Confirmatory field study for the evaluation of ciclosporin at a target dose of 7.0 mg/kg (3.2 mg/lb) in the control of feline hypersensitivity dermatitis.

Objectives This study was designed to confirm the efficacy and tolerability of a daily dose of 7.0 mg/kg (3.2 mg/lb) ciclosporin (CsA) in the treatment of feline hypersensitivity dermatitis (HD), as this includes some of the most frequently suspected skin diseases in cats and recent publications have reported the successful use of CsA in the treatment of feline HD. Methods In total, 217 cats with feline HD were treated daily for 42 days with a target dose of 7 mg/kg CsA (n = 144) or a placebo control (n = 73) administered either in the food or directly in the mouth following feeding. Clinical and dermatological evaluations were conducted on days 0, 21 and 42, or study exit. Safety was evaluated through physical examinations, clinical pathology and the monitoring of adverse events (AEs). Results Administration of CsA at 7.0 mg/kg produced a significant improvement in the total lesion score ( P <0.0001). The average reduction from visit 1 to visit 3 was 65.1% in the CsA group (9.2% for the placebo). In addition, owners assessed 78.3% of the cases in the CsA group as a success. Statistically significant recoveries were also seen in extent of lesions, investigator assessment of overall improvement, and mean improvement in both the investigators' and owners' assessment of pruritus. Mild gastrointestinal disorders were the most common AEs but did not require cessation of therapy. Conclusions and relevance Results confirm that 7.0 mg/kg CsA dosed daily in food or orally for up to 6 weeks is effective and well tolerated by cats with feline HD.

Use of activity monitors for assessment of pruritus in an acute model of canine atopic dermatitis.

BACKGROUND: We developed a canine model of acute atopic dermatitis to evaluate the potential of compounds to treat pruritus and skin lesions induced in Dermatophagoides farinae (Df)-sensitized dogs. HYPOTHESIS/OBJECTIVES: The aim was to investigate the effectiveness of long-term recording activity monitors to assess pruritus induced by allergen challenges. ANIMALS: Thirty-two Df-sensitized laboratory dogs. METHODS: In two blinded crossover studies, 28 Df-sensitized dogs were challenged on 3 days with a Df slurry applied to clipped abdominal skin. Dogs were treated with a positive control (prednisolone 1 mg/kg once daily for 5 days, starting 1 day before challenge) or left untreated; all were fitted with activity monitors. To confirm pruritus, a parallel study with four dogs was conducted, filming the dogs before and during challenge and assessing the film for pruritic behaviour. RESULTS: The activity of dogs treated with prednisolone was significantly lower between 00.00 and 03.00 h and between 03.00 and 06.00 h compared with untreated dogs (repeated-measures ANCOVA; P < 0.0001). To determine whether the recorded night-time activity corresponded to pruritic manifestations, we compared activity monitor and video recordings of four dogs for two periods (16.30-20.30 and 24.00-03.00 h) before and during a Df challenge. The correlation between night-time activity monitor activity and observed pruritic behaviour was highly significant (test of correlation coefficient versus zero: r = 0.57, P < 0.0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Determination of night-time activity with activity monitors after allergen challenge appears to be an objective and practical way to assess pruritus in this experimental model of canine atopic dermatitis.

Dose tapering for ciclosporin in cats with nonflea-induced hypersensitivity dermatitis.

