TROXIP

Troxipide: From Bench to Bed-side

Product Monograph

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.

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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

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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.

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]

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 antisecretory 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, antiinflammatory and mucus secreting properties. The chemical formula of Troxipide is 3,4,5-

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).

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 ulcer mechanisms
[6]

of rate

the of

gastric mucosa, thereby aiding in healing. The glucosamine incorporation into the acid-insoluble fraction of the gastric mucosa, indicative of increased Figure 3: Microscopic view of stained Gastric
Mucosa
[7]

glycoprotein

synthesis,

was

significantly increased by Troxipide.

This was also found to occur after treatment with Troxipide in experimental models of
[9]

gastric ulcer induced by steroids. [7,8] Mucopolysaccharides are important for the structural integrity of the gastric mucosal. 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. healing. [11]
[10]

Thus, by stimulating the content of mucopolysaccharides and by

restitution of collagen fibers, Troxipide helps to accelerate epithelial restitution and mucosal

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. epithelial restitution and mucosal healing. Suppression of Gastric Mucosal Inflammation Gastric inflammation is a highly complex biochemical protective response to cellular injury.
[13] [12]

Thus, Troxipide

also resulted in an increase in PG-stimulated increase in gastric mucosal output, accelerated

In the multitude of mechanisms involved in the development of gastric mucosal

[14]

inflammation, derangement of the microcirculatory system is a common initial pathway. microcirculatory system, thereby restoring the normal gastric mucosa.

Troxipide inhibits various proinflammatory mediators present at different stages of the 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, IL8 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 Figure 4: Endoscopic view of inflamed
gastric mucosal surface

Troxipide include the formyl-methionylleucyl-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.

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 Figure 5: Gastric Mucosal
Microcirculation

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]

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 neutrophils. pylori suppressing responses. [15] of
[22]

the

oxidative urease,

burst

in

Troxipide inhibits this H. thereby Figure 6: Effects of H. pylori on the

Gastric mucosa

derived

further

inflammatory

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]

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-2receptor 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]

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 stomachs 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 g 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]

1000 900 800 700 600 500 400 300 200 100 0 0 5 10 15 20 25 30

Conc (ng/mL)

Time (hrs)

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.

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Table 1: Pharmacokinetic Parameters of Troxipide

Parameters Cmax (ng/ml) AUC(0-t) (ng/ml*h) AUC(0-) (ng/ml*h) tmax (h) Kel (h-1) t (h)

Troxipide (mean S.D.) 1052.47 254.41 8737.48 1545.24 9622.12 1692.57 3.04 0.93 0.10 0.06 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%. patients with gastric ulcers
[11]

A study evaluating the efficacy of Troxipide (100mg t.i.d) in

[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.

11

60 50
Change in levels

40 30 20 10 0 -1 0 -20
6-ket o PGF1 PGE2 PGD2

Prostaglandins studied Cim etidine Cim etidine + T rox ipide

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-2receptor antagonist, 150mg b.i.d) when administered over 28 days to gastritis patients
[26]

12

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

13

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.
120
96.77 91.04 93.88

98.31

97.77

Proportion of Patients (%)

78.95

71.43

78.18

78.95

100 80

88.14

91.04

71.43

97.96

56.36

60 40 20 0

Erosion

46.51

Redness

Erosion

Redness

Oozing

Odema

Oozing

Complete Healing
Troxipide

Improvement
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 postmarketing 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.

14

Odema

69.77

Figure 12: Comparative Assessment of Tolerability of Troxipide and Ranitidine by Investigators (PI) and Patients

15

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.

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APPENDICES
APPENDIX I: PRESCRIBING INFORMATION OF TROXIP
Composition: Each tablet contains Troxipide Description: Troxipide is a novel cytoprotective compound. Its chemical name is 3, 4, 5- trimethoxy- N-3piperidylbenzamide. 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-leucylphenylalanine (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 1052.47151.9318 ng/ml is obtained within 3.0420.1896 hrs of drug administration and the resultant area under the curve is 8737.481315.4253 ng/ml*hr. It is found that, at any time, a mean concentration of 5.3- 8.9 g 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 7.6150.3782 hrs, and is mainly excreted in the urine (96%) as metabolites [61% after 24hrs and 87% after 48hrs]. Indications and Usage: 100mg

17

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 25C (77F); excursions permitted to 15-30C (59-86F) in a dry place.

