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\begin{document}

\title{Plasma Kinins- A Pharmacological Perspective}



\author[1]{Jefry Winner G}%
\author[1]{Anusha Natarajan}%
\affil[1]{JIPMER}%


\vspace{-1em}



  
  \date{May 23, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Abstract: Background: Plasma kinins are known for decades but the
understanding of them is not up-to the mark and the complexity is the
reason. There are many drugs and trials undertaken with these as drug
targets but only very few have been successfully marketed and used. Rest
all others have resulted in failure during various phases of the trial.
Purpose: The purpose of this review is to explain and explore the
complexity of plasma kinins and to explore the relations between Kinins
and to analyse the failures in drug development with these receptors as
targets. Implication: This extensive review might help in understanding
the complexity and ensure the reduction of drug development failures in
these molecules as drug targets Conclusion: kinins have important role
in homeostatic functions of the body physiologically. The
pathophysiological roles in inflammation are also known. The complexity
of these systems is well established.%
\end{abstract}%



\sloppy


\textbf{Plasma Kinins- A Pharmacological Perspective}

\textsuperscript{1}Dr. Jefry Winner G, Postgraduate student Department
of Pharmacology, JIPMER

Contact details: Jefrywinner0@gmail.com

\textsuperscript{2}Dr. Anusha N, Assistant Professor Department of
Pharmacology, JIPMER

\textbf{Data availability statement:} The data that supports the
findings of this study are available from corresponding author upon
reasonable request. Some data may not be made available because of
privacy or ethical restrictions

\textbf{Conflicts of interest:} The authors don't have any conflicts of
interest

\textbf{Background:}

Plasma kinins are known for decades but the understanding of them is not
up-to the mark and the complexity is the reason. There are many drugs
and trials undertaken with these as drug targets but only very few have
been successfully marketed and used. Rest all others have resulted in
failure during various phases of the trial.

\textbf{Purpose:}

The purpose of this review is to explain and explore the complexity of
plasma kinins and to explore the relations between Kinins and to analyse
the failures in drug development with these receptors as targets.

\textbf{Implication:}

This extensive review might help in understanding the complexity and
ensure the reduction of drug development failures in these molecules as
drug targets

\textbf{Conclusion:}

kinins have important role in homeostatic functions of the body
physiologically. The pathophysiological roles in inflammation are also
known. The complexity of these systems is well established.



\textbf{Introduction:}

Plasma that constitutes more than half of the circulating extracellular
volume is of utmost importance in sustaining life. But the fact to be
understood here is that even such a vital component has got ironical
characteristics of its own. These are undeniably true in case of
peptides in the blood which culminates both peptides and peptidases side
by side. This we mean for the kinins in plasma which are ubiquitous
throughout with kininases alongside. Even though their absolute roles
are yet to be established their definitive roles are brought to light by
the extensive research which is being done today. This has become an
area of interest in the recent years in the fields of physiology,
pharmacology, pathology and therapeutics. This review narrates about the
kinins commencing from their discovery to their physiological roles and
its implications in drug development, and tries to analyse the most
noted part which is the failures that overshadows the drug development
in case of kinins.

\textbf{History of Plasma kinins:}

Kinins in Greek means ``to move'' and their role is also such that it
moves or takes forward the process of inflammation. Bradykinin one of
the most important kinin and extensively studied has its roots
originating from 1948 from biological institute at Sao Paulo which was
discovered by a team of physiologists and pharmacologists led by Dr.
Mauricio Rocha e silva.\textsuperscript{1} This research later on
continued and led to the development of captopril initially referred as
``Bradykinin potentiating factor ``. The discovery of bradykinin has led
to a new understanding of many physiological and pathological phenomena
including circulatory shock induced by venoms and toxins.

