翻开抗微生物药物厚厚的“族谱”

抗微生物药物是一个很大的“家族”,包括很多成员,按照药物作用的对象（即八大类微生物）可分为：抗茵药物、抗病毒药物、抗真菌药物、抗支原体药物、抗衣原体药物、抗立克次体药物、抗分支杆菌药物、抗螺旋体药物等,通常不包括抗寄生虫药物,但广义的抗微生物药物有时把抗寄生虫药物也包括在内。     

神经系统用药市场前景看好

中枢神经系统药物的市场有多方面，包括：抗抑郁症药物、抗老年性痴呆（AD）药物、注意力缺陷与多动障碍（ADHD）药物、失眠药物、抗癫痫药物、神经性疼痛药物、抗精神病药物和抗精神分裂症药物市场。其中以抗抑郁药物、抗癫痫药、抗精神病药物和抗精神分裂症药物的市场为主，近年来人们对老年性痴呆的认识增多和生活工作压力的增大，抗老年性痴呆药物和失眠药物的市场规模亦有所上升。     

生物技术制药与基因重组技术研究现状

1 生物技术药物 1.1 生物药物与生物技术药物的范畴 由于生物技术的崛起和基因工程的发展,提出了生物药物.20世纪90年代将生物药物分为:生化药物、生物制品、微生物药物和生物技术药物.     

剂量与药物治疗及药物发现的关系

药物剂量是影响药物效应的重要因素。不同的剂量可以激活剂量相关靶，所以同一种药物的多种作用及其不良反应与剂量也有着密切的关系。药物剂量与药物发现存在着相互联系。一种药物在使用过程中，由于剂量的不同，会出现新的药物效应，有利于发现新的药物靶点，加快药物发现的速度；相反，药物发现的研究方法，尤其是涉及药物安全性评价的方法，直接影响着药物剂量的确定。     

肝脏转运蛋白在药物肝胆转运中的作用

目的对肝脏转运蛋白在药物肝胆转运中的作用作一综述,为药物肝靶向提供依据。方法根据文献,从药物不良反应、药物的矢量转运、药物肝靶向性、药物之间相互作用4个方面阐述肝脏转运蛋白对药物肝胆排泄产生的影响。结果肝脏转运蛋白引起的药物矢量转运影响药物的肝脏摄取,药物肝靶向性影响药物的疗效,药物之间相互作用影响临床用药安全和不良反应。结论肝脏转运蛋白在药物肝胆转运中起到了重要的作用,它与药物在体内各组织分布、临床疗效均有密切的联系。     

正在开发中的132个老年病治疗药

根据药品研究和生产商协会（PhRMA）的最新调查，美国1994年有对家制药公司正在开发132个新药用于治疗老年性疾病。而1993年有6O家公司开发125个老年病用药。正在开发药物的适应证以及药物数目如下：治疗类风湿性关节炎的药物最多，有ZO个；呼吸道／肺疾病药物18个；糖尿病药物17个；骨质疏松症药物15个；阿尔兹海默病药物14个；膀肥和肾病药物11个；帕金森病药物10个；抗抑郁药物9个；眼病药物7个；骨关节炎药物7个；前列腺病药物7个；脓毒症药物7个；皮肤疾病药物5个；治疗阳萎药物4个以及变形性骨炎药物3个。这些药物中有60个药物在进…     

药物流行病学与药物警戒

药物流行病学学科的形成，起源于药物警戒的开展。经过不断地发展，现在的药物流行病学早已不仅仅是药物警戒，而药物警戒仍是药物流行病学研究的一个重要方面。本文就药物流行病学的专业特征和面临的任务，特别是药物流行病学与药物警戒之间的关系，作如下交流。     

患者的依从性与药物利用

药物利用研究是指全社会的药物市场、供给、处方及其使用的研究,其重点是药物利用所引起的医药的、社会和经济的后果以及各种药物和非药物因素对药物利用的影响.由此可见,影响药物利用因素,除药物本身外,还要受诸多非药物因素的影响.比如医生、药师是药物利用的主导者,药品生产企业是药物利用的原动力,保险公司是药物利用的协调监控者,政府的宏观决策、管理决定着药物利用的走向,这些因素都在药物利用中发挥着独特的作用.而患者作为药物利用的主体,许多方面都影响着药物的利用.如患者的年龄、性别、受教育的程度、经济状况、对医药知识的认识程度等都直接或间接地影响药物的利用,在此就患者的依从性与药物利用的关系进行讨论.     

