Doramectin   中文名称: 多拉菌素

多拉菌素 (10 mg/kg) 在体内有效，曼氏链球菌感染小鼠的蠕虫负担减少了 60.1%[3]。

Absorption, Distribution and Excretion
In the first study, 10 Holstein cows received topical doramectin at a dose of 0.58 mg/kg body weight and were treated again with the same dose after 56 days. Milk samples were collected on days 49 and 10 after the first and second treatments, respectively. Samples were collected twice daily until day 7; once daily on days 10, 13, 16, 19, 22, 25, 28, 32, 36, 40, and 49. Upon retreatment, samples were collected twice daily until day 7; once daily on day 10. The doramectin residue concentration in milk peaked at an average of 22 mg/kg 72 hours post-treatment. The average doramectin residue concentration decreased below the limit of quantitation (3 mg/kg) 384 hours (16 days) post-treatment. Following re-administration, doramectin residual concentrations gradually increased, reaching a mean peak of 12 mg/kg at 48 hours post-administration and decreasing to below 4 mg/kg at 240 hours (10 days). Milk fat analysis was performed at 1, 4, and 10 days post-administration. At these time points, the mean concentrations of doramectin residuals in milk fat were 171 mg/kg, 501 mg/kg, and 114 mg/kg, respectively. The residual concentration factors of doramectin in milk fat were 29.6, 32.2, and 24.7, respectively. In a second study, 10 dairy cows received topical doramectin drops at a dose of 0.58 mg/kg and were re-treated at the same dose after 56 days. Milk samples were collected twice daily. Forty-five hours post-treatment, the mean doramectin concentration in milk reached a mean peak of 9 mg/kg and decreased to below the limit of quantitation at 237 hours (10 days). Following a repeat treatment on day 56, the residual concentration reached a mean maximum of 8 mg/kg after 93 hours and decreased below the limit of quantitation (LOQ) after 237 hours (10 days). The mean concentrations of doramectin residue in milk fat were 91 mg/kg, 142 mg/kg, and 55 mg/kg on days 1, 4, and 10, respectively. The concentration factors of doramectin residue in milk fat compared to that in milk were 14.2, 20.9, and 14.1, respectively. A third study determined the depletion of doramectin residue after subcutaneous injection of a 0.23 mg/kg body weight doramectin formulation in lactating cows, followed by a repeat administration of the same dose 56 days later. …The doramectin concentration in milk gradually increased, reaching a mean maximum of 45 mg/kg at 67 hours. Subsequently, the doramectin residue gradually decreased, reaching a mean below the LOQ at 523 hours (22 days). After a repeat administration, the doramectin residue increased to a mean maximum of 53 mg/kg at 56 hours. 237 hours (10 days) after re-treatment, the residual concentration decreased to an average of 25 mg/kg. At any time point, the residual amount from injectable treatment was higher than that from topical treatment. Milk fat samples were collected at milking on the mornings of days 1, 4, and 10 post-treatment for analysis. The average concentrations of doramectin residues in milk fat at these time points were 557 mg/kg, 1036 mg/kg, and 354 mg/kg, respectively. The milk fat concentration factors were 24, 24.2, and 23.4, respectively.
Licking behavior in cattle has recently been identified as a determinant of the kinetic distribution of topically administered ivermectin. This study documented the occurrence and extent of transfer of three topically administered endoparasitic agents among cattle herds due to heterologous licking. Four groups of Holstein cows, two cows per group, received topical doramectin, ivermectin, or moxicillin, or no treatment. These cows were then housed in the same pen. In six untreated dairy cows, at least five showed systemic exposure to each topical anthelmintic. Plasma and fecal drug concentration profiles in untreated animals varied considerably between different animals and between different sites within the same animal, sometimes reaching levels seen in treated animals. Drug exchange was quantified by measuring plasma and fecal clearance after simultaneous intravenous administration of the three drugs (a mixture). Plasma clearances for doramectin, ivermectin, and moxicillin were 185±43, 347±77, and 636±130 ml/kg/day, respectively, with fecal clearances representing 75±26%, 28±13%, and 39±30% of plasma clearances, respectively. Untreated cows ingested 1.3%–21.3% (dramectin), 1.3%–16.1% (ivermectin), and 2.4%–10.6% (moxicillin) of the applied dose (500 μg/kg), respectively. The total amount of drugs ingested by untreated cattle accounted for 29% (dolacritin), 19% (ivermectin), and 8.6% (moxicillin) of the total amount of each drug applied to the back of treated cattle. The cumulative amount of endocytic drugs ingested by each untreated cattle ranged from 1.3% to 27.4% of the applied dose. Following ingestion through licking, the oral bioavailability of dolacritin, ivermectin, and moxicillin was 13.5 ± 9.4%, 17.5 ± 3.5%, and 26.1 ± 11.1%, respectively. The extent of drug exchange shown here raises concerns about drug efficacy and safety, the emergence of resistance, unexpectedly high residual levels in treated and/or untreated animals, and a high environmental burden. For more complete data on the absorption, distribution, and excretion of dolacritin (7 types), please visit the HSDB record page.
Metabolism/Metabolites

