for Pfizer, Amgen, AbbVie, GSK, Bayer, Valeo, Boehringer, Eli-Lilly, Elvium, Takeda, Bausch, AstraZeneca, Novartis, Lundbeck, Novo Nordisk, Janssen, Eisai, HLS, Otsuka, Idorsia, MDBriefcase, Liv, MedPlan, Master Clinician Alliance, Academy, Bridge, PeerVoice, Seacourses, Thrombosis Canada, Meducom, CHRC, CTC, STA, CCRN, CPD Network, Telus Health, EOCI, AgenceUnik, Humber Hospital, ABPHE, and CSEM; ZI has received grant support from CIHR, NIH, Brain Canada, and Weston Foundation, and has served as a consultant for Eisai, Lundbeck, Novo Nordisk, Otsuka, and Roche. Additionally, his institution has received funds on his behalf from Biogen and Roche; RSM has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences. He is a CEO of Braxia Scientific Corp; EMM was a full-time employee of Lundbeck Canada Inc. at the time of this work.

Background: Rebamipide has been widely co-prescribed with non-steroidal anti-inflammatory drugs (NSAIDs) in Japan for decades. This study aimed to evaluate the effectiveness of rebamipide in preventing upper gastrointestinal bleeding in new users of NSAIDs without risk factors of NSAID-induced ulcers other than age., Methods: A nested case-control study was conducted using medical claims data of 1.66 million inhabitants of 17 municipalities participating in Japan's Longevity Improvement & Fair Evidence study. The cohort entry (t0) corresponded to a new user of NSAIDs for osteoarthritis or low back pain. Patients with risk factors of NSAID-induced ulcers other than age were excluded. Cases were defined as patients who underwent gastroscopy for upper gastrointestinal bleeding (occurrence date was defined as index date). A maximum of 10 controls were selected from non-cases at the index date of each case by matching sex, age, follow-up time, and type and dosage of NSAIDs. Exposure to rebamipide was defined as prescription status from t0 to index date: Non-user (rebamipide was not co-prescribed during the follow-up period), Continuous-user (rebamipide was co-prescribed from t0 with the same number of tablets as NSAIDs), and Irregular-user (neither Non-user nor Continuous-user). Conditional logistic regression analysis was conducted to estimate each category's odds ratio compared to non-users., Findings: Of 67,561 individuals who met the inclusion criteria, 215 cases and 1,516 controls were selected. Compared with that of Non-users, the odds ratios and 95% confidence interval were 0.65 (0.44-0.96) for Continuous-users and 2.57 (1.73-3.81) for Irregular-users., Conclusions: Continuous co-prescription of rebamipide significantly reduced the risk of upper gastrointestinal bleeding in an Asian cohort of new users of NSAIDs with osteoarthritis or low back pain without risk factors other than age., Competing Interests: Authors with competing interests I have read the journal’s policy and the authors of this manuscript have the following competing interests:Yasuharu Nakashima received research grants from Chugai Pharmaceutical Co., Ltd., AYUMI Pharmaceutical Corporation, EA Pharma Co., Ltd., KYOCERA Corporation, and Zimmer Biomet G.K. All other authors have no conflicts of interest to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Yamate 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.)

