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BACKGROUNDS: There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due to immune-related adverse events (irAEs) or progressive disease (PD). Here, we performed a meta-analysis to elucidate the possible benefits of ICI rechallenge in patients with cancer. METHODS: Systematic searches were conducted using PubMed, Embase, and Cochrane Library databases. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of irAEs were the outcomes of interest. RESULTS: Thirty-six studies involving 2026 patients were analyzed. ICI rechallenge was associated with a lower incidence of all-grade (OR, 0.05; 95%CI, 0.02-0.13, Pâ <â .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, Pâ <â .05) when compared with initial ICI treatment. Though no significant difference was observed between rechallenge and initial treatment regarding ORR (OR, 0.69; 95%CI, 0.39-1.20, Pâ =â .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, Pâ =â 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, Pâ <â .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, Pâ <â .05) than those who discontinued ICI therapy permanently. Subgroup analysis revealed that for patients who stopped initial ICI treatment because of irAEs, rechallenge showed similar safety and efficacy with initial treatment, while for patients who discontinued ICI treatment due to PD, rechallenge caused a significant increase in the incidence of high-grade irAEs (OR, 4.97; 95%CI, 1.98-12.5, Pâ <â .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, Pâ <â .05). CONCLUSION: ICI rechallenge is generally an active and feasible strategy that is associated with relative safety, similar efficacy, and improved survival outcomes. Rechallenge should be considered individually with circumspection, and randomized controlled trials are required to confirm these findings.
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BACKGROUND: Ferroptosis has recently been associated with multiple degenerative diseases. Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases. However, the association of iron proliferation-related genes with prognosis in HER2+ breast cancer (BC) patients is unclear. AIM: To identify and evaluate fresh ferroptosis-related biomarkers for HER2+ BC. METHODS: First, we obtained the mRNA expression profiles and clinical information of HER2+ BC patients from the TCGA and METABRIC public databases. A four-gene prediction model comprising PROM2, SLC7A11, FANCD2, and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort. Patients were stratified into high-risk and low-risk groups based on their median risk score, an independent predictor of overall survival (OS). Based on these findings, immune infiltration, mutations, and medication sensitivity were analyzed in various risk groupings. Additionally, we assessed patient prognosis by combining the tumor mutation burden (TMB) with risk score. Finally, we evaluated the expression of critical genes by analyzing single-cell RNA sequencing (scRNA-seq) data from malignant vs normal epithelial cells. RESULTS: We found that the higher the risk score was, the worse the prognosis was (P < 0.05). We also found that the immune cell infiltration, mutation, and drug sensitivity were different between the different risk groups. The high-risk subgroup was associated with lower immune scores and high TMB. Moreover, we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses. HRisk-HTMB patients had the worst prognosis, whereas LRisk-LTMB patients had the best prognosis (P < 0.0001). Analysis of the scRNA-seq data showed that PROM2, SLC7A11, and FANCD2 were significantly differentially expressed, whereas FH was not, suggesting that these genes are expressed mainly in cancer epithelial cells (P < 0.01). CONCLUSION: Our model helps guide the prognosis of HER2+ breast cancer patients, and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.
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OBJECTIVES: Small bowel (SB) endoscopic healing has not been well explored in patients with Crohn's disease (CD). This study aimed to assess the clinical utility of SB endoscopic mucosal and histological healing in patients with CD. METHODS: In total, 99 patients with CD in clinical-serological remission were retrospectively followed after they underwent colonoscopy and double-balloon enteroscopy. Time until clinical relapse (CD activity index of >150 with an increase of >70 points) and serological relapse (abnormal elevation of C-reactive protein levels) constituted the primary endpoints. RESULTS: Of the 99 patients, 75 (74.7%) exhibited colonoscopic healing and 43 (43.4%) exhibited SB endoscopic healing. Clinical relapse, serological relapse, hospitalization, and surgery occurred in 8 (18.6%), 11 (25.6%), 11 (25.6%), and 2 (4.6%) patients, respectively. Of the 43 patients who exhibited SB endoscopic healing, 21 (48.8%) achieved histological healing. Clinical relapse, serological relapse, hospitalization, and surgery occurred in 4 (19.0%), 7 (33.3%), 7 (33.3%), and 1 (4.8%) patient, respectively. There was no statistically significant difference in the number of patients who relapsed, were hospitalized, or underwent surgery between those who exhibited histological healing and those who did not. CONCLUSION: A substantial number of patients who were in clinical-serological remission did not undergo SB endoscopic healing, and the lesions increased their risk of clinical relapse. Thus, endoscopic healing may be of greater clinical value than histological healing when evaluating the remission of patients with CD.
