Literature analysis of cutaneous adverse reactions induced by tislelizumab.

OBJECTIVE: Tislelizumab may induce immune-related adverse events, especially adverse skin events. Early detection and timely intervention of cutaneous adverse events are crucial to improve patients' quality of life and reduce the disruption of therapeutic regimens. This study aimed to determine the clinical characteristics of cutaneous adverse reactions to tislelizumab and offer a reference for its rational clinical use. METHODS: Case reports of cutaneous adverse reactions induced by tislelizumab were collected from the relevant databases (up to 31 March 2023). Patient age, sex, primary disease, medication use, occurrence of adverse skin conditions, treatment, and outcomes were recorded and descriptively analysed. RESULTS: A total of 13 patients were enrolled, including six males and seven females, aged 55-79 years, with a median age of 75 years and a mean age of 70.92 ± 8.84 years. The original disease was lung carcinoma in none patients, cervical carcinoma in two, and urothelial carcinoma and squamous cell carcinoma in one each. The time from the initiation of medication use to the occurrence of cutaneous adverse reactions ranged from 7 to 177 days. Among the 13 patients, 10 showed improvement after drug withdrawal or symptomatic treatment. Two patients died (one died of disease progression and multiorgan failure, one died of acute coronary syndrome), and one patient's adverse skin reactions persisted without treatment. CONCLUSIONS: Tislelizumab-related cutaneous adverse reactions mostly occur after several days to months of treatment. In clinical practice, evaluation and monitoring should be strengthened. More attention should be paid to erythema and rashes, which may be signs of serious adverse skin reactions. Early detection and intervention can ensure the safe use of drugs and provide greater clinical benefits to patients.

The association between polymorphisms in miRNA and the cholinesterase activity of workers in an omethoate-exposed environment.

To explore the association between polymorphisms in microRNAs (miRNAs) and the cholinesterase (ChE) activity in omethoate-exposed workers, we recruited 180 omethoate-exposed workers and 115 controls to measure their ChE activity using acetylcholine and dithio-bis-(nitrobenzoic acid) and genotype susceptible SNPs in their miRNA by time-of-flight mass spectrometry. ChE activity in the exposure group was lower than that in the control group (P < 0.001). The analysis of covariance result showed that ChE activity was lower in the (- -/- T) genotype in miR-30a rs111456995 (1.97 ± 0.47) than in the TT genotype (2.23 ± 0.59) of the exposure group (P = 0.004). Multivariate linear regression was performed to find influencing factors on ChE activity, and variables kept in the model included omethoate exposure (b = -1.094, P < 0.001), gender (b = -0.381, P < 0.001), miR-30a rs111456995 (- -/- T)(b = -0.248, P < 0.001), and drinking (b = 0.258, P =0.019). The results suggest that individuals carrying a (- -/- T) genotype in miR-30a rs111456995 were more susceptible to damage in their cholinesterase induced by omethoate exposure.

Benchmark dose estimation for coke oven emissions based on oxidative damage in Chinese exposed workers.

Coke oven emissions (COEs) can cause oxidative stress of the body, which in turn induces the occupational lung disease and also increases the risk of other diseases. COEs are the major occupational hazard factors for coke oven workers. The aim of the study is to explore the influences of COEs exposure on oxidative damage and estimate the benchmark dose (BMD) of COEs. A group of 542 workers exposed to COEs and 237 healthy controls from the same city were recruited in this study. The corresponding measuring kits were used to determine the plasma biomarkers of oxidative damage level. Generalized linear models and trend tests were used to analyze the relationship between COEs exposure and biomarkers. EPA Benchmark Dose Software was performed to calculate BMD and the lower confidence limit of the benchmark dose (BMDL) of COEs exposure. A significant association was observed between COEs exposure and oxidative damage with T-AOC as a biomarker. The BMD of COEs exposure were 2.83 mg/m3 and 1.39 mg/m3 for males and females, respectively, and the corresponding BMDL were 1.47 mg/m3 and 0.75 mg/m3, respectively. Our results suggested that the exposure level of COEs below the current national occupational exposure limits (OELs) would induce oxidative damage, and the OEL of COEs based on the T-AOC damage was suggested at 0.03 mg/m3 in this study.

