486
LETTERS TO THE EDITORS
sometimes in absence of the classical cerebeliar signs (Stores, 1975). Diagnosis may be extremely difficult in patients with associated psychiatric illness. The situation may be further complicated by the fact that phenytoin levels may rise gradually as a result of the interaction so the toxic signs develop insidiously and apparently unrelated to their actual cause. We feel that close clinical observation and periodic measurement of serum phenytoin levels should be performed when psychotropic drugs are added to phanytoin medication. We would like to thank Dr John Laidlaw for permission to study patients under his care. Dr Emilio Perucca is supported by a grant from the Anna Villa Rusconi Foundation. E. PERUCCA
Chalfont Centre for Epilepsy, Chalfont St Peter, Bucks. A. RICHENS Department of Clinical Pharmacology, St Bartholomew's Hospital, London, ECIA 7BE
Br. J. clin. Pharmac. (1977), 4 References
HOUGHTON, G.W. & RICHENS, A. (1974) Phenytoin intoxication induced by sulthiame in epileptic patients. J. Neurol. Neurosurg. Psychiat., 37, 275-281. HOUGHTON, G.W., RICHENS, A. & LEIGHTON, M. (1975). Effect of age, height, weight and sex on serum phenytoin concentration in epileptic patients. Br. J. clin. Pharmac., 2,251-256. KUTT, H. (1972). Diphenylhydantoin. Interaction with other drugs in man. In Antlepileptic Drugs, ods Woodbury, D.M., Penry, J.K. & Schmidt, R.P., pp. 169-180. New York: Raven Press. RICHENS, A. & HOUGHTON, G.W. (1975). Effect of drug therapy on the metabolism of phenytoin. In Clinical Pharmacology ofA nti-Epikptic Drugs, eds Schneider, H., Janz, D., Gardner-Thorpe, G., Meinardi, H. & Sherwin, A.L., pp. 87-96, Berlin: Springer-Verlag. STORES, G. (1975). Behavioural effects of antiepileptic drugs. Development. Med. Child. Neurol., 17,647-658.
Received January 17, 1977
ANTAGONISM OF BETHANIDINE BY MAZINDOL Mazindol (Teronac) is an aryl-substituted tricyclic compound marketed as an anorectic agent. Drugs with a tricyclic structure, i.e. with three fused rings, are known to interact with adrenergic neurone blocking agents, causing reversal of their antihypertensive effect. The tricyclic antidepressant agent, desipramine, has been shown to antagonize the antihypertensive effect of bethanidine (Orme, 1972), and the phenothiazine derivative, chlorpromazine, to antagonize that of guanethidine (Fann, Janowsky, Davis & Oates, 1971). This effect can be overcome by increasing the dose of the antihypertensive agent, but if while the larger dose is being administered the tricyclic agent is withdrawn, a profound fall in blood pressure might occur (Smith, 1974). The mechanism of interaction is presumed to be competition for uptake into the adrenergic neurone. Because obesity and hypertension not infrequently occur together, it was decided to perform an interaction study in man to determine to what extent mazindol might interfere with the antihypertensive effect of bethanidine. The volunteer subject for the study was a medically qualified, 54 year old male with mild hypertension (155/95 mmHg supine; 165/100 mmHg standing) of several years duration. He had taken reserpine in the past, but had been untreated for 4 years. His hypertension had never been accompanied by retinopathy
