J Alzheimers Dis. 2024 Nov 13:JAD240491. doi: 10.3233/JAD-240491. Online ahead of print.

ABSTRACT

BACKGROUND: A 12-week randomized controlled trial demonstrated that brexpiprazole is efficacious for treating agitation in patients with dementia due to Alzheimer's disease.

OBJECTIVE: To assess the long-term safety and tolerability of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer's disease.

METHODS: This 12-week, active-treatment (oral brexpiprazole 2 or 3 mg/day) extension trial ran from October 2018-September 2022 at 66 sites in Europe/US. Patients with agitation in dementia due to Alzheimer's disease in a care facility/community-based setting who completed the randomized trial were eligible (N = 259 enrolled/analyzed for safety; 88.4% completed). Stable Alzheimer's disease medications were permitted. The primary safety endpoint was the frequency and severity of treatment-emergent adverse events (TEAEs). Change in Cohen-Mansfield Agitation Inventory (CMAI) total score was an exploratory efficacy endpoint.

RESULTS: Mean (SD) age was 74.3 (7.6) years, 145 patients (56.0%) were female, and 248 (95.8%) were White. TEAEs were reported by 67 patients (25.9%), most commonly headache (3.5%) and fall (2.3%). Most TEAEs were mild or moderate in severity; 5 patients (1.9%) reported a severe TEAE, including 3 severe falls attributed to tripping, misjudging sitting, or dehydration. Twelve patients (4.6%) discontinued due to TEAEs. No patients died. Mean CMAI total score improved by 9.1 points over 12 weeks.

CONCLUSIONS: Considering the randomized and extension trials together, brexpiprazole 2 or 3 mg was generally well tolerated for up to 24 weeks in elderly patients with agitation associated with dementia due to Alzheimer's disease. Patients showed continued improvement in agitation.

CLINICALTRIALS.GOV IDENTIFIER: NCT03594123 (registration date: July 11, 2018).

PMID:39534972 | DOI:10.3233/JAD-240491

Front Cell Neurosci. 2024 Oct 29;18:1493644. doi: 10.3389/fncel.2024.1493644. eCollection 2024.

ABSTRACT

The pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter system facilitates the active net uptake of several marketed organic cationic drugs across the blood-brain barrier (BBB). This rare phenomenon has garnered interest in the H+/OC antiporter system as a potential target for CNS drug delivery. However, analysis of pharmacovigilance data has uncovered a significant association between substrates of the H+/OC antiporter and neurotoxicity, particularly drug-induced seizures (DIS) and mood- and cognitive-related adverse events (MCAEs). This preclinical study aimed to elucidate the CNS regional disposition of H+/OC antiporter substrates at therapeutically relevant plasma concentrations to uncover potential pharmacokinetic mechanisms underlying DIS and MCAEs. Here, we investigated the neuropharmacokinetics of pyrilamine, diphenhydramine, bupropion, tramadol, oxycodone, and memantine. Using the Combinatory Mapping Approach for Regions of Interest (CMA-ROI), we characterized the transport of unbound drugs across the BBB in specific CNS regions, as well as the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). Our findings demonstrated active net uptake across the BBB and BSCB, with unbound ROI-to-plasma concentration ratio, Kp,uu,ROI, values consistently exceeding unity in all assessed regions. Despite minor regional differences, no significant distinctions were found when comparing the whole brain to investigated regions of interest, indicating region-independent active transport. Furthermore, we observed intracellular accumulation via lysosomal trapping for all studied drugs. These results provide new insights into the CNS regional neuropharmacokinetics of these drugs, suggesting that while the brain uptake is region-independent, the active transport mechanism enables high extracellular and intracellular drug concentrations, potentially contributing to neurotoxicity. This finding emphasizes the necessity of thorough neuropharmacokinetic evaluation and neurotoxicity profiling in the development of drugs that utilize this transport pathway.

PMID:39534684 | PMC:PMC11554538 | DOI:10.3389/fncel.2024.1493644

Pharmacoecon Open. 2024 Nov 12. doi: 10.1007/s41669-024-00542-2. Online ahead of print.

ABSTRACT

OBJECTIVE: The aim of this study was to define the economic and organizational impacts related to a broader utilization of bictegravir/emtricitabine/alafenamide (BIC/FTC/TAF) in Italian clinical practice.

METHODS: A budget impact analysis-representing the evolution of the Italian National Healthcare Service (NHS) healthcare expenditure over 3 years-was developed, considering the overall Italian population treated for human immunodeficiency virus (HIV). Model input variables were treatment history, therapeutic regimen, development of adverse events, achievement of an undetectable viral load and total direct healthcare costs. Besides the BIA, an organizational impact assessment was conducted to determine the impact on the use of healthcare resources, assessing the release of organizational hospital assets, focusing on the management of drug-related adverse events. Data were collected from scientific evidence, Italian national and regional legislations and healthcare professionals' reports. To verify the robustness of the economic and organizational impact assessment, sensitivity analyses were performed.

