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作用以及多种药物的安全性和有效性的数据开始出现。然而，招募女性从事临床研究是不够的，特别是在第一阶段。通常，雄性和雌性之间的药代动力学差异比药效学上的差异更为广泛和一致。但是，现在越来越多地在分子水平上发现性别药效差异。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。已经报道了几个参数的性别相关差异，并且始终表明，女性的安全性较差，与男性相比，女性的药物不良反应更为频繁和严重。总体而言，与男性相比，女性的药理状况研究较少，应引起更多关注。临床和临床前研究的设计应采用基于性别的方法，目的是根据个体的需要和关注量身定制疗法。

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： ：别嘌呤醇是最广泛用于降低血尿酸盐浓度的药物，因此可减少痛风的反复发作次数。别嘌呤醇被迅速广泛地代谢为氧嘌呤醇（oxipurinol），别嘌呤醇的降尿血药功效在很大程度上归因于这种代谢产物。口服后别嘌醇的药代动力学参数包括79 /-20％（平均/-SD）的口服生物利用度，1.2 /-0.3小时的消除半衰期（t（（1/2））），明显的口腔清除率（ CL / F）为15.8 /-5.2 mL / min / kg，口服后的表观分布体积（V（d）/ F）为1.31 / 0.41 L / kg。假设每100mg别嘌呤醇可形成90mg羟嘌呤醇，那么在肾功能正常的受试者中，氧嘌呤醇的药代动力学参数为（（1/2））为23.3 /-6.0小时，CL / F为0.31 /-0.07 mL / min / kg，V（d）/ F为0.59 /-0.16 L / kg，相对于肌酐清除率的肾清除率（CL（R））为0.19 /-0.06。氧嘌呤醇几乎全部通过尿排泄清除，多年来，建议在肾功能不全时应减少别嘌呤醇的剂量。降低肾功能不全的初始目标剂量仍然是合理的，但是有关别嘌呤醇毒性的最新数据表明，如果血浆尿酸盐浓度的降低不足，则可以将剂量增加到当前指导值以上。在选定的患者中，特别是患有肾功能不全的患者中，测定氧嘌呤醇的血浆浓度可能有助于降低中毒风险并改善低尿毒症反应。监测氧嘌呤醇的血浆浓度也应有助于确定依从性差的患者。尿酸药物，如丙磺舒，对别嘌呤醇的降尿血药功效具有潜在的相反作用。它们的尿尿排尿作用降低了血浆尿酸盐的浓度。但是，它们会增加氧嘌呤醇的CL（R），因此有可能降低别嘌呤醇的影响。净效应是低尿酸血症程度的增加，但这种相互作用可能仅限于肾功能正常或仅有中度损害的患者。

BACKGROUND & AIMS: BACKGROUND:The levonorgestrel-releasing intrauterine system (LNG-IUS) is an effective contraceptive and has many non-contraceptive health benefits. However, it is commonly associated with irregular endometrial bleeding. Metalloproteinases contribute to extracellular matrix (ECM) remodelling and regulate bleeding during the menstrual cycle. Enhanced metalloproteinase expression participates in the pathogenesis of breakthrough bleeding. Thus the objective of this study was to compare matrix metalloproteinase (MMP) expression in endometrium during luteal phase and in short-term (1 month) and long-term (> or =6 months) LNG-IUS users. METHODS:MMP expression was analysed by semi-quantitative RT-PCR and immunohistochemistry. Gelatinase activity was determined by gelatin zymography. RESULTS:MMP-1, -2, -3, -7, -9 and -12 mRNAs levels were increased, whereas that of MMP-26 was decreased in the endometrium of LNG-IUS users. MMP-1, -2, -3, -7 and -9 were localized by immunohistochemistry in all biopsies in the short-term group but in only 0-27% in the control group. The incidence of positive immunostaining for MMP-2 and -3 decreased significantly in the long-term compared with short-term LNG-IUS users. MMP-26 was localized in all biopsies from the control group but in only 14 and 25% from the short- and long-term LNG-IUS groups, respectively. In both LNG groups, the numbers of macrophages (the major source of MMP-12) was increased. CONCLUSIONS:MMP-1, active MMP-2, MMP-3, MMP-7, MMP-9 and MMP-12 are more prevalent in the short-term LNG-IUS group, suggesting their important contribution to ECM breakdown and transient bleeding. The decrease in the percentage of women expressing MMP-2 and -3 might contribute to the decreased occurrence of unwanted spotting and bleeding in long-term LNG-IUS users.

