Gastric Protective Activity Research Articles

Ticlopidine prevents the formation but delays the healing of ethanol-induced gastric lesions in the rat

The effects of acute or long-term oral ticlopidine administration in normal rat gastric mucosa or on gastric lesions induced by ethanol 50% (EtOH, 1 ml/rat, os) were examined and compared with those of acetylsalicylic acid (ASA). Ticlopidine does not affect gastric mucosal integrity either after acute (100 and 300 mg kg −1) or 1-week (100 mg kg −1, die) oral administration. Ticlopidine (30–300 mg kg −1, os) administered 1 h before EtOH dose-dependently prevented the development of gastric haemorragic lesions. When ticlopidine was administered 1 h after EtOH, it significantly ( p < 0.05) delays gastric lesions healing. Acute ASA (50 and 100 mg kg −1, os) administration causes a mild irritant activity similar to that observed after 1 week of ASA (50 mg kg −1, os/die) administration. In condition of mucosal damage, ASA does not modify either the induction or the healing of EtOH-induced gastric lesions. To assess the possible involvement of endogenous nitric oxide (NO) or prostaglandins (PG) in the gastric protective activity of ticlopidine, the rats were pretreated with an inhibitor of NO-synthesis, l-NAME (70 mg kg −1, s.c.) or the inhibitor of PG synthesis, indomethacin (Indo, 10 mg kg −1, s.c.). Indo, but not l-NAME, was able to significantly counteract the gastroprotective activity of ticlopidine against EtOH injury. Furthermore, ticlopidine increases (47%) gastric PGE 2 content in normal mucosa compared to the one detected in control rats, thus suggesting that endogenous PGs contribute to enhanced mucosal resistance by ticlopidine. These results indicate that ticlopidine exerts dual effects during the development and healing of gastric lesions induced by EtOH.

A novel phenol-bound pectic polysaccharide fromDecalepis hamiltoniiwith multi-step ulcer preventive activity

To investigate H(+), K(+)-ATPase inhibition, anti-H pylori, antioxidant, and the in vivo antiulcer potential of a pectic polysaccharide from Swallow root (Decalepis hamiltonii; SRPP). SRPP, with known sugar composition [rhamnose: arabinose: xylose: galactose in the ratio of 16:50:2:32 (w/w), with 141 mg/g of uronic acid] was examined for anti-ulcer potency in vivo against swim/ethanol stress-induction in animal models. Ulcer index, antioxidant/antioxidant enzymes, H(+), K(+)-ATPase and gastric mucin levels were determined to assess the anti-ulcer potency. Anti-H pylori activity was also determined by viable colony count and electron microscopic studies. SRPP, containing phenolics at 0.12 g GAE/g, prevented stress-induced gastric ulcers in animal models by 80%-85%. Down regulation of gastric mucin 2-3 fold, antioxidant/antioxidant enzymes and upregulation of 3 fold of H(+), K(+)-ATPase in ulcerous animals were normalized upon treatment with SRPP. Histopathological analysis revealed protection to the disrupted gastric mucosal layer and epithelial glands. SRPP also inhibited H(+), K(+)-ATPase in vitro, at an IC(50) of 77 microg/mL as opposed to that of 19.3 microg/mL of Lansoprazole and H pylori growth at Minimum Inhibitory Concentration (MIC) of 150 microg/mL. In addition, free radical scavenging (IC(50)-40 microg/mL) and reducing power (3200 U/g) activities were also observed. SRPP, with defined sugar composition and phenolics, exhibited multi-potent free radical scavenging, antioxidant, anti-H pylori, inhibition of H(+), K(+)-ATPase and gastric mucosal protective activities. In addition, SRPP is non-toxic as opposed to other known anti-ulcer drugs, and therefore may be employed as a potential alternative for ulcer management.

Biological activity of an Indian medical plant, Indigofera cordifolia

The ethanol extract of Indigofera cordifolia was studied for in vivo gastroprotective activity, cytotoxic activity against oral tumor and normal cells, multidrug resistance (MDR) reversal activity, anti-human immunodeficiency virus (HIV) activity and radical scavenging activity. The extract of I. cordifolia showed potent gastric mucosal protective activity against stomach injury induced by HCl/EtOH solution. However, the gastroprotective activity could not be related to the radical mechanism, because the extract weakly scavenged both OH radical and <TEX>$O_2*^-$</TEX>. The extract also showed promising levels of MDR-reversing activity. This study demonstrates the tumor-specific cytotoxic action of the plant extract. However, the extract had no anti-HIV activity. From above results, the study suggests the medicinal importance of I. cordiforia extract.

