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Advanced cancer is a leading cause of disability and mortality globally, with an ever-increasing incidence. In China, icaritin (ICT), a naturally occurring compound with established efficacy and safety, is widely administered orally for treating advanced cancer. However, due to significant phase II metabolism with a positional preference on 3-OH, its usage in clinical settings is restricted. To minimize the phase II metabolism, we synthesized N-monomethyl carbamate and N-monoethyl carbamate (3N-Me and 3N-Et) that were modified on the 3-OH group of ICT. Just as we expected, 3N-Me and 3N-Et remained stable during the absorption process, and they were metabolized in plasma to the ICT. The rate of phase II metabolism of carbamate in vitro was significantly lower compared to ICT. Additionally, the different forms of the carbamate resulted in similar or stronger cytotoxicity than ICT. Furthermore, the pharmacokinetics of 3N-Me and 3N-Et were studied after oral administration. Compared to ICT, the oral administration of 3N-Me led to a significantly enhanced bioavailability of ICT and 3N-Me in rats. It was found that 3N-Me was more effective in exerting its anticancer pharmacological activity and was equally safe as the form of ICT alone. Additionally, our results indicated that ICT and 3N-Me both have beneficial effects on immunotoxicity and spleen functions altered by cancer. This suggests the potential for further development of 3N-Me medicine in the anticancer field for oral administration. [ABSTRACT FROM AUTHOR]

Introduction: This study assessed the safety, tolerability, and PK/PD of HSK7653 tablets in Chinese patients with type 2 diabetes mellitus (T2DM). Methods: This was a Phase IIa, multicenter, randomized, double-blind, placebo-controlled, and dose-increasing study with 48 Chinese diabetes patients. Subjects were randomly assigned to placebo and 10/25/50 mg dose groups, and they received oral administration once every two weeks for a total of six times. Safety and tolerability were assessed throughout this study, and PK/PD parameters were analyzed using non-compartment model with WinNonlin. Results: The three doses of HSK7653 were well tolerated, and the incidence of TEAE and ADR was not significantly increased compared with the placebo group. Cmax increased linearly with the increasing dose, and the mean t1/2 was 64.0–87.0 h. The first dose and last dose PK parameters were similar. After oral administration of 10–50 mg HSK7653 every two weeks, the average Rac_Cmax and Rac_AUC were 0.9–1.0 and 1.0–1.1 respectively; therefore, HSK7653 was not accumulated in vivo. All three doses significantly inhibited DPP-4 activity and increased plasma GLP-1 level and serum insulin levels. When the plasma concentration of HSK7653 was ≥ 20.0 ng/mL, the DPP-4 inhibition rate in all subjects was maintained at > 80.0%. In 10 and 25 mg dose groups, the HbA1c levels maintained a downward trend compared with the placebo group. Discussion: HSK7653 showed desirable pharmacokinetic and pharmacodynamic properties with good safety and tolerability in Chinese T2DM patients. DPP-4 inhibition rate and plasma GLP-1 levels were higher in each dose group than in placebo group. Trial Registration Number: CTR20182505 (Drug Clinical Trial Registration and Information Disclosure Platform, www.chinadrugtrials.org.cn). [ABSTRACT FROM AUTHOR]

Contezolid acefosamil (also known as MRX-4), a prodrug of contezolid, is under development for treatment of multidrug-resistant Gram-positive bacterial infections. A phase I single ascending dose (SAD) and multiple-dose placebo-controlled study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of contezolid acefosamil in healthy Chinese subjects following intravenous (IV) and oral administration. Adverse events (AEs) and PK parameters were assessed appropriately. All subjects ( n = 70) completed the trial. Overall, 67 cases of treatment-emergent adverse events (TEAEs) were observed in 49.1% (27 of 55) of the subjects receiving contezolid acefosamil. All TEAEs were mild in severity. No serious AEs or deaths were reported. After IV SAD (500-2,000 mg), the corresponding C max of the active drug contezolid increased from 1.95 ± 0.57 to 15.61 ± 4.88 mg/L, AUC 0-inf from 40.25 ± 10.12 to 129.41 ± 38.30 h·mg/L, median T from 13.33 to 16.74 h. Plasma contezolid reached steady state on day 6 after multiple IV doses, with an accumulation ratio of 2.20-2.96. Oral SAD of 500 and 1,500 mg resulted in contezolid max from 2.00 to 2.75 h, and mean t 1/2 of 2.50 and 2.98 h. Contezolid reached steady state on day 5 after multiple oral doses of 1,500 mg without significant accumulation. Contezolid C max of 8.66 ± 2.60 and 37.10 ± 8.66 mg/L, AUC 0-inf of 30.44 ± 7.33 and 162.36 ± 47.08 h·mg/L, and median T max of 2.50 and 2.98 h. Contezolid reached steady state on day 5 after multiple oral doses of 1,500 mg without significant accumulation. Contezolid C max and AUC 0-inf increased with the dose of contezolid acefosamil. The good safety and PK profiles in this SAD and multiple-dose study can support further clinical development of contezolid acefosamil., Competing Interests: Hailin Wang, Hong Yuan and Huahui Yang are full-time employees of Shanghai MicuRx Pharmaceutical Co., Ltd. Other authors declare no competing interests.

C. officinalis Kuan is the dry root of Cyathula officinalis Kuan. Clinically, it is used for fall and flutter injury, rheumatism and arthralgia. Phytoecdysteroids have significant anti-inflammatory effects, and the phytoecdysteroids present in C. officinalis Kuan exhibit potential for treating rheumatoid arthritis. This study first developed a selective, accurate and efficient LC-MS/MS method for 12-day pharmacokinetic studies regarding the simultaneous determination of cyasterone, 25-epi-28-epi-cyasterone, precyasterone and capitasterone from C. officinalis Kuan phytoecdysteroids extract in normal and adjuvant arthritis rats. An Agilent Eclipse Plus C18 RRHD column (1.8 µm, 50mm × 2.1 mm) with a gradient mobile phase consisting of water (A) and acetonitrile (B) was used for analysis. The mass analysis was performed in an Agilent 6430 QQQ-MS mass spectrometer with positive mode multiple reaction monitoring (MRM). The results indicated that the AUC0-t and AUC0-∞ values of the four phytoecdysteroids in adjuvant arthritis rats were different from those in normal rats on the first day, which could provide a helpful reference for pharmacological and toxicological studies, as well as clinical applications of C. officinalis Kuan in the treatment of rheumatoid arthritis. 1. C. officinalis Kuan is the dry root of Cyathula officinalis Kuan which has been used for the treatment of flapping injury, rheumatism arthralgia, foot flaccidity, and tendon contracture thousands of years in China, and has been officially included in the Chinese Pharmacopoeia. 2. A highly accurate, stable, and sensitive ultra-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method was first established and validated for simultaneously determination four phytoecdysteroids: cyasterone, 25-epi-28-epi-cyasterone, precyasterone and capitasterone in normal and adjuvant arthritis rats plasma samples 12 days of continuous gavage of C. officinalis Kuan phytoecdysteroids extract. 3. The phytoecdysteroids is the important component of C. officinalis Kuan, which is difficult to separated. And there is no report for the pharmacokinetic study of phytoecdysteroids from C. officinalis Kuan. And the method provides a good reference for the follow-up studies clinical medication of the phytoecdysteroids from C. officinalis Kuan. [ABSTRACT FROM AUTHOR]

Purpose: The incidence and prevalence of food allergy have sharply risen over the past several decades. Oral administration of probiotic stains has been proven as a safe and effective method to control food allergy. In this study, it aims to comprehensively investigate the anti-allergic effect of Lactobacillus plantarum JC7. Methods: Balb/c mice were randomly divided into three groups and received OVA (20 µg/mouse, intraperitoneal injection), L. plantarum JC7 (2 × 108 CFU/mouse, intragastric administration) + OVA (20 µg/mouse, intraperitoneal injection) or 0.9% saline (intragastric administration) for 3 weeks. Body weight was monitored weekly, and allergic reactions were evaluated after challenge of OVA. Serum levels of OVA-specific immunoglobulins and various cytokines were tested using ELISA, and the cecum microbiota was analysed by 16S rRNA sequencing to explore the relationships between these indicators and OVA-induced food allergy. Western blotting was used to identify the expression levels of phosphorylated IκBα and nuclear factor kappa B p65. Results: OVA-sensitised mice showed mitigation of respiratory manifestations, alleviation of lung inflammation and congestion, and the presence of an intact intestinal villus structure. Furthermore, OVA-specific immunoglobulin E (IgE), OVA-specific-IgG1, and plasma histamine levels were declined in mice treated with L. plantarum JC7 than in OVA-sensitised mice. In addition, interferon-γ (IFN-γ) and interleukin 10 (IL-10) levels were significantly increased, while IL-4 and IL-17A levels were clearly decreased in mice that had undergone oral administration of L. plantarum JC7, compared with OVA-sensitised mice. These findings indicated imbalances of T helper cell type 1 (Th1)/Th2 and regulatory T cells (Treg)/Th17, which were confirmed by quantitative polymerase chain reaction (PCR). Western blotting demonstrated that the expression levels of phosphorylated IκBα and nuclear factor kappa B p65 were significantly increased in OVA-sensitised mice, but these changes were partly reversed after treatment with L. plantarum JC7. Oral administration of L. plantarum JC7 increased the richness, diversity, and evenness of cecum microbiota, characterised by higher Bacteroidetes abundance and lower Firmicutes abundance. Additionally, the intestinal microbial community composition was significantly altered in the OVA-sensitised group, indicating a disordered intestinal microbiota that was restored by the oral administration of L. plantarum JC7. Conclusion: Overall, L. plantarum JC7 can prevent food allergy by rectifying Th1/Th2 and Treg/Th17 imbalances, combined with modifications of disordered intestinal microbiota. [ABSTRACT FROM AUTHOR]

