Efficacy of a Chitosan-curcumin Mixture in Treating Indomethacininduced Acute Gastric Ulcer in Rats.

BACKGROUND: Curcumin is claimed as a potent protectant against Gastric Ulcer (GU) induced by strong necrotizing agents, including NSAIDs through its antioxidant, anti-inflammatory and gastroprotective activities. However, it was found to exert opposite effects to either delay ulcer healing or exacerbate ulcer inflammation through some curative mechanisms differently modified by curcumin dosage. Its ability to inhibit the expression of COX-2 may also delay the healing of NSAIDs-induced GU. Recently, a topical chitosan-curcumin solution has been found to be a safe and potential alternative agent in treating oral ulcer. Therefore, an oral chitosan-curcumin mixture was developed and determined for its efficacy in treating NSAIDs-induced GU in the rat. METHODS: A chitosan (150 mg)-curcumin (20 mg) mixture with optimal gastric pH was developed. Indomethacin (30 mg/kg) was given orally to the rat and test preparations were administered orally at 5 h later and then every 24 h for two consecutive days. The sum of all gastric ulcerated areas (mm2) for each stomach was used as ulcer index. Gastric pro-inflammatory mediators and cytoprotective factors were determined. RESULTS: An oral administration of a chitosan-curcumin mixture exerted a superior efficacy than curcumin, chitosan or lansoprazole (a standard antiulcer agent) in healing indomethacin-induced GU. It was revealed that the mixture exhibited the highest anti-oxidant, anti-inflammatory and gastric mucus producing activities including the high potency in down-regulating pro-inflammatory COX-2 and iNOS expression but up-regulating cytoprotective COX-1, nNOS and eNOS expression. CONCLUSION: The present findings indicated the benefit of a chitosan-curcumin mixture as a potential alternative agent in treating NSAIDs-induced gastric ulcers.

Comparative Inhibitory Efficacy on the iNOS/NO System of Curcuminand Tetrahydrocurcumin-Self-Microemulsifying Liquid Formulation in Chronic Gastric Ulcer Model.

BACKGROUND: Curcumin was found to accelerate gastric ulcer healing by the main mechanism, i.e., the suppression of iNOS mediated inflammation. Although Tetrahydrocurcumin (THC) is claimed to be an active antioxidant element of curcumin, its antiulcer activity has not been systematically examined. The utility of Self-Microemulsifying Drug Delivery Systems (SMEDDSs) for curcumin and THC formulations in the liquid form was also found to increase the rate and extent of release of curcumin- and THC-SMEDDS. Nevertheless, the beneficial antiulcer effect of these nanoproducts has not yet been evaluated. OBJECTIVE: This study aimed to evaluate and compare the antiulcer efficacy of curcumin- and THCSMEDDS through the inhibition of the iNOS/NO system in the rat model. METHODS: Antiulcer efficacy was compared in terms of the ability to accelerate healing of gastric ulcer including the efficient inhibitory action on inflammatory NO production in activated macrophages and iNOS mRNA expression at the ulcerated area. RESULTS: THC was found to have less ulcer healing capacity than curcumin with a lack of significant inhibitory effect on the iNOS/NO system. The SMEDDS used in the study significantly increased the inhibitory efficacy of THC on iNOS/NO production and iNOS mRNA expression compared to the inhibitory potency of curcumin. An oral administration of curcumin- or THC-SMEDDS once a day was appropriate for exerting a comparable curative efficacy to a twice-daily oral administration of curcumin or THC. CONCLUSION: The SMEDDS used in the study was observed to enhance the inhibitory efficacy of the antiulcer drug on the iNOS/NO system, leading to a reduction of daily dosing and dosing frequency.

Efficacy of An Aqueous Morinda citrifolia Fruit Extract-Phytosome Gel in Treating Oral Inflammatory Ulcer in Rabbit Model.

