地高辛血药浓度数据处理程序的研制及有效血药浓度范围的调整

目的 :开发地高辛血药浓度数据处理 (DBDP)程序 ,确定地高辛有效血药浓度范围。方法 :采用VB6 0开发DBDP程序 ,在WIN95操作系统上运行 ;对经荧光偏振免疫法测定的血药浓度数据运用DBDP程序处理。结果 :该程序具有估算药动学参数、建立有效血药浓度范围、管理血药浓度监测数据、自动添加患者档案、多功能模糊查询、回顾性分析等综合功能及临床用药查询等综合功能 ;确定地高辛的理想有效血药浓度范围为0 58～2 01ng/ml。结论 :DBDP程序是开展治疗药物监测工作非常实用的工具。开展血药浓度监测并建立理想的有效血药浓度范围是非常必要的。     

肝、肾移植术后受者环孢素A血药浓度监测的评估

目的探讨肝、肾移植受者环孢素A(CsA)理想的血药浓度监测指标。方法采用荧光偏振免疫法,对65例肝移植受者及136例肾移植受者进行CsA谷浓度(C0)及服药后2 h血药浓度(C2)监测,并对数据进行归纳和分析。结果肝移植受者C2/C0均值为3.56,肾移植受者C2/C0均值为4.8,肝、肾移植受者C2/C0均值有极显著差异(P<0.001);肝移植受者男性CsA血药浓度较女性低。结论C0+C2和C2/C0作为CsA血药浓度监测指标,能更全面地反映CsA体内药物暴露情况和监测CsA肝、肾毒性。     

76例肾移植受者环孢素A的有效血药浓度范围及其伍用药物影响的分析

目的:探讨肾移植术后患者在不同时期内环孢素A(CsA)的血药浓度与临床的关系.方法:采用荧光偏振免疫(FPIA)法,对肾移植受者进行常规CsA血药浓度监测;结合患者临床症状对76例受者632人次的有效血药浓度和伍用药物对血药浓度影响进行分析.结果:CsA在肾移植术后＜1月、1～3月、3～6月、6～12月、1年以上的有效血药浓度范围分别为220～480,200～360,120～320,100～280,100～250 ng/mL.伍用药物酮康唑、黄连素、硝苯地平、联苯双酯等对CsA的血药浓度有影响,且与临床症状呈正相关.结论:根据患者的实际病情及伍用药物情况具体分析,调整给药方案,将CsA血药浓度控制在有效治疗浓度范围内,可有效避免毒性反应和排异反应的发生.     

肾移植术后环孢素A有效血药浓度范围的研究

目的:探讨肾移植术后不同时期内患者体内的环孢素 A(CsA)有效血药浓度范围.方法:采用荧光偏振免疫法 (FPIA)检测肾移植受者的常规 CsA血药浓度,将临床表现正常的肾移植受者的数据进行归纳、分析、统计.结果:肾移植患者术后 < 1月, 1～ 3月, 3～ 6月, 6～ 12月, > 12月的有效血药浓度范围分别为 220～ 450, 220～ 390, 152～ 300, 100～ 260, 90～ 220 ng/mL.结论:根据患者实际情况,将 CsA血药浓度控制在有效血药浓度范围内,可避免毒性反应和排斥反应的发生; CsA血药浓度监测具有重要意义.     

治疗药物监测系统的开发及其在回顾性分析中的应用

目的:为临床药学工作者提供可自动进行多功能回顾性分析、查询及输入数据简便的治疗药物监测系统(TDMS程序)。方法:TDMS程序用VISUAL BASIC 5.0开发,在Windows 95操作系统上运行;对我院1997、1998两年用荧光偏振免疫法所测定血药浓度数据运用TDMS程序分析。结果:TDMS程序可自动增添病人档案、自动给出血药浓度参考值、能进行有效血药浓度范围情况分析、血药浓度次数比较、病人血药浓度的统计数据等回顾性分析及多功能查询。结论:TDMS程序是开展治疗药物监测(TDM)工作非常实用的工具,我院医生对TDM的依从性正逐渐增强。     

