topical selamectin flea and heartworm trial safe effective

[malernee]

Efficacy and safety of selamectin against fleas and heartworms in dogs and cats presented as veterinary patients in North America.
Vet Parasitol 91[3-4]:233-50 2000 Aug 23

Boy MG, Six RH, Thomas CA, Novotny MJ, Smothers CD, Rowan TG, Jernigan AD
A series of randomized, controlled, masked field studies was conducted to assess the efficacy and safety of selamectin in the treatment of flea infestations on dogs and cats, and in the prevention of heartworm infection in dogs. In addition, observations were made on the beneficial effect of selamectin treatment on dogs and cats showing signs of flea allergy dermatitis (FAD). In all studies selamectin was applied topically, once per month, in unit doses providing a minimum dosage of 6mgkg(-1). Dogs and cats with naturally occurring flea infestations, some of which also had signs associated with FAD, were assigned randomly to receive three months of topical treatment with selamectin (220 dogs, 189 cats) or a positive-control product (dogs: fenthion, n=81; cats: pyrethrins, n=66). Selamectin was administered on days 0, 30, and 60. Day 0 was defined as the day that the animal first received treatment. Flea burdens were assessed by flea comb counts and clinical evaluations of FAD were performed before treatment, and on days 14, 30, 60, and 90. On days 30, 60, and 90, mean flea counts in selamectin-treated dogs were reduced by 92.1, 99.0, and 99.8%, and mean flea counts in fenthion-treated dogs were reduced by 81.5, 86.8, and 86.1%, respectively, compared with day 0 counts. Also, on days 30, 60, and 90, mean flea counts in selamectin-treated cats were reduced by 92.5, 98.3, and 99.3%, and mean flea counts in pyrethrin-treated cats were reduced by 66.4, 73.9, and 81.3%, respectively, compared with day 0 counts. Selamectin also was beneficial in alleviating signs in dogs and cats diagnosed clinically with FAD. A total of 397 dogs free of adult heartworm infection from four heartworm-endemic areas of the USA were allocated randomly to six months of treatment with selamectin (n=298) or ivermectin (n=99). Selamectin achieved a heartworm prevention rate of 100%, with all dogs testing negative for microfilariae and adult heartworm antigen on days 180 and 300. Selamectin was administered to a total of 673 dogs and 347 cats having an age range of 6 weeks to 19 years (3954 doses). The animals included 19 purebred or crossbred Collies (Bearded, Border, and unspecified). There were no serious adverse events. Results of these studies indicated that selamectin was highly effective in the control of flea infestations in dogs and cats without the need for simultaneous treatment of the environment or of in-contact animals and also was beneficial in alleviating signs associated with FAD. Selamectin also was 100% effective in preventing the development of canine heartworms and was safe for topical use in dogs and cats.


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[malernee]

Pharmacokinetics of selamectin following intravenous, oral and topical administration in cats and dogs.

Sarasola P, Jernigan AD, Walker DK, Castledine J, Smith DG, Rowan TG.

Veterinary Medicine Clinical Development, Pfizer Animal Health Group, Pfizer Ltd, Sandwich, Kent, UK.

The pharmacokinetics of selamectin were evaluated in cats and dogs, following intravenous (0.05, 0.1 and 0.2 mg/kg), topical (24 mg/kg) and oral (24 mg/kg) administration. Following selamectin administration, serial blood samples were collected and plasma concentrations were determined by high performance liquid chromatography (HPLC). After intravenous administration of selamectin to cats and dogs, the mean maximum plasma concentrations and area under the concentration-time curve (AUC) were linearly related to the dose, and mean systemic clearance (Clb) and steady-state volume of distribution (Vd(ss)) were independent of dose. Plasma concentrations after intravenous administration declined polyexponentially in cats and biphasically in dogs, with mean terminal phase half-lives (t(1/2)) of approximately 69 h in cats and 14 h in dogs. In cats, overall Clb was 0.470 +/- 0.039 mL/min/kg (+/-SD) and overall Vd(ss) was 2.19 +/- 0.05 L/kg, compared with values of 1.18 +/- 0.31 mL/min/kg and 1.24 +/- 0.26 L/kg, respectively, in dogs. After topical administration, the mean C(max) in cats was 5513 +/- 2173 ng/mL reached at a time (T(max)) of 15 +/- 12 h postadministration; in dogs, C(max) was 86.5 +/- 34.0 ng/mL at T(max) of 72 +/- 48 h. Bioavailability was 74% in cats and 4.4% in dogs. Following oral administration to cats, mean C(max) was 11,929 +/- 5922 ng/mL at T(max) of 7 +/- 6 h and bioavailability was 109%. In dogs, mean C(max) was 7630 +/- 3140 ng/mL at T(max) of 8 +/- 5 h and bioavailability was 62%. There were no selamectin-related adverse effects and no sex differences in pharmacokinetic parameters. Linearity was established in cats and dogs for plasma concentrations up to 874 and 636 ng/mL, respectively. Pharmacokinetic evaluations for selamectin following intravenous administration indicated a slower elimination from the central compartment in cats than in dogs. This was reflected in slower clearance and longer t(1/2) in cats, probably as a result of species-related differences in metabolism and excretion. Inter-species differences in pharmacokinetic profiles were also observed following topical administration where differences in transdermal flux rates may have contributed to the overall differences in systemic bioavailability.

