替米考星的应用研究进展

替米考星（Tilmicosin）是一种以泰乐菌素为前体半合成的大环内酯类畜禽专用抗生素。80年代由英国Elanco动物保健品公司首先开发成功,替米考星抗菌谱广,具有很强的抗菌活性,与其他大环内酯类药物相似。该药在国外已用于猪、牛、山羊、兔、肉鸡、火鸡等动物因敏感菌引起的感染性疾病,具有良好的治疗效果,特别是呼吸道感染。在国内也已有进口注册产品用于临床,亦有药厂进行替米考星的合成与产品的申报。2005年初,农业部批准山东济兴医化有限公司济宁兽药厂申报的替米考星原料、替米考星预混剂、替米考星注射液为三类新兽药网。为了解替米考星及其应用进展,现将有关抗菌活性、药动学、药效学及药物残留等方面的研究分别概述如下。     

兽用抗菌新药替米考星的研究

替米考星为畜禽专用大环内酯类新型抗生素,国内三类新兽药。本文综述了替米考星的合成、抗菌活性、药代动力学特征、毒性残留、临床应用等方面的特点与研究概况。     

畜禽专用抗生素替米考星

替米考星是半合成大环内酯类畜禽专用抗生素.研究表明,替米考星除了具有抑菌作用外,还构可作为免疫介质-调节动物体免疫功能,促进机体自身防御方面的独特机制也引起了广泛的关注.由于其独特的作用机制,因而在治疗猪呼吸道病综合征和猪繁殖与呼吸综合征时表现出显著的优越性.文章主要对替米考星的作用机理、临床应用、不良反应、残留检测以及公共健康风险评估等方面进行了概述.     

替米考星对机体免疫系统调节的研究进展

替米考星是动物专用的新一代大环内酯类抗生素,近年来广泛应用于畜禽养殖中,用于呼吸系统疾病的防控。有学者提出替米考星对免疫系统的调节作用在疾病治疗过程中起着重要作用,本文阐述了近年来替米考星在促进机体防御功能方面所取得的最新进展。     

磷酸替米考星预混剂和替米考星溶液对人工感染猪传染性胸膜肺炎的疗效试验

为客观地评价国产磷酸替米考星预混剂和替米考星溶液对猪人工感染猪胸膜肺炎的治疗效果，笔者委托河南农业大学兽药研究所，根据农业部颁发的《兽药实验技术规范》，对磷酸替米考星预混剂和替米考星溶液进行了临床试验，现将结果报告如下。     

兽用抗菌新药替米考星的研究

替米考星为畜禽专用大环内酯类新型抗生素，国内三类新兽药。本文综述了替米考星的合成、抗菌活性、药代动力学特征、毒性残留、临床应用等方面的特点与研究概况。     

替米考星固体分散体的制备及质量评价

制备替米考星固体分散体并对其进行质量评价。建立替米考星含量测定方法,采用熔融法,以Poloxamer188为载体制备替米考星固体分散体,并通过X-射线衍射扫描测定、溶出度测定、吸湿量测定、稳定性考察等评价其质量。替米考星在40~400μg·m L-1范围内线性关系良好,r=0.999 9;所制备的替米考星固体分散体,能有效地提高替米考星的溶出速率;但易于吸湿,应置于密闭干燥条件下保存。     

不同剂量替米考星对雏鸡心功能的影响

替米考星是一种由泰乐菌素经酸水解后半合成的大环内酯类畜禽专用抗生素[1-2].具有谱广、抗菌作用,同时可作为免疫介质,调节机体免疫功能,促进机体自身防御功能的独特机制[4].替米考星的药动学已在牛、羊、猪及家禽[5]等动物上进行过研究,内服和皮下注射给药吸收快,血中药物半衰期长,药物组织穿透力强,体内分布范围广[6].替米考星的靶器官为心脏,对动物心血管系统具有影响作用[8-9],但现在的仅有关于牛、猪、羊、犬等注射替米考星后对心功能影响的报道,而未见关于鸡的研究.因此,本试验对此进行了试验.     

