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Biomedical subjects

A Bennett

Publications and source records attributed to A Bennett.

At least 37 records · Page 2Linked to original sources
PubMed1990

Smoking, eicosanoids and ulcerative colitis.

In this study, which is the first of its kind using normal tissue samples that are very difficult to obtain, we have investigated the hypothesis that smoking protects against ulcerative colitis by altering the colonic mucosal formation of prostaglandins and related substances. Colonic mucosa biopsied from healthy young men produced prostaglandin E, 6-keto-PGF1 alpha (formed from PGI2), leukotriene B4 and leukotriene C4/D4/E4 as determined by radioimmunoassay. With each substance, the median yield was lower in the group of smokers who smoked 3 cigarettes in the 2 h before biopsy, than in the non-smokers. However, with each eicosanoid the statistical probability approached only the 10% level, but the fact that the trend was the same for all eicosanoids somewhat strengthens the possibility of a real difference between the groups.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Polyphloretin phosphate (PPP) antagonists of prostaglandin action also inhibit prostaglandin biosynthesis in-vitro.

Several polyphloretin phosphate (PPP) fractions (low mol. wt LC1259; high mol. wt LC1261; crude mixture, LC101) were confirmed in their established property as antagonists of the pharmacological actions of prostaglandins in a preparation of guinea-pig isolated ileum stimulated by prostaglandin (PG)E2. Further samples of the same material were then compared in-vitro with indomethacin in their ability to inhibit prostaglandin biosynthesis from arachidonic acid by a microsomal enzyme preparation. All three PPP fractions potently inhibited prostaglandin generation, with the rank order of potency LC1259 = LC101 = indomethacin greater than LC1261. The oral LD50 in mice was 25 mg kg-1 for indomethacin and greater than 1 g kg-1 for LC101. PPP fractions (especially LC101) may therefore have therapeutic potential as anti-inflammatory agents.

Animals↗
PubMed1990

Effect of pirazolac on prostanoid synthesis by human gastric mucosa in vitro.

Pirazolac concentration-relatedly inhibited the accumulation of prostanoids in incubates of human gastric mucosa, but this inhibition was less than that by indomethacin and other commonly used non-steroidal anti-inflammatory drugs. This difference may explain the claim that pirazolac is less damaging to the stomach.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Breast cancer, prostaglandins and patient survival.

Prostaglandins may have both undesirable and desirable effects in malignant disease. Their possible roles in breast cancer were studied by examining the relationships between different variables and the amounts of prostaglandin-like material (PG-LM) extracted from 141 breast carcinomas. Univariate analysis indicates a direct correlation with patient age and menopausal status, with a greater yield from cancers of post- compared with pre-menopausal women. Tumours up to 2 cm diameter yielded more PG-LM than those measuring greater than 2-5 cm. Although there was also a direct correlation with bone metastasis near to the time of surgery, this was because no positive bone scans occurred in patients whose tumours yielded little total PG-LM (less than 16 ng PGE2 equivalents per g tissue). Since tumour PG-LM did not predict later spread to bone, and yields of greater than 16 ng g-1 were similar in the positive and negative bone scan groups, tumour PG-LM appears to be unimportant for skeletal metastasis. There was no obvious relationship of tumour PG-LM to the grade of malignancy, tumour type, amounts of fibrous tissue (and therefore malignant cells), invasion of blood vessels and lymphatics or presence of plasma cells. Multivariate analysis indicates that disease-free survival is longest with an intermediate production of tumour total PG-LM. Of the 82 patients now dead, the cause was attributed to metastatic disease in 69 cases. No relationship of PG-LM to the length of survival was seen with univariate or multivariate analysis. However, when just the post-menopausal patients who died within the first 3 postoperative years were analysed, there was a highly significant inverse correlation between the tumour total PG-LM and the time to death. The reason(s) for these different findings on overall survival compared with just the patients who died are not understood, but the results may indicate that one or more other variables must co-exist with a high tumour PG-LM to hasten death.

Bone Neoplasms↗
PubMed1989

Stimulation of gastric and colonic mucosal eicosanoid synthesis by plantain banana.

Extracts of plantain banana (Musa sapientum Linn var. paradisiaca) were studied on the accumulation of eicosanoids in incubates of human gastric and colonic mucosa. The ethanolic extract caused a concentration-dependent increase in the eicosanoid accumulation but the water extract was ineffective. Since all the eicosanoids studied tended to increase, banana may act by increasing the availability of arachidonate. In control tissues the accumulation of PGE and TXB2 in the incubates decreased with time while that of 6-keto-PGF1 alpha increased (colon only, studied).

Eicosanoids↗
PubMed1989

The effects of dipyridamole and indomethacin on methotrexate cytotoxicity in LoVo human colon cancer cells.

