Patient Tolerance Research Articles

Localized Sustained Release of Copper Enhances Antitumor Effects of Disulfiram in Head and Neck Cancer.

Drug repurposing uses approved drugs as candidate anticancer therapeutics, harnesses previous research and development efforts, and benefits from available clinically suitable formulations and evidence of patient tolerability. In this work, the drug used clinically to treat chronic alcoholism, disulfiram (DSF), was studied for its antitumor efficacy in a copper-dependent manner. The combination of DSF and copper could achieve a tumor cell growth inhibition effect comparable to those of 5-fluorouracil and taxol on head and neck cancer cells. Both bulk dendrimer hydrogel and microsized dendrimer hydrogel particles were utilized for the localized sustained release of copper in the tumor site. The localized sustained release of copper facilitated the tumor inhibition effect following intratumoral injection in a mouse's head and neck cancer model.

Prevalence of Impaired Glucose Tolerance in Nonpregnant Polycystic Ovarian Syndrome Patients in a Hospital

Prevalence of Impaired Glucose Tolerance in Nonpregnant Polycystic Ovarian Syndrome Patients in a Hospital

Effect of benign prostatic hyperplasia surgery on ejaculatory function

Introduction. There are a wide range of techniques available for the removal of hyperplastic prostate tissue. However, the choice of method rarely considers its effect on ejaculatory function.Objectives. To evaluate the effect of surgery for benign prostatic hyperplasia (BPH) by endovideosurgical posterior adenomectomy (EVS AE) and transurethral electroenucleation of the prostate (TUEB) on copulatory function and its ejaculatory component.Materials & methods. Sixty sexually active patients aged 58 to 78 years with indications for surgical treatment of BPH were included in the study. The patients were randomized into two equal groups. The first group (30 patients) underwent EVS AE by standard technique without preservation of the prostatic urethra. The second group (30 patients) underwent TUEB. Before treatment, standard questionnaires used in urologic practice were completed: IIEF-5, IPSS-QOL, and the scale of quantitative assessment of male copulatory function (scale “MCF”). The block of questions specifically characterizing the ejaculatory component and the "Male Sexual Health Questionnaire", namely the section " Ejaculatory function domain", were analyzed separately. The assessment was conducted before treatment and at the 12th week following surgery. No significant differences were found between the groups on any of the questionnaires prior to surgery.Results. Three months following surgery, there was a significant improvement in the IPSS-QOL scores for the EVS AE group, by 24 points and 4.3, respectively, and for the TUEB group, 25.6 points and 4.3 (both p < 0.0001). No change was observed in the IIEF-5 questionnaire (p > 0.05). A slight reduction in scores was noted on the MCF scale for the TUEB group (by 2.9 points, p < 0.05), indicating that the general state of erectile function remained unchanged. However, reductions were seen in the "MCF — Ejaculatory Component" and "Male Sexual Health Questionnaire — Ejaculatory function domain" scales for the TUEB group, with ballpark scores decreasing by 3.2 and 6.8 points, respectively (both p = 0.0326 and p = 0.0254), indicating a worsening in ejaculatory function following TUEB treatment.Conclusion. When selecting a specific surgical approach for BPH management, consideration should be given to the patient's tolerance for the degree of invasiveness of the procedure while preserving ejaculatory function, and adherence to a treatment strategy that aligns with the patient's individual preferences and expectations.

Dexmedetomidine versus ketamine in improving tolerance to noninvasive ventilation after blunt chest trauma: A randomized, double-blinded, placebo-controlled trial

