INTRODUCTION:

A peptic ulcer is a lesion in the upper gastrointestinal mucosa that penetrates into the deeper layers of the gut wall through the muscularis mucosa. When the cells on the exterior of the stomach lining become inflamed and die, peptic ulcers occur. The stomach's inner lining (gastric ulcer) or the small intestine's inner lining (intestinal ulcer) can both develop ulcers (duodenal ulcer) Both the ulcers are also cumulatively referred as peptic ulcers. It affects nearly 10% of world population. Etiology of peptic ulcer is not clearly known. It results probably due to an imbalance between the aggressive (acid, pepsin, bile and h pylori) and the defensive (gastric mucus and bicarbonate secretion, prostaglandin, nitric oxide, high mucosal blood flow, innate resistance of mucosal cell) factors. ^1–4A peptic ulcer, also known as ulcus pepticum, PUD or peptic ulcer disease, defined as gastric mucosal erosions of a gastro intestinal tract that is usually acidic and extremely painful.⁵

1. Histology of The Stomach:⁶

2. HCl Secretion in Stomach:

Parietal cells secrete hydrogen ions (H+) and chloride ions (Cl^-) into the stomach lumen independently, resulting in hydrochloric acid secretion (HCl). H⁺–K⁺ ATPases drive proton pumps, which transport H⁺ into the lumen while bringing potassium ions (K⁺) into the cell. Cl^- and K⁺difuse out into the lumen through Cl^- and K⁺ channels in the apical membrane at the same time. Carbonic anhydrase is an enzyme that catalyses the synthesis of carbonic acid (H₂CO₃) from water (H₂O) and carbon dioxide (CO₂). It is found in abundance in parietal cells (CO₂). Carbonic acid dissociates, providing a ready supply of H+ for the proton pumps while simultaneously producing bicarbonate ions (HCO₃^-). HCO₃^- accumulates in the cytosol and exits the parietal cell via Cl ^–-HCO₃^- antiporters in the basolateral membrane in exchange for Cl^- (next to the lamina propria). HCO3 diffuses into blood capillaries nearby. After a meal, the "alkaline tide" of bicarbonate ions entering the bloodstream may be large enough to slightly raise blood pH and make urine more alkaline. Acetylcholine (ACh) generated by parasympathetic neurons, gastrin secreted by G cells, and histamine, a paracrine substance released by mast cells in the adjacent lamina propria, can all stimulate HCl secretion by parietal cells. In the presence of histamine, acetylcholine and gastrin induce parietal cells to secrete more HCl. In other sense, histamine enhances the actions of acetylcholine and gastrin by acting synergistically. The plasma membrane of parietal cells has receptors for all three substances. H2 receptors are histamine receptors found on parietal cells that mediate distinct responses than H1 receptors involved in allergy reactions.^6–8

3. Pathogenesis of Ulcer:

The pathophysiology of peptic ulcer disease involves an imbalance between offensive (acid, pepsin, and Helicobacter pylori) and defensive factors (mucin, prostaglandin, bicarbonate, nitric oxide, and growth factors). NSAIDS drugs, emotional stress, alcohol abuse, and smoking are the principal etiological factors associated with peptic ulcer. A peptic ulcer principally occurs due to difference between aggressive factors like pepsin, gastric acid, H. pylori, NSAIDs, prostaglandins, mucous, bicarbonate and blood flow to mucosa etc.⁹

3.1 H. pylori:

It is one the major causes of the peptic ulcer disease. It was previously named as Campylobacter pylori is a gram-negative, microaerophilic bacterium found usually in the stomach. It was identified in 1982 by Australian scientists Barry Marshall and Robin Warren. It is linked with development of duodenal and peptic ulcers but 80% of the people infected with the bacteria are asymptomatic and it plays a important role in maintaining proper stomach ecology. Type I strains of H. pylori are pathogenic which encodes the protein cag-A (Cytotoxin-associated gene A). The presence of cag-A gene is probably the best marker of virulence. More powerful release of proinflammatory cytokines with a subsequent potential of mucosal damage is induced by H. pylori bacteria that are cag-A positive. After translocation into host cells, it disrupts cell motility, effects cell shape, disrupts cell junction activity and thus responsible for gastric carcinomas and ulcers. It also causes expression of cytokines like TNF- α in gastritis. Acid Hypersecretion occurs when there is pronounced H. pylori induced inflammation of the antral mucosa in the presence of gastric mucosa.^10–15

3.2 NSAIDs (Non-Steroidal Anti-Inflammatory Drugs):

NSAIDS like indomethacin and acetyl salicylic acid is most commonly used as a treatment against arthritis, cardiovascular protection and inflammation. The complication caused due to this usage is the gastric disturbances such as ulcers and erosions. 25% of NSAID users develop gastric complications. The pathophysiology of these complications seems to take place due to their action on COX (cyclo-oxygenase) inhibition and prostaglandin (PG) deficiency. PGs play a vital role in the mucosal defence system. Any decrease in the COX (cyclooxygenase) leads to a decrease in PG. This is considered as the most important factor of NSAID induced gastric mucosal damage. Till date there are two COX forms known.COX-1and COX-2.COX-1 is considered as the” housekeeper” of gastric mucosa i.e., it is responsible for maintaining gastric mucosal integrity whereas COX-2 is responsible for inflammation. Earlier it was considered that, for ulceration to take place COX-1 should be reduced. So, gastric injury was thus considered to the gastric mucosal PG-deficiency by COX-1 inhibition. Treatment of NSAID induced peptic ulcer involves usage of medications other than conventional histamine 2 receptor blockers and proton pump inhibitors.^16–19

3.3 Gastric Acid Secretions:

Hydrochloric acid is one of the most important components of gastric juice. It is secreted from the parietal or oxyntic cells. Gastric acid is considered as a major ulcerogenic factor in humans and about 50% of the ulcer patients are acid and pepsin hyper secretors. On the other hand, it also plays a protective role by forming the first line of defence of the gastric mucosa against bacterial colonization. Parietal cells bear three stimulators histamine, acetylcholine and gastrin reflecting a triumvirate of neural paracrine and endocrine control. Histamine, secreted from enterochromaffin-like cells may be the primary modulator but the degree of the stimulus appears to be the complex additive or multiplication interactions of each type of signal. Low amounts of histamine only weakly stimulate gastric acid secretions. But if all of the three components are in low proportion then gastric acid secretion rises. There are receptors on the surface of parietal cell which includes Histamine 2 receptor which respond to histamine released from mast cells, receptors that are sensitive to muscarinic effects of acetylcholine and receptors that are sensitive to gastrin. Various studies indicate that there are numerous epithelial cells at the base of pyloric glands which contain histamine and histamine decarboxylase, the enzyme responsible for histamine synthesis.^20,21

