Achromobacter seleniivolatilans sp. nov. and Buttiauxella selenatireducens sp. nov., isolated from the rhizosphere of selenium hyperaccumulator Cardamine hupingshanesis.

Two Gram-stain-negative bacterial strains, R39T and R73T, were isolated from the rhizosphere soil of the selenium hyperaccumulator Cardamine hupingshanesis in China. Strain R39T transformed selenite into elemental and volatile selenium, whereas strain R73T transformed both selenate and selenite into elemental selenium. Phylogenetic and phylogenomic analyses indicated that strain R39T belonged to the genus Achromobacter, while strain R73T belonged to the genus Buttiauxella. Strain R39T (genome size, 6.68 Mb; G+C content, 61.6 mol%) showed the closest relationship to Achromobacter marplatensis LMG 26219T and Achromobacter kerstersii LMG 3441T, with average nucleotide identity (ANI) values of 83.6 and 83.4 %, respectively. Strain R73T (genome size, 5.22 Mb; G+C content, 50.3 mol%) was most closely related to Buttiauxella ferragutiae ATCC 51602T with an ANI value of 86.4 %. Furthermore, strain A111 from the GenBank database was found to cluster with strain R73T within the genus Buttiauxella through phylogenomic analyses. The ANI and digital DNA-DNA hybridization values between strains R73T and A111 were 97.5 and 80.0% respectively, indicating that they belong to the same species. Phenotypic characteristics also differentiated strain R39T and strain R73T from their closely related species. Based on the polyphasic analyses, strain R39T and strain R73T represent novel species of the genera Achromobacter and Buttiauxella, respectively, for which the names Achromobacter seleniivolatilans sp. nov. (type strain R39T=GDMCC 1.3843T=JCM 36009T) and Buttiauxella selenatireducens sp. nov. (type strain R73T=GDMCC 1.3636T=JCM 35850T) are proposed.

Amorphous structure and crystal stability determine the bioavailability of selenium nanoparticles.

Microorganisms play a critical role in the biogeochemical cycling of selenium, often reducing selenite/selenate to elemental selenium nanoparticles (SeNPs). These SeNPs typically exist in an amorphous structure but can transform into a trigonal allotrope. However, the crystal structural transition process and its impact on selenium bioavailability have not been well studied. To shed light on this, we prepared chemosynthetic and biogenic SeNPs and investigated the stability of their crystal structure. We found that biogenic SeNPs exhibited a highly stable amorphous structure in various conditions, such as lyophilization, washing, and laser irradiation, whereas chemosynthetic SeNPs transformed into a trigonal structure in the same conditions. Additionally, a core-shell structure was observed in biogenic SeNPs after electron beam irradiation. Further analysis revealed that biogenic SeNPs showed a coordination reaction between Se atoms and surface binding biomacromolecules, indicating that the outer layer of Se-biomacromolecules complex prevented the SeNPs from crystallizing. We also investigated the effects of SeNPs crystal structures on the bioavailability in bacteria, yeast, and plants, finding that the amorphous structure of SeNPs determined Se bioavailability.

Safety, tolerability, pharmacokinetics and pharmacodynamics of a novel farnesoid X receptor (FXR) agonist-TQA3526 in healthy Chinese volunteers: a double-blind, randomized, placebo-controlled, dose-escalation, food effect phase I study.

Background: TQA3526 is a novel farnesoid X receptor agonist developed to treat non-alcoholic steatohepatitis (NASH) or primary biliary cholangitis (PBC). This study aimed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of TQA3526 in healthy Chinese patients.Methods: Healthy subjects aged 18-55 years were enrolled in this double-blinded, first-in-human, placebo-controlled single ascending dose (1, 2, 5, and 10 mg) comprising food effect investigation (10 mg) and multiple dose study (2 mg and 0.2 + 0.5 + 1 mg). Safety was assessed on the basis of adverse events. The TQA3526 concentrations were analysed in the PK study. Alkaline phosphatase (ALP), fibroblast growth factor-19 (FGF19), bile acid precursor C4 (7α-hydroxy-cholest-4-ene-3-one), cholesterol, and bile acid were selected for PD analysis.Results: TQA3526 was well tolerated, and the primary adverse drug reaction was pruritus, as expected. The exposure to TQA3526 increased in a dose-dependent manner after a single dose of 1-10 mg. The exposure was higher after food intake. A steady state was reached around 5 days, and obvious plasma accumulation of TQA3526 was observed in the multiple dose study. TQA3526 increased circulating FGF-19 and decreased C4 levels in a dose-dependent manner. ALP increased only mildly in the 2 mg multiple dose cohort.Conclusions: TQA3526 (<10 mg/day) was safe and tolerable in healthy Chinese subjects. The safety profile and PK/PD characteristics of TQA3526 support further evaluation of patients with NASH or PBC. This study was registered at https://www.chictr.org.cn/ under the identifier ChiCTR1800019570.

