A Phase I Clinical Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of GB221 Injection and Trastuzumab (Herceptin®) in Healthy Chinese Adults.

BACKGROUND AND OBJECTIVE: GB221 is a recombinant humanized anti-HER2 monoclonal antibody. The purpose of this study was to evaluate the pharmacokinetic, safety, and immunogenicity of GB221 in healthy Chinese adults in comparison to trastuzumab (Herceptin®). METHODS: In this randomized, double-blind, parallel-group phase I clinical trial, 88 subjects were randomized 1:1 to receive a single intravenous infusion (90-100 min) of GB221 or trastuzumab (6 mg/kg). The primary pharmacokinetic parameters-maximum observed serum concentration (Cmax), area under the serum concentration-time curve from zero to the last quantifiable concentration at time t (AUC0-t), and area under the serum concentration-time curve from time zero to infinity (AUC0-∞)-of GB221 and trastuzumab were compared to establish whether the 90% confidence interval (CI) attained the 80-125% bioequivalence standard. Safety and immunogenicity were also evaluated. RESULTS: The GB221 group (n = 43) and the trastuzumab group (n = 44) showed similar pharmacokinetic characteristics. The geometric mean ratios (90% CI) of Cmax, AUC0-t, and AUC0-∞ between the two groups were 107.53% (102.25-113.07%), 108.31% (103.57-113.26%), and 108.34% (103.57-113.33%), respectively. The incidence of treatment-emergent adverse events (TEAEs) was 83.7% (36/43) of the subjects in the GB221 group and 95.5% (42/44) of the subjects in the trastuzumab group. No subjects withdrew from the trial due to TEAEs, and there were no occurrences of serious adverse events. All subjects tested negative for antidrug antibodies (ADA). CONCLUSION: GB221 demonstrated similar pharmacokinetics to trastuzumab and comparable safety and immunogenicity in healthy Chinese adults.

First-in-human trial of SAR107375E, a novel small molecule anticoagulant with dual inhibition of factor Xa and factor IIa.

BACKGROUND: SAR107375E is a direct dual inhibitor of both Factor Xa and Factor IIa and has shown potent anticoagulation activity in vitro and animals. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending intravenous doses of SAR107375E in healthy Chinese adult subjects. METHODS: In this randomized, double-blind, placebo-controlled trial, 60 healthy Chinese adult subjects were administered intravenously single ascending doses (0.5, 1.5, 3.0, 5.0, 7.5, 10.0, 15.0, or 20.0 mg) of SAR107375E (N = 44) or placebo (N = 16). Plasma and urine concentrations of SAR107375E were measured and used to calculate pharmacokinetic parameters. Coagulation functions were measured and compared with baseline values. Treatment-emergent adverse events were recorded to evaluate safety. RESULTS: In plasma, from the 0.5 to 20.0 mg dose group, t1/2 is 1.51-4.00 h, Cmax is 59.05-1360 ug/L, and AUC0-t is 25.01-528.45 h*ug/L. And it shows dose proportionality in the 5.0-20.0 mg range. Activated partial thromboplastin time and Ecarin clotting time correlated linearly with drug plasma concentration. No serious adverse events were reported during the study. CONCLUSION: SAR107375E exhibits good safety and tolerability, predictable pharmacokinetics and pharmacodynamics. CLINICAL TRIAL REGISTRATION: www.chinadrugtrials.org.cn, identifier is CTR20211082.

Phase I, Randomized, Placebo-Controlled, Dose-Escalation Study of GB223, a Fully-Humanized Monoclonal Antibody to RANKL, in Healthy Chinese Adults.

