建立同时测定人血浆中拉莫三嗪和奥卡西平的HPLC法

目的:建立同时测定人血浆中拉莫三嗪和奥卡西平的方法。方法:采用高效液相色谱法进行测定。以氯唑沙宗为内标,色谱柱为DikmaC18,流动相为甲醇-水-三氟乙酸(40:60:0.0005),流速为1ml/min,检测波长为240nm。结果:拉莫三嗪、奥卡西平血药浓度均在0.5～50μg/ml范围内线性关系良好(r分别为0.9940、0.9925),提取回收率分别为92.50%～95.33%、88.78%～93.12%。拉莫三嗪、奥卡西平3种质量浓度(25、10、2μg/ml)的5个平行样品连续测定的RSD分别为4.01%、6.15%、4.64%和3.05%、4.27%、9.01%。结论:本方法操作简单、回收率高、精密度好,可以同时用于测定拉莫三嗪和奥卡西平的血药浓度。     

用RP-HPLC法同时测定拉莫三嗪和奥卡西平的血药浓度

目的：用RP-HPLC法同时测定人血浆中抗癫药拉莫三嗪和奥卡西平的浓度。方法：以艾司唑仑为内标,色谱柱为Agilent Zorbax XDB-C18柱（150 mm×4.6 mm,5μm）;流动相为甲醇-0.1%三氟乙酸（38∶62）;流速为1.0 mL/min;检测波长为240 nm。结果：拉莫三嗪和奥卡西平的血药浓度分别在1.00-50.00μg/mL（Y=0.214 6c-0.010 9,r=0.999 4）和0.50-50.00μg/mL（Y=0.396 6c＋0.006 1,r=0.999 1）范围内线性良好;平均回收率分别为97.64%和97.67%（n=5）。拉莫三嗪2.5、10.0和40.0μg/mL的日内RSD分别为4.6%、3.7%和2.8%（n=5）,日间RSD分别为5.9%、6.4%和4.8%（n=5）;奥卡西平1.0、10.0和40.0μg/mL的日内RSD分别为3.6%、3.4%和4.0%（n=5）,日间RSD分别为5.5%、3.7%和4.3%（n=5）。结论：本方法操作简单,回收率高,精密度好,适用于临床上常规监测拉莫三嗪和奥卡西平的血药浓度。     

高效液相色谱法同时测定人血浆中拉莫三嗪和奥卡西平活性代谢物血药浓度及其临床应用分析

目的：建立HPLC法同时测定人血浆中拉莫三嗪和奥卡西平活性代谢物血药浓度的方法，应用于临床常规检测，为患者个体化用药提供依据。方法：采用反相高效液相色谱法建立同时测定人血浆中拉莫三嗪（LTG）和奥卡西平活性代谢物（MHD）血药浓度的方法，方法学验证合格后用于治疗药物浓度监测（TDM），2013年8月-2016年3月，共完成1 611人次LTG和MHD血药浓度的监测，并对监测结果进行统计分析。结果：991人次（61.51%）在有效血药浓度范围内，13例患者进行了多次LTG血药浓度监测，达有效血药浓度的比例从61.54%上升至84.62%；23例患者进行了多次MHD血药浓度监测，达有效血药浓度的比例从34.78%上升至91.30%。结论：该方法适用于癫痫患者服用拉莫三嗪和奥卡西平后临床常规的TDM，为患者个体化用药提供依据，提高临床疗效、降低不良反应。     

反相-高效液相色谱法测定奥卡西平活性代谢物及其在健康人体的药代动力学特征

目的建立测定奥卡西平活性代谢物的高效液相色谱法并进行药代动力学研究。方法10名健康志愿者单剂量口服奥卡西平300mg;血浆样品经液-液萃取,用高效液相色谱法检测奥卡西平10-单羟基代谢物(MHD)。用3P87程序进行数据处理。结果此方法适于血浆MHD浓度的检测。单剂量口服奥卡西平后,MHD的血浆浓度符合一级吸收的一室模型;其主要药代动力学参数为:tmax=(4.10±0.79)h,Cmax=(4.64±0.53)mg·L-1,t1/2ke=(15.05±2.32)h,AUC0-48=(112.97±14.25)mg·h·L-1。结论该法能高效、灵敏、准确地测定血浆中MHD。     

