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1.
Safety,Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy Volunteers
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Viktoria Werkström Susanne Prothon Ella Ekholm Carin Jorup Staffan Edsbäcker 《Basic & clinical pharmacology & toxicology》2016,119(6):574-581
AZD5423 is a selective glucocorticosteroid receptor modulator developed for the inhaled use in asthma and COPD. This study reports the initial, first‐in‐man, single and repeat dose‐escalating studies in healthy male individuals, including one cohort of male Japanese individuals. Inhaled, nebulized AZD5423 was safe and well tolerated up to and including the highest doses tested for up to 2 weeks of once‐daily treatment. Plasma exposure suggested dose‐proportional pharmacokinetics and dose‐related effects on 24‐hr plasma and urine cortisol. There were no or marginal effects on other biomarkers tested (osteocalcin, TRAP5b, DHEA‐S and 4β‐OH‐cholesterol). No clinically relevant differences in safety or pharmacokinetics could be distinguished between the two study populations, although hypothalamus–pituitary–adrenal (HPA) effects appeared to be marginally greater in the Japanese‐ versus the Caucasian‐dominant study population. AZD5423, inhaled via nebulization, can be used in healthy individuals at doses of at least 300 μg for 2 weeks. The effects on the HPA axis reported herein, together with efficacy data reported elsewhere, indicate that benefit–risk ratio may be improved relative to conventional inhaled steroids. 相似文献
2.
目的:研究羟基红花黄色素A(HSYA)在健康人体内的药效学及药动学(PD/PK)特征。方法:采用三交叉拉丁方设计,对9名健康志愿者按不同顺序分别静脉滴注注射用红花黄色素高、中、低剂量。用药后按不同时间点取静脉血检测血流变、凝血、血脂;超声彩色多普勒监测肝动脉、肾动脉及子宫动脉相应时间点的血流量;采用高效液相色谱-紫外检测法测定血浆药物浓度。结果:血液流变学、凝血用药前后有显著差异,脏器动脉血液灌注量用药前后有改善但不十分明显,初步判断该药起效时间为0.5~12h,中剂量最大药效时间3.5h。受试者血药浓度-时间数据用DAS2.0软件拟合,符合一级消除的二房室模型,主要药动学参数:Cm ax(实测值)按低、中、高剂量分别为(2.02±0.18)、(7.47±0.67)、(14.48±4.70)mg.L-1;t1/2β分别为(3.05±0.70)、(3.56±0.77)、(3.35±0.91)h;AUC0~15(以梯形法计算)分别为(6.79±1.29)、(26.75±5.46)、(49.81±13.75)μg.h.mL-1。结论:HSYA有改善血液流变学及抗凝血的作用,其体内代谢过程符合二室模型;高、中、低单剂量组的消除半衰期较快,体内平均驻留时间相近,AUC0~15、AUC0~∞和Cm ax均与剂量呈线性关系。 相似文献
3.
目的:研究非洛地平片在人体内药动学与药效学的相关性。方法:采用液-质联用法测定10名健康受试者单剂量口服非洛地平10mg后的血药浓度,并以DAS2.0药动学模块程序处理药-时数据及计算药动学参数。分别于服药前及服药后不同时间对收缩压(SBP)、舒张压(DBP)、心率(HR)、平均动脉压(MAP)进行监测。结果:平均药动学参数tmax、Cmax、AUC0~48、AUC0~∞、Ka、t1/2分别为(3.88±0.35)h、(5.94±1.45)μg·L-1、(61.73±15.54)μg·h·L-1、(67.62±16.09)μg·h·L-1、(0.73±0.33)h-1、(15.43±4.15)h,以不同时间血药浓度分别对SBP、DBP、HR和MAP进行回归分析,其相关系数分别为0.614 6、0.985 6、0.907 7和0.568 6。用药2~8 h内DBP下降明显(P<0.05或P<0.01)。结论:非洛地平血药浓度与药效相关,其有效血药浓度约为2.64~5.84μg·L-1,临床应用非洛地平应重点监测DBP、HR。 相似文献
4.
