Люфенурон инструкция по применению в ветеринарии

Indications and clinical uses

Lufenuron is used to control flea infestations by preventing hatching of eggs. It has been used as part of flea control, often with other drugs that kill adult fleas. Lufenuron has been combined with milbemycin in formulations for small animals, and additional details may be found in the section on milbemycin. There are clinical reports of the use of lufenuron for treating dermatophyte infections in small animals—particularly cats—at high doses of 80-100 mg/kg orally. However, endorsement of this use has diminished, and dermatologists have disputed the efficacy and have observed a high incidence of recurrence. In horses, lufenuron was not absorbed orally and is not effective for treating fungal infections. It does not have any in vitro effect on Aspergillus fumigatus or Coccidioides immitis.

Indications and Clinical Uses

Lufenuron is used to control flea infestations by preventing hatching of eggs. It has been used as part of flea control, often with other drugs that kill adult fleas. Lufenuron has been combined with milbemycin in formulations for small animals, and additional details may be found in the section on milbemycin.

There are isolated clinical reports of the use of lufenuron for treating dermatophyte infections in small animals, particularly cats, at high dosages of 80–100 mg/kg PO. However, endorsement of this use has diminished, and dermatologists have observed a high incidence of recurrence and disputed the reports of efficacy. In horses, lufenuron was not absorbed orally and is not effective for treating fungal infections. It does not have any in vitro effect on Aspergillus fumigatus or Coccidioides immitis.

7. How is lufenuron different from other IGRs?

Lufenuron is classified as an insect development inhibitor (IDI). Lufenuron’s mechanism of action is interference with chitin synthesis, polymerization, and deposition. It is administered orally with food or may be injected into cats. Lufenuron is taken up by the female flea as she consumes a blood meal. The lufenuron disrupts the ability of the larva to emerge from the egg, thereby halting reproduction. Lufenuron is excreted unchanged in the flea feces. If a larva consumes the feces with lufenuron, it prevents a normal pupa from developing. Ultimately, the net effect is environmental control. Lufenuron must be given orally monthly or injected every 6 months in cats to be effective. Also, the flea must feed for lufenuron to work. Other IGRs can be applied to the pet or to the environment and will work without the flea feeding first.

Lufenuron

Lufenuron is a benzoylphenylurea drug that disrupts chitin synthesis and is used for flea control. Chitin is a critical component of the outer cell wall of fungi, and drugs that disrupt chitin synthesis also may have antifungal activity. In 2000, a retrospective study suggested lufenuron treatment was associated strongly with recovery in a large number of dogs and cats with a variety of fungal infections, including dermatophyte infections.³⁰

Since that report, the use of lufenuron has been a widely debated topic in the lay and veterinary literature and has been the focus of numerous anecdotal and published reports.^15,31-33 Two reports exist of controlled blinded studies that evaluate the efficacy of lufenuron to prevent or alter the course of experimentally induced M. canis infections in cats.^32,33 Two oral doses (30 or 133 mg/kg) of lufenuron were evaluated; after 2 months of pretreatment, the kittens were challenged with infective M. canis spores. In this study, neither dose of lufenuron prevented infection nor altered the course of infection; however, the challenge was markedly larger than what would occur under field exposure.³³

In a follow-up study, two groups of cats were pretreated with either oral or injectable lufenuron before exposure to a subclinically infected cat.³² Cats received four doses of lufenuron at monthly intervals (100 to 133 mg/kg PO or 40 mg SQ) before exposure to the infected cat, and monthly treatments thereafter for an additional 5 months. In this study, lufenuron did not prevent infection in either treatment group. In addition, infections in the control and two treatment groups resolved at about the same time. What was noticed in this study was that infections were established more slowly in the lufenuron-treated groups when compared with the control group. In a clinical field study involving 100 cats in two catteries with naturally occurring dermatophytosis, cats were divided randomly into two treatment groups.¹⁵ Both groups were treated topically with enilconazole once weekly, but one group received griseofulvin (25 mg/kg PO q24h) and the other lufenuron (60 mg/kg). Although the investigators reported a decrease in fungal culture counts over 90 days and resolution of clinical signs, cures were not reported.¹⁵ At this time, we do not recommend lufenuron for the treatment or prevention of dermatophytosis.

