克林霉素局部给药与口服给药药动学比较研究

目的:研究克林霉素磷酸酯阴道凝胶局部给药与盐酸克林霉素片口服给药后克林霉素药动学特征,并进行比较。方法:10名健康女性志愿者单剂量阴道局部给予克林霉素磷酸酯阴道凝胶5g(相当于克林霉素100mg),1mo后志愿者单剂量口服盐酸克林霉素片150mg,分别用液/质联用法检测血清中克林霉素的浓度,并经DAS药动学程序进行数据处理,计算药动学参数。结果:克林霉素磷酸酯阴道凝胶与盐酸克林霉素片的t1/2分别为(15.30±2.62)、(3.64±0.78)h,tm ax分别为(4.88±0.94)、(1.00±0.33)h,Cm ax分别为(38.30±22.77)、(1 334.13±535.91)ng.mL-1,AUC0~48为(686.62±316.73)、(3 357.70±1 013.32)ng.h.mL-1,AUC0~∞为(783.45±351.19)、(3 393.33±1 037.40)ng.h.mL-1。克林霉素磷酸酯阴道凝胶阴道局部给药相对于盐酸克林霉素片的生物利用度为(29.5±6.8)%。结论:克林霉素磷酸酯阴道凝胶阴道局部给药后克林霉素主要滞留于阴道局部,能更好地发挥局部治疗作用,更安全。     

阿奇霉素软胶囊在健康志愿者的药代动力学与相对生物利用度

目的建立人血浆中阿奇霉素(大环内酯类抗生素)的高效液相色谱-质谱测定方法,用于研究阿奇霉素软胶囊在人体的药代动力学及相对生物利用度。方法18例健康男性志愿者单剂量口服阿奇霉素软胶囊受试制剂或参比制剂500mg后,用建立的方法测定阿奇霉素的血药浓度,用3P97药代动力学软件求算药代动力学参数,以双单侧t检验进行生物等效性评价。结果受试制剂与参比制剂的主要药代动力学参数:Cmax分别为(676.6±283.1),(663.4±298.3)ng·mL-1;tmax分别为(1.9±0.5),(2.0±0.6)h;t1/2分别为(50.4±14.3),(49.1±14.5)h;AUC0-144分别为(5025.1±881.9),(4857.5±946.8)ng·h·mL-1;AUC0-∞分别为(5827.3±898.0),(5638.9±998.5)ng·h·mL-1。相对生物利用度为F0-144=(105.8±22.8)%。结论2制剂为生物等效制剂。     

氯沙坦及其代谢物在维吾尔族和汉族健康志愿者的药代动力学

目的 研究维吾尔族和汉族健康受试者单剂量口服氯沙坦钾片(抗高血压药)的药代动力学特征.方法 20名健康受试者(其中维吾尔族10名,汉族10名,男女各半),单剂量口服氯沙坦钾片50 mg;用高效液相色谱-荧光法测定氯沙坦及其代谢物E-3174血药浓度,用DAS软件进行数据处理、SPSS 13.0软件进行统计学分析.结果 维吾尔族受试者单剂量口服氯沙坦钾片50 mg后氯沙坦和代谢物E-3174的主要药代动力学参数分别为:Cmax(344±153),(477±166)μg·mL-1;tmax(1.0±0.3),(2.6±0.5)h;t1/2(1.0±0.4),(2.9±0.8)h;AUG0-24h(598±216),(2243±518)μg·h·mL-1;AUC0-∞(632±242),(2429±552)μg.h·mL-1.汉族受试者单剂量口服氯沙坦钾片50 mg后氯沙坦和代谢物E-3174的主要药代动力学参数分别为:Cmax(351±168),(242±60)ng·mL-1;tmax(1.4±1.1),(3.6±1.7)h;t1/2(0.8±0.4),(4.7±1.1)h;AUC0-24h(497±172),(1853±194)ng·h·mL-1;AUC0-∞(523±184),(1960±182)ng·h·mL-1.结论 氯沙坦的代谢物E-3174的药代动力学参数t1/2、Vd、Cmax在维吾尔族和汉族健康受试者间的差异有显著性意义(P＜0.05),不同性别间药代动力学参数的差异无显著性意义(P＞0.05),所有药代动力学参数在同一民族和不同民族的个体间差异都很大,临床治疗中应实行个体化给药方案.     

