Bacterial Flagellum-Drug Nanoconjugates for Carrier-Free Immunochemotherapy.

The combination of immunotherapy and chemotherapy to ablate tumors has attracted substantial attention due to the ability to simultaneously elicit antitumor immune responses and trigger direct tumor cell death. However, conventional combinational strategies mainly focus on the employment of drug carriers to deliver immunomodulators, chemotherapeutics, or their combinations, always suffering from complicated preparation and carrier-relevant side effects. Here, the fabrication of bacterial flagellum-drug nanoconjugates (FDNCs) for carrier-free immunochemotherapy is described. FDNCs are simply prepared by attaching chemotherapeutics to amine residues of flagellin through an acid-sensitive and traceless cis-aconityl linker. By virtue of native nanofibrous structure and immunogenicity, bacterial flagella not only show long-term tumor retention and highly efficient cell internalization, but also provoke robust systemic antitumor immune responses. Meanwhile, conjugated chemotherapeutics exhibit an acid-mediated release profile and durable intratumoral exposure, which can induce potent tumor cell inhibition via direct killing. More importantly, this combination is able to augment immunoactivation effects associated with chemotherapy-enabled immunogenic tumor cell death to further enhance antitumor efficacy. By leveraging the innate response of the immune system to pathogens, the conjugation of therapeutic agents with self-adjuvant bacterial flagella provides an alternative approach to develop carrier-free nanotherapeutics for tumor immunochemotherapy.

Methylomonas defluvii sp. nov., a type I methane-oxidizing bacterium from a secondary sedimentation tank of a wastewater treatment plant.

An aerobic methanotroph was isolated from a secondary sedimentation tank of a wastewater treatment plant and designated strain OY6T. Cells of OY6T were Gram-stain-negative, pink-pigmented, motile rods and contained an intracytoplasmic membrane structure typical of type I methanotrophs. OY6T could grow at a pH range of 4.5-7.5 (optimum pH 6.5) and at temperatures ranging from 20 °C to 37 °C (optimum 30 °C). The major cellular fatty acids were C14 : 0, C16 : 1ω7c/C16 : 1ω6c and C16 : 1ω5c; the predominant respiratory quinone was MQ-8. The genome size was 5.41 Mbp with a DNA G+C content of 51.7 mol%. OY6T represents a member of the family Methylococcaceae of the class Gammaproteobacteria and displayed 95.74-99.64 % 16S rRNA gene sequence similarity to the type strains of species of the genus Methylomonas. Whole-genome comparisons based on average nucleotide identity (ANI) and digital DNA-DNA hybridisation (dDDH) confirmed that OY6T should be classified as representing a novel species. The most closely related type strain was Methylomonas fluvii EbBT, with 16S rRNA gene sequence similarity, ANI by blast (ANIb), ANI by MUMmer (ANIm) and dDDH values of 99.64, 90.46, 91.92 and 44.5 %, respectively. OY6T possessed genes encoding both the particulate methane monooxygenase enzyme and the soluble methane monooxygenase enzyme. It grew only on methane or methanol as carbon sources. On the basis of phenotypic, genetic and phylogenetic data, strain OY6T represents a novel species within the genus Methylomonas for which the name Methylomonas defluvii sp. nov. is proposed, with strain OY6T (=GDMCC 1.4114T=KCTC 8159T=LMG 33371T) as the type strain.

Surface-modified bacteria: synthesis, functionalization and biomedical applications.

The past decade has witnessed a great leap forward in bacteria-based living agents, including imageable probes, diagnostic reagents, and therapeutics, by virtue of their unique characteristics, such as genetic manipulation, rapid proliferation, colonization capability, and disease site targeting specificity. However, successful translation of bacterial bioagents to clinical applications remains challenging, due largely to their inherent susceptibility to environmental insults, unavoidable toxic side effects, and limited accumulation at the sites of interest. Cell surface components, which play critical roles in shaping bacterial behaviors, provide an opportunity to chemically modify bacteria and introduce different exogenous functions that are naturally unachievable. With the help of surface modification, a wide range of functionalized bacteria have been prepared over the past years and exhibit great potential in various biomedical applications. In this article, we mainly review the synthesis, functionalization, and biomedical applications of surface-modified bacteria. We first introduce the approaches of chemical modification based on the bacterial surface structure and then highlight several advanced functions achieved by modifying specific components on the surface. We also summarize the advantages as well as limitations of surface chemically modified bacteria in the applications of bioimaging, diagnosis, and therapy and further discuss the current challenges and possible solutions in the future. This work will inspire innovative design thinking for the development of chemical strategies for preparing next-generation biomedical bacterial agents.

