Marine natural products: potential agents for depression treatment.

Depression is a common psychiatric disorder. Due to the disadvantages of current clinical drugs, including poor efficacy and unnecessary side effects, research has shifted to novel natural products with minimal or no adverse effects as therapeutic alternatives. The ocean is a vast ecological home, with a wide variety of organisms that can produce a large number of natural products with unique structures, some of which have neuroprotective effects and are a valuable source for the development of new drugs for depression. In this review, we analyzed preclinical and clinical studies of natural products derived from marine organisms with antidepressant potential, including the effects on the pathophysiology of depression, and the underlying mechanisms of these effects. It is expected to provide a reference for the development of new antidepressant drugs.

Pharmacokinetics, mass balance, and metabolism of [14C]envonalkib (TQ-B3139), a novel ALK tyrosine kinase inhibitor, in healthy Chinese subjects.

PURPOSE: Envonalkib (TQ-B3139) is a novel, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used to treat ALK-positive non-small cell lung cancer. This phase I mass balance study investigated the pharmacokinetics, metabolism, and excretion of 14C-radiolabeled envonalkib in healthy Chinese male subjects. METHODS: A single oral dose of 600 mg (150 µCi) [14C]envonalkib was administered to healthy male subjects under fasted state. Samples of blood, urine and feces were collected for quantitative determination of total radioactivity and unchanged envonalkib, and the metabolites identification. RESULTS: After dosing, the median Tmax of radioactivity was 4 h and the mean t1/2 was 65.2 h in plasma. The exposure of total radioactivity was much higher than that of unchanged envonalkib in plasma. The mean total recovery of the radiolabeled dose was 93.93% over 504 h post-dose, with 15.23% in urine and 78.71% in feces. Envonalkib underwent extensive metabolism and a total of 15 metabolites were identified in plasma, urine, and feces. Unchanged envonalkib and its major metabolite M315 were the main components in plasma, accounting for 20.37% and 33.33% of total plasma radioactivity. In urine, O-dealkylation metabolite M315 was the major component accounted for 7.98% of dose. In feces, 16.01% of dose was excreted as cysteine conjugate M434-1. Envonalkib was well tolerated and there were no serious adverse events observed in the study. CONCLUSION: Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces.

Burnout and associative emotional status and coping style of healthcare workers in COVID-19 epidemic control: A cross-sectional study.

Objective: The aim of this study was to evaluate the prevalence of burnout, clinical anxiety, depression, and insomnia and to estimate the associations of adverse emotional status, coping style, and level of self-efficacy with burnout of healthcare workers in the Shenzhen Longgang District Frontline District Headquarters of COVID-19 epidemic control, China. Methods: In this cross-sectional study, 173 staff completed the anonymous questionnaires of the Maslach Burnout Inventory, Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7-item Scale (GAD-7), Insomnia Severity Index (ISI), General Self-efficacy Scale, and Simplified Coping Style Questionnaire electronically (https://www.wjx.cn/) in June 2022. Hierarchical logistic regression was used to explore the associated factors of burnout in this study. Results: The prevalence of burnout in our participants (defined as high emotional exhaustion or high depersonalization) was 47.40%, and reduced personal accomplishment was 92.49%. The prevalence of clinically significant depression (the cutoff score of ≥15), anxiety (the cutoff score of ≥10), and insomnia (the cutoff score of ≥15) was 11.56, 19.08, and 19.08%, respectively. There was a degree of overlap between burnout and other measures of adverse mental status, most notably for anxiety (odds ratio, 27.049; 95% CI, 6.125-117.732; p < 0.001). Hierarchical logistic regression demonstrated that burnout was strongly associated with anxiety (OR = 23.889; 95% CI, 5.216-109.414; p < 0.001) and negative coping style (OR = 1.869; 95% CI, 1.278-2.921; p < 0.01) independently. Conclusion: Medical staff involved in COVID-19 epidemic control in the post-epidemic era were at high risk of burnout, and most of them were in low personal accomplishment. Reducing anxiety and improving coping style by medical management institutions from the system level may be effective in alleviating burnout in healthcare workers.

First-in-human phase I study of TQ-B3139 (CT-711) in advanced non-small cell lung cancer patients with ALK and ROS1 rearrangements.

