- Email: [email protected]
AMPHETAMINE WITHDRAWAL: DEPRESSION AND M.H.P.G. EXCRETION
485 This abnormal circulation could be the flow of portal blood through collaterals or through abnormal liver sinusoids (with damaged Kupffer cells ?). It is important to remember that increased serum-immunoglobulins are found in infective as well as dietetic 13 or toxic damage. 14 When the experimental dietetic or toxic damage disThe appears, the immunoglobulins decrease again. fact is liver and the not its apparently lesion, important
aetiology. This hypothesis is supported by the observation that immunoglobulins increase after the establishment of a
portacaval shunt in test the hypothesis
cirrhosis.16,16 A more direct way to would be to measure the antibody titre to common intestinal bacteria. If the hypothesis is correct, antibody titres should be higher in the blood of patients with cirrhosis than in patients with normal livers. The observation of Mr. Protell and his co-workers may in fact be a confirmation of this hypothesis. Bispebjerg Hospital, Copenhagen, Denmark.
MØGENS BJØRNEBOE.
AMPHETAMINE WITHDRAWAL: DEPRESSION AND M.H.P.G. EXCRETION
SiR,—The administration of large doses of amphetamines
produce hypomania-like states, and depressions particularly after prolonged use." The mechanism of action of the amphetamines has not been definitively established, but numerous findings indicate that these drugs may release catecholamines-noradrenaline or dopamine-from presynaptic occur
can
upon withdrawal of these agents,
and increase levels of these monoamines at postsynaptic receptors in the brain.1S-21 A number of lines of evidence suggest that the urinary excretion of 3-methoxy-
neurons
4-hydroxyphenylglycol (M.H.P.G.), primarily conjugate, may provide the best index of
as a
the
sulphate synthesis
and metabolism of noradrenaline in the brain.22-24 M.H.P.G. excretion has been examined in patients with affective disorders, and in one study of a heterogeneous group of depressed patients the urinary excretion of M.H.P.G. was found to be decreased.25 In another longitudinal study of a small group of manic-depressive patients, M.H.P.G. excretion was decreased during depression and increased upon remission; but in manic patients M.H.P.G. was higher during mania than after remission.26 It was, therefore, of interest to us to examine the changes in affective state and M.H.P.G. excretion which accompanied the withdrawal of amphetamines in four patients who had regularly selfadministered high doses (50-400 mg. daily) of these drugs and who entered the hospital for the purposes of amphetamine withdrawal. While still taking amphetamines, these patients were clinically hypomanic, and this was documented by ratings 13. Zaki, F. G., Hoffbauer, F. W. Archs Path. 1964, 77, 1. 14. Cook, H. A., Griffin, A. C., Luck, J. M. J. biol. Chem. 1949, 177, 373. 15. Eszer, G. Pfortaderhochdruck und Einweissstoffwechsel. Berlin, 1969. 16. Bjørneboe, M. Unpublished. 17. Innes, I. R., Nickerson, M. in The Pharmacological Basis of Therapeutics (edited by L. S. Goodman and A. Gilman); p. 502. New York, 1970. 18. Stein, L. Fedn Proc. 1964, 23, 836. 19. Glowinski, J., Axelrod, J., Iversen, L. L. J. Pharmac. exp. Ther. 1966, 153, 30. 20. Carr, L. A., Moore, K. E. Science, 1969, 164, 332. 21. Schildkraut, J. J. Am. J. Psychiat. 1970, 126, 925. 22. Schanberg, S. M., Schildkraut, J. J., Breese, G. R., Kopin, I. J. Biochem. Pharmac. 1968, 17, 247. 23. Schanberg, S. M., Breese, G. R., Schildkraut, J. J., Gordon, E. K., Kopin, I. J. ibid. p. 2006. 24. Maas, J. W., Landis, D. H. J. Pharmac. exp. Ther. 1968, 163, 147. 25. Maas, J. W., Fawcett, J., Dekirmenjian, H. Archs gen. Psychiat. 1968, 19, 129. 26. Greenspan, K., Schildkraut, J. J., Gordon, E. K., Baer, L., Aronoff, M. S., Durell, J. J. psychiat. Res. 1970, 7, 171.