高效液相色谱法同时测定人血浆中卡马西平、奥卡西平及其活性代谢产物的浓度和临床应用

目的：建立同时测定人血浆中卡马西平（CBZ）、10,11-环氧卡马西平（CBZE）、奥卡西平（OXC）和单羟基卡马西平（MHD）浓度的高效液相色谱法,并将其应用于临床中卡马西平、奥卡西平及其活性代谢产物血药浓度的测定。方法：以苯巴比妥为内标,血浆经乙醚-二氯甲烷（2∶1）提取。色谱柱为WondaSil C₁₈柱（150 mm×4.6 mm,5 μm）,流动相为甲醇∶水=50∶50,柱温30℃,流速1.0 mL·min^-1,检测波长215 nm,进样量20 μL。结果：卡马西平、10,11－环氧卡马西平、奥卡西平和单羟基卡马西平标准曲线范围分别为0.1~20,0.05~10,0.05~20,0.2~50 mg·L^-1,最低检测限分别为0.1,0.05,0.05,0.2 mg·L^-1,日内、日间精密度均小于10%。结论：该方法灵敏准确,简便快速,适用于卡马西平、奥卡西平及其代谢产物血药浓度检测。     

同位素稀释-HPLC-ESI-MS/MS法同时测定癫痫患儿血浆中左乙拉西坦、奥卡西平活性代谢物和拉莫三嗪的药物浓度

目的：建立基于高效液相色谱串联质谱技术（HPLC-ESI-MS/MS）同时测定癫痫患儿血浆中左乙拉西坦（levetiracetam,LEV）、奥卡西平活性代谢物10-羟基卡马西平（monohydroxy-carbazepine,MHD）和拉莫三嗪（lamotrigine,LTG）浓度的方法。方法：样品经沉淀蛋白法进行前期处理,分别以LEV-D6、奥卡西平-D4、LTG-¹³C3-D3为内标,采用Phenomenex Kinetex^®EVO C₁₈色谱柱（2.1 mm×50 mm,26 μm）,以0.07%甲酸-1 mmoL乙酸铵-水（A）和甲醇（B）为流动相进行梯度洗脱,流速为0.5 mL·min^-1。质谱检测采用电喷雾离子源正离子模式,多离子反应监测模式扫描。考察该方法的专属性、定量下限（LLOQ）、标准曲线、残留和稀释效应、准确度精密度、基质效应和稳定性。结果：LEV和MHD的血药浓度在0.1~50 μg·mL^-1内线性关系良好（r>0.999 1）,LLOQ均为0.1 μg·mL^-1;LTG的血药浓度在0.05~25 μg·mL^-1内线性关系良好（r>0.999 2）,LLOQ为0.05 μg·mL^-1。批内和批间精密度RSD ≤ 7.0%,稳定性良好,不受正常血浆和溶血血浆（溶血程度≤ 5%）基质的影响,方法学验证均符合《中国药典》2020年版规定。结论：本方法快速、简便、稳定、经济,可应用于左乙拉西坦、奥卡西平和拉莫三嗪儿童治疗药物监测和药动学研究。     

过量奥卡西平致定向力障碍及共济失调

1例6岁男性癫痫患儿,曾先后口服苯妥英钠、拉莫三嗪、丙戊酸钠、苯巴比妥治疗,因不能规律服药致使癫痫反复发作且进行性加重,家属自行给予其口服奥卡西平300 mg、3次/d,上述症状未再发作。但40 d后出现行走不稳、反应迟钝,且癫痫症状也加重。入院诊断为癫痫,全身强直-阵挛发作,奥卡西平致定向力障碍及共济失调。停用奥卡西平,给予丙戊酸钠、还原性谷胱甘肽、维生素C,次日癫痫得到控制。第8天定向力障碍及共济失调消失,癫痫未再发作,遂出院。出院后规律服用丙戊酸钠和氯硝西泮。随访1个月,未再出现癫痫发作、定向力障碍和共济失调。     