RESULTS: Results demonstrate economic savings of about 26 million euros in total health spending, assuming a higher penetration rate for BIC/FTC/TAF. This change in the current case mix would lead to a reduction in the specific costs related to adverse event management (0.9 million euros; - 2.09%) and in the medical management of patients (38 million euros; - 7.79%), with a positive impact on the achievement of virological control. From an organizational perspective, a wider use of BIC/FTC/TAF generates a reduction in the utilization of healthcare resources due to a decrease in adverse events and complications. The model estimated a 19.64% reduction in HIV-related inpatient days, which freed up healthcare professional time.

CONCLUSIONS: Capable of improving both economic and organizational sustainability for the entire HIV care continuum, BIC/FTC/TAF is an efficient therapeutic strategy for people with HIV.

PMID:39532817 | DOI:10.1007/s41669-024-00542-2

Clin Kidney J. 2024 Oct 30;17(11):sfae324. doi: 10.1093/ckj/sfae324. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: After the risk of drug-induced liver injury was detected during tolvaptan clinical development for the treatment of autosomal dominant polycystic kidney disease (ADPKD), a post-marketing pharmacovigilance study was required for European Union regulatory approval.

METHODS: This is an interim analysis from a prospective, observational study enrolling patients prescribed tolvaptan for ADPKD in routine clinical practice. Data were obtained through physician records collected during regular care. Per the prescribing label, liver transaminases were to be monitored monthly for the first 18 months of treatment and once every 3 months thereafter. Patients and physicians were required to report adverse events suggestive of serious and potentially fatal liver injury. Data collection was from October 2016 to April 2022.

RESULTS: Of 2074 patients (median follow-up 528 days), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥3 times the upper limit of normal (ULN) were reported in 75 (3.6%) patients. At data cut-off, the enzyme elevations were confirmed for 65 patients. Among the 65 confirmed patients, in addition to transaminase elevations, there were 69 adverse events suggestive of liver injury. Tolvaptan was interrupted or withdrawn in 59/65 (90.8%) participants with confirmed ALT or AST ≥3 times the ULN, with most transaminase elevations and adverse events resolved or resolving at data cut-off. No liver enzyme elevations met laboratory criteria for Hy's law cases.

CONCLUSIONS: Transaminase elevations occurred post-marketing in a similar proportion of patients as reported in clinical trials (4.4-5.6%). Regular monitoring per label facilitates prompt detection of liver adverse events and intervention to mitigate the risk of severe injury.

PMID:39530110 | PMC:PMC11551523 | DOI:10.1093/ckj/sfae324

Curr HIV Res. 2024 Nov 8. doi: 10.2174/011570162X301403241104043813. Online ahead of print.

ABSTRACT

INTRODUCTION: People living with HIV (PLHIV) suffer from a range of consequences related to infection, including hyperlipidemia and neurologic and sleep disorders. Supplements containing phenolic compounds with high antioxidant properties can reduce these side effects. Resveratrol is a phenolic compound that improves the symptoms of diabetes, cancer, and viral infections. This study aimed to evaluate the effects of resveratrol on hyperlipidemia and neurological problems in PLHIV in Iran.

METHOD: In this double-blind, randomized clinical trial, 41 PLHIV were randomly assigned to two groups: a placebo group (n=21) and a resveratrol group (n=20). Triglyceride and cholesterol levels were determined for all the subjects before and one month after they used the medication. Additionally, standard questionnaires were used to evaluate the quality of sleep, stress, depression, and quality of life of the participants. The data were analyzed via analysis of covariance in Stata 17.0.

RESULTS: The study population did not significantly differ in terms of age (p=0.49), sex (p=0.09), marital status (p=0.90), level of education (p=0.90), duration of HIV infection (p=0.54), or mode of HIV transmission (p=0.51). The administration of resveratrol did not affect psychological parameters or blood cholesterol (p=0.091) or triglyceride (p=0.932) levels.

CONCLUSION: The administration of resveratrol did not affect cholesterol or triglyceride levels or the rates of depression, anxiety, sleep quality, or quality of life in PLHIV. The resveratrol supplementation in a large-scale clinical study involving more patients for a longer course of treatment may have had more significant effects on the serum levels of lipids and psychological factors.

PMID:39528454 | DOI:10.2174/011570162X301403241104043813

Acta Pharm Sin B. 2024 Oct;14(10):4413-4430. doi: 10.1016/j.apsb.2024.05.024. Epub 2024 Jun 4.