Sensitive and rapid detection of tet(X2) ~ tet(X5) by loop-mediated isothermal amplification based on visual OTG dye.

The emergence of tigecycline-resistant tet(X2/X3/X4/X5) genes poses a new threat to the efficacy of anti-infective therapy and the safety of our food and environment. To control the transfer of such genes, a sensitive and rapid molecular method is warranted to detect tet(X2/X3/X4/X5) genes in clinical isolates. Herein, we established a loop-mediated isothermal amplification (LAMP) assay to rapidly detect tet(X2/X3/X4/X5) genes, and the results were assessed by chromogenic visualization. The specificity and sensitivity of the primers during the LAMP assay for the simultaneous detection of tet(X2/X3/X4/X5) genes were determined in this study. All 48 clinical strains without tet(X2/X3/X4/X5) genes yielded negative results during the LAMP assay, substantiating the high specificity of the LAMP primers. The detection thresholds of this assay were 1.5 × 102 CFU/ml and 0.2 fg/uL corresponding to a 10 to 100-fold and 100-fold increase in sensitivity compared to polymerase chain reaction (PCR) assays. Out of 52 bacterial strains tested, using PCR as a reference, our research revealed that the LAMP assay demonstrated a sensitivity and specificity of 100%. To sum up, our novel approach has huge prospects for application in the simultaneous detection of tet(X2/X3/X4/X5) genes and can be applied to detect other drug-resistance genes.

LncRNA CYP4A22-AS1 promotes the progression of lung adenocarcinoma through the miR-205-5p/EREG and miR-34c-5p/BCL-2 axes.

OBJECTIVES: Lung adenocarcinoma (LUAD) exhibits a higher fatality rate among all cancer types worldwide, yet the precise mechanisms underlying its initiation and progression remain unknown. Mounting evidence suggests that long non-coding RNAs (lncRNAs) exert significant regulatory roles in cancer development and progression. Nevertheless, the precise involvement of lncRNA CYP4A22-AS1 in LUAD remains incompletely comprehended. METHODS: Bioinformatics analyses evaluated the expression level of CYP4A22-AS1 in lung adenocarcinoma and paracancer. The LUAD cell line with a high expression of CYP4A22-AS1 was constructed to evaluate the role of CYP4A22-AS1 in the proliferation and metastasis of LUAD by CCK8, scratch healing, transwell assays, and animal experiments. We applied transcriptome and microRNA sequencing to examine the mechanism of CYP4A22-AS1 enhancing the proliferation and metastasis of LUAD. Luciferase reporter gene analyses, west-blotting, and qRT-PCR were carried out to reveal the interaction between CYP4A22-AS1, miR-205-5p/EREG, and miR-34c-5p/BCL-2 axes. RESULTS: CYP4A22-AS1 expression was significantly higher in LUAD tissues than in the adjacent tissues. Furthermore, we constructed a LUAD cell line with a high expression of CYP4A22-AS1 and noted that the high expression of CYP4A22-AS1 significantly enhanced the proliferation and metastasis of LUAD. We applied transcriptome and microRNA sequencing to examine the mechanism of CYP4A22-AS1 enhancing the proliferation and metastasis of LUAD. CYP4A22-AS1 increased the expression of EREG and BCL-2 by reducing the expression of miR-205-5p and miR-34-5p and activating the downstream signaling pathway of EGFR and the anti-apoptotic signaling pathway of BCL-2, thereby triggering the proliferation and metastasis of LUAD. The transfection of miR-205-5p and miR-34-5p mimics inhibited the role of CYP4A22-AS1 in enhancing tumor progression. CONCLUSION: This study elucidates the molecular mechanism whereby CYP4A22-AS1 overexpression promotes LUAD progression through the miR-205-5p/EREG and miR-34c-5p/BCL-2 axes.

