盐酸奈福泮缓释片药代动力学及生物等效性

目的 :验证盐酸奈福泮缓释片的缓释特性并判定其生物等效性。方法 :18名健康受试者随机分成两组 ,采用双周期交叉试验设计 ,单剂量、多剂量连续给药 ,用高效液相色谱法测定血药浓度 ,以3p97药代动力学程序求算相关参数。结果 :单剂量给药的结果表明 :缓释片在给药后 2～ 12h内血药浓度维持在 2 0～ 4 0mg·L- 1之间 ,cmax 为 (45 .8±15 .7)mg·L- 1,tpeak为 (3.4± 0 .8)h ;普通片在给药后 0 .5～ 8h内血药浓度维持在 2 0mg·L- 1以上 ,cmax为 (72 .7± 2 6 .0 )mg·L- 1,tpeak为 (1.6± 0 .6 )h。两制剂的AUC分别为 (36 3.4± 10 7.7)及 (374 .8±12 5 .7)mg·h·L- 1,平均相对生物利用度为 1.0 2±0 .2 5。多剂量给药的结果表明 :缓释片和普通片的cmax分别为 (31.5± 12 .7)及 (33.7± 10 .5 )mg·L- 1,cmin分别为 (13.4± 4 .4 )及 (10 .9± 5 .4 )mg·L- 1,tpeak分别为 (2 .6± 0 .6 )及 (1.2± 0 .5 )h ,FI分别为0 .77± 0 .2 6及 1.0 4± 0 .18。结论 :该缓释片具有缓释特征 ,两制剂生物利用度 (AUC)具有等效性     

氢溴酸加兰他敏缓释片的人体药代动力学及缓释特性评价

目的研究氢溴酸加兰他敏缓释片和普通片单剂量和多剂量给药后在健康受试者体内的药代动力学特征,并评价缓释片的缓释特性。方法建立以纳洛酮(naloxone)为内标的LC-MS测定方法,测定20名健康男性受试者按双交叉试验单剂量和多剂量服用氢溴酸加兰他敏缓释片与普通片后血浆中加兰他敏的浓度,并计算药代动力学参数和生物利用度,并评价缓释片的缓释特性。结果单剂量给药后,缓释片与普通片的HVD12Cmax分别为(15.4±1.7)h和(5.4±2.5)h;与普通片相比缓释片的延迟商R△为3.4±1.4;缓释片与普通片的Tmax分别为(4.4±1.5)h和(1.3±1.2)h;Cmax分别为(27.5±2.9)μg·L-1和(53.7±12.7)μg·L-1;缓释片的缓释特征明显。缓释片的相对生物利用度为(95.9±14.2)%。多剂量给药后,缓释片与普通片的CmSSax分别为(58.8±9.4)μg·L-1和(52.0±6.9)μg·L-1,CSmSin分别为(16.2±4.0)μg·L-1和(22.5±5.0)μg·L-1,Cav分别为(39.0±3.9)μg·L-1和(37.1±5.0)μg·L-1,DF分别为1.1±0.3和0.8±0.1;双单侧t检验结果表明两制剂的AUCss、CmSSax、Cav生物等效。结论缓释片与普通片吸收程度生物等效,该缓释片显示出明显的缓释特征。     

洛伐他汀缓释片在Beagle犬体内的药动学特性与生物等效性

目的:研究洛伐他汀缓释片在Beagle犬体内的药动学特征及其口服相对生物利用度。方法:Beagle 犬12条随机分为2组,分别单次口服洛伐他汀缓释片和普通片备60 mg,用RP-HPLC法检测血药浓度。药动学参数用3P97软件分析。结果:洛伐他汀缓释片和普通片的tmax分别为(2．7±5 0．8)和(2．8±1．0)h,cmax分别为(137±43)和(176±59)μg·L-1,t1／2分别为(11±4)和(10±5)h;AUC0-(?)分别为(956±146)和(1 005± 147)μg·h·L-1。以AUC0-(?)计算,与普通片相比,洛伐他汀缓释片的相对生物利用度为(95±6)％。洛伐他汀缓释片和普通片AUC0-(?)对数比值的90％可信限为81．6％-112．2％。结论:洛伐他汀缓释片具有一定缓释特性,与普通片相比具有生物等效性。     

