Paper 214 DISC

Veterinary Dermatology 2001, 12, 2939

Clinical and histological evaluation of an analogue of

palmitoylethanolamide, PLR 120 (comicronized
Palmidrol INN) in cats with eosinophilic granuloma and
eosinophilic plaque: a pilot study
FABIA SCARAMPELLA,* FRANCESCA ABRAMO{ and CHIARA NOLI*
*Studio Dermatologico Veterinario, Via Sismondi 62, 20133 Milan, Italy
{Dipartimento di Patologia Animale, Universita di Pisa, Pisa, Italy
(Received 16 August 1999; accepted 20 December 1999)

Abstract Fifteen cats with eosinophilic granuloma or eosinophilic plaque were given PLR 120 at the dosage
of 10 mg kg71 twice daily for one month. PLR-120 down-modulates mast cell degranulation via a receptormediated mechanism. No other drugs were permitted and cats were kept free of parasites throughout the
study. A clinical evaluation and skin biopsies were performed before and after the treatment. Clinical
improvement was assessed at 15 and 30 days. Mast cell numbers were counted and their granular content was
assessed by densitometric analysis on toluidine blue-stained sections before and after the treatment. Ten of 15
(67%) cats showed clinical improvement of signs and lesions. There was no signicant dierence between mast
cell numbers in skin biopsies taken before and after the trial, whereas the number of granules was signicantly
increased (P 5 0.009). This pilot study suggests that PLR-120 might be a useful drug for the treatment of
eosinophilic granuloma and eosinophilic plaque.

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Keywords: ALIAmides, cats, eosinophilic granuloma, eosinophilic plaque, mast cells, Palmidrol, PLR-120,
skin disease.

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INTRODUCTION
The eosinophilic plaque (EP) and the eosinophilic
granuloma (EG) are cutaneous lesions commonly
seen in cats and are usually considered possible
reaction patterns to underlying allergic skin diseases
(ea bite allergy, atopic dermatitis, food hypersensitivity, mosquito bite dermatitis).16 EP is a wellcircumscribed area of erosion and exudation, with
marked erythema and self-induced alopecia. Lesions
may appear anywhere in the body; the inguinal,
perianal and medial thigh regions are most commonly involved.3 EG occurs mainly as a raised,
alopecic, erythematous area, usually along the caudal
aspect of the rear limbs.5,7 Alternatively, the lesions
may appear in the oral cavity, chin and extremities.3
The histopathological features of EP include a
supercial and deep eosinophilic, mastocytic diuse
inltrate with epidermal hyperplasia, spongiosis and
ulceration.8 EG is characterized histologically by a
nodular to diuse granulomatous dermatitis, with
areas of collagenolysis surrounded by macrophages,
giant cells, eosinophils and mast cells under an intact
epidermis.8 Although the clinical appearance and
aetiology may vary, these lesions are characterized

Correspondence: Dr Chiara Noli, Studio Dermatologico Veterinario, Via Sismondi 62, 20133 Milano, Italy. E-mail: [email protected]
# 2001 Blackwell Science Ltd

by a mixed inammatory cell inltration of the

dermis, which predominantly contains eosinophils
and mast cells.8
In the feline skin, mast cells are observed in the
epidermis9 and in the dermis next to supercial blood
vessels and local nerve endings.10 They play a key role
in eliciting cutaneous allergic reactions1115 as they
are the only cells in the body which are able to store
and release a wide variety of biological mediators. A
physiological level of mast cell stimulation and
consequent degranulation is important for maintenance of tissue homeostasis.1618 Excessive mast cell
degranulation is triggered by immunological (i.e.
antigenantibody binding) or nonimmunological
(i.e. neuropeptides) hyperactivation and causes a
pathological inammatory response. Type I hypersensitivity reactions occur after interaction of allergens with antigen-specic immunoglobulin E (IgE)
bound on the mast cell surface. Upon stimulation,
mast cells immediately release pro-inammatory
mediators, including preformed biogenic amines
(histamine, serotonin), serine proteases (tryptase,
chymase), chemotactic factors, cytokines (interleukins, tumour necrosis factor), and newly synthesized
arachidonic acid metabolites (prostaglandins, leukotrienes). The mediators are able to elicit an acute
inammatory cascade and cause a chronic late phase
response by recruiting circulating inammatory
leukocytes (among others eosinophils).13,14,19,20
29

