Gastroprotective effect from Calophyllum brasiliense Camb. bark on experimental gastric lesions in rats and mice.

In order to establish the pharmacological basis for the ethnomedicinal use of stem bark extracts of Calophyllum brasiliense Camb. in gastrointestinal affections, this study examined the effects of a dichloromethane fraction (DCMF), obtained from the hexane extract of bark, on ethanol, indomethacin and hypothermic restraint stress-induced gastric lesions in mice and rats, respectively. Oral administration of DCMF at doses ranging from 12.5-250 mg/kg significantly inhibited the development of gastric lesions in all the three test models. It caused significant decreases of the pyloric-ligation and bethanechol-stimulated gastric secretion, and also the free and total acidities. Besides, DCMF offered protection against ethanol-induced depletion of stomach wall mucus and reduction in nonprotein sulfhydryl concentration. The results indicate that DCMF from C. brasiliense possesses antisecretory, antiulcer and cytoprotective properties.

Effects of Cistus laurifolius L. flowers on gastric and duodenal lesions.

The flowers and flower buds of Cistus laurifolius L. are used for the treatment of peptic ulcers. Through the bioassay-guided fractionation of the material, using water immersion and immobilisation-induced stress ulcer model, the EtOH-precipitated part from the aqueous extract (E-H2O decreases) was determined to be the active fraction. For the evaluation of the mode of action, the activity of E-H2O decreases was tested using various ulcer models in rats and mice and this fraction was found active against pylorus ligation-, abs. ethanol-, indomethacin-, indomethacin plus HCl/EtOH-induced gastric and cysteamine-induced duodenal lesions while ineffective against serotonin-induced gastric lesions. The active fraction showed its activity not only on per os administration but also after subcutanous injection. According to the results of biochemical studies, the active fraction showed a potent antiacid activity. In addition, histopathological, and toxicological studies were conducted with the active fraction.

[Effect of shashen maidong decoction on gastric motility in vivo].

Effect of Shashen Maidong Decoction (SSMDD) on the gastric motility of mice and rats was observed in vivo. Results showed that the gastric phenol red excretion rate of mice could be reduced markedly by SSMDD given in various dosages (23 g.kg-1.d-1, 9 g.kg-1.d-1 or 23 g.kg-1.d-1 for 5 days successively), P < 0.05. By administration of 9 g.kg-1.d-1 or 23 g.kg-1.d-1 could antagonize the acceleration of gastric emptying induced by neostigmine in mice (P < 0.05, P < 0.01). 7 g/kg of SSMDD by gastrogavage could inhibit the frequency and amplitude of contraction of fundic longitudinal muscle using strain gauge transducer in rats, but the effect was not obvious on that of antral circular muscle. By water-ballon method, it was observed that SSMDD 3.5 g/kg or 7 g/kg intraduodenal perfusion could slow down the frequency and decrease the amplitude of gastric peristalsis, 7 g/kg could inhibit significantly the gastric hypermotility induced by subcutaneous injection of indomethacin (40 mg/kg), but had no obvious effect on the gastric hypermotility induced by intramuscular injection of reserpine (0.4 mg.kg-1.d-1 x 4 d).

Effect of fish oil on indometacin-induced gastric lesions in rats.

The effect of fish oil in promoting the healing of indomethacin-induced gastric lesions was investigated in Wistar albino rats. After indomethacin treatment (30 mg/kg, s.c.), animals were given fish oil, olive oil, or normal diet for 48 h. The ulcer index was found to be decreased to 2.1 +/- 1.8 mm with fish oil, 13.7 +/1 5.4 mm with olive oil, and 14.6 +/- 2.4 mm with normal diet. Fish oil showed a potent healing-promoting effect on acute gastric erosions and ulcers induced by indomethacin and significantly enhanced the mucus content of the mucosa (p < 0.05).

Evaluation of Caralluma tuberculata pretreatment for the protection of rat gastric mucosa against toxic damage.

