Chemo-enzymatic synthesis of levodropropizine

Levodropropizine, an antitussive drug, was prepared in high enantiomeric excess in three steps, starting from dichloroacetone (2). Monosubstitution of 2 with sodium benzoate and subsequent baker's yeast reduction stereoselectively afforded the corresponding chlorohydrin in 73% ee, which was converted to levodropropizine and enantiomerically enriched up to 95% ee by fractional crystallisation.     

Virus-induced airway inflammation and hyperresponsiveness in the guinea-pig is inhibited by levodropropizine

Summary Intratracheal Parainfluenza type 3 (PI-3) virus inoculation of guinea pigs leads to a non-specific airway hyperresponsiveness in vivo and in vitro which coincides with a significant increase in the number of inflammatory cells in the broncho-alveolar lavage fluid (90% increase, 4 days after inoculation). The activity of the bronchoalveolar cells, as measured by the chemiluminescence production of infected animals is significantly diminished (34.2%, 4 days after inoculation) after renewed stimulation with PI-3 virus in vitro as compared to the chemiluminescence production by bronchoalveolar cells obtained from control guinea pigs.Pretreatment of the guinea-pigs with the antitussive agent levodropropizine, administered intra-peritoneally twice a day for five successive days at a dose of 10 mg/kg, prevents the virus-induced airway hyperresponsiveness in vivo and in vitro, and inhibits the influx of broncho-alveolar cells. Levodropropizine at a dose of 1 mg/kg did not modulate these responses. Further, the decrease in chemiluminescence production of broncho-alveolar cells obtained from virus-infected animals after PI-3 virus stimulation in vitro was inhibited by levodropropizine (10 mg/kg).These data demonstrate the ability of levodropropizine to counteract the hyperresponsiveness phenomenon and the associated inflammatory event induced by PI-3 virus, an effect which may be due to its capacity to act on the peptidergic system or may be due to the anti-allergic/bronchoconstrictor property of this compound. Correspondence to G. Folkerts at the above address     

来立信治疗脑血管病气管切开术后肺部感染临床疗效观察

目的；了解来立信治疗脑血管病气管切开术后肺部感染的疗效。方法：根据入院时间顺序将４０例院内感染，且对多种药物耐药的脑血管病气管切开术后患者随机分为两组，分别给予来立信４００ｍｇ／ｄ或菌必治２．０ｇ／ｄ治疗，疗程７￣１４天，结果：来立信组与菌必治组的临床有效率分别是９０％和３５％，痊愈率分别是６０％和２０％，细菌清除率分别是９０％和４５％，不良反应发生率两组均为５．０％，结论：来立信对脑血管病气管切     

镇咳药左旋羟丙哌嗪的合成

用D-甘露醇1,2,5,6二缩酮作为起始化合物,经5步反应合成左旋羟丙哌嗪。对氧化和还原反应进行了讨论。     

左羟丙哌嗪镇咳作用的临床研究

目的　评价左羟丙哌嗪治疗咳嗽的有效性和安全性。方法　采用随机双盲对照试验的方法 ,将有干咳症状的患者 5 0例随机分为两组 ,治疗组 2 6例患者每次给予左羟丙哌嗪口服液 10mL ,po ,tid ;对照组 2 4例患者每次给予右美沙芬糖浆 10mL ,po ,tid ,均连续用药 5d。结果　治疗组临床有效率 69 5 7% ,对照组 61 90 % ,两组比较差异无显著性 (P >0 0 5 ) ;对重度咳嗽的临床有效率 ,治疗组和对照组分别为 93 3 3 % ,69 2 3 % ,经Ridit分析 ,差异有显著性(P <0 0 5 )。不良反应的发生率分别为 2 3 0 7%和 41 67% ,差异有显著性 (P <0 0 5 )。结论　左羟丙哌嗪对咳嗽的治疗效果确切 ,安全性好。     