Paper 214 DISC

30

F. Scarampella et al.

A local feedback mechanism called ALIA (autacoid local injury antagonism) that down-regulates
mast cell degranulation during damaging processes
has been recently identied.21,22 In pathological
conditions, tissue accumulation of N-acylethanolamine-related lipid amides,23,24 such as palmitoylethanolamide, seems to play a local autacoid role in
down-modulating mast cell degranulation by exerting
local anti-inammatory eects.21,25 Palmitoylethanolamide and its derivatives bind peripheral cannabinoid receptors (CB2) present on mast cells,26 which in
turn down-regulate mast cell degranulation. The
therapeutic implications of the existence of this
specic binding mechanism include the development
of innovative anti-inammatory drugs specically
targeted to control mast cell activation and inammatory tissue injury (ALIAmides).
The aim of the present pilot study was to assess
clinically and histologically the pharmacological
eect of the oral pharmaceutical formulation of an
analogue of palmitoylethanolamide called PLR-120
(comicronized Palmidrol INN, Innovet, Milan, Italy)
in cats with EG and EP.
MATERIALS AND METHODS
Animals
Seventeen privately owned European shorthaired cats
were included in the study (Table 1). The cats were
referred to the investigators by colleagues specically
for this study. All owners were previously informed
and agreed with its aims and procedures. The cats
were four intact females, two intact males, ve spayed
females and six castrated males. The age of the cats
ranged from 7 to 123 months (mean, 34 months).
Clinical lesions compatible with EP and EG were
Table 1. Signalment and clinical and histological diagnosis of the
15 cats included in the study. Cats nos. 2 (an intact male with EP)
and 11 (a castrated male with EG) were excluded because they
improved between day T715 and day T0
Case no. Age (mo)

Sex

Clinical
diagnosis

Histological
diagnosis

1
3
4
5
6
7
8
9
10
12
13
14
15
16
17

mc
fc
mc
f
f
f
f
mc
fc
fc
mc
fc
m
mc
fc

EG
EP
EP
EP
EG
EG
EG
EG
EP
EG
EP
EP
EG
EP
EG

ED
ED
EP
EP
EG
EG
ED
EG
ED
EG
EP
EP
EG
EP
EP

123
21
48
24
10
11
11
10
48
22
24
50
7
120
12

f, female; fc, castrated female; m, male; mc, castrated male; ED,

eosinophilic dermatitis; EG, eosinophilic granuloma; EP, eosinophilic plaque.
# 2001 Blackwell Science Ltd, Veterinary Dermatology, 12, 2939

diagnosed in eight and nine cats, respectively. None

of the cats had received oral steroids or antihistamines in the 2 weeks prior to inclusion, and steroids
had not been injected in the 6 weeks prior to the
study. All cats were otherwise healthy; skin scrapings
and fungal cultures were negative in all cases.
Run-in period
A run-in period of 15 days was scheduled prior to
taking part in the study. At day15 (T715) (rst day
of run-in period), ivermectin was administered
subcutaneously (0.3 mg kg71, Ivomec, Merck, Sharp
& Dohne S.p.A., Rome, Italy), and pronil was
applied to the interscapular skin (Frontline Spot on,
Merial, Italia S.p.A., Milan, Italy). Two animals, an
intact male with an EP and a castrated male with an
EG, showed marked improvement during the run-in
fortnight and were excluded from the study (cats nos.
2 and 11). The nal number of cats evaluated was 15,
seven of which had EP and eight EG (Table 1).
Treatment with ivermectin and pronil was repeated
in all included animals at day 15 (T15).
Administration of the drug
Tablets containing 120 mg of PLR-120 were divided
into quarters and administered to the cats at the dose
of 10 mg kg71 twice daily for 30 days, from day 1 (T0)
to day 30 (T30). No other concomitant therapy of any
kind was allowed during the study period, with the
exception of the aforementioned antiparasitic drugs.
Clinical evaluation
On day 1, clinical signs (pruritus, erythema and
alopecia) and clinical lesions (EP and EG) were
evaluated separately on four dierent locations on
the cat's body (head, trunk, forelimbs, hindlimbs) and
scored according to a numerical scale (0 = absent,
1 = mild, 2 = moderate, 3 = severe). For each value, a
multiplication factor was applied on the basis of the
extension of skin area (l6 = head; 46 = trunk;
26 = forelimbs; 36 = hindlimbs), following a modied psoriasis area and severity index scale.2729
Individual scores were added together and a total
score between 0 and 120 was obtained for each animal.
Signs and lesions were assessed for improvement or
clinical resolution by the investigators on day 15 and
on day 30 for each body location. For analytical
purposes, for each body location initial scores were
lowered by 50% in animals that showed improvement,
were zeroed in animals that obtained clinical resolution and were left unchanged in animals that did not
improve, then new total scores were calculated. The
real degree of improvement of signs and lesions was
not scored, because evaluation of the percentage of
cats that improved vs. those that did not improve was
considered sucient for a preliminary pilot study.
Skin biopsies
Biopsies were obtained from the lesional skin of each
cat under general anaesthesia (ketamine and diaze-

