Gastric Prostaglandin Research Articles

Etodolac utility in osteoarthritis: drug delivery challenges, topical nanotherapeutic strategies and potential synergies.

Osteoarthritis (OSA) is a prevalent joint disorder characterized by losing articular cartilage, primarily affecting the hip, knee and spine joints. The impact of OSA offers a major challenge to health systems globally. Therapeutic approaches encompass surgical interventions, non-pharmacological therapies (exercise, rehabilitation, behavioral interventions) and pharmacological treatments. Inflammatory processes within OSA joints are regulated by pro-inflammatory and anti-inflammatory cytokines. Etodolac, a COX-2-selective inhibitor, is the gold standard for OSA management and uniquely does not inhibit gastric prostaglandins. This comprehensive review offers insights into OSA's pathophysiology, genetic factors and biological determinants influencing disease progression. Emphasis is placed on the pivotal role of etodolac in OSA management, supported by both preclinical and clinical evidences in topical drug delivery. Notably, in-silico docking studies suggested potential synergies between etodolac and baicalein, considering ADAMTS-4, COX-2, MMP-3 and MMP-13 as essential therapeutic targets. Integration of artificial neural network (ANN) techniques with nanotechnology approaches emerges as a promising strategy for optimizing and personalizing topical etodolac delivery. Furthermore, the synergistic potential of etodolac and baicalein warrants in-depth exploration. Hence, by embracing cutting-edge technologies like ANN and nanomedicine, the optimization of topical etodolac delivery could guide a new era of OSA treatment.

Neuropeptide W facilitates chronic gastric ulcer healing by the regulation of cyclooxygenase and NF-κB signaling pathways

AimsPutative beneficial effects of neuropeptide W (NPW) in the early phase of gastric ulcer healing process and the involvement of cyclooxygenase (COX) enzymes were investigated in an acetic acid-induced gastric ulcer model.Main methodsIn anesthetized male Sprague–Dawley rats, acetic acid was applied surgically on the serosa and then a COX-inhibitor (COX-2-selective NS-398, COX-1-selective ketorolac, or non-selective indomethacin; 2 mg/kg/day, 3 mg/kg/day or 5 mg/kg/day; respectively) or saline was injected intraperitoneally. One h after ulcer induction, omeprazole (20 mg/kg/day), NPW (0.1 μg/kg/day) or saline was intraperitoneally administered. Injections of NPW, COX-inhibitors, omeprazole or saline were continued for the following 2 days until rats were decapitated at the end of the third day.Key findingsNPW treatment depressed gastric prostaglandin (PG) I2 level, but not PGE2 level. Similar to omeprazole, NPW treatment significantly reduced gastric and serum tumor necrosis factor-alpha and interleukin-1 beta levels and depressed the upregulation of nuclear factor kappa B (NF-κB) and COX-2 expressions due to ulcer. In parallel with the histopathological findings, treatment with NPW suppressed ulcer-induced increases in myeloperoxidase activity and malondialdehyde level and replenished glutathione level. However, the inhibitory effect of NPW on myeloperoxidase activity and NPW-induced increase in glutathione were not observed in the presence of COX-1 inhibitor ketorolac or the non-selective COX-inhibitor indomethacin.SignificanceIn conclusion, NPW facilitated the healing of gastric injury in rats via the inhibition of pro-inflammatory cytokine production, oxidative stress and neutrophil infiltration as well as the downregulation of COX-2 protein and NF-κB gene expressions.

Targeting NF-κB/COX-2 signaling by soyasaponin I alleviates diclofenac-induced gastric ulceration in male albino rats.

