大剂量甲氨蝶呤治疗急性淋巴细胞白血病患儿群体药动学研究

目的建立儿童急性淋巴细胞白血病（ALL）患儿静脉使用大剂量甲氨蝶呤（HDMTX）稀疏点血药浓度数据库,估算群体药动学参数,结合Bayesian反馈法,估算个体药动学参数。方法132例ALL患儿接受HDMTX（3g·m^-2）静脉滴注后,不同时间点采血样,用荧光偏振免疫法（FPIA）测定MTX的血浆浓度,收集24—68h左右稀疏血药浓度数据510个。用NONMEM软件进行模型拟合和PPK参数的估算,并定量分析患儿年龄、性别、体重、身高、ALT、AST、CREA、UA等固定效应参数对甲氨蝶呤PPK参数的影响,得到最终拟合药动学模型。结果PPK模型为：中央室清除率CLli（L·h^-1·kg^-1）=5．84×10^0.017·（age-9.2）＋0．0150×WT^10685×e^CLli,周边室清除率CL2i（L·h^-1·k^-1）=0．265×10^0.029＊（age-10）＋0．00067×WT^1.178×e^CLli,中央室表观分布容积Vli（L·kg^-1）=2．42×10（WT-1.47）＋15．45×10^0.0046＊（age-4.8×e^VIi,外周室表观分布容积V2i（L·kg^-1）=1．85×10^0.063＊（148-Height）＋0．042×10（WT＋0.32×e^V2i;其中建模型组CL1、V1、CL2、V2的群体间标准值（个体问RSD）分别为6．272L·h^-1·kg^-1（17．62％）,1．136L／kg（7．39％）,0．28L·h^-1·kg^-1（7．5％）,3．453L／kg（25．98％）;年龄、体重对CL的影响具有统计学意义（P〈0．05）;预测MTX达到0．1μmol／L的时间是46．85h,个体间标准差（RSD）为5．19％。结论本实验模型拟合情况较好,该模型可用于临床制定个体化给药方案。     

中国成年患者万古霉素群体药动学研究

目的:利用万古霉素治疗药物监测(TDM)数据建立群体药动学(PPK)模型,用于估算个体化药动学参数。方法:选择使用万古霉素成年患者,详细记录用药、TDM数据以及病理生理资料。采用非线性混合效应模型(NONMEM)法建立万古霉素群体药动学模型。结果:169例患者数据来源于血液科及重症监护(ICU)病房等9个科室,共获得385个血药浓度数据,其中峰浓度39个,谷浓度346个。根据文献资料及TDM数据建立二室PPK模型,万古霉素清除率(CL)、中央室(V1)及外周室(V2)分布容积、室间清除率分别为4.08 L·h-1、21.7 L、65.3 L、5.95 L·h-1,患者肌酐清除率及体重分别对CL及V2具有显著影响。根据模型预测169位患者AUC0-24h为(450.1±231.8)mg·L-1·h。结论:本研究建立的万古霉素PPK模型可以用于中国成年患者个体化药动学参数估算。     

左旋多巴中国人群药动学模型的建立

目的:建立中国人群左旋多巴/苄丝肼复合制剂中左旋多巴的群体药动学模型。方法:前瞻性收集服用多巴丝肼片的帕金森病(PD)门诊患者稳态谷浓度97例102个血样和健康志愿者13例153个密集血样,高效液相色谱-电化学(HPLC-ECD)法测定左旋多巴(LD)血药浓度。应用NONMEM软件进行群体药动学数据分析,Bootstrap重复抽样用于模型的内部验证。另收集20例PD患者22个血样点作为验证组进行模型外部验证,计算最简模型和最终模型对验证组的平均预测误差(MPE)和平均绝对误差(MAE)对模型进行外部验证。结果:数据采用一房室模型拟合,年龄(AGE)对LD清除率有显著影响,性别(SEX)、体质量(WT)、给药剂量(TAMT)、合并用药不影响LD的药动学参数。LD的基础模型为:CL(CL/F)(L.h-1)=18.2×EXP[ETA(1)],V(V/F)(L)=48.4,ka(h-1)=2.13×EXP[ETA(2)];最终模型为:CL(CL/F)(L.h-1)=17.9×(55/AGE)0.59×(EXP[ETA(1)],V(V/F)(L)=47.5,ka(h-1)=2.14×EXP[ETA(2)]。CL、V、ka的群体典型值分别为17.9 L.h-1、47.5 L、2.14 h-1。Bootstrap重复抽样显示所建立的最终模型稳定、可靠,最终模型对验证组的MPE和MAE较最简模型有显著改善,显示模型有效,且有一定代表性。结论:根据患者的生理用药资料,结合上述模型,可估算个体药动学参数,为临床个体化给药提供参考。     