Guy Aymard Dominique Warot Pierre Dmolis Jean Franois Giudicelli Philippe Lechat Marie Emmanuelle Le Guern Christine Alquier Bertrand Diquet 《Basic & clinical pharmacology & toxicology》2003,92(6):279-286
Abstract: To determine the pharmacokinetic, subjective effects of a single 20 mg dose of nefopam administered either intravenously or orally in healthy volunteers, twenty‐four healthy Caucasian men received 20 mg nefopam orally+placebo intravenous infusion and placebo orally+intravenous infusion of 20 mg nefopam with one week interval, in a double‐blind, double‐dummy cross‐over study. Nefopam and desmethyl‐nefopam plasma concentrations were measured by HPLC with UV detection up to 48 hr after drug administration. Self‐rating questionnaires (Mood and vigilance Visual Analogue Scales, Addiction Research Centre Inventory) and drug safety were investigated. The F value (bioavailability) of the parent drug was 0.36±0.13. The AUCoral/AUCiv ratio of nefopam+desmethyl‐nefopam was 0.62±0.23. The half–life of nefopam was similar whether administered orally (5.1±1.3 hr) or intravenously (5.1±0.6 hr). The half‐life of desmethyl‐nefopam was two to three times longer than that of the parent molecule (orally: 10.6±3.0 versus 5.1±1.3 hr, P<10?4 and intravenously: 15.0±2.4 versus 5.1±0.6 hr, P<10?4). As assessed by the Addiction Research Centre Inventory, no evidence of abuse liability in healthy, drug‐naive volunteers was observed. On visual analogue scales, volunteers rated themselves as more drowsy, less alert, less energetic and less anxious after oral compared to intravenous administration. The AUC0→24 hr of anxiety and energy parameters were not different after oral and intravenous administration: 90±142 versus 35±84 (P=0.27) and 66±74 versus 46±54 mm.hr (P=0.36), respectively. The AUC0→24 hr of drowsiness and alertness parameters were significantly greater after oral than after intravenous administration: 68±65 versus 27±30 (P=0.005) and 54±63 versus 28±48 mm.hr (P=0.03), respectively. A clockwise hysteresis loop was observed for drowsiness in 16 out of 24 volunteers after oral administration. The results suggest that in healthy volunteers desmethyl‐nefopam may contribute to the pharmacodynamic effects of single dose nefopam solution administered orally. This study shows a rather low bioavailability of nefopam given in intravenous solution when administered orally. Nevertheless, when the main metabolite desmethyl‐nefopam is taken into account, the ratio of the areas under the curves is almost doubled. 相似文献
5.
Tommy Andersson Peter Nagy Mohammad Niazi Sven Nylander Hal Galbraith Santosh Ranjan Lars Wallentin 《Am J Cardiovasc Drugs》2014,14(3):217-227
Objective
The effect of proton pump inhibitors (PPIs) on the pharmacokinetics and pharmacodynamics of clopidogrel was assessed in two healthy volunteer crossover studies.Subjects and methods
Study 1: subjects received clopidogrel alone (300-mg loading dose, then 75 mg/day for 28 days) and two of three PPIs (omeprazole 80 mg, esomeprazole 40 mg or lansoprazole 60 mg) plus clopidogrel for 29 days in three treatment periods (randomized treatment sequence assignment). Study 2: subjects received clopidogrel alone (75 mg/day for 9 days) and clopidogrel alone for 4 days followed by clopidogrel plus fixed-combination esomeprazole 20 mg/low-dose acetylsalicylic acid (ASA) 81 mg for 5 days in two treatment periods (randomized treatment sequence assignment). Pharmacokinetic effects were estimated by measuring active metabolite of clopidogrel, and pharmacodynamic effects by inhibition of adenosine diphosphate (ADP)-induced platelet aggregation.Results
There was a relative decrease of up to 50 % in exposure to the active metabolite of clopidogrel with the different PPIs (study 1), and close to 40 % with esomeprazole/low-dose ASA (study 2), compared with clopidogrel alone. There was an absolute decrease of up to 17 % in inhibition of ADP-induced platelet aggregation with co-administration of different PPIs, compared with clopidogrel alone; however, no differences in platelet inhibition were observed during co-administration with the esomeprazole/low-dose ASA fixed-dose combination.Conclusion
Omeprazole, esomeprazole and lansoprazole decreased systemic exposure to the active metabolite of clopidogrel in healthy volunteers, leading to modest decreases in its antiplatelet effect. However, no apparent differences in platelet inhibition were observed when esomeprazole was co-administered with low-dose ASA as a fixed-dose combination. 相似文献6.
