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- Risk of Osteoarthritis and Arthroplasty Between Baclofen and Tizanidine: A
Target Trial Emulation Study-
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Abstract: Background Preclinical studies have shown that baclofen may reduce the risk of osteoarthritis through its anti-inflammatory effect. Objective We aimed to clarify this association by comparing the risks of osteoarthritis and joint replacement surgery in patients receiving baclofen and tizanidine. Methods This retrospective cohort study was conducted on the global TriNetX platform (October 31, 2024). New users of baclofen and tizanidine aged ≥40 years were included in the baclofen and tizanidine group, respectively. The propensity score matching method was used. The primary outcomes were osteoarthritis and joint replacement surgery. The secondary outcomes included all-cause mortality, a composite outcome of osteoarthritis and all-cause mortality, and a composite outcome of joint replacement surgery and all-cause mortality. Cause specific hazard ratios (HRs) with 95% confidence intervals (CIs) of the outcomes were calculated with Cox regression using the TriNetX platform. Results Two well-balanced groups containing 68,210 patients each were generated by propensity score matching (age: 57.8 years; female: 55.6% in both groups). Baclofen users had a significantly lower risk of developing osteoarthritis than tizanidine users (HR: 0.965, 95% CI: 0.941 to 0.989). A similar relationship was observed for joint replacement surgery (HR: 0.847, 95% CI: 0.750 to 0.956). However, the composite outcome of osteoarthritis or death had a HR of 1.129 (95% CI: 1.109 to 1.150), and the HR of joint replacement surgery or death was 1.509 (95% CI: 1.463 to 1.556). The HR of death was 1.577 (95% CI: 1.527 to 1.629), suggesting a higher risk of mortality in the baclofen group. Conclusion The surviving baclofen users had a lower risk of osteoarthritis and joint replacement surgery compared to surviving tizanidine users. However, baclofen users exhibited a higher risk of mortality than tizanidine users. Future studies are necessary to clarify the impact of baclofen on osteoarthritis and joint replacement surgery while accounting for mortality.
PubDate: 2025-05-19
- Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Axatilimab
in Healthy Japanese Male Participants: Results from a Phase 1, Randomized,
Double-Blind, Dose-Escalation Study-
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Abstract: Background Axatilimab, an anti-colony-stimulating factor 1 receptor (CSF-1R) antibody, blocks colony-stimulating factor 1 (CSF-1) and interleukin-34 (IL-34) binding to CSF-1R on macrophages and monocytes. Axatilimab has demonstrated efficacy and safety in chronic graft-versus-host disease, and its safety, pharmacokinetics (PK), and pharmacodynamics (PD) were characterized in healthy Western participants. Objective The objective of this study was to evaluate the safety, PK, and PD of axatilimab among healthy Japanese men. Methods In this double-blind, randomized, dose-escalation study, eligible participants were healthy Japanese men aged 18–55 years, with a body weight of 50–100 kg, a body mass index of 18.0–30.0 kg/m2, and no clinically significant findings on screening evaluation (clinical, laboratory, electrocardiogram, and physical exam). Participants were randomized to receive axatilimab or placebo in a 3:1 ratio in a blinded manner. Safety (30 d follow-up; primary endpoint), PK, and PD were evaluated at a clinic in Japan following single-dose infusions of axatilimab 0.3 mg/kg (n = 6), axatilimab 1.0 mg/kg (n = 9), or placebo (n = 5). Results Three participants receiving axatilimab experienced a nonserious treatment-emergent adverse event (nasopharyngitis [0.3-mg/kg dose], amylase level increased [1.0-mg/kg dose], and headache [1.0-mg/kg dose]), with no clinically meaningful trends in hematology, urinalysis, physiologic, and most clinical chemistry measures. PK exposure increased with the 1.0 mg/kg versus 0.3 mg/kg dose, with greater than dose-proportional increases in area under the curve. CSF-1 and IL-34 levels had dose-dependent increases following axatilimab infusion. A transient increase in nonclassical monocytes was observed for 8 h following axatilimab infusion and then decreased below baseline until day 8 (0.3 mg/kg) or day 15 (1.0 mg/kg). The inverse effect was observed with classical monocytes. Intermediate monocytes had similar transient increases as nonclassical monocytes. Conclusions A single dose of axatilimab 0.3 mg/kg and 1.0 mg/kg was generally well tolerated in healthy Japanese men. Safety, PK, and PD findings were consistent with those observed in healthy Western participants. Trial Registration Japan Registry for Clinical Trials, jRCT2071220109; 27 February 2023.
