Ascorbic acid releases dormancy and promotes germination by an integrated regulation of abscisic acid and gibberellin in Pyrus betulifolia seeds.

Seed dormancy is an important life history state in which intact viable seeds delay or prevent germination under suitable conditions. Ascorbic acid (AsA) acts as a small molecule antioxidant, and breaking seed dormancy and promoting subsequent growth are among its numerous functions. In this study, a germination test using Pyrus betulifolia seeds treated with exogenous AsA or AsA synthesis inhibitor lycorine (Lyc) and water absorption was conducted. The results indicated that AsA released dormancy and increased germination and 20 mmol L-1 AsA promoted cell division, whereas Lyc reduced germination. Seed germination showed typical three phases of water absorption; and seeds at five key time points were sampled for transcriptome analysis. It revealed that multiple pathways were involved in breaking dormancy and promoting germination through transcriptome data, and 12 differentially expressed genes (DEGs) related to the metabolism and signal transduction of abscisic acid (ABA) and gibberellins (GA) were verified by subsequent RT-qPCR. For metabolites, exogenous AsA increased endogenous AsA and GA3 but reduced ABA and the ABA/GA3 ratio. In addition, three genes regulating ABA synthesis were downregulated by AsA, while five genes mediating ABA degradation were upregulated. Taken together, AsA regulates the pathways associated with ABA and GA synthesis, catalysis, and signal transduction, with subsequent reduction in ABA and increase in GA and further the balance of ABA/GA, ultimately releasing dormancy and promoting germination.

Janus ACSP Nanoparticle for Synergistic Chemodynamic Therapy and Radiosensitization.

Protective autophagy and DNA damage repair lead to tumor radio-resistance. Some hypoxic tumors exhibit a low radiation energy absorption coefficient in radiation therapy. High doses of X-rays may lead to side effects in the surrounding normal tissues. In order to overcome the radio-resistance and improve the efficacy of radiotherapy based on the characteristics of the tumor microenvironment, the development of radiosensitizers has attracted much attention. In this study, a Janus ACSP nanoparticle (NP) was developed for chemodynamic therapy and radiosensitization. The reactive oxygen species generated by the Fenton-like reaction regulated the distribution of cell cycles from a radioresistant phase to a radio-sensitive phase. The high-Z element, Au, enhanced the production of hydroxyl radicals (•OH) under X-ray radiation, promoting DNA damage and cell apoptosis. The NP delayed DNA damage repair by interfering with certain proteins involved in the DNA repair signaling pathway. In vivo experiments demonstrated that the combination of the copper-ion-based Fenton-like reaction and low-dose X-ray radiation enhanced the effectiveness of radiotherapy, providing a novel approach for synergistic chemodynamic and radiosensitization therapy. This study provides valuable insights and strategies for the development and application of NPs in cancer treatment.

Differentiation of cancer of unknown primary and lymphoma in head and neck metastatic poorly differentiated cancer using 18 F-FDG PET/CT tumor metabolic heterogeneity index.

OBJECTIVE: To explore the value of 18 F-FDG PET/CT tumor metabolic heterogeneity index (HI) and establish and validate a nomogram model for distinguishing head and neck cancer of unknown primary (HNCUP) from lymphoma with head and neck metastatic poorly differentiated cancer. METHODS: This retrospective analysis was conducted on 1242 patients with cervical metastatic poorly differentiated cancer. 108 patients, who were clinically and pathologically confirmed as HNCUP or lymphoma, were finally enrolled. Two independent sample t-tests and χ 2 test were used to compare the clinical and imaging features. Binary logistic regression was used to screen for independent predictive factors. RESULTS: Among the 108 patients), 65 patients were diagnosed with HNCUP and 43 were lymphoma. Gender ( P  = 0.001), SUV max ( P  < 0.001), SUV mean ( P  < 0.001), TLG ( P  = 0.012), and HI ( P  < 0.001) had statistical significance in distinguishing HNCUP and lymphoma. Female ( OR  = 4.546, P  = 0.003) and patients with HI ≥ 2.37 ( OR  = 3.461, P  = 0.047) were more likely to be diagnosed as lymphoma. CONCLUSION: For patients with cervical metastatic poorly differentiated cancer, gender and HI were independent predictors of pathological type. For such patients, clinical attention should be paid to avoid misdiagnosing lymphoma as HNCUP, which may delay treatment.

