Can J Urol. 2025 Mar 18;32(1):29-36. doi: 10.32604/cju.2025.064710.

ABSTRACT

INTRODUCTION: Non-muscle-invasive bladder cancer (NMIBC) is a common malignancy worldwide. While Bacillus Calmette-Guérin (BCG) is standard of care for treatment for most patients with high-risk NMIBC, many will either not respond to BCG initially or will eventually develop BCG-unresponsive disease. A treatment option in BCG-unresponsive disease is nadofaragene firadenovec-vncg (Adstiladrin), a nonreplicating adenoviral vector-based gene therapy approved by the US Food and Drug Administration (FDA) for the treatment of adults with high-risk BCG-unresponsive NMIBC with carcinoma in situ with or without papillary tumors.

OBJECTIVE: To review safety outcomes of participants who received the FDA-approved dose of nadofaragene firadenovec (3 × 1011 vp/mL) across phase 2 (NCT01687244) and phase 3 (NCT02773849) studies.

METHODS: Data from the phase 2 and phase 3 studies were collected and analyzed. The findings were reported using descriptive statistics to summarize the key outcomes observed across studies.

RESULTS: Common adverse events (AEs) among nadofaragene firadenovec recipients were leakage of fluid around the urinary catheter, fatigue, bladder spasm, chills, dysuria, and micturition urgency. Most study drug-related AEs were mild and localized, with no grade 4 or 5 study drug-related AEs observed in either study. Study drug-related AEs were generally transient, with most study drug-related AEs having a median duration of ≤2.0 days in the phase 3 study. Discontinuation rates due to study drug-related AEs were low, with none (0%) in the phase 2 study and three (1.9%) in the phase 3 study. No specific postmarketing surveillance was required by the FDA besides routine pharmacovigilance monitoring; no new real-world safety signals have been observed.

CONCLUSION: Nadofaragene firadenovec demonstrated a favorable and tolerable safety profile across its clinical study program, allowing for broad patient selection among those with high-risk BCG-unresponsive NMIBC.

PMID:40194933 | DOI:10.32604/cju.2025.064710

Br J Clin Pharmacol. 2025 Apr 7. doi: 10.1002/bcp.70064. Online ahead of print.

ABSTRACT

AIMS: The incidence of osteoporosis is projected to exceed 70 million people over the age of 65 years by 2030. Osteoanabolic agents, such as teriparatide and abaloparatide, are not only effective in reducing fracture incidence but also improve skeletal microstructure-an important need not met by antiresorptive agents. However, anabolic agents must be administered by daily subcutaneous injections which can be a challenge in older women. To address this need, we have developed an oral robotic pill (RP) designed to deliver biotherapeutics safely and painlessly.

METHODS: This report describes the results of a 2-part Phase 1 study conducted to evaluate the safety, tolerability and pharmacokinetics of single (Part 1) and repeat doses (Part 2) of teriparatide delivered via the RP (RT-102) in healthy and postmenopausal women.

RESULTS: Teriparatide, administered by the RP, was measurable in 26/29 and 63/69 of participants in Part 1 and Part 2, respectively. RT-102 at the 20-μg dose yielded a lower maximum observed serum concentration (98 ± 10 vs. 128 ± 20 pg mL-1), delayed time to reach maximum observed serum concentration (68 ± 15 vs. 13 ± 2 min) and higher area under the curve to infinity (342 ± 44 vs. 126 ± 29 h pg mL-1) resulting in a 3-fold higher bioavailability than subcutaneous injection. RT-102 was well tolerated with only 5 mild to moderate adverse events (AEs) related to the RP that resolved without intervention and no serious AEs. Drug-related AEs were similar in severity and frequency between RT-102 and subcutaneous teriparatide.

CONCLUSION: These data demonstrate that RT-102 can safely and reliably deliver therapeutic levels of teriparatide.

CLINICALTRIALS: GOV: NCT#05164614.

PMID:40194767 | DOI:10.1002/bcp.70064

Neurology. 2025 Apr 8;104(7_Supplement_1):4960. doi: 10.1212/WNL.0000000000212037. Epub 2025 Apr 7.

ABSTRACT

OBJECTIVE: The safety and efficacy of subcutaneous forms of levodopa/carbidopa.

BACKGROUND: Parkinson's is a motor degenerative disease. The cardinal motor manifestations of Parkinson disease are postural instability, short shuffling gait, cogwheel rigidity of extremities and head, tremors at rest, writing changes (e.g. small handwriting) and bradykinesia. The known and acceptable treatment is oral levodopa/carbidopa but the patients experience (on off phenomenon) where the patients encounter sudden halt of the drug effect so subcutaneous sustained release form is now in trials to assess its efficacy and safety.