PubDate: 2025-05-17
- Super Responder Profile Under Bimekizumab Treatment in Moderate-to-Severe
Psoriasis: A Short Term Real-Life Observation—IL PSO (Italian Landscape
Psoriasis)-
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PubDate: 2025-05-15
- Risk of Ophthalmotoxicity Associated with Antibody-Drug Conjugates: A
Systematic Review and Meta-analysis-
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Abstract: Background Antibody-drug conjugates provide significant advantages in cancer therapy, but their associated ophthalmotoxicity remains insufficiently explored. Objective Our objective was to determine the prevalence and risk of ophthalmotoxicity in patients receiving antibody-drug conjugates. Methods We conducted a systematic search in MEDLINE, Embase, Web of Science, Cochrane, and ClinicalTrials.gov for phase II or III randomized clinical trials reporting ocular adverse events linked to antibody-drug conjugates up to 5 March, 2025. The Cochrane Bias Risk Assessment Tool was used to assess the risk of bias. The primary outcome was the risk of all-grade ocular adverse events induced by antibody-drug conjugates, measured by the risk ratio (RR) with 95% confidence intervals (CIs). Results Thirty-one trials consisting of 18,490 patients were ultimately included. The pooled incidence of all-grade ocular adverse events following antibody-drug conjugate therapy was 10.45% (95% CI 4.51–18.42). Antibody-drug conjugates were linked to a potentially increased risk of ophthalmotoxicity (RR = 1.76, 95% CI 1.25–2.48), particularly with monomethyl auristatin E (RR = 2.73, 95% CI 1.42–5.28) and monomethyl auristatin F (RR = 3.01, 95% CI 2.58–3.52) payloads. Dry eye was the most common ocular manifestation (15.49%, 95% CI 7.66–25.38). Conclusions Antibody-drug conjugate therapy has been associated with an elevated risk of ophthalmotoxicity. Further research is needed to explore the influence of antibody-drug conjugate components, disease characteristics, and treatment regimens on ophthalmotoxicity risk. Clinical Trial Registration PROSPERO register name and registration number: Antibody-drug conjugates-related to ocular toxicity: a network meta-analysis and real-world pharmacovigilance study of the FAERS database (CRD42023458065).