Recent Progress of Low Dielectric and High-Performance Polybenzoxazine-Based Composites.

With the rapid advancement of intelligent electronics, big data platforms, and other cutting-edge technologies, traditional low dielectric polymer matrix composites are no longer sufficient to satisfy the application requirements of high-end electronic information materials, particularly in the realm of high integration and high-frequency, high-speed electronic communication device manufacturing. Consequently, resin-based composites with exceptional low dielectric properties have garnered unprecedented attention. In recent years, benzoxazine-based composites have piqued the interest of scholars in the fields of high-temperature-resistant, low dielectric electronic materials due to their remarkable attributes such as high strength, high modulus, high heat resistance, low curing shrinkage, low thermal expansion coefficient, and excellent flame retardancy. This article focuses on the design and development of modification of polybenzoxazine based on low dielectric polybenzoxazine modification methods. Studies on manufacturing polybenzoxazine co-polymers and benzoxazine-based nanocomposites have also been reviewed.

Study of the Self-Polymerization of Epoxy/Phthalonitrile Copolymers and Their High-Performance Fiber-Reinforced Laminates.

Self-polymerization epoxy/phthalonitrile (APPEN) pre-polymers were studied systematically, and then, gelation time and differential scanning calorimetry (DSC) were employed to investigate their curing behaviors. Taking advantage of orthogonal test analysis, the key factors that affected the co-polymerization of APPEN were defined and the appropriate pre-polymerization conditions were analyzed. A possible curing mechanism of APPEN was proposed. Then, the thermomechanical and mechanical properties of glass-fiber-reinforced APPEN laminates (APPEN/GF) prepared at 180 °C were analyzed to understand the cross-linked and aggregation structures. Fracture surface of the composite laminates was also investigated to reveal the copolymerization degree and the interfacial binding. The results indicated that APPEN/GF composites exhibit outstanding mechanical and thermomechanical properties (flexural strength, 712 MPa, flexural modulus, 38 GPa, and Tg > 185 °C). The thermal stability (T5% > 334 °C and IPDT reached 1482 °C) of APPEN/GF composites was also investigated to further reveal the copolymerization between epoxy resin and aminophthalonitrile, which may be beneficial to the application of epoxy-matrix-based composites in the field of high-performance polymer composites.

Multi-task deep learning-based radiomic nomogram for prognostic prediction in locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: Prognostic prediction is crucial to guide individual treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients. Recently, multi-task deep learning was explored for joint prognostic prediction and tumor segmentation in various cancers, resulting in promising performance. This study aims to evaluate the clinical value of multi-task deep learning for prognostic prediction in LA-NPC patients. METHODS: A total of 886 LA-NPC patients acquired from two medical centers were enrolled including clinical data, [18F]FDG PET/CT images, and follow-up of progression-free survival (PFS). We adopted a deep multi-task survival model (DeepMTS) to jointly perform prognostic prediction (DeepMTS-Score) and tumor segmentation from FDG-PET/CT images. The DeepMTS-derived segmentation masks were leveraged to extract handcrafted radiomics features, which were also used for prognostic prediction (AutoRadio-Score). Finally, we developed a multi-task deep learning-based radiomic (MTDLR) nomogram by integrating DeepMTS-Score, AutoRadio-Score, and clinical data. Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were used to evaluate the discriminative ability of the proposed MTDLR nomogram. For patient stratification, the PFS rates of high- and low-risk patients were calculated using Kaplan-Meier method and compared with the observed PFS probability. RESULTS: Our MTDLR nomogram achieved C-index of 0.818 (95% confidence interval (CI): 0.785-0.851), 0.752 (95% CI: 0.638-0.865), and 0.717 (95% CI: 0.641-0.793) and area under curve (AUC) of 0.859 (95% CI: 0.822-0.895), 0.769 (95% CI: 0.642-0.896), and 0.730 (95% CI: 0.634-0.826) in the training, internal validation, and external validation cohorts, which showed a statistically significant improvement over conventional radiomic nomograms. Our nomogram also divided patients into significantly different high- and low-risk groups. CONCLUSION: Our study demonstrated that MTDLR nomogram can perform reliable and accurate prognostic prediction in LA-NPC patients, and also enabled better patient stratification, which could facilitate personalized treatment planning.