Gastric ulceration is a prevalent worldwide clinical presentation due to altered gastric defense mechanisms. Nonsteroidal anti-inflammatory drugs are one of the common causes of gastric ulcers mediated by the release of inflammatory mediators. The study aimed to investigate the potential protective effect of soyasaponin I (soya) against diclofenac (DIC)-induced gastric ulcer in rats and to highlight the underlying mechanisms. The experiment was conducted on 40 male Wistar albino rats, equally distributed into five groups: control, DIC-induced ulcer (9 mg/kg/d, orally, twice daily for 3 days), ulcer/soya-, ulcer/ranitidine-, and ulcer/soya/selective nuclear factor kappa B inhibitor (JSH-23)-treated groups. The doses of soya, ranitidine, and JSH were 20, 25, and 5 mg/kg/d, respectively, given orally. Gastric specimens were prepared for gene and histological study and for biochemical analysis of gastric prostaglandin E2 (PGE2), oxidative markers, and inflammatory cytokines. The gastric samples were formalin-fixed, paraffin-embedded, and subjected to hematoxylin and eosin (H&E), PAS staining, and immunohistochemical assay for identification of nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2), and proliferation marker (Ki67) expressions. The findings revealed decreased gastric PGE2 and altered inflammatory and oxidative markers in the ulcer model group. The H&E staining showed mucosal injury characterized by mucosal surface defects and inflammatory cell infiltrations. The polymerase chain reaction (PCR) and immunohistochemistry demonstrated an upregulation of NF-κB and COX-2 expression at gene/protein levels; meanwhile, Ki67 downregulation. The soya-treated group showed maintained biochemical, histological, and PCR findings comparable to the ranitidine-treated group. The JSH-23-treated group still showed partial gastric protection with biochemical and immunohistochemical changes. Soyasaponin I ameliorated DIC-induced gastric ulcers by targeting the COX-2 activity through modulation of NF-κB signaling.

The Protective Effect of Walnut Oligopeptides against Indomethacin-Induced Gastric Ulcer in Rats

The aim of this study was to investigate the potential protective effects of walnut oligopeptides (WOPs) on indomethacin-induced gastric ulcers in rats. The rats were divided into the following groups: normal group, model group, omeprazole group (0.02 g/kg), and WOPs groups (0.22, 0.44, and 0.88 g/kg, respectively). After receiving gavage once per day for 30 consecutive days, the rats were injected intraperitoneally with indomethacin 48 mg/kg to induce gastric ulcers. Then, the serum inflammatory cytokines and gastric prostaglandin E2 (PGE2), oxidative stress-related indicators, and the RNA expression of COX-1 and COX-2 were measured. The results revealed that WOPs confer significant gastroprotection on gastric ulcers caused by indomethacin, regulating inflammatory cytokines, oxidative stress, and prostaglandins synthesis, and enhancing the expression of COX-1 and COX-2 in gastric tissue, thus exerting its protective effect on gastric mucosa. The gastroprotective mechanism may be related to the involvement of the arachidonic acid metabolism and upregulation of tryptophan, phenylalanine, tyrosine, and alpha-Linolenic acid metabolism synthesis in vivo.

Different protective capability of chlorogenic acid and quercetin against indomethacin-induced gastrointestinal ulceration.

The study compared the protective effects against indomethacin-induced GI ulceration of chlorogenic acid with quercetin in rats. Rats were orally given chlorogenic acid or quercetin (100 mg/kg; 5 days), followed by indomethacin (40 mg/kg; single dose). After 24 h, GI tissues were assessed for histopathological damages, then analysed by ELISA and western blot methods. Cell viability was measured in vitro by MTT assay. Unlike quercetin, chlorogenic acid could not prevent gastric ulcers in indomethacin-treated rats. The levels of gastric prostaglandin E2 (PGE2) and Bax/Bcl-2 ratio in the chlorogenic acid-treated group were not different from those receiving indomethacin alone. Nevertheless, both compounds alleviated jejunum ulcers through suppression of PERK/eIF-2/ATF-4/CHOP-related endoplasmic reticulum (ER) stress and decrease Bax/Bcl-2 ratio. Moreover, at 100 µM, they abolished the cytotoxicity of tunicamycin (an ER stress inducer) in gastric (AGS) and intestinal (Caco-2) cells. In silico docking studies suggested that both compounds could interact with key amino acid residues in the -catalytic domain of PERK. Chlorogenic acid and quercetin exerted comparable protective effects against indomethacin-induced intestinal ulcer through suppression of ER stress-mediated apoptosis but, unlike quercetin, chlorogenic acid offered no protection against gastric ulceration due to its -inability to increase PGE2 production.

A Review on Incidence of Gastric Ulcer and its Herbal Remedies

Gastric ulcer is basically an inflamed break in the mucus lining membrane on the gastrointestinal alimentary track. The most common causes of gastric ulcers include H. pylori and gastric prostaglandin loss associated with the use of NSAIDs medication. Gastric ulcer formation depends on the presence of pepsin and acid secretions in gastric juice which breakdown the mucosal defences. It may be caused due to excessive stress or irregular food habits. Many synthetic drugs are used for the treatment of ulcer but they may have certain side effects. On the other hand, herbal medicines are completely safe and beneficial for treating ulcers. This review brings to light that the major incidence of gastric ulcer varies worldwide and the complications thereof put a heavy yet preventable burden on the healthcare expenditure. Some herbal plants helpful in the treatment of ulcer have also been discussed here.

