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GAMMA-GLUTAMYL TRANSPEPTIDASE IN CHRONIC ALCOHOLISM
1139
heparinised saline for a maximum of two weeks. Increasing doses of noradrenaline (0-2-4 g. per kg.) were injected intracavally at three-minute intervals before the antidepressant was given and thirty minutes afterwards. When amitriptyline was injected into the inferior vena cava, 4 of 12 rabbits died within a few minutes. Death was preceded by an abrupt fall in blood-pressure and heart-rate, which began during the injection. Most other tricyclic antidepressants also reduced blood-pressure and heart-rate, but caused no deaths. Noradrenaline did not raise the blood-pressure in the rabbits which died. Different antidepressants were injected in random order at intervals of one to two days. When similar doses of the same drugs were injected into the marginal ear vein of the intact rabbit they stimulated respiration, dilated the pupils, and caused sedation and analgesia, but there were no deaths. We believe the deaths after amitriptyline were of cardiac origin, probably caused by too high concentrations of the drug entering the heart after intracaval injection. Since we were actually investigating the pressor responses to noradrenaline, it is possible that noradrenaline or the previous anaesthesia had affected the heart and modified the drug effects, but amitriptyline still proved more toxic than other antidepressants in these circumstances. Our observations support the view of Dr. Coull and his colleagues that amitriptyline may be more toxic than other antidepressants in patients liable to develop cardiac disturbances. Department of Pharmacology, M. J. MATTILA University of Helsinki, LAILA SAARNIVAARA. Helsinki, Finland.
out
STEROID ABNORMALITIES IN LUNG CANCER
SIR,-Dr. Rao (Aug. 29, p. 441) describes changes in the pattern of steroid excretion in men with lung cancer. They excreted more 17-hydroxycorticosteroid and less ll-deoxy-17-oxosteroid than sick and healthy controls. Such changes in steroid excretion are known also to be associated with psychological stress ", but in the absence of details about the psychological characteristics of these particular cancer patients this explanation for their pattern of steroid excretion must remain speculative. However, Katz et al.1 have demonstrated a similar relationship between urinary steroid excretion in women awaiting biopsy of breast lumps and the effectiveness of their psychological defence mechanisms in preventing " distress ". We have found that adrenocortical activity in medical students is related to their usual sleeping habits. Students selected as poor " sleepers on the basis of responses to a "
"
significantly more urinary free 11-OHc.s. than " good " sleepers throughout each day and night for the 3 days of the experiment.2 There were also significant psychological differences between the 2 groups. It is suggested that, as well as having a diurnal rhythm, sleep questionary
excreted
have a fairly characteristic range of adrenocortical activity from day to day reflecting the level of activation of we
central nervous system. Even mild increases in this level of activation as a result of psychological distress would usually be reflected both in disturbances to sleep and increased corticosteroid secretion, especially at night. It would be interesting to know whether there was any evidence for such sleep disturbances in Dr. Rao’s cancer patients assessed by a sleep questionary such as we have used.3 It is reasonable to suppose that many male our
"
"
smokers admitted to hospital for investigation of their chest complaint would suspect that they may have lung cancer. This suspicion, and the later confirmation of it, may be sufficient to explain their pattern of steroid excretion. The use of early-morning urine specimens for steroid assays in this experiment makes it imperative that we know how well the patients were sleeping. Sleep Laboratory, Department of Surgery, Monash University, Alfred Hospital, Prahrah, Victoria 3181, Australia.
1970, ii, 509.
JOHNS.
GAMMA-GLUTAMYL TRANSPEPTIDASE IN CHRONIC ALCOHOLISM view of the interest in the enzyme gammaSIR,-In glutamyl transpeptidase (G.G.T.P.), and the suggestion by Professor Ideo and Dr. Dioguardi (Nov. 14, p. 1036) that in liver disease the serum level of this enzyme is correlated with that of alkaline phosphatase and with cholestasis, we wish to draw attention to our work on serum-G.G.T.P. activity in chronic alcoholics and heavy drinkers.1 In a series of 50 patients, serum G.G.T.P. determination was a far more sensitive indicator of hepatic involvement than the aminotransferases or alkaline phosphatase. Increased G.G.T.P. values were observed in 37 (74%) of these patients, compared with raised serum-aspartateaminotransferase (G.O.T.) activity in 13 of 44 (29-5%) and increased alanine-aminotransferase activity (G.P.T.) in 9 of 44 (20-5%). Alkaline-phosphatase activity was increased in only 3 of 42 (7-1%) of these patients, and no correlation between
alkaline-phosphatase and G.G.T.P. levels was observed. No patient was jaundiced or had a bilirubin level above 3 mg. per 100 ml., and only 6 of 41 (14-6%) patients had levels above 1 mg. per 100 ml., the upper limit of normal for our method. In view of these findings we do not accept that in alcoholic hepatic involvement G.G.T.P. elevation is a result of cholestasis, or that in this condition G.G.T.P. and alkalinephosphatase levels are significantly correlated.