Spatial topological analysis of sympathetic neurovascular characteristic of acupoints in Ren meridian using advanced tissue-clearing and near infrared II imaging.

Acupuncture has been used for treating various medical conditions in traditional Chinese medicine. Both manual and electro-acupuncture stimulate specific acupoints to obtain local and systemic biological effects, but the underlying mechanisms remain unclear. Here, we used three-dimensional tissue-clearing technology to study acupoints on the Ren meridian of mice to reveal the distribution, density, branching, and relationships between blood vessels and nerves. Using topological Mapper methods, we found that sympathetic neurovascular networks were denser in the CV 4 acupoint compared with surrounding non-acupoints. Furthermore, high resolution in vivo real-time vascular imaging using the near infrared-II probe LZ-1105 demonstrated increased blood flow in the CV 4 acupoint compared with neighboring non-acupoints after manual or electro-acupuncture. Consistent with earlier findings, our research indicated that acupuncture could enhance local blood flow, and our high-resolution 3D images show for the first time the important role of sympathetic neurovascular networks in the CV 4 acupoint.

Role of Glucuronidation Pathway in Quetiapine Metabolism: An In vivo Drug-Drug Interaction Study between Quetiapine and Probenecid.

BACKGROUND: Uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes play a significant role in the metabolism of quetiapine, and coadministration with a UGT inhibitor/inducer drug may change its pharmacokinetic profile. OBJECTIVE: The objective of this study was to assess the impact of probenecid, a UGT enzyme inhibitor, on the pharmacokinetic profile of quetiapine. MATERIALS AND METHODS: Twelve treatment-naïve, 7-week-old male Sprague-Dawley rats (weighting 161 ± 22 g) were randomly and equally divided into control, quetiapine-alone and quetiapine plus probenecid groups. The quetiapine plus probenecid group received a single oral dose of probenecid (50 mg/kg) followed by 50 mg/kg of quetiapine; the quetiapine-alone group only received 50 mg/kg of quetiapine. Blood samples (0.2 ml) were collected from all rats after 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h of the drug administration in heparinized tubes. The pre-established liquid chromatography-mass spectrometry method was utilized to ascertain the plasma concentration of quetiapine and the control group was used to prepare the controlled standard. RESULTS: Significant pharmacokinetic differences were observed between the quetiapine-alone and quetiapine plus probenecid groups in terms of Cmax (392 ± 209 vs. 1323 ± 343 ug/L, respectively, P = 0.004), AUC0-∞ (P = 0.04) and Tmax (P = 0.004). Further, in the combined drug group, there was a decrease in drug clearance (CL/F) (from 27 ± 11 to 16 ± 3 L/h/kg; P = 0.005) and an increase in the volume of distribution (Vd) (P = 0.01), but there was no significant difference between both groups in terms of half-lives (P = 0.27). No significant within-group variability of pharmacokinetic parameters was observed (P = 0.25). CONCLUSION: The results of this animal study suggest that glucuronidation by UGT enzyme system may also play an important role in quetiapine metabolism, which, if proven in future human studies, would imply that the bioavailability and pharmacokinetic parameters of quetiapine may require alterations when co-administered with probenecid to avoid development of quetiapine toxicity.

