抗菌药物的药动学和药效学参数对临床用药的指导作用

目的 探讨抗菌药物的药动学/药效学(PK/PD)参数与临床用药方案的关系.方法 参阅相关文献,依据药效学和药动学理论,结合临床用药实际,确定抗茵药物的用药方案.结果 抗菌药物可分为浓度依赖性抗菌药物和时间依赖性抗菌药物.结论 依据PK/PD综合参数对制定合理给药方案、提高临床疗效有重要意义.     

临床用药问题解答

1 抗菌药物根据其药效学特征分为哪几类,其给药方案有 何特点 抗菌药物依照药效学特征可分为浓度依赖型和时间依赖型两大类。不同类型的抗菌药物应从药效学方面的不同来制定不同的给药方案。药效学是衡量药物浓度、药理作用及毒副作用的一门学科。目前,用于指导临床用药的药效学参数包括:①药物浓度高于MIC的时间占给药间期的百分比(T>MIC％),受此参数制约的抗生素主要是β-内酰胺类和大环内酯类。②24小时曲线下面积(AUC)与MIC的比率(24hAUIC),其相关抗菌药物是氨基苷类及喹诺酮类等。③峰浓度(Peak)与MIC的比率,其相关抗菌药物有四环素、氨基苷类及喹诺酮类。     

伏立康唑的药动学/药效学及其药物监测

伏立康唑为新一代三唑类抗真菌药,抗菌谱广,抗菌作用强,主要用于治疗患有进展性、可能威胁生命的真菌感染的患者。其药动学呈非线性,个体差异大。本文对伏立康唑药动学影响因素,药动学/药效学特性,血药浓度与治疗效果、不良反应间关系以及不同类患者伏立康唑药物监测作一综述,以指导临床制定个性化给药方案,提高药物治疗效果。     

以药动学/药效学相关参数为依据优化抗菌药物给药方案

目的：概述药动学／药效学相关参数与临床给药方案的关系。方法：参考国内外有关文献，综合、分析和归纳。结果：抗菌药动学／药效学相关参数对优化抗菌药物给药方案具有重要作用。结论：依据以药动学／药效学相关参数，优化抗菌药物给药方案，可以更好地发挥抗菌药物的临床治疗效果，降低不良反应和耐药性的发生率，提高患者的依从性，对减轻患者的病痛缩短治疗时间和节约有限的医药资源有着极大意义。     

抗菌药物的药动学和药效学参数对临床用药的意义

目的:概述抗菌药物的药动学/药效学(PK/PD)参数与临床用药方案的关系.方法:参阅相关文献,综合、分析和归纳.结果:抗菌药物可分为浓度依赖性、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(PAE)较长者三类.结论:依据PK/PD综合参数对制定合理给药方案、提高临床疗效有重要意义.     

胆道感染时抗菌药物的合理应用

胆道感染的治疗要重视病原菌变迁和细菌学检查。选择抗菌药物应从抗菌活性、药动学特点、药物在胆汁中浓度、毒副作用、细菌耐药性综合考虑。用药效学参数评价联合用药和设计最佳给药方案，这样才能把药物、细菌、机体三者的作用关系进行整合，指导临床更加合理地使用抗菌药物。     

万古霉素个体化给药方案的研究进展及展望

目的:为临床制订万古霉素的个体化给药方案提供参考。方法:以"万古霉素""药动学""药效学""Vancomycin""Pharmacokinetics""Therapeutic drug monitoring"等为关键词,组合查询2000-2017年在中国知网、万方、维普、PubMed等数据库中的相关文献,从药动学、药效学和个体化给药等方面对万古霉素目前在临床应用中的现状进行综述,并对理想的万古霉素个体化给药方案进行展望。结果:共检索到相关文献1 986篇,其中有效文献32篇。万古霉素药动学特性受个体年龄、肥胖和肾功能等多种因素影响,从而导致疗效的个体差异。评价其药效最佳的指标为药-时曲线下面积/最低抑菌浓度,但是该值所需样品数量较大,临床为了应用方便,一般以其稳态血药谷浓度作为参考。蒙特卡洛模拟和群体药动学软件已开始应用于万古霉素的个体化给药,发现不同患者群体应采用不同的给药方案,目前已有学者根据群体药动学模型对其初始剂量进行设计,并实现了预测值与实测值的显著相关。结论:理想的个体化给药方案应首先根据群体药动学模型结合患者个体生理指标,设计初始给药方案,然后在用药过程中及时根据治疗药物监测结果进行调整,期间密切进行药学监护,将极大提高其治疗有效率,并减少不良反应发生率。     