国产雷米普利胶囊在健康人体的药代动力学和相对生物利用度

目的研究健康受试者口服雷米普利胶囊(抗高血压药)的药代动力学和相对生物利用度。方法20名健康受试者随机服用雷米普利受试和参比制剂各10mg,用HPLC-MS/MS法测定血浆中雷米普利和雷米普利拉的浓度。结果主要药代动力学参数,试验与参比制剂中雷米普利的tmax分别为(0.60±0.17),(0.63±0.25)h;Cmax分别为(40.11±14.48),(41.78±13.18)ng·mL-1;t1/2分别为(2.75±1.36),(2.28±1.28)h;AUC0-12分别为(42.09±11.22),(41.81±12.89)ng·h·mL-1;试验制剂的相对生物利用度为(101.47±16.02)%。试验与参比制剂中雷米普利拉的tmax分别为(2.70±0.47),(2.60±0.60)h;Cmax分别为(42.02±12.53),(41.80±14.65)ng·mL-1;t1/2分别为(17.99±6.28),(18.51±5.81)h;AUC0-72分别为(310.65±91.42),(310.21±102.74)ng·h·mL-1。试验制剂的相对生物利用度为(101.09±15.28)%。结论参比与试验制剂具有生物等效性。     

甲硝唑结肠定位肠溶片在健康人体的药代动力学和生物等效性

目的评价甲硝唑结肠定位肠溶片(抗厌氧菌感染药)在健康人体的药代动力学和相对生物利用度。方法20名男性健康志愿者分别单剂、多剂交叉口服甲硝唑结肠定位肠溶片(受试制剂)和甲硝唑普通片(参比制剂)200mg,HPLC法测定甲硝唑浓度,DAS2.1软件计算主要药代动力学参数。结果主要药代动力学参数如下。单剂量:Cmax分别为(3.05±0.63),(4.44±0.56)μg·mL-1;tmax分别为(9.10±1.90),(1.50±0.60)h;t1/2分别为(9.93±2.14),(9.36±2.40)h;AUC0-48h分别为(48.74±11.56),(53.79±9.25)μg·h·mL-1;F为(91.30±18.60)%。多剂量:Cmax分别为(7.75±2.57),(10.27±2.08)μg·mL-1;Cmin(6.86±2.36),(6.34±1.48)μg·mL-1;Cav分别为(4.83±1.66),(7.65±1.59)μg·mL-1;DF分别为(0.31±1.26),(0.52±0.10);t1/2分别为(10.51±2.39),(9.97±2.40)h,AUCss分别为(38.65±13.30),(61.23±12.71)μg·h·mL-1,AUC0-48h分别为(158.23±66.84),(144.39±48.50)μg·h·mL-1,F为(110.10±25.20)%。结论2制剂吸收等效;但在胃肠道的吸收部位与速度不同;有良好的靶向结肠定位效果。     

丁苯酞及其代谢物在中国健康人体的药代动力学

目的 评价丁苯酞软胶囊在中国健康人体的药代动力学.方法 12名中国健康受试者单次空腹口服丁苯酞软胶囊200 mg,用液相色谱-串联质谱法测定血浆样本中丁苯酞(NBP)和丁苯酞代谢物1(NBP-M1)的浓度;用Phoenix WinNolin计算药代动力学参数.结果 NBP和NBP-M1的主要药代动力学参数,t1/2分别为(10.35 ±0.79),(3.69±0.93)h;tmax分别为(1.23±0.73),(1.90±0.76)h;Cmax分别为(196.95±165.2),(1174.29±322.33) ng·mL-1;AUCo-t分别为(360.92±342.8),(5918.10±1627.51)h·ng·mL-1;CL/F分别为(977.03±664.06),(35.82±10.39) L·h-1.结论 丁苯酞口服吸收迅速,除原型物外,体内还可检测出较大浓度的代谢物.     

