• 【Tafluprost,一种新型的强效类前列腺素受体激动剂:对健康志愿者的药效学和耐受性的剂量反应研究。】 复制标题 收藏 收藏
    DOI:10.5414/cpp46400 复制DOI
    作者列表:Sutton A,Gouws P,Ropo A
    BACKGROUND & AIMS: OBJECTIVE:Prostaglandin receptor analogs lower intraocular pressure (IOP) and are used for the treatment of glaucoma. This study aimed to compare the safety, tolerability and pharmacodynamics of four doses of the new, selective-prostanoid receptor agonist, tafluprost (AFP-168) in a Phase I placebo-controlled study. METHODS:Healthy volunteers (n = 16) received sequentially ascending doses of tafluprost (0.0001%, 0.0005%, 0.0025% and 0.005%) in one eye, and placebo in the other. Each treatment period consisted of 2 days of treatment, with 5 days between the treatment periods. Safety and tolerability assessments, as well as IOP measurements, were performed at defined intervals. RESULTS:Tafluprost was generally well tolerated and no volunteer discontinued due to adverse events (AEs). The most common ocular AE was ocular hyperemia, which was mild-to-moderate, and highly concentration-dependent. All doses of tafluprost decreased IOP, with the maximum effect occurring 12 hours after treatment. The decrease in IOP relative to placebo was significantly more effective with tafluprost 0.0025% and 0.005%, compared with tafluprost 0.0001% (p pound 0.005). CONCLUSION:Tafluprost was well tolerated and effective in lowering IOP. These data support further testing of tafluprost 0.0025% and 0.005%.
    背景与目标: 目的:前列腺素受体类似物可降低眼压(IOP),用于治疗青光眼。这项研究旨在在I期安慰剂对照研究中比较四种剂量的新型选择性前列腺素受体激动剂tafluprost(AFP-168)的安全性,耐受性和药效学。
    方法:健康志愿者(n = 16)在一只眼睛中依次接受塔氟前列素(0.0001%,0.0005%,0.0025%和0.005%)的剂量,而另一只则接受安慰剂。每个治疗期包括2天的治疗,每个治疗期之间有5天。安全性和耐受性评估以及IOP测量均按规定的时间间隔进行。
    结果:塔夫前列素一般耐受良好,没有志愿者因不良事件(AE)而停药。最常见的眼部AE是眼部充血,轻度至中度且高度依赖浓度。所有剂量的tafluprost均可降低IOP,最大作用发生在治疗后12小时。相对于安慰剂,IOP的降低在使用Tafluprost为0.0025%和0.005%时显着更有效,而在Tafluprost中为0.0001%(P磅为0.005)。
    结论:Tafluprost具有良好的耐受性,可有效降低眼压。这些数据支持进一步对他氟普罗斯特进行0.0025%和0.005%的测试。
  • 【在健康的日本人和高加索受试者中评估TV-1106(一种长效生长激素)的单剂量的药代动力学,药效学和安全性。】 复制标题 收藏 收藏
    DOI:10.1002/cpdd.294 复制DOI
    作者列表:Cohen-Barak O,Barkay H,Rasamoelisolo M,Butler K,Yamada K,Bassan M,Yoon E,Spiegelstein O
    BACKGROUND & AIMS: :TV-1106 is a human serum albumin genetically fused to recombinant human growth hormone, designed to provide a long-acting alternative to daily growth hormone (GH) injections in patients with GH deficiency. This study investigated the pharmacokinetics, pharmacodynamics, and safety of single subcutaneous doses of TV-1106 (7.5, 15, 50, and 100 mg) in Japanese (n = 44) and caucasian (n = 44) healthy subjects. TV-1106 pharmacokinetics and pharmacodynamics were comparable in Japanese and caucasian populations. TV-1106 demonstrated relatively slow absorption (median tmax , 10-30 hours) and a mean elimination half-life of 26-36 hours. Apparent clearance and volume of distribution decreased with increasing TV-1106 doses in both populations and appeared to increase more than dose proportionality across the tested doses. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) increased in a dose-related manner, with maximum responses observed at 33-96 and 42-109 hours, respectively. IGF-1 and IGFBP-3 returned to baseline values at 168 hours following 7.5 and 15 mg of TV-1106, and 336 hours following 50 and 100 mg of TV-1106. TV-1106 appeared safe in both populations. There was no evidence of differences in pharmacokinetics, pharmacodynamics, or safety of TV-1106 between Japanese and caucasian populations. The data also demonstrate long-acting growth hormone properties of TV-1106 and support its potential for once-weekly dosing.
