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

1824 An initial dosage of 50 mg/day is prescribed, followed by
increases of 25 mg/day at weekly intervals, titrated to the minimal
dosage necessary for effect, always with appropriate laboratory testing.
Potential side effects of dapsone include methemoglobinemia
and hemolysis. The glucose-6-phosphate dehydrogenase (G6PD)
level should be checked in all patients before initiating dapsone
therapy because dapsone hydroxylamine, the toxic metabolite of
dapsone formed by hydroxylation, depletes glutathione within
G6PD-deficient cells. The nitroso derivative then causes peroxidation
reactions, leading to rapid hemolysis. A maximum dosage of
150-300 mg/day should be given in divided doses to minimize the
risks of methemoglobinemia. The H 2
blocker cimetidine, at a dose of
400 mg three times daily, alters the degree of methemoglobinemia by
competing with dapsone for CYPs. Toxicities include agranulocytosis,
peripheral neuropathy, and psychosis.
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
Thalidomide. Thalidomide (THALOMID) is an antiinflammatory,
immunomodulating, anti-angiogenic
agent experiencing resurgence in the treatment of dermatological
diseases (see Chapter 35). Its structure is:
The mechanisms that underlie the pharmacological
properties of thalidomide are not clear, although modulation
of inflammatory cytokines such as TNF-, IFN-,
IL-10, IL-12, cyclooxygenase-2, and possibly nuclear
factor B (NF-B) may be involved (Franks et al., 2004).
It also can modulate T cells by altering their patterns of
cytokine release and can increase keratinocyte migration
and proliferation (Wines et al., 2002).
Thalidomide is FDA approved for the treatment of erythema
nodosum leprosum. There are reports suggesting its efficacy in actinic
prurigo, aphthous stomatitis, Behçet’s disease, Kaposi sarcoma, and
the cutaneous manifestations of lupus erythematosus, as well as
prurigo nodularis and uremic prurigo. Thalidomide has been associated
with increased mortality when used to treat toxic epidermal
necrolysis. In utero exposure can cause limb abnormalities (phocomelia),
as well as other congenital anomalies. It also may cause an
irreversible neuropathy. Because of its teratogenic effects, thalidomide
use is restricted to specially licensed physicians who fully understand
the risks. Thalidomide should never be taken by women who are pregnant
or who could become pregnant while taking the drug.
BIOLOGICAL AGENTS
Biological agents (see Chapters 35 and 62) are compounds
derived from living organisms that target
specific mediators of immunological reactions. Classes
of biologicals include recombinant cytokines, interleukins,
growth factors, antibodies, and fusion proteins.
Currently, five biological agents are approved for the
treatment of psoriasis (Table 65–10).
Psoriasis is a disorder of Th1 cell-mediated
immunity (Figure 65–4), with the epidermal changes
being secondary to the effect of released cytokines.
Biological therapies modify the immune response in
psoriasis through 1) reduction of pathogenic T cells, 2)
inhibition of T-cell activation, 3) immune deviation
(from a Th1 to a Th2 immune response), and 4) blockade
of the activity of inflammatory cytokines
(Weinberg, 2003). The appeal of biological agents in
the treatment of psoriasis is that they specifically target
the activities of T lymphocytes and cytokines that mediate
inflammation versus traditional systemic therapies
that are broadly immunosuppressive or cytotoxic. Thus,
the use of these agents theoretically should result in
fewer toxicities and side effects.
When evaluating the efficacy of biological agents, it is important
to understand the standard measurement of efficacy in psoriasis
treatment, the Psoriasis Area and Severity Index (PASI). The PASI
quantifies the extent and severity of skin involvement in different
body regions as a score from 0 (no lesions) to 72 (severe disease). To
gain FDA approval for the treatment of psoriasis, a biological agent
must decrease the PASI by 75%. Although such quantification is an
essential element in controlled clinical trials, many patients in practice
may gain clinically significant benefit from biological treatment
without achieving this degree of PASI improvement.
T-cell Activation Inhibitors
Alefacept. Alefacept (AMEVIVE) was the first immunobiological
agent approved for the treatment of moderate to
severe psoriasis. Alefacept consists of a recombinant
fully human fusion protein composed of the binding site
of the leukocyte function–associated antigen 3 (LFA-3)
protein and a human IgG 1
Fc domain. The LFA-3 portion
of the alefacept molecule binds to CD2 on the surface
of T cells, thus blocking a necessary co-stimulation step
in T-cell activation (Figure 65–5). Importantly, because
CD2 is expressed preferentially on memory-effector
T cells, naive T cells are largely unaffected by alefacept.
A second important action of alefacept is its ability to
induce apoptosis of memory-effector T cells through
simultaneous binding of its IgG 1
portion to immunoglobulin
receptors on cytotoxic cells and its LFA-3 portion
to CD2 on T cells, thus inducing granzyme-mediated
apoptosis of memory-effector T cells. This may lead to
a reduction in CD4 + lymphocyte counts, requiring a
baseline CD4 + lymphocyte count before initiating alefacept
and then biweekly during therapy.