A double-blind, randomized, two-part, two-period crossover study to evaluate the pharmacokinetics of caffeine versus d9-caffeine in healthy subjects.

The deuterium kinetic isotope effect has been used to affect the cytochrome P450 metabolism of the deuterated versions of substances. This study compares the pharmacokinetics of caffeine, a Generally Recognized As Safe food and beverage ingredient, versus d9-caffeine, a potential caffeine alternative, and their respective metabolites at two dose levels in 20 healthy adults. A single dose of 50 mg or 250 mg of caffeine, or a molar-equivalent dose of d9-caffeine, were orally administered in solution with blood samples collected for up to 48 h post-dose. Plasma concentrations of parent and metabolites were analyzed using validated LC-MS/MS methods. Both d9-caffeine and caffeine were rapidly absorbed; however, d9-caffeine exhibited a higher (ca. 29%-43%) Cmax and 4-5-fold higher AUClast than caffeine, and lower Cmax, lower AUClast, and a 5-10-fold reduction in the relative exposure to the active metabolites of caffeine. Results were consistent in normal and rapid metabolizers, and both substances were well tolerated.

Pharmacokinetic, pharmacological, and genotoxic evaluation of deuterated caffeine.

Altering caffeine's negative physiological effects and extending its duration of activity is an active area of research; however, deuteration as a means of achieving these goals is unexplored. Deuteration substitutes one or more of the hydrogen atoms of a substance with deuterium, a stable isotope of hydrogen that contains an extra neutron. Deuteration can potentially alter the metabolic profile of a substance, while maintaining its pharmacodynamic properties. d9-Caffeine is a deuterated isotopologue of caffeine with the nine hydrogens contained in the 1, 3, and 7 methyl groups of caffeine substituted with deuterium. d9-Caffeine may prove to be an alternative to caffeine that may be consumed with less frequency, at lower doses, and with less exposure to downstream active metabolites of caffeine. Characterization of d9-caffeine's genotoxic potential, pharmacodynamic, and pharmacokinetic behavior is critical in establishing how it may differ from caffeine. d9-Caffeine was non-genotoxic with and without metabolic activation in both a bacterial reverse mutation assay and a human mammalian cell micronucleus assay at concentrations up to the ICH concentration limits. d9-Caffeine exhibited a prolonged systemic and brain exposure time in rats as compared to caffeine following oral administration. The adenosine receptor antagonist potency of d9-caffeine was similar to caffeine.

Tracking of fluorescent antibiotic conjugate in planta utilizing fluorescence lifetime imaging.

MAIN CONCLUSION: Excited state lifetime-based separation of fluorophore-tagged antibiotic conjugate emission from the spectrally broad plant autofluorescence enables in planta tracking of the translocation of systemic cargo such as antibiotics via fluorescence lifetime imaging. The efficacy of antibiotic treatments in citrus crops is uncertain due to mixed results from in-field experiments and a lack of study on their systemic movement. As of yet there has been an inability to track treatments using traditional fluorescence microscopy due to treatments having little fluorescence characteristics, and signal convolution due to plant autofluorescence. In this study, we used streptomycin sulfate, a commercially available antibiotic, and conjugated it to a modified tris(bipyridine) ruthenium (II) chloride, a dye with an excited state lifetime magnitudes higher than other commonly used organic fluorescent probes. The resultant is a fluorescence lifetime imaging (FLIM) trackable antibiotic conjugate, covalently attached via an amide linkage that is uniquely distinguishable from plant autofluorescence. Characterization of the fluorescent antibiotic conjugate showed no mitigation of excited state lifetime, and a distinct IR peak not found in any synthetic components. Subsequent tracking using FLIM in citrus tissue was achieved, with identification of movement through citrus plant vasculature via tissue localization in xylem and phloem. Results indicated upwards systemic movement of the conjugate in both xylem and phloem after 48 h of incubation. However, the conjugate failed to move down towards the root system of the plant by 168 h. Mechanistically, it is likely that xylem contributes heavily in the translocation of the conjugate upwards; however, phloem led flow due to growth changes could act as a contributor. This proof-of-concept sets groundwork for subsequent studies regarding antibiotic localization and movement in citrus.

Sedation with Propofol During Catheter-Directed Thrombolysis for Acute Submassive Pulmonary Embolism Is Associated with Increased Mortality.