Raw Pinelliae Rhizoma: examination of sedative and hypnotic effects in mice and chemical analysis.

PURPOSE: Raw "Pinelliae Rhizoma" (RPR) is widely used in Chinese clinics to treat insomnia. This study investigated its underlying sedative and hypnotic mechanisms and main active components. METHODS: A locomotor activity test was used to evaluate the sedative effects of RPR at three dosages (0.2 g/mL, 0.4 g/mL, and 0.8 g/mL) in mice. Polysomnography was used to assess its ability to improve sleep. Ultra-performance liquid chromatography/time of flight/mass spectrometry (UPLC-TOF-MS) analysis was used to identify the potential active components of RPR. RESULTS: Mice in the RPR groups were less active than mice in the vehicle group; this difference was greatest in the 0.8 g/mL RPR group. Compared with the vehicle, 0.8 g/mL RPR increased the duration of rapid eye movement (REM) sleep in the dark phase. In addition, the duration of wakefulness in the 0.8 g/mL RPR group decreased with increasing durations of nonrapid eye movement (NREM) and REM sleep. Compared with diazepam, 0.8 g/mL RPR increased REM sleep duration in both the light and dark phases and increased the number of transitions both from NREM sleep to REM sleep and from REM sleep to wakefulness. A total of 33 RPR constituents, including 15 alkaloids, were identified. CONCLUSION: The results preliminarily indicated that RPR exerts sedative and hypnotic effects in mice, mainly leading to improvements in REM sleep. These effects are possibly due to the alkaloid constituents of RPR.

Treatment and economic burden of mucormycosis in China: Case report review and burden estimation.

WHAT IS KNOWN AND OBJECTIVE: Mucormycosis is an opportunistic fungal infection associated with low incidence but high mortality. Few studies have shown the treatment and disease burden of mucormycosis in China. This study aims at collecting all the reported cases to describe the characteristics and treatment patterns and to assess the economic burden of mucormycosis in China. METHODS: We conducted a literature review of mucormycosis case reports in Chinese patients to summarize the characteristics and treatment patterns of the disease in China. An economic model was built to evaluate the total cost of mucormycosis per person, including direct medical cost, direct non-medical cost and indirect cost. RESULTS AND DISCUSSION: A total of 676 case reports showed that the most common type of mucormycosis was pulmonary mucormycosis (299/676, 44.2%), and rhinocerebral mucormycosis had the highest case fatality rate (122/185, 68.5%). Among those who used empiric therapies, 48.8% (231/473) did not include anti-mucor drugs; 79.8% (336/421) of the therapies include amphotericin B (AMB) or AMB-lipo after detection of mucormycetes; 98.6% (69/70) of the reported adverse events were associated with AMB and AMB-lipo. The duration of treatment ranged from 90 to 180 days; the length of stay ranged from 22 to 95 days. The average total cost per patient was 166 thousand Chinese Yuan (CNY), of which 93.1% was the direct medical cost (155 thousand CNY). WHAT IS NEW AND CONCLUSION: There are a limited number of antifungal treatment options for mucormycosis in China. This study highlights the critical need to introduce innovative and broader spectrum antifungal drugs with improved safety, better clinical efficacy, easier administration and reduced economic burden to Chinese mucormycosis patients.

Decorating Bacteria with Triple Immune Nanoactivators Generates Tumor-Resident Living Immunotherapeutics.

An approach of decorating bacteria with triple immune nanoactivators is reported to develop tumor-resident living immunotherapeutics. Under cytocompatible conditions, tumor-specific antigens and checkpoint blocking antibodies are simultaneously conjugated onto bacterial surface and then polydopamine nanoparticles are formed via in situ dopamine polymerization. In addition to serving as a linker, polydopamine with its photothermal effect can repolarize tumor-associated macrophages to a pro-inflammatory phenotype. The linked antigens promote the maturation of dendritic cells and generate tumor-specific immune responses, while the anchored antibodies block immune checkpoints and activate cytotoxic T lymphocytes. Decorated bacteria show spatiotemporal tumor retention and proliferation-dependent drug release, achieving potent antitumor effects in two antigen-overexpressing tumor models. This work provides a versatile platform to prepare multimodal and long-acting therapeutics for cancer immunotherapy.

