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CHLORPROMAZINE REVERSAL OF THE ANTIHYPERTENSIVE ACTION OF GUANETHIDINE
436 EFFICACY OF VARIOUS DISCRIMINANT FUNCTIONS IN SEPARATING PATIENTS WITH CIRRHOSIS FROM
*
Cirrhotic patients in
are
question. They
those from the C.S.L. study.’ Controls comprise patients without liver disease admitted to one of the collaborating departments during the C.S.L. study.
other disease known
to
influence the test
were
of the analysis are certainly not fulfilled. Since some multivariate statistical methods require weighty assumptions, it should be emphasised that they may occasionally fail to bring about optimal solutions of differential diagnostic
problems. Klinisk datalogisk afdeling, Medicinsk afdeling B, Rigshospitalet,
PER WINKEL.
Medicinsk afdeling B,
Bispebjerg Hospital, Copenhagen.
or
CONTROLS*
ERIK
JUHL.
CHLORPROMAZINE REVERSAL OF THE ANTIHYPERTENSIVE ACTION OF GUANETHIDINE SiR,-Tricyclic antidepressants inhibit the neuronal
uptake of a wide variety of ring-substituted bases, including guanethidine.6 Because of this inhibition, access of guanethidine to its site of action is blocked, and consequently it fails to exert its hypotensive effects. Chlorpromazine also inhibits amine uptake in a manner similar to tricyclic drugs.7 Our preliminary finding indicates that chlorpromazine does antagonise the hypotensive effects of guanethidine. It is obviously important to learn of drug antagonism in the controlled experimental situation
Discontinuance of the 1041-4 mm. Hg (P< 0.0006). chlorpromazine resulted in a further rise of the pressure to 115 ±1.8 mm. Hg (p < 0-000002). The pressure remained raised for 12 days, followed by a gradual reduction to 95 ±2 mm. Hg (p < 0-000001). In all three instances, after a lag period, chlorpromazine blocked the hypotensive action of guanethidine, causing the standing diastolic pressure to rise significantly. Furthermore, there was a secondary rise after discontinuance of chlorpromazine, which was clinically and statistically significant in the second patient. The probable mechanism of action for this phenomenon is that chlorpromazine blocks the uptake of guanethidine into the neuron, where guanethidine exerts its hypotensive action. Since guanethidine is commonly used in the treatment of hypertension in middle-aged and elderly mental-hospital patients and these patients are often concurrently receiving chlorpromazine, this drug interaction is likely to occur. The antagonism seen in this study was impressive: both
rather than from clinical misfortunes. Two severely hypertensive patients were admitted to the research ward. The standing diastolic pressure over a period of days under each drug regimen was averaged to give a mean standing diastolic blood-pressure +s.E.M. After the blood-pressure was lowered with guanethidine, a control period was obtained with the patient on an effective dose of guanethidine (80 mg. daily). In the first patient (see figure), upon the addition of chlorpromazine (200-300 mg. daily) to this regimen, the standing diastolic pressure rose from 94±3-1 mm. Hg to 112:4-6 mm. Hg (p < 0-002). Following discontinuance of the chlorpromazine the pressure rose to 116±3.3 mm. Hg before falling to When chlorpromazine 103±3.6 mm. Hg (P< 0.005). (300 mg. daily) was added to guanethidine therapy, the second patient’s diastolic pressure rose from 105±2.5 mm. Hg to 127+-1-9 mm. Hg (P< 0°000001). When chlorpromazine was discontinued the diastolic pressure rose further to 150±3.4 mm. Hg (p < 0-000001). After the dose of guanethidine was increased from 80 mg. daily to 150 mg. daily and the pressure was decreased to 95=2°5 mm. Hg, chlorpromazine (400 mg. daily) was again added to this regimen, resulting in a rise in the diastolic pressure to 5.
Copenhagen Study Group for Liver Diseases. Lancet, 1969, i,
6.
Mitchell, J. R., Cavanaugh, J. H., Arias, L., Oates, J. A. J. clin. Invest. 1970, 49, 1596. Iversen, L. L. Adv. Drug Res. 1965, 2, 5.
119.
7.
Antagonism by chlorpromazine of the hypotensive properties of guanethidine.
Each point represents a mean±S.E.M. over a period of days. GE=guanethidine mg./day; cpz=chlorpromazine mg./day.