5-tritium-labeled doramectin was administered via single-dose gavage to Sprague-Dawley rats (2 males, 5 mg/kg body weight dissolved in propylene glycol:glycerol), beagle dogs (1 female, 3.5 mg/kg body weight dissolved in sesame oil, via gavage), and cattle (5 males, 0.2 mg/kg body weight subcutaneously). The following metabolites were identified in the liver and feces of each animal and in the fat of cattle: unchanged doramectin, 3"-O-demethyldramectin, 24-hydroxymethyldramectin, and 24-hydroxymethyl-3"-O-demethyldramectin.
The metabolites of doramectin were similar across all studied species (rats, dogs, pigs, and cattle). These metabolites were more polar than doramectin and resulted from the combined effects of distal sugar ring O-demethylation, 24-methyl hydroxylation, and both biotransformations.

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Biological Half-Life
Using the original commercial formulation (75% sesame oil/25% ethyl oleate), doramectin was administered intramuscularly at 0.3 mg/kg body weight (3H). Plasmokinetic studies were performed on 8 pigs (4 castrated males and 4 females, each weighing approximately 40 kg). …The apparent terminal half-lives of total (3H) labeled substances and unmetabolized doramectin eliminated from plasma were 7.7 days and 6.4 days, respectively.

Non-Human Toxicity Values
Mice (CD-1) Oral LD50 >2000 mg/kg body weight / 0.1% methylcellulose aqueous solution / /Taken from table / Rat (Sprague-Dawley, male) Intraperitoneal LD50 >300 mg/kg body weight / 0.1% methylcellulose aqueous solution / /Taken from table /

[1]. Davey RB, Pound JM, Klavons JA, Lohmeyer KH, Freeman JM, Olafson PU. Analysis of doramectin in the serum of repeatedly treated pastured cattle used to predict the probability of cattle fever ticks (Acari: Ixodidae) feeding to repletion. Exp Appl Acarol. 2012 Apr;56(4):365-74.

[2]. Wang XJ, Zhang J, Wang JD, Huang SX, Chen YH, Liu CX, Xiang WS. Four new doramectin congeners with acaricidal and insecticidal activity from Streptomyces avermitilis NEAU1069. Chem Biodivers. 2011 Nov;8(11):2117-25.

[3]. Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni. PLoS Negl Trop Dis. 2015 Jul 31;9(7):e0003962.

Doramectin is a veterinary drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of bovine parasites, such as gastrointestinal nematodes, lungworms, eyeworms, maggots, lice, and scabies mites. See also: doramectin; levamisole (component); doramectin; levamisole hydrochloride (component). Mechanism of Action: Avermectins induce rapid, non-spastic paralysis in nematodes and arthropods. A common characteristic of avermectins appears to be the modulation of transmembrane chloride (Cl-) channel activity in nematode nerve cells and arthropod nerve and muscle cells. These Cl- channels can be activated by various neurotransmitter receptors, including gamma-aminobutyric acid (GABA), glutamate, and acetylcholine. Avermectin activates chloride channels, leading to increased chloride conductance, which in turn alters membrane potential and ultimately inhibits the electrical activity of target nerve or muscle cells. Gamma-aminobutyric acid (GABA) is also a major inhibitory neurotransmitter in the mammalian central nervous system (CNS), and avermectin has intrinsic activity against mammalian GABA receptor/chloride channel complexes. Avermectin has also been reported to bind to glycine receptor/chloride channel complexes specific to the mammalian CNS. Avermectin has extremely poor penetration of the blood-brain barrier, which may explain why these compounds have a high safety profile in mammals. /Avermectin/