Ovarian Innervation Coupling With Vascularity: The Role of Electro-Acupuncture in Follicular Maturation in a Rat Model of Polycystic Ovary Syndrome.

Low-frequency electro-acupuncture (EA) has been shown to restore ovulation in patients with polycystic ovary syndrome (PCOS), and previous animal experiments showed that EA improves ovarian blood flow and angiogenesis. We performed EA for 4 weeks in dihydrotestosterone (DHT)-induced PCOS-like rats and investigated the three-dimensional (3D) ovarian innervation to determine the role of innervation in folliculogenesis and vascularity. Ovarian tissues were made transparent following the CUBIC 3D tissue-clearing protocol and were immunostained using antibodies against platelet endothelial cell adhesion molecule-1 and tyrosine hydroxylase to visualize the ovarian vasculature and innervation, respectively. This was followed by 3D imaging using lightsheet microscopy and analysis using the Imaris software. In control rats, ovarian innervation increased with age, and the neuronal branching started from the ovarian hilum and reached the individual follicles at different follicle stages. At the individual follicle level, each follicle was mainly innervated by one neuronal fiber. Compared with control rats, ovaries from DHT-treated PCOS-like rats had more antral follicles and fewer preovulatory follicles and corpora lutea. Furthermore, PCOS ovaries showed decreased innervation of blood vessels near the hilum and the surrounding individual antral follicles. EA in PCOS-like rats led to increased numbers of preovulatory follicles and corpora lutea together with increased innervation of blood vessels near the hilum. To determine the role of ovarian innervation, we further performed unilateral sectioning of the superior ovarian nerve (SON) in PCOS + EA rats and found that the left sectioned ovary had fewer preovulatory follicles and corpora lutea compared with those in the right non-sectioned ovary. In conclusion, ovarian innervation likely played an important role in folliculogenesis, and EA might restore PCOS pathophysiology by regulating ovarian innervation, at least partially mediated through the SON.

The Adsorption of Methylene Blue by an Amphiphilic Block Co-Poly(Arylene Ether Nitrile) Microsphere-Based Adsorbent: Kinetic, Isotherm, Thermodynamic and Mechanistic Studies.

Dye pollution is a serious problem in modern society. We desired to develop an efficient adsorbent for the decontamination of discharged dyes. In this work, the polymeric microspheres derived from a kind of amphiphilic block of co-poly(arylene ether nitrile) (B-b-S-P) were prepared on the basis of "oil-in-water" (O/W) microemulsion method. The B-b-S-P microspheres were found competent to remove the cationic dye, methylene blue (MB); and various influential factors, such as contact time, initial concentration, solution pH and temperature were investigated. Results indicated that the maximum adsorption capacity of B-b-S-P microspheres for MB was 119.84 mg/g at 25 °C in neutral conditions. Adsorption kinetics and isotherm dates were well fitted to a pseudo-second-order kinetic model and the Langmuir isotherm model, and thermodynamic parameters implied that the adsorption process was endothermic. The B-b-S-P microspheres also exhibited a highly selective adsorption for cationic dye MB, even in the presence of anionic dye methyl orange (MO). In addition, the possible adsorption mechanism was studied, suggesting that the electrostatic interaction and π-π interaction could be the main force in the adsorption process.

Bladder Outlet Obstruction Induced by the Compression of Displaced Hemipelvic Prosthesis After Pelvic Reconstruction: A Case Report.

Bladder outlet obstruction (BOO) is a common urological condition usually caused by benign prostatic hyperplasia, prostate cancer, urethral stricture, rarely by compression of surrounding organs. Herein we presented a BOO patient caused by the compression of displaced hemipelvic prosthesis after pelvic reconstruction. This report may help to increase awareness of BOO as a late complication of pelvic reconstruction.

