ISRAEL JOURNAL OF
VETERINARY MEDICINE
Review
Vol. 58 (2-3)
2003
RECENT DEVELOPMENTS IN THE CONTROL OF
ECTOPARASITES AND ENDOPARASITES OF DOGS
AND CATS WITH SELAMECTIN
E. Pipano.
The Koret School of Veterinary Medicine, The Hebrew University of
Jerusalem. P.O. Box 12, 76100 Rehovot, Israel.
Ecto-and- endoparasites cause heavy burden, clinical disease and death in
dogs and cats. In addition to the damage they cause as pests, ectoparasites act as
vectors of veterinary and medical pathogens of importance while endoparasites
frequently cause zoonoses.
The last two decades have witnessed important changes in the provision of
veterinary services to pet animals. Animal owners have increasing expectations
of what can be achieved in terms of treatment and prevention of disease
conditions and tremendous expansion in veterinary pharmaceutical products has
resulted from the great effort to satisfy these expectations.
The list (published in 2001) of pesticides licensed by the Israeli Veterinary
Services, for treatment of pet animals comprises 110 compounds based mainly on
acetylcholinesterase inhibiting organophosphors and carbamates, synthetic
pyrethroids, natural pyrethrum, insect growth regulators, phenylpyrasoles,
nitromethylenes, amitraz, and natural etheric oils. Chlorinated hydrocarbons have
been banned for use with pet animals and livestock or in their surroundings.
Avermectins and milbemicins emerged as compounds having a high efficacy
against ectoparasites and effective in simultaneously killing nematode worms in
the host. As a result ivermectin, doramectin and milbemicin became well
accepted for the treatment of parasitic invasions in livestock. However,
avermectin and milbemycin compounds do not possess a therapeutic ratio
(chemotherapeutic index) in dogs and cats, adequate to achieve efficacious
treatment against ecto- and endopasites in these animals, and at the same time
having a high safety profile.
The recently developed endoctocide, selamectin, combines complete safety
with high anti-ectoparasitic and anti-helmintic activity in dogs and cats. The
following describes the characteristics of this product registered, in 2002 in
Israel, as a prescribed drug.
Selamectin
Selamectin is a semi-synthetic modification of doramectin produced from a
bio-engineered new strain of Streptomyces avermitilis (1). Similar to other
macrolitic lactones, it has a mechanism of action that may involve more than one
site (2). Selamectin causes neuromuscular paralysis in target parasites by
increasing permeability in neuronal chloride channels primarily through
glutamate-gaited channels. A possible target of GABA g-amino-butiric acid) modulated chloride channels is also suggested. Once selamectin is bound to the
receptor the chloride channels remains open and chloride ions flow into the nerve
cell. At the ultrastructural level, damage restricted to nerves and muscles are seen
one hour after feeding fleas on selamectin-treated animals. After 24 h an overall
cell lysis, including also epidermal, intestinal or sexual cell system is observed
(3). Because chloride channels in mammals are less accessible and less sensitive
to avermectins than those in arthropod parasites and nematodes, this class of
compounds possesses a wide therapeutic safety margin.
Bioavailability after dermal application in cats and dogs is 74% and 4.4%,
respectively. Grooming, resulting in oral ingestion of topically applied
selamectin, may account for its high bioavailability in cats. Selamectin is
absorbed rapidly after topical application and achieves a peak plasma
concentration three days after treatment. Following topical application,
selamectin is absorbed into the bloodstream and some of the compound is
excreted into the intestinal tract. Substantial amounts of circulating selamectin
are deposited in the sebaceous glands, which then act as reservoirs to provide
persistent activity against various ectoparasitic infections. (2). In both dogs and
cats the half life of selamectin (11 and 8 days respectively) following topical
application was substantially longer than the half life following intravenous
administration, indicating that a continuous and prolonged absorption occurs
from an extravascular site. Autoradiography studies of biopsy sites along the
dorsal, lateral and ventral thorax and abdomen revealed that selamectin was
present at all sites. In a microscopic evaluation of biopsy sites, selamectin was
identified in the sebaceous glands, hair follicles, and basal layers of the
epithelium. Following topical application, selamectin persist for extend periods at
concentrations that are effective against both internal and external parasites (1)
and the compound is taken up by ectoparasites mainly during the blood meal (3).
