甲磺酸酚妥拉明口腔崩解片在健康人体的药代动力学和生物等效性

目的 研究甲磺酸酚妥拉明(抗男性勃起功能障碍药)口腔崩解片和分散片在健康人体的药代动力学及生物等效性.方法 20名健康志愿者随机双交叉、单剂量口服受试制剂和参比制剂,剂量均为40 mg,剂间间隔为1周,用反相高效液相色谱-紫外检测法测定血浆中甲磺酸酚妥拉明浓度,用DAS药代动力学程序计算有关药代动力学参数、相对生物利用度,并评价2种制剂生物等效性.结果 受试与参比制剂的药代动力学参数tmax分别为(0.69±0.20)和(0.81±0.32)h,t1/2分别为(4.99±1.48)和(4.41±1.73)h,Cmax分别为(34.50±8.79)和(35.17±11.19)mg·L-1,AUC0-t分别为(100.30±23.14)和(99.95±27.51)mg·h·L-1,AUC0-∞分别为(104.81±23.46)和(104.85±28.61)mg·h·L-1.甲磺酸酚妥拉明的相对生物利用度为(103.10±20.60)%.结论 2种制剂具有生物等效性.     

莫西沙星的药物动力学

莫西沙星口服后吸收迅速、良好 ,口服 4 0 0 mg后 ,绝对生物利用度约为 86 % ,2 h内达到平均血药峰浓度3.5 6 mg/ L。典型的 4 0 0 mg/ d疗程 10 d疗法 ,在第 10天血药峰浓度为 4 .5 2 mg/ L,于 1.2 4 h达峰。口服 5 0、10 0、2 0 0、4 0 0、6 0 0和 80 0 mg莫西沙星 ,达血药峰浓度(Cmax)的时间范围是 0 .5～ 4 h,血药峰浓度从 5 0 mg剂量的 0 .2 9mg/ L到 80 0 mg剂量的 4 .73mg/ L。进食或胃 p H升高不会明显影响吸收速率和程度。一般而言 ,莫西沙星的分布体积大 ,蛋白质结合率相对较低 ,对大多数组织和液体腔隙的渗透良好 ,在大多数组…     

单次口服甲磺酸酚妥拉明片耐受性试验

目的在中国男性健康志愿者中评价单次口服Ⅳ+V类新药甲磺酸酚妥拉明片的安全性、耐受性.方法根据新药临床试验指导原则设计试验方案,并获得解放军总医院医学伦理委员会审查通过.按照赫尔辛基宣言和GCP指导原则,试验前由研究人员向受试者解释研究性质、目的、风险及其权益,受试者须自愿签署知情同意书.选择18～50岁健康成人,经体检及实验室检查,各项指标均在正常范围内方可入选.用区组随机化设计方法,按随机表将36名受试者随机分配至10mg、20mg、30mg、40mg、50mg和60mg剂量组,每组6名受试者.观察指标为临床症状、生命体征、心电图、血常规、尿常规、肝功能、肾功能、电解质等.结果单次口服10mg～60mg甲磺酸酚妥拉明片,志愿者体温、脉搏、呼吸频事、卧立位血压、心电图、血常规、肝功能、肾功能、电解质等各项指标测定值均在正常范围内,仅见面部潮红、鼻塞、头晕头痛或脉率增快(20例)等与药物可能有关的一过性轻微不良反应.9例志愿者在给药后20～30分钟后发生阴茎勃起现象,约持续5分钟左右.结论36名中国男性健康受试者单次口服甲磺酸酚妥拉明片最大剂量至60mg比较安全,耐受性较好.     

