Objective To evaluate the treatment efficacy of a topical spray containing hydrocortisone aceponate (HCA) on dogs with flea-allergy dermatitis (FAD).
Design A controlled clinical study was conducted on dogs with experimentally induced FAD. Sixteen laboratory beagles with mild to moderate clinical signs were divided into two groups. The test group received HCA by topical spray once daily for 7 days, while the control group did not. Pruritic events (time and frequency) were videotaped and then scored. Clinical signs (erythema, papules, excoriation and alopecia) present on four anatomical regions were monitored and their severity directly assessed.
Results After 2 days, pruritus was reduced by 94% in the treatment group and by 24% in the control group (P = 0.014) in cumulative time, and by 86% versus 34% (P = 0.034) in frequency. The HCA spray also resulted in significant improvements in overall clinical signs: 23% versus 0% in the control group (P = 0.0006) on day 3 and 43% versus 15% in the control group (P = 0.0006) on day 7. During the 7-day trial, no drug-related adverse effects were observed.
Conclusions Topical treatment with HCA showed a rapid and potent antipruritic effect on dogs with FAD. HCA also demonstrated significant overall therapeutic effects on FAD-associated skin lesions.
Flea-allergy dermatitis (FAD) is a pruritic dermatitis with skin inflammation and associated lesions in dogs and cats that have been sensitised to the bites of fleas. Although prevalence varies depending on season and geography, FAD is among the most significant skin disease motivating veterinary consultations.1,2 Despite this, effective treatment and control of FAD still remain a considerable challenge.
Current treatments for FAD hinge on two major strategies. The first basic strategy is direct control of infesting fleas by means of insecticides.3 The second strategy is anti-inflammatory/antipruritic therapy based on antihistamines, glucocorticoids and other immunomodulatory drugs. The two strategies are complementary, and concomitant treatments are highly useful in controlling FAD.
In canine pruritic dermatoses, antipruritic/anti-inflammatory therapy is the first-aid therapy bringing instant relief to the distressed animal. The need for such relief therapy is compelling, even after complete elimination of infesting fleas, because pruritus and other FAD-associated clinical signs can persist for 1 week or more. Indeed, it is not uncommon that complete resolution of clinical signs is attained only after 2 to 3 months of symptomatic therapy. Antipruritic/anti-inflammatory therapy is also useful and sometimes necessary as an adjunct therapy to allergen-specific immunotherapy for atopic dermatitis.4,5 Corticosteroid molecules, such as betamethasone, dexamethasone and other prednisolone-derivatives, are frequently administered by the topical and systemic routes6–8 for the treatment of dermatoses in general and FAD in particular. The glucocorticoids have a range of local and systemic adverse effects that render glucocorticoid therapy highly complex and/or restricted to short-term management of dermatological disorders. Recently, new generation topical corticosteroids have been developed, featuring potent pharmacological activity with low risk–benefit ratios. These have the potential to be the basis of effective and safe treatment of atopic dermatitis and other allergic reactions.7,9 The present study was undertaken to evaluate the therapeutic efficacy and profile of a topical formula of hydrocortisone diester (17,21-hydrocortisone aceponate (HCA)) for canine FAD.
Materials and methods
The study was a randomised trial performed in accordance with the current ethics committee recommendations10 and Good Laboratory Practice guidelines of the Organization for Economic Co-operation and Development.
The study used 16 beagle dogs (9 males, 7 females) with a mean age of 4.6 years and a mean weight of 11.2 kg. The animals were housed in individual pens under controlled environments (18°C, 55% relative humidity, 12-h dark/light cycle). Animals were fed once daily with a commercial pet food (Vet Complex Adult, Virbac A.H., Carros, France) and given free access to water.
Induction of FAD
FAD was induced by controlled challenge infestation with fleas (Ctenocephalides felis, newly emerged, unfed adults) following an established two-step protocol developed in-house. Starting with 20 dogs, the first step consisted of sensitisation to flea bites by a series of four bi-weekly challenge infestations with 100 fleas/dog. This was followed by a rest period of 4 months in order to ensure that the dogs had no apparent FAD-associated clinical signs. The second step was hypersensitisation of the dogs and clinical development of the FAD signs, consisting of four successive challenge infestations on days −13, −9, −5, and −2. The objective was to induce sufficient yet moderate levels of pruritus and associated clinical signs, while avoiding excessive conditions of FAD. For this, the number of fleas was adjusted from 40 fleas/dog used in the first challenge to 5 to 30 fleas/dog for the second and successive ones. On day −2, pruritic status was assessed, and 16 dogs presenting minor to moderate signs of FAD were selected for the subsequent study program. Two dogs were excluded because of insufficient pruritus and two for having too severe clinical signs. The four excluded dogs received immediate antiparasitic treatment. The 16 participating dogs were then randomly assigned to two groups: HCA-treated and untreated (control), according to sex using the permutation tables. On day 0, the dogs were given oral antiparasitic tablets (Capstar®, Novartis A.H., Basel, Switzerland) to remove infesting fleas. Day 0 also corresponded to the first day of treatment with the HCA formulation.