7.
Marc M. Perreault Pharm.D. David J. Kazierad Pharm.D. John H. Wilton Ph.D. Joseph L. Izzo Jr. M.D. 《Pharmacotherapy》1993,13(2):149-153
The effects of isradipine 2.5 mg and 5 mg on the disposition of theophylline were investigated in a placebo-controlled, randomized, three-way, crossover trial. Eleven healthy, nonsmoking men each received a treatment of placebo, and isradipine 2.5 mg and 5 mg every 12 hours for 6 consecutive days. On the morning of day 6, 2 hours after the isradipine dose, theophylline (solution) 5.0 mg/kg was administered orally, and blood samples were collected over 24 hours. A 2-week washout period separated treatment sequences. Plasma samples were analyzed for theophylline using high-performance liquid chromatography. Using a two-way analysis of variance, no significant changes in apparent theophylline clearance were observed between placebo, and isradipine 2.5 and 5 mg (0.815 ± 0.164, 0.870 ± 0.212, and 0.827 ± 0.164 ml/min/kg, respectively; p=0.136). Similarly, no significant change in volume of distribution was noted. These findings suggest that isradipine at recommended dosages does not impair theophylline metabolism. 相似文献
8.
目的进行健康志愿者单次和多次静脉给药后奥拉西坦人体药代动力学研究. 方法 10名健康志愿者单次静脉输注2 000 mg奥拉西坦和每次2 000 mg, 静脉输注7天后, HPLC法测得奥拉西坦血清浓度, DAS软件进行药代动力学参数计算.结果单次给药, 奥拉西坦AUC0~12, AUC0~∞, Ke, t1/2, MRT分别为256.26±16.84 μg·mL-1·h-1, 276.74±18.11 μg·mL-1·h-1, 0.18±0.03 h-1, 3.84±0.64 h和4.39±0.39 h; 多次给药后AUC0~12, AUC0~∞, Ke, t1/2, MRT分别为259.36±25.43 μg·mL-1·h-1, 285.59±27.38 μg·mL-1·h-1, 0.17±0.04 h-1, 4.14±0.82 h和4.87±0.69 h.结论奥拉西坦单次和多次给药后药动学参数无明显差异, 奥拉西坦多次给药后无蓄积. 相似文献
9.
健康受试者口服Levofloxacin的药动学研究 总被引:2,自引:0,他引:2
本文报道8例健康志愿者体内单次及多次给予300mgLevofloxacin后的药代动力学研究。血药浓度及尿药浓度采用微生物和HPLC测定。单次及多次给药后的数据分别采用3p87及SSD程序处理,药-时曲线符合二室模型。单次口服300mgLevofloxacin,其微生物和HPLC测定结果分别为Tmax1.31和1.43h,Cmax3.84和4.20mg/L,t1/226.12和6.06h。0~24h尿药回收率分别为68.79和66.43%。经t检验两种方法的测定结果无显著性差异(p>0.05)。在每日300mgq12h连续8天的多次口服给药实验中,第1天和第8天的药代动力学参数经t-检验无显著性差异(p>0.05),说明本品每日2次重复给药无明显蓄积现象。 相似文献
10.
本文采用高效液相法,对盐酸洛美沙星在健康人体内的生物利用度进行了试验研究。10名男性健康志愿者单剂量口服盐酸洛美沙星胶囊剂各400mg,尔后经时采集静脉血,测定血药浓度,得药-时数据,经PKBP-N1程序处理,得洛美沙星的药动学参数:Lagtime0.25±0.075h,Tmax1.30±0.45h,Cmax3.29±0.79μg/ml,t1/2α1.81±1.53h,t1/2β8.88±0.69h,VC86.71±33.74L,K210.26±0.15,K120.264±0.24,K100.187±0.074。 相似文献
11.
