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As a new generation of oxazolidinone antibacterial drugs, contezolid has been shown to have comparable or even stronger activity than linezolid and has a low risk of adverse reactions such as bone marrow suppression toxicity. However, there are currently very few clinical reports and pharmacokinetic data of contezolid on the anti-tuberculosis therapy. Therefore, we report a case study of the pharmacokinetic study of contezolid in elderly patients with renal insufficiency and tuberculosis. The patient's condition improved after receiving an anti-tuberculosis regimen containing contezolid, with significant absorption of pleural effusion and lung plaques and nodules reduced. During the treatment, the patients' platelet and white blood cell levels fluctuated within normal ranges, but hemoglobin levels significantly decreased and did not recover after discontinuation of contezolid. The trough concentration of contezolid and the concentration at 2, 4, 6, and 10 h after administration were 1.27µg/mL, 3.88µg/mL, 6.32µg/mL, 8.99µg/mL, and 3.14µg/mL, respectively. The plasma concentrations of bedaquiline and cycloserine during the treatment were also monitored. This study demonstrated the efficacy and safety of contezolid in the treatment of multidrug-resistant tuberculosis and analyzed its pharmacokinetic changes in elderly patients with renal insufficiency, providing a reference for the clinical use of contezolid.
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Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it need for analgesics during oncology treatment, particularly in the context ofthe coronavirus disease, where patients are more susceptible to contract high fever and sore throat. This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression. Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.
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Purpose: Previous studies have indicated that the development of severe adverse events is associated with linezolid peak concentration (Cmax), but the factors affecting linezolid Cmax and evidences on therapeutic drug monitoring to anticipate toxicity in drug-resistant tuberculosis (DR-TB) patients have not been clarified clearly. This study aimed to explore the factors influencing linezolid Cmax and investigate the association between linezolid concentration and hematological toxicity. Patients and Methods: This study included patients with drug-resistant tuberculosis treated with linezolid from January 2022 to September 2023. We analyzed the factors affecting linezolid Cmax using chi-squared and binary logistic regression. The diagnostic utility of linezolid Cmax in predicting hematological toxicity was evaluated using receiver operating characteristic (ROC) analysis. Results: A total of 76 patients were enrolled in the study. 63.20% met the standard rates for linezolid Cmax. Age (P=0.036), weight (P=0.0016), and creatinine clearance (P=0.0223) significantly correlated with the Cmax. Hematological toxicity was observed in 46.05% (35/76) of patients, characterized by thrombocytopenia (31.58%, 24/76), anemia (6.58%, 5/76), and leukopenia (21.05%, 16/76). ROC curve analysis confirmed the predictive value of linezolid Cmax for thrombocytopenia with an area under curve of 0.728. Conclusion: Suboptimal linezolid Cmax was prevalent among patients with DR-TB, with age, weight, and renal function emerging as influential factors. Elevated linezolid Cmax increases the risk of thrombocytopenia. Meticulous monitoring of linezolid Cmax is imperative during anti-DR-TB therapy to tailor treatment and mitigate hematological toxicity.
