温针灸联合玻璃酸钠关节腔内注射治疗膝骨性关节炎Meta分析

目的:系统评价温针灸联合玻璃酸钠治疗膝骨性关节炎的疗效。方法:计算机检索自建库截止至2018年7月PubMed,Wed of Science CBM,The Cochrane Library,EMBase,中国期刊全文数据库(CNKI)、万方数据库(Wan Fang Data)、维普中文科技期刊数据库(VIP)中关于温针灸联合玻璃酸钠治疗膝骨性关节炎的随机对照试验(RCTs)。由2位研究员分别进行文献筛选、数据提取和质量评价后,采用Rev Man 5.3软件进行Meta分析。结果:有15篇RCTs纳入本研究,共1247例膝骨性关节炎患者(试验组628例,对照组619例)。试验组:温针灸联合玻璃酸钠;对照组:玻璃酸钠/温针灸/其他治疗。Meta分析结果:试验组治疗膝骨性关节炎总有效率比玻璃酸钠组、温针灸组、其他组分别高15%、20%及24%,且差异有统计学意义(RR=1.15,95%CI:1.10～1.21,P<0.00001;RR=1.20,95%CI:1.05～1.36,P=0.005;RR=1.36,95%CI:1.11～1.66,P=0.003)。试验组治疗膝骨性关节炎改善视觉模拟(VAS)评分优于玻璃酸钠组、温针灸组及其他组,且差异有统计学意义(MD=-1.46,95%CI:-1.84～-1.08,P=0.009;MD=-4.73,95%CI:-6.46～-3.01,P<0.00001;MD=-1.83,95%CI:-2.39～-1.28,P<0.00001);试验组治疗膝骨性关节炎改善WOMAC评分优于温针灸组,且差异有统计学意义(MD=-37.11,95%CI:-49.36～-24.85,P<0.00001)。试验组治疗膝骨性关节炎改善膝关节(LKSS)评分优于玻璃酸钠组及温针灸组,且差异有统计学意义(MD=39.14,95%CI:20.87～57.42,P<0.0001;MD=41.05,95%CI:27.77～54.33,P<0.00001)。结论:温针灸联合玻璃酸钠治疗膝骨性关节炎疗效优于单一用药及其他组,不过本研究纳入文献的质量及数量有限,故仍需更多长时间随访且高质量的RCTs试验进一步验证。     

MiR-92b-3p ameliorates inflammation and autophagy by targeting TRAF3 and suppressing MKK3-p38 pathway in caerulein-induced AR42J cells

Acute pancreatitis (AP) is an inflammatory disease with high morbidity and mortality. Dysregulation of microRNAs (miRNAs) was involved in human diseases, including AP. However, the effects of miR-92b-3p on AP process and its mechanism remain not been fully clarified. The expression levels of miR-92b-3p and tumor necrosis factor receptor-associated factor-3 (TRAF3) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of TRAF3, tumor necrosis factor α (TNF-α) TNF-α, interleukin-6 (IL-6), phosphorylated mitogen-activated protein kinase kinase 3 (p-MKK3), MKK3, p38 and phosphorylated p38 (p-p38) were detected by western blot. The concentration of TNF-α and IL-6 in the medium was measured using ELISA kits. The possible binding sites of miR-92b-3p and TRAF3 were predicted by TargetScan and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The expression level of miR-92b-3p was decreased and TRAF3 expression was increased in AR42J cells stimulated with caerulein. Moreover, the protein levels of pro-inflammatory cytokines (TNF-α and IL-6) were markedly elevated, and the expression levels of autophagy-related markers Beclin1 as well as the ratio of LC3-II/I were obviously increased in AR42J cells treated with caerulein. In addition, overexpression of miR-92b-3p or knockdown of TRAF3 significantly suppressed the release of pro-inflammatory cytokines and autophagy in caerulein-induced AR42J cells. Furthermore, TRAF3 was a direct target of miR-92b-3p and its upregulation reversed the effects of miR-92b-3p overexpression on inflammatory response and autophagy. Besides, overexpression of miR-92b-3p inhibited the activation of the MKK3-p38 pathway by affecting TRAF3 expression. In conclusion, miR-92b-3p attenuated inflammatory response and autophagy by downregulating TRAF3 and suppressing MKK3-p38 pathway in caerulein-induced AR42J cells, providing a novel avenue for treatment of AP.     