Brexpiprazole is a relatively new drug that has no published research or applications within the paediatric population. Brexpiprazole targets multiple receptors and can manifest as multisystem symptoms when ingested in supratherapeutic quantities. In this report, we discuss the case of a child in early childhood who presented with delayed neurological and cardiac symptoms 24 hours after accidental ingestion of brexpiprazole. Due to delayed onset, this case highlights that a high index of suspicion and prolonged observation are necessary to appropriately manage brexpiprazole overdose or accidental ingestion., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The use of elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis (pwCF) after solid organ transplantation is controversial because of potential drug-drug interactions (DDI) with tacrolimus. We aimed to improve insight into the safety and clinical benefits of co-administration of ETI and tacrolimus in liver or kidney transplanted adult pwCF., Methods: In 5 pwCF, tacrolimus concentrations were monitored during 2 weeks before and 4 weeks after starting ETI treatment. Trough levels, area under the curve (AUC) and clinical effect of ETI were investigated. During the study (6 weeks in total) adverse events were monitored., Results: The DDI between tacrolimus and ETI resulted in an increased exposure of tacrolimus in all subjects, the dose adjusted AUC 0-24h was 1.79 (median) times higher at the end of the study. Five dose adjustments were performed in 4 subjects in order to attain tacrolimus target range. No adverse events were reported and all subjects showed clinical improvement during ETI treatment., Conclusion: The clinical value of ETI treatment in kidney and liver transplanted pwCF is clear. The use of ETI may increase tacrolimus levels moderately. Therefore, we recommend close monitoring of tacrolimus trough levels in patients who start ETI., Competing Interests: Declaration of competing interest We hereby declare that none of the authors have received any financial support or other benefits from commercial sources for the work reported in this manuscript; neither do they have any financial interest which could create a potential conflict of interest., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF., Methods: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements., Results: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed., Conclusions: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age., Competing Interests: Declaration of competing interest MR has received research grant funding and an advisory board role for Vertex Pharmaceuticals Incorporated for which her institution received payment. AS has received grants/contracts as a principal investigator from Vertex Pharmaceuticals Incorporated. SAM has received compensation to institution as principal investigator and advisory board consulting fees from Vertex Pharmaceuticals Incorporated. PM has received compensation to his institution as co-investigator, advisory board participation, and honoraria for speaker events from Vertex Pharmaceuticals Incorporated. JD has received payment for clinical trial leadership, advisory board participation, and speaker events from Vertex Pharmaceuticals Incorporated. MH, ML, JL, and VR-R are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: The efficacy and safety of elexacaftor/tezacaftor/ivacaftor (ETI) have been established in prospective clinical trials. Liver function test elevations were observed in a greater proportion of patients receiving ETI compared with placebo; however, the relatively small number of patients and short duration of study preclude detection of rare but clinically significant associations with drug-induced liver injury (DILI). To address this gap, we assessed the real-world risk of DILI associated with ETI through data mining of the FDA adverse event reporting system (FAERS)., Methods: Disproportionality analyses were conducted on FAERS data from the fourth quarter of 2019 through the third quarter of 2022. Comparative patient demographics, onset time and outcomes for ETI-DILI were also obtained., Results: 452 reports of DILI associated with ETI were found, representing 2.1 % of all adverse event reports for ETI. All disproportionality measures were significant for ETI-DILI at p < 0.05; the reporting odds ratio (ROR) (2.82) was comparable to that of drugs classified by FDA as "Most-DILI concern". The most notable demographic finding was a male majority (5:4 male to female ratio) for ETI-DILI compared to a female majority (4:5 male to female ratio) for non ETI-DILI. Median ETI-DILI onset time was 50.5 days, and hospitalization was the second most common complication., Conclusion: Using FAERS data, ETI was found to be disproportionately associated with DILI. Future research is needed to investigate the hepatotoxic mechanisms and assess potential mitigation strategies for ETI-induced hepatotoxicity., Competing Interests: Declaration of competing interest All authors declared no competing interests for this work., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Cystic Fibrosis (CF) liver disease progresses to liver failure requiring transplantation in about 3 % of patients, 0.7 % of CF patients are post liver transplant. The prognosis of CF has improved with the introduction of elexacaftor/tezacaftor/ivacaftor (ETI). Due to the paucity of data and concerns regarding interactions with immunosuppressive drug regimens, there is no general consensus on use of ETI post