Clin Kidney J. 2024 Dec 3;18(1):sfae394. doi: 10.1093/ckj/sfae394. eCollection 2025 Jan.

ABSTRACT

BACKGROUND: Sparsentan, a dual-acting antagonist for both the angiotensin II receptor type 1 and the endothelin receptor type A, has emerged as a promising therapeutic agent for the treatment of IgA nephropathy (IgAN). Following the publication of the PROTECT trial, sparsentan recently received approval for the treatment of IgAN in Europe. However, it remains uncertain whether an additive effect can be observed in the context of existing treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors, given that the PROTECT study did not investigate this dual therapy approach.

METHODS: A total of 23 patients with IgAN were treated with sparsentan via the Managed Access Programme between December 2023 and August 2024. The patients were stable on maximum tolerated doses of renin-angiotensin system (RAS) and SGLT2 inhibitors, with an estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m² and a urine protein/creatinine ratio (UPCR) >0.75 g/g.

RESULTS: In the 23 patients, median (IQR) baseline eGFR (CKD-EPI) was 42 mL/min/1.73 m2 (32-63) and median baseline UPCR was 1.5 g/g (0.9-1.8). After initiation of sparsentan, UPCR significantly decreased (P < 0.0001) to a median of 0.85 g/g (0.42-1.15) in the 2-week follow-up and further declined (P = 0.001) to a median of 0.60 g/g (0.32-0.82) after 14 weeks, equivalent to a relative reduction in proteinuria up to 62% (45-74). A similar significant reduction was observed for the urine albumin/creatinine ratio. No drug-related serious adverse events were reported.

CONCLUSIONS: In this real-world setting, sparsentan shows a significant impact on proteinuria, leading to a relative reduction of 62% in UPCR after 14 weeks and beyond, even in patients already receiving SGLT2 inhibitors.

PMID:39872637 | PMC:PMC11770278 | DOI:10.1093/ckj/sfae394

Drug Ther Bull. 2025 Jan 27;63(2):18. doi: 10.1136/dtb.2025.000004.

NO ABSTRACT

PMID:39870392 | DOI:10.1136/dtb.2025.000004

Drug Ther Bull. 2025 Jan 27:dtb-2025-000002. doi: 10.1136/dtb.2025.000002. Online ahead of print.

NO ABSTRACT

PMID:39870391 | DOI:10.1136/dtb.2025.000002

Front Immunol. 2025 Jan 10;15:1496095. doi: 10.3389/fimmu.2024.1496095. eCollection 2024.

ABSTRACT

PURPOSE: The α-FAtE score, composed of alpha-fetoprotein, alkaline phosphatase, and eosinophil levels, has been reported as a predictor of prognosis in hepatocellular carcinoma (HCC) patients treated with atezolizumab plus bevacizumab. This study aimed to investigate the predictive ability of α-FAtE score for the efficacy and safety of locoregional immunotherapy as the treatment of HCC patients.

METHODS AND PATIENTS: We conducted a retrospective study of 446 HCC patients at Sun Yat-sen University Cancer Center from January 1st 2019 to January 1st 2023. The predictive performance was evaluated by the concordance index, the area under the receiver operating characteristics curve, the Kaplan-Meier curve and multiple Cox regression analysis.

RESULTS: 446 patients were divided into the α-FAtE 0-1 group (n=211) and α-FAtE 2-3 group (n=235). The median progression-free survival(PFS) of the α-FAtE 0-1 group and 2-3 group was 7.3 months (95%CI 6.6-8.7 months), and 12.3 months (95% CI 10.4-14.1 months; P<0.001), respectively. The median overall survival (OS) of the α-FAtE 0-1 group and 2-3 group was 16.3 months (95%CI 13.7-21.5 months) and 34.1 months (95% CI 27.6-NA months; P<0.001), respectively. HCC patients in the α-FAtE 2-3 group had higher complete response (CR) rate and experienced less drug-related adverse events than those in the α-FAtE 0-1 group. Moreover, a lower α-FAtE score was identified as an independent prognostic indicator for both OS and PFS of advanced HCC patients receiving locoregional immunotherapy.

CONCLUSION: The α-FAtE score is a superior predictor of prognosis in HCC patients receiving locoregional immunotherapy, offering a valuable tool for patient stratification and treatment planning.

