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Biomedical subjects

R Botting

Publications and source records attributed to R Botting.

14 recordsLinked to original sources
PubMed2000

Paracetamol-inhibitable COX-2.

Although paracetamol potently reduces pain and fever, its mechanism of action has so far not been satisfactorily explained. It inhibits both COX-1 and COX-2 weakly in vitro, but reduces prostaglandin synthesis markedly in vivo. In mouse macrophage J774.2 cells, COX-2 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin-induced COX-2. In the rat pleurisy model of inflammation, a second peak of COX-2 protein appears 48 hr after administration of the inflammatory stimulus, during the resolution phase of the inflammatory process. Inhibition of the activity of this late-appearing COX-2 with indomethacin or a selective COX-2 inhibitor, delays resolution and the inflammation is prolonged. Cultured lung fibroblasts also express COX-2 activity after stimulation with IL-1beta which is highly sensitive to inhibition with paracetamol. Thus, evidence is accumulating for the existence of a COX-2 variant or a new COX enzyme which can be inhibited with paracetamol.

Acetaminophen↗
PubMed1993

Modulation of platelet function by free radicals and free-radical scavengers.

Platelets have the capacity to generate oxygen-derived free radicals and are often present at inflammatory foci with other free-radical-generating cells such as white blood cells. Free radicals can modify platelet adhesion and aggregation directly or through effects on the vascular endothelium, which generates prostacyclin and nitric oxide. To defend against the overproduction of free radicals the body manufactures endogenous scavengers, which can be of enzymic or non-enzymic origin. Daniela Salvemini and Regina Botting describe how free-radical scavengers may be used therapeutically to regulate the platelet reactivity involved in many pathological phenomena.

Animals↗
PubMed1989

Mediators and the anti-thrombotic properties of the vascular endothelium.

This review discusses the role of three mediators synthesized by the vascular endothelium, which are involved in maintaining the surface of the endothelial cells in a non-thrombogenic state. Prostacyclin, discovered in 1976, is a product of arachidonic acid metabolism. This labile prostanoid, with a chemical half life of approximately three minutes, relaxes vascular smooth muscle and inhibits the aggregation of blood platelets. Endothelium-derived relaxing factor (EDRF), discovered in 1980, is even more labile than prostacyclin with a half life counted in seconds. It also relaxes smooth muscle and inhibits the aggregation and adhesion of platelets. Recently, it has been identified as nitric oxide. Prostacyclin and EDRF are released together following stimulation of receptors on endothelial cells and cooperate to inhibit platelet aggregation and adhesion. 13-HODE, acts from inside the cell to make the endothelial surface less adhesive and is not released. These mediators act together to form the endothelial defence mechanism against adhering blood cells. Underproduction can lead to diseases such as hypertension or atherosclerosis. A mainly fish diet, rich in eicosapentaenoic acid alters the prostacyclin/thromboxane balance in favour of prostacyclin-like activity. This type of diet may provide protection against atherosclerosis and myocardial infarction.

Antithrombins↗
PubMed1989

Vasoactive mediators derived from the endothelium.

Two of the many mediators synthesized by vascular endothelial cells (EC), are involved in maintaining the surface of the normal, healthy endothelium in a non-thrombogenic state. The first is prostacyclin, a product of arachidonic acid metabolism, discovered in 1976. This labile prostanoid, with a half life of approximately 3 minutes, relaxes vascular smooth muscle and inhibits the aggregation of blood platelets. Prostacyclin and its analogues are currently being tested in the clinic for cardiovascular diseases such as primary pulmonary hypertension. A number of drugs including defibrotide, nafazatrom, ronicol and cicletanine may exert their therapeutic effects by releasing prostacyclin from the EC. The second mediator discussed is endothelium-derived relaxing factor (EDRF), discovered in 1980, which also relaxes smooth muscle and inhibits the aggregation and adhesion of platelets. Substances which stimulate release of EDRF include acetylcholine, bradykinin and ADP. EDRF is even more labile than prostacyclin with a half life counted in seconds. It has recently been identified as nitric oxide formed from L-arginine by an unknown mechanism. Prostacyclin and EDRF are released together following stimulation of endothelial receptors and synergize to inhibit platelet aggregation. It is suggested that these mediators form the endothelial defence mechanism against blood-borne cells and chemicals and that breakdown of this barrier results in diseases such as hypertension and atherosclerosis. The peptide, endothelin is the third mediator under discussion. Characterised and synthesised in 1988, it is the most potent vasoconstrictor so far discovered. Three isomers of endothelin have been identified. Paradoxically, endothelin strongly releases both prostacyclin and EDRF thus modulating its own vasoconstrictor actions.