肾移植患者环孢素A的药效学研究

目的:分析肾移植患者术后环孢素A(CsA)血药浓度与剂量、疗效的关系。方法:采用荧光偏振免疫法(FPIA)对70例肾移植患者进行251次CsA全血药物浓度测定。结果:肾移植术后不同时间段CsA血药谷浓度0～3个月时为(336.99±224.89)ng/mL,3～6个月为(252.07±113.71)ng/mL,6～12个月为(195.83±105.11)ng/mL,1～2年为(179.64±85.48)ng/mL,2年以上则为(144.95±55.68)ng/mL。结论:CsA药物浓度的跟踪检测对观察肾移植术后的排异反应、减少药物不良反应具有重要的临床意义。     

老年与中青年肾移植患者环孢素A血药浓度比较分析

目的:探讨老年肾移植患者环孢素A(CsA )血药浓度的特点及临床意义。方法:查阅242例肾移植患者病历资料及移植后CsA血药浓度监测值,根据年龄分为中青年组(18a～60a ,218例)及老年组(>60a ,24例) ,比较不同时期2组患者的血药浓度值。结果:在口服CsA剂量接近的情况下,术后<1mo、1mo～3mo、3mo～6mo、1y～2y4个时间段内,老年组CsA血药浓度均显著高于中青年组(P<0 05或P<0. 01)。结论:应监测老年肾移植患者CsA血药浓度,以防止CsA致肝、肾中毒等不良反应的发生。     

肾移植患者口服国产环孢素A软胶囊后治疗药物监测指标的选择

目的:探讨肾移植患者口服国产环孢素A(CsA)软胶囊后治疗药物监测的适宜指标。方法:采集10例肾移植术后稳定期患者口服国产CsA软胶囊后12h内不同时间点的血样,以单克隆荧光偏振免疫(mFPIA)法测定血药浓度。计算各采样点CsA浓度与AUC0～12和AUC0～4的相关系数,考察相关系数间的差异性。结果:除0.5、0.75h外,其余各时间点与0h的相关系数两两间检验未显示有统计学意义的差异(P>0.05)。结论:对于肾移植术后稳定期口服国产CsA软胶囊患者,谷浓度(c0)仍然可以作为适宜的治疗药物监测指标之一。     

肾移植术后环孢素血药浓度监测指标的探讨

目的探讨肾移植受者环孢素(CsA)满意的血药浓度监测指标。方法采用荧光偏振免疫(FPIA)法,对136例肾移植受者进行全血中CsA谷浓度(ρ0)及服药后2 h血药浓度(ρ2)监测,并对数据进行归纳分析。结果肾移植术后2 a内ρ0均值为(221.54±100.41)μg.L-1,ρ2均值为(963.91±379.43)μg.L-1,ρ0 ρ2均值为(1 185.44±433.14)μg.L-1,ρ2/ρ0均值为(4.80±2.29)。结论ρ0 ρ2和ρ2/ρ0作为CsA血药浓度监测指标,能更全面反映CsA体内药物暴露情况和监测CsA肝肾毒性,作为环孢素A血药浓度监测指标是合理的。     

个体化给药程序及阿米卡星临床监测分析

目的 :为降低阿米卡星的耳毒性、肾毒性 ,为提高临床药物治疗效果 ,研制了阿米卡星个体化给药系统程序 (I ASP)。方法 :IASP程序用VB6 .0开发 ;血药浓度监测用荧光偏振免疫法 ,数据采用自编的IASP程序进行回顾性分析。结果 :IASP程序具有目前国内首创的有效血药浓度范围的建立、药动学参数估算、个体化给药方案设计、血药浓度监测数据管理、自动添加患者档案、多功能模糊查询和回顾性分析等综合功能 ;在所监测的抗龟分支杆菌的阿米卡星中 ,6 1.77%的峰值在有效血药浓度范围内 ,99.14 %的谷值在有效血药浓度范围内 ,经卡方检验 ,差异有极显著性 (P<0 .0 1)。结论 :通过治疗药物监测和个体化给药 ,该 133例患者感染全部控制 ,并且无一例发生肾功能损害或器质性耳损害。     