Ameliorative effects of ribes rubrum oil against gastric ulcers caused by indomethacin in experimental models

The objective of this study was to assess the anti-inflammatory effects of ribes rubrum oil at three different doses (5, 10 and 15 ml/kg b.w/day) in adult male albino rats with indomethacin-induced stomach ulcers (IND). Forty rats (135 ± 5 g) categorized into 5 groups (n = 8), for 45 days. Group (1) normal control, thirty-two rats were gavaged IND as single oral dose (30 mg/Kg b.w) resulted in gastric ulcer, then distributed to four groups, group (2) IND-intoxicated control, Groups 3, 4 and 5 were administrated ribes rubrum oil at levels of (5, 10 & 15 ml/kg b.w) respectively. Administrated levels of ribes rubrum oil found to have remarkable elevation in food conversion efficiency in experimental rats, gastric juice pH, in compared to the drunken control group, gastric prostaglandin E2 and gastric cytochrome P450 reductase levels were lower. The levels of pro-inflammatory cytokines NO, TNF-, and IL-1 were dramatically reduced, which was related with an increase in blood hemoglobin (Hb), packed cell volume (PCV), and red blood cells (RBCs)in ulcerogenic rats compared to intoxicated control. Data showed that, the main components of ribes rubrum oil are β-Pinene, γ-linolenic and Linalool oxide levels (25.9%, 23.10% and 10.5%, respectively) for their antioxidant activity. Findings showed that administrate ribes rubrum oil at dose 15 ml/kg followed by 10 ml/kg had the best results against ulcerogenic rats. In conclusion, the outcomes are consistent with the concept that ribes rubrum oil had a gastroprotective and antisecretory effects against gastric ulcer that may be attributed to the antioxidant properties of the oil that ameliorates the damage occur in gastric of rats.

Costus afer (Costaceae, Zingiberales) leaf extract ameliorates naproxen-induced gastric ulcer in rats

Purpose: To examine Costus afer leaf extract (CALE) protective effects against naproxen-induced gastric ulcer and the mechanisms of protection.Methods: Rats with naproxen-induced ulcer were pretreated with either CALE (800 mg/kg), pantoprazole (20 mg/kg), or a combination of both. Then the ulcer index, total gastric acidity, gastric pH, and curative index were evaluated. In addition, gastric mucin, pepsin, prostaglandin E2, nitric oxide, reduced glutathione, lipid peroxide, and superoxide dismutase were quantified. The gastric pathologicalchange was also evaluated.Results: Rats treated with CALE, pantoprazole, and their combination significantly decreased ulcer index, total gastric acidity, and gastric pH. All treatments induced a significant curative index in favor of the combination. The CALE significantly increased gastric mucin, prostaglandin E2, nitric oxide, reduced glutathione, and superoxide dismutase. However, the CALE significantly decreased pepsin and lipid peroxide product.Conclusion: These results reveal that CALE protects the stomach against naproxen-induced ulcer. This action is linked to increased gastroprotective factors, increased antioxidants, and decreased lipid peroxidation. The CALE may be used as an adjunctive treatment for ulcers caused by NSAIDs.
 Keywords: Costus afer, Naproxen, Gastric ulcer, Antioxidants, Lipid peroxidation

Phenylbutazone induces equine glandular gastric disease without decreasing prostaglandin E2 concentrations.

In equids, phenylbutazone at high doses induces gastric disease, primarily in the glandular portion of the stomach. However, the mechanism of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric disease in horses has yet to be determined. While phenylbutazone-associated ulceration is often attributed to a decrease in basal gastric prostaglandins, this has not been demonstrated in the horse. Twelve horses were randomly assigned to treatment (n=6; 4.4mg/kg phenylbutazone PO in 20ml molasses q 12hr for 7days) or placebo (n=6; 20ml molasses PO q 12hr for 7days) groups. Before treatment and 3 and 7days after initiation of treatment, gastroscopy was performed and glandular gastric biopsies were collected and frozen at -80°C. Glandular disease was assessed on a scale of 0-4. Prostaglandin E2 concentrations in biopsies were measured using a commercially available enzyme-linked immunosorbent assay. All phenylbutazone-treated horses developed grade ≥2 glandular disease. Prostaglandin concentrations increased over time (p=.0017), but there was no effect of treatment (p=.49). These findings indicate that despite induction of glandular disease grade ≥2, phenylbutazone did not decrease basal glandular gastric prostaglandin E2 concentration.