Abstract Background and Aims: Even though patient tolerance is critical to the success of noninvasive ventilation (NIV), research on using sedation to improve tolerance to NIV after traumatic chest injuries is limited. We hypothesized that dexmedetomidine would be superior to ketamine in terms of patient tolerance and lengthening the NIV sessions after blunt chest trauma. Material and Methods: This randomized, double-blinded, placebo-controlled trial included 45 patients of both genders aged 18–60 who needed NIV after blunt chest trauma. The patients were randomly assigned to one of three groups (n = 15) for receiving dexmedetomidine, ketamine, or placebo (0.9% sodium chloride solution) infusion to maintain a Richmond Agitation Sedation Scale (RASS) score between 0 and − 3 during two successive NIV sessions. Patients were evaluated for the duration of the NIV sessions, RASS, Visual Analog Scale (VAS), and the total amount of rescue analgesia consumed. Results: The mean duration of the NIV sessions was significantly longer in patients who received dexmedetomidine (P < 0.001) or ketamine (P < 0.001) compared to placebo. However, the NIV durations did not differ significantly between the dexmedetomidine and ketamine groups (P > 0.05). The dexmedetomidine group had a significantly lower RASS score compared to the ketamine (P < 0.001) and placebo (P < 0.001) groups, whereas the ketamine group had a significantly lower VAS compared to the dexmedetomidine (P = 0.005) and placebo (P = 0.022) groups and required significantly less total morphine (P = 0.001) compared to the other groups. Conclusion: The duration of the NIV sessions for patients with blunt chest trauma did not differ significantly between the dexmedetomidine and ketamine groups.

Low-dose lenvatinib and anti-programmed cell death protein-1 combination therapy in patients with heavily pre-treated recurrent ovarian and endometrial cancer: a pilot study

ObjectiveTreatment options for heavily pre-treated recurrent ovarian and endometrial cancer are limited. Lenvatinib plus anti-programmed cell death protein-1 (PD-1) combination therapy has been efficacious in advanced endometrial cancer, but at...

Body weight loss is a simple and useful indicator of prognosis and predictive tolerability in the first year of nintedanib therapy in patients with interstitial lung disease

BackgroundNintedanib is generally safe and well tolerated and can improve prognosis in patients with various interstitial lung diseases (ILDs). Appropriate management of adverse events of nintedanib is important to ensure its long-term persistent use. Weight loss is a routinely assessed adverse event in clinical practice. This study aimed to elucidate whether body weight change in the first year of nintedanib therapy can indicate prognosis and predict tolerability in patients with ILD. MethodsWe analysed 245 consecutive ILD patients treated with nintedanib. We calculated the slope of body weight change using baseline weight and that recorded closest after the first year and then categorized percent change in body weight at this time. Significant weight loss was defined as that ≥5%. ResultsSubjects included 67 patients with idiopathic pulmonary fibrosis (IPF) and 76 with non-IPF progressive fibrosing-ILD including fibrotic hypersensitivity pneumonitis (n = 16), unclassifiable (n = 35), connective tissue disease-ILD (n = 21), and nonspecific interstitial pneumonia (n = 4). Older age, low body weight at initial examination, significant weight loss, and lower %FVC were significant predictors of discontinuation of nintedanib. Patients with weight loss ≥5% over the first year showed worse survival than those with weight loss <5% regardless of whether IPF existed or BMI indicated obesity. ConclusionsCareful monitoring of body weight change might suggest useful information for predicting long-term use of nintedanib and mortality risk in ILD patients treated with nintedanib. Appropriate body weight management is needed to prevent adverse events of nintedanib itself.

OA26 Paired bulk and single cell analysis of transitional B cells in systemic sclerosis highlights defective peripheral tolerance

