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Fleischer
corticosteroid agents are not ideal agents because when used over the long
term, they may cause cutaneous atrophy (5–7). Not infrequently, patients
display disease refractory to short-term topical corticosteroid agents. Indeed, the majority of patients with atopic dermatitis fail to clear their skin
by the end of the approved durations of treatment. Clinicians and patients
must then decide whether the benefits of ongoing topical therapy outweigh
its associated ever-increasing risks. Clinicians have been searching for corticosteroid-sparing agents that can be used when long-term topical therapies
are required, yet lack the expense, inconvenience, and monitoring required
of phototherapy and systemic immunosuppressive therapy. The recent development of topical tacrolimus may fill this role.
Tacrolimus is a 23-member macrolide of molecular mass 822 Dalton
(Fig. 1) produced by Streptomyces tsukabaensis, a fungus found in the soil of
Mount Tsukuba, Japan (8). The drug’s name is derived as follows: t—Mount
Tsukuba, acrol—macrolide, imus—immunosuppressant. It is frequently also
Figure 1
Chemical structure of tacrolimus.
Reduction in Itch Severity with Topical Immunomodulators
317
referred to as FK506, its research compound designation. There are a series of
complex immunodysregulatory activities within patients with atopic dermatitis and other chronic inflammatory dermatoses. T lymphocytes are activated, release cytokines, and interact with a broad range of other cell types in
the dermis and epidermis. Tacrolimus acts directly on the T lymphocytes,
especially CD4+ cells, by binding to immunophilins (FK-binding protein)
(9). This tacrolimus–immunophilin complex then binds to and competitively
inhibits calcineurin, a phosphatase that is active only when bound to calcium
and calmodulin. This binding phenomenon inhibits the ability of calcineurin
to activate the promoter region of the gene for IL-2, IL-3, IL-4, IL-5, GMCSF, and TNF-a, all of which participate in the early immune response and
are postulated to play a role in atopic dermatitis pathogenesis (10–12).
Tacrolimus may also bind to cell surface steroid receptors, inhibit the release
of mast cell preformed mediators, downregulate IL-8 receptor expression,
decrease ICAM-1 and E-selectin lesional blood vessel expression, and downregulate Fc RI on Langerhans cells (13). This broad range of inflammatory
inhibition mechanisms may decrease antigen recognition and downregulate
the entire inflammatory cascade leading to clinical disease and itch. Once itch
occurs, scratching likely perpetuates the inflammatory condition.
It should be noted that topical tacrolimus does not have the potential
to affect collagen synthesis. Reitamo et al. (14) conducted a randomized,
double-blind, placebo-controlled trial to assess the atrophogenicity of tacrolimus ointment. In a combined group of atopic dermatitis patients (n =14)
and healthy volunteers (n =12), 0.3% tacrolimus, 0.1% tacrolimus, betamethasone valerate, and a vehicle control were applied in a randomized
order to nonsymptomatic 4 Â 4-cm regions of abdominal skin. After 7 days
of treatment under occlusion, the carboxy-terminal and amino-terminal propeptides of procollagen I (PICP, PINP) and the amino-terminal propeptide
of procollagen III (PIIINP) were measured from suction blister fluid with
specific radioimmunoassays, and ultrasound measurements of skin thickness
were taken. Betamethasone-treated areas showed median PICP, PINP, and
PIIINP concentrations of 17.0%, 17.6%, and 39.5% of the vehicle control
at the end of the treatment period, respectively, whereas the 0.1% and 0.3%
tacrolimus-treated areas showed median concentrations of approximately
100% of the vehicle control. Betamethasone was also the only treatment to
significantly decrease skin thickness; the median decrease in skin thickness
was 7.4% relative to 0.1% tacrolimus, 7.1% relative to 0.3% tacrolimus,
and 8.8% relative to the vehicle control. Results for atopic dermatitis patients and healthy volunteers were similar. These findings suggest that tacrolimus does not cause skin atrophy that a medium potency corticosteroid
agent can produce in 1 week of therapy. These results are supported by longterm trials conducted with up to 4 years of continuous treatment without
demonstrated atrophy (15,16).