动物专用抗菌新药替米考星

替米考星 (Tilmicosin)是一种以泰乐菌素为前体半合成的大环内酯类畜禽专用抗生素 ,80年代由英国Elanco动物保健品公司首先开发成功 ,已被批准临床使用于牛 (商品名MICOTIL30 0 )和猪 (商品名PULMOTIL90 ) ,并在国外部分国家上市。在我国 ,美国礼来公司有用于猪的替米考星预混剂产品销售。近年来 ,替米考星原料药和制剂产品的国产化研制开发进展迅速 ,目前国内已有浙江海正药业股份有限公司等兽药企业在进行新产品开发申报 ,并向市场提供替米考星原料。替米考星主要用于牛、猪、鸡、羊等动物由敏感菌引起的感染性疾病 ,特别是畜禽呼…     

抗菌新药替米考星在临床上的应用

替米考星(Tilmicosin)是一种以泰乐菌为前体半合成的大环内酯类畜禽专用抗生,80年代由英国Elanco动物保健品公司首开发成功,已被批准临床用于牛(商品名ICOTIL300)和猪(商品名PULMOTIL90),在部分国家上市。在我国,美国礼来公司用于猪的替米考星预混剂产品销售。近年,替米考星原料药和制剂产品的国产化研开发进展迅速,目前国内已有浙江海正药股份有限公司等兽药企业在进行新产品开申报,并向市场提供替米考星原料。替米考星临床上主要用于防治家畜肺炎胸膜肺炎放线杆菌、巴氏杆菌、霉形体等感),家禽支原体病和泌乳动物乳房炎等。预和治…     

Tilmicosin-induced bovine neutrophil apoptosis is cell-specific and downregulates spontaneous LTB4 synthesis without increasing Fas expression

The pathology of bacterial pneumonia, such as seen in the bovine lung infected with Mannheimia haemolytica, is due to pathogen virulence factors and to inflammation initiated by the host. Tilmicosin is a macrolide effective in treating bacterial pneumonia and recent findings suggest that this antibiotic may provide anti-inflammatory benefits by inducing polymorphonuclear neutrophilic leukocyte (PMN) apoptosis. Using an in vitro bovine system, we examined the cell-specificity of tilmicosin, characterized the changes in spontaneous leukotriene B4 (LTB4) synthesis by PMN exposed to the macrolide, and assessed its effects on PMN Fas expression. Previous findings demonstrated that tilmicosin is able to induce PMN apoptosis. These results were confirmed in this study by the Annexin-V staining of externalized phosphatidylserine and the analysis with flow cytometry. The cell-specificity of tilmicosin was assessed by quantification of apoptosis in bovine PMN, mononuclear leukocytes, monocyte-derived macrophages, endothelial cells, epithelial cells, and fibroblasts cultured with the macrolide. The effect of tilmicosin on spontaneous LTB4 production by PMN was evaluated via an enzyme-linked immunosorbent assay. Finally, the mechanisms of tilmicosin-induced PMN apoptosis were examined by assessing the effects of tilmicosin on surface Fas expression on PMN. Tilmicosin-induced apoptosis was found to be at least partially cell-specific, as PMN were the only cell type tested to die via apoptosis in response to incubation with tilmicosin. PMN incubated with tilmicosin under conditions that induce apoptosis spontaneously produced less LTB4, but did not exhibit altered Fas expression. In conclusion, tilmicosin-induced apoptosis is specific to PMN, inhibits spontaneous LTB4 production, and occurs through a pathway independent of Fas upregulation.     

