His bundle pacing versus right ventricular pacing: A comparative study.

BACKGROUND: Pacing is the most effective and dependable method for treating complete atrioventricular block (AVB). OBJECTIVE: The purpose of this study is to investigate the use of His bundle pacing (HBP) in patients with atrioventricular block. METHODS: Patients who underwent HBP or right ventricular pacing (RVP) were enrolled and divided into two groups: the HBP group and the RVP group, respectively. We compared baseline clinical data, fluoroscopy duration, operation duration, pacing electrode parameters during the operation or follow-up, baseline QRS duration, and pacing QRS duration. RESULTS: HBP was attempted in 48 patients and was successful in 34 patients who were included in the HBP group. In addition, 30 RVP patients were included in the RVP group. Fluoroscopy duration and operation duration were significantly longer in the HBP group compared to the RVP group. Compared to the RVP group, the HBP group had a higher pacing threshold, a lower R wave amplitude, and a shorter pacing QRS duration. At 6 months of follow-up, the pacing threshold remained higher, the R wave amplitude was significantly lower, and the end-diastolic diameter of the left ventricle was smaller in the HBP group. CONCLUSION: HBP was safe and effective for atrioventricular block despite the longer fluoroscopy and operation duration in the HBP group when compared to the RVP group.

Imatinib-induced hepatotoxicity via oxidative stress and activation of NLRP3 inflammasome: an in vitro and in vivo study.

Imatinib (IM), a milestone drug used in the field of molecular targeted therapy, has been reported to cause serious adverse liver effects, including liver failure and even death. Immune-mediated injury and mitochondrial dysfunction are involved in drug-induced liver injury. However, the mechanism of IM-induced hepatotoxicity remains unclear and warrants further study. In our study, Sprague Dawley rats were administered IM by gavage with 50 mg/kg body weight (BW) once daily for 10 days. Drug-induced liver injury accompanied by inflammatory infiltration was observed in rats following IM exposure, and the expression of NOD-like receptor protein 3 (NLRP3) inflammasome-related proteins was significantly increased compared with that of the control. HepG2 cells were exposed to 0-100 µM IM for 24 h. The results showed that IM decreased cell viability in a dose-dependent manner. Moreover, IM induced a state of obvious oxidative stress and activation of nuclear factor kappa B (NF-κB) in cells, which resulted in the activation of NLRP3 inflammasomes, including caspase 1 cleavage and IL-1ß release. These results were significantly reduced after the use of the antioxidants N-acetyl-l-cysteine or the NF-κB inhibitor pyrrolidine di-thio-carbamate. Furthermore, NLRP3 knockdown significantly reduced the release of inflammatory cytokines and improved cell viability. In summary, our data demonstrated that oxidative stress and NLRP3 inflammasome activation are involved in the process of IM-induced hepatotoxicity. The results of this study provide a reference for the prevention and treatment of IM-induced hepatotoxicity.

Corosolic acid and its structural analogs: A systematic review of their biological activities and underlying mechanism of action.

BACKGROUND: The corosolic acid (CA), also known as plant insulin, is a pentacyclic triterpenoid extracted from plants such as Lagerstroemia speciosa. It has been shown to have anti-diabetic, anti-inflammatory and anti-tumor effects. Its structural analogs ursolic acid (UA), oleanolic acid (OA), maslinic acid (MA), asiatic acid (AA) and betulinic acid (BA) display similar individual pharmacological activities to those of CA. However, there is no systematic review documenting pharmacological activities of CA and its structural analogues. This study aims to fill this gap in literature. PURPOSE: This systematic review aims to summarize the medical applications of CA and its analogues. METHODS: A systematic review summarizes and compares the extraction techniques, pharmacokinetic parameters, and pharmacological effects of CA and its structural analogs. Hypoglycemic effect is one of the key inclusion criteria for searching Web of Science, PubMed, Embase and Cochrane databases up to October 2020 without language restrictions. 'corosolic acid', 'ursolic acid', 'oleanolic acid', 'maslinic acid', 'asiatic acid', 'betulinic acid', 'extraction', 'pharmacokinetic', 'pharmacological' were used to extract relevant literature. The PRISMA guidelines were followed. RESULTS: At the end of the searching process, 140 articles were selected for the systematic review. Information of CA and five of its structural analogs including UA, OA, MA, AA and BA were included in this review. CA and its structural analogs are pentacyclic triterpenes extracted from plants and they have low solubilities in water due to their rigid scaffold and hydrophobic properties. The introduction of water-soluble groups such as sugar or amino groups could increase the solubility of CA and its structural analogs. Their biological activities and underlying mechanism of action are reviewed and compared. CONCLUSION: CA and its structural analogs UA, OA, MA, AA and BA are demonstrated to show activities in lowering blood sugar, anti-inflammation and anti-tumor. Their oral absorption and bioavailability can be improved through structural modification and formulation design. CA and its structural analogs are promising natural product-based lead compounds for further development and mechanistic studies.

Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects.

