202 from anoxia, the cardiac output is usually normal so that the pulmonary arterial blood-pressure is raised"-but not usually to the levels seen in patients with the other conditions I have mentioned.
marily
Department of Cardiology, General Infirmary,
W. WHITAKER
Leeds 1
THYROID-HORMONE LEVELS IN PROTEIN-CALORIE MALNUTRITION
SiR,—Dr Ingenbleek and Professor Beckers (Nov. 1, p. 845) described very low serum-total-triiodothyronine (T3) concentrations in severe malnutrition and implied that these were due to decreased peripheral (e.g., hepatic) conversion of thyroxine (T4) and T3 as has been postulated to explain a similar finding in cirrhosis of the liver.’2 They also suggested that a defect in the feedback mechanism might explain the observed lack of a negative correlation between serum-total-T3 and serum-
thyroid-stimulating-hormone (T.S.H.) concentrations. We believe that decreased circulating levels of the three thyroxinebinding proteins (thyroxine-binding globulin [T.B.G.], thyroxine-binding prealbumin [T.B.P.A.], and albumin) played a bigger part than the authors suggested and may in fact have been the main factor involved. Typical mean serum-concentrations
of total T3, total T4, T.B.G., T.B.P.A., and albumin for the malnourished children described are 25%, 40%,3 56%,3 29%,4 and 53%4 of the control mean values. At a physiological pH, T.B.G., T.B.P.A., and albumin bind respectively 78%, 9%, and 13% of serum-T3 and 72%, 19%, and 9% of serum-T4.’ From these Chopra, I. J., Solomon, D. H., Chopra, U., Young, R. T., Guadalupe, C. T. J. clin. Endocr. Metab. 1974, 39, 501. 2. Nomura, S., Pittman, C. S., Chambers, J. B., Buck, M. W., Shimizu, T. J. clin. Invest. 1975, 56, 643. 3. Ingenbleek, Y., De Nayer, Ph., De Visscher, M. J. clin. Endocr. Metab. 1974, 39, 178. 4. Ingenbleek, Y., De Visscher, M., De Nayer, Ph. Lancet, 1972, ii, 106. 5. Davis, P. J., Handwerger, B. S., Gregerman, R. I. J. clin. Invest. 1972, 51, 515. 1.
account for all of the observed fall in serum-total-T4 and for 47% of the observed 77% fall in serum-total-T3 concentration. It is only the other 30% of the decrease in serum-total-T3 concentration which may perhaps be due to decreased peripheral deiodination of T4 to T3. Furthermore, the rise in serum total T3 and T4 concentrations which occurs on refeeding can be largely accounted for by the increasing concentrations of T.B.G., T.B.P.A., and albumin344 (see figure). The authors’ observation that the maximum rise in serum-T.s.H. occurred at a time when the mean serum-total-T3 concentration was nearly normal may indicate that thyroxine-binding-protein production increased faster than T3 production, thus causing a low-serum-free-T3 concentration and hence a rise in serum-T.s.H. concentration. It may not therefore be necessary to postulate a defect in the feedback mechanism. The contribution of changes of thyroxine-binding proteins to the abnormalities of thyroid hormones which occur in malnutrition and refeeding could be clarified if the serum-free-concentrations of T3 and T4 were accurately measured.
data, decreased protein-binding could
Institute of Medical and
Veterinary Science, Adelaide, South Australia, 5000.
R. W. PAIN P. J. PHILLIPS
HOW DOES BLOOD-PRESSURE CAUSE STROKE?
SIR,-Iread with interest the hypothesis put forward by Dr (Dec. 27, p. 1283) in his admirable article on blood-pressure and strokes. However, his statement, in the section on the control of cerebral blood-flow, that the intrinsic Ross Russell
autoregulatory mechanism does not depend on vascular innervation needs fuller support. How can this fact be known for man, bearing in mind the complexity of the suggested vasodilator pathways? Indeed animal data strongly suggest the
opposite.6-8 Medical Unit, Royal Free Hospital, Pond Street, London NW3 2QG.