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APPENDIX II: REFERENCES

1. Sanders S. W & Krosnick A. Pathogenesis and treatment of acid peptic disorders: Comparison of proton pump inhibitors with other antiulcer agents. Clin Therap. 1996; 18 (1): 1-34. 2. Wallace J.L & Granger D.N. The cellular and molecular basis of gastric mucosal defense. FASEB J. 1996; 10: 731-40. 3. Laine L, Takeuchi K & Tarnawski A. Gastric mucosal defense and cytoprotection: Bench to Bedside. Gastroenterol. 2008; 135: 41-60. 4. Jain K.S, Shah A.K, Bariwal J et al. Recent advances in proton pump inhibitors and management of acid peptic disorders. Bioorg Med Chem. 2007; 15: 1181-1205. 5. Sharma M.P & Ahuja V. Current Management of Acid Peptic Disorders. JIACM. 2003; 4 (3): 228-33. 6. Sethumadhavan S, Rangasamy A, Theruvathil K.S. & Paruthapara T.M. Protective effect of glucosamine against ibuprofen-induced peptic ulcer in rats. J Gastroenterol Hepatol. 2007; 22 (6): 949 - 953. 7. Abe Y, Sekiguchi H, Tsuru K & Irikura T. Effects of 3,4,5-trimethoxy-N-(3-piperidyl) benzamide (KU-54) on the incorporation (excretion) of 14C-glucosamine in the gastric mucosa and the liver of rats. Nippon Yakurigaku Zasshi. 1984; 84 (1): 11-8. 8. Inoue M, Takahashi M, Ishibashi Y et al. Effects of troxipide on the prednisoloneinduced aggravation of gastric mucosal lesions occurred by HC1 in rats. Yakuri to chiryo. 2005; 33 (8): 757-763. 9. Clamp J.R, Cooper B, Creeth J.M et al. The presence of polysaccharide in normal human gastric mucus. Biochem J. 1983; 215: 421-23. 10. Castro G.A, Sgarbieri V.C, Carvalho JE et al. Protective effects of collagen derivatives on the ulcerative lesions caused by oral administration of ethanol. J Med Food. 2007; 10 (1): 154-58. 11. Kyorin Pharma. Prescribing information of APLACE (Troxipide). 2008 12. Mine T, Kataoka A, Fujisaki J et al. Effects of cimetidine and troxipide on gastric mucosal prostaglandin synthesis in patients with chronic gastric ulcer. Curr Ther Res. 1991; 50 (6): 878-87. 13. Yoshikawa T & Naito Y. The role of neutrophils and inflammation in gastric mucosal injury. Free Radical Research. 2000; 33 (6): 785-794. 14. Suzuki H, Masaoka T, Suzuki M and Ishii H. Microvascular Pathophysiology in Gastric Mucosal Inflammation Associated with Helicobacter pylori Infection. 2005; 13(2): 63-72. 15. Kusugami K, Ina K, Hosokawa T et al. Troxipide, a novel antiulcer compound, has inhibitory effects on human neutrophil migration and activation induced by various stimulants. Dig Liver Dis. 2000; 32 (4): 305-11. 16. Momo K, Hoshina K, Ishibashi Y et al. Preventive effects of troxipide on a newly developed model of acute gastric mucosal lesion (AGML) induced by

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ischemia/reperfusion plus ammonia in the rat. Nippon Yakurigaku Zasshi. 1994; 104 (4): 313-23. 17. Matsui H, Murata Y, Kobayashi F et al. Diclofenac-induced gastric mucosal fluorescence in rats. Dig Dis Sci. 2001; 46 (2): 338-44. 18. Wang J, Zhang L, Fang Z et al. The pharmacodynamics of troxipide on experimental gastric ulcers in rats. Hua Xi Yi Ke Da Xue Xue Bao. 1993; 24 (3): 313-6. 19. Pan JS, He SZ, Xu HZ et al. Oxidative stress disturbs energy metabolism of mitochondria in ethanol-induced gastric mucosa injury. World J Gastroenterol. 2008; 14 (38): 5857-5867. Available from: URL: http://www.wjgnet.com/10079327/14/5857.asp 20. Abe Y, Sekiguchi H, Tsuru K & Irikura T. Effects of 3,4,5-trimethoxy-N-(3-piperidyl) benzamide (KU-54) on respiration of the gastric mucosa and liver in rats. Nippon Yakurigaku Zasshi. 1984; 83 (4): 317-24. 21. Abe Y & Irikura T. Influence of 3-(3, 4, 5-trimethoxybenzamido) piperidine (KU-54) on gastric mucosal blood flow (author's transl). Nippon Yakurigaku Zasshi. 1980; 76 (5): 355-61. 22. Mobley HL. The role of Helicobacter pylori urease in the pathogenesis of gastritis and peptic ulceration. Aliment Pharmacol Ther. 1996 Apr;10 Suppl 1:57-64. 23. Sekiguchi H, Hamada K, Taga F & Nishino K. Effects of the new histamine H2receptor antagonist N-ethyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl] urea with potent gastric mucosal protective activity on acute gastric lesions and duodenal ulcers in rats. Arzneimittelforschung. 1993; 43 (2): 134-8. 24. Sekiguchi H, Hamada K, Okada Y & Taga F. Effects of troxipide on acute gastric lesions in rats. Nippon Yakurigaku Zasshi. 1987; 89 (3): 111-9. 25. Yanan Z, Furong Q, Weiijia W et al. Relative bioavailability and bioequivalance of troxipide capsules in healthy volunteers after a single oral administration. Chinese J Clin Pharmacol. 2000; 19 (6). 26. Data on file 27. Hyeoyun et al. Peptic ulcers for the clinical effectiveness of Troxipide. Latest Med. 1989; 32 (3): 125-31. 28. Robinson M & Shaw K. Survey. P&T. 2002; Proton Pump Inhibitor Attitudes and Usage: A Patient 27 (4): 202-06. Available from: URL:

http://www.pharmscope.com/ptjournal/fulltext/27/4/PTJ2704202.pdf 29. Scarpignatoa C. New drugs to suppress acid secretion: current and future developments. Drug Discovery Today: Therapeutic Strategies. 2007; 4 (3): 155-163.

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