聚氧乙烯蓖麻油C-125及吐温80对维生素D2的增溶与稳定性的研究

维生素D₂的表观饱和溶解度与增溶剂的浓度呈直线关系,聚氧乙烯蓖麻油C-125的增溶效能,约相当吐温80的4倍多。紫外吸收光谱法推测在聚氧乙烯蓖麻油C-125胶团中维生素D₂分子更近于聚氧乙烯基的栅层部位,这可能是使增溶效能不同的1个重要原因。用初均速法测定了维生素D₂的稳定性,在聚氧乙烯蓖麻油C-125溶液中t_0.8^20°为1294.9 h,在吐温80中为153.5 h,反应活化能测得分别为14.2及9.3 kcal/mol,因而使维生素D₂的稳定性呈现差异。     

聚氧乙烯蓖麻油EL-40、吐温80于维生素D2增溶体系中稳定性的研究

胶团状态下聚氧乙烯蓖麻油EL-40(Ⅰ)与吐温80(Ⅱ)于维生素D₂(Ⅲ)增溶体系中可进水解,呈伪一级反应,受特殊酸碱催化,干pH 6附近最稳定,Ⅰ稳定性优于Ⅱ。离子强度、初浓度、一般酸碱催化诸影响因素实验表明,于pH 6 Ⅰ,Ⅱ的酯羰基与催化剂间的极性效应微弱,在实用处方添加适量强电解质原辅料、枸橼酸、磷酸二氢盐或Ⅰ,Ⅱ浓度由1%增至2%时,均不影响稳定性。增溶后位于胶团中心的Ⅲ,由于相互作用可增加Ⅰ,Ⅱ的稳定性,而位于胶团较外层的亲油基、亲水基夹层的鲸蜡醇及更外层氧乙烯链上的对羟基苯甲酸,则对Ⅰ,Ⅱ稳定性无显著影响。     

双重作用的多巴胺D2/5-HT2A受体拮抗剂比较药效团分析

双重作用的多巴胺D₂/5-HT_2A受体拮抗剂是开发非典型抗精神病药物的有效途径,但最新研究显示, 非典型抗精神病药物将显著增加患者因心律失常及其他心脏疾病而猝死的风险,本文对D₂/5-HT_2A受体拮抗剂的药效团模型以及可能引起心血管风险的α_1A肾上腺素受体拮抗剂和hERG K⁺通道阻断剂的药效团模型进行比较分析,从药效团模型的角度分析多靶点药物的设计。     

正相-反相两步高效液相色谱法制备毫克量级维生素D3异构体

利用正相半制备柱和反相分析柱的两步高效液相色谱法,在实验室规模制备了毫克是级维生素D₃的三个重要异构体——维生素D₃前体、光甾醇₃和速甾醇₃·维生素D₃原体,7-去氢胆固醇的光照是在一个装有UVB荧光灯的光治疗室中进行。采用紫外分光光度法和高效液相色谱法对制得的三个异构体进行了定性定量分析。在这三个异构体检测极限下,除了维生素D₃前体中有不超过0.25%的维生素D₃杂质外,三个产品中均没有发现任何除它本身之外的其他异构体杂质。     

维生素D2果糖酸钙注射液稳定性的研究

维生素D₂果糖酸钙注射液为非均匀体系的乳浊液。维生素D₂在油溶液中很稳定,而在此注射液中不稳定,其主要原因在于为非均匀体系乳浊所致,以界面对稳定性的影响最大。乳化剂用量增加维生素D₂稳定性亦降低。根据此注射液不稳定的主要原因,采用了添加油溶性抗氧剂和充以惰性气体的抗氧化措施,结合乳浊液的特点,此种措施是合理的,留样观察证明也是有效的。     

