353

Index

a amitraz 97, 98, 100, 101, 152, 171, 172, 176, abametapir‐based formulation 130 178, 179, 232, 308 absorption, distribution, and Anaplasma phagocytophilum 44, 276, 309 excretion (ADME) 263, 274, 280–282 ancestral ticks 25, 32 acaricide classes 96, 98, 101, 110, 116 animal ectoparasiticide products 8 acaricide resistance 101, 102, 110–112, animal vector‐transmitted pathogens 64–74 115, 116 resistance 7, 13, 14 acetylcholine (AChE) 97 drugs 12, 15–16, 151, 245, acetylcholinesterase 100, 114, 121 254, 260 active pharmaceutical ingredient (API) 13, anti‐tick vaccines 143, 144, 156, 157, 16, 274, 321 195, 211 adult immersion test (AIT) 111–112 aquaporins 30, 145 afoxolaner arsenicals 97 –– chemical‐biological structure‐activity Argasidae 25, 60, 61, 81, 86, 141, 144 relationships 261–266 arthropod ectoparasites 245–246 –– distribution and clearance in artificial feeding systems (AFSs) dogs 282–284 –– blood meal 189–190 –– dose level selection 277–279 –– components 188–191 –– flea control 259 –– ectoparasiticide drug discovery 197–198 –– formulation selection 279–280 –– fleas 191 –– mode of action 266–270 –– flies 196 –– naphthalene chemistry 260 –– hematophagous hemiptera 196–197 ® –– NexGard 235 –– insect laboratory cultures 188 –– oral in dogs 280–282 –– lice 196 –– plasma concentration 198, 277–279, –– membranes 188–189 281–283, 291 –– methods and applications 191–196 –– proof of concept in dogs 277 –– mites 196–197 –– protein binding 283 –– mosquitoes 195–196 –– safety in dogs 284–285 –– temperature control systems 190–191 –– safety pharmacology profile 284 –– ticks 191–195 –– study compliance with regulatory ATP‐binding cassette (ABC) requirements 275–276 transporter 126, 152 –– topical and oral treatment 259 agricultural pests 7, 18, 183 b agrochemical pesticide development 15 Babesia spp. 276 Amblyomma hebraeum voraxin 145 babesiosis 6 Amblyomma maculatum 297 Bayer Animal Health 10, 16

Ectoparasites: Drug Discovery Against Moving Targets, First Edition. Edited by Charles Q. Meng and Ann E. Sluder © 2018 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2018 by Wiley-VCH Verlag GmbH & Co. KGaA.

