Avermectin Ivermectin

Avermectin (Ivermectin) (Doramectin) (Abamectin) (Eprinomectin) Mites, lice, Horn fly. Warble-fly larvae Solution (pour on) Parenteral solution (S.C. injection) Controlled-release ruminal bolus (ivermectin)... 

Avermectins and Ivermectin. The avermectias are pentacycHc lactones isolated from fermentation products of Streptomjces avermitilis and ivermectin is a semisynthetic chemical, 22,23-dihydroavermectia (46). Ivermectin is effective in very low doses for the control of red spider mites on deciduous fmits, in baits for the control of imported fire ants, and as a parasiticide for Onchocerca volvulus in humans and for catde gmbs. These insecticides appear to function as agonists for the neuroinhibitory transmitter y-aminobutyric acid (GABA) (see Antiparasitic agents, avermectins). 

Ivermectin is the catalytic reduction product of avermectin, a macroHde containing a spiroketal ring system. Two other related antibiotics having significantly different stmctural features and biological properties, moxidectin and milbemycin oxime, were more recentiy introduced into the market. Although these compounds have no antimicrobial activity, they are sometimes referred to as antibiotics because they are derived from fermentation products and have very selective toxicities. They have potent activity against worms or helminths and certain ectoparasites such as mites and ticks. 

Two avermectins, abamectin (the avermectin B ) [71751 -41 -2] and ivermectin [70288-86-7] which is saturated at C22—C23, have been commercialized to date. These two marketed avermectins have been described in considerable detail (Table 1) (13). 

Selective reduction of the 22,23-olefin of avermectin yields the 22,23-dihydro derivative assigned the nonproprietary name ivermectin (18). The stmcture shown depicts the 25-j -butyl derivative [70161 -11-4] but it should be noted that both commercial products contain up to 20% of the 25-isopropyl... 

Since the avermectins exhibit unprecedented potency, they are used at unusually low doses of 6 —300 )-lg/kg, which makes the detection and isolation of residues and metaboUtes from animal tissue a new challenge. For this reason a sensitive analytical assay requires a derivative suitable for detection at concentrations down to 1/10 or 1/100 of one ppm. Ivermectin and avermectin B are therefore converted into an aromatic derivative which allows detection by fluorescence absorbance. To achieve this derivatization, avermectin B, ivermectin, or their derivatives are heated with acetic anhydride in pyridine at 100°C for 24 h (30). The reaction time can be reduced to 1 h by using /V-methylimidazole as a catalyst (31). The resultant... 

The avermectins also possess a number of aUyflc positions that are susceptible to oxidative modification. In particular the 8a-methylene group, which is both aUyflc and alpha to an ether oxygen, is susceptible to radical oxidation. The primary product is the 8a-hydroperoxide, which has been isolated occasionally as an impurity of an avermectin B reaction (such as the catalytic hydrogenation of avermectin B with Wilkinson s rhodium chloride-triphenylphosphine catalyst to obtain ivermectin). An 8a-hydroxy derivative can also be detected occasionally as a metaboUte (42) or as an impurity arising presumably by air oxidation. An 8a-oxo-derivative can be obtained by oxidizing 5-0-protected avermectins with pyridinium dichromate (43). This also can arise by treating the 8a-hydroperoxide with base. 

Since ivermectin (= 22,23-dihydroavermectin B ) is obtained by catalytic reduction of avermectin B, the same procedure using tritium gas convenientiy affords tritiated ivermectin (22,23- [JT]-22,23-dihydroavermectin B ). The preparation of a tritiated derivative containing a 22,23-double bond starts with the readily available 5-ketone, which is reduced with [JT]-sodium borohydride stereospecificaHy to a 5- [JT]-derivative (40). Carbon-14 labeled avermectins can be obtained by a biosynthetic process using sodium (l- C)propionate as labeled precursor (48). 

Methylation of avermectins B and B2 leads to the corresponding derivatives of the A series (49). A procedure involving the oxidation of the 5-methoxy group with mercuric acetate and NaBH reduction of the 5-keto-intermediate allows the conversion of the A to the B components (50). The 23-hydroxy group of the "2" components, after selective protection of the other secondary hydroxy groups, is converted to a thionocarbonate, which can be elirninated to give the 22,23-double bond of the "1" components alternatively it can be reduced with tributyltin hydride to the 22,23-dihydro derivatives (= ivermectins) (51). 

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. 

Ivermectin, a semisynthetic macrocyclic lactone, is a mixture of avermectin Bia and avermectin Bib. It... 

Included in this group are avermectins and milbemycins, which are fermentation products possessing a 16-member cyclic lactone, a spirochetal moiety, and a disaccharide unit. Abamycin, ivermectin, doramectin, and eprinomectin are major avermectins available for anthelminthic treatment of livestock, whereas moxidectin is a milbemycin with worldwide acclaim as a cattle anthelminthic (Fig. 4.7). 

Metabolism studies showed that the major metabolites of the components of ivermectin in cattle, sheep, and rats were 24-hydroxymethyl compounds, whereas major metabolites in swine were 3-0-desmethyl compounds. Identification of the 24-hydroxymethyl metabolites has not been yet achieved in swine, whereas identification of Hie 3-O-desmetlryl metabolites has not been made possible in cattle or sheep (54, 55). Recent metabolism studies (56) in cattle, swine, and rats have indicated, however, diat the metabolism of avermectins was qualitatively similar for all three species. There were quantitative differences both between species and between compounds for a given species, but all three species produced... 

Doramectin, unlike ivermectin components, possesses a double bond between C22 and C23 and a cyclohexyl ring on C25. This novel avermectin is intended for use in cattle and sheep in the form of a single subcutaneous injection at a dosage of 0.2 mg/kg bw, or in pigs in the form of a single intramuscular injection at a dosage of 0.3 mg/kg bw (58). 

Immunoaffinity chromatography cleanup has also been applied as an ideal and reliable strategy for residue analysis. Immunoaffinity columns prepared by coupling the antibodies to a cyanogen bromide-activated support were used to analyze avermectin BI residues in cattle tissues (359) and ivermectin in sheep serum (376). An immunoaffinity column prepared by an alternative activation/ coupling procedure with carbonyl diimidazole was also employed to analyze ivermectin residues in swine liver (361) since the earlier-reported methods did not work well in the analysis of this matrix. This recent work demonstrated the high specificity of tire antibody-mediated cleanup, but also showed that the immunoaffinity procedures could not always or completely eliminate matrix interference of samples. Therefore, application of additional cleanup steps before or after these procedures is often inevitable. 

The high cost of developing compounds with limited markets has reversed the trend to narrower spectrum agents. The reversal began with the pyrethroids and has continued with the discovery, from fermentation sources, of the avermectins. In addition to their anthelmintic properties (see Section 1.08.2), a semisynthetic derivative, ivermectin (16), is in use in the control of lice, mites and warbleflies. Activity against Boophilus ticks, including all... 

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