BACKGROUND: GB223 is a novel, fully-humanized monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL). In this phase I study, the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of GB223 were investigated. PATIENTS AND METHODS: This was a randomized, double-blinded, placebo-controlled, single-dose escalation study conducted in 44 healthy Chinese adults. Participants were randomly assigned to receive a single subcutaneous injection dose of 7, 21, 63, 119, or 140 mg of GB223 (n = 34) or placebo (n = 10) and were followed up for 140-252 days. RESULTS: The results of noncompartmental analysis showed that GB223 was slowly absorbed after dosing, with a time to reach maximum concentration (Tmax) ranging from 5 to 11 days. Serum GB223 concentrations decreased slowly, with a long half-life ranging from 7.91 to 19.60 days. A two-compartment Michaelis-Menten model was found to best describe the pharmacokinetics of GB223, and the absorption rate of GB223 differed between males (0.0146 h-1) and females (0.0081 h-1). Serum C-terminal telopeptide of type I collagen decreased significantly postdose, and the inhibition lasted 42-168 days. No deaths or drug-related serious adverse events occurred. The most frequent adverse events were blood parathyroid hormone increased (94.1%), blood phosphorus decreased (67.6%) and blood calcium decreased (58.8%). In the GB223 group, 44.1% (15/34) of subjects were antidrug antibody positive after dosing. CONCLUSION: In this study, we demonstrated for the first time that a single subcutaneous injection of GB223, from 7 to 140 mg, is safe and well tolerated in healthy Chinese subjects. GB223 has a nonlinear pharmacokinetic profile, and sex was a potential covariate that may affect the absorption rate of GB223. CLINICAL TRIAL REGISTRATION: NCT04178044 and ChiCTR1800020338.

Biosimilarity Assessment of the Biosimilar Teriparatide Candidate and the Reference Drug in Healthy Subjects.

SAL001, a recombinant form of parathyroid hormone, is a biosimilar drug to teriparatide and is planned to be used in osteoporosis treatment. A single-dose, randomized, open-label, 2-way crossover trial was conducted in healthy subjects to compare the pharmacokinetics (PK) and safety between SAL001 and the reference drug. Sixty-four subjects were enrolled in the study, and 61 subjects completed the study. In each period, 20 µg of the test or reference formulation was administered subcutaneously. SAL001 was administered by autoinjector pen, whereas the reference drug was administered by a self-matched injection pen. Serial blood samples were obtained for the analyses of PK and serum calcium concentration. Geometric mean ratios with 90%CIs for the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) were estimated. The safety of these 2 formulations was also evaluated. Overall, the 90%CIs for the geometric mean ratios of Cmax , AUC from time 0 to the last quantifiable time point, and AUC from time 0 extrapolated to infinity of the test or reference product were within 80.0%-125.0% of biosimilarity criteria. Other PK parameters, serum calcium concentration, and safety profiles had no significant differences between the 2 formulations. SAL001 demonstrated PK similarity to the reference drug, and the serum calcium concentration and safety profiles of SAL001 were also considered comparable to the reference drug.

Encapsulating MoO2 Nanocrystals into Flexible Carbon Nanofibers via Electrospinning for High-Performance Lithium Storage.

Design and synthesis of flexible and self-supporting electrode materials in high-performance lithium storage is significant for applications in the field of smart wearable devices. Herein, flexible carbon nanofiber membranes with uniformly distributed molybdenum dioxide (MoO2) nanocrystals are fabricated by a needlefree electrospinning method combined with the subsequent carbonization process, which exhibits outstanding structural stability under abrasion and deformation. The as-fabricated lithium-ion batteries (LIBs) exhibit a high discharge of 450 mAh g-1 after 500 cycles at 2000 mA g-1 by using the MoO2/C nanofiber membrane as the self-supporting anode. Further, the nanofibers structure remains intact after 500 cycles, which reflects the excellent stability of the materials. This study provides a simple and effective method for the preparation of MoO2/C nanofiber materials, which can not only maintain its excellent electrochemical and physical properties, but also easily realize large-scale production. It is undoubtedly beneficial for the development of flexible LIBs and smart wearable devices.

Adsorption of Cu(II) by phosphogypsum modified with sodium dodecyl benzene sulfonate.