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Fleischer
Although there is a vast amount of information about topical tacrolimus, and tacrolimus improves atopic dermatitis severity (17–19), the relationship between the use of topical tacrolimus and itch has not been fully
described to date. Moreover, the relationship between the change in quality
of life (QOL) and the change in itch severity needs further exploration as well.
II.
METHODS
We reviewed data from the Phase III clinical trials of topical tacrolimus used
for the treatment of atopic dermatitis in the United States. These studies
included 233 evaluable pediatric patients (from Fujisawa trial 97-0-037) and
412 evaluable adult patients (from Fujisawa trials 97-0-035 and 97-0-036)
enrolled in 12-week double-blind, parallel group, vehicle-controlled clinical
trials. In the study designs of the controlled trials, at baseline, subjects were
randomized to receive tacrolimus 0.03% ointment BID, tacrolimus 0.1%
ointment BID, or vehicle. For purposes of this analysis, treatment groups were
grouped together and compared at week 12 with baseline values. The safety
and efficacy results of these trials have previously been reported (15–17).
The severity of disease was assessed using the eczema area severity
index. The itch score was evaluated by patients, using a visual analog scale.
The quality of life scores differed by the age of the subjects, and were grouped
into Toddlers, Children, and Adults. Surveys used to assess QOL include the
Toddler QOL Survey (age 2–4 years), Children’s DLQI (CDLQI) (5–15
years), and the Dermatology Life Quality Index (DLQI) (16 years and older).
Statistical treatment consisted of correlation and regression of the
change in the EASI score with the change in the itch score. Correlation
analysis and regression analysis were performed to explore the relationship
between itch and the EASI score, and between the itch score and the change
in the QOL score. Analyses were performed based on the data from patients
in two tacrolimus concentration groups (0.03% and 0.1%) in three Phase III
studies. For the analysis of pediatric and adult studies, results were not
pooled across populations. For QOL, analyses were also performed by three
age groups because different QOL instruments were used for each age group.
III.
RESULTS
A.
Effect of Topical Tacrolimus on Itch Severity
Topical tacrolimus treatment clearly reduced itch severity. Statistically significant correlations were seen between reduction in itch score and reduction
in EASI score. We found that correlation coefficients and regression
Reduction in Itch Severity with Topical Immunomodulators
319
Table 1 Correlation Between Itch and EASI Score
n
Overall
Children (2–15 years)
Adults
(16 years or older)
Correlation
coefficient
645
233
412
r = 0.412 ( p < 0.001)
r = 0.424 ( p < 0.001)
r = 0.404 ( p < 0.001)
Regression equation
( Y=reduction in EASI
score; X=reduction in
itch score)
Y = À8.40 + 1.54X
Y = À9.44 + 1.47X
Y = À7.86 + 1.56X
equations are similar between children and adults (Table 1). Because of this
homogeneity, it appears valid to present the overall results (Fig. 2).
B.
Effect of Topical Tacrolimus on Quality of Life
Topical tacrolimus treatment also clearly improved QOL. A statistically
significant correlation was seen between reduction in itch score and reduc-
Figure 2 The relationship between the change in the itch score and the change in
the eczema area severity index (EASI) is presented, with linear regression (solid line)
and 95% confidence interval (dashed lines).
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Fleischer
Figure 3
Total quality of life score change from baseline to the end of treatment.
tion in total QOL score (Fig. 4). Analyses were also performed by three age
groups because different QOL instruments were used for each age group.
Subjects using tacrolimus significantly improved their QOL scores (Fig. 3).
Correlation coefficients and regression equations are somewhat different
among age groups. Therefore, it may be better to present the result by each
age group (Table 2).
There is a highly statistically significant relationship between the
change in itch and the change in QOL.
IV.
