BACKGROUND & AIMS: :Pharmacological response depends on multiple factors and one of them is sex-gender. Data on the specific effects of sex-gender on pharmacokinetics, as well as the safety and efficacy of numerous medications, are beginning to emerge. Nevertheless, the recruitment of women for clinical research is inadequate, especially during the first phases. In general, pharmacokinetic differences between males and females are more numerous and consistent than disparities in pharmacodynamics. However, sex-gender pharmacodynamic differences are now increasingly being identified at the molecular level. It is now even becoming apparent that sex-gender influences pharmacogenomics and pharmacogenetics. Sex-related differences have been reported for several parameters, and it is consistently shown that women have a worse safety profile, with drug adverse reactions being more frequent and severe in women than in men. Overall, the pharmacological status of women is less well studied than that of men and deserves much more attention. The design of clinical and preclinical studies should have a sex-gender-based approach with the aim of tailoring therapies to an individual's needs and concerns.

背景与目标： : 药理反应取决于多种因素，其中之一是性别。有关性别对药代动力学的特定影响以及许多药物的安全性和有效性的数据开始出现。然而，招募女性进行临床研究是不够的，尤其是在第一阶段。通常，男性和女性之间的药代动力学差异比药效学差异更多且一致。然而，性别-性别药效学差异现在越来越多地在分子水平上被发现。现在甚至变得很明显，性别会影响药物基因组学和药物遗传学。已经报告了几个参数的性别相关差异，并且一直显示女性的安全性较差，女性的药物不良反应比男性更为频繁和严重。总体而言，女性的药理状况比男性研究得少，值得更多关注。临床和临床前研究的设计应采用基于性别的方法，目的是根据个人的需求和关注点定制疗法。

BACKGROUND & AIMS: :Allopurinol is the drug most widely used to lower the blood concentrations of urate and, therefore, to decrease the number of repeated attacks of gout. Allopurinol is rapidly and extensively metabolised to oxypurinol (oxipurinol), and the hypouricaemic efficacy of allopurinol is due very largely to this metabolite. The pharmacokinetic parameters of allopurinol after oral dosage include oral bioavailability of 79 +/- 20% (mean +/- SD), an elimination half-life (t((1/2))) of 1.2 +/- 0.3 hours, apparent oral clearance (CL/F) of 15.8 +/- 5.2 mL/min/kg and an apparent volume of distribution after oral administration (V(d)/F) of 1.31 +/- 0.41 L/kg. Assuming that 90 mg of oxypurinol is formed from every 100mg of allopurinol, the pharmacokinetic parameters of oxypurinol in subjects with normal renal function are a t((1/2)) of 23.3 +/- 6.0 hours, CL/F of 0.31 +/- 0.07 mL/min/kg, V(d)/F of 0.59 +/- 0.16 L/kg, and renal clearance (CL(R)) relative to creatinine clearance of 0.19 +/- 0.06. Oxypurinol is cleared almost entirely by urinary excretion and, for many years, it has been recommended that the dosage of allopurinol should be reduced in renal impairment. A reduced initial target dosage in renal impairment is still reasonable, but recent data on the toxicity of allopurinol indicate that the dosage may be increased above the present guidelines if the reduction in plasma urate concentrations is inadequate. Measurement of plasma concentrations of oxypurinol in selected patients, particularly those with renal impairment, may help to decrease the risk of toxicity and improve the hypouricaemic response. Monitoring of plasma concentrations of oxypurinol should also help to identify patients with poor adherence. Uricosuric drugs, such as probenecid, have potentially opposing effects on the hypouricaemic efficacy of allopurinol. Their uricosuric effect lowers the plasma concentrations of urate; however, they increase the CL(R) of oxypurinol, thus potentially decreasing the influence of allopurinol. The net effect is an increased degree of hypouricaemia, but the interaction is probably limited to patients with normal renal function or only moderate impairment.