BACKGROUND: Oral inflammatory ulcers are one of the common complaints of patients attending out-patient clinics. Previous in vivo studies had shown that an Aqueous M. citrifolia Fruit Extract (AMFE) possessed anti-inflammatory and ulcer healing activities. Therefore, a standardized topical bioadhesive gel containing AMFE-phytosome was developed and determined for its oral ulcer healing efficacy in a rabbit model. METHODS: The AMFE phytosome (AMFE-P) was prepared by a complexation method with the required amount of AMFE: Phosphatidylcholine: Tween 80 to weigh ratio of 2:1:0.2. Poloxamer 407 was used as a gelling agent. The oral ulcer was induced in male New Zealand white rabbits by topical application of acetic acid. Each test compound was applied to the ulcer for 10 days beginning on the second day after the ulcer induction. Complete ulcer healing on the specimen obtained on day 12 was observed histologically using the histological scoring protocol. RESULTS: The optimized gel containing AMFE-P equivalent to AMFE 10%w/w (10%AMFE-P gel) showed the best bioadhesive gel quality, a smooth and homogeneous texture with an optimum viscosity and pH range used in human oral cavity, a good physical and chemical stability and the highest percentage cumulative release of total phenolic and scopoletin content. It was found that a daily application of 10% AMFE-P gel exerted a superior ulcer healing efficacy and a significantly rapid ulcer healing process than a twice daily application of topical gel containing AMFE 10%w/w or chlorhexidine 0.2%. CONCLUSION: These findings demonstrated that 10% AMFE-P gel has potential as a safe and effective alternative therapeutic agent for oral ulcers.

Raft-forming gastro-retentive formulations based on Centella asiatica extract-solid dispersions for gastric ulcer treatment.

Liquid raft-forming formulations comprising solid dispersions of glycoside-rich Centella asiatica extract and Eudragit® EPO (GR-SD) were developed to achieve prolonged delivery of the glycosides, asiaticoside (AS) and madecassoside (MS) in the stomach and thus increase the effectiveness of gastric ulcer treatment. Solid dispersions of GR extract and Eudragit® EPO (GR-SD, weight ratio 1:0.5) resulted in the highest solubility of AS (41.7 mg/mL) and MS (29.3 mg/mL) and completed dissolution of both glycosides occurred in SGF within 10 min. The optimized raft-forming formulation was composed of alginate (2%), HPMC K-100 (0.5%), GR-SD (1.2%), and calcium carbonate (0.5%) as a calcium source and carbon dioxide producer. The formulation provided sufficient raft strength (> 7.0 g), rapid floating behavior in SGF (~30 s), and sustained release of AS (more than 80%) and MS (85%) over 8 h. GR-SD-based formulations administered once daily to rats for two days at a dose of 10 mg AS/kg reduced the severity of gastric ulcer induced by indomethacin with a greater curative efficacy than those of unformulated GR extract and a standard antiulcer agent: lansoprazole (p < 0.05). These findings demonstrate that GR-SD-based raft-forming systems offer significant promise for improving the treatment of gastric ulcers induced by non-steroidal anti-inflammatory drugs.

Effectiveness of an Alcohol-Free Chitosan-Curcuminoid Mouthwash Compared with Chlorhexidine Mouthwash in Denture Stomatitis Treatment: A Randomized Trial.

Objective: An alcohol-free mouthwash of curcuminoids purified from the turmeric (Curcuma longa Linn.) rhizome was formulated using a cosolvent system, comprising chitosan and polyethylene glycol (PEG) 400, and determined for its efficacy and safety in management of denture stomatitis (DS) in comparison with a chlorhexidine (CHX) mouthwash. Design: A single-center, randomized, controlled parallel-arm trial was conducted. Setting: The study took place at the Faculty of Dentistry, Prince of Songkla University, Hat-Yai, Thailand, between June 2016 and June 2017. Subjects: Participants were 20 years old or older adults of both genders, using removable dentures, and with a confirmed diagnosis of DS from an oral medicine specialist. Interventions: A total of 30 patients were randomly assigned to 3 different interventions, including the chitosan-curcuminoid (CHI-CUR) mouthwash, CHX mouthwash, and a vehicle formulation comprising chitosan and PEG 400. Ten milliliters of each intervention was given to the patient to be used for 30 sec, three times a day at 8 am, 12 pm, and 4 pm, for 2 weeks. Outcome measures: Outcome measures included complete relief of erythematous lesions under the denture and reduction in the number of candida colonies present in the denture-fitting surface. Results: Eight of 10 patients (80%) using the CHI-CUR mouthwash had a complete response after the 2-week treatment course compared with 30% of patients using the CHX mouthwash (p < 0.05). Both interventions exerted comparable anticandida efficacy. No oral or systemic adverse events that could possibly be related to the use of mouthwash were documented. Conclusions: The finding indicated that an alcohol-free CHI-CUR mouthwash may serve as a safe and potential topical therapeutic alternative in treating generalized or candida-associated DS.