Multiparametric classification of sub‐acute ischemic stroke recovery with ultrafast diffusion, 23Na,and MPIO‐labeled stem cell MRI at 21.1 T

MRI leverages multiple modes of contrast to characterize stroke. High‐magnetic‐field systems enhance the performance of these MRI measurements. Previously, we have demonstrated that individually sodium and stem cell tracking metrics are enhanced at ultrahigh field in a rat model of stroke, and we have developed robust single‐scan diffusion‐weighted imaging approaches that utilize spatiotemporal encoding (SPEN) of the apparent diffusion coefficient (ADC) for these challenging field strengths. Here, we performed a multiparametric study of middle cerebral artery occlusion (MCAO) biomarker evolution focusing on comparison of these MRI biomarkers for stroke assessment during sub‐acute recovery in rat MCAO models at 21.1 T. T₂‐weighted MRI was used as the benchmark for identification of the ischemic lesion over the course of the study. The number of MPIO‐induced voids measured by gradient‐recalled echo, the SPEN measurement of ADC, and ²³Na MRI values were determined in the ischemic area and contralateral hemisphere, and relative performances for stroke classification were compared by receiver operator characteristic analysis. These measurements were associated with unique time‐dependent trajectories during stroke recovery that changed the sensitivity and specificity for stroke monitoring during its evolution. Advantages and limitations of these contrasts, and the use of ultrahigh field for multiparametric stroke assessment, are discussed.     

Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.     

双氯芬酸钠滴眼液抑菌剂剂量筛选及抑菌效力考察

目的研究双氯芬酸納滴眼液的抑菌效力,探索抑菌剂的合理添加量。方法按《中国药典》2015年版四部,以大肠埃希菌、金黄色葡萄球菌、铜绿假单胞菌、白色念珠菌和黑曲霉为实验菌株,测定10家企业双氯芬酸钠滴眼液的抑菌效力,并对硫柳汞、羟苯乙酯和苯扎氯铵3种抑菌剂的最低有效量进行研究。结果10家企业中没有一家抑菌效力达到A级,有3家企业:达到B级,另外7家均未达到B级。抑菌剂剂量筛选实验中,当双氯芬酸钠滴眼液含硫柳汞质量农度达到0.01 mg·mL^-1,羟苯乙酯质量浪浓度达到0.3 mg·mL^-1时,抑菌效力可达到B级,苯扎氯铵质量农浓度达到0.01 mg·mL^-1时,抑菌效力即可达到A级。结论市售双氯芬酸钠滴眼液的抑菌效力不容乐观,建议企业合理添加抑菌剂,对抑菌剂的理化指标和生物指标一同评价保证药品质量安全可靠。     

