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177 DISC

Veterinary Dermatology 2000, 11, 37

Safety of long-term administration of a 0.01%


uocinolone shampoo in allergic dogs
KARIN M. BEALE,* GAIL A. KUNKLE,* PAMELA GINN{ and KAREN KEISLING*
*University of Florida, College of Veterinary Medicine, Department of Small Animal, Clinical Sciences and
{Pathobiology, PO Box 100126 HSC, University of Florida, Gainesville, Florida 326100126, USA
(Received 11 January 1996; accepted 22 August 1997)

Abstract Nine dogs with allergic dermatitis were bathed twice weekly with a 0.01% uocinolone shampoo
for 6 months to evaluate the shampoo's eects on the adrenalpituitary axis, serum chemistries, complete
blood counts and cutaneous histology. A group of 5 normal control dogs were bathed twice weekly for 6
months with the shampoo vehicle to determine whether or not the stress of bathing would have any eects on
the monitored indices. Skin biopsies were evaluated at the beginning and end of the study, and serum
chemistries and serum cortisols postadrenocorticotrophic hormone administration were evaluated every 8
weeks. There was no eect of the drug over time on serum chemistries or cortisol. Individual dogs in the
treatment group had decreased epidermal and dermal thickness as well as decrease in size or number of
sebaceous glands after treatment. None of the dogs exhibited the combination of morphologic changes
characteristic of an atrophic dermatosis due to hyperadrenocorticism.
Keywords: uocinolone, cortisol, allergy, shampoo.

INTRODUCTION

MATERIALS AND METHODS

Canine allergic dermatoses such as ea allergic


dermatitis and atopy aect large areas of a dog's
skin. Symptomatic management of these problems
often requires treatment with oral anti-inammatory
products because treatment with topical anti-inammatory creams and lotions would require application
to excessively large areas. The use of a topical antiinammatory product that could easily be applied to
a large area of skin, such as a shampoo, might be
more practical and eective.
The topical application of glucocorticoid-containing medications both in the ear and on the skin has
been shown to cause suppression of the adrenal
pituitary axis and elevations in liver enzymes.15
The dogs used in these studies, however, were dogs
with normal skin. Dogs with allergic dermatitis and
inamed skin might absorb more of the topically
applied glucocorticoids and thus be even more
susceptible to adrenal suppression. The purpose of
the study described here was to determine if longterm use of a 0.01% uocinolone shampoo on
inamed skin would result in detectable changes in
skin histology, cortisol concentrations and/or serum
liver enzymes.

Fifteen dogs were used in this study (Group 1,


n = 10; Group 2, n = 5, control). Dogs were excluded
from the study if they had been treated with topical
glucocorticoids within four weeks of the start of the
study, or systemic glucocorticoids within 6 weeks of
the start of the study.
The treatment group comprised 10 dogs with ea
allergic dermatitis and/or atopy that had been
presented to the University of Florida, College of
Veterinary Medicine Dermatology Service with ea
allergic dermatitis and/or atopy. The dogs had
positive intradermal skin test results (immediate
and/or delayed) to ea antigen and/or inhalent
allergens (Greer Laboratories, Lenoir, NC), and
pruritus. The ve control dogs were healthy research
dogs (n = 3) or investigator owned dogs (n = 2).

Correspondence: Karin Beale, Gulf Coast Veterinary Dermatology


and Allergy, 1111 West Loop South, Suite 120, Houston, Texas
77027, USA. Reprints will not be available from the author.
This study was supported by a grant from Hills Dermaceuticals,
Orlando, Florida.
# 2000 Blackwell Science Ltd

Treatment protocol
Dogs in group 1 were bathed twice weekly (34 days
apart) for 6 months by their owners using the
following protocol: each dog was rst bathed with a
cleansing oatmeal-based shampoo (Florida Foam
shampoo, Hills Dermaceuticals, Orlando, FL) to
remove dirt and grease from the hair. The dog was
then thoroughly rinsed and then bathed with a 0.01%
uocinolone containing shampoo (FS shampoo, Hills
Dermaceuticals, Orlando, FL). The owners were
instructed to apply sucient shampoo to completely
cover the dog's coat, and enough to penetrate the
coat and contact the skin over the entire body. The
shampoo was massaged into the coat and remained in
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177 DISC
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K. M. Beale et al.

contact with the skin for 10 min before rinsing.