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Background: Lymphoma is complicated by intricate infections, notably Pneumocystis jirovecii pneumonia (PJP), marked by rapid progression, respiratory failure, and high mortality. Rapid diagnosis of PJP and effective administration of the first-line treatment trimethoprim-sulfamethoxazole (TMP-SMX) are important. For patients intolerant to TMP-SMX, selecting appropriate alternatives is challenging, necessitating careful decisions to optimize diagnosis and treatment. We present a lymphoma case complicated by PJP, illustrating medication adjustment until a positive response was observed. Case Description: A 41-year-old male patient with lymphoma presented with a week-long history of fever, fatigue, cough, sputum, chest tightness, and exertional dyspnea, unresponsive to treatment. Routine laboratory examinations revealed no pathogenic bacteria. PJ and Mycobacterium tuberculosis (MTB) were detected in bronchoalveolar lavage fluid (BALF) using metagenomic next-generation sequencing (mNGS). On Day 1 of admission, meropenem, TMP-SMX, and rifampicin+isoniazid+levofloxacin were administered. However, the patient developed drug-induced hepatotoxicity and gastrointestinal adverse reactions after six days of treatment. After a multidisciplinary team discussion, anti-tuberculosis therapy was stopped because of insufficient evidence of tuberculosis infection. A reduced dose of TMP-SMX with micafungin was used for PJP; however, symptoms persisted and repeated computed tomography showed extensive deterioration of bilateral pulmonary plaques. The PJP regimen was modified to include a combination of TMP-SMX and caspofungin. Due to the high fever and elevated infection indices, the patient was treated with teicoplanin to enhance the anti-infection effects. By Day 13, the patient's temperature had normalized, and infection control was achieved by Day 30. CT revealed that the infection in both lung lobes fully resolved. Subsequently, lymphoma treatment commenced. Conclusion: BALF-NGS facilitates early and rapid diagnosis of PJP. mNGS reads of MTB bacillus <5 may indicate a bacterial carrier state, warranting other detection techniques to support it. There is insufficient evidence for using TMP-SMX with micafungin to treat PJP; however, TMP-SMX combined with caspofungin is suitable.
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AIMS: Isoniazid (INH) has been used as a first-line drug to treat tuberculosis (TB) for more than 50 years. However, large interindividual variability was found in its pharmacokinetics, and effects of nonadherence to INH treatment and corresponding remedy regime remain unclear. This study aimed to develop a population pharmacokinetic (PPK) model of INH in Chinese patients with TB to provide model-informed precision dosing and explore appropriate remedial dosing regimens for nonadherent patients. METHODS: In total, 1012 INH observations from 736 TB patients were included. A nonlinear mixed-effects modelling was used to analyse the PPK of INH. Using Monte Carlo simulations to determine optimal dosage regimens and design remedial dosing regimens. RESULTS: A 2-compartmental model, including first-order absorption and elimination with allometric scaling, was found to best describe the PK characteristics of INH. A mixture model was used to characterize dual rates of INH elimination. Estimates of apparent clearance in fast and slow eliminators were 28.0 and 11.2 L/h, respectively. The proportion of fast eliminators in the population was estimated to be 40.5%. Monte Carlo simulations determined optimal dosage regimens for slow and fast eliminators with different body weight. For remedial dosing regimens, the missed dose should be taken as soon as possible when the delay does not exceed 12 h, and an additional dose is not needed. delay for an INH dose exceeds 12 h, the patient only needs to take the next single dose normally. CONCLUSION: PPK modelling and simulation provide valid evidence on the precision dosing and remedial dosing regimen of INH.
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Nirmatrelvir/ritonavir (N/r) has received emergency use authorization for mild-to-moderate COVID-19 treatment in adult and pediatric patients (aged and weighing at least 12 years and 40 kg, respectively) presenting positive direct SARS-CoV-2 viral testing results and a high risk of disease progression to severe COVID-19. However, information remains limited concerning the corresponding drug safety, efficacy, and pharmacokinetics in patients with severe renal impairment. In this study, we present the case of a 91-year-old Chinese man who, despite exhibiting recurrent positive SARS-CoV-2 results and progression to severe COVID-19, was treated with N/r. Due to severe renal impairment and concurrent administration of continuous renal replacement therapy (continuous venovenous hemofiltration) during medication, we aimed to determine the serum N/r drug concentration in the patient. Our analysis revealed Cmax values of 12.42 and 2.001 µg/mL for nirmatrelvir and ritonavir, respectively. Despite the particularly high serum N/r concentration in this patient, the clinical and laboratory test analyses confirmed that the treatment was safe and effective. Nevertheless, N/r should be used with caution and at lower doses in patients with severe renal impairment to avoid potential high N/r concentration-related adverse reactions and events.