    背景与目标: :TV-1106是人血清白蛋白,与重组人生长激素基因融合,旨在为GH缺乏症患者的日常生长激素(GH)注射提供长效替代品。这项研究调查了日本(n = 44)和高加索人(n = 44)健康受试者单次皮下注射TV-1106(7.5、15、50和100 mg)的药代动力学,药效学和安全性。在日本和白种人中,TV-1106的药代动力学和药效学相当。 TV-1106表现出相对较慢的吸收(tmax中位数为10-30小时),平均消除半衰期为26-36小时。在两个人群中,表观清除率和分布体积均随着TV-1106剂量的增加而降低,并且似乎在整个测试剂量中的增加均大于剂量比例。胰岛素样生长因子-1(IGF-1)和IGF结合蛋白-3(IGFBP-3)以剂量相关的方式增加,分别在33-96和42-109小时观察到最大反应。 IGF-1和IGFBP-3在7.5和15 mg TV-1106服用后168小时以及在50和100 mg TV-1106服用后336小时回到基线值。 TV-1106在两种人群中均显示安全。没有证据表明日本人和白种人之间的药代动力学,药效学或TV-1106的安全性存在差异。数据还证明了TV-1106的长效生长激素特性,并支持其每周一次给药的潜力。
  • 【对两种低剂量口服避孕药的功效,周期控制进行了为期十二个月的比较临床研究,这些口服避孕药分别含20毫克乙炔雌二醇/ 75毫克孕二烯和20毫克乙炔雌二醇/ 150毫克去氧孕烯。】 复制标题 收藏 收藏
    DOI:10.1016/0010-7824(95)00191-c 复制DOI
    作者列表:Endrikat J,Jaques MA,Mayerhofer M,Pelissier C,Müller U,Düsterberg B
    BACKGROUND & AIMS: The aim of this study was to compare contraceptive reliability, cycle control and tolerance of an oral contraceptive containing 20 micrograms ethinylestradiol and 75 micrograms gestodene, with a reference preparation containing the same dose of estrogen combined with 150 micrograms desogestrel. This article presents interim data from centers in France and Austria, involving a total of 479 women and 4,991 cycles. Contraceptive reliability was good with both preparations. Two pregnancies occurred in the gestodene group, but neither were due to method failure. In the desogestrel group there were also two pregnancies, of which one was due to method failure. With respect to cycle control, there is a trend towards a lower incidence of intermenstrual bleeding in the gestodene group. The incidence of spotting (scanty bleeding) during the important first three cycles was 3.5% lower in the gestodene group, and over the first six cycles, it was 7.6% lower. Amenorrhea was similar in both groups, but the incidence of dysmenorrhea was significantly lower in the gestodene group (p=0.001). Adverse events were similar in both groups, with headache, breast tension and nausea the most frequently reported symptoms. Body weight remained relatively constant during treatment in both groups, and no hypertension was reported for any woman during the course of the study. In each treatment group, 19 women discontinued because of adverse events. It is concluded that both preparation are reliable and well tolerated oral contraceptives are reliable and well tolerated oral contraceptives; however, there is a more favourable effect on dysmenorrhea by the gestodene formulation.

    背景与目标: 这项研究的目的是比较口服避孕药的避孕可靠性,周期控制和耐受性,口服避孕药中含有20毫克乙炔雌二醇和75毫克孕二烯酮,而参比制剂中含有相同剂量的雌激素和150毫克地索孕酮。本文介绍了来自法国和奥地利的中心的临时数据,涉及总共479名妇女和4,991个周期。两种制剂的避孕可靠性均良好。孕二烯酮组发生了两次怀孕,但都不是由于方法失败而引起的。在去氧孕烯组中也有两次怀孕,其中一次是由于方法失败而引起的。关于周期控制,孕二烯酮组月经间出血的发生率有降低的趋势。孕二烯酮组在重要的前三个周期中出现斑点(少量出血)的发生率降低了3.5%,而在前六个周期中,则降低了7.6%。两组的闭经情况相似,但孕二烯酮组的痛经发生率显着降低(p = 0.001)。两组的不良事件相似,头痛,乳房紧张和恶心是最常报告的症状。两组患者在治疗期间体重均保持相对恒定,并且在研究过程中未见任何女性患有高血压。在每个治疗组中,有19名妇女因不良事件而停药。结论是,两种制剂都是可靠且耐受性良好的口服避孕药;是可靠且耐受性良好的口服避孕药。但是,孕二烯酮制剂对痛经有更有利的作用。

  • 【药物开发中的综合药代动力学和药效学。】 复制标题 收藏 收藏
    DOI:10.2165/00003088-200746090-00001 复制DOI
    作者列表:Dingemanse J,Appel-Dingemanse S
    BACKGROUND & AIMS: :Drug development is a complex, lengthy and expensive process. Pharmaceutical companies and regulatory authorities have recognised that the drug development process needs optimisation for efficiency in view of the return on investments. Pharmacokinetics and pharmacodynamics are the two main principles determining the relationship between dose and response. This article provides an update on integrated approaches towards drug development by linking pharmacokinetics, pharmacodynamics and disease aspects into mathematical models. Gradually, a transition is taking place from a rather empirical approach towards a modelling- and simulation-based approach to drug development. The main learning phases should be phases 0, I and II, whereas phase III studies should merely have a confirmatory purpose. In model-based drug development, mechanism-based mathematical models, which are iteratively refined along the path of development, incorporate the accumulating knowledge of the investigational drug, the disease and their mutual interference in different subsets of the target population. These models facilitate the design of the next study and improve the probability of achieving the projected efficacy and safety endpoints. In this article, several theoretical and practical aspects of an integrated approach towards drug development are discussed, together with some case studies from different therapeutic areas illustrating the application of pharmacokinetic/pharmacodynamic disease models at different stages of drug development.