Huangqi Jianzhong Tang (HQJZ), a famous traditional Chinese medicine formula, is widely used in the treatment of gastrointestinal diseases in China. In this study, an ultra-high-performance liquid chromatography coupled with quadrupole-Exactive mass spectrometry was used to identify the metabolites in rat urine and feces after oral administration of HQJZ coupled with Compound Discover 3.0 software. The possible metabolic pathways were calculated and deduced based on 71 previous detected prototype compounds. As results, 88 compounds were identified in urine and feces, respectively. In urine sample, we identified 20 prototype compounds and 68 related metabolites. Meanwhile, a total of 21 prototype compounds and 67 related metabolites were identified in feces. Among them, flavonoids and saponins were the main ingredients in vivo. Further, we also speculated that HQJZ experienced oxidation, reduction, acetylation, methylation and glucuronic acid reaction in urine and feces. This study established a reliable method for the detection of prototype components and metabolites of traditional Chinese medicines, which would provide helpful information for further research into the active substances of HQJZ. [ABSTRACT FROM AUTHOR]

Zuogui Pill is a kidney-yin-tonifying formula in traditional Chinese medicine that is widely used to manage osteoporosis with kidney-yin-deficiency in China. Herein, an efficient and accurate high-performance liquid chromatography-tandem mass spectrometry method was developed to determine the concentrations of 5 bioactive compounds in rat plasma following oral administration of Zuogui Pill. Because drug absorption and distribution differ under physiological and pathological conditions, the established method was used to quantify blood components and dynamic change in osteoporotic rats with different syndrome types. Moreover, integrated pharmacokinetic study was conducted to describe the overall pharmacokinetic characteristics of traditional Chinese medicine. The results showed that the absorption, distribution, and metabolism of Zuogui Pill varied widely under different states. The bioavailability of most active components showed significant advantages in osteoporotic rats with kidney-yin-deficiency, which corresponds to the opinion that Zuogui Pill has the effect of nourishing kidney-yin. It is hoped that this finding could interpret the pharmacodynamic substances and mechanism of Zuogui Pill in the treatment of osteoporosis with kidney-yin-deficiency. [ABSTRACT FROM AUTHOR]

Eldecalcitol is an active vitamin D 3 derivative that is used for the prevention and treatment of osteoporosis. The objectives of this study were to evaluate the bioequivalence and safety of 2 formulations of eldecalcitol capsule (0.75 μg) in healthy Chinese male and female volunteers, as well as to investigate the food effect on the pharmacokinetics of this drug. An open label, randomized, 3-period, 3-sequence, reference replicated crossover clinical study was performed in 27 healthy Chinese volunteers under fasting conditions, while a 2-way crossover study was carried out in 28 healthy Chinese volunteers under fed conditions. Volunteers were administered a single oral dose of 0.75 μg eldecalcitol after fasting overnight. Blood samples were collected at scheduled time points from 0 to 168 hours after administration of eldecalcitol. The 90%CIs of the test/reference geometric mean ratio (area under the plasma concentration-time curve and maximum plasma concentration) of eldecalcitol after a single-dose administration were within the acceptance criteria based on the average bioequivalence method. The time to maximum concentration of the test and reference formulations were elevated by ≈2.3-fold and 1.7-fold, respectively, after a high-fat meal. Only mild and transient adverse events were reported in this study, and no severe adverse events occurred. These results indicated that the 2 formulations of eldecalcitol were bioequivalent under both fasting and fed conditions. Food intake prolonged the oral absorption of eldecalcitol but did not significantly influence systemic exposure., (© 2022, The American College of Clinical Pharmacology.)

Ziziphi Spinosae Semen (ZSS), a traditional Chinese medicine, is used in clinics for the treatment of insomnia in China and other Asian countries. Herein, we described for the first time a comparative pharmacokinetics study of the six major compounds of ZSS in normal control (NC) and para -chlorophenylalanine (PCPA)-induced insomnia model (IM) rats that were orally administered the aqueous extract of ZSS. An ultra-high-performance liquid chromatography coupled with quadrupole orbitrap mass (UHPLC-Q-Orbitrap-MS) method was developed and validated for the simultaneous determination of coclaurine, magnoflorine, spinosin, 6 ‴ -feruloylspinosin, jujuboside A (JuA), and jujuboside B (JuB) in ZSS in rat plasma. The established approach was successfully applied to a comparative pharmacokinetic study. The systemic exposures of spinosin and 6 ‴ -feruloylspinosin were decreased in the IM group compared to the NC group, while plasma clearance (CL) was significantly increased. The T max values of JuA and JuB in IM rats were significantly lower than those in NC rats. The T 1/2 of JuA in the IM group was significantly accelerated. The pharmacokinetic parameters of coclaurine and magnoflorine were not evidently affected between the two groups. These results indicate that the pathological state of insomnia altered the plasma pharmacokinetics of spinosin, 6 ‴ -feruloylspinosin, JuA, and JuB in the ZSS aqueous extract, providing an experimental basis for the role of ZSS in insomnia treatment. The comparative pharmacokinetics-based UHPLC-Q-Orbitrap-MS using full-scan mode can therefore provide a reliable and suitable means for the screening of potentially effective substances applied as quality markers of ZSS. Image 1 • A UPLC-MS method was validated for assaying 6 major compoundsofZSS in rat plasma. • This is the first report on in vivo ZSS extractexposure in normal and insomnia rat. • The pathological state of insomnia altered rat plasma pharmacokinetic behaviors. • The findings might provide a means for screening potentially effective substances. [ABSTRACT FROM AUTHOR]

Gerberae Piloselloidis Herba, a traditional Chinese medicine, is often employed to treat such lung‐related diseases as coughs, asthma, and pulmonary carbuncles in southwest China. Our previous study demonstrated that its active fraction, prepared from Gerberae Piloselloidis Herba, exerts an obvious beneficial effect on asthma. However, the pharmacokinetics of its major constituents remain unclear. Therefore, an ultra‐performance mass spectrometry‐electrospray ionization‐tandem mass spectrometry method was successfully established to simultaneously perform the pharmacokinetics of the main 11 components of the active fraction between normal and ovalbumin‐induced asthmatic mice. Compared to the normal group, in asthmatic mice the peak concentration of arbutin, marmesin, caffeoylquinic acids, and flavonoid glycosides clearly increased, while for luteolin it significantly declined; the area under the curve for arbutin and luteolin showed an increase, but the values of marmesin, caffeoylquinic acids, and flavonoid glycosides revealed a decline; the peak time for arbutin, caffeoylquinic acids and flavonoid glycosides decreased, while for marmesin and luteolin it significantly augmented; apart from marmesin, the half‐life for all compounds shortened significantly. It is indicated that the pathology of asthma could lead to an alteration in the pharmacokinetic profiles of the 11 components in plasma, providing a reference for further exploration of the pharmacodynamic basis of the anti‐bronchial effect of Gerberae Piloselloidis Herba. [ABSTRACT FROM AUTHOR]

TPN729, a novel phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), is in phase II clinical trials in China. Previous studies suggested that TPN729 possesses promising therapeutic value. In previous non-radiolabeled rat excretion studies, the recovery of TPN729 and its major metabolites accounted for approximately 8.58% of the administration dose in urine and faeces by 48 h post-dose. To solve this problem and further study the metabolism of TPN729 in rats, we used the radio-isotopic tracing technique for the first time. In this study, the mass balance, tissue distribution, and metabolism of TPN729 were evaluated in rats after a single oral dose of 25 mg/kg [14C]TPN729 (150 μCi/kg). At 168 h post-dose, the mean total radioactivity recovery of the dose was 92.13%. Faeces was the major excretion route, accounting for 74.63% of the dose, and urine excretion accounted for 17.50%. After oral administration of [14C]TPN729, radioactivity was widely distributed in all examined tissues, and a higher radioactivity concentration was observed in the stomach, large intestine, lung, liver, small intestine, and eyes. The concentration of drug-related materials were similar in plasma and blood cells. A total of 51 metabolites were identified in rat plasma, urine, faeces, and bile, and the predominant metabolically susceptible position of TPN729 was the pyrrolidine moiety. The main metabolic pathways were N-dealkylation, oxidation, and dehydrogenation. In summary, we solved the previous problem of low drug recovery, elucidated the major excretion pathway, determined the tissue distribution patterns, and investigated the metabolism of TPN729 in rats by using a radioisotopic tracing technique. [ABSTRACT FROM AUTHOR]

