国产与进口地高辛片人体生物利用度的研究

目的：国产地高辛片长期以来存在着生物利用度差的问题,为此杭州民生药厂进行了工艺改进。方法：以英国Ｌａｎｏｘｉｎ片为对照,采用荧光偏振免疫分析法测定了８名健康男性受试者口服单剂量０．５ｍｇ地高辛片的药时数值,经ＰＫＢＰＮ１程序拟合,计算其药动学参数。结果：国产和进口的Ｃｍａｘ分别为３．０±０．６ｎｇ·ｍｌ－１和２．５±０．５ｎｇ·ｍｌ－１;Ｔｍａｘ分别为１．１±０．６ｈ和１．１±０．４ｈ;ＡＵＣ分别为３７．９±４．２ｎｇ·ｈ·ｍｌ－１和３７．２±６．１ｎｇ·ｈ·ｍｌ－１;杭州民生药厂工艺改进后的片剂相对生物利用度为１０３．８％±１７．０％。结论：国产片与进口片地高辛完全等效。这为临床应用提供参考,也为药品的国际接轨提供依据     

人体卡托普利的药代动力学及其生物利用度

目的：比较Ａ、Ｂ两厂复方卡托普利片的生物利用度和药代动力学。方法：９名健康志愿者随机交叉口服单剂量３０ｍｇ复方卡托普利片,以对溴苯乙酰基溴（ＰＢＰＢ）为衍生化试剂,采用反相高效液相色谱法。结果：测得Ａ、Ｂ药厂生产的复方卡托普利片剂在血浆中Ｃａｐ浓度达峰时间分别为（０．９４±０．１３）ｈ和（１．００±０．１５）ｈ;达峰浓度Ｃｍａｘ分别为（９２．０３±２７．３６）ｎｇ／ｍｌ、（７４．６７±１９．２９）ｎｇ／ｍｌ;药时曲线下面积（ＡＵＣ）分别为（２５２．７８±６８．１４）ｎｇ／（ｈ·Ｌ）、（２５１．１９±５０．１３）ｎｇ／（ｈ·Ｌ）。血药浓度—时间曲线符合二房室模型。结论：以Ａ厂复方卡托普利片为标准算得Ｂ厂复方卡托普利片中卡托普利的相对生物利用度（Ｆ）为９９．３７％。     

枢复宁在肺癌患者体内的药物动力学和生物利用度

９名接受顺铂化疗的原发性肺癌患者单次口服和静脉注射枢复宁８ｍｇ后，用反相高效液相色谱法测定血浆药物浓度。经用ＰＫＢＰ－Ｎ１程序在计算机上拟合计算表明，枢复宁在人体内表现为二房室模型。口服后主要药动学参数：Ｔ１／２Ｋａ＝０．４１±０．３０ｈ，Ｔ１／２α＝０．９±０．４３ｈ，Ｔ１／２β＝３．３±１．２ｈ，Ｃｍａｘ＝２８．６±９．５ｎｇ／ｍｌ，Ｔｍａｘ＝１．７±０．９ｈ，ＡＵＣ＝１５８±７３ｎｇ·ｈ／ｍｌ，绝对生物利用度为５５％。     

盐酸特拉唑嗪胶囊人体生物利用度及药物动力学研究

目的：对盐酸特拉唑嗪胶囊的人体内生物利用度进行研究。方法：单剂量口服盐酸特拉唑嗪胶囊和片剂２ｍｇ。血药浓度采用ＨＰＬＣ测定，数据用３Ｐ８７计算药动学参数。结果：盐酸特拉唑嗪胶囊剂的药动学参数：Ｋａ为８．２±４．０ｈ－１，Ｔ１／２为８．２±２．５ｈ，Ｔｍａｘ为０．６１±０．１１ｈ，Ｃｍａｘ为４３．５±８．５ｎｇ·ｍｌ－１，ＡＵＣ为３６７．４±３４．６ｎｇ·ｈ·ｍｌ－１；盐酸特拉唑嗪片剂的药动学参数：Ｋａ为６．４±７．４ｈ－１，Ｔ１／２为７．４±２．１ｈ，Ｔｍａｘ为０．９±０．４ｈ，Ｃｍａｘ为４３．１±４．８ｎｇ·ｍｌ－１，ＡＵＣ为３７１．３±４４．４ｎｇ·ｈ·ｍｌ－１。结论：两种剂型的药物动力学参数之间差异均无显著性（Ｐ＞０．０５），胶囊剂的相对生物利用度为９９．８８％。     