    背景与目标: :药物开发是一个复杂,漫长且昂贵的过程。制药公司和监管机构已经认识到,鉴于投资回报率,药物开发过程需要优化以提高效率。药代动力学和药效学是决定剂量与反应之间关系的两个主要原理。本文通过将药代动力学,药效学和疾病方面链接到数学模型中,提供了有关药物开发综合方法的更新。逐渐地,正在从一种基于经验的方法向药物开发的基于建模和模拟的方法过渡。主要学习阶段应为阶段0,阶段I和阶段II,而阶段III的研究仅应具有确定性的目的。在基于模型的药物开发中,基于机理的数学模型在开发过程中进行了迭代完善,将对研究药物,疾病及其相互干扰的累积知识纳入了目标人群的不同子集。这些模型有助于进行下一个研究的设计,并提高了达到预期功效和安全性终点的可能性。在本文中,讨论了药物开发综合方法的几个理论和实践方面,以及来自不同治疗领域的一些案例研究,这些案例研究说明了药物代谢动力学/药效学疾病模型在药物开发不同阶段的应用。
  • 【肥胖患者长期输注哌拉西林和他唑巴坦的稳态药代动力学和药效学。】 复制标题 收藏 收藏
    DOI:10.1016/j.ijantimicag.2012.09.004 复制DOI
    作者列表:Cheatham SC,Fleming MR,Healy DP,Chung CE,Shea KM,Humphrey ML,Kays MB
    BACKGROUND & AIMS: :The study objective was to evaluate steady-state pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese patients. Fourteen hospitalised patients weighing >120kg received piperacillin/tazobactam 4.5 g every 8 h (q8h) or 6.75 g q8h infused over 4h. Blood samples were collected at steady-state and drug concentrations were determined. Pharmacokinetic parameters were estimated and 5000-patient Monte Carlo simulations were performed for four prolonged-infusion dosing regimens. The probability of target attainment (PTA) for ≥50% fT>MIC was calculated for piperacillin at various MICs, and the PTA for fAUC(0-24)≥96 mg h/L was calculated for tazobactam. Mean±S.D. patient demographics were: age 49±10 years; weight 161±29 kg; and body mass index 52.3±10.8 kg/m(2). For piperacillin and tazobactam, respectively, the mean±S.D. elimination rate was 0.440±0.177 h(-1) and 0.320±0.145 h(-1), volume of distribution was 33.4±14.0L (0.21±0.07L/kg) and 37.5±15.3L (0.23±0.08 L/kg), and systemic clearance was 13.7±5.2L/h and 11.1±4.2L/h. For piperacillin, the PTA was ≥91% for doses ≥4.5g q8h at MICs≤16 μg/mL. For tazobactam, the PTA was 57%, 84% and 94% for doses of 4.5, 6.75 and 9.0g q8h, respectively. The pharmacokinetics of piperacillin and tazobactam are altered in obese patients. To ensure adequate tazobactam concentrations for β-lactamase inhibition, it may be prudent to employ larger initial doses for empirical therapy in obese patients.
    背景与目标: :本研究的目的是评估在肥胖患者中长期输注哌拉西林和他唑巴坦的稳态药代动力学和药效学。体重大于120kg的14例住院患者每8小时(q8h)接受4.5 g哌拉西林/他唑巴坦或4h输注6.75 g q8h。以稳态收集血样并确定药物浓度。估计了药代动力学参数,并针对四种延长输液方案进行了5000名患者的Monte Carlo模拟。对于哌拉西林,在各种MIC下计算≥50%fT> MIC的目标达成概率(PTA),对于他唑巴坦计算fAUC(0-24)≥96mg h / L的PTA。平均值±标准差患者人口统计学特征是:年龄49±10岁;体重161±29 kg;体重指数52.3±10.8 kg / m(2)。对于哌拉西林和他唑巴坦,平均值±S.D。消除速度为0.440±0.177 h(-1)和0.320±0.145 h(-1),分布体积为33.4±14.0L(0.21±0.07L / kg)和37.5±15.3L(0.23±0.08 L / kg) ,全身清除率分别为13.7±5.2L / h和11.1±4.2L / h。对于哌拉西林,当MIC≤16μg/ mL时,≥4.5g q8h剂量的PTA≥91%。对于他唑巴坦,每4.5g,6.75和9.0g q8h剂量的PTA分别为57%,84%和94%。肥胖患者的哌拉西林和他唑巴坦的药代动力学发生变化。为了确保适当的他唑巴坦浓度足以抑制β-内酰胺酶,在肥胖患者中以较大的初始剂量进行经验治疗可能是明智的。
  • 【吸乳期对哺乳期乙醇的药代动力学和药效学的影响。】 复制标题 收藏 收藏
    DOI:10.1038/clpt.2008.119 复制DOI
    作者列表:Pepino MY,Mennella JA
    BACKGROUND & AIMS: :This study tested two hypotheses. First, that breast pumping contributes to the previously observed decrease in ethanol bioavailability in lactating women. Second, that the effects of breast pumping are more pronounced when ethanol is consumed after a meal. The within-subject factor was test condition (fed or fasted) and the between-subject factor was experimental group (pumped before, PB; pumped after, PA). Those randomly assigned to the PB group (N = 8) breast pumped 1 h before drinking, whereas those assigned to the PA group (N = 8) breast pumped 0.6 h after drinking. Pumping before drinking significantly decreased blood ethanol concentration (P < 0.05) and ethanol bioavailability (P = 0.05). Pumping after drinking sped up elimination (P = 0.008), attenuated ethanol-induced hypothermia (P = 0.002), and increased feelings of stimulation (P = 0.03). The effects were more pronounced when ethanol was consumed after a meal. Common neural/hormonal responses to food and suckling may contribute additive effects in altering the pharmacokinetics/pharmacodynamics of ethanol, and perhaps of other drugs, during lactation.