Electrochemical Selenylation of Sulfoxonium Ylides for the Synthesis of gem-Diselenides as Antimicrobials against Fungi.

Organoselenium compounds are important scaffolds in pharmaceutical molecules. Herein, we report metal-free, electrochemical, highly chemo- and regioselective synthesis of gem-diselenides through the coupling of α-keto sulfoxonium ylides with diselenides. The versatility of the electrochemical manifold enabled the selenylation with ample scope and broad functional group tolerance, as well as setting the stage for modification of complex bioactive molecules. Detailed mechanistic studies revealed that the key C-Se bond was constructed using n-Bu4NI as an electrolyte and catalyst through the electrosynthetic protocol. Finally, the desired α-keto gem-diselenides showed excellent antimicrobial activity against Candida albicans, which can be identified as the lead compounds for further exploration.

Comparing the bioequivalence and safety of liraglutide in healthy Chinese subjects: an open, single-dose, randomized, repeated, two-sequence, two-cycle phase I clinical trial.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is an endogenous incretin hormone. Liraglutide, a GLP-1 receptor agonist, can lower blood sugar by increasing insulin production and inhibiting the production of glucagon. This study researched the bioequivalence and safety of the test and reference drugs in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: Subjects (N = 28) were randomly divided into group A and group B at a ratio of 1:1 for a two-cycle cross-over study. There was single dose per cycle with subcutaneous injection of the test and reference drugs, respectively. The washout was set at 14 days. Plasma drug concentrations were detected by specific liquid chromatography and tandem mass spectrometry (LC-MS/MS) assays. Statistical analysis of major pharmacokinetic (PK) parameters was conducted to assess drug bioequivalence. In addition, we evaluated the safety of the drugs throughout the trial. RESULTS: The geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ for the test and reference drugs were 107.11%, 106.56%, 106.09%, respectively. The 90% confidence intervals (CIs) were all within 80%-125%, meeting the bioequivalence standards. In addition, both had good safety in this study. CONCLUSION: The study shows that the two drugs had similar bioequivalence and safety. CLINICAL TRIAL REGISTRATION: DCTR: CTR20190914; ClinicalTrials.gov: NCT05029076.

Disruption of the sensor kinase phoQ gene decreases acid resistance in plant growth-promoting rhizobacterium Rahnella aquatilis HX2.

AIMS: Rahnella aquatilis HX2, a promising plant growth-promoting rhizobacterium (PGPR) in the field, contains genes homologous to the PhoP/PhoQ two-component regulatory system. Although this system regulates stress response in numerous pathogens, PhoP/PhoQ characterization in a PGPR has not received in-depth exploration. METHODS AND RESULTS: The phoQ gene was mutated in strain HX2 using an in-frame deletion strategy. Compared to the wild type, the phoQ mutant exhibited increased sensitivity to acidic conditions (pH 4.0) in a chemically defined medium and in mild acidic natural soil (pH 5.7). The phoQ mutant also exhibited increased swimming motility under acidic conditions. Acid resistance was restored in the mutant by introducing the phoQ gene on a plasmid. Three acid resistance genes, add, cfa, and fur were downregulated significantly, whereas the chaperone encoding gene, dnak, was upregulated when the phoQ mutant was exposed to acid stress. CONCLUSIONS: This study suggested that the PhoP/PhoQ system positively regulates the acid resistance of R. aquatilis HX2.

Population pharmacokinetic/pharmacodynamic models of JNJ-64794964, a toll-like receptor 7 agonist, in healthy adult participants.