The next in this group is referred as Tachykinins as the name suggests
and in contrary to Bradykinins, they cause rapid action and also
homologous to bradykinin it also helps to sustain inflammation. The
discovery of this substance came during the early
20\textsuperscript{th}century. In 1931, while investigating the tissue
distribution of the newly characterized transmitter acetylcholine, Von
Euler and Gaddum noted in acid ethanol extracts of equine intestine a
hypotensive and spasmogenic activity that differed from acetylcholine in
that it contracted the rabbit jejunum in the presence of atropine. The
activity of this preparation, first referred to as P on kymograph
tracings, was distinct from the biologically active principles known at
that time. The active component was soon termed substance P (P for
preparation), and early experiments suggested that SP was peptide or
protein in nature.\textsuperscript{2} Tachykinins include 10-12 amino
acid containing peptides that include Neurokinin k, Neurokinin A,
substance P and Neuropeptide gamma. So, these kinins have an important
role in various physiological processes and thereby they could be
manipulated to produce various pharmacological effects.

\textbf{Physiology of Bradykinin:}

The synthesis of bradykinin takes place in plasma and tissues by
proteolytic cleavage of HMWK (High Molecular Weight Kininogen) and LMWK
(Low Molecular Weight Kininogen) respectively. The synthesis of Kinins
is triggered by various factors one of them includes endothelial injury
which is hence the name contact system which is accompanied by Factor
XII to XI. Factor XIIa converts pre-kallikrein into plasma kallikrein,
and they autoactivate through a positive feedback loop. Plasma
kallikrein cleaves high-molecular-weight kininogen (HMWK) into
bradykinin.\textsuperscript{3} Bradykinin then binds to B2-receptors,
inducing vasodilation and increased endothelial permeability, leading to
the characteristic swelling of an angioedema
attack.\textsuperscript{4}Their actions are mainly mediated through B1
and B2 receptors. Bradykinin receptors are cell surface, G-protein
coupled receptors of the seven-transmembrane domain family. The
existence of two subtypes of bradykinin receptor, B1 and B2, has been
confirmed through the use of high affinity peptide and nonpeptide
receptor antagonists, radioligand binding studies and, recently,
receptor cloning and expression studies.\textsuperscript{5} \textbf{For
synthesis and functional roles of bradykinin refer Figure 1 Appendix 1}

In vitro studies show stimulation of endogenous B1R promotes cell
growth, migration, and invasion.\textsuperscript{6} A study found that,
when B2 is inhibited or absent, receptor B1 is upregulated and might
develop some B2 hemodynamic properties, which indicates that they both
play a role in the maintenance of normal Vaso regulation or the
development of hypertension.\textsuperscript{7} The vascular effects of
B1 receptor activation may be a result of the release of endothelial NO,
prostaglandins, and possibly endothelium-derived hyperpolarizing
factors.\textsuperscript{8,9}

B\textsubscript{2}~bradykinin receptors are present in neurons of the
brain stem, basal nuclei, cerebral cortex, thalamus and hypothalamus.
B\textsubscript{2}~immunolabelling was also observed in the endothelial
lining of the superior sagittal Dural sinus and ependyma of the lateral
and third ventricles. B\textsubscript{1}~kinin receptors have been
localised on neurones of the thalamus, spinal cord and
hypothalamus.\textsuperscript{10} In studies that investigated the role
in FGF-2 pathway in the BK-mediated human endothelial cell permeability
and migration, and the role of the B2 receptor (B2R) of BK in this
cross-talk. Is established. B2R blockade by the selective antagonist,
fasitibant, significantly inhibited FGF-2/FGFR-1 signalling, and in
turn, BK-mediated endothelial cell permeability and
migration.\textsuperscript{11} The B\textsubscript{2}~receptor is
believed to play an important role in the beneficial effects of
angiotensin- 1 converting enzyme inhibitors used in the treatment of
cardiovascular diseases, yet it is involved in the acute phase of
inflammation and of somatic and visceral pain. An additional role was
introduced for B\textsubscript{2}~BK receptor demonstrating its
proliferative effects.\textsuperscript{10} Some studies also show that
bradykinin can also induce anti-mitogenic effects in proliferating cells
using an alternative signal transduction pathway involving a protein
tyrosine phosphatase.\textsuperscript{12} Thus the role of bradykinin as
a homeostatic plasma kinin is undeniable as suggested by the available
literature.