Antisecretory and gastroprotective activities of compounds endowed with H 2 antagonistic and nitric oxide (NO) donor properties

In spite of the well recognized gastric antisecretory activity, the gastroprotective potential of histamine H 2 receptor antagonists is controversial. Most clinical studies in fact indicate that these drugs do not substantially protect the gastric mucosa from aggressive factors. Nitric oxide (NO) has been recently recognized as a fundamental mediator in gastric defence mechanisms, due to its ability to increase gastric mucosal blood flow and mucus production and to inhibit neutrophils adherence to endothelial cells. The aim of this study was to investigate the gastroprotective and H 2 receptor antagonistic activity of a series of lamtidine analogues which contain different NO-releasing moieties (furoxan, nitroxy and nitrosothiol). These compounds were tested, in comparison with related H 2 antagonists devoid of NO-donor structures, in different H 2 receptor assays and in the conscious rat against 0.6 N HCl-induced gastric lesions. All the compounds tested were able to antagonize histamine-mediated responses at cardiac and gastric H 2 receptors; however, furoxan and nitroxy derivatives were 10-fold less potent than the analogues devoid of NO-donor properties. By contrast, NO-donor compounds were more active than reference H 2 antagonists as gastroprotective agents against mucosal injury induced by 0.6 N HCl. Among the different NO-donor moieties, the furoxan group conferred to the H 2 antagonist molecule the highest gastroprotective potential; this finding closely correlates with the characteristics of NO release. In conclusions, lamtidine-analogue H 2 antagonists combined with NO-donor moieties are endowed with gastric antisecretory and protective activity and could be the prototypes of a new class of anti-ulcer drugs. Finally, the furoxan NO donor group seems to be the most favourable among the different moieties tested.

Growth Factors in Gastrointestinal Diseases

This review focuses on the recent investigations demonstrating a pharmacological and pathophysiological role for basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) in ulcerative and inflammatory lesions in the upper and lower gastrointestinal (GI) tract. Our initial experiments revealed that intragastric administration of bFGF-w, acid-resistant bFGF-CS23 and PDGF-BB healed chronic cysteamine (mercaptamine)-induced duodenal ulcer in rats, without decreasing gastric acid secretion or concentration. Subsequently we and others have demonstrated that these peptides accelerate the healing of chronic gastric ulcers, chronic erosive gastritis and ulcerative colitis although they have no or modest acute gastric protective activity. Our recent results revealed a decreased bioactivity of bFGF and PDGF in the presence of certain strains of Helicobacter pylori, and this might explain, at least in part, the poor rates of ulcer healing in H. pylori-positive patients. VEGF, in addition to stimulating angiogenesis and granulation tissue production in duodenal ulcer healing, also has an acute gastroprotective effect. New biochemical, molecular biological and immunohistochemical studies indicate that bFGF, PDGF and VEGF play a pathophysiological role in the natural history of ulcer healing. Thus, growth factor research, especially regarding their possible use as a therapeutic tool in duodenal ulcer and colitis, is challenging. On the other hand, in some GI malignancies the diagnostic use of bFGF might be of clinical benefit. However, much research work is needed to transform these 'endogenous drugs' to 'diagnostic tools' and 'exogenous drugs'.

Antiulcer Activity of Grape Seed Extract and Procyanidins

It is known that procyanidins, which are contained in grape seeds, are antioxidative and have certain biological effects. Antiulcer activities of grape seed extracts (GSE-I and GSE-II) and procyanidins were investigated using rats. GSE-I (with low flavanol content), GSE-II (with high flavanol content), and procyanidins at a dose of 200 mg/kg strongly inhibited the stomach mucosal injury induced by 60% ethanol containing 150 mM hydrochloride. This suppressive effect seems dependent on the content of procyanidin oligomers. Procyanidin oligomers (dimers to hexamers) were prepared and studied for their antiulcer activities at a dose of 200 mg/kg. The gastric protective activity of a series of procyanidins increased with the increasing polymerization of catechin units. Oligomers longer than tetramers showed a strong protective effect against gastric mucosal damage. The binding ability of procyanidin oligomers to bovine serum albumin in the acidified solution was strengthened with the increase of molecules. The mechanism of antiulcer activity may be the protection by radical scavenging activity on the stomach surface against radical injury induced by HCl/EtOH solution and the defense action of procyanidins covering the stomach surface by their strong ability to bind protein. Keywords: Grape seed extract; antiulcer activity; procyanidin; oligomer; radical scavenging activity; HCl/EtOH-induced ulcer