BACKGROUND: JNJ-4964 is a TLR7 agonist, which, via a type I interferon (IFN)-dependent mechanism, may enhance host immunity suppressed by persistent exposure to hepatitis B antigens in chronic hepatitis B. METHODS: PK and PD data were pooled from 2 studies involving 90 participants (n = 74 JNJ-4964, dose range 0.2-1.8 mg; n = 16 placebo) in a fasted state. Food effects on PK were studied in 24 participants (1.2 or 1.25 mg). A population PK model and PK/PD models were developed to characterize the effect of JNJ-4964 plasma levels on the time course of IFN-α, IFN-γ-inducible protein 10 (IP-10 or CXCL10), IFN-stimulated gene 15 (ISG15), neopterin and lymphocytes following single and weekly dosing in healthy adults. Covariate effects, circadian rhythms and negative feedback were incorporated in the models. RESULTS: A 3-compartment linear PK model with transit absorption adequately described JNJ-4964 PK. Bioavailability was 44.2% in fed state relative to fasted conditions. Indirect response models with maximum effect (Emax) stimulation on production rate constant (kin) described IFN-α, IP-10, ISG15 and neopterin, while a precursor-dependent indirect response model with inhibitory effect described the transient lymphocyte reduction. Emax, EC50 and γ (steepness) estimates varied according to PD markers, with EC50 displaying substantial between-subject variability. Female and Asian race exhibited lower EC50, suggesting higher responsiveness. CONCLUSIONS: PK/PD models well characterized the time course of immune system markers in healthy adults. Our results supported sex and race as covariates on JNJ-4964 responsiveness, as well as circadian rhythms and negative feedback as homeostatic mechanisms that are relevant in TLR7-induced type I IFN responses.

Pharmacokinetics and bioequivalence of two pomalidomide capsules in healthy chinese subjects under fasting and fed conditions.

OBJECTIVE: Imnovid® is an immunomodulatory drug with antineoplastic activity. The aim of this study was to evaluate the bioequivalence and safety of the generic drug pomalidomide (Chia Tai Tianqing Pharmaceutical Group Co., Ltd) and its originator product Imnovid® (Celgene Europe Ltd) in the fasting and fed states, respectively. METHODS: The research consisted of two parts: one with a dose of 1 mg and the other with a dose of 4 mg. 48 healthy subjects were included in each study and were divided into two groups (fasting group and fed group) at a 1:1 ratio to administrate study drugs orally. The plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: The 90% CI of GMR for main pharmacokinetic (PK) parameters (Cmax, AUC0 - t and AUC0-∞) met the requirements of bioequivalence standards. The incidence and severity of AEs associated with pomalidomide and Imnovid® were similar. CONCLUSION: The results proved the PK parameters of pomalidomide and Imnovid® were similar and bioequivalent. Both drugs showed safety profile well.

One hundred and ninety-two weeks treatment of entecavir maleate for Chinese chronic hepatitis B predominantly genotyped B or C.

BACKGROUND: Entecavir (ETV) is a potent and selective nucleotide analog with significant activity against hepatitis B virus (HBV). ETV maleate is a derivative compound of ETV and was reported to have an efficacy and safety profile that is comparable to ETV (Baraclude) when used in Chinese patients with chronic hepatitis B (CHB) in phase III clinical trials (Clinical Trials.gov number, NCT01926288) at weeks 48, 96, and 144. AIM: To investigate the antiviral potency and safety of ETV maleate at week 192 in Chinese CHB patients predominantly genotyped B or C. METHODS: In this double-blind study, we randomly assigned patients to receive 0.5 mg/d ETV (Group A) or ETV maleate (Group B) (ratio, 1:1), each with a placebo tablet for 48 wk. Then, all patients received open-label treatment with 0.5 mg/d ETV maleate starting at week 49. The primary efficacy endpoint was the reduction in HBV DNA levels from baseline. Secondary endpoints included the proportion of patients with undetectable HBV DNA (< 20 IU/mL), serologic response, serum alanine aminotransferase (ALT) normalization and development of resistance mutations. RESULTS: Two hundred eighteen patients who were hepatitis B e antigen (HBeAg) positive and 57 who were HBeAg negative were analyzed and predominantly presented with genotype B (49.82%) or C (48.73%). For the HBeAg-positive CHB patients, the mean HBV DNA level decrease (6.61 Log10 IU/mL vs 6.69 Log10 IU/mL, P > 0.05), viral suppression with HBV DNA < 20 IU/mL (83.33% vs 79.17%, P > 0.05) and HBeAg seroconversion (28.77% vs 20.00%, P > 0.05) occurred similarly between Groups A and B at week 192. However, there was a significant difference in the proportion of patients with normal ALT levels (91.14% vs 78.38%, P < 0.05). For the HBeAg-negative CHB patients, no significant difference was found between Groups A and B at week 192 in terms of reductions in HBV DNA levels from baseline (6.05 Log10 IU/mL vs 6.03 Log10 IU/mL, P > 0.05), percentages of patients who achieved undetectable HBV DNA (100% vs 100%, P > 0.05) and rates of ALT normalization (95.65% vs 100.00%, P > 0.05). Safety and adverse event profiles were similar between Groups A and B. Two HBeAg-positive patients in Group A and 5 in Group B developed genotypic resistance to ETV. CONCLUSION: Long-term ETV maleate treatment for up to 192 wk is effective and safe in Chinese CHB patients predominantly genotyped as B or C.