\textbf{Physiology of tachykinins:}

The tachykinins are a group of plasma kinins that play a major role in
inflammation and neurotransmission hence most of them are referred to as
neuropeptides.\textsuperscript{13,14,15,16} The two human tachykinin
genes are called~TAC1~and~TAC3.\textsuperscript{17}

The major source of tachykinins is in the gut are enteric neurons,
followed by nerve fibres from dorsal root and vagal ganglia.
Tachykinin-containing fibres surround enteric ganglia, ramify through
muscle, form a perivascular mesh around submucosal arteries, and supply
the mucosa. This explains the fact of isolation of substance P from
Gut.\textsuperscript{2} The important roles of tachykinins include
Neuro-neuronal transmission, Protective secretory responses to
infection.\textsuperscript{18,19,20,21,22} Tachykinins also participate
in the inflammatory responses to infection, including formation of
granulomas, sites of chronic inflammation that prevent spread of
infectious agents.\textsuperscript{23} Tachykinins stimulate smooth
muscle contraction of the human ureter, mostly by activating the
NK\textsubscript{2}R.\textsuperscript{24} \emph{Tac1} ,~\emph{Tac3} ,
and~\emph{Tac4} ~are expressed by human sperm, and tachykinins increase
sperm motility by NK\textsubscript{1}R- and
NK\textsubscript{2}R-dependent mechanisms.\textsuperscript{25} Mouse and
human keratinocytes express NK\textsubscript{1}R and
NK\textsubscript{2}R. The consensus of multiple studies is that SP and
NKA control the capacity of keratinocytes to serve as cytokine factories
by regulating production of proinflammatory
cytokines.\textsuperscript{26} Thus tachykinins are involved in a vast
array of physiological functions that makes them a potential target for
drug development.

\textbf{For synthesis of Tachykinins refer figure 2 Appendix 2}

\textbf{The Role of plasma kinins in Diseases}

\textbf{Bradykinins:}

The role of bradykinin in various disease states is undisputable.
Studies in a mouse strain with targeted disruption of the
BK\textsubscript{2}~receptor gene have given important new insights into
the role of the kallikrein/kinin system in the pathogenesis of
hypertension and heart failure.\textsuperscript{27} Neuropathic pain is
a leading debilitating morbidity resulting from Spinal Cord Injury, and
it remains an unmet medical demand. In a rat model of contusion SCI,
more than twofold increase was observed for the expression of B1BKR and
vanilloid-1 (TRPV-1) receptor genes in the injured segment dorsal horn
region of the spinal cord in rats manifesting hyperalgesia behaviour
compared with SCI rats that did not show
hyperalgesia.\textsuperscript{28} Bradykinin may be a competitive
substrate of DPP-4, and decreased bradykinin levels may enhance
protective effects against ischemia/reperfusion injury during
Leukotrienes.\textsuperscript{29} There is a well-established role of
Bradykinin in Hereditary angioedema and some forms of acquired
angioedema which are especially due to increased bradykinin
levels.\textsuperscript{30} \textbf{For pathophysiology of hereditary
angioneurotic oedema refer figure 3 appendix 2}