治疗阳痿药物的进展

治疗阳痿的药物有口服药物、注射药物与局部外用药物。口服药物中西地那芬是疗效显著的新型药物。注射药物中前列腺素E1是效果较好、副作用较少的药物。局部外用药目前尚无理想的药物     

剂量-依赖性药物动力学与癌症的化学治疗

大多数药物的体内消除过程遵循一级动力学规律,在治疗剂量范围内描述药物消除的动力学参数不变。为数不多的药物显示剂量-依赖性药物动力学(亦称非线性药物动力学),其动力学参数依赖所用药物的剂量。某些情况下,单剂药物在消除期间的动力学参数随体内药物浓度而变化。剂量-依赖性药物动力学的类型产生剂量-依赖性药物动力学的主要原因     

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.     

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.     

Inhibition of synaptosomal uptake of amino acid transmitters by diamines

Reports of the inhibitory effects of diaminocarboxylic acids on the uptake of amino acid transmitters led the present authors to examine the effects of simple aliphatic diamines on the synaptosomal uptake of glutamate, aspartate, GABA and glycine. The diamines studied were the series from ethylenediamine through to 1,7-diaminoheptane; DL-2,4-diaminobutyric acid (DABA) was also tested for comparative purposes. The greatest inhibition seen was on the uptake of glycine and GABA. Weaker effects on uptake were seen with glutamate, while aspartate was unaffected. The patterns of inhibition for glycine and GABA were similar and the effects were dose-dependent. 1,2-Diaminopropane was the most inhibitory, followed by ethylenediamine and 1,7-diaminoheptane. The reported inhibitory effects of DL-2,4-diaminobutyric acid on the uptake of GABA and glutamate were confirmed; comparable inhibition of the uptake of glycine and aspartate was seen but the effects on GABA were most potent. Inhibition of the uptake of GABA by 1,2-diaminopropane was approximately one fifteenth that reported for DL-2,4-diaminobutyric acid. The inhibition by diamine of the uptake of glycine and GABA can provide an explanation of the depressant effects of diamines, seen after ventricular administration; however, the excitotoxic effects of the diamines 1,3-diaminopropane through to 1,7-diaminoheptane could not be explained by the present results.     

Inhaled therapeutics for prevention and treatment of pneumonia

The lungs are the most common site of serious infection owing to their large surface area exposed to the external environment and minimum barrier defense. However, this architecture makes the lungs readily available for topical therapy. Therapeutic aerosols include those directed towards improving mucociliary clearance of pathogens, stimulation of innate resistance to microbial infection, cytokine stimulation of immune function and delivery of antibiotics. In our opinion inhaled antimicrobials are underused, especially in patients with difficult-to-treat lung infections. The use of inhaled antimicrobial therapy has become an important part of the treatment of airway infection with Pseudomonas aeruginosa in cystic fibrosis and the prevention of invasive fungal infection in patients undergoing heart and lung transplantation. Cytokine inhaled therapy has also been explored in the treatment of neoplastic and infectious disease. The choice of pulmonary drug delivery systems remains critical as air-jet and ultrasonic nebulizer may deliver sub-optimum drug concentration if not used properly. In future development of this field, we recommend an emphasis on the study of the use of aerosolized hypertonic saline solution to reduce pathogen burden in the airways of subjects infected with microbes of low virulence, stimulation of innate resistance to prevent pneumonia in immunocompromised subjects using cytokines or synthetic pathogen-associated molecular pattern analogues and more opportunities for the use of inhaled antimicrobials. These therapeutics are still in their infancy but show great promise.     

Recommandations de bon usage des carbapénèmes

Carbapenems are being increasingly used because of the widespread dissemination of antibiotic resistance among Gram-negative bacilli, especially of extended-spectrum beta-lactamases; this increasing use raises the concern of loss of activity for this antimicrobial class following the emergence of carbapenemases. The current guideline from the Anti-infective drugs Committee of the Assistance publique-Hôpitaux de Paris (AP–HP) group emphasizes the careful and limited use of carbapenems, comparing the respective characteristics of the four available molecules, and specifies their indications in clinical hospital practice, with possible alternatives.     

Antifungal drugs in pregnancy: a review

The use of any medication in pregnant women requires careful consideration of benefit to the mother versus risk posed to the fetus. Fungal infections are not uncommon in pregnant women; in fact, the incidence of certain infections such as Candida vaginitis is increased in this patient population. A variety of antimycotic agents are currently available to treat systemic or mucocutaneous fungal infections. Many of these agents are capable of penetrating the placental barrier and entering fetal cord blood, therefore adverse effects of these agents on the fetus are a valid concern. The use of topical azoles for the treatment of superficial fungal infections is safe and efficacious. However, there are some data suggesting a dose-related increase in the risk of teratogenicity associated with the use of systemic azoles. Amphotericin B remains the drug of choice for the treatment of systemic fungal infections in pregnancy. There are serious risks of fetal malformations associated with the use of griseofulvin, ketoconazole, voriconazole, flucytosine and potassium iodide. These drugs are contraindicated in pregnancy. There are insufficient data regarding the use of caspofungin in pregnancy. This article will review available data regarding the safety of antifungal drug use in pregnant women.     