437 CHANGES IN ZUNG’S S.D.S. WITH AMANTADINE AND PLACEBO IN CHRONIC DEPRESSION
rose to pretreatment levels. The observation of an apparent antagonism in two patients neither proves beyond a reasonable doubt that it occurs generally, nor that it occurs by the mechanism postulated here. These observations, plus the information that chlorpromazine is an uptake-pump inhibitor and that, clinically, uptake-pump inhibitors do markedly antagonise guanethidine, make the phenomena worthy of further investigation. Until more data are available, the observations would warrant careful blood-pressure monitoring if chlorpromazine and guanethidine are used together.
patients’ blood-pressures
to acknowledge the help of Dr. Hans Vorbusch and nursing staff. This investigation was supported in part by
We wish our
grants HE 05545, GM 23168, GM 15431, HE 10842, RR0009510.
WILLIAM E. FANN* Vanderbilt University Medical School, DAVID S. JANOWSKY Department of Medicine, DAVIS M. JOHN and Pharmacology Psychiatry, JOHN A. OATES. Nashville, Tennessee, U.S.A.
I
I
* Median ==53 points;;.:’ distribution= 5.6;
d.f.=l; p<0.05.
20% of the patients after several (mean, 10 days). Changes in Zung’s days’ S.D.S. were taken as the main criteria for evaluating the results of the drug’s actions. No significant differences
lessness
were
apparent in
treatment
found in groups A and B, so these groups were combined for purposes of comparison with the control group C. 14 out of 18 patients in group AB showed a response for the better, whereas in group C, 6 out of 16 improved. The difference is statistically significant (X2= The median test, using the 10.3, d.f.=l, p< 0.001). central tendencies of the medians from Zung’s S.D.S., shows significant differences between group AB and group C beyond the 0-05 level of probability (see table). Comparing the mean scores of improvement in Zung’s S.D.S. with other antidepressants,9 amantadine seems to be less effective than amitriptyline. We believe that our findings need further evaluation, but we wish to stress
were
AMANTADINE IN DEPRESSION SIR,—Amantadine is reported to be an effective antiviral 1 and antiparkinsonian2 drug. Two of us have also described its usefulness in the tardive-dyskinesia syndrome.3 The toxic effects of the drug when used in appropriate doses are negligible.4,5 In the central nervous system, amantadine is believed to be a dopamine releaser, though it may possibly release other catecholamines from neuronal storage sites.6 Such properties could be of interest in the treatment of the depressive syndromes, in view of current theories about biogenic-amine disturbances in the affective disorders.’ We report here a controlled trial of amantadine in depression. 40 patients were selected for the trial. The major criterion for acceptance was the clinical diagnosis by two independent examiners of " chronic depressive syndrome " and a rating over 53 or more points in Zung’s self-rating depression scale (s.D.S.).B There were 32 women and 8 men, mean age 34; all were ambulant and attended weekly for assessment. The drugs they had been taking were continued unchanged and each patient received at random one of the following three treatments:
points: (a) amantadine, like some other dopaminergic drugs," has antidepressant properties; and (b) though amantadine is known to be beneficial in extrapyramidal disease, some of the patients’ subjective improvement may be due to the antidepressant effects of the drug.
two
Departamento de Psiquiatria, Facultad de Medicina, Universidad Nacional Autónoma de Mexico, Mexico City, Mexico.
Group A-10 patients were given amantadine 100 mg. daily for the lst and 2nd weeks and 200 mg. daily for the 3rd and 4th
VIRUSES IN BRAIN CELLS
weeks.
Group B-10 patients had amantadine 200 mg. daily for the 1st and 2nd weeks and 100 mg. daily for the 3rd and 4th weeks. Group C-20 patients were given an inactive preparation for the four weeks, the number of pills being increased and decreased as in groups A and B. One of us supplied the drug and gave instructions to the patient, while the two other examiners were unaware of the type of treatment being given. 34 patients completed the trial, 18 from groups A and B and 16 from group C. Side-effects were minimal and never made it necessary to suspend treatment. Anxiety and rest*
Present address: Department of Psychiatry, Duke University Medical School, Durham, North Carolina 27706. 1.