or ECG changes. Apart from raised blood pressure he was quite healthy save for some degree of obesity (height 169 cm; weight 76 kg). Bethanidine was administered three times daily, 2-3 h after meals, and the dose increased until satisfactory control of blood pressure was achieved. The blood pressure was measured approximately 2 h after the first of the three daily doses, using the London School of Hygiene and Tropical Medicine Sphygmomanometer, which is designed to eliminate observer bias. Observations were recorded without prior discussion of symptoms. The subject knew that once an optimum dose of bethanidine had been found he would receive in addition, on different occasions, mazindol (2 mg daily) or an identical dummy tablet, to be taken after the blood pressure measurement, but the details of experimental design were concealed from him. In fact, he received them in the following order: dummy tablets (9 days); active mazindol (3 days); dummy tablets (6 days); active mazindol (11 days). This part of the experiment was performed double blind. Figure 1 shows the changes in the mean postexercise blood pressure which occurred throughout the study. (Exercise consisted of ascending and descending a 23 cm high step 24 times in 1 min). A satisfactory fall in blood pressure was produced by
LETTERS TO THE EDITORS
Br. J. clin. Pharmac. (1977), 4 U)
100r 50c cot -cC) E 0~
D co
m-
* c = Placebo
Mazindol
(2mg/day)
E 130 E )
120
CO)
1 10
.0 100 0 0 n a)
90
,
0
a)
70-
C,-0
a
-
0
10
20
30
40
50
60
70
Time (days) Figure 1
mazindol, a single 2 mg tablet, was sufficient to completely reverse the antihypertensive effect of bethanidine. After 3 days the dummy tablets were re' introduced and the blood pressure fell rapidly to the previous bethanidine-controlled level. When active mazindol was reintroduced the blood pressure immediately returned to the pre-bethanidine level and remained at that level until the end of the study. In addition to the changes in blood pressure which accompanied the addition and withdrawal of active mazindol, it is interesting to note that the addition of active mazindol also resulted in the loss of bethanidine-induced side effects, which consisted of stuffy nose, snoring (reported by spouse) postural giddiness, nocturia and failure of ejaculation The study demonstrates that mazindol should be added to the list of drugs with a tricyclic structure which should not be given to hypertensive patients whose blood pressure is controlled with one of the adrenergic neurone blocking agents. A.J. BOAKES
60L
co
487
Department of Clinical Epidemiology in General Practice (Cardiothoracic Institute), 11, Birkenhead Avenue, Kingston-upon-Thames, Surrey
Mean post-exercise blood pressure
Received January 24, 1977
(diastolic+ 1/3 pulse pressure) showing response to bethanidine alone and in combination with mazindol or placebo.
bethanidine 30 mg three times daily, and this dose was continued throughout the remainder of the study. The addition of dummy tablets, identical in appearance with active mazindol, had no effect on the blood pressure. However, with substitution of active
References FANN, W.E., JANOWSKY, D.S., DAVIS, J.M. & OATES, J.A. (1971). Chlorpromazine reversal of the antihypertensive action of guanethidine. Lancet, I, 436-437. ORME, M.L'E. (1972). latrogenic disease. Medicine, 4, 302-316. SMITH, AJ. (1974). Drug treatment of hypertension. Br. J. Hosp. Med., 11, 533-550.