The test substance was an HCA formulation containing 0.0635% (w/w) HCA (or 0.584 mg HCA/mL) in propylene glycol methyl ether (Cortavance®, Virbac A.H.). This product is designed to be used as a topical spray, each pump activation delivering 130 µL to an area of 10 × 10 cm when maintained at a distance of 10 cm from the skin.
The dogs were kept in individual pens in a room throughout the study. They were treated with the HCA once daily for 7 consecutive days with two complete pump activations on four regions of the body (lumbodorsal, sacrocaudal, ventral abdomen and ventral thorax). Each dog received a mean dose of 4.7 mL/day; control dogs received none. The study director dispensed the treatment in a manner blinded to all other study personnel. The treatment was given after monitoring on the day of assessing pruritus and clinical signs.
Pruritus was assessed by counting the number and duration of pruritic events including chewing, scratching, biting, licking, rolling and rubbing. The pruritic activities of each dog were observed for a 45-min period at a fixed time (from 10 am) of days −2, 2 and 7, and videotaped via closed-circuit video recorders in groups of four dogs. Pruritic events (time and frequency) of each dog were then evaluated by a trained group of observers. The pruritic time was defined as the cumulative time of the pruritic events recorded in the 45-min period on the given day, and the frequency as the number of pruritic events recorded in the same 45-min period.
Clinical signs and severity scoring
A single veterinarian assessed FAD-associated skin lesions on days −1, 3 and 7. The veterinarian, unaware of the grouping status of the dogs, also performed daily inspection of the dogs for general welfare conditions. Clinical signs were monitored with a focus on four parameters (erythema, papules/pustules, excoriation/erosion, and alopecia/epilation) present on the four body regions. Clinical scores were assigned according to a dual scale in which the severity of lesions and the extent of affected area were taken into account (Table 1). The score ranged from 0 (absence) to 6 (severe and >50% of the observed area affected).
Table 1. Scoring system used for assessing clinical signs of flea-allergy dermatitis: erythema, papules/pustules, excoriation/erosion and alopecia/epilation
Affected area comprises four regions of the body: lumbodorsal, sacrocaudal, ventral thorax and ventral abdomen.
Animals were checked daily by the veterinarian for morbidity, body weight, food consumption, vomiting, diarrhoea, polyuria and polydipsia.
The two groups were compared on day −2 for pruritus scores (time and frequency) and on day −1 for FAD clinical scores and general/physical parameters. The calculations were made using Student's t test, Wilcoxon rank sum test and Fisher's exact test, depending on the validity of assumptions. The pruritic time and frequency on days 2 and 7 were compared between groups by an analysis of covariance using the values on day −2 as covariates. FAD clinical scores on days 3 and 7 were compared between groups by an analysis of covariance using the FAD scores on day −1 as covariates. For analyses of covariance, non-significance of the interaction term was tested and if it was non-significant, it was discarded from the model. In the case of significance of the interaction, no adjustment of day −1 values was made, and the groups were compared using Student's t test or Wilcoxon rank sum test. All statistical analyses were performed using S-PLUS® 6.2 software (Insightful France, Paris, France). Differences were considered statistically significant at P < 0.05.
The HCA and control group animals were indistinguishable in their basal general/physical parameters (sex, age and weight) and also in their FAD clinical parameters (pruritic time, pruritus frequency and total lesion scores) (Table 2). Erythema and papules were the most prominent signs, with respective mean baseline scores of 10.4 and 9.7 (of maximum 24) (Table 3). Alopecia and excoriation were relatively mild, with mean scores ranging from 3.2 to 4.4. Clinical scores were observed in the order of ventral abdomen (10.8), sacrocaudal (9.4), ventral thorax (5.2), and lumbodorsal (2.5).
Table 2. Baseline status of the dogs: general/physical and clinical parameters
HCA group (n = 8)
Control group (n = 8)
Where applicable, the values are mean ± SD. The maximum possible lesion score is 48. P-value by aFisher's exact test, bStudent's t-test and cWilcoxon rank sum test.
Table 3. Distribution of baseline clinical scores on day −1
Group (n = 8)
Scores are mean (± SD).
HCA, hydrocortisone aceponate.
Time course of pruritus
The time course of pruritus is shown in Figure 1. Compared with the baseline values (on day −2), the control group showed a reduction in pruritic time by 24.3% and 45.3% on days 2 and 7, respectively. In the meantime, the HCA group showed reductions of 94.2% (P = 0.014) and 96.3% (P = 0.001), respectively.
Regarding pruritus frequency (Figure 2), the control group showed reductions of 33.6% and 63.7% on days 2 and 7, respectively, while the HCA group showed reductions of 86.1% (P = 0.034) and 94.8% (P = 0.001), respectively.
Time course of clinical scores
The HCA formulation resulted in statistically significant therapeutic effects on clinical signs (Figure 3a). Compared with the baseline scores (on day −1), the total clinical scores of the control group decreased by 0% and 15% on days 3 and 7, respectively, while those of the HCA group decreased by 23.3% and 43.0% (both P = 0.0006).