Phosphogypsum (PG) is a solid waste generated during the wet production of phosphoric acid, and stockpiling PG causes serious pollution to the environment. Therefore, we prepared an adsorption material modified with sodium dodecyl benzene sulfonate (SDBS) based on PG (SDBS@PG). SDBS@PG can be regenerated and used in several adsorption-desorption cycles. The optimum conditions for Cu(II) removal are as follows: the Cu(II) concentration is 10 mg/L, the amount of adsorbent is 1.6 g/L, the pH is 6, and the contact time is 60 min. Under these conditions, the removal rate is 99.23 %. The kinetic data of adsorption conform to the pseudo-second-order model. The equilibrium isotherm results are consistent with the Langmuir isotherm equation. Furthermore, plausible mechanisms were proposed: PG was modified with SDBS, which greatly improved the adsorption of Cu(II) onto PG. The main reason is that SDBS is adsorbed on the surface of PG by chemical action in the form of micelles and then Cu(II) is adsorbed on the anionic SDBS micelles of SDBS@PG due to chemical and electrostatic interactions. This work indicates that SDBS@PG can be used for the removal of Cu(II) and is qualified for practical application.

Tubular microscopes discectomy versus conventional microdiscectomy for treating lumbar disk herniation: Systematic review and meta-analysis.

BACKGROUND: The application of tubular microscopes discectomy (TMD) was supposed to have similar or better results than conventional microdiscectomy (CMD). However, this conclusion had not been verified by sufficient evidence. Therefore, the focus of this meta-analysis was to assess the efficiency, safety, and clinical outcome of these 2 surgical procedures for treating lumbar disk herniation (LDH). METHODS: PubMed, Embase, and Cochrane Collaboration Central databases were searched for studies which compared the results of TMD and CMD for the treatment of LDH up to July 2017. Data analysis was conducted using RevMan 5.3. A standardized electronic form of 17 predefined criteria from the Consort statement was used for the quality assessment. RESULTS: Eight randomized controlled trials (RCT) and 2 retrospective studies were included in this review, including 804 patients. The pooled analysis showed that there was no significant difference in operative time (P = .38), blood loss (P = .14), the length of hospital stay (P = .47), the rate of intraoperative complications (P = .79), postoperative complications (P = .16), dural tear (P = .87), the reoperation (P = .20), the short-term back visual analog scale (VAS) scores (P = .76), the long-term back VAS scores (P = .64), the short-term leg VAS scores (P = .09), the long-term leg VAS scores (P = .35), and the Oswestry disability index (ODI) scores (P = .41). CONCLUSION: The results of this meta-analysis demonstrate that TMD and CMD are both safe and effective surgical procedures which can be recommended for treating LDH. Additionally, the conclusion should be cautiously treated, because it was reached in the context of limited amount of studies and relatively small sample size. Therefore, future studies with good design and more large samples are required to validate this conclusion.

Development of relative risk model for regional groundwater risk assessment: a case study in the lower Liaohe River Plain, China.

Increasing pressure on water supply worldwide, especially in arid areas, has resulted in groundwater overexploitation and contamination, and subsequent deterioration of the groundwater quality and threats to public health. Environmental risk assessment of regional groundwater is an important tool for groundwater protection. This study presents a new approach for assessing the environmental risk assessment of regional groundwater. It was carried out with a relative risk model (RRM) coupled with a series of indices, such as a groundwater vulnerability index, which includes receptor analysis, risk source analysis, risk exposure and hazard analysis, risk characterization, and management of groundwater. The risk map is a product of the probability of environmental contamination and impact. The reliability of the RRM was verified using Monte Carlo analysis. This approach was applied to the lower Liaohe River Plain (LLRP), northeastern China, which covers 23604 km2. A spatial analysis tool within GIS which was used to interpolate and manipulate the data to develop environmental risk maps of regional groundwater, divided the level of risk from high to low into five ranks (V, IV, III, II, I). The results indicate that areas of relative risk rank (RRR) V cover 2324 km2, covering 9.8% of the area; RRR IV covers 3986 km2, accounting for 16.9% of the area. It is a new and appropriate method for regional groundwater resource management and land use planning, and is a rapid and effective tool for improving strategic decision making to protect groundwater and reduce environmental risk.