the mania-depression rating scale.27 Upon the abrupt withdrawal of these drugs, the hypomanic state rapidly subsided and patients began to show evidence of depression within 24-48 hours after the withdrawal of the drug. The depression reached its peak 48-72 hours after the last dose of the drug and then decreased substantially (but not completely in all patients) over the course of the next 24-48 The urinary excretion of M.H.P.G., which was hours. measured in 24-hour urine samples by the method of Dekirmenjian and MaaS 5211 was raised during the administration of amphetamines and rapidly declined upon withdrawal of these drugs. Levels of M.H.P.G. were lowest between 24-60 hours after drug withdrawal and then progressively increased. The changes in M.H.P.G. excretion occurred with, or possibly preceded, the clinical changes. These findings followed a similar pattern in all four subjects, and the data from one of them are illustrated in the accompanying figure. Amphetamines have lately been found to increase levels of tyrosine hydroxylase (the rate-limiting enzyme of noradrenaline biosynthesis) in animal brain.29 This could account, at least in part, for the apparent increase in noradrenaline synthesis and metabolism in brain (as reflected by the raised M.H.P.G. excretion) observed during chronic administration of amphetamines in the present study. It is unlikely that the increase in M.H.P.G. results from an increase in intraneuronal deamination and inactivation of noradrenaline, as may occur with reserpine 30 since, in animals, amphetamine decreases the deamination of noradrenaline in the brain.19,21,31-33 The increase in M.H.P.G. excretion during administration of amphetamines thus suggests that, in man as in animals, these drugs may increase noradrenaline available to receptors in brain; conversely, the decrease in M.H.P.G. excretion observed after the withdrawal of amphetamines suggests that the amphetamine-withdrawal syndrome may be associated with a decrease in noradrenaline at receptor sites. The catecholamine hypothesis of affective disorders proposes that some, if not all, depressions may be associated with an absolute or relative deficiency of noradrenaline or other catecholamines at critical receptor sites in brain, whereas manias may be associated with an excess of these monoamines.34 The present findings of an increase in on
27. 28. 29. 30. 31. 32. 33. 34.
Schildkraut, J. J. Unpublished. Dekirmenjian, H., Maas, J. W. Analyt. Biochem. 1970, 35, 113. Mandell, A. J. Personal communication. Youdim, M. B. H., Sandler, M. Nature, 1968, 217, 771. Glowinski, J., Axelrod, J. J. Pharmac. exp. Ther. 1965, 149, 43. Cook, J. D., Schanberg, S. M. Biochem. Pharmac. 1970, 19, 1165. Rutledge, C. O. J. Pharmac. exp. Ther. 1970, 171, 188. Schildkraut, J. J. Am. J. Psychiat. 1965, 122, 509.
HOURS BEFORE ANO AFTER LAST DOSE OF AMPHETAMINES
Clinical state and M.H.P.G. excretion before and after withdrawal of amphetamines.
The last dose of amphetamines was taken at 0 hours. Each value for M.H.P.G. was plotted at the midpoint of the 24-hour urine collection period. Each clinical rating was plotted at the midpoint of the 24-hour period covered by that rating. Mania
ratings (+); depression ratings (-).
486 excretion and hypomania during administration amphetamines, and a decrease in M.H.P.G. excretion and depression upon withdrawal of amphetamines, may thus be added to the accumulating body of data compatible with this hypothesis. 35
M.H.P.G.
of
This work was supported in part 15413 and MH 14520.
by U.S.P.H.S. grants MH
relatively mild mitral-valve disease who are still in sinus rhythm. 66% of initial systemic emboli were cerebral, and the effects were often disastrous. Our study, extending over a period of 9! years, shows that the embolic incidence can be greatly reduced by use of long-term anticoagulants, and it has long been our policy to advise this treatment, unless there are special factors against it, in all
patients
Neuropsychopharmacology Laboratory,
with
more
than trivial mitral-valve disease.
Papworth Hospital, Papworth Everard, Cambridge CB3 8RE.