Effect of some indigenous drugs on cold immobilization stress induced gastric ulcer

The effect of an alcoholic extract of P. cerasoides Bedd., A. muricata Linn., M. heyneana Thw. and P. nyctaginifolia Juss. on cold immobilization stress induced gastric ulceration was investigated in albino rats. All these indigenous drugs effectively protected stress induced gastric ulceration. However, of these drugs, the extract of P. cerasoides exhibited maximum gastric ulcer protective activity. © 1998 John Wiley & Sons, Ltd.

Gastric cytoprotective activity of dehydroleucodine in rats. Role of prostaglandins.

Previously, we reported that dehydroleucodine (DhL), a sesquiterpene lactone, protected the gastric mucosa of rats from absolute ethanol-induced lesions in a dose-dependent fashion. The mechanism is not mediated by an antiacid secretory action and DhL stimulated mucous production. In the present study, we report the effect of DhL on the mucosal production of prostaglandin E (PGE) and the mucosal release of PGE2 in rats stomach. DhL in acute treatment does not modify these values decreased by previous treatment with indomethacin or absolute ethanol. However, DhL in subchronic treatment significantly enhanced the mucosal production of PGE and the mucosal release of PGE2. Also, indomethacin pretreatment resulted in a significant reduction of the cytoprotective action of DhL. These results indicate the participation of endogenous prostaglandins in DhL protection against ethanol damage. Moreover, we suggest that the gastric protective activity of DhL against ethanol induced gastric mucosal damage is mediated, at least in part, through PGE and PGE2 in subchronic treatment.

Synthesis and antiulcer activity of N-substituted N'-[3-[3-(piperidinomethyl)phenoxy]propyl]ureas: histamine H2-receptor antagonists with a potent mucosal protective activity.

As an aim toward developing new antiulcer agents, new N-substituted N'-[3-[3-(piperidinomethyl)phenoxy]propyl]ureas were synthesized and evaluated for histamine H2-receptor antagonistic, gastric antisecretory, and gastric mucosal protective activities. A QSAR study showed that the most favorable N-substituents were electron-donating straight-chain alkyl groups of short length such as ethyl group from the viewpoint of dual action, i.e., gastric antisecretory and mucosal protective actions. Among the ureas studied, compounds 4, 5, and 8-10 were selected as candidates for further study.

Sterol-dependence of gastric protective activity of unsaturated phospholipids

The major aim of this study was to investigate the gastric protective effect of unsaturated phospholipids and to determine the ability of neutral lipids to enhance this activity. We found that although a liposomal suspension of unsaturated phosphatidylcholine (PC) administered intragastrically failed to protect rats from acid-induced gastric ulcer formation, addition of cholesterol to unsaturated PC induced a dose-dependent protective response with the maximally effective dose, reducing lesion score greater than 70%. This effect also was seen with the plant sterol, beta-sitosterol (reducing lesion score by 81.6 +/- 36%) but was blocked if cholesterol was esterified to fatty acids of varying chain length. Addition of sterols to liposomes of saturated dipalmitoylphosphatidylcholine, in contrast, attenuated the gastric protective action of the saturated PC. It appears that the protective mechanism elicited by sterols and unsaturated PC is not mediated by alterations in gastric emptying rate or prostaglandin biosynthesis, although maintenance of surface hydrophobicity may be involved. These results suggest that the sterol may promote the packing of adjacent unsaturated phospholipid molecules of either the cell membrane or a putative extracellular hydrophobic lining of the gastric epithelium to provide the mucosa with protection against luminal acid.

