Treatment of canine atopic dermatitis with

zafirlukast, a leukotriene-receptor antagonist:

a single-blinded, placebo-controlled study
David A. Senter, Danny W. Scott, William H. Miller Jr.

Abstract Zafirlukast and placebo were administered orally as individual agents to 20 dogs with
atopic dermatitis. The pruritus was effectively reduced by at least 50% in 2/18 (11%) dogs that com-
pleted the trial with zafirlukast. Two dogs vomited after administration of the active drug.

Rsum Traitement de la dermatite atopique du chien par le zafirlukast, un antago-

niste des rcepteurs aux leucotrines : tude simple insu avec groupe placebo. Le zafirlukast
et un placebo ont t administrs par voie orale comme mdicaments individuels 20 chiens
atteints de dermatite atopique. Le prurit a t effectivement rduit par au moins 50 % chez 2/18 (11 %)
des chiens ayant complt ltude au zafirlukast. Deux chiens ont vomi aprs ladministration de la
drogue active.
(Traduit par Docteur Andr Blouin)
Can Vet J 2002;43:203206

Introduction effective in, the prophylactic and chronic treatment of

A topic dermatitis is the second most common skin
disease in dogs; it is estimated to affect 10% of the
canine population (1). The exact pathogenesis of canine
atopic dermatitis (CAD) has not been established, but it
is thought to involve IgE-mediated early and late phase
hypersensitivity reactions to environmental allergens (1).
Mast cell degranulation is known to play an important
role, and results in the release of preformed and newly
synthesized inflammatory mediators (1,2). Preformed
mediators, such as histamine, are involved in the early
phase reaction, while newly formed mediators, such
as leukotrienes and prostaglandins, are important in
the late phase reaction (2). Leukotrienes comprise a
group of inflammatory mediators that are formed
from the metabolism of arachidonic acid through the
5-lipoxygenase pathway (3,4); they are believed to play
an important role in atopic dermatitis in humans (2,5,6)
and dogs (7).
Canine atopic dermatitis is a chronic disease, and
its management can be both difficult and frustrating
for veterinarians and pet owners. Systemic glucocorti-
coids are the most consistently effective palliative treat-
ment for CAD, but if given long term, they can cause
potentially serious side effects, such as iatrogenic
Cushings syndrome and secondary adrenocortical
insufficiency (1,8). Other commonly used treatments
include specific immunotherapy, antihistamines, fatty
acid supplements, and antipruritic shampoos and con-
ditioners (1,8). These treatments are variably effec-
tive, so the safety and efficacy of newer nonsteroidal anti-
inflammatory drugs for CAD need to be determined.
Zafirlukast is an orally active leukotriene-receptor
antagonist that was developed for, and shown to be
Department of Clinical Sciences, College of Veterinary
Medicine, Cornell University, Ithaca, New York 14853-6401
USA.
Address correspondence and reprint requests to Dr. Danny W.
Scott.
asthma in humans (9,10). Further studies have shown that
zafirlukast; montelukast (Singulair, 10 mg tablets;
Merck, West Point, Pennsylvania, USA), another
leukotriene-receptor antagonist; and zileuton (Zyflo,
600 mg tablets; Abbott, Abbott Park, Illinois, USA), an
inhibitor of leukotriene synthesis, have all been effective
in the treatment of atopic dermatitis in humans (1114).
Zafirlukast is absorbed in dogs following oral admin-
istration. It is extensively metabolized in the liver and
is excreted primarily in the feces, with less than 3%
excreted in the urine (17). In humans, the presence of
food reduces its bioavailability by 40%, which neces-
sitates the drug being taken on an empty stomach (9,18).
Zafirlukast is well tolerated in humans, with the most
common adverse effects being pharyngitis and headache
(9,18), although there have been rare reports of elevations
in alanine transaminase activity after the drug had been
taken at 4X the approved dose (9). Zafirlukast also
inhibits cytochrome P450 isoenzymes, which poten-
tially could lead to drug interactions, but it can be used
in combination with antihistamines in humans (9,18). It
appears to be a safe drug in dogs and has been used in
experimental studies with no reported adverse effects
(17,18). In preclinical toxicity studies, no deaths occurred
in dogs when it was used at 500 mg/kg body weight
(BW), which is approximately 333X the maximum
dose that was administered in this trial. The dosage we
chose was comparable on a mg/m2 basis with the recom-
mended dosage in humans.
The purpose of this study was to evaluate the efficacy
of zafirlukast in controlling the pruritus in dogs affected
with CAD.
Materials and methods
Twenty dogs examined at the Cornell University Hospital
for Animals were randomly entered into this study, and
their owners agreed to the protocol. Various purebred
dogs and mongrels were represented, and included
10 males and 10 females (Table 1). Their ages ranged

