822 POSSIBLE ROLE FOR CHLORPROMAZINE IN PROTECTION AGAINST MYOCARDIAL INFARCTION
SIR,-There is increasing evidence, recently summarised,lI that the sudden
unpredictable event responsible for initiating high proportion of myocardial infarcts is the fissuring of an atheromatous plaque in the supplying artery. The associated haemorrhage into the arterial wall induces aggregation of platelets as a thrombus, just as arterial haemorrhages elsewhere induce platelet aggregation as "hxmostatic plugs." Crucial questions are, therefore, how arterial haemorrhages cause platelet aggregation and how aggregation may be prevented or reversed in coronary arteries. An explanation recently proposed’·2 is that the process depends mainly on the activation of platelets by A.D.P. coming from the red blood-cells which are subjected to excessive haemodynamic stress at the a
site of haemorrhage. Some time ago I had the idea that drugs capable of counteracting hxmolysis3 might diminish this activating effect of red cells on platelets and so inhibit their aggregation as thrombi. Experimental evidence for this idea came with the demonstration4 that chlorpromazine added to anticoagulated human blood in concentrations which in vitro diminish hypotonic haemolysis, but have no direct effect on platelet aggregation,5 prolong the bleeding-time from small holes in artificial vessels where extravasation is terminated, as in vivo, by aggregated platelets. Experiments by A. Wehmeier and myself (unpublished) support the conclusion that this effect is accounted for by the antihxmolytic action of chlorpromazine. This has led to the suggestion’’’* that other drugs possessing this effect of chlorpromazine may diminish the incidence of arterial, particularly of coronary, thrombosis when it is induced by conditions of abnormal stress on the red cells, such as through haemorrhage into atheromatous lesions. Evidence for or against this proposition could perhaps be obtained by comparing the incidence of acute coronary occlusions in populations on long-term treatment with chlorpromazine (or other drugs acting in this respect like chlorpromazine) with the incidence in control populations not on such drugs. The only conceivably relevant evidence of which I have been made aware up to now (through the courtesy of Dr J. A. Baldwin, director of the Oxford University Unit of Clinical Epidemiology) is an investigation of mortality in Norwegian psychiatric hospitals during the period 1950 to 1962.6 This concluded that mortality from circulatory disease, predominantly "coronary disease" and "infarction", was higher in the mental-hospital population than in the general population, although the excess was not as much as that from most other causes. Within the patient population, the excess mortality from coronary disease and infarction was less for schizophrenics than for all other psychoses. Furthermore, the excess mortality from circulatory disease diminished strikingly after 1957, particularly when compared with the period 1926-41, because the mortality did not rise to the same extent in the hospital as in the general population. These conclusions, if confirmed, are of course open to different interpretations. Epidemiological considerations apart, chlorpromazine has many effects in the body, and also a large number of metabolites. Furthermore, the concentration of chlorpromazine in patients’ plasma is one to two orders of magnitude lower than that required to prolong the ex-vivo bleeding-time described above. Therefore, if patients’ blood were used for determining this bleeding-time, a prolongation 1
Born, G. V. R. Plenary lecture
to
the VIIIth World
Congress
of Cardiology,
Tokyo. Amsterdam (in the press). in Blood Cells and Vessel Walls: functional interactions (Ciba Fndn Symp. no. 71). Amsterdam (in the press). 3. Seeman, P Pharmac. Rev. 1972, 24, 583. 4. Born, G. V R. Bergquist, D., Arfors, K.-E. Nature. 1976, 259, 233. 5 Mills, D. C. B., Roberts, G. C. K. ibid. 1967, 213, 35 6. Odegard, O. Acta genet , Basel, 1967, 17, 137. 7. Mackay, A V. P , Healey, A. F., Baker, J. Br. J. clin. pharmac. 1974, 1, 425.
2.