Abstract Background/Aims Transitional B cells comprise a distinct population of B cells that have recently migrated to the periphery from the bone marrow. In systemic sclerosis (SSc), there are differences in the number and function of transitional B cells compared with healthy controls (HCs). In addition, we have previously shown that transitional B cells evade peripheral tolerance from SSc patients who are seropositive for anti-topoisomerase I autoantibodies (ATA). To investigate mechanisms that underpin this defect, we performed a paired bulk and single-cell RNA sequencing study of transitional B cell subsets in treatment-naïve ATA-positive patients with diffuse cutaneous SSc (dcSSc) and HCs. Methods CD19+CD24hiCD38hi transitional B cells (5000) were sorted from four HCs and four treatment-naïve ATA-positive dcSSc patients. Single-cell RNA-sequencing was performed on the sorted B cells and the data was analysed using Seurat in RStudio. Paired bulk RNA-sequencing of the sorted transitional T1 (CD19+CD24hiCD38hi CD27-IgMhiIgDmed) and T2 (CD19+CD24hiCD38hiCD27-IgMhiIgDhi) subsets was undertaken in a subset of this cohort. Results From the sorted CD19+CD24hiCD38hi lymphocytes single cell transcriptomics identified six B cell clusters in SSc patients and HCs with differential expression of key genes such as CD19 and TCL1A. This included a cluster of marginal zone precursor cells expressing PLD4 and MZB1 which is expanded in SSc. We also identified an interesting memory-like B cell cluster which was diminished in the SSc group and expresses genes such as TNFRSF13B (BAFF), AICDA (AID) and S100A10. In the HCs, this cluster also expresses genes such as CD27 and IGHA1 which are absent in SSc indicating that B cell development is impaired in the disease. Subsequent pathway analyses provided evidence for the molecular bases of defective tolerance in SSc patients. This appears to be related to dysregulated NF-κB signalling and aberrant extrafollicular B cell development as evidenced through pseudotime trajectory analysis. Differential gene expression analyses using bulk RNA-sequencing of sorted T1 and T2 transitional B cells further identified five candidate gene signatures such as MYC-targets and DNA repair which are significantly enriched in the T2 subset. This latter finding is in congruence with the single cell data and provides further evidence to support the existence of a peripheral tolerance/selection checkpoint at the transitional B cell stage. Conclusion We have identified four transitional B cell subsets and have characterised their transcriptomic profile in SSc. Additionally, we provide new evidence for a potential breach in peripheral tolerance of SSc patients. Further studies are underway to identify key pathways that underpin B cell dysregulation in SSc and explore the relevance of such findings for better targeted therapies. Disclosure C. Beesley: Grants/research support; C.B. is supported through Versus Arthritis (grant number 558800). N. Goldman: None. D. Abraham: None. C. Denton: None. R. Mageed: None. V.H. Ong: None.

Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers

The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1–6. Despite advances in treatment with immune checkpoint inhibitors7–10, there is an unmet need in the treatment of MSI cancers11–14. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells. Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours.

Transcutaneous electric nerve stimulation of acupuncture points improves tolerance in adults undergoing diagnostic upper gastrointestinal endoscopy: a single-center, double-blinded, randomized controlled trial.

Oesophagogastroduodenoscopy (OGDS) is the most common diagnostic procedure for upper gastrointestinal diseases. It often causes discomfort and anxiety, which are only mitigated by systemic sedation. However, sedation poses additional risks of adverse cardiopulmonary events, increased medical costs, and prolonged recovery. Transcutaneous electrical nerve stimulation of acupuncture points (Acu-TENS) is a non-invasive and innovative approach that induces analgesic effect during endoscopy. This trial is the first to be reported in English that explores the potential of Acu-TENS to increase patient tolerance during non-sedated elective diagnostic OGDS. A double-blinded randomized controlled trial involving 348 subjects was conducted at a tertiary hospital to evaluate the success rate of OGDS with Acu-TENS. Subjects aged 18-75years scheduled for their first elective diagnostic OGDS were randomized into the intervention (Acu-TENS) and placebo arms. OGDS success was assessed based on subjects' satisfaction ratings on a Likert scale and procedure's technical adequacy. Secondary measures included subjects' willingness to undergo future OGDS under similar conditions, procedure duration, and the endoscopist's perceived ease of the procedure. OGDS success rates were significantly higher with Acu-TENS (77.8%) than with the placebo (68.0%; odds ratio [OR] 1.64, 95% confidence interval [CI] 1.01-2.66, p = 0.043). Subjects who received Acu-TENS expressed higher willingness for future OGDS (78.9%) than those who received the placebo (68.6%; OR 1.71, 95% CI 1.04-2.79, p = 0.031). Procedure duration were significantly shorter in the intervention arm (6.0min) than in the placebo arm (10.0min; p = 0.002). No adverse effects were reported, and endoscopists perceived similar procedure ease in both arms. Acu-TENS improved OGDS success and enhanced patients' experiences during non-sedated OGDS. It demonstrated safety with no side effects and reduced the procedure completion time. It could be used as an adjunct in non-sedated diagnostic OGDS.