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Although the 3 d transition-metal catalyzed C-H functionalization have been extensively employed to promote the formation of valuable carbon-carbon bonds, the persistent problems, including the use of sensitive Grignard reagents and the rigorous operations (solvent-drying, inert gas protection, metal pre-activation and RMgX addition rate control), still leave great room for further development of sustainable methodologies. Herein, we report a mechanochemical technology toward in-situ preparation of highly sensitive organomagnesium reagents, and thus building two general 3 d transition-metal catalytic platforms that enables regioselective arylation and alkylation of indoles with a wide variety of halides (including those containing post transformable functionalities and heteroaromatic rings). This mechanochemical strategy also brings unique reactivity and high step-economy in producing functionalized N-free indole products.
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INTRODUCTION: Linezolid, moxifloxacin, rifapentine, rifabutin, cycloserine, clofazimine, bedaquiline, levofloxacin, prothionamide, and ethionamide are commonly used second-line antituberculosis (anti-TB) drugs. To support therapeutic drug monitoring in regular clinical practice, the authors sought to develop a method based on ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) that would allow for the simultaneous quantification of multiple second-line anti-TB drugs in human serum. METHODS: Analytes were extracted from human serum by protein precipitation. UHPLC-MS/MS was performed using a gradient at a flow rate of 0.3 mL/min, and each sample was taken for 7.5 minutes. The mass spectrometry scanning mode used was electrospray ionization with multiple reaction monitoring in the positive mode. RESULTS: Validation showed that endogenous substances in the sample did not interfere with the assay, and the relationship between X and Y was highly linear, with a coefficient of determination (R 2 ) >0.9954 for each curve. The accuracy (85.0%-114.7%) and precision (intraday: 0.27%-9.32%; interday: 0.20%-7.66%) were less than 15.0%, and the internal standard-normalized matrix effects were consistent (coefficient of variation ≤4.40%). The analytes were stable in the final extract and human serum under various storage conditions (recovery: 87.0%-115.0%). The clinical applicability of the method was demonstrated by quantitative determination of analytes in serum samples obtained from patients with TB. Reproducibility of the drug concentrations measured in clinical samples was confirmed by incurred sample reanalysis. CONCLUSIONS: A simple and reliable analytical method was developed and validated for the simultaneous determination of 10 anti-TB drugs in human serum using UHPLC-MS/MS. Quantitation of anti-TB drugs in clinical samples confirmed that the assay is suitable for therapeutic drug monitoring in regular clinical practice.
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Antituberculosos , Monitoramento de Medicamentos , Espectrometria de Massas em Tandem , Humanos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Antituberculosos/sangue , Antituberculosos/farmacocinética , Monitoramento de Medicamentos/métodos , Reprodutibilidade dos Testes , Masculino , Adulto , FemininoRESUMO
Background: Gliomas are characterized by high mortality rates and resistance. Even with conventional chemotherapy the prognosis of glioblastoma remains poor. Many medications are not optimally effective due to limited bioavailability. The bioavailability of medicine can be enhanced by borneol, a monoterpenoid substance. In this study, we investigated the effect of borneol, a commonly used Chinese medicine, on chemosensitivity in C6 glioma and U251 human glioma cell lines and elucidated its therapeutic molecular targets. Methods: The chemosensitivity-inducing effects of borneol in C6 and U251 cells were examined using CCK8 and clonal formation assays. The mechanism underlying the effect of borneol was evaluated through immunohistochemistry and western blotting assays. Further, the number of autophagosomes was determined via transmission electron microscopy. Finally, the chemical sensitization effect of borneol was evaluated in SD rats after C6 orthotopic tumor transplantation. Results: Borneol increased cytotoxicity in C6 and U251 cells in response to temozolomide (TMZ). In addition, through transmission electron microscopy, western blotting, and immunohistochemical tests, we found that borneol combined with TMZ significantly increased the level of autophagy and that hypoxia inducible factor-1(HIF-1α) is a candidate target through which borneol enhances the cytotoxic effect of TMZ. Borneol's ability to enhance HIF-1α degradation was counteracted following the administration of autophagy inhibitors. In vivo, borneol treatment was found to enhance the anticancer effect of TMZ and delay tumor progression, and this effect was closely related to its ability to promote the autophagic degradation of HIF-1α. Conclusions: HIF-1α might be a valid therapeutic target of borneol, which can be potentially applied as a chemosensitizing drug used for glioma treatment.
