In vitro pharmacokinetic behavior in lung of harringtonine, an antagonist of SARS-CoV-2 associated proteins: New insights of inhalation therapy for COVID-19.

BACKGROUND: Recent studies have shown that harringtonine (HT) could specifically bind with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein and host cell transmembrane serine protease 2 (TMPRSS2) to block membrane fusion, which is an effective antagonist for SARS-CoV-2. PURPOSE: Our study focused on in-depth exploration of in vitro pharmacokinetic characteristics of HT in lung. METHODS: HPLC-fluorescence detection method was used to detect changes of HT content. Incubation systems of lung microsomes for phase I metabolism and UGT incubation systems for phase II metabolism were performed to elucidate metabolites and metabolic mechanisms of HT, and then the metabolic enzyme phenotypes for HT were clarified by chemical inhibition method and recombinant enzyme method. Through metabolomics, we comprehensively evaluated the physiological dynamic changes in SD rat and human lung microsomes, and revealed the relationship between metabolomics and pharmacological activity of HT. RESULTS: HPLC-fluorescence detection method showed strong specificity, high accuracy, and good stability for rapid quantification of HT. We confirmed that HT mainly underwent phase I metabolism, and the metabolites of HT in different species were all identified as 4'-demethyl HT, with metabolic pathway being hydrolysis reaction. CYP1A2 and CYP2E1 participated in HT metabolism, but as HT metabolism was not NADPH dependent, the esterase HCES1 in lung also played a role. The main KEGG pathways in SD rat and human lung microsomes were cortisol synthesis and secretion, steroid hormone biosynthesis and linoleic acid metabolism, respectively. The downregulated key biomarkers of 11-deoxycortisol, 21-deoxycortisol and 9(10)-EpOME suggested that HT could prevent immunosuppression and interfere with infection and replication of SARS-CoV-2. CONCLUSION: HT was mainly metabolized into 4'-demethyl HT through phase I reactions, which was mediated by CYP1A2, CYP2E1, and HCES1. The downregulation of 11-deoxycortisol, 21-deoxycortisol and 9(10)-EpOME were key ways of HT against SARS-CoV-2. Our study was of great significance for development and clinical application of HT in the treatment of COVID-19.

Analysis of Fever Following Bronchoscopy and Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration.

Objective: Bronchoscopy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are two essential methods for obtaining the pathological diagnosis of central lung masses or hilar and mediastinal lymphadenopathy. We can observe that many patients have a fever after examinations, but the pathogenesis is not yet fully clear. We tried to comprehensively assess the occurrence of postoperative fever and bacterial infections in patients undergoing bronchoscopy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) procedures. Methods: We retrospectively analyzed 512 patients undergoing bronchoscopy or EBUS-TBNA examination. According to examination methods, all patients were classified into three groups: Only perform bronchoscopy examination (BO) group (122 cases)，both perform bronchoscopy and biopsy (BB) group (262 cases), and EBUS-TBNA after bronchoscopy (EBUS) group (128 cases). Peripheral blood leucocyte, neutrophil count, and serum IL-6 test results were obtained before and after the examination. A blood culture was performed when the body temperature was higher than 38.5°C. Results: Among the three groups, the onset time (5.5h), average duration (6h), and peak temperature (37.7°C) of fever in the BO group were lower than those in the BB and EBUS groups. Still, there was no significant difference in onset time (11.66h, 11.83h), average duration (12.86h, 13.56h), and peak temperature (39.1°C, 39.1°C) between the BB group and EBUS group. There was no significant difference in the peripheral blood leukocyte count, neutrophil count or IL-6 level before the operation (P > .05). Compared with the preoperative, the leukocyte count, neutrophil count and IL-6 level in the three groups were increased after the operation (P < .05). Positive blood cultures were diagnosed as normal oropharyngeal flora. Conclusions: Postoperative fever after bronchoscopy is a relatively common complication, most of which do not require special treatment. Individuals with concomitant diseases such as diabetes may have postoperative infections after EBUS-TBNA, and they should be emphatically observed. The findings could potentially extend to similar diagnostic procedures or situations in pulmonary medicine. Understanding the risk factors associated with postoperative fever can help healthcare providers manage patient expectations and monitor certain groups more closely.