I. M. JAMES
METHYLDOPA AND FORGETFULNESS
SIR,-Disorders of cerebral functions (i.e., depression, disturbed sleep, unpleasant dreams, and hallucinations) have been noted as side-effects from methyldopa therapy in hypertension, but I wonder if forgetfulness has been recorded. An intelligent nursing sister aged 36 was admitted with a history of shortness of breath, dizziness, and feeling faint while hurrying to catch a bus on the morning of admission. The only significant abnormality was raised blood-pressure, ranging between 170/110 and 180/120 mm Hg. The usual investigations proved normal. Methyldopa (’Aldomet’) 250 mg twice a day was started. The dose was increased to 250 mg three times a day 4 days later. Triamterene and hydrochlorothiazide (’Dyazide’), one tablet daily, was added after a fortnight. The blood-pressure returned to normal on this treatment and she was allowed to return to work. 47 days after starting methyldopa therapy and 43 days after dose she began to be forgetful. She would walk the other end of the ward to bring an article which a patient had requested, but when she reached the cupboard she would forget what the patient had asked her to get. On another occasion she went shopping in her car, but returned home by bus without realising that she had left her car in town. Methyldopa was withdrawn and replaced by debrisoquine sulphate. Dyazide was maintained. Her memory started improving within 2 days, resulting in complete recovery in a fortnight. 6 weeks later at follow-up she confirmed no further
increasing the to
problem. ’
°
DAYS
W
OF
22
REFEEDING
Average changes in thyroid hormones and thyroxine-binding proteins infants with protein-calorie malnutrition and upon refeeding.
in
6. James, I. M., Millar, R. A., Purves, M. J. Circulation Res. 1969, 25, 7. Ponte, J., Purves, M J. J. Physiol. Lond. 1974, 237, 465. 8. James, I. M., MacDonell, L. Clin. Sci. mol. Med. 1975, 49, 465.
72.
203 reasonable to conclude that methyldopa for sponsible the temporary derangement of memory. It
seems
was re-
West Lane Hospital,
Middlesbrough, Cleveland TS5 4EE.
S. K. GHOSH
EFFECTS OF LOW DOSES OF A
DOPAMINE-RECEPTOR STIMULATOR IN MANIA
S!R,—Piribedil (ET-495) and apomorphine are thought to predominantly by directly stimulating dopamine receptors.1However, a variety of indirect evidence suggests that low doses of these dopamine-receptor stimulators can produce effects opposite of those obtained with usual or higher doses. Carlsson’ and Angrist4 report that low doses of apomorphine and piribedil are associated not with hyperactivity act
and stereotypy but with motor inhibition. Carlsson et awl. also reported the suppression of ethanol-induced motor stimulation by low doses of piribedil. Buckett and Shaw6 found that low doses of apomorphine and piribedil inhibited effects of cyclazocine in rats. Finally, Chase and Shoulson’ found that piribedil can block neuroleptic-induced tardive dyskinesias. We now report preliminary evidence in 2 manic patients diagnosed by the criteria of Spitzer et al. that low oral doses of piribedil (60 mg/day) administered under double-blind conditions may produce antimanic effects. a
Patient 5013 illustrated in the figure was a 22-year-old woman with history of severe manic episodes admitted to the National Institute
1. Corrodi, H., Farnebo, L. O., Fuxe, K., Hamberger, B., Ungerstedt, U. Eur. J. Pharmac. 1972, 20, 195. 2. Creese, I. ibid. 1974, 28, 55. 3. Carlsson, A. in Pre- and Post-Synaptic Receptors (edited by E. Usdin and W. E. Bunney); p. 49. New York, 1975. 4. Angrist, B. in Symposium on Contemporary Issues in Stimulant Research (in the press).
5. Carlsson, A., Engel, J., Strombom, U., Svensson, T. H., Waldeck, B. Naunym-Schmiedebergs Arch. exp. Path. Pharmak. 1974, 283, 117. 6. Buckett, W. R., Shaw, J. S. Psychopharmacologia, 1975, 42, 293. 7. Chase, T. N., Shoulson, I. in Advances in Neurology (edited by D. Calne, T. N. Chase, and A. Barbeau); vol. 9, p. 359. New York, 1975. 8. Spitzer, R. L., Endicott, J., Robins, E. Am. J. Psychiat. 1975, 132, 1187.
