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Statistical analysis | SD | Pharmacokinetic parameters were determined by non-compartmental analysis using PK solutions software, version 2.0 (Summit Research Services). The maximum concentration of four targeted compounds (CStatistical analysis was performed using STATA statistical software (StataCorp, USA). Continuous data were illustrated as mean ± SD, while half-life and T | PMC9924185 |
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Data availability | The datasets generated and/or analyzed during the present study are not publicly available due to ethical concerns and confidentiality agreements but are available from the corresponding author on reasonable request that needs a consensus from colleagues. | PMC9924185 |
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Results | PMC9924185 |
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Screening and identification of the analyte and metabolite profiling using LC-QTOF/MS analysis | The compound profiling after oral administration of Compound screening and identification after oral administration of *The tentative conjugated of AP3 sulfate and AP6 sulfate were omitted in this table due to the detection limit of LC-QTOF/MS technique, when low concentration of untargeted metabolite was used for analysis. To obtain the concentrated metabolites, the additional process of sample preparation needs to be considered in further studies.MS/MS spectra of compounds or tentative metabolites detected in human urine after a single oral administration of A | PMC9924185 |
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Compound 1 (M1, t | The MS data detected a deprotonated ion [M–H] | PMC9924185 |
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Compound 2 (M2, t | The extracted-ion chromatogram (EIC) at 507.2188 (calculated m/z 507.2236) in negative ESI of a deprotonated molecule [M-H] | PMC9924185 |
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Compound 3 (M3, t | The MS chromatogram of M3 demonstrated the presence of the molecular structure of glucuronide. The deprotonated ion [M–H] | PMC9924185 |
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Compound 4 (M4, t | Compound 4 (M4) at retention time 10.15 min, showed a deprotonated molecule [M–H] | PMC9924185 |
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Selection of analytes for further quantitative determination | The WHO monograph on selected medicinal plants indicated the major compounds of | PMC9924185 |
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Chromatographic and mass spectrometry conditions of LC-QqQ-MS/MS | PMC9924185 |
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LC optimization | SEPARATION | Chromatographic conditions were optimized to obtain a maximum intensity, and a high sensitivity with well-quantified chromatograms of each candidate analyte (AP1, AP3, AP4 and AP6). Addition of formic acid resulted in peak distortion and a decrease in negative signal intensity of the AP1 parent compound, as described by Xu et al.Finally, optimal chromatographic separation was achieved by using a mobile phase of Milli-Q water (A) and acetonitrile (B) following elution gradients: during 0–1.5 min maintained at 40%B, then increased to 100%B during 1.5–3.0 min, and maintained at 100%B for 3.0–4.5 min. The gradient was returned to 40%B at 4.6–6.0 min. Column temperature was maintained at 40 °C during the LC separation with a constant flow rate of 0.5 mL/min, and 10 μL of injection volume. | PMC9924185 |
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Mass spectrometric conditions | HEAT | The MS system, coupled with a (-)ESI ion source, was used in this analytical method due to the significant intensity observed in the negative ionization. The MS quantification was obtained by monitoring precursor/product ion transitions (m/z) at 349.1/287.2, 331.1/239.2, 479.2/161.0, 333.1/285.2 and 779.3/649.2 for AP1, AP3, AP4, AP6, and IS, respectively (Table In summary, the instrument settings for MS analyses were as follows: nebulizer gas flow = 3 L/min, heating gas flow = 10 L/min, drying gas flow = 10 L/min, interface temperature = 150 °C, heat block temperature = 250 °C, and DL temperature = 200 °C. | PMC9924185 |
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Method validation results | The new validated method in this study has the ability to fully determine the four major diterpenoids in both plasma and urine, using a small volume of sample (50 µL) and only requiring a short analysis time (6 min) with the lower limit of quantification < 1.00 ng/mL. | PMC9924185 |
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Selectivity and specificity | There was no interference effect from the endogenous matrix at the retention time of all analytes and IS. The representative chromatograms of blank plasma and urine; and the chromatograms with the retention times of the spiked four diterpenoid standards or IS in methanol, blank plasma and blank urine, are shown in Figs. S2, S3 and S4, respectively. | PMC9924185 |
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Accuracy and precision | SD | The %CV for intra-day and inter-day precision of each analyte in plasma sample (Table The intra-day and inter-day accuracy and precision of four major diterpenoids: andrographolide (AP1); 14-deoxy-11, 12-didehydroandrographolide (AP3); neoandrographolide (AP4); and 14-deoxyandrographolide (AP6) in plasma (a) and in urine (b) samples.Data expressed as mean ± SD, (n = 5).Lower limit of quantitation (LLOQ).Low quality control concentration (LQC concentration), medium quality control concentration (MQC concentration), high quality control concentration (HQC concentration). | PMC9924185 |
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Linearity, range and lower limit of quantification (LLOQ) | Three calibration curves were calculated based on data from three consecutive days using twelve concentrations for each standard in plasma and urine. The coefficients of variation of AP1, AP3, AP4, and AP6, were 0.24–9.76, 0.58–11.48, 0.20–10.64, 0.53–10.26 for plasma, and 2.71–13.43, 2.57–10.46, 2.55–10.13, 1.69–10.88 for urine, respectively. Percent accuracies were 85.50–109.02%, 94.26–106.46%, 90.93–101.04%, 92.75–110.08% for plasma, and 91.14–103.01%, 92.41–106.39%, 90.39–105.42%, 91.22–110.17% for urine, respectively. The results show good linearity (> 0.99) for both plasma and urine over the range of 0.98–1000.00 ng/mL. This method established LLOQ for the four diterpenoids at 0.98 ng/mL in both plasma and urine. (Supporting information, Tables S3 and S4). | PMC9924185 |
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Recovery | SD | Mean extraction recovery for each analyte and IS in plasma and urine is summarized in Table Mean extraction recovery, matrix effect, and hemolyzed plasma effect for andrographolide (AP1); 14-deoxy-11, 12-didehydroandrographolide (AP3); neoandrographolide (AP4); and 14-deoxyandrographolide (AP6) in plasma (a) and in urine (b) samples.Data expressed as mean ± SD, (n = 5).Low quality control concentration (LQC concentration), medium quality control concentration (MQC concentration), high quality control concentration (HQC concentration). | PMC9924185 |
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Matrix effects | The matrix effects at three levels of QC concentrations are presented in Table | PMC9924185 |
