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Reduction in Itch Severity with Topical Immunomodulators: A New Approach for Patients with Inflammatory Disease

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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

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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–

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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



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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

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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).



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