Page 1217 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 87 Immunomodulating Pharmaceuticals 1181

Mycophenolatemofetil CH 3 CH 2
CH 3 CH
O OH 2
CH 2 CH C CH 2 CH 2 CH 2
O CH 3 CH 3 CH 3 OH
O C C
(CH ) 2 3 CH 3 (CH ) (CH ) O C CH 3 O CH 3
O O 2 3 N 2 2
CH 3 CH 3 CH 2 C C N CH C N C C N CC N CO
O OCH CH O CH
CH 2 3 3 2
N CH 3
Cyclosporine

O N C C NH C C NH C C N C C NH C N CH 3
FIG 87.7 Mycophenolate mofetil – chemical structure. CH 3 O CH 3 O CH 3 O (CH ) CH 3 O (CH ) O C
2 3
2 3
CH 3 CH 3 (CH )
2 3
lymphocytes is suppressed. Antibody production and NK-cell CH
activity are also reduced, and in vitro cytokine production by 3
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activated human mononuclear cells is affected. In addition, FIG 87.8 Cyclosporine—chemical structure.
delayed-type hypersensitivity responses are suppressed. Although
effective in a subset of patients with psoriasis and RA, myco- Tacrolimus CH
phenolate mofetil has not been widely used in these conditions 2
because other more effective medications are available. It is,
however, becoming more popular in the treatment of some H CO CH
3
diseases, such as myositis, systemic contact dermatitis, severe
atopic dermatitis, chronic urticaria, refractory pyoderma gan- C CH 3 C OH
grenosum, bullous pemphigoid, pemphigus vulgaris, and C O
pemphigus foliaceus, where it is effective with a low risk of side CH 2
effects. N O CH O
Adverse Effects O C C CH 2 CH CH 2
Absolute contraindications for mycophenolate mofetil are drug O C CH H O
2
3
allergy and pregnancy (Category D). Relative contraindications H C OH C CH 3
include lactation; renal, hepatic, or cardiopulmonary disease; O
and peptic ulcer. It is generally well tolerated when used in
autoimmune diseases, such as RA. The most common side effects H CO C CH 2 C CH 2
are nausea, vomiting, abdominal discomfort, diarrhea, fever, 3 OCH 3 CH 3
headache, skin rash, back pain, and tremor, but these do not FIG 87.9 Tacrolimus—chemical structure.
usually lead to discontinuation. Rarely reported side effects include
leukopenia and other cytopenias, cutaneous and noncutaneous
malignancies, and pancreatitis. Toxic doses have not been ORAL CYCLOSPORINE AND TACROLIMUS (FK506)
established for this medication. One patient suffered only moder-
ate leukopenia with no significant GI side effects after ingesting Cyclosporine (Fig. 87.8) and tacrolimus (Fig. 87.9) are structur-
25g of mycophenolate mofetil. Up to 4 g/day have been used in ally similar drugs that have been widely used in solid organ
cardiac and up to 5 g/day in hepatic transplantation patients. transplantation as well as in the treatment of immunological
However, increased efficacy was not observed above 2 g/day, and diseases. Cyclosporine has potent inhibitory effects in dampening
patients were more likely to experience GI symptoms and the production of proinflammatory mediators, such as IL-2,
neutropenia at higher doses. For this reason, doses up to 2 g/ by immunocompetent cells, most importantly T lymphocytes.
day are usually employed to treat inflammatory conditions. It does so through binding cyclophilin, which produces a
cyclosporine–cyclophilin complex. This complex binds the
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HYDROXYUREA serine/threonine phosphatase calcineurin. This disrupts the
phosphorylation of regulatory proteins for which the nucleated
Hydroxyurea is urea with one additional hydroxyl group. It inhibits factor of activated T cells (NF-ATs) is a critical component,
ribonucleotide reductase, which catalyzes the reduction of preventing these proteins from translocating into the nucleus.
ribonucleotides to deoxyribonucleotides, and is thus essential Thus the transcription of genes, such as IL-2, which induces
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in DNA synthesis. It is effective in the treatment of psoriasis. mitogenesis in activated T cells, cannot be effectively activated.
Hydroxyurea is well tolerated, with the most common side effects A number of other cytokines are affected, including IL-3, IL-6,
being hematological, usually megaloblastic anemia, but also transforming growth factor (TGF)-β, and interferon (IFN)-γ.
leukopenia and thrombocytopenia. Other significant but rare Another T cell–specific immunophilin, FK506-binding protein
adverse effects include renal and GI toxicity, a dermatomyositis- (FKBP), binds tacrolimus to form a FK506-FKBP complex with
like syndrome, leg ulcers, radiation recall, and leukemias. similar resultant inhibitory activity on calcineurin. 14