Preparation of tilmicosin-resin complex microsphere and its Pharmacokinetics study in rat.

The objective of this study is to mask the extremely bitter taste of tilmicosin, and the tilmicosin-resin complex (DRC) microsphere were prepared by entrapping tilmicosin into resins (Tulsion® 339 and Eudragit® RS/ RL 100) for further pharmacokinetics study in rat. The DRC was characterized by FTIR and X-ray diffraction, and the microsphere containing DRC and Eudragit® RS/RL 100 were characterized by scanning electron microscopy (SEM). The rats were orally administrated with tilmicosin phosphate (10 mg/kg) and the microsphere containing the same dose of tilmicosin, respectively. These microspheres do not taste bitter and the kinetics study suggests that the drug released from microsphere meet the first order kinetics (r = 0.9911). The experimental results showed that T½ and Tmax of microsphere were much longer than tilmicosin phosphate, which indicates that the oral microsphere can be a promising long-active formulation for taste masking of tilmicosin.

Absorption properties and effects of caffeic acid phenethyl ester and its p-nitro-derivative on P-glycoprotein in Caco-2 cells and rats.

CONTEXT: Caffeic acid phenethyl ester (CAPE), isolated from honeybee propolis, has pharmacological applications. A synthesized CAPE derivative, p-nitro-caffeic acid phenethyl ester (CAPE-NO2), showed similar activities with CAPE. The pharmacological activities of CAPE and CAPE-NO2 are related to their absorption properties. OBJECTIVE: To understand the pharmacokinetic profiles of CAPE and CAPE-NO2 in rats and investigate the absorption mechanisms and effects on P-glycoprotein in Caco-2 cells. MATERIALS AND METHODS: The pharmacokinetic profiles of CAPE and CAPE-NO2 were obtained after oral administration (10 mg/kg) to rats. Transport studies of CAPE and CAPE-NO2 (5, 10, 20 µM) were performed in Caco-2 cell model. P-gp activities were assayed by rhodamine 123 cellular retention. Expression of P-gp was determined after the cells were administrated with CAPE and CAPE-NO2 (5, 20 µM) for 48 and 72 h. RESULTS: The AUC(0-t) of CAPE-NO2 (3239.9 ± 352 ng × h/mL) was two-time greater than CAPE (1659.6 ± 152 ng × h/mL) in rats. The Papp values of CAPE and CAPE-NO2 were (4.86 ± 0.90) × 10-6 cm/s and (12.34 ± 1.6) × 10-6 cm/s, respectively. The accumulation of rhodamine 123 was increased by 1.3- to 1.9-fold and 1.4- to 2.3-fold in CAPE and CAPE-NO2 groups after 1 h administration, respectively. However, CAPE and CAPE-NO2 increased the P-gp levels by 2.1- and 1.7-fold, respectively. CONCLUSION: The absorption of CAPE-NO2 can be enhanced in rats and Caco-2 cells compared with CAPE. The two compounds are potential inhibitors of P-gp. The increased P-gp levels generated by CAPE and CAPE-NO2 played a role as a defense mechanism by limiting intracellular xenobiotic levels.

Efficacy and safety of Aprepitant-containing triple therapy for the prevention and treatment of chemotherapy-induced nausea and vomiting: A meta-analysis.

BACKGROUND: Most cancer patients suffer from the pain of chemotherapy-induced nausea and vomiting (CINV). This meta-analysis was performed to evaluate the efficacy and safety of a regimen consisting of aprepitant, dexamethasone, and 5-HT3 receptor antagonists in the prevention and treatment of CINV. METHODS: A systematic literature search was conducted across multiple databases, including PubMed, EMbase, Cochrane Library, MEDLINE, CENTRAL, HEED, CNKI, Wanfang, and VIP, to identify randomized controlled trials (RCTs) investigating the use of triple therapy (aprepitant, 5-HT3 receptor antagonist, and dexamethasone) to prevent and treat CINV. Meta-analysis was performed using RevMan 5.4 and Stata17 software, employing either a fixed-effect or random-effect model based on statistical heterogeneity. RESULTS: A meta-analysis of 23 randomized controlled trials (RCTs) involving 7956 patients was conducted. Efficacy: Results showed significantly improved complete responses (CRs) for CINV in the test group versus the control group in the overall, acute, and delayed phases. Furthermore, in the test group, substantial alleviation of nausea symptoms was observed in the delayed and overall phases but not in the acute phase. Safety: There was no statistically significant difference in the incidence of febrile neutropenia, diarrhea, anorexia, and headache between the 2 groups. The incidence of fatigue and hiccups in the test group was higher than that in the control group; however, the incidence of constipation was significantly lower. CONCLUSIONS: Aprepitant-containing triple therapy is highly effective in the prevention and treatment of CINV, with reliable medication safety.

