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At least 1,135 records · Page 63Linked to original sources
PubMed1988

Ultrastructural aspects of prostaglandin cytoprotection in an alcohol injury model.

The effects of absolute ethanol (EtOH) and 16,16-dimethyl-prostaglandin E2 (PGE2) on the ultrastructure of rat gastric mucosa were assessed using standard electron microscopic techniques. Fasted rats were injected subcutaneously with 10 micrograms/kg body weight of PGE2 or saline. After 30 min, animals received orally 100% EtOH or an equal volume of saline. Gastric mucosa was sampled at 5 min and 1, 2, 8, and 24 h post-EtOH and tissues procured for scanning and transmission electron microscopy. Both mucosal epithelial and connective tissue compartments were assessed. At 5 min after EtOH, in saline-pretreated animals, tissues showed extensive destruction of epithelium and connective tissue; major breaks in the basal laminae were coincident with hemorrhage. Deep-lying epithelial cells and most of the basal lamina were spared in tissues exposed to PGE2 prior to EtOH, permitting nearly complete repair within 24 h. Restitution proceeded over small breaks or pleats of basal lamina but failed in regions of total destruction of this structure. These data indicate that PGE2 protects not only deep-lying epithelial cells from EtOH damage but associated connective tissue as well and that sparing of both compartments leads to orderly and rapid epithelial restitution.

16,16-Dimethylprostaglandin E2↗
PubMed1990

In vitro adaptive cytoprotection in gastric cells isolated from rat stomach.

The effects of mild irritants (2-5% ethanol or water at 45-55 degrees C) on production of prostaglandins (PGs) in gastric cells isolated from rat stomach and the damage caused by 15% ethanol were assessed. Gastric cells were isolated by the method of Matuoka et al., by which a suspension rich in surface epithelial cells was obtained. Synthesis of PGE2 by the cells was stimulated by 3% ethanol or water at 50 degrees C. The damage caused by 15% ethanol was much less in the cells treated with 3% ethanol or 50 degrees C water beforehand than in untreated cells. This protective effect by 3% ethanol or 50 degrees C water was abolished when the cells were treated with 10(-4) M indomethacin. These results suggest that 3% ethanol or 50 degrees C water protects the gastric cells from damage caused by 15% ethanol, possibly via endogenous PGs.

Animals↗
PubMed1991

Gastric cytoprotection by ornoprostil, a PGE1 analogue, in human subjects.

Ornoprostil, a methyl derivative of PGE1 developed in Japan, was tested for its effect on gastric mucosal damage caused by ethanol in human subjects. Sixteen healthy volunteers were given either ornoprostil or a placebo, followed by 20 ml of 70% ethanol instilled into the gastric antral mucosa. Fifteen minutes later, visible mucosal lesions were evaluated endoscopically. The biopsy specimens were obtained from mucosa that had been exposed to ethanol but looked normal. The specimens were assessed by light microscopy and scanning electron microscopy. The gross mucosal damage demonstrated endoscopically was significantly less (p less than 0.05) in the subjects receiving ornoprostil than those receiving placebo. Hyperemia and hemorrhage in the mucosa were also significantly less (p less than 0.05) in the subjects given ornoprostil pretreatment. Ornoprostil, however, failed to prevent the disruption of surface epithelial cells as assessed by scanning electron microscopy. These data suggest that ornoprostil protects gastric mucosa against damage caused by concentrated ethanol.

Adult↗
PubMed1989

Myocardial cytoprotective efficacy of azapropazone in a canine heart model of regional ischemia and reperfusion.

The present study assessed the efficacy of azapropazone (AZA) in pentobarbital-anesthetized dogs subjected to 120 min of regional ischemia [left anterior descending coronary artery (LAD) ligation] followed by 5 h of reperfusion. Azapropazone was given 30 min prior to LAD occlusion (100 mg/kg i.v.), 35 min prior to LAD release (50 mg/kg, i.v.), and at 2.5 h postreperfusion (50 mg/kg i.v.). Regional myocardial blood flow (RMBF) and area at risk (AAR) were determined with radiolabeled microspheres. The degree and extent of ischemia (anaerobic metabolism) and necrosis were delineated with 14C-deoxy-2-D-glucose (14C-DG) and 111In-antimyosin, respectively, in control (n = 7) and AZA (n = 7)-treated groups. In mild (60-80% normal RMBF) and moderate (30-60% normal RMBF) flow-restricted areas, AZA resulted in a significant decrease in the degree and extent of ischemia (p less than 0.01) with the limitation of infarct size (p less than 0.01). However, AZA did not produce a significant infarct size limitation in the severe flow-restricted area (0-30% of normal RMBF). The effect of AZA is expressed primarily in moderate flow-restricted myocardium with the subsequent infarct size limitation.