PMID:39867887 | PMC:PMC11757168 | DOI:10.3389/fimmu.2024.1496095

Perspect Clin Res. 2025 Jan-Mar;16(1):31-37. doi: 10.4103/picr.picr_20_24. Epub 2024 Aug 7.

ABSTRACT

AIM: The study aimed to determine the incidence of adverse drug reactions (ADRs) among newly diagnosed tuberculosis (TB) patients receiving daily drug regimen with fixed-dose combination treatment under the National Tuberculosis Elimination Program.

MATERIALS AND METHODS: A community-based prospective cohort study was carried out in the Udupi district. Over 12 months, all newly diagnosed TB patients of either gender were included from 63 primary health centers and 6 community health centers, and ADRs were recorded by personal interviews.

RESULTS: A total of 710 patients were enrolled, among whom 453 (63.8%), were males, and 257 (36.2%) were females. Pulmonary TB was diagnosed among 510 (71.8%) and 200 (28.2%) were extrapulmonary cases. During the intensive phase (IP) of treatment, 480 (67.6%) patients reported at least one ADR and 79 (11.1%) experienced two ADRs during IP and 31 (6.5%) had ADRs during the continuation phase. Out of 480, 140 (29.2%) had gastritis, 132 (27.5%) had vomiting, 105 (21.9%) had nausea, 60 (12.5%) had skin rashes, 27 (5.6%) had drug-induced hepatitis, and 16 (3.3%) had vision problems. Among 480 patients with ADRs, 462 (96.3%) had successful treatment outcomes, the remaining 17 patients (3.5%) died, and one (0.2%) had treatment failure.

CONCLUSIONS: Adverse events were more common in the 1st few months of treatment than in subsequent months. All mild-to-moderate ADRs were effectively managed, and most had successful treatment outcomes.

PMID:39867528 | PMC:PMC11759235 | DOI:10.4103/picr.picr_20_24

BMJ Open. 2025 Jan 25;15(1):e086446. doi: 10.1136/bmjopen-2024-086446.

ABSTRACT

OBJECTIVES: To describe the prevalence of sub-optimal monitoring for selected higher-risk medicines in older community-dwelling adults and to evaluate patient characteristics and outcomes associated with sub-optimal monitoring.

STUDY DESIGN: Retrospective observational study (2011-2015) using historical general practice-based cohort data and linked dispensing data from a national pharmacy claims database.

SETTING: Irish primary care.

PARTICIPANTS: 625 community-dwelling adults aged ≥70 years and prescribed at least one higher-risk medicine during the 5-year study period.

PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the prevalence of sub-optimal laboratory monitoring using a composite measure of published medication monitoring indicators, with a focus on commonly prescribed higher-risk medicines such as diuretics and anticoagulants. Poisson regression was used to assess the patient characteristics associated with sub-optimal monitoring and explanatory variables included the number of medicines, age, sex, deprivation and anxiety/depression symptoms. Logistic regression was used to explore the association between baseline sub-optimal monitoring and the odds of adverse health outcomes (unplanned healthcare utilisation, adverse drug reactions and mortality).

RESULTS: Of 625 participants, the mean age was 77.7 years, 53% were female, the mean number of drugs was 7.3 (SD 3.3) and 499 (79.8%) had ≥1 unmonitored dispensing over 5 years. The number of drugs, deprivation and anxiety/depression symptoms were significantly associated with sub-optimal monitoring, with the strongest association seen for anxiety/depression symptoms (incidence rate ratio: 1.33, 95% CI 1.05 to 1.68). There was a small but significant association between baseline sub-optimal monitoring and emergency department visits at follow-up, but no evidence of an association with unplanned hospital admissions, mortality or adverse drug reactions.

CONCLUSION: The prevalence of sub-optimal medication monitoring was high, and number of drugs, deprivation and anxiety/depression symptoms were significantly associated with sub-optimal monitoring. However, the public health impact of these findings remains uncertain, as there was no clear evidence of an association between sub-optimal monitoring and adverse health outcomes. Further research is needed to evaluate the effect of improved monitoring strategies and the optimal timing for drug monitoring of higher risk medications.

