盐酸左氧氟沙星片剂和胶囊剂人体生物等效性研究

目的:评价受试制剂盐酸左氧氟沙星片和胶囊与参比片剂人体生物等效性。方法:采用3制剂3周期的优化拉丁方试验设计,24名健康男性受试者分别口服单剂量3种左氧氟沙星制剂200 mg,HPLC法测定血浆中左氧氟沙星的浓度。结果:受试制剂盐酸左氧氟沙星片、盐酸左氧氟沙星胶囊和参比制剂的cm ax分别为(2.24±0.33)、(2.37±0.48)和(2.05±0.37)μg/m l;tm ax分别为(0.94±0.43)、(0.85±0.38)和(1.07±0.42)h;t1/2分别为(6.46±0.56)、(6.50±0.68)和(6.40±0.66)h;AUC0-24分别为(16.13±2.00)、(17.12±2.47)和(15.37±2.20)μg.h.m l-1;AUC0-∞分别为(17.46±2.34)、(18.53±2.83)和(16.63±2.59)μg.h.m l-1。受试制剂盐酸左氧氟沙星片和盐酸左氧氟沙星胶囊相对于参比制剂的生物利用度分别为(105.6±8.7)%和(112.0±11.6)%。结论:受试制剂盐酸左氧氟沙星片和盐酸左氧氟沙星胶囊与参比制剂盐酸左氧氟沙星片具有生物等效性。     

盐酸坦洛新肠溶缓释微丸的制备及其体内外评价

目的:制备盐酸坦洛新肠溶缓释微丸,并与参比制剂进行体内外一致性评价。方法:分别以乙基纤维素和羟丙甲纤维素为缓释包衣材料,以聚丙烯酸树脂为肠溶性包衣材料,采用流化床底喷包衣技术对载药微丸包衣,制备肠溶缓释微丸;考察释放度主要影响因素;采用多条释放曲线对比考察受试制剂与参比制剂体外一致性;双周期交叉试验设计,考察Beagle犬口服单剂量受试制剂与参比制剂后血浆中的药物浓度,评价受试制剂与参比制剂的体内一致性;考察受试制剂的体内外相关性。结果:确定了影响盐酸坦洛新释放的主要处方工艺因素;多条释放曲线测定结果表明,所制备的微丸与参比制剂体外一致性较好;Beagle犬体内药动学研究结果表明,受试制剂与参比制剂生物等效且体内外相关性良好。结论:成功制备了盐酸坦洛新肠溶缓释微丸,且与参比制剂体内外一致性良好。     

Absorption of ranolazine in a rat model of in-situ single-pass intestine perfusion 

目的：研究不同浓度雷诺嗪在大鼠肠段的吸收特征,并比较Beagle犬经口给予国外雷诺嗪缓释片(参比制剂)和国产雷诺嗪缓释片(受试制剂)的药动学。方法：以酚红为标示物,采用在体单向灌流法进行大鼠肠吸收研究,高效液相法测定灌流液中雷诺嗪和酚红的浓度并计算吸收参数。采用双交叉实验设计,6只Beagle犬分别经口给予受试制剂和参比制剂,高效液相法测定血药浓度,BAPP 3.0程序处理药动学参数。结果：10～40 mg•L-1的雷诺嗪在大鼠各肠段的表观通透系数(Papp)、吸收速率常数(Ka)的差异均无显著性意义(P>0.05)。Beagle犬经口给予单剂量国产雷诺嗪缓释片的相对生物利用度为(104.5±30.1)%。结论：在10～40 mg•L-1内雷诺嗪在大鼠肠道的吸收机制以被动吸收为主。国产和进口雷诺嗪缓释片在Beagle犬体内的药时曲线相似,2种缓释制剂均无突释现象。     