Paper 214 DISC

PLR-120 in feline eosinophilic dermatitis
pam) by means of a 4, 6 or 8 mm punch (Stiefel Biopsy
Punch, SFM, Wachtersbach, Germany) on day 1 and,
on the same site, on day 30. Biopsies were cut in two
halves with a scalpel blade (one was used for the present study and the other for other study purposes) and
were xed in 10% buered formalin. Although formalin xation has been reported to be able to decrease
mast cell numbers in bovine and canine skin biopsies,30,31 the xative was chosen because another study
determined that it is not true for feline skin samples.32
Histology
Specimens were paran embedded, sectioned at 5 mm
and stained with haematoxylin-eosin and with
toluidine blue following standard techniques.33 Skin
sections were evaluated microscopically for the
presence of crusts, ulceration, hyperkeratosis, hyperplasia, spongiosis, exocytosis and dyskeratosis in the
epidermis, and for cell inltrates, collagenolysis and
oedema in the dermis.
Mast cell counts
Toluidine blue-stained sections were screened morphometrically for mast cells using a Quantimet 400
analyser system (Leica Microsystems S.p.A., Milan,
Italy). Although astra blue was considered superior to
toluidine blue for image analysis in other studies,34 we
found toluidine blue gave much better results, perhaps
due to formalin xation which may enhance the
staining.35 Mast cells were identied by their characteristic morphology and the presence of metachromatic granules. Fifty-six and 112 high-power
microscopic elds (406) (1.2 and 2.4 mm2) were
selected for ED/EP and EG, respectively, and the
mean number of mast cells for each site was calculated.
The elds were chosen at all levels of the dermis, and
areas occupied by follicles and collagenolysis were not
considered for counting. Data were expressed as
number of toluidine blue-positive cells per mm2 (one
mm2 equals about 47 high-power elds).
Densitometry
In order to assess granulation status, the aforementioned image analyser system was used to perform
densitometric analysis of toluidine blue-stained mast
cells using a technique previously described, with
modications.36 Daily calibration was undertaken to
ensure constant conditions throughout the study. The
images were taken through an oil immersion objective (1006) with a black and white television camera
and transferred to the screen. Seven elds in the
dermis were selected at random in each section, and
three mast cells in the same eld were evaluated under
oil immersion (total of 21 mast cells every section).
For each pixel of the digitalized image, a value from 0
(white) to 255 (black) was attributed proportionally
to the video signal level. Black and white images were
digitalized and inverted and, for each mast cell,
almost 200 pixels were evaluated and the mean
(+ SD) was calculated (Fig. 1).

31

Statistical analysis
Statistical analyses were performed with the programme Statistica for Windows 5.1, 1997 edition
(Statsoft Inc, Tuls, OK, USA). Student's t-test was
used to determine dierences in pre-treatment scores
of cats with EG and those with EP. Analysis of
covariance (ANCOVA) for repeated measures was used
to determine the dierence trend between the two
groups with time. Mast cell counts were analysed by
means of Student's t-test. A Shapiro-Wilk test
conrmed a normal distribution of the data. Densitometric data were analysed by means Student's t-test.
To determine the relationship of clinical improvement and densitometric response, a linear Pearson's
correlation test was used.37
RESULTS
Clinical evaluation
Improvement of signs and improvement of lesions
were evaluated separately for all animals (Table 2).
Furthermore, a global improvement comprising signs
and lesions was also calculated. The are results
divided by groups and are presented below.
Evaluation of signs (erythema, pruritus and alopecia)
in all animals. Fourteen of 15 cats were evaluated,
since one cat with granuloma showed no erythema,
pruritus or alopecia (free of any sign). Five of the 14
cats (35.7%) showed improvement after 15 days of
therapy and nine of the 14 cats (64.3%) had improved
after 30 days.
Evaluation of lesions (granuloma or plaque) in all
animals. Eight of 15 cats (53.3%) showed improvement in extension and severity of lesions already
after 15 days of therapy, and 10 of 15 (66.7%) had
improved after 30 days (three were judged completely cured).
Global improvement. When the results of the aforementioned evaluations were considered together,
global improvement of all cats was 46.7% after 15
days (seven of 15 cats) and 66.7% after 30 days (10 of
15 cats).
As the initial score was lower in cats with EG than
in those with EP (Fig. 2), the two groups were
compared using Student's t-test. A signicant dierence was observed in pre-treatment scores (T0)
(P 5 0.01). It was thus decided to also evaluate the
improvement separately according to the clinical
diagnosis (EG vs. EP).
Evaluation of signs and lesions in cats with EP
(n = 7). Three out of seven cats with EP (42.9%)
showed improvement of signs and lesions and 3 of the
lesions (42.9%) after 30 days of therapy.
# 2001 Blackwell Science Ltd, Veterinary Dermatology, 12, 2939

