Development and validation of a sensitive liquid chromatography-tandem mass spectrometry method for the assay of 12 substances in rat plasma and its application to rat pharmacokinetics of Epimedium and Psoraleae Fructus herb pair after oral administration.

Epimedium (EM) and Psoraleae Fructus (PF) are a traditional herb combination often used as a fixed form to treat osteoporosis disease in the clinic. However, the intricate interactions of this pair remain unknown. In our study, we undertook a comprehensive examination of their compatibility behaviors. Concurrently, a precise and sensitive quantitation method was successfully developed and validated using liquid chromatography-tandem mass spectrometry for the determination of 12 components. This method was applied in analyzing herbal extracts and biological samples (both in the portal vein and systemic plasma), which was also used to study the pharmacokinetics of the herb pair. The results indicated that the combination of EM and PF enhanced the dissolution of chemical components from PF in extracts, but it had a negligible influence on the contents of the components from EM. On the contrary, the in vivo exposure of the lowly exposed EM flavonoids significantly increased following the combination of EM and PF, whereas the highly exposed psoralen and isopsoralen were greatly reduced. These interactions might be crucial for the synergy and toxicity reduction of the herbal pair in disease treatment, which pave the way for further exploration into the clinical application and pharmacological mechanisms of EM and PF.

Pharmacokinetic and metabolite profile of orally administered anemoside B4 in rats with an improved exposure in formulations of rectal suppository.

ETHNOPHARMACOLOGICAL RELEVANCE: Pulsatilla chinensis (Bunge) Regel is a traditional Chinese herbal medicine used to treat intestinal amebiasis, malaria, vaginal trichomoniasis, and bacterial infections. Anemoside B4 (AB4), a pentacyclic triterpenoid saponin, is one of the primary bioactive substances in Pulsatilla chinensis (Bunge) Regel, and gavage administration of AB4 to animals has been demonstrated to exhibit anticancer, anti-inflammatory, and antiviral actions. However, AB4 exposure in plasma is very low after oral administration, and the biotransformation of AB4 in vivo after oral administration remains unknown. AIM OF THE STUDY: The reason for conducting this research was to explore at the metabolite profile of AB4 in rats following oral administration. Additionally, we aimed to develop an appropriate extravascular formulation to increase the exposure and duration of AB4 in vivo. MATERIALS AND METHODS: A well-validated HPLC-QQQ-MS/MS method was used for the quantification of AB4 in plasma and was further applied to evaluate and compare the pharmacokinetic properties of AB4 dissolved in a saline solution and AB4 formulations in a rectal suppository or enteric capsule. Reliable UHPLC coupled to Q-Exactive Plus high-resolution MS was used to identify the metabolites in rat plasma, bile, urine, and faeces. RESULTS: AB4 was extensively metabolized, and a total of 29 metabolites were identified. The primary metabolic routes included deglycosylation, oxidation, dehydrogenation, reduction, sulfation, hydration, acetylation, and glucuronidation. The pharmacokinetic comparison showed that both the rectal suppository and enteric capsule increased the exposures of AB4 and one of its active metabolites, 23-hydroxybetulinic acid (23-HA). Notably, rectal suppositories increased systemic AB4 exposure (AUC0-∞) by approximately 49 and 28 times higher than that of the AB4 saline solution and enteric capsules, respectively. The t1/2 of AB4 was extended to approximately 7 h after rectal administration compared to 2 h after oral administration. CONCLUSION: Overall, our study demonstrated that the mismatched exposure-response relationship of AB4 could result from extensive metabolism in the gastrointestinal and circulatory systems. Thus, a rectal suppository could be an alternative formulation of AB4 to obtain both higher and longer exposure.

Electrochemically Enabled Selenium Catalytic Synthesis of 2,1-Benzoxazoles from o-Nitrophenylacetylenes.

The study reported an electrochemically mediated method for the preparation of 2,1-benzoxazoles from o-nitrophenylacetylenes. Different from the traditional electrochemical reduction of nitro to nitroso, the nitro group directly underwent a cyclization reaction with the alkyne activated by selenium cation generated by the anodic oxidation of diphenyl diselenide and finally produced the desired products.

Intraoperative Radiotherapy Is Not a Better Alternative to Whole Breast Radiotherapy as a Therapeutic Option for Early-Stage Breast Cancer.