背景与目标： : 别嘌醇是最广泛用于降低尿酸盐血药浓度的药物，因此，减少痛风反复发作的次数。别嘌醇迅速而广泛地代谢为氧嘌呤醇 (oxipurinol)，别嘌醇的低尿酸功效很大程度上归因于这种代谢物。口服后别嘌醇的药代动力学参数包括口服生物利用度79 +/- 20% (平均值 +/- SD)，消除半衰期 (t((1/2) 1.2 +/- 0.3小时，15.8 +/- 5.2 ml/min/kg的表观口服清除率 (CL/F) 和1.31 +/- 0.41 L/kg的口服施用后的表观分布体积 (V(d)/F)。假设每100毫克别嘌醇形成90毫克氧嘌呤醇，肾功能正常的受试者中氧嘌呤醇的药代动力学参数为23.3 +/- 6.0小时的t((1/2))，0.31 +/- 0.07毫升/分钟/千克的CL/F，V(d)/F为0.59 +/- 0.16 L/kg，肾清除率 (CL(R)) 相对于肌酐清除率为0.19 +/- 0.06。氧嘌呤醇几乎完全通过尿排泄清除，多年来，建议在肾功能损害时应减少别嘌醇的剂量。减少肾功能损害的初始目标剂量仍然是合理的，但是有关别嘌醇毒性的最新数据表明，如果血浆尿酸盐浓度的降低不足，则该剂量可能会增加到本指南以上。在选定的患者中，尤其是那些患有肾功能不全的患者中，测量氧尿醇的血浆浓度可能有助于降低毒性风险并改善低尿酸反应。监测氧脲醇的血浆浓度也应有助于识别依从性差的患者。尿尿药物，如丙磺舒，对别嘌醇的低尿酸疗效具有潜在的相反作用。它们的尿尿作用降低了尿酸盐的血浆浓度; 但是，它们会增加氧嘌呤醇的CL(R)，从而可能降低别嘌醇的影响。净效应是低尿酸血症的程度增加，但相互作用可能仅限于肾功能正常或仅中度受损的患者。

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：

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是一种与重组人生长激素基因融合的人血清白蛋白，旨在为GH缺乏症患者提供日常生长激素 (GH) 注射的长效替代品。这项研究调查了日本 (n = 44) 和白种人 (n = 44) 健康受试者单次皮下剂量的TV-1106 (7.5、15、50和100 mg) 的药代动力学，药效学和安全性。TV-1106药代动力学和药效学在日本和高加索人群中具有可比性。TV-1106显示相对缓慢的吸收 (中值tmax，10-30小时) 和26-36小时的平均消除半衰期。在两个群体中，表观清除率和分布体积随着TV-1106剂量的增加而降低，并且似乎在整个测试剂量中增加的剂量比例超过剂量比例。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后168小时以及50mg和100 mg TV-1106后336小时恢复到基线值。在这两个人群中，TV-1106似乎都是安全的。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。

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、漫长和昂贵的过程。制药公司和监管机构已经认识到，鉴于投资回报，药物开发过程需要优化效率。药代动力学和药效学是决定剂量和反应之间关系的两个主要原则。本文通过将药代动力学，药效学和疾病方面联系到数学模型中，提供了有关药物开发综合方法的最新信息。逐渐地，正在从相当经验的方法过渡到基于建模和模拟的药物开发方法。主要学习阶段应该是0、I和II阶段，而III阶段研究应该只是具有确认性目的。在基于模型的药物开发中，沿着开发路径迭代完善的基于机制的数学模型结合了研究药物，疾病及其在目标人群的不同子集中的相互干扰的积累知识。这些模型有助于下一项研究的设计，并提高实现预期疗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，说明了药代动力学/药效学疾病模型在药物开发的不同阶段的应用。

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： : 研究目的是评估长期输注的哌拉西林和他唑巴坦在肥胖患者中的稳态药代动力学和药效学。14名体重> 120千克的住院患者每8小时 (q8h) 接受哌拉西林/他唑巴坦4.5g，或在4小时内输注6.75g q8h。在稳态下收集血样并确定药物浓度。估计药代动力学参数，并对四种延长输注给药方案进行5000患者蒙特卡洛模拟。计算哌拉西林在各种MIC下 ≥ 50% fT>MIC的目标达到 (PTA) 的概率，并计算他唑巴坦的fAUC(0-24)≥ 96 mg h/L的PTA。平均 ± s.d。患者人口统计学特征为: 年龄49 ± 10岁; 体重161 ± 29千克; 体重指数52.3 ± 10.8千克/m(2)。哌拉西林和他唑巴坦的平均消除率分别为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)，全身清除率为13.7 ± 5.2L/h和11.1 ± 4.2L/h。对于哌拉西林，在mics ≤ 16 μ g/mL时，对于 ≥ 4.5g q8h的剂量，PTA ≥ 91%。对于他唑巴坦，PTA分别为4.5、6.75和9.0g q8h的剂量57% 、84% 和94%。在肥胖患者中，哌拉西林和他唑巴坦的药代动力学发生了变化。为了确保他唑巴坦的浓度足以抑制 β-内酰胺酶，在肥胖患者中采用较大的初始剂量进行经验性治疗可能是谨慎的。

