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Lufenuron and Fipronil. Current Uses in
Insecticides-Current Uses in Pets
Fleas, ticks and mites are the major parasites that affect the skin and haircoat of dogs and cats. Radical changes have occurred in the veterinary usage of insecticides in the last 10 years. Prior to that time, regardless of the pest, in most cases, veterinarians were advocating an attack on the outdoor and indoor environment, as well as all of the pets in the household for fleas, ticks and most mite infestations other than demodex.
However, in the past decade, many new insecticides have been developed. First, we were introduced to the idea of growth hormone regulators (IGR's) interfering with insects' development; initially methoprene (Siphotrol¨- VetKem) was offered as one of the first insect directed products which was non-toxic to mammals,. Although it had disadvantages such as ultraviolet light instability, and translocation properties, most small animal veterinarians found it very useful to use in the indoor environment, and later on the pet. Then after many years of hearing about lufenuron (Program¨- Novartis)) marketed in many other countries, we finally found this systemic chitin inhibitor available in the United States. This drug proved to be very useful in certain settings, but as with all things for which one waits with anticipation, the drug is not a panacea for all situations, but rather an effective tool for flea control. Amitraz¨-Virbac collars arrived on the scene to help us with tick control.
More recently we have had the fortune to have two new on-animal topical insecticides marketed for small animal veterinary usage: Merial's fipronil in the form of TopSpot¨ and Frontline Spray¨, and Bayer's imidacloprid as Advantage¨. These insecticides have totally changed our view to treatment and management of flea control. Fipronil is also effective against ticks, and appears to have some miticidal activity (although it is not labeled for this). Most recently Pfizer has entered the market with selemectin, sold under the trade name of Revolution¨. This drug has the widest range of label usage for various parasites.
In addition, to the aforementioned drugs, we have seen wider spread use of OTC pour-on permethrins replace the use of pour-on organophosphates. A very stable broader spectrum and more stable insect growth regulator, pyriproxifen, Nylar¨ is widely available for use in environments both outdoor and indoor. It is available in collars, foggers,, and on-animal sprays. Sodium polyborate application for the indoor environment became popular for its long-term residual activity. Finally, biological control of fleas with nematodes has been found useful in certain settings. Additionally, as we have learned more about the biology of the flea, the use of mechanical devices such as vacuuming has become more important for management. Environmental cleaning outdoors can also be useful in techniques for controlling ticks and harvest mite infestations.
LESS FREQUENTLY USED INSECTICIDES TODAY Some Botanticals: Rotenone and d-limonene are botanical compounds which are used infrequently today for long term usage as insecticides.
Chlorinated hydrocarbons: These compounds are highly toxic, stored in body fat, and have long residual accumulation in the environment. For this reason, they are no longer labeled for use on pets and rarely used by licensed pest control operators.
Organophosphates: These compounds are still widely available over the counter (OTC) for the treatment of the yard and garden. The toxicity of organophosphates is variable depending on the type with toxic signs being either muscarinic or nicotinic. These products inhibit cholinesterase. Few veterinarians today in North America would use these products in pets, although for many years, cythioate and fenthion were used for pets. Diazinon, malathion, and phosmet are available in a variety of products. In most circumstances in which organophosphates are being used, they are being applied outdoors or indoors by licensed pest control operators for broader insect control which may include ticks.
Carbamates: Available as methylcarbamate insecticides, carbaryl and propoxur have similar activity but less toxicity than organophosphates. They also are less commonly used today, primarily because of their earlier over usage and current lack of efficacy in some situations.
MORE COMMON INSECTICIDE PRODUCTS USED TODAY
Other Botanticals: Initially this group of insecticides was derived from plants. However synthetic pyrethroids based on the esters that make up natural pyrethrins are now included in this group. Pyrethrins are still widely used. They are viscous, nonpolar liquids, insoluble in water, and easily decomposed by ultraviolet light. They have poor residual activity but provide excellent rapid kill of many insects. They have low mammalian toxicity and are usually combined with piperonyl butoxide as a synergist which helps to prevent the pyrethrin break-down by flea microsomal enzymes.