Final phase 1 substudy results of ivosidenib for patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome

AbstractIvosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor with efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in frontline and relapsed/refractory (R/R) mIDH1 acute myeloid leukemia. We report final data from a phase 1 single-arm substudy of once-daily ivosidenib in patients with R/R mIDH1 myelodysplastic syndrome (MDS) after failure of standard-of-care therapies. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy end point was the complete remission (CR) + partial remission (PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in 8 (42.1%) patients, including a grade 1 QT interval prolongation in 1 (5.3%) patient and grade 2 differentiation syndrome in 2 (10.5%) patients. Rates of CR + PR and objective response (CR + PR + marrow CR) were 38.9% (95% confidence interval [CI], 17.3-64.3) and 83.3% (95% CI, 58.6-96.4), respectively. Kaplan-Meier estimates showed a 68.6% probability of patients in CR achieving a remission duration of ≥5 years, and a median overall survival of 35.7 months. Of note, 71.4% and 75.0% baseline red blood cell (RBC)- and platelet-transfusion-dependent patients, respectively, became transfusion independent (TI; no transfusion for ≥56 days); 81.8% and 100% of baseline RBC and platelet TI patients, respectively, remained TI. One (5.3%) patient proceeded to a hematopoietic stem cell transplant. In conclusion, ivosidenib is clinically active, with durable remissions and a manageable safety profile observed in these patients. This trial was registered at www.ClinicalTrials.gov as #NCT02074839.

Meta-analysis: Persistence of advanced therapies in the treatment of inflammatory bowel disease.

The expanding options in advanced therapies for ulcerative colitis (UC) and Crohn's disease (CD) present challenges in treatment selection. Persistence analysis assesses drug durability in real-world settings, acting as a surrogate marker for medication efficacy and tolerance. Unlike traditional comparative studies, persistence analysis provides insights extending beyond the initial year of treatment. To provide real-world evidence on treatment effectiveness, tolerability and preferences of physicians and patients regarding various advanced therapies for IBD. We conducted a systematic review of observational studies up to March 2023 assessing advanced therapies' persistence in UC and CD. Advanced therapies under examination included infliximab, adalimumab, vedolizumab, ustekinumab, golimumab, certolizumab and tofacitinib. We pooled the persistence of each agent and conducted a meta-analysis to compare the persistence of newer agents with traditional TNF inhibitors (TNFi)-specifically infliximab and adalimumab. Among 63 observational studies, vedolizumab had the highest 1-year persistence in UC (73.8%, 95% CI: 70.0%-77.6%) and ustekinumab in CD (77.5%, 95% CI: 72.9%-82.1%). Compared to TNFi, vedolizumab demonstrated increased persistence with a relative risk (RR) of 1.30 (95% CI: 1.19-1.41) for UC and 1.14 (95% CI: 1.09-1.20) for CD at 1 year, while ustekinumab demonstrated a RR of 1.15 (95% CI: 1.07-1.23) for CD at 1 year. Vedolizumab exhibited sustained increased persistence in UC over 2 years compared to TNFi (RR: 1.33, 95% CI 1.14-1.54). This meta-analysis highlights the superior persistence of ustekinumab and vedolizumab over TNFi, and offers valuable insights for clinicians navigating the challenging landscape of UC and CD therapeutic choices.

1206 Combination of Nasal Steroid and Nasal Oxymetazoline: A Way to Improve PAP Tolerance in OSA Patients with Rhinitis

1206 Combination of Nasal Steroid and Nasal Oxymetazoline: A Way to Improve PAP Tolerance in OSA Patients with Rhinitis

A phase IV study to evaluate the safety of fruquintinib in Chinese patients in real-world clinical practice.

Fruquintinib is approved in China for patients with metastatic colorectal cancer (CRC) who progressed after 2 lines of chemotherapy. This postmarketing study was conducted to evaluate the safety of fruquintinib in the Chinese population, including previously treated patients with advanced CRC and other solid tumors. Patients in the first cycle of fruquintinib or expected to start fruquintinib within a week were enrolled. Fruquintinib was administrated according to the label or per physicians' discretion. Patient characteristics and safety information were collected at baseline, 1 month, and 6 months after consent (or 30 days after the last dose). Overall, 3005 patients enrolled between April 24, 2019 and September 27, 2022. All enrolled patients received at least one dose of fruquintinib. Most patients had metastases at baseline. The median age was 60 years. More than half (64.0%) of the patients started fruquintinib at 5 mg, and the median treatment exposure was 2.7 months. Nearly one-third (32.5%) of patients with CRC received fruquintinib with concomitant antineoplastic agents. Treatment-emergent adverse events (TEAEs) leading to dose modification were reported in 626 (20.8%) patients, and 469 (15.6%) patients experienced TEAEs leading to treatment discontinuation. The most common grade ≥ 3 TEAEs were hypertension (6.6%), palmar-plantar erythrodysesthesia syndrome (2.2%), and platelet count decreased (1.0%). Combination therapy did not lead to excessive toxicities. The safety profile of fruquintinib in the real world was generally consistent with that in clinical studies, and the incidence of TEAEs was numerically lower than known VEGF/VEGFR inhibitor-related AEs. Fruquintinib exhibited manageable safety and tolerability in Chinese patients in the real-world setting.

