国产格列本脲和二甲双胍复方制剂在健康志愿者的药动学和相对生物利用度

目的:比较国产格列本脲和二甲双胍复方制剂在健康志愿者的药动学和相对生物利用度。方法:20例受试者随机交叉单剂量口服国产格列本脲和二甲双胍复方制剂(盐酸二甲双胍:格列本脲=500 mg:5 mg,简称试验制剂)与格列本脲片和盐酸二甲双胍片2个相同剂量单药(简称参比制剂),用液相色谱-质谱法和高效液相色谱法测定血清中格列本脲和二甲双胍的浓度。结果:试验与参比制剂中格列本脲的药动学参数分别为:AUC0-t为(1 184．8±369．4)和(1 110．5±437.2)μg·h·L-1,Cmax为(211．8±57．8)和(176．7±46．0)μg·L-1,Tmax为(3．38±0．94)和(3．43±1．03)h;2种制剂中二甲双胍药动学参数分别为:AUC0-t为(7 219．8±1 964．6)和(7 376．8±2 060．2)μg·h·L-1,Cmax为(924．7±206．2)和(1 01 1．9±331．7)μg·L-1,Tmax为(3．60±1．20)和(3．55±1．09)h。试验制剂中格列本脲和二甲双胍的相对生物利用度分别为(109．5±17．0)％和(105．2±33．4)％。结论:国产格列本脲和二甲双胍复方制剂与组成复方的2个相同剂量单药的药动学比较显示相同的相对生物利用度。     

复方盐酸二甲双胍片的人体相对生物利用度

目的研究国产复方盐酸二甲双胍片(含盐酸二甲双胍和格列本脲)与盐酸二甲双胍片和格列本脲片的人体相对生物利用度。方法采用随机交叉、自身对照试验设计,18名健康男性志愿者单剂量口服复方盐酸二甲双胍片(含盐酸二甲双胍500 mg,格列本脲2.5 mg)或同时口服盐酸二甲双胍片500 mg和格列本脲片2.5 mg,在不同时间点取静脉血,盐酸二甲双胍血药浓度采用HPLC-UV测定,格列本脲血药浓度采用HPLC-MS测定。以方差分析对主要药动学参数进行差别检验,以双单侧t检验进行生物等效性判定。结果单剂量口服复方盐酸二甲双胍片(含盐酸二甲双胍500 mg,格列本脲2.5 mg)或同时服用盐酸二甲双胍片500 mg和格列本脲片2.5 mg后,盐酸二甲双胍的药动学参数:AUC0~24分别为(6 252.9±2 628.3)、(6 270.6±2 202.6)ng.h.mL-1,AUC0~∞分别为(6 764.4±2 895.2)、(7 195.1±4 153.1)ng.h.mL-1,Cmax分别为(1 082.4±348.2)、(1 111.0±343.3)ng.mL-1,tmax分别为(1.5±0.5)、(1.7±0.6)h。试验制剂中盐酸二甲双胍的相对生物利用度为99.72%±13.59%。格列本脲的药物动力学参数AUC0~36分别为(533.5±247.0)、(495.7±223.3)ng.h.mL-1,AUC0~∞分别为(578.8±263.8)、(525.4±253.5)ng.h.mL-1,Cmax分别为(94.1±19.1)和(87.39±20.72)ng.mL-1,tmax分别为(1.8±0.4)和(1.9±0.4)h。与参比制剂相比,试验制剂中格列本脲的相对生物利用度为103.83%±12.94%。方差分析结果表明试验制剂与参比制剂的主要药物动力学参数之间无明显差异,双单侧t检验结果表明试验制剂与参比制剂为生物等效制剂。结论复方盐酸二甲双胍片与同时口服相同剂量的盐酸二甲双胍片和格列本脲片生物等效。     

甲砜霉素胶囊人体生物等效性研究

目的:进行试验制剂甲砜霉素胶囊与参比制剂市售甲砜霉素胶囊生物等效性研究。方法:男性健康志愿者20名,随机分为2组,分别交叉单剂服用试验制剂或参比制剂甲砜霉素胶囊500mg,采用高效液相色谱法测定甲砜霉素经时血药浓度,计算药动学参数,评价2制剂的生物等效性。结果:试验制剂和参比制剂主要药动学参数t1/2为(3.7±s0.5)h和(3.1±0.6)h,tmax为(2.0±0.3)h和(2.0±0.3)h,cmax为(2.3±0.6)mg·L-1和(2.3±0.5)mg·L-1,AUC0～12为(9.0±1.4)mg·h·L-1和(9.0±1.6)mg·h·L-1,AUC0～∞为(9.8±1.8)mg·h·L-1和(9.8±1.6)mg·h·L-1。试验制剂甲砜霉素胶囊相对生物利用度(F)为(101±6)%。结论:甲砜霉素胶囊试验制剂和参比制剂为生物等效制剂。     

