利奈唑胺是否需要血药浓度监测?

利奈唑胺非肝药酶代谢,约35%以原型经肾排泄,说明书提示其浓度受其他药物影响轻微,肾功能不全患者无需调整剂量,但临床研究表明肾功能不全患者利奈唑胺所致血小板减少症或贫血发生率增高与利奈唑胺高暴露相关,且利奈唑胺与某些药物存在的相互作用可显著影响其血药浓度、利奈唑胺的血药浓度在危重症患者中个体差异大,应进行血药浓度监测。     

1例肾功能不全患者使用万古霉素抗感染治疗分析

临床药师对1例肾功能不全患者使用万古霉素进行血药浓度监测．同时进行临床治疗观察。血药浓度采用高效液相色谱法测定,万古霉素在肾动能不全患者体内不易排泄,易蓄积。通过连续三次测得血药浓度,调整临床用药剂量,减少药物毒性,提高使用疗效。万古霉素血药浓度监测在肾功能不全患者的临床治疗中具有积极的指导意义。     

肝功能不全分级方法概述

肝脏是人体最大的实质性脏器和消化腺体,具有分泌、合成、代谢和排泄等多种功能,病毒、病理和化学物质等各种因素均可影响肝实质细胞及肝组织正常结构,引起肝功能不全[1],使药物的肝脏代谢受阻而引发意外.恰当评估肝功能,有利于适当调整用药剂量,保证用药安全.     

细胞毒性药物在肝肾功能不全患者中的剂量调整

目的：探索细胞毒性药物在肝肾功能不全患者中的剂量调整。方法：以"细胞毒性药物","肝功能不全","肾功能不全"为关键词对Pubmed,EMbase,Cochrane Library,中国知网,万方,维普等数据库进行检索,以整理和归纳细胞毒性药物在肝肾功能不全患者中的剂量调整策略。结果：肝肾功能不全可影响药物的代谢动力学,进而影响药物的安全性和有效性。45种常见细胞毒性药物,当肝功能不全时,有41种药物需要进行剂量调整;当肾功能不全时,有33种药物需要进行剂量调整。结论：应重视细胞毒性药物在肝肾功能不全患者中的剂量调整,以保障患者用药的安全性和有效性。     

抗菌药物临床应用的基本原则(续三)

②药物主要经肝脏或有相当量经肝脏清除或代谢,肝功能减退时清除减少,并可导致毒性反应的发生,肝功能减退患者应避免使用此类药物,氯霉素、利福平、红霉素酯化物等属此类。③药物经肝、肾两途径清除,肝功能减退者药物清除减少,血药浓度升高,同时有肾功能减退的患者血药浓度     

抗凝药物在肝肾功能不全患者中的临床应用进展

肝肾功能不全病理生理状态对各种抗凝药物在患者体内的代谢和排泄都会产生一定的影响,使抗凝药物在患者体内的暴露增加,肾脏清除率降低和半衰期延长,从而导致抗凝效果增强,出血风险增加。临床上在肝肾功能不全的患者中使用抗凝药物应当密切监测相关指标,根据患者具体情况调整使用剂量,进行个体化用药,降低患者出血风险。     

卡马西平浓度监测在抗癫痫治疗中的临床价值

本文通过对一线广谱抗癫痫药物卡马西平血药浓度监测分析,评估血药浓度与应用剂量、疗效、药物毒副作用的内在关系;阐明卡马西平在不同人群不同时段肝药酶诱导代谢和药物相关基因多态性及个体基因变异均是血药浓度差异的关键因素。卡马西平用药,宜从小剂量开始在浓度监测下逐步增量,达到有效浓度剂量,以避免过量或治疗窗窄出现不良反应,若在有效血药浓度内难以控制癫痫,建议联合用药或更换药物。     

血透患者应用多联抗癫痫药物治疗抽搐1例

目的:探讨血液透析患者应用多联抗癫痫药物治疗难治性抽搐过程中的给药方案,学习抗癫痫药物血药浓度检测值的解读。方法:以治疗药物监测和透析药物代谢动力学知识分析1例血液透析患者应用多联抗癫痫药物的治疗过程,并对患者用药的有效性和安全性进行监护。结果:合理解读血药浓度检测值,对于解释患者病情变化的原因、提高药物疗效和减少不良反应均有意义,通过药学专业知识的支持,难治性抽搐得到控制,并优化了给药方案。结论:对于血透患者的多联抗癫痫药物治疗,应当结合血药浓度监测,关注药物不良反应,运用血液透析的药物代谢动力学和药物相互作用进行合理解读,制定个体化给药方案。     

药源性肾损害(二)

