Chemotherapeutics for control and treatment of ectoparasites in companion animals.
The major arthropod parasites causing severe clinical infestations in canines include fleas (Ctenocephalides canis, Ctenocephalides felis felis), lice (Trichodectes canis, Linognathus setosus, Heterodoxus spiniger), mosquitoes (Aedes, Culex), flies (sand fly, Stomoxys, Haematobia) ticks (Rhipicephalus, Ixodes, Amblyomma, Haemaphysalis, Dermacentor) and mites (Demodex canis, Sarcoptes scabiei canis). The ectoparasites of pets can be divided in two groups: the ones that induce disease and the other that act as vectors of pathogens. In the first group, various mites such as Demodex, Otodectes, Notoedres and Sarcoptes are present for which there is no need for a long-lasting protection as treatment is done mostly after confirmatory diagnosis by skin scraping examination. Fleas, sand flies, mosquitoes and ticks are in the second group which may induce clinical signs such as itching, hair loss, allergy dermatitis, anaemia and also represent a major threat as vectors for various infectious agents viz. Ehrlichia canis (canine monocytic ehrlichiosis), Anaplasma phagocytophilum (canine granulocytic ehrlichiosis), Borrelia burgdorferi (Lyme disease), Hepatozoon canis (Hepatozoonosis), Babesia canis (canine babesiosis), Babesia gibsoni (canine babesiosis), Dirofilaria immitis (Heartworm disease), Leishmania tropica (canine leishmaniosis) and Dipylidium caninum (intermediate host) (Soulsby, 1982). The control measures against these are based on both curative and preventive requiring long-acting formulations.
Presently the most commonly used strategy for control of canine ectoparasites involves occasional or regular use of external antiparasitic drugs which represent 75 percent of all antiparasitic drugs used in dogs (Vetnosis, 2008). In addition to molecules and their modes of action, it is important to consider formulations that will either facilitate application of products, which is case for spot-ons, palatable tablets and collars or modify the pharmacokinetics to increase the long-acting effect of these products. The objectives of this review are to show the innovations in both active ingredients and also in the formulations to improve prevention of ectoparasitosis in dogs.
Insecticides-acaricides used in dogs
Old chemical groups have been succeeded by phenylpyrazoles, neonicotinoids, oxadiazines, spinosyns along with insect and mite growth inhibitors (IGRs). The main chemical groups and their properties are as follows:
The most frequently used cyclodiene organochlorine on animals was Lindane, isolated in 1912 and used on animals beginning in 1943, although it is now banned in most countries of world. Organochlorines exert an inhibitory action on [gamma]-aminobutyric acid (GABA) and/or a stimulating action on opening of [Na.sup.+] channels located on nerve cell membrane. They have a broad spectrum of activity on arthropods but were not free from toxicity and persist in environment, milk, meat and are retained in fat of vertebrates.
Organophosphates exhibit an anticholinesterase activity which results in acetylcholine accumulation in synapses thus exerting a postsynaptic stimulating action causing hyperactivity and death in arthropods. Apart from particular formulations (such as collars), they do not have a long residual action (a few days) and are hydrolyzed rather rapidly in environment. The molecules belonging to this group are numerous as well as formulations, in solutions, sprays, powders, spot-ons and collars form are available in global veterinary health market. The most widely used molecules in pets are: coumaphos, cythioate, diazinon or dimpylate, dichlorvos, fenitrothion and fenthion (Agbolade et al., 2008).
Carbamates are esters of carbamic acid and classified as methyl or dimethyl carbamates and inhibit acetylcholinesterase. Except for collars, they are not long acting (2-4 days) and are neither retained in animal tissue nor environment and have low toxicity as they are rapidly hydrolyzed. Carbamates exhibit mainly insecticidal action and in Veterinary medicine, they are mainly used in form of collars or powders. The most frequently used are: bendiocarb, carbaryl and propoxur.
