Search

Background: Novel abortive treatments for migraine, ditans and gepants, have promising implications in triptan-insufficient responders with minimal existing comparative data. Our study aims to synthesize evidence through a systematic review and network meta-analysis to assess the comparative efficacy of lasmiditan, rimegepant and ubrogepant in triptan-insufficient responders., Method: We searched PubMed, Embase, CENTRAL, and EBSCO Open Dissertations up to May 2024. We included randomized controlled trials (RCTs) that compared novel abortive treatments, including lasmiditan, rimegepant, and ubrogepant, in migraine patients who self-reported insufficient response to triptans. Outcomes are represented using relative risks with corresponding 95% confidence intervals (CI). The surface under the cumulative ranking curve (SUCRA) was used to rank each medication., Results: A total of five phase 3 RCTs involving 3,004 patients were included in the analysis. All three agents were significantly superior to placebo for two-hour pain freedom (RR = 1.93, 95% CI [1.52, 2.46]), freedom from the most bothersome symptoms at two hours (RR = 1.55, 95% CI [1.37, 1.75]), and pain relief at two hours (RR = 1.46, 95% CI [1.35, 1.58]). No statistically significant differences in efficacy outcomes were observed among the three agents. However, lasmiditan 200 mg had the highest cumulative probability for two-hour pain freedom and relief (SUCRA 0.9, 0.8, respective), while rimegepant led in relieving the most bothersome symptoms (SUCRA 0.7)., Conclusion: Lasmiditan, rimegepant, and ubrogepant are effective for acute treatment of migraine in triptan-insufficient responders, with high-dose lasmiditan showing the highest efficacy for pain control., (© 2024. The Author(s).)

Intranasal tumors in dogs are malignant solid tumors that are primarily treated with radiotherapy and often recur post-treatment. Combination therapy is pivotal in cancer therapy. Effective drugs include fluoropyrimidine 5-fluorouracil (5-FU) and toceranib phosphate. TS-1, an oral formulation containing the 5-FU prodrug tegafur and enzyme modulators gimeracil and oteracil, is proven to be safe in dogs with solid tumors. While the oral drug toceranib phosphate (Palladia ® ) is safely administered, the combined toxicity with TS-1 is unknown. We aimed to determine the dosage of this combination in dogs. In the preclinical/clinical trials conducted here, we used a standard 3+3 cohort design with fixed doses of toceranib phosphate (2.4 mg/kg) administered thrice weekly. TS-1 administration was initiated at a dose of 0.5 mg/kg (upper limit 2.0 mg/kg) thrice weekly. Four cohorts were included to confirm the safety of TS-1 and toceranib phosphate. Each cohort was followed up for 1 month. The intranasal tumor types included in the clinical trial (n=13) were adenocarcinoma (n=7), squamous cell carcinoma (n=1), non-epithelial malignancy (n=2), undifferentiated carcinoma (n=1), and transitional carcinoma (n=2). The TS-1 dosage could be increased up to its dose limit in the preclinical/clinical trials. The TS-1 dose to combine with toceranib phosphate thrice weekly was 2.0 mg/kg. This regimen was well-tolerated in dogs. Thus, combined TS-1 and toceranib phosphate therapy is safe for dogs with intranasal tumors.

Objective: To assess the real-world effectiveness of ubrogepant by evaluating self-reported satisfaction with pain relief, ability to think clearly, and return to normal function in individuals who had used ubrogepant to treat a migraine episode within the preceding 14 days., Background: Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine in adults. Few studies have evaluated the real-world effectiveness of ubrogepant., Methods: The UNIVERSE study was an observational, cross-sectional survey conducted between February 2021 and April 2021 in US adult Migraine Buddy application (app) users currently treated with ubrogepant. Individuals who were 18 years of age or older and reported at least one dose of ubrogepant in the previous 14 days completed a 30-question survey in the app. The survey assessed respondent demographics, migraine history, acute treatment patterns, and treatment satisfaction with ubrogepant. Respondents also reported prior acute medication use and reasons for switching to ubrogepant., Results: Of the 1303 ubrogepant users contacted, 302 (23.2%; 50 mg, 120 participants; 100 mg, 182 participants) were included in this study. The mean (standard deviation) age was 41.9 (11.2) years, and 90.1% (272/302) were female. Satisfaction with migraine relief at 2, 4, and 24 h post-dose was reported by 75.8% (229/302), 83.4% (252/302), and 78.5% (237/302) of participants, respectively. Satisfaction with the ability to think clearly after taking ubrogepant was reported by 85.1% (257/302) of participants, and 83.8% (253/302) were satisfied with their ability to return to normal function. Furthermore, 90.7% (274/302) of participants reported that they were likely to continue using ubrogepant to treat their migraine. Most participants (n = 264 [87%]) reported switching to ubrogepant due to inadequate treatment response with their previous treatment. In this subgroup, comparable outcomes were observed with respect to satisfaction with migraine relief, ability to think clearly, and return to normal function., Conclusions: Ubrogepant demonstrated real-world effectiveness in the acute treatment of migraine, as evidenced by high levels of treatment satisfaction and a strong indication of their intent to continue using the medication., (© 2024 The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Background: Helicobacter pylori ( H. pylori ), prevalent in developing regions, is a key factor in gastrointestinal diseases. Despite the common use of bismuth-based quadruple therapy, its drawbacks have prompted the search for alternatives. Recently, vonoprazan, a novel acid suppressant, has shown promise in combination with antibiotics as a dual therapy for H. pylori eradication. This study aimed to assess the therapeutic outcomes and adverse events of vonoprazan-amoxicillin dual therapy compared to quadruple therapy., Methods: A randomized controlled trial (RCT) enrolled H. pylori -infected patients at Zhejiang Hospital. Participants were randomly assigned to dual and quadruple therapy groups. The primary endpoints were H. pylori eradication and adverse events., Results: Of the 400 patients studied from April 2022 to June 2023, In the intention-to-treat (ITT) analysis, the eradication rates of H. pylori in vonoprazan-amoxicillin dual therapy group and quadruple therapy group were 94.0% and 87.0%, respectively, p  = 0.017. In the per-protocol (PP) analysis were 97.9% and 93.0%, p  = 0.022. Additionally, the dual therapy group had a significantly lower incidence of adverse events (19%) compared to the quadruple therapy group (53%) ( p  < 0.001)., Conclusion: Vonoprazan-amoxicillin dual therapy demonstrates superior eradication efficacy and reduced adverse events compared to quadruple therapy in H. pylori -infected patients, suggesting its potential for clinical application and promotion.

Background: Vonoprazan is a new acid-suppressing drug that provides an additional choice for eradicating Helicobacter pylori. The effectiveness and safety of vonoprazan and high-dose amoxicillin (VHA) dual therapy requires study in a systematic analysis., Materials and Methods: A comprehensive search of the literature from the PubMed, Embase, Cochrane Library, and Web of Science databases was conducted up to 16 May 2024. Trials comparing H. pylori eradication rates, adverse events, and compliance of VHA dual therapy with that of other therapies were included. RevMan 5.4 was used for statistical analysis., Results: Eleven randomised controlled trials (RCTs) and two retrospective clinical studies with 4570 samples were included. VHA dual therapy had superior H. pylori eradication rates (intention-to-treat [ITT]: 86.0% vs. 80.7%; odds ratio [OR]=1.36; 95% confidence interval [CI] 1.07-1.73; P=0.01; per-protocol [PP]: 90.6% vs. 85.7%; OR=1.42; 95% CI 1.07-1.88; P=0.02), fewer adverse events (15.4% vs. 27.7%; OR=0.49; 95% CI 0.35-0.68, P<0.0001), and similar compliance (94.6% vs. 93.2%; OR=1.27; 95% CI 0.98-1.64; P=0.07) compared with other guideline therapies. According to subgroup analysis with PP data, VHA dual therapy is more effective than bismuth quadruple therapy based on proton-pump inhibitors (P-BQT) (93.5% vs. 89.3%; OR=1.76; 95% CI 1.03-3.00; P=0.04). In addition, the eradication rates for 7-day, 10-day and 14-day VHA dual therapy were 65% (95% CI 0.55-0.75), 92% (95% CI 0.91-0.94) and 93% (95% CI 0.90-0.97), respectively., Conclusion: VHA dual therapy for 10 or 14 days showed superior efficacy and safety compared with therapies recommended by the guidelines and should be prioritised for adoption., Competing Interests: Declarations Funding: This work was supported by grants from Shaanxi Health Scientific Research Innovation Team Project (No. 2024TD-06) and Shaanxi Key Research & Development Project (No. 2023-ZDLSF-35). Competing Interests: None. Ethical Approval: Not required. Sequence Information: Not applicable., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A 70-year-old man who had undergone treatment for gastroesophageal reflux disease (GERD) by a family doctor presented to our hospital with severe heartburn and dysphagia despite taking vonoprazan (20 mg) for 3 months. A diagnosis of vonoprazan-refractory nonerosive reflux disease was made based on esophagogastroduodenoscopy and esophageal function examinations. The patient elected to undergo endoscopic treatment for GERD. Therefore, we performed endoscopic treatment using the endoscopic submucosal dissection (ESD-G) technique developed at our institution. After endoscopic treatment, his GERD symptoms disappeared and he no longer required GERD-related medications. An examination of his esophageal function revealed the improvement of items related to GERD.