GASTROPROTECTIVE EFFECT OF ARTICHOKE (CYNARA SCOLYMUS L.) LEAVES AND PULP EXTRACTS ON PEPTIC ULCER IN MALE RATS

The phytochemical screening of artichoke leaves aqueous extract (ALE) and artichoke pulp aqueous extract (APE) were undertaken and its protective effect against aspirin-induced peptic ulcer in rats was studied. Forty-two mature male rats were randomized into 6 equal groups as follows: (1) negative control rats, (2) positive control rats , Groups (3)and (4) rats pretreated with (ALE) at doses of 200 and 400 mg/kg b.wt, respectively .Groups (5) and (6) rats pretreated with (APE) at doses of 200 and 400 mg/kg b.wt, respectively for 28 days . At the last day of the experimental period all groups were given aspirin 400 mg/Kg b.wt , to induce peptic ulcer except group (1) kept as a normal rats . At the end of the experimental period rats were sacrificed and blood samples were collected for serum biochemical analyses. Stomach of the sacrificed rats was taken for determination of biomarkers of gastric ulcer and histopathological examination. The phytochemical screening revealed that both ALE and APE contains flavonoids, saponins, alkaloids, tannins, glycosides, and devoid of resins and triterpenes. Oral pretreatments with both ALE and APE at 400 mg/kg b.wt showed a promising antioxidant effect represented by significant reduction in the volume of gastric juice, total acidity of gastric juice, gastric ulcer index , concentration of pepsin enzyme ,serum interleukin-1 IL-1, serum tumor necrosis factor-alpha TNF-α and lipid peroxidation along with a significant elevation in, gastric prostaglandin PGE2 level and antioxidant enzymes compared to control positive group. Histopathological examination of the stomach showed alleviation of histological degeneration changes caused by aspirin. The study recommends that intake of artichoke in food or its use as herbal tea may be beneficial for patients who might use irritant drugs to their stomach , due to its antioxidant properties. Moreover, isolation of bioactive constituents of artichoke plant is necessary to search for safe natural agents to be developed for therapy instead of chemically synthesized drugs which are usually accompanied by deleterious side effects.

Changes to the gastrointestinal tract

This article explores changes in the ageing gastrointestinal tract, including: » Diminished sense of taste and smell. » Shrinking of the maxillary and mandibular bones in the jaw. » Slowing of oesophageal peristalsis giving a feeling that something is 'stuck in the throat'. » Relaxation of the lower sphincter leading to gastro-oesophageal reflux. » Reduction in gastric bicarbonate and prostaglandin in mucus increasing susceptibility to stomach ulcers. » Changes in villi in the small intestine reducing the area for absorption. » Overpopulation of bacteria in the small intestine leading to decreased absorption of folic acid and minerals.

Nebivolol prevents indomethacin-induced gastric ulcer in rats

Gastric ulcer is a very common gastrointestinal disease that may lead to dangerous complications and even death. This study was conducted to evaluate the prophylactic effect of nebivolol against indomethacin [INDO]-induced gastric ulcer. Male Wistar rats were divided into four groups: normal control, ulcer control (INDO only), omeprazole before INDO and nebivolol before INDO. Each rat to receive nebivolol and omeprazole was given the agent orally (by gavage) daily for 10 days prior to induction of ulcer by oral dosing with INDO. Four hours after INDO treatment, all rats were euthanized and their stomachs obtained for measures of gastric acidity, oxidative stress and inflammatory markers, as well as cytoprotective mediators. The results showed that a single oral dose of INDO (100 mg/kg) induced gastric acidity, an ulcer index of 2900 and significantly increased levels of gastric tumor necrosis factor (TNF)-α and malondialdehyde (MDA) and significantly decreased levels of gastric prostaglandin E2 (PGE2), glutathione (GSH) and nitric oxide (NO), compared to in normal control counterpart stomachs. Giving nebivolol before INDO corrected the gastric acidity and resulted in a significant increase in GSH, PGE2 and NO and a significant decrease in TNFα and MDA gastric levels, compared to ulcer control values. Results obtained with nebivolol were comparable to those with omeprazole; the preventive index in the nebivolol group was 90.7% compared to 94.5% in rats in the omeprazole group. These studies showed that nebivolol provided a valuable role in preventing gastric ulcers induced by INDO and provided a promise for potentially protecting hypertensive patients from experiencing gastric ulcer. Thus, it is possible that, pending further studies, nebivolol could be used for pre-exposure prophylaxis from gastric ulcer in these patients.