Simple Summary: Doxycycline, an approved aquacultural antibiotic, is extensively used in the treatment of bacterial diseases in fish. Since fish are poikilothermic organisms, their body temperature and metabolic rate are primarily influenced by the temperature of the water. Therefore, temperature may be affected by pharmacokinetic behavior and withdrawal times of drugs. The current study was undertaken to look at the differences in pharmacokinetics, tissue residues, and withdrawal times of doxycycline following oral administration in rainbow trout reared at 10 and 17 °C. The increment of water temperature from 10 to 17 °C decreased the elimination half-life, the body clearance, and the distribution volume of doxycycline and increased plasma concentrations. The withdrawal times for plasma and tissues decreased with the temperature increase. The results contributed to the determination of an optimal dosing regimen and the safe consumption of edible tissues in rainbow trout that were administered doxycycline and reared at different temperatures. The purpose of this study was to compare the pharmacokinetics, tissue residues, and withdrawal times of doxycycline after oral administration in rainbow trout reared at 10 and 17 °C. Fish received a 20 mg/kg oral dose of doxycycline after a single or 5-day administration. Six rainbow trout were used at each sampling time point for plasma and tissue samples, including liver, kidney, and muscle and skin. The doxycycline concentration in the samples was determined using high-performance liquid chromatography with ultraviolet detector. The pharmacokinetic data were evaluated by non-compartmental kinetic analysis. The WT 1.4 software program was used to estimate the withdrawal times. The increase of temperature from 10 to 17 °C shortened the elimination half-life from 41.72 to 28.87 h, increased the area under the concentration–time curve from 173.23 to 240.96 h * μg/mL, and increased the peak plasma concentration from 3.48 to 5.50 μg/mL. At 10 and 17 °C, the doxycycline concentration was obtained in liver > kidney > plasma > muscle and skin. According to the MRL values stated for muscle and skin in Europe and China (100 μg/kg) and in Japan (50 μg/kg), the withdrawal times of doxycycline at 10 and 17 °C were 35 and 31 days, respectively, for Europe and China and 43 and 35 days, respectively, for Japan. Since temperature significantly affected pharmacokinetic behavior and withdrawal times of doxycycline in rainbow trout, temperature-dependent dosing regimens and withdrawal times of doxycycline might be necessary. [ABSTRACT FROM AUTHOR]

Poria cocos (Schw.) Wolf, is a fungus that is widely used as medicine and dietary supplement in China. But its action mechanism is still not very clear. In this paper, a rapid, specific and sensitive high performace liquid chromatography coupled with hybrid quadrupole - orbitrap mass sepctrometry (UPLC - Q - Orbitrap MS) method has been developed and validated to simultaneously determine of four triterpenoids including Dehydrotumulosic acid (DTA), Dehydropachymic acid (DPA), Pachymic acid (PA), Dehydrotrametenolic acid (DMA) from Poria cocos in rat plasma and tissues. The analyte was extracted from rat plasma and tissue homogenates by protein precipitation with acetonitrile using glibenclamide as the internal standard (IS). Chromatographic separation was carried out on ACQUITY UPLC BEH - C 18 column (2.1 mm × 50 mm, 1.7 μm) with a mobile phase composed of acetonitrile - water (containing 1.0 mmol/L ammonium acetate) using gradient elution at a flow rate of 0.2 mL/min. Electrospray ionization (ESI -) under negative ion mode was used, and its quantization was performed with multiple reaction monitoring (MRM) mode. The method was fully validated and successfully applied to pharmacokinetics and tissue distribution study in rats after oral administration of ethanol extracts of Poria cocos. Compared with that of plasma exporsure, triterpenoids could be detected in various tissues with a relatively high degree of tissue distribution. After oral administration, the concentration orders in seven different tissues were ranked as DTA > PA > DPA > DMA in intestine and stomach, wheras DTA > DMA > PA > DPA in heart, liver, spleen, lung and kidney tissues, which is speculated that DPA, PA may be converted into DMA in vivo. In conclusion, this results may provide a material basis for study of the pharmacological actions of triterpenoids in Poria cocos., Competing Interests: Declaration of Competing Interest No conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behave of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2021. Published by Elsevier B.V.)

Background: Yiganmingmu oral liquid (YGMM), a well known over-the-counter (OTC) drug in China, is composed of 12 types of valuable herbal medicines and has been widely used in clinical for the treatment of soreness and weakness of waist and knees, dizziness, memory loss, and fatigue. However, the chemical compositions of YGMM and its absorbed compounds in plasma remain unclear. Methods: Since chemical investigation is the first important step to reveal effects and action mechanisms of traditional Chinese medicine (TCM), in this study, based on the self built components database, systematic characterization of the chemical profile of YGMM in vitro was carried out by using a reliable UPLC-Q-TOF-MS method. Moreover, to obtain better understanding of the absorbed prototypes in plasma, serum pharmacochemistry analysis of YGMM after oral administration was conducted by using cynomolgus monkeys as animal model. Results: A total of 667 constituents from the 12 single herbal medicines were collected in the self built components database by searching the reported literatures, and 415 of them were initially screened as candidate compounds in YGMM by comparison of their experimental accurate mass measurements with those theoretical values. After that, 117 compounds including 17 phenolic acids, 25 flavonoids, 4 alkaloids, 10 phthalides, 5 monoterpenes, 8 triterpenoid saponins, 9 anthraquinones, and 39 other compounds, were unambiguously identified or tentatively characterized by analysing their MS/MS fragmentation patterns, and also by comparison with reference standards and those data reported in the literatures. 61 prototypes absorbed in plasma of cynomolgus monkey, including 13 phenolic acids, 21 flavonoids, 8 phthalides, 3 monoterpenes, 4 triterpenoid saponins, and 12 other compounds were tentatively assigned by serum pharmacochemistry analysis after oral administration. Conclusion: It was the first comprehensive analysis of chemical constituents of YGMM and prototypes in plasma, and the data analysis strategy developed in this study showed high efficiency in the structural elucidations. The results might provide scientific evidence for further research on material basis of YGMM. [ABSTRACT FROM AUTHOR]

Farfarae flos (FF) is widely used for cough over thousands of years in China, but little is known about their pharmacokinetics properties. This study was aimed to establish a rapid and accurate ultraperformance liquid chromatography with triple-quadrupole tandem mass spectrometry method for compare pharmacokinetics studies of eight active compounds after oral administration between raw and honey-processed farfarae flos extracts. Optimum separation was performed on a Thermo Hypersil GOLD C18 column (100 mm × 2.1 mm, 1.9 µm particles size) with a gradient elution of acetonitrile as mobile phase A and 0.3% formic acid aqueous solution as mobile phase B. The flow rate was set as 0.3 mL/min and separated for 34.0 minutes. Electrospray ionization in the negative ion mode and selected reaction monitoring were used to identify and separate active components. The results met the acceptance criteria and showed that this method exhibited good linear, precision, accuracy, and stability. The extraction recoveries ranged from 81.54% to 104.48%, and the matrix effects ranged from 81.94% to 103.02%. These results show that the validated method could be successfully applied to evaluate the pharmacokinetic study in rats after oral administration of raw farfarae flos (R-FF) and honey-processed farfarae flos (H-FF). [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of oral administration of branched-chain amino acids (BCAA) supplementation on the mortality of patients with hepatocellular carcinoma (HCC) after treatment. Methods: Computer searching of PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Biomedical Literature Database was conducted to search for clinical controlled trials and randomized controlled trials (RCTs) on the effect of oral administration of BCAA on the mortality of patients with HCC. The retrieval time limit was from the time of the establishment of each database to December 30, 2019. Two researchers independently screened the literature and extracted the data. Another researcher assessed the risk of bias in the included studies and then used RevMan 5.3 software for meta-analysis. Results: A total of 14 studies were included with 1 179 patients. The overall results showed that oral administration of BCAA had no significant effect on the mortality of HCC patients at 1 year after treatment ( RR= 0.85, 95% CI: 0.68-1.06, P= 0.16), while the mortalities of patients at 3 years ( RR= 0.73, 95% CI: 0.61-0.88, P= 0.000 7) and 5 years ( RR= 0.57, 95% CI: 0.34-0.96, P= 0.03) after treatment were significantly lower than those of the control group. The subgroup analysis showed that for radiofrequency ablation (RFA) patients, there was no significant difference in 1-year mortality between the BCAA group and the control group ( RR= 0.96, 95 %CI :0.14-6.5, P= 0.97), while 3-year mortality was significantly reduced ( RR= 0.59, 95% CI: 0.43-0.81, P= 0.001); for hepatectomy patients, there was no significant differences in 1 -and 3-year mortality between the two groups ( RR= 0.90, 95% CI: 0.44-1.88, P= 0.79; RR= 0.97, 95 %CI :0.71-1.33, P= 0.85, respectively). In addition, as for albumin levels, BCAA supplementation significantly increased albumin levels without considering the treatment of HCC ( SD =0.45, 95 %CI : 0.29-0.90; P= 0.000 1), but had no significant effect on hepatectomy patients ( SD =0, 95 %CI : -0.41-0.41, P= 0.99). Conclusion: BCAA supplementation might improve liver reserve function and long-term prognosis of HCC patients, which was related to the surgical method. Supplementing BCAA reduced the long-term mortality of RFA patients, but had no significant effect on hepatectomy patients.

