- Email: [email protected]
NUMBERS FOR A CONTROLLED CLINICAL TRIAL
1465 dition and the blood-picture. Corticoid therapy and high doses of androgens were also without effect. The patient died a few months later after being discharged. CASE 2.-This was a seventeen-year-old boy with idiopathic aplastic anaemia whose cytogenetic study revealed trisomy-21 and partial endoreduplication.29 Repeated whole-blood trans-
fusions, prednisolone, and androgens produced only transient improvement. P.H.A. was tried, and twenty-one intravenous injections were given in four series. No clinical or haematoamelioration followed this treatment, after which high doses of androgens, combined with corticosteroids, were started, and continued for about five months. After this treatment the patient improved considerably and is now in good condition. His haematological data are as follows: red blood-cells 4,140,000 per c.mm., hxmoglobin 11-5 g. per 100 ml., hxmatocrit 41%, white blood-cells 6800 per c.mm.,
logical
platelets 125,000
per
c.mm.
CASE 3.-This was a forty-six-year-old man with normochromic anxmia refractory to treatment. His platelet count was normal. White-blood-cell count ranged between 8000 and 15,000 per c.mm. with a differential count of 54% neutrophils, 36% lymphocytes, 6% monocytes, 3%band forms, and 1% eosinophils. The bone-marrow was hypocellular with a normal differential count. Serum-iron values were high. The lifespan of erythrocytes measured with chromium-51 was normal. There were no biochemical and hxmatological findings indicating the presence of abnormal haemoglobins or thalassaemia. The diagnosis was possibly acquired pure red-cell anaemia. The patient was kept alive only by the aid of repeated wholeblood transfusions. Long continued treatment with high doses of corticosteroids and androgens produced no appreciable effect on the clinical state and
blood-picture. was given eighteen intravenous injections in
P.H.A.
as
three series
at
ir-
regular intervals. No beneficial effects were observed during the next three months, Bone-marrow showing atypical lymphoafter the which cytes and orthochromatic normoblasts white-blood-cell in case 3. count rose from 8200 to 40,000 per c.mm., 77% of which were lymphocytes, most resembling monocytes as seen in infectious mononucleosis. The same lymphocytic infiltration was seen on sternal bonemarrow puncture which showed: 10’0 myeloblasts, 2% promyelocytes, 4% metamyelocytes, 12% band forms, 1 % plasmocytes, 68% atypical lymphocytes, and 7% polychromatic and 5% orthochromatic normoblasts (see accompanying figure). Paul-Bunnell reaction at this time was negative. The lymphocytic proliferation persisted for about six months, after which the white-blood-cell count gradually decreased to 17,000 per c.mm. with 92% atypical lymphocytes. Simultaneously with the lymphocytic proliferation, the hxmatological picture began to improve: red blood-cells 3,840,000 per c.mm., haemoglobin 9%1 g. per 100 ml., hxmatocrit 38%, platelets 284,000 per c.mm., and reticulocytes 2%. The patient, who received whole-blood transfusions every two months, is now in good health, and has been given no transfusions for the past ten months. P.H.A. was without effect in our first case. In our second case, with combined therapy with P.H.A., androgens, and corticosteroids, a possible late effect can be considered. In our third case there was a striking lymphocytic reaction three months after P.H.A. was given, followed by an amelioration of both the clinical condition and the blood-picture. This is in 29.
Erdogan, G., Aksoy, M., Dinçol, K.
Acta hœmat.
(in the press).
accordance with Humble’s suggestion that P.H.A.-treated lymphocytes transform into heemocytoblasts and other primi-
tive bone-marrow cells. Capa Internal Clinic of Istanbul Medical School, Vakif Guraba Hospital, Istanbul, Turkey.
MUZAFFER AKSOY
ŞAKIR KORAY
ERDEM
DINÇOL.
NUMBERS FOR A CONTROLLED CLINICAL TRIAL the method described by Mr. Clark and SIR,-Underlying Dr. Downie (Dec. 17, p. 1357) is the rarely fulfilled assumption that diagnostic groups are homogeneous. Their method leaves no scope for the possibility that, following the main assessment, within-group comparisons will often yield useful information. For example: a trial is conducted comparing the effect of a placebo and a new phenothiazine drug in minor depressive illnesses; the result demonstrates a significant advantage for the drug. The question at once arises as to whether this is a specific psychotropic effect directed at the symptom of depression, or whether the apparent benefit is due to the sedative side-effect calming those patients whose illness has a strong anxiety component. If there has been a generous intake to the trial the question may be answered there and then. If not, a completely new investigation has to be mounted. With so many imponderables, does it really pay to be overscientific ? I suggest that as good a rule as any is " double the number you first thought of ". A. M. W. PORTER.
