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Supplementary Information | The online version contains supplementary material available at 10.1186/s12913-022-08994-0. | PMC9807970 | ||
Keywords | PMC9807970 | |||
Background | SECONDARY | Out-of-hours primary care service is a crucial part of a well-functioning health care system, which provides health care when general practitioners’ (GPs) offices are closed. The member countries of the Organisation for Economic Co-operation and Development have selected different models to provide this kind of service... | PMC9807970 | |
Methods | PMC9807970 | |||
Study design | This is a pragmatic randomized controlled educational intervention among Norwegian telephone triage nurses working in out-of-hours GP cooperatives. All Norwegian out-of-hours GP cooperatives that met our inclusion criteria were included in the study (Table Inclusion criteria for out-of-hours GP cooperativesThe out-of-h... | PMC9807970 | ||
The intervention | RTIs | MAY, APPENDIX | The intervention consisted of two parts:
A 90 minute e-learning course about acute RTIs and general communication techniques for telephone triage nurses (see Appendix A 90 minute group discussion for the telephone triage nurses. Dedicated local nurses led the group sessions based on a written guide (Appendix The interv... | PMC9807970 |
Variables | infection, pneumonia | PNEUMONIA, ACUTE BRONCHITIS, ACUTE TONSILLITIS, URINARY TRACT INFECTIONS, ACUTE SINUSITIS, EAR INFECTIONS, INFECTION, SECONDARY, ACUTE LARYNGITIS, INFLUENZA | GP offices and out-of-hours GP cooperatives send electronic compensation claims to the Norwegian Health Economics Administration. The claims contain data on date and type of contact (phone, consultation, or home visit) with GP offices and out-of-hours GP cooperatives as well as age, gender, and diagnosis of the caller/... | PMC9807970 |
Statistical analysis | REGRESSION | We used frequencies and percentages to describe the distribution of the sample population and count data relating to contacts and consultations made in the control and intervention arms, and StataSE 17 (StataCorp. 2021. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC) for the statistical anal... | PMC9807970 | |
Results | PMC9807970 | |||
Population and epidemiology at baseline | sore throat, Laryngitis | EAR INFECTIONS, RTI, SORE THROAT, LARYNGITIS | The 59 out-of-hours cooperatives served 3.12 million inhabitants (59% of the Norwegian population) in 198 (of 356) municipalities. There were 4.72 million contacts in primary health care in these municipalities in the baseline period, of which 4.37 million were list-holding GPs’ consultations and 0.35 million were GP c... | PMC9807970 |
Discussion | The patient population attending the out-of-hours service during the winter season was younger and had a higher proportion of RTIs than the population attending the regular GP offices. The educational intervention about RTIs and communication skills for telephone triage nurses did not decrease the number of consultatio... | PMC9807970 | ||
Population and epidemiology at baseline | sore throat, sinusitis, streptococci | SORE THROAT, SINUSITIS, ACUTE LARYNGITIS, STREPTOCOCCAL TONSILLITIS | The out-of-hours patient population is characterized by a higher proportion of children and teenagers compared with list-holding GPs’ patient population, especially for RTIs. Danish parents reported a perceived need for prompt action, unpleasant symptoms and worry as some of the main reasons for contacting the out-of-h... | PMC9807970 |
Effect of the intervention | SECONDARY | Dutch GPs believe that a stricter triage and annual feedback to triage nurses will reduce the number of non-urgent visits to the out-of-hours cooperatives [The decision to seek health care is a complex process influenced by several factors, such as personal, social, and cultural, as well as characteristics of the healt... | PMC9807970 | |
