头孢克肟咀嚼片与胶囊的相对生物利用度比较

目的 :比较头孢克肟咀嚼片与胶囊在健康人体内的相对生物利用度。方法 :反相高效液相色谱法测定 2 0例健康受试者随机交叉单剂量口服4 0 0mg头孢克肟咀嚼片以及胶囊后头孢克肟的血药浓度 ,3P87程序计算药动学参数 ,并对AUC ,Cmax进行方差分析及双单侧t检验。结果 :头孢克肟咀嚼片和胶囊的主要药动学参数分别为 :AUC0 ∞(2 9±s 10 ) ,(30± 9)mg·h·L- 1;AUC0 16 (2 8± 9) ,(2 8± 9)mg·h·L- 1;Tmax(4 .0± 0 .4 ) ,(4 .0± 0 .3)h ;Cmax(4 .8± 1.1) ,(4 .8± 1.1)mg·L- 1,T1/ 2(3.2± 0 .5 ) ,(3.0± 0 .4 )h ;MRT0 16 (5 .8± 0 .6 ) ,(5 .8± 0 .6 )h。以头孢克肟胶囊为参比 ,头孢克肟咀嚼片相对生物利用度F0 16 为 (98± 8) % ,F0 ∞ 为(98± 8) %。结论 :头孢克肟咀嚼片与胶囊具有生物等效性     

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     

国产亚叶酸钙片、胶囊与进口亚叶酸钙片的人体相对生物利用度比较

目的 :研究 3种亚叶酸钙制剂 (国产片剂、胶囊和进口片剂 )在 12名健康志愿者体内的相对生物利用度。方法 :同体交叉试验后 ,测定血浆中亚叶酸钙浓度 ,计算主要药物动力学参数和相对生物利用度 ,并进行统计学分析。结果 :国产片、胶囊和进口片单剂量 75mg ,po后 ,Tmax 分别为 ( 2 .5±s0 .3)h ,( 2 .5± 0 .3)h和 ( 2 .4± 0 .3)h ;Cmax为 ( 654± 146) μg·L- 1,( 599± 132 ) μg·L- 1和 ( 640± 163)μg·L- 1;AUC0～∞ 为 ( 7811± 1481) μg·h·L- 1,( 70 91± 1397) μg·h·L- 1和 ( 7898± 1855) μg·h·L- 1;T12 为 ( 8.7± 0 .6)h ,( 8.6± 0 .4 )h和 ( 8.6±0 .5)h。国产片、胶囊相对生物利用度分别为 ( 10 1± 14) % ,( 93± 11) %。结论 :3种制剂生物等效。     

多西环素肠溶微粒胶囊与片剂的人体生物等效性

目的 :研究多西环素肠溶微粒胶囊和多西环素片的人体生物等效性与药动学。方法 :2 0名男性健康志愿者随机分 2组 ,按双周期交叉口服单剂量 2 0 0mg多西环素的 2种制剂 ,分别于服药前及服药后 0 5 ,1,1 5 ,2 ,2 5 ,3,4,6 ,8,12 ,2 4,48,72h取血样 ,以HPLC法测定血浆中多西环素浓度 ,计算 2种制剂相对生物利用度参数 ,并评价其生物等效性。结果 :口服受试制剂多西环素肠溶微粒胶囊和参比制剂多西环素片的药动学参数 :cmax分别为 (3 6 5± 0 81) μg·mL-1和 (3 6 5± 0 73) μg·mL-1,tmax分别为 (2 5± 0 3)h和 (2 2± 0 7)h ,T1/ 2 (消除半衰期 )分别为 (2 1 4 8± 3 2 0 )h和 (2 1 85± 3 11)h ,AUC0→ 72 分别为 (72 18±2 2 6 8) μg·h·mL-1和 (72 0 6± 2 1 0 8) μg·h·mL-1,AUC0→∞ 分别为 (81 4 4± 2 4 94) μg·h·mL-1和 (81 82± 2 3 19) μg·h·mL-1,多西环素肠溶微粒胶囊相对生物利用度为 (10 1 9± 2 5 2 ) %,对参数cmax,AUC0→ 72 先进行方差分析 ,再进行双单侧t检验 ,表明 2种制剂的参数生物等效 ,tmax经非参数检验表明无统计学差异。结论 :多西环素肠溶微胶囊和多西环素片具有生物等效性。     

