Ivermectin production

The early 90 s saw 3 other companies launch competitor products with Pfizer s doramectin (Figure 11) establishing the highest market share. This gives better persistent anthelmintic activity than the early ivermectin products. 

Praziquantel is indicated for use in the horse in several coimtries as a component of a combination ivermectin product (Mercier et al 2001). The mode of action of praziquantel has been studied extensively in trematodes (Harnett 1998) and the anticestodal effects of this compoimd are assumed to have a similar basis. Praziquantel increases the permeability of tegumental and muscle cells to calcium ions, which results in parasitic muscular contraction and paralysis. In the horse, praziquantel has a narrow spectrum of activity against tapeworm, with 89-100% efficacy at dose rates of 0.75-1 mg/kg (Lyons et al 1992). 

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. 

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... 

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. 

Gunn A. and J.W. Sadd (1994). The effect of ivermectin on the survival, behavior and cocoon production of the earthworm Eisenia foetida. Pedobiologia 38 327-333. 

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). 

Ivermectin is produced from abamectin by reduction of the double bond at the C22-C23 position, a process that leads to formation of dihydroavermectin Bia and dihydroavermectin Bib. The reaction product that contains no less than 80% dihydroavermectin Bia and no more than 20% dihydroavermectin Bib constitutes ivermectin. 

Residues of arsenical compounds were tested in 1056 monitoring samples of poultry. Three violations were detected in each of young chicken and turkey samples. Testing for ivermectin residues showed tliat 6 of 3327 samples taken from 10 production classes contained violative residues two violations occurred... 

Another important class of anti-infective natural products introduced in recent years is the avermectins, polyketide-derived macrolides that were originally isolated from several species of Streptomyces. The major drug in this class, ivermectin, was originally developed to treat and control nematodes and parasites in livestock. In recent years, however, the potential of ivermectin for the treatment of human disease has also been realized, and it is now used to treat onchocerciasis (river blindness), a disease that afflicts 40 million people worldwide (De Smet, 1997). 

Olefins are susceptible to isomerization. The API ivermectin undergoes isomerization under basic conditions due to the weak acidity of the allylic proton (which is also alpha to a carbonyl) on C2. The two resulting degradants can be derived from the delocalized carbanion formed from dissociation of the proton at C2. Reprotonation at C2 generates the epimeric product and reprotonation at C4 generates the structural isomer (Fig. 103) (147). 

However, no one will deny that new remedies like those offered by the broad spectrum ivermectin or by prophylactics, in the form of specific vaccines, must eventually become available to boost food production and fight famine and disease in Africa. 

It seems that the general perception of high profits is very much influenced by the commercial success of a few "blockbuster" products like the H2-receptor antagonists, ivermectin or the recently launched erythropoeitin. These are the exceptions, whereas extremely hopeful candidates rendering moderate success seem to to be more the rule. 

Avermectins (113, 114) are a series of macrocyclic lactones that are broad-spectrum, highly potent, glutamate-gated, chloride chaimel-modulator antiparasitic agents produced by Strep-tomyces avermitilis (146, 147). Ivermectin, 23,24-dihydroaver-mectin (115), was the first product approved in the... 

Baggott, D.G. Ross, D.B. Preston, J.M. Gross, S.J. Nematode burdens and productivity of grazing cattle treated with a prototype sustained-release bolus containing ivermectin. Vet. Rec. 1994, 135, 503-506. 

A role for the release of Wolbachia bacterial endosym-bionts has been suggested in the pathogenesis of the Mazzotti reaction (SEDA-26, 345). There was a good correlation between Wolbachia DNA, serum TNF-alfa, and the antibacterial peptides calprotectin and calgranu-lin after treatment with ivermectin or diethylcarbamazine, supporting a role for Wolbachia products in mediating these inflammatory responses (27). 

Ivermectins B1 are derived from the avermectines Bl, the natural fermentation products of Streptomyces avermitilis. The avermectins Bl have double bonds between carbon atoms at 22 and 23, whereas the ivermectins Bl have single bonds in these positions (Fig. 2a). They have an intermediate polarity. The ivermectins Bl are a mixture of two major homologs, ivermectins Bla (>80%) and ivermectins Bib (<20%), but a crude ivermectin complex also contains various minor components. Ivermectins Bl are broad-spectrum antiparasitic agents used against Onchocerca volvulus in human medicine and for food production animals such as cattle, swine, and horses. 

Ivermectins B1 are broad-spectrum antiparasitic agents widely used for food-producing animals such as cattle, swine, and horse.They are derived from avermec-tins Bl, the natural fermentation products of Strepto-myces avermitilis. 

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