DESIGN/METHODS: We searched six different databases for RCTs and single arm studies until November 2024 to screen included studies talking about Subcutaneous forms of levodopa/carbidopa such as subcutaneous levodopa/carbidopa known as ND0612 and Foslevodopa/Foscarbidopa known as ABBV-951. We included 6 studies (2 RCTs and 4 single arm studies). There were adverse events related to the drug such as hallucinations and anxiety and adverse events related to infusion site such as infusion site nodules and infusion site erythema.

RESULTS: 658 total patients, of which 565 experienced side effects with a percentage of 85.86%. ND0612: subcutaneous levodopa/carbidopa, patients experienced 263 side effects events while ABBV-951: Foslevodopa/Foscarbidopa, experienced a total of 256 side effects events. Continuation of subcutaneous form is accompanied with serious adverse events related to the infusion site: complications like pain, erythema, nodules, cellulitis, haemorrhage and hematoma and events leads to discontinuation. there were also drug related adverse events in some studies such as hallucinations and anxiety.

CONCLUSIONS: Our pooling analysis focused on serious and highly distressing adverse effects related to the site of infusion of subcutaneous forms of ND0612 and ABBV-951 which evoked strong negative reactions in patients leading to high rate of discontinuation. Limitations: our analysis included single arm studies. Implications of this study include a need for further research with an extended follow-up period. Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff. Disclosure: Dr. Fathy has nothing to disclose. Ms. Ibrahim has nothing to disclose. Dr. Al Haj Ali has nothing to disclose. Mr. Saad has nothing to disclose. Dr. Abd El Aziz has nothing to disclose. Dr. Nasser has nothing to disclose. Dr. Hegazy has nothing to disclose. Dr. Shaheen has a non-compensated relationship as a A Research Position Candidate Under Trial Task with Solvemed Company that is relevant to AAN interests or activities. Dr. Saha has nothing to disclose.

PMID:40193855 | DOI:10.1212/WNL.0000000000212037

Medicine (Baltimore). 2025 Apr 4;104(14):e42031. doi: 10.1097/MD.0000000000042031.

ABSTRACT

A laboratory-initiated preemptive and reactive cytochrome P450 and SLCO1B1 PGx testing protocol was evaluated in a private toxicology laboratory with the intent of identifying enzyme frequencies and associated adverse drug events. This study involved non-experimental observational research. During the retrospective medical chart review, patient demographics, statements of medical necessity, and PGx testing data were collected. Frequencies and percentages were calculated for the collected data, and statistical analysis was performed using Intellectus online software. A total of 192 PGx patient records from September 2019 to October 2021 were retrospectively reviewed. For patient demographics, men (n = 118; (61%)) were the majority gender identified among the patient population and Caucasians (n = 112; (58%)) followed by African Americans (n = 37; (19%)) were the most identified ancestry. The mean age of the patients was 69 (±9) years. CYP1A2 hyperinducers, followed by CYP3A5 poor metabolizers and CYP2B6 intermediate metabolizers, are the most encountered cytochrome P450 and SLCO1B1 enzymes. Regarding drug-gene interactions, 41 patients had 1 interaction, 29 had 2, and 31 had 3 or more interactions. For drug-drug interactions, 35 patients had 1 interaction, 15 had 2, and 30 had 3 or more interactions. Overall, 123 patients showed a minor or greater impact on drug-drug or drug-gene interactions. Overall, our study identified cytochrome P450 and SCLCO1B1 enzyme frequencies and patients experiencing actionable adverse drug events. By raising awareness of PGx test results through individualized clinician training, education, and interventions, these adverse events can be promptly identified and resolved.

PMID:40193664 | DOI:10.1097/MD.0000000000042031

PLOS Digit Health. 2025 Apr 7;4(4):e0000785. doi: 10.1371/journal.pdig.0000785. eCollection 2025 Apr.

ABSTRACT

Chronic pain is commonly treated with long-term opioid therapy, but rapid opioid dose tapering has been associated with increased adverse events. Little is known about heterogeneity in the population of patients on high dose opioids and their response to different treatments. Our aim was to examine opioid dose management and other patient characteristics in a longitudinal, clinically diverse, national population of opioid dependent patients. We used spectral clustering, an unsupervised artificial intelligence (AI) approach, to identify patients in a national claims data warehouse who were on an opioid dose tapering regimen from 2008-2018. Due to the size and heterogeneity of our cohort, we did not impose any restrictions on the kind or number of clusters to be identified in the data. Of 113,618 patients with 12 consecutive months at a stable mean opioid dose of ≥ 50 morphine milligram equivalents, 30,932 had one tapering period that began at the first 60-day period with ≥ 15% reduction in average daily dose across overlapping 60-day windows through 7 months of follow-up. We identified 10 clusters that were similar in baseline characteristics but differed markedly in the magnitude, velocity, duration, and endpoint of tapering. A cluster comprising 42% of the sample, characterised by moderately rapid, steady tapering, often (73%) to a final dose of zero, had excess drug-related events, mental health events, and deaths, compared with a cluster comprising 55% of the sample, characterised by slow, steady tapering. Four clusters demonstrated tapers of various velocities followed by complete or nearly complete reversal, with combined drug-related event rates close to that of the slowest tapering cluster. Unsupervised AI methods, such as spectral clustering, are powerful to identify clinically meaningful patterns in opioid prescribing data and to highlight salient subpopulation characteristics for designing safe tapering protocols. They are especially useful for identifying rare events in large data. Our findings highlight the importance of considering tapering velocity along with duration and final dose and should stimulate research to understand the causes and consequences of taper reversals in the context of patient-centered care.