BACKGROUND: Little information is available on the ciclosporin dose-tapering regimen and clinical response in the treatment of feline hypersensitivity dermatitis. HYPOTHESIS/OBJECTIVES: To test a dose-tapering regimen and assess efficacy and clinical safety for up to 18 weeks. ANIMALS: Eighty-eight client-owned cats with feline hypersensitivity dermatitis. METHODS: Cats that received either a placebo or ciclosporin at 2.5 mg/kg or 7 mg/kg daily for 6 weeks were given 7 mg/kg ciclosporin daily for 4 weeks. Depending on the clinical response, the dose was tapered from daily to every other day over the next 4 weeks and further to twice a week for an additional 4 weeks. RESULTS: After all cats received 7 mg/kg for 4 weeks, the dose could be tapered to every other day for the next 4 weeks in 70% of cats remaining in the study. During the next 4 weeks, 57, 15 and 22% of cats remaining in the study could be treated at twice a week, every other day or daily, respectively. After the first 4 weeks, the mean lesion score and owner-assessed pruritus improved over baseline by 69 and 61%, respectively, and remained stable during the following 8 weeks. Approximately 65% of the cats in the study were reported to have an adverse event (AE), very often mild and resolving spontaneously. The most frequent AEs were gastrointestinal and included primarily vomiting and diarrhoea. Eighty per cent of AEs occurred when cats were on daily treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that the induction dose of 7 mg/kg ciclosporin can be tapered as soon as 4 weeks without deterioration of the clinical response. Establishment of the lowest effective dosing regimen of ciclosporin reduced the frequency of AEs.

A randomized double-blinded placebo-controlled study to evaluate an effective ciclosporin dose for the treatment of feline hypersensitivity dermatitis.

BACKGROUND: Hypersensitivity dermatitides (HD) are frequently suspected in cats, but there are few clinical studies on safe and effective treatments in the published literature. OBJECTIVES: To establish a safe and effective dose of ciclosporin in the treatment of feline HD. ANIMALS: One hundred client-owned cats with feline HD. METHODS: Double-blind study, with cats randomly assigned to receive ciclosporin at either 7.0 mg/kg once daily (n = 33) or 2.5 mg/kg once daily (n = 32) or a placebo (n = 35) for 6 weeks. RESULTS: Mean Total Lesion Scores with 7.0 mg/kg ciclosporin were significantly lower than with 2.5 mg/kg ciclosporin (P = 0.0047) or placebo (P = 0.0003) at study end. Individual Total Lesion Scores improved by >50% in 70% of the 7.0 mg/kg group, compared with 47% in the 2.5 mg/kg group and 23% in the placebo group (P = 0.0006). The investigators' Global Assessment of Improvement was 'excellent' or 'good' in 61% of cats treated with 7.0 mg/kg ciclosporin, compared with 47% of cats given 2.5 mg/kg and 23% given placebo. The improvement in Investigator Pruritus Scores was significantly greater in cats treated with 7.0 mg/kg ciclosporin (54%) compared with both 2.5 mg/kg ciclosporin (32%; P = 0.0232) and placebo (21%; P = 0.0063). Mild gastrointestinal disorders were the most common adverse events, but these did not require cessation of therapy. CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that 7.0 mg/kg ciclosporin once daily in food or per os for 6 weeks is effective and well tolerated in feline HD.

Responsiveness and validity of the SCORFAD, an extent and severity scale for feline hypersensitivity dermatitis.

BACKGROUND: Hypersensitivity (allergic) dermatitis (HD) is commonly seen in cats, causing pruritus and various patterns of skin lesions, including at least one of the following: head and neck excoriations, self-induced alopecia, eosinophilic plaques and miliary dermatitis. Few studies have evaluated the efficacy of therapeutic interventions for feline HD, and although various scales have been considered, none has been formally validated for the assessment of disease severity and its response to therapy. OBJECTIVE: To design and validate a novel scale (SCORing Feline Allergic Dermatitis; SCORFAD) to assess the value of different criteria used as outcome measures for the treatment of feline HD and to set minimal thresholds for defining the clinical success of tested interventions. ANIMALS: One hundred client-owned cats. METHODS: The SCORFAD scale was designed to include the four most frequently identified lesion types in feline HD (eosinophilic plaque, head and neck excoriations, self-induced alopecia and miliary dermatitis) across 10 body regions. The extent and severity of each lesion type were graded prior to inclusion and after 3 and 6 weeks in a clinical study to compare the efficacy of two doses of ciclosporin with placebo. RESULTS: The SCORFAD scale was found to exhibit satisfactory content, construct, criterion and sensitivity to change. The percentage reduction in SCORFAD from baseline was determined to be the most valid assessment of clinical response. Inter- and intra-observer reliability was not assessed. CONCLUSIONS AND CLINICAL IMPORTANCE: The SCORFAD scale is proposed for use as a validated tool for the assessment of disease severity and response to therapeutic interventions in clinical trials for feline HD.

