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

agent that ameliorates auto-immune disease by altering
signals through the T cell–receptor complex.
For relapsing-remitting attacks and for secondary
progressive MS, the alkylating agent cyclophosphamide
(De Jager and Hafler, 2007) and the anthracenedionederivative
mitoxantrone (NOVANTRONE, others) currently
are used in patients refractory to other immunomodulators.
These agents, primarily used for cancer
chemotherapy, have significant toxicities (see Chapter
61 for structures and pharmacology). Although
cyclophosphamide in patients with MS may not be limited
by an accumulated dose exposure, mitoxantrone
generally can be tolerated only up to an accumulated
dose of 100-140 mg/m 2 (Crossley, 1984). However,
because decreases in left- ventricular ejection fraction
(LVEF) and frank congestive heart failure have occurred
in patients who have received <100 mg/m 2 , the FDA
now recommends that LVEF be evaluated before initiating
therapy, prior to each dose, and annually after
patients have finished treatment to detect late-occurring
cardiac toxicity. The utility of interferon therapy in
patients with secondary progressive MS is unclear. In
primary progressive MS, with no discrete attacks and
less observed inflammation, suppression of inflammation
seems to be less helpful. A minority of patients at
this stage will respond to high doses of glucocorticoids.
Table 35–3 summarizes current immunomodulatory
therapies for MS.
Table 35–3
Pharmacotherapy of Multiple Sclerosis
THERAPEUTIC BRAND NAME
AGENT (DOSE, REGIMEN) INDICATIONS RESULTS MECHANISM OF ACTION
IFN-β-1a AVONEX (30 μg, IM, Treatment of Reduction of relapses by Acts on blood-brain barrier by
weekly) RRMS one-third interfering with T-cell adhesion
REBIFF (22 or 44 μg, Reduction of new MRI T2 to the endothelium by binding
SC, 3 times weekly) lesions and the volume of VLA-4 on T cells or by inhibiting
enlarging T2 lesions the T-cell expression of MMP
Reduction in the number Reduction in T cell activation by
and volume of Gd- interfering with HLA class II and
enhancing lesions
co-stimulatory molecules
Slowing of brain atrophy B7/CD28 and CD40:CD40L
Immune deviation of Th2 over
Th1 cytokine profile
IFN-β-1b BETASERON (0.25 mg, Treatment of Same as IFN-β-1a, above Same as IFN-β-1a, above
SC, every other RRMS
day after 6-week
titration)
Glatiramer COPAXONE (20 mg, Treatment of Reduction of relapses by Induces T-helper type 2 cells that
acetate SC, daily) RRMS one-third enter the CNS; mediates
Reduction in the number bystander suppression at sites
and volume of Gd- of inflammation
enhancing lesions
Mitoxantrone NOVANTRONE, generic Worsening Reduction in relapses Intercalates DNA (see Chapter 61)
(12 mg/m 2 , as short forms of by 67% Suppresses cellular and
[5–15 minute] IV RRMS Slowed progression on humoral immune response
infusion every SPMS EDSS, ambulation index,
3 months) and MRI disease activity
EDSS, Expanded Disability Status Scale, a neurologic assessment scale for MS pathology. Gd, gadolinium, used in Gd-enhanced MRI to assess the
number and size of inflammatory brain lesions; IFN, interferon; IM, intramuscularly; IV, intravenously; MMP, matrix metalloprotease; MS, multiple
sclerosis; RRMS, relapsing-remitting MS; SC, subcutaneously; SPMS, secondary progressive MS; MRI, magnetic resonance imaging.