troxip monograph
DESCRIPTION
An up to date compilation of the various characteristic features of TroxipideTRANSCRIPT
TROXIP
Troxipide: From Bench to Bed-side
Product Monograph
ii
PREFACE
In case of patients with gastrointestinal disorders like gastritis and peptic ulcers, “symptom
resolution” assumes great importance. Many pharmacotherapeutic arsenals have been used
to assist these patients including the antacids, histamine-2-receptor antagonists and the
proton-pump inhibitors. Although their efficacy is well established, there are several reasons
to examine the available knowledge about these disease conditions and drugs.
There has been considerable progress made in our understanding of the pathogenesis of
gastrointestinal diseases, and it has now been identified that the “gastric defensive factors”
play a much more significant role in these diseases. Thus, there is a need for drugs that
normalize the gastric mucosal constitution and other defensive mediators including
Cytoprotective prostaglandins, and the gastric microcirculation. Thus, a natural
pharmacological step forward would be the development of certain mucoprotective (or
Cytoprotective) molecules on the lines of sucralfate and colloidal bismuth.
One such molecule is Troxipide, an anti-ulcerative agent, with a very unique mechanism of
action involving collagen fibers, mucopolysaccharides, glucosamine, oxygen free radicals
and interleukin-8 to name a few. Troxipide has been found to be a safe and efficacious
agent; the indications till date are encouraging with respect to the clinical responses,
thereby ensuring its place among the currently available conventional therapeutics. From
the Indian market perspective, it is a first of its kind molecule to be launched.
This monograph, dedicated to Troxipide, presents an up to date compilation of the various
characteristic features that make it novel and the scientific data that compares it to other
therapies in the control and management of gastrointestinal disorders, thereby supporting
the use of Troxipide as an effective alternative in Acid Peptic Diseases.
Dr. Bhupesh Dewan, M.D.
Director Medical Services
Zuventus Healthcare Ltd.
iii
TABLE OF CONTENTS
PREFACE ......................................................................................................................................... ii
ACID-PEPTIC DISORDERS ........................................................................................................... 1
Introduction ................................................................................................................................ 1
Gastric Mucosal Defense & Major Pathogenic Factors ............................................................. 1
Conventional approach to Acid-peptic disorder therapy: Acid Suppression ........................... 2
Limitations of Acid suppressive agents ................................................................................ 2
Ulcer healing by Strengthening of Mucosal Defense: An alternate approach to therapy ....... 3
In Perspective: TROXIP ......................................................................................................... 3
TROXIP: A NOVEL CYTOPROTECTIVE AGENT ......................................................................... 5
Characteristic Pharmacological Features of TROXIP: An Insight into its MOA ..................... 5
Fortification of Gastric Mucosal Constitution ..................................................................... 5
Stimulation of Mucosal Cytoprotective Prostaglandins ..................................................... 6
Suppression of Gastric Mucosal Inflammation ................................................................... 6
Effects of Acid on Activities of Troxipide .............................................................................. 7
Troxipide and Mucosal Metabolism ..................................................................................... 7
Troxipide: Role in Mucosal Microcirculation ...................................................................... 7
Anti- Helicobacter pylori Action ...........................................................................................8
Experimental Acid Peptic Disease Models: Effect of Troxipide ...............................................8
Acute Gastric Mucosal Lesions (AGML) ...............................................................................8
Gastric Ulcers .........................................................................................................................8
Comparison with other Pharmacotherapeutics .................................................................. 9
CLINICAL EXPERIENCES WITH TROXIPIDE .......................................................................... 10
Pharmacokinetic Data ............................................................................................................... 10
Healthy Human Volunteers ................................................................................................ 10
Efficacy Data ...............................................................................................................................11
Patients with Gastric Ulcer ..................................................................................................11
Patients with Duodenal Ulcer ............................................................................................. 12
Patients with Gastritis and gastric mucosal lesions ......................................................... 12
Comparison with Acid-Suppressive agents ............................................................................. 12
Resolution of Clinical Signs of Gastritis ............................................................................. 13
Resolution of Endoscopic Evidences ................................................................................... 13
Safety and Tolerability Data ..................................................................................................... 14
Safety of Troxipide ............................................................................................................... 14
Tolerability of Troxipide ...................................................................................................... 14
CONCLUSION ............................................................................................................................... 16
APPENDICES................................................................................................................................. 17
APPENDIX I: PRESCRIBING INFORMATION OF TROXIP ................................................ 17
APPENDIX II: REFERENCES ................................................................................................. 19
1
ACID-PEPTIC DISORDERS
Introduction
Acid peptic disorders, including gastric ulcers, duodenal ulcers, and gastroesophageal reflux
disease, are commonly occurring conditions with high direct and indirect costs. The
pathogenesis of these disorders involves an imbalance between acid secretion and gastric
mucosal defenses. Pharmacologic treatment of acid peptic disorders has focused on correcting
this imbalance by either improving mucosal defenses with drugs such as sucralfate, bismuth,
and prostaglandin analogs, neutralizing acid with antacids, or decreasing acid secretion with
histamine-2-receptor antagonists, or, more recently, proton pump inhibitors. [1]
Gastric Mucosal Defense & Major Pathogenic Factors
With the advent of the Schwarz dictum "no acid, no ulcer" in the early 1900s, particularly
strong attention has been given to the role of gastric acid in the pathogenesis of APD.