Lufenuron.

Lufenuron is an IGR or insect development inhibitor that works by inhibiting chitin biosynthesis (Fig. 6.1) (Insecticide Resistance Action Committee [IRAC], 2017). Lufenuron is available in an injectable formulation (Program 6-Month Injectable for Cats) that is designed to allow application every 6 months for control of fleas. Adverse reactions after injection include pain on injection, injection site lumps/granulomas, vomiting, listlessness, lethargy, and anorexia. The drug is highly lipophilic, resides in the fat tissues of the pet, and redistributes into the bloodstream. Adult fleas ingest lufenuron when they feed, and the drug is passed transovarially to the flea egg. Most flea eggs exposed to lufenuron fail to hatch, and the few flea larvae that do hatch die during their first molt. The action on the immature flea is thought to be owing to disruption of chitin synthesis and deposition. Lufenuron is a convenient and effective agent for flea control in pets. It is known to be safe in pets of all ages, as well as in breeding dogs and cats.

Concurrent use of lufenuron and nitenpyram was discussed in the Nitenpyram section. Lufenuron is also available in combination with milbemycin oxime (Sentinel Flavor Tabs), as well as with milbemycin oxime and praziquantel (Sentinel Spectrum) for control of fleas and internal parasites in dogs; see the combination products in the Anthelmintics section of this chapter for more information (pg 331 and 332).

6.2 Effect on Predators

Lufenuron was found harmful to some predatory insects like the lacewing, Ceraeochrysa cubana Hagen (Carvalho et al., 2011) and the bugs, Orius laevigatus (Say) (Angeli et al., 2005) and Pilophorus typicus (Nakahira et al., 2010). Hexaflumuron was toxic by contact or by ingestion to the predatory bug, O. laevigatus (Angeli et al., 2005). Zhao et al. (2012) found that hexaflumuron and chlorfluazuron were the least toxic compounds among 30 insecticides tested on the wasp, T. japonicum, an egg parasitoid of crop pests. Cutler et al. (2006) showed that Novaluron was toxic to the predatory bugs, Podisus maculiventris (Say) (a natural enemy of the Colorado potato beetle) and mirid bugs, P. typicus (Nakahira et al., 2010). Toxicity of pyriproxyfen to predatory beetles of scale insects was recorded by Mendel et al. (1994) and Hattingh (1996).

Etoxazole was toxic to the eggs of predatory mites, Amblyseius womersleyi Schicha (Kim and Seo, 2001), Phytoseiulus persimilis (Athias-Henroit) (Kim and Yoo, 2002), Neoseiulus californicus and Neoseiulus womersleyi Schicha (Amano et al., 2004). Etoxazole was found toxic against predatory mites, Orius insidiosus (Say) and Orius strigicollis (Poppius), natural enemies of phytophagous mites and thrips, respectively (Ashley et al., 2006).

Mechanism of action

The precise mechanism of action of lufenuron, a member of the benzoylphenylurea (BPU) class, is not known. However, while it does not directly inhibit chitin synthase, there is evidence that it inhibits the γ-S-GTP stimulated uptake of Ca²⁺ by chitin microfiber-containing excretory vesicles, disrupting vesicle fusion with the outer cell membrane and cuticle formation in exposed insects. Lufenuron is both ovicidal and larvicidal. The ovicidal action is most notable with higher concentrations of lufenuron. As concentrations deplete, eggs will hatch; however, the larvae are reduced in size and further development to pupae is inhibited. Excretion of lufenuron in flea feces provides a source of exposure to flea larvae, whose continued development is then impaired. In vitro studies of adult fleas have shown that sustained lufenuron exposure can be adulticidal. This activity is not encountered in vivo, as the concentrations of lufenuron in host blood are inadequate to disrupt adult flea chitin synthesis.