7肾功能损害时药物应用原则肾功能损害时应用药物的常规剂量,可因肾脏对这些药物的代谢和排泄障碍使其在血液和组织中蓄积达到中毒水平,促使肾功能进一步减损。这种药物的中毒表现可被患者原有疾病的症状所掩盖,不易引起医生重视。因此,肾功能不全者必须根据以下原则综合考虑。7.1用药需有明确适应证。7.2根据内生肌酐清除率正确判断肾功能状态。7.3熟悉所用药物如药物的代谢方式、排泄途径、有效血药浓度、肾毒性大小以及透析对该种药物的清除能力。同样有效的几种抗生素中,应选用肾毒性较低者,避免使用长效药物。7.4根据药物的清除速率调…     

左乙拉西坦治疗药物监测的研究进展

左乙拉西坦（LEV）是第二代广谱抗癫痫药物,具有起效快、半衰期短、疗效确切、耐受性好、药物相互作用少等优点。为提高LEV的临床效果,减少不良反应的发生,应对儿童、妊娠期妇女、老年人、肾功能不全等特殊人群予以治疗药物监测（TDM）。临床上LEV监测样本常选择血浆或血清,监测方法多选择免疫分析法或色谱分析法。LEV的有效浓度范围目前尚无统一意见,血药浓度与不良反应的相关性也不明确。影响LEV血药浓度的因素主要有年龄、妊娠及患者用药依从性等。如何解读TDM结果并根据结果调整给药剂量是今后工作的重点。     

Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed?

A new generation of antiepileptic drugs (AEDs) has reached the market in recent years with ten new compounds: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide. The newer AEDs in general have more predictable pharmacokinetics than older AEDs such as phenytoin, carbamazepine and valproic acid (valproate sodium), which have a pronounced inter-individual variability in their pharmacokinetics and a narrow therapeutic range. For these older drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined 'therapeutic range', representing an interval where most patients are expected to show an optimal response. However, such ranges must be interpreted with caution, since many patients are optimally treated when they have serum concentrations below or above the suggested range. It is often said that there is less need for therapeutic drug monitoring (TDM) with the newer AEDs, although this is partially based on the lack of documented correlation between serum concentration and drug effects. Nevertheless, TDM may be useful despite the shortcomings of existing therapeutic ranges, by utilisation of the concept of 'individual reference concentrations' based on intra-individual comparisons of drug serum concentrations. With this concept, TDM may be indicated regardless of the existence or lack of a well-defined therapeutic range.The ten newer AEDs all have different pharmacological properties, and therefore, the usefulness of TDM for these drugs has to be assessed individually. For vigabatrin, a clear relationship between drug concentration and clinical effect cannot be expected because of its unique mode of action. Therefore, TDM of vigabatrin is mainly to check compliance. The mode of action of the other new AEDs would not preclude the applicability of TDM. For the prodrug oxcarbazepine, TDM is also useful, since the active metabolite licarbazepine is measured.For drugs that are eliminated renally completely unchanged (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate), the pharmacokinetic variability is less pronounced and more predictable. However, the dose-dependent absorption of gabapentin increases its pharmacokinetic variability. Drug interactions can affect topiramate concentrations markedly, and individual factors such as age, pregnancy and renal function will contribute to the pharmacokinetic variability of all renally eliminated AEDs. For those of the newer AEDs that are metabolised (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the older AEDs. Therefore, TDM is likely to be useful in many clinical settings for the newer AEDs. The purpose of the present review is to discuss individually the potential value of TDM of these newer AEDs, with emphasis on pharmacokinetic variability.     

The pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with varying degrees of renal function

An open-label pharmacokinetic and pharmacodynamic study of zoledronic acid (Zometa) was performed in 19 cancer patients with bone metastases and known, varying levels of renal function. Patients were stratified according to creatinine clearance (CLcr) into different groups of normal (CLcr > 80 mL/min), mildly (CLcr = 50-80 mL/min), or moderately/severely impaired (CLcr = 10-50 mL/min) renal function. Three intravenous infusions of 4 mg zoledronic acid were administered at 1-month intervals between doses. Plasma concentrations and amounts excreted in urine were determined in all subjects, and 4 patients were administered 14C-labeled zoledronic acid to assess excretion and distribution of drug in whole blood. In general, the drug was well tolerated by the patients. Mean area under the plasma concentration versus time curve and mean concentration immediately after cessation of drug infusion were lower, and mean amounts excreted in urine over 24 hours from start of infusion were higher in normal subjects than in those with impaired renal function (36% vs. 28% of excreted dose), although the differences were not significant. Furthermore, with repeated doses, there was no evidence of drug accumulation in plasma or changes in drug exposure in any of the groups, nor was there any evidence of changes in renal function status. Serum levels of markers of bone resorption (serum C-telopeptide and N-telopeptide) were noticeably reduced after each dose of zoledronic acid across all three renal groups. It was concluded that in patients with mildly to moderately reduced renal function, dosage adjustment of zoledronic acid is likely not necessary.     

