benzofurans and Stomach-Ulcer

The rhizome of Ligusticum porteri Coulter& Rose (LP) has been traditionally used by the ethnic group Raramuri in the North of México for treatment of diabetes, tuberculosis, stomachaches, diarrhea and ritual healing ceremonies. It is use as antiulcer remedy has been extended to all Mexico.. To evaluate the gastroprotective activity of LP organic extracts and the major natural product diligustilide (DLG),using as experimental model the inhibition of the ethanol-induced lesions in rats.. Gastric ulcers were induced by intragastric instillation of absolute ethanol (1 mL). We tested the gastroprotective activity of the organic extracts of LP and the pure compound DLG. The ulcer index (UI) was determined to measure the activity. In order to elucidate the action mechanism of DLG the animals were treated with L-NAME, N-ethylmalemide, Forskolin, 2',5'-dideoxyadenosine, Indomethacin, Glibenclameide, Diazoxide, NaHS and DL-Propargylglycine. The pylorus-ligated rat model was used to measure gastric secretion.. The oral administration of organic extracts of Ligusticum porteri showed gastroprotective effect at 30 mg/Kg on ethanol induced gastric lesions; hexane and dichloromethane extracts were the most active. DLG was the major compound in the hexane extract. This compound at 10 mg/kg prevented significantly the gastric injuries induced by ethanol. The alkylation of endogenous non-protein-SH groups with N-ethylmaleimide abolished the gastroprotective effect of DLG and blocking the formation of endogenous prostaglandins by the pretreatment with indomethacin attenuated the gastroprotective effect of DLG.. The gastroprotective activity demonstrated in this study tends to support the ethnomedical use of Ligusticum porteri roots. DLG, isolated as major compound of this medicinal plant has a clear gastroprotective effect on the ethanol-induced gastric lesions. The results suggest that the antiulcer activity of DLG depends on the participation of the endogenous non-protein -SH groups and prostaglandins.

Topics: Alkylation; Animals; Anti-Ulcer Agents; Benzofurans; Central Nervous System Depressants; Dose-Response Relationship, Drug; Ethanol; Gastric Mucosa; Ligusticum; Male; Plant Extracts; Plant Roots; Prostaglandins; Rats; Rats, Wistar; Rhizome; Stomach Ulcer

To investigate the restorative effect of Pterocarpus erinaceus (P. erinaceus) and homopterocarpin, an isoflavonoid isolated from it, on indomethacin-induced disruption in gastric homeostasis in rats.. Adult rats were divided into five groups and fasted for 48 h before treatment. Group 1 received olive oil (vehicle), group 2 received 25 mg/kg indomethacin while groups 3-5 received cimetidine (100 mg/kg), homopterocarpin (25 mg/kg) and P. erinaceus ethanolic stem bark extract (100 mg/kg) respectively. After 1 h, all the groups except group 2 were administered 25 mg/kg of indomethacin. One hour later, the rats were sacrificed and the ulcer index and other gastroprotective indices were evaluated.. Indomethacin caused significant injury to the stomach of the rats as reflected in the ulcer indices (9.0±1.4) as compared with that of control (2.0±0.0). Equally, there were significant increases in gastric acid concentration and malondialdehyde level in the stomachs of the ulcerated animals compared with the control. However mucus content, reduced gluthatione level and gastric pH were significantly reduced in the ulcerated animals compared with the control. Pretreatment with either Pterocarpus bark extract or homopterocarpin reversed the effects of indomethacin on the evaluated parameters.. These results indicate that both homopterocarpin and Pterocarpus extract offered gastroprotection against indomethacin-induced ulcer by antioxidative mechanism and the modulation of gastric homeostasis. The results also suggest that homopterocarpin might be responsible for, or contribute to the antiulcerogenic property of P. erinaceus.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Benzofurans; Benzopyrans; Cimetidine; Ethanol; Indomethacin; Plant Bark; Plant Extracts; Pterocarpus; Rats; Rats, Wistar; Stomach Ulcer

