Cardiovascular toxicities following the use of tyrosine kinase inhibitors in hepatocellular cancer patients: a retrospective, pharmacovigilance study.

BACKGROUND: Cardiac adverse events (AEs) are common in tyrosine kinase inhibitors(TKIs). This study explored the cardiac AEs of TKIs through the Food and Drug Administration's Adverse Event Reporting System (FAERS). METHODS: Disproportionality analysis and Bayesian analysis were utilized for data mining of the suspected cardiac AEs of TKIs, based on FAERS data from January 2004 to December 2021. RESULTS: A total of 4708 cardiac AEs reports of sorafenib, regorafenib, lenvatinib, and cabozantinib were identified. Hypertension accounts for the most reported cardiac AE. Lenvatinib appears to induce cardiac failure with the highest signals strength [ROR = 7.7 (3.46,17.17)]. Acute myocardial infarction was detected in lenvatinib [ROR = 7.91 (5.64,11.09)] and sorafenib [ROR = 2.22 (1.74, 2.84)]. Acute coronary syndrome was detected in lenvatinib [ROR = 11.57 (6.84, 19.58)] and sorafenib [ROR = 2.81 (1.87,4.24)]. Atrial fibrillation was detected in sorafenib [ROR = 1.82 (1.55,2.14)] and regorafenib [ROR = 1.36 (1.03,1.81)]. Meanwhile, aortic dissections were detected in sorafenib [ROR = 5.08 (3.31,7.8)] and regorafenib [ROR = 3.39 (1.52,7.56)]. Most patients developed hypertension and cardiac failure within 30 days of initiating TKI treatments. Patients taking lenvatinib had an increased incidence of developing acute coronary syndrome after 180 days of treatment. CONCLUSION: Analysis of FAERS data provides a precise profile on the characteristics of cardiac AEs associated with different TKI regimens. Distinct monitoring and appropriate management are needed in the care of TKI recipients.

Anti-inflammatory effect and component analysis of Chaihu Qingwen granules.

ETHNOPHARMACOLOGICAL RELEVANCE: As prevalent acute respiratory condition in clinical practice, acute lung injury has a quick start and severe symptoms which can harm patients physically. Chaihu Qingwen granules (CHQW) is a classic formula for the treatment of respiratory diseases. Clinical observation shows that CHQW has good efficacy in treating colds, coughs, and fevers. AIM OF THE STUDY: The aim of this study was to investigate the anti-inflammatory effect of CHQW on lipopolysaccharide (LPS)-induced acute lung injury (ALI) model in rats and to explore its potential mechanism, as well as to clarify its substance composition. MATERIALS AND METHODS: Male SD rats were randomly divided into the blank group, the model group, the ibuprofen group, the Lianhua Qingwen capsule group and the CHQW group (2, 4 and 8 g/kg, respectively). The LPS-induced acute lung injury (ALI) model in rats was established after pre-administration. The histopathological changes in the lung and the levels of inflammatory factors in bronchoalveolar lavage fluid (BALF) and serum of ALI rats were observed. The inflammation-related proteins toll-like receptor 4 (TLR4), inhibitory kappa B alpha (IκBα), phospho-IκBα (p-IκBα), nuclear-factor-kappa B (NF-κB), and NLR family pyrin domain containing 3(NLRP3) expression levels were measured by western blotting analysis and immunohistochemical analysis. The chemical composition of CHQW was identified by liquid chromatography-quadrupole-time of flight-mass spectrometry (LC-Q-TOF-MS). RESULTS: CHQW significantly ameliorated lung tissue pathological injury in LPS-induced ALI rats and decreased the release of inflammatory cytokines (interleukin-1ß, interleukin-17 and tumor necrosis factor-α) in BALF and serum. In addition, CHQW decreased the expression of TLR4, p-IκBα and NF-κB proteins, increased the level of IκBα, regulated the TLR4/NF-κB signaling pathway, and inhibited the activation of NLRP3. The chemical components of CHQW were analyzed by LC-Q-TOF-MS, and a total of 48 components were identified by combining information from the literature, mainly flavonoids, organic acids, lignans, iridoids and phenylethanoid glycosides. CONCLUSION: The results of this study showed that the pretreatment of CHQW had a strong protective effect on LPS-induced ALI in rats, reducing lung tissue lesions and decreasing inflammatory cytokines released in BALF and serum. The protective mechanism of CHQW may be related to the inhibition of the TLR4/NF-κB signaling pathway and NLRP3 activation. The main active ingredients of CHQW are flavonoids, organic acids, lignans, iridoids and phenylethanoid glycosides.