bindex.indd 353 5/3/2018 2:48:08 PM 354 Index

bedbugs 216–217 concealed antigens 26, 28, 35, 144, 156 benzyl alcohol‐containing formulations 128 Ctenocephalides felis 189, 215, 231, 245, bioassays 251, 263, 276, 296, 333 –– adult immersion test 111 current Good Manufacturing Process –– ectoparasiticide discovery 111 (cGMP) 275 –– larval immersion test (LIT) 112–113 cysteine‐loop ligand‐gated chloride channels –– larval packet test (LPT) 112 (CysLGCCs) 247 –– larval tarsal test (LTT) 113–114 cytochrome P450 monooxygenases 123, biochemical tools 114 126 Biopharmaceutics Classification System (BCS) 281 d blood coagulation processes 32 demodicosis 288, 289, 307 blood‐feeding ectoparasites 43 Dermacentor variabilis 6, 30, 63, 85, 154, body louse prevalence 6 177–179, 213, 269, 277, 297 Boophilus yolk pro‐cathepsin D (BYC) 154 –– vs. afoxolaner plasma concentration 279 Borrelia burgdorferi 5, 6, 25, 44, 58, 66, 86, dieldrin 97, 100, 246–247, 254, 270, 298 276, 289, 290, 306, 309, 310, 312 dieldrin‐resistant 198, 249 Borrelia duttoni 61, 86 diethylmaleate (DEM) 99 bradykinin 35, 36 dimethicone‐based formulations 128–129 ® Bravecto 16, 235, 248, 255, 256, 5,5ʹ‐dimethyl‐2,2ʹ‐bipyridyl 130 310–312, 321 dimeticone‐based anti‐louse product 129 Dipylidium caninum 4, 44, 74, 276 c divalent metal‐transporter 1 (DMT1) 151, carbamates 8, 97, 121, 175, 176, 179, 184, 155 232 dog adult flea model 230 carbaryl 97, 121, 184 98, 237 carboxylesterases 114, 126, 131 dose confirmation carrier proteins (CPs) 151, 153 –– additional efficacy studies 288–290 cat fleas 52, 174, 189, 191, 207, 215, 216, –– field trials 287–288 231, 232, 260, 261, 263, 269, 276, 296, –– fleas 285–287 322, 333 –– ticks 287 cathepsin B (CatB) 148–150 drug sensitivity status, of tick populations cathepsin C (CatC) 147–149 –– acaricide resistance 110–111 cathepsin D (CatD) 147, 148, 154 –– adult immersion test (AIT) 111–112 cathepsin L (CatL) 148, 151 –– biochemical tools 114 cattle ticks –– larval immersion test (LIT) 112–113 –– arsenicals 97 –– larval packet test (LPT) 112 –– carbamates 97 –– larval tarsal test (LTT) 113–114 –– formamidines 97–98 –– molecular tools 114–115 –– growth regulators 98–99 –– resistance bioassays 115–116 –– Rhipicephalus (Boophilus) microplus 95 –– resistance management 116 –– macrocyclic lactones 98 Drugs for Neglected Diseases Initiative –– natural products 99 (DNDi) 16 –– organochlorine 97 –– organophosphates (OP) 97 e –– phenylpyrazoles 98 ectoparasite and endoparasite control –– resistance management 100–103 –– adult flea infestation 5 –– resistance mechanisms of 99–100 –– advantage 167–168 –– synthetic pyrethroids 98 –– approaches for 4–7 central nervous system (CNS) 247, 284 –– assay implementation 171–172 chloride channels 249–252, 254, 256 –– body louse prevalence 6 chlorpyrifos 173, 175 –– canine and feline heartworm prevention 7 Companion Animal Parasite Council –– ectoparasite challenges 10–12 (CAPC) 5 –– ectoparasiticides 7–9

bindex.indd 354 5/3/2018 2:48:08 PM Index 355

–– endoparasite challenges 12–14 –– flow charts 224 –– endoparasiticides 9–10 –– host animal models 230 –– energy balance 5 –– laboratory animal models 229 –– flow charts 168 –– pre‐clinical development studies 226 –– fly repellents 5 –– product characteristics 237–229 –– heartworm larvae 7 –– role of animal models 223–227 –– host physiology 167 ectoparasiticide products –– limitations 167–168 –– companion animals –– livestock 237 –– control collars for 232–233 –– macrocyclic lactone (ML)‐based –– macrocyclic lactone (ML) 236 anthelmintic 7 –– oral administration 233–236 –– malaria deaths 6 –– topical administration 230–232 –– new antiparasitic drugs 15–16 –– control of livestock –– of horses 5 ectoparasites 236–237 –– parasite lifecycle 5 Ehrilichia spp. 276 ® –– prevention and control 16–18 Elimax lotion 130 ® –– primary ectoparasites of horses 5 Elimax shampoo 130, 131 –– principles 170 endoparasiticides 9–10, 256 –– prophylaxis 4 epiparasites 3 –– Rocky Mountain spotted fever 6 esterases 97, 99, 114, 123, 126 –– scabies and head lice 6 European Medicines Agency –– screen execution 171 (EMEA) 16, 255 –– tick‐borne diseases 5 exploratory dose characterization –– ticks 6 studies 277 ® –– tungiasis 6 Exspot 230, 233 –– viral diseases 6 –– whole organism ectoparasite assays 172 f ® ectoparasite efficacy model 224 Famacha 14 ectoparasite infestation 5, 6, 9, 11, 207–209, FAO Working Group on Parasite Resistance 224, 232, 235 (WGPR) 111 ectoparasite models 209–211, 216–218 farm animal vector‐transmitted ectoparasite vaccines 12 pathogens 75 ectoparasiticide discovery and development ferritin 1 (Fer1) 155 –– afoxolaner 259 ferritin 2 (Fer2) 156 –– artificial feeding system (AFS) 197–198 ferritins 29–30, 155, 156 –– control 7–9 fipronil 9, 98, 100, 101, 113, 171, 172, –– laboratory animal models testing 174, 175, 180, 182, 184, 194, 198, 213, –– animal and human health 206 215, 216, 228, 229, 231, 232, 246–255, –– bedbugs 216–217 259, 269, 270, 284, 306, 307, 320, –– chemistry optimization 206 326, 327 –– ectoparasite infestation 207–209 flea allergic dermatitis (FAD) 233, 234, –– flea models 215–216 305–307 –– flying insects 217–218 fleas –– lice 217 –– artificial feeding systems 191 –– mange mites 218 –– contact assay 174–175 –– principal features of 210 –– dose confirmation 285–287 –– tick models 211–215 –– ectoparasiticide 214–215 –– sarolaner discovery 296–299 –– efficacy 299–300 –– target hosts testing –– egg/larval assays 176–177 –– alignment of animal model –– ingestion assay 175–176 assays 227–229 –– models 215–216 –– discovery campaign 224 –– species 276 –– ectoparasiticide products 230 –– speed of kill 303–304 –– extension to human conditions 237–238 –– topical and oral products 310–312