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Stability | The stability of the four major diterpenoids in biological matrices was evaluated under different conditions. The results showed that AP1, AP3, AP4 and AP6 were stable in plasma and urine during five cycles of freeze–thaw storage. The analytes were also found to be stable after 3 months of “long-term” storage at − 80 °C. The extracted samples kept in the autosampler (at 4 °C) were stable for at least 24 h. No significant levels of degradation products were detected during the sample preparation process. The samples were stable for up to 8 h at room temperature as determined by quantitative analysis of all four analytes. The stability results in plasma and urine are summarized in Table Stability of andrographolide (AP1); 14-deoxy-11, 12-didehydroandrographolide (AP3); neoandrographolide (AP4); and 14-deoxyandrographolide (AP6) in (a) human plasma and (b) urine under different storage conditions.Short term stability8 h at room temperatureFreeze–thaw stability5 cyclesLong term stability3 months at − 80 °CPost preparative stability24 h at autosamplerShort term stability8 h at room temperatureFreeze–thaw stability5 cyclesLong term stability3 months at − 80 °CPost preparative stability24 h at autosamplerShort term stability8 h at room temperatureFreeze–thaw stability5 cyclesLong term stability3 months at − 80 °CPost preparative stability24 h at autosamplerShort term stability8 h at room temperatureFreeze–thaw stability5 cyclesLong term stability3 months at − 80 °CPost preparative stability24 h at autosamplerShort term stability8 h at room temperatureFreeze–thaw stability5 cyclesLong term stability3 months at -80 °CPost preparative stability24 h at autosamplerShort term stability8 h at room temperatureFreeze–thaw stability5 cyclesLong term stability3 months at − 80 °CPost preparative stability24 h at autosamplerShort term stability8 h at room temperatureFreeze–thaw stability5 cyclesLong term stability3 months at − 80 °CPost preparative stability24 h at autosamplerShort term stability8 h at room temperatureFreeze–thaw stability5 cyclesLong term stability3 months at − 80 °CPost preparative stability24 h at autosamplerData expressed as mean ± SD (n = 5).Low quality control concentration (LQC concentration), medium quality control concentration (MQC concentration), high quality control concentration (HQC concentration). | PMC9924185 |
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Hemolyzed plasma effects | There was no interference observed in the hemolyzed plasma blank at the retention time of each analyte and of IS. As indicated in Table | PMC9924185 |
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Conclusion | This newly developed LC–MS/MS method provides a thorough analytical method for the intended purposes of quantitative determination of the four major parent compounds (andrographolide; 14-deoxy-11, 12-didehydroandrographolide; neoandrographolide; and 14-deoxyandrographolide) in both plasma and urine samples. In this way, this method offers a solution to the limitations inherent in other methods and enables a more complete pharmacokinetic analysis. This highly sensitive method (LLOQ < 1.00 ng/mL), with requiring a short analysis time (6.0 min), was successfully applied in a pharmacokinetic study of orally administered | PMC9924185 |
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Supplementary Information |
Supplementary Information. | PMC9924185 |
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Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-28612-1. | PMC9924185 |
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Acknowledgements | This study was supported in part by a grant from Thailand Science Research and Innovation (TSRI), Chulabhorn Research Institute (grant number: 36822/4274380) and a grant from Thai Traditional Medicinal Knowledge Fund, the Department of Thai Traditional and Alternative Medicine, Ministry of Public Health, Thailand. The authors would like to thank all subjects who kindly participated in this study. Lastly, we are grateful to Dr. James M. Dubbs for proofreading. | PMC9924185 |
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Author contributions | Conceptualization and Methodology, P.S., N.P., T.S., N.R., D.P., P.P. and J.S.; Subject management and Clinical investigation, P.P.; Method validation, P.S.; Data interpretation and Statistical analysis, P.S.; Writing original draft manuscript, P.S.; Review, N.P., T.S., N.R., D.P., P.P. and J.S.; Supervision, J.S.; Funding Acquisition, J.S. | PMC9924185 |
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Competing interests | The authors declare no competing interests. | PMC9924185 |
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References | PMC9924185 |
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1. Introduction | intellectual impairments, neurodevelopmental disorders, intellectual disabilities, autism | DISORDERS | The purpose of this study was to examine how 14 parents of children with autism and intellectual impairments responded to an Acceptance and Commitment Therapy (ACT)-based psychological flexibility intervention programme. A randomised clinical trial was conducted. Parents were randomly assigned to the training programme group (The Diagnostic and Statistical Manual of Mental Disorders 5 [Parenting a child with neurodevelopmental disorders and/or intellectual disabilities can be a stressful and challenging experience, requiring complex skills, which often has repercussions on the family members’ general health. Parents of children with neurodevelopmental disorders and/or intellectual disabilities are more at risk of psychological stress or burnout than other parents [ | PMC10002330 |
2. Materials and Methods | PMC10002330 |
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2.1. Design | This study was approved by the European University of Madrid Ethics Committee (CIPI/20/153). The trial was registered on ClinicalTrials.gov (ID: NCT05611554). Randomisation was completed by the Principal Investigator using an online service and randomly sized, permeated blocks to each arm (ratio: 1:1). The trial was a single-centre RCT with two arms, with participants assigned to: (1) psychological flexibility programme for parents (intervention group) or (2) waiting list (control group). Participants were assessed at baseline (pre-treatment), at the end of the programme (post-treatment), and 3 months after the end of the programme (follow-up). Participants on the waiting list condition remained in the study after assessment and received psychological intervention. | PMC10002330 |
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2.2. Participants | neurodevelopmental disorder, neurodevelopmental disorders, intellectual disability | Convenience sampling was carried out based on the availability of participants. The eligibility requirements included being over 18 years old, not currently receiving psychological treatment, being fluent in Spanish, and having a child diagnosed with a neurodevelopmental disorder or intellectual disability. The participants did not receive any financial incentive for participating. Twenty parents were recruited through a non-governmental organization for those affected by neurodevelopmental disorders in the region of Madrid, of whom 10 were assigned to the intervention condition and 10 to the control condition (see CONSORT flow diagram, | PMC10002330 |
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2.4. Procedure | The brief group intervention protocol for family members (9 h) followed a similar structure to the programme implemented in the previous study [ | PMC10002330 |
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2.5. Statistical Analysis | Pre-treatment, post-treatment, and follow-up (3 months) variables were analysed and described. To evaluate the effectiveness of the intervention protocol, two complementary strategies were used. On the one hand, the scores of the participants on each instrument before the intervention programme were compared to those obtained after the intervention programme (i.e., pre–post) and three months later (i.e., pre–follow-up). For this purpose, a Wilcoxon W test was applied to each comparison. Likewise, the effect size [ | PMC10002330 |
