舒马普坦胶囊和片剂人体药物动力学及相对生物利用度研究

目的 研究国产舒马普坦胶囊、片剂在人体内的药物动力学及相对生物利用度。方法 采用随机、开放、3×3拉丁方设计,18名男性健康受试者分别单剂量口服试验制剂或参比制剂100 mg。采用HPLC-MS法测定给药后不同时间的血药浓度,采用双单侧t检验进行生物等效性判断。结果 进口参比制剂中舒马普坦的主要药物动力学参数Cmax为(41.68±18.38)μg·L-1;tmax为(2.08±0.65)h;AUC0→12为(152.14±61.63)μg·h·L-1;t1/2为(2.7±0.8)h。国产舒马普坦胶囊的主要药物动力学参数Cmax为(38.01±17.01)μg·L-1;tmax为(1.83±0.45)h;AUC0→12为(136.68±60.71)μg·h·L-1;t1/2为(2.7±1.0)h。国产舒马普坦片剂的主要药物动力学参数Cmax为(38.78±17.67)μg·L-1;tmax为(1.83±0.45)h;AUC0→12为(136.68±60.71)μg·h·L-1;t1/2为(2.7±1.0)h。国产胶囊剂和国产片剂对进口片剂的相对生物利用度分别为91.0％±14.8％和92.0％±11.6％。结论 经统计学分析,国产舒马普坦片剂和胶囊剂与进口制剂具有生物等效性,制剂间药物动力学参数无显著差异。     

帕罗西汀片在健康志愿者体内的生物等效性

目的评价2种国产盐酸帕罗西汀片剂的生物等效性。方法采用自身交叉试验方法。20名健康志愿者顿服40mg盐酸帕罗西汀片后,在规定时间内采血。以HPLC法测定血清药物浓度;以3P87药动学软件计算主要药动学参数,并评价2种国产帕罗西汀片之间的生物等效性。结果受试制剂和参比制剂的主要药动学参数tmax分别为(5.3±2.0)、(5.5±2.0)h;cmax分别为(31.0±12.1)(、30.2±12.3)μg.L-1;AUC0→t分别为(727.9±306.6)、(719.8±316.7)μg.h.L-1;T1/2分别为(19.7±7.3)(、19.2±7.0)h。2制剂间参数比较,P>0.05,受试制剂相对于参比制剂的相对生物利用度为(103.80±16.99)%。结论2种帕罗西汀片剂为生物等效制剂。     

国产阿呋唑嗪片剂健康人体生物等效性研究

目的研究国产阿呋唑嗪片剂的相对生物利用度并求证该制剂的生物等效性.方法采用随机交叉分组试验设计,18名成年健康男性受试者分别空腹口服单剂量国产阿呋唑嗪片(试验制剂)及进口片(参比制剂),采集12h内动态血标本,用反相HPLC法测定血浆药物浓度,计算两者的药代动力学参数及相对生物利用度,并求证国产片剂和进口片剂的生物等效性.结果口服阿呋唑嗪5mg国产及进口片剂的主要药代动力学参数t1/2β分别为3.19±0.60和2.96±0.39h,tmax分别为1.89±0.72和1.53±0.40h;c分别为18.40±5.94和18.99±7.39 μg@L-1;AUC0～12分别为78.70±118.19和78.57±20.46μg@h@L-1;AUC0～∞分别为87.45±19.05和86.34±29.60μg@h@L-1.经计算试验制剂与参比制剂的平均相对生物利用度AUC0～12为101.14%±7.70%,AUC00～∞为102.13%±9.21%.两种片剂的AUC0～12'AUC0～∞,Cmax经对数转换后多因素方差分析结果表明两制剂间无显著性差异(P＞0.05);经双单侧t检验接受两种片剂生物等效的假设;AUC0-1290%置信区间为96.08%～105.8%,AUC0～∞为96.97%～106.8%.且试验制剂AUC的90%可信区间落在标准参比制剂的80%～125%之间,故认为两者等效.结论国产与进口阿呋唑嗪片为生物等效制剂.     

