1.0 INTRODUCTION:

Ulcers are open sores on the skin or mucus membrane characterized by a superficial loss of tissue. Our digestive tract consists of the esophagus, stomach, duodenum and intestine. Most ulcers are located in the duodenum (duodenal ulcers) and on stomach (gastric ulcers).Dull or sharp upper abdominal pain with burning sensation are the major symptoms of a stomach or duodenal ulcer. Acid reflux or heartburn, feeling satiated (full) when eating are also associated in ulcer condition¹.In the USA, bleeding gastrointestinal tract led to 796 000 emergency department visits and 435 000 admissions in 2012, comprehending 20% of gastrointestinal emergency admissions that year².

Major causes of ulcers are infection of the stomach by a bacterium "Helicobacter pylori" (H. pylori) and chronic use of non-steroidal anti-inflammatory medications or NSAIDs, including aspirin, ibuprofen, naproxen, etodolac etc. Smoking of cigarette and like products also an important cause of ulcers but it also increases the risk of complications, such as bleeding, obstruction, and perforation. It is also is a leading cause of failure of treatment for ulcers. There is a belief that, excessive consumption of coffee, colas, spicy foods also causes ulcers^3-4.

Ulcers are mainly occurs due to the disturbance of the normal equilibrium caused by either enhanced aggression or diminished mucosal resistance to possible ulcerative agents. Presently, there are two main techniques for treating peptic ulcer, the first is reducing the production of gastric acid and the second is gastric mucosal protection from causative agents.If untreated may lead to further complications such as gastrointestinal bleeding, perforation, spreading of ulcer to adjacent organs and may lead to cancer^5-6.

The identification of H. pylori ulcers has led to a cure for this subtype that was discovered as recently as 1982, modern treatment involves killing the H. pylori bacteria or removing the underlying NSAID’S medication. Antiulcer medications with proven efficacy in the treatment of acute ulcers include H₂-receptor antagonists, H⁺/K⁺ATPase (proton pump) inhibitors, antacids, sucralfate and prostaglandin analogues, but clinical evaluation of these drugs has shown more adverse effects like neuropsychiatric disorders, gynecomastia, impotence, loss of libido, elevation of serum creatinine and serum transaminases concentrations, and drug interactions in some H₂-receptor antagonists, diarrhea or constipation and have been associated with low serum phosphorus concentrations, and metabolic alkalosis in antacids⁷. Acid inhibition incidence of H⁺/K⁺ATPase (proton pump) inhibitors may lead to Collagenous colitis, Gastrointestinal infection, Changes in gut microbiome, Dementia etc.⁸ relapses and drug interactions^9-10. Licorice, honey, garlic, cranberry, mastic, banana, gooseberry etc are used as natural and home remedies for ulcers¹¹.

In animal models peptic ulcers can be induced by methods like physiological, pharmacological or surgical manipulations. However, most experiments in peptic ulcer studies are carried out using rodents like mice or rats. Several In-Vivo, In-vitro and in silico models are used experimentally for screening or evaluating antiulcer activity of drugs/agents. The methods used for evaluating antiulcer activity are^12-16.

In-Vivo models:

· Stress ulcer models

· Pylorus ligation in rats

· Histamine induced gastric ulcer

· Ethanol induced mucosal damage

· Acetic acid induced gastric ulcer

· Cystamine induced gastric ulcer

· Indomethacin induced gastric ulcer

· NSAID’s induced gastric ulcer

· Reserpine induced ulcer.

In-Vivo models:

· Neutralization effects of prepared preparation on artificial gastric acid

· Detection of the duration of neutralization capacity of prepared preparation on artificial gastric acid

· Fordtran’s titration method for determination of neutralization capacity

· Assessment of H⁺/K⁺-ATPase activity

· H.Pylori antimicrobial assay

Synthetic drugs:

A number of classes of antiulcer drugs are available and numerous agents are available within each class. There are differences in mechanism of action amongst groups and in potency amongst individual agents. Therapeutic agents cure the diseases via. antisecreatory or healing activities. Antisecreatory activity has the of histaminergic antagonism and cholinergic effects on gastric secretion or by proton pump inhibition mechanism. Healing activity works by making ulcer to heal by local mucosal repair and development. No potentially life-threatening effects have been reported with antiulcer agents. Main adverse effects were reported for synthetic medicines available in market, involve the gastrointestinal tract and discomfort. Long-term use of proton pump inhibitors (PPIs) may increase the potential for gastrointestinal infection due to reduced gastric acidity. Adverse effects of some other include sodium and water retention and hypokalemia, which may lead to impaired neuromuscular function and muscle damage and possibly renal damage if prolonged usage¹⁷. The treatment, mode of action (MOA) and their side effects of synthetic drugs used in the treatment listed in the table no.1

Plant based medicines:

Since early civilization humans have used herbal based medicines as an alternative treatment method in different forms like powders, decoction, churnas, bhasmas etc¹⁸ for gastrointestinal disorders as they proved to be effective. Currently use of traditional medicine prepared from herbs is now broadly considered for the treatment of ulcer worldwide, and has been proven as one of the best and safest strategies for the management and treatment of ulcer^19-20_.The previous literatures, and ethnobotonical surveys reported in several articles about GI effects of different parts of plants^20-24_.Preliminary tests for screening of photochemicals in the plants identified the presence of various bioactive secondary metabolites. As reported active principles for antiulcer activity are flavonoids, tannins and terpenoids.Hence, herbal medicines are generally useful in such chronic cases, wherein drugs are required to be used for long periods^25-27.