Pathology Department, St. Mary’s Hospital, London W.2.
S. B. ROSALKI D. RAU D. LEHMANN M. PRENTICE.
BETA-BLOCKING EFFECT OF PRACTOLOL AND PROPRANOLOL IN ASTHMATICS SIR,-I agree with Dr. Kerr and Dr. Patel (Oct. 10, p. 777) that practolol is a safer preparation in asthmatics than propranolol, as the experiments of my co-workers Dr. Bernecker and Dr. Roetscher suggest (Sept. 26, p. 662). However, I am not convinced that the decrease in lung function by intravenous propranolol cannot be reversed
by isoprenaline, as McNeillhas found. We 3,4 have always been able to reverse the bronchial obstruction caused by propranolol aerosol, but we sometimes had to use large amounts of isoprenaline. Thus, it looks as if propranolol aerosol does not block all bronchial beta-receptors, or not irreversibly. Perhaps appropriate doses of isoprenaline might unblock even intravenous propranolol. London N.3.
1.
Katz, J. L., Ackman, P., Rothwax, Y., Sachar, E. J. Weiner, Hellman, L., Gallagher, T. F. Psychosom. Med. 1970, 32, 1. 2. Johns, M. W., Gay, T. J. A., Masterton, J. P., Bruce, D. W. Unpublished. 3. Johns, M. W., Egan, P., Gay, T. J. A., Masterton, J. P. Br. med. J.
M. W.
1.
H. HERXHEIMER.
Rosalki, S. B., Rau, D., Lehmann, D., Prentice, M. Ann. clin. Biochem. (in the press). McNeill, R. S. Lancet, 1964, ii, 1102. Herxheimer, H., Langer, I. Klin. Wschr. 1967, 45, 1149.
2. 3. 4. Langer, I. J. Physiol., Lond. 1967, 190, 41P.
heparinised saline for a maximum of two weeks. Increasing doses of noradrenaline (0-2-4 g. per kg.) were injected intracavally at three-minute intervals before the antidepressant was given and thirty minutes afterwards. When amitriptyline was injected into the inferior vena cava, 4 of 12 rabbits died within a few minutes. Death was preceded by an abrupt fall in blood-pressure and heart-rate, which began during the injection. Most other tricyclic antidepressants also reduced blood-pressure and heart-rate, but caused no deaths. Noradrenaline did not raise the blood-pressure in the rabbits which died. Different antidepressants were injected in random order at intervals of one to two days. When similar doses of the same drugs were injected into the marginal ear vein of the intact rabbit they stimulated respiration, dilated the pupils, and caused sedation and analgesia, but there were no deaths. We believe the deaths after amitriptyline were of cardiac origin, probably caused by too high concentrations of the drug entering the heart after intracaval injection. Since we were actually investigating the pressor responses to noradrenaline, it is possible that noradrenaline or the previous anaesthesia had affected the heart and modified the drug effects, but amitriptyline still proved more toxic than other antidepressants in these circumstances. Our observations support the view of Dr. Coull and his colleagues that amitriptyline may be more toxic than other antidepressants in patients liable to develop cardiac disturbances. Department of Pharmacology, M. J. MATTILA University of Helsinki, LAILA SAARNIVAARA. Helsinki, Finland.