3.4 Ethanol:

One of the most common causes of ulcers is ethanol. Ethanol damages the gastrointestinal mucosa severely, starting with microvascular injury and continuing to increased vascular permeability, edema, and epithelial lifting. The development of haemorrhagic mucosal erosions by vasoconstriction was preceded by a prompt and time-dependent release of endothelin-1 into the systemic circulation after intragastric ingestion of ethanol. Ethanol also reduces bicarbonate secretion and mucus production, and it causes necrotic ulcers in the stomach mucosa. Ethanol should cause apoptosis, which results in cell death. ²²

4. Plants Having Antiulcer Activity:

5.1 Aegle marmelos:

In this study, an aqueous extract of Aegle marmelos leaves was produced and studied. A daily dose of 1 gm/kg body weight of the extract was given orally for 21 days. The volume of gastric secretion, ulcer lesion count, pepsin content, PH, total acidity, hexose, and hexosamine content were all measured. There was a significant reduction in ulcer lesion count, volume of gastric juice, and acidity after extract administration, as well as an increase in pH and hexosamine.²³

5.2 Glycyrrhiza Glabra:

In mice, the antiulcerogenic activity and acute toxicity profile of the hydroalcoholic extract of Glycyrrhiza glabra L. (HEGG) were investigated. In HCl/Ethanol-induced ulcers, the HEGG (50–200 mg/kg) showed a significant reduction in ulcer index. The antiulcer activity of G. glabra extract (50-150 mg/kg) against indomethacin-induced gastric lesions was dose dependent. The extract significantly inhibited ethanol-induced gastric lesions from forming. G. glabra hydroalcoholic extract had an anti-ulcergenic effect, which might be associated to an elevation in gastric mucosal defensive factors, according to the findings.²⁴

5.3 Azadirachta indica:

They investigated the antiulcer activity of the aqueous extract (AE) of A. indica leaves in Wistar rats in this study. Pyloric ligation, aspirin, and cold restraint stress all caused gastric ulcers. The dosages of AE employed per os were 150, 300, and 600 mg/kg body weight. Each model's ulcer index (UI) and percentage inhibition (PI) values were determined. In all of the models used, AE showed a dose-dependent and significant (p 0.05) drop in the UI and an increase in the PI when compared to the control group. The gastric content volume, free acidity, and total acidity all decreased in a dose-dependent manner after administration to AE. They discovered that the leaves of A. indica have potent antiulcer properties that are mediated by multiple mechanisms.²⁵

5.4 Cibotium barometz:

The gastroprotective effect of Cibotium barometz leaves against ethanol-induced gastric hemorrhagic abrasions in Sprague Dawley rats was investigated in this study. In comparison to the ulcerated group, rats pretreatment with plant extract showed a substantial reduction in ulcer area in a dose-dependent manner.²⁶

5.5 Cyperus conglomeratus Rottb.:

The researchers discovered the various metabolites in the Cyperus conglomeratus Rottb. methanol extract and evaluated its in vivo gastroprotective effects in rats with an ethanol-induced gastric ulcer in this study. C. conglomeratus was given in doses of 25, 50, and 100 mg/kg to healthy control rats, ulcer control rats, standard drug group rats, and C. conglomeratus treated rats. Further histological and histochemical examinations in the ulcer group indicated considerable epithelial degradation, a small number of infiltrating inflammatory cells, and glycoprotein depletion in the gastric tissue. It may be concluded that C. conglomeratus extract has significant gastroprotective effect in the treatment of ethanol-induced gastric ulcers and should be included in nutraceuticals for ulcer treatment in the future.²⁶

5.6 Gallesia integrifolia:

The gastroprotective effect of the essential oil from the inner stem bark of G. integrifolia (EOGi)was assessed in acidified ethanol and piroxicam and ulcer healing on acetic acid -induced ulcer models in rodents. Anti-secretory, mucus, K+ - ATP channels, prostaglandins (PGs), nitric oxide (NO), TNF-a, IL-1b, IL-10, catalase (CAT) and myeloperoxidase (MPO) activities and in vitro Helicobacter pylori action by EOGi were evaluated. EOGi exhibited cytotoxic effects only at 72 h and no acute toxicity. EOGi showed gastroprotective and ulcer healing effects. EOGi gastroprotection was attenuated by indomethacin pre-treatment. Gastric volume and total acidity were reduced, while gastric pH was elevated. EOGi increased mucus and NO productions and CAT activity, and inhibited MPO activity, TNF-a and IL-1b concentrations and augmented IL-10. EOGi was not active against H. pylori. These results indicated that EOGi is safe and exerts preventive and curative gastric ulcer effects by multitarget actions. Twenty compounds were identified and (-)-alphasantalene was the main compound.²⁷

5.7 Juniperus phoenicea L.

In this study they evaluated the ulceroprotective and antioxidant activity of essential oil extracted from the leaves of J. phoenicea (EOJp) against hydrogen chloride (HCl)/ethanol-induced ulcers in rats. The antiulcer activities of 50, 75 and 100 mg/kg body weight (b.w.) EOJp were investigated on 0.3 M HCl/ethanol-induced ulcers in rats. The essential oil yield was 0.69% with 48 compounds; α-pinene was the principal component (20.24%). In vivo pre-treatment with EOJp given orally provided dose-dependent protection against HCl/ethanol-induced gastric ulcers in rats. Furthermore, pre-treatment with EOJp significantly decreased malondialdehyde (MDA) content and increased the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). The activity of the antiulcerogenic EOJp could be from synergistic antioxidant and anti-secretory effects. Oral use of EOJp has excellent preventive effects on induced gastric ulcers comparable to those of the proton pump inhibitor (PPI) omeprazole.²⁸

