抗菌药物的PK/PD参数与优化抗菌治疗

目的概述了抗菌药物药动学/药效学(PK/PD)参数与临床优化抗菌治疗的关系。方法参阅相关文献,进行综合、分析和归纳。结果根据PK/PD参数,抗菌药物大致可分为浓度依赖性、时间依赖性且半衰期较短、时间依赖性且抗菌活性持续时间(如PAE)较长者三类。结论 PK/PD参数对临床优化抗菌治疗和合理应用抗菌药物都具有重要意义。

腹膜透析并金黄色葡萄球菌感染哌拉西林他唑巴坦用药方案分析及优化

目的促进临床合理用药。方法选择2012年7月至2014年6月经病原菌确诊为金黄色葡萄球菌且对哌拉西林他唑巴坦(PIP/TAZ)敏感的住院腹膜透析患者51例,统计其给药方案,利用抗菌药物药效学/药动学(PK/PD)理论的主要评价参数以及内生肌酐清除率(CCr)分析PIP/TAZ的给药方案,并以此为依据优化其用药方案。结果 51例患者中有23例PIP/TAZ的给药方案为每8 h 1次,28例为12 h 1次4.5 g,给药剂量或给药频次明显超过PK/PD理论以及CCr原则对抗菌药物用药的分析结果;通过PK/PD理论和CCr原则分析,对该类患者可推荐采用每24 h 1次1.5 g的给药方案。结论 PK/PD理论及CCr原则是腹膜透析并感染患者抗菌药物有效应用和优化给药方案的依据,经验用药应以药学理论为指导,为患者提供安全、有效和合理的个体化用药方案。

蒙特卡洛模拟评价替加环素治疗革兰阴性菌感染给药方案

目的:应用蒙特卡洛模拟方法评价替加环素治疗临床常见革兰阴性杆菌引起的医院获得性肺炎(HAP)、复杂腹腔感染(cIAI)以及复杂皮肤软组织感染(cSSSI)的给药方案。方法:收集2018年中国CHINET耐药性监测网相关替加环素对鲍曼不动杆菌、大肠埃希菌、肺炎克雷伯菌以及阴沟肠杆菌的最低抑菌浓度(MIC)数据,结合药动学/药效学(PK/PD)理论利用蒙特卡洛模拟,计算不同给药方案的达标概率(PTA)和累计反应分数(CFR)。结果:治疗革兰阴性菌引起的医院获得性肺炎,当MIC≤0.5μg/mL时,替加环素50 mg q12h给药剂量的PTA>90%,当MIC≥1μg/mL,100 mg q12h剂量的PTA和CFR均大于90%,当MIC≥2μg/mL,50 mg q12h、75 mg q12h和100 mg q12h给药剂量的PTA小于90%。当替加环素治疗复杂腹腔感染,MIC≤0.5μg/mL时,50 mg q12h的PTA达到目标值,当MIC=1μg/mL时,仅100 mg q12h给药剂量的PTA大于90%。对复杂皮肤软组织感染,当MIC≤0.25μg/mL时,75 mg q12h和100 mg q12h的剂量可使PTA大于90%,当MIC≥0.5μg/mL,所有给药方案的PTA和CFR均小于90%。结论:替加环素50 mg q12h的剂量更适合用于治疗HAP。当敏感菌MIC>0.5μg/mL时,替加环素治疗cIAI可能需要100mg q12h的剂量获得最佳临床疗效。替加环素治疗cSSSI,只有当MIC≤0.25μg/mL,可以选用75 mg q12h、100 mg q12h的给药方案。对大肠埃希菌引起的三种感染,替加环素50 mg q12h的给药剂量可能获得较好的临床疗效。

细胞药代动力学研究进展

经典的药物代谢动力学理论是建立在血浆药物浓度测定的基础上,常难以真实有效地预测体内药物的药效。很多药物必须穿透多重生物屏障,与细胞内的靶点相结合才能发挥药效。因此药代动力学研究迫切需要从"宏观"的血浆药物浓度深入到"微观"的细胞/亚细胞水平。综述细胞药代动力学研究领域取得的进展,重点介绍细胞药代动力学理论的提出、技术体系的建立及其在药物研发、筛选、临床方面的应用。

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.