国产盐酸尼卡地平缓释胶囊人体药代动力学及生物利用度

目的　比较国产和进口盐酸尼卡地平 (Nic)缓释胶囊的药代动力学及生物利用度。方法　选择 12名健康志愿者随机交叉单剂量及多剂量口服两种Nic缓释胶囊 ,采用GC ECD检测 ,内标法定量测定其血药浓度。结果　两种缓释胶囊空腹给药 ,其单剂量及多剂量达稳态后经时血药浓度均呈双峰曲线 ,国产胶囊单剂量给药的主要参数 :Cmax1( 14 2± 8 2 ) μg·L-1,Cmax2 ( 16 9± 5 8) μg·L-1,Tmax1( 0 79±0 45 )h ,Tmax2 ( 5 0 8± 0 79)h ,T1/2Ke( 5 49± 2 5 3)h ,AUC0～ 2 4 ( 97 9± 2 4 8) μg·h·L-1。多剂量给药的主要参数 :Cmax( 36 7± 6 1) μg·L-1,Cmin( 7 3± 1 6 ) μg·L-1,Cav( 18 9± 3 2 ) μg·L-1,FI( 1 5 6± 0 2 6 ) ,AUC0～ 36( 341 4±48 5 ) μg·h·L-1。国产Nic缓释胶囊单剂量及多剂量给药与进口制剂比较的相对生物利用度各为 97 5 %± 19 3 %和98 2 %± 16 5 %。结论　方差分析及双单侧t检验表明 ,两种制剂具有生物等效性     

两种硝酸异山梨醇酯缓释胶囊的人体药动学比较

目的 :选择 12名男性健康志愿者 ,进行单剂量口服硝酸异山梨醇酯缓释胶囊的人体药动学研究。方法 :采用毛细管气相色谱法 ,测定单剂量口服 4 0mg国产与进口硝酸异山梨醇酯缓释胶囊在健康人体内的硝酸异山梨醇酯浓度。结果 :硝酸异山梨醇酯缓释胶囊的体内动态过程呈一级吸收的二房室开放模型 ,国产与进口缓释胶囊的Cmax分别为 (2 3.6± 6 .2 ) μg·L-1和 (2 3.7± 5 .1) μg·L-1,tmax分别为 (3.3± 0 .6 )h和 (3.8± 0 .6 )h ,MRT分别为 (9.1± 0 .8)h和 (9.1± 0 .7)h ,t1/ 2 分别为 (8.2± 1.0 )h和 (8.1± 0 .9)h ,AUC0～ 2 4分别为 (12 6 .3± 15 .4 ) μg·h·L-1和 (12 4 .0± 14 .1) μg·h·L-1,AUC0→∞ 分别为 (139.4±14 .8) μg·h·L-1和 (136 .7± 13.8) μg·h·L-1。结论 :国产与进口硝酸异山梨醇酯缓释胶囊具有相似的人体药动学特征     

双氯芬酸钠迟效制剂的药动学

目的 :以双氯芬酸钠普通肠溶片 (R)为对照 ,比较国产双氯芬酸钠迟效制剂 (T)的相对生物利用度和药动学。方法 :采用双交叉、自身对照的方法 ,将 2 4名受试者分为 2组 ,单剂量组分别口服T和R各 10 0mg ;多剂量组 ,每日分别口服T和R各10 0mg ,共 4d。结果 :单剂量组T和R的Cmax,Tmax,T1/2 ,MRT ,AUC0～τ分别为 (115 6±s 36 1)和(3910± 96 8) μg·L- 1,(3.0± 1.0 )和 (2 .3± 0 .5 )h ,(6 .6± 2 .3)和 (2 .9± 1.5 )h ,(12 .3± 2 .3)和 (4.4±1.0 )h ,(92 37± 994 )和 (874 5± 12 16 ) μg·h·L- 1,T的F为 (10 7± 12 ) %。多剂量口服T和R的Cav,FI分别为 (343± 4 6 ) μg·L- 1和 (333± 6 4) μg·L- 1,(2 5 4± 82 ) %和 (40 4± 97) %。结论 :2种制剂口服吸收相似 ,迟效制剂具有峰谷浓度差异小 ,血药浓度波动幅度小等缓释药动学特征。     

国产和进口单硝酸异山梨酯缓释胶囊单次和多次给药的人体药动学(英文)