bindex.indd 355 5/3/2018 2:48:08 PM 356 Index

fluazuron 98, 99, 101 host inflammatory and immune fluid‐phase endocytosis (FPE) 143, 147 responses 35–37 flubendiamide 319, 326 host interface 31 fluralaner 198, 235, 248, 249, 251, 252, 254, human head and body lice 255, 295, 297, 310, 312–315, 319, 321, 322, –– abametapir‐based formulation 130 324, 325, 330, 332, 339 –– benzyl alcohol‐containing fluxametamide 322, 333 formulations 128 fly repellents 5 –– dimethicone‐based formamidines 97–98 formulations 128–129 fully engorged female ticks 26, 27, 30, 33, 35 –– in vitro rearing system 122 –– in vitro louse rearing system 120 g –– ‐based formulations 129–130 GABA‐gated chloride channels (GABA‐Cls) –– kdr‐type resistance allele 124 9, 100, 259, 267, 269, 270, 284, 298, 320 –– living and feeding behaviors 120 γ‐aminobutyric acid‐gated chloride –– malathion resistance 126 channels (GABA-Cls) 247, 251, 252, –– metabolic synergists 131 254, 255 –– noninvasive induction assay 126–127 ® Gavac 27 –– pediculosis 120–121 glutathione S‐transferase (GST) –– repellents/deterrents and odorant receptor –– esterases 99, 123 discovery 130 –– ticks 152–153 –– sequencing 123 greyhound 191, 192, 197, 198, 283 –– spinosad‐based formulation 130 growth regulators 98–99 –– sustainable resistance management 131 –– transcriptomes 123 h human vector‐transmitted pathogens 46–63 hard ticks 25, 45, 55, 63, 64, 75, 81, 85, 86, hydroxylated afoxolaner 283 141, 142, 144, 145, 191 hyperparasitism 3 head lice infestations 11 ® HeartGard Plus 280 i heartworm larvae 7 insect growth regulators (IGRs) 170 –– prevention 7 insecticide resistance 7, 8, 121–124, 126, ® Hedrin 128 132, 174 helminth infections 4, 6 Insecticide Resistance Action Committee hematophagous arthropods (IRAC) 8, 174 –– blood meal 189–190 Institutional Animal Care and Use –– components 188 Committee (IACUC) 276, 296 –– ectoparasiticide drug discovery 197–198 integrated parasite management (IPM) 17 –– flies 196 interleukin‐2 production 37 –– fleas 191 international nonproprietary names –– hematophagous hemiptera 196–197 (INNs) 248 –– insect laboratory cultures 188 in vitro feeding methods –– mites 196 –– artificial feeding methods and –– mosquitoes 195–196 applications 191–196 –– temperature control systems 190–191 –– blood meal 189–190 –– ticks 191–195 –– in ectoparasiticide drug heme‐binding vitellogenin 153 discovery 197–198 heme detoxification –– hematophagous hemiptera 196–197 –– by heme 147 –– membranes 188–189 –– hemosomes formation 150 –– temperature control systems 190–191 –– intracellular transport 150–153 in vitro rearing system 120, 122 –– ticks 152 iron responsive element (IRE) 156 hemoglobinase 148 isoxazoline‐containing products 280 Hemotek system 195, 196 isoxazolines histamine 36 –– agrochemical applications 321–322

