STRUCTURE AND ACTIVITY OF AVERMECTINS AND MILBEMYCINS IN ANIMAL HEALTH

The avermectins and, to a lesser extent, the milbemycins, have revolut ionized antiparasitic and antipest control over the last decade. Both avermectins and milbemycins have macrocyclic lactone structures that a re superimposable, they are produced by the same genus of soil dwellin g organisms, they have the same mode of action, they exert this action against the same nematode/acarine/insect spectrum of targets, and the y show the same mechanism-based toxicity in mammals. Reports suggestin g that milbemycins have a different mode of action from avermectins wi th implications that there will be no mutual resistance to the groups have been shown to be false. Contributing to the belief that there wer e differences in mode of action between the two groups are the vague d efinitions of resistance presently in use which rely on the ability of the parasite to survive treatment at the manufacturer's recommended u se level. More appropriately, drug resistance should be defined as 'a change in gene frequency of a population, produced by drug selection, which renders the minimal, effective dosage previously used to kill a defined portion (e.g. 95%) of the population no longer equally effecti ve'. This type of definition would allow us to detect changes in susce ptibility of a population earlier and is essential when comparing diff erent chemicals to determine if there is mutual resistance to them. It is concluded that much effort has been expended by pharmaceutical, go vernment, and academic scientists searching for broad-spectrum second generation avermectin and milbemycin products, but none has exceeded t he original avermectin in any fundamental way. The newer avermectin an d milbemycin compounds that have appeared claim niches in the market p lace based on emphasis of certain narrow parts of the overall spectrum . Consequently, there are no second generation avermectins and milbemy cins at present and all newer compounds from this mode of action class are viewed as siblings of the first generation.