Angelicae Pubescentis Radix (APR) is a typical Traditional Chinese Medicine (TCM) and has been widely used to treat rheumatism and headache diseases in China. This research aimed to illustrate the metabolites of APR in vivo to lay a foundation for the clinics application. A UPLC-Q-TOF-MS method combined with metabonomics approaches is used to address this objective. The separation was achieved on an Agilent SB-C18 column (1.8 μm, 2.1 × 50 mm) with a gradient elution system (ACN and 0.1 % formic acid-water). An electrospray ionization (ESI) was used for mass spectrometer and operated in a full-scan mode at m/z 100 - 800. The data were collected in the positive ion mode and analyzed by the Masslynx 4.1 and SIMCA 13.0 software. Furthermore, an orthogonal partial least-squares discriminant analysis (OPLS-DA) using SIMCA 13.0 software was applied to investigate the differences between the blank and drug groups in bio-samples of rats (plasma, urine, feces). Totally 213 compounds including 41 prototype ingredients, 107 phase I and 65 phase II metabolites were detected, according to the MS and MS/MS data. Among them, 134 metabolites are potential new compounds., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The exploration of an old drug for new biomedical applications has an absolute predominance in shortening the clinical conversion time of drugs for clinical application. In this work, carbon nanoparticles suspension injection (CNSI), the first clinically approved carbon nanoparticles in China, is explored as a new nano-radioprotective agent for potent intestinal radioprotection. CNSI shows powerful radioprotective performance in the intestine under oral administration, including efficient free radical scavenging ability, good biosafety, high chemical stability, and relatively long retention time. For example, CNSI shows high reactive oxygen species (ROS) scavenging activities, which effectively alleviates the mitochondrial dysfunction and DNA double-strand breaks to protect the cells against radiation-induced damage. Most importantly, this efficient ROS scavenging ability greatly helps restrain the apoptosis of the small intestinal epithelial and crypt stem cells, which decreases the damage of the mechanical barrier and thus relieves radiation enteritis. Moreover, CNSI helps remove the free radicals in the intestinal microenvironment and thus maintain the balance of intestinal flora so as to mitigate the radiation enteritis. The finding suggests a new application of clinically approved carbon nanoparticles, which not only promotes the development of new intestinal radioprotector, but also has a great potential for clinical transformation., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Edwardsiellosis, an extremely harmful disease can be caused by Edwardsiella tarda , severely restricts the development of turbot (Scophthalmus maximus) farming worldwide, especially in China. This study aimed to establish an effective and feasible prophylaxis by feeding chitosan-alginate coated egg yolk immunoglobulin (IgY) against E. tarda 2CDM001 infections in the process of turbot farming. Enzyme-linked immunosorbent assays proved that the obtained specific IgY could specifically target E. tarda 2CDM001 and five other E. tarda isolates (1a5p, Hz-s, 1a1s, fs-a1 and 58p8). In-vitro, the bacteriostatic effects of specific IgY showed dose dependencies at concentrations ranging from 1 to 10 mg/mL. Moreover, E. tarda 2CDM001 incubated with 10 mg/mL specific IgY could induce the destruction of cell wall structures and significantly decrease the bacterial surface hydrophobicity (p < 0.05). In this study, turbots were challenged with 107 CFU E. tarda 2CDM001 after seven days of continuous feeding with basal diets containing microencapsulated IgYs. Survival rates of the 5%, 3% and 1% microencapsulated specific IgY groups were 63.3%, 56.7% and 20% on the tenth day post infection, respectively, while the turbots in the positive control and non-specific IgY groups all died within ten days. Oral administration of basal diets containing 5% microencapsulated specific IgY significantly reduced IL-1β, IL-8, TNF-α and C3 transcript levels in the head kidney and spleen of turbots compared with the positive and non-specific IgY groups at 24 h after E. tarda 2CDM001 challenging (p < 0.05). Pathological increase of leukocytes in the specific IgY group was significantly lower than that in the positive control and non-specific IgY groups (p < 0.05), decreasing slowly after 24 h of infection and showing a recovery trend. Erythrocyte counts and hemoglobin concentrations of turbots in positive and non-specific IgY groups showed a marked decrease compared with the negative and specific groups at 96 h after E. tarda 2CDM001 infection (p < 0.05). These results suggest that passive immunity via feeding microencapsulated specific IgY could be used as a valuable preventative in turbot against E. tarda 2CDM001 infections. • Specific IgY could effectively inhibit the growth of E. tarda 2CDM001 in vitro. • Pre-feeding chitosan-alginate coated specific IgY could improve the survival rate of E. tarda 2CDM001-infected turbots. • Specific IgY could significantly reduce the inflammatory responses of turbots after E. tarda 2CDM001 infection. • CRediT authorship contribution statement. [ABSTRACT FROM AUTHOR]

Chimonanthi Radix (CR) is widely used in the treatment of influenza in China. Extensive studies revealed that the major bioactive constituents of CR were coumarins. However, pharmacokinetic study of coumarins in CR has not been fully studied. The purpose of this study was to establish a convenient and effective high-performance liquid chromatography–tandem mass spectrometry method that was used to simultaneously determine scopoletin, scopolin and isofraxidin in rat plasma after oral administration of CR extract using xanthotoxin as the internal standard. The chromatographic separation was carried out on a COSMOCORE C18 column (100 × 2 mm, 2.6 μm), using gradient elution with the mobile phase consisting of 0.1% formic acid (A) and acetonitrile (B). Three coumarins and IS were quantified by positive ion electrospray ionization in multiple reaction monitoring mode. The method was fully validated in terms of specificity, accuracy, precision (intra- and inter-day), matrix effect, recovery as well as the stability of the analytes under various conditions. The results could provide further research foundation for anti-influenza mechanism of three coumarins in CR. [ABSTRACT FROM AUTHOR]

Huang-Lian Jie-Du decoction (HLJDD) has been used to treat cardiovascular and cerebrovascular disease for many years in China. Currently, the determination of effect components in HLJDD is focusing either on the formula or on the extract, while quantification of that in biological samples is scarce, especially simultaneous determination of multicomponent. In this paper, a rapid, specific, and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry method was developed and fully validated for the simultaneous determination of seven main active constituents, i.e., baicalin, baicalein, wogonoside, wogonin, berberine, palmatine, jatrorrhizine in rat plasma. The method was also successfully applied to a quantitative study after oral administration of HLJDD at different doses of 1.5, 3, and 6 g/kg body weight to high fat-induced atherosclerosis rats. The analytes were detected by ESI source and multiple reactions monitoring (MRM) using positive scanning mode. The blood was collected from the abdominal aorta of rats at predetermined time and preprepared with icariin and tetrahydropalmatine as internal standards (IS). Sample preparation was achieved by protein precipitation (PPT). The validation parameters (linearity, sensitivity, intra-/interday precision and accuracy, extraction recovery, and matrix effect) were within acceptable ranges, and biological extracts were stable during the entire storing and preparing process. And the result of determination of HLJDD-containing plasma, baicalin, baicalein, wogonoside, and wogonin could be highly detected in a dose-dependent manner while berberine, jatrorrhizine, and palmatine were determined in a very low level and in a dose-independent mode. Thus, the established method was sensitive enough and successfully applied to the determination of seven effective components in plasma taken from 24 high fat-induced atherosclerosis rats after oral administration of three dosages of HLJDD. [ABSTRACT FROM AUTHOR]

Abstract Niuhuang Shangqing tablet (NHSQT), a well-known traditional Chinese medicine preparation, has been used as an over- the- counter drug for the treatment of headache, dizziness in China. The flavonoids are the main active components in NHSQT, however, there have no reports about their distribution and metabolic fate in vivo after oral administration of NHSQTs so far. An novel UHPLC-QTOF-MS/MS method combined with in silico approach was applied to identify the flavonoids and metabolites profiling in biological samples following oral administration NHSQTs for the first time. As a result, 127 compounds including 34 original compounds of flavonoids and 93 metabolites were identified. There were 20 flavones, 9 flavonols, 4 flavanones and 1 flavan-3, 4-diol found in biological samples. Rutin, wogonoside, apigenin, baicalein, wogonin, oroxylin A, quercetin and acacetin were considered as the potential flavonoids in NHSQT against brain diseases. The docking-based metabolism models were established and applied to propose the sites of hydroxylation of flavonoids, which indicated baicalin was engaged in dihydroxylation at C2′, C3′, tilianin was engaged in hydroxylation at C3, wogonin and wogonside were engaged in dihydroxylation at C3′, C4′. Some novel metabolic pathways were discovered for oroxylin A, acacetin, diosmetin, tilianin. The metabolic spots and pathways of flavonoids vary as much between flavones, flavonols and flavanones. The results presented here would be helpful for the further study of pharmacokinetics and quality control of NHSQT. Highlights • An novel UHPLC-QTOF-MS/MS method combined with in silico approach was applied to identify the compounds in vivo. • The docking-based metabolism models were established and applied to propose the sites of hydroxylation of flavonoits. • 127 compounds, including 34 flavonoid prototypes and 93 metabolites in biological samples were identified. • Some novel or unusual metabolites were discovered for oroxylin A, acacetin, diosmetin, tilianin. [ABSTRACT FROM AUTHOR]

