Macrolide;Toxoplasma

用螺旋霉素（24小时；1-1000 μM；弓形虫感染的HeLa细胞和HeLa细胞）处理可降低细胞毒性并表现出抗弓形虫活性，HeLa细胞的IC50值为189 μM，弓形虫的IC50值为262 μM -感染的HeLa细胞[3]。

用螺旋霉素（100 mg/kg；腹腔注射；每天；持续 4 天；雌性 KM 小鼠）治疗可减少速殖子和肝毒性，并大大增强抗氧化作用。吡霉素治疗还可以减轻肝脏的肉芽肿性炎症[3]。

细胞系：弓形虫感染的HeLa细胞和HeLa细胞
浓度：1-1000 μM
孵育时间：24小时
结果：细胞毒性降低。

Animal Model: 36 female KM mice with T.gondii[3]
Dosage: 100 mg/kg
Administration: Intraperitoneal injection; every day; for 4 days
Result: Tachyzoites were considerably fewer in number. decreased hepatotoxicity and markedly increased antioxidative benefits. Formation of cysts and granulomas was inhibited.

Absorption, Distribution and Excretion
The extent of absorption of Spiramycin was shown to be incomplete. Oral bioavailability ranges from 30-39%. Spiramycin has slower rate of absorption than Erythromycin. It has a high pKa (7.9) which could be a result of high degree of ionization in acidic medium of the stomach.
Fecal-biliary route is the primary route of elimination. The secondary route is renal-urinary route.
The tissue distribution of spiramycin is extensive. The volume of distribution is in excess of 300 L, and concentrations achieved in bone, muscle, respiratory tract and saliva exceed those found in serum. Spiramycin showed high concentrations in tissues such as: lungs, bronchi, tonsils, and sinuses.
80% of the administered dose excreted in the bile, which makes the fecal-biliary route is the most important route of elimination. Enterohepatic recycling could also occur. Only 4 to 14% of an administered dose is eliminated through renal-urinary excretion route.
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.
/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.
For more Absorption, Distribution and Excretion (Complete) data for SPIRAMYCIN (13 total), please visit the HSDB record page.

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Metabolism / Metabolites
Spiramycin is less metabolised than some of the other macrolides. Metabolism has not been well studied. It is mainly done in the liver to the active metabolites.
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.
Spiramycin is metabolized in the liver to active metabolites; substantial amounts are excreted in the bile and about 10% in the urine.

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Biological Half-Life
Intravenous: Young persons (18 to 32 years of age): Approximately 4.5 to 6.2 hours. Elderly persons (73 to 85 years of age): Approximately 9.8 to 13.5 hours. Oral: 5.5-8 hours, Rectal in children: 8 hours
An oral dose of 6 million units produces ... /a/ half life is about 5 to 8 hours.

Protein Binding
Low level of protein binding (10-25%).

[1]. Post-PKS tailoring steps of the spiramycin macrolactone ring in Streptomyces ambofaciens. Antimicrob Agents Chemother. 2013 Aug;57(8):3836-42.

[2]. Assessment of spiramycin-loaded chitosan nanoparticles treatment on acute and chronic toxoplasmosis in mice. J Parasit Dis. 2018 Mar;42(1):102-113.

[3]. Synthesis and Biological Evaluation of (+)-Usnic Acid Derivatives as Potential Anti-Toxoplasma gondii Agents. J Agric Food Chem. 2019 Aug 28;67(34):9630-9642.

Spiramycin is a primarily bacteriostatic macrolide antimicrobial agent with activity against Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium. Spiramycin is a 16-membered ring macrolide discovered in 1952 as a product of Streptomyces ambofaciens that has been available in oral formulations since 1955, and parenteral formulations since 1987. Resistant organisms include Enterobacteria, pseudomonads, and moulds.
Spiramycin is a macrolide originally discovered as product of Streptomyces ambofaciens, with antibacterial and antiparasitic activities. Although the specific mechanism of action has not been characterized, spiramycin likely inhibits protein synthesis by binding to the 50S subunit of the bacterial ribosome. This agent also prevents placental transmission of toxoplasmosis presumably through a different mechanism, which has not yet been characterized.

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Drug Indication
Macrolide antibiotic for treatment of various infections.

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Mechanism of Action
The mechanism of action of macrolides has been a matter of controversy for some time. Spiramycin, a 16-membered macrolide, inhibits translocation by binding to bacterial 50S ribosomal subunits with an apparent 1 : 1 stoichiometry. This antibiotic is a potent inhibitor of the binding to the ribosome of both donor and acceptor substrates. The primary mechanism of action is done by stimulation of dissociation of peptidyl-tRNA from ribosomes during translocation.I

C43H74N2O14

843.0527

842.513

C, 61.26; H, 8.85; N, 3.32; O, 26.57

8025-81-8

8025-81-8;24916-52-7 (III);67724-08-7 (Embonate);68880-55-7 (adipate);

5289394

White to off-white solid powder

1.2±0.1 g/cm3

913.7±65.0 °C at 760 mmHg

506.4±34.3 °C

0.0±0.6 mmHg at 25°C

1.550

3.06

195

4

16

11

59

1370

19

O1[C@@]([H])(C([H])([H])[H])[C@@]([H])([C@@]([H])([C@@]([H])([C@@]1([H])O[C@]1([H])[C@]([H])([C@@]([H])(C([H])([H])C(=O)O[C@]([H])(C([H])([H])[H])C([H])([H])C([H])=C([H])C([H])=C([H])[C@@]([H])([C@]([H])(C([H])([H])[H])C([H])([H])[C@]1([H])C([H])([H])C([H])=O)O[C@@]1([H])C([H])([H])C([H])([H])[C@@]([H])([C@]([H])(C([H])([H])[H])O1)N(C([H])([H])[H])C([H])([H])[H])O[H])OC([H])([H])[H])O[H])N(C([H])([H])[H])C([H])([H])[H])O[C@]1([H])C([H])([H])[C@@](C([H])([H])[H])([C@@]([H])([C@@]([H])(C([H])([H])[H])O1)O[H])O[H] |c:39,43|

ACTOXUHEUCPTEW-AQKFJFIXSA-N

InChI=1S/C43H74N2O14/c1-24-21-29(19-20-46)39(59-42-37(49)36(45(9)10)38(27(4)56-42)58-35-23-43(6,51)41(50)28(5)55-35)40(52-11)31(47)22-33(48)53-25(2)15-13-12-14-16-32(24)57-34-18-17-30(44(7)8)26(3)54-34/h12-14,16,20,24-32,34-42,47,49-51H,15,17-19,21-23H2,1-11H3/b13-12+,16-14+/t24-,25-,26-,27-,28+,29+,30+,31-,32+,34+,35+,36-,37-,38-,39+,40+,41+,42+,43?/m1/s1

2-[(4R,5S,6S,7R,9R,10R,11E,13E,16R)-6-{[(2S,3R,4R,5S,6R)-5-{[(2S,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy}-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-10-{[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy}-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde

HSDB-7027; Rovamycin; HSDB7027; HSDB 7027

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 100~157 mg/mL ( 118.62~186.22 mM )
Ethanol : ~157 mg/mL

配方 1 中的溶解度: ≥ 2.5 mg/mL (2.97 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (2.97 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (2.97 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (2.97 mM)

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。