Investigators subjectively monitored shampoo bottles
requested by owners to ensure that appropriate
amounts of shampoo were being utilized, based on
the dog's size and density of the coat. The protocol
was reviewed at each follow-up examination to
ensure that dogs were being bathed correctly. Control
dogs were bathed twice weekly by the investigators in
a similar manner, using only the oatmeal-based
shampoo, then rinsed thoroughly.
Dogs were not treated with any other medications
containing glucocorticoids during the treatment
period. Any dog with pyoderma was treated with
cephalexin (22 mg kg71 twice daily for 3 weeks) prior
to starting the study. Dogs that developed pyoderma
during the study period were treated with cephalexin
as previously described. If necessary, antihistamines
and/or fatty acid supplements were administered to
provide relief from pruritus. Topical treatment with
ea control products was encouraged.
The following indices were monitored before
bathing therapy was initiated and every 8 weeks until
the end of the study: serum alanine aminotransferase
(ALT), serum aspartate aminotransferase (AST),
serum cholesterol (Chol), serum alkaline phosphatase
(SAP), serum glucose (Gluc), total white blood cell
count (WBC), neutrophil count (Neut), eosinophil
count (Eos), monocyte count (Monos) and serum
cortisol concentration pre- and 2 h post-administration of 20 IU adrenocorticotrophic hormone (ACTH
gel, Phoenix Pharmaceuticals, St. Josteph, MO)
intramuscularly. Serum and whole blood were
collected and analysed on the day of the visit for
routine biochemistries and haematology. Serum for
cortisol concentrations was collected, and frozen at
720 8C. Cortisol concentrations were measured; all
samples were tested at the end of the study using a
commercial enzyme-linked immunosorbent assay
previously validated.6
Skin biopsies
Skin biopsies were obtained before and after the study;
specimens were obtained from the right inner thigh in
the mid-femur region and dorsal to the iliac crest. Tissue
was collected using a 6-mm skin biopsy punch and local
anaesthesia (lidocaine injectable 2%, Butler Company,
Columbus, OH). Biopsy specimens were xed in 10%
neutral buered formalin and processed routinely. Five

micron sections were stained with haematoxylin and


eosin and evaluated for epidermal thickness (mean
number of cell layers over 5 high power elds, 1006),
dermal thickness (subjective evaluation of a thicker or
thinner than normal dermis for area evaluated,
described as increased or decreased), and changes in
the number or size of sebaceous glands. Sebaceous
glands were considered normal in number when each
follicle was associated with at least one sebaceous
lobule. The size of the sebaceous glands was considered
normal when lobules containing fully dierentiated,
highly vacuolated cells were readily identied. Sebaceous glands were considered prominent if multiple
lobules (4 3) were associated with each adnexal unit.
Tissues were examined and scored by one investigator
(PG) who was blinded to the treatment and control
groups. The results of histological scoring were not
submitted to statistical analysis due to the subjective
nature of scoring.
Statistical analysis of data
Repeated measures analysis of variance, univariate
tests of hypotheses for within subject eects was used
to determine if there was an eect of the drug over
time on ALT, AST, ALP, Chol, Gluc, WBC, Neuts,
Eos, Monos, pre-ACTH cortisol, post-ACTH cortisol and an increase in cortisol after ACTH. A P-value
5 0.05 was considered signicant.
RESULTS
Fourteen of the 15 dogs completed the study. Owners
reported bathing the dogs as directed and the amounts
of shampoo utilized by owners appeared to be
appropriate. All the dogs in the control group had
no history of skin disease with the exception of dog 12,
who had dietary hypersensitivity, but all symptoms
were controlled with a hypoallergenic diet (D/D, Hills
Pet Products, Topeka, KS). One of the dogs (dog 10)
in the treatment group was omitted from the study
after 2 months because the dog had severe ea allergic
dermatitis which could not be controlled with the
uocinolone shampoo, ea control, antihistamines
and fatty acid supplements. This patient was in an
environmental situation in which complete ea control was dicult. All the other dogs in the treatment
group remained in the study, and the owners felt their