    背景与目标: :这项研究检验了两个假设。首先,吸乳会导致先前观察到的哺乳期妇女乙醇生物利用度下降。其次,饭后食用乙醇时,吸乳的效果更加明显。受试者内部因素为测试条件(进食或禁食),受试者间因素为实验组(PB之前泵送,PA之后泵送)。随机分配到PB组(N = 8)的人在饮水前1 h抽水,而分配到PA组(N = 8)的人在饮水后0.6 h抽水。饮酒前抽水会显着降低血液中的乙醇浓度(P <0.05)和乙醇生物利用度(P = 0.05)。饮酒后的抽气加快了消除速度(P = 0.008),减弱了乙醇诱导的体温过低(P = 0.002),并增加了刺激感(P = 0.03)。饭后食用乙醇时,效果更为明显。常见的对食物和哺乳的神经/激素反应可能在哺乳期间改变乙醇(可能还有其他药物)的药代动力学/药效学中发挥加和作用。
  • 【静脉和口服咪达唑仑在早产儿中的药效学。】 复制标题 收藏 收藏
    DOI:10.2165/00044011-200323010-00004 复制DOI
    作者列表:de Wildt SN,Kearns GL,Sie SD,Hop WC,van den Anker JN
    BACKGROUND & AIMS: OBJECTIVE:The aim of this study was to evaluate the pharmacodynamics and safety of midazolam after intravenous infusion or oral administration in preterm infants. METHODS ]PATIENTS WERE RANDOMLY ASSIGNED TO INITIALLY RECEIVE MIDAZOLAM 0.1 MG/KG AS A 30-MINUTE INTRAVENOUS INFUSION OR AN ORAL BOLUS DOSE. IF PATIENTS STILL MET THE INCLUSION CRITERIA, THEY THEN RECEIVED MIDAZOLAM VIA THE ALTERNATE ROUTE (AFTER AN INTERVAL OF ≥72 HOURS). PHARMACODYNAMIC MEASUREMENTS CONSISTED OF A COMFORT® SCORE (A PREVIOUSLY VALIDATED SEDATION SCALE FOR PAEDIATRIC PATIENTS) AT BASELINE AND AT 0.5, 1, 2, 4 AND 6 HOURS POSTDOSE. MIDAZOLAM AND 1-OH-MIDAZOLAM CONCENTRATIONS WERE MEASURED AND VITAL SIGNS WERE RECORDED AT ALL PHARMACODYNAMIC MEASUREMENT TIMEPOINTS: RESULTS:A total of 24 infants were enrolled of whom seven received both intravenous and oral midazolam, 13 received only intravenous midazolam, and four received only oral midazolam. Overall, mean COMFORT® scores decreased (i.e. sedation increased) significantly within 30 minutes after intravenous (p S 0.05) and within 1 hour after oral (p = 0.003) midazolam administration. In 45% of patients the COMFORT® scores decreased little or not at all after midazolam, which was similar after both oral and intravenous administration. The sedative response to midazolam did not differ after intravenous or oral administration. No relationship was found between overall COMFORT® scores or change in COMFORT® score from baseline and midazolam, 1-OH-midazolam, or midazolam plus 1-OH-midazolam concentrations. Diastolic blood pressure decreased significantly after intravenous (approximately 11%) but not after oral midazolam administration. No serious adverse events were reported. CONCLUSIONS:Midazolam administered as a 30-minute intravenous infusion or oral bolus dose appears to be effective and well tolerated in a small majority of preterm infants. However, a considerable number of neonates do not appear to respond to midazolam. The lack of response may be due to the fact that patients truly experienced therapeutic failure and/or consequent to the inability of the COMFORT® score to adequately reflect sedation uniformly in sick preterm infants.
    背景与目标: 目的:本研究旨在评估咪达唑仑在静脉输注或口服后对早产儿的药效学和安全性。方法随机分配患者30分钟静脉输注或口服口服剂量的咪达唑仑0.1毫克/千克。如果患者仍然符合纳入标准,则他们会通过替代路线(间隔≥72小时后)接收到咪达唑仑。基线时以及服药后0.5、1、2、4和6小时,由COMFORT®分数(一种经过验证的小儿患者镇静分数)组成的药动学测量。在所有药代动力学测量时间点测量了咪达唑仑和1-OH-咪唑啉的浓度,并记录了生命体征:
    结果:共纳入24例婴儿,其中7例同时接受静脉和口服咪达唑仑治疗,13例仅接受静脉注射咪达唑仑治疗,4例仅接受口服咪达唑仑治疗。总体而言,静脉给予咪达唑仑后30分钟内(PS 0.05)和口服咪达唑仑1小时内(P = 0.003),平均COMFORT®评分显着降低(即镇静作用增加)。在咪达唑仑用药后,COMFORT®评分在45%的患者中几乎没有或根本没有下降,这在口服和静脉内给药后均相似。静脉或口服给药后,对咪达唑仑的镇静反应无差异。在总体COMFORT®分数或分数与基线和咪达唑仑,1-OH-咪达唑仑或咪达唑仑或咪达唑仑加1-OH-咪达唑仑浓度之间的变化之间未发现任何关系。静脉注射后舒张压显着下降(约11%),但口服咪达唑仑后并未降低。没有严重的不良反应的报道。
    结论:咪达唑仑以30分钟静脉滴注或口服推注剂量给药对多数早产儿似乎是有效且耐受性良好的。但是,相当多的新生儿似乎对咪达唑仑没有反应。缺乏反应可能是由于患者确实经历了治疗失败和/或由于COMFORT®评分无法充分反映病态早产儿的镇静作用。
  • 【腺病毒在小鼠内耳组织内分布的药效学。】 复制标题 收藏 收藏
    DOI:10.1016/j.heares.2006.07.002 复制DOI
    作者列表:Praetorius M,Baker K,Brough DE,Plinkert P,Staecker H
    BACKGROUND & AIMS: :Recent studies have demonstrated that delivery of genes to the inner ear can achieve a variety of effects ranging from support of auditory neuron survival to protection and restoration of hair cells, demonstrating the utility of vector based gene delivery. Translation of these findings to useful experimental systems or even clinical applications requires a detailed understanding of the pharmacokinetics of gene delivery in the inner ear. Ideal gene delivery systems will employ a well tolerated vector which efficiently transduces the appropriate target cells within a tissue, but spare non-target structures. Adenovectors based on serotype 5 (Ad 5) are commonly used vectors, are easy to construct and have a long track record of efficacious gene transfer in the inner ear. In this study we demonstrate that distribution of Ad5 vector occurs in a basal to apical gradient with rapid distribution of vector to the vestibule after delivery via a round window cochleostomy. Transduction of the vector and expression of the delivered transgene occurs by 10 min post vector delivery. At 24 h post delivery only 16% of vector that was initially detectable within the inner ear by quantitative PCR remained. Perilymph sampling was used to determine that vector concentrations in perilymph peaked at 30 min post delivery and then declined rapidly. Understanding these basic distribution patterns and parameters for delivery are important for the design of gene delivery vectors and vital for modeling dose responses to achieve safe efficacious delivery of a therapeutic agent.