DISCUSSION
The cardinal symptom of atopic dermatitis, as with many inflammatory skin
diseases, is itch. This chapter describes the relationship between improveTable 2 Reduction in EASI and QOL Scores with Topical Tacrolimus
Correlation
coefficient
Overall
Toddler (2–4 years)
Children (5–15 years)
Adults (z16 years)
608
96
126
386
r = 0.472
r = 0.532
r = 0.258
r = 0.511
( p < 0.001)
( p < 0.001)
( p = 0.004)
( p < 0.001)
Regression equation
( Y=reduction in EASI
score; X=reduction in
total QOL score)
Y = À14.03
Y = À16.63
Y = À19.00
Y = À11.60
+
+
+
+
3.01X
3.72X
1.40X
3.32X
Reduction in Itch Severity with Topical Immunomodulators
321
Figure 4 Correlation between itch and QOL. The relationship between the change
in the itch score and the change in the QOL score is presented, with linear regression
(solid line) and 95% confidence interval (dashed lines).
ment in disease severity and improvement in QOL with improvement in itch.
Topical tacrolimus clearly has demonstrated its ability to decrease the severity of itching in a large cohort of study subjects with moderate to severe
atopic dermatitis. This reduction in itch severity is closely related to improvement in the signs of atopic dermatitis, as measured by the EASI, and
with improvement in QOL, as measured by the three study instruments.
Thus, tacrolimus is a safe, long-term, anti-inflammatory and antipruritic treatment for atopic dermatitis. Unlike corticosteroid agents, tacrolimus appears to have no potential to cause cutaneous atrophy, yet is a highly
effective therapy for improving the itch and lessening the severity of atopic
dermatitis. The agent may be of particular benefit to children, among whom
an alternative to the chronic use of corticosteroids, either topically or
systemically, is highly desirable. Whether this agent will be used primarily
as an independent therapy, or as part of a combination therapeutic regimen
with corticosteroid agents is unknown. It is certain, however, that topical
tacrolimus will find a unique place in the treatment of atopic dermatitis and
other inflammatory dermatoses.
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Fleischer
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Umeki S. Allergic cycle: relationships between asthma, allergic rhinitis, and
atopic dermatitis. J Asthma 1994; 31:19–26.
Sampson HA. Atopic dermatitis. Ann Allergy 1992; 69:469–481.
Hanifin JM. Assembling the puzzle pieces in atopic inflammation. Arch Dermatol 1996; 132:1230–1232.
Rudikoff D, Lebwohl M. Atopic dermatitis. Lancet 1998; 351:1715–1721.
Smith EW. Four decades of topical corticosteroid assessment. Curr Probl
Dermatol 1995; 22:124–131.
Lubach D, Rath J, Kietzmann M. Skin atrophy induced by initial continuous
topical application of clobetasol followed by intermittent application. Dermatology 1995; 190:51–55.
Pierard GE, Pierard-Franchimont C, Ben Mosbah T, Arrese Estrada J. Adverse
effects of topical corticosteroids. Acta Dermato-Venereol 1989; 151 (suppl):26–
30.
Spencer CM, Goa KL, Gillis JC. Tacrolimus. An update of its pharmacology
and clinical efficacy in the management of organ transplantation. Drugs 1997;
54:925–975.
Kelly PA, Burckart GL, Venkataramana R. Tacrolimus: a new immunosuppressive agent. Am J Heath Syst Pharm 1995; 52:1521–1535.
Mori A, Suko M, Nishizaki Y, Kaminuma O, Matsuzaki G, Ito K, et al.
Regulation of interleukin-5 production by peripheral blood mononuclear cells
from atopic patients with FK506, cyclosporin A and glucocorticoid. Int Arch
Allergy Immunol 1994; 104(suppl 1):32–35.
De Paulis A, Stellato C, Cirillo R, Ciccarelli A, Oriente A, Marone G. Antiinflammatory effect of FK-506 on human skin mast cells. J Invest Dermatol
1992; 99:723–728.
Eberlein-Konig B, Michel G, Ruzicka T, Przybilla B. Modulation of histamine
release in vitro by FK506 and interleukin-3 is determined by sequence of incubation. Arch Dermatol Res 1997; 289:606–608.
Lawrence ID. Tacrolimus (FK506): experience in dermatology. Dermatol Ther
1998; 5:74–84.