Paper 214 DISC

32

F. Scarampella et al.

Figure
1. Case
number
3:
densitometric image of mast cells
before (a) and after (b) treatment
with PLR-120 (black and white
images from toluidine blue-stained
sections have been inverted). Arrow
indicates mast cells.

Table 2. Evaluation scores of signs and lesions before, during and after treatment
No.

T0

Signs
T15

T30

T0

Lesions
T15

T30

Signs + lesions (global)

T0
T15

T30

1
3
4
5
6
7
8
9
10
12
13
14
15
16
17

24
41
62
45
9
12
15
6
27
18
21
29
24
28
0

12
37
52
48
6
9
7.5
6
16.5
9
21
14.5
24
28
0

5.5
21.5
48
48
3
4.5
3.75
1.5
11.25
4.5
21
14
24
14
0

6
20
36
23
6
3
6
9
5
9
11
18
6
12
6

3
16
27
23
0
1.5
3
4.5
3
4.5
10
9
6
12
3

1.5
12
23
23
0
0.75
0
2.25
1
2.25
9
4.5
6
6
0

30
61
98
71
15
15
21
21
32
27
32
47
30
40
6

7
33.5
71
71
3
5.25
3.75
3.75
12.25
6.75
30
18.5
30
20
0

# 2001 Blackwell Science Ltd, Veterinary Dermatology, 12, 2939

15
53
79
71
6
10.5
10.5
10.5
19.5
13.5
31
23.5
30
40
3

Paper 214 DISC

PLR-120 in feline eosinophilic dermatitis

33

120
T0

100

T15

80

T30

60
40
20
0

1
6
7
8
9
12
15
17
3
4
5
10
13
14
16
[_______Eosinophilic Granuloma___________________] [____________Eosinophilic Plaque___________]
Figure 2. Histogram of the same data as Table 2, with cases according to clinical diagnosis.

Evaluation of signs and lesions in cats with EG

(n = 8). Six of seven cats (85.7%) showed improvement of signs (one cat in the group was free of signs
at day 1), and seven of eight cats (87.5%) showed
improvement of lesions after 30 days of treatment.
Three of the latter (37.5% of the cats with EG) were
judged to be completely cured.
Comparison of improvement scores of the two groups.
Comparison of the improvement scores of the two
groups by means of ANCOVA showed that, when the
diversity in pre-treatment scores between groups was
considered, the two groups presented a similar
improvement trend after treatment. This means that
cats improved with the treatment, independent of the
initial diagnosis.
Histological evaluation (Table 1)
Six cats (one with EG and ve with EP) had
histological lesions represented by a dense supercial
and deep interstitial inltrate of eosinophils and mast
cells, with occasional small foci of collagenolysis and
wide ulceration of the overlaying epidermis. These
lesions were similar to those previously described for
the eosinophilic plaque.8 Five cats (all with EG) had
histological lesions represented by large collagenolytic foci and surrounding granulomas in the deep
dermis and a few inltrating eosinophils and mast
cells under an intact epidermis. These lesions were
identical to those reported in the eosinophilic
granuloma.8 Four cats (two with EG and two with
EP) had histological lesions represented by a mild
perivascular to interstitial supercial inltrate of
eosinophils and mast cells associated with an intact
hyperplastic epidermis. These lesions were morphologically diagnosed as eosinophilic dermatitis (ED).
Thus the diagnosis was conrmed histologically in
ve of the eight cats with a clinical diagnosis of EG,
and in ve of the seven cats with a clinical diagnosis
of EP.

Mast cell counts

The mean number of mast cells/mm2 in biopsies
obtained before and after treatment is reported in Table
3. No statistically signicant dierence was observed
between pre-and post-treatment morphometric values
using Student's t-test or the Wilcoxon method for
coupled samples. It was concluded that the treatment
did not inuence the number of mast cells in the skin.
Densitometry
Results of densitometric analysis of mast cells in skin
biopsies before and after treatment are reported in
Table 3. Comparison of data at T0 and T30 by
Student's t-test revealed a signicant (P = 0.009)
increase in granular density of cutaneous mast cells
(Table 4 and Figs 1 and 3). When cats with EG and
those with EP were compared with Student's t-test,
no signicant dierence was found in pre-treatment
or in post-treatment values.
Table 3. Mast cell counts/mm2 in lesional skin biopsies before
and after treatment
Case no.