《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(6):683-692
1. The pharmacokinetics of rolipram were studied in healthy male volunteers using 3H-rolipram and a radioimmunoassay for measurement of unchanged drug.2. Rolipram was rapidly and completely absorbed after an oral dose of 1?mg. Bioavailability was 73%.3. Plasma levels of the unchanged drug declined with a terminal half-life of 2?h. The total clearance of rolipram was 2 ml/min per kg.4. Labelled rolipram was excreted rapidly and completely. The main route of elimination was via the urine. 相似文献
12.
Yani Liu Shaojun Shi Jianhong Wu Zhongfang Li Xingqin Zhou Fandian Zeng 《Basic & clinical pharmacology & toxicology》2012,110(2):154-161
Abstract: Recombinant human parathyroid hormone [rhPTH(1–84)] represents a new class of anabolic agents for the treatment of osteoporosis. The present study was designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of rhPTH(1–84) after single‐ and multiple‐dose subcutaneous administration in healthy Chinese volunteers. Six cohorts of 32 volunteers received a single dose of rhPTH(1–84) at 0.5–5.0 μg/kg, and two cohorts of 12 volunteers received 2.0 and 3.0 μg/kg of rhPTH(1–84) once daily for 7 consecutive days to assess its safety and tolerability. The results indicated that rhPTH(1–84) appeared to be safe and well tolerated. Additionally, pharmacokinetics of rhPTH(1–84) and its active N‐terminal fragment rhPTH(1–34) were investigated after administration of single 1.0, 2.0 and 4.0 μg/kg doses of rhPTH(1–84) in 30 other volunteers and after multiple doses of 2.0 μg/kg once daily for 7 consecutive days. The pharmacokinetic parameters for rhPTH(1–84) and rhPTH(1–34) after subcutaneous administration of a single dose of 1.0, 2.0 and 4.0 μg/kg were as follows: Cmax = (110.54 ± 59.18), (149.70 ± 50.61) and (372.52 ± 94.96) pg/mL; (53.93 ± 6.27), (61.12 ± 11.28) and (89.04 ± 7.08) pg/mL, respectively. AUC0–10 = (268.87 ± 47.72), (538.93 ± 146.89) and (1364.11 ± 176.82) pg hr/mL; (197.20 ± 50.78), (207.15 ± 72.08) and (344.05 ± 77.06) pg hr/mL, respectively. t1/2 = (2.34 ± 1.93), (2.58 ± 1.18) and (2.74 ± 1.31) hr; (3.37 ± 1.82), (4.39 ± 3.79), and (3.99 ± 1.85) hr, respectively. Plasma Cmax and AUC values of rhPTH(1–84) and rhPTH(1–34) were found to be dose proportional. The pharmacokinetic parameters for rhPTH(1–84) and rhPTH(1–34) after administration of multiple doses of 2.0 μg/kg were as follows: Css_max = (164.96 ± 52.61) and (75.05 ± 7.31) pg/mL; Css_min = (6.99 ± 7.73) and (2.05 ± 2.82) pg/mL; AUCss = (567.26 ± 118.41) and (306.02 ± 77.55) pg hr/mL; t1/2 = (1.81 ± 0.89) and (2.27 ± 1.11) hr; DF = (6.93 ± 2.64) and (6.00 ± 1.37), respectively. After multiple doses, the pharmacokinetic parameters for rhPTH(1–84) were consistent with those after single dose. However, the mean Cmax and AUC0–10 of rhPTH(1–34) after multiple dosing were significantly higher than the corresponding values obtained after single‐dose administration. Serum total calcium and phosphate concentrations increased and decreased significantly at 4 hr post‐dosing, respectively. 相似文献
13.
格列喹酮在中国健康受试者体内的生物等效性研究 总被引:5,自引:0,他引:5
建立了测定格列喹酮血浆浓度的HPLC-荧光检测法,并对10名健康受试者随机交叉口服60 mg 格列喹酮胶囊和格列喹酮片后的药代动力学性质及其生物等效性进行了研究.以黄豆苷元二甲醚为内标,血浆样品经液-液萃取处理,荧光检测波长为315/410 nm;线性范围为50~2000 μg·l-1;本法的相对偏差(RE)< 4.5 %,日内RSD< 8.6 %,日间RSD< 5.2 %.格列喹酮胶囊和片剂的Tmax分别为2.70±0.48和2.35±0.75 h; Cmax分别为1532.3±481.8和1588.2±822.2 μg· l-1; t1/2分别为4.82±2.18和4.47±1.77 h; AUC0-t分别为6872.8±2575.1和6942.2±3747.8μμg· l-1· h.以AUC0-t计算相对生物利用度为103.8 %±15.7 %.统计分析表明,两种制剂在人体内生物等效. 相似文献
14.