Usnea longissima, a medicinal lichen of Anatolia (Turkey), is used in the treatment of gastric ulcer in local folk medicine. In this paper, the gastroprotective effect of usnic acid (UA) isolated from Usnea longissima was investigated in the indomethacin-induced gastric ulcers in rats at doses of 25, 50, 100 and 200 mg/kg body weight. The gastric lesions were significantly reduced by all doses of UA as compared with the indomethacin (25 mg/kg body weight) treated group. In the stomach tissues of treated animals, the in vivo antioxidant levels were evaluated. The administration of indomethacin caused a significant decrease in the levels of superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH), and an increase in the lipid peroxidation (LPO) level (p < 0.05). The administration of all doses of UA reversed the trend, inducing a significant increase of SOD, GSH and GPx levels and a reduction in LPO level in tissues. However, catalase (CAT), glutathione reductase (GR) and myeloperoxidase (MPx) activities, increased by indomethacin, were found to be lower in the UA- and ranitidine-treated groups. The gastric mucosal constitutive NO synthase (cNOS) and inducible NO synthase (iNOS) activities were also investigated in tissues of UA- (100 mg/kg), ranitidine- (50 mg/kg) and indomethacin-treated rat groups. The administration of UA and ranitidine increased the cNOS activity and lowered the iNOS activity as compared with indomethacin-treated group. These results suggest that the gastroprotective effect of UA can be attributed to its reducing effect on the oxidative damage and neutrophil infiltration in tissues.

Topics: Animals; Antioxidants; Benzofurans; Cytoprotection; Gastric Mucosa; Glutathione Peroxidase; Indomethacin; Male; Neutrophil Infiltration; Nitric Oxide; Peroxidase; Rats; Rats, Wistar; Stomach Ulcer; Superoxide Dismutase

Studies were performed in three models of acute gastric mucosal damage (induced by oral ethanol, aspirin and indomethacin) and a model of chronic gastritis (induced by 7 day treatment with iodoacetamide) in rats to establish the role of leukotrienes (LTs) in the pathogenesis of these lesions. The protective effects of highly selective 5-lipoxygenase (5-LO) inhibitors and leukotriene antagonists were thus examined in rats given these ulcerogens. Ethanol (1 mL, p.o.)-induced haemorrhagic lesions were significantly reduced by prior oral administration of the 5-LO inhibitor L-656224 (50 mg/kg), whereas lower doses of this drug were ineffective. Prior treatment with oral doses (5 and 10 mg/kg) of the 5-LO inhibitor L-655224 or the LT antagonists L-649923 or L-660711, failed to affect lesions induced by aspirin (100 mg/kg, p.o.) and indomethacin (400 mg/kg, s.c.), whereas higher doses of all three drugs (50 mg/kg) showed protective effects. Repeated prior dosing up to 5 h with the novel five lipoxygenase activating protein (FLAP) inhibitor, MK886 (50 and 100 mg/kg), reduced the lesions developed by indomethacin (30 mg/kg, s.c.). Twice daily dosing with the 5-LO inhibitor L-656224 (5 mg/kg) or the LT antagonist L-649923 (2 or 5 mg/kg) for 7 days significantly reduced the development of iodoacetamide-induced gastritis during the period of induction of this condition, but higher doses of these inhibitors were not protective. We conclude that 5-LO products partially mediate the production of gastric mucosal lesions induced by damaging agents, which varies according to the ulcer model employed; the limited protective effects of the respective 5-LO inhibitors and LT antagonists depend on their individual pharmacokinetics and their time of dosing.

Topics: Animals; Aspirin; Benzofurans; Ethanol; Female; Gastritis; Indomethacin; Iodoacetamide; Leukotriene D4; Leukotrienes; Lipoxygenase Inhibitors; Peptic Ulcer Hemorrhage; Phenylbutyrates; Propionates; Quinolines; Rats; Rats, Sprague-Dawley; Stomach Ulcer

2-Methyl-5-(3-phenylpropionyl)-1-benzoxolane (CAS 159264-96-7) was synthesized and studied for anti-inflammatory properties. This new aryl ketone was more active than the previously reported 5-acyl substituted 1-benzoxolanes except 5-cinnamoyl-2-methyl-1-benzoxolane (the unsaturated analogue) which exhibited similar anti-inflammatory activity and similar toxicity but was more gastrotoxic. Anti-inflammatory and analgesic effects of 2-methyl-5-(3-phenylpropionyl)-1-benzoxolane were less pronounced than those of indometacin but greater than those of acetylsalicylic acid (ASA). The new ketone was less toxic and less gastrotoxic than both the reference drugs mentioned above. Therapeutic indices of the new compound were significantly greater than those of ASA and indometacin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bentonite; Benzofurans; Carrageenan; Edema; Gossypium; Granuloma; Lethal Dose 50; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred BALB C; Pain Measurement; Rats; Rats, Wistar; Spectrophotometry, Ultraviolet; Stomach Ulcer