5.8 Mangifera indica:

In this study they analysed the antiulcer potential of ethanol extracts of M. indica seed kernel against acid alcohol induced gastric ulcer. The ethanolic extracts (400mg/kg) of M. indica seed kernel significantly reduced the ulcer index, pH, total acidity, LPO and protein levels. It also acted as good antioxidant agent. They concluded study provide preliminary data on the antiulcer potential of M. indica seed kernel and support the traditional uses of the plant for the treatment of gastric ulcer.²⁹In Recent Studies, the flower decoction was administered in the doses of 250, 500, and 1000 mg/kg orally, in rats with gastric lesions in dose-dependent manner. Thus, the extract significantly reduced the gastric juice volume and gastric acidity.³⁰

5.9 Manuka honey:

In this study investigated the gastroprotective effects of manuka honey against ethanol-induced gastric ulcers in rats. They concluded that Manuka honey likely exerted its antiulcer, effect by keeping enzymatic (GPx and SOD) in a reduced form, inhibited lipid peroxidation (MDA), and preserved mucous glycoproteins levels.³¹

5.10 Musa paradisiaca (BANANA):

In this study evaluated the antiulcer potentials of the tepal and skin extracts of banana Musa paradisiaca. The mice were treated with 100 mg/kg of tepal and skin extract as well as cimetidine for seven days followed by administration of indomethacin. Findings from this study shows that banana’s tepal and skin were able to prevent IND+PYL induced ulcer by strengthening the gastric mucosa and decreasing the gastric juice acidity.³²

5.11 Ocimum forskolei:

The present study detected the bioactive metabolites from Ocimum forskolei aerial parts which are responsible for the antiulcer activity of the total ethanol extract (TEE) as well as different fractions (petroleum ether, dichloromethane, ethyl acetate and aqueous). It concluded that salvitin was the leader compound responsible for the excellent antiulcer potential of O. forskolei.³³

5.12 Ostericum koreanum:

In this study evaluated the antiulcer activity of iso-imperatorin isolated from the roots of O. koreanum. Iso-imperatorin demonstrated significant inhibitory activity against urease as compared to the standard drug thiourea without cytotoxic effects. It provided 70.9%, 67.65% and 54.25% protection in ulcer models induced by ethanol, indomethacin and pyloric ligation, respectively. Iso-imperatorin may be used to develop antiulcer drugs with decreased side effects.³³

5.13 Osyris quadripartite:

The anti-ulcer activity of 80 % methanol leaf extract of Osyris quadripartita was tested in rats in this study. Volume and pH of gastric fluid, total acidity, ulcer score, percent inhibition of ulcer score, ulcer index, and percent inhibition of ulcer index were among the variables studied. The data were examined using one-way analysis of variance and Tukey's post hoc test, with a statistical significance of P<0.05. OQ significantly (P<0.001) reduced gastric ulcer index by 55.82% and 62.11% respectively, in pylorus ligation induced and ethanol induced ulcer models at the 400 mg/kg dose, which is comparable to the standard drugs. ³⁴

5.14 Peltophorum Pterocarpum:

The antiulcer activity of a methanolic extract of Peltophorum pterocarpum leaves (MEPP) was tested on albino rats in this study. Indomethacin (20 mg/kg) was given orally, followed by pylorus ligation, to cause gastric lesions. When MEPP-treated groups were compared to control groups, histological examination confirmed the gastroprotective effect. MEPP indicated potential antiulcer activity and a dose-dependent antiulcer impact, according to the findings.³⁵

5.15 Phyllanthus niruri L.:

Phyllanthus niruri L. (Euphorbiaceae) is generally used in traditional medicine to treat ulcer and inflammation. In this Study investigated the methanolic extract of leaves of Phyllanthus niruri for anti-inflammatory and anti-ulcer activity. Antiulcer activity of methanolic extract of P. niruri leaves at the doses of 100, 200 and 400 mg/kg, p.o. were examined against ethanol-acid induced gastric mucosal injury in the Swiss albino rats - keeping omeprazole (20 mg/kg, p.o.) as reference. The investigation suggests that methanolic extract of P. niruri leaf promotes ulcer protection as ascertained by regeneration of mucosal layer and substantial prevention of the formation of haemorrhage and edema.³⁶

5.16 Plantago ovata seed:

The effects of an aqueous extract of Plantago ovata seed (AEPOS) on a peptic ulcer produced by indomethacin (IND) in rats were examined in this study. The rats were euthanized 4 hours after receiving IND orally, and their stomachs and livers were fixed in 10% formalin and cut into 5 mm diameter slices. Hematoxylin and eosin (H&E) staining were used to evaluate the histological and morphological characteristics of the stomach and liver. When compared to the IND group, AEPOS (100 mg/kg) demonstrated a substantial (p 0.05) reduction in microscopic and macroscopic ulcer indices. According to histological study, AEPOS has a hepatoprotective effect and can protect the stomach mucosa from injury. According to the findings, AEPOS possesses anti-ulcer and hepatoprotective properties.³⁷

5.17 Porphyra vietnamensis:

In this study investigated the anti-inflammatory, analgesic and antiulcer effects of red seaweed Porphyra vietnamensis (P. vietnamenis). Aqueous (POR) and alcoholic (PE) fractions were successfully isolated from P. vietnamenis. Further investigations were performed induced gastro-duodenal ulcer. Among the fractions POR showed better activity. POR showed comparable ulcers reducing potential (p<0.01) to that of omeprazole, and has more ulcer reducing potential then PE. The study demonstrated that P. vietnamenis aqueous fraction possesses biological activity that is close to the standards taken for the treatment of ulcer conditions.³⁸

5.18 Pycnanthus angolensis:

Pycnanthus angolensis, family-Myristicaceae, is used in Nigeria folk medicine to treat complaints such as toothache, headache, sore throat, ulcers and wounds. In this study investigated the antinociceptive and antiulcer activities of the stem bark extract of Pycnanthus angolensis. Acute toxicity was conducted with a single oral dose of 5 g/kg. Antiulcer activity was evaluated in ethanol and indomethacin-induced models in rats. The extract prevented the gastric ulceration caused by ethanol and indomethacin treatments compared to control.³⁹