塞克硝唑人体药动学及生物等效性研究

目的:评价国产塞克硝唑片、塞克硝唑胶囊与进口塞克硝唑片的人体生物等效性。方法:将18名健康男性志愿者随机分为3组,分别口服国产塞克硝唑片、塞克硝唑胶囊和进口塞克硝唑片1g,采用交叉自身对照方法,3次给药的间隔清洗期为14d。采用高效液相色谱-紫外检测法测定人血浆中塞克硝唑的药物浓度。结果:国产片剂、国产胶囊、进口片剂的tmax分别为(2.00±1.93)、(2.67±2.14)、(1.54±1.53)h,t1/2分别为(28.56±4.98)、(29.69±6.81)、(27.16±5.06)h,Cmax分别为(25.50±2.74)、(24.27±3.76)、(25.64±4.10)μg/ml,AUC0~t分别为(736.03±73.20)、(704.78±88.51)、(737.77±76.02)(μg·h)/ml,AUC0~∞分别为(886.36±114.50)、(864.57±172.27)、(870.64±100.21)(μg·h)/ml;相对生物利用度国产片剂为(100.02±6.73)%,国产胶囊为(95.91±10.66)%。结论:3种制剂具有生物等效性。     

国产酒石酸唑吡坦片剂人体生物等效性研究

目的:研究国产酒石酸唑吡坦片剂和进口酒石酸唑吡坦片剂的人体生物等效性。方法:采用高效液相荧光检测法,测定18例男性健康受试者单剂量口服10 mg国产和进口酒石酸唑吡坦片剂的唑吡坦血浆浓度。采用3p97程序对主要的药动学参数Cmax,AUC0-12h,Tmax进行统计分析。结果:国产和进口酒石酸唑吡坦片剂的Cmax、分别为(113．73±11．40)和(116．58±16．13)ng·mL-1,Tmax分别为(1．01±0．25)和(1．03±0．24)h,t1/2 ke分别为(3．02±0．29)和(2．92±0．42)h,AUC0-12 h分别为(413．81±61．64)和(434．0±62．20)ng·h·mL-1。2种制剂的Cmax,AUC0-12h和Tmax无显著性差异。国产酒石酸唑吡坦片剂相对生物利用度为(95．50±7．50)％。结论:国产和进口酒石酸唑吡坦片剂两种制剂具有生物等效性。     

国产格列美脲片的药代动力学及相对生物利用度

目的 :研究健康受试者口服国产格列美脲片的人体相对生物利用度及生物等效性。方法 :2 0例健康志愿者采用随机交叉自身对照试验 ,分别单次口服国产及进口格列美脲片剂各 4mg ,用HPLC法检测血药浓度 ,以内标法定量。结果 :国产片与进口片的Cmax分别为 (462 .3± 1 32 .2 )及 (41 2 .4± 1 1 7.7) μg·L- 1 ;Tmax分别为 (3 .2± 0 .6)及(3 .3± 0 .8)h;t1 / 2 分别为 (7.1± 1 .5)及 (7.5± 1 .7)h ;AUC0 -t分别为 (2 571 .6± 564 .9)及 (2 362 .3± 51 9.6) μg·h·L- 1 ;AUC0～∞ 分别为 (2 769.8± 60 8.2 )及 (2 592 .4± 572 .5) μg·h·L- 1 。国产片与进口片比较生物利用度为 (1 1 1 .3±2 3 .3) %。Cmax,AUC0～t及AUC0～∞ 经生物等效性检验均为等效。结论 :国产格列美脲片相对进口品具生物等效性     

托吡酯片人体生物等效性研究

目的研究国产与进口托吡酯片口服给药后的人体生物等效性。方法采用两制剂双周期交叉试验设计,18名健康男性受试者分别单剂量口服国产或进口托吡酯片100mg,采用高效液相色谱-质谱法测定人血浆中托吡酯的浓度。结果国产片与进口片的Cmax分别为(1222±237)、(1274±180)μg/L,tmax分别为(1.5±1.0)、(1.2±0.9)h,AUC0~120分别为(40520±7524)、(40458±4731)(μg.h)/L,AUC0~∞分别为(44379±8082)、(44380±4952)(μg.h)/L,t1/2分别为(34.4±5.0)、(35.5±4.8)h;国产片的相对生物利用度为(100.8±19.2)%。结论国产与进口托吡酯片具有生物等效性。     