Background & Aims: Potassium-competitive acid blockers have documented efficacy for erosive esophagitis. We performed a randomized trial in United States subjects diagnosed with non-erosive reflux disease of vonoprazan vs placebo for 4 weeks, followed by a 20-week active-treatment extension., Methods: Adult subjects with heartburn ≥4 days/week during screening without erosive esophagitis on endoscopy were randomized to placebo, vonoprazan 10 mg, or vonoprazan 20 mg. After 4 weeks, subjects on placebo were re-randomized to vonoprazan 10 mg or 20 mg, and those already on vonoprazan continued at the same dose for 20 weeks. Electronic diaries were completed twice daily. The primary endpoint was percentage of days without daytime or nighttime heartburn (24-hour heartburn-free days)., Results: Among 772 randomized subjects, the percentage of 24-hour heartburn-free days was 27.7% for placebo vs 44.8% for vonoprazan 10 mg (least squares mean difference, 17.1%; P < .0001) and 44.4% for vonoprazan 20 mg (least squares mean difference, 16.7%; P < .0001). Differences in percentage of subjects with a 24-hour heartburn-free day for vonoprazan 10 mg vs placebo and vonoprazan 20 mg vs placebo were 8.3% and 11.6% on day 1 and 18.1% and 23.2% on day 2. The mean/median percentages of 24-hour heartburn-free days over the extension period were similar across the 4 study arms: 61%-63%/76%-79%., Conclusions: Vonoprazan reduced heartburn symptoms in subjects diagnosed with non-erosive reflux disease, with the benefit appearing to begin as early as the first day of therapy. Treatment effect persisted after the initial 4-week placebo-controlled period throughout the 20-week extension period. The 2 vonoprazan doses (10 mg and 20 mg) were similar in efficacy. (ClinicalTrials.gov: NCT05195528)., (Published by Elsevier Inc.)

Vonoprazan (VPZ) has been shown to have superior acid-inhibitory effects compared to proton pump inhibitors (PPIs). However, there is a paucity of research examining the efficacy of vonoprazan-based bismuth quadruple therapy (VBQT) in the eradication of primary Helicobacter pylori infection. This study aimed to evaluate the effectiveness and safety of VBQT as a first-line treatment for H pylori eradication. This retrospective, real-world, single-arm study included consecutive treatment-naive patients who received VBQT (VPZ 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, bismuth potassium citrate 220 mg, all administered twice daily for 14 days) for H pylori eradication between March 1, 2021, and May 30, 2023. The study included both outpatients and inpatients. Eradication rates were assessed using 13C-urea breath tests or 14C-urea breath tests performed 4 to 6 weeks after treatment. The primary outcomes included eradication rates, adverse events, and treatment compliance. A total of 612 H pylori-infected patients were included in the study. The intention-to-treat (ITT), modified ITT (MITT), and per-protocol analyses showed H pylori eradication rates of 84.3% (95% CI: 812% to 87.1%), 95.9% (95% CI: 93.9% to 97.4%), and 96.4% (95% CI: 94.4% to 97.8%), respectively. In the ITT analysis, the adverse event rate was 12.7%, and the treatment compliance rate was 96.9%. In real-world practice, the VBQT regimen demonstrates excellent efficacy and favorable tolerability as a first-line therapy for H pylori eradication., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Tissue cytokines in chronic hand eczema (CHE) can predict targeted therapy with novel drugs including JAK inhibitors. Our primary objective was to assess the tissue expression of cytokines of Th1 and Th2 cell lines in CHE patients and to study the efficacy of oral tofacitinib. We recruited patients presenting with recalcitrant CHE. Lesional and non-lesional tissue samples were assessed for Th1(IFN-γ, TNF-α) and Th2 related cytokines (IL-4, IL-13, IL-2,) using real time PCR. Tofacitinib 5 mg twice daily was initiated with 4 weekly assessment and we also noted relapses post therapy.Of 21 refractory hyperkeratotic CHE patients, cytokine analysis was performed in 11 patients which showed upregulation of IL-4 [n = 5/11, 1.87-fold increase], TNF-α (n = 5/11, 5.13-fold) and IFN-γ (n = 6/11, 1.98-fold) as compared to uninvolved skin. All patients (100%) had used topical corticosteroids (TCS) and 4/21 (19%) had failed methotrexate and 2/21 (9.5%) had failed acitretin. Tofacitinib 5 mg twice daily was given in 15/21 patients. The mean time to achieve hand eczema severity index 90 (HECSI 90) was 4 weeks (mean duration of treatment:5.8 months, n = 12). Side effects were observed in 4/12 (33.3%) patients and relapse was noted in 3/12 (25%) patients after a mean duration of 7 months after discontinuation of tofacitinib. Tofacitinib (pan-JAK inhibitor) showed an excellent response in refractory CHE patients with predominant tissue Th1/Th2 cells related cytokine expression., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Evidence on the comparative efficacy and safety of approved therapies for ulcerative colitis (UC) during induction and maintenance, including upadacitinib (UPA), vedolizumab (VEDO), ustekinumab (UST), and tofacitinib (TOFA), is limited., Methods: Using data from phase 3 trials, three placebo (PBO)-anchored matching-adjusted indirect comparisons of the efficacy and safety of UPA versus VEDO, UST, and TOFA (U-ACHIEVE and U-ACCOMPLISH, GEMINI-1, UNIFI, and OCTAVE induction and maintenance trials) have been conducted. Baseline characteristics from UPA trials were weighted separately to match each comparator trial. Induction responders were re-randomized to oral UPA 15 or 30 mg, VEDO 300 mg intravenously every 8 weeks (Q8W), UST 90 mg SC Q8W, or oral TOFA 5 mg, or PBO in maintenance. Treat-through efficacy outcomes at weeks 44(UST)/46(VEDO)/52(UPA/TOFA) were adjusted by the likelihood of induction response and included clinical response, clinical remission, and endoscopic improvement. Safety outcomes included adverse events (AEs), serious AEs (SAEs), and AEs leading to discontinuation (except UPA vs. VEDO). Benefit-risk was assessed by numbers needed to treat (NNT)/harm, calculated as the inverse of the difference in proportions of patients achieving each efficacy/safety outcome for UPA versus comparator., Results: The proportions of patients who demonstrated clinical response or endoscopic improvement was greater with UPA 15 mg versus VEDO and TOFA (p < 0.05). The proportions of patients demonstrating all treat-through efficacy outcomes were significantly greater with UPA 30 mg versus VEDO, UST, or TOFA with NNTs 3.2-8.7. No significant differences in proportions of AEs, SAEs, and AEs leading to discontinuation were observed between the two doses of UPA and comparators., Conclusion: In patients with active UC, greater clinical efficacy, and similar safety after 1 year of maintenance were observed with UPA versus VEDO, UST, and TOFA, suggesting a favorable benefit-risk profile for UPA. Despite matched baseline characteristics, differences in trial design and endpoints may persist., (© 2024. The Author(s).)

Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a high degree of selectivity within the human genome's set of protein kinases. Currently approved formulations for tofacitinib citrate are immediate-release (IR) tablets, modified-release (MR) tablets, and IR solution. A once daily MR microsphere formulation was developed for use in pediatric patients. Demonstration of bioequivalence (BE) between the 10 mg once daily (q.d.) MR microsphere formulation and 5 mg twice daily (b.i.d.) IR solution is needed to enable the exposure-response analyses-based bridging to support regulatory approval. To assess BE between MR microsphere and IR solution, an innovative approach was utilized with physiologically-based pharmacokinetic (PBPK) virtual BE trials (VBE) in lieu of a clinical BE trial. A PBPK model was developed to characterize the absorption of different formulations of tofacitinib using Simcyp ADAM module. VBE trials were conducted by simulating PK profiles using the verified PBPK model and integrating the clinically observed intrasubject coefficient of variation (ICV) where BE was assessed with a predetermined sample size and prespecified criteria. The VBE trials demonstrated BE between IR solution 5 mg b.i.d. and MR microsphere 10 mg q.d. after a single dose on day 1 and after multiple doses on day 5. This research presents an innovative approach that incorporates clinically observed ICV in PBPK model-based VBE trials, which could reduce unnecessary drug exposure to healthy volunteers and streamline new formulation development strategies., (© 2024 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

This study aimed to identify factors associated with a strong home blood pressure (BP)-lowering effect of esaxerenone and the incidence of elevated serum potassium levels in hypertensive patients treated with esaxerenone. A pooled analysis of five multicenter, prospective, open-label single-arm studies was conducted, including 479 patients in the full analysis set (FAS) and 492 patients in the safety analysis set. Multivariate linear regression analysis of morning home systolic BP (SBP) and diastolic BP (DBP) changes from baseline to Week 12 in the FAS (primary endpoint) showed that male sex (estimated change 4.37 mmHg), office pulse rate ≥100 beats/min (25.10 mmHg), and calcium channel blocker (CCB) use as a basal antihypertensive agent (4.53 mmHg) were significantly associated with a positive estimated change (weaker BP-lowering effect) in morning home SBP. CCB use (3.70 mmHg) was associated with a positive estimated change in morning home DBP. Urine albumin-to-creatinine ratio 30 to <300 mg/gCr (-4.13 mmHg) was significantly associated with a negative estimated change (stronger BP-lowering effect) in morning home SBP. Based on multivariate logistic regression analysis, elevated baseline serum potassium level (≥4.5 vs < 4.5 mEq/L, odds ratio 13.502) was significantly associated with a high incidence of serum potassium level ≥5.5 mEq/L after esaxerenone treatment. In conclusion, factors associated with a strong BP-lowering effect of esaxerenone were female sex and use of renin-angiotensin system inhibitors as a basal antihypertensive drug. Patients with baseline serum potassium levels ≥4.5 mEq/L had an increased risk of developing elevated serum potassium levels (≥5.5 mEq/L) after esaxerenone treatment., (© 2024. The Author(s).)

