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 dairy Holstein cows were treated with a pour-on formulation of doramectin at a dose of 0.58 mg/kg bw and were retreated with the same dose 56 days later. ... Samples of milk were collected for 49 days and 10 days, respectively, after the first and second treatments. Samples were collected twice daily until day 7, and once daily on days 10, 13, 16, 19, 22, 25, 28, 32, 36, 40 and 49. On retreatment, samples were taken twice daily until day 7 and once at day 10. ... The concentrations of doramectin residue in milk increased to a maximum mean value of 22 mg/kg at 72 hr after treatment. Mean concentrations of doramectin residues decreased to below the limit of quantitation (3 mg/kg) at 384 hr (16 days). After retreatment, concentrations of doramectin residues increased gradually to a maximum mean value of 12 mg/kg at 48 hr after dosing; and decreased to <4 mg/kg at 240 hr (10 days) after dosing. The milk/fat analyses were conducted 1, 4, and 10 days after dosing. Mean concentrations of doramectin residues in the milk fat at these time points were 171 mg/kg, 501 mg/kg and 114 mg/kg, respectively. Concentration factors for doramectin residues in milk fat were 29.6, 32.2 and 24.7, respectively.
In the second study, 10 cows were treated with doramectin by topical application of a pour-on formulation at a dose of 0.58 mg/kg and were re-treated with the same dose 56 days later. Samples of milk were collected twice daily. Concentrations of doramectin in milk increased to a maximum mean value of 9 mg/kg at 45 hr after treatment and decreased to below the LOQ by 237 hr (10 days) after treatment. After re-treatment on day 56, concentrations of residues increased to a mean maximum value of 8 mg/kg after 93 hr and decreased to less than the LOQ after 237 hr (10 days). Mean concentrations of doramectin residues in the milk fat at 1, 4, and 10 days were 91 mg/kg, 142 mg/kg and 55 mg/kg, respectively. Concentration factors for doramectin residues in milk fat versus milk were 14.2, 20.9 and 14.1, respectively.
The third study determined the residue depletion profile of doramectin following the subcutaneous administration of doramectin formulation at 0.23 mg/kg bw in lactating cattle, followed by retreatment at the same dose 56 days later. ... Doramectin concentrations in milk increased gradually to a maximum mean value of 45 mg/kg at 67 hr. Subsequently, doramectin residues gradually declined, with mean residues below LOQ at 523 hr (22 days). After re-treatment, doramectin residues increased to a maximum mean value of 53 mg/kg at 56 hr. Residue concentrations then decreased to a mean value of 25 mg/kg at 237 hr (10 days) after re-treatment. Residues resulting from treatment by injection were consistently higher at any given timepoint than were those resulting from treatment with the pour-on formulation. Milk fat analyses were conducted using samples collected at the morning milking on days 1, day 4 and day 10 after treatment. Mean concentrations of doramectin residues in milk fat at these time-points were 557 mg/kg, 1036 mg/kg and 354 mg/kg, respectively. Milk fat concentration factors were 24, 24.2 and 23.4, respectively.
Self-licking behavior in cattle has recently been identified as a determinant of the kinetic disposition of topically-administered ivermectin. /The present study documents/ the occurrence and extent of transfer between cattle of three topically-administered endectocides, as a consequence of allo-licking. Four groups of two Holstein cows each received one pour-on formulation of doramectin, ivermectin, or moxidectin, or no treatment. The cows were then kept together in a paddock. Systemic exposure to each topically-administered endectocide was observed in at least five of six non-treated cattle. Plasma and fecal drug concentration profiles in non-treated animals were highly variable between animals and within an animal, and sometimes attained those observed in treated animals. Drug exchanges were quantified by measuring plasma and fecal clearances after simultaneous i.v. administration of the three drugs as a cocktail. Plasma clearances were 185 + or - 43, 347 + or - 77 and 636 + or - 130 ml/kg/day, fecal clearances representing 75 + or - 26, 28 + or - 13, and 39 + or - 30% of the plasma clearance for doramectin, ivermectin and moxidectin, respectively. The amount of drug ingested by non-treated cattle attained 1.3-21.3% (doramectin), 1.3-16.1% (ivermectin), 2.4-10.6% (moxidectin) of a pour-on dose (500 ug/kg). The total amount of drug ingested by all non-treated cattle represented 29% (doramectin), 19% (ivermectin), and 8.6% (moxidectin) of the total amount of each drug poured on the backs of treated animals. The cumulative amounts of endectocide ingested by each non-treated cow ranged from 1.3 to 27.4% of a pour-on dose. Oral bioavailability after drug ingestion due to allo-licking was 13.5 + or - 9.4, 17.5 + or - 3.5 and 26.1+ or - 11.1% for doramectin, ivermectin and moxidectin, respectively. The extent of drug exchange demonstrated here raises concerns for drug efficacy and safety, emergence of drug resistance, presence of unexpectedly high residue levels in treated and/or untreated animals and high environmental burdens.
For more Absorption, Distribution and Excretion (Complete) data for DORAMECTIN (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Doramectin labelled with tritium in the 5-position was administered as a single dose to Sprague-Dawley rats (2 males given 5 mg/kg bw in propylene glycol:glycerol by gavage), a beagle dog (1 female given 3.5 mg/kg bw in sesame oil by gavage) and cattle (5 males given 0.2 mg/kg bw subcutaneously). /The following metabolites were identified in/... the liver and feces from each species and the fat of cattle... /unchanged doramectin, 3"-O-desmethyl doramectin, 24-hydroxymethyl doramectin, and 24-hydroxymethyl-3"-O-desmethyl doramectin./
The products of doramectin metabolism were similar in all species investigated /rats, dogs, pigs, cattle/. The metabolites were more polar than doramectin and were the result of O-demethylation in the distal saccharide ring, of hydroxylation of the 24-methyl group and a combination of both of these biotransformations.

