Drug Des Devel Ther. 2024 Aug 13;18:3617-3628. doi: 10.2147/DDDT.S475706. eCollection 2024.

ABSTRACT

OBJECTIVE: Hepatotoxicity is an important cause of early withdrawal of voriconazole (VCZ). The role of the plasma trough concentration of VCZ (C0) in hepatotoxicity is confusion. VCZ N-oxide is the primary metabolite of VCZ in plasma. We investigated the role of VCZ C0 and plasma trough concentration of VCZ N-oxide (CN) in hepatotoxicity in adult patients.

MATERIALS AND METHODS: This was a prospective study. VCZ C0 and CN were measured using liquid chromatography-tandem mass spectrometry.

RESULTS: In total, 601 VCZ C0 and CN from 376 adult patients were included. The percentage of grade 1 or higher adverse events for ALP, ALT, AST, γ-GT, and TBIL were 35.4%, 21.0%, 30.1%, 56.2%, and 22.2%, respectively. Compared with younger adult patients, elderly patients (≥65 years) had a higher rate of grade 1 or higher adverse events of ALP. In the multivariate analysis, VCZ C0 was a risk factor for grade 1 or higher adverse events of AST in elderly patients and TBIL in younger adult patients, and VCZ CN was a risk factor for grade 1 or higher adverse events of ALT, AST, and TBIL. Results of the receiver operating characteristic curve analysis indicated that when the VCZ C0 was higher than 4.0 μg/mL, or the VCZ CN was lower than 1.7 μg/mL, the incidence of grade 1 or higher adverse events of AST and TBIL increased.

CONCLUSION: VCZ C0 and CN were associated with liver function-related adverse events. Measurement of VCZ CN should be considered for VCZ therapeutic drug monitoring.

PMID:39156484 | PMC:PMC11330242 | DOI:10.2147/DDDT.S475706

Cureus. 2024 Jul 16;16(7):e64703. doi: 10.7759/cureus.64703. eCollection 2024 Jul.

ABSTRACT

The immune checkpoint inhibitor pembrolizumab is now considered a first-line treatment for recurrent or metastatic head and neck squamous cell cancer. Pembrolizumab is less toxic than conventional chemotherapy but may result in immune-related adverse events. We report a case in which liver injury occurred just two days after the administration of pembrolizumab plus chemotherapy. A 48-year-old woman achieved a complete response after chemoradiotherapy for cT2N3bM0 squamous cell carcinoma of the oropharynx with multiple lymph node metastases. However, the tumor recurred one year later, and she was started on pembrolizumab plus chemotherapy. On day 3, her alanine aminotransferase and aspartate transaminase concentrations markedly increased. She was initially diagnosed with drug-induced liver injury and all medications were withdrawn. Her liver function recovered within two weeks without intervention. The lymphocyte transformation test was only positive for pembrolizumab. Clinicians should consider pembrolizumab-induced allergic hepatitis as a possible cause of liver injury after excluding liver metastasis and immune-related adverse events.

PMID:39156358 | PMC:PMC11327630 | DOI:10.7759/cureus.64703

Vaccine. 2024 Sep 17;42(22):126197. doi: 10.1016/j.vaccine.2024.126197. Epub 2024 Aug 15.

ABSTRACT

BACKGROUND: In 2016, the World Health Organization recommended that a fractional dose of yellow fever (YF) vaccine could be used in persons 2 years of age or older in response to an emergency that resulted in a global shortage of available YF vaccine. However, this recommendation did not extend to the youngest age group licensed for YF vaccine because there were no published data on the use or safety of fractional dose YF vaccination in children aged 9-23 months. We conducted a single-blind randomized controlled trial, comparing the immunogenicity and safety of fractional one-fifth and one-half doses of Bio-Manguinhos 17DD YF vaccine with full dose in children aged 9-23 months old in Uganda. In this paper, we present the interim analysis on safety.

METHODS: Children aged 9-23 months presenting for routine well-child services were recruited for inclusion at one of three study sites. We collected data during March 26, 2019-August 31, 2020, on all adverse events following immunization (AEFI) during active surveillance for 28 days post-vaccination using multiple collection tools including a diary card with an objective measurement of fever. An independent team from the Uganda national AEFI Committee investigated and classified serious AEFI (SAE) according to Brighton Collaboration Criteria.

