Effectiveness and safety of glucagon-like peptide 1 receptor agonists in patients with type 2 diabetes: evidence from a retrospective real-world study.

Introduction: Global phase III clinical trials have shown superior hypoglycemic efficacy to insulin and other oral hypoglycemic agents. However, there is a scarcity of real-world data comparing different glucagon-like peptide 1 receptor agonist (GLP-1RA) directly. This study aimed to assess the safety and effectiveness of various GLP-1RA in treating type 2 diabetes mellitus (T2DM) in a real-world clinical setting and identify predictive factors for favorable treatment outcomes. Methods: This was a retrospective, single-center, real-world study. The changes in HbA1c, fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), and the percentage of participants who achieved HbA1c of <7%, 7%-8%, and ≥ 8% after GLP-1RA treatment was analyzed. The clinical factors that affect the effectiveness of GLP-1RA were analyzed. Results: At baseline, the 249 participants had a mean baseline HbA1c of 8.7 ± 1.1%. After at least three months of follow-up, the change in HbA1c was -0.89 ± 1.3% from baseline. Dulaglutide exerted a more significant hypoglycemic effect than immediate-release exenatide. The percentage of participants who achieved HbA1c<7% was substantial, from 6.0% at baseline to 28.9%. Average body weight decreased by 2.02 ± 3.8 kg compared to baseline. After GLP-1RA treatment, the reduction in SBP was 2.4 ± 7.1 mmHg from baseline. A shorter duration of diabetes and a higher baseline HbA1c level were more likely to achieve a good response in blood glucose reduction. Conclusions: This study provided real-world evidence showing that GLP-1RA significantly improved HbA1c, body weight, and SBP. The results can inform the decision-making about GLP-1RA treatment in daily clinical practice.

Cardiovascular adverse events induced by immune checkpoint inhibitors: A real world study from 2018 to 2022.

Background: The reported rate of cardiovascular adverse events (CAE) caused by immune checkpoint inhibitors (ICI) is low but potentially fatal. Assess the risk of CAE in cancer patients and compare the incidence of CAE between Chinese developed ICIs and imported ICIs. Methods: A retrospective analysis was performed on cancer patients treated with ICI for at least four cycles in the Second Affiliated Hospital of Dalian Medical University from January 2018 to March 2022. Baseline characteristics, physiological and biochemical values, electrocardiographic and echocardiographic findings were compared between patients with and without CAE. Results: Among 495 patients treated with ICIs, CAEs occurred in 64 patients (12.93%). The median time to the event was 105 days (61-202). The patients with low neutrophil-to-lymphocyte ratio (L-NLR) were significantly associated with the risk of developing CAE (hazard ratio HR 3.64, 95% confidence ratio CI 1.86-7.15, P = 0.000). Patients with higher comorbidity burden significantly increased the risk of developing CAE (HR 1.30, 95% CI 1.05-1.61, P = 0.014). Those who received a combination of ICI and vascular endothelial growth factor receptor (VEGFR) inhibitors (HR 2.57, 95% CI 1.37-4.84, P = 0.003) or thoracic radiation therapy (HR 32.93, 95% CI 8.81-123.14, P = 0.000) were at a significantly increased risk of developing CAE. Compared to baseline values, creatine kinase is -oenzymes (CK-MB) (95% CI -9.73 to -2.20, P = 0.003) and cardiac troponin I (cTnI) (95% CI -1.06 to -0.06, P = 0.028) were elevated, and the QTc interval prolonged (95% CI -27.07 to -6.49, P = 0.002). Using nivolumab as a control, there was no difference in CAE risk among the eight ICIs investigated. However, the results of the propensity matching showed that programmed death-ligand 1 (PD-L1) inhibitors had lower CAE occurrence compared with programmed cell death protein 1 (PD-1) inhibitors (adjusted HR = 0.38, P = 0.045). Conclusion: Patients who received concurrent VEGFR inhibitors and ICIs had a history of thoracic radiation therapy, L-NLR, and higher comorbidity burden had an increased risk of CAEs. Elevated cTnI, CK-MB, and QTc, can be used to monitor CAEs. There was no significant difference in CAE risks between Chinese domestic and imported ICIs. PD-L1 inhibitors had lower CAE occurrence than PD-1 inhibitors.

