A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects.

AIM: The trial (NCT04016974) investigated the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide, the first orally administered glucagon-like peptide-1 analogue for type 2 diabetes, in healthy Chinese subjects. MATERIALS AND METHODS: This single-centre, multiple-dose, placebo-controlled trial randomized 32 healthy Chinese adults to once-daily oral semaglutide (3 mg escalating to 14 mg) or placebo for 12 weeks. Blood samples were collected regularly during treatment and follow-up. The primary endpoint was the area under the semaglutide concentration-time curve over a dosing interval (0-24 h) at steady state (AUC0-24h,sema,SS). Secondary pharmacokinetic endpoints included the maximum observed semaglutide plasma concentration at steady state (Cmax,sema,SS). Supportive secondary pharmacodynamics endpoints included changes in body weight and fasting plasma glucose. RESULTS: Treatment with all oral semaglutide doses showed dose-dependent increases in semaglutide exposure in healthy Chinese subjects at steady state, determined by AUC0-24h,sema,SS (233, 552 and 1288 h·nmol/L for 3, 7 and 14 mg of oral semaglutide, respectively) and Cmax,sema,SS. Oral semaglutide treatment was associated with significant reductions in body weight (p = .0001) and fasting plasma glucose (p = .0011) versus placebo at the end of treatment. The safety and tolerability of oral semaglutide were consistent with the known profile of glucagon-like peptide-1 receptor agonists, with no severe or blood-glucose-confirmed symptomatic hypoglycaemic events, serious adverse events or deaths. The most frequent adverse events were gastrointestinal disorders. CONCLUSIONS: At steady state, oral semaglutide exposure was dose dependent and close to dose proportionality in healthy Chinese subjects. This is consistent with previous clinical pharmacology results for oral semaglutide.

Clinical characteristics and effects of inhaled corticosteroid in patients with post-COVID-19 chronic cough during the Omicron variant outbreak.

BACKGROUND: Chronic cough is a common symptom in patients post the coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate the efficacy of inhaled corticosteroids (ICS) and the clinical characteristics of patients with post-COVID-19 chronic cough during the Omicron era. METHODS: An ambispective, longitudinal cohort study was conducted that included patients with post-COVID-19 who attended the respiratory clinic at our hospital between January 1, 2023, and March 31, 2023 with a complaint of persistent cough lasting more than 8 weeks. At 30 and 60 days after the first clinic visit for post-COVID-19 chronic cough, enrolled patients were prospectively followed up. We compared the changes in symptoms and pulmonary function between patients receiving ICS treatment (ICS group) and those not receiving ICS treatment (NICS group) at the two visits. RESULTS: A total of 104 patients with post-COVID-19 chronic cough were enrolled in this study (ICS group, n = 51; NICS group, n = 53). The most common symptoms accompanying post-COVID-19 chronic cough were sputum (58.7%, 61/104) and dyspnea (48.1%, 50/104). Seventy-one (82.6%, 71/86) patients had airway hyperresponsiveness, and 49 patients (47.1%, 49/104) were newly diagnosed with asthma. Most patients (95.2%, 99/104) exhibited improvement at 60 days after the first visit. The pulmonary function parameters of the patients in the ICS group were significantly improved compared to the baseline values (P < 0.05), and the improvement in the FEV1/FVC was significantly greater than that in the NICS group (P = 0.003) after 60 days. CONCLUSIONS: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may contribute to the pathogenesis of asthma, which could be the underlying cause of persistent cough post-COVID-19 infection. Post-COVID-19 chronic cough during the Omicron era was often accompanied by sputum, dyspnea, and airway hyperresponsiveness. ICS treatment did not have a significant impact on symptom management of post-COVID-19 chronic cough; however, it can improve impaired lung function in in these individuals.

Ethnicity evaluation of ferric pyrophosphate citrate among Asian and Non-Asian populations: a population pharmacokinetics analysis.