Abri Herba and Abri mollis Herba both were important members of the Leguminosae family in southwestern China. Abri mollis Herba was often used as Abri Herba due to their proximity, but there are few studies on pharmacokinetics to compare their main identical active compositions. A sensitive and selective high‐performance liquid chromatography with tandem mass spectrometry method in the positive/negative electrospray ionization switching mode was developed and validated for the simultaneous analysis of four flavonoids and two alkaloids in rat plasma. The chromatographic separation was carried out on a C18 column with a gradient mobile phase consisting of methanol and 0.5% acetic acid. The detection of the target compounds was conducted in multiple‐reaction monitoring mode with a hybrid triple quadrupole linear ion trap mass spectrometer equipped with positive/negative ion‐switching electrospray ion source. The differences in pharmacokinetics were discovered, which indicated that the substitution between them is some degree of irrationality. The validated method was successfully applied to pharmacokinetic study of the six components in male rat plasma after oral administration of Abri Herba and Abri mollis Herba extract and the results in the study would provide a useful guide for the clinical application of Abri Herba with those in Abri mollis Herba. [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinical effect of acupuncture at Sifeng (EX-UE10) combined with Wang's Baochi Pills in the treatment of pediatric malnutrition, so as to provide a more effective method for pediatric malnutrition., Methods: A total of 201 children with malnutrition were randomly divided into combined treatment group ( n ＝102) and control (Baochi Pill) group ( n ＝99). The children in the combined treatment group were treated by acupuncture stimulation of Sifeng (EX-UE10, till no more yellowish-white effusion out) and oral administration of Wang's Baochi Pills, and those in the control group treated by oral administration of Wang's Baochi Pills only. The course of treatment was one month for both groups. The integral score of symptom was assessed according to the main symptoms as body weight and height and food-intake, and to the secondary symptoms including mentality, agitation, sleep, hair gloss, susceptibility to cold, hydrosis, abdominal distension, and susceptibility to diarrhea or constipation. The therapeutic effect was assessed by consulting the "Criteria for Diagnosis and Therapeutic Effect Evaluation of Syndromes/Illnesses of Traditional Chinese Medicine (TCM)" and "TCM Professional Criteria of the People's Republic of China for Diagnosis and Therapeutic Effect Evaluation of Syndromes/Diseases of TCM Pediatric"., Results: After the treatment, the total symptom scores of both groups were significantly decreased in comparison with their own pre-treatment ( P <0.05), and the scores of total symptom after the treatment and the 1 st , 2 nd and 3 rd follow-up surveys were obviously lower in the combined treatment group than in the control group ( P <0.05). Of the 99 and 102 cases in the control and combined treatment groups, 47 and 59 were cured, 39 and 37 experienced improvement in their symptoms, and 13 and 6 failed, with the effective rate being 86.87% (86/99) and 94.11%(96/102), respectively. The effective rate of the combined treatment was evidently higher than that of the simple medication ( P <0.05)., Conclusion: Acupuncture of Sifeng (EX-UE10) combined with Wang's Baochi Pills is better than administration of Wang's Baochi Pills alone in the therapeutic effect for pediatric malnutrition.

In China, Semen Cassiae has long been used to protect liver, brighten eyes, and relieve constipation. Prepared Semen Cassiae is produced from raw Semen Cassiae by processing, the two forms of Semen Cassiae have different clinical applications. Pathological state is an important factor affecting the efficacy of drugs, the pharmacokinetic behavior of drugs could be significantly changed when people or animal were under different pathological state. To clarify the effect of processing mechanism and pathological state for pharmacokinetic behavior, the pharmacokinetics of nine components of raw and prepared Semen Cassiae under normal and acute liver injury rats were examined. The results showed that the bimodal phenomenon appeared on the plasma concentration‐time profiles of obtusin, emodin, chrysophanol, aloe emodin and rhein. The Tmax of aurantio‐obtusin, obtusin, chrysoobtusin, emodin, chrysophanol, aloe emodin, physcion in normal groups administrated prepared Semen Cassiae were shorter than those administrated raw Semen Cassiae. For the AUC0–t, aurantio‐obtusin, obtusin, chrysoobtusin, chrysophanol, aloe emodin and physcione in model groups administrated prepared Semen Cassiae were significantly higher than other groups, unlike above components, rhein had poor absorption in model groups. The study would be useful for further studies on pharmacokinetics and clinical application of raw and prepared Semen Cassiae. [ABSTRACT FROM AUTHOR]

Papaveris pericarpium, a natural source of morphine and codeine, is the principal active component in many antitussive traditional Chinese medicines. We herein report the first PK study of papaveris pericarpium in human plasma and urine following oral administration of single (15, 30, 60 mL) and multiple dose (15 mL) of Qiangli Pipa Syrup (MOR 0.1 mg/mL, COD 0.028 mg/mL) by monitoring morphine and codeine using a HPLC-MS/MS method. Their T max and t 1/2 values are independent of dosages, while the AUC 0-t linearly increased with higher dosages, indicating linear PK characteristics. AUC 0-t increased obviously after multiple doses, indicating possible risk of accumulative toxicity. Urine studies suggested risks of positive opiate drug tests with a cutoff of 300 ng/mL, which lasted 6-14 h at different doses. These results provide important information for clinical safety, efficacy and rational drug use of Qiangli Pipa Syrup and also guide the related judicial expertise of its administration., (© 2017 American Academy of Forensic Sciences.)

Simple Summary: Crucian carp (Carassius auratus) is a freshwater fish that is popular due to its high nutritional value and delicious taste. It has become one of the most commonly farmed fish species, particularly in China. With the rapid development of intensive aquaculture, fish are becoming increasingly vulnerable to various pathogens that can cause significant economic losses. To reduce these losses, treatment with effective antibacterials is necessary. Although not approved in China, difloxacin is being used extensively in an extra-label manner to treat infections in aquaculture. However, the dosage guidelines specific to fish have not been established, resulting in the extrapolation of mammalian dosing regimens. Because fish are poikilotherms with unique physiologies and anatomies, dosing regimens intended for mammals may not be appropriate for them. In this research paper, we have employed a sparse sampling method and non-linear mixed effect modeling to develop population pharmacokinetics models. In addition, we have determined the values of the PK/PD parameter (free AUC/MIC) by utilizing previously published MIC data. Based on the free AUC/MIC values calculated herein, the current oral dose of difloxacin (20 mg/kg body weight) might be not enough to treat infections in crucian carp. This study aimed to investigate the population pharmacokinetics of difloxacin in crucian carp (Carassius auratus) orally provided a single dose of 20 mg/kg body weight (BW). To achieve this, fish were sampled at various intervals using a sparse sampling strategy, and plasma samples were analyzed using the high-performance liquid chromatography (HPLC) method. Subsequently, naïve average data were analyzed using a non-compartmental method, and a population model was developed based on the nonlinear mixed effects approach. The covariate of BW and the relationship between covariances were sequentially incorporated into the population model. However, it was found that only covariance and not BW affected the population parameters. Therefore, the covariance model was taken as the final population model, which revealed that the typical values of the absorption rate constant (tvKa), apparent volume of distribution per bioavailability (tvV), and clearance rate per bioavailability (tvCl) were 1.18 1/h, 14.18 L/kg, and 0.20 L/h/kg, respectively. Based on the calculated free AUC/MIC values, the current oral dose of difloxacin (20 mg/kg BW) cannot generate adequate plasma concentrations to inhibit pathogens with MIC values above 0.83 μg/mL. Further study should be carried out to collect the pathogens from crucian carp and determine the MIC data of difloxacin against them. Pharmacodynamic experiments must also be further carried out to determine the optimal therapeutic dose for the treatment of Aeromonas hydrophila infection. [ABSTRACT FROM AUTHOR]

Naoxintong capsule (NXTC) was a famous patent medicine of Traditional Chinese Medicine (TCM) to treat cerebrovascular diseases in China. An LC-MS/MS method was developed for simultaneous determination of 11 major ingredients (paeoniflorin, ecdysterone, amygdalin, mulberroside A, caffeic acid, ferulic acid, salvianolic acid B, astragaloside IV, formononetin, cryptotanshinone, and tanshinone IIA) in NXTC in rat plasma. All analytes were separated on an Eclipse plus C18 column using a gradient mobile phase system of acetonitrile-0.1% formic acid aqueous solution. The lower limits of quantification of 11 ingredients were between 0.075 and 10 ng mL−1. The precision was less than 15% and the accuracies were between 85% and 115%. The results showed that caffeic acid, ferulic acid, formononetin, cryptotanshinone, and tanshinone IIA could be detected after oral administration of NXTC. The validated method was successfully applied to pharmacokinetic study of the caffeic acid, ferulic acid, formononetin, cryptotanshinone, and tanshinone IIA in rats after oral administration of NXTC at single and triple dose. [ABSTRACT FROM AUTHOR]

Compound Danshen Dripping Pills (CDDP), a herbal patent medicine, is widely used in China for the prevention and treatment of cardiovascular diseases. A simple, sensitive and reliable method for simultaneous determination of danshensu (DSS), protocatechuic aldehyde (PCA), and their related metabolites, 4-hydroxy-3-methyloxyphenyl lactic acid (HMLA) and protocatechuic acid (PAA) in human plasma was developed and validated based on liquid chromatography tandem mass spectrometry (LC-MS/MS). The analytes and internal standard (IS), vanillic acid (VAA), were extracted from plasma with ethyl acetate and separated on a C 18 column by using the mobile phase consisted of methanol-0.1% formic acid via gradient elution. The electrospray ionization (ESI) source was applied and operated under the multiple reaction monitoring (MRM) mode. The linear calibration curves were obtained at the concentration ranges of 0.46-1000ng/mL for DSS and PAA, and 1.38-1000ng/mL for PCA and HMLA, respectively. The inter- and intra-day precisions (RSD%) were less than 13.5%, and the accuracy (±RE%) was within 13.4%. The described method was successfully applied for the clinical pharmacokinetics of CDDP in Chinese healthy volunteers., (Copyright © 2017. Published by Elsevier B.V.)