Erythema showed the most prominent therapeutic effect (Figure 3b). On day 3, the score of the HCA group showed a reduction of 21%, and the control group showed an increase of 16% (P < 0.0001). On day 7, erythema scores were reduced by 45% and 4% in the HCA and control groups, respectively (P = 0.035).
Papules also showed a significant score reduction on day 3 (Figure 3c): 35% in the HCA group versus 5% in the control group (P = 0.033), respectively. On day 7, they were reduced by 57% and 36% in the HCA and control groups, respectively (P = 0.13). The effect of HCA treatment on excoriation was indistinguishable between the groups because of the relatively high background scatter of the data (Figure 3d).
Alopecia continued to increase during the test period; however, the HCA treatment tended to reduce the rate by 20% (P = 0.17) and 30% (P = 0.10) on days 3 and 7, respectively (Figure 3e).
No adverse events were observed in any of the dogs during the trial period.
The present study was undertaken to evaluate the efficacy and safety of a topical HCA formulation in the treatment of pruritus and other clinical signs associated with FAD, under the specific conditions of the dispensing mode.
A prerequisite for such a study, and other studies of pruritic dermatitis in general, is an accurate, consistent, and reliable scoring system for pruritus on the one hand and for other clinical signs on the other. Indeed, developing a standard scale for assessing pruritus has been quite challenging and controversial.11–14 Developing a standard severity scale for skin lesions is another matter, with its own complexities related to the diverse clinical manifestations (multiple symptoms and affected areas) and assessor subjectivity. The recently developed scoring system, CADESI (Canine Atopic Dermatitis Extent and Severity Index), is perhaps the most comprehensive and well suited to field clinical trials,13,15 but as such, it may be too complicated to be directly useful in the laboratory setting.
Our present model involved a single breed of dogs in which FAD was induced by controlled flea-challenge infestation. The relative homogeneity and simplicity of the model under the controlled environment allowed the development and use of a better adapted, streamlined scoring system for the clinical signs (Table 1). The experimental conditions also permitted relatively accurate scoring of pruritus by direct timing and counting of pruritic events. Although straightforward and relatively bias-free, the assessment of pruritus and clinical signs was highly labour-intensive, the reason why baseline values could not all be taken on day 0 (elimination of fleas and first treatment), but also included those obtained on day −1 (clinical scores) and day −2 (pruritus scores).
Overall, the baseline clinical scores (on day −1) were mild to moderate, with even group distribution (Table 3). With regard to clinical signs, the scores were in the order of erythema ≥ papules/pustules > alopecia/epilation ≈ excoriation/erosion. With regard to anatomical region, the scores were distributed in the order of ventral abdomen ≥ sacrocaudal > ventral thorax > lumbodorsal. These clinical features generally corresponded to those of the early phase of FAD and thus fitted the purpose of the present trial. As such, however, they were slightly different from those observed in veterinary clinics where excoriation and lichenification tend to be the next highest scorers to erythema. The main reason for this is that dogs presented to clinics generally have longer histories and/or recurrent episodes of dermatological problems, not to mention their diverse origins.
Under the present experimental conditions, daily topical spray of the HCA formulation exerted immediate and substantial therapeutic effects on pruritus, resulting in approximately 90% reduction in both pruritic time and frequency after only 2 days’ treatment. Although less pronounced than for pruritus, the therapeutic effect of the HCA was also significantly manifest on other clinical signs, especially erythema and somewhat for papules. Compared with the pruritic events, which reflect behavioural modifications and consequent rapid response to the treatment, the skin lesions, for their physical characters and associated healing process, turned out to be more slowly responsive to the same treatment. It is also important to note that the therapeutic effects of topical HCA are not limited to FAD. Indeed, our preliminary data from field clinical trials on dogs with pruritic dermatoses indicate that 92% of the HCA-treated dogs responded favourably while only 47% of the dogs were diagnosed as FAD cases (unpublished data).
As a new generation dermocorticoid, HCA has a potent pharmacological activity and yet, unlike other corticosteroids of similar or higher potency, has remarkably low adverse effects.7 These advantageous characteristics are attributed to the balanced hydrophilicity and lipophilicity of the HCA molecule. Compared with the parent drug, hydrocortisone, the enhanced lipophilicity of HCA is derived from the esterifications at C21-acetate and C17-propionate, which provide the HCA molecule with important double benefits: a higher capacity to permeate the stratum corneum and a lower propensity to reach the blood circulation, thereby accumulating in the epidermis–dermis in a high concentration and exerting potent antipruritic/anti-inflammatory activity.
Under the protocol conditions, the repeated use of the HCA formulation elicited no observable adverse reactions in the dogs. Under normal conditions of use, the 7-day treatment with the HCA formulation should be sufficient to bring immediate relief from pruritus and accelerate clinical recovery. Whereas prompt and potent antipruritic activity of HCA can be generally expected in FAD and other pruritic dermatoses, the therapeutic effects on skin lesions may be less pronounced, especially for dogs with hardened skin or chronic clinical signs. Ideally, HCA therapy for pruritic dermatitis should be prescribed in conjunction with other treatments aimed at eliminating the underlying cause such as bacteria, parasites, fungal infection, insects, arachnids and/or environmental allergens.