左羟丙哌嗪的大鼠在体肠吸收特性

目的研究左羟丙哌嗪大鼠的在体肠吸收特性。方法采用大鼠在体小肠循环灌注模型,用HPLC同时测定灌注液中酚红和左羟丙哌嗪的含量。结果左羟丙哌嗪12.8~80.0μg.ml-1与小肠吸收量呈线性关系,吸收速率常数Ka几乎不变;各肠道间Ka值无显著性差异(P>0.05),十二指肠、空肠、回肠和结肠的Ka值分别为0.039±0.004、0.042±0.010、0.037±0.003、0.034±0.004 h-1。结论左羟丙哌嗪浓度12.8~80.0μg.ml-1在小肠段的吸收呈一级动力学过程,吸收机制为被动扩散,主要吸收部位在小肠段,且无特定的吸收窗。     

HPLC determination and steady-state bioavailability study of levodropropizine sustained-release tablets in dogs

A simple HPLC method using UV detection was developed and validated for the determination of levodropropizine (LDP) in dog plasma. The sample was prepared for injection using a liquid-liquid extraction method with 1-phenypiperazine as the internal standard. The mobile phase was methanol-diethylamine solution (0.05 M) (20:80, v/v, pH adjusted to 3.0 with H3PO4) with a detection wavelength of 240 nm. The limit of quantitation (LOQ) of LDP in a biological matrix was determined to be 25.25 ng/mL. The calibration curve was linear across the concentration range of 25.25 to 2020 ng/mL. The intra-day and inter-day precision values (CV %) were within 7% and accuracy (R.E. %) was within 6% of the nominal values for medium (252.5 ng/mL) and high (2020 ng/mL) LDP concentrations. For the LDP concentration at the LOQ, the intra-day and inter-day precision and accuracy were within 20% and 10%, respectively. The average absolute recovery for LDP was 70.28%. This method was successfully used to analyze plasma samples in a steady-state bioavailability study of a newly developed sustained-release LDP tablets (SR) using immediate-release tablets (IR) as the reference. The relative bioavailability of the SR was determined to be 106.3 +/- 12.8% (n=6). The Cmax of the SR was significantly lower (P<0.05), and the tmax was significantly longer than that of the IR (P<0.05). The results of ANOVA and two one-sided tests indicated that the SR exhibited acceptable sustained release properties and was bioequivalent to the IR.     

A Case of Immunoglobulin E Mediated Anaphylaxis to Levodropropizine

We experienced a case of immunoglobulin E (IgE) mediated anaphylaxis to levodropropizine. The patient was an 18-year old Korean woman. After taking the common cold medication including acetaminophen, domperidone, and levodropropizine, skin rash, angioedema and anaphylaxis were developed immediately. As she was tolerable to acetaminophen alone, we thought the culprit agent was maybe a levodropropizine tablet. To confirm the culprit, she underwent skin prick test and oral drug provocation test with the suspected one. Finally we detected levodropropizine specific IgE and confirmed the specificity by inhibition enzyme-linked immunosorbent assay (ELISA).     

左羟丙哌嗪口腔崩解片的制备与质量控制

目的 制备左羟丙哌嗪口腔崩解片并建立其质量控制方法 . 方法 采用直接压片法制备,高效液相色谱（HPLC）法测定其含量. 结果 制备的左羟丙哌嗪口腔崩解片外观光洁,硬度为3.5 kg,崩解时间<30 s; 检测浓度线性范围为8.48～42.4 μg.mL^-1（r＝0.999 9）,平均回收率为99.85%,RSD为0.71%（n＝9）. 结论 该制备方法 简单,含量测定方法 简便、准确,可用于左羟丙哌嗪口崩片的制备及含量测定.     

左羟丙哌嗪缓释胶囊的制备与体外释药研究

目的:制备含左羟丙哌嗪的速释及缓释微丸。方法:考察速释部分、缓释部分及两部分不同比例混合对药物释放度的影响,同时比较制剂在不同释放介质中的释放行为。结果:确定的最佳包衣增重为12%,素丸与包衣微丸的最佳装囊比例为1:2。结论:速释部分对药物整体的前期释放影响较大;缓释部分对药物整体的后期释放影响较大;包衣膜的增重对缓释部分的释放度具有影响。缓释胶囊的体外释放不受介质pH的影响。