罗红霉素胶囊人体生物等效性研究

目的 研究两种罗红霉素胶囊在健康受试者体内的药代动力学与相对生物利用度,评价其生物等效性.方法 将健康受试者20例随机分成两组,每组10例,采用双交叉给药方案,分别口服受试胶囊和参比胶囊各300 mg,于规定时间取血,以克拉霉素为内标,以超高效液相色谱-串联质谱法测定人血浆中罗红霉素浓度,所得数据经BECS软件处理,对血浆药物浓度-时间曲线下面积0-t(AUC0-t)、血浆药物浓度、时间曲线下面积0-∞(AUC0-∞.)、达峰浓度(Cmax)进行方差分析和双单侧t检验,对达峰时间(Tmax)进行非参数检验.结果 受试胶囊和参比胶囊Tmax分别为(2.367±1.295)、(2.134±1.537)h,Cmax分别为(7.702±1.902)、(7.920±1.957) μg/mL,AUC0-t分别为(103.77±31.46)、(103.10±31.76)μg/(h ·mL),AUC0-t分别为(110.05±35.25)、( 107.97±34.72)μg/(h·mL),差异无统计学意义.结论 经过对比研究2种罗红霉素胶囊人体内药代动力学和相对生物利用度,受试制剂和参比制剂生物等效.     

罗红霉素颗粒的人体生物等效性研究

目的 评价国内不同厂家罗红霉素颗粒的相对生物利用度和生物等效性.方法 18名男性健康受试者采用随机、自身对照、交叉法单剂量口服两个不同厂家的罗红霉素颗粒后,采用微生物法测定血浆中罗红霉素浓度.结果 单剂量口服300mg罗红霉素颗粒受试和参比制剂后的达峰时间Tmax分别为(1.20±5.50)h和(1.70±0.50)h;峰值血药浓度Cmax分别(6.84±2.57)h;药时曲线下面积AUC(0→48)分别为94.03±15.85)μg·h·mL-1和(100.25±15.27)μg·h·mL-1.两种片剂所有的药物动力学参数均无显著性差异(P＞0.05),受试制剂的相对生物利用度F为(95.0±16.2)%.结论 两种制剂生物等效.     

国产阿奇霉素颗粒剂在健康受试者中的生物等效性

目的:测定国产阿奇霉素颗粒剂生物等效性。方法:采用随机双周期、双交叉试验设计,20名健康志愿者分别单剂空腹口服阿奇霉素受试和参比颗粒剂1000 mg,于不同时间采集血样,以微生物法测定其血清药物浓度,以DAS统计软件计算药动学参数,并进行生物等效性评价。结果:20名受试者单剂空腹口服阿奇霉素受试和参比颗粒剂后,Cmax分别为(1.419±0.262)和(1.481±0.272)μg.mL-1,Tmax分别为(1.15±0.37)和(1.08±0.18)h,AUC0~144 h分别为(12.62±2.23)和(11.95±2.01)μg.h.mL-1,AUC0~∞分别为(13.74±2.31)和(13.21±2.29)μg.h.mL-1,平均消除半衰期(t1/2β)分别为(50.44±18.19)和(53.09±14.49)h。两制剂间主要药动学参数均无统计学意义(P>0.05)。以参比颗粒剂为对照,受试颗粒剂相对生物利用度为(104.10±15.15)%。结论:阿奇霉素受试颗粒剂与参比颗粒剂具生物等效性。     

2种进口索他洛尔片在中国健康人体内的生物等效性研究

目的 评价2种进口索他洛尔片荆在中国健康人体内的生物等效性.方法 采用高效液相色谱-荧光检测法,测定12名中国健康志愿者交叉口服受试和参比索他洛尔片160mg后的血药浓度经时过程.由DAS 2.0药学与统计程序处理计算药代动力学参数及生物等效性评价.结果 最佳房室模型为二室模型(Wi=1),受试制剂和参比制剂的峰质量浓度分别为(1.214±0.279)μg/mL和(1.29±0.262)μg/mL,消除半衰期分别为(8.891±4.906)h和(8.780.4-3.034)h,达峰时间分别为(3.583±0.669)h和(3.042±0.753)h,药-时曲线下面积(AUC)分别为(16.221±3.098)μg·h/mL和(15.932±2.675)μg·h/mL,以AUC→t计算的受试制剂的平均相对生物利用度为(108.0±0.146)%.结论 两制荆生物等效.     