Development and evaluation of gastroretentive raft forming systems incorporating curcumin-Eudragit® EPO solid dispersions for gastric ulcer treatment.

Novel raft forming systems incorporating curcumin-Eudragit® EPO solid dispersions were developed to prolong the gastric residence time and provide for a controlled release therapy of curcumin to treat gastric ulcers. The solid dispersions of curcumin with Eudragit® EPO were prepared by the solvent evaporation method at various ratios to improve the solubility and the dissolution of curcumin. The optimum weight ratio of 1:5 for curcumin to Eudragit® EPO was used to incorporate into the raft forming systems. The raft forming formulations were composed of curcumin-Eudragit® EPO solid dispersions, sodium alginate as a gelling polymer and calcium carbonate for generating divalent Ca(2+) ions and carbon dioxide to form a floating raft. All formulations formed a gelled raft in 1min and sustained buoyancy on the 0.1N hydrochloric acid (pH 1.2) surface with a 60-85% release of curcumin within 8h. The curative effect on the acetic acid-induced chronic gastric ulcer in rats was determined. The curcumin raft forming formulations at 40mg/kg once daily showed a superior curative effect on the gastric ulcer in terms of the ulcer index and healing index than the standard antisecretory agent: lansoprazole (1mg/kg, twice daily) and a curcumin suspension (40mg/kg, twice daily). These studies demonstrated that the new raft forming systems containing curcumin solid dispersions are promising carriers for a stomach-specific delivery of poorly soluble lipophilic compounds.

Gastrokinetic activity of Morinda citrifolia aqueous fruit extract and its possible mechanism of action in human and rat models.

AIMS OF THE STUDY: This study was to investigate the gastrokinetic activity of Morinda citrifolia aqueous fruit extract (AFE) in human subjects by examining the GI absorption of ranitidine, a putative indicator of GI motility and to elucidate its possible gastrokinetic mechanism of action in rats. MATERIALS AND METHODS: The single-dose, randomized, open-label and 2-period crossover study was performed on 20 Thai healthy volunteers with a washout period of 14 day between the doses. AFE or drinking water was administered orally 30 min prior to a single oral administration of ranitidine (300 mg). Blood samples were collected over a 12 h period after drug administration and the pharmacokinetic parameters of ranitidine were calculated. The gastrokinetic mechanism of action of AFE was elucidated by measurement of its contractile response on the isolated rat gastric fundus strip. RESULTS: The area under the plasma ranitidine concentration-time curve and the maximal plasma ranitidine concentration were significantly increased after pretreatment with AFE (p=0.001). The plasma ranitidine concentrations were significantly greater at 30-120 min after its administration. AFE produced a definite contractile response of a rat gastric fundus strip with a dose dependency. Scopoletin at the same equivalent dose present in AFE elicited a concentration-dependent contraction that amounted to 45% of the maximal response to AFE. The contractile response of both AFE and scopoletin was mediated through the 5-HT(4) receptor. CONCLUSION: AFE has a unique gastrokinetic activity in enhancement of the rate and the extent of ranitidine absorption. The underlying mechanism can be attributed, at least in part, to the ability of its active component: scopoletin to stimulate the 5-HT(4) receptor.

Effects of Morinda citrifolia aqueous fruit extract and its biomarker scopoletin on reflux esophagitis and gastric ulcer in rats.

