geranylgeranylacetone and Peptic-Ulcer

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Bicarbonates; Carnosine; Chalcone; Chalcones; Diterpenes; Enprostil; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Mucus; Organometallic Compounds; Peptic Ulcer; Piperidines; Prostaglandins; Sucralfate

Proton-pump inhibitors are known to be effective in the treatment and prevention of ulcers related to low-dose aspirin (LDA), but few reports address H2 -receptor antagonists (H2RAs) and gastroprotective agents (GPs). This study was intended to compare the therapeutic effects of an H2RA and a GP against gastroduodenal mucosal injuries in patients taking LDA.. The subjects consisted of patients requiring continuous LDA treatment, in whom no peptic ulcer was found on endoscopy at enrollment. The patients were randomized to either famotidine 20 mg/day (group F) or teprenone 150 mg/day (group T). The study medication was administered for 12 weeks. The patients underwent endoscopy after administration of the study medication in order to obtain a Lanza score.. A total of 66 patients (38 in group F, 28 in group T) were included in the efficacy analysis population. The Lanza score changed as follows: in group F, it improved significantly, from 0.89±1.03 (mean±standard deviation) before medication to 0.39±0.75 after medication (P=0.006); in group T, no significant difference was observed: 0.75±0.93 before medication and 0.68±0.82 after medication.. Famotidine is better than teprenone in terms of reducing the number of the erosions under use of LDA.

Topics: Aged; Anti-Ulcer Agents; Aspirin; Diterpenes; Famotidine; Female; Histamine H2 Antagonists; Humans; Male; Middle Aged; Peptic Ulcer; Prospective Studies; Treatment Outcome

Little information is available regarding the prevention and treatment of small intestinal mucosal injuries caused by non-steroidal anti-inflammatory drugs (NSAIDs). We planned a pilot study to investigate the protective effects of geranylgeranylacetone (GGA) against NSAID-induced small intestinal injuries using video capsule endoscopy (VCE).. Ten healthy male volunteers took oral GGA 300 mg/day (regimen A) or placebo (regimen B) in addition to diclofenac 75 mg/day + rabeprazole 20 mg/day for 7 days. We conducted a cross-over trial of regimens A and B with a 2-week washout period. All subjects underwent VCE before and after each administration period, and were evaluated for NSAID-induced gastric and small intestinal mucosal lesions.. The number of mucosal lesions (erosions, ulcers and a red spot with possible bleeding) detected in both stomach and small bowel changed between prior to and immediately after administration period, with significantly fewer lesions for regimen A after administration period (mean +/- SD A:B = 2.6 +/- 3.2:9.5 +/- 8.5; p = 0.027).. Combination therapy with GGA and rabeprazole reduced the incidence of gastroenteropathy induced by 1-week administration of diclofenac. Our findings suggest this therapy as a candidate for protecting patients on long-term NSAID therapy.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Capsule Endoscopy; Cross-Over Studies; Diclofenac; Diterpenes; Double-Blind Method; Humans; Male; Peptic Ulcer; Prospective Studies; Rabeprazole; Young Adult

Teprenone, an anti-ulcer drug, has been reported to promote the healing of acetic acid-induced chronic gastric ulcers in rats by stimulating gastric mucus synthesis and secretion. Recently, it has been implicated that neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues have an inhibitory effect on the healing of acetic acid-induced chronic gastric ulcers in rats. Therefore, we attempted to clarify whether teprenone exerts a healing-promoting effect on acetic acid-induced chronic gastric ulcers through its inhibitory effect on neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues. In rats with chronic gastric ulcers made by applying acetic acid to the stomach, gastric ulcer healing started later than 3 days after the acetic acid application. Gastric mucosal myeloperoxidase (MPO) activity, an index of tissue neutrophil infiltration, and lipid peroxide content were higher in the ulcerated region than in the intact region on the 8th, 15th, and 22nd day after the acetic acid application. Gastric mucosal non-protein SH content was lower in the ulcerated region than in the intact region on the 8th, 15th, and 22nd day after the acetic acid application, and gastric mucosal adherent mucus content was lower in the ulcerated region than in the intact region on the 8th and 15th day. Daily oral administration of teprenone (100 mg kg(-1)x 2) for 7 or 14 days, starting on the 8th day after the application of acetic acid to the stomach, enhanced the reduction of the ulcer area with attenuation of all these biochemical changes found in the ulcerated region. The teprenone administration caused a decrease in MPO activity and an increase in adherent mucus content in the gastric mucosa of the intact region. These results suggest that the healing-promoting effect of teprenone on acetic acid-induced chronic gastric ulcers in rats could be due not only to stimulation of gastric mucus secretion but also to inhibition of neutrophil infiltration and enhanced lipid peroxidation in the ulcerated gastric tissue.

