左氧氟沙星药代动力学/药效动力学参数与金黄色葡萄球菌耐药的相关性研究

目的:探讨左氧氟沙星药代动力学/药效动力学(PK/PD)参数与金黄色葡萄球菌耐药的相关性。方法:建立兔组织笼金黄色葡萄球菌感染模型,给予不同剂量的左氧氟沙星灌胃治疗。抽取组织笼内组织液进行药代动力学测定,计算PK/PD参数,同时监测组织笼内细菌药物敏感性变化。结果:PK/PD参数AUC24/MIC、AUC24/MPC、Cmax/MIC、Cmax/MPC、T>MPC和Tmsw和耐药发生相关(MIC:最小抑菌浓度,MPC:防耐药变异浓度,MSW:耐药突变选择窗),T>MIC与耐药的发生无相关性。当AUC24/MIC在20～150h时,容易发生耐药,保持药物AUC24/MPC>25h可以限制耐药的发生。体内MSW的上、下限分别为AUC24/MPC=25h和AUC24/MIC=20h。结论:AUC24/MPC、Cmax/MPC和T>MPC可能是预测耐药发生的独立参数。

生理药代动力学模型的发展应用动态及其与其他建模方法的融合

生理药代动力学(physiologically based pharmacokinetics,PBPK)是定量药理学的主要研究领域之一,其在新药研发和临床医疗实践的各个阶段均发挥着重要作用,包括药物早期开发阶段的人体药动学(pharmacokinetics,PK)预测、临床研究阶段考察各种生理和病理等因素对PK的影响、特殊人群剂量调整、药物相互作用等。近年来,PBPK模型在工业界的应用越来越广泛,监管机构也认可PBPK模型在药物研发中的积极指导作用。随着模型指导的药物研发的发展和普及,将PBPK模型与其他常用建模方法,包括群体药代动力学(population pharmacokinetics,PopPK)、药代动力学/药效动力学(pharmacokinetic/pharmacodynamic,PK/PD)模型和基于模型的Meta分析(model-based meta-analysis,MBMA)相融合可实现优势互补。本文简介了PBPK的起源、发展和应用现状,并对其与PopPK、PK/PD和MBMA的融合应用进展进行综述。

药代动力学/药效动力学模型结合蒙特卡罗模拟优化儿童耐甲氧西林金黄色葡萄球菌感染的万古霉素给药方案

目的优化儿童耐甲氧西林金黄色葡萄球菌(MRSA)感染的万古霉素的经验给药方案。方法根据万古霉素的药代动力学/药效动力学(PK/PD)模型,对不同剂量的万古霉素的给药方案进行蒙特卡罗模拟模拟,从而得出最佳的给药方案。结果随着万古霉素的日剂量增加,预期AUC_(0-24)/MIC>400的百分比亦相应增加。当MIC为0.5 mg·L^(-1)时,万古霉素的剂量为35 mg·kg^(-1)·d^(-1),AUC_(0-24)/MIC>400的比例即可达99.41%。当MIC为1 mg·L^(-1)时,剂量增加至65 mg·kg^(-1)·d^(-1)时,AUC_(0-24)/MIC>400才能达到97.55%。当MIC为2 mg·L^(-1)及以上时,没有剂量能达到AUC_(0-24)/MIC>400的要求。结论儿童MRSA感染时,当MIC为0.5 mg·L^(-1)时,万古霉素的经验治疗剂量应大于35 mg·kg^(-1)·d^(-1);当MIC为1.0mg·L^(-1)时,推荐剂量应大于65 mg·kg^(-1)·d^(-1)。

药代动力学/药效动力学研究的文献分析

目的从文献计量角度分析药代动力学/药效动力学(pharmacokinetic/pharmacodynamic,PK/PD)研究概况。方法检索Web of Science数据库,对PK/PD研究的相关情况进行整理。结果 PK/PD研究的年发文量和引文数均呈逐年递增趋势,临床研究相关杂志的载文量居前。我国的发文量居全球第15位,虽然临床前研究较多,但文章的影响力不足。结论我国发表文章的质量与国际前沿研究存在较大差距,建议要加强与国际合作,以提高我国的研究水平。

抗菌药物药代动力学／药效动力学研究进展

抗菌药物药代动力学／药效动力学（ PK／PD）研究将浓度-时间-效应三者有机地结合起来，用以说明给予特定剂量药物后其在体内的药理作用随时间的变化趋势。 PK／PD研究的应用有助于临床医师优化给药方案、减少药物不良反应的发生、控制耐药率，同时对推进敏感性折点改进和新药研发亦有重要作用。该文综述近年来有关抗细菌药物和抗真菌药物的PK／PD研究，以期为临床制订安全、有效的个体化给药方案提供理论依据。