ABSTRACT

Ototoxicity and nephrotoxicity are the most prevalent side effects of aminoglycoside antibiotics (gentamicin, amikacin, neomycin) and platinum anti-tumor drugs (cisplatin, carboplatin). The inner ear and kidney share similarities in drug deposition and toxicity, but the underlying pathophysiological mechanisms remain unclear. Investigating the shared mechanisms and metabolic alterations in these distinct organs will provide valuable insights for clinical therapy. A strong correlation has been identified between the spatiotemporal accumulation patterns of neomycin and the specific occurrence of lipid metabolism disorders in these two organs. The primary allocation of neomycin to mitochondria results in a notable escalation in the accumulation of lipid droplets (LDs) and more interactions between mitochondria and LDs, leading to a sequence of disturbances in lipid metabolism, such as increased lipid ROS and the blocked transfer of fatty acids from LDs to mitochondria. PGC-1α deficiency worsens the neomycin-induced disorders in lipid metabolism and intensifies the pathological interactions between mitochondria and LDs, as indicated by the exacerbated disturbance of dynamic LD turnover, increased level of oxidized lipids and decreased use of fatty acids. This investigation provides a fresh perspective on the lipid metabolic dysfunction related to mitochondria-LD interactions in drug-induced ototoxicity and nephrotoxicity, potentially providing novel avenues for intervention strategies.

PMID:39525588 | PMC:PMC11544387 | DOI:10.1016/j.apsb.2024.05.024

Comput Biol Med. 2024 Nov 8;184:109321. doi: 10.1016/j.compbiomed.2024.109321. Online ahead of print.

ABSTRACT

Identifying the potential side effects for the interested drugs can help reduce harm to patients caused by drugs in clinical use and decrease the risk of drug development failure. Multiple functionally similar drugs often have multiple similar side effects, resulting in the closed relationships among these nodes. However, most of previous methods did not completely encode the features from the biological perspective to mine the complex associations between the drugs and side effects. A prediction model based on interactive multi-hypergraph inferring and channel-enhanced and attribute-enhanced learning, ICAL, was proposed to fuse the global correlations reflected by multiple hypergraphs and to learn the attributes of a pair of drug and side effect nodes enhanced by the channels and attributes. First, we designed a hypergraph architecture where a hyperedge reflects the complex correlations between a single drug (side effect) and all the drugs and side effects, and the entire hypergraph composed of the hyperedges reveals the global correlations of all the drugs and side effects. Two hypergraphs were established based on two types of drug similarities, and each hypergraph implies its specific complex relationships among multiple drugs and side effects. Second, we proposed an interactive hypergraph neural network to enable the learning of global correlation features of drugs and side effects from the two hypergraphs. It propagated the node features across multiple hypergraphs and encoded the context relationships within these hypergraphs. Besides, the attentions at the channel level and at the attribute level were proposed to integrate the semantic correlations among multiple channels and to encode the long-distance dependence within the attributes of a pair of drug and side effect. The experimental results based on cross-validation showed that our new model outperformed seven advanced prediction methods in terms of AUC, AUPR, and recall rates for the top-ranked candidates. The ablation studies showed the effectiveness of global correlation learning, node feature propagation across multiple hypergraphs, and channel and attribute enhanced pairwise attribute learning. The case studies on the candidate side effects related to five drugs further demonstrated ICAL's effective application in discovering the reliable candidates.

PMID:39522133 | DOI:10.1016/j.compbiomed.2024.109321

Sci Rep. 2024 Nov 9;14(1):27355. doi: 10.1038/s41598-024-78474-4.

ABSTRACT

Polypharmacy in older adults increases the risk of adverse drug reactions (ADRs), but studying this relationship is complex. In real-world data, the high number of medications, coupled with rare drug combinations, results in high-dimensional datasets that are difficult to analyze using conventional statistical methods. This study applies horseshoe and lasso regression for analyzing rare events in polypharmacy contexts, focusing on severe ADRs such as falls and bleedings. These regression models are executed on a multi-center dataset compiling 7175 cases from the ADRED project to detect potential ADR-associated drugs among 100 most common drugs in emergency department admissions. Positive predictors are classified by using 50% and 90% credibility intervals. This study demonstrates that regression models with horseshoe or lasso priors are effective for analyzing ADRs, providing a comprehensive consideration of multiple factors in large, sparse datasets and improving signal detection in polypharmacy, addressing a significant challenge in pharmacovigilance. Both priors yielded consistent and clinically meaningful results. The horseshoe regression resulted in fewer potential positive predictors overall, which could make it suitable as a diagnostic tool. While these regressions generate valuable information, there are still challenges in setting appropriate thresholds for determining and interpreting the positive results.