Methodological considerations | coronavirus disease 2019 | REGRESSION, DISEASE, CORONAVIRUS DISEASE 2019, SECONDARY | The data from the Norwegian Directory of Health are reliable and a good source of information about the study population as well as activity in primary health care [The large proportion of the population being covered by the included out-of-hours GP cooperatives, in addition to narrow confidence intervals, indicate tha... | PMC9807970 |
Conclusion | SECONDARY | The described educational intervention for telephone triage nurses did not influence the out-of-hours attendance for RTIs or list-holding GPs’ attendance. Changing a population’s health service attendance is complicated, and the intervention’s pragmatic design with a lack of control on the proportion of participating n... | PMC9807970 | |
Acknowledgements | RESPIRATORY TRACT INFECTIONS, SCHMIDT, EMERGENCY, HANSEN | Ibrahimu Mdala (Researcher, Department of General Practice, Institute of Health and Society, University of Oslo) provided invaluable help with the statistical analyses and descriptions. Arngeir Berge (Senior Adviser and Educationalist, National Centre for Emergency Primary Health Care, Norway) converted our texts about... | PMC9807970 | |
Authors’ contributions | All authors contributed to the study design and the educational intervention. IKR identified the out-of-hours cooperatives that met the inclusion criteria. BHL administrated the intervention, prepared the raw data for analysis, and performed the analysis with support from SH. All the authors contributed to the interpre... | PMC9807970 | ||
Funding | This work was supported by The Norwegian Research Fund for General Practice as a PhD grant to the first author. | PMC9807970 | ||
Availability of data and materials | The raw data analysed during the current study contains person sensitive information and publication of these data has not been approved by The Norwegian Data Protection Authority. However, a modified dataset is available from the corresponding author on reasonable request. | PMC9807970 | ||
Declarations | PMC9807970 | |||
Ethics approval and consent to participate | The study protocol was assessed by The Regional Committee for Research Ethics (2018/1080/REK sør-øst C), which concluded that the study, according to the Norwegian Act on medical and health research, did not need ethical approval [ | PMC9807970 | ||
Consent for publication | Not applicable. | PMC9807970 | ||
Competing interests | The authors declare that they have no competing interests. | PMC9807970 | ||
References | PMC9807970 | |||
Background | migraines | MIGRAINES | The phase 3 randomized PERSIST study demonstrated the efficacy and tolerability of galcanezumab, a humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody for prevention of episodic migraines. We present findings from the open-label extension (OLE) of PERSIST, which evaluated the long-term efficacy an... | PMC10401806 |
Methods | migraine headache | MIGRAINE HEADACHE | Patients completing the 3-month double-blind period of PERSIST were eligible for the 3-month OLE. Patients previously randomized to galcanezumab (GMB/GMB group) continued to receive galcanezumab 120 mg at all three visits during the OLE whereas patients randomized to placebo received a 240 mg loading dose of galcanezum... | PMC10401806 |
Results | ADVERSE EVENT | Overall, 99% of patients completing the double-blind period entered the OLE, and 96% completed through month 6. Patients in the GMB/GMB group achieved continued improvements in efficacy, with the reduction from baseline in the mean number of monthly MHDs, and slightly increasing from 4.01 days at the end of the double-... | PMC10401806 | |
Conclusions | migraine | MIGRAINE | Galcanezumab was efficacious and well-tolerated in patients with episodic migraine from China, India and Russia, for up to 6 months. | PMC10401806 |
Trial registration | MAY | ClinicalTrisABSTRACT_pals.gov NCT03963232, registered May 24, 2019. | PMC10401806 | |
Supplementary Information | The online version contains supplementary material available at 10.1186/s10194-023-01613-1. | PMC10401806 | ||
Keywords | PMC10401806 | |||