Pharmacokinetic, pharmacodynamic, and pharmacogenetic targeted therapy of antiepileptic drugs

Therapeutic drug monitoring (TDM) is widely accepted as a method to improve the effectiveness and safety of the first generation antiepileptic drugs (AEDs) and to identify an individual's optimum concentration. Like the older AEDs, the new AEDs also have significant pharmacokinetic variability. A similar relationship between concentration and effect for the new and old AEDs in experimental seizure models suggests that it is reasonable to use TDM for the new AEDs. With the addition of generic formulations of the new AEDs, TDM can play an important role to validate bioequivalence in patients. There is a history of problems with generics of the older AEDs, primarily carbamazepine and phenytoin. The Biopharmaceutics Classification System, which correlates the solubility and permeability of a drug with oral drug absorption, predicts that there should be no significant problems with the majority of the new AEDs. Because of the controversy over the risk-benefit of generic substitution of AEDs, the use of TDM will provide a way to ensure patient safety while establishing that generics of AEDs proven to be bioequivalent in population studies are also bioequivalent in individuals. The goal of personalized medicine is to use genetic testing to target therapy and identify those individuals unlikely to respond to a drug or likely to respond adversely to the same drug. Of all the AEDs, only phenytoin undergoes significant metabolism by cytochrome P450 isozymes with significant genetic polymorphisms (CYP2C9, CYP2C19). Studies are still needed to identify genetic and biomarkers to identify patients at risk for serious idiosyncratic reactions. There have been significant advances in the understanding of the role of genetics in idiopathic as well as acquired epilepsies. Identification of experimental and clinical evidence linking functional changes associated with gene mutations to epilepsy syndromes will help provide new molecular targets for future AEDs.     

Pharmacokinetics of ceftriaxone in subjects with renal insufficiency

The pharmacokinetics of ceftriaxone was studied in 14 men and women volunteers with renal insufficiency. Subjects were grouped by renal function: those with end-stage renal disease (CLcr less than 15 mL/min/1.73 sq m) but not receiving dialysis, those with severe renal insufficiency (CLcr 16-30 mL/min/1.73 sq m), and those with moderate renal insufficiency (CLcr 31-60 mL/min/1.73 sq m). Ceftriaxone 1 g as the sodium salt was administered by i.v. infusion over 30 minutes, and blood and urine samples were collected before and up to 48 hours after drug administration. The pharmacokinetic data were described using a nonlinear least-squares computer program. For volunteers with a creatinine clearance of less than 15 mL/min/1.73 sq m, the mean half-life was 15.6 hours. For subjects with a creatinine clearance of 31-60 mL/min/1.73 sq m, the mean half-life was 11.9 hours. Plasma ceftriaxone concentrations measured at the conclusion of the infusion (mean peak concentration 122 +/- 53.1 micrograms/mL) or 24 hours after the infusion (mean concentration 20.2 +/- 6.14 micrograms/mL) were similar in each study group. A dose of ceftriaxone 1 g every 24 hours in patients with renal insufficiency is probably adequate for inhibiting most susceptible gram-positive and gram-negative microorganisms.     

血药浓度监测下大剂量甲氨蝶呤24h滴注疗法延迟排泄分析

目的:研究非霍奇金淋巴瘤患者大剂量甲氨蝶呤(HD-MTX)24 h滴注疗法延迟排泄影响因素、不良反应和解救措施。方法:收集某院2009-2014年之间122个患者的377次疗程的HD-MTX 24 h滴注疗法的资料,运用统计学方法分析延迟排泄和疗程、年龄、性别、剂量、血药浓度及不良反应的相关关系,探讨了延迟排泄的解救措施。结果:延迟排泄发生率与疗程、年龄、性别无关,但与剂量相关,当剂量大于4.0 g时发生率高。延迟排泄患者滴注完12 h以后的MTX血药浓度明显升高,高浓度MTX延迟排泄的可引起肾功能损伤。结论:延迟排泄更多发生在低浓度点,但高浓度的延迟排泄肾功能损伤大,因此血药浓度监测是实施HD-MTX疗法必不可少的安全保证措施。在及时的亚叶酸钙(CF)解救和充分的水化碱化下,延迟排泄的不良反应完全可以很好地预防和控制。     

儿童抗癫痫药物治疗药物监测

抗癫痫药物（AEDs）是治疗癫痫的主要药物,现有27种抗癫痫药物,这使得治疗药物监测（TDM）的应用越来越广泛,同时,抗癫痫药物也是进行TDM最常见的药物。第一代抗癫痫药物卡马西平、苯巴比妥、苯妥英钠、乙琥胺、扑米酮、丙戊酸在TDM方面积累了很多经验,现在TDM将更多地应用于新的抗癫痫药物如醋酸艾司利卡西平、非氨酯、加巴喷丁、拉科酰胺、拉莫三嗪、左乙拉西坦、奥卡西平、吡仑帕奈、哌拉西坦、普瑞巴林、瑞替加滨、卢非酰胺、司替戊醇、噻加宾、托吡酯、氨己烯酸和唑尼沙胺。本文通过对样本类型、样本的采集和处理、参考范围的概念进行综述,旨在为儿童抗癫痫用药的药物监测提供依据。     