Pyrethroids are synthesized chemicals modeled on the natural pyrethrin molecule, but these are more stable and more potent. They are also combined with synergists. A third generation pyrethroid, permethrin, is very popular for both its rapid insect kill and its repellant activity in the dog and horse with insect hypersensitivity.
For dogs with multiple exposure to flea environments or concerns about frequent bathing with degreasing shampoos or frequent swimming, spray adulticides containing a combination of permethrin and pyriproxifen are commonly used, especially because of the reported repellancy effect of permethrin and its benefit to the flea allergic dog. Permethrin concentration levels can be very toxic to cats at 2% so care should be taken to only use permethrin products labeled for cat usage, if used at all.
Insect Growth Regulators (IGRs)and Insect Development Inhibitors (IDI's):
These are available for systemic use as oral once monthly flea growth inhibitors, as impregnated collars, as sprays for on -pet use and as foggers and sprays for the environment. Because these products target systems unique to insects, they are essentially nontoxic to mammals and thus highly desirable for safety. One of the advantages of indoor treatments using IGRs is their residual activity. They are frequently used in conjunction with an insect adulticide for more immediate killing effect.
The oral product lufenuron (Program¨- Novartis) given once monthly affects both flea egg hatch and flea larvae development. Resistance has not yet been reported in the literature with lufenuron but there are pitfalls we have all been made aware of through its usage. It is only effective in an environment which is closed to stray animals and wild animals acting as transporters for fleas. A wide variety of nondomesticated hosts have been reported to harbor C.felis, including coyote, foxes, bobcats, skunk, raccoon, opossum, and several rodent species. Lufenuron must be given with a meal and administered to all the animals in the household on a regular basis. If the lufenuron-treated pet leaves the premises and travels regularly to infested areas, lufenuron will not be effective in flea allergic animals in that household. However, in a closed environment with flea allergic pet(s), lufenuron can be highly effective after the first few months of administration. Each situation must be treated individually.
Methoprene is a terpenoid compound which mimics a juvenile insect hormone and is not easily removed by water. It is still an extremely effective IGR as long as the user has respect for its limitations. It is unstable to ultraviolet light and thus cannot be used outside or on animals with significant sunlight exposure. It has the ability to translocate or be moved easily from one area to another. It is very effective in the household and maintains a long residual effect on cats housed indoors and treated either with spray or collars.
Pyriproxifen (Nylar¨) is an IGR whose action is similar to that of methoprene but its potency is increased. At low concentrations it has both strong ovicidal and larvicidal properties. According to Dryden, pyriproxifen appears to have some delayed flea adulticidal effects as well. It may be eventually available as a systemic like lufenuron. Currently it is readily available as a spray, in impregnated collars, and in some states in OTC foggers and environmental and on- animal sprays.In the highest application of pyriproxifen to soil, 75% flea control was realized for 11 months. It does have IGR activity against other crop insects.
Even with the use of the IGR's, frequent vacuuming of the pet's bedding area is useful. Maintenance of a clean outdoor environment without a lot of brush, shaded leaf-filled areas and high moisture, organic areas also is among the long-term recommendations for optimal flea control management, and is especially advantageous prior to the use of IGR's.
New Insect Adulticides
Fipronil is a phenylpyrazole compound which blocks transmission of signals by the inhibitory neurotransmitter GABA. Fipronil binds within the chloride channel and consequently inhibits the flux of chloride ions into the nerve cell resulting in nervous system hyperexcitation. Fipronil has a greater specificity for the GABA receptors found in insects than mammals. This topical compound (Frontline ¨or TopSpot¨-Merial) is highly effective for fleas and ticks as an adulticides with death of the flea occurring within 24 hours of exposure. Fipronil is used worldwide in agriculture. It is poorly soluble in water, delivered in very small amounts and does not leach into the groundwater. Sunlight, immersion in water, and bathing do not significantly impact the performance of this product under most circumstances.
Pharmocovigilance survey results demonstrated excellent safety. It is safe for use on puppies and kittens and not teratogenic or mutagenic. It has also been used successfully to treat some mite infestations.