Vaccination with recombinant flagellar proteins FlgJ and FliN induce protection against Brucella abortus 544 infection in BALB/c mice.

Brucella has been considered as a non-motile, facultative intracellular pathogenic bacterium. However, the genome sequences of different Brucella species reveal the presence of the flagellar genes needed for the construction of a functional flagellum. Due to its roles in the interaction between pathogen and host, we hypothesized that some of the flagellar proteins might induce protective immune responses and these proteins will be good subunit vaccine candidates. This study was conducted to screening of protective antigens among these flagellar proteins. Firstly, according to the putative functional roles, a total of 30 flagellar genes of Brucella abortus were selected for in vitro expression. 15 of these flagellar genes were successfully expressed as his-tagged recombinant proteins in Escherichia coli ER2566. Then, these proteins were purified and used to analyze their T cell immunity induction activity by an in vitro gamma interferon (IFN-γ) assay. Five of the flagellar proteins could stimulate significantly higher levels of IFN-γ secretion in splenocytes from S19 immunized mice, indicating their T cell induction activity. Finally, immunogenicity and protection activity of these 5 flagellar proteins were evaluated in BALB/c mice. Results showed that immunization with FlgJ (BAB1_0260) or FliN (BAB2_0122) plus adjuvant could provide protection against B. abortus 544 infection. Furthermore, mice immunized with FlgJ and FliN developed a vigorous immunoglobulin G response, and in vitro stimulation of their splenocytes with immunizing proteins induced the secretion of IFN-γ. Altogether, these data suggest that flagellar proteins FlgJ and FliN are protective antigens that could produce humoral and cell-mediated responses in mice and candidates for use in future studies of vaccination against brucellosis.

Identification of Brucella abortus virulence proteins that modulate the host immune response.

Brucellosis is an important zoonotic disease of almost worldwide distribution. One significant immune phenomenon of this disease is the ability of the pathogen to hide and survive in the host, establishing long lasting chronic infections. Brucella was found to have the ability to actively modulate the host immune response in order to establish chronic infections, but the mechanism by which the pathogen achieves this remains largely unknown. In our screening for protective antigens of Brucella abortus, 3 proteins (BAB1_0597, BAB1_0917, and BAB2_0431) were found to induce significantly higher levels of gamma interferon (IFNγ) in splenocytes of PBS immunized mice than those immunized with S19. This finding strongly implied that these three proteins inhibit the production of IFNγ. Previous studies have shown that LPS, PrpA, and Btp1/TcpB are three important immunomodulatory molecules with the capacity to interfere with host immune response. They have been shown to have the ability to inhibit the secretion of IFNγ, or to increase the production of IL-10. Due to the role of these proteins in virulence and immunomodulation, they likely offer significant potential as live, attenuated Brucella vaccine candidates. Understanding the mechanisms by which these proteins modulate the host immune responses will deepen our knowledge of Brucella virulence and provide important information on the development of new vaccines against Brucellosis.

Antifungal activity and cytotoxicity of zinc, calcium, or copper alginate fibers.