PubDate: 2025-05-14
- Comment on: “An Early Cost-Utility Model of mRNA-Based Therapies for the
Treatment of Methylmalonic and Propionic Acidemia in the United Kingdom”
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PubDate: 2025-05-09
- Author’s Reply to Perera et al.: A Commentary on “An Early
Cost–Utility Model of mRNA-Based Therapies for the Treatment of
Methylmalonic and Propionic Acidemia in the United Kingdom”-
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PubDate: 2025-05-09
- Cost-Effectiveness Analysis of Nirsevimab for the Prevention of
Respiratory Syncytial Virus among Italian Infants-
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Abstract: Background and Objective Respiratory syncytial virus (RSV) is a major global cause of childhood respiratory infections, globally linked to significant morbidity and mortality, particularly leading in hospitalizations and death among infants below 1 year of age. A cost-effectiveness analysis was conducted to estimate the economically justifiable price (EJP) of nirsevimab, a new prophylaxis strategy protecting all infants against RSV lower respiratory tract infections (LRTIs), compared with a strategy consisting of palivizumab, protecting only high-risk infants and no preventive intervention for others. Methods A static decision tree model previously published to evaluate the clinical and economic burden of RSV in Italy was used to determine the EJP of nirsevimab for the prevention of RSV medically attended lower respiratory tract infections (RSV-MA-LRTIs) in all infants experiencing their first RSV season, to become a cost-effective alternative compared with palivizumab only in high-risk infants and no preventive intervention for others. The EJP was estimated considering three different willingness-to-pay (WTP) thresholds. The National Health Service (NHS) perspective was considered in the base-case. Direct costs considered in the analysis were acquisition and administration costs of prophylaxis, costs of managing RSV infection (inpatient and outpatient care, and emergency department visits) and costs of handling complications following hospitalization per RSV event. Indirect costs were evaluated in the scenario analysis as productivity loss due to premature death for RSV infection. A discount rate of 3.0% was applied only to mid-long-term costs and outcomes. Results From the NHS perspective, over the first RSV season, nirsevimab in an all-infants population could be a cost-effective approach compared with palivizumab only in high-risk infants, with an EJP equal to €267, €365, and €400 considering a WTP threshold of €0, €22,000, and €30,000 per QALY saved, respectively. Considering only the palivizumab-eligible population, the model estimated that nirsevimab could be a cost-effective approach with an EJP equal to €3,467, €3,633, and €3,694 considering a WTP threshold of €0, €22,000, and €30,000 per QALY saved, respectively. Conclusions A prophylaxis strategy against RSV infection targeting all infants with nirsevimab could represent a cost-effective option for both NHS and societal perspectives, and supports the implementation and the equity of RSV prevention for all infants.
PubDate: 2025-05-03
- Cost-Effectiveness Analysis of Pembrolizumab Plus Chemotherapy Compared
with Chemotherapy as First-Line Treatment for Advanced PD-L1-Positive
Triple-Negative Breast Cancer from a Japanese Healthcare Perspective-
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Abstract: Background and Objectives Pembrolizumab has been approved for the immunotherapy of programmed death ligand 1 (PD-L1)-positive triple-negative breast cancer (TNBC) based on the KEYNOTE-355 trial. However, cost-effectiveness evidence is limited. The purpose of this study was to evaluate the cost-effectiveness of pembrolizumab plus chemotherapy compared with chemotherapy alone for patients with PD-L1-positive inoperable or metastatic TNBC from a Japanese healthcare perspective. Methods The cost-effectiveness analysis was performed for pembrolizumab, of which the drug price was determined at 214,498 Japanese yen (JPY), or 1631 US dollars (USD) (1 USD = 131.5 JPY) for KEYTRUDA® (100 mg), using a partition survival model based on the KEYNOTE-355 trial subgroup analysis in Japan. The comparison was made using quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER). One-way deterministic and probabilistic sensitivity analyses (PSA), which evaluate the impact of parameter uncertainty, were performed to assess the robustness and calculate the acceptable probability, defined as the probability of the ICER being below the willingness-to-pay (WTP). Results Pembrolizumab plus chemotherapy provided an additional 0.676 QALYs at an incremental cost of 8,503,072 JPY. The ICER for pembrolizumab plus chemotherapy compared with conventional chemotherapy was 12,577,178 JPY (95,644 USD) per QALY. The ICER per QALY was below the willingness-to-pay threshold of 15,000,000 JPY. PSAs revealed that the acceptable probability was 83.9% at 15,000,000 JPY. Conclusions The pembrolizumab plus chemotherapy is likely to be a cost-effective option compared with conventional chemotherapy for patients with PD-L1-positive inoperable or metastatic TNBC in a Japanese medical environment from a healthcare system.
