Addition of Cationic Surfactants to Lipid-Based Formulations of Poorly Water-Soluble Acidic Drugs Alters the Phase Distribution and the Solid-State Form of the Precipitate Upon In Vitro Lipolysis

It has been previously shown that the interaction of some weakly basic drugs with oppositely charged fatty acids during digestion can influence the solid-state form of the drug if it precipitates. The present study hypothesized the opposite effect for weakly acidic drugs. Tolfenamic acid (TA) and an oppositely charged cationic surfactant, didodecyldimethylammonium bromide (DDAB) were combined in a model medium chain lipid formulation. The phase distribution upon in vitro lipolysis was determined using HPLC and the solid-state form of precipitated TA was determined using X-ray diffraction and crossed polarized light microscopy. TA precipitated in a different polymorphic crystalline form to the starting reference material in the absence of DDAB but precipitated in an amorphous form when DDAB was included in the same formulation. The solubility of TA upon dispersion and digestion of the formulation was considerably higher in the presence of DDAB. The findings point to ionic interactions between TA and DDAB as the reason for the improved drug solubility throughout digestion, and precipitation of drug in an amorphous salt form, analogous to what has been observed in the past for some poorly water-soluble weakly basic drugs with anionic co-formers.     

Adaptation of Quality by Design-Based Development of Isradipine Nanostructured–Lipid Carrier and Its Evaluation for In Vitro Gut Permeation and In Vivo Solubilization Fate

The present study demonstrated the systematic adaptation of quality by design-integrated approach for the development of novel nanostructured lipid carrier (NLC) of an anti-hypertensive drug isradipine (ISD) to address the inherent challenges such as low solubility and low oral bioavailability. Plackett-Burman design was used for preliminary screening of significant process and formulation variables (p <0.05), which were further processed using Box-Behnken design for the attainment of optimization goal that is, mean particle size (85.7 ± 7.3 nm), drug entrapment efficiency (87.4 ± 3.29%), and in vitro drug release characteristics (92.89 ± 5.47%). The optimized ISD-NLC formulation also demonstrated well-dispersed uniform-shaped particles (polydispersity index 0.207 ± 0.029), high gastrointestinal fluid stability (zeta potential ?10.17 ± 0.59 mV), and higher in vitro gut permeation (21.69 ± 2.38 μg/cm² of ISD-NLC as compared to 11.23 ± 1.74 μg/cm² in ISD suspension). Furthermore, lipolysis studies were performed for the purpose of in vivo fate, and significantly higher drug content of ISD from ISD-NLC in aqueous phase was found (72.34 ± 4.62%) as compared to drug suspension (3.01 ± 0.91%). Relative bioavailability of ISD-NLC and ISD suspension was increased by 4.2-fold and 1.78-fold in the absence and presence of cycloheximide which is a lymphatic uptake inhibitor revealing lymphatic uptake of ISD-NLC in bioavailability improvement. Hence, systematic adaptation of quality by design integrated approach improved gut permeation and potential solubilizaton fate (dynamic lipolysis) of ISD-NLC, which further improved the lymphatic uptake and biodistribution of drug thereby promisingits in vivo prospect and clinical efficacy.     

丁苯酞联合较高剂量阿托伐他汀治疗急性脑梗死临床观察

摘 要 目的：观察丁苯酞联合较高剂量阿托伐他汀治疗急性脑梗死的疗效,及对患者炎性反应、氧化应激和动脉粥样斑块的影响。 方法: 146例急性脑梗死患者随机分为观察组和对照组各73例。对照组给予丁苯酞联合常规剂量阿托伐他汀治疗,观察组给予丁苯酞联合较高剂量阿托伐他汀治疗。评价两组治疗总有效率,比较两组患者治疗前后血浆同型半胱氨酸(Hcy)、C 反应蛋白(CRP)、丙二醛（MDA）、超氧化物歧化酶(SOD)、总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇(LDL C)、 氧化修饰低密度脂蛋白 （oxLDL）、基质金属蛋白酶 9(MMP 9)水平,和颈动脉内膜中层厚度(cIMT)、颈动脉粥样斑块面积、不稳定斑块数量变化情况。对Hey、MDA、斑块面积、不稳定斑块变化幅度与年龄、入院NHSS评分、脑梗死体积及丁苯酞联合降脂、联合一般降脂、联合强化降脂等指标的相关性进行分析。出院后进行3个月的预后随访。结果: 治疗后观察组总有效率为81.2%,明显高于对照组的61.4%（P＜0.05）。治疗后两组患者的Hcy、CRP、MDA、TC、TG、LDL、oxLDL、MMP 9、cIMT及颈动脉斑块面积、不稳定斑块数量等指标均较治疗前明显降低(P＜0.05),SOD则较治疗前升高(P＜0.05),且观察组各项指标均优于对照组(P＜0.05)。Hcy、MDA、斑块面积、不稳定斑块变化值与丁苯酞联合降脂呈正相关,而与强化降脂的相关性更高（P＜0.05）。观察组预后良好率明显优于对照组（P＜0.05）。结论: 丁苯酞联合阿托伐他汀强化降脂治疗急性脑梗死的效果明显,可有效改善患者炎性反应和氧化应激状态,有利于促进神经功能恢复和抑制动脉斑块形成。     