盐酸特拉唑嗪在健康人体内的药物动力学

目的：在８名健康志愿者体内研究了国产盐酸特拉唑嗪胶囊和进口片剂的药物动力学和生物利用度。方法：受试者交叉口服单剂量（２ｍｇ）盐酸特拉唑嗪胶囊和片剂后,采用高效液相色谱法和荧光检测器测定血药浓度。结果：胶囊和片剂的药时曲线均符合二室模型,其Ｔｍａｘ分别为１．３±０．６ｈ和１．３±０．４ｈ,Ｃｍａｘ分别为４９．５±８．６ｎｇ·ｍｌ－１和５０．３±５．２ｎｇ·ｍｌ－１,ＡＵＣ０→∞分别为５３６．５±３９．８ｎｇ·ｍｌ－１和５８６．６±５２．８ｎｇ·ｍｌ－１·ｈ,测试药品的相对生物利用度为９２．３０％±１２．９１％。结论：经方差分析两药药物动力学参数间差异均无显著性（Ｐ＞０．０５）;结果表明两药具有生物等效性。     

Pharmacokinetics of Controlled Release and Immediate Release Morphine Sulphate Tablets after a Single Dose and Multiple Doses in Chinese Volunteers

健康志愿者１０名，随机交叉口服硫酸吗啡控释片（ＣＲＭＳ）３０ｍｇ（３０ｍｇ×１）和硫酸吗啡普通片（ＩＲＭＳ）２０ｍｇ（１０ｍｇ×２），分别于服药前后各时点取静脉血，用ＧＣＭＳ测定血浆中吗啡含量。以药代软件程序处理，分别求得ＣＲＭＳ和ＩＲＭＳ的Ｃｍａｘ为１９．３８±３．８０和２１．２７±６．２１ｎｇ／ｍｌ；ｔｍａｘ为２．３６±０．３７ｈ和０．５５±０．１６ｈ；ｔ１／２β为３．５３±０．８７ｈ和３．０３±０．７４ｈ，曲线下面积ＡＵＣ为１４５．１５±１７．６５和９３．０８±１６．６５ｎｇ·ｈ／ｍｌ。癌症病人多次口服硫酸吗啡至稳态，ＣＲＭＳ和ＩＲＭＳ的峰浓度分别为２７．４３±０．３３ｎｇ／ｍｌ，２２．６８±０．１６ｎｇ／ｍｌ；谷浓度分别为１９．４５±１．４４ｎｇ／ｍｌ；１８．１４±０．４９ｎｇ／ｍｌ。     

国产芦氟沙星人体药代动力学与生物利用度研究

报道９ 名男性健康志愿者随机自身交叉对照口服芦氟沙星国产片剂、国产胶囊和进口片剂各２００ｍ ｇ 后的药代动力学与相对生物利用度研究结果。采用反相高效液相色谱法测定血、尿药物浓度,该药体内过程符合二室开放模型。国产片剂、胶囊与进口片剂分别在３．３１±１．９１、２．３２±１．４２和２．５２±２．１８ｈ 达血药峰浓度,其均值分别为２．２５±０．４７、２．２２±０．５９ 和２．４５±０．７３ｍ ｇ／Ｌ;药时曲线下面积（ＡＵＣ０～ｉｎｆ）分别为１１７．４８±１２．０８、１２０．９３±２１．８０ 和１１７．２１±１７．６１ｈ·ｍ ｇ／Ｌ;消除半衰期分别为４８．７±９．２、５７．９±１７．２ 和４７．５±１４．０ｈ。服用上述３ 种制剂后１０８ｈ 内尿中原型药物排出率分别占给药量的（５２．９±５．１）％ 、（７０．９±９．５）％ 和（５７．８±１０．１）％ 。３ 种制剂的药代动力学参数相互比较均无显著性差异;相对生物利用度研究结果表明,３种芦氟沙星制剂具有生物等效性。     

