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CLOFIBRATE AND THE FIBRINOLYTIC SYSTEM
263 The unusual feature of this skin reaction is that cyclophosphamide is an immunosuppressive drug, and the skin response is obtained when the suppression of the immune response should be at its maximum-i.e., when any antibody reaction would be expected to be least likely. Royal Albert Edward Infirmary, P. S. SILVER. Wigan, Lancashire.
CLOFIBRATE AND THE FIBRINOLYTIC SYSTEM :SlRłin their paperDr. Chakrabarti and his colleagues The state that clofibrate has antifibrinolytic properties. evidence for this statement was the findings of increased blood-lysis times in 5 patients with occlusive vascular disease while receiving clofibrate (’Atromid-S ’) for seven months. We have recently analysed results of the effect of clofibrate on fibrinolytic activity in 12 patients who had had an attack of coronary thrombosis more than six months before. Their serum-cholesterol levels had been persistently above 270 mg. per 100 ml. None of these patients had any other diseases,
including infection, which could affect the fibrinolytic system. Fibrinolytic activity was measured by the euglobulin-clot-lysis technique.2 Plasma-fibrinogen levels were measured by a The mean pretreatment values were obtained from results on at least 3 blood-samples taken on different days between 9.30 A.M. and 10.30 A.M. The results (see accompanying table) show that treatment with clofibrate produced a
tyrosine method.3
EFFECT OF CLOFIBRATE ON EUGLOBULIN-LYSIS ACTIVITY AND PLASMAFIBRINOGEN CONCENTRATION
Figures in parentheses =number of patients investigated. . P<0·Ol. t p
statistically significant increase in fibrinolytic activity, as assessed by shortening of the euglobulin-clot-lysis time (E.L.T.), which persisted over the 9 months of observation, and a significant and sustained reduction in fibrinogen concentration. We have previously shown that clofibrate plus androsterone (’Atromid’) produced a sustained reduction in fibrinogen concentration,4 and continued observations have shown that this reduction was maintained to a significant degree (p < 0.001) seventeen months after starting treatment. Gajewski et al.5 showed that clofibrate plus androsterone produced a significant reduction in E.L.T. in patients with hypercholesterolxmia and coronary-artery disease. They did not, however, investigate the effect of clofibrate alone on fibrinolytic activity. Thus we have evidence that both clofibrate and clofibrate plus androsterone persistently lower raised plasma-fibrinogen levels and increase euglobulin-lysis activity in this type of patient. We do not, therefore, share the views of Dr. Chakrabarti and his colleagues that atromid and atromid-S have opposite effects on the fibrinolytic system because of the presence or absence of androsterone. Why our results on the effect of clofibrate on fibrinolysis differ from theirs is difficult to explain. Admittedly, instead of the whole-blood-lysis time, we used the euglobulin-clot-lysis technique, which is believed to 1. 2. 3.
Chakrabarti, R., Fearnley, G. R., Evans, J. F. Lancet, 1968, ii, 1007. Niewiarowski, S. Acta physiol. pol. 1952, 3, 375. Lempert, H. in Practical Clinical Biochemistry (edited by H. Varley);
4. 5.
p. 191. London, 1962. Cotton, R. C., Wade, E. G. J. atheroscler. Res. 1966, 6, 98. Gajewski, Z., Skorykow, A., Ciświcka-Sznajderman, M., Ignarowska, H., Sznajderman, M. Arch. med. Wewn. 1964, 34, 1647.
measure plasminogen-activator activity, but the results of these two methods are highly correlate .6-However, clofibrate has no effect on the fibrinolytic system if the level of fibrinogen is normal before treatment1O; and we have also observed that it does not prevent the rise in fibrinogen levels, or impaired fibrinolytic activity (as assessed by E.L.T.), which occurs in patients in the week or two after major surgery, coronary thrombosis, or an infective illness. The pathways causing changes in the fibrinolytic system following such stimuli probably differ from those in patients with disturbances of lipid metabolism. There are therefore aspects of the action of clofibrate on the fibrinolytic system which require further investigation. To state, however, that clofibrate has antifibrinolytic properties on the evidence offered by Dr. Chakrabarti and his colleagues is not iustifiable without further confirmation. Research Department, Imperial Chemical Industries Ltd., Alderley Park, Macclesfield, and R. C. COTTON University Department of Cardiology, E. G. WADE. Manchester Royal Infirmary.