Comparing the Risk of Infusion-Related Reactions and Tolerability in Patients Given Cetirizine or Diphenhydramine Prior to Ocrelizumab Infusion (PRECEPT).

Background: Ocrelizumab is an effective medication for multiple sclerosis. However, infusion-related reactions (IRRs) are a concern for patients and may lead to discontinuation of ocrelizumab. To minimize IRRs, pre-medications are administered. However, from our experience, these medications, especially diphenhydramine, can cause marked drowsiness. The primary objective of this study was to evaluate whether cetirizine is non-inferior to diphenhydramine in limiting the proportion and severity of reactions from ocrelizumab infusions. Methods: Twenty participants were serially randomized in a 1:1 ratio to receive 10 mg of cetirizine or 25 mg of diphenhydramine orally prior to their first three ocrelizumab infusions. Results: The rate of IRRs in this study was similar across both treatment groups with no increase in the risk of severity, and no grade 3 IRRs. Further, patients receiving cetirizine experienced a reduction in fatigue. While there was not a significant difference in global satisfaction, this score increased over time in the cetirizine arm while it remained unchanged in the diphenhydramine arm. Conclusions: Overall, our results suggest that cetirizine does not increase the risk of infusion-related reactions compared to diphenhydramine.

Immunotherapy utilization patterns in patients with advanced cancer and autoimmune disease.

Immunotherapy has been shown to improve cancer survival, but there are no consensus guidelines to inform use in patients with both cancer and autoimmune disease (AD). We sought to examine immunotherapy utilization patterns between cancer patients with and without AD. This retrospective cohort study utilized data from a de-identified nationwide oncology database. Patients diagnosed with advanced melanoma, non-small cell lung cancer, and renal cell carcinoma were included. Outcomes of interest included first-line immunotherapy, overall immunotherapy, and number of immunotherapy cycles. We used logistic and Poisson regression models to examine associations between AD and immunotherapy utilization patterns. A total of 25,076 patients were included (796 with AD). Patients with AD were more likely to be female, White, receive care at academic centers, and have ECOG ≥ 3. Controlling for demographic and clinical variables, AD was associated with lower odds of receiving first-line (odds ratio [OR] = 0.68, 95% confidence interval [CI] 0.56-0.82) and overall (OR = 0.80, 95% CI 0.67-0.94) immunotherapy. Among patients who received at least one cycle of immunotherapy, there was no difference in mean number of cycles received between patients with and without AD (11.3 and 10.5 cycles respectively). The incident rate of immunotherapy cycles received for patients with AD was 1.03 times that of patients without AD (95% CI 1.01-1.06). Patients with AD were less likely to receive immunotherapy as first-line and overall therapy for treatment of their advanced cancer. However, among those who did receive at least one cycle of immunotherapy, patients with AD received a similar number of cycles compared to patients without AD. This not only indicates that AD is not an absolute contraindication for immunotherapy in clinical practice but may also demonstrate overall treatment tolerability and net benefit in patients with AD.

Lenvatinib‑based treatment regimens in conversion therapy of unresectable hepatocellular carcinoma: A systematic review and meta‑analysis.