Antiulcerogenic activity of the hydroalcoholic extract of leaves of Annona muricata Linnaeus in mice.

Annona muricata Linnaeus, popularly known as “graviola” and also called soursop, is a species typical of countries with a tropical climate, and it is used in folk medicine as an anticancer, analgesic and antispasmodic agent. The aim of the present study was to validate the gastroprotective activity of the hydroalcoholic extract of the leaves of A. muricata (HEAM) and to investigate the underlying mechanisms of action for this effect. Gastric lesions were induced in mice by absolute ethanol, acidified ethanol or indomethacin. Before, the animals were pretreated with saline, omeprazole or HEAM orally at doses of 50–400 mg/kg. To determine the mechanism of action of the extract, we investigated, using specific inhibitors, the involvement of nitric oxide (NO), prostaglandins (PGEs), ATP-dependent K+ channels and α2-noradrenergic receptors. HEAM showed significant antiulcer activity against lesions induced by absolute ethanol, acidified ethanol or indomethacin, which was mediated by endogenous gastric prostaglandins.

Gastroprotective effect and mechanism of patchouli alcohol against ethanol, indomethacin and stress-induced ulcer in rats

Pogostemonis Herba is an important Chinese medicine widely used in the treatment of gastrointestinal dysfunction. Patchouli alcohol (PA), a tricyclic sesquiterpene, is the major active constituent of Pogostemonis Herba. This study aimed to investigate the possible anti-ulcerogenic potential of PA and the underlying mechanism against ethanol, indomethacin and water immersion restraint-induced gastric ulcers in rats. Gross and histological gastric lesions, biochemical and immunological parameters were taken into consideration. The gastric mucus content and the antisecretory activity were analyzed through pylorus ligature model in rats. Results indicated that oral administration with PA significantly reduced the ulcer areas induced by ethanol, indomethacin and water immersion restraint. PA pretreatment significantly promoted gastric prostaglandin E2 (PGE2) and non-protein sulfhydryl group (NP-SH) levels, upregulated the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) mRNA expression, and considerably boosted the gastric blood flow (GBF) and gastric mucus production in comparison with vehicle. In addition, PA modulated the levels of interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α). The levels of glutathione (GSH), catalase (CAT) and malonaldehyde (MDA) were also restored by PA. However, the gastric secretion parameters (pH, volume of gastric juice and pepsin) did not show any significant alteration. These findings suggest that PA exhibited significant gastroprotective effects against gastric ulceration. The underlying mechanisms might involve the stimulation of COX-mediated PGE2, improvement of antioxidant and anti-inflammatory status, preservation of GBF and NP-SH, as well as boost of gastric mucus production.

Gastroprotective effect of taurine zinc solid dispersions against absolute ethanol-induced gastric lesions is mediated by enhancement of antioxidant activity and endogenous PGE2 production and attenuation of NO production

Zinc plays a key role in maintaining gastric mucosal integrity, while alcohol dependency can lead to low zinc status. Complexes containing zinc have been reported to have better ability to protect gastric mucosa than the compounds alone. In this study, taurine zinc [Zn(NH3CH2CH2SO3)2] solid dispersions (SDs) were synthesized and investigated in an ethanol-induced ulcer model in rats. Gastric ulcer index; gastric mucosa malondialdehyde (MDA) level, glutathione (GSH) content, superoxide dismutase (SOD) activity and prostaglandin E2 (PGE2) production; and serum nitric oxide (NO) were assessed and histological analysis of the gastric mucosa tissue was performed. Taurine zinc (100, 200mg/kg) SDs protected rat gastric mucosa from ethanol-induced injury. Moreover, the gastroprotective effect of taurine zinc SDs was accompanied by a decrease in serum NO and significant increase in gastric prostaglandin E2 (PGE2). When indomethacin, a non-selective COX inhibitor was administered before the last dose of taurine zinc, the gastroprotective effect of taurine zinc was weakened. Furthermore, taurine zinc (200mg/kg) SDs protected against ulceration more significantly than the same dose of taurine alone, suggesting a synergistic effect between taurine and zinc. These results indicate taurine zinc protects the gastric mucosa against ethanol-induced damage by elevating antioxidants, decreasing lipid peroxidation and inhibiting the production of nitric oxide. The gastroprotective effect of taurine zinc was also partially mediated by endogenous PGE2 production.