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Canfanos , Glioma , Humanos , Animais , Ratos , Ratos Sprague-Dawley , Canfanos/farmacologia , Glioma/tratamento farmacológico , Autofagia , Temozolomida/farmacologiaRESUMO
Aspergillus tubingensis spondylitis (AS) is a rare spinal infectious disease with severe clinical symptoms and a challenging diagnosis. Treatment of AS is challenging due to its prolonged duration, substantial side effects, and complex drug-drug interactions. However, there is a lack of experience in individualized pharmaceutical care of AS by clinical pharmacists, especially in the presence of rifampicin, which has sustained liver enzyme induction after discontinuation. Our case described an immunocompetent patient infected with Aspergillus tubingensis spondylitis. Clinical pharmacists proposed an individualized treatment regimen for AS, after considering the effects of sustained liver enzyme induction of rifampicin (after discontinuation) on voriconazole, and utilized caspofungin as a bridge-connection scheme. We also paid attention to changes in indicators during treatment and managed adverse reactions. Therapeutic drug monitoring of voriconazole was also used to optimize the dosing regimen. With the individualized pharmaceutical care of clinical pharmacists and the efforts of clinicians, the patient's incision healed well after 33 days of hospitalization, and she was discharged with significant improvement. Therefore, individualized pharmaceutical care by a clinical pharmacist can help optimize the treatment of Aspergillus tubingensis spondylitis. In clinical practice, drug-drug and drug-diet interactions may affect voriconazole efficacy, and individualized dose adjustment using therapeutic drug monitoring (TDM) is critical to improve efficacy and reduce adverse reactions.
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INTRODUCTION: Isoniazid (INH) plays an important role in prevention and treatment of tuberculosis (TB). However, large pharmacokinetic (PK) variations are observed in patients receiving standard INH dosages. Considering the influence of PK variations on INH efficacy or adverse reactions, we reviewed the population PK studies of INH and explored significant covariates that influence INH PK. METHODS: The PubMed and Embase databases were systematically searched from their inception to 30 January 2023. PPK studies on INH using a parametric nonlinear mixed-effect approach were included in this review. The characteristics and identified significant covariates of the included studies were summarized. RESULTS: Twenty-one studies conducted in adults, and seven in pediatrics were included. A two-compartment model with first-order absorption and elimination was the frequently used structural model for INH. NAT2 genotype, body size, and age were identified as significant covariates affecting INH PK variation. The median clearance (CL) value in the fast metabolizers was 2.55-fold higher than that in the slow metabolizers. Infants and children had higher CL per weight values than adults with the same metabolic phenotype. In pediatric patients, CL value increased with postnatal age. CONCLUSIONS: Compared with slow metabolizers, the daily dose of INH should be increased by 200-600 mg in fast metabolizers. To achieve effective treatment, pediatric patients need a higher dose per kilogram than adults. Further PPK studies of anti-tuberculosis drugs are needed to comprehensively understand the covariates that affect their PK characteristics and to achieve accurate dose adjustments.
