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

alterations of single amino acids, but more than 30 different alleles
have been found in different kindreds. Transgenic mice expressing
mutant human SOD1 develop a progressive degeneration of motor
neurons that closely mimics the human disease, providing an important
animal model for research and pharmaceutical trials.
Interestingly, many of the mutations of SOD1 that can cause disease
do not reduce the capacity of the enzyme to perform its primary
function, the catabolism of superoxide radicals. Thus, as may be the
case in HD, mutations in SOD1 may confer a toxic “gain of function,”
the precise nature of which is unclear.
More recently, mutations in the TARDBP gene encoding TAR
DNA-binding protein (TDP-43) and in the FUS/TLS gene have been
identified as causes of FALS (Lagier-Tourenne and Cleveland,
2009). Both TDP-43 and FUS/TLS bind DNA and RNA, and regulate
transcription and alternative splicing.
More than 90% of ALS cases are sporadic. Of these, a few are
caused by de novo mutations in SOD1, TDP-43, FUS/TLS, or other
genes, but for the majority of sporadic cases the etiology remains
unclear. Possible pathogenic mechanisms underlying sporadic ALS
include autoimmunity, excitotoxicity, free radical toxicity, and viral
infection (Rothstein, 2009), although none is well supported by
available data. There is evidence that glutamate reuptake may be
abnormal in the disease, leading to accumulation of glutamate and
excitotoxic injury (Rothstein et al., 1992). The only currently
approved therapy for ALS, riluzole, is based on these observations
(Brooks, 2009).
Treatment of ALS
Riluzole. Riluzole (2-amino-6-[trifluoromethoxy]
benzothiazole; RILUTEK) is an agent with complex
actions in the nervous system (Doble, 1996; Zarate and
Manji, 2008).
Riluzole is absorbed orally and is highly protein
bound. It undergoes extensive metabolism in the liver
by both CYP–mediated hydroxylation and glucuronidation.
Its t 1/2
is about 12 hours. In vitro studies have shown
that riluzole has both presynaptic and postsynaptic
effects. It inhibits glutamate release, but it also blocks
postsynaptic NMDA- and kainate-type glutamate receptors
and inhibits voltage-dependent Na + channels. Some
of the effects of riluzole in vitro are blocked by pertussis
toxin, implicating the drug’s interaction with an as
yet-unidentified G protein–coupled receptor (GPCR). In
clinical trials riluzole has modest but genuine effects on
the survival of patients with ALS.
Meta-analyses of the available trials indicate that riluzole
extends survival by 2-3 months (Miller et al., 2007). The recommended
dose is 50 mg twice daily, taken 1 hour before or 2 hours
after a meal. Riluzole usually is well tolerated, although nausea or
diarrhea may occur. Rarely, riluzole may produce hepatic injury with
elevations of serum transaminases, and periodic monitoring of these
is recommended. Although the magnitude of the effect of riluzole on
ALS is small, it represents a significant therapeutic milestone in the
treatment of a disease refractory to all previous treatments.
Symptomatic Therapy of ALS: Spasticity. Spasticity is
an important component of the clinical features of ALS
and the feature most amenable to present forms of treatment.
Spasticity often leads to considerable pain and
discomfort and further reduces mobility, which already
is compromised by weakness. Spasticity is defined as
an increase in muscle tone characterized by an initial
resistance to passive displacement of a limb at a joint,
followed by a sudden relaxation (the so-called claspedknife
phenomenon). Spasticity results from loss of
descending inputs to the spinal motor neurons, and the
character of the spasticity depends on which nervous
system pathways are affected (Sheean, 2008). Whole
repertoires of movement can be generated directly at
the spinal cord level; it is beyond the scope of this chapter
to describe these in detail. The monosynaptic tendon-stretch
reflex is the simplest of the spinal
mechanisms contributing to spasticity. Primary Ia afferents
from muscle spindles, activated when the muscle is
stretched rapidly, synapse directly on motor neurons
going to the stretched muscle, causing it to contract and
resist the movement. A collateral of the primary Ia
afferent synapses on a “Ia-coupled interneuron” that
inhibits the motor neurons innervating the antagonist
of the stretched muscle, allowing contraction of the
muscle to be unopposed. Upper motor neurons from the
cerebral cortex (the pyramidal neurons) suppress spinal
reflexes and the lower motor neurons indirectly by activating
the spinal cord inhibitory interneuron pools
(Figure 22–8).
The pyramidal neurons use glutamate as a neurotransmitter.
When the pyramidal influences are removed, the reflexes are released
from inhibition and become more active, leading to hyperreflexia.
Other descending pathways from the brainstem, including the rubro-,
reticulo-, and vestibulospinal pathways and the descending catecholamine
pathways, also influence spinal reflex activity. When just
the pyramidal pathway is affected, extensor tone in the legs and flexor
tone in the arms are increased. When the vestibulospinal and catecholamine
pathways are impaired, increased flexion of all extremities
is observed, and light cutaneous stimulation can lead to disabling
whole-body spasms. In ALS, pyramidal pathways are impaired with
relative preservation of the other descending pathways, resulting in
hyperactive deep-tendon reflexes, impaired fine motor coordination,
increased extensor tone in the legs, and increased flexor tone in the
arms. The gag reflex often is overactive as well.
The best agent for the symptomatic treatment of spasticity in
ALS is baclofen (LIORESAL), a GABA B
receptor agonist. Initial doses
625
CHAPTER 22
TREATMENT OF CENTRAL NERVOUS SYSTEM DEGENERATIVE DISORDERS