Endothelins↗
PubMed1987

Inflammation and the mechanism of action of anti-inflammatory drugs.

Inflammation is caused by release of chemicals from tissues and migrating cells. Most strongly implicated are the prostaglandins (PGs), leukotrienes (LTs), histamine, bradykinin, and, more recently, platelet-activating factor (PAF) and interleukin-1. Evidence for their involvement comes from studies with competitive antagonists for their receptors and inhibitors of their synthesis. H1 histamine antagonists are effective for hay fever and some skin allergies such as urticaria, which indicates the importance of histamine in these conditions. Symptoms of rheumatoid arthritis are alleviated by the aspirinlike anti-inflammatory drugs, which inhibit the cyclo-oxygenase enzyme and reduce synthesis of prostanoids. Corticosteroids prevent the formation of both PGs and LTs by causing the release of lipocortin, which by inhibition of phospholipase A2 reduces arachidonic acid release. They suppress the inflammation of rheumatoid arthritis and asthma. Currently, high doses of nonsedating H1 antihistamines and PAF antagonists are being tested for the treatment of allergic asthma.

Animals↗
PubMed1984

Effect of nonselective and selective inhibitors of monoamine oxidases A and B on pethidine toxicity in mice.

The LD50 of pethidine was determined in mice pretreated (4 h) either with the nonselective monoamine oxidase (MAO) inhibitor, phenelzine or with clorgyline, a selective inhibitor of MAO A or deprenyl, a selective inhibitor of MAO B. Phenelzine or combined clorgyline plus deprenyl pretreatments decreased pethidine LD50. Clorgyline or deprenyl alone did not affect pethidine toxicity. Whole brain 5-hydroxytryptamine (5-HT) concentrations were measured in the pretreated mice. 5-HT levels were approximately doubled (P less than 0.001) after phenelzine or clorgyline plus deprenyl treatment, but not after clorgyline or deprenyl given alone. These results indicate that both MAO A and MAO B need to be inhibited to increase pethidine toxicity and brain 5-HT levels. They support the involvement of 5-HT in the toxic interaction between pethidine and MAO inhibitors.

Animals↗
PubMed1982

Involvement of 5-hydroxytryptamine in the analgesic action of pethidine and morphine in mice.

1 Groups of mice were pretreated with the 5-hydroxytryptamine (5-HT) depletors, fenfluramine or p-chlorophenylalanine (PCPA), followed by pethidine or morphine. 2 Fenfluramine alone produced a short lasting analgesia but PCPA was without any effect. 3 Pethidine and morphine both increased hot plate reaction times measured after 30 min. 4 Pretreatment with PCPA attenuated morphine analgesia but did not affect pethidine analgesia. Fenfluramine did not alter the response to either analgesic. 5 PCPA produced a significant depletion of brain 5-HT levels which was not reversed by the analgesics. The fenfluramine-induced decrease in 5-HT was reversed by morphine but not by pethidine. 6 The results support the involvement of 5-HT in the antinociceptive action of morphine in the mouse.

Analgesics↗
PubMed1978

Modification by monoamine oxidase inhibitors of the analgesic, hypothermic and toxic actions of morphine and pethidine in mice.

A single injection of phenelzine 100 mg kg-1 given 18 h before, decreased the analgesia and hypothermia induced by morphine, but potentiated the analgesic and hypothermic effects of pethidine, when the analgesics were administered either intraperitoneally, or intracerebroventricularly. The modification of pethidine analgesia and hypothermia, but not morphine analgesia, was antagonized by methysergide (10 mg lg-1, s.c.). The LD50 of pethidine, but not that of morphine, was 30-40% lower in mice treated with phenelzine tranylcypromine or iproniazid 6 h before the test. The increased lethality of a single dose of pethidine induced by phenelzine was also prevented by methysergide. Pretreatment of mice with 100 mg kg-1 phenelzine was followed by a significant rise in both brain tryptophan and 5-hydroxytryptamine (5-HT) concentrations which lasted for 24 h. Therefore, the changes in pethidine effects could have been due to raised brain tryptophan and 5-HT concentrations.

Analgesics↗