Hepatocellular carcinoma (HCC) is a malignancy associated with high morbidity and mortality rates. Conversion therapy provides patients with unresectable HCC (uHCC) the opportunity to undergo radical treatment and achieve long-term survival. Despite accumulating evidence regarding the efficacy of conversion therapy, the optimal treatment approach for such therapy remains uncertain. Lenvatinib (LEN) has shown efficacy and tolerable rates of adverse events (AEs) when applied in combination with immune checkpoint inhibitors (ICIs) or locoregional therapy (LRT) over the past decade. Therefore, the present meta-analysis was performed to systematically assess the safety and efficacy of LEN-based treatment regimens in conversion therapies for uHCC. Data on outcomes, including the conversion rate, objective response rate (ORR), disease control rate (DCR) and AE incidence in patients with uHCC, were collected. A systematic literature search was performed using MEDLINE, Embase, Web of Science and Cochrane Library databases, up to the date of September 1, 2023. In total, 16 studies, encompassing a total of 1,650 cases of uHCC, were included in the final meta-analysis. The pooled conversion rates for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were calculated to be 0.04 (95% CI, 0.00-0.07; I2=77%), 0.23 (95% CI, 0.16-0.30; I2=66%), 0.14 (95% CI, 0.10-0.18; I2=0%) and 0.35 (95% CI, 0.23-0.47; I2=88%), respectively. The pooled ORRs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were found to be 0.45 (95% CI, 0.23-0.67; I2=96%), 0.49 (95% CI, 0.39-0.60; I2=78%), 0.43 (95% CI, 0.24-0.62; I2=88%) and 0.69 (95% CI, 0.56-0.82; I2=92%), respectively. The pooled DCRs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were observed to be 0.77 (95% CI, 0.73-0.81; I2=23%), 0.82 (95% CI, 0.69-0.95; I2=90%), 0.67 (95% CI, 0.39-0.94; I2=94%) and 0.87 (95% CI, 0.82-0.93; I2=67%), respectively. The pooled grade ≥3 AEs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were 0.25 (95% CI, 0.14-0.36; I2=89%), 0.43 (95% CI, 0.34-0.53; I2=23%), 0.42 (95% CI, 0.19-0.66; I2=81%) and 0.35 (95% CI, 0.17-0.54; I2=94%), respectively. These findings suggested that LEN-based combination strategies may confer efficacy and acceptable tolerability for patients with uHCC. In particular, LEN + ICI, with or without LRT, appears to represent a highly effective conversion regimen, with an acceptable conversion rate and well-characterized safety profile.

Next-Generation Anti-TNFα Agents: The Example of Ozoralizumab.

Biologic therapy involving anti-tumor necrosis factor-α (anti-TNFα) agents has fundamentally changed the management of patients with immune-mediated inflammatory diseases, including rheumatoid arthritis, thus benefiting many patients. Nevertheless, the inability of some patients to achieve low disease activity or clinical remission remains a major concern. To address such concerns, next-generation anti-TNFα agents that differ from the immunoglobulin G-format anti-TNFα agents that have been used to date are being developed using antibody-engineering technology. Their unique design employing novel molecular characteristics affords several advantages, such as early improvement of clinical symptoms, optimization of drug bioavailability, enhancement of tissue penetration, and a reduction in side effects. This holds promise for a new paradigm shift in biologic therapy via the use of next-generation anti-TNFα agents. Ozoralizumab, a next-generation anti-TNFα agent that was recently approved in Japan, comprises a variable region heavy-chain format. It has a completely different structure from conventional therapeutic antibodies, such as a small molecular size, an albumin-binding module, and a unique format that produces an avidity effect. Ozoralizumab exhibited rapid biodistribution into joints, provided attenuation of Fcγ receptor-mediated inflammatory responses, and had a high binding affinity to TNFα in non-clinical studies. In clinical trials, ozoralizumab yielded an early improvement in clinical symptoms, a sustained efficacy for up to 52 weeks, and an acceptable tolerability in patients with rheumatoid arthritis. This review focuses on the results of pre-clinical and clinical trials for ozoralizumab and outlines the progress in next-generation antibody development.

