Bioequivalence and Safety Assessment of 2 Formulations of Low-Dose Metformin Hydrochloride under Fasting Conditions in Healthy Chinese Participants: A Randomized Phase 1 Clinical Trial.

The incidence of type 2 diabetes is high, and the existing metformin hydrochloride (MH) tablets of 250 mg cannot meet the demands of the Chinese drug market. This study aimed to evaluate the bioequivalence and safety of generic formulations of MH tablets (test formulation [T], 250 mg/tablet) and innovative products (reference formulation [R], 250 mg/tablet) under fasting conditions. This was an open-label, single-dose, 2-period, 2-sequence crossover, single-center, randomized phase I clinical trial. T and R were considered bioequivalent if the adjusted geometric mean ratios (GMRs) and 90% confidence intervals of the area under the curve (AUC) and maximum concentration (Cmax ) were within the range of 0.8-1.25. Thirty-five participants completed the trial. The T/R adjusted GMRs (95.7% for Cmax , 98.7% for AUC0→t , 98.8% for AUC0→∞ ) were within the acceptable bioequivalence range of 80%-125%. No serious adverse events or suspected or unexpected serious adverse reactions occurred during this trial. The study findings confirmed that generic MH is a well-tolerated and bioequivalent alternative to innovative products under fasting conditions in healthy Chinese participants. (www.chinadrugtrials.org.cn; registration no. CTR20190356).

Bioequivalence and safety evaluation of two preparations of metformin hydrochloride sustained-release tablets (Boke® and Glucophage®-XR) in healthy Chinese volunteers: a randomized phase I clinical trial.

BACKGROUND: As per the National Medical Products Administration (NMPA) requirements, the quality and efficacy of generic drugs must be consistent with those of the innovator drug. We aimed to evaluate the bioequivalence and safety of generic metformin hydrochloride sustained-release (MH-SR) tablets (Boke®) developed by Beijing Wanhui Double-crane Pharmaceutical Co. Ltd., China and the innovator product metformin hydrochloride extended-release tablets (Glucophage®-XR) manufactured by Bristol-Myers Squibb Company, New York, NY, in healthy Chinese volunteers. MATERIALS AND METHODS: We performed a bioequivalence and safety assessment of MH-SR (500 mg/tablet) and Glucophage®-XR (500 mg/tablet) tablets in a randomized, open-label, two-period, two-sequence crossover, single-dose oral study in 48 healthy Chinese adult participants under fasting conditions (Chinese Clinical Trial Registration No. CTR20171306). The washout period was seven days. Bioequivalence (80.00-125.00%) was assessed using adjusted geometric mean ratios (GMRs) and two-sided 90% confidence intervals (CIs) of the area under the curve (AUC) and maximum concentration (Cmax) for each component. RESULTS: The 90% CIs of the test/reference preparation for key pharmacokinetic parameters were 97.36-108.30% for AUC0→t, 97.26-108.09% for AUC0→∞ and 96.76-111.37% for Cmax. No severe adverse events (AEs) were observed. However, 38 adverse drug reactions (ADRs) occurred, including metabolic or nutritional conditions (n = 8), infections (n = 2), gastrointestinal conditions (n = 10) and abnormal inspection (n = 18). No significant difference was observed between MH-SR (23 ADRs, 10 participants) and Glucophage®-XR (15 ADRs, 12 participants) (p = .500). Bioequivalence was concluded since the 90% CIs of the main pharmacokinetic parameters were within the equivalence interval (80.00-125.00%). CONCLUSIONS: MH-SR (500 mg/tablet) and Glucophage®-XR (500 mg/tablet) were found to be bioequivalent and safe under fasting conditions in healthy Chinese participants. Thus, the market demand for MH-SR tablets (500 mg/tablet) can be met using the generic alternative.KEY MESSAGESGeneric MH-SR tablets (500 mg, Beijing Wanhui Double-crane Pharmaceutical Co. Ltd., Beijing, China) and innovator MH-SR tablets (Glucophage®-XR, 500 mg, Bristol-Myers Squibb Company, New York, NY, USA) were bioequivalent and safe in healthy Chinese volunteers under single-dose administration and fasting conditions.The main goal of this study is to support an increase in the supply of MH-SR tablets in China by proving the efficacy and safety of a generic alternative.Although no sugar was administered in the BE trial of the MH-SR tablets under fasting conditions, no hypoglycaemic event occurred. The method used in this study is expected to serve as a reference for BE studies of different MH-SR formulations.

Microbial community and functional prediction during the processing of salt production in a 1000-year-old marine solar saltern of South China.