Efficacy against fleas
Fleas are one of the main target pests for which selamectin is indicated. The
life cycle of the cat flea (Ctenocephalides felis felis) has been researched
extensively and under common environmental conditions is completed in 35weeks (4). Once attached to a host, newly emerged adult fleas begin feeding
within a few minutes. Fleas mate after feeding and egg production begins within
24-48 h of the first blood meal. Eggs are laid on the host, but fall out of the hairy
coat (pellage), with approximately 70 % being dislodged within 8 h, and usually
accumulate in areas where pets sleep or rest (4). Hatching occurs in 1-6 days and
larvae develop in habitats where moderate temperatures and high relative
humidity occur. The newly hatched larvae are free- living, feeding on adult flea
fecal blood and on organic debris and tend to move down (because of positive
geotaxis and negative phototaxis) between carpet fibres, organic materials or in
the soil. The larva produces a silk cocoon inside which a pupa develops and the
later molts to the adult stage. The fully developed adult stage can survive in the
cocoon up to five months, and during this time it is extremely difficult to kill the
flea with insecticides because they do not penetrate into the base of the carpet or
the debris, rather than being due to any protective effect of the cocoon (5). Only
a very small portion ( about 5%) of the flea population lives and feeds on animals
, the remaining portion (95%) comprising eggs , larvae and pupae are spread
around the indoor habitat (6), while not all insecticides are efficacious on the
preimaginal stages.
The cat flea, C. felis felis, is widespread in Israel and although mainly
associated with the cat this arthropod has a low host specificity and can feed on a
large range of hosts including humans. Fleas have a direct effect on the host and
produce allergic conditions and anemia. Allergic dermatitis is a hypersensitive
state produced by the inoculation of saliva during feeding and is characterized by
intense pruritus, resulting in licking, chewing and scratching. The allergic
response is characterized by an immediate (10-15 min.) and delayed response
(24-48 h.) following repeated exposure to flea bites (7). Since fleas are
hematophagous insects they produce iron deficiency anemia particularly in
young animals while heavy infestations can lead to death of the host (8,9). Fleas
are vectors of Rickettsiae (murine typhus), bacteria (Yersinia), nematodes
(Dipetalonema) and cestodes (Dipyllidium and Hymenolepis). Dipylidium
caninum is very common among dogs in Israel and is often found in cats. The
eggs of this cestode are eaten by the flea larva and an oncosphere emerges from
each egg in the intestine of the larval flea and remains in the insect tissues until
the latter develops into an adult flea where it transforms to cysticercoid. Dogs
and cats infect themselves by eating infected fleas. Dogs and cats chew fleas
when grooming and set free cysticercoid on their coat, around the mouth and on
their tongue. Humans, especially children, may become infected accidentally by
swallowing cysticercoids which develop in their intestines to a medium sized
(25-40 cm.) tapeworm, and motile proglottids, the size of a rice grain, are passed
in the stool.
Studies for controlling C.felis were conducted to evaluate: 1) adulticidal
efficacy (killing adult fleas); 2) adulticidal efficacy following bathing of pets ; 3)
ovicidal and larvicidal efficacy (resulting in prevention of flea infestation) and 4)
effect of “debris” (dander, hair, scales and flea feces) from animals treated with
selamectin on the viability of flea eggs, larvae and adults (1).
Selamectin provided long-term efficacy against fleas for a period of at least 28
days after topical application (10). Dosages of 3,6,or 9 mg/kg were applied to a
single spot at the base of the neck in front of the scapulae. Dogs and cats were
infested with 100 (50 female and 50 male) viable C. felis on days 4,11,18, and 27
after the application of selamectin. The inert formulation ingredients (vehicle)
was used as the control. Seventy-two hours after each infestation (days 7,14, 21
and 30), a comb count to determine the number of viable fleas present on each
animal was performed. Up to day 21 the three dosages were so highly effective
that it was not possible to discriminate among them. On day 30, the 6 and 9 mg
dosages killed almost all fleas and were not different, which indicated that the
appropriate dosage of selamectin against adult fleas on dogs and cats for a period
of at least 27-30 days was 6 mg/kg (11).
