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.

Pomalidomide combined with dexamethasone for the treatment of relapsed/refractory multiple myeloma: a systematic review and meta-analysis.

BACKGROUND: To evaluate the efficacy and safety of pomalidomide in combination treatment of relapsed/refractory multiple myeloma (RRMM). METHODS: Published clinical trials were searched in the Cochrane Library, PubMed, EMBASE to February 2023. The literature was screened and evaluated according to the inclusion criteria, and the data were analyzed by a random effect model. Overall response rate (ORR), overall survival (OS), progression-free survival (PFS) and full grade or ≥ 3 adverse events (AEs) were the outcomes. RESULTS: This study included 31 clinical trials, which included 4776 patients. The pooled ORR of the doublet regimens was 33.3% (95%CI: 27-39%) and the triplet regimens was 66% (95%CI: 58-74%). Among the 25 included studies, the median PFS was 8.29 months (95%CI: 7.27-9.31), and nine studies reported median OS of 19.43 months (95%CI: 14.56-24.30). In terms of safety, the most common hematologic AEs of grade ≥ 3 were neutropenia (41%) and anemia (20%); Non-hematologic AEs were pneumonia (14%) and infection/febrile neutropenia (14%). CONCLUSIONS: Pomalidomide combined treatment regimens have shown good clinical efficacy, especially in pomalidomide + dexamethasone combined with other drugs. In terms of safety, it's important to pay attention to the likelihood of hematological adverse events when used clinically. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42023420644.

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.

DYW deaminase domain has a distinct preference for neighboring nucleotides of the target RNA editing sites.

C-to-U RNA editing sites in plant organelles show a strong bias for neighboring nucleotides. The nucleotide upstream of the target cytidine is typically C or U, whereas A and G are less common and rare, respectively. In pentatricopeptide repeat (PPR)-type RNA editing factors, the PPR domain specifically binds to the 5' sequence of target cytidines, whereas the DYW domain catalyzes the C-to-U deamination. We comprehensively analyzed the effects of neighboring nucleotides of the target cytidines using an Escherichia coli orthogonal system. Physcomitrium PPR56 efficiently edited target cytidines when the nucleotide upstream was U or C, whereas it barely edited when the position was G or the nucleotide downstream was C. This preference pattern, which corresponds well with the observed nucleotide bias for neighboring nucleotides in plant organelles, was altered when the DYW domain of OTP86 or DYW1 was adopted. The PPR56 chimeric proteins edited the target sites even when the -1 position was G. Our results suggest that the DYW domain possesses a distinct preference for the neighboring nucleotides of the target sites, thus contributing to target selection in addition to the existing selection determined by the PPR domain.

Protease Inhibitor-Dependent Inhibition of Light-Induced Stomatal Opening.

Stomata in the epidermis of plants play essential roles in the regulation of photosynthesis and transpiration. Stomata open in response to blue light (BL) by phosphorylation-dependent activation of the plasma membrane (PM) H+-ATPase in guard cells. Under water stress, the plant hormone abscisic acid (ABA) promotes stomatal closure via the ABA-signaling pathway to reduce water loss. We established a chemical screening method to identify compounds that affect stomatal movements in Commelina benghalensis. We performed chemical screening using a protease inhibitor (PI) library of 130 inhibitors to identify inhibitors of stomatal movement. We discovered 17 PIs that inhibited light-induced stomatal opening by more than 50%. Further analysis of the top three inhibitors (PI1, PI2, and PI3; inhibitors of ubiquitin-specific protease 1, membrane type-1 matrix metalloproteinase, and matrix metalloproteinase-2, respectively) revealed that these inhibitors suppressed BL-induced phosphorylation of the PM H+-ATPase but had no effect on the activity of phototropins or ABA-dependent responses. The results suggest that these PIs suppress BL-induced stomatal opening at least in part by inhibiting PM H+-ATPase activity but not the ABA-signaling pathway. The targets of PI1, PI2, and PI3 were predicted by bioinformatics analyses, which provided insight into factors involved in BL-induced stomatal opening.

Probiotics for the treatment of women with bacterial vaginosis: A systematic review and meta-analysis of randomized clinical trials.