In order to investigate new antiulcer agents, spizofurone 1 (AG-629) was fragmented and reassembled to generate 5-phenyl-2,2-dimethyl-3(2H)-furanone (bullatenone, 2). Because of the antiulcer activity of 2,5-phenyl-substituted 2,2-dimethyl-3(2H)-furanones (3-6) were made and shown to have poor activity. Insertion of an ethenyl link between the furanone and phenyl rings gave 5-(2-phenylethenyl)-2,2-dimethyl-3(2H)- furanone (7). This compound had better activity than 2. Compounds 8-41 were synthesized to evaluate the SAR in 5-(2-ethenyl substituted)-3(2H)-furanones. Electron-withdrawing substituents on the aromatic ring (8, 10, 19, and 20) gave 2-3-fold higher activity. Further increases in the activity were found when the phenyl ring was replaced by heterocyclic nuclei. Compounds that contained a thiophene (29), pyridine (24-26), or quinoline ring (32) had the best activity. Replacement of the methyl group on the furanone ring with a phenyl (34) or p-fluorophenyl (40) substituent in the 2-pyridine series gave compounds with activity that ranked with the best obtained in this study. The best compounds from the above SAR studies were evaluated in the ethanol-necrosis model for duration of cytoprotection action. Compounds 19, 24, and 29, which had the best duration of action, were tested with AG-629 in the acidified aspirin and indomethacin-induced lesion models. Only compound 24 had equivalent activity with AG-629 in both models.

Topics: Animals; Anti-Ulcer Agents; Aspirin; Benzofurans; Ethanol; Furans; Indomethacin; Male; Molecular Structure; Rats; Rats, Inbred Strains; Stomach Ulcer; Structure-Activity Relationship

The effect of a methanol extract of Sophora flavescens root was examined on gastric ulcers induced in rats by HCl/ethanol in order to substantiate its reputed protective properties. Oral doses of 1 g/kg completely suppressed ulceration. Results suggest that oral administration of 50 mg/kg of vexibinol, a flavanol found in the extract, inhibited ulceration more effectively than spizofurone at 100 mg/kg.

Topics: Animals; Anti-Ulcer Agents; Benzofurans; Ethanol; Flavanones; Flavonoids; Male; Methanol; Plant Extracts; Plants, Medicinal; Rats; Rats, Inbred Strains; Stomach Ulcer

Leukotrienes (LT's) are produced in a number of hypersensitivity and in inflammatory conditions in the gastro-intestinal (GI) tract and may contribute to the pathogenesis of GI mucosal injury in their states. LT's do not appear to be produced by the GI mucosa in appreciable quantities under basal "physiological" conditions. Another important leucocyte derived mediator, platelet activating factor (PAF), which is produced in large quantities in hypersensitivity and inflammatory conditions, when given i.v. induces hyperaemia, vascular status and accompanying lesions of the gastric mucosa in rats. This might be related to its hypotensive effects or other actions on the microvasculature of the stomach. Thus PAF may have particular significance in those conditions where there is a profound leucocyte response. It might be an important link between the leucocyte activation that occurs in burn injury and the GI ulceration and haemorrhage that is observed in such patients. There does not appear to be any involvement of PAF in non-inflammatory gastric ulceration induced by aspirin or ethanol+HCl, since the PAF antagonist kadsurenone fails to exert any protective effects when co-administered with either of these drugs.

Topics: Animals; Aspirin; Benzofurans; Ethanol; Gastric Mucosa; Intestinal Mucosa; Lignans; Male; Platelet Activating Factor; Rats; Rats, Inbred Strains; SRS-A; Stomach Ulcer

The protective effect of spizofurone (AG-629) on the rat gastric mucosa was studied in the presence of various stimuli. Spizofurone given orally markedly inhibited gastric lesions induced by ethanol (ED50 = 6.5 mg/kg). Spizofurone inhibited ethanol-induced gastric lesions even when administered intraperitoneally (i.p.), but the onset of action after oral administration was shorter. Spizofurone given orally or i.p. in a dose range of 25-200 mg/kg inhibited indomethacin-induced gastric antral ulcers in re-fed rats. Furthermore, spizofurone potentiated the inhibitory effect of prostaglandin E2 on indomethacin-induced gastric antral ulcers. Spizofurone given i.p. prevented a decrease in potential difference and the formation of gastric lesions induced by intragastric instillation of 30 mM aspirin in 0.1 N HCl. Spizofurone given i.p. inhibited the increase in net fluxes of H+ and Na+ caused by intragastric instillation of 15% ethanol in 0.1 N HCl. These findings indicate that spizofurone, like prostaglandin E2, exerts gastric mucosal protection and even potentiates the anti-ulcer effect of prostaglandin E2. The gastric mucosal protection by spizofurone is ascribed in part to preservation of the mucosal barrier.