Background and Objectives: Ubrogepant is a calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine. The PRODROME trial previously demonstrated that ubrogepant treatment during prodrome prevents the onset of moderate or severe headache. In this analysis of the PRODROME trial, the benefits of ubrogepant treatment during the prodrome on patient-reported outcomes (PROs) are evaluated., Methods: PRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial that enrolled adults who experienced 2-8 migraine attacks per month with moderate-severe headache pain. Eligible participants treated 2 qualifying prodrome events, defined as a migraine attack with prodromal symptoms when the participant was confident a headache would follow within 1-6 hours. Participants were randomized to treatment sequence A (placebo then ubrogepant 100 mg) or sequence B (ubrogepant 100 mg then placebo). This analysis evaluated the ability to function normally over 24 hours (secondary end point) and at specific time points after dose (additional end point). Other PRO end points included activity limitation over 24 hours and satisfaction with study medication at 8 and 24 hours., Results: Of 518 randomized participants, 477 comprised the modified intent-to-treat population. After treatment of qualifying prodrome events, a significantly greater ability to function normally over 24 hours was observed for participants after treatment with ubrogepant 100 mg compared with placebo (odds ratio [OR] 1.66, 95% CI 1.40-1.96; p < 0.0001). As early as 2 hours after dose, a greater proportion of ubrogepant-treated participants reported "no disability, able to function normally" compared with placebo (OR 1.76, 95% CI 1.32-2.35; nominal p = 0.0001). Ubrogepant administered during the prodrome was also associated with a greater reduction in activity limitations over 24 hours after dose (OR 2.07, 95% CI 1.61-2.67; nominal p < 0.0001). At 8 and 24 hours after dose, rates of being "satisfied" or "extremely satisfied" were greater for ubrogepant than for placebo (8 hours: OR 2.37, 95% CI 1.78-3.15; nominal p < 0.0001; 24 hours: OR 2.32, 95% CI 1.78-3.02; nominal p < 0.0001)., Discussion: Ubrogepant 100 mg administered during the prodrome was associated with significantly greater ability to function normally, greater reduction in activity limitations over 24 hours, and greater satisfaction with study medication, compared with placebo., Trial Registration Information: ClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; first patient enrolled: August 21, 2020. clinicaltrials.gov/ct2/show/NCT04492020., Classification of Evidence: This study provides Class II evidence that taking ubrogepant 100 mg during a migraine prodrome allows more patients to function normally over the next 24 hours.

Objective: The aim of this study was to evaluate the effectiveness and safety of the nine most widely studied Vonoprazan (VPZ)-based treatment regimens along with traditional Proton pump inhibitor (PPI)-based treatment regimens in eradicating Helicobacter pylori (H. pylori) infection., Design: Through searching PubMed, Embase, Cochrane Library, Web of Science, we exclusively included randomized controlled trials (RCTs) to investigate the efficacy of VPZ-based and PPI-based therapies for H. pylori infection. The included studies were evaluated for methodological quality using the Cochrane bias risk assessment tool, and the data analysis software was used to analyze the data accordingly., Results: The RCTs were collected from the earliest available date up to August 2023. Twenty-one RCTs were included, with a total sample size of 5481. The results of the network meta-analysis showed that the eradication rate of the VPZ-based quadruple 14-day (VPZ-Q14) treatment regimen in Intention-to-treat (ITT) analysis was the highest (SUCRA: 0.874); The eradication rate of the VPZ-based quadruple 10-day (VPZ-Q10) treatment plan in Per-protocol (PP) analysis was the highest (SUCRA: 0.849). All regimens were well tolerated without significant differences. According to the probability ranking of safety, high-dose VPZ-based dual 14-day therapy (H-VPZ-D14) ranked first in SUCRA, reaching 0.952. This indicates that H-VPZ-D14 treatment is the safest with a relatively low incidence of adverse effect. Therefore, VPZ-based therapies not only have a higher eradication rate, but also possess satisfactory safety., Conclusion: Compared with traditional PPI-based therapies, VPZ-based therapies have shown superior eradication effects. Based on the Ranking Plot of the Network, the VPZ-Q14 or VPZ-Q10 treatment regimen for H. pylori has a higher eradication rate and acceptable differences compared to other treatment regimens. In addition, for regions with high antibiotic resistance rates, we recommend a 14-day quadruple therapy with bismuth based on VPZ., (© 2024. The Author(s).)

Background: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier., Methods: European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors., Results: The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm., Conclusions: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: The management of inflammatory bowel disease [IBD] patients with concurrent liver transplantation is challenging, and data regarding the safety and efficacy of Janus kinase [JAK] inhibitors with anti-rejection medications are required. We report the experience of all liver transplant recipients receiving tofacitinib and/or upadacitinib for IBD across three states in Australia., Methods: All liver transplant recipients from the Australian states of Victoria, New South Wales, and Tasmania, who required tofacitinib or upadacitinib for the treatment of IBD, were identified using prospectively maintained liver transplant databases. Patients were followed up until medication cessation or last follow-up. Clinical safety and efficacy data were collected., Results: Eight patients [median age 30 years] were included, seven of whom received first-line JAK inhibition with tofacitinib. All patients had failed one or more biologic therapies prior to commencing JAK inhibition, including six patients who had failed two or more agents. JAK inhibition was continued for a median of 17 months, with 143 patient-months of combined follow-up. The anti-rejection medication tacrolimus was prescribed in all patients. Overall, seven [88%] patients achieved clinical remission, including all three patients who were switched from tofacitinib to upadacitinib. One patient required colectomy after 1 month of treatment. There were no other cases of serious infection, venous thromboembolism, or major adverse cardiovascular events during follow-up., Conclusions: As the largest case series to date, these data indicate that combining JAK inhibition with transplant anti-rejection medication may be a safe and clinically effective method of treating IBD in patients with prior biologic failure., (© 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.)

Background: We compared efficacy of vonoprazan-dual or triple therapies and bismuth-quadruple therapy for treatment-naive Helicobacter pylori (HP) infection in Southern China, where primary resistance rates of clarithromycin and levofloxacin are >30%., Methods: This was an investigator-initiated, three-arm, randomized clinical trial in Southern China. Between March 2022 and August 2023, treatment-naïve HP-infected adults were randomly assigned to receive one of three 14-day regimens (1:1:1 ratio): vonoprazan-dual (VA-dual; vonoprazan 20 mg twice daily and amoxicillin 1 g thrice daily), vonoprazan-triple (VAC-triple; vonoprazan 20 mg/amoxicillin 1 g/clarithromycin 500 mg twice daily), or bismuth-quadruple therapy containing bismuth, esomeprazole, tetracycline, and metronidazole. Primary outcome was noninferiority in HP eradication, evaluated by UBT 4-6 weeks post-treatment by intention-to-treat (ITT) and per-protocol (PP) analysis (based on subjects who completed 14-day treatment and rechecked UBT). Bonferroni-adjusted p-value of <0.017 was used to determine statistical significance., Results: A total of 298 subjects (mean age: 35.7 ± 8.4 years; male: 134 [45.0%]; VC-dual: 100, VAC-triple: 98, bismuth-quadruple: 100) were enrolled, and 292 (98.0%) had UBT rechecked. ITT analysis showed that both VA-dual (eradication rate of 96.0%) and VAC-triple therapies (95.9%) were noninferior to bismuth-quadruple therapy (92.0%) (difference: 4.0%, 95% CI: -2.9% to 11.5%, p < 0.001; and 3.9%, 95% CI: -3.1% to 11.5%, p < 0.001, respectively). PP analysis also revealed noninferiority (96.7% or 96.7% vs. 97.4%, with difference: -2.9% and -2.9%, p = 0.009 and 0.010, respectively). The frequency of adverse events was 39.0%, 56.1%, and 71.0% in VA-dual, VAC-triple, and bismuth-quadruple therapies, respectively., Conclusions: VA-dual and VA-triple therapies are highly effective and noninferior to bismuth-quadruple therapy in Southern China. Given the lower adverse effects and fewer antibiotic use, VA-dual therapy is the preferred first-line treatment for HP infection., Trial Registration: Chinese Clinical Trial Registry (No. ChiCTR2200056375). Registered on February 4, 2022, https://www.chictr.org.cn/showproj.aspx?proj=14131., (© 2024 The Author(s). Helicobacter published by John Wiley & Sons Ltd.)