[malernee]

Pharmacokinetics of selamectin in dogs after topical application.
Vet Res Commun 28[5]:407-13 2004 Jul

Dupuy J, Derlon AL, Sutra JF, Cadiergues MC, Franc M, Alvinerie M
Some pharmacokinetic parameters of selamectin were determined in male (n = 5) and female (n = 5) Beagle dogs following a topical application at a dose rate of 6 mg/kg. The plasma concentration versus time data for the drug were analysed using a one-compartment model. The maximum plasma concentrations of 12.72 +/- 5.13 ng/ml for males and 22.65 +/- 11.95 ng/ml for females occurred around 5 days after administration. The area under the concentration-time curve (AUC) was 192.08 +/- 63.85 ng.day/ml for males and 370.97 +/- 146.87 ng.day/ml for females. The mean residence time was the same in males and females (12.55 days). This study reveals a sex-influence on the disposition of selamectin in the plasma of dogs, which implies that further information will be needed for correlation with efficacy studies in dogs.

[malernee]

Efficacy of Selamectin in the Treatment of Nasal Mite (Pneumonyssoides caninum) Infection in Dogs.
J Am Anim Hosp Assoc 40[5]:400-4 2004 Sep-Oct

Gunnarsson L, Zakrisson G, Christensson D, Uggla A
In a laboratory study to evaluate the efficacy of selamectin for treatment of canine nasal mite infection, 12 purpose-bred beagles were experimentally infected with Pneumonyssoides caninum (P. caninum). Six of the dogs were treated with selamectin applied to the skin of the back at dosages of 6 to 24 mg/kg for three times at 2-week intervals. The remaining six dogs were an untreated control group. At necropsy 39 to 46 days after inoculation, no P. caninum mites were found in any of the treated dogs. In contrast, nasal mites were found in five of the untreated dogs. This difference was statistically significant at P=0.015.

[malernee]

http://www.fda.gov/cvm/index/ade/ade_web_rpts2000.htm

[guest]