*** This letter has been shown to Dr. Chakrabarti and Fearnley, whose reply follows.-ED. L.
Dr.
SIR, We are not altogether surprised that Dr. Cotton and Dr. Wade, using the euglobulin-lysis time, obtained results which seem to contradict those we obtained with the dilutetime. We originally showed 11 that the effects of blood-clot-lysis ’ Atromid ’ (clofibrate plus androsterone) on these two measurements differed in that reduction of the blood-clot-lysis time by this drug was temporary whereas that of the euglobulin time Whilst it is generally true that the two tests was sustained. correlate well, there are in our experience many exceptions, and the most likely explanation for these is that whereas antiplasmin is absent from the euglobulin test it is present in the diluteblood-clot method, its effect being diminished but not removed by dilution. Discrepancies may be expected therefore when both tests are set up on patients with high levels of plasmin inhibitor, or for that matter on patients treated with a drug which raises the level of plasmin inhibition. Even if clofibrate increases activator activity as measured by the euglobulin time, though here the results of Dr. Cotton and Dr. Wade conflict with those of Sweet et al.12 who found no such effect, it is possible that this drug also raises the level of antiplasmin, which could account for the discrepancies between results obtained with the two methods. There is, however, a further possibility. An increase of activator activity in vitro, which in some way is dependent on the presence of Hageman factor," 14 can occur during preparation of the euglobulin fraction; and we have recently shown how small variations in ambient conditions can influence this and hence the results obtained with this test.15 The conflicting results in the literature on the effect of lipidsemia on fibrinolysis, depending on the method of measurement used, may owe their explanation to this artefact. It is not impossible that, because of its influence on lipids, clofibrate might indirectly enhance activator activity of the euglobulin fraction in vitro during its preparation, an effect which would not be manifest in the dilute-blood-clot-lysis time. Both methods are artificial tests of fibrinolytic activity, but of the two the euglobulin-lysis time is the more removed from reality and the more subject to alteration by artefacts. Recently we have been able to show that phenformin plus ethvloestrenol 6. Lackner, H., Merskey, C. Br. J. Hœmat. 1960, 6, 402. 7. Flute, P. J. Br. med. Bull. 1964, 20, 195. 8. Grace, C. S., Goldrick, R. B. J. atheroscler. Res. 1968, 8, 705. 9. Sweet, B., Rifkind, B. M., McNicol, G. P. ibid. 1966, 6, 359. 10. Sweet, B., Rifkind, B. M., McNicol, G. P. ibid. 1965, 5, 347. 11. Hocking, E. D., Chakrabarti, R., Evans, J., Fearnley, G. R. J. atheroscler. Res. 1967, 7, 121. 12. Sweet, B., Rifkind, B. M., McNicol, G. P. ibid. 1965, 5, 347. 13. Iatridis, S. G., Ferguson, J. H. J. clin. Invest. 1962, 41, 1277. 14. Iatridis, S. G., Ferguson, J. H. J. appl. Physiol. 1963, 18, 337. 15. Chakrabarti, R., Bielawiec, M., Evans, J., Fearnley, G. R. J. clin. Path. 1968, 21, 698.
264
produces a pronounced increase of fibrin-degradation products (F.D.P.) in the sera of treated patients, which parallels the behaviour of the dilute-blood-clot-lysis time (to be published). We believe that measurements of F.D.P. provide reliable evidence of pharmacological fibrinolysis in vivo; and if Dr. Cotton and Dr. Wade were to show that clofibrate causes an increase of F.D.P. we would accept their belief that this substance is a fibrinolytic drug. Meanwhile our findings with the dilute-blood-clot-lysis time lead us to conclude, as stated in our paper, that clofibrate has antifibrinolytic properties. R. CHAKRABARTI Gloucestershire Royal Hospital, G. R. FEARNLEY. Gloucester.
uniformly negative results in this population for antibody steroid-producing cells in the gonads, and we could find no statistically significant difference in the incidence of other antibodies in this population compared with controls.
obtained
to ova or to
Department of Endocrinology, Royal Infirmary, Edinburgh 3.