PMID:39863414 | DOI:10.1136/bmjopen-2024-086446

J Clin Med. 2025 Jan 9;14(2):377. doi: 10.3390/jcm14020377.

ABSTRACT

Background: Rigid bronchoscopy (RB) is the gold standard for managing central airway obstruction (CAO), a life-threatening condition caused by both malignant and benign etiologies. Anesthetic management is challenging as it requires balancing deep sedation with maintaining spontaneous breathing to avoid airway collapse. There is no consensus on the optimal anesthetic approach, with options including general anesthesia with neuromuscular blockers or spontaneous assisted ventilation (SAV). Methods: This case series presents our anesthetic protocol using remifentanil-propofol-ketamine total intravenous anesthesia (TIVA) with SAV in four patients with airway obstructions. Muscle relaxants were avoided in all cases. Results: Ketamine's ability to preserve respiratory drive and airway reflexes, along with its bronchodilating properties, made it ideal for managing CAO. All procedures successfully restored airway patency without complications or drug-related side effects. Conclusions: Our findings suggest that remifentanil-propofol-ketamine TIVA combined with SAV is a viable anesthetic approach for therapeutic RB, offering effective sedation, maintaining airway patency, and minimizing perioperative complications.

PMID:39860383 | DOI:10.3390/jcm14020377

Molecules. 2025 Jan 10;30(2):260. doi: 10.3390/molecules30020260.

ABSTRACT

Drug development faces significant financial and time challenges, highlighting the need for more efficient strategies. This study evaluated the druggability of the entire human proteome using Fpocket. We identified 15,043 druggable pockets in 20,255 predicted protein structures, significantly expanding the estimated druggable proteome from 3000 to over 11,000 proteins. Notably, many druggable pockets were found in less studied proteins, suggesting untapped therapeutic opportunities. The results of a pairwise pocket similarity analysis identified 220,312 similar pocket pairs, with 3241 pairs across different protein families, indicating shared drug-binding potential. In addition, 62,077 significant matches were found between druggable pockets and 1872 known drug pockets, highlighting candidates for drug repositioning. We repositioned progesterone to ADGRD1 for pemphigus and breast cancer, as well as estradiol to ANO2 for shingles and medulloblastoma, which were validated via molecular docking. Off-target effects were analyzed to assess the safety of drugs such as axitinib, linking newly identified targets with known side effects. For axitinib, 127 new targets were identified, and 46 out of 48 documented side effects were linked to these targets. These findings demonstrate the utility of pocket similarity in drug repositioning, target expansion, and improved drug safety evaluation, offering new avenues for the discovery of new indications and side effects of existing drugs.

PMID:39860130 | DOI:10.3390/molecules30020260

Int J Mol Sci. 2025 Jan 13;26(2):622. doi: 10.3390/ijms26020622.

ABSTRACT

To enhance the treatment of tumors that are resistant to radio- and chemotherapy while minimizing the side effects of radiochemotherapy, researchers are continuously seeking new active compounds for use in combination with radiotherapy. Therefore, the aim of our study was to examine the cytotoxic and radiosensitizing effects of an extract from St. John's Wort (Hypericum perforatum), referred to as HP01, on human epithelial tumor cells in vitro. The growth of MCF-7 (breast carcinoma) and HT-29 (colon carcinoma) cells was examined under the influence of HP01. In combination with radiation, the effects of HP01 on cytotoxicity and long-term survival were assessed using a colony formation assay. The number of DNA double-strand breaks was analyzed using the γH2AX assay, while cell cycle distribution was examined via flow cytometry. A growth-inhibiting and cytotoxic effect was observed for both tumor cell lines starting at a concentration of 10 µg/mL HP01. Treatment with HP01 resulted in an inhibition of clonogenic survival of tumor cells after ionizing radiation (6 Gy). The number of DNA double-strand breaks (DSBs) in tumor cells increased with HP01 treatment, but the repair of radiation-induced DNA DSBs was not affected. Cell cycle analysis revealed that HP01, in addition to radiation, enhanced G2/M arrest in MCF-7 and HT-29 cells. Overall, HP01 not only showed a growth-inhibiting effect but also demonstrated a radiosensitizing effect on human tumor cells for the first time. We conclude that the HP01-induced G2/M accumulation of cells may be the main rationale for the drug-induced radiosensitivity. It is therefore a promising candidate for combined therapy in tumor diseases and warrants further investigation.