The aim of this review was to present some evaluated and proved herbal plants for the prevention and treatment of ulcers. Phytoconstituents and the models used for their study are reported in the present review.

MATERIALS AND METHODS:

In this review, the medicinal plants evaluated by researchers for their Antiulcer activity on various models are based on traditionally and ethno medical knowledge available from surveys, interviews or literatures available. Data collected from research papers available in electronic databases. Table 2 summarizes the results obtained from the evaluation of some medicinal plants with gastro-protective or antiulcer effects.

CONCLUSION:

Natural products have been the most successful source of potential drugs since ancient period⁷³. Continuous screening of extracts from medicinal plants is going on for the treatment of Ulcer and various diseases on the basis of traditional claims, knowing the adverse effects of the synthetic drugs available for the treatment. The validation of secondary metabolites in the form of drug identification/designing needs to be carried out. Isolation of active chemical constituents from the extracts showing potential healing activity is the key. Different in-silico approaches like target identification, active site prediction, drug likeliness properties, biological activity and molecular docking of selected phytoligands are the key features for identifying for functional aspects of any drug.

From this review it is evident that experimental evaluation of herbal drugs for the treatment of gastric ulcer is promising. Hence, more research is needed in evaluation of herbal drugs for potential antiulcer activity and standardization of such herbal drugs to be clinically effective, safe and globally competitive.

Table.1 Synthetic drugs used in the treatment, mode of action (MOA) and their side effects ⁷².

Drug class	Medicines used	MOA	Side Effects
Anti-Muscarinic agents	Pirenzepine	Blocks M1 muscarinic receptor Decrease vagal stimulation Inhibits gastric secretion. Decrease pepsin secretion	Dry mouth, Blurred Vision, Tachycardia.
Antacids	Sodium bicarbonate, Calcium bicarbonate, Aluminiumhydroxide.	Neutralize the HCl Reduces pepsin formation	Diarrhea, Constipation Hypokalemia, Alkalosis.
H2-receptor blockers	Cimetidine, Famotidine, Ranitidine.	Inhibitor of H2 receptor (CYP450)	Headaches, Myalgia Diarrhea, Renal impairment, Confusion
Prostaglandins	Misoprostol	Inhibits the acid secretion Promotes mucus and bicarbonate secretion	Diarrhea, Abdominal pain, Vomiting and nausea, Headache
Proton pump inhibitors	Omeprazole, Esomeprazole, Pantoprazole	Inhibits H+/K+ ATPase in parietal cells	Risk of Pneumonia, Headaches, Diarrhea, Nausea, Weakness
Mucosal protective agents	Sucralfate, Bismuth Subsalicylate	Forms a protective layer by binding with proteins found in base of the ulcer. Stimulates angiogenesis for healing. Inhibits pepsin activity. Antimicrobial activity against H. pylori	Dry mouth, Skin rash, Headaches, Darkening of stools, Severe Constipation.