Nauclea officinalis has long been used in China for the treatment of cold, fever, swelling of throat, pink eyes, and so on; however, the in vivo integrated metabolism of its multiple bioactive components remains unknown. In this paper, an ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) method was established to identify chemical constituents in N. officinalis and metabolites in rat biological fluids after oral administration of N. officinalis . First, 40 chemical constituents in N. officinalis were detected within 19 min by UPLC-QTOF/MS. Among them, 18 alkaloids and 7 phenolic acids and iridoids were identified or tentatively characterized. Secondly, 22 metabolites were identified after oral administration of N. officinalis extract, including 3, 9, 6 and 4 metabolites in the plasma, feces, urine and bile samples, respectively. Finally, the metabolic pathway was proposed, which were the hydroxylation, the hydroxylation of deglycosyation product of parent compound, the hydroxylation and dehydrogenation product of parent compound, and acetylation. Among these, hydroxylation was considered as the main metabolic processes. This work suggests that the integrative metabolism approach makes a useful template for drug metabolism research of traditional Chinese medicine (TCM). [ABSTRACT FROM AUTHOR]

Iris tectorum Maxim, a well-known herb medicine, is commonly used for treatment of inflammation, cough, and pharyngitis for a long time in China. Tectoridin, main active ingredient of Iris tectorum Maxim, is often used for its quality control. This study was aimed to analyze the pharmacokinetic profile of tectorigenin (the metabolite of tectoridin) after oral administration of I. tectorum Maxim extract, and to compare the pharmacokinetic characterization of tectorigenin after oral administration of I. tectorum Maxim extract (ITME) and pure tectoridin (PT) in rats. In addition, a simple, reliable and sensitive UPLC–MS/MS method was developed for determination of tectorigenin in rat plasma, using kaempferol as internal standard. The processed samples were separated on a Poroshell 120 SB-C 18 column and detected by positive electrospray ionization in multiple reaction monitoring (MRM) mode. The method validation results indicated that the established method was simple, specific and reliable. The pharmacokinetic results showed that the plasma concentration of tectorigenin in ITME group was much higher than that of the PT group ( p < 0.01). Moreover, compared to PT group, t 1/2 value and AUC 0–∞ value were also notably increased in ITME group ( p < 0.01). In conclusion, potential interaction exists between those chemical components in ITME, and the co-existing components in ITME could notably promote the absorption of tectoridin in rats, however, the exact compound(s) which enhance the absorption of tectoridin should be investigated in future study. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Eucommiae cortex (EC), the bark of Eucommia ulmoides Oliv., has been traditionally used to treat many diseases in China for more than 2000 years. The pharmacological effects are primarily attributed to the presence of lignans, iridoids and phenolics, which are main active ingredients in EC. Aim of the study First, to investigate the active ingredients that can be absorbed into the rat plasma according to which ingredients exhibit significant correlation of drug concentration–time curve. Second, to establish an efficient ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method for simultaneous determination of ingredients absorbed in rat plasma. Finally, to investigate gender effect on the pharmacokinetics of the ingredients absorbed in male and female rats plasma after oral administration with EC extract. Materials and methods 18 ingredients from EC were detected by UPLC-MS/MS, 9 out of 18 ingredients were absorbed into rat plasma. And 5 ingredients exhibit significant correlation of drug concentration–time curve. They were pinoresinol di-O- β -d-glucopyranoside (PDG), geniposide (GE), geniposidic acid (GA), aucubin (AN) and chlorogenic acid (CA). The analytes were extracted from rat plasma via a simple protein precipitation procedure and osalmid was used as the internal standard. Chromatographic separation was achieved on a Waters ACQUITY HSS T3 column (2.1 mm×100 mm, 1.8 μm) using a gradient elution program with acetonitrile and 0.1% formic acid water as the mobile phase, with a flow rate of 0.3 mL min −1 . The detection was performed on a triple-quadrupole tandem mass spectrometer by multiple reactions monitoring (MRM) mode in a positive ion mode via electrospray ionization (ESI). The transition monitored were / z 683.00[M+H] + →235.10 for PDG, / z 389.00[M+H] + →208.80 for GE, m / z 375.00[M+H] + →194.79 for GA, m / z 364.00[M+NH 4 ] + →148.81 for AN, m / z 355.10[M+H] + →162.84 for CA and m / z 230.03[M+H] + →120.77 for internal standard. Results The developed method showed good linearity over a wide concentration range, the lower limits of quantification and higher accuracy and precision for determination of the 5 analytes. Then the method was applied to study the pharmacokinetics in rats, and the results indicated that there were significant differences in pharmacokinetic parameters of the analytes between the male and female rats, and absorptions of these analytes in male group were all significantly higher than those in female group. Conclusion This study established an efficient, sensitive and selective UPLC-MS/MS method for simultaneous determination of the five ingredients in rat plasma, and it could be successfully applied to the comparative pharmacokinetic studies in male and female rats after oral administration with EC extract. [ABSTRACT FROM AUTHOR]

Purpose: A new generic formulation of cycloserine has been developed in China but the pharmacokinetic properties of cycloserine in the Chinese population have not been reported. The aim of our study was to evaluate the pharmacokinetic properties and tolerability of single and multiple oral administrations of cycloserine capsules in healthy Chinese volunteers. Methods: This open-label, single- and multiple-dose 3-way crossover study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of cycloserine (250, 500, or 1000 mg) in separate trial periods, with a 1-week washout between periods. Those allocated to the 250-mg dose continued into the multiple-dose phase, in which they received 250 mg BID for 5 consecutive days. During the single-dose phase, blood samples were collected at regular intervals from 0 to 72 hours after drug administration and the concentrations of cycloserine were determined using LC-MS/MS. During the multiple-dose phase, blood samples were obtained before drug administration on Days 4, 5, and 6 to determine the Cmin at steady state. On Day 6, blood samples were also collected from 0 to 72 hours after drug administration. Pharmacokinetic parameters were estimated using noncompartmental methods. Tolerability was determined using clinical evaluation and monitoring of adverse events. Findings: The study enrolled 12 healthy Chinese volunteers (6 men: mean [SD] age = 23.0 [2.6] years, weight = 60.2 [6.2] kg, height = 170.0 [3.0] cm, and body mass index = 20.7 [1.7]; 6 women: mean [SD] age = 25.3 [1.4] years, weight = 51.5 [3.3] kg, height = 160.0 [4.0] cm, and body mass index = 20.1 [0.9]). After administration of a single dose, cycloserine was rapidly absorbed, reaching peak plasma concentrations approximately 0.84 hours after oral administration, and t1/2 in plasma was about 13.0 hours. The geometric mean (SD) Cmax value increased in proportion to cycloserine dose, from 19.42 (5.89) to 84.76 (21.74) mg/L, and the geometric mean (SD) AUC0-72h value increased from 264.16 (133.37) to 1153.87 (522.16) mg ⋅ h/L in the range of a 250- to 1000-mg dose. After administration of multiple doses of cycloserine 250 mg BID, the mean (SD) t1/2 was 13.56 (4.38) hours, the apparent total clearance of the drug from plasma after oral administration was 1.02 (0.42) L/h, and the apparent volume of distribution was 18.22 (5.25) L, which were comparable with those after single dosing. The accumulation index was 2.19 (0.51), and the fluctuation was 1.05 (0.35). Results of the t tests of Cmax and AUC found no significant differences between the male and female groups. No serious adverse events were reported, and there were no discontinuations due to adverse events. Implications: The pharmacokinetic properties of cycloserine were linear at doses from 250 mg to 1000 mg. After multiple doses, the pharmacokinetic properties of cycloserine were consistent with those after single doses. At the doses studied, cycloserine appears to be well tolerated in these healthy volunteers. [ABSTRACT FROM AUTHOR]

To develop a population-based pharmacokinetic model for the oral antiepileptic drug zonisamide using a cohort of healthy (nonepileptic) subjects and evaluate the effect of individual factors on the pharmacokinetics of zonisamide. 30 young adults (21-39 years) in good health were randomly assigned to 3 equal groups (1:1 sex ratio) for single-dose administration of zonisamide at 200 mg, 300 mg, or 400 mg. An additional 9 subjects (22-24 years) were administered once daily zonisamide at 300 mg for 14 days, and comprised the multiple dosing group. Venous blood samples were collected for analysis prior to (baseline, 0 hours) and after (1-300 hours) drug administration, providing 607 total samples used to build the pharmacokinetic model. The population pharmacokinetic analysis was performed by ICON's nonlinear mixed-effect modeling (NONMEM) software. Validation of the final model was carried out by nonparametric bootstrapping and visual predictive check. The zonisamide pharmacokinetics was best described by a two-compartment model with first-order elimination. In the final model, the estimated value of clearance (CL) was 23.25 L/h, the volume of distribution of the central compartment (Vc) was 34.50 L, the intercompartmental clearance (Q) was 20.22 L/h, and the Ka was 0.026 h(-1). The peripheral volume of distribution (Vp) was 1,429 L for single dose and 1,003 L for multiple doses. Body weight was the significant covariate affecting CL, Vc, Vp, and Q. Otherwise, female subjects had a lower Q than male subjects. The pharmacokinetics of zonisamide after oral administration could be described using a linear first-order elimination two-compartment model, which may provide a reference for clinical use of zonisamide in Chinese adults.

