盐酸昂丹司琼口腔崩解片的人体药动学和生物利用度研究

目的建立LC-MS方法测定健康志愿者血浆中盐酸昂丹司琼的浓度,观察昂丹司琼的血药浓度经时过程,估算相应的药代动力学参数。方法血浆中加入内标后,用乙酸乙酯提取,采用选择性离子检测方法测定其血药浓度。流动相为:甲醇∶水=80∶20,流速0.2 ml.min-1,色谱柱为Shim-packODS 250 mm×2.0 mm,柱温40℃。采用双交叉实验设计,剂量为8 mg。结果盐酸昂丹司琼线性范围为1～50μg.L-1,检测限为0.2μg.L-1,日内日间变异均小于10%。20名健康志愿者口服8 mg盐酸昂丹司琼后,测得盐酸昂丹司琼Cmax为(29.09±5.61)μg.L-1,Tmax为(2.2±0.8)h,AUC0-τ为(159.5±29.1)μg.h-1.L-1的。盐酸昂丹司琼口腔崩解片的相对生物利用度为(103.3±19.5)%,两制剂生物等效。结论该方法专属性强,准确性好,可用于盐酸昂丹司琼血药浓度测定和药代动力学研究。     

马来酸依那普利片的健康人体生物等效性

目的:研究马来酸依那普利片的人体相对生物利用度和生物等效性.方法:健康志愿者20名,随机双交叉单剂量口服马来酸依那普利片试验制剂和参比制剂,剂量分别为20 mg,用高效液相色谱(HPLC)法测定血浆中依那普利的浓度.用DAS药动学程序计算相对生物利用度并评价两种制剂生物等效性.结果:受试制剂与参比制剂的Cmax分别为(272.6±42.2)μg·L-1和(263.5±42.2)μg·L-1;tmax分别为(0.81±0.11)h和(0.80±0.10)h;AUC(0-∞)分别为(664.7±105.1)μg·h·L-1和(661.2±99.5)μg·h·L-1)AUC(0-inf)分别为(698.0±116.3)μg·h·L-1和(689.0±106.0)μg·h·L-1.试验制剂与参比制剂的人体相对生物利用度为(102.3±19.7)%,结论:试验制剂与参比制剂具有生物学等效性.     

盐酸昂丹司琼口崩片在健康人体内的药动学及生物等效性研究

目的建立测定血浆中盐酸昂丹司琼浓度的高效液相色谱法,并以盐酸昂丹司琼片为参比制剂进行生物等效性研究。方法 20例健康男性志愿者单剂量随机交叉口服受试制剂和参比制剂各8 mg,应用RP-HPLC法测定血浆中昂丹司琼浓度,进行药物动力学及相对生物利用度研究。结果受试制剂与参比制剂的主要药动学参数:Cmax分别为(48.21±0.34)、(46.30±18.77)ng/mL;AUC0-t分别为(203.48±56.80)、(206.03±53.60)ng.h/mL;AUC0-∞分别为(223.24±55.74)、(227.14±55.59)ng.h/mL;t1/2分别为(4.39±1.75)、(4.22±1.27)h。受试制剂的相对生物利用度为101.1%±0.2%。结论两种制剂具有生物等效性。     

盐酸特比萘芬片的人体生物等效性研究

目的:评价盐酸特比萘芬片人体生物等效性.方法:18例健康志愿者随机交叉口服单剂量(0.25 g)盐酸特比萘芬片试验制剂与参比制剂,采用LC-MS/MS法测定血浆中特比萘芬的血药浓度.结果:试验制剂与参比制剂的主要药动学参数Cmax分别为(941.6±196.5)和(917.1±264.8)μg·L-1,Tmax分别为(1.38±0.39)和(1.38±0.61)h,AUC0～72h分别为(4 696.4±1 192.8)和(4 596.9±1 189.8)μg·h·L-1,AUC0～∞分别为(4 838.7±1 188.1)和(4 755.9±1 183.2)μg·h·L-1.试验制剂对参比制剂的相对生物利用度F(以AUC0～72h作为评价依据)为(98±9)%.结论:盐酸特比萘芬片试验制剂与参比制剂生物等效.     

盐酸托莫西汀胶囊的人体生物等效性

目的:研究国产盐酸托莫西汀胶囊的人体生物等效性。方法:20名健康男性志愿者按2×2交叉试验方案设计,分别口服受试制剂和参比制剂各20mg,并采集24h内动态血标本;用HPLC-MS-MS法测定血浆中托莫西汀浓度,计算药动学参数,并判定2种制剂的生物等效性。结果:受试制剂和参比制剂的主要药动学参数Cmax分别为(257.1±57.8)μg.L-1和(260.6±51.6)μg.L-1,tmax分别为(1.6±0.9)h和(1.5±1.0)h,t1/2分别为(3.5±1.3)h和(3.3±1.2)h,AUC0-24分别为(939.8±179.2)μg.L-1.h和(983.6±177.3)μg.L-1.h,AUC0-∞分别为(965.2±174.8)μg.L-1.h和(993.8±170.5)μg.L-1.h,2种制剂主要药动学参数经对数转换后进行方差分析及双单侧t检验,并计算90%置信区间,表明2种制剂生物等效,受试制剂的人体生物利用度为(95.6±16.9)%。结论:2种制剂生物等效。     

盐酸吡格列酮胶囊的人体相对生物利用度

目的:评价盐酸吡格列酮胶囊的人体生物等效性.方法:18名男性健康志愿者随机交叉口服受试制剂盐酸吡格列酮胶囊和参比制剂盐酸吡格列酮片30 mg,采用反相高效液相色谱-紫外检测法测定血浆药物浓度.结果:受试制剂和参比制剂的Tmax分别为(1.9±0.5),(2.1±0.6)h;Cmax分别为(1 480.0±234.9),(1 436.5±206.4)μg·L-1;t1/2β分别为(6.0±1.4),(6.4±1.4)h;AUC0→24分别为(8 893.6±1979.9),(8893.2±1913.8)μg·L-1·h;AUC0→∞.分别为(9 706.4±2 394.5),(9928.3±2512.4)μg·L-1·h,盐酸吡格列酮胶囊的相对生物利用度为(101.4±17.5)%.结论:经统计学分析,盐酸吡格列酮胶囊与盐酸吡格列酮片具有生物等效性.     