PMID:40193396 | DOI:10.1371/journal.pdig.0000785

Aging Clin Exp Res. 2025 Apr 7;37(1):120. doi: 10.1007/s40520-025-03025-4.

ABSTRACT

BACKGROUND: Real-world data on adverse drug reactions (ADRs) associated with idarucizumab and andexanet alfa are limited.

AIM: This study aimed to assess the frequency, the characteristics and clinical and demographic factors associated with ADRs related to their use.

METHODS: This is a retrospective analysis of ADR reports collected in Vigibase® until May 31, 2023. Multivariable logistic regression estimated reporting odds ratios (RORs) for serious ADRs, death, and thromboembolic events according to demographical and clinical covariates.

RESULTS: A total of 1095 Individual Case Safety Reports (ICSRs) reporting idarucizumab (72%) or andexanet alfa (28%) as suspected/interacting agents were collected. Most of the subjects were males (44.5%), with a median age of 78 years, and exposed to only one suspected/interacting medication (73.6%). ADRs were defined as serious in 88.6% of cases, with a total of 614 (56.1%) fatal cases. Compared to patients without concomitant medications, probability of serious ADRs and death were both higher in those receiving ≥ 5 concomitant medications in the idarucizumab subgroup (ROR 4.04 and 1.66, respectively) and in those receiving 1-4 concomitant medications in the andexanet alfa subgroup (ROR 5.66 and 4.80, respectively). Moreover, the probability of thromboembolic events was significantly lower for subjects aged > 75 years (ROR for 75-84 years 0.55; ROR for ≥ 85 years 0.50).

DISCUSSION: In real-world, ADRs associated with idarucizumab and andexanet alfa use are generally serious, resulting in death in a high percentage of subjects.

CONCLUSION: Clinicians should pay particular attention when managing individuals needing these drugs, especially if vulnerable and requiring polytherapy.

PMID:40192996 | DOI:10.1007/s40520-025-03025-4

Front Pharmacol. 2025 Mar 21;16:1549526. doi: 10.3389/fphar.2025.1549526. eCollection 2025.

ABSTRACT

Drug-induced liver injury (DILI) results from the liver toxicity caused by drugs or their metabolites. Gallic acid (GA) is a naturally occurring secondary metabolite found in many fruits, plants, and nuts. Recently, GA has drawn increasing attention due to its potent pharmacological properties, particularly its anti-inflammatory and antioxidant capabilities. To the best of our knowledge, this is the first review to focus on the pharmacological properties of GA and related molecular activation mechanisms regarding protection against hepatotoxicity. We also provide a thorough explanation of the physicochemical properties, fruit sources, toxicity, and pharmacokinetics of GA after reviewing a substantial number of studies. Pharmacokinetic studies have shown that GA is quickly absorbed and eliminated when taken orally, which restricts its use in development. However, the bioavailability of GA can be increased by optimizing its structure or changing its form of administration. Notably, according to toxicology studies conducted on a range of animals and clinical trials, GA rarely exhibits toxicity or side effects. The antioxidation mechanisms mainly involved Nrf2, while anti-inflammatory mechanisms involved MAPKs and NF-κB signaling pathways. Owing to its marked pharmacological properties, GA is a prospective candidate for the management of diverse xenobiotic-induced hepatotoxicity. We also discuss the applications of cutting-edge technologies (nano-delivery systems, network pharmacology, and liver organoids) in DILI. In addition to guiding future research and development of GA as a medicine, this study offers a theoretical foundation for its clinical application.

PMID:40191418 | PMC:PMC11968354 | DOI:10.3389/fphar.2025.1549526

Curr Med Res Opin. 2025 Apr 7:1-17. doi: 10.1080/03007995.2025.2470755. Online ahead of print.

ABSTRACT

Some current prostate cancer (PCa) treatment regimens are known to have adverse effects on bone, for example androgen deprivation therapy (ADT), and on cardiovascular health, for example ADT and antiandrogen therapy. Strengthened recommendations for the practical assessment and management of bone and cardiovascular health in men with PCa are needed. This review aims to provide practical guidance for healthcare providers along the continuum of patient care on the management of bone and cardiovascular health in men with PCa undergoing ADT and antiandrogen therapy based on real-world evidence. Evidence was identified by searching PubMed for publications that reported the effects of PCa treatment on bone or cardiovascular health in a real-world setting and were published between January 2017 and August 2023. Review articles were excluded. The evidence identified indicates that ADT decreases bone mineral density (BMD) and increases the risk of osteoporosis and fractures. Bone-protecting agents (BPAs) are effective at improving bone health in patients undergoing ADT and antiandrogen therapy at all stages of the PCa pathway. Despite this, the use and timing of initiation of BPAs are variable. Furthermore, real-world studies have confirmed an association between ADT and cardiovascular risk. As survival outcomes improve, maintenance of bone and cardiovascular health is increasingly important in men with PCa. Risk is a continuous variable that must be assessed throughout the continuum of PCa treatment. Therefore, all men starting ADT should be assessed for bone and cardiovascular risk. Lifestyle adjustments, dietary supplementation and pharmacological intervention may be advised.