Background | migraine, Migraine, migraines | MIGRAINE, MIGRAINE, MIGRAINES | Migraine was estimated to affect more than one billion individuals worldwide in 2019 [Among individuals affected by migraines, around one-third (34–39%) may be candidates for preventive therapy [Calcitonin gene-related peptide (CGRP) has a key pathophysiological role in migraine and is expressed widely in the central a... | PMC10401806 |
Methods | PMC10401806 | |||
Study design and treatment | The phase 3 PERSIST study (NCT03963232) was conducted at 26 centers in China, 20 in India, and 4 in Russia (40 total). There were five study periods (Suppl. Figure | PMC10401806 | ||
Patients | Eligibility criteria for the PERSIST trial have been described previously [ | PMC10401806 | ||
Assessments and endpoints | reductions of ≥, deaths, migraine-associated, headaches | ADVERSE EVENTS | The primary efficacy measure was mean change in the number of monthly MHDs from double-blind baseline (the prospective baseline period) to month 6. Secondary endpoints included response rates (based on percent reduction in monthly MHDs from double-blind baseline to month 6), functional outcomes, safety and tolerability... | PMC10401806 |
Statistical analysis | Efficacy and safety analyses were performed in all randomized patients who received at least one dose of the study drug in groups defined by treatment assignment during the double-blind period, i.e., patients previously randomized to galcanezumab (GMB/GMB group) or to placebo (PBO/GMB group). The efficacy analysis incl... | PMC10401806 | ||
Results | PMC10401806 | |||
Immunogenicity | Among 482 evaluable patients treated with galcanezumab during the double-blind and/or OLE period, 71 (14.7%) had ADAs present at baseline, with 37 patients (7.7%) having neutralizing ADAs. TE-ADAs were detected during galcanezumab treatment in 63 (13.1%) patients, including 59 patients (12.2%) who developed neutralizin... | PMC10401806 | ||
Discussion | migraine | MIGRAINE | In this 3-month OLE of the PERSIST study, galcanezumab 120 mg continued to be efficacious in patients from China, India and Russia with episodic migraine for up to 6 months, with a generally good safety profile.The findings in predominantly Asian patients are consistent with published results from the OLE of the phase ... | PMC10401806 |
Conclusions | migraine | MIGRAINE | Once-monthly galcanezumab 120 mg was efficacious and well-tolerated for up to 6 months in patients from China, India, and Russia with episodic migraine. Our results support the long-term findings from OLEs of prior pivotal phase 3 studies of galcanezumab in patients with migraine [ | PMC10401806 |
Acknowledgements | The authors wish to acknowledge Stephanie Carter PhD, CMPP and Jake Burrell PhD (Rude Health Consulting Ltd.) for medical writing support, which was paid for by Eli Lilly and Company. The authors thank Yu Mao from Eli Lilly and Company for project management and medical writing assistance. The authors thank Yan Cheng a... | PMC10401806 | ||
Authors’ contributions | SY was involved in study design, data acquisition and interpretation. JZ, LZ, DC, KS, GL, XY, and MZ were involved in data acquisition and interpretation. LS, HL and CQ were involved in data analysis and interpretation. All the authors revised the manuscript critically and approved the final version of the manuscript. | PMC10401806 | ||
Funding | The PERSIST study was funded by Eli Lilly and Company. | PMC10401806 | ||
Availability of data and materials | Lilly provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data. Data are available upon reasonable request. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after... | PMC10401806 | ||
Declarations | PMC10401806 | |||
Ethics approval and consent to participate | This study was conducted in accordance with the Declaration of Helsinki, Council for International Organizations of Medical Sciences International Ethical Guidelines, International Conference on Harmonisation guidelines for Good Clinical Practice, and applicable local laws and regulations. Patients provided written inf... | PMC10401806 | ||