Analysis based on Monte Carlo simulation: How effective is tigecycline in routine antimicrobial therapy?

OBJECTIVE: This paper aims to assess the efficacy of tigecycline in the treatment of several different infections from a pharmacokinetic/pharmacodynamic (PK/PD) perspective. MATERIALS AND METHODS: The minimum inhibitory concentration (MIC) test strip test was used to determine the MICs of clinical isolates of tigecycline. A 5,000-subjects simulation was performed by Crystal Ball software to calculate the probability of achieving the required PK/PD exposure. RESULTS: The use of standard tigecycline dosing is predicted to have a good clinical outcome for patients suffering from complicated skin and skin structure infection (cSSSI) with MICs ≤ 0.25 mg×L-1, patients suffering from complicated intra-abdominal infection (cIAI) with MICs ≤ 1 mg×L-1, and patients suffering from hospital-acquired pneumonia (HAP) with MICs ≤ 0.5 mg×L-1. Generally, Gram-positive bacteria are highly sensitive to tigecycline, while Gram-negative bacteria are less sensitive: for patients with HAP and cIAI, the tolerable outcome was achieved using the standard regimen for most Gram-negative pathogens; the desired outcomes could be obtained for the increased-dose treatment; with increasing dose (100 mg every 12 hours), the average cumulative fractions of response (CFRs) markedly increased from 38.18 to 56.21% for cSSSI patients. When tigecycline, a standard regimen, was used to treat carbapenem-resistant Klebsiella pneumoniae (CRKP) and carbapenem-resistant Enterobacter spp. (CRE) infections, the cumulative response scores were 4.96 - 66.39% and 13.14 - 95.18%, respectively, and the CFRs of the increased dose also increased correspondingly. CONCLUSION: Currently, the standard dose of tigecycline is feasible in the treatment of common bacterial infections, and PK/PD indexes are needed to optimize the regimens for refractory carbapenem-resistant bacterial infections.

The optimization conditions of establishing an H9c2 cardiomyocyte hypoxia/reoxygenation injury model based on an AnaeroPack System.

Ischemia-reperfusion (I/R) injury is a major cause of cardiomyocyte apoptosis after vascular recanalization, which was mimicked by a hypoxia/reoxygenation (H/R) injury model of cardiomyocytes in vitro. In this study, we explored an optimal H/R duration procedure using the AnaeroPack System. To study the H/R procedure, cardiomyocytes were exposed to the AnaeroPack System with sugar and serum-free medium, followed by reoxygenation under normal conditions. Cell injury was detected through lactate dehydrogenase (LDH) and cardiac troponin (c-Tn) release, morphological changes, cell apoptosis, and expression of apoptosis-related proteins. The results showed that the damage to H9c2 cells increased with prolonged hypoxia time, as demonstrated by increased apoptosis rate, LDH and c-Tn release, HIF-1α expression, as well as decreased expression of Bcl-2. Furthermore, hypoxia for 10 h and reoxygenation for 6 h exhibited the highest apoptosis rate and damage and cytokine release; in addition, cells were deformed, small, and visibly round. After 12 h of hypoxia, the majority of the cells were dead. Taken together, this study showed that subjecting H9c2 cells to the AnaeroPack System for 10 h and reoxygenation for 6 h can achieve a practicable and repeatable H/R injury model.

Safety and Efficacy of Tigecycline in Intensive Care Unit Patients Based on Therapeutic Drug Monitoring.