\textbf{Tachykinins:}

Many types of tumour cells express NKRs, and tachykinins from tumour
cells or infiltrating nerves or immune cells can influence
proliferation, apoptosis, and metastasis of tumour cells in an
autocrine, paracrine, or neurocrine manner.\textsuperscript{31,32, 33}In
case of pulmonary diseases that affect the lungs by inducing
inflammation substance P has a substantial role as elucidated by various
animal studies.\textsuperscript{34} SP stimulates the generation and
release of cytokines, chemokines, matrix metalloproteases, and ROS from
neutrophils thus playing a major role in
inflammation.\textsuperscript{35,36} Tachykinins also stimulate
secretion from airway seromucous glands thus plays an important role in
airway inflammation.\textsuperscript{37} The role of tachykinins in Post
operative nausea and vomiting is undisputable and the respective
antagonists are highly effective in treatment and prevention of this
aspect.\textsuperscript{38}

\textbf{Pharmacological implications of Bradykinins:}

With such important roles in various physiological and pathological
processes the role of Bradykinins and their receptors as drug targets is
quite justifiable. The signalling of bradykinin receptors is mediated by
kinins. Following ligand-binding, B1R and B2R signal through associated
G proteins to activate signalling molecules like protein kinase C and
phospholipases, and secondary messengers like inositol-1,4,5,
-triphosphate, diacylglycerol, calcium, and arachidonic acid. These
secondary messengers go on to modulate other signalling processes (e.g.,
nitric oxide or prostaglandin production).\textsuperscript{39} Following
the discovery of bradykinin by Roche et al there are various research
that has been undertaken to exploit its role in drug development. The
invitro synthesis of BK peptide was introduced by solid phase
preparation strategy by Merrifield.\textsuperscript{40} Since then, many
kinin derivatives have been synthesized and investigated. These
sequences include modifications (e.g., amino acid substitutions,
reduction of amide bonds, N-terminal capping) that are aimed at
conferring selectivity, stability to peptidases, agonist/antagonist
properties and prolonging in vivo pharmacological
effects.\textsuperscript{41} Icatibant, a B2R antagonist, is the only
kinin to receive U.S. Food and Drugs Administration approval. It is
indicated for the treatment of acute attacks of hereditary angioedema in
adults with C1-esterase inhibitor
deficiency.\textsuperscript{42}Anatibant and fasitibant, B2R
antagonists, advanced into clinical testing for treatment of traumatic
brain injury and knee osteoarthritis, respectively. However, their
development was discontinued due to the lack of
efficacy.\textsuperscript{43,44} The hope is that new scaffolds will be
able to find clinical utility in other disease setting

Table 1\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
Drug & Target & Clinical phase & indications & comments &
Reference\tabularnewline
\midrule
\endhead
HOE-140 (Icatibant) & B2R antagonist & Approved & Hereditary angioedema
& Shortened the duration of acute attacks & {[}41{]}\tabularnewline
& & Phases I-IV & Cardiopulmonary bypass, inflammation, fibrinolysis,
surgery, ischaemic heart diseases, ischaemic reperfusion, heart failure,
ACE inhibitor associated angioedema, angioneurotic edema & Many
completed and ongoing studies. Decreased intraoperative fibrinolytic
capacity in cardiopulmonary bypass. No efficacy demonstrated for
angioedema and ischemia-reperfusion injury & {[}45-47{]}\tabularnewline
& & Phase II & Mitochondria and chronic kidney disease & Completed, no
evidence of efficacy & NCT03177798\tabularnewline
& & Phase II & Knee pain in osteoarthritis & Completed, results not
available & NCT00303056\tabularnewline
MEN16132 (Fasitibant) & B2R antagonist & Phase II & Knee pain in
osteoarthritis & Two studies completed. No direct evidence of efficacy,
treated patients used less rescue medication. & NCT01091116
NCT02205814\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
CP-0127 (Deltibant)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
B2R antagonist\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Phase II\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Severe traumatic brain injury sepsis\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Ineffective for sepsis. Discontinued due to unexpected preclinical
findings.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
{[}48{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
LF16-0687 (Anatibant)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
B2R antagonist\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Phase II\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Severe traumatic brain injury\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Inconclusive results and possible safety issues. Trial halted.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
{[}43{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
RMP-7 (Lobradimil)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
B2R agonist\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Phase II\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Childhood brain tumors\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Completed. No improved efficacy\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
{[}49{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Phase I\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
HIV infection and cryptococcal meningitis\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Completed, results not available\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
NCT00002316\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
FOV-2304 (Safotibant)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
B1R antagonist\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Phase II\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Diabetic macular edema\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Discontinued, results not available.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
{[}50,51{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
MK-0686\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
B1R antagonist\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Phase II\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Postherpetic neuralgia, postoperative dental pain, osteoarthritis
Terminated for postherpetic neuralgia, completed for dental pain and
osteoarthritis.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
No results disclosed\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
{[}50{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
BI-113823\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
B1R antagonist\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Phase I\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Osteoarthritis\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Terminated\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
NCT01207973\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
SSR-240612\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
B1R antagonist\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Phase II\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Inflammation and neuropathic pain\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Halted for undisclosed reasons.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
{[}52{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
B9870 (Breceptin) Phase I\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Dual B1R and B2R antagonist\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Phase I\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Small cell lung cancer\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
No information available.\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
{[}50{]}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