RESULTS: Among 1053 enrolled children, 672 (64%) were reported to have a non-serious AEFI (NSAE) and 17 (2%) were reported to have a SAE. The most common AEFI were diarrhoea, fever, and rash, each reported by 355 (34%), 338 (33%), and 188 (18%) participants, respectively. Among 17 participants with SAE, eight were reported to have had seizures and five were hospitalised for seizures or other causes (respiratory symptoms, gastrointestinal illness, malaria). Four SAEs (deaths) occurred >28 days after vaccination. There were no reported cases of pre-specified or vaccine-related SAEs. We observed no significant difference in frequency or severity of adverse events among the study groups.

CONCLUSIONS: Using comprehensive active surveillance monitoring, we did not identify any unexpected safety concerns among children aged <2 years receiving YF vaccination, including with the fractional doses. Although we identified a high number of both serious and non-serious AEFI, none were determined to be causally related to YF vaccination. These results provide evidence for the safety of fractional dose YF vaccination among children aged 9-23 months.

PMID:39153293 | DOI:10.1016/j.vaccine.2024.126197

Pharmazie. 2024 Aug 1;79(7):163-168. doi: 10.1691/ph.2024.4548.

ABSTRACT

In recent years, there has been a growing trend in the use of immune checkpoint inhibitors (ICIs) for treating a larger patient population. However, it is important to note that immune-related adverse events (irAEs) frequently arise as a result. Therefore, precise patient monitoring becomes essential. We present the findings of a retrospective study conducted at the International University of Health and Welfare Narita Hospital (referred to as "our hospital") that aimed to identify risk factors linked to the occurrence of irAEs. The study focused on analyzing various factors, including therapeutic and lifestyle backgrounds, as well as laboratory values of patients who received ICI treatment and were subsequently diagnosed with irAE. The study included patients who met the eligibility criteria for ICIs (both single agent and combination therapy) as well as ICI in combination with anticancer drugs. The inclusion period for the study encompassed April 2020 to May 2022 at our hospital. The fifty patients were divided into two groups based on the severity of irAEs: the first group consisted of patients with irAE Grade 2 or lower (referred to as irAE Grade under 2), while the second group included patients with irAE Grade 3 or higher (referred to as irAE Grade over 3). Statistical analysis revealed significant differences in age (p=0.027) and CRP (C-reactive protein) levels (p=0.008) among the background factors when comparing the two groups. Additionally, statistically significant differences were observed among different ICI treatment groups in the occurrence of irAEs (p=0.035). however, it was indicated to be a relatively weak correlation. Moving forward, we shifted our focus to examine the frequency of irAEs in relation to exposure. However, we did not observe any significant correlation between exposure and irAE grade. Additionally, even when exposure was doubled through the use of ipilimumab in combination with ICIs (referred to as "Mod exposure"), no correlation was found. Exposure was further categorized into three groups: the PD-1 group, PD-L1 group, and PD-1 + CTLA-4 group. However, no significant correlation was observed between exposure in any of these groups and the grade of irAEs. Similarly, no significant correlation was observed between the dosage of ICI in the fixed-dose group and the weight-based dosage group with exposure and irAE Grade. Based on our study findings, there is a suggestive relationship between age and CRP levels and the occurrence of irAEs of Grade 3 or higher. These factors may play a role in contributing to the development of more severe irAEs.

PMID:39152557 | DOI:10.1691/ph.2024.4548

Int J Antimicrob Agents. 2024 Aug 14:107301. doi: 10.1016/j.ijantimicag.2024.107301. Online ahead of print.

ABSTRACT

BACKGROUND: Tenofovir containing antiretroviral therapy regimens may bring long-term toxicity-related side effects. We aimed to assess the virological efficacy of co-formulated darunavir-ritonavir plus lamivudine compared to darunavir-ritonavir plus tenofovir and emtricitabine or lamivudine.

METHODS: The ANDES study was a 48-week, phase 4, randomized, open-label, non-inferiority trial in naïve adults living with HIV. Patients were randomized 1:1 to receive a daily oral regimen of either dual therapy based on a generic co-formulation of darunavir-ritonavir (800/100 mg) plus a generic lamivudine 300 mg pill, or triple therapy with darunavir-ritonavir plus tenofovir/emtricitabine (300/200 mg) or tenofovir/lamivudine (300/300 mg). The primary endpoint was the proportion of patients with a viral load of less than 50 copies/mL at week 48 in the intention-to-treat population. We used the FDA snapshot algorithm and a non-inferiority margin of -12%. Secondary objectives included safety analysis in the per-protocol population. This study is registered at ClinicalTrials.gov, NCT02770508.