左乙拉西坦在癫痫患儿中的群体药动学研究

目的建立癫痫患儿口服左乙拉西坦的群体药动学(PPK)模型,并用此模型探讨左乙拉西坦在儿童患者群体内的药动学特征。方法收集344例癫痫患儿口服左乙拉西坦后的血药浓度数据和临床资料。将患儿随机分为两组,模型组(n=259)采用NLME程序进行PPK分析,建立一房室药动学模型(个体间变异采用指数模型,残差变异采用加法模型表示),考察各协变量对参数Ka、Vd和CL的影响。用拟合优度、自举法对最终模型的性能进行内部验证。采用最终模型预测验证组(n=85)患儿的血药浓度,计算平均预测误差(MPE)、平均绝对预测误差(MAE)、平均预测误差平方(MSE)和均方根预测误差(RMSE)对最终模型进行外部验证。结果 PPK最终模型为:Ka(h-1)=1.01×eηKa,Vd(L·kg-1)=[0.42+0.000 35×(AGE-56)]×eηVd,CL(L·kg-1·h-1)=[0.05-0.009 5×(ln WT-2.83)]×eηCl;年龄(AGE)正相关影响Vd,体重的自然对数值(ln WT)负相关影响CL。拟合优度、自举验证的评价结果表明最终模型稳定、预测结果可靠。外部验证最终模型结果为:MPE=0.01 mg·L-1,MAE=0.91 mg·L-1,MSE=1.16(mg·L-1)2,RMSE=1.08 mg·L-1。血药浓度实测值和最终模型的个体预测值的决定系数R2=0.990 6。外部验证说明最终模型预测准确度高。结论本研究成功建立了癫痫患儿口服左乙拉西坦后的PPK模型,模型结构表明左乙拉西坦体重校正的清除率随患儿年龄和体重的增加有下降趋势。     

万古霉素在新生儿和小婴儿患者中的群体药动学研究

目的建立万古霉素在新生儿和小婴儿患者的群体药动学(PPK)模型,为临床个体化用药提供参考。方法收集85例新生儿科患者静脉注射使用万古霉素后的血药浓度数据和临床资料。将患者分为两组,模型组(n=71)采用Phoenix~NLME~(TM)1.3软件进行PPK分析,建立一房室药动学模型(个体间变异采用指数模型,个体内变异采用混合误差模型),考察各协变量对参数V和CL的影响。用拟合优度、自举法对最终模型的性能进行内部验证。采用验证组(n=14)患者的血药浓度,计算平均预测误差(MPE)、平均绝对预测误差(MAE)、平均预测误差均方(MSPE)对最终模型进行外部验证。结果 PPK最终模型为V(L)=3.167,CL(L·h~(-1))=0.413×(WT/3.32)~(0.747)×(PNA/25)~(0.402)×e~(ηCL),体重(WT)和产后日龄(PNA)对CL有影响。拟合优度、自举验证的结果表明最终模型稳定、预测结果可靠。外部验证最终模型计算MPE、MAE和MSPE值分别为(-0.843±1.347)、(1.462±1.175)和(2.432±4.293)mg·L~(-1)。血药浓度实测值和最终模型的个体预测值的决定系数R=0.955,外部验证说明最终模型预测准确度较好。结论本研究建立的万古霉素新生儿和小婴儿患者的PPK模型预测能力和稳定性良好,可为其个体化给药方案的制订提供参考。     

非线性混合效应模型法估算癫痫患者卡马西平的群体药动学参数

目的:建立癫痫患者卡马西平(CBZ)的群体药动学(PPK)模型。方法:采集我院服用CBZ的270例门诊癫痫患者的稳态血药浓度数据(共316个样本)以及患者相关资料数据。应用非线性混合效应模型(NONMEM)法估算癫痫患者CBZ的PPK参数值,建立PPK模型。并运用自举法(Bootstrap)验证模型的可靠性。结果:年龄(AGE)、每日服药剂量(DKG)、体质量(BW)均为CBZ清除率(CL)的影响因素。最终模型:当AGE≤14岁时,CL(L/h)=[2.55+0.013×(AGE-15)]×(DKG/0.011)0.443×(BW/40)0.392;AGE>14岁时,CL(L/h)=2.55×(DKG/0.011)0.443×(BW/40)0.392。表观分布容积(Vd)=85L。经Bootstrap法验证,本模型稳定、可靠。结论:用NONMEM软件成功建立我院癫痫患者服用CBZ的PPK模型。根据本院癫痫患者的PPK模型,结合患者DKG、BW和合并用药可估算其CL,优化临床个体化用药方案。     