PURPOSE: To evaluate the potential ethnic differences of ferric pyrophosphate citrate (FPC, Triferic) in healthy subjects and patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) and identify covariates that may influence pharmacokinetics (PK) of FPC. METHODS: Data were collected from 2 Asian and 4 non-Asian clinical studies involving healthy subjects and CKD-5HD patients. Three population PK models were developed: M1 for intravenous (IV) administration of FPC in healthy subjects; M2 for dialysate administration of FPC in CKD-5HD patients; M3 for pre-dialyzer administration of FPC in CKD-5HD patients. All the models were fitted to concentration versus time data of FPC using the nonlinear mixed effect approach with the NONMEM® program. All statistical analyses were performed using SAS version 9.4. RESULTS: In total, 26 Asians and 65 non-Asians were included in the final model analysis database. Forty healthy subjects were administered FPC via intravenous (IV) route and 51 patients with CKD-5HD via dialysate (N = 50) and pre-dialyzer blood circuit administration (N = 51). The PK parameters of FPC IV were similar. The population PK model showed good parameter precision and reliability as shown by model evaluation, and no relevant influence of ethnicity on PK parameters was observed. In healthy subjects, the maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) decreased with increase in lean body mass (LBM) and the average serum total iron at 6 h before the baseline period (Feav), whereas, in both patient populations, Cmax and AUC decreased with increase in LBM and decrease in Febaseline. Other factors such as gender, age, Feav, and ethnicity had no influence on PK exposures in patients. The influence of LBM on PK exposures in patients was smaller than that in healthy subjects (ratio of AUC0-24 for the 5th [68 kg] and 95th [45 kg] patient's LBM was almost 1). The influence of Feav and LBM on PK exposures was < 50%. CONCLUSION: The population pharmacokinetics model successfully described the PK parameters of FPC in healthy subjects and CKD-5HD patients and were comparable between Asian and non-Asian populations.

Plasma and intracerebral pharmacokinetics and pharmacodynamics modeling for the acetylcholine releasing effect of ginsenoside Rg1 in mPFC of Aß model rats.

Ginsenoside Rg1 is a major bioactive component of ginseng. Limited information is available regarding Rg1 concentrations in the central neural system and the corresponding relationship of plasma/intracerebral concentrations, and intracerebral effects of Rg1. Awake Aß model rats received a single subcutaneous administration of Rg1. Concentrations of unbound Rg1 and acetylcholine in the brain extracellular fluid and Rg1 in plasma were then determined. An Emax-two compartment pharmacokinetic/pharmacodynamics (PK/PD) model without effect compartment was finally obtained by evaluating three mechanism-based models. The corresponding relationship between the plasma PK and PD of Rg1 can be described as E = 119.05•C/(73.42 + C).[Formula: see text].

Advantage of surgical intensive care unit (SICU) predominant by cardiothoracic surgeons in multiple trauma management in a primary hospital.

PURPOSE: It is a challenge for the primary hospitals to manage multiple trauma patients. In this article, we explored the advantage of establishing a surgical intensive care unit (SICU) predominant by cardiothoracic surgeons in the early management of multiple trauma. METHODS: This was a retrospective study and patients with multiple trauma in our hospital were collected and divided into two groups, based on time period and treat modes: group A (retrospective observation group) where patients were treated with the traditional treatment mode from January 2017 to December 2017 and group B (study group) where patients were treated in the SICU predominant by cardiothoracic surgeons from January 2018 to December 2018. Clinical data including demographics, injury severity score (ISS), causes of injury, time intervals from reception to entering SICU or operating room and mortality three days after injuries were collected. Data were analyzed by SPSS 20.0 software. Categorical variables were presented as number and/or frequency and continuous variables as mean ± SD. RESULTS: Altogether 406 patients were included in this study, including 217 patients in group A and 189 patients in group B. General data between the two groups revealed no significant difference: mean age (years) (35.51 ± 12.97 vs. 33.62 ± 13.61, p = 0.631), gender distribution (mean/female, 130/87 vs. 116/73, p = 0.589) and ISS (15.92 ± 7.95 vs. 16.16 ± 6.89, p = 0.698). Fall from height were the dominant mechanism of injury, with 135 cases in group A (71.4%) and 121 cases in group B (55.8%), followed by traffic accidents. Injury mechanism showed no significant differences between two groups (p = 1.256). Introduction of the SICU significantly improved the care of trauma patients, regarding speed and mortality. Time intervals between reception and entering SICU or operating room was (108.23 ± 6.72) min and (45.67 ± 7.96) min in group A and B, respectively (p = 0.001). Mortality three days after injuries was 13.89% and 5.53% in group A and B, respectively (p = 0.005). CONCLUSION: Establishing a SICU predominant by cardiothoracic surgeons can reduce the early mortality rates in multiple trauma patients.

Hypoxia-responsive miR-141-3p is involved in the progression of breast cancer via mediating the HMGB1/HIF-1α signaling pathway.