No. of mast cells/mm2

T0
T30

1
3
4
5
6
7
8
9
10
12
13
14
15
16
17
Mean
Standard deviation

503.0
170.3
218.5
331.5
349.8
182.5
367.7
304.1
454.6
508.7
441.6
314.1
159.6
640.7
1013.5
397,35
219,90

314.2
454.0
544.2
183.0
198.4
294.0
269.0
345.2
112.0
519.8
465.4
282.7
459.5
265.9
1483.0
412,69
322,66

P (Student's t) 0.81 = not signicant

# 2001 Blackwell Science Ltd, Veterinary Dermatology, 12, 2939

Paper 214 DISC

34

F. Scarampella et al.

Table 4. Densitometric evaluation of toluidine blue-stained mast cells before and after treatment
2 Case no.

Basal mean

Basal SD

Final mean

Final SD

Valid counts

1
3
4
5
6
7
8
9
10
12
13
14
15
16
17
Total

67540.00
69287.23
73102.05
89704.55
62498.76
64608.24
84981.80
75554.62
58257.29
62330.95
71007.14
58684.95
72403.19
80970.91
66335.09
70484.45

12576.83
17738.15
18663.66
18572.97
13633.22
16952.60
32780.71
17892.78
10862.72
18289.67
15792.77
17378.43
12965.56
12641.58
11567.36
9284.77

103565.2
79397.1
104514.3
94274.1
73047.1
73795.7
69198.5
86321.8
63356.5
55755.7
71253.9
78195.4
77086.2
97573.2
99648.3
81798.87*

43690.29
20282.70
26118.83
24659.65
10089.40
19603.63
18135.27
19661.52
22512.58
13606.97
16193.18
9325.46
19831.12
14440.14
25868.73
15126.19

21
21
21
20
21
21
20
21
21
21
21
21
21
21
21
313

*P = 0.009

Basal mean
Final mean

Density

120000
100000
80000
60000
40000
20000
0

1 3 4 5 6 7 8 9 10 12 13 14 15 16 17 Total
Cases

Figure 3. Histogram of densitometric evaluation of toluidine blue-stained mast cells before and after treatment (same data as in Table 4).

Correlation of clinical response with densitometry

A signicant correlation between the clinical improvement and the densitometric response was
determined by means of linear regression for the cats
with EP (r = 0.74370, P = 0.05), whereas it was
absent in the cats with EG and when the all the
animals were considered together.
Tolerability
In all cases, tolerability of the treatment was judged
by the owner and by the investigators to be good
or excellent.
DISCUSSION
EP and collagenolytic granulomas may represent
clinical signs of underlying allergic conditions, such
as eabite allergy or other insect hypersensitivities,
food allergy and atopic dermatitis.1,3,4,6 Clinicians
should make an attempt to nd the underlying cause
in case of EP or EG and anti-inammatory therapy
should be used as an adjunctive therapy and not as a
replacement for a diagnosis. However, there may be
# 2001 Blackwell Science Ltd, Veterinary Dermatology, 12, 2939

clinical situations, in which the clinician is confronted

with cats who refuse an elimination diet, do not
improve on a diet trial, are skin-test negative or do
not improve on hyposensitization. Such animals are
often destined to life-long intermittent or continuous
corticosteroid treatment and may experience numerous side-eects of the drugs. The cats in the present
study were screened for eabite allergy and other
parasitic skin diseases, but not for food allergy or
atopy. This was done on purpose and was considered
a good representation of such dicult clinical
situations. The aim of the study was to evaluate
PLR-120 as a possible alternative to steroids for the
treatment of cases of EG and EP where the underlying cause cannot be identied or controlled. PLR120 was chosen for its mechanism of action, which is
able to improve inammatory conditions by downmodulating mast cell degranulation.
The results demonstrated that after one month of
treatment 64.3% of all animals given PLR-120
showed improvement of pruritus, erythema and
alopecia and 66.7% showed improvement of the
extent and severity of the lesions. However, these are
results of a noncontrolled pilot study and can only be