Consent for publication | Not applicable. | PMC10401806 | ||
Competing interests | Headache, Pain | LS, HL and CQ are full-time employees of Eli Lily and Company. SY serves as associated editor of the Journal of Headache and Pain and as a member of the International Headache Society. MZ has no competing interests. JZ, LZ, DC, KS, GL, XY and SY declare receiving clinical research fees from Eli Lilly and Company for pa... | PMC10401806 | |
References | PMC10401806 | |||
Purpose: |
CB-103 selectively inhibits the CSL–NICD (Notch intracellular domain) interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This dose-escalation/expansion study aimed to determine safety, pharmacokinetics, and preliminary antitumor activity. | PMC10501326 | ||
Experimental Design: | toxicities, tumor, DLT, hematologic malignancies | DISEASE PROGRESSION, TUMOR, SOLID TUMORS, HEMATOLOGIC MALIGNANCIES, ADENOID CYSTIC CARCINOMA | Patients ≥18 years of age with selected advanced solid tumors [namely, adenoid cystic carcinoma (ACC)] and hematologic malignancies were eligible. CB-103 was dosed orally in cycles of 28 days at escalating doses until disease progression. Notch-activating mutations were required in a dose confirmatory cohort. Endpoints... | PMC10501326 |
Results: | tumor, DLTs, toxicity, anemia, deaths | ADVERSE EVENTS, TUMOR, ANEMIA, DISEASE | Seventy-nine patients (64, 12 dose-escalation cohorts; 15, confirmatory cohort) enrolled with 54% receiving two or more lines of prior therapy. ACC was the dominant tumor type (40, 51%). Two DLTs were observed [elevated gamma-glutamyl transferase (GGT), visual change]; recommended phase II dose was declared as 500 mg t... | PMC10501326 |
Conclusions: | CB-103 had a manageable safety profile and biological activity but limited clinical antitumor activity as monotherapy in this first-in-human study. | PMC10501326 | ||
Significance: | DISEASE | CB-103 is a novel oral pan-Notch inhibitor that selectively blocks the CSL–NICD interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This first-in-human dose-escalation and -confirmation study aimed to determine the safety, pharmacokinetics, and preliminary antitumor efficacy of ... | PMC10501326 | |
Introduction | human cancer, cancer, T-ALL/LBL, hematologic cancer, T-cell acute lymphoblastic leukemia/lymphoma | PROLIFERATION, CANCER, METASTASIS, HEMATOLOGIC CANCER | Notch signaling plays a critical role in many cellular processes during development to promote cell-cell communication, whereas dysregulation leads to sustained cell proliferation and potential for invasion or metastasis—the hallmarks of cancer. Signaling of the pathway occurs when ligands bind one of four Notch recept... | PMC10501326 |
Materials and Methods | PMC10501326 | |||
Study Population | malignant glomus tumor, T-ALL/LBL, cardiac disease, tumor | GASTROINTESTINAL TUMORS, TUMOR, THROMBOEMBOLIC EVENT, BREAST CANCER, DISEASE, SOLID TUMORS, OSTEOSARCOMA, HEPATOCELLULAR CARCINOMA, CARDIAC DISEASE, ONCOLOGY | The study enrolled adults with histologically confirmed, locally advanced and/or metastatic solid tumors who had progressed on at least one line of prior systemic therapy (except for ACC) and relapsed/refractory T-ALL/LBL for whom no standard therapy was available. In dose escalation, participants with solid tumors wit... | PMC10501326 |
Study Design | cancer, intercurrent illness, ≤28 | ADVERSE EVENT, DISEASE PROGRESSION, CANCER, ADVERSE EVENT, STAGGERED, REGRESSION | The study was an open-label, nonrandomized, phase I/II dose-escalation study with planned expansion cohorts. In Part A, participants received CB-103 orally on a once daily schedule (28-day cycle length) which could be adapted during escalation to twice daily or intermittent dosing based on pharmacokinetic and safety si... | PMC10501326 |
Study Endpoints | SD | DISEASE | The primary endpoint for dose escalation was the number of patients experiencing DLT during the first 28-day cycle of CB-103 and for the confirmatory phase, the incidence rate, severity, and relationship of AEs to CB-103. Secondary endpoints included assessment of clinical benefit rate [CBR; defined as achieving comple... | PMC10501326 |
