Indirect Comparison of Cryoablation and Radiofrequency Ablation as Initial Therapy for Symptomatic Paroxysmal Atrial Fibrillation: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Data on first-line ablation treatment for patients with symptomatic atrial fibrillation (AF) are scarce. This study indirectly compared the efficacy and safety of cryoballoon ablation (CBA) versus radiofrequency ablation (RFA) as initial therapy for symptomatic AF. METHODS: We searched the EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov databases for randomized controlled trials (RCTs) that compared CBA or RFA with antiarrhythmic drugs (AADs) as first-line treatment for AF from the time of database establishment up to December 2021. The odds ratio (OR) with a 95% confidence interval (CI) was used as a measure of the treatment effect. RESULTS: Six RCTs (3 CBA, 3 RFA) that enrolled a total of 1,215 patients were included in this analysis. There were no significant differences in atrial arrhythmia (AA) (OR 0.993, 95% CI: 0.602-1.638), symptomatic AA (OR 0.638, 95% CI: 0.344-1.182), or serious adverse events (OR 1.474, 95% CI: 0.404-5.376) between the two ablation techniques. The incidences of additional CBA therapy (OR 2.693, 95% CI: 1.277-5.681) and patients who crossed over to AAD therapy (OR 0.345, 95% CI: 0.179-0.664) in the CBA group were significantly lower than those in the RFA group. CONCLUSION: Among patients with paroxysmal AF receiving initial therapy, CBA and RFA share a similar efficacy and safety profile. When pulmonary vein isolation is performed by CBA, study crossover and the need for additional ablation are substantially lower.

Meta-analysis of medical management versus catheter ablation for atrial fibrillation.

Several observational studies have shown a survival benefit for patients with atrial fibrillation (AF) who are treated with catheter ablation (CA) rather than medical management (MM). However, data from randomized controlled trials (RCTs) are uncertain. Therefore, we performed a meta-analysis of RCTs that compared the benefits of CA and MM in treatment of AF. We searched the Cochrane Library, PubMed, and EMBASE databases for RCTs that compared AF ablation with MM from the time of database establishment up to January 2020. The risk ratio (RR) with a 95% confidence interval (CI) was used as a measure treatment effect. Twenty-six RCTs that enrolled a total of 5788 patients were included in the meta-analysis. In this meta-analysis, the effect of AF ablation depended on the baseline level of left ventricular ejection fraction (LVEF) in the heart failure (HF) patients. AF ablation appears to be of benefit to patients with a lesser degree of advanced HF and better LVEF by reducing mortality. Meanwhile, this mortality advantage was manifested in long-term follow-up. CA increased the risk for hospitalization when it was used as first-line therapy and decreased the risk when used as second-line therapy. CA reduced recurrence of atrial arrhythmia for different types of AF (paroxysmal or persistent AF) and CA-related complications were non-negligible. There was no convincing evidence for a reduction in long-term stroke risk after AF ablation, and additional high quality RCTs are needed to address that issue.

sFRP1 protects H9c2 cardiac myoblasts from doxorubicin-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway.

Doxorubicin (Dox) is an effective chemotherapy drug against a wide range of cancers, including both hematological and solid tumors. However, the serious cardiotoxic effect restricted its clinical application. We previously have illuminated the protective role of canonical Wnt/ß-catenin signaling in Dox-induced cardiotoxicity. Secreted frizzled-related protein 1 (sFRP1) is one of the endogenous inhibitors of both canonical and noncanonical Wnt signaling. In this study, we investigated the relationship between sFRP1 and noncanonical Wnt/PCP-JNK (Wnt/planar cell polarity-c-Jun N-terminal kinase) pathway in Dox-induced cardiotoxicity in vitro and in vivo. We showed that treatment of H9c2 cardiac myoblasts with Dox (1 µM) time-dependently suppressed cell viability accompanied by significantly decreased sFRP1 protein level and increased Wnt/PCP-JNK signaling. Pretreatment with SP600125, the Wnt/PCP-JNK signaling inhibitor, attenuated Dox-induced apoptosis of H9c2 cells. Overexpression of sFRP1 protected H9c2 cells from Dox-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. After intraperitoneal injection of a cumulative dose of 15 mg/kg Dox, rats displayed significant cardiac dysfunction; their heart showed inhibited Wnt/ß-catenin signaling and activated Wnt/PCP-JNK signaling. These results suggest that sFRP1 may be a novel target for Dox-induced cardiotoxicity.

Enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7.

UDP-glucuronosyltransferases (UGTs)-catalyzed glucuronidation conjugation reaction plays an important role in the elimination of many important clinical drugs and endogenous substances. The present study aims to investigate the enantioselective inhibition of carprofen towards UGT isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation mixture was used to screen the inhibition potential of (R)-carprofen and (S)-carprofen towards multiple UGT isoforms. The results showed that (S)-carprofen exhibited stronger inhibition potential than (R)-carprofen towards UGT2B7. However, no significant difference was observed for the inhibition of (R)-carprofen and (S)-carprofen towards other UGT isoforms. Furthermore, the inhibition kinetic behavior was compared for the inhibition of (S)-carprofen and (R)-carprofen towards UGT2B7. A Lineweaver-Burk plot showed that both (S)-carprofen and (R)-carprofen exhibited competitive inhibition towards UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameter (Ki ) was calculated to be 7.0 µM and 31.1 µM for (S)-carprofen and (R)-carprofen, respectively. Based on the standard for drug-drug interaction, the threshold for (S)-carprofen and (R)-carprofen to induce a drug-drug interaction is 0.7 µM and 3.1 µM, respectively. In conclusion, enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7 was demonstrated in the present study. Using the in vitro inhibition kinetic parameter, the concentration threshold of (S)-carprofen and (R)-carprofen to possibly induce the drug-drug interaction was obtained. Therefore, clinical monitoring of the plasma concentration of (S)-carprofen is more important than (R)-carprofen to avoid a possible drug-drug interaction between carprofen and the drugs mainly undergoing UGT2B7-catalyzed metabolism.

Regulation profile of phosphatidylcholines (PCs) and lysophosphatidylcholines (LPCs) components towards UDP-glucuronosyltransferases (UGTs) isoforms.

1.Endogenous compounds have been reported to be the regulators of UDP-glucuronosyltransferases (UGTs) isoforms. This study aims to investigate the regulatory effects of the activity of UGT isoforms by two important lipid components phosphatidylcholine (PC) and lysophosphatidylcholines (LPC) using in vitro incubation system. 2.UGTs supersomes-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as the probe reaction to evaluate the inhibition of compounds towards UGT isoforms except UGT1A4, and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation reaction was utilized to phenotype the activity of UGT1A4. 3.About 50 µM of LPC15:0, LPC16:0, LPC17:0, LPC18:0, LPC18:1 and PC16:0, 2:0 exhibited inhibition towards more than 90% activity of UGT isoforms, and other LPC and PC components showed negligible inhibitory potential towards all the UGT isoforms. UGT1A6 and UGT1A8 were identified to be the most sensitive UGT isoforms susceptible for the inhibition by LPC15:0, LPC16:0, LPC17:0, LPC18:0, LPC18:1 and PC16:0, 2:0, indicating the strong influence of these LPC and PC components towards UGT1A6 and UGT1A8-catalyzed metabolic reaction when the concentrations of these components increased.

Arbidol exhibits strong inhibition towards UDP-glucuronosyltransferase (UGT) 1A9 and 2B7.

The aim of the present study was to investigate arbidol's inhibition towards UDP-glucuronosyltransferase (UGT) 1A9 and 2B7. The nonspecific probe substrate 4-methylumbelliferone (4-MU) and recombinant UGT enzymes (UGT1A9, UGT2B7) were firstly used to evaluate the inhibition of arbidol towards UGT1A9 and UGT2B7. Furthermore, specific substrates of UGT1A9 and UGT2B7 propofol and zidovudine (AZT) were used to determine the inhibition of arbidol towards UGT1A9 and UGT2B7. Inhibition type and inhibition kinetic parameters (Ki) were determined. In vitro-in vivo extrapolation (IV-IVE) was performed to predict in vivo DDI magnitude induced by arbidol. Arbidol was demonstrated to exhibit competitive inhibition towards UGT1A9 and UGT2B7 without substate-dependent behaviour. The inhibition kinetic parameters (Ki) were calculated to be 0.5 microM, 3.5 microM, 2.8 microM, 29.7 microM for UGT2B7-mediated 4-MU glucuronidation, UGT1A9-mediated 4-MU glucuronidation, UGT2B7-mediated AZT glucuronidation, and UGT1A9-mediated propofol glucuronidation, respectively. Using these parameters, the in vivo alteration of area under of concentration-time curve (AUC) was calculated to be 156%, 22%, 28% and 2.6%, respectively. Given that arbidol exhibits strong inhibition towards UGT1A9 and UGT2B7, clinical monitoring should be given when arbidol was co-administered with drugs mainly undergoing UGT1A9, UGT2B7-mediated metabolism.

