Nowadays a number of different anthelmintics are available to counteract helminth infections. Table 1.5 gives a brief overview of some anthelmintic classes, active ingredients and some commercial products, including those used in these studies.
Table 1.5 – Overview of active ingredients of available anthelmintics, their classes and some examples of commercially available products.
Active Ingredient Class (Acronym) Active ingredient in ivermectin macrocyclic lactone (ML)
avermectin milbemycin
Ivomec®
abamectin Startect®, Matrix®
moxidectin
levamisole imidazole Scanda®, Matrix®
albendazole benzimidazole (BZ)
oxfendazole Scanda®, Matrix®
monepantel1 amino-acetonitrile derivative (AAD) Zolvix® derquantel1 spiroindole (SI) Startect®
1 = not licensed for use in cattle
The class of the macrocyclic lactones (ML) contains the chemical groups of the milbemycins and avermectins. Both are fermentation products from the actinomycete genus Streptomyces, which were found to have antiparasitic properties in the mid 1970’s by scientists at Merck (Burg et al., 1979; Chabala et al., 1980; Egerton et al.,
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1979, 1980). The main structural difference between the two groups is a disaccharide substituent on the C-13 in the avermectins compared to the milbemycins (Shoop et al., 1995). The first commercially available ML for animal use was ivermectin (IVM; 22,23- dihydroavermectin B1a and B1b) which showed a high efficacy against a broad spectrum
of invertebrate ecto- and endoparasites as displayed in Table 1.6 (Campbell, 1981; Campbell et al., 1983). In humans IVM is commonly used to control onchocerciasis, lymphatic filariasis and scabies (Hodges et al., 2010; Hotez et al., 2007; Meinking et al., 1995; Mohammed et al., 2006; Molyneux et al., 2003)
Early studies indicated that the mode of action of IVM was by interacting with GABA receptors (Holden-Dye and Walker, 1990). However, subsequent reports revealed a glutamate-gated chloride channel (GluCL) could be sensitive to IVM (Arena et al., 1991) and this was later accepted as the more likely mode of action in nematodes and other invertebrates for chemotherapeutically relevant concentrations of IVM (Cully et al., 1994).
For the treatment of nematode infections levamisole is an important derivate in the class of the imidazole/imidazothiazoles. Historically tetramisole, a racemic mixture of dexamisole and levamisole was used, however, both isomers share the same side effects but only the L-isomer levamisole possesses efficacy against nematodes. On nematodes it acts as an acetylcholine mimetic agent resulting in a prolonged activation of the muscle cells in the body wall of nematode (Atchison et al., 1992; Coles et al., 1975)
The first benzimidalzole available was thiabendazole in 1961 followed by various other derivates such as oxfendazole. The likely mode of action for all benzimidazoles (BZs) is an interaction with the ß-tubulin compromising the cytoskeleton which is subsequently lethal by disrupting the metabolic processes in the nematode cells (Lacey, 1990).
Introduction and Literature Review
Table 1.6 – Internal and external parasites of cattle against which subcutaneous ivermectin was shown to be effective at a dose of 0.2mg/kg (Shoop et al., 1995).
Nematoda Arthropoda Gastrointestinal worms Bunostomum phlebotomum Cooperia oncophora Cooperia pectinata Cooperia punctata Cooperia spp. Haemonchus placei Mecistocirrus digitatus Nematodirus helvetianus Nematodirus spathiger Oesophagostomum radiatum Ostertagia ostertagi Strongyloides papillosus Toxocara vitulorum Trichostrongylus axei Trichostrongylus colubriformis Trichuris spp. Lungworms Dictyocaulus viviparous Skin worms Parafilaria bovicola Eye worms Thelazia spp. Cattle grubs Dermatobia hominis Hypoderma bovis Hypoderma lineatum
Screw worm fly larvae
Chrysomya bezziana Cochliomyia hominivorax Sucking lice Haematopinus eurysternus Linognathus vituli Solenopotes capillatus Biting lice Bovicola bovis Mange mites Psoroptes ovis
Sarcoptes scabiei vat. bovis Chorioptes bovis Ticks Boophilus microplus Boophilus decoloratus Ornithodoros savignyi 1.6.2 Pharmacokinetics
Anthelmintics can be administered as a topical application, as a pour-on, by subcutaneous injection or oral application although not all routes are applicable for all types of anthelmintics. The pharmacokinetic profile of an anthelmintic is usually measured as the concentration of the drug in the plasma which is acting as a proxy measurement for the concentration at the site of the nematode. In contrast the time to reach maximal plasma concentration of topically applied IVM is extended by the time needed to penetrate the skin although different formulations have been found to increase the rate of transdermal delivery (Yazdanian and Chen, 1995). Additionally, the
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fatty layer of subcutaneous tissue interacts with IVM delivered by topical or subcutaneous application delaying the passage into the plasma (Herd et al., 1996). However, when applied as an oral dose MLs interact strongly with digestive material (Hennessy and Alvinerie, 2002) resulting in a lower systemic availability (Lifschitz et al., 2005), but is otherwise unaffected by the rumen fluid (Andrew and Halley, 1996; Lifschitz et al., 2005). Nevertheless, this has important implications on the efficacy on different gastrointestinal nematodes with subcutaneous and pour-on application showing a decreased efficacy against Cooperia compared to oral application (Leathwick and Miller, 2013). When IVM is given to sheep via the subcutaneous or oral route, the plasma concentration was highest after 36 or 24 hours, respectively, and was not detectable 14 days after oral but still detectable 28 days after subcutaneous application (Marriner et al., 1987). This is in accordance with later findings in sheep which also showed that no residues were found in abomasal fluid 96 hours after the oral but still found 21 days after the subcutaneous application (Bogan and McKellar, 1988).
In contrast to IVM, levamisole is fast-acting, reaching the maximal plasma concentration in 1-3 hours followed by a rapid decrease to undetectable levels within 6-10 hours (Forsyth et al., 1983; Manger, 1991; Oakley, 1980; Sangster et al., 1988). For the anthelmintic efficacy of levamisole it is not the duration of exposure but the maximal concentration (Marriner, 1986) whereas the pharmacokinetics of oxfendazole indicate that the maximum plasma concentration is reached later when compared to IVM with a shorter half-life (Marriner and Bogan, 1980, 1981).