Pharmacokinetics | Plasma pharmacokinetics were assessed for CB-103 via blood samples taken on days 1 (predose, 0.5, 1, 2, 4, 6, 8 hours postdose ± 5 minutes, and 12 hours postdose ± 15 minutes), 2 (24-hour post-day 1, predose), 3 (predose), 8 (predose, 0.5, 1, 2, 4, 6, and 8 hour postdose ± 5 minutes), 9 (24-hour post-day 8, predose), 1... | PMC10501326 | ||
Pharmacodynamics and Biomarker Assessments | tumor | DISEASE PROGRESSION, TUMOR | Archival tumor tissue (not older than 6 months prior to screening) or fresh tumor biopsy was required to characterize Notch alteration status by targeted genomic sequencing and/or NICD1 expression (via IHC) among the confirmatory cohort at baseline. Repeat biopsy on cycle 2 day 15 and at disease progression was optiona... | PMC10501326 |
Statistical Analysis | The safety set (SS) consisted of all patients who received at least one dose of CB-103 and who had at least one postbaseline safety assessment. The SS was the primary population for all safety and efficacy analyses, except for determination of dose-DLT relationship. The dose-determining set was used to determinate the ... | PMC10501326 | ||
Study Oversight and Data Availability | The study was performed in accordance with the Declaration of Helsinki statement on ethical biomedical research and with the International Conference on Harmonization Guidelines for Good Clinical Practice. The study was approved by the local Institutional Review Boards for each study site. All patients provided written... | PMC10501326 | ||
Results | PMC10501326 | |||
Patient Characteristics | ALL | ACUTE LYMPHOBLASTIC LEUKEMIA, LYMPHOBLASTIC LYMPHOMA, ONCOLOGY, ADENOID CYSTIC CARCINOMA | From December 2017 to January 2022, a total of 79 patients enrolled to the study, including 64 subjects to 12 escalating dose cohorts (ranging from 13 mg once daily to 500 mg twice daily 5 days on and 2 days off each week), and 15 subjects to a single confirmatory cohort dosed at 500 mg once daily (Patient demographics... | PMC10501326 |
Safety and Tolerability | DLTs, TRAEs | Two DLTs were observed across 12 dose-escalation cohorts (Among the SS population (TRAEs reported per-patient with incidence ≥10%NOTE:
| PMC10501326 | |
Efficacy and Survival | ADENOID CYSTIC CARCINOMA, SOLID TUMOR | Among all 76 solid tumor patients (including the confirmatory cohort and all patients with ACC), there were 37 (49%) demonstrating SD but no objective responses (Efficacy and survival outcomes for patients with solid tumorAbbreviations: ACC = adenoid cystic carcinoma, CI = confidence interval, NR = not reached, PFS = p... | PMC10501326 | |
Pharmacokinetics | Robust pharmacokinetic sampling was performed across 7 days in cycle 1, 2 days in cycle 2, and before and after CB-103 dosing in cycles 3–6. Mean pharmacokinetic plasma concentrations (ng/mL) increased across dose-escalation cohorts 1 through 8 (522 mg once daily) demonstrating a peak (t | PMC10501326 | ||
Exploratory Biomarkers | Among the study cohort (Percent change (%) in peripheral blood cell Notch target gene expression was monitored among a subset of patients with ACC receiving twice daily dosing ( | PMC10501326 | ||
Discussion | ACC-I, fatigue, diarrhea, toxicity, toxicities, anemia, aggressive disease, deaths | DISEASE, ANEMIA, SOLID TUMOR | This phase I/II study of the novel, oral pan-Notch inhibitor CB-103 determined the RP2D as 500 mg twice daily utilizing a 5 day on and 2 day off weekly schedule. Overall, CB-103 was well tolerated with 15 of 79 patients (19%) experiencing grade 3 or 4 AEs which were all reversible, with no deaths related to study drug,... | PMC10501326 |
Supplementary Material | toxicity | Study design, dose escalation, and confirmatory dosing cohorts (Part A) for CB-103Click here for additional data file.Pharmacokinetic parametersClick here for additional data file.Biomarkers of Clinical Benefit for ACC patientsClick here for additional data file.Safety and toxicity monitoring throughout the CB-103 clin... | PMC10501326 | |