PubDate: 2025-05-03
- Early Cost-Effectiveness Analysis of Intra-articular Delivery of a
PBAE-DEX Conjugate for Osteoarthritis in a UK Population-
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Abstract: Background Osteoarthritis affects the cartilage tissue lining the joint. Current management plans often require intra-articular injections to relieve symptoms. This approach is hindered by the difficulty in localising the drug released in the synovial fluid into the cartilage surrounding the affected joint. Drug delivery systems have been developed to support cartilage drug uptake, potentially reducing the number of injections required. We developed an approach to drug localisation that exploits the highly electrostatically charged nature of cartilage constituents through binding biologically active molecules to positively charged polymers, and demonstrated high efficacy and safety in ex vivo tests. Objectives We wanted to demonstrate the potential value of cartilage drug localisation technology beyond a clinical perspective, through health economic considerations and cost-effectiveness analysis, in order for these technologies to reach patients. We also conducted threshold analyses to determine, for different effectiveness levels of reducing injections, at what price the treatment will be cost-effective. Methods We conducted an early health economic analysis of our technology, developing a cost-effectiveness model with a Markov structure. The analyses were conducted from an NHS perspective and the model was also used to estimate potential cost-effectiveness depending on target product profiles. The health states quality of life values were derived for a UK population through EQ-5D questionnaires collected and analysed in a Bayesian framework. Results At the cost and effectiveness values set for the new treatment, it was cost-effective (increased costs of £16.28 and 0.001126 QALY per patient, resulting in an incremental cost-effectiveness ratios [ICER] of £14,459/QALY) but the results were highly uncertain (at a willingness-to-pay [WTP] of £20,000 and £30,000/QALY the probability of being cost-effective was 56.5% and 67.3%, respectively); while sensitivity analyses (one-way deterministic and probabilistic), within plausible ranges of model parameters, revealed that the efficacy of the technology in reducing intra-articular injections and its cost are the most influential parameters. Conclusions Clinical trials are needed to validate the in vivo drug delivery system efficacy, but our study suggests that the system is likely to be a cost-effective use of NHS resources, also improving healthcare providers capacity.
PubDate: 2025-04-30
- A Comprehensive Systematic Review of Natural Biomedicines for
Immune-Mediated and Inflammatory Dermatologic Diseases-
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Abstract: Background Natural biomedicines (NBMs) are frequently used to manage immune-mediated and inflammatory dermatologic diseases (IMIDDs). This systematic review evaluates the efficacy, safety, and clinical relevance of NBMs in IMIDDs, providing an evidence-based analysis to guide dermatologic practice. Methods Following PRISMA guidelines, a systematic search was conducted in PubMed, Embase, Medline, and Google Scholar for randomized controlled trials (RCTs) investigating NBMs in IMIDDs from 1990 to 2023. Studies were included if they met predefined eligibility criteria: RCT design, relevant IMIDD condition, NBM intervention, and quantitative outcome measures. Risk of bias was assessed using the Jadad scale. Results were synthesized qualitatively due to heterogeneity in study designs and outcome measures. Results Of 1364 records screened, 95 RCTs were included, encompassing 5265 participants across 23 countries. Indigo naturalis, fish oil (⍵-3), and aloe vera demonstrated the most consistent efficacy in managing psoriasis, systemic lupus erythematosus (SLE), atopic dermatitis (AD), and lichen planus (LP). Indigo naturalis significantly improved erythema, scaling, and PASI scores in psoriasis patients. Fish oil showed benefits in SLE disease activity indices and AD severity, while aloe vera demonstrated improvements in SCORAD and LP severity criteria. Most NBMs exhibited favorable safety profiles, although adverse event reporting was inconsistent. Discussion While these findings highlight the potential of NBMs in dermatologic care, methodological limitations, including small sample sizes, heterogeneity in study designs, and lack of direct comparisons to conventional therapies, limit definitive conclusions. Additionally, not all natural agents can be easily searched and captured in systematic reviews, which may have restricted the scope of included NBMs. Future research should emphasize high-quality RCTs, standardized outcome measures, and comparative studies against conventional treatments. Trial Registration The review protocol is registered with Open Science Framework (OSF) (https://doi.org/10.17605/OSF.IO/UH9XJ).