5.19 Salvadora indica (W.):

In this study investigated the antiulcer activity of ethanolic extract of Salvadora indica W. leaves (ESIL) on albino rats. The present study was carried by pylorus ligation, ethanol and cysteamine induced ulcer models in albino rats. The antiulcer activity of ESIL (150, 300 and 600 mg/kg p.o. for 7 days) was compared with standard drugs (Ranitidine).The results of the study indicates that the ESIL have better potential against ulcer which supports the traditional claims in folklore medicine.⁴⁰

5.20 Zataria multiflora Boiss:

The effect of Z. multiflora hydro-alcoholic extract (ZMHE) on indomethacin-induced peptic ulcer in rats was examined in this study. In this investigation, 72 male Wistar rats were randomly divided into 12 groups, each with six animals: normal rats, control rats, ranitidine-treated rats, and ZMHE (100, 200, 400 mg/kg)-treated rats. After oral and parenteral administration, ZMHE (at all doses) significantly reduced ulcer area and severity compared to the control group. Only ZMHE 400mg/kg showed a significant difference in stomach pH after parenteral treatment when compared to the control group. It was determined that ZMHE could protect against indomethacin-induced experimental stomach ulcers.⁴¹

5.21 Spondias mombin L:

In this study investigated the antiulcer activity of S. mombin ethanolic extract (SmEE) and its majority compounds gallic acid (GA) and ellagic acid (EA). Phytochemical characterization was performed by HPLC. The SmEE was screened for in vitro antioxidant activities using phosphomolybdenum, ABTS, DPPH, and FRAP assays. The antiulcer activity of SmEE, GA, EA, or GA + EA was evaluated by gastric lesion models induced by absolute ethanol and indomethacin. In chronic ulcer model, SmEE reduced the gastric area lesion. SmEE showed anti-H. pylori activity. In conclusion, our study showed that SmEE has antiulcerogenic activity. GA and EA are isolated gastric protectors and, when associated, acted synergistically to protect the gastric mucosa.⁴²

5.22 Spondias purpurea L. (Anacardiaceae):

Spondias purpurea is used in folk medicine to treat diarrhea and diuresis. In this study evaluated the phytochemical profile and antioxidant and antiulcer activities of the hexane extract of the leaves of S. purpurea (SpHE). Phytochemical profile was evaluated via thin layer chromatography (TLC) and HPLC. After gastric ulcer induction by using HCl/ethanol, SpHE reduced the area of ulcerative lesions by 82, 91, and 88%, respectively. In ethanol, SpHE reduced the area of ulcerative lesions by 77, 93, and 92%, respectively. In the NSAID, the percentages of protection were 70, 76, and 78%, respectively. SpHE promoted the minimization of ulcers, increased the levels of reduced glutathione, and decreased tumor necrosis factor. S. purpurea has antioxidant and antiulcer properties.⁴³

5.23 Terminalia catappa L:

The antiulcer mechanism of action in experimental rodent models and its effectiveness against Helicobacter pylori were investigated in this work, as well as the gastroprotective and healing effect of the aqueous fraction (FrAq) obtained from the leaves of Terminalia catappa. Microdilution was used to assess the anti-Helicobacter pylori activity. The number of ulcerative lesions induced by ethanol and ischemia/reperfusion injury were significantly reduced when FrAq (25mg/kg) given orally. When compared to the negative control group, oral therapy with FrAq for seven and 14 days significantly reduced the lesion area (80% and 37%, respectively). This extract also presented considerable activity against Helicobacter pylori. They concluded that FrAq derived from Terminalia catappa leaves had significant preventative and therapeutic effects on acute and chronic caused stomach ulcers.⁴⁴

5.24 Euphorbia umbellate:

The anti-ulcer properties of methanolic bark fraction (MF) were assessed in this study using in vivo and in vitro assays, as well as an antioxidant, antibacterial, and chromatographic analysis of this fraction. Ethanol and indomethacin models with varying MF concentrations (50, 100, or 200mg/Kg) were used to evaluate in vivo anti-ulcer activity. The animals' stomachs were subjected to histopathological examination. The 200mg/kg dose was utilised to investigate the processes underlying the methanolic fraction's antiulcerogenic properties. Several antioxidant assays, as well as anti-Helicobacter pylori and anti-urease investigations, were used to assess in vitro activity. LC-MS analysis was used to carry out the chromatographic study. In ethanol and indomethacin in vivo assays, pharmacological examination of the MF revealed anti-ulcer potential.⁴⁵

5.25 Tamarindus indica:

Recent Research in a pylorus ligation induced ulcer model, the methanolic extract of the seed coat of T. indica at doses of 100 and 200mg/kg significantly reduces the total volume of gastric juice and the free and total acidity of gastric secretion when compared to the control.⁴⁶

5.26 Solanum nigrum:

Recent Research in rats, aqueous leaf extract of Solanum nigrum protected against gastric ulcers caused by pylorus ligation.⁴⁷

5.27 Shorea robusta:

Recent Research in rats, the extract of S. robusta was given orally at doses of 150 and 300mg/kg to prevent gastric ulcers caused by ethanol and pylorus ligation. In comparison to the control, the extract significantly increases gastroprotective activity. Constituents that are active: Ursolic acid and amyrin.⁴⁸

5.28 Rhus coriaria:

In Recent Studies, the hydro alcoholic extract of R. coriaria was administered at the doses of 145 and 248mg/kg orally in rats against ethanol induced gastric ulcer. The extract significantly increases the healing of gastric ulcers.⁴⁹

5.29 Psidium guyava:

Recent Research in rats, the methanol leaf extract of P. guyava was administered orally at doses of 500 and 1000 mg/kg for 10 days to prevent ethanol-induced gastric ulcers. In comparison to the control, the extract reduces ulcer indices substantially.⁵⁰

5.30 Ficus religiosa:

Recent Research In rats, the hydro alcoholic extract leaves of F. religiosa were tested against absolute ethanol, aspirin, and pylorus ligation induced gastric ulcer at two dose levels (250 and 500mg/kg, oral). When compared to the control, the extract considerably lowers the ulcer index value.⁵¹

5.31 Careya arborea:

Recent Research In rats, the ethanol stem bark extract of C. arborea was administered orally at doses of 300 and 600mg/kg for 5 days to prevent ulcers caused by ethanol, cold restraint stress, and pylorus ligation. When compared to a control group, the extract significantly improves gastric ulcer healing.⁵²