240-week entecavir maleate treatment in Chinese chronic hepatitis B predominantly genotype B or C.

This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double-blind, double-dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty-seven (71 in group A) patients with HBeAg-positive CHB and 46 (21 in group A) patients with HBeAg-negative CHB completed the 240-week treatment and follow-up. Baseline characteristics were well balanced between the two groups. For the HBeAg-positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log10 IU/ml vs. B: by 6.74 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA (<20 IU/ml) at Week 240 were similar between groups (A:91.55% vs. B:87.88%; p > .05). Both groups achieved similar HBeAg seroconversion rates at week 240 (A:26.98% vs. B:20.97%; p > .05). Both groups achieved similar normalization of ALT (A:87.32% vs. B:83.61%; p > .05) at Week 240 (p > .05). For the HBeAg-negative CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.05 log10 IU/ml vs. B: by 6.10 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA at Week 240 were similar between groups (A:100% vs. B:100%). Both groups achieved similar normalization rates (A:90.91% vs. B: 95.45%; p > .05) of ALT at Week 240 (p > .05). In conclusion, long-term ETV maleate treatment was safe and efficient in Chinese CHB predominantly of genotype B or C.

Pharmacokinetics, safety, and tolerability of TQC3564, a novel CRTh2 receptor antagonist: report of the first-in-human single- and multiple-dose escalation trials in healthy Chinese subjects.

BACKGROUND: This is the first-in-human study to evaluate the pharmacokinetics, safety, and tolerability of TQC3564 (a novel CRTh2 receptor antagonist) in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: This project was a phase Ia clinical study of TQC3564 as a single-ascending dose (SAD) (25 to 1200 mg) and a multiple-ascending dose (MAD) (100 or 500 mg, QD) as well as a two-period crossover food-effect study (300 mg). RESULTS:     In the SAD and MAD study, TQC3564 were found to be safe and well tolerated, without dose-dependent adverse events (AEs), and all AEs were mild or moderate in severity. In the SAD study, the median tmax of TQC3564 was 2.5-4.5 h, and t1/2 was 8.13-35.7 h. Exposure was increased after food intake. The MAD study results showed that steady-state was achieved on day 4. Moreover, no apparent TQC3564 plasma accumulation was detected on day 7. CONCLUSIONS: In healthy subjects, TQC3564 at a single dose of 25-1200 mg or 100-500 mg at multiple doses (QD) was safe and tolerable with acceptable PK profiles, indicating that TQC3564 has potential as a therapeutic option for asthma. (This study has been registered at http://www.chinadrugtrials.org.cn/ under identifier CTR20192397.).

A randomized, open-label, single-dose, two-cycle crossover study to evaluate the bioequivalence and safety of lenvatinib and Lenvima® in Chinese healthy subjects.

BACKGROUND: Lenvatinib is a tyrosine kinase receptor inhibitor that inhibits vascular and endothelial growth factor receptor kinase activity. This study evaluated the bioequivalence and safety of lenvatinib with Lenvima® . RESEARCH DESIGN AND METHODS: The fasting and postprandial groups were two independent trials. Subjects were randomly divided into two sequences at a ratio of 1:1 for two-cycle crossover administration. Subjects took 10 mg lenvatinib or Lenvima® once per cycle. The wash-out period was 14 days. Detected the plasma drug concentrations and assessed the bioequivalence of two drugs. Besides, we evaluated the safety of the drugs throughout the trial. RESULTS: In the fasting state, the GMRs of Cmax, AUC0-t, and AUC0-∞ were 99.89%, 102.98% and 103.19%, respectively. The 90% CIs were all within 80%-125%. In the postprandial state, the GMRs of Cmax, AUC0-t, and AUC0-∞ were 98.96%, 94.25% and 95.27%, respectively. The 90% CIs were all within 80%-125%. All results met the bioequivalence criteria. Both drugs had good safety and tolerance in this trial. CONCLUSION: This study showed that lenvatinib and Lenvima® had similar bioequivalence and safety in healthy Chinese subjects under fasting and postprandial conditions. CLINICAL TRIAL REGISTRATION: This trial is registered at the Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html # CTR20191172).