Bioavailabilities of rectal and oral methadone in healthy subjects

AIMS: Rectal administration of methadone may be an alternative to intravenous and oral dosing in cancer pain, but the bioavailability of the rectal route is not known. The aim of this study was to compare the absolute rectal bioavailability of methadone with its oral bioavailability in healthy humans. METHODS: Seven healthy subjects (six males, one female, aged 20-39 years) received 10 mg d(5)-methadone-HCl rectally (5 ml in 20% glycofurol) together with either d(0)-methadone intravenously (5 mg) or orally (10 mg) on two separate occasions. Blood samples for the LC-MS analyses of methadone and it's metabolite EDDP were drawn for up to 96 h. Noninvasive infrared pupillometry was performed at the same time as blood sampling. RESULTS: The mean absolute rectal bioavailability of methadone was 0.76 (0.7, 0.81), compared to 0.86 (0.75, 0.97) for oral administration (mean (95% CI)). Rectal absorption of methadone was more rapid than after oral dosing with Tmax values of 1.4 (0.9, 1.8) vs. 2.8 (1.6, 4.0) h. The extent of formation of the metabolite EDDP did not differ between routes of administration. Single doses of methadone had a duration of action of at least 10 h and were well tolerated. CONCLUSIONS: Rectal administration of methadone results in rapid absorption, a high bioavailability and long duration of action. No evidence of presystemic elimination was seen. Rectal methadone has characteristics that make it a potential alternative to intravenous and oral administration, particularly in cancer pain and palliative care.     

《儿科阿奇霉素注射使用的快速建议指南》临床问题与结局指标的调查分析

目的:通过总结《儿科阿奇霉素注射使用的快速建议指南》临床问题与结局指标的前期调查结果,与指南专家评估结果进行对比,探讨开展该工作的意义。方法:通过电子问卷,对临床一线医务人员进行调查,调查内容主要包括参与者的基本信息、对指南拟纳入的临床问题(5分制)和结局指标(9分制)进行重要程度评分以及补充。计算各题平均分,采用变异系数表示一致性,采用Wilcoxon秩和检验,对比参与者和专家评估结果,对补充的内容进行描述性分析。结果:共纳入155位参与者的调查结果,各年龄段、文化程度和职称等均有分布。结果显示,注射用阿奇霉素的用法用量(4.56分)和有效性指标(7.28分)最受关注,特殊人群用药(42.71%)和安全性(34.52%)的一致性较差;与专家评估对比分析显示,对于大部分问题和指标,前期调研和专家评估的评分差异无显著性,专家评估的变异系数更低;共收集有效补充15条,最终将新生儿的使用问题纳入。结论:在指南制订前期,有必要对临床问题和结局指标进行广泛调查,收集并分析评估和补充意见,这对指南专家组的评估具有一定的参考意义。     

Current concepts of the actions of paracetamol (acetaminophen) and NSAIDs

There is much uncertainty about the mechanism of action of paracetamol (acetaminophen). It is commonly stated that, unlike the non-steroidal anti-inflammatory drugs (NSAIDs), it is a weak inhibitor of the synthesis of prostaglandins. This conclusion is made largely from studies in which the synthesis of prostaglandins was measured in homogenized tissues. However, in several cellular systems, paracetamol is an inhibitor of the synthesis of prostaglandins with IC₅₀ values ranging from approximately 4 μM to 200 μM. Paracetamol is not bound significantly to plasma proteins and therefore the concentrations in plasma can be equated directly with those used in in vitro experiments. After oral doses of 1 g, the peak plasma concentrations of paracetamol are approximately 100 μM and the plasma concentrations are therefore in the range where marked inhibition of the synthesis of prostaglandins should occur in some cells. Paracetamol is metabolized by the peroxidase component of prostaglandin H synthase but the relationship of this to inhibition of the cyclooxygenase or peroxidase activities of the enzyme is unclear. Paracetamol is also metabolized by several other peroxidases, including myeloperoxidase, the enzyme in neutrophils which is responsible for the production of hypochlorous acid (HOCl). The metabolism of paracetamol by myeloperoxidase leads to the decreased total production of HOC1 by both intact neutrophils and isolated myeloperoxidase, even though the initial rate of production of HOC1 is increased. The IC₅₀ value, derived from inhibition of the total production of HOC1 by isolated myeloperoxidase, is 81 μM. Several NSAIDs inhibit functions of neutrophils in media containing low concentrations of protein but their effects, in contrast to that of paracetamol, are generally produced only at concentrations greater than those of the unbound drug in plasma during treatment with the NSAIDs. However, neutrophils isolated during treatment with NSAIDs, such as piroxicam, ibuprofen and indomethacin show decreased function. Paracetamol has little or no anti-inflammatory activity by itself but may potentiate the clinical activity of NSAIDs in the treatment of rheumatoid arthritis.