复方烟酸缓释片与烟酸普通片在犬体内药代动力学的比较研究

目的比较复方烟酸缓释片与烟酸普通片中烟酸及其代谢物烟尿酸在Beagle犬体内的药代动力学。方法6只Beagle犬采用随机交叉给药方案,单剂量口服500mg复方烟酸缓释片或烟酸普通片后,用RP-HPLC法同时测定Beagle犬血浆中烟酸及其主要代谢物烟尿酸的药物浓度,计算药动学参数和相对生物利用度。结果Beagle犬单剂量口服500mg复方烟酸缓释片和烟酸普通片后,烟酸主要药代动力学参数tmax分别为(2.17±0.61)h和(1.04±0.49)h,Cmax分别为(30.85±4.50)mg·mL-1和(68.05±20.48)mg·mL-1,t1/2分别为(0.69±0.43)h和(0.43±0.10)h,MRT分别为(2.12±0.62)h和(1.72±0.40)h,AUC0-12h分别为(62.17±21.13)mg·h·L-1和(138.67±44.86)mg·h·L-1;烟尿酸主要药代动力学参数tmax分别为(2.42±0.49)h和(1.50±0.45)h,Cmax分别为(0.76±0.34)mg·mL-1和(1.66±0.63)mg·mL-1,t1/2分别为(1.74±1.24)h和(1.64±1.03)h,MRT分别为(2.42±0.62)h和(1.79±0.38)h,AUC0-12h分别为(1.55±0.76)mg·h·L-1和(3.25±1.16)mg·h·L-1。结论单剂量口服复方烟酸缓释片,测得的Cmax、tmax和AUC与烟酸普通片均有显著性差异,受试缓释片的tmax长于参比普通片,Cmax低于参比普通片,说明受试缓释片无突释现象,有一定缓释效果。     

苦参素胃内滞留缓释片的研制及犬体内生物利用度研究

目的:制备苦参素胃内滞留缓释片,考察其体外释放度和体内血药浓度.方法:以羟丙甲基纤维素(HPMC)为骨架材料,十六醇作为助漂剂,碱式碳酸镁作为产气剂,制备了一天给药2次的苦参素缓释片,考察其在0.1 mol·L-1盐酸溶液中的释放度.建立HPLC法测定血浆中的药物浓度,采用BAPP2.0程序估算beagle犬服用市售苦参素普通胶囊(参比制剂)和受试制剂后的各个药动学参数,进行统计学分析,并采用Loo-Riegelman法考察体内外相关性.结果:所得胃内滞留缓释片体外释放度良好,在犬体内与市售胶囊相比有缓释效果,相对生物利用度为110.5%.结论:苦参素制成胃内滞留缓释片缓释效果明显,与受试制剂相比有显著差异,体内外相关性良好.     

液质联用测定Beagle犬血浆N-去二甲基西布曲明浓度及其药动学

目的建立液相色谱-质谱(LC-MS)法测定Beagle犬血浆N-去二甲基西布曲明浓度,并用于药动学研究。方法6条Beagle犬随机分成2组,采用自身对照交叉实验设计,分别单次口服盐酸西布曲明胶囊(参比制剂)和自制盐酸西布曲明固体分散体(受试制剂)各2.5 mg,以地西泮为内标,采用Phenomenex-Lunal00-3 C_(18)色谱柱,流动相为甲醇-4 mmol·L~(-1)乙酸铵-甲酸(70.5:29:0.5,V:V:V),电喷雾正离子选择反应监测,测定血药浓度。结果受试制剂与参比制剂的代谢物N-去二甲基西布曲明的c_(max)分别为(7.8±s 1.2)和(7.4±1.3)μg·L~(-1),t_(max)分别为(4.2±0.9)和(4.6±0.8)h,t_(1/2)分别为(21±3)和(20.1±2.7)h,AUC_(0～∞)分别为(179±46)和(169±43)μg·h·L~(-1),与参比制剂相比受试制剂的相对生物利用度为(105±14)%。结论该方法快速、准确,适用于N-去二甲基盐酸西布曲明在Beagle犬体内的药动学研究,主要药动学参数经方差分析和双向单侧t检验证明,2种制剂生物等效。     