A randomized, crossover, phase I clinical study to evaluate bioequivalence and safety of tofacitinib and Xeljanz® in Chinese healthy subjects.

OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor that has been marketed and approved in the USA for the clinical treatment of rheumatoid arthritis, psoriasis and other inflammatory and autoimmune diseases. A phase I clinical trial was conducted to compare the bioequivalence and safety of tofacitinib (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.) and Xeljanz® (Pfizer Inc.) in healthy Chinese subjects, providing basis for the clinical application of tofacitinib. METHODS: Healthy Chinese subjects (N = 32) were randomly assigned to two groups at a 1:1 ratio. Subjects orally took 5 mg tofacitinib or Xeljanz® per cycle in random sequence. Blood samples were collected at 15 sampling points per cycle, and plasma drug concentrations of tofacitinib or Xeljanz® were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and statistical analysis for the pharmacokinetic (PK) parameters. Subjects' physical indicators were monitored during the whole process to evaluate drug safety. RESULTS: The adjusted geometric mean ratios (GMRs) of the peak concentration (Cmax), area under the curve (AUC) from time zero to the last measurable concentration (AUC0-t) and AUC from time zero to observed infinity (AUC0-∞) were all within the range of 80-125%. The other PK parameter values were similar. The above values were all meeting the bioequivalence criteria with well safety. CONCLUSION: The pharmacokinetic parameters and safety profile of tofacitinib were similar to those of Xeljanz® in healthy Chinese subjects. Therefore, tofacitinib can be considered bioequivalent to Xeljanz®, and the findings of this trial will promote the clinical application of tofacitinib.

A randomized, double-blind, single-dose, two-way, parallel phase I clinical study comparing the pharmacokinetics and safety of adalimumab injecta and Humira® in healthy Chinese male volunteers.

BACKGROUND: Humira® is a fully humanized anti-tumor necrosis factor (TNF-α) monoclonal antibody that has been marketed and approved in the United States for the clinical treatment of rheumatoid arthritis (RA), ankylosing spondylitis, psoriasis and other immune-mediated diseases. This study compared the bioequivalence, immunogenicity and safety of adalimumab injecta (a biosimilar of Humira® produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd) and Humira® in healthy Chinese male subjects in a phase I clinical study. METHODS: Healthy Chinese male subjects (N = 164) were randomly given a subcutaneous injection of 40 mg adalimumab or Humira® at a 1:1 ratio. Plasma drug concentrations were detected by enzyme-linked immunosorbent assay (ELISA), and primary pharmacokinetic (PK) parameters were statistically analyzed. To evaluate drug immunogenicity, anti-drug antibody (ADA) and neutralizing antibody (nAb) levels were detected. To evaluate the safety of the drugs, the subjects' physical indicators, such as multiple vital signs and routine blood tests, were continuously monitored. RESULTS: The similarity ratios of adalimumab and Humira® PK parameters were all within 80%-125%, meeting the bioequivalence standards. Drug-induced ADA and nAb levels were similar, and the drug safety in subjects was also similar. CONCLUSIONS: All study drugs showed similar bioequivalence, immunogenicity and safety. CLINICAL TRIAL REGISTRATION: CTR20182070 (Chinese Clinical Trial Registry).

A randomized, double-blind, single-dose, single-center, parallel phase I clinical study comparing the pharmacokinetics, immunogenicity, safety, and tolerance of pertuzumab injection and Perjeta® in healthy Chinese male subjects.