Massachusetts Mental Health
Center, Department of Psychiatry,
H. A. FLEMING.
Harvard Medical School,
Boston, Massachusetts,
ASPIRIN, THROMBOSIS, AND THE FUTURE SIR,-In your editorial, Management of Thrombosis,
and
Sleep and Dream Laboratory, Boston State Hospital, Department of Psychiatry, Tufts University School of
Medicine, Boston, Massachusetts.
JOSEPH J. SCHILDKRAUT ROBERT WATSON PAUL R. DRASKOCZY ERNEST HARTMANN.
UNRELIABILITY OF FETAL SEXING USING CERVICAL MATERIAL
SiR,—The affinity of the quinacrine dyes has enabled
human Y chromosome for male cells to be positively identified under the fluorescence microscope.36 It has been claimedthat, using this technique, male cells can be identified in cervical smears from pregnant women carrying male fetuses. We have examined cervical smears and mid-cervical-mucus samples from 9 cases. Material was fixed in 3/1 methanol/acetic acid and stained as Fetuses were sexed by clinical described previously. examination at term birth or by examination of Barr bodies and Y bodies from aborted fetal material. 3 of the pregnancies were male and 6 female. The proportion of Y-positive cells in the cervical smears 6 "female" pregnancies, ranged from 0 to 5 % in the " and from 2 to 3% in the 3 male " pregnancies. Pooling results from all cases, the male pregnancies had 3-04% positive cells against 2-52% in the female pregnancies This order of positive cells is similar to the (p > 0-75). proportion of false-positive cells scored in known female material-e.g., buccal smears. We are therefore unable to substantiate the claim that fetal sexing can be achieved by examination of material from the cervix uteri. It is important to appreciate that the small fluorescent Y body can be mimicked by clumps of condensed chromatin and other artefacts. Although material can be reliably sexed when a range of cells are examined, it is not possible to be certain that one individual cell with a fluorescent dot contains a Y chromosome. Any procedure which depends on correctly identifying a very low proportion of positive cells is therefore likely to be unreliable in practice. M.R.C.
Population Genetics Unit,
Old Road, Headington, Oxford.
Watford General Hospital.
MARTIN BOBROW.
out the effect of aspirin on it has not been suggested as a but platelet aggregation, practical antithrombotic agent." This cannot pass without comment. I was not the first to make these observations and we all 1-3 suggested aspirin might be clinically useful in thrombosis. Indeed, already three such studies have been published 4-6 and I know of current studies on both arterial and venous thrombosis in this country and elsewhere. Very recently a close connection has been shown between the anti-inflammatory drugs-sometimes called membrane stabilisers7 -and the prostaglandins. For example, there is an exact parallelism between the relative activity of indomethacin, aspirin, and salicylate to inhibit P.G.E’2 release, and probably its synthesis, from platelets,8 and the ability of these drugs to inhibit collagen-induced aggregation in vivo9 and in vitro. 10 P.G.E’1 strongly inhibits platelet aggregation and also increases cyclic a.M..l-13 These findings emphasise again that the platelet is an excellent cell model to study, and this work should lead to a better understanding of platelet physiology and of basic cellular physiology in general. Perhaps more antiplatelet drugs will also emerge with better antithrombotic
you say, " O’Brien
pointed
properties. Portsmouth and Isle of Wight Area
Pathology Service, St. Mary’s Hospital, Portsmouth PO3 6AG.
J. R. O’BRIEN.
CORRECTION OF HÆMOSTATIC DEFECT IN CYANOTIC CONGENITAL HEART-DISEASE
SrR,-Last year Gralnick 14 described the use of e-aminocaproic acid (E.A.c.A.) in the preoperative correction of hxmostatic defects in cyanotic congenital heart-disease. In view of the continuing controversy over whether this is syndrome of primary fibrinolysis or disseminated intravascular coagulation,15 and therefore whether E.A.C.A. or heparin is the more appropriate therapeutic agent, we thought our experience with the following case would be of interest. a
B. V. LEWIS. Evans, G., Packham, M. A., Nishizawa, E. E., Mustard, J. F., Murphy, E. A. J. exp. Med. 1968, 128, 877. 2. Zucker, M. B., Peterson, J. Proc. Soc. exp. Biol. Med. 1968, 127, 1.
