细菌耐药拮抗剂的研究

本文介绍了具有拮抗细菌耐药性作用的物质的研究进展情况，包括灭活酶抑制剂、药物渗透促进剂、外输泵抑制剂、细菌生物被膜抑制剂、抗菌药物增强剂、耐药质粒消除剂等。     

细菌天然群体感应信号分子抑制剂研究进展

长期抗生素滥用导致了多重耐药菌株及其超级细菌的出现,由密度感应系统调控的生物被膜的形成和成熟是造成细菌感染的机制之一。自然界存在的生物活性物质能够淬灭密度感应系统,这些生物活性物质被称为群体感应信号分子抑制剂(quorum sensing inhibitor,QSI)。近年来,群体感应抑制剂成为细菌抗感染药物开发的靶点,有必要对细菌群体感应信号分子抑制剂种类、作用机制进行研究,本文综述了细菌天然群体感应信号分子抑制剂,干扰群体感应系统,从而治疗细菌感染。绝大多数原核生物能够产生群体感应抑制剂,这被认为是安全的。动物、豆类、传统的药用植物、海洋生物均能产生群体感应抑制剂。这些天然抑制剂可能替代传统抗生素,具有广阔的研究和应用前景。     

中药对细菌群体感应系统的抑制作用研究进展

细菌的群体感应系统控制着细菌生物膜的形成、毒力因子的表达和耐药性的产生等过程,群体感应抑制剂可在一定程度上减弱细菌的致病性和耐药性,给临床感染性疾病的防治带来福音。中药群体感应抑制剂通过抑制细菌信号分子的合成、促进信号分子的降解以及抑制信号分子与受体蛋白相结合,对细菌群体感应系统起到抑制作用。文章综述了中药对革兰氏阴性细菌和革兰氏阳性细菌群体感应系统的抑制作用,以期为新型抗菌药物的筛选提供新的思路。     

金黄色葡萄球菌氟喹诺酮的耐药抑制剂研究进展

金黄色葡萄球菌是引起人和动物感染的一种重要病原菌,它可以对氟喹诺酮等多种抗菌药物产生耐药性,严重影响临床治疗效果。NorA蛋白介导的药物主动外排成为葡萄球菌对氟喹诺酮类药物耐药的重要机制,利血平等作为NorA外排蛋白抑制剂,可有效降低其耐药性的产生。CCCP等能量抑制剂可加强细菌对氟喹诺酮类药物的摄取量。文章从葡萄球菌对氟喹诺酮类药物耐药机制、耐药抑制剂作用途径和能量抑制剂影响等方面,简要介绍金黄色葡萄球菌氟喹诺酮的耐药抑制剂研究进展。     

畜牧养殖中细菌耐药性产生机制与对策

畜牧养殖中抗菌药物耐药性问题日趋严重.细菌耐药性产生机制主要有产生钝化酶、改变药物作用靶点、通过主动外排或形成非渗透性膜、形成生物被膜、增加代谢颉颃物等.近几年研究又发现常用抗菌药的多种耐药新机制.针对细菌耐药机制,提出合理用药、加强饲养管理、研制开发耐酶药物、抗菌药物替代品、耐药抑制剂及破坏耐药基因新技术等对策,减少耐药性的产生与传播.     

中药有效成分对细菌溶血素的抑制作用

在防制细菌性疾病方面,抗菌药物起着非常重要的作用,但是随着抗菌药物在临床上的广泛应用,细菌的耐药问题日益突出,给临床治疗带来极大困难。近年来,以中药抑制细菌毒力因子控制细菌感染的治疗策略已引起国内外学者的广泛关注。细菌溶血素是细菌产生的主要毒力因子之一,随着研究的不断深入,开发溶血素抑制剂成为解决细菌感染问题的关键。现针对中药对细菌溶血素的抑制作用进行综述,以期为临床治疗细菌性疾病提供理论依据。     

间充质干细胞发挥抗菌作用的机制研究进展

对抗菌药物具有强耐药性的“超级细菌”对人和家畜健康造成巨大威胁。广泛、高频使用种类有限的抗菌药物治疗人、家畜以及宠物细菌感染性疾病是产生“超级细菌”的根源。寻找现有常规抗菌药物的替代品或增强剂是当前热点研究方向之一。研究表明,间充质干细胞（mesenchymal stem cells,MSCs）具有抗菌特性。理论上,MSCs有可能成为治疗细菌感染性疾病的有效手段。对MSCs影响细菌存活的作用机制以及抗菌药物可能对MSCs功能产生的影响等方面的研究进展进行综述,以期为进一步阐明MSCs抗菌作用机制、挖掘MSCs作为治疗细菌感染性疾病新方法的潜力提供参考。     