来氟米特人体耐受性试验研究

目的 研究正常国人对来氟米特（Leflunomide,Lef)的耐受程度。方法 选择22名健康志愿,男11人,女11人,按男女随机分成4组,每组男女各半,每组人数分别为4、6、6、6人,按从低到高递增的顺序10、20、40、80mg,单次口服Lef,观察给药前、给药后1h、24h和48h各种不良反应和试验前后的血尿常规及肝肾功能。结果 Lef(10-80)各剂量组试验中,志愿均无明显不良反应,试验前后血尿常规及肝肾功能无显性变化。结论 22名健康志愿口服Lef(10-80mg)均能很好在耐受,Ⅱ期临床试验可以参考此剂量范围选择临床试验剂量。     

中国健康男性志愿者单次口服甲磺酸酚妥拉明片耐受性研究

目的：在中国男性健康志愿中评价单次口服Ⅳ＋Ⅴ类新药甲磺酸酚妥拉明片的安全性、耐受性。方法：根据新药临床试验指导原则设计试验方案，按照赫尔辛基宣言和GCP指导原则，选择18－50岁健康成人，用区组随机化设计方法，按随机表将36名受试随机分配至10、20、30、40、50和60mg剂量组，每组6名受试。观察指标为临床症状、生命体征、心电图、血常规、尿常规、肝功能、肾功能、电解质等。结果：单次口服10-60mg甲磺酸酚妥拉明片，志愿体温、脉搏、呼吸频率、卧立位血压、心电图、血常规、肝功能、肾功能、电解质等各项指标测定值均在正常范围内，仅见面部潮红、鼻塞、头晕头痛或脉率增快（20例）等与药物可能有关的一过性轻微不良反应。9例志愿在给药后20-30min后发生阴茎勃起现象，约持续5min左右。结论：36名中国男性健康受试单次口服甲磺酸酚妥拉明片最大剂量至60mg比较安全、耐受性较好。     

静脉应用负荷剂量抗癫痫药物的安全性

目的探讨静脉给予负荷剂量抗癫痫药物(AED)治疗成人全面惊厥性癫痫持续状态(GCSE)的安全性。方法采用合并数据的方法收集首都医科大学宣武医院2007年1月至2010年1月和2011年6月至2012年5月进行的2项前瞻性随机对照试验(RCT)的结果,分析比较地西泮组、地西泮后续丙戊酸组和地西泮后续苯巴比妥组患者的临床数据。3组患者一线AED治疗均为静脉注射负荷剂量地西泮(0.2 mg/kg,5 mg/min)。二线AED治疗方案:地西泮组为静脉注射负荷剂量地西泮(0.2 mg/kg,5 mg/min)后继续静脉泵注维持量地西泮(4 mg/h,每3分钟增加1μg/kg),地西泮后续丙戊酸组为静脉注射负荷剂量丙戊酸[30 mg/kg,6 mg/(kg·min)]后继续静脉泵注维持量丙戊酸[1～2 mg/(kg·h)],地西泮后续苯巴比妥组为静脉注射负荷剂量苯巴比妥(20 mg/kg,50 mg/min)后继续静脉注射维持量苯巴比妥(100 mg/6 h,50 mg/min),治疗持续至癫痫发作终止后24 h,以后逐渐减量。严密监测患者用药后反应。结果 101例患者纳入研究,男性53例,女性48例;平均年龄(42±16)岁。地西泮组男性20例,女性18例,平均年龄(41±19)岁;地西泮后续丙戊酸组男性22例,女性18例,平均年龄(45±15)岁;地西泮后续苯巴比妥组男性11例,女性12例,平均年龄(41±14)岁。3组患者基线资料差异无统计学意义。地西泮组、地西泮后续丙戊酸组和地西泮后续苯巴比妥组GCSE终止率分别为63.2%(24/38)、57.5%(23/40)和60.9%(14/23),差异无统计学意义(P=0.902)。地西泮组6例(15.8%)出现不良反应,其中呼吸抑制、循环抑制和骨髓抑制分别为2、3和1例;地西泮后续丙戊酸组11例(27.5%)出现不良反应,其中不伴高血氨脑病的轻度血氨升高、轻度肝功能异常和骨髓抑制分别为8、2和1例;地西泮后续苯巴比妥组11例(47.8%)出现不良反应,其中呼吸抑制、循环抑制、轻度肝功能异常和骨髓抑制分别为3、2、5和1例。地西泮组不良反应发生率明显低于地西泮后续苯巴比妥组(P=0.033)。上述不良反应经停药与对症治疗后均可消除。结论静脉给予负荷剂量地西泮或丙戊酸或苯巴比妥治疗成人GCSE均安全有效。用药过程中应密切监测患者的不良反应,特别是对地西泮与苯巴比妥联用的患者。一旦出现不良反应,应及时停药并予以对症治疗。     