Decorating Bacteria with a Therapeutic Nanocoating for Synergistically Enhanced Biotherapy.

Disorders in the gut microbiota have been implicated in various diseases, such as inflammatory bowel diseases, diabetes, and cancers. Oral microecologics are of great importance due to their ability to directly intervene the gut microbiome as well as their noninvasiveness and low side effects, while have suffered from low bioavailability and a single therapeutic effect. Here, probiotics are coated with a therapeutic nanocoating for synergistically enhanced biotherapy, a method inspired by the robust protective and therapeutic effectiveness of silkworm cocoon. With its transition from a random coil to ß-sheet conformation, silk fibroin can self-assemble onto the surface of bacteria. By a simple layer-by-layer procedure, an entire nanocoating can be formed along with a near quantitative coating ratio and almost uninfluenced bacterial viability. Thanks to its protective barrier role and innate pharmaceutical activity, silk fibroin nanocoating endows the coated bacteria with a markedly improved survival against gastric insults and a synergistically enhanced therapeutic effect in a murine model of intestinal mucositis. This work demonstrates how therapeutic elements can be combined with probiotics via a simple coating strategy and proposes an alternative to enhance bioavailability and treatment efficacy of oral microecologics.

Identification of 5S and 45S rDNA sites in Chrysanthemum species by using oligonucleotide fluorescence in situ hybridization (Oligo-FISH).

Fluorescence in situ hybridization (FISH) is a conventional method used to visualize the distribution of DNA elements within a genome. To examine the relationships within the Chrysanthemum genus, ribosomal DNA (rDNA), a popular cytogenetic marker, was utilized as a probe for FISH within this genus. Based on the genome data of Chrysanthemum nankingense, C. seticuspe and its allied genera in the Compositae(Asteraceae), we explored rDNA sequences to design oligonucleotide probes and perform oligonucleotide fluorescence in situ hybridization (Oligo-FISH) in eight Chrysanthemum accessions. The results showed that the majority of 5S rDNA signals were located in subterminal chromosome regions and that the number of 5S rDNA sites might be tightly associated with ploidy. For 45S rDNA sites, the number and intensity of signals differed from those of previously investigated Chrysanthemum resources. These findings may provide an optimally reliable method of examining the chromosome composition and structural variation of Chrysanthemum and its related species and allow researchers to understand the evolutionary history and phylogenetic relationships of Chrysanthemum.

Experimental postoperative ileus: is Th2 immune response involved?

Rationale: Postoperative ileus (POI) is a frequent complication arising after gastrointestinal surgery but pathogenesis of POI is still not fully understood. While Th1 immune cells are implicated in POI, the involvement of Th2 cells has not yet been clarified. Given the impact of reactive oxygen species (ROS) in the regulation of Th1 and Th2 balance, we hypothesized that not only Th1 but also Th2 immune response can be involved in the development of experimental POI. Methods: The intestinal transit test was performed using carbon gum arabic. Electron microscopy was employed to assess tissue morphology and the presence of immune cells. Cytokines, IgE and ROS were measured. Immune cells from Peyer's patches were analyzed by Flow Cytometry and toluidine blue staining was used for detection of mast cells. Transcriptional factors were analyzed by Western blot. Results: POI is associated with an increase in both Th2 cytokines and Th2 cells. We have further demonstrated that POI induces a Th2-dependent activation of memory and non-memory B cells. This was accompanied by an increase in a number of mast cells in the colon of POI mice as well by an increased IgE and histamine plasma levels. We found that POI-induced accumulation of ROS was associated with an increased expression of the transcriptional factors HMBGI, NF-κB, and p38. This increased expression seemed to be associated with a Th2 response. Conclusion: Th2 immune response can be involved in the activation of mast cells in POI, which was associated with ROS mediated activation of NF-κB and p38 MAPK signaling pathway.

Evaluation of pharmacokinetics and safety with bioequivalence of Amlodipine in healthy Chinese volunteers: Bioequivalence Study Findings.