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Arilamina N-Acetiltransferase , Isoniazida , Humanos , Criança , Isoniazida/farmacocinética , Isoniazida/uso terapêutico , Antituberculosos , Genótipo , Fenótipo , Área Sob a Curva , Arilamina N-Acetiltransferase/genética , Arilamina N-Acetiltransferase/metabolismoRESUMO
Radiotherapy is an effective therapy in tumour treatment. However, the characteristics of the tumour microenvironment, including hypoxia, low pH, and interstitial fluid pressure bring about radioresistance. To improve the anti-tumour effect of radiotherapy, it has been demonstrated that antiangiogenic therapy can be employed to repair the structural and functional defects of tumour angiogenic vessels, thereby preventing radioresistance or poor therapeutic drug delivery. In this study, we prepared triptolide (TP)-loaded Asn-Gly-Arg (NGR) peptide conjugated mPEG2000-DSPE-targeted liposomes (NGR-PEG-TP-LPs) to induce tumour blood vessel normalisation, to the end of increasing the sensitivity of tumour cells to radiotherapy. Further, to quantify the tumour vessel normalisation window, the structure and functionality of tumour blood vessels post NGR-PEG-TP-LPs treatment were evaluated. Thereafter, the anti-tumour effect of radiotherapy following these treatments was evaluated using HCT116 xenograft-bearing mouse models based on the tumour vessel normalisation period window. The results obtained showed that NGR-PEG-TP-LPs could modulate tumour vascular normalisation to increase the oxygen content of the tumour microenvironment and enhance the efficacy of radiotherapy. Further, liver and kidney toxicity tests indicated that NGR-PEG-TP-LPs are safe for application in cancer treatment.
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Diterpenos , Neoplasias , Humanos , Camundongos , Animais , Lipossomos/química , Lipopolissacarídeos , Sistemas de Liberação de Medicamentos/métodos , Diterpenos/química , Linhagem Celular TumoralRESUMO
Nanoparticle delivery systems have been shown to improve the therapeutic efficacy of anti-cancer drugs, including a variety of drugs for the treatment of hepatocellular carcinoma (HCC). However, the current systems show some limitations, and the delivery of more effective nanoparticle systems for anti-HCC drugs with better targeting ability are needed. Here, we created paclitaxel (PTX)/norcantharidin (NCTD)-loaded core-shell lipid nanoparticles modified with a tumor neovasculature-targeted peptide (Ala-Pro-Arg-Pro-Gly, APRPG) and investigated their anti-tumor effects in HCC. Core-shell-type lipid nanoparticles (PTX/NCTD-APRPG-NPs) were established by combining poly(lactic-co-glycolic acid) (PLGA)-wrapped PTX with phospholipid-wrapped NCTD, followed by modification with APRPG. For comparison, PTX-loaded PLGA nanoparticles (PTX-NPs) and PTX/NCTD-loaded core-shell-type nanoparticles without APRPG (PTX/NCTD-NPs) were prepared. The in vitro and in vivo anti-tumor effects were examined in HepG2 cells and tumor-bearing mice, respectively. Morphological and release characterization showed that PTX/NCTD-APRPG-NPs were prepared successfully and achieved up to 90% release of PTX in a sustained manner. Compared with PTX/NCTD-NPs, PTX/NCTD-APRPG-NPs significantly enhanced the uptake of PTX. Notably, the inhibition of proliferation and migration of hepatoma cells was significantly higher in the PTX/NCTD-APRPG-NP group than those in the PTX-NP and PTX/NCTD-NP groups, which reflected significantly greater anti-tumor properties as well. Furthermore, key molecules in cell proliferation and apoptosis signaling pathways were altered most in the PTX/NCTD-APRPG-NP group, compared with the PTX-NP and PTX/NCTD-NP groups. Collectively, PTX/NCTD-loaded core-shell lipid nanoparticles modified with APRPG enhance the effectiveness of anti-HCC drugs and may be an effective system for the delivery of anti-HCC drugs.
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Multidrug-resistant tuberculosis (MDR-TB) remains a main global health concern as there is no comprehensive therapeutic intervention yet and numerous adverse effects follow the therapeutic process. In recent years, linezolid has been frequently used for treating MDR-TB. However, peripheral neuropathy associated with linezolid has reduced patient compliance. The current study explored the mechanism underlying linezolid-induced peripheral neuropathy in MDR-TB. Autophagy plays a neuroprotective role against peripheral nerve injury. We hypothesized that autophagy might also play a neuroprotective role against linezolid-induced peripheral neuropathy. In this study, we collected 12 questionnaires from MDR-TB patients in our hospital, and 10 of them developed linezolid-induced pain. The pain is mainly concentrated in the feet and accompanied by numbness. Subsequently, we used Sprague-Dawley (SD) rats and Schwann cells (SCs) to explore the mechanism. We found that linezolid causes a sparse arrangement of sciatic nerve tissue with associated loss of neurons, myelin sheaths, and down-regulation of LC3B expression. These results were also confirmed by in vitro experiments, showing that linezolid inhibited the proliferation of SCs. And the expression of P-AKT and P62 was elevated, and the expression of LC3B declined compared with the control group. Moreover, chloroquine (CQ), an autophagy inhibitor, also exhibited experimental results similar to linezolid. In summary, we conclude that linezolid-induced peripheral neuropathy is associated with the inhibition of autophagy flux.
