2-[(11Z,13Z)-6-[5-(4,5-dihydroxy-4,6-dimethyloxan-2-yl)oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde | 8025-81-8

• 物质功能分类: 原料药 - 抗生素类药物
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-[(11Z,13Z)-6-[5-(4,5-dihydroxy-4,6-dimethyloxan-2-yl)oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde
• CAS: 8025-81-8
• 化学式: C₄₃H₇₄N₂O₁₄
• 分子量: 843.1
• InChiKey: ACTOXUHEUCPTEW-GRWVDKKHSA-N

物化性质

• 熔点：
  126-128 °C
• 沸点：
  914℃
• 比旋光度：
  D20 -80° (methanol)
• 闪点：
  >110°(230°F)
• 溶解度：
  乙醇：50 mg/mL，清澈至微浑浊，淡黄色
• 颜色/状态：
  Amorphous
• 蒸汽压力：
  9.9X10-31 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation: -80 deg at 20 °C/D
• 分解：
  When heated to decomposition it emits acrid smoke & irritating fumes.
• 解离常数：
  pKa1 = 7.88; pKa2 = 9.28 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  59
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  195
• 氢给体数：
  4
• 氢受体数：
  16

ADMET

代谢

在牛体内，形成了新斯皮拉霉素这种代谢物，它是脱糖基衍生物。在给药后14-28天，肌肉和肾脏中新斯皮拉霉素的浓度略高于 spiramycin；在肌肉中，新斯皮拉霉素和 spiramycin的水平大约相等。

In cattle, the metabolite neospiramycin, the demycarosyl derivative, is formed. Concentrations of neospiramycin in muscle and kidney were marginally higher than those of spiramycin 14-28 days after dosing; in muscle, levels of neospiramycin and spiramycin were approximately equal.

来源:Hazardous Substances Data Bank (HSDB)

代谢

spiramycin在肝脏中被代谢成活性代谢物；大量通过胆汁排出，约10%通过尿液排出。

Spiramycin is metabolized in the liver to active metabolites; substantial amounts are excreted in the bile and about 10% in the urine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：螺旋霉素是一种大环内酯类抗生素，用于治疗和控制动物中的一些细菌和支原体感染。它以螺旋霉素松酯的形式用于动物饲料，并作为更易溶的螺旋霉素戊酸盐形式用于其他给药途径。它还被用于治疗原虫感染，如隐孢子虫病和弓形虫病。人类暴露和毒性：据报道，螺旋霉素在职业环境中会引起接触性皮炎。一名在饲料厂工作的男子由于空气中的螺旋霉素发生了过敏性接触性皮炎。患者在工作期间裸露区域反复出现湿疹性皮损。螺旋霉素还据报道会引起超敏反应。一名34岁的女性在制药厂处理螺旋霉素粉末时出现了鼻炎和刺激性咳嗽。接触药物后几小时内出现症状，并在离开工作场所后持续数小时。一名35岁的非过敏性维护工程师在制药行业工作一年后出现了打喷嚏、咳嗽和呼吸困难的发作。在医院进行的逐渐增加螺旋霉素剂量的吸入挑战测试复现了他的症状，并导致了迟发型哮喘反应的发生。此外，还报告了两例制药厂工人由于螺旋霉素引起的支气管哮喘。这些工人在接触螺旋霉素粉末时出现咳嗽、呼吸困难和哮喘症状。离开工作超过3或4天后症状消失。动物研究：每组2只雄性和2只雌性猴子（Macaca fascicularis）每天静脉注射0、240,000、360,000和540,000 IU/kg bw的螺旋霉素戊酸盐，持续5天。所有剂量组在注射期间都出现过度流涎。在几只高剂量猴子和一只低剂量猴子中出现了肌肉张力减退和恶心性痉挛。体重没有异常，但所有处理动物的食物消耗量都减少了。在高剂量动物中注意到血红蛋白、红细胞数量和血细胞比容的轻微下降。在一项大鼠短期饮食研究中，给予相当于最高3900 mg/kg bw的剂量，持续13周，注意到的主要影响是一些中剂量和高剂量动物的粒细胞计数减少，以及盲肠扩张。在另一项大鼠饮食研究中，动物被给予相当于最高720 mg/kg bw/day的剂量，持续一年。注意到的显著影响是高剂量雌性动物的体重减轻，以及高剂量水平下，两种性别动物的相对肝、肾和肾上腺重量增加。在所有剂量水平下都发生了肝糖原耗竭，但对照组没有。在给予杂种犬500 mg/kg bw/day，持续最多56天的研究中，观察到精子生成减少和睾丸萎缩。还看到了肾脏损伤。当比格犬口服相当于最高150 mg/kg bw/day的螺旋霉素，持续两年时，没有观察到睾丸损伤，尽管其他器官发生了退行性变化。在小鼠的致畸性研究中，从妊娠第5天到第15天口服螺旋霉素，剂量高达400 mg/kg bw，对妊娠结果没有影响。在大鼠妊娠第6天到第15天和兔妊娠第6天到第19天，静脉注射高达84 mg/kg bw/day的剂量，对发育没有影响，但在兔口服200和400 mg/kg bw/day的剂量时，母兔产生了盲肠扩大。在妊娠第6天到第15天，对20只怀孕大鼠静脉注射0、90,000、180,000和270,000 IU/kg bw/day的螺旋霉素戊酸盐。给予的最高剂量产生了短暂的（5分钟）共济失调和震颤。在中间剂量下，胎儿体重显著降低，但所有值都在历史对照范围内。在这项研究中没有注意到胎儿异常的发生率增加。在一项研究中，给雄性大鼠以30 mg/kg bw/day的剂量，通过未指明的途径给药8天，注意到精原细胞中的有丝分裂和减数分裂异常。在体外哺乳动物细胞正向突变试验、体外细胞遗传学分析和小鼠微核试验中，螺旋霉素戊酸盐和螺旋霉素松酯得到了阴性结果。