Although chitin occurs in most invertebrate phyla (the chitin content of the cuticle of larval insects is 30–60% while the weight of chitin in the cuticle of ticks is around 3%), it is absent among vertebrates, accounting for the high margin of mammalian safety associated with lufenuron.

Treatment of infestations with Ctenocephalides.

Dogs and cats have enjoyed the possibility of living a flea-free existence for the past 25 years since the 1994 launch of lufenuron as a direct-to-pet flea product with remarkable efficacy. The current pharmacopeia for flea control contains some molecules that have been developed as FDA-approved products that are internalized by the pet or molecules in EPA-approved products that are topically distributed on the surface of the pet (see Chapter 6). Veterinarians and the public have come to expect these products to work very well, so the bar has been set very high, and the products do deliver.

Things changed again in 2014 when the first of two new FDA-approved products of the isoxazoline class entered the market and were soon followed by two more, providing four excellent new compounds for flea control, that is, products containing afoxolaner, fluralaner, lotilaner, and sarolaner. These products are formulated to be applied orally or topically and have been developed now for both dogs and cats. After administration, whether absorbed from the gastrointestinal tract or through the skin, the products are distributed throughout the body and kill arthropods, insects, and acarids that bite and take in blood. They work mainly on the chloride channels that are gamma-aminobutyric acid (GABA)-gated and a lesser extent glutamate-gated with a GABA-channel target. These products are marvelous in their ability to kill fleas, sucking lice, bugs, some diptera, ticks, and mites. For fleas, all four of the products have great killing power, and can rapidly halt the flea cycle in a home environment.

Other FDA-approved products for flea control include the drugs lufenuron, nitenpyram, spinosad, and selamectin; the first three products are administered orally, and the last, selamectin, is applied topically but enters the bloodstream transdermally. All four products have been approved for cats. Lufenuron, with no adulticide action, works by inhibiting chitin synthesis and when a flea feeds on a treated dog or cat, the drug makes its way into the flea and then into the larvae, which then will fail to develop. This product persists in the body of the animal and is used as a monthly flea preventive or as an injectable 6-month formulation for cats. In treating dogs, lufenuron has been combined with milbemycin oxime to provide flea control along with heartworm prevention and treatment and control of internal nematode infections. Nitenpyram is a neonicotinoid insecticide that undergoes rapid oral absorption and rapidly spreads throughout the body of the dog and cat after ingestion; it is known for its very rapid knock-down. Nitenpyram is designed to be given daily as needed to kill adult fleas, and it is approved to be used in conjunction with lufenuron for flea control within a given environment. Spinosad kills adult fleas through activation of the nicotinic acetylcholine receptors of the flea at a distinct binding site. Spinosad has been formulated to kill adult fleas for a full month after oral treatment, and for dogs, it has been combined with milbemycin oxime, when it functions as a month-long flea adulticide along with the heartworm prevention and internal parasite treatment and control provided by milbemycin oxime. Selamectin is a specially formulated macrocyclic lactone that is administered to animals for heartworm prevention and flea control. This formulation of a macrocyclic lactone is absorbed and then is redeposited in the dermal layer; it persists in the skin of the animal for an extended period to provide flea control.

Products approved by the EPA for use on dogs and cats for flea control are fipronil, imidacloprid, dinotefuran, flumethrin, indoxacarb, pyriproxyfen, and methoprene; the products cyphenothrin and deltamethrin are for use on dogs only. These EPA-approved products are not internalized by the animal. Fipronil, active at the GABA-gated chloride channel, kills adult fleas through contact and ingestion and has been formulated into topical products that provide flea control for a full month. Imidacloprid binds to the nicotinic acetylcholine receptor sites and appears in another set of topical products designed for monthly application. Dinotefuran, another neonicotinoid insecticide, has also been formulated for topical monthly protection. These compounds are sometimes combined with an insect growth regulator—methoprene or pyriproxyfen. These combination products then kill adult fleas and have deleterious effects on the larvae developing in the eggs and on developing larvae that do hatch. Fipronil also has activity against ticks, and because imidacloprid and dinotefuran do not, they have been mixed with permethrin products to provide tick control for dogs. Fipronil has also been mixed with amitraz or cyphenothrin to increase its activity against ticks. Two long-acting collars are also available in the United States: one lasts 8 months and contains a mixture of imidacloprid for flea prevention and flumethrin, a second-generation pyrethroid, for tick control on dogs and cats; the other collar for dogs contains a fourth-generation pyrethroid, deltamethrin, and provides 6 months of protection against both fleas and ticks. Imidacloprid has also been combined with topically applied and absorbed moxidectin in a product that is designed for monthly application to dogs and cats for flea prevention, heartworm prevention, and treatment and control of various intestinal parasites. Indoxacarb is a proinsecticide that is rapidly metabolized to an active moiety in the flea; it is available as a stand-alone product for flea control on cats and is combined with permethrin to control fleas and ticks on dogs.

