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Lithium carbonate in schizoaffective states.

lysosomes are of interest since lysosomal enzymes are involved in the acute inflammatory reaction.2 In previous observations we have found that the actions of some antiinflammatory aromatic acids and antiinflammatory steroids are concentrationdependent.3 The anti-inflammatory activity of steroids has been related to their stabilising action on lysosomes.5 It was therefore of interest to investigate the effect of concentration of the non-steroidal anti-inflammatory drugs azapropazone, oxyphenbutazone, and phenylbutazone on lysosomes. The gastrointestinal ulcerogenic action of antiinflammatory drugs may result, in part at all events, from lysosomal damage consequent on high local concentration of these compounds, such as may be achieved after oral administration. We have shown that this may result in the intracellular release of acid hydrolases such as cathepsins, with consequent damage to surrounding tissues.3 In experiments on isolated lysosomes we have consistently shown a biphasic effect of azapropazone, oxyphenbutazone, and phenylbutazone on the release of acid hydrolases. The equilibrium concentrations which are attained under normal therapeutic conditions stabilise lysosomes, and this property may be a significan factor in their anti-inflammatory action.' However, at higher concentrations, such as may be attained locally in the gastrointestinal tract, lysis of lysosomes with liberation of powerful proteolytic enzymes has been demonstrated. The effect of phenylbutazone was very much more powerful than that of the other drugs. Phenylbutazone was shown to have a much more powerful ulcerogenic action than azapropazone in experimental animals (rats, rabbits), though the latter drug was not devoid of action in high concentrations such as those which may be released locally after oral administration of therapeutic doses. Both drugs were demonstrated to be capable of producing ulcers in the pyloric region, with which lysosomal damage was correlated, while duodenal ulceration was induced by phenylbutazone but not by azapropazone. Using the quantitiative index of ulcerogenic effect proposed by Munchow6 as a measure of the severity of ulceration azapropazone was less than one-quarter and one-half as strongly ulcerogenic as phenylbutazone and flufenamic acid respectively. Its effect was approximately equal to that of mefenamic acid. The therapeutic ratio between ulcerogenicity ED50 and anti-inflammatory ED50 was 2-2-5 for azapropazone, 10 for phenylbutazone, 2-0-2-5 for mefenamic acid, and 12 for flufenamic acid and indomethacin. Evidence of liberation of lysosomal enzymes in the tissues was histochemically demonstrable in subulcerogenic doses, thus raising the possibility that these drugs may induce a preulcerogenic state in concentrations insufficient to produce ulcers. Thus our results have shown that even in the absence of anticoagulants azapropazone has ulcerogenic potential, though admittedly much less than that of phenylbutazone. The importance of Dr Powell-Jackson's observations is that an enhanced ulcerogenic activity of azapropazone is demonstrable in the case of patients concurrently treated with warfarin and is presumed to be due to an interaction between the drug and warfarin analogous to that which takes place with phenylbutazone. No studies appear to have been carried out on the' interaction between azapropazone and warfarin. However, azapropazone has no significant effect on normal prothrombin time, and does not enhance the effect of nicoumalone. The mechanism of the ulcerogenic action of azapropazone in patients on anticoagulants is clearly worthy of further investigation, but the conclusions to be derived from our experimental work is that ulcerogenesis can occur with this drug even in the absence of anticoagulants, though it is far less likely than with phenylbutazone. R J ANCILL