    背景与目标: :最近的研究表明,向内耳传递基因可以实现多种效果,从支持听觉神经元存活到保护和恢复毛细胞,证明了基于载体的基因传递的实用性。将这些发现转化为有用的实验系统甚至临床应用,都需要对内耳基因传递的药代动力学的详细了解。理想的基因递送系统将采用耐受性良好的载体,该载体可有效地转导组织内适当的靶细胞,但保留非靶结构。基于血清型5(Ad 5)的腺载体是常用的载体,易于构建并且在内耳中有效基因转移具有悠久的记录。在这项研究中,我们证明了Ad5载体的分布发生在基础到顶端的梯度中,通过圆形窗口耳蜗切开术递送后,载体迅速分布到前庭。在载体递送后10分钟发生载体的转导和递送的转基因的表达。分娩后24小时,仅剩下16%的最初可通过定量PCR在内耳中检测到的载体。外周淋巴取样用于确定外周淋巴中的载体浓度在分娩后30分钟达到峰值,然后迅速下降。理解这些基本的分布模式和传递参数对于基因传递载体的设计很重要,对于建模剂量反应以实现安全有效的治疗药物传递也至关重要。
  • 【新型蒽吡咯烷酮(NSC 349174)的I期研究和药效学。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Hantel A,Donehower RC,Rowinsky EK,Vance E,Clarke BV,McGuire WP,Ettinger DS,Noe DA,Grochow LB
    BACKGROUND & AIMS: :Piroxantrone (PRX, NSC 349174) is one of the first of a new class of intercalating agents, the anthrapyrazoles, to undergo clinical evaluation. Additionally, it is the first drug trial to prospectively test a new pharmacology-based dose escalation schema proposed for Phase I trials of anticancer compounds. In this Phase I trial, PRX was administered as a 1-h infusion every 3 weeks to patients with advanced cancer. Forty-four evaluable patients received 116 courses at doses ranging from 7.5 to 190 mg/m2. The dose-limiting toxicity was myelosuppression with leukopenia predominating. Nonhematological toxicities were minimal and consisted of nausea and vomiting, alopecia, mucositis, and phlebitis. Based on this trial, the maximum tolerated and recommended Phase II doses for PRX administered on this schedule are 190 and 150 mg/m2, respectively. PRX plasma elimination was rapid and best fit by a two-compartment model for 17 of 24 patients receiving greater than or equal to 90 mg/m2. The plasma clearance rate was 1290 +/- 484 ml/min (720 +/- 210 ml/min/m2) and did not vary with dose. The t1/2 alpha was 2.9 +/- 5.3 (SD) min and the t1/2 beta was 18.7 +/- 36.5 min. Area under the concentration versus time curve (AUC) at the maximal tolerated dose (MTD) was 435 mumol.min/liter, 40% higher than the predicted AUC from preclinical testing. The percentage decrease in WBC and neutrophil count was correlated with the AUC. The potential advantage of pharmacology-based dose escalation was limited in this study by assay insensitivity, extremely rapid plasma elimination, and the proximity of the starting dose to the dose where the target AUC was achieved and standard dose escalations were to begin. Consequently, there was no reduction in the number of dose escalations required to define the maximum tolerated dose. However, the practical aspects of this approach have been established and its use is recommended for further trials where detailed preclinical pharmacological studies are available.
    背景与目标: 吡咯酮(PRX,NSC 349174)是新型插层剂中的第一类,蒽吡唑类经过临床评估。此外,这是第一个前瞻性测试针对抗癌化合物的I期临床试验提出的基于新药理学的剂量递增方案的药物试验。在该I期试验中,PRX每3周输注1小时给晚期癌症患者。四十四名可评估的患者接受了116个疗程,剂量范围为7.5至190 mg / m2。剂量限制性毒性为以白细胞减少为主的骨髓抑制。非血液学毒性最小,包括恶心和呕吐,脱发,粘膜炎和静脉炎。根据该试验,按此时间表施用的PRX的最大II期耐受剂量和推荐剂量分别为190 mg / m2和150 mg / m2。通过两室模型,对于接受大于或等于90 mg / m2的患者中的17名,PRX血浆清除速度很快且最合适。血浆清除率是1290 /-484 ml / min(720 /-210 ml / min / m2),并且不随剂量而变化。 t1 / 2 alpha为2.9 /-5.3(SD)分钟,t1 / 2 beta为18.7 /-36.5分钟。在最大耐受剂量(MTD)下,浓度-时间曲线下的面积(AUC)为435摩尔/分钟/升,比临床前测试中预测的AUC高40%。 WBC和中性粒细胞计数的百分比降低与AUC相关。在这项研究中,基于药理学的剂量递增的潜在优势受到测定法的不敏感性,极快的血浆消除以及起始剂量与达到目标AUC并开始进行标准剂量递增的剂量的接近程度的限制。因此,定义最大耐受剂量所需的剂量递增次数没有减少。但是,已经建立了该方法的实践方面,建议将其用于可进行详细临床前药理学研究的进一步试验。
  • 【人参和丹参与5-氟尿嘧啶的相互作用对大鼠药代动力学和人体细胞药效学的初步评估。】 复制标题 收藏 收藏
    DOI:10.1142/S0192415X13500328 复制DOI
    作者列表:Gu C,Qiao J,Zhu M,Du J,Shang W,Yin W,Wang W,Han M,Lu W
    BACKGROUND & AIMS: :An increasing number of cancer patients are using herbs in combination with conventional chemotherapeutic treatment. It is therefore important to study the potential consequences of the interactions between herbs and anticancer drugs. The effects of extracts from Panax ginseng (PGS) and Salvia miltiorrhiza Bunge (SMB) on the pharmacokinetics of 5-fluorouracil (5-FU) were performed in vivo and detected by high performance liquid chromatography (HPLC), while, an ATP assay was used to study the pharmacodynamic interactions in vitro. The results of the pharmacokinetic experiments showed a significant increase in the elimination half-life (t1/2(k e )) of 5-FU in the PGS-pretreated group and in the area under the curve (AUC) in the SMB-pretreated group compared with the control group. However, after SMB pretreatment, weight loss was observed in rats. The results of pharmacodynamic experiments showed that neither PGS nor SMB, when used alone, directly inhibited cancer cell growth at 0.1-100 μg/ml. Moreover, PGS had a synergistic cytotoxic effect with 5-FU on human gastric cancer cells but not on normal gastric cells. The results imply that when combined with 5-FU, PGS may be a better candidate for further study. This study might provide insights for the selection of herbal-chemotherapy agent interactions.