bindex.indd 356 5/3/2018 2:48:08 PM Index 357

–– antiparasitic agents 255 larval tarsal test (LTT) 113–114 –– binding site 251 Lepeophtheirus salmonis 322 –– companion animal applications 321 lice –– derived parasiticides 248 –– abametapir‐based formulation 130 –– GABACls and GluCls 247 –– allele frequency 124–125 –– mode of action 251, 320 –– benzyl alcohol‐containing –– origins 319 formulations 126 –– patent literature 327–329 –– dimethicone‐based –– physicochemical properties 325–327 formulations 126–127 –– production animal applications 322 –– ectoparasiticide 217 –– sarolaner 255 –– human louse genomes and –– selectivity and safety profile 254 transcriptomes 123–124 –– structural variations –– in vitro feeding 196 –– active amide substitution –– ivermectin‐based formulations 129–130 pattern 333–336 –– maintenance of insecticide –– amido‐substitution 333 susceptible 122–123 –– aromatic backbone 330–332 –– malathion carboxylesterase (MCE) 126 –– biologically active amides 332–333 –– metabolic synergists 131 –– core of 336–341 –– noninvasive induction assay 126–127 –– fused‐ring derivatives 342 –– pediculicides and resistance 121–122 –– geminal relationship 329–330 –– pediculosis and medical importance –– ketones 335 of 120–121 –– opening ring 342 –– pyrethrins 124 –– synthesis 323–325 –– pyrethroids 124 ivermectin 7, 9, 16, 98, 113, 126, 127, –– repellents/deterrents and odorant receptor 129–130, 171, 174, 180, 194, 197, 198, discovery 130–131 213, 215, 216, 229, 236, 237, 247, 250, –– spinosad‐based formulation 130 253, 256 –– sustainable resistance ivermectin‐based formulations 129–130 management 131–132 Ixodes dammini 35, 146 ligand‐gated chloride channels Ixodes ricinus (LGCCs) 246–248, 250, 251, 255, 269 –– artificial membrane feeding 155 living fossil tick 145 –– cathepsin B (CatB) 149 longistatin 34 ® –– cathepsin C (CatC) 149 LongRange 16 –– cathepsin D (CatD) 148 lotilaner 255, 321, 322, 324, 330 –– cathepsin L (CatL) 148 Lyme disease 6 –– ferritin 1 (Fer1) 155 –– cp3 ortholog 153 m –– type 2 transferrins (Tf2) 156 macrocyclic lactones (MLs) 7, 13, 96, 98, Ixodes scapularis 6, 29, 44, 142, 194, 277, 297 110, 129, 130, 171, 175, 176, 180, 184, 229, Ixodidae 25, 32, 45, 55, 60, 64, 75, 81, 141, 233, 236, 247, 250 144 macroparasites 3 ixodid ticks 25, 29, 30, 189, 193–195, 198, malaria 6, 46, 142, 148, 150, 152 199, 211 malaria‐causing Plasmodium 142 ixophilin 34 malathion 9, 121, 124, 126, 132 malathion carboxylesterase (MCE) 126 k malathion‐containing formulations 121, 128 kdr‐type resistance allele 124 malathion resistance 121, 126 keyhole limpet hemocyanin (KLH) 29 mange mites 218, 230, 255, 288, 290 knockdown resistance (kdr) 6, 124 Mectizan Donation Program 16 metabolic synergists 124, 128, 131 l metaflumizone 232 larval immersion test (LIT) 112–113 metalloprotease (Metis1) 33, 36, 130 larval packet test (LPT) 112 Metarhizium anisopliae 103

