Cyclo-oxygenase inhibitors and cell killing by cytotoxic drugs.
Explore the source record for details and available documents.
Breast Neoplasms↗
Biomedical subjects
A Bennett
Publications and source records attributed to A Bennett.
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↗
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↗
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↗
Acute inversion of the uterus at caesarean section. Implications for the anaesthetist.
Two cases of acute inversion of the uterus that occurred through the uterine incision at the time of Caesarean section are described. These represent only the sixth and seventh cases reported in the literature at this time. The implications for the anaesthetist are discussed.
Acute Disease↗
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↗
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↗
10 rules key to developing new managers.
Explore the source record for details and available documents.
Health Facility Administrators↗
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↗
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↗
Childbirth research data: medical records or women's reports?
Medical records and women's reports were compared as sources of data for childbirth research. Three weeks after they had given birth in 1982 at five teaching hospitals in Sydney, Australia, 397 low-risk primiparous women in a random sample were interviewed about their birth experiences. The women's reports were compared with data from their medical records. Error sources in data collection were identified at four points: from the actual event to hospital recording, in the abstraction of data from medical records, in women's memory of the actual events, and in women's reporting of their encoded information. Both corrected data sources were accurate for most major variables. It is concluded that both data sources are subject to variation from the actual events they represent and that the assumption that medical records are always more accurate and acceptable is not supported.
Adolescent↗
Inhibition of prostanoid synthesis by human gastric mucosa.
Non-steroidal anti-inflammatory drugs (NSAIDs) damage the gastric mucosa, and an important part of this effect is probably due to inhibition of prostaglandin synthesis. We have therefore studied various drugs for their ability to reduce prostaglandin and thromboxane formation by human isolated gastric mucosa. The overall relative potencies for inhibiting the endogenous production of PGE, 6-keto-PGF1 alpha and thromboxane B2 by mucosal pieces was generally: indomethacin = naproxen greater than ibuprofen greater than piroxicam; diflunisal, the prodrug sulindac, and the analgesic paracetamol usually had small or variable effects. This rank order was mainly similar to the inhibition of gastric microsomal PGE2 formation from exogenous arachidonic acid, the relative potencies being: indomethacin greater than naproxen greater than ibuprofen = piroxicam = diflunisal; again sulindac and paracetamol had little or no effect. The relative propensity of NSAIDs to cause gastric mucosal damage is controversial, but aspirin and indomethacin may be worst, and ibuprofen seems to be among the safest. Potency as an inhibitor of prostaglandin synthesis correlates better with the reported propensity for damage than does potency x dose. For reasons that are given in the discussion, this may indicate that gastric mucosal damage by NSAIDs with short or moderate half-lives is due largely to locally absorbed drug. Whereas inhibition of prostaglandin synthesis is probably the major cause of the damage, the simultaneous reduction of thromboxane formation might be advantageous for gastric mucosal integrity. Various implications arise from our hypotheses concerning the design of anti-inflammatory drugs.
Anti-Inflammatory Agents, Non-Steroidal↗
The use of epidural bupivacaine for the relief of childbirth pain.
Epidural anaesthesia is now a widely used method for pain relief in childbirth, particularly using the drug Bupivacaine. There are nevertheless differing opinions in the research literature about the advisability of its routine use. While it is clearly very effective in relieving labour pain, there are some consistent, troublesome patterns; for example, a strong association between epidural use and other interventions, such as instrumental delivery. Further, there are no clear answers from the research to date concerning the risks and benefits of epidural anaesthesia for infant and mother. Answers could be provided by randomized clinical trials, but meanwhile a conservative approach to its use is recommended for uncomplicated labours.
Anesthesia, Epidural↗
Studies on the mechanism by which indomethacin increases the anticancer effect of methotrexate.
The effect of indomethacin on the response of the NC carcinoma to methotrexate has been examined in vivo and in vitro. Survival was prolonged in mice treated with indomethacin 1.25 mg kg-1 twice daily plus methotrexate 4 mg kg-1 daily, compared to mice given either drug alone or controls. Indomethacin 1 microgram ml-1 increased the killing of cultured NC cells by methotrexate. This was not due to displacement of methotrexate from binding sites on the serum proteins. Nor was it due (entirely) to inhibition of prostaglandin synthesis, since flurbiprofen did not mimic the effect. Inhibition of cyclic AMP phosphodiesterase seems unlikely to explain the effect of indomethacin since theophylline had little or no effect on NC cell killing by methotrexate. Indomethacin 1 microgram ml-1 increased the accumulation of tritium in NC cells incubated with [3H]-methotrexate. In contrast, with normal epithelial cells from human embryonic intestine, indomethacin 1 microgram ml-1 did not alter the cytotoxicity of methotrexate or the accumulation of tritium during incubation with [3H]-methotrexate. The beneficial interaction between indomethacin and methotrexate may have therapeutic potential in man.
Animals↗
Nitrates do not affect prostacyclin formation by rat arteries: this is unrelated to increased vascular prostacyclin formation with age.
The question of whether vasodilator nitrates act by releasing prostacyclin is controversial. Since the ability of blood vessels to form prostacyclin changes with age, we have investigated whether this may explain the discrepancies in the literature. It does not, since isosorbide dinitrate or glyceryl trinitrate incubated with rat aorta or vena cava from male Wistar rats had little or no effect on the release of prostacyclin, measured as 6-keto-PGF1 alpha. We confirm that the aorta produces substantially more prostacyclin than the vena cava. The arterial production of prostacyclin was greater in rats weighing 350-400 g than in those weighing 116-152 g, but the production by the veins was similar in both groups.
6-Ketoprostaglandin F1 alpha↗
Tamoxifen inhibits 5-lipoxygenase in human polymorphonuclear leucocytes.
Breast cancer patient survival is increased by tamoxifen, and we therefore need to understand how this drug exerts its effect. We describe a novel action of tamoxifen, the inhibition of LTB4 and 5-HETE production from [14C]-arachidonic acid by human polymorphonuclear leucocytes.
Arachidonate Lipoxygenases↗
Measurement of arachidonate and its metabolites extracted from human normal and malignant gastrointestinal tissues.
This is the first report of human gastrointestinal arachidonate and prostanoids measured quantitatively by gas chromatography-mass spectrometry (GC-MS) in extracts of human cancers and macroscopically normal tissues from the stomach and colon. There were microgram/g amounts of arachidonate, and the particularly high yield from the tumours may explain why they usually produce more prostaglandins than the normal tissues in which they arise. There was only a small conversion of the arachidonate into prostanoids. 6-Keto-PGF1 alpha was the most abundant metabolite measured, particularly in the tumour extracts, with smaller amounts of prostaglandins E2, F2 alpha and D2.
Arachidonic Acid↗