目的 :比较国产和进口单硝酸异山梨酯缓释胶囊的人体药动学和相对生物利用度。方法 :采用单次和多次给药的 4周期双交叉设计 ,气相色谱 电子捕获检测法 (GC ECD)测定 2 2名健康男性志愿者血浆中单硝酸异山梨酯的浓度。结果 :单次 (2 5mg)口服国产和进口单硝酸异山梨酯缓释胶囊后的药动学参数分别为 :Tmax为 (5 .7±s 0 .5 )h和 (5 .8±1 .0 )h ,Cmax为 (2 3 6± 62 ) μg·L-1和 (2 42± 62 )μg·L-1,T1/ 2 为 (8.3± 1 .6)h和 (8.4± 2 .1 )h ,AUC0 3 6为 (3 .7± 0 .9)mg·h·L-1和 (3 .6±0 .9)mg·h·L-1,AUC0 ∞ 为 (4 .0± 0 .9)mg·h·L-1和 (3 .8± 0 .8)mg·h·L-1,平均滞留时间MRT为 (1 1 .5±0 .8)h和 (1 1 .4± 0 .7)h。多次 (2 5mg,6d)口服国产和进口单硝酸异山梨酯缓释胶囊后的稳态药动学参数分别为 :Tmax 为 (5 .2± 0 .7)h和 (5 .4±0 .9)h,Cmax为(3 1 4± 67) μg·L-1和 (3 1 0± 5 8) μg·L-1,Cmin为(63± 1 4) μg·L-1和 (65± 1 6) μg·L-1,稳态血药浓度均值Cav为 (1 87± 3 8) μg·L-1和 (1 83± 3 8) μg·L-1,AUC0 3 6h为 (5 .0± 1 .0 )mg·h·L-1和 (4 .9± 1 .0 )mg·h·L-1,波动度DF为 (1 3 4± 2 0 )%和 (1 3 4± 1 8) %。单次和多次口服国产与进口单硝酸异山梨酯     

3种伊曲康唑胶囊的人体相对生物利用度

目的 :比较 3种市售伊曲康唑胶囊的生物等效性 ,为临床合理用药提供参考。方法 :15名健康男性受试者 ,随机分为3组 ,采用 3制剂、3周期的拉丁方设计 ,单剂量口服 2 0 0mg伊曲康唑后 ,采用HPLC法测定血浆药物浓度。cmax,tmax采用实测值 ,AUC用梯形法计算 ,并用双单侧t检验评价 3种制剂之间的生物等效性。结果 :口服制剂A ,B和参比制剂后的cmax分别为(197± 92 ) ,(2 16± 76 ) ,(2 72± 10 9) μg·L-1;tmax分别为 (4 17± 1 2 5 ) ,(4 2 7± 1 16 ) ,(4 0 0± 1 0 7)h ;T1/2 为 (2 5 2± 4 9) ,(2 4 6±5 5 ) ,(2 4 9± 3 9)h ;AUC0→ 72h分别为 (32 31± 1195 ) ,(30 38± 980 ) ,(4 2 97± 12 99) μg·h·L-1。制剂A ,B相对参比制剂的生物利用度分别为 (75 2 1± 9 18) %和 (71 72± 14 2 1) %。结论 :制剂A ,B与参比制剂的AUC ,cmax,均有显著性差异 (P <0 0 5 ) ;双单侧t检验结果显示A ,B制剂和参比制剂生物不等效     

HPLC法测定血浆中奥美拉唑及其人体药动学研究

目的建立测定血浆中奥美拉唑的HPLC法 ,并对其进行药代动力学研究。方法以CapcellPak C18柱 ,(4 6mm× 15 0mm ,5 μm,SHISEIDOFINECHEMICALS ,日本 )为色谱柱 ,以乙腈 0 0 5mol·L-1磷酸二氢铵 (V∶V =35∶6 5 )为流动相 ,测定了 18名健康男性志愿受试者单剂量口服奥美拉唑胶囊后的不同时刻血浆中奥美拉唑的质量浓度 ,并根据测定结果求算奥美拉唑的药代动力学参数。结果 18名健康受试者口服奥美拉唑胶囊后 ,血浆中的tmax为 (2 3± 0 8)h ;ρmax为(10 5 0 0± 396 0 ) μg·L-1;t1/ 2 为 (1 3± 0 5 )h ;AUC0 -10 为 (32 4 8 9± 2 15 2 1) μg·h·L-1;AUC0 -∞ 为 (3393 9± 2 342 6 ) μg·h·L-1。结论该方法适合临床药代动力学研究     

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.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

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.

---

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.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.