ANTICOAGULANTS IN RHEUMATIC HEART-DISEASE
SIR,-In your otherwise excellent editorial, Management of Thrombosis (Aug. 14, p. 361), I would like to take issue with the remark, " Long-term anticoagulant treatment should be used for patients who have had one attack of arterial embolism ...". This policy would not avoid many tragedies, and our studies 38 on patients with mitralvalve disease show that many emboli occur in people with Schildkraut, J. J. Neuropsychopharmacology and the Affective Disorders. Boston, 1970. 36. Pearson, P. L., Bobrow, M., Vosa, C. G. Nature, 1970, 226, 78. 37. Shettles, L. B. ibid. 1971, 230, 52. 38. Fleming, H. A., Bailey, S. M. Postgrad. med. J. 1971, 47, 525. 35.
547. 3. 4. 5. 6. 7. 8. 9. 10. 11.
12. 13. 14. 15.
Weiss, H. J., Aledort, L. M. Lancet, 1967, ii, 495. Salzman, E. W., Harris, W. H., De Sanctis, R. W. New Engl. J. Med. 1971, 284, 1287. Breddin, K. Acta med. scand. 1971, suppl. 525, p. 224. O’Brien, J. R. Tulevski, V., Etherington, M. Lancet, 1971, i, 399. Inglot, A. D., Wolna, E. Biochem. Pharmac. 1968, 17, 269. Smith, J. B., Willis, A. L. Nature New Biol. 1971, 231, 235. O’Brien, J. R., Finch, W., Clark, E. J. clin. Path. 1970, 23, 522. O’Brien, J. R. Lancet, 1968, i, 894. Marquis, N. R., Vigdahl, R. L., Tavormina, P. A. Biochem. biophys. Res. Commun. 1969, 36, 965. Mills, D. C. B., Smith, J. B. Biochem. J. 1971, 121, 185. Haslam, R. J., Taylor, A. in Platelet Aggregation (edited by J. Caen); p. 85. Paris, 1971. Gralnick, H. R. Lancet, 1970, i, 1204. Dennis, L. H., Stewart, J. L., Conrad, M. E. ibid. 1967, i, 1088.
aetiology. This hypothesis is supported by the observation that immunoglobulins increase after the establishment of a
portacaval shunt in test the hypothesis
cirrhosis.16,16 A more direct way to would be to measure the antibody titre to common intestinal bacteria. If the hypothesis is correct, antibody titres should be higher in the blood of patients with cirrhosis than in patients with normal livers. The observation of Mr. Protell and his co-workers may in fact be a confirmation of this hypothesis. Bispebjerg Hospital, Copenhagen, Denmark.
MØGENS BJØRNEBOE.
AMPHETAMINE WITHDRAWAL: DEPRESSION AND M.H.P.G. EXCRETION
SiR,—The administration of large doses of amphetamines
produce hypomania-like states, and depressions particularly after prolonged use." The mechanism of action of the amphetamines has not been definitively established, but numerous findings indicate that these drugs may release catecholamines-noradrenaline or dopamine-from presynaptic occur
can
upon withdrawal of these agents,
and increase levels of these monoamines at postsynaptic receptors in the brain.1S-21 A number of lines of evidence suggest that the urinary excretion of 3-methoxy-
neurons
4-hydroxyphenylglycol (M.H.P.G.), primarily conjugate, may provide the best index of
as a
the
sulphate synthesis
and metabolism of noradrenaline in the brain.22-24 M.H.P.G. excretion has been examined in patients with affective disorders, and in one study of a heterogeneous group of depressed patients the urinary excretion of M.H.P.G. was found to be decreased.25 In another longitudinal study of a small group of manic-depressive patients, M.H.P.G. excretion was decreased during depression and increased upon remission; but in manic patients M.H.P.G. was higher during mania than after remission.26 It was, therefore, of interest to us to examine the changes in affective state and M.H.P.G. excretion which accompanied the withdrawal of amphetamines in four patients who had regularly selfadministered high doses (50-400 mg. daily) of these drugs and who entered the hospital for the purposes of amphetamine withdrawal. While still taking amphetamines, these patients were clinically hypomanic, and this was documented by ratings 13. Zaki, F. G., Hoffbauer, F. W. Archs Path. 1964, 77, 1. 