Can Vet J Volume 43, March 2002 203

 Table 1. Clinical data on 20 atopic dogs treated with zafirlukast
Duration of
Case Breed Age (y) Sex Weight (kg) disease (y)
1 German shepherd 8 MC 45 4
2 Welsh terrier 4 F 7.7 3
3 Mixed 4 MC 27.2 3
4 Boxer 3 FS 24 2
5 Mixed 3 FS 5.5 1
6 Jack Russell terrier 2 MC 5.9 1.5
7 Beagle 3 FS 15.4 1.5
8 Yorkshire terrier 5 FS 3.2 4.5
9 Golden retriever 4 MC 50.4 3
10 Mixed 9 MC 10.4 3
11 Golden retriever 5 MC 57.2 3
12 Boston terrier 7 FS 12.7 6
13 Mixed 8 MC 7.2 3
14 German shepherd 4 FS 77 3
15 Jack Russell terrier 1 FS 5 0.5
16 Wirehaired fox terrier 3 FS 8.1 2
17 Boxer 6 MC 30.9 4
18 Golden retriever 2.5 MC 37.7 1.5
19 Golden retriever 7 FS 25.4 6
20 Golden retriever 6 MC 33.1 4
MC castrated male; F female; FS spayed female

from 1 y to 9 y, and they weighed from 3.2 kg to 57.2 kg.
The duration of clinical signs ranged from 1 y to 6 y. All
dogs were affected by nonlesional pruritus in one or
more of the following areas: face, feet, ears, axillae, ven-
trum, paws, and lumbosacral area. Thirteen of the dogs
had nonseasonal pruritus, and 5 dogs had nonseasonal
pruritus with seasonal exacerbations (4 in summer, 1 in
winter). Only 2 dogs had seasonal (spring through fall)
pruritus. All dogs except for 1 with seasonal pruritus had
completed one or more restrictive dietary trials for at least
4 wk (range 4 to 8 wk). Twelve dogs had been fed a com-
mercial novel protein diet, 5 dogs had been fed a home-
cooked diet, and 3 dogs had been through trials with both
commercial and home-cooked diets. Pruritus did not
decrease in any of the dogs during the dietary trials.
Nineteen dogs received from 1 to 6 different antihista-
mines, but they provided inadequate control of the pru-
ritus. Fourteen dogs received fatty acids, delivered
either in the commercial diet or via supplements, with no
response, and all dogs were known to respond to anti-
inflammatory doses of glucocorticoids. All dogs had mul-
tiple positive reactions with intradermal skin testing
(3 dogs), serological allergy testing (6 dogs), or both
(12 dogs). Any dog with concurrent bacterial pyoderma,
Malassezia dermatitis, or ectoparasites was treated
appropriately prior to the beginning of the clinical trial.
All dogs had moderate to severe pruritus. Seventeen
of the dogs were not receiving any steroidal or non-
steroidal antipruritic medications during the trial, and had
not received these medications for at least 3 wk prior to
the trial. Three dogs were in severe discomfort and
glucocorticoids could not be eliminated during the trial.
In these dogs, the steroid dose was reduced until sig-
nificant pruritus returned prior to the clinical trial.
The dogs were treated with zafirlukast (Accolate,
20 mg tablets; Astra Zeneca Pharmaceuticals,
Wilmington, Delaware, USA) during the first 2 wk of the
trial, followed by a placebo (Placebo, 1 g tablets; B&L
Sales, Worcester, Massachusetts, USA) for the second
2 wk. A 2-week trial period has been recommended
previously to assess the efficacy of nonsteroidal med-
ications in pruritic dogs (15). The owners were not aware
that a placebo was included in the trial. The dosage of
zafirlukast was 5 mg, q12h, if the dog weighed less
than 11.4 kg (25 lb); 10 mg, q12h, if 11.422.3 kg
(2549 lb); 20 mg, q12h, if 22.734.1 kg (5075 lb); and
30 mg, q12h, if greater than 34.1 kg (75 lb). It was to be
given on an empty stomach, 1 h before, or 2 h after,
meals. The placebo dosage was 0.5 g/dog, q12h.
After the 2 wk trial with each product, owners were
asked to evaluate the reduction in pruritus as either
poor (0% to 25% reduction), fair (26% to 50%), good
(51% to 75%), or excellent (76% to 100%). If there
was a fair, good, or excellent response to either product,
the owners were asked to readminister that product for
an additional 30-day period to document a repeatable and
sustainable response.
Results
A total of 18 dogs completed the study. Two dogs
(cases 5 and 6) had a repeatable response and sustained
control of the pruritus during the 30-day extended
period of treatment with zafirlukast. They were cate-
gorized by the owner as a fair (50% decrease) and a
good (75% decrease) reduction in pruritus. Both dogs
had nonseasonal pruritus, and neither dog was receiving
other nonsteroidal anti-inflammatory medications or
glucocorticoids during the trial. In 1 of the dogs (case 6),
pruritus would increase prior to the next scheduled dose,
and severe pruritus and self-excoriation occurred 1 d after
discontinuing the zafirlukast on 2 occasions. One dog
(case 3) was thought to have a good response, and
another dog (case 2), a fair response to the initial
14-day trial period with zafirlukast, but they did not have
a repeatable or sustained response during the 30-day
period. Another dog (case 1) was thought to have a
fair response to zafirlukast during the initial 14-day