PMID:39859336 | DOI:10.3390/ijms26020622

Medicina (Kaunas). 2025 Jan 14;61(1):123. doi: 10.3390/medicina61010123.

ABSTRACT

Background and Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but their use is associated with a spectrum of immune-related adverse events (irAEs), including endocrine disorders. This study aims to investigate the incidence, timing, treatment modalities, and impact of ICI-related endocrine side effects in cancer patients. Materials and Methods: This retrospective study analyzed 139 cancer patients treated with ICIs between 2016 and 2022. Data regarding endocrine irAEs, including hypothyroidism, hyperthyroidism, hypophysitis, and diabetes mellitus, were collected. The study examined the timing of irAE onset, management approaches, and the association between irAEs and treatment outcomes. Results: The most common endocrine irAE was hypothyroidism (65.5%), followed by hyperthyroidism (2.3%), hypophysitis (8.6%), and diabetes mellitus (0.7%). These disorders typically emerged within the first six months of ICI therapy. Most cases were managed conservatively or with hormone replacement therapy. Patients who developed endocrine irAEs exhibited a higher objective response rate (ORR) and clinical benefit rate (CBR) compared to those without irAEs. Conclusions: Endocrine dysfunction is a significant toxicity of ICI therapy. Early recognition, prompt diagnosis, and appropriate management are crucial to minimize their impact on patient health and quality of life. This study highlights the potential association between irAEs and improved clinical outcomes. Further research is needed to elucidate the underlying mechanisms and identify predictive biomarkers for irAE development.

PMID:39859105 | DOI:10.3390/medicina61010123

Diagnostics (Basel). 2025 Jan 17;15(2):205. doi: 10.3390/diagnostics15020205.

ABSTRACT

Drug-induced gingival overgrowth is associated with various systemic diseases, including epilepsy. Among antiepileptic medications, phenytoin is commonly reported to cause this condition. In contrast, sodium valproate (VPA), another widely used antiepileptic drug, rarely induces gingival overgrowth. This difference in side effects highlights the variability in drug-induced oral complications among different antiepileptic medications. This case study presents a patient who developed significant gingival overgrowth after using VPA for over 10 years. The study aims to identify VPA as the causative agent and observe changes during long-term administration and after dose reduction. Our findings demonstrate that even long-standing gingival overgrowth can improve rapidly following discontinuation of the causative medication, providing valuable insights for managing similar cases in the future.

PMID:39857089 | DOI:10.3390/diagnostics15020205

BMC Cancer. 2025 Jan 24;25(1):139. doi: 10.1186/s12885-025-13566-6.

ABSTRACT

BACKGROUND: Patients who developed immune-related adverse events (irAEs) could benefit more from treatment with immune checkpoint inhibitors (ICIs) than those who did not develop irAEs. This study was designed to assess whether the occurrence of irAEs or their characteristics are correlated with survival in advanced patients treated with ICIs.

METHODS: This retrospective cohort study enrolled a panel of cancer patients who received ICIs at a single institute. Kaplan‒Meier curves were generated to describe progression-free survival (PFS) and overall survival (OS) in patients with irAEs or specific irAE characteristics.

RESULTS: A total of 238 patients were enrolled, 83 (34.9%) of whom developed at least one irAE. Overall, irAE development was associated with prolonged OS (not reached vs. 17.8 months, P < 0.001), PFS (8.7 vs. 4.8 months, P = 0.003), and an improved objective response rate (24.1% vs. 10.3%, P = 0.005). Furthermore, only skin or endocrine toxicities were associated with improved OS and PFS. On the basis of the results from organ-specific irAEs, the first development of skin or endocrine toxicities as protective irAEs rather than other irAEs was an independent indicator for predicting OS (P < 0.001) and PFS (P < 0.001). A protective irAE burden score based on organ-specific irAEs was further developed to show the significant protective effect of total irAEs on patient outcomes.

CONCLUSIONS: Not all irAEs are associated with prolonged survival. The identification of organ-specific irAEs is useful for stratifying patients who actually respond to and benefit from ICIs across different cancer types.