out
STEROID ABNORMALITIES IN LUNG CANCER
SIR,-Dr. Rao (Aug. 29, p. 441) describes changes in the pattern of steroid excretion in men with lung cancer. They excreted more 17-hydroxycorticosteroid and less ll-deoxy-17-oxosteroid than sick and healthy controls. Such changes in steroid excretion are known also to be associated with psychological stress ", but in the absence of details about the psychological characteristics of these particular cancer patients this explanation for their pattern of steroid excretion must remain speculative. However, Katz et al.1 have demonstrated a similar relationship between urinary steroid excretion in women awaiting biopsy of breast lumps and the effectiveness of their psychological defence mechanisms in preventing " distress ". We have found that adrenocortical activity in medical students is related to their usual sleeping habits. Students selected as poor " sleepers on the basis of responses to a "
"
significantly more urinary free 11-OHc.s. than " good " sleepers throughout each day and night for the 3 days of the experiment.2 There were also significant psychological differences between the 2 groups. It is suggested that, as well as having a diurnal rhythm, sleep questionary
excreted
have a fairly characteristic range of adrenocortical activity from day to day reflecting the level of activation of we
central nervous system. Even mild increases in this level of activation as a result of psychological distress would usually be reflected both in disturbances to sleep and increased corticosteroid secretion, especially at night. It would be interesting to know whether there was any evidence for such sleep disturbances in Dr. Rao’s cancer patients assessed by a sleep questionary such as we have used.3 It is reasonable to suppose that many male our
"
"
smokers admitted to hospital for investigation of their chest complaint would suspect that they may have lung cancer. This suspicion, and the later confirmation of it, may be sufficient to explain their pattern of steroid excretion. The use of early-morning urine specimens for steroid assays in this experiment makes it imperative that we know how well the patients were sleeping. Sleep Laboratory, Department of Surgery, Monash University, Alfred Hospital, Prahrah, Victoria 3181, Australia.
1970, ii, 509.
JOHNS.
GAMMA-GLUTAMYL TRANSPEPTIDASE IN CHRONIC ALCOHOLISM view of the interest in the enzyme gammaSIR,-In glutamyl transpeptidase (G.G.T.P.), and the suggestion by Professor Ideo and Dr. Dioguardi (Nov. 14, p. 1036) that in liver disease the serum level of this enzyme is correlated with that of alkaline phosphatase and with cholestasis, we wish to draw attention to our work on serum-G.G.T.P. activity in chronic alcoholics and heavy drinkers.1 In a series of 50 patients, serum G.G.T.P. determination was a far more sensitive indicator of hepatic involvement than the aminotransferases or alkaline phosphatase. Increased G.G.T.P. values were observed in 37 (74%) of these patients, compared with raised serum-aspartateaminotransferase (G.O.T.) activity in 13 of 44 (29-5%) and increased alanine-aminotransferase activity (G.P.T.) in 9 of 44 (20-5%). Alkaline-phosphatase activity was increased in only 3 of 42 (7-1%) of these patients, and no correlation between
alkaline-phosphatase and G.G.T.P. levels was observed. No patient was jaundiced or had a bilirubin level above 3 mg. per 100 ml., and only 6 of 41 (14-6%) patients had levels above 1 mg. per 100 ml., the upper limit of normal for our method. In view of these findings we do not accept that in alcoholic hepatic involvement G.G.T.P. elevation is a result of cholestasis, or that in this condition G.G.T.P. and alkalinephosphatase levels are significantly correlated.
Pathology Department, St. Mary’s Hospital, London W.2.
S. B. ROSALKI D. RAU D. LEHMANN M. PRENTICE.
BETA-BLOCKING EFFECT OF PRACTOLOL AND PROPRANOLOL IN ASTHMATICS SIR,-I agree with Dr. Kerr and Dr. Patel (Oct. 10, p. 777) that practolol is a safer preparation in asthmatics than propranolol, as the experiments of my co-workers Dr. Bernecker and Dr. Roetscher suggest (Sept. 26, p. 662). However, I am not convinced that the decrease in lung function by intravenous propranolol cannot be reversed
by isoprenaline, as McNeillhas found. We 3,4 have always been able to reverse the bronchial obstruction caused by propranolol aerosol, but we sometimes had to use large amounts of isoprenaline. Thus, it looks as if propranolol aerosol does not block all bronchial beta-receptors, or not irreversibly. Perhaps appropriate doses of isoprenaline might unblock even intravenous propranolol. London N.3.
1.
Katz, J. L., Ackman, P., Rothwax, Y., Sachar, E. J. Weiner, Hellman, L., Gallagher, T. F. Psychosom. Med. 1970, 32, 1. 2. Johns, M. W., Gay, T. J. A., Masterton, J. P., Bruce, D. W. Unpublished. 3. Johns, M. W., Egan, P., Gay, T. J. A., Masterton, J. P. Br. med. J.
M. W.
1.
H. HERXHEIMER.
Rosalki, S. B., Rau, D., Lehmann, D., Prentice, M. Ann. clin. Biochem. (in the press). McNeill, R. S. Lancet, 1964, ii, 1102. Herxheimer, H., Langer, I. Klin. Wschr. 1967, 45, 1149.
2. 3. 4. Langer, I. J. Physiol., Lond. 1967, 190, 41P.