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Enfermedad de Crohn , Humanos , Enfermedad de Crohn/patología , Estudios Retrospectivos , Intestino Delgado/patología , Colonoscopía , Inducción de Remisión , Recurrencia , Índice de Severidad de la EnfermedadRESUMEN
Rice grain is a poor dietary source of zinc (Zn) but the primary source of cadmium (Cd) for humans; however, the molecular mechanisms for their accumulation in rice grain remain incompletely understood. This study functionally characterized a tonoplast-localized transporter, OsMTP1. OsMTP1 was preferentially expressed in the roots, aleurone layer, and embryo of seeds. OsMTP1 knockout decreased Zn concentration in the root cell sap, roots, aleurone layer and embryo, and subsequently increased Zn concentration in shoots and polished rice (endosperm) without yield penalty. OsMTP1 haplotype analysis revealed elite alleles associated with increased Zn level in polished rice, mostly because of the decreased OsMTP1 transcripts. OsMTP1 expression in yeast enhanced Zn tolerance but did not affect that of Cd. While OsMTP1 knockout resulted in decreased uptake, translocation and accumulation of Cd in plant and rice grain, which could be attributed to the indirect effects of altered Zn accumulation. Our results suggest that rice OsMTP1 primarily functions as a tonoplast-localized transporter for sequestrating Zn into vacuole. OsMTP1 knockout elevated Zn concentration but prevented Cd deposition in polished rice without yield penalty. Thus, OsMTP1 is a candidate gene for enhancing Zn level and reducing Cd level in rice grains.
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Oryza , Zinc , Humanos , Zinc/metabolismo , Cadmio/metabolismo , Oryza/metabolismo , Vacuolas/metabolismo , Raíces de Plantas/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Grano Comestible/metabolismoRESUMEN
BACKGROUND: 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (BT2) is a benzothiophene carboxylate derivative that can suppress the catabolism of branched-chain amino acid (BCAA)-associated mammalian target of rapamycin complex 1 (mTORC1) activation. Previous studies have demonstrated the therapeutic effects of BT2 on arthritis, liver cancer, and kidney injury. However, the effects of BT2 on ulcerative colitis (UC) are unknown. AIM: To investigate the anti-UC effects of BT2 and the underlying mechanism. METHODS: Mouse UC models were created through the administration of 3.5% dextran sodium sulfate (DSS) for 7 d. The mice in the treated groups were administered salazosulfapyridine (300 mg/kg) or BT2 (20 mg/kg) orally from day 1 to day 7. At the end of the study, all of the mice were sacrificed, and colon tissues were removed for hematoxylin and eosin staining, immunoblot analyses, and immunohistochemical assays. Cytokine levels were measured by flow cytometry. The contents of BCAAs including valine, leucine, and isoleucine, in mouse serum were detected by liquid chromatography-tandem mass spectrometry, and the abundance of intestinal flora was analyzed by 16S ribosomal DNA sequencing. RESULTS: Our results revealed that BT2 significantly ameliorated the inflammatory symptoms and pathological damage induced by DSS in mice. BT2 also reduced the production of the proinflammatory cytokines interleukin 6 (IL-6), IL-9, and IL-2 and increased the anti-inflammatory cytokine IL-10 level. In addition, BT2 notably improved BCAA catabolism and suppressed mTORC1 activation and cyclooxygenase-2 expression in the colon tissues of UC mice. Furthermore, high-throughput sequencing revealed that BT2 restored the gut microbial abundance and diversity in mice with colitis. Compared with the DSS group, BT2 treatment increased the ratio of Firmicutes to Bacteroidetes and decreased the abundance of Enterobacteriaceae and Escherichia-Shigella. CONCLUSION: Our results indicated that BT2 significantly ameliorated DSS-induced UC and that the latent mechanism involved the suppression of BCAA-associated mTORC1 activation and modulation of the intestinal flora.