PMID:40190143 | DOI:10.1080/03007995.2025.2470755

Lancet Infect Dis. 2025 Apr 3:S1473-3099(25)00073-8. doi: 10.1016/S1473-3099(25)00073-8. Online ahead of print.

ABSTRACT

BACKGROUND: The substantial burden of post-COVID-19 condition (also known as long COVID) underscores the need for effective pharmacological interventions. Given that viral persistence has been hypothesised as a potential cause of long COVID, antiviral therapy might offer a promising approach to alleviating long COVID symptoms. We therefore investigated the efficacy, safety, and tolerability of nirmatrelvir-ritonavir for treating long COVID.

METHODS: In this phase 2, decentralised, double-blind, randomised controlled trial, adults (aged ≥18 years) from the 48 states across the contiguous USA, with previous documented SARS-CoV-2 infection and long COVID symptoms starting within 4 weeks of initial infection and persisting for at least 12 weeks, were eligible for inclusion. Key exclusion criteria were use of nirmatrelvir-ritonavir within the previous 2 months, CYP3A4-dependent medications, or strong CYP3A4 inducers; acute medical illness such as SARS-CoV-2 infection within the past 2 weeks; active liver disease; renal impairment; and immunocompromise. Using software for 1:1 stratified block random assignment, participants were randomly allocated to receive either two tablets of nirmatrelvir (150 mg each) and one tablet of ritonavir (100 mg), or placebo and one tablet of ritonavir (100 mg), orally administered twice daily for 15 days, stratified by age, sex at birth, and COVID-19 vaccination status. Participants, clinicians, and the study team were masked to treatment allocation. The primary efficacy endpoint was the change in the Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Physical Health Summary Score (PHSS) from baseline to day 28, analysed by intention to treat. Safety endpoints were reported from baseline to week 6 in all participants who were exposed to the study treatment. This trial is registered with ClinicalTrials.gov (NCT05668091) and is now closed to new participants.

FINDINGS: Between April 14, 2023, and Feb 26, 2024, 119 participants were screened. 100 were enrolled (66 [66%] female participants and 34 [34%] male participants), with 49 assigned to the nirmatrelvir-ritonavir group and 51 to the placebo-ritonavir group (intention-to-treat population). Three participants in the nirmatrelvir-ritonavir group and two in the placebo-ritonavir group withdrew before starting treatment and were excluded from the safety population. The mean PROMIS-29 PHSS at baseline was 39·6 (95% CI 37·4 to 41·9) in the nirmatrelvir-ritonavir group and 36·3 (34·4 to 38·2) in the placebo-ritonavir group. The adjusted change from baseline to day 28 was 0·45 (-0·93 to 1·83) in the nirmatrelvir-ritonavir group and 1·01 (-0·30 to 2·31) in the placebo-ritonavir group (adjusted mean difference -0·55 [95% CI -2·32 to 1·21; p=0·54]). No deaths or serious adverse events were recorded between baseline and week 6. Study drug-related treatment-emergent adverse events were reported in more participants in the nirmatrelvir-ritonavir group (35 [76%] of 46) compared with the placebo-ritonavir group (27 [55%] of 49), mostly driven by dysgeusia. Early treatment termination due to an adverse event occurred in two participants in the nirmatrelvir-ritonavir group and one in the placebo-ritonavir group.

INTERPRETATION: Nirmatrelvir-ritonavir administered for 15 days did not significantly improve health outcomes in participants with long COVID compared with placebo-ritonavir at day 28. However, the study showed the feasibility of large-scale, decentralised trials in long COVID.

FUNDING: Pfizer, Fred Cohen, and Carolyn Klebanoff.

PMID:40188838 | DOI:10.1016/S1473-3099(25)00073-8

Sci Rep. 2025 Apr 4;15(1):11628. doi: 10.1038/s41598-025-96427-3.