维生素D3辅助治疗咳嗽变异性哮喘患儿的疗效观察

目的 探讨维生素D₃辅助治疗对咳嗽变异性哮喘（cough variant asthma,CVA）患儿的疗效。方法 随机分配122例CVA患儿为对照组和观察组,各61例。对照组给予丙酸氟替卡松+硫酸沙丁胺醇吸入治疗,观察组基于对照组治疗基础上给予维生素D₃,对比2组治疗前及治疗6个月后的临床症状、肺功能、T淋巴细胞亚群含量和25羟维生素D₃[25-dihydroxyvitamin D₃,25（OH）D₃]、基质金属蛋白酶9（matrix metalloproteinase 9,MMP-9）、白细胞介素-10（interleukin-10,IL-10）。结果 与治疗前比较,治疗后2组临床症状评分显著降低（P<0.05）,肺功能指标中第1秒末用力呼气量、肺活量及呼气峰流速百分比显著提高（P<0.05）,观察组变化幅度显著大于对照组;治疗后,观察组CD4⁺及CD4⁺/CD8⁺含量显著低于治疗前及对照组（P<0.05）,CD8⁺含量显著高于治疗前及对照组（P<0.05）;治疗后,2组患儿血清25（OH）D₃、IL-10水平升高（P<0.05）,MMP-9水平显著降低（P<0.05）,观察组变化幅度显著大于对照组（P<0.05）;2组患儿均未见有明显不良反应。结论 维生素D₃联合常规疗法可明显改善CVA患儿咳嗽等症状,提高肺功能,纠正T淋巴细胞亚群失衡,改善气道高反应及气道炎性反应,安全性良好。     

维生素B2和B6的同步荧光分析法及其在维生素复合制剂中的应用

本文建立了维生素B₂和B₆的同步荧光分析法。以△λ=58nm进行同步扫描所得的两个同步荧光峰(以发射波长表示,分别位于526nm和389nm)可用以同时分别定量维生素B₂和B₆。方法快速、灵敏。维生素B₂和B₆的工作曲线线性范围分别为0～1μg/ml和0～1.5μg/ml,检出限分别为0.5ng/ml和1ng/ml。方法已应用于三种复合维生素B制剂中维生素B₂和B₆的分析。     

肌注维生素K1致湿疹型皮肤反应及文献回顾

目的：总结维生素K₁注射液肌肉注射后引起皮肤反应的临床特征及治疗方法。方法：对1例产妇肌注维生素K₁致湿疹型皮肤反应进行报道,并对相关文献报道的情况进行回顾性汇总分析。结果：维生素K₁注射液导致的皮肤反应为非Ig E介导的Ⅳ型过敏反应,主要由增溶剂聚山梨酯80所引起,抗过敏治疗效果不显著。结论：应严格掌握用药的适应证,加强用药监测,提高用药警惕性,保障患者用药安全。     

UHILIC-MS/MS法同时测定复方三维右旋泛酸钙糖浆中5种维生素的含量

目的 建立一种超高效亲水作用色谱串联三重四极杆质谱法（UHILIC-MS/MS）,同时测定复方三维右旋泛酸钙糖浆中维生素B₁、维生素B₂、维生素B₆、烟酰胺和泛酸钙的含量。方法 采用超高效液相色谱仪,Waters ACQUITY BEHHILIC Amide色谱柱（2.1 mm×100 mm,1.7 μm）,以90%乙腈（含0.5%甲酸）-10 mmol/L甲酸铵水（含0.5%甲酸）为流动相,进行梯度洗脱,流速0.30 ml/min;在电喷雾（ESI）正离子模式下,用多反应监测（MRM）模式进行含量测定。结果 在5 min内,样品中5种维生素分别在各自考察的浓度范围内呈良好的线性关系,相关系数（r）均大于0.998 4;整体加样回收率在93.27%~100.39%之间,RSD为1.41%~4.96%;10批样品中维生素B₁、维生素B₂、维生素B₆、烟酰胺、泛酸钙的含量测定结果分别为32.40~38.91、7.002~8.462、9.677~11.17、33.64~39.58、3.276~3.771 mg/250 g。结论 本研究建立的UHILIC-MS/MS方法可快速实现对复方三维右旋泛酸钙糖浆中5种维生素类成分定性鉴定或定量检测,为复方三维右旋泛酸钙糖浆的开发利用和质量评价提供了可靠的技术检测方法。     