Elexacaftor, tezacaftor, ivacaftor (ETI) is a CFTR modulator combination approved for use in ∼90 % of people with cystic fibrosis (pwCF) over 2 years old. While most pwCF tolerate this therapy well, some are intolerant to standard dosing, and others show little response. Clinical providers may adjust ETI dosing to combat these issues, but these adjustments are not well guided by pharmacokinetic evidence. Our post-approval study aimed to describe pharmacokinetic variability of ETI plasma concentrations in 15 participants who were administered a standard or reduced dose. ETI were quantified by LC-MS/MS in plasma samples taken prior to the morning dose. Results showed non-significant differences for each compound regardless of dosing regimen and after dose equivalence normalization. The majority of participants in both dosing groups had concentrations expected to elicit clinical response to ETI therapy. These findings indicate that dose reduction may be a viable strategy to maintain clinical benefit while managing intolerance., Competing Interests: Declaration of competing interest Dr. Guimbellot reports consulting fees from Vertex Pharmaceuticals Incorporated, outside the submitted work. All other authors have no conflicts of interest to report., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: There is a paucity of knowledge on the longer-term effects of CF transmembrane conductance regulator (CFTR) modulator therapies upon the gut microbiome and associated outcomes. In a pilot study, we investigated longitudinal Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy on the gut microbiota, metabolomic functioning, and clinical outcomes in people with CF (pwCF)., Study Design: Faecal samples from 20 pwCF were acquired before and then following 3, 6, and 17+ months of ETI therapy. Samples were subjected to microbiota sequencing and targeted metabolomics to profile and quantify short-chain fatty acid composition. Ten healthy matched controls were included for comparison. Clinical data, including markers of intestinal function were integrated to investigate relationships., Results: Extended ETI therapy increased core microbiota diversity and composition, which translated to gradual shifts in whole microbiota composition towards that observed in healthy controls. Despite becoming more similar over time, CF microbiota and functional metabolite compositions remained significantly different to healthy controls. Antibiotic treatment for pulmonary infection significantly explained a relatively large degree of variation within the whole microbiota and rarer satellite taxa. Clinical outcomes were not significantly different following ETI., Conclusions: Whilst differences persisted, a positive trajectory towards the microbiota observed in healthy controls was found. We posit that progression was predominately impeded by pulmonary antibiotics administration. We recommend future studies use integrated omics approaches within a combination of long-term longitudinal patient studies and model experimental systems. This will deepen our understanding of the impacts of CFTR modulator therapy and respiratory antibiotic interventions upon the gut microbiome and gastrointestinal pathophysiology in CF., Competing Interests: Declaration of competing interest RM, CDS, ND, and CH have nothing to disclose. DR and CvdG report grant funding from Vertex Pharmaceuticals outside of the submitted work. AY, CN, GM, and ARS report grants and speaker honorarium from Vertex Pharmaceuticals outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Inflammatory skin diseases are typically managed with semi-solid formulations such as creams and ointments. These treatments often fail to remain on the skin for long, as they can be easily wiped off by clothing, necessitating frequent reapplication throughout the day and resulting in poor patient adherence. Therefore, this study sought to fabricate an electrospun dressing as an alternative dosage form that provides a sustained release of the anti-inflammatory agent tofacitinib over three days. In this study, three types of electrospun fiber dressings - uniaxial, coaxial, and layer-by-layer - were produced and examined for their morphological, mechanical, and release characteristics. In addition to a comprehensive characterization, another objective was to analyze the drug permeation behavior from these fiber dressings on porcine skin, comparing their performance to that of a tofacitinib cream. The layer-by-layer system notably exhibited a delayed drug release, while the uniaxial and coaxial systems demonstrated an initial burst release. However, the permeation studies revealed no significant differences between these systems, underscoring the necessity of conducting such studies - a crucial aspect often overlooked in research on electrospun fiber dressings. Overall, this study highlights the potential of electrospun, drug-loaded dressings for the treatment of inflammatory skin diseases., 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.)

Alopecia areata totalis and universalis are disabling conditions and therapeutically challenging as they are refractory to conventional options. Tofacitinib is a Janus-kinase (JAK) inhibitor utilized to treat alopecia areata (AA) as an off-label drug. In India, FDA-approved JAK inhibitors such as baricitinib and ritlecitinib are not available. There are only a few case reports on tofacitinib in AA in the Indian population. We present the data of 9 pediatric cases of clinically and histologically proven alopecia areata totalis (AT) and alopecia universalis (AU), for whom oral tofacitinib was given after baseline investigations. The following parameters were analysed: Photographic image and severity of alopecia tool (SALT) score at baseline, 3 months and 6 months, and Children Dermatology Life Quality Index (cDLQI) at baseline and 6 months. The mean ± standard deviation ( M  ± SD) of the SALT score and cDLQI( M  ± SD) at baseline were 95 ± 5 and 17 ± 2. At weeks 4 and weeks 12, the SALT ( M  ± SD) score was 92.7 ± 6.1 and 34.35 ± 11.16, respectively. At weeks 24, the SALT ( M  ± SD) score and cDLQI ( M  ± SD) were 3.33 ± 5 and 6 ± 2. The final reduction in SALT score from the baseline was 100% in 6/9 cases (66.67%), 75% to 99% in 3/9 (22.23%), and 50 to 75% in 1/9 (11.12%). We also observed minimal adverse effects (one child developed herpes zoster) with tofacitinib. Our study demonstrates that oral tofacitinib represents a viable modality in managing difficult-to-treat pediatric AA, such as AT and AU, with a good safety profile., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The escalating challenges of Helicobacter pylori-induced gastric complications, driven by rising antibiotic resistance and persistent cancer risks, underscore the demand for innovative therapeutic strategies. This study addresses this urgency through the development of tailored semi-interpenetrating polymer networks (semi-IPN) serving as gastroretentive matrices for amoxicillin (AMOX). They are biodegradable, absorb significant volume of simulated gastric fluid (swelling index > 360 %) and exhibit superporous microstructures, remarkable mucoadhesion, and buoyancy. The investigation includes assessment at pH 1.2 for comparative analysis with prior studies and, notably, at pH 5.0, reflecting the acidic environment in H. pylori-infected stomachs. The semi-IPN demonstrated gel-like structures, maintaining integrity throughout the 24-hour controlled release study, and disintegrating upon completing their intended function. Evaluated in gastroretentive drug delivery system performance, AMOX release at pH 1.2 and pH 5.0 over 24 h (10 %-100 %) employed experimental design methodology, elucidating dominant release mechanisms. Their mucoadhesive, buoyant, three-dimensional scaffold stability, and gastric biodegradability make them ideal for accommodating substantial AMOX quantities. Furthermore, exploring the inclusion of the potassium-competitive acid blocker (P-CAB) vonoprazan (VONO) in AMOX-loaded formulations shows promise for precise and effective drug delivery. This innovative approach has the potential to combat H. pylori infections, thereby preventing the gastric cancer induced by this pathogen., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: High-dose proton pump inhibitor (PPI) therapy has been recommended to prevent rebleeding of high-risk peptic ulcer (PU) after hemostasis. Vonoprazan has been proven to be noninferior to PPIs in various acid-related diseases. This study aimed to compare the efficacy of vonoprazan vs PPI for preventing high-risk PU rebleeding after hemostasis., Methods: A multicenter, randomized, noninferiority study was conducted in 6 centers. Pre-endoscopic and endoscopic therapy were performed according to standard protocol. After successful hemostasis, patients with high-risk PU bleeding (Forrest class Ia/Ib, IIa/IIb) were randomized into 1:1 to receive vonoprazan (20 mg twice a day for 3 days, then 20 mg once a day for 28 days) or high-dose PPI (pantoprazole intravenous infusion 8 mg/h for 3 days, then omeprazole 20 mg twice a day for 28 days). The primary outcome was a 30-day rebleeding rate. Secondary outcomes included 3- and 7-day rebleeding rate, all-cause and bleeding-related mortality, rate of rescue therapy, blood transfusion, length of hospital stay, and safety., Results: Of 194 patients, baseline characteristics, severity of bleeding, and stage of ulcers were comparable between the 2 groups. The 30-day rebleeding rates in vonoprazan and PPI groups were 7.1% (7 of 98) and 10.4% (10 of 96), respectively; noninferiority (within 10% margin) of vonoprazan to PPI was confirmed (%risk difference, -3.3; 95% confidence interval, -11.2 to 4.7; P < .001). The 3-day and 7-day rebleeding rates in the vonoprazan group remained noninferior to PPI (P < .001 by Farrington and Manning test). All secondary outcomes were also comparable between the 2 groups., Conclusion: In patients with high-risk PU bleeding, the efficacy of vonoprazan in preventing 30-day rebleeding was noninferior to intravenous PPI. (ClinicalTrials.gov, Number: NCT05005910)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Therapeutic drug monitoring (TDM) of elexacaftor, tezacaftor, ivacaftor (ETI) could be a useful tool to increase efficacy and decrease the risk of adverse effects in people with Cystic Fibrosis (pwCF). It is however unclear whether drug exposure should be monitored by assessment of trough (C min ) levels or determination of the area under the curve (AUC). Hence, in this study the correlation between measured C min concentration and AUC was evaluated. Serial plasma samples, including C min , were drawn after administration of ETI in order to calculate the AUC and assess the correlation between the two parameters. A linear correlation between C min and AUC 0-24h was found, with Pearson's r correlation coefficients of 0.963, 0.908 and 0.860 for elexacaftor, tezacaftor and ivacaftor, respectively. Exposure of ETI may be monitored by assessment of C min levels., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