The efficacy of 6 mg/kg dose was evaluated in eight controlled studies with
dogs and cats against C. felis and C.canis. Groups of 8-12 dogs or cats were
allocated randomly for each study. In dogs, a 99.2% and 91.8% efficacy was
obtained against C. felis and C. canis respectively, at the day 30 count. Groups of
12 dogs that received a single topical dose of 6 mg/kg selamectin were immersed
in water 2 h post application or bathed with shampoo at 2, 6, or 24 h post
application of the drug and before infestation with C. felis. The reduction of fleas
on day 30 after the application of selamectin ranged from 99.7% to 100%.
Similar experiments with C. felis on cats showed 98.8% of reduction for
unbathed cats, and 97.1 % to 99.4 % for bathed cats immersed in water after
application of selamectin (12).
The speed of kill efficacy of selamectin against adult fleas (adulticidal effect)
was evaluated with 44 dogs and 44 cats including control animals. Each animal
was infested with 100 unfed viable adult C. felis and flea comb counts were
performed every 12 hours for 48 h (a total of 4 counts) after treatment
application. The percentage of reduction for cats was 98.9 % after 24 h and for
dogs 99.8 % after 36 h. Both host species were completely free of fleas 48 h after
application of selamectin (13).
For egg hatch and larval development studies dogs and cats were housed in
cages designed for the collection of flea eggs. Each animal was experimentally
infested with 600 unfed viable adult C. felis on the day of application of
selamectin and on days 4,11,18, and 27 after the application. Flea eggs were
collected 72 h after each infestation over a period of 3 h after which any
remaining eggs or fleas were removed by combing. Usually adult fleas begin
feeding a few minutes after infesting a new host, and mating females begin to
produce eggs 24-48 h following their first blood meal. It follows that selamectin
with an about 98% adulticidal efficacy 24-36 h after application, may provide
only a short period over which flea eggs can be produced and shed into the
environment. In fact an approximate 98% reduction in eggs collected from fleainfested dogs treated with selamectin was observed. A reduction of 92.2 % and
95.6 % reduction in hatched eggs and larvae occurred in fleas from selamectintreated cats (13).
At the same time that adult female fleas lay eggs, they produce copious
amount of feces containing a high proportion of virtually undigested blood on
which larvae can feed. Debris, including flea feces, falling from selamectintreated dogs was also shown to have high ovicidal and larvicidal activity because
of their content of active selamectin, further reducing the possibility of any flea
eggs or larvae already in the environment of completing their life cycle. Most
debris and flea eggs tend to fall from animals where they stay longer, such as
favorite resting places, both indoor and outside. Therefore, control via exposure
to debris is targeted at areas more likely to have high pre-adult flea populations
(13). The efficacy of selamectin in treatment and prevention of C. felis was
evaluated in a simulated home environment (5). Cats were housed in carpeted
rooms and dogs were housed in accommodation with raised, carpeted sleeping
areas. Each of the 48 cats and 44 dogs allocated for the experiment was infested
with 100 fleas, 28 and 21 days before treatment with selamectin in order to
establish an environment of flea infestation. Selamectin was applicated to the
animals in the medicated groups three times at 30 days apart and six comb counts
were performed every 15 days starting from day 14 after the first treatment. By
day 90 of the experiment the mean number of fleas for each dog was 366.9 in the
controls versus 0.9 in the treated (99.8 % reduction) and for each cat, 435.7
versus 3.0 (99.3% reduction). In another environmental exposure experiment
dogs and cats were infested one and 7 days after treatment, a second treatment
being administered 30 days later. The percentage of reduction of flea infestation
was 99.8% for dogs and 100% for cats (5). In a third study (14), dogs and cats
were given five treatments at 30 days intervals and infested with fleas 28 and 21
days before treatment and then at weekly intervals. In the first treatment against
the pre-established infestation selamectin achieved over 97 % reduction and an
efficacy of 99.9% was maintained for the duration of the study. In comparative
studies selamectin was as effective as fipronil in treating cats and as effective as
fipronil and imidacloprid in treating dogs housed for three months in a fleainfested environment (15,16) or in controlled experiments (17). These results
show that monthly topical administration of selamectin is effective against flea
infestation of dogs and cats housed in heavily flea-infested environments and
also prevented the establishment of an environmental infestation, even when
fleas are introduced into conditions that are highly suited for their development.