PMID:39856626 | DOI:10.1186/s12885-025-13566-6

J Invest Dermatol. 2025 Jan 21:S0022-202X(25)00034-X. doi: 10.1016/j.jid.2024.12.025. Online ahead of print.

ABSTRACT

TRIAL DESIGN: This two-part, double-blinded trial assessed the truncated retinoic acid-related orphan receptor γ (RORγt) inhibitor BI 730357 in plaque psoriasis.

METHODS: Part 1: patients were randomized 2:2:2:2:1 to BI 730357 25, 50, 100, 200 mg, or placebo once daily (qd; fasting conditions); non-responders switched to higher doses. Part 2: a separate patient set was randomized 4:4:1 to BI 730357 400 mg qd, 200 mg twice daily, or placebo (fed conditions). Patients from Parts 1 and 2 could enter a long-term extension (LTE) trial. Co-primary endpoints: ≥75% reduction from baseline in Psoriasis Area Severity Index (PASI 75) and static physician's global assessment (sPGA) score 0/1 (clear/almost clear) at week 12.

RESULTS: 274 patients were treated (178 [Part 1]; 96 [Part 2]). Part 1: 12 (30.0%) patients achieved PASI 75 (P=0.0062) and 11 (27.5%) achieved sPGA 0/1 (P=0.0095) with BI 730357 200 mg versus none receiving placebo. Exposure-response plateaued at BI 730357 ≥200 mg qd. Drug-related adverse events occurred in ≤15.8% of patients. Of 165 patients who entered the LTE, 93 (56.4%) achieved PASI 75 during treatment and ≤18.5% experienced a drug-related adverse event.

CONCLUSIONS: BI 730357 was well-tolerated with moderate efficacy versus placebo in plaque reduction.

PMID:39848568 | DOI:10.1016/j.jid.2024.12.025

Schmerz. 2025 Jan 23. doi: 10.1007/s00482-024-00857-3. Online ahead of print.

ABSTRACT

The spontaneous reporting system for cases of suspected side effects is a central instrument for detecting possible side effects after a pharmaceutical preparation has received marketing authorization. It provides important information (signals) on the occurrence of rare, previously unknown side effects, on increases in the frequency of known side effects that may also be due to quality defects, or on changes in the type or severity of known side effects. In recent decades, this system has made a significant contribution to the identification of drug-related risks that only arise upon widespread use following approval and to the introduction of appropriate measures to minimize risk.

PMID:39847136 | DOI:10.1007/s00482-024-00857-3

Pediatr Radiol. 2025 Jan 23. doi: 10.1007/s00247-024-06153-7. Online ahead of print.

ABSTRACT

The bone marrow of immunocompromised patients may exhibit abnormalities due to the underlying disease, adverse treatment effects, and/or complications arising from either source. Such complexity poses a significant diagnostic challenge, particularly in children. Magnetic resonance imaging (MRI) is the modality of choice when evaluating bone marrow in these patients. The high soft tissue contrast of MRI studies allows for detailed evaluation of bone marrow composition, including fat content, cellularity, and vascularisation. During the early years of life, bone marrow undergoes physiological maturation manifesting as a wide range of MRI findings. Understanding the most common MRI features during this phase of development is essential. However, it is equally critical to recognise physiological variations that can mimic pathological changes, as distinguishing between variations and truly pathological abnormalities is crucial for accurate diagnosis and management. This article reviews normal bone marrow and its variations during childhood, as well as the most common alterations presenting in immunocompromised patients.

PMID:39847093 | DOI:10.1007/s00247-024-06153-7

Acta Endocrinol (Buchar). 2024 Apr-Jun;20(2):249-255. doi: 10.4183/aeb.2024.249. Epub 2025 Jan 18.

ABSTRACT

INTRODUCTION: Diabetes mellitus, a chronic metabolic disorder stemming from pancreatic dysfunction, is surging in India, notably among those aged 60 and above. The escalating disease prevalence in this demographic necessitates heightened medication use, escalating the risk of Adverse Drug Reactions (ADRs). This underscores the vital role of ADR monitoring to curtail potential harm.