The ethanolic extract of Caralluma tuberculata N. E. Brown has been screened for its potential to protect gastric mucosa against the injuries caused by 80% ethanol, 0.2 M NaOH, hypertonic saline, and indomethacin. C. tuberculata at doses of 250, 500, and 1000 mg/kg body wt given 30 min before the necrotizing agents provided dose-dependent protection against the damage caused by all tested agents. The effects caused by ethanol were further investigated. Treatment of rats with 1 ml of 80% ethanol (gavage) was found to cause depletion of stomach-wall mucus, to lower the concentrations of proteins, nucleic acids, and nonprotein sulfhydryl groups in the stomach wall, and to cause histopathological lesions, including necrosis, erosions, congestion, and hemorrhage, of the stomach wall. C. tuberculata treatment caused a dose-dependent protection against all these effects. In the same manner it affected malondialdehyde concentrations altered by ethanol treatment. C. tuberculata also offered protection against mucosal damage caused by indomethacin. The protective effects of C. tuberculata in addition to its effects on mucus production and nonprotein sulfhydryl concentration may be mediated through its free radical scavenging and prostaglandin inducing properties.

Occurrence of endothelium-derived relaxing factor--nitric oxide in the lamb ductus arteriosus.

To determine whether the ductus arteriosus can form endothelium-derived relaxing factor--nitric oxide, we used isolated ductal strips from near-term fetal lamb and examined their response to bradykinin (a nitric oxide stimulator), L-arginine (a nitric oxide precursor), and agents interfering with the synthesis (N omega-nitro-L-arginine) and action (methylene blue) of nitric oxide. Bradykinin relaxed the indomethacin-contracted ductus dose dependently from a threshold of about 10(-10) M, and peak relaxation was greater at high (176-210 mmHg; 1 mmHg = 133.3 Pa) than low (15-25 mmHg) PO2. Bradykinin relaxation was nearly completely or completely abolished in endothelium-denuded preparations and, in its place, there was often a small contraction. Pretreatment with nitric oxide inhibitors also prevented, in part (methylene blue, 1 microM) or in full (N omega-nitro-L-arginine, 100 microM), the relaxant effect of bradykinin. Paradoxically, L-arginine (10 microM) had an inhibiting rather than an enhancing effect on the bradykinin relaxation. N omega-Nitro-L-arginine (100 microM) and methylene blue (1-100 microM) contracted by themselves the untreated ductus, and their action persisted after removal of the endothelium. These findings indicate the presence in the ductus arteriosus of a nitric oxide based relaxing mechanism, which may supplement prostaglandin E2 in keeping the vessel patent in the fetus. This mechanism may, on one hand, afford protection against nonsteroidal anti-inflammatory drugs in utero and may, on the other hand, complicate the management of prematures with persistent ductus and account for failures of the indomethacin therapy.

Primary culture of rat gastric epithelial cells as an in vitro model to evaluate antiulcer agents.

Primary rat gastric cell cultures were investigated as an in vitro model for evaluating antiulcer agents. Following exposure to concentrations of up to 5 mg/mL of an antiulcer agent sucralfate, an aluminum hydroxide complex of sucrose octasulfate, cultured cells were treated with either pH 3.5 medium or 3.5 mM indomethacin. Cytoprotection was evaluated by colony forming efficiency, neutral red uptake, and 3-(4,5-dimethyl-2-thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) hydrolysis. By each measure, and depending on damaging agent, 2 and 5 mg/mL sucralfate provided partial (50% of untreated control) to near-complete (90% of untreated control) cytoprotection, respectively. Aluminum hydroxide also provided partial (55% of untreated control) to near-complete (more than 90% of untreated control) cytoprotection at 2 and 5 mg/mL, respectively, for the pH 3.5 medium-induced damage. Over a concentration range of 0.05 to 5 mg/mL, the potassium salt of sucrose octasulfate, KSOS, stimulated cell growth up to 40-60% over untreated controls but had little or no cytoprotective action in the presence of either 3.5 mM indomethacin or pH 3.5 medium. Overall results suggested that sucralfate may have at least two roles in influencing gastric epithelial cell function, cytoprotection and stimulation of cell growth in vitro. These observations serve as a basis for further study of in vitro models in evaluating the cytoprotective activity of antiulcer agents and their respective mechanisms of action.