2种盐酸阿呋唑嗪制剂的生物等效性研究

目的:比较盐酸阿呋唑嗪缓释片和盐酸阿呋唑嗪进口普通片的人体生物等效性。方法:20名健康男性志愿者自身交叉单剂量口服盐酸阿呋唑嗪缓释片和盐酸阿呋唑嗪进口普通片5mg,用高效液相色谱法测定人血浆中盐酸阿呋唑嗪浓度,计算药动学参数,并进行统计学分析及生物等效性评价。结果:盐酸阿呋唑嗪缓释片和盐酸阿呋唑嗪进口普通片的Cmax分别为(28·92±9·63)、(32·92±10·23)μg·L-1,tmax分别为(2·7±0·6)、(1·4±1·0)h,AUC0～∞分别为(221·14±59·46)、(245·68±67·20)μg·h·L-1,t1/2分别为(6·68±0·85)、(4·73±1·22)h,AUC0～24分别为(215·20±49·63)、(226·30±53·60)μg·h·L-1。盐酸阿呋唑嗪缓释片的相对生物利用度为(92·2±13·2)%。结论:2种制剂具有生物等效性。     

盐酸伪麻黄碱缓释片的人体药动学及生物等效性

目的研究盐酸伪麻黄碱(d-peseudoephedrine hydrochloride)缓释片与普通片在正常人体内的药动学和相对生物利用度.方法高效液相色谱法测定20名男性健康志愿者交叉po 60 mg普通片和缓释片后的血药浓度,求算药动学参数并进行统计学评价.结果单剂量po普通片和缓释片主要药动学参数Cmax分别为(317.9±99.6)μg·L-1和(205.1±29.8)μg·L-1;t1/2(Ke)分别为(3.9±0.5)h和(5.7±1.2)h;AUC0～24分别为(2 386.8±246.1)h·μg·L-1和(2 310.9±171.9)h·μg·L-1,相对生物利用度为(97.4±8.8)%.多剂量po普通片和缓释片Cmin分别为(126.6±18.2)μg·L-1和(147.9±18.2)μg·L-1;Cmax分别为(307.9±24.1)μg·L-1和(275.2±26.8)μg·L-1;FI分别为(0.79±0.22)和(0.58±0.14).结论两种制剂生物等效.     

多剂量口服盐酸氨溴索缓释胶囊的人体药代动力学及相对生物利用度

目的　研究多剂量口服盐酸氨溴索缓释胶囊的人体药代动力学和相对生物利用度。方法　选择盐酸奎宁为定量内标物 ,采用反相高效液相色谱法测定了多剂量口服 75mg盐酸氨溴索国产缓释胶囊和进口缓释胶囊在健康人体内的盐酸氨溴索血药浓度 ,以考察盐酸氨溴索缓释胶囊多剂量口服达稳态过程和稳态药代动力学特征。结果　 75mg盐酸氨溴索缓释胶囊连续口服d 4起 ,体内盐酸氨溴索血药浓度基本达稳态水平。国产缓释胶囊和进口缓释胶囊的稳态药代动力学参数Tmax分别为 (4 2± 0 7)h和 (4 1± 0 8)h ,Cmax分别为 (2 0 8 73± 31 91) μg·L-1和 (2 12 5 6± 2 9 6 4) μg·L-1,Cmin分别为 30 76± 10 47μg·L-1和 (2 9 80± 10 2 3)μg·L-1,AUCss分别为 (2 113 90± 430 6 0 ) μg·h·L-1和2 0 88 2 2± 40 2 5 2 μg·h·L-1,Cav分别为 (88 0 8± 17 94) μg·L-1和 (87 0 1± 16 77) μg·L-1,DF分别为 (2 0 7± 0 31)和(2 16± 0 37) ,多剂量口服 75mg国产盐酸氨溴索缓释胶囊的相对生物利用度为 10 1 10 %± 6 33 %。结论　盐酸氨溴索国产缓释胶囊和进口缓释胶囊的主要稳态药代动力学参数差异均无显著性 ,两种制剂具有生物等效性     

别嘌醇缓释片人体药物动力学与生物等效性研究

目的　研究别嘌醇缓释片在健康受试者体内的药物动力学和生物等效性。方法　健康男性受试者单剂量或多剂量口服别嘌醇缓释片和普通片。用高效液相色谱法测定血浆中别嘌醇和氧别嘌醇浓度, 计算两药的药物动力学参数。结果　受试者口服单剂量别嘌醇缓释片和普通片后的别嘌醇 AUC0~12 分别为 (4. 58±1. 52) mg·h·L-1 和(4 43±1. 40) mg·h·L-1, tmax分别为 (2 .00±0. 41) h和 (1 .25±0 .41) h, cmax分别为 (1 .75±0 .49) mg·L-1和 (2. 06±0 .40) mg·h·L-1。氧别嘌醇 AUC0~72 分别为 (123. 94±23 .39) mg·h·L-1 和 (126. 52±27. 47)mg·h·L-1, tmax分别为 (6 .42±3. 47) h 和 (4. 18±1. 59) h, cmax 分别为 (3 .70±0 .52) mg·L-1 和 (3 99±0 61) mg·L-1。口服多剂量别嘌醇缓释片和普通片后的氧别嘌醇的稳态谷浓度 cmin分别为 (4. 41±0. 76) mg·L-1和 (4 07±0. 76) mg·L-1, 稳态峰浓度cmax分别为 (7. 33±1 .31) mg·L-1 和 (7 .31±1. 25) mg·L-1, tmax分别为 (2. 58±1. 44) h和 (5 .68±2 .03) h, 波动度 DF分别为 (0 .52±0 .18) 和 (0 .58±0 .13)。结论　每日 1次口服别嘌醇缓释片250 mg与每日2次口服普通片相同剂量在吸收程度上具有生物等效性。     