头孢克洛胶囊人体药代动力学和生物等效性评价

目的考察国产头孢克洛胶囊与参比制剂在健康人体内的生物等效性。方法采用高效液相色谱法测定血浆中头孢克洛的质量浓度,通过对20名男性健康受试者单次交叉口服750 mg头孢克洛的受试制剂和参比制剂,计算其药物动力学参数及相对生物利用度。结果受试制剂和参比制剂的0～t药时曲线下面积(AUC0-t)分别为(29.460±5.731)和(30.106±5.349)μg/(mL.h),0～∞药时曲线下面积(AUC0～∞)分别为(30.327±6.128)和(30.909±5.497)μg/(mL.h),峰浓度(Cmax)分别为(20.901±4.070)和(21.067±3.422)μg/mL,达峰时间(tmax)分别为(0.900±0.462)和(0.800±0.208)h,半衰期(t1/2)分别为(0.660±0.082)和(0.666±0.070)h,受试制剂的相对生物利用度为(98.0±9.6)%。结论受试制剂头孢克洛胶囊与参比制剂生物等效。     

那格列奈分散片的人体生物等效性研究

目的 研究两种那格列奈片剂的人体相对生物利用度,评价其生物等效性.方法 选择20名健康男性志愿者,按照两制剂两周期的随机交叉试验设计,分别单剂量口服参比制剂(普通片)和受试制剂(分散片),剂量均为120mg,采用液相色谱-串联质谱(LC-MS/MS)法测定其血浆中那格列奈的质量浓度,用DAS1.0软件计算各药物代谢动力学参数并进行生物等效性统计分析.结果 受试制剂和参比制剂的主要药物代谢动力学参数,峰浓度(Cmax)分别为(9.1±1.7)μg/mL和(7.7±2.1)mg/L,达峰时间(tmax)分剐为(0.7±0.3)h和(1.9±1.1)h,0～10 h药时曲线下面积(AUC0-10)分别为(19.7±4.0)mg/(L·h)和(20.8±3.0)mg/(L·h),0～∞药时曲线下面积(AUC0-∞)分别为(20.0±4.1)μg/(mL·h)和(21.3±3.3)mg/(L·h),半衰期(t1/2)分别为(1.7±0.2)h和(1.6±0.2)h.两制剂的Cmaxtmax,AUC0-10均存在显著性差异.双单侧t检验结果表明,受试制剂Cmax的90%置信区间落在参比制剂的75%～133%范围内,AUC的90%置信区间均落在参比制剂的80%～125%范围内,相对生物利用度为(94.9±14.4)%.结论 两制剂具有生物等效性.     

阿莫西林脉冲释放片在比格犬体内的药动学和生物等效性

目的研究阿莫西林脉冲释放片在比格犬体内的药动学和生物等效性。方法将10只比格犬随机分成两组,采用自身对照交叉给药设计,分别单次灌胃给予775 mg自行研制制剂(受试制剂)和国外上市的阿莫西林脉冲释放片(参比制剂),于不同时间点采集血样,采用液相色谱-二级质谱联用法测定比格犬体内阿莫西林的血药浓度,计算药动学参数并进行生物等效性评价。结果参比制剂和受试制剂的ρmax分别为(26.25±10.24)μg·mL-1和(28.06±7.37)μg·mL-1;AUC0-12 h分别为(80.21±35.41)μg·h·mL-1和(72.08±24.48)μg·h·mL-1;t1/2分别为(2.35±1.89)h和(2.75±2.23)h;tmax分别为(2.35±0.67)h和(2.40±0.50)h。受试制剂相对参比制剂的生物利用度为(96.4±15.4)%。结论以AUC0-12 h和ρmax为等效性评价指标,结果显示自行研制的阿莫西林脉冲释放片与国外上市的参比制剂在比格犬体内生物等效。     

