家兔静注蝮蛇抗栓酶的药物动力学

以家兔凝血时间的延长作为分级定量的药理指标,测定了蝮蛇抗栓酶 iv 给药的药动学参数和 ig给药的生物利用度。按二室开放模型拟合的结果如下:t_(1/2α)=1.12h;t_(1/2β)=3.8h;k_(12)=0.039h~(-1);k_(21)=0.56h~(-1);k_(10)=0.21h~(-1);CL=0.021kg/kg·h;V_c=0.098kg/kg;V_p=0.0069kg/kg;V_(ss)=0.105kg/kg;F=10.9%。     

盐酸川芎嗪静脉注射的药物动力学研究

大鼠按30mg/kg静脉注射盐酸川芎嗪,体内药物动力学呈开放性二室模型。将每组所得数据的均数按Marquardt法迭代拟合,多项指标帮助选择最佳模型。模型分析得其参数为:t_(1/2α)=0.144lh,t_(1/2α)=1.6953h,K_(21)=2.2850h~(-1),K_(10)=0.8605h~(-1),K_(12)=2.0723h~(-1),AUC=83.3660mg·L·h,CL=0.3597L·kg·h~(-1),V_c=0.4182L·kg~(-1),V_(ss)=0.7975L·kg~(-1).分析结果表明:川芎嗪主要分布于血流丰富的大循环和组织,肾脏排泄少,肝脏为主要消除器官。     

血卟啉单甲醚（PsD—044）在家兔体内的药物动力学

用荧光分光光度法测定血卟啉单甲醚(PsD-044)的血药浓度激发光波长为395nm;发射光波长为613nm。PsD-044血浆浓度为10和20μg/ml时,测定回收率分别为98.31±1.17％(cv=1.19％)和97.76±6.35％(cv=6.80％)。PsD-044在家兔体内的药物动力学按三房室拟合。其主要药物动力学参数分别为:π=16.60h~(-1);α=0.546h~(-1);β=0.0303h~(-1);t_(1/2π)=0.0427h;t_(1/2α)=1.31h;t_(1/2β)=28.08h;V_c=0.0704L/kg;V_(area)=16.19L/kg;V_(ss)=6.26L/kg;Cl=0.487L/kg·h。     

吗丙嗪的药物动力学研究

按75mg/kg给家兔灌胃吗丙嗪,体内药物动力学呈开放性二室模型。将每组数据按Marquardt法迭代拟合,多项指标帮助选择最佳模型。模型分析得其参数为:T_(1/2)α=0.19h,T_(1/2)β=4.96h,K_(21)=2.94h~(-1),K_(10)=0.69h~(-1),K_(12)=3.75h~(-1),AUC=98.91h·mg/L,CLs=0.76L·kg~(-1)·h~(-1),V/f(c)=1.09L·kg~(-1),Vss=1.51L·kg~(-1),分析结果表明:吗丙嗪主要分布于血流丰富的大循环和组织,肝脏为主要消除器官,肾脏及胃肠道均有排泄。     

葡萄糖酸钙片的人体药物动力学研究

用原子吸收分光光度法测定人体口服葡萄糖酸钙片后的血钙浓度,其体内过程符合一室模型。主要动力学参数为:k_a=2.874 h~(-1);k_e=2.396 h~(-1);T_(2ke)~1=0.291 h;T_(max)=1.175 h;C_(max)=8.995μg/ml;AUC=9.638mg/(L·h);V=0.135 L;CL=0.333 Lh~(-1);T_(lag)=0.768 h;初步认为缺钙患者的临床给药方案应为每次 Ca~(2 )3 mg/kg,每1.5 h一次。     