liver transplantation. The aim of this review is to report the safety and efficacy of ETI in CF patients who underwent liver transplantation., Methods: A systematic review was conducted through MEDLINE/Pubmed and EMBASE databases. English-written articles reporting clinical data on liver transplanted CF patients treated with ETI were included. Article quality was evaluated using the Critical Appraisal Checklist for Case Reports., Results: Twenty cases were retrieved from 6 reports. Temporary discontinuation and/or dose reduction due to elevated transaminases was required in 5 cases. ETI restarted on a reduced dose was tolerated in 3 out of 5 patients, 1 patient tolerated full dose. Tacrolimus dose change was required in 14 cases, in 1 case ETI was discontinued due to tacrolimus toxicity. Improvement in percentage predicted FEV1 was noted in 15/19 patients (median +17 %, range 8 %-38 %)., Conclusions: In the majority of liver transplanted patients ETI is well tolerated, although adverse events and liver function abnormalities may occur. Close monitoring of liver function and tacrolimus level is warranted. Significant improvement in lung function after ETI initiation is confirmed, highlighting the importance of accessing this medication for this group of patients., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Brexpiprazole is a new antipsychotic drug from the group of dopamine D2/D3 receptor partial agonists. It represents a development of the second-generation antipsychotics and is an important addition to the pharmacological treatment options for schizophrenia. The purpose of this article is to present, illustrated by the case of brexpiprazole, how advances in the pharmacological properties of new antipsychotics translate into improved results in the treatment of schizophrenia, not only in terms of symptom reduction, but also in terms of functional improvement. The ratio of activation to blocking of the D2/D3 receptor is lower for brexpiprazole than for aripiprazole and cariprazine, which may translate into a lower risk of akathisia. Brexpiprazole has also stronger antihistaminic activity, which is likely to be associated with a stronger sedative effect, a lower risk of akathisia, excessive agitation and insomnia. Brexpiprazole meets the traditional requirements for an antipsychotic drug's efficacy, i.e., compared to placebo, it brings a greater reduction in schizophrenia symptoms in short-term studies and prevents schizophrenia relapses in long-term follow-up. The highest antipsychotic efficacy was found with the highest registered dose (4 mg/day). In addition to reducing positive symptoms, brexpiprazole treatment also leads to a reduction in negative and depressive symptoms, as well as anxiety. It has also a positive effect on patients' social and personal functioning and quality of life. This action of the drug is in line with the expectations of patients and their families regarding effective treatment. It should not only reduce symptoms, but also enable a return to health, i.e., a state that, in addition to optimal health and a sense of psychological well-being, also makes it possible to maintain proper social relations.

Introduction: Tuberculosis is an infectious disease that continues to plague the world today, causing concerns due to its high mortality rate. The therapy regimens used for the treatment of tuberculosis today have demonstrated high efficacy and safety, potentially reducing the disease's burden, but the use of some standardized medications has caused many resistances to emerge. Over the last decade, researchers have been looking for suitable alternatives, with quinolones emerging as the most promising candidate due to their efficacy, safety, and availability. However, their efficacy as a first-line treatment remains debatable., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Treatment of antibiotic-resistant Gram-positive infections (GPIs), including methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly difficult, particularly in patients with multiple co-morbidities who require antibiotics with greater safety and a consistent pharmacokinetic/pharmacodynamic (PK/PD) profile. Such difficult-to-treat GPIs are often associated with poor outcomes, extended hospital stay and increased expenditure. This can be partly attributed to the limited safety and aberrant PK/PD profile of existing anti-MRSA antibiotics. In this context, intravenous levonadifloxacin and its oral prodrug alalevonadifloxacin are novel anti-MRSA antibiotics that have significant advantages over conventional anti-Gram-positive antibiotics. The purpose of this paper was to generate a consensus on the optimal use of levonadifloxacin and alalevonadifloxacin for tackling resistant Gram-positive infections in patients with multiple co-morbidities., Method: Using a modified Delphi approach that combines critical appraisal of evidence and expert opinion, therapeutic use of levonadifloxacin and alalevonadifloxacin in various clinical scenarios and specific unmet conditions was deliberated. Fifteen expert members from medicine, critical-care, emergency, microbiology, and intensive-care disciplines participated and voted on 11 pre-conceived statements. When there was at least 70 % agreement, a consensus was reached., Results: Following the voting, agreements were reached on 10 out of the 11 statements. Broadly, a consensus was reached in defining the therapeutic role of levonadifloxacin and alalevonadifloxacin in the treatment of various clinical indications involving