Dysregulation of acid secretion as observed in APD affects the entire profile of acid secretion
such as basal acid output, maximum acid output, sensitivity of the parietal cells to exogenous
and endogenous stimuli, nocturnal and food-stimulated acid secretion and a disturbed
feedback of antral acidity on gastrin release and gastric acid secretion. [2,3,4]
Disturbed gastrointestinal motility, especially accelerated emptying of gastric contents
in duodenal ulcer patients & delayed gastric emptying in gastric ulcer patients, have also been
associated with APDs. The disturbance may be related to a defective feedback from gastric or
duodenal mucosa. [2,3,4]
The notion that APDs can only develop when mucosal defense is defective is crucial for the
understanding of the pathogenic mechanisms in these disorders. The mechanisms underlying
mucosal protection are multi-factorial (as seen in Fig.1) and include pre-epithelial (mucus
bicarbonate- phospholipid “barrier”) and epithelial factors (surface epithelial cells
connected by tight junctions and generating bicarbonate, mucus, phospholipids, trefoil
peptides, prostaglandins (PGs), and heat shock proteins), continuous cell renewal
accomplished by proliferation of progenitor cells (regulated by growth factors and PGE2),
continuous blood flow through mucosal microvessels, an endothelial “barrier”, sensory
innervations, and generation of PGs and nitric oxide. [2,3,4]
The above described factors contribute with varying degree to the development of APDs.
Many additional factors such as genetic predisposition, psychological stress and
alcohol intake, play a significant role in addition to the triad of acid, Helicobacter pylori
infection and NSAID medication.
2
Figure 1: Diagrammatic representation of gastric mucosal defense [3]
Conventional approach to Acid-peptic disorder therapy: Acid Suppression
The therapeutic goals in the therapy of APDs should be the elimination of symptoms, ulcer
healing, prevention of ulcer recurrence and complications. Conventional therapeutic approach
for APDs focuses on the inhibition of acid section, the main pillar of the triad. This can be
achieved by antacids, specific antagonists of muscarinic –M1 receptors, gastrin receptors,
histamine-H2 receptors, proton pump inhibitors (PPIs), eradication of H. pylori, and agonists
of prostaglandins/somatostatin receptors. [4]
Limitations of Acid suppressive agents
Associated effects of antacids like constipation or diarrhea limit their patient compliance
and are today mainly used for fast symptomatic relief. Muscarinic antagonists like
pirenzepine inhibit gastric acid secretion as well as decrease gastric motility, but clinical use of
these drugs is now limited because of availability of more effective anti-secretory medications.