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4. Discussion | neurodevelopmental impairments, fatigue, neurodevelopmental disabilities, neurodevelopmental disorders, disability, intellectual disabilities, autism | EVENTS | The ACT-based intervention for parents of children with neurodevelopmental disorders and intellectual disabilities was followed by a significant reduction in perceived stress, thought suppression, and PI. Additionally, changes in the suppression of private events and PF variables were statistically significant at post-intervention and follow-up. Statistical significance was also reached in changes in perceived stress during the follow-up period. The responses to punitive and hostile interactions with children who have intellectual and neurodevelopmental disabilities considerably decreased while responses to supportive and accompanying interactions rose. The effect size was large–medium for all the studied variables. In addition, the application of the intervention programme in the usual care context of the parents supports the ecological validity of the intervention. The results are similar to those found in recent ACT studies on parents of children with autism and neurodevelopmental disorders [The analysis of clinical change, as assessed through the RCI, allowed for us to conduct a more individualised study of behavioural changes. In line with the ACT hypotheses [The findings of this randomised clinical trial give us reason to assume that teaching parents in a group setting can be more efficient and effective because certain parents act as role models for others, forming a network of support among family members, particularly among women [Traditional behaviour modification programmes typically offer specific behavioural management instructions for the child with neurodevelopmental impairments and disabilities. However, ACT interventions focus not only on parents’ public behaviour but also on increasing their psychological well-being, not by promoting the control or reduction of discomfort but by incorporating strategies that allow for them to more flexibly relate to their private events, orienting them towards value-based parenting. Therefore, our intervention is focused at the stress derived from raising a child with neurodevelopmental disorders and intellectual disabilities, so that the improvement in the relationship with the unpleasant private events experienced by the parents may also affect the behaviour of the diagnosed child [However, there are still substantial limitations to this randomised clinical trial. Firstly, there are limitations derived from the small sample size of participants, which were revealed by the power analysis. The vital condition of the family members, the need for care for the diagnosed minors, and the fatigue derived from the journey through the care systems favour low adherence of the participants and the loss of experimental subjects. The results would be more generalisable if they included even more participants. Additionally, the majority of participants were females, in whom, it seems, the training is probably effective. Future research should, however, look at whether the same training is effective in a sample made up primarily of males. The different degrees of disability associated with the diagnosis of autism and the behavioural problems and different levels of punitive/hostile behaviours pre-intervention may be variables that interfere with the results and may affect the analysis of the intervention’s efficacy [This study aims to continue providing scientific evidence from the perspective of functional contextualism on the relevance of PF and its relationship with improvements in the quality of life of families with children with neurodevelopmental disorders and intellectual disabilities. Thus, PF acts as a core variable to facilitate conscious, self-directed and value-based parenting. | PMC10002330 |
Author Contributions | Conceptualisation, D.L. and F.M.; methodology, D.L., F.M. and E.P.; software, D.L. and F.M; validation, D.L. and F.M.; formal analysis, D.L., F.M. and E.P.; investigation, D.L. and F.M.; resources, D.L., F.M. and E.P.; data curation, D.L. and F.M.; writing—original draft preparation, D.L. and F.M.; writing—review and editing, E.P. and S.C.; visualisation, D.L. and F.M.; supervision, F.M.; project administration, F.M.; funding acquisition, F.M. and D.L. All authors have read and agreed to the published version of the manuscript. | PMC10002330 |
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Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of European University of Madrid (protocol code CIPI/20/153 and date of approval 29 July 2020). | PMC10002330 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10002330 |
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Data Availability Statement | Not applicable. | PMC10002330 |
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Conflicts of Interest | The authors declare no conflict of interest. | PMC10002330 |
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Abstract | These authors contributed equally to this work and share first authorship. | PMC10321207 |
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Purpose | breast cancer | BONE METASTASIS, BREAST CANCER | Due to the poor and unpredictable prognosis of breast cancer (BC) patients with bone metastasis, it is necessary to find convenient and available prognostic predictors. This study aimed to recognize the clinical and prognostic factors related to clinical laboratory examination and to construct a prognostic nomogram for BC bone metastasis. | PMC10321207 |
Methods | REGRESSION, BONE METASTASIS | We retrospectively analyzed 32 candidate indicators from clinical features and laboratory examination data of 276 BC patients with bone metastasis. Univariate and multivariate regression analyses were performed to identify significant prognostic factors related to BC with bone metastasis. Nomogram was constructed and estimated by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. | PMC10321207 |
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Results | Patients were randomly grouped into training ( | PMC10321207 |
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Conclusion | BONE METASTASIS | This study constructed a novel prognostic nomogram for BC patients with bone metastasis. It could serve as a potential tool of survival assessment to help individual treatment decision-making for clinicians. | PMC10321207 |
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KEY MESSAGES | breast cancer | BONE METASTASIS, BREAST CANCER |
Our study investigated potential prognostic value of indicators from biochemical and blood routine examination for breast cancer patients with bone metastasis.Our study established a nomogram based on the indicators from biochemical and blood routine examination, which might enhance the ability to predict prognosis of breast cancer patients with bone metastasis. | PMC10321207 |
Keywords | PMC10321207 |
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Introduction | cancers, tumor, malignancy, Breast cancer, cancer death | BREAST CANCER, BONE METASTASIS, CANCERS, TUMOR | Breast cancer (BC), the most frequently diagnosed malignancy, is one of the main causes of cancer death in women [Currently, the prognostic predictors of bone metastasis include the features of original tumor, tumor markers, expression of selected genes, and related clinical manifestations [Increasing studies demonstrated that indicators from blood routine test and biochemical examination might be used for prognostic prediction of cancers [ | PMC10321207 |
Materials and methods | PMC10321207 |
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Research design and patient population | death, primary breast cancer, Cancer | BRAIN METASTASIS, PRIMARY TUMORS, LUNG METASTASIS, BLOOD, BONE METASTASIS, PRIMARY TUMOR, LIVER METASTASIS, CANCER | This was a retrospective study based on patients’ records. From 2010 to 2022, 679 BC patients with bone metastasis were treated in the Cancer Hospital of Shantou University Medical College. We applied strict inclusion and exclusion criteria during the enrollment process. Patients met the following inclusion criteria: (1) were diagnosed as primary breast cancer with histopathological analysis; (2) had no other primary tumors; (3) were confirmed with bone metastasis by bone scan and/or CT [Flow chart of the study.In the enrolled patients, comprehensive datasets for the relevant parameters (including clinical factors, results of laboratory examination before treatment of bone metastasis, and survival information) were provided. The clinical factors that may be relevant to prognosis were collected, including age, treatment of primary tumor, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (Her2) status, histological type, T stage, lymph node metastasis, liver metastasis, brain metastasis and lung metastasis. The laboratory examination indicators contained blood routine and biochemical examination. Blood routine included white blood cell count (WBC), red blood cell count (RBC), hemoglobin (HGB), red blood cell specific volume (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count (PLT), lymphocyte ratio (LY%), monocyte ratio (MO%), and neutrophil ratio (NE%). Biochemical examination enrolled lactate dehydrogenase (LDH), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), total protein (TP), albumin (ALB), globulin (GLB), glucose (GLU), blood urea nitrogen (BUN), creatinine (CREAT), uric acid (UA), calcium (Ca), and serum phosphonium (Pi). In this study, the primary endpoint was overall survival (OS), calculated from the date of BC bone metastasis diagnosis to death or last follow-up time. | PMC10321207 |