基于Excel函数设计抗菌药物间歇静脉滴注给药方案

目的:设计抗菌药物间歇静脉滴注给药方案。方法:以头孢唑啉钠、头孢曲松钠、阿米卡星为例,采用多剂量函数法处理相关药动学数据,将药动学与药效学(PK/PD)参数相结合,应用Excel软件编写计算程序,设计合理给药方案。结果:时间依赖性抗菌药物的杀菌效应主要取决于血药浓度高于细菌最低抑菌浓度(MIC)的时间;对于血浆消除半衰期短的抗菌药物宜采取小剂量均匀分次给药,甚至持续给药;半衰期较长者12～24h给药1次即可。浓度依赖性抗菌药物优化临床抗菌疗效的最佳PK/PD参数为Cmax/MIC,适宜日剂量单次给予。结论:基于PK/PD,应用Excel函数设计抗菌药物间歇静脉滴注给药方案,方法简便、可靠、直观。     

药物动力学和药效动力学在抗菌药物新药开发和临床治疗上的应用

制定合理的给药方案是抗菌药物开发中临床试验成败的关键。近十年来群体药物动力学和药效动力学的发展和在抗菌药新药开发上的应用，对抗菌药物合理给药方案的制定有了突破性进展，已基本上形成了抗菌药物新药开发的一个模式。这一模式以药动药效学理论指导下的体外动力学模型、动物体内感染模型和Ⅰ期临床药动学试验为基础，以随机化统计模型和蒙地卡罗模拟为手段对Ⅲ期临床试验的给药方案进行统计比较以确定最佳的给药剂量和频率。本文系统性地描述如何从临床前和临床试验中获得准确可靠的数据进而建立药动药效学数学模型，着重于阐述抗菌药物药效学的基本概念、试验方法学的基本原理并简单介绍药动药效学的计算方法.     

PK/PD与抗菌药物的合理应用

目的介绍了抗菌药物药动学/药效学(PK/PD)参数与临床合理用药的关系。方法查阅有关文献,进行分析和归纳。结果依据PK/PD参数,抗菌药物可分为浓度依赖性、时间依赖性、时间依赖性且抗菌活性持续时间较长即有明显的PAE者。结论依据PK/PD对优化临床给药方案,合理应用抗菌药物具有重要意义。     

Cerebral metabolism of [3H]-p-chloroamphetamine

The time-dependent metabolism of intraventricularly administered $\text{[}{}^3\text{H}\text{]-p-}\text{chloroamphetamine}$ was followed. The parent compound and its metabolites were recovered by high pressure liquid chromatography and characterized by high pressure liquid chromatography, thin-layer chromatography, and gas chromatography-mass spectrometry. By 4 hr after injection, two major toluene-soluble metabolites were present in brain. Their biological half-lives were different from the parent compound. On the basis of their analyses, one of the metabolites is p-chloronorephedrine, the other (P₃) is as yet unidentified. Pretreatment with Lilly 110140 prevented or markedly reduced the synthesis of both p-chloronorephedrine and P₃. Iprindole prevented the synthesis of p-chloronorephedrine. The P₃ appeared first in the brain then in the liver, suggesting that both of these organs can metabolize p-chloroamphetamine to this compound. The metabolites were recovered primarily from the nuclear and microsomal fractions following subcellular fractionation of the brain, with small quantities present in the synaptosomal fraction. The level of metabolites was higher in the brainstem than in the neocortex. Glutathione, administered simultaneously with p-chloroamphetamine either intraventricularly or intraperitoneally failed to alter the toxicity of p-chloroamphetamine.     

Clevudine University of Georgia/Abbott/Bukwang/Triangle/Yale University

The pyrimidine analog, clevudine (L-FMAU: 2'-fluoro-5-methyl-beta-L-arabinofuranosyluridine) is a potent antihepatitis B virus (HBV) and anti-Epstein-Barr virus (EBV) agent, discovered by researchers at the University of Georgia, in collaboration with Yale University and Bukwang. Bukwang transferred its technology to Triangle Pharmaceuticals in 1998 together with a license to develop clevudine worldwide except Korea [279649], [281942]. In June 1999, Triangle and Abbott Laboratories entered into a strategic alliance to copromote antiviral products including L-FMAU [326798]. In September 2000, Triangle Pharmaceuticals Inc initiated a 30-day phase I/II evaluation of clevudine in HBV-infected patients [381755]. Clevudine is a much less toxic derivative of the toxic agent P-D-FMAU. The mechanism of action of clevudine is not yet clear, but the agent induces a rapid decrease in HBV nucleic acid as doses increase from 0.3 to 10 mg/kg [319145]. It is believed that the target for clevudine lies in the viral replication mechanism. Clevudine is phosphorylated to the triphosphate form intracellularly. This is removed slowly from the cells, thus exerting a sustained inhibitory antiviral activity [178173], [320720], [320721].     

