国产硫酸奈替米星注射液的药动学研究

采用微生物法对８名健康受试者单剂静脉滴注和肌注１００ｍｇ硫酸奈替米星注射液进行药动学研究，测定了给药后不同时间的血、尿药浓度，并经计算机程序计算药动学参数。结果显示：单剂静滴和肌注后的药动学符合二室开放模型，静滴药动学方程式为：Ｃ＝１０．８１２２ｅ－３．６７１４ｔ＋４．８８３１ｅ－０．２２０５ｔ；肌注药动学方程式为：Ｃ＝９．６８６８ｅ－１．４９１８ｔ＋５．４７５４ｅ－０．２０８６ｔ－１０．９７７０ｅ－３．７２５９ｔ。Ｔ１／２α分别为０．７４７８和０．４１２１ｈ，Ｔ１／２β分别为３．２３０８和２．８７４０ｈ，峰浓度分别为１３．１１和７．６０μｇ／ｍｌ，肌注后达峰时间为０．４８ｈ，总清除率分别为３．２２和３．２６（Ｌ／ｈ），２４ｈ肾排出率分别为５９．０６％和６８．５７％。给药后６ｈ内血药浓度及２４ｈ内尿药浓度＞１μｇ／ｍｌ，尿药浓度明显高于血药浓度。本研究结果与进口硫酸奈替米星注射液药动学过程基本一致。根据其药动学特征，建议一般给药方案为１００ｍｇ每日２次，可达到和维持有效血药浓度。     

硫酸奈替米星在肾功能受损时的药物动力学

目的：测定不同肾功能患者体内单剂量静脉滴注５ｍｇ·ｋｇ－１硫酸奈替米星（ＮＴＭ）后的血清药物浓度，并计算药物动力学参数；同时测定了尿药浓度及原形药物回收率。方法：采用高效液相色谱－间接光度检测（ＨＰＬＣ－ＩＰＤ）法，以烟酰胺为检测剂，庚烷磺酸钠为反离子。结果：ＮＴＭ在肾功能正常组和受损组的Ｔ１／２β分别为３．５±１．４ｈ和５．８±１．４ｈ，ＡＵＣ０～２４ｈ６３．４±３２．１ｍｇ·ｈ·Ｌ－１和８９．５±３５．９ｍｇ·ｈ·Ｌ－１，２４ｈ尿中回收率也有明显差异。结论：表明肾功能受损患者每２４ｈ给药一次体内仍有蓄积     

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。     

奈替米星两种给药方案的临床疗效比较

目的 通过比较奈替米两种给药方案,优选其最佳给药方案。方法 血药浓度用ＴＤｘ（荧光偏振免疫法）测定。体内杀菌活性用微量稀释法测定。结果 日剂量相同时,奈替米星一天一次给药（ＯＤ）,谷浓度均低于２μｇ．ｍｌ＾－１,且较一天两次给药（ＴＤ）有显著性降低（Ｐ〈０．０５）,而其峰浓度较ＴＤ给药有显著性增高（Ｐ〈０．０１）。结论奈替米星ＯＤ比ＴＤ给药能够获得较高的峰浓度与体内杀菌活性及较低的谷浓度,有利于提     

12例COPD患者奈替米星药动学及其下呼吸道浓度测定

目的:探讨COPD老年患者奈替米星的药代动力学特性及其下呼吸道浓度分布.方法:一天一次静脉滴注奈替米星7mg/kg,以尿素作为肺泡液稀释内标,用荧光偏振免疫法测定血清、支气管分泌液和肺泡液中奈替米星浓度.结果:奈替米星7mg/kg一天一次静脉滴注30min,血清峰浓度26.71±4.95mg/L,消除半衰期3.69h;肺泡液中药物峰浓度7.76±2.13mg/L ,相当于血清峰浓度的29%,两者具有显著相关性(r=0.986),且超过常见肺炎致病菌的MIC 值;支气管分泌液药物浓度与血清峰浓度无相关性(r=0.687).结论:奈替米星一天一次静脉滴注7mg/kg用于COPD老年患者能有效治疗肺部感染.     