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Biological Half-Life
The plasma kinetics of doramectin were determined in eight pigs (4 male castrates and 4 females, each weighing approximately 40 kg) dosed im with (3H)doramectin at 0.3 mg/kg bw using a prototype commercial formulation (75% sesame oil/25% ethyl oleate). ... The apparent terminal half-lives of elimination from plasma of total (3H)labelled materials and unchanged doramectin were 7.7 and 6.4 days, respectively.

Non-Human Toxicity Values
LD50 Mouse (CD-1) oral >2000 mg/kg bw /in 0.1% aqueous methylcellulose/ /from table/
LD50 Rat (Sprague-Dawley, male) ip >300 mg/kg bw /in 0.1% aqueous methylcellulose/ /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 Food and Drug Administration for the treatment of parasites such as gastrointestinal roundworms, lungworms, eyeworms, grubs, sucking lice and mange mites in cattle.
See also: Doramectin; Levamisole (component of); Doramectin; levamisole hydrochloride (component of).

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Mechanism of Action
Avermectins induce rapid, non-spastic paralysis in nematodes and arthropods. One common feature of avermectins appears to be the modulation of trans-membrane chloride ion (Cl-) channel activity in nematode nerve cells, and in both nerve and muscle cells of arthropods. These Cl- channels may be gated by a variety of neurotransmitter receptors including gamma-aminobutyric acid (GABA), glutamate and acetylcholine. Activation of the Cl- channels by avermectins leads to an increase in Cl- conductance which results in a changed membrane potential and this causes inhibition of electrical activity in the target nerve or muscle cell. GABA is also a major inhibitory neurotransmitter in the mammalian CNS and avermectins do have intrinsic activity on the mammalian GABA receptor/Cl- channel complex. Avermectins have been reported to bind to glycine receptor/Cl- channel complexes which are restricted to the CNS in mammals. Penetration of the blood brain barrier by avermectins is extremely poor and this may account for the wide margin of safety exhibited by these compounds following administration to mammals. /Avermectins/

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Therapeutic Uses
MEDICATION (VET): Antiparasitic
VET: Doramectin is an ecto- and endoparasiticide for use in cattle and pigs. It is a semisynthetic member of the avermectin class, structurally similar to abamectin and ivermectin.
VET: Doramectin (NADA 141-095) is approved for topical use to treat and control various worms (roundworms, lungworms, and eyeworms), grubs, lice, horn flies, and mange mites. It is also approved to control infections and to protect from reinfection with Cooperia oncophora and Dictyocaulus viviparus for 21 days, Ostertagia ostertagi, C. punctata, and Oesophagostomum radiatum for 28 days, and Haemonchus placei for 35 days after treatment.
VET: Objective: To determine effectiveness of a pour-on formulation of doramectin against Damalinia bovis, Haematopinus eurysternus, Linognathus vituli, Solenopotes capillatus, Chorioptes bovis, Sarcoptes scabiei, Hypoderma bovis, and Hypoderma lineatusm. Animals: Cattle of various ages with naturally acquired or artificial infestations with 1 or more species of lice, mites, or grubs. Procedure: In 10 louse and 6 mite studies, cattle were treated with doramectin (500 mug/kg, topicaly) on day 0, and p 28 days after treatment. Burdens of C. bovis and S. scabiei decreased to 0 in naturally infested cattle and approximately 0 in artificially infested cattle by day 14 to 15. In grub studies, 107 of 136 control cattle had warbles, whereas 2 of 136 doramectin-treated cattle had 1 warble each, which represented a cure rate of 98.5%.
For more Therapeutic Uses (Complete) data for DORAMECTIN (6 total), 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。