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降低。其次，当饭后食用乙醇时，吸乳的效果更加明显。受试者内因素为测试条件 (进食或禁食)，受试者间因素为实验组 (泵送前，PB; 泵送后，PA)。那些随机分配到PB组 (N = 8) 的人在饮酒前1小时吸乳，而分配到PA组 (N = 8) 的人在饮酒后0.6小时吸乳。饮用前抽血显著降低血液乙醇浓度 (P < 0.05) 和乙醇生物利用度 (P = 0.05)。饮酒后的抽水加速消除 (P = 0.008)，减弱乙醇诱导的体温过低 (P = 0.002) 和增加的刺激感觉 (P = 0.03)。饭后食用乙醇时，效果更加明显。对食物和哺乳的常见神经/激素反应可能会在哺乳期间改变乙醇和其他药物的药代动力学/药效学方面产生累加效应。

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：

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，将基因递送到内耳可以实现多种效果，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递送的实用性。将这些发现转化为有用的实验系统甚至临床应用，需要对内耳基因传递的药代动力学有详细的了解。理想的基因递送系统将采用耐受性良好的载体，该载体可以有效地转导组织内的适当靶细胞，但保留非靶标结构。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的记录很长。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，并且通过圆窗耳蜗造口术将载体快速分布到前庭。载体的转导和递送的转基因的表达发生在载体递送后10分钟。在递送后24小时，仅保留通过定量PCR在内耳内最初可检测到的载体的16%。外淋巴采样用于确定外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。了解这些基本的分布模式和递送参数对于基因递送载体的设计很重要，并且对于模拟剂量反应以实现治疗剂的安全有效递送至关重要。

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： : 吡罗克蒽醌 (PRX，NSC 349174) 是首批接受临床评估的新型插层剂-蒽唑。此外，这是第一个前瞻性测试新的基于药理学的剂量递增方案的药物试验，该方案为抗癌化合物的I期试验提出。在此I期试验中，PRX每3周以1小时输注的方式向晚期癌症患者施用。44名可评估的患者接受了116疗程，剂量范围为7.5至190 mg/m2。剂量限制性毒性是骨髓抑制，白细胞减少为主。非血液学毒性很小，包括恶心和呕吐，脱发，粘膜炎和静脉炎。基于该试验，按本方案施用的PRX的最大耐受剂量和推荐的II期剂量分别为190和150 mg/m2。对于接受大于或等于90 mg/m2的24名患者中的17名，PRX血浆消除是快速且最适合的两室模型。血浆清除率为1290 +/-484毫升/min (720 +/-210毫升/min/m2)，且不随剂量变化。t1/2α 为2.9 +/- 5.3 (SD) 分钟，t1/2β 为18.7 +/- 36.5分钟。在最大耐受剂量 (MTD) 下的浓度与时间曲线 (AUC) 下的面积为435 mumol.min/l，40% 高于临床前测试的预测AUC。WBC和中性粒细胞计数下降的百分比与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不敏感性，极其快速的血浆消除以及起始剂量与达到目标AUC并开始标准剂量升级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升级数量没有减少。然而，这种方法的实际方面已经建立，并建议将其用于可获得详细的临床前药理学研究的进一步试验。

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正在使用草药与常规化学治疗相结合。因此，研究草药与抗癌药物之间相互作用的潜在后果非常重要。研究了人参 (PGS) 和丹参 (SMB) 提取物对5-氟尿嘧啶 (5-FU) 药代动力学的影响，并通过高效液相色谱 (HPLC) 检测，同时使用ATP测定法研究了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(k e )) 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，SMB预处理后，大鼠体重减轻。药效学实验结果表明，单独使用时，PGS和SMB都不能直接抑制0.1-100 μ g/ml的癌细胞生长。此外，PGS与5-FU对人胃癌细胞具有协同的细胞毒性作用，但对人胃癌细胞没有协同作用。结果表明，与5-FU联合使用时，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-化疗药物相互作用提供见解。

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：

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。将5-HT以恒定的速率从循环中除去，并完全代谢成5-羟基吲哚乙酸，该乙酸从肺排出到循环中。开发了两种方法来确定5-HT的恒定去除速率 (1) 恒定速率等于流入肺的5-HT浓度与流出物中的5-HT浓度之间的差乘以流速和 (2) 将流出物中放射性的出现速率外推至零时间。通过这些方法，我们已经确认5-HT通过载体介导的Na依赖性转运系统被肺去除。对灌注器官中运输系统的研究需要向肺提供足够的化学物质。小于去除率的供应速率将导致对恒定去除率的错误测量。分析了清除率，灌注液浓度和灌注率之间的关系。

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：

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：