resistant Gram-positive pathogens, including MRSA, in patients with co-morbidities, such as co-existing or increased risk for kidney dysfunction or hepatic disease and/or immunosuppression; also, in therapeutically challenging conditions caused by Gram-positive bacteria such as bacteraemia, bone and joint infection, diabetic foot infection, febrile neutropenia, and hospital-acquired pneumonia., Conclusions: This consensus supports the therapeutic use of levonadifloxacin and alalevonadifloxacin in the treatment of antibiotic-resistant GPIs, including those caused by MRSA and certain polymicrobial infections, in patients with multiple co-morbidities requiring drug with adequate safety and consistent efficacy., Competing Interests: Declaration of competing interest None, (Copyright © 2024 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: This review highlights the problem of neuropsychiatric adverse effects (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI), current suboptimal mitigation approaches, a novel testable mechanistic hypothesis, and potential solutions requiring further research., Recent Findings: Studies show that a minority of persons with cystic fibrosis (PwCF) initiating cystic fibrosis transmembrane conductance regulator (CFTR) modulators experience neuropsychiatric AEs including worsening mood, cognition, anxiety, sleep, and suicidality. The GABA-A receptor is a ligand-gated chloride channel, and magnetic resonance spectroscopy neuroimaging studies have shown that reduced GABA expression in rostral anterior cingulate cortex is associated with anxiety and depression. Recent research details the impact of peripheral inflammation and the gut-brain axis on central neuroinflammation. Plasma ETI concentrations and sweat chloride have been evaluated in small studies of neuropsychiatric AEs but not validated to guide dose titration or correlated with pharmacogenomic variants or safety/efficacy., Summary: Although ETI is well tolerated by most PwCF, some experience debilitating neuropsychiatric AEs. In some cases, these AEs may be driven by modulation of CFTR and chloride transport within the brain. Understanding biological mechanisms is a critical next step in identifying which PwCF are likely to experience AEs, and in developing evidence-based strategies to mitigate them, while retaining modulator efficacy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Due to the customary delay between medication approvals in adult and adolescent populations, adolescents with schizophrenia may receive off-label antipsychotic treatment, without empirically justified dosing recommendations. In order to accelerate pediatric drug development, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents based on a pharmacokinetic (PK) analysis to support dose selection, plus a safety study. The aim of the present article is to describe the population PK analysis that was submitted to the FDA to inform brexpiprazole dose selection in adolescents with schizophrenia. Using a population PK model with brexpiprazole clearance and volume of distribution allometrically scaled by body weight, PK simulations showed comparable brexpiprazole dose-exposure between adults and adolescents aged 13-17 years following oral daily doses of brexpiprazole 1-4 mg, indicating that the target brexpiprazole dose of 2-4 mg/day in adults with schizophrenia is also suitable for adolescents. Based on this population PK analysis, together with a safety study in adolescents, the FDA approved brexpiprazole for the treatment of schizophrenia in adolescents aged 13-17 years, via extrapolation of the efficacy of brexpiprazole from adults to adolescents., (© 2023 Otsuka Pharmaceutical Inc and H. Lundbeck A/S. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Hypothesis: Tetracyclines are less cytotoxic to tympanic membrane (TM) fibroblasts than quinolones., Background: Use of quinolone ear drops after tympanostomy tube placement and for acute otitis externa has been linked to an increased risk of TM perforation. This has been verified in animal models. Cell culture studies have shown quinolones to be highly toxic to TM fibroblasts. Tetracyclines are a potential alternative to quinolones as they have been used to treat acute otitis externa and are thought to be nontoxic to the inner ear. We aimed to determine if tetracyclines are cytotoxic to TM fibroblasts., Methods: Human TM fibroblasts were treated with 1:10 dilutions of ofloxacin 0.3%, ciprofloxacin 0.3%, doxycycline 0.3 and 0.5%, minocycline 0.3 and 0.5%, tetracycline 0.3 and 0.5%, or dilute HCl (control), twice within 24 hours or four times within 48 hours. After 2 hours of treatment, cells were returned to growth media. Cells were observed with phase-contrast microscopy until cytotoxicity was measured., Results: Fibroblasts had lower survival with ciprofloxacin 0.3% and doxycycline 0.5% treatment compared with the control after 24 and 48 hours (all p < 0.0001). Fibroblasts treated with minocycline 0.5% had increased cell survival after 24 hours. Minocycline 0.3 and 0.5% showed increased TM fibroblast survival after 48 hours (all p < 0.0001). Phase-contrast images mirrored the cytotoxicity findings., Conclusions: Tetracyclines are less toxic to cultured TM fibroblasts than ciprofloxacin. Fibroblast tetracycline toxicity is drug and dose specific. Minocycline shows the most promise for possible otic applications in which fibroblast toxicity is a concern., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2023, Otology & Neurotology, Inc.)

