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

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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

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91.0

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93.8

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97.9

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78.9

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71.4

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Ero

sio

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Complete Healing Improvement

Pro

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f P

ati

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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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