背景与目标： 背景：左炔诺孕酮宫内节育系统（LNG-IUS）是一种有效的避孕方法，具有许多非避孕的健康益处。但是，它通常与子宫内膜不规则出血有关。金属蛋白酶在月经周期内有助于细胞外基质（ECM）重塑并调节出血。增强的金属蛋白酶表达参与突破性出血的发病机理。因此，本研究的目的是比较黄体期，短期（1个月）和长期（>或= 6个月）LNG-IUS使用者子宫内膜中基质金属蛋白酶（MMP）的表达。
方法：采用半定量RT-PCR和免疫组化方法检测MMP的表达。通过明胶酶谱法测定明胶酶活性。
结果：LNG-IUS使用者子宫内膜中MMP-1，-2，-3，-7，-9和-12的mRNA水平升高，而MMP-26的mRNA水平下降。 MMP-1，-2，-3，-7和-9在短期组的所有活检组织中均通过免疫组织化学定位，而在对照组中仅为0-27％。与长期使用LNG-IUS的用户相比，长期而言，MMP-2和-3阳性免疫染色的发生率显着降低。 MMP-26位于对照组所有活检组织中，而短期和长期LNG-IUS组仅分别占14％和25％。在两个液化天然气组中，巨噬细胞（MMP-12的主要来源）的数量均增加了。
结论：短期LNG-IUS组中MMP-1，活性MMP-2，MMP-3，MMP-7，MMP-9和MMP-12更为普遍，表明它们对ECM的分解和短暂性出血具有重要作用。表达MMP-2和-3的女性百分比的降低可能有助于减少长期使用LNG-IUS的使用者出现不必要的斑点和出血的情况。

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。

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。这项研究调查了在日本（n = 44）和白种人（n = 44）健康受试者中单次皮下注射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。

BACKGROUND & AIMS: OBJECTIVE:To assess the relative contraceptive effectiveness, tolerability and acceptability of the levonorgestrel-releasing (20 microg per day) intrauterine system (LNG-20) compared with reversible contraceptive methods in women of reproductive age. DESIGN:A systematic review and meta-analysis of randomised controlled trials. IDENTIFICATION:Studies were identified through seven databases, and by contacting investigators and organisations working in the contraceptive field. MAIN OUTCOME MEASURES:Unplanned pregnancy and continuation of contraceptive method. RESULTS:Five of the seven randomised controlled trials which met the inclusion criteria were included in the meta-analyses; four were comparisons of the LNG-20 intrauterine system with nonhormonal intrauterine devices. LNG-20 intrauterine systems were compared with intrauterine devices divided into two categories, those > 250 mm3 (Copper T 380 Ag and Copper T 380A intrauterine devices) and those < or = 250 mm3 (Nova-T, Copper T 220C and Copper 200 intrauterine devices). Pregnancy rates for the LNG-20 intrauterine system users were significantly less likely to become pregnant compared with users of intrauterine devices < or = 250 mm3, and significantly less likely to have an ectopic pregnancy. LNG-20 intrauterine system users were more likely to experience amenorrhoea and device expulsion than women using intrauterine devices > 250 mm3. LNG-20 intrauterine system users were significantly more likely than all the intrauterine device users to discontinue because of hormonal side effects and amenorrhoea. When the LNG-20 intrauterine system was compared with Norplant-2, the LNG-20 users were significantly more likely to experience oligo-amenorrhoea, but significantly less likely to experience prolonged bleeding and spotting. CONCLUSIONS:The effectiveness of the LNG-20 intrauterine system was similar to or better than other contraceptive methods with which it was compared. Amenorrhoea was the main reason for the discontinuation of the LNG-20 intrauterine system, usually unnecessarily, since this end-organ suppression of bleeding is benign, associated with normal oestrogen levels. Women choosing this method should be informed of potential amenorrhoea when having pre-contraceptive counselling and that absent bleeding may be viewed as a positive outcome.