基于PK/PD理论评价泊沙康唑在恶性血液病患者的给药方案

目的应用蒙特卡洛模拟(Monte Carlo simulation,MCS)评价泊沙康唑静脉给药方案对恶性血液病患者曲霉菌感染的疗效。方法结合恶性血液病患者的药动学参数和曲霉菌最低抑菌浓度(minimal inhibitory concentration,MIC)分布,以f_(AUC/MIC)为PK/PD模型进行蒙特卡洛模拟,得到两种静脉给药治疗5种曲霉菌感染的达标概率(PTA)及累积反应分数(CFR)。结果当MIC≤0.064mg/L时,200mg qd和300mg qd静脉输注PTA均达到90%以上;当MIC=0.125mg/L时,仅300mg qd达到PTA>90%;当MIC≥0.25mg/L时,两种给药方案均未达到90%。泊沙康唑治疗土曲霉感染,给药方案300mg qd可达到CFR>90%;对黄曲霉、烟曲霉、黑曲霉和构巢曲霉,两种方案CFR均小于90%。结论在恶性血液病患者中,泊沙康唑对不同菌种曲霉菌的疗效相差较大,建议根据不同菌种选择相应给药方案。

模型引导的药物开发在新药研发中的应用

模型引导的药物开发(MIDD)通过应用各类数学模型进行定量分析,从而指导新药开发和决策。MIDD在先进药物研发企业中的研发决策应用,以及先进监管部门的监管决策尤其美国FDA的应用,已较为普遍和成熟,但在国内创新药研究中的普及率还相对较低。本文根据作者实际工作经验,基于当前新药临床药理专业审评中常见的模型研究内容和有代表性的案例,结合国内外MIDD相关技术指导原则,对MIDD的主要应用范畴进行了探讨,并简要讨论了MIDD应用于新药研发的几点建议和注册申报的一般考虑,供新药开发企业和研究者讨论或参考。

Pharmacokinetics of Scutellarin in Dogs

Aim To establish an RP-HPLC method for the determination of scutellarin in plasma and study its pharmacokinetics in dogs. Methods Scutellarin was given to dogs by intravenous injection and determined by RP-HPLC, the mean plasma concentration-time curve was plotted and pharmacokinetic parameters were calculated by program 3p87. Resu;ts The concentration-time curve of scutellarin could be fitted to three-compartment model with T1/2 pi, T1/2 α and T1/2 β being 1.05 ± 0.80 min, 6.99 + 2.76 min and 51.61 + 28.78 min, respectively, Vc being 880.1 + 508.3 mL, CL being 189.6 + 53.8 mL@ min- 1, and AUC0-90 and AUC0-∞ being 574.43 + 133.95 μg@ min@ mL - 1 and 599.34 ± 132.00μg@ min@mL- 1, respectively. Conclusion The fact that the concentrations of scutellarin in plasma declined rapidly after the medication suggested that the T1/2 of scutellarin should be taken into account in drug administration and preparation development.

Pharmacokinetic-Pharmacodynamic Studies on Propra-nolol and 4-Hydroxypropranolol

The pharmacokinetic-pharmacodynamics of propranolol (PPL) and its activemetabolite 4-hydroxypropranolol (4-OH-P) was studied on Chinese subJects by single or multipleoral administration. The efficiency of beta-blockade was measured as the reduction of heart rates orblood pressure in the supine and upnght positions during rest or exercise period. After a single doseof 40 mg PPL, the plasma concentration of 4-OH-P was quite high, C (m) max and AUC (m) were26. 1±13.2 ng/ml and 180±69 ng.h/ml respectively, which were 50% and 73% of those of PPL.Whileafter multiple dose administration, the plasma PPL concentration increased much greater than that insingle administration and the 4-OH-P/PPL plasma level ratio fell from 0.79±0.64 at single dose toonly 0.48±0.32 at steady-state. The pharmacodynamic half-life of PPL on inbibiting exercising heart-rate was much longer than the halflife of drug concentration (8.78±2.27 vs 4.23±1.33 h. P<0.0 1).The Css 50. plasma concentration at steady-state producing 50% maximal efficacy, was 44.66±35.24ng/ml. The study showed that 4-OH-P is an important active metabolite of PPL and one of thepossible factors causing the considering variations in the response to PPL in Chinese people.