国产醋氯芬酸胶囊剂与片剂人体相对生物利用度研究

目的评价国产醋氯芬酸胶囊剂、片剂和进口醋氯芬酸片剂3种制剂的生物等效性.方法18名健康男性志愿者按3个周期拉丁方交叉口服单剂量(100mg) 醋氯芬酸制剂,用HPLC法测定血清中醋氯芬酸的浓度,并对试验数据进行统计处理及对3种制剂进行生物等效性评价.结果口服国产待测胶囊剂、片剂及进口醋氯芬酸片剂的Cmax分别为(9.85±3.21),(10.11±3.50)及(8.68±2.65)μg@mL-1;Tmax分别为(1.83±1.00),(2.31±1.25)及(2.42±1.29)h;AUC0～12h分别为(27.09±5.90),(28.16±6.47)及(26.00±4.87)μg@h@mL-1;AUC0～∞分别为(28.29±6.03 ),(29.39±6.66)及(27.11±5.15)μg@h@mL-1;国产醋氯芬酸胶囊、片剂的相对生物利用度为(104.83±15.54)%和(108.97±17.35)%.结论国产胶囊剂、片剂均与进口参比醋氯芬酸片剂具有生物等效性.     

枸橼酸莫沙必利口服液与片剂人体生物等效性评价

目的建立测定枸橼酸莫沙必利血浆浓度的高效液相色谱(HPLC)法,并对枸橼酸莫沙必利的口服液与片剂进行人体相对生物利用度和生物等效性研究.方法20名健康志愿者分别单剂量口服枸橼酸莫沙必利口服液或片剂10 mg,HPLC测定血药浓度,采用DAS 1.0程序进行药动学分析,并评价两制剂的生物等效性.结果单剂量口服10 mg枸橼酸莫沙必利口服液和片剂的药动学参数,AUC0→t分别为(170.2±40.7)μg·h·L-1和(176.6±69.4)μg·h·L-1,AUC0→∞分别为(182.2±43.7)μg·h·L-1和(193.2±73.3)μg·h·L-1;Cmax分别为(61.3±17.0)μg·L-1和(58.6±22.0)μg·L-1;tmax分别为(0.60±0.21)h和(0.8±0.4)h.分别以AUC→t与AUC0→∞计算其相对生物利用度分别为(105.8±36.0)%和(102.9±35.1)%.结论两种制剂具生物等效性.     

国产与进口替米沙坦片的人体生物等效性

目的 :评价国产和进口替米沙坦片剂的生物等效性。方法 :采用随机交叉试验 ,HPLC荧光法测定 2 0名中国健康男性受试者口服替米沙坦的血药浓度。药动学参数用 3P97程序进行计算。结果 :国产与进口替米沙坦片的主要药动学参数 :AUC0→t分别为 (2 381 2 0± 10 98 5 1)、(2 333 36± 114 5 75 ) μg·h·L-1;AUC0→∞ 为 (2 4 86 4 4± 1135 70 )、(2 4 4 0 35± 1190 37) μg·h·L-1;cmax为 (5 71 99± 36 8 2 7)、(5 30 97± 2 5 6 38) μg·L-1;tmax为 (1 15± 0 6 8)、(1 2 0± 1 6 0 )h ;T1/ 2 为 (19 0 8± 2 91)、(18 99±2 92 )h。国产替米沙坦片的相对生物利用度是 (10 4 2 9± 2 1 17) % (n =2 0 )。国产和进口替米沙坦片主要药动学参数经统计学(ANOVA)处理均无显著性差异 (P >0 0 5 ) ;AUC0→t、cmax经对数转换后的双单侧t检验示无显著性差异。结论 :国产和进口替米沙坦片具有生物等效性     

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.     

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.     

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.