Multi-center field studies were conducted in veterinary clinics in Europe (
UK, France, Germany and Italy ) and the USA. Dogs and cats infested with fleas
presented at the clinics were treated with commercial selamectin formulation at
presentation and subsequently after 30 and 60 days. Flea counts and clinical
observations were made on days 14,30,60 and 90. The animals designated as the
control group were treated with a fention (cholinesterase inhibitor
organophosphorus insecticide) preparation accompanied in some of the cases
with the use of an environmental spray containing insect growth regulator and
pyrethroid insecticide. An environmental spray was not used with selamectin.
Treatment of control animals with inactive ingredient was not applicable in the
veterinary field study because of ethical considerations. Cats in the USA
experiment were treated topically with pyrethroids. Dogs and cats treated with
selamectin showed a reduction of infestation between 90.7% and 99.8% for the
whole period of observation. Slightly lower percentages of reduction were
obtained with fention combined with pyrethrins and insect growth regulator
environment treatment (18). In pyrethrin-treated cats fleas were reduced by
66.4% to 81.3% (19). In the USA, supplementary clinical criteria such as
pruritus, erythema, scaling, alopecia, papules and dermatitis were used to
evaluate the beneficial results of selamectin treatment. A significant proportion
of flea-infested animals develop hypersensitivity to flea allergens resulting in
dermatitis. This condition is difficult to treat, because exposure to small numbers
of fleas may provoke a significant reaction. The percentage of dogs and cats
showing these dermatological conditions decreased significantly in selamectin
treated animal compared to the animals treated with other preparations. However
a total cure of all dermatological manifestations could not be achieved during the
experimental observation period (19).
Efficacy against mites
Sarcoptic mange
Sarcoptes scabiei is a parasitic mite that borrows into the skin of animals and
man causing a disease condition known as scabies or sarcoptic mange. The mites
of this species, that may be found on different hosts, are usually regarded as
being a variety of the species S. scabiei that are physiologically adapted to one or
more usual hosts, but can live, temporarily at least, on other unusual hosts. Adult
mites penetrate initially the skin of a new host by attaching to the skin with the
suckers of the two first pair of legs and then cutting the skin with the helicera and
the cutting-hooks of the last segment of the first two pairs of legs. The mite
usually borrows below the horny layer of the skin (Stratum corneum). The
burrows contain male and female mites, their feces, their eggs, hatched larvae
and nymphs. Eggs laid in the burrow hatch in 3-5 days. Six days later the sixlegged larva molt and become an eight-legged nymph and the latter molt to adult
female or male mites. Two stages of females are known, a first pubescent female
that moult two days later to a mature (ovigerous) female. The whole life history
from egg to mature female takes about two weeks. All developmental stages of S.
scabiei, except the egg, create burrows in the skin.
Canine scabies is a severely debilitating highly contagious condition, which
spreads through close contact between infested dogs or by contaminated fomites
(20). The mites suck the tissue fluid of the host and eventually feed on the horny
cells. They cause marked irritation of the skin and itching, which provokes
scratching or biting of the skin. Red papules and vesicles appear on the skin that
are followed by appearance of crusts formed of dry lymph. The connective tissue
of the skin proliferates and keratinisation is increased so that the skin becomes
thickened and wrinkled. The hair that are deprived of blood supply fall out
creating bald patches. Secondary bacterial infection makes the condition worse
and when large areas of skin are affected progressive emaciation and eventually
death occur. S. scabiei is considered to be a frequently transmitted zoonotic agent
(21). Forty two dogs with naturally acquired infestation of S. scabiei obtained
from commercial dog kennels where an outbreak followed an inadvertent
introduction of infested dogs (USA) or from a private hunting kennel which
experienced an outbreak of scabies (Europe) were treated on day 0 and day 30
with selamectin at the recommended dose and or with an inert vehicle mixture.
Counts of S.scabiei from skin scrapings were performed every 14-15 days up to
60 days after treatment. S.scabiei mites were reduced 93.5 % (USA) and 98.1 %
(Europe) on the first count after treatment and by 100 % for all remaining counts.
There was a clear reduction of the severity of the clinical signs for the selamectin
treated dogs compared with those treated with the vehicle mixture (22).