ACE- Angiotensin Converting Enzyme; B1R- Bradykinin Receptor; B2R-
Bradykinin receptor;

NCT- National clinical Trial

\textbf{Pharmacological implications of tachykinins:}

Tachykinins have got some important implications as pharmacological
agents since the approval of their first agent Aprepitant by FDA in 2003
which is now widely used CINV.\textsuperscript{53}

Various other congeners of Aprepitant were also approved subsequently.
Casopitant, Netupitant and Rolapitant were approved later
on.\textsuperscript{54, 55, 56}Apart from vomiting Aprepitant was also
tried as an agent for Depression.\textsuperscript{57} This compound has
also shown antiproliferative properties in tumoral cell lines of glioma,
neuroblastoma, retinoblastoma, pancreas, larynx, colon, and gastric
carcinoma.\textsuperscript{58, 59, 60, 61}Experimental studies in the
rabbit colon suggest that NK2 receptors antagonist MEN 11420
(Nepadutant) may also dose-dependently modulate colonic
transit.\textsuperscript{62}The selective inhibition of peripheral NK3
receptors by SB-235375 (Talnetant) reduced the nociceptive response to
colorectal distension in the rat model.\textsuperscript{63, 64}According
to these studies, specific NK3 receptor antagonists exhibit potential as
analgesic agents for visceral pain in IBS patients. Recombinant NEP and
NK1 receptor antagonist SR140333 prevented the exacerbated inflammation
in NEP knockout mice.\textsuperscript{65, 66, 67} Selective tachykinin
receptors antagonists tested on guinea pigs have been shown to inhibit
the late allergic and airway hyperresponsiveness and reduce eosinophilic
infiltration and vascular
permeability.\textsuperscript{68,69,70}~However, all these studies were
at a very preliminary stage and little of therapeutic benefit could be
inferred for humans. Some of the important clinical indications for
which tachykinin antagonists are tried are listed in the table

Table 2\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
Drug molecule\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
TK receptors\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
Clinical condition\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Aprepitant\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NK1\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
CINV PONV HIV Hot flashes Alcohol craving/PTSD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Fosaprepitant\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NK1\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
CINV PONV\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Casopitant\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NK1\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
CINV PONV Primary insomnia Fibromyalgia Overactive bladder\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Rolapitant\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
NK1\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
PONV\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Orvepitant\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
NK1\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
MDD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
LY-686017\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NK1\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
SAD Alcohol craving\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Vofopitant\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NK1\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Social phobia Primary insomnia PTSD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Vestipitant\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NK1\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
SAD Primary insomnia Tinnitus/hearing loss\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
AZD-2624\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
NK1\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Schizophrenia\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
SSR-240600\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NK1\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Overactive bladder/urge urinary incontinence\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TA-5538\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
NK1\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Overactive bladder\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Saredutant\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NK2\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
MDD GAD Asthma\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Nepadutant\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NK2\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
IBS Asthma POI\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Ibodutant\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
NK2\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
IBS\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
DNK-333\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NK1/NK2\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Asthma IBS\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
AVE-5883\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
NK1/NK2\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Asthma\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
CS-003\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
NK1/NK2/NK3\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Asthma\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Osanetant\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NK3\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Schizophrenia Panic disorder Depression\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Talnetant\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NK3\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Schizophrenia IBS\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
SSR-241586\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
NK2/NK3\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Schizophrenia\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Red ones are the drugs that are discontinued during trials and not
discussed