PMID:39521861 | DOI:10.1038/s41598-024-78474-4

An Bras Dermatol. 2024 Nov 8:S0365-0596(24)00207-1. doi: 10.1016/j.abd.2023.12.010. Online ahead of print.

ABSTRACT

Drug-induced hypersensitivity syndrome, also known as DRESS syndrome, is a serious and potentially fatal reaction that occurs in response to prolonged use (generally between 14 and 60 days) of certain drugs, and which has no predilection for gender or age group. It is believed that DRESS syndrome has a genetic basis and results from the interaction between metabolites of certain pharmacological groups, reactivation of latent viruses (especially from the Herpesviridae family), and a cellular immune response. The classic manifestation of DRESS syndrome includes a generalized rash accompanied by fever, eosinophilia, lymphadenopathy, and systemic involvement such as hepatitis, nephritis, or pneumonitis. With the continuous increase in the availability of drugs and the aging of the population, there is a favorable scenario for the development of adverse drug reactions. Physicians should be prepared for the early diagnosis of DRESS syndrome, the identification and immediate suspension of the drug involved, and also manage systemic involvement, which may require prolonged immunosuppressive therapy. This article provides an update on the clinical, physiopathological and therapeutic aspects of DRESS syndrome.

PMID:39521708 | DOI:10.1016/j.abd.2023.12.010

Drug Ther Bull. 2024 Nov 9:dtb-2024-000058. doi: 10.1136/dtb.2024.000058. Online ahead of print.

NO ABSTRACT

PMID:39521607 | DOI:10.1136/dtb.2024.000058

Am J Kidney Dis. 2024 Nov 7:S0272-6386(24)01043-6. doi: 10.1053/j.ajkd.2024.09.006. Online ahead of print.

ABSTRACT

RATIONALE & OBJECTIVE: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) may offer an alternative erythropoiesis-stimulating agents (ESA) for the treatment of anemia in the setting of CKD. To investigate the efficacy and safety of conversion from long-acting erythropoiesis-stimulating agent (ESA) methoxy polyethylene glycol-epoetin beta (MPG-EPO) to the oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) vadadustat 3-times-weekly versus maintenance on MPG-EPO.

STUDY DESIGN: Phase 3b, open-label, noninferiority trial.

SETTING & PARTICIPANTS: Multicenter study in United States; 456 patients adults with anemia and dialysis-dependent chronic kidney disease.

INTERVENTION: Participants were randomized 1:1:1 either to vadadustat (starting dose: 600 mg thrice weekly), vadadustat (starting dose: 900 mg thrice weekly), or MPG-EPO, for up to 52 treatment weeks and 4 safety follow-up weeks after the end of treatment or early termination.

OUTCOMES: Primary and secondary efficacy endpoints were the mean change in hemoglobin from baseline during primary (weeks 20-26) and secondary (weeks 46-52) evaluation periods, respectively. Noninferiority was specified as a lower bound of the 95% CI above -0.75 g/dL for the difference in mean change in hemoglobin from baseline. Other efficacy endpoints were the proportion of participants with hemoglobin levels within the target range and the proportions of participants requiring ESA or red blood cell transfusion rescue for anemia during the evaluation periods. Transfusion rates were low and occurred at similar rates across treatment groups (2.7% and 4.0% in the combined vadadustat and MPG-EPO groups, respectively). Primary safety endpoints were any treatment-emergent and serious adverse events (AEs).

RESULTS: After combining the vadadustat groups (600 mg and 900 mg thrice weekly, n=304), vadadustat was noninferior to MPG-EPO (n=152) for both primary (least squares mean treatment difference, -0.33; 95% CI, -0.53 to -0.13) and secondary efficacy endpoints (-0.33; -0.56 to -0.09). Mean hemoglobin concentrations were stable for all groups, except for an initial slight decline in the vadadustat 600 mg group, which stabilized by week 12. ESA rescue for anemia was more frequent in the MPG-EPO group (primary evaluation period, 27.7%; secondary evaluation period, 16.2%) than in the combined vadadustat (14.2%; 7.3%) groups. The incidences of any treatment-emergent and serious treatment-emergent AEs were similar across treatment groups.

LIMITATIONS: Potential errors in attribution of AEs as drug related.

CONCLUSIONS: Three-times-weekly vadadustat was noninferior to MPG-EPO on their effect on hemoglobin levels without detectable differences in AEs.

PMID:39521398 | DOI:10.1053/j.ajkd.2024.09.006

Lupus. 2024 Nov 8:9612033241299175. doi: 10.1177/09612033241299175. Online ahead of print.