PubDate: 2025-04-28
- Economic Evaluation of Penpulimab Plus Paclitaxel and Carboplatin
Combination Therapy as First-Line Treatment for Locally Advanced or
Metastatic Squamous Non-small Cell Lung Cancer in China-
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Abstract: Introduction Penpulimab is a PD-1 monoclonal antibody recommended for treating squamous non-small cell lung cancer (sqNSCLC) in combination with paclitaxel and carboplatin. This study aimed to assess the cost-effectiveness of penpulimab combined with paclitaxel and carboplatin against paclitaxel plus carboplatin as first-line treatment for locally advanced or metastatic sqNSCLC in China. Methods A three-state partitioned survival model was constructed using the efficacy outcomes obtained by digitizing the AK105-302 trial and was extrapolated to the lifetime horizon. Data on direct medical costs and utilities was gathered from the literature and commercial databases from the perspective of the Chinese healthcare system. Outcomes included quality-adjusted life years (QALYs), life years (LYs), and the incremental cost-effectiveness ratio (ICER). Sensitivity analysis and scenario analysis were performed to test the model robustness. Results The incremental efficacy of penpulimab plus paclitaxel and carboplatin was 0.821 QALYs and 1.176 LYs with an incremental cost of $20,335 compared with paclitaxel plus carboplatin combination therapy. The ICER was $24,778 per QALY, falling below the threshold of three times the per capita gross domestic product of China, a commonly applied benchmark. The results of the one-way sensitivity analysis demonstrated that the ICER values were primarily influenced by the utility of progression-free state and cost of penpulimab. Probabilistic sensitivity analysis showed that penpulimab plus paclitaxel and carboplatin was cost-effective for 98.3% of the cases. Scenario analysis yielded results similar to those of the base–case analysis. Conclusions Our analysis suggests that penpulimab plus paclitaxel and carboplatin combination therapy is cost-effective for patients with locally advanced or metastatic sqNSCLC in China.
PubDate: 2025-04-21
- Efficacy and Safety of Ligelizumab in Chronic Spontaneous Urticaria: A
Systematic Review and Meta-analysis of Randomized Controlled Trials-
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Abstract: Background and Objective This meta-analysis aims to evaluate ligelizumab’s efficacy and safety for chronic spontaneous urticaria (CSU) treatment by analyzing recent clinical trials and comparing it with placebo and omalizumab. Methods PubMed, Embase, and Cochrane were searched up to October 2024. Eligible studies were randomized controlled trials (RCTs) comparing ligelizumab with placebo or omalizumab, reporting relevant outcomes. Nonrandomized studies, or those without control groups, were excluded. Risk of bias was assessed using the Cochrane RoB-2 tool, and the Grading of Recommendation, Assessment, Development, and Evaluations approach rated evidence certainty. Statistical analysis used R software (v.4.4.2), assessing heterogeneity by Cochran Q and I2 statistics. Results Four RCTs with 2488 patients were included. Ligelizumab (
PubDate: 2025-04-04
- Summary of Research: Comparable Efficacy and Safety of Brodalumab in Obese
and Nonobese Patients with Psoriasis: Analysis of Two Randomized
Controlled Trials-
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Abstract: Obesity is associated with increased psoriasis severity and reduced effectiveness of psoriasis treatments. This is a summary of a research article that reports a study evaluating the efficacy and safety of brodalumab (a subcutaneous injectable therapy) in participants with and without obesity who have moderate-to-severe psoriasis. Data were analyzed from two large, phase 3 clinical trials (AMAGINE-2 and AMAGINE-3) of participants with psoriasis who were treated with brodalumab or another subcutaneous injectable therapy, ustekinumab. After brodalumab treatment for 52 weeks, participants with obesity experienced similar rates of skin clearance to those without obesity (90% improvement: 88% versus 85%; 100% improvement: 65% versus 73%, respectively). Brodalumab safety profiles were generally similar between participants with and without obesity. This study demonstrated that brodalumab is effective and safe for treating moderate-to-severe psoriasis, regardless of obesity status.