The protective effect of apelin against water-immersion and restraint stress-induced gastric damage.

The aim of the present study was to investigate the gastroprotective effect of apelin on water-immersion and restraint stress (WIRS)-induced gastric lesions. Male Wistar rats were divided into four groups: control, WIRS, F13A + WIRS and F13A. APJ receptor antagonist F13A was administered to rats to determine the influence of apelin on stress-induced gastric injury. WIRS administered for 6 h resulted in the development of gastric mucosal lesions accompanied by a significant increase in plasma corticosterone. WIRS increased the concentration of 4-hydroxynonenol (4-HNE) + malondialdehyde (MDA) and the expression of apelin and hypoxia inducible factor-1α (HIF-1α) in gastric mucosa. In addition, WIRS reduced the mucosal blood flow and gastric prostaglandin E(2) (PGE(2)) concentration. Plasma corticosterone, which was increased due to stress, was significantly decreased in the F13A + WIRS group. Gastric lesions and the 4-HNE + MDA concentration were also higher in the F13A + WIRS compared to the WIRS group. We conclude that apelin has a gastroprotective effect against stress-induced lesions possibly by reducing lipid peroxidation in gastric mucosa.

The Dual Positive Actions of Colonic Release of Ibuprofen in TNBS-Induced Colitis Wistar Rats

Ibuprofen is a relatively safe anti inflammatory drug among other NSAIDs. However, frequent and long-term administration of ibuprofen in conventional oral preparation is still considered for ulceration. As previously reported, the daily administration of the ibuprofen orally for 14 days in rats caused the gastroduodenal ulcer. Several mechanisms have been reported: the suppression of the gastric prostaglandin synthesis and the local irritant effect on epithelium due to the direct contact of drug with mucosal wall. In this work, developed ibuprofen pellet with double coatings aimed to release ibuprofen only when reaching colonic compartment. The results of pharmacokinetic study reported previously suggested that this might be a successful target. Present study described the potential benefits of this formula in exhibiting effective local anti inflammatory action in colon. Male Wistar rats were induced for ulcerative colitis with 2,4,6-trinitrobenzene sulfonic acid. Twenty four hours after induction, treatments were given using either ibuprofen suspension or pellet for 14 days. Ulcerations were observed visually, with gross anatomic and microscopic examinations. Group treated with ibuprofen pellet showed best recovery nearly close to healthy group. Moreover, the group did not develop ulceration in upper part of GIT. Colonic targeted ibuprofen pellet showed most effective local antiinflammatory action and at the same time reduced the ulcer formation in the upper part of GIT.

Efficacy of rebamipide-gargle for chemotherapy-induced oral mucositis.