The gut microbiota is a complex ecosystem, home to hundreds of bacterial species and a vast repository of enzymes capable of metabolising a wide range of pharmaceuticals. Several drugs have been shown to affect negatively the composition and function of the gut microbial ecosystem. Janus Kinase (JAK) inhibitors and Sphingosine-1-phosphate (S1P) receptor modulators are drugs recently approved for inflammatory bowel disease through an immediate release formulation and would potentially benefit from colonic targeted delivery to enhance the local drug concentration at the diseased site. However, their impact on the human gut microbiota and susceptibility to bacterial metabolism remain unexplored. With the use of calorimetric, optical density measurements, and metagenomics next-generation sequencing, we show that JAK inhibitors (tofacitinib citrate, baricitinib, filgotinib) have a minor impact on the composition of the human gut microbiota, while ozanimod exerts a significant antimicrobial effect, leading to a prevalence of the Enterococcus genus and a markedly different metabolic landscape when compared to the untreated microbiota. Moreover, ozanimod, unlike the JAK inhibitors, is the only drug subject to enzymatic degradation by the human gut microbiota sourced from six healthy donors. Overall, given the crucial role of the gut microbiome in health, screening assays to investigate the interaction of drugs with the microbiota should be encouraged for the pharmaceutical industry as a standard in the drug discovery and development process., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

A 67-year-old man had taken the janus kinase (JAK) inhibitor, tofacitinib, for ulcerative colitis. He was referred to our department for a refractory ulcer on his lower leg. We suspected vasculitis and performed skin biopsy. Histopathological examination showed multinucleated giant cells in the epidermis and fibrinoid degeneration of small vessels in the upper dermis. Varicella zoster virus (VZV) DNA was detected by polymerase chain reaction and we diagnosed the patient with atypical vasculitis-like herpes zoster. The patient was treated with oral valacyclovir, but the rash persisted and took 2 months to heal. Immunostaining using anti-VZV antibody was positive mainly in epidermal keratinocytes, but was also observed to be positive in cells in the dermis. We further performed RNA in situ hybridization using a VZV ORF9 mRNA probe and clearly showed that the distribution of VZV mRNA extended into the dermis, including the dermal vessel walls and the eccrine sweat glands as well as the epidermis. The internal administration of JAK inhibitors may induce regional widespread VZV infection including vessels and involved in the formation of prolonged vasculitis-like manifestation. RNA in situ hybridization can be a potent tool for detecting the spread of VZV infection in the skin., (© 2024 Japanese Dermatological Association.)

Background: Alopecia areata (AA) is a recurrent immune-mediated disorder causing hair loss without any scarring being present. It affects hairs on the head or other parts of the body and can occur at any age and in both genders. It seems that AA is associated with a higher rate of psychological disorders resulting from hair loss and the esthetic and social repercussions of it. Common treatments like corticosteroids do not work for every patient and recent treatment options focusing on the immunologic mechanisms like tofacitinib have shown some promising results., Methods: It's a retrospective study on patients with AA, AT, AU taking oral tofacitinib as a treatment for at least 6 months. Scalp hair loss was assessed before treatment and at each visit using the Severity of Alopecia Tool (SALT) score., Results: Of 97 cases, 69.1% demonstrated over 50% SALT score improvement, with 44.3% having 90% or more decrease in SALT score. Patients who suffered from patchy AA were more responsive compared to patients with AT and AU subtypes and had a greater percent change in SALT score. Tofacitinib was tolerated quite well and no significant adverse events were reported., Conclusions: Tofacitinib should be taken into consideration as an efficacious treatment option for patients with AA, AT and AU., (© 2024 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Elexacaftor/tezacaftor/ivacaftor (ETI) is a CFTR modulator therapy that has dramatically improved the health outcomes for many people with cystic fibrosis (pwCF). There is increasing interest in the role of CFTR modulators in the prevention and treatment of respiratory infections in pwCF. A male patient with F508del homozygous cystic fibrosis developed cavitary Mycobacteroides abscessus subspecies bolletii & massiliense respiratory infection. Antimycobacterial treatment was not given as, in discussion with the patient's family, it was deemed unlikely that the intensive regimen would be tolerated by the patient on account of his autism spectrum disorder. Following initiation of ETI, there was a rapid clinical and radiological improvement in this patient's cavitary lung disease. This case adds to the evidence base that suggests CFTR modulators, particularly ETI, may restore innate immune function leading to improved outcomes for pulmonary infection in pwCF., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Abstract: Helicobacter pylori is the most common chronic bacterial infection worldwide. Because of the risk for chronic gastritis, peptic ulcer disease, and gastric malignancy, all patients with H. pylori should be treated. Unfortunately, eradication rates remain low, and barriers to successful treatment include inadequate acid suppression, locoregional antibiotic resistance, and patient nonadherence to complicated treatment regimens. Vonoprazan, a new medication for the treatment of H. pylori infections, provides more potent acid suppression and is simpler to dose than proton pump inhibitors. This article provides a data-driven algorithm for incorporating vonoprazan into the treatment of patients with H. pylori infections., (Copyright © 2024 American Academy of Physician Associates.)

Objective: To review the pharmacology, efficacy, and safety of capivasertib for the treatment of adults with hormone receptor-positive, HER2-negative (HR+/HER2-) locally advanced or metastatic breast cancer with 1 or more PIK3CA/AKT1/PTEN alterations., Data Sources: A literature search was conducted using PubMed and MEDLINE databases, published abstracts, and studies from ClinicalTrials.gov between 2003 and February 2024. Keywords included capivasertib, AZD5363, PI3K/AKT/mTOR pathway, and breast cancer., Data Extraction: All applicable publications, package inserts, meeting abstracts, and clinical trials with capivasertib were reviewed., Data Synthesis: Capivasertib is a first-in-class inhibitor of 3 isoforms of AKT (AKT-1, AKT-2, and AKT-3) which is an essential component in the PI3K/AKT/mTOR signaling pathway involved in oncogenesis. In the phase III CAPItello-291 trial, capivasertib in combination with fulvestrant (C+F) demonstrated improved progression-free survival (PFS) (7.3 vs 3.1 months) compared with placebo-fulvestrant (P+F) cohort in AKT-altered pathway patients who had progressed through prior aromatase inhibitor. The most common adverse reactions of any grade reported in the C+F group were diarrhea, cutaneous skin reactions, nausea, fatigue, and vomiting., Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs: HR+/HER2- advanced breast cancer patients experience progression following endocrine therapies and cyclin-dependent kinase (CDK) 4/6 inhibitors. Capivasertib is a viable treatment option for patients with PIK3CA/AKT1/PTEN activating mutations following progression on endocrine-based regimens in the metastatic setting or recurrence within 12 months of completing adjuvant therapy., Conclusion: Integration of capivasertib into clinical practice is ongoing; intermittent dosing and favorable toxicity are attractive for future novel combination prospective trials., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rosacea is a chronic inflammatory skin disease characterized by facial erythema and telangiectasia. Despite ongoing research, the pathogenesis of rosacea remains incompletely understood, and current therapies are not entirely satisfactory. The JAK/STAT signaling pathway plays an essential role in immunoregulation, inflammation, and neurovascular regulation. Inhibition of the JAK/STAT pathway appears to hold promise as a potential therapy for rosacea. This study aimed to investigate the effects of the JAK inhibitor tofacitinib on rosacea and to preliminarily explore its therapeutic mechanism. To this end, a rosacea-like mouse model was induced using LL37 and treated with a 2% tofacitinib emulsion. The results demonstrated that topical application of tofacitinib significantly ameliorated rosacea-like phenotype, reduced the infiltration of CD4 + T cells and mast cells, and suppressed dermal angiogenesis. RT-qPCR analysis revealed a reduction in mRNA expression levels of STAT1, STAT4, and STAT5a in skin lesions following topical tofacitinib treatment. Additionally, three patients diagnosed with erythematotelangiectatic rosacea (ETR) were included in the study and treated with oral tofacitinib, leading to a significant improvement in erythema and flushing symptoms. These findings collectively suggest that tofacitinib alleviates LL37-induced rosacea-like skin inflammation in mice and rosacea skin lesions by inhibiting the JAK/STAT signaling pathway., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to identify the safety and effectiveness of tofacitinib in patients with UC in routine clinical settings in Korea., Methods: This open-label, observational, prospective, post-marketing surveillance study was conducted at 22 hospitals in the Republic of Korea. Patients with moderate to severe active UC who received tofacitinib were included and followed up for up to 52 weeks. Tofacitinib was administered at a dosage of 10 mg twice daily for at least 8 weeks, followed by 5 or 10 mg twice daily at the investigator's discretion based on clinical evaluation according to the approved Korean label. Safety including adverse events (AEs) and effectiveness including clinical remission, clinical response, and endoscopic mucosal healing were evaluated. Safety analysis set was defined as all patients registered for this study who received at least one dose of tofacitinib according to the approved Korean label and followed up for safety data. Effectiveness analysis set included patients in the safety analysis set who were evaluated for overall effectiveness assessment and excluded patients who had received tofacitinib less than 8 weeks., Results: A total of 110 patients were enrolled, of whom 106 patients were included in the safety population. The median duration of treatment was 370 days and the treatment duration ranged from 16 to 684 days for the safety population. AEs occurred in 42 patients (39.6%). Serious AEs (SAEs) occurred in 7 patients (6.6%) and of them, there were 2 cases of serious infections. These serious infections were reported as Adverse Event of Special Interest (AESI) in this study and no other AESI were reported. There were no cases of death during the study period. Clinical remission rates were 40.0%, 46.7%, 57.6%, and 55.1% at 8, 16, 24, and 52 weeks, and clinical response rates were 77.8%, 87.9%, 56.6%, and 81.4% at each visit, respectively. Endoscopic mucosal healing rates were 58.7% at 16 weeks and 46.2% at 52 weeks., Conclusion: Tofacitinib was effective in Korean patients with moderate to severe active UC and the safety findings were consistent with the known safety profile of tofacitinib. This study confirmed the safety and effectiveness of tofacitinib in Korean patients with moderate to severe active UC in routine clinical settings., Trial Registration: This study is registered in the ClinicalTrials.gov under the identifier NCT04071405, registered on 28 August 2019., (© 2024. The Author(s).)