Imadacloprid is a synthesized compound (Advantage¨-Bayer) which was developed in the mid- 80's and is a chlorinated derivative of nicotine that is stable long enough to kill target insects but not long enough to accumulate in the environment. This compound has also found widespread application in agriculture as a systemic in the root system, soil, or seeds of plants. As a spot-on product, it has met with great success in the USA and kills adult fleas with 98-100% efficacy in 24 hrs. It has aalso been demonstrated to have a favorable toxicology profile with low oral, dermal and inhalation toxicity to mammals. Like fipronil, it is non- teratogenic and non-mutagenic in mammals.
Both fipronil and imidacloprid appear to be safe in their mechanism of action and in short-term toxicity studies. They are regulated by the EPA instead of the FDA and the guidelines for each are slightly different. Insecticides in general are overseen by the EPA. Lufenuron was FDA registered because it was given orally and absorbed systemically.
Dryden has recently reported that although fipronil and imidacloprid are excellent adulticides, there is potential that females may survive and reproduce between applications. Looking at the percentage of fleas that fed prior to being killed by residual insecticides, the majority were able to take a blood meal. At 20 day reinfestation a few viable flea eggs were collected from treated cats with both compounds. Dryden thus concludes that these adulticides should be used in combination with juvenile hormone analogs or insect development inhibitors for the most effective flea control and prevention of subsequent flea generations. He strongly recommends that combination of compounds with completely different modes of action should delay the onset of resistance by fleas. There are some other concerns regarding these new adulticides. Fipronil offers the positive aspect of being effective against ticks as well as fleas. However, label instructions indicate that it should not be applied any more often than every 30 days. Imidacloprid does not carry this label warning and can be applied as often as weekly if necessary.
Selemectin (Revolution ¨-Pfizer) is the newest flea adulticide marketed, but fits best in the same category of drug as ivermectin and milbemycin oxime. These are macrocyclic lactones or semisynthetic derivatives of avermectin. Selemectin was developed by Pfizer Animal Health specifically for dogs and cats and is derived by chemical modification of a precursor avermectin and is produced by bioengineering techniques. Pfizer advertizes it as a unique Endectocide because it provides optimal efficacy against internal and external parasites of dogs and cats with good safety. Although it is a pour-on topical, because it is absorbed into the blood stream, it went through FDA approval prior to marketing. This compound is believed to target more than one biochemical site in the parasite dependant upon the type of parasite. It has a much broader label for parasites and in the dog and cat is effective against adult fleas and prevents egg hatch. It is also labeled for kill of the tick, D. variabilis, in the dog. It is a heartworm preventative labeled for both dogs and cats as well as having a label for ear mites in both species. It also currently is labeled for A. tubaeforme and T. cati in the cat only. For dermatologists its efficacy label for Sarcoptes mites allows us a better option than the off- label usage of previous avermectins. Also, because it is absorbed and then re-positioned into the skin, topical therapy should have less effect in removing the drug. Although its efficacy data for flea kill appears to be slightly longer than fipronil or imidacloprid, it offers the wide spectrum of parasite activity. Its major disadvantage may be cost to the client.
Other Macrocyclic lactones: Ivermectin (Ivomec ¨- Merial) is a semisynthetic derivative of avermectin with a broad spectrum of activity against a variety of arthropods and nematodes. It can be given by injection, orally, or topically but has only an oral label for heartworm prevention, so there has been much off- label usage of the compound. It has also been used effectively in the treatment of demodicosis. Although this compound has a substantial margin of safety, some breeds such as Collie dogs appear to be sensitive to the drug, and idiosyncratic reactions occur in other breeds.
Milbemycin oxime (Interceptor ¨- Novartis) is another oral heartworm preventative and anthelmintic labeled for these uses. It has also been found to be effective at rather high levels when it is used orally, daily for demodicosis. Its cost limits this usage in general to small dogs.
Formamidines: These compounds are monoamine oxidase inhibitors and they are effective acaricides. Amitraz is the only approved one for use in small animals and its primary use is in collars for tick control and as a dip for canine demodicosis. Toxicosis in mammals is manifest by sedation and lethargy. A reversal agent is available.
Borates: There is still interest and there are faithful users of borates applied to carpets to interrupt the flea life cycle. Concentrations that are toxic orally to humans would far exceed what is applied in the average household. The product has a long residual activity although it is messy for the first few weeks after application. It has been very successful for treatment indoors, especially in carpeted homes.