Amitraz is a formamidine that is selective towards acarians and has been used to control ticks and mites. It binds to octopamine receptors leading to stimulation of monoamine oxidases (adenylate cyclase activity) and G protein. Amitraz is used on dogs to control ticks (Rhipicephalus, Dermacentor, Ixodes, Haemaphysalis, Amblyomma) or to treat mite infections such as demodicosis (Demodex canis) or sarcoptic mange (Sarcoptes scabiei var. canis). A synergistic combination of amitraz with other insecticide/acaricide such as fipronil, would further significantly reduce risk of ticks transmitting pathogenic agents (Pfister, 2011). Currently, it is used in form of collars to prevent tick infestations, as lotions to treat demodicosis, and as spot-on solutions in combination with other drugs (metaflumizone or fipronil) to treat and prevent flea and tick infestations (Prullage et al., 2011).
Pyrethrins and pyrethroids
Natural pyrethrins are compounds extracted from flower heads of pyrethrum and are esters of chrysanthemic acid and pyrethric acid. Modifications to chrysanthemic acid led to introduction of the synthetic pyrethrins or pyrethroids viz. allethrin, bioallethrin, tetramethrin, phenothrin, resmethrin, bioresmethrin, kadethrin, permethrin, cypermethrin, fenvalerate, deltamethrin and flumethrin. They act by contact with insects and mites by opening of sodium channels, inducing nerve cell membrane depolarization. The rapid action on cerebral ganglia of insects results in a sudden shock of insects, known as 'knock-down' effect which can lead to death (Sharma et al., 2012). The spectrum of activity varies upon molecules as permethrin and deltamethrin are both insecticides and acaricides, whereas flumethrin is mainly an acaricide. Pyrethroids are applied on dogs in form of sprays, shampoos, lotions, collars or spot-ons. They are also used in environment, sometimes combined with insect growth regulators in form of sprays, diffusers and solutions. Pyrethroids are mainly used to prevent flea and tick infestation, but also to repel flying insects, especially sand flies, mosquitoes, and biting flies (Anadon et al., 2009).
Neonicotinoids (or chloronicotinyl guanidines)
Neonicotinoids act like agonists on post synaptic nicotinic acetylcholine receptors, mainly in motor neurons, inducing nerve membrane depolarization causing spastic paralysis in insects. Imidacloprid is used in dogs as spot-on formulation and its residual activity on the coats lasts approximately 1 month. To broaden its spectrum of activity, imidacloprid is now combined in formulations with moxidectin, ivermectin, permethrin and/or pyriproxyfen (Dryden et al., 2006). Nitenpyram has the same mode of action but it is a systemic insecticide and is administered orally as a tablet in dogs (Dobson et al., 2000). While feeding on blood, fleas ingest nitenpyram and die within the next 15-30 min. Dinotefuran acts through contact similar to imidacloprid. It has similar pharmacological properties and is hence used in form of spot-ons with long-lasting action. In dogs, its spectrum is broadened to include ticks and immature stages of fleas with the combination of permethrin and pyriproxyfen. Nitenpyram and dinotefuran are used to control flea infestation (Murphy et al., 2009).
Fipronil acts by binding to GABA and glutamate receptors which inhibits opening of the chloride ion channels and consequently leads to neuronal hyperactivity and inhibition of depolarization. The spectrum of activity includes insects as well as acarians. This molecule is photostable hence spot-on formulation or spray have long-lasting effect varying from 15 days to 2 months. Owing to its lipophilicity, the molecule remains active on animals subject to rain or shampoo. It acts on contact with fleas which die within approximately 6 hours (maximum of 24 hours) and ticks within 48 hours (Bonneau and Cadiergues, 2010). Fipronil may be combined with S-methoprene to obtain action on immature stages of fleas (Franc and Beugnet, 2008). Its synergistic combination with amitraz enables prevention of tick attachment, inhibition of feeding, as well as a lethal effect in less than 24 hours (Pfister, 2011). Pyriprole, similar to fipronil, is lipophilic thus used for treatment and prevention of flea and tick infestations on dogs as a spot-on solution.
Metaflumizone is a contact insecticide acting as antagonist of sodium channels. This insecticide is used in combination with amitraz in dogs as spot-on formulation to provide broad-spectrum activity on both fleas and ticks (Franc and Beugnet, 2008).
