Targeted interleukin-10 plasmid DNA therapy in the treatment of osteoarthritis: Toxicology and pain efficacy assessments

Osteoarthritis results in chronic pain and loss of function. Proinflammatory cytokines create both osteoarthritis pathology and pain. Current treatments are poorly effective, have significant side effects, and have not targeted the cytokines central to osteoarthritis development and maintenance. Interleukin-10 is an anti-inflammatory cytokine that potently and broadly suppresses proinflammatory cytokine activity. However, interleukin-10 protein has a short half-life in vivo and poor joint permeability. For sustained IL-10 activity, we developed a plasmid DNA-based therapy that expresses a long-acting human interleukin-10 variant (hIL-10var). Here, we describe the 6-month GLP toxicology study of this therapy. Intra-articular injections of hIL-10var pDNA into canine stifle joints up to 1.5 mg bilaterally were well-tolerated and without pathologic findings. This represents the first long-term toxicologic assessment of intra-articular pDNA therapy. We also report results of a small double-blind, placebo-controlled study of the effect of intra-articular hIL-10var pDNA on pain measures in companion (pet) dogs with naturally occurring osteoarthritis. This human IL-10-based targeted therapy reduced pain measures in the dogs, based on veterinary and owner ratings, without any adverse findings. These results with hIL-10var pDNA therapy, well-tolerated and without toxicologic effects, establish the basis for clinical trials of a new class of safe and effective therapies for OA.     

帕拉米韦注射液治疗儿童流感的临床疗效分析

目的探讨儿童流感应用帕拉米韦注射液治疗的临床疗效以及用药安全性。方法随机选定在2016年1月-2019年1月期间佛山市高明区人民医院儿科住院治疗并确诊流感A或B型患儿200例,通过随机数字法将其分为治疗组和对照组。治疗组100例用帕拉米韦注射液治疗,对照组100例用国产磷酸奥司他韦颗粒治疗,评价两组患儿治疗前后症状评分、治疗效果、治疗指标以及不良反应发生情况。结果两组患儿治疗前流感样症状评分无统计学意义(P>0.05),两组患儿治疗后较治疗前流感样症状评分均下降,差异有统计学意义(P<0.05);治疗组治疗后流感样症状评分略小于对照组,但是无统计学意义(P>0.05);治疗组治疗总有效率高于对照组,治疗组患儿发热症状缓解、全部症状缓解以及住院时间均小于对照组,存在统计学意义(P<0.05)。治疗组与对照组不良反应发生率较低,且无统计学意义(P>0.05)。结论帕拉米韦注射液可用于儿童流感治疗,不仅能够保证临床疗效,而且可加快症状缓解,同时存在较高用药安全性。     

益气复脉注射液治疗急性心衰临床疗效观察

目的探讨益气复脉注射液治疗急性心功能不全的临床疗效。方法将2012年6月至2013年12月在我院急诊科治疗的85例急性心功能不全患者分为2组。对照组41例给予常规西医抗心衰治疗,给予利尿剂、血管紧张素转换酶抑制剂、β受体阻滞剂、洋地黄等。治疗组44例在西医治疗的基础上应用益气复脉注射液5.2 g加入5%葡萄糖250 m L,1次/d静滴。观察患者的症状、体征、心功能分级。两组患者治疗前及治疗14 d后测定脑钠肽(BNP)。超声心动图检查测定左房径(LAD),左室舒张末期容积(EDV),左室射血分数(LVEF),二尖瓣口舒张早期最大血流速度(E峰)、舒张晚期最大血流速度(A峰)。结果治疗组总有效率高于对照组,差异有统计学意义(P<0.05);观察组患者疲乏、心悸、呼吸困难、心绞痛等症状缓解时间均短于对照组,差异有统计学意义(P<0.05)。治疗后,治疗组BNP浓度低于对照组射血分数及E/A高于对照组,左房内径及左室舒张末期容积低于对照组,差异均有统计学意义(P<0.05)。结论益气复脉注射液能明显改善心衰患者的临床症状及心脏功能,无明显不良反应,是治疗急性心功能不全较理想的药物。     

Does Reduction of Number of Intradetrusor Injection Sites of aboBoNTA (Dysport?) Impact Efficacy and Safety in a Rat Model of Neurogenic Detrusor Overactivity?

Intradetrusor injections of Botulinum toxin A—currently onabotulinumtoxinA—is registered as a second-line treatment to treat neurogenic detrusor overactivity (NDO). The common clinical practice is 30 × 1 mL injections in the detrusor; however, protocols remain variable and standardization is warranted. The effect of reducing the number of injection sites of Dysport^® abobotulinumtoxinA (aboBoNTA) was assessed in the spinal cord-injured rat (SCI). Nineteen days post-spinalization, female rats received intradetrusor injections of saline or aboBoNTA 22.5 U distributed among four or eight sites. Two days after injection, continuous cystometry was performed in conscious rats. Efficacy of aboBoNTA 22.5 U was assessed versus aggregated saline groups on clinically-relevant parameters: maximal pressure, bladder capacity, compliance, voiding efficiency, as well as amplitude, frequency, and volume threshold for nonvoiding contractions (NVC). AboBoNTA 22.5 U significantly decreased maximal pressure, without affecting voiding efficiency. Injected in four sites, aboBoNTA significantly increased bladder capacity and compliance while only the latter when in eight sites. AboBoNTA significantly reduced NVC frequency and amplitude. This preclinical investigation showed similar inhibiting effects of aboBoNTA despite the number of sites reduction. Further studies are warranted to optimize dosing schemes to improve the risk-benefit ratio of BoNTA-based treatment modalities for NDO and further idiopathic overactive bladder.     