14. Cook, H. A., Griffin, A. C., Luck, J. M. J. biol. Chem. 1949, 177, 373. 15. Eszer, G. Pfortaderhochdruck und Einweissstoffwechsel. Berlin, 1969. 16. Bjørneboe, M. Unpublished. 17. Innes, I. R., Nickerson, M. in The Pharmacological Basis of Therapeutics (edited by L. S. Goodman and A. Gilman); p. 502. New York, 1970. 18. Stein, L. Fedn Proc. 1964, 23, 836. 19. Glowinski, J., Axelrod, J., Iversen, L. L. J. Pharmac. exp. Ther. 1966, 153, 30. 20. Carr, L. A., Moore, K. E. Science, 1969, 164, 332. 21. Schildkraut, J. J. Am. J. Psychiat. 1970, 126, 925. 22. Schanberg, S. M., Schildkraut, J. J., Breese, G. R., Kopin, I. J. Biochem. Pharmac. 1968, 17, 247. 23. Schanberg, S. M., Breese, G. R., Schildkraut, J. J., Gordon, E. K., Kopin, I. J. ibid. p. 2006. 24. Maas, J. W., Landis, D. H. J. Pharmac. exp. Ther. 1968, 163, 147. 25. Maas, J. W., Fawcett, J., Dekirmenjian, H. Archs gen. Psychiat. 1968, 19, 129. 26. Greenspan, K., Schildkraut, J. J., Gordon, E. K., Baer, L., Aronoff, M. S., Durell, J. J. psychiat. Res. 1970, 7, 171.
the mania-depression rating scale.27 Upon the abrupt withdrawal of these drugs, the hypomanic state rapidly subsided and patients began to show evidence of depression within 24-48 hours after the withdrawal of the drug. The depression reached its peak 48-72 hours after the last dose of the drug and then decreased substantially (but not completely in all patients) over the course of the next 24-48 The urinary excretion of M.H.P.G., which was hours. measured in 24-hour urine samples by the method of Dekirmenjian and MaaS 5211 was raised during the administration of amphetamines and rapidly declined upon withdrawal of these drugs. Levels of M.H.P.G. were lowest between 24-60 hours after drug withdrawal and then progressively increased. The changes in M.H.P.G. excretion occurred with, or possibly preceded, the clinical changes. These findings followed a similar pattern in all four subjects, and the data from one of them are illustrated in the accompanying figure. Amphetamines have lately been found to increase levels of tyrosine hydroxylase (the rate-limiting enzyme of noradrenaline biosynthesis) in animal brain.29 This could account, at least in part, for the apparent increase in noradrenaline synthesis and metabolism in brain (as reflected by the raised M.H.P.G. excretion) observed during chronic administration of amphetamines in the present study. It is unlikely that the increase in M.H.P.G. results from an increase in intraneuronal deamination and inactivation of noradrenaline, as may occur with reserpine 30 since, in animals, amphetamine decreases the deamination of noradrenaline in the brain.19,21,31-33 The increase in M.H.P.G. excretion during administration of amphetamines thus suggests that, in man as in animals, these drugs may increase noradrenaline available to receptors in brain; conversely, the decrease in M.H.P.G. excretion observed after the withdrawal of amphetamines suggests that the amphetamine-withdrawal syndrome may be associated with a decrease in noradrenaline at receptor sites. The catecholamine hypothesis of affective disorders proposes that some, if not all, depressions may be associated with an absolute or relative deficiency of noradrenaline or other catecholamines at critical receptor sites in brain, whereas manias may be associated with an excess of these monoamines.34 The present findings of an increase in on
27. 28. 29. 30. 31. 32. 33. 34.