新药研发中的me-too, me-better, me-new

文中根据作者对我国新药研发的认识和理解,提出了新药研发过程中me-too,me-better和me-new类新药的概念,并对新药研发过程中的这3类创新活动之间的关系、新药研发的创新程度与经济效益的关系,以及目前我国新药研发的途径选择做了简要的论述。     

Design of anti-bacterial drug and anti-mycobacterial drug for drug delivery system

Liposome-encapsulated drugs often exhibit reduced toxicity and have also been shown to enhance retention of drugs in the tissues. Thus, encapsulation of drugs in liposomes has often resulted in an improved overall therapeutic efficacy. The results of efficacy of liposome-encapsulated ciplofloxacin or azithromycin for therapy of intracellular M. avium infection show enhanced cellular delivery of liposome-encapsulated antibiotics and suggest that efficiency of intracellular targeting is sufficient to mediate enhanced antimycobacterial effects. The antitubercular drugs encapsulated in lung specific stealth liposomes have enhanced efficacies against tuberculosis infection in mice. These results from stealth liposome study indicate that antitubercular drugs encapsulated in liposome may provide therapeutic advantages over the existing chemotherapeutic regimen for tuberculosis. Liposomes with encapsulated amikacin are able to protect collagen almost completely from adherence of bacterial cells of all strains examined and prevent from invading of bacteria.     

Increased drug sensitivity in the drug discrimination procedure afforded by drug versus drug training

Rats were trained to discriminate norfenfluramine (NF) 1.4 mg/kg from its vehicle or amphetamine (AMPH) 0.8 mg/kg or pentobarbital (PB) 6.0 mg/kg in order to determine the role that drug combination training plays in the rate of learning and sensitivity to lower drug doses. The results suggest that drug versus drug training can increase the rate of drug discrimination learning for some drugs that are learned slowly when trained in a drug versus vehicle training procedure, whereas drug versus drug training does not increase the rate of learning for other drugs that are learned rapidly. Drug versus drug training does, however, appear to increase the level of stimulus control of the training drug for all drugs examined in this study.     

Compliance spectrum as a drug fingerprint of drug intake and drug disposition

Since drug related variability arises from different origins, particularly driven by the behaviour or physiology of the patient, the problems of drug intake and drug disposition are separately presented in general. To overcome the potential drawbacks of this artificial split, we propose in this paper a combined illustrative approach, named compliance spectrum, such that these two subprocesses can be equitably studied and visualized. We construct the compliance spectrum based on the Bayesian decision method we previously developed for the inverse problem of patient compliance within the framework of Population-PK. This spectrum provides an intuitive and interactive way to evaluate the relationship between drug intake and drug disposition along with their consequences on PK profile. As well, it opens a new direction for model quality diagnostic.     