In Hainan Island, South China, a 1000-year-old marine saltern has been identified as an intangible cultural heritage due to its historical complicated salt-making techniques, whereas the knowledge about this saltern is extremely limited. Herein, DNA sequencing and biochemical technologies were applied to determine bacterial and fungal communities of this saltern and their possible functions during four stages of salt-making, i.e. seawater storage, mud solarization, brine concentrating, and solar crystallization. The results showed that both of bacterial and fungal communities were suffered from significant changes during processing of salt-making in Danzhou Ancient Saltern, whereas the richness and diversity of bacterial community dominated by Proteobacteria, Bacteroidota and Cyanobacteria was considerably greater than that of fungal community dominated by Ascomycota, Basidiomycota and Mortierellomycota. Additionally, the succession of bacterial community was closely associated with both of salt physicochemical properties (Na+, Cl-, total phosphorus, total nitrogen, Ca2+ and Mg2+) and bacteria themselves, whereas fungal community was more closely associated with physicochemical properties than fungi themselves. Importantly, Cyanobium_PCC-6307, Synechococcus_CC9902, Marinobacter, Prevotella and Halomonas as dominant bacterial genera respectively related to the metabolisms of amino acid, carbohydrate, terpenoids/polyketides, lipid and nucleotide were correlated with salt flavors. Saprophytic and saprotroph-symbiotroph fungi dominated by Aspergillus, Mortierella, Amanita, Neocucurbitaria and Tausonia also played core roles in the formation of salt flavors including umami and sweet smells. These findings revealed the highly specified microbiome community in this 1000-year-old saltern that mainly selected by brine solarization on basalt platforms, which is helpful to explore the underlying mechanisms of traditional salt-making techniques and to explore the useful microbes for nowadays food, medicine and chemical industries.

Laterally spreading tumor-like primary rectal mucosa-associated lymphoid tissue lymphoma: A case report.

BACKGROUND: Colorectal mucosa-associated lymphoid tissue (MALT) lymphoma is a rare disease, and only a few cases have been reported to date. It has no specific clinical presentations and shows various endoscopic appearances. There is no uniform consensus on its treatment. With the advancement of endoscopic technology, endoscopic treatment has achieved better results in individual case reports of early-stage patients. CASE SUMMARY: We report a case of rectal MALT in a 57-year-old Chinese man with no symptoms who received endoscopy as part of a routine physical examination, which incidentally found a 25 mm × 20 mm, laterally spreading tumor (LST)-like elevated lesion in the rectum. Therefore, he was referred to our hospital for further endoscopic treatment. Complete and curable removal of the tumor was performed by endoscopic submucosal dissection. We observed enlarged and dilated branch-like vessels similar to those of gastric MALT lymphoma on magnifying endoscopy with narrow-band imaging. And immunopathological staining showed hyperplastic capillaries in the mucosa. Histopathological findings revealed diffusely hyperplastic lymphoid tissue in the lamina propria, with a visible lymphoid follicle structure surrounded by a large number of diffusely infiltrated lymphoid cells that had a relatively simple morphology and clear cytoplasm. In addition, immunohistochemical analysis suggested strongly positive expression for CD20 and Bcl-2. Gene rearrangement results showed positivity for IGH-A, IGH-C, IGK-B, and IGL. Taking all the above findings together, we arrived at a diagnosis of extranodal marginal zone B-cell lymphoma of MALT lymphoma. Positron emission tomography-computed tomography examination showed no other lesions involved. The patient will be followed by periodic endoscopic observation. CONCLUSION: In conclusion, we report a case of rectal MALT with an LST-like appearance treated by endoscopic submucosal dissection. Further studies will be needed to explore the clinical behavior, endoscopic appearance, and treatment of rectal MALT.

Pharmacokinetic bioequivalence and safety assessment of two metformin hydrochloride tablet formulations using a phase I, randomized, open, two-period, two cross-over, single-dose, fed study in healthy Chinese adult subjects.

OBJECTIVES: To assess the bioequivalence and safety of generic metformin hydrochloride (test preparation) and glucophage (reference preparation) in healthy Chinese subjects. MATERIALS AND METHODS: A bioequivalence and safety assessment of two formulations of metformin (850 mg) using a randomized, open, two-period, two cross-over, single-dose, fed trial in 36 healthy Chinese adult subjects was performed at our center from March 22, 2018, to April 9, 2018. Bioequivalence was determined as two-sided 90% confidence intervals (CI) of the test-to-reference ratio of area under the curve (AUC) and peak concentration (Cmax) for each constituent within 80.00 - 125.00%. SAS 9.4 software was employed for the statistical analysis. RESULTS: One subject was excluded from the trial. The 90% CIs (95.36 - 101.43% for AUC0→t, 95.65 - 101.66% for AUC0→∞; 94.43 - 101.74% for Cmax) of test/reference preparation for these pharmacokinetic parameters were within the range of 80.00 - 125.00%. No severe adverse events were observed during this trial. The two preparations were safe and well-tolerated. CONCLUSION: It was concluded that generic metformin was bioequivalent and as safe as glucophage under fed conditions in healthy Chinese subjects.

Exploring the cause of the inhibitor 4AX attaching to binding site disrupting protein tyrosine phosphatase 4A1 trimerization by molecular dynamic simulation.

Ectopic overexpression of protein tyrosine phosphatase of liver regeneration-1 (PTP4A1, also called PRL-1) markedly enhanced hepatocellular carcinoma (HCC) cells migration and invasion. The PTP4A1 trimerization played a vital role in mediating cell proliferation and motility. Biochemical and structural studies have proved that the compound 4AX, a well-known inhibitor for PRL1, directly binds to the PTP4A1 trimer interface and obstructs trimer formation of PTP4A1. However, the molecular basis of the ligand-4AX inhibition on PTP4A1 trimer conformations remains unclear. In this study, the docking analysis and the molecular dynamics simulation (MD simulation) study were performed to investigate how the molecule binding at each interface disrupted the trimer formation. The results suggested that the ligand-4AX attaching to the binding site changed the conformation of A:Q131, A:Q135 in the AC interface, C:R18, C:P96 in the CA interface and B:Q131 in the BA interface, leading to the weak interactions between subunits and thus resulting in the disruption of the PTP4A1 trimerization.