Gastric protective activity of mixtures of saturated polar and neutral lipids in rats

It has been shown that intragastric treatment of rats with a suspension of dipalmitoylphosphatidylcholine and tripalmitin at a 1:4 ratio (5 mg lipid/mL per rat) provided rats with highly efficaceous and consistent protection against a variety of ulcerogenic agents and conditions. The gastric protective activity of this mixture was of long duration (t½ ~ 9 hours). In an attempt to understand the mechanism of protection, it was determined that the ulcerogen-induced reduction in gastric surface hydrophobicity was reversed in rats pretreated with the mixture. However, the lipid mixture did not affect the gastric emptying rate and maintained its cytoprotective activity in indomethacin-treated rats. These results indicate that the mixture's protective effect was not mediated by alterations in either gastrointestinal motility or the gastric accumulation of lipids or “cytoprotective” metabolites (prostaglandins). The mixture also appreciably reduced gastric lesion score in response to acid if one or both the lipids was substituted for a metabolically inert ether analogue, suggesting that lipid metabolism makes a negligible contribution to the protective response. Electron microscopic observation indicated that the predominent structure in the mixture is a microemulsion in which a dipalmitoylphosphatidylcholine monolayer encapsulates a tripalmitin core. Last, the improved gastric protective activity of the mixture in comparison to dipalmitoylphosphatidylcholine liposomes is discussed regarding marked differences in the physical structure of the two suspensions and the rate at which lipids in these states adsorb to a surface to enhance its hydrophobic properties.

Synthesis and gastrointestinal pharmacology of the 4-fluoro analogue of enisoprost.

A 4-fluoro analogue of enisoprost was prepared and evaluated for gastric antisecretory and mucosal protective activity in animals. The synthesis centered upon cuprate chemistry but also involved a Wittig reaction to produce a cis fluoro olefinic moiety, a furan rearrangement/isomerization reaction to provide the necessary hydroxycyclopentenone, and a two-carbon-homologation procedure. The fluoro analogue was much less potent as a gastric antisecretory and mucosal protective agent than enisoprost.

Comparison of gastric and intestinal antisecretory and protective effects of prostacyclin and its stable thia-amino-analogue (HOE 892) in consious rats

The effects of prostacyclin (PGI 2) and its stable thia-thimo-analogue (Hoe 892) on gastric and intestinal secretions and gastric mucosal lesions have been determined in conscious rats. Both PGI 2 and Hoe 892 given subcutaneously (s.c.) reduced dose-dependent gastric acid secretion, the ID 50 (dose producing 50% inhibition) being about 48.6 and 11.8 gmg/kg, respectively. In contrast, intragastric (i.g.) PGI 2 and Hoe 892 did not cause any change in gastric acid secretion at doses ranging from 1 to 100 gmg/kg. Both PGI 2 and Hoe 892 reduced significantly intestinal fluid secretion (antienteropooling activity). PGI 2 and Hoe 892 given i.g. or s.c. reduced dose-dependent gastric ulcer formation induced by acidified aspirin (ASA), Hoe 892 being somewhat less potent than PGI 2. Both PGI 2 and Hoe 892 were equally effective against mucosal necrosis induced by absolute ethanol and this effect was observed both after i.g. and s.c. administration of these agents. We conclude that stable thia-amino-PGI 2 analogue, Hoe 892, has similar gastric and intestinal antisecretory and protective activity as PGI 2 and may be useful in the prevention of gastric damage by various noxious agents.

Spirocyclopropane compounds. III. Synthesis of spiro[benzofuran-2(3H),1'-cyclopropan]-3-ones for evaluation as gastric antisecretory and antiulcer agents.

Spiro [benzofuran-2 (3H), 1'-cyclopropan]-3-one (VI-1) and its derivatives (VI-2-VI-75) were synthesized in the same manner as described previously for the synthesis of spiro [cyclopropane-1, 2'-[2H] indol]-3'(1'H)-ones (I). These spiro [benzofuran-2 (3H), 1'-cyclopropan]-3-ones were evaluated for gastric antisecretory activity and protective activity against lesions induced by water-immersion restraint stress in the rat. The most potent antiulcer compounds (VI-17 and VI-55) were obtained by the introduction of an acetyl or dimethylamino group at the 5-position on the benzene ring. The most interesting member of the series, 5-acetylspiro [benzofuran-2 (3H), 1'-cyclopropan]-3-one (VI-17, AG-629), was selected as a candidate for clinical studies.