Establishment of diagnostic criteria for feline nonflea-induced hypersensitivity dermatitis.

Hypersensitivity dermatitides (HD) are commonly seen in cats, and they are usually caused by environmental, food and/or flea allergens. Affected cats normally present with one of the following clinical reaction patterns: head and neck excoriations, usually symmetrical self-induced alopecia, eosinophilic skin lesions or miliary dermatitis. Importantly, none of these clinical presentations is considered to be pathognomonic for HD skin diseases, and the diagnosis of HD is usually based on the exclusion of other pruritic diseases and on a positive response to therapy. The objectives of this study were to propose sets of criteria for the diagnosis of nonflea-induced HD (NFHD). We recruited 501 cats with pruritus and skin lesions and compared clinical parameters between cats with NFHD (encompassing those with nonflea, nonfood HD and those with food HD), flea HD and other pruritic conditions. Using simulated annealing techniques, we established two sets of proposed criteria for the following two different clinical situations: (i) the diagnosis of NFHD in a population of pruritic cats; and (ii) the diagnosis of NFHD after exclusion of cats with flea HD. These criteria sets were associated with good sensitivity and specificity and may be useful for homogeneity of enrolment in clinical trials and to evaluate the probability of diagnosis of NFHD in clinical practice. Finally, these criteria were not useful to differentiate cats with NFHD from those with food HD.

A prospective study on the clinical features of chronic canine atopic dermatitis and its diagnosis.

Canine atopic dermatitis (CAD) is a multifaceted disease associated with exposure to various offending agents such as environmental and food allergens. The diagnosis of this condition is difficult because none of the typical signs are pathognomonic. Sets of criteria have been proposed but are mainly used to include dogs in clinical studies. The goals of the present study were to characterize the clinical features and signs of a large population of dogs with CAD, to identify which of these characteristics could be different in food-induced atopic dermatitis (FIAD) and non-food-induced atopic dermatitis (NFIAD) and to develop criteria for the diagnosis of this condition. Using simulated annealing, selected criteria were tested on a large and geographically widespread population of pruritic dogs. The study first described the signalment, history and clinical features of a large population of CAD dogs, compared FIAD and NFIAD dogs and confirmed that both conditions are clinically indistinguishable. Correlations of numerous clinical features with the diagnosis of CAD are subsequently calculated, and two sets of criteria associated with sensitivity and specificity ranging from 80% to 85% and from 79% to 85%, respectively, are proposed. It is finally demonstrated that these new sets of criteria provide better sensitivity and specificity, when compared to Willemse and Prélaud criteria. These criteria can be applied to both FIAD and NFIAD dogs.

A systematic review and meta-analysis of the efficacy and safety of cyclosporin for the treatment of atopic dermatitis in dogs.

The efficacy of cyclosporin A (CsA) for the treatment of canine atopic dermatitis was evaluated based on the systematic review of prospective clinical trials published between 2001 and 2005. Ten studies with adequate design characteristics were included. These studies enrolled 799 dogs, 672 (84%) treated with CsA, 160 (20%) with placebo, 74 (9%) with oral glucocorticoids and 23 (3%) with antihistamines. Treatment duration varied from 2 weeks to 6 months. For safety analysis, data were available from 660 dogs. Lesion scores were improved from baseline in the range of 30-52%, 53-84% and 52-69% after 4, 6 and 16 weeks, respectively. The percentage of dogs with only mild pruritus rose from 0-13% at inclusion to 32-59% and 46-90% after 4 and 12 weeks, respectively. In most studies, the frequency of CsA administration could be reduced to every other day in 40% to 50% of patients after 4 weeks and to twice weekly in 20-26% of the dogs after 12-16 weeks. Meta-analysis confirmed highly significant effects of CsA compared to placebo, but none between oral CsA and glucocorticoids. The initial disease severity, age or body weight of subjects did not influence treatment success. Improvement by more than 50% over baseline of lesion scores was predictive of a better response during treatment maintenance. Vomiting and soft stools/diarrhoea were the most frequent adverse events seen at least once during the studies. These occurred in 25% and 15% of subjects, respectively. The frequency of each other type of adverse events was lower than 2.1%. In summary, the administration of CsA for the treatment of canine AD was found to be as effective as that of glucocorticoids, and adverse effects were minimal.