RESULTS: Between November 2015 to October 31, 2020, 336 participants were randomly assigned either to the triple therapy arm (165) or the dual therapy arm (171). After 48 weeks, 153 patients in the triple therapy group (93%) and 155 patients in the double therapy group (91%) achieved virological suppression (difference -2·1%, 95%CI -7·0 to 2·9). Drug-related adverse events were more common in the triple therapy group (p=0·04). Two toxicity-related events led to discontinuation in each group.

INTERPRETATION: Co -formulated darunavir/ ritonavir plus lamivudine has shown non-inferiority and a safer toxicity profile compared to a standard-of-care triple regimen including tenofovir in treatment-naïve patients.

PMID:39151647 | DOI:10.1016/j.ijantimicag.2024.107301

Am J Manag Care. 2024 Aug 1;30(8):e233-e239. doi: 10.37765/ajmc.2024.89592.

ABSTRACT

OBJECTIVES: To evaluate the FeelBetter machine learning system's ability to accurately identify older patients with multimorbidity at Brigham and Women's Hospital at highest risk of medication-associated emergency department (ED) visits and hospitalizations, and to assess the system's ability to provide accurate medication recommendations for these patients.

STUDY DESIGN: Retrospective cohort study.

METHODS: The system uses medications, demographics, diagnoses, laboratory results, health care utilization patterns, and costs to stratify patients' risk of ED visits and hospitalizations. Patients were assigned 1 of 22 risk levels based on their system-generated risk percentile of either ED visits or hospitalizations. Logistic regression models were used to estimate the odds of ED visits and hospitalizations associated with each successive risk level compared with the 45th to 50th percentiles. After stratification, 100 high-risk (95th-100th percentiles) and 100 medium-risk (45th-55th percentiles) patients were randomly selected for generation of medication recommendations. Two clinical pharmacists reviewed the system-generated medication recommendations for these patients.

RESULTS: Logistic regression models predicting 3-month utilization showed that compared with the 45th to 50th percentiles, patients in the top 1% risk percentile had ORs of 7.9 and 17.3 for ED visits and hospitalizations, respectively. The first 5 high-priority medications on each patient's medication list were associated with a mean (SD) of 6.65 (4.09) warnings. Of 1290 warnings reviewed, 1151 (89.2%) were assessed as correct.

CONCLUSIONS: The FeelBetter system effectively stratifies older patients with multimorbidity at risk of ED use and hospitalizations. Medication recommendations provided by the system are largely accurate and can potentially be beneficial for patient care.

PMID:39146480 | DOI:10.37765/ajmc.2024.89592

J Thorac Dis. 2024 Jul 30;16(7):4702-4710. doi: 10.21037/jtd-23-1851. Epub 2024 Jul 11.

ABSTRACT

BACKGROUND: The prognosis and first-line treatment response of patients with borderline resectable esophageal squamous cell carcinoma (ESCC) are unsatisfactory. We are conducting the borderline resectable esophageal squamous (BRES-1) study to evaluate the safety and efficacy of camrelizumab combined with chemotherapy in patients with borderline resectable ESCC.

METHODS: A total of 30 patients with borderline resectable ESCC will be enrolled in the BRES-1 study. These patients will undergo three stages of treatment: neoadjuvant therapy, surgery, and adjuvant therapy. Preoperative therapies will include camrelizumab, cisplatin, and nab-paclitaxel. Preoperative therapies will include camrelizumab, which will be given every 3 weeks for 6 weeks at a dose of 200 mg (baseline weight <50 kg, 3 mg/kg), nab-paclitaxel (130 mg/m2 on days 1 and 8 of one period with 21 days, a total of two cycles), and cisplatin (75 mg/m2 on day 1 of one period with 21 days, a total of two cycles). Patients will undergo esophagectomy 3-6 weeks after completing the neoadjuvant treatment. Three weeks after surgery, camrelizumab combined with chemotherapy will continue to be used for two cycles of maintenance therapy. Then, only camrelizumab will be administered for an entire year. The primary endpoint of this study will be pathological complete response (pCR).

DISCUSSION: The BRES-1 trial will evaluate the efficacy and safety of camrelizumab combined with chemotherapy for patients with borderline resectable ESCC. Translational research will explore perioperative complications and drug-related adverse events (AEs).

TRIAL REGISTRATION: ChiCTR, ChiCTR2200056728. Registered 11 February 2022. https://www.chictr.org.cn/index.aspx.