Variable selection and nomogram construction | REGRESSION, BONE METASTASES | We randomly partitioned the dataset into training and validation cohorts using R programming language. According to clinical significance, we screened a total of 33 prognostic-related variables in the first step, which consisted of 10 categorical variables and 23 continuous variables. The optimal cut-off values for these continuous variables were then determined using X-tile software (Version 3.6.1, Yale University), following which they were converted into categorical variables. The cut-off values obtained from the X-tile analysis were utilized to stratify patients into high-risk and low-risk groups based on the values of age, LDH, ALP, GGT, TP, ALB, GLB, GLU, BUN, CREAT, UA, CA, Pi, WBC, RBC, HGB, HCT, MCV, MCH, MCHC, PLT, LY%, MO%, and NE%. The corresponding cut-off values were as follows: 58 years, 357 U/L, 349 U/L, 125 U/L, 79.5 g/L, 37.09 g/L, 28.09 g/L, 5.09 mmol/L, 5.92 mmol/L, 67.99 μmol/L, 357 μmol/L, 2.34 mmol/L, 1.31 mmol/L, 10.3×10Cox proportional hazards regression analysis was performed using SPSS software to calculate the hazard ratio (HR) and 95% confidence interval (CI) for factors associated with OS. First, the variables with Based on the Cox regression model, we constructed a nomogram for the prediction of 1-, 3- and 5-year OS rates in BC patients with bone metastases by the package of | PMC10321207 |
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Nomogram evaluation | To evaluate the discriminative ability, we constructed a receiver operating characteristic (ROC) curve. The nomogram discrimination efficacy was assessed by concordance index (C-index) and the area under the ROC curve (AUC). They basically ranged from 0.5 (random prediction) to 1.0 (excellent prediction). In general, a value greater than 0.7 indicated that the performance of model was good with moderate prediction capacity [Finally, we used the β-coefficients derived from the final Cox model to weight individual factors and then summed all of their contribution to generate raw prognostic scores. To normalize these subsequent scores to a range between 0 and 5, we employed the following equation: (5–0) × (raw prognostic score – min_score)/(max_score – min_score) + 0 [ | PMC10321207 |
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Statistical analysis | In this study, all analyses, figures and tables were performed by IBM SPSS Statistics 26 (La Jolla, CA, USA), Microsoft Excel (Redmond, WA, USA), X-tile version 3.6.1 (Version 3.6.1, Yale University) and R version 4.1.3 ( | PMC10321207 |
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Results | PMC10321207 |
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Baseline characteristics | After patients’ enrollment, we analyzed the demographic and clinical characteristic of 276 enrolled patients (Patient characteristics in the study.IQR: interquartile range | PMC10321207 |
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Cox proportional hazards regression analysis | breast cancer | REGRESSION, METASTASIS, BONE METASTASES, BREAST CANCER | In the training cohort, after univariate Cox regression analysis, 20 variables were significantly associated with OS, including age, ER status, other organ metastasis, and some laboratory test factors consisting of LDH, ALP, GGT, ALB, GLB, BUN, CREAT, UA, WBC, RBC, HGB, MCV, MCH, MCHC, LY%, MO%, and NE%. We drafted Kaplan-Meier survival curve to show that the different levels of laboratory examination indicators had significant impacts on the OS of patients (all Kaplan-Meier survival curve to show that the different levels of laboratory examination indicators had a significant impact on the OS of patients.After controlling for confounding variables with multivariate Cox regression, a prognostic model was constructed. In this model (Univariate and multivariate Cox regression analysis in breast cancer patients with bone metastases.HR: hazard ratio; CI: confidence interval; ER: estrogen receptor; PR: progesterone receptor; Her2: human epidermal growth factor receptor 2; LDH: lactate dehydrogenase; ALP: alkaline phosphatase; GGT: γ-glutamyl transpeptidase; TP: total protein; ALB: albumin; GLB: globulin; GLU: glucose; BUN: blood urea Nitrogen; CREAT: creatinine; UA: uric acid; Ca: calcium; Pi: serum phosphonium; WBC: white blood cell count; RBC: red blood cell count; HGB: hemoglobin; HCT: red blood cell specific volume; MCV: mean corpuscular volume; MCH: mean corpuscular hemoglobin; MCHC: mean corpuscular hemoglobin concentration; PLT: platelet; LY%: lymphocyte ratio; MO%: Monocyte ratio; NE%: neutrophil ratio; Surgery: surgery of the primary site; Radiation therapy: radiation of the primary site. The bold values were considered statistically significant. | PMC10321207 |
Construction of 1-, 3-, and 5-year OS predicting nomogram | breast cancer | BONE METASTASIS, BREAST CANCER | Based on the prognostic factors selected in the training cohort, a nomogram was developed for the prediction of OS (Nomogram for 1, 3, and 5-year OS prediction of the breast cancer patients with bone metastasis. Each prognostic factor was assigned a point on the scale, and the sum of the total points projected on the bottom scale represent the probabilities of 1, 3, and 5-year OS. | PMC10321207 |
Evaluation of the OS predicting nomogram | ALL, breast cancer | BONE METASTASIS, BREAST CANCER | As shown in Receiver operating characteristic (ROC) curves of 1, 3, and 5-year in the training (A) and validation cohorts (B), respectively. The area under the ROC curve (AUC) was 0.797, 0.782, and 0.794 in the training cohort, and 0.723, 0.742, and 0.704 in the validation cohort, respectively.In both training and validation cohorts, the calibration curves were generated to suggest that the nomogram-predicted OS had good accordance with the actual OS (The calibration curves of the prognostic nomogram for the 1, 3, and 5-year OS prediction of the training (A–C) and validation group (D–F). the calibration curves suggested that the predictive outcome have good accordance with the actual 1, 3, and 5-year OS in both training and validation group.DCA of the nomogram for the survival prediction of breast cancer patients with bone metastasis in the training and validation groups. (A–C) 1, 3, and 5-year survival benefit in training cohort; (D-F) 1, 3, and 5-year survival benefit in validation cohort. The ‘ALL’, ‘none’ and ‘nomogram’ lines are represented as ‘intervention for all’ (blue dashed line), ‘intervention for none’ (green dashed line), and ‘result for the nomogram’ (red line). the ‘none’ and ‘ALL’ lines would show the expected net benefit without and with the intervention development respectively. DCA curves showed that nomogram manifested a higher net clinical benefit than ‘none’ and ‘all’.After that, we obtained the normalized prognostic scores derived from the Cox model and grouped patients into low-risk and high-risk groups based on the median value of these scores. Specifically, patients with a normalized prognostic score less than or equal 1.93 were classified as low-risk, while those with a score greater than to 1.93 were classified as high-risk. Kaplan-Meier survival analysis and log-rank tests were then used to compare the overall survival (OS) between these two groups. Our findings revealed that patients in the high-risk group had a significantly shorter OS compared to those in the low-risk group (Kaplan-Meier curve of risk stratification for OS based on nomogram. The low-risk and high-risk meant normalized prognostic scores ≤ 1.93 and >1.93 for OS, respectively. Log-rank test was applied to estimate the significant difference. | PMC10321207 |