BACKGROUND: Hypoxia-responsive miRs have been frequently reported in the growth of various malignant tumors. The present study aimed to investigate whether hypoxia-responsive miR-141-3p was implicated in the pathogenesis of breast cancer via mediating the high-mobility group box protein 1 (HMGB1)/hypoxia-inducible factor (HIF)-1α signaling pathway. MATERIALS AND METHODS: miRs expression profiling was filtrated by miR microarray assays. Gene and protein expression levels, respectively, were examined by a quantitative reverse transcriptase-polymerase chaion reaction and western blotting. Cell migration and invasion were analyzed using a transwell assay. Cell growth was determined using nude-mouse transplanted tumor experiments. RESULTS: miR-141-3p was observed as a hypoxia-responsive miR in breast cancer. miR-141-3p was down-regulated in breast cancer specimens and could serve as an independent prognostic factor for predicting overall survival in breast cancer patients. In addition, the overexpression of miR-141-3p could inhibit hypoxia-induced cell migration and impede human breast cancer MDA-MB-231 cell growth in vivo. Mechanistically, the hypoxia-related HMGB1/HIF-1α signaling pathway might be a possible target of miR-141-3p with respect to preventing the development of breast cancer. CONCLUSIONS: Our finding provides a new mechanism by which miR-141-3p could prevent hypoxia-induced breast tumorigenesis via post-transcriptional repression of the HMGB1/HIF-1α signaling pathway.

Identification of multiple sources of the acidic charge variants in an IgG1 monoclonal antibody.

Charge variants, especially acidic charge variants, of recombinant monoclonal antibodies are the major critical quality attributes in the biotechnology industry due to their potential influence on stability and biological activity. The chemical properties of the acidic charge variants have been challenging to fully characterize, and it is critical for process development and optimization. To completely understand the multiple sources of acidic charge variants, the major charge forms of an IgG1 monoclonal antibody were firstly isolated and then analyzed by a battery of characterization tools. It was found that various degrees of disulfide bond reduction, the deamination of HC-T8 Asn84 and HC-T35 Asn388 and aggregation account for the majority of acidic charge heterogeneity and the terminal galactosylation content was in relation to the acidic charge heterogeneity. The correlation between acidic charge heterogeneity and galactosylation content was further explored by weak cation exchange chromatography with the use of ß1-4 galactosidase digestion. The results showed that galactosylation was not the source of the acidic charge variants per se. Meanwhile, to gain insights into the impact on binding affinity of monoclonal antibody to IgE and FcRn, charge variants were also analyzed by competitive ELISA and surface plasmon resonance, respectively. All isolated charge variants had similar affinity binding to IgE and FcRn binding relative to the starting material.

Elucidating the effects of pH shift on IgG1 monoclonal antibody acidic charge variant levels in Chinese hamster ovary cell cultures.

Charge variants, especially acidic charge variants, in recombinant monoclonal antibodies are critical quality attributes, which can affect antibodies' properties in vitro and in vivo. Meanwhile, charge variants are cumulative effects of various post-translational modifications and chemical degradations on antibody. In this work, to investigate the effect of lowering culture pH in the stationary phase on acidic charge variant contents in fed-batch cultures and its mechanism, cell culture experiments in 2-L bioreactors were firstly performed to explore the changes in the charge distribution under the pH downshift condition using weak cation exchange chromatography. It is found that acidic charge variant contents were significantly decreased by pH downshift. Then, to reveal the mechanism by which the content of acidic charge variants is reduced under pH downshift condition, the variation of post-translational modifications and chemical degradations under the pH downshift condition was explored. Meanwhile, the structure of the acidic charge variants was characterized. Several analysis experiments including size exclusion chromatography, capillary electrophoresis-sodium dodecyl sulfate under non-reducing conditions, tryptic peptide map, and reduced antibody mass were applied in this study. The results show that the mechanism by which the content of acidic charge variants is reduced is that the contents of disulfide bond reduction, galactosylation, and asparagine deamination of the HC-N388 in the Fc domain were reduced by pH downshift.

Effects of cadmium on bioaccumulation and biochemical stress response in rice (Oryza sativa L.).

This study investigated the effects of various Cd concentrations on the bioaccumulation, antioxidative defense, and stress responses of rice (Oryza sativa L.). The distribution characteristics of Cd in rice were in the following order: roots>stems>grains. The bioconcentration factor values of Cd increased at concentrations lower than 3.00 mg Cd/kg and approximately decreased to a constant value at concentrations higher than 3.00 mg Cd/kg. Rice showed a higher Cd accumulation potential at low Cd concentrations than at high Cd concentrations. The Freundlich isotherm model described well the adsorption isotherms of Cd in rice roots. The biosorption mechanism of rice roots was determined to be cooperative adsorption. The malondialdehyde (MDA) content increased at a concentration range of 0.00-5.00 mg/L, indicating the enhancement of lipid peroxidation. By contrast, the MDA content slightly decreased at concentrations higher than 5.00 mg/L. Peroxidase (POD) activity exhibited active response to oxidative stress at concentrations lower than 5.00 mg/L but was inhibited at concentrations higher than 5.00 mg/L. The response to Cd stress of the N-H, O-H and C-O functional groups in rice shoots was observed via Fourier transform infrared spectroscopy.