细菌耐药适应性研究进展

细菌耐药适应性现象在耐药细菌中普遍存在，其指细菌为了在高于自身耐药水平的抗生素压力下能够继续生存与繁殖而对自身代谢进行调节，以适应抗生素压力环境。近年来，相关研究发现，对细菌耐药适应性的改变可直接影响细菌耐药性的产生，其主要通路中相关基因具有潜在药物靶点的研究价值。文中对耐药适应性、耐药适应性机制及适应性代价与补偿等方面进行了综述，以期为基于耐药适应性靶点的新型耐药抑制剂研究提供参考。     

不同免疫增强剂影响肉鸡禽流感免疫效果及生长的试验

免疫调节剂是用于调节和控制免疫功能的药物,包括免疫抑制剂和免疫增强剂。免疫增强剂是一类单独使用或抗原同时使用、通过非特异性途径增强机体的免疫应答的物质。它可增强机体的免疫系统功能,缓解由环境造成的免疫功能紊乱,有利于预防和治疗传染性和条件性疾病。目前在临床上常用的免疫增强剂有很多,如：卡介苗、盐酸左旋咪唑、香菇多糖、胸腺素、白细胞介素-2（白介素-2）和黄芪多糖等等。本试验选用黄芪多糖粉剂、黄芪多糖注射液、盐酸左旋咪唑药物作为免疫增强剂,来探明不同免疫增强剂对肉鸡禽流感免疫功能和生长促进的影响差异。     

抗菌肽开发与应用的研究进展

抗菌肽是一类普遍存在于生物体内的阳离子两亲性多肽,是机体天然免疫系统的重要组成部分。抗菌肽不仅能够有效杀灭细菌,还能抑制真菌、某些有包膜的病毒、寄生虫以及肿瘤细胞的活性。抗菌肽作为多功能效应分子,如信号分子、免疫调节剂、促细胞分裂剂、抗肿瘤剂、避孕剂和饲料添加剂,被认为是种有潜力的替代药物并应用于预防和治疗研究。除了这些特性,抗菌肽还能作为载体将药物传送到细胞内。本文重点阐述了抗菌肽多功能生物活性及其作为一种有潜力和前景的替代药物可能被应用于制药行业中。     

Penicillins and beta-lactamase inhibitor combinations.

beta-Lactamase production by bacteria continues to be one of the main mechanisms of bacterial resistance to beta-lactam antibiotics, and it seems likely to remain so. beta-Lactamase inhibitors provide 1 strategy to overcome this mechanism of bacterial resistance. Although 3 beta-lactamase inhibitor/antibiotic combinations are currently available, only 1 is approved for veterinary use. Because the beta-lactamase inhibitor must be present concurrently with the antibiotic for synergistic activity, it is important to consider the pharmacokinetic profile of these drugs in combination. These combinations were developed and optimized for human patients, so it is unlikely that they would achieve the ideal plasma and tissue concentrations and ratios in veterinary patients. Indeed, several differences in pharmacokinetic variables of beta-lactam antibiotic/beta-lactamase inhibitor agents have been described in dogs, compared with people. Such pharmacokinetic differences should be considered when interpreting in vitro susceptibility results in veterinary species, because these tests use ratios of drug that were established for humans. The beta-lactamase inhibitors represent a successful example of targeted drug development. However, the currently available inhibitors are active primarily against class-A beta-lactamases. Because the frequency with which class-C beta-lactamases are recognized is rapidly increasing in human isolates, and because beta-lactamase enzymes continue to evolve, new beta-lactamase inhibitors will need to be developed to target these enzymes.     

Cytochrome P450 and its role in veterinary drug interactions.

Cytochrome P450 (CYP) enzymes are common sites of drug interactions in human beings. Drugs may act as inhibitors or inducers of CYPs, leading to altered clearance of a second drug. Clinically relevant drug interactions involving various CYP isoforms in people, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4, have been well documented. Analogous interactions are beginning to be characterized in dogs, for which canine CYPs share many of the same substrate ranges as in human beings.     

