Palladium-catalyzed stereoselective ring-opening reaction of aryl cyclopropyl ketones.

Herein, we report that α,ß-unsaturated ketones could be obtained by palladium-catalyzed ring-opening of mono-substituted cyclopropyl ketones efficiently and systematically. (E)-1-Arylbut-2-en-1-ones were generated from aryl cyclopropyl ketones stereoselectively in yields of 23-89% by the Pd(OAc)2/PCy3 catalytic system. The reaction exhibited stereoselectivity (only E products were found) and was suitable for both phenyl and heteroaryl cyclopropyl ketones.

A network meta-analysis: evaluating the efficacy and safety of concurrent proton pump inhibitors and clopidogrel therapy in post-PCI patients.

Introduction: The objective of this research was to evaluate the risk of major adverse cardiovascular events (MACEs) associated with the use of various proton pump inhibitors (PPIs) in combination with clopidogrel in patients who underwent percutaneous coronary intervention (PCI). Methods: To accomplish this, we analyzed data from randomized controlled trials and retrospective cohort studies sourced from key electronic databases. These studies specifically examined the effects of different PPIs, such as lansoprazole, esomeprazole, omeprazole, rabeprazole, and pantoprazole, when used in conjunction with clopidogrel on MACEs. The primary focus was on the differential impact of these PPIs, while the secondary focus was on the comparison of gastrointestinal (GI) bleeding events in groups receiving different PPIs with clopidogrel vs. a placebo group. This study's protocol was officially registered with INPLASY (INPLASY2024-2-0009). Results: We conducted a network meta-analysis involving 16 studies with a total of 145,999 patients. Our findings indicated that rabeprazole when combined with clopidogrel, had the lowest increase in MACE risk (effect size, 1.05, 95% CI: 0.66-1.66), while lansoprazole was associated with the highest risk increase (effect size, 1.48, 95% CI: 1.22-1.80). Esomeprazole (effect size, 1.28, 95% CI: 1.09-1.51), omeprazole (effect size, 1.23, 95% CI: 1.07-1.43), and pantoprazole (effect size, 1.38, 95% CI: 1.18-1.60) also significantly increased MACE risk. For the secondary outcome, esomeprazole (effect size, 0.30, 95% CI: 0.09-0.94), omeprazole (effect size, 0.34, 95% CI: 0.14-0.81), and pantoprazole (effect size, 0.33, 95% CI: 0.13-0.84) demonstrated an increased potential for GI bleeding prevention. Conclusions: In conclusion, the combination of lansoprazole and clopidogrel was found to significantly elevate the risk of MACEs without offering GI protection in post-PCI patients. This study is the first network meta-analysis to identify the most effective regimen for the concurrent use of clopidogrel with individual PPIs. Systematic Review Registration: https://inplasy.com/inplasy-2024-2-0009/, identifier (INPLASY2024-2-0009).

Precipitating factors of bradycardia after remdesivir administration: ICU admission and cutoff value for declining heart rate.

BACKGROUND: Despite increasing concerns about the association between remdesivir and bradycardia in severe coronavirus disease 2019 (COVID-19) patients receiving remdesivir, information on its clinical course and precipitating factors is limited. Our aim was to investigate possible triggers of bradycardia after remdesivir administration. METHODS: We retrieved the medical records of hospitalized severe and critical COVID-19 patients who received remdesivir from May 1, 2021 to June 30, 2021. Bradycardia was defined as two episodes of a heart rate (HR) < 60 bpm in 24 h. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the discriminability of heart rate pattern on the occurrence of bradycardia. The precipitating factors of bradycardia were examined by a logistic regression model. RESULTS: Regardless of bradycardia status, the median heart rate dropped during remdesivir treatment (from 85 to 72 bpm, p < 0.001), with the heart rate dropping considerably within the first two days of remdesivir treatment. Among various heart rate descriptors, HR ratiomin (d2-d1) had the best discrimination (AUC = 0.7336), and a reduction in HR ratiomin (d2-d1) by 14.65% was associated with bradycardia. Intensive care unit (ICU) admission was associated with an increased risk of bradycardia (odds ratio: 3.41; 95% CI: 1.12-10.41). CONCLUSIONS: In severe COVID-19 patients receiving remdesivir, the risks of bradycardia were influenced by a substantial reduction in heart rate during the first two days of remdesivir treatment and ICU admission. These findings suggest that clinical practitioners should intensively monitor heart rates during remdesivir treatment.

Combined Effects of Frailty and Polypharmacy on Health Outcomes in Older Adults: Frailty Outweighs Polypharmacy.