Effects of lead on tolerance, bioaccumulation, and antioxidative defense system of green algae, Cladophora.

Effects of various concentrations (0.5, 1.0, 2.5, 5.0, 7.5, and 10.0 mg/L) of lead (Pb(2+)) on the growth, bioaccumulation, and antioxidative defense system of green algae, Cladophora, was investigated. Low concentrations of Pb(2+) accelerated Cladophora growth, but concentrations of 10.0 mg/L and above inhibited the growth because of the hinderance to photosynthesis. The total soluble sugar content of Cladophora was affected by Pb(2+) treatment, but the protein content showed no significant changes. The malondialdehyde (MDA) content and peroxidase(POD) activity of Cladophora gradually increased whereas superoxide dismutase(SOD) decreased with Pb(2+) concentrations. Catalase (CAT) activity exhibited no significant changes following Pb(2+) treatment. Pb(2+) accumulated in Cladophora and that the lead content in Cladophora was correlated with POD growth, MDA, and Metallothionein (MT). POD and MT play a role in the survival of Cladophora in Pb-contaminated environments. This study suggests that Cladophora can be a choice organism for the phytoremediation of Pb-polluted coastal areas.

[Enhancement of enzyme activity and thermostability of N-acylhomoserine lactonase by site-directed mutagenesis].

OBJECTIVE: To enhance enzymatic activity and thermostability of N-acylhomoserine lactonase (AiiA). METHODS: We performed site-directed mutagenesis based on AiiA homologous 3-D protein structure, and analyzed enzymatic activity and thermostability of both wild type and mutated AiiA. RESULTS: The wild type AiiA lost its N-acylhomoserine lactone (AHL) degrading activity after being incubated at 45 degrees C for 30 min or after being stored at 4 degrees C for 5 days. By comparison, the AHL-degrading activities of three types of mutated AiiA (N65K, T195R, and A206E) were enhanced, and their storage periods at 4 degrees C were extended to 7 days. In addition, the N65K mutant acquired higher temperature tolerance with remain of more than 45% of its enzymatic activity after being incubated at 45 degrees C and 5.0% enzymatic activity after being incubated at 55 degrees C as compared to the wild type. CONCLUSION: Molecular modulation by site-directed mutagenesis could significantly improve enzymatic activity and thermostability of AiiA.

Efficacy and Safety of Rivaroxaban and Enoxaparin for Thromboprophylaxis Among Total Hip Arthroplasty Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Venous thromboembolism (VTE) is one of the major and potentially life-threatening complications following major orthopedic surgeries. Research evidence comparing the effectiveness of rivaroxaban and enoxaparin for thromboprophylaxis specific to total hip arthroplasty (THA) has been limited. Hence, this review was done to compare the efficacy and safety of rivaroxaban against enoxaparin for thromboprophylaxis after THA. MATERIALS AND METHODS: We conducted a search in databases including Medline, EMBASE, ScienceDirect, Google Scholar, and Cochrane Library from inception until May 2021. Randomized controlled trials directly comparing the effectiveness of rivaroxaban and enoxaparin for thromboprophylaxis among patients undergoing THA were eligible for inclusion. Outcome parameters assessed were efficacy in terms of total VTE and all-cause mortality, major VTE, deep vein thrombosis, symptomatic VTE, and safety in terms of major bleeding events, clinically relevant nonmajor bleeding events, minor bleeding events, total bleeding events, drug-related adverse events, and wound infection. We performed a meta-analysis with a random effects model and reported a pooled risk ratio (RR) with a 95% confidence interval (CI). RESULTS: Eleven studies, including 9057 participants, were analyzed. Amongst efficacy outcomes, VTE and all-cause mortality pooled an RR of 0.58 (95% CI: 0.34-0.99), major VTE pooled an RR of 0.37 (95% CI: 0.15-0.90), deep vein thrombosis pooled an RR of 0.57 (95% CI: 0.32-1.02), and symptomatic VTE pooled an RR of 0.51 (95% CI: 0.30-0.87). Amongst safety outcomes, major bleeding events pooled an RR of 1.18 (95% CI: 0.77-1.80), total bleeding events pooled an RR of 1.12 (95% CI: 0.93-1.34), drug-related adverse event pooled an RR of 0.99 (95% CI: 0.87-1.12), and wound infection pooled an RR of 1.11 (95% CI: 0.58-2.14). CONCLUSION: Rivaroxaban is a more efficacious drug in terms of VTE and all-cause mortality compared to enoxaparin following THA, and rivaroxaban was non-inferior in terms of safety profiles such as wound infection, bleeding, and drug-related adverse events.