奥卡西平治疗癫痫发作血药浓度与临床疗效的关联性评价

目的：探讨奥卡西平的血药浓度与癫痫治疗疗效间的变量关系。方法：选择于我院就诊的癫痫患者100例,给予所有患者奥卡西平治疗。以300mg/日为起始剂量逐渐加量用药,加药程度根据患者的实际情况而定。测定患者血浆中奥卡西平10-羟基衍生物（MHD）浓度,并对疗效进行评价,统计分析记录所得数据。结果：不超过有效剂量内治疗效果与药物血药浓度呈正相关。在治疗条件相同的情况下,血药浓度每增加1%,疗效增强0.19%。结论：在安全使用剂量内,奥卡西平的血药浓度越高,对患者的治疗效果越好。     

RP-HPLC法测定癫痫患者血浆中奥卡西平血药浓度和药动学研究

目的建立人血浆中奥卡西平药物浓度的RP-HPLC检测方法,并研究其在人体内的药动学。方法采用液–液萃取法,用萃取液甲基叔丁基醚萃取癫痫患者血浆中的奥卡西平后,以阿普唑仑为内标。色谱柱为Kromasil 100A C18(250mm×4.6 mm,5μm),柱温40℃,流动相为甲醇–乙腈–水–磷酸(30∶30∶40∶0.04),体积流量1.0 mL/min,紫外检测波长243 nm,固定进样量20μL。以3p97软件计算10名受试者清晨空腹单剂量口服奥卡西平片600 mg后的平均药动学参数。结果血浆中内源性杂质对样品测定无干扰,奥卡西平在21.6~2 160.0μg/L(r=0.999 2)线性关系良好,最低定量限21.6μg/L;方法回收率为95.45%~107.69%;日内RSD值为4.97%~7.35%,日间RSD值为4.81%~11.27%。含药血浆经3次冻融后稳定性良好。结论本方法操作快速、简便、灵敏度高、准确度好,可用于含奥卡西平血样的即时检测分析和临床药动学研究。     

抗癫痫新药的治疗药物监测进展

抗癫痫新药包括:非尔氨酯、加巴喷丁、拉莫三嗪、左乙拉西坦、奥卡西平、托吡酯、氨己烯酸、唑尼沙胺、噻加宾等.自从左乙拉西坦、拉莫三嗪、奥卡西平、托吡酯引入国内以来,给医生提供了治疗癫痫的更多的选择,疗效与传统抗癫痫药物不相上下,保证新抗癫痫药物的合理使用,有效控制癫痫发作非常必要.     

Safety assessment of poloxamers 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, and 407, poloxamer 105 benzoate, and poloxamer 182 dibenzoate as used in cosmetics

