Repurposing of parenterally administered active substances used to treat pain both systemically and locally

Pain is a constant in our lives. The efficacy of drug therapy administered by the parenteral route is often limited either by the physicochemical characteristics of the drug itself or its adsorption–distribution–metabolism–excretion (ADME) mechanisms. One promising alternative is the design of innovative drug delivery systems that can improve the pharmacokinetics |(PK) and/or reduce the toxicity of traditionally used drugs. In this review, we discuss several products that have been approved by the main regulatory agencies (i.e., nano- and microsystems, implants, and oil-based solutions), highlighting the newest technologies that govern both locally and systemically the delivery of drugs. Finally, we also discuss the risk assessment of the scale-up process required, given the impact that this approach could have on drug manufacturing.Teaser: The management of pain by way of the parenteral route can be improved using complex drug delivery systems (e.g., micro- and nanosystems) which require high-level assessment and shorten the regulatory pathway.     

Colon and rectal cancer risk after bariatric surgery in a multicountry Nordic cohort study

Obesity is a risk factor for colorectal cancer. Yet, some research indicates that weight-reducing bariatric surgery also increases colorectal cancer risk. Our study was undertaken because current evidence examining bariatric surgery and risk of colorectal cancer is limited and inconsistent. This population-based cohort study included adults with a documented obesity diagnosis in Denmark, Finland, Iceland, Norway or Sweden in 1980–2015. The incidence of colorectal cancer in participants with obesity who had and had not undergone bariatric surgery was compared to the incidence in the corresponding background population by calculating standardized incidence ratios (SIR) with 95% confidence intervals (CI). Additionally, operated and nonoperated participants with obesity were compared using multivariable Cox regression, providing hazard ratios (HR) with 95% CIs adjusted for confounders. Among 502,772 cohort participants with an obesity diagnosis, 49,931(9.9%) underwent bariatric surgery. The overall SIR of colon cancer was increased after bariatric surgery (SIR 1.56; 95% CI 1.28–1.88), with higher SIRs ≥10 years postsurgery. The overall HR of colon cancer in operated compared to nonoperated participants was 1.13 (95% CI 0.92–1.39) and 1.55 (95% CI 1.04–2.31) 10–14 years after bariatric surgery. Bariatric surgery did not significantly increase the risk of rectal cancer (SIR 1.14, 95% CI 0.83–1.52; HR 1.08, 95% CI 0.79–1.49), but the risk estimates increased with longer follow-up periods. Our study suggests that bariatric surgery is associated with an increased risk of colon cancer, while the support for an increased risk of rectal cancer was weaker.     

利胆软坚方降脂减肥作用及其对胆汁酸代谢轮廓谱的影响

目的:基于肥胖“从胆论治”的学术观点,研究利胆软坚方对高脂饮食诱导肥胖大鼠的降脂减肥作用及其对血清胆汁酸轮廓谱的影响,探讨其作用机制。方法:42只大鼠高脂饲料喂养9周建立肥胖大鼠模型,取24只造模成功大鼠随机分为模型组、利胆软坚方高、低剂量组(30,15 g·kg^-1),每组8只,另取8只正常大鼠作为正常组,模型组和正常组给予生理盐水,给药组给予相应剂量药物,灌胃4周。测定大鼠体质量、肝脏质量、脂肪质量等肥胖指标;胆管插管术引流监测2 h内胆汁流量;全自动生化仪测定血清总胆固醇(TC),甘油三酯(TG),高密度脂蛋白胆固醇(HDL-C),低密度脂蛋白胆固醇(LDL-C)水平;超高效液相色谱-质谱联用(UPLC-MS/MS)法测定大鼠血清胆汁酸代谢轮廓谱中各胆汁酸的含量。结果:与正常组比较,模型组体质量、肝脏质量、脂肪质量均显著升高(P<0.01),血清TC,TG,LDL-C水平明显上升(P<0.05,P<0.01),2 h内胆汁总分泌量及各测试点胆汁流量均降低,初级胆汁酸占比明显下降(P<0.05),血清总胆汁酸含量显著降低(P<0.01),血清胆汁酸轮廓谱中胆酸(CA),脱氧胆酸(DCA),鹅去氧胆酸(CDCA),猪去氧胆酸(HDCA),牛磺胆酸(TCA),牛磺去氧胆酸(TDCA),牛磺鹅去氧胆酸(TCDCA),牛磺猪去氧胆酸(THDCA),甘氨去氧胆酸(GDCA)含量明显降低(P<0.05,P<0.01);与模型组比较,利胆软坚方高、低剂量组体质量、肝脏质量明显降低(P<0.05,P<0.01),利胆软坚方高剂量组血清TC,TG,LDL-C水平明显下降(P<0.05,P<0.01),低剂量组TG水平明显下降(P<0.05),高剂量组在给药后1~1.5 h胆汁流量明显增加(P<0.05),高、低剂量组初级胆汁酸占比明显升高(P<0.05),利胆软坚方高剂量组TCA,DCA,甘氨胆酸(GCA),GDCA水平明显升高(P<0.05,P<0.01),低剂量组仅TCA,TCDCA水平明显升高(P<0.05)。结论:利胆软坚方具有降脂减肥作用,其机制可能与其增加胆汁分泌量,增加初级胆汁酸合成及调节胆汁酸轮廓谱有关。     