PMID:39144354 | PMC:PMC11320267 | DOI:10.21037/jtd-23-1851

Eur J Obstet Gynecol Reprod Biol. 2024 Aug 2;301:166-172. doi: 10.1016/j.ejogrb.2024.07.050. Online ahead of print.

ABSTRACT

OBJECTIVE: We hypothesized that combination therapy would provide a synergistic effect to improve treatment outcomes for overactive bladder (OAB), thus enhancing the motivation for continuous exercise, and that it would be associated with fewer adverse events than monotherapy. Therefore, we investigated whether biofeedback-assisted pelvic floor muscle training (PFMT), drug therapy, or a combination of both would be more effective in improving the symptoms of OAB.

STUDY DESIGN: This randomized controlled trial included women diagnosed with OAB. Group 1 received biofeedback-assisted pelvic muscle floor training (PFMT) for 12 weeks; group 2 took 5 mg of solifenacin/day for 12 weeks; and group 3 received 5 mg of solifenacin/day in combination with biofeedback-assisted PFMT during the first 4 weeks and biofeedback-assisted PFMT for another 8 weeks. All participants had 5 follow-up visits. The primary outcomes were objective improvement of OAB symptoms and quality of life. The secondary outcomes were treatment-related adverse events, subjective improvement of OAB symptoms, and electromyographic activity of pelvic floor muscle (PFM) contraction.

RESULTS: All participants reported significant improvement of OAB symptoms and quality of life. Participants in group 2 experienced more pronounced adverse events than those in group 3. Intervention duration was positively associated with subjective improvement in OAB symptoms in groups 2 and 3. Drug-related adverse events, including dry mouth, myalgia, and restlessness, had a negative impact on the subjective improvement of OAB symptoms in group 2. In group 1, exercise adherence was positively correlated with subjective improvement of OAB symptoms, whereas in group 3, PFM contraction and biofeedback effect were positively correlated with symptom improvement.

CONCLUSION: Combination therapy is efficacious in treating women with OAB.

PMID:39142059 | DOI:10.1016/j.ejogrb.2024.07.050

J Clin Endocrinol Metab. 2024 Aug 14:dgae560. doi: 10.1210/clinem/dgae560. Online ahead of print.

ABSTRACT

IMPORTANCE: Thyroid eye disease (TED) negatively impacts quality of life. TED occurs predominantly in Graves' disease (GD). Teprotumumab improves TED but concern for hearing adverse events (AEs) has emerged. Hearing dysfunction is reported in thyroid autoimmune disease but the background prevalence in GD/TED without teprotumumab remains uncertain.

OBJECTIVE: To quantify ear-related diagnostic codes/hearing AEs in GD, TED, and patients receiving teprotumumab by examining medical claims and clinical trials.

DESIGN AND PARTICIPANTS: Deidentified claims for ear/labyrinth-related ICD-10 codes (KOMODO®) were examined in GD patients without TED, and TED patients without/with teprotumumab treatment. Hearing AE incidence/severity was evaluated in teprotumumab clinical trials. Graves' Ophthalmopathy QOL (GO-QOL) scores were compared in teprotumumab TED trial patients without/with hearing AEs.

RESULTS: GD (469,720), TED (38,566) and teprotumumab-treated (967) patients were identified in the claims database. Ear-related codes (including those not specific for hearing) occurred in 24% GD, 33% TED, and 32% teprotumumab-treated patients. "Sensorineural hearing loss bilateral" was most frequent: 32,961/469,720 (7%) GD, 4,279/38,566 (11.1%) TED, and 104/967 (10.8%) teprotumumab patients. Pre-teprotumumab use,165 (17.1%) patients had ear-related codes while 98 (10.1%) had new ear-related codes post-treatment.Eight teprotumumab oncology trials revealed 8.1% (51/633) had Ear/Labyrinth Disorders with 2.1% (13) considered study-drug-related and 3.8% (24) hearing impairment/tinnitus-related AEs, with 1.3% (8) considered teprotumumab-related. Similar rates occurred in TED trials.GO-QOL improved in teprotumumab-treated patients without/with hearing AEs. Incidence/severity was consistent across patients with chronic and acute TED.

CONCLUSIONS: These analyses indicate similar occurrence of hearing claims in patients with GD/TED alone as following teprotumumab treatment. Future analyses of incremental hearing risk from teprotumumab should utilize a priori study designs accounting for background hearing dysfunction in patients with GD/TED.

