ARACHIDONIC ACID AND PLATELET AGGREGATION
1
1080 often given like this, and unless a high free-water input is given the invariable result is progressive hypernatraemia. Mannitol will only cause hyponatraemia if the kidneys cannot excrete it. Southampton General Hospital, Shirley, Southampton SO9 4XY. P. J. HORSEY. CLINICAL TRIALS WITH VITAMIN C SIR,-Dr Lee (Sept. 28, p. 775) mentions many clinical conditions in which ascorbic-acid therapy has been sug- gested to be of use. In many cases its efficacy has by no means been adequately substantiated and further research is needed. However, low levels of tissue-vitamin-C has been proven, and verified to be associated with the long-term institutionalisation of the elderly (e.g., in National Health Service long-stay patients and in residents of local-authority old people’s homes), although the clinical significance of these low biochemical levels has yet to be fully worked out. Little if any work has, however, been carried out on the vitamin-C status of the young institutionalised (e.g., in the mentally subnormal) compared with levels found in the same age-group living in the community. Until this very much needed research is carried out it will be difficult to judge whether the low levels found in the elderly are associated with institutionalisation only or whether they are also connected with the ageing process. Thus any advocacy of supplementation with ascorbic acid of long-stay hospital patients would rest on doubtful evidence until such research is carried out. West Middlesex Hospital, Isleworth, Middlesex TW7 6AF. JAMES ANDREWS. RAUWOLFIA DERIVATIVES AND BREAST CANCER SIR,-Critical comments have been made on the design and conclusion of the three papers in your issue of Sept. 21, concerning the association between rauwolfia derivatives and breast cancer. The authors of the papers are themselves critical about the selection of controls and admit that the use of hypotensive drugs may be associated with other risk factors. However, whereas the risk ratio is about 3 for rauwolfia users it is close to 1 for users of methyldopa and other hypotensive drugs. In the opinion of the authors this supports the hypothesis of a direct association between rauwolfia and breast cancer. This would have been a strong argument if the users of rauwolfia and those using other hypotensive drugs had been drawn from the same patient population. Obviously this cannot be the case since rauwolfia derivatives were intro- duced on the market about a decade earlier than other hypotensive drugs. This has been mentioned in one of the papers (Sept. 21, p. 671) and vaguely discussed, but the consequences of this fact have not been fully considered. According to the design of the studies rauwolfia users must on average have had their hypertension diagnosed at an earlier date as well as a longer period of medication than users of other hypotensive drugs. Possible conclusions, in addition to the one given in the three papers, might therefore be: long-term hypotensive medication irrespective of preparation, or long-term hypertension or associated factors, such as overweight, may enhance the risk of breast cancer. Cancer Registry of Norway, Norwegian Radium Hospital, Montebello, Oslo 3, Norway. KNUT MAGNUS. ARACHIDONIC ACID AND PLATELET AGGREGATION SIR,-Reports in your columns suggest a recent surge in the application of polyunsaturated fatty acids in new and unusual ways.l.2 In the midst of this swell of enthusiasm, might I sound a note of warning in regard to arachidonic acid ? Arachidonic acid is an essential fatty acid with a 20-carbon skeleton and four double bonds. Although found only in animal sources, the fatty acid is readily synthesised from dietary linoleic acid.3 Mammalian enzyme systems quickly convert free arachidonic acid into short-lived endoperoxides that are subsequently metabolised into prostaglandins E2 and F2a.4-6 1 These labile intermediates are potent triggers of irreversible platelet aggregation and thrombosis.7,s Intravenously, arachidonic acid can produce rapid respira- tory death in rabbits from platelet occlusion of the pul- monary microvasculature.9 Intra-arterially, minute amounts of the polyene fatty acid cause stroke in rats by the same mechanism. 1 0 Needless to say, human platelets are quite susceptible in vitro to the aggregating property of arachidonic acid." Hence, unwary investigators should heed these ominous experiments before administering large parenteral (and possibly oral) doses of arachidonic acid to humans. University of Virginia Medical Center, Charlottesville, Virginia 22901, U.S.A. THOMAS W. FURLOW. E-AMINOCAPROIC ACID AND SUBARACHNOID HÆMORRHAGE SIR,-In 1968, the reports quoted by Mr Shaw and Mr Miller (Oct. 5, p. 847) prompted us to undertake a pilot study of the efficacy of e-aminocaproic acid (E.A.C.A.) in reducing the risk of recurrent subarachnoid haemorrhage in the interval before surgical management. E.A.C.A. (3 g. 3-hourly) was given to 45 patients, 42 of whom had proven aneurysms. 