Toward liquid biopsies in cancer treatment: application of circulating tumor DNA

Circulating tumor DNA (ctDNA) refers to the fraction of cell‐free DNA in a patient's blood originating from tumor cells. Increased knowledge about tumor genomics, improvements in targeted therapies, and accompanying advances in DNA‐sequencing technologies have increased the interest in using ctDNA as a minimally invasive tool in cancer diagnostics and treatment. Especially, early tumor detection including identification of minimal residual disease and stratification of adjuvant therapy are promising approaches. Also, ctDNA showed to be reliable in treatment monitoring and can be used to assess therapy resistance due to the broad variety of tumor subclones captured in ctDNA. Therefore, using ctDNA in the clinical setting has the potential to improve therapeutic outcomes. In the present review, we summarize the status of ctDNA in oncology with focus of being an alternative to tissue biopsies in early detection and treatment monitoring.     

CYP2C19*3基因多态性对癫痫患者奥卡西平活性代谢产物MHD浓度的影响

目的：分析CYP2C19*3基因多态性与癫痫患者奥卡西平（oxcarbazepine，OXC）活性代谢产物10，11-二氢-10-羟基卡马西平（monohydroxycarbazepine，MHD）血药浓度的相关性。方法：纳入120例OXC单药治疗1个月以上且症状控制良好的癫痫患者，采集清晨服药前空腹血，采用高效液相色谱法测定MHD稳态谷浓度。通过PCR和sanger测序判定患者CYP2C19*3基因型。结果：120例癫痫患者快代谢患者64例，MHD血浆浓度为（18.17±7.34）μg·mL^-1；中代谢型患者36例，MHD血浆浓度为（19.31±9.17）μg·mL^-1；慢代谢型患者20例，MHD血浆浓度为（25.79±7.51）μg·mL^-1，3种基因型的MHD浓度有显著性差异（F=7.077，P=0.0013）。多因素分析显示，日剂量作为影响血药浓度的重要指标呈现出显著相关性（P<0.05）。结论：CYP2C19*3基因多态性影响MHD血药浓度，并且日剂量越高，MHD血药浓度越大，两者成显著正相关，临床应进行血药浓度监测。     

大黄素治疗代谢相关脂肪性肝病的作用机制研究进展

代谢相关脂肪性肝病既往称为非酒精性脂肪肝，与肥胖、糖尿病、高脂血症等关系密切，还明显增加心血管死亡的风险。大黄素是大黄、何首乌中主要的活性成分，具有多种生物学功能。大黄素可通过降低肝细胞脂质沉积、抑制肝脏炎症反应、抗胰岛素抵抗、抑制肝纤维化、抗氧化应激反应等多种途径对代谢相关脂肪性肝病发挥治疗作用。总结了大黄素治疗代谢相关脂肪性肝病的作用机制，为代谢相关脂肪性肝病的治疗提供参考。