Does Mixing Activated Charcoal With Cola Improve Tolerability Without Affecting Pharmacokinetics? A Randomized Controlled Crossover Trial

IntroductionActivated charcoal is the most common form of gastrointestinal decontamination used for the poisoned patient. One limitation to its use is patient tolerability due to palatability. Some recommend mixing activated charcoal with cola to improve palatability. An important question is whether mixing activated charcoal with cola affects the ability of the activated charcoal to adsorb xenobiotic. MethodsThis was a prospective randomized controlled crossover trial. Five healthy adults aged 18 to 40 years were recruited. Participants received 45 mg/kg acetaminophen rounded down to the nearest whole tablet. One hour later, they were randomized to receive 50 g of an activated charcoal-water premixture alone or mixed with cola. Acetaminophen levels were collected. The area under the curve of acetaminophen concentrations over time was measured as a marker for degree of absorption. Participants also completed an appeal questionnaire in which they rated the activated charcoal preparations. Participants would then return after at least 7 days to repeat the study with the other activated charcoal preparation. ResultsFour male participants and 1 female participant were recruited. There was no statistical difference in preference score for activated charcoal alone versus the cola-activated charcoal mixture. There was no statistical difference in the area under the curve of acetaminophen concentrations over time between activated charcoal alone and the cola-activated charcoal mixture. Of note, the study is limited by the small sample size, limiting its statistical power. DiscussionThe absorption of acetaminophen in an overdose model is no different when participants received activated charcoal alone or a cola-activated charcoal mixture as suggested by area under the curve. In this small study, there was no difference in preference for activated charcoal alone or a cola-activated charcoal mixture across a range of palatability questions. On an individual level, some participants preferred the activated charcoal-cola mixture, and some preferred the activated charcoal alone.

Identification of potential therapeutic targets for breast cancer using Mendelian randomization analysis and drug target prediction.

Breast cancer stands as the foremost cause of cancer-related mortality among women, presenting a substantial economic impact on society. The limitations in current therapeutic options, coupled with poor patient tolerance, underscore the urgent need for novel treatments. Our study embarked on a genomic association exploration of breast cancer, leveraging whole-genome sequencing data from the Finngen database, complemented by expression quantitative trait loci (eQTL) insights from the eQTLGen and GTEx Consortiums. An initial investigation was conducted through summary-based Mendelian randomization (MR) to pinpoint primary eQTLs. Analysis of blood specimens revealed 103 eQTLs significantly correlated with breast cancer. Focusing our efforts, we identified 19 candidates with potential therapeutic significance. Further scrutiny via two-sample MR pinpointed UROD, LMO4, HORMAD1, and ZSWIM5 as promising targets for breast cancer therapy. Our research sheds light on new avenues for the treatment of breast cancer, highlighting the potential of genomic association studies in uncovering viable therapeutic targets.

Treatment of Atrophic Acne Scarring with Fractional Microplasma Radiofrequency: A Multicentric Experience

BackgroundAtrophic scarring is a severe form-disfiguring sequela of acne, which can lead to negative effect on patients’ life. Fractional microplasma radiofrequency (RF) has emerged as a promising modality, leveraging dermal fibroblast remodeling to enhance aesthetic results for scars and hyperpigmentation. This study evaluates the efficacy and safety of high-power fractional microplasma RF for atrophic acne scars, considering patient tolerance to procedural discomfort. MethodsIn this prospective study, 95 Chinese patients with atrophic facial acne scars underwent three sessions of fractional microplasma RF treatment, with assessments at 1, 3, and 6 months post-treatment. Patients were categorized based on treatment power: Group A (50-70 W) and Group B (70-85 W). Efficacy was determined by three independent dermatologists using digital photographs and Echelle d'Evaluation Clinique des Cicatrices d'Acné (ECCA) scores, and patient-reported outcomes gauged satisfaction levels. ResultsEighty-six patients completed the study. Significant improvements were observed, with a reduction in ECCA scores from 107.21 to 42.27 (P<0.05), demonstrating notable scar amelioration across both groups, albeit with a superior outcome in Group B. All patients experienced transient side effects such as pain, erythema, and edema, deemed tolerable with no long-term adverse effects reported. The treatment was well-received, with high satisfaction rates, underscoring its efficacy and acceptable safety profile. ConclusionFractional microplasma RF therapy, particularly at higher power settings, is an effective and safe option for treating atrophic acne scars, offering significant aesthetic improvement with manageable discomfort. This modality presents a valuable addition to acne scar management strategies, especially for patients with darker skin tones seeking minimal downtime and reduced risk of hyperpigmentation.