W. J. IRVINE.
PHENACETIN SIR,-Your leading articleon phenacetin and its nephrotoxicity prompts some comments. Phenacetin is almost never taken as the plain drug but in various mixtures, and your conclusion is that, " if restrictions are to be applied to the sale of analgesics... they should apply equally to pyrazolone derivatives, salicylates, phenacetin, and possibly paracetamol ". I note that you mentioned phenacetin in the third place and paracetamol with hesitation.
PREMATURE MENOPAUSE IN AUTOIMMUNE DISEASES SIR,—Ishould like to make the following comments on the letter of Dr. Vallotton and Dr. Forbes (Jan. 18, p. 156). The implication of phenacetin as the offending drug in analAt the time of serological study, the 77 patients with idiopathic Addison’s disease in our series1 had a mean age of 43 gesic nephropathy rests on circumstantial evidence. There are now many hundred cases reported on the association of years (range 8-77, s.D. 16). This is comparable with the age chronic abuse of phenacetin-containing drugs and renal damdistribution of 42 patients with tuberculous Addison’s disease S.D. whose sera were (mean 42, range 19-72, 15), uniformly age with a high frequency of papillary necrosis. In Sweden, negative for adrenal antibodies and for antibodies reactive with and certainly in other countries too, this association is a comthe steroid-producing cells of the gonads. monplace, and physicians have long ago ceased to report new cases. With rare exceptions, phenacetin has been the only Blizzard et al. did not refer to premature menopause in their I denominator common to all the analgesic mixtures in these and was interested to learn of the 5 female that, paper patients over the age of 16 years in his series of 74 women with reports. However, it has also been emphasised that antiidiopathic hypoparathyroidism, 2 had premature menopause. inflammatory agents such as salicylates or pyrazolones are common to most analgesic mixtures, and that these agents This emphasises the strong association that seems to exist between idiopathic hypoparathyroidism and premature ovarian might be the offending ones rather than phenacetin.23 Is there failure in young subjects,! although our patients with these two any circumstantial evidence in support of the latter hypothesis ? conditions also had idiopathic Addison’s disease. Did those of Most cases of renal damage associated with salicylates have been Blizzard et al. ? reported after acute massive overdosage (accidental or suicidal), Dr. Lillian Haddock and Dr. Robert Blizzard kindly let me but these cases are of minor interest in the present discussion. study the serum of a 20-year-old girl with idiopathic hypo- I have been able to find only five cases of chronic nephroparathyroidism followed by idiopathic Addison’s disease. Her pathy after long-continued consumption of plain aspirin or serum was positive for antibodies to the oxyphil and chief cells salicylates combined with drugs other than phenacetin.4-6 This is a tiny number compared with the innumerable cases of renal of human parathyroid,3 adrenocortical cells, ova, theca-interna disease ascribable to phenacetin-containing drugs, particularly cells of ovary, interstitial cells of testis, and placental trophoblasts, although her menstruation continues. She is the first in view of the immense consumption of salicylates, which is woman of reproductive age in my series who has gonadal anticertainly far larger than that of any other analgesic. Longcontinued consumption of phenacetin-containing drugs or bodies and normal menstruation. It may be that she will have a salicylates is usually due to self-medication. Salicylates are, premature menopause. yet I have not so far observed a comparably high incidence of however, also prescribed in large amounts, and over long periods of time when there is continuous medical supervision, premature ovarian failure in adult patients with addisonian and any adverse effects should easily be discovered. and adult do pernicious-anaemia patients pernicious anaemia, not have a high incidence of autoantibodies reactive with Paracetamol, the major metabolite of phenacetin, is excreted steroid-producing cells in human gonads. The situation may in the urine. In an epidemiological study in Switzerland there be different in young female subjects with addisonian pernicious was a high incidence of regular analgesic intake. In individuals ansemia, as suggested by the inclusion of pernicious anaemia excreting paracetamol in the urine there was a positive correlain the disease complex of patient B in our paper. The one tion with abnormal renal findings, whereas patients excreting serum reported in that paper that reacted with the cytoplasm salicylate compared well with controls with no metabolites in of ovum did so in apparently