替米考星纳米乳对人工感染鸡毒支原体病的治疗效果研究

为了解替米考星纳米乳对鸡毒支原体病的治疗效果,采用替米考星纳米乳(以替米考星计)高(100 mg/L)、中(75 mg/L)、低(50 mg/L)剂量饮水治疗人工感染鸡毒支原体S6菌株的肉仔鸡,同时设替米考星溶液(100 mL∶10 g)高、中、低剂量组和阳性、阴性对照组,连续给药5 d。结果表明,替米考星纳米乳各剂量组对鸡毒支原体病的治疗效果均优于替米考星溶液相应剂量组;替米考星纳米乳高、中剂量组的适口性优于替米考星溶液。研究为替米考星纳米乳在兽医临床上的应用提供理论依据。     

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。     

磷酸替米考星可溶性粉对人工感染鸡支原体的治疗试验

本试验在人工感染鸡支原体肺炎模型中,通过受试鸡气囊损伤评分等指标的检测,评估了不同剂量磷酸替米考星可溶性粉对支原体肺炎感染鸡的治疗效果.结果显示,60～ 80 mg/L剂量组10％磷酸替米考星可溶性粉治疗支原体肺炎感染鸡的治愈率和有效率分别可达70％和100％,与目前已经上市销售的10％替米考星可溶性粉(75 mg/L水,以替米考星计)的效果相当,而且由于磷酸替米考星通过增加磷酸基团而显著增加了该药的水溶性,使得该药在临床使用中更加便捷.     

兔传染性鼻炎的药物治疗试验和防治方法

试验对自然感染、症状轻重不同的兔进行鱼腥草注射液、鱼腥草注射液和5%替米考星联合应用、5%替米考星、青霉素和链霉素联合应用治疗的效果进行了对比,以期为临床药物防治兔传染性鼻炎提供参考.     

磷酸替米考星对肺炎支原体自然感染猪的治疗试验

为了评价磷酸替米考星对仔猪自然感染肺炎支原体的治疗效果,选取支原体肺炎患猪,10%磷酸替米考星可溶性粉混饮给药,每日1次,连用7 d,通过检测各组受试猪死亡率、治愈率、有效率、增重效果、感染仔猪的肺部病变评分等指标对受试药物的临床治疗效果进行研究。结果显示:10%磷酸替米考星可溶性粉80 mg/L剂量组治愈率最佳,与其他2个药物治疗组相比差异显著(P0.05);药物治疗有效率10%磷酸替米考星可溶性粉80 mg/L剂量组最高,但3个药物治疗组之间差异不显著(P0.05);10%磷酸替米考星可溶性粉60~80 mg/L能有效改善猪群相对增重率(P0.05),但仍显著低于健康猪群(P0.05);10%磷酸替米考星可溶性粉60~80 mg/L剂量组、10%替米考星可溶性粉组均可明显降低病猪肺脏病变评分(P0.05)。结果表明:60~80 mg/L剂量的10%磷酸替米考星可溶性粉饮水治疗猪自然感染肺炎支原体的效果显著,且治疗效果与10%替米考星可溶性粉相当。     

替米考星溶液对肉仔鸡人工感染鸡败血霉形体所致慢性呼吸道病的疗效试验

肉仔鸡人工感染霉形体S6株后,用替米考星溶液(以替米考星计)50mg/L、100mg/L、200mg/L进行饮水治疗,同时设酒石酸泰乐菌素可溶性粉饮水对照组,于感染后第2天起连续用药5d。试验结果表明替米考星溶液100mg/L、200mg/L剂量组效果优于替米考星溶液50mg/L和酒石酸泰乐菌素可溶性粉500mg/L组,替米考星溶液治疗慢性呼吸道病的推荐应用剂量为100mg/L。     

替米考星预混剂对人工诱发猪气喘病的疗效试验

本试验利用人工诱发猪气喘病的动物模型,设计高、中、低剂量(剂量分别为400、200、100mg/kg饲料)的替米考星治疗试验组和阳性对照组(不用药、强毒感染)、阴性对照组(不用药不感染),通过观察、检测试验猪在试验前后的增重变化和试验治疗后肺部病变率来判定替米考星的治疗效果。结果成功建立了人工诱发的猪气喘病模型,替米考星高、中剂量组的治疗效果显著,在增重和肺部病变率方面和阴性对照组差异不显著(P>0.05),而替米考星低剂量组的治疗效果略差,在增重方面和阴性对照组差异不显著(P>0.05),但在肺部病变率方面和阴性对照组差异显著(P<0.05)。这些结果为临床合理地使用替米考星防治猪气喘病提供了科学依据。     