Mechanistic evaluation of the inhibitory effect of four SGLT-2 inhibitors on SGLT 1 and SGLT 2 using physiologically based pharmacokinetic (PBPK) modeling approaches.

Sodium-glucose co-transporter type 2 (SGLT 2, gliflozins) inhibitors are potent orally active drugs approved for managing type 2 diabetes. SGLT 2 inhibitors exert a glucose-lowering effect by suppressing sodium-glucose co-transporters 1 and 2 in the intestinal and kidney proximal tubules. In this study, we developed a physiologically based pharmacokinetic (PBPK) model and simulated the concentrations of ertugliflozin, empagliflozin, henagliflozin, and sotagliflozin in target tissues. We used the perfusion-limited model to illustrate the disposition of SGLT 2 inhibitors in vivo. The modeling parameters were obtained from the references. Simulated steady-state plasma concentration-time curves of the ertugliflozin, empagliflozin, henagliflozin, and sotagliflozin are similar to the clinically observed curves. The 90% prediction interval of simulated excretion of drugs in urine captured the observed data well. Furthermore, all corresponding model-predicted pharmacokinetic parameters fell within a 2-fold prediction error. At the approved doses, we estimated the effective concentrations in intestinal and kidney proximal tubules and calculated the inhibition ratio of SGLT transporters to differentiate the relative inhibition capacities of SGLT1 and 2 in each gliflozin. According to simulation results, four SGLT 2 inhibitors can nearly completely inhibit SGLT 2 transporter at the approved dosages. Sotagliflozin exhibited the highest inhibition activity on SGLT1, followed by ertugliflozin, empagliflozin, and henagliflozin, which showed a lower SGLT 1 inhibitory effect. The PBPK model successfully simulates the specific target tissue concentration that cannot be measured directly and quantifies the relative contribution toward SGLT 1 and 2 for each gliflozin.

Pharmacokinetics and Safety of iGlarLixi in Healthy Chinese Participants: Results of a Phase 1 Randomized Study.

INTRODUCTION: The Chinese Diabetes Society recommends basal insulin and glucagon-like peptide-1 receptor agonists as an add-on therapy to first-line oral antihyperglycemic drugs for people with type 2 diabetes (T2D). Fixed-ratio combination of insulin glargine 100 U/ml (iGlar) and lixisenatide (iGlarLixi) is known to improve glycemic control in adults with T2D. However, the pharmacokinetics of iGlarLixi has not been evaluated in Chinese participants. The present study evaluated pharmacokinetics and safety of two iGlarLixi (10 U/10 µg and 30 U/15 µg) doses following single subcutaneous administration in healthy Chinese participants. METHODS: This was a Phase 1, single-center, open-label, parallel-group, randomized study in healthy Chinese adults who were randomized to receive a single dose of iGlarLixi with either 1:1 (10 U/10 µg) or 2:1 (30 U/15 µg) ratio of iGlar and lixisenatide. Primary objectives include assessment of pharmacokinetics of iGlar in iGlarLixi 30 U/15 µg group and the pharmacokinetics of lixisenatide in both the groups (iGlarLixi 10 U/10 µg and iGlarLixi 30 U/15 µg). Safety and tolerability were also assessed. RESULTS: In iGlarLixi 30 U/15 µg group, iGlar concentrations were low and quantifiable in three of ten participants, while its main metabolite (M1) was quantifiable in all participants, reflecting rapid conversion of iGlar to M1. Median INS-tmax was 14.00 h for iGlar and 13.00 h post-dose for M1. Absorption of lixisenatide was similar in both dose groups with median tmax of 3.25 and 2.00 h post-dose in both groups. The exposure increase was dose proportionate with a 1.5-fold increase in the lixisenatide dose. Adverse events observed were consistent with those previously reported with iGlar or lixisenatide. CONCLUSION: iGlarLixi administration resulted in early absorption of both iGlar and lixisenatide with a good tolerability profile in healthy Chinese participants. These results are consistent with the previously published data from other geographic regions. TRIAL REGISTRATION: U1111-1194-9411.