Reitamo S, Rissanen J, Remitz A, Granlund H, Erkko P, Elg P, et al. Tacrolimus ointment does not affect collagen synthesis: results of a single-center
randomized trial. J Invest Dermatol 1998; 111:396–398.
Paller A, Caro I, Weinstein G, Rico MJ, and the Tacrolimus Ointment Study
Group. Long-term safety and efficacy of tacrolimus ointment monotherapy in
atopic dermatitis patients: open-label study results (poster). Presented at the
20th World Congress of Dermatology, Paris, July 2002.
Koo JYM, Prose N, Fleischer A, Rico MJ, and the Tacrolimus Ointment Study
Group. Safety and efficacy of tacrolimus ointment monotherapy in over 7,900
atopic dermatitis patients: results of an open label study (poster). Presented at
the 20th World Congress of Dermatology, Paris, July 2002.
Paller A, Eichenfield LF, Leung DYM, Stewart D, Appell M, the Tacrolimus
Reduction in Itch Severity with Topical Immunomodulators
323
Ointment Study Group. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001;
44(suppl):S47–S57.
18. Hanifin JM, Ling MR, Langley R, Breneman D, Rafal E. Tacrolimus ointment
for the treatment of atopic dermatitis in adult patients: Part I. Efficacy. J Am
Acad Dermatol 2001; 44(suppl):S28–S38.
19. Soter N, Fleischer AB, Webster GF, Monroe E, Lawrence I. Tacrolimus
ointment for the treatment of atopic dermatitis in adult patients: Part II. Safety.
J Am Acad Dermatol 2001; 44(suppl):S39–S46.
31
5-HT3 Receptor Antagonists
as Antipruritics
Elke Weisshaar
University of Heidelberg, Heidelberg, Germany
I.
SEROTONIN AND ITCH
Serotonin (5-hydroxytryptamine or 5-HT) is a biogenic amine found in
platelets and serum. It is stored in the platelets in an inactive form and
released when platelets aggregate. Mast cells of mice and rats contain
serotonin, but not those of humans. It has been known for many years that
5-HT can excite nociceptive C-fibers (1). Serotonin produces algesic or
analgesic effects, depending on where in the nervous system it is released.
Peripherally, it depolarizes afferent fibers and causes pain, as well as potentiates the algesic action of other substances (2). When serotonin is injected
intradermally or induced by iontophoresis, it induces itch but is less potent
than histamine (3–5). Serotonin is also vasoactive, contributing to the
pathophysiology of diseases such as carcinoid syndrome, hypertension,
atherosclerosis, and ischemic heart disease.
Because serotonin is synthesized in the proximal tubular cells of the
kidney, it may play a role in the pathogenesis of various kidney diseases.
Raised levels of serotonin have been detected in patients with renal impairment, especially those on hemodialysis (HD) but also on continuous ambulatory peritoneal dialysis (CAPD) (6–9). There was no positive correlation of
serotonin levels with pruritus (6,7). In a recent study investigating platelet325
326
Weisshaar
poor plasma of patients on HD, serotonin levels ranged within normal limits
(10). Most likely, elevated serotonin levels in previous studies (Balakas et al.,
1998; (7)) were obtained by measuring the total blood pool of serotonin
including the intraplatelet component (7).
II.
5-HT3 RECEPTORS AND THEIR ANTAGONISTS
Serotonin receptors are widely distributed throughout the body and there are
at least seven different types as well as 14 serotonin receptor subtypes. They
are present exclusively on peripheral and central neurons. The 5-HT3 receptor
is a ligand-gated cation channel belonging to the nicotine/GABA receptor
superfamily (11). 5-HT3 receptors are mainly found in the substantia gelatinosa of the spinal cord, in multiple nucleoli of the brainstem, in the area
postrema, and in the enteric nervous system. They are linked to several
serotonin-mediated processes including vasomotor reflexes, pain, cardiovascular regulation, behavior and limbic–cortical functioning, and the enteric
nervous system (12). 5-HT3 receptor antagonists (serotonin type 3 receptor
antagonists) were developed for relief of chemotherapy-induced nausea and
vomiting. Further established indications are radiotherapy-induced and
postoperative emesis (11). There are several 5-HT3 receptor antagonists such
as ondansetron, tropisetron, granisetron, dolasetron, azasetron, and ramosetron. In vitro studies demonstrated differences in receptor binding: tropisetron has a high affinity for the 5-HT3 receptor and a weak affinity for the
5-HT4 receptor. Ondansetron has low affinity for the 5-HT1b, 5-HT1c,
adrenergic, and opioid receptors. Thus, pharmacokinetic differences among
these drugs are unlikely to contribute significantly to clinical differences in
activity (13,14).