Current Progress and Outlook for Agrimonolide: A Promising Bioactive Compound from Agrimonia pilosa Ledeb.

Agrimonolide (AM), which is a derivative of isocoumarins, is found mainly in the herb Agrimonia pilosa Ledeb. This compound is highly lipophilic and readily crosses the blood-brain barrier. In recent years, interest has grown in the use of AM as a multitarget natural treatment for various diseases, such as cancer, inflammation, hepatic injury, myocardial damage, and diabetes mellitus. The potential mechanisms of these pharmacological effects have been clarified at cellular and molecular levels. AM shows no cytotoxicity over a range of concentrations in different types of cells, providing evidence for its good safety profile in vitro. These findings indicate that AM is a promising medicinal agent. However, most studies on AM's pharmacological activities, mechanisms of action, and safety lack substantial animal or human data. Additionally, the pharmacokinetics, metabolism, and disposition of this compound have received little attention. This review highlights the status of current information regarding the sources, properties, pharmacological effects, and safety of AM. Furthermore, potential strategies to resolve problematic issues identified in previous studies are fully discussed. This summary and analysis of the research progress of AM may inspire deeper investigations and more extensive applications of AM in the future.

Drug-Drug Interactions Potential of Icariin and Its Intestinal Metabolites via Inhibition of Intestinal UDP-Glucuronosyltransferases.

Icariin is known as an indicative constituent of the Epimedium genus, which has been commonly used in Chinese herbal medicine to enhance treat impotence and improve sexual function, as well as for several other indications for over 2000 years. In this study, we aimed to investigate the effects of icariin and its intestinal metabolites on the activities of human UDP-glucuronosyltransferase (UGT) activities. Using a panel of recombinant human UGT isoforms, we found that icariin exhibited potent inhibition against UGT1A3. It is interesting that the intestinal metabolites of icariin exhibited a different inhibition profile compared with icariin. Different from icariin, icariside II was a potent inhibitor of UGT1A4, UGT1A7, UGT1A9, and UGT2B7, and icaritin was a potent inhibitor of UGT1A7 and UGT1A9. The potential for drug interactions in vivo was also quantitatively predicted and compared. The quantitative prediction of risks indicated that in vivo inhibition against intestinal UGT1A3, UGT1A4, and UGT1A7 would likely occur after oral administration of icariin products.

Meta-analysis of cryoballoon ablation versus antiarrhythmic drugs as initial therapy for symptomatic atrial fibrillation.

BACKGROUND: The optimal first-line approach for patients with symptomatic atrial fibrillation (AF) remains unclear. We compared the efficacy and safety of cryoballoon ablation (CBA) and antiarrhythmic drugs (AADs) in the initial management of symptomatic AF. HYPOTHESIS: CBA is superior to AAD as initial therapy for symptomatic AF. METHODS: We searched the EMBASE, PubMed, and Cochrane Library databases for randomized controlled trials (RCTs) that compared CBA with AAD as first-line treatment for AF from the date of database establishment until March 18, 2021. The risk ratio (RR) with a 95% confidence interval (CI) was used as a measure of treatment effect. RESULTS: Three RCTs that enrolled 724 patients in total were included in this meta-analysis. Majority of the patients were relatively young and had paroxysmal AF. CBA was associated with a significant reduction in the recurrence of atrial arrhythmia compared with AAD therapy, with low heterogeneity (RR, 0.59; 95% CI, 0.49-0.71; p < .00001; I2  = 0%). There was a significant difference in the rate of symptomatic atrial arrhythmia recurrence (RR, 0.44; 95% CI, 0.29-0.65; p < .0001; I2  = 0%); however, the rate of serious adverse events was similar between the two treatment groups (RR: 1.18; 95% CI: 0.71-1.97, p = .53; I2  = 0%). Transient phrenic nerve palsy occurred in four patients after the CBA procedure. CONCLUSION: The current meta-analysis suggests that CBA is more effective than AAD as initial therapy in patients with symptomatic paroxysmal AF. Serious iatrogenic adverse events are uncommon in CBAs.