Indoxacarb is an insecticide molecule acting mainly through ingestion by insects as to be active, it must undergo bioactivation in insects by their enzymes. By binding a specific receptor, it induces a voltage-dependent blockade of sodium channels, causing inhibition of nerve activity and lethal paralysis. Indoxacarb is used in form of spot-ons for dogs to control fleas (Dryden et al., 2013). A combination with permethrin in dogs has been developed to add tick elimination.
Macrocyclic lactones (Spinosyn group)
They are isolated from bacterial culture of actinomycete species and act by binding and stimulation of nicotinic acetylcholine receptors, which leads to stimulation of postsynaptic neurons. Spinosyns are most active as insecticides but show little acaricidal activity. They can affect insects on contact or after ingestion. Spinosad, a mixture of spinosyns A and D, is used in form of palatable tablets in dogs for existing flea infestations. Anti-flea effects are then persistent for approximately 1 month against new infestations, with maximum effectiveness within 48 hours (Wolken et al., 2012). A combination with milbemycin oxime extends the spectrum of activity to include nematodes.
Macrocyclic lactones (avermectins/ milbemycins group)
Macrocyclic lactones derived from the fermentation of Streptomyces actinomycete bacteria. Active ingredients are produced by semisynthesis and are considered endectocides as their spectrum of activity includes internal nematodes and some external arthropod parasites such as lice, flies, mange mites, Demodex and sometimes fleas. Avermectins/milbemycins produce GABA-mimetic effects by binding to glutamate-gated chloride channels. After spot-on application, avermectins/milbemycins are absorbed transcutaneously, circulate in plasma and are stored in fat tissues. Currently, several avermectins/milbemycins are marketed in dogs: (i) milbemycin oxime, used mainly as a broad-spectrum anthelmintic but may be indicated in dogs with demodicosis is administered orally. (ii) Selamectin, in addition to its nematodicidal action is used in dogs as a spot-on for treatment of ectoparasites. (iii) Moxidectin available as a spot-on treatment in combination with imidacloprid for very similar indications: nematodicidal spectrum plus insecticidal/acaricidal spectrum.
Growth or development inhibitors
Insect growth regulators (IGRs) are molecules that interfere with hormones or enzymes. They inhibit reproduction in insect adults and block organogenesis of immature stages. Their use in Veterinary medicine began for domestic carnivores to control fleas. IGRs may be classified into two groups: juvenile hormone analogs and chitin synthesis inhibitors. Juvenile hormone or neotenin analogs act by contact or ingestion. These analogs are either used in the environment, in the form of sprays or diffusers often combined with insecticide, or applied directly on animals. Juvenile hormone analogs include methoprene and S-methoprene (active isomer), pyriproxyfen and fenoxycarb. Fenoxycarb is only used in the environment. In most cases, these analogs are used in animals in combination with an insecticide/acaricide such as fipronil, permethrin, dinotefuran or imidacloprid (Young et al., 2004). These molecules are lipophilic and persist for several weeks, which allows for residual IGR effects ranging from 1 to 3 months. Chitin synthesis inhibitors exert an effect on fecundity and prolificacy of insect females and inhibit egg hatching and larval molting. In Veterinary medicine, these molecules are used in the environment (flufenoxuron) or directly on the animal (lufenuron) (Jacobs et al., 2001). Lufenuron acts systemically and is administered either via subcutaneous injection or orally and stored in fat tissues or fixed fixation to plasma proteins.
The active molecules used as ectoparasiticides in dogs and their formulations alone or in combination along with their activity spectrum and safety measures are presented in Table 1 and 2. Collars are made of plastic polymers of which the matrix is impregnated with insecticide/acaricide. The rubbing against skin leads to continuous and gradual release of active ingredients. The molecules formulated as tablets act systemically and may provide a short term effect or a persistent efficacy. Whereas powders, aerosols, shampoos and lotions are generally short acting (less than a week), spot-ons are designed to have long lasting effects, at least for fleas and ticks. They now represent majority of external antiparasitic drugs and are based on pharmacological properties of active ingredients and excipients, which for some allows for transdermal delivery followed by plasma distribution and for others diffusion across the entire skin due to lipophilic properties (Lienard et al., 2013). Active ingredients remain present in sebum and in sebaceous glands for several weeks (Cochet, 1997). For optimal effectiveness, they must be applied to dry skin, and it is therefore best not to wash the animal just before (which enables the skin lipid film to rebuild). Regular shampoos will remove the active ingredients and reduce their persistence.