all stages of its development, the urine. Paracetamol is concentrated in the papilla.No including the primordial follicles of both rabbit and human similar concentration of salicylate has been demonstrated.8 ovary and the mature graafian follicle of the rabbit ovary. As regards the pyrazolones we are mainly concerned with Staining of the acellular " zona pellucida ", referred to by (antipyrine). The use of the similar pyrazolone, phenazone Vallotton Dr. Dr. and Forbes, may have been present in amidopyrine, has been sharply curtailed for many years because relation to some primordial follicles in the human ovary but of the risk of agranulocytosis. Phenazone is an old drug used in was not noted when rabbit ovary was used. The different different mixtures, except in phenacetin-containing ones. staining patterns of the steroid-producing cells of the ovary many I have found only one reported case of chronic nephropathy various antisera are to be in documented fuller given 4by with papillary necrosis attributed to the abuse of phenazone detail. and caffeine.9 With reference to gonadal dysgenesis associated with chromo1. Lancet, 1968, ii, 717. some abnormality and Klinefelter’s syndrome, our findings5 2. Gilman, A. Am. J. Med. 1964, 36, 167. differ from those of Vallotton and Forbes 6 in that we have 3. Haley, T. J. J. new Drugs, 1966, 6, 193. 4. Harvald, B. Am. J. Med. 1963, 35, 481. 1. Irvine, W. J., Chan, M. M. W., Scarth, L., Kolb, F. O., Hartog, M., JJ1
V
LL VLV
Bayliss, R. I. S., Drury, M. I. Lancet, 1968, ii, 883. Blizzard, R. M., Chee, D., Davis, W. Clin. exp. Immun. 1966, 1, 119. Irvine, W. J., Scarth, L. ibid. (in the press). Irvine, W. J., Chan, M. M. W., Scarth, L. Clin. exp. Immun. 1969 (in the press). 5. Price, W. H., Irvine, W. J. ibid, 1969, 4, 365. 6. Vallotton, M. B., Forbes, A. P. Lancet, 1967, i, 648. 2. 3. 4.
Olafsson, O., Gudmundsson, K. R., Brekkan, A. Acta med. scand. 1966, 179, 121. 6. Lawson, A. A. H., MacLean, N. Ann. rheum. Dis. 1966, 25, 441. 7. Dubach, U. C., Minder, P., Gsell, O. 3rd Int. Congr. nephrol. 1967, 2, 300. 8. Bluemle, L. W., Goldberg, M. Clin. Res. 1967, 15, 351. 9. Axelsson, U. Nord. Med. 1958, 59, 903.
5.
CLOFIBRATE AND THE FIBRINOLYTIC SYSTEM :SlRłin their paperDr. Chakrabarti and his colleagues The state that clofibrate has antifibrinolytic properties. evidence for this statement was the findings of increased blood-lysis times in 5 patients with occlusive vascular disease while receiving clofibrate (’Atromid-S ’) for seven months. We have recently analysed results of the effect of clofibrate on fibrinolytic activity in 12 patients who had had an attack of coronary thrombosis more than six months before. Their serum-cholesterol levels had been persistently above 270 mg. per 100 ml. None of these patients had any other diseases,
including infection, which could affect the fibrinolytic system. Fibrinolytic activity was measured by the euglobulin-clot-lysis technique.2 Plasma-fibrinogen levels were measured by a The mean pretreatment values were obtained from results on at least 3 blood-samples taken on different days between 9.30 A.M. and 10.30 A.M. The results (see accompanying table) show that treatment with clofibrate produced a
tyrosine method.3
EFFECT OF CLOFIBRATE ON EUGLOBULIN-LYSIS ACTIVITY AND PLASMAFIBRINOGEN CONCENTRATION
Figures in parentheses =number of patients investigated. . P<0·Ol. t p
statistically significant increase in fibrinolytic activity, as assessed by shortening of the euglobulin-clot-lysis time (E.L.T.), which persisted over the 9 months of observation, and a significant and sustained reduction in fibrinogen concentration. We have previously shown that clofibrate plus androsterone (’Atromid’) produced a sustained reduction in fibrinogen concentration,4 and continued observations have shown that this reduction was maintained to a significant degree (p < 0.001) seventeen months after starting treatment. Gajewski et al.5 showed that clofibrate plus androsterone produced a significant reduction in E.L.T. in patients with hypercholesterolxmia and coronary-artery disease. They did not, however, investigate the effect of clofibrate alone on fibrinolytic activity. Thus we have evidence that both clofibrate and clofibrate plus androsterone persistently lower raised plasma-fibrinogen levels and increase euglobulin-lysis activity in this type of patient. We do not, therefore, share the views of Dr. Chakrabarti and his colleagues that atromid and atromid-S have opposite effects on the fibrinolytic system because of the presence or absence of androsterone. Why our results on the effect of clofibrate on fibrinolysis differ from theirs is difficult to explain. Admittedly, instead of the whole-blood-lysis time, we used the euglobulin-clot-lysis technique, which is believed to 1. 2. 3.