Discussion | esophageal cancer, malignancies, cancer | METASTASIS, OESOPHAGEAL CANCER, INFLAMMATION, CANCER, BONE METASTASIS, MALIGNANT TUMORS, MALIGNANCIES, NASOPHARYNGEAL CARCINOMA, INFLAMMATION, REGRESSION, METASTASES | Although great progress has been made in the diagnosis and treatment of BC, the occurrence of bone metastasis still brings great challenges to the clinicians. Advanced BC is regarded as incurable with current therapeutic strategy [Among our study, the prognosis of patients with additional organ metastatic sites was usually poorer than that of patients with bone-only metastasis. Consistently, studies have demonstrated that patients with bone-only metastasis have prolonged survival and a better prognosis than those with additional visceral metastases [Previous analyses about prognosis of BC patients with bone metastasis clarified that HR+/Her2+ subtype was an independent protection factor of prognosis, and indicated the most favorable prognosis among all subtypes [The development, progression and prognosis of malignancies were closely related to the systemic inflammation, immunity, and nutrition status of patients [MCH means the average amount of hemoglobin content in each red blood cell. With regarding to MCH as a prognostic factor, various studies have reached conflicting conclusions. Recently, Liang et al. [Significantly, the high level of MCV in the univariate Cox regression analysis was determined as a protective factor but as a risk factor in multiple Cox regression analysis. This phenomenon indicated that there were one or more potential confounding factors confusing the true effect of MCV in the univariate analysis, and revealing it as an independent prognostic risk factor after adjustment of multiple analysis. The result of MCV in our final model was consistent with a previous study that preoperative MCV was a poor prognostic factor for esophageal cancer [Inflammation is a recognized hallmark feature of cancer, which plays an important role in the development and progression of malignant tumors, including BC [WBC are widely used peripheral blood indicators to reflect the systemic inflammation. A retrospective study with 6668 patients determined the prognostic value between low WBC and high LY% and the poor prognosis of non-metastatic nasopharyngeal carcinoma [In our study, almost all of the enrolled patients received therapy for primary BC before bone metastasis, such as radiotherapy, chemotherapy, endocrine therapy and surgery. Although different treatments for primary BC may influence the levels of blood indicators, we considered blood indicators tested at the time of bone metastasis diagnosis as baseline level to investigate the association with prognosis of BC bone metastasis, which was consistent with those previous studies [There were several unavoidable limitations in our study. First, this was a single-center retrospective study of which model validation was based on internal validation In conclusion, in this study, we developed a prognostic nomogram of predicting OS of BC patients with bone metastasis, and our study suggested that two clinical features (age and other organ metastasis sites) and six clinical laboratory examination indicators (LDH, GLB, WBC, MCV, MCH, and MO%) could estimate the prognosis among the patients who were undergoing BC bone metastasis. Our model employed a blend of clinical features and laboratory examination indicators that reflect various aspects of a patient’s condition, resulting in enhanced prediction accuracy. Moreover, the Cox regression model results were expressed through a nomogram visualization tool, offering simple and direct interpretation for the clinical doctors. Our nomogram model might assist doctors in assessing the risk factors and prognosis of BC patients with bone metastasis. It might be suggested that patients at high risk based on the nomogram may require more aggressive treatment strategies. | PMC10321207 |
Author contributions | Conceptualization, Bo Huang, Fang-Cai Wu, Xin-Jia Wang and Yi-Wei Xu; Data curation, Bo Huang and Fang-Cai Wu; Formal analysis, Bo Huang and Fang-Cai Wu; Funding acquisition, Xin-Jia Wang and Yi-Wei Xu; Investigation, Wei-Dong Wang, Can-Tong Liu, Xiao-Mei Wang, Bu-Qing Shao, Ying-Miao Lin, Guo-Xing Zheng and Ming-Ming Dong; Methodology, Bo Huang and Fang-Cai Wu; Software, Can-Tong Liu; Visualization, Bo Huang and Fang-Cai Wu; Writing – original draft, Bo Huang and Fang-Cai Wu; Writing – review & editing, Xin-Jia Wang and Yi-Wei Xu. All authors have read and agreed to the published version of the manuscript. | PMC10321207 |
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Disclosure statement | No potential conflict of interest was reported by the author(s). | PMC10321207 |
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Institutional review board statement | Cancer | CANCER | This research was conducted in the Cancer Hospital of Shantou University Medical College, and this study followed the 2008 Declaration of Helsinki’s ethical guidelines and our hospital code of ethics (2022094). | PMC10321207 |
Data availability statement | The raw data and the R codes supporting the conclusions of this article will be made available by the corresponding authors, without undue reservation. | PMC10321207 |
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References | PMC10321207 |
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Abstract | PMC9977742 |
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Objective | epilepsy | EPILEPSY | The objective of this study is to evaluate the safety and tolerability of intravenous (IV) lacosamide infusion in patients aged ≥1 month to <17 years with epilepsy. | PMC9977742 |
Methods | ADVERSE EVENTS | This Phase 2/3 open‐label trial (EP0060; NCT02710890) enrolled patients in two age cohorts (cohort 1: ≥8 to <17 years; cohort 2: ≥1 month to <8 years). Eligible patients were receiving oral lacosamide as adjunctive treatment or monotherapy (in an open‐label long‐term trial or by prescription) or were not receiving lacosamide before enrolment. Patients initiated IV lacosamide (2‐12 mg/kg/day or 100‐600 mg/day; 15‐60 minutes infusion) as a replacement for oral lacosamide or as adjunctive treatment. The primary outcomes were treatment‐emergent adverse events (TEAEs) and discontinuations due to TEAEs. | PMC9977742 |
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Results | TEAEs, seizures | GENERALIZED SEIZURES, FOCAL SEIZURES | In total, 103 patients were enrolled and completed the trial; 55 patients were included in cohort 1 (≥8 to <17 years), 48 in cohort 2 (≥1 month to <8 years). During the 4 weeks before screening, 74 (71.8%) patients had focal seizures, 12 (11.7%) had generalized seizures, and two (1.9%) had unclassified seizures. Most patients (74 [71.8%]) initiated lacosamide as adjunctive IV treatment. The mean overall duration of exposure to IV lacosamide was 1.18 days. Seventy‐nine (76.7%) patients had one IV lacosamide infusion, 20 (19.4%) had two, one (1.0%) had three, and three (2.9%) had 10 infusions. Overall, five (4.9%) patients had a total of seven TEAEs. The only TEAEs reported in two or more patients were increased blood triglycerides (two [1.9%]). No serious or severe TEAEs were reported, and no patients discontinued due to TEAEs. No TEAEs were considered drug‐related by the investigator. No consistent or clinically relevant treatment‐related changes from baseline were observed for hematology, clinical chemistry parameters, vital signs, or 12‐lead electrocardiograms. | PMC9977742 |
Significance | epilepsy | EPILEPSY | IV lacosamide was generally well tolerated in pediatric patients (≥1 month to <17 years) with epilepsy, and no new safety concerns were identified.