Environmental manipulation remains a major aid in controlling fleas, and it does not necessarily require chemicals. A vacuum cleaner will markedly reduce the numbers of eggs, larvae, pupae, and unfed adult fleas in an environment (make certain to close and dispose of the bag after vacuuming to prevent the fleas from escaping). Control efforts should concentrate on places where the dog or cat habitually rests because this is where eggs and flea feces, the provender of larvae, are most likely to be deposited, and the development of adult fleas is likely to follow. If cage-confined animals are kept in wire-bottom cages elevated at least 13 inches (33 cm) above the ground or floor, any fleas that develop underneath the cage will not be able to jump high enough to get back onto a host (Rothschild et al, 1973). This method has been used successfully in a commercial beagle breeding establishment housing several thousand dogs. Application of this latter environmental control method is clearly limited to strictly confined animals.

Although the excellent products listed earlier often can bring heavy flea infestations under control, it will sometimes be necessary to treat the environment with insecticides or other mechanical methods. Steam cleaning may be necessary, and it can sometimes help in larger areas. It may be necessary to clean an area and remove all rugs, blankets, sand, or sawdust where animals may have been resting. When in the outdoors, treatment should concentrate in areas that are shaded and out of direct sunlight. Yards and other buildings may be sprayed with cyfluthrin or fenvalerate pyrethroids, but treatments need to be applied as per label instructions.

Other available methods for the control of fleas differ widely in their apparent effects on flea populations under various conditions. Several traps are commercially available for the capture of adult fleas. Some of these traps collect more than 85% of released fleas, whereas others collect only slightly more than 10% (Dryden and Broce, 1993). Brewer’s yeast failed as a repellent to fleas on dogs when fed as a dietary supplement at the rate of 14 g/day (Baker and Farver, 1983). Ultrasonic flea collars also do not repel fleas from dogs, at least under certain laboratory conditions (Dryden et al, 1989).

It is important to remember that all insecticides are toxicants, and they are safety tested only for certain animals. Thus fipronil, which is very, very safe for dogs and cats, has been found to cause severe toxic reactions in rabbits treated for flea control. It is actually against the law to apply EPA-approved products except as stated on the label.

Milbemycin Oxime

Milbemycin oxime is approved as a monthly oral tablet for dogs and cats. This drug is also available in combination with other active ingredients, lufenuron with or without praziquantel or spinosad, which can extend the labeled indications to include flea immature stages +/- tapeworms or adult fleas, respectively.^1,15 Milbemycin oxime at a minimum target dose of 0.5 mg/kg PO in dogs and 2 mg/kg PO in cats is indicated for the prevention of heartworm disease, treatment of Ancylostoma spp. and Toxocara spp. infections in dogs and cats, and T. leonina and T. vulpis infection in dogs.¹ Milbemycin oxime is safe for use in pregnant animals^1,15 and the oral formulation has been used extra-label for the treatment of B. procyonis, C. vulpis, Demodex spp., D. immitis microfilaria, Eucoleus spp., and Spirocerca lupi.^2,5,8,9 Outside the United States, milbemycin oxime has been combined with afoxolaner as a monthly broad-spectrum parasite control product.³⁵

Treatment of Unaffected Pets