头孢呋辛酯制备工艺的改进

以头孢呋辛钠为原料，从制备（R，S）-乙酸1-溴乙酯开始。经酯化反应的溶剂沉淀过程无须分离直接制得高纯度非晶型的头孢呋辛酯。本制备方法简便，适于工为化生产。     

氟比洛芬酯对大鼠局灶性脑缺血-再灌注损伤的保护作用

目的 探讨氟比洛芬酯(FA)对脑缺血-再灌注(I-R)损伤的保护作用.方法 40只雄性SD大鼠,随机均分为五组,即A组(I-R)、B组(I-R FA5 mg/kg)、C组(I-R FA 10 mg/kg)、D组(I-R FA 20 mg/kg)和E组(脂微球对照组).采用颈内动脉丝线栓塞致大脑中动脉栓塞(MCAO)模型,再灌注后24、48、72 h观察神经功能缺损评分(NDS评分)并于72 h后处死动物,取大脑切片行10 g/L 2,3,5-氯化三苯四唑(TTC)染色,测量并计算脑梗死容积百分比.结果 72 hNDS评分:B、C、D组明显高于A、E组(P<0.05);梗死容积百分比,B、C、D组明显低于A、E组(P<0.01),B、C、D组间24、48、72 h NDS评分差异无统计学意义;梗死容积百分比B组明显高于C、D组(P<0.05).结论 FA可明显减轻大鼠局灶性脑缺血-再灌注损伤.     

Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma

Bradykinin, a nonapeptide cleavage product of high molecular weight kininogen, is a potent bronchoconstrictor agonist in asthma; however, its mechanism of action is not known. Since bradykinin has been shown to stimulate mediator release from mast cells and augment the release of prostanoids, we have examined the effect of a selective histamine H1 receptor antagonist, terfenadine and a potent cyclooxygenase inhibitor, flurbiprofen on bronchoconstriction provoked by inhaled bradykinin in asthma. As a bronchial provocation procedure bradykinin challenge was repeatable to within 1 doubling dilution. In nine atopic asthmatic subjects, terfenadine 180 mg, when compared to placebo, increased the geometric mean provocation concentration of inhaled agonist required to reduce FEV1 by 20% of baseline (PC20) from 0.7 to greater than 22.9 mg/ml for histamine (P less than 0.01) and 0.3 to 0.5 mg/ml for bradykinin (P less than 0.01). In a further nine atopic asthmatics, flurbiprofen 150 mg when compared to placebo produced a small but significant protection of the airways against bradykinin, geometric mean PC20 increasing from 0.40 to 0.79 mg/ml (P less than 0.05). We conclude that bradykinin is a potent bronchoconstrictor agonist in asthma, being approximately 9.5 times more potent than histamine in molar terms. Pharmacological intervention with terfenadine and flurbiprofen led to a significant protection of the airways against the constrictor effect of bradykinin but the effect in each case was small. Thus, while histamine and prostanoids may contribute as mediators of bradykinin-induced bronchoconstriction, they are unlikely to account for the majority of the response.     

Laser induced thermal injury of rabbit cornea and treatment with anti-inflammatory agents

A moderately severe thermal injury of the central cornea of 48 Dutch-belted rabbit eyes was produced with a carbon (CO₂) laser. The lesions were photographed with a slit lamp (SL) camera immediately following the injury and at 1, 2, 4, 7, 14, 21, 30 and 60 days after the exposure. Lesion size, opaqueness, and depth were graded clinically by SL biomicroscopy at the same intervals. No significant differences were found (p 0.05) between groups of eyes treated with flurbiprofen (0.03%), prednisolone acetate (1%), and vehicle control four-times-a-day for three weeks following injury. Additionally, eyes were studied histopathologically at 3 and 60 days following injury by light and transmission electron microscopy, and clinically at 30 and 60 days by endothelial specular microscopy. Important clinical and histopathological findings included coagulative necrosis of the corneal epithelium, epithelial sloughing, fusion of stromal collagen, stromal edema and inflammatory cell infiltration, stromal scar formation, corneal thinning, endothelial hyperplasia and metaplasia, fibrinous anterior chamber reaction with hypopyon, and retrocorneal fibrous membrane formation.     

Relationship between the ocular and systemic disposition of flurbiprofen: The effect of altered protein dynamics at steady state

The differences in flurbiprofen disposition in the aqueous humor and the plasma were examined after systemic doses. Steady state plasma concentrations of flurbiprofen (20–60 g/mL) were achieved via intravenous infusion to albino rabbits. Flurbiprofen demonstrated linear systemic kinetics throughout the dosing range, with constant body clearance and unbound fraction in plasma. At steady state, aqueous humor drug concentrations depended on the corresponding plasma drug concentration. Two clearance terms—CL_so, the systemic clearance to ocular tissues, and CL_os, the ocular clearance to systemic circulation—were used. After systemic doses, the drug concentration in the aqueous humor was related to that in the plasma as well as to the ratio of these two clearances. Flurbiprofen was extensively bound to plasma proteins and showed limited ocular distribution; its CL_so to CL_so tratio was very small. Thus, the concentration of flurbiprofen in the aqueous humor after systemic doses was lower than that obtained after ophthalmic doses. A plasmapheresis technique was utilized to lower the plasma protein concentrations to 60% of normal levels. As a consequence, flurbiprofen demonstrated reduced aqueous humor protein concentrations, increased unbound fractions in the plasma and the aqueous humor, elevated aqueous humor drug concentrations, and elevated total body clearance. The unbound body clearance stayed unchanged. Our study indicated that a drug should present a significant CL_so/CL_os ratio in order to achieve therapeutic concentrations in the eye via systemic doses. The drug-protein binding kinetics can be different between the plasma and the aqueous humor circulations. Because the ocular compariment is very small compared to the overall systemic distribution of flurbiprofen, it has little effect on the steady state systemic concentrations.     