OBJECTIVES: Existing studies cannot evaluate the time-varying properties of frailty and polypharmacy despite raising concerns about their combined effects in older individuals. This study investigated the longitudinal association between different combined statuses of frailty and polypharmacy on risks of adverse outcomes. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Subjects aged between 65 and 100 years (n = 100,000) were identified from Taiwan's National Health Insurance Research Database. MEASURES: Frailty was categorized into fit, mild, moderate, and severe frailty based on the multimorbidity frailty index. Concomitant use of 5 to 9 and ≥10 chronic medications was considered polypharmacy and excessive polypharmacy. We used generalized estimating equation models to examine the association among 12 groups of combined effects of frailty and polypharmacy and risks of all-cause mortality, all-cause hospitalization, and unplanned hospitalization. Age-stratified analyses were conducted for those aged 65 to 74, 75 to 84, and 85+ years. RESULTS: Compared with fit without polypharmacy, severe frailty with excess polypharmacy was associated with increased risks of adverse outcomes, particularly unplanned hospitalization (adjusted relative risk (aRR): 20.01 [95% confidence interval (CI)] 19.30-20.75). However, the combined effects varied in distinct groups. Within each polypharmacy category, there were dose-response associations between frailty category and adverse outcomes. For instance, within the polypharmacy group, the aRRs of mortality were 1.58 (1.52-1.64), 2.70 (2.60-2.80), 4.62 (4.44-4.82), and 6.81 (6.50-7.13) for the fit and mild, moderate, and severe frailty groups, respectively. By contrast, within each frailty category, the dose-response association between polypharmacy and adverse outcomes was limited to fit and mildly frail people. Age-stratified analyses yielded similar results. CONCLUSIONS AND RELEVANCE: Both frailty and polypharmacy modified the risks of mortality and hospital admissions in older people, but the combined effects varied in distinct groups. This study thus highlights the potential to optimize care of older people by capturing the dynamic and combined changes related to frailty and polypharmacy.

Influence of sulfation on anti-myocardial ischemic activity of Ophiopogon japonicus polysaccharide.

Ophiopogon japonicus polysaccharide (FOJ-5) from Radix ophiopogonis has shown anti-myocardial ischemic action in vitro and in vivo in our previous studies. In order to clarify the influence of chemical modifications on the action, a series of sulfated FOJ-5 (FOJ-5-S) with different substitution degrees were prepared and the anti-myocardial ischemic action of the natural FOJ-5 and the FOJ-5-S were studied in vitro and in vivo. Langendorff isolated rat hearts and acute myocardial ischemic rats induced by isoprenaline were employed as myocardial ischemic models in our experiments. The amplitude and frequency of cardiac contraction, coronary blood flow at different time points after ischemia/reperfusion were measured in vitro. The ST segment shift in electrocardiogram and lactate dehydrogenase level in blood plasma were observed on the in vivo model. The results indicated that FOJ-5 and FOJ-5-S had the anti-myocardial ischemic action compared with non-treated vehicle groups. Furthermore, it was found that FOJ-5-S had significant action on the in vivo model compared with FOJ-5 (P < 0.05). And the obtained results from the further study also indicated that only when the degree of substitution was in a certain range, the FOJ-5-S had excellent anti-myocardial ischemic activity.

The preparation, characterization, and pharmacokinetic studies of chitosan nanoparticles loaded with paclitaxel/dimethyl-ß-cyclodextrin inclusion complexes.

A novel biocompatible and biodegradable drug-delivery nanoparticle (NP) has been developed to minimize the severe side effects of the poorly water-soluble anticancer drug paclitaxel (PTX) for clinical use. PTX was loaded into the hydrophobic cavity of a hydrophilic cyclodextrin derivative, heptakis (2,6-di-O-methyl)-ß-cyclodextrin (DM-ß-CD), using an aqueous solution-stirring method followed by lyophilization. The resulting PTX/DM-ß-CD inclusion complex dramatically enhanced the solubility of PTX in water and was directly incorporated into chitosan (CS) to form NPs (with a size of 323.9-407.8 nm in diameter) using an ionic gelation method. The formed NPs had a zeta potential of +15.9-23.3 mV and showed high colloidal stability. With the same weight ratio of PTX to CS of 0.7, the loading efficiency of the PTX/DM-ß-CD inclusion complex-loaded CS NPs was 30.3-fold higher than that of the PTX-loaded CS NPs. Moreover, it is notable that PTX was released from the DM-ß-CD/CS NPs in a sustained-release manner. The pharmacokinetic studies revealed that, compared with reference formulation (Taxol(®)), the PTX/DM-ß-CD inclusion complex-loaded CS NPs exhibited a significant increase in AUC(0→24h) (the area under the plasma drug concentration-time curve over the period of 24 hours) and mean residence time by 2.7-fold and 1.4-fold, respectively. Therefore, the novel drug/DM-ß-CD inclusion complex-loaded CS NPs have promising applications for the significantly improved delivery and controlled release of the poorly water-soluble drug PTX or its derivatives, thus possibly leading to enhanced therapeutic efficacy and less severe side effects.