Paper 214 DISC

PLR-120 in feline eosinophilic dermatitis
regarded as preliminary. Although they may appear
encouraging, the cure rate using the protocol as
described was only 6% (animal 17). Therefore, a
longer controlled study is required to determine
whether continued use of this drug would eventually
lead to a satisfactory resolution rate. Furthermore,
some of the cats may have improved because of the
antiparasitic treatment and not the drug. However, in
most cases, antiparasitic treatment alone does not
lead to resolution of eosinophilic plaques and
granulomas because of the severity of dermal
inammation that is present, and concurrent therapy
is usually required.
The results are comparable or better than those
obtained with other products used for other feline
allergic conditions, such as miliary dermatitis and
pruritus. With essential fatty acids (EFA), a good to
excellent response was observed in 5775% of treated
animals in 218 weeks.3841 Clinical improvement
was observed after antihistamine administration to
cats in 5073% of the animals.42,43 However, studies
investigating the ecacy of antihistamines or EFA in
cats with EP or EG have not yet been performed and
may yield dierent results.
Drug combinations (antihistamines and EFA) have
been reported to be more eective than single drugs
used alone.44,45 PLR-120 combined with other nonsteroidal antipruritic drugs has not yet been investigated, and better success rates might be obtained.
Cats with EG seem to respond better than cats with
EP, perhaps due to a dierent pathogenesis of the
lesions, to the fact that EP is often complicated by
secondary infections (which could impair healing and
which were not treated in this study), or to the fact
that occasionally EG may spontaneously resolve.3,6
Another possibility is that animals with milder lesions
respond better than those with more severe disease,
which might require a higher dosage of the drug. In
fact, cats with EG had a signicantly lower pretreatment score than cats with EP.
However, when data were evaluated by ANCOVA,
considering the initial dierence in scores, the
improvement trend was not signicantly dierent
between cats with EP and those with EG. Most of the
cats with EG (lower score) sensitive to PLR-120 had
already improved after 15 days of treatment, whereas
cats with EP (higher score) took a longer time to
improve. It is proposed that rstly, at least 24 weeks
of treatment are necessary to obtain improvement,
and secondly, more severe cases may need a longer
treatment time to improve. Furthermore, similarly to
other nonsteroidal antipruritic drugs (i.e. EFAs), the
eect may be dose dependent, and a higher dosage
could have given better results.
The histological ndings conrmed the clinical
diagnosis in 10 out of 15 cats, and in four cases (two
EG and two EP) only a eosinophilic dermatitis (ED)
was observed. In previous reports, a clinical diagnosis
of EP or EG has almost always been associated with
typical histological lesions.7,8,46,47 Nonspecic lesions

35

of ED could be explained by the fact that the biopsies

were cut in half prior to xation. In some cases, the
typical lesions might have not been centred, and only
the periphery (characterized in EG and EP by a
perivascular mast cell and eosinophilic inltrate) may
have been included. Alternatively, as histological
sections represent only one moment in the whole
disease process and lesional evolution, it may be that
the skin was sampled at a nondiagnostic stage of the
process, e.g. at the beginning or at the end of the
disease. Finally, it may be that in some individuals,
typical clinical appearance of EP or EG may not
always be associated with the typical histological
patterns usually seen in these diseases.
The mean number of mast cells obtained from
lesional skin in the study (range 1601013/mm2) is
higher than that observed in normal feline skin by
other authors.10,32,48,49 Increased mast cell numbers
in diseased skin were expected by the investigators, in
view of reports in the literature for other feline
inammatory skin conditions48 (Greek, J. S. unpublished data: Feline pemphigus foliaceus: a retrospective study of 23 cases. Proceedings of the Annual
Meeting of the American Academy of Veterinary
Dermatology. San Diego, 1993: 278). However mast
cells have not been counted in lesional skin with EP
or EG and our data cannot be compared with any
other study.
No signicant change in the number of cutaneous
mast cells was observed after treatment with PLR120. In fact, the drug does not inuence mast cell
viability, as steroids are known to do. Glucocorticoids deplete mast cell populations in tissues5052 by
inhibiting the production of the stem cell factor.53,54
Such mechanisms create an imbalance of the
inammatory response, which in turn may not be
favourable, reducing the initial `wheal and are'
reaction55 and increasing the `late phase' response.56
By modulating mast cell responses without killing
them, PLR-120 acts as an anti-inammatory drug,
whose function is to restore the cutaneous homeostatic balance.16
Evaluation of mast cell degranulation has been
described as a useful means for assessment of drugs
that act on mast cells,57,58 including the drug used in
the present pilot study25 in mice and rats. A
computerized image analyser system (Quantimet 400,
Leica) was used for such a purpose. To the authors'
knowledge, this is the rst report of densitometric
analysis of mast cell granules in the cat. The method
proved to be useful and reliable. Treatment for 30 days
with PLR-120 signicantly increased densitometric
values of cutaneous mast cells. The result suggests that
PLR-120 is eectively able to decrease mast cell
degranulation and increase intracellular concentration
of mast cell granules. A PLR-120-induced increase in
granule production is less probable, considering its
known mechanism of action. The mechanism, called
ALIA,21,22 acts as an antagonist of mast cell hyperactivity and is receptor mediated.
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Paper 214 DISC