Wingfield, W. L., Pollack, D., Grunert, R. R. New Engl. J. Med. 1969, 281, 579. 2. Schwab, R. S., England, A. C., Poskanzer, D. C., Young, R. R. J. Am. med. Ass. 1969, 208, 1168. 3. Vale, S., Espejel, M. A. New Engl. J. Med. 1971, 284, 673. 4. Welten, J. B. V. Ned. Tijdschr. Geront. 1970, 1, 23. 5. J. Am. med. Ass. 1969, 208, 1180. 6. Grelak, R. P., Clark, R., Stump, J. M., Vernier, V. G. Science, 1970, 169, 203. 7. Schildkraut, J. J., Kety, S. S. ibid. 1967, 156, 21. 8. Zung, W. W. K., Richards, C. B., Short, M. J. Archs gen. Psychiat. 1965, 13, 508.
SALVADOR VALE M. ANGELES ESPEJEL J. CESAR DOMINGUEZ.
SIR,—Dr. Webb
and his colleagues (July 3, p. 4) point that measles virus infecting brain cells in culture apparently altered the growth pattern of these cells. This was evident from loss of contact inhibition. Their observation parallels one reported by us 11 in brain-cell cultures from patients with subacute sclerosing panencephalitis (S.S.P.E.). These cells, which were persistently infected with S.S.P.E. virus but which did not yield infectious virus directly, also showed changes in their growth pattern, characterised by proliferative activity and loss of contact inhibition. Moreover, their karyotypes became aneuploid. The second point made by Dr. Webb and his colleagues, that electroencephalographic (E.E.G.) abnormalities may signal presence of virus in the brain, also parallels our observations in animal experiments with S.S.P.E. viruses and rabies virus. Ferrets injected with brain homogenates of S.S.P.E. patients, or with tissue-culture cells infected with S.S.P.E. viruses, developed encephalitis but exhibited few or no clinical symptoms. However, their E.E.G. patterns
out
L. E., Overall, J. E., Shelton, J., Pennington, V., Kimbell, I., Johnson, M. ibid. 1967, 17, 486. 10. O’Brien, C. P., DiGiacomo, J. N., Fahn, S., Schwarz, G. A. ibid. 1971, 24, 61. 11. Katz, M., Koprowski, H., Moorhead, P. Expl Cell Res. 1969, 57, 148. 9.
Hollister,
*
Cirrhotic patients in
are
question. They
those from the C.S.L. study.’ Controls comprise patients without liver disease admitted to one of the collaborating departments during the C.S.L. study.
other disease known
to
influence the test
were
of the analysis are certainly not fulfilled. Since some multivariate statistical methods require weighty assumptions, it should be emphasised that they may occasionally fail to bring about optimal solutions of differential diagnostic
problems. Klinisk datalogisk afdeling, Medicinsk afdeling B, Rigshospitalet,
PER WINKEL.
Medicinsk afdeling B,
Bispebjerg Hospital, Copenhagen.
or
CONTROLS*
ERIK
JUHL.
CHLORPROMAZINE REVERSAL OF THE ANTIHYPERTENSIVE ACTION OF GUANETHIDINE SiR,-Tricyclic antidepressants inhibit the neuronal
uptake of a wide variety of ring-substituted bases, including guanethidine.6 Because of this inhibition, access of guanethidine to its site of action is blocked, and consequently it fails to exert its hypotensive effects. Chlorpromazine also inhibits amine uptake in a manner similar to tricyclic drugs.7 Our preliminary finding indicates that chlorpromazine does antagonise the hypotensive effects of guanethidine. It is obviously important to learn of drug antagonism in the controlled experimental situation
Discontinuance of the 1041-4 mm. Hg (P< 0.0006). chlorpromazine resulted in a further rise of the pressure to 115 ±1.8 mm. Hg (p < 0-000002). The pressure remained raised for 12 days, followed by a gradual reduction to 95 ±2 mm. Hg (p < 0-000001). In all three instances, after a lag period, chlorpromazine blocked the hypotensive action of guanethidine, causing the standing diastolic pressure to rise significantly. Furthermore, there was a secondary rise after discontinuance of chlorpromazine, which was clinically and statistically significant in the second patient. The probable mechanism of action for this phenomenon is that chlorpromazine blocks the uptake of guanethidine into the neuron, where guanethidine exerts its hypotensive action. Since guanethidine is commonly used in the treatment of hypertension in middle-aged and elderly mental-hospital patients and these patients are often concurrently receiving chlorpromazine, this drug interaction is likely to occur. The antagonism seen in this study was impressive: both