Is the required therapeutic effect always achieved by racemic switch of proton-pump inhibitors?

Many of the drugs currently used in medical practice are racemates. The enantiomers of a racemic drug differ in pharmacodynamics and/or pharmacokinetics, thus in some cases it is preferable to develop pure enantiomers by racemic switch. In a recent study by Pai et al, dexrabeprazole [R(+)-rabeprazole] (10 mg) was found to be more effective than rabeprazole (20 mg) in the treatment of gastroesophageal reflux disease. We read with great interest in this study and discussed whether such racemic switch would be applicable to other proton-pump inhibitors (PPIs). A literature review indicates that stereoselective pharmacokinetics, rather than stereoselective pharmacological activity, is the main cause of differences in clinical efficacy between pure enantiomer and racemic PPI. Racemic switches of PPI provide the therapeutic advantages such as reducing metabolic load on the body, simplifying pharmacokinetics, providing benefit to the non-responders to standard dose of racemate, more homogenous response to treatment and better efficacy with equal safety. Further studies in quantitative structure-activity relationships (QSARs) are needed to address the fact that the preferred enantiomer of PPI is not always in the same absolute configuration, i.e., S-form is for omeprazole, pantoprazole and tenatoprazole whereas R-form is for lansoprazole and rabeprazole.

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.

Study of Linearization of Hill Dose-Effect Curve with Metabolic Velocity Instead of Drug Concentration

Objective To explore the velocity-effect relationship in order to the establish linearization of effect on an equation with regard to the consistency of the Hill dose-effect expression with the metabolic kinetics of receptors.Methods The linear velocity-effect expression was obtained by solving multivariant differential equation groups,which were established to compare the coincidences and basic relations between the Hill dose-effect and metabolic kinetic Michaelis-Menten equation for receptors.The validation test was conducted with acetylcholine,adrenaline,and their mixture as model drugs.Results The linear velocity-effect modelling was represented in vivo or in vitro,for single and multidrug systems.Pharmacodynamic parameters,especially suitable for multicomponent CMM formulas,could be determined and calculated for single or multicomponent formulas at high saturating or low linear concentration for receptors.The validation test showed that the pharmacodynamic parameters of acetylcholine were:k,2.675×10^-3s^-1;ka,5.786×10^-9s^-1;km,2.500×10^-7s^-1;α,4.619×10^9张s·mg^-1;E0,13张(P<0.01)and those of adrenaline were:k,1.415×10^-3s^-1;ka,5.846×10^-9s^-1;km,2.300×10^-7s^-1;α,-1.627×10^9张s·m g^-1;E0,9.2张(P<0.01).For the mixture of the two components,the values were:α,1.375×1010张s·m g^-1;-6.150×10^9张s m g^-1for acetylcholine and adrenaline,respectively,and E0was7.08张in both,with the other parameters unchanged(P<0.01).Conclusion The velocity-effect equation can linearize the Hill dose-effect relationship,which can be applied to study the pharmacodynamics and availability of CMM formulations in vivo and in vitro.