甲磺酸加替沙星片在健康志愿者体内的药动学

目的 :研究健康志愿者口服甲磺酸加替沙星片后的药动学特征 ,为临床安全、合理用药提供参考依据。方法 :18名健康男性单剂量口服甲磺酸加替沙星片 4 0 0mg ,以高效液相色谱法测定服药后 2 4h内的血药浓度 ,计算其药动学参数。结果 :甲磺酸加替沙星片在健康人体内的处置符合一级吸收的一室代谢模型 ,主要药动学参数Tmax,Cmax,T12 β,AUC( 0 2 4 ) 分别为 :(1.5±s 0 .4 )h ,(3.4± 1.0 )mg·L- 1,(6 .6± 1.0 )h ,(33± 10 )mg·h·L- 1。结论 :甲磺酸加替沙星在人体内的药动学特征与文献报道的盐酸加替沙星相似 ,口服吸收快 ,生物利用度高、体内平均滞留时间长 ,且存在个体差异。     

人血浆中氟康唑的LC-MS/MS法测定及药动学

建立了LC-MS/MS法测定人血浆中的氟康唑(1).采用C18色谱柱,以甲磺酸酚妥拉明(2)为内标,2 mmol/L乙酸铵溶液(含0.05%甲酸)-甲醇(40:60)为流动相,电喷雾离子化源,选择性正离子多反应监测,检测离子分别为m/z 307.2→238.2(1)和m/z 282.2→212.2(2).1在0.03～10 μg/ml浓度范围内线性关系良好,方法回收率大于94%,提取回收率大于90%,日内和日间RSD均小于5.4%.20名男性健康志愿者单剂量口服1片150 mg,主要药动学参数为Cmax(3.26±0.54)μg/ml,tmax(1.42±0.65)h,t1/2(29.75±4.89)h,AUC0→120 h(131.4±23.4) μg·ml-1·h和AUC0→∞(140.5±26.3) μg·ml-1·h.     

瑞波西汀在中国男性健康志愿者体内的药动学研究

目的:考察瑞波西汀在中国男性健康志愿者体内的药动学特点.方法:14例男性健康志愿者单次口服每片含4 mg(R*,R*)-(±)瑞波西汀的甲磺酸瑞波西汀1片,服药前及服药后0.5,1,1.5,2,2.5,3,6,12,24,36,48,60和72 h采取静脉血5 mL,肝素抗凝.给药后各时间点血浆中瑞波西汀的浓度采用高效液相色谱紫外检测法,以210nm波长测定.采用DAS药动学程序求算药动学参数.结果:单次口服甲磺酸瑞波西汀片后,瑞波西汀的血药浓度-时间曲线符合一室模型,主要药动学参数Cmax为(116.91±25.08)ng·mL-1,Tmax为(1.57±0.62)h,t1/2为(12.91±3.32)h,AUC0～72 h为(2 137.27±1 085.93)ng·h·mL-1,AUC0～∞为(2 145.37±1 087.65)ng·h·mL-1,表观分布容积Vd为(36.00±7.16)L,清除率CL/F为(2.12±0.85)L·h-1.受试者服药后的心率和血压有轻度增加,但无心悸的主诉.出现的其他不良反应有恶心、出汗、头晕、排尿不畅、困倦等.这些不良反应均为轻度,无须治疗,可自行缓解.结论:瑞波西汀在中国男性健康志愿者体内的药动学过程与国外文献报道相当.健康志愿者单次口服瑞波西汀4 mg的不良反应轻,耐受性良好.     