Benzoxazine Containing Fluorinated Aromatic Ether Nitrile Linkage: Preparation, Curing Kinetics and Dielectric Properties.

Benzoxazine containing fluorinated aromatic ether nitrile linkage (FAEN-Bz) had been synthesized from 2,6-dichlorobenzonitrile, 4,4'-(hexafluoroisopropylidene)diphenol (bisphenol AF), 3-Aminophenol, formaldehyde, phenol by condensation polymerization and Mannich ring-forming reaction. Structures of the monomer were verified by Proton NMR spectrum (1H-NMR) and Fourier transform infrared spectroscopy (FTIR). Curing behaviors and curing kinetics of designed monomers were investigated and discussed. The activation energy was calculated and possible polymerization mechanisms were also proposed. Then, properties of cured polymers including crosslinking degrees, thermal decomposition, surface wettability and energy, and dielectric properties were studied and discussed. Additionally, programmed integral decomposition temperature (IPDT) was also used to evaluate the thermal stability of final polymers. Results indicated that the incorporation of benzoxazine and nitrile resulted in increased thermal stability and char yields. Moreover, the surface wettability and dielectric properties of poly(FAEN-Bz) can be easily controlled by tuning the curing temperatures and time.

Synergistic Effects of Functional CNTs and h-BN on Enhanced Thermal Conductivity of Epoxy/Cyanate Matrix Composites.

Epoxy/cyanate resin matrix composites (AG80/CE) with improved thermal conductivity and mechanical properties were obtained with synergetic enhancement with functional carbon nanotubes (f-CNTs) and hexagonal boron nitride (h-BN). AG80/CE performed as polymeric matrix and h-BN as conductivity filler which formed the main thermal conductivity channels. Small amounts of f-CNTs were introduced to repair defects in conductivity channels and networks. To confirm the synergetic enhancements, the thermal conductivity was investigated and analyzed with Agari's model. Results indicated that with introduction of 0.5 wt% f-CNTs, the thermal conductivity coefficient (ƛ) increased to 0.745 W/mk, which is 1.38 times that of composites with just h-BN. Furthermore, the flexural strength and modulus of composites with 0.5 wt% f-CNTs were 85 MPa and 3.5 GPa. The glass transition temperature (Tg) of composites with 0.4 wt% was 285 °C and the initial decomposition temperature (T5%) was 385 °C, indicating outstanding thermal stability. The obtained h-BN/f-CNTs reinforced AG80/CE composites present great potential for packaging continuous integration and miniaturization of microelectronic devices.

Micro/Mesoporous Fe3O4/Fe-Phthalocyanine Microspheres and Effects of Their Surface Morphology on the Crystallization and Properties of Poly(Arylene Ether Nitrile) Composites.

The surface morphology of nanoparticles significantly affects the final properties and interfacial characteristics of their composites. Thus, investigations on the surface morphology of the nanoparticles is essential to fabricate improved nanoparticle-reinforced composites. Fe3O4/Fe-phthalocyanine (FePc) hybrid microspheres with micro/mesoporous structures were prepared via a solvothermal process and solvent etching method. The surface morphology and compositional distribution were respectively investigated using a scanning electron microscope (SEM) and a transmission electron microscope (TEM) to rule out that FePc monomers have been blended with Fe3O4 to form Fe3O4/FePc hybrid microspheres without serious agglomeration. The surface roughness of Fe3O4/FePc microspheres was investigated by the scanning probe microscope (SPM), and confirmed by the adsorption and desorption isotherms of N2. The effects of the various surface morphologies on the crystallization behavior of crystallizable poly(arylene ether nitrile) (c-PEN) were first employed to confirm the surface characteristics of the resulted microspheres. Results indicated that the etched Fe3O4/FePc microspheres would improve the crystallization degree of c-PEN, due to their much more micro/mesoporous structures than that of original Fe3O4/FePc. Then, Fe3O4/FePc hybrid microspheres reinforced PEN composite films were prepared and their interfacial compatibility was monitored using an SEM. Excellent thermal stability and improved mechanical properties were obtained by combining the etched Fe3O4/FePc and PEN matrix. The excellent surface properties and micro/mesoporous structures make the novel Fe3O4/FePc an excellent candidate of organic/inorganic hybrid fillers and micro/mesoporous materials.