硼替佐米皮下注射方案治疗3例POEMS综合征并文献复习

目的:探讨含硼替佐米方案治疗POEMS综合征的有效性和安全性。方法:报道3例POEMS综合征经含硼替佐米方案治疗的过程及结果，并对相关文献进行复习。结果:3例病人经化疗后1例神经症状得到明显改善，1例腹胀症状消失，1例神经症状及胸闷、气短症状改善。结论:含硼替佐米方案治疗POEMS综合征患者取得了较好疗效，未出现神经毒副作用。     

加味丹参饮通过PTEN/PI3K/Akt信号通路抑制IRI作用的研究

目的:探讨加味丹参饮预处理通过抑瘤基因/磷脂酰肌醇-3激酶/蛋白激酶B(PTEN/PI3K/Akt)信号通路对大鼠心肌缺血再灌注损伤(IRI)的保护作用及机制。方法:将75只雄性远交群(SD)大鼠随机分为5组:假手术组、模型组、加味丹参饮组、加味丹参饮+PI3K/Akt通路抑制剂(LY294002)组、LY294002组,采用结扎大鼠冠状动脉左前降支30min后再灌注60min的方法制备IRI模型。采用酶联免疫吸附测定(ELISA)法检测各组大鼠心肌肌钙蛋白I(c Tn I)表达;取心肌梗死边缘区心肌组织,采用脱氧核糖核苷酸末端转移酶介导的缺口末端标记(TUNEL)法检测心肌凋亡指数,采用免疫组化法检测各组大鼠心肌组织Akt、PTEN的表达。结果:与假手术组比较,模型组c Tn I水平显著升高,大鼠心肌凋亡指数增加,PTEN、Akt表达均显著升高(P<0.05);与模型组比较,加味丹参饮组c Tn I水平均显著降低,Akt表达升高,心肌凋亡指数和PETN表达降低(P<0.05);与加味丹参饮组比较,加入抑制剂后,c Tn I水平均明显降低,Akt表达降低,PTEN表达升高(P<0.05)。结论:大鼠心肌缺血再灌注时,加味丹参饮可以通过降低PTEN表达,激活PI3K/Akt信号通路,抑制大鼠心肌细胞的凋亡,从而减轻心肌损伤,保护心肌。     

Combined therapy of hypertensive nephropathy with ginkgo leaf extract and dipyridamole injection and antihypertensive drugs: A systematic review and meta-analysis

Background:In recent years, the incidence rate of hypertensive nephropathy has been increasing quickly, which has been a major threat to people''s health. Renin-angiotensin-aldosterone system blockers have certain curative effects. However, there are some patients having serious adverse reactions, and the benefit population is limited, so the treatment of hypertensive renal damage is necessary to have beneficial supplement. More and more clinical studies have shown that ginkgo leaf extract and dipyridamole injection (GDI) combined with antihypertensive drugs has achieved good results in the treatment of hypertensive renal damage. It is supposed to be a supplementary treatment in hypertensive nephropathy.Objectives:To systematically assess the efficacy and safety of GDI combined with antihypertensive drugs on hypertensive renal injury.Methods:Seven databases including PubMed, Cochrane Library, Embase, Wanfang database, China biomedical literature service system (Sino Med), VIP Chinese Sci-tech journal database (VIP), and China national knowledge internet (CNKI) were retrieved to collect randomized controlled trials (RCTs) in the experimental group containing combined therapy of hypertensive nephropathy with GDI and antihypertensive drugs. The retrieval time was from the establishment of database to July 8, 2020. Two researchers independently selected literature, extracted data, and evaluated the risk of bias in the study. The methodological quality was evaluated with Cochrane handbook and meta-analysis was performed with Stata 14.0 software.Results:Eight studies were included in this study which involved 556 patients. The meta-analyses indicated that, compared with using antihypertensive drugs alone, combined treatment of GDI with antihypertensive drugs can decrease 24-hour urinary total protein (weighted mean difference [WMD] –0.61, 95% confidence interval [CI]: –0.82, –0.39; k = 6, P ≤ .001), blood urea nitrogen (WMD –1.27, 95% CI: –2.45, –0.10; k = 6, P = .033, serum creatinine (WMD –29.50, 95% CI: –56.44, –2.56; number of estimates [k] = 6, P = .032).Conclusions:Our meta-analyses showed that GDI combined with antihypertensive drugs can improve the renal function of hypertensive patients with renal injury.