Biomedical Engineering Reference
In-Depth Information
In contrast, F15845 is a benzoxathiepine derivative in phase II clinical trials for
the treatment of angina that blocks selectively the sodium current (Fig.
7
)[
178
,
189
]. Moreover, it exerts short- and long-term cardioprotection after myocardial
infarction and, at pharmacologically active doses, F15845 does not affect peak Na
+
current in normal polarized myocytes. This feature clearly distinguishes this
promising compound from the commercially available Na
V
1.5 blockers, as class I
antiarrhythmics [
188
,
189
].
RSD1235 (Vernakalant, Fig.
7
) is a novel antiarrhythmic drug currently in
clinical trials for the acute conversion of atrial fibrillation [
190
]. It achieves action
potential interference through blockade of sodium and potassium currents, also
having only minimal effects on ventricular
repolarization at
therapeutic
concentrations [
191
,
192
].
AZD7009 is a mixed ion channel blocker, acting on potassium and sodium
currents, with electrophysiological effects predominantly on the atrial
tissue
(Fig.
7
)[
193
].
3.3.4 Neurodegenerative Diseases
VGSCs are probably involved in the neurodegeneration that occur in several
diseases, such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS),
Huntington, Parkinson, and Alzheimer disease.
Patients with MS often show both positive (pain and dysesthesia) and negative
(paresis, ataxia, and hypesthesia) symptoms [
194
,
195
]. Lidocaine and mexiletine
are able to block the positive symptoms of MS, blocking Na
+
channels in a voltage-
and frequency-dependent manner, thus acting selectively on fibers that mediate
positive symptoms (Figs.
4
and
5
)[
196
]. Moreover, several clinical trials regarding
neuroprotection using VGSC blockers are under way; in particular, riluzole,
topiramate, and lamotrigine are under investigation (Fig.
3
)[
197
-
199
].
The mechanism leading to selective degeneration of motor neurons in ALS are
far from being understood, but several hypotheses have been proposed, including
altered functionality of VGSCs [
200
]. Riluzole is the drug used to treat ALS and it
preferentially blocks TTX sensitive VGSCs, whose abnormal function is associated
with damaged neurons (Fig.
3
)[
201
,
202
]. It seems that riluzole also exhibits a
neuroprotective action in a model of Parkinson's disease in the rat [
203
]. This
pathology is a degenerative disorder of the central nervous system that often
impairs the sufferer's motor skills, speech, and other functions [
204
]. Other inter-
esting sodium channel blockers in clinical trials for the treatment of this disease are
remacemide and safinamide (Fig.
8
)[
205
-
207
]. Another progressive neurodegen-
erative disorder is Huntington's disease, characterized by loss of muscle coordina-
tion, cognitive decline, and dementia [
208
]. Remacemide seems to improve motor
function also in this pathology [
209
]. Finally, there are many evidences that
b
-
subunits of VGSCs are sequentially processed by
b
-site amyloid precursor protein-
cleaving enzyme (BACE1) and
-secretase, and these results may provide new
insights into the underlying pathology of Alzheimer disease [
210
].
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