BACKGROUND AND OBJECTIVE: Amlodipine, a main series of L-type calcium channel blockers (CCBs), exerts potent antihypertensive effects. The aim of this trial was to explore the pharmacokinetics (PK) and safety with bioequivalence of orally administered Amlodipine provided by two sponsors in healthy volunteers (HVs). METHODS: Two separate randomized, open-label, single-dose, crossover-design studies were conducted: a fasting study (n = 24) and a fed study (n = 24). In each study, HVs were randomized to Fangming Pharmaceutical Group (Test, T) followed by NORVASC® (Reference, R), or vice versa. Each study subject received a 5-mg Amlodipine tablet with a 15-day washout. The plasma concentrations of Amlodipine were measured using a LC-MS/MS method, and PK parameters were determined by noncompartmental model. RESULTS: Forty-eight healthy volunteers were enrolled. And overall demographics were as follows: the fasting study: female (n = 16/24), age (18-54 years), weight (47-76 kg), and BMI (19.5-26.0). The fed study: female (n = 16/24), age (20-49 years), weight (45.5-69 kg), and BMI (19.1-25.0). All PK endpoints met the pre-specific criteria for PK equivalence. In fasting subjects, the maximum plasma concentration (Cmax ) was 3.881 ± 0.982 ng/mL at 6 hours (median) of sponsor T, and 4.042 ± 1.147 ng/mL at 6 hours (median) of sponsor R. In fed subjects, Cmax was 3.312 ± 0.789 ng/mL at 6 hours (median) of sponsor T, and 3.392 ± 0.902 ng/mL at 5 hours (median) of sponsor R. Both fasting and fed studies achieved a plausible bioequivalence. CONCLUSIONS: Amlodipine is well tolerated and have a favorable safety profile. The observed adverse events were mild (the severity was assessed according to the Common Terminology Criteria for Adverse Events [version CTCAE4.03]) and all of them were recovered without severe sequences. And the bioequivalence is achieved under fasting and fed conditions, supporting the demonstration of biosimilarity.

Reactive oxygen species and colorectal cancer.

Colorectal cancer (CRC) has become the fourth leading cause of cancer-related death in the worldwide. It is urgent to find more effective therapeutic strategies for it. Reactive oxygen species (ROS) play multiple roles in normal cellular physiology processes. Thus, a certain level of ROS is essential to keep normal cellular function. However, the accumulation of ROS shows dual roles for cells, which is mainly dependent on the concentration of ROS, the origin of the cancer cell and the activated signaling pathways during tumor progression. In general, moderate level of ROS leads to cell damage, DNA mutation and inflammation, which promotes the initiation and development of cancer. Excessive high level of ROS induces cancer cell death, showing an anti-cancer role. ROS are commonly higher in CRC cells than their normal counterpart cells. Therefore, it is possible that ROS induce cell death in cancer cells while not affecting the normal cells, demonstrating lower side effects. Besides, ROS also play a role in tumor microenvironment and drug resistance. These multiple roles of ROS make them a promising therapeutic target for cancer. To explore potential ROS-target therapies against CRC, it is worth to comprehensively understanding the role of ROS in CRC and therapy. In this review, we mainly discuss the strategies of ROS in CRC therapy, including direct CRC cell target and indirect tumor environment target. In addition, the influences of ROS in drug resistance will also been discussed.

Psychiatric diagnoses and their influencing factors in patients complaining of sleep problems: A study of a psychiatric consultation-liaison service.

Objective This study aimed to identify misdiagnosed or undiagnosed psychiatric disorders and the factors associated with these disorders in patients with sleep problems who are referred to a consultation-liaison service. Method Records of all inpatients receiving a consultation from the Psychiatry Department between January and December 2016 were retrospectively reviewed. Psychiatric diagnoses were analyzed using descriptive statistics, and the factors associated with the risk of these disorders in patients with sleep problems were determined by multiple logistic regression analysis. Results Of the 331 referral patients whose referral reason was simply having trouble in sleeping, only 97 patients were diagnosed with primary sleep disorder after consultation. The recognition rate of psychiatric disorders in inpatients with sleep problems among nonpsychiatric physicians was 29.3%. Anxiety (107, 45.7%) was the most common psychiatric diagnosis in patients with sleep problems followed by organic mental disorder (83, 35.5%), depression (37, 15.8%), and other mental disorders (8, 3.4%). Multiple logistic regression analysis revealed that a course >1 month (OR = 3.656, 95% CI = 2.171-6.156, p = 0.000) and sleep-wake rhythm disturbances (OR = 25.008, 95% CI = 5.826-107.341, p = 0.000) were associated with increased risks of psychiatric disorders. Conclusions The study showed that recognition rate of psychiatric disorders in inpatients with sleep problems was very low. A course >1 month and sleep-wake rhythm disturbances were associated with increased risks of disorders and could be used as indicators by nonpsychiatric physicians to improve diagnoses.