OBJECTIVE: Intraoperative radiotherapy (IORT) in early-stage breast cancer has been studied over the years. However, it has not been demonstrated whether IORT is more suitable as a therapeutic option for early-stage breast cancer than whole breast radiotherapy (WBRT). Therefore, we performed a meta-analysis to compare the efficacy and safety of IORT to those of WBRT as therapeutic options for early-stage breast cancer patients receiving breast-conserving surgery (INPLASY2020120008). METHODS: PubMed, Embase, and Cochrane Library databases were searched from inception to October 2021. Computerized and manual searches were adopted to identify eligible randomized control trials from online databases. Risk ratio (RR) and 95% confidence intervals (CI) were calculated by random-effect models to assess the relative risk. Potential publication bias was quantified by Begg's and Egger's tests. RESULTS: Based on our inclusion criteria, 10 randomized control trials involving 5,698 patients were included in this meta-analysis. This meta-analysis showed that the IORT group was associated with a higher local recurrence risk (RR = 2.111, 95% CI, 1.130-3.943, p = 0.0191), especially in the long-term follow-up subgroup or published after 2020 subgroup or Caucasian subgroup (RR = 2.404, 95% CI, 1.183-4.885, p = 0.0154). Subgroup analysis showed that the IORT group had a higher recurrence risk than the WBRT group in the polycentric randomized controlled trial subgroup (RR = 1.213, 95% CI, 1.030-1.428, p = 0.0204). Pooled analysis showed that there was no statistically significant difference in overall survival, recurrence-free survival, distant metastasis-free survival, and cancer-specific survival between IORT and WBRT groups. Additionally, the risk of skin toxicity was reduced, but the incidences of fat toxicity, edema, and scar calcification were significantly increased in the patients who underwent IORT in comparison to those who underwent WBRT. CONCLUSION: This meta-analysis revealed that IORT was not a better alternative to WBRT. More large-scale and well-designed clinical trials with longer follow-up periods are encouraged to further investigate the value of IORT. SYSTEMATIC REVIEW REGISTRATION: https://inplasy.com/inplasy-2020-12-0008/.

Quantifying the uncertainty in model parameters using Gaussian process-based Markov chain Monte Carlo in cardiac electrophysiology.

Model personalization requires the estimation of patient-specific tissue properties in the form of model parameters from indirect and sparse measurement data. Moreover, a low-dimensional representation of the parameter space is needed, which often has a limited ability to reveal the underlying tissue heterogeneity. As a result, significant uncertainty can be associated with the estimated values of the model parameters which, if left unquantified, will lead to unknown variability in model outputs that will hinder their reliable clinical adoption. Probabilistic estimation of model parameters, however, remains an unresolved challenge. Direct Markov Chain Monte Carlo (MCMC) sampling of the posterior distribution function (pdf) of the parameters is infeasible because it involves repeated evaluations of the computationally expensive simulation model. To accelerate this inference, one popular approach is to construct a computationally efficient surrogate and sample from this approximation. However, by sampling from an approximation, efficiency is gained at the expense of sampling accuracy. In this paper, we address this issue by integrating surrogate modeling of the posterior pdf into accelerating the Metropolis-Hastings (MH) sampling of the exact posterior pdf. It is achieved by two main components: (1) construction of a Gaussian process (GP) surrogate of the exact posterior pdf by actively selecting training points that allow for a good global approximation accuracy with a focus on the regions of high posterior probability; and (2) use of the GP surrogate to improve the proposal distribution in MH sampling, in order to improve the acceptance rate. The presented framework is evaluated in its estimation of the local tissue excitability of a cardiac electrophysiological model in both synthetic data experiments and real data experiments. In addition, the obtained posterior distributions of model parameters are interpreted in relation to the factors contributing to parameter uncertainty, including different low-dimensional representations of the parameter space, parameter non-identifiability, and parameter correlations.

Non-invasive epicardial and endocardial electrocardiographic imaging for scar-related ventricular tachycardia.

Aims: Contact mapping is currently used to guide catheter ablation of scar-related ventricular tachycardia (VT) but usually provides incomplete assessment of 3D re-entry circuits and their arrhythmogenic substrates. This study investigates the feasibility of non-invasive electrocardiographic imaging (ECGi) in mapping scar substrates and re-entry circuits throughout the epicardium and endocardium. Methods and results: Four patients undergoing endocardial and epicardial mapping and ablation of scar-related VT had computed tomography scans and a 120-lead electrocardiograms, which were used to compute patient-specific ventricular epicardial and endocardial unipolar electrograms (CEGMs). Native-rhythm CEGMs were used to identify sites of myocardial scar and signal fractionation. Computed electrograms of induced VT were used to localize re-entrant circuits and exit sites. Results were compared to in vivo contact mapping data and epicardium-based ECGi solutions. During native rhythm, an average of 493 ± 18 CEGMs were analysed on each patient. Identified regions of scar and fractionation comprised, respectively, 25 ± 4% and 2 ± 1% of the ventricular surface area. Using a linear mixed-effects model grouped at the level of an individual patient, CEGM voltage and duration were significantly associated with contact bipolar voltage. During induced VT, the inclusion of endocardial layer in ECGi made it possible to identify two epicardial vs. three endocardial VT exit sites among five reconstructed re-entry circuits. Conclusion: Electrocardiographic imaging may be used to reveal sites of signal fractionation and to map short-lived VT circuits. Its capacity to map throughout epicardial and endocardial layers may improve the delineation of 3D re-entry circuits and their arrhythmogenic substrates.