PubDate: 2025-03-29
- An Overview of Isavuconazole Clinical Use: A Multicentre Analysis of
Indications, Exposure and Hepatic Safety-
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Abstract: Background Isavuconazole is a recent broad-spectrum triazole indicated for the treatment of invasive aspergillosis and mucormycosis when amphotericin B is inappropriate. However, limited information exists on its clinical use. Objective We set up a retrospective multicentre study to describe the clinical practice of isavuconazole including indications, exposure, and hepatic safety. Methods From January 2021 to June 2023, all patients who received isavuconazole and had at least one therapeutic drug monitoring (TDM) measurement, were included. To identify independent predictors of isavuconazole trough concentrations (Cmin), linear regression analyses were performed. Causal relationship between the occurrence of liver injury and isavuconazole was also analysed. Results Most of the included patients (n = 102) were admitted into haematology units (41.1% [n = 42]) or intensive care units (ICU) (30.4% [n = 31]). Aspergillosis (47.0% [n = 48]), mucormycosis (25.6% [n = 26]), and off-label empirical treatments (18.6% [n = 19]), were the three most common indications. About half of the patients (46.1% [n = 47]) had an optimal exposure, while 42.2% (n = 43) were underexposed, and 11.7% (n = 12) were overexposed. Albumin level on the day of TDM was a significant factor associated with an increase in isavuconazole Cmin (p = 0.010). Among the 11 patients who had liver test abnormalities, isavuconazole was discontinued in six (n = 6) patients and liver injury was attributable to isavuconazole in two (n = 2) patients. Conclusions This multicentre analysis highlighted the common use of isavuconazole as an off-label indication, as well as the frequent underexposure of patients to isavuconazole. Albumin on the day of TDM appeared to be an important factor driving isavuconazole exposure, especially in ICU patients.
PubDate: 2025-03-28
- Reporting Quality in Health Economic Evaluation Studies of Immune
Checkpoint Inhibitors: A Systematic Review-
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Abstract: Background and Objective The introduction of immune checkpoint inhibitors (ICIs) in oncology presents a critical healthcare policy challenge for resource allocation due to their substantial financial burden. This study assessed the reporting quality of health economic evaluation (HEE) studies of ICIs. Methods This study conducted a systematic literature search of four databases (PubMed, EMBASE, Cochrane CENTRAL, and the International HTA Database) for studies published between January 1, 2014 and December 31, 2022. All ICIs approved up to December 31, 2022, in the USA, EU, China, and Japan were included. Reporting quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards published in 2013 (CHEERS 2013), which is the most widely recognised and implemented reporting guideline for HEE studies. Subgroup analyses were also performed based on the risk of sponsorship bias or citation of CHEERS 2013. Results A total of 5368 records were identified, 252 of which were included after full-text review. The study design, setting, and ICIs most frequently observed were cost-effectiveness and cost-utility analyses (63.5%), the USA (46.0%), and pembrolizumab (38.1%), respectively. Of the 24 items of CHEERS 2013, fully reported items were limited, particularly in the Methods section. Setting and location were not reported in 94.4% of the records. Subgroup analyses also revealed insufficient reporting of items in the Methods section, particularly “Setting and location”. Conclusion Health economic evaluation studies on ICIs between 2014 and 2022 had limited reporting across the 24 items of CHEERS 2013, regardless of sponsorship bias risk or citations. The items on setting and location in the Methods section were particularly underreported, emphasising the need for transparent reporting in HEE studies of ICIs.