[4,5]
3
A new era in the treatment of acid-peptic disorders dawned with the launch of H2-receptor
antagonist, cimetidine, in 1976. These agents completely inhibit the interaction of histamine
3 with H2 receptors, thereby reducing both volume and H+ ion concentration of the gastric
juice. They also inhibit acid secretion elicited by gastrin, muscarinic agonists, food, sham
feeding, fundic distension, as well as other pharmacological agents. They also inhibit basal
and nocturnal acid secretion. This class of drugs, however, has a short duration of action. [4,5]
Peptic ulcers caused by H. pylori can be treated by combination of antibiotics and anti-
secretory medications. However, complex drug regimen and associated side effects may
limit usefulness. [4,5]
Launch of omeprazole in 1988 introduced a conceptually new approach of inhibition of proton
pump in the management of acid-related disorders. The proton pump inhibitors (PPIs)
bind to the gastric proton pump on the parietal cell membrane, irreversibly inhibiting the
release of hydrogen ions from the parietal cells into the lumen of the gastric glands and hence
stomach. Acid secretion is therefore blocked at the final step of its production independent of
the different kind of its stimulation. PPIs proved to be superior to any of the previously used
drugs including H2-antagonists. [4,5]
Today, almost two decades after introduction of the first PPI, the apparent drawbacks of
irreversible proton pump inhibitors, mainly because of their extended periods of
hypergastrinemia which is associated with the formation of precancerous changes in human
gastric mucosa, are becoming a cause of concern. [4,5] PPIs may fail to provide 24-hour
suppression of gastric acid, and nocturnal acid breakthrough, defined as a drop of intragastric
pH under 4 for more than one hour, can occur even with twice-daily dosing. Moreover,
despite high compliance with prescribed PPI regimens, 46% of daily PPI users experienced
breakthrough symptoms, which occurrs on 28% of treatment days. [28,29]
Ulcer healing by Strengthening of Mucosal Defense: An alternate approach to
therapy
While reducing acid secretion has been the main stay in the therapeutic approach to healing
of APDs, it is aimed at only one side of the disease equation, namely the aggressive factors.
Ulcer healing is a very complex process, requiring the interaction of different tissue and
cellular systems. It involves filling the mucosal defects with proliferating and migrating
epithelial cells, reconstructing the glandular structures, and reepithelializing the mucosal
surface with connective components (cells, microvessels and extracellular matrix). Clinical
and experimental data indicate that healing of gastroduodenal ulcers can be successfully
accomplished without the inhibition of acid secretion by topically active agents such as
prostaglandins, low dose aluminium containing antacids, sucralfate and colloidal bismuth.
In Perspective: TROXIP
TROXIP contains Troxipide, a novel gastric Cytoprotective agent, with antiulcer, anti-
inflammatory and mucus secreting properties. The chemical formula of Troxipide is 3,4,5-
4
trimethoxy-N-(3-piperidyl) benzamide as seen in figure 2. Its molecular formula is
C15H22N2O4 and its molecular weight is 294.4.
Figure 2: Chemical Structure of Troxipide
Troxipide has been used for the treatment of acid peptic disorders in Japan and China since
mid-1900s. Although it has no effect on gastric acid secretion, Troxipide enhances mucosal
defense and mucosal repair. Its anti-ulcerous activities are not related with the content and
pH of the gastric juice. It is known to heal acid peptic disorders by fortifying the gastric
mucosal constitution, stimulating Cytoprotective prostaglandins, suppressing the gastric
inflammation and enhancing gastric metabolism and microcirculation (explained in the
subsequent sections of this monograph).
5
TROXIP: A NOVEL CYTOPROTECTIVE AGENT
Characteristic Pharmacological Features of TROXIP: An Insight into its MOA
Troxip (Troxipide) is a novel drug molecule used in the therapy of acid peptic disorders
including acute gastric ameliorations, gastritis as well as peptic ulcers. Its unique “gastric
pH & content independent” properties, which have led it to being described as a
“multifaceted cytoprotective agent” include:
Ability to fortify the gastric mucosa by increasing its glucosamine,
mucopolysaccharide and collagen content
Ability to stimulate the secretion of cytoprotective prostaglandins including PGI2 and
PGD2
Ability to prevent mucosal inflammation induced by interleukin stimulated
neutrophil migration and oxidative stress
Ability to increase gastric mucosal metabolism, microcirculation, and cell
proliferation, restitution and repair.
No effect on gastric acid secretion
Fortification of Gastric Mucosal Constitution
The gastric mucosa typically is composed of salts and other dialyzable components, free
proteins, carbohydrate rich glycoprotein and water. Troxipide fortifies this gastric mucosal
barrier by increasing the content of glucosamine, mucopolysaccharides and collagen.
Glucosamine is an amino-sugar that is known to stimulate glycoprotein synthesis and the
protective mechanisms of the
gastric mucosa, thereby aiding in
ulcer healing. [6] The rate of
glucosamine incorporation into the
acid-insoluble fraction of the gastric
mucosa, indicative of increased
glycoprotein synthesis, was
significantly increased by Troxipide.