Pollution and health-risk assessments of Cr-contaminated soils from a tannery waste lagoon, Hebei, north China: With emphasis on Cr speciation.

In this paper, heavy metals (i.e., V, Cr, Co, Cu, Zn, Cd, Pb, and Sb) in soils from a tannery waste lagoon, Hebei, north China were investigated. Element concentrates were determined by a portable X-ray fluorescence in situ and an inductively coupled plasma mass spectrometry in the lab. Two sets of indexes, including geological accumulation index, contamination factor, and pollution load index, and hazard quotient and total carcinogenic risk were adopted to evaluate the pollution and health-risk of heavy metals. A scanning electron microscopy in conjunction with an energy dispersive X-ray spectroscopy and an X-ray photoelectron spectroscopy was used to observe chromium occurrence and speciation. With an average of 6493.11 mg/kg, chromium contents in the lagoon soils reached up to 12971.19 mg/kg, 211-times higher than the threshold of Chinese soils (61.00 mg/kg). Elevated Cr contents resulted in significantly high pollution and noncarcinogenic and carcinogenic risks in the studied area. Chromium in most soils occurred predominately as Cr3+ (60-74%), and to a lesser extent, Cr6+. The mechanism responsible for decreasing Cr6+ percentages in soils with increasing depth was summarized: Cr6+ favors aqueous environment; soil moisture decreased with increasing depth; in soils especially in the lower portion, Cr6+ was reduced by Fe0 and Fe2, transforming into Cr3+ and Fe3+. In addition, the alkaline condition promoted Cr3+ to precipitate, resulting more Cr3+ absorbing in soils. The intimate association of Cr and Fe in soils (i.e., Cr mainly occurred in Fe oxides and dolomite) further confirmed our assumptions. A combined application of microorganism (e.g., Aeromonas hydrophila) and biochar (prepared from maize stalk or peanut shells) were recommended to alleviate Cr pollution in the soils.

Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Sotagliflozin After Multiple Ascending Doses in Chinese Healthy Subjects.

Background: Sotagliflozin (LX4211) is a dual inhibitor of sodium-glucose cotransporter (SGLT)1 and SGLT2 being investigated to improve glycemic control in adults with diabetes. This study was firstly conducted to assess the pharmacokinetic (PK), pharmacodynamic (PD) profiles, safety and tolerability in Chinese healthy subjects after administration of sotagliflozin. Methods: This was a Phase I, randomized, double-blind, placebo-controlled, ascending multiple-dose study. Healthy subjects received 200mg or 400mg of sotagliflozin or placebo once daily for 8 days, respectively. PK parameters of sotagliflozin and LX4211-GLU (main metabolite), as measured by blood samples collected pre/postdose on Day 1/predose on Day 2-Day 8/postdose on Day 8, and PD parameters of absolute urinary glucose excretion (UGE) were determined. Treatment-emergent adverse events (TEAEs) were evaluated. Results: Overall, 24 subjects were enrolled and randomized to sotagliflozin 200 mg (N = 9), sotagliflozin 400 mg (N = 9), or placebo (N = 6) group, and all subjects completed the study. Sotagliflozin was rapidly absorbed with dose-proportional systemic exposure and a moderate degree (less than 2-fold) of accumulation. Sotagliflozin plasma concentrations peaked at 1.0 h post dose. On Day 8, the estimated increases for Cmax and AUCtau were 1.89-fold and 1.70-fold. The pooled accumulation ratio of sotagliflozin was 1.57 for Cmax and 1.84 for AUCtau. LX4211-GLU had similar PK features. UGE was significantly elevated in both sotagliflozin groups relative to the placebo group. All TEAEs were mild and resolved without sequelae. There were no serious AEs or other significant TEAEs. Conclusion: Sotagliflozin was rapidly absorbed with dose-proportional systemic exposure and a moderate degree of accumulation. Both 200 mg and 400 mg sotagliflozin per day were well tolerated in Chinese healthy subjects.

Mechanism of Astragali Radix for the treatment of osteoarthritis: A study based on network pharmacology and molecular docking.