In another study dogs and cats presented at veterinary clinics in the USA and
Europe were treated against scabies infection with selamectin or other
insecticides containing phosmet or amitraz or N-(mercaptomethyl) phthalimide
S-(0,0-dimethyl phosphoro-didithioate). No S. scabiei were detected in over 95
% of the selamectin treated dogs, 30 days after a single dose and no mites were
recovered from any of the selamectin treated dogs after the second treatment. A
dramatic improvement in all six clinical signs of S. scabiei (pruritus, erythema,
crusting, papulae, alopecia and pyodermatitis) was observed in the course of
treatment. Similar results were achieved with the control products while repeat
treatments were necessary to control the infestation. When a dog is diagnosed
with S. scabiei infestation it is recommended that all dogs in contact also be
treated irrespective of whether they are showing clinical signs (23).
Ear mange
Otodectes cynotis is a psoroptic mite, which inhabits the depths of the ear
canal, near the eardrum, of dogs, cats and some other carnivores. Otodectes are
non-borrowing mites that complete their life cycle (egg to egg), in about two
weeks (minimum 11 days), on the skin of the host. The larva molts in 2-4 days to
a protonymph, which is followed by a tritonymph the latter giving rise to an adult
male or immature female. Female tritonymph attach to the male and remain so
until they molt into mature (ovigerous) females when insemination occurs. A
female lives 2 to 6 weeks and lay 30-40 eggs.
This mite sucks the host tissue fluid, causing inflammation and exudate of
lymph and the formation of crusts in the ears. Dogs begin to suffer earlier than
cats which are affected only after the disease is well established. The affected
animal shakes its head and scratches at the base of the ears and this symptom
may be followed by a discharge from the ears. Torticollis may result, or the
animal may turn in a circle or suffer from convulsions and epileptiform fits.
Bacterial infection of the ear may lead to ulceration and perforation of the ear
drum with resultant infection of the internal ear and possibly of the brain.
Human infestations by the dog ear mite have been reported (24).
The efficacy of the commercial preparation of selametin in the treatment of
naturally acquired aural infestation of O. cynotis on dogs and cats was evaluated
under experimental conditions in 48 dogs and 32 cats. The cats received one
treatment and the dogs two treatments, one month apart. Percentage reductions in
mean mite counts for selamectin treatment compared to the dogs and cats treated
with vehicle solution were 100% for all animals on all counts (24). In a field
study with a variety of breeds and ages, dogs (83) and cats (144) presenting as
clinical cases in veterinary practices in USA and Europe (UK, France and Italy)
were treated by topical application of selamectin at the base of the neck or by
other approved otic preparations (positive control group) instilled directly in the
external ear canal. Selamectin eliminated mites in cats 94.3 % (Europe) and 100
% (USA), versus 87.9 % and 92.9 % respectively by the instilled otic products. In
dogs the percentages of efficacy were 90.4 % for selamectin and 65 % for otic
products (23).
Otic preparations currently available for treatment of ear mites require daily
applications for up to four weeks, while the otitis causes acute pains whenever
the ears are handled. The topical application of selamectin on an unaffected area
of the body and the prolonged activity after application circumvent the above
posology.
Efficacy against ticks
R. sanguineus (the brown dog tick) belongs to the family Ixodidae (hard ticks)
which are large blood-sucking acari with a terminal capitulum in all stages and a
dorsal shield (scutum) which shows sexual dimorphism - small in the female and
almost covering the dorsal surface in the male. This tick species parasitizes
mainly dogs and other canines but it may feed on a wide variety of mammals
including man and also birds. Domestic cats are infrequent hosts of this tick. R.
sanguineus is one of the most widespread ticks in the world and causes heavy
infestation of dogs in Israel. It may appear as an urban tick infesting homes and
kennels or as a field tick feeding on rodents, hares, hedgehogs, domestic animals,
wild carnivores and dogs. In the Mediterranean coastal area it readily attaches to
man (25).
There are four stages in the life cycle of hard ticks: egg, larva, nymph and
adult. The female drops off its vertebrate host and seeks a sheltered site to lay a
single large batch of 2 to 4 thousand brown globular eggs, after which she dies.
Depending upon environmental conditions the eggs hatch in two weeks to several
months giving rise to a hexapod larva. Each of the parasitic stages engorge on a
host and then drop on the ground, the larva and nymph in order to molt, and the
adult female for oviposition. Unfed larvae or nymphs may survive for about six
months without a meal, and adults for more than one year, though two or three
generations a year seem to occur in subtropical areas. According to
environmental conditions, the length of the life cycle of this tick may be a
minimum of two months to a maximum of more than one year. As they feed,
ticks alternate between imbibing blood components present in the feeding lesion,
and returning excess fluid back to the host via saliva, thus concentrating on the
blood meal nutrients and regulating haemolymph volume and ionic composition
(26).
