The effect of fenclofenac on the regeneration of white blood cells in Sprague - Dawley rats following total body irradiation was investigated. The lowest dose of total body irradiation that would suppress the peripheral blood lymphocyte count by at least 50% was found to be 1.0 Gray in a preliminary experiment. Fenclofenac in a dose of 150 mg/kg/day retarded the regeneration of lymphocytes following total body irradiation of 1 Gray: this effect was also seen in the CD4, CD8 and B-lymphocyte subsets. This suppressive effect in vivo may be due to interference with replicative growth of white blood cells since previous in vitro experiments have shown suppression of lymphocyte growth at a stage later than activation in the cell cycle.The suppressive effects on leucocyte regeneration in vivo suggest that fenclofenac may have promise as an immunosuppressive drug with fewer serious side effects than the currently available immunosuppressive drugs.

In vitro, CsA is capable of suppressing mitogen-stimulated growth of human peripheral blood lymphocytes. Dose--response studies on lymphocytes from normal volunteers have shown that the variation between subjects is greater than the variation between repeated studies on the same subject in the 72 h uptake of 3H-TdR. The tests are easy to perform and they could be used to help in deciding, prior to transplantation, the dose of CsA to be used and whether other immunosuppressive therapy is needed. Activation of lymphocyte proliferation in vivo is a continuous process and recruitment to growth in vitro takes place over 24 h after mitogen stimulation. CsA was most effective in suppressing the replicative growth of lymphocytes in vitro when added up to 4 h after the start of the culture, but it was much less effective when added at 8 h. The experiments suggest that 8 hourly administration of CsA will optimise suppression of activation of the lymphocytes in vivo. If the suppressive activity of the metabolite M17 and the individual variation in sensitivity of the patients' lymphocytes to CsA are also taken into account it may be possible to reduce the dose of CsA to achieve effective immunosuppression and thereby minimise toxicity.

between idiopathic polymyalgia rheumatica and hypo- thyroidism is unlikely.

Representatives of seven chemical groups of non-steroidal anti-inflammatory drugs were tested for their effect on activation and replicative growth of phytohaemagglutinin stimulated normal human lymphocytes in vitro at concentrations in the high therapeutic range, and, where possible, at 10 times that concentration. Fenclofenac was noted to be suppressive. Fenclofenac and diclofenac (the only available phenylacetic acid derivatives) were studied in more detail. The two drugs were equipotent in vitro. At low concentrations they enhanced replicative growth, due to cyclo-oxygenase inhibition of cells from some subjects, but at higher concentration they suppressed replicative growth of cells from all subjects, with only a minor effect on activation at very high concentration. However, the potency for clinical effect of fenclofenac and diclofenac is very different, because fenclofenac at therapeutic blood concentrations suppressed replicative growth in vitro, whereas therapeutic concentrations of diclofenac were inactive in lymphocyte suppression. It is suggested that the phenylacetic acid derivative non-steroidal anti-inflammatory drugs may have a composite action in vivo: by inhibition of cyclo-oxygenase they reduce prostaglandin production (and so produce some symptomatic relief in the same manner as the drugs in the other chemical groups of non-steroidal anti-inflammatory agents) and by suppression of lymphocyte replication they may interfere with the pathogenesis of certain chronic rheumatic diseases.

Certain barbiturates (the intermediate- and short-acting drugs) reduce the growth of PHA-stimulated peripheral blood mononuclear cells, but phenobarbitone (a long-acting drug) is ineffective: replicative growth is more sensitive than activation. This action is associated with a marked reduction in the density of interleukin-2 receptors on the cell membrane and of the numbers of cells expressing them, but the growth rate cannot be restored by supplementation of the tissue culture medium with exogenous interleukin-2. The affected cells show swelling of the mitochondria and cytoplasmic fat globules: the presence of residual bodies and myelin figures indicate an increase in the rate of degradation of organelles. There was no appreciable increase in the number of necrotic cells seen on electron microscopy of cultures exposed to high concentrations of thiopentone or other potent barbiturates, but the presence of debris in the DNA cytogram at 72 h indicated some increase in the death rate of cells exposed to the growth suppressing barbiturates. It would be inadvisable to administer these short- and intermediate-acting barbiturates over long periods, particularly at high dosage, because of the potential danger of iatrogenic immunosuppression.