IDENTIFICATION AND USE: Spiramycin is a macrolide antibiotic used for the treatment and control of a number of bacterial and mycoplasmal infections in animals. It is available as a spiramycin embonate for use in animal feed, and as the adipate, a more soluble form, for administration by other routes. It has also been used in the protozoal infections cryptosporidiosis and toxoplasmosis. HUMAN EXPOSURE AND TOXICITY: Spiramycin is reported to cause contact dermatitis in occupational settings. A man who worked in a feed factory developed allergic contact dermatitis due to airborne spiramycin. The patient suffered recurrent outbreaks of eczematous lesions on uncovered areas during working periods. Spiramycin is also reported to cause hypersensitivity reactions. Rhinoconjunctivitis and spasmodic cough are reported in a 34 year-old female handling spiramycin powder in a pharmaceutical factory. The symptoms appeared within the first few hours of coming into contact with the drug and continued for several hours after leaving her place of work. One year after starting work in the pharmaceutical industry a 35-year-old non-atopic maintenance engineer developed attacks of sneezing, coughing and breathlessness. Inhalation challenge tests carried out in the hospital with gradually increasing quantities of spiramycin reproduced his symptoms and led to the development of late asthmatic reactions. Additionally, two cases of bronchial asthma due to spiramycin in workers of a pharmaceutical factory were reported. The subjects complained of cough, breathlessness and symptoms of asthma at work when coming into contact with spiramycin's powder. The symptoms cleared when away from work for more than 3 or 4 days. ANIMAL STUDIES: Groups of 2 male and 2 female monkeys (Macaca fascicularis) were given daily intravenous injections of 0, 240,000, 360,000, and 540,000 iu/kg bw/day spiramycin adipate for 5 days. Hypersalivation occurred during injection in all dose groups. Muscle hypotonia and nauseous spasticity occurred in several high dose monkeys and in one given the low dose. No abnormalities of body weights occurred but food consumption was reduced in all treated animals. A slight decrease in hemoglobin, red cell numbers and hematocrit was noted in high dose animals. In a short-term dietary study in which rats were given the equivalent of up to 3900 mg/kg bw for 13 weeks, the only major effects noted were a reduction in neutrophil counts in some mid- and high-dose animals, and the dilatation of the caecum. In another dietary study in the rat, animals were given up to the equivalent of 720 mg/kg bw/day for one year. The only notable effects were reductions in the body weights of females receiving the high doses, and increases in relative liver, kidney, and adrenal weights at high dose levels in animals of both sexes. Hepatic glycogen depletion occurred at all dose levels but not in controls. In mongrel dogs given 500 mg/kg bw/day for up to 56 days, reductions in spermatogenesis and testicular atrophy occurred. Kidney damage was also seen. When beagles were given orally spiramycin at up to the equivalent of 150 mg/kg bw/day for two years, testicular damage was not seen although degenerative changes occurred in other organs. In teratogenicity studies in mice, oral doses of spiramycin of up to 400 mg/kg bw given over days 5-15 of gestation had no effects on the outcome of pregnancy. intravenous doses of up to 84 mg/kg bw/day given on days 6-15 of gestation to rats and day 6-19 to rabbits had no effect on developmental, but oral dose of 200 and 400 mg/kg bw/day in rabbit produced caecal enlargement in mothers. Groups of 20 pregnant rats were treated intravenously on days 6-15 of gestation with doses of 0, 90 000, 180 000, and 270 000 iu/kg bw/day with spiramycin adipate. The highest dose given produced brief (5 minutes) ataxia and tremors immediately after dosing. A slight but significant reduction in fetal weight occurred at the intermediate dose but all values were within historical control ranges. There were no increased incidences of any fetal anomaly noted in this study. In a study where male rats were given doses of 30 mg/kg bw/day for 8 days by an unspecified route, mitotic and meiotic abnormalities in spermatogonia were noted. Negative result were obtained with spiramycin adipate and embonate in a forward-mutation test in mammalian cells in vitro, in an in vitro cytogenic assay, and in the mouse micronucleus test.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 副作用