Table 2: Medicinal plants with Anti- Ulcer activity

Botanical Name and Family	Parts Used	Extract	Active constituents	Antiulcer Models	Reference
Aegle marmelos (L.) Correa Family: Rutaceae	Roots	Ethanol	Alkaloids, flavonoids, saponins, steroids, terpenoids, and tannins	Aspirin, Indomethacin and ethanol induced.	28, 29
Abrus precatorius Family: Rutaceae	Leaves	Ethanol	Alkaloids, steroids, triterpenoids, isoflavanoquinones, anthocyanins, starch, tannin, protein, flavanoids, phenolic compound, fixed oil, amino acid and flavones	Acetic acid-induced gastric ulcers in rats	30,31
Aphanmixis polystachya Family: Meliaceae	stem bark	Ethanol	Alkaloids, anthraquinones, cardiac glycosides, flavonoids and terpenoids	Pylorus ligation method, indomethacin induced, Stress ulcer through cold water immersion	32,33
Azadirachta indica Family: Meliaceae.	Leaves	Aqueous	Alkaloids, glycosides, flavonoids, reducing sugars, Terpenoids, saponins, tannins	Pyloric ligation, Aspirin-induced, Cold restraint stress-induced ulcer	34-36
Barleria Family: Acanthaceae	Leaves	Ethanol	alkaloids, saponins, terpenoids, flavonoids, steroids, cardiac glycosides, tannins, aminoacids, and proteins	pylorus ligation‑induced ulcer	37
Beta vulgaris Family: Chenopodiacea	Roots	Methanol	flavonoids, saponins, sterols, and alkaloids	pyloric-ligation, ethanol induced gastric lesion and cold restraint stress induced ulcer models	38
Chrozophora plicata, Family: Euphorbiaceae	Leaves	Chloroform	alkaloids, flavonoids, tannins	pylorus ligation and indomethacin models	39
Cissus setosa Family: Vitaceae	Aerial Parys	Methanol	saponins, terpenoids, flavonoids, steroids, cardiac glycosides, tannins, aminoacids, and proteins	pylorus ligated and ethanol induced gastric ulcer	40,41
Clitorea ternatea Family: Fabaceae	Leaves	petroleum ether, chroloform and ethanol	Alkaloids, tannins, flavonoids, glycosides and steroids.	Pylorus ligation Ethanol induced ulcer	42
Curcuma longa Family: Zingiberaceae	Rhizome	50% ethanol using	nonvolatile curcuminoids, volatile oil, polyphenolic derivatives of curcumin, sesquiterpenoids and monoterpenoids	Pylorus ligation Ethanol induced ulcer	43-45
Delosperma Resei Family: Aizoaceae	Leaves	Aqueous	polyphenols and tannins.	Phenylbutazone induced	46
Enicosanthellum pulchrum Family: Annonaceae	Leaves and stems	Methanol	Alkaloids, acetogenins, terpenoids or steroids.	Ethanol induced ulcer	47
Eupatorium aschenbornianum Family: Asteraceae	Stem	Hexane	terpenes, flavonoids and alkaloids	Pylorus ligation Ethanol induced ulcer	48-50
Ficus. Thonningii Family: Moraceae	Stem bark	Hydroalchholic	polyphenols, saponins, alkaloids, flavonoids, catechic tannins, coumarins, quinones, phlobotanins, anthocyanins	Ethanol induced ulcer	51
Hyptis suaveolens Family: Lamiaceae.	Leaves	Aqueous Extract	Flavonoids and Triterpenoids	Ethanol-Induced Gastric Ulcer	52
Jatropha gossypifolia Family: Euphorbiaceae	root, leaf and stem bark	n-Butanol and ethyl acetate	coumarins, alkaloids, terpenoids, tannins, phenolic acids.	α-glucosidase and α-chymotrypsin inhibitory activity	53
Madhuca indica Family: Sapotaceae.	Leaves	Aqueous Extract	Flavonoids, coumarins, alkaloids, gaycoside, terpenoids, tannins, phenolic acids.	Naproxen induced gastric mucosal injury	54
Mangifera indica Family: Anacardiaceae	Seed kernel	Ethanol	tannins, oxalates, cyanogenic glycosides, phytic acid, trypsin inhibitors, and alkaloids	Alcohol induced gastric ulcer	55,56
Ostericum koreanum Family: Apiaceae	Roots	Methanol	Flavonoids, alkaloids, terpenoids, tannins, phenolic acids.	ethanol-, indomethacin- and pyloric ligation-induced ulcers	57
Parathenium Hysterophorus Family: Asteraceae	Leaves	Aqueous and alcoholic extracts	Alkaloids, proteins, saponins, tannins, carbohydrate, glycosides, terpenoids, steroids, volatile oils, amino acids, amino sugars, lignans, phenolic compounds, flavonoids, metallic elements, organic acids, terpenoids	pyloric ligation-induced ulcers	58, 59
Salvadora Indica Family: Salvadoraceae	Leaves	Ethanol	flavonoids, alkaloids, phenolics, terpenoids, tannins, saponins, carbohydrates and amino acids.	pyloric ligation-induced ulcers	60, 61
Swietenia mahagoni Family:	Leaves	Ethanol	Limonoids, triterpens, tetranortriterpenes, and chlorgenic acid, fatty acids	Alcohol Induced	62
Tamarindus indica Family: Leguminosae	Seeds	Methanol	Pphenolic compounds, polymeric tannins, catechin, procyanidin B2, (-) epicatechin, procyanidin trimer, procyanidin tetramer, procyanidin pentamer, procyanidin hexamer, taxifolin, apigenin, eriodictyol, luteolin, and naringenin.	Ibuprofen-induced ulcer model, Alcohol Induced and pyloric ligation-induced ulcers	63
Tephrosia purpurea Family: Fabaceae	Aerial parts	Aqueous	Flavanones and prenylated flavonoids, chalcones and rotenoids	pyloric ligation-induced ulcers	64-66
Vernonia amygdalina Family: Asteraceae	Leaves	Ethanol	Saponins, alkaloids terpenes, steroids, coumarins, flavonoids, phenolic acids, lignans, xanthones and anthraquinone, edotides and sesquiterpenes	gastric-induced rats using acetosal dose 800 mg/kg	67,68
Ziziphus rugosa Lam.	Bark	Ethanol	Alkaloids, Anthracene Glycosides, Flavonoids, Tannins, Saponins, Carbohydrates, Steroids, Terpenoids and Phenolic compounds	Ethanol and Indomethacin induced.	69

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Received on 12.01.2021 Modified on 17.07.2021

Res. J. Pharmacognosy and Phytochem. 2022; 14(1):37-42.

DOI: 10.52711/0975-4385.2022.00009