Diclofenac sodium (Voltaren") is a non-steroid anti-inflammatory agent of a new chemical structure, which in animal experiments shows a high degree of antiinflammatory, analgesic, and antipyretic activity in various pharmacological models. It inhibits prostaglandin biosynthesis in vitro and in vivo, and this inhibitory effect at least partly explains the mechanism of action of the preparation. In animal experiments diclofenac sodium is characterised by a broad therapeutic range. Also, its gastrointestinal tolerability is better than that of other highly effective non-steroid anti-inhmmatory agents. Two of the metabolites produced during the biotransformation of diclofenac sodium in man are also biologically active. The activity of these two metabolites, however, is very much weaker than that of unchanged diclofenac sodium and is comparable to that of phenylbutazone. S a n d J Rheumutology, Suppl. 22 Scand J Rheumatol Downloaded from informahealthcare.com by University of Guelph on 10/19/12 For personal use only. Scand J Rheumatology. Suppl. 22 Scand J Rheumatol Downloaded from informahealthcare.com by University of Guelph on 10/19/12 For personal use only. Scand J Rheurnatology. Suppl. 22 Scand J Rheumatol Downloaded from informahealthcare.com by University of Guelph on 10/19/12 For personal use only. 'I Dose leading to a blood loss of IS0 wl/72 h. ' ' No effect observed at this dose level. ' Marginal. though statistically significant, increase over the control level observed at 300 mg/kg p.0. '' No mortality observed at this dose level. Metabolite I M > I 0 0 18 M 240 (203-287) 70 70 60 60 70 70 20 50Scand J Rheumatol Downloaded from informahealthcare.com by University of Guelph on 10/19/12For personal use only.

It has been known for some time that addition of antigen to the heparinized blood of sensitized rabbits in vitro usually results in the appearance of considerable quantities of histamine in the plasma. In his earlier work (1944) Code considered that the histamine came from the white cells, but in a recent review (Code, 1952) he concluded that, in the rabbit, platelets were probably the major source. He also pointed out that a similar release of histamine from blood cells into plasma occurred during clotting, as a result of mechanical trauma, and on addition of proteolytic enzymes or peptone to the blood. McIntire, Roth & Richards (1949), who studied the release of histamine from the cells of the blood of rabbits sensitized to egg white, when incubated in the presence of the antigen, concluded that neither thrombin nor prothrombin were involved, and furthermore found no inhibition even when large amounts of trypsin inhibitor were added.Our interest in this phenomenon arose in, the course of studies on the effect of antigen-antibody reactions on white cells in vitro, during which we observed that purified antigen-antibody systems did not cause histamine release from the washed buffy'layer of rabbit blood unless plasma were also present. Further study showed that free calcium ions were essential, and we also observed that, besides histamine, 5-hydroxytryptamine (serotonin) was released concomitantly. A limited survey of the histamine and 5-hydroxytryptamine content of the platelets and white cells of various species showed striking inter-species variation (Humphrey & Jaques, 1954). In this paper are reported some observations on the mechanism of histamine and 5-hydroxytryptamine release, which are largely concerned with rabbit blood, although other species are considered briefly. A preliminary account has already been published

In a recent review on 'Histamine in blood', Code (1952) discussed the existing literature relating to the distribution of histamine within the leucocytes and platelets of different species, and he drew attention to the relative paucity of information concerning species other than the rabbit. In the course of work on the release of histamine and of 5-hydroxytryptamine from platelets by antigen-antibody reactions in vitro, of which a preliminary account has already appeared (Humphrey & Jaques, 1953), we have had occasion to estimate the concentration of these two substances in the platelets and polymorphonuclear leucocytes of various species. We have also obtained further evidence upon the question, which Code regards as not yet conclusively settled, of the relative contributions of platelets and polymorphonuclear leucocytes to the histamine content of whole rabbit blood. Since the matter is one of some general interest, it seemed worth while to present these findings in a separate report. METHODSHistamine assay. Histamine was assayed, in the saline extracts or the body fluids, upon the atropinized guinea-pig ileum by comparison with a histamine acid phosphate standard. Results are expressed in terms of the free base. The preparation used, although sensitive to serotonin (5-hydroxytryptamine) is less than 1/10 as sensitive as it is to histamine, and the amounts present in platelet extracts did not usually interfere seriously with histamine assays. In most instances the extracts were re-assayed after inhibition of histamine contractions by mepyramine maleate (which inhibits histamine much more than serotonin) and the difference was taken to represent true histamine activity.Serotonin (5-hydroxytryptamine) assay. This was performed on rats' atropinized colon preparation

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