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BACKGROUND: Latamoxef shows excellent antibacterial activity against anaerobic bacteria such as Bacteroides fragilis. Reports of thrombocytopenic toxicity of latamoxef are limited. This report presents a case of severe thrombocytopenia possibly induced by latamoxef, an infrequent adverse drug reaction in a young patient with tuberculosis and Crohn's disease in China. CASE SUMMARY: We reported a case of severe thrombocytopenia induced by latamoxef in a 28-year-old man with tuberculosis and Crohn's disease. On admission, the patient presented with a cough productive of bloody sputum, a chest computed tomogram suggested scattered mottled, high-density shadows in both lungs. Laboratory tests indicated a platelet count of 140000/µL. Considered a pulmonary bacterial infection, the patient received anti-infection therapy with latamoxef (dose: 2.0 g) intravenously Q12h. On the 9th day of treatment, the platelet count decreased to 44000/µL. On the 12th day, scattered purpura and ecchymosis appeared on the patient's limbs and trunk, and the platelet count decreased to 9000/µL after latamoxef treatment for 15 d. Three days after discontinuation of latamoxef, the platelet count recovered to 157000/µL, and the area of scattered purpura and ecchymosis on the limbs and trunk decreased. The platelet counts remained in the normal range, and no thrombocytopenia was found at follow-up 15 mo after discharge. CONCLUSION: For patients treated with latamoxef, platelet counts should be carefully followed, and caregivers should be vigilant for the appearance of scattered ecchymosis.
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Linezolid is an oxazolidinone antibacterial drug, and its therapeutic drug monitoring and individualized treatment have been challenged since its approval. With the in-depth clinical research of linezolid, we have changed our attitude toward its therapeutic drug monitoring and our view of individualized treatment. On the basis of summarizing the existing clinical studies, and based on the practical experience of each expert in their respective professional fields, we have formed this expert consensus. Our team of specialists is a multidisciplinary team that includes pharmacotherapists, clinical pharmacology specialists, critical care medicine specialists, respiratory specialists, infectious disease specialists, emergency medicine specialists and more. We are committed to the safe and effective use of linezolid in patients in need, and the promotion of its therapeutic drug monitoring.
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Monitoramento de Medicamentos , Oxazolidinonas , Antibacterianos , Humanos , LinezolidaRESUMO
Background: This study sought to examine whether candesartan induces tumor vascular normalization in a narrow therapeutic window to increase perfusion and oxygen content, and thus enhance the effect of radiotherapy (RT). Methods: Candesartan was administered to tumor-bearing mice to induce the normalization of tumor vessels, and the time window for normalization was determined. Then, tumor vascular density, perfusion, pericyte coverage, hypoxia of tumor-bearing mice was detected at 3, 6, 9, 12 days, respectively. In the treatment window, RT was administered to enhance the anti-tumor effect, which was evaluated based on relevant anti-tumor indicators. The tumor volume and tumor weight were recorded. Next, tumor growth inhibition rate was calculated according to the tumor weight. The Tunnel and Ki-67 expression of the tumor tissues of every group was measured to evaluate the effects on tumor proliferation and apoptosis. Results: Based on tumor vascular density, perfusion, pericyte coverage, hypoxia, and other indicators, the tumor vascular normalization window occurred 9 days after the administration of candesartan. The anti-tumor results showed that administering RT during the therapeutic window enhanced anti-tumor efficacy, with a tumor growth inhibition rate of 66.67%. The results of Tunnel and Ki-67 expression showed that window-period RT significantly promoted tumor cell apoptosis and limited proliferation compared to the control group (P<0.05 in Tunnel expression and P<0.01 in Ki-67 expression). Conclusions: Candesartan regulates the normalization of tumor vessels and increases the sensitivity of RT in the therapeutic window.
