Anthelmintic drugs for zoonotic pathogens

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1 Anthelmintic drugs for zoonotic pathogens Claudio Genchi Eleventh Workshop of National Reference Laboratories for Parasites Rome, ISS May 23 rd -24 th 2016 Galli-Valerio in one of the first treatise on zoonotic infections [Galli-Valerio: Zoonosi, Malattie degli animali trasmissibili all uomo, 1894, U. Hoepli, Milano], recounted four parasitic zoonoses [distomatosis (Fasciola hepatica), taeniosis, trichinellosis and mange] and nine microbial diseases [actynomicosis, tuberculosis, anthrax, rage, glanders, epizootic aphtha, diphtheria, smallpox and tetanus]. Docente di Patologia Generale alla R. Scuola superiore di Medicina Veterinaria di Milano e poi Ordinario di Igiene e Parassitologia all Università di Losanna. Parasitic zoonoses Currently, the parasites able to cause human infections are more than 480 and probably the list will increase considering the diminished resistance to different pathogens and opportunistic agents that currently characterizes animal populations, including humans. The risk of zoonotic infections listed by Galli-Valerio were all from the rural word [production animals]. The reinforced control of food production have decreased such a risks and nowadays, many [most?] zoonotic infection are as a consequence of the presence of companion animals in the households. 1

2 Main helminthic zoonotic infections in dogs, cats and wild carnivores Companion animals For instance, seroprevalence of human toxocariasis [Toxocara spp.] ranges 5% in urban areas >40% in rural areas. T. canis and T. cati are ascarid worms living in the small intestine of dogs and cats, respectively, where the parasites develop to adult worm. After about 25 days that eggs are lied in the environment by faeces of infected hosts, an embryo develops in the eggs, which are able to resist for long time to environmental conditions. Humans, mainly children, can accidentally ingest the infective form [embrionated eggs]. In humans the parasite is not able to develop to adult stage and the migrating larvae are responsible of visceral larva migrans and ocuar larva migrans which are the most frequent syndromes, but other localizations, as brain, have been reported. Nematoda Cestoda Ascaridida [roundworms] Ankilostomatidae [hookworms] Onchocercidae Trichuridea Strongyloididae Spirurida Taenidae Dilepididae Diphyllobotriidae Trematoda Opisthorchiidae Opisthorchis felineus Wild carnivores Nematodes Ascaridida Toxocara canis, T. cati, Toxascaris leonina Ancylostoma caninum, A. tubaeforme, Uncinaria stenocephala Dirofilaria repens, D. immitis, Onchocerca lupi Trichuris vulpis Strongyloides stercoralis Thelazia callipeda Echinococcus granulosus Taenia [Muticeps] multiceps Dipylidium caninum Diphyllobotrium latum, Diphyllobotrium spp. Spirometra erinaceieuropaei, Spirometra spp. Baylisascaris procionis Cestoda Taenidae Echinococcus multilocularis Trematoda Diplostomatidae Alaria alata Main helminthic zoonotic infections in domestic and wild ungulates Domestic animals Nematoda Ascaridida [roundworms] Trichostringylidae Trichuridea Trichinellidae Ascaris sum [Toxocara canis, T. cati, hosts] Trichostrongylus spp. Trichuris suum Trichinella spiralis, T. britovi, T. pseudospiralis Cestoda Taenidae Taenia saginata, Taenia solium Taenia multiceps [cerebral coenurosis] Trematoda Wild ungulates Fasciolidae Dicrocoelidae Nematodes Trichinellidae Fasciola hepatica Dicrocoelium dendriticum Trichinella spiralis, T. britovi, T. pseudospiralis Many parasites have long life cycles, with one or more intermediate hosts, however, the infective stages for animals and human are the same. Toxocara spp: embryonated eggs in the environment Opisthorchis felineus: metacercariae in flesh of fresh water fish Fasciola hepatica: metarcercariae on vegetables Dicrocoelium dendriticum: ants or part of ants infected by metacercariae Cestoda Taenidae Taenia multiceps [cerebral coenurosis] 2