29 were considered unfit for surgery by virtue of extensive cerebral vasospasm, or a deteriorating neurological status; the optimum time for surgery was awaited in the remaining 13. There were recurrent haemorrhages in 8 patients, of whom 7 died. All these patients were unsuitable for surgery, and, as 4 of them had been on the treatment regimen for less than 72 hours at the time of their second haemorrhage, it was presumed that adequate antifibrinolytic levels in the cerebrospinal fluid had not been established.12 In the survivors there were no neurological complications directly attributable to E.A.C.A. On clinical grounds it was felt that 1 patient had had a pulmonary embolus, but he made a full recovery. No other systemic complications were encountered. Bearing in mind the parlous condition of the majority of the cases, the results of this preliminary work were not sufficiently daunting to discourage us from embarking on 1. Press, M., Hartop, P. J., Prottey, C. Lancet, 1974, i, 597. 2. Field, E. J., Shenton, B. K. ibid. Sept. 21, 1974, p. 725. 3. Documenta Geigy Scientific Tables; p. 492. Basle, 1970. 4. Van Dorp, D. A., Beerthuis, R. K., Nugteren, D. H., Vonkeman, H. Biochim. biophys. Acta, 1964, 90, 204. 5. Bergström, S., Danielsson, H., Samuelsson, B. ibid. p. 207. 6. Hamberg, M., Samuelsson, B. Proc. nat. Acad. Sci. U.S.A. 1973, 70, 899. 7. Willis, A. L. Prostaglandins, 1974, 5, 1. 8. Hamberg, M., Svensson, J., Wakabayashi, T., Samuelsson, B. Proc. nat. Acad. Sci. U.S.A. 1974, 71, 345. 9. Silver, M. J., Hoch, W., Kocsis, J. J., Ingerman, C. M., Smith, J. B. Science, 1974, 183, 1085. 10. Furlow, T. W., Bass, N. H. Unpublished. 11. Silver, M. J., Smith, J. B., Ingerman, C., Kocsis, J. J. Prostaglandins, 1973, 4, 863. 12. Tovi D. Umea University, Medical Dissertations, 1972; no. 8.
Transcript of ARACHIDONIC ACID AND PLATELET AGGREGATION
1080
often given like this, and unless a high free-water input isgiven the invariable result is progressive hypernatraemia.Mannitol will only cause hyponatraemia if the kidneyscannot excrete it.
Southampton General Hospital,Shirley,
Southampton SO9 4XY. P. J. HORSEY.
CLINICAL TRIALS WITH VITAMIN C
SIR,-Dr Lee (Sept. 28, p. 775) mentions many clinicalconditions in which ascorbic-acid therapy has been sug-gested to be of use. In many cases its efficacy has by nomeans been adequately substantiated and further researchis needed. However, low levels of tissue-vitamin-C hasbeen proven, and verified to be associated with the long-terminstitutionalisation of the elderly (e.g., in National HealthService long-stay patients and in residents of local-authorityold people’s homes), although the clinical significance ofthese low biochemical levels has yet to be fully worked out.
Little if any work has, however, been carried out on thevitamin-C status of the young institutionalised (e.g., inthe mentally subnormal) compared with levels found inthe same age-group living in the community. Until thisvery much needed research is carried out it will be difficultto judge whether the low levels found in the elderly areassociated with institutionalisation only or whether theyare also connected with the ageing process. Thus anyadvocacy of supplementation with ascorbic acid of long-stayhospital patients would rest on doubtful evidence untilsuch research is carried out.
West Middlesex Hospital,Isleworth,
Middlesex TW7 6AF. JAMES ANDREWS.
RAUWOLFIA DERIVATIVES ANDBREAST CANCER
SIR,-Critical comments have been made on the designand conclusion of the three papers in your issue of Sept. 21,concerning the association between rauwolfia derivativesand breast cancer. The authors of the papers are themselvescritical about the selection of controls and admit that theuse of hypotensive drugs may be associated with other riskfactors. However, whereas the risk ratio is about 3 forrauwolfia users it is close to 1 for users of methyldopa andother hypotensive drugs. In the opinion of the authors thissupports the hypothesis of a direct association betweenrauwolfia and breast cancer.
This would have been a strong argument if the users ofrauwolfia and those using other hypotensive drugs had beendrawn from the same patient population. Obviously thiscannot be the case since rauwolfia derivatives were intro-duced on the market about a decade earlier than otherhypotensive drugs. This has been mentioned in one of thepapers (Sept. 21, p. 671) and vaguely discussed, but theconsequences of this fact have not been fully considered.According to the design of the studies rauwolfia users muston average have had their hypertension diagnosed at anearlier date as well as a longer period of medication thanusers of other hypotensive drugs.