An open-label, single-center, phase I study was conducted to determine the absolute bioavailability and absorption, distribution, metabolism, and excretion of capivasertib-a potent, selective AKT serine/threonine kinase inhibitor-in healthy males. In part 1, six participants received a single oral dose of capivasertib (400 mg; tablets) followed by a [ 14 C]-radiolabeled intravenous microdose of capivasertib (100 μ g). After a 14-day washout, five of the participants proceeded to part 2 and received a single oral dose of [ 14 C]capivasertib (400 mg; solution). In part 1, median time of maximum observed concentration for capivasertib was 1.7 hours, geometric mean terminal elimination half-life was 12.9 hours, and absolute bioavailability was estimated at 28.6% (90% confidence interval, 23.9 to 34.2). In part 2, a high proportion of the administered radioactivity was recovered over the 168-hour sampling period [mean recovery: 95.1% (feces, 50.4%; urine, 44.7%)]. Unchanged capivasertib in urine accounted for 7.4% of the total dose and 21.1% of the systemically available drug. Geometric mean renal clearance was 8.3 L/h, suggesting active tubular secretion. Twelve metabolites were identified in plasma. M11 (AZ14102143)-the glucuronide conjugate of capivasertib, inactive as an AKT serine/threonine kinase inhibitor-was the most abundant, accounting for a mean 78.4% of the plasma drug-related area under the curve. Of 22 metabolites identified in excreta, M11 was the most abundant (mean 28.2% of administered dose), indicating direct glucuronidation as one of the major routes of metabolism. No new safety concerns were identified. SIGNIFICANCE STATEMENT: This study provides characterization of the pharmacokinetics of capivasertib-a potent, selective AKT serine/threonine kinase (AKT) inhibitor-including absolute bioavailability, mass balance, and metabolic fate in humans; the findings are being used to inform further clinical development. Absolute bioavailability was estimated at 28.6%, and mean recovery of the administered dose in excreta over 168 hours was 95.1%. M11 (AZ14102143)-the glucuronide conjugate, inactive as an AKT inhibitor-was the most abundant identified metabolite in plasma and excreta., (Copyright © 2024 by The Author(s).)

Background and Aims: This study aimed to evaluate the efficacy and safety of vonoprazan and tetracycline (VT) dual therapy as first-line treatment for Helicobacter pylori infection in patients with penicillin allergy., Methods: In this randomised controlled trial, treatment-naïve adults with H. pylori infection and penicillin allergy were randomised 1:1 to receive either open-label VT dual therapy (vonoprazan 20 mg two times per day+tetracycline 500 mg three times a day) or bismuth quadruple therapy (BQT; lansoprazole 30 mg two times per day+colloidal bismuth 150 mg three times a day+tetracycline 500 mg three times a day+metronidazole 400 mg three times a day) for 14 days. The primary outcome was non-inferiority in eradication rates in the VT dual group compared with the BQT group. Secondary outcomes included assessing adverse effects., Results: 300 patients were randomised. The eradication rates in the VT group and the BQT group were: 92.0% (138/150, 95% CI 86.1% to 95.6%) and 89.3% (134/150, 95% CI 83.0% to 93.6%) in intention-to-treat analysis (difference 2.7%; 95% CI -4.6% to 10.0%; non-inferiority p=0.000); 94.5% (138/146, 95% CI 89.1% to 97.4%) and 93.1% (134/144, 95% CI 87.3% to 96.4%) in modified intention-to-treat analysis (difference 1.5%; 95% CI -4.9% to 8.0%; non-inferiority p=0.001); 95.1% (135/142, 95% CI 89.7% to 97.8%) and 97.7% (128/131, 95% CI 92.9% to 99.4%) in per-protocol analysis (difference 2.6%; 95% CI -2.9% to 8.3%; non-inferiority p=0.000). The treatment-emergent adverse events (TEAEs) were significantly lower in the VT group (14.0% vs 48.0%, p=0.000), with fewer treatment discontinuations due to TEAEs (2.0% vs 8.7%, p=0.010)., Conclusions: VT dual therapy demonstrated efficacy and safety as a first-line treatment for H. pylori infection in the penicillin-allergic population, with comparable efficacy and a lower incidence of TEAEs compared with traditional BQT., Trial Registration Number: ChiCTR2300074693., 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.)

Inflammatory diseases including rheumatoid arthritis are major health problems. Although different techniques and drugs are clinically available for the diagnosis and therapy of the disease, novel approaches regarding radiolabeled drug delivery systems are researched. Hence, in the present study, it was aimed to design, prepare, and characterize 99m Tc-radiolabeled and tofacitinib citrate-encapsulated microsphere loaded poloxamer in situ gel formulations for the intra-articular treatment. Among nine different microsphere formulations, MS/TOFA-9 was chosen as the most proper one due to particle size, high encapsulation efficiency, and in vitro drug release behavior. Poloxamer 338 at a concentration of 15% was used to prepare in situ gel formulations. For intra-articular administration, microspheres were dispersed in an in situ gel containing 15% Poloxamer 338 and characterized in terms of gelation temperature, viscosity, rheological, mechanical, and spreadability properties. After the determination of the safe dose for MS/TOFA-9 and PLX-MS/TOFA-9 as 40 µL/mL in the cell culture study performed on healthy cells, the high anti-inflammatory effects were due to significant cellular inhibition of fibroblasts. In the radiolabeling studies with 99m Tc, the optimum radiolabeling condition was determined as 200 ppm SnCl 2 and 0.5 mg ascorbic acid, and both 99m Tc-MS/TOFA-9 and 99m Tc-PLX-MS/TOFA-9 exhibited high cellular binding capacity. In conclusion, although further in vivo experiments are required, PLX-MS/TOFA-9 was found to be a promising agent for intra-articular injection in rheumatoid arthritis., (© 2024 The Author(s). Drug Development Research published by Wiley Periodicals LLC.)

Background and Purpose: Cystic fibrosis (CF) patients are living longer and healthier due to improved treatments, e.g. cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI), with treatment possibly occurring in pregnancy. The risk of ETI to foetuses remain unknown. Thus the effect of maternally administered ETI on foetal genetic and structural development was investigated., Experimental Approach: Pregnant Sprague Dawley rats were orally treated with ETI (6.7 mg·kg -1 ·day -1 elexacaftor + 3.5 mg·kg -1 ·day -1 tezacaftor + 25 mg·kg -1 ·day -1 ivacaftor) for 7 days from E12 to E19. Tissue samples collected at E19 were analysed using histology and RNA sequencing. Histological changes and differentially expressed genes (DEG) were assessed., Key Results: No overt structural abnormalities were found in foetal pancreas, liver, lung and small intestine after 7-day ETI exposure. Very few non-functionally associated DEG in foetal liver, lung and small intestine were identified using RNA-seq. 29 DEG were identified in thymus (27 up-regulated and two down-regulated) and most were functionally linked to each other. Gene ontology enrichment analysis revealed that multiple muscle-related terms were significantly enriched. Many more DEG were identified in cortex (44 up-regulated and four down-regulated) and a group of these were involved in central nervous system and brain development., Conclusion and Implication: Sub-chronic ETI treatment in late pregnancy does not appear to pose a significant risk to the genetic and structural development of many foetal tissues. However, significant gene changes in foetal thymic myoid cells and cortical neuronal development requires future follow-up studies to assess the risk to these organs., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Gastroesophageal reflux disease (GERD) symptoms frequently recur after cessation of acid blockers. The presence of a hiatal hernia may worsen GERD symptoms and increase the risk of esophageal malignancy. The aim of this study is to clarify the timing and predictors for recurrence of GERD symptoms after cessation of vonoprazan (VPZ) therapy., Methods: A retrospective observational study involved 86 patients who underwent cessation of VPZ therapy for symptomatic GERD. Collated data from medical record review included the endoscopic findings and Izumo scale score., Results: The mean duration of continuous VPZ therapy before cessation was 7.9 months. GERD symptoms requiring the resumption of VPZ therapy recurred in 66 of 86 patients (77%). Kaplan-Meier analysis showed that overall recurrence-free rates at 6 months, one and two years after VPZ cessation were 44%, 32% and 23%, respectively. Alcohol use, the presence of a hiatal hernia and long-term therapy for more than six months were identified as significant positive predictors for symptomatic recurrence. Notably, hiatal hernia had the highest hazard ratio in both univariate and multivariate analyses. The recurrence-free rate in patients with a hiatal hernia was much lower at 6 months than in patients without a hiatal hernia (15% and 51%, respectively p  = 0.002). After the symptomatic recurrence, GERD symptoms improved significantly after one-month VPZ therapy., Conclusion: The rate of symptomatic recurrence after VPZ cessation in patients with GERD is considerable. Cessation of acid suppression therapy should be cautious in patients with both a hiatal hernia and GERD.