Osteoarthritis (OA) is a degenerative joint disease caused by many factors. Astragali Radix (Huangqi), a traditional Chinese medicine (TCM), is widely used to treat OA. Although it can inhibit the progression of OA, its pharmacological mechanism is unclear. In this study, we used a network pharmacological approach to determine the mechanism by which Huangqi inhibits the progression of OA. We obtained the active ingredients of Huangqi from the Traditional Chinese Systems Pharmacology database and identified potential targets of these ingredients. Next, we identified the OA-related targets by using the GeneCards and Online Mendelian Inheritance in Man databases. Then, a protein-protein interaction (PPI) network was established based on the overlapping genes between the Huangqi targets and the OA targets, and the interactions were analyzed. Subsequently, the Metascape database was used to perform the Gene Ontology biological functions and Kyoto Encyclopedia of Genes and Genomes pathways enrichment analysis. Furthermore, selected active ingredients and corresponding targets were investigated through molecular docking. In total, 20 active ingredients and 206 related targets were identified. The results of Gene Ontology enrichment analysis showed that the intersection targets were mainly involved in immune inflammation, proliferation, and apoptosis. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that Huangqi might exert antiosteoarthritis effect mainly through the PI3K-Akt signaling pathway, apoptosis, the mitogen-activated protein kinases signaling pathway, and the p53 signaling pathway. Moreover, the molecular docking results indicated that quercetin and kaempferol exhibited the good binding capacity to transcription factor JUN, tumor necrosis factor, and protein kinase B. In summary, we investigated the therapeutic effects of Huangqi from a systemic perspective. These key targets and pathways provide promising directions for future studies to reveal the exact regulating mechanism of Huangqi against OA.

[Comparison of clinical efficacy of subchondral blocking technique combined with plate-screw biplanar fixation and simple plate-screw support peripheral block fixation in the treatment of complex posterior wall acetabular fracture].

OBJECTIVE: To investigate the clinical effect of subchondral blocking technique combined with plate and screw biplane fixation in the treatment of complex acetabular posterior wall fractures. METHODS: From July 2015 to December 2019, a total of 47 cases of acetabular posterior wall fractures were treated. According to the different internal fixation techniques, they were divided into the external blocking fixation group supported by lateral plate and screw(control group of 23 cases) and the subchondral blocking technique combined with lateral plate and screw support biplane fixation group(study group of 24 cases). In the control group, there were 15 males and 8 females, aged 18 to 68 years old with an average of (40.9±7.2) years;preoperative preparation was 4 to 13 days with an average of (7.9±1.5) days. In the study group, there were 14 males and 10 females, aged 20 to 71 years old with an average of (41.7±7.9) years;preoperative preparation was 4 to 12 days with an average of (7.5±1.9) days. Kocher-Langenbeck approach was used in both groups and all patients were followed up for at least 1 year. The operation time, intraoperative blood loss, hospitalization time, quality of fracture reduction after operation, modified Merle D'Aubigne Postel score of hip joint one year after operation and postoperative complication rate of two groups were statistically analyzed and compared. RESULTS: The patients in both groups were followed up for at least 1 year. One year after operation, the Merled'Aubigne Postel score(16.042±1.517) of hip function improvement in the study group was significantly higher than that in the control group (14.696±1.222)(P<0.05). There was no significant difference in operation time and intraoperative bleeding between the two groups(P>0.05). One year after operation, there was a significant difference between two groups in the evaluation results of Matta fracture reduction quality(P<0.05). There was no significant difference in postoperative complications between two groups(P>0.05). CONCLUSION: The treatment of complex acetabular posterior wall fracture with subchondral blocking technique combined with plate and screw biplane fixation technique has lower postoperative complication rate, better functional recovery of hip joint and satisfactory clinical effect.

[Effect analysis of trajectory screw technique in fragility fracture of pelvic ring].

