DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1822 Tacrolimus. Tacrolimus (FK506, PROTOPIC), a metabolite
of Streptomyces tsukubaensis, was discovered in 1984.
tacrolimus had a higher incidence of lymphoma and, after exposure to
UV radiation, showed decreased time to skin tumor formation.
Therefore, it is recommended that patients using tacrolimus use sunscreen
and avoid excessive UV exposure. The risk of lymphoma development
in humans is uncertain.
Pimecrolimus. Pimecrolimus 1% cream (ELIDEL), a macrolide
derived from ascomycin, is FDA approved for the treatment
of atopic dermatitis in patients >2 years of age.
Cl
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
It is a potent macrolide immunosuppressant traditionally
used to prevent kidney, liver, and heart allograft rejection. Like
cyclosporine, tacrolimus works mainly by inhibiting early activation
of T lymphocytes, thereby inhibiting the release of IL-2, suppressing
humoral and cell-mediated immune responses, and suppressing mediator
release from mast cells and basophils (Assmann and Ruzicka,
2002). In contrast to cyclosporine, this effect is mediated by binding
to the intracellular protein FK506-binding protein 12, generating a
complex that inhibits the phosphatase activity of calcineurin.
Tacrolimus is available in a topical form for the treatment of
skin disease and also is marketed in oral and injectable formulations
(PROGRAF). Systemic tacrolimus has shown some efficacy in
the treatment of inflammatory skin diseases such as psoriasis, pyoderma
gangrenosum, and Behçet’s disease (Assmann and Ruzicka,
2002). When administered systemically, the most common side
effects are hypertension, nephrotoxicity, neurotoxicity, GI symptoms,
hyperglycemia, and hyperlipidemia. Topical formulations of
tacrolimus penetrate into the epidermis.
In commercially available topical formulations (0.03% and
0.1%), tacrolimus ointment is effective in and approved for the treatment
of atopic dermatitis in adults (0.03% and 0.1%) and children
(0.03%) >2 years of age. Other uses in dermatology include intertriginous
psoriasis, vitiligo, mucosal lichen planus, graft-versus-host disease,
allergic contact dermatitis, and rosacea (Ngheim et al., 2002). It is
applied to the affected area twice a day and generally is well tolerated.
A major benefit of topical tacrolimus compared with topical
glucocorticoids is that tacrolimus does not cause skin atrophy and therefore
can be used safely in locations such as the face and intertriginous
areas. Common side effects at the site of application are transient erythema,
burning, and pruritus, which tend to improve with continued
treatment. Other reported adverse effects include skin tingling, flu-like
symptoms, headache, alcohol intolerance, folliculitis, acne, and hyperesthesia
(Ngheim et al., 2002). Systemic absorption generally is very
low and decreases with resolution of the dermatitis. However, topical
tacrolimus should be used with extreme caution in patients with
Netherton’s syndrome because these patients have been shown to
develop elevated blood levels of the drug after topical application
(Assmann and Ruzicka, 2002). Mice treated with 0.1% topical
Its mechanism of action and side-effect profile are similar to
those of tacrolimus. Burning, although occurring in some patients,
appears to be less common with pimecrolimus than with tacrolimus
(Ngheim et al., 2002). In addition, pimecrolimus has less systemic
absorption. Similar precautions with regard to UV exposure should
be taken during treatment with pimecrolimus.
Due to the potential for malignancy production, topical
calcineurin inhibitors are not considered first-line therapy
in childhood atopic dermatitis. Tacrolimus and
pimecrolimus should only be used as second-line
agents for short-term and intermittent treatment of
atopic dermatitis (eczema) in patients unresponsive to,
or intolerant of, other treatments. The effect of these
drugs on the developing immune system in infants and
children is not known; therefore, these drugs should be
avoided in children <2 years of age. In clinical studies,
infants and children <2 years of age treated with
tacrolimus had a higher rate of upper respiratory infections
than did those treated with placebo cream. Higher
doses cause malignancies in animal studies.
OTHER IMMUNOSUPPRESSIVE
AND ANTI-INFLAMMATORY AGENTS
Mycophenolate mofetil. Mycophenolate mofetil (CELL-
CEPT), a prodrug, and mycophenolate sodium (MYFORTIC)
are immunosuppressants approved for prophylaxis of
organ rejection in patients with renal, cardiac, and hepatic
transplants (see Chapter 35). Mycophenolic acid, the