氨氯地平片在健康人和高血压患者中的药物动力学

采用反相高效液相色谱法测定了健康志愿者及高血压患者共３３名单剂量口服５ｍｇ苯磺酸氨氯地平片后的血清药物浓度，研究了该药在中国人体内的药物动力学。经ＰＫＢＰ－Ｎ１程序拟合表明，氨氯地平主要呈现二房室模型。其主要药动学参数分别为：健康人Ｔ１／２α＝０．６±０．５ｈ，Ｔ１／２β＝３５±９ｈ，Ｔｍａｘ＝８±４ｈ，Ｃｍａｘ＝２．４±０．８ｎｇ／ｍｌ；中青年高血压患者Ｔ１／２α＝０．６±０．４ｈ，Ｔ１／２β＝３６±９ｈ，Ｔｍａｘ＝１１±４ｈ，Ｃｍａｘ＝２．３±１．２ｎｇ／ｍｌ；老年高血压患者Ｔ１／２α＝０．４９±０．３３ｈ，Ｔ１／２β＝４２±１４ｈ，Ｔｍａｘ＝１０±４ｈ，Ｃｍａｘ＝２．８±１．４ｎｇ／ｍｌ。结果表明，中国人体内的氨氯地平药动学参数与报道的外国人相似。     

新型双氯芬酸钠缓释片的人体相对生物利用度研究

８名健康男性志愿者单剂量交叉口服１００ｍｇ受试双氯芬酸钠缓释片、扶他林或ＶｏｌｔａｒｅｎＳＲ１００后,Ｔｍａｘ分别为２．４±１．０、２．１±０．５和４．４±１．８ｈ;Ｃｍａｘ分别为６０２．６±９２．８、３３３７．６±１０８８．２　７６１．０±３４２．０ｎｇ／ｍｌ;ＭＲＴ分别为１３．２±４．８、２．９±０．８和７．９±１．９ｈ;ＡＵＣ０分别为４８６６．２±６４４．６、５３１４．３±５３４．３和４８２９．１±５８２．８ｎｇ／（ｍｌ－１·ｈ）;双氯芬酸钠缓释片和ＶｏｌｔａｒｅｎＳＲ１００相对于扶他林的生物利用度分别为８８．３±１３．２％和８６．３±１２．６％。另８名志愿者交叉口服受试双氯芬酸钠缓释片（１００ｍｇ,ｐｄ）和扶他林（５０ｍｇ,ｂｉｄ〕,连服５天。Ｃｍａｘ分别为５９３．９±１３４．１、１２４７．８±５２７．５ｎｇ／ｍｌ,峰谷波动率（ＰＴＦ）分别为３．３±１．２、５．３±２．１。本研究将为新型双氯芬酸钠缓释片的临床应用提供依据。     

放射免疫法测定睾丸移植病人环孢素浓度和药物动力学研究

用瑞士山德士（ＳＡＮＤＯＺ）出品的环孢素Ａ（ＣｙｃｌｏｓｐｏｒｉｎｅＡ，ＣｓＡ）的放射免疫（ＲＩＡ）测定药盒，通过液体闪烁仪对口服ＣｓＡ的两例睾丸移植患者分别进行了服药３ｄ（达稳态）后的１２ｈ内ＣｓＡ全血浓度测定及药动学研究，并追踪监测了调整剂量后的全血浓度。其峰浓度（Ｃｍａｘ）分别为２２４．０ｎｇ／ｍｌ及２１５．２ｎｇ／ｍｌ，达峰时间（Ｔｍａｘ）分别为４ｈ及３．５ｈ；口服ＣｓＡ后在１２ｈ内其药时曲线为二房室模型，Ｔ１／２α分别为１．５４ｈ及２．５７ｈ，Ｔ１／２β分别为６０．４ｈ及１３．０４ｈ。     

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.