Pharmacokinetics of tilmicosin in beef cattle following intravenous and subcutaneous administration

The intravenous pharmacokinetic profile of tilmicosin is yet to be achieved because of the cardiovascular effects of tilmicosin. This study summarizes two pharmacokinetic studies that provided complete pharmacokinetic profile of tilmicosin in cattle. The first study was a pharmacokinetic study of tilmicosin in beef calves dosed by i.v. infusion over 5 h. The second study was a subcutaneous (s.c.) pharmacokinetic study comparing the pharmacokinetic profile of tilmicosin in light (approximately 170 kg) and heavy (approximately 335 kg) beef cattle and comparing the labeled dose range of 10 or 20 mg/kg dose. The data from the two different studies were used to calculate bioavailability values, which support the assumption that tilmicosin is 100% bioavailable in cattle. The results from the second study showed that the weight of an animal when administered tilmicosin does not have a significant effect on exposure, but did demonstrate that doubling the dose of tilmicosin administered doubles the systemic exposure to tilmicosin.     

替米考星固体分散体的制备与物相鉴定

为改善替米考星的水溶性，提高其生物利用度，试验选用聚乙二醇6000和泊洛沙姆188作为载体，采用熔融法制备替米考星固体分散体。以体外累积溶出度为评价指标，通过正交试验筛选最佳制备工艺，选用X-射线衍射法、傅里叶红外光谱法、扫描电镜法进行物相鉴定。结果显示，替米考星固体分散体最佳制备工艺为联合载体PEG6000：P188=20:1、药载比1:3、搅拌时间1 h、固化时间12 h；物相鉴定表明，替米考星为非晶态，固体分散体为晶体结构，替米考星以无定形态分散于载体中；替米考星固体分散体在2 min时溶出度达到71.8%，15 min时完全溶解，显著提高了替米考星的溶出速率。该制备工艺简单，选用联合载体制备替米考星固体分散体，能够有效避免单一载体制备替米考星固体分散体出现的缺陷，有效提高溶出度，方便临床饮水用药。     

替米考星肠溶微丸的质量评价

采用高效液相色谱法和体外溶出度试验测定替米考星肠溶微丸的载药量和溶出度,对自行研制的替米考星肠溶微丸进行初步质量评价。结果显示,制剂含量平均在20%,在人工胃液中不溶出,在人工肠液中溶出度达90%以上,达到了肠溶效果。     

紫外分光光度法测定替米考星预混剂的含量

采用紫外分光光度法测定替米考星预混剂的含量。结果表明,在5~25μg/mL浓度范围内,浓度与吸光度值呈良好的线性关系,相关系数r=0.999 8,平均回收率为99.42%;相对标准偏差RSD=1.10%。本方法适合于替米考星预混剂含量的快速测定。     

替米考星治疗人工感染巴氏杆菌病仔猪试验

研究了国产替米考星注射用药对人工感染多杀性巴氏杆菌病猪的治疗效果,用断奶仔猪进行试验,为临床使用提供了依据.结果表明,替米考星治疗急性猪肺疫效果确实, 推荐剂量为10 mg/kg体重.     

Tilmicosin reduces lipopolysaccharide-stimulated bovine alveolar macrophage prostaglandin E(2) production via a mechanism involving phospholipases

Tilmicosin is a potent antimicrobial with broad-spectrum activity against the bacterial agents involved in the bovine respiratory disease complex. Recent studies indicate that in addition to being bactericidal, tilmicosin is capable of modulating inflammation in the lung. A series of experiments were designed to determine whether tilmicosin alters alveolar macrophage-prostaglandin E(2) (PGE(2)) production induced by Escherichia coli (O55:B5) lipopolysaccharide (LPS). Twenty-two healthy Holstein bull calves were used to study the effects of LPS-induced PGE(2) production of alveolar macrophages after in vivo or in vitro treatment with tilmicosin. In Experiment 1, tilmicosin was given by subcutaneous injection (15 mg/kg) twice, 48 hours apart, to four calves; four control calves received no treatment. Twenty-four hours after the second treatment, alveolar macrophages were stimulated with LPS in vitro. In Experiment 2, alveolar macrophages from five untreated calves were harvested and treated in vitro with tilmicosin, followed by LPS stimulation. In Experiment 3, the ability of in vitro tilmicosin treatment to alter the expression of LPS-induced cyclooxygenase-2 (COX-2) mRNA was evaluated. In Experiments 4 and 5, secretory phospholipase A(2) activity was examined in untreated calves. Treatment of calves with tilmicosin resulted in reduced LPS-induced alveolar macrophage PGE(2) production. Similar reductions in PGE(2) by LPS-stimulated alveolar macrophages after in vitro tilmicosin treatment were noted. This in vitro tilmicosin treatment was not associated with reduction of the expression of LPS-induced COX-2. Alveolar macrophage phospholipase A(2) activity induced by LPS was significantly reduced by prior tilmicosin treatment in vitro. Tilmicosin (in vivo and in vitro) appears to reduce the PGE(2) eicosanoid response of LPS-stimulated alveolar macrophages by reducing the in vitro substrate availability without altering in vitro COX-2 mRNA expression.     