Sinomenium acutum stem is widely used to treat rheumatoid arthritis, gout, ankylosing spondylitis and other diseases in China. However, its metabolism in vivo is still unclear. In this study, UPLC-Q-TOF/MS was used to analyze the main components and their metabolites in rats after oral administration of Sinomenium acutum stem extract. A total of 41 compounds were identified from the ethanol extract of Sinomenium acutum stem based on the established database and the reference substance; a total of 25 prototype components and 107 metabolites (74 phase I metabolites and 33 phase II metabolites) were speculated and identified in the plasma, urine, bile and feces of rats administered. The metabolic pathways included hydroxylation, demethylation, dehydrogenation, glucuronidation and acetylation. In conclusion, this study revealed the metabolism of Sinomenium acutum stem in vivo , which may provide a better basis for the study of Sinomenium acutum stem and provide useful chemical information on the material basis and pharmacological mechanism of drug efficay. • 25 prototypes and 107 metabolites were characterized in rat bio-samples. • Elucidated the fragmentation rules and metabolic pathways of different alkaloids. • A total of 35 alkaloids were characterized in Sinomenium acutum stem extract. [ABSTRACT FROM AUTHOR]

Pharmacokinetic characters of rhynchophylline (RIN), gastrodin (GAS), and gastrodigenin (p-hydroxybenzyl alcohol, HBA) were investigated after oral administration of different prescriptions of Yizhi: Yizhi tablets or effective partsof tianma (total saponins from Gastrodiae, EPT) and gouteng (rhynchophylla alkaloids, EPG). At different predetermined time points after administration, the concentrations of GAS, HBA, and RIN in rat plasma were determined by anHPLC-ESI/MSmethod, and themain pharmacokinetic parameters were investigated. The results showed that the pharmacokinetic parameters Cmax and AUC0-∞ (P < 0.05) were dramatically different after oral administration of different prescriptions of Yizhi. The data indicated that the pharmacokinetic processes of GAS, HBA, and RIN in rats would interact with each other or be affected by other components in Yizhi. The rationality of the compatibility of Uncaria and Gastrodia elata as a classic "herb pair" has been verified from the pharmacokinetic viewpoint. [ABSTRACT FROM AUTHOR]

Abstract: Taxus yunnanensis (T. yunnanensis) is endemic to China and has been used in traditional medicine for the treatment of cancer, diabetic ailments and others. Paclitaxel is a representative antitumor compound in the Taxus species. The pharmacokinetic behavior of paclitaxel after oral administration of the crude extract of T. yunnanensis has not been investigated. This study attempts to compare the pharmacokinetics of paclitaxel after an oral administration of the crude extract of the twigs and leaves of T. yunnanensis and pure paclitaxel. A UPLC and a UPLC/MS/MS analysis method were developed for the determination of paclitaxel in T. yunnanensis extract and in the comparative pharmacokinetic study. Caco-2 cells were used to investigate the transport profile of paclitaxel in vitro. In the pharmacokinetic study, rats were randomly grouped and administered with T. yunnanensis extract or pure paclitaxel. The results showed that the AUC and Cmax of paclitaxel in rats receiving the T. yunnanensis extract were significantly increased than those receiving the pure paclitaxel, and the in vitro Caco-2 cell monolayer transport study found that the coexisting constituents in the extract of T. yunnanensis could inhibit the efflux of paclitaxel. These findings suggested that the oral absorption and bioavailability of paclitaxel in T. yunnanensis extract were remarkably higher when compared with the pure paclitaxel, and the coexisting constituents in the T. yunnanensis extract might play an important role for the enhancement of the oral absorption and bioavailability of paclitaxel. [Copyright &y& Elsevier]

Citrus × aurantium L., Chinese name: Fructus Aurantii (FA) has been largely used as Qi-invigorating herb in China for centuries. The main components (meranzin hydrate, naringin, neohesperidin, meranzin, nobiletin) have good physiological activity with relatively high abundance in FA. Few multi-component comparative pharmacokinetics are simultaneously accessible for the flavone glycosides, polymethoxy flavones, and coumarins in FA. In this work, a reliable and rapid ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was established and validated to determine the five ingredients in the SD rat plasma, and further applied to the pharmacokinetic studies after oral administration of monomer, drugs in compatibility, and FA extract. After hydrolysis with β -glucuronidase and sulfatase, the concentration of naringin and neohesperidin in rat plasma were expressed respectively by the total concentration of naringenin and hesperitin which was determined by UPLC-MS/MS. Double-peak phenomenon was observed for naringin and neohesperidin, which may be due to the enterohepatic circulation or multiple site absorption of the two flavone glycosides. Meranzin hydrate and meranzin (coumarins) were absorbed rapidly (Tmax, about 1.0 h) but eliminated slowly (t1/2z exceeds 6.5 h). Nobiletin, a typical polymethoxy flavone, was also rapidly absorbed according to Tmax and AUC(0-t). DAS 3.1 software suggests the pharmacokinetic profiles of the five components in rats be depicted as a two-compartment pharmacokinetic model. There were significant differences in pharmacokinetic parameters for naringenin and hesperetin between the compatibility, FA extract group vs monomer group: ① remarkable increases in the values of AUC(0–∞), AUC(0–t) and Cmax; ② obvious decrease of CLZ/F; and ③ longer tmax and t1/2z. The results suggest that compatibility can promote mutual absorption and affect the elimination behaviors. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Traditional Chinese medicine (TCM) has been used in clinical practice for several thousand years. TCM has played an indispensable role in the prevention and treatment of diseases, especially the complicated and chronic ones. Pharmacokinetic study on active constituents in herbal preparations is a good way for us to explain and predict a variety of events related to the efficacy and toxicity of TCM. Aim of the study: A selective and sensitive HPLC–MS/MS method was first developed and validated for the determination of luteolin, kaempferol, apigenin, quercetol, and isorhamnetin in rat plasma. Materials and methods: The LC system consisted of an Agilent Technologies Series 1200 system (Agilent, USA) equipped with an automatic degasser, a quaternary pump, and an autosampler. Chromatographic separations were performed on a Waters SunFire™ C18 column (150mm×4.6mm, 5μm), and the column temperature was maintained at 25°C and the sample injection volume was 20μL. The current LC–MS/MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability. Results: The validated method was successfully applied to monitoring the concentrations and pharmacokinetic studies of five flavone compounds in rat plasma after a single oral administration of Verbena officinalis L. extract with a dosage of 8.0mL/kg. The time to reach the maximum plasma concentration (T max1) was 0.48±2.14h for luteolin, 0.25±0.13h for kaempferol, 0.97±1.08h for apigenin, 1.04±4.25h for quercetol and 0.25±0.16h for isorhamnetin, and the maximum plasma concentration (T max2) was 3.97±1.48h, 4.05±0.46h, 4.33±0.58h, 2.99±0.48h and 4.02±0.34h. The elimination half-time (t 1/2) of luteolin, kaempferol, apigenin, quercetol and isorhamnetin was 4.02±0.81, 7.65±0.71, 3.30±0.83, 4.55±0.49 and 5.56±1.32h, respectively. Conclusions: This paper described a simple, sensitive and validated LC–MS/MS method for simultaneous determination of luteolin, kaempferol, apigenin, quercetol and isorhamnetin in rat plasma after oral administration of V. officinalis L. extract, and investigated on their pharmacokinetic studies as well, with a short run time of 5min. [Copyright &y& Elsevier]

Abstract: Chinese Holstein, bred by mating the Holstein-Friesian to Chinese Yellow Cattle, is a major dairy cattle breed in China. Eprinomectin is widely used in the treatment of nematode and ectoparasite infections in lactating cattle. The pharmacokinetics of eprinomectin in the plasma and milk were determined in Chinese Holstein cows following topical (at 0.5mgkg−1) or oral (at 0.2mgkg−1) administration. For topical administration, the concentrations of eprinomectin in plasma reached peak values (C max) of 16.16±6.02ngml−1 at 3.20±1.30 days (T max). In milk, the C max values of 2.28±0.85ngml−1 were obtained at 3.48±0.65 days. The MRT values were 5.00±0.96 days for plasma and 4.65±0.60 days for milk. The AUC values were 91.00±25.32ngdml−1 for plasma and 10.53±1.55ngdml−1 for milk. The ratio of AUC milk/plasma was 0.124±0.041. Significant differences were found in C max and AUC of eprinomectin in plasma between Chinese Holstein and Prim Holstein following topical administration. It was probably due to the lower storage of body fat in Chinese Holstein than in Prim Holstein. For oral administration, the concentrations of eprinomectin reach peak values of 30.02±5.73ngml−1 at 1.60±0.55 days in plasma and 3.14±0.88ngml−1 at 1.40±0.27 days in milk. The MRT values for plasma and milk were 3.00±0.46 and 3.18±0.55 days, respectively. The AUC values were 98.46±24.75ngdml−1 for plasma and 10.42±4.22ngdml−1 for milk. The ratio of AUC milk/plasma was 0.104±0.022. Compared with the topical administration, a significantly shorter MRT of eprinomectin in plasma was obtained following oral administration, which would shorten residue time of this compound in faeces and reduce its ecotoxicological effect. The low exposure of eprinomectin in milk would favor the use of eprinomectin in lactating Chinese Holstein for topical or oral administration. [Copyright &y& Elsevier]