BACKGROUND: TQ-B3139 is a novel ALK tyrosine kinase inhibitor (TKI) against a broad range of ALK mutations. The aim of this first-in-human phase I trial was to investigate the safety, tolerability, pharmacokinetics, and clinical efficacy of TQ-B3139 in ALK or ROS1 positive advanced NSCLC patients. METHODS: Following a 3 + 3 design, patients received escalating daily dose of TQ-B3139 (50-800 mg) continuously in 28-day cycles. Expansion stage started at dose of 200 mg twice daily (BID). The primary objectives were the safety, dose-limited toxicities (DLT) and recommended phase II dose (RP2D); secondary objectives included pharmacokinetics and antitumor activity. Non-obligatory tumor samples at baseline were collected and sequenced. RESULTS: The study enrolled 63 patients. Fifty-nine (93.4%) patients experienced treatment-related adverse events (TRAEs), mostly grade 1-2 vomiting (79.3%), diarrhea (76.1%) or nausea (68.2%). 1 (1/6) DLT occurred at 600 mg BID and 1 (1/3) at 800 mg BID. Based on safety and pharmacokinetics data, the RP2D was selected as 600 mg BID. At a dose level ≥200 mg BID, the overall response rate (ORR) was 76.7% (33/43), and the median progression free survival (mPFS) was 25.2 months (95%CI 11.9-NR) for TKI-naive patients. For TKI-treated patients, the ORR was 37.5% (6/16), and the mPFS was 5.4 months (95%CI 3.6-9.1). The ORR was 66.7% (2/3) in patients with ROS1 fusion at dose level ≥200 mg BID. In patients with measurable brain metastases, the intracranial ORR was 70% (7/10), with median intracranial PFS of 15.9 months. In TKI-treated patients, variant 3 and TP53 alteration were associated with poor PFS. CONCLUSIONS: TQ-B3139 was well-tolerated and exhibited promising anti-tumor activities in patients with ALK and ROS1 positive advanced NSCLC. CLINICAL TRIAL NUMBER: NCT03099330.

Depressive, anxiety, and insomnia symptoms between population in quarantine and general population during the COVID-19 pandemic: a case-controlled study.

BACKGROUND: The COVID-19 pandemic have caused mental and psychological problems on the general population, patients, and related workers. Our study is to determine the impact of mental and psychological symptoms among population in quarantine for 2 weeks during COVID-19 pandemic. METHODS: A case-controlled study design have conducted at department of psychiatry of Shenzhen Longgang Center for Chronic Disease Control in Shenzhen, China mainland from 7th April to 15th June 2020.1674 participants (aged 18 to 65 years) in quarantine for 2 weeks and 1743 age-sex matched controls living in Shenzhen were recruited between 7th April 2020 and 15th June 2020. The assessment of depressive, anxiety, and insomnia symptoms were determined by self-reported questionnaires PHQ-9, GAD-7, and ISI, respectively. RESULTS: A total of 1674 participants in quarantine for 2 weeks and 1743 age-sex matched controls (32.6 ± 9.3 years vs. 32.7 ± 10.7 years, 49.8% vs. 47.8% females) were recruited. Population in quarantine had higher score on PHQ-9 (6.1 ± 5.5 vs. 3.0 ± 3.7, p < 0.001), GAD-7 (4.2 ± 4.7 vs. 1.9 ± 3.7, p < 0·001), and ISI (5.5 ± 5.8 vs. 3.1 ± 5.0%, p < 0.001) compared to general population. Population in quarantine showed significantly higher risks of depression (OR: 4.55, 95% CI: 3.82-5.41), anxiety (OR: 2.92, 95% CI: 2.43-3.51), and insomnia (OR: 2.40, 95% CI: 2.02-2.89), when compared to the general population. Younger, more education, non-married and lower household income showed higher risks of mental health problems. CONCLUSIONS: Population in quarantine had a higher level of depressive, anxiety, and insomnia symptoms than controls. Specifically, they were at a higher risk prevalence of depression, anxiety, and insomnia, especially the severity of depression, when compared to controls. Younger, more education, non-married, and lower income population in quarantine were at higher risks of mental health problems. Mental health professionals should pay attention to the mental and psychological symptoms for population in quarantine.

Longitudinal Pharmacometabonomics for Predicting Malignant Tumor Patient Responses to Anlotinib Therapy: Phenotype, Efficacy, and Toxicity.

Anlotinib is an oral small molecule inhibitor of multiple receptor tyrosine kinases (RTKs), which was approved by the National Medical Products Administration (NMPA) of China in 2018 for the third-line treatment of non-small cell lung cancer (NSCLC). Here, for the first time, the longitudinal pharmacometabonomics was explored for predicting malignant tumor patient responses to anlotinib, including the metabolic phenotype variation, drug efficacy, and toxicity. A total of 393 plasma samples from 16 subjects collected from a phase I additional study of anlotinib (NCT02752516) were submitted to targeted metabolomics analysis. The orthogonal partial least-squares discriminant analysis (OPLS-DA) models were constructed for the predication of anlotinib efficacy and toxicity based on the longitudinal pharmacometabonomics data. Statistical results showed that 38 metabolites, mainly involved in aminoacyl-tRNA biosynthesis, alanine, aspartate, and glutamate metabolism, and steroid hormone biosynthesis, were all significantly upregulated attributing to anlotinib treatment. The anti-tumor efficacy and occurrence of proteinuria after anlotinib administration can be predicted with 100% accuracy using the established OPLS-DA models. Glycodeoxycholic acid and glycocholic acid possessed the most excellent sensitivity and specificity in predicting the efficacy of anlotinib, with area under the receiver operating characteristic curve (AUC of ROC curve) 0.847 and 0.828, respectively. NG, NG-dimethylarginine was the most promising biomarker for the prediction of proteinuria occurrence after anlotinib administration, with AUC of ROC curve 0.814. In conclusion, this work developed efficient and convenient discriminant models that can accurately predict the efficacy and toxicity of anlotinib based on longitudinal pharmacometabonomics study.