PROPRANOLOL IN MYOCARDIAL INFARCTION SiR,-The clinical investigations of Dr. Balcon and his colleagues (Oct. 29, p. 917), Dr. Clausen and his colleagues (Oct. 29, p. 920), and some of the writers of the ensuing correspondence seem to us to have been well designed and to focus on the complex problem of arrythmias in myocardial infarction. The suggestion by Dr. Pentecost (Nov. 12, p. 1078) that lack of absorption might have been responsible for the ineffectiveness of propranolol needs further comment. For one thing, the presence of sinus bradycardia in a significant number of patients in Dr. Balcon and his colleagues’ series should be construed as evidence of satisfactory absorption of propranolol. Moreover, the results of the studies of experimental myocardial infarction in the dog in our laboratoryare in general agreement with these clinical findings. These studies involved acute ligation of the anterior descending coronary artery in 40 dogs divided into two comparable control and experimental groups. Intravenous infusion of propranolol calculated to achieve complete p-adrenergic blockade did not result in statistically significant decrease either in the incidence of ventricular beats or in mortality. Another point that emerges from these clinical investigations is the absence of any significant decrease in the recurrence of pain among treated patients. This is striking when contrasted with the reported effectiveness of propranolol in decreasing the incidence of pain in chronic angina pectoris.2 One possible explanation for this unexpected finding is the local release of noradrenaline in myocardial infarction.3 It is known that p-adrenergic blockade increases the pressor effect of noradrenaline, 4 especially in the heart,e leading to coronary vasoconstriction and ischasmia. This effect of propranolol on coronary vasoconstriction would be variable, depending on the local and general state of adrenergic stimulation. Thus it could
ectopic
Proger, S., Sharma, A., Naimi, S. in Proceedings of the 5th World Congress of Cardiology (in the press). 2. Wolfson, S., Heinle, R. A., Herman, M. V., Kemp, H. G., Sullivan, J. M., Gorlin, R. Am. J. Cardiol. 1966, 18, 345. 3. Harris, A. S., Bisteni, A. Am. J. Physiol. 1955, 181, 559. 4. Glover, W. E., Hutchinson, K. J. J. Physiol., Lond. 1965, 177, 59p. 5. Gaal, P. G., Kattus, A. A., Ross, G. Br. J. Pharmac. Chemother. 1966, 26, 713. 1.
fusions, prednisolone, and androgens produced only transient improvement. P.H.A. was tried, and twenty-one intravenous injections were given in four series. No clinical or haematoamelioration followed this treatment, after which high doses of androgens, combined with corticosteroids, were started, and continued for about five months. After this treatment the patient improved considerably and is now in good condition. His haematological data are as follows: red blood-cells 4,140,000 per c.mm., hxmoglobin 11-5 g. per 100 ml., hxmatocrit 41%, white blood-cells 6800 per c.mm.,
logical
platelets 125,000
per
c.mm.
CASE 3.-This was a forty-six-year-old man with normochromic anxmia refractory to treatment. His platelet count was normal. White-blood-cell count ranged between 8000 and 15,000 per c.mm. with a differential count of 54% neutrophils, 36% lymphocytes, 6% monocytes, 3%band forms, and 1% eosinophils. The bone-marrow was hypocellular with a normal differential count. Serum-iron values were high. The lifespan of erythrocytes measured with chromium-51 was normal. There were no biochemical and hxmatological findings indicating the presence of abnormal haemoglobins or thalassaemia. The diagnosis was possibly acquired pure red-cell anaemia. The patient was kept alive only by the aid of repeated wholeblood transfusions. Long continued treatment with high doses of corticosteroids and androgens produced no appreciable effect on the clinical state and
blood-picture. was given eighteen intravenous injections in
P.H.A.