    背景与目标: :越来越多的癌症患者将草药与常规化学疗法结合使用。因此,重要的是研究草药与抗癌药物之间相互作用的潜在后果。人参(PGS)和丹参(SMB)的提取物对5-氟尿嘧啶(5-FU)药代动力学的影响在体内进行,并通过高效液相色谱(HPLC)检测,而ATP测定用于研究体外药效学相互作用。药代动力学实验的结果表明,在PGS预处理组中,5-FU的消除半衰期(t1 / 2(ke))显着增加;在SMB预处理组中,曲线下面积(AUC)显着增加与对照组相比。然而,在SMB预处理后,在大鼠中观察到体重减轻。药效学实验的结果表明,单独使用PGS和SMB均不能以0.1-100μg/ ml的浓度直接抑制癌细胞的生长。而且,PGS与5-FU对人胃癌细胞具有协同的细胞毒性作用,而对正常胃细胞则没有。结果表明,当与5-FU结合使用时,PGS可能是进一步研究的更好候选者。这项研究可能为选择草药-化学治疗剂相互作用提供见解。
  • 【每周一次依泊汀β在肺癌患者中的药代动力学和药效学。】 复制标题 收藏 收藏
    DOI:10.1093/jjco/hyl074 复制DOI
    作者列表:Fujisaka Y,Tamura T,Ohe Y,Kunitoh H,Sekine I,Yamamoto N,Nokihara H,Horiike A,Kodama T,Saijo N
    BACKGROUND & AIMS: BACKGROUND:To assess the pharmacokinetic profile and time-course of trough concentrations and hemoglobin levels associated with subcutaneous weekly administration of epoetin beta in lung cancer patients with chemotherapy-induced anemia. METHODS:Epoetin beta was subcutaneously administered to 15 anemic lung cancer patients once weekly for 8 weeks at doses of 9000, 18,000 and 36,000 IU. Pharmacokinetic parameters (C(max), AUC(inf) and T(1/2)) were determined after the first single dose administration on a model-independent basis, and the relationship between the dose and these parameters was examined for linearity. RESULTS:Weekly administration of epoetin beta at 9000, 18,000 and 36,000 IU produced C(max) values of 308 +/- 117 (mean +/- standard deviation), 678 +/- 86.7 and 1316 +/- 766 mIU/ml, and AUC(inf) values of 15,300 +/- 9524, 54,574 +/- 16,265 and 88,501 +/- 55,687 hr mIU/ml, respectively, showing dose-proportional increases. Trough concentrations tended to increase in the presence of severe bone marrow suppression induced by chemotherapy or other factors. Extremely high values were seen in three patients, but there was no apparent trend toward an increase with repeated doses. After 8 weeks' administration at 9000, 18,000 and 36,000 IU, hemoglobin levels were changed by -0.37 +/- 1.26, 2.15 +/- 1.36 and 2.82 +/- 2.17 g/dl, respectively. CONCLUSIONS:Epoetin beta exhibited linear pharmacokinetics when administered to anemic cancer patients at weekly doses of 9000-36,000 IU and did not cause drug accumulation. Hemoglobin levels increased with weekly doses of 18,000 or 36,000 IU.
    背景与目标: 背景:为了评估与化疗引起的贫血的肺癌患者每周皮下注射依泊汀β相关的药代动力学特征,谷浓度和血红蛋白水平的时程变化。
    方法:Epoetin beta每周一次皮下注射15例贫血性肺癌患者,共9000、18,000和36,000 IU,共8周。在不依赖模型的基础上首次单次给药后确定药代动力学参数(C(max),AUC(inf)和T(1/2)),并检查剂量与这些参数之间的线性关系。
    结果:每周以9000、18,000和36,000 IU施用epoetin beta产生的C(max)值为308 /-117(平均值/-标准偏差),678 /-86.7和1316 /-766 mIU / ml和AUC(inf )分别为15,300 /-9524、54,574 /-16,265和88,501 /-55,087 hr mIU / ml,表明剂量成比例增加。在由化学疗法或其他因素引起的严重骨髓抑制的情况下,谷浓度趋于增加。在三名患者中观察到极高的值,但是并没有明显的趋势表明重复剂量会增加。在9000、18,000和36,000 IU给药8周后,血红蛋白水平分别改变了-0.37 /-1.26、2.15 /-1.36和2.82 /-2.17 g / dl。
    结论:Epoetinβ每周以9000-36,000 IU的剂量向贫血癌症患者给药时显示出线性的药代动力学,并且不会引起药物蓄积。血红蛋白水平随着每周18,000或36,000 IU的剂量而增加。
  • 【分离的灌注兔肺吸收和代谢5-羟色胺的药效学。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Pickett RD,Anderson MW,Orton TC,Eling TE
    BACKGROUND & AIMS: We have investigated the dynamics for the removal of 5-hydroxytryptamine (5-HT) from the circulation using the isolated perfused rabbit lung. 5-HT was removed from the circulation at a constant rate and metabolized completely to 5-hydroxyindoleacetic acid which effluxed from the lung into the circulation. Two methods were developed to determine the constant rate of removal of 5-HT(1) the constant rate is equal to the difference between the 5-HT concentration flowing into the lung and the 5-HT concentration in the effluent times the flow rate and (2) extrapolation of the rate of appearance of radioactivity in the effluent to zero time. With these methods, we have confirmed the 5-HT is removed by the lung by a carrier-mediated Na+-dependent transport system. Studies of transport systems in perfused organs required an adequate supply of the chemical to the lung. Supply rates less than removal rate will result in erroneous measurements of the constant removal rate. The relationships between the rate of removal, perfusate concentration and perfusion rate were analyzed.