5.32 Annona squamosa:

Recent Research. In rats, the aqueous leaf extract protected them from pylorus ligation and ethanol-induced gastric ulcers.⁵³

5.33 Basil Oil:

The anti-ulcer activity of tulsi leaves in albino rats was investigated in this study. Albino rats were assigned to different experimental groups at random and given aqueous leaf extract of Tulsi (Ocimum sanctum) for seven days. Cold restrain methods were used to create gastric ulcers, and the results were compared to distilled water and the standard drug Ranitidine as a control. With the cold restraint model, the anti-ulcer effect of Tulsi aqueous extract was considerable in a dose-dependent way. Tulsi leaf extract showed 68.85% ulcer protection at 100mg/kg and 65.66% at 200mg/kg, while the standard drug Ranitidine showed 78.23 percent ulcer protection, which is significant (p0.05). The study found that when Tulsi (Ocimum sanctum) was given to rats at a dose of 100-200mg/kg for 7 days as a pre-treatment for anti-ulcer effect, it resulted in a significant reduction in ulcer scores and ulcer index when compared to the control group, as evidenced by the gross appearance and histological findings of gastric mucosa in rats.⁵⁴ In this study, the fixed oil of Ocimum sanctum L. (Labiatae) was found to have significant antiulcer activity in experimental animal models induced by aspirin, indomethacin, alcohol, histamine, reserpine, serotonin, and stress.⁵⁵

6 Formulations:

6.1 A.V.S. Praveen Kumar et al was formulated antiulcer Polyherbal suspension and evaluated for preliminary phytochemical screening, standardisation and experimental antiulcer activity. Allophylus serratus, Psidium gujava L, Adathoda vasica L., Eclipta alba L., and Emblica officinalis L. are included in the Polyherbal suspension. In adult albino wistar rats, the Polyherbal suspension was investigated for acute toxicity and antiulcer activity at 400mg/kg and 800mg/kg in ulcer models induced by ethanol (1ml/kg), indomethacin (40 mg/kg), and aspirin (150mg/kg). After a standard phytochemical and pharmacognostical study, the Polyherbal suspension exhibited significant anti-ulcerogenic activity at a dose of 800mg/kg.⁵⁶

6.2 Mukesh B Chawda et al was carried out the pilot study on Plantacid® and evaluated the antiulcer activity of Plantacid® suspension on non-steroidal anti-inflammatory drugs (NSAID’s) -induced ulcers in the rat model. They found Significant decrease in ulcer score (p<0.05), total number of ulcers (p<0.0001) ulcer index (p<0.0001) and % inhibition of ulcer was reduced by 82.06%, and 90.04% in Plantacid® suspension and Ranitidine treated groups respectively, as compared to the indomethacin group. They concluded that Plantacid® suspension has showed antiulcer activity in experimental animals and corroborates Ayurvedic use of Plantacid® suspension in gastric ulcers.⁵⁷

6.3 Santhosha Dasarapu and Ramesh Alluri was formulated a polyherbal formulation which is more effective at a lesser dose. They investigated for its anti-ulcer activity against ethanol induced ulcer in rats at 100 and 200mg/kg body weight p.o. Omeprazole was used as standard at a dose of 20mg/kg. Rats were sacrificed and the ulcer areas of the gastric walls were determined. They found the protection was statistically significant and reduced the severity of ulcer and caused a significant reduction of ulcer index in this model. For polyherbal formulation they used rhizomes of Zingiber officinale, Curcuma longa and leaves of Azadirachta indica therapeutic dose of three plants is in the ratio of 1: 1.42: 2.51 respectively.⁵⁸

6.4 Shahabuddin Bahmani et al was formulated Surasa A poly herbal formulation which consisting of Phyllanthus embelica, Withania somnifera, Glycyrrhiza glabra, Cuminum cyminum, Eclipta alba and Shanka bhasma. Surasa's anti-secretory and ulcer-protective properties were evaluated in a pylorus-ligated rat model. For the pylorus-ligated rats' model, Wistar rats weighing 180-200g were employed, using Ranitidine as the standard. Surasa was given to test groups at three different dosage levels: 137, 205, and 274 mg/kg.b.w for acute study and 137 and 205 mg/kg for chronic study. Antisecrtroy and antiulcer activity of Surasa was very significant (p<0.05) reduced gastric secretions and ulcer score.⁵⁹

6.5 G. ROOPA et al Formulated and evaluated antacid and anti-ulcer suspension containing herbal drugs like Glycyrrhiza glabra, Terminalia belerica, Terminalia chebula, Emblica officinalis and mineral Turbinella rapa. The pH, viscosity, sedimentation volume, redispersibility, antacid, and antiulcer activities of the suspensions were then determined. All of the formulations had a pH of around 8.2, an acid neutralising capability of 2-3mEq/ml, a high sedimentation volume, and good redispersibility. In comparison to a formulation comprising the powders of these drugs, the one including extracts of the herbs showed a considerable reduction in the ulcer index.⁶⁰

6.6 Ibrahim A Al Mofleh et al examines the effect of “Black seed” or “Black Cumin” Nigella sativa (NS) aqueous suspension on experimentally induced gastric ulcers and basal gastric secretion in rats to rationalize its use by herbal and Unani medicine practitioners. Acute gastric ulceration was produced by various noxious chemicals (80% ethanol, 0.2 M NaOH, 25% NaCl and indomethacin) in Wistar albino rats. Black seed aqueous suspension significantly reduced the formation of gastric ulcers caused by necrotizing agents. In pylorus-ligated Shay rats, it also significantly reduced ulcer severity and basal gastric acid output. Furthermore, the suspension considerably replaced the ethanol-induced reduced gastric wall mucus content and non-protein sulfhydryl concentration in the gastric mucosa. The anti-ulcer effect was further confirmed histopathologically.⁶¹

6.7 Ibrahim A Al Mofleh et al formulated and evaluated aqueous suspension of anise “Pimpinella anisum”. They found Anise significantly inhibited gastric mucosal damage induced by necrotizing agents and indomethacin. The anti-ulcer effect was further confirmed histologically. In pylorus-ligated Shay rats, anise suspension significantly reduced the basal gastric acid secretion, acidity and completely inhibited the rumenal ulceration.⁶²

6.8 Sameena Alam et al investigated the antiulcer potential of poly herbal formulation (Piper betel, Acacia catechu, Foeniculam vulgare, Eugenia caryophyllus) in experimental rats. The two dose levels, 250mg and 500 mg/kg body weight, were then chosen and tested for antiulcer effectiveness in wistar rats using an aspirin-induced gastric ulcer model and an ethanol-induced gastric ulcer model. At a dosage of 250mg/kg body weight, the aqueous extract of poly herbal recorded the maximum percentage inhibition (p<0.01) in an ethanol-induced gastric ulcer model. This study suggested that the formulation shows synergistic effect in the treatment of ulcer.⁶³

7 Marketed Preparations:

8 CONCLUSION:

The present study indicated that the various plants parts containing active constituent possesses anti-ulcer activity in animal models. The antiulcer activity of polyherbal suspension was investigated in various researches and their findings shows safety and efficacy of polyherbal suspension.