METHOD: A 12-month cross-sectional, prospective, observational study engaged 200 participants from the geriatric Outpatient Department (OPD). Diabetic patients in the geriatric OPD, willing to participate, underwent face-to-face evaluations using a structured questionnaire focused on adverse reactions to anti-diabetic medications. The study also included a Knowledge, Attitude, and Practice (KAP) assessment.

RESULTS: Of the 200 patients, 57% were male, 43% female. Thirteen participants (7 male, 6 female) reported ADR encounters during therapy, predominantly categorized as mild in causality and severity. KAP assessments unveiled a robust understanding of ADRs, primarily shaped by physicians and reinforced by pharmacists. Anticipation of ADR occurrence was noted in 70% of respondents, linked to non-compliance and lifestyle factors.

CONCLUSION: Educating caregivers about the critical importance of monitoring medication adherence among the elderly is imperative. Cultivating an attitude of reporting even minor ADRs to appropriate authorities is essential for harm prevention.

PMID:39845748 | PMC:PMC11750232 | DOI:10.4183/aeb.2024.249

Clin Transl Sci. 2025 Jan;18(1):e70134. doi: 10.1111/cts.70134.

ABSTRACT

The Timor-Leste Pharmacovigilance (PV) became an associate member of the WHO Programme for International Drug Monitoring in 2019; however, the adverse drug reaction (ADR) reporting rate remains low, with only nine reports per 1342 million inhabitants over 5 years. This study aimed to evaluate the knowledge, attitude, practice, and barriers related to ADRs, pharmacovigilance, and ADR reporting among healthcare professionals (HCPs) in Timor-Leste. A cross-sectional survey with a validated, self-administered questionnaire was conducted among 600 HCPs, including clinical doctors, nurses, and pharmacy employees from one national referral and five referral hospitals. Of the 461 HCPs who responded (76.8% response rate), 98 were clinical doctors (21.3%), 311 nurses (67.4%), and 52 pharmacy employees (11.3%). The knowledge score on ADRs was 3.81 ± 0.36 out of 8, with clinical doctors, nurses, and pharmacy employees scoring 4.49 ± 0.51, 3.47 ± 0.24, and 4.56 ± 0.26, respectively. On pharmacovigilance and ADR reporting, the score was 3.00 ± 0.16 out of 8, with clinical doctors, nurses, and pharmacy employees scoring 3.36 ± 0.26, 2.81 ± 0.08, and 3.50 ± 0.24, respectively. All scores referred to the number of correctly answered questions. Positive attitudes were observed, with 53.4% agreeing that ADR reporting is crucial for drug safety, although only 22.0% reported observed ADRs. Key barriers included unavailability of reporting forms (81.0%), insufficient financial support (71.9%), and lack of reporting by colleagues (71.4%). These findings highlight the need for increased awareness, training, and resources to improve ADR reporting in Timor-Leste.

PMID:39844473 | DOI:10.1111/cts.70134

BMC Immunol. 2025 Jan 23;26(1):4. doi: 10.1186/s12865-025-00682-y.

ABSTRACT

Vanishing bile duct syndrome (VBDS) is a serious drug induced liver injury characterized by chronic cholestasis and loss of intrahepatic bile ducts. VBDS has been reported also following checkpoint inhibitor treatment. We compared CD3 + , CD4 + , CD8 + , CD20 + , CD57 + , PD-1 + and PD-L1 + lymphocyte infiltrates in liver biopsies of patients that encountered VBDS (n = 2) or hepatotoxicity (n = 3) after pembrolizumab (n = 4) or nivolumab (n = 1) treatment with samples from normal liver (n = 10), non-alcohol steatohepatitis (NASH, n = 10), primary biliary cholangitis (PBC, n = 10) or pembrolizumab-treated patients without adverse events (n = 2). Notably, none of the cancer patients had primary nor metastatic liver tumors. We also studied direct growth effects of pembrolizumab on primary human intrahepatic biliary epithelial cells (HIBEpiC) in vitro. Liver sections of all checkpoint inhibitor- treated patients exhibited significantly higher CD3 + infiltration than normal livers, and significantly higher PD-L1 + , CD4 + and CD8 + infiltration, than other groups. PD-1 + infiltration was significantly increased in livers of patients with severe hepatic adverse event. CD57 + infiltration was similar in normal livers, NASH- and PBC groups, but highly increased in the checkpoint inhibitor-treated patients. Immune cell infiltrates were similar between NASH and normal livers. PBC samples had significantly higher CD3 + , CD4 + , CD8 + and CD20 + infiltrates than normal livers. HIBEpiC express PD-L1 but pembrolizumab did not affect their viability in vitro. Our findings suggest that VBDS is not due to direct cytotoxicity of checkpoint inhibitors and that the immunological attack against livers induced by these drugs is different from other cholestatic liver conditions.Biological insight: Checkpoint inhibitors upregulate PD-1 and PD-L1, as well as cytotoxic CD57 + cells in the non-cancerous liver tissues and this may be associated with checkpoint inhibitor-induced hepatotoxicity.