爱普列特正常人体药代动力学研究 总被引:7,自引:0,他引:7
目的研究爱普列特单次和连续给药的药代动力学。方法在单次给药试验中,按照拉丁方设计,进行了9名受试者口服5,10,20mg爱普列特的药代动力学研究,在连续给药试验中,8名受试者每次口服爱普列特5mgq12h连续8d。用HPLC法测定血清、尿液、粪便(仅10mg组)中的药物浓度。结果单次给药计算所得主要药代动力学参数分别为Cmax=0.103±0.019mg·L-1,0.171±0.037mg·L-1,0.345±0.047mg·L-1;T1/2β=7.511±2.073h,7.299±1.555h,7.589±2.459h;AUC=1.327±0.513mg·h·L-1,2.417±0.574mg·h·L-1,4.914±1.327mg·h·L-1;V(c)/F=31.77±5.90L,37.89±7.44L,32.84±11.36L;Tpeak=3.677±1.336h,3.871±0.831h,3.861±0.657h。3个剂量组24h内原型药物在尿中累积排泄量分别为0.33±0.07%,0.26±0.14%,0.23±0.12%。10mg剂量组24h内原型药物在粪便中排泄率平均为19%。爱普列特蛋白结合率为97.0%。连续给药试验中,受试者血药浓度于第6天达到稳态。结论单次给药结果显示爱普列特具有剂量无关的药代动力学特性。连续给药结果显示,在试验期间,爱普列特可以达到稳态。尿和粪便中的回收率表明肾脏不是原形药的主要排泄途径,爱普列特在体内可能主要经过代谢消除。 相似文献
15.
目的:研究单剂量和多剂量口服给予普卢利沙星胶囊的药动学。方法:12名健康成年受试者按3×3拉丁方随机分组,分别单次口服132、264、528mg普卢利沙星胶囊,多次口服264mg普卢利沙星胶囊,连续6d。采用高效液相色谱法测定给药后不同时间普卢利沙星代谢产物NM394的血药浓度。应用DASver1·0软件进行模拟拟合及参数计算。结果:12名受试者全部完成单次给药试验,试验期间未发生任何药品不良反应。各受试者血样中检测不到普卢利沙星,只能测定其代谢产物NM394。高、中、低3个剂量组均符合二室模型,在人体内的药动学过程符合一级动力学,无性别差异。多次给药未见蓄积现象和药动学参数的改变,表明本品无自身酶抑制或诱导作用。结论:本方法灵敏、准确、可靠、特异性强,可满足普卢利沙星临床药动学试验要求,其参数与国外文献报道一致,在我国成人中无性别差异。 相似文献
16.
采用单剂量交叉实验设计,考察24名健康受试者I=1服雷米普利胶囊(受试制剂)及其片剂(参比制剂)5mg后的药物动力学.建立了LC-MS法测定血浆中代谢物雷米普利拉的浓度.采用C18柱,贝那普利为内标,以多反应监测(MRM)模式监测.两种制剂的cmax和tmax分别为(6.42±3.18)、(6.48±3.31)ng/ml和(3.31±1.47)、(3.04±1.14)h.受试制剂的相对生物利用度为(101.72±18.34)%.两者在人体的吸收速度和吸收程度无显著差异,表明两者生物等效. 相似文献
17.
盐酸左氧氟沙星在健康人体内的药代动力学研究 总被引:1,自引:1,他引:1
目的研究盐酸左氧氟沙星在健康人体内的药代动力学。方法20例健康男性志愿者均单剂量口服盐酸左氧氟沙星片200mg,采用高效液相色谱法测定给药前及给药后24h内不同时点的血药浓度,采用DAS1.0程序计算药代动力学参数。结果盐酸左氧氟沙星在健康人体内的主要药代动力学参数吸收相半衰期t1/2ks为(0.233±0.060)h、消除相半衰期t1—2β为(9.628±5.213)h、表观分布容积Vd为(1.795±0.918)L、分布相半衷期t1-2α为(1.188±0.726)h、药时曲线下面积(AUC0→24)为(24.385±3.222)mg/(L·h)、药时曲线下总面积AUC0→∞(29.866±3.892)mg/(L·h)。结论盐酸左氧氟沙星的药代动力学过程符合一级吸收二室模型。 相似文献
18.