This systematic review and meta-analysis systematically evaluated the efficacy of probiotic monotherapy and combination therapy for bacterial vaginosis (BV). Published randomized controlled trials were searched in the Cochrane Library, PubMed, EMBASE, OVID Database and ClinicalTrials.gov from the inception dates to 12 July 2019. The literature was screened and evaluated according to the inclusion criteria, and the data were analysed by a random effect model. A chi-square test was used to test heterogeneity between trials. This study included 13 randomized controlled trials (RCTs), which included 1258 patients, and the cure rate of BV was analysed. Three RCTs compared probiotics with a placebo (control) [risk ratios (RR) = 4.39, 95% CI (2.05, 9.41), P = 0.0001]. Two RCTs compared probiotics with antibiotics (control) [RR = 1.03, 95% CI (0.38, 2.81), P = 0.95]. Nine of 13 RCTs compared the combination of probiotics and antibiotics with antibiotics alone [RR = 1.28, 95% CI (1.05, 1.56), P = 0.02]. Despite the high heterogeneity of the pooled analysis, neither the subgroup analysis results nor the sensitivity analysis results were statistically significant. Probiotics may have a positive effect on the treatment of BV, but there is a lack of strong evidence.

Effect of oral nut supplementation on endothelium-dependent vasodilation - a meta-analysis.

BACKGROUND: An inverse association was found between nut supplementation and the risk of cardiovascular disease. Identifying the direct effect of nut supplementation on endothelium-dependent vasodilation may partly explain that association. METHODS: Human intervention studies were identified by systematic electronic search of the databases EMBASE, MEDLINE, Pubmed, and Web of Science through January 2017 and by manually searching related articles. Subgroup analyses were performed to identify the source of heterogeneity among studies. RESULTS: In total, 11 eligible articles involving 468 participants were included in the meta-analysis. Overall, the results of the 13 trials showed that nut supplementation significantly increased flow-mediated dilation [weighted mean differences (WMD): 1.03 %; 95 % CI: 0.26-1.79 %, P = 0.008]. There was significant heterogeneity among studies (P = 0.006) that might partly be explained by the different types of nuts. No significant association between nut supplementation and endothelium-independent vasodilatation was observed in a fixed effect model (WMD: 1.10 %, 95 % CI: -0.19-2.38 %, P = 0.09). CONCLUSIONS: Supplementation of nuts significantly improves the vascular endothelial function without affecting endothelium-independent vasodilatation.

Application of HPLC-LTQ Orbitrap MS for metabolic profiles of Polygonum multiflora extract in rats.

The root of Polygonum multiflorum (PM) is an important Chinese herbal medicine for treatment of various diseases. Extensive pharmacological studies have been conducted and demonstrated that it shows a wide range of bioactivities. Meanwhile, a considerable number of hepatotoxicity cases owing to oral administration of PM have been reported and have attracted great attention. However, the limited knowledge regarding the metabolism of PM restricts the deeper studies on its pharmacological/toxicological mechanism and therapeutic material basis. The present study aimed to develop a high-performance liquid chromatography coupled with a linear ion trap-Orbitrap hybrid mass spectrometry method for separation and identification of metabolites in rat urine and plasma after oral administration of PM. Based on the proposed strategy, metabolism profiles of PM in rats were proposed for the first time and 43 metabolites were characterized or tentatively identified. Phase II metabolism, such as glucuronidation and sulfation, are the principal pathways of the main components. These findings will be beneficial to further understanding of the pharmacological mechanism and pharmacodynamic material basis of PM.

Moderate alcohol consumption and atherosclerosis : Meta-analysis of effects on lipids and inflammation.

OBJECTIVE: Alcohol consumption plays an important role in the risk of major cardiovascular diseases. We conducted a meta-analysis to summarize the association between moderate alcohol consumption and atherosclerosis. DESIGN: In this study four databases and reference lists of retrieved articles were searched to identify eligible studies. A meta-analysis was carried out of all interventional studies that assessed the effects of moderate alcohol consumption on concentrations of low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, apolipoprotein A I, interleukin 6, plasminogen activator inhibitor 1, fibrinogen, and other biomarkers previously found to be associated with risk of atherosclerosis. RESULTS: A total of 31 studies met the eligibility criteria. In response to moderate alcohol consumption, low density lipoprotein cholesterol decreased by 0.08 mmol/l (P = 0.05), and high density lipoprotein cholesterol increased by 0.08 mmol/l (P < 0.00001), whereas total cholesterol and triglyceride remained the same. Moreover, interleukin 6 decreased by 0.43 pg/ml (P = 0.03), whereas C­reactive protein and tumor necrosis factor a remained the same. Several hemostatic factors and adiponectin were modestly affected by alcohol consumption. CONCLUSION: Moderate alcohol consumption is causally related to lower risk of atherosclerosis through changes in lipid profiles and inflammation.