氢溴酸右美沙芬片健康人体生物等效性

目的 :研究氢溴酸右美沙芬片在健康人体的药动学及相对生物利用度。方法 :8名健康受试者单剂量随机交叉口服氢溴酸右美沙芬片参比制剂和被试制剂 6 0mg ,采用HPLC法测定用药后不同时间的血药浓度。结果 :2种制剂的体内过程均符合一房室开放模型 ,参比制剂和被试制剂的tmax分别为 (2 72± 0 2 1)h和 (2 74± 0 19)h ,cmax分别为 (5 5 1± 0 4 4) μg·L-1和(5 5 8± 0 2 7) μg·L-1,AUC分别为 (4 5 3± 2 9) μg·h·L-1和 (4 5 7± 3 0 ) μg·h·L-1,被试制剂的相对生物利用度为 (10 1±5 9) %。结论 :2种制剂具有生物等效性。     

国产双氯芬酸钠缓释栓与普通栓的生物等效性

目的 :研究国产双氯芬酸钠缓释栓和普通栓的生物等效性。方法 :2 0名健康志愿者随机分成 2组 ,采用双周期交叉试验设计 ,单剂量 (10 0mg)或多剂量连续给药 ,用HPLC法测定血浆中双氯芬酸钠的血药浓度。结果 :缓释栓和普通栓的主要药动学参数分别如下 :单剂量cmax为 (1 0 87± 0 2 98)、(1 2 0 2± 0 4 11)mg·L-1;tmax为 (1 6 92± 0 6 6 5 )、(1 10 8± 0 4 30 )h ;AUC0 -12为 (3 770± 1 2 2 3)、(3 2 34± 0 737)mg·h·L-1;T1/ 2 (ke) 为 (2 346± 0 5 77)、(2 132± 0 6 99)h ;平均相对生物利用度F0 -12 为(115 5± 19 8) %。多剂量cmax分别为 (1 370± 0 315 )、(1 6 4 1± 0 5 18)mg·L-1;cmin为 (0 10 3± 0 0 32 )、(0 0 76± 0 0 35 )mg·L-1;tmax为 (2 175± 0 6 5 4 )、(1 4 5 8± 0 4 5 8)h ;AUC0 -12 为 (5 4 5 9± 1 2 78)、(5 2 99± 0 96 4 )mg·h·L-1;血药浓度的波动度分别为(2 79 4 35± 4 7 0 4 1) %、(347 195± 71 6 5 5 ) %。经方差分析和双单侧t检验 ,2种制剂间AUC无显著性差异 (P >0 0 5 ) ;tmax(P <0 0 5 ) ,缓释栓达峰时间明显延长 ;多剂量缓释栓cmax小于普通栓 (P <0 0 5 )。结论 :2种制剂具有生物等效性 ,双氯芬酸钠缓释栓具有缓释特征     

国产替米沙坦片的人体生物等效性

目的　评价单剂量口服国产与进口替米沙坦片的人体药动学特性和生物等效性。方法　采用随机、交叉试验设计,2 0名男性健康志愿者单剂量口服80mg替米沙坦片,用HPLC -荧光检测法测定了体内替米沙坦的血药浓度。结果　口服国产和进口替米沙坦片的主要药动学参数分别为:T1/ 2 (2 0 9±6 5 4 )、(19 8±5 6 6 )h ;cmax(313 2±10 6 3)、(310 7±91 6 ) μg·L-1;tmax(0 98±0 35 )、(1 0 1±0 4 0 )h ;AUC0→48(14 98 0±5 72 2 )、(14 6 1 7±5 37 1) μg·h·L-1;AUC0→∞(1718 9±6 6 2 8)、(16 4 8 5±5 77 4 ) μg·h·L-1。经方差分析,国产与进口替米沙坦片主要药动学参数比较均无统计学意义。国产替米沙坦片的相对生物利用度为(10 2 8±13 4 ) % ,经双单侧t检验,2种制剂生物等效。结论　国产与进口替米沙坦片生物等效     

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.