复方苯磺酸氨氯地平/盐酸贝那普利片在健康志愿者的生物等效性

目的:评价2种复方苯磺酸氨氯地平/盐酸贝那普利制剂生物等效性。方法:20名健康男性志愿者随机交叉单剂量口服复方苯磺酸氨氯地平/盐酸贝那普利受试制剂和参比制剂,采用LC-MS/MS法测定血清中氨氯地平、贝那普利及其代谢产物贝那普利拉浓度,DAS2.0软件计算药动学参数与生物等效性。结果:单剂口服受试和参比制剂后的苯磺酸氨氯地平主要药动学参数Cmax分别为(6.6±1.9)μg.L-1和(7.5±2.3)μg.L-1,tmax分别为(6.2±1.4)h和(5.7±1.2)h,AUC0-t分别为(264.2±90.5)μg.h.L-1和(271.3±94.9)μg.h.L-1,受试制剂的苯磺酸氨氯地平相对生物利用度为(97.41±6.04)%;单剂口服受试和参比制剂后的贝那普利主要药动学参数Cmax分别为(136.6±66.1)μg.L-1和(143.3±50.9)μg.L-1,tmax分别为(0.6±0.2)h和(0.6±0.2)h,AUC0-t分别为(139.3±54.0)μg.h.L-1和(137.8±47.2)μg.h.L-1,受试制剂的贝那普利相对生物利用度为(100.8±7.55)%;单剂口服受试和参比...     

国产与进口盐酸沙格雷酯片在健康人体的生物等效性

目的 研究国产与进口盐酸沙格雷酯片(抗血栓药)的相对生物利用度,评价2者的生物等效性.方法 采用双周期自身交叉试验设计,单剂量口服给药.24名健康男性受试者分别单剂量口服受试制剂和参比制剂,血浆样品采用高效液相色谱-串联质谱法检测.结果 受试制剂及参比制剂盐酸沙格雷酯片的主要药代动力学参数:Cmax分别为(710.25±305.79),(653.33±311.06)μg·L-1;tmax分别为(0.39±0.23),(0.38±0.19)h;t1/2分别为(0.72±0.10),(0.67±0.10)h;AUC0-tn分别为(473.80±216.83),(440.17±440.17)μg·h·L-1;AUC0-∞分别为(479.88±224.77),(443.79±144.70)μg·h·L-1;受试制剂盐酸沙格雷酯片的相对生物利用度F0-tn、F0-∞分别为(110.24±38.24)%,(110.64±39.07)%.结论 受试制剂和参比制剂具有生物等效性.     

盐酸曲美他嗪胶囊的人体生物等效性

目的 评价国产盐酸曲美他嗪胶囊和进口盐酸曲美他嗪包衣片的人体生物等效性.方法 20名健康男性受试者按两制剂两周期的交叉试验设计单剂量口服20 mg的参比制剂和受试制剂后,采用LE-MS法测定血浆中盐酸曲美他嗪的浓度,使用DAS 1.0软件计算药动学参数并进行生物等效性统计分析.结果 参比制剂和受试制剂的ρmax分别为(55.9±9.2)和(56.4±12.2)μg·L-1;tmax分别为(2.5±0.8)和(2.7±0.9)h;AUC0→24h分别为(493.8±82.8)和(489.8±108.4)μg·h·L-1;AUC0→∞分别为(513.7±88.6)和(510.1±116.8)μg·h·L-1;t1/2分别为(4.8±0.4)和(4.7±0.4)h.双单侧t检验结果显示受试制剂的ρmax、AUC0→24h的90%置信区间分别为参比制剂相应参数的92.0%～108.4%和91.5%～105.3%,受试制剂的相对生物利用度为(99.6±16.5)%(以AUC0→24h计算).结论 国产盐酸曲美他啶胶囊与其进口包衣片具有生物等效性.     

乌苯美司胶囊人体药代动力学和生物等效性试验

目的:采用HPLC-MS/MS法研究乌苯美司胶囊在人体的药代动力学,并评价生物等效性。方法:24例健康男性受试者单次交叉口服30 mg乌苯美司胶囊受试制剂和参比制剂,测定给药后不同时间点血浆中乌苯美司经时血药浓度,采用DAS 2.0软件进行药代动力学参数计算和生物等效性评价。结果:受试者单次口服试验制剂与参比制剂后,达峰时间分别为(0.72±0.28)和(0.80±0.15)h;峰浓度分别为(2 416.83±379.56)和(2 291.57±418.92)μg.L-1;AUC0～t分别为(3 950.66±589.84)和(4 012.93±521.49)μg.L-1.h;AUC0～∞分别为(3 957.04±590.19)和(4 016.23±520.60)μg.L-1.h;t1/2分别为(3.49±1.91)和(2.80±1.51)h。试验制剂与参比制剂的生物等效性为98.0%(94.2%～101.9%)。结论:乌苯美司胶囊试验制剂与参比制剂生物等效。     

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.