The Relationship of Diastereomer Hydrolysis Kinetics to Shelf-Life Predictions for Cefuroxime Axetil

Cefuroxime axetil, an ester prodrug of cefuroxime, is comprised of a 50:50 mixture of diastereomers A and B. The first-order hydrolysis kinetics of cefuroxime axetil were investigated as a function of pH, temperature, buffers, and ionic strength. Chromatographically identified hydrolysis products were cefuroxime, ²-cefuroxime axetil, and ,-sulfoxides. Buffer catalysis was observed in acetate and phosphate buffers. No significant kinetic effect was observed for ionic strength in the range µ = 0.1-1.0. The pH–rate profiles for hydrolysis of cefuroxime axetil isomeric mixture were obtained at 45, 35, and 25°C. The equation defining the cefuroxime axetil hydrolysis rate constant as a function of pH was k _obs = k _H(a _H) + k _s + k _OH(K _w/a _H), exhibiting maximal stability in the pH range 3.5 to 5.5. The predicted profile at 5°C was in excellent agreement with experimental data in the pH range 3.6 to 5.5. In the pH range 1 to 9, the maximum difference observed for individual hydrolysis constants of isomers was 27%. Shelf-life estimates based on the hydrolysis rate constants for cefuroxime axetil as an isomeric mixture were shown to be equivalent to those based on individual hydrolysis rate constants for isomers A and B.     

桔青霉对头孢呋辛酯的代谢转化

利用微生物转化的方法，选取桔青霉(Penicillium citrinum)为转化菌株，对头孢呋辛酯转化产率等方面进行了研究。采用枯草芽孢杆菌[CMCC(B)63501]作为检测菌株检测转化产物，结果表明，桔青霉能产生稳定的具抗菌活性的转化产物，且重现性好，转化产物的平均产率71．9％。高效液相色谱检测证明转化产物为头孢呋辛。     

氟比洛芬酯脂微球注射液对38例癌症疼痛镇痛效果的临床观察

目的：观察氟比洛芬酯脂微球载体注射液（商品名凯纷）治疗癌痛的疗效和副作用。方法：38例未使用阿片类药物的中重度癌性疼痛患者每天静脉注射50mg/5ml氟比洛芬酯脂微球载体注射液．分别就其疗效、生活质量改善情况以及不良反应等方面进行评价。结果：氟比洛芬酯脂微球载体注射液治疗中重度癌痛的有效率为71．05％．生活质量改善情况治疗前后有显著差异（P〈0．05）。但未见一般非甾体类药物常见腹痛、消化道出血等副作用；也未见便秘、恶心、呕吐、嗜睡等阿片类药物常见不良反应。结论：氟比洛芬酯脂微球载体注射液治疗中重度癌痛疗效可靠．生活质量可得到改善．但氟比洛芬酯脂微球载体注射液不良反应发生率较低，可部分作为临床候选药品或口服吗啡替代药。     

Solubilization of flurbiprofen into aptamer-modified PEG–PLA micelles for targeted delivery to brain-derived endothelial cells in vitro

Abstract

Novel aptamer-functionalized polyethylene glycol–polylactic acid (PEG–PLA) (APP) micelles were developed with the objective to target the transferrin receptor on brain endothelial cells. Flurbiprofen, a potential drug for therapeutic management of Alzheimer’s disease (AD), was loaded into the APP micelles using the co-solvent evaporation method. Results indicated that 9.03% (w/w) of flurbiprofen was entrapped in APP with good retention capacity in vitro. Targeting potential of APPs was investigated using the transferring receptor-expressing murine brain endothelial bEND5 cell line. APPs significantly enhanced surface association of micelles to bEND5 cells as quantified by fluorescence spectroscopy. Most importantly, APPs significantly enhanced intracellular flurbiprofen delivery when compared to unmodified micelles. These results suggest that APP micelles may offer an effective strategy to deliver therapeutically effective flurbiprofen concentrations into the brain for AD patients.     

氟比洛芬酯注射液对食管癌术后止痛泵用药剂量及凝血功能的影响

目的探究氟比洛芬酯注射液对食管癌术后患者止痛效果、止痛泵用量及不良反应情况的影响。方法选取2014年2月~2015年8月在该院就诊的食管癌患者98例,将患者随机均分为治疗组及对照组,每组49例,对照组给予常规术后自控止痛泵进行止痛处理并辅以常规术后治疗护理措施;治疗组在此基础上加用小剂量氟比洛芬酯注射液。观察比较2组患者术后即刻及术后36h的各项指数及镇痛效果总满意度。结果术前2组患者的心率(HR)、收缩压(SAP)、血氧饱和度(SaO2)、凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、凝血酶时间(TT)、纤维蛋白原(FIB)、血小板计数(PLT)、呼吸抑制、恶心、腹痛及大便潜血阳性例数比较,差异无统计学意义(P>0.05);术后36h治疗组患者的HR、SAP及SaO2明显高于对照组,治疗组患者的呼吸抑制及恶心例数明显少于对照组(P<0.05);治疗组患者术后治疗过程中的主动镇痛次数7.85±1.47次、用药量107.53±12.72mL、ICU留观时间18.54±2.67h及咳痰不畅例数(3,6.12%)明显低于对照组9.31±2.89次、115.37±15.29mL、20.47±3.53h、11(22.45%)(P<0.05);治疗组患者镇痛总满意度(47,95.92%)明显高于对照组(41,83.67%)(P<0.05)。结论小剂量应用氟比洛芬酯注射液可明显促进患者术后呼吸系统功能恢复,降低镇痛泵用药量及不良反应发生率,且无明显凝血指标异常等不良反应。