Acknowledgments | tumor | TUMOR | The authors thank the patients and their families, all coinvestigators, and research coordinators for participating in the study. We thank Professor Jon Aster for his support and scientific contribution to evaluating the tumor
| PMC10501326 |
Authors’ Disclosures | Cancer, Pierre, Leukemia, fromAstraZeneca, P., Schönborn-Kellenberger, Oncology/Cancer | ONCOLOGY, LEUKEMIA, CANCER | G. J. Hanna reports relevant consulting/advisory for Kura, Prelude, and Remix; research support to institution from AACRF, Actuate, Elevar, Gateway for Cancer Research, Genentech, Immunitybio, and V Foundation. A. Stathis reports other, institutional, travel grant from AstraZeneca, Incyte; expert testimony, institution... | PMC10501326 |
Authors’ Contributions | PMC10501326 | |||
References | PMC10501326 | |||
Introduction | CORONAVIRUS, CORONAVIRUS DISEASE 2019, SEVERE ACUTE RESPIRATORY SYNDROME | Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health crisis that is driving efforts to identify alternative medicinal plants to be used in COVID-19 treatment. There is evidence that the Acanthaceae family member Liquid chromatography-tandem ... | PMC9924185 | |
Materials and methods | PMC9924185 | |||
Materials | Standards of andrographolide, AP1 (purity = 100.00%); 14-deoxy-11, 12-didehydroandrographolide, AP3 (purity = 99.80%); neoandrographolide, AP4 (purity = 99.67%); and 14-deoxyandrographolide, AP6 (purity = 100.00%) were supplied by Phytolab GmbH & Co.KG (Vestenbergsgreuth, Germany). The internal standard (IS) of digoxin... | PMC9924185 | ||
Methods | PMC9924185 | |||
Screening and identification of the analyte and metabolite profiling using LC-QTOF/MS analysis | SEPARATION | For qualitative determination of untargeted compounds, liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) was performed on an Agilent 6540 QTOF/MS (Agilent Technologies, USA) equipped with an Agilent 1260 infinity liquid chromatography system. The stationary phase of the chromatographic sepa... | PMC9924185 | |
Development of analytical and instrument conditions for quantitative determination of four major diterpenoids using LC-QqQ-MS/MS analysis | PMC9924185 | |||
LC and MS condition optimization | SEPARATION | Liquid chromatography-tandem mass spectrometry (LC–MS/MS) was performed using a Nexera X2 LCMS-8060NX triple quadrupole mass spectrometer (Shimadzu, Japan) equipped with a SIL-40C XR autosampler, CTO-40C column oven, CBM-40lite system controller, FCV-20AH2 switching valve, DGU-403 degasser, and LC-40D XR solvent delive... | PMC9924185 | |
Preparation of stock standards and working solutions | The primary stock solution (1.00 mg/mL) of the four standard diterpenoids (AP1, AP3, AP4, and AP6) and an internal standard (digoxin) were prepared and then stored at − 20 °C. Briefly, each standard was accurately weighed and dissolved in the appropriate volume of methanol (HPLC grade). Working solutions containing the... | PMC9924185 | ||
Preparation of calibration standards and quality control (QC) samples | A calibration curve was generated from different standard concentrations that were prepared by spiking a small volume of the working solution (not more than 5% of the total volume) into blank human plasma or urine to obtain twelve final concentrations ranging between 0.98 and 1000.00 ng/mL for each analyte. Quality Con... | PMC9924185 | ||
Plasma and urine samples extraction | An aliquot of 50 µL of plasma or urine was placed in a 1.5 mL of polypropylene centrifuge micro-tube. Protein was removed from the sample by adding 200 µL of methanol (containing 50.00 ng/mL of IS). The mixture was vortexed for 10 min and was then centrifuged at 12,000 rpm, 4 °C for 10 min. The supernatant was filtered... | PMC9924185 | ||
Method validation | The bioanalytical method of LC-QqQ-MS/MS analysis was fully validated for (1) selectivity and specificity, (2) accuracy and precision, (3) linearity, range and lower limit of quantification, (4) recovery, (5) matrix effect, (6) stability, and (7) hemolyzed plasma effect, according to the US FDA Bioanalytical Method Val... | PMC9924185 | ||