替米考星肠溶微丸的制备及其评价

采用挤出滚圆法制备含药微丸,药物以固体分散体的形式存在微丸中,流化床进行肠溶包衣,制得替米考星肠溶微丸。通过不同的工艺处方筛选,考察其理化性质及体外释放特性。分别采用紫外分光光度计测定替米考星的含量,电子显微镜、红外分光光度法和差示扫描量热法确证微丸的特性。结果显示,微晶纤维素在一定程度上对微丸骨架的成型有影响,而包衣的厚度影响微丸的体外释放行为。释放度实验表明替米考星肠溶微丸能达到肠溶制剂的效果。     

替米考星、红霉素体外诱导猪胸膜肺炎放线杆菌耐药性的初步研究

采用微量稀释法测定了替米考星和红霉素对5株临床分离猪胸膜肺炎放线杆菌(App)的最小抑菌浓度,并用药物浓度递增法体外诱导App对两种药物的耐药性。结果表明替米考星和红霉素对App都具有很高的体外抑菌活性;经15代诱导,App对替米考星的最高耐受浓度没发生明显变化,而对红霉素的最高耐受浓度有了较大程度的提高,表明App对替米考星不易产生耐药,而对红霉素可缓慢产生耐药。试验结果提示替米考星是治疗App感染的理想药物。     

Intracellular accumulation,subcellular distribution and efflux of tilmicosin in swine phagocytes

Tilmicosin is a semi-synthetic macrolide antibiotic, currently approved for veterinary use in cattle and swine respiratory disease. As the concentrations of tilmicosin are generally low in swine lung tissue, the interaction of tilmicosin with three types of swine phagocytes (monocyte-macrophages, alveolar macrophages, and neutrophils) was evaluated to provide an understanding of clinical efficacy. After incubation with radiolabelled tilmicosin, uptake was determined and expressed as the ratio of the intracellular (Ci) to the extracellular (Ce) drug concentration (Ci/Ce). Tilmicosin was avidly accumulated by the swine phagocytes (Ci/Ce 48–69 at 4 h incubation) with 51 to 85% localized in the lysosomes. Uptake was dependent on cell viability, temperature and pH, but was not influenced by the metabolic inhibitors, sodium cyanide or potassium fluoride. However, lipopolysaccharide (LPS) exposure increased tilmicosin uptake by the swine phagocytes. In neutrophils, upon removal of extracellular tilmicosin, 60% of the intracellular tilmicosin was effluxed within the first 30 min, but after 4 h of incubation in drug-free medium, 25% remained cell-associated. In contrast, after 4 h of incubation in drug-free medium, 60% and 45% of tilmicosin remained cell-associated, within alveolar macrophages and monocyte-derived macrophages, respectively. Tilmicosin uptake was observed to increase lysosomal enzyme (acid phosphatase, lysozyme and β-glucuronidase) production. Finally, neutrophils were shown to transport and efflux bioactive tilmicosin in a test system measuring both neutrophil chemotaxis under agarose and a bioassay measuring inhibition of bacterial growth in the presence of antibiotic in agar. These in vitro interactions of tilmicosin with swine phagocytes suggest an integral role in effecting clinical efficacy.