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The Pharmacology of Halogenated Salicylanilides and Their Anthelmintic Use in Animals

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The Pharmacology of Halogenated Salicylanilides and Their Anthelmintic Use in Animals Review article — Oorsigartikel The pharmacology of halogenated salicylanilides and their anthelmintic use in animals G E Swana The structural criteria for fasciolicidal ABSTRACT action has been described as the need for The halogenated salicylanilides are a large group of compounds developed mainly for their electron-withdrawing substitutes on both antiparasitic activity in animals. Several halogenated salicylanilides with potent the salicylic and anilide rings, together antiparasitic activity have been synthesised of which only closantel, niclosamide, with a lipophilic group, such as tert-butyl oxyclozanide, rafoxanide and resorantel are commercially available. Closantel and in the 3-position66. Improved fasciolicidal rafoxanide, which represent the most important drugs in the group, are used extensively activity of salicylanilides has been for the control of Haemonchus spp. and Fasciola spp. infestations in sheep and cattle and achieved in compounds such as closantel Oestrus ovis in sheep in many parts of the world. Niclosamide is used extensively for its and rafoxanide by the incorporation of an anticestodal activity in a wide range of animals. Antiparasitic activity of the halogenated aryl chain in the aniline moiety of the salicylanilides has also been demonstrated against a large number of other internal anilide12. In both drugs the active parasites, in particular haematophagous helminths, and external parasites including ticks and mites, in a variety of animal species. Several cases of toxicity and mortality have been pharmacophore is 3,5-diiodosalicyl- 110 reported for closantel and rafoxanide in sheep and goats. Their unique pharmacokinetic oyol . behaviour appears to play an important role in the efficacy and safety of these compounds. Depending on the type of structural The chemical and physical characteristics, mode of action, pharmacokinetics, antiparasitic substitution, salicylanilides have been activity and toxicity of the halogenated salicylanilides in animals are reviewed. subdivided into a number of different groups, including halogenated and Key words: animals, antiparasitic activity, halogenated salicylanilides, pharmacology, review, safety. non-halogenated derivatives, acetyl- salicylanilides, dichlorosalicylanilides Swan G E The pharmacology of halogenated salicylanilides and their anthelmintic use in and benzoylsalicylanilides. Acetylsalicyl- animals. Journal of the South African Veterinary Association (1999) 70(2): 61–70 (En.). Depart- ment of Pharmacology and Toxicology, Faculty of Veterinary Science, University of anilide derivatives, e.g. clioxanide, are Pretoria, Private Bag X04, Onderstepoort, 0110 South Africa. activated in vivo. This is presumably achieved by hydrolysis of the acetyl group to free the hydroxyl derivative38. INTRODUCTION many years and the extensive use of these All salicylanilides developed for use as Salicylanilides are a very large group of products, no definitive review of these anthelmintics in animals are halogenated compounds, originally developed as products has been published. and include: clioxanide (N-(4’-chloro- fungicides for topical use and as antimi- phenol)-3,5-diiodo-acetylsalicylamide); crobial agents in soaps64. Later these com- CHEMICAL AND PHYSICAL closantel (N-(5-chloro-4[(4-chlorophenyl) pounds were shown to possess potent CHARACTERISTICS cyano-methyl]-2-methylphenyl)-2-hydro anthelmintic activity of which the niclo- xy-3,5-diiodo-benzamide), dibromsalan samides54 tribromsalans8 and clioxanide9 Chemical structure (4’,5’-dibromosalicylanilide); oxycloza- were some of the 1st agents to be used. Salicylanilides, also referred to as nide (3,3’,5,5’,6-pentachloro-2-hydroxy- Since then, a wide range of halogenated benzamides or salicylamides54, are weak, salicylanilide), niclosamide (5-chloro-N- salicylanilide congeners active against acidic phenolic compounds. The basic (2-chloro-4-nitrophenyl-2-hydroxy- helminth parasites have been synthe- chemical structure consists of a salicylic salicylanilide); rafoxanide (3’-chloro-4’- sised11,12,32,37,66,76,102,110,126. The halogenated acid ring and an anilide ring (Fig. 1). (p-chlorophenoxy)-3,5-diiodosalicyl- salicylanilides available in South Africa are summarised in Table 1113. Halogenated salicylanilides, in particu- Table 1: Halogenated salicylanilides registered for use in animals in South Africa. lar closantel and rafoxanide, are impor- Drug Trade names Manufacturer/Supplier tant anthelmintics that are used extensively in the control of Haemonchus Closantel Flukiver, Seponver Janssen AH spp. and Fasciola spp. infestation in sheep Pro-inject Yellow, Prodose Yellow, and cattle, and Oestrus ovis in sheep in Ranide Super, Vetdose 4, Vetdose 4 injectable Logos Agvet many parts of the world. Niclosamide is Oxyclozanide Milborrow Liverfluke Remedy Bayer AH widely used for the treatment and control Niclosamide Ex-A-Lint Hoechst Roussel Vet of cestode infections in several animal Lintex Bayer AH species. Despite being available over Prodose Lint Logos Agvet Rafoxanide Nasalcur Hoechst Roussel Vet Ovinox Bayer AH aDepartment of Pharmacology and Toxicology, Faculty of Ranide Logos Agvet Veterinary Science, University of Pretoria, Private Bag X04, Onderstepoort, 0110 South Africa. Ranox Pfizer AH Resorantel Terenol-S Hoechst Roussel Vet Received: December 1998. Accepted: May 1999. 