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Therapeutic Uses
Veterinary Drugs: Antiparasitic Drugs
Veterinary: Doramectin is an in vitro and in vivo parasite killer used in cattle and pigs. It is a semi-synthetic avermectin drug with a structure similar to avermectin and ivermectin.
Veterinary: Doramectin (NADA 141-095) is approved for external use to treat and control various worms (roundworms, lungworms, and eye worms), larvae, lice, hornflies, and scabies mites. It is also approved for infection control and can prevent reinfection by Cooperia oncophora and Dictyocaulus viviparus for 21 days after treatment, by Ostertagia ostertagi, C. punctata and Oesophagostomum radiatum for 28 days, and by Haemonchus placei for 35 days.
Veterinary: Objective: To determine the efficacy of topical doramectin against Damalinia bovis, Haematopinus eurysternus, Linognathus vituli, Solenopotes capillatus, Chorioptes bovis, Sarcoptes scabiei, Hypoderma bovis, and Hypoderma lineatus. Animals: Cattle of various ages naturally or artificially infected with one or more lice, mites, or larvae. Methods: In 10 lice studies and 6 mite studies, cattle were treated with doramectin (500 μg/kg, topical) on day 0 and retreated 28 days later. The numbers of bovine scabies mites and mange mites in naturally infected cattle decreased to zero by day 14-15, and the number of bovine scabies mites in artificially infected cattle also approached zero. In the larval study, 107 out of 136 control cattle developed mange, while only 2 out of 136 cattle in the doramectin-treated group developed mange, resulting in a cure rate of 98.5%. For more complete data on the therapeutic uses of doramectin (out of 6), please visit the HSDB record page.

C50H74O14

899.12

898.507

C, 66.79; H, 8.30; O, 24.91

117704-25-3

117704-25-3;

9832750

White to off-white solid powder

1.3±0.1 g/cm3

967.4±65.0 °C at 760 mmHg

116 - 119ºC

274.4±27.8 °C

0.0±0.6 mmHg at 25°C

1.580

7.16

170.06

3

14

7

64

1790

19

C[C@H]1/C=C/C=C/2\CO[C@H]3[C@@]2([C@@H](C=C([C@H]3O)C)C(=O)O[C@H]4C[C@@H](C/C=C(/[C@H]1O[C@H]5C[C@@H]([C@H]([C@@H](O5)C)O[C@H]6C[C@@H]([C@H]([C@@H](O6)C)O)OC)OC)\C)O[C@]7(C4)C=C[C@@H]([C@H](O7)C8CCCCC8)C)O

QLFZZSKTJWDQOS-CYWJOYLHSA-N

InChI=1S/C50H74O14/c1-27-13-12-16-34-26-57-47-42(51)30(4)21-37(50(34,47)54)48(53)60-36-22-35(63-49(25-36)20-19-29(3)45(64-49)33-14-10-9-11-15-33)18-17-28(2)44(27)61-41-24-39(56-8)46(32(6)59-41)62-40-23-38(55-7)43(52)31(5)58-40/h12-13,16-17,19-21,27,29,31-33,35-47,51-52,54H,9-11,14-15,18,22-26H2,1-8H3/b13-12+,28-17+,34-16+/t27-,29-,31-,32-,35+,36-,37-,38-,39-,40-,41-,42+,43-,44+,45-,46-,47+,49+,50+/m0/s1

(1'R,2S,4'S,5S,6R,8'R,10'E,12'R,13'S,14'E,20'R,21'R,24'S)-6-Cyclohexyl-21',24'-dihydroxy-12'-{[(2R,4S,5S,6S)-5-{[(2S,4S,5S,6S)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy}-4-methoxy-6-methyloxan-2-yl]oxy}-5,11',13',22'-tetramethyl-5,6-dihydro-3',7',19'-trioxaspiro[pyran-2,6'-tetracyclo[15.6.1.14,8.020,24]pentacosane]-10',14',16',22'-tetraen-2'-one

Dectomax;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

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

DMSO : 50~100 mg/mL (55.61~111.22 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (2.78 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 (2.78 mM) 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), 悬浊液; 超声助溶。
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 (2.78 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 (2.78 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。