Schildkraut, J. J. Unpublished. Dekirmenjian, H., Maas, J. W. Analyt. Biochem. 1970, 35, 113. Mandell, A. J. Personal communication. Youdim, M. B. H., Sandler, M. Nature, 1968, 217, 771. Glowinski, J., Axelrod, J. J. Pharmac. exp. Ther. 1965, 149, 43. Cook, J. D., Schanberg, S. M. Biochem. Pharmac. 1970, 19, 1165. Rutledge, C. O. J. Pharmac. exp. Ther. 1970, 171, 188. Schildkraut, J. J. Am. J. Psychiat. 1965, 122, 509.
HOURS BEFORE ANO AFTER LAST DOSE OF AMPHETAMINES
Clinical state and M.H.P.G. excretion before and after withdrawal of amphetamines.
The last dose of amphetamines was taken at 0 hours. Each value for M.H.P.G. was plotted at the midpoint of the 24-hour urine collection period. Each clinical rating was plotted at the midpoint of the 24-hour period covered by that rating. Mania
ratings (+); depression ratings (-).
486 excretion and hypomania during administration amphetamines, and a decrease in M.H.P.G. excretion and depression upon withdrawal of amphetamines, may thus be added to the accumulating body of data compatible with this hypothesis. 35
M.H.P.G.
of
This work was supported in part 15413 and MH 14520.
by U.S.P.H.S. grants MH
relatively mild mitral-valve disease who are still in sinus rhythm. 66% of initial systemic emboli were cerebral, and the effects were often disastrous. Our study, extending over a period of 9! years, shows that the embolic incidence can be greatly reduced by use of long-term anticoagulants, and it has long been our policy to advise this treatment, unless there are special factors against it, in all
patients
Neuropsychopharmacology Laboratory,
with
more
than trivial mitral-valve disease.
Papworth Hospital, Papworth Everard, Cambridge CB3 8RE.
Massachusetts Mental Health
Center, Department of Psychiatry,
H. A. FLEMING.
Harvard Medical School,
Boston, Massachusetts,
ASPIRIN, THROMBOSIS, AND THE FUTURE SIR,-In your editorial, Management of Thrombosis,
and
Sleep and Dream Laboratory, Boston State Hospital, Department of Psychiatry, Tufts University School of
Medicine, Boston, Massachusetts.
JOSEPH J. SCHILDKRAUT ROBERT WATSON PAUL R. DRASKOCZY ERNEST HARTMANN.
UNRELIABILITY OF FETAL SEXING USING CERVICAL MATERIAL
SiR,—The affinity of the quinacrine dyes has enabled
human Y chromosome for male cells to be positively identified under the fluorescence microscope.36 It has been claimedthat, using this technique, male cells can be identified in cervical smears from pregnant women carrying male fetuses. We have examined cervical smears and mid-cervical-mucus samples from 9 cases. Material was fixed in 3/1 methanol/acetic acid and stained as Fetuses were sexed by clinical described previously. examination at term birth or by examination of Barr bodies and Y bodies from aborted fetal material. 3 of the pregnancies were male and 6 female. The proportion of Y-positive cells in the cervical smears 6 "female" pregnancies, ranged from 0 to 5 % in the " and from 2 to 3% in the 3 male " pregnancies. Pooling results from all cases, the male pregnancies had 3-04% positive cells against 2-52% in the female pregnancies This order of positive cells is similar to the (p > 0-75). proportion of false-positive cells scored in known female material-e.g., buccal smears. We are therefore unable to substantiate the claim that fetal sexing can be achieved by examination of material from the cervix uteri. It is important to appreciate that the small fluorescent Y body can be mimicked by clumps of condensed chromatin and other artefacts. Although material can be reliably sexed when a range of cells are examined, it is not possible to be certain that one individual cell with a fluorescent dot contains a Y chromosome. Any procedure which depends on correctly identifying a very low proportion of positive cells is therefore likely to be unreliable in practice. M.R.C.
Population Genetics Unit,
Old Road, Headington, Oxford.
Watford General Hospital.