Hyperprolactinemia and metabolic disturbance are common side effects of antipsychotics that cause intolerance. Despite its potential influence on relapse, there are no established guidelines for antipsychotic switching. This naturalistic study explored the association between antipsychotic switching, baseline clinical status, metabolic changes, and relapse in patients with schizophrenia. In total, 177 patients with amisulpride-induced hyperprolactinemia and 274 with olanzapine-induced metabolic disturbance were enrolled. Relapse was determined by assessing changes in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to 6 months (increased over 20% or 10% reaching 70). Metabolic indices were measured at baseline and 3 months. Patients with baseline PANSS >60 were more likely to relapse. Further, patients switching to aripiprazole had a higher risk of relapse regardless of their original medication. Participants who originally used amisulpride had reduced prolactin levels following medication change, while switching to olanzapine caused increased weight and blood glucose levels. In patients originally using olanzapine, only switching to aripiprazole reduced insulin resistance. Adverse effects on weight and lipid metabolism were observed in patients who switched to risperidone, while amisulpride improved lipid profiles. Changing schizophrenia treatment requires careful consideration of multiple variables, particularly the choice of substituted drug and the patient's baseline symptoms., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Somatic symptoms, which are common in major depressive disorder (MDD), are associated with a worse prognosis and increased health costs., Aims: This randomized, double-blind, placebo-controlled study evaluated the efficacy of aripiprazole augmentation in MDD patients with somatic symptoms., Methods: In all, 41 MDD patients with somatic symptoms completed the study. Participants who had been on a stable dose of antidepressants for at least 1 month were randomly assigned to receive an 8-week adjunctive treatment with either aripiprazole or placebo. The initiation dose of aripiprazole was 2 mg/day, which was later adjusted to 1-10 mg/day. The primary endpoint was the change in the Symptom Checklist-90-Revised-Somatization (SCL-90-R-SOM) score. We collected quantitative electroencephalogram data and performed spectral analyses to obtain the absolute power of frequency bands., Results/outcomes: The aripiprazole group ( n  = 20; 2.98 ± 1.75 mg/day) showed a significant improvement in SCL-90-R-SOM scores compared to the placebo group ( n  = 21; F  = 8.56, p  = 0.006), without significant differences in changes in depression and anxiety symptoms. Compared to the control, the aripiprazole group showed a greater decrease in total alpha power ( F  = 7.03, p  = 0.01). Changes in frontal alpha power were positively correlated with changes in SCL-90-R-SOM scores in the aripiprazole group ( r  = 0.53, p  = 0.014)., Conclusions/interpretation: Aripiprazole adjunctive to antidepressants in patients with MDD and somatic symptoms improved somatic symptom severity without significant safety concerns, and this improvement correlated with a decrease in total and frontal alpha power. Trial Registration: https://cris.nih.go.kr; identifier: KCT0004607.

Background: Delayed eardrum healing has been observed in the ear opposite to the ear treated with otic quinolones (OQ) in rats. Case reports describe tendinopathies after OQ treatment, suggesting adverse systemic effects., Methods: We studied patients aged 19 to 64 years with diagnosis of otitis externa or media in private insurance between 2005 and 2015. We compared OQ treatment against otic neomycin, oral amoxicillin, or azithromycin. Outcomes included Achilles tendon rupture (ATR), Achilles tendinitis (AT), and all-type tendon rupture (ATTR). We applied an active comparator, new-user design with 1-year look-back and ceased follow-up at initiation of systemic steroids or oral quinolones, external injury, hospitalization, and after 35 days. We used trimmed stabilized inverse probability of treatment weights to balance comparison groups in a survival framework. Negative outcomes (clavicle fractures or sports injuries) were examined to rule out differences from varied physical activity (unmeasured confounding)., Results: We examined 1 501 009 treated otitis episodes. Hazard ratios (HR) for OQ exposure associated with ATR were 4.49 (95% confidence interval [CI], 1.83-11.02), AT 1.04 (95% CI, 0.73-1.50), and ATTR 1.71 (95% CI, 1.21-2.41). Weighted risk differences (RD) per 100 000 episodes for OQ exposure were ATR 7.80 (95% CI, 0.72-14.89), AT 1.01 (95% CI, -12.80 to 14.81), and ATTR 18.57 (95% CI, 3.60-33.53). Corresponding HRs for clavicle fractures and sports injuries were HR,1.71 (95% CI, 0.55-5.27) and HR,1.45 (95% CI, 0.64-3.30), suggesting limited residual confounding., Conclusions: OQ exposure may lead to systemic consequences. Clinicians should consider this potential risk and