Protective effect of Swertia chirata against indomethacin and other ulcerogenic agent-induced gastric ulcers.

The effect of Swertia chirata has been studied on experimentally induced gastric ulcers in rats. The ethanolic extract of chirata significantly reduced the intensity of gastric mucosal damage induced by indomethacin and necrotizing agents. It produced a significant decrease in gastric secretion in pylorus-ligated rats. The extract inhibited acetylcholine-induced contraction of guinea pig ileum, suggesting its anti-cholinergic activity. Pretreatment of rats with the extract significantly prevented ethanol-induced gastric wall mucus depletion and restored the non-protein sulfhydryl (NP-SH) content in the glandular stomachs. These findings support the use of chirata for the treatment of gastric ulcers in traditional medicine.

Cod liver oil inhibits indomethacin induced gastropathy without affecting its bioavailability and pharmacological activity.

The upper gastrointestinal toxicity is one of the most common side effects associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Many attempts to prepare potent NSAIDs free from gastrotoxicity have failed. Hence, development of formulations to mask the gastropathy of NSAIDs are warranted. The present study was undertaken to investigate the effect of concomitant use of cod liver oil (CLO) on pharmacological activity and gastropathy of indomethacin in rats. The animals were treated with CLO (5 and 10 ml/kg body weight) along with indomethacin (30 mg/kg, body weight). Blood samples were collected for analysis of indomethacin at 0.25, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0 and 24 hours. The anti-inflammatory activity of indomethacin alone and in combination with CLO was studied using carrageenan-induced paw oedema. Our studies related to the effect of these drugs on gastrointestinal tract showed that concurrent use of CLO protects gastric mucosa against indomethacin induced depletion of gastric wall mucus, non protein sulfhydryl (NP-SH) levels and gastric lesions. The result of this study also showed that the concurrent use of the CLO does not affect the bioavailability and anti-inflammatory activity of indomethacin while it inhibits the ulcerogenic effect of indomethacin in a dose dependent manner. These findings suggest that NSAIDs formulations containing CLO may reduce gastrotoxicity without affecting their therapeutic efficacy.

Gastric cytoprotective properties of SCH 32651, a novel antiulcer agent.

The antisecretory activity of SCH 32651 (3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a] pyrazine HCl . 1/3 H2O) has been described in a preceding paper. This report describes its gastric cytoprotective properties. SCH 32651 inhibited the gastric lesions due to ethanol in a dose-dependent manner (ID50 = 5 mg/kg p.o.) and exerted its maximal effect when given 30 min before ethanol and had a duration of at least 90 min at 30 mg/kg p.o. The activity of SCH 32651 against ethanol was unaffected by indomethacin pretreatment. Furthermore, SCH 32651 produced significant increases in gastric mucus release (10-100 mg/kg p.o.) and rapidly reversed ethanol-induced (30-100 mg/kg p.o.) fall in gastric potential difference (PD). SCH 32651 displayed significant antiulcer activity in indomethacin-(30-100 mg/kg p.o.), aspirin - (30-100 mg/kg p.o.), "aspirin + acid" - (10-100 mg/kg p.o.), reserpine - (10-100 mg/kg p.o.), stress - (30-100 mg/kg p.o.), and cysteamine (10-100 mg/kg p.o.) ulcers. The present data in conjunction with those reported in a preceding paper indicate that SCH 32651 is an orally effective novel antiulcer drug with both gastric antisecretory and cytoprotective properties.

Synthesis and gastrointestinal pharmacology of some 15- and 16- modified (+/-)-11-deoxyprostaglandins.

The synthesis and gastrointestinal pharmacology of some 11-deoxyprostaglandin E1 analogues are described with results analysed for selectivity from side effects. 11-Deoxygenation reduced potency relative to PGE2 but, as has been reported for natural PGs, 15- or 16-methyl analogues were more potent than the unsubstituted parent compound in the order 16-methyl greater than 15-methyl greater than 16,16-dimethyl. The results suggest that a complex interaction between C-15 and C-16 in methyl analogues affects their profile of activity, but that none of the modifications studied conferred a substantial potency or selectivity advantage over PGE2.