rather than from clinical misfortunes. Two severely hypertensive patients were admitted to the research ward. The standing diastolic pressure over a period of days under each drug regimen was averaged to give a mean standing diastolic blood-pressure +s.E.M. After the blood-pressure was lowered with guanethidine, a control period was obtained with the patient on an effective dose of guanethidine (80 mg. daily). In the first patient (see figure), upon the addition of chlorpromazine (200-300 mg. daily) to this regimen, the standing diastolic pressure rose from 94±3-1 mm. Hg to 112:4-6 mm. Hg (p < 0-002). Following discontinuance of the chlorpromazine the pressure rose to 116±3.3 mm. Hg before falling to When chlorpromazine 103±3.6 mm. Hg (P< 0.005). (300 mg. daily) was added to guanethidine therapy, the second patient’s diastolic pressure rose from 105±2.5 mm. Hg to 127+-1-9 mm. Hg (P< 0°000001). When chlorpromazine was discontinued the diastolic pressure rose further to 150±3.4 mm. Hg (p < 0-000001). After the dose of guanethidine was increased from 80 mg. daily to 150 mg. daily and the pressure was decreased to 95=2°5 mm. Hg, chlorpromazine (400 mg. daily) was again added to this regimen, resulting in a rise in the diastolic pressure to 5.
Copenhagen Study Group for Liver Diseases. Lancet, 1969, i,
6.
Mitchell, J. R., Cavanaugh, J. H., Arias, L., Oates, J. A. J. clin. Invest. 1970, 49, 1596. Iversen, L. L. Adv. Drug Res. 1965, 2, 5.
119.
7.
Antagonism by chlorpromazine of the hypotensive properties of guanethidine.
Each point represents a mean±S.E.M. over a period of days. GE=guanethidine mg./day; cpz=chlorpromazine mg./day.
437 CHANGES IN ZUNG’S S.D.S. WITH AMANTADINE AND PLACEBO IN CHRONIC DEPRESSION
rose to pretreatment levels. The observation of an apparent antagonism in two patients neither proves beyond a reasonable doubt that it occurs generally, nor that it occurs by the mechanism postulated here. These observations, plus the information that chlorpromazine is an uptake-pump inhibitor and that, clinically, uptake-pump inhibitors do markedly antagonise guanethidine, make the phenomena worthy of further investigation. Until more data are available, the observations would warrant careful blood-pressure monitoring if chlorpromazine and guanethidine are used together.
patients’ blood-pressures
to acknowledge the help of Dr. Hans Vorbusch and nursing staff. This investigation was supported in part by
We wish our
grants HE 05545, GM 23168, GM 15431, HE 10842, RR0009510.
WILLIAM E. FANN* Vanderbilt University Medical School, DAVID S. JANOWSKY Department of Medicine, DAVIS M. JOHN and Pharmacology Psychiatry, JOHN A. OATES. Nashville, Tennessee, U.S.A.
I
I
* Median ==53 points;;.:’ distribution= 5.6;
d.f.=l; p<0.05.
20% of the patients after several (mean, 10 days). Changes in Zung’s days’ S.D.S. were taken as the main criteria for evaluating the results of the drug’s actions. No significant differences
lessness
were
apparent in
treatment
found in groups A and B, so these groups were combined for purposes of comparison with the control group C. 14 out of 18 patients in group AB showed a response for the better, whereas in group C, 6 out of 16 improved. The difference is statistically significant (X2= The median test, using the 10.3, d.f.=l, p< 0.001). central tendencies of the medians from Zung’s S.D.S., shows significant differences between group AB and group C beyond the 0-05 level of probability (see table). Comparing the mean scores of improvement in Zung’s S.D.S. with other antidepressants,9 amantadine seems to be less effective than amitriptyline. We believe that our findings need further evaluation, but we wish to stress
were
AMANTADINE IN DEPRESSION SIR,—Amantadine is reported to be an effective antiviral 1 and antiparkinsonian2 drug. Two of us have also described its usefulness in the tardive-dyskinesia syndrome.3 The toxic effects of the drug when used in appropriate doses are negligible.4,5 In the central nervous system, amantadine is believed to be a dopamine releaser, though it may possibly release other catecholamines from neuronal storage sites.6 Such properties could be of interest in the treatment of the depressive syndromes, in view of current theories about biogenic-amine disturbances in the affective disorders.’ We report here a controlled trial of amantadine in depression. 40 patients were selected for the trial. The major criterion for acceptance was the clinical diagnosis by two independent examiners of " chronic depressive syndrome " and a rating over 53 or more points in Zung’s self-rating depression scale (s.D.S.).B There were 32 women and 8 men, mean age 34; all were ambulant and attended weekly for assessment. The drugs they had been taking were continued unchanged and each patient received at random one of the following three treatments:
points: (a) amantadine, like some other dopaminergic drugs," has antidepressant properties; and (b) though amantadine is known to be beneficial in extrapyramidal disease, some of the patients’ subjective improvement may be due to the antidepressant effects of the drug.