Evaluation of drug–drug interactions with fesoterodine

Purpose  To assess drug–drug interactions of fesoterodine with cytochrome P450 (CYP) 3A4 inhibitor (ketoconazole), inducer (rifampicin), and substrates (ethinylestradiol and levonorgestrel). Methods  Effects of ketoconazole 200 mg twice daily and rifampicin 600 mg twice daily on fesoterodine 8 mg once daily were investigated in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) based on 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics (principal active fesoterodine metabolite and CYP3A4 substrate). Effects of fesoterodine 8 mg versus placebo once daily on ethinylestradiol and levonorgestrel were investigated based on oral contraceptive pharmacokinetics and on pharmacodynamic effects on progesterone, luteinizing hormone, follicle-stimulating hormone, and estradiol plasma levels. Results  Compared with fesoterodine alone, coadministration of fesoterodine with ketoconazole resulted in increases in mean 5-HMT maximum concentration in plasma (C_max; from 3.0 to 6.0 ng/mL in EMs and from 6.4 to 13.4 ng/mL in PMs) and mean area under the plasma concentration time curve (AUC; from 38.2 to 88.3 ng h/mL in EMs and 88.3 to 217.2 ng h/mL in PMs). Coadministration of festerodine with rifampicin resulted in decreases in mean 5-HMT C_max (from 5.2 to 1.5 ng/mL in EMs and from 6.8 to 1.9 ng/mL in PMs) and mean AUC (from 62.4 to 14.4 ng h/mL in EMs and from 87.8 to 19.6 ng h/mL in PMs). Fesoterodine did not affect oral contraceptive pharmacokinetics or pharmacodynamics or the suppression of ovulation. Conclusions  Fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors. Coadministration of CYP3A4 inducers with fesoterodine may produce subtherapeutic 5-HMT exposures. No dose adjustment is necessary for concomitant use of fesoterodine with oral contraceptives. Funding for this study was provided by Schwarz Biosciences GmbH, and Pfizer Inc.     

Drug discrimination procedures: Differential characteristics of the drug A vs drug B and the drug A vs drug B vs no drug cases

Two groups of pigeons with a history of two choice operant drug discrimination tasks (3.0 mg/kg morphine versus 5.6 mg/kg cocaine, and 3.0 mg/kg morphine versus 3.0 mg/kg cocaine, respectively; Swedberg and Järbe 1985) were subjected to three choice tasks in which responses on a third manipulandum were reinforced in the no drug condition. Training drugs generalization gradients in both groups were similar to those normally obtained in two choice drug versus no drug tasks. The salience differences between the training stimuli within the groups observed in the previous two choice task did not differentially affect the three choice discrimination gradients. Tests with novel drugs after the introduction of the no drug condition yielded increased responding to the no drug condition with the exception of the dopamine agonist apomorphine. Results are discussed in terms of a discrimination learning model specifying principles of relative discriminative stimulus control in various discrimination cases.Portions of these data were presented at the International Union of Pharmacology, IUPHAR, 9th International Congress of Pharmacology Satellite Meeting: European Study Group for Internal Stimulus Control by Electrical Stimulation, Drugs and Other Means, ESISC, London, July 29–August 3, 1984 (Swedberg and Järbe 1984). An earlier version of this work appears in the doctoral thesis by the first author (Swedberg 1985).     

抗心律失常药物不良反应分析

目的：探讨抗心律失常药物所致不良反应(ADR)的发生情况,为临床安全、合理用药提供参考。方法130例抗心律失常药物所致不良反应报告,对患者的年龄、性别、基础疾病、用药途径、用药剂量、不良反应史、所用药物、不良反应的临床表现等进行统计分析。结果上报的抗心律失常药物所致不良反应发生在21~97岁;不良反应主要包括致心律失常作用及其他系统损害。结论医疗机构应重视抗心律失常药物引起的不良反应,加强抗心律失常药物的合理应用。     

Therapeutic drug monitoring in drug overdose

The treatment of poisoned patients is still largely defined by history, clinical assessment and interpretation of ancillary investigations. Measurement of drug concentrations is clinically important for relatively few compounds. Most measurements form an adjunct to and should not be considered a substitute for clinical assessment. Drug concentrations are particularly important for those compounds where the concentration is predictive of serious toxicity in an otherwise asymptomatic patient.     

Therapeutic drug monitoring in drug overdose

The treatment of poisoned patients is still largely defined by history, clinical assessment and interpretation of ancillary investigations. Measurement of drug concentrations is clinically important for relatively few compounds. Most measurements form an adjunct to and should not be considered a substitute for clinical assessment. Drug concentrations are particularly important for those compounds where the concentration is predictive of serious toxicity in an otherwise asymptomatic patient.