Targeted delivery of hyaluronic acid-coated solid lipid nanoparticles for rheumatoid arthritis therapy

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease. Long-term, high-dose glucocorticoid therapy can be used to treat the disease, but the fact that the drug distributes systemically can give rise to severe adverse effects. Here we develop a targeted system for treating RA in which the glucocorticoid prednisolone (PD) is encapsulated within solid lipid nanoparticles (SLNs) coated with hyaluronic acid (HA), giving rise to HA-SLNs/PD. HA binds to hyaluronic receptor CD44, which is over-expressed on the surface of synovial lymphocytes, macrophages and fibroblasts in inflamed joints in RA. As predicted, HA-SLNs/PD particles accumulated in affected joint tissue after intravenous injection into mice with collagen-induced arthritis (CIA), and HA-SLNs/PD persisted longer in circulation and preserved bone and cartilage better than free drug or drug encapsulated in SLNs without HA. HA-SLNs/PD reduced joint swelling, bone erosion and levels of inflammatory cytokines in serum. These results suggest that encapsulating glucocorticoids such as PD in HA-coated SLNs may render them safe and effective for treating inflammatory disorders.     

新诊断2型糖尿病患者骨钙素与胰岛素抵抗、胰岛β细胞功能及血脂的相关性研究

目的探讨新诊断2型糖尿病(T2DM)患者血清骨钙素(OC)与胰岛素抵抗、胰岛β细胞功能及血脂的关系。方法本研究为病例对照研究,病例组为2016年1月至2017年7月间我院内分泌科新诊断的2型糖尿病患者(符合WHO 1999年糖尿病诊断标准)150人,对照组来源于同期于我院进行健康体检的人群,共50人。比较两组的OC水平,并分析T2DM患者OC与空腹血糖(FBG)、糖化血红蛋白(HbA1c)、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)、胰岛β细胞功能指数(HOMA-β)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)和高密度脂蛋白(HDL)等指标的相关性。结果病例组OC低于对照组[(16.85±5.60)ng/ml vs(24.63±6.93)ng/ml],HOMA-IR高于对照组(10.88±8.71 vs 1.33±0.95),HOMA-β低于对照组(28.42±17.72 vs 134.65±67.73),TG高于对照组[(4.28±2.38)ng/ml vs(1.37±0.38)mmol/L],HDL低于对照组[(0.76±0.18)ng/ml vs(1.11±0.26)mmol/L],P均<0.001;新诊断T2DM患者OC与FBG、HbA1c呈负相关,与空腹C肽(FCP)呈正相关,相关系数分别为-0.315、-0.321、0.434(P<0.05)。结论新诊断T2DM患者的血清骨钙素低于健康人群,其对2型糖尿病的发生及监测有一定临床意义。     

利用面板数据模型研究血脂对血压的影响

目的 利用面板数据模型,探讨血脂四项指标对血压的影响。 方法 收集社区居民连续5年的血脂、血压及身高、体重、腰围等体检数据,建立以血压为因变量,以血脂四项指标为自变量,以BMI和腰围为控制变量的面板数据模型,分析血脂水平变化对血压的影响。 结果 单因素模型中,影响收缩压的有甘油三酯、低密度脂蛋白;影响舒张压的有总胆固醇、甘油三酯、低密度脂蛋白。多因素模型中,影响收缩压的有高密度脂蛋白与低密度脂蛋白,影响舒张压的是低密度脂蛋白与甘油三酯,总胆固醇未能进入两个方程。 结论 血脂四项中,总胆固醇不能影响血压,甘油三酯增高会导致舒张压上升,高密度脂蛋白增高会降低收缩压,低密度脂蛋白增高会导致收缩压与舒张压的上升。居民膳食指南中,对于胆固醇的摄入,作出不再受限制的简单的建议是不够的,应该综合当前的研究结果,对脂肪的摄入提出更精准的推荐。     

