Page 1218 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1182 Part tEN Prevention and Therapy of Immunological Diseases

KEY CONCEPt Imiquimod
Cyclosporine: Mechanism of Action NH
N 2
Association with cyclophilin
Formation of cyclosporine–cyclophilin complex
Binds calcineurin
Inactivates calcineurin N
Regulatory proteins unable to translocate into nucleus
Transcription of proinflammatory genes affected CH 2
CH
Adverse Effects CH 3 CH 3
The most common side effects of cyclosporine are hypertension, FIG 87.10 Imiquimod—chemical structure.
hyperkalemia, hypomagnesemia, and hyperlipidemia. More
importantly, cyclosporine has well-documented short-term and
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long-term adverse effects on kidney function. These data come
from patients who had received solid organ transplants, most SIROLIMUS
notably renal transplants. In such patients, initial doses of
15–25 mg/kg/day led to a reduction in the glomerular filtration Sirolimus is a macrolide that binds the cytosolic protein FK-binding
rate (GFR) and rise in serum creatinine in a percentage of patients, protein 12 (FKBP12). In contrast to the tacrolimus–FKBP12
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as well as histologically proven nephropathy. The pathogenic complex, which inhibits calcineurin, the sirolimus–FKBP12
mechanism of kidney damage is poorly understood but is believed complex directly binds the mammalian target of rapamycin
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to consist of two phases. The first is a period of partial ischemia (mTOR) complex1 (mTORC1), thereby inhibiting the mTOR
secondary to vascular contraction, which is reversible with dose pathway. Thus it inhibits the response to IL-2, blocking activa-
reduction or drug discontinuation. The later, irreversible phase tion of T and B cells. It has shown promise in the treatment
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results from chronic scarring of the glomeruli. Treatment recom- for systemic lupus erythematosus (SLE); Sjögren syndrome ;
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mendations for some diseases, such as psoriasis, have therefore RA ; psoriasis; genetic disorders, such as tuberous sclerosis;
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been targeted at much lower maximum daily doses of 5 mg/kg/ and neoplastic disorders, such as Kaposi sarcoma. The main
day, with a reduced dose if creatinine rises 30% above baseline. advantage of sirolimus over tacrolimus or cyclosporine is reduced
Otherwise healthy patients treated at these dosage levels have renal toxicity.
been successfully managed for many years on cyclosporine with
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no impact on the GFR. Nephrotoxicity has also been a concern IMIQUIMOD
during tacrolimus therapy. Other adverse effects include increased
rate of infections, malignancy, hepatotoxicity, GI upset, rash, Imiquimod (Fig. 87.10), an imidazoquinoline drug, activates
tremor, headache, and insomnia. Toll-like receptor (TLR)-7 and possesses both antiviral and
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antitumor activities. As a cream preparation, it is effective in
TOPICAL PIMECROLIMUS AND the treatment of external genital warts caused by infection with
TACROLIMUS (FK506) human papillomavirus (HPV). Immune amplification responses
are induced through stimulation of inflammatory cytokines. 23,24
Tacrolimus is also available in topical formulation. Pimecrolimus Production of IFN-α is stimulated, and this suppresses replication
is an alternative topical calcineurin inhibitor with similar structure of viruses in infected keratinocytes. NK-cell activity is also
and identical mechanisms of action. The cyclosporine molecule increased, partly through the induction of oligoadenylate synthase.
is too large to penetrate skin (1203 Da), whereas tacrolimus and The increase of dermal IFN-α transcript levels is rapid and
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pimecrolimus can, as they are much smaller molecules (804 and dramatic. Other cytokines modulated by imiquimod include
80 daltons [Da], respectively). Both have been approved by the TNF-α and IL-12, especially in peripheral blood monocytes. 26,27
FDA for the treatment of atopic dermatitis but have found The overall effect is a shift from a T-helper-2 (Th2)-cytokine–
widespread use in many other conditions (psoriasis, oral and predominant profile toward a Th1-cytokine–predominant profile.
cutaneous lichen planus, vitiligo, pemphigoid, and pemphigus). Other conditions where imiquimod is effective include actinic
They are most often used when long-term topical corticosteroids keratosis, herpes simplex, basal cell carcinoma, and molluscum
are contraindicated. contagiosum.
Adverse Effects Adverse Effects
The most common side effect is local irritation at the site of Inflammation at the site of application represents the most
application in severely inflamed skin. Therefore initial short-term common adverse reaction. However, nondermatological side
treatment is often combined with topical steroids. An association effects, such as fever, fatigue, myalgia, and headache, have also
with malignancy remains controversial. In 2005, 17 case reports been described.
of malignancy in patients using these topicals resulted in a
black-box warning, although further studies suggested that the 5-FLUOROURACIL
rate of lymphoma from these case reports was lower than the
rate observed in the general population in the United States. In 5-Fluorouracil is a uracil analogue that has two modes of
2006, the FDA revised the wording, but a black-box warning action. First, it inhibits cell proliferation via direct incorpora-
about these products remains in place. tion into RNA causing abnormal base pairing. Second, it binds