BACKGROUND: Perjeta® is a recombinant, humanized monoclonal antibody that has been marketed and approved for the targeted therapy of human epidermal growth factor receptor (HER2) positive breast cancer in the United States. This study compared the bioequivalence, immunogenicity, and safety of pertuzumab injection (a biosimilar of Perjeta® produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd) and Perjeta® (produced by Roche Pharma AG) in healthy Chinese males. RESEARCH DESIGN AND METHODS: Healthy Chinese male subjects (N = 87) were randomly given intravenous injection of 5 mg/kg pertuzumab or Perjeta® at a 1:1 ratio. Plasma drug concentrations were detected by enzyme-linked immunosorbent assay, and primary pharmacokinetic parameters were statistically analyzed. We detected the levels of anti-drug antibody (ADA) and neutralizing antibody (nAb) to evaluate drug immunogenicity and safety of the drugs throughout the study. RESULTS: The geometric mean ratios of AUC0-t, Cmax, and AUC0-∞ for pertuzumab and Perjeta® were 100.42%, 96.71%, and 101.47%, respectively. The 90% CIs were all within 80%-125%, meeting the bioequivalence standards. The levels of ADA and nAb were similar. In addition, both had good safety in the study. CONCLUSION: The study shows that pertuzumab injection and Perjeta® had similar bioequivalence, immunogenicity, and safety.

Electrochemical regioselective C-H selenylation of 2H-indazole derivatives.

Selenium-substituted heteroarenes are biologically active compounds and useful building blocks. In this study, we have developed a metal- and oxidant-free, environmentally friendly protocol for the regioselective selenylation of 2H-indazole derivatives by an electrochemical strategy. A number of selenylated 2H-indazoles with a wide range of functional groups have been synthesized in moderate to good yields under mild and environment-friendly reaction conditions.

First-in-Human, Double-Blind, Randomized, Placebo-Controlled Trial of TQ-F3083, a New Dipeptidyl Peptidase-4 Inhibitor, in Healthy Chinese Adults.

Background: As a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, TQ-F3083 represents a promising new drug for type 2 diabetes mellitus (T2DM). This phase I, first-in-human study evaluated the tolerability, pharmacokinetics, and pharmacodynamics of TQ-F3083 in healthy Chinese adults. Methods: Sixty healthy participants total were enrolled in the single-ascending dose, multiple-dose, and food-effect studies. Safety endpoints included adverse events (AEs), vital signs, 12-lead electrocardiogram, abdominal ultrasound, chest X-ray, physical examination, and clinical laboratory tests. Blood, urine, and feces samples were collected for pharmacokinetic analyses. Pharmacodynamic parameters were evaluated based on DPP-4 activity and the active glucagon-like peptide-1 concentration. Results: In total, 22 treatment-related AEs, mostly grade 1 or 2, were reported in 14 individuals. No deaths, serious AEs, or grade ≥4 AEs occurred, and no dose-dependent AEs were demonstrated. For pharmacokinetic characteristics, dose linearity was analyzed using power model. The slopes (90% CIs) were 1.08 (1.02-1.13) and 1.05 (0.99-1.11) for AUC0-t and AUC0-∞, suggesting liner pharmacokinetic characteristic after oral dose TQ-F3083 from 2 to 160 mg. The accumulation factor was 1.39 after multiple dose for 7 days. Decreased plasma exposure (84.87% decrease in Cmax, 49.23% in AUC0-t, and 47.77% in AUC0-∞) was observed with administration after a high-fat and high-calorie standardized breakfast. The 0-72 h TQ-F3083 excretion recovery percentages were 7.84% in urine and 5.76% in feces. Over 80% DPP-4 inhibition for 24 h was observed in the 20-160 mg cohorts, and the model-estimated 50% effective concentration was 1.10 ng/ml. The concentration of active glucagon-like peptide-1 increased after TQ-F3083 administration, but no obvious dose dependency was observed. Conclusion: TQ-F3083 was well tolerated in healthy Chinese adults, and the pharmacokinetic and pharmacodynamic characteristics support further evaluation of TQ-F3083 in a trial in T2DM patients.

Direct Electrochemical Selenylation/Cyclization of Alkenes: Access to Functionalized Benzheterocycles.

A catalyst-free, environmentally friendly, and efficient electrochemical selenylation/cyclization of alkenes has been developed with moderate to excellent yields. This selenylated transformation proceeds smoothly and tolerates a wide range of synthetically useful groups to deliver diverse functionalized benzheterocycles, including iminoisobenzofuran, lactones, oxindoles, and quinolinones. Moreover, the present synthetic route could also be readily scaled up to gram quantity with convenient operation in an undivided cell.