吡罗昔康贴片在中国健康志愿者的药代动力学

目的研究吡罗昔康贴片在中国健康志愿者的药代动力学。方法按平行设计方法,健康受试者33例,随机分为3组,分别单次贴吡罗昔康贴片48,96和144mg后,用高效液相色谱法测定血液中吡罗昔康浓度,用DAS软件进行数据处理,计算药代动力学参数。结果在给药72h后,各剂量组吡罗昔康吸收总量分别为(3.74±1.66),(7.47±2.49),(10.57±4.03)mg;主要药代动力学参数Cmax分别为(34.57±8.01),(57.89±13.84),(90.99±20.77)ng·mL-1;AUC0-∞分别为(4.06±0.71),(6.88±2.35),(9.95±2.81)μg·h·mL-1;tmax分别为(48.64±16.35),(46.91±15.37),(50.27±14.91)h;t1/2分别为(57.74±23.27),(58.63±16.73),(58.91±20.23)h;3组药代动力学参数经方差分析差异无统计学意义。结论在48~144mg内,吡罗昔康贴片具有线性动力学特征,和口服吡罗昔康相比,吡罗昔康贴片具备经皮给药系统的特征。     

氯沙坦及其代谢物在朝鲜族和汉族健康人体内的药代动力学

目的:研究朝鲜族和汉族健康受试者口服单剂量氯沙坦钾片的药代动力学.方法:健康受试者20名(朝鲜族10名,汉族10名,男女各半),口服单剂量氯沙坦钾片剂50mg;用HPLC-荧光法测定氯沙坦及其代谢物E-3174血药浓度,采用DAS软件和SPSS软件进行数据处理和统计学分析.结果:单剂量口服50 mg氯沙坦钾片后,朝鲜族受试者的氯沙坦和E-3174的主要药动学参数如下:Cmax分别为(524±349),(493±188)ng·mL-1;tmax分别为(0.9±0.4),(2.4±0.8)h;t1/2(1.5±0.4),(3.1±0.7)h;AUC0-24分别为(682±319),(2563±752) ng·h·mL-1;AUC0-∞分别为(752±331),(2608±766)ng·h·mL-1.汉族受试者的氯沙坦和E-3174的主要药动学参数如下:Gmax分别为(351±168),(242±60)ng·mL-1;tmax分别为(1.4±1.1),(3.6±1.7)h;t1/2分别为(0.8±0.4),(4.7±1.1)h;AUC0-24分别为(498±172),(1853±194) ng·h·mL-1;AUC0-∞分别为( 523±184),(1960±182) ng-h·mL-1.结论:氯沙坦钾片在朝鲜族和汉族健康受试者体内药动学参数差异存在统计学意义,在不同性别间药动学参数差异无统计学意义,个体间药动学参数存在较大差异,临床治疗中应实行个体化给药方案.     

洛伐他汀胶囊在健康人体的生物等效性研究

目的:考察两种洛伐他汀胶囊在健康人体的生物等效性.方法:20名健康男性志愿者单剂量口服试验制剂或参比制剂,采用LC/MS/MS法测定全血中药物浓度,用DAS2.1软件计算药代动力学参数.结果:试验制剂和参比制剂的主要药代动力学参数如下:t1/2分别为(4.67±2.34),(5.30±2.62)h;tmax分别为(1.90±0.50),(2.13±0.39)h;Cmax分别为(8.37±0.84),(8.29±1.00)ng·mL-1;AUC0-t分别为(32.25±6.49),(32.71±7.59)ng.h·mL-1;AUC0-∞分别为(33.62±6.94),(34.71±8.62)ng·h·mL-1.试验制剂的相对生物利用度F=(99.60±8.30)%.结论:受试制剂和参比制剂具有生物等效性.     

扎鲁司特胶囊在健康人体的生物等效性

目的评价扎鲁司特胶囊与扎鲁司特片(均平喘药)在健康人体内的生物等效性。方法 20名健康男性志愿受试者随机分为2组,用双周期自身交叉、单剂量口服扎鲁司特胶囊(受试制剂)和扎鲁司特片(参比制剂)各20 mg后,用HPLC/MS-MS法测定扎鲁司特的血浆浓度,并计算药代动力学参数。结果受试制剂和参比制剂的主要药代动力学参数:tmax分别为(1.50±0.76),(1.63±0.48)h;Cmax分别为(505.34±208.73),(449.62±191.80)ng·mL-1;t1/2分别为(7.60±4.87),(7.36±4.50)h;AUC0-48分别为(1362±534),(1260±581)ng·h·mL-1;AUC0-∞分别为(1371±537),(1268±588)ng·h·mL-1。受试制剂的相对生物利用度为(113.6±29.7)%。结论扎鲁司特胶囊与扎鲁司特片具有生物等效性。     

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.