ABSTRACT

OBJECTIVE: Although belimumab has been widely used in patients with systemic lupus erythematosus (SLE) globally, real-world safety data among Chinese patients are limited, particularly for children. This study assessed the safety and tolerability of belimumab in adult and paediatric patients with SLE in China in real-world clinical practice.

METHODS: This Phase 4, multicentre, prospective, observational study enrolled patients prescribed intravenous belimumab by their physicians in tertiary hospitals, independent of a clinical study, during routine clinical visits between May 2021 and May 2022. Patients could have been receiving belimumab prior to enrolment. The primary objective was to describe the incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs) and AEs of special interest (AESIs) over the 24-week follow-up period. Data were collected at enrolment and approximately 4, 12 and 24 weeks post-enrolment, during routine clinical visits. AEs, ADRs and SAEs were collected as independent events. The safety population comprised patients who received ≥1 dose of belimumab and completed ≥1 follow-up visit.

RESULTS: Overall, 417 patients were included in the analysis (safety population); 89.2% were female and mean (standard deviation) age was 35.5 (11.9) years. AEs were reported in 158 patients (37.9%) and were mostly mild (79.1%). The most common AEs were upper respiratory tract infections (n = 19, 4.6%) and hypokalaemia (n = 18, 4.3%; all mild). Among 22 patients (5.3%) with SAEs, four patients (1.0%) had drug-related SAEs (pneumonia, respiratory tract infection, gingivitis and decreased white blood cell and neutrophil count). ADRs were experienced by 25 patients (6.0%), most commonly urinary tract infections (n = 5, 1.2%). There were no fatal SAEs. AESIs occurred in 14 patients (3.4%), including infections of interest (n = 5, 1.2% all herpes zoster), serious selected psychiatric events (n = 3, 0.7%) and infusion-related systemic and anaphylactic reactions (n = 7, 1.7%). Of 14 paediatric patients enrolled, six experienced AEs, zero ADRs, two SAEs and one AESI.

CONCLUSION: Belimumab was generally well tolerated in adult and paediatric patients with SLE in this real-world setting in China, with no new safety signals identified. Future assessment of long-term belimumab safety in China beyond 24 weeks will extend this current body of evidence.

PMID:39517123 | DOI:10.1177/09612033241299175

Parasit Vectors. 2024 Nov 8;17(1):457. doi: 10.1186/s13071-024-06494-0.

ABSTRACT

BACKGROUND: The standard method to diagnose Loa loa infection and quantify microfilarial density (MFD) is the microscopic examination of calibrated thick blood smears (TBSs). In 1950, it was noticed that successive L. loa MFD samples from a single capillary puncture could exhibit up to 20% variation. Although loiasis treatment allocation is based on MFD to prevent serious adverse events (SAEs), data on this variability are scarce. There are also no guidelines supporting the collection and analysis of one or two TBSs.

METHODS: We assessed the variability of two successive L. loa MFD samples (MFD1 and MFD2), collected from 255 patients. We analyzed the influence of sex, age, weight, heart rate, arterial pressure, body temperature, and sampling time on MFD variability, as well the impact of MFD variability on MFD thresholds relevant to loiasis treatment protocols.

RESULTS: The MFD2 was found to have increased in 63% (1145/1826) of TBS pairs and to have decreased in 37% (681/1826) of TBS pairs. The MFD2 were on average 28% higher than the MFD1. These variations drove a total of 333 (17.4%) changes in MFD classes according to loiasis treatment protocol, including 210 (11.3%) class increases. TBSs generated from blood samples from subjects with lower MFD (1-1000 mf/ml) or lower mean arterial pressure (MAP; 55-80 mmHg), or from blood samples collected at an earlier hour time-point (10:00-10:59 a.m.) were more subject to MFD2 variability in a multivariate analysis. The MFD relative change was not constant over time for a given person.

CONCLUSIONS: We observed a trend towards an increase in MFD2 with an important variability between samples that may impact loiasis treatment allocation. We suggest that systematically sampling at least two successive TBSs might allow better MFD assessments to prevent post-treatment SAEs. Further studies are needed to verify this variability in larger samples as well as confirm the potential explanatory variables identified.

PMID:39516832 | DOI:10.1186/s13071-024-06494-0

BMC Pediatr. 2024 Nov 8;24(1):714. doi: 10.1186/s12887-024-05185-0.

ABSTRACT

BACKGROUND: Drug-related problems (DRPs) are frequently observed in intensive care units, resulting in a higher occurrence of drug side effects and increased treatment expenses. This study aimed to assess the prevalence of DRPs in pediatric patients admitted to the most prominent surgical and medical pediatric intensive care units (PICUs) in southern Iran, given the susceptibility of children to the effects of DRPs.