Spotlight from the American Society for Preventive Cardiology on Key Features of the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guidelines on the Management of Blood Cholesterol

The 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol retains focus on recommendations for statin treatment in the original four statin-eligible groups [those with atherosclerotic cardiovascular disease (ASCVD), diabetes, low-density lipoprotein cholesterol (LDL-C) ≥ 190 mg/dL, and higher risk primary prevention] without the use of treatment initiation or target LDL-C levels from the earlier 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline, but has several new features. First, patients with primary prevention are divided into those who are at low (< 5%), borderline (5% to < 7.5%), intermediate (7.5% to < 20%), and high (≥ 20%) risk based on the ASCVD risk estimator. Moreover, the new guideline goes further to consider a wider range of factors [now called “risk enhancers”—premature family history of ASCVD, persistently high LDL-C, chronic kidney disease (CKD), metabolic syndrome, conditions specific to women, inflammatory diseases, and high-risk ethnicities] that can be used to better inform the treatment decision. Moreover, more detailed recommendations on how the results of coronary calcium scanning can be used to inform the treatment decision are provided, including how it may be used to “de-risk” certain patients for delaying or avoiding the use of statin therapy. There are also specific sections for cholesterol management in other patient subgroups including women, children, certain ethnic groups, those with CKD, chronic inflammatory disorders and HIV, as well as discussion on the management of hypertriglyceridemia. Importantly, for persons with known ASCVD, a distinction is made for those who are at “very high risk” based on having had two major ASCVD events or one major event and two or more other high risk conditions, such as diabetes or other major risk factors, or bypass surgery or percutaneous intervention. Finally, the concept of a threshold LDL-C for initiating a non-statin therapy (after considering highest tolerated statin dosage) is provided, with ezetimibe recommended as the key non-statin to be added if the LDL-C still remains ≥ 70 mg/dL for all ASCVD patients, and in those who are at “very high risk”, further consideration for using a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. While the new guideline does have greater detail (and arguably, complexity), the refinements provide a strategy for guiding the clinician to target both statin and non-statin therapy to those most likely to derive benefit.     

Pitavastatin Nissan/Kowa Yakuhin/Novartis/Sankyo

Pitavastatin (nisvastatin) is an HMG CoA reductase inhibitor being developed jointly by Nissan, Kowa Kogyo, Novartis and Sankyo for the potential treatment of atherosclerosis and hyperlipidemia.     

Amlodipine/Valsartan/Hydrochlorothiazide

Amlodipine/valsartan/hydrochlorothiazide (HCTZ) is a fixed-dose combination of the well established antihypertensive agents amlodipine (a calcium channel antagonist), valsartan (an angiotensin II receptor antagonist), and HCTZ (a thiazide diuretic). In patients with moderate or severe hypertension, triple combination therapy with amlodipine + valsartan + HCTZ produced significantly greater reductions from baseline in mean sitting systolic and diastolic BP (msSBP and msDBP) than either valsartan + HCTZ, amlodipine + HCTZ, or amlodipine + valsartan in a large, 8-week, randomized, double-blind, multinational, phase III trial. Furthermore, the proportion of patients achieving overall BP control at endpoint was significantly greater with the triple combination regimen than with any of the dual regimens, with significantly more triple combination recipients achieving msSBP and msDBP control at each assessment throughout the trial. Subgroup analyses of this study suggested that amlodipine + valsartan + HCTZ was generally more effective in reducing BP and providing overall BP control than the dual combination therapies, irrespective of age, race, gender, ethnicity, or hypertension severity. Several smaller studies provide data that support the efficacy of amlodipine + valsartan + HCTZ in patients whose BP is inadequately controlled with amlodipine + valsartan, amlodipine + HCTZ, or valsartan + HCTZ dual combination therapy. Treatment with amlodipine + valsartan + HCTZ for up to 8 weeks was generally well tolerated in the large, phase III trial, with most adverse events being transient and of mild to moderate severity.     

N-Nitroso-N-Methyldodecylamine and N-Nitroso-N-Methyltetradecylamine in household dishwashing liquids

Eleven household dishwashing liquids and four household surface cleaners were analysed for N-nitroso-N-methyldodecylamine and N-nitroso-N-methyltetradecylamine by gas chromatography with detection using a Thermal Energy Analyzer. Both nitrosamines were found in three of the dishwashing detergents and one of the surface cleaners. [1-¹⁴C]-N-Nitroso-N-methyldodecylamine was used to determine recoveries, which were between 65 and 88%. Levels of N-nitroso-N-methyldodecylamine ranged from 112 to 661 ppb and those of N-nitroso-N-methyltetradecylamine from 46 to 151 ppb. A simple method was developed to screen the products for N,N-dimethyldodecylamine-N-oxide, a surfactant ingredient suspected of being the source of these nitrosamines. By application of this method it was established that all of the products formulated with this amine oxide contained these two nitrosamines, whereas in products that did not contain this ingredient, these nitrosamines were not detected.     

PROTON AND POTASSIUM TRANSPORT BY H+/K+-ATPases

1. H⁺/K⁺-ATPases are members of the P-type ATPase multigene family. The prototypical H⁺/K⁺-ATPase is the protein that acidifies gastric luminal contents. The physiological and pharmacological significance of this pump has led to a detailed investigation of its biochemistry and molecular and cell biology. 2. Recently, a number of closely related H⁺/K⁺-ATPase isoforms have been discovered. These isoforms are present in organs other than the stomach, including the colon and kidney, where they contribute to acid—base and potassium homeostasis. The structure, expression and physiological roles of the gastric H⁺/K⁺-ATPase and other isoforms are reviewed.