PMID:39138817 | DOI:10.1210/clinem/dgae560

J Neural Transm (Vienna). 2024 Sep;131(9):1117-1134. doi: 10.1007/s00702-024-02818-7. Epub 2024 Aug 13.

ABSTRACT

Clozapine is a second-generation antipsychotic drug that offers superior treatment results in patients with schizophrenia but is also associated with significant risks. This study analyzes data on pharmacotherapy with clozapine and the associated adverse drug reactions (ADRs) in an inpatient setting including 38,349 patients. Data about the use of clozapine and reports of severe ADRs within the period 1993-2016 were obtained from the multicentered observational pharmacovigilance program "Arzneimittelsicherheit in der Psychiatrie" (AMSP). In total, 586 severe clozapine-associated ADRs were documented (1.53% of all patients exposed). Patients aged ≥65 years had a higher risk of ADRs than patients aged <65 years (1.96 vs. 1.48%; p = 0.021). Significantly more ADRs were attributed to clozapine alone (396; 67.6% of all 586 ADRs) than to a combination with other drugs. The most frequent ADRs were grand mal seizures (0.183% of all 38,349 patients exposed), delirium (0.180%), increased liver enzymes (0.120%), and agranulocytosis (0.107%). We detected 24 cases (0.063%) of clozapine-induced extrapyramidal symptoms, of which 8 (0.021%) were attributed to clozapine alone. Five ADRs resulted in death (0.013%): 2 due to agranulocytosis (41 cases total) (mortality = 4.88%) and 3 due to paralytic (sub)ileus (16 cases) (mortality = 18.75%). The median dose of clozapine in all patients treated was 300 mg/day, in patients who developed ADRs 250 mg/day. The main risk factor for an ADR was pre-existing damage of the affected organ system. Overall, the results of this study highlight the importance of alertness-especially of frequently overlooked symptoms-and appropriate monitoring during treatment with clozapine, even at low doses.

PMID:39136776 | DOI:10.1007/s00702-024-02818-7

BMC Pharmacol Toxicol. 2024 Aug 13;25(1):50. doi: 10.1186/s40360-024-00768-0.

ABSTRACT

This study reports a novel, eco-friendly; fast and cost-effective microwave method for synthesizing carboxymethylated graphene oxide (CMGO) from sugarcane residues. Fourier-transform infrared spectroscopy (FTIR) confirmed successful CMGO synthesis through the presence of characteristic peaks at 1567.93 and 1639.29 cm-1 (COONa vibrations) and increased CH2 intensity compared to unmodified graphene oxide (GO). Furthermore, CMGO derived from sugarcane residues demonstrated potential in mitigating the side effects of toxic materials like carbon tetrachloride (CCl4). Treatment with CMGO partially reduced elevated levels of liver enzymes (ALT and AST) and nitrogenous waste products (urea and uric acid) in CCl4-induced liver damage models, suggesting an improvement in liver function despite ongoing cellular damage.This work paves the way for a sustainable and economical approach to produce functionalized graphene oxide with promising biomedical applications in alleviating toxin-induced liver injury.

PMID:39138519 | DOI:10.1186/s40360-024-00768-0

Clin Cardiol. 2024 Aug;47(8):e24334. doi: 10.1002/clc.24334.

ABSTRACT

BACKGROUND: It remains controversial whether adding ezetimibe to low/moderate-intensity statins has a more beneficial impact on the treatment efficacy and safety of patients with existing atherosclerotic cardiovascular disease (ASCVD) compared to high-intensity statin regimens.

HYPOTHESIS: A combination of low/moderate-intensity statins plus ezetimibe might be more effective and safer than high-intensity statin monotherapy.

METHODS: We searched databases for randomized controlled trials comparing lipid profile alterations, drug-related adverse events, and MACE components between high-intensity statin monotherapy and low/moderate-intensity statin plus ezetimibe combination therapy. Pooled risk ratios (RR), mean differences (MD), and 95% confidence intervals (95% CI) were estimated using a random-effects model.

RESULTS: Our comprehensive search resulted in 32 studies comprising 6162 patients treated with monotherapy against 5880 patients on combination therapy. Combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels compared to monotherapy (MD = -6.6, 95% CI: -10.6 to -2.5); however, no significant differences were observed in other lipid parameters. Furthermore, the combination therapy group experienced a lower risk of myalgia (RR = 0.27, 95% CI: 0.13-0.57) and discontinuation due to adverse events (RR = 0.61, 95% CI: 0.51-0.74). The occurrence of MACE was similar between the two treatment groups.