PMID:39844069 | DOI:10.1186/s12865-025-00682-y

Pharmacoepidemiol Drug Saf. 2025 Feb;34(2):e70104. doi: 10.1002/pds.70104.

ABSTRACT

PURPOSE: The p.G12C mutation in KRAS is commonly found in many cancers and was previously untreatable until drugs like sotorasib were developed. However, up to 15% of patients treated with sotorasib have experienced hepatobiliary adverse events. To investigate whether these side effects are more common among sotorasib users, a pharmacovigilance study is necessary.

METHODS: This study used the FDA adverse event reporting system (FAERS) database, a publicly available repository of reported drug adverse events, and AERSMine, an open-access pharmacovigilance tool, to investigate these adverse events.

RESULTS: A total of 428 hepatobiliary adverse events were linked to sotorasib. Hepatic cytolysis had the highest reported relative risk at 26.541 and a safety signal of 4.726. Elevated liver and biliary enzymes such as AST, ALT, ALP, and GGT were commonly observed, but with lower reported relative risk and safety signal values, which supports previous real-world reports.

CONCLUSIONS: These findings highlight the hepatobiliary risks associated with sotorasib and underscore the importance of closely monitoring liver function in patients who are using the medication. This is particularly crucial for patients with hepatobiliary cancers, as disease progression and adverse events could be misinterpreted.

PMID:39842846 | DOI:10.1002/pds.70104

Am J Med. 2025 Jan 20:S0002-9343(25)00042-7. doi: 10.1016/j.amjmed.2025.01.011. Online ahead of print.

ABSTRACT

BACKGROUND: Amiodarone is a widely used antiarrhythmic agent with significant toxicities and drug interactions more likely to affect older adults. Nevertheless, data regarding amiodarone safety in this population are limited.

METHODS: We conducted a retrospective analysis of FDA Adverse Event Reporting System (FAERS) data from 2003 to 2024 . Reports with amiodarone as the primary suspect were compared to other antiarrhythmics (sotalol, dronedarone, flecainide, propafenone, dofetilide). Disproportionality analysis assessed reporting odds ratios (RORs) for predefined adverse events in adults (<75 years) and older adults (≥75 years). Interaction analysis evaluated differences between age groups.

RESULTS: Among 9,196 amiodarone FAERS reports, 4,129 (44.9%) involved older adults. Hyperthyroidism (ROR 39.1, 95% CI [25-61] and ROR of 23.4 [11-49.8]) and hypothyroidism (ROR 36.9 [15.2-89.8] and ROR 24.5 [11.5-52.1]) were substantially over-reported in amiodarone users among both adults and older adults, respectively. Drug-induced liver injury and peripheral neuropathy were also over-reported without a significant age interaction. Interstitial lung disease was reported more frequently in amiodarone users overall, with significantly higher reporting in older adults (ROR 11.4 [6.9-18.6] vs. 4.9 [3.4-7.0], Pinteraction=0.007). Bradycardia was also over-reported in older adults compared to adults (ROR 1.6 [1.3-2] vs. 1.0 [0.8-1.3], Pinteraction=0.003). Torsades de Pointes/QT prolongation were less frequently reported in both age groups.

CONCLUSIONS: In this global postmarketing study, interstitial lung disease and bradycardia were more frequently reported in older adults treated with amiodarone. These findings support vigilant monitoring for these adverse events, particularly in older patients.

PMID:39842538 | DOI:10.1016/j.amjmed.2025.01.011