口服"纯中药"患儿的抗痫西药血浓度监测

目的：用治疗药物监测(TDM)方法监测口服“纯中药”患儿的抗痫西药血浓度,及时发现和调整患儿的不合理用药。方法：凡是临床上出现药物中毒、无法解释的药理现象或者怀疑服有中药掺杂西药的癫痫患者,用HPLC法和PLIA法监测其血药浓度．并动态地现察疗效。结果：45例服用“纯中药”的癫痫患儿,血清中检测出1．5种常用抗痫西药,其中苯巴比妥最多(42例)。其次为卡马西平、丙戊酸钠、苯妥英纳和氯硝西泮,有些已达中毒浓度。这种现象给病人造成极大的诊疗困难、中毒危险、心理创伤及经济     

Dose adjustment in patients with liver disease.

Unfortunately, there is no endogenous marker for hepatic clearance that can be used as a guide for drug dosing. In order to predict the kinetic behaviour of drugs in cirrhotic patients, agents can be grouped according to their extent of hepatic extraction. For drugs with a high hepatic extraction (low bioavailability in healthy subjects), bioavailability increases and hepatic clearance decreases in cirrhotic patients. If such drugs are administered orally to cirrhotic patients, their initial dose has to be reduced according to hepatic extraction. Furthermore, their maintenance dose has to be adapted irrespective of the route of administration, if possible, according to kinetic studies in cirrhotic patients. For drugs with a low hepatic extraction, bioavailability is not affected by liver disease, but hepatic clearance may be affected. For such drugs, only the maintenance dose has to be reduced, according to the estimated decrease in hepatic drug metabolism. For drugs with an intermediate hepatic extraction, initial oral doses should be chosen in the low range of normal in cirrhotic patients and maintenance doses should be reduced as for high extraction drugs. In cholestatic patients, the clearance of drugs with predominant biliary elimination may be impaired. Guidelines for dose reduction in cholestasis exist for many antineoplastic drugs, but are mostly lacking for other drugs with biliary elimination. Dose adaptation of such drugs in cholestatic patients is, therefore, difficult and has to be performed according to pharmacological effect and/or toxicity. Importantly, the dose of drugs with predominant renal elimination may also have to be adapted in patients with liver disease. Cirrhotic patients often have impaired renal function, despite a normal serum creatinine level. In cirrhotic patients, creatinine clearance should, therefore, be measured or estimated to gain a guideline for the dosing of drugs with predominant renal elimination. Since the creatinine clearance tends to overestimate glomerular filtration in cirrhotic patients, the dose of a given drug may still be too high after adaptation to creatinine clearance. Therefore, the clinical monitoring of pharmacological effects and toxicity of such drugs is important. Besides the mentioned kinetic changes, the dynamics of some drugs is also altered in cirrhotic patients. Examples include opiates, benzodiazepines, NSAIDs and diuretics. Such drugs may exhibit unusual adverse effects that clinicians should be aware of for their safe use. However, it is important to realise that the recommendations for dose adaptation remain general and cannot replace accurate clinical monitoring of patients with liver disease treated with critical drugs.     

Urinary excretion ofD-glucaric acid,an indicator of drug metabolizing enzyme activity,in patients with impaired renal function

Summary The urinary excretion rate ofD-glucaric acid, an in vivo parameter of the activity of drug metabolizing enzymes, has been determined in patients with chronic renal insufficiency (glomerular filtration rate 4.5–80 ml/min/1.73 m²). The mean value of 22.3 µmoles/d (SD 7.2; n 28) was almost identical to that of healthy controls (22.1 µmoles/d, SD 7.3; n 22). Thus, no inhibitory or enhancing effect of renal insufficiency could be detected. The ability of this parameter to indicate alterations in the activity of hepatic drug metabolism, even in patients with renal insufficiency, was demonstrated by the increased excretion rate of glucaric acid (107 µmoles/d, SD 43.5; n 8; p<0.001) after treatment for 7 days with the enzyme inducer phenobarbital. No significant correlation was found between glucaric acid excretion and sex, age, body weight or body surface in 50 patients. Glucaric acid excretion, therefore, should not be related to the creatinine content of urine samples, since creatinine excretion decreases with severity of renal insufficiency and varies with sex, age, body weight and many other conditions. A single dose of dipyrone (Novalgin^®), a further in vivo indicator of drug metabolism, increased glucaric acid excretion on the same day, but no interference was found after a single dose of cortisol.