Physiologically-based pharmacokinetic modeling-guided rational combination of tacrolimus and voriconazole in patients with different CYP3A5 and CYP2C19 alleles.

The drug-drug interactions (DDIs) between tacrolimus and voriconazole are highly variable among individuals. We aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the DDIs in people with different CYP3A5 and CYP2C19 alleles. First, pharmacokinetic data of humans receiving tacrolimus with or without voriconazole from the literature were used to construct and validate the PBPK model. Thereafter, we developed a model incorporating the metabolism of voriconazole mediated by CYP2C19 and the inhibitory effect of voriconazole on CYP3A4/5. Finally, the model was used to evaluate the dose adjustment of tacrolimus in people with different CYP3A5 and CYP2C19 alleles. When tacrolimus was administered alone (3 mg PO, single dose), the predicted AUC0-∞ of tacrolimus in CYP3A5 nonexpressers (19.22) was 3.5-fold higher than that in expressers (5.48). Following voriconazole (200 mg PO, bid) administration in human with different CYP2C19 genotypes, the AUC0-∞ of tacrolimus increased by 5.1- to 8.3-fold in CYP3A5 expressers and by 5.3- to 10.2-fold in CYP3A5 nonexpressers. The lower the gene expression level of CYP2C19 in the population, the higher the exposure to tacrolimus. When tacrolimus was combined with voriconazole (200 mg, bid; 400 mg, bid, on Day 1), the final model simulations suggested that the dose regimen of tacrolimus should be regulated to 0.15 mg/kg/day (qd) in CYP3A5 expressers with different CYP2C19 genotypes. For CYP3A5 nonexpressers, the dosing schedule of tacrolimus should be modified to 0.05 mg/kg/24 h for patients with 2C19 EM, 0.05 mg/kg/48 h for 2C19 IM and 0.05 mg/kg/72 h for 2C19 PM. In conclusion, a PBPK model with CYP3A5 and CYP2C19 polymorphisms was successfully established, providing more insights regarding the DDIs between tacrolimus and voriconazole to guide the clinical use of tacrolimus.

Lanostane triterpenoids from Ganoderma lucidum and their inhibitory effects against FAAH.

Ganoderma lucidum is a famous edible and medicinal fungus. Through a bioactive phytochemical investigation of the ethanolic extracts of the fruiting bodies of G. lucidum, twenty-nine triterpenoids, including eleven previously undescribed triterpenoids, were isolated and characterized based on spectroscopic data. The inhibitory effects of all the triterpenes against fatty acid amide hydrolase (FAAH) were found to be in the range of 30-60% at 100 µM. Methyl ganoderate A displayed the strongest inhibitory activity (61%) against FAAH. Furthermore, all compounds displayed no cytotoxicity against LOVO and MCF-7 human cancer cells. Hence, our present study provides information about G. lucidum as a functional food or pharmaceutical supplement for the treatment of neuroinflammation.

COVID-19 and gastroenteric manifestations.

Coronavirus disease 2019 (COVID-19), caused by the infection of a novel coronavirus [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)], has become a pandemic. The infection has resulted in about one hundred million COVID-19 cases and millions of deaths. Although SARS-CoV-2 mainly spreads through the air and impairs the function of the respiratory system, it also attacks the gastrointestinal epithelial cells through the same receptor, angiotensin converting enzyme 2 receptor, which results in gastroenteric symptoms and potential fecal-oral transmission. Besides the infection of SARS-CoV-2, the treatments of COVID-19 also contribute to the gastroenteric manifestations due to the adverse drug reactions of anti-COVID-19 drugs. In this review, we update the clinical features, basic studies, and clinical practices of COVID-19-associated gastroenteric manifestations.

Inhibition of the PD-1/PD-L1 signaling pathway enhances innate immune response of alveolar macrophages to mycobacterium tuberculosis in mice.