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Colitis Ulcerosa , Colitis , Microbioma Gastrointestinal , Animales , Ratones , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Colitis/inducido químicamente , Colon/patología , Citocinas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , MamíferosRESUMEN
Renal fibrosis is an inevitable outcome of various manifestations of progressive chronic kidney diseases (CKD). The need for efficacious treatment regimen against renal fibrosis can therefore not be overemphasized. Here we show a novel protective role of Bacteroides fragilis (B. fragilis) in renal fibrosis in mice. We demonstrate decreased abundance of B. fragilis in the feces of CKD patients and unilateral ureteral obstruction (UUO) mice. Oral administration of live B. fragilis attenuates renal fibrosis in UUO and adenine mice models. Increased lipopolysaccharide (LPS) levels are decreased after B. fragilis administration. Results of metabolomics and proteomics studies show decreased level of 1,5-anhydroglucitol (1,5-AG), a substrate of SGLT2, which increases after B. fragilis administration via enhancement of renal SGLT2 expression. 1,5-AG is an agonist of TGR5 that attenuates renal fibrosis by inhibiting oxidative stress and inflammation. Madecassoside, a natural product found via in vitro screening promotes B. fragilis growth and remarkably ameliorates renal fibrosis. Our findings reveal the ameliorative role of B. fragilis in renal fibrosis via decreasing LPS and increasing 1,5-AG levels.
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Productos Biológicos , Microbioma Gastrointestinal , Enfermedades Renales , Insuficiencia Renal Crónica , Obstrucción Ureteral , Adenina/metabolismo , Animales , Bacteroides fragilis , Productos Biológicos/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Riñón/metabolismo , Enfermedades Renales/patología , Lipopolisacáridos/metabolismo , Lipopolisacáridos/toxicidad , Ratones , Insuficiencia Renal Crónica/patología , Transportador 2 de Sodio-Glucosa/metabolismo , Obstrucción Ureteral/metabolismoRESUMEN
INTRODUCTION: A hypersensitivity response akin to immune reconstitution inflammatory syndrome (IRIS) has been proposed as a mechanism responsible for anti-PD-1 therapy-induced tuberculosis. IRIS is associated with enhanced activation of IL-17A-expressing CD4 + T cells (Th17). Gut microbiota is thought to be linked to pulmonary inflammation through the gut-lung axis. MATERIALS AND METHODS: We used ImmuCellAI to investigate the T cell population in lung cancer and tuberculosis samples. Then, we applied flow cytometry to monitor the expression levels of the Th17 cell activation marker CD38 in the peripheral blood of a patient experiencing adverse events, including tuberculosis, in response to pembrolizumab. The gut microbiome was examined by 16S rRNA sequencing to examine the alterations caused by pembrolizumab. RESULTS: The percentage of Th17 cells was increased in both lung cancer and tuberculosis. FACS analysis showed that pembrolizumab induced substantial CD38 expression in Th17 cells. The patient's fecal samples showed that the diversity of the gut microbiota was significantly increased in response to the pembrolizumab cycle. One enriched genus was Prevotella, which has previously been linked to lung inflammation and Th17 immune activation. DISCUSSION: The observed Th17 activation in our patient was consistent with a role of Th17-mediated IRIS in pembrolizumab-triggered tuberculosis. Pembrolizumab might trigger airway inflammation with a Th17 phenotype through microbiota interactions in the gut-lung axis.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Microbioma Gastrointestinal/inmunología , Síndrome Inflamatorio de Reconstitución Inmune/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Células Th17/inmunología , Tuberculosis/inmunología , Antituberculosos/uso terapéutico , ADN Bacteriano/aislamiento & purificación , Conjuntos de Datos como Asunto , Microbioma Gastrointestinal/genética , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/sangre , Síndrome Inflamatorio de Reconstitución Inmune/inducido químicamente , Síndrome Inflamatorio de Reconstitución Inmune/microbiología , Pulmón/diagnóstico por imagen , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/microbiología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/aislamiento & purificación , Prevotella/genética , Prevotella/inmunología , Prevotella/aislamiento & purificación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , ARN Ribosómico 16S/genética , Células Th17/efectos de los fármacos , Tomografía Computarizada por Rayos X , Tuberculosis/inducido químicamente , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiologíaRESUMEN
The samples of Huangqi injection (HI) were analyzed by liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (LC-TOF-MS), and both positive and negative ion modes were employed to obtain the LC-TOF-MS analysis information of chemical compounds in HI. Then the mass defect filtering (MDF) approach, which was developed based on the previously published articles, was utilized to rapidly screen the astragalosides from the obtained LC-TOF-MS data. Each screened astragaloside was confirmed by the presence of no less than 2 quasi-molecular ions. All the screened astragalosides were then tentatively assigned according to the parent ion and daughter ion information. Finally, a total of 62 astragalosides were screened and characterized from the HI samples, including 15 new detected ones. The identification results indicated that acetylation, hydrogenation, dehydrogenation, methoxylation and hydration might be the major conversion reactions involved in the formation of the astragalosides. The LC-TOF-MS-based MDF approach was proved to be a feasible and efficient tool to screen the chemical constituents in complex matrices such as herbal medicines.
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Medicamentos Herbarios Chinos/química , Saponinas/análisis , Astragalus propinquus , Cromatografía Liquida , Plantas Medicinales/química , Espectrometría de Masas en TándemRESUMEN
The side effects of cisplatin (CDDP), notably nephrotoxicity, greatly limited its use in clinical chemotherapy. HuangQi Injections (HI), a commonly used preparation of the well-known Chinese herbal medicine Astragali radix, appeared to be promising treatment for nephrotoxicity without compromising the anti-tumor activity of CDDP. In this study, the urinary metabolomics approach using liquid chromatography time of flight mass spectrometry (LC-TOF/MS) was developed to assess the toxicity-attenuation effects and corresponding mechanisms of HI on CDDP-exposed rats. As a result, successive administration of HI significantly recovered the decline of body weight and downregulated the abnormal increase of serum creatinine and urea. HI partly restored the CDDP-induced alteration of metabolic profiling back into normal condition. Totally 43 toxicity-attenuation potential biomarkers were screened and tentatively identified, which were involved in important metabolic pathways such as amino acid metabolism, TCA cycle, fatty acid metabolism, vitamin B6 metabolism and purine metabolism. The results clearly revealed that HI could alleviate CDDP-induced nephrotoxicity and improve the disturbed metabolic balance induced by repeated CDDP exposure. The present study provided reliable evidence for the protective effect of HI on CDDP-induced toxicity with the multi-target pharmacological characteristics.
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Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Metaboloma , Metabolómica , Animales , Biomarcadores/orina , Cromatografía Liquida , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/orina , Masculino , Redes y Vías Metabólicas , Metabolómica/métodos , Ratas , Espectrometría de Masas en TándemRESUMEN
San Leng powder extract has been used as medicinal compound for the prevention and treatment of cancers. The antitumor activity of SLPE was determined by treating BALB/C mice harboring a human gastric cancer xenograft with SPLE for 17 days. Mice were also treated with fluorouracil (5-Fu, 25 mg/kg) or a combination of SLPE and 5-Fu. Our results indicate that the inhibition of tumor growth by SLPE might be due to a block in the cell cycle and the induction of apoptosis. These results suggest that SLPE might be useful in the treatment of gastric cancer.