Tenofovir disoproxil fumarate in Chinese chronic hepatitis B patients: Results of a multicenter, double-blind, double-dummy, clinical trial at 96 weeks.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is a prodrug of a nucleotide analogue. As an antiviral drug, TDF has been proposed in the first-line treatment of chronic hepatitis B (CHB). Qingzhong, a brand name of TDF, commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd., and Viread, another brand name of TDF, commercialized by GlaxoSmithKline, have both been approved by the State Food and Drug Administration, China. AIM: To investigate the efficacy and safety of the two TDF agents in the treatment of Chinese CHB patients. METHODS: This trial was registered at ClinicalTrials.gov with the identifier number of NCT02287857. A total of 330 Chinese CHB patients, among which 232 were hepatitis B e antigen (HBeAg)-positive, were included in this 5-year-long, multicenter, double-blinded, double-dummy, randomized-controlled, non-inferiority phase III trial. The participants were initially randomized into two groups: Group A (n = 161), in which the participants received 300 mg Qingzhong once a day for 48 wk; and Group B, in which the participants received 300 mg Viread once a day for 48 wk. Starting from week 49, all the participants in Groups A and B received 300 mg Qingzhong once a day until the 96th week. In this study, the primary endpoint was the decrease in plasma level of hepatitis B virus (HBV) DNA at the 96th week, while the secondary endpoints were suppression of HBV replication, alanine aminotransferase (ALT) normalization, HBeAg loss, and HBeAg seroconversion rates. RESULTS: For the participants with HBeAg-positive CHB, the decrease in mean HBV DNA level relative to the baseline value was comparable between Groups A and B (5.77 vs 5.73 log10 IU/mL, P > 0.05) at the 96th week. In addition, similar percentages of HBeAg-positive participants in the two groups exhibited undetectable levels of HBV DNA, HBeAg loss, and HBeAg seroconversion (71.05% vs 77.97%, 31.00% vs 27.27%, and 20.22% vs 15.79%, respectively, in Group A vs Group B; P > 0.05). For the participants with HBeAg-negative CHB, the decrease in mean HBV DNA level relative to the baseline value was also comparable between Groups A and B (4.46 vs 4.70 log10 IU/mL, P > 0.05) at the 96th week. In addition, similar percentages of HBeAg-negative participants in the two groups exhibited undetectable levels of HBV DNA (87.23% vs 94.12% in Group A vs Group B, respectively; P > 0.05). Finally, similar percentages of CHB patients (HBeAg-positive or HBeAg-negative) in the two groups exhibited normalization of ALT (80.14% vs 84.57% in Group A vs Group B, respectively; P > 0.05), and similar incidences of adverse events were observed (106 vs 104 in Group A vs Group B, respectively; P > 0.05). CONCLUSION: Both Qingzhong and Viread are effective and safe in the treatment of Chinese CHB patients according to the results of our clinical trial.

Comparison of the Pharmacokinetics of Generic Versus Branded Obeticholic Acid in a Chinese Population: Effects of Food and Sex.

The present study assessed the pharmacokinetics and bioequivalence of a single 10-mg dose of a generic and the branded formulation (Ocaliva) of obeticholic acid (OCA) in healthy Chinese subjects under fasting and fed conditions. The possible effects of food and sex on the pharmacokinetics of OCA and its 2 active metabolites (glyco-OCA and tauro-OCA) were evaluated. Plasma concentrations of OCA and its 2 active metabolites were measured by liquid chromatography-tandem mass spectrometry. The 90%CIs of the ratios of the test and reference formulations for Cmax , AUC0-t , and AUC0-∞ of OCA, glyco-OCA, and tauro-OCA were contained entirely within the 80% to 125% range required for bioequivalence under fasting and fed conditions. Plasma exposure of OCA was 30% to 36% higher under fed compared with fasting conditions. Plasma exposure of OCA, glyco-OCA, and tauro-OCA was 39% to 66%, 22% to 58%, and 37% to 84% higher, respectively, in women compared with men under fasting and fed conditions. In conclusion, OCA was well tolerated in healthy Chinese subjects under fasting and fed conditions. The single 10-mg dose of a generic OCA formulation was bioequivalent to Ocaliva. Food and sex impacted the pharmacokinetics of OCA and/or its 2 active metabolites. Further studies are required to determine if these effects are clinically relevant.