AIMS OF THE STUDY: The present study was carried out to evaluate the effect of dried mature unripe Morinda citrifolia L. (Rubiaceae) fruit, commonly known as "Noni", in an aqueous extract preparation (AFE) as used in Thai traditional medicine and its biomarker scopoletin on gastro-esophageal inflammatory models that are related to the claimed pharmacological properties of AFE and/or resembled the human esophagitis or gastric ulcer. MATERIALS AND METHODS: The powder of dried mature unripe Noni fruit was boiled in water until it became a sticky paste and was then dried into a powder by lyophilization. The pharmacological activity of AFE and pure scopoletin at the same equivalent dose present in AFE was investigated in rat on gastro-esophageal inflammatory models (acid reflux esophagitis, acute gastritis induced by ethanol and serotonin, and chronic gastric ulcer induced by acetic acid); gastric biochemical parameters and gastrointestinal motility. RESULTS: AFE (0.63-2.50 g/kg) significantly prevented the formation of acid reflux esophagitis, reduced the formation of ethanol-induced acute gastric lesions, suppressed the development of gastric lesions in response to serotonin, and accelerated the healing of acetic acid-induced chronic gastric ulcer in rats with equal potency to those obtained by standard antisecretory agents (ranitidine and lansoprazole). AFE also significantly inhibited gastric acid secretion and pepsin activity in pylorus ligated rats. Additionally, AFE strongly increased the gastrointestinal transit of charcoal meal with a higher potency than cisapride. Pure scopoletin, when compared at the same equivalent dose containing in AFE, possessed similar antiulcer and antisecretory properties to that of AFE although it exerted a less prokinetic activity than AFE. CONCLUSION: The findings indicated that AFE as well as its biomarker: scopoletin may be beneficial as a potential preventive and therapeutic agent for gastro-esophageal inflammatory diseases, mainly through its antisecretory and prokinetic activities including an inhibitory activity on serotonin, free radicals, and cytokine-mediated inflammation. Additionally, scopoletin might be one of the biomarker constituents to use for the quality assessment of Noni fruit products used for treating gastro-esophageal inflammatory diseases.

Effects of curcumin on reflux esophagitis in rats.

The preventive effect of curcumin, a compound isolated from the rhizome of Curcuma longa, on experimental reflux esophagitis in rats was investigated in order to validate its potential therapeutic use for gastroesophageal reflux disease. Curcumin (20 mg/kg, i.d.), the antioxidative agent dimethyl sulfoxide (DMSO) (1 ml/kg, i.p.) or the proton pump inhibitor lansoprazole (1 mg/kg, i.d.) inhibited the formation of acute acid reflux esophagitis by 52.5, 61.5 and 70.9% respectively. Curcumin alone was not effective in preventing chronic acid reflux esophagitis, but the combination of curcumin and DMSO reduced the mortality rate and the severity of the esophagitis ulcer index to the same extent (56.5%) as did the lansoprazole (53.9%). Intraduodenal administration of curcumin also markedly prevented the formation of acute mixed reflux esophagitis, together with reducing the incidence or the severity of neutrophil infiltration, when compared to a control group. In contrast, lansoprazole tended to increase the severity of all histopathological changes, when compared to either the control or the curcumin-treated group. Aminoguanidine, a specific inducible nitric oxide synthase inhibitor, had no preventive effect against both types of acute reflux esophagitis models, and increased the mortality in the chronic acid reflux esophagitis model. From these results, it is indicated that curcumin can effectively prevent acute reflux esophagitis formation. Although curcumin is less potent than lansoprazole in inhibiting acid reflux esophagitis, it is superior to lansoprazole in inhibiting mixed reflux esophagitis. The antiulcerogenic mechanisms are considered to be closely associated with its antioxidant nature and antiinflammatory property.

Preventive and curative effects of curcumin on the development of gastric inflammatory diseases in rats.

Preventive and curative effects of curcumin on experimental acute and chronic gastric ulcers were investigated to validate its clinical application on a remedy for peptic ulcer. Intraduodenal administration of curcumin, 5-20 mg/kg, inhibited gastric acid secretion in pylorus-ligated rats, and oral administration prevented ethanol-induced acute gastric mucosal lesions. Curcumin (20-80 mg/kg, p.o.) dose-dependently prevented both serotonin-induced gastric mucosal lesions and compound 48/80-induced gastric mucosal lesions in rats. Furthermore, oral administration of curcumin, 10-80 mg/kg, twice daily for 10 days, significantly accelerated the healing of acetic acid-induced chronic gastric ulcer and promoted mucosal regeneration in the ulcerated portion in a dose-related manner. Cimetidine prevented the formation of ethanol-induced gastric mucosal lesions, but not of serotonin-induced and compound 48/80-induced gastric mucosal lesions. Consecutive administration of cimetidine showed a marked acceleration in the healing of acetic acid-induced ulcer. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, showed anti-ulcerogenic effects similar to those oberved for curcumin. The present results indicate that curcumin exhibits gastric cytoprotection in the acute lesion models and ulcer healing promotion in the chronic ulcer model. The preventive and curative effects of curcumin might be due to an increase in the mucosal defensive mechanism through its antioxidant property and inhibition of NO or cytokine-mediated inflammation.