Dependency of Gastrointestinal Toxicity on Release Rate of Tiaprofenic Acid: A Novel Pharmacokinetic-Pharmacodynamic Model

Purpose. To test the hypothesis that modification of release pattern of nonsteroidal anti-inflammatory drugs (NSAIDs) formulations shifts gastrointestinal (GI) toxicity of the drugs from the upper GI region to the distal intestine. Methods. We assessed tiaprofenic acid (TA)-induced upper and lower increased GI permeability (a surrogate marker of toxicity) after administration of 20 mg and 40 mg/kg regular release (powder) and modified release formulations [sustained release (SR) beads and diethyl--cyclo-dextrin (DCD):TA inclusion complex (INC)]. Urinary excretion of oral doses of GI permeability probes sucrose and ⁵¹Cr-EDTA was determined as measures of gastroduodenal and distal intestine, respectively. Pharmacokinetics of TA enantiomers were also studied following administration of a single 20 mg/kg dose of racemic TA as oral SR beads and iv solution. For powder and INC, previously reported pharmacokinetic data were used. Results. Regular powder significantly increased the permeability at the gastroduodenal level. Modified-release formulations, on the other hand, did not cause damage in the gastroduodenum but produced significant increase in the permeability of the lower intestine. Consequently, to assess the pharmacokinetic-pharmacodynamic relationship, a new model was developed in which contribution of toxicity resulted from direct exposure to the drug was considered. Conclusions. Since the observed site of GI damage corresponds to the site of release and absorption of NSAID from the formulation, the possibility of a shift in the site of damage must be considered for the modified release formulations. A parallel evaluation of upper and lower GI toxicity is essential for a complete assessment of NSAID-induced GI damage.     

马来酸依那普利片的药物动力学及相对生物利用度

10名健康志愿者随机交叉口服10mg国产和进口马来酸依那普利片后,采用高效液相色谱法测得血浆中依那普利浓度分别在（0.83±0.21）h和（0.85±0.17）h达到峰值（69.3±27.7）ng／ml和（71.3）±29.5）ng／ml。血药浓度曲线下面积（AUC0→8）分别为（121.4±39.0）h·ng／ml和（121.6±40.5）h·ng／ml。以进口片为参比,国产片的相对生物利用废为（100.6±8.4）％。经统计分析,两种制剂具有生物等效性。     

A Validated High-performance Liquid Chromatograhy Method for Estimation of Ferulic Acid in Asafoetida and Polyherbal Preparation

A high-performance liquid chromatography method was developed for the estimation of ferulic acid from asafoetida and a polyherbal preparation. The separation was carried out on HiQSil ODS C-18 column with a mobile phase of acetonitrile: 10% acetic acid (20:80 v/v). The developed method was validated as per International Conference of Harmonization guidelines for various parameters such as accuracy, precision, linearity, limit of detection, limit of quantification and specificity; and found to be reliable. Linear regression analysis showed a good corelation between peak area and concentration with a corelation coefficient r²=0.996 in the range 200-7000 ng/ml. The developed method can be utilized for standardization of herbal formulation comprising asafoetida.     

硝苯地平缓释片联合依那普利治疗高血压病48例疗效观察

目的观察硝苯地平缓释片联合依那普利的降压作用、不良反应及对代谢的影响。方法将96例原发性高血压病患者随机分为治疗组和对照组各48例，治疗组服用硝苯地平缓释片及依那普利，对照组单纯服用依那普利，疗程4周，由固定医生测坐位血压，于治疗前后测血糖、血脂、电解质、肝功能、肾功能，并行心电图检查。结果治疗组和对照组在服药4周后显效率分别为45．8％、25．O％，总有效率分别为95．8％、68．7％，两组比较差异有统计学意义（P〈0．05或P〈0．01），而两组治疗对糖代谢、脂代谢、电解质、肝功能、肾功能及心电图并无明显影响。结论硝苯地平联合依那普利降压效果好，副作用小，值得临床推广应用。     

Honey in dermatology and skin care: a review

Honey is a bee‐derived, supersaturated solution composed mainly of fructose and glucose, and containing proteins and amino acids, vitamins, enzymes, minerals, and other minor components. Historical records of honey skin uses date back to the earliest civilizations, showing that honey has been frequently used as a binder or vehicle, but also for its therapeutic virtues. Antimicrobial properties are pivotal in dermatological applications, owing to enzymatic H₂O₂ release or the presence of active components, like methylglyoxal in manuka, while medical‐grade honey is also available. Honey is particularly suitable as a dressing for wounds and burns and has also been included in treatments against pityriasis, tinea, seborrhea, dandruff, diaper dermatitis, psoriasis, hemorrhoids, and anal fissure. In cosmetic formulations, it exerts emollient, humectant, soothing, and hair conditioning effects, keeps the skin juvenile and retards wrinkle formation, regulates pH and prevents pathogen infections. Honey‐based cosmetic products include lip ointments, cleansing milks, hydrating creams, after sun, tonic lotions, shampoos, and conditioners. The used amounts range between 1 and 10%, but concentrations up to 70% can be reached by mixing with oils, gel, and emulsifiers, or polymer entrapment. Intermediate‐moisture, dried, and chemically modified honeys are also used. Mechanisms of action on skin cells are deeply conditioned by the botanical sources and include antioxidant activity, the induction of cytokines and matrix metalloproteinase expression, as well as epithelial‐mesenchymal transition in wounded epidermis. Future achievements, throwing light on honey chemistry and pharmacological traits, will open the way to new therapeutic approaches and add considerable market value to the product.     