Interaction of enrofloxacin with breast cancer resistance protein (BCRP/ABCG2): influence of flavonoids and role in milk secretion in sheep

The ATP-binding cassette (ABC) transporter breast cancer resistance protein (BCRP)/ABCG2 is a high-capacity efflux transporter with wide substrate specificity located in apical membranes of epithelia, which is involved in drug availability. BCRP is responsible for the active secretion of clinically and toxicologically important substrates to milk. The present study shows BCRP expression in sheep and cow by immunoblotting with MAb (BXP-53). Vanadate-sensitive ATPase activity with specific BCRP substrates and inhibitors was measured in bovine mammary gland homogenates. To assess the role of BCRP in ruminant mammary gland we tested the fluoroquinolone enrofloxacin (ENRO). In polarized cell lines, ENRO was transported by Bcrp1/BCRP with secretory/absorptive ratios of 6.5 and 2 respectively. The efflux was blocked by the BCRP inhibitor Ko143. ENRO pharmacokinetics in plasma and milk was studied in sheep after co-administration of drug (2.5 mg/kg, i.v.) and genistein (0.8 mg/kg, i.m.) or albendazole sulfoxide (2 mg/kg, i.v) as BCRP inhibitors. Concomitant administration of BCRP inhibitors with ENRO had no significant effect on the plasma disposition kinetics of ENRO but decreased ENRO concentrations in milk.     

The ACVD task force on canine atopic dermatitis (XXII): nonsteroidal anti-inflammatory pharmacotherapy.

The pharmacotherapy of canine atopic dermatitis has relied primarily on the use of glucocorticoids and anti-histamines. During the last decade, other anti-inflammatory drugs have been investigated in clinical trials. This paper will review the studies using misoprostol, cyclosporine, tacrolimus, phosphodiesterase inhibitors, capsaicin, leukotriene inhibitors and serotonin-reuptake inhibitors for treatment of dogs with atopic dermatitis. For each drug the mechanism of action, the rationale for use in atopic dermatitis, the clinical efficacy, reported adverse effects and strength of recommendation for treatment of canine atopic dermatitis are described. At the time of this writing, there is fair evidence to support the recommendation for using cyclosporine, misoprostol and pentoxifylline for treatment of canine atopic dermatitis. This recommendation can be strengthened by the performance of additional blinded randomized controlled trials with larger number of dogs. In contrast, there is insufficient evidence to recommend for or against treatment with tacrolimus, leukotriene inhibitors, serotonin-reuptake antagonists and capsaicin.     

Pregnancy termination in the bitch and queen

Mismate or pregnancy termination is one of the most common "reproductive" requests from dog and cat owners. Ovariohysterectomy is the best alternative for those clients who do not really have a valid reason for keeping a reproductively intact animal. If the animal is a potential breeder, drugs are available that can prevent or terminate pregnancy. The use of these drugs must be based on the safety, efficacy, convenience, compliance in treatment, and cost of the drug. Drugs that can be given during estrus to prevent pregnancy include estrogens and tamoxifen. However, because most dogs presented for mismate are not truly pregnant, a pregnancy examination should be performed before any drug is given to terminate pregnancy. If a dog is known to be pregnant, multiple doses of natural or synthetic prostaglandins can be used throughout pregnancy, whereas multiple doses of prolactin inhibitors (cabergoline, bromocriptine, metergoline) or dexamethasone can be used in the second half of pregnancy. Combined protocols of prostaglandin and prolactin inhibitors are also effective at terminating pregnancy. Progesterone blockers such as mifepristone and aglepristone are effective, but very expensive. Other drugs, such as the isoquinolones and progesterone synthesis inhibitor epostane are available outside of the United States and appear to be very effective at terminating pregnancy. No drug, however, meets all the following criteria of a perfect mismate drug: possible to give at any stage of estrus or pregnancy, 100% effective, causes no vaginal discharge, has no side effects, does not impair future fertility, is readily available, and is inexpensive.     