BACKGROUND: Mycobacterium tuberculosis (TB) is a pathogen that consequently leads to TB infection, which remains a significant global health concern. Programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling pathway is critical for terminating immune responses. The present study aimed to elucidate the regulatory role of the PD-1/PD-L1 signaling pathway in alveolar macrophages against Mycobacterium TB in mice. METHODS: Specific pathogen free mice were initially prepared for Mycobacterium TB model establishment. The alveolar macrophages of the successfully modeled rats were evaluated to determine the levels of PD-1, PD-L1, AKT, mTOR, TNF-α, NF-κB, IL-2, IL-4, IL-6, IL-10, IL-17, IL-17A, and IFN-γ. The surface makers of macrophages (CD11c, CD16, CD86, CD163, CD206, CX3CR-1 and CSF-1R), level of ROS, apoptosis and cell cycle, were all assessed. RESULTS: Elevated levels of PD-1 and PD-L1, decreased levels of AKT and mTOR, along with elevated levels of TNF-α, NF-κB, IL-17, IL-2, IL-6, IL-17A and IFN-γ were identified in the alveolar macrophages infected with Mycobacterium TB, while an opposite trend was observed when PD-1/PD-L1 signaling pathway was inhibited. Additionally, elevated protein levels of CD11c, CD16 and CD86, as well as an increased rate of positive ROS and cell apoptosis, levels of Bax, and a diminished percentage of alveolar macrophages at the S and G2/M stages were detected in the event of Mycobacterium TB infection. A contrasting trend to the aforementioned findings was detected when the PD-1/PD-L1 signaling pathway was inhibited. CONCLUSION: Taken together, these results suggested that inhibition of the PD-1/PD-L1 signaling pathway enhanced the innate immune response of alveolar macrophages to Mycobacterium TB in mice.

Identification of Epitopes for Neutralizing Antibodies Against H10N8 Avian Influenza Virus Hemagglutinin.

Objective To develop neutralizing monoclonal antibodies (MAbs) against H10N8 avian influenza virus hemagglutinin and to identify the binding sites. Methods MAbs against hemagglutinin of H10N8 avian influenza virus were developed by genetic engineering. Neutralizing MAbs were screened by microneutralization assay,and then tested by enzyme-linked immunosorbent assay and Western blot to identity the binding sites.The homology modeling process was performed using Discovery Studio 3.5 software,while the binding epitopes were analyzed by BioEdit software. Results One MAb that could neutralize the H10N8 pseudovirus was obtained and characterized. Analysis about epitopes suggested that the antibody could bind to the HA1 region of hemagglutinin,while the epitopes on antigen were conserved in H10 subtypes.Conclusions One neutralizing antibody was obtained by this research.The MAb may potentially be further developed as a pre-clinical candidate to treat avian influenza H10N8 virus infection.

[GC-MS analysis for volatile components from alpiniae katsumadai semen by three extraction methods].

OBJECTIVE: To analysis the volatile components in Alpiniae Katsumadai Semen. METHODS: The volatile components were extracted from Alpiniae Katsumadai Semen by steam distillation, head space injection and supercritical fluid extraction respectively, and then analyzed by GC-MS combined with Kovat's retention index. RESULTS: The volatile components extracted by steam distillation or head space extraction were found more likely to be terpenoids, whereas components extracted by supercritical fluid extraction were more likely to be alkenes, alcohols and aromatic compounds. CONCLUSION: Different sample pre-treatment methods are focused on different types of volatile components; Identification of the volatile components by GC-MS combined with Kovat's retention index is more accurate and rapid.

Molecular cloning and characterization of Babesia orientalis rhoptry-associated protein 1.

The rhoptry-associated protein 1 (RAP-1) gene of Babesia orientalis was obtained from a cDNA expression library by immunoscreening with B. orientalis-infected water buffalo sera. The nucleotide sequence of the cDNA was 1732 bp with an open reading frame (ORF) of 1434 bp, encoding a polypeptide of 478 amino acid residues with a predicted size of 52.5 kDa. The ORF was cloned into a pGEX-KG plasmid and subsequently expressed as a GST-fusion protein. The recombinant RAP-1 of B. orientalis (rBoRAP-1) was purified and evaluated as an antigen using Western blotting. The native BoRAP-1 was recognized by the antibodies raised in rabbits against rBoRAP-1. Strong immunofluorescence signals were observed in erythrocytes infected with B. orientalis. Phylogentic analysis revealed that B. orientalis fell into a Babesia clade and most closely related to Babesia bovis and Babesia ovis, which was similar to the previous reported trees based on 18S rRNA and HSP70 genes. The present study suggests that the BoRAP-1 might be a potential diagnostic antigen, and the RAP-1 genes can aid in the classification of Babesia and Theileria species.