0038-2809 Jl S.Afr.vet.Ass. (1999) 70(2): 61–70 61 Closantel has a molecular weight of 663.0714. It is weakly acidic (pKa = 4.28) and is highly lipid-soluble (log P = 7.15, n-octanol/buffer pH 6.98)72. MODE OF PHARMACOLOGICAL ACTION The primary action of salicylanilides has generally been associated with the un- coupling of oxidative phosphorylation. Early in vitro studies, using houseflies as well as rat liver mitochondria, showed several salicylanilides as potent inhibitors of this electron transport associated phosphorylation127. Salicylanilides were approximately 1000–10000 times more potent than dinitrophenol, an earlier compound known to inhibit oxidative phosphory- lation. In vitro activity of inhibition of electron transport associated phospho- rylation in Fasciola hepatica and Ascaris lumbricoides were later reported for oxyclozanide, rafoxanide and closan- tel24,25,26,62,121,123. Several workers have subsequently confirmed the proposed mechanism in vivo25,87,123. In vitro inhibition of succinate dehydro- genase activity with a wide range of salicylanilides38 and inhibition of the fumarate reductase system by oxycloza- nide and rafoxanide in F.hepatica (unpub- lished information as cited in Coles23) Fig. 1: Chemical structures of the halogenated salicylanilides developed for use as anthelmintics in animals1,14. have also been reported. These effects may be due to the interrelationship of the both towards aqueous solubility and succinate dehydrogenase activity to the stability in suspension. Absorbed or fumarate reductase system and oxidative occluded impurities are thought to play phosphorylation. It has been suggested an important role in the polymorphic that rafoxanide diminishes ATP-syn- behaviour of the drug. thesis, resulting in increased internal Fig. 2: Basic structure of salicylanilides: salicylic ring (A) and anilide ring (B). Anthelmintic activity of rafoxanide is intermediate pools in the pathway. Later, inversely related to the size of crystalline as an independent effect, the further particles present in a 2.5 % oral suspen- metabolism of succinate is inhibited. anilide); resorantel (N-(4’-bromo- sion4. According to the chemiosmotic theory phenyl)-6-hydroxysalicylamide) and of Mitchell73, hydrogen-ionophores act by tribromsalan (3,4’,5-tri-bromosalicyl- Physicochemical characteristics uncoupling of phosphorylation by the anilide). The chemical structures of these The salicylanilides are generally weakly translocation of protons through the compounds are given in Fig.2.1,14. acidic, highly lipid-soluble compounds. inner mitochondrial membrane. The Very little information on the physico- maintenance of the proton gradient Crystal structure and polymorphic chemical characteristics of the individual across the inner mitochondrial mem- forms salicylanilides has been reported. Of the brane is essential for the continued pro- The 2 aromatic rings of the salicylanilide salicylanilide group, rafoxanide and duction of ATP. The inner mitochondrial moeity are approximately co-planar with closantel are the most widely used and membrane is normally impermeable to a dihedral angle between them101. There are therefore more extensively described protons, but can be rendered permeable are significant conformational differences in literature. Rafoxanide has a molecular by the addition of uncouplers of oxidative between the various halogenated salicyl- weight of 626.01 and a melting point of phosphorylation that act by destroying anilides and analogues regarding their 173–7 °C2. It is a greyish-white crystalline the proton gradient. This activity selec- crystalline forms. Interatomic dimensions powder, moderately soluble in acetone, tively prevents the utilisation of the in the salicylanilide moiety are consistent chloroform, ethyl acetate, acetonitrile and chemical energy derived from electron within the halogenated salicylanilides. methanol but insoluble in water76. transport for the net phosphorylation of The crystalline forms of closantel have Ultraviolet light absorption of a 0.004 % ADP to ATP,thus depriving the cell of its not been reported. w/v solution in 0.1 M methanolic hydro- normal source of energy103. Polymorphic forms of salicylanilides
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