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在肝脏中代谢为活性代谢物；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.
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
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 regard & not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes & the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin & midecamycin) form complexes to a lesser extent & rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin & azithromycin) do not inactivate cytochrome P450 & are unable to modify the pharmacokinetics of other cmpds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 & the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group & the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decr of the metab of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) & triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids & cholestatic jaundice in those taking oral contraceptives. Erythromycin & its different prodrugs appear to be less potent inhibitors of drug metab. Case reports & controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide & bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these cmpds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined admin should be carried out only with careful patient monitoring.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
已报告在给予螺旋霉素时，左旋多巴的血浆浓度降低。
Reduced plasma concentrations of levodopa have been reported when given with spiramycin.
The authors report the case of a 21 year old woman with a congenital long QT syndrome who had several syncopal attacks at least one of which was caused by torsades de pointes. This sudden complication was attributed to the simultaneous prescription of Spiramycine and Mequitazine over a 48 hour period. These two drugs are not considered to be predisposing factors for torsades de pointes despite the fact that they belong to two families of drugs which can trigger this type of arrhythmia. The withdrawal of this treatment led to the complete regression of the syncopal episodes with a follow-up of two years and a significant shortening of the initial QTc interval which remained, nevertheless, longer than normal. This case underlines the potential risks of drug associations of these two families of drugs, especially in patients with the congenital long QT syndrome.
Spiramycin is well absorbed in humans after oral administration. Oral administration of 15-30 mg/kg bw to healthy young male adults resulted in peak plasma levels in 3-4 hours and plasma concentrations of 0.96-1.65 mg/l. After intravenous dosing (7.25 mg/kg b.w.) a large volume of distribution (Vdss 5.6 l/kg) was observed indicating extensive tissue distribution. Biotransformation did not appear to be important. Biliary excretion was the main route of excretion; only 7-20% of an oral dose was excreted in the urine. Spiramycin is known to achieve high tissue:serum concentrations in pulmonary and prostatic tissues, and in skin.
Spiramycin crosses the placenta to the fetus. Concns of the antibiotic in maternal serum, cord blood, & the placenta after a dosage regimen of 2 g/day were 1.19 ug/ml, 0.63 ug/ml, & 2.75 ug/ml, respectively. When the maternal dose was increased to 3 g/day, the levels were 1.69 ug/ml, 0.78 ug/ml, & 6.2 ug/ml, respectively. Based on these results, the cord:maternal serum ratio is approx 0.5. Moreover, at these doses, spiramycin is concentrated in the placenta with levels approx 2-4 times those in the maternal serum. ... Spiramycin is excreted into breast milk. Nursing infants of mothers receiving 1.5 g/day for 3 days had spiramycin serum concns of 20 ug/ml. This concn was bacteriostatic.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
spiramycin是一种对来自乳腺炎牛牛奶中的大多数微生物具有活性的大环内酯类抗生素。本工作研究了静脉注射、肌内注射和皮下给药后spiramycin在血浆和牛奶中的处置情况。12头健康奶牛按每种途径单次注射spiramycin,剂量为30,000 IU / kg。在注射后收集血浆和牛奶。采用高效液相色谱法测定血浆中spiramycin的浓度,采用微生物法测定牛奶中spiramycin的浓度。静脉给药后的平均滞留时间在牛奶中明显长于血浆中(20.7土2.7 h对4.0土1.6 h,P <0.01)。从面积浓度-时间曲线计算出平均牛奶-血浆比值为36.5土15。研究了几个药代动力学参数,以确定两种非血管途径的生物等效性。肌内或皮下给药后吸附的剂量分数几乎为100% ,对于非血管途径是生物等效的,但两种途径的吸收速率、最高浓度和达到最高浓度的时间存在显著差异。牛奶中排泄的spiramycin量在两种非血管途径之间没有差异,但后一种途径在牛奶中最高浓度的生物等效性较差。然而,这两种途径在牛奶浓度超过各种病原体引起乳腺感染的最小抑菌浓度(MIC)的时间上是生物等效的。
/MILK/ Spiramycin is a macrolide antibiotic that is active against most of the microorganisms isolated from the milk of mastitic cows. This work investigated the disposition of spiramycin in plasma & milk after iv, intramuscular & subcutaneous admin. Twelve healthy cows were given a single injection of spiramycin at a dose of 30,000 IU/kg by each route. Plasma & milk were collected post injection. Spiramycin concn in the plasma was determined by a high performance liquid chromatography method, & in the milk by a microbiological method. The mean residence time after iv admin was significantly longer (P<0.01) in the milk (20.7 +/- 2.7 h) than in plasma (4.0 +/- 1.6 h). An average milk-to-plasma ratio of 36.5 +/- 15 was calculated from the area concn-time curves. Several pharmacokinetic parameters were examined to determine the bioequivalence of the two extravascular routes. The dose fraction adsorbed after intramuscular or subcutaneous admin was almost 100% & was bioequivalent for the extravascular routes, but the rates of absorption, the max concns & the time to obtain them differed significantly between the two routes. Spiramycin quantities excreted in milk did not differ between the two extravascular routes but the latter were not bioequivalent for max concn in the milk. However, the two routes were bio-equivalent for the duration of time the milk concn exceeded the minimal inhibitory concn (MIC) of various pathogens causing infections in the mammary gland.