ABSTRACT

Proteasome inhibitor analogs (PIs) have significantly improved the degree of remission and survival rate of patients with multiple myeloma. However, serious adverse events (AEs) have hindered their clinical application. This study analyzed the AEs reported in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database to determine the safety profile and differences for the PI drugs bortezomib, carfilzomib, and ixazomib. The reporting odds ratio (ROR) was used to detect safety signals. Significant safety signals were detected based on system-organ classification (SOC). For bortezomib, the most significant SOC signal was "blood and lymphatic system disorders" (ROR = 3.47, 95% CI 3.37-3.57), while the most significant PT signal was "enteric neuropathy" (ROR = 134.96, 95% CI 45.67-398.79). For carfilzomib, the most significant SOC signal being "blood and lymphatic system disorders" (ROR = 4.34, 95% CI 4.17-4.53), while the most significant PT signal was "light chain analysis increased" (ROR = 76.65, 95% CI 57.07-102.96). For ixazomib, the most significant SOC signal was "gastrointestinal disorders" (ROR = 2.04, 95% CI 1.96-2.12), while the most significant PT signal was "light chain analysis increased" (ROR = 67.15, 95% CI 45.36-99.42). For bortezomib and carfilzomib, the top 20 reported PTs were consistent with AEs listed in the drug information. For ixazomib, six unexpected AEs were observed: asthenia, malaise, pyrexia, decreased appetite, dehydration, and falls. The PIs were consistent with the early failure model based on time-series analysis of the occurrence of adverse reactions to the drug. The data mined from FAERS generates new AE signals, and further clinical studies are needed to validate these findings.

PMID:40185858 | DOI:10.1038/s41598-025-96427-3

Colloids Surf B Biointerfaces. 2025 Mar 26;252:114652. doi: 10.1016/j.colsurfb.2025.114652. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal, progressive lung disease characterized by extensive scarring and thickening of lung tissue that leads to respiratory failure. Early and accurate diagnosis is crucial for monitoring disease progression and assessing therapeutic efficacy. While imaging modalities such as radiological X-rays and high-resolution computed tomography (HRCT) are commonly employed, magnetic resonance imaging (MRI) offers significant advantages, including superior soft tissue contrast and the absence of ionizing radiation. However, in lung MRIs are hindered by short transverse relaxation times, low proton density, and motion artifacts which is addressed herein by developing theranostic platform combining MRI imaging with targeted drug delivery using melanin nanoparticles conjugated with nintedanib (MNP-NIN). Chelation with ferric ions (MNP-NIN-Fe³⁺) enhanced MRI visibility enabling non-invasive imaging and drug tracking. MNP-NIN and MNP-NIN-Fe³ ⁺ nanoparticles were built with mean diameters of 189 ± 44 nm and 182 ± 35 nm, respectively and demonstrating successful NIN conjugation. Controlled NIN release followed zero-order kinetics over 36 days. MNP conjugation reduced cytotoxicity in BEAS-2B and A549 cells improving the drug's safety. MRI experiments conducted with a 7.0 T animal scanner demonstrated enhanced imaging contrast with MNP-NIN-Fe solutions compared to saline underscoring their potential for localized visualization and tracking within lung tissues. By integrating MRI diagnostics and targeted drug delivery, the MNP-NIN-Fe³ ⁺ system offers a promising solution to overcome current challenges in IPF management. This theranostic platform addresses the limitations of conventional imaging techniques while providing an innovative strategy for reducing drug-related systemic side effects and improving therapeutic efficacy.

PMID:40184721 | DOI:10.1016/j.colsurfb.2025.114652

Medicine (Baltimore). 2025 Jan 3;104(1):e40958. doi: 10.1097/MD.0000000000040958.

ABSTRACT

RATIONALE: Taxanes, derived from Taxus chinesnsis, stabilize microtubules and include drugs like Paclitaxel, Docetaxel, and Nab-paclitaxel. These are commonly used to treat various malignant tumors. However, Taxane-drug-induced cystoid macular edema (TDICME) is a rare and often under-recognized complication.

PATIENT CONCERNS: A male patient, aged sixty-three, who was diagnosed with poorly differentiated gastric adenocarcinoma, experienced a progressive decline in visual acuity in both eyes after a 4-month course of nab-paclitaxel therapy.

DIAGNOSES: Upon Fundus examination, bilateral cystoid macular edema (CME) was seen.

INTERVENTIONS: Undergo treatment with carbonic anhydrase inhibitors and discontinue the use of nab-paclitaxel.

OUTCOMES: After eleven days of treatment with carbonic anhydrase inhibitors, the patient reported significant improvement in visual acuity. Furthermore, CME was completely resolved in both eyes 8 weeks after stopping nab-paclitaxel.

LESSONS: This case highlights the potential therapeutic effectiveness of topical carbonic anhydrase inhibitors in treating TDICME. Our findings underscore the importance of monitoring and addressing ocular side effects in patients undergoing Taxane therapy, ultimately contributing to enhanced patient quality of life and treatment outcomes.

PMID:40184125 | DOI:10.1097/MD.0000000000040958

Front Pharmacol. 2025 Mar 13;16:1542269. doi: 10.3389/fphar.2025.1542269. eCollection 2025.

ABSTRACT

INTRODUCTION: Drug-related problems (DRPs) are a significant concern in many patient populations, including breastfeeding women. This study aimed to identify and characterize those problems in a group of breastfeeding women seeking specialized pharmaceutical care.

