Shoop W L, Mrozik H, Fisher M H
Merck Research Laboratories, Rahway, NJ 07065-0900, USA.
Vet Parasitol. 1995 Sep;59(2):139-56. doi: 10.1016/0304-4017(94)00743-v.
The avermectins and, to a lesser extent, the milbemycins, have revolutionized antiparasitic and antipest control over the last decade. Both avermectins and milbemycins have macrocyclic lactone structures that are superimposable, they are produced by the same genus of soil dwelling organisms, they have the same mode of action, they exert this action against the same nematode/acarine/insect spectrum of targets, and they show the same mechanism-based toxicity in mammals. Reports suggesting that milbemycins have a different mode of action from avermectins with implications that there will be no mutual resistance to the groups have been shown to be false. Contributing to the belief that there were differences in mode of action between the two groups are the vague definitions of resistance presently in use which rely on the ability of the parasite to survive treatment at the manufacturer's recommended use 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 effective'. This type of definition would allow us to detect changes in susceptibility of a population earlier and is essential when comparing different chemicals to determine if there is mutual resistance to them. It is concluded that much effort has been expended by pharmaceutical, government, and academic scientists searching for broad-spectrum second generation avermectin and milbemycin products, but none has exceeded the original avermectin in any fundamental way. The newer avermectin and milbemycin compounds that have appeared claim niches in the market place based on emphasis of certain narrow parts of the overall spectrum. Consequently, there are no second generation avermectins and milbemycins at present and all newer compounds from this mode of action class are viewed as siblings of the first generation.
在过去十年中，阿维菌素以及在较小程度上的米尔倍霉素，彻底改变了抗寄生虫和防虫控制领域。阿维菌素和米尔倍霉素都具有可叠加的大环内酯结构，它们由同一属的土壤栖息生物产生，具有相同的作用方式，对相同的线虫/蜱螨/昆虫目标谱发挥作用，并且在哺乳动物中表现出相同的基于机制的毒性。有报告表明米尔倍霉素与阿维菌素的作用方式不同，这意味着两组之间不会产生交叉抗性，但事实证明这些报告是错误的。目前使用的抗性模糊定义导致人们认为这两组药物的作用方式存在差异，这些定义依赖于寄生虫在制造商推荐使用水平下经治疗后存活的能力。更恰当的是，耐药性应定义为“药物选择导致种群基因频率发生变化，使先前用于杀死一定比例（如95%）种群的最小有效剂量不再同样有效”。这种定义将使我们能够更早地检测到种群易感性的变化，并且在比较不同化学物质以确定它们是否存在交叉抗性时至关重要。得出的结论是，制药公司、政府和学术科学家们付出了巨大努力来寻找广谱第二代阿维菌素和米尔倍霉素产品，但没有一种产品在任何根本方面超越了原始的阿维菌素。已出现的新型阿维菌素和米尔倍霉素化合物基于强调整个谱中某些狭窄部分而在市场上占据特定细分市场。因此，目前不存在第二代阿维菌素和米尔倍霉素，并且来自这一作用方式类别的所有新型化合物都被视为第一代的同类产品。