RATIONAL BASIS FOR THE APPLICATION OF CIMETIDINE IN THE THERAPY OF HUMAN GASTRIC HYPERSECRETION The development of specific H2-receptor antagonists opened a new field of conservative therapy. It has been shown that disorders associated with increased gastric secretion can be successfully treated with these new compounds (Haggie, Fermont & Wylie, 1976; Pounder, Hunt, Stekelman, Milton-Thompson & Misiewicz, 1976). In contrast to burimamide and metiamide no serious side-effects were reported from clinical studies with cimetidine. The effect of cimetidine is due to inhibition of the secretagogue effect of histamine. In amphibia and rat 32
stimulation of adenylate cyclase from gastric mucosa has been shown to be an important step in histamine action (Ray & Forte, 1974; Ohkura & Hattori, 1975). In these species H2-receptor antagonists have been reported to exert a competitive inhibition of histamine stimulation of the enzyme system. Activation of the human gastric adenylate cyclase activity by histamine has not yet been documented. Therefore, the molecular mechanism of H2-receptor blocking agents in human beings remained to be elucidated. We were previously able to demonstrate
LETTERS TO THE EDITORS
sometimes in absence of the classical cerebeliar signs (Stores, 1975). Diagnosis may be extremely difficult in patients with associated psychiatric illness. The situation may be further complicated by the fact that phenytoin levels may rise gradually as a result of the interaction so the toxic signs develop insidiously and apparently unrelated to their actual cause. We feel that close clinical observation and periodic measurement of serum phenytoin levels should be performed when psychotropic drugs are added to phanytoin medication. We would like to thank Dr John Laidlaw for permission to study patients under his care. Dr Emilio Perucca is supported by a grant from the Anna Villa Rusconi Foundation. E. PERUCCA
Chalfont Centre for Epilepsy, Chalfont St Peter, Bucks. A. RICHENS Department of Clinical Pharmacology, St Bartholomew's Hospital, London, ECIA 7BE
Br. J. clin. Pharmac. (1977), 4 References
HOUGHTON, G.W. & RICHENS, A. (1974) Phenytoin intoxication induced by sulthiame in epileptic patients. J. Neurol. Neurosurg. Psychiat., 37, 275-281. HOUGHTON, G.W., RICHENS, A. & LEIGHTON, M. (1975). Effect of age, height, weight and sex on serum phenytoin concentration in epileptic patients. Br. J. clin. Pharmac., 2,251-256. KUTT, H. (1972). Diphenylhydantoin. Interaction with other drugs in man. In Antlepileptic Drugs, ods Woodbury, D.M., Penry, J.K. & Schmidt, R.P., pp. 169-180. New York: Raven Press. RICHENS, A. & HOUGHTON, G.W. (1975). Effect of drug therapy on the metabolism of phenytoin. In Clinical Pharmacology ofA nti-Epikptic Drugs, eds Schneider, H., Janz, D., Gardner-Thorpe, G., Meinardi, H. & Sherwin, A.L., pp. 87-96, Berlin: Springer-Verlag. STORES, G. (1975). Behavioural effects of antiepileptic drugs. Development. Med. Child. Neurol., 17,647-658.
Received January 17, 1977
ANTAGONISM OF BETHANIDINE BY MAZINDOL Mazindol (Teronac) is an aryl-substituted tricyclic compound marketed as an anorectic agent. Drugs with a tricyclic structure, i.e. with three fused rings, are known to interact with adrenergic neurone blocking agents, causing reversal of their antihypertensive effect. The tricyclic antidepressant agent, desipramine, has been shown to antagonize the antihypertensive effect of bethanidine (Orme, 1972), and the phenothiazine derivative, chlorpromazine, to antagonize that of guanethidine (Fann, Janowsky, Davis & Oates, 1971). This effect can be overcome by increasing the dose of the antihypertensive agent, but if while the larger dose is being administered the tricyclic agent is withdrawn, a profound fall in blood pressure might occur (Smith, 1974). The mechanism of interaction is presumed to be competition for uptake into the adrenergic neurone. Because obesity and hypertension not infrequently occur together, it was decided to perform an interaction study in man to determine to what extent mazindol might interfere with the antihypertensive effect of bethanidine. The volunteer subject for the study was a medically qualified, 54 year old male with mild hypertension (155/95 mmHg supine; 165/100 mmHg standing) of several years duration. He had taken reserpine in the past, but had been untreated for 4 years. His hypertension had never been accompanied by retinopathy
