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. 

Fig. 1. Ivermectin [70288-86-7] is a mixture containing at least 80% 22,23-drhydroavemiectrn [70161 -11-4] wherein R = and not more than 20%...

Systemic reactions are less severe than with diethylcarbama2ine. The most commonly seen reactions are fever, rash, and lymph-node pain or swelling. Suppressive ivermectin therapy consists of a single oral dose every 6—18 months. The required duration of suppressive therapy is unknown, probably at least three years (36). Ivermectin is available from the CDC Dmg Service on request. It is manufactured by Merck Sharp and Dohme in the United States and England. 

Informational Materialfor Physicians, Ivermectin, Centers for Disease Control, Adanta, Ga., 1986, pp. 1—23. 

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... 

Ivermectin is active against two significant phyla of animal parasite the Nemathehninthes or nematodes (roundworms) and the Arthropoda (insects, ticks, and mites). Ivermectin is inactive against platyhehninthes (flukes and tapeworms). 

Ivermectin has an extremely broad spectmm of antinematodal activity in a variety of domestic animals. Indeed, among the many nematodes against which it has been tested, none has been found that is not affected by ivermectin during at least one stage of the life cycle. In all but a few instances the dmg is highly active against both immature and mature worms (19). 

The activity of ivermectin against the filarial parasite Dirofilaria immitis in dogs suggested a possible role for the control of filarial parasites of humans (20). It has been extensively tested in human onchocerciasis and is now considered to be the dmg of choice. In a single yearly oral dose, it suppresses microfilariae in the skin and eyes and, in most cases, prevents the progression of the disease to blindness. Table 4 shows the results of a 30-patient double-blind study recorded over one year. 

Table 4. Ivermectin and Diethylcarbamazine Against Onchocerca volvulus Infections ...

Ten patients received a single oral dose of ivermectin, 12 mg. 

Two forms of lymphatic filariasis are found in India. The Bancroftian form is the most common and accounts for more than 90% of the disease whereas Bmgian filariasis accounts for the rest. In a study carried out in India (6) in 40 patients with Wuchereria Bancwfti filariasis treated with single oral doses, all of the dose levels chosen (25, 50, 100, and 200 mg/kg) were efficacious in clearing microfilariae from the blood of all patients treated. However, after three months some microfilaria recurred in the blood of most patients (Table 5). Further studies are planned and some are underway using different doses and regimens. Ivermectin still appears to hold promise as a new treatment for lymphatic filariasis. 

Table 5. Efficacy of Ivermectin in the Treatment of Wuchereria Filariasis...

Ivermectin is widely used as an endectocide for catde as an injectable, oral, topical, or slow release bolus for sheep as an injectable or oral formulation for swine as an injectable for horses as a paste or drench and for goats as an injectable or oral formulation. Ivermectin has recently been introduced for heartworm prophylaxis in dogs and it is being studied for use with cats, many other mammals, birds, fish, and reptiles. 

Ivermectin is used in cattle, sheep and horses at 0.2 mg/kg swine at 0.3 mg/kg dogs at 0.006 mg/kg and man at 0.05 —0.2 mg/kg. It is effective against parasitic nematodes, gmbs, Hce, mites, ticks, and bots. Ivermectin is not active against tapeworms, flatworms, bacteria, or fungi. 

Fig. 4. Treatment of ivermectin with methanolic potassium hydroxide solution (25).

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). 

---