5-HT3 receptor antagonists are rapidly absorbed and penetrate the
blood–brain area easily. They are metabolized by diverse subtypes of the cytochrome P450 system and the metabolites are excreted mainly in urine (11).
Ondansetron is rapidly and completely absorbed from the gastrointestinal tract after oral administration. Due to a significant first-pass metabolism, only 60% is bioavailable. Maximum plasma concentrations occur after
1–2 hr. There is no evidence of accumulation after repeated oral administration (12). Ondansetron is mainly metabolized by the liver to inactive
glucuronide and sulfate conjugates that are excreted in the urine and feces.
As a result, a reduced dosage schedule should be employed when prescribing
ondansetron to patients with hepatic impairement. However, no such adjustment is necessary in renal failure. The standard oral dose is 8 mg twice daily.
Tropisetron is almost completely absorbed from the gastrointestinal
tract and undergoes dose-dependent first-pass metabolism. The peak plasma
5-HT3 Receptor Antagonists as Antipruritics
327
concentration occurs approximately 1 hr postdose (15). The bioavailability of
oral tropisetron exhibits a wide range at therapeutic doses (16). The mean
half-life period is 7–10 hr. It is metabolized to inactive metabolites by the
hydroxylation of the indole moiety and further conjugation to glucuronides
and sulfates. Approximately 80% of a dose is excreted via the kidneys, mainly
as metabolites. Clearance is decreased in patients with impaired hepatic or
renal function, but dose adjustment is not required. The recommended dose is
5 mg/day (15).
Adverse effects of 5-HT3 receptor antagonists include headache, dizziness, sedation, abnormalities of liver biochemistry, and, rarely, anaphylaxis
(12). When prescribing 5-HT3 receptor antagonists, the physician should be
aware of the serotonin syndrome that has been reported when they were
given in combination with other drugs such as mirtazapine and fentanyl (17).
The serotonin syndrome is characterized by a triad of clinical manifestations:
altered mental status, autonomic dysfunction, and neuromuscular abnormalities such as cogwheel rigidity, hyperreflexia, and myoclonus.
5-HT3 receptor antagonists may pose a potential risk when used in
severely ill patients with multidrug therapy, especially with central acting
substances. Perhaps, blocking one type of serotonin receptor and functionally
increasing systemic and central nervous system levels of serotonin simultaneously (hence presenting excessive serotonin to other receptors) increase the
risk of serotonin syndrome.
III.
ANTIPRURITIC POTENCY OF 5-HT3 RECEPTOR
ANTAGONISTS
The widespread distribution of 5-HT3 receptors in the peripheral and central
nervous systems indicates that this receptor type may have a role in various
disease states. This has resulted in the investigation of 5-HT3 receptor
antagonists in the treatment of pruritus.
Relief of itch by ondansetron was first reported by Schworer and
¨
Ramadori (18,19) in a patient suffering from cholestatic pruritus. Several
reports and clinical trials followed and demonstrated benefit from the use of
5-HT3 receptor antagonists in various types of pruritus (Fig. 1). In cholestatic pruritus, opioid levels are raised and facilitate itch (20). Greater
central opioid tone can cause increased serotonergic tone, perhaps accounting for the anecdotal reports of beneficial effects of ondansetron in cholestatic pruritus (21,22). Equivocal results have been obtained in controlled
studies investigating cholestatic pruritus. Intravenous ondansetron reduced
or abolished pruritus in 10 patients within 30–60 min after injection, with a
more prolonged effect when the dose of 8 mg was compared to 4 mg (23).