R. sanguineus transmits many pathogens among dogs and other vertebrates:
Babesia canis and B. vogeli, Hepatozoon canis, Rickettsia conori, R. canis, R.
rickettsii, Ehrlichia canis, Pasteurella tularensis, Borrelia hispanica and
Coxiella burnetti. In Israel this tick species appears to be the sole vector of
canine babesiosis, hepatozoonosis and ehrlichiosis, and is responsible for the
transmission of the Israeli-Mediterranean spotted fever (caused by R. conori)
(25). Saliva of R. sanguineus has a marked immunosuppresive activity by
impairing T cell-proliferation, antigen presentative and IFN-g induced
macrophage microbicidal activity (26). A series of controlled studies was
conducted to investigate the efficacy of selamectin against weekly infestation
with 50 adult R. sanguineus. A two-week interval treatment regimen provided an
efficacious control against this tick. Monthly treatment with selamectin was also
effective and the addition of a treatment at 14 days after the first treatment
improved efficacy, particularly in the several weeks following the additional
treatment (27). Selamectin controlled also against the American dog tick
(Dermacentor variabilis), which is not present so far in Israel. This drug,
however, has no practical repellent activity as shown by a test with Ixodes ricinus
ticks (28).
Efficacy against nematodes
Three species of ascarids are commonly found in Israel: Toxocara canis
(infecting dogs), Toxocara cati (infecting cats), and Toxascaris leonina (infecting
dogs and cats). The adult females of this worm may reach a length of 18 cm for
T. canis and 10 cm for the other two species. Transmission in all species may be
direct by ingesting eggs or transuterine by larvae from the tissues of infected
females to the fetuses. The life cycle of the ascarids comprises eggs produced by
the female and five larval stages that develop in various organs and the intestine
of the host.
A female may lay about 200.000 eggs per day, which are excreted in the feces
of the host and shed in the environment. An infective larval stage develops within
the eggs on the ground in 3-7 days between a wide temperature range (150 to
350 C). The eggs which posses a thick protective shell may survive in the
environment for more than one year. After ingestion by the host, the eggs hatch
to release the second stage larva. Extensive somatic and tracheal types of
migrations of the larvae occur before they develop to adults. The larvae migrate
from the intestine through the liver to the lungs and then through the trachea and
the oesophagus to the intestine.
Prenatal infection is extremely common in T. canis infection, however
infection occurs also by ingestion of eggs by adult dogs as well as by young
puppies. After the initial infection larvae are able to remain dormant in the bitch
in various tissues for nearly all her lifetime and she may transmit infection to
several litters. Coprologic examination of bitches infected with tissue larvae may
show negative results, however, they are still capable of transmitting infection to
their progeny. Activation of the larvae in the bitch, followed by migration to the
fetus, occurs usually around the 42nd day of pregnancy and third stage larvae
(1.0 mm of length) are found in the lungs of the fetuses before birth. A molt to
the fourth larval stage (5-7 mm) occurs in puppies during the first week after
birth when they are found in the intestine. Throughout the second and third week
after birth a fifth larva stage grow rapidly to become an adult worm.
Rodents and some invertebrates are susceptible to Toxocara and Toxascaris
infections and second stage larvae that develop in these paratenic hosts may
infect dogs and cats predating on infected mice or cockroaches.
Ascarids are particularly injurious to puppies and kittens. The commonest
signs are unthriftiness, digestive disturbances, bloated and pot bellied
appearance. Puppies with heavy prenatal infection with T. canis suffer from
mucoidal diarrhea, show frequent vomiting and occasionally die from intestinal
obstruction or perforation. Anemia and nervous disturbances are observed
although no satisfactory explanation for this manifestation exists. Migration
through the lungs may trigger pneumonia which is complicated by secondary
infections.
Toxocariasis in man (observed mostly in children) is caused mainly by T.
canis, but also T.cati and T.leonina have been incriminated. The visceral larva
migrans symptoms are provoked by lesions in the brain, eyes or other organs and
are accompanied by persistent eosinophilia. Ocular larva migrans causes
granulomatous inflammation, which may result in a variety of other clinical
symptoms including keratitis, iridocyclitis, chronic endophthalmitis and detached
retina. Treatment with antinematodal drugs (diethyl carbamazine, thiabendazole,
mebendazole) has little effect and may worsen the situation by killing the parasite
in situ.