[7] This was also found to occur after treatment with Troxipide in experimental models of
gastric ulcer induced by steroids. [7,8]
Mucopolysaccharides are important for the structural integrity of the gastric mucosal. [9]
Collagen imparts properties like ionic capability to attract blood componenets essential to
tissue regeneration, mechanical protection, high tensile strength and slow digestibility to the
gastric mucosa. [10] Thus, by stimulating the content of mucopolysaccharides and by
restitution of collagen fibers, Troxipide helps to accelerate epithelial restitution and mucosal
healing. [11]
Figure 3: Microscopic view of stained Gastric Mucosa
6
Stimulation of Mucosal Cytoprotective Prostaglandins
Almost all of the gastric mucosal defense mechanisms are stimulated and/or facilitated by
prostaglandins (PGs), especially PGE2. These Cytoprotective PGs stimulate mucus,
bicarbonate, and phospholipid secretion; increase mucosal blood flow; and accelerate
epithelial restitution and mucosal healing. They also inhibit mast cell activation and leukocyte
and platelet adherence to the vascular endothelium. The importance of PGE2 in gastric
mucosal defense is demonstrated by the fact that immunoneutralizing antibodies to these PGs
cause development of gastric and duodenal ulcers in rabbits and dogs identical to those
produced by NSAIDs that inhibit PG generation. Thus, the continuous generation of PGE2 by
the mucosa is crucial for the maintenance of mucosal integrity and protection against
ulcerogenic and necrotizing agents. [3]
Troxipide has been shown to stimulate the release of PGE2 and PGD2 in in-vitro models as
well as in clinical studies. These increases were found in combination with cimetidine also,
but they were greater than that obtained with cimetidine monotherapy. [12] Thus, Troxipide
also resulted in an increase in PG-stimulated increase in gastric mucosal output, accelerated
epithelial restitution and mucosal healing.
Suppression of Gastric Mucosal Inflammation
Gastric inflammation is a highly complex biochemical protective response to cellular injury.
[13] In the multitude of mechanisms involved in the development of gastric mucosal
inflammation, derangement of the microcirculatory system is a common initial pathway. [14]
Troxipide inhibits various proinflammatory mediators present at different stages of the
microcirculatory system, thereby restoring the normal gastric mucosa.
Interleukin-8 (IL-8), a pro-inflammatory mediator produced by macrophages and other
cell types, induces an increase in oxidative
stress mediators by increasing the
recruitment of inflammatory cells. Thus, IL-
8 increases intracellular calcium, exocytosis
of cells (histamine release) and respiratory
burst. Troxipide caused the inhibition of
recombinant IL-8 induced migration of the
inflammatory cells. [15]
Two other pro-inflammatory mediators
causing oxidative stress that are inhibited by
Troxipide include the formyl-methionyl-
leucyl-phenylalanine (fMLP) and the
Platelet Activating Factor (PAF). [15]
fMLP is known to stimulate neutrophil aggregation, increase the release of myeloperoxidase
enzymes, subsequently resulting in increased superoxide anion production and gastric
mucosal inflammation. PAF, in addition to increasing oxidative stress, also activates the
mobilization of calcium ions and affects mucosal vascular permeability.
Figure 4: Endoscopic view of inflamed gastric mucosal surface
7
Troxipide also directly acts on the enzymes that generate free oxygen radicals. Troxipide is
known to inhibit in-vitro xanthine oxidase and myeloperoxidase activity in gastric
mucosal homogenates. [16]
Troxipide, a radical scavenging substance, has demonstrated in in-vitro experimental models
that it can restrain NSAID induced generation of porphyrins, tissue peroxidation and
gastric lesion formation. [17]
Thus, Troxipide results in an overall decrease in gastric mucosal inflammation by its actions
on varied inflammatory mediators.
Effects of Acid on Activities of Troxipide
It has been found that the anti-ulcerous actions of Troxipide are not related with the content
and the pH of the gastric juice. Thus, irrespective of the pH of the stomach or duodenum,
Troxipide will be effective in curing the disease. Further, it has also been found that Troxipide
does not inhibit the gastric acid secretion nor does it neutralize it. Thus, it may be assumed
that the incidences of adverse events like constipation, abdominal swelling and fullness seen
with acid-suppressants will be lower in patients treated with Troxipide. [18]
Troxipide and Mucosal Metabolism
Gastric parietal cells are rich in mitochondria which provide energy in the form of ATP for
cells by oxidative phosphorylation, critical to maintain the proper morphology and function of
gastric mucosa. However, these mitochondria are easily injured organelle and the major
target of intracellular oxidative stress associated with aggressive factors like H.pylori, alcohol
and NSAIDs. [19]
It has been found tat the principal active site of
Troxipide on tissue respiration is the gastric mucosa.