METHOD: This cross-sectional study was conducted at Namazi Hospital, which is affiliated with Shiraz University of Medical Sciences in Shiraz, Iran, from June 2022 to March 2023. The research focused on identifying and detecting drug-related problems (DRPs) among pediatric patients during their hospital stays across three medical wards, two pediatric intensive care units, and a surgical intensive care unit. The identification process occurred concurrently with patient treatment and utilized the Pharmaceutical Care Network of Europe's data collection form for DRPs version 8.01. Before any documentation, all cases were thoroughly reviewed and validated by a professional focus group. The data gathered were then statistically analyzed using SPSS to evaluate the study's outcomes.

RESULT: During the study, 323 pediatric patients were involved, of whom 57% experienced at least one DRP. The primary issues identified during the study were suboptimal drug treatment, accounting for 41.13% of cases, followed by concerns related to treatment safety, which constituted 38.53% of cases. Drug-drug interactions were found to be the leading cause of DRPs, accounting for 36.26% of cases. Two significant factors associated with DRP occurrence were the number of prescribed drugs and the number of prescribed anticonvulsants. Out of all clinical pharmacist interventions, 97% were accepted.

CONCLUSION: Patients admitted to the PICUs experience a high occurrence of DRPs. It is essential to consider optimal dosage adjustment, particularly for pediatric patients with impaired kidney function.

PMID:39516792 | DOI:10.1186/s12887-024-05185-0

BJC Rep. 2024 Jan 23;2(1):3. doi: 10.1038/s44276-023-00028-4.

ABSTRACT

BACKGROUND: Nivolumab with modified FOLFIRINOX (mFOLFIRINOX) may have additive antitumour effects while minimising chemotherapy cytotoxicity. We assessed the efficacy and safety of nivolumab+mFOLFIRINOX in metastatic pancreatic cancer.

METHODS: Thirty-one treatment-naïve patients aged ≥20 years with metastatic unresectable/recurrent pancreatic cancer (≥1 measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1) and Eastern Cooperative Oncology Group 0/1 score and life expectancy ≥90 days received nivolumab (480 mg, every 4 weeks) plus mFOLFIRINOX. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS) and safety.

RESULTS: At the median follow-up of 13.4 months, the ORR was 32.3% (complete response 0%; partial response 32.3%) and the median duration of response was 7.4 (range: 3.5-21.9) months; the primary endpoint was not met. Median OS and PFS were 13.4 (95% confidence interval [CI]: 10.6-16.6) months and 7.4 (95% CI: 3.9-9.2) months, respectively. The 1-year survival rate was 54.8% (95% CI: 36.0%-70.3%). Drug-related serious adverse events were reported in 29.0% of the patients; 3.2% drug-related adverse events led to discontinuation, and none led to death within 30-day safety window.

CONCLUSION: Nivolumab+mFOLFIRINOX was tolerable in patients with metastatic pancreatic cancer. ORR and survival were comparable to previously reported data. (JapicCTI-184230).

PMID:39516689 | DOI:10.1038/s44276-023-00028-4

BJC Rep. 2024 May 22;2(1):41. doi: 10.1038/s44276-024-00064-8.

ABSTRACT

Most patients with cancer receive chemotherapy. Unfortunately, chemotherapy is associated with a number of potentially life-threatening side effects. There is a need to ameliorate chemotoxicity to improve therapeutic outcomes and quality of life. Chemotoxicity arises from systemic DNA damage and inflammation in healthy cells due to chemotherapy drugs. Traditionally, these processes are believed to be caused by the direct death of normal cells by chemotherapeutic drugs. However, new research has challenged this dogma by suggesting that chemotoxicity is a secondary effect associated with the release of cell-free chromatin particles (cfChPs) from cells subjected to drug-induced death. Released cfChPs can freely enter into bystander healthy cells to inflict double-strand (dsDNA) breaks and activate inflammatory and apoptotic pathways. The drug-induced cell death and cfChPs release have cascading effects that exaggerate and prolong chemotoxicity. Furthermore, evidence has emerged from laboratory and preclinical studies, and two phase II clinical trials, indicating that chemotoxicity can be minimised by deactivating cfChPs. Three cfChPs-deactivating agents have been identified, of which the nutraceutical combination resveratrol and copper (R-Cu)-easily administered orally and with little toxicity-is the agent of choice for human therapeutic use. This article aims to provide practising medical oncologists with a perspective on this emerging research on chemotoxicity and its prevention and its potential implications for the future. Well-designed randomised clinical trials will be necessary to establish the true clinical value of these findings in day-to-day practice.

PMID:39516565 | DOI:10.1038/s44276-024-00064-8

JMIR Form Res. 2024 Nov 8;8:e58176. doi: 10.2196/58176.