甲磺酸左氧氟沙星与左氧氟沙星临床验证比较

目的 :比较甲磺酸左氧氟沙星与左氧氟沙星治疗细菌性感染的有效性和安全性。方法 :采用随机对照试验将 12 6例细菌性感染病人分为甲磺酸左氧氟沙星组和左氧氟沙星组 ,其中甲磺酸左氧氟沙星组 6 3例 ,男性 30例 ,女性 33例 ,年龄 ( 41±s6 )a;左氧氟沙星组 6 3例 ,男性 36例 ,女性 2 7例 ,年龄 ( 40± 9)a。2组分别给予甲磺酸左氧氟沙星片和左氧氟沙星片各 10 0mg ,po,tid ,疗程 7～ 14d。结果 :2组临床总有效率分别为 89% ( 56 /6 3)和 84 %( 53/6 3) ,细菌清除率分别为 89%和 89% ,不良反应发生率分别为 2 1% ( 13/6 3)和 18% ( 11/6 3) ,经统计学处理均差异无显著意义 (P >0 .0 5)。结论 :甲磺酸左氧氟沙星和左氧氟沙星治疗细菌性感染安全、有效     

Stability of papaverine hydrochloride and phentolamine mesylate in injectable mixtures

The stability of papaverine hydrochloride and phentolamine mesylate combined in a single vial was studied. Injectable mixtures (10 mL) of papaverine hydrochloride 300 mg and phentolamine mesylate 5 mg (from two sources) were prepared by adding the contents of one vial of lyophilized phentolamine mesylate to the contents of one vial of papaverine hydrochloride injection. The vials were stored at 5 degrees C and 25 degrees C. Duplicate aliquots of the mixtures were obtained, and the concentrations of papaverine hydrochloride and phentolamine mesylate remaining at time 0 and after 1, 2, 5, 10, 20, and 30 days were determined in triplicate by a stability-indicating high-performance liquid chromatographic assay. The concentration of papaverine hydrochloride stored in the vials remained constant (less than 1% loss) over the 30-day period at both 5 degrees C and 25 degrees C. Phentolamine mesylate was less stable than papaverine but still retained more than 97% of its original concentration after 30 days at 5 degrees C and more than 95% of its original concentration at 25 degrees C. Papaverine hydrochloride and phentolamine mesylate are stable in injectable mixtures when stored for up to 30 days at 5 degrees C or 25 degrees C.     

The effects of ritonavir and lopinavir/ritonavir on the pharmacokinetics of a novel CCR5 antagonist, aplaviroc, in healthy subjects

AIMS: This study assessed the effects of the CYP3A inhibitors lopinavir/ritonavir (LPV/r) on the steady-state pharmacokinetics (PK) of aplaviroc (APL), a CYP3A4 substrate, in healthy subjects. METHODS: In Part 1, APL PK was determined in eight subjects who received a single oral 50-mg APL test dose with/without a single dose of 100 mg ritonavir (RTV). Part 2 was conducted as an open-label, single-sequence, three-period repeat dose study in a cohort of 24 subjects. Subjects received APL 400 mg every 12 h (b.i.d.) for 7 days (Period 1), LPV/r 400/100 mg b.i.d. for 14 days (Period 2) and APL 400 mg + LPV/r 400/100 mg b.i.d. for 7 days (Period 3). All doses were administered with a moderate fat meal. PK sampling occurred on day 7 of Periods 1 and 3 and day 14 of Period 2. RESULTS: In Part 1, a single RTV dose increased the APL AUC(0-infinity) by 2.1-fold [90% confidence interval (CI) 1.9, 2.4]. Repeat dose coadministration of APL with LPV/r increased APL exposures to a greater extent with the geometric least squares mean ratios (90% CI) being 7.7 (6.4, 9.3), 6.2 (4.8, 8.1) and 7.1 (5.6, 9.0) for the APL AUC, C(max), and C(min), respectively. No change in LPV AUC or C(max) and a small increase in RTV AUC and C(max) (28% and 32%) were observed. The combination of APL and LPV/r was well tolerated and adverse events were mild in severity with self-limiting gastrointestinal complaints most commonly reported. CONCLUSIONS: Coadministration of APL and LPV/r was well tolerated and resulted in significantly increased APL plasma concentrations.     