Thermal Stability of Allyl-Functional Phthalonitriles-Containing Benzoxazine/Bismaleimide Copolymers and Their Improved Mechanical Properties.

Copolymerization is the typical method to obtain the high-performance resin composites, due to its universality and regulation performance. It can be employed among various resin matrices with active groups to obtain the desired structures, and subsequently, the outstanding properties. In this work, the copolymerization between the allyl-functional phthalonitrile-containing benzoxazine resin (DABA-Ph) and 4,4'-bis(Maleimidodiphenyl)methane (BMI) were monitored. The interactions among the active groups including allyl moieties, maleimide, benzoxazine rings and nitrile groups were investigated. Differential scanning calorimetry (DSC) and dynamic rheological analysis (DRA) were used to study the curing behaviors and the processing properties. The possible curing processes were proposed and confirmed by Fourier transform infrared spectroscopy (FTIR). Then, glass fiber-reinforced DABA-Ph/BMI composites were designed, and their thermal-mechanical properties were studied. Results indicated that all the composites exhibited outstanding flexural strength, flexural modulus, and high glass-transition temperatures (Tg > 450 °C). The thermal stability of the composites was studied by thermogravimetry (TGA) and evaluated by the integral program decomposition temperature (IPDT). it is believed that the excellent thermal mechanical properties and outstanding Tg as well as good thermal stability would enable the reinforced copolymer-based laminates to be applied in wider fields.

Designing and Preparation of Fiber-Reinforced Composites with Enhanced Interface Adhesion.

The interfacial properties between fibers and resin matrices show great influence on the properties of fiber-reinforced composites. In this work, phthalonitrile containing benzoxazine (BA-ph) was chosen as the resin matrix, which combined with the glass fiber (GF) to prepare reinforced composite laminates at low temperature (200 °C). The poly(arylene ether nitrile) (PEN) was used to modify the GF and BA-ph matrix. Curing behaviors of the BA-ph/PEN were investigated with Differential scanning calorimetric (DSC) and Dynamic rheological analysis (DRA), and results indicated that the polymerization would be hindered by PEN due to the dilution effects. Moreover, the formation of triazine rings which assigning to the ring-forming polymerization of nitrile groups in BA-ph and PEN could improve the compatibility of BA-ph and PEN in the matrix. The SEM images of the fracture surface of the composites revealed that the brittleness of BA-ph matrix and interfacial adhesion between GFs and matrix was improved. The enhanced interfacial adhesion was detailedly discussed from the perspective of physical entanglement and the copolymerization between PEN chains on the surface of GFs and BA-ph/PEN matrix. The results of DMA also explained the toughness of BA-ph/PEN matrix, the semi-interpenetrating polymer networks and the interfacial adhesion. In sum, a feasible strategy that modifies the surface of GFs and the brittleness of the thermosetting matrix by high-performance thermoplastic polymers, which can be employed to prepare the composite laminates with improved properties.

Chronic Olanzapine Treatment Induces Disorders of Plasma Fatty Acid Profile in Balb/c Mice: A Potential Mechanism for Olanzapine-Induced Insulin Resistance.