MARTIN BOBROW.
out the effect of aspirin on it has not been suggested as a but platelet aggregation, practical antithrombotic agent." This cannot pass without comment. I was not the first to make these observations and we all 1-3 suggested aspirin might be clinically useful in thrombosis. Indeed, already three such studies have been published 4-6 and I know of current studies on both arterial and venous thrombosis in this country and elsewhere. Very recently a close connection has been shown between the anti-inflammatory drugs-sometimes called membrane stabilisers7 -and the prostaglandins. For example, there is an exact parallelism between the relative activity of indomethacin, aspirin, and salicylate to inhibit P.G.E’2 release, and probably its synthesis, from platelets,8 and the ability of these drugs to inhibit collagen-induced aggregation in vivo9 and in vitro. 10 P.G.E’1 strongly inhibits platelet aggregation and also increases cyclic a.M..l-13 These findings emphasise again that the platelet is an excellent cell model to study, and this work should lead to a better understanding of platelet physiology and of basic cellular physiology in general. Perhaps more antiplatelet drugs will also emerge with better antithrombotic
you say, " O’Brien
pointed
properties. Portsmouth and Isle of Wight Area
Pathology Service, St. Mary’s Hospital, Portsmouth PO3 6AG.
J. R. O’BRIEN.
CORRECTION OF HÆMOSTATIC DEFECT IN CYANOTIC CONGENITAL HEART-DISEASE
SrR,-Last year Gralnick 14 described the use of e-aminocaproic acid (E.A.c.A.) in the preoperative correction of hxmostatic defects in cyanotic congenital heart-disease. In view of the continuing controversy over whether this is syndrome of primary fibrinolysis or disseminated intravascular coagulation,15 and therefore whether E.A.C.A. or heparin is the more appropriate therapeutic agent, we thought our experience with the following case would be of interest. a
B. V. LEWIS. Evans, G., Packham, M. A., Nishizawa, E. E., Mustard, J. F., Murphy, E. A. J. exp. Med. 1968, 128, 877. 2. Zucker, M. B., Peterson, J. Proc. Soc. exp. Biol. Med. 1968, 127, 1.
ANTICOAGULANTS IN RHEUMATIC HEART-DISEASE
SIR,-In your otherwise excellent editorial, Management of Thrombosis (Aug. 14, p. 361), I would like to take issue with the remark, " Long-term anticoagulant treatment should be used for patients who have had one attack of arterial embolism ...". This policy would not avoid many tragedies, and our studies 38 on patients with mitralvalve disease show that many emboli occur in people with Schildkraut, J. J. Neuropsychopharmacology and the Affective Disorders. Boston, 1970. 36. Pearson, P. L., Bobrow, M., Vosa, C. G. Nature, 1970, 226, 78. 37. Shettles, L. B. ibid. 1971, 230, 52. 38. Fleming, H. A., Bailey, S. M. Postgrad. med. J. 1971, 47, 525. 35.
547. 3. 4. 5. 6. 7. 8. 9. 10. 11.
12. 13. 14. 15.
Weiss, H. J., Aledort, L. M. Lancet, 1967, ii, 495. Salzman, E. W., Harris, W. H., De Sanctis, R. W. New Engl. J. Med. 1971, 284, 1287. Breddin, K. Acta med. scand. 1971, suppl. 525, p. 224. O’Brien, J. R. Tulevski, V., Etherington, M. Lancet, 1971, i, 399. Inglot, A. D., Wolna, E. Biochem. Pharmac. 1968, 17, 269. Smith, J. B., Willis, A. L. Nature New Biol. 1971, 231, 235. O’Brien, J. R., Finch, W., Clark, E. J. clin. Path. 1970, 23, 522. O’Brien, J. R. Lancet, 1968, i, 894. Marquis, N. R., Vigdahl, R. L., Tavormina, P. A. Biochem. biophys. Res. Commun. 1969, 36, 965. Mills, D. C. B., Smith, J. B. Biochem. J. 1971, 121, 185. Haslam, R. J., Taylor, A. in Platelet Aggregation (edited by J. Caen); p. 85. Paris, 1971. Gralnick, H. R. Lancet, 1970, i, 1204. Dennis, L. H., Stewart, J. L., Conrad, M. E. ibid. 1967, i, 1088.