6-甲氧基正丁苯酞的体内代谢转化研究

大鼠用6-甲氧基正丁苯酞(MBP)灌胃,收集0～24h尿液,经酶水解、提取浓缩、衍生化处理后用GC/MS分析。在大鼠0～24h尿液中,6-甲氧基正丁苯酞原药含量很低,主要以代谢物形式存在,依次为C-6脱甲基产物、C₃-C_α环氧化物、γ-羟化物、β-羟化物以及两个次级代谢产物。6-甲氧基正丁苯酞体内代谢结果与其在肝微粒体中代谢结果基本一致。     

6－甲氧基正丁苯酞在大鼠肝微粒体中的代谢研究

报道了用ＧＣ／ＭＳ方法及衍生化技术研究６甲氧基正丁苯酞（ＭＢＰ）在大鼠肝微粒体中的代谢转化结果。６甲氧基正丁苯酞在苯巴比妥（ＰＢ）诱导的大鼠肝微粒体中主要转化为３羟基、γ羟基取代物，６羟基正丁苯酞与一个环氧化代谢产物     

莫雷西嗪及其代谢产物莫雷西嗪亚砜在健康愿者的药物动力学

建立测定莫雷西嗪（Ｍｏｒ）及其代谢产物Ｍｏｒ－ＳＯ２，Ｍｏｒ－ＳＯ血浆和尿液浓度的ＨＰＬＣ法。健康志愿６人ｐｏＭｏｒ６００ｍｇ后，Ｍｏｒ血浓达峰时间（Ｔｍａｘ）为１．６±０．６ｈ，峰浓度（Ｃｍａｘ）为２．１±０．４μｇ·ｍｌ＾－１，清除率（Ｃｌ）为１．８±０．５Ｌ·ｋｇ＾－１·ｈ＾－１。Ｍｏｒ－ＳＯ的Ｃｍａｘ为０．１９±０．０６μｇ·ｍｌ＾－１，消除半衰期（Ｔ１／２）为２．３±１．０ｈ。４８ｈ…     

6-甲氧基正丁苯酞在大鼠肝微粒体中的代谢研究

报道了用GC/MS方法及衍生化技术研究6-甲氧基正丁苯酞(MBP)在大鼠肝微粒体中的代谢转化结果。6-甲氧基正丁苯酞在苯巴比妥(PB)诱导的大鼠肝微粒体中主要转化为3-羟基、γ-羟基取代物,6-羟基正丁苯酞与一个环氧化代谢产物。     

用固相萃取—核磁共振氢谱法研究大鼠尿液中R—（—）—布洛芬光活代谢

目的 用固相萃取－核磁共振氢谱法研究大鼠尿液中Ｒ－（－）－布洛芬后０～２４ｈ大鼠尿液经固相萃取柱处理、核磁共振氢谱测定代谢产物的结构。结果 尿液中含有４个主要代谢产物：２′－羟基－布洛芬及其葡苷酸结合物、１′－羧基－布洛芬葡糖苷酸和布洛芬葡糖苷酸。后两为非对映异构体混合物。结论 Ｒ－（－）－布洛芬在大鼠体内发生了异构体转化,异丁基侧链中末端甲基的氧化代谢具有立体选择性。     

咖啡因试验与氯氮平体内代谢的相关性

通过检测尿中咖啡因（Ｃａｆ）及其代谢产物,探讨细胞色素Ｐ４５０ １Ａ２（ＣＹＰ１Ａ２）与体内氯氮平（ＣＬＺ）去甲基代谢物的关系。方法单剂ｐｏ Ｃａｆ１５０ｍｇ,ｈ５末采取尿样,以Ｃａｆ代谢产物和Ｃａｆ的比值「（１７Ｘ＋１７Ｕ）／１３７Ｘ」反映ＣＹＰ１Ａ２活性。２ｄ后单剂ｐｏＣＬＺ１０ｍｇ,收集０－２４ｈ尿样。０－２４ｈ悄中ＣＬＺ剩余量占给药剂量的分率（ＣＬＺ％）反映ＣＬＺ清除;０－２４ｈ尿中去甲     