    背景与目标: 我们已经研究了使用分离的灌注兔肺从循环中去除5-羟色胺(5-HT)的动力学。以恒定的速率从循环中除去5-HT,并完全代谢为5-羟基吲哚乙酸,其从肺排入循环中。开发了两种方法来确定5-HT的恒定去除率(1),该恒定率等于流入肺中的5-HT浓度与流出物中的5-HT浓度之差乘以流速和(2)将废水中放射性物质的出现率外推至零时间。通过这些方法,我们已经证实5-HT通过载体介导的Na依赖性转运系统被肺部清除。对灌注器官中运输系统的研究要求向肺部提供足够的化学物质。供给速率小于去除速率会导致恒定去除速率的错误测量。分析了去除率,灌注液浓度和灌注率之间的关系。

  • 【通过单次硬膜外注射向健康志愿者施用布比卡因脂质体的药代动力学和药效学。】 复制标题 收藏 收藏
    DOI:10.1097/AAP.0b013e318269d29e 复制DOI
    作者列表:Viscusi ER,Candiotti KA,Onel E,Morren M,Ludbrook GL
    BACKGROUND & AIMS: BACKGROUND AND OBJECTIVES:The objective of this study was to assess the pharmacokinetics, sensory/motor effects, and safety of epidurally administered liposome bupivacaine versus bupivacaine HCl in healthy volunteers. METHODS:Thirty subjects were randomized to receive liposome bupivacaine 89, 155, or 266 mg, or bupivacaine HCl 50 mg in a double-blind fashion. Occurrence/duration of motor blockade, pinprick/cold sensitivity, and plasma bupivacaine levels were assessed for 96 hours after study drug administration. Tolerability parameters were also assessed. RESULTS:All doses of liposome bupivacaine resulted in greater area under the curve and a longer time to observed maximum plasma concentration and terminal elimination half-life than bupivacaine HCl 50 mg. Mean maximum plasma concentration with liposome bupivacaine 89 and 155 mg (but not 266 mg) was statistically significantly lower than with bupivacaine HCl 50 mg (P < 0.001). Median duration of motor blockade with liposome bupivacaine 266 mg was 1 hour versus 2.8 hours for bupivacaine HCl. Of subjects who received liposome bupivacaine 266 mg, 29% (2/7) were unable to ambulate at 4 hours postdose versus 67% (4/6) of those receiving bupivacaine HCl. Median durations of pinprick/cold sensitivity loss were 36 and 69 hours, respectively, in the liposome bupivacaine 266-mg group versus 12 hours for both pinprick and cold in the bupivacaine HCl group. Liposome bupivacaine was well tolerated; the most common adverse event in all treatment groups was injection site pain, which resolved within 30 days for most subjects. CONCLUSIONS:Epidurally administered liposome bupivacaine 266 mg resulted in a longer duration of sensory blockade than liposome bupivacaine 89 or 155 mg or bupivacaine HCl 50 mg. Duration of motor blockade was shorter with liposome bupivacaine 266 mg versus bupivacaine HCl.
    背景与目标: 背景与目的:这项研究的目的是评估健康志愿者中硬膜外给予布比卡因脂质体对盐酸布比卡因的药代动力学,感觉/运动作用和安全性。
    方法:将30名受试者随机分为双盲方式接受89、155或266 mg布比卡因脂质体或50 mg盐酸布比卡因脂质体。在服用研究药物后的96小时内,评估了运动阻滞的发生/持续时间,针刺/感冒敏感性和血浆布比卡因水平。还评估了耐受性参数。
    结果:与50 mg盐酸布比卡因相比,所有剂量的布比卡因脂质体均能产生更大的曲线下面积,并具有更长的观察到最大血浆浓度和最终消除半衰期的时间。用布比卡因脂质体89和155 mg(但不是266 mg)的平均最大血浆浓度在统计学上显着低于50 mg盐酸布比卡因(P <0.001)。用266mg布比卡因脂质体进行运动阻滞的中位时间为1小时,而盐酸布比卡因为2.8小时。在接受266 mg布比卡因脂质体的受试者中,服药后4小时29%(2/7)不能行走,而接受盐酸布比卡因的受试者中67%(4/6)无法行走。脂质体布比卡因266-mg组的针刺/冷敏性丧失中位持续时间分别为36和69小时,而盐酸布比卡因组的针刺和感冒则分别为12小时和12小时。布比卡因脂质体耐受性良好;在所有治疗组中,最常见的不良事件是注射部位疼痛,大多数受试者在30天内即可缓解。
    结论:硬膜外给药266 mg布比卡因脂质体比89%或155 mg布比卡因脂质体或50 mg盐酸布比卡因导致更长的感觉阻滞持续时间。与布比卡因盐酸盐相比,使用266 mg布比卡因脂质体可以缩短运动阻滞的持续时间。
  • 【omalizumab的药效学:对优化剂量策略和治疗过敏性哮喘的临床疗效的影响。】 复制标题 收藏 收藏
    DOI:10.1185/030079903125002171 复制DOI
    作者列表:Hochhaus G,Brookman L,Fox H,Johnson C,Matthews J,Ren S,Deniz Y