Topics: Animals; Anti-Ulcer Agents; Aspirin; Benzofurans; Dinoprostone; Electrolytes; Ethanol; Gastric Mucosa; Indomethacin; Male; Prostaglandins E; Rats; Rats, Inbred Strains; Stomach Ulcer

The effects of 5-acetylspiro[benzofuran-2(3H),1'-cyclopropan]-3-one (AG 629), a newly synthesized compound, on various experimentally induced ulcers were investigated. Oral or intraduodenal administration of AG 629 in a dose range of 25-100 mg/kg inhibited water-immersion stress ulcer, exertion ulcer, Shay ulcer, indometacin- and acetylsalicylic acid (ASA)-induced gastric ulcer, and indomethacin-induced small intestinal ulcer in rats, histamine-induced gastric ulcer in guinea pigs, and ASA-induced gastric ulcer in dogs, though it was not effective against cysteamine-induced duodenal ulcer in rats. AG 629 in doses of 6.3-25 mg/kg p.o. twice a day significantly promoted the healing of acetic acid- or thermal-cortisone-induced gastric ulcers and acetic acid-induced duodenal ulcers in rats. AG 629 (25-100 mg/kg i.d.) inhibited the secretion of gastric acid and pepsin in pylorus-ligated rats and the acid secretion stimulated by distension of the rat stomach with air, whereas this compound did not affect acid secretion stimulated by histamine, pentagastrin, carbachol or 2-deoxy-D-glucose. This study shows that AG 629 has both prophylactic and curative effects on various ulcers. The anti-ulcer effect of this agent seems to be mediated primarily by increasing mucosal resistance and secondarily by an antisecretory activity.

Topics: Acetates; Acetic Acid; Acute Disease; Animals; Anti-Ulcer Agents; Aspirin; Benzofurans; Chronic Disease; Cysteamine; Dogs; Duodenal Ulcer; Female; Gastric Acid; Guinea Pigs; Histamine; Hot Temperature; Indomethacin; Male; Physical Exertion; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Psychological

A series of 2,3-dihydrobenzofuran-2-one analogues of the mold metabolite wortmannin, which is a powerful antiinflammatory compound, was synthesized. Most of these compounds were tested for their ability to inhibit the carrageenin paw edema and the adjuvant-induced arthritis of the rat and for their ability to inhibit prostaglandin synthesis in vitro. Indomethacin and diclofenac were used as references. The results show that compounds bearing an alkyl or aryl group in position 6 and an additional substituent, preferably chlorine, in position 5 are very powerful antiinflammatory agents and inhibitors of prostaglandin synthesis. The most active among these compounds, 5-chloro-6-cyclohexyl-2,3-dihydrobenzofuran-2-one, was significantly more potent than diclofenac in all testing models, more powerful than indomethacin in inhibiting acute inflammation and prostaglandin synthesis, and somewhat less potent than the latter compound in the adjuvant arthritis model.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Benzofurans; Cattle; Chemical Phenomena; Chemistry; Depression, Chemical; Edema; In Vitro Techniques; Male; Prostaglandins; Rats; Stomach Ulcer; Structure-Activity Relationship

Topics: Animals; Anti-Ulcer Agents; Benzofurans; Dogs; Ethylenediamines; Rats; Stomach Ulcer

Topics: Acids; Adolescent; Adult; Benzofurans; Female; Gastric Juice; Humans; Male; Middle Aged; Stomach Ulcer

Topics: Animals; Antacids; Benzofurans; Bridged-Ring Compounds; Depression, Chemical; Desipramine; Drug Antagonism; Female; Gastric Juice; Histamine; Imipramine; Methyltyrosines; Norepinephrine; Peptides; Rats; Reserpine; Stomach Ulcer; Structure-Activity Relationship; Succinates; Tranquilizing Agents

Topics: Animals; Benzofurans; Depression, Chemical; Desipramine; Gastric Juice; Heart; Imipramine; Male; Mice; Myocardium; Norepinephrine; Peptides; Rats; Stomach; Stomach Ulcer; Tritium