Clinical trial evaluating the efficacy and safety of cyclosporine in dogs with atopic dermatitis.

OBJECTIVE: To determine efficacy and safety of cyclosporine in the treatment of atopic dermatitis among dogs in North America. DESIGN: Randomized controlled (phase 1) and open-label (phase 2) trials. ANIMALS: 268 dogs with atopic dermatitis. PROCEDURE: In phase 1, dogs were randomly assigned to be treated with cyclosporine (5 mg/kg [2.3 mg/Ib], PO, q 24 h) or a placebo. In phase 2, all dogs were treated with cyclosporine for 16 weeks. Frequency of cyclosporine administration was decreased if dogs improved clinically. RESULTS: At the end of phase 1, canine atopic dermatitis extent and severity index (CADESI) scores for dogs treated with cyclosporine were significantly lower than scores for control dogs. Percentage of dogs with severe pruritus decreased from 67% to 16% for the cyclosporine group but from 66% to only 61% for the control group. During phase 2, cyclosporine dosage was decreased to every-other-day administration in 39% of the dogs after 4 weeks. After 12 weeks, 22% of the dogs were treated twice weekly and 36% were treated every other day. After 16 weeks, CADESI score had decreased > 50% in 68% of the dogs and 47% of dogs had no or mild pruritus. The most frequent adverse reactions were gastrointestinal tract signs. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that cyclosporine is efficacious for the treatment of atopic dermatitis in dogs and that frequency of cyclosporine administration can be reduced following an initial induction period. The drug was well tolerated.

Determination of the dosage of clomipramine for the treatment of urine spraying in cats.

OBJECTIVE: To determine the optimal dosage of clomipramine for the treatment of urine spraying in cats. DESIGN: Randomized controlled multicenter clinical trial. ANIMALS: 67 neutered cats. PROCEDURE: Cats with a minimum 1-month history of spraying urine against vertical surfaces at least twice per week were randomly assigned to be treated with a placebo or with clomipramine at a dosage of 0.125 to 0.25 mg/kg (0.057 to 0.11 mg/lb), 0.25 to 0.5 mg/kg (0.11 to 0.23 mg/lb), or 0.5 to 1 mg/kg (0.23 to 0.45 mg/lb), p.o., every 24 hours for up to 12 weeks. Owners of all cats were given information on behavioral treatment and environmental modification. RESULTS: Prior to treatment, mean number of urine spraying events ranged from 0.9 to 1.3 urine spraying events/d for the 4 groups, and mean percentage of days with urine spraying events ranged from 62% to 69%. All 3 dosages of clomipramine were associated with significant reductions in frequency of urine spraying. Sedation was the most common adverse effect and was identified in 27 of the 50 cats treated with clomipramine; however, treatment was not discontinued in any cat because of sedation. CONCLUSIONS AND CLINICAL RELEVANCE: Results of the present study suggest that compared with a placebo, clomipramine significantly reduces the frequency of urine spraying in cats in terms of the number of urine spraying events per day and the number of days with urine spraying events. For cats with urine spraying, the recommended initial dosage of clomipramine is 0.25 to 0.5 mg/kg, p.o., every 24 hours.

Cyclosporin A: a new drug in the field of canine dermatology.