OBJECTIVE: Tigecycline exerts significant beneficial effects against drug-resistant bacterial infections. The largely empirical medications used in clinical practice are often associated with wide individual differences in efficacy and safety. We investigated the associations between the pharmacokinetics of tigecycline and its efficacy and safety in intensive care unit (ICU) patients, with the aim of facilitating clinical applications of tigecycline. METHODS: ICU patients who were prescribed tigecycline in a hospital setting were prospectively included. Factors related to the clinical efficacy and safety of tigecycline were assessed by univariate and multivariate analyses. RESULTS: This study included 45 patients, from whom a total of 63 blood samples were collected to determine steady-state trough plasma concentrations (Cmin) of tigecycline. The Cmin of tigecycline was 417.1 ± 263.8 ng/mL (mean ± SD). The multivariate analysis showed that the APACHE II scores [odds ratio (OR) = 0.874, 95% confidence interval (CI) = 0.733-0.901, P = 0.048] were significantly correlated with the efficacy of tigecycline, whereas there was no correlation between Cmin of tigecycline and efficacy. In safety, the risk factors significantly associated with hepatotoxicity were sex (OR = 0.562, 95% CI = 0.191-0.774, P = 0.023), APACHE II score (OR = 1.061, 95% CI = 1.039-1.392, P = 0.045), and Cmin (OR = 1.210, 95% CI = 1.014-1.336, P = 0.008). The optimal cut-off for hepatotoxicity in ICU patients treated with tigecycline was 474.8 ng/mL. CONCLUSIONS: There was considerable variability in the Cmin of tigecycline among the ICU patients in this study and it is at risk of high exposure in women. Cmin can be a useful predictor of hepatotoxicity with a cut-off of 474.8 ng/mL.

Geniposide Alleviates Traumatic Brain Injury in Rats Via Anti-Inflammatory Effect and MAPK/NF-kB Inhibition.

We aimed to investigate whether geniposide, a main component extracted from Gardenia jasminoides Ellis fruit, could exert neuroprotective functions against traumatic brain injury (TBI). Enzyme-linked immunosorbent assay (ELISA) was used for detection of plasma cytokines. Real-time polymerase chain reaction (RT-PCR) was employed for measurements of mRNA levels of cytokines. Neurological outcomes were evaluated by modified neurological severity score (mNSS) and Rota-Rod. Blood-brain barrier (BBB) integrity and brain edema were assessed. Protein expression was tested by Western blot. The plasma levels of interleukin (IL)-1ß, IL-6, IL-8 and IL-10 were all elevated in patients with TBI compared to those of healthy controls. TBI rats treated with geniposide showed lower mNSS and longer fall latency time than untreated TBI rats. BBB integrity was maintained and brain edema was reduced by geniposide treatment in TBI rats. Plasma levels of IL-1ß, IL-6 and IL-8 were significantly repressed by geniposide treatment in TBI rats, whereas IL-10 level was upregulated. mRNA expression levels of these cytokines in the brain tissues of TBI rats exhibited the same trends of changes. By testing p38 mitogen-activated protein kinase and NF-κB p65 activities, it was observed that phosphorylated (p)-p38 and p-p65 were dramatically inhibited by geniposide. In conclusion, geniposide exerts neuroprotective functions against TBI by inhibiting p-p38 and p-p65.

Simultaneous Quantification of Methotrexate and Its Metabolite 7-Hydroxy-Methotrexate in Human Plasma for Therapeutic Drug Monitoring.