背景与目标： 目的：评估育龄妇女左炔诺孕酮释放（每天20微克）子宫内系统（LNG-20）与可逆避孕方法的相对避孕效果，耐受性和可接受性。
设计：对随机对照试验的系统评价和荟萃分析。
鉴定：通过七个数据库，并与从事避孕领域工作的研究人员和组织联系，对研究进行了鉴定。
主要观察指标：计划外怀孕和继续避孕方法。
结果：符合纳入标准的七项随机对照试验中，有五项纳入荟萃分析。四是将LNG-20子宫内系统与非激素子宫内装置进行比较。将LNG-20子宫内系统与子宫内设备进行了比较，分为两类，即> 250 mm3的设备（铜T 380 Ag和铜T 380A子宫设备）和≤250 mm3的设备（Nova-T，T 220C铜和200子宫内设备）设备）。与宫内节育器使用者小于或等于250 mm3相比，LNG-20宫腔内系统使用者的怀孕率显着降低，而异位妊娠的可能性也大大降低。与使用宫内节育器> 250 mm3的女性相比，LNG-20宫内节育器系统使用者更容易发生闭经和排出装置。由于激素的副作用和闭经，LNG-20宫内节育器使用者比所有宫内节育器使用者停药的可能性要高得多。当将LNG-20子宫内系统与Norplant-2进行比较时，LNG-20使用者经历寡聚性羊水的可能性明显更高，但经历长时间的出血和斑点的可能性明显降低。
结论：LNG-20子宫内系统的有效性与其他避孕方法相近或优于其他避孕方法。闭经是终止LNG-20子宫内系统的主要原因，通常是不必要的，因为这种终末器官出血抑制作用是良性的，与正常的雌激素水平有关。选择避孕方法的妇女在接受避孕前咨询时应被告知可能的闭经，并且将无出血视为积极的结果。

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。

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。

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。

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。

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，载体快速分布到前庭。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。

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。

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，但对正常胃细胞没有协同作用。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。

BACKGROUND & AIMS: :Acceptability and social characteristics of a cohort of Norplant, IUD, pill and depo-med-roxyprogesterone acetate (DMPA) acceptors who were seen at the University of Ilorin Family Planning Clinic over a 10-week period of the pre-introductory clinical trial of Norplant, are compared. Findings indicate that Norplant and DMPA are adopted as an alternative to sterilization by women advanced in reproductive age and of high parity. The pill and IUD are adopted mainly as birth-spacing methods. Women's education, but not previous use of a contraceptive method, influenced the adoption of Norplant. The continuation rate at 12 months, a measure of acceptability, was highest, 93.7 per 100 women, for Norplant and 77.9, 46.7 and 27.7 per 100 women for the IUD, DMPA and the pill, respectively. The need to address the high family size norms in the African subregion is discussed.

背景与目标： ：Norplant，IUD，药丸和醋酸去氧孕酮孕酮（DMPA）接受者队列的可接受性和社会特征，这些接受者在Ilorin大学计划生育诊所进行了为期10周的临床前临床试验Norplant，进行比较。研究结果表明，育龄高龄和高产妇均采用Norplant和DMPA作为绝育的替代方法。避孕药和宫内节育器主要被用作生育间隔的方法。对妇女的教育影响了Norplant的采用，但以前并未使用避孕方法。在12个月的持续接受率（接受程度）最高，Norplant为每100名妇女93.7分，IUD，DMPA和该药为每100名妇女77.9分，46.7分和27.7分。讨论了解决非洲次区域高家庭规模的规范的必要性。

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：为了评估化疗诱导的贫血的肺癌患者每周皮下注射依泊汀β的相关药物的药动学特征，谷浓度和血红蛋白水平的时程变化。
方法：Epoetinβ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：每周分别以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。