皮肤致敏剂 - 一种可以诱导皮肤产生过敏反应的制剂。

Skin Sensitizer - An agent that can induce an allergic reaction in the skin.

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

毒理性

• 相互作用

大环内酯类抗生素包括天然成员、前药和半合成衍生物。这些药物适用于多种感染，并且常常与其他药物疗法联合使用，因此存在产生药物动力学相互作用的潜在风险。大环内酯类药物可以通过形成复合物并使微粒体药物氧化酶失活来抑制肝脏中的药物代谢，同时通过其抗生素效果干扰肠内微生物群。在过去20年中，有多份报告指出大环内酯类药物可能是临床严重药物相互作用的潜在来源。然而，不同的大环内酯类药物在这方面存在差异，并非所有的大环内酯类药物都会引起药物相互作用。随着许多半合成大环内酯类抗生素的最近出现，现在很明显，它们可能被分为三类，以引起药物相互作用。第一组（例如多莱随机霉素、红霉素）是那些容易形成亚硝基烷烃并因此形成不活跃的细胞色素P450-代谢物复合物的药物。第二组（例如约沙霉素、氟红霉素、罗西红霉素、克拉霉素、米卡霉素和米地卡霉素）形成复合物的程度较小，很少产生药物相互作用。最后一组（例如螺旋霉素、罗吉红霉素、地红霉素和阿奇霉素）不使细胞色素P450失活，无法改变其他化合物的药物动力学。似乎有两个结构因素对于大环内酯类抗生素导致细胞色素P450的诱导以及体内或体外形成抑制性的细胞色素P450-铁-亚硝基烷烃代谢物复合物非常重要：大环内酯分子中存在一个非阻碍性的、易于接近的N-二甲氨基团以及药物的疏水性特征。多莱随机霉素是最强的微粒体肝酶抑制剂，能显著减少甲基强的松龙、茶碱、卡马西平、非那宗（安替比林）和三唑仑的代谢。多莱随机霉素可能会导致服用麦角生物碱的患者出现麦角病，以及服用口服避孕药的患者出现胆汁淤积性黄疸。红霉素及其不同的前药似乎是对药物代谢的较不强的抑制剂。然而，案例报告和控制研究已经表明，红霉素可能会与茶碱、卡马西平、甲基强的松龙、华法林、环孢素、三唑仑、咪达唑仑、阿芬太尼、双异丙吡胺和溴隐亭发生相互作用，减少药物清除率。红霉素似乎也能增加服用大量还原型地高辛代谢物患者的地高辛的生物利用度，这可能是由于破坏了负责形成这些化合物的肠内微生物群。这些有争议的大环内酯类抗生素不应与其他已知受其代谢影响的药物同时使用，或者至少，联合使用应仅在仔细监测患者的情况下进行。

The macrolide antibiotics include natural members, prodrugs & semisynthetic derivatives. These drugs are indicated in a variety of infections & are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metab in the liver by complex formation & inactivation of microsomal drug oxidising enzymes & also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 yrs, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this r