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

1022 with erythema nodosum leprosum (Chapter 56) and
multiple myeloma. In addition, it has orphan drug status
for mycobacterial infections, Crohn’s disease, HIVassociated
wasting, Kaposi sarcoma, lupus, myelofibrosis,
brain malignancies, leprosy, graft-versus-host disease,
and aphthous ulcers.
Its mechanism of action is unclear (see Figure
62–4). Reported immunological effects vary substantially
under different conditions. For example, thalidomide
has been reported to decrease circulating TNF-α
in patients with erythema nodosum leprosum but to
increase it in patients who are HIV seropositive.
Alternatively, it has been suggested that the drug affects
angiogenesis (Paravar and Lee, 2008). The anti–TNF-α
effect has led to its evaluation as a treatment for severe,
refractory rheumatoid arthritis.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Lenalidomide. Lenalidomide (REVLIMID), 3-(4-amino-1-oxo 1,
3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione, is a thalidomide
analog with immunomodulatory and anti-angiogenic properties.
Lenalidomide is FDA approved for the treatment of patients with
transfusion-dependent anemia due to low- or intermediate risk
myelodysplastic syndromes associated with a deletion 5q cytogenetic
abnormality with or without additional cytogenetic abnormalities.
The usual starting dose is 10 mg/day. Because lenalidomide
causes significant neutropenia and thrombocytopenia in almost all
patients, patients have to be closely monitored with weekly blood
counts and lenalidomide dose adjusted according to the labeling
information. Lenalidomide also is associated with a significant risk
for deep vein thrombosis. Lenalidomide carries the same risk of teratogenicity
as thalidomide, and pregnancy has to be avoided.
Lenalidomide’s availability is limited to a special distribution program
administered by the manufacturer.
Bacillus Calmette-Guérin (BCG). Live BCG (TICE BCG,
THERACYS) is an attenuated, live culture of the bacillus
of Calmette and Guérin strain of Mycobacterium bovis
that induces a granulomatous reaction at the site of
administration. By unclear mechanisms, this preparation
is active against tumors and is indicated for the
treatment and prophylaxis of carcinoma in situ of the
urinary bladder and for prophylaxis of primary and
recurrent stage Ta and/or T1 papillary tumors after
transurethral resection (Patard et al., 1998). Adverse
effects include hypersensitivity, shock, chills, fever,
malaise, and immune complex disease.
Recombinant Cytokines
Interferons. Although interferons (α, β, and γ) initially
were identified by their antiviral activity, these agents
also have important immunomodulatory activities
(Ransohoff, 1998). The interferons bind to specific cellsurface
receptors that initiate a series of intracellular
events: induction of certain enzymes, inhibition of cell
proliferation, and enhancement of immune activities,
including increased phagocytosis by macrophages and
augmentation of specific cytotoxicity by T lymphocytes.
Recombinant IFN-α-2b (INTRON A) is obtained
from Escherichia coli by recombinant expression. It is
a member of a family of naturally occurring small proteins
with molecular weights of 15,000-27,600 Da, produced
and secreted by cells in response to viral
infections and other inducers. IFN-α-2b is indicated in
the treatment of a variety of tumors, including hairy cell
leukemia, malignant melanoma, follicular lymphoma,
and AIDS-related Kaposi sarcoma (Sinkovics and
Horvath, 2000). It also is indicated for infectious diseases,
chronic hepatitis B, and condylomata acuminata.
In addition, it is supplied in combination with ribavirin
(REBETRON) for treatment of chronic hepatitis C in
patients with compensated liver function not treated
previously with IFN-α-2b or who have relapsed after
IFN-α-2b therapy (Lo Iacono et al., 2000).
Flu-like symptoms, including fever, chills, and headache, are
the most common adverse effects after IFN-α-2b administration.
Adverse experiences involving the cardiovascular system (e.g.,
hypotension, arrhythmias, and rarely cardiomyopathy and myocardial
infarction) and CNS (e.g., depression, confusion) are less frequent
side effects. All α interferons carry a boxed warning regarding
development of pulmonary hypertension.
IFN-γ-1b (ACTIMMUNE) is a recombinant polypeptide that
activates phagocytes and induces their generation of oxygen
metabolites that are toxic to a number of microorganisms.
It is indicated to reduce the frequency and
severity of serious infections associated with chronic
granulomatous disease and to delay the time to progression
in severe malignant osteopetrosis. IFN-γ-1b is not
effective and may increase mortality in patients with idiopathic
pulmonary fibrosis. Adverse reactions include
fever, headache, rash, fatigue, GI distress, anorexia,
weight loss, myalgia, and depression.
IFN-β-1a (AVONEX, REBIF), a 166–amino acid
recombinant glycoprotein, and IFN-β-1b (BETASERON),
a 165–amino acid recombinant protein, have antiviral
and immunomodulatory properties. They are FDAapproved
for the treatment of relapsing MS to reduce
the frequency of clinical exacerbations (see “Multiple
Sclerosis”). The mechanism of their action in MS is
unclear. Flu-like symptoms (e.g., fever, chills, myalgia)
and injection-site reactions have been common adverse
effects.
Further discussion of the use of these and other
interferons in the treatment of viral diseases can be
found in Chapter 58.