Anaerobiosis↗
PubMed1995

Attenuation by R 56865, a novel cytoprotective drug, of regional myocardial ischemia- and reperfusion-induced electrocardiographic disturbances in anesthetized rabbits.

We investigated the antiischemic and antiarrhythmic effects of R 56865 in pentobarbital-anesthetized, open-chest rabbits subjected to 10 min regional myocardial ischemia and 20 min reperfusion, using two experimental protocols. In the first, R 56865 (0.02-0.16 mg/kg) was administered as a bolus intravenous (i.v.) injection 5 min before ligation of a branch of the left circumflex coronary artery (LCX); in the second, the drug, at the highest dose studied (0.16 mg/kg), was injected by the same route during ischemia, 5 min after coronary artery ligation. Ischemia-induced ST segment increase and reperfusion-induced ventricular arrhythmias were determined in lead II of the four-limb ECG. Mean carotid arterial pressure and heart rate (HR) were also measured. When given before ischemia, R 56865 dose-dependently prevented ischemia-induced ST segment increase and reperfusion arrhythmias. The antiischemic and antiarrhythmic dose-response curves were superimposable, suggesting a common mechanism of action. R 56865 (0.16 mg/kg) fully attenuated ischemia-induced ST segment shift and ventricular arrhythmias on reperfusion. These protective effects were not associated with systemic hypotension or bradycardia. When high-dose R 56865 (0.16 mg/kg) was given during ischemia, ST segment shift and ventricular arrhythmias on reperfusion were not attenuated. The results strongly suggest that R 56865 affords protection against the deleterious effects of moderate ischemia by mechanisms not associated with an indirect reduction of cardiac work. R 56865 may elicit cardioprotection directly in ischemic tissue.

Analysis of Variance↗
PubMed2005

Hypofractionated accelerated radiotherapy with cytoprotection combined with trastuzumab, liposomal doxorubicine, and docetaxel in c-erbB-2-positive breast cancer.

OBJECTIVES: Trastuzumab, an antic-erbB-2 monoclonal antibody, has become a standard component of chemotherapy for c-erbB-2-positive advanced breast carcinoma. Despite the experimental evidence of its radiosensitizing properties, trastuzumab has never been used in combination with radiotherapy for the treatment of patients with locally advanced disease. PATIENTS AND METHODS: Twenty-two patients with c-erbB-2-positive locally advanced chemoresistant (7 patients) or with high-risk breast cancer (15 patients) were recruited in a treatment protocol combining hypofractionated/accelerated radiotherapy (hypoARC) supported with high-dose amifostine (1000 mg subcutaneous), concurrently with trastuzumab (4 mg/kg every 2 weeks). Thirteen of these patients (including all 7 inoperable cases) received concurrently chemotherapy with liposomal doxorubicin and docetaxel (25 mg/m2 and 40 mg/m2 every 2 weeks, respectively). RESULTS: Administration of trastuzumab together with highly accelerated amifostine-supported radiotherapy was feasible without an increase in early and late radiation toxicity. This was obtained despite the concurrent administration of aggressive chemotherapy. Complete responses were noted in 5 of 7 patients with locally, often far advanced, chemoresistant disease. None of the complete responders or the 15 high-risk breast cancer patients relapsed within the 3- to 26-month follow-up period. CONCLUSION: Inclusion of trastuzumab in the radiochemotherapy protocols for breast cancer does not increase radiation or systemic toxicity. The concurrent administration of aggressive radiotherapy with docetaxel and liposomal doxorubicin is feasible when supported with amifostine. The value of such regimens in the treatment of locally advanced or high risk c-erbB-2 positive breast cancer patients deserves further evaluation.

Adult↗
PubMed1997

Cytoprotective effect of epidermal growth factor on acid- and pepsin-induced damage to rat gastric epithelial cells: roles of Na+/H+ exchangers.

We have previously established a cell damage model, with damage induced by either acid or pepsin treatment for 30 min, involving a rat gastric epithelial cell line (RGM1). In the present study, pretreatment of cells with epidermal growth factor (EGF; 0.1-10 ng/mL) or sucralfate (0.1-3 mg/mL) for 4 h prevented such cell damage in a concentration-dependent manner. Protection of cells by these drugs was not affected by pretreatment with indomethacin (10(-5) mol/L) for 4 h. Removal of Na+, but not Ca2+, from the acidified medium totally abolished the inhibitory effect of EGF, but not that of sucralfate. Genistein (a tyrosine kinase inhibitor) apparently reduced the inhibitory effect of EGF. DNA synthesis by RGM1 cells did not increase when cells were incubated with EGF for 4 h. We conclude that both EGF and sucralfate protect RGM1 cells from acid- and pepsin-induced damage and that the mechanism of protection by EGF against acid-induced damage seems to be via activation of Na+/H+ exchangers.