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Key Points | epilepsy | EPILEPSY |
Safety and tolerability of IV lacosamide infusions were evaluated in 103 pediatric patients (≥1 month to <17 years of age) with epilepsy.Seventy‐nine (76.7%) patients had one IV lacosamide infusion, 20 (19.4%) had two, one (1.0%) had three, and three (2.9%) had 10 infusions.The only TEAEs reported in ≥2 patients were increased blood triglycerides. No serious, severe, or drug‐related TEAEs were reported.No consistent or clinically relevant changes were observed for hematology, clinical chemistry parameters, vital signs, or 12‐lead ECGs.IV lacosamide was generally well tolerated, and no new safety concerns were identified. | PMC9977742 |
INTRODUCTION | epilepsy | FOCAL SEIZURES, EPILEPSY | Lacosamide is an antiseizure medication (ASM). It is a functionalised amino acid that selectively enhances slow inactivation of neuronal voltage‐gated sodium channels.Several trials have investigated the efficacy and safety of oral formulations of lacosamide in pediatric patients. The efficacy and tolerability of adjunctive lacosamide in patients aged 4 to 17 years with uncontrolled focal seizures was demonstrated in a Phase 3 double‐blind trial.The safety and tolerability of IV lacosamide has been established in adults with focal seizures.At the time that this trial (EP0060; NCT02710890) was conducted, the IV formulation of lacosamide was indicated in the United States for temporary use in patients aged 17 years and older only. The primary objective of this trial was to evaluate the safety and tolerability of IV lacosamide infusions in pediatric patients with epilepsy ≥1 month to <17 years of age. | PMC9977742 |
METHODS | EP0060 was a Phase 2/3, multicentre, open‐label trial. The trial was conducted in accordance with the International Council for Harmonization Good Clinical Practice requirements, the ethical tenets that have their origin in the principles of the Declaration of Helsinki, and the local laws of the countries involved. Written informed consent was provided by the patient or their legal representative(s) before enrolment. Legal guardians were provided with a written explanation of the study design prior to providing consent for their child's participation. The study protocol, amendments, and patient informed consent were reviewed and approved by a national, regional, or Independent Ethics Committee or Institutional Review Board.Approximately 100 patients were planned for enrolment in two age‐based cohorts: cohort 1 was planned to include at least 40 patients aged ≥8 to <17 years, and cohort 2 was planned to include approximately 44 patients aged from ≥1 month to <8 years. Enrolment began with cohort 1. When the trial was initially conceived, the planned age range for cohort 2 was ≥4 to <8 years. A protocol amendment dated April 30, 2018 lowered the minimum age to 1 month based on newly available safety and efficacy data indicating no specific risk in this age group. After completion of the first 20 patients in cohort 1, an Independent Data Monitoring Committee (IDMC) reviewed the safety and tolerability data and recommended that additional patients could be enrolled in cohort 1 and enrolment into cohort 2 could be initiated. | PMC9977742 |
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Patient eligibility | epilepsy | APPENDIX, FOCAL SEIZURES, CLONIC SEIZURES, EPILEPSY | Patients could be enrolled if they were ≥1 month to <17 years of age, had a diagnosis of epilepsy with focal seizures or primary generalized tonic–clonic seizures, weighed ≥4 kg, and were considered an acceptable candidate for venipuncture and IV infusion. In addition, eligible patients were (i) receiving oral lacosamide as adjunctive treatment or monotherapy in an open‐label long‐term trial (SP848 or EP0034); (ii) receiving prescribed oral lacosamide from a commercial supply as adjunctive treatment or monotherapy; or (iii) not receiving lacosamide treatment before enrolment (would receive IV lacosamide as a new adjunctive treatment in EP0060).For patients who were receiving lacosamide upon enrolment, oral lacosamide must have been administered at a dose of 2‐12 mg/kg/day (in patients <50 kg) or 100‐600 mg/day (in patients ≥50 kg) for ≥2 weeks before screening. Oral lacosamide dose must have been stable for at least 3 days before the first lacosamide infusion. Patients initiating lacosamide had to be on a stable dosage regimen of at least one ASM, which must have been kept constant for ≥2 weeks before screening, and must not have received lacosamide within the 3 months before screening. Further details of eligibility and withdrawal criteria may be found in Supporting Information (Appendix | PMC9977742 |
Lacosamide dosing | epilepsy | EPILEPSY | The trial consisted of a screening and/or baseline period of up to 7 days; a treatment period; a final visit (1 day); and a safety follow‐up via telephone over a period of 1‐3 days. Patients received IV lacosamide based on clinical need or elective administration. Clinical need administration applied to patients who needed to undergo a procedure and were being treated at an epilepsy monitoring unit or healthcare facility or were in other situations where IV administration was clinically appropriate and oral administration was not feasible (e.g., surgery). For these patients, the maximum number of IV lacosamide doses was 10 (administered twice daily with an interval of approximately 12 hours, over a duration of ≤5 days). Elective administration applied to patients who were taking oral lacosamide (or any enteric lacosamide administration, e.g., by feeding tube), and elected to receive IV lacosamide at an epilepsy monitoring unit or healthcare facility. For these patients, a maximum of two IV lacosamide doses were permitted (over approximately 24 hours). Patients who only required one IV lacosamide infusion could complete all the trial periods in 1 day, provided there was sufficient time for all examinations and the final visit assessments.Patients receiving lacosamide before this trial received IV lacosamide (as adjunctive treatment or monotherapy) as a replacement for oral lacosamide in a twice‐daily regimen at the same stable daily dose they had been receiving before the present trial: 2‐12 mg/kg/day or 100‐600 mg/day, with a maximum dose of 12 mg/kg/day or 600 mg/day, whichever was lower. Patients initiating lacosamide received IV lacosamide as adjunctive treatment only (initiation of IV lacosamide monotherapy was not permitted) in a twice‐daily regimen at a dose of 2 mg/kg/day for patients weighing <50 kg, and 100 mg/day for patients weighing ≥50 kg (the dose was to remain unchanged for the duration of the treatment period).The first 20 patients enrolled in cohort 1 had a target IV lacosamide infusion duration of 30‐60 minutes. Following IDMC recommendations, the remaining patients in cohort 1 had a target infusion duration of 15‐30 minutes, provided that the investigator considered that they would directly benefit from an increased infusion rate. Patients who would not directly benefit from a faster infusion (in the opinion of the investigator) had a target infusion duration of 30‐60 minutes. For the first 20 patients in cohort 2, IV lacosamide was infused over a target duration of 30‐60 minutes whenever possible. Once these patients had completed the trial, a second IDMC review took place and recommended that a 30‐60 minutes infusion duration should continue to be used in cohort 2, as no previous participants had a clinical need necessitating a dose infusion time of 15‐30 minutes.Patients who entered EP0060 from an open‐label, long‐term trial (SP848 or EP0034) suspended their participation in that trial temporarily to receive IV lacosamide. Upon completion of the EP0060 trial, eligible patients who had received prescribed lacosamide from commercial supply or who were not receiving lacosamide before enrolment had the option to continue oral lacosamide in another open‐label trial (SP848). | PMC9977742 |