Key performance characteristics of method validation | PMC9924185 | |||
Selectivity and specificity | The selectivity and specificity were evaluated by comparing between the retention time of the extracted blank plasma or blank urine and the retention time of each spiked standard or IS in the extracted samples. If any interferences were observed, the signal of their peak area should be less than 20% of the peak area of... | PMC9924185 | ||
Accuracy and precision | For within-day accuracy and precision, four concentration levels at LLOQ, LQC, MQC, and HQC in five replicates, were determined in the same day. For determination of inter-day accuracy and precision, the same concentrations were extracted and analyzed on separate days (three different days) and used for three batch run... | PMC9924185 | ||
Linearity, range and lower limit of quantification (LLOQ) | REGRESSION | A twelve-point calibration curve was constructed by plotting the peak-area ratio (analyte:IS) against the concentration of the calibration standards. Determination of linearity was done using 3 calibration curves from each day (three separate days). The analysis requirement of linear regression was determined by the co... | PMC9924185 | |
Recovery | The recovery of the four diterpenoids in plasma and urine was measured at three different QC concentrations: LQC, MQC and HQC (n = 5 for each concentration) for both pre-spiked standard of QC samples and post-spiked standard of blank plasma or urine. Extraction recoveries were calculated by comparing the peak area of p... | PMC9924185 | ||
Matrix effect | Matrix effects at three levels of QC concentrations (LQC, MQC and HQC) were determined by comparing the mean peak area of the samples prepared by spiking post-extracted samples with the analytes and IS in solution (without extraction) at corresponding concentrations. The %CV of the matrix effect should be within the ac... | PMC9924185 | ||
Stability | The stability of plasma and urine samples were evaluated at three different QC concentration levels (LQC, MQC and HQC, n = 3 for each level); the conditions were freeze–thaw stability, long-term stability, short-term stability, and post preparative stability in an autosampler. The evaluation of stability under freeze–t... | PMC9924185 | ||
Hemolyzed plasma effect | hemolysis | HEMOLYSIS | To evaluate the effect of hemolysis of red blood cells on the quantification of analytes, hemolyzed plasma was prepared by adding hemolyzed whole blood (3% V/V) into blank plasma | PMC9924185 |
Quantitative determination of conjugated metabolites using enzymatic digestion assay | PMC9924185 | |||
Optimized enzymatic digestion | To optimize the hydrolysis process for determination of conjugated metabolites, enzymatic digestion with glucuronidase and sulfatase was performed under different incubation conditions. The hydrolysis reaction was initiated by adding 50 µL of either enzyme into a 50 µL of plasma or urine sample using different enzyme c... | PMC9924185 | ||
Method application to pharmacokinetic study | The validated method was applied in pharmacokinetic investigation of four major diterpenoids in healthy subjects after oral administration of | PMC9924185 | ||
Institutional review board and informed consent statement | The study protocol was approved by the Institutional Review Board of the Chulabhorn Research Institute (approval date: 28/08/2020, IRB number: 062/2563) and also registered with the Thai Clinical Trials Registry (approval date: 01/02/2021, TCTR20210201005). All clinical procedures were performed in compliance with the ... | PMC9924185 | ||
Study design and eligibility criteria | The clinical pharmacokinetic study was designed as an open-labeled, with a single oral dosing, and conducted under a fasting condition. Four healthy subjects were recruited according to the following inclusion criteria: 18—55 years old with a body mass index (BMI) of 18–30 kg/m | PMC9924185 |
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