ABSTRACT

BACKGROUND: Clinical trials demonstrate the efficacy and tolerability of medications targeting calcitonin gene-related peptide (CGRP) signaling for migraine prevention. However, these trials may not accurately reflect the real-world experiences of more diverse and heterogeneous patient populations, who often have higher disease burden and more comorbidities. Therefore, postmarketing safety surveillance is warranted. Regulatory organizations encourage marketing authorization holders to screen digital media for suspected adverse reactions, applying the same requirements as for spontaneous reports. Real-world data from social media platforms constitute a potential venue to capture diverse patient experiences and help detect treatment-related adverse events. However, while social media holds promise for this purpose, its use in pharmacovigilance is still in its early stages. Computational linguistics, which involves the automatic manipulation and quantitative analysis of oral or written language, offers a potential method for exploring this content.

OBJECTIVE: This study aims to characterize adverse events related to monoclonal antibodies targeting CGRP signaling on Reddit, a large online social media forum, by using computational linguistics.

METHODS: We examined differences in word frequencies from medication-related posts on the Reddit subforum r/Migraine over a 10-year period (2010-2020) using computational linguistics. The study had 2 phases: a validation phase and an application phase. In the validation phase, we compared posts about propranolol and topiramate, as well as posts about each medication against randomly selected posts, to identify known and expected adverse events. In the application phase, we analyzed posts discussing 2 monoclonal antibodies targeting CGRP signaling-erenumab and fremanezumab-to identify potential adverse events for these medications.

RESULTS: From 22,467 Reddit r/Migraine posts, we extracted 402 (2%) propranolol posts, 1423 (6.33%) topiramate posts, 468 (2.08%) erenumab posts, and 73 (0.32%) fremanezumab posts. Comparing topiramate against propranolol identified several expected adverse events, for example, "appetite," "weight," "taste," "foggy," "forgetful," and "dizziness." Comparing erenumab against a random selection of terms identified "constipation" as a recurring keyword. Comparing erenumab against fremanezumab identified "constipation," "depression," "vomiting," and "muscle" as keywords. No adverse events were identified for fremanezumab.

CONCLUSIONS: The validation phase of our study accurately identified common adverse events for oral migraine preventive medications. For example, typical adverse events such as "appetite" and "dizziness" were mentioned in posts about topiramate. When we applied this methodology to monoclonal antibodies targeting CGRP or its receptor-fremanezumab and erenumab, respectively-we found no definite adverse events for fremanezumab. However, notable flagged words for erenumab included "constipation," "depression," and "vomiting." In conclusion, computational linguistics applied to social media may help identify potential adverse events for novel therapeutics. While social media data show promise for pharmacovigilance, further work is needed to improve its reliability and usability.

PMID:39515814 | DOI:10.2196/58176

BMC Pharmacol Toxicol. 2024 Nov 7;25(1):84. doi: 10.1186/s40360-024-00813-y.

ABSTRACT

INTRODUCTION: Drug-induced sarcopenia has not received adequate attention. Meanwhile, there is growing recognition of the importance of effective pharmacovigilance in evaluating the benefits and risks of medications.

AIMS: The primary aim of this study is to investigate the potential association between drug use and sarcopenia through an analysis of adverse event reports from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and to evaluate the genetic factors contributing to drug-induced sarcopenia using summary-data-based Mendelian randomization (SMR).

METHODS: We obtained reports of adverse drug reactions from FAERS. Primary outcomes included sarcopenia and potential sarcopenia. We calculated the Proportional reporting ratio (PRR) to assess the risk of specific adverse events associated with various drugs, applying chi-square tests for statistical significance. Additionally, we used SMR based on Genome-wide association study (GWAS) to evaluate the potential associations between drug target genes of some significant medications and sarcopenia outcomes. The outcome data for sarcopenia included metrics as hand grip strength and appendicular lean mass (ALM).

RESULTS: A total of 55 drugs were identified as inducing potential sarcopenia, and 3 drugs were identified as inducing sarcopenia. The top 5 drugs causing a potential risk of sarcopenia were levofloxacin (PRR = 9.96, χ2 = 1057), pregabalin (PRR = 7.20, χ2 = 1023), atorvastatin (PRR = 4.68, χ2 = 903), duloxetine (PRR = 4.76, χ2 = 527) and venlafaxine (PRR = 5.56, χ2 = 504), and the 3 drugs that had been proved to induced sarcopenia included metformin (PRR = 7.41, χ2 = 58), aspirin (PRR = 5.93, χ2 = 35), and acetaminophen (PRR = 4.73, χ2 = 25). We identified electron-transfer flavoprotein dehydrogenase (ETFDH) and protein Kinase AMP-Activated Non-Catalytic Subunit Beta 1 (PRKAB1) as the primary drug target genes for metformin, while Prostaglandin-endoperoxide Synthase 1 (PTGS1) and Prostaglandin-endoperoxide Synthase 2 (PTGS2) were considered the primary action target genes for aspirin and acetaminophen according to DrugBank database. SMR showed that the expression abundance of ETFDH was negatively correlated with right hand grip strength (blood: OR = 1.01, p-value = 1.27e-02; muscle: OR = 1.01, p-value = 1.42e-02) and negatively correlated with appendicular lean mass (blood: OR = 1.03, p-value = 7.73e-08; muscle: OR = 1.03, p-value = 1.67e-07).

