The pathway overwhelmed with failures:
Failure is a common pathway especially when it comes to drug
development. Even though we have understanding of these Kinins long back
like decades ago the drug development targeting these kinins possess a
humongous task and still challenging. Till this date we could
successfully develop and market only a single bradykinin antagonist
Icatibant.41All others were unable to produce clinical
benefit to be approved for marketing.
In case of tachykinins the story is little bit different although the
first one among the class Aprepitant has been approved in
2003.52 There are some congeners of it that are
marketed but still despite their varied and ubiquitous roles they don’t
show any clinical benefit in other conditions that are good enough to be
marketed. We tried to analyse the reasons behind the failures of these
drugs. The important reason being the complexity of the systems in
maintaining the bodily homeostasis and its interconnections with various
pathways accounts for its complexity. One of the well-established
inter-connections is with RAAS and this is thought to compensate for the
effect of Bradykinin Receptor blockers and lead to sub-optimal
therapeutic or clinical response. Some studies suggest that Synergistic
vasodilatory effect of AT and Bradykinin in Kininogen knockout rat
models.89 C5-9 induced vascular leakage is blocked by
B1R antagonist which again shows the interconnection between complement
system and Kinins.90 Similarly such issues are
alongside tachykinins also their diverse nature is also evident. There
are studies that show interconnections between both kinins itself, both
of them are in fact linked with release of Cys-LT in
asthma.91Tachykinins are also known to induce the
broncho constrictive effects of Captopril thereby shows its potentiating
effect via bradykinins.92 All these suggest these
peptides are more complex to comprehend than anticipated. This warrants
further research is needed to elucidate the exact mechanisms which might
fuel-up drug development in a more organized and successful pathway.