Troxipide was found to significantly accelerate the
oxygen intake of marginal gastric mucosa; this was
two-times greater than that seen with Gefarnate.
Troxipide also significantly accelerated the glycogen
consumptive stimulation of the gastric mucosa of the
corpus. [20]
Troxipide: Role in Mucosal Microcirculation
The microcirculation is a secondary defense barrier
present in the gastric mucosa. In addition to supplying
nutrients and oxygen to the epithelium, the
microcirculation also removes, dilutes, and neutralizes
toxic substances that have diffused into the mucosa from
the lumen. When the epithehium is damaged, the
microcirculation also plays a critical role in creating a microenvironment over the site of
injury conducive for repair. [2]
Figure 5: Gastric Mucosal Microcirculation
8
Troxipide brought about an increase in mucosal blood flow, the increment being more
successive in the gastric antrum than in the gastric corpus. Similarly, the main period of
gastric mucosal blood flow increment produced by Troxipide in fasting rabbits was more
successive than that seen in non-fasting animals. This increase in gastric mucosal
microcirculation by Troxipide was found to be greater than that produced by Gefarnate, a
standard anti-ulcer drug. [21]
Anti- Helicobacter pylori Action
Helicobacter pylori, one of the most common causative agents of peptic acid disorders,
produce a multimeric, nickel-containing
urease that catalyses the hydrolysis of urea
to yield ammonia and carbonic acid. Host
tissues can be damaged directly by this
urease-mediated generation of ammonia
and indirectly by urease-induced
stimulation of the inflammatory response,
including recruitment of leukocytes and
triggering of the oxidative burst in
neutrophils. [22] Troxipide inhibits this H.
pylori derived urease, thereby
suppressing further inflammatory
responses. [15]
Experimental Acid Peptic Disease Models: Effect of Troxipide
The pharmacodynamic properties of Troxipide have been established in different
experimental models of gastric mucosal diseases as given below:
Acute Gastric Mucosal Lesions (AGML)
Troxipide at 50-200mg/kg p.o. dose-dependently prevented the ischemia/ reperfusion plus
0.2% ammonia (I/R.NH3) induced development of AGML. It also prevented the increase of
gastric mucosal thiobarbituric acid (TBA) reactive substances and inhibited the xanthine
oxidase activity. Thus, it was found to be highly effective for various AGMLs with multifactor
involvement. [16]
Gastric Ulcers
Troxipide shows a dose-dependant anti-ulcerous action at 100, 200 & 300mg/kg p.o. in
water-immersion stress, pylorus ligated and acetic acid reduced rats. The effect of Troxipide
was found to be higher than that of cimetidine on the pylorus ligated and acetic acid reduced
ulcer models. Further, the anti-ulcerous actions of Troxipide were not related with the content
and the pH of the gastric juice. [18]
Figure 6: Effects of H. pylori on the Gastric mucosa
9
Comparison with other Pharmacotherapeutics
Troxipide has been found to significantly prevent the formation of gastric lesions by
necrotizing agents like 0.6 N HCl, absolute ethanol and 1% NH3, unlike the histamine-2-
receptor antagonists like cimetidine, ranitidine & famotidine which had no protective
effects. [23]
The protective effects of Troxipide have also been established as much more potent than those
of cetraxate against aspirin, 0.6N HCl and water immersion stress induced gastric lesions.
The Cytoprotective effects of Troxipide were found to be almost remarkable 30-60 mins after
administration and lasted up to 240mins. [24]
10
CLINICAL EXPERIENCES WITH TROXIPIDE
Troxipide represents an alternative healing approach to stomach ailments. As already seen,
instead of obstructing an action of the stomach – blocking acid production & neutralizing the
gastric acid- Troxipide strengthens the stomachs mucosal defenses. Thus, Troxipide harnesses
the stomach’s natural ability to fight diseases, battle infection and heal itself, making it a
valuable treatment modality for acid peptic disorders. The clinical evidences that support the
use of Troxipide in these ailments are described in this section.