3 Dipylidium caninum life cycle egg capsule ingestion adult cestodes develop in the intestine of dogs, cats and humans and gravid proglottids are voided in the faeces Anthelmintic drugs Imidazothiazoles Levamisole, Tetramisole Tetrahyropyrimidines Pyrantel, Oxantel, Morantel Benzimidazoles Tiabendazole, Mebendazole, Parbendazole, Oxybendazolo, Cambendazole, Flubendazole, Fenbendazole, Oxfendazole, Triclabendazole, Albendazoloe, Luxabendazole soil contamination role of humans in parasite life cycle parasitic stage disease Pro-benzimidazoles Salicylanilides Febantel, Netobimin Oxyclozanide, Nitroxinil, Rafoxanide, Niclosamide, Closantel Helminth Ancylostoma caninum Ancylostoma tubeforme Ascaris suum Toxocara spp. Strongyloides stercoralis Trichuris vulpis Fasciola epatica Dicrocoelium dendriticum definitive/ definitive definitive definitive adult/ adult adult adult cutaneous larva migrans cutaneous larva migrans ascaridiosis visceral larva migrans strongilidosis trichurosis distomatosis distomatosis Avermectins and Abamectin, Ivermectin, Doramectin, Selamectin, Milbemycin ossime, Moxidectin, Milbemycins Cydectin Compounds belonging to a Sulfonamides Clorsulon different chemical groups Substituted phenols Nitroscanate Isoquinolines Praziquantel Nytrofenoles Disofenolo Cyclooctadepsipeptides Emodepside Amino-acetonitrile derivates Monepantel 3

4 energetic metabolism inibitory neurotransmittes β-tubulin bindig of worm intestinal cells Anthelmintic drugs: mode of action interference on the oxidative phosphorylation ADP- ATP; spastic paralysis: salicylanilides and nitroxynil agonists at synaptic and extrasynaptic nicotinic acetylcholine receptors on nematode muscle cells: imidazothiazoles and tetrahydropyrimidines binding allosterically to irreversibly open the chloride channel leading to a permanent hyperpolarisation of the cells and flaccid paralysis. They may also have effects on other ligand-gated chloride channels such as glutamate-gated and dopamine-gated chloride channels; flaccid paralysis: avermectins and milbemycins binding the acetylcholine-23 nicotinic receptor, specific for nematodes: amino-acetonytrile derivates (AADs) pre-synaptic binding at neuromuscolar junctions [Ca2+-dependent K+ channel]: emodepside inibition of microtubule formation, β-tubulin bindig, and depolarization blocking cell-living process: benzimidazoles and pro-bzd Companion animals: main anthelmintic drugs used for the treatment/control of main zoonotic parasites Active compound levamisole pyrantel fenbendazole febantel ivermectin selamectina milbemycine oxime moxidectin nitroscanate praziquantel emodepside Toxocara Ancylostoma Toxascaris Uncinaria Trichuris Echinococcus Dipylidium Dirofilaria : not advised in red: advised/very effective * larvicidal efficacy; ** larvicidal and adulticidal efficacy against D. repens * * * ** Large animals: main anthelmintic drugs used for the treatment/ control of main zoonotic parasites Broad spectrum efficacy of modern anthelmintic drugs Active compound levamisole pyrantel fenbendazole febantel ivermectin doramectin moxidectin praziquantel clorsulon monepantel Ascaris Trichostrongylidae Trichuris Cestoda Trematoda : not advised in red: advised/very effective BZ and pro-bz: Nematodes [gastrointestinal and broncopulmonar] Cestodes [flat worms] Trematodes Protozoa (Giardia spp.) Macrocyclic lactones: IVM, MLB and MOXI [endectocides] Nematodes (gastrointestinal e broncopulmonary) Insects and mites Both BZs and MLs can be combined with other drugs to expand their efficacy to other groups of parasites 4