替米考星注射剂治疗人工感染猪传染性胸膜肺炎的效果观察

摘要：本试验将替米考星注射剂以高、中、低（15mg/kg、 10mg/kg、5mg/kg体重）三个剂量, 1次/d和头孢唑林钠以25mg/kg体重, 2次/d,皮下注射治疗猪传染性胸膜肺炎,均连用3d,停药。结果表明,替米考星注射剂三个剂量组和头孢唑林钠对照组对猪传染性胸膜肺炎均有明显的治疗效果,成活率可达70%-100%,极显著的高于感染对照组（P<0.01）。尤其是替米考星低剂量组成活率显著高于替米考星高、中剂量组及头孢唑林钠组 (P<0.01)。增重效果统计结果表明,替米考星高、中、低三个剂量组与药物对照组及健康对照组之间增重效果无明显差异 (P>0.05)。本试验表明,替米考星能减少人工感染引起的临床症状、降低死亡率和提高日增重。作为注射剂治疗急性猪胸膜肺炎放线杆菌感染,以剂量（5mg/kg体重）为佳。 关键词：替米考星,头孢唑林钠,仔猪,胸膜肺炎放线杆菌     

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。     

恩诺沙星伍用替米考星对鸡慢呼病疗效试验

鸡毒支原体病又称鸡慢性呼吸道性疾病,该病常和其他疾病混合感染,一旦发病,传播速度快,预防和治疗本病常用的药物为大环内酯类抗生素,其中以新一代泰乐菌素衍生物替米考星的效果较好,但成本高.研究采用替米考星和氟喹诺酮类药物配伍,再添加一定量的增效剂,制成复方制剂,通过体外抑菌质量浓度和适口性来评定复方制剂处方的优劣.结果表明替米考星与恩诺沙星配伍,最小抑菌质量浓度仅为1/mL,不影响饲料适口性且性质稳定,为优化处方.     

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。     

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。     

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.     

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.     

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。     

Effect of tilmicosin on chemotactic, phagocytic, and bactericidal activities of bovine and porcine alveolar macrophages

OBJECTIVE: To evaluate chemotactic, phagocytic, and bactericidal activities of bovine and porcine alveolar macrophages (AM) exposed to tilmicosin. ANIMALS: 12 healthy calves and 12 healthy pigs. PROCEDURES: Lungs were obtained immediately after euthanasia; AM were collected by means of bronchoalveolar lavage and density gradient centrifugation. Chemotactic activity was evaluated by exposing AM to lipopolysaccharide or macrophage inhibitory peptide during incubation with tilmicosin. Phagocytic activity was evaluated by incubating AM with tilmicosin for 24 hours and then with tilmicosin-resistant Salmonella serotype Typhimurium. Bactericidal activity was evaluated by incubating AM with tilmicosin (0, 10, or 20 microg/ml for bovine AM; 0 or 10 microg/ml or 10 microg/ml but washed free of tilmicosin for porcine AM) and then with Mannheimia haemolytica (bovine AM) or with Actinobacillus pleuropneumoniae or Pasteurella multocida (porcine AM). RESULTS: Tilmicosin had no significant effects on chemotactic or phagocytic activities of bovine or porcine AM. The time-course of bactericidal activity was best described by polynomial equations. Time to cessation of bacterial growth and area under the time versus bacterial number curve were significantly affected by incubation of AM with tilmicosin. CONCLUSIONS AND CLINICAL RELEVANCE: Results show that bactericidal activity of bovine and porcine AM was enhanced by tilmicosin, but not in proportion to the reported ability of AM to concentrate tilmicosin intracellularly. With or without exposure to tilmicosin, the time-course of bactericidal activity of bovine AM against M haemolytica and of porcine AM against A pleuropneumoniae or P multocida was too complex to be reduced to a simple linear equation.     

Pharmacokinetics of tilmicosin in equine tissues and plasma

The macrolide antibiotic tilmicosin has potential for treating bacterial respiratory tract infections in horses. A pharmacokinetic study evaluated the disposition of tilmicosin in the horse after oral (4 mg/kg) or subcutaneous (s.c.) (10 mg/kg) administration. Tilmicosin was not detected in equine plasma or tissues after oral administration at this dose. With s.c. injection, tilmicosin concentrations reached a maximum concentration of approximately 200 ng/mL in the plasma of the horses. Tilmicosin concentrations in plasma persisted with a mean residence time (MRT) of 19 h. Maximum tissue residue concentrations (C(max)) of tilmicosin measured in equine lung, kidney, liver and muscle tissues after s.c. administration were 2784, 4877, 1398, and 881 ng/g, respectively. The MRT of tilmicosin in these tissues was approximately 27 h. Subcutaneous administration of tilmicosin resulted in severe reactions at the injection sites.     

替米考星对雏鸡增重及预防人工感染禽巴氏杆菌的效果观察

将替米考星以 3个剂量 (10 0mg/L、 2 0 0mg/L、 30 0mg/L)和泰乐菌素以 50 0mg/L给雏鸡饮水给药 5d,结果 2种药物对雏鸡均有明显的增重效果 ,且替米考星给药量与增重效果呈正相关。人工感染试验结果显示 ,替米考星 3个剂量预防组及泰乐菌素预防组对抗御人工感染禽巴氏杆菌均有明显的效果 ,但替米考星 3个剂量预防组的抗感染效果均极显著高于泰乐菌素预防组 (P <0 0 1)。试验结果表明 ,替米考星饮水给药对雏鸡除具有增重作用外 ,还具有抗感染 ,降低发病率 ,减少病理损害 ,提高成活率的作用 ;预防呼吸道疾病的效果明显优于泰乐菌素     

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。