PURPOSE: To evaluate if sedation with propofol during catheter-directed thrombolysis (CDT) in patients with acute submassive pulmonary embolism (PE) affects survival. MATERIALS AND METHODS: This single-institution, retrospective study identified 136 patients from 2011-2017 who underwent CDT for acute submassive PE. Patients were grouped based on procedural sedation-propofol versus fentanyl and/or midazolam. Groups were compared for differences in baseline characteristics. Primary endpoint was in-hospital mortality. Logistic regression analysis was performed to evaluate for independent variables predictive of mortality. Propensity-matched analysis was also performed. RESULTS: Propofol was given to 18% (n = 25) of patients, and fentanyl and/or midazolam was given to 82% (n = 111) of patients. Mortality was 28% (n = 7) in the propofol group versus 3% (n = 3) in the fentanyl/midazolam group (P = .0003). Patients receiving propofol had 10.4 times the risk of cardiopulmonary arrest or dying during hospitalization compared with patients receiving fentanyl and/or midazolam (95% confidence interval, 2.9-37.3, P = .0003). The number needed to harm was 4 (95% confidence interval, 2.8-6.8). Logistic regression model analysis including Pulmonary Embolism Severity Index score, right-to-left ventricle diameter ratio and age was not predictive of mortality (P = .19). Adding type of sedation made the model predictive of mortality (P < .001). Propensity-matched analysis controlling for baseline differences in age, adjunctive maneuvers, American Society of Anesthesiologists class, and intubation before the procedure revealed that statistical significance between groups remained (P = .01). CONCLUSIONS: Sedation with propofol during CDT for acute submassive PE is associated with increased mortality and should be used with caution.

Anomalous Coronary Anatomy with Fistula Diagnosed on Coronary Computed Tomography Angiography.

Anomalous coronary vasculature is a rare finding among the general population. Identifying such cases is important for preventing adverse outcomes such as sudden cardiac death. We present two rare cases of aberrant coronary anatomy. In Case 1, a 4-year-old male who presented with non-exertional chest pain was found to have anomalous coronary architecture on echocardiogram. Coronary computed tomography angiogram (CCTA) confirmed an anomalous origin of the left coronary artery from the right coronary sinus with a malignant interarterial course and myocardial bridging of the left anterior descending (LAD) artery. The patient underwent a successful surgical correction of the defects. In Case 2, a full-term infant female was born with a hypoplastic right ventricle and pulmonary atresia. CCTA showed a large fistula originating from the coronary sinus on the left that drained into the superior aspect of the mid right ventricular cavity, an anomalous bridge between the left and right atrial appendages, and five fistulous connections between various vessels. The patient was transferred to another facility for cardiac transplant.

The Association between Transcatheter Aortic Valve Replacement (TAVR) Approach and New-Onset Bundle Branch Blocks.

INTRODUCTION: Transcatheter aortic valve replacement (TAVR) has become a widely accepted treatment option for patients with severe aortic stenosis (AS) who are considered intermediate- and high-risk surgical candidates. The purpose of this study was to test the hypothesis that trans-apical TAVR would be associated with increased risk of new-onset intraventricular conduction delay (LBBB or RBBB). METHODS: We conducted a retrospective observational study of consecutive patients undergoing TAVR at a large, single institution. The incidence of new LBBB or RBBB was compared between femoral and apical TAVR patients. Multivariate analysis was performed to account for confounding variables, which included age, gender, CAD, PAD, hypertension, and diabetes. RESULTS: A total of 467 TAVR patients were included in the study, with 283 (60.6%) femoral approach and 184 (39.4%) apical approach. In univariate analysis, the apical approach (when compared to the femoral approach) was associated with a higher incidence of both new-onset LBBB (12.79 vs. 3.40%, p = 0.0002) and RBBB (5.49 vs. 0.81%, p = 0.0039). After controlling for potential confounding variables, the apical approach continued to be associated with a higher incidence of both new-onset LBBB (p = 0.0010) and RBBB (p = 0.0115). There was also a trend towards an association between diabetes and new-onset LBBB (p = 0.0513) in apical TAVR patients. In subgroup analysis, LBBB/RBBB occurring as a result of transapical TAVR was associated with more frequent hospitalizations > 30 days after TAVR, compared to transfemoral TAVR. Other post-procedural complications noted more frequently among patients undergoing transapical TAVR include arrhythmias including atrial fibrillation, peri-procedural myocardial infarction (within 72 h), mortality from unknown cause, and mortality from non-cardiac cause. CONCLUSIONS: Relative to transfemoral TAVR, patients undergoing transapical TAVR are at increased risk for new-onset bundle branch block, peri-procedural myocardial infarction, rehospitalization, TAV-in-TAV deployment, and all-cause mortality at 1 year. Interventional cardiologists and cardiothoracic surgeons alike should take these findings into consideration when choosing which approach is most suitable for patients undergoing TAVR for severe aortic stenosis.