In the last few years, there has been growing interest in the use of cyclosporin to treat canine skin diseases. Cyclosporin exhibits potent immunomodulating properties that reflect its ability to block the transcription of cytokines genes in activated T lymphocytes. Cyclosporin also inhibits a number of immune allergic reactions that occur after activation of mast cells, Langerhans cells, eosinophils and keratinocytes. In randomized controlled trials, cyclosporin has proven to be as effective as glucocorticoids for treatment of canine atopic dermatitis at the inducing dosage of 5 mg kg(-1). The drug has also proven beneficial for the treatment of perianal fistulas in dogs. Other potential applications are suggested from small pilot open trials using dogs affected with various immune-mediated dermatological diseases. The pharmacokinetic properties of cyclosporin are very similar in dogs and man, but its safety margin is much wider in dogs. Therefore, routine cyclosporin blood level monitoring does not appear necessary. Although in man renal impairment and hypertension are often seen, even at low doses, these effects are not observed in dogs. Adverse reactions consist mainly of transient emesis and diarrhoea occurring during the first days of treatment. Other adverse reactions, such as gingival hyperplasia, verruciform lesions and hypertrichosis, appear to be dose-dependent, and occur rarely at therapeutic doses. An increased susceptibility to infections has not been reported in dogs receiving this drug.

Comparative efficacies of oral ketoconazole and terbinafine for reducing Malassezia population sizes on the skin of Basset Hounds.

The objective of this study was to compare the efficacy of oral ketoconazole and terbinafine for reducing population sizes of Malassezia yeasts on canine skin. Twenty-one Basset Hounds were randomised in three groups of seven according to Malassezia populations. Dogs in the first group were treated by oral administration of ketoconazole (Ketofungol) 200 mg, Janssen-Cilag) at 10 mg x kg-1, every 24 h with food, for 3 weeks. Dogs in the second group were treated by oral administration of terbinafine (Lamisil) 250 mg, Novartis) at 30 mg x kg-1, every 24 h with food, for 3 weeks. The seven remaining dogs were used as controls. Malassezia population sizes were assessed by use of contact plates on four cutaneous sites at days 7, 14 and 21. Both ketoconazole and terbinafine were effective in reducing the baseline levels of Malassezia organisms with no significant difference between the two drugs. In further studies, oral terbinafine should be evaluated for the management of canine cases of Malassezia dermatitis.

Comparison of cyclosporine A with methylprednisolone for treatment of canine atopic dermatitis: a parallel, blinded, randomized controlled trial.

The objective of this multicentre, parallel, blinded, randomized controlled study was to evaluate the efficacy and the safety of cyclosporine (CsA group, 117 dogs) in comparison with methylprednisolone (MP group, 59 dogs) in the treatment of atopic dermatitis for 4 months. Mean induction dose of both drugs (5 mg/kg CsA, 0.75 mg/kg MP) was tapered over time according to the clinical response. At the end of the study, the mean estimated percentage reduction from baseline (confidence interval) of lesion scores was 52% (44-59) and 45% (35-56), and the reduction in pruritus score was 36% (27-43) and 33% (23-43) in dogs in the CsA and MP groups, respectively. These percentages were not significantly different between groups. A significantly better overall assessment of efficacy was obtained in the CsA-treated dogs (76 vs. 63% responses excellent or good in the CsA compared with MP group). CsA-treated dogs presented a higher frequency of gastrointestinal disorders, mainly vomiting, but MP dogs tended to be more susceptible to infections. There was no remarkable change over baseline of the haematological and biochemical parameters in the two groups.