Time

Treatment group (n = 9)
mean pre (+ SD) mean post (+ SD)

Control group (n = 5)
mean pre (+ SD) mean post (+ SD)

Baseline
2 months
4 months
6 months

66.2
85.0
111.7
68.7

69.3
69.8
81.7
72.8

(22.9)
(61.0)
(52.1)
(32.6)

296.6
294.4
276.2
252.4

(91.6)
(99.3)
(106.5)
(63.5)

(14.6)
(45.8)
(41.1)
(27.0)

319.5
280.0
258.2
267.3

(87.2)
(88.0)
(53.0)
(70.6)

The treatment group was bathed twice weekly for 6 months in a 0.01% uocinolone shampoo. The
control group was bathed twice weekly in the vehicle.
Serum cortisol concentrations were evaluated in dogs before and 2 h after administration of 20 IU
ACTH gel IM. Normal cortisols for this laboratory are 13.8165.5 nmol L71 pre-ACTH and 165.5
469.0 post-ACTH administration.
# 2000 Blackwell Science Ltd, Veterinary Dermatology, 11, 37

Table 1. Mean serum cortisol concentrations (nmol L71) in dogs


treated with 0.01% uocinolone
shampoo and control dogs preand post-ACTH administration

177 DISC
Long-term use of a steroid shampoo on dogs
pruritus was suciently controlled with the shampoo
and ea control. Two dogs in the treatment group and
one dog in the control group (dog with dietary
hypersensitivity) required treatment with antibiotics
for a supercial pyoderma during the course of the
study. All three dogs had a history of previous
pyoderma. One dog in the treatment group developed
bacterial otitis externa which was treated with a
topical gentocin preparation (gentocin ophthalmic
solution, Schering Plough Animal Health, Kenilworth, NJ) containing no glucocorticoids. Dog 5
developed aspiration pneumonia on week 5 and
shampooing was discontinued for 4 weeks, then
resumed for an additional 4 months. The cause of
the pneumonia was not determined.
Dogs were of various sizes and haircoat types. The
treatment group included a Yorkshire terrier, two
Retriever mixes (long coats), two Beagles, two
Greyhounds, a terrier-mix and a Springer Spaniel.
The control group included a Husky, a Greyhound,
a Labrador Retriever, a Bassett Hound and a
German Shepherd.
There was no signicant dierence over time
between the treatment group and the control group
with respect to laboratory tests (Table 1). No
individual dogs exhibited an abnormal response to
ACTH stimulation suggestive of iatrogenic Cushing's
disease (low-normal baseline serum cortisol with little
or no response to exogenous ACTH administration).
Individual dogs in both the treatment and control
groups exhibited changes in the histology of the
tissues (Tables 2 & 3). Five of nine dogs in the
treatment group had a decrease in either the size or the
number of sebaceous glands post-treatment. Six of
nine dogs had decreased epidermal thickness posttreatment. When pre-treatment biopsies were comTable 3. Changes in sebaceous
gland size and number in biopsies
from dogs treated with a 0.01%
uocinolone shampoo and a control shampoo

pared to post-treatment biopsies, three dogs in the


treatment group had a decrease in dermal thickness
and one dog exhibited a thickening of the dermis after
6 months of treatment with uocinolone shampoo.
However, the post-treatment specimens were still
judged to be of normal thickness. There were no
changes in dermal thickness in the control group.
DISCUSSION
In this study, the shampoo was used in a manner that
would be recommended in a clinical situation.
Shampoo was not dispensed on a volume/weight
Table 2. Mean epidermal thickness in dogs treated with a 0.01%
uocinolone shampoo and control dogs
Treatment group