counsel patients accordingly. Risk factors and mechanisms for this rare, adverse effect deserve further evaluation. Mechanistic and other clinical studies are warranted to corroborate this finding., Competing Interests: Potential conflicts of interest. A. W. reports grants or contracts from Merch, Sharpe, Dohme; NIH; AHRQ; PCORI, FDA, Bill and Melinda Gates Foundation; state of Florida; none related to this work; consulting fees from Arbor Pharmaceuticals; Genentech. P. J. A. reports a research grant on ototoxicity of agents used to clear bacterial biofilms from NextScience; payment or honoraria from UpToDate for authoring a chapter on cochlear implant infections and from Stryker for teaching a temporal bone dissection course; payment for expert testimony on numerous cases, none pertaining to topic of this manuscript; US patents for otologic devices, none related to the topic of this manuscript; participation on otologic advisory board for Janssen Research & Development and Akouos; role as Past-President, executive council, unpaid, for American Otological Society; PA reports grants or contracts from Merch, Sharpe, Dohme; none related to this work., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Given the great importance of treating patients with bipolar disorder, the aim of this study was to compare the efficacy of aripiprazole with other second-generation antipsychotics in relieving acute symptoms of mania., Materials and Methods: In this study, 50 patients with bipolar I disorder, manic episode, were divided into two groups receiving aripiprazole ( n  = 25) and other second-generation antipsychotics (risperidone, olanzapine, and quetiapine) ( n  = 25) for 6 weeks. The disease severity was evaluated and compared according to YMRS and CGI criteria., Results: The mean severity of mania according to YMRS and CGI, at week 0 in comparison with weeks 2, 4 and 6 in both groups was significantly different ( p  < 0.0001) and the treatment with Aripiprazole at week 2 ( p  < 0.0001) and 4 ( p  = 0.0002) was significantly better than the other second-generation antipsychotics. The two groups also showed an overall improvement in CGI-based results at weeks 4 and 6 ( p  = 0.002). In addition, the efficacy index for aripiprazole at weeks 4 ( p  = 0.011) and 6 ( p  < 0.0001) as well as disease improvement in the second ( p  < 0.0001) and fourth ( p  = 0.026) weeks after treatment were better than the other second-generation antipsychotics., Conclusions: Aripiprazole and other second-generation antipsychotics, 2 weeks after initiation of treatment, significantly reduced mania severity in patients with bipolar disorder, however, aripiprazole seems to be more efficient and faster for controlling mania in patients with bipolar disorder.KEY POINTSAripiprazole and other second-generation antipsychotics, 2 weeks after initiation of treatment, significantly reduced mania severity in patients with bipolar disorder.Comparison between the two drugs, aripiprazole showed a more beneficial role in the second and fourth weeks than second-generation antipsychotics.Due to the fact that the possible mechanisms involved in the role of aripiprazole have not been considered compared to other antipsychotics in patients with bipolar disorder, there is a need for more extensive studies in this field.

Background: Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited., Methods: We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results., Results: Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar., Conclusions: Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: Quinolones are popular antibiotics that are known for their potency, broad coverage, and reasonable safety. Concerns have been raised about a possible association between quinolones and retinal detachment (RD)., Methods: We conducted a nested case-control study using electronic health records (EHR) from the Health Facts® Database. The initial cohort included all patients who were admitted between 2000 and 2016, with no history of eye disease, and had a minimum medical history of one year. Eligible cases comprised inpatients who were first admitted with a primary diagnosis of RD between 2010 and 2015. Each eligible case was matched without replacement to five unique controls by sex, race, age, and period-at-risk. We used conditional logistic regression to calculate RD risk, adjusting for exposure to other medications, and major risk factors., Results: We identified 772 cases and 3860 controls. Whereas our primary analysis of all subjects revealed no quinolone-associated RD risk, elevated but non-significant risks were noted in African Americans (ciprofloxacin and levofloxacin), those aged 56-70 years old (moxifloxacin), and women (ciprofloxacin)., Conclusion: Our study did not identify an elevated RD risk within 30 days following systemic administration of quinolone antibiotics. Suggestions of increased risk observed in some population subgroups warrant further investigation., (© 2022. The Author(s).)