King Shang-Ying P. Joslin Mark A. Raudibaugh Karen Pieniaszek Henry J. Benedek Irma H. 《Pharmaceutical research》1995,12(12):1874-1877
Purpose. To examine the pharmacokinetics of warfarin after administration of single oral doses (2, 5, and 10 mg) to healthy male volunteers.
Methods. A sensitive reverse-phase HPLC method was used to quantify warfarin plasma concentrations as low as 6 ng/ml. Blood samples were collected for up to 120 hours following administration of these doses.
Results. As the dose decreased from 5 to 2 mg, the apparent volume of distribution (V/F) increased from 12 to 21 liters and the terminal half-life (t1/2) increased from 47 to 71 hours. Oral clearance remained unchanged over the examined dose range. These apparent dose-dependent changes in warfarin's t1/2 and V/F may be due to saturable tissue binding of this drug. It appears that a previously undetected and prolonged terminal phase may exist but can not be adequately characterized with the 120-hour sampling interval. To evaluate this long t1/2, a follow-up study was conducted to examine warfarin's pharmacokinetics for up to 21 days following a 10-mg dose. The prolonged terminal phase started to become apparent when plasma levels declined to less than 100 ng/ml. The t1/2 of this terminal phase was determined to be approximately one week.
Conclusions. This is the first report that documents the dose-dependent pharmacokinetics of warfarin and the previously unreported long t1/2 of one week for warfarin in humans. 相似文献
19.
人体卡托普利的药代动力学及其生物利用度 总被引:1,自引:0,他引:1
目的:比较A、B两厂复方卡托普利片的生物利用度和药代动力学。方法:9名健康志愿者随机交叉口服单剂量30mg复方卡托普利片,以对溴苯乙酰基溴(PBPB)为衍生化试剂,采用反相高效液相色谱法。结果:测得A、B药厂生产的复方卡托普利片剂在血浆中Cap浓度达峰时间分别为(0.94±0.13)h和(1.00±0.15)h;达峰浓度Cmax分别为(92.03±27.36)ng/ml、(74.67±19.29)ng/ml;药时曲线下面积(AUC)分别为(252.78±68.14)ng/(h·L)、(251.19±50.13)ng/(h·L)。血药浓度—时间曲线符合二房室模型。结论:以A厂复方卡托普利片为标准算得B厂复方卡托普利片中卡托普利的相对生物利用度(F)为99.37%。 相似文献
20.
盐酸雷尼替丁片在健康志愿者的人体药代动力学和生物等效性 总被引:3,自引:0,他引:3
目的:研究国产盐酸雷尼替丁片和葛兰素威康生产的雷尼替丁片(商品名:善卫得)在健康人体内的药代动力学过程,并评价这两种制剂的生物等效性。方法:20例健康男性受试者随机分组、自身对照单次po盐酸雷尼替丁片300 mg后,用反相HPLC法测定血浆中雷尼替丁的浓度,依据血药浓度一时间数据进行有关参数计算及生物等效性评价。结果:对照制剂与试验制剂主要药代动力学参数C_(max)分别为1278.3±449.5 μg·L~(-1)及1200.5±433.1 μg·L~(-1);t_(max)分别为2.73±0.80 h及2.95±0.83 h;t_(1/2)分别为2.97±0.43 h及2.98±0.49 h;AUC_(0→t)分别为5582.2±1428.7 μg·h·L~(-1)及5199.0±1275.0μg·h·L~(-1); AUC_(0→∞)分别为5928.2±1389.3μg·h·L~(-1)及5413.3±1318.0 μg·h·L~(-1);试验制剂相对于对照制剂的生物利用度F为(94.6±16.1)%。结论:试验制剂与对照制剂生物等效。 相似文献