Ragaglitazar: the pharmacokinetics, pharmacodynamics, and tolerability of a novel dual PPAR alpha and gamma agonist in healthy subjects and patients with type 2 diabetes

Ragaglitazar is a novel dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist intended to restore insulin sensitivity and correct diabetic dyslipidemia. These studies assessed single-dose pharmacokinetics and tolerability of ragaglitazar in healthy subjects, as well as multiple-dose pharmacokinetics, pharmacodynamics, and tolerability of ragaglitazar in healthy subjects and in patients with type 2 diabetes. Healthy subjects received a single oral dose (1-120 mg), and healthy subjects and type 2 diabetic patients received a loading dose and thereafter once-daily doses (0.5-16 mg) of ragaglitazar for 6 and 20 days, respectively. Ragaglitazar was rapidly absorbed (tmax: 1.5-1.7 h), with mean AUC0-24 h and Cmax proportional to dose after single and multiple dosing; t1/2 was 80 hours following a single dose and 104 hours in healthy subjects and 122 hours in patients after multiple dosing. Administration of 4 mg ragaglitazar to patients (n = 4) for 21 days resulted in mean decreases from baseline in fasting levels of plasma glucose (18%), C-peptide (18%), fructosamine (6%), triglycerides (36%), free fatty acids (49%), total cholesterol (11%), low-density lipoprotein (LDL) cholesterol (21%), and very low-density lipoprotein (VLDL) cholesterol (15%), as well as an increase in high-density lipoprotein (HDL) cholesterol (33%). Overall, ragaglitazar was well tolerated; with multiple dosing, there was a higher incidence of adverse events for patients that, at the highest dose level (16 mg), included peripheral edema and anemia.     

创新药吡非尼酮胶囊在中国健康人体耐受性和安全性研究

目的：评价中国健康受试者单次和多次口服1.1类创新药吡非尼酮胶囊后的人体耐受性和安全性。方法：依据动物实验结果推算起始和最大剂量，以健康受试者为研究对象，从安全起始剂量开始，进行单次和多次给药耐受性试验。采用随机单中心临床研究，统一餐后给药。单次给药耐受性试验：36例，随机分成6个剂量组：200 mg（2例），400 mg（4例），800 mg（6例），1 200 mg（8例），1 800 mg（8例），2 400 mg（8例）；多次给药耐受性试验：12例，分成2个剂量组：400 mg（6例），600 mg（6例），每天3次，连续给药7 d。观察受试者用药前后症状、生命体征、实验室检查变化（包括血尿常规、肝肾功能、心电图等）、并记录药品不良事件。结果：单次和多次给药耐受性试验的受试者用药前后生命体征和心电图无显著变化，实验室检查等表明无器质性损伤。依据试验终止标准，20例受试者完成4个剂量组的单次耐受性研究。其中单次给药耐受性试验有12例，多次给药耐受性试验有7例受试者在口服药物后出现轻中度恶心、呕吐、烧心、食欲不振、头晕和头痛等不良事件，未经处理自行缓解。本试验过程中未发生严重不良事件。结论：中国健康人体对吡非尼酮胶囊单次（200~1 200 mg）或多次（400~600 mg，tid×7 d）给药的安全性和耐受性良好，将为临床合理应用提供依据。     

Intravenous pharmacokinetics and absolute oral bioavailability of dolasetron in healthy volunteers: part 1

In this first part of a two-part investigation, the intravenous dose proportionality of dolasetron mesylate, a 5-HT3 receptor antagonist, and the absolute bioavailability of oral dolasetron mesylate were investigated. In an open-label, randomized, four-way crossover design, 24 healthy men between the ages of 19 and 45 years received the following doses: 50, 100, or 200 mg dolasetron mesylate administered by 10-min intravenous infusion or 200 mg dolasetron mesylate solution administered orally. Serial blood and urine samples were collected for 48 h after dosing. Following intravenous administration, dolasetron was rapidly eliminated from plasma, with a mean elimination half-life (t1/2) of less than 10 min. Dolasetron was rarely detected in plasma after oral administration of the 200 mg dose. Hydrodolasetron, the active primary metabolite of dolasetron, appeared rapidly in plasma following both oral and intravenous administration of dolasetron mesylate, with a mean time to maximum concentration (t(max)) of less than 1 h. The mean t1/2 of hydrodolasetron ranged from 6.6-8.8 h. The plasma area under the concentration-time curve (AUC0-infinity)) for both dolasetron and hydrodolasetron increased proportionally with dose over the intravenous dose range of 50-200 mg dolasetron mesylate. Approximately 29-33%) and 22% of the dose was excreted in urine as hydrodolasetron following intravenous and oral administration of dolasetron, respectively. For dolasetron as well as hydrodolasetron, mean systemic clearance (C1), volume of distribution (Vd), and t1/2 were similar at each dolasetron dose. The mean 'apparent' bioavailability of dolasetron calculated using plasma concentrations of hydrodolasetron was 76%. The R(+) enantiomer of hydrodolasetron represented the majority of drug in plasma (> 75%) and urine (> 86%). Dolasetron was well tolerated following both oral and intravenous administration.     