CoQ10软胶囊在Beagle犬体内的相对生物利用度评价

目的:比较在 Beagle 犬体内3种辅酶 Q_(10)(CoQ_(10))制剂的相对生物利用度。方法:采用三制剂三周期(3×3拉丁方)自身对照交叉多剂量口服给药方式,周期间清洗1周。用高效液相色谱法测定6条健康 Beagle 犬口服 CoQ_(10)软胶囊(受试制剂A)、CoQ_(10)普通胶囊(参比制剂 B)和进口 CoQ_(10)软胶囊(参比制剂 C)后不同时间点血浆中 CoQ_(10)的浓度,扣除内源性 CoQ_(10)本底,绘制血药浓度-时间曲线,计算相对生物利用度。结果:受试犬口服 CoQ_(10)60mg 的受试制剂(A)和参比制剂(B,C)后,血浆中 CoQ_(10)AUC_(0-t)(μg·h·mL~(-1))分别为69.31±40.49,62.38±59.05,104.90±64.32。与参比制剂 B 与 C 相比,受试制剂中的相对生物利用度平均为(144.07±79.48)%和(78.60±54.28)%。结论:CoQ_(10)受试制剂 A 生物利用度高于参比制剂 B 而低于参比制剂 C。     

盐酸左氧氟沙星胶囊的生物等效性研究

［摘要］目的研究盐酸左氧氟沙星胶囊的人体生物等效性。方法健康志愿者20例,随机双交叉单剂量口服盐酸左氧氟沙星胶囊受试和参比制剂,分别于服药后24 h内多点抽取静脉血,采用反相高效液相色谱（RP HPLC）法测定血浆左氧氟沙星浓度,计算其药动学参数和相对生物利用度,评价其生物等效性。 结果单剂量口服受试和参比制剂后血浆左氧氟沙星峰浓度（Cmax）分别为（3.05±0.64）和（3.25±0.82） μg •mL 1;达峰时间（tmax）分别为（1.00±0.30）和（1.10±0.50） h, 半衰期（t1/2）分别为（7.51±1.26）和（7.45±1.30） h,血药浓度 时间曲线下面积（AUC0～t）分别为（17.58±3.25）和（18.21±2.96） μg•h•mL 1;AUC（0 ∞）分别为（19.04±3.35）和（18.96±3.12） μg•h•mL 1。受试制剂AUC0～t的90%置信区间为参比制剂相应参数的90.9%～102.5%;Cmax的90%置信区间为参比制剂相应参数的84.7%～105.4%。结论盐酸左氧氟沙星受试制剂与参比制剂的人体相对生物利用度为（98.5±16.3）%,受试制剂与参比制剂具有生物等效性。     

辛伐他汀缓释片在比格犬体内的药动学及生物等效性研究

目的:研究辛伐他汀缓释片在比格犬体内的药动学和生物等效性。方法:将6只比格犬随机分成2组,分别单剂量灌服20 mg辛伐他汀缓释片(受试制剂)和市售辛伐他汀片(参比制剂),不同时间采集血样,采用液相- 质谱- 质谱联用法测定比格犬体内的血药浓度并计算药动学参数。结果:参比制剂与受试制剂的C_(max)分别为(23.461±6.043)、(13.942±3.236)ng.mL~(-1);t_(max)分别为(2.158±0.396)、(4.116±1.145 3)h;t_(1/2) 分别为(4.564±0.645)、(8.143±0.679)h;AUC_(0～24 h) 分别为(118.647±31.989)、(129.977±29.853)ng.h.mL~(-1)。结论:受试制剂与参比制剂在吸收速率方面具有显著差异,二者不具有生物等效性。     

泼尼松择时释放片的制备及其体内外评价

目的 制备泼尼松择时释放片,评价其体内外的释药.方法 采用水不溶性包衣材料,干法压制包衣制备泼尼松择时释放片,用HPLC法测定泼尼松体外释放度,LC-MS/MS测定Beagle犬随机交叉口服单剂量泼尼松择时释放片与泼尼松普通速释片后血浆中泼尼松的浓度,计算药动学参数.结果 所制泼尼松择时释放片的体外时滞时间为4～5h,时滞后药物可达到0.5h内释放大于85％的爆破型脉冲释药效果.受试制剂与参比制剂泼尼松在Beagle犬体内的AUC0-t分别为62.01±3.57、59.96 ±2.72 ng·mL-1 ·h;AUC0-∞分别为63.35±3.51、62.76±3.27ng·mL-1 ·h;t1/2分别为1.00±0.16、1.22±0.54 h;Tmax分别为4.67±0.26、0.97±0.30 h;Cmax分别为27.84±3.03、28.05±1.94 ng·mL-1;Tlag分别为3.83±0.26、0h.结论 犬体内外的结果均证明该制剂具有延迟释放特性,其设计方案可行.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.