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Growing evidence shows that miRNA plays an important role in the development and progression of cancer. In this study, we found that the expression levels of miR-29 family were dramatically decreased in hepatocellular carcinoma (HCC) cell lines and clinical tissues. Then, we demonstrated that ectopic expression of miR-29 family could signiï¬cantly suppress cell proliferation and induce apoptosis in HCC cells. Luciferase assay together with western blot assay confirmed that miR-29 family bound directly to the 3'-untranslated region (3'-UTR) of RPS15A and reduced the expression of RPS15A. In addition, the cell cycle related gene including cyclinA, cyclin D1 and p21 were also down-regulated when increased the expression of miR-29 family, which is similar as silencing RPS15A expression. Moreover, co-transfection of miR-29 mimics with 3'UTR-deleted RPS15A could rescue the expressions of cyclin A and cyclin D1 while down-regulate the p21 expression. In conclusion, miR-29 family functions as a novel tumor suppressor in HCC by regulate cell growth and cell cycle through binding to RPS15A 3'UTR. These findings may be utilized in developing novel therapeutic tools for HCC.
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Liquid chromatography with quadrupole time-of-flight mass spectrometry coupled with automated data analysis by Peakview software was employed to systematically screen and characterize the astragalosides in Radix Astragali, a Chinese medical preparation. The separation was performed on a poroshell 120 SB-C18 column equipped in a conventional liquid chromatography system. After being separated using a general gradient elution, the analytes were detected by the triple quadrupole time-of-flight mass spectrometer in both positive- and negative-ion modes. The mass defect filtering function built in the Peakview software was utilized to rapidly screen the potential ions of interest, while some functions of Peakview such as Formula Finder, XIC manager, and IDA Explorer were employed to facilitate the assignment or characterization of the screened astragalosides. A total of 42 astragalosides were screened and tentatively characterized or assigned, and 20 of them were firstly detected in Radix Astragali. According to the screened astragalosides, acetylation, glycosidation, hydrogenation, oxidation, and hydration were considered to be the major secondary metabolic pathways involved in the formation of the astragalosides. The combination of liquid chromatography with quadrupole time-of-flight mass spectrometry and automated Peakview analysis is a feasible and efficient tool to screen and identify the constituents in complex matrices of herbal medicines.
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Planta del Astrágalo/química , Medicamentos Herbarios Chinos/análisis , Glucósidos/análisis , Plantas Medicinales/química , Programas Informáticos , Astragalus propinquus , Cromatografía Líquida de Alta Presión , Medicamentos Herbarios Chinos/administración & dosificación , Glucósidos/administración & dosificación , Espectrometría de Masas , Soluciones/química , Factores de TiempoRESUMEN
To establish a LC-MS/MS method for determination of tripterine in Beagle plasma and study its pharmacokinetics after oral administration of tripterygium tablet. Plasma samples were extracted with dichloromethane and separated on a Phenomenex Luna C8 (2.0 mm×50 mm, 3 µm) column with methanol-acetonitrile isopropanol(1â¶1)-1formic acid (15â¶55 â¶30) as the mobile phase. Tripterine ([M+H] âº, m/z 451.3/201.1) and internal standard prednisolone ([M+H] âº, m/z 361.1/147.1) were monitored in multiple reaction monitoring (MRM). The concentration-time curves were simulated by drug and statistic software 1.0 and the pharmacokinetic parameters were calculated. There was a good linear relationship between peak area ratio and concentration of tripterine and internal standard prednisolone within range of 0.680 0-136.0 µgâ¢L⻹. The limit of quantitation was 0.680 0 µgâ¢L⻹ and the intra- and inter-day precision was within 6.15%. The absolute recovery rate was between 50.42% to 51.65%. The concentration-time curves were consistent with the one-compartment model(w=1/cc). The main pharmacokinetic parameters after a single dose were as followsï¼ Cmax (35.64±9.540) µg â¢L⻹,Tmax(2.62±0.69) h,T1/2(2.93±0.29) h, CL (0.308±0.056) Lâ¢kg⻹â¢h⻹, AUC0-12 (131.16±31.94) µgâ¢Lâ¢h⻹, AUC0-∞ (142.83±37.57) µgâ¢Lâ¢h⻹. The established LC-MS/MS method was proved to be sensitive, accurate and convenient, suitable for the pharmacokinetic study of Tripterygium tablet in Beagle dogs.