Table 2

Among the drugs mentioned in the table only aprepitant and fosaprepitant
could be marketed. Many others have been discontinued in the
developmental stage itself. Some trials are ongoing like Aprepitant for
Advanced small cell carcinoma(NCT04840004). Aprepitant was also tried
for Alcohol craving and PTSD(NCT00896038) which was completed but trial
results were not available. Interestingly aprepitant was also tried for
HIV infection which failed to show viral load
reduction.\textsuperscript{71} DNK-333 which was tried for IBS in two
trials {[}(NCT00699166) and (NCT00394173){]} produced significant
subjective relief of symptoms in IBS but not with stool consistency
which was the primary endpoint of the trial. Vestipitant was another
agent tried for Tinnitus but showed no clinically significant
results.\textsuperscript{72}Vofopitant was another drug tried for PTSD
but showed efficacy not better than
placebo.\textsuperscript{73}Ibodutant another drug which was evaluated
for IBS showed better efficacy when compared to placebo in symptomatic
improvement when compared to placebo.\textsuperscript{74}TA-5538 was
tried for overactive bladder in a trial in Japan and was discontinued
for undisclosed reasons. SSR 240600 was tried in a trial called BILADY
for which results were not published (NCT00564226). LY-686017 which was
tried for social anxiety disorder showed no significant difference in
Leibowitz social anxiety scale (LSAS) when compared to placebo
(NCT00191002).\textsuperscript{75} Orvepitant was tried for MDD but the
trial was terminated since seizures occurred in patients during the
trial period (NCT00880399). Rolapitant was studied for its effects in
PONV but the results of the trial were not published (NCT00539721).
Casopitant was another drug which was tried for a number of conditions,
its efficacy for overactive bladder was evaluated but terminated due to
undisclosed reasons (NCT00332319). The same drug was tried for
fibromyalgia and this trial was completed but results were not published
(NCT00264628). Similar is the case with primary insomnia
{[}(NCT00280423), (NCT00280436), (NCT00354809){]}. For CINV the
manufacturers approached European medicines agency for marketing
authorisation application but withdrawn in September 2009 by the
manufacturers\textsuperscript{76} So again as like bradykinins the
modalities to target tachykinins were also not so straightforward other
than cases of PONV and CINV Even though research continues in this field
and successful drug development for other indications might become
feasible.

\textbf{Aprepitant Anticipation:}

This was the first drug to be approved as a Tachykinin
antagonist.\textsuperscript{52}Since then this has been tried in
numerous clinical trials for numerous indications. There are various
trials that have tried the role of aprepitant as an antiemetic drug for
the treatment of highly emetogenic conditions like following cancer
chemotherapy and some following surgical procedures for PONV. The trial
done with aprepitant in HIV infected individuals showed no viral load
reduction despite reduction in biological activity.\textsuperscript{71}A
few trials were successful but for many trials the information was not
available and some were terminated. Aprepitant was tried in germ cell
tumours and was found to have a complete remission rate as compared to
placebo (NCT00572572). Another study that involved aprepitant in its
well-known indication for CINV following cisplatin chemotherapy
(NCT00619359). Again, trials involving Aprepitant in PONV and with other
drugs like granisetron, dexamethasone, prochlorperazine and palonosetron
(NCT00475085 and NCT00819039) showed it to be an effective drug for
antiemesis, but still its effect in other indications is still in the
line and yet to be established this might become feasible in the near
future if research continues to flourish.