9. CONFLICT OF INTEREST:

The author declare no conflict of interest.

10. REFERENCES:

1. Kavitt, R. T., Lipowska, A. M., Anyane-Yeboa, A. and Gralnek, I. M. Diagnosis and Treatment of Peptic Ulcer Disease. The American Journal of Medicine 132, 447–456 (2019).

2. Sverdén, E., Agréus, L., Dunn, J. M. and Lagergren, J. Peptic ulcer disease. The BMJ 367, 1–8 (2019).

3. Meshram, N. et al. Significance of Medicinal Plant used for the Treatment of Peptic Ulcer. Asian Journal of Pharmacy and Technology 5, 32 (2015).

4. Patidar, K. and Patel, N. A Study to assess the Effectiveness of Structured Teaching Programme (STP) on Knowledge regarding risk factors and prevention of Peptic ulcer among the middle age Population in selected urban area at Mehsana City. Asian Journal of Nursing Education and Research 9, 370 (2019).

5. Anand, S. J. T. and Sara, B. A study to assess the effectiveness of Video Teaching Programme on Diet and Stress Management among patients with Peptic Ulcer Disease in RMMCH, Annamalai University, Chidambaram. Asian Journal of Nursing Education and Research 5, 389 (2015).

6. Tortora, G. and BRYAN, D. Principles of Anatomy and Physiology. (WileyPLUS, 2017).

7. Smith, M. E. and Morton, D. G. 4 - The Stomach: Control. in The Digestive System (Second Edition) 51–69 (Churchill Livingstone, 2010).

8. Mahurkar, N. and Sayeed Ul Hasan, S. M. Synergistic Antiulcer Effect of Melatonin and Esomeprazole Combination in Pylorus Ligation, Ethanol, Aspirin induced Peptic Ulcers. Asian Journal of Pharmaceutical Research 5, 10 (2015).

9. Goudanavar, P. S., Ramesh, B. and Fattepur, S. R. Gastro retentive dosage forms: An excellent carrier system for treatment of peptic ulcer. Research Journal of Pharmacy and Technology 14, 2316–2320 (2021).

10. Fan, X. G., Kelleher, D., Fan, X. J., Xia, H. X. and Keeling, P. W. Helicobacter pylori increases proliferation of gastric epithelial cells. Gut 38, 19–22 (1996).

11. Blaser, M. J. Not all Helicobacter pylori strains are created equal: should all be eliminated? Lancet (London, England) 349, 1020–1022 (1997).

12. Narayanan, M., Reddy, K. M. and Marsicano, E. Peptic Ulcer Disease and Helicobacter pylori infection. Missouri medicine 115, 219–224 (2018).

13. Warzecha, Z. et al. Deleterious effect of Helicobacter pylori infection on the course of acute pancreatitis in rats. Pancreatology: official journal of the International Association of Pancreatology (IAP) 2, 386–395 (2002).

14. Buti, L. et al. Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host. Proceedings of the National Academy of Sciences of the United States of America 108, 9238–9243 (2011).

15. Thulluru, A. et al. Optimization of HPMC K100M and Sodium Alginate Ratio in Metronidazole Floating Tablets for the Effective Eradication of Helicobacter pylori. Asian Journal of Pharmacy and Technology 9, 195 (2019).

16. Scarpignato, C. and Hunt, R. H. Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention. Gastroenterology clinics of North America 39, 433–464 (2010).

17. Vane, J. R. and Botting, R. M. Mechanism of action of nonsteroidal anti-inflammatory drugs. The American journal of medicine 104, 2S-8S; 21-22S (1998).

18. Laine, L., Takeuchi, K. and Tarnawski, A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology 135, 41–60 (2008).

19. Griffin, M. R., Piper, J. M., Daugherty, J. R., Snowden, M. and Ray, W. A. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Annals of internal medicine 114, 257–263 (1991).

20. Szabo, S. et al. Vascular approach to gastroduodenal ulceration: new studies with endothelins and VEGF. Digestive diseases and sciences 43, 40S-45S (1998).

21. Aihara, T. et al. Pharmacological control of gastric acid secretion for the treatment of acid-related peptic disease: past, present, and future. Pharmacology and therapeutics 98, 109–127 (2003).

22. Mahmood, A. A. et al. Enhancement of gastric ulcer by Areca catechu nut in ethanol-induced gastric mucosal injuries in rats. Journal of Medicinal Plants Research 5, 2562–2569 (2011).

23. Ilavarasan, J. R., Monideen, S. and Vijayalakshmi, M. Antiulcer Activity of Aegle Marmelos Linn. Ancient science of life 21, 256–259 (2002).

24. Jalilzadeh-Amin, G., Najarnezhad, V., Anassori, E., Mostafavi, M. and Keshipour, H. Antiulcer properties of glycyrrhiza glabra L. Extract on experimental models of gastric ulcer in mice. Iranian Journal of Pharmaceutical Research 14, 1163–1170 (2015).

25. Bhajoni, P. S., Meshram, G. G. and Lahkar, M. Evaluation of the Antiulcer Activity of the Leaves of Azadirachta indica: An Experimental Study. Integrative Medicine International 3, 10–16 (2016).

26. Al-Wajeeh, N. S. et al. The antiulcer effect of Cibotium barometz leaves in rats with experimentally induced acute gastric ulcer. Drug Design, Development and Therapy 11, 995–1009 (2017).