Outcomes | ADVERSE EVENTS | The primary outcomes were treatment‐emergent adverse events (TEAEs), reported spontaneously by the patient and/or caregiver or observed by the investigator, and discontinuations due to TEAEs. Other safety outcomes included changes in 12‐lead electrocardiograms (ECGs), vital sign measurements (blood pressure and pulse rate), physical examinations, and neurological examinations. The Safety Set (SS) was defined as all patients who received at least one dose of lacosamide (oral and/or IV) in this open‐label trial. The SS‐IV was defined as all patients in the SS who received at least one dose of IV lacosamide and was the primary analysis set for the safety data. | PMC9977742 |
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RESULTS | PMC9977742 |
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Patient disposition and baseline characteristics | antiseizure, seizure, Epilepsy, epilepsy | MAY, EPILEPSY, EPILEPSY | This open‐label trial was conducted between May 2017 and June 2019; 103 patients were enrolled and completed the trial (SS; 77 from Europe, 26 from North America). Most patients (96 [93.2%]) were White. Fifty‐five patients were ≥8 to <17 years of age (cohort 1) and 48 were ≥1 month to <8 years of age (cohort 2). Patients had a mean age of 8.6 years, and 57 (55.3%) were female (Table Baseline demographics, medical conditions, epilepsy characteristics, concomitant ASMs, and target infusion duration (SS‐IV)Abbreviations: ASM, antiseizure medication; IV, intravenous; SD, standard deviation; SS‐IV, intravenous Safety Set.Trial SP848 or EP0034.n = 54.n = 102.Patients could have more than one response in a classification level and/or category; seizure types are listed per the International League Against Epilepsy 1981 classification, with the newer terminology provided in parentheses.Concomitant medications are medications taken on ≥1 day in common with IV lacosamide during the treatment period.Lacosamide was reported as a concomitant ASM in patients who replaced one of their two daily oral doses with IV lacosamide. | PMC9977742 |
Lacosamide exposure | Most patients (74 [71.8%]) initiated lacosamide as adjunctive IV treatment upon enrolment, 26 (25.2%) received IV lacosamide as a replacement for prescribed oral lacosamide from a commercial supply, and three (2.9%) patients received IV lacosamide as a replacement for oral lacosamide received in another open‐label, long‐term trial. The mean overall duration of exposure to IV lacosamide was 1.18 days (median: 1 day; range: 1‐5 days; standard deviation [SD]: 0.71). The mean duration of exposure was 1.10 days (range: 1.0‐2.0 days; SD: 0.31) for patients ≥1 month to <8 years of age, and 1.25 days (range: 1.0–5.0 days; SD: 0.93) for patients ≥8 years to <17 years of age. Most (81 [78.6%]) patients had a target IV lacosamide infusion duration of 30‐60 minutes rather than 15‐30 minutes (22 [21.4%]). Seventy‐nine (76.7%) patients had one IV lacosamide infusion, 20 (19.4%) had two infusions, one (1.0%) had three infusions, and three (2.9%) had 10 infusions (Figure Number of infusions by cohort and overall (SS‐IV). SS‐IV, intravenous safety set | PMC9977742 |
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Safety and tolerability of | ADVERSE EVENTS, EVENT, ADVERSE EVENT, APPENDIX | A total of seven TEAEs were reported in five (4.9%) patients following treatment with IV lacosamide (Table Treatment‐emergent adverse events (SS‐IV)Abbreviations: IV, intravenous; SS‐IV, intravenous Safety Set; TEAE, treatment‐emergent adverse event.Medical Dictionary for Regulatory Activities Version 16.1 Preferred Term.The only TEAEs reported in two or more patients were increased blood triglycerides. One event occurred in a 10‐year‐old male who had a blood triglyceride level of 1.72 mmol/L at screening and 2.52 mmol/L at the final visit (normal range: 0.27–1.55 mmol/L). This TEAE was considered moderate in severity. The patient was taking oral lacosamide and levetiracetam at baseline and had discontinued oxcarbazepine 8 days previously. The other event occurred in a 12‐year‐old female who had a blood triglyceride level of 1.45 mmol/L at screening, 0.90 mmol/L at baseline, and 1.71 mmol/L at the final visit (normal range: 0.42–1.47 mmol/L). This TEAE was considered mild in severity. The patient was taking oral lacosamide and levetiracetam at baseline. Of note, triglyceride levels rise after eating. Patients were not required to fast prior to assessment of lipid panel.Mean values for the majority of hematology and clinical chemistry parameters remained within the normal ranges for the duration of the trial (Appendix | PMC9977742 |
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DISCUSSION | critically ill, epilepsy | CRITICALLY ILL, EPILEPSY | This open‐label, multicentre trial is the largest prospective investigation of the safety and tolerability of IV lacosamide in pediatric patients with epilepsy. IV lacosamide (2–12 mg/kg/day or 100‐600 mg/day) was generally well tolerated in patients ≥1 month to <17 years of age, and no new safety concerns were identified. Nearly 72% of patients had not received lacosamide treatment in the 3 months preceding the trial, and most of the remaining patients were receiving oral lacosamide from a commercial supply. There was a mean overall exposure of IV lacosamide of 1.18 days, and most patients received one dose as a 30‐ to 60‐minute infusion.Bioequivalence of IV and oral lacosamide has been established in adults.As has been previously observed in studies of IV lacosamide in pediatric patients with epilepsy and in critically ill children, TEAEs were reported in few patients.The design of this trial was intended to maximize the available pool of patients by allowing for entry of individuals who were receiving oral lacosamide as adjunctive treatment or monotherapy (in an open‐label long‐term trial or by prescription), in addition to those who initiated IV lacosamide as adjunctive treatment following enrolment. Patients with ongoing oral lacosamide treatment were on a stable dose. | PMC9977742 |
Limitations | epilepsy | FOCAL SEIZURES, CLONIC SEIZURES, EPILEPSY | This trial is limited by its open‐label, uncontrolled design with no comparator or placebo group. The patient population was mostly White; the results may not be generalizable across racial groups. However, no relevant differences in the pharmacokinetics of lacosamide have been observed between healthy Asian, Black, and Caucasian individuals.Overall, IV lacosamide had an acceptable tolerability profile in pediatric patients ≥1 month to <17 years of age with epilepsy and focal seizures or primary generalized tonic–clonic seizures. No new safety concerns were identified. | PMC9977742 |
AUTHOR CONTRIBUTIONS | Mark Kristof Farkas and Iryna Makedonska were involved in execution of the trial as study investigators. Cynthia Beller was involved in analysis and interpretation of the data. Ali Bozorg and Nancy Yuen were involved in study design, and analysis and interpretation of the data. Carrie McClung and Robert Roebling were involved in study execution, and analysis and interpretation of the data. Tanisia Yates was involved in study design and execution. All authors critically reviewed the manuscript and approved the final version for submission. | PMC9977742 |
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CONFLICTS OF INTEREST | Mark Kristof Farkas and Iryna Makedonska each report no conflicts of interest. Cynthia Beller, Ali Bozorg, Carrie McClung, Robert Roebling, Tanisia Yates, and Nancy Yuen are employees of UCB Pharma. | PMC9977742 |
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ETHICAL APPROVAL | We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | PMC9977742 |