MATERIALS AND METHODS: A prospective observational study was conducted among women who registered for a pharmacist's online consultation regarding medication safety in lactation. 200 patients were enrolled. Patient medical history, medication use, breastfeeding practices, and DRPs were assessed. DRPs were classified using the Pharmaceutical Care Network Europe Association (PCNE) classification system. Causality assessment for adverse events was performed using the Naranjo algorithm and the Liverpool Causality Assessment Tool (LCAT).

RESULTS: This study found a high prevalence of DRPs among 190 out of 200 breastfeeding women. Of these, 27 experienced potential DRPs, and 163 manifested actual DRPs. A total of 218 DRPs were identified, with ineffective therapy being the most frequent (63.3%, n = 138). Among all identified causes (n = 265), the most common were patient-related factors (47.5%, n = 126) and dispensing-related issues, particularly regarding the information provided to patients about medication safety during lactation. Pharmacist interventions were accepted by 79.5% (n = 151) of patients, with 70% (n = 133) of DRPs successfully resolved.

CONCLUSION: This study highlights the significant burden of DRPs among breastfeeding women and the potential for medical professionals to improve patient outcomes through evidence-based interventions. Future research should focus on developing evidence-based guidelines for medication use during lactation and improving healthcare provider education to optimize maternal and infant health.

PMID:40183105 | PMC:PMC11965936 | DOI:10.3389/fphar.2025.1542269

Cancer Pathog Ther. 2024 May 31;3(2):129-134. doi: 10.1016/j.cpt.2024.05.003. eCollection 2025 Mar.

ABSTRACT

BACKGROUND: Whole-tissue autologous therapeutic vaccines (WATVs) are a form of cancer immunotherapy that use a patient's own pathological tissue. Concerns exist regarding the potential of WATVs to induce autoimmunity or the spread of cancer; however, their adverse events (AEs) have not been adequately studied. This literature review primarily aimed to evaluate the risks of autoimmunity and cancer seeding associated with using WATVs in human clinical trials. Its secondary objectives included assessing the incidence of AEs graded 1-5 using the Common Terminology Criteria for Adverse Events v5.0.

METHODS: The inclusion criteria were any clinical trial using human subjects in which at least part of the cancer vaccine was derived from the patient's own tumor tissue, which likely preserved the unique tumor-associated antigens (TAAs) present in the patient's tumor (i.e., whole-tissue). Tumor vaccine trials that used limited TAAs or highly processed tumor antigens were excluded. Published clinical trials were searched using Google Scholar until March 2024. The authors elaborated on the risk of bias in such cases, as indicated. All reviewed publications were searched for evidence of autoimmunity, cancer seeding, and other AEs. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement guided the review.

RESULTS: Data from 55 human clinical trials, abstracts, case reports, and unpublished data were analyzed, including 3323 patients treated with WATVs for various cancers. The primary outcomes were: (1) no documented cases of WATV-induced autoimmunity, (2) no documented cases of WATV-induced spreading or seeding of noninfectious cancers, and (3) the observed 0.24% (2/838) risk of spreading or seeding infectious cancers was attributed to inadequate sterilization. The secondary outcomes were: (1) no deaths were attributed to WATV therapy, (2) 0.18% (6/3323) incidence of grade 4 AEs, (3) 0.42% (14/3323) incidence of grade 3 AEs, (4) the incidence of grades 1-2 AEs was 52.21% (478/916).

CONCLUSIONS: WATVs carry no risk of inducing autoimmunity and essentially no risk of cancer seeding if properly sterilized. WATVs also exhibit a side effect profile comparable to that of routine vaccinations, with common, mild, and transient adverse effects. The combined risk of grade 3 and 4 AEs was 0.60% (20/3323). No deaths were causally associated with WATV treatment.

PMID:40182122 | PMC:PMC11963168 | DOI:10.1016/j.cpt.2024.05.003

BMC Pharmacol Toxicol. 2025 Apr 3;26(1):74. doi: 10.1186/s40360-025-00915-1.

ABSTRACT

BACKGROUND: Sickle cell disease (SCD) is a severe genetic disorder causing anemia, pain, and organ damage, affecting millions globally. Voxelotor, approved in the United States in 2019, targeted sickle cell disease pathophysiology. Despite its therapeutic benefits, concerns remain regarding its long-term safety and potential side effects, including headaches and gastrointestinal disturbances. This study used the FDA Adverse Event Reporting System (FAERS) to assess voxelotor's safety, aiming to enhance treatment strategies and clinical decision-making in SCD management.

METHODS: In this study, we utilized the FAERS to extract voxelotor-related adverse event reports from 2019 to 2024. We conducted descriptive and disproportionality analyses using four algorithms: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinkage (MGPS) to identify significant adverse event signals. The reliability of voxelotor adverse drug reactions (ADRs) was further improved by comparing with hydroxyurea ADRSs. Finally, adverse reactions were divided into acute ADRS, delayed ADRs and efficacy related reports to analyze the adverse event onset time.