Precipitation of the Renin Inhibitor Ditekiren Upon iv Infusion; in Vitro Studies and Their Relationship to in Vivo Precipitation in the Cynomolgus Monkey

Ditekiren is a pseudo-octapeptide being developed as an inhibitor of human renin. Preclinical drug safety studies with this drug involved continuous iv infusions through indwelling catheters in the right internal jugular vein of the cynomolgus monkey for up to 30 days. The following physicochemical properties of ditekiren make it susceptible to intravascular precipitation immediately following iv infusion: (1) the water solubility of ditekiren is high at acidic pH where the drug is formulated (pH 4) but low at physiologic pH, and (2) the water solubility of ditekiren decreases by roughly 50% from room temperature (25°C) to physiologic temperature (37°C). Studies of 28-and 30-day infusion durations revealed intravascular precipitation in monkeys using drug solutions and rates of infusion that were expected to be precipitation-free, based on the solubility of ditekiren and assumptions about blood flow in the monkey right internal jugular vein. Therefore, an in vitro apparatus was used to study the relationship among the drug concentration in the infusate, the rate of infusion, and the occurrence of precipitation in a fluid stream of phosphate-buffered bovine serum albumin solution (a facsimile of plasma). Maximum rates of infusion without precipitation were determined for a range of concentrations of drug in two separate formulations. Infusion conditions identified by the in vitro method as precipitation-free were then tried in a definitive 14-day monkey study. Of 24 monkeys infused with solutions of ditekiren, none showed evidence of intravascular precipitation. This study demonstrates that the in vitro precipitation system is useful in establishing drug concentrations and rates of injection which avoid the problem of intravascular precipitation in preclinical animal studies.     

Pharmacokinetics and converting enzyme inhibition after morning and evening administration of oral enalapril to healthy subjects

Summary Possible circadian changes in the pharmacokinetics and effect on serum angiotensin-converting enzyme (ACE) activity of the ACE inhibitor enalapril have been studied in 8 healthy subjects after oral ingestion of 10 mg enalapril maleate either at 08.00 h or 20.00 h. The time to peak serum concentration (t_max) of enalapril was increased after administration at 20.00 h compared to 08.00 h (2.4 h versus 1.3 h), where as other kinetic parameters were not significantly altered. The 24 h-kinetics of the active metabolite enalaprilat did not differ significantly between the two treatments, but the area under the curve (AUC (0–24)) and the peak serum concentration (C_max) were slightly higher after intake at 20.00 h. The relationship between the measured serum enalaprilat level and the degree of inhibition of serum ACE was the same after both treatments. Overall, the evening and morning administration of enalapril did not differ markedly in the pharmacokinetics and the time course of ACE inhibition.This report is part of the thesis to be presented by K. Weisser in partial fulfillment of the requirements for the degree of Doctor of Natural Science.     

Enalapril和Captopril对大鼠急性心肌梗塞后血流动力学影响的比较

目的　旨在观察Enalapril和Captopril对心肌梗塞后大鼠血流动力学的影响 ,以探讨左室重构的机制 ,并比较两药的差异。方法　选用大鼠心肌梗塞模型 ,分为假手术组、心肌梗塞组、梗塞给药Enalapril组和梗塞给药Captopril组。梗塞前 3d开始饲以Enalapril和Captopril。 结果　心梗后LVEDP明显增加 ,使用Enalapril和Captopril后LVEDP明显降低 ,亦使MAP、LVSP及±dp/dtmax降低 (P <0 .0 1) ,但用药两组无差异 (P <0 .0 1)。结论　心梗后应用Enalapril和Captopril可改善心功能 ,两药无差异     

依那普利、硝苯吡啶对高原负荷运动后视网膜的干预作用

目的 :探索药物改善低氧环境负荷运动后视网膜的动态改变 ;方法 :选择移居海拔 3 70 0m 6个月的健康男性青年 1 0人 ,给予口服依那普利、硝苯吡啶 1 5天 ,于服药前、服药 1 5天、停药 1 0天时采用EGM型自行车功量仪进行负荷运动 (负荷指标W2 2 5、P1 75次 /分～ 1 80次 /分 ) ,于每次运动结束后 1 0分钟应用可调强光眼底镜检眼 ;结果 :服药前运动前视乳头充血 ,视网膜静脉怒张 ,动脉痉挛 ,视网膜渗出发生率为 1 0 0 % ,改变程度均为±(轻度 ) ,服药前运动后上述观察项目发生率为 1 0 0 % ,改变程度均转为 (中度 ) ,服药 1 5天运动后与停药 1 0天运动后视网膜改变发生率明显降低 ,改变程度均减轻为± ;结论 :依那普利、硝苯吡啶能明显减轻和降低高原低氧条件下负荷运动后缺氧性视网膜的改变程度和发生率     

依那普利和硝苯地平控释片对早期糖尿病肾病合并高血压的疗效比较

目的　观察依那普利和硝苯地平控释片对早期糖尿病肾病合并高血压患者血压及尿白蛋白排泄率 (UAER)的影响。方法　随机将 44例病人分为 2组 :依那普利组 (10 mg,2次 /d,2 2例 ) ;硝苯地平控释片组 (30 mg,1次 /d,2 2例 )。疗程 6个月 ,观察治疗前后血压及 UAER的变化。结果　两组治疗后均能明显降低血压 (P <0 .0 1)及 UAER,由 90 .2和 86 .0分别降至 6 7.4和70 .8,下降 2 9.1%和 2 3.5 % ,P值均 <0 .0 1,但两组比较差异无显著性 (P>0 .0 5 )。两组治疗后U AER下降幅度与收缩压、舒张压下降幅度之间比较无显著相关性 (P值均 >0 .0 5 )。结论　依那普利和硝苯地平控释片均能有效降低血压 ,减少尿蛋白的排泄 ,保护肾脏功能