Dipyridamole and indomethacin were studied for their effects in the in-vitro response of LoVo colon cancer cells to methotrexate (MTX) using a dye elution method. Dipyridamole 0.5-5 micrograms mL-1 or indomethacin 1 microgram mL-1 alone had little or no effect on cell growth. The tumour cells were refractory to even high concentrations of MTX (2.5-10 micrograms mL-1) alone or with indomethacin 1 microgram mL-1. In contrast, dipyridamole 0.5-5 micrograms mL-1 sensitized the cells to MTX 5 micrograms mL-1 (their growth was reduced by 25 to 69%), possibly by inhibiting thymidine salvage.

Cell Division↗
PubMed1989

Effects of gastrointestinal hormones on the growth of human intestinal epithelial cells in vitro.

The growth of cultured epithelium like cells from human normal embryonic intestine was studied in response to various hormones using a method that quantifies the number of cells by the amount of dye that they bind after fixation. Gastrin and neurotensin in the pg/ml range and higher caused small increases in cell growth. Glucagon and VIP were stimulatory in the low ng/ml range, whereas somatostatin and bombesin had no effect at the lower concentrations but were stimulatory at the highest concentration tested (10 and 100 ng/ml respectively). Secretin and pancreozymin (cholecystokinin) seemed to be ineffective.

Cell Division↗
PubMed1989

Some new aspects of gastric mucosal protection and damage.

Much of the research on gastric mucosal protection has concerned prostaglandins. Some of the recent studies consolidate aspects first investigated a few years ago, but whose importance is now becoming established more clearly. This short review will mention some of the more recent work demonstrating the importance of prostaglandins in preventing stasis of gastric mucosal blood flow, effects on cell senescence and exfoliation, and the protection of a severe mucosal lesion by a mucus-containing plug which facilitates healing. The leukotrienes are other substances formed in the gastric mucosa from the same precursors as the prostaglandins. Their roles are not well understood, but may include participation in gastric inflammation, and in mucosal damage by nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol. The NSAIDs may damage the gastric mucosa not only by reducing the formation of protective prostaglandins, but also by increasing the metabolism of prostaglandin precursors into leukotrienes. Another factor is thromboxane A2, a substance that is damaging to the gastric mucosa but whose synthesis is inhibited by NSAIDs. The prostaglandin analogues produced for the treatment of peptic ulcer may find a major use in the protection against damage by NSAIDs. Not only may they act as 'replacement therapy' for the inhibited prostaglandins, but they protect against damage from substances that do not inhibit prostaglandin synthesis. In doses that raise the gastric pH, the prostaglandins reduce the local absorption of NSAIDs by increasing their ionisation. In rats, paracetamol protects against damage by aspirin, but whether this occurs in man is controversial. Work not previously published demonstrates that paracetamol does not affect the inhibition of prostaglandin formation by indomethacin in human isolated gastric mucosa.

Animals↗
PubMed1989

Gastric mucosal damage by nonsteroidal anti-inflammatory drugs.

This brief review on gastric mucosal damage by nonsteroidal antiinflammatory drugs (NSAIDS) considers some aspects that generally receive little attention. Inhibition of prostaglandin (PG) synthesis is generally thought to be an important, but not the only, cause of the damage. Consideration should be made of the length of time and extent to which PG synthesis must be inhibited for damage to occur, of a possible differential effect on the various prostanoids, and of whether leukotrienes are involved. NSAID inhibition of PG synthesis may differ in the gastric mucosa as compared to other sites. Some evidence indicates that gastric mucosal damage correlates better with the drug potency for inhibition of PG synthesis than with potency x dose, particularly with drugs having a short or moderate half-life. The dose, which determines how much drug reaches the gastric mucosa via the blood-stream, might assume a progressively greater importance as the half-life increases. Inhibiting the synthesis of damaging thromboxane A2 by NSAIDs might help counteract the deleterious block of PG synthesis. If these hypotheses are correct, the gastric mucosal damage from NSAIDs absorbed locally may be less with low-potency/high-dose drugs having low gastric absorption and retention, and which dissolve in gastric juice without leaving particles in contact with the mucosa. With NSAIDs reaching the gastric mucosa locally or via the blood circulation, the damage at therapeutic doses might be less with drugs having a weaker effect on gastric as compared to other types of cyclo-oxygenases, a short or moderate half-life, and strong anti-thromboxane/antileukotriene activity.

Animals↗
PubMed1988

Potentiation by phenolphthalein of the responses of guinea-pig ileum and rat stomach strip to PGE2 and other agonists.