The antifungal properties and cytotoxicity of alginate fibers were investigated to widen their application in tissue engineering. Calcium, zinc, and copper alginate fibers were separately prepared by replacing Na(+) with Ca(2+), Zn(2+), or Cu(2+). The antifungal properties of the three alginate fibers were studied after coming into contact with Candida albicans. Then, the fungal inhibitory rates were measured using the plate-count method following shake-flask test. Moreover, an inhibition-zone test and observation by scanning electron microscopy were carried out. The inhibitory rate of the calcium, copper, and zinc alginate fibers were, respectively, 49.1, 68.6, and 92.2 %. The results from inhibition-zone test and shake-flask test show that zinc alginate fibers have the most significant antifungal action and that copper alginate fibers have obvious inhibitory action, but the calcium alginate fibers have weak inhibitory effects. The scanning electron micrographs similarly illustrate that the fungal surfaces show most scraggly after the interaction between C. albicans and zinc alginate fibers. Moreover, the relative growth rates of zinc or calcium alginate fibers in human embryonic kidney cells and human fibroblast cells were more than 100 %. No significant results were obtained (P>0.05). The calcium alginate fibers in human fibroblast cells were not much different from the negative control group (P>0.05). However, zinc alginate fibers had a significant change (P<0.05). Therefore, the excellent antifungal property of zinc alginate fibers demonstrates potential application in skin tissue engineering comparing with calcium or copper alginate fibers.

Immunization of mice with recombinant protein CobB or AsnC confers protection against Brucella abortus infection.

Due to drawbacks of live attenuated vaccines, much more attention has been focused on screening of Brucella protective antigens as subunit vaccine candidates. Brucella is a facultative intracellular bacterium and cell mediated immunity plays essential roles for protection against Brucella infection. Identification of Brucella antigens that present T-cell epitopes to the host could enable development of such vaccines. In this study, 45 proven or putative pathogenesis-associated factors of Brucella were selected according to currently available data. After expressed and purified, 35 proteins were qualified for analysis of their abilities to stimulate T-cell responses in vitro. Then, an in vitro gamma interferon (IFN-γ) assay was used to identify potential T-cell antigens from B. abortus. In total, 7 individual proteins that stimulated strong IFN-γ responses in splenocytes from mice immunized with B. abortus live vaccine S19 were identified. The protective efficiencies of these 7 recombinant proteins were further evaluated. Mice given BAB1_1316 (CobB) or BAB1_1688 (AsnC) plus adjuvant could provide protection against virulent B. abortus infection, similarly with the known protective antigen Cu-Zn SOD and the license vaccine S19. In addition, CobB and AsnC could induce strong antibodies responses in BALB/c mice. Altogether, the present study showed that CobB or AsnC protein could be useful antigen candidates for the development of subunit vaccines against brucellosis with adequate immunogenicity and protection efficacy.

[Rapid determination of pyrethroids in tomatoes using gas chromatography combined with dispersive liquid-liquid microextraction].

An analytical method was established for the determination of three pyrethroids (bifenthrin, fenpropathrin and flucythrinate) in tomatoes using the quick, easy, cheap, effective, rugged and safe (QuEChERS) cleanup and gas chromatography. The tomato samples were extracted with acetonitrile, cleaned-up by dispersive solid-phase extraction using primary secondary amine as sorbents, concentrated by dispersive liquid-liquid microextraction (DLLME), and analyzed by gas chromatography. Factors affecting the extraction efficiency such as the type and volume of extraction solvent and the volume of dispersive and extraction time were investigated in detail. In the DLLME procedure, 40 microL chloroform was used as the extraction solvent and 1 000 microL acetonitrile was used as the dispersive solvent and the extraction time was 60 s. Under the optimized conditions, the limits of detection for bifenthrin, fenpropathrin and flucythrinate were 0.5, 0.5 and 0.3 microg/kg, and the average recoveries in tomato samples at the spiked levels of 1, 10 and 50 microg/kg were 89% - 109%, 92.5% - 105% and 90% - 108% with the relative standard deviations of 2.5% - 7.6%, 2.8% - 5.7% and 3.8% - 9.1%, respectively. The proposed method is simple, quick, safe, reliable and applicable to analyze pyrethroid residues in tomato samples.

[Influence of consumables on performance of gas chromatography].

The consumable materials of GC have a great influence on its performance. Usually, the materials are filters, column ferrules, septa, liners and so on. The points on their properties, how to choose them, how to install them and how they may affect the performance of GC are described.