Background: The introduction of CFTR modulators has changed the landscape in the treatment of cystic fibrosis (CF) and early case series have shown improvements in sinonasal outcomes in this patient population., Methodology: A real-word data study was performed to evaluate the impact of dual therapy with tezacaftor/ivacaftor (TEZ/IVA) and triple therapy with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on CF-related chronic rhinosinusitis (CRS), by comparing subjective and objective outcome measures at baseline, 12 months after treatment with TEZ/IVA and six months after treatment with ELX/TEZ/IVA., Results: In total, 43 CF patients, with a mean age of 32 years, were included. After triple therapy, significant improvements in overall visual analogue scale, SNOT-22, Lund Kennedy, nasal polyps, and Lund-Mackay scores were observed, whereas no beneficial effect could be seen in patients treated with dual therapy. Bacterial upper airway colonization did not differ pre- and postmodulator therapy in the present study. The number of responders to dual and triple therapy is 23.8% and 63.2% of the patients, respectively., Conclusions: Triple therapy with ELX/TEZ/IVA is superior to dual therapy with TEZ/IVA in the treatment of CF-CRS, as significantly reduced sinonasal complaints, nasal endoscopy and CT scores were observed after triple therapy, whereas this was not the case for dual therapy.

Vonoprazan (VPZ) has been available in Japan since 2015. Endoscopic features of proton-pump inhibitor (PPI)-related gastric mucosal changes, including fundic gland and hyperplastic polyps, have been observed. However, the relationship between gastric polyps and VPZ remains unclear. A 65-year-old man with reflux esophagitis-associated symptoms refractory to PPI was referred to our hospital. VPZ (20 mg) was administered for 3 weeks, which proved effective. Afterward, VPZ dose was reduced to 10 mg; the reflux symptoms worsened, and 20 mg VPZ was restarted. Afterward, esophagogastroduodenoscopy (EGD) revealed a gradually enlarging gastric polyp in the cardia. After 5 years of VPZ administration, the patient developed a reddish polyp (approximately 10 mm) with a whitish substance in the cardia. Based on the clinical course, the polyp was considered to have enlarged because of the long-term VPZ administration. After being informed of the endoscopic findings, the patient decided to discontinue VPZ. One year after VPZ discontinuation, EGD revealed a shrunken polyp (5 mm). Long-term acid suppression causes hypergastrinemia, which may lead to gastric mucosal changes, including gastric polyps. There are few case reports of a decrease in the number and size of gastric polyps after VPZ discontinuation. Hence, some VPZ-induced endoscopic changes may be reversible., (© 2024. Japanese Society of Gastroenterology.)

Purpose: Capivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials in advanced breast and prostate cancer. This study evaluated the drug-drug interaction risk of capivasertib with the cytochrome P450 3A substrate midazolam in previously treated adults with advanced solid tumors., Methods: Patients received oral capivasertib 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 days off) starting on day 2 of cycle 1 (29 days) and on day 1 of each 28-day cycle thereafter. In cycle 1 only, patients received oral midazolam (1 mg) on day 1 (alone), and days 8 and 12 (3rd day off and 4th day on capivasertib, respectively). Midazolam pharmacokinetics on days 8 and 12 were analyzed versus day 1. Capivasertib, with or without standard-of-care treatment, was continued in patients deemed likely to benefit. Safety and exploratory efficacy analyses were conducted., Results: Capivasertib-midazolam coadministration increased midazolam exposure (n = 21): geometric mean ratio (90% confidence interval) AUC inf and C max was 1.13 (0.97-1.32) and 1.15 (0.99-1.33) for day 8 versus day 1, and 1.75 (1.50-2.05) and 1.25 (1.08-1.46) for day 12 versus day 1. The capivasertib safety profile was manageable when administered with or without midazolam. Two patients had partial responses to treatment., Conclusion: The up to 1.75-fold increase in midazolam exposure indicates capivasertib is a weak CYP3A inhibitor at 400 mg BID on an intermittent schedule. Capivasertib was well tolerated; exploratory efficacy analysis demonstrated evidence of clinical activity in this heavily pre-treated population., Clinicaltrials: gov: NCT04958226., (© 2024. The Author(s).)

Objective: Granulocyte-monocyte apheresis (GMA) has shown to be safe and effective in treating ulcerative colitis (UC), also in combination with biologics. The objective of this study is to evaluate the efficacy and safety of combining GMA after primary non-response (PNR) or loss of response (LOR) to tofacitinib (TOFA) in patients with UC., Patients and Methods: Retrospective study including all patients with refractory UC who received GMA plus TOFA. Efficacy was assessed 1 and 6 months after finishing GMA by partial Mayo score, C-reactive protein (CRP) and fecal calprotectin (FC). Descriptive statistics and non-parametric tests were used in the statistical analysis., Results: Twelve patients were included (median 46 years [IQR, 37-58]; 67% female; 67% E3). Patients were mostly receiving TOFA 10mg bid (75%), and 33% also concomitant steroids at baseline. Median partial Mayo score at baseline was 7 (IQR, 5-7), and it decreased to a median of 2 (IQR, 0-3) and 0 (IQR, 0-3) after 1 and 6 months (p=0.027 and 0.020, respectively), while no differences were found in CRP and FC. Clinical remission was achieved by 6 patients both at 1 (50%) and 6 months (67%). CF values<250mg/kg were achieved by 2 and 4 patients at 1 and 6 months (data available in 5 and 7 patients, respectively). No patient required dose-escalation of TOFA, and one patient was able to de-escalate the drug. No patient required colectomy and all patients under steroids were able to stop them., Conclusion: The combination of GMA and TOFA can be effective in selected cases of UC after PNR or LOR to this drug., (Copyright © 2024 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Vitiligo is a chronic skin condition caused by an autoimmune response that results in the progressive loss of melanocytes and recent studies have suggested that Janus kinase inhibitors (JAKi) are emerging as a promising new treatment modality. Therefore, to assess and understand the extent of knowledge in the emerging field of JAKi use in vitiligo, a scoping review of the literature was undertaken. The reviewed articles explored a wide variety of JAKi administered either orally or topically for vitiligo. There were no injectable JAKi studied. Tofacitinib was the most commonly studied oral JAKi in 16 of the 35 studies selected for review, followed by baricitinib (n = 3), and one study each with ritlecitinib, ruxolitinib, and upadacitinib. Ruxolitinib (n = 6) and tofacitinib (n = 6) were the most often studied topical JAKi, followed by delgocitinib (n = 1). Potential benefits may vary between JAKi based on their receptor selectivity profile and coexistent autoimmune diseases. A topical JAKi would be advantageous in limited body area involvement and in adolescents. Concurrent use of JAKi with phototherapy or sun exposure appears beneficial. Most studies permitted the use of other topical agents. Acne-related events, though frequent yet mild, were reported with both oral and topical JAKi. Nasopharyngitis, upper respiratory tract infections, and headaches were the most common adverse effects seen in the larger trials with JAKi. No serious or clinically meaningful hematology or thromboembolic events were detected. Treatment of vitiligo with oral or topical JAKi seems to be promising and the growing evidence shows a favorable risk-benefit profile., (© 2024 The Authors. International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.)

Background and Objective: Overactivation of the PI3K/AKT pathway can occur in many cancers. Capivasertib is a potent, selective pan-AKT inhibitor. The objectives of this analysis were to develop a population pharmacokinetic model for capivasertib and to quantitatively assess the impact of intrinsic and extrinsic factors on the pharmacokinetics of capivasertib., Methods: Pharmacokinetic data from four phase I and II studies were combined. Capivasertib was administered orally at a dose range of 80-800 mg twice daily over 28-day and 21-day cycles as monotherapy or in combination with paclitaxel or fulvestrant, using continuous dosing or one of two intermittent dosing schedules: either 4 days on, 3 days off (4/3) or 2 days on, 5 days off (2/5). Several models and approaches were tested for their ability to describe capivasertib disposition. The covariates assessed included dose, schedule, age, body weight, race, sex, creatinine clearance, hepatic function, renal function, smoking status, food effect, formulation, and concomitant use with paclitaxel, fulvestrant, cytochrome P450, family 3, subfamily A (CYP3A) inducers, CYP3A inhibitors and acid-reducing agents., Results: A total of 3963 capivasertib plasma concentrations from 441 patients were included. Capivasertib pharmacokinetics was adequately described by a three-compartment model where the apparent clearance (CL/F) presented a moderate time-dependent and dose-dependent clearance. Following oral administration of multiple doses of capivasertib (400 mg twice daily; [4/3]), the initial CL/F was 62.2 L/h (between-subject variability 39.3%), and after approximately 120 hours, CL/F decreased by 18%. The effective half-life was 8.34 h. Steady state was predicted to be reached on every third and fourth dosing day each week from the second week with exposure levels that produced robust inhibition of AKT but not of other related kinases. The area under the plasma concentration-time curve and maximum plasma concentration of capivasertib were proportional between the dose levels of 80-480 mg after multiple doses but more than proportional beyond 480 mg. Schedule, age, race, sex, creatinine clearance, hepatic function, renal function, smoking status and concomitant use with fulvestrant, CYP3A inducers, CYP3A inhibitors or acid-reducing agents were not significant covariates for capivasertib pharmacokinetics. Concomitant use of paclitaxel, food effect and formulation statistically significantly affected capivasertib pharmacokinetics, but the effect was low. Body weight was statistically significantly related to capivasertib CL/F, with a 12% reduction in CL/F at steady state and a 14% increase in the area under the curve for 12 hours at steady state and maximum concentration at steady state at a lower body weight (47 kg vs 67 kg reference)., Conclusions: Capivasertib pharmacokinetics showed moderate between-subject variability, and most covariates assessed had no significant impact. Body weight, dose, concomitant use of paclitaxel, food effect and formulation showed statistically significant effects. However, these were predicted to impact exposure to capivasertib by  <20% and were not expected to be clinically relevant. Based on the population pharmacokinetics, no a priori dose adjustment is needed for intrinsic and extrinsic factors., (© 2024. The Author(s).)