204 Can Vet J Volume 43, March 2002

treatment period, but upon readministration of the drug,
the dog became polydipsic, and the owner discontinued
the trial. Furthermore, one owner thought that her dog
(case 4) had a fair response to the placebo, but this was
not repeatable. All other dogs received no benefit from
the zafirlukast or the placebo.
Three dogs experienced side effects while receiving
zafirlukast. One dog (case 7) vomited shortly after
the first dose, and the owner removed the dog from
the trial. The vomiting ceased shortly after. Another
dog (case 9) vomited 48 h after starting zafirlukast.
The drug was stopped, the condition resolved, and the
trial was resumed with no further complications. The dog
(case 1) that experienced polydipsia upon readminis-
tration of the zafirlukast had also been given pred-
nisone for 3 d prior to the zafirlukast due to a marked
increase in pruritus while on the placebo.
Discussion
The role of leukotrienes in CAD has not been fully
elucidated. A recent study failed to find a significant dif-
ference in sulphido-leukotriene (LTC4, LTD4, LTE4)
concentrations in skin and peripheral leukocytes between
clinically normal and atopic dogs (19). However, a larger
sample size may be needed to detect significant dif-
ferences, as the atopic dogs did have consistently higher
values of cutaneous sulphido-leukotrienes.
To our knowledge, this is the first reported clinical trial
using a leukotriene-receptor antagonist for CAD. How-
ever, there are 2 reported studies on using 5-lipoxygenase
inhibitors in atopic dogs: no significant clinical improve-
ment in pruritus was observed, although erythema scores
were significantly decreased in dogs treated with zileu-
ton (20,21).
In this study, zafirlukast reduced pruritus by at least
50% in 2 of the 18 dogs (11%) that completed the trial.
The success rate of zafirlukast is not unlike that of
several commonly used antihistamines. Previously pub-
lished trials using chlorpheniramine, diphenhydramine,
and hydroxyzine for CAD reported satisfactory con-
trol of pruritus in 8.9% to 10%, 6.7%, and 6.7% to
10% of dogs, respectively (15).
In our study, zafirlukast was well tolerated, with
only 3 dogs (15%) experiencing side effects. Two dogs
vomited shortly after starting zafirlukast. In 1 of these
dogs, the zafirlukast was successfully readministered after
the initial vomiting episode resolved. The owner of the
other dog refused to readminister the zafirlukast, and a
cause-and-effect relationship could not be established.
The third dog developed polydipsia, which was most
likely secondary to the prednisone (16).
A point of possible contention in this study is the
duration of the novel protein diets. Two studies involv-
ing dogs with food hypersensitivity have suggested
that the duration of a novel protein diet should be 10 wk
(22) to 13 wk (23). These recommendations are quite
controversial (2427). The major point of controversy is
the fact that duration recommendations were based on the
time required for maximal improvement (maximum
reduction in pruritus) (22,23). While most dermatologists
would agree with the recommendations based on max-
imal improvement, many would expect to see some
Can Vet J Volume 43, March 2002
degree of improvement within 4 to 6 wk (2427). The
authors have never seen a dog with food hypersensi-
tivity fail to show at least some improvement within
4 wk.
Based on the results of this study, further studies
with zafirlukast to determine the optimum dose and
possible synergism with glucocorticoids and other non-
steroidal anti-inflammatory agents are indicated.
References
1. Scott DW, Miller WH Jr, Griffin CE. Muller & Kirks Small
Animal Dermatology VI. Philadelphia: WB Saunders, 2001:
543666.
2. Koro O, Furutani K, Hide M, et al. Chemical mediators in atopic