Chakrabarti, R., Fearnley, G. R., Evans, J. F. Lancet, 1968, ii, 1007. Niewiarowski, S. Acta physiol. pol. 1952, 3, 375. Lempert, H. in Practical Clinical Biochemistry (edited by H. Varley);
4. 5.
p. 191. London, 1962. Cotton, R. C., Wade, E. G. J. atheroscler. Res. 1966, 6, 98. Gajewski, Z., Skorykow, A., Ciświcka-Sznajderman, M., Ignarowska, H., Sznajderman, M. Arch. med. Wewn. 1964, 34, 1647.
measure plasminogen-activator activity, but the results of these two methods are highly correlate .6-However, clofibrate has no effect on the fibrinolytic system if the level of fibrinogen is normal before treatment1O; and we have also observed that it does not prevent the rise in fibrinogen levels, or impaired fibrinolytic activity (as assessed by E.L.T.), which occurs in patients in the week or two after major surgery, coronary thrombosis, or an infective illness. The pathways causing changes in the fibrinolytic system following such stimuli probably differ from those in patients with disturbances of lipid metabolism. There are therefore aspects of the action of clofibrate on the fibrinolytic system which require further investigation. To state, however, that clofibrate has antifibrinolytic properties on the evidence offered by Dr. Chakrabarti and his colleagues is not iustifiable without further confirmation. Research Department, Imperial Chemical Industries Ltd., Alderley Park, Macclesfield, and R. C. COTTON University Department of Cardiology, E. G. WADE. Manchester Royal Infirmary.
*** This letter has been shown to Dr. Chakrabarti and Fearnley, whose reply follows.-ED. L.
Dr.
SIR, We are not altogether surprised that Dr. Cotton and Dr. Wade, using the euglobulin-lysis time, obtained results which seem to contradict those we obtained with the dilutetime. We originally showed 11 that the effects of blood-clot-lysis ’ Atromid ’ (clofibrate plus androsterone) on these two measurements differed in that reduction of the blood-clot-lysis time by this drug was temporary whereas that of the euglobulin time Whilst it is generally true that the two tests was sustained. correlate well, there are in our experience many exceptions, and the most likely explanation for these is that whereas antiplasmin is absent from the euglobulin test it is present in the diluteblood-clot method, its effect being diminished but not removed by dilution. Discrepancies may be expected therefore when both tests are set up on patients with high levels of plasmin inhibitor, or for that matter on patients treated with a drug which raises the level of plasmin inhibition. Even if clofibrate increases activator activity as measured by the euglobulin time, though here the results of Dr. Cotton and Dr. Wade conflict with those of Sweet et al.12 who found no such effect, it is possible that this drug also raises the level of antiplasmin, which could account for the discrepancies between results obtained with the two methods. There is, however, a further possibility. An increase of activator activity in vitro, which in some way is dependent on the presence of Hageman factor," 14 can occur during preparation of the euglobulin fraction; and we have recently shown how small variations in ambient conditions can influence this and hence the results obtained with this test.15 The conflicting results in the literature on the effect of lipidsemia on fibrinolysis, depending on the method of measurement used, may owe their explanation to this artefact. It is not impossible that, because of its influence on lipids, clofibrate might indirectly enhance activator activity of the euglobulin fraction in vitro during its preparation, an effect which would not be manifest in the dilute-blood-clot-lysis time. Both methods are artificial tests of fibrinolytic activity, but of the two the euglobulin-lysis time is the more removed from reality and the more subject to alteration by artefacts. Recently we have been able to show that phenformin plus ethvloestrenol 6. Lackner, H., Merskey, C. Br. J. Hœmat. 1960, 6, 402. 7. Flute, P. J. Br. med. Bull. 1964, 20, 195. 8. Grace, C. S., Goldrick, R. B. J. atheroscler. Res. 1968, 8, 705. 9. Sweet, B., Rifkind, B. M., McNicol, G. P. ibid. 1966, 6, 359. 10. Sweet, B., Rifkind, B. M., McNicol, G. P. ibid. 1965, 5, 347. 11. Hocking, E. D., Chakrabarti, R., Evans, J., Fearnley, G. R. J. atheroscler. Res. 1967, 7, 121. 12. Sweet, B., Rifkind, B. M., McNicol, G. P. ibid. 1965, 5, 347. 13. Iatridis, S. G., Ferguson, J. H. J. clin. Invest. 1962, 41, 1277. 14. Iatridis, S. G., Ferguson, J. H. J. appl. Physiol. 1963, 18, 337. 15. Chakrabarti, R., Bielawiec, M., Evans, J., Fearnley, G. R. J. clin. Path. 1968, 21, 698.