RESULTS: A total of 16,677,340 case reports were collected in the FAERS database, of which 20,902 reports related to voxelotor were identified. Voxelotor induced adverse events occurred in 27 system organ categories (SOC). Key system organ classes affected were the blood and gastrointestinal systems. Notably, some adverse events, such as priapism and osteonecrosis, were not listed on the drug's label. The median adverse event onset time of acute ADRs, delayed ADRs and efficacy related reports were 1, 189.5 and 271 days, respectively.

CONCLUSION: This study systematically analyzed ADRs of voxelotor, highlighting the need for ongoing monitoring and further research on voxelotor's long-term safety and efficacy in treating sickle cell disease.

PMID:40181444 | DOI:10.1186/s40360-025-00915-1

J Transl Med. 2025 Apr 3;23(1):393. doi: 10.1186/s12967-024-06057-y.

ABSTRACT

BACKGROUND: Non-small cell lung cancer (NSCLC) is highly heterogeneous, leading to varied treatment responses and immune-related adverse reactions (irAEs) among patients. Habitat radiomics allows non-invasive quantitative assessment of intratumor heterogeneity (ITH). Therefore, our objective is to employ habitat radiomics techniques to develop a robust approach for predicting the efficacy of Immune checkpoint inhibitors (ICIs) and the likelihood of irAEs in advanced NSCLC patients.

METHODS: In this retrospective two center study, two independent cohorts of patients with NSCLC were used to develop (n = 248) and validate signatures (n = 95). After applying four kinds of machine learning algorithms to select the key preoperative CT radiomic features, we used clinical, radiomics and habitat radiomic features to develop the clinical signature, radiomics signature and habitat radiomic signature for ICIs prognostics and irAEs prediction. By combining habitat radiomic features with corresponding clinicopathologic information, the nomogram signature was constructed in the training cohort. Next, the internal validation cohort (n = 75) of patients, and the external validation cohort (n = 20) of patients treated with ICIs were included to evaluate the predictive value of the four signatures, and their predictive performance was assessed by the area under operating characteristic curve (AUC).

RESULTS: Our study introduces a radiomic nomogram model that integrates clinical and habitat radiomic features to identify patients who may benefit from ICIs or experience irAEs. The Radiomics Nomogram model exhibited superior predictive performance in the training, validation, and external validation sets, with AUCs of 0.923, 0.817, and 0.899, respectively. This model outperformed both the Whole-tumor Radiomics Signature model (AUCs of 0.870, 0.736, and 0.626) and the Habitat Signature model (AUCs of 0.900, 0.804, and 0.808). The radiomics model focusing on tumor sub-regional habitat showed better predictive performance than the model derived from the entire tumor. Decision Curve Analysis (DCA) and calibration curves confirmed the nomogram's effectiveness.

CONCLUSION: By leveraging machine learning to predict the outcomes of ICIs, we can move closer to achieving tailored ICIs for lung cancer. This advancement will assist physicians in selecting and managing subsequent treatment strategies, thereby facilitating clinical decision-making.

PMID:40181378 | DOI:10.1186/s12967-024-06057-y

Korean J Anesthesiol. 2025 Apr 4. doi: 10.4097/kja.24815. Online ahead of print.

ABSTRACT

BACKGROUND: We hypothesized that intranasal combination of dexmedetomidine (2 μg/kg) and ketamine (3 mg/kg) (IN DEXKET) improves the success rate of sedation in pediatric patients compared with chloral hydrate (CH; 50 mg/kg).

METHODS: This prospective, two-center, single-blinded, randomized controlled trial involved 136 pediatric patients (aged < 7 years) requiring procedural sedation. The participants were randomized to receive CH or IN DEXKET via a mucosal atomizer device. The primary outcome was the success rate of sedation (Pediatric Sedation State Scale, scores 1-3) within 15 min. The secondary outcomes included sedation failure at 30 min and overall complications of first-attempt sedation.

RESULTS: After excluding eight patients, 128 were included (CH = 66, IN DEXKET = 62). IN DEXKET showed a similar sedation success rate (75.8% [47/62] vs. 66.7% [44/66]; P = 0.330) but a lower complication rate (3.2% [2/62] vs. 16.7% [11/66]; P = 0.017) than CH. In the subgroup analysis for patients aged < 1 year, IN DEXKET showed a reduced complication rate than CH (2.6% [1/38] vs. 22.9% [8/35]; P = 0.012). In the subgroup analysis of children aged 1-7 years, IN DEXKET showed a higher sedation success rate within 15 min (79.2% [19/24] vs. 51.6% [16/31]; P = 0.049) and a lower sedation failure after 30 min (0% vs. 29.0% [9/31]; P = 0.003) than CH.

CONCLUSIONS: The intranasal combination of dexmedetomidine (2 μg/kg) and ketamine (3 mg/kg) is a safe and effective alternative to CH (50 mg/kg) for sedation in pediatric patients aged < 7 years.