Phenolphthalein was examined for its effect on the activity of isolated muscle (guinea-pig ileum and colon, rat stomach), and on the tissue responses to PGE2, histamine and 5-HT. The ileal circular muscle and both muscle layers of the colon were unaffected by phenolphthalein. In contrast, the laxative potentiated the responses of the longitudinal muscle of guinea-pig isolated ileum and the rat stomach strip to the agonists, particularly PGE2. This potentiation was reduced by indomethacin in vivo, but mepyramine or methysergide had little or no effect. Augmentation of muscle activity by phenolphthalein, particularly in the response to PGE2, may contribute to the laxative effect.

Animals↗
PubMed1988

Delayed-release mesalazine (5-aminosalicylic acid): coat dissolution and excretion in ileostomy subjects.

1. Delayed-release mesalazine has been formulated to deliver 5-aminosalicylic acid to the colon. We have therefore studied the ileostomy excretion and coat dissolution of this preparation. 2. Following ingestion of a single tablet 88% (range 69-114%) of the 400 mg dose appeared unchanged in the ileosomy effluent over the subsequent 12 h. 3. Ileostomy effluent pH appeared to be a major determinant of 5-aminosalicylic acid release. 4. In vitro studies revealed rapid coat dissolution above pH 7.0, slow dissolution between pH 6.0 and 7.0 and non-dissolution at pH 2.0 and 4.0.

Adult↗
PubMed1988

The role of biochemical mediators in peripheral nociception and bone pain.

There are various substances that mediate or modulate pain, but most of the studies have been in human skin or in laboratory animals. It is not known whether the same substances are involved in the pain of bone metastases, and the tentative conclusions made here are by extrapolation and by inference from the effects of drugs whose actions have been characterized. Prostaglandins E2 and I2 cause hyperalgesia to bradykinin and histamine, and they increase oedema formation. Other lipids may also have a similar potentiating role in pain and inflammation. Pain can be sensed from the periosteum, and from within the bone due to increased pressure. NSAIDs act mainly at peripheral sites to inhibit the formation of prostaglandins, and so lessen the hyperalgesia and oedema production, but a central inhibition of prostaglandin synthesis may also contribute to the analgesia. Opioid peptides have important roles in pain, mainly as analgesic substances, but in contrast some may have a role as algesic agents by an action on different receptors. The importance of these and other possible mediators and modulators of pain has not been fully assessed, but advances will be made when selective antagonists of lipoxygenases and kinins become available for use in humans.

Adrenal Cortex Hormones↗
PubMed1987

Eicosanoid formation by mammalian intestine. Effects of some intestinal secretagogues.

Intestinal tissues of man, rat, mouse, guinea-pig and rabbit were preincubated with laxatives, homogenised, and incubated with [14C]arachidonic acid. After extraction into chloroform, the eicosanoids were separated by thin layer chromatography. Metabolism of [14C]arachidonic acid into prostaglandins (PGs), and the lipoxygenase products LTB4 and 5-HETE, was stimulated by ricinoleic acid (100 micrograms/ml) or phenolphthalein (100 micrograms/ml), and to a lesser extent by picosulphate (125 micrograms/ml) and sulfosuccinate (200 micrograms/ml). Mannitol (500 micrograms/ml) had no effect. Indomethacin (1 microgram/ml) inhibited the stimulation of PG formation. The dual pathway inhibitor BW755C (1 microgram/ml) reduced the formation of prostaglandins, LTB4 and 5-HETE. In some experiments on rat colon, prostanoids were separated from lipoxygenase products, characterised by their chromatographic mobility and quantitated (relative amounts PGE2 greater than PGF2 alpha greater than TXB2 greater than PGD2). Their formation was enhanced by ricinoleic acid (100 micrograms/ml) and inhibited by either indomethacin or BW 755C (1 microgram/ml). The present results indicate that mammalian isolated gut tissue can convert [14C]arachidonic acid into both cyclo-oxygenase and lipoxygenase products, and support the suggestion that eicosanoids may participate in the laxative effect of some secretagogues.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

Cancer in mice: effects of prednisolone or mepacrine alone and with cytotoxic drugs.

WHT/Ht mice were transplanted s.c. with NC carcinoma, and the tumours were excised after 2 weeks. The mice were treated orally throughout the experiments with prednisolone 500 micrograms kg-1 or mepacrine 3.6 mg kg-1, starting the day after tumour transplantation or, with prednisolone, the day after tumour excision. In some experiments the mice were also treated with the cytotoxic drugs methotrexate 2 mg kg-1 and melphalan 1.4 mg kg-1. The excised tumours were weighed; some of them, and samples of serum, were extracted for prostanoids which were measured by radioimmunoassay. The chemotherapy lengthened the survival of the mice, but prednisolone or mepacrine had little or no effect on survival, metastasis, the response to chemotherapy, tumour size or the formation of tumour prostanoids.

6-Ketoprostaglandin F1 alpha↗