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Medicamentos Herbarios Chinos/farmacocinética , Tripterygium/química , Triterpenos/sangre , Animales , Cromatografía Liquida , Perros , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , Triterpenos/farmacocinéticaRESUMEN
To observe the serum samples and the anti-inflammatory effect of Tripterygium wilfordii in treating RA by using the pharmacokinetic-pharmacodynamic model, make a correlation analysis on concentration-time and effect-time curves, and explore RORγt, IL-17, STAT3, IL-6 mRNA transcriptional levels in rats by PCR. Methotrexate, tripterine and high-dose T. wilfordii could down-regulate RORγt, IL-17, STAT3, IL-6 mRNA transcriptional levels in AA rat lymph nodes. The study on PK-PD model showed correlations between inflammatory factors and blood concentration of T. wilfordii. T. wilfordii and its main active constituent tripterine could show the inflammatory effect and treat RA by inhibiting IL-17 cytokine.
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Artritis Reumatoide/tratamiento farmacológico , Fitoterapia , Tripterygium , Animales , Artritis Reumatoide/inmunología , Biomarcadores , Femenino , Interleucina-17/antagonistas & inhibidores , Interleucina-17/genética , Interleucina-6/genética , Triterpenos Pentacíclicos , Ratas , Ratas Sprague-Dawley , Triterpenos/farmacocinética , Triterpenos/farmacologíaRESUMEN
Multiple phenolic compounds in the extract of Erigeron breviscapus synergistically contribute to the neurovascular protective effects. We conducted a phase I and pharmacokinetic study with the phenolic compound-enriched product extracted from Erigeron breviscapus, Erigerontis hydroxybenzenes injection (EHI), in healthy Chinese volunteers. A randomized, open-label, single-center, double-arm, dose-escalation study of EHI was conducted. The tolerability of intravenously EHI administrated in single- or multiple-dose (once daily for 7 days) was studied in 40 healthy Chinese volunteers and the pharmacokinetics of EHI was studied in additional 10 volunteers. The tolerated dose of intravenous infusion of EHI in healthy Chinese volunteers was 6 vials (equivalent to 90 mg bioactive phenolic compounds). The main limitations to dose escalation of EHI were transit changes in electrocardiogram and mild, transit increase in alanine aminotransferase. After intravenous administration of EHI, the average systemic clearance of multiple phenolic compounds of scutellarin, 1,3-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, and 3,4-dicaffeoylquinic acid were 131, 29, 262, 112 L/h for male volunteers and 202, 28, 252, 117 L/h for female volunteers. The intervention of intravenous infusion of EHI in healthy Chinese volunteers was generally tolerated. The findings from this study provide data on the tolerability and pharmacokinetics of the extract from Erigeron breviscapus and support further trials.