of Mental Health during a florid manic episode, which was treated with the neuroleptic, thioridazine. Several weeks after the drug was discontinued a full-blown manic episode recurred, and she was started on low doses of piribedil. Within four days the patient showed a marked improvement, returning to an essentially normal state after 12 days. A sustained remission occurred during treatment with low doses of piribedil, and no rebound manic episode occurred when the drug was withdrawn. Patient 5034 was a 41-year-old woman, also with a history of recurrent and severe mood swings. She was hyperactive, hyperverbal, abusive, and grandiose and was very labile in affect. She required seclusion up to 17 hours per day before piribedil administration. After 9 days on piribedil she became less hyperactive, hyperverbal, and provocative and was able to rejoin many ward group meetings and mix with other patients. After withdrawal of piribedil severe mania gradually returned. Low-dose piribedil was begun again, but because of the patient’s severe mania and the evidence that piribedil required more than a week to induce improvement, it was discontinued after 4 days, and high doses of chlorpromazine were begun in hopes of producing antimanic effects more quickly. The patient remained manic, and after 12 days of chlorpromazine treatment, lithium carbonate was added to the medication regimen, finally producing striking improvement. The responses in these 2 patients are in part consistent with the data of Arbuthnott and Murray,9 who reported dramatic antimanic effects of piribedil in 2 of 7 patients, although the precise dose-response relationships were not indicated.
The apparent neuroleptic-like effects of an agent which has typically been associated with stimulation, rather than blockade, of dopamine receptors requires careful explanation. Carlsson et al.,3 Bunney and Aghajanian,!O and Roth et al." have suggested that low doses of catecholamine-receptor-stimulating agents may be associated with preferential presynaptic-receptor stimulation. The message to the presynaptic dopaminergic neuron may be that enough transmitter is available at the synapse and that no more should be synthesised or released. Since the postsynaptic receptors would be less fully occupied, the net effect might be decreased postsynaptic dopamine-receptor stimulation-a situation functionally similar to that pro9.
Arbuthnott, G. W., Murray, L. G. in Advances in Neurology (edited by D. Calne, T. N. Chase, and A. Barbeau); vol. 9, p. 345. New York, 1975. 10. Bunney, B. S., Aghajanian, G. W. in Pre- and Post-Synaptic Receptors (edited by E. Usdin and W. E. Bunney); p. 89. New York, 1975. 11. Roth, P. H., Walters, J. R., Marrin, L. C., Morgenroth, V. H. ibid. p.5.
DAYS Effects of low-dose CPZ
piribedil in 2 manic patients. chlorpromazine.
=
marily
Department of Cardiology, General Infirmary,
W. WHITAKER
Leeds 1
THYROID-HORMONE LEVELS IN PROTEIN-CALORIE MALNUTRITION
SiR,—Dr Ingenbleek and Professor Beckers (Nov. 1, p. 845) described very low serum-total-triiodothyronine (T3) concentrations in severe malnutrition and implied that these were due to decreased peripheral (e.g., hepatic) conversion of thyroxine (T4) and T3 as has been postulated to explain a similar finding in cirrhosis of the liver.’2 They also suggested that a defect in the feedback mechanism might explain the observed lack of a negative correlation between serum-total-T3 and serum-
thyroid-stimulating-hormone (T.S.H.) concentrations. We believe that decreased circulating levels of the three thyroxinebinding proteins (thyroxine-binding globulin [T.B.G.], thyroxine-binding prealbumin [T.B.P.A.], and albumin) played a bigger part than the authors suggested and may in fact have been the main factor involved. Typical mean serum-concentrations
of total T3, total T4, T.B.G., T.B.P.A., and albumin for the malnourished children described are 25%, 40%,3 56%,3 29%,4 and 53%4 of the control mean values. At a physiological pH, T.B.G., T.B.P.A., and albumin bind respectively 78%, 9%, and 13% of serum-T3 and 72%, 19%, and 9% of serum-T4.’ From these Chopra, I. J., Solomon, D. H., Chopra, U., Young, R. T., Guadalupe, C. T. J. clin. Endocr. Metab. 1974, 39, 501. 2. Nomura, S., Pittman, C. S., Chambers, J. B., Buck, M. W., Shimizu, T. J. clin. Invest. 1975, 56, 643. 3. Ingenbleek, Y., De Nayer, Ph., De Visscher, M. J. clin. Endocr. Metab. 1974, 39, 178. 4. Ingenbleek, Y., De Visscher, M., De Nayer, Ph. Lancet, 1972, ii, 106. 5. Davis, P. J., Handwerger, B. S., Gregerman, R. I. J. clin. Invest. 1972, 51, 515. 1.