The Anti-Inflammatory Effect and Intestinal Barrier Protection of HU210 Differentially Depend on TLR4 Signaling in Dextran Sulfate Sodium-Induced Murine Colitis.

BACKGROUND: Ulcerative colitis (UC) is strongly associated with inflammation and intestinal barrier disorder. The nonselective cannabinoid receptor agonist HU210 has been shown to ameliorate inflamed colon in colitis, but its effects on intestinal barrier function and extraintestinal inflammation are unclear. AIMS: To investigate the effects and the underlying mechanism of HU210 action on the UC in relation to a role of TLR4 and MAP kinase signaling. METHODS: Wild-type (WT) and TLR4 knockout (Tlr4 -/-) mice were exposed to 4% dextran sulfate sodium (DSS) for 7 days. The effects of HU210 on inflammation and intestinal barrier were explored. RESULTS: Upon DSS challenge, mice suffered from bloody stool, colon shortening, intestinal mucosa edema, pro-inflammatory cytokine increase and intestinal barrier destruction with goblet cell depletion, increased intestinal microflora accompanied with elevated plasma lipopolysaccharide, reduced mRNA expression of the intestinal tight junction proteins, and abnormal ratio of CD4+/CD8+ T cells in the intestinal Peyer's patches. Pro-inflammatory cytokines in the plasma and the lung, as well as pulmonary myeloperoxidase activity, indicators of extraintestinal inflammation were increased. Protein expression of p38α and pp38 was up-regulated in the colon of WT mice. Tlr4 -/- mice showed milder colitis. HU210 reversed the intestinal barrier changes in both strains of mice, but alleviated inflammation only in WT mice. CONCLUSIONS: Our study indicates that in experimental colitis, HU210 displays a protective effect on the intestinal barrier function independently of the TLR4 signaling pathway; however, in the extraintestinal tissues, the anti-inflammatory action seems through affecting TLR4-mediated p38 mitogen-activated protein kinase pathway.

BIG1, a brefeldin A-inhibited guanine nucleotide-exchange protein modulates ATP-binding cassette transporter A-1 trafficking and function.

OBJECTIVE: Cell-surface localization and intracellular trafficking are essential for the function of ATP-binding cassette transporter A-1 (ABCA1). However, regulation of these activities is still largely unknown. Brefeldin A, an uncompetitive inhibitor of brefeldin A-inhibited guanine nucleotide-exchange proteins (BIGs), disturbs the intracellular distribution of ABCA1, and thus inhibits cholesterol efflux. This study aimed to define the possible roles of BIGs in regulating ABCA1 trafficking and cholesterol efflux, and further to explore the potential mechanism. METHODS AND RESULTS: By vesicle immunoprecipitation, we found that BIG1 was associated with ABCA1 in vesicles preparation from rat liver. BIG1 depletion reduced surface ABCA1 on HepG2 cells, and inhibited by 60% cholesterol release. In contrast, BIG1 overexpression increased surface ABCA1 and cholesterol secretion. With partial restoration of BIG1 through overexpression in BIG1-depleted cells, surface ABCA1 was also restored. Biotinylation and glutathione cleavage revealed that BIG1 small interfering RNA dramatically decreased the internalization and recycling of ABCA1. This novel function of BIG1 was dependent on the guanine nucleotide-exchange activity and achieved through activation of ADP-ribosylation factor 1. CONCLUSIONS: BIG1, through its ability to activate ADP-ribosylation factor 1, regulates cell-surface levels and function of ABCA1, indicating a transcription-independent mechanism for controlling ABCA1 action.

Safety, Tolerability, and Pharmacokinetics of Voriconazole for Injection in Two Preparations in Chinese Healthy Adult Volunteers.