Poloxamers are polyoxyethlyene, polyoxypropylene block polymers. The impurities of commercial grade Poloxamer 188, as an example, include low-molecular-weight substances (aldehydes and both formic and acetic acids), as well as 1,4-dioxane and residual ethylene oxide and propylene oxide. Most Poloxamers function in cosmetics as surfactants, emulsifying agents, cleansing agents, and/or solubilizing agents, and are used in 141 cosmetic products at concentrations from 0.005% to 20%. Poloxamers injected intravenously in animals are rapidly excreted in the urine, with some accumulation in lung, liver, brain, and kidney tissue. In humans, the plasma concentration of Poloxamer 188 (given intravenously) reached a maximum at 1 h, then reached a steady state. Poloxamers generally were ineffective in wound healing, but were effective in reducing postsurgical adhesions in several test systems. Poloxamers can cause hypercholesterolemia and hypertriglyceridemia in animals, but overall, they are relatively nontoxic to animals, with LD(50) values reported from 5 to 34.6 g/kg. Short-term intravenous doses up to 4 g/kg of Poloxamer 108 produced no change in body weights, but did result in diffuse hepatocellular vacuolization, renal tubular dilation in kidneys, and dose-dependent vacuolization of epithelial cells in the proximal convoluted tubules. A short-term inhalation toxicity study of Poloxamer 101 at 97 mg/m(3) identified slight alveolitis after 2 weeks of exposure, which subsided in the 2-week postexposure observation period. A short-term dermal toxicity study of Poloxamer 184 in rabbits at doses up to 1000 mg/kg produced slight erythema and slight intradermal inflammatory response on histological examination, but no dose-dependent body weight, hematology, blood chemistry, or organ weight changes. A 6-month feeding study in rats and dogs of Poloxamer 188 at exposures up to 5% in the diet produced no adverse effects. Likewise, Poloxamer 331 (tested up to 0.5 g/kg day(-1)), Poloxamer 235 (tested up to 1.0 g/kg day(-1)), and Poloxamer 338 (at 0.2 or 1.0 g/kg day(-1)) produced no adverse effects in dogs. Poloxamer 338 (at 5.0 g/kg day(-1)) produced slight transient diarrhea in dogs. Poloxamer 188 at levels up to 7.5% in diet given to rats in a 2-year feeding study produced diarrhea at 5% and 7.5% levels, a small decrease in growth at the 7.5% level, but no change in survival. Doses up to 0.5 mg/kg day(-1) for 2 years using rats produced yellow discoloration of the serum, high serum alkaline phosphatase activity, and elevated serum glutamicpyruvic transaminase and glutamic-oxalacetic transaminase activities. Poloxamers are minimal ocular irritants, but are not dermal irritants or sensitizers in animals. Data on reproductive and developmental toxicity of Poloxamers were not found. An Ames test did not identify any mutagenic activity of Poloxamer 407, with or without metabolic activation. Several studies have suggested anticarcinogenic effects of Poloxamers. Poloxamers appear to increase the sensitivity to anticancer drugs of multidrug-resistant cancer cells. In clinical testing, Poloxamer 188 increased the hydration of feces when used in combination with a bulk laxative treatment. Compared to controls, one study of angioplasty patients receiving Poloxamer 188 found a reduced myocardial infarct size and a reduced incidence of reinfarction, with no evidence of toxicity, but two other studies found no effect. Poloxamer 188 given to patients suffering from sickle cell disease had decreased pain and decreased hospitilization, compared to controls. Clinical tests of dermal irritation and sensitization were uniformly negative. The Cosmetic Ingredient Review (CIR) Expert Panel stressed that the cosmetic industry should continue to use the necessary purification procedures to keep the levels below established limits for ethylene oxide, propylene oxide, and 1,4-dioxane. The Panel did note the absence of reproductive and developmental toxicity data, but, based on molecular weight and solubility, there should be little skin penetration and any penetration of the skin should be slow. Also, the available data demonstrate that Poloxamers that are introduced into the body via routes other than dermal exposure have a rapid clearance from the body, suggesting that there would be no risk of reproductive and/or developmental toxicity. Overall, the available data do not suggest any concern about carcinogenesis. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used, and at what concentration, indicates a pattern of use. Based on these safety test data and the information that the manufacturing process can be controlled to limit unwanted impurities, the Panel concluded that these Poloxamers are safe as used.     

HPLC法测定抗妇炎胶囊中木兰花碱、黄柏碱、药根碱、巴马汀、小檗碱、槐果碱、苦参碱、氧化槐果碱、槐定碱和氧化苦参碱

目的 采用高效液相色谱（HPLC）法同时测定抗妇炎胶囊中木兰花碱、黄柏碱、药根碱、巴马汀、小檗碱、槐果碱、苦参碱、氧化槐果碱、槐定碱和氧化苦参碱10种活性成分。方法 采用InerSustain AQ-C₁₈色谱柱（250 mm×4.6 mm,5 μm）,流动相A：乙腈–无水乙醇（80∶20）,流动相B：0.1%磷酸溶液,梯度洗脱,检测波长220 nm,体积流量1.0 mL/min,柱温30℃,进样量10 μL。结果 木兰花碱、黄柏碱、药根碱、巴马汀、小檗碱、槐果碱、苦参碱、氧化槐果碱、槐定碱和氧化苦参碱分别在2.69～134.50、1.95～97.50、0.63～31.50、0.86～43.00、11.95～597.50、0.59～29.50、6.08～304.00、4.85～242.50、1.66～83.00、19.79～989.50 μg/mL线性关系良好（r≥0.999 3）;平均回收率分别为99.11%、98.23%、96.95%、97.78%、100.02%、97.21%、99.66%、99.52%、98.81%、100.08%,RSD值分别为1.04%、1.23%、1.37%、1.65%、0.70%、1.28%、0.65%、0.81%、1.11%、0.63%。结论 建立的HPLC法可用于抗妇炎胶囊中10种活性成分的测定,作为抗妇炎胶囊质量控制方法。     

Arformoterol: (R,R)-eformoterol, (R,R)-formoterol, arformoterol tartrate, eformoterol-sepracor, formoterol-sepracor, R,R-eformoterol, R,R-formoterol