Pharmacokinetic Data
Healthy Human Volunteers
Troxipide has been studied in healthy human volunteers for evaluating its pharmacokinetic
parameters. In general, it has been found to be well absorbed throughout the gastrointestinal
tract after administration, with a relative bioavailability of 99.6%. [25]
It is found that, at any time, a mean concentration of 5.3- 8.9 µg is present per gram of tissue,
which is capable of inhibiting the chemotactic migration and superoxide generation in the
gastric mucosa. Thus, even 3 hrs after attaining peak serum levels, as seen in figure 7,
Troxipide is found in therapeutically active concentrations in the small intestine, liver and
stomach. [15]
0
100
200
300
400
500
600
700
800
900
1000
0 5 10 15 20 25 30
Time (hrs)
Co
nc
(n
g/m
L)
Figure 7: Plasma Concentration Vs Time Curve of Troxipide
It is mainly excreted in the urine (96%) as metabolites [61% after 24hrs and 87% after 48hrs].
[11,25]
A bioequivalence study conducted in 24 healthy Indian volunteers administered Troxipide
found the formulation to be similar to the internationally available innovator molecule, and
that it was well tolerated by the volunteers. The various pharmacokinetic parameters of
Troxipide [26] obtained are given in Table 1.
11
Table 1: Pharmacokinetic Parameters of Troxipide
Parameters Troxipide (mean ± S.D.)
Cmax (ng/ml) 1052.47 ± 254.41
AUC(0-t) (ng/ml*h) 8737.48 ± 1545.24
AUC(0-∞) (ng/ml*h) 9622.12 ± 1692.57
tmax (h) 3.04 ± 0.93
Kel (h-1) 0.10 ± 0.06
t½ (h) 7.44 ± 1.85
Efficacy Data
Patients with Gastric Ulcer
Troxipide has been well established in the treatment of gastric ulcers showing an overall
amelioration rate of 79.4%. [11] A study evaluating the efficacy of Troxipide (100mg t.i.d) in
patients with gastric ulcers [27] found an overall rate of complete endoscopic healing of 66.7%
at 8 weeks & 80% at 12 weeks of drug administration in these patients (Fig.8). Further, the
overall rate of gastric ulcer improvement at the end of treatment was 86.6% and no adverse
events were reported.
Figure 8: Comparative endoscopic healing rates of Troxipide in Peptic ulcers
The combination of Troxipide with Cimetidine was evaluated in patients with chronic gastric
ulcers. [12] This study revealed that administration of Troxipide – Cimetidine combination,
unlike cimetidine monotherapy, could result in about a two fold increase in the synthesis of
Cytoprotective PGE2 and PGD2 as seen in Figure 9. This could be attributed to the fact that
Troxipide has shown to increase the levels of Cytoprotective PGs in-vitro, and has thus, found
to bring about relief in these patients with gastric ulcer.
12
Figure 9: Effects of Cimetidine Monotherapy & Cimetidine + Troxipide Combination
Therapy on Gastric Mucosal Prostaglandins
Patients with Duodenal Ulcer
A study evaluating the efficacy of Troxipide (100mg t.i.d) in patients with duodenal ulcers [27]
found an overall rate of complete endoscopic healing of 53.3% at 8 weeks & 73% at 12 weeks of
drug administration in these patients (Fig.8). However, the overall rate of gastric ulcer
improvement at the end of treatment was very high, with over 93.3% showing duodenal ulcer
improvement. There were no adverse events reported.
Patients with Gastritis and gastric mucosal lesions
Clinical trials with Troxipide in patients suffering from acute gastritis and acute gastric
mucosal lesions have found it to be an effective agent with an overall amelioration rate of
82.9%. [11]
A study evaluating the efficacy of Troxipide (100mg t.i.d for 28 days) in a sample of Indian
patients suffering from gastritis [26] showed that Troxipide significantly decreased the clinical
signs of gastritis including abdominal pain, bloating, belching, loss of appetite and heartburn.
Troxipide administration also caused a marked reduction in the number of patients having
gastritis at the end of therapy and a marked overall improvement in the endoscopic evidences
of gastritis (gastric mucosal erosion, oozing, redness and edema). Moreover, it was found that
Troxipide completely resolved the symptoms & eradicated the causative agent H. pylori in
patients who tested positive for the bacteria at the baseline.
Comparison with Acid-Suppressive agents
There is a paucity of clinical studies comparing the efficacy of Troxipide with other agents
used in acid peptic disorders, especially the acid suppressive agents. A clinical study
comparing the efficacy and safety of Troxipide (100mg t.i.d) with Ranitidine (a Histamine-2-
receptor antagonist, 150mg b.i.d) when administered over 28 days to gastritis patients [26]
-20
-10
0
10
20
30
40
50
60
6-keto
PGF1
PGE2 PGD2
Prostaglandins studied
Ch
an
ge
in
le
ve
ls
Cim etidine Cim etidine + T roxipide
13
found that Troxipide was statistically superior to Ranitidine, both with respect to resolution of
gastritis clinical signs as well as the endoscopic evidences.