264
produces a pronounced increase of fibrin-degradation products (F.D.P.) in the sera of treated patients, which parallels the behaviour of the dilute-blood-clot-lysis time (to be published). We believe that measurements of F.D.P. provide reliable evidence of pharmacological fibrinolysis in vivo; and if Dr. Cotton and Dr. Wade were to show that clofibrate causes an increase of F.D.P. we would accept their belief that this substance is a fibrinolytic drug. Meanwhile our findings with the dilute-blood-clot-lysis time lead us to conclude, as stated in our paper, that clofibrate has antifibrinolytic properties. R. CHAKRABARTI Gloucestershire Royal Hospital, G. R. FEARNLEY. Gloucester.
uniformly negative results in this population for antibody steroid-producing cells in the gonads, and we could find no statistically significant difference in the incidence of other antibodies in this population compared with controls.
obtained
to ova or to
Department of Endocrinology, Royal Infirmary, Edinburgh 3.
W. J. IRVINE.
PHENACETIN SIR,-Your leading articleon phenacetin and its nephrotoxicity prompts some comments. Phenacetin is almost never taken as the plain drug but in various mixtures, and your conclusion is that, " if restrictions are to be applied to the sale of analgesics... they should apply equally to pyrazolone derivatives, salicylates, phenacetin, and possibly paracetamol ". I note that you mentioned phenacetin in the third place and paracetamol with hesitation.
PREMATURE MENOPAUSE IN AUTOIMMUNE DISEASES SIR,—Ishould like to make the following comments on the letter of Dr. Vallotton and Dr. Forbes (Jan. 18, p. 156). The implication of phenacetin as the offending drug in analAt the time of serological study, the 77 patients with idiopathic Addison’s disease in our series1 had a mean age of 43 gesic nephropathy rests on circumstantial evidence. There are now many hundred cases reported on the association of years (range 8-77, s.D. 16). This is comparable with the age chronic abuse of phenacetin-containing drugs and renal damdistribution of 42 patients with tuberculous Addison’s disease S.D. whose sera were (mean 42, range 19-72, 15), uniformly age with a high frequency of papillary necrosis. In Sweden, negative for adrenal antibodies and for antibodies reactive with and certainly in other countries too, this association is a comthe steroid-producing cells of the gonads. monplace, and physicians have long ago ceased to report new cases. With rare exceptions, phenacetin has been the only Blizzard et al. did not refer to premature menopause in their I denominator common to all the analgesic mixtures in these and was interested to learn of the 5 female that, paper patients over the age of 16 years in his series of 74 women with reports. However, it has also been emphasised that antiidiopathic hypoparathyroidism, 2 had premature menopause. inflammatory agents such as salicylates or pyrazolones are common to most analgesic mixtures, and that these agents This emphasises the strong association that seems to exist between idiopathic hypoparathyroidism and premature ovarian might be the offending ones rather than phenacetin.23 Is there failure in young subjects,! although our patients with these two any circumstantial evidence in support of the latter hypothesis ? conditions also had idiopathic Addison’s disease. Did those of Most cases of renal damage associated with salicylates have been Blizzard et al. ? reported after acute massive overdosage (accidental or suicidal), Dr. Lillian Haddock and Dr. Robert Blizzard kindly let me but these cases are of minor interest in the present discussion. study the serum of a 20-year-old girl with idiopathic hypo- I have been able to find only five cases of chronic nephroparathyroidism followed by idiopathic Addison’s disease. Her pathy after long-continued consumption of plain aspirin or serum was positive for antibodies to the oxyphil and chief cells salicylates combined with drugs other than phenacetin.4-6 