奥兰替胃康片I期临床耐受性试验

 　目的：观察奥兰替胃康片（枳实总黄酮苷提取物）在健康志愿者中的安全性和耐受性。方法：单次给药组38名健康志愿者分为7个剂量组,分别给予奥兰替胃康片100,300,600,1 000,1 600,2 400和3 000 mg (1片,n=4;3片,n=4;6片,n=6;10片,n=6;16片,n=6;24片,n=6;30片,n=6)。多次给药组12名健康志愿者分为2个剂量组,分别给予奥兰替胃康片200 mg（2片,n=6）或400 mg（4片,n=6）,tid,连续给药7 d。观察受试者的临床症状和体征、生命体征、实验室检查、心电图检查、腹部彩色B超及不良事件。结果：共32名健康志愿者完成了耐受性试验。单次、多次试验均未发生严重不良事件。单次给药试验和多次给药试验中,受试者均未出现有临床意义的体格检查、实验室检查、心电图检查异常。单次给药1 000 mg组发生了5例不良事件,很可能与试验药物有关;1 600,2 400,3 000 mg组停止进行试验。多次给药试验中无不良事件发生。结论：奥兰替胃康片在100~600 mg范围内用药的安全性和耐受性良好。单次给药的最大耐受剂量为600 mg。多次给药每次200~400 mg,tid,连续7 d安全且耐受性好。推荐的II期临床试验的给药方案为每次400 mg,tid。     

羟戊基苯甲酸钾片在健康人体单次给药的耐受性

目的评价中国健康受试者单次口服不同剂量羟戊基苯甲酸钾片的安全性和耐受性。方法采用随机、双盲、安慰剂对照、单一剂量递增的单中心临床研究。合格的46例受试者随机进入5个递增剂量试验组(100 mg、200 mg、300 mg、400 mg和500 mg),100 mg和500 mg剂量组8例,其余各组10例,每个剂量组中有2例受试者口服安慰剂。用药后对受试者临床观察,定时进行实验室检查、心电图检查。结果46例受试者全部完成了研究,研究期间,共有6例受试者发生10例次不良事件,试验组有5例受试者发生9例次不良事件,对照组有1例受试者发生1例次不良事件。试验组不良事件主要表现为恶心、头晕、碰伤、谷丙转氨酶(GPT)升高、血清淀粉酶(S-Amy)升高、肌酸激酶(CK)升高。结论在100~500 mg剂量范围内单次口服羟戊基苯甲酸钾片耐受性良好。     

Rabeprazole produces rapid, potent, and long-acting inhibition of gastric acid secretion in subjects with Helicobacter pylori infection