Résumé Le but de cette étude contrôlée, multicentrique, parallèle, en aveugle et randomisée, était d'évaluer l'efficacité et l'inocuité de la cyclosporine (groupe CsA, 117 chiens) en comparaison de la methylprednisolone (groupe MP, 59 chiens) pour le traitement de la dermatite atopique pendant 4 mois. La dose moyenne d'induction pour les deux molécules (5 mg kg−1 CsA, 0.75 mg kg−1 MP) était progressivement diminuée en fonction de la réponse clinique observée. A la fin de l'étude, le pourcentage moyen de réduction des scores lésionnels et les intervalles de confiance étaient de 52% (44-59) pour le groupe CsA et de 45% (35-56) pour le groupe MP, alors que le pourcentage moyen de réduction du prurit était de 36 % (27-43) pour la CsA et de 33% (23-43) pour la MP. Ces pourcentages ne sont pas significativement différents entre les groupes. L'amélioration a été jugée significativement meilleure dans le groupe CsA (76% vs 63% des réponses étaient cotées excellentes ou bonnes dans le groupe CsA comparé au groupe MP). Les chiens traités par la CsA ont présenté significativement plus de troubles gastro-intestinaux (notamment des vomissements) mais les chiens du groupe MP se sont avérés plus sensibles aux infections. Aucune modification remarquable des paramètres hématologiques ou biochimiques n'a été remarquée dans les deux groupes de chiens.

Resumen El objetivo de este estudio multicéntrico, en paralelo, ciego y al azar controlado fue evaluar la eficacia y seguridad de la ciclosporina (grupo CsA, 117 perros) en comparación con la metilprednisolona (grupo MP, 59 perros) en el tratamiento de dermatitis atópica durante 4 meses. La dosis media de inducción para ambas drogas (5 mg kg−1 CsA, 0.75 mg kg−1 MP) fue disminuida con el tiempo de acuerdo con la respuesta clínica. Al final del estudio, el porcentaje de reducción medio estimado desde la línea basal (intervalo de confianza) de la puntuación de las lesiones fue del 52% (44-59) y 45% (35-56), y la reducción de la puntuación del prurito fue del 36% (27-43) y 33% (23-43) en los perros de los grupos de CsA y MP, respectivamente. La diferencia entre los porcentajes de ambos grupos no fue significativa. En la estimación global, la eficacia fue mejor en el grupo de perros tratados con CsA (76% de respuestas excelentes o buenas en el grupo CsA comparado con el 63% en el grupo MP). Los perros tratados con CsA mostraron una mayor frecuencia de alteraciones gastro-intestinales, principalmente vómitos, mientras que los perros tratados con MP presentaron mayor susceptibilidad a infecciones. No se observaron diferencias remarcables en los niveles basales de los parámetros hematológicos y bioquímicos en ambos grupos.

Randomized controlled trial of the efficacy of cyclosporine in the treatment of atopic dermatitis in dogs.

OBJECTIVE: To evaluate efficacy of cyclosporine A, administered at either of 2 dosages, in dogs with atopic dermatitis (AD). DESIGN: Multicenter randomized controlled trial. ANIMALS: 91 dogs with AD. PROCEDURE: Dogs were assigned to receive placebo (30 dogs), cyclosporine at a low dosage (2.5 mg/kg [1.1 mg/lb], PO, q 24 h for 6 weeks; 30 dogs), or cyclosporine at a high dosage (5.0 mg/kg [2.3 mg/lb], PO, q 24 h for 6 weeks; 31 dogs). RESULTS: After 6 weeks, mean percentage reductions, compared with baseline scores, in scores of lesion severity were 34, 41, and 67% for dogs treated with the placebo, cyclosporine at the low dosage, and cyclosporine at the high dosage, respectively. Similarly, mean percentage reductions in pruritus scores were 15, 31, and 45%, respectively. Percentage reductions in skin lesion and pruritus scores were significantly higher for dogs given cyclosporine at the high dosage than for dogs given the placebo. Treatment efficacy was significantly associated with whether dogs had a history of seasonal AD. Percentage reductions in skin lesion and pruritus scores were high for dogs treated with cyclosporine at the highest dosage that had a history of nonseasonal AD. Dogs in all groups with seasonal AD improved during the study period. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that oral administration of cyclosporine at a dosage of 5.0 mg/kg once daily is effective in reducing severity of pruritus and skin lesions in dogs with AD, especially those with nonseasonal disease.