Treatment failures in dogs
Failures in control of tick or flea infestations are to be attributed to ecological and biological reasons. Regarding ticks, it is often the high level of environmental infestation that explains why infestations keep occurring in carnivores. Further, acaricides used in carnivores have certain speed of kill; it is therefore possible to see attached and engorging ticks on regularly treated dogs. The release of active ingredients may have been irregular on dog's body, or concentration may have been reduced by frequent exposure to shampoo. Also, dog's weight might have been underestimated when choosing the dosage form. There are possibilities that the product may not have been applied properly within the guidelines-sites of application, dry coat, application on skin and not on hair or application of entire contents of treatment (Castro-Janer et al., 2010). Regarding dog flea, similar observations apply to choice of product and its method of use. Pupae are extremely resistant in environment (4 to 6 months on average), and new adult fleas may thus emerge and infest carnivores. It is unlikely that all dogs living in same area are treated on regular basis. Therefore, fleas may easily appear as soon as preventive treatment is discontinued or at the end of their activity period.
The indiscriminate use of acaricides over the years has led to development of acaricide resistance which is a serious problem worldwide and is well documented in other tick species, such as Rhipicephalus (Boophilus) microplus as compared to common dog tick R. sanguineus (Davey et al., 2006). R. sanguineus ticks highly resistant to permethrin, DDT and Coumaphos, moderately resistant to amitraz and not resistant to Fipronil has been reported from Panama (Miller et al., 2001). Similarly, in R. sanguineus populations from Spain, low to moderate resistance against propoxur, very high resistance against deltamethrin and no resistance against amitraz was found (Estrada-Pena, 2005). These studies suggest that the resistance against a given acaricide may vary among different tick, populations and that certain R. sanguineus populations appear to be highly resistant to pyrethroid acaricides (Dantas-Torres, 2008). However, a recent study from Ludhiana, Punjab on comparative efficacy of OP compound (Malathion) and SPs (Cypermethrin and Deltamethrin) against dog tick R. sanguineus has shown development of resistance against malathion and cypermethrin (personal communication, unpublished data).
External antiparasitic drugs have evolved in recent years with the development of new active ingredients and formulations. However, older molecules are still being used primarily due to their low cost. The number of external antiparasitic drugs available on the market has increased within the past 10 years, with some clear tendencies: (i) introduction of many generic products; (ii) development of combination drugs to either obtain a broader spectrum or to obtain improved properties, such as rapid action, inhibition of attachment, or repellency; (iii) research for new insecticidal families acting through different modes of action and likely to be used in new formulations, such as oral insecticide formulations; and (iv) increased protection to reduce the risk of transmission of arthropod borne pathogens (Beugnet and Marie, 2009). Further, as vaccines against ectoparasitosis do not exist, external antiparasitic drugs will probably remain the only therapeutic and preventive solution for many years.
Anadon, A., Martinez-Larranaga, M.R. and Martinez, M.A. (2009). Use and abuse of pyrethrins and synthetic pyrethroids in veterinary medicine. Vet. J. 182: 7-20.
Beugnet, F. and Marie, J.L. (2009). Emerging arthropod borne diseases of companion animals in Europe. Vet. Parasitol. 163: 298-05.
Bonneau, S. and Cadiergues, M.C. (2010). Comparative efficacy of two fipronil spot-on formulations against experimental tick infestations (Ixodes ricinus) in dogs. Parasitol. Res. 107: 735-39.
Castro-Janer, E., Martins, J.R., Mendes, M.C., Namindome, A., Klafke, G.M., Schumaker, T.T.S. (2010). Diagnoses of fipronil resistance in Brazilian cattle ticks (Rhipicephalus Boophilus, microplus) using in vitro larval bioassays. Vet. Parasitol. 173: 300-06.
Cochet, P. (1997). Skin distribution of fipronil by microautoradiography following topical administration to the Beagle dog. Eur. J. Drug Metab. Pharmacokenet. 22: 211-16.