Possible conclusions, in addition to the one given in thethree papers, might therefore be: long-term hypotensivemedication irrespective of preparation, or long-termhypertension or associated factors, such as overweight, mayenhance the risk of breast cancer.
Cancer Registry of Norway,Norwegian Radium Hospital,Montebello, Oslo 3, Norway. KNUT MAGNUS.
ARACHIDONIC ACID AND PLATELETAGGREGATION
SIR,-Reports in your columns suggest a recent surge inthe application of polyunsaturated fatty acids in new andunusual ways.l.2 In the midst of this swell of enthusiasm,might I sound a note of warning in regard to arachidonicacid ?
Arachidonic acid is an essential fatty acid with a 20-carbonskeleton and four double bonds. Although found only inanimal sources, the fatty acid is readily synthesised fromdietary linoleic acid.3 Mammalian enzyme systems quicklyconvert free arachidonic acid into short-lived endoperoxidesthat are subsequently metabolised into prostaglandins E2and F2a.4-6 1 These labile intermediates are potent triggersof irreversible platelet aggregation and thrombosis.7,sIntravenously, arachidonic acid can produce rapid respira-tory death in rabbits from platelet occlusion of the pul-monary microvasculature.9 Intra-arterially, minuteamounts of the polyene fatty acid cause stroke in rats bythe same mechanism. 1 0
Needless to say, human platelets are quite susceptible invitro to the aggregating property of arachidonic acid."Hence, unwary investigators should heed these ominousexperiments before administering large parenteral (andpossibly oral) doses of arachidonic acid to humans.
University of Virginia MedicalCenter,
Charlottesville, Virginia 22901,U.S.A. THOMAS W. FURLOW.
E-AMINOCAPROIC ACID AND SUBARACHNOIDHÆMORRHAGE
SIR,-In 1968, the reports quoted by Mr Shaw andMr Miller (Oct. 5, p. 847) prompted us to undertake apilot study of the efficacy of e-aminocaproic acid (E.A.C.A.)in reducing the risk of recurrent subarachnoid haemorrhagein the interval before surgical management. E.A.C.A.
(3 g. 3-hourly) was given to 45 patients, 42 of whom hadproven aneurysms. 29 were considered unfit for surgeryby virtue of extensive cerebral vasospasm, or a deterioratingneurological status; the optimum time for surgery wasawaited in the remaining 13. There were recurrent
haemorrhages in 8 patients, of whom 7 died.All these patients were unsuitable for surgery, and, as
4 of them had been on the treatment regimen for less than72 hours at the time of their second haemorrhage, it waspresumed that adequate antifibrinolytic levels in the
cerebrospinal fluid had not been established.12In the survivors there were no neurological complications
directly attributable to E.A.C.A. On clinical grounds it wasfelt that 1 patient had had a pulmonary embolus, but hemade a full recovery. No other systemic complicationswere encountered.
Bearing in mind the parlous condition of the majorityof the cases, the results of this preliminary work were notsufficiently daunting to discourage us from embarking on
1. Press, M., Hartop, P. J., Prottey, C. Lancet, 1974, i, 597.2. Field, E. J., Shenton, B. K. ibid. Sept. 21, 1974, p. 725.3. Documenta Geigy Scientific Tables; p. 492. Basle, 1970.4. Van Dorp, D. A., Beerthuis, R. K., Nugteren, D. H., Vonkeman, H.
Biochim. biophys. Acta, 1964, 90, 204.5. Bergström, S., Danielsson, H., Samuelsson, B. ibid. p. 207.6. Hamberg, M., Samuelsson, B. Proc. nat. Acad. Sci. U.S.A. 1973,
70, 899.7. Willis, A. L. Prostaglandins, 1974, 5, 1.8. Hamberg, M., Svensson, J., Wakabayashi, T., Samuelsson, B.
Proc. nat. Acad. Sci. U.S.A. 1974, 71, 345.9. Silver, M. J., Hoch, W., Kocsis, J. J., Ingerman, C. M., Smith, J. B.
Science, 1974, 183, 1085.10. Furlow, T. W., Bass, N. H. Unpublished.11. Silver, M. J., Smith, J. B., Ingerman, C., Kocsis, J. J. Prostaglandins,
1973, 4, 863.12. Tovi D. Umea University, Medical Dissertations, 1972; no. 8.