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Supporting information | APPENDIX |
Appendix S1–S2
Click here for additional data file. | PMC9977742 |
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ACKNOWLEDGMENTS | APPENDIX | The authors thank the patients, their caregivers, and the investigators and their teams who contributed to this trial (Appendix | PMC9977742 |
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DATA AVAILABILITY STATEMENT | Underlying data from this manuscript may be requested by qualified researchers 6 months after product approval in the United States and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymised individual patient‐level data and redacted trial documents which may include analysis‐ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at | PMC9977742 |
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REFERENCES | PMC9977742 |
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Methods | HOA | GROUP B | Fifty-seven patients with a lipid layer thickness (LLT) ≤ 75 interferometric colour units (ICU) were included in the study. In group A (20 patients) the effect of a single drop of F6H8 or CN on HOA and LLT was assessed immediately after application and up to two hours later. For long term effects (Group B) 37 patients applied CN or F6H8 five times a day for 12 weeks. Measurement of LLT, HOA, non-invasive-tear-break-up-time (NIBUT) and meibography were assessed prior to as well as at 4 weeks and 12 weeks after initiation of treatment. Our study is registered in the “German Clinical Trials Register” under the trial number: DRKS00028696. | PMC9847907 |
Results | HOA | CN led to an increase of the LLT from 46.8 ± 16.9 ICU to 76.3 ± 23.5 ICU (p = 0.021) and to an increase of HOA from 0.43 ± 0.06 μm to 0.48 ± 0.08 μm immediately after application (p = 0.027). There was no correlation between the increase of LLT and HOA (r = -0.04; p = 0.90). In group B an increase of LLT was observed in the F6H8 group from 45.8 ± 8.8 ICU at baseline to 66.7 ± 19.5 ICU at 12 weeks (p = 0.002). No changes of HOA were measured throughout the observation period in group B. After 12 weeks CN increased NIBUT from 9.9 ± 5.3 seconds to 15.5 ± 5.6 seconds (p = 0.04). F6H8 increased NIBUT from 12.4 ± 5.9 seconds to 16.9 ± 4.7 seconds (p = 0.02) after 12 weeks. | PMC9847907 |
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Conclusion | HOA | CN leads to a short-term increase in LLT and HOA, but only immediately after application. In contrast F6H8 does lead to an increase of LLT after regular long-term use but has no effect on HOA. The regular application of lipid-based products does not seem to decrease the quality of vision as measured in HOA. Instead, CN and F6H8, both are able to stabilize the tear film after regular application. | PMC9847907 |
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Data Availability | All relevant data are within the paper. | PMC9847907 |
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Introduction | neurosensory abnormalities, inflammation, Dry Eye Disease, disease of the ocular surface, hyperosmolarity | INFLAMMATION, DRY EYE DISEASE | Dry Eye Disease (DED) is defined as a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage as well as neurosensory abnormalities play etiological roles [The healthy tear film provides a smooth refractive surface which is of vital importance for optimal visual acuity [A large number of lipid containing lubricants is now available. These can be prepared as emulsions [ | PMC9847907 |
Materials and methods | PMC9847907 |
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Trial design | This was a parallel-group, randomized, active-controlled trial. | PMC9847907 |
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Participants, eligibility criteria, and settings | Eighty-two patients were included in this study. Two separate cohorts were recruited, one (A) to evaluate the immediate effect of a single application of two different lipid-based lubricants and a second (B) to assess the effect of a 12-week treatment with regular application five times per day.In cohort A (short term effect) after baseline measurement one single drop of study medication was applied. Both eyes were timed separately to ensure the same interval for all measurements. In 10 controls, one eye did not receive study medication. All measurements were taken immediately, 15 and 120 minutes after the application. To avoid disturbances of the tear film that would affect the continuous measurements, we resigned from further evaluation of other tear film parameters.In cohort B (long term effect) all participants applied the study medication 5 times per day for 12 weeks. All examinations were performed at baseline, and at 4- and 12-week follow-up as described above. They were advised to suspend the application of study medication 12 hours prior to the measurements. For cohort B an age- and sex-matched control group of healthy volunteers was recruited, which did not receive any treatment.Inclusion criteria were a lipid layer deficit, defined as less than 75 interferometric color units (ICU) measured with the LipiViewThe study took place at the Department of Ophthalmology at the University Hospital in Düsseldorf, Germany. | PMC9847907 |
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Interventions | Participants in both cohorts were randomized to either receive a cationic nanoemulsion (CN, Cationorm | PMC9847907 |
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Outcome measurements | DISEASE | All measurements followed the same protocol: First, symptoms were assessed using the Ocular Surface Disease Index (OSDIHOA were calculated from wavefront data based on the ray tracing method and corneal front surface data obtained with a rotating Scheimpflug camera (PentacamNon-invasive measurements of the lipid layer thickness were performed with the LipiViewNIBUT was determined non-invasively using the Oculus Keratograph 5M (OculusMeibography was also performed with the Oculus Keratograph 5M (Oculus | PMC9847907 |
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Sample size consideration | Sample size calculation is obtained from previous studies. | PMC9847907 |
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Randomization | Using a simple unrestricted system using the random generator function of Excel (Microsoft Excel 2017, Microsofta—CONSORT Flow Diagram for short-term effect group. b—CONSORT Flow Diagram for long-term effect group. | PMC9847907 |
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Ethics approval | RECRUITMENT, EYE | This prospective interventional randomized study included patients who were referred to Dry Eye clinic of the Department of Ophthalmology, University Hospital Duesseldorf, Germany, and healthy individuals without a history of DED who served as controls. All participants gave written informed consent for pseudonymized data analysis and anonymous publication during the recruitment process. The study and consent procedure were approved by the ethics committee of the University of Duesseldorf (no. 6057R), Germany, and adhered to the tenets of the Declaration of Helsinki. Our study is registered in the “German Clinical Trials Register” under the trial number: DRKS00028696. The results reported in this study are long-term data. Our reporting of results is completely transparent, and our clinical trial is registered in detail, so the quality remains high and retrospective registration did not influence the outcome of this study. The reason why we did not register our study in a registry is because we were under the impression that our local ethics committee´s approval was sufficient. The authors confirm that all ongoing and related trials for this drug/intervention are registered. | PMC9847907 |