Resolution of Clinical Signs of Gastritis
The reduction of the severity of the clinical signs of gastritis (abdominal pain, bloating,
belching, nausea, vomiting, loss of appetite and heartburn) measured using a Visual Analog
Scale (VAS) was found to be consistently greater with Troxipide than Ranitidine throughout
the study period. Troxipide was also found to bring about a higher proportion of patients
showing
Overall symptom relief
Substantial clinical symptom relief (reduction in VAS scores of at least 50 points
from the baseline VAS score to week 4), especially for abdominal pain, bloating,
belching and heartburn (Fig.10)
Noticeable symptom relief (reduction of at least 20 points from baseline VAS score
to week 4)
In a subgroup of patients with abdominal pain, bloating, belching and heartburn, Noticeable
symptom relief was found among 83.67% patients receiving Troxipide as compared to 52.38%
receiving Ranitidine.
Figure 10: Substantial clinical symptom relief with Troxipide and Ranitidine
Resolution of Endoscopic Evidences
Patients, irrespective of the treatment administered, showed an improvement in the severity
of endoscopic findings. The reduction in the mean severity scores of the various endoscopic
findings (erosion, oozing, redness and edema) from baseline to week 4 was greater with
Troxipide than Ranitidine. As seen in Figure 11, Troxipide, in comparison to Ranitidine, had a
higher proportion of patients with
complete resolution of erosion, oozing and edema
improvement in the severity of all the endoscopic evidences
14
Of the patients showing the presence of all the four endoscopic evidences at baseline,
complete endoscopic healing was seen in 77.77% of the patients receiving Troxipide and
29.41% of those receiving Ranitidine.
Figure 11: Comparison of Troxipide and Ranitidine in Complete Resolution of Endoscopic
Evidences
Safety and Tolerability Data
Troxipide has been established as a safe and tolerable molecule in various clinical and post-
marketing studies.
Safety of Troxipide
A post-marketing study, conducted by the innovator, in over 12,000 patients being
administered Troxipide [11] found that only 0.75% of them developed adverse events
attributable to the drug. These adverse reactions were mild to moderate, resolving when the
drug was discontinued and included constipation (0.19%) and increase in levels of liver
enzymes, AST (0.17%) and ALT (0.25%).
The clinical study in Indian patients found that Troxipide was well tolerated with no
significant changes in body weight, blood pressure, pulse, or laboratory results including
thyroid function. No patients were withdrawn from the therapy. Mild to moderate adverse
events (constipation and headache) were reported for four patients receiving Troxipide. [26]
Tolerability of Troxipide
The tolerability of Troxipide was compared with that of Ranitidine in a study conducted in
patients with gastritis. [26] The investigators and the patients per protocol, found Troxipide to
be a more tolerable medication than Ranitidine (Fig.12). A favorable tolerability profile for
Troxipide was reported by 95.45% of the investigators as compared to 65.45% for Ranitidine
while favorable tolerability profile was reported by 93.67% of the patients for Troxipide and
64.55% for Ranitidine.
88.1
4
96.7
7
91.0
4
93.8
8
98.3
1
97.7
7
91.0
4
97.9
6
56.3
6
78.9
5
71.4
3
46.5
1
78.1
8
78.9
5
71.4
3
69.7
7
0
20
40
60
80
100
120
Ero
sio
n
Oo
zin
g
Red
ness
Od
em
a
Ero
sio
n
Oo
zin
g
Red
ness
Od
em
a
Complete Healing Improvement
Pro
po
rtio
n o
f P
ati
en
ts (
%)
Troxipide Ranitidine
15
Figure 12: Comparative Assessment of Tolerability of Troxipide and Ranitidine by
Investigators (PI) and Patients
16
CONCLUSION
Troxipide is a novel Cytoprotective agent developed for the treatment of acid peptic diseases,
especially gastritis, gastric and duodenal ulcers. Troxipide, a molecule that neither inhibits
gastric acid secretion nor has acid-neutralizing capacity, boasts of a multi-modal, potent
armamentarium of properties that include fortification of the gastric mucosal constitution,
suppression of inflammation, stimulation of Cytoprotective prostaglandins, gastric mucosal
metabolism and microcirculation as well as suppression of H. pylori.
