Ivermectin antiparasitic activity

A pharmacological effect may be observed only when food contains elevated concentrations of potent therapeutics, as in the case of the -blocker carazo-lol whose residues in tissues caused sedation residues of the -agonist clenbuterol that produced bronchodilatory action and residues of the anthelminthic ivermectin that produced antiparasitic activity (51). 

Ivermectin possesses a broad spectrum of antiparasitic activities [51] and is a 22,23-dihydro analogue of the macrocyclic lactone, avermectin B,. Ivermectin is highly effective against microfilariae of O. volvulus at very low doses (50-200/ig/kg) [52] and in comparison with DEC, induces only mild mazzotti reactions and other side-effects. Its effectiveness against D. viteae in M. natalenis [38] and D. immitis [53] is also documented. 

This class of macrolide antibiotic has mostly antiparasitic activity. Avermectin Bia (45) and ivermectin (46) (O Scheme 18) are used mostly in veterinary medicine, however, some semisynthetic derivatives are also used for treatment of onchocerciasis in humans [59]. The action of avermectin is believed to stimulate specific chloride ion transport systems increasing the membrane permeability to Cl ions via GABA (y-butyrate) receptors and non-GABA receptors [60]. 

The aglycon of avermectin has poor antiparasitic activity. Positions 4 and 4" of the olean-drose moieties were modified partly because of feasibility. The synthesis of the 4 -amino-4 G deoxyoleandrose derivative of avermectin Bi and ivermectin was based on the observation that most macrolide antibiotics contained a basic amino group [61]. One of the derivatives, 4 -e/7t-acetamido-4 -deoxyavermectin Bi, is currently under development as a novel avermectin endectoside [61]. Besides, also 2"-a-fluoro (ax.) and 2"- 8-fluoro (eq.) derivatives of avermectins were prepared to strengthen the glycosidic bond. These derivatives have interesting activities in some bioassays compared to the parental compounds [62]. 

The naturally occuring avermectins are a family of eight, pentacyclic structures containing a sixteen-membered macrolide ring which are produced by Streptomyces avermitilis (Fig. 6) [60]. These eight compounds differ in structure due to the variability of PKS starter unit at C-25, the 0-methylation pattern at C-5, and the hydration-dehydration pattern at C-22/C-23. Other closely related natural products include the milbemycins and the nemadectins. The avermectins exhibit potent broad spectrum antiparasitic activity, and the semi-synthetic Ivermectin 29 (hydrogenated avermectin Bl) displays even greater efficacy [60,61]. 

In the universe of biologically active natural products, the spirocyclic moiety is a unique and key structural motif. For example, there are over 300 spiroketal natural products including the aver-mectins and milbemycins, which demonstrate a range of antiparasitic activity with low toxicity (Figure 7.4). ° A semisynthetic derivative, ivermectin, is used in animals to treat parasite infestations. The spongistatins exhibit anticancer activity by disrupting mbulin polymerization. Okadaic acid is a cytotoxin found in marine sponges. 

The microorganism was classified as a new species of actinomycete. Streptomyces avermitilis. Its anthelmintic activity was shown to reside in 8 closely related macrocyclic lactones, named avermectins, which were also found to possess activity against free-living and parasitic arthropods. One of the natural components, avermectin is now being evaluated as a pesticide for the control of mites of citrus and cotton crops and control of the Red Imported Fire Ant. A chemical derivative, 22,23-dihydroavermectin or ivermectin, has been developed as an antiparasitic agent. It is being marketed for use in cattle, horses and sheep and is expected to become available for swine and dogs. 

It has been shown for avermectin B that the hydroxyl group at C-5 and a disaccharide moiety are essential for antiparasitic, mitocidal and selective insecticidal activities. Chemical modification of the macrolide-type avermectins resulted in ivermectin which was commercialized to be used in agriculture and animal health care as well as in human medicine. 

Ivermectin has found wide use as a systemic antiparasitic agent against endo and ectoparasites of animals. Ivermectin is also used as a treatment for human filarial worm infections Onchocerca volvulus) [220]. The monosaccharides were 2 to 4 times less active than the disaccharide, and dihydroavermectin B1 aglycone was 30 times less potent [219]. 

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