This is a tiny number compared with the innumerable cases of renal of human parathyroid,3 adrenocortical cells, ova, theca-interna disease ascribable to phenacetin-containing drugs, particularly cells of ovary, interstitial cells of testis, and placental trophoblasts, although her menstruation continues. She is the first in view of the immense consumption of salicylates, which is woman of reproductive age in my series who has gonadal anticertainly far larger than that of any other analgesic. Longcontinued consumption of phenacetin-containing drugs or bodies and normal menstruation. It may be that she will have a salicylates is usually due to self-medication. Salicylates are, premature menopause. yet I have not so far observed a comparably high incidence of however, also prescribed in large amounts, and over long periods of time when there is continuous medical supervision, premature ovarian failure in adult patients with addisonian and any adverse effects should easily be discovered. and adult do pernicious-anaemia patients pernicious anaemia, not have a high incidence of autoantibodies reactive with Paracetamol, the major metabolite of phenacetin, is excreted steroid-producing cells in human gonads. The situation may in the urine. In an epidemiological study in Switzerland there be different in young female subjects with addisonian pernicious was a high incidence of regular analgesic intake. In individuals ansemia, as suggested by the inclusion of pernicious anaemia excreting paracetamol in the urine there was a positive correlain the disease complex of patient B in our paper. The one tion with abnormal renal findings, whereas patients excreting serum reported in that paper that reacted with the cytoplasm salicylate compared well with controls with no metabolites in of ovum did so in apparently all stages of its development, the urine. Paracetamol is concentrated in the papilla.No including the primordial follicles of both rabbit and human similar concentration of salicylate has been demonstrated.8 ovary and the mature graafian follicle of the rabbit ovary. As regards the pyrazolones we are mainly concerned with Staining of the acellular " zona pellucida ", referred to by (antipyrine). The use of the similar pyrazolone, phenazone Vallotton Dr. Dr. and Forbes, may have been present in amidopyrine, has been sharply curtailed for many years because relation to some primordial follicles in the human ovary but of the risk of agranulocytosis. Phenazone is an old drug used in was not noted when rabbit ovary was used. The different different mixtures, except in phenacetin-containing ones. staining patterns of the steroid-producing cells of the ovary many I have found only one reported case of chronic nephropathy various antisera are to be in documented fuller given 4by with papillary necrosis attributed to the abuse of phenazone detail. and caffeine.9 With reference to gonadal dysgenesis associated with chromo1. Lancet, 1968, ii, 717. some abnormality and Klinefelter’s syndrome, our findings5 2. Gilman, A. Am. J. Med. 1964, 36, 167. differ from those of Vallotton and Forbes 6 in that we have 3. Haley, T. J. J. new Drugs, 1966, 6, 193. 4. Harvald, B. Am. J. Med. 1963, 35, 481. 1. Irvine, W. J., Chan, M. M. W., Scarth, L., Kolb, F. O., Hartog, M., JJ1
V
LL VLV
Bayliss, R. I. S., Drury, M. I. Lancet, 1968, ii, 883. Blizzard, R. M., Chee, D., Davis, W. Clin. exp. Immun. 1966, 1, 119. Irvine, W. J., Scarth, L. ibid. (in the press). Irvine, W. J., Chan, M. M. W., Scarth, L. Clin. exp. Immun. 1969 (in the press). 5. Price, W. H., Irvine, W. J. ibid, 1969, 4, 365. 6. Vallotton, M. B., Forbes, A. P. Lancet, 1967, i, 648. 2. 3. 4.
Olafsson, O., Gudmundsson, K. R., Brekkan, A. Acta med. scand. 1966, 179, 121. 6. Lawson, A. A. H., MacLean, N. Ann. rheum. Dis. 1966, 25, 441. 7. Dubach, U. C., Minder, P., Gsell, O. 3rd Int. Congr. nephrol. 1967, 2, 300. 8. Bluemle, L. W., Goldberg, M. Clin. Res. 1967, 15, 351. 9. Axelsson, U. Nord. Med. 1958, 59, 903.
5.