BACKGROUND: Atypical antipsychotics such as olanzapine cause metabolic side effects leading to obesity and insulin resistance. The underlying mechanisms remain elusive. In this study we investigated the effects of chronic treatment of olanzapine on the fatty acid composition of plasma in mice. METHODS: Twenty 8-week female Balb/c mice were randomly assigned to two groups: the OLA group and the control group. After treatment with olanzapine (10 mg/kg/day) or vehicle intraperitoneally for 8 weeks, fasting glucose, insulin levels and oral glucose tolerance test were determined. Effects on plasma fatty acid profile and plasma indices of D5 desaturase, D6 desaturase and SCD1 activity were also investigated. RESULTS: Chronic administration of olanzapine significantly elevated fasting glucose and insulin levels, impaired glucose tolerance, but did not increase body weight. Total saturated fatty acids and n-6 polyunsaturated fatty acids were significantly increased and total monounsaturated fatty acids were significantly decreased, while total n-3 polyunsaturated fatty acids showed no prominent changes. Chronic olanzapine treatment significantly up-regulated D6 desaturase activity while down-regulating D5 desaturase activity. Palmitic acid (C16:0), dihomo-γ-linolenic acid (C20:3n-6) and D6 desaturase were associated with an increase probability of insulin resistance, whereas nervonic acid (C24:1) and SCD1 were significantly associated with a lower insulin resistance probability. CONCLUSIONS: All results indicated that such drug-induced effects on fatty acid profile in plasma were relevant for the metabolic adverse effects associated with olanzapine and possibly other antipsychotics. Further studies are needed to investigate geneticand other mechanisms to explain how plasma fatty acids regulate glucose metabolism and affect the risk of insulin resistance.

Pharmacokinetic Properties of Oral Lafutidine Tablets and the Effect of Food on its Pharmacokinetics in Healthy Chinese Subjects.

INTRODUCTION: The aim of this study was to evaluate the pharmacokinetics (PK) of single and multiple doses of oral lafutidine tablets and the effect of food on the PK properties in healthy Chinese subjects. The tolerability and the effect of gender on the PK properties were also evaluated to acquire more PK information. METHODS: Three PK studies were conducted in 12 healthy Chinese subjects (6 male, 6 female). Study 1 was a single-dose, three-period, three-dose level (10, 20, and 40 mg), three-sequence cross-over study under fasting conditions. Study 2 was a repeat-dose study (10 mg twice daily over 6 days; all 12 subjects). Study 3 was a two-period, two-sequence cross-over single-dose (10 mg) food interaction study. All randomizations (study 1, study 3) were done to ascertain 1:1 gender ratio per sequence. A validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method was used to determine plasma lafutidine concentrations. PK parameters were calculated by the non-compartmental method. RESULTS: The area under the time-concentration curve (AUC) and maximum plasma concentration (C max) of lafutidine tablets were dose-independent in the single-dose study among these healthy volunteers. The PK parameters of the multiple-dose study were inconsistent with the single study. After administration of a single dose of 10 mg under either fed or fasting conditions, we found that food may not affect the degree of absorption of the lafutidine tablets, but it may slow down the absorption rate. This is shown by the fact that the AUC showed no significant difference while the peak time was significantly delayed under fed conditions. CONCLUSION: The PK of lafutidine showed dose proportionality. There was no significant accumulation of lafutidine tablets with multiple dosing. Food did not affect the degree of lafutidine absorption, but it did reduce the rate of absorption. Further study is needed regarding the effect of gender on lafutidine. Lafutidine was well tolerated within the dose range 10-40 mg, and no serious adverse events were observed.

Development and validation of a rapid LC-MS/MS method for simultaneous determination of netupitant and palonosetron in human plasma and its application to a pharmacokinetic study.

A simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was firstly developed and validated for simultaneous determination of netupitant and palonosetron in human plasma using ibrutinib as the internal standard (IS). Following liquid-liquid extraction, the compounds were eluted isocratically on a Phenomenex C18 column (50mm×2.0mm, 3µm) with the mobile phase consisting of acetonitrile and 10mM ammonium acetate buffer (pH 9.0) (89:11, v/v) at the flow rate of 0.3mL/min. The monitored ion transitions were m/z 579.5→522.4 for netupitant, m/z 297.3→110.2 for palonosetron and m/z 441.2→138.1 for IS. Chromatographic run time was 2.5min per injection, which made it possible to analyze more than 300 of samples per day. The assay exhibited a linear dynamic range of 5-1000ng/mL for netupitant and 0.02-10ng/mL for palonosetron in plasma. The values for both within- and between-day precision and accuracy were well within the generally accepted criteria for analytical methods (<15%). Selectivity, linearity, lower limit of quantification (LLOQ), accuracy, precision, stability, matrix effect, recovery and carry-over effect were evaluated for all analytes. The method is simple, rapid, and has been applied successfully to a pharmacokinetic study of netupitant and palonosetron in healthy volunteers.