27. Arunachalam, K. et al. Chemical characterization, toxicology and mechanism of gastric antiulcer action of essential oil from Gallesia integrifolia (Spreng.) Harms in the in vitro and in vivo experimental models. Biomedicine and Pharmacotherapy 94, 292–306 (2017).

28. Jemaї, M. et al. Investigation of Antiulcer and Antioxidant Activity of Juniperus phoenicea L. (1753) Essential Oil in an Experimental Rat Model. Biol Pharm Bull. 2015;38(11):1738-46. doi: 10.1248/bpb.b15-00412.

29. Prabhu K and Rajan S. Assessment of Antiulcer Activity of Ethanolic Extract of Mangifera indica Seed Kernel Using Acid Ethanol Induced Ulcer Model. Int. J. Curr. Microbiol. App. Sci (2015) 4(4): 854-860

30. Neelima, N., Sudhakar, M., Patil, M. B. and Lakshmi, B. V. S. Anti-ulcer Activity and HPTLC Analysis of Mangifera indica L. Leaves. International Journal of Pharmaceutical and Phytopharmacological Research 2012, 146–155 (2012).

31. Saad B. Almasaudi, Nagla A. El-Shitany, Aymn T. Abbas, Umama A. Abdel-dayem, Soad S. Ali, Soad K. Al Jaouni, Steve Harakeh, "Antioxidant, Anti-inflammatory, and Antiulcer Potential of Manuka Honey against Gastric Ulcer in Rats", Oxidative Medicine and Cellular Longevity, vol. 2016, 10 pages, (2016).

32. Antiulser, A. et al. Antiulcer activity of musa paradisiaca (banana) tepal and skin extracts in ulcer induced albino mice. 20, 1203–1216 (2016).

33. Raza H, Abbas Q, Hassan M, Eo SH, Ashraf Z, Kim D, Phull AR, Kim SJ, Kang SK, Seo SY. Isolation, characterization, and in silico, in vitro and in vivo antiulcer studies of isoimperatorin crystallized from Ostericum koreanum. Pharm Biol. 2017 Dec;55(1):218-226. doi: 10.1080/13880209.2016.1257641.

34. Abebaw, M., Mishra, B., and Gelayee, D. A. (2017). Evaluation of anti-ulcer activity of the leaf extract of Osyris quadripartita Decne. (Santalaceae) in rats. Journal of experimental pharmacology, 9, 1–11. https://doi.org/10.2147/JEP.S125383.

35. Pradeepkumar, B., Bhavyamadhuri, C. P., Padmanabha reddy, Y., Veerabhadrappa, K. V., Narayana, G., Haranath, C., Somasekhar reddy, K., and Sudheer, A. (2017). Evaluation of Antiulcer Activity of Peltophorum Pterocarpum. Journal of clinical and diagnostic research: JCDR, 11(6), FF01–FF03. https://doi.org/10.7860/JCDR/2017/26171.9998.

36. Mostofa, R., Ahmed, S., Begum, M. M., Sohanur Rahman, M., Begum, T., Ahmed, S. U., Tuhin, R. H., Das, M., Hossain, A., Sharma, M., and Begum, R. (2017). Evaluation of anti-inflammatory and gastric anti-ulcer activity of Phyllanthus niruri L. (Euphorbiaceae) leaves in experimental rats. BMC complementary and alternative medicine, 17(1), 267. https://doi.org/10.1186/s12906-017-1771-7.

37. Bagheri, S. M. et al. Antiulcer and hepatoprotective effects of aqueous extract of Plantago ovata seed on indomethacin-ulcerated rats. Biomedical Journal 41, 41–45 (2018).

38. Bhatia, S., Sharma, K., Sharma, A., Nagpal, K. and Bera, T. Anti-inflammatory, Analgesic and Antiulcer properties of Porphyra vietnamensis. Avicenna journal of phytomedicine 5, 69–77 (2015).

39. Sofidiya, M. O. and Awolesi, A. O. Antinociceptive and antiulcer activities of Pycnanthus angolensis. Revista Brasileira de Farmacognosia 25, 252–257 (2015).

40. Sahoo, S. K. et al. Antiulcer activity of ethanolic extract of Salvadora indica (W.) leaves on Albino rats. Journal of Clinical and Diagnostic Research 10, FF07-FF10 (2016).

41. Minaiyan, M., Sajjadi, S.-E. and Amini, K. Antiulcer effects of Zataria multiflora Boiss. on indomethacin-induced gastric ulcer in rats. Avicenna journal of phytomedicine, 408–415 (2018).

42. Brito, S. A. et al. Antiulcer activity and potential mechanism of action of the leaves of Spondias mombin L. Oxidative Medicine and Cellular Longevity 2018, (2018).

43. de Almeida, C. L. F. et al. Spondias purpurea L. (Anacardiaceae): Antioxidant and antiulcer activities of the leaf hexane extract. Oxidative Medicine and Cellular Longevity 2017, (2017).

44. Silva, L. P. et al. Terminalia catappa L.: A medicinal plant from the Caribbean pharmacopeia with anti-Helicobacter pylori and antiulcer action in experimental rodent models. Journal of Ethnopharmacology 159, 285–295 (2015).

45. Minozzo, B. R. et al. Anti-ulcer mechanisms of polyphenols extract of Euphorbia umbellata (Pax) Bruyns (Euphorbiaceae). Journal of Ethnopharmacology 191, 29–40 (2016).

46. Kumar, S., Suman, Sharma, S. and Kalra, P. Antiulcer effect of the methanolic extract of Tamarindus indica seeds in different experimental models. Journal of Pharmacy and Bioallied Sciences 3, 236–241 (2011).

47. Shree, G. K., Parvathi, S., Ramkumar, P. S. S., and Priya, S. S. Pharmacological and phytochemical evaluation of anti-ulcerogenic potential of Solanum nigrum. International Journal of Pharmaceutical Sciences and Research, 3(8), 2837, (2012).

48. Santhoshkumar, M., Anusuya, N. and Bhuvaneswari, P. Antiulcerogenic effect of resin from Shorea robusta Gaertn. F. on experimentally induced ulcer models. International Journal of Pharmacy and Pharmaceutical Sciences 5, 269–272 (2013).