Topics: Acetic Acid; Administration, Oral; Animals; Anti-Ulcer Agents; Chronic Disease; Diterpenes; Gastric Mucosa; Lipid Peroxidation; Lipid Peroxides; Male; Mucus; Neutrophil Infiltration; Peptic Ulcer; Peroxidase; Rats; Rats, Wistar; Sulfhydryl Compounds

Recently, we demonstrated that teprenone, an anti-ulcer agent, exerts protective and preventive actions against water immersion restraint (WIR) stress-induced gastric mucosal lesions in rats both by inhibiting neutrophil infiltration into the gastric mucosal tissue and by preserving gastric mucus synthesis and secretion. In rats with WIR stress we have also found a decrease in gastric mucosal constitutive nitric oxide synthase (cNOS) activity and a drastic increase in gastric mucosal inducible nitric oxide synthase (iNOS) activity. The decrease in gastric mucosal cNOS activity is closely related to an increase in neutrophil infiltration into the gastric mucosa and a decrease in the level of gastric mucus. In this study of WIR-stressed rats, therefore, we examined whether the inhibitory actions of teprenone on neutrophil infiltration and decreases in mucus synthesis and secretion in the gastric mucosa of rats are related to the change in gastric mucosal cNOS activity during the development of gastric mucosal lesions. Pre-administration of teprenone (200 mg kg-1) prevented the decrease in gastric mucosal cNOS activity with attenuations of neutrophil infiltration into gastric mucosal tissues and decreased levels of gastric mucosal hexosamine, an index of gastric mucin, and adherent mucus in rats with 3 or 6 h of WIR stress. These preventive effects of teprenone on the gastric mucosal neutrophil infiltration and the decrease in gastric mucus levels in rats with WIR stress were completely reversed with inhibition of gastric mucosal cNOS activity by co-administration of NG-monomethyl L-arginine (L-NMMA), a non-selective NOS inhibitor. These results suggest that the inhibitory actions of teprenone on neutrophil infiltration and decreases in mucus synthesis and secretion in the gastric mucosa of rats with WIR stress are closely related to the maintenance of cNOS activity in the gastric mucosal tissue.

Topics: Animals; Diterpenes; Enzyme Inhibitors; Gastric Mucosa; Hexosamines; Immersion; Male; Mucus; Neutrophils; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; omega-N-Methylarginine; Peptic Ulcer; Peroxidase; Rats; Rats, Wistar; Stress, Physiological

Topics: Anti-Ulcer Agents; Cyclohexanecarboxylic Acids; Diterpenes; Gefarnate; Humans; Peptic Ulcer; Recurrence; Sucralfate; Tranexamic Acid

Recently, three new drug types have emerged to treat peptic ulceration. We compared the mechanism of action of omeprazole and somatostatin-14, both inhibitors of gastric acid, with that of tetraprenylacetone, a drug thought to be cytoprotective in the upper gut. Omeprazole and somatostatin-14 caused potent inhibition of meal-stimulated acid secretion in the dog (92% +/- 6% and 97% +/- 1%, respectively). On the other hand, tetraprenylacetone had no significant inhibitory effect on acid secretion (4% +/- 17%). In separate studies, tetraprenylacetone was shown to be a stimulant of gastric bicarbonate secretion in the rabbit, increasing bicarbonate secretion from a basal level of 0 to 86 +/- 28 pmol/2 h. Tetraprenylactone was also found to be a strong stimulant of canine pancreatic bicarbonate secretion. The ability of tetraprenylacetone to stimulate endogenous bicarbonate secretion may explain its ability to heal ulcers both experimentally and clinically.

Topics: Animals; Anti-Ulcer Agents; Bicarbonates; Diterpenes; Dogs; Gastric Acid; Gastric Mucosa; Omeprazole; Pancreas; Peptic Ulcer; Rabbits; Somatostatin; Statistics as Topic

The serum concentration of geranylgeranylacetone (GGA) was estimated in four patients with peptic ulcer following oral administration of a 100-mg dose. The area under the serum concentration-time curve (AUC) after oral dosing of the patients 30 min after a meal was 30- to 45-fold larger than that in the fasted state. Distribution of GGA in the stomach removed surgically from the patients was also examined after oral administration of 50 mg thrice daily for 1-13 days prior to surgery. The tissue level of GGA in the ulcer region was higher than that in the surrounding normal region.

Topics: Administration, Oral; Anti-Ulcer Agents; Biological Availability; Diterpenes; Female; Gastric Mucosa; Humans; Male; Peptic Ulcer