Dantas-Torres, F. (2008). The brown dog tick, Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae): from taxonomy to control. Vet Parasitol. 152:173-85.
Davey, R.B., George, J.E., Miller, R.J. (2006). Comparison of the reproductive biology between acaricide-resistant and acaricide-susceptible Rhipicephalus (Booplilus) microplus (Acari: Ixodidae). Vet. Parasitol. 139:211-20.
Dobson, P., Tinembart. O., Fisch, R.D. and Junquera, P. (2000). Efficacy of nitenpyram as a systemic flea adulticide in dogs and cats. Vet. Rec. 147: 709-13.
Dryden, M.W., Payne, P.A., Smith, V. and Hostetler, J. (2006). Evaluation of an imidacloprid (8.8% w/w)-permethrin (44% w/w) topical spot-on and a fipronil (9.8% w/w)-(S)-methoprene (8.8% w/w) topical spot-on to repel, prevent attachment, and kill adult Rhipicephalus sanguineus and Dermacentor variabilis ticks on dogs. Vet. Ther. 7: 187-98.
Dryden, M.W., Payne, P.A., Smith, V., Heaney, K. and Sun, F. (2013). Efficacy of indoxacarb applied to cats against the adult cat flea, Ctenocephalides felis, flea eggs and adult flea emergence. Parasit Vectors 6:126.
Estrada-Pena, A. (2005). Etude de la resistance de la tique brune du chien, Rhipicephalus sanguineus aux acaricides. Rev. Med. Vet. 156: 67-69.
Franc, M. and Beugnet, F. (2008). A comparative evaluation of the speed of kill and duration of efficacy against weekly infestations with fleas on cats treated with fipronil-(S) methoprene or metaflumizone. Vet. Ther. 9: 102-10.
Jacobs, D.E., Hutchinson, M.J. and Ryan W.G. (2001). Control of flea populations in a simulated home environment model using lufenuron, imidacloprid or fipronil. Med. Vet. Entomol. 25: 73-77.
Lienard, E., Bouhsira, E., Jacquiet, P., Warin, S., Kaltsatos, V. and Franc, M. (2013). Efficacy of dinotefuran, permethrin and pyriproxyfen combination spot-on on dogs against Phlebotomus perniciosus and Ctenocephalides canis. Parasitol. Res. 112:3799-3805.
Miller, R.J., George, J.E., Guerrero, F., Carpenter, L. and Welch, J.B. (2001). Characterization of acaricide resistance in Rhipicephalus sanguineus (Latreille) (Acari: Ixodidae) collected from the Corozal Army Veterinary Quarantine Center, Panama. J. Med. Entomol. 38: 298-02.
Pfister, K. (2011). Fipronil, amitraz and (S)-methoprene --a novel ectoparasiticide combination for dogs. Vet. Parasitol. 179: 293-56.
Prullage, J., Hair, J.A., Everett, W.R., Yoon, S.S., Cramer, L.G., Franke, S., Cornelison, K. and Hunter III, J.S. (2011). The prevention of attachment and the detachment effects of a novel combination of fipronil, amitraz and (S)-methoprene for Rhipicephalus sanguineus and Dermacentor variabilis on dogs. Vet. Parasitol. 179: 311-17.
Sharma, A.K., Kumar, R., Kumar, S., Nagar, G., Singh, N.K., Rawat, S.S., Dhakad, M.L., Rawat, A.K.S., Ray, D.D. and Ghosh, S. (2012). Deltamethrin and cypermethrin resistance status of Rhipicephalus (Boophilus) microplus collected from six agro-climatic regions of India. Vet. Parasitol. 188: 337-45.
Soulsby, E.J.L. (1982). Helminths, Arthropods and Protozoa of Domesticated Animals. Bailliere Tindal.
Vetnosis (2008). Animal Health 2008 Industry Outlook and Review, Avril.
Young, D.R., Jeannin, P.C. and Boeckh, A. (2004). Efficacy of fipronil/(S)-methropene combination spoton for dogs against shed eggs, emerging and existing adult cat fleas (Ctenocephalides felis, Bouche). Vet. Parasitol. 125: 397-407.