Background/objective: To assess safety/efficacy of tofacitinib and tumor necrosis factor inhibitors (TNFi) in patients from Latin America (LATAM) in ORAL Surveillance., Methods: In ORAL Surveillance, 4362 patients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily or TNFi. This post hoc analysis stratified patients by geographical location (LATAM, n = 1202; non-LATAM, n = 3160). Incidence rates (IRs; patients with first event/100 patient-years) and hazard ratios for adverse events of special interest were reported. Efficacy outcomes included Clinical Disease Activity Index and American College of Rheumatology 20/50/70 responses., Results: Risk factors associated with cardiovascular disease and malignancies were less prevalent in the LATAM cohort compared with the non-LATAM cohort. IRs for patients receiving tofacitinib (combined doses) versus TNFi were 0.54 versus 0.28 (LATAM) and 1.14 versus 0.92 (non-LATAM) for major adverse cardiovascular events; 0.58 versus 0.27 (LATAM) and 1.33 versus 0.95 (non-LATAM) for malignancies excluding nonmelanoma skin cancer; and 0.69 versus 0.35 (LATAM) and 0.63 versus 0.33 (non-LATAM) for all-cause death. IRs for nonmelanoma skin cancer and venous thromboembolism were also numerically higher with tofacitinib versus TNFi and in the non-LATAM cohort versus LATAM. Efficacy was similar across treatment groups within each cohort., Conclusions: Adverse events of special interest were generally less frequent in LATAM versus non-LATAM patients, reflecting differences in baseline characteristics, and higher with tofacitinib versus TNFi in both cohorts, consistent with the overall findings of ORAL Surveillance. Our findings emphasize the importance of assessing individual risk factors to guide benefit/risk assessment and treatment decisions., Clinical Trial Registration Number: NCT02092467., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: Corticotropin-releasing factor (CRF), the apical stress-inducing hormone, exacerbates stress and addictive behaviors. TCAP-1 is a peptide that directly inhibits both CRF-mediated stress and addiction-related behaviors; however, the direct action of TCAP-1 on morphine withdrawal-associated behaviors has not previously been examined., Objective: To determine whether TCAP-1 administration attenuates behavioral and physiological consequences of morphine withdrawal in mice., Methods: Mice were administered via subcutaneous route TCAP-1 either before or after initial morphine exposure, after which jumping behavior was quantified to assess the effects of TCAP-1 on naloxone-precipitated morphine withdrawal. As a comparison, mice were treated with nonpeptide CRF 1 receptor antagonist CP-154,526. In one experiment, plasma corticosterone (CORT) was also measured as a physiological stress indicator., Results: Pretreatment with TCAP-1 (10-250 nmol/kg) before morphine treatment significantly inhibited the development of naloxone-precipitated withdrawal. TCAP-1 (250-500 nmol/kg) treatment administered after morphine treatment attenuated the behavioral expression of naloxone-precipitated withdrawal. TCAP-1 (250 nmol/kg) treatment during morphine treatment was more effective than the optimal dosing of CP-154,526 (20 mg/kg) at suppressing the behavioral expression of naloxone-precipitated withdrawal, despite similar reduction of withdrawal-induced plasma CORT level increases., Conclusions: These findings establish TCAP-1 as a potential therapeutic candidate for the prevention and treatment of morphine withdrawal., (© 2024. The Author(s).)

Background: The efficacy of Vonoprazan-amoxicillin dual therapy (VAT) in the treatment of Helicobacter pylori ( H. pylori ) is controversial., Aim: To evaluate the efficacy of VAT in the Chinese population., Methods: This prospective, multicenter, randomized, open-label, and two-stage study was conducted at 23 centers in Fujian, China (May 2021-April 2022). H. pylori -infected patients were randomized to bismuth quadruple therapy (BQT), BQT-Vonoprazan (BQT-V), seven-day VAT (VAT-7), ten-day VAT (VAT-10), and fourteen-day VAT (VAT-14) groups. The primary endpoint was the H. pylori eradication rate. The secondary endpoint was the frequency of adverse events. This study was registered with the Chinese Clinical Trial Registry, ChiCTR2100045778., Results: In the first stage, VAT-7 and BQT-V groups were selected for early termination because less than 23 among 28 cases were eradicated. In the second stage, the eradication rates for BQT, VAT-10, and VA-14 were 80.2% [95% confidence interval (95%CI): 71.4%-86.8%], 93.2% (86.6%-96.7%), 92.2% (85.3%-96.0%) in the intention-to-treat (ITT) analysis, and 80.9% (95%CI: 71.7%-87.5%), 94.0% (87.5%-97.2%), and 93.9% (87.4%-97.2%) in the per-protocol analysis. The ITT analysis showed a higher eradication rate in the VAT-10 and VAT-14 groups than in the BQT group ( P = 0.022 and P = 0.046, respectively). The incidence of adverse events in the VAT-10 and VAT-14 groups was lower than in the BQT group (25.27% and 13.73% vs 37.62%, respectively; P < 0.001)., Conclusion: VAT with a duration of 10 or 14 days achieves a higher eradication rate than the BQT, with a more tolerable safety profile in H. pylori -infected patients in Fujian., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aims: Objective methods to determine statin adherence are requested to improve lipid management. We have recently established a method to detect reduced adherence to atorvastatin therapy with cut-off values based on the sum of atorvastatin and its major metabolites in the blood. We aimed to validate this method in patients with and without cardiovascular disease, and optimize previous cut-off values., Methods and Results: The pharmacokinetic study included 60 participants treated with atorvastatin 20 mg (N = 20), 40 mg (N = 20), and 80 mg (N = 20). Atorvastatin was then stopped and blood samples collected from day zero to day four. Quantification of the parent drug and its metabolites in blood plasma was performed with a liquid chromatography-tandem mass spectrometry assay. The cut-off values for reduced adherence were validated and optimized by calculating diagnostic sensitivity and specificity. Our candidate cut-off value of dose-normalized six-component sum of atorvastatin plus metabolites <0.10 nM/mg provided a sensitivity of 97% and a specificity of 93% for detecting ≥2 omitted doses. An optimized cut-off <0.062 nM/mg provided a sensitivity of 90% and a specificity of 100%. An alternative simplified two-component metabolite sum with a cut-off value <0.05 nM/mg provided a sensitivity of 98% and a specificity of 76%. An optimized cut-off <0.02 nM/mg provided a sensitivity of 97% and a specificity of 98%., Conclusion: This validation study confirms that our direct method discriminates reduced adherence from adherence to atorvastatin therapy with high diagnostic accuracy. The method may improve lipid management in clinical practice and serve as a useful tool in future studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Alopecia areata (AA) is an autoimmune pathology manifested by loss of hair., Objective: To evaluate and compare the efficacy and safety of tofacitinib and azathioprine in patients with AA and variants., Methods: In this double-blind randomized controlled trail (RCT) carried out at the Department of Dermatology, Medical Teaching Institute-Lady Reading Hospital (MTI-LRH), Peshawar, Pakistan, patients aged ≥ 12 years diagnosed with AA, alopecia totalis (AT) or alopecia universalis (AU) with minimum 50% scalp hair loss for a period ≥ 06 years were included. Patients were randomly assigned to receive oral tofacitinib 5 mg twice daily (Group I) or oral azathioprine 2 mg/kg body weight once daily (Group II). The primary endpoint was Severity of Alopecia Tool (SALT) score, evaluated at baseline and 06 months follow-up. Safety was consistently assessed during the study., Results: A total of 104 patients underwent random allocation into either the tofacitinib group (n = 52) or the azathioprine group (n = 52). The mean (SD) age of patients was 20.23 (7.14) years and 22.26 (8.07) years, while the mean (SD) disease duration was 6.59 (4.01) years and 7.98 (4.40) years in in Group I and II, respectively. Overall, 40 (38.5%) patients were adolescents while 70 (67.3%) were male. 52 (50%) had AA, 37 (35.5%) had AT and 15 (14.5%) had AU. Mean baseline SALT score in tofacitinib group was 91.02 ± 10.21 and azathioprine group was 91.02 ± 10.63, which at 06 months follow-up improved to 14.1 ± 24.6 and 63.9 ± 33.9, respectively (difference, 11.5 points; 95% confidence interval, 38.3-61.3, p < 0.0001). Overall, no major adverse effects and no difference among the minor adverse effects in the two groups (04 adverse events for tofacitinib group and 08 for azathioprine group: p = 0.23) was observed., Conclusions: Efficacy of tofacitinib was significantly higher than azathioprine, whilst both drugs were well-tolerated in patients with AA and variants., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)