甲泼尼龙琥珀酸钠对自身免疫性肺气肿模型大鼠氧化应激和抗内皮细胞抗体的影响

目的:研究甲泼尼龙琥珀酸钠对自身免疫性肺气肿模型大鼠氧化应激和抗内皮细胞抗体(AECA)的影响。方法:将雄性SD大鼠随机分为对照组、模型组和干预组,每组8只。除对照组大鼠腹腔注射等体积的完全弗氏佐剂外,模型组和干预组大鼠均腹腔注射体外培养的人脐静脉内皮细胞+完全弗氏佐剂混合物以复制自身免疫性肺气肿模型;造模给药后第2天,干预组大鼠腹腔注射甲泼尼龙琥珀酸钠10 mg/(kg·d),对照组和模型组大鼠均腹腔注射等体积的生理盐水,每日1次,连续21 d。末次给药后,取各组大鼠右肺组织制作石蜡切片并行苏木精-伊红染色,观察肺组织病理变化,测量单位面积内的肺泡数(MAN)和内衬间隔(MLI);检测左肺肺泡灌洗液(BALF)中丙二醛(MDA)、还原型谷胱甘肽(GSH)含量和超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性,以及BALF和血清中AECA含量。采用Pearson分析模型组大鼠BALF中AECA与MDA、GSH、SOD、GSH-Px的相关性。结果:与对照组比较,模型组大鼠肺组织可见明显的肺气肿病理变化,其MAN显著减少,MLI显著延长(P<0.01);BALF中GSH含量和SOD、GSH-Px活性均显著降低,BALF中MDA含量以及BALF、血清中AECA含量均显著升高(P<0.01)。与模型组比较,干预组大鼠肺组织的肺气肿病理变化明显改善,其MAN显著增加,MLI显著缩短(P<0.01);BALF中GSH含量和SOD、GSH-Px活性均显著升高;BALF中MDA含量以及BALF、血清中AECA含量均显著降低(P<0.01)。模型组大鼠BALF中的AECA与MDA呈正相关(r=0.710,P<0.05),与GSH、SOD、GSH-Px呈负相关(r=-0.754、-0.781、-0.736,P<0.05)。结论:甲泼尼龙琥珀酸钠可能通过减轻氧化应激反应、抑制AECA的表达,从而达到预防自身免疫性肺气肿的目的。     

Assessing the Effects of Geniculate Artery Embolization in a Nonsurgical Animal Model of Osteoarthritis

PurposeTo create a nonsurgical animal model of osteoarthritis (OA) to evaluate the effects of embolotherapy during geniculate artery embolization (GAE).Materials and MethodsFluoroscopy-guided injections of 700 mg of sodium monoiodoacetate were performed into the left stifle in 6 rams. Kinematic data were collected before and after induction. At 10 weeks after induction, Subjects 1 and 4–6 underwent magnetic resonance (MR) imaging with dynamic contrast enhancement (DCE) and Subjects 1, 3, and 4–6 underwent angiography with angiographic scoring to identify regions with greatest disease severity for superselective embolization (75–250-μm microspheres). Target vessel size was measured. At 24 weeks after angiography, DCE-MR imaging, angiography, and euthanasia were performed, and bilateral stifles were harvested. Medial/lateral tibial and femoral condylar, patellar, and synovial samples were cut, preserved, decalcified, and scored using the Osteoarthritis Research Society International criteria. The stifle and synovium Whole-Organ Magnetic Resonance Imaging Score and Multicenter Osteoarthritis Study score were determined. The volume transfer constant (K_trans) and extracellular volume fraction (v_e) were calculated from DCE-MR imaging along the lateral synovial regions of interest.ResultsThe mean gross and microscopic pathological scores were elevated at 38 and 61, respectively. Mean synovitis score was elevated at 9.2. Mean pre-embolization and postembolization angiographic scores were 5 and 3.8, respectively. Mean superior, transverse, and inferior geniculate artery diameters were 3.1 mm ± 1.21, 2.0 mm ± 0.50, and 1.6 mm ± 0.41 mm, respectively. Mean pre-embolization and postembolization cartilage and synovitis scores were elevated at 35.13 and 73.3 and 5.5 and 9.2, respectively. The K_trans/v_e values of Subjects 4, 5, and 6 were elevated at 0.049/0.38, 0.074/0.53, and 0.065/0.51, respectively. Altered gait of the hind limb was observed in all subjects after induction, with reduced joint mobility. No skin necrosis or osteonecrosis was observed.ConclusionsA nonsurgical ovine animal knee OA model was created, which allowed the collection of angiographic, histopathological, MR imaging, and kinematic data to study the effects of GAE.