Biomedical Engineering Reference
In-Depth Information
A-803467 (Fig.
4
): is a subtype selective blocker of Nav1.8 discovered by
Abbott and Incagen [
152
]. In vivo, this compound reduces spontaneous and evoked
firing of spinal dorsal horn neurons in spinal nerve ligated rats [
153
]. A-803467 is
able to reduce pain in several animal models. The observation that this compound
do not significantly alter motor coordination may provide the first experimental
evidence that a subtype selectivity would translate into safer sodium channel
blockers.
3.3 For the Treatment of Other Diseases
3.3.1 Migraine
As specified above, FHM3 is a rare subtype of FHM due to a mutation in SCN1A,
the gene encoding for the voltage-gated Na
V
1.1 channel [
19
,
154
-
156
], and some
sodium channels blockers (i.e., topiramate, carbamazepine, and lamotrigine) seems
to be efficacious in the treatment of migraine, reducing aura and migraine attacks
(Fig.
3
)[
4
,
157
,
158
]. Nevertheless, the mechanism of action of these drugs in the
treatment of this disease has to be clarified.
3.3.2 Myotonic Syndromes
Mutations in the gene encoding COC-1, a chloride channel, together with mutations
in
SCN4A
, the gene encoding the
-subunit of the skeletal muscle sodium channel
Na
V
1.4 seem to be involved in the physiopathology of myotonic dystrophy
[
159
-
162
]. At the moment it is impossible to cure the cause of the disorder and
only symptomatic treatments are available, such as sodium channel blockers, that
reduce the excitability of the cell membrane. Nevertheless, these drugs, such as
procainamide, tocainide, mexiletine, flecainide, and phenytoin are not selective
toward the Na
V
1.4 VGSC isoform, and they could have serious side effects (Figs.
3
and
4
)[
163
,
164
]. Instead, several studies suggest that mexiletine is the agent of
choice in the treatment of nondystrophic myotonia, even if its use is restricted by
the side effects on cardiac functions, on the CNS and on the hematopoietic system
[
165
-
167
]. Considering that sodium channels on cardiac and skeletal muscle tissues
are different, there is the possibility to design use-dependent sodium channel
blockers that preferentially block skeletal muscle isoforms. Many efforts have
been made to develop this class of molecules but, so far, it has been impossible to
obtain a pharmacological differentiation, even by synthesizing compounds more
potent than mexiletine in vitro [
168
]. Similar, flecainide, an IC class antiarrythmic,
improves myotonia, still retaining the same side effects observed for mexiletine.
However, the drug seems useful in situations where mexiletine is less efficient
[
169
-
171
]. Also, tocainide is among the few drugs clinically used for the symp-
tomatic treatment of muscle hyperexcitability in myotonic syndromes, but with the
a
