Troxipide is a drug used in the treatment of

gastroesophageal reflux disease Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is one of the upper gastrointestinal chronic diseases where stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/ ...

. Troxipide is a systemic non-antisecretory gastric cytoprotective agent with anti-ulcer, anti-inflammatory and mucus secreting properties irrespective of pH of stomach or duodenum. Troxipide is currently marketed in Japan (Aplace), China (Shuqi), South Korea (Defensa), and India (Troxip). It is used for the management of gastric ulcers, and amelioration of gastric mucosal lesions in acute

gastritis Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possi ...

and acute exacerbation of chronic gastritis.

Mechanism of action

The gastric pH and content independent properties of troxipide include the following:

Gastric mucosal protection

Gastric mucosa The gastric mucosa is the mucous membrane layer of the stomach, which contains the glands and the gastric pits. In humans, it is about 1 mm thick, and its surface is smooth, soft, and velvety. It consists of simple columnar epithelium, lamina ...

typically is composed of salts and other dialyzable components, free proteins, carbohydrate rich glycoprotein and water. Troxipide fortifies this

gastric mucosal barrier The gastric mucosal barrier is the property of the stomach that allows it to safely contain the gastric acid required for digestion. If the barrier is broken, as by acetylsalicylic acid (ASA, aspirin) in acid solution, acid diffuses back into the ...

by increasing the content of

glucosamine Glucosamine (C6H13NO5) is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of two polysaccharides, chitosan and chitin. Glucosamine is one of the most ...

mucopolysaccharides Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case o ...

and collagen.Prescribing information of APLACE (Troxipide). 2008. Kyorin Pharmaceutical Co., Ltd., Japa

/ref> Glucosamine is an amino-sugar that is known to stimulate glycoprotein synthesis and protective mechanisms of the gastric mucosa, thereby aiding in ulcer healing. Mucopolysaccharides impart structural integrity to the gastric mucosa and collagen imparts properties like ionic capability to attract blood components essential to tissue regeneration, mechanical protection, high tensile strength and slow digestibility to the gastric mucosa.

Stimulation of cytoprotective prostaglandins

Almost all of the gastric mucosal defense mechanisms are stimulated and/or facilitated by

prostaglandins The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are deriv ...

(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 A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...

activation, and leukocyte and

platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...

adherence to the vascular endothelium. Thus, continuous generation of PGE₂ by gastric mucosa is crucial for the maintenance of mucosal integrity and protection against ulcerogenic and necrotizing agents. Troxipide is known to stimulate the release of PGE₂ and PGD₂ in experimental as well as clinical studies. Troxipide has been observed to enhance PG-stimulated increase in gastric mucosal output, accelerated epithelial restitution and mucosal healing.

Suppression of gastric inflammation

Gastric inflammation is a highly complex biochemical protective response to cellular injury. In the multitude of mechanisms involved in the development of gastric mucosal inflammation, derangement of the microcirculatory system is a common initial pathway. Troxipide inhibits various proinflammatory mediators present at different stages of the microcirculatory system, thereby restoring the normal gastric mucosa. Troxipide caused the inhibition of recombinant

interleukin-8 Interleukin 8 (IL-8 or chemokine (C-X-C motif) ligand 8, CXCL8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage ...

(IL-8) induced migration of the inflammatory cells. 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). In addition to inhibition of pro-inflammatory mediators, troxipide directly acts on the enzymes such as xanthine oxidase and myeloperoxidase that generate free oxygen radicals in gastric mucosa. Experimental studies have demonstrated that troxipide restrains

NSAID Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...

-induced generation of porphyrins, tissue peroxidation and gastric lesion formation.

Enhancement of mucosal metabolism

Gastric

parietal cell Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions of the s ...

s 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. The mitochondrion is the major target of intracellular oxidative stress associated with aggressive factors like ''

H. pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape (from which the genus name, helicobacter, derives) is thoug ...

'', alcohol and

s, which disturb the energy metabolism of mitochondria. Troxipide accelerates oxygen intake of marginal gastric mucosa and glycogen consumptive stimulation of the gastric mucosa of the corpus, thereby elevating the tissue respiration and energy metabolism.

Stimulation of mucosal microcirculation

Troxipide enhances mucosal blood flow, which is the secondary defense barrier of gastric mucosa that supplies nutrients and oxygen to the epithelium, and removes, dilutes and neutralizes toxic substances that have diffused into the mucosa from the lumen. The increment in mucosal blood flow with troxipide is more pronounced in the gastric antrum than in the gastric corpus.

Anti-''Helicobacter pylori'' action

Troxipide inhibits ''

''-derived urease, a multimeric nickel-containing enzyme that catalyses the hydrolysis of urea to yield ammonia and carbonic acid, which damage host tissues and trigger inflammatory response, including recruitment of

leukocytes White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

and triggering of the oxidative burst in neutrophils.

Pharmacokinetics

Troxipide is well absorbed throughout the gastrointestinal tract with a relative bioavailability of 99.6%. At any time, a mean concentration of 5.3- 8.9 μg of troxipide 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. The elimination half-life of troxipide is 7.5 hours, and is mainly excreted in urine (96% as metabolites).