two
Departamento de Psiquiatria, Facultad de Medicina, Universidad Nacional Autónoma de Mexico, Mexico City, Mexico.
Group A-10 patients were given amantadine 100 mg. daily for the lst and 2nd weeks and 200 mg. daily for the 3rd and 4th
VIRUSES IN BRAIN CELLS
weeks.
Group B-10 patients had amantadine 200 mg. daily for the 1st and 2nd weeks and 100 mg. daily for the 3rd and 4th weeks. Group C-20 patients were given an inactive preparation for the four weeks, the number of pills being increased and decreased as in groups A and B. One of us supplied the drug and gave instructions to the patient, while the two other examiners were unaware of the type of treatment being given. 34 patients completed the trial, 18 from groups A and B and 16 from group C. Side-effects were minimal and never made it necessary to suspend treatment. Anxiety and rest*
Present address: Department of Psychiatry, Duke University Medical School, Durham, North Carolina 27706. 1.
Wingfield, W. L., Pollack, D., Grunert, R. R. New Engl. J. Med. 1969, 281, 579. 2. Schwab, R. S., England, A. C., Poskanzer, D. C., Young, R. R. J. Am. med. Ass. 1969, 208, 1168. 3. Vale, S., Espejel, M. A. New Engl. J. Med. 1971, 284, 673. 4. Welten, J. B. V. Ned. Tijdschr. Geront. 1970, 1, 23. 5. J. Am. med. Ass. 1969, 208, 1180. 6. Grelak, R. P., Clark, R., Stump, J. M., Vernier, V. G. Science, 1970, 169, 203. 7. Schildkraut, J. J., Kety, S. S. ibid. 1967, 156, 21. 8. Zung, W. W. K., Richards, C. B., Short, M. J. Archs gen. Psychiat. 1965, 13, 508.
SALVADOR VALE M. ANGELES ESPEJEL J. CESAR DOMINGUEZ.
SIR,—Dr. Webb
and his colleagues (July 3, p. 4) point that measles virus infecting brain cells in culture apparently altered the growth pattern of these cells. This was evident from loss of contact inhibition. Their observation parallels one reported by us 11 in brain-cell cultures from patients with subacute sclerosing panencephalitis (S.S.P.E.). These cells, which were persistently infected with S.S.P.E. virus but which did not yield infectious virus directly, also showed changes in their growth pattern, characterised by proliferative activity and loss of contact inhibition. Moreover, their karyotypes became aneuploid. The second point made by Dr. Webb and his colleagues, that electroencephalographic (E.E.G.) abnormalities may signal presence of virus in the brain, also parallels our observations in animal experiments with S.S.P.E. viruses and rabies virus. Ferrets injected with brain homogenates of S.S.P.E. patients, or with tissue-culture cells infected with S.S.P.E. viruses, developed encephalitis but exhibited few or no clinical symptoms. However, their E.E.G. patterns
out
L. E., Overall, J. E., Shelton, J., Pennington, V., Kimbell, I., Johnson, M. ibid. 1967, 17, 486. 10. O’Brien, C. P., DiGiacomo, J. N., Fahn, S., Schwarz, G. A. ibid. 1971, 24, 61. 11. Katz, M., Koprowski, H., Moorhead, P. Expl Cell Res. 1969, 57, 148. 9.
Hollister,