Dr. Pathak bestowed with Honorary Doctorate
On 7th October' 2013, during the third convocation of Nanaji Deshmukh Veterinary Science University (NDVSU, Jabalpur), Prof. K.M.L. Pathak, Deputy Director General (Animal Sciences), Indian Council of Agricultural Research (ICAR) was conferred 'Honorary Doctorate of Science' for his significant contribution in field of Veterinary Science and Technology.
The honour was bestowed to him by Shri Ram Naresh Yadav, Governor of Madhya Pradesh and Chancellor, NDVSU along with Dr. Govind Prasad Mishra, Vice Chancellor, NDVSU; Dr. V.S. Tomar, Vice Chancellor, JNKVV and Dr. D. P. Lokwani, Vice Chancellor, Medical University, Jabalpur.
N.K. Singh, S.N.S. Randhawa (1) and Jyoti
Department of Veterinary Parasitology College of Veterinary Science Guru Angad Dev Veterinary and Animal Sciences University Ludhiana--141004 (Punjab)
(1.) Director of Research-cum-Dean (Postgraduate Studies) and Corresponding author
Table 1: Ectoparasiticide compounds internationally available for dogs Compound Dose-rate Formulation (per kg b.wt.) Indoxacarb 15mg Spot on Imidacloprid 10 mg Spot on Amitraz 0.05% Dm Emulsifiable 0.025% Sm concentrate Nitenpyram 1 mg Tablet Spinosad 45 mg Chewable tablet Fipronil 6.7 mg Spot on Fipronil 7.5 mg Spray Pyriprole 12.5 mg Spot on Lufenuron 10 mg Tablet Deltamethrin 0.0025% Emulsifiable concentrate Selamectin 6 mg Spot on Ivermectin 0.2 mg Injectable/ tablet Permethrin 50 mg Soap/Shampoo Compound Spectrum of Minimum Use in activity age of use Pregnancy Indoxacarb Flea 8 weeks No Imidacloprid Flea, tick 8 weeks +/- Amitraz Demodex/ 3 months No Sarcoptes Nitenpyram Flea 4 weeks Yes Spinosad Flea 14 weeks +/- Fipronil Flea, tick, lice, 2 months +/- mange mites Fipronil Flea, tick, lice, 2 months +/- mange mites Pyriprole Flea, tick 8 weeks +/- Lufenuron Flea Weaned Yes Deltamethrin Flea, tick, lice, 7 weeks Yes mange mites Selamectin Flea, lice, tick, 6 weeks Yes mange mites Ivermectin Flea, lice, tick, 6 weeks Yes mange mites Permethrin Flea, lice, tick 6 weeks Yes Dm--Demodectic mange Sm--Sarcoptic mange Table 2: Ectoparasiticide combinations internationally available for dogs Active Dose-rate Formulation ingredients (per kg b.wt.) Imidacloprid 10 mg Spot on Permethrin 50 mg Imidacloprid 10 mg Spot on Moxidectin 2.5 mg Fipronil 6.7 mg Spot on (S)-Methoprene 6 mg Amitraz 8 mg Fipronil 6.7 mg Spot on (S)-Methoprene 6 mg Permethrin 50 mg Spot on Pyriproxyfen 1 mg Cyphenothrin 30% Spot on Pyriproxyfen 2.0% Fipronil 6.7mg Spot on Cyphenothrin 30% Active Spectrum Minimum Use in ingredients of activity age of use Pregnancy Imidacloprid Flea, tick, lice, 7 weeks Yes Permethrin mange mites Imidacloprid Flea, lice, tick, 7 weeks +/- Moxidectin mange mites Fipronil Flea, tick, lice, (S)-Methoprene mange mites 8 weeks Yes Amitraz Fipronil Flea, tick, lice, (S)-Methoprene mange mites 8 weeks Yes Permethrin Flea, tick, lice, 8 weeks Yes Pyriproxyfen mange mites Cyphenothrin Flea, tick, lice, 8 weeks Yes Pyriproxyfen mange mites Fipronil Flea, tick, lice, 8 weeks Yes Cyphenothrin mange mites
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|Author:||Singh, N.K.; Randhawa, S.N.S.; Jyoti|
|Date:||Jul 1, 2013|
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