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What are salicylanilides?

Salicylanilides are a chemical class of antiparasitic active ingredients with efficacy against certain roundwormstapeworms and/or flukes. All salicylanilides have a narrow spectrum of activity, and each one is effective only against certain parasites. They are used mainly in cattle and sheep, very sporadically in pets or horses.

Anthelmintic salicylanilides were introduced in the 1960's and 1970's by several pharmaceutical companies.

All salicylanilides are veteran anthelmintics that have lost patent protection long ago. Those still in use are available as generics manufactured by numerous chemical companies (typically in China, India, Israel, Brazil, etc.).


Active ingredients and parasites controlled

Molecular structure of closantelThe most relevant salicylanilides for veterinary use are the following ones:

Two other veteran salicylanilides were used in the past as livestock anthelmintics: brotianide (effective against certain flukes) and resorantel (effective against various tapeworms and against rumen flukes). Both are nowadays vastly abandoned.

Closantel is an interesting case. It is one of the few real endectocides, i.e. it controls several endoparasites and ectoparasites at the usual therapeutic dose. However it is only a narrow-spectrum and not a broad-spectrum endectocide such as the macrocyclic lactones. Closantel is highly effective against adult and immature liver flukes (Fasciola hepatica), against several gastrointestinal roundworms (e.g. Bunostomum spp, Haemonchus spp, Oesophagostomum spp, Strongyloides spp,Trichostrongylus spp) and against a few external parasites such as screwworms  (Cochliomyia spp, Chrysomya spp), sheep nasal bots (Oestrus ovis), and sheep keds (Melophagus ovinus). It is certainly the most vastly used salicylanilide.

Niclosamide is effective against various tapeworms (e.g. Taenia spp, Moniezia spp), rumen flukes (Paramphistomum spp) and against several blood flukes (Schistosoma spp.) but is only scarcely used on livestock and pets. It is approved as a human medicine in some countries. It was originally introduced as a molluscicide, i.e. a snail killer, to control those snails that transmit schistosomiasis (also called bilharziosis or snail fever), a serious human disease in numerous tropical countries. In certain countries niclosamide is used in the form of its lithium or sodium salts, which are slightly more effective.

Oxyclozanide is effective against adult liver fluke (Fasciola hepatica), but only partially against late immature stages. Efficacy against rumen flukes (Paramphistomum spp) is also limited. It is very scarcely used in livestock.

Molecular structure of rafoxanide.Rafoxanide is highly effective against adults and late immature stages of liver fluke (Fasciola hepatica), as well as against a few roundworms such as Haemonchus spp and Bunostomum spp. There are still a few products with rafoxanide for livestock.

Brotianide is effective against adults and late immature stages of liver flukes (Fasciola hepatica and Fasciola gigantica) but not against rumen flukes (Paramphistomum spp). It has been replaced by more efficacious compounds.

Resorantel is highly effective against certain livestock tapeworms (e.g. Moniezia spp, Avitellina spp) and against rumen flukes (Paramphistomum spp). It has been also replaced by more efficient compounds.

Click here for a general introduction to parasiticides and their most important features.


Delivery forms of salicylanilides

Salicylanilides are available in the following delivery forms:

Mixtures with other anthelmintics compounds are very common. Closantel is often used in combination with nematicides (e.g. ivermectin, levamisole, fenbendazole, albendazole, etc.) to add flukicidal efficacy and also to overcome resistance to key gastrointestinal roundworms to those nematicides.


Mechanism of action of salicylanilides

The molecular mode of action of salicylanilides is not completely elucidated. They all are uncouplers of the oxidative phosphorylation in the cell mitochondria, which disturbs the production of ATP, the cellular "fuel". This impairs the parasites motility and probably other processes as well.

Niclosamide acts on the tapeworms also through inhibition of glucose absorption.


Pharmacokinetics of salicylanilides

Molecular structure of oxyclozanide.After oral administration oxyclozanide is found mainly in liver, kidneys and gut. It is slowly metabolized and excreted through the bile and the feces.

Rafoxanide and closantel are quickly absorbed to blood after administration. They bind strongly to blood proteins, which prolongs their presence in blood for weeks. This explains their excellent efficacy against migrating fluke larvae that are exposed to blood in the tissues before they reach the bile ducts. Half-life in the host is about 15 days, which explains the long residual effect of up to 60 days against liver fluke and Haemonchus spp roundworms.

Niclosamide is poorly absorbed in the gut and is excreted through the feces almost completely as the unchanged parent compound. This may explain its low toxicity for livestock and pets.


Safety of salicylanilides

Livestock and pets usually tolerate salicylanilides very well. The safety margins range from ~3 for brotianide, ~6 for closantel and rafoxanide, and >20 for niclosamide.
Niclosamide is allowed for use in humans, even during pregnancy.

Meat withholding periods are about one month for closantel and rafoxanide in most countries and these compounds are usually not allowed for use in lactating dairy animals whose milk is intended for human consumption.

Additional specific information (toxicity, intoxication symptoms, adverse drug reactions, antidote, etc.) on the safety for veterinary use of the most used sylicylanilides is available in specific articles in this site:

General information on the safety of veterinary antiparasitics is available in specific articles in this site (click to visit):

WARNING

Never use livestock, horse or poultry products on dogs and/or cats, unless explicitly approved for dogs and/or cats too. Without reliable use instructions they can be easily overdosed, and pets may not tolerate formulations developed for use on livestock, horses and/or poultry.  Some active ingredients may be toxic to particular animals.

Never use agricultural or hygiene products on livestock, horses, poultry or pets, unless explicitly approved for veterinary use, which is quite unusual. Even if the specific active ingredient is approved for some veterinary use. The formulations for agricultural and/or hygiene use are mostly different than those for veterinary use and  may be toxic to or not be tolerated by animals.

It is obvious that veterinary medicines are not intended for and should never be used on humans!!!


Parasite resistance to salicylanilides

There are reports of resistance of Haemonchus spp to closantel and rafoxanide, and of liver fluke (Fasciola) to closantel, mainly in sheep. However, it seems not to be a widespread problem in those countries were it has been detected.

Visit also the articles in this site about parasite resistance to antiparasitics and  how it develops.

Other articles in this site

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