Biomedical Engineering Reference
In-Depth Information
nonmalignant pain and remains a clinical challenge for treatment. Pharmacotherapy
is the mainstay for treating neuropathic pain. The numerous analgesic compounds
currently available are largely ineffective for chronic nerve pain and can control
many short-term aches and pains. Even the most potent painkillers available,
known as narcotics or opioids, cannot adequately treat some people's lasting
pain. Medications from several different drug classes are used to treat neuropathic
pain, including topical agents, tricyclic antidepressants, anticonvulsants, and
nonopioid analgesics. Anticonvulsant drugs for epilepsy sometime are used to
reduce the pain by decreasing the nerve cell excitability, but have serious side
effects such as lethargy, fatigue, clouding of mental state and weight gain [
85
-
87
].
The treatment of chronic and neuropathic pain remains an area of utmost
priority. NCC has long been recognized as suitable targets for pain management.
Strategies for direct inhibition of NCC by peptide toxins and small organic blockers
have been realized only recently. Moreover, potential ways to target specifically
and selectively the NCC are not fully exploited. One of the main reasons could be
due to the nonavailability of the experimental structure of NCC [
1
].
The most selective inhibitors of NCC known to date do not cross the blood-brain
barrier. So synthetically feasible small drug-like compounds, which can selectively
inhibit NCC was essential for the treatment of pain in different diseases. Further, to be
maximally useful in treatment, it is also helpful to assess the side reactions (adverse
drug action), which might occur. Thus, in addition of being able to modulate a
particular Ca
2+
channel, it is desirable that the compound has very low activity with
respect to the hERG K
+
channel inhibition. Compounds that block this channel with
high potency may cause cardiotoxicity, which are fatal [
63
]. Similarly, it would be
undesirable for the compound to inhibit Cytochrome P450 enzymes, since these
enzymes are required for drug detoxification. Finally, the compound will be evaluated
for Ca
2+
ion channel-type specificity by comparing its activity among various other
types of Ca
2+
channels, as described earlier, and specificity for one particular channel
type is preferred. The compounds which progress through these ADME/T tests
successfully are then examined in animal models as actual drug candidates [
88
,
89
].
7 Conclusions and Future Prospective
The voltage-dependent NCCs act as an important target in the pain pathway. Several
NCC blocking small-molecule compounds and their clinical as well as preclinical
efficacies have been tested and reported. Inhibitory activity of all currently remerging
small molecule NCC blockers is mostly within the submicromolar to micromolar
range, which are not comparable to those of peptide drugs. It still remains to be
determined whether the inhibitory activity of these organic blockers can lead to an
efficacious clinical potential similar to ziconotide, and how their unique selectivity/
specificity over other type of channel improves the ADME/T profile and efficacy
in human.