9637 Background: Chemotherapy-induced oral mucositis (CIOM) is a severe adverse event resulting from cancer chemotherapy, and causes severe pain which impacts eating, nutrition, infection and overall quality of life. CIOM can result in unplanned treatment interruptions including dose reduction or treatment delay. Toxic free radicals and several pro-inflammatory cytokines produced by anti-cancer drugs have been reported to correlate with CIOM. Rebamipid, an endogenous inducer of prostaglandins, is widely used for gastric ulcers and gastritis in Asia. It has been shown to increase gastric endogenous prostaglandin E2 and I2, to promote gastric epithelial mucin, to behave as an oxygen–free radical scavenger, and to have other anti-inflammatory actions. In this study, we made a rebamipide gargle using rebamipide and ultrahydrogel, which is added for mucosal protection and to sustain the rebamipide on oral mucosa for a long time. Methods: The objective of this study is to evaluate the efficacy of the rebamipide gargle in relieving CIOM. Each 300ml of rebamipide gargle is made by combining rebamipide 600mg, high molecular weight polyethylene oxide 3g, carrageenin 1.2g, pineapple flavor and water. Patients were instructed to use the rebamipide gargle 5-6 times a day. The severity of CIOM was assessed according to the National Cancer Institute Common TerminologyCriteria for Adverse Events (CTCAE version 4.0). Results: From November 2009 to December 2012, 175 patients with CIOM were enrolled in this study (colorectal cancer 95 patients, breast cancer 32, gastric cancer 22, lung cancer 14, and other cancers 12). The patients’ CTCAE grades (3/2/1/0) changed from (n=13/64/98/0) to (0/10/103/62) respectively after initiation of rebamipide gargle (p<.01; paired t test). A decrease in CTCAE was observed in 142 patients (81.1%) including 62 patients (35.4%) achieving grade 0. The mean duration to best response was 14 days (range: 1-49), and rebamipide gargle was continued 42 days (range: 5-970).There were no unexpected safety events. Conclusions: Rebamipide gargle was well tolerated and demonstrated significant therapeutic response for CIOM.

Positional Isomers of Aspirin Are Equally Potent in Inhibiting Colon Cancer Cell Growth: Differences in Mode of Cyclooxygenase Inhibition

We compared the differential effects of positional isomers of acetylsalicylic acid (o-ASA, m-ASA, and p-ASA) on cyclooxygenase (COX) inhibition, gastric prostaglandin E2 (PGE2), malondialdehyde, tumor necrosis factor-alpha (TNF-α) levels, superoxide dismutase (SOD) activity, human adenocarcinoma colon cancer cell growth inhibition, cell proliferation, apoptosis, and cell-cycle progression. We also evaluated the gastric toxicity exerted by ASA isomers. All ASA isomers inhibit COX enzymes, but only the o-ASA exerted an irreversible inhibitory profile. We did not observe a significant difference between ASA isomers in their ability to decrease the in vivo synthesis of PGE2 and SOD activity. Furthermore, all isomers increased the levels of gastric and TNF-α when administered orally at equimolar doses. We observed a dose-dependent cell growth inhibitory effect; the order of potency was p-ASA > m-ASA ≈ o-ASA. There was a dose-dependent decrease in cell proliferation and an increase in apoptosis, with a concomitant Go/G1 arrest. The ulcerogenic profile of the three ASA isomers showed a significant difference between o-ASA (aspirin) and its two positional isomers when administered orally at equimolar doses (1 mmol/kg); the ulcer index (UI) for o-ASA indicated extensive mucosal injury (UI = 38), whereas m-ASA and p-ASA produced a significantly decreased toxic response (UI = 12 and 8, respectively) under the same experimental conditions. These results suggest that the three positional isomers of ASA exert practically the same biologic profile in vitro and in vivo but showed different safety profiles. The mechanism of gastric ulcer formation exerted by aspirin and its two isomers warrants a more detailed and thorough investigation.

Identification of a unique nsaid, fluoro-loxoprofen with gastroprotective activity

We previously proposed that direct cytotoxicity of NSAIDs due to their membrane permeabilization activity, together with their ability to decrease gastric prostaglandin E2, contributes to production of gastric lesions. Compared to loxoprofen (LOX), fluoro-loxoprofen (F-LOX) has much lower membrane permeabilization and gastric ulcerogenic activities but similar anti-inflammatory activity. In this study, we examined the mechanism for this low ulcerogenic activity in rats. Compared to LOX, the level of gastric mucosal cell death was lower following administration of F-LOX. However, the gastric level of prostaglandin E2 was similar in response to treatment with the two NSAIDs. Oral pre-administration of F-LOX conferred protection against the formation of gastric lesions produced by subsequent administration of LOX and orally administered F-LOX resulted in a higher gastric pH value and mucus content. In the presence of a stimulant of gastric acid secretion, the difference in the ulcerogenic activity of F-LOX and LOX was less apparent. Furthermore, an increase in the mucus was observed in gastric cells cultured in the presence of F-LOX in a manner dependent of increase in the cellular level of cAMP. These results suggest that low ulcerogenic activity of F-LOX involves its both low direct cytotoxicity and protective effect against the development of gastric lesions. This protective effect seems to be mediated through an increase in a protective factor (mucus) and a decrease in an aggressive factor (acid).