as
three series
at
ir-
regular intervals. No beneficial effects were observed during the next three months, Bone-marrow showing atypical lymphoafter the which cytes and orthochromatic normoblasts white-blood-cell in case 3. count rose from 8200 to 40,000 per c.mm., 77% of which were lymphocytes, most resembling monocytes as seen in infectious mononucleosis. The same lymphocytic infiltration was seen on sternal bonemarrow puncture which showed: 10’0 myeloblasts, 2% promyelocytes, 4% metamyelocytes, 12% band forms, 1 % plasmocytes, 68% atypical lymphocytes, and 7% polychromatic and 5% orthochromatic normoblasts (see accompanying figure). Paul-Bunnell reaction at this time was negative. The lymphocytic proliferation persisted for about six months, after which the white-blood-cell count gradually decreased to 17,000 per c.mm. with 92% atypical lymphocytes. Simultaneously with the lymphocytic proliferation, the hxmatological picture began to improve: red blood-cells 3,840,000 per c.mm., haemoglobin 9%1 g. per 100 ml., hxmatocrit 38%, platelets 284,000 per c.mm., and reticulocytes 2%. The patient, who received whole-blood transfusions every two months, is now in good health, and has been given no transfusions for the past ten months. P.H.A. was without effect in our first case. In our second case, with combined therapy with P.H.A., androgens, and corticosteroids, a possible late effect can be considered. In our third case there was a striking lymphocytic reaction three months after P.H.A. was given, followed by an amelioration of both the clinical condition and the blood-picture. This is in 29.
Erdogan, G., Aksoy, M., Dinçol, K.
Acta hœmat.
(in the press).
accordance with Humble’s suggestion that P.H.A.-treated lymphocytes transform into heemocytoblasts and other primi-
tive bone-marrow cells. Capa Internal Clinic of Istanbul Medical School, Vakif Guraba Hospital, Istanbul, Turkey.
MUZAFFER AKSOY
ŞAKIR KORAY
ERDEM
DINÇOL.
NUMBERS FOR A CONTROLLED CLINICAL TRIAL the method described by Mr. Clark and SIR,-Underlying Dr. Downie (Dec. 17, p. 1357) is the rarely fulfilled assumption that diagnostic groups are homogeneous. Their method leaves no scope for the possibility that, following the main assessment, within-group comparisons will often yield useful information. For example: a trial is conducted comparing the effect of a placebo and a new phenothiazine drug in minor depressive illnesses; the result demonstrates a significant advantage for the drug. The question at once arises as to whether this is a specific psychotropic effect directed at the symptom of depression, or whether the apparent benefit is due to the sedative side-effect calming those patients whose illness has a strong anxiety component. If there has been a generous intake to the trial the question may be answered there and then. If not, a completely new investigation has to be mounted. With so many imponderables, does it really pay to be overscientific ? I suggest that as good a rule as any is " double the number you first thought of ". A. M. W. PORTER.
PROPRANOLOL IN MYOCARDIAL INFARCTION SiR,-The clinical investigations of Dr. Balcon and his colleagues (Oct. 29, p. 917), Dr. Clausen and his colleagues (Oct. 29, p. 920), and some of the writers of the ensuing correspondence seem to us to have been well designed and to focus on the complex problem of arrythmias in myocardial infarction. The suggestion by Dr. Pentecost (Nov. 12, p. 1078) that lack of absorption might have been responsible for the ineffectiveness of propranolol needs further comment. For one thing, the presence of sinus bradycardia in a significant number of patients in Dr. Balcon and his colleagues’ series should be construed as evidence of satisfactory absorption of propranolol. Moreover, the results of the studies of experimental myocardial infarction in the dog in our laboratoryare in general agreement with these clinical findings. These studies involved acute ligation of the anterior descending coronary artery in 40 dogs divided into two comparable control and experimental groups. Intravenous infusion of propranolol calculated to achieve complete p-adrenergic blockade did not result in statistically significant decrease either in the incidence of ventricular beats or in mortality. Another point that emerges from these clinical investigations is the absence of any significant decrease in the recurrence of pain among treated patients. This is striking when contrasted with the reported effectiveness of propranolol in decreasing the incidence of pain in chronic angina pectoris.2 One possible explanation for this unexpected finding is the local release of noradrenaline in myocardial infarction.3 It is known that p-adrenergic blockade increases the pressor effect of noradrenaline, 4 especially in the heart,e leading to coronary vasoconstriction and ischasmia. This effect of propranolol on coronary vasoconstriction would be variable, depending on the local and general state of adrenergic stimulation. Thus it could
ectopic
Proger, S., Sharma, A., Naimi, S. in Proceedings of the 5th World Congress of Cardiology (in the press). 2. Wolfson, S., Heinle, R. A., Herman, M. V., Kemp, H. G., Sullivan, J. M., Gorlin, R. Am. J. Cardiol. 1966, 18, 345. 3. Harris, A. S., Bisteni, A. Am. J. Physiol. 1955, 181, 559. 4. Glover, W. E., Hutchinson, K. J. J. Physiol., Lond. 1965, 177, 59p. 5. Gaal, P. G., Kattus, A. A., Ross, G. Br. J. Pharmac. Chemother. 1966, 26, 713. 1.