dermatitis: involvement of leukotriene B4 released by a type 1 aller-
gic reaction in the pathogenesis of atopic dermatitis. J Allergy Clin
Immunol 1999;103:663670.
3. Lewis RA, Austen KF, Soberman RJ. Leukotrienes and other
products of the 5-lipoxygenase pathway. Biochemistry and rela-
tion to pathobiology in human disease. N Engl J Med
1990;323:645655.
4. Henderson WR Jr. The role of leukotrienes in inflammation.
Ann Intern Med 1994;121:684697.
5. Shichijo M, Ebisawa M, Miura K, et al. Relationship between his-
tamine release and leukotrienes production from human basophils
derived from atopic dermatitis donors. Int Arch Allergy Immunol
1995;107:587591.
6. Schneider LC, Lester MR. Atopic disease, rhinitis and conjunc-
tivitis, and upper respiratory infections. Curr Opin Pediatr
1997;9:537547.
7. Kietzmann M. Eicosanoid levels in canine inflammatory skin
disease. In: Von Tsharner C, Halliwell REW, eds. Advances
in Veterinary Dermatology. Vol 1. London: Baillire Tindall,
1990:211220.
8. Reedy LM, Miller WH Jr, Willemse T. Allergic Skin Diseases of
Dogs and Cats. 2nd ed. London: WB Saunders, 1997:150172.
9. Kelloway JS. Zafirlukast: the first leukotriene-receptor antagonist
approved for the treatment of asthma. Ann Pharmacother 1997;
31:10121021.
10. Suissa S, Dennis R, Ernst P, et al. Effectiveness of the leukotriene
receptor antagonist zafirlukast for mild-to-moderate asthma. Ann
Intern Med 1997;126:177183.
11. Carucci JA, Washenik K, Weinstein A, et al. The leukotriene
antagonist zafirlukast as a therapeutic agent for atopic dermatitis.
Arch Dermatol 1998;134:785786.
12. Zabawski EJ JR, Kahn MA, Gregg LJ. Treatment of atopic der-
matitis with zafirlukast. Dermatol Online J 1999;5:10.
13. Yanase DJ, David-Bajar K. The leukotriene antagonist mon-
telukast as a therapeutic agent for atopic dermatitis. J Am Acad
Dermatol 2001;44:8993.
14. Woodmansee DP, Simon RA. A pilot study examining the role of
zileuton in atopic dermatitis. Ann Allergy Asthma Immunol
1999;83:548552.
15. Scott DW, Miller WH Jr. Antihistamines in the management of
allergic pruritus in dogs and cats. J Small Anim Pract 1999;40:
359364.
16. Scott DW, Miller WH Jr, Griffin CE. Muller & Kirks Small
Animal Dermatology VI. Philadelphia: WB Saunders, 2001:
207273.
17. Savidge RD, Bui KH, Birmingham BK, et al. Metabolism and
excretion of zafirlukast in dogs, rats, and mice. Drug Metab
Dispos 1998;26:10691076.
18. Physicians Desk Reference. 55th ed. Montvale: Medical
Economics, 2001:611613.
19. Marsella R, Nicklin CF. Sulphido-leukotriene production from
peripheral leukocytes and skin in clinically normal dogs and
house dust mite positive atopic dogs. Vet Dermatol 2001;12:312.
20. Crow DW, Marsella R, Nicklin CF. Double-blinded, placebo
controlled, cross-over pilot study on the efficacy of zileuton for
canine atopic dermatitis. Proc World Congr Vet Dermatol
2000:45.
21. DeBoer DJ, Moriello KA, Pollet RA. Inability of a short duration
treatment with a 5-lipoxygenase inhibitor to reduce clinical signs
of canine atopy. Vet Dermatol 1994;5:1316.
205
22. Rosser EJ. Diagnosis of food allergy in dogs. J Am Vet Med
Assoc 1993;203:259263.
23. Denis S, Paradis M. Lallergie alimentaire chez le chien et le
chat 2. Etude rtrospective. Md Vt Qubec 1994;24:1520.
24. Kwochka KW. Food allergy-intolerance update. Proc World
Small Anim Vet Assoc Congr 1994;19:216217.
BOOK REVIEW
Cowart RP, Casteel SW. An Outline of Swine Diseases:
A Handbook, 2nd ed. Iowa State University Press,
Ames, 2001, 205 pp, ISBN 0-8138-2898-8, US$34.95.
I t would appear that cost was a primary considera-
tion in creating this text. The book is a small and
simple handbook (no photographs or illustrations) that
provides a point-form review of pig diseases. The book
is divided into 10 chapters. Chapter 1 touches on the vet-
erinarians role, namely, the concept of biosecurity and