大剂量甲氨蝶呤在急性淋巴细胞白血病患儿体内的药动学研究

目的研究急性淋巴细胞白血病(ALL)患儿接受大剂量甲氨蝶呤(HDMTX)静脉滴注联合甲酰四氢叶酸钙解救方案治疗时甲氨蝶呤的药动学。方法采用高效液相色谱法测定16例ALL患儿使用甲氨蝶呤后不同时间点血清药物浓度,所得血药浓度-时间数据经DAS软件拟合,优化药动学房室模型,计算其药动学参数。结果大剂量甲氨蝶呤在急性淋巴细胞白血病患儿体内的经时过程符合二房室模型,主要药动学参数分别为:t1/2α=(1.61±0.43)h,t1/2β=(11.05±3.54)h,V1=(18.552±5.902)L·m-2,Cl=(4.525±1.181)L.h-1.m-2,k10=(0.254±0.053)h-1,k12=(0.194±0.043)h-1,k21=(0.074±0.025)h-1,AUC(0-t)=(1064.0±258.6)μmol.h.L-1,AUC(0-∞)=(1433.6±485.2)μmol·h·L-1,tmax=24h,Cmax=(40.1±10.3)μmol·L-1。结论大剂量甲氨蝶呤在急性淋巴细胞白血病患儿体内的药动学符合二房室模型,主要药动学参数有较明显的个体差异。     

基于NONMEN法建立万古霉素新生儿群体药动学模型

目的:建立新生儿万古霉素群体药动学模型,为临床个体化给药方案提供参考。方法:回顾性收集80例静脉使用万古霉素新生儿的170个稳态血药浓度数据及临床资料,运用非线性混合效应模型(NONMEM),建立新生儿万古霉素群体药动学(PPK)模型;考察各项协变量对药动学参数的影响,对最终模型进行拟合优度、自举法(Bootstrap)及正态预测分布误差法(NPDE)验证。利用蒙特卡洛法评估患儿在不同给药方案下的血药浓度范围。结果:一室模型能较好地拟合万古霉素体内过程,清除率(CL)和表观分布容积(V)的群体典型值分别为0.297L·h-1和2.230L,表观分布容积对CL有显著影响。拟合优度、Bootstrap和NPDE表明最终模型稳定、预测结果可靠。建立不同体质量范围新生儿万古霉素初始剂量推荐表。结论:本研究建立的新生儿万古霉素PPK模型稳定可靠,可为优化新生儿给药方案提供依据。     

万古霉素的群体药动学研究

目的研究万古霉素在革兰氏阳性菌感染患者中的群体药动学(PPK),指导临床合理用药。方法通过监测103个被诊断为革兰氏阳性菌感染患者的血清浓度,同时考虑患者的年龄、性别、身高及合并用药,以非线性混合效应模型(NONMEM)程序,按照线性二房室模型,建立并验证万古霉素PPK模型,根据患者的PPK模型参数制定个体化给药方案。结果最终模型中,万古霉素的清除率CL(L/h)与肌酐清除率CLCr(mL.min-1)呈线性关系:CL=0.044×CLCr;同时中央室的表观分布容积V1(L)与年龄呈线性相关:V1=0.542×Age;在验证组中,最终模型用于预测万古霉素的血药浓度,所建立的最终模型经验证具有良好稳定性和预测效能。结论肾功能和年龄对去甲万古霉索药动学参数有显著影响;根据上述研究结果可以给相似身体状况的患者制定万古霉素的个体化给药方案。     

Bayesian反馈法估算静脉输注伏立康唑的群体药动学参数

目的用Bayesian反馈法估算临床患者静脉输注伏立康唑的群体药动学(PPK)参数。方法收集静脉输注给药不同时间后的血样,采用HPLC法测定伏立康唑血药浓度,用Bayesian反馈法估算PPK参数。结果以二室模型拟合伏立康唑的药动学过程,得PPK参数为Vss为(46.58±19.35)L,CL为(4.76±2.64)L/h,k10为(0.187±0.006)h-1k,12为(4.97±0.02)h-1,k21为(0.895±0.308)h-1。结论此PPK模型能够较准确地描述伏立康唑在临床患者静脉输注的药动学特征,其预测能力尚待进一步评估。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

2-(Acetoxyphenyl)-(Z)-styryl sulfides as cyclooxygenase inhibitors

2-(Acetoxyphenyl)-(Z)-styryl sulfides are described as selective cyclooxygenase-2 (COX-2) inhibitors, useful for treating inflammation and COX-2-mediated disorders including neoplasia. 2-(Acetoxyphenyl)-(Z)-styryl sulfide is claimed to be the most potent COX inhibitor in the series with a COX-2 selectivity ratio of 33. This compound is also claimed to be superior to celecoxib (Celebrex^®, Pfizer) in inhibiting cell growth of colorectal carcinoma cells. In this evaluation, the COX inhibitory activity of this compound is compared to that previously disclosed for diarylheterocycles and 2-(acetoxyphenyl)alkyl sulfides. The validity of the DLD-1 cell line in the growth inhibition studies is questioned based on recent literature reports indicating the lack of COX-2 expression in this cell line.     

Sleep-disordered breathing with chronic opioid use

Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. μ-Opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in ～ 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.     

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer's disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA_A α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.