Dorsal hip area


pre
post

Inner thigh area


pre
post

dog
dog
dog
dog
dog
dog
dog
dog
dog

1.5
7.5
4
2.5
3.5
3.5
3.5
3.5
6

NC
3.5
NC
2
7
NC
NC
1.5
NC

1.5
3.5
11
4
3.5
2.5
3
3.5
3.5

NC
2
3.5
NC
NC
1.5
4
2
2.5

2
6.5
3
2
2.5

NC
NC
1.5
NC
4

2
4
2.5
2
4

NC
NC
NC
NC
NC

1
2
3
4
5
6
7
8
9

Control group
dog 11
dog 12
dog 13
dog 14
dog 15

Epidermal thickness is expressed in number of cell layers.


Histological features were evaluated before treatment and after 6
months of treatment with a 0.01% uocinolone shampoo or the
vehicle control. NC = no change in dermal thickness.

Treatment group

Dorsal hip area


pre
post

Inner thigh area


pre
post

dog
dog
dog
dog
dog

1
2
3
4
5

normal
normal
prominent
normal
normal

dog
dog
dog
dog

6
7
8
9

Control group
dog 11
dog 12
dog 13
dog 14
dog 15

decreased
normal
prominent
normal

NC
decrease in size and number
decrease in size
decrease in number

prominent
numerous
normal
normal

NC
NC
NC
NC
increase in size
and number
decrease in size
NC
NC
decrease in size

normal
normal
normal
normal
normal

NC
decrease in size
NC
NC
decrease in size

normal
prominent
prominent
normal
normal

NC
NC
decrease in size
NC
NC

normal
normal
normal
normal
normal

NC
NC
NC
NC
NC

Treatment group dogs were bathed twice weekly in a 0.01% uocinolone shampoo on a twice weekly
basis for 6 months. Control group dogs were bathed in the same manner using a vehicle-control
shampoo. Sebaceous glands were dened as normal when lobules containing fully dierentiated, highly
vacuolated cells were readily identied. Sebaceous glands were dened as prominent if multiple lobules
(4 3) were associated with each adnexal unit. Post-treatment samples were compared to pre-treatment
samples for either a decrease in size or number of sebaceous glands. NC = no change.
# 2000 Blackwell Science Ltd, Veterinary Dermatology, 11, 37

177 DISC
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K. M. Beale et al.

basis based on the dog's size because dogs with


dierent coat thicknesses would require dierent
amounts of shampoo to achieve good penetration
through the coat and contact with the skin. After six
months of use, this 0.01% uocinolone shampoo
caused no detectable adverse eects.
Histologically, there was evidence of decreased
sebaceous gland size or number in ve of nine dogs
treated with the uocinolone shampoo. However,
none of the dogs exhibited any clinical symptoms that
might be expected, such as dry, scaly skin. Eight of
the 18 biopsies from the post-treatment group dogs
exhibited some degree of epidermal thinning compared to pre-treatment samples. Since the normal
canine epidermis may only be 13 cell layers thick, it
is unlikely that this was directly due to the treatment.
Interestingly, some of the dogs had a hyperplastic
epidermis initially, which normalized with treatment
with the uocinolone shampoo.
A previous study documented signicant suppression of the adrenalpituitary axis with topically
applied triamcinolone acetonide, uocinolide and
betamethasone valerate to the dorsal cervical area
for 5 consecutive days.2 Because topical otic preparations have caused adrenal suppression and elevations
in liver enzymes after as little as one week of
treatment, we were interested to see if this would
occur in this study.3,4 The nine dogs in group A were
bathed twice weekly in a uocinolone shampoo for a
period of 6 months and exhibited no evidence of
adrenal suppression. The manner in which the products containing steroids are applied to the skin may
account for dierences in observed eects on adrenal
function. In this study, the systemic absorption of the
glucocorticoid was limited because of limited contact
time; occlusive ointments or solutions applied to the
skin, ears or conjunctiva are designed to enhance the
absorption of the active ingredient.
Several dogs in the study required treatment for
dermatologic disorders. Three dogs were treated for
pyoderma. Two were in the treatment group and one
was in the control group. The control dog had dietary
hypersensitivities and symptoms had been well
controlled for over a year with dietary management.
To the best of our knowledge, this episode of
pyoderma was not associated with any diet changes;
the owner did not change the diet. It is possible that
the frequent bathing might have altered the epidermal
barrier making the dog more susceptible to pyoderma. It is also possible that the dog ingested an
oending food. Although it is reasonable to be