or ECG changes. Apart from raised blood pressure he was quite healthy save for some degree of obesity (height 169 cm; weight 76 kg). Bethanidine was administered three times daily, 2-3 h after meals, and the dose increased until satisfactory control of blood pressure was achieved. The blood pressure was measured approximately 2 h after the first of the three daily doses, using the London School of Hygiene and Tropical Medicine Sphygmomanometer, which is designed to eliminate observer bias. Observations were recorded without prior discussion of symptoms. The subject knew that once an optimum dose of bethanidine had been found he would receive in addition, on different occasions, mazindol (2 mg daily) or an identical dummy tablet, to be taken after the blood pressure measurement, but the details of experimental design were concealed from him. In fact, he received them in the following order: dummy tablets (9 days); active mazindol (3 days); dummy tablets (6 days); active mazindol (11 days). This part of the experiment was performed double blind. Figure 1 shows the changes in the mean postexercise blood pressure which occurred throughout the study. (Exercise consisted of ascending and descending a 23 cm high step 24 times in 1 min). A satisfactory fall in blood pressure was produced by
LETTERS TO THE EDITORS
Br. J. clin. Pharmac. (1977), 4 U)
100r 50c cot -cC) E 0~
D co
m-
* c = Placebo
Mazindol
(2mg/day)
E 130 E )
120
CO)
1 10
.0 100 0 0 n a)
90
,
0
a)
70-
C,-0
a
-
0
10
20
30
40
50
60
70
Time (days) Figure 1
mazindol, a single 2 mg tablet, was sufficient to completely reverse the antihypertensive effect of bethanidine. After 3 days the dummy tablets were re' introduced and the blood pressure fell rapidly to the previous bethanidine-controlled level. When active mazindol was reintroduced the blood pressure immediately returned to the pre-bethanidine level and remained at that level until the end of the study. In addition to the changes in blood pressure which accompanied the addition and withdrawal of active mazindol, it is interesting to note that the addition of active mazindol also resulted in the loss of bethanidine-induced side effects, which consisted of stuffy nose, snoring (reported by spouse) postural giddiness, nocturia and failure of ejaculation The study demonstrates that mazindol should be added to the list of drugs with a tricyclic structure which should not be given to hypertensive patients whose blood pressure is controlled with one of the adrenergic neurone blocking agents. A.J. BOAKES
60L
co
487
Department of Clinical Epidemiology in General Practice (Cardiothoracic Institute), 11, Birkenhead Avenue, Kingston-upon-Thames, Surrey
Mean post-exercise blood pressure
Received January 24, 1977
(diastolic+ 1/3 pulse pressure) showing response to bethanidine alone and in combination with mazindol or placebo.
bethanidine 30 mg three times daily, and this dose was continued throughout the remainder of the study. The addition of dummy tablets, identical in appearance with active mazindol, had no effect on the blood pressure. However, with substitution of active
References FANN, W.E., JANOWSKY, D.S., DAVIS, J.M. & OATES, J.A. (1971). Chlorpromazine reversal of the antihypertensive action of guanethidine. Lancet, I, 436-437. ORME, M.L'E. (1972). latrogenic disease. Medicine, 4, 302-316. SMITH, AJ. (1974). Drug treatment of hypertension. Br. J. Hosp. Med., 11, 533-550.
RATIONAL BASIS FOR THE APPLICATION OF CIMETIDINE IN THE THERAPY OF HUMAN GASTRIC HYPERSECRETION The development of specific H2-receptor antagonists opened a new field of conservative therapy. It has been shown that disorders associated with increased gastric secretion can be successfully treated with these new compounds (Haggie, Fermont & Wylie, 1976; Pounder, Hunt, Stekelman, Milton-Thompson & Misiewicz, 1976). In contrast to burimamide and metiamide no serious side-effects were reported from clinical studies with cimetidine. The effect of cimetidine is due to inhibition of the secretagogue effect of histamine. In amphibia and rat 32
stimulation of adenylate cyclase from gastric mucosa has been shown to be an important step in histamine action (Ray & Forte, 1974; Ohkura & Hattori, 1975). In these species H2-receptor antagonists have been reported to exert a competitive inhibition of histamine stimulation of the enzyme system. Activation of the human gastric adenylate cyclase activity by histamine has not yet been documented. Therefore, the molecular mechanism of H2-receptor blocking agents in human beings remained to be elucidated. We were previously able to demonstrate