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Erigeron/química , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacocinética , Adulto , Apigenina/sangre , Ácido Clorogénico/análogos & derivados , Ácido Clorogénico/sangre , Femenino , Glucuronatos/sangre , Voluntarios Sanos , Humanos , Inyecciones Intravenosas , Masculino , Extractos Vegetales/efectos adversos , Ácido Quínico/análogos & derivados , Ácido Quínico/sangre , Adulto JovenRESUMEN
A rapid and specific high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed for the quantification of hydroxysafflor yellow A (HSYA) in human urine with isorhamnetin-3-O-neohespeidoside as internal standard (IS). HSYA and IS were extracted from urine samples by simple solid-phase extraction and separated on an Agilent Zorbax SB C18 column (4.6 mm × 150 mm, 5 µm) with the mobile phase of 0.2 mM ammonium acetate: methanol (30/70, v/v) at a flow rate of 0.4 mL/min. Polar endogenous interferences eluted in 0.1-2.5 min were switched into waste channel by the Valve Valco, to reduce the possible matrix effect for MS detection in each run. The MS detection of analytes was performed on a tandem mass spectrometer equipped with an electrospray ionization source in negative mode using multiple-reaction monitoring. The MS/MS ion transitions monitored were m/z 611.3â491.2 for HSYA and m/z 623.2â299.2 for IS. The method was fully validated for selectivity, sensitivity, linearity, precision, accuracy, recovery, matrix effect and stability, and then was applied to the urinary excretion study of injectable powder of pure HSYA in healthy Chinese volunteers for the first time. The results suggested that urine was the main excretion way of HSYA in healthy volunteers, further demonstrating the feasibility and necessity of our current method.
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Chalcona/análogos & derivados , Cromatografía Líquida de Alta Presión/métodos , Quinonas/orina , Espectrometría de Masas en Tándem/métodos , Adulto , Chalcona/aislamiento & purificación , Chalcona/orina , Humanos , Masculino , Quinonas/aislamiento & purificación , Sensibilidad y Especificidad , Extracción en Fase Sólida , Adulto JovenRESUMEN
AIM: To establish an LC-MS/MS method for determination of isorhamnetin-3-O-neohesperidoside and investigate its application on pharmacokinetic study in rats. METHODS: Eight rats were given 5 mg·kg(-1) isorhamnetin-3-O-neohesperidoside after intravenous administration. A highly sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of isorhamnetin-3-O-neohesperidosidein rat plasma using rutin as internal standard. The analytes and rutin (internal standard) were extracted with methanol followed by a rapid isocratic elution with 10 mmol·L(-1) ammonium acetate buffer/methanol (20 : 80, V/V) on a C18 column (150 mm × 2.1 mm, I.D., 5 µm) and subsequent analysis by mass spectrometry in the multi-eaction-monitoring mode. RESULTS: The assays were linear over the concentration range of 0.01-10 µg·mL(-1) for isorhamnetin-3-O-neohesperidosidein rat plasma. The lower limit of quantifications for isorhamnetin-3-O-neohesperidoside was 0.01 µg·mL(-1). CONCLUSION: The validated method is successfully applied to determine the plasma concentrations of isorhamnetin-3-O-neohesperidosidein in rats.
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Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/farmacocinética , Espectrometría de Masas en Tándem/métodos , Typhaceae/química , Animales , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/análisis , Flavonoles/administración & dosificación , Flavonoles/sangre , Flavonoles/farmacocinética , Polen/química , Ratas , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
To establish a LC-MS/MS method to determine caffeic acid, chlorogenic acid in rat plasma and study their pharmacokinetics in rats. Six Sprague-Dawley rats were intravenously injected with 4 mL x kg(-1) of Dengzhanxixin injection, respectively. Their drug plasma concentration was determined by LC-MS/MS, with tinidazole as an internal standard. The pharmacokinetic parameters were calculated by DAS 1.0. The linear concentration ranges of caffeic acid, and chlorogenic acid were 2-128 microg x L(-1) (r = 0.998 1) and 3-384 microg x L(-1) (r = 0.998 7), respectively. The methodological test showed conformance to the requirements. The intraday and inter-day variable coefficients were both less than 10.0%, indicating that both of legitimate precise and accuracy were in conformity with the requirements of biological sample analysis. For caffeic acid, the pharmacokinetic parameter t1/2beta AUC0-t, and CL were (130.91 +/- 38.77) min, (4.89 +/- 0.96) mg x min x L(-1) and (0.12 +/- 0.02) L x min(-1) x kg(-1), respectively. For chlorogenic acid, the pharmacokinetic parameter t1/2beta , AUC0-t, and CL were (49.38 +/- 8.85) min, (9.54 +/- 0.95) mg x min x L(-1) and (0.09 +/- 0.003) L x min(-1) x kg(-1), respectively. The LC-MS/MS analysis method established in this study was proved to be so accurate and sensitive that it can be applied to the pharmacokinetic study of caffeic acid and chlorogenic acid.