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BACKGROUND: Qingfeiyin (QFY) is a common Chinese herbal formula for the treatment of acute lung injury (ALI). However, its mechanisms of action are unclear. In this study, we systematically explored the effects and mechanism of action of QFY in ALI using network pharmacology and molecular docking. METHODS: Active compounds and targets of QFY were obtained from TCMSP and TCMID. ALI-related targets were retrieved from GEO datasets combined with GeneCards, OMIM, and TTD databases. A protein-protein interaction (PPI) network was built to screen the core targets. DAVID was used for GO and KEGG pathway enrichment analyses. The tissue and organ distribution of targets was evaluated. Interactions between potential targets and active compounds were assessed by molecular docking. A molecular dynamics simulation was conducted for the optimal core protein-compound complexes obtained by molecular docking. RESULTS: In total, 128 active compounds and 121 targets of QFY were identified. A topological analysis of the PPI network revealed 13 core targets. GO and KEGG pathway enrichment analyses indicated that the effects of QFY are mediated by genes related to inflammation, apoptosis, and oxidative stress as well as the MAPK and PI3K-Akt signaling pathways. Molecular docking and molecular dynamics simulations revealed good binding ability between the active compounds and screened targets. CONCLUSIONS: This study successfully predict the effective components and potential targets and pathways involved in the treatment of ALI for QFY. We provided a novel strategy for future research of molecular mechanisms of QFY in ALI treatment. Moreover, the potential active ingredients provide a reliable source for drug screening for ALI.
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Lesão Pulmonar Aguda , Medicamentos de Ervas Chinesas , Lesão Pulmonar Aguda/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fosfatidilinositol 3-QuinasesRESUMO
Arsenic trioxide (ATO) has efficient anticancer effect on hepatocellular carcinoma (HCC) in clinical trials, but its off-target distribution and side effects have limited its use. Here, we demonstrate an albumin-embellished ATO-loaded polyethylene glycol-polycaprolactone-polyethyleneimine (PEG-PCL-PEI) nanoparticle (AATONP) to enhance the tumor distribution and intratumor drug release of ATO for HCC therapy. AATONP is prepared by surface embellishment with albumin on the cationic ATO-loaded PEG-PCL-PEI nanoparticles (CATONP). Albumin embellishment can reduce the cationic material's hemolytic toxicity in blood cells while maintaining the rapid internalization and lysosome escape abilities of the positively charged CATONP. AATONP provides sustained and low pH-responsive drug release, facilitating the targeted drug release in the intratumor acidic microenvironment. Moreover, AATONP can significantly improve the circulation time and tumor distribution of ATO via albumin-mediated transcytosis in HCC tumor-bearing mice. Compared with free ATO and the clinically used nanomedicine Genexol/PM, AATONP shows potent antitumor activity against a human HCC xenograft mouse model, leading to a higher tumor inhibition rate of 89.4% in HCC therapy. In conclusion, this work presents an efficient strategy to achieve tumor accumulation and the intratumor drug release of ATO for HCC therapy. An albumin-embellished arsenic trioxide (ATO)-loaded polyethylene glycol-polycaprolactone-polyethyleneimine nanoparticle (AATONP) is designed to enhance tumor distribution and intratumor drug release of ATO for hepatocellular carcinoma therapy. AATONP can achieve enhanced tumor distribution via albumin-mediated transcytosis and exhibit intratumor drug release of ATO via tumor acidic microenvironment-response, leading to potent antitumor activity.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Albuminas , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Trióxido de Arsênio/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Polietilenoglicóis/uso terapêutico , Polietilenoimina , Transcitose , Microambiente TumoralRESUMO
[This corrects the article DOI: 10.7150/jca.45304.].