Translational pain research: Evaluating analgesic effect in experimental visceral pain models

Deep visceral pain is frequent and presents major challenges in pain management, since its pathophysiology is still poorly understood. One way to optimize treatment of visceral pain is to improve knowledge of the mechanisms behind the pain and the mode of action of analgesic substances. This can be achieved through stand-ardized experimental human pain models. Experimental pain models in healthy volunteers are advantageous for evaluation of analgesic action, as this is often diff icult to assess in the clinic because of confounding factors such as sedation, nausea and general malaise. These pain models facilitate minimizing the gap between knowledge gained in animal and human clinical studies. Combining experimental pain studies and pharmacokinetic stud- ies can improve understanding of the pharmacokinetic-pharmacodynamic relationship of analgesics and, thus, provide valuable insight into optimal clinical treatment of visceral pain. To improve treatment of visceral pain, it is important to study the underlying mechanisms of pain and the action of analgesics used for its treatment. An experimental pain model activates different modalities and can be used to investigate the mechanism of action of different analgesics in detail. In combination with pharmacokinetic studies and objective assessment such as electroencephalography, new information re-garding a given drug substance and its effects can be obtained. Results from experimental human visceral pain research can bridge the gap in knowledge between animal studies and clinical condition in patients suffering from visceral pain, and thus constitute the missing link in translational pain research.

Pharmacokinetic Study of a Novel Recombinant Human Granulocyte Colony-stimulating Factor in Rats

Objective To study the pharmacokinetics of a novel recombinant human granulocyte colonystimulating factor (rhG-CSFa) in rats and to determine the proteolytic rates of rhG-CSFa in the whole blood and serum of rats in vitro. Methods The pharmacokinetics of rhG-CSFa and conventional (wild type,WT) granulocyte colonystimulating factor (G-CSF) were investigated in Sprague-Dawley rats which received either intravenous or subcutaneous injection of rhG-CSFa or WT G-CSF at three different doses (20,50,or 100 μg/kg). The blood samples of rats were collected at multiple time points (from 0.08 to 12 h) and the concentrations of rhG-CSFa and WT G-CSF in serum were determined with a sandwich enzyme-linked immunosorbent assay (ELISA). For the study of proteolytic rates in vitro,the concentrations of rhG-CSFa or WT G-CSF were determined at 3-minute intervals after addition of the respective drug to rat’s whole blood or serum. Results Pharmacokinetic analysis of serum rhG-CSFa or WT G-CSF levels indicated that,at each dose tested,for either route of drug administration,the area under concentration-time curve values and the maximum serum concentration of rhG-CSFa were higher than those of WT G-CSF,and the serum half life of rhG-CSFa was longer than that of WT G-CSF. Subsequent in vitro whole blood and serum stability study showed that the rates of drug degradation in WT G-CSF were 1.8 folds and 1.5 folds higher than those in rhG-CSFa,respectively. Conclusion rhG-CSFa has better serum and whole blood stability in vitro and higher bioavailability in vivo as compared to WT G-CSF.

Pharmacokinetics and Pharmacodynamics of Subcutaneous Single Doses of Pegylated Human G-CSF Mutant(PEG30-rhG-CSF) in Beagle Dogs

OBJECTIVE To compare the pharmacokinetics and pharmacodynamics of PEG30-rhG-CSF administered to beagle dogs at three different dosages with PEG20-rhG-CSF administered at one dosage, and to provide an experimental basis for clinical trials.METHODS Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200 μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzymeqinked immunosorbent assay （ELISA）. WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis software.METHODS Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzyme-linked immunosorbent assay （ELISA）. WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis software. RESULTS The pharmacokinetic parameters of PEG30-rhG-CSF calculated from the serum concentration data determined by ELISA were as follows： the mean elimination half-life （t1/2ke） was 40.6 h （33.5-45.4 h）; the mean time to reach peak concentration （Tmax） was 19.2 h （11.7-24.0 h）; the drug clearance from the serum （CL） was decreased with increasing doses; the peak concentration （Cmax） and the area under the serum concentration-time curve （AUC） were increased with increasing doses. For PEG20-rhG- CSF, the half-life was shorter （12 h） and Tmax was achieved much earlier （10 h） relative to PEG30-rhG-CSF. The AUC of PEG30- rhG-CSF was much greater than that of PEG20-rhG-CSF, and the relative bioavailability with a subcutaneous injection was 158.7%. Administration of single doses of PEG30-rhG-CSF resulted in substantial increases in the absolute The time to reach ANC （ANCTmax） neutrophil count （ANC）. was 72 h. The maximum observed absolute neutrophil counts （ANCmax） and the area over the baseline effect curve （AOBEC） was increased with increasing doses. The effect-elimination half-life （t1/2E） ranged from 60 h to 80 h after subcutaneous administration. The PLT count was slightly elevated 8-12 h after s.c. injection, and declined after 24 h. CONCLUSION The mean elimination half-life of PEG30-rhG- CSF was longer than that of PEG20-rhG-CSF at the same dose, and the other main pharmacokinetic and pharmacodynamic parameters of PEG30-rhG-CSF, including C ANCmax, AUC and AOBEC were much greater than those following PEG20-rhG-CSF injection.