36

F. Scarampella et al.

Mast cells express on their surface the cannabinoid

receptor CB2, for which palmitoylethanolamide is the
natural ligand. The substance is produced by the
surrounding tissues following injury or inammation
and, after binding to CB2 receptors, exerts a downmodulating eect on mast cell degranulation. PLR120, a synthetic analogue of palmitoylethanolamide,
is able to decrease several inammatory reactions, as
observed in vivo and in vitro.25,26,5962 In particular,
PLR-120 was able to reduce, in a dose-dependent
way, hyperalgesia and plasmatic extravasation caused
by mast cell immunological (passive cutaneous
anaphylaxis) and neurogenic (subcutaneous injection
of substance P) stimulation.25 Local administration
of PLR-120 has also proved to be active in reducing
formalin-induced licking behaviour in mice59 and the
peripheral nervous sensitization associated with skin
inammation.60,61 PLR-120, through CB2 receptormediated down-modulation of mast cell degranulation, is thus able to decrease the production of
mediators (such as nerve growth factor, histamine
and serotonin) responsible for lowering the excitability threshold of peripheral nervous C-bres,
which are known to mediate sensations of pain and
pruritus.63,64
In the cats with EP, the clinical improvement was
directly correlated to the increase in mast cell
densitometry. The correlation is highly signicant,
even in spite of the small number of cases (seven
cats). This was expected, as EP is considered (more
than EG) an epiphenomenon of feline allergies6
which is complicated by constant licking and
bacterial infections. The role of mast cells in allergies
is considered pivotal for the development of allergic
reactions,1315,65 and the signicant correlation
between clinical improvement and densitometric
data conrms the usefulness of anti-inammatory
drugs (which are able to modulate mast cell
activation) in these skin diseases. The fact that no
signicant correlation was found between the clinical
scores of cats with EG and their densitometric results
could reect either the small case numbers and high
inter-individual variability of the data, or the fact
that the initial clinical score was lower in cats with
EG than in those with EP.
In EP and EG, particularly in recurrent idiopathic
cases, drugs should be administered for long treatment courses or even as a maintenance therapy and
high drug tolerability becomes very important. PRL120 proved to have a good palatability, and no sideeect or adverse reaction was observed. The good
tolerability of PLR-120 is an undoubted advantage
over other medications used for EG and EP. Sideeects are often seen with the long-term use of
corticosteroids66 and hormone preparations (e.g.
megestrol acetate)67 and occasionally with antihistamines68 and EFA.69,70
In conclusion, the pilot study showed that PLR120 may be useful in the treatment of cats with EP or
EG and that it could represent a valid alternative to
# 2001 Blackwell Science Ltd, Veterinary Dermatology, 12, 2939

long-term corticosteroid therapy. A double-blind

placebo controlled study is necessary to conrm the
data and to determine the most eective dosage.
ACKNOWLEDGEMENTS
The study was kindly sponsored by a grant from the
European Society of Veterinary Dermatology
(ESVD) and by Innovet, Milan, Italy. The authors
would like to thank the European Society of
Veterinary Dermatology and Innovet, Milan, Italy,
for the nancial support, Dr Salvatore Bellinvia for
help in drafting the protocol and evaluating the
results, Dr Carlo Baggio for the statistical analysis,
and Drs Federica della Valle and Alda Miolo for
their help in analysing the results and suggesting
discussion points. We also thank Ms Betty Johnston
and Mr John Hemingway for editing the manuscript.

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Resume Quinze chats presentant un granulome eosinophilique ou une plaque eosinophilique ont ete traites
avec le PLR 120 a la dose de 10 mg kg1 deux fois par jour pendant un mois. Le PLR-120 diminue la
degranulation mastocytaire par l'intermediaire d'une action sur les recepteurs. Aucun autre traitement n'etait
autorise et les chats etaient traites contre les parasites pendant toute l'etude. Une evaluation clinique, et des
biopsies cutanees, etaient realisees avant et apres le traitement. L'amelioration clinique etait evaluee apres 15
et 30 jours. Les mastocytes etaient comptes, et les granulations etaient evaluees par une analyse
densitometrique sur des sections colorees au bleu de toluidine, avant et apres le traitement. Dix des 15
chats (67%) ont presente une amelioration clinique et lesionnelle. Il n'a ete observee aucune dierence
signicative pour le nombre de mastocytes avant et apres le traitement, bien que le nombre de granulations ait
statistiquement augmente (P 5 0.009). Cette etude preliminaire suggere que le PLR-120 pourrait constituer
une molecule interessante dans le traitement des granulomes eosinophiliques et des plaques eosinophiliques.
[Scarampella, F., Abramo, F. et Noli, C. Clinical and histological evaluation of an analogue of
palmitoylethanolamide, PLR 120 (comicronized Palmidrol INN) in cats with eosinophilic granuloma and
eosinophilic plaque: a pilot study. (Evaluation clinique et histologique d'un analogue du
palmitoylethanolamide, PLR 120 (comicronized Palmidrol INN) chez des chats presentant un granulome
eosinophilique ou une plaque eosinophilique: etude preliminaire.) Veterinary Dermatology 2001; 12: 2939.]
# 2001 Blackwell Science Ltd, Veterinary Dermatology, 12, 2939

