Treatment of canine atopic dermatitis with zafirlukast, a leukotriene-receptor antagonist: a single-blinded, placebo-controlled study

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 completed the trial with zafirlukast. Two dogs vomited after administration of the active drug.

Introduction

Atopic 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 glucocorticoids are the most consistently effective palliative treatment for CAD, but if given long term, they can cause potentially serious side effects, such as iatrogenic Cushing's syndrome and secondary adrenocortical insufficiency (1,8). Other commonly used treatments include specific immunotherapy, antihistamines, fatty acid supplements, and antipruritic shampoos and conditioners (1,8). These treatments are variably effective, 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 effective in, the prophylactic and chronic treatment of 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 (11,12,13,14).

Zafirlukast is absorbed in dogs following oral administration. 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 necessitates 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 potentially 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 recommended 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 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, ventrum, 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 commercial 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 antihistamines, but they provided inadequate control of the pruritus. 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 multiple 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 nonsteroidal 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 significant pruritus returned prior to the clinical trial.

Table 1.

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 medications 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 11.4–22.3 kg (25–49 lb); 20 mg, q12h, if 22.7–34.1 kg (50–75 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 categorized 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 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 readministration of the zafirlukast had also been given prednisone 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 difference 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 differences, 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. However, there are 2 reported studies on using 5-lipoxygenase inhibitors in atopic dogs: no significant clinical improvement in pruritus was observed, although erythema scores were significantly decreased in dogs treated with zileuton (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 published trials using chlorpheniramine, diphenhydramine, and hydroxyzine for CAD reported satisfactory control 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 involving 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 (24,25,26,27). 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 “maximal improvement,” many would expect to see some degree of improvement within 4 to 6 wk (24,25,26,27). The authors have never seen a dog with food hypersensitivity 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 nonsteroidal anti-inflammatory agents are indicated.