OBJECTIVE: To establish and validate a simple, sensitive, and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the determination of methotrexate (MTX) and its major metabolite 7-hydroxy-methotrexate (7-OH-MTX) in human plasma. METHOD: The chromatographic separation was achieved on a Zorbax C18 column (3.5 µm, 2.1 × 100 mm) using a gradient elution with methanol (phase B) and 0.2% formic acid aqueous solution (phase A). The flow rate was 0.3 mL/min with analytical time of 3.5 min. Mass spectrometry detection was performed in a triple-quadruple tandem mass spectrometer under positive ion mode with the following mass transitions: m/z 455.1/308.1 for MTX, 471.0/324.1 for 7-OH-MTX, and 458.2/311.1 for internal standard. The pretreatment procedure was optimized with dilution after one-step protein precipitation. RESULTS: The calibration range of methotrexate and 7-OH-MTX was 5.0-10000.0 ng/mL. The intraday and interday precision and accuracy were less than 15% and within ±15% for both analytes. The recovery for MTX and 7-OH-MTX was more than 90% and the matrix effect ranged from 97.90% to 117.60%. CONCLUSION: The method was successfully developed and applied to the routine therapeutic drug monitoring of MTX and 7-OH-MTX in human plasma.

Genetic association between CD86 polymorphisms and the risk of sepsis in a Chinese Han population.

BACKGROUND: Sepsis is a clinical syndrome that is frequently observed after injury or infection, representing a leading cause of mortality worldwide. CD86 (B7-2) is a co-stimulatory molecule on antigen-presenting cells, and plays critical roles in immune responses. METHODS: A total of 135 sepsis patients and 151 healthy controls were recruited in the current case-control study. Hardy-Weinberg equilibrium (HWE) conformity was examined to assess the representativeness of the study population. CD86 gene polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The relative expression of CD86 mRNA was estimated via quantitative real-time PCR (qRT-PCR). Chi-square test was performed to estimate the associations between CD86 gene polymorphisms and sepsis risk, and the results were presented through odds ratio (OR) and 95% confidence intervals (CI). RESULTS: The genotype distributions of CD86 polymorphisms in the case and control groups conformed to HWE. The GA genotype of the polymorphism rs1129055 was significantly correlated with an increased risk of sepsis (OR = 2.540, 95%CI = 1.288-5.008). The TT genotype of rs1915087 was a risk factor for sepsis (OR = 2.769, 95%CI = 1.292-5.935). High linkage disequilibrium was observed between the two polymorphisms (D' = 1.0, r2 = 0.955). However, no significant association was observed between CD86 polymorphisms and its gene expressions (P > 0.05 for all). CONCLUSION: CD86 gene polymorphisms rs1129055 and rs1915087 may increase the risk of sepsis.

Stereoselective activity of 2-(4-amino-3-chloro-5- trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride to improve the pulmonary function in asthma.

Asthma is a chronic airway disease that is characterized by significantly exacerbated bronchospasms and marked inflammation of the airways. Although the etiology of asthma remains to be determined, genetic predisposition is one of the factors involved. ß2-agonists compounds may serve as options for the treatment of bronchial asthma. The aim of the present study was to investigate the effects of 2-(4-amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride (SPFF) and its enantiomers with regard to improving asthmatic pulmonary function and selective binding to ß2-adrenergic receptor. The bronchoconstrictor action of histamine in guinea pigs was conducted and the results demonstrated that (-)SPFF and (±)SPFF could significantly inhibit the increase of bronchoconstriction induced by histamine, while (+)SPFF did not show an effect. Inflammatory mediator release from allergic lung tissues was determined and it was found that (±)SPFF showed the highest activity among all the tested compounds, while the efficacy of (-)SPFF was similar to that of (+)SPFF. SPFF and its enantiomers stimulated cyclic adenosine monophosphate (cAMP) production in the asthmatic lung tissues examined, showing that asthmatic lung tissues had a significant cAMP enhancement in response to (-)SPFF and (±)SPFF compared with (+)SPFF. Cardiac contractility of the right atria was assessed in the guinea pigs to establish the receptor selectivity of the compounds. The results indicated that all the compounds had high affinities to the ß2 receptor. In conclusion, with regards to asthmatic pulmonary function improvement, (-)SPFF was more efficient as compared to (+)SPFF, while no significant difference was observed for the receptor selectivity of (-)SPFF and (+)SPFF.