Sepracor in the US is developing arformoterol [R,R-formoterol], a single isomer form of the beta(2)-adrenoceptor agonist formoterol [eformoterol]. This isomer contains two chiral centres and is being developed as an inhaled preparation for the treatment of respiratory disorders. Sepracor believes that arformoterol has the potential to be a once-daily therapy with a rapid onset of action and a duration of effect exceeding 12 hours. In 1995, Sepracor acquired New England Pharmaceuticals, a manufacturer of metered-dose and dry powder inhalers, for the purpose of preparing formulations of levosalbutamol and arformoterol. Phase II dose-ranging clinical studies of arformoterol as a longer-acting, complementary bronchodilator were completed successfully in the fourth quarter of 2000. Phase III trials of arformoterol began in September 2001. The indications for the drug appeared to be asthma and chronic obstructive pulmonary disease (COPD). However, an update of the pharmaceutical product information on the Sepracor website in September 2003 listed COPD maintenance therapy as the only indication for arformoterol. In October 2002, Sepracor stated that two pivotal phase III studies were ongoing in 1600 patients. Sepracor estimates that its NDA submission for arformoterol, which is projected for the first half of 2004, will include approximately 3000 adult subjects. Sepracor stated in July 2003 that it had completed more than 100 preclinical studies and initiated or completed 15 clinical studies for arformoterol inhalation solution for the treatment of bronchospasm in patients with COPD. In addition, Sepracor stated that the two pivotal phase III studies in 1600 patients were still progressing. In 1995, European patents were granted to Sepracor for the use of arformoterol in the treatment of asthma, and the US patent application was pending.     

欧洲刺柏（Juniper）

活性成分与药理作用欧洲刺柏药用部位是其浆果，具有促水排泄、防腐、抗胃肠胀气和抗风湿作用，还可改善胃功能。用作促水排泄药可增加尿量（水丢失），但不增加钠排泄。成分萜品烯-4-醇可增加肾小球滤过率，但刺激肾。欧洲刺柏浆果对单纯疱疹病毒体外显示抗病毒活性，并具抗真菌活性。动物实验显示，欧洲刺柏浆果提取物具有堕胎、抗生育、抗炎、抗胚胎植入、降血压、升血压和降血糖作用。欧洲刺柏浆果油具有兴奋子宫的活性，以及利尿、胃肠道抗菌和刺激作用，该油对平滑肌有阻止解痉作用。     

Oral Presentations (LDD, LPES, LNM, LPAT, LNT, LPPT, LPM)

Probiotic microorganisms have been shown to provide specific health benefits when consumed as food supplements or as food components. The main problem of such products is the poor survival of the probiotic bacteria in the low pH of gastric fluid. However the use of synthetic excipients for enteric coating to prevent the exposure of microorganisms to gastric fluid is limited in food supplementary industry. Therefore the aim of this study was to develop an enteric coating formulation containing shellac as a natural polymer. Shellac possesses good resistance to gastric juice; the major disadvantage of this polymer is its low solubility in the intestinal fluid [1, 2]. Thus films containing different ratios of shellac and water-soluble polymers (sodium alginate, hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidon (PVP)) or plasticizers (glycerol and glyceryl triacetate (GTA)) were prepared in order to analyse the films’ melting temperatures (T_m), the changes in enthalpy (ΔH), their capability of taking up water, and their solubility in different media. The release characteristics of the films were studied by loading pellets with Enterococcus faecium M74 and coating them with formulations containing different amounts of shellac and polymer or plasticized shellac. Using dissolution tests, performed according to USP XXXI paddle method, the resistance of the coatings to simulated gastric fluid (SGF, pH 1.2) and the release of cells in simulated intestinal fluid (SIF, pH 6.8) was investigated.The trials showed that an increasing amount of plasticizer results in a decrease of T_m and ΔH of the films whereat glycerol had a superior plasticization effect to GTA. The compatibility of films made of water-soluble polymers and shellac was also concentration dependent. HPMC and PVP showed superior compatibility with shellac compared to sodium alginate, since films containing shellac and more than 10% [w/w] sodium alginate tended to separate into two phases. In the end five formulations containing shellac and either 5% [w/w] glycerol, 10% [w/w] PVP, 20% [w/w] PVP, 10% [w/w] HPMC, or 5% [w/w] sodium alginate emerged as feasible for enteric coating purposes.