维生素D缺乏和过剩对大鼠脑内P-糖蛋白和乳腺癌耐药蛋白表达的影响

目的 研究维生素D缺乏和过剩对大鼠脑内P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）功能和表达的影响。方法 18只雄性SD大鼠随机分为对照组、去维生素D（NVD）组和高维生素D（HVD）组,分别使用标准饲料（1 000 IU/kg维生素D）、去维生素D（0 IU/kg维生素D）饲料和高维生素D（20 000 IU/kg维生素D）饲料饲养12周,诱导维生素D缺乏和过剩模型,测定大鼠血清中25-羟基维生素D₃[25（OH） D₃]、1α,25二羟基维生素D₃[1α,25（OH）₂D₃]水平以确证模型。造模成功后,尾iv含罗丹明123（0.2 mg/kg）、哌唑嗪（1 mg/kg）和荧光素钠（2 mg/kg）的混合探针,采用LC-FLU或LC-MS法分别测定大鼠脑皮层、海马和血浆中罗丹明123、哌唑嗪和荧光素钠的浓度,计算脑血比,评价P-gp、BCRP功能和血脑屏障完整性;采用Western blotting法测定大鼠脑皮层和海马P-gp和BCRP的相对表达量。用25（OH） D₃、1α,25（OH）₂D₃分别温孵人微血管内皮细胞（hCMEC/D3）,以罗丹明123、哌唑嗪为探针评价细胞中P-gp和BCRP的功能。结果 维生素D缺乏大鼠脑内P-gp功能和表达下调,而维生素D过剩大鼠脑内P-gp功能和表达上调,维生素D缺乏和过剩均不影响大鼠脑内BCRP的功能和表达。25（OH） D₃不影响hCMEC/D3细胞P-gp和BCRP的功能,而1α,25（OH）₂D₃上调hCMEC/D3细胞中P-gp的功能。结论 维生素D缺乏导致的体内1α,25（OH）₂D₃水平降低可能是下调大鼠脑内P-gp的功能和表达的原因之一,而维生素D过剩导致的体内1α,25（OH）₂D₃水平升高可能是上调大鼠脑内P-gp的功能和表达的原因之一。     

Effects of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on the acetylation of 2-aminofluorene and DNA-2-aminofluorene adducts in the rat.

The effects of the synthetic phenolic antioxidants (butylated hydroxyanisole and butylated hydroxytoluene) on the in vivo acetylation of 2-aminofluorene and formation of DNA-2-aminofluorene adducts were investigated in male Sprague-Dawley rats. For in vitro examination, cytosols and intact cells, with or without butylated hydroxyanisole and butylated hydroxytoluene co-treatment, showed different percentages of 2-aminofluorene acetylation and DNA-2-aminofluorene adducts. For in vivo examination, pre-treatment of male rats with butylated hydroxyanisole and butylated hydroxytoluene (10 mg/kg) 48 h prior to the administration of 2-aminofluorene (50 mg/kg) resulted in 34% and 18%, 29% and 20% decreases, respectively, in the urinary and fecal recovery of N-acetyl-2-aminofluorene, and 34% and 19% decreases, respectively, in the metabolic clearance of 2-aminofluorene to N-acetyl-2-aminofluorene. Following exposure of rats to the 2-aminofluorene, with or without pretreatment with butylated hydroxyanisole and butylated hydroxytoluene, DNA-2-aminofluorene adducts were observed in the target tissues of liver and bladder, and also in circulating leukocytes. The DNA-2-aminofluorene adducts in liver, bladder, and leukocytes were decreased by pretreatment with butylated hydroxyanisole and butylated hydroxytoluene. This is the first demonstration that synthetic phenolic antioxidants decrease the N-acetylation of carcinogens and formation of DNA-carcinogen adducts in vivo.     

Toxicity studies of butylated hydroxyanisole and butylated hydroxytoluene. I. Genetic and cellular effects

The cellular effects of the antioxidants butylated hydroxyanisole and butylated hydroxytoluene were studied in a battery of in vitro tests. No evidence of genotoxicity was obtained for either compound in the hepatocyte primary culture/DNA repair test, the Salmonella/microsome mutagenesis test, the adult rat liver epithelial cell/hypoxanthine-guanine phosphoribosyl transferase test, or for butylated hydroxyanisole in the Chinese hamster ovary cell/sister chromatid exchange test. Both compounds inhibited intercellular molecular exchange between cultured liver cells, an effect that has been observed for many agents with neoplasm-promoting activity.     