茶碱非线性清除的临床考察

目的：对常规剂量时茶碱非线性代谢进行研究。方法：２０例肝肾功能正常，呼吸道疾病患者，给予二个不同剂量的氨茶碱（０．３～０．６ｇ·ｄ－１）治疗，达稳态后，用高效液相色谱法分别测定二个谷浓度值，以Δ％浓度比Δ％剂量≥１．５为判定非线性代谢的标准。结果：有１１例患者出现了非线性代谢，发生率５５％。其药动学常数：Ｖｍ＝７０７．７±１７５．４ｍｇ·ｄ－１，Ｋｍ＝５．８±３．８μｇ·ｍｌ－１。结论：本实验结果对临床更安全的应用氨茶碱有新的提示。     

反相高效液相色谱法测定人血浆中萘普生含量

目的：建立ＲＰ－ＨＰＬＣ测定人血浆中萘普生含量的方法，研究该药在人体内药物动力学。方法：血浆在酸性介质中以氯仿提取，Ｃ１８色谱柱，２３０ｎｍ波长紫外检测，以甲基炔诺酮为内标，流动相为甲醇∶水（６５∶３５，预先用磷酸调至ｐＨ３．０～３．１）；所得药时数据采用ｍｉｎｉｍ３．０８程序拟合计算药动学参数。结果：萘普生血药浓度在０．１～２００μｇ·ｍｌ－１范围内与色谱峰高比呈线性关系，ｒ＝０．９９９９（ｎ＝８）。４名健康受试者单剂量口服５００ｍｇ萘普生片后，药时曲线呈一室模型。Ｃｍａｘ＝７３．６±８．３μｇ·ｍｌ－１，Ｔｍａｘ＝２．３±０．５ｈ，Ｔ１／２Ｋｅ＝９．７±３．５ｈ，Ｋｅ＝０．０８±０．０４ｈ－１，ＡＵＣ０→２４＝８２０．０±８５．７μｇ·ｈ·ｍｌ－１。结论：本法简单、快捷、灵敏，能满足药动学研究的需要     

非小细胞肺癌患者低剂量口服鬼臼乙叉苷软胶囊药物动力学

目的：研究非小细胞肺癌患者单次低剂量口服鬼臼乙叉苷软胶囊药物动力学,并设计较为合理的给药方案。方法：ＨＰＬＣ法测定血药浓度,ＭＣＰＫＰ程序处理数据。结果：其药动学参数符合一室开放模型,Ｋａ 为１ ．８ ±２．２ ｈ－ １ ,Ｋ 为０．１９ ±０．０２ ｈ－１ ,Ｔ１／２Ｋａ１ ．０±０．８ ｈ,Ｔ１／２Ｋ为３．６±０．４ ｈ,Ｔｍａｘ 为２ ．４ ±１ ．２ ｈ,Ｃｍａｘ 为３ ．３±１．１ ｍｇ·Ｌ－１ ,ＡＵＣ为２６ ．１±６ ．２ ｍｇ·ｈ·Ｌ－１ 。药动学参数经血管外多次重复给药方案设计程序处理。结论：２５ ｍｇ·ｍ － ２ ,每天２ 次的治疗方案较为合理。     

家兔静注水杨醛-N'-(2-呋喃硫羰基)腙铜配合物的药物动力学

目的：研究水杨醛－Ｎ′－（２－呋喃硫羰基）腙铜配合物（ＣＳＦＣ）在兔体内的药物动力学。方法：１０只家兔静脉注射ＣＳＦＣ５ｍｇ·ｋｇ－１，用反相ＨＰＬＣ法测定血清药物浓度。结果：ＣＳＦＣ的血药浓度－时间曲线符合二室开放模型，主要药动学参数为：Ｔ１２α＝３．４±１．７ｍｉｎ，Ｔ１２β＝６５．５±１４．６ｍｉｎ，Ｋ１２＝０．１１８３±０．０６６９ｍｉｎ－１，Ｋ２１＝０．０２２８±０．００６５ｍｉｎ－１，Ｋ１０＝０．１２０２±０．０４０７ｍｉｎ－１，Ｖ０＝０．３０５±０．１８４Ｌ·ｋｇ－１，ＣＬ＝１．８９６±０．４７０Ｌ·ｋｇ－１·ｈ－１，ＡＵＣ＝１７０．１±５７．０ｍｇ·ｍｉｎ－１·Ｌ－１。结论：ＣＳＦＣ在兔体内分布迅速而广泛，消除也较快。家兔静注５ｍｇ·ｋｇ－１，可维持抗结核杆菌有效血浓度６ｈ。     

烫伤对头孢哌酮药物动力学的影响

目的：研究烫伤对头孢哌酮药物动力学的影响。方法：利用ＨＰＬＣ法测定头孢哌酮血药浓度并对８只家兔烫伤前后头孢哌酮药动学进行研究。结果：该药静脉注射给药后药动学符合二室开放模型。烫伤对头孢哌酮药动学有显著影响，烫伤前Ｔ１／２为１．２６±０．１４ｈ，Ｖｄ为０．４２±０．１８Ｌ·ｋｇ－１，烫伤后Ｔ１／２比烫伤前延长，为２．１４±０．３６ｈ（Ｐ＜０．０１），Ｖｄ增加，为０．６４±０．２１Ｌ·ｋｇ－１（Ｐ＜０．０１）。结论：烫伤病人在用药时需考虑烫伤引起的药动学改变     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

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.

     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

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.