Plasma protein binding ranges from 10 to 25%. An oral dose of 6 million units produces peak blood concentrations of 3.3 ug/mL after 1.5 to 3 hours; the half life is about 5 to 8 hours. High tissue concentrations are achieved and persist long after the plasma concentration has fallen to low levels.
Direct Synthesis of Nitriles from Aldehydes Using an O-Benzoyl Hydroxylamine (BHA) as the Nitrogen Source
摘要：
The direct synthesis of nitriles from commercially available or easily prepared aldehydes has been achieved. O-(4-CF3-benzoyl)-hydroxylamine (CF3-BHA) was utilized as the nitrogen source to generate O-acyl oximes in situ with aldehydes, which can be converted to a nitrile with the assistance of a Bronsted acid. Several aliphatic, aromatic, and alpha,beta-unsaturated nitriles that contain different functional groups were prepared in high yields (up to 94% yield). This method has notable advantages, such as simple and mild conditions, high yields, and good functional group tolerance.
Rh-catalyzed C–C bond cleavage by transfer hydroformylation
作者：Stephen K. Murphy、Jung-Woo Park、Faben A. Cruz、Vy M. Dong
DOI：10.1126/science.1261232
日期：2015.1.2
that a rhodiumcatalyst can achieve selective dehydroformylation of a diverse range of compounds under mild conditions (see the Perspective by Landis). The protocol relies on effective transfer of the CO and H2 equivalents to a sacrificial strained olefin added to the mix. Science, this issue p. 56; see also p. 29 A catalyst to selectively reverse a common chemical reaction offers versatile opportunities
Association of adenine nucleotides with the macrocyclic antibiotic Spiramycin and two of its aromatic derivatives was studied by potentiometric titrations, 1H and 31P NMR spectrometry and molecular modelling. Spiramycin binds adenine nucleotides with K ≈ 103–104 M−1 and selectivity for ADP over ATP or AMP. The introduction of aromatic moieties reduces the strength of the binding but, selectivity order
通过电位滴定、1H 和 31P NMR 光谱法和分子建模研究了腺嘌呤核苷酸与大环抗生素螺旋霉素及其两种芳香衍生物的关联。Spiramycin 结合腺嘌呤核苷酸，K ≈ 103–104 M-1，对 ADP 的选择性超过 ATP 或 AMP。芳香部分的引入降低了结合强度，但选择性顺序变为 ATP > ADP > AMP。分子模型表明，复合物主要通过受体的质子化氨基和核苷酸的磷酸基团之间的静电相互作用来稳定。
Nitrosopyridine Probe To Detect Polyketide Natural Products with Conjugated Alkenes: Discovery of Novodaryamide and Nocarditriene
作者：Gabriel Castro-Falcón、Natalie Millán-Aguiñaga、Catherine Roullier、Paul R. Jensen、Chambers C. Hughes
DOI：10.1021/acschembio.8b00598
日期：2018.11.16
An optimized nitroso-based probe that facilitates the discovery of conjugated alkene-containing naturalproducts in unprocessed extracts was developed. It chemoselectively reacts with conjugated olefins via a nitroso-Diels–Alder cyclization to yield derivatives with a distinct chromophore and an isotopically unique bromine atom that can be rapidly identified using liquid chromatography/mass spectrometry
Regio- and Stereoselective Functionalization of 16-Membered Lactone Aglycone of Spiramycin via Cascade Strategy
作者：Katarzyna Klich、Krystian Pyta、Piotr Przybylski
DOI：10.1021/acs.joc.5b00847
日期：2015.7.17
Functionalization of 16-membered aglycone of spiramycin with the use of intramolecular cascade strategy yielded access to novel types of diastereopure bicyclic spiramycin derivatives containing tetrahydrofuran ring. Experimental results shows that a specific sequence of regio- and stereoselective transformations, based on the intramolecular transesterification, E1cB tandem eliminations, 1,2-addition
Direct Synthesis of Nitriles from Aldehydes Using an <i>O</i>-Benzoyl Hydroxylamine (BHA) as the Nitrogen Source
作者：Xiao-De An、Shouyun Yu
DOI：10.1021/acs.orglett.5b02547
日期：2015.10.16
The direct synthesis of nitriles from commercially available or easily prepared aldehydes has been achieved. O-(4-CF3-benzoyl)-hydroxylamine (CF3-BHA) was utilized as the nitrogen source to generate O-acyl oximes in situ with aldehydes, which can be converted to a nitrile with the assistance of a Bronsted acid. Several aliphatic, aromatic, and alpha,beta-unsaturated nitriles that contain different functional groups were prepared in high yields (up to 94% yield). This method has notable advantages, such as simple and mild conditions, high yields, and good functional group tolerance.