血管移植物感染影像学特征及评价

血管移植物感染(VGI)是血管移植术后的罕见但严重的并发症,其高致死率和致残率对病人的健康构成重大威胁。明确诊断和及时治疗对于改善病人预后具有重要意义。VGI的诊断主要依赖于临床表现、实验室检查和影像学检查。影像学检查在早期发现感染灶、评估病变范围和性质方面发挥了关键作用。临床表现方面,VGI通常表现为发热、不明原因的菌血症、体重减轻、局部疼痛等非特异性症状。实验室检查中常见炎症指标如白细胞计数、C反应蛋白和红细胞沉降率升高,但特异性较低,基因检测等新兴技术可显著提高病原体检测的阳性率。影像学检查包括超声、CT、MRI和核医学成像。CT血管成像(CTA)是疑似VGI的首选检查,可直观显示感染特征,如血管周围的积气、积液和假性动脉瘤等。18氟-脱氧葡萄糖正电子发射计算机断层扫描(18F-FDG PET/CT)具有较高的敏感度,可显示感染的代谢信息,在诊断和鉴别诊断中提供重要依据。主动脉移植物感染管理协作组(MAGIC)标准为VGI的诊断提供了系统的分类方法,包括主要指标和次要指标,当满足一个主要指标或来自不同类别的两个次要指标时,需高度怀疑VGI。通过影像学检查、实验室检测与临床表现的综合评估,可实现对VGI的早期识别和诊断,为后续治疗提供可靠依据。影像学技术在确定病变范围、指导手术规划及治疗效果评估中具有不可替代的价值。未来,随着成像技术的进一步发展,VGI的诊断和治疗将更加精确高效。

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.

Preparation and evaluation of docetaxel-loaded albumin nanoparticles for intravenous administration

Docetaxel （DTX） was incorporated into albumin nanoparticles to form the docetaxel loaded nanoparticles （DTX-NPs） with a high-pressure homogenization method. The purpose of this procedure was to improve the solubility, stability and biocompatibility of DTX. In our study, particle size, zeta potential, size distribution, and encapsulation efficiency were investigated. The crystalloid state of DTX in nanoparticles was further determined by the X-ray diffraction technique. The hemolysis rate, pharmacokinetics and pharmacodynamics of the DTX-NPs were analyzed and compared with the injectable docetaxel solution （DTX-Sol）, which was fabricated according to the formulation of the commercial Taxotere. It demonstrated that the DTX-NPs were prepared successfully with these properties, including the （193±4） nm size, （-30±1） mV zeta potential and 69%±2% encapsulation efficiency. Higher stability was achieved in the lyophilized nanoparticles compared to that in the nanoparticle suspension. Furthermore, less hemolysis effect was observed in the DTX-NPs than that in the DTX-Sol. The pharmacokinetic and pharmacodynamic behaviors of the DTX-NPs were similar as that of DTX-Sol based on the in vivo experiments. In conclusion, albumin nanoparticles may act as a useful and safe carder for DTX.

Pharmacological and clinical evaluation of a new anti-flu drug, baloxavir marboxil

Baloxavir marboxil is a polymerase acidic(PA)endonuclease inhibitor,which is approved by the U.S Food and Drug Administration(FDA)on October 25,2018,for the treatment of uncomplicated influenza patients aged 12 years and older.In the present work,we reviewed the pharmacodynamics,pharmacokinetics,drug interactions,clinical trials and adverse reactions of baloxavir marboxil.

Mechanism-based pharmacokinetic/pharmacodynamic modeling of the effects of sitagliptin on DPP-4 activity, insulin and glucose in diabetic rats

Dipeptidyl peptidase-4（DPP-4） inhibitors exert their antihyperglycemic effects through repressing inactivation of certain incretin hormones and thus increasing insulin secretion and controlling glucose level. In this study, the plasma concentrations of sitagliptin, a potent DPP-4 inhibitor, after a single oral dose of 300 mg/kg in streptozotocin-induced type 2 diabetic rats were determined by HPLC. A one-compartment pharmacokinetic（PK） model with first order absorption was developed to describe the PK profile of sitagliptin, and the drug concentrations at the doses given in the pharmacodynamic（PD） study were simulated accordingly. The dynamic changes in DPP-4 activity, insulin concentration and blood glucose level in diabetic rats at doses of 1, 5 and 10 mg/kg were measured, and a mechanism-based PK/PD model was established subsequently. In this model, the inhibitory effect of sitagliptin on DPP-4 activity was demonstrated using the Hill＇s function with direct link, and the downstream increase in insulin secretion and inhibition of glucose production were characterized using indirect response（IDR） models. This model interpreted the mechanism of antihyperglycemic action of sitagliptin, and may be modified and applied to other species or other agents in this class.