PMID:40180590 | DOI:10.4097/kja.24815

Lung Cancer. 2025 Mar 12;203:108478. doi: 10.1016/j.lungcan.2025.108478. Online ahead of print.

ABSTRACT

OBJECTIVES: To evaluate the safety and effectiveness of entrectinib, an orally-administered potent multi-kinase inhibitor, for the treatment of proto-oncogene tyrosine-protein kinase-1 (ROS1) gene fusion-positive, unresectable, advanced/recurrent non-small cell lung cancer (NSCLC) in Japan.

MATERIALS AND METHODS: Patients with ROS1 gene fusion-positive, unresectable, advanced/recurrent NSCLC who initiated entrectinib therapy were enrolled in this all-case post marketing surveillance between February 21, 2020 and November 30, 2021. Outcomes were to identify the: (1) type and onset of initial cognitive disorder and ataxia during entrectinib therapy; (2) status of treatment and outcome of drug-related cognitive disorder and ataxia events; (3) incidence of other adverse drug reactions (ADRs) of safety concern: cognitive disorder and/or ataxia, cardiac disorder (excluding QT interval prolongation), QT interval prolongation, syncope, and interstitial lung disease; (4) incidence of serious adverse events (AEs) and ADRs; and (5) effectiveness.

RESULTS: Of the 276 patients who initiated entrectinib, 269 and 260 were included in the safety and effectiveness analysis sets, respectively. Cognitive disorder/ataxia was the most common ADR of safety concern, occurring in 72 patients (26.8 %). The median time to onset of initial cognitive disorder/ataxia symptoms was 2.0 days. Overall, entrectinib dose reduction, interruption, or discontinuation occurred in 9.7 %, 28.3 %, and 15.2 % of patients, respectively. Most ADRs of safety concern were manageable; 86.9 % of patients with ADRs were recovered/recovering. Serious AEs were reported in 42.8 % of patients. The overall response rate (ORR) was 38.8 % and median time to treatment failure was 6.4 months. ORR was 70.8 % versus 26.8 % to 34.7 % with entrectinib as first-line versus second- or later-line treatment, and 65.3 % versus 28.2 % in patients without versus with a history of tyrosine kinase inhibitor treatment.

CONCLUSIONS: Consistent with clinical trials, entrectinib is tolerable and effective in Japanese patients with ROS1 gene fusion-positive, unresectable, advanced/recurrent NSCLC.

STUDY REGISTRATION: UMIN Clinical Trials Registry (UMIN000046619).

PMID:40179540 | DOI:10.1016/j.lungcan.2025.108478

Rev Med Suisse. 2025 Apr 2;21(912):660-663. doi: 10.53738/REVMED.2025.21.912.660.

ABSTRACT

In everyday practice, many patients experience reactions to substances from different drug families. Multiple Drug Hypersensitivity Syndrome (MDHS) and Multiple Drug Intolerance Syndrome (MDIS) both involve reactions to several unrelated drugs but differ in pathophysiology and clinical presentation. Rare and immune-mediated, MDHS involves T lymphocytes and presents with severe delayed exanthems, eosinophilia, and moderate hepatic cytolysis triggered by at least two chemically distinct drugs. In contrast, MDIS is a diagnosis of exclusion, characterized by adverse reactions-often pseudoallergic and immediate-to three or more unrelated drugs, occurring upon separate exposures with negative allergy tests.

PMID:40176614 | DOI:10.53738/REVMED.2025.21.912.660

Int J Clin Pharm. 2025 Apr 3. doi: 10.1007/s11096-025-01904-4. Online ahead of print.

ABSTRACT

BACKGROUND: Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment. However, patients using MTX often experience drug-related problems (DRPs), negatively affecting adherence and persistence.

AIM: To identify the number and type of DRPs experienced by RA patients during the first 3 months of MTX treatment.

METHOD: A longitudinal observational study was conducted in the Sint Maartenskliniek, The Netherlands, between March and August 2023. Adult RA patients were interviewed at 2, 6 and 12 weeks after MTX initiation using the United Kingdom's New Medicines Service interview guide. DRPs were categorized using a classification system for patient-reported DRPs, and analyzed descriptively.

RESULTS: All fifty participants (median age 62 years (IQR 51-68), 66% female) reported a DRP, with a median of 6 (IQR 3-8) DRPs per patient and a total of 301 DRPs. The top 5 most frequently reported DRPs were concerns about (long-term) side-effects, nausea, fatigue, remembering intake and information needs regarding dose instructions. Of the DRPs reported at weeks 2 and 6, 33% were unresolved at week 12.

CONCLUSION: Patients with RA experience numerous DRPs in the first 3 months of MTX use. Resolving DRPs soon after occurrence may reduce the burden of drug treatment and improve adherence and/or persistence.

PMID:40178797 | DOI:10.1007/s11096-025-01904-4