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.