Comparative proteomic analysis of alfalfa revealed new salt and drought stress-related factors involved in seed germination.

Salinity and drought are two major environmental factors that limit the growth and yield of many forage crops in semi-arid and arid regions. Alfalfa (Medicago sativa L.) is one of the most important forage crops in many countries. We aim to investigate the molecular mechanisms of alfalfa in response to salt and drought stresses in this study. Physiological and proteomic analyses were applied to examine the Zhongmu NO.3 alfalfa seed germination stage with 200 mM NaCl and 180 g·L-1 polyethylene glycol (PEG) treatments. The germination ability of the seed and the accumulation of osmotic solutes were quite different between the NaCl and PEG treatments. More than 800 protein spots were detected by proteomics technology on two-dimensional electrophoresis (2-DE) gels. The abundance of twenty-eight proteins were decreased or increased after salt and drought stress. Seventeen of these proteins were identified and classified into six functional categories through mass spectrometry (MS). The six groups involved in salt- and PEG-mediated stress included defense response, energy metabolism, protein synthesis and degradation, oxidative stress, carbohydrate metabolism-associated proteins, and unknown proteins. We discovered that some proteins related to carbohydrate metabolism and energy production increased in abundance under salt- and PEG-mediated drought stress. This demonstrates a common mechanism of energy consumption during abiotic stresses. Further study of these proteins with unknown function will provide insights into the molecular mechanisms of abiotic stress and the discovery of new candidate markers.

Application of Ultra-High-Performance Liquid Chromatography Coupled with LTQ-Orbitrap Mass Spectrometry for the Qualitative and Quantitative Analysis of Polygonum multiflorum Thumb. and Its Processed Products.

In order to quickly and simultaneously obtain the chemical profiles and control the quality of the root of Polygonum multiflorum Thumb. and its processed form, a rapid qualitative and quantitative method, using ultra-high-performance liquid chromatography coupled with electrospray ionization-linear ion trap-Orbitrap hybrid mass spectrometry (UHPLC-LTQ-Orbitrap MS(n)) has been developed. The analysis was performed within 10 min on an AcQuity UPLC™ BEH C18 column with a gradient elution of 0.1% formic acid-acetonitrile at flow rate of 400 µL/min. According to the fragmentation mechanism and high resolution MS(n) data, a diagnostic ion searching strategy was used for rapid and tentative identification of main phenolic components and 23 compounds were simultaneously identified or tentatively characterized. The difference in chemical profiles between P. multiflorum and its processed preparation were observed by comparing the ions abundances of main constituents in the MS spectra and significant changes of eight metabolite biomarkers were detected in the P. multiflorum samples and their preparations. In addition, four of the representative phenols, namely gallic acid, trans-2,3,5,4'-tetra-hydroxystilbene-2-O-ß-d-glucopyranoside, emodin and emodin-8-O-ß-d-glucopyranoside were quantified by the validated UHPLC-MS/MS method. These phenols are considered to be major bioactive constituents in P. multiflorum, and are generally regarded as the index for quality assessment of this herb. The method was successfully used to quantify 10 batches of P. multiflorum and 10 batches of processed P. multiflorum. The results demonstrated that the method is simple, rapid, and suitable for the discrimination and quality control of this traditional Chinese herb.

Cytotoxic ent-kaurane diterpenoids from Isodon nervosus.

Four new ent-kaurane diterpenoids, rabdonervosins G-J (1-4, resp.), were isolated from the leaves and stems of Isodon nervosus. Their structures were elucidated by extensive spectroscopic analyses, including 1D-, 2D-NMR and HR mass spectra. Compound 2 showed potent cytotoxicity against the HepG2 and PC-9/ZD cell lines with IC50 values of 2.36 and 6.07 µM, respectively, and compound 3 exhibited cytotoxicity against the HepG2 and CNE2 cell lines with IC50 values of 8.64 and 9.77 µM, respectively.