The efficacy of selamectin against experimentally induced and naturally
acquired T. canis and T. leonina in dogs was evaluated in controlled and field
studies. For induced infections, there were significant reductions in the mean
numbers of adult
T. canis after a single application of selamectin( 93.9 - 98.1 %), after two
monthly applications (88.3 - 98.6 %), and 100 % after three monthly
applications. In the naturally infected dogs in the controlled studies, when
selamectin was administered twice at an interval of 30 days, the percentage of
reductions in mean numbers of adult T. canis at necropsy were 84.6, 91.3, and
97.9%. When selamectin was adminitered on days 0, 14, and 30, the percentage
reductions were 91.1 and 97.6 %. Mean fecal T. canis eggs counts were reduced
by > 92.9 % at the end of the controlled studies. In the field studies mean fecal
egg counts were reduced by 89.5 and 95.5%, for 14 and 30 days respectively
after a single treatment with selamectin, and by 94.0 %, 30 days after the second
treatment with selamectin (29). To prevent intrauterine infection of pups
endemically infected with T. canis, bitches were treated with selamectin at
presumed 40 and 10 days before parturition and 10 and 40 days after parturition
(selamectin was not given to the pups). A reduction in egg count of 99.7 % in the
bitches and 96.1 to 98.2 % in the pups was observed following treatment
compared to the infestation recorded in the dogs treated with inactive ingredients.
It appears that somatic larvae that are usually reactivated during the last three
weeks of pregnancy (and migrate through the placenta ) were killed by
selamectin before being established in the fetus. The treatment also prevented
possible milk infestation of the pups (30).
In cats a study of the efficacy of selamectin against experimental (500
embryonated eggs, 56 days prior to treatment) and naturally acquired infections
with T. cati was carried out by a count of adult worms at necropsy, performed 14
days after treatment. A single application of selamectin provided 100 %
reduction in adult worms for both experimentally and naturally acquired
infections (31).
Ancylostominae (hookworms) are strongylid nematodes with a well-developed
buccal capsule armed on its ventral margin with teeth or chitinous cutting plates.
Eggs of A. tubaeforme have been detected at coprologic examinations of cat
feces in Israel. The life cycle of this parasite includes a larva that hatches on the
soil and becomes infective in about one week and four stages that develop in the
host. Infection is oral or by skin penetration, a prenatal (intra-uterine) and
lactogenic (colostral) similar to the A. caninun pathway were also suggested. A.
tubaeforme is a voracious bloodsucker and anemia accompanied by iron
depletion is the principal consequence of its infestation. Topical treatment with
selamectin of cats infected with A. tubaeforme only or cats carrying both A.
tubaeforme and T. cati was highly effective in naturally acquired or
experimentally induced infections (31).
A total of 19 veterinary practices in USA, France, Germany and Italy
participated in a series of studies including 298 cats of various ages and breeds
that carried one or more of the following parasites: Toxocara cati, Toxascaris
leonina, Ancylostoma spp. and Uncinaria stenocephala. Cats with confirmed, by
egg count, ascarid and hookworm infections were treated twice with commercial
preparation of selamectin at monthly intervals. Two additional quantitative fecal
examinations were performed on days 30 and 60 after the treatment. A reduction
of the pretreatment individual count of 99 % to total disappearance of eggs from
the feces was observed at the second and third quantitative counts (32).
Heartworm
Heartworm (Dirofilaria immitis) is a nematode that can reach 25 - 30 cm in
length mainly in the right ventricle of the heart and pulmonary artery of dogs,
cats and wild canids. The female worm is ovoviviparous and microfilariae may
be found in the blood during the whole period of the infection. This parasite is
transmitted by several genera of mosquitoes (intermediate hosts) in which it
undergoes development and migration. Maturity in the final host is reached about
five months after infection. Selamectin was 100% effective in preventing
heartworm development in dogs when administered as a single topical dose 30,
45, or 60 days after infection in laboratory and field studies. A single dose also
induced total protection in cats. Selamectin remained 100 % effective at half (3.0
mg/kg) the recommended dosage (33,34). Autochthonous infection with
heartworm has not yet been diagnosed in Israel, but selamectin treatment can be
administered when pets are taken to endemic areas.