CONCLUSIONS: We find that metformin, aspirin, and acetaminophen are specifically noted for their potential to induce sarcopenia based on the analyses conducted. We perform signal mining for drug-associated sarcopenia events based on real-world data and provides certain guidance for the safe use of medications to prevent sarcopenia.

PMID:39511635 | DOI:10.1186/s40360-024-00813-y

Cancer Immunol Immunother. 2024 Nov 7;74(1):14. doi: 10.1007/s00262-024-03869-1.

ABSTRACT

Immunotherapy with PD-1 or PD-L1 inhibitors has become an essential treatment strategy for a growing number of malignancies. These treatments have a risk for immune-related adverse events (IRAEs). Pooled analyses based on clinical trials show a favorable toxicity profile for treatment with PD-L1 compared to PD-1 inhibitors. This study aimed to investigate differences in IRAEs between patients with advanced solid malignances treated with PD-L1 and PD-1 inhibitors in a real-world setting. We conducted a retrospective cohort study at four Swedish Regions. Patients (n = 605) treated for advanced cancer with a PD-L1 or PD-1 inhibitor in monotherapy between June 2016 and August 2022 were included. Non-small cell lung cancer (NSCLC) was the most common malignant disease (n = 251; 41.5%), followed by malignant melanoma (n = 173; 28.6%), renal cell carcinoma (n = 71; 11.7%) and urothelial carcinoma (n = 35; 5.8%). Among patients receiving PD-L1 inhibitors, NSCLC (94.4%) was the predominant malignancy, whereas for those treated with PD-1 inhibitor, malignant melanoma constituted the most prevalent malignancy (34.5%). Discontinuation of treatment due to IRAEs overall and IRAEs grade ≥ 2 were significantly less common in patients treated with PD-L1 compared to PD-1 inhibitors [Odds Ratio (OR): 0.38 (95% Confidence Interval (CI) 0.16-0.88) and OR: 0.63 (95% CI 0.35-0.98) respectively]. Any grade IRAE, IRAE grade ≥ 3 and multiple IRAEs were numerically more frequent in patients treated with PD-1 inhibitors.In conclusion, our study of patients with advanced solid malignancies in a real-world setting supports the results from clinical trials demonstrating a favorable toxicity profile for PD-L1 inhibitors versus PD-1 inhibitors.

PMID:39508883 | DOI:10.1007/s00262-024-03869-1

Open Forum Infect Dis. 2024 Oct 18;11(11):ofae630. doi: 10.1093/ofid/ofae630. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: The efficacy and safety of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) have been demonstrated in treatment-naive clinical trials. However, real-world evidence for this regimen in late-presenting patients with HIV-1 (PWH) is lacking. We investigated the virologic and safety outcomes of BIC/FTC/TAF in late-presenting PWH.

METHODS: This retrospective cohort analysis consisted of late-presenting PWH who initiated an antiretroviral regimen of BIC/FTC/TAF between June 2021 and June 2023. Treatment effectiveness, defined as HIV-1 RNA <50 copies/mL, was analyzed. Changes in immunologic, metabolic, liver, and renal parameters were evaluated. Late-presenting PWH were defined as surviving PWH with CD4 <200 cells/μL or surviving patients who met the criteria for AIDS-defining conditions with a CD4 ranging from 200 to 499 cells/μL.

RESULTS: A total of 130 participants were included in the study. At week 48, 93.8% (122/130) of the patients achieved HIV-1 RNA levels <50 copies/mL. CD4 increased by 150.0 cells/μL, and CD4/CD8 increased by 0.16 (P < .001). Sixteen (12.3%) participants experienced adverse events, and 6 (4.6%) experienced drug-related adverse events. None of the participants discontinued treatment due to either a lack of effectiveness or adverse events.

CONCLUSIONS: BIC/FTC/TAF demonstrated robust virologic suppression and tolerability in patients presenting late in the course of HIV infection.

PMID:39507881 | PMC:PMC11540140 | DOI:10.1093/ofid/ofae630