if the drug or a similarly active metaconcentrated in red cell membranes. On the other hand, it has been observed8 that single clinical doses (5-20 mg)11 of chlorpromazine injected intramuscularly into apparently healthy volunteers caused the Ivy bleeding-time to be signifi-
might
be
bolite
were
expected only
cantly prolonged. Our experimental observations with chlorpromazine make It attractive to suggest that the general introduction of this drug for the control of schizophrenic inpatients from about 1955 onwards accounts for their relative protection against cardiac mortality at a time when it was increasing rapidly in Norway and elsewhere, including Britain. It would be interesting to learn of other information which may support or, just as important, invalidate this line of thought. It may be worthwhile to investigate appropriate populations from this point of view. Department of Pharmacology, King’s College, University of London, London WC2R 2LS
G. V. R. BORN
COMPUTERISED TOMOGRAPHY AND SUBDURAL HÆMATOMAS
S!R,—Mr Galbraith and Mr Teasdale (March 3, p. 504). out that acute and chronic subdural hasmadiffer in clinical features, surgical approach, and prognosis. They also state that in my letter of Jan. 13 (p. 110) I failed to make this distinction. However, that letter was concerned with acute as well as chronic subdural hsematomas. If only acute subdural hsematomas are considered, the possibility of false-negatives in c.T. scanning still remains. An acute subdural haematoma may present as an isodense lesion if the extravasated blood has low haemoglobin concentration’ or if it arises from rebleeding into a more chronic lesion.2 Recurrent bleeding and anxmia are common among chronic alcoholic patients, .3 a group particularly prone to subdural hxmorrhage That isodense lesions occur in acute cases is corroborated by the Glasgow workers’ own report of such lesions in four of their fifty patients with acute traumatic intracranial bleeding.’ The lesions were unilateral, and thus easily diagnosed by the concomitant ventricular distortion, but had they been bilateral they could have been missed altogether. Bilateral collections are not uncommon in cases of acute subdural haemorrhage. Furthermore, Galbraith et al. selected as controls cases of trauma with a negative c.T. scan and a diagnosis of "diffuse cerebral damage". That all the cases of subdural bleeding had been excluded from their control group can only be accepted by first accepting that false-negatives never occur on c.T. scan-
correctly point tomas
ning. The diagnostic reliability of c.T. scanning in cases of acute subdural hsematoma is high. The reports so far published, however, do not support Galbraith and Teasdale’s view that there are no false-negatives. Neurology Service, Medical Center,
Portland, Oregon 97201, U.S.A.
LUIS GARCIA-BUÑUEL
SHOULD THE LAX SET THE PACE?
SiR,—Iwas most interested in Professor Schou’s letter (March 31, p. 730) dealing with the problems of conference
proceedings and multiauthor books. I think that these are two separate problems-whilst it is clearly practical to ask contributors to congresses to deliver their papers by a set date or run the risk of their papers being excluded, this is hardly prac-
Born, G. V. R.
8.
Zahavi, J , Schwartz, G. Lancet, 1978, ii, 164.
1. New, P. F J., Aronow, S. Radiology, 1976, 121, 635. 2. French, B. N., Dublin, A. B. Surg Neurol. 1977, 7, 171. 3. Merrit, H. H. A Textbook of Neurology; p. 329. Philadelphia, 1973. 4. Galbraith, S., Teasdale, G., Blaiklock, C. Br. Med. J. 1976, ii, 1371
SIR,-There is increasing evidence, recently summarised,lI that the sudden
unpredictable event responsible for initiating high proportion of myocardial infarcts is the fissuring of an atheromatous plaque in the supplying artery. The associated haemorrhage into the arterial wall induces aggregation of platelets as a thrombus, just as arterial haemorrhages elsewhere induce platelet aggregation as "hxmostatic plugs." Crucial questions are, therefore, how arterial haemorrhages cause platelet aggregation and how aggregation may be prevented or reversed in coronary arteries. An explanation recently proposed’·2 is that the process depends mainly on the activation of platelets by A.D.P. coming from the red blood-cells which are subjected to excessive haemodynamic stress at the a
site of haemorrhage. Some time ago I had the idea that drugs capable of counteracting hxmolysis3 might diminish this activating effect of red cells on platelets and so inhibit their aggregation as thrombi. Experimental evidence for this idea came with the demonstration4 that chlorpromazine added to anticoagulated human blood in concentrations which in vitro diminish hypotonic haemolysis, but have no direct effect on platelet aggregation,5 prolong the bleeding-time from small holes in artificial vessels where extravasation is terminated, as in vivo, by aggregated platelets. Experiments by A. Wehmeier and myself (unpublished) support the conclusion that this effect is accounted for by the antihxmolytic action of chlorpromazine. This has led to the suggestion’’’* that other drugs possessing this effect of chlorpromazine may diminish the incidence of arterial, particularly of coronary, thrombosis when it is induced by conditions of abnormal stress on the red cells, such as through haemorrhage into atheromatous lesions. Evidence for or against this proposition could perhaps be obtained by comparing the incidence of acute coronary occlusions in populations on long-term treatment with chlorpromazine (or other drugs acting in this respect like chlorpromazine) with the incidence in control populations not on such drugs. The only conceivably relevant evidence of which I have been made aware up to now (through the courtesy of Dr J. A. Baldwin, director of the Oxford University Unit of Clinical Epidemiology) is an investigation of mortality in Norwegian psychiatric hospitals during the period 1950 to 1962.6 This concluded that mortality from circulatory disease, predominantly "coronary disease" and "infarction", was higher in the mental-hospital population than in the general population, although the excess was not as much as that from most other causes. Within the patient population, the excess mortality from coronary disease and infarction was less for schizophrenics than for all other psychoses. Furthermore, the excess mortality from circulatory disease diminished strikingly after 1957, particularly when compared with the period 1926-41, because the mortality did not rise to the same extent in the hospital as in the general population. These conclusions, if confirmed, are of course open to different interpretations. Epidemiological considerations apart, chlorpromazine has many effects in the body, and also a large number of metabolites. Furthermore, the concentration of chlorpromazine in patients’ plasma is one to two orders of magnitude lower than that required to prolong the ex-vivo bleeding-time described above. Therefore, if patients’ blood were used for determining this bleeding-time, a prolongation 1
Born, G. V. R. Plenary lecture
to
the VIIIth World
Congress
of Cardiology,
Tokyo. Amsterdam (in the press). in Blood Cells and Vessel Walls: functional interactions (Ciba Fndn Symp. no. 71). Amsterdam (in the press). 3. Seeman, P Pharmac. Rev. 1972, 24, 583. 4. Born, G. V R. Bergquist, D., Arfors, K.-E. Nature. 1976, 259, 233. 5 Mills, D. C. B., Roberts, G. C. K. ibid. 1967, 213, 35 6. Odegard, O. Acta genet , Basel, 1967, 17, 137. 7. Mackay, A V. P , Healey, A. F., Baker, J. Br. J. clin. pharmac. 1974, 1, 425.