高脂血症患者细胞色素P450 3A4~* 18B基因多态性对辛伐他汀稳态血药浓度及其对降脂疗效的影响

目的分析高脂血症患者细胞色素P450 3A4~*18B(CYP3A4~*18B)基因多态性对辛伐他汀稳态血药浓度及其对降脂疗效的影响。方法 115名高脂血症患者均予以辛伐他汀每次20 mg,qd,口服,连续用药4周。在治疗前和治疗后,分别抽取空腹外周静脉血2 mL,用聚合酶链反应-限制性片段长度多态性分析法分析CYP3A4~*18B的等位基因,用全自动生化分析仪测定血总胆固醇、低密度脂蛋白胆固醇等。在最后一次服药前0.5 h内,抽取外周静脉血4 mL,用HPLC法测定血中辛伐他汀的稳态药物浓度。结果 115名高血脂症患者中,CYP3A4~*18B基因型分布符合Hardy-Weinberg遗传平衡(P>0.05),CYP3A4~*18B等位基因突变率为41.74%。CYP3A4~*1/~*1、CYP3A4~*1/~*18B和CYP3A4~*18B/~*18B的辛伐他汀稳态血药浓度分别为(4.88±0.44),(4.90±0.38)和(4.71±0.36)ng·mL^-1,总胆固醇分别为(5.78±0.47),(5.84±0.47)和(5.82±0.52)mmol·L^-1,低密度脂蛋白胆固醇分别为(2.63±0.04),(2.60±0.08)和(2.58±0.12)mmol·L^-1,差异均无统计学意义(均P>0.05)。结论 CYP3A4~*18B基因多态性对辛伐他汀稳态血药浓度及降脂疗效无明显影响。     

A safety evaluation of evolocumab

Introduction: Evolocumab is an injectable, fully human monoclonal antibody and a member of the newest class of low density lipoprotein cholesterol (LDL-C) lowering agents called proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The PCSK9 inhibitors are the most significant advance in lipid therapy since the introduction of the first statin 30 years ago.

Areas covered: The PCSK9 monoclonal antibodies have demonstrated a consistently high LDL-C lowering efficacy with and without statins and/or other lipid lowering therapies (LLT). LDL-C levels achieved with these agents are lower than has ever been possible before. This review will focus on the overall safety of evolocumab including cognitive impairment, very low LDL-C levels, new onset diabetes and glucose abnormalities, effect on vitamin E and steroid hormones, liver and muscle abnormalities, and immunogenicity and injection site reactions. The phase II and III clinical trials had relatively low patient-years of exposure, but the open label extension studies and the recently published outcomes trial, FOURIER, will be the focus of this paper. The safety profile of evolocumab to date is remarkable and extremely encouraging as will be demonstrated.

Expert opinion: The PCSK9 inhibitors will be responsible for a new era in lipid therapy that will expand our knowledge of lipid levels and cardiovascular disease (CVD) prevention with an efficacy and safety profile not previously available in clinical practice.     

Effect of size and shape on toxicity of zinc oxide (ZnO) nanomaterials in human peripheral blood lymphocytes

The multi-industrial applications of zinc oxide nanomaterials (ZnO NMs) lead to increasing exposure to humans. Though the ZnO nanoparticles (NPs) toxicity had been evaluated previously, toxicity of other forms of ZnO nanomaterials has not been evaluated. In this study, cytotoxicity and genotoxicity of four different types of ZnO NMs were evaluated using human peripheral blood lymphocytes (HPBL). In addition, the effect of anti-oxidants on ZnO NMs induced toxicity was also evaluated. Our results suggest that, size and shape of the nanomaterials have profound effects on their toxicity. The NPs and nanorods (NRs) possessed higher level of oxidative potential and ROS generation capacity than microparticles (MPs) and microrods (MRs). In contrast, MPs and MRs possessed higher level of lipid peroxidation capacity. The smaller NPs are more genotoxic while larger MPs and MRs were more cytotoxic in nature. Treatment with vitamin C or Quercetin significantly reduces the genotoxicity associated with ZnO NMs. The influence of size and shape in mediating NMs toxicity should be taken into account and the possible supplementation of anti-oxidants might mitigate the toxicity.