PubDate: 2025-03-27
- Fremanezumab for the Treatment of Migraine Complicated by Medication
Overuse: A Systematic Review-
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Abstract: Background Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, such as fremanezumab, are effective for migraine prevention. However, their effectiveness in treating migraine complicated by medication overuse, remains underexplored. Objective This systematic review aims to evaluate the effectiveness of fremanezumab in adults with migraine complicated by medication overuse. Methods We systematically searched PubMed and Embase (Ovid) databases for studies on fremanezumab, selecting primary studies that included adults with migraine complicated by medication overuse and reported at least one efficacy outcome. The search was performed in January 2024 and then updated in June 2024. Risk of bias for randomized controlled trials was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool, while real-world studies were evaluated using both the ROBINS-I and ROB-ME tools. Data extraction and analysis followed established guidelines. Results Our search identified 176 records, of which 2 clinical trials and 7 real-world studies were included. Included studies recruited a total of 1422 adults with migraine complicated by medication overuse. In post hoc analyses from clinical trials, fremanezumab significantly reduced monthly migraine days, days with acute headache medication use, and Headache Impact Test (HIT-6) scores compared to placebo during a 12-week period. The real-world studies reported a reduction in monthly headache days at 6 months, and a high reversion rate from medication overuse headache (MOH) after one year of treatment. Conclusion Both post hoc analyses from clinical trials and real-world studies support fremanezumab benefits in reducing migraine frequency, medication use, and headache-related disability in adults with migraine complicated by medication overuse. Given the limited quality of data, further real-world research with standardized reporting criteria is needed to substantiate long-term benefits and establish optimal treatment protocols.
PubDate: 2025-03-22
- Effect of Food on the Pharmacokinetic Characteristics of a Single Oral
Dose of D-1553, a Selective Inhibitor of KRASG12C, in Healthy Chinese
Subjects-
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Abstract: Background and Objective D-1553 (garsorasib) is a novel and selective oral KRASG12C inhibitor. This study aims to evaluate the effect of food on the single-dose pharmacokinetics (PK) of D-1553 tablet in healthy Chinese subjects. Also the safety and tolerability of single-dose D-1553 in subjects are also evaluated. Methods A randomized, open-label, single-dose, two-intervention (fed vs fasting), two-period, two-sequence crossover study was performed on 14 healthy Chinese subjects. Plasma concentrations of D-1553 were determined by the liquid chromatography-tandem mass spectrometry method. Safety evaluations were carried out during the study period. The main PK parameters of the two formulations of D-1553 were calculated by non-compartmental analysis using Phoenix WinNonlin (Version 8.3) software. Results The geometric mean ratios (90% confidence interval [CI]) of AUC0-t and AUC0-∞ in the high-fat meal condition versus the fasting condition were 86.19% (78.30%, 94.87%) and 83.30% (75.77%, 91.58%), respectively. The geometric mean ratio (90% CI) of Cmax values in high-fat meal condition to that observed in fasting condition were 109.74% (100.22%,120.15%). The p value of Tmax was 0.1484 (fed vs fasting). Two subjects (14.3%) reported 4 treatment-emergent adverse events (TEAEs) in the fasting condition, and no subjects reported TEAEs in the fed condition. All adverse reactions were mild and had recovered by the end of the study. Conclusion The study indicated that a high-calorie and high-fat meal has no clinically relevant impact on the PK and bioavailability of D-1553 in healthy Chinese subjects. D-1553 was generally safe and well-tolerated under both fasting and fed conditions. The findings suggest that D-1553 could be administered orally with or without food. Clinical Trials ClinicalTrials.gov Identifer CTR20212761; registered on 4 Nov 2021.