Identification and characterization of the cofactor-independent phosphoglycerate mutases of Dirofilaria immitis and its Wolbachia endosymbiont

Drug treatments for heartworm disease have not changed significantly in the last decade. Due to concerns about possible drug resistance and their lower efficacy against adult worms, there is a need for the development of new antifilarial drug therapies. The recent availability of genomic sequences for the related filarial parasite Brugia malayi and its Wolbachia endosymbiont enables genome-wide searching for new drug targets. Phosphoglycerate mutase (PGM) enzymes catalyze the critical isomerization of 3-phosphoglycerate (3-PG) and 2-phosphoglycerate (2-PG) in glycolytic and gluconeogenic metabolic pathways. There are two unrelated PGM enzymes, which are structurally distinct and possess different mechanisms of action. The mammalian enzyme requires 2,3-bisphosphoglycerate as a cofactor (dependent PGM or dPGM), while the other type of PGM does not (independent PGM or iPGM). In the present study, we have determined that Dirofilaria immitis and its Wolbachia endosymbiont both possess active iPGM. We describe the molecular characterization and catalytic properties of each enzyme. Our results will facilitate the discovery of selective inhibitors of these iPGMs as potentially novel drug treatments for heartworm disease.     

蜱半胱氨酸蛋白酶抑制分子研究进展

蜱是以吸血为生的体外寄生虫,能传播多种病原体。控制蜱的传统方法是使用杀虫剂,但会产生药物残留等问题。为了找到控制蜱及蜱传病的新方法,必须在分子水平上了解蜱的相关生理过程。蜱半胱氨酸蛋白酶抑制分子是一类抗蛋白酶分子,主要作用于半胱氨酸蛋白酶的抑制调控。论文介绍了蜱半胱氨酸蛋白酶抑制分子的结构和分类,以及在蜱的吸血、血液消化、蜱的先天免疫及对宿主免疫调节等生理过程的重要作用,同时也综述了半胱氨酸蛋白酶抑制分子具有抗寄生虫和抗癌的作用,为全面了解蜱半胱氨酸蛋白酶抑制分子提供参考。     

New drugs for horses and production animals in 2010

In 2010, three new active pharmaceutical ingredients were released on the German market for horses and food-producing animals. These were gamithromycin (Zactran?), a new macrolide antibiotic, Monepantel (Zolvix?), a broad spectrum anthelmintic with a novel mechanism, and Pergolide (Prascend?), the first dopamine receptor agonist for animals. Two substances have been approved for additional species. The tetracycline antibiotic doxycycline is now also authorized for turkeys and the nonsteroidal anti-inflammatory drug firocoxib from the group of cyclo-oxygenase-2 (COX-2) inhibitors is now available for horses. Furthermore, four new preparations with an interesting new pharmaceutical form, one drug with a new formulation and two drugs, which are interesting because of other criteria, were added to the market for horses and food producing animals.     

Flow cytometric evaluation of multidrug resistance proteins on grossly normal canine nodal lymphocyte membranes

OBJECTIVE: To demonstrate efficacy of flow cytometric evaluation of expression and activity of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) efflux pumps and characterize and correlate their expression and activity in grossly normal canine nodal lymphocytes. SAMPLE POPULATION: Nodal lymphocytes from 21 clinically normal dogs. PROCEDURES: Pump expression was assessed by use of fluorescent-labeled mouse antihuman P-gp (C494) and MRP1 (MRPm6) antibodies and expressed as median values (antibody value divided by isotype control value). The P-gp and MRP activities were assessed by measuring cellular retention of rhodamine 123 and 5(6)-carboxyfluorescein diacetate in the absence and presence of inhibitors (verapamil and PSC833 for P-gp, probenecid and MK-571 for MRP). Protein activity was expressed as median fluorescence of cells with inhibitors divided by that without inhibitors. RESULTS: Expression of P-gp was (mean +/- SEM) 50.62 +/- 13.39 (n = 21) and that of MRP was 2.16 +/- 0.25 (13). Functional activity was 1.27 +/- 0.06 (n = 21) for P-gp and both inhibitors and 21.85 +/- 4.09 (21) for MRP and both inhibitors. Function and expression were not correlated. CONCLUSIONS AND CLINICAL RELEVANCE: Use of flow cytometry effectively assessed P-gp and MRP expression and activity in canine lymphocytes. Optimization of the flow cytometric assay was determined for evaluating activity and expression of these pumps in canine lymphoid cells. Evaluation of expression or activity may offer more meaning when correlated with clinical outcome of dogs with lymphoproliferative diseases. Cell overexpression of P-gp and MRP can convey drug resistance.