5 BZs and pro-bzs Companion animals: pyrantel, BZ and pro-bz, emodepside and praziquantel recommended doses Drug dog cats BZs are drugs that need to be metabolized by the liver to reach their full efficacy. BZs and pro-bzs are mainly recommended in ruminants, where the rumen acts as a reservoir to set out the drug to be metabolized by the liver in compounds. Nevertheless, they are extensively used in companion animals because of the low toxicity and the broad efficacy. pyrantel embonato fenbendazolo febantel emodepside praziquantel 14.4 mg/kg 50 mg/kg 15 mg/kg 1 mg/kg 5 mg/kg 57.5 mg/kg 50 mg/kg 15 mg/kg 3 mg/kg [spot on] 12 mg/kg [spot on] Companion animals: ML recommended dose [safety]/broad efficacy Macrocyclic lactone Dog Cat Active compound combinations to expand the broad efficacy of the anthelmintic products Ivermectin oral 6 mcg/kg Dirofilaria immitis larvae 24 mcg/kg D. immitis larvae, D. repens Toxocara cati,ancylostoma tubaeforme Combinations Trade Marks Active compounds formulation Selamectin topial Milbemycin oxime oral Moxidectin Oral/topical 6mg/kg D immitis larvae, T. canis ectoparasies 0.5mg/kg D immitis larvae, T. canis, T. vulpis, Ancylostomatidae, Angiostrongylus vasorum 2.5 mg/kg D immitis larvae, D repens larvae and adult, T. canis, T. vulpis, Ancylostomatidae, Angiostrongylus, Thelazia fleas and mites [Demodex] 6 mg/kg D immitis larvae, T. cati ectoparasites 2 mgr/kg D immitis larvae, Ancylostomatidae, 1 mg/kg D immitis larvae, D repens larvae, T. cati, Ancylostomatidae fleas and mites Canitel Drontal plus Drontal gatti Profender for dogs Profender for cats Advocate Milbemax pyrantel/praziquantel febantel/pyrantel/praziquantel pyrante/praziquantel emodepside/praziquantel emodespide/praziquantel moxidectin/imidacloprid milbemycine oxime/praziquantel tablets flavored tablets tablets flavored tablets spot-on spot-on flavored tablets 5

6 mange clinical score mite density mange clinical score mite density Where possible, it is advisable to use drugs with a single target [diagnosis specific medicinal] or single drugs with a broad spectum of efficay [1 medicinal 1 toxicity: less dispersion of compounds in the environment, less risk of resistance] The pharmacokinetics and the availability of a drug to the target [parasite] are biased by clinical conditions of the host. 55,0 50,0 45,0 40,0 4,5 4 3,5 55,0 50,0 45,0 40,0 4,5 4 3,5 Examples: praziquantel: cestoda [Echinoccoccus spp] milbemycine oxime: heartworm prevention, ascardia, ancylostomatidae and Trichuris selamectin: heartworm prevention, ascaridia, ancylostomatidae, fleas, lice, sarcoptes and otodectes mange ivermectin concentration ng/ml 35,0 30,0 25,0 20,0 15,0 10,0 5,0 0,0 0 0,25 0, days 3 2,5 2 1,5 1 0,5 0 Relationship between ivermectin kinetics, mange scores ( ) and density mites scores ( ) ivermectin concentration ng/ml 35,0 30,0 25,0 20,0 15,0 10,0 5,0 0,0 0 0,25 0, days 3 2,5 2 1,5 1 0,5 0 Companion animals must be free of parasites [endoand ectoparasites] Companion animals must be free of parasites [endoand ectoparasites] They share the same environment with humans They have frequent and sometime strict contact with people with a less effective immune response such as children, pregnant women, ill individuals or with immunodeficiency Puppies: Toxocara canis starting from 2 weeks of age, then fortnightly until two weeks and monthly or 45 days to six months Kittens: Toxocara cati, the same regimen starting from 3 weeks of age, and then fortnightly until after weaning To minimize the risk of parasitic zoonotic infections, the adult animals should be treated at least four time a year against helminth infections with a broad spectrum efficacy anthelmintic¹ or, examined for parasites, and in case treated. ¹ To note, that even with this treatment regimen, it is not possible to exclude that the animal could have helminth eggs in its feces Sager et al, 2006 Parasitol Res 98:

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