OBJECTIVE: To assess the clinical efficacy of minimally invasive technology with trajectory screw fixation for fragility fractures of pelvic(FFP). METHODS: A retrospective case control study was performed to analyze the clinical data of 35 patients with FFP who were treated and followed up between January 2016 and December 2019. There were 12 males and 23 females, aged from 65 to 99 years with an average of(75.4±7.8) years old. There were 13 cases of type Ⅱb, 7 cases of type Ⅱc, 8 cases of type Ⅲa, 2 cases of type Ⅲb, 2 cases of type Ⅲc, 1 case of type Ⅳb, and 2 cases of type Ⅳc according to Rommens FFP comprehensive classification. All patients received the treatment of minimally invasive technology with trajectory screws fixation. According to the different methods of anterior pelvic ring fixation, FFP patients were divided into two groups:12 cases were fixed with the pedicle screw rod system in the anterior pelvic subcutaneous internal fixator (INFIX) group;23 cases were fixed with hollow screws of the pubic symphysis, superior ramus of pubis or acetabular anterior column in the screw group. The operation time, intraoperative blood loss, intraoperative fluoroscopy times, length of hospital stay, cost of internal fixation, pre- and post-operative visual analogue scale(VAS) were compared between the two groups. The fracture reduction quality was evaluated according to the Matta criteria, and the clinical function was evaluated by the Majeed functional scoring system respectively. RESULTS: All patients were followed up for 12 to 39(16.5±5.4) months after surgery. There was no statistically significant difference in the operation time, intraoperative blood loss, intraoperative fluoroscopy time, and length of hospital stay between the two groups(P>0.05). As for the cost of internal fixation, the cost of internal fixation in the screw group [2 914 (2 914, 4 371) yuan] was significantly lower than that of the INFIX group [6 205 (6 205, 6 205) yuan] (P<0.05). No significant difference was observed in the incidence of postoperative complications between the two groups (P>0.05). There was no significant difference in VAS assessment at admission, 1 week, and 3 months after surgery between the two groups(P>0.05). However, the VAS assessment at 1 week and 3 months after surgery of the two groups were significantly better than those at admission(P<0.05). There was no significant difference in the quality of fracture reduction after the operation and the efficacy evaluation at the last follow-up between the two groups(P>0.05). CONCLUSION: For the treatment of fragility fractures, minimally invasive technology with trajectory screw fixation can achieve good clinical efficacy. It has the advantages of being relatively minimally invasive, less bleeding, relieving the pain. It deserves clinical application.

Pharmacokinetics and Safety of Ferric Pyrophosphate Citrate in Chinese Subjects with and without Hemodialysis-Dependent Stage 5 Chronic Kidney Disease.

BACKGROUND AND OBJECTIVE: Anemia caused by iron depletion is common in patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) patients. To maintain the iron levels, external administration of iron is essential. Ferric pyrophosphate citrate (FPC) is a novel, water-soluble complex iron salt. The present study was conducted to evaluate the pharmacokinetic (PK) parameters and safety of FPC in adult healthy Chinese subjects and patients with CKD-5HD. METHODS: Two open-label, single-center studies were conducted in healthy subjects and patients with CKD-5HD. Healthy subjects received a single intravenous dose of 6.5 mg FPC solution, while CKD-5HD patients were randomized to two different sequences of FPC administration at two sequential hemodialysis (HD) treatments (dose 1 and dose 2). Patients received 27.2 mg of FPC at a dialysate concentration of 95 µg/L for 4 h or a single 6.5 mg dose of FPC administered intravenously via the pre-dialyzer blood circuit. The primary objective was to determine the PK parameters of total serum iron (Fetot), while the secondary objective was the safety of the FPC solution. PK parameters were calculated using Phoenix WinNonlin 8.1 and other parameters were analyzed using SAS 9.4 software. Comparison between HD dose 2 and HD dose 1 was performed using the Wilcoxon rank-sum test and analysis of variance (ANOVA). RESULTS: A total of 14 healthy subjects with a mean age of 30.8 ± 5.92 years and 12 HD patients with a mean age of 54.3 ± 16.47 years were included. In healthy subjects, the peak serum concentration was reached at the end of infusion of FPC, with an adjusted mean maximum concentration (Cmax,) of 33.46 ± 4.83 µmol/L at a mean time to reach Cmax (Tmax) of 4.09 ± 0.19 h. In patients with CKD-5HD, the adjusted mean Cmax of HD dose 2 was 25.37 ± 4.30 µmol/L at a Tmax, of 3.09 ± 0.32 h, whereas the Cmax, of HD dose 1 was 24.59 ± 4.77 µmol/L at a Tmax, of 3.96 ± 0.26 h. The Fetot concentration-time curves were observed to be similar for both administration methods (HD doses 1 and 2), while the PK parameters differed significantly for Tmax (p = 0.001; baseline correction) and area under the concentration-time curve from time zero to time t (AUCt) [p = 0.031 for cycle variance; without baseline correction] between HD doses 1 and 2. The geometric mean ratios (HD dose 1/HD dose 2) for Cmax and AUCt were within the 85-125% range (Cmax 96.56%; AUCt 96.07%). A total of three and two incidences of adverse events were reported in healthy subjects and patients with CKD-5HD, respectively. CONCLUSION: FPC showed a good PK and safety profile and hence can be used as maintenance therapy for patients with CKD-5HD by choosing a better method of administration based on clinical feasibility and requirement. CLINICAL TRIAL REGISTRATION: CTR20181113 and CTR20181119.