HPLC-MS法测定人血浆中酮康唑浓度及其生物等效性研究

目的:建立人血浆中酮康唑的高效液相色谱-质谱测定方法.研究受试制剂酮康唑片在人体内的药代动力学特征,评价其相对生物利用度和生物等效性.方法:20 名男性健康受试者随机分成2组,进行双交叉试验,受试及参比制剂剂量均为200 mg.采用高效液相色谱-质谱法测定血药浓度.结果:志愿者口服受试和参比制剂后,酮康唑的药动学参数如下:峰浓度分别为(4.77±1.63)μg·mL-1和(5.09±1.64)μg·mL-1,达峰时间分别为(1.37±0.71) h和(1.19±0.61)h,消除半衰期分别为(1.89±0.80) h和(2.13±0.91)h,平均驻留时间分别为(3.02±0.81) h和(3.04±0.81)h,AUC0-24分别为(13.03±5.65)μg·h·mL-1和(13.99±6.54)μg·h·mL-1;相对生物利用度为95.6%±12.5%.结论:建立的分析方法准确、灵敏、可靠、简便,统计结果表明受试制剂和参比制剂生物等效.     

氟康唑在健康人体的药物动力学和生物等效性

目的 研究氟康唑(抗真菌药)在健康人体的药物动力学及生物等效性.方法 20名健康志愿者随机双交叉、单剂量口服受试制剂和参比制剂150 mg,用高效液相色谱-串联质谱联法测定人血浆中氟康唑的浓度.使用DAS软件拟合计算药物动力学参数和相对生物利用度,评价两制剂的生物等效性.结果 受试制剂和参比制剂药物动力学参数:Cmax分别为(3.26±0.54),(3.17±0.41)μg·mL-1;tmax分别为(1.42±0.65),(1.62±0.75)h;t1/2分别为(29.75±4.89),(30.34±4.67)h;AUC0-120h分别为(131.4 ±23.4),(135.2±20.6)μg·mL-1·h;AUC0-∞分别为(140.5±26.3),(145.0±23.6)μg·mL-1·h.受试制剂相对于参比制剂的生物利用度为(97.2±7.6)%.结论 2种制剂具有生物等效性.     

两种枸橼酸坦度螺酮制剂的人体生物等效性

目的研究枸橼酸坦度螺酮胶囊和片剂在健康志愿受试者中的药动学和人体生物等效性。方法 20例男性受试者交叉单剂量(10 mg)口服受试制剂枸橼酸坦度螺酮胶囊和参比制剂枸橼酸坦度螺酮片,用高效液相色谱法测定血药浓度。主要药动学参数峰浓度(Cmax)、平均血药浓度-时间曲线下面积(AUC0-12、AUC0-∞)对数转换后经方差分析,双向单侧t检验和[1-2α]%置信区间评价两制剂的生物等效性。结果受试制剂和参比制剂主要药动学参数:达峰时间(tmax)分别为(0.81±0.16)与(0.87±0.10)h,Cmax分别为(1.66±0.32)与(1.71±0.29)μg·mL-1,AUC0-12分别为(14.56±3.95)与(14.82±3.66)μg·mL-1.h,AUC0-∞分别为(15.05±3.90)与(15.31±3.61)μg·mL-1.h,半衰期(t1/2)分别为(1.24±0.21)与(1.29±0.17)h。与参比制剂相比,受试制剂相对生物利用度为(102.6±5.8)%。结论两种枸橼酸坦度螺酮制剂具有生物等效性。     

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.     

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.     

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.