Page 1216 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1180 Part tEN Prevention and Therapy of Immunological Diseases

Cyclophosphamide CH CH CL Leflunomide O
2
2
O N C NH CF
P CH CH CL 2
2
2
O N
N O CH 3
FIG 87.4 Cyclophosphamide—chemical structure. FIG 87.5 Leflunomide—chemical structure.

Mechanisms of Action of Cyclophosphamide A77 1726 O
This alkylating process has immunomodulating effects on resting N C C C NH CF 3
and actively dividing cells. The numbers of circulating CD4 T
lymphocytes and, to a lesser extent, CD8 T lymphocytes are CH 3 OH
reduced, thus reducing the CD4/CD8 ratio. Despite an apparent FIG 87.6 A77 1726—chemical structure.
increase in immunoglobulin-secreting cells, B-cell function is
suppressed, and overall immunoglobulin synthesis is reduced.
synthesis. Because of this long half-life, therapy with leflunomide
Adverse Effects is usually started with a loading dose to quickly achieve therapeutic
The best known toxicity is hemorrhagic cystitis. Since this occurs levels. A77 1726 is highly plasma-protein bound and undergoes
more frequently following oral dosing, this route of adminis- enterohepatic recirculation.
tration is rarely used. This may relate to continuous exposure
of the bladder to acrolein, so the acrolein-neutralizing agent Mechanisms of Action of Leflunomide
2-mercaptoethane sulfonate (Mesna) is used prophylactically By inhibiting pyrimidine synthesis, pyrimidine nucleotide avail-
along with copious hydration. Hemorrhagic myocarditis can also ability becomes insufficient for proliferation of immune-response
occur and may cause myocardial necrosis, hemopericardium, cells. This deficiency is inadequately replenished by the salvage
and congestive cardiac failure. However, survivors of acute pathways, rendering cell proliferation inefficient and limiting
cardiac toxicity do not show any residual electrocardiographic the clonal expansion of T cells. B-cell proliferation is similarly
or echocardiographic abnormalities. suppressed with reduction of Cdk2, a cyclin-dependent kinase.
Besides bone marrow suppression, reduction of fertility, and Leflunomide also inhibits NF-κB activation. Although the effects
a heightened risk of infection, cyclophosphamide therapy has of moderate concentrations are reversed by uridine in vitro, this
been associated with secondary malignancies, which may occur reversal does not occur at higher concentrations, suggesting
years after drug cessation. Malignancies of the bladder, often of possible involvement of other mechanisms. Leflunomide is known
a transitional cell type, tend to occur only in those with a history to inhibit tyrosine kinase activity at higher concentrations,
of treatment-related hemorrhagic cystitis. Myeloproliferative and although the relevance of this effect to therapeutic concentrations
lymphoproliferative disorders have also been associated with achievable in vivo remains questionable.
cyclophosphamide use.
Adverse Effects
Other Nitrogen Mustard Derivatives GI symptoms are the most common side effect, and hepatic
Chlorambucil, or 4-[bis(2chlor-ethyl)amino]benzenebutanoic damage is the most important toxicity. Although there are
acid, has wide distribution in tissue and 87% oral bioavailability, similarities to the toxicity profile of methotrexate, clinical trials
but unlike cyclophosphamide, it does not require metabolism have shown that leflunomide and methotrexate can be safely
7
by the liver to become metabolically active. The only indication and effectively given together to patients with RA, but transami-
approved by the US Food and Drug Administration (FDA) is nasemia occurs more often than with methotrexate alone. 9,10
for treatment of chronic lymphocytic leukemia (CLL), but like Fulminant hepatic failure is rare, but fatal cases have occurred.
cyclophosphamide, chlorambucil has been reported to be used Skin reactions are mostly minor; however, more serious manifesta-
in treatments for the same wide range of inflammatory conditions. tions, such as Stevens-Johnson syndrome and toxic epidermal
The mechanism of action and side effect profile is also similar necrolysis, have been reported.
to those of cyclophosphamide, but with a higher risk of permanent
aplasia. 8 MYCOPHENOLATE MOFETIL
Melphalan is another phenylalanine derivative of nitrogen
mustard, mainly used in treating multiple myeloma. It has been Mycophenolate mofetil (Fig. 87.7) is widely used in solid organ
less widely adopted but has been used off-label in a variety of transplantation and has also been increasingly employed in
inflammatory conditions. Adverse effects and mechanism are treatment of autoimmune diseases. It is rapidly absorbed and
the same as those of cyclophosphamide, as described above. hydrolyzed into the active compound, mycophenolic acid, which
is a reversible inhibitor of inosine monophosphate dehydrogenase.
LEFLUNOMIDE Since inosine monophosphate dehydrogenase is a key enzyme
in the de novo synthesis of guanine nucleotides, its inhibition is
Leflunomide is an inhibitor of de novo pyrimidine synthesis. most significant in T and B lymphocytes, which are reliant on
Leflunomide (Fig. 87.5) is converted into the long-acting active this pathway, as they lack the hypoxanthine-guanine phospho-
compound A77 1726 (2-cyano-3-hydroxy-N-[4-trifluoromethyl]- ribosyl transferase salvage pathway. The immunological effects
butenamide) (Fig. 87.6), a reversible inhibitor of the enzyme are numerous. DNA synthesis in lymphocytes requires the
dihydroorotate dehydrogenase that is involved in pyrimidine incorporation of guanine nucleotides so that proliferation of