Mechanical Control: This is still strongly encouraged and a very effective means of assisting in flea control. Vacuuming with a beater-bar type vacuum will remove up to 90% of the eggs and 50 % of the larvae from some carpets; this percentage varies with the density of the carpet pile.
Nematodes: Steinernema carpocapsae is a nematode that will attack and kill flea larvae, prepupae, and pupae. Moist substrates are necessary for the nematode to survive long enough to infect more than one generation of fleas. Since watering the soil can wash away larva, it some situations where watering is necessary to maintain nematode populations, it is questionable whether the nematodes are responsible for the perceived decrease in fleas.
FLEA ALLERGIC DERMATITIS AND INSECTICIDE USAGE
Future of Flea Control:
Recommendations for flea control are likely to continue changing in the future. Attempts are being made to develop better diagnostics for FAD and possible immunotherapy. Even if an effective vaccine were developed to prevent FAD, flea populations would need to be controlled because they are a blood sucking parasite and can make a patient anemic as well as transmit disease. The familiar term today is Integrated Flea Control, simply indicating that the veterinarian and the client have many options and it is important to select the proper treatment for each situation. In most cases this will involve more than one form of flea control. At the present time and with our current information, the ideal flea control consists of using insect growth regulators systemically and/or in the environment together with other adjunctive management.
This may include the routine use of an on-animal flea adulticide, especially in households where a FAD patient resides. Although these adulticides alone may be effective it is less likely that resistance will occur if more than one type of control is used concurrently.
Future Prevention of FAD
Veterinarians are major role-players today in the prevention of many animal diseases with vaccinations and prophylactic drugs like oral heartworm prevention. Once good preventative techniques have been developed, this route is generally preferred rather than treatment of the primary disease. If we could prevent the occurrence of FAD, this would be preferable to treatment. However, even if FAD prophylaxis is developed, there will always be pets that do not receive it or pets for which it is ineffective. FAD is likely to always be a disease that veterinarians are called upon to treat in pet animals.
When new products or new methodologies for application of flea control products have entered the market, initial responses are often good. Later reports of decreased efficacy may follow. Flea resistance is possible and has been documented with organophosphates. However, many more of the failures of flea control have simply been laxity in compliance or alteration of protocols by veterinarians and/or owners. The importance of proper usage of any flea control product cannot be overemphasized. The treatment should be used as recommended in frequency and it should be continued indefinitely and prior to and throughout the entire flea season ( year round in more areas). The newer flea control products can be increasingly helpful in the prevention of the development of FAD by simply decreasing antigen exposure in pets. Thus, it is highly important that the veterinarian continue to stress flea control not only as a treatment for the FAD pet but as a prevention for the development of FAD in pets.
Recent Changes in FAD Management
In addition to the concept of all encompassing treatment, we repeatedly told clients that one flea bite was all that was necessary to initiate the itch reflex in hypersensitive animals. This may be the case in exquisitely allergic dogs and cats. But with the availability of adulticides which kill within 24 hrs but do not repel and the study of Dryden that indicates some of these fleas do indeed take a blood meal with both fipronil and imidacloprid, the clinical signs of many FAD cases respond remarkably to these adulticides alone. So flea burdens in numbers likely do contribute to the seriousness of the clinical signs.
One major factors has always made it difficult to prove that more fleas were present : dogs and cats with flea allergy rarely have fleas or evidence of fleas readily found on their haircoat. This is likely due to the fact that FAD pets are excellent at grooming away the fleas immediately after the fleas bite.
FOR MITE INFESTATIONS
We now currently have three protocols for demodicosis, one labeled product- Mitoban¨‰w*- UpJohn, and the systemic options of milbemycin or ivermectin.
For ear mites and now for Sarcoptic mange treatment and prevention, we have the label claim and effectiveness of selemectin.
We now have Amitraz collars, Fipronil topical, and Selemectin.
Thanks to Dr. Sandra Merchant-Staff Dermatologist at LSU Veterinary School for this article
© Columbia Animal Hospital
Hawthorne Professional Park
10788 Hickory Ridge Rd.
Columbia, MD 21045
phone: (410) 730-2122
phone: (301) 596-5549
fax: (410) 992-9511