AIM: To compare acid inhibiting activity and duration of action of different doses of rabeprazole, a substituted benzimidazole characterized as a highly potent and irreversible H+, K+-ATPase inhibitor, administered for 7 days to subjects infected with Helicobacter pylori. METHODS: A total of 38 subjects (mean age 39.3 years) were enrolled in a single-centre, double-blind, randomized, crossover study. All subjects were confirmed positive for H. pylori by 14C urea breath test and ELISA serologies. Subjects were divided into two groups of 19 to receive two doses of rabeprazole, either 5 and 20 mg or 10 and 40 mg, and placebo, given in random order daily in the morning for 7 days. Peptone-stimulated acid, pH, and gastrin measurements were made for 24 h after the 1st dose and for 48 h after the 7th dose. RESULTS: Peptone-stimulated acid secretion rates were decreased from 12.5 to 6.7, 4.0, 1.5, and 0.26 h after initial 5, 10, 20, and 40 mg doses, respectively; to 7.3, 4.3, 2.1, and 1.2 mmol/h 23 h after the initial dose; and to 2.4, 2.6, 0.6, and 0.8 mmol/h 23 h after the 7th dose. After 48 h, stimulated acid secretion had recovered less than 40% for all treatment groups compared to placebo. Median intragastric pH also increased from 2.0 with placebo to 4.9, 6.2, 6.6 and 6.9 during the 24-h period after the 7th dose of 5, 10, 20, and 40 mg. The 20 mg dose of rabeprazole produced equivalent acid inhibition to the 40 mg dose with less increase in plasma gastrin. CONCLUSION: Rabeprazole in doses from 5 to 40 mg was a highly effective inhibitor of gastric acid secretion in subjects infected with H. pylori. The inhibition was rapid, dose-related, and long-acting, with less than 50% recovery of acid by 48 h after the 7th dose. The optimal acid inhibitory dose in these subjects appeared to be 20 mg daily, however 5 mg and 10 mg doses produced potent inhibition of gastric acid secretion.     

Induction of tirilazad clearance by phenytoin

Tirilazad is a membrane lipid peroxidation inhibitor being studied for the management of subarachnoid hemorrhage; phenytoin is used for seizure prophylaxis in the same disorder. The induction of tirilazad clearance by phenytoin was assessed in 12 volunteers (6 male, 6 female). Subjects received phenytoin orally every 8 h for 7 days (200 mg for nine doses and 100 mg for 13 doses) in one phase of a crossover study. In both study phases, 1.5 mg kg⁻¹ tirilazad mesylate was administered by IV infusion every 6 h for 29 doses. Tirilazad mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. After the final dose, tirilazad clearance was increased by 91.8% in subjects receiving phenytoin+tirilazad versus tirilazad alone. AUC_0–6 for U-89678 after the last tirilazad dose was reduced by 93.1% by concomitant phenytoin. These effects were statistically significant. The time course of induction was consistent with that of phenytoin's effect on the ratio of urinary 6β -hydroxycortisol to cortisol, a measure of hepatic CYP3A activity. The results show that phenytoin induces metabolism of tirilazad and U-89678 in healthy subjects and that, under these conditions, tirilazad clearance approaches liver blood flow. © 1998 John Wiley & Sons, Ltd.     

Single and repeated dose comparison of three antihistamines and phenylpropanolamine: psychomotor performance and subjective appraisals of sleep.

1 In a double-blind cross-over study, nine healthy male students received placebo, brompheniramine 12 mg), carbinoxamine (12 mg), clemastine (1 mg), and phenylpropanolamine (50 mg) orally. Three doses of each drug were given: at 08.30 h and 21.00 h on the first day of treatment and at 08.30 h on the following day. 2 Psychomotor skills and subjective feelings were recorded before and 2, 6 and 12 h after the first dose on day 1 as well as before and 2 and 6 h after the third dose on day 2. Subjective appraisals of sleep were requested on the morning of day 2. 3 All antihistamines tended to cause subjective drowsiness on the first day of treatment. Drowsiness was felt for a maximum of 2 h after carbinoxamine, 6 h after brompheniramine, and 12 h after clemastine. In contrast to antihistamines, phenylpropanolamine made subjects more alert and quick witted. Tolerance to the antihistamine-induced drowsiness developed on the second day. 4 Divided attention, tracking, speed anticipation and sleep were not affected by any drug. Carbinoxamine slowed reactions 2 h after the first dose, but no impairment was measured in objective tests after brompheniramine or clemastine. 5 Phenylpropanolamine improved reaction speed and reaction accuracy and enhanced flicker recognition throughout the study. Phenylpropanolamine plasma levels and improvement in flicker fusion test results correlated with each other on day 2. 6 The results suggest that phenylpropanolamine and the antihistamines studied are comparatively harmless to psychomotor performance and driving skills.