CONCLUSIONS: Adding ezetimibe to low/moderate-intensity statins resulted in a greater reduction in LDL-C levels, a lower rate of myalgia, and less drug discontinuation compared to high-intensity statin monotherapy in patients with existing cardiovascular disease. However, according to our meta-analysis, the observed reduction in LDL-C levels in the combination group did not correlate with a reduction in MACE compared to the high-intensity statin group.

PMID:39135464 | DOI:10.1002/clc.24334

Intern Med. 2024 Aug 10. doi: 10.2169/internalmedicine.4105-24. Online ahead of print.

ABSTRACT

Hydroxycarbamide, an antimetabolic agent used to treat myeloproliferative disorders, causes side effects, including myelosuppression, skin ulcers, and oral mucositis. Gastrointestinal ulcers are uncommon, and esophageal ulcers have not been previously reported. We present the case of a 74-year-old woman who developed esophageal and ileal ulcers after hydroxycarbamide treatment. Our case and previous reports suggest that hydroxycarbamide can cause ulcers throughout the gastrointestinal tract, which can improve rapidly after discontinuing medication. When new signs and symptoms occur, drug-induced etiologies should be considered as a potential cause. Timely diagnostic treatment with discontinuation of medication is crucial in such cases.

PMID:39135249 | DOI:10.2169/internalmedicine.4105-24

Arch Dermatol Res. 2024 Aug 12;316(8):518. doi: 10.1007/s00403-024-03267-8.

ABSTRACT

Vitiligo, an autoimmune condition characterized by depigmented skin patches due to the loss of functional melanocytes, has been linked to dysregulation in the JAK-STAT signaling pathway, particularly in IFN-g signaling. The use of JAK inhibitors, such as ruxolitinib cream, a JAK1 and JAK2 inhibitor, presents a promising approach for vitiligo treatment. This study aims to systematically assess the effectiveness and safety of ruxolitinib cream in patients with vitiligo. We conducted a systematic review and meta-analysis following PRISMA guidelines to evaluate the efficacy and safety of ruxolitinib cream for the treatment of vitiligo. A comprehensive search of PubMed, Google Scholar, and Cochrane Library databases for randomized controlled trials (RCTs). Data selection, screening, extraction, and risk of bias assessment were meticulously performed. Statistical analysis was conducted using Review Manager Software, version 5.4, with significant heterogeneity addressed through appropriate methods. Our meta-analysis included 3 studies with 830 vitiligo patients. Significant improvements were observed in F-VASI, T-VASI, F-BSA, and T-BSA scores, with greater efficacy at 24 weeks compared to 12 weeks [MD -24.17, 95% CI (-31.78 to -16.56), P < 0.00001], [MD -14.12, 95% CI (-20.54 to -7.70); P < 0.0000], [MD -16.25, 95% CI (-22.20 to -10.31), P < 0.00001], [MD -9.19, 95% CI (-13.47 to -4.92); P < 0.00001]. Ruxolitinib showed increased risk ratios for F-VASI75, F-VASI90, and F-VASI50, indicating better outcomes with longer treatment durations [MD 2.9, 95% CI 1.88-4.49; P < 0.00001], [MD 4.66, 95% CI 2.09-10.39; P = 0.0002], [MD 2.53, 95% CI 1.84-3.46; P < 0.00001]. No significant differences were found in mild and moderate adverse events, while severe cases favored ruxolitinib. Placebo had a significant advantage in any adverse events, with no significant difference in drug-related adverse events. Serious adverse events did not significantly differ between groups. The findings strongly support the efficacy of ruxolitinib therapy in improving various parameters over time for treating vitiligo. However, thorough consideration of its safety profile, particularly concerning adverse events and potential side effects, is warranted. Further studies with larger sample sizes are needed to confirm these conclusions.

PMID:39134884 | DOI:10.1007/s00403-024-03267-8

Gastro Hep Adv. 2023 Dec 7;3(3):417-425. doi: 10.1016/j.gastha.2023.11.016. eCollection 2024.

ABSTRACT

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis is an advanced form of nonalcoholic fatty liver disease and a leading cause of end-stage liver disease and transplantation. Insulin resistance and inflammation underlie the pathogenesis of the disease.

METHODS: This double-blind, randomized, placebo-controlled, multicenter feasibility clinical trial aimed to determine the safety of oral 8 mg insulin in patients with metabolic dysfunction-associated steatohepatitis and type 2 diabetes mellitus. Patients were treated twice daily for 12 weeks with an 8 mg insulin (n = 21) or placebo (n = 11) capsule. Safety was monitored throughout the study. MRI-proton density fat fraction assessed liver fat content, and Fibroscan® measured liver fibrosis and steatosis levels at screening and after 12 weeks of treatment.