Safety of selamectin
The clinical safety of selamectin was evaluated in oral and topical application
of single and multiple doses to dogs and cats of various ages, breeds and
physiological conditions.
Safety in dogs
In a margin safety study 20 male and 20 female 6 weeks old beagles received
topical application of saline or 1x, 3x, 5x, and 10x multiples of the unit dosage (6
mg/kg) of selamectin for a total of 7 treatments. Despite the extremely high
dosages in some of the treated animals none displayed clinical or neurologic
signs or developed clinical or pathological abnormalities as a result of the
treatment.
In 12 dogs (including saline treated controls) a single unit oral dose of
selamectin caused no adverse effects or signs of toxicosis during 30 days after
application. In reproductive safety studies, fertility of each animal was proven by
siring or bearing at least two litters of four or more pups per litter. Female dogs
were treated every 28 days with a 3x multiple dosage unit of selamectin before
mating. After mating treatment was adjusted to the day of mating or 15 days after
mating until the pups were weaned at 6 weeks of age. Male dogs received every
two weeks a 3x multiple unit dosage (a total of 17 dosages) until each male had
mated with two females in estrous. Conception rates and whelping indices
(number of total live pups/ number of pregnant animals per treatment) for both
control and selamectn treated male dogs were similar. Conception rates of
females were 90 % for the selamectin treated versus 90 and 100 % in the controls
in the various experimental groups. About the same numbers of non-viable pups
and perinatal death were observed in litters of treated and control beaches. None
of the pups had congenital abnormalities (35).
Rough-coated Collies are more sensitive to central nervous system toxicity
associated with avermectins (36). A single topical dose of 40 mg/kg selamectin
produced no abnormalities in avermectin-sensitive Collies. Three treatments
every 28 days with five times the recommended dosage of selamectin or with
saline resulted in sporadic mild salivation in both groups (35).
Special attention was paid to the safety of selamectin treatment in animals
suffering from parasite burden. Neither adult heartworms nor circulating
microfilariae posed risk when selamectin was administered topically at three
times the recommended dose (35). In a total of 648 doses of selamectin
administered to 168 dogs infested with the dog tick only some of them displayed
mild salivation about two hours after the first treatment (27). No adverse
reactions in dogs were observed in five consecutive treatments aimed to prevent
repeat flea infestations (19), or in animals infected with gastrointestinal
nematodes (32).
Safety in cats
Safety of selamectin to cats was tested in a similar experiment to the dog
safety studies. Topical application of up to 10 times the recommended dose to six
week and adult cats, and to fertile female and male cats yielded no evidence of
toxicosis. Oral administration of the topical solution to cats provoked transient
salivation and intermittent vomiting for up to 56 h after dosing, but cats
exhibiting these signs recovered completely without supportive medication.
Selamectin had no adverse effects on clinical pathology markers of liver and
kidney functions of cats with multiple unit doses (37).
Conclusions
Selamectin is a single broad-spectrum parasiticide that combines antiarthropod with anti-nematodal activity (1). It kills more than 98% of the fleas
present on the host within 24 to 36 h of application. It also breaks the life cycle
by killing adult fleas and flea eggs and by reducing maturation of eggs to larvae
and adults. Monthly treatment not only directly protected host animals from flea
infestation but also interrupted the flea’s breeding cycle and severely diminished
the residual population of fleas in the household environment. Elimination of
mange and ear mites is achieved by two topical applications one month apart.
Monthly treatment with an additional treatment at 14 days after the first treatment
proved a high efficacy against the wide spread brown dog tick in Israel.
Selamectin acted as an effective drug against hookworms and ascarids by
eliminating more than 99% of the roundworm intestinal burden. It represents the
only “spot on” that is active against external and internal parasites and has a
therapeutic effect in pups nursing on selamectin treated dams. Successful
treatment of pests and worms in domestic pets as well as improving animal
health contributes to promoting public health by decreasing or eliminating the
risk of zoonotic infections.
Selamectin possesses a high safety profile in six weeks old and older puppies
and kittens, in breeding dogs and cats, in ivermectin sensitive breeds, in heavily
parasitised animals with ecto- and endo-parasites and heartworm, and following
accidental oral ingestion by treated animals. It is the only “spot on”
recommended for 6-week old pups.
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