盐酸二甲双胍/格列本脲复方片剂在人体的药代动力学

目的　建立人血浆中格列本脲的HPLC ESI MS测定法 ,研究志愿者口服格列本脲与二甲双胍的复方片剂后的药代动力学行为。方法　人血浆样品中格列本脲的测定方法 :血浆样品以 1mol·L- 1的盐酸酸化后用乙酸乙酯提取 ,进行HPLC ESI MS分析 ,色谱柱为LichrospherC18(dp 5μm ,4 6mmID× 2 5cm ) ,流动相为甲醇 -10mmol·L- 1醋酸铵水溶液 (78∶2 2 ,V/V) ,检测方式为SIM方式 ,检测离子为m/z 492 1(格列本脲 )、m /z 444 1(内标 )。 2 0名健康志愿者交叉口服供试片和参比片 ,剂量均为格列本脲 2 5mg和盐酸二甲双胍 50 0mg。 结果　在 0 3 10～ 413 μg·L- 1范围内格列本脲峰面积与内标峰面积的比值与浓度的线性关系良好。格列本脲受试制剂与参比制剂的T1/2 分别为(5 4± 0 8)h、(5 9± 1 0 )h ,Cmax 分别为 (14 6± 2 2 ) μg·L- 1、(12 3± 16) μg·L- 1,Tmax分别为 (2 7± 0 9)h、(3 0±0 7)h ,AUC0～ 3 6 分别为 (73 0± 14 0 ) μg·h·L- 1、(63 2± 117)μg·h·L- 1;二甲双胍受试制剂与参比制剂的T1/2 分别为(3 0± 0 6)h、(3 0± 0 4)h ,Cmax分别为 (1 61± 0 3 2 )mg·L- 1、(1 62± 0 3 3 )mg·L- 1,Tmax分别为 (1 8± 0 2 )h、(1 7± 0 4)h ,AUC0～ 15 分别为 (7 3 7± 1 3 4 )     

复方盐酸二甲双胍片的人体生物等效性

目的研究试验制剂国产复方盐酸二甲双胍片与参比制剂格列本脲片、盐酸二甲双胍片的人体生物等效性。方法健康志愿者20名,随机双交叉单剂量口服2种制剂,2次服药间隔为2 wk。分别于服药后24 h内多点抽取静脉血,用RP-HPLC测定血浆中格列本脲和盐酸二甲双胍的浓度。血药浓度经3P97程序处理,用非房室模型估算药动学参数。结果试验制剂和参比制剂血浆中格列本脲的ρmax分别为(190.91±45.01)(、175.71±27.47)μg.L-1,tmax分别为(2.60±0.87)、(2.35±0.71)h,AUC0→24分别为(1 110.85±275.12)(、1 074.77±202.76)μg.h.L-1,AUC0→∞分别为(1 187.91±275.55)(、1 168.52±168.65)μg.h.L-1;二甲双胍的ρmax分别为(3.06±0.63)、(3.06±0.55)mg.L-1,tmax分别为(1.57±0.37)(、1.65±0.37)h,AUC0→12分别为(12.05±1.92)、(12.05±1.79)mg.h.L-1,AUC0→∞分别为(12.47±1.97)(、12.51±1.80)mg.h.L-1。以格列本脲和盐酸二甲双胍计算的人体相对生物利用度分别为(103.8±17.9)%和(100.7±13.0)%。结论2种制剂具有生物等效性。     

氯雷他定片的人体相对生物利用度

目的研究氯雷他定片在健康人体内的相对生物利用度.方法18名健康男性志愿者按随机交叉试验设计口服单剂量受试制剂和参比制剂40mg,用高效液相色谱-质谱(HPLC-MS)法测定血药浓度,NDSr程序作统计学处理.结果受试制剂和参比制剂在血浆中的cmax分别为(51.05±23.16),(47.55±20.22)μg·L-1;tmax分别为(1.35±0.35),(1.44±0.53)h;T1/2分别为(13.16±5.20),(13.25±4.08)h;AUC0→36h分别为(135.27±62.82),(130.59±55.58)μg·h·L-1.主要药动学参数AUC0→36h,tmax,cmax经方差分析均无显著性差异.以AUC0→36h计算,受试制剂的相对生物利用度为(103.5±24.7)%.结论2种制剂具有生物等效性.     