49. Ahmad, H., Wadud, A., Jahan, N., Khazir, M. and Sofi, G. Evaluation of Anti-ulcer activity of hydro alcoholic extract of Post Sumaq (Rhus coriaria Linn.) in Ethanol induced Gastric ulcer in experimental Rats. International Research Journal of Medical Sciences 1, 7–12 (2013).

50. Uduak, E. U. et al. Ulceroprotective Effect of Methanol Extract of Psidium guajava Leaves on Ethanol Induced Gastric Ulcer in Adult Wistar Rats. Asian Journal of Medical Sciences 4, 75–78 (2012).

51. Gregory, M. et al. Anti-ulcer activity of Ficus religiosa leaf ethanolic extract. Asian Pacific Journal of Tropical Biomedicine 3, 554–556 (2013).

52. Kumar, K., Mruthunjaya, K., Kumar, S. and Mythreyi, R. Anti ulcer activity of ethanol extract of the stem bark of Careya arborea Roxb. International Current Pharmaceutical Journal 2, 78–82 (2013).

53. CH. Madhu*, P. Jonathan Brainard, G. Prithvi Raj, J. S. and A. S. S. R. Antiulcer activity of aqueous extract of annona squamosa leaves on rats. IJPSR 3, 4429–4433 (2012).

54. Vaseem, A., Ali, M. and Afshan, K. Activity of Tulsi leaves (Ocimum sanctum linn) in protecting gastric ulcer in rats by cold restrain method. IJBCP 6, 2343–2347 (2017).

55. Singh, S., and Majumdar, D. K. (1999). Evaluation of the gastric antiulcer activity of fixed oil of Ocimum sanctum (Holy Basil). Journal of ethnopharmacology, 65(1), 13–19. https://doi.org/10.1016/s0378-8741(98)00142-1.

56. Lakshmi, M. Pharmacognostical, Phytochemical and Pharmacological evaluation for the antiulcer activity of Polyherbal suspension. Journal of Pharmacognosy and Phytochemistry, 2(3), 128-135 (2013).

57. Vahalia, M., Vemula, S., Chawada, M. and Thakur, K. Antiulcer activity of Amlapitta Mishran suspension in rats: A pilot study. Ancient Science of Life 32, 112 (2012).

58. Dasarapu, S. and Alluri, R. Evaluation of Antiulcer Activity of Polyherbal Formulation Against Ethanol Induced Gastric Ulcer in Albino Rats. International Journal of Innovation Sciences and Research 5, 761–765 (2016).

59. Bahmani, S., Harish, M. S., Iqbal, M. and Rao, K. S. Anti-secretory and anti-ulcer activity of Surasa, a poly herbal formulation in pylorus ligated (Shay) rat model. Biosciences Biotechnology Research Asia 5, 295–300 (2008).

60. Roopa, G., Bhat, R. S. and Dakshina, M. S. Formulation and evaluation of an antacid and anti-ulcer suspension containing herbal drugs. Biomedical and Pharmacology Journal 3, 01–06 (2010).

61. al Mofleh, I. et al. Gastroprotective effect of an aqueous suspension of black cumin Nigella sativa on necrotizing agents-induced gastric injury in experimental animals. Saudi Journal of Gastroenterology 14, 128–134 (2008).

62. al Mofleh, I. A., Alhalder, A. A., Mossa, J. S., Al-Soohalbani, M. O. and Rafatullah, S. Aqueous suspension of anise “Pimpinella anisum” protects rats against chemically induced gastric ulcers. World Journal of Gastroenterology 13, 1112–1118 (2007).

63. Sameena Alam, Mohammed Mohiuddin, Kumar Linga Swamy, Abdullah Baig1, M. Venkata Reddy, Rajesh Kumar Gupta, S. D. Evaluation of Antiulcer and Antioxidant Activity of Polyherbal Formulation in Wistar Rats. International Journal of Pharmaceutical and Phytopharmacological Research 2, 407–411 (2013).

64. Dizester Herbal, Dr. Willmar Schwabe India, Accessed January 06, 2022 https://www.schwabeindia.com/

65. Amlapitta Mishran Suspension, Shree Dhootapapeshwar Ltd., Accessed January 06, 2022 https://sdlindia.com/

66. Himcocid-SF, Himalaya Wellness Company, Accessed January 06, https://himalayawellness.in/products/himcocid-sf

67. Ulcercare Capsules, TVS Biotech, Accessed January 06, https://www.tvsbiotech.com/health-wellness-products-suppliers-india.html

68. Yashtimadhu, Himalaya Wellness Company, Accessed January 06, https://himalayawellness.in/products/yashtimadhu

Received on 24.01.2022 Modified on 27.02.2022

Res. J. Pharmacognosy and Phytochem. 2022; 14(2):89-97.

DOI: 10.52711/0975-4385.2022.00017

Sr. No.	Product Name	Company Name	Ingredients	Activity
1	Dizester Herbal⁶⁴	Willmar Schwabe India	Carum carvi, Cassia angustifolia, Cassia fistula, Cuminum cyminum, Ferula asafoetida, Foeniculum vulgare, Mentha piperita, Moringa oleifera, Myristica fragrans, Terminalia chebula, Trachyspermum ammi, Zingiber officinale	Anti spasmodic and helpful in stomach pain, Beneficial in Acidity, Flatulence, Nausea, Vomiting Acid reflux.
2	Dhootapapeshwar Amlapitta Mishran Suspension 450 ml⁶⁵	Shree Dhootapapeshwar LTD.	Vasa, Guduchi, Pittapapada, Nimba, Chiraita, Bhrungaraj, Triphala, Patol, Yashtimadhu, Shouktik Bhasma.	Reduce heartburn, nausea, Epigastric pain, Balances the Pitta secretion
3	Himalaya Himcocid Suspension (Mint) (200ml)⁶⁶	Himalaya Wellness Company	Cowrie Shell Ash (Varatika), Indian Gooseberry (Amalaki)	Ulcer-healing and gastroprotective properties.
4	Ulcercare Capsules⁶⁷	TVS Biotech	YASHTIMADHU(Licorice)	anti-ulcer, anti-arthritic, anti-allergic
5	Yashti madhu Tablet⁶⁸	Himalaya Wellness Company	Yashtimadhu	Healing of gastric and duodenal ulcers