Voriconazole is a second-generation, synthetic, triazole antifungal drug based on the structure of fluconazole. We compared the safety, tolerability, and pharmacokinetic characteristics of voriconazole for injection (200 mg) manufactured by at a dose of 6 mg/kg in Chinese healthy adult volunteers. This was a single-center, randomized, open, 2-preparation, single-dose, 2-period, 2-sequence, crossover bioequivalence clinical trial. Twenty-four eligible, healthy, male, and female volunteers were assigned randomly to one of 2 dose-sequence groups (test-reference group or reference-test group) in a 1:1 block. The voriconazole concentration in plasma was determined by protein precipitation and high-performance liquid chromatography-tandem mass spectrometry. The main PK parameters were calculated on the basis of a noncompartmental model. The ratio of the geometric mean of the maximum plasma drug concentration, area under the plasma concentration-time curve from time 0 to the last time of quantifiable concentration, and area under the plasma concentration-time curve from time 0 to infinity of the test preparation, and the reference preparation was 100.4%, 102%, and 102.2%, respectively. The 90% confidence intervals were between 80% and 125%, indicating that the 2 preparations were bioequivalent. The adverse events experienced by healthy adult volunteers were mild. Both preparations had a good safety profile.

Bioequivalence Study of Tebipenem Pivoxil in Healthy Chinese Adults.

BACKGROUND AND OBJECTIVE: Tebipenem pivoxil (TP) is a carbapenem and is applied against pneumonia, otitis media, and sinusitis. This study compared the pharmacokinetics (PK) and safety of a test (T) preparation and reference (R) preparation of TP in healthy Chinese adults. METHODS: This study was a single-center, randomized, open, single-dose (fasting/postprandial) oral administration, two-agent, two-sequence, two-cycle, crossover bioequivalence trial. A total of 60 participants were enrolled (24 fasting and 36 postprandial). All participants were randomly assigned to the TR sequence and RT sequence. Subsequently, they switched T sequences or R sequences 7 days later. PK blood samples were collected according to the protocol, plasma TP concentration was determined by liquid chromatography-mass spectrometry, main PK parameters were calculated based on a non-compartment model, and adverse events were recorded during the test. RESULTS: In the feeding arm, the geometric mean ratio of maximum concentration (Cmax) was 89.84% (90% confidence interval 84.33-95.70), the geometric mean ratio of area under the plasma concentration-time curve from time 0 to last time of quantifiable concentration (AUC0-t) was 86.80% (83.62-90.10), and the geometric mean ratio of area under the plasma concentration-time curve from time 0 to infinity time of quantifiable concentration (AUC0-∞) was 86.90% (83.73-90.20), which were within the acceptable range of bioequivalence (80-125%). In the fasting arm, the geometric mean ratio of Cmax was 96.07% (89.62-102.99), the geometric mean ratio of AUC0-t was 93.09% (90.47-95.78), and the geometric mean ratio of AUC0-∞ was 93.09% (90.48-95.77), which was within the acceptable range of bioequivalence (80-125%). Hence, the T preparation and R preparation of TP had bioequivalence in the fasting arm and feeding arm of the clinical trial. In addition, all adverse events were mild, and no severe adverse events were noted. CONCLUSION: Preparations T and R of TP were bioequivalent in the fasting and postprandial groups in clinical trials, and TP was safe.

A real-world pharmacovigilance study of FDA adverse event reporting system events for Capmatinib.

Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world evidence is very limited, this study evaluated capmatinib-induced adverse events through data mining of the FDA Adverse Event Reporting System database. Four disproportionality analysis methods were employed to quantify the signals of capmatinib-related adverse events. The difference in capmatinib-associated adverse event signals was further investigated with respect to sex, age, weight, dose, onset time, continent, and concomitant drug. A total of 1518 reports and 4278 adverse events induced by capmatinib were identified. New significant adverse event signals emerged, such as dysphagia, dehydration, deafness, vocal cord paralysis, muscle disorder, and oesophageal stenosis. Notably, higher risk of alanine aminotransferase and aspartate aminotransferase increases were observed in females, especially when capmatinib was combined with immune checkpoint inhibitors. Compared with Europeans and Asians, Americans were more likely to experience peripheral swelling, especially in people > 65 years of age. Renal impairment and increased blood creatinine were more likely to occur with single doses above 400 mg and in Asians. This study improves the understanding of safety profile of capmatinib.