Relationship between miRNAs polymorphisms and peripheral blood leukocyte DNA telomere length in coke oven workers: A cross-sectional study.

OBJECTIVE: The purpose of this study was to investigate the factors affecting telomere length (TL) in coke oven workers by analyzing the interaction between miRNAs polymorphisms and coke oven emissions (COEs) exposure. METHODS: A total of 544 coke oven workers and 238 healthy controls were recruited. Peripheral blood was collected from the subjects, genomic DNA was extracted, leukocyte TL was detected by real-time quantitative polymerase chain reaction, and fifteen polymorphisms of eight miRNAs were genotyped by flight mass spectrometry. RESULTS: Statistical analysis showed that the peripheral blood DNA TL in the exposure group was shorter than that in the control group (P < 0.001). Generalized linear model found that COEs-exposure [ß (95%CI) = -0.427 (-0.556, -0.299), P < 0.001], genotype CC+CT for miR-612 rs1144925 [ß (95%CI) = -0.367 (-0.630, -0.104), P = 0.006], and the interaction of miR-181B1 rs12039395 TT genotype and COEs-exposure [ß (95% CI) = 0.564 (0.108, 1.020), P = 0.015] were associated with the shortened TL. CONCLUSION: COEs-exposure and miR-612 rs1144925 TT could promote telomere shortening in coke oven workers. The interaction of miR-181B1 rs12039395 TT genotype and COEs-exposure could protect telomere. This provides clues for further mechanistic studies between miRNA and telomere damage.

Benchmark dose analysis for PAHs hydroxyl metabolites in urine based on mitochondrial damage of peripheral blood leucocytes in coke oven workers in China.

OBJECTIVES: The aim was to explore the dose-response relationship between occupational polycyclic aromatic hydrocarbons (PAHs) exposure and mitochondrial damage in coke oven plants workers. METHODS: 544 workers and 238 healthy people were recruited. The ultra-high performance liquid chromatography was used to determine the level of 1-hydroxypyrene, 1-hydroxynaphthalene, 2-hydroxynaphthalene and 3-hydroxyphenanthrene. The real-time fluorescence quantitative polymerase chain reaction was used to determine the mitochondrial DNA copy number (mtDNAcn). The benchmark dose software was used to analyze the benchmark dose. RESULTS: The mtDNAcn in the exposure group was lower than that in the control group. The concentrations of 1-hydroxypyrene, 1-hydroxynaphthalene, 2-hydroxynaphthalene and 3-hydroxyphenanthrene in the exposure group were higher than those in the control group. There is a dose-response relationship between 1-hydroxypyrene, 3-hydroxyphenanthrene and mitochondrial DNA damage. The benchmark dose lower confidence limit (BMDL) of 1-hydroxypyrene were 0.045, 0.004, and 0.058 pg/µg creatinine in the total, male, and female population, respectively. The BMDL of 3-hydroxyphenanthrene were 5.142, 6.099, and 2.807 pg/µg creatinine in the total, male, and female population, respectively. CONCLUSIONS: The BMDL of 1-hydroxypyrene and 3-hydroxyphenanthrene initially explored can provide a reference to establish occupational exposure biological limits.

Estimations of benchmark dose for urinary metabolites of coke oven emissions among workers.