盐酸二甲双胍缓释片药物动力学及生物等效性研究

目的 建立人血浆中二甲双胍浓度的RP-HPLC测定方法,研究二甲双胍在人体中药物动力学行为,评价其生物等效性。方法 采用双交叉实验设计和单剂量、多剂量2种给药方案,测定了20名健康受试者口服盐酸二甲双胍普通片和缓释片后不同时间后的血药浓度。结果 受试者单剂量口服普通片和缓释制剂后估算的药动学参数AUC0-τ分别为(9.41±1.21)mg·h·L-1和(10.79±1.50)mg·h·L-1;t1/2分别为(2.94±0.57)h,(4.55±0.82)h,tmax分别为(1.5±0.7)h和(3.1±0.6)h;Cmax分别为(2.28±0.44)mg·L-1和(1.72±0.54)mg·L-1;MRT分别为(4.12±0.87)h和(7.32±1.45)h,相对生物利用度F为114.9％±10.7％。受试者多剂量口服普通片和缓释制剂后估算的药物动力学参数AUCss分别为(10.64±1.35)mg·h·L-1、(17.97±2.22)mg·h·L-1,Cmax分别为(2.33±0.43)mg·L-1、 (1.98±0.30)mg·L-1,Cmin分别为(0.18×0.04)mg·L-1、 (0.10±0.03)mg·L-1,Cav分别为(0.89±0.11)mg·L-1、(0.75±0.09)mg·L-1,tmax分别为(1.9±0.6)h、(2.9±0.9)h,相对生物利用度F为为85.0％±8.8％。结论 盐酸二甲双胍普通片和缓释片口服时吸收程度等效,吸收速度不等效。     

阿莫西林/克拉维酸钾(14:1)咀嚼片与分散片在健康人体的生物等效性

目的研究阿莫西林克拉维酸钾(14∶1)咀嚼片、分散片与普通片的生物等效性。方法用三制剂、三周期(周期间隔为5天)三交叉试验方法,18名健康男性志愿者分别口服受试或参比制剂1片(每片含阿莫西林600mg,克拉维酸钾42.9mg)。用微生物学方法测定血浆中药物浓度。结果咀嚼片、分散片及普通片的主要药动学参数分别为:阿莫西林AUC0-8h分别为(22.48±4.5),(22.16±3.79)和(22.51±4.31)mg·h·L-1;Cmax分别为(9.079±1.86),(8.822±1.84)和(8.6892±1.13)mg·L-1。克拉维酸钾的AUC0-8h分别为(1.11±0.455),(1.204±0.45)和(1.23±0.505)mg·h·L-1;Cmax分别为(0.553±0.260),(0.613±0.241)和(0.602±0.206)mg·L-1。结论咀嚼片、分散片与普通片具有生物等效性。     

替米沙坦片在健康人体的药代动力学和相对生物利用度

目的研究国产和进口替米沙坦片在健康人体的药代动力学并评价2制剂的生物等效性。方法20名健康志愿者单次、交叉口服替米沙坦片80mg后,用高效液相色谱-荧光检测法测定血浆替米沙坦浓度。用3P97药代动力学软件计算药代动力学参数。结果2种替米沙坦片在健康志愿者体内的药-时曲线均符合二室模型,2种制剂的主要药代动力学参数:Cmax分别为(944.71±376.08),(852.72±333.78)ng·mL-1;tmax分别为(0.98±0.60),(1.28±0.65)h;t1/2β分别为(28.78±13.88),(25.83±9.25)h;AUC0-t分别为(4.14±2.44),(3.83±1.97)mg·h·L-1;AUC0-∞分别为(4.64±2.84),(4.17±2.22)mg·h·L-1。国产对进口制剂的平均相对生物利用度F0-t为(99.64±23.93)%,F0-∞为(97.97±26.20)%。结论国产和进口替米沙坦片剂为生物等效制剂。     

奈韦拉平胶囊人体相对生物利用度和生物等效性研究

目的比较奈韦拉平胶囊与奈韦拉平片的人体相对生物利用度,并进行生物等效性评价.方法按照两制剂两周期随机交叉设计,选择20名健康志愿者单剂量口服试验制剂或参比200mg,采用HPLC-UV法测定其血药浓度.DAS软件处理血药浓度数据和计算参数,并进行统计学分析,对两种制剂作出生物等效性评价.结果建立血浆奈韦拉平血浆浓度的HPLC测定法.该加权线性回归方程为A=3.72C-0.008 2(r=0.999 1),线性范围为0.05～5.0 mg·L-1,最低检测浓度为0.05 mg·L-1.单剂量口服200 mg的奈韦拉平试验和参比制剂,得AUC0→t(梯形法)分别为(152.7±23.1)mg·h·L-1和(150.5±18.7)mg·h·L-1,AUC0→∞(梯形法)分别为(167.2±27.2)mg·h·L-1和(164.8±22.4)mg·h·L-1;Cmax(实测)分别为2.5±0.4)mg·L-1和(2.5±0.4 mg·L-1;tmax(实测)分别为(3.2±1.2)h和(3.1±1.2)h.用药时曲线下面积AUC0→t计算,20名健康志愿者单剂量口服奈韦拉平胶囊(试验制剂)相对生物利用度为(102.0±24.3)%.结论本项目研究所用奈韦拉平血药浓度监测方法可满足生物利用度试验方法学的要求.试验制剂(奈韦拉平胶囊)与参比制剂(奈韦拉平片)相比较的人体相对生物利用度按AUC0→t计为(102.0±24.3)%,统计学检验表明,试验制剂与参比制剂具生物等效性.     

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.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

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.