Pharmacokinetics and Tolerability of Rufinamide Following Single and Multiple Oral Doses and Effect of Food on Pharmacokinetics in Healthy Chinese Subjects.

BACKGROUND: Rufinamide is a triazole derivative that is structurally unrelated to currently marketed antiepileptic medications for add-on treatment of seizures in the setting of Lennox-Gastaut syndrome in patients from the age of 4 years. OBJECTIVE: The purpose of this study was to determine the pharmacokinetic and safety profile of single and multiple doses of rufinamide in healthy Chinese subjects. The effects of food and gender on the pharmacokinetic properties of rufinamide were also evaluated. METHODS: In the single-dose study, volunteers were randomly assigned to 4 dose groups and received a single dose of 200, 400, 800, 1200 mg rufinamide tablets under fasting condition. Ten subjects in the 200-mg dose group were randomly assigned to either a high-fat or non-high-fat breakfast group in each study period. The drug administration was separated by a washout period of 7 calendar days. In the multiple-dose study, 10 subjects were administered on an empty stomach rufinamide 200 mg twice daily for 6 consecutive days. Liquid chromatography tandem mass spectrometry (LC-MS/MS) method was applied to determine plasma concentration of rufinamide. Pharmacokinetic parameters, including the maximum plasma concentration (C max), the time to peak concentration (t max), the area under the plasma concentration versus time curve from time 0 to the last measurable concentration (AUC0-t ) and from time 0 to infinity (AUC0-∞), terminal elimination half-life (t 1/2), apparent volume of distribution (V d), apparent clearance (CL), average residence time (MRT), area under the plasma concentration versus time curve from time 0 to the last measurable concentration at steady state (AUCss), peak concentration (C max,ss) and trough level concentration (C min,ss) at steady state were calculated using non-compartmental models. Tolerability was assessed based on investigator inquiries, spontaneous reports and clinical evaluations. RESULTS: Rufinamide displayed a dose-dependent, but sub-proportional increase in exposure following single-dose and repeated dose administration. After administration of single dose of 200, 400, 800 and 1200 mg, without food, the rufinamide mean C max (standard deviation, SD) was 1806.5 (526.4), 2490 (564.8), 3719 (976.1) and 4166 (1187.1) µg/L, respectively. Mean AUC0-t (SD) was 34,571 (9484), 56,246 (18,077), 89,022 (23,379) and 107,316 (34,766) µg·h/L, respectively. While in fed condition at the dosage of 200 mg, mean C max (SD) and mean AUC0-t (SD) were 2363 (582) µg/L and 40,593 (10,516) µg·h/L, respectively. After administration of multiple doses, arithmetic mean (SD) values of C max and AUC0-t were 3566 (873) µg/L and 62,803 (19,873) µg·h/L, respectively. The steady state was achieved by day 3 of multiple dosing after 2 daily doses (twice a day), the corresponding accumulation factor (AUCss/AUC0-t) was 0.9057. Although there were no substantial effects on exposure resulting from gender differences, a notable food effect was observed, with AUC and C max increased by 17.4 and 30.8 %, respectively. Single- and multiple-dose phases were generally safe and well tolerated. CONCLUSION: Overall, 15 % (6/40) of subjects experienced a mild indisposition with no serious adverse events. On single and multiple dosing, rufinamide exhibited nonlinear pharmacokinetics and was well tolerated in healthy Chinese subjects.