Table 3\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
S.No\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Trial no\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Title\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Phase\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00428519\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Effects of treatment with aprepitant (Emend\_) in HIV-infected
individuals\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
I\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00835965\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Oral aprepitant and lower dose dexamethasone versus aprepitant alone for
preventing postoperative nausea and vomiting (PONV) after elective
laparoscopic surgeries\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IV\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00738621\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Combination antiemetic regimen for prevention of PONV in breast
surgery\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IV\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00717054\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Comparison of oral aprepitant alone versus oral aprepitant and
transdermal scopolamine for preventing postoperative nausea and
vomiting\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
III\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00572572\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aprepitant + 5HT3 + dexamethasone in patients with germ cell tumours
(there is significant increase in CR rate)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IV\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00659737\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
A randomized, double-blind comparison of oral aprepitant alone versus
oral aprepitant and transdermal scopolamine for preventing postoperative
nausea and vomiting\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
II\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00869310\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aprepitant in the prevention of cisplatin-induced delayed emesis\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IV\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00651755\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aprepitant effect on drug metabolism in multi-day combination
(CHOP/R-CHOP) chemotherapy regimen in lymphoma patients\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
IV\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00659945\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Effectiveness of aprepitant in the treatment of postoperative nausea and
vomiting (PONV) in patients undergoing outpatient plastic surgery\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
III\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
10\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT01534637\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aprepitant in preventing nausea and vomiting in patients undergoing
chemotherapy and radiation therapy for pancreatic cancer\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
III\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00415103\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aprepitant plus palonosetron versus granisetron in the prevention of
nausea and the emesis induced by chemotherapy in patients treated with
hematopoietic progenitors\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
II\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00734929\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aprepitant with dexamethasone versus ondansetron with dexamethasone for
postoperative nausea and vomiting (PONV) prophylaxis in patients having
craniotomy\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
II\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
13\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00869973\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aprepitant in the prevention of delayed emesis induced by
cyclophosphamide plus anthracyclines in breast cancer Condition: nausea,
vomiting\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
II\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
14\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00619359\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Emesis Prevention of chemotherapy-induced nausea and vomiting (CINV)
associated with cisplatin chemotherapy noninferior\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
II\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00719173\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Effect of aprepitant on cyclophosphamide pharmacokinetics in patients
with breast cancer\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
II\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00736073\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
A trial of aprepitant for prevention of post-endoscopic retrograde
cholangiopancreatography (ERCP) pancreatitis\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
II\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00631930\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Palonosetron, aprepitant, and low-dose dexamethasone in preventing
nausea and vomiting in patients undergoing high-dose chemotherapy and
stem cell transplant for multiple myeloma or lymphoma\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
II\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
18\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00895245\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Fosaprepitant dimeglumine, palonosetron hydrochloride, and dexamethasone
in preventing nausea and vomiting caused by cisplatin in patients with
stage III or stage IV head and neck cancer undergoing chemotherapy and
radiation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
II\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
19\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00293384\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Aprepitant, granisetron, and dexamethasone in preventing nausea and
vomiting in patients receiving cyclophosphamide before a stem cell
transplant\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
II\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
20\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
NCT00314743\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Oral neurokinin-1 antagonist, aprepitant, in combination with
ondansetron and dexamethasone in patients undergoing autologous
peripheral blood stem cell transplantation\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
IV\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
21\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
NCT00588835\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Pharmacokinetic study on the addition of aprepitant to
cisplatin--etoposide treatment in lung cancer patients\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
III\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00571168\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Efficacy and safety of aprepitant in subjects with multiple myeloma
during and after high-dose chemotherapy\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
III\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
23\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00475085\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Granisetron, dexamethasone, prochlorperazine, aprepitant, and
palonosetron in preventing nausea in women undergoing chemotherapy for
breast cancer\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
III\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
24\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
NCT00888329\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Aprepitant for prevention of postoperative nausea and vomiting in
elective hysterectomy Condition: postoperative nausea and vomiting\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
I\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
25\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NCT00819039\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
A study of aprepitant (MK0869) in paediatric patients undergoing surgery
condition: postoperative nausea and vomiting\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
I\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
26\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
NCT00818259\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Recruiting a study of aprepitant (MK0869) and fosaprepitant (MK0517) in
paediatric patients receiving chemotherapy Condition:
chemotherapy-induced nausea and vomiting\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
II\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
27\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
NCT00896038\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
The effect of NK1R antagonism on alcohol craving and PTSD symptoms in
alcohol dependent patients with PTSD Conditions: alcoholism; alcohol
dependence; post-traumatic stress disorder; FMRI\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
II\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Terminated Trials Completed trials