concerned that a steroid-containing shampoo might


make a dog more susceptible to pyoderma, this only
occurred in two of the treated dogs, and both dogs
had a history of pyoderma. One dog in the treatment
group also developed otitis. It is unlikely that this was
related to the shampoo, because this dog was atopic
and also had a history of ear infections. Finally, one
dog in the treatment group developed pneumonia and
was temporarily withdrawn from the study. The
cause of the pneumonia was unknown, but it seems
unlikely that it was related to the shampoo therapy.
Based upon the ndings of this study, twice weekly
bathing with a 0.01% uocinolone shampoo caused
no detectable adverse eects. These types of products
may be useful in the management of pruritic
dermatoses, particularly in dogs that do not tolerate
systemic glucocorticoid therapy and are nonresponsive to nonsteroidal anti-inammatory medications.

REFERENCES
1. Glaze, M.B., Crawford, M.A., Nachreiner, R.F., Casey,
H.W., Nafe, L.A., Kearney, M.T. Ophthalmic corticosteroid therapy. Systemic eects in the dog. Journal of
the American Veterinary Medical Association 1988; 192:
735.
2. Zenoble, R.D., Kemppainen, R.J. Adrenocortical
suppression by topically applied corticosteroids in
healthy dogs. Journal of the American Veterinary
Medical Association 1987; 191: 6858.
3. Moriello, K.A., Fehrer-Sawyer, S.L., Meyer, D.J.,
Feder, B. Adrenocortical suppression associated with
topical otic administration of glucocorticoids in dogs.
Journal of the American Veterinary Medical Association
1988; 193: 32931.
4. Meyer, D.J., Moriello, K.A., Feder, B.M., FehrerSawyer, S.L., Maxwell, A.K. Eect of otic medications
containing glucocorticoids on liver function test results
in healthy dogs. Journal of the American Veterinary
Medical Association 1990; 196: 7434.
5. Roberts, S.M., Lavacxh, J.D., Macy, D.W., Severin,
G.A. Eect of ophthalmic prednisolone acetate on the
canine adrenal gland hepatic function. American Journal
of Veterinary Research 1984; 45: 17114.
6. Moriello, K.A., Halliwell, R.E.W., Oakes, M.
Determination of thyroxine, triiodothyronine and
cortisol changes during simultaneous adrenal and
thyroid function tests in healthy dogs. American
Journal of Veterinary Research 1987; 48: 45862.
7. Feldman, E.C., Nelson, R.W. Hyperadrenocorticism. In:
Canine and Feline Endocrinology and Reproduction, 2nd
edn. Philadelphia; W.B. Saunders Co, 1996: 187255.

