Description
Doramectin[117704-25-3] is a novel avermectin with a cyclohexyl substituent on the previously inaccessible C-25 position of the molecule; the substitution was facilitated by mutational biosynthesis. The discovery of doramectin involved feeding carboxylic acids or their precursors to a fermentation of Streptomyces avermitilis that lacked branched-chain 2-oxo acid dehydrogenase activity, and then screening the resultant fermentation products for anthelmintic and ectoparasiticidal activity. Two dosage forms of doramectin have been developed for use as an endectocide on cattle, an injectable formulation for subcutaneous administration and a pouron formulation. An injectable formulation is also approved for use on pigs.
Chemical Properties
White solid or slightly yellow-brown powder with poor water solubility, low stability, easily decomposed and deactivated by sunlight. The remaining drug residue is toxic to fish and aquatic organisms, requiring water source protection.
Application
Doramectin is a mutational biosynthetic antiparasitic antibiotic structurally related to the avermectins. Avermectins are a group of agents that occurs naturally as a product of fermenting Streptomyces avermitilis, isolated from the soil. Avermectins are composed of a structurally similar 16-membered macrocyclic lactone, and widely used as insecticidal and antiparasitic agents. Doramectin is one of the best of a series of avermectins with antiparasitic activity.
Uses
Doramectin is a biosynthetic avermectin derived from a mutant strain of Streptomyces avermitilis, supplemented with a cyclohexylcaboxylic acid starting unit. Doramectin was developed as an anthelmintic for internal parasite control. The presence of the cyclohexyl group replacing the sec-butyl moiety affords greater hydrophobicity and longer biological half-life compared to avermectin. Like the other milbemycin/avermectins, it selectively binds to parasite glutamate-gated chloride ion channels and disrupts neurotransmission leading to paralysis and death of the parasite.
Pharmacokinetics
Doramectin is used for the treatment of livestock diseases such as nematodes and mites ectoparasitosis,it is fermented by recombinant avermitilis (Streptomyces avermitilis) new strain, and the main difference from ivermectin is that C25 is substituted by cyclohexyl. It is a new, broad-spectrum antiparasitic drug,and is efficient for gastrointestinal nematodes, lung nematodes, Euglena, lice, ticks, mites and wound maggots , also has a good effect on internal and external parasites especially certain nematodes (round worms) and arthropods , but invalid to tapeworms, flukes and protozoa.
Veterinary Drugs and Treatments
Doramectin injection is indicated for the treatment and control of
the following endo- and ectoparasites in cattle: roundworms (adults
and some fourth stage larvae)—Ostertagia ostertagi
(including inhibited
larvae), O. lyrata, Haemonchus placei, Trichostrongylus axei,
T. colubriformis,
T. longispicularis, Cooperia oncophora, C. pectinata,
C. punctata, C. surnabada (syn. mcmasteri),
Bunostomum phlebotomum,
Strongyloides papillosus, Oesophagostomum radiatum,
Trichuris spp.; lungworms (adults and fourth stage larvae)—Dictyocaulus
viviparus; eyeworms (adults)—Thelazia
spp.; grubs (parasitic
stages)—Hypoderma bovis, H. lineatum; lice—Haematopinus
eurysternus,
Linognathus vituli, Solenopotes capillatus; and mange
mites—Psoroptes bovis, Sarcoptes scabiei.
In swine the injection is labeled for the treatment and control
gastrointestinal roundworms (adults and 4th stage Ascaris suum,
adults and 4th stage Oesophagostomum dentatum, Oesophagostomum
quadrispinolatum adults, Strongyloides ransomi adults, and
Hydrostrongylus rubidus adults), lungworms (Stephanurus dentatus
adults), mange mites (adults and immature stages Sarcoptes
scabeii var. suis), and sucking lice (adults and immature stages
Haematopinus suis)
The manufacturer states the doramectin protects cattle against
infection or reinfection with Ostertagia ostertagi for up to 21 days.
Doramectin topical (pour-on) is approved for use in cattle and
has a similar spectrum of action against a variety of endo- and ectoparasites,
including biting lice.
Injectable doramectin has been used for treating a variety of
nematode and arthropod parasites in companion animals, including
generalized demodicosis in dogs and cats and spirocercosis in
dogs.
Mode of action
Its mechanism of action is to increase the release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) of the worm, thereby blocking the transmission of nerve signals, so that muscle cells lose their ability to contract, resulting in death of the parasites. the neurotransmitter of Peripheral nerves of mammals is acetylcholine,and will not be affected by Doramectin, doramectin can not go through the blood-brain barrier easily , minimal damage to the central nervous system,safe to cattle. The main feature is that the plasma concentration and half-life are higher or twice than Ivermectin.
Structure and conformation
Doramectin is a macrolide drug of the avermectin family, which is very similar in structure to ivermectin. Doramectin C25 is cyclohexane, and ivermectin is a mixture of several homologues. The C25 of its highly active component B1a (80%) is CH(CH3)C2H5, and the C25 of another component B1b (20%) is CH(CH3)-CH3. Doramectin has a double bond between C22 and C23, while ivermectin has a single bond.
Precautions
1, doramectin is unstable and decomposes rapidly in the sunlight to be inactivated, its remnants of drugs are toxic to fish and aquatic organisms, so pay attention to water protection.
2, pour-on: bovine application, not rain within 6 hours.
3, use with caution in dogs.
4, the goods will be placed out of reach of children, the operator should not eat or smoking, wash hands after handling.
5, withdrawal period, 35 days of cattle, pigs 24 days.
References
1. Production of doramectin by rational engineering of the avermectin biosynthetic pathway. DOI:
10.1016/j.bmcl.2011.04.0082. Construction of a doramectin producer mutant from an avermectin-overproducing industrial strain of Streptomyces avermitilis.DOI:
10.1139/W09-0983. An alternative derivatization reaction to the determination of doramectin in bovine milk using spectrofluorimetry.DOI:
10.1016/j.saa.2012.02.0844. Doramectin - a potent novel endectocide. DOI:
10.1016/0304-4017(93)90218-C5. Avermectin derivatives, pharmacokinetics, therapeutic and toxic dosages, mechanism of action, and their biological effects (a review). DOI:
10.3390/ph130801966. Research progress of avermectin: A minireview based on the structural derivatization of avermectin. DOI:
10.1016/j.aac.2022.11.0017. Positive and negative electrospray LC-MS-MS methods for quantitation of the antiparasitic endectocide drugs, abamectin, doramectin, emamectin, eprinomectin, ivermectin, moxidectin and selamectin in milk. DOI:
10.1016/J.JCHROMB.2006.11.0148.
https://www.fda.gov/animal-veterinary/cvm-updates/fda-approves-first-generic-doramectin-topical-solution-treatment-certain-parasites-cattle
