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.     

Interleukin-1β and tumor necrosis factor-α affect cytochrome P450 expression in cynomolgus macaque hepatocytes

The cynomolgus macaque, partly due to its evolutionary closeness to humans, is an important nonhuman primate species used in drug metabolism studies. In humans, expressions of cytochromes P450 (P450s), including the important drug-metabolizing enzyme P450 3A4, are affected by various cytokines. However, this phenomenon has not been fully investigated in cynomolgus macaques. In this study, the effects of cytokines on P450 expression were investigated using the quantitative polymerase chain reaction to evaluate mRNA expression. Hepatocytes from cynomolgus macaques were treated with lipopolysaccharide and various cytokines, including interleukin (IL)-1β, IL-2, IL-6, interferon-γ, and tumor necrosis factor-α, and the expression levels of 11 P450s were compared with those of solvent-treated controls. Tumor necrosis factor-α significantly decreased cynomolgus P450 2C8 and 2C76 mRNA expression in multiple lots of cynomolgus hepatocytes investigated. IL-1β significantly decreased cynomolgus P450 1A1, 2C8, 2C19, and 2C76 mRNA expression, but increased P450 3A5 mRNA expression in multiple lots of hepatocytes. Moreover, P450 1A1-and 2C19-mediated drug oxidations were significantly and dose-dependently suppressed by IL-1β, under the present limited conditions. These results suggest that cytokines can influence hepatic P450 mRNA expression levels in cynomolgus macaques, just as cytokines are reported to affect P450 expression in humans.     

基于关节液代谢组学变化研究刺络药物罐疗法治疗膝骨性关节炎的机制

目的：基于关节液代谢组学变化分析刺络药物罐疗法治疗膝骨性关节炎（KOA）的作用机制。方法：选取2018年4月至2019年5月深圳市宝安区中医院收治的KOA患者98例作为研究对象，按照治疗方法不同分为西药观察组(n=52)和刺络药物罐疗法组(n=46)；比较所有患者治疗前后VAS评分和WOMAC评分；统计不同手段治疗前后血尿酸、C反应蛋白和红细胞沉降率；分离来自膝骨关节的关节液进行NMR分析。结果：治疗前，刺络药物罐疗法组和西药观察组VAS和WOMAC评分以及血尿酸、C反应蛋白和红细胞沉降率差异无统计学意义（P>0.05）；治疗后，刺络药物罐疗法组和西药观察组VVAS和WOMAC评分以及血尿酸、C反应蛋白含量和红细胞沉降率均降低，其中刺络药物罐疗法降低幅度更大，差异有统计学意义（P<0.05）；治疗后，刺络药物罐疗法组和西药观察组异丁酸和葡萄糖增加，羟脯氨酸，天冬酰胺，丝氨酸和尿苷均降低，差异有统计学意义（P<0.05）。结论：刺络药物罐疗法可以有效地改善KOA患者的治疗效果和身体功能。     

药物性肝损伤生物标志物

生物标志物是源于机体器官、组织、细胞、亚细胞器中的标志性和(或)功能性分子,可以标记器官、组织、细胞及亚细胞结构或功能的改变。药物性肝损伤(DILI)一般会临床表型几乎涉及所有急慢性肝脏疾病,其发生发展过程的动态监控一直是基础和应用药理学研究领域面临的巨大挑战。除了传统的ALT,ASP,AST等指标外,目前许多新型生物分子作为生物标志物被报道,组学技术的发展也为DILI检测提供了更多的生物标志物分子,本文综述了导致肝损伤的药物类型,并对肝损伤的生物标志物进行综述,为DILI的研究提供选择和指导。     

An off-the-shelf plasma-based material to prevent pacemaker pocket infection

Bacterial infection of subcutaneous “pockets” housing cardiovascular implantable electronic devices is a significant clinical complication. In this study, pacemakers encapsulated in a blood plasma-based material (PBM) composited with antibiotics were investigated for use as prophylactics against such infections. PBMs, which are made from pooled allogeneic plasma and platelets, are off-the-shelf biomaterials that can be manufactured in the form of complex 3D shapes, extrudable putties, or injectable pastes. In vitro studies with PBM pastes formulated with rifampicin and minocycline demonstrated antibiotic release over 6 days, activity against Escherichia coli, and reduced cytotoxic effects of the antibiotics on fibroblasts. The materials were also evaluated in vivo in a rabbit model in which pacemaker pockets were inoculated with methicillin-resistant Staphylococcus aureus (S. aureus) strain and examined 1 week later. The pockets containing the pacemaker plus S. aureus were grossly purulent and culture positive, whereas pockets into which PBM with antibiotics were injected around the pacemaker were free of purulence and culture negative (p < 0.001). None of the pockets into which PBM without antibiotics were placed demonstrated purulence, but 60% were culture positive. These results demonstrate the potential of PBMs to deliver antibiotics to diminish the incidence of pocket infections for pacemakers and other implantable devices.     

Efficacy and safety of aripiprazole augmentation of clozapine in schizophrenia: A systematic review and meta-analysis of randomized-controlled trials

Limited options are available for clozapine-resistant schizophrenia and intolerable side effects of clozapine. We conducted a systematic review of randomized-controlled trials (RCTs) to determine the efficacy and safety of aripiprazole augmentation of clozapine for schizophrenia. Electronic databases searched included PubMed, Scopus, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science. This review synthesized the data of four short-term (8–24 weeks), placebo-controlled trials (N = 347). The overall relative risk (RR, 95% confidence interval) of discontinuation rates was not significantly different between groups (RR = 1.41, 95% CI = 0.78 to 2.56). The pooled standardized mean differences (SMDs, 95% CIs) (Z-test; number of study; I²-index) suggested trends of aripiprazole augmentation benefits on overall psychotic [−0.40 (−0.87 to 0.07) (n = 3; Z = 1.68, p = 0.09; I² = 68%)], positive [−1.05 (−2.39 to 0.29) (n = 3; Z = 1.54, p = 0.12; I² = 94%)], and negative [−0.36 (−0.77 to 0.05) (n = 3; Z = 1.74, p = 0.08; I² = 54%)] symptoms. Despite of no benefit on three cardiometabolic indices (i.e., fasting plasma glucose, triglyceride, and high-density lipoprotein), aripiprazole augmentation was superior for weight change with a mean difference (95% CI) of −1.36 kg (−2.35 to −0.36) (n = 3; Z = 2.67, p = 0.008; I² = 39%) and LDL-cholesterol with a mean difference of −11.06 mg/dL (−18.25 to −3.87) (n = 3; Z = 3.02, p = 0.003; I² = 31%). Aripiprazole augmentation was not correlated with headache and insomnia but significantly associated with agitation/akathesia (RR = 7.59, 95% CI = 1.43 to 40.18) (n = 3; Z = 2.38, p = 0.02; I² = 0%) and anxiety (RR = 2.70, 95% CI = 1.02 to 7.15) (n = 1; Z = 2.00, p = 0.05). The limited short-term data suggested that aripiprazole augmentation of clozapine can minimize the cardiometabolic risk, causes agitation/akathesia, and may be effective in attenuating psychotic symptoms.