Coke oven emissions (COEs), usually composed of polycyclic aromatic hydrocarbons (PAHs) and so on, may alter the relative telomere length of exposed workers and have been linked with adverse health events. However, the relevant biological exposure limits of COEs exposure has not been evaluated from telomere damage. The purpose of this study is to estimate benchmark dose (BMD) of urinary PAHs metabolites from COEs exposure based on telomere damage with RTL as a biomarker. A total of 544 exposed workers and 238 controls were recruited for participation. High-performance liquid chromatography and qPCR were used to detect concentrations of urinary mono-hydroxylated PAHs and relative telomere length in peripheral blood leukocytes for all subjects. The benchmark dose approach was used to estimate benchmark dose (BMD) and its lower 95% confidence limit (BMDL) of urinary OH-PAHs of COEs exposure based on telomere damage. Our results showed that telomere length in the exposure group (0.75 (0.51, 1.08)) was shorter than that in the control group (1.05 (0.76,1.44))(P < 0.05), and a dose-response relationship was shown between telomere damage and both 1-hydroxypyrene and 3-hydroxyphenanthrene in urine. The BMDL of urinary 1-hydroxypyrene from the optimal model for telomere damage was 1.96, 0.40, and 1.01 (µmol/mol creatinine) for the total, males, and females group, respectively. For 3-hydroxyphenanthrene, the BMDL was 0.94, 0.33, and 0.49 (µmol/mol creatinine) for the total, males, and females. These results contribute to our understanding of telomere damage induced by COEs exposure and provide a reference for setting potential biological exposure limits.

Protective effects of p-nitro caffeic acid phenethyl ester on acute myocardial ischemia-reperfusion injury in rats.

Myocardial ischemia-reperfusion (IR) causes widespread cardiomyocyte dysfunction, including apoptosis and necrosis. The present study aimed to investigate the possible cardioprotective effects of p-nitro caffeic acid phenethyl ester (CAPE-NO2) on myocardial IR-induced injury in vivo. To generate a rat model of myocardial IR, the left anterior descending coronary artery was occluded for 30 min, followed by reperfusion for 2 h. The rats were administered either the sham treatment (the sham and IR control groups) or the therapeutic agents [the caffeic acid phenethyl ester (CAPE) and CAPE-NO2 groups] 10 min prior to the occlusion. Myocardial IR-induced injury is characterized by: A significant increase in the levels of myocardial enzymes, including creatine kinase, lactate dehydrogenase and aspartate transaminase; a marked increase in intercellular adhesion molecule 1 expression levels, lipid peroxidation products and inflammatory mediators; and a significant decrease in myocardial antioxidants, including catalase, total superoxide dismutase and glutathione peroxidase. In the present study, pretreatment with CAPE-NO2 significantly ameliorated these changes, and decreased the infarct size, as compared with the IR control group (10.32±3.8 vs. 35.65±5.4%). Furthermore, western blotting demonstrated that pretreatment with CAPE-NO2 downregulated the myocardial IR-induced protein expression levels of B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax), cleaved caspase-3, P38 and the Bax/Bcl-2 ratio. CAPE-NO2 also upregulated the myocardial IR-induced expression levels of Bcl-2, phosphoinositide-3-kinase, phosphorylated Akt and mammalian target of rapamycin. In conclusion, the results of the present study indicated that CAPE-NO2 demonstrated improved cardioprotective effects, as compared with CAPE; therefore, CAPE-NO2 may represent a novel approach to pharmacological cardioprotection.

Effect of baicalin-copper on the induction of apoptosis in human hepatoblastoma cancer HepG2 cells.

The medical properties of baicalin have been well known for many years. However, the discovery that baicalin in the presence of metal ions is more effective than baicalin alone changed the course of drug research. The present study was designed to investigate the effect and possible mechanism of apoptosis induced by baicalin-copper in a human hepatoblastoma cancer cell line (HepG2) and in vivo. This study demonstrated that baicalin-copper suppresses the proliferation of HepG2 cells in a dose-dependent manner. Intraperitoneal injection of baicalin-copper resulted in a significant decrease in tumor growth in xenografts in nude mice. Acridine orange staining and flow cytometry analysis demonstrated that baicalin-copper induced apoptosis in HepG2 cells and caused cells to arrest in G2-M phase of the cell cycle. Furthermore, baicalin-copper treatment significantly increased the Bax/Bcl-2 ratio and p38 levels, as well as decreased the expression of caspase-3, p-PI3K, p-Akt and p-mTOR (P < 0.01). All of the evidences above indicate that baicalin-copper induces apoptosis in HepG2 cells by down-regulating the PI3K/Akt/mTOR signaling pathway.