用小鼠急性死亡率法测定山莨菪碱的表观药动学参数

用小白鼠急性死亡率法测定了山莨菪碱ip时的经时过程和药动学参数。山莨菪碱在小鼠体内的经时过程为二室开放模型,1.5h之前为分布相,1.5h之后为消除相。用最小二乘法和残余量法求得α、β、A和B四项表现动力学参数分别为3.608h~(-1),0.238h~(-1),529mg/kg(200.2％)和 95mg/kg(35.9％);按药动学公式分别求得分布相表观半寿期(t_(1/2)α)和消除相表现半寿期(t_(1/2)β)为0.2h和2.9h,表观转运速率常数k_(12),k_(21)和k_(10)分别为1.952h~(-1),0.749h~(-1)和1.144h~(-1);表观曲线下面积(AUC)是546mg.h/kg;表观清除率(CI)是0.48kg/(kg.h),表观分布容积V_c,V_p,V_t,和V_b分别为0.42kg/kg,1.10kg/kg,1.53kg/kg和2.04kg/kg.     

双黄连粉针中绿原酸在大白鼠中的药物动力学

目的:研究双黄连粉针在大鼠体内的药物动力学.方法:采用HPLC法测定大鼠血浆中双黄连粉针中绿原酸的血药浓度.流动相甲醇:磷酸缓冲液(pH2.7)(10:90),色谱柱ERC-ODS-1161(6mm×100mm),紫外检测波长274nm,柱温55℃,流速1ml/min.结果:当剂量为60mg/kg时,药物动力学参数为Vc=0.09L,Ke=0.68/h,K_(12)=2.66/h,K_(21)=1.67/h,T_(1/2)=1.14h,α=4.77h~(-1),β=0.55h~(-1),AUC=1.73μg·h/ml.结论:双黄连粉针中绿原酸在大白鼠体内呈二室模型分布.     

硫酸锌在兔体内的药物动力学研究

用原子吸收分光光度法测定兔血清锌、铜浓度。在1.53～15.3μmol/L 范围内为直线,r=0.9996,日内、日间变异系数小于4%,回收率99%,血清中最低检测限为0.122μmol/L。硫酸锌(Zn~(2 ),1mg/kg)静脉注射后,药时曲线符合二室开放模型:α=4.838h~(-1),β=0.320h~(-1),T_(1/2)α=0.149h,T_(1/2)β=2.25h,Vc=0.087L/kg,K_(12)=2.354h~(-1),K_(21)=2.051h~(-1),K_(10)=0.753h~(-1),AUC=34.316h·μg/ml。静注硫酸锌后,兔血清铜浓度降低,提示补锌时应注意对其他微量元素的影响。     

头孢羟氨苄赖氨酸盐在家兔体内的药代动力学研究

采用微生物法测定家兔血浆中的活性成分研究头孢羟氨苄赖氨酸盐的药代动力学.实验结果表明,静脉注射羟氨苄头孢菌素在家兔体内的药代动力学符合三室开放模型,其数学表达式分别为C=620.3e~(-26.02)t+78.3e~(-2.07)t+3.91e~(0.224)t.主要药代动力学参数:三相半衰期为t_(1/2)α=0.027±0.014小时,t_(1/2)β=0.34±0.1小时,t_(1/2)γ=0.09±0.65小时;消除速度常数:K_(10)=8.87±3.3小时~(-1);总表观分布容积Vd=7.22±2.9L.     

甲氨碟呤多相脂质体药物动力学和药物分布的研究

采用荧光法测定血和织组中MTX含量,用阻尼非线性最小二乘法及矩量法处理和比较MTX多相脂质体(PL—MTX)及MTX水溶液(F-MTX),尾静脉一次给药18mg/kg后,9hr内小鼠体内的药物动力学和药物分布。得到PL-MTX的药-时曲线为:C(μg)=30.5e~(-3.771)+3.27e~(0.381),具有开放二房室模型特征,清除率Cl:为927ml/h,血药平均滞留时间MRT为100min;F-MTX的药-时曲线为:C(μg)=39.7e~(-13.2t)+15.1e~(-2.77t)+0.633e~(-0.216t),具有开放三房室模型特征,Cl_s为1579ml/h,MRT为57min。两者结果存在显著差异。另外,PLMTX较F-MTX在脾、肺、肝、骨髓的药量分布有显著提高。表明多相脂质体剂型可能增加化疗药物在上述器官为病灶的癌细胞的药物浓度。     

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.