Paper 214 DISC

PLR-120 in feline eosinophilic dermatitis

39

Resumen Se administro PLR 120 a una dosicacion de 10 mg kg1 dos veces al d a durante un mes, a quince
gatos con granuloma eosinof lico o placa eosinof lica. El PLR-120 reduce la degranulacion de mastocitos
mediante un mecanismo mediado por receptor. No se permitieron otros farmacos y los gatos fueron
mantenidos libres de parasitos durante todo el estudio. Se realizo una evaluacion cl nica y biopsias cutaneas
antes y despues del tratamiento. La mejor a cl nica se evaluo a los 15 y 30 d as. Se conto el numero de
mastocitos y su contenido en granulos fue evaluado por analisis densitometrico en secciones tenidas con azul
de toluidina antes y despues del tratamiento. Diez de 15 (67%) gatos mostraron mejor a cl nica de los
s ntomas y de las lesiones. No se produjo una diferencia signicativa entre el numero de mastocitos en biopsias
cutaneas tomadas antes y despues de la prueba, mientras que el numero de granulos se vio signicativamente
incrementado (P 5 0.009). Este estudio piloto sugiere que el PLR-120 podr a ser un farmaco util para el
tratamiento del granuloma eosinof lico y la placa eosinof lica. [Scarampella, F., Abramo, F. y Noli, C.
Clinical and histological evaluation of an analogue of palmitoylethanolamide, PLR 120 (comicronized
Palmidrol INN) in cats with eosinophilic granuloma and eosinophilic plaque: a pilot study. (Evaluacion
cl nica e histologica de un analogo de la palmitoiletanolamida, PLR 120 (Palmidrol INN comicronizado) en
gatos con granuloma eosinof lico y placa eosinof lica: un estudio piloto.) Veterinary Dermatology 2001; 12:
2939.]
Zusammenfassung Funfzehn Katzen mit eosinophilem Granulom oder eosinophilen Plaques wurde PLR 120
in einer Dosierung von 10 mg kg1 zweimal taglich fur einen Monat gegeben. PLR-120 vermindert
Mastzellendegranulation durch einen Rezeptor-vermittelten Mechanismus. Andere Medikamente wurden
nicht erlaubt und die Katzen wurden wahrend der Studie von Parasiten freigehalten. Klinische Bewertung
sowie Entnahme von Hautbiopsien erfolgten vor und nach der Behandlung. Eine klinische Besserung wurde
nach 15 und 30 Tagen bewertet. Vor und nach der Behandlung wurde die Anzahl von Mastzellen bestimmt
und Mastzellengranula durch densimetrische Analyse von mit Toluidinblau gefarbten Schnitten bewertet.
Zehn von 15 Katzen (67%) zeigten klinische Besserung der Symptome und Lasionen. Ein signikanter
Unterschied in der Anzahl der Mastzellen vor und nach der Behandlung konnte nicht festgestellt werden,
wahrend die Granula-Anzahl sich erheblich erhohte (P 5 0.009). Diese Pilotstudie deutet darauf hin, da
PLR-120 fur die Behandlung des eosinophilen Granuloms und der eosinophilen Plaques nutzlich sein konnte.
[Scarampella, F., Abramo, F. und Noli, C. Clinical and histological evaluation of an analogue of
palmitoylethanolamide, PLR 120 (comicronized Palmidrol INN) in cats with eosinophilic granuloma and
eosinophilic plaque: a pilot study. (Klinische und histologische Bewertung eines PalmitoylethanolamidAnalogs, PLR 120 (komikronisiertes Palmidrol INN) bei Katzen mit eosinophilem Granulom und
eosinophilen Plaques: Eine Pilotstudie.) Veterinary Dermatology 2001; 12: 2939.]

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