Veterinary Parasitology 116 (2003) 45–50
Comparison of the activity of selamectin, fipronil,
and imidacloprid against flea larvae
(Ctenocephalides felis felis) in vitro
T.L. McTier a,∗, N.A. Evans b, M. Martin-Short c, K. Gration c
a Pfizer Animal Health Group, Veterinary Medicine Research and Development,
Eastern Point Road, Mail Stop 8200-40, Groton, CT 06340, USA
b Pfizer Animal Health Group, Technical Product Development, New York, NY, USA
c Pfizer Animal Health Group, Veterinary Medicine Research and Development,
Sandwich, Kent CT13 9NJ, Kent, UK
Received 23 October 2002; received in revised form 14 April 2003; accepted 15 April 2003
Abstract
The activity of selamectin, fipronil and imidacloprid against larval cat fleas (Ctenocephalides
felis felis) was evaluated in an in vitro potency assay system. One hundred microliters of each
compound at various concentrations in acetone were added to glass vials (1.5 by 3 cm) to which
had been previously added 20 mg of sand and 10 mg of flea feces. Vials were then ball milled to
allow the acetone to evaporate. Selamectin and fipronil were tested at 0.001, 0.003, 0.005, 0.01,
0.03, 0.05, 0.11, 0.3, and 0.5
g of active compound per tube. Imidacloprid was tested at 0.01,
0.03, 0.05, 0.1, 0.3, 0.5, 1.0, 3.0, and 5.0
g of active compound per tube. Thirty first instar C. felis
larvae were added to each vial. The number of larvae remaining alive in each vial was determined
once daily for 72 h. With selamectin, reductions of ≥93.5% were achieved at 24 h after exposure
at doses of ≥0.3
g. In contrast, at 24 h neither fipronil nor imidacloprid reached 90% reduction,
even at the highest doses tested (0.5
g for fipronil and 5.0
g for imidacloprid). Selamectin was
significantly (P ≤ 0.05) more potent than imidacloprid and fipronil at levels ≥0.03
g. A similar
pattern of activity was observed at both 48 and 72 h, but higher percentages of larvae were killed
for each of the compounds as the incubation time increased. At 72 h selamectin was significantly
(P ≤ 0.05) more potent than imidacloprid at levels of 0.01–0.1
g and significantly (P ≤ 0.05)
more potent than fipronil at levels of 0.003–0.01
g. Therefore, selamectin was more potent than
either fipronil or imidacloprid in killing flea larvae in this in vitro assay system.
© 2003 Published by Elsevier B.V.
Keywords: Selamectin; Fipronil; Imidacloprid; Larval fleas; Ctenocephalides felis; In vitro assay
∗ Corresponding author. Tel.: +1-860-441-6454; fax: +1-860-715-9031.
E-mail address: tom l mctier@groton.pfizer.com (T.L. McTier).
0304-4017/$ – see front matter © 2003 Published by Elsevier B.V.
doi:10.1016/S0304-4017(03)00163-8
46 T.L. McTier et al. / Veterinary Parasitology 116 (2003) 45–50
1. Introduction
The activity of selamectin (Revolution®/Stronghold®, Pfizer Animal Health), a monosaccharide
avermectin endectocide, against adult cat fleas, Ctenocephalides felis felis, (hereafter
referred to as C. felis) has been well documented (McTier et al., 2000a). The ability
of selamectin to control environmental flea infestation has been demonstrated in several
different types of study designs (Shanks et al., 2000; Dryden et al., 2001a). The potent activity
of selamectin in debris (dander, flea feces, hair) from selamectin-treated dogs against
normal flea eggs and larvae has been demonstrated in vitro (McTier et al., 2000b). In addition,
previous work has shown that selamectin has potent ovicidal activity in vivo (McTier
et al., 2000b; Dryden et al., 2001b). The objective of the present study was to compare the
activity of selamectin, fipronil, and imidacloprid against larval fleas (C. felis) using an in
vitro potency assay.
2. Materials and methods
Selamectin, fipronil and imidacloprid were made up as stock solutions consisting of
500
g of active compound per milliliter in acetone. From 8 to 10 different test concentrations
of each compound were formulated from these stock solutions by dilution with
acetone. One hundred microliters of each test solution were added to glass vials (1.5 by
3 cm) to which had been previously added 20 mg of sand and 10 mg of flea feces. The vials
were then ball milled to allow the acetone to evaporate. Selamectin and fipronil were tested
at 0.001, 0.003, 0.005, 0.01, 0.03, 0.05, 0.11, 0.3, and 0.5
g of active compounds per tube.
Imidacloprid was tested at 0.01, 0.03, 0.05, 0.1, 0.3, 0.5, 1.0, 3.0, and 5.0
g of active
compound per tube. Approximately 30 first instar C. felis larvae were then added to each
vial, the vials were closed with a porous plug and incubated under appropriate conditions
to maintain the flea larvae. The number of live flea larvae remaining in each vial was determined
once daily over a 72 h period following incubation. Four separate replicates were
conducted using the same protocol, and results were combined.
Percentage of dead flea larvae in each tube was transformed using an arcsine square root
transformation of the proportion. Data were analyzed using a mixed model for repeated
measures. Fixed effects included compound, dose, time and the interaction of those effects.
Random effects included residual and replicate. Contrasts among least squares means of
transformed percent death data were used to assess differences among treatment combinations
at each time point. The 5% level of significance (P ≤ 0.05) was used to assess
statistical differences. Efficacy was calculated as a mean percentage of flea larvae killed
from four separate replicates combined.
3. Results
For selamectin, reductions of ≥93.5% were achieved at 24 h after exposure at doses of
≥0.3
g per tube (Fig. 1). At 24 h neither fipronil nor imidacloprid reached 90% reduction,
even at the highest doses tested (0.5
g for fipronil and 5.0
g for imidacloprid). Selamectin
was significantly (P ≤ 0.05) more potent than imidacloprid and fipronil at levels ≥0.03
g.
T.L. McTier et al. / Veterinary Parasitology 116 (2003) 45–50 47
Fig. 1. Activity of selamectin, imidacloprid, and fipronil in killing flea larvae in vitro at 24 h after exposure.
At 48 h selamectin reached the 90% reduction level at a dose of 0.03
g, and a 100%
reduction was achieved at ≥0.1
g (Fig. 2). In contrast fipronil did not reach the 90% level
until a 3×higher dose (0.1
g), and imidacloprid did not reach this level until a 100×higher
dose (3.0
g). Selamectin was significantly (P ≤ 0.05) more potent than imidacloprid at
all commonly used levels tested (0.01–0.5
g) and significantly (P ≤ 0.05) more potent
than fipronil at levels of 0.003–0.01
g.
Fig. 2. Activity of selamectin, imidacloprid, and fipronil in killing flea larvae in vitro at 48 h after exposure.
48 T.L. McTier et al. / Veterinary Parasitology 116 (2003) 45–50
Fig. 3. Activity of selamectin, imidacloprid, and fipronil in killing flea larvae in vitro at 72 h after exposure.
At 72 h, a pattern similar to that at 48 h was observed. Selamectin killed 98.5% of the
larvae at the 0.03
g level and killed 100% of the larvae at doses of ≥0.05
g (Fig. 3).
Reductions of 94 and 100% were observed for fipronil at 0.05
g and≥0.3
g, respectively.
Imidacloprid was obviously less potent, with a 98.5% reduction at 0.3
g and a 100%
reduction at ≥0.5
g, excluding the 1
g dose. Selamectin was significantly (P ≤ 0.05)
more potent than imidacloprid at levels of 0.01–0.1
g and significantly (P ≤ 0.05) more
potent than fipronil at levels of 0.003–0.01
g.
4. Discussion
Selamectin demonstrated potent activity against flea larvae in this in vitro assay system.
Overall selamectin was more potent than either fipronil or imidacloprid. In this assay, flea
larvae received not only direct contact exposure, but also had the opportunity for systemic
exposure via oral ingestion of the flea feces. Such a design mimics the potential exposure
routes for flea larvae in home environments where pets have been treated with topical
parasiticides. Selamectin’s activity against adult fleas is known to have both systemic and
contact components, with the primary activity probably systemic through ingestion of blood
containing selamectin (Bishop et al., 2000; Melhorn et al., 2001). Imidacloprid’s activity
against adult fleas seems to be primarily through contact, but interestingly fipronil’s activity
seems to be primarily systemic (Melhorn et al., 2001). Flea feces from fleas that have fed on
selamectin-treated animals contain detectable levels of selamectin (Pfizer, data on file), and
debris (flea feces, dander, hair) from selamectin-treated dogs is known to be both ovicidal
and larvicidal (McTier et al., 2000b). For larval fleas in the environment, ingestion of flea
T.L. McTier et al. / Veterinary Parasitology 116 (2003) 45–50 49
feces containing compounds systemically active against larval fleas may represent a more
important route of exposure, as larvae are attracted to adult flea feces as the preferred, even
essential, source of nutrition (Rust and Dryden, 1997). In addition, more eggs, debris and flea
feces tend to fall in areas where the host animal spends the most time, and most flea larvae
remain within the vicinity of where the eggs fall into the environment (Rust and Dryden,
1997). Thus, flea feces containing selamectin would automatically be targeted to areas most
likely to have higher egg and larval flea populations. Therefore, in the environment, flea
larvae would be more likely killed by ingesting feces, containing a drug like selamectin,
to which they are attracted than through incidental contact exposure of larvae to hair and
debris, from a pet treated with a drug like imidacloprid. Several studies have shown that
imidacloprid kills adult fleas faster than selamectin on dogs (Everett et al., 2000; Melhorn,
2000; Melhorn et al., 2001). However, speed of kill appears less critical in actual use
situations, as studies in both dogs and cats have shown that selamectin is as effective as
imidacloprid and fipronil in controlling environmental flea infestation, as assessed by animal
flea counts as well as light traps to capture adult fleas in the environment (Ritzhaupt et al.,
2000a,b; Dryden et al., 2001a). It is likely that a substantial component of selamectin’s
ability to control environmental infestation is due to activity against flea eggs and larvae.
Although selamectin was more potent than either imidacloprid or fipronil in this in vitro
system, care should be taken in extrapolating these results to a product use situation where
dose levels of products to which larval flea populations may actually be exposed are unknown.
However, it is noteworthy that the actual minimum dose actually applied to the
animal as per label instructions is lower for selamectin (6 mg/kg) than for either imidacloprid
(10 mg/kg) or fipronil (7.5 mg/kg).
5. Conclusions
Selamectin was more potent in killing flea larvae in this in vitro assay system than either
fipronil or imidacloprid, achieving higher reductions more quickly at lower doses.
Acknowledgements
This study was funded by Pfizer Inc., New York, NY.
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Holbert, M.S., Blagburn, B.L., 2000b. Evaluation of the effects of selamectin against adult and immature
stages of fleas (Ctenocephalides felis felis) on dogs and cats. Vet. Parasitol. 91, 201–212.
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Melhorn, H., Hansen, O., Mencke, N., 2001. Comparative study on the effects of three insecticides (fipronil,
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Ritzhaupt, L.K., Rowan, T.G., Jones, R.L., 2000b. Evaluation of efficacy of selamectin and fipronil against
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Rust, M.K., Dryden, M.W., 1997. The biology, ecology, and management of the cat flea. Ann. Rev. Entomol. 42,
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Safety of selamectin in cats.
Vet Parasitol 91[3-4]:393-403 2000 Aug 23