Clinical experience

Troxipide has been well established in the treatment of gastric ulcers showing an overall amelioration rate of 79.4%. An overall endoscopic healing rate of 66.7% after 8 weeks and 80% after 12 weeks of drug administration was achieved with troxipide (100 mg t.i.d. (three times a day)). In patients with duodenal ulcers, troxipide showed endoscopic healing rate of 53.3% and 73% at 8 weeks and 12 weeks respectively. At the end of the treatment, an overall improvement of 86.6% and 93.3% was achieved in patients with gastric ulcer and duodenal ulcer respectively. In patients with acute

and acute gastric mucosal lesions, an overall amelioration rate of 82.9% has been observed with troxipide. In a comparative study evaluating the efficacy of troxipide (100 mg t.i.d.) with

Ranitidine Ranitidine, sold under the brand name Zantac among others, is a medication used to decrease stomach acid production. It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome ...

(150 mg b.i.d. (two times a day)), administered over 28 days in patients with gastritis, troxipide was statistically superior to Ranitidine, both with respect to resolution of gastritis clinical signs (

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...

bloating Abdominal bloating (or simply bloating) is a short-term disease that affects the gastrointestinal tract. Bloating is generally characterized by an excess buildup of gas, air or fluids in the stomach. A person may have feelings of tightness, pres ...

belching Burping (also called belching and eructation) is the release of gas from the upper digestive tract (esophagus and stomach) of animals through the mouth. It is usually audible. In humans, burping can be caused by normal eating processes, or as ...

and

heartburn Heartburn, also known as pyrosis, cardialgia or acid indigestion, is a burning sensation in the central chest or upper central abdomen. Heartburn is usually due to regurgitation of gastric acid (gastric reflux) into the esophagus. It is the m ...

) as well as the endoscopic evidences (erosion, oozing, redness and edema). A study comparing the efficacy of troxipide (100 mg t.i.d for 28 days) with

Rabeprazole Rabeprazole, sold under the brand name Aciphex, among others, is a medication that decreases stomach acid. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and excess stomach acid production such as in Zollinger–Elli ...

(20 mg o.d. for 28 days) in patients suffering from gastritis showed that improvement in abdominal pain and

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

was significantly superior with troxipide at the end of 14 days. Troxipide administration caused a marked reduction in clinical (abdominal pain, bloating, belching, nausea,

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

loss of appetite Anorexia is a medical term for a loss of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while others i ...

and heartburn) and endoscopic signs of gastritis by the end of the treatment, though it did not significantly differ from that of Rabeprazole.A Parallel, Randomized, Comparative, Double-Blind, Double-Dummy Clinical Trial to Evaluate the Efficacy and Safety of Troxipide versus Rabeprazole in the Treatment of Gastritis. Data on file (appears on zuventus healthcare website www.zuventus.co.in). In patients with APDs like

dyspepsia Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier ...

, gastritis,

GERD Gerd or GERD may refer to: * Gerd (given name), a list of people with the given name or nickname * Gerd (moon), a moon of Saturn * Gerd Island, South Orkney Islands, Antarctica * Gastroesophageal reflux disease, a chronic symptom of mucosal damage ...

and/or gastric ulcer, uncontrolled with acid inhibitors viz.

proton pump inhibitor Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitor ...

s (PPIs),

histamine receptor antagonist Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides re ...

s (H2RAs) etc., troxipide (100 mg t.i.d. for 28 days) showed significant improvement in all major symptoms such as nausea, vomiting, belching, heartburn,

epigastric pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a more ...

, acid regurgitation, abdominal bloating & loss of appetite.An Open-Label, Multicentric Study to Assess the Symptomatic Efficacy and Safety of Troxipide roxipTMIn the Management of Acid Peptic Disorders in Indian Patients. Data on file (appears on zuventus healthcare website www.zuventus.co.in).

Safety and tolerability

A post-marketing study, conducted by the innovator, in over 12,000 patients showed that only 0.75% of them developed adverse events attributable to the drug. The adverse reactions were mild to moderate, which resolved when the drug was discontinued. Commonly observed adverse events included constipation (0.19%) and increase in levels of liver enzymes, AST (0.17%) and ALT (0.25%). In a post-marketing study conducted in 1500 Indian patients, only 9 adverse events were reported in 9 patients (0.63%) that were of mild to moderate intensity. Adverse events observed included constipation, acidity, nausea, fatigue and headache, and were of mild to moderate intensity. In all clinical studies, troxipide was well tolerated. In a comparative study with

ranitidine Ranitidine, sold under the brand name Zantac among others, is a medication used to decrease stomach acid production. It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome ...

, troxipide was assessed as a more tolerable medication than ranitidine. 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.

References

{{Drugs for peptic ulcer and GORD 3-Piperidinyl compounds Benzamides Phenol ethers ru:Противоязвенные препараты и препараты для лечения гастроэзофагеального рефлюкса#Троксипид