辛伐他汀胶囊中抗氧剂的优化

目的：考察抗氧剂组成及用量对辛伐他汀胶囊的影响,提高制剂稳定性。方法：分别制备含叔丁基羟基茴香醚、没食子酸丙酯、焦亚硫酸钠、维生素C、枸橼酸等不同抗氧剂的辛伐他汀胶囊,HPLC法测定加速实验6个月及长期留样12个月后制剂中的主药含量、溶出度和有关物质。结果：抗氧剂对制剂含量、溶出度、有关物质有显著影响,其提高制剂稳定性的顺序为：叔丁基羟基茴香醚〉没食子酸丙酯〉L-半胱氨酸〉焦亚硫酸钠〉维生素C;枸橼酸对没食子酸丙酯具有抗氧增效作用,没食子酸丙酯：枸橼酸=0．69mg：0．46mg（3：2,W／W）时抗氧化作用最佳。结论：加入优化后的抗氧剂可提高辛伐他汀胶囊的稳定性。     

Effect of four synthetic antioxidants on the formation of ethylene from methional in rat liver microsomes

Four commonly used food antioxidants, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate and octyl gallate, were tested for their ability to inhibit the formation of ethylene from methional in NADPH-oxidizing rat liver microsomes. It is assumed that the action of the antioxidants on ethylene formation reflects their free radical scavenging activity. Only propyl gallate and octyl gallate are efficient inhibitors of ethylene formation. BHT is inhibitory only at very high concentrations, and BHA tends to increase ethylene formation. It is concluded that gallic acid ester antioxidants may possess a protective potential during chemical-induced microsomal oxidations.     

Methodology for studying antioxidant activity and mechanisms of action of antioxidants

A brief survey of the main reactions involved in lipid peroxidation and of the principal methods used for the detection of lipid peroxidation in authentic food, in model systems and in biological material is given. The reaction of phenolic antioxidants with various radicals generated during lipid peroxidation and the synergism between individual antioxidants are outlined. The biological consequences of lipid peroxidation and the protective properties of antioxidants are discussed. In addition, the scavenger action of antioxidants toward inorganic oxygen radicals is described, and it is demonstrated that propyl gallate surpasses butylated hydroxyanisole and butylated hydroxytoluene in its capacity to remove hydroxyl radicals and superoxide radicals from aqueous model media and from biological material. Biochemical actions of antioxidants that may be involved in the anti-carcinogenic and proliferation-stimulating effects of antioxidants in vivo are listed.     

Metabolic aspects of antioxidants and preservatives

The use of chemical preservatives serves to ensure the nutritional adequacy, palatability and safety of processed foods and beverages. The toxicity of some of the more ubiquitous antimicrobial agents (sorbic acid, p-hydroxybenzoates, sulphur dioxide) and antioxidants (propyl gallate, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT] is reviewed together with the role of metabolic data in assessing the 'safety-in-use' of these and other food-additives.     

Toxicity studies of butylated hydroxyanisole and butylated hydroxytoluene. II. Chronic feeding studies

The antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) were fed in the diet to male F344 rats in two chronic feeding studies. In one study, feeding BHT for 76 wk at concentrations ranging from 100 to 6000 ppm produced no increase in neoplasms at any site. In a second study, feeding 12,000 ppm BHT for 110 wk had no neoplastic effect at any site, whereas feeding BHA at 12,000 ppm resulted in a small increase in squamous cell papillomas of the non-glandular squamous portion of the stomach.     

Metabolic aspects of antioxidants and preservatives

The use of chemical preservatives serves to ensure the nutritional adequacy, palatability and safety of processed foods and beverages. The toxicity of some of the more ubiquitous antimicrobial agents (sorbic acid, p-hydroxybenzoates, sulphur dioxide) and antioxidants (propyl gallate, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT)) is reviewed together with the role of metabolic data in assessing the safety-in-use of these and other food-additives.     

The interaction of antioxidants and structurally related compounds with mitochondrial oxidative phosphorylation.

The antioxidants, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), interact with mitochondrial oxidative phosphorylation in two ways. They uncouple phosphorylation from oxidation by making the mitochondrial inner membrane more permeable to protons. They also inhibit respiration by a direct interaction with the electron transport chain. Here we separated out these two properties of BHA and BHT by determining their effects on respiration in coupled and uncoupled mitochondria. Similar experiments were carried out with compounds structurally related to BHA and BHT. Most of these compounds had uncoupling and inhibitory properties essentially similar to BHA and BHT. In contrast, the dimer of BHA had no inhibitory effects on uncoupled respiration and little uncoupling activity. The implications of these results for the interactions of BHA and BHT with mitochondrial oxidative phosphorylation and the design of antioxidants are discussed.