Transcript Worms
Anthelmintics Or ‘Why I like drugs” Nick Sangster Faculty of Veterinary Science University of Sydney Worms Objectives • Understand the need and market for anthelmintic drugs • Describe the features of the major anthelmintic groups • Explain spectrum of activity Antiparasitic drugs • Anthelmintics – helminths, worms • Antiprotozoals – Protozoa • Ectoparasiticides – insects and acarines Actions and use differ, but the same principles apply to control and registration Internet Resources • • • • www.sheepwormcontrol.com Vich.eudra.org www.apvma.gov.au http://www.worminfo.org/decision_analysis /tropical_worm_world/ What are anthelmintics? • Anti helminth drugs • Act to kill/remove/control – Nemathelminthes (roundworms) – Platyhelminthes (flatworms) • Used widely in animal and human health • A range of chemical types with different actions and efficacy. Why know about anthelmintics? • Dispel the myth ‘but they have a drug for that’ • Know how to read and understand the label • Know enough to make usage decisions in the face of: – Drug resistance (when drugs stop working) – Off label use (to use in an animal outside registration) • Antiparasitics major part of market • This sector employs a lot of vets The world animal product market 1996 $M USD Livestock Companion Parasiticides Performance Antimicrobial Other pharms Biologicals 1403 310 1705 795 1585 1295 355 585 610 % Australian market Ectoparasiticides Anthelmintics Vaccines Vitamins Antibacterials Coccidiostats Others Challenges in anthelmintic discovery • Kill (or remove) worms in a single dose • Cannot target cell division • Parasite phylogenetically close to the host e.g. – some of the same neurotransmitters, – same ribosomal machinery • There are some very good drugs on the market Discovery and dose rates 1000 dose rate mg/kg Phenothiazine 100 10 Thiabendazole Levamisole 1 Ivermectin 0.1 1920 1940 1960 1980 Year 2000 2020 Requirements of anthelmintics • Effective, safe, non toxic to consumer. • Narrow spectrum, broad spectrum • Stock Medicines Act 1989 and vets – Anyone can give stock medicines to non-food producing animals (we eat horses!) – Only vets can vary label directions in food producers but MUST supply (in writing) species, withholding, dose rate, frequency of treatment, manner of administration. – No one can use an unregistered stock medicine except under permit or order Aspects of commercial anthelmintics • • • • • • • Establishing a need/market Research Screening Refinement Development Marketing Technical support Anthelmintic modes of action Class example MOA Benzimidazoles Albendazole Tubulin binding and cellular disruption Tetrahydropyrimidine Levamisole Nicotinic-like agonists Organophosphates Dichorvos Acetylcholine esterase inhibitors Piperazines Piperazine GABA agonists Macrocyclic lactones Ivermectin GluCl- potentiators Praziquantel Enhance Ca++ permeability Closantel Proton ionophores Salicylanilides Benzimidazoles • Many members such as fenbendazole and albendazole • Effective against nematodes (adults and larvae) and some flukes • Given as oral liquids to all hosts • Act by binding to tubulin leading to loss of cell transport and shape • (Triclabendazole- flukicide) Levamisole • Levamisole and pyrantel • Effective against nematodes • Given as an oral liquid (levamisole-sheep; pyranteldogs) • Act on Acetylcholine receptors of worms to cause paralysis Piperazine • Tablet of liquid for dogs • Used for roundworm control • Acts like GABA to relax body muscle and paralyse worms Macrocyclic lactones • Ivermectin, moxidectin etc. • Broadspectrum including ectoparasites • Oral, injection or backline • Act on GluCl- channels to cause paralysis of pharynx and body muscle Salicylanilides • Closantel • Blood sucking parasites (Haemonchus and Fasciola) • Oral for sheep • Uncouples energy generation in worm mitochondria Spectrum of activity + + + + + + + + + + + + + + + + +a + +/- Dirofilaria microfilariae + + + + + + Dirofilaria larvae +/+ Trichuris + + Dirofilaria adults 80-100 14 (56 in cats) 15 25 20 (3-5 days) 22 50 (3d) 5 or 10 50 2 bid, 2d. IV IM 2.2 bid, 2d. IV 10 0.5 0.006 0.05 0.003 6 6 5 or b 100 Lungworms piperazine tetrahydropyrimidine tetrahydropyrimidine pro-benzimidazole benzimidazole benzimidazole benzimidazole Imidothiazole Isothiocyanate Arsenical Arsenical Arsenical piperazine macrocyclic lactone macrocyclic lactone macrocyclic lactone macrocyclic lactone macrocyclic lactone macrocyclic lactone Ancylostoma Piperazine Pyrantel Oxantel Febantel Mebendazole Flubendazole *Fenbendazole Levamisole Nitroscanate Arsenamide Melarsomine Thiacetarsamide Diethylcarbamazine Milbemycin oxime Ivermectin *Ivermectin Moxidectin Selamectin (dogs) Selamectin (cats) Praziquantel Niclosamide Ascaridoids DOSE (mg/kg) Echinococcus chemical class Taenia COMPOUND Dipylidium Anthelmintics for dogs and cats + + + + + + + + + + + + + + + + + + + + + a, for Aelurostrongylus in cats; b, 20 mg/kg for Spirometra; * off label use; check all labels and dose rates before use. + New chemicals on the horizon • Bay 44-4400 – Novel mode of action – GI nematodes at 1 mg/kg • 2-deoxyParaherquamide – Cholinergic antagonist (novel action) – GI nematodes – Sheep industry product?