Resume Neuf chiens presentant une dermatite allergique ont ete shampooines deux fois par semaine pendant
6 mois avec un shampooing contenant 0.01% de uocinolone an d'evaluer les eets du shampooing sur l'axe
hypophyso-adrenalien, sur les constantes biochimiques et hematologiques, et sur l'aspect histologique de la
peau. Un groupe de 5 chiens normaux a servi de groupe controle et a ete shampooine avec le vehicule pour
determiner si le stress du traitement pouvait inuencer les indices surveilles. Des biopsies cutanees ont ete
realisees au debut et a la n de l'etude. Les valeurs biochimiques et des mesures du cortisol, avant et apres
stimulation a l'ACTH, ont ete etudiees toutes les 8 semaines. Aucun eet du traitement n'a ete observe sur les
valeurs biochimiques ou sur celles du cortisol. Quelques chiens du groupe traite ont presente une diminution
# 2000 Blackwell Science Ltd, Veterinary Dermatology, 11, 37

177 DISC
Long-term use of a steroid shampoo on dogs

de l'epaisseur epidermique et dermique et une diminution du nombre ou de la taille des glandes sebacees apres
traitement. Aucun chien ne presentait de modications compatibles avec une dermatose atrophique due a une
hyperadrenocorticisme. [Beale, K. M., Kunkle, G. A., Ginn, P. et Keisling, K. (Securite d'utilisation d'un
shampooing a 0.01% de uocinolone chez les chiens allergiques.) Veterinary Dermatology 2000; 11: 37.]
Resumen Nueve perros con dermatitis alergica fueron banados semanalmente con un champu con un 0,01%
de uocinolona durante 6 meses para evaluar los efectos del champu sobre el eje adrenalpituitario, los
analisis bioqu micos sericos, los contajes hematicos y la histolog a cutanea. Un grupo de 5 perros control
normales fueron banados dos veces a la semana durante 6 meses con el veh culo del champu para determinar
si el estres del bano ten a algun efecto sobre los ndices monitorizados. Las biopsias cutanas fueron evaluadas
al principio y al nal del estudio, y la bioqu mica serica y los cortisoles sericos despues de la administracion de
hormona adrenocorticotropica fueron evaluados cada 8 semanas. No hubo efecto del farmaco a lo largo del
tiempo sobre las bioqu micas sericas o el cortisol. Los perros en el grupo de tratamiento ten an una
disminucion del grosor epidermico y dermico as como una disminucion en el tamano o numero de glandulas
sebaceas despues del tratamiento. Ninguno de los perros mostro la combinacion de cambios morfologicos
caracter sticos de una dermatosis atroca debida al hiperadrenocorticismo. [Beale, K. M., Kunkle, G. A.,
Ginn, P. y Keisling, K. (Seguridad de la administracion prolongada de un champu con un 0,01% de
uocinolona en perros alergicos.) Veterinary Dermatology 2000; 11: 37.]
Zusammenfassung Neun Hunde mit allergischer Dermatitis wurden fur sechs Monate zweimal wochentlich
mit einem 0.01%-igen Fluocinolonshampoo gebadet, um die Auswirkungen des Shampoos auf die
Nebennieren-Hypophysenachse, Serum- und Blutwerte und kutane Histopathologie zu bewerten. Eine
Gruppe mit funf normalen Hunden wurde fur 6 Monate zweimal wochentlich mit dem Konstituens gebadet,
um festzustellen, ob der Badestress irgendeinen Einuss auf die Bewertungsindices hatte. Hautbiopsien
wurden zu Beginn und am Ende der Studie, Serumwerte und Kortisolwerte nach Verabreichung von
adrenokortikotrophem Hormon alle 8 Wochen bewertet. Serum- und Kortisolwerte wurden durch das
Shampoo nicht beeinusst. Einzelne Hunde in der Behandlungsgruppe hatten am Ende der Behandlung
dunnere Epidermis und Dermis sowie verminderte Anzahl und Grosse der Talgdrusen. Keiner der Hunde
zeigte die fur eine durch Hyperadrenokortizismus hervorgerufene atrophische Dermatitis kennzeichnenden
morphologischen Veranderungen. [Beale, K. M., Kunkle, G. A., Ginn, P. und Keisling, K.
(Langzeitverwendung eines 0.01%-igen Fluocinolon Shampoos bei allergischen Hunden.) Veterinary
Dermatology 2000; 11: 37.]

# 2000 Blackwell Science Ltd, Veterinary Dermatology, 11, 37