RESULTS: No severe drug-related adverse events were reported during the study. After 12 weeks of treatment, mean percent reductions in whole-liver (-11.2% vs -6.5%, respectively) and liver segment 3 (-11.7% vs +0.1%, respectively) fat content was higher in the insulin than in the placebo arm. Patients receiving insulin showed a median -1.2 kPa and -21.0 dB/m reduction from baseline fibrosis and steatosis levels, respectively, while placebo-treated patients showed median increases of 0.3 kPa and 13.0 dB/m, respectively. At Week 12, oral insulin was associated with a mean of 0.27% reduction and placebo with a 0.23% increase from baseline hemoglobin A1c levels. Mean percent changes from baseline alanine aminotransferase, and aspartate aminotransferase levels were -10% and -0.8%, respectively, in the oral insulin and 3.0% and 13.4%, in the placebo arm.

CONCLUSION: The results of this feasibility study support the safety and potential therapeutic effect of orally delivered insulin on liver fibrosis, fat accumulation, and inflammatory processes (NIH Clinical Trials No. NCT04618744).

PMID:39131144 | PMC:PMC11308786 | DOI:10.1016/j.gastha.2023.11.016

Middle East J Dig Dis. 2024 Apr;16(2):109-113. doi: 10.34172/mejdd.2024.377. Epub 2024 Apr 30.

ABSTRACT

BACKGROUND: Emergency use of remdesivir was approved for COVID-19 in some countries. Based on the promising results of remdesivir, the most common side effects were nausea, worsening respiratory failure, increased alanine aminotransferase levels, and constipation. The aim of this study was to determine the incidence of elevated liver enzymes in patients with COVID-19 receiving remdesivir.

METHODS: In this retrospective study, information was collected from patients' files. The study population included patients with moderate to severe COVID-19 who were admitted to Rouhani Babol Hospital. For daily patient selection, the list of patients was extracted from the system, and based on the census, the patient file was selected. Data were analyzed using Stata 16.

RESULTS: 620 patients suffering from moderate to severe COVID-19 were included in this study, 43% of whom were men. Of these patients, 120 were selected as the control group who did not receive remdesivir. The increase in liver enzymes in patients receiving remdesivir compared with the control, for alanine transaminase (ALT) and aspartate transaminase (AST), respectively, was 6.20 and 3.64 times, but it was not statistically significant for alkaline phosphatase (ALP). Also, the increase in bilirubin levels in patients receiving remdesivir was not statistically significant.

CONCLUSION: The recipients of remdesivir had high liver enzymes, which is one of the possible side effects of this drug. The intensity of the enzymes was mild and moderate, and they were not dangerous to the health of any of the consumers. Deaths in patients with COVID-19 were not due to drug-induced liver complications but to other factors such as disease-related complications.

PMID:39131106 | PMC:PMC11316192 | DOI:10.34172/mejdd.2024.377

Future Oncol. 2024 Aug 12:1-19. doi: 10.1080/14796694.2024.2373680. Online ahead of print.

ABSTRACT

Aim: Vascular endothelial growth factor receptor inhibitors (VEGFRIs) have been common used for recurrent ovarian cancer (ROC), but insufficient high-level evidence on verifying its efficacy and safety. Methods: Randomized controlled trials (RCTs) were searched under eight electronic databases. Stata 14.0 and Review Manager 5.3 were used for data analysis. Certainty of the evidence was assessed using the GRADE profiler. This systematic review (SR) was registered under INPLASY (INPLASY202120019). Conclusion: Totally 23 RCTs involving 2810 patients were included in this SR. Current evidence revealed that VEGFRIs had better efficacy, survival and quality of life in the treatment of ROC. Though VEGFRIs increase some drug-related adverse events (AEs), all the AEs could be manageable in the clinical practice.

PMID:39129672 | DOI:10.1080/14796694.2024.2373680

Expert Opin Drug Saf. 2024 Aug 12. doi: 10.1080/14740338.2024.2386374. Online ahead of print.

ABSTRACT

BACKGROUND: This study aimed to investigate the association between phosphodiesterase-5 inhibitors (PDE-5i) and hearing impairment adverse events (HIAEs) while providing an overview of the characteristics of drug-related HIAEs.