account for all of the observed fall in serum-total-T4 and for 47% of the observed 77% fall in serum-total-T3 concentration. It is only the other 30% of the decrease in serum-total-T3 concentration which may perhaps be due to decreased peripheral deiodination of T4 to T3. Furthermore, the rise in serum total T3 and T4 concentrations which occurs on refeeding can be largely accounted for by the increasing concentrations of T.B.G., T.B.P.A., and albumin344 (see figure). The authors’ observation that the maximum rise in serum-T.s.H. occurred at a time when the mean serum-total-T3 concentration was nearly normal may indicate that thyroxine-binding-protein production increased faster than T3 production, thus causing a low-serum-free-T3 concentration and hence a rise in serum-T.s.H. concentration. It may not therefore be necessary to postulate a defect in the feedback mechanism. The contribution of changes of thyroxine-binding proteins to the abnormalities of thyroid hormones which occur in malnutrition and refeeding could be clarified if the serum-free-concentrations of T3 and T4 were accurately measured.
data, decreased protein-binding could
Institute of Medical and
Veterinary Science, Adelaide, South Australia, 5000.
R. W. PAIN P. J. PHILLIPS
HOW DOES BLOOD-PRESSURE CAUSE STROKE?
SIR,-Iread with interest the hypothesis put forward by Dr (Dec. 27, p. 1283) in his admirable article on blood-pressure and strokes. However, his statement, in the section on the control of cerebral blood-flow, that the intrinsic Ross Russell
autoregulatory mechanism does not depend on vascular innervation needs fuller support. How can this fact be known for man, bearing in mind the complexity of the suggested vasodilator pathways? Indeed animal data strongly suggest the
opposite.6-8 Medical Unit, Royal Free Hospital, Pond Street, London NW3 2QG.
I. M. JAMES
METHYLDOPA AND FORGETFULNESS
SIR,-Disorders of cerebral functions (i.e., depression, disturbed sleep, unpleasant dreams, and hallucinations) have been noted as side-effects from methyldopa therapy in hypertension, but I wonder if forgetfulness has been recorded. An intelligent nursing sister aged 36 was admitted with a history of shortness of breath, dizziness, and feeling faint while hurrying to catch a bus on the morning of admission. The only significant abnormality was raised blood-pressure, ranging between 170/110 and 180/120 mm Hg. The usual investigations proved normal. Methyldopa (’Aldomet’) 250 mg twice a day was started. The dose was increased to 250 mg three times a day 4 days later. Triamterene and hydrochlorothiazide (’Dyazide’), one tablet daily, was added after a fortnight. The blood-pressure returned to normal on this treatment and she was allowed to return to work. 47 days after starting methyldopa therapy and 43 days after dose she began to be forgetful. She would walk the other end of the ward to bring an article which a patient had requested, but when she reached the cupboard she would forget what the patient had asked her to get. On another occasion she went shopping in her car, but returned home by bus without realising that she had left her car in town. Methyldopa was withdrawn and replaced by debrisoquine sulphate. Dyazide was maintained. Her memory started improving within 2 days, resulting in complete recovery in a fortnight. 6 weeks later at follow-up she confirmed no further
increasing the to
problem. ’
°
DAYS
W
OF
22
REFEEDING
Average changes in thyroid hormones and thyroxine-binding proteins infants with protein-calorie malnutrition and upon refeeding.
in
6. James, I. M., Millar, R. A., Purves, M. J. Circulation Res. 1969, 25, 7. Ponte, J., Purves, M J. J. Physiol. Lond. 1974, 237, 465. 8. James, I. M., MacDonell, L. Clin. Sci. mol. Med. 1975, 49, 465.
72.
203 reasonable to conclude that methyldopa for sponsible the temporary derangement of memory. It
seems
was re-
West Lane Hospital,
Middlesbrough, Cleveland TS5 4EE.