Krautmann MJ, Novotny MJ, De Keulenaer K, Godin CS, Evans EI, McCall JW, Wang C, Rowan TG, Jernigan AD
Animal Health Clinical Affairs, Central Research Division, Pfizer Inc., Groton, CT 06340, USA. matthew_j_krautmann@groton.pfizer.com
The safety of the avermectin, selamectin, was evaluated for topical use on the skin of cats of age six weeks and above, including reproducing cats and cats infected with adult heartworms. All studies used healthy cats. Acute safety was evaluated in domestic cross-bred cats. Margin of safety was evaluated in domestic-shorthaired cats, starting at six weeks of age. Reproductive, heartworm-infected, and oral safety studies were conducted in adult, domestic-shorthaired cats. Studies were designed to measure the safety of selamectin at the recommended dosage range of 6-12mgkg(-1) of body weight. Assessments included clinical, biochemical, pathologic, and reproductive indices. Selected variables in the margin of safety study and the reproductive studies were subjected to statistical analyses by using a mixed linear model. Cats received large doses of selamectin at the beginning of the margin of safety study when they were six weeks of age and at their lowest body weight, yet displayed no clinical or pathologic evidence of toxicosis. Similarly, selamectin had no adverse effect on reproduction in adult male and female cats. There were no adverse effects in heartworm-infected cats. Oral administration of the topical formulation, which might occur accidentally, caused mild, intermittent, self-limiting salivation and vomiting. Selamectin is a broad-spectrum avermectin endectocide that is safe for use in cats starting at six weeks of age, including heartworm-infected cats and cats of reproducing age, when administered topically to the skin monthly at the recommended dosage to deliver at least 6mgkg(-1).