bindex.indd 357 5/3/2018 2:48:08 PM 358 Index

microparasites 3 peptidase inhibitor (OmC2) 36 oxime 98, 234, 235, 256, permethrin 87, 100, 121, 124, 125, 129, 274–276, 290, 308, 310–312 131, 132, 174, 175, 180, 182, 184, 213, mite assays 180–181 230–231, 313 molecular tools 28, 114–115 persistent, bioaccumulative and toxic (PBT) mosquitoes substance 16 –– artificial feeding system 195–196 PF1022A 10 –– mosquito larval assay (MLA) 172 p‐glycoprotein 284, 285 multiple‐dose afoxolaner kinetics 282 3‐phenoxybenzyl hexanoate (PBH) 131 phenylpyrazoles 98, 110, 246, 247, 255, 270 n PhumOR2 131 ® Natroba 130 piperonyl butoxide (PBO) 99, 131 natural products 96, 99, 216 platelet activation 33 ® ® NexGard 274 Proban 214, 230, 233 ® NexGard Spectra 256, 274, 275, 281, produce recombinant Bm86 protein 27 ® 290–291 Profender 10 ® nicotinic acetylcholine receptors ProHeart 16 ® (nAChRs) 9, 130, 267 ProSpot 230, 233 ® ® Nix 122, 125 Proto Plus 122 noninvasive induction assay 126–127 pyrethroids 5, 8, 9, 87, 96, 98, 100, 110, 115, N‐tert‐butyl nodulisporamide 229, 234 121, 124, 125, 130, 131, 146, 168, 171, 175, nutraceuticals 17 179, 184, 230 Nuttalliella namaqua 141, 145 pyridine isoxazoline 266 ® NYDA 129 q o quantitative sequencing (QS) 125 odorant receptor co‐receptor (Orco) 131 odorant receptors (ORs) 131 r open ring isoxazoline replacements 343 rapid engorgement, ticks 145 optimal flea control program 276 R. appendiculatus serine protease inhibitors oral ectoparasiticides 9, 295 RAS 1–4 35 oral pharmacokinetics 280–282 refugia‐based approach 14 Ornithodoros 61, 86 resistance bioassays 115–116 Ornithodoros turicata 235, 296 Rhipicephalus appendiculatus 30, 79, organochlorine (OC) 97, 110, 121 145, 190 organophosphates (OP) 8, 96, 97, Rhipicephalus (Boophilus) 110, 171, 173, 175, 179, 184, 230, 232, microplus 11, 95–103, 109, 142, 211, 291 233 Rhipicephalus sanguineus 29, 65, 87, 211, Otodectes cynotis 236, 289, 308 277, 278, 297, 333 Otodectic mange 308 ribosomal P0 antigen 29 ® Ovide 121, 122, 132 Rickettsia felis 52, 276 Rickettsia spp. 276 p Rickettsia typhi 276 ® parasiticidal isoxazolines 321, 323–325, Rid 122 328, 344 RmAQP1 30, 145 parasiticide 12, 14, 197, 247, 249, 250, 253, Rocky Mountain spotted fever 6, 56 290, 296, 323, 324 roundworms 4, 18, 274 parasitiformes 25, 320 Rutledge feeding system 192, 195 parasitism 3, 17 pediculicides 9, 120–122, 124, 125, 128, s 131, 132 salivary gland extracts (SGE) 35 pediculosis 9, 120–122, 124, 125, 128, salivary gland serine protease inhibitor 131, 132 (IRIS) 37