PubDate: 2025-03-18
- Frequency of Acute Kidney Injury After the Initiation of Vitamin D
Receptor Activators: A Multicenter Retrospective Observational Study-
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Abstract: Background and Objectives Vitamin D receptor activators (VDRAs) are widely used in patients with osteoporosis; however, the frequency of acute kidney injury (AKI) due to VDRAs is unclear. This study aimed to investigate whether the incidence of AKI after VDRA initiation differed among patients with different renal functions. Methods The medical records of Japanese patients who were newly prescribed with VDRAs for osteoporosis at the Fujita Health University Hospital or Kyoto University Hospital between April 2012 and March 2022 were retrospectively reviewed in this study. The RIFLE (Risk, Injury, Failure, Loss of function, End-stage kidney disease) criteria were used to assess the incidence of AKI within 7 days after initiation of VDRA therapy. Additionally, the AKI algorithm was used to assess the incidence of AKI from 8 to 365 days after initiation of VDRA therapy. Results The incidence of AKI, as defined by the RIFLE criteria, was significantly higher in patients with normal renal function or end-stage renal failure than in those with mild renal decline (p < 0.05); the incidence of AKI, defined using the AKI algorithm, showed a similar trend. We found that the lack of serum calcium level monitoring before the initiation of VDRAs might be a risk factor for AKI defined by the RIFLE criteria (odds ratio = 2.004, p = 0.096). Conclusions The incidence of AKI after the initiation of VDRA therapy was high, even if renal function was normal. Thus, our results suggest that monitoring serum calcium levels before the initiation of VDRA therapy is necessary, regardless of renal function. Graphical abstract
PubDate: 2025-03-13
- Pharmacokinetics, Pharmacodynamics, and Safety Evaluation of the Novel
HIF-PH Inhibitor Enarodustat: An Open-Label Phase I Study in Healthy
Chinese Participants-
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Abstract: Background and Objectives Enarodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor. We evaluated the pharmacokinetics, pharmacodynamics, and safety profile of domestic enarodustat (SAL-0951) and analyzed the influence of ethnic factors. Methods In this phase I study, healthy Chinese participants received single and multiple oral doses (1, 5, and 15 mg) of SAL-0951 while in a fasted state. We monitored the pharmacokinetics, pharmacodynamics, and safety characteristics and analyzed the impact of ethnicity on pharmacokinetic characteristics. Results In total, 33 healthy Chinese participants were enrolled; the mean age was 31.2 ± a standard deviation of 5.5 years. After single doses of 1, 5, and 15 mg were administered under fasted conditions, SAL-0951 was rapidly absorbed. Mean maximum plasma concentration and area under the plasma concentration–time curve from time 0 to the last quantifiable concentration increased dose proportionately from 0.14 to 2.54 μg/mL and from 0.63 to 9.50 h × μg/mL, respectively. The elimination half-life was 6.13, 6.32, and 6.74 h, respectively, in these three groups, and the mean value of apparent clearance ranged from 1.64 to 1.89 L/h. SAL-0951 was excreted mostly as the parent compound. It reached a stable concentration after 5 days of multiple-dose administration. We observed no drug accumulation or time-dependent pharmacokinetic characteristics and no significant difference in pharmacokinetic characteristics between Chinese and Japanese participants. Conclusion SAL-0951 was safe and well tolerated in healthy Chinese participants and had a linear pharmacokinetic profile. We found no ethnic differences in the pharmacokinetic characteristics of the drug between Chinese and Japanese populations. Clinical Trial Registration Registered at Chinadrugtrials.org.cn, registration number CTR2020245.
PubDate: 2025-03-13
- Guanfacine Use in the ICU for Management of Sedation Weaning
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Abstract: Recent evidence highlights the increasing utilization of guanfacine in the intensive care unit. While dexmedetomidine is a widely used sedative and anti-anxiety agent in the intensive care unit, prolonged use can lead to withdrawal effects when attempting to reduce the dosage. This has generated interest in using guanfacine to manage agitation in patients being weaned off dexmedetomidine. Clonidine has been used for dexmedetomidine weaning, but its use has been associated with adverse cardiovascular events. Some observational studies and case reports have explored the use of guanfacine and have shown its benefits and tolerability for patients taking dexmedetomidine experiencing adverse effects. Guanfacine is increasingly being used in the intensive care unit instead of clonidine and is commonly prescribed for the management of withdrawal effects. While there are limited data from observational studies, it holds promise for future clinical research and broader adoption of guanfacine in the intensive care unit.
PubDate: 2025-03-12
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