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Safety of selamectin in dogs.
Vet Parasitol 91[3-4]:377-91 2000 Aug 23

Novotny MJ, Krautmann MJ, Ehrhart JC, Godin CS, Evans EI, McCall JW, Sun F, Rowan TG, Jernigan AD
Animal Health Clinical Affairs, Pfizer Central Research, Groton, CT 06340, USA. mark_j_novotny@groton.pfizer.com
Selamectin is a broad-spectrum avermectin endectocide for treatment and control of canine parasites. The objective of these studies was to evaluate the clinical safety of selamectin for topical use in dogs 6 weeks of age and older, including breeding animals, avermectin-sensitive Collies, and heartworm-positive animals. The margin of safety was evaluated in Beagles, which were 6 weeks old at study initiation. Reproductive, heartworm-positive, and oral safety studies were conducted in mature Beagles. Safety in Collies was evaluated in avermectin-sensitive, adult rough-coated Collies. Studies were designed to measure the safety of selamectin at the recommended dosage range of 6-12mgkg(-1) of body weight. Endpoints included clinical examinations, clinical pathology, gross and microscopic pathology, and reproductive indices. Selected variables in the margin of safety and reproductive safety studies were subjected to statistical analyses. Pups received large doses of selamectin at the beginning of the margin of safety study when they were 6 weeks of age and at their lowest body weight, yet displayed no clinical or pathologic evidence of toxicosis. Similarly, selamectin had no adverse effects on reproduction in adult male and female dogs. There were no adverse effects in avermectin-sensitive Collies or in heartworm-positive dogs. Oral administration of the topical formulation caused no adverse effects. Selamectin is safe for topical use on dogs at the recommended minimum dosage of 6mgkg(-1) (6-12mgkg(-1)) monthly starting at 6 weeks of age, and including dogs of reproducing age, avermectin-sensitive Collies, and heartworm-positive dogs.