S. K. GHOSH
EFFECTS OF LOW DOSES OF A
DOPAMINE-RECEPTOR STIMULATOR IN MANIA
S!R,—Piribedil (ET-495) and apomorphine are thought to predominantly by directly stimulating dopamine receptors.1However, a variety of indirect evidence suggests that low doses of these dopamine-receptor stimulators can produce effects opposite of those obtained with usual or higher doses. Carlsson’ and Angrist4 report that low doses of apomorphine and piribedil are associated not with hyperactivity act
and stereotypy but with motor inhibition. Carlsson et awl. also reported the suppression of ethanol-induced motor stimulation by low doses of piribedil. Buckett and Shaw6 found that low doses of apomorphine and piribedil inhibited effects of cyclazocine in rats. Finally, Chase and Shoulson’ found that piribedil can block neuroleptic-induced tardive dyskinesias. We now report preliminary evidence in 2 manic patients diagnosed by the criteria of Spitzer et al. that low oral doses of piribedil (60 mg/day) administered under double-blind conditions may produce antimanic effects. a
Patient 5013 illustrated in the figure was a 22-year-old woman with history of severe manic episodes admitted to the National Institute
1. Corrodi, H., Farnebo, L. O., Fuxe, K., Hamberger, B., Ungerstedt, U. Eur. J. Pharmac. 1972, 20, 195. 2. Creese, I. ibid. 1974, 28, 55. 3. Carlsson, A. in Pre- and Post-Synaptic Receptors (edited by E. Usdin and W. E. Bunney); p. 49. New York, 1975. 4. Angrist, B. in Symposium on Contemporary Issues in Stimulant Research (in the press).
5. Carlsson, A., Engel, J., Strombom, U., Svensson, T. H., Waldeck, B. Naunym-Schmiedebergs Arch. exp. Path. Pharmak. 1974, 283, 117. 6. Buckett, W. R., Shaw, J. S. Psychopharmacologia, 1975, 42, 293. 7. Chase, T. N., Shoulson, I. in Advances in Neurology (edited by D. Calne, T. N. Chase, and A. Barbeau); vol. 9, p. 359. New York, 1975. 8. Spitzer, R. L., Endicott, J., Robins, E. Am. J. Psychiat. 1975, 132, 1187.
of Mental Health during a florid manic episode, which was treated with the neuroleptic, thioridazine. Several weeks after the drug was discontinued a full-blown manic episode recurred, and she was started on low doses of piribedil. Within four days the patient showed a marked improvement, returning to an essentially normal state after 12 days. A sustained remission occurred during treatment with low doses of piribedil, and no rebound manic episode occurred when the drug was withdrawn. Patient 5034 was a 41-year-old woman, also with a history of recurrent and severe mood swings. She was hyperactive, hyperverbal, abusive, and grandiose and was very labile in affect. She required seclusion up to 17 hours per day before piribedil administration. After 9 days on piribedil she became less hyperactive, hyperverbal, and provocative and was able to rejoin many ward group meetings and mix with other patients. After withdrawal of piribedil severe mania gradually returned. Low-dose piribedil was begun again, but because of the patient’s severe mania and the evidence that piribedil required more than a week to induce improvement, it was discontinued after 4 days, and high doses of chlorpromazine were begun in hopes of producing antimanic effects more quickly. The patient remained manic, and after 12 days of chlorpromazine treatment, lithium carbonate was added to the medication regimen, finally producing striking improvement. The responses in these 2 patients are in part consistent with the data of Arbuthnott and Murray,9 who reported dramatic antimanic effects of piribedil in 2 of 7 patients, although the precise dose-response relationships were not indicated.
The apparent neuroleptic-like effects of an agent which has typically been associated with stimulation, rather than blockade, of dopamine receptors requires careful explanation. Carlsson et al.,3 Bunney and Aghajanian,!O and Roth et al." have suggested that low doses of catecholamine-receptor-stimulating agents may be associated with preferential presynaptic-receptor stimulation. The message to the presynaptic dopaminergic neuron may be that enough transmitter is available at the synapse and that no more should be synthesised or released. Since the postsynaptic receptors would be less fully occupied, the net effect might be decreased postsynaptic dopamine-receptor stimulation-a situation functionally similar to that pro9.
Arbuthnott, G. W., Murray, L. G. in Advances in Neurology (edited by D. Calne, T. N. Chase, and A. Barbeau); vol. 9, p. 345. New York, 1975. 10. Bunney, B. S., Aghajanian, G. W. in Pre- and Post-Synaptic Receptors (edited by E. Usdin and W. E. Bunney); p. 89. New York, 1975. 11. Roth, P. H., Walters, J. R., Marrin, L. C., Morgenroth, V. H. ibid. p.5.
DAYS Effects of low-dose CPZ
piribedil in 2 manic patients. chlorpromazine.
=