    BACKGROUND & AIMS: OBJECTIVE:Omalizumab (Xolair), is a recombinant humanised monoclonal anti-immunoglobulin E (IgE) antibody, for the treatment of allergic asthma. This review describes how the correlation between clinical outcomes and a suitable surrogate marker (free serum IgE) led to the development of an individualised dosing strategy for omalizumab. It also demonstrates how subsequent studies using this dosing strategy were able to achieve low levels of IgE and clinical benefit. DATA SOURCES:Published articles and data on file (Novartis Pharma AG, Genentech). RESULTS:Studies in patients with IgE-mediated diseases of the airways have shown that clinical benefit with omalizumab is observed when free IgE levels in serum are reduced to 50 ng/ml (20.8 IU/ml) or less (target 25 ng/ml (10.4 IU/ml)). The ability of omalizumab to reduce free IgE levels to such levels is dependent on dose, the patient's weight and baseline IgE level. To simplify dosing, and ensure that free IgE reduction is achieved, an individualised tiered dosing table was developed from which patients with asthma, depending on weight and starting IgE level, receive omalizumab 150-375 mg by subcutaneous injection every 2 or 4 weeks. This dosing strategy has proved clinically efficacious for improving disease control in patients with allergic asthma, as shown by significantly lower exacerbation rates and decreased dependence on treatment with inhaled corticosteroids, along with improvements in symptoms, lung function and usage of rescue bronchodilators. CONCLUSIONS:The clinical efficacy of omalizumab has been optimised through the development of an individualised dosing table that emerged from an understanding of the pharmacodynamics of this agent.
    背景与目标: 目的:奥马珠单抗(Xolair)是一种重组人源化单克隆抗免疫球蛋白E(IgE)抗体,用于治疗过敏性哮喘。这篇综述描述了临床结果与合适的替代指标(游离血清IgE)之间的相关性如何导致奥马珠单抗的个体化给药策略的发展。它还证明了使用该剂量策略的后续研究如何能够实现低水平的IgE和临床益处。
    数据来源:已发表的文章和数据存档(Novartis Pharma AG,Genentech)。
    结果:对IgE介导的气道疾病患者的研究表明,当血清中的游离IgE水平降低至50 ng / ml(20.8 IU / ml)或更低(目标25 ng / ml( 10.4 IU / ml)。奥马珠单抗将游离IgE水平降低至此类水平的能力取决于剂量,患者体重和基线IgE水平。为了简化剂量,并确保实现免费的IgE降低,开发了个性化的分层剂量表,根据体重和起始IgE水平,哮喘患者每2或4周通过皮下注射接受奥马珠单抗150-375 mg。这种给药策略已被证明在临床上可有效改善过敏性哮喘患者的疾病控制,这表现为明显降低了急性发作率,降低了对吸入性糖皮质激素治疗的依赖性,并改善了症状,改善了肺功能并使用了挽救性支气管扩张剂。
    结论:奥马珠单抗的临床疗效已通过开发个性化剂量表而得以优化,该剂量表是从对该药的药效学理解中得出的。
  • 【吸入GLP-1(MKC253)的药代动力学和药效学:在健康正常志愿者和2型糖尿病患者中的概念验证研究。】 复制标题 收藏 收藏
    DOI:10.1038/clpt.2010.85 复制DOI
    作者列表:Marino MT,Costello D,Baughman R,Boss A,Cassidy J,Damico C,van Marle S,van Vliet A,Richardson PC
    BACKGROUND & AIMS: :MKC253 is glucagon-like peptide 1 (GLP-1, 7-36 amide) adsorbed onto Technosphere microparticles for oral inhalation. The pharmacokinetics of inhaled GLP-1 and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between inhaled GLP-1 and insulin were analyzed in two trials, one in healthy normal volunteers and the other in patients with type 2 diabetes. Inhaled GLP-1 was absorbed quickly, with peak concentrations occurring within 5 min, and levels returned to baseline within 30 min. Inhaled GLP-1 appeared to produce plasma levels of GLP-1 comparable to those of parenteral administration and sufficient to induce insulin secretion resulting in attenuation of postmeal glucose excursions in subjects with type 2 diabetes. An E(max) (maximum effect) model described the relationship between GLP-1 concentration and insulin release. The variability in the E(max) may be due to differences in baseline glucose levels, differences resulting from genetic polymorphisms in GLP-1 receptors (GLP-1Rs), or the stage of diabetes of the patient.
    背景与目标: :MKC253是胰高血糖素样肽1(GLP-1,7-36酰胺),吸附在Technosphere微粒上,可以口服吸入。在两项试验中分析了吸入GLP-1的药代动力学以及吸入GLP-1和胰岛素之间的药代动力学-药效学(PK-PD)关系,一项是健康正常志愿者,另一项是2型糖尿病患者。吸入的GLP-1很快被吸收,在5分钟内达到峰值浓度,并在30分钟内恢复到基线水平。吸入的GLP-1似乎产生与胃肠外给药相当的GLP-1血浆水平,并且足以诱导胰岛素分泌,从而导致2型糖尿病患者餐后葡萄糖偏移减少。 E(max)(最大作用)模型描述了GLP-1浓度与胰岛素释放之间的关系。 E(max)的可变性可能是由于基线葡萄糖水平的差异,GLP-1受体(GLP-1Rs)的遗传多态性导致的差异或患者的糖尿病分期所致。

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