Acids↗
PubMed1987

Gastric mucosal cytoprotection in the rat by cysteine.

The free radical scavengers methyl-methionine sulphonium bromide and cysteine (5%) protected the rat gastric mucosa against ischaemic injury produced by reserpine (5 mg kg-1 i.p.). Pretreatment with 1 mL of 5% cysteine by gavage completely protected against injury rats with no ligation and 70% of rats with pyloric ligation after they had been given aspirin (200 mg kg-1 by gavage), a dose that produced gastric mucosal injury in 40% of rats with no ligation and 70% of rats with pyloric ligation after 4 h. Ethanol (1 mL of 40% solution by gavage) after 1 h produced gastric mucosal injury in all animals and pretreatment with 1 mL of 5% cysteine by gavage completely protected 80% of non-ligated and 70% of pyloric-ligated rats against this injury. This protection was not associated with any significant effect on H+ output. The data suggest that cysteine maintains gastric mucin by a mechanism independent of acid secretion.

Animals↗
PubMed1990

Gastric mucosal cytoprotection in the rat by naftidrofuryl oxalate.

Ischaemic gastric mucosal injury was assessed in the rat by measurement of the area of the injury produced after 6 h by reserpine (5 mg kg-1 i.p.) or 5-hydroxytryptamine (5-HT) (50 mg kg-1 i.p.). Pretreatment with naftidrofuryl 1 mL, 1% by gavage significantly (P less than 0.001) protected the rat stomach against the reserpine (24 +/- 2.7 mm2 vs 40 +/- 4.7 mm2, mean +/- s.e.m., n = 10) and 5-HT injury (11.4 +/- 1.7 mm2 vs 27 +/- 4.1 mm2, mean +/- s.e.m., n = 10). Naftidrofuryl 1 mL 2% by gavage was more effective (P less than 0.001) in this respect and mucosal injury only developed in 50% of rats injected with reserpine (9.4 +/- 1.1 mm2) and 30% of those injected with 5-HT (3.2 +/- 0.4 mm2). Administration of naftidrofuryl 1 mL 5% by gavage completely protected the rat against both the reserpine- and 5-HT-induced acute gastric mucosal injury. This protection was not associated with any significant influence on the H+ output.

Animals↗
PubMed1990

Cytoprotection against neutrophil derived hypochlorous acid: a potential mechanism for the therapeutic action of 5-aminosalicylic acid in ulcerative colitis.

The aim of the present study was to investigate the effects of 5-aminosalicyclic acid (5-ASA) on the cell injury mediated by activated neutrophils. We used a system constituted of neutrophils, triggered with phorbol myristate acetate, and 51Cr-labelled Daudi cells as targets. The results show that 5-ASA is capable of efficiently preventing neutrophil-mediated lysis. 5-ASA was up to 10-fold more effective than taurine, which acts as an hypochlorous acid scavenger. Moreover, 5-ASA was found to compete with taurine for the neutrophil derived hypochlorous acid. The results are consistent with the conclusion that 5-ASA is capable of limiting the neutrophil mediated cell damage by scavenging the generated hypochlorous acid. This may represent a potential mechanism for the therapeutic action of 5-ASA in ulcerative colitis.

Aminosalicylic Acids↗
PubMed1992

Morphological and functional gastric cytoprotection by prostaglandin in rats receiving absolute ethanol orally.

Pretreatment with prostaglandins at non-antisecretory doses protects the gastric mucosa, including the parietal cells, from deep necrosis produced by intragastric administration of necrotising agents such as absolute ethanol. Whether the parietal cells also retained their ability to secrete acid when rats were pretreated with a prostaglandin, in spite of exposure to ethanol, was investigated. Gastric acid secretion was abolished 4 hours after ethanol, and secretion returned to control values only after 5-6 days. Pretreatment with a single, non-antisecretory dose of 16, 16-dimethyl prostaglandin E2 (dm PGE2) maintained acid secretion, in spite of exposure to absolute ethanol. Absolute ethanol caused histological changes - extensive gastric mucosal necrosis (through the muscularis mucosae), oedema, haemorrhages, polymorphonuclear infiltration, and formation of granulation tissue - that were maximal 24-48 hours after ethanol and persisted for 2 to 4 weeks. None of these changes were present in animals treated with the prostaglandin. It is concluded that a single oral pretreatment with dmPGE2 protects the gastric mucosa against not only the morphological damage of absolute ethanol (preventing necrosis, haemorrhages, and polymorphonuclear infiltration) but also the functional damage (maintaining the acid secretory function of parietal cells).

16,16-Dimethylprostaglandin E2↗