Clinical studies suggest that Troxipide produces a sustained Cytoprotective effect in patients
with gastritis or peptic ulcers, with the effect being predominant within the first two weeks of
therapy. Exposure to a maximum of 12 weeks treatment with Troxipide have confirmed the
efficacy of the drug in treating acid peptic disorders with a favorable overall safety profile.
Open-labeled clinical data also indicate that it is superior to the histamine-2-receptor
antagonist, Ranitidine, in producing symptom relief as well as resolution of the endoscopic
evidences of gastritis.
Clearly, there is a prospect for Troxipide monotherapy in patients with acid peptic disorders
along side the conventional therapeutic agents like the Proton-pump inhibitors and
Histamine-2-receptor antagonists. In addition, Troxipide also represents an attractive partner
agent for future combination therapies. Thus, Troxipide, with its multi-pronged mechanism of
action, established efficacy and excellent tolerability profile, is an attractive alternative in the
treatment of acid peptic diseases.
17
APPENDICES
APPENDIX I: PRESCRIBING INFORMATION OF TROXIP
Composition:
Each tablet contains
Troxipide 100mg
Description:
Troxipide is a novel cytoprotective compound. Its
chemical name is 3, 4, 5- trimethoxy- N-3-
piperidylbenzamide. It has a molecular formula of
C15H22N2O4 and a molecular weight of 294.4. The
molecular structure is given below:
Clinical Pharmacology:
Pharmacodynamics:
Troxipide is proposed to act by the inhibition the Interleukin 8 (IL-8) stimulated migration of
neutrophils in the gastric mucosa. Troxipide also suppresses formyl-methionyl-leucyl-
phenylalanine (fMLP) or Platelet Activating Factor (PAF) stimulated superoxide generation
and decreases the inflammation in mucosal tissues. Troxipide protects against mucosal
fragility and disruption of gastric mucosal barrier by stimulating the regeneration of collagen
fibers, synthesis of Cytoprotective prostaglandins and by increasing the gastric mucosal
content of glucosamine and mucopolysaccharides. It also increases the gastric mucosal blood
flow and metabolism.
Pharmacokinetics:
It is well absorbed throughout the gastrointestinal tract after administration. Troxipide was
detected in plasma from 0.05 hr after oral administration of 100 mg of film coated tablets,
suggesting a rapid absorption. Bioavailability of Troxipide is 99.40%. A peak serum
concentration of 1052.471±51.9318 ng/ml is obtained within 3.042±0.1896 hrs of drug
administration and the resultant area under the curve is 8737.481±315.4253 ng/ml*hr. It is
found that, at any time, a mean concentration of 5.3- 8.9 µg is present per gram of tissue,
which is capable of inhibiting the chemotactic migration and superoxide generation in the
gastric mucosa. Thus, even 3 hrs after attaining peak serum levels, Troxipide is found in
therapeutically active concentrations in the small intestine, liver and stomach. It has a half life
of 7.615±0.3782 hrs, and is mainly excreted in the urine (96%) as metabolites [61% after
24hrs and 87% after 48hrs].
Indications and Usage:
18
Troxipide is intended for use in the treatment of acute gastritis, acute exacerbation of chronic
gastritis and peptic ulcers.
Dosage and Administration
The recommended dose of Troxipide is 100mg thrice daily after meals, for 8-12 weeks.
Contraindication:
Troxipide is contraindicated in patients with hypersensitivity to Troxipide, individuals with
impaired renal or hepatic functions and in pregnant women.
Precautions:
Troxipide should used with caution in children and pregnant women due to lack of safety
data. It is known that sexual cycle dysfunctions occurred in rats treated with troxipide. Hence,
caution should be administered while treating women in the reproductive age group. It has to
be used with caution in breast feeding women; they should stop breast feeding when on the
drug. Troxipide has to be cautiously used in geriatric population. There have been no reports
of interactions with other drugs.
Adverse Reactions:
Adverse reactions are found in only 2.1% of individuals administered Troxipide and include:
Gastrointestinal effects like occasional constipation, abdominal swelling, stomach
discomfort
Abnormality in liver functions (raised SGOT, SGPt, ALP levels)
General malaise
Presentation:
A blister strip of 10 tablets.
Storage:
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) in a dry place.
19
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