Factors that affect the transdermal penetration of glucocorticoids in dogs

Liisa Ahlstrom (2010). Factors that affect the transdermal penetration of glucocorticoids in dogs PhD Thesis, School of Veterinary Science, The University of Queensland.

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Author Liisa Ahlstrom
Thesis Title Factors that affect the transdermal penetration of glucocorticoids in dogs
School, Centre or Institute School of Veterinary Science
Institution The University of Queensland
Publication date 2010-08
Thesis type PhD Thesis
Supervisor Associate Professor Paul Mills
Dr Sheree Cross
Total pages 172
Total colour pages 6
Total black and white pages 166
Subjects 07 Agricultural and Veterinary Sciences
Abstract/Summary This PhD thesis presents important new findings on factors that affect the transdermal penetration of glucocorticoids in dogs, and provides veterinary practitioners with evidence of efficacy and guidelines for the use of topical glucocorticoids in canine patients. Studies were performed to validate a method of skin storage and demonstrated that freezing dog skin at −20 oC significantly increased the transdermal penetration of hydrocortisone (the basic glucocorticoid molecule) in vitro and that the extent of this enhancement was positively correlated with the duration of freezing up to 12 months. However, only the magnitude, not the shape of the permeation profiles of hydrocortisone appeared altered through the frozen compared to the fresh skins, suggesting that canine skin frozen for up to 12 months would still be useful to compare or rank the effects of altering a variable, such as formulation or skin treatment, on hydrocortisone penetration. These findings enabled canine skin to be collected opportunistically and then stored at −20 oC until required for subsequent in vitro studies in this thesis. Studies were then performed to determine if commonly performed skin preparations would enhance the transdermal penetration of glucocorticoids in dogs. This question was relevant to the treatment of dogs with allergic skin disease, as some form of surface preparation, such as hair removal or cleaning, often precedes the application of topical formulations to the skin of dogs, to improve the contact between the drug and the skin. Results from penetration studies using skin from five dogs revealed that shaving or cleaning skin with alcoholic chlorhexidine significantly increased the penetration of hydrocortisone through canine skin in vitro. Consequently, preparing a canine patient’s skin by shaving or cleaning prior to the application of a topical glucocorticoid may enhance the transdermal penetration of the drug, leading to higher than expected systemic concentrations and an increased potential for adverse, systemic effects. Studies to investigate the effect of allergic skin disease, demonstrated that the transdermal penetration of hydrocortisone may be greatly increased through the lesional compared to the non-lesional skin of individual dogs with suspected flea allergy dermatitis. However, this trend was not consistent for all five skin donors and was likely to have been affected by variables, such as disease severity, concurrent infections and inter-individual differences in skin characteristics. Nonetheless, it is important for veterinarians to be aware that higher than anticipated penetration and potentially, systemic side effects, may result from the topical application of glucocorticoids to the lesional skin of dogs with allergic skin disease. Next, the effect that the formulation (or vehicle) that carries a drug may have on the transdermal penetration of glucocorticoids in dogs was evaluated. A study comparing six different, commercially-available, topical creams containing 1% hydrocortisone or hydrocortisone acetate revealed significant differences in their rates of transdermal hydrocortisone penetration when applied to skin from the same region of one dog in vitro. Similarly, when equal amounts of a more lipophilic glucocorticoid (budesonide) were applied to canine skin in three different vehicles, there were differences in transdermal flux and skin retention of budesonide of up to 100-fold and five-fold, respectively, between the formulations, confirming that the excipients within a topical formulation can greatly affect these parameters. Finally, a randomised, placebo-controlled, double-blinded clinical trial to determine the efficacy of the budesonide-containing formulation that had shown the highest penetration and retention in canine skin in vitro was performed in 29 dogs with atopic dermatitis. This study demonstrated that a topical budesonide formulation applied once-weekly at 1 g/kg was a more efficacious treatment than placebo for reducing the clinical signs of atopic dermatitis in dogs. Treatment with the topical glucocorticoid reduced the extent and severity of skin lesions, reduced pruritus and improved the quality of life of the dogs within three weeks, compared to treatment with placebo. In summary, this thesis adds to the state of knowledge in veterinary dermatopharmacology and presents important new findings on factors that affect the transdermal penetration of glucocorticoids in dogs, specifically surface preparations, skin disease and the physicochemical properties of the drug and the vehicle. Additionally, the results of this research provide veterinary practitioners with guidelines for the use and evidence for the efficacy and safety of topical glucocorticoids in canine patients, which may improve the management of allergic skin disease in dogs.
Keyword Dermatopharmacology
Transdermal Penetration
canine atopy
Topical medication
Percutaneous Absorption
skin disease
diffusion cell
skin reservoir effect
Additional Notes Colour pages: 19, 20, 39, 100, 108, 111 (= 6 colour pages in total) Landscape pages: 64, 70, 71, 83, 101, 132 (= 6 landscape pages in total; N.B. these landscape pages have already been rotated so that they are ready to print in portrait format)

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Created: Mon, 06 Dec 2010, 07:30:59 EST by Miss Liisa Ahlstrom on behalf of Library - Information Access Service