minimal disease, and discusses vaccine and drug use; it
is directed to an American readership, so some of this
material relative to drug use reviews American rules and
regulations and is not directly relevant to Canadian
veterinarians. The following 2 chapters consist of point-
form summaries of diseases grouped according to body
systems, with chapter 2 devoted to polysystemic diseases.
The final chapter lists diseases caused by toxic agents and
is the largest chapter in the book. Toxicity problems tend
to be rare in modern confinement pig farming, and so it
is surprising that they receive this much attention from
the authors.
Diseases are presented with the usual headings of
etiology, epidemiology, pathogenesis, clinical signs,
diagnosis, treatment, prevention, and control. Typical of
this type of handbook, each disease receives about
equal space. The drawback to this approach is that the
reader may find it difficult to determine which dis-
eases are important and which are either very rare or
nonsignificant.
The authors have done a thorough job and have
included several recent diseases not listed in their
1st edition, including postweaning multisystemic wast-
ing syndrome. There are a few relatively common dis-
eases that are not covered, possibly because the authors
considered them to be not very important. Under integu-
mentary diseases, for example, pityriasis rosae and
ringworm are not mentioned, but swine pox is.
This text would have been more useful as a study guide
or veterinary manual had the authors included tables
206
25. Fadok VA. Diagnosing and managing the food allergic dog.
Comp Cont Educ Pract Vet 1994;16:15411545.
26. Paterson S. Food hypersensitivity in 20 dogs with skin and gas-
trointestinal signs. J Small Anim Pract 1995;36:529534.
27. Hill P. Diagnosing cutaneous food allergies in dogs and cats
some practical considerations. In Pract 1999;21:288294.
COMPTE RENDU DE LIVRE
or charts. The differential diagnosis of swine diseases is
generally aided by knowing the age or production group
affected, the pattern of spread, and other key points of
history or clinical signs. A chart showing how the var-
ious diseases could be differentiated on this basis also
would have helped pull the information together.
Streptococcal meningitis, for example, is listed under
polysystemic diseases and not neurological diseases.
I think someone using this book as a quick refer-
ence might miss a likely rule-out, such as streptococcal
meningitis by scanning the chapter relating to the
body system.
The authors do not reference their work but they do
provide a list of suggested readings after some of the
disease entries. The information provided in the book
is accurate and up-to-date, but is not extensive. The
scope of the book is similar to other disease guides
currently available, including: Pig Diseases by David
Taylor (Burlington Press), Swine Disease Manual by
C.E. Whiteman and R.D. Glock (University of Colorado),
and A Pocket Guide to Recognizing and Treating Pig
Diseases by M.R. Muirhead and T.J.L. Alexander
(5M Enterprises Inc.).
Cowart and Casteel do not attempt to deal with the
complexities of swine practice, such as the interaction of
disease, management, and the environment, and do not
discuss production records or economics. Therefore,
veterinarians in swine practice are likely to be disap-
pointed by the limited depth of the book, but for the
mixed practitioner who rarely deals with pigs, this book
may be a useful guide. The main readership is likely to be
undergraduate veterinary students preparing for board
examinations or anyone else wishing a quick review of
pig diseases.
Reviewed by Robert Friendship, DVM, MSc, DipABVP,
Professor, Department of Population Medicine,
University of Guelph, Guelph, Ontario N1G 2W1.
Can Vet J Volume 43, March 2002