2.
if the drug or a similarly active metaconcentrated in red cell membranes. On the other hand, it has been observed8 that single clinical doses (5-20 mg)11 of chlorpromazine injected intramuscularly into apparently healthy volunteers caused the Ivy bleeding-time to be signifi-
might
be
bolite
were
expected only
cantly prolonged. Our experimental observations with chlorpromazine make It attractive to suggest that the general introduction of this drug for the control of schizophrenic inpatients from about 1955 onwards accounts for their relative protection against cardiac mortality at a time when it was increasing rapidly in Norway and elsewhere, including Britain. It would be interesting to learn of other information which may support or, just as important, invalidate this line of thought. It may be worthwhile to investigate appropriate populations from this point of view. Department of Pharmacology, King’s College, University of London, London WC2R 2LS
G. V. R. BORN
COMPUTERISED TOMOGRAPHY AND SUBDURAL HÆMATOMAS
S!R,—Mr Galbraith and Mr Teasdale (March 3, p. 504). out that acute and chronic subdural hasmadiffer in clinical features, surgical approach, and prognosis. They also state that in my letter of Jan. 13 (p. 110) I failed to make this distinction. However, that letter was concerned with acute as well as chronic subdural hsematomas. If only acute subdural hsematomas are considered, the possibility of false-negatives in c.T. scanning still remains. An acute subdural haematoma may present as an isodense lesion if the extravasated blood has low haemoglobin concentration’ or if it arises from rebleeding into a more chronic lesion.2 Recurrent bleeding and anxmia are common among chronic alcoholic patients, .3 a group particularly prone to subdural hxmorrhage That isodense lesions occur in acute cases is corroborated by the Glasgow workers’ own report of such lesions in four of their fifty patients with acute traumatic intracranial bleeding.’ The lesions were unilateral, and thus easily diagnosed by the concomitant ventricular distortion, but had they been bilateral they could have been missed altogether. Bilateral collections are not uncommon in cases of acute subdural haemorrhage. Furthermore, Galbraith et al. selected as controls cases of trauma with a negative c.T. scan and a diagnosis of "diffuse cerebral damage". That all the cases of subdural bleeding had been excluded from their control group can only be accepted by first accepting that false-negatives never occur on c.T. scan-
correctly point tomas
ning. The diagnostic reliability of c.T. scanning in cases of acute subdural hsematoma is high. The reports so far published, however, do not support Galbraith and Teasdale’s view that there are no false-negatives. Neurology Service, Medical Center,
Portland, Oregon 97201, U.S.A.
LUIS GARCIA-BUÑUEL
SHOULD THE LAX SET THE PACE?
SiR,—Iwas most interested in Professor Schou’s letter (March 31, p. 730) dealing with the problems of conference
proceedings and multiauthor books. I think that these are two separate problems-whilst it is clearly practical to ask contributors to congresses to deliver their papers by a set date or run the risk of their papers being excluded, this is hardly prac-
Born, G. V. R.
8.
Zahavi, J , Schwartz, G. Lancet, 1978, ii, 164.
1. New, P. F J., Aronow, S. Radiology, 1976, 121, 635. 2. French, B. N., Dublin, A. B. Surg Neurol. 1977, 7, 171. 3. Merrit, H. H. A Textbook of Neurology; p. 329. Philadelphia, 1973. 4. Galbraith, S., Teasdale, G., Blaiklock, C. Br. Med. J. 1976, ii, 1371