\textbf{Saredutant for depression and anxiety}

This is a tachykinin antagonist with a higher selectivity for NK2
receptor which was assumed to be effective from the preclinical
data.\textsuperscript{80} The results of a double-blind, randomized,
placebo- and fluoxetine-controlled multicentre Phase IIb clinical trial
performed with saredutant in patients which showed a good sustained
response in the treatment group compared to
placebo.\textsuperscript{81}The favourable safety and tolerability
profile of saredutant was also confirmed in the elderly (INDIGO study)
as well as in long-term treatment (MAGENTA
study).\textsuperscript{83,84} But still the drug was not found to
affect the outcome significantly as compared to existing standard of
care and placebo. This was also tried for GAD but the results were
inconclusive and the drug was yet to show its impact to be used
clinically.

\textbf{NK3 receptor Antagonists}

These are found exclusively in brain and spinal cord but their location
is quite restricted and this also possess challenges in development of
NK3 antagonists which are limited
comparitivley.\textsuperscript{85,86}Osanetant was the first non-peptide
NK3 antagonist described; it was derived from the known NK2 antagonist
saredutant. Osanetant was compared

with three other potential antipsychotics such as the 5-HT2a/5-HT2c
receptor antagonist SR-46349B, the cannabinoid CB1 receptor antagonist
rimonabant and the neurotensin receptor antagonist SR-48692, as well as
with the classical antipsychotic haloperidol and with placebo. There was
no significant difference between the efficacy of Osanetant and
haloperidol in that study.\textsuperscript{87} Talnetant in a
placebo-controlled trial showed a reduction in clinical symptoms not
better than risperidone however the study showed a good tolerability as
compared to risperidone. \textsuperscript{88} But this drug has been
abandoned by the researchers for undisclosed reasons. With all these
inconclusive and a bit contradictory evidences long-term trials of
further improved NK3 antagonists may confirm the positive results
obtained so far with regard to efficacy and tolerability.

\textbf{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.\textsuperscript{41}All 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.\textsuperscript{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.\textsuperscript{89} C5-9 induced vascular leakage is blocked by
B1R antagonist which again shows the interconnection between complement
system and Kinins.\textsuperscript{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.\textsuperscript{91}Tachykinins are also known to induce the
broncho constrictive effects of Captopril thereby shows its potentiating
effect via bradykinins.\textsuperscript{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.

\textbf{Conclusion}

With this comprehensive review it is evident these kinins have important
role in homeostatic functions of the body physiologically. Again, the
pathophysiological roles in inflammation and most important being
sustainability of inflammation rather than inciting itself is evident.
These makes them a potential target for drug development and the drugs
developed were extensively discussed and the failures with respective
clinical trials. The complexity of these systems and interconnections
are evident and sounds like we are still ``scratching the surface'' of a
complicated puzzle. The time to explore the complexity and fit the
puzzle would be in the near future with advancements in the field of
research day by day. Still, this seems to be an evolving science and an
area to be explored to pave a way for upcoming drug discoveries.

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