Isradipine could be used for the treatment of high blood pressure or Parkinsonism, yet the study on pharmacokinetics (PK) of isradipine is lacking in the Chinese population. The current study aims to assess the dose proportionality, pharmacokinetics and gender effect of isradipine following oral single and multiple doses in Chinese subjects. A randomized, open-label, parallel-group trial was conducted in 30 healthy Chinese volunteers. Subjects randomly received a single dose of 2.5, 5 or 10 mg, and multiple doses (2.5 mg) of isradipine. Blood samples were collected pre-dose (0 h) and 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 36 and 48 h post-dose. Isradipine was rapidly absorbed with the time to maximum concentration <1.27 h for all dosage groups. The maximum concentrations were 2.46, 5.34, 10.93 and 3.32 ng/mL and area under the concentration-time curve from time zero to the last time point (AUClast ) were 7.05, 12.58, 24.68 and 5.31 ng/ml · h for the 2.5, 5 and 10 mg single-dose and 2.5 mg multiple-dose groups, respectively. The half-life ranged from 5.76 to 7.94 h. The maximum concentration and AUC were found to increase linearly and dose-dependently for isradipine. No statistical gender differences were found. These findings indicated that the pharmacokinetic parameters of isradipine in Chinese population were dose-proportional and predictable over a range of 2.5-10 mg isradipine oral doses., (Copyright © 2013 John Wiley & Sons, Ltd.)

Ethnopharmacological relevance: Ajuga decumbens Thunb is a medicinal plant native to China popularly used to treat chronic pelvic inflammation and hysteromyoma. Its main bioactive components are iridoid glycosides, such as 8-O-acetylharpagide and harpagide that had presented antibacterial, anti-inflammatory, and antiviral activities. Aim of the study: To establish a sensitive LC–MS/MS method and compare the pharmacokinetics of 8-O-acetylharpagide and harpagide in rats after oral administration of their pure forms and from compounds obtained from Ajuga decumbens extract. Materials and methods: Rats received orally 15mg/kg (equivalent of 6mg/kg 8-O-acetylharpagide and 1.5mg/kg harpagide), 30mg/kg and 60mg/kg of Ajuga decumbens Thunb extract and were compared to animals that received 12mg/kg of 8-O-acetylharpagide or 3mg/kg of harpagide p.o. Concentrations of 8-O-acetylharpagide and harpagide in plasma were determined by LC–MS/MS method at different time points and all pharmacokinetic parameters were estimated by non-compartmental analysis. Results: Results showed that the iridoid glycosides were quickly absorbed by oral route and showed a dose-dependence profile. Pharmacokinetic parameters of both glycosides were essentially the same except Tmax when dosed as the extract or pure forms. Conclusion: 8-O-acetylharpagide was metabolized to harpagide, which affected the pharmacokinetic profiles of harpagide when dosed as the extract. This pharmacokinetic study seems to be useful for a further clinical study of Ajuga decumbens Thunb extract. [Copyright &y& Elsevier]

Abstract: This study aims to observe the effects of gestational stage on the pharmacokinetics of puerarin after oral administration in rats. The pharmacokinetics of puerarin was studied in pregnant rats using a sensitive and reproducible high-performance liquid chromatography/ultraviolet method. The concentration–time curves in both normal and pregnant rats were fit into a two-compartment model. The results indicated that gestation influences the pharmacokinetics of puerarin at different levels, especially during the early stages of pregnancy. Furthermore, puerarin penetrates the placental barrier and maintains high concentrations in fetal rat plasma. Therefore, puerarin administration should be carefully considered in pregnant women. [Copyright &y& Elsevier]

Abstract: A high performance liquid chromatography–hydride generation–atomic fluorescence spectrometry (HPLC–HG–AFS) method was developed for the simultaneous determination of four arsenic species (As(III), dimethylarsinic acid (DMA), monomethylarsonic acid (MMA) and arsenate As(V)) in dog plasma. Good separation of the four arsenic species was achieved within 15min on an anion-exchange column with isocratic elution using 15mmol/L KH2PO4 (pH 5.9) as eluent at a flow rate of 1.0mL/min. The assay was linear over the range of 1.25–200, 1.56–200, 1.34–172, and 2.50–200ng/mL with the detection limits of 0.80, 1.00, 0.86 and 2.00ng/mL for As(III), DMA, MMA and As(V), respectively. The method was validated for selectivity, precision, accuracy and recovery and then applied to a comparative pharmacokinetic study of the arsenic species in beagle dogs after a single oral administration of Realgar (24.32mg/kg, equivalent to 11.31mgAs/kg) alone or Niu Huang Jie Du Pian (a patent traditional Chinese medicine (TCM), 380mg/kg, equivalent to 28.45mgAs/kg), respectively. DMA was found to be the predominant species in the dog plasma after dosing, with As(V) appeared as the quickly eliminating one. No traces of MMA and As(III) were detected at any sampling time points. The main pharmacokinetic parameters found for DMA p.o. administration of Realgar and Niu Huang Jie Du Pian were as follows: C max (14.7±4.2) and (57.0±32.0)ng/mL, T max (2.4±0.5) and (2.5±0.5)h, AUC0–36 (151.1±12.9) and (635.9±418.2)ngh/mL, AUC0–∞ (206.0±44.5) and (687.2±425.1)ngh/mL, t 1/2 (16.2±7.9) and (9.4±2.2)h, respectively. The influence of compounding in Niu Huang Jie Du Pian on the pharmacokinetics of arsenics was shown with increased transformation of DMA and its faster elimination rate. [Copyright &y& Elsevier]

Alkylglycerols (AKGs) from shark liver oil (SLO) were demonstrated to have strong potency to stimulate immune response. However, no study has been conducted on the effects of AKGs on diet-induced obesity and metabolic inflammatory disorder. The purpose of the present study was to investigate the effect of two AKGs isoforms on obesity and insulin resistance in mice fed high fat (HF) diet. Forty-eight C57BL/6 mice were divided into normal, HF, HF + 20mg/kg selachyl alcohol (SA), HF + 200 mg/kg SA, HF + 20mg/kg batyl alcohol (BA), and HF + 200 mg/kg BA groups. Body weight, fasting glucose, lipids, insulin and leptin levels, serum IL-1β, and TNF-α levels were compared among different groups. Our results showed that high-dose SA decreased body weight, serum triglyceride, cholesterol, fasting glucose level, insulin level, and serum leptin level of the HF fed mice, while high dose BA increased fasting insulin level of the HF fed mice. Pretreatment of primary adipocytes with 10 μM SA or BA differentially modulates LPS-mediated MAPK and NF-κB signaling. Our study demonstrated that oral administration of AKGs has differential effects on HF-induced obesity and metabolic inflammatory disorder in mice. [ABSTRACT FROM AUTHOR]

Abstract: Stemonae Radix (Stemona tuberosa Lour, Bai Bu) is an important traditional Chinese medicinal (TCM) plant known for its antitussive activity. Croomine, neotuberostemonine and tuberostemonine alkaloids of Stemonae Radix are major components responsible for antitussive action. In this work, plasma pharmacokinetic and biodistribution characteristics of the three alkaloids after oral administration of Stemonae Radix are investigated using a rapid and sensitive UPLC-Q-TOF–HDMS method. Mass spectrometry (MS) was performed on a Waters Micromass high-definition technology with an electrospray ionization source in positive ion mode, with excellent MS mass accuracy and enhanced MS data acquisition. Separation of main alkaloids was achieved on a Waters BEH C18 column by linear gradient elution. Data were analyzed and estimated by compartmental methods and pharmacokinetic parameters calculated using WinNonlin Professional version 5.1. It was found that croomine, neotuberostemonine and tuberostemonine had faster absorbed into the bloodstream, maintain the high plasma concentration, and pose a large AUC value. The biodistribution of neotuberostemonine and tuberostemonine showed that the higher levels were in liver, and lung. Croomine was discovered in brain and showed that it could cross the blood–brain barrier, indicating that croomine plays an antitussive effect as acting on the central nervous system. Neotuberostemonine and tuberostemonine were not discovered in brain, demonstrating that they play an antitussive effect as peripheral antitussive. This work suggests that the pharmacokinetics and biodistribution based-UPLC-Q-TOF–HDMS can provide a reliable tools for screening bioactive components contributing to pharmacological effects of medicinal herbs. [Copyright &y& Elsevier]