RESEARCH DESIGN AND METHODS: We conducted a detailed pharmacovigilance analysis using data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, covering 2004 to 2022. By calculating the reporting odds ratio (ROR) and the information component (IC), we identified signals that indicate the association between PDE-5i use and HIAEs.

RESULTS: Among the 191,398 reports related to PDE-5i, we identified 2,608 cases of HIAEs. Signals were observed for both PDE-5i monotherapy and polytherapy, indicating combinations of drugs. Avanafil exhibited the strongest signal (ROR: 4.35, 95% CI: 2.56-7.41, IC: 2.09, 95% CI: 0.10-3.51), while vardenafil showed the weakest signal (ROR: 2.69, 95% CI: 2.21-3.28, IC: 1.14, 95% CI: 0.74-2.04). Sildenafil had the highest reported cases (ROR: 3.03, 95% CI: 2.82-3.24, IC: 1.57, 95% CI: 1.34-1.80).

CONCLUSION: These findings highlight a significant correlation between PDE-5i use and HIAEs, emphasizing the need for careful evaluation in clinical practice and providing appropriate guidance to patients before initiating treatment.

PMID:39129501 | DOI:10.1080/14740338.2024.2386374

Expert Rev Clin Pharmacol. 2024 Aug 12. doi: 10.1080/17512433.2024.2390927. Online ahead of print.

ABSTRACT

INTRODUCTION: Assessment of drug-related adverse events is essential to fully understand the benefit-risk balance of any drug exposure, weighing efficacy versus safety. This is needed for both drug labeling and clinical decision making. Assessment is based on seriousness, severity and causality, be it more difficult to apply in neonates. Adverse event detection or prevention in the neonatal clinical setting is also more complicated because of polypharmacy, and off-label or unlicensed pharmacotherapy.

AREAS COVERED: Tools became available to assess severity and causality of adverse events in neonates recruited in clinical trials. The first version of the Neonatal Adverse Event severity score (NAESS) reduced the inter-observer variability. Causality tools like the Naranjo score were also tailored to neonates. These tools are also instrumental to support proactive pharmacovigilance in clinical care, while multidisciplinary care teams and computerized pharmacovigilance using advanced data analysis, like machine learning are emerging approaches to develop effective decision strategies.

EXPERT OPINION: All stakeholders involved in development of medicines or its clinical use should be aware of the limitations of the currently available assessment tools. Extension and optimization of these tools, advanced data analysis approaches, and capturing the variability in time-dependent physiology are warranted to improve pharmacovigilance in neonates.

PMID:39129478 | DOI:10.1080/17512433.2024.2390927

Sleep Med. 2024 Aug 7;122:64-70. doi: 10.1016/j.sleep.2024.07.036. Online ahead of print.

ABSTRACT

OBJECTIVE/BACKGROUND: The short-term efficacy and safety of daridorexant, a dual orexin receptor antagonist, has been demonstrated in Japanese patients with insomnia disorder. The objective of this study was to evaluate, in a non-overlapping patient population to the short-term study, the long-term safety and efficacy of daridorexant in Japanese patients with insomnia disorder.

PATIENTS/METHODS: In this Phase 3 open-label study conducted in Japan, 154 patients with insomnia disorder were randomized to daridorexant 50 mg (n = 102) or 25 mg (n = 52) for 52 weeks. The primary objective was to assess the safety and tolerability of daridorexant for up to 1 year. Secondary exploratory objectives were to evaluate the long-term efficacy of daridorexant on subjective sleep parameters (total sleep time, latency to sleep onset and wake after sleep onset) and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire).

RESULTS: The incidence of treatment-emergent adverse events (TEAEs) was 74 % and 58 % in the 50 mg and 25 mg groups respectively. No serious drug-related TEAEs were reported. Both doses improved next-morning sleepiness (Visual Analog Scale) throughout the study. Five adjudicated adverse events of special interest were reported; excessive daytime sleepiness (n = 1, 25 mg; n = 2, 50 mg), sleep paralysis (n = 1, 50 mg) and nightmare (n = 1, 25 mg). Improvements in sleep and daytime functioning were maintained from Week 2 (first assessment) through to Week 52 in both dose groups.

CONCLUSIONS: Up to 52-weeks, daridorexant was well tolerated with sustained improvement in sleep onset, sleep maintenance and daytime functioning, supporting its long-term use in Japanese patients with insomnia disorder.

PMID:39128336 | DOI:10.1016/j.sleep.2024.07.036