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Ácidos Cafeicos/farmacocinética , Ácido Clorogénico/farmacocinética , Medicamentos Herbarios Chinos/farmacocinética , Espectrometría de Masas en Tándem/métodos , Animales , Ácidos Cafeicos/sangre , Ácido Clorogénico/sangre , Medicamentos Herbarios Chinos/análisis , Femenino , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
A highly sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of limonin in beagle dog plasma using nimodipine as internal standard. The analyte and internal standard (IS) were extracted with ether followed by a rapid isocratic elution with 10 mm ammonium acetate buffer-methanol (26:74, v/v) on a C18 column (150 × 2.1 mm i.d.) and subsequent analysis by mass spectrometry in the multiple reaction monitoring mode. The precursor to product ion transitions of m/z 469.4 â 229.3 and m/z 417.2 â 122.0 were used to measure the analyte and the IS. The assay was linear over the concentration range of 0.625-100 ng/mL for limonin in dog plasma. The lower limit of quantification was 0.312 ng/mL and the extraction recovery was >90.4% for limonin. The inter- and intra-day precision of the method at three concentrations was less than 9.9%. The method was successfully applied to pharmacokinetic study of limonin in dogs.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Limoninas/sangre , Espectrometría de Masas en Tándem/métodos , Acetatos/química , Animales , Tampones (Química) , Perros , Femenino , Límite de Detección , Masculino , Nimodipina/sangre , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
Forsythoside A (FTA), one of the main active ingredients in weeping forsythia extract, possesses strong antibacterial, antioxidant and antiviral effects, and its content was about 8% of totally, higher largely than that of other ingredients, but the absolute bioavailability orally was approximately 0.5%, which is significant low influencing clinical efficacies of its oral preparations. In the present study, in vitro Caco-2 cell, in situ single-pass intestinal perfusion and in vivo pharmacokinetics study were performed to investigate the effects of absorption enhancers based on tight junctions: sodium caprate and water-soluble chitosan on the intestinal absorption of FTA, and the eventual mucosal epithelial damage resulted from absorption enhancers was evaluated by MTT test, measurement of total amount of protein and the activity of LDH and morphology observation, respectively. The pharmacological effects such as antioxidant activity improvement by absorption enhancers were verified by PC12 cell damage inhibition rate after H2O2 insults. The observations from in vitro Caco-2 cell showed that the absorption of FTA in weeping forsythia extract could be improved by absorption enhancers. Meanwhile, the absorption enhancing effect of water-soluble chitosan may be almost saturable up to 0.0032% (w/v), and sodium caprate at concentrations up to 0.64 mg/ml was safe for the Caco-2 cells, but water-soluble chitosan at different concentrations was all safe for these cells. The observations from single-pass intestinal perfusion in situ model showed that duodenum, jejunum, ileum and colon showed significantly concentration-dependent increase in P(eff)-value, and that P(eff)-value in the ileum and colon groups, where sodium caprate was added, was higher than that of duodenum and jejunum groups, but P(eff)-value in the jejunum group was higher than that of duodenum, ileum and colon groups where water-soluble chitosan was added. Intestinal mucosal toxicity studies showed no significant toxicity below 800 µg/ml sodium caprate and water-soluble chitosan at different concentrations. In pharmacokinetics study, water-soluble chitosan at dosage of 50mg/kg improved the bioavailability of FTA in weeping forsythia extract to the greatest extent, and was safe for gastrointestine from morphological observation. Besides, treatment with weeping forsythia extract with water-soluble chitosan at dosage of 50 mg/kg prevented PC12 cell damage upon H2O2 stimulation better than that of control. All findings above suggested that water-soluble chitosan at dosage of 50 mg/kg might be safe and effective absorption enhancer for improving the bioavailability of FTA and the antioxidant activity in vivo in weeping forsythia extract.