Polydrug use and its association with drug treatment outcomes among primary heroin, methamphetamine, and cocaine users.

BACKGROUND: Polydrug use may challenge effective treatment for substance use disorders. We evaluate whether secondary substance use modifies the association between treatment and primary drug use among primary heroin, cocaine and methamphetamine (MA) users. METHODS: Data were obtained from prospective cohort studies on people who use illicit drugs (PWUD) in California, USA. Using repeated monthly data on self-reported secondary substance use (heroin, cocaine, MA, alcohol or marijuana; ≥1day in a month), primary drug use (≥1day in a month), and treatment participation, collected via timeline follow-back, we fitted generalized linear mixed multiple regression models controlling for potential confounders to examine the interactions between treatment and secondary substance use on the odds of primary heroin, cocaine and MA use, respectively. RESULTS: Included in our study were 587 primary heroin, 444 primary MA, and 501 primary cocaine users, with a median of 32.4, 13.3 and 18.9 years of follow-up, respectively. In the absence of secondary substance use, treatment was strongly associated with decreased odds of primary drug use (adjusted odds ratios (aORs): 0.25, 95% CI: 0.24, 0.27, 0.07 (0.06, 0.08), and 0.07 (0.07, 0.09)) for primary heroin, MA, and cocaine users, respectively. Secondary substance use of any kind moderated these associations (0.82 (0.78, 0.87), 0.25 (0.21, 0.30) and 0.53 (0.45, 0.61), respectively), and these findings were consistent for each type of secondary substance considered. Moreover, we observed different associations in terms of direction and magnitude between secondary substance use and primary drug use during off-treatment periods across substance types. CONCLUSION: This study demonstrates secondary substance use moderates the temporal associations between treatment and primary drug use among primary heroin, MA and cocaine users. Disparate patterns of polydrug use require careful measurement and analysis to inform targeted treatment for polydrug users.

Noninvasive transmural electrophysiological imaging based on minimization of total-variation functional.

While tomographic imaging of cardiac structure and kinetics has improved substantially, electrophysiological mapping of the heart is still restricted to the surface with little or no depth information beneath. The progress in reconstructing 3-D action potential from surface voltage data has been hindered by the intrinsic ill-posedness of the problem and the lack of a unique solution in the absence of prior assumptions. In this work, we propose a novel adaption of the total-variation (TV) prior to exploit the unique spatial property of transmural action potential of being piecewise smooth with a steep boundary (gradient) separating depolarized and repolarized regions. We present a variational TV-prior instead of a common discrete TV-prior for improved robustness to mesh resolution, and solve the TV-minimization by a sequence of weighted, first-order L2-norm minimization. In a large set of phantom experiments, the proposed method is shown to outperform existing quadratic methods in preserving the steep gradient of action potential along the border of infarcts, as well as in capturing the disruption to the normal path of electrical wavefronts. Real-data experiments also further demonstrate the potential of the proposed method in revealing the location and shape of infarcts when quadratic methods fail to do so.

Transmural imaging of ventricular action potentials and post-infarction scars in swine hearts.

The problem of using surface data to reconstruct transmural electrophysiological (EP) signals is intrinsically ill-posed without a unique solution in its unconstrained form. Incorporating physiological spatiotemporal priors through probabilistic integration of dynamic EP models, we have previously developed a Bayesian approach to transmural electrophysiological imaging (TEPI) using body-surface electrocardiograms. In this study, we generalize TEPI to using electrical signals collected from heart surfaces, and we test its feasibility on two pre-clinical swine models provided through the STACOM 2011 EP simulation Challenge. Since this new application of TEPI does not require whole-body imaging, there may be more immediate potential in EP laboratories where it could utilize catheter mapping data and produce transmural information for therapy guidance. Another focus of this study is to investigate the consistency among three modalities in delineating scar after myocardial infarction: TEPI, electroanatomical voltage mapping (EAVM), and magnetic resonance imaging (MRI). Our preliminary data demonstrate that, compared to the low-voltage scar area in EAVM, the 3-D electrical scar volume detected by TEPI is more consistent with anatomical scar volume delineated in MRI. Furthermore, TEPI could complement anatomical imaging by providing EP functional features related to both scar and healthy tissue.

Computational reduction for noninvasive transmural electrophysiological imaging.

Noninvasive transmural electrophysiological imaging (TEPI) combines body-surface electrocardiograms and image-derived anatomic data to compute subject-specific electrical activity and the relevant diseased substrates deep into the ventricular myocardium. Based on the Bayesian estimation where the priors come from probabilistic simulations of high dimensional EP models, TEPI engages intensive computation that hinders its clinical translation. We present a reduced-rank square-root (RRSR) algorithm for TEPI that reduces computational time by neglecting minor components of estimation uncertainty and improves numerical stability by the square-root structure. Phantom and real-data experiments demonstrate the ability of RRSR-TEPI to bring notable computational reduction without significant sacrifice of diagnostic efficacy, particularly in imaging and quantifying post-infarct substrates.