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Technical Manual for Download

For further information download the Advocate Technical Manual.

Moxidectin

Moxidectin is a potent broad-spectrum endectocide of the macrocyclic lactone (macrolide) antimicrobial class. The macrocyclic lactones consist of two closely related chemical groups – avermectins and milbemycins. These compounds share in common a large complex macrocyclic backbone and are produced through fermentation of soil dwelling fungal organisms of the genus Streptomyces.

Since that time, a number of lactones have been identified and developed with unique activity against endo- and ectoparasites – hence "endectocide" – in both humans and animals. The availability of these broadly effective and well-tolerated compounds has had a tremendous impact on internal and external parasite control in companion animals and livestock.

Chemical Properties

Moxidectin is a 16-member pentacyclic lactone of the milbemycin class. The milbemycins differ structurally from the avermectins, such as ivermectin, primarily in the absence of a disaccharide chain at C-13. Moxidectin has a unique structure characterized by a methoxime moiety at C-23 and an olefinic side chain at C-25 (Fig.1, Table 1).

Fig.1: Moxidectin – Chemical Structure

Table 1: Physicochemical Properties of Moxidectin

Empirical formula

C37H53NO8

Molecular weight

639.84

Physical appearance

White to pale yellow powder

Melting point

145-154 °C

Solubility (mg/1000ml)

Water: 0.51
Organic solvents: readily

Mode of Action

Fig.2: Moxidectin site of action

Moxidectin works in two ways: In common with other macrocyclic lactones, it displays a high affinity for the glutamate-gated ion channels specific to invertebrates. These glutamate-gated binding sites apparently occur in close proximity to GABA-gated sites, and the macrolide endectocides may increase GABA-gated sites as well.

Moxidectin binds to receptors on neuronal membranes of nematodes and myoneural junctions of arthropods. The chloride ion influx lowers cell membrane resistance and causes a hyperpolarization of the post-synaptic cells (Fig 4). This in turn makes neurotransmission more difficult and results in flaccid paralysis, death and/or expulsion of the parasite.1, 2

Spectrum of Activity

The broad spectrum of activity of moxidectin includes a biologically diverse range of invertebrate parasites in cats and dogs:

  • Nematodes of the gastrointestinal tract
  • Developmental stages of filarial nematodes (e.g. Dirofilaria immitis)
  • Arachnids such as mites

Historically, moxidectin has been demonstrated to be effective at relatively low dosages for a variety of parasites. It is licensed in cattle for the treatment of gastrointestinal parasites, lungworms, grubs, mites, lice and hornflies, and for the treatment of gastrointestinal parasites in sheep and horses.

Moxidectin has been proven effective and used for the prevention of heartworm infection in dogs and cats. Moxidectin is also currently under development for the treatment of human onchocerciasis (river blindness), a debilitating filiarial parasitic disease endemic in parts of Africa, the Arabian peninsula and Central and South America.

Advocate for cats

Advocate for dogs

1 also known as French Heartworm
2 Registration for A.vasorum in Europe only
3 In th US, Advantage Multi Dog is not approved for Otodectes, Sarcoptes nor Demodex mites.
5 Registration for lice in Europe, Australia and New Zealand.

Toxicology

The toxicological profile of moxidectin has been extensively evaluated during the development processes for use in various species globally, including ongoing investigations for human use. Numerous laboratory studies indicate a generous range of tolerance in mammals, especially in relation to the therapeutic doses for approved formulations.

Tables 2 and 3 list some of the acute and chronic toxicity studies conducted in laboratory animals. In addition to acute, sub-chronic and chronic exposure studies, reproductive and developmental studies were conducted in rabbits and rodents3.

No developmental effects were observed on fetuses of pregnant rabbits administered as high as 10 mg/kg/day of moxidectin, indicating no evidence of developmental toxicity. In rats, adverse effects on embryo-fetal development occurred only at dosages toxic to the dams, also supporting a lack of specific teratogenic effects from moxidectin. Mutagenicity and carcinogenicity studies indicated no mutagenic effects or oncogenic potential for moxidectin, respectively3.

Table 2: Moxidectin Acute Toxicology Studies

Species

Route of Administration

Level

Mouse

Oral
Intraperitoneal
Subcutaneous

42 – 84 mg/kg   LD50
86 mg/kg   LD50
263 mg/kg   LD50 

Rat

Oral
Intraperitoneal
Inhalation (5 hours)

106 mg/kg   LD50
<640 mg/kg   LD50
3.28 mg/l   LC50

Rabbit

Dermal Application

>2000 mg/kg   LD50

LD50/ LC50=Dosage/Concentration producing 50% mortality in treatment group

Table 3: Moxidectin Chronic Toxicology Studies

Species

Dosing (mg/kg/day)

NOEL (mg/kg)

Mouse
28-day feeding
2-year feeding


0, 6.9, 17.7, 23.2, 24.1, 32.2
0, 2.49, 5.1, 7.8. 11.8


6.9
5

Rat
28-day feeding
90-day feeding
2-year feeding


0, 12.2, 22.8, 26.4, 31.2
0, 1.9, 3.9, 7.9, 12.2
0, 0.8, 3.2, 5.1, 9.8


<12
4
6

Dog
28-day feeding
91-day feeding
52-week feeding


0, 0.5, 2, 4
0, 0.3, 0.9, 1.6
0, 0.25, 0.49, 1.12


0.5
0.3
1.1

NOEL=No Observable Effect Level

Questions about the product?

If you have any questions about the product, please contact our Veterinary Service.

References

  1. Boothe, D.M. "Small Animal Clinical Pharmacology and Therapeutics" – First Edition Saunders, Philadelphia, London, New York (2001).
  2. Tracy, J.W., Webster, L. T. (1996) "Drugs used in the chemotherapy of helminthiasis". Goodman & Gilman’s The Pharmacological Basis of Therapeutics Ninth Edition, Eds H.J.G and L.E. Limbird McGraw-Hill, New York. pp 1017-1018
  3. Rock DW, DeLay RL, Gliddon MJ. Chemistry, Pharmacology and Safety: moxidectin. In Vercruysse J, Rew RS (eds.): Macrocytic Lactones in Antiparasitic Therapy. CABI Publishing, Wallingford, UK, 2002, p.75-96

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