BACKGROUND: Our study aims to explore the effect of genetics on the pharmacodynamics (PD) and pharmacokinetics (PK) of cinacalcet in healthy Chinese subjects; to investigate the effect of dietary factors on cinacalcet, and to evaluate the safety of cinacalcet under fasting and non-fasting conditions using a bioequivalence trial. METHODS: We investigated the relationship of cinacalcet PK with single nucleotide polymorphisms (SNPs) of CYP3A4, CYP1A2 and CYP2D6, and of cinacalcet PD with SNPs of calcium-sensitive receptors (CASR) and vitamin D receptors (VDR) in 65 healthy Chinese subjects recruited to participate in this study. Our study was a phase I, open-label, randomized, two-period, two-sequence crossover, a single-center clinical study designed under both fasting and non-fasting conditions to investigate the effect of dietary factors on cinacalcet. Plasma cinacalcet concentrations were analyzed using a validated HPLC-MS/MS assay. Clinical laboratory tests evaluated safety. Thirteen SNPs of CASR, VDR, and CYP genes were selected for pharmacogenetic analysis. RESULTS: CYP3A4 rs4646437 was found to be associated with the PK of cinacalcet under fasting conditions (P<0.01). Subjects carrying T alleles of rs4646437 appeared to metabolize cinacalcet poorly. The Cmax and AUC of subjects in the non-fasting group were significantly higher (P<0.0001) than those in the fasting group. The Tmax, CL/F, and Vd/F in the fasting group were significantly higher (P<0.0001) than those in the non-fasting group. In the fasting group, the geometric least square mean ratios (T/R) of the Cmax and AUC0-t were 109.89% and 105.33%, and the corresponding 90% CIs were 98.36-122.79% and 98.04-113.15%, respectively. In the non-fasting group, the T/R of the Cmax and AUC0-t were 100.74% and 99.09%, and the corresponding 90% CIs were 92.65-109.54% and 94.79-103.58%, respectively. All adverse events (AEs) were mild, and no serious adverse events (SAEs) occurred during the bioequivalence trial. CONCLUSIONS: Following our investigation, we reached the following conclusions: CYP3A4 rs4646437 may affect cinacalcet PK; the reference and test preparations of cinacalcet were bioequivalent under fasting and non-fasting conditions and were safe to use; and dietary factors had a significant effect on the PK of cinacalcet, in that exposure to the drug increased when cinacalcet was taken after eating.

[The predictive value of mild renal insufficiency on the prognosis of patients with acute coronary syndrome].

OBJECTIVE: To investigate the predictive value of mild renal insufficiency on the endpoint events in patients with acute coronary syndrome (ACS). METHODS: A total of 552 patients with ACS were enrolled in the present study. According to the levels of estimated glomerular filtration rate (eGFR), patients were divided into two groups, normal renal function (eGFR ≥ 90 ml×min(-1)×1.73 m(-2)) and mild renal insufficiency (60 ≤ eGFR<90 ml×min(-1)×1.73 m(-2)). The primary and secondary events were collected and analyzed through the present prospective follow-up study. RESULTS: The patients in mild renal insufficiency group had a higher incidence of the primary endpoint events than normal renal function group [31 cases (12.6%) vs 15 cases (4.9%), P = 0.001]. There was no difference of the secondary endpoint events incidence in the two groups. The incidence rate of all-cause mortality [8.9% (22 cases) vs 2.2% (7 cases), P < 0.001] and cardiac death [6.5% (16 cases) vs 1.3% (4 cases), P = 0.001] was higher in mild renal insufficiency group, but there was no statistical difference of incidence rate of no fatal stroke and myocardial infarction in the two groups. The results of COX regression analysis showed that the incidence of primary endpoint events in patients with mild renal dysfunction was 2.265 folds (95%CI 1.076-4.771, P = 0.031) of patients with normal renal function. Further analysis indicated that the predictive value of mild renal insufficiency was only for all-cause mortality (HR 3.118, 95%CI 1.197-8.125, P = 0.020), not for heart failure and revascularization. According to the Kaplan-Meier curves results, the incidences of the primary endpoint events (P = 0.004) and all-cause mortality (P = 0.001) were higher in mild renal insufficiency group than in normal renal function group. CONCLUSION: Mild renal insufficiency has important predictive value for primary endpoint events in patients with ACS.

Total cholesterol content of erythrocyte membranes levels are associated with the presence of acute coronary syndrome and high sensitivity C-reactive protein.

In this study we assessed whether total cholesterol content of erythrocyte membranes (CEM) was associated with the presence of acute coronary syndrome (ACS) and high sensitivity C-reactive protein (hs-CRP). Consecutive angina patients were assessed; 98 had ACS and 45 had stable angina pectoris (SAP). CEM in the ACS group was significantly higher compared with the SAP group (p< 0.05). Multiple logistic regression analyses revealed a significant independent relation between CEM and the presence of ACS (OR 24.990, p<0.001). CEM was positively correlated with serum hs-CRP levels (r=0.328, p<0.001). These findings suggest a potential role of CEM as a marker of vulnerable plaque.