Identification and human exposure prediction of two aldehyde oxidase-mediated metabolites of a methylquinoline-containing drug candidate

1. Aldehyde oxidase (AO enzymes)-mediated oxidation predominantly occurs at a carbon atom adjacent to the nitrogen on aromatic azaheterocycles. In the current report, we identified that AO enzymes oxidation took place at both the C-2 and C-4 positions of the methylquinoline moiety of Compound A based on data from mass spectrometric analysis, AO enzymes “litmus” test, and comparison with authentic standards.

2. To assess the potential for inadequate coverage for these two AO enzyme-mediated metabolites in nonclinical safety studies, given concerns due to differences in AO enzymes expression between preclinical species and humans, the human circulating levels of the two AO enzyme-mediated metabolites were predicted prospectively using in vitro and in vivo models. Both formation clearance and elimination clearance of the two metabolites were predicted based on in vitro to in vivo correlation and comparison with in vivo data from rats.

3. The result showed that the 4-OH metabolite of Compound A would account for less than 3% of the total drug-related exposure in human plasma, while the exposure to the 2-oxo metabolite would be relatively high (～70%).

4. The predicted human exposure levels for the two metabolites are in similar ranges as those observed in monkeys. These data taken together support the advancement to clinical development of Compound A.     

An eco-friendly HPLC-UV method for the determination of risedronate in its bulk and tablet dosage form with application to content uniformity,dissolution and stability testing

Risedronate is a nitrogen-containing bisphosphonate for the treatment and prevention of postmenopausal osteoporosis. The current work aims to develop a novel green HPLC-UV method for the rapid analysis of risedronate sodium in bulk and tablet formulation. The analyzed samples were separated on Waters Atlantis dC18 (150 mm × 3.9 mm; 5 μm) column using a green mobile phase consisting of potassium phosphate buffer pH 2.9 and potassium edetate buffer pH 9.5 in a ratio of 1:2, the final pH was adjusted to 6.8 with phosphoric acid, the mobile phase was pumped at a rate of 1.0 mL/min, with column temperature set at 30 °C, eluted samples were detected at 263 nm and the chromatographic run time was 3.0 min. The method was found to be linear over the concentration range of 14–140 μg/mL with a correlation coefficient (r²) of 0.9994. Accuracy and precision were evaluated from three QC samples (LQC, MQC and HQC) together with the five calibrators where the percentage accuracy was found to be 101.84%. Processed quality control samples of risedronate sodium were tested for stability at different conditions, short term, long term and freeze- thaw stability. The current method was further extended to study the content uniformity of Actonel® tablets following United States Pharmacopoeia (USP) guidelines. The proposed method was fully validated as per ICH guidelines.     

Reproducibility of LI-RADS treatment response algorithm for hepatocellular carcinoma after locoregional therapy

PurposeTo determine inter-reader agreement in categorizing hepatocellular carcinoma (HCC) treated with locoregional therapy using the Liver Imaging Reporting and Data System (LI-RADS) treatment response (LR-TR) algorithm.Materials and methodsA total of 93 patients with a total of 112 HCC nodules that were treated using thermal ablation or transarterial chemoembolization were prospectively included. There were 79 men and 14 women with a mean age of 55 ± 2.6 (SD) years (range: 48–63 years). All patients underwent magnetic resonance imaging (MRI) examination of the liver and MR images were analyzed by two independent observers. Treated HCC nodules were categorized into four groups according to LR-TR scoring system including: (i) LR-TR non-evaluable (treated, response not evaluable); (ii) LR-TR nonviable (treated, probably or definitively not viable); (iii) LR-TR equivocal (treated, equivocally viable) and (iv) LR-TR viable (treated, probably or definitively viable). The inter-observer agreement in LR-TR categorization was assessed using the kappa statistics.ResultsThere was excellent inter-observer agreement between the two reviewers for overall treated HCC according to LR-TR algorithm (kappa = 0.938; 95% CI: 0.89–1.00; P = 0.001) with 97.31% agreement. The LR-TR categories by both reviewers were non-viable (77/112; 69.6% and 76/112; 67.9%), viable (30/112; 26.8% and 32/112; 27.7%) and equivocal (5/112; 4.4% and 4/112; 3.6%). There was excellent inter-observer agreement for LR-TR nonviable (kappa = 0.938; 95% CI: 0.87–1.0; P = 0.001) with 97.3% agreement, LR-TR viable (kappa = 0.955; 95% CI: 0.89–1.00; P = 0.001) with 98.2% agreement and good inter-observer agreement for LR-TR equivocal (kappa = 0.700; 95% CI: 0.28–1.0; P = 0.001) with 97.3% agreement.ConclusionLR-TR algorithm conveys high degrees of inter-observer agreement for the evaluation of treatment response of HCC after thermal ablation and transarterial chemoembolization.     

基于“脾肾相关”论治疗骨质疏松症的研究进展

骨质疏松症常见于中老年人群，是由多种原因导致骨组织显微结构受损、易发脆性骨折的一种全身性骨代谢障碍疾病。中医学认为肾虚是骨质疏松症发病的重要病机，因此以补肾壮骨为主要治法已达成普遍共识。笔者通过大量文献搜索发现，脾虚在骨质疏松症的致病过程中亦起着关键作用。肾、脾两脏为先后天之本，是维持人体正常生理活动的根本所在。因此本文着眼于“脾肾相关”理论，从中医基础理论、实验研究及临床观察等角度综述其防治疗骨质疏松症的科学内涵，并试探讨中医“脾肾相关”理论防治骨质疏松症的作用机制，找寻中医基础理论在防治骨质疏松症中的理论渊源，优化中医药防治骨质疏松症的诊疗方案，为更好得将祖国医学运用于临床提供新的思路与方法。     

Impact of Venous Collaterals on Clinical Outcomes in Paget–Schroetter Syndrome

Purpose

To characterize the degree of venous collateralization before and after endovascular therapy and determine the effect of collateralization on success of thrombolysis and rate of repeat intervention in patients with Paget–Schroetter syndrome.