头孢拉定对奈替米星药代动力学的影响

目的 观察头孢拉定对奈替米星药代动力学的影响。方法１４例感染患者随机分成单用奈替米星组（ＮＴＭ）和奈替米星＋头孢拉定组（ＮＴＭ＋ＣＰＲ）。采用高效液相色谱一间接光度检测（ＨＰＬＣ－ＩＰＤ）法，测定患者单剂量静脉滴注 ５ ｍｇ ＮＴＭ后的血清药物浓度，并计算主要药动学参数；同时测定尿液药物浓度及药物回收率。结果ＮＴＭ组和ＮＴＭ＋ＣＰＲ组的Ｔ１／１／２β分别为２．４０±１．０１ｈ和 ４．３３± １．４３ｈ（Ｐ＜ ０．０１），ＡＵＣ０～２４ｈ６３．４２± ３０．００ｍｇ／Ｌ·ｈ和 ７８．５４± ３２．８８ｍｇ／Ｌ·ｈ（ｐ＜ ０．０ １），２４ｈ尿中 ＮＴＭ Ｗ收率也有显著性差异。结论 ＮＴＭ＋ＣＰＲ联用时 ＮＴＭ生物利用度增高，尿中回收率下降，连续长期联用将导致体内蓄积。     

CYP1A2在体内氯氮平去甲基代谢中的作用

通过检测咖啡国及其代谢产物,探讨细胞色素Ｐ４５０酶的亚型１Ａ２（ＣＹＰ１Ａ２）在体内氯氮平去甲基代谢的作用。９例男性健康志愿者口服单剂咖啡因１５０ｍｇ,５ｈ时采用取血样的尿样,咖啡因代谢产物与咖啡因的比值反映ＣＹＰ１Ａ２活性。两天后单剂氯氮平１０ｍｇ,收集０～２４ｈ尿和药代动力学设计的血样。０～２４ｈ尿中氯氮平剩余量占给药剂量的百分率（ＣＬＺ％ｄｏｓｅ）以及氯氮平０～２４药时曲线下面积（ＡＵＣ０→     

8例中国病人茶碱代谢物的药物动力学

目的：研究病人常规剂量茶碱治疗后代谢物的动力学。方法：病人静滴茶碱（６．６μｍｏｌ·ｋｇ＾－１）。ＨＰＬＣ法测定给药前后２４ｈ茶碱及其代谢物：１，３－二甲基尿酸（ＤＭＵＡ），３－甲基黄嘌呤（３－ＭＸ），１－甲基尿酸（ＭＵＡ），中间代谢产物１－甲基黄嘌呤（１－ＭＸ）的浓度。结果：ＤＭＵＡ是代谢物中浓度最高的。３－ＭＸ的清除速率最低。１－ＭＸ很快转化成ＭＵＡ，体内浓度很低，但是，翌晨，１－ＭＸ又回升到     

尼莫地平在健康男性国人中药物代谢动力学变异性

对２６名健康男性国人ｐｏ６０ｍｇ尼莫地平普通片后药代动力学进行研究．Ｃｍａｘ，Ｔｍａｘ，ｔ１／２，ＭＲＴ和ＡＵＣ分别为６９±３４μｇ·Ｌ－１，１．１±０．３ｈ，２．２±０．６ｈ．３３±０９ｈ和１８６±７３μｇ·ｈ·Ｌ－１．ＡＵＣ和Ｃｍａｘ有较大的个体差异．对ＡＵＣ值作频数和机率图分析结果表明存在双态分布．提示尼莫地平药代动力学存在多态性．根据ＡＵＣ值大小，将受试者分成快代谢型和慢代谢型两类，结果显示受试者大多（２４／２６）属于快代谢型（ＡＵＣ＞３００μｇ·ｈ·Ｌ－１）．     

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.