bindex.indd 358 5/3/2018 2:48:08 PM Index 359

Sarcoptes scabiei 236, 289 t Sarcoptes scabiei var. canis 308 tannin‐rich plants (TRP) 18 sarolaner tick‐borne diseases 5, 9, 88, 96, 109, 157, –– commercialization of 315 304, 310, 313, 314 –– discovery 296–298 tick‐borne encephalitis (TBE) 6, 25, 256 –– environmental flea control 303–304 tick control 9, 96, 97, 99, 101, 103, 109, 110, –– flea and tick field studies 304–307 116, 142, 259, 266, 267, 269, 276, 279, 288, –– flea control 303 298, 310, 319, 321, 344 ® –– flea efficacy 299–300 TickGARD 27 ® –– dose confirmation 299 TickGARDPlus 27 –– topical and oral products 310–312 tick histamine releasing factor (tHRF) 36 –– flea speed of kill 303–304 ticks –– in vitro activity 297 –– artificial feeding systems 191 –– laboratory studies 299 –– blood digestion, guts –– mechanism of action and pharmacology –– asparaginyl endopeptidases 148 of 298 –– blood‐filled midgut lumen 146 –– mite efficacy –– cathepsin B (CatB) 149 –– demodicosis 307–308 –– cathepsin C (CatC) 149 –– Otodectes cynotis infestations, dogs 308 –– cathepsin L (CatL) 149 –– Sarcoptes scabiei infestations, –– chitinase 146 dogs 308–309 –– heterophagy 147 –– screening strategy 296 –– intracellular transport and –– structure of 296 degradation 147 –– tick‐borne disease transmission, –– leucine aminopeptidase 150 prevention of 309–310 –– molecular identification and –– tick efficacy 300–303 targeting 148 –– tick speed of kill 304, 312–315 –– nomenclature of 146 scabies and head lice 6 –– physiological processes 143 scaffold‐hopping 337 –– serine carboxypeptidase 150 ® Scalibor 9 –– blood‐feeding lifestyle 141 ® Seresto 9, 233 –– blood meal processing 142 serial invasive signal amplification (SISAR) –– blood meal uptake and digestion 144 technique 124 –– cell biology 29 serine protease inhibitor (AAS19) 32–35, 37 –– commercially available vaccines 26–27 Sigmoidal Emax model 277 –– development 30 ® silicone‐reinforced Parafilm –– ectoparasiticide membrane 122 –– Ixodes holocyclus 211 ® Simparica 16, 255, 256, 295–315, 321 –– rabbits 211 ® Sklice 129, 130, 237 –– rodents 212 slow feeding period, ticks 144 –– embryogenesis and fertility 154 softbacked ticks 86 –– evolution and life cycle 25, 26 soft ticks 25, 31, 34, 36, 60, 61, 81, 86, 88, –– gerbils 213, 215 141, 142, 145, 146, 150, 155, 188, 191, 235, –– hard 141 296, 297 –– heme detoxification 150 speed of kill 44, 88, 172, 224, 227, 231, –– host inflammatory and immune 303–305, 310–315 responses 35, 37 spinosad 9, 99, 130, 176, 180, 181, 183, 184, –– host interface 31 217, 234, 235, 259, 305, 306, 310–312 –– infectious diseases 141 spiroazetidinebenzofuran 296 –– inter‐tissue transport of heme 153 stable fly contact assay 181–182 –– intracellular transport 150 subolesin/akirin 29 –– iron acquisition and metabolism 155 synthetic pyrethroids (SP) 8, 87, 96, 98, 110, –– mating factors 145 115, 121 –– metalloproteases 33

bindex.indd 359 5/3/2018 2:48:08 PM 360 Index

ticks (contd.) veterinary ectoparasites 7 –– on‐host feeding 144 viral diseases 6 –– physiology 29 vitellogenin degrading cysteine –– reproduction 30–31 endopeptidase (VTDCE) 154 –– secretion of blood meal water 145 vitellogenin receptor (VgR) 151, 154 –– soft 141 voltage‐sensitive sodium channel Triatoma infestan 190 (VSSC) 121 Trichodectes canis 4 triphenyl phosphate (TPP) 99 w tungiasis 6, 9 whole organism ectoparasite assays type 2 transferrins (Tf2) 156 –– agricultural chemicals 183 –– flea u –– contact assay 174 ® Ulesfia 128 –– egg/larval assays 176 –– ingestion assay 175 v –– mosquito larval assay 172 vector‐borne diseases –– mite assays 180 –– drug profile 86–87 –– stable fly contact assay 181 –– transmission time 45–86 –– tick –– transmitted pathogens 45–46, 86 –– contact assay 177 very persistent and very bioaccumulative –– ingestion assay 180 (vPvB) substance 16

bindex.indd 360 5/3/2018 2:48:08 PM