P-glycoprotein mediated interactions between Chinese materia medica and pharmaceutical drugs

P-glycoprotein(P-gp)is an important transmembrane ATP-binding cassette(ABC)drug efflux transporter expressed in various human tissues such as the intestines,liver,kidneys,and bloodbrain barrier.It limits the intracellular concentration of xenobiotics by pumping them out of the cells,affecting drug pharmacokinetics and therapeutic effects.With its broad substrate specificity,it has the potential to remove a wide range of drugs from Chinese materia medica(CMM),including conventional medicines and active compounds.Increasing evidence has confirmed the superior therapeutic effectiveness of CMM in treating a wide range of diseases worldwide,as well as in conjunction with western drugs.As a result,herbal medicine-drug compounds have prompted widespread concern,with the majority of these interactions involving transporters such as P-gp.This review systematically summarizes the inhibition or induction of P-gp expression/function by active CMM compounds and the underlying regulatory mechanisms.It will aid in improving understanding of the synergistic or inhibiting effects associated with transporter P-gp as well as rational safety concerns for using CMM,particularly in combination with drugs.

Comparison of pharmacokinetics,efficacy and toxicity profile of gemcitabine using two different administration regimens in Chinese patients with non-small-cell lung cancer

Objective： To conduct a randomized comparative trial of pharmacokinetics, efficacy and toxicity profile treatment with 1200 mg/m^2 gemcitabine using standard 30-min infusion or fixed dose rate （FDR） infusion [10 mg/（m^2-min）] on days 1 and 8 plus carboplatin AUC （area under curve） 5 on day 1 in Chinese non-small-cell cancer patients. Twelve patients were enrolled in this study. Methods： Plasma gemcitabine concentrations were measured by ion-pair reversed phase high performance liquid chromatography. Antitumoral activity and toxicity of gemcitabine was assessed according to World Health Organization criteria. Results： The obtained mean parameters, such as T1/2 （elimination half time）, AUC, and CL （clearance）, were consistent with those reported in literature. Qualified response rate in our study was 33.3% for standard arm and 50% for FDR ann. Additional 50% and 33.3% patients contracted stable disease （SD） in standard arm and FDR arm, respectively. The predominant toxicity was hematologic, and patients in the standard infusion ann experienced consistently more hematologic toxicity, Conclusion： Pharmacokinetic and clinical data in this trial support the continued evaluation of the FDR infusion strategy with gemcitabine.

Preparation and evaluation of sinomenine hydrochloride patch

The sinomenine hydrochloride （SH） patch, a topical drug delivery system, was prepared and characterized. The in vitro release was studied according to the paddle-over-disk method in the appendix of Chinese Pharmacopeia （appendix XD, 2005）. Stability of SH patch was evaluated at accelerated testing conditions （40 ℃, 75% RH）. Pharmacological and pharmacokinetics study were also performed. It was found that the release of SH from patches depended on pH value of the release medium. There were no significant differences between SH patches stored for 6 mon and those stored for 0 mon in the drug content, initial adhesion, lasting stickiness, peeling strength and in vitro release. SH patches exhibited better anti-inflammatory activity as well as analgesic efficacy. More importantly, primary pharmacokinetic parameters of SH patch, such as Cmax and AUC, were much lower than those of SH solution dosed orally. In conclusion, the patch might be a promising delivery system for SH, which bypassed the gastrointestinal tract and was a convenient, efficacious, safe and non-invasive delivery method.

肾功能亢进在危重症患者中的研究进展

近年来,国外学者提出了'肾功能亢进'(ARC)的概念,将其定义为肾脏对药物的清除能力增强,当肌酐清除率(CrCl)>130 mL·(min·1.73 m2)-1时即认为患者存在ARC。ARC在危重症患者中较为多见,其发生和多种因素有关,炎症反应综合征和肾功能储备可能是其发生的主要机制。目前研究认为ARC对危重症患者的抗菌药物的药动学影响显著,增加的肌酐清除率与抗菌药物血药浓度呈负相关,可能需要增加给药剂量或延长输注时间来确保疗效,必要时根据治疗药物监测(TDM